Cyclin-dependent kinase degraders and methods of use thereof

Abstract

The present disclosure relates to novel compounds and pharmaceutical compositions thereof, as well as methods for degrading CDK2 and / or CCNE1 with the disclosed compounds and compositions. Additionally, the present disclosure relates to, but is not limited to, methods for treating disorders associated with CDK2 and / or CCNE1 with the disclosed compounds and compositions.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to and the benefit of U.S. Provisional Patent Application No. 63 / 445,271, filed February 13, 2023, U.S. Provisional Patent Application No. 63 / 445,272, filed February 13, 2023, and U.S. Provisional Patent Application No. 63 / 509,837, filed June 23, 2023, the entire contents of which are incorporated herein by reference.

[0002] The present invention relates to compounds and methods useful for modulating cyclin-dependent kinase 2 (CDK2) and / or cyclin E (CCNE1 and / or CCNE2) via ubiquitination and / or degradation by the compounds of the invention. The invention also provides pharmaceutically acceptable compositions comprising the compounds of the invention and methods of using the compositions in the treatment of various disorders. [Background technology]

[0003] Cyclin-dependent kinases (CDKs) are a family of serine / threonine kinases. CDKs become fully active upon heterodimerization with regulatory subunits known as cyclins, regulating key cellular processes, including cell cycle progression and cell division (Morgan, DO, Annu Rev Cell Dev Biol, 1997.13:261-91). Uncontrolled proliferation is a hallmark of cancer cells. Deregulation of CDK activity is associated with cell cycle dysregulation and is detected in virtually all forms of human cancer (Sherr, CJ, Science, 1996.274(5293):1672-7).

[0004] CDK2 is of particular interest because deregulation of CDK2 activity frequently occurs in various human cancers. CDK2 plays a crucial role in promoting the G1 / S transition and S-phase progression. When complexed with cyclin E (CCNE), CDK2 phosphorylates members of the retinoblastoma pocket protein family (p107, p130, and pRb), which leads to the derepression of E2F transcription factors, the expression of G1 / S transition-related genes, and the transition from G1 to S phase (Henley, SA and FADick, Cell Div, 2012, 7(1):p.10). This, in turn, allows the activation of CDK2 / cyclin A, which phosphorylates endogenous substrates that enable DNA synthesis, replication, and centrosome duplication (Ekholm, SV and SI Reed, Curr Opin Cell Biol, 2000, 12(6):676-84). The CDK2 pathway has been reported to influence tumorigenesis primarily through amplification and / or overexpression of CCNE1 and mutations that inactivate endogenous inhibitors of CDK2 (e.g., p27), respectively (Xu, X., et al., Biochemistry, 1999.38(27):8713-22).

[0005] CCNE1 copy number gain and overexpression have been identified in ovarian, gastric, endometrial, breast, and other cancers and are associated with poor outcomes in these tumors (Keyomarsi, K., et al., N Engl J Med, 2002. 347(20): 1566-75; Nakayama, N., et al., Cancer, 2010. 116(11): 2621-34; Au-Yeung, G., et al., Clin Cancer Res, 2017. 23(7): 1862-1874; Rosen, DG, et al., Cancer, 2006. 106(9): 1925-32). Amplification and / or overexpression of CCNE1 has also been reported to contribute to trastuzumab resistance in HER2-positive breast cancer and resistance to CDK4 / 6 inhibitors in estrogen receptor-positive breast cancer (Scaltriti, M., et al., Proc Natl Acad Sci USA, 2011, 108(9):3761-6; Herrera-Abreu, MT, et al., Cancer Res, 2016, 76(8):2301-13). Various approaches targeting CDK2 have been shown to induce cell cycle arrest and tumor growth inhibition (Chen, Y N., et al., Proc Natl Acad Sci USA, 1999, 96(8):4325-9; Mendoza, N., et al., Cancer Res, 2003, 63(5):1020-4). In addition, inhibition of CDK2 has been reported to restore sensitivity to trastuzumab treatment in resistant HER2-positive breast tumors in preclinical models (Scaltriti, supra).

[0006] The ubiquitin-proteasome pathway (UPP) is a crucial pathway that regulates key regulatory proteins and degrades misfolded or abnormal proteins. The UPP is central to multiple cellular processes, and defects or imbalances can lead to the pathogenesis of various diseases. Covalent attachment of ubiquitin to specific protein substrates is achieved through the action of E3 ubiquitin ligases.

[0007] There are over 600 E3 ubiquitin ligases that promote the ubiquitination of different proteins in vivo, which can be classified into four families: HECT domain E3s, U-box E3s, monomeric RING E3s, and multisubunit E3s. Generally, Li et al. (PLOS One, 2008, 3, 1487) titled "Genome-wide and functional annotation of human E3 ubiquitin ligases identifies MULAN, a mitochondrial E3 that regulates the organelle's dynamics and signaling.", Bendsen et al. (Nat. Struct. Mol. Biol., 2014, 21, 301-307) titled "New insights into ubiquitin E3 ligase mechanism.", Deshaies et al. (Ann. Rev. Biochem., 2009, 78, 399-434) titled "RING domain E3 ubiquitin ligases.", and Spratt et al. (Biochem. 2014, 458, 421-437) titled "RBR E3 ubiquitin ligases: new structures, new insights, new questions." and Wang et al. (Nat. Rev. Cancer., 2014, 14, 233-347) entitled "Roles of F-box proteins in cancer."

[0008] UPP is used to induce selective protein degradation, including the use of fusion proteins to artificially ubiquitinate target proteins and synthetic small molecule probes to induce proteasome-dependent degradation. Bifunctional compounds consisting of a target protein-binding ligand and an E3 ubiquitin ligase ligand induce proteasome-mediated degradation of selected proteins through their recruitment to E3 ubiquitin ligases and subsequent ubiquitination. These drug-like molecules offer the possibility of temporal control over protein expression. Such compounds can induce the inactivation of target proteins upon addition to cells or administration to animals or humans, and may be useful as biochemical reagents, leading to a new paradigm for disease treatment by removing pathogenic or oncogenic proteins (Crews C, Chemistry & Biology, 2010, 17(6):551-555; Schnnekloth JS Jr., Chembiochem, 2005, 6(1):40-46).

[0009] In the art, there is a continuing need for effective treatment for diseases, especially cancer.Therefore, the small molecule therapeutic agent that utilizes UPP-mediated proteolysis to target cancer-related proteins, such as cyclin-dependent kinase 2 ("CDK2"), cyclin E ("CCNE1" and / or "CCNE2"), or CDK2 and CCNE (CCNE1 and / or CCNE2) proteins, is promising as a therapeutic agent.Therefore, there is still a need to find compounds that are useful as CDK2 decomposition agents, CCNE (CCNE1 and / or CCNE2) decomposition agents, or CDK2 and CCNE (CCNE1 and / or CCNE2) dual decomposition agents. Summary of the Invention

[0010] In one embodiment, formula A

[0011] [ka] or a pharmaceutically acceptable salt thereof, wherein Ring A is phenyl, 3- to 14-membered cycloalkyl, or 4- to 14-membered heterocyclyl containing 1-3 heteroatoms independently selected from N, O, and S; R 1 -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -C 1-6 Haloalkyl, -C 1-6 Heteroalkyl, -C3- 14 Cycloalkyl, 6- to 14-membered aryl, 4- to 14-membered heterocyclyl, 5- to 14-membered heteroaryl, -C 1-4 Alkyl-C 3-14 Cycloalkyl, -C 1-4 Alkyl-(6-14 membered aryl), -C 1-4 Alkyl-(4-14 membered heterocyclyl), and -C 1-4 alkyl (5-14 membered heteroaryl), heterocyclyl and heteroaryl each containing 1-3 heteroatoms independently selected from N, O, and S, and alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl each selected from R 6 is replaced by 0, 1, 2, 3, or 4 instances of R 2 and R 3 are each independently -C 1-6 Alkyl, -C 1-6 Haloalkyl, -C 1-6 Heteroalkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -C 3-7 cycloalkyl, phenyl, 4- to 7-membered heterocyclyl, and 5- to 6-membered heteroaryl, wherein the heterocyclyl and heteroaryl each contain 1-3 heteroatoms independently selected from N, O, and S; and the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl each are selected from R Bis replaced by 0, 1, 2, 3, or 4 instances of Or R 2 and R 3 together with the carbon atoms to which they are attached form ring B, ring B being a 3- to 7-membered cycloalkyl ring or a 4- to 7-membered heterocyclyl ring containing 1 or 3 heteroatoms independently selected from N, O, and S, ring B being R B is replaced by 0, 1, 2, 3, or 4 instances of L is a covalent bond or a divalent, saturated, or unsaturated, straight or branched chain C 1-50 a hydrocarbon chain, wherein 0 to 6 methylene units of L are independently replaced by -Cy-, -CH(R)-, -C(R)2-, -O-, -NR-, -S-, -OC(=O)-, -C(=O)O-, -C(=O)-, -S(=O)-, -S(=O)2-, -NRS(=O)2-, -S(=O)2NR-, -NRC(=O)-, -C(=O)NR-, -OC(=O)NR-, or -NRC(=O)O-; -Cy- each independently represents phenylene, 8- to 10-membered bicyclic arylene, 4- to 7-membered monocyclic carbocyclylene, 5- to 11-membered spirocarbocyclylene, 4- to 10-membered bicyclic carbocyclylene, 5- to 10-membered bridged carbocyclylene, 4- to 7-membered monocyclic heterocyclylene having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 11-membered spiroheterocyclylene having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 4- to 10-membered monocyclic heterocyclylene having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 11-membered spiroheterocyclylene having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 10-membered bridged bicyclic saturated or partially unsaturated heterocyclylene having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5- to 6-membered heteroarylene having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an 8- to 10-membered bicyclic heteroarylene having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and phenylene, arylene, carbocyclylene, heterocyclylene, and heteroarylene are each independently selected from R Cis replaced by 0, 1, 2, 3, or 4 instances of LMB is

[0012] [ka] is selected from R A , R B , R C , R 4 , R 5 , and R 6 The entities are each independently oxo, deuterium, halogen, -C 1-6 Alkyl, -C 1-6 Heteroalkyl, -C 1-6 Haloalkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -S(O)(NR)R, -S(O)(NCN)R, -S(NCN)R, -C(O)R, -C(O)OR, -C(O)NR2, -C( O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2, -N(R)S(O)2R, -P(O)R2, -P(O)(R)OR 、 -C 3-7 selected from cycloalkyl, phenyl, 4- to 7-membered heterocyclyl, and 5- to 6-membered heteroaryl, wherein the heterocyclyl and heteroaryl each contain 1-3 heteroatoms independently selected from N, O, and S; Each instance of R is independently hydrogen, -C 1-6 Alkyl, -C 1-6 Haloalkyl, -C 1-6 Heteroalkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -C 3-7cycloalkyl, phenyl, 4- to 7-membered heterocyclyl, and 5- to 6-membered heteroaryl, wherein the heterocyclyl and heteroaryl each contain 1-3 heteroatoms independently selected from N, O, and S, or two R groups attached to the same nitrogen optionally combine with the nitrogen to which they are attached to form an optionally substituted 4- to 7-membered heterocyclyl having 0, 1, or 2 additional heteroatoms independently selected from N, O, and S; n is 0, 1, 2, 3, or 4; r is 0, 1, 2, 3, or 4; s is 0, 1, 2, 3, or 4, or a pharmaceutically acceptable salt thereof.

[0013] In one embodiment, a compound of Formula I or Formula I-1

[0014] [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -C 1-6 Haloalkyl, -C 1-6 Heteroalkyl, -C3- 14 Cycloalkyl, 6- to 14-membered aryl, 4- to 14-membered heterocyclyl, 5- to 14-membered heteroaryl, -C 1-4 Alkyl-C 3-14 Cycloalkyl, -C 1-4 Alkyl-(6-14 membered aryl), -C 1-4 Alkyl-(4-14 membered heterocyclyl), and -C 1-4 alkyl (5-14 membered heteroaryl), heterocyclyl and heteroaryl each containing 1-3 heteroatoms independently selected from N, O, and S, and alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl each selected from R 6is replaced by 0, 1, 2, 3, or 4 instances of L is a covalent bond or a divalent, saturated, or unsaturated, straight or branched chain C 1-50 a hydrocarbon chain, wherein 0 to 6 methylene units of L are independently replaced by -Cy-, -CH(R)-, -C(R)2-, -O-, -NR-, -S-, -OC(=O)-, -C(=O)O-, -C(=O)-, -S(=O)-, -S(=O)2-, -NRS(=O)2-, -S(=O)2NR-, -NRC(=O)-, -C(=O)NR-, -OC(=O)NR-, or -NRC(=O)O-; -Cy- each independently represents phenylene, 8- to 10-membered bicyclic arylene, 4- to 7-membered monocyclic carbocyclylene, 5- to 11-membered spirocarbocyclylene, 4- to 10-membered bicyclic carbocyclylene, 5- to 10-membered bridged carbocyclylene, 4- to 7-membered monocyclic heterocyclylene having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 11-membered spiroheterocyclylene having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 4- to 10-membered monocyclic heterocyclylene having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 11-membered spiroheterocyclylene having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 10-membered bridged bicyclic saturated or partially unsaturated heterocyclylene having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5- to 6-membered heteroarylene having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an 8- to 10-membered bicyclic heteroarylene having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and phenylene, arylene, carbocyclylene, heterocyclylene, and heteroarylene are each independently selected from R C is replaced by 0, 1, 2, 3, or 4 instances of LMB is

[0015] [ka] is selected from R A , R B , R C , R4 , R 5 , and R 6 The entities are each independently oxo, deuterium, halogen, -C 1-6 Alkyl, -C 1-6 Heteroalkyl, -C 1-6 Haloalkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -S(O)(NR)R, -S(O)(NCN)R, -S(NCN)R, -C(O)R, -C(O)OR, -C(O)NR2, -C( O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2, -N(R)S(O)2R, -P(O)R2, -P(O)(R)OR 、 -C 3-7 selected from cycloalkyl, phenyl, 4- to 7-membered heterocyclyl, and 5- to 6-membered heteroaryl, wherein the heterocyclyl and heteroaryl each contain 1-3 heteroatoms independently selected from N, O, and S; Each instance of R is independently hydrogen, -C 1-6 Alkyl, -C 1-6 Haloalkyl, -C 1-6 Heteroalkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -C 3-7 cycloalkyl, phenyl, 4- to 7-membered heterocyclyl, and 5- to 6-membered heteroaryl, wherein the heterocyclyl and heteroaryl each contain 1-3 heteroatoms independently selected from N, O, and S, or two R groups attached to the same nitrogen optionally combine with the nitrogen to which they are attached to form an optionally substituted 4- to 7-membered heterocyclyl having 0, 1, or 2 additional heteroatoms independently selected from N, O, and S; m is 0, 1, 2, 3, or 4; n is 0, 1, 2, 3, or 4; r is 0, 1, 2, 3, or 4; s is 0, 1, 2, 3, or 4, or a pharmaceutically acceptable salt thereof.

[0016] In one embodiment, there is provided a pharmaceutical composition comprising a compound of Formula A, Formula I or Formula I-1 described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or diluent.

[0017] In one embodiment, a method is provided for inhibiting CDK2 and / or CCNE (CCNE1 and / or CCNE2) signaling in a sample, e.g., in vivo or in vitro, by contacting CDK2 and / or CCNE (CCNE1 and / or CCNE2) with a compound described herein or a pharmaceutically acceptable salt or composition thereof.

[0018] In one embodiment, there is provided the use of a compound described herein or a pharmaceutically acceptable salt thereof or composition in a method for inhibiting CDK2 and / or CCNE (CCNE1 and / or CCNE2) signaling in a sample, e.g., in vivo or in vitro, by contacting CDK2 and / or CCNE (CCNE1 and / or CCNE2) with a compound or composition described herein.

[0019] In one embodiment, there is provided the use of a compound or a pharmaceutically acceptable salt thereof or composition described herein in the manufacture of a medicament for inhibiting CDK2 and / or CCNE (CCNE1 and / or CCNE2) signaling in a sample, for example in vivo or in vitro.

[0020] In one embodiment, a compound described herein or a pharmaceutically acceptable salt thereof or composition is provided for use in a method of inhibiting CDK2 and / or CCNE (CCNE1 and / or CCNE2) signaling in a sample, e.g., in vivo or in vitro, by contacting CDK2 and / or CCNE (CCNE1 and / or CCNE2) with a compound or composition described herein.

[0021] In one embodiment, there is provided a compound described herein or a pharmaceutically acceptable salt thereof or composition for use in the manufacture of a medicament for inhibiting CDK2 and / or CCNE (CCNE1 and / or CCNE2) signaling in a sample, e.g., in vivo or in vitro, by contacting CDK2 and / or CCNE (CCNE1 and / or CCNE2) with a compound or composition described herein.

[0022] In one embodiment, there is provided a method of inhibiting CDK2 signaling in a sample, e.g., in vivo or in vitro, by contacting CDK2 with a compound described herein or a pharmaceutically acceptable salt thereof, or a composition thereof.

[0023] In one embodiment, there is provided the use of a compound described herein, or a pharmaceutically acceptable salt thereof, or a composition thereof, in a method of inhibiting CDK2 signaling in a sample, e.g., in vivo or in vitro, by contacting CDK2 with a compound described herein, or a pharmaceutically acceptable salt thereof, or a composition thereof.

[0024] In one embodiment, there is provided the use of a compound or a pharmaceutically acceptable salt thereof or composition as described herein in the manufacture of a medicament for inhibiting CDK2 signaling in a sample, e.g., in vivo or in vitro.

[0025] In one embodiment, there is provided a compound as described herein, or a pharmaceutically acceptable salt thereof, or a composition, for use in a method of inhibiting CDK2 signaling in a sample, e.g., in vivo or in vitro, by contacting CDK2 with a compound as described herein, or a pharmaceutically acceptable salt thereof, or a composition.

[0026] In one embodiment, there is provided a compound or a pharmaceutically acceptable salt thereof, or a composition as described herein, for use in the manufacture of a medicament for inhibiting CDK2 signaling in a sample, e.g., in vivo or in vitro.

[0027] In one embodiment, a method is provided for inhibiting CCNE (CCNE1 and / or CCNE2) signaling in a sample, e.g., in vivo or in vitro, by contacting CCNE (CCNE1 and / or CCNE2) with a compound described herein or a pharmaceutically acceptable salt or composition thereof.

[0028] In one embodiment, there is provided the use of a compound described herein or a pharmaceutically acceptable salt thereof or a composition thereof in a method for inhibiting CCNE (CCNE1 and / or CCNE2) signaling in a sample, for example in vivo or in vitro, by contacting CCNE (CCNE1 and / or CCNE2) with a compound described herein or a pharmaceutically acceptable salt thereof or composition thereof.

[0029] In one embodiment, there is provided the use of a compound described herein or a pharmaceutically acceptable salt thereof or composition in the manufacture of a medicament for inhibiting CCNE (CCNE1 and / or CCNE2) signaling in a sample, for example in vivo or in vitro.

[0030] In one embodiment, a compound described herein or a pharmaceutically acceptable salt thereof or a composition thereof is provided for use in a method of inhibiting CCNE (CCNE1 and / or CCNE2) signaling in a sample, e.g., in vivo or in vitro, by contacting CCNE (CCNE1 and / or CCNE2) with a compound described herein or a pharmaceutically acceptable salt thereof or composition.

[0031] In one embodiment, there is provided a compound or a pharmaceutically acceptable salt thereof or composition described herein for use in the manufacture of a medicament for inhibiting CCNE (CCNE1 and / or CCNE2) signaling in a sample, e.g., in vivo or in vitro.

[0032] In one embodiment, a method is provided for inhibiting CDK2 and CCNE (CCNE1 and / or CCNE2) signaling in a sample, e.g., in vivo or in vitro, by contacting CDK2 and / or CCNE (CCNE1 and / or CCNE2) with a compound described herein or a pharmaceutically acceptable salt or composition thereof.

[0033] In one embodiment, there is provided the use of a compound described herein or a pharmaceutically acceptable salt thereof or a composition thereof in a method for inhibiting CDK2 and CCNE (CCNE1 and / or CCNE2) signaling in a sample, e.g., in vivo or in vitro, by contacting CDK2 and / or CCNE (CCNE1 and / or CCNE2) with a compound described herein or a pharmaceutically acceptable salt thereof or composition.

[0034] In one embodiment, there is provided the use of a compound or a pharmaceutically acceptable salt thereof or composition described herein in the manufacture of a medicament for inhibiting CDK2 and CCNE (CCNE1 and / or CCNE2) signaling in a sample, for example in vivo or in vitro.

[0035] In one embodiment, there is provided a compound described herein, or a pharmaceutically acceptable salt thereof, or a composition thereof, for use in a method of inhibiting CDK2 and CCNE (CCNE1 and / or CCNE2) signaling in a sample, e.g., in vivo or in vitro, by contacting CDK2 and / or CCNE (CCNE1 and / or CCNE2) with a compound described herein, or a pharmaceutically acceptable salt thereof, or a composition thereof.

[0036] In one embodiment, there is provided a compound or a pharmaceutically acceptable salt thereof or composition described herein for use in the manufacture of a medicament for inhibiting CDK2 and CCNE (CCNE1 and / or CCNE2) signaling in a sample, e.g., in vivo or in vitro.

[0037] In one embodiment, a method is provided for treating a CDK2 and / or CCNE (CCNE1 and / or CCNE2) mediated disorder in a patient in need of such treatment, comprising administering to the patient a compound or a pharmaceutically acceptable salt thereof or a composition described herein.

[0038] In one embodiment, there is provided the use of a compound described herein, or a pharmaceutically acceptable salt thereof, or a composition thereof, in a method for treating a CDK2 and / or CCNE (CCNE1 and / or CCNE2) mediated disorder in a patient in need of such treatment, the method comprising administering to the patient a compound described herein, or a pharmaceutically acceptable salt thereof, or a composition thereof.

[0039] In one embodiment, there is provided the use of a compound or a pharmaceutically acceptable salt thereof or composition described herein in the manufacture of a medicament for treating a CDK2 and / or CCNE (CCNE1 and / or CCNE2) mediated disorder in a patient in need of such treatment.

[0040] In one embodiment, there is provided a compound or a pharmaceutically acceptable salt thereof, or a composition as described herein, for use in a method of treating a CDK2 and / or CCNE (CCNE1 and / or CCNE2)-mediated disorder in a patient in need of such treatment, the method comprising administering to the patient a compound or a pharmaceutically acceptable salt thereof, or a composition as described herein.

[0041] In one embodiment, there is provided a compound or a pharmaceutically acceptable salt thereof, or composition as described herein, for use in the manufacture of a medicament for treating a CDK2 and / or CCNE (CCNE1 and / or CCNE2) mediated disorder in a patient in need of such treatment.

[0042] In one embodiment, there is provided a method of treating a CDK2-mediated disorder in a patient in need of such treatment, comprising administering to said patient a compound or a pharmaceutically acceptable salt thereof, or a composition described herein.

[0043] In one embodiment, there is provided use of a compound as described herein, or a pharmaceutically acceptable salt thereof, or a composition thereof, in a method of treating a CDK2-mediated disorder in a patient in need of such treatment, the method comprising administering to the patient a compound as described herein, or a pharmaceutically acceptable salt thereof, or a composition thereof.

[0044] In one embodiment, there is provided the use of a compound or a pharmaceutically acceptable salt thereof, or a composition as described herein in the manufacture of a medicament for treating a CDK2-mediated disorder in a patient in need thereof.

[0045] In one embodiment, there is provided a compound or a pharmaceutically acceptable salt thereof, or a composition as described herein for use in a method of treating a CDK2-mediated disorder in a patient in need of such treatment, the method comprising administering to said patient a compound or a pharmaceutically acceptable salt thereof, or a composition as described herein.

[0046] In one embodiment, there is provided a compound or a pharmaceutically acceptable salt thereof, or composition as described herein for use in the manufacture of a medicament for treating a CDK2-mediated disorder in a patient in need thereof.

[0047] In one embodiment, a method of treating a CCNE (CCNE1 and / or CCNE2)-mediated disorder in a patient in need of such treatment is provided, comprising administering to the patient a compound or a pharmaceutically acceptable salt thereof or a composition described herein.

[0048] In one embodiment, there is provided the use of a compound described herein, or a pharmaceutically acceptable salt thereof, or a composition thereof, in a method for treating a CCNE (CCNE1 and / or CCNE2)-mediated disorder in a patient in need of such treatment, the method comprising administering to the patient a compound described herein, or a pharmaceutically acceptable salt thereof, or a composition thereof.

[0049] In one embodiment, there is provided the use of a compound or a pharmaceutically acceptable salt thereof or composition described herein in the manufacture of a medicament for treating a CCNE (CCNE1 and / or CCNE2)-mediated disorder in a patient in need of such treatment.

[0050] In one embodiment, there is provided a compound or a pharmaceutically acceptable salt thereof, or a composition described herein for use in a method of treating a CCNE (CCNE1 and / or CCNE2)-mediated disorder in a patient in need of such treatment, the method comprising administering to the patient a compound or a pharmaceutically acceptable salt thereof, or a composition described herein.

[0051] In one embodiment, there is provided a compound or a pharmaceutically acceptable salt thereof or composition described herein for use in the manufacture of a medicament for treating a CCNE (CCNE1 and / or CCNE2)-mediated disorder in a patient in need of such treatment.

[0052] In one embodiment, a method is provided for treating a CDK2 and CCNE (CCNE1 and / or CCNE2) mediated disorder in a patient in need of such treatment, comprising administering to the patient a compound or a pharmaceutically acceptable salt thereof or a composition described herein.

[0053] In one embodiment, there is provided the use of a compound described herein, or a pharmaceutically acceptable salt thereof, or a composition thereof, in a method for treating a CDK2- and CCNE (CCNE1 and / or CCNE2)-mediated disorder in a patient in need of such treatment, the method comprising administering to the patient a compound described herein, or a pharmaceutically acceptable salt thereof, or a composition thereof.

[0054] In one embodiment, there is provided the use of a compound or a pharmaceutically acceptable salt thereof or composition described herein in the manufacture of a medicament for treating a CDK2 and CCNE (CCNE1 and / or CCNE2) mediated disorder in a patient in need of such treatment.

[0055] In one embodiment, there is provided a compound or a pharmaceutically acceptable salt thereof, or a composition as described herein, for use in a method of treating a CDK2- and CCNE (CCNE1 and / or CCNE2)-mediated disorder in a patient in need of such treatment, the method comprising administering to the patient a compound or a pharmaceutically acceptable salt thereof, or a composition as described herein.

[0056] In one embodiment, there is provided a compound or a pharmaceutically acceptable salt thereof, or composition as described herein, for use in the manufacture of a medicament for treating a CDK2- and CCNE (CCNE1 and / or CCNE2)-mediated disorder in a patient in need of such treatment. DETAILED DESCRIPTION OF THE INVENTION

[0057] definition As used in this disclosure, the following words and phrases are generally intended to have the meanings set forth below, unless expressly indicated otherwise or the context in which they are used dictates otherwise.

[0058] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this invention belongs.The abbreviations used herein have their conventional meanings in the chemical and biological fields.The chemical structures and formulas described herein are constructed according to the standard rules of chemical valence known in the chemical field.

[0059] Throughout this specification, when compositions and kits are described as having, including, or comprising particular components, or when processes and methods are described as having, including, or comprising particular steps, it is further contemplated that there are compositions and kits of the invention that consist essentially of or consist of the recited components, and that there are processes and methods of the invention that consist essentially of or consist of the recited processing steps.

[0060] In this application, when an element or component is referred to as being included in and / or selected from a list of described elements or components, it is to be understood that the element or component can be any one of the described elements or components, or the element or component can be selected from a group consisting of two or more of the described elements or components.

[0061] Furthermore, it should be understood that the elements and / or features of the compositions or methods described herein, whether expressly or implicitly stated herein, can be combined in various ways without departing from the spirit and scope of the invention. For example, when a particular compound is referenced, unless otherwise understood from the context, that compound can be used in various embodiments of the compositions of the invention and / or methods of the invention. When elements are presented as a list, e.g., in Markush group format, each subgroup of the elements is also disclosed, and any element can be removed from the group. In other words, within the scope of this application, embodiments have been described and illustrated in a manner that allows the application to be clearly and concisely written and illustrated, but it is intended and understood that those embodiments may be combined or separated in various ways without departing from the present teachings and invention. For example, it will be understood that all features described and illustrated herein may be applicable to all aspects of the invention described and illustrated herein.

[0062] In this disclosure, unless the context is inappropriate, the articles "a" and "an" are used to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. As an example, in some contexts, "an element" may mean one element, and / or in some contexts, more than one element. As another example, in some contexts, "a compound" may mean one compound, and / or in some contexts, more than one compound (e.g., a mixture of two or more compounds).

[0063] In this disclosure, the term "and / or" is used to mean either "and" or "or," unless otherwise indicated.

[0064] The phrase "at least one of," unless otherwise understood from context and usage, should be understood to include each of the listed objects following the phrase individually and various combinations of two or more of the listed objects. The phrase "and / or" in connection with more than two listed objects should be understood to have the same meaning unless otherwise understood from context.

[0065] The use of the terms "include," "includes," "including," "have," "has," "having," "contain," "contains," or "containing" is to be understood as generally open-ended and open-ended, and as not excluding, for example, additional, unrecited elements or steps, unless specifically stated otherwise or understood otherwise from the context. When the term "about" is used before a quantitative value, the present invention also includes the specific quantitative value itself, unless specifically stated otherwise. As used herein, the term "about" refers to a ±10% variation from the nominal value, unless otherwise indicated or inferred from the context.

[0066] At various places in this specification, variables or parameters are disclosed in groups or ranges. The description is specifically intended to include all individual subcombinations of the members of such groups and ranges. For example, an integer in the range of 0 to 40 is specifically intended to individually disclose 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, and 40, and an integer in the range of 1 to 20 is specifically intended to individually disclose 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20.

[0067] Any and all examples herein, or the use of exemplary language, e.g., "such as" or "including," are intended merely to better illustrate the invention and do not pose a limitation on the scope of the invention unless claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention.

[0068] chemical definition These and other exemplary substituents are described in further detail in the detailed description, examples, and claims. The present invention is not intended to be limited in any way by the recitation of exemplary substituents above.

[0069] Definitions of specific functional groups and chemical terms are described in more detail below. Chemical elements are identified according to the CAS Periodic Table of the Elements, Handbook of Chemistry and Physics, 75th Edition, inside cover, and specific functional groups are generally defined as described therein. In addition, general principles of organic chemistry, as well as specific functional moieties and reactivities, are defined in accordance with the principles of organic chemistry, as described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5 th Edition, John Wiley & Sons, Inc., New York, 2001, Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989, and Carruthers, Some Modern Methods of Organic Synthesis, 3 rd Edition, Cambridge University Press, Cambridge, 1987.

[0070] The compounds described herein may contain one or more asymmetric centers and therefore may exist in various isomeric forms, such as enantiomers and / or diastereomers. For example, the compounds described herein may be in the form of individual enantiomers, diastereomers, or geometric isomers, or may be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high-pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts, or preferred isomers can be prepared by asymmetric synthesis. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981), Wilen et al., Tetrahedron 33:2725 (1977), Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962), and Wilen, Tables of Resolving Agents and Optical Resolutions p. 268 (EL Eliel, Ed., University of Notre Dame Press, Notre Dame, IN 1972). Additionally, the compounds described herein are encompassed as individual isomers substantially free of other isomers, or alternatively, as mixtures of various isomers.

[0071] As used herein, "enantiomeric excess" ("ee") or "% enantiomeric excess" ("%ee") of a composition refers to the excess of one enantiomer over the other enantiomer present in the composition. For example, a composition may contain 90% of one enantiomer, e.g., the S enantiomer, and 10% of the other enantiomer, i.e., the R enantiomer. ee=(90-10) / 100=80%.

[0072] Thus, a composition containing 90% of one enantiomer and 10% of the other is said to have an enantiomeric excess of 80%.

[0073] As used herein, "diastereomeric excess" ("de") or "% diastereomeric excess" ("% de") of a composition refers to the excess of one diastereomer over one or more different diastereomers present in the composition. For example, a composition may contain 90% of one diastereomer and 10% of one or more different diastereomers. de=(90-10) / 100=80%.

[0074] Thus, a composition that contains 90% of one diastereomer and 10% of one or more different diastereomers is said to have a diastereomeric excess of 80%.

[0075] In alternative embodiments, the compounds described herein may also contain one or more isotopic substitutions. For example, hydrogen may be replaced by: 2 H (D or deuterium) or 3 H (T or tritium), and carbon can be, for example, 13 C or 14 C, and oxygen may be, for example, 18 O, and the nitrogen may be, for example, 15 In other embodiments, specific isotopes (e.g., 3 H, 13 C. 14 C. 18 O, or 15N) can represent at least 1%, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or at least 99.9% of the total isotopic abundance of the element occupying a particular site in the compound.

[0076] During the ceremony,

[0077] [ka] is a single bond without specifying the stereochemistry of the moiety directly attached to it.

[0078] When a range of values ​​is listed, it is intended that each value and subrange within the range be encompassed. For example, "C 1-6 "Alkyl" refers to C1, C2, C3, C4, C5, C6, C 1-6 , C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-5 , C 2-4 , C 2-3 , C 3-6 , C 3-5 , C 3-4 , C 4-6 , C 4-5 , and C 5-6 Alkyl is intended to be included.

[0079] As described herein, it should be understood that any of the moieties defined below may be substituted with various substituents, and that each definition is intended to include such substituted moieties within its scope, as set forth below. Unless otherwise specified, the term "substituted" shall be defined as set forth below. It should further be understood that, as used herein, the terms "group" and "radical" can be considered interchangeable. The articles "a" and "an" may be used herein to refer to one or more than one (i.e., at least one) of the object of the article. By way of example, "analog" means one analog or more than one analog.

[0080] The term "unsaturated bond" refers to a double or triple bond.

[0081] The terms "unsaturated" or "partially unsaturated" refer to a moiety that contains at least one double or triple bond.

[0082] The term "saturated" refers to a moiety that does not contain any double or triple bonds; ie, the moiety contains only single bonds.

[0083] The suffix "-ene" added to a group indicates that the group is a divalent moiety. For example, alkylene is a divalent moiety of alkyl, alkenylene is a divalent moiety of alkenyl, alkynylene is a divalent moiety of alkynyl, heteroalkylene is a divalent moiety of heteroalkyl, heteroalkenylene is a divalent moiety of heteroalkenyl, heteroalkynylene is a divalent moiety of heteroalkynyl, carbocyclylene is a divalent moiety of carbocyclyl, heterocyclylene is a divalent moiety of heterocyclyl, arylene is a divalent moiety of aryl, and heteroarylene is a divalent moiety of heteroaryl.

[0084] The term "azido" refers to the radical -N3.

[0085] "Aliphatic" refers to an alkyl, alkenyl, alkynyl, or carbocyclyl group, as defined herein.

[0086] "Cycloalkylalkyl" refers to an alkyl radical in which the alkyl group is substituted with a cycloalkyl group. Typical cycloalkylalkyl groups include, but are not limited to, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, cyclooctylmethyl, cyclopropylethyl, cyclobutylethyl, cyclopentylethyl, cyclohexylethyl, cycloheptylethyl, and cyclooctylethyl.

[0087] "Heterocyclylalkyl" refers to an alkyl radical in which the alkyl group is substituted with a heterocyclyl group. Typical heterocyclylalkyl groups include, but are not limited to, pyrrolidinylmethyl, piperidinylmethyl, piperazinylmethyl, morpholinylmethyl, pyrrolidinylethyl, piperidinylethyl, piperazinylethyl, morpholinylethyl, and the like.

[0088] "Aralkyl" or "arylalkyl" is a subset of alkyl and aryl, as defined herein, and refers to an optionally substituted alkyl group substituted by an optionally substituted aryl group.

[0089] "Alkyl" means a straight or branched chain saturated hydrocarbon group having 1 to 20 carbon atoms ("C 1-20 In one embodiment, an alkyl group has 1 to 12 carbon atoms ("C 1-12 In one embodiment, an alkyl group has 1 to 10 carbon atoms ("C 1-10 In one embodiment, an alkyl group has 1 to 9 carbon atoms ("C 1-9 In one embodiment, the alkyl group has 1 to 8 carbon atoms ("C 1-8In one embodiment, the alkyl group has 1 to 7 carbon atoms ("C 1-7 In one embodiment, an alkyl group has 1 to 6 carbon atoms ("C 1-6 In one embodiment, an alkyl group has 1 to 5 carbon atoms ("C 1-5 In one embodiment, the alkyl group has 1 to 4 carbon atoms ("C 1-4 In one embodiment, an alkyl group has 1 to 3 carbon atoms ("C 1-3 In one embodiment, the alkyl group has 1 to 2 carbon atoms ("C 1-2 In one embodiment, the alkyl group has 1 carbon atom ("C alkyl"). In one embodiment, the alkyl group has 2 to 6 carbon atoms ("C 2-6 alkyl). C 1-6 Examples of alkyl groups include methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), iso-butyl (C4), n-pentyl (C5), 3-pentanyl (C5), amyl (C5), neopentyl (C5), 3-methyl-2-butanyl (C5), tertiary amyl (C5), and n-hexyl (C6). Additional examples of alkyl groups include n-heptyl (C7), n-octyl (C8), and the like. Unless otherwise specified, each alkyl group instance is independently optionally substituted; that is, unsubstituted ("unsubstituted alkyl") or substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent ("substituted alkyl"). In certain embodiments, an alkyl group is an unsubstituted C 1-10 In certain embodiments, the alkyl group is a substituted C 1-10 Alkyl. Common abbreviations for alkyl are Me(-CH3), Et(-CH2CH3), i Pr(-CH(CH3)2), n Pr(-CH2CH2CH3), nBu(-CH2CH2CH2CH3), or i Contains Bu(-CH2CH(CH3)2).

[0090] "Alkylene" refers to an alkyl group in which two hydrogens are removed to provide a divalent radical, which can be substituted or unsubstituted. Unsubstituted alkylene groups include, but are not limited to, methylene (-CH-), ethylene (-CHCH-), propylene (-CHCHCH-), butylene (-CHCHCHCHCH-), pentylene (-CHCHCHCHCHCH-), hexylene (-CHCHCHCHCHCHCH-), and the like. Exemplary substituted alkylene groups, e.g., substituted with one or more alkyl (methyl) groups, include, but are not limited to, substituted methylene (-CH(CH)-, (-C(CH)-), substituted ethylene (-CH(CH)CH-, -CHCH(CH)-, -C(CH)CH-, -CHC(CH)-), substituted propylene (-CH(CH)CHCH-, -CHCH(CH)CH-, -CHCHCH(CH)CH-, -CHCHCH(CH)-, -C(CH)CHCH-, -CHC(CH)CH-, -CHCHC(CH)-), and the like. When a range or number of carbons is provided for a particular alkylene group, it is understood that the range or number refers to the range or number of carbons in a linear divalent chain of carbons. An alkylene group can be substituted or unsubstituted with one or more substituents, as described herein.

[0091] "Alkenyl" refers to the radical of a straight- or branched-chain hydrocarbon group having 2 to 20 carbon atoms, one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds), and optionally one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds) ("C 2-20 In certain embodiments, the alkenyl does not contain any triple bonds. In one embodiment, the alkenyl group has 2 to 10 carbon atoms ("C 2-10In one embodiment, an alkenyl group has 2 to 9 carbon atoms ("C 2-9 In one embodiment, an alkenyl group has 2 to 8 carbon atoms ("C 2-8 In one embodiment, an alkenyl group has 2 to 7 carbon atoms ("C 2-7 In one embodiment, an alkenyl group has 2 to 6 carbon atoms ("C 2-6 In one embodiment, an alkenyl group has 2 to 5 carbon atoms ("C 2-5 In one embodiment, an alkenyl group has 2 to 4 carbon atoms ("C 2-4 In one embodiment, an alkenyl group has 2 to 3 carbon atoms ("C 2-3 In one embodiment, the alkenyl group has two carbon atoms ("C2 alkenyl"). The one or more carbon-carbon double bonds can be internal (e.g., in 2-butenyl) or terminal (e.g., in 1-butenyl). C 2-4 Examples of alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. 2-6 Examples of alkenyl groups include the above-mentioned C 2-4 Alkenyl groups include pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like. Unless otherwise specified, each instance of an alkenyl group is independently optionally substituted; that is, unsubstituted ("unsubstituted alkenyl") or substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent ("substituted alkenyl"). In certain embodiments, an alkenyl group is an unsubstituted C 2-10 In certain embodiments, the alkenyl group is a substituted C 2-10 It is alkenyl.

[0092] "Alkynyl" refers to the radical of a straight- or branched-chain hydrocarbon group having 2 to 20 carbon atoms, one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds), and optionally one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds) ("C 2-20 In certain embodiments, alkynyl does not contain any double bonds. In one embodiment, an alkynyl group has 2 to 10 carbon atoms ("C 2-10 In one embodiment, an alkynyl group has 2 to 9 carbon atoms ("C 2-9 In one embodiment, an alkynyl group has 2 to 8 carbon atoms ("C 2-8 In one embodiment, an alkynyl group has 2 to 7 carbon atoms ("C 2-7 In one embodiment, an alkynyl group has 2 to 6 carbon atoms ("C 2-6 In one embodiment, an alkynyl group has 2 to 5 carbon atoms ("C 2-5 In one embodiment, an alkynyl group has 2 to 4 carbon atoms ("C 2-4 In one embodiment, an alkynyl group has 2 to 3 carbon atoms ("C 2-3 In one embodiment, the alkynyl group has two carbon atoms ("C2 alkynyl"). The one or more carbon-carbon triple bonds can be internal (e.g., in 2-butynyl) or terminal (e.g., in 1-butynyl). C 2-4 Examples of alkynyl groups include, but are not limited to, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. 2-6 Examples of alkenyl groups include the above-mentioned C 2-4Examples of alkynyl groups include pentynyl (C5), hexynyl (C6), and the like. Additional examples of alkynyl include heptynyl (C7), octynyl (C8), and the like. Unless otherwise specified, each instance of an alkynyl group is independently optionally substituted; that is, unsubstituted ("unsubstituted alkynyl") or substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent ("substituted alkynyl"). In certain embodiments, an alkynyl group is an unsubstituted C 2-10 In certain embodiments, the alkynyl group is a substituted C 2-10 It is alkynyl.

[0093] The term "heteroalkyl," as used herein, refers to an alkyl group, as defined herein, further comprising one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus) in the main chain, where one or more heteroatoms are inserted between adjacent carbon atoms in the main carbon chain and / or one or more heteroatoms are inserted between a carbon atom and the parent molecule, i.e., between the points of attachment. In certain embodiments, a heteroalkyl group is a saturated group having 1 to 10 carbon atoms and 1, 2, 3, or 4 heteroatoms ("heteroC"). 1-10 In one embodiment, a heteroalkyl group refers to a saturated group having 1 to 9 carbon atoms and 1, 2, 3, or 4 heteroatoms ("heteroC 1-9 In one embodiment, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1, 2, 3, or 4 heteroatoms ("heteroC 1-8 In one embodiment, a heteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1, 2, 3, or 4 heteroatoms ("heteroC 1-7 In one embodiment, a heteroalkyl group is a group having 1 to 6 carbon atoms and 1, 2, or 3 heteroatoms ("heteroC 1-6In one embodiment, a heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms ("heteroC 1-5 In one embodiment, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and 1 or 2 heteroatoms ("heteroC 1-4 In one embodiment, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom ("heteroC 1-3 In one embodiment, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom ("heteroC 1-2 In one embodiment, the heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom ("heteroC1 alkyl"). In one embodiment, the heteroalkyl group is a saturated group having 2 to 6 carbon atoms and 1 or 2 heteroatoms ("heteroC 2-6 Unless otherwise specified, each instance of a heteroalkyl group is independently unsubstituted ("unsubstituted heteroalkyl") or substituted with one or more substituents ("substituted heteroalkyl"). In certain embodiments, a heteroalkyl group is an unsubstituted heteroC 1-10 In certain embodiments, the heteroalkyl group is a substituted heteroC 1-10 Exemplary heteroalkyl groups include -CHOH, -CHOCH, -CHNH, -CHNH(CH), -CHN(CH), -CHCHOH, -CHCHOCH, -CHCHNH, -CHCHNH(CH), -CHCHN(CH).

[0094] "Aryl" refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4π+2 aromatic ring system (e.g., 6, 10, or 14 π electrons shared in a cyclic arrangement) having 6 to 14 ring carbon atoms and 0 heteroatoms present in the aromatic ring system ("C 6-14In one embodiment, an aryl group has 6 ring carbon atoms ("C aryl", e.g., phenyl). In one embodiment, an aryl group has 10 ring carbon atoms ("C 10 aryl," e.g., naphthyl, such as 1-naphthyl and 2-naphthyl). In one embodiment, an aryl group has 14 ring carbon atoms ("C 14 "Aryl," e.g., anthracyl). "Aryl" also includes ring systems in which an aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups. In this case, the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continues to indicate the number of carbon atoms in the aryl ring system. Aryl groups include, among others, phenyl, naphthyl, indenyl, and tetrahydronaphthyl. Unless otherwise specified, each instance of an aryl group is independently optionally substituted; that is, unsubstituted ("unsubstituted aryl") or substituted with one or more substituents ("substituted aryl"). In certain embodiments, an aryl group is an unsubstituted C 6-14 In certain embodiments, the aryl group is a substituted C 6-14 It is aryl.

[0095] In certain embodiments, the aryl group is selected from halo, C 1- Substituted with one or more groups selected from C8 alkyl, C1-C8 haloalkyl, cyano, hydroxy, C1-C8 alkoxy, and amino.

[0096] Representative examples of substituted aryl include the following:

[0097] [ka] Examples include: In the formula, R 56 and R 57 may be hydrogen, and R 56 and R 57At least one of the groups independently represents C1-C8 alkyl, C1-C8 haloalkyl, 4- to 10-membered heterocyclyl, alkanoyl, C1-C8 alkoxy, heteroaryloxy, alkylamino, arylamino, heteroarylamino, -NR 58 COR 59 , -NR 58 SOR 59 NR 58 SO2R 59 , -COO alkyl, -COO aryl, -CONR 58 R 59 , -CONR 58 OR 59 , -NR 58 R 59 , -SO2NR 58 R 59 , -S-alkyl, -SOalkyl, -SO2alkyl, -Saryl, -SOaryl, -SO2aryl, or R 56 and R 57 may be linked to form a cyclic ring (saturated or unsaturated) of 5 to 8 atoms, optionally containing one or more heteroatoms selected from the group consisting of N, O, or S. R 60 and R 61 are independently hydrogen, -C1-C8 alkyl, -C1-C4 haloalkyl, -C3-C 10 Cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 Aryl, substituted C6-C 10 It is aryl, 5- to 10-membered heteroaryl, or substituted 5- to 10-membered heteroaryl.

[0098] "Fused aryl" refers to an aryl that shares two of its ring carbons with a second aryl or heteroaryl ring, or a carbocyclyl or heterocyclyl ring.

[0099] "Heteroaryl" refers to the radical of a 5- to 10-membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., 6 or 10 pi electrons shared in a cyclic arrangement) having ring carbon atoms and 1 to 4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5- to 10-membered heteroaryl"). In heteroaryl groups containing one or more nitrogen atoms, the point of attachment can be a carbon atom or a nitrogen atom, valence permitting. Heteroaryl bicyclic ring systems can contain one or more heteroatoms in one or both rings. "Heteroaryl" also includes ring systems in which a heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups, where the point of attachment is on the heteroaryl ring, and in such instances, unless otherwise specified, the number of ring members continues to refer to the number of ring members in the heteroaryl ring system. "Heteroaryl" also includes ring systems in which a heteroaryl ring, as defined above, is fused to one or more aryl groups, where the point of attachment can be on either the aryl or heteroaryl ring, and in such instances the number of ring members refers to the number of ring members in the fused (aryl / heteroaryl) ring system. In bicyclic heteroaryl groups in which one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, etc.), the point of attachment can be on either ring, i.e., the ring containing the heteroatom (e.g., 2-indolyl) or the ring without the heteroatom (e.g., 5-indolyl).

[0100] In one embodiment, a heteroaryl group is a 5- to 10-membered aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, each independently selected from nitrogen, oxygen, and sulfur ("5- to 10-membered heteroaryl"). In one embodiment, a heteroaryl group is a 5- to 8-membered aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, each independently selected from nitrogen, oxygen, and sulfur ("5- to 8-membered heteroaryl"). In one embodiment, a heteroaryl group is a 5- to 6-membered aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, each independently selected from nitrogen, oxygen, and sulfur ("5- to 6-membered heteroaryl"). In one embodiment, a 5- to 6-membered heteroaryl has 1 to 3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In one embodiment, a 5- to 6-membered heteroaryl has 1 to 2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In one embodiment, a 5- to 6-membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each entity of a heteroaryl group is independently optionally substituted; that is, unsubstituted ("unsubstituted heteroaryl") or substituted with one or more substituents ("substituted heteroaryl"). In certain embodiments, a heteroaryl group is an unsubstituted 5- to 14-membered heteroaryl. In certain embodiments, a heteroaryl group is a substituted 5- to 14-membered heteroaryl. In one embodiment, a heteroaryl group is a bicyclic 8- to 12-membered aromatic ring system having ring carbon atoms and 1 to 6 ring heteroatoms provided in the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("8- to 12-membered bicyclic heteroaryl"). In one embodiment, the heteroaryl group is an 8-10 membered bicyclic aromatic ring system having ring carbon atoms and 1-6 ring heteroatoms provided in the aromatic ring system, where the heteroatoms are each independently selected from nitrogen, oxygen, and sulfur (an "8-10 membered bicyclic heteroaryl").In one embodiment, a heteroaryl group is a 9- to 10-membered bicyclic aromatic ring system having ring carbon atoms and 1 to 6 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("9- to 10-membered bicyclic heteroaryl"). Unless otherwise specified, each entity of the heteroaryl group is independently unsubstituted ("unsubstituted heteroaryl") or substituted with one or more substituents ("substituted heteroaryl"). In certain embodiments, a heteroaryl group is an unsubstituted 5- to 14-membered heteroaryl. In certain embodiments, a heteroaryl group is a substituted 5- to 14-membered heteroaryl.

[0101] Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0102] Representative examples of heteroaryl include:

[0103] [ka] are listed, In the formula, Z is carbonyl, N, NR 65 , O, and S, and R 65 are independently hydrogen, -C1-C8 alkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 aryl, and 5- to 10-membered heteroaryl.

[0104] In the structures described herein, a substituent attached to a polycyclic (e.g., bicyclic or tricyclic) cycloalkyl, heterocyclyl, aryl, or heteroaryl with a bond spanning more than one ring is understood to mean that the substituent can be attached at any position on either ring. "Heteroaralkyl" or "heteroarylalkyl" is a subset of "alkyl" and refers to an alkyl group substituted with a heteroaryl group, where the point of attachment is on the alkyl portion.

[0105] The term "carbocyclyl" or "carbocyclic" refers to a radical of a non-aromatic monocyclic, bicyclic, tricyclic, or polycyclic hydrocarbon ring system having 3 to 14 ring carbon atoms and zero heteroatoms in the non-aromatic ring system ("C 3-14 Carbocyclyl groups include fully saturated ring systems (e.g., cycloalkyl) and partially saturated ring systems. In one embodiment, a carbocyclyl group has 3 to 10 ring carbon atoms ("C 3-10 In one embodiment, a carbocyclyl group has 3 to 8 ring carbon atoms ("C 3-8 In one embodiment, a carbocyclyl group has 3 to 7 ring carbon atoms ("C 3-7 In one embodiment, a carbocyclyl group has 3 to 6 ring carbon atoms ("C 3-6 In one embodiment, a carbocyclyl group has 4 to 6 ring carbon atoms ("C 4-6 In one embodiment, the carbocyclyl group has 5 to 6 ring carbon atoms ("C 5-6In one embodiment, a carbocyclyl group has 5 to 10 ring carbon atoms ("C 5-10 carbocyclyl). Exemplary C 3-6 Carbocyclyl groups include, but are not limited to, cyclopropyl (C), cyclopropenyl (C), cyclobutyl (C), cyclobutenyl (C), cyclopentyl (C), cyclopentenyl (C), cyclohexyl (C), cyclohexenyl (C), cyclohexadienyl (C), and the like. 3-8 The carbocyclyl group includes, but is not limited to, the above-mentioned C 3-6 In addition to carbocyclyl groups, examples include cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), and the like. Exemplary C 3-10 The carbocyclyl group includes, but is not limited to, the above-mentioned C 3-8 In addition to carbocyclyl groups, cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C 10 ), spiro[4.5]decanyl (C 10 ) etc.

[0106] As the foregoing examples illustrate, in certain embodiments, a carbocyclyl group is either monocyclic ("monocyclic carbocyclyl") or polycyclic (including, for example, fused, bridged, or spiro ring systems such as a bicyclic system ("bicyclic carbocyclyl") or a tricyclic system ("tricyclic carbocyclyl")), and may be saturated or contain one or more carbon-carbon double or triple bonds. "Carbocyclyl" also includes ring systems in which a carbocyclyl ring, as defined above, is fused to one or more aryl or heteroaryl groups, where the point of attachment is on the carbocyclyl ring, and in such instances, the number of carbons continues to refer to the number of carbons in the carbocyclic ring system. Unless otherwise specified, each instance of a carbocyclyl group is independently unsubstituted ("unsubstituted carbocyclyl") or substituted with one or more substituents ("substituted carbocyclyl"). In certain embodiments, the carbocyclyl group is an unsubstituted C 3-14 In certain embodiments, the carbocyclyl group is a substituted C 3-14 It is a carbocyclyl.

[0107] As used herein, the term "cycloalkyl" refers to a saturated cyclic, bicyclic, tricyclic, or polycyclic hydrocarbon group having 3 to 14 carbons, including the indicated number of rings and carbon atoms (e.g., C3-C 14 Monocyclic, C4-C 14 Bicyclic, C5-C 14 Tricyclic, or C6-C 14 In one embodiment, a "cycloalkyl" is a monocyclic cycloalkyl. In one embodiment, a monocyclic cycloalkyl has 3 to 14 ring carbon atoms ("C 3-14 In one embodiment, a monocyclic cycloalkyl group has 3 to 10 ring carbon atoms ("C 3-10 In one embodiment, a monocyclic cycloalkyl group has 3 to 8 ring carbon atoms ("C 3-8 In one embodiment, a monocyclic cycloalkyl group has 3 to 6 ring carbon atoms ("C 3-6In one embodiment, a monocyclic cycloalkyl group has 4 to 6 ring carbon atoms ("C 4-6 In one embodiment, a monocyclic cycloalkyl group has 5 to 6 ring carbon atoms ("C 5-6 In one embodiment, a monocyclic cycloalkyl group has 5 to 10 ring carbon atoms ("C 5-10 Monocyclic cycloalkyl). Exemplary C 5-6 Monocyclic cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). Exemplary C 3-6 The cycloalkyl group includes the above-mentioned C 5-6 Cycloalkyl groups include cyclopropyl (C3) and cyclobutyl (C4). Exemplary C 3-8 The cycloalkyl group includes the above-mentioned C 3-6 Other cycloalkyl groups include cycloheptyl (C7) and cyclooctyl (C8).

[0108] In one embodiment, a "cycloalkyl" is a bicyclic cycloalkyl. In one embodiment, a bicyclic cycloalkyl has 4 to 14 ring carbon atoms ("C 4-14 In one embodiment, a bicyclic cycloalkyl group has 4 to 12 ring carbon atoms ("C 4-12 In one embodiment, a bicyclic cycloalkyl group has 4 to 10 ring carbon atoms ("C 4-10 In one embodiment, a bicyclic cycloalkyl group has 5 to 10 ring carbon atoms ("C 5-10 In one embodiment, a bicyclic cycloalkyl group has 6 to 10 ring carbon atoms ("C 6-10 In one embodiment, a bicyclic cycloalkyl group has 8 to 10 ring carbon atoms ("C 8-10 In one embodiment, a bicyclic cycloalkyl group has 7 to 9 ring carbon atoms ("C 7-9Bicyclic cycloalkyls). Examples of bicyclic cycloalkyls include bicyclo[1.1.0]butane (C4), bicyclo[1.1.1]pentane (C5), spiro[2.2]pentane (C5), bicyclo[2.1.0]pentane (C5), bicyclo[2.1.1]hexane (C6), bicyclo[3.1.0]hexane (C6), spiro[2.3]hexane (C6), bicyclo[2.2.1]heptane (norbornane) (C7), bicyclo[3.2.0]heptane (C7), bicyclo[3.1.1]heptane (C7), bicyclo[3.1.1]heptane (C7), bicyclo[4.1.0]heptane (C7), spiro[2 .4]heptane (C7), spiro[3.3]heptane (C7), bicyclo[2.2.2]octane (C8), bicyclo[4.1.1]octane (C8), octahydropentalene (C8), bicyclo[3.2.1]octane (C8), bicyclo[4.2.0]octane (C8), spiro[2.5]octane (C8), spiro[3.4]octane (C8), bicyclo[3.3.1]nonane (C9), octahydro-1H-indene (C9), bicyclo[4.2.1]nonane (C9), spiro[3.5]nonane (C9), spiro[4.4]nonane (C9), bicyclo[3.3.2]decane (C 10 ), bicyclo[4.3.1]decane (C 10 ), spiro[4.5]decane (C 10 ), bicyclo[3.3.3]undecane (C 11 ), decahydronaphthalene (C 10 ), bicyclo[4.3.2]undecane (C 11 ), spiro[5.5]undecane (C 11 ), and bicyclo[4.3.3]dodecane (C 12 ) are mentioned.

[0109] In one embodiment, "cycloalkyl" is a tricyclic cycloalkyl. In one embodiment, a tricyclic cycloalkyl has 6-14 ring carbon atoms ("C 6-14 In one embodiment, a tricyclic cycloalkyl group has 8 to 12 ring carbon atoms ("C 8-12In one embodiment, a tricyclic cycloalkyl group has 10 to 12 ring carbon atoms ("C 10-12 Tricyclic cycloalkyls are exemplified by adamantane (C 12 ) are mentioned. Unless otherwise specified, each instance of a cycloalkyl group is independently unsubstituted ("unsubstituted cycloalkyl") or substituted with one or more substituents ("substituted cycloalkyl"). In certain embodiments, a cycloalkyl group is an unsubstituted C 3-14 In certain embodiments, the cycloalkyl group is a substituted C 3-14 It is cycloalkyl.

[0110] "Heterocyclyl" or "heterocyclic" refers to the radical of a 3- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, each independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("3- to 10-membered heterocyclyl"). In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment may be at a carbon atom or a nitrogen atom, valence permitting. Heterocyclyl groups may be either monocyclic ("monocyclic heterocyclyl"), or fused, bridged, or spiro ring systems, such as bicyclic systems ("bicyclic heterocyclyl"), and may be saturated or partially unsaturated. Heterocyclyl bicyclic ring systems may contain one or more heteroatoms in one or both rings. "Heterocyclyl" also includes ring systems in which a heterocyclyl ring, as defined above, is fused to one or more carbocyclyl groups, where the point of attachment is on either the carbocyclic ring or the heterocyclyl ring, or in which a heterocyclyl ring, as defined above, is fused to one or more aryl or heteroaryl groups, where the point of attachment is on the heterocyclyl ring; in such instances, the number of ring members continues to indicate the number of ring members in the heterocyclyl ring system. Unless otherwise specified, each heterocyclyl instance is independently optionally substituted; that is, unsubstituted ("unsubstituted heterocyclyl") or substituted with one or more substituents ("substituted heterocyclyl"). In certain embodiments, a heterocyclyl group is an unsubstituted 3- to 10-membered heterocyclyl. In certain embodiments, a heterocyclyl group is a substituted 3- to 10-membered heterocyclyl.

[0111] In one embodiment, a heterocyclyl group is a 5- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, each independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (a "5- to 10-membered heterocyclyl"). In one embodiment, a heterocyclyl group is a 5- to 8-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, each independently selected from nitrogen, oxygen, and sulfur (a "5- to 8-membered heterocyclyl"). In one embodiment, a heterocyclyl group is a 5- to 6-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, each independently selected from nitrogen, oxygen, and sulfur (a "5- to 6-membered heterocyclyl"). In one embodiment, a 5- to 6-membered heterocyclyl has 1 to 3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In one embodiment, a 5- to 6-membered heterocyclyl has 1 to 2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In one embodiment, a 5- to 6-membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0112] Exemplary 3-membered heterocyclyl groups containing one heteroatom include, but are not limited to, aziridinyl, oxiranyl, and thiorenyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azocanyl, oxecanyl, and thiocanyl. Exemplary 5-membered heterocyclyl groups (also referred to herein as 5,6-bicyclic heterocycles) fused to a C6 aryl ring include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like.Exemplary bicyclic heterocyclyl groups include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl, decahydronaphthyridinyl, decahydro-1,8-naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl, phthalimidyl, naphthalimidyl, chromanyl, chromenyl, 1H-benzo[e][1,4]diazepinyl, and the like. Examples include 1,4,5,7-tetrahydropyrano[3,4-b]pyrrolyl, 5,6-dihydro-4H-furo[3,2-b]pyrrolyl, 6,7-dihydro-5H-furo-[3,2-b]pyranyl, 5,7-dihydro-4H-thieno[2,3-c]pyranyl, 2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, 2,3-dihydrofuro[2,3-b]pyridinyl, 4,5,6,7-tetrahydro-1H-pyrrolo-[2,3-b]pyridinyl, 4,5,6,7-tetrahydrofuro[3,2-c]pyridinyl, 4,5,6,7-tetrahydrothieno[3,2-b]pyridinyl, and 1,2,3,4-tetrahydro-1,6-naphthyridinyl. Exemplary 6-membered heterocyclyl groups (also referred to herein as 6,6-bicyclic heterocycles) fused to an aryl ring include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like. A "nitrogen-containing heterocyclyl" group refers to a 4- to 7-membered non-aromatic cyclic group containing at least one nitrogen atom, including, but not limited to, morpholine, piperidine (e.g., 2-piperidinyl, 3-piperidinyl, and 4-piperidinyl), pyrrolidine (e.g., 2-pyrrolidinyl and 3-pyrrolidinyl), azetidine, pyrrolidone, imidazoline, imidazolidinone, 2-pyrazoline, pyrazolidine, piperazine, and N-alkylpiperazines such as N-methylpiperazine. Specific examples include azetidine, piperidone, and piperazone.

[0113] When used to describe a compound or a group present on a compound, "hetero" means that one or more carbon atoms in the compound or group are replaced by a nitrogen, oxygen, or sulfur heteroatom. Hetero may apply to any of the above hydrocarbon groups, such as alkyl (e.g., heteroalkyl), cycloalkyl (e.g., heterocyclyl), aryl (e.g., heteroaryl), cycloalkenyl (e.g., cycloheteroalkenyl), etc., having 1 to 5, especially 1 to 3, heteroatoms.

[0114] "Acyl" means R 20 is a radical —C(═O)R, where —C(═O)R is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, as defined herein. 20 "Alkanoyl" refers to R 20 is an acyl group where the aryl group is a group other than hydrogen. Representative acyl groups include formyl (-CHO), acetyl (-C(=O)CH3), cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl (-C(=O)Ph), benzylcarbonyl (-C(=O)CH2Ph), -C(=O)-C1-C8 alkyl, and -C(=O)-(CH2). t (C6-C 10 aryl), -C(=O)-(CH2) t (5-10 membered heteroaryl), -C(=O)-(CH2) t (C3-C 10 cycloalkyl), and -C(=O)-(CH2) t (4-10 membered heterocyclyl), where t is an integer from 0 to 4. In certain embodiments, R 21 is C1-C8 alkyl substituted with halo or hydroxy, or C3-C 10 Cycloalkyl, 4-10 membered heterocyclyl, C6-C 10Aryl, arylalkyl, 5-10 membered heteroaryl, or heteroarylalkyl, each of which is substituted with unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy.

[0115] The term aminoalkyl refers to a substituted alkyl group in which one or more hydrogen atoms are independently replaced by an —NH 2 group.

[0116] The term hydroxyalkyl refers to a substituted alkyl group in which one or more hydrogen atoms are independently replaced by an —OH group.

[0117] The terms "alkylamino" and "dialkylamino" refer to the -NH(alkyl) and -N(alkyl) radicals, respectively. In one embodiment, alkylamino is -NH(C1-C4 alkyl). In one embodiment, alkylamino is methylamino, ethylamino, propylamino, isopropylamino, n-butylamino, iso-butylamino, sec-butylamino, or tert-butylamino. In one embodiment, dialkylamino is -N(C1-C6 alkyl). In one embodiment, dialkylamino is dimethylamino, methylethylamino, diethylamino, methylpropylamino, methylisopropylamino, methylbutylamino, methylisobutylamino, or methyltertbutylamino.

[0118] The term "aryloxy" refers to an -O-aryl radical. In one embodiment, the aryloxy group is phenoxy.

[0119] The term "haloalkoxy" refers to an alkoxy structure substituted with one or more halo groups, or combinations thereof. For example, the term "fluoroalkoxy" includes haloalkoxy groups in which the halo is fluorine. In one embodiment, haloalkoxy groups are difluoromethoxy and trifluoromethoxy.

[0120] "Alkoxy" means R 29 is a substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 29 Particular alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy. Particular alkoxy groups are lower alkoxy, i.e., alkoxy having between 1 and 6 carbon atoms. Further particular alkoxy groups have between 1 and 4 carbon atoms.

[0121] In certain embodiments, R 29 is amino, substituted amino, C6-C 10 Aryl, aryloxy, carboxyl, cyano, C3-C 10 A group having one or more substituents, for example, 1 to 5 substituents, particularly 1 to 3 substituents, and especially 1 substituent, selected from the group consisting of cycloalkyl, 4- to 10-membered heterocyclyl, halogen, 5- to 10-membered heteroaryl, hydroxyl, nitro, thioalkoxy, thioaryloxy, thiol, alkyl-S(O)—, aryl-S(O)—, alkyl-S(O)2—, and aryl-S(O)2—. Exemplary "substituted alkoxy" groups include -O-(CH2) t (C6-C 10 aryl), -O-(CH2) t (5-10 membered heteroaryl), -O-(CH2) t (C3-C 10cycloalkyl), and -O-(CH2) t (4-10 membered heterocyclyl), where t is an integer from 0 to 4, and any aryl, heteroaryl, cycloalkyl, or heterocyclyl group present may itself be substituted by unsubstituted C-C alkyl, halo, unsubstituted C-C alkoxy, unsubstituted C-C haloalkyl, unsubstituted C-C hydroxyalkyl, or unsubstituted C-C haloalkoxy or hydroxy. Certain exemplary "substituted alkoxy" groups are -OCF, -OCHCF, -OCHPh, -OCH-cyclopropyl, -OCHCHOH, and -OCHCHN(CH).

[0122] "Amino" refers to the radical -NH2.

[0123] An "oxo group" refers to -C(=O)-.

[0124] "Substituted amino" means R 38 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or an amino protecting group; 38 )2, where R 38 At least one of R 38 are each independently hydrogen, -C1-C8 alkyl, -C3-C8 alkenyl, -C3-C8 alkynyl, C6-C 10 Aryl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocyclyl, or C3-C 10 cycloalkyl, or C1-C8 alkyl substituted with halo or hydroxy, C3-C8 alkenyl substituted with halo or hydroxy, C3-C8 alkynyl substituted with halo or hydroxy, or -(CH2) t (C6-C 10 aryl), -(CH2) t(5-10 membered heteroaryl), -(CH2) t (C3-C 10 cycloalkyl), or -(CH2) t (4-10 membered heterocyclyl), where t is an integer from 0 to 8, each of which is substituted with unsubstituted C1-C4 alkyl, halogen, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy, or both R 38 The groups are linked to form an alkylene group.

[0125] Exemplary "substituted amino" groups include -NR 39 -C1-C8 alkyl, -NR 39 -(CH2) t (C6-C 10 aryl), -NR 39 -(CH2) t (5-10 membered heteroaryl), -NR 39 -(CH2) t (C3-C 10 cycloalkyl), and -NR 39 -(CH2) t (4-10 membered heterocyclyl), where t is an integer of 0 to 4, e.g., 1 or 2, and R 39 each independently represent H or C1-C8 alkyl, and any alkyl group present may itself be substituted by halo, substituted or unsubstituted amino, or hydroxy, and any aryl, heteroaryl, cycloalkyl, or heterocyclyl group present may itself be substituted by unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C 1-It may be substituted by C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy. For the avoidance of doubt, the term "substituted amino" includes alkylamino, substituted alkylamino, alkylarylamino, substituted alkylarylamino, arylamino, substituted arylamino, dialkylamino, and substituted dialkylamino groups as defined below. Substituted amino includes both mono- and di-substituted amino groups.

[0126] In certain embodiments, the substituent present on the nitrogen atom is a nitrogen protecting group (also referred to herein as an "amino protecting group"). Nitrogen protecting groups include -OH, -OR aa , -N(R cc )2, -C(=O)R aa , -C(=O)N(R cc )2, -CO2R aa , -SO2R aa , -C(=NR cc )R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , -C 1-10 Alkyl (e.g., aralkyl, heteroaralkyl), -C 2-10 Alkenyl, -C 2-10 Alkynyl, Hetero C 1-10 Alkyl, Hetero C 2-10 Alkenyl, Hetero C 2-10 Alkynyl, C 3-10 Carbocyclyl, 3-14 membered heterocyclyl, C 6-14aryl, and 5- to 14-membered heteroaryl groups, wherein alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aralkyl, aryl, and heteroaryl each independently have 0, 1, 2, 3, 4, or 5 R dd group, where R aa , R bb , R cc , and R dd is as defined herein. Nitrogen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T.W. Greene and P.G.M. Butts, 3rd Edition, John Wiley & Sons, 1999, which is incorporated herein by reference. R aa Each instance of -C 1-10 Alkyl, -C 1-10 perhaloalkyl, -C 2-10 Alkenyl, -C 2-10 Alkynyl, Hetero C 1-10 Alkyl, Hetero C 2-10 Alkenyl, Hetero C 2-10 Alkynyl, C 3-10 Carbocyclyl, 3-14 membered heterocyclyl, C 6-14 aryl, and 5- to 14-membered heteroaryl, or two R aa groups joined to form a 3- to 14-membered heterocyclyl ring or a 5- to 14-membered heteroaryl ring, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl are independently selected from 0, 1, 2, 3, 4, or 5 R dd is substituted with a group, R bb are each independently hydrogen, -OH, -OR aa , -N(R cc )2, -CN, -C(=O)R aa , -C(=O)N(Rcc )2, -CO2R aa , -SO2R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , -P(=O)(R aa )2, -P(=O)(OR cc )2, -P(=O)(N(R cc )2)2, -C 1-10 Alkyl, -C 1-10 Perhaloalkyl, -C 2-10 Alkenyl, -C 2-10 Alkynyl, Hetero C 1-10 Alkyl, Hetero C 2-10 Alkenyl, Hetero C 2-10 Alkynyl, C 3-10 Carbocyclyl, 3-14 membered heterocyclyl, C 6-14 aryl, and 5- to 14-membered heteroaryl, or two R bb groups combine to form a 3- to 14-membered heterocyclyl ring or a 5- to 14-membered heteroaryl ring, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl each independently have 0, 1, 2, 3, 4, or 5 R dd substituted with a group, where X - is the counterion. R cc The entities are each independently hydrogen, -C 1-10 Alkyl, -C 1-10 Perhaloalkyl, -C 2-10 Alkenyl, -C 2-10 Alkynyl, Hetero C 1-10 Alkyl, Hetero C 2-10 Alkenyl, Hetero C 2-10Alkynyl, C 3-10 Carbocyclyl, 3-14 membered heterocyclyl, C 6-14 aryl, and 5- to 14-membered heteroaryl, or two R cc groups joined to form a 3- to 14-membered heterocyclyl ring or a 5- to 14-membered heteroaryl ring, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl are independently selected from 0, 1, 2, 3, 4, or 5 R dd is substituted with a group, R dd are each independently a halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR ee , -ON(R ff )2, -N(R ff )2, -N(R ff )3 + X - , -N(OR ee )R ff , -SH, -SR ee , -SSR ee , -C(=O)R ee , -CO2H, -CO2R ee , -OC(=O)R ee , -OCO2R ee , -C(=O)N(R ff )2, -OC(=O)N(R ff )2, -NR ff C(=O)R ee , -NR ff CO2R ee , -NR ff C(=O)N(R ff )2, -C(=NR ff ) OR ee , -OC(=NR ff )R ee , -OC(=NR ff ) OR ee , -C(=NR ff )N(R ff )2, -OC(=NR ff )N(R ff )2, -NR ff C(=NR ff )N(Rff )2, -NR ff SO2R ee , -SO2N(R ff )2, -SO2R ee , -SO2OR ee , -OSO2R ee , -S(=O)R ee , -Si(R ee )3, -OSi(R ee )3, -C(=S)N(R ff )2, -C(=O)SR ee , -C(=S)SR ee , -SC(=S)SR ee , -P(=O)(OR ee )2, -P(=O)(R ee )2, -OP(=O)(R ee )2, -OP(=O)(OR ee )2, -C 1-6 Alkyl, -C 1-6 Perhaloalkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, Hetero C 1-6 Alkyl, Hetero C 2-6 Alkenyl, Hetero C 2-6 Alkynyl, C 3-10 Carbocyclyl, 3-10 membered heterocyclyl, C 6-10 aryl, and 5- to 10-membered heteroaryl, wherein alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl are each independently selected from 0, 1, 2, 3, 4, or 5 R gg substituted with a group or two geminal R dd The substituents can combine to form =O or =S, where X - is the counterion, R ee Each instance of -C 1-6 Alkyl, -C 1-6 Perhaloalkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, Hetero C 1-6 Alkyl, Hetero C 2-6 Alkenyl, Hetero C2-6 Alkynyl, C 3-10 Carbocyclyl, C 6-10 aryl, 3- to 10-membered heterocyclyl, and 3- to 10-membered heteroaryl, wherein alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl are independently selected from 0, 1, 2, 3, 4, or 5 R gg is substituted with a group, R ff The entities are each independently hydrogen, -C 1-6 Alkyl, -C 1-6 Perhaloalkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, Hetero C 1-6 Alkyl, Hetero C 2-6 Alkenyl, Hetero C 2-6 Alkynyl, C 3-10 Carbocyclyl, 3-10 membered heterocyclyl, C 6-10 aryl, and 5- to 10-membered heteroaryl, or two R ff groups combine to form a 3- to 10-membered heterocyclyl ring or a 5- to 10-membered heteroaryl ring, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl each independently have 0, 1, 2, 3, 4, or 5 R gg is substituted with a group, R gg The entities are each independently halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC 1-6 Alkyl, -ON(C 1-6 alkyl)2, -N(C 1-6 alkyl)2, -N(C 1-6 alkyl)3 + X - , -NH(C 1-6 alkyl)2 + X - , -NH2(C 1-6 alkyl) + X - , -NH3 +X - , -N(OC 1-6 Alkyl)(C 1-6 alkyl), -N(OH)(C 1-6 alkyl), -NH(OH), -SH, -SC 1-6 Alkyl, -SS(C 1-6 alkyl), -C(=O)(C 1-6 alkyl), -CO2H, -CO2(C 1-6 alkyl), -OC(=O)(C 1-6 alkyl), -OCO2(C 1-6 alkyl), -C(=O)NH2, -C(=O)N(C 1-6 alkyl)2, -OC(=O)NH(C 1-6 alkyl), -NHC(=O)(C 1-6 alkyl), -N(C 1-6 alkyl)C(=O)(C 1-6 alkyl), -NHCO2(C 1-6 alkyl), -NHC(=O)N(C 1-6 alkyl)2, -NHC(=O)NH(C 1-6 alkyl), -NHC(=O)NH2, -C(=NH)O(C 1-6 alkyl), -OC(=NH)(C 1-6 alkyl), -OC(=NH)OC 1-6 Alkyl, -C(=NH)N(C 1-6 alkyl)2, -C(=NH)NH(C 1-6 alkyl), -C(=NH)NH2, -OC(=NH)N(C 1-6 alkyl)2, -OC(NH)NH(C 1-6 alkyl), -OC(NH)NH2, -NHC(NH)N(C 1-6 alkyl)2, -NHC(=NH)NH2, -NHSO2(C 1-6 alkyl), -SO2N(C 1-6 alkyl)2, -SO2NH(C 1-6 alkyl), -SO2NH2, -SO2C 1-6 Alkyl, -SO2OC 1-6 Alkyl, -OSO2C 1-6 Alkyl, -SOC 1-6 Alkyl, -Si(C 1-6 alkyl)3, -OSi(C 1-6alkyl)3-C(=S)N(C 1-6 alkyl)2, -C(=S)NH(C 1-6 alkyl), -C(=S)NH2, -C(=O)S(C 1-6 alkyl), -C(=S)SC 1-6 Alkyl, -SC(=S)SC 1-6 Alkyl, -P(=O)(OC 1-6 alkyl)2, -P(=O)(C 1-6 alkyl)2, -OP(=O)(C 1-6 alkyl)2, -OP(=O)(OC 1-6 alkyl)2, -C 1-6 Alkyl, -C 1-6 Perhaloalkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, Hetero C 1-6 Alkyl, Hetero C 2-6 Alkenyl, Hetero C 2-6 Alkynyl, C 3-10 Carbocyclyl, C 6-10 aryl, 3- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, or two geminal R gg The substituents can combine to form =O or =S, where X - is the counterion.

[0127] For example, an amide group (e.g., —C(═O)R aaNitrogen protecting groups such as acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropanamide, picolinamide, 3-pyridylcarboxamide, N-benzoylphenylalanyl derivatives, benzamide, p-phenylbenzamide, o-nitrophenylacetamide, o-nitrophenoxyacetamide, acetoacetamide, (N'-dithiobenzyloxyacylamino)acetamide, 3-(p-hydroxyphenyl)propanamide, 3-(o-nitrophenyl)propanamide, 2-methyl-2-(o-nitrophenoxy)propanamide, 2-methyl-2-(o-phenylazophenoxy)propanamide, 4-chlorobutanamide, 3-methyl-3-nitrobutanamide, o-nitrocinnamide, N-acetylmethionine derivatives, o-nitrobenzamide, and o-(benzoyloxymethyl)benzamide.

[0128] Carbamate groups (e.g., -C(=O)OR aa), nitrogen protecting groups such as methyl carbamate, ethyl carbamate, 9-fluorenylmethyl carbamate (Fmoc), 9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluorenylmethyl carbamate, 2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methyl carbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2-trimethyl Silylethyl carbamate (Teoc), 2-phenylethyl carbamate (hZ), 1-(1-adamantyl)-1-methylethyl carbamate (Adpoc), 1,1-dimethyl-2-haloethyl carbamate, 1,1-dimethyl-2,2-dibromoethyl carbamate (DB-t-BOC), 1,1-dimethyl-2,2,2-trichloroethyl carbamate (TCBOC), 1-methyl-1-(4-biphenylyl)ethyl carbamate (Bpoc), 1-(3,5-di-t-butylphenyl)-1-methylethyl carbamate (t-Bum eoc), 2-(2'- and 4'-pyridyl)ethyl carbamate (Pyoc), 2-(N,N-dicyclohexylcarboxamido)ethyl carbamate, t-butyl carbamate (BOC or Boc), 1-adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl carbamate (Alloc), 1-isopropylallyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), 8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, a alkyldithiocarbamate, benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz), p-nitrobenzyl carbamate, p-bromobenzyl carbamate, p-chlorobenzyl carbamate, 2,4-dichlorobenzyl carbamate, 4-methylsulfinylbenzyl carbamate (Msz), 9-anthrylmethyl carbamate, diphenylmethyl carbamate, 2-methylthioethyl carbamate, 2-methylsulfonylethyl carbamate, 2-(p-toluenesulfonyl)ethyl carbamate, [2-(1,3-dithianyl)]methyl carbamate (Dmoc), 4-methylthiophenylcarbamate (Mtpc), 2,4-dimethylthiophenylcarbamate (Bmpc), 2-phosphonioethylcarbamate (Peoc), 2-triphenylphosphonioisopropylcarbamate (Ppoc), 1,1-dimethyl-2-cyanoethylcarbamate, m-chloro-p-acyloxybenzylcarbamate, p-(dihydroxyboryl)benzylcarbamate, 5-benzisoxazolylmethylcarbamate, 2-(trifluoromethyl)-6-chromo Nylmethyl carbamate (Tcroc), m-nitrophenyl carbamate, 3,5-dimethoxybenzyl carbamate, o-nitrobenzyl carbamate, 3,4-dimethoxy-6-nitrobenzyl carbamate, phenyl(o-nitrophenyl)methyl carbamate, t-amyl carbamate, S-benzylthiocarbamate, p-cyanobenzyl carbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentyl carbamate, cyclopropylmethyl carbamate, p-decyloxybenzyl carbamate, 2,2 -Dimethoxyacylvinylcarbamate, o-(N,N-dimethylcarboxamido)benzylcarbamate, 1,1-dimethyl-3-(N,N-dimethylcarboxamido)propylcarbamate, 1,1-dimethylpropynylcarbamate, di(2-pyridyl)methylcarbamate, 2-furanylmethylcarbamate, 2-iodoethylcarbamate, isobornylcarbamate, isobutylcarbamate, isonicotinylcarbamate, p-(p'-methoxyphenylazo)benzylcarbamate, 1-methylcyclobutylcarbamate, 1- Methylcyclohexyl carbamate, 1-methyl-1-cyclopropylmethyl carbamate, 1-methyl-1-(3,5-dimethoxyphenyl)ethyl carbamate, 1-methyl-1-(p-phenylazophenyl)ethyl carbamate, 1-methyl-1-phenylethyl carbamate, 1-methyl-1-(4-pyridyl)ethyl carbamate, phenyl carbamate, p-(phenylazo)benzyl carbamate, 2,4,6-tri-t-butylphenyl carbamate, 4-(trimethylammonium)benzyl carbamate, and 2,4,Examples include, but are not limited to, 6-trimethylbenzylcarbamate. Sulfonamide groups (e.g., -S(=O)R aa Nitrogen protecting groups such as p-toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6-trimethyl-4-methoxybenzenesulfonamide (Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb), 2,6-dimethyl-4-methoxybenzenesulfonamide (Pme), 2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte), 4-methoxybenzenesulfonamide (Mbs), 2,4,6-trimethylbenzenesulfonamide (Mts), These include, but are not limited to, 2,6-dimethoxy-4-methylbenzenesulfonamide (iMds), 2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide (Ms), β-trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide, 4-(4',8'-dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS), benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide.

[0129] Other nitrogen protecting groups include phenothiazinyl-(10)-acyl derivatives, N'-p-toluenesulfonylaminoacyl derivatives, N'-phenylaminothioacyl derivatives, N-benzoylphenylalanyl derivatives, N-acetylmethionine derivatives, 4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dithiasuccinimide (Dts), N-2,3-diphenylmaleimide, N-2,5-dimethylpyrrole, and N-1,1,4,4-tetramethyldisilylazacylate. Clopentane adduct (STABASE), 5-substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-one, 5-substituted 1,3-dibenzyl-1,3,5-triazacyclohexan-2-one, 1-substituted 3,5-dinitro-4-pyridone, N-methylamine, N-arylamine, N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine, N-(1-isopropyl-4-nitro-2-oxo-3-pyrrolin-3-yl)amine amine, quaternary ammonium salts, N-benzylamine, N-di(4-methoxyphenyl)methylamine, N-5-dibenzosuberylamine, N-triphenylmethylamine (Tr), N-[(4-methoxyphenyl)diphenylmethyl]amine (MMTr), N-9-phenylfluorenylamine (PhF), N-2,7-dichloro-9-fluorenylmethyleneamine, N-ferrocenylmethylamino (Fcm), N-2-picolylamino N'-oxide, N-1,1-dimethylthio Methyleneamine, N-benzylideneamine, Np-methoxybenzylideneamine, N-diphenylmethyleneamine, N-[(2-pyridyl)mesityl]methyleneamine, N-(N',N'-dimethylaminomethylene)amine, N,N'-isopropylidenediamine, Np-nitrobenzylideneamine, N-salicylideneamine, N-5-chlorosalicylideneamine, N-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine, N-cyclohexylideneamine, N-(5,Examples of suitable amines include, but are not limited to, 5-dimethyl-3-oxo-1-cyclohexenyl)amine, N-borane derivatives, N-diphenylboronic acid derivatives, N-[phenyl(pentaacylchromium or tungsten)acyl]amine, N-copper chelates, N-zinc chelates, N-nitroamines, N-nitrosamines, amine N-oxides, diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt), diphenylthiophosphinamide (Ppt), dialkylphosphoramidates, dibenzylphosphoramidates, diphenylphosphoramidates, benzenesulfenamide, o-nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide, triphenylmethylsulfenamide, and 3-nitropyridine sulfenamide (Npys).

[0130] In certain embodiments, the substituent present on the oxygen atom is an oxygen protecting group (also referred to herein as a "hydroxyl protecting group"). Oxygen protecting groups include -R aa , -N(R bb )2, -C(=O)SR aa , -C(=O)R aa , -CO2R aa , -C(=O)N(R bb )2, -C(=NR bb )R aa , -C(=NR bb ) OR aa , -C(=NR bb )N(R bb )2, -S(=O)R aa , -SO2R aa , -Si(R aa )3, -P(R cc )2, -P(R cc )3 + X - , -P(OR cc )2, -P(OR cc )3 + X - , -P(=O)(R aa )2, -P(=O)(OR cc)2, and -P(=O)(N(R bb )2)2, where R aa , R bb , and R cc is as defined herein. Oxygen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T.W. Greene and P.G.M. Butts, 3rd Edition, John Wiley & Sons, 1999, which is incorporated herein by reference.

[0131] Exemplary oxygen protecting groups include methyl, methoxymethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), t-butoxymethyl, 4-pentenyloxymethyl (POM), siloxymethyl, and 2-methoxyethoxymethyl (MEM). , 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl (SEMOR), tetrahydropyranyl (THP), 3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl (MTHP), 4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranyl S,S-dioxide, 1-[(2-chloro-4-methyl)phenyl]-4- Methoxypiperidin-4-yl (CTMP), 1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl, 2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl, 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl, 1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl, 2,2,2-trichloroethyl , 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl, t-butyl, aryl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, benzyl (Bn), p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2-picolyl, 4-picolyl, 3-methyl-2-picolyl N-oxide, diphenylmethyl, p,p'-Dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl, α-naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl, tri(p-methoxyphenyl)methyl, 4-(4'-bromophenacyloxyphenyl)diphenylmethyl, 4,4',4"-tris(4,5-dichlorophthalimidophenyl)methyl, 4,4',4"-tris(levulinoyloxyphenyl)methyl, 4,4',4"-tris(benzoyloxyphenyl)methyl methyl, 3-(imidazol-1-yl)bis(4',4"-dimethoxyphenyl)methyl, 1,1-bis(4-methoxyphenyl)-1'-pyrenylmethyl, 9-anthryl, 9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl, 1,3-benzodithiolan-2-yl, benzisothiazolyl S,S-dioxide, trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl propylsilyl (DEIPS), dimethylthexylsilyl, t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl (DPMS), t-butylmethoxyphenylsilyl (TBMPS), formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate , phenoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4-oxopentanoate (levulinate), 4,4-(ethylenedithio)pentanoate (levulinoyl dithioacetal), pivaloate, adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate, 2,4,6-trimethylbenzoate (mesitoate), methyl carbonate, 9-fluorenylmethyl carbonate (Fmoc), ethyl carbonate, 2,2,2-Trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate (TMSEC), 2-(phenylsulfonyl)ethyl carbonate (Psec), 2-(triphenylphosphonio)ethyl carbonate (Peoc), isobutyl carbonate, vinyl carbonate, aryl carbonate, t-butyl carbonate (BOC or Boc), p-nitrophenyl carbonate, benzyl carbonate, p-methoxybenzyl carbonate, 3,4-dimethoxybenzyl carbonate, o-nitrobenzyl carbonate, p-nitrobenzyl carbonate, S-benzylthiocarbonate, 4-ethoxy-1-naphthyl carbonate, methyl dithiocarbonate, 2-iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoate, 2-formylbenzenesulfone ester, 2-(methylthiomethoxy)ethyl, 4-(methylthiomethoxy)butyrate, 2-(methylthiomethoxymethyl)benzoate, 2,6-dichloro-4-methylphenoxyacetate, 2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetate, 2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinate, (E)-2-methyl-2-butenoate, o-(methoxyacyl)benzoate, α-naphthoate, nitrate, alkyl N,N,N',N'-tetramethylphosphorodiamidate, alkyl N-phenylcarbamate, borate, dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenate, sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate (Ts). ,

[0132] In certain embodiments, the substituent present on the sulfur atom is a sulfur protecting group (also referred to herein as a "thiol protecting group"). Sulfur protecting groups include, but are not limited to, -R aa , -N(R bb )2, -C(=O)SR aa , -C(=O)R aa , -CO2R aa , -C(=O)N(Rbb )2, -C(=NR bb )R aa , -C(=NR bb ) OR aa , -C(=NR bb )N(R bb )2, -S(=O)R aa , -SO2R aa , -Si(R aa )3, -P(R cc )2, -P(R cc )3 + X - , -P(OR cc )2, -P(OR cc )3 + X - , -P(=O)(R aa ) 2、 -P(=O)(OR cc )2, and -P(=O)(N(R bb )2)2 is mentioned, and in this case, R aa , R bb、 and R cc is as defined herein. Sulfur protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T.W. Greene and P.G.M. Butts, 3rd Edition, John Wiley & Sons, 1999, which is incorporated herein by reference.

[0133] The term "leaving group" has its usual meaning in the field of synthetic organic chemistry and refers to an atom or group that can be dissociated by a nucleophile. Examples of suitable leaving groups include, but are not limited to, halogens (such as F, -Cl, -Br, or I (iodine)), alkoxycarbonyloxy, aryloxycarbonyloxy, alkanesulfonyloxy, arenesulfonyloxy, alkyl-carbonyloxy (e.g., acetoxy), arylcarbonyloxy, aryloxy, methoxy, N,O-dimethylhydroxylamino, pixyl, and haloformates. In certain embodiments, the leaving group is halogen, alkanesulfonyloxy, arenesulfonyloxy, diazonium, alkyldiazene, aryldiazene, alkyltriazene, aryltriazene, nitro, alkylnitrate, arylnitrate, alkylphosphate, arylphosphate, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxyammonia, alkylamine, arylamine, hydroxyl group, alkyloxy group, or aryloxy. In some cases, the leaving group is a sulfonate ester such as toluenesulfonate (tosylate, -OTs), methanesulfonate (mesylate, -OMs), p-bromobenzenesulfonyloxy (brosylate, -OB), -OS(=O)2(CF2)3CF3 (nonaflate, -ONf), or trifluoromethanesulfonate (triflate, -OTf). In some cases, the leaving group is a brosylate such as p-bromobenzenesulfonyloxy. In some cases, the leaving group is a nosylate such as 2-nitrobenzenesulfonyloxy. In one embodiment, the leaving group is a sulfonate-containing group. In one embodiment, the leaving group is a tosylate group. The leaving group may also be a phosphine oxide (e.g., as formed during a Mitsunobu reaction), or an internal leaving group such as an epoxide or a cyclic sulfate. Other non-limiting examples of leaving groups include water, ammonia, alcohols, ether moieties, thioether moieties, zinc halides, magnesium moieties, diazonium salts, and copper moieties.

[0134] "Carboxy" refers to the radical -C(=O)OH.

[0135] "Cyano" refers to the radical -CN.

[0136] "Halo" or "halogen" refers to fluoro (F), chloro (Cl), bromo (Br), and iodo (I). In certain embodiments, a halo group is either fluoro or chloro.

[0137] "Haloalkyl" refers to an alkyl radical in which the alkyl group is substituted with one or more halogens. Typical haloalkyl groups include, but are not limited to, trifluoromethyl (-CF), difluoromethyl (-CHF), fluoromethyl (-CHF), chloromethyl (-CHCl), dichloromethyl (-CHCl), tribromomethyl (-CHBr), and the like.

[0138] "Hydroxy" refers to the radical --OH.

[0139] "Nitro" refers to the radical -NO2.

[0140] "Thioketo" refers to the group =S.

[0141] Alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups defined herein are optionally substituted (e.g., "substituted" or "unsubstituted" alkyl, "substituted" or "unsubstituted" alkenyl, "substituted" or "unsubstituted" alkynyl, "substituted" or "unsubstituted" carbocyclyl, "substituted" or "unsubstituted" heterocyclyl, "substituted" or "unsubstituted" aryl, or "substituted" or "unsubstituted" heteroaryl group). In general, whether preceded by the term "optionally," the term "substituted" means that at least one hydrogen present on the group (e.g., a carbon or nitrogen atom) is replaced with an acceptable substituent, e.g., a substituent whose substitution results in a stable compound, e.g., a compound that does not spontaneously undergo transformation by rearrangement, cyclization, elimination, or other reaction. Unless otherwise specified, a "substituted" group has a substituent at one or more substitutable positions of the group, and when more than one position is substituted in any given structure, the substituents are either the same or different at each position. The term "substituted" is intended to include substitution with all permissible substituents of organic compounds and any of the substituents described herein that result in the formation of a stable compound. Any and all such combinations are contemplated in order to arrive at a stable compound. For purposes of this disclosure, heteroatoms such as nitrogen may have hydrogen substituents and / or any suitable substituents described herein that satisfy the valence of the heteroatom and result in the formation of a stable moiety.

[0142] Exemplary carbon atom substituents include -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR aa , -ON(R bb )2, -N(R bb )2, -N(R bb )3 + X - , -N(OR cc )R bb , -SH, -SR aa , -SSR cc , -C(=O)R aa、-CO2H、-CHO、-C(OR cc )2、-CO2R aa 、-OC(=O)R aa 、-OCO2R aa 、-C(=O)N(R bb )2、-OC(=O)N(R bb )2、-NR bb C(=O)R aa 、-NR bb CO2R aa 、-NR bb C(=O)N(R bb )2、-C(=NR bb )R aa 、-C(=NR bb )OR aa 、-OC(=NR bb )R aa 、-OC(=NR bb )OR aa 、-C(=NR bb )N(R bb )2、-OC(=NR bb )N(R bb )2、-NR bb C(=NR bb )N(R bb )2、-C(=O)NR bb SO2R aa 、-NR bb SO2R aa 、-SO2N(R bb )2、-SO2R aa 、-SO2OR aa 、-OSO2R aa 、-S(=O)R aa 、-S(=O)(=NR bb )R aa 、-OS(=O)R aa 、-Si(R aa )3、-OSi(R aa )3-C(=S)N(R bb )2、-C(=O)SR aa 、-C(=S)SR aa 、-SC(=S)SR aa 、-SC(=O)SR aa 、-OC(=O)SR aa 、-SC(=O)OR aa 、-SC(=O)R aa, -P(=O)2R aa , -OP(=O)2R aa , -P(=O)(R aa )2, -OP(=O)(R aa )2, -OP(=O)(OR cc )2, -P(=O)2N(R bb )2, -OP(=O)2N(R bb )2, -P(=O)(NR bb )2, -OP(=O)(NR bb )2, -NR bb P(=O)(OR cc )2, -NR bb P(=O)(NR bb )2, -P(R cc )2, -P(R cc )3, -OP(R cc )2, -OP(R cc )3, -B(R aa )2, -B(OR cc )2, -BR aa (OR cc ), -C 1-10 Alkyl, -C 1-10 Haloalkyl, -C 2-10 Alkenyl, -C 2-10 Alkynyl, C 3-10 Carbocyclyl, 3-14 membered heterocyclyl, C 6-14 aryl, and 5- to 14-membered heteroaryl, wherein alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl each independently have 0, 1, 2, 3, 4, or 5 R dd groups, or the two geminal hydrogens on the carbon atom are ═O, ═S, ═NN(R bb )2, =NNR bb C(=O)R aa , =NNR bb C(=O)OR aa , =NNR bb S(=O)2R aa , =NR bb , or =NOR cc is replaced by a group R aa The entities of are independently C 1-10Alkyl, -C 1-10 Haloalkyl, -C 2-10 Alkenyl, -C 2-10 Alkynyl, C 3-10 Carbocyclyl, 3-14 membered heterocyclyl, C 6-14 aryl, and 5- to 14-membered heteroaryl, or two R aa groups are joined to form a 3- to 14-membered heterocyclyl ring or a 5- to 14-membered heteroaryl ring, wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl are independently selected from 0, 1, 2, 3, 4, or 5 R dd is substituted with a group, R bb are each independently hydrogen, -OH, -OR aa , -N(R cc )2, -CN, -C(=O)R aa , -C(=O)N(R cc )2, -CO2R aa , -SO2R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , -P(=O)2R aa , -P(=O)(R aa )2, -P(=O)2N(R cc )2, -P(=O)(NR cc )2, -C 1-10 Alkyl, -C 1-10 Haloalkyl, -C 2-10 Alkenyl, -C 2-10 Alkynyl, C 3-10 Carbocyclyl, 3-14 membered heterocyclyl, C 6-14 aryl, and 5- to 14-membered heteroaryl, or two R bbare joined to form a 3- to 14-membered heterocyclyl ring or a 5- to 14-membered heteroaryl ring, wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl are independently selected from 0, 1, 2, 3, 4, or 5 R dd is substituted with a group, R cc The entities are independently hydrogen, C 1-10 Alkyl, -C 1-10 Haloalkyl, -C 2-10 Alkenyl, -C 2-10 Alkynyl, C 3-10 Carbocyclyl, 3-14 membered heterocyclyl, C 6-14 aryl, and 5- to 14-membered heteroaryl, or two R cc groups are joined to form a 3- to 14-membered heterocyclyl ring or a 5- to 14-membered heteroaryl ring, wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl are independently selected from 0, 1, 2, 3, 4, or 5 R dd is substituted with a group, R dd are each independently a halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR ee , -ON(R ff )2, -N(R ff )2, -N(R ff )3 + X - , -N(OR ee )R ff , -SH, -SR ee , -SSR ee , -C(=O)R ee , -CO2H, -CO2R ee , -OC(=O)R ee , -OCO2R ee , -C(=O)N(R ff )2, -OC(=O)N(R ff )2, -NR ff C(=O)R ee , -NR ff CO2R ee , -NR ff C(=O)N(R ff)2, -C(=NR ff ) OR ee , -OC(=NR ff )R ee , -OC(=NR ff ) OR ee , -C(=NR ff )N(R ff )2, -OC(=NR ff )N(R ff )2, -NR ff C(=NR ff )N(R ff )2, -NR ff SO2R ee , -SO2N(R ff )2, -SO2R ee , -SO2OR ee , -OSO2R ee , -S(=O)R ee , -Si(R ee )3, -OSi(R ee )3, -C(=S)N(R ff )2, -C(=O)SR ee , -C(=S)SR ee , -SC(=S)SR ee , -P(=O)2R ee , -P(=O)(R ee )2, -OP(=O)(R ee )2, -OP(=O)(OR ee )2, -C 1-6 Alkyl, -C 1-6 Haloalkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, C 3-10 Carbocyclyl, 3-10 membered heterocyclyl, C 6-10 aryl, and 5- to 10-membered heteroaryl, wherein alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl are each independently selected from 0, 1, 2, 3, 4, or 5 R gg substituted with a group or two geminal R dd the substituents can be linked to form =O or =S; R ee The entities of are independently C 1-6 Alkyl, -C1-6 Haloalkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, C 3-10 Carbocyclyl, C 6-10 aryl, 3- to 10-membered heterocyclyl, and 3- to 10-membered heteroaryl, wherein alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl are independently selected from 0, 1, 2, 3, 4, or 5 R gg is substituted with a group, R ff The entities are each independently hydrogen, -C 1-6 Alkyl, -C 1-6 Haloalkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, C 3-10 Carbocyclyl, 3-10 membered heterocyclyl, C 6-10 aryl, and 5- to 10-membered heteroaryl, or two R ff groups are joined to form a 3- to 14-membered heterocyclyl ring or a 5- to 14-membered heteroaryl ring, wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl are independently selected from 0, 1, 2, 3, 4, or 5 R gg is substituted with a group, R gg The entities are each independently halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC 1-6 Alkyl, -ON(C 1-6 alkyl)2, -N(C 1-6 alkyl)2, -N(C 1-6 alkyl)3 + X - , -NH(C 1-6 alkyl)2 + X - , -NH2(C 1-6 alkyl) + X - , -NH3 + X - , -N(OC 1-6 Alkyl)(C 1-6 alkyl), -N(OH)(C 1-6alkyl), -NH(OH), -SH, -SC 1-6 Alkyl, -SS(C 1-6 alkyl), -C(=O)(C 1-6 alkyl), -CO2H, -CO2(C 1-6 alkyl), -OC(=O)(C 1-6 alkyl), -OCO2(C 1-6 alkyl), -C(=O)NH2, -C(=O)N(C 1-6 alkyl)2, -OC(=O)NH(C 1-6 alkyl), -NHC(=O)(C 1-6 alkyl), -N(C 1-6 alkyl)C(=O)(C 1-6 alkyl), -NHCO2(C 1-6 alkyl), -NHC(=O)N(C 1-6 alkyl)2, -NHC(=O)NH(C 1-6 alkyl), -NHC(=O)NH2, -C(=NH)O(C 1-6 alkyl), -OC(=NH)(C 1-6 alkyl), -OC(=NH)OC 1-6 Alkyl, -C(=NH)N(C 1-6 alkyl)2, -C(=NH)NH(C 1-6 alkyl), -C(=NH)NH2, -OC(=NH)N(C 1-6 alkyl)2, -OC(NH)NH(C 1-6 alkyl), -OC(NH)NH2, -NHC(NH)N(C 1-6 alkyl)2, -NHC(=NH)NH2, -NHSO2(C 1-6 alkyl), -SO2N(C 1-6 alkyl)2, -SO2NH(C 1-6 alkyl), -SO2NH2, -SO2C 1-6 Alkyl, -SO2OC 1-6 Alkyl, -OSO2C 1-6 Alkyl, -SOC 1-6 Alkyl, -Si(C 1-6 alkyl)3, -OSi(C 1-6 alkyl)3-C(=S)N(C 1-6 alkyl)2, -C(=S)NH(C 1-6alkyl), -C(=S)NH2, -C(=O)S(C 1-6 alkyl), -C(=S)SC 1-6 Alkyl, -SC(=S)SC 1-6 Alkyl, -P(=O)2(C 1-6 alkyl), -P(=O)(C 1-6 alkyl)2, -OP(=O)(C 1-6 alkyl)2, -OP(=O)(OC 1-6 alkyl)2, -C 1-6 Alkyl, -C 1-6 Haloalkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, C 3-10 Carbocyclyl, C 6-10 aryl, 3- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, or two geminal R gg The substituents can be linked to form =O or =S, where X - is the counterion.

[0143] A "counterion" or "anionic counterion" is a negatively charged group associated with a cationic quaternary amino group to maintain electrical neutrality. Exemplary counterions include halide ions (e.g., F - , Cl - , Br - , I - ), NO3 - , ClO4 - , O.H. - , H2PO4 - , HSO4 - , SO4 -2 Examples of suitable cations include sulfonate ions (e.g., methanesulfonate, trifluoromethanesulfonate, p-toluenesulfonate, benzenesulfonate, 10-camphorsulfonate, naphthalene-2-sulfonate, naphthalene-1-sulfonic acid-5-sulfonate, ethane-1-sulfonic acid-2-sulfonate, etc.), and carboxylate ions (e.g., acetate, ethanoate, propanoate, benzoate, glycerate, lactate, tartrate, glycolate, etc.).

[0144] Nitrogen atoms may be substituted or unsubstituted, where valence allows, and include primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents include hydrogen, -OH, -OR aa , -N(R cc )2, -CN, -C(=O)R aa , -C(=O)N(R cc )2, -CO2R aa , -SO2R aa , -C(=NR bb )R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , -P(=O)2R aa , -P(=O)(R aa )2, -P(=O)2N(R cc )2, -P(=O)(NR cc )2, -C 1-10 Alkyl, -C 1-10 Haloalkyl, -C 2-10 Alkenyl, -C 2-10 Alkynyl, C 3-10 Carbocyclyl, 3-14 membered heterocyclyl, C 6-14 aryl, and 5- to 14-membered heteroaryl, or two R cc The groups are joined to form a 3- to 14-membered heterocyclyl or heteroaryl ring, where the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl are each independently selected from 0, 1, 2, 3, 4, or 5 R dd group, where R aa , R bb , R cc , and R dd is as defined herein.

[0145] These and other exemplary substituents are described in further detail in the detailed description, examples, and claims. The present invention is not intended to be limited in any way by the recitation of exemplary substituents above.

[0146] Other definitions As used herein, a "pharmaceutical composition" or "pharmaceutical formulation" refers to a combination of a therapeutically active agent with a pharmaceutically acceptable excipient, making the composition particularly suitable for in vivo or in vitro diagnostic or therapeutic use.

[0147] "Pharmaceutically acceptable" refers to a compound, molecular entity, composition, material, and / or dosage form that does not produce an adverse, allergic, or other untoward reaction when administered to animals or humans, as the case may be. Alternatively, it means approved or approvable by a federal or state regulatory agency in the United States, or a corresponding agency in a country other than the United States, or listed in the United States Pharmacopeia or other generally recognized pharmacopoeia for use in animals, especially humans.

[0148] As used herein, "pharmaceutically acceptable salt" refers to a salt of an acidic or basic group that may be present in a compound of the present disclosure (e.g., a compound of Formula A, Formula I, or Formula I-1), which salt is compatible with pharmaceutical administration.

[0149] As known to those skilled in the art, the "salt" of a compound can be derived from inorganic or organic acids and inorganic or organic bases.Examples of acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, perchloric acid, fumaric acid, maleic acid, phosphoric acid, glycolic acid, lactic acid, salicylic acid, succinic acid, toluene-p-sulfonic acid, tartaric acid, acetic acid, citric acid, methanesulfonic acid, ethanesulfonic acid, formic acid, benzoic acid, malonic acid, naphthalene-2-sulfonic acid, and benzenesulfonic acid.Other acids, such as oxalic acid, may not be pharmaceutically acceptable per se, but can be used to prepare salts useful as intermediates in obtaining the compounds described herein and their pharmaceutically acceptable acid addition salts.

[0150] Examples of bases include alkali metal (e.g., sodium and potassium) hydroxides, alkaline earth metal (e.g., magnesium and calcium) hydroxides, ammonia, and bases of the formula NW4 + wherein W is C1-4 alkyl.

[0151] Examples of salts include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, flucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, and the like. Examples of salts include, but are not limited to, nitrite, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, palmoate, pectinate, persulfate, phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, undecanoate, etc. Other exemplary salts include anions of the compounds of the present disclosure combined with appropriate cations, such as Na, K, Ca, NH, and NW (where W can be a C alkyl group).

[0152] For therapeutic use, salts of the compounds of the present disclosure are contemplated as pharmaceutically acceptable. However, salts of acids and bases that are non-pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound.

[0153] As used herein, "pharmaceutically acceptable excipient" refers to a substance that can be included in the compositions of the present disclosure, which aids in the administration and / or absorption of an active agent by a subject, without causing significant toxicological effects in patients. Non-limiting examples of pharmaceutically acceptable excipients include binders, diluents, carriers, adjuvants, fillers (e.g., brittle diluents or fillers, and ductile diluents or fillers), disintegrants, lubricants, coating agents, sweeteners, flavorings, carbohydrates such as gelatin, lactose, amylose, or starch, fatty acid esters, hydroxypropylmethylcellulose, polyvinylpyrrolidine, and coloring agents. For examples of excipients, see Gennaro, Remington's Pharmaceutical Sciences, 18th ed., Mack Publ. Co., Easton, PA (1990) or Shesky, Hancock, Moss and Goldfarb, Handbook of Pharmaceutical Excipients, 9th ed., Pharmaceutical Press, London, UK (2020).

[0154] Examples of diluents or fillers include, but are not limited to, sugars (e.g., mannitol, lactose, sorbitol, lactitol, erythritol, sucrose, fructose, glucose, agarose, maltose, isomalt, polydextrose, and combinations thereof), inorganic materials (e.g., calcium hydrogen phosphate, hydroxyapatite, sodium carbonate, sodium bicarbonate, calcium carbonate, calcium sulfate, magnesium carbonate, magnesium oxide, bentonite, kaolin), calcium lactate, starch (e.g., pregelatinized starch), microcrystalline cellulose, silicified microcrystalline cellulose, polysaccharides, cellulose (e.g., hydroxypropyl cellulose, hypromellose, carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose), dextrin, maltodextrin, alginate, collagen, polyvinylpyrrolidone, polyvinyl acrylate, polyethylene oxide, and polyethylene glycol. As used herein, sugar is defined to include sugar alcohols.

[0155] Examples of disintegrants include, but are not limited to, alginic acid, alginates, primogel, celluloses (e.g., hydroxypropyl cellulose), polacrilin potassium, sodium starch glycolate, croscarmellose sodium, polyplasdones (e.g., crospovidone), and starches (e.g., corn starch, pregelatinized starch, hydroxypropyl starch, and carboxymethyl starch).

[0156] Examples of binders include, but are not limited to, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose (e.g., low viscosity hydroxypropyl methylcellulose), sugar, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl acetate, polydextrose, chitosan, carrageenan, carbophil, microcrystalline cellulose, tragacanth gum, guar gum, gellan gum, gelatin, and starch (e.g., corn starch).

[0157] Examples of wetting agents include, but are not limited to, poloxamers (e.g., poloxamer 407), sodium dodecyl sulfate, sodium lauryl sulfate (SLS), sodium stearyl fumarate (SSF), polydimethylsiloxane, polysorbates (e.g., polyoxyethylene 20 sorbitan monooleate (Tween® 20)), sorbitan monooleate, sorbitan trioleate, sorbitan laurate, sorbitan stearate, sorbitan monopalmitate, lecithin, sodium taurocholate, ursodeoxycholate, polyethoxylated castor oil, cetyltrimethylammonium bromide, nonoxynol, α-tocopherol polyethylene glycol 1000 succinate, and docusate sodium.

[0158] Examples of lubricants and glidants include, but are not limited to, waxes, glycerides, light mineral oil, polyethylene glycol, sodium stearyl fumarate, magnesium stearate, stearic acid, hydrogenated oils (e.g., hydrogenated vegetable oils), alkyl sulfates, sodium benzoate, sodium acetate, glyceryl behenate, palmitic acid, and coconut oil. Examples of glidants include, but are not limited to, colloidal silicon dioxide, talc, kaolin, bentonite, and activated carbon / charcoal.

[0159] Examples of colorants include, but are not limited to, titanium dioxide, aluminum lake, iron oxide, and carbon black.

[0160] Examples of coating agents include, but are not limited to, film-forming polymers (e.g., hypromellose, methylcellulose, ethylcellulose, cellulose acetate, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose acetate succinate, cellulose acetate phthalate, polyvinylpyrrolidone, polyvinyl alcohol, Eudragit / acrylate) and plasticizers (e.g., triacetin, polyethylene glycol, propylene glycol).

[0161] Pharmaceutical compositions for oral administration (e.g., pharmaceutical compositions of compounds of Formula A, Formula I, or Formula I-1 described herein) can take the form of bulk liquid solutions or suspensions, or bulk powders. More commonly, however, these compositions are provided in unit dosage forms to facilitate accurate administration. The term "unit dosage form" refers to physically discrete units suitable as single doses for human subjects and other mammals, each unit containing a predetermined amount of active material calculated to produce the desired therapeutic effect in association with suitable pharmaceutical excipients. Typical unit dosage forms include pills, tablets, capsules, etc., for solid compositions.

[0162] "Subjects" to which administration is contemplated include, but are not limited to, humans (i.e., males or females of any age, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or elderly adults)) and / or non-human animals, e.g., mammals such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cows, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In certain embodiments, the subject is a human. In certain embodiments, the subject is a non-human animal.

[0163] As used herein, "solid dosage form" means a pharmaceutical dose in solid form, such as, for example, tablets, capsules, granules, powders, minitablets, sachets, stick packs, reconstitutable powders, dry powder inhalers, lozenges, and chewable tablets.

[0164] As used herein, "administering" refers to oral, pulmonary, suppository, intramuscular, intrathecal, intranasal, or subcutaneous administration, or the implantation of a sustained-release device, such as a mini-osmotic pump, into a subject. Administration is by any route, including transmucosal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal). Parenteral administration includes, for example, intramuscular and subcutaneous. Other delivery modes include, but are not limited to, the use of liposomal formulations and the like. "Co-administering" means that the compositions described herein are administered simultaneously with, immediately before, or immediately after the administration of one or more additional treatments (e.g., anti-cancer agents, chemotherapeutic agents, or neurodegenerative disease treatments). Compounds of Formula A, Formula I, or Formula I-1 can be administered alone or co-administered to a patient. Co-administration is meant to include administering compounds individually or in combination (more than one compound or agent), simultaneously, or sequentially. Thus, if desired, the preparations can also be combined with other active substances (eg, to reduce metabolic degradation). The terms "disease," "disorder," and "condition" are used interchangeably herein.

[0165] As used herein, unless otherwise specified, the terms "treat," "treatment," and "treatment" contemplate actions that occur while a subject is suffering from a particular disease, disorder, or condition and that reduce the severity of the disease, disorder, or condition or delay or slow the progression of the disease, disorder, or condition ("therapeutic treatment"), as well as actions that occur before a subject begins to suffer from a particular disease, disorder, or condition ("prophylactic treatment"). In one embodiment, the compounds provided herein are contemplated for use in methods of therapeutic treatment that act while a subject is suffering from a particular disease, disorder, or condition and result in a reduction in the severity of the disease, disorder, or condition or a delay or slow down of the progression of the disease, disorder, or condition. In another embodiment, the compounds provided herein are contemplated for use in methods of prophylactic treatment that act before a subject begins to suffer from a particular disease, disorder, or condition, thereby preventing the disease, disorder, or condition, or one or more symptoms associated with the disease, disorder, or condition, or preventing the recurrence of the disease, disorder, or condition.

[0166] In general, an "effective amount" of a compound refers to an amount sufficient to elicit a desired biological response, such as treating a disease or disorder described herein. As will be understood by those skilled in the art, the effective amount of a compound of the present disclosure may vary depending on factors such as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, health, disease, etc. of the subject. An effective amount encompasses therapeutic and prophylactic treatments (i.e., a "therapeutically effective amount" and a "prophylactically effective amount").

[0167] As used herein, and unless otherwise specified, a "therapeutically effective amount" of a compound is an amount sufficient to provide a therapeutic benefit in the therapeutic treatment of a disease, disorder, or condition, or to delay or minimize one or more symptoms associated with that disease, disorder, or condition. A therapeutically effective amount of a compound means an amount of a therapeutic agent that, alone or in combination with other treatments, provides a therapeutic benefit in the therapeutic treatment of a disease, disorder, or condition. The term "therapeutically effective amount" can encompass an amount that improves overall treatment, an amount that reduces or avoids the symptoms or causes of a disease or condition, or an amount that improves the therapeutic efficacy of another therapeutic agent.

[0168] As used herein, and unless otherwise specified, a "prophylactically effective amount" of a compound is an amount sufficient to prevent or prevent the recurrence of a disease, disorder, or condition, or one or more symptoms associated with the disease, disorder, or condition. A prophylactically effective amount of a compound means an amount of a therapeutic agent that, alone or in combination with other agents, provides a prophylactic benefit in the prevention of a disease, disorder, or condition. The term "prophylactically effective amount" can encompass an amount that improves overall prevention or an amount that improves the prophylactic efficacy of another prophylactic agent.

[0169] As used herein, the term "selective" refers to a compound that is at least about three times (e.g., 3, 5, 10, 20, 30, 50, 100, 500, 1000) more potent against one target compared to another. For example, a CDK2 degrader selective for CCNE (CCNE1 and / or CCNE2) has at least three times (e.g., 3, 5, 10, 20, 30, 50, 100, 500, 1000) more potent against CDK2 than against CCNE (CCNE1 and / or CCNE2). For example, a CCNE (CCNE1 and / or CCNE2) degrading agent selective for CDK2 has at least 3-fold (e.g., 3-fold, 5-fold, 10-fold, 20-fold, 30-fold, 50-fold, 100-fold, 500-fold, 1000-fold) greater potency against CCNE (CCNE1 and / or CCNE2) than against CDK2. The difference in potency can be, for example, due to differences in the potency of DCs against different targets. 50 This can be determined by comparing the values.

[0170] compound Provided herein are compounds of Formula A, Formula I, or Formula I-1. Unless the context requires otherwise, throughout this specification, references to "a compound described herein," "a compound of Formula A, Formula I, and / or Formula I-1," or "compounds of Formula A, Formula I, and / or Formula I-1" include, for example, compounds of Formula A, Formula I, Formula I, and / or Formula I-1. " refers to all embodiments of Formula A, Formula I, and Formula I-1, including compounds of I-1-B, III-1-C, III-1-D, III-1-E, IV, IV-A, IV-B, IV-C, IV-1, IV-1-A, IV-1-B, V, VA, VB, VC, VD, VE, VF, VG, V-1, V-1-A, V-1-B, V-1-C, V-1-D, V-1-E, as well as compounds in Table 1. In one embodiment, compounds of Formula A, Formula I, and Formula I-1, or pharmaceutically acceptable salts thereof, are provided. In one embodiment, compounds of Formula A, Formula I, and Formula I-1 are provided as pharmaceutically acceptable salts. In one embodiment, compounds of Formula A, Formula I, and Formula I-1 are provided as the corresponding free base (i.e., not a salt).

[0171] The present specification includes all stereoisomers of a compound, including diastereomers and enantiomers, where chemically relevant. Also included are mixtures of possible stereoisomers, in all ratios, including, but not limited to, racemic mixtures. Unless the stereochemistry of a structure is explicitly shown, the structure is intended to encompass all possible stereoisomers of the represented compound. When stereochemistry is explicitly shown for one portion or portions of a molecule but not for another portion or portions of the molecule, the structure is intended to encompass all possible stereoisomers of the portion or portions for which stereochemistry is not explicitly shown.

[0172] In one embodiment, formula A

[0173] [ka] or a pharmaceutically acceptable salt thereof, wherein: Ring A is phenyl, 3- to 14-membered cycloalkyl, or 4- to 14-membered heterocyclyl containing 1-3 heteroatoms independently selected from N, O, and S; R 1 -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -C 1-6 Haloalkyl, -C 1-6 Heteroalkyl, -C 3-14 Cycloalkyl, 6- to 14-membered aryl, 4- to 14-membered heterocyclyl, 5- to 14-membered heteroaryl, -C 1-4 Alkyl-C 3-14 Cycloalkyl, -C 1-4 Alkyl-(6-14 membered aryl), -C 1-4 Alkyl-(4-14 membered heterocyclyl), and -C 1-4alkyl (5-14 membered heteroaryl), heterocyclyl and heteroaryl each containing 1-3 heteroatoms independently selected from N, O, and S, and alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl each selected from R 6 is replaced by 0, 1, 2, 3, or 4 instances of R 2 and R 3 are each independently -C 1-6 Alkyl, -C 1-6 Haloalkyl, -C 1-6 Heteroalkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -C 3-7 cycloalkyl, phenyl, 4- to 7-membered heterocyclyl, and 5- to 6-membered heteroaryl, wherein the heterocyclyl and heteroaryl each contain 1-3 heteroatoms independently selected from N, O, and S; and the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl each are selected from R B is replaced by 0, 1, 2, 3, or 4 instances of Or R 2 and R 3 together with the carbon atoms to which they are attached form ring B, ring B being a 3- to 7-membered cycloalkyl ring or a 4- to 7-membered heterocyclyl ring containing 1 or 3 heteroatoms independently selected from N, O, and S, ring B being R B is replaced by 0, 1, 2, 3, or 4 instances of L is a covalent bond or a divalent, saturated, or unsaturated, straight or branched chain C 1-50 a hydrocarbon chain, wherein 0 to 6 methylene units of L are independently replaced by -Cy-, -CH(R)-, -C(R)2-, -O-, -NR-, -S-, -OC(=O)-, -C(=O)O-, -C(=O)-, -S(=O)-, -S(=O)2-, -NRS(=O)2-, -S(=O)2NR-, -NRC(=O)-, -C(=O)NR-, -OC(=O)NR-, or -NRC(=O)O-; -Cy- each independently represents phenylene, 8- to 10-membered bicyclic arylene, 4- to 7-membered monocyclic carbocyclylene, 5- to 11-membered spirocarbocyclylene, 4- to 10-membered bicyclic carbocyclylene, 5- to 10-membered bridged carbocyclylene, 4- to 7-membered monocyclic heterocyclylene having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 11-membered spiroheterocyclylene having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 4- to 11-membered aryl heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 0-membered bicyclic heterocyclylene, a 5-10-membered bridged bicyclic saturated or partially unsaturated heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6-membered heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10-membered bicyclic heteroarylene having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and phenylene, arylene, carbocyclylene, heterocyclylene, and heteroarylene are each a bivalent ring selected from R C is replaced by 0, 1, 2, 3, or 4 instances of LMB is

[0174] [ka] is selected from R A , R B , R C , R 4 , R 5 , and R 6 The entities are each independently oxo, deuterium, halogen, -C 1-6 Alkyl, -C 1-6 Heteroalkyl, -C 1-6 Haloalkyl, -C 2-6 Alkenyl, -C 2-6Alkynyl, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -S(O)(NR)R, -S(O)(NCN)R, -S(NCN)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O )N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2, -N(R)S(O)2R, -P(O)R2, -P(O)(R)OR, -C 3-7 selected from cycloalkyl, phenyl, 4- to 7-membered heterocyclyl, and 5- to 6-membered heteroaryl, wherein the heterocyclyl and heteroaryl each contain 1-3 heteroatoms independently selected from N, O, and S; Each instance of R is independently hydrogen, -C 1-6 Alkyl, -C 1-6 Haloalkyl, -C 1-6 Heteroalkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -C 3-7 cycloalkyl, phenyl, 4- to 7-membered heterocyclyl, and 5- to 6-membered heteroaryl, wherein the heterocyclyl and heteroaryl each contain 1-3 heteroatoms independently selected from N, O, and S, or two R groups attached to the same nitrogen optionally combine with the nitrogen to which they are attached to form an optionally substituted 4- to 7-membered heterocyclyl having 0, 1, or 2 additional heteroatoms independently selected from N, O, and S; n is 0, 1, 2, 3, or 4; r is 0, 1, 2, 3, or 4; s is 0, 1, 2, 3, or 4.

[0175] In one embodiment, formula A

[0176] [ka] or a pharmaceutically acceptable salt thereof, wherein: Ring A is a 3- to 14-membered cycloalkyl or a 4- to 14-membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S; R 1 -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -C 1-6 Haloalkyl, -C 1-6 Heteroalkyl, -C 3-14 Cycloalkyl, 6- to 14-membered aryl, 4- to 14-membered heterocyclyl, 5- to 14-membered heteroaryl, -C 1-4 Alkyl-C 3-14 Cycloalkyl, -C 1-4 Alkyl-(6-14 membered aryl), -C 1-4 Alkyl-(4-14 membered heterocyclyl), and -C 1-4 alkyl (5-14 membered heteroaryl), heterocyclyl and heteroaryl each containing 1-3 heteroatoms independently selected from N, O, and S, and alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl each selected from R 6 is replaced by 0, 1, 2, 3, or 4 instances of R 2 and R 3 are each independently -C 1-6 Alkyl, -C 1-6 Haloalkyl, -C 1-6 Heteroalkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -C 3-7 cycloalkyl, phenyl, 4- to 7-membered heterocyclyl, and 5- to 6-membered heteroaryl, wherein the heterocyclyl and heteroaryl each contain 1-3 heteroatoms independently selected from N, O, and S; and the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl each are selected from R B is replaced by 0, 1, 2, 3, or 4 instances of Or R 2 and R3 together with the carbon atoms to which they are attached form ring B, ring B being a 3- to 7-membered cycloalkyl ring or a 4- to 7-membered heterocyclyl ring containing 1 or 3 heteroatoms independently selected from N, O, and S, ring B being R B is replaced by 0, 1, 2, 3, or 4 instances of L is a covalent bond or a divalent, saturated, or unsaturated, straight or branched chain C 1-50 a hydrocarbon chain, wherein 0 to 6 methylene units of L are independently replaced by -Cy-, -CH(R)-, -C(R)2-, -O-, -NR-, -S-, -OC(=O)-, -C(=O)O-, -C(=O)-, -S(=O)-, -S(=O)2-, -NRS(=O)2-, -S(=O)2NR-, -NRC(=O)-, -C(=O)NR-, -OC(=O)NR-, or -NRC(=O)O-; -Cy- each independently represents phenylene, 8- to 10-membered bicyclic arylene, 4- to 7-membered monocyclic carbocyclylene, 5- to 11-membered spirocarbocyclylene, 4- to 10-membered bicyclic carbocyclylene, 5- to 10-membered bridged carbocyclylene, 4- to 7-membered monocyclic heterocyclylene having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 11-membered spiroheterocyclylene having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 4- to 11-membered aryl heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 0-membered bicyclic heterocyclylene, a 5-10-membered bridged bicyclic saturated or partially unsaturated heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6-membered heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10-membered bicyclic heteroarylene having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and phenylene, arylene, carbocyclylene, heterocyclylene, and heteroarylene are each a bivalent ring selected from R C is replaced by 0, 1, 2, 3, or 4 instances of LMB is

[0177] [ka] is selected from R A , R B , R C , R 4 , R 5 , and R 6 The entities are each independently oxo, deuterium, halogen, -C 1-6 Alkyl, -C 1-6 Heteroalkyl, -C 1-6 Haloalkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -S(O)(NR)R, -S(O)(NCN)R, -S(NCN)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O )N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2, -N(R)S(O)2R, -P(O)R2, -P(O)(R)OR, -C 3-7 selected from cycloalkyl, phenyl, 4- to 7-membered heterocyclyl, and 5- to 6-membered heteroaryl, wherein the heterocyclyl and heteroaryl each contain 1-3 heteroatoms independently selected from N, O, and S; Each instance of R is independently hydrogen, -C 1-6 Alkyl, -C 1-6 Haloalkyl, -C 1-6 Heteroalkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -C 3-7cycloalkyl, phenyl, 4- to 7-membered heterocyclyl, and 5- to 6-membered heteroaryl, wherein the heterocyclyl and heteroaryl each contain 1-3 heteroatoms independently selected from N, O, and S, or two R groups attached to the same nitrogen optionally combine with the nitrogen to which they are attached to form an optionally substituted 4- to 7-membered heterocyclyl having 0, 1, or 2 additional heteroatoms independently selected from N, O, and S; n is 0, 1, 2, 3, or 4; r is 0, 1, 2, 3, or 4; s is 0, 1, 2, 3, or 4.

[0178] In one embodiment, the present invention provides a compound of formula I-1

[0179] [ka] or a pharmaceutically acceptable salt thereof, wherein: R 1 -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -C 1-6 Haloalkyl, -C 1-6 Heteroalkyl, -C 3-14 Cycloalkyl, 6- to 14-membered aryl, 4- to 14-membered heterocyclyl, 5- to 14-membered heteroaryl, -C 1-4 Alkyl-C 3-14 Cycloalkyl, -C 1-4 Alkyl-(6-14 membered aryl), -C 1-4 Alkyl-(4-14 membered heterocyclyl), and -C 1-4 alkyl (5-14 membered heteroaryl), heterocyclyl and heteroaryl each containing 1-3 heteroatoms independently selected from N, O, and S, and alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl each selected from R 6 is replaced by 0, 1, 2, 3, or 4 instances of L is a covalent bond or a divalent, saturated, or unsaturated, straight or branched chain C 1-50 a hydrocarbon chain, wherein 0 to 6 methylene units of L are independently replaced by -Cy-, -CH(R)-, -C(R)2-, -O-, -NR-, -S-, -OC(=O)-, -C(=O)O-, -C(=O)-, -S(=O)-, -S(=O)2-, -NRS(=O)2-, -S(=O)2NR-, -NRC(=O)-, -C(=O)NR-, -OC(=O)NR-, or -NRC(=O)O-; -Cy- each independently represents phenylene, 8- to 10-membered bicyclic arylene, 4- to 7-membered monocyclic carbocyclylene, 5- to 11-membered spirocarbocyclylene, 4- to 10-membered bicyclic carbocyclylene, 5- to 10-membered bridged carbocyclylene, 4- to 7-membered monocyclic heterocyclylene having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 11-membered spiroheterocyclylene having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 4- to 11-membered aryl heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 0-membered bicyclic heterocyclylene, a 5-10-membered bridged bicyclic saturated or partially unsaturated heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6-membered heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10-membered bicyclic heteroarylene having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and phenylene, arylene, carbocyclylene, heterocyclylene, and heteroarylene are each a bivalent ring selected from R C is replaced by 0, 1, 2, 3, or 4 instances of LMB is

[0180] [ka] is selected from R A , R B , R C , R 4 , R 5, and R 6 The entities are each independently oxo, deuterium, halogen, -C 1-6 Alkyl, -C 1-6 Heteroalkyl, -C 1-6 Haloalkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -S(O)(NR)R, -S(O)(NCN)R, -S(NCN)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O )N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2, -N(R)S(O)2R, -P(O)R2, -P(O)(R)OR, -C 3-7 selected from cycloalkyl, phenyl, 4- to 7-membered heterocyclyl, and 5- to 6-membered heteroaryl, wherein the heterocyclyl and heteroaryl each contain 1-3 heteroatoms independently selected from N, O, and S; Each instance of R is independently hydrogen, -C 1-6 Alkyl, -C 1-6 Haloalkyl, -C 1-6 Heteroalkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -C 3-7 cycloalkyl, phenyl, 4- to 7-membered heterocyclyl, and 5- to 6-membered heteroaryl, wherein the heterocyclyl and heteroaryl each contain 1-3 heteroatoms independently selected from N, O, and S, or two R groups attached to the same nitrogen optionally combine with the nitrogen to which they are attached to form an optionally substituted 4- to 7-membered heterocyclyl having 0, 1, or 2 additional heteroatoms independently selected from N, O, and S; m is 0, 1, 2, 3, or 4; n is 0, 1, 2, 3, or 4; r is 0, 1, 2, 3, or 4; s is 0, 1, 2, 3, or 4.

[0181] In one embodiment, a compound of Formula I or Formula I-1:

[0182] [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 , R A , L, LBM, m, and n are as defined in any of the embodiments described herein.

[0183] In one embodiment, the compound is a compound of Formula I.

[0184] In one embodiment, the compound is a compound of formula I-1.

[0185] As generally defined herein, Ring B is a 3- to 7-membered cycloalkyl ring or a 4- to 7-membered heterocyclyl ring containing 1 or 3 heteroatoms independently selected from N, O, and S, and Ring B is R B is replaced by 0, 1, 2, 3, or 4 instances of R B is as defined in any of the embodiments described herein. In one embodiment, Ring B is unsubstituted.

[0186] In one embodiment, ring B is R B is a 3- to 7-membered cycloalkyl ring substituted with 0, 1, 2, 3, or 4 instances of R B is as defined in any of the embodiments described herein. In one embodiment, Ring B is an unsubstituted 3- to 7-membered cycloalkyl ring. In one embodiment, Ring B is R B is a 3- to 7-membered monocyclic cycloalkyl ring substituted with 0, 1, 2, 3, or 4 instances of B is as defined in any of the embodiments described herein. In one embodiment, Ring B is an unsubstituted 3-7 membered monocyclic cycloalkyl ring.

[0187] In some embodiments, Ring B is chosen from cyclopropyl and cyclobutyl.

[0188] In one embodiment, ring B is R B is selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl substituted with 0, 1, 2, 3, or 4 instances of R B is as defined in any of the embodiments described herein. In one embodiment, ring B is R B and R is selected from cyclopropyl and cyclobutyl substituted with 0, 1, 2, 3, or 4 instances of B is as defined in any of the embodiments described herein. In one embodiment, Ring B is selected from unsubstituted cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In one embodiment, Ring B is selected from unsubstituted cyclopropyl and cyclobutyl. In one embodiment, Ring B is selected from R B is a cyclopropyl substituted with 0, 1, 2, 3, or 4 instances of R B is as defined in any of the embodiments described herein. In one embodiment, ring B is R B is a cyclopropyl substituted with 0, 1, or 2 instances of R B is as defined in any of the embodiments described herein. In one embodiment, Ring B is unsubstituted cyclopropyl.

[0189] In one embodiment, ring B is R B is a cyclobutyl substituted with 0, 1, 2, 3, or 4 instances of R B is as defined in any of the embodiments described herein. In one embodiment, Ring B is unsubstituted cyclobutyl. In one embodiment, Ring B is R B cyclopentyl substituted with 0, 1, 2, 3, or 4 instances of R Bis as defined in any of the embodiments described herein. In one embodiment, Ring B is unsubstituted cyclopentyl. In one embodiment, Ring B is R B is cyclohexyl substituted with 0, 1, 2, 3, or 4 instances of R B is as defined in any of the embodiments described herein. In one embodiment, Ring B is unsubstituted cyclohexyl.

[0190] In one embodiment, Ring B is a 4-7 membered heterocyclyl containing 1 or 3 heteroatoms independently selected from N, O, and S (e.g., azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, morpholinyl, piperazinyl, tetrahydropyranyl), and Ring B is R B In one embodiment, Ring B is an unsubstituted 4-7 membered heterocyclyl containing 1 or 3 heteroatoms independently selected from N, O, and S (e.g., azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, morpholinyl, piperazinyl, tetrahydropyranyl).

[0191] As generally defined herein, Ring A is phenyl, 3-14 membered cycloalkyl, or 4-14 membered heterocyclyl containing 1-3 heteroatoms independently selected from N, O, and S.

[0192] In one embodiment, ring A is a 3-14 membered cycloalkyl or a 4-14 membered heterocyclyl containing 1-3 heteroatoms independently selected from N, O, and S.

[0193] In one embodiment, ring A is a monocyclic 3-7 membered cycloalkyl (e.g., cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane). In one embodiment, ring A is selected from cyclopropane, cyclobutane, cyclopentane, cyclohexane, and cycloheptane.

[0194] In one embodiment, ring A is a monocyclic 4-7 membered heterocyclyl containing 1-2 heteroatoms independently selected from N, O, and S (including S(O) and S(O)2). In one embodiment, ring A is a monocyclic 4-7 membered heterocyclyl containing 1-2 heteroatoms independently selected from N and O. In one embodiment, ring A is a monocyclic 4-7 membered heterocyclyl containing 1-2 nitrogen atoms. In one embodiment, ring A is a monocyclic 4-7 membered heterocyclyl containing 1 nitrogen atom. In one embodiment, ring A is a monocyclic 4-7 membered heterocyclyl containing 2 nitrogen atoms.

[0195] In one embodiment, ring A is selected from azetidine, pyrrolidine, piperidine, azepane, oxetane, tetrahydrofuran, tetrahydropyran, piperazine, morpholine, and diazepane.

[0196] In one embodiment, ring A is selected from azetidine, pyrrolidine, piperidine, and azepane.

[0197] In one embodiment, Ring A is azetidine. In one embodiment, Ring A is pyrrolidine. In one embodiment, Ring A is piperidine. In one embodiment, Ring A is azepane. In one embodiment, Ring A is piperidin-4-yl. In one embodiment, Ring A is

[0198] [ka] where the nitrogen atom is bonded to the S(=O)2 group and the carbon at position 4 is bonded to NH of the compound of formula I.

[0199] In one embodiment, ring A is phenyl. In one embodiment, ring A is

[0200] [ka] is.

[0201] As generally defined herein, R 1 -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -C 1-6 Haloalkyl, -C 1-6 Heteroalkyl, -C 3-14 Cycloalkyl, 6- to 14-membered aryl, 4- to 14-membered heterocyclyl, 5- to 14-membered heteroaryl, -C 1-4 Alkyl-C 3-14 Cycloalkyl, -C 1-4 Alkyl-(6-14 membered aryl), -C 1-4 Alkyl-(4-14 membered heterocyclyl), and -C 1-4 alkyl (5-14 membered heteroaryl), heterocyclyl and heteroaryl each containing 1-3 heteroatoms independently selected from N, O, and S, and alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl each selected from R 6 is replaced by 0, 1, 2, 3, or 4 instances of each R 6 is as defined herein.

[0202] In one embodiment, R 1 -C 1-6 Haloalkyl, -C 3-7 cycloalkyl, phenyl, 4-7 membered heterocyclyl (e.g., heterocyclyl containing 1 or 2 atoms independently selected from N, O, and S, including S(O) and S(O)), and 5-6 membered heteroaryl (e.g., heteroaryl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S), each selected from R 6 is replaced by 0, 1, 2, 3, or 4 instances of R 6 Each of the entities is as defined in any of the embodiments described herein.

[0203] In one embodiment, R 1 is C 1-6Haloalkyl, C 3-7 cycloalkyl, and phenyl, each R 6 is replaced by 0, 1, 2, 3, or 4 instances of R 6 Each of the entities is as defined in any of the embodiments described herein.

[0204] In one embodiment, R 1 -C 3-7 Cycloalkyl, phenyl, and -C 1-4 Alkyl-C 3-14 cycloalkyl, each R 6 is replaced by 0, 1, 2, 3, or 4 instances of R 6 Each of the entities is as defined in any of the embodiments described herein.

[0205] In one embodiment, R 1 is cyclopentyl, cyclohexyl, phenyl, or -CH(CH3)-cyclopropyl, and R 6 is replaced by 0, 1, 2, 3, or 4 instances of R 6 Each of the entities is as defined in any of the embodiments described herein.

[0206] In one embodiment, R 1 is cyclopentyl, cyclohexyl, phenyl, or -CH(CH3)-cyclopropyl, and R 6 is replaced by 0, 1, or 2 instances of R 6 Each of the entities is as defined in any of the embodiments described herein.

[0207] In one embodiment, R 1 is cyclopentyl or cyclohexyl, and R 6 is replaced by 0, 1, 2, 3, or 4 instances of R 6 Each of the entities is as defined in any of the embodiments described herein.

[0208] In one embodiment, R 1 is R 6 C replaced with 0, 1, 2, 3, or 4 instances of 3-7 is cycloalkyl, and R 6 Each of the entities is as defined in any of the embodiments described herein.

[0209] In one embodiment, R 1 is R 6 Monocyclic C substituted with 0, 1, 2, 3, or 4 instances of 3-7 is cycloalkyl, and R 6 Each of the entities is as defined in any of the embodiments described herein.

[0210] In one embodiment, R 1 is R 6 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl substituted with 0, 1, 2, 3, or 4 instances of R 6 Each of the entities is as defined in any of the embodiments described herein.

[0211] In one embodiment, R 1 is R 6 cyclopentyl substituted with 0, 1, 2, 3, or 4 instances of R 6 Each of the entities is as defined in any of the embodiments described herein.

[0212] In one embodiment, R 1 is R 6 is cyclohexyl substituted with 0, 1, 2, 3, or 4 instances of R 6 Each entity is as defined in any of the embodiments described herein. 1is selected from 1,1-difluorobutan-2-yl, cyclopentyl, 2-methylcyclopentyl, 3-hydroxycyclohexyl, 2-hydroxy-2-methylcyclopentyl, 2-methylphenyl, 2-chloro-5-fluorophenyl, 1,5-dimethyl-1H-pyrazol-4-yl, 7-chloro-1,2,3,4-tetrahydroisoquinolin-6-yl, and 1-cyclopropylethyl.

[0213] In one embodiment, R 1 is selected from cyclopentyl, 2-methylcyclopentyl, 3-hydroxycyclohexyl, 2-methylphenyl, and 1,1-difluorobutan-2-yl.

[0214] In one embodiment, R 1 is selected from cyclopentyl, 2-methylcyclopentyl, 2-methylphenyl, and 1,1-difluorobutan-2-yl. 1 is selected from 2-methylcyclopentyl and 3-hydroxycyclohexyl.

[0215] In one embodiment, R 1 teeth,

[0216] [ka] is selected from.

[0217] In one embodiment, R 1 teeth,

[0218] [ka] is selected from.

[0219] In one embodiment, R 1 teeth,

[0220] [ka] is selected from.

[0221] In one embodiment, R 1 teeth,

[0222] [ka] is selected from.

[0223] In one embodiment, R 1 teeth,

[0224] [ka] is selected from.

[0225] In one embodiment, R 1 is 2-methylcyclopentyl. In one embodiment, R 1 teeth,

[0226] [ka] In one embodiment, R 1 teeth,

[0227] [ka] In one embodiment, R 1 teeth,

[0228] [ka] In one embodiment, R 1 teeth,

[0229] [ka] In one embodiment, R 1 teeth,

[0230] [ka] In one embodiment, R 1 teeth,

[0231] [ka] In one embodiment, R 1 is 3-hydroxycyclohexyl. In one embodiment, R 1 teeth,

[0232] [ka] In one embodiment, R 1 teeth,

[0233] [ka] In one embodiment, R 1 teeth,

[0234] [ka] In one embodiment, R 1 teeth,

[0235] [ka] In one embodiment, R 1 teeth,

[0236] [ka] In one embodiment, R 1 teeth,

[0237] [ka] In one embodiment, R 1 teeth,

[0238] [ka] is.

[0239] In one embodiment, R 1 -C 1-6 Haloalkyl (e.g., —CH2CF3, CH2CHF2, CH2CH2F).

[0240] In one embodiment, R 1 is R 6 phenyl substituted with 0, 1, 2, 3, or 4 instances of R 6 Each of the entities is as defined in any of the embodiments described herein.

[0241] In one embodiment, R 1 are 4-7 membered heterocyclyls containing 1 or 2 atoms independently selected from N, O, and S, including S(O) and S(O)2 (e.g., oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperidinyl, piperazinyl, azepanyl), and R 6 is replaced by 0, 1, 2, 3, or 4 instances of R 6 Each of the entities is as defined in any of the embodiments described herein.

[0242] In one embodiment, R 1 are 5-6 membered monocyclic heteroaryls containing 1, 2, or 3 atoms independently selected from N, O, and S (e.g., furanyl, pyrrolyl, thiophenyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, pyrazolyl, imidazolyl, triazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, diazinyl, triazinyl), and each R 6 is replaced by 0, 1, 2, 3, or 4 instances of R 6 Each of the entities is as defined in any of the embodiments described herein.

[0243] As generally defined herein, R 2 and R 3 are each independently -C 1-6 Alkyl, -C 1-6 Haloalkyl, -C 1-6 Heteroalkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -C 3-7 cycloalkyl, phenyl, 4- to 7-membered heterocyclyl, and 5- to 6-membered heteroaryl, wherein the heterocyclyl and heteroaryl each contain 1-3 heteroatoms independently selected from N, O, and S; and the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl each are selected from R B is replaced by 0, 1, 2, 3, or 4 instances of each R B is as defined herein.

[0244] In one embodiment, R 2 and R 3 are each independently -C 1-6 In one embodiment, R 2 and R 3 are each independently -Me, -Et-, -Pr, - i Pr, and t In one embodiment, R 2 and R 3 are -Me, respectively.

[0245] In one embodiment, R 2 and R 3 together with the carbon atoms to which they are attached form ring B.

[0246] As generally defined herein, L is a covalent bond or a divalent, saturated, or unsaturated, straight or branched chain C 1-50is a hydrocarbon chain, wherein 0 to 6 methylene units of L are independently replaced with -Cy-, -CH(R)-, -C(R)2-, -O-, -NR-, -S-, -OC(=O)-, -C(=O)O-, -C(=O)-, -S(=O)-, -S(=O)2-, -NRS(=O)2-, -S(=O)2NR-, -NRC(=O)-, -C(=O)NR-, -OC(=O)NR-, or -NRC(=O)O-, each of which is as defined in any of the embodiments described herein.

[0247] In one embodiment, L is

[0248] [ka] are selected from R 7 is replaced by 0, 1, 2, or 3 instances of R 7 are each independently as defined in any of the embodiments described herein; wherein the left attachment point is connected to the -S(O)2- group and the right attachment point is connected to the LBM; L 1 and L 2 are each independently selected from a bond and —N(R′), and R′ is selected from H and C 1-6 alkyl, q is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0249] In one embodiment, L is

[0250] [ka]

[0251] [ka] is selected from wherein the left attachment point is connected to the -S(O)2- group and the right attachment point is connected to the LBM; L 1and L 2 are each independently selected from a bond and —N(R′), and R′ is selected from H and C 1-6 alkyl, q is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0252] In one embodiment, L is

[0253] [ka] wherein the left attachment point is connected to the -S(O)2- group, the right attachment point is connected to the LBM, and L 1 , L 2 , -Cy-, and q are as defined in any of the embodiments described herein.

[0254] In one embodiment, L is

[0255] [ka] wherein the left attachment point is connected to the -S(O)2- group, the right attachment point is connected to the LBM, and L 1 , L 2 , -Cy-, and q are as defined in any of the embodiments described herein.

[0256] In one embodiment, L is

[0257] [ka] wherein the left attachment point is connected to the -S(O)2- group and the right attachment point is connected to the LBM.

[0258] In one embodiment, L is

[0259] [ka] are selected from R7 is replaced by 0, 1, 2, or 3 instances of R 7 is as defined in any of the embodiments described herein, where the left attachment point is connected to the -S(O)2- group and the right attachment point is connected to the LBM.

[0260] In one embodiment, L is R 7 replaced with 0, 1, 2, or 3 instances of

[0261] [ka] and R 7 is as defined in any of the embodiments described herein, wherein the left attachment point is connected to the -S(O)- group and the right attachment point is connected to the LBM. 7 replaced with 0, 1, 2, or 3 instances of

[0262] [ka] and R 7 is as defined in any of the embodiments described herein, wherein the left attachment point is connected to the -S(O)- group and the right attachment point is connected to the LBM. 7 replaced with 0, 1, 2, or 3 instances of

[0263] [ka] and R 7 is as defined in any of the embodiments described herein, wherein the left attachment point is connected to the -S(O)- group and the right attachment point is connected to the LBM. 7 replaced with 0, 1, 2, or 3 instances of

[0264] [ka] and R7 is as defined in any of the embodiments described herein, wherein the left attachment point is connected to the -S(O)- group and the right attachment point is connected to the LBM. 7 replaced with 0, 1, 2, or 3 instances of

[0265] [ka] and R 7 is as defined in any of the embodiments described herein, wherein the left attachment point is connected to the -S(O)- group and the right attachment point is connected to the LBM. 7 replaced with 0, 1, 2, or 3 instances of

[0266] [ka] and R 7 is as defined in any of the embodiments described herein, wherein the left attachment point is connected to the -S(O)- group and the right attachment point is connected to the LBM.

[0267] [ka] wherein the left attachment point is connected to the -S(O)- group and the right attachment point is connected to the LBM.

[0268] [ka] wherein the left attachment point is connected to the -S(O)- group and the right attachment point is connected to the LBM.

[0269] [ka] wherein the left attachment point is connected to the -S(O)- group and the right attachment point is connected to the LBM.

[0270] [ka] wherein the left attachment point is connected to the -S(O)- group and the right attachment point is connected to the LBM.

[0271] [ka] wherein the left attachment point is connected to the -S(O)- group and the right attachment point is connected to the LBM.

[0272] [ka] wherein the left attachment point is connected to the -S(O)- group and the right attachment point is connected to the LBM.

[0273] [ka] wherein the left attachment point is connected to the -S(O)- group and the right attachment point is connected to the LBM.

[0274] [ka] wherein the left attachment point is connected to the -S(O)- group and the right attachment point is connected to the LBM.

[0275] [ka] wherein the left attachment point is connected to the -S(O)- group and the right attachment point is connected to the LBM.

[0276] [ka] wherein the left attachment point is connected to the -S(O)- group and the right attachment point is connected to the LBM.

[0277] [ka] wherein the left attachment point is connected to the -S(O)- group and the right attachment point is connected to the LBM.

[0278] [ka] wherein the left attachment point is connected to the -S(O)- group and the right attachment point is connected to the LBM.

[0279] [ka] wherein the left attachment point is connected to the -S(O)- group and the right attachment point is connected to the LBM.

[0280] [ka] wherein the left attachment point is connected to the -S(O)- group and the right attachment point is connected to the LBM.

[0281] [ka] wherein the left attachment point is connected to the -S(O)- group and the right attachment point is connected to the LBM.

[0282] [ka] where the left attachment point is connected to the -S(O)2- group and the right attachment point is connected to the LBM.

[0283] [ka] wherein the left attachment point is connected to the -S(O)2- group and the right attachment point is connected to LBM, or a pharmaceutically acceptable salt thereof.

[0284] [ka] wherein the left attachment point is connected to the -S(O)- group and the right attachment point is connected to the LBM.

[0285] [ka] wherein the left attachment point is connected to the -S(O)- group and the right attachment point is connected to the LBM.

[0286] [ka] wherein the left attachment point is connected to the -S(O)- group and the right attachment point is connected to the LBM.

[0287] [ka] wherein the left attachment point is connected to the -S(O)- group and the right attachment point is connected to the LBM.

[0288] [ka] wherein the left attachment point is connected to the -S(O)- group and the right attachment point is connected to the LBM.

[0289] [ka] wherein the left attachment point is connected to the -S(O)- group and the right attachment point is connected to the LBM.

[0290] [ka] wherein the left attachment point is connected to the -S(O)- group and the right attachment point is connected to the LBM.

[0291] [ka] wherein the left attachment point is connected to the -S(O)- group and the right attachment point is connected to the LBM.

[0292] [ka] wherein the left attachment point is connected to the -S(O)- group and the right attachment point is connected to the LBM.

[0293] [ka] wherein the left attachment point is connected to the -S(O)- group and the right attachment point is connected to the LBM.

[0294] [ka] wherein the left attachment point is connected to the -S(O)- group and the right attachment point is connected to the LBM.

[0295] [ka] wherein the left attachment point is connected to the -S(O)- group and the right attachment point is connected to the LBM.

[0296] [ka] wherein the left attachment point is connected to the -S(O)- group and the right attachment point is connected to the LBM.

[0297] [ka] wherein the left attachment point is connected to the -S(O)- group and the right attachment point is connected to the LBM.

[0298] [ka] wherein the left attachment point is connected to the -S(O)- group and the right attachment point is connected to the LBM.

[0299] [ka] wherein the left attachment point is connected to the -S(O)- group and the right attachment point is connected to the LBM.

[0300] [ka] wherein the left attachment point is connected to the -S(O)- group and the right attachment point is connected to the LBM.

[0301] [ka] wherein the left attachment point is connected to the -S(O)- group and the right attachment point is connected to the LBM.

[0302] [ka] wherein the left attachment point is connected to the -S(O)- group and the right attachment point is connected to the LBM.

[0303] [ka] wherein the left attachment point is connected to the -S(O)- group and the right attachment point is connected to the LBM.

[0304] [ka] wherein the left attachment point is connected to the -S(O)- group and the right attachment point is connected to the LBM.

[0305] [ka] wherein the left attachment point is connected to the -S(O)- group and the right attachment point is connected to the LBM.

[0306] [ka] wherein the left attachment point is connected to the -S(O)- group and the right attachment point is connected to the LBM.

[0307] [ka] wherein the left attachment point is connected to the -S(O)- group and the right attachment point is connected to the LBM.

[0308] [ka] wherein the left attachment point is connected to the -S(O)- group and the right attachment point is connected to the LBM.

[0309] [ka] wherein the left attachment point is connected to the -S(O)- group and the right attachment point is connected to the LBM.

[0310] [ka] wherein the left attachment point is connected to the -S(O)- group and the right attachment point is connected to the LBM.

[0311] [ka] wherein the left attachment point is connected to the -S(O)- group and the right attachment point is connected to the LBM.

[0312] [ka] wherein the left attachment point is connected to the -S(O)- group and the right attachment point is connected to the LBM.

[0313] [ka] wherein the left attachment point is connected to the -S(O)- group and the right attachment point is connected to the LBM.

[0314] [ka] wherein the left attachment point is connected to the -S(O)- group and the right attachment point is connected to the LBM.

[0315] [ka] wherein the left attachment point is connected to the -S(O)- group and the right attachment point is connected to the LBM.

[0316] [ka] wherein the left attachment point is connected to the -S(O)- group and the right attachment point is connected to the LBM.

[0317] [ka] wherein the left attachment point is connected to the -S(O)- group and the right attachment point is connected to the LBM.

[0318] [ka] wherein the left attachment point is connected to the -S(O)- group and the right attachment point is connected to the LBM.

[0319] [ka] wherein the left attachment point is connected to the -S(O)- group and the right attachment point is connected to the LBM.

[0320] [ka] wherein the left attachment point is connected to the -S(O)- group and the right attachment point is connected to the LBM.

[0321] [ka] wherein the left attachment point is connected to the -S(O)- group and the right attachment point is connected to the LBM.

[0322] [ka] wherein the left attachment point is connected to the -S(O)- group and the right attachment point is connected to the LBM.

[0323] [ka] wherein the left attachment point is connected to the -S(O)- group and the right attachment point is connected to the LBM.

[0324] [ka] wherein the left attachment point is connected to the -S(O)- group and the right attachment point is connected to the LBM.

[0325] [ka] wherein the left attachment point is connected to the -S(O)- group and the right attachment point is connected to the LBM.

[0326] [ka] wherein the left attachment point is connected to the -S(O)- group and the right attachment point is connected to the LBM.

[0327] [ka] wherein the left attachment point is connected to the -S(O)- group and the right attachment point is connected to the LBM.

[0328] [ka] wherein the left attachment point is connected to the -S(O)- group and the right attachment point is connected to the LBM.

[0329] [ka] wherein the left attachment point is connected to the -S(O)- group and the right attachment point is connected to the LBM.

[0330] [ka] wherein the left attachment point is connected to the -S(O)- group and the right attachment point is connected to the LBM.

[0331] [ka] wherein the left attachment point is connected to the -S(O)- group and the right attachment point is connected to the LBM.

[0332] [ka] wherein the left attachment point is connected to the -S(O)- group and the right attachment point is connected to the LBM.

[0333] [ka] wherein the left attachment point is connected to the -S(O)- group and the right attachment point is connected to the LBM.

[0334] [ka] wherein the left attachment point is connected to the -S(O)2- group and the right attachment point is connected to the LBM.

[0335] [ka] where L 1 , -Cy-, L 2 and q are as defined in any of the embodiments described herein, with the left attachment point connecting to the -S(O)2- group and the right attachment point connecting to the LBM.

[0336] In one embodiment,

[0337] [ka] teeth,

[0338] [ka] wherein the left attachment point is connected to -S(O)2- and the right attachment point is connected to LBM.

[0339] In one embodiment,

[0340] [ka] teeth,

[0341] [ka] wherein the left attachment point is connected to -S(O)2- and the right attachment point is connected to LBM.

[0342] In some embodiments,

[0343] [ka] teeth,

[0344] [ka] wherein the left attachment point is connected to -S(O)- and the right attachment point is connected to LBM.

[0345] [ka] teeth,

[0346] [ka] wherein the left attachment point is connected to -S(O)- and the right attachment point is connected to LBM.

[0347] [ka] teeth,

[0348] [ka] wherein the left attachment point is connected to -S(O)- and the right attachment point is connected to LBM.

[0349] [ka] teeth,

[0350] [ka] wherein the left attachment point is connected to -S(O)- and the right attachment point is connected to LBM.

[0351] [ka] teeth,

[0352] [ka] wherein the left attachment point is connected to -S(O)- and the right attachment point is connected to LBM.

[0353] [ka] teeth,

[0354] [ka] wherein the left attachment point is connected to -S(O)- and the right attachment point is connected to LBM.

[0355] [ka] teeth,

[0356] [ka] wherein the left attachment point is connected to -S(O)- and the right attachment point is connected to LBM.

[0357] [ka] teeth,

[0358] [ka] wherein the left attachment point is connected to -S(O)- and the right attachment point is connected to LBM.

[0359] [ka] teeth,

[0360] [ka] wherein the left attachment point is connected to -S(O)- and the right attachment point is connected to LBM.

[0361] [ka] teeth,

[0362] [ka] wherein the left attachment point is connected to -S(O)- and the right attachment point is connected to LBM.

[0363] [ka] teeth,

[0364] [ka] wherein the left attachment point is connected to -S(O)- and the right attachment point is connected to LBM.

[0365] [ka] teeth,

[0366] [ka] wherein the left attachment point is connected to -S(O)- and the right attachment point is connected to LBM.

[0367] [ka] teeth,

[0368] [ka] wherein the left attachment point is connected to -S(O)- and the right attachment point is connected to LBM.

[0369] [ka] teeth,

[0370] [ka] wherein the left attachment point is connected to -S(O)- and the right attachment point is connected to LBM.

[0371] [ka] teeth,

[0372] [ka] wherein the left attachment point is connected to -S(O)- and the right attachment point is connected to LBM.

[0373] [ka] teeth,

[0374] [ka] wherein the left attachment point is connected to -S(O)- and the right attachment point is connected to LBM.

[0375] [ka] teeth,

[0376] [ka] wherein the left attachment point is connected to -S(O)- and the right attachment point is connected to LBM.

[0377] [ka] teeth,

[0378] [ka] where the left attachment point is connected to -S(O)2- and the right attachment point is connected to LBM.

[0379] In one embodiment, L is

[0380] [ka] wherein q is as defined in any of the embodiments described herein, and the left attachment point is connected to -S(O)2- and the right attachment point is connected to LBM.

[0381] In one embodiment, L is

[0382] [ka] wherein q is as defined in any of the embodiments described herein, and the left attachment point is connected to -S(O)2- and the right attachment point is connected to LBM.

[0383] In one embodiment, L is

[0384] [ka] wherein q is as defined in any of the embodiments described herein, and the left attachment point is connected to -S(O)2- and the right attachment point is connected to LBM.

[0385] In one embodiment, L is

[0386] [ka] wherein q is as defined in any of the embodiments described herein, and the left attachment point is connected to -S(O)2- and the right attachment point is connected to LBM.

[0387] In one embodiment, L is

[0388] [ka] wherein q is as defined in any of the embodiments described herein, the left attachment point is connected to -S(O)- and the right attachment point is connected to LBM. In one embodiment, L is

[0389] [ka] wherein q is as defined in any of the embodiments described herein, the left attachment point is connected to -S(O)- and the right attachment point is connected to LBM. In one embodiment, L is

[0390] [ka] wherein q is as defined in any of the embodiments described herein, the left attachment point is connected to -S(O)- and the right attachment point is connected to LBM. In one embodiment, L is

[0391] [ka] wherein q is as defined in any of the embodiments described herein, the left attachment point is connected to -S(O)- and the right attachment point is connected to LBM. In one embodiment, L is

[0392] [ka] wherein q is as defined in any of the embodiments described herein, the left attachment point is connected to -S(O)- and the right attachment point is connected to LBM. In one embodiment, L is

[0393] [ka] wherein q is as defined in any of the embodiments described herein, the left attachment point is connected to -S(O)- and the right attachment point is connected to LBM. In one embodiment, L is

[0394] [ka] wherein q is as defined in any of the embodiments described herein, the left attachment point is connected to -S(O)- and the right attachment point is connected to LBM. In one embodiment, L is

[0395] [ka] wherein q is as defined in any of the embodiments described herein, the left attachment point is connected to -S(O)- and the right attachment point is connected to LBM. In one embodiment, L is

[0396] [ka] wherein q is as defined in any of the embodiments described herein, the left attachment point is connected to -S(O)- and the right attachment point is connected to LBM. In one embodiment, L is

[0397] [ka] wherein q is as defined in any of the embodiments described herein, the left attachment point is connected to -S(O)- and the right attachment point is connected to LBM. In one embodiment, L is

[0398] [ka] wherein q is as defined in any of the embodiments described herein, the left attachment point is connected to -S(O)- and the right attachment point is connected to LBM. In one embodiment, L is

[0399] [ka] wherein q is as defined in any of the embodiments described herein, the left attachment point is connected to -S(O)- and the right attachment point is connected to LBM. In one embodiment, L is

[0400] [ka] wherein q is as defined in any of the embodiments described herein, the left attachment point is connected to -S(O)- and the right attachment point is connected to LBM. In one embodiment, L is

[0401] [ka] wherein q is as defined in any of the embodiments described herein. In one embodiment, L is

[0402] [ka] wherein q is as defined in any of the embodiments described herein, the left attachment point is connected to -S(O)- and the right attachment point is connected to LBM. In one embodiment, L is

[0403] [ka] wherein q is as defined in any of the embodiments described herein, the left attachment point is connected to -S(O)- and the right attachment point is connected to LBM. In one embodiment, L is

[0404] [ka] wherein q is as defined in any of the embodiments described herein, the left attachment point is connected to -S(O)- and the right attachment point is connected to LBM. In one embodiment, L is

[0405] [ka] where q is as defined in any of the embodiments described herein, the left attachment point is connected to -S(O)2- and the right attachment point is connected to LBM.

[0406] As generally defined herein, -Cy- is each independently selected from phenylene, 8- to 10-membered bicyclic arylene, 4- to 7-membered monocyclic carbocyclylene, 5- to 11-membered spirocarbocyclylene, 4- to 10-membered bicyclic carbocyclylene, 5- to 10-membered bridged carbocyclylene, 4- to 7-membered monocyclic heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 11-membered spiroheterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 11-membered spiroheterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 4- to 10-membered bicyclic heterocyclylene having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5- to 6-membered heteroarylene having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an 8- to 10-membered bicyclic heteroarylene having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and phenylene, arylene, carbocyclylene, heterocyclylene, and heteroarylene are each a bivalent ring selected from R C is replaced by 0, 1, 2, 3, or 4 instances of R C is as defined in any of the embodiments described herein.

[0407] In one embodiment, -Cy- is each independently a divalent ring selected from phenylene, a 4-7 membered monocyclic heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-11 membered spiroheterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 4-10 membered bicyclic heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and phenylene, heterocyclylene, and heteroarylene are each independently selected from R C is replaced by 0, 1, 2, 3, or 4 instances of R Cis as defined in any of the embodiments described herein.

[0408] In one embodiment, each -Cy- is independently R C and R is phenylene substituted with 0, 1, 2, 3, or 4 instances of C is as defined in any of the embodiments described herein. In one embodiment, -Cy- is each independently a 4-7 membered monocyclic heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R C is replaced by 0, 1, 2, 3, or 4 instances of R C is as defined in any of the embodiments described herein. In one embodiment, each -Cy- is a 5- to 11-membered spiroheterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R C is replaced by 0, 1, 2, 3, or 4 instances of R C is as defined in any of the embodiments described herein. In one embodiment, each -Cy- is a 4-10 membered bicyclic heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R C is replaced by 0, 1, 2, 3, or 4 instances of R C is as defined in any of the embodiments described herein. In one embodiment, each -Cy- is a 5-6 membered heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R C is replaced by 0, 1, 2, 3, or 4 instances of R C is as defined in any of the embodiments described herein. In one embodiment, Cy is

[0409] [ka] are selected from R C is replaced by 0, 1, 2, 3, or 4 instances of R Cis as defined in any of the embodiments described herein, where the left attachment point is L 1 The right-hand attachment point is L 2 Connect to.

[0410] In one embodiment, Cy is

[0411] [ka] are selected from R C is replaced by 0, 1, 2, 3, or 4 instances of R C is as defined in any of the embodiments described herein, where the left attachment point is L 1 The right-hand attachment point is L 2 Connect to.

[0412] In one embodiment, -Cy- is unsubstituted. In one embodiment, -Cy- is R C In one embodiment, -Cy- is substituted with 0 or 1 instance of R C In one embodiment, -Cy- is substituted with 0, 1, or 2 instances of R C In one embodiment, -Cy- is substituted with 0, 1, 2, or 3 instances of R C In one embodiment, -Cy- is substituted with one instance of R C In one embodiment, -Cy- is substituted with two entities: C In one embodiment, -Cy- is substituted with three entities: C is replaced by four entities:

[0413] In one embodiment, Cy is

[0414] [ka] each of which is not further substituted, wherein the left attachment point is L 1 The right-hand attachment point is L 2 Connect to.

[0415] In one embodiment, Cy is

[0416] [ka] each of which is not further substituted, wherein the left attachment point is L 1 The right-hand attachment point is L 2 Connect to.

[0417] In one embodiment, Cy is

[0418] [ka] where the left attachment point is L 1 The right-hand attachment point is L 2 In one embodiment, Cy is

[0419] [ka] where the left attachment point is L 1 The right-hand attachment point is L 2 In one embodiment, Cy is

[0420] [ka] where the left attachment point is L 1 The right-hand attachment point is L 2 In one embodiment, Cy is

[0421] [ka] where the left attachment point is L 1 The right-hand attachment point is L 2 In one embodiment, Cy is

[0422] [ka] where the left attachment point is L 1 The right-hand attachment point is L 2 In one embodiment, Cy is

[0423] [ka] where the left attachment point is L 1 The right-hand attachment point is L 2 In one embodiment, Cy is

[0424] [ka] where the left attachment point is L 1 The right-hand attachment point is L 2 In one embodiment, Cy is

[0425] [ka] where the left attachment point is L 1 The right-hand attachment point is L 2 In one embodiment, Cy is

[0426] [ka] where the left attachment point is L 1 The right-hand attachment point is L 2 In one embodiment, Cy is

[0427] [ka] where the left attachment point is L 1 The right-hand attachment point is L 2 In one embodiment, Cy is

[0428] [ka] where the left attachment point is L 1 The right-hand attachment point is L 2 In one embodiment, Cy is

[0429] [ka] where the left attachment point is L 1 The right-hand attachment point is L 2 In one embodiment, Cy is

[0430] [ka] where the left attachment point is L 1 The right-hand attachment point is L 2 In one embodiment, Cy is

[0431] [ka] where the left attachment point is L 1 The right-hand attachment point is L 2 In one embodiment, Cy is

[0432] [ka] where the left attachment point is L 1 The right-hand attachment point is L 2 In one embodiment, Cy is

[0433] [ka] where the left attachment point is L 1 The right-hand attachment point is L 2 In one embodiment, Cy is

[0434] [ka] where the left attachment point is L 1 The right-hand attachment point is L 2 In one embodiment, Cy is

[0435] [ka] where the left attachment point is L 1 The right-hand attachment point is L 2 Connect to.

[0436] As broadly defined herein, LBM is:

[0437] [ka] wherein R 4 , R 5 , r, and s are each as defined in any of the embodiments described herein.

[0438] In one embodiment, the LBM comprises:

[0439] [ka] wherein R 4 , R 5 , r, and s are each as defined in any of the embodiments described herein.

[0440] In one embodiment, the LBM comprises:

[0441] [ka] where R 4 , R 5 , r, and s are each as defined in any of the embodiments described herein. In one embodiment, the LBM comprises:

[0442] [ka] where R 4 , R 5 , r, and s are each as defined in any of the embodiments described herein. In one embodiment, the LBM comprises:

[0443] [ka] where R 4 , R 5 , r, and s are each as defined in any of the embodiments described herein. In one embodiment, the LBM comprises:

[0444] [ka] where R 4 , R 5 , r, and s are each as defined in any of the embodiments described herein. In one embodiment, the LBM comprises:

[0445] [ka] where R 4 , R 5 , r, and s are each as defined in any of the embodiments described herein. In one embodiment, the LBM comprises:

[0446] [ka] where R 4 , R 5 , r, and s are each as defined in any of the embodiments described herein. In one embodiment, the LBM comprises:

[0447] [ka] where R4 , R 5 , r, and s are each as defined in any of the embodiments described herein. In one embodiment, the LBM comprises:

[0448] [ka] where R 4 , R 5 , r, and s are each as defined in any of the embodiments described herein. In one embodiment, the LBM comprises:

[0449] [ka] where R 4 , R 5 , r, and s are each as defined in any of the embodiments described herein. In one embodiment, the LBM comprises:

[0450] [ka] where R 4 , R 5 , r, and s are each as defined in any of the embodiments described herein. In one embodiment, the LBM comprises:

[0451] [ka] where R 4 , R 5 , r, and s are each as defined in any of the embodiments described herein. In one embodiment, the LBM comprises:

[0452] [ka] where R 4 , R 5, r, and s are each as defined in any of the embodiments described herein. In one embodiment, the LBM comprises:

[0453] [ka] where R 4 , R 5 , r, and s are each as defined in any of the embodiments described herein.

[0454] In one embodiment, the LBM comprises:

[0455] [ka] is selected from.

[0456] In one embodiment, the LBM comprises:

[0457] [ka] is selected from.

[0458] In one embodiment, the LBM comprises:

[0459] [ka] is selected from.

[0460] In one embodiment, the LBM comprises:

[0461] [ka] is selected from.

[0462] In one embodiment, the LBM comprises:

[0463] [ka] is selected from.

[0464] In one embodiment, the LBM comprises:

[0465] [ka] is selected from.

[0466] In one embodiment, the LBM comprises:

[0467] [ka] is selected from.

[0468] In one embodiment, the LBM comprises:

[0469] [ka] is selected from.

[0470] In one embodiment, the LBM comprises:

[0471] [ka] In one embodiment, the LBM is

[0472] [ka] In one embodiment, the LBM is

[0473] [ka] In one embodiment, the LBM is

[0474] [ka] In one embodiment, the LBM is

[0475] [ka] In one embodiment, the LBM is

[0476] [ka] In one embodiment, the LBM is

[0477] [ka] In one embodiment, the LBM is

[0478] [ka] In one embodiment, the LBM is

[0479] [ka] In one embodiment, the LBM is

[0480] [ka] In one embodiment, the LBM is

[0481] [ka] In one embodiment, the LBM is

[0482] [ka] In one embodiment, the LBM is

[0483] [ka] In one embodiment, the LBM is

[0484] [ka] In one embodiment, the LBM is

[0485] [ka] In one embodiment, the LBM is

[0486] [ka] In one embodiment, the LBM is

[0487] [ka] is.

[0488] As generally defined herein, R A The entities are each independently oxo, deuterium, halogen, -C 1-6 Alkyl, -C 1-6 Heteroalkyl, -C 1-6 Haloalkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -S(O)(NR)R, -S(O)(NCN)R, -S(NCN)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O )N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2, -N(R)S(O)2R, -P(O)R2, -P(O)(R)OR, -C 3-7 is selected from cycloalkyl, phenyl, 4- to 7-membered heterocyclyl, and 5- to 6-membered heteroaryl, wherein the heterocyclyl and heteroaryl each contain 1-3 heteroatoms independently selected from N, O, and S, and each R is as defined in any of the embodiments described herein.

[0489] In one embodiment, R A The entities are each independently oxo, deuterium, halogen, -C 1-6 Alkyl, -C 1-6 Heteroalkyl, -C 1-6 Haloalkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -CN, -OR, -SR, -NR2, -C 3-7 and R is selected from cycloalkyl, phenyl, 4- to 7-membered heterocyclyl, and 5- to 6-membered heteroaryl, wherein the heterocyclyl and heteroaryl each contain 1-3 heteroatoms independently selected from N, O, and S, and each R is as defined in any of the embodiments described herein. A The entities are each independently oxo, deuterium, halogen, -C 1-6 Alkyl, -C 1-6 Heteroalkyl, -C 1-6 Haloalkyl, -C 2-6 Alkynyl, -CN, -OR, -NR2, -C 3-7 cycloalkyl, and 4- to 7-membered heterocyclyl, wherein heterocyclyl and heteroaryl each contain 1 or 2 heteroatoms independently selected from N and O, and each R is as defined in any of the embodiments described herein.

[0490] In one embodiment, R A The entities are each independently oxo, deuterium, halogen, -C 1-6 Alkyl, -C 1-6 Haloalkyl, -OR, -C 3-7 cycloalkyl, and 4- to 7-membered heterocyclyl, wherein heterocyclyl and heteroaryl each contain 1 or 2 heteroatoms independently selected from N and O, and each R is as defined in any of the embodiments described herein.

[0491] In one embodiment, R AEach of the entities independently represents oxo, deuterium, -F, -Cl, -Me, -Et, -Pr, - i Pr, - t It is selected from Bu, —CF 3 , —OH, —OMe, cyclopropyl, cyclobutyl, azetidinyl, and oxetanyl.

[0492] In one embodiment, R A Each instance of is independently selected from oxo, deuterium, -F, and -Me.

[0493] In one embodiment, R A Each instance of is independently a halogen and -C 1-6 alkyl.

[0494] In one embodiment, R A are each independently selected from -F and -Me.

[0495] In one embodiment, R A is -F.

[0496] In one embodiment,

[0497] [ka] or

[0498] [ka] The part represented by

[0499] [ka] is selected from.

[0500] In one embodiment,

[0501] [ka] or

[0502] [ka] The part represented by

[0503] [ka] In one embodiment,

[0504] [ka] or

[0505] [ka] The part represented by

[0506] [ka] is.

[0507] In one embodiment, -NH- and F- are in a cis configuration.

[0508] In one embodiment, -NH- and F- are in a trans configuration.

[0509] In one embodiment,

[0510] [ka] or

[0511] [ka] The part represented by

[0512] [ka] is.

[0513] In one embodiment, -NH- and Me- are in a cis configuration.

[0514] In one embodiment, -NH- and Me- are in a trans configuration.

[0515] In one embodiment,

[0516] [ka] or

[0517] [ka] The moiety represented by is selected from:

[0518] [ka]

[0519] In one embodiment,

[0520] [ka] or

[0521] [ka] The part represented by

[0522] [ka] is selected from.

[0523] In one embodiment,

[0524] [ka] or

[0525] [ka] The part represented by

[0526] [ka] In one embodiment,

[0527] [ka] or

[0528] [ka] The part represented by

[0529] [ka] is.

[0530] As generally defined herein, R B The entities are each independently oxo, deuterium, halogen, -C 1-6 Alkyl, -C 1-6 Heteroalkyl, -C 1-6 Haloalkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -S(O)(NR)R, -S(O)(NCN)R, -S(NCN)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O )N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2, -N(R)S(O)2R, -P(O)R2, -P(O)(R)OR, -C 3-7is selected from cycloalkyl, phenyl, 4- to 7-membered heterocyclyl, and 5- to 6-membered heteroaryl, wherein the heterocyclyl and heteroaryl each contain 1-3 heteroatoms independently selected from N, O, and S, and each R is as defined in any of the embodiments described herein.

[0531] In one embodiment, R B The entities are each independently oxo, deuterium, halogen, -C 1-6 Alkyl, -C 1-6 Heteroalkyl, -C 1-6 Haloalkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -CN, -OR, -SR, -NR2, -C 3-7 and R is selected from cycloalkyl, phenyl, 4- to 7-membered heterocyclyl, and 5- to 6-membered heteroaryl, wherein the heterocyclyl and heteroaryl each contain 1-3 heteroatoms independently selected from N, O, and S, and each R is as defined in any of the embodiments described herein. B The entities are each independently oxo, deuterium, halogen, -C 1-6 Alkyl, -C 1-6 Heteroalkyl, -C 1-6 Haloalkyl, -C 2-6 Alkynyl, -CN, -OR, -NR2, -C 3-7 cycloalkyl, and 4- to 7-membered heterocyclyl, wherein heterocyclyl and heteroaryl each contain 1 or 2 heteroatoms independently selected from N and O, and each R is as defined in any of the embodiments described herein.

[0532] In one embodiment, R B The entities are each independently oxo, deuterium, halogen, -C 1-6 Alkyl, -C 1-6 Haloalkyl, -OR, -C 3-7cycloalkyl, and 4- to 7-membered heterocyclyl, wherein heterocyclyl and heteroaryl each contain 1 or 2 heteroatoms independently selected from N and O, and each R is as defined in any of the embodiments described herein.

[0533] In one embodiment, R B The entities are each independently deuterium, -F, -Cl, -Me, -Et, -Pr, - i Pr, - t It is selected from Bu, —CF 3 , —OH, —OMe, cyclopropyl, cyclobutyl, azetidinyl, and oxetanyl.

[0534] In one embodiment, R B are each independently selected from deuterium, -F, and -Me.

[0535] As generally defined herein, R C The entities are each independently oxo, deuterium, halogen, -C 1-6 Alkyl, -C 1-6 Heteroalkyl, -C 1-6 Haloalkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -S(O)(NR)R, -S(O)(NCN)R, -S(NCN)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O )N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2, -N(R)S(O)2R, -P(O)R2, -P(O)(R)OR, -C 3-7 is selected from cycloalkyl, phenyl, 4- to 7-membered heterocyclyl, and 5- to 6-membered heteroaryl, wherein the heterocyclyl and heteroaryl each contain 1-3 heteroatoms independently selected from N, O, and S, and each R is as defined in any of the embodiments described herein.

[0536] In one embodiment, R C The entities are each independently oxo, deuterium, halogen, -C 1-6 Alkyl, -C 1-6 Heteroalkyl, -C 1-6 Haloalkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -CN, -OR, -SR, -NR2, -C 3-7 is selected from cycloalkyl, phenyl, 4- to 7-membered heterocyclyl, and 5- to 6-membered heteroaryl, wherein the heterocyclyl and heteroaryl each contain 1-3 heteroatoms independently selected from N, O, and S, and each R is as defined in any of the embodiments described herein.

[0537] In one embodiment, R C The entities are each independently oxo, deuterium, halogen, -C 1-6 Alkyl, -C 1-6 Heteroalkyl, -C 1-6 Haloalkyl, -C 2-6 Alkynyl, -CN, -OR, -NR2, -C 3-7 cycloalkyl, and 4- to 7-membered heterocyclyl, wherein heterocyclyl and heteroaryl each contain 1 or 2 heteroatoms independently selected from N and O, and each R is as defined in any of the embodiments described herein.

[0538] In one embodiment, R C The entities are each independently oxo, deuterium, halogen, -C 1-6 Alkyl, -C 1-6 Haloalkyl, -OR, -C 3-7 cycloalkyl, and 4- to 7-membered heterocyclyl, wherein heterocyclyl and heteroaryl each contain 1 or 2 heteroatoms independently selected from N and O, and each R is as defined in any of the embodiments described herein.

[0539] In one embodiment, R C Each of the entities independently represents oxo, deuterium, -F, -Cl, -Me, -Et, -Pr, - i Pr, - t It is selected from Bu, —CF 3 , —OH, —OMe, cyclopropyl, cyclobutyl, azetidinyl, and oxetanyl.

[0540] In one embodiment, R C Each instance of is independently selected from oxo, deuterium, -F, and -Me.

[0541] As generally defined herein, R 4 The entities are each independently oxo, deuterium, halogen, -C 1-6 Alkyl, -C 1-6 Heteroalkyl, -C 1-6 Haloalkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -S(O)(NR)R, -S(O)(NCN)R, -S(NCN)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O )N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2, -N(R)S(O)2R, -P(O)R2, -P(O)(R)OR, -C 3-7 is selected from cycloalkyl, phenyl, 4- to 7-membered heterocyclyl, and 5- to 6-membered heteroaryl, wherein the heterocyclyl and heteroaryl each contain 1-3 heteroatoms independently selected from N, O, and S, and each R is as defined in any of the embodiments described herein.

[0542] In one embodiment, R 4 The entities are each independently oxo, deuterium, halogen, -C 1-6 Alkyl, -C 1-6 Heteroalkyl, -C 1-6Haloalkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -CN, -OR, -SR, -NR2, -C 3-7 is selected from cycloalkyl, phenyl, 4- to 7-membered heterocyclyl, and 5- to 6-membered heteroaryl, wherein the heterocyclyl and heteroaryl each contain 1-3 heteroatoms independently selected from N, O, and S, and each R is as defined in any of the embodiments described herein.

[0543] In one embodiment, R 4 are independently deuterium, halogen, -C 1-6 Alkyl, -C 1-6 haloalkyl, -CN, -OR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -S(O)(NR)R, -C(O)NR2, -C(O)N(R)OR, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)S(O)2NR2, and -N(R)S(O)2R, where R is H or C 1-6 It is alkyl.

[0544] In one embodiment, R 4 The entities are each independently oxo, deuterium, halogen, -C 1-6 Alkyl, -C 1-6 Heteroalkyl, -C 1-6 Haloalkyl, -C 2-6 Alkynyl, -CN, -OR, -NR2, -C 3-7 cycloalkyl, and 4- to 7-membered heterocyclyl, wherein heterocyclyl and heteroaryl each contain 1 or 2 heteroatoms independently selected from N and O, and each R is as defined in any of the embodiments described herein.

[0545] In one embodiment, R 4 The entities are each independently oxo, deuterium, halogen, -C 1-6 Alkyl, -C 1-6 Haloalkyl, -OR, -C 3-7cycloalkyl, and 4- to 7-membered heterocyclyl, wherein heterocyclyl and heteroaryl each contain 1 or 2 heteroatoms independently selected from N and O, and each R is as defined in any of the embodiments described herein.

[0546] In one embodiment, R 4 are each independently selected from -Me, -Et, -F, -Cl, -CF3, -CN, -OH, -OMe, -NH2, -NHMe, and -NMe2.

[0547] In one embodiment, R 4 The entities are each independently deuterium, -F, -Cl, -Me, -Et, -Pr, - i Pr, - t It is selected from Bu, —CF 3 , —OH, —OMe, cyclopropyl, cyclobutyl, azetidinyl, and oxetanyl.

[0548] In one embodiment, R 4 Each instance of R is independently selected from deuterium, -F, and -Me. 4 are each independently selected from -Me and -F.

[0549] As generally defined herein, R 5 The entities are each independently oxo, deuterium, halogen, -C 1-6 Alkyl, -C 1-6 Heteroalkyl, -C 1-6 Haloalkyl, -C 2-6 Alkenyl, -C 2-6Alkynyl, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -S(O)(NR)R, -S(O)(NCN)R, -S(NCN)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O )N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2, -N(R)S(O)2R, -P(O)R2, -P(O)(R)OR, -C 3-7 is selected from cycloalkyl, phenyl, 4- to 7-membered heterocyclyl, and 5- to 6-membered heteroaryl, wherein the heterocyclyl and heteroaryl each contain 1-3 heteroatoms independently selected from N, O, and S, and each R is as defined in any of the embodiments described herein.

[0550] In one embodiment, R 5 The entities are each independently oxo, deuterium, halogen, -C 1-6 Alkyl, -C 1-6 Heteroalkyl, -C 1-6 Haloalkyl, -C 2-6 Alkynyl, -CN, -OR, -NR2, -C 3-7 cycloalkyl, and 4- to 7-membered heterocyclyl, wherein heterocyclyl and heteroaryl each contain 1 or 2 heteroatoms independently selected from N and O, and each R is as defined in any of the embodiments described herein.

[0551] In one embodiment, R 5 The entities are each independently oxo, deuterium, halogen, -C 1-6 Alkyl, -C 1-6 Haloalkyl, -OR, -C 3-7 cycloalkyl, and 4- to 7-membered heterocyclyl, wherein heterocyclyl and heteroaryl each contain 1 or 2 heteroatoms independently selected from N and O, and each R is as defined in any of the embodiments described herein.

[0552] In one embodiment, R 5 are each independently selected from -Me, -Et, -F, -Cl, -CF3, -CN, -OH, -OMe, -NH2, -NHMe, and -NMe2.

[0553] In one embodiment, R 5 The entities are each independently deuterium, -F, -Cl, -Me, -Et, -Pr, - i Pr, - t It is selected from Bu, —CF 3 , —OH, —OMe, cyclopropyl, cyclobutyl, azetidinyl, and oxetanyl.

[0554] In one embodiment, R 5 Each instance of R is independently selected from deuterium, -F, and -Me. 5 are each independently selected from -F and -Me.

[0555] As generally defined herein, R 6 The entities are each independently oxo, deuterium, halogen, -C 1-6 Alkyl, -C 1-6 Heteroalkyl, -C 1-6 Haloalkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -S(O)(NR)R, -S(O)(NCN)R, -S(NCN)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O )N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2, -N(R)S(O)2R, -P(O)R2, -P(O)(R)OR, -C 3-7is selected from cycloalkyl, phenyl, 4- to 7-membered heterocyclyl, and 5- to 6-membered heteroaryl, wherein the heterocyclyl and heteroaryl each contain 1-3 heteroatoms independently selected from N, O, and S, and each R is as defined in any of the embodiments described herein.

[0556] In one embodiment, R 6 The entities are each independently oxo, deuterium, halogen, -C 1-6 Alkyl, -C 1-6 Heteroalkyl, -C 1-6 Haloalkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -CN, -OR, -SR, -NR2, -C 3-7 is selected from cycloalkyl, phenyl, 4- to 7-membered heterocyclyl, and 5- to 6-membered heteroaryl, wherein the heterocyclyl and heteroaryl each contain 1-3 heteroatoms independently selected from N, O, and S, and each R is as defined in any of the embodiments described herein.

[0557] In one embodiment, R 6 The entities are each independently oxo, deuterium, halogen, -C 1-6 Alkyl, -C 1-6 Heteroalkyl, -C 1-6 Haloalkyl, -C 2-6 Alkynyl, -CN, -OR, -NR2, -C 3-7 cycloalkyl, and 4- to 7-membered heterocyclyl, wherein heterocyclyl and heteroaryl each contain 1 or 2 heteroatoms independently selected from N and O, and each R is as defined in any of the embodiments described herein.

[0558] In one embodiment, R 6 The entities are each independently oxo, deuterium, halogen, -C 1-6 Alkyl, -C 1-6 Haloalkyl, -OR, -C 3-7cycloalkyl, and 4- to 7-membered heterocyclyl, wherein heterocyclyl and heteroaryl each contain 1 or 2 heteroatoms independently selected from N and O, and each R is as defined in any of the embodiments described herein.

[0559] In one embodiment, R 6 are halo, -OH, and -C 1-6 alkyl.

[0560] In one embodiment, R 6 Each of the entities independently represents oxo, deuterium, -F, -Cl, -Me, -Et, -Pr, - i Pr, - t It is selected from Bu, —CF 3 , —OH, —OMe, cyclopropyl, cyclobutyl, azetidinyl, and oxetanyl.

[0561] In one embodiment, R 6 -F, -Cl, -OH, -Me, -Et-, - i Pr is selected from.

[0562] In one embodiment, R 6 Each instance of R is independently selected from oxo, deuterium, -F, and -Me. 6 are each independently selected from -OH, -F, and -Me.

[0563] In one embodiment, R 6 Each instance of R is independently selected from -F and -Me. 6 are each independently selected from -OH and -Me.

[0564] In one embodiment, R 6 is -Me.

[0565] In one embodiment, R 6 is -OH.

[0566] As generally defined herein, R 7 are each independently -C 1-4 In one embodiment, R 7 The entities are, independently, -Me, - i In one embodiment, R 7 Each instance of R is independently selected from -Me and -F. 7 is -Me. In one embodiment, R 7 is -F.

[0567] As generally defined herein, each instance of R is independently hydrogen, —C 1-6 Alkyl, -C 1-6 Haloalkyl, -C 1-6 Heteroalkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -C 3-7 cycloalkyl, phenyl, 4- to 7-membered heterocyclyl, and 5- to 6-membered heteroaryl, wherein the heterocyclyl and heteroaryl each contain 1-3 heteroatoms independently selected from N, O, and S, or two R groups attached to the same nitrogen optionally join with the nitrogen to which they are attached to form an optionally substituted 4- to 7-membered heterocyclyl having 0, 1, or 2 additional heteroatoms independently selected from N, O, and S. In one embodiment, each instance of R is independently selected from hydrogen, -C 1-6 Alkyl, -C 1-6 Haloalkyl, -C 1-6 Heteroalkyl, -C 3-7 A cycloalkyl and a 4-7 membered heterocyclyl containing 1-3 heteroatoms independently selected from N, O, and S, or two R groups attached to the same nitrogen optionally taken together with the nitrogen to which they are attached form a 4-7 membered heterocyclyl having 0, 1, or 2 additional heteroatoms independently selected from N, O, and S and substituted with 0, 1, 2, or 3 substituents independently selected from -F, -Me, oxo, -OH-, or -OMe.

[0568] In one embodiment, each instance of R is independently hydrogen, —C 1-6 Alkyl, -C 1-6 Haloalkyl, -C 1-6 Heteroalkyl, or -C 3-7 Two R groups that are cycloalkyl or that are attached to the same nitrogen optionally together with the nitrogen to which they are attached form a 4- to 7-membered heterocyclyl having 0, 1, or 2 additional heteroatoms independently selected from N, O, and S, and substituted with 0, 1, 2, or 3 substituents independently selected from -F, -Me, oxo, -OH-, or -OMe.

[0569] In one embodiment, two R groups attached to the same nitrogen optionally together with the nitrogen to which they are attached form an azetidine, pyrrolidine, piperidine, piperazine, morpholine, or azepane substituted with 0, 1, 2, or 3 substituents independently selected from -F, -Me, oxo, -OH-, or -OMe.

[0570] In one embodiment, each instance of R is independently selected from hydrogen and —C 1-6 In one embodiment, R is selected from alkyl. In one embodiment, R is H. In one embodiment, R is selected from -C 1-6 In one embodiment, R is selected from H and -Me. In one embodiment, R is -Me.

[0571] As generally defined herein, L 1 are each independently selected from a bond and —N(R′), where R′ is as defined in any of the embodiments described herein. 1 is a bond. In one embodiment, L 1 is —N(R′), where R′ is as defined in any of the embodiments described herein. 1 is selected from a bond, —NH—, and —NMe—. 1is selected from a bond and -NH-. 1 is selected from a bond, -NMe-. 1 is —NH—. In one embodiment, L 1 is -NMe-.

[0572] As generally defined herein, L 2 are each independently selected from a bond and —N(R′), where R′ is as defined in any of the embodiments described herein.

[0573] In one embodiment, L 2 is a bond. In one embodiment, L 2 is —N(R′), where R′ is as defined in any of the embodiments described herein. 2 is selected from a bond, —NH—, and —NMe—. 2 is selected from a bond and -NH-. 2 is selected from a bond, -NMe-. 2 is —NH—. In one embodiment, L 2 is -NMe-.

[0574] In one embodiment, L 1 is a bond and L 2 is a bond or -N(R'). In one embodiment, L 1 is a bond and L 2 is a bond or NMe-.

[0575] In one embodiment, L 1 is a bond and L 2 is a bond or -NH-. As generally defined herein, each R' is independently H and C 1-6 alkyl.

[0576] As generally defined herein, n is 0, 1, 2, 3, or 4. In one embodiment, n is 0, 1, 2, or 3. In one embodiment, n is 0, 1, or 2. In one embodiment, n is 0 or 1. In one embodiment, n is 0. In one embodiment, n is 1. In one embodiment, n is 2. In one embodiment, n is 3. In one embodiment, n is 4.

[0577] As generally defined herein, r is 0, 1, 2, 3, or 4. In one embodiment, r is 0, 1, 2, or 3. In one embodiment, r is 0, 1, or 2. In one embodiment, r is 0 or 1. In one embodiment, r is 0. In one embodiment, r is 1. In one embodiment, r is 2. In one embodiment, r is 3. In one embodiment, r is 4.

[0578] As generally defined herein, s is 0, 1, 2, 3, or 4. In one embodiment, s is 0, 1, 2, or 3. In one embodiment, s is 0, 1, or 2. In one embodiment, s is 0 or 1. In one embodiment, s is 0. In one embodiment, s is 1. In one embodiment, s is 2. In one embodiment, s is 3. In one embodiment, s is 4.

[0579] As generally defined herein, m is 0, 1, 2, 3, or 4. In one embodiment, m is 0, 1, 2, or 3. In one embodiment, m is 0, 1, or 2. In one embodiment, m is 0 or 1. In one embodiment, m is 0. In one embodiment, m is 1. In one embodiment, m is 2. In one embodiment, m is 3. In one embodiment, m is 4.

[0580] As generally defined herein, p is 0, 1, 2, 3, or 4. In one embodiment, p is 0, 1, 2, or 3. In one embodiment, p is 0, 1, or 2. In one embodiment, p is 0 or 1. In one embodiment, p is 0. In one embodiment, p is 1. In one embodiment, p is 2. In one embodiment, p is 3. In one embodiment, p is 4.

[0581] As generally defined herein, q is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In one embodiment, q is 1, 2, 3, 4, 5, 7, or 9. In one embodiment, q is 0. In one embodiment, q is 1. In one embodiment, q is 2. In one embodiment, q is 3. In one embodiment, q is 4. In one embodiment, q is 5. In one embodiment, q is 6. In one embodiment, q is 7. In one embodiment, q is 8. In one embodiment, q is 9. In one embodiment, q is 10.

[0582] In one embodiment, formula B

[0583] [ka] wherein ring B, R 1 , R A , R B , L, LBM, m, and n are as defined in any of the embodiments described herein.

[0584] In one embodiment, the compound of formula C

[0585] [ka] wherein R 1 , R A , R B , L, LBM, m, and n are as defined in any of the embodiments described herein.

[0586] In one embodiment, the compound of formula D

[0587] [ka] wherein R 1 , R A , L, LBM, and n are as defined in any of the embodiments described herein.

[0588] In one embodiment, the compound of formula E

[0589] [ka] wherein R 1 , R 2 , R 3 , R A , L, LBM, and n are as defined in any of the embodiments described herein.

[0590] In one embodiment, the compound of formula F

[0591] [ka] wherein ring B, R 1 , R A , R B , L, LBM, m, and n are as defined in any of the embodiments described herein.

[0592] In one embodiment, a compound of formula G

[0593] [ka] wherein R 2 , R 3 , R 6 , R A , L, LBM, p, and n are as defined in any of the embodiments described herein.

[0594] In one embodiment, the compound of formula H

[0595] [ka] wherein ring B, R 6 , R A , R B , L, LBM, m, p, and n are as defined in any of the embodiments described herein.

[0596] In one embodiment, the formula J

[0597] [ka] wherein R 2 , R 3 , R 6 , R A , L, LBM, p, and n are as defined in any of the embodiments described herein.

[0598] In one embodiment, the compound of formula K

[0599] [ka] wherein ring B, R 6 , R A , R B , L, LBM, m, p, and n are as defined in any of the embodiments described herein. In one embodiment, the formula L

[0600] [ka] wherein R 2 , R 3 , R A , L, LBM, and n are as defined in any of the embodiments described herein. In one embodiment,

[0601] [ka] wherein ring B, R A , R B , L, LBM, m, and n are as defined in any of the embodiments described herein. In one embodiment,

[0602] [ka] wherein R 2 , R 3 , R A , L, LBM, and n are as defined in any of the embodiments described herein. In one embodiment,

[0603] [ka] wherein ring B, R A , R B , L, LBM, m, and n are as defined in any of the embodiments described herein.

[0604] In one embodiment, the compound of formula IA

[0605] [ka] wherein R 1 , R A , L, LBM, and n are each as defined in any of the embodiments described herein.

[0606] In one embodiment, formula IB

[0607] [ka] wherein R 1 , L, and LBM are each as defined in any of the embodiments described herein.

[0608] In one embodiment, the compound of formula IC

[0609] [ka] wherein R 1 , L, and LBM are as defined in any of the embodiments described herein.

[0610] In one embodiment, the compound of formula I-1-A

[0611] [ka] wherein R 1 , R A , L, LBM, and n are each as defined in any of the embodiments described herein.

[0612] In one embodiment, formula IB

[0613] [ka] wherein R 1 , L, and LBM are each as defined in any of the embodiments described herein.

[0614] In one embodiment, Formula II

[0615] [ka] wherein R 6 , R A , R B , L, LBM, m, n, and p are each as defined in any of the embodiments described herein.

[0616] In one embodiment, Formula II-A

[0617] [ka] wherein R 6 , R A , L, LBM, n, and p are each as defined in any of the embodiments described herein.

[0618] In one embodiment, Formula II-B

[0619] [ka] wherein R 6 , L, LBM, and p are each as defined in any of the embodiments described herein.

[0620] In one embodiment, Formula II-C

[0621] [ka] wherein R 6 , R A , p, L, and LBM are as defined in any of the embodiments described herein.

[0622] In one embodiment, Formula II-1

[0623] [ka] wherein R 6 , R A , R B , L, LBM, m, n, and p are each as defined in any of the embodiments described herein.

[0624] In one embodiment, the compound of formula II-1-A

[0625] [ka] wherein R 6 , R A , L, LBM, n, and p are each as defined in any of the embodiments described herein.

[0626] In one embodiment, the compound of formula II-1-B

[0627] [ka] wherein R 6 , L, LBM, and p are each as defined in any of the embodiments described herein.

[0628] In one embodiment, a compound of formula III

[0629] [ka] wherein R A , R B , L, LBM, m, and n are each as defined in any of the embodiments described herein.

[0630] In one embodiment, Formula III-A

[0631] [ka] wherein R A , L, LBM, and n are each as defined in any of the embodiments described herein.

[0632] In one embodiment, Formula III-B

[0633] [ka] wherein L and LBM are each as defined in any of the embodiments described herein.

[0634] In one embodiment, Formula III-C

[0635] [ka] wherein R A , R B , L, LBM, m, and n are each as defined in any of the embodiments described herein.

[0636] In one embodiment, Formula III-D

[0637] [ka] wherein R A , L, LBM, and n are each as defined in any of the embodiments described herein.

[0638] In one embodiment, Formula III-E

[0639] [ka] wherein L and LBM are each as defined in any of the embodiments described herein.

[0640] In one embodiment, the compound has formula III-F

[0641] [ka] wherein R A , L, and LBM are each as defined in any of the embodiments described herein.

[0642] In one embodiment, Formula III-G

[0643] [ka] wherein R A , L, and LBM are each as defined in any of the embodiments described herein.

[0644] In one embodiment, the compound of formula III-1

[0645] [ka] wherein R A , R B , L, LBM, m, and n are each as defined in any of the embodiments described herein.

[0646] In one embodiment, the compound of formula III-1-A

[0647] [ka] wherein R A , L, LBM, and n are each as defined in any of the embodiments described herein.

[0648] In one embodiment, the compound of formula III-1-B

[0649] [ka] wherein L and LBM are each as defined in any of the embodiments described herein.

[0650] In one embodiment, the compound of formula III-1-C

[0651] [ka] wherein R A , R B, L, LBM, m, and n are each as defined in any of the embodiments described herein.

[0652] In one embodiment, the compound of formula III-1-D

[0653] [ka] wherein R A , L, LBM, and n are each as defined in any of the embodiments described herein.

[0654] In one embodiment, the compound of formula III-1-E

[0655] [ka] wherein L and LBM are each as defined in any of the embodiments described herein.

[0656] In one embodiment, a compound of formula IV

[0657] [ka] wherein R B , R 6 , R A , L, LBM, m, n, and p are each as defined in any of the embodiments described herein.

[0658] In one embodiment, Formula IV-A

[0659] [ka] wherein R 6 , R A , L, LBM, n, and p are each as defined in any of the embodiments described herein.

[0660] In one embodiment, Formula IV-B

[0661] [ka] wherein R 6 , L, LBM, and p are each as defined in any of the embodiments described herein.

[0662] In one embodiment, Formula IV-C

[0663] [ka] wherein R 6 , R A , p, L, and LBM are as defined in any of the embodiments described herein.

[0664] In one embodiment, Formula IV-1

[0665] [ka] wherein R B , R 6 , R A , L, LBM, m, n, and p are each as defined in any of the embodiments described herein.

[0666] In one embodiment, the compound of formula IV-1-A

[0667] [ka] wherein R 6 , R A , L, LBM, n, and p are each as defined in any of the embodiments described herein.

[0668] In one embodiment, the compound of formula IV-1-B

[0669] [ka] wherein R 6 , L, LBM, and p are each as defined in any of the embodiments described herein.

[0670] In one embodiment, formula V

[0671] [ka] wherein R A , R B , L, LBM, m, and n are each as defined in any of the embodiments described herein.

[0672] In one embodiment, the formula VA

[0673] [ka] wherein R A , L, LBM, and n are each as defined in any of the embodiments described herein.

[0674] In one embodiment, a compound of formula VB

[0675] [ka] wherein L and LBM are each as defined in any of the embodiments described herein.

[0676] In one embodiment, the formula V

[0677] [ka] wherein R A , R B, L, LBM, m, and n are each as defined in any of the embodiments described herein.

[0678] In one embodiment, a compound of formula VD

[0679] [ka] wherein R A , L, LBM, and n are each as defined in any of the embodiments described herein.

[0680] In one embodiment, the formula VE

[0681] [ka] wherein L and LBM are each as defined in any of the embodiments described herein.

[0682] In one embodiment, a compound of formula VF

[0683] [ka] wherein R A , L, and LBM are each as defined in any of the embodiments described herein.

[0684] In one embodiment, the formula VG

[0685] [ka] wherein R A , L, and LBM are each as defined in any of the embodiments described herein.

[0686] In one embodiment, Formula V-1

[0687] [ka] wherein R A , R B , L, LBM, m, and n are each as defined in any of the embodiments described herein.

[0688] In one embodiment, a compound of formula V-1-A

[0689] [ka] wherein R A , L, LBM, and n are each as defined in any of the embodiments described herein.

[0690] In one embodiment, a compound of formula V-1-B

[0691] [ka] wherein L and LBM are each as defined in any of the embodiments described herein.

[0692] In one embodiment, a compound of formula V-1-C

[0693] [ka] wherein R A , R B , L, LBM, m, and n are each as defined in any of the embodiments described herein.

[0694] In one embodiment, the compound of formula V-1-D

[0695] [ka] wherein R A, L, LBM, and n are each as defined in any of the embodiments described herein.

[0696] In one embodiment, the compound of formula V-1-E

[0697] [ka] wherein L and LBM are each as defined in any of the embodiments described herein.

[0698] In embodiments of the compounds of Formula A, Formula I, or Formula I-1, the compound is selected from the compounds disclosed in Table 1, or a pharmaceutically acceptable salt thereof, or those described elsewhere herein and in the figures.

[0699] In one embodiment herein, there is provided a composition comprising a compound described herein and a pharmaceutically acceptable excipient.

[0700] In one embodiment, the compound is a compound identified in Table 1 below, or a pharmaceutically acceptable salt thereof.

[0701] Unless otherwise specified, the absolute stereochemistry of all chiral atoms is as stated. Compounds marked with (or) or (rel) in Table 1 and the Examples are single enantiomers to which the absolute stereochemistry has been arbitrarily assigned (e.g., based on the chiral SFC elution described in the Examples section). Compounds marked with (and) or (rac) are mixtures of enantiomers with the relative stereochemistry as indicated. Compounds with a stereocenter whose configuration is not shown in the depicted structure and no designation in the stereochemistry column of Table 1 are mixtures of enantiomers at that center. Compounds with a stereocenter whose configuration is shown in the depicted structure and no designation in the stereochemistry column of Table 1 or marked with (abs) are single enantiomers with the absolute stereochemistry as indicated.

[0702] One skilled in the art would be able to separate racemic compounds into their corresponding enantiomers using methods known in the art, such as chiral chromatography or chiral recrystallization, and references to compounds that are racemic mixtures are intended to include individual enantiomers within the mixture.

[0703] [Table 1-1]

[0704] [Table 1-2]

[0705] [Table 1-3]

[0706] [Table 1-4]

[0707] [Table 1-5]

[0708] [Table 1-6]

[0709] [Table 1-7]

[0710] [Table 1-8]

[0711] [Table 1-9]

[0712] Table 1-10

[0713] Table 1-11

[0714] Table 1-12

[0715] Table 1-13

[0716] Table 1-14

[0717] Table 1-15

[0718] Table 1-16

[0719] Table 1-17

[0720] Table 1-18

[0721] Table 1-19

[0722] Table 1-20

[0723] Table 1-21

[0724] Table 1-22

[0725] Table 1-23

[0726] Table 1-24

[0727] Table 1-25

[0728] Table 1-26

[0729] Table 1-27

[0730] Table 1-28

[0731] Table 1-29

[0732] Table 1-30

[0733] Table 1-31

[0734] Table 1-32

[0735] Table 1-33

[0736] Table 1-34

[0737] Table 1-35

[0738] Table 1-36

[0739] Table 1-37

[0740] Table 1-38

[0741] Table 1-39

[0742] Table 1-40

[0743] Table 1-41

[0744] Table 1-42

[0745] Table 1-43

[0746] Table 1-44

[0747] Table 1-45

[0748] Table 1-46

[0749] Table 1-47

[0750] Table 1-48

[0751] Table 1-49

[0752] Table 1-50

[0753] Table 1-51

[0754] Table 1-52

[0755] Table 1-53

[0756] Table 1-54

[0757] Table 1-55

[0758] Table 1-56

[0759] Table 1-57

[0760] Table 1-58

[0761] Table 1-59

[0762] Table 1-60

[0763] [Table 1-61]

[0764] [Table 1-62]

[0765] [Table 1-63]

[0766] [Table 1-64]

[0767] [Table 1-65]

[0768] Alternative Embodiments In alternative embodiments, the compounds described herein may also contain one or more isotopic substitutions. For example, hydrogen may be replaced by 2 H (D or deuterium) or 3 H (T or tritium), and carbon can be, for example, 13 C or 14 C, and oxygen can be, for example, 18 O, and nitrogen can be, for example, 15 In other embodiments, a specific isotope (e.g., 3 H, 13 C. 14 C. 18 O, or 15N) may represent at least 1%, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or at least 99.9% of the total isotopic abundance of the element occupying a particular site on the compound.

[0769] In one embodiment, a pharmaceutical composition is provided comprising a pharmaceutically acceptable carrier and an effective amount of a compound described herein (e.g., a compound of Formula A, Formula I, Formula I-1, or a compound of Table 1), or a pharmaceutically acceptable salt thereof.

[0770] The term "pharmaceutically acceptable carrier or adjuvant" refers to a carrier or adjuvant that may be administered to a patient in combination with a compound provided herein, which does not destroy its pharmacological activity, and which is non-toxic when administered in dosages sufficient to deliver a therapeutic amount of the compound.

[0771] Pharmaceutically acceptable carriers, adjuvants, and vehicles that may be used in the pharmaceutical compositions provided herein include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as d-α-tocopherol polyethylene glycol 1000 succinate, surfactants used in pharmaceutical dosage forms such as Tween or other similar polymeric delivery matrices, serum proteins such as human serum albumin, buffer substances such as phosphate, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts, or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulosic substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, polyethylene glycol, and wool fat. Cyclodextrins, such as α-, β-, and γ-cyclodextrin, or chemically modified derivatives such as hydroxyalkyl cyclodextrins, including 2 and 3 hydroxypropyl-β-cyclodextrin, or other solubilized derivatives, may also be advantageously used to enhance delivery of compounds of the formulae described herein.

[0772] When used as medicine, the compound provided herein is typically administered in the form of pharmaceutical composition.This composition can be prepared by a method well known in the pharmaceutical field, and comprises at least one active compound.In one embodiment, for this pharmaceutical composition, carrier is parenteral carrier, oral or topical carrier.

[0773] Also provided is a compound described herein (e.g., a compound of Formula A, Formula I, Formula I-1, or a compound of Table 1) (or a pharmaceutical composition thereof) for use as a drug or medicament (e.g., a medicament for treating a CDK2- or CCNE (CCNE1 and / or CCNE2)-mediated disease or disorder in a subject in need thereof). In one embodiment, the disease is a CDK2-mediated disease. In one embodiment, the disease is a CCNE (CCNE1 and / or CCNE2)-mediated disease. In one embodiment, the disease or disorder is a proliferative disease or disorder. In a further embodiment, the disease or condition is cancer. In one embodiment, the cancer is selected from ovarian cancer, gastric cancer, uterine cancer (e.g., endometrial cancer), and breast cancer (e.g., triple-negative breast cancer (TNBC), hormone receptor-positive (HR+) breast cancer, HER2-positive (HER2+)-positive breast cancer).

[0774] Also provided is a compound described herein (e.g., a compound of Formula A, Formula I, Formula I-1, or a compound of Table 1) (or a pharmaceutical composition thereof) for use in treating a CDK2- or CCNE (CCNE1 and / or CCNE2)-mediated disease or disorder in a subject in need thereof. In one embodiment, the disease is a CDK2-mediated disease. In one embodiment, the disease is a CCNE (CCNE1 and / or CCNE2)-mediated disease. In one embodiment, the disease is a CDK2- and CCNE (CCNE1 and / or CCNE2)-mediated disease. In one embodiment, the disease or disorder is a proliferative disease or disorder. In a further embodiment, the disease or condition is cancer. In one embodiment, the cancer is selected from ovarian cancer, gastric cancer, uterine cancer (e.g., endometrial cancer), and breast cancer (e.g., triple-negative breast cancer (TNBC), hormone receptor-positive (HR+) breast cancer, HER2-positive (HER2+)-positive breast cancer).

[0775] Also provided is a compound described herein (e.g., a compound of Formula A, Formula I, Formula I-1, or a compound of Table 1) (or a pharmaceutical composition thereof) for use in the manufacture of a medicament (e.g., a medicament for treating a CDK2- or CCNE (CCNE1 and / or CCNE2)-mediated disease or disorder in a subject in need thereof). In one embodiment, the disease or disorder is a proliferative disease or disorder. In one embodiment, the disease is a CDK2-mediated disease. In one embodiment, the disease is a CCNE (CCNE1 and / or CCNE2)-mediated disease. In one embodiment, the disease is a CDK2- and CCNE (CCNE1 and / or CCNE2)-mediated disease. In a further embodiment, the disease or condition is cancer. In one embodiment, the cancer is selected from ovarian cancer, gastric cancer, uterine cancer (e.g., endometrial cancer), and breast cancer (e.g., triple-negative breast cancer (TNBC), hormone receptor-positive (HR+) breast cancer, HER2-positive (HER2+)-positive breast cancer). Generally, the compounds provided herein are administered in an effective amount (e.g., a therapeutically effective amount). The amount of compound actually administered will typically be determined by a physician in light of the relevant circumstances, including the disease being treated, the selected route of administration, the compound actually administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, etc.

[0776] The pharmaceutical compositions provided herein can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, bucally, vaginally, or via an implanted reservoir, preferably by oral administration or injection. The pharmaceutical compositions provided herein may contain any conventional non-toxic, pharmaceutically acceptable carrier, adjuvant, or vehicle. Optionally, the pH of the formulation may be adjusted with a pharmaceutically acceptable acid, base, or buffer to improve the stability of the formulated compound or its delivery form. The term parenteral as used herein includes subcutaneous, intradermal, intravenous, intramuscular, intra-articular, intra-arterial, intrasynovial, intrasternal, intrathecal, intralesional, and intracranial injection or infusion techniques.

[0777] Compositions for oral administration can be in the form of bulk liquid solutions or suspensions, or bulk powders. However, more commonly, compositions are provided in unit dosage forms to facilitate accurate dosing. The term "unit dosage form" refers to physically discrete units suitable as single doses for human subjects and other mammals, each unit containing a predetermined amount of active ingredient calculated to produce the desired therapeutic effect in combination with a suitable pharmaceutical excipient. Typical unit dosage forms include prefilled and measured ampoules or syringes for liquid compositions, or pills, tablets, capsules, etc. for solid compositions. In such compositions, the compound is usually the minor component (about 0.1 to about 50% by weight, or preferably about 1 to about 40% by weight), with the remainder consisting of various vehicles or carriers and processing aids useful in forming the desired dosage form.

[0778] Liquid forms suitable for oral administration may include a suitable aqueous or nonaqueous vehicle with buffers, suspending or dispersing agents, colorants, flavors, etc. Solid forms may include, for example, any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth, or gelatin; an excipient such as starch or lactose; a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; a sweetener such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavor.

[0779] Injectable compositions are typically based on injectable sterile saline or phosphate-buffered saline, or other injectable carriers known in the art. As mentioned above, the active compound in such compositions is typically a minor component, often about 0.05 to 10% by weight, with the remainder being the injectable carrier and the like. Pharmaceutical compositions may be in the form of sterile injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions. These suspensions may be formulated according to techniques known in the art using suitable dispersing and wetting agents (e.g., Tween 80, etc.) and suspending agents. Sterile injectable preparations may also be sterile injectable solutions or suspensions in non-toxic, parenterally acceptable diluents or solvents, such as solutions in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are mannitol, water, Ringer's solution, and isotonic saline. Additionally, sterile fixed oils are commonly employed as solvents or suspending media. For this purpose, any blended fixed oil, including synthetic mono- or diglycerides, may be employed. Fatty acids such as oleic acid and its glyceride derivatives are useful in injectable preparations, as are natural pharmaceutically acceptable oils such as olive oil and castor oil, especially in their polyoxyethylated forms. These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants, or carboxymethylcellulose or similar dispersants, commonly used in the preparation of pharmaceutically acceptable dosage forms such as emulsions and / or suspensions. Other commonly used surfactants, such as Tween or Span, and / or other similar emulsifiers or bioavailability enhancers commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms, may also be used for formulation purposes.

[0780] Transdermal compositions are typically formulated as topical ointments or creams containing the active ingredient in an amount generally ranging from about 0.01 to about 20% by weight, preferably from about 0.1 to about 20% by weight, preferably from about 0.1 to about 10% by weight, and more preferably from about 0.5 to about 15% by weight. When formulated as an ointment, the active ingredient is typically combined with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredient may be formulated in a cream, e.g., an oil-in-water cream base. Such transdermal formulations are well known in the art and generally contain additional ingredients that enhance the stability of the active ingredient or the formulation for dermal penetration. All such known transdermal formulations and ingredients are included within the scope provided herein. The compounds provided herein can also be administered by transdermal devices. Thus, transdermal administration can be accomplished using a patch, either of the reservoir or porous membrane type or of the solid matrix variety.

[0781] The pharmaceutical compositions provided herein can also be administered in the form of suppositories for rectal administration.These compositions can be prepared by mixing the compounds provided herein with suitable non-irritating excipients that are liquid at room temperature and at rectal temperature, so that they melt in the rectum and release active ingredient.Such materials include but are not limited to cocoa butter, beeswax, and polyethylene glycol.

[0782] The pharmaceutical compositions provided herein may be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation and may be prepared as a solution in saline, utilizing benzyl alcohol or other suitable preservatives, absorption enhancers to improve bioavailability, fluorocarbons, and / or other solubilizing or dispersing agents known in the art.

[0783] The above-mentioned components in orally administrable, injectable or topically administrable, rectally administrable, and nasally administrable compositions are merely examples.Other materials as well as processing techniques etc. are described in Part 8 of Remington's Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, which is incorporated herein by reference.The compounds described herein can also be administered in sustained-release form or from sustained-release drug delivery system.The description of representative sustained-release materials can be found in Remington's Pharmaceutical Sciences.

[0784] When the compositions provided herein include a combination of a compound of a formula described herein with one or more therapeutic or prophylactic agents, both the compound and the additional agent should be present at dosage levels between about 1-100%, more preferably about 5-95%, of the dosage normally administered in a monotherapy regimen. The additional agent may be administered separately from the compound provided herein as part of a multiple-dose regimen. Alternatively, the agents may be part of a single dosage form, mixed together with the compound provided herein in a single composition. Pharmaceutically acceptable acid addition salts of the compounds described herein (e.g., compounds of Formula A, Formula I, Formula I-1, or Table 1) are also provided.

[0785] Acids that can be used to prepare pharmaceutically acceptable salts are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as hydrochloride, hydroiodide, hydrobromide, nitrate, sulfate, bisulfate, phosphate, acetate, lactate, citrate, tartrate, succinate, maleate, fumarate, benzoate, para-toluenesulfonate, and the like.

[0786] The compounds described herein can be administered, for example, by injection, intravenously, intraarterially, subcutaneously, intraperitoneally, intramuscularly, or subcutaneously; or orally, bucally, nasally, transmucosally, topically, in ophthalmic solutions, or by inhalation, at doses ranging from about 0.5 to about 100 mg per kg of body weight, alternatively at doses between 1 mg and 1000 mg per dose, every 4 to 120 hours, or according to the requirements of the particular drug. The methods herein contemplate administering an effective amount of a compound or compound composition to achieve a desired or stated effect. Typically, the pharmaceutical compositions provided herein will be administered about 1 to 6 times daily, or alternatively as a continuous infusion. Such administration can be used for chronic or acute therapy. The amount of active ingredient that can be combined with the carrier materials to produce a single dosage form will vary depending on the host treated and the particular mode of administration. Typical preparations contain from about 5% to about 95% active compound (w / w). Alternatively, such preparations contain from about 20% to about 80% active compound.

[0787] Lower or higher doses than those recited above may be necessary. The specific dosage and treatment regimen for any particular patient will depend on a variety of factors, including the activity of the particular compound utilized, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, the severity and course of the disease, disorder, or condition, the patient's predisposition to the disease, disorder, or condition, and the judgment of the attending physician.

[0788] After the improvement of patient's condition, if necessary, provided herein can be administered with compound, composition or combination at a maintenance dose.Then, depending on symptoms, dosage or administration frequency, or both, can be reduced to a level that maintains the improvement of condition when symptoms are alleviated to desired level.However, patient may need to be intermittently treated for a long period of time after any disease symptoms recur.

[0789] Treatment method The compounds of the present disclosure can inhibit CDK2 and / or CCNE (CCNE1 and / or CCNE2) and are therefore useful for treating diseases whose underlying pathology is mediated, in whole or in part, by CDK2 and / or CCNE (CCNE1 and / or CCNE2). In one embodiment, the disease pathology is mediated, in whole or in part, by CDK2. In one embodiment, the disease pathology is mediated, in whole or in part, by CCNE (CCNE1 and / or CCNE2). In one embodiment, the disease pathology is mediated, in whole or in part, by CDK2 and CCNE (CCNE1 and / or CCNE2). Such diseases include cancer and other diseases involving proliferative disorders.

[0790] In one embodiment, the compounds of Formula A, Formula I, and Formula I-1 inhibit both CDK2 and CCNE (CCNE1 and / or CCNE2). In one embodiment, the compounds of Formula A, Formula I, and Formula I-1 inhibit CDK2 (e.g., inhibit CDK2 selectively over CCNE (CCNE1 and / or CCNE2)). In one embodiment, the compounds of Formula A, Formula I, and Formula I-1 inhibit CCNE (CCNE1 and / or CCNE2) (e.g., inhibit CCNE (CCNE1 and / or CCNE2) selectively over CDK2).

[0791] In one embodiment, the present disclosure provides for the in vivo treatment of an individual or patient with a compound of Formula A, Formula I, or Formula I-1, or a salt thereof, to inhibit the growth of cancerous tumors. A compound of Formula A, Formula I, Formula I-1, or any of the formulas described herein, or a compound listed in any of the claims and described herein, or a salt thereof, can be used to inhibit the growth of cancerous tumors with abnormalities that activate CDK2 kinase activity. These include, but are not limited to, diseases (e.g., cancers) characterized by amplification or overexpression of CCNE (CCNE1 and / or CCNE2), such as ovarian cancer, uterine carcinosarcoma, and breast cancer, and p27 inactivation, such as breast cancer and melanoma. Thus, in one embodiment of this method, the patient has previously been determined to have amplification of the cyclin E (CCNE (CCNE1 and / or CCNE2)) gene and / or an expression level of CCNE (CCNE1 and / or CCNE2) higher than the control expression level of CCNE (CCNE1 and / or CCNE2) in a biological sample obtained from the human subject. In some embodiments, the cancer is characterized by the amplification or overexpression of CCNE1.Accordingly, in one embodiment of the method, the patient has previously been determined to have the amplification of the cyclin E1 gene and / or CCNE1 expression levels higher than the control expression level of CCNE1 in a biological sample obtained from a human subject.Alternatively, the compound of any of Formula A, Formula I, Formula I-1, or any of the formulas described herein, or any of the compounds listed in any of the claims and described herein, or salts thereof, can be used in combination with other drugs or standard cancer treatments.

[0792] In one embodiment, the present disclosure provides a method of inhibiting tumor cell growth in vivo, comprising contacting tumor cells in vitro with a compound of Formula A, Formula I, Formula I-1, or any of the formulae described herein, or a compound recited in any of the claims and described herein, or a salt thereof.

[0793] In one embodiment, the present disclosure provides a method for inhibiting the growth of tumor cells with amplification and overexpression of CCNE (CCNE1 and / or CCNE2) in an individual or patient, the method comprising administering to the individual or patient in need of such inhibition a therapeutically effective amount of a compound of Formula A, Formula I, Formula I-1, or any of the formulas described herein, or a compound listed in any of the claims and described herein, or a salt or stereoisomer thereof.

[0794] In one embodiment, provided herein is a method of inhibiting and / or degrading CDK2 and / or CCNE (CCNE1 and / or CCNE2), comprising contacting CDK2 and / or CCNE (CCNE1 and / or CCNE2) with a compound of Formula A, Formula I, Formula I-1, or any of the formulas described herein, or a compound recited in any of the claims and described herein, or a salt thereof. In one embodiment, provided herein is a method of inhibiting and / or degrading CDK2, comprising contacting CDK2 with a compound of Formula A, Formula I, Formula I-1, or any of the formulas described herein, or a compound recited in any of the claims and described herein, or a salt thereof. In one embodiment, provided herein is a method of inhibiting and / or degrading CCNE (CCNE1 and / or CCNE2), comprising contacting CCNE (CCNE1 and / or CCNE2) with a compound of Formula A, Formula I, Formula I-1, or any of the formulas described herein, or a compound recited in any of the claims and described herein, or a salt thereof. In one embodiment, provided herein is a method of inhibiting and / or degrading CDK2 and CCNE (CCNE1 and / or CCNE2), comprising contacting CDK2 and CCNE (CCNE1 and / or CCNE2) with a compound of Formula A, Formula I, Formula I-1, or any of the formulas described herein, or a compound recited in any of the claims and described herein, or a salt thereof.

[0795] In one embodiment, provided herein is a method for inhibiting and / or degrading CDK2 and / or CCNE (CCNE1 and / or CCNE2) in a patient, comprising administering to the patient a compound of Formula A, Formula I, Formula I-1, or any of the formulas described herein, or a compound listed in any of the claims and described herein, or a salt thereof.

[0796] In one embodiment, provided herein is a method of treating cancer, comprising administering to a patient (in need of such treatment) a therapeutically effective amount of a compound of Formula A, Formula I, Formula I-1, or any of the formulae described herein, or a compound listed in any of the claims and described herein, or a salt thereof.

[0797] In one embodiment, the cancer is characterized by amplification or overexpression of CCNE (CCNE1 and / or CCNE2). In one embodiment, the cancer is ovarian cancer or breast cancer characterized by amplification or overexpression of CCNE (CCNE1 and / or CCNE2).

[0798] In one embodiment, provided herein is a method of treating a disease or disorder associated with CDK2 and / or CCNE (CCNE1 and / or CCNE2) in a patient, comprising administering to the patient a therapeutically effective amount of a compound of Formula A, Formula I, Formula I-1, or any of the formulas described herein, or a compound listed in any of the claims and described herein, or a salt thereof. In one embodiment, provided herein is a method of treating a disease or disorder associated with CDK2 in a patient, comprising administering to the patient a therapeutically effective amount of a compound of Formula A, Formula I, Formula I-1, or any of the formulas described herein, or a compound listed in any of the claims and described herein, or a salt thereof. In one embodiment, provided herein is a method of treating a disease or disorder associated with CCNE (CCNE1 and / or CCNE2) in a patient, comprising administering to the patient a therapeutically effective amount of a compound of Formula A, Formula I, Formula I-1, or any of the formulas described herein, or a compound listed in any of the claims and described herein, or a salt thereof. In one embodiment, provided herein is a method of treating a disease or disorder associated with CDK2 and CCNE (CCNE1 and / or CCNE2) in a patient, comprising administering to the patient a therapeutically effective amount of a compound of Formula A, Formula I, Formula I-1, or any of the formulas described herein, or a compound listed in any of the claims and described herein, or a salt thereof.

[0799] In one embodiment, the disease or disorder associated with CDK2 and / or CCNE (CCNE1 and / or CCNE2) is associated with amplification of the cyclin E1 (CCNE1) gene and / or overexpression of CCNE1. In one embodiment, the disease or disorder associated with CDK2 and / or CCNE (CCNE1 and / or CCNE2) is N-myc amplified neuroblastoma cells (see Molenaar et al., Proc Natl Acad Sci USA 106(31):12968-12973), K-Ras mutant lung cancer (see Hu, S. et al., Mol Cancer Ther, 2015.14(11):2576-85), and cancer with FBW7 mutation and CCNE (CCNE1 and / or CCNE2) overexpression (see Takada et al., Cancer Res, 2017.77(18):4881-4893).

[0800] In one embodiment, the disease or disorder associated with CDK2 and / or CCNE (CCNE1 and / or CCNE2) is lung squamous cell carcinoma, lung adenocarcinoma, pancreatic adenocarcinoma, breast invasive carcinoma, uterine carcinosarcoma, ovarian serous cystadenocarcinoma, gastric adenocarcinoma, esophageal carcinoma, bladder urothelial carcinoma, mesothelioma, or sarcoma.

[0801] In one embodiment, the disease or disorder associated with CDK2 and / or CCNE (CCNE1 and / or CCNE2) is lung adenocarcinoma, breast invasive carcinoma, uterine carcinosarcoma, ovarian serous cystadenocarcinoma, or gastric adenocarcinoma.

[0802] In one embodiment, the disease or disorder associated with CDK2 and / or CCNE (CCNE1 and / or CCNE2) is adenocarcinoma, carcinoma, or cystadenocarcinoma. In one embodiment, the disease or disorder associated with CDK2 and / or CCNE (CCNE1 and / or CCNE2) is uterine cancer, ovarian cancer, gastric cancer, esophageal cancer, lung cancer, bladder cancer, pancreatic cancer, or breast cancer.

[0803] In one embodiment, the disease or disorder associated with CDK2 and / or CCNE (CCNE1 and / or CCNE2) is cancer.

[0804] In one embodiment, the cancer is characterized by amplification or overexpression of CCNE (CCNE1 and / or CCNE2). In one embodiment, the cancer is ovarian cancer or breast cancer characterized by amplification or overexpression of CCNE (CCNE1 and / or CCNE2).

[0805] In any of the embodiments described herein, the CCNE is CCNE1. In one embodiment, the CCNE is CCNE2. In one embodiment, the CCNE is CCNE1 and CCNE2.

[0806] In one embodiment, the cancer has primary or acquired resistance to CDK4 / 6 inhibition (eg, is resistant to treatment with a CDK4 / 6 inhibitor).

[0807] In one embodiment, the breast cancer is chemotherapy- or radiotherapy-resistant breast cancer, endocrine-resistant breast cancer, trastuzumab-resistant breast cancer, or breast cancer that exhibits primary or acquired resistance to CDK4 / 6 inhibition. In one embodiment, the breast cancer is advanced or metastatic breast cancer.

[0808] Additionally, the present disclosure includes refractory or recurrent malignancies whose growth can be inhibited using the compounds of the present disclosure.

[0809] In one embodiment, the compounds of the invention prevent or reduce the risk of developing any of the diseases mentioned herein, for example, are useful in preventing or reducing the risk of developing a disease, condition, or disorder in individuals who may be predisposed to the disease, condition, or disorder but who have not yet experienced or exhibited any pathology or symptoms of the disease.

[0810] Selected Embodiments Embodiment 1. Formula A

[0811] [ka] or a pharmaceutically acceptable salt thereof, wherein Ring A is phenyl, 3- to 14-membered cycloalkyl, or 4- to 14-membered heterocyclyl containing 1-3 heteroatoms independently selected from N, O, and S; R 1 -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -C 1-6 Haloalkyl, -C 1-6 Heteroalkyl, -C 3-14 Cycloalkyl, 6- to 14-membered aryl, 4- to 14-membered heterocyclyl, 5- to 14-membered heteroaryl, -C 1-4 Alkyl-C 3-14 Cycloalkyl, -C 1-4 Alkyl-(6-14 membered aryl), -C 1-4 Alkyl-(4-14 membered heterocyclyl), and -C 1-4 alkyl (5-14 membered heteroaryl), heterocyclyl and heteroaryl each containing 1-3 heteroatoms independently selected from N, O, and S, and alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl each selected from R 6 is replaced by 0, 1, 2, 3, or 4 instances of R 2 and R 3 are each independently -C 1-6 Alkyl, -C 1-6 Haloalkyl, -C 1-6 Heteroalkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -C 3-7 cycloalkyl, phenyl, 4- to 7-membered heterocyclyl, and 5- to 6-membered heteroaryl, wherein the heterocyclyl and heteroaryl each contain 1-3 heteroatoms independently selected from N, O, and S; and the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl each are selected from R Bis replaced by 0, 1, 2, 3, or 4 instances of Or R 2 and R 3 together with the carbon atoms to which they are attached form ring B, ring B being a 3- to 7-membered cycloalkyl ring or a 4- to 7-membered heterocyclyl ring containing 1 or 3 heteroatoms independently selected from N, O, and S, ring B being R B is replaced by 0, 1, 2, 3, or 4 instances of L is a covalent bond or a divalent, saturated, or unsaturated, straight or branched chain C 1-50 a hydrocarbon chain, wherein 0 to 6 methylene units of L are independently replaced by -Cy-, -CH(R)-, -C(R)2-, -O-, -NR-, -S-, -OC(=O)-, -C(=O)O-, -C(=O)-, -S(=O)-, -S(=O)2-, -NRS(=O)2-, -S(=O)2NR-, -NRC(=O)-, -C(=O)NR-, -OC(=O)NR-, or -NRC(=O)O-; -Cy- each independently represents phenylene, 8- to 10-membered bicyclic arylene, 4- to 7-membered monocyclic carbocyclylene, 5- to 11-membered spirocarbocyclylene, 4- to 10-membered bicyclic carbocyclylene, 5- to 10-membered bridged carbocyclylene, 4- to 7-membered monocyclic heterocyclylene having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 11-membered spiroheterocyclylene having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 4- to 10-membered monocyclic heterocyclylene having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 11-membered spiroheterocyclylene having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 10-membered bridged bicyclic saturated or partially unsaturated heterocyclylene having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5- to 6-membered heteroarylene having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an 8- to 10-membered bicyclic heteroarylene having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and phenylene, arylene, carbocyclylene, heterocyclylene, and heteroarylene are each independently selected from R Cis replaced by 0, 1, 2, 3, or 4 instances of LMB is

[0812] [ka] is selected from R A , R B , R C , R 4 , R 5 , and R 6 The entities are each independently oxo, deuterium, halogen, -C 1-6 Alkyl, -C 1-6 Heteroalkyl, -C 1-6 Haloalkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -S(O)(NR)R, -S(O)(NCN)R, -S(NCN)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O )N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2, -N(R)S(O)2R, -P(O)R2, -P(O)(R)OR, -C 3-7 selected from cycloalkyl, phenyl, 4- to 7-membered heterocyclyl, and 5- to 6-membered heteroaryl, wherein the heterocyclyl and heteroaryl each contain 1-3 heteroatoms independently selected from N, O, and S; Each instance of R is independently hydrogen, -C 1-6 Alkyl, -C 1-6 Haloalkyl, -C 1-6 Heteroalkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -C 3-7cycloalkyl, phenyl, 4- to 7-membered heterocyclyl, and 5- to 6-membered heteroaryl, wherein the heterocyclyl and heteroaryl each contain 1-3 heteroatoms independently selected from N, O, and S, or two R groups attached to the same nitrogen optionally combine with the nitrogen to which they are attached to form an optionally substituted 4- to 7-membered heterocyclyl having 0, 1, or 2 additional heteroatoms independently selected from N, O, and S; n is 0, 1, 2, 3, or 4; r is 0, 1, 2, 3, or 4; s is 0, 1, 2, 3, or 4, or a pharmaceutically acceptable salt thereof.

[0813] Embodiment 2. Formula B

[0814] [ka] wherein ring B is a 3- to 7-membered cycloalkyl ring or a 4- to 7-membered heterocyclyl ring containing 1 or 3 heteroatoms independently selected from N, O, and S, or a pharmaceutically acceptable salt thereof.

[0815] Embodiment 3. The compound of embodiment 1 or 2, or a pharmaceutically acceptable salt thereof, wherein ring B is a 3- to 7-membered cycloalkyl ring.

[0816] Embodiment 4. A compound of embodiment 1 or 2, or a pharmaceutically acceptable salt thereof, wherein Ring B is selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0817] Embodiment 5. A compound of embodiment 1 or 2, or a pharmaceutically acceptable salt thereof, wherein Ring B is selected from cyclopropyl and cyclobutyl.

[0818] Embodiment 6. A compound of embodiment 1 or 2, or a pharmaceutically acceptable salt thereof, wherein Ring B is cyclobutyl.

[0819] Embodiment 7. A compound of embodiment 1 or 2, or a pharmaceutically acceptable salt thereof, wherein Ring B is cyclopropyl.

[0820] Embodiment 8. A compound according to any one of embodiments 1 to 7, or a pharmaceutically acceptable salt thereof, wherein m is 0 and ring B is unsubstituted.

[0821] Embodiment 9. Formula C

[0822] [ka] wherein m is 0, 1, 2, 3, or 4, or a pharmaceutically acceptable salt thereof.

[0823] Embodiment 10. Formula D

[0824] [ka] or a pharmaceutically acceptable salt thereof.

[0825] Embodiment 11. A compound of any one of embodiments 1 to 10, or a pharmaceutically acceptable salt thereof, wherein ring A is a monocyclic 3- to 7-membered cycloalkyl.

[0826] Embodiment 12. A compound of any one of embodiments 1 to 10, or a pharmaceutically acceptable salt thereof, wherein ring A is monocyclic 4- to 7-membered heterocyclyl.

[0827] Embodiment 13. A compound of any one of embodiments 1-10, or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from azetidine, pyrrolidine, piperidine, and azepane.

[0828] Embodiment 14. A compound of any one of embodiments 1 to 10, or a pharmaceutically acceptable salt thereof, wherein Ring A is piperidine.

[0829] Embodiment 15. A compound of any one of embodiments 1 to 10, or a pharmaceutically acceptable salt thereof, wherein Ring A is piperidin-4-yl.

[0830] Embodiment 16. Formula E

[0831] [ka] or a pharmaceutically acceptable salt thereof.

[0832] Embodiment 17. Formula F

[0833] [ka] or a pharmaceutically acceptable salt thereof.

[0834] Embodiment 18. Formula I or Formula I-1

[0835] [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -C 1-6 Haloalkyl, -C 1-6 Heteroalkyl, -C 3-14 Cycloalkyl, 6- to 14-membered aryl, 4- to 14-membered heterocyclyl, 5- to 14-membered heteroaryl, -C 1-4 Alkyl-C 3-14 Cycloalkyl, -C 1-4 Alkyl-(6-14 membered aryl), -C 1-4Alkyl-(4-14 membered heterocyclyl), and -C 1-4 alkyl (5-14 membered heteroaryl), heterocyclyl and heteroaryl each containing 1-3 heteroatoms independently selected from N, O, and S, and alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl each selected from R 6 is replaced by 0, 1, 2, 3, or 4 instances of L is a covalent bond or a divalent, saturated, or unsaturated, straight or branched chain C 1-50 a hydrocarbon chain, wherein 0 to 6 methylene units of L are independently replaced by -Cy-, -CH(R)-, -C(R)2-, -O-, -NR-, -S-, -OC(=O)-, -C(=O)O-, -C(=O)-, -S(=O)-, -S(=O)2-, -NRS(=O)2-, -S(=O)2NR-, -NRC(=O)-, -C(=O)NR-, -OC(=O)NR-, or -NRC(=O)O-; -Cy- each independently represents phenylene, 8- to 10-membered bicyclic arylene, 4- to 7-membered monocyclic carbocyclylene, 5- to 11-membered spirocarbocyclylene, 4- to 10-membered bicyclic carbocyclylene, 5- to 10-membered bridged carbocyclylene, 4- to 7-membered monocyclic heterocyclylene having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 11-membered spiroheterocyclylene having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 4- to 10-membered monocyclic heterocyclylene having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 11-membered spiroheterocyclylene having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 10-membered bridged bicyclic saturated or partially unsaturated heterocyclylene having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5- to 6-membered heteroarylene having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an 8- to 10-membered bicyclic heteroarylene having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and phenylene, arylene, carbocyclylene, heterocyclylene, and heteroarylene are each independently selected from R Cis replaced by 0, 1, 2, 3, or 4 instances of LMB is

[0836] [ka] is selected from R A , R B , R C , R 4 , R 5 , and R 6 The entities are each independently oxo, deuterium, halogen, -C 1-6 Alkyl, -C 1-6 Heteroalkyl, -C 1-6 Haloalkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -S(O)(NR)R, -S(O)(NCN)R, -S(NCN)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O )N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2, -N(R)S(O)2R, -P(O)R2, -P(O)(R)OR, -C 3-7 selected from cycloalkyl, phenyl, 4- to 7-membered heterocyclyl, and 5- to 6-membered heteroaryl, wherein the heterocyclyl and heteroaryl each contain 1-3 heteroatoms independently selected from N, O, and S; Each instance of R is independently hydrogen, -C 1-6 Alkyl, -C 1-6 Haloalkyl, -C 1-6 Heteroalkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -C 3-7cycloalkyl, phenyl, 4- to 7-membered heterocyclyl, and 5- to 6-membered heteroaryl, wherein the heterocyclyl and heteroaryl each contain 1-3 heteroatoms independently selected from N, O, and S, or two R groups attached to the same nitrogen optionally combine with the nitrogen to which they are attached to form an optionally substituted 4- to 7-membered heterocyclyl having 0, 1, or 2 additional heteroatoms independently selected from N, O, and S; m is 0, 1, 2, 3, or 4; n is 0, 1, 2, 3, or 4; r is 0, 1, 2, 3, or 4; s is 0, 1, 2, 3, or 4, or a pharmaceutically acceptable salt thereof.

[0837] Embodiment 19. A compound according to embodiment 18, wherein the compound is a compound of formula I, or a pharmaceutically acceptable salt thereof.

[0838] Embodiment 20. A compound according to embodiment 18, which is a compound of formula I-1, or a pharmaceutically acceptable salt thereof.

[0839] Embodiment 21. Formula IA

[0840] [ka] or a pharmaceutically acceptable salt thereof.

[0841] Embodiment 22. Formula IB

[0842] [ka] or a pharmaceutically acceptable salt thereof.

[0843] Embodiment 23. Formula IC

[0844] [ka] or a pharmaceutically acceptable salt thereof.

[0845] Embodiment 24. Formula I-1-A

[0846] [ka] or a pharmaceutically acceptable salt thereof.

[0847] Embodiment 25. Formula I-1-B

[0848] [ka] or a pharmaceutically acceptable salt thereof.

[0849] Embodiment 26.R 1 But -C 3-7 Cycloalkyl, phenyl, and -C 1-4 Alkyl-C 3-14 cycloalkyl, each R 6 26. The compound of any one of embodiments 1-25, or a pharmaceutically acceptable salt thereof, substituted with 0, 1, 2, 3, or 4 instances of:

[0850] Embodiment 27.R 1 But -C 1-6 Haloalkyl, -C 3-7 cycloalkyl, phenyl, 4- to 7-membered heterocyclyl, and 5- to 6-membered heteroaryl, each of which is R 6 26. The compound of any one of embodiments 1-25, or a pharmaceutically acceptable salt thereof, substituted with 0, 1, 2, 3, or 4 instances of:

[0851] Embodiment 28.R 1 But C 1-6 Haloalkyl, C 3-7cycloalkyl, and phenyl, each R 6 26. The compound of any one of embodiments 1-25, or a pharmaceutically acceptable salt thereof, substituted with 0, 1, 2, 3, or 4 instances of:

[0852] Embodiment 29.R 1 But R 6 C replaced with 0, 1, 2, 3, or 4 instances of 3-7 26. The compound of any one of embodiments 1-25, or a pharmaceutically acceptable salt thereof, wherein:

[0853] Embodiment 30.R 1 But R 6 23. The compound of any one of embodiments 1-22, wherein R is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl substituted with 0, 1, 2, 3, or 4 instances of R, ...

[0854] Embodiment 31.R 1 is cyclopentyl, cyclohexyl, phenyl, or -CH(CH3)-cyclopropyl, and R 6 26. The compound of any one of embodiments 1-25, or a pharmaceutically acceptable salt thereof, substituted with 0, 1, 2, 3, or 4 instances of:

[0855] Embodiment 32.R 1 is cyclopentyl, cyclohexyl, phenyl, or -CH(CH3)-cyclopropyl, and R 6 26. The compound of any one of embodiments 1-25, or a pharmaceutically acceptable salt thereof, substituted with 0, 1, or 2 instances of:

[0856] Embodiment 33.R 1 is cyclopentyl or cyclohexyl, and R 6 26. The compound of any one of embodiments 1-25, or a pharmaceutically acceptable salt thereof, substituted with 0, 1, 2, 3, or 4 instances of:

[0857] Embodiment 34.R 1 But R 6 26. The compound of any one of embodiments 1-25, wherein R is cyclopentyl substituted with 0, 1, 2, 3, or 4 instances of: or a pharmaceutically acceptable salt thereof.

[0858] Embodiment 35. Formula G

[0859] [ka] wherein p is 0, 1, 2, 3, or 4, or a pharmaceutically acceptable salt thereof.

[0860] Embodiment 36. Formula H

[0861] [ka] wherein p is 0, 1, 2, 3, or 4, or a pharmaceutically acceptable salt thereof.

[0862] Embodiment 37. Formula II

[0863] [ka] wherein p is 0, 1, 2, 3, or 4, or a pharmaceutically acceptable salt thereof.

[0864] Embodiment 38. Formula II-A

[0865] [ka] wherein p is 0, 1, 2, 3, or 4, or a pharmaceutically acceptable salt thereof.

[0866] Embodiment 39. Formula II-B

[0867] [ka] wherein p is 0, 1, 2, 3, or 4, or a pharmaceutically acceptable salt thereof.

[0868] Embodiment 40. Formula II-C

[0869] [ka] wherein p is 0, 1, 2, 3, or 4, or a pharmaceutically acceptable salt thereof.

[0870] Embodiment 41. Formula II-1

[0871] [ka] wherein p is 0, 1, 2, 3, or 4, or a pharmaceutically acceptable salt thereof.

[0872] Embodiment 42. Formula II-1-A

[0873] [ka] wherein p is 0, 1, 2, 3, or 4, or a pharmaceutically acceptable salt thereof.

[0874] Embodiment 43. Formula II-1-B

[0875] [ka] wherein p is 0, 1, 2, 3, or 4, or a pharmaceutically acceptable salt thereof.

[0876] Embodiment 44.R 1 But R 6 26. The compound of any one of embodiments 1-25, wherein R is 1, 2, 3, or 4 substituted with cyclohexyl; or a pharmaceutically acceptable salt thereof.

[0877] Embodiment 45. Formula J

[0878] [ka] wherein p is 0, 1, 2, 3, or 4, or a pharmaceutically acceptable salt thereof.

[0879] Embodiment 46. Formula K

[0880] [ka] 18. The compound of any one of embodiments 1-17, wherein p is 0, 1, 2, 3, or 4, or a pharmaceutically acceptable salt thereof.

[0881] Embodiment 47. Formula IV

[0882] [ka] wherein p is 0, 1, 2, 3, or 4, or a pharmaceutically acceptable salt thereof.

[0883] Embodiment 48. Formula IV-A

[0884] [ka] wherein p is 0, 1, 2, 3, or 4, or a pharmaceutically acceptable salt thereof.

[0885] Embodiment 49. Formula IV-B

[0886] [ka] wherein p is 0, 1, 2, 3, or 4, or a pharmaceutically acceptable salt thereof.

[0887] Embodiment 50. Formula IV-C

[0888] [ka] wherein p is 0, 1, 2, 3, or 4, or a pharmaceutically acceptable salt thereof.

[0889] Embodiment 51. Formula IV-1

[0890] [ka] wherein p is 0, 1, 2, 3, or 4, or a pharmaceutically acceptable salt thereof.

[0891] Embodiment 52. Formula IV-1-A

[0892] [ka] wherein p is 0, 1, 2, 3, or 4, or a pharmaceutically acceptable salt thereof.

[0893] Embodiment 53. Formula IV-1-B

[0894] [ka] wherein p is 0, 1, 2, 3, or 4, or a pharmaceutically acceptable salt thereof.

[0895] Embodiment 54.R 6 but halo, -OH, and -C 1-6 54. The compound of any one of embodiments 1-53, or a pharmaceutically acceptable salt thereof, wherein:

[0896] Embodiment 55.R 6 -F, -Cl, -OH, -Me, -Et-, and - i Pr, or a pharmaceutically acceptable salt thereof.

[0897] Embodiment 56.R 6 The compound of any one of embodiments 1-53, or a pharmaceutically acceptable salt thereof, wherein is selected from -OH, -F, and -Me.

[0898] Embodiment 57.R 6 is selected from -F and -Me, or a pharmaceutically acceptable salt thereof.

[0899] Embodiment 58.R 6 is selected from -OH and -Me, or a pharmaceutically acceptable salt thereof.

[0900] Embodiment 59.R 6 The compound of any one of embodiments 1-53, or a pharmaceutically acceptable salt thereof, wherein is —OH.

[0901] Embodiment 60.R 6 The compound of any one of embodiments 1-53, or a pharmaceutically acceptable salt thereof, wherein is -Me.

[0902] Embodiment 61.R 1 is selected from 1,1-difluorobutan-2-yl, cyclopentyl, 2-methylcyclopentyl, 3-hydroxycyclohexyl, 2-hydroxy-2-methylcyclopentyl, 2-methylphenyl, 2-chloro-5-fluorophenyl, 1,5-dimethyl-1H-pyrazol-4-yl, 7-chloro-1,2,3,4-tetrahydroisoquinolin-6-yl, and 1-cyclopropylethyl, or a pharmaceutically acceptable salt thereof.

[0903] Embodiment 62.R 1 is selected from cyclopentyl, 2-methylcyclopentyl, 3-hydroxycyclohexyl, 2-methylphenyl, and 1,1-difluorobutan-2-yl, or a pharmaceutically acceptable salt thereof.

[0904] Embodiment 63.R 1 26. The compound of any one of embodiments 1-25, or a pharmaceutically acceptable salt thereof, wherein is selected from cyclopentyl, 2-methylcyclopentyl, 2-methylphenyl, and 1,1-difluorobutan-2-yl.

[0905] Embodiment 64.R 1 26. The compound of any one of embodiments 1-25, or a pharmaceutically acceptable salt thereof, wherein is selected from 2-methylcyclopentyl and 3-hydroxycyclohexyl.

[0906] Embodiment 65.R 1 26. The compound of any one of embodiments 1-25, or a pharmaceutically acceptable salt thereof, wherein is 3-hydroxycyclohexyl.

[0907] Embodiment 66.R 1 The compound of any one of embodiments 1-25, or a pharmaceutically acceptable salt thereof, wherein is 2-methylcyclopentyl.

[0908] Embodiment 67.R 1 but,

[0909] [ka] 26. The compound of any one of embodiments 1-25, selected from:

[0910] Embodiment 68.R 1 but,

[0911] [ka] 26. The compound of any one of embodiments 1-25, selected from:

[0912] Embodiment 69.R 1 but,

[0913] [ka] 26. The compound of any one of embodiments 1-25, selected from:

[0914] Embodiment 70.R 1 but,

[0915] [ka] 26. The compound of any one of embodiments 1-25, selected from:

[0916] Embodiment 71. Formula L

[0917] [ka] or a pharmaceutically acceptable salt thereof.

[0918] Embodiment 72. Formula M

[0919] [ka] 18. The compound of any one of embodiments 1-17, which is a compound of the formula: or a pharmaceutically acceptable salt thereof.

[0920] Embodiment 73. Formula N

[0921] [ka] or a pharmaceutically acceptable salt thereof.

[0922] Embodiment 74. Formula O

[0923] [ka] 18. The compound of any one of embodiments 1-17, which is a compound of the formula: or a pharmaceutically acceptable salt thereof.

[0924] Embodiment 75. Formula III

[0925] [ka] or a pharmaceutically acceptable salt thereof.

[0926] Embodiment 76. Formula III-A

[0927] [ka] or a pharmaceutically acceptable salt thereof.

[0928] Embodiment 77. Formula III-B

[0929] [ka] or a pharmaceutically acceptable salt thereof.

[0930] Embodiment 78. Formula III-C

[0931] [ka] or a pharmaceutically acceptable salt thereof.

[0932] Embodiment 79. Formula III-D

[0933] [ka] or a pharmaceutically acceptable salt thereof.

[0934] Embodiment 80. Formula III-E

[0935] [ka] or a pharmaceutically acceptable salt thereof.

[0936] Embodiment 81. Formula III-F

[0937] [ka] or a pharmaceutically acceptable salt thereof.

[0938] Embodiment 82. Formula III-G

[0939] [ka] or a pharmaceutically acceptable salt thereof.

[0940] Embodiment 83. Formula III-1

[0941] [ka] or a pharmaceutically acceptable salt thereof.

[0942] Embodiment 84. Formula III-1-A

[0943] [ka] or a pharmaceutically acceptable salt thereof.

[0944] Embodiment 85. Formula III-1-B

[0945] [ka] or a pharmaceutically acceptable salt thereof.

[0946] Embodiment 86. Formula III-1-C

[0947] [ka] or a pharmaceutically acceptable salt thereof.

[0948] Embodiment 87. Formula III-1-D

[0949] [ka] or a pharmaceutically acceptable salt thereof.

[0950] Embodiment 88. Formula III-1-E

[0951] [ka] or a pharmaceutically acceptable salt thereof.

[0952] Embodiment 89. Formula V

[0953] [ka] or a pharmaceutically acceptable salt thereof.

[0954] Embodiment 90. Formula VA

[0955] [ka] or a pharmaceutically acceptable salt thereof.

[0956] Embodiment 91. Formula VB

[0957] [ka] or a pharmaceutically acceptable salt thereof.

[0958] Embodiment 92. Formula VC

[0959] [ka] or a pharmaceutically acceptable salt thereof.

[0960] Embodiment 93. Formula VD

[0961] [ka] or a pharmaceutically acceptable salt thereof.

[0962] Embodiment 94. Formula VE

[0963] [ka] or a pharmaceutically acceptable salt thereof.

[0964] Embodiment 95. Formula VF

[0965] [ka] or a pharmaceutically acceptable salt thereof.

[0966] Embodiment 96. Formula VG

[0967] [ka] or a pharmaceutically acceptable salt thereof.

[0968] Embodiment 97. Formula V-1

[0969] [ka] or a pharmaceutically acceptable salt thereof.

[0970] Embodiment 98. Formula V-1-A

[0971] [ka] or a pharmaceutically acceptable salt thereof.

[0972] Embodiment 99. Formula V-1-B

[0973] [ka] or a pharmaceutically acceptable salt thereof.

[0974] Embodiment 100. Formula V-1-C

[0975] [ka] or a pharmaceutically acceptable salt thereof.

[0976] Embodiment 101. Formula V-1-D

[0977] [ka] or a pharmaceutically acceptable salt thereof.

[0978] Embodiment 102. Formula V-1-E

[0979] [ka] or a pharmaceutically acceptable salt thereof.

[0980] Embodiment 103.R A But halogen and -C 1-6 103. The compound of any one of embodiments 1-102, or a pharmaceutically acceptable salt thereof, wherein:

[0981] Embodiment 104.RA The compound of any one of embodiments 1-102, or a pharmaceutically acceptable salt thereof, wherein is selected from -F and -Me.

[0982] Embodiment 105.R A The compound according to any one of embodiments 1-102, or a pharmaceutically acceptable salt thereof, wherein is -F.

[0983] Embodiment 106.

[0984] [ka] or

[0985] [ka] The part represented by

[0986] [ka] 103. The compound of any one of embodiments 1-102, selected from:

[0987] Embodiment 107.

[0988] [ka] or

[0989] [ka] The part represented by

[0990] [ka] 103. The compound of any one of embodiments 1-102, wherein:

[0991] Embodiment 108. A compound according to embodiment 106 or 107, or a pharmaceutically acceptable salt thereof, wherein -NH- and F- are in the cis configuration.

[0992] Embodiment 109. A compound according to embodiment 106 or 107, or a pharmaceutically acceptable salt thereof, wherein -NH- and F- are in the trans configuration.

[0993] Embodiment 110.

[0994] [ka] or

[0995] [ka] The part represented by

[0996] [ka] 103. The compound of any one of embodiments 1-102, wherein:

[0997] Embodiment 111. A compound according to embodiment 106 or 110, or a pharmaceutically acceptable salt thereof, wherein -NH- and Me- are in the cis configuration.

[0998] Embodiment 112. A compound according to embodiment 106 or 110, or a pharmaceutically acceptable salt thereof, wherein -NH- and Me- are in the trans configuration.

[0999] Embodiment 113.

[1000] [ka] or

[1001] [ka] The part represented by

[1002] [ka] 103. The compound of any one of embodiments 1-102, selected from:

[1003] Embodiment 114.

[1004] [ka] or

[1005] [ka] The part represented by

[1006] [ka] 103. The compound of any one of embodiments 1-102, selected from:

[1007] Embodiment 115.

[1008] [ka] or

[1009] [ka] The part represented by

[1010] [ka] 103. The compound of any one of embodiments 1-102, wherein:

[1011] Embodiment 116.L is

[1012] [ka] are selected from R 7 is replaced by 0, 1, 2, or 3 instances of R 7 are each independently -C 1-4 selected from alkyl and halo; wherein the left attachment point is connected to the -S(O)2- group and the right attachment point is connected to the LBM; L 1 and L 2 are each independently selected from a bond and —N(R′), and R′ is selected from H and C 1-6 alkyl, 116. The compound of any one of embodiments 1-115, wherein q is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, or a pharmaceutically acceptable salt thereof.

[1013] Embodiment 117.R 7 However, each independently, -Me, - i 117. The compound of embodiment 116, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from: —Pr, and —F.

[1014] Embodiment 118.R 7 is each independently selected from -Me and -F, or a pharmaceutically acceptable salt thereof.

[1015] Embodiment 119.L is

[1016] [ka]

[1017] [ka] is selected from wherein the left attachment point is connected to the -S(O)2- group and the right attachment point is connected to the LBM; L1 and L 2 are each independently selected from a bond and —N(R′), and R′ is selected from H and C 1-6 alkyl, 116. The compound of any one of embodiments 1-115, wherein q is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, or a pharmaceutically acceptable salt thereof.

[1018] Embodiment 120.L is

[1019] [ka] is selected from wherein the left attachment point is connected to the -S(O)2- group and the right attachment point is connected to the LBM; L 1 and L 2 are each independently selected from a bond and —N(R′), and R′ is selected from H and C 1-6 alkyl, 116. The compound of any one of embodiments 1-115, wherein q is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, or a pharmaceutically acceptable salt thereof.

[1020] Embodiment 121.L is

[1021] [ka] is selected from wherein the left attachment point is connected to the -S(O)2- group and the right attachment point is connected to the LBM; L 1 and L 2 are each independently selected from a bond and —N(R′), and R′ is selected from H and C 1-6 alkyl, 116. The compound of any one of embodiments 1-115, wherein q is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, or a pharmaceutically acceptable salt thereof.

[1022] Embodiment 122.L is

[1023] [ka] are selected from R 7 is replaced by 0, 1, 2, or 3 instances of A compound according to any one of embodiments 116 to 118, or a pharmaceutically acceptable salt thereof, wherein the left attachment point is connected to the -S(O)2- group and the right attachment point is connected to the LBM.

[1024] Embodiment 123.L is R 7 replaced with 0, 1, 2, or 3 instances of

[1025] [ka] wherein the left attachment point is connected to the -S(O)2- group and the right attachment point is connected to LBM, or a pharmaceutically acceptable salt thereof.

[1026] Embodiment 124.L is R 7 replaced with 0, 1, 2, or 3 instances of

[1027] [ka] wherein the left attachment point is connected to the -S(O)2- group and the right attachment point is connected to LBM, or a pharmaceutically acceptable salt thereof.

[1028] Embodiment 125.L is R 7 replaced with 0, 1, 2, or 3 instances of

[1029] [ka] wherein the left attachment point is connected to the -S(O)2- group and the right attachment point is connected to LBM, or a pharmaceutically acceptable salt thereof.

[1030] Embodiment 126.L is R 7 replaced with 0, 1, 2, or 3 instances of

[1031] [ka] wherein the left attachment point is connected to the -S(O)2- group and the right attachment point is connected to LBM, or a pharmaceutically acceptable salt thereof.

[1032] Embodiment 127.L is R 7 replaced with 0, 1, 2, or 3 instances of

[1033] [ka] wherein the left attachment point is connected to the -S(O)2- group and the right attachment point is connected to LBM, or a pharmaceutically acceptable salt thereof.

[1034] Embodiment 128.L is R 7 replaced with 0, 1, 2, or 3 instances of

[1035] [ka] wherein the left attachment point is connected to the -S(O)2- group and the right attachment point is connected to LBM, or a pharmaceutically acceptable salt thereof.

[1036] Embodiment 129.L is

[1037] [ka] wherein the left attachment point is connected to the -S(O)2- group and the right attachment point is connected to LBM, or a pharmaceutically acceptable salt thereof.

[1038] Embodiment 130.L is

[1039] [ka] wherein the left attachment point is connected to the -S(O)2- group and the right attachment point is connected to LBM, or a pharmaceutically acceptable salt thereof.

[1040] Embodiment 131.L is

[1041] [ka] wherein the left attachment point is connected to the -S(O)2- group and the right attachment point is connected to LBM, or a pharmaceutically acceptable salt thereof.

[1042] Embodiment 132.L is

[1043] [ka] wherein the left attachment point is connected to the -S(O)2- group and the right attachment point is connected to LBM, or a pharmaceutically acceptable salt thereof.

[1044] Embodiment 133.L is

[1045] [ka] wherein the left attachment point is connected to the -S(O)2- group and the right attachment point is connected to LBM, or a pharmaceutically acceptable salt thereof.

[1046] Embodiment 134.L is

[1047] [ka] wherein the left attachment point is connected to the -S(O)2- group and the right attachment point is connected to LBM, or a pharmaceutically acceptable salt thereof.

[1048] Embodiment 135.L is

[1049] [ka] wherein the left attachment point is connected to the -S(O)2- group and the right attachment point is connected to LBM, or a pharmaceutically acceptable salt thereof.

[1050] Embodiment 136.L is

[1051] [ka] wherein the left attachment point is connected to the -S(O)2- group and the right attachment point is connected to LBM, or a pharmaceutically acceptable salt thereof.

[1052] Embodiment 137.L is

[1053] [ka] wherein the left attachment point is connected to the -S(O)2- group and the right attachment point is connected to LBM, or a pharmaceutically acceptable salt thereof.

[1054] Embodiment 138.L is

[1055] [ka] wherein the left attachment point is connected to the -S(O)2- group and the right attachment point is connected to LBM, or a pharmaceutically acceptable salt thereof.

[1056] Embodiment 139.L is

[1057] [ka] wherein the left attachment point is connected to the -S(O)2- group and the right attachment point is connected to LBM, or a pharmaceutically acceptable salt thereof.

[1058] Embodiment 140.L is

[1059] [ka] wherein the left attachment point is connected to the -S(O)2- group and the right attachment point is connected to LBM, or a pharmaceutically acceptable salt thereof.

[1060] Embodiment 141.L is

[1061] [ka] wherein the left attachment point is connected to the -S(O)2- group and the right attachment point is connected to LBM, or a pharmaceutically acceptable salt thereof.

[1062] Embodiment 142.L is

[1063] [ka] wherein the left attachment point is connected to the -S(O)2- group and the right attachment point is connected to LBM, or a pharmaceutically acceptable salt thereof.

[1064] Embodiment 143.L is

[1065] [ka] wherein the left attachment point is connected to the -S(O)2- group and the right attachment point is connected to LBM, or a pharmaceutically acceptable salt thereof.

[1066] Embodiment 144.L is

[1067] [ka] wherein the left attachment point is connected to the -S(O)2- group and the right attachment point is connected to LBM, or a pharmaceutically acceptable salt thereof.

[1068] Embodiment 145.L is

[1069] [ka] wherein the left attachment point is connected to the -S(O)2- group and the right attachment point is connected to LBM, or a pharmaceutically acceptable salt thereof.

[1070] Embodiment 146.L is

[1071] [ka] wherein the left attachment point is connected to the -S(O)2- group and the right attachment point is connected to LBM, or a pharmaceutically acceptable salt thereof.

[1072] Embodiment 147.L is

[1073] [ka] wherein the left attachment point is connected to the -S(O)2- group and the right attachment point is connected to LBM, or a pharmaceutically acceptable salt thereof.

[1074] Embodiment 148.L is

[1075] [ka] wherein the left attachment point is connected to the -S(O)2- group and the right attachment point is connected to LBM, or a pharmaceutically acceptable salt thereof.

[1076] Embodiment 149.L is

[1077] [ka] wherein the left attachment point is connected to the -S(O)2- group and the right attachment point is connected to LBM, or a pharmaceutically acceptable salt thereof.

[1078] Embodiment 150.L is

[1079] [ka] wherein the left attachment point is connected to the -S(O)2- group and the right attachment point is connected to LBM, or a pharmaceutically acceptable salt thereof.

[1080] Embodiment 151.L is

[1081] [ka] wherein the left attachment point is connected to the -S(O)2- group and the right attachment point is connected to LBM, or a pharmaceutically acceptable salt thereof.

[1082] Embodiment 152.L is

[1083] [ka] wherein the left attachment point is connected to the -S(O)2- group and the right attachment point is connected to LBM, or a pharmaceutically acceptable salt thereof.

[1084] Embodiment 153.L is

[1085] [ka] wherein the left attachment point is connected to the -S(O)2- group and the right attachment point is connected to LBM, or a pharmaceutically acceptable salt thereof.

[1086] Embodiment 154.L is

[1087] [ka] wherein the left attachment point is connected to the -S(O)2- group and the right attachment point is connected to LBM, or a pharmaceutically acceptable salt thereof.

[1088] Embodiment 155.L is

[1089] [ka] wherein the left attachment point is connected to the -S(O)2- group and the right attachment point is connected to LBM, or a pharmaceutically acceptable salt thereof.

[1090] Embodiment 156.L is

[1091] [ka] wherein the left attachment point is connected to the -S(O)2- group and the right attachment point is connected to LBM, or a pharmaceutically acceptable salt thereof.

[1092] Embodiment 157.L is

[1093] [ka] wherein the left attachment point is connected to the -S(O)2- group and the right attachment point is connected to LBM, or a pharmaceutically acceptable salt thereof.

[1094] Embodiment 158.L is

[1095] [ka] wherein the left attachment point is connected to the -S(O)2- group and the right attachment point is connected to LBM, or a pharmaceutically acceptable salt thereof.

[1096] Embodiment 159.L is

[1097] [ka] wherein the left attachment point is connected to the -S(O)2- group and the right attachment point is connected to LBM, or a pharmaceutically acceptable salt thereof.

[1098] Embodiment 160.L is

[1099] [ka] wherein the left attachment point is connected to the -S(O)2- group and the right attachment point is connected to LBM, or a pharmaceutically acceptable salt thereof.

[1100] Embodiment 161.L is

[1101] [ka] wherein the left attachment point is connected to the -S(O)2- group and the right attachment point is connected to LBM, or a pharmaceutically acceptable salt thereof.

[1102] Embodiment 162.L is

[1103] [ka] wherein the left attachment point is connected to the -S(O)2- group and the right attachment point is connected to LBM, or a pharmaceutically acceptable salt thereof.

[1104] Embodiment 163.L is

[1105] [ka] wherein the left attachment point is connected to the -S(O)2- group and the right attachment point is connected to LBM, or a pharmaceutically acceptable salt thereof.

[1106] Embodiment 164.L is

[1107] [ka] wherein the left attachment point is connected to the -S(O)2- group and the right attachment point is connected to LBM, or a pharmaceutically acceptable salt thereof.

[1108] Embodiment 165.L is

[1109] [ka] wherein the left attachment point is connected to the -S(O)2- group and the right attachment point is connected to LBM, or a pharmaceutically acceptable salt thereof.

[1110] Embodiment 166.L is

[1111] [ka] wherein the left attachment point is connected to the -S(O)2- group and the right attachment point is connected to LBM, or a pharmaceutically acceptable salt thereof.

[1112] Embodiment 167.L is

[1113] [ka] wherein the left attachment point is connected to the -S(O)2- group and the right attachment point is connected to LBM, or a pharmaceutically acceptable salt thereof.

[1114] Embodiment 168.L is

[1115] [ka] wherein the left attachment point is connected to the -S(O)2- group and the right attachment point is connected to LBM, or a pharmaceutically acceptable salt thereof.

[1116] Embodiment 169.L is

[1117] [ka] wherein the left attachment point is connected to the -S(O)2- group and the right attachment point is connected to LBM, or a pharmaceutically acceptable salt thereof.

[1118] Embodiment 170.L is

[1119] [ka] wherein the left attachment point is connected to the -S(O)2- group and the right attachment point is connected to LBM, or a pharmaceutically acceptable salt thereof.

[1120] Embodiment 171.L is

[1121] [ka] wherein the left attachment point is connected to the -S(O)2- group and the right attachment point is connected to LBM, or a pharmaceutically acceptable salt thereof.

[1122] Embodiment 172.L is

[1123] [ka] wherein the left attachment point is connected to the -S(O)2- group and the right attachment point is connected to LBM, or a pharmaceutically acceptable salt thereof.

[1124] Embodiment 173.L is

[1125] [ka] wherein the left attachment point is connected to the -S(O)2- group and the right attachment point is connected to LBM, or a pharmaceutically acceptable salt thereof.

[1126] Embodiment 174.L is

[1127] [ka] wherein the left attachment point is connected to the -S(O)2- group and the right attachment point is connected to LBM, or a pharmaceutically acceptable salt thereof.

[1128] Embodiment 175.L is

[1129] [ka] wherein the left attachment point is connected to the -S(O)2- group and the right attachment point is connected to LBM, or a pharmaceutically acceptable salt thereof.

[1130] Embodiment 176.L is

[1131] [ka] wherein the left attachment point is connected to the -S(O)2- group and the right attachment point is connected to LBM, or a pharmaceutically acceptable salt thereof.

[1132] Embodiment 177.L is

[1133] [ka] wherein the left attachment point is connected to the -S(O)2- group and the right attachment point is connected to LBM, or a pharmaceutically acceptable salt thereof.

[1134] Embodiment 178.L is

[1135] [ka] wherein the left attachment point is connected to the -S(O)2- group and the right attachment point is connected to LBM, or a pharmaceutically acceptable salt thereof.

[1136] Embodiment 179.L is

[1137] [ka] wherein the left attachment point is connected to the -S(O)2- group and the right attachment point is connected to LBM, or a pharmaceutically acceptable salt thereof.

[1138] Embodiment 180.L is

[1139] [ka] wherein the left attachment point is connected to the -S(O)2- group and the right attachment point is connected to LBM, or a pharmaceutically acceptable salt thereof.

[1140] Embodiment 181.L is

[1141] [ka] wherein the left attachment point is connected to the -S(O)2- group and the right attachment point is connected to LBM, or a pharmaceutically acceptable salt thereof.

[1142] Embodiment 182.L is

[1143] [ka] wherein the left attachment point is connected to the -S(O)2- group and the right attachment point is connected to LBM, or a pharmaceutically acceptable salt thereof.

[1144] Embodiment 183.L is

[1145] [ka] wherein the left attachment point is connected to the -S(O)2- group and the right attachment point is connected to LBM, or a pharmaceutically acceptable salt thereof.

[1146] Embodiment 184.L is

[1147] [ka] wherein the left attachment point is connected to the -S(O)2- group and the right attachment point is connected to LBM, or a pharmaceutically acceptable salt thereof.

[1148] Embodiment 185.L is

[1149] [ka] wherein the left attachment point is connected to the -S(O)2- group and the right attachment point is connected to LBM, or a pharmaceutically acceptable salt thereof.

[1150] Embodiment 186.L is

[1151] [ka] wherein the left attachment point is connected to the -S(O)2- group and the right attachment point is connected to LBM, or a pharmaceutically acceptable salt thereof.

[1152] Embodiment 187.L is

[1153] [ka] wherein the left attachment point is connected to the -S(O)2- group and the right attachment point is connected to LBM, or a pharmaceutically acceptable salt thereof.

[1154] Embodiment 188.L is

[1155] [ka] wherein the left attachment point is connected to the -S(O)2- group and the right attachment point is connected to LBM, or a pharmaceutically acceptable salt thereof.

[1156] Embodiment 189.L is

[1157] [ka] wherein the left attachment point is connected to the -S(O)2- group and the right attachment point is connected to LBM, or a pharmaceutically acceptable salt thereof.

[1158] Embodiment 190.L is

[1159] [ka] wherein the left attachment point is connected to the -S(O)2- group and the right attachment point is connected to LBM, or a pharmaceutically acceptable salt thereof.

[1160] Embodiment 191.L is

[1161] [ka] wherein the left attachment point is connected to the -S(O)2- group and the right attachment point is connected to LBM, or a pharmaceutically acceptable salt thereof.

[1162] Embodiment 192.L is

[1163] [ka] wherein the left attachment point is connected to the -S(O)2- group and the right attachment point is connected to LBM, or a pharmaceutically acceptable salt thereof.

[1164] Embodiment 193.L is

[1165] [ka] wherein the left attachment point is connected to the -S(O)2- group and the right attachment point is connected to LBM, or a pharmaceutically acceptable salt thereof.

[1166] Embodiment 194.L is

[1167] [ka] wherein the left attachment point is connected to the -S(O)2- group and the right attachment point is connected to LBM, or a pharmaceutically acceptable salt thereof.

[1168] Embodiment 195.L is

[1169] [ka] wherein the left attachment point is connected to the -S(O)2- group and the right attachment point is connected to LBM, or a pharmaceutically acceptable salt thereof.

[1170] Embodiment 196.L is

[1171] [ka] wherein the left attachment point is connected to the -S(O)2- group and the right attachment point is connected to LBM, or a pharmaceutically acceptable salt thereof.

[1172] Embodiment 197.L is

[1173] [ka] wherein the left attachment point is connected to the -S(O)2- group and the right attachment point is connected to LBM, or a pharmaceutically acceptable salt thereof.

[1174] In an embodiment 198.Cy,

[1175] [ka] are selected from R Cwhere the left attachment point is L 1 The right-hand attachment point is L 2 198. The compound of any one of embodiments 1-121 and 197, or a pharmaceutically acceptable salt thereof, wherein

[1176] In an embodiment 199.Cy,

[1177] [ka] each of which is not further substituted, wherein the left attachment point is L 1 The right-hand attachment point is L 2 199. The compound of any one of embodiments 1-121, 197, and 198, or a pharmaceutically acceptable salt thereof, wherein

[1178] Embodiment 200.Cy

[1179] [ka] each of which is not further substituted, wher...

Claims

1. Formula A 【Chemistry 1】 or a pharmaceutically acceptable salt thereof, wherein Ring A is phenyl, 3- to 14-membered cycloalkyl, or 4- to 14-membered heterocyclyl containing 1-3 heteroatoms independently selected from N, O, and S; R １ is -C １－６ Alkyl, -C ２－６ Alkenyl, -C ２－６ Alkynyl, —C １－６ Haloalkyl, —C １－６ Heteroalkyl, —C ３ - １４ cycloalkyl, 6- to 14-membered aryl, 4- to 14-membered heterocyclyl, 5- to 14-membered heteroaryl, —C １－４ Alkyl-C ３－１４ cycloalkyl, —C １－４ alkyl-(6- to 14-membered aryl), -C １－４ alkyl-(4- to 14-membered heterocyclyl), and —C １－４ alkyl (5-14 membered heteroaryl), heterocyclyl and heteroaryl each containing 1-3 heteroatoms independently selected from N, O, and S, and alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl each selected from R ６ is replaced by 0, 1, 2, 3, or 4 instances of R ２ and R ３ are each independently -C １－６ Alkyl, -C １－６ Haloalkyl, —C １－６ Heteroalkyl, —C ２－６ Alkenyl, -C ２－６ Alkynyl, —C ３－７ cycloalkyl, phenyl, 4- to 7-membered heterocyclyl, and 5- to 6-membered heteroaryl, wherein said heterocyclyl and said heteroaryl each contain 1-3 heteroatoms independently selected from N, O, and S; and wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl each are selected from R Ｂ is replaced by 0, 1, 2, 3, or 4 instances of Or R ２ and R ３ together with the carbon atoms to which they are attached form ring B, ring B being a 3- to 7-membered cycloalkyl ring or a 4- to 7-membered heterocyclyl ring containing 1 or 3 heteroatoms independently selected from N, O, and S, ring B being R Ｂ is replaced by 0, 1, 2, 3, or 4 instances of L is a covalent bond or a divalent, saturated, or unsaturated, straight or branched chain C １－５０ is a hydrocarbon chain, and 0 to 6 methylene units of L are independently -Cy-, -CH(R)-, -C(R) ２ -, -O-, -NR-, -S-, -OC(=O)-, -C(=O)O-, -C(=O)-, -S(=O)-, -S(=O) ２ -, -NRS (=O) ２ -, -S(=O) ２ replaced with NR—, —NRC(═O)—, —C(═O)NR—, —OC(═O)NR—, or —NRC(═O)O—; -Cy- is independently selected from phenylene, 8- to 10-membered bicyclic arylene, 4- to 7-membered monocyclic carbocyclylene, 5- to 11-membered spirocarbocyclylene, 4- to 10-membered bicyclic carbocyclylene, 5- to 10-membered bridged carbocyclylene, 4- to 7-membered monocyclic heterocyclylene having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 11-membered spiroheterocyclylene having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 4- to 10-membered monocyclic heterocyclylene having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 11-membered spiroheterocyclylene having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 11-membered aryl ... a 5- to 10-membered bridged bicyclic saturated or partially unsaturated heterocyclylene having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5- to 6-membered heteroarylene having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an 8- to 10-membered bicyclic heteroarylene having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and phenylene, arylene, carbocyclylene, heterocyclylene, and heteroarylene are each selected from R Ｃ is replaced by 0, 1, 2, 3, or 4 instances of LMB is 【Chemistry 2】 is selected from R Ａ , R Ｂ , R Ｃ , R ４ , R ５ , and R ６ Each of the entities may independently be oxo, deuterium, halogen, or —C １－６ Alkyl, -C １－６ Heteroalkyl, —C １－６ Haloalkyl, —C ２－６ Alkenyl, -C ２－６ Alkynyl, —CN, —NO ２ , -OR, -SR, -NR ２ , -S(O) ２ R, -S(O) ２ NR ２ , -S(O)R, -S(O)NR ２ , -S(O)(NR)R, -S(O)(NCN)R, -S(NCN)R, -C(O)R, -C(O)OR, -C(O)NR ２ , -C(O)N(R)OR, -OC(O)R, -OC(O)NR ２ , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR ２ , -N(R)C(NR)NR ２ , -N(R)S(O) ２ NR ２ , -N(R)S(O) ２ R, -P(O)R ２ , -P(O)(R)OR 、 -C ３－７ selected from cycloalkyl, phenyl, 4- to 7-membered heterocyclyl, and 5- to 6-membered heteroaryl, wherein said heterocyclyl and said heteroaryl each contain 1-3 heteroatoms independently selected from N, O, and S; Each instance of R is independently hydrogen, —C １－６ Alkyl, -C １－６ Haloalkyl, —C １－６ Heteroalkyl, —C ２－６ Alkenyl, -C ２－６ Alkynyl, —C ３－７ cycloalkyl, phenyl, 4- to 7-membered heterocyclyl, and 5- to 6-membered heteroaryl, wherein said heterocyclyl and said heteroaryl each contain 1-3 heteroatoms independently selected from N, O, and S, or two R groups attached to the same nitrogen optionally join with the nitrogen to which they are attached to form an optionally substituted 4- to 7-membered heterocyclyl having 0, 1, or 2 additional heteroatoms independently selected from N, O, and S; n is 0, 1, 2, 3, or 4; r is 0, 1, 2, 3, or 4; s is 0, 1, 2, 3, or 4, or a pharmaceutically acceptable salt thereof.

2. Formula B 【Transformation 3】 wherein ring B is a 3- to 7-membered cycloalkyl ring or a 4- to 7-membered heterocyclyl ring containing 1 or 3 heteroatoms independently selected from N, O, and S, or a pharmaceutically acceptable salt thereof.

3. Formula I or Formula I-1 【Chemistry 4】 or a pharmaceutically acceptable salt thereof, wherein R １ is -C １－６ Alkyl, -C ２－６ Alkenyl, -C ２－６ Alkynyl, —C １－６ Haloalkyl, —C １－６ Heteroalkyl, —C ３ - １４ cycloalkyl, 6- to 14-membered aryl, 4- to 14-membered heterocyclyl, 5- to 14-membered heteroaryl, —C １－４ Alkyl-C ３－１４ cycloalkyl, —C １－４ alkyl-(6- to 14-membered aryl), -C １－４ alkyl-(4- to 14-membered heterocyclyl), and —C １－４ alkyl (5-14 membered heteroaryl), heterocyclyl and heteroaryl each containing 1-3 heteroatoms independently selected from N, O, and S, and alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl each selected from R ６ is replaced by 0, 1, 2, 3, or 4 instances of L is a covalent bond or a divalent, saturated, or unsaturated, straight or branched chain C １－５０ is a hydrocarbon chain, and 0 to 6 methylene units of L are independently -Cy-, -CH(R)-, -C(R) ２ -, -O-, -NR-, -S-, -OC(=O)-, -C(=O)O-, -C(=O)-, -S(=O)-, -S(=O) ２ -, -NRS (=O) ２ -, -S(=O) ２ replaced with NR—, —NRC(═O)—, —C(═O)NR—, —OC(═O)NR—, or —NRC(═O)O—; -Cy- is independently selected from phenylene, 8- to 10-membered bicyclic arylene, 4- to 7-membered monocyclic carbocyclylene, 5- to 11-membered spirocarbocyclylene, 4- to 10-membered bicyclic carbocyclylene, 5- to 10-membered bridged carbocyclylene, 4- to 7-membered monocyclic heterocyclylene having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 11-membered spiroheterocyclylene having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 4- to 10-membered monocyclic heterocyclylene having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 11-membered spiroheterocyclylene having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 11-membered aryl ... a 5- to 10-membered bridged bicyclic saturated or partially unsaturated heterocyclylene having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5- to 6-membered heteroarylene having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an 8- to 10-membered bicyclic heteroarylene having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and phenylene, arylene, carbocyclylene, heterocyclylene, and heteroarylene are each selected from R Ｃ is replaced by 0, 1, 2, 3, or 4 instances of LMB is 【Transformation 5】 is selected from R Ａ , R Ｂ , R Ｃ , R ４ , R ５ , and R ６ Each of the entities may independently be oxo, deuterium, halogen, or —C １－６ Alkyl, -C １－６ Heteroalkyl, —C １－６ Haloalkyl, —C ２－６ Alkenyl, -C ２－６ Alkynyl, —CN, —NO ２ , -OR, -SR, -NR ２ , -S(O) ２ R, -S(O) ２ NR ２ , -S(O)R, -S(O)NR ２ , -S(O)(NR)R, -S(O)(NCN)R, -S(NCN)R, -C(O)R, -C(O)OR, -C(O)NR ２ , -C(O)N(R)OR, -OC(O)R, -OC(O)NR ２ , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR ２ , -N(R)C(NR)NR ２ , -N(R)S(O) ２ NR ２ , -N(R)S(O) ２ R, -P(O)R ２ , -P(O)(R)OR 、 -C ３－７ selected from cycloalkyl, phenyl, 4- to 7-membered heterocyclyl, and 5- to 6-membered heteroaryl, wherein said heterocyclyl and said heteroaryl each contain 1-3 heteroatoms independently selected from N, O, and S; Each instance of R is independently hydrogen, —C １－６ Alkyl, -C １－６ Haloalkyl, —C １－６ Heteroalkyl, —C ２－６ Alkenyl, -C ２－６ Alkynyl, —C ３－７ cycloalkyl, phenyl, 4- to 7-membered heterocyclyl, and 5- to 6-membered heteroaryl, wherein said heterocyclyl and said heteroaryl each contain 1-3 heteroatoms independently selected from N, O, and S, or two R groups attached to the same nitrogen optionally join with the nitrogen to which they are attached to form an optionally substituted 4- to 7-membered heterocyclyl having 0, 1, or 2 additional heteroatoms independently selected from N, O, and S; m is 0, 1, 2, 3, or 4; n is 0, 1, 2, 3, or 4; r is 0, 1, 2, 3, or 4; s is 0, 1, 2, 3, or 4, or a pharmaceutically acceptable salt thereof.

4. 4. The compound of claim 3, which is a compound of Formula I, or a pharmaceutically acceptable salt thereof.

5. 4. The compound of claim 3, which is a compound of formula I-1, or a pharmaceutically acceptable salt thereof.

6. Formula IA 【Transformation 6】 4. The compound of claim 3, which is a compound of the formula: or a pharmaceutically acceptable salt thereof.

7. Formula I-B 【Transformation 7】 4. The compound of claim 3, which is a compound of the formula: or a pharmaceutically acceptable salt thereof.

8. Formula IC 【Transformation 8】 4. The compound of claim 3, which is a compound of the formula: or a pharmaceutically acceptable salt thereof.

9. Formula I-1-B 【Chemistry 9】 4. The compound of claim 3, which is a compound of the formula: or a pharmaceutically acceptable salt thereof.

10. R １ But, -C ３－７ Cycloalkyl, phenyl, and —C １－４ Alkyl-C ３－１４ cycloalkyl, each R ６ 10. The compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, substituted with 0, 1, 2, 3, or 4 instances of:

11. R １ But, R ６ C substituted with 0, 1, 2, 3, or 4 instances of ３－７ 10. The compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, which is cycloalkyl.

12. R １ is cyclopentyl, cyclohexyl, phenyl, or —CH(CH ３ )-cyclopropyl, and each R ６ 10. The compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, substituted with 0, 1, 2, 3, or 4 instances of:

13. R １ is cyclopentyl or cyclohexyl, and R ６ 10. The compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, substituted with 0, 1, 2, 3, or 4 instances of:

14. R １ But, R ６ 10. The compound of any one of claims 1 to 9, wherein R is cyclopentyl substituted with 0, 1, 2, 3, or 4 instances of: or a pharmaceutically acceptable salt thereof.

15. Formula II-A 【Chemistry 10】 is a compound of 5. The compound of claim 3 or 4, wherein p is 0, 1, 2, 3, or 4, or a pharmaceutically acceptable salt thereof.

16. Formula II-B 【Chemistry 11】 is a compound of 5. The compound of claim 3 or 4, wherein p is 0, 1, 2, 3, or 4, or a pharmaceutically acceptable salt thereof.

17. Formula II-C 【Chemistry 12】 is a compound of 5. The compound of claim 3 or 4, wherein p is 0, 1, 2, 3, or 4, or a pharmaceutically acceptable salt thereof.

18. Formula II-1-B 【Chemistry 13】 is a compound of 6. The compound of claim 3 or 5, wherein p is 0, 1, 2, 3, or 4, or a pharmaceutically acceptable salt thereof.

19. R １ But, R ６ 10. The compound of any one of claims 1 to 9, wherein R is 1, 2, 3, or 4 of the following: or a pharmaceutically acceptable salt thereof.

20. Formula K 【Chemistry 14】 is a compound of 3. The compound of claim 1 or 2, wherein p is 0, 1, 2, 3, or 4, or a pharmaceutically acceptable salt thereof.

21. Formula IV-A 【Chemistry 15】 is a compound of 5. The compound of claim 3 or 4, wherein p is 0, 1, 2, 3, or 4, or a pharmaceutically acceptable salt thereof.

22. Formula IV-B 【Chemistry 16】 is a compound of 5. The compound of claim 3 or 4, wherein p is 0, 1, 2, 3, or 4, or a pharmaceutically acceptable salt thereof.

23. Formula IV-C 【Chemistry 17】 is a compound of 5. The compound of claim 3 or 4, wherein p is 0, 1, 2, 3, or 4, or a pharmaceutically acceptable salt thereof.

24. Formula IV-1-B [Chemistry 18] 6. The compound of claim 3 or 5, wherein p is 0, 1, 2, 3, or 4, or a pharmaceutically acceptable salt thereof.

25. R ６ is halo, -OH, and -C １－６ 25. The compound of any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, wherein:

26. R ６ 25. The compound of any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, wherein is selected from -OH and -Me.

27. R ６ The compound of any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, wherein is -OH.

28. R ６ 25. The compound of any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, wherein is -Me.

29. R １ 10. The compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein is selected from 2-methylcyclopentyl and 3-hydroxycyclohexyl.

30. R １ The compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein is 3-hydroxycyclohexyl.

31. R １ The compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein is 2-methylcyclopentyl.

32. R １ but, 【Chemistry 19】 10. The compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, selected from:

33. R １ but, 【Chemistry 20】 10. The compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, selected from:

34. R １ but, 【Chemistry 21】 10. The compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, selected from:

35. R １ but, 【Chemistry 22】 10. The compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, selected from:

36. Formula M 【Chemistry 23】 3. The compound of claim 1 or 2, which is a compound of the formula: or a pharmaceutically acceptable salt thereof.

37. Formula III-A 【Chemistry 24】 5. The compound of claim 3 or 4, which is a compound of the formula: or a pharmaceutically acceptable salt thereof.

38. Formula III-B 【Chemistry 25】 5. The compound of claim 3 or 4, which is a compound of the formula: or a pharmaceutically acceptable salt thereof.

39. Formula III-F 【Chemistry 26】 5. The compound of claim 3 or 4, which is a compound of the formula: or a pharmaceutically acceptable salt thereof.

40. Formula III-1-B 【Chemistry 27】 6. The compound of claim 3 or 5, which is a compound of the formula: or a pharmaceutically acceptable salt thereof.

41. Formula V-D 【Chemistry 28】 5. The compound of claim 3 or 4, which is a compound of the formula: or a pharmaceutically acceptable salt thereof.

42. Formula VE 【Chemistry 29】 5. The compound of claim 3 or 4, which is a compound of the formula: or a pharmaceutically acceptable salt thereof.

43. Formula V-G 【Transformation 30】 5. The compound of claim 3 or 4, which is a compound of the formula: or a pharmaceutically acceptable salt thereof.

44. Formula V-1-E 【Chemistry 31】 6. The compound of claim 3 or 5, which is a compound of the formula: or a pharmaceutically acceptable salt thereof.

45. R Ａ is halogen and -C １－６ 45. The compound of any one of claims 1 to 44, or a pharmaceutically acceptable salt thereof, wherein:

46. R Ａ 45. The compound of any one of claims 1 to 44, or a pharmaceutically acceptable salt thereof, wherein is selected from -F and -Me.

47. R Ａ 45. The compound of any one of claims 1 to 44, or a pharmaceutically acceptable salt thereof, wherein is -F. 【Request Item 48】 【Chemistry 32】 or 【Transformation 33】 The part represented by 【Transformation 34】 45. The compound of any one of claims 1 to 44, or a pharmaceutically acceptable salt thereof, selected from: 【Request Item 49】 【Chemistry 35】 or 【Transformation 36】 The part represented by 【Chemistry 37】 45. The compound of any one of claims 1 to 44, or a pharmaceutically acceptable salt thereof, selected from: 【Request Item 50】 【Chemistry 38】 or 【Chemistry 39】 The part represented by 【Chemistry 40】 45. The compound of any one of claims 1 to 44, or a pharmaceutically acceptable salt thereof, selected from:

51. L, 【Chemistry 41】 【Chemistry 42】 and each R ７ is replaced with 0, 1, 2, or 3 instances of R ７ are each independently -C １－４ selected from alkyl and halo; In the formula, the left attachment point is -S(O) ２ - group, and the right attachment point is connected to the LBM, L １ and L ２ are each independently selected from a bond and —N(R′), where R′ is H and C １ - ６ alkyl, 51. The compound of any one of claims 1 to 50, or a pharmaceutically acceptable salt thereof, wherein q is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

52. R ７ are each independently -Me, - ｉ 52. The compound of claim 51, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from -Pr, and -F.

53. R ７ is each independently selected from -Me and -F, or a pharmaceutically acceptable salt thereof.

54. L, 【Chemistry 43】 【Chemistry 44】 【Chemistry 45】 is selected from In the formula, the left attachment point is -S(O) ２ - group, and the right attachment point is connected to the LBM, L １ and L ２ are each independently selected from a bond and —N(R′), where R′ is H and C １ - ６ alkyl, 51. The compound of any one of claims 1 to 50, or a pharmaceutically acceptable salt thereof, wherein q is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

55. L, 【Chemistry 46】 and each R ７ is replaced by zero, one, two, or three instances of In the formula, the left attachment point is -S(O) ２ 54. The compound of any one of claims 51 to 53, or a pharmaceutically acceptable salt thereof, wherein the - group is connected to the - group and the right attachment point is connected to the LBM.

56. L, 【Chemistry 47】 where the left attachment point is -S(O) ２ 51. The compound of any one of claims 1 to 50, or a pharmaceutically acceptable salt thereof, wherein the - group is connected to the - group and the right attachment point is connected to the LBM.

57. Cy is, 【Chemistry 48】 each of which is not further substituted, wherein the left attachment point is L １ The right-hand attachment point is L ２ 57. The compound of any one of claims 1 to 54 and 56, or a pharmaceutically acceptable salt thereof, wherein [Request Item 58] [Chemistry 49] but, [Transformation 50] wherein the left attachment point is selected from -S(O) ２ 57. The compound of any one of claims 51 to 54 and 56, or a pharmaceutically acceptable salt thereof, wherein the right attachment point is attached to LBM.

59. R ４ are each independently deuterium, halogen, -C １－６ Alkyl, -C １－６ Haloalkyl, —CN, —OR, —NR ２ , -S(O) ２ R, -S(O) ２ NR ２ , -S(O)R, -S(O)NR ２ , -S(O)(NR)R, -C(O)NR ２ , -C(O)N(R)OR, -OC(O)NR ２ , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR ２ , -N(R)S(O) ２ NR ２ , and —N(R)S(O) ２ R, where R is H or C １－６ 59. The compound of any one of claims 1 to 58, or a pharmaceutically acceptable salt thereof, which is alkyl.

60. R ４ are each independently -Me, -Et, -F, -Cl, or -CF ３ , -CN, -OH, -OMe, -NH ２ , -NHMe, and -NMe ２ 59. The compound of any one of claims 1 to 58, or a pharmaceutically acceptable salt thereof, selected from:

61. R ４ is each independently selected from -Me and -F, or a pharmaceutically acceptable salt thereof.

62. R ５ are each independently deuterium, halo, halogen, —CN, —OR, or —NR ２ , -S(O) ２ R, -S(O) ２ NR ２ , -S(O)R, -S(O)NR ２ , -S(O)(NR)R, -C(O)NR ２ , -C(O)N(R)OR, -OC(O)NR ２ , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR ２ , -N(R)S(O) ２ NR ２ , and —N(R)S(O) ２ C substituted with 0 to 3 instances of R １－６ aliphatic chains, R is H or C １－６ 62. The compound of any one of claims 1 to 61, or a pharmaceutically acceptable salt thereof, which is alkyl.

63. R ５ are each independently -Me, -Et, -F, -Cl, or -CF ３ , -CN, -OH, -OMe, -NH ２ , -NHMe, and -NMe ２ 62. The compound of any one of claims 1 to 61, or a pharmaceutically acceptable salt thereof, selected from:

64. R ５ is each independently selected from -Me and -F, or a pharmaceutically acceptable salt thereof.

65. 65. The compound of any one of claims 1 to 64, or a pharmaceutically acceptable salt thereof, wherein r is 0, 1, or 2.

66. 65. The compound of any one of claims 1 to 64, or a pharmaceutically acceptable salt thereof, wherein r is 0.

67. 65. The compound of any one of claims 1 to 64, or a pharmaceutically acceptable salt thereof, wherein r is 1.

68. 65. The compound of any one of claims 1 to 64, or a pharmaceutically acceptable salt thereof, wherein r is 2.

69. 65. The compound of any one of claims 1 to 64, or a pharmaceutically acceptable salt thereof, wherein s is 0, 1, or 2.

70. 65. The compound of any one of claims 1 to 64, or a pharmaceutically acceptable salt thereof, wherein s is 0.

71. 65. The compound of any one of claims 1 to 64, or a pharmaceutically acceptable salt thereof, wherein s is 1.

72. 65. The compound of any one of claims 1 to 64, or a pharmaceutically acceptable salt thereof, wherein s is 2.

73. LBM, 【Chemistry 51】 59. The compound of any one of claims 1 to 58, or a pharmaceutically acceptable salt thereof, selected from:

74. LBM, 【Chemistry 52】 59. The compound of any one of claims 1 to 58, or a pharmaceutically acceptable salt thereof, selected from:

75. The compound is 【Chemistry 53】 【Chemistry 54】 【Transformation 55】 【Transformation 56】 【Chemistry 57】 【Chemistry 58】 【Chemistry 59】 【Transformation 60】 【Chemistry 61】 【Transformation 62】 【Transformation 63】 【Chemistry 64】 【Transformation 65】 【Chemical Formula 66】 【Transformation 67】 【Transformation 68】 【Transformation 69】 【Transformation 70】 【Chemistry 71】 【Chemistry 72】 【Transformation 73】 【Chemistry 74】 75. The compound of any one of claims 1 to 74, or a pharmaceutically acceptable salt thereof, selected from:

76. 76. A pharmaceutical composition comprising a compound according to any one of claims 1 to 75, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or diluent.

77. A method for inhibiting CDK2 and / or CCNE (CCNE1 and / or CCNE2) signaling in a sample by contacting CDK2 and / or CCNE (CCNE1 and / or CCNE2) with a compound described in any one of claims 1 to 75, or a pharmaceutically acceptable salt thereof, or a composition described in claim 76.

78. 77. A method of inhibiting CDK2 signaling in a sample by contacting CDK2 with a compound according to any one of claims 1 to 75, or a pharmaceutically acceptable salt thereof, or a composition according to claim 76.

79. A method for inhibiting CCNE (CCNE1 and / or CCNE2) signaling in a sample by contacting CCNE (CCNE1 and / or CCNE2) with a compound described in any one of claims 1 to 75, or a pharmaceutically acceptable salt thereof, or a composition described in claim 76.

80. A method for inhibiting CDK2 and CCNE (CCNE1 and / or CCNE2) signaling in a sample by contacting CDK2 and / or CCNE (CCNE1 and / or CCNE2) with a compound described in any one of claims 1 to 75, or a pharmaceutically acceptable salt thereof, or a composition described in claim 76.

81. 77. A method of treating a CDK2 and / or CCNE (CCNE1 and / or CCNE2) mediated disorder in a patient in need thereof, comprising administering to said patient a compound of any one of claims 1 to 75, or a pharmaceutically acceptable salt thereof, or a composition of claim 76.

82. 82. The method of claim 81, wherein the CDK2 and / or CCNE (CCNE1 and / or CCNE2) mediated disorder is cancer.

83. 77. A method of treating a CDK2-mediated disorder in a patient in need thereof, comprising administering to said patient a compound according to any one of claims 1 to 75, or a pharmaceutically acceptable salt thereof, or a composition according to claim 76.

84. 84. The method of claim 83, wherein the CDK2-mediated disorder is cancer.

85. 76. A method of treating a CCNE (CCNE1 and / or CCNE2) mediated disorder in a patient in need thereof, comprising administering to said patient a compound of any one of claims 1 to 75, or a pharmaceutically acceptable salt thereof, or a composition of claim 76.

86. 86. The method of claim 85, wherein the CCNE (CCNE1 and / or CCNE2) mediated disorder is cancer.

87. 77. A method of treating a CDK2 and CCNE (CCNE1 and / or CCNE2) mediated disorder in a patient in need thereof, comprising administering to said patient a compound of any one of claims 1 to 75, or a pharmaceutically acceptable salt thereof, or a composition of claim 76.

88. 88. The method of claim 87, wherein the CCNE (CCNE1 and / or CCNE2) mediated disorder is cancer.

89. 89. The method of any one of claims 82, 84, 86, and 88, wherein the cancer is selected from ovarian cancer, gastric cancer, uterine cancer, and breast cancer.

90. 90. The method of any one of claims 82, 84, 86, 88, and 89, wherein the cancer is resistant to treatment with a CDK4 / 6 inhibitor.

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