The present disclosure also relates to, in part, methods and compositions for treating anti-TNFa resistance in a subject with an NLRP3 antagonist. The present disclosure also relates, in part, to methods, combinations and compositions for treating TFN ^ related diseases and anti-TNFa resistance in a subject that include administration of an NLRP3 antagonist, an NLRP3 antagonist and an anti-TNFa agent, or a composition encompassing an NLRP3 antagonist and an anti-TNFa agent. BACKGROUND The NLRP3 inflammasome is a component of the inflammatory process and its aberrant activation is pathogenic in inherited disorders such as the cryopyrin associated periodic syndromes (CAPS). The inherited CAPS Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS) and neonatal onset multi-system inflammatory disease (NOMID) are examples of indications that have been reported to be associated with gain of function mutations in NLRP3.

NLRP3 can form a complex and has been implicated in the pathogenesis of a number of complex diseases, including but not limited to metabolic disorders such as type 2 diabetes, atherosclerosis, obesity and gout, as well as diseases of the central nervous system, such as Alzheimer’s disease and multiple sclerosis and Amyotrophic Lateral Sclerosis and Parkinson disease, lung disease, such as asthma and COPD and pulmonary idiopathic fibrosis, liver disease, such as NASH syndrome, viral hepatitis and cirrhosis, pancreatic disease, such as acute and chronic pancreatitis, kidney disease, such as acute and chronic kidney injury, intestinal disease such as Crohn’s disease and Ulcerative Colitis, skin disease such as psoriasis, musculoskeletal disease such as scleroderma, vessel disorders, such as giant cell arteritis, disorders of the bones, such as Osteoarthritis , osteoporosis and osteopetrosis disorders eye disease, such as glaucoma and macular degeneration, diseased caused by viral infection such as HIV and AIDS, autoimmune disease such as Rheumatoid Arthritis, Systemic Lupus Erythematosus, Autoimmune Thyroiditis, Addison's disease, pernicious anemia, cancer and aging.

In light of the above, it would be desirable to provide compounds that modulate (e.g., antagonize) NLRP3.

Separately, several patients having inflammatory or autoimmune diseases are treated with anti-TNFa agents. A subpopulation of such patients develop resistance to treatment with the anti-TNFa agents. It is desirable to develop methods for reducing a patient’s resistance to anti-TNFa agents. In light of the this, it would also be desirable to provide alternative therapies for treating inflammatory or autoimmune diseases (for example NLRP3 inflammasome inhibitors) to avoid or minimise the use of anti-TNFa agents.

Intestinal bowel disease (IBD), encompassing Ulcerative Colitis (UC) and Crohn’s disease (CD), are chronic diseases characterized by barrier dysfunction and uncontrolled inflammation and mucosal immune reactions in the gut. A number of inflammatory pathways have been implicated in the progression of IBD, and anti-inflammatory therapy such as tumor necrosis factor-alpha (TNF-a) blockade has shown efficacy in the clinic (Rutgeerts P et al N Engl J Med 2005; 353:2462-76). Anti-TNFa therapies, however, do not show complete efficacy, however, other cytokines such as IL-1b, IL-6, IL-12, IL-18, IL-21, and IL-23 have been shown to drive inflammatory disease pathology in IBD (Neurath MF Nat Rev Immunol 2014;14;329-42). IL-1b and IL-18 are produced by the NLRP3 inflammasome in response to pathogenic danger signals, and have been shown to play a role in IBD. Anti-IL-1b therapy is efficacious in patients with IBD driven by genetic mutations in CARD8 or IL-10R (Mao L et al, J Clin Invest 2018;238:1793-1806, Shouval DS et al, Gastroenterology 2016;151:1100- 1104), IL-18 genetic polymorphisms have been linked to UC (Kanai T et al, Curr Drug Targets 2013;14:1392-9), and NLRP3 inflammasome inhibitors have been shown to be efficacious in murine models of IBD (Perera AP et al, Sci Rep 2018;8:8618). Resident gut immune cells isolated from the lamina propria of IBD patients can produce IL-1b, either spontaneously or when stimulated by LPS, and this IL-1b production can be blocked by the ex vivo addition of a NLRP3 antagonist. Based on strong clinical and preclinical evidence showing that inflammasome-driven IL-1b and IL-18 play a role in IBD pathology, it is clear that NLRP3 inflammasome inhibitors could be an efficacious treatment option for UC, Crohn’s disease, or subsets of IBD patients. These subsets of patients could be defined by their peripheral or gut levels of inflammasome related cytokines including IL-1b, IL-6, and IL-18, by genetic factors that pre-dispose IBD patients to having NLRP3 inflammasome activation such as mutations in genes including ATG16L1, CARD8, IL-10R, or PTPN2 (Saitoh T et al, Nature 2008;456:264, Spalinger MR, Cell Rep 2018;22:1835), or by other clinical rationale such as non-response to TNF therapy.

Though anti-TNF therapy is an effective treatment option for Crohn’s disease, 40% of patients fail to respond. One-third of non-responsive CD patients fail to respond to anti-TNF therapy at the onset of treatment, while another third lose response to treatment over time (secondary non-response). Secondary non-response can be due to the generation of anti-drug antibodies, or a change in the immune compartment that desensitizes the patient to anti-TNF (Ben-Horin S et al, Autoimmun Rev 2014;13:24-30, Steenholdt C et al Gut 2014;63:919-27). Anti-TNF reduces inflammation in IBD by causing pathogenic T cell apoptosis in the intestine, therefore eliminating the T cell mediated inflammatory response (Van den Brande et al Gut 2007:56:509-17). There is increased NLRP3 expression and increased production of IL-1b in the gut of TNF-non-responsive CD patients (Leal RF et al Gut 2015;64:233-42) compared to TNF-responsive patients, suggesting NLRP3 inflammasome pathway activation. Furthermore, there is increased expression of TNF-receptor 2 (TNF-R2), which allows for TNF-mediated proliferation of T cells (Schmitt H et al Gut 2018;0:1-15). IL-1b signaling in the gut promotes T cell differentiation toward Th1/17 cells which can escape anti-TNF-a mediated apoptosis. It is therefore likely that NLRP3 inflammasome activation can cause non-responsiveness in CD patients to anti-TNF-a therapy by sensitizing pathogenic T cells in the gut to anti-TNF-a mediated apoptosis. Experimental data from immune cells isolated from the gut of TNF-resistant Crohn’s patients show that these cells spontaneously release IL-1b, which can be inhibited by the addition of an NLRP3 antagonist. NLRP3

inflammasome antagonists - in part by blocking IL-1b secretion - would be expected to inhibit the mechanism leading to anti-TNF non-responsiveness, re-sensitizing the patient to anti-TNF therapy. In IBD patients who are naive to anti-TNF therapy, treatment with an NLRP3 antagonist would be expected to prevent primary- and secondary-non responsiveness by blocking the mechanism leading to non-response. NLRP3 antagonists that are efficacious locally in the gut can be efficacious drugs to treat IBD; in particular in the treatment of TNF-resistant CD alone or in combination with anti-TNF therapy. Systemic inhibition of both IL-1b and TNF-a has been shown to increase the risk of opportunistic infections (Genovese MC et al, Arthritis Rheum 2004;50:1412), therefore, only blocking the NLRP3 inflammasome at the site of inflammation would reduce the infection risk inherent in neutralizing both IL-1b and TNF-a. NLRP3 antagonists that are potent in NLRP3-inflammasome driven cytokine secretion assays in cells, but have low permeability in vitro in a permeability assay such as an MDCK assay, have poor systemic bioavailability in a rat or mouse pharmacokinetic experiment, but high levels of compound in the colon and/or small intestine could be a useful therapeutic option for gut restricted purposes.

In light of the above, the present invention also provides alternative therapies for the treatment of inflammatory or autoimmune diseases, including IBD, that solves the above problems associated with anti-TNFa agents. SUMMARY

This disclosure features chemical entities (e.g., a compound that modulates (e.g., antagonizes) NLRP3, or a pharmaceutically acceptable salt, and/or hydrate, and/or cocrystal, and/or drug combination of the compound) that are useful, e.g., for treating a condition, disease or disorder in which a decrease or increase in NLRP3 activity (e.g., an increase, e.g., a condition, disease or disorder associated with NLRP3 signaling).

In some embodiments, provided herein is a compound of Formula AA

or a pharmaceutically acceptable salt thereof, wherein the variables in Formula AA can be as defined anywhere herein.

In some embodiments, provided herein is a compound of Formula AB

or a pharmaceutically acceptable salt thereof, wherein the variables in Formula AA can be as defined anywhere herein.

The present invention is also relates to the Applicant’s discovery that inhibition of NLRP3 inflammasomes can increase a subject’s sensitivity to an anti-TNFa agent or can overcome resistance to an anti-TNFa agent in a subject, or indeed provide an alternative therapy to anti-TNFa agents.

Provided herein are methods of treating a subject that include: (a) identifying a subject having a cell that has an elevated level of NLRP3 inflammasome activity and/or expression as compared to a reference level; and (b) administering to the identified subject a therapeutically effective amount of an compound of Formula I or a pharmaceutically acceptable salt, solvate, or co-crystal thereof.

Provided herein are methods for the treatment of inflammatory or autoimmune disease including IBD, such as UC and CD in a subject in need thereof, comprising administering to said subject a therapeutically effective amount a compound for Formula I or a pharmaceuticalltreat”y acceptable salt, solvate, or co-crystal thereof, wherein the NLRP3 antagonist is a gut-targeted NLRP3 antagonist.

Provided herein are methods of treating a subject in need thereof, that include: (a) identifying a subject having resistance to an anti-TNFa agent; and (b) administering a treatment comprising a therapeutically effective amount of a compound for Formula I, or a pharmaceutically acceptable salt, solvate, or co-crystal thereof to the identified subject.

Provided herein are methods of treating a subject in need thereof, that include:

administering a treatment comprising a therapeutically effective amount of a compound for Formula I or a pharmaceutically acceptable salt, solvate, or co-crystal thereof to a subject identified as having resistance to an anti-TNFa agent.

Provided herein are methods of selecting a treatment for a subject in need thereof, that include: (a) identifying a subject having resistance to an anti-TNFa agent; and (b) selecting for the identified subject a treatment comprising a therapeutically effective amount of a compound for Formula I or a pharmaceutically acceptable salt, solvate, or co-crystal thereof. Provided herein are methods of selecting a treatment for a subject in need thereof, that include selecting a treatment comprising a therapeutically effective amount of a compound for Formula I or a pharmaceutically acceptable salt, solvate, or co-crystal thereof for a subject identified as having resistance to an anti-TNFa agent.

In some embodiments of any of the methods described herein, the treatment further includes a therapeutically effective amount of an anti-TNFa agent, in addition to the NLRP3 antagonist. This disclosure also features compositions as well as other methods of using and making the same.

An "antagonist" of NLRP3 includes compounds that inhibit the ability of NLRP3 to induce the production of IL-1b and/or IL-18 by directly binding to NLRP3, or by inactivating, destabilizing, altering distribution, of NLRP3 or otherwise.

In one aspect, pharmaceutical compositions are featured that include a chemical entity described herein (e.g., a compound described generically or specifically herein or a pharmaceutically acceptable salt thereof or compositions containing the same) and one or more pharmaceutically acceptable excipients.

In one aspect, methods for modulating (e.g., agonizing, partially agonizing, antagonizing) NLRP3 activity are featured that include contacting NLRP3 with a chemical entity described herein (e.g., a compound described generically or specifically herein or a pharmaceutically acceptable salt thereof or compositions containing the same). Methods include in vitro methods, e.g., contacting a sample that includes one or more cells comprising NLRP3, as well as in vivo methods.

In a further aspect, methods of treatment of a disease in which NLRP3 signaling contributes to the pathology and/or symptoms and/or progression of the disease are featured that include administering to a subject in need of such treatment an effective amount of a chemical entity described herein (e.g., a compound described generically or specifically herein or a pharmaceutically acceptable salt thereof or compositions containing the same).

In a further aspect, methods of treatment are featured that include administering to a subject a chemical entity described herein (e.g., a compound described generically or specifically herein or a pharmaceutically acceptable salt thereof or compositions containing the same), wherein the chemical entity is administered in an amount effective to treat a disease in which NLRP3 signaling contributes to the pathology and/or symptoms and/or progression of the disease, thereby treating the disease. Embodiments can include one or more of the following features.

The chemical entity can be administered in combination with one or more additional therapies with one or more agents suitable for the treatment of the condition, disease or disorder.

Examples of the indications that may be treated by the compounds disclosed herein include but are not limited to metabolic disorders such as type 2 diabetes, atherosclerosis, obesity and gout, as well as diseases of the central nervous system, such as Alzheimer’s disease and multiple sclerosis and Amyotrophic Lateral Sclerosis and Parkinson disease, lung disease, such as asthma and COPD and pulmonary idiopathic fibrosis, liver disease, such as NASH syndrome, viral hepatitis and cirrhosis, pancreatic disease, such as acute and chronic pancreatitis, kidney disease, such as acute and chronic kidney injury, intestinal disease such as Crohn’s disease and Ulcerative Colitis, skin disease such as psoriasis, musculoskeletal disease such as scleroderma, vessel disorders, such as giant cell arteritis, disorders of the bones, such as osteoarthritis , osteoporosis and osteopetrosis disorders, eye disease, such as glaucoma and macular degeneration, diseases caused by viral infection such as HIV and AIDS, autoimmune disease such as rheumatoid arthritis, systemic Lupus erythematosus, autoimmune thyroiditis; Addison's disease, pernicious anemia, cancer and aging.

The methods can further include identifying the subject.

Other embodiments include those described in the Detailed Description and/or in the claims.

Additional Definitions

To facilitate understanding of the disclosure set forth herein, a number of additional terms are defined below. Generally, the nomenclature used herein and the laboratory procedures in organic chemistry, medicinal chemistry, and pharmacology described herein are those well-known and commonly employed in the art. Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Each of the patents, applications, published applications, and other publications that are mentioned throughout the specification and the attached appendices are incorporated herein by reference in their entireties.

As used herein, the term“NLRP3” is meant to include, without limitation, nucleic acids, polynucleotides, oligonucleotides, sense and antisense polynucleotide strands, complementary sequences, peptides, polypeptides, proteins, homologous and/or orthologous NLRP3 molecules, isoforms, precursors, mutants, variants, derivatives, splice variants, alleles, different species, and active fragments thereof.

The term“acceptable” with respect to a formulation, composition or ingredient, as used herein, means having no persistent detrimental effect on the general health of the subject being treated.

“API” refers to an active pharmaceutical ingredient.

The terms“effective amount” or“therapeutically effective amount,” as used herein, refer to a sufficient amount of a chemical entity (e.g., a compound exhibiting activity as a modulator of NLRP3, or a pharmaceutically acceptable salt and/or hydrate and/or cocrystal thereof;) being administered which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result includes reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an“effective amount” for therapeutic uses is the amount of the composition comprising a compound as disclosed herein required to provide a clinically significant decrease in disease symptoms. An appropriate“effective” amount in any individual case is determined using any suitable technique, such as a dose escalation study.

The term “excipient” or “pharmaceutically acceptable excipient” means a pharmaceutically-acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, carrier, solvent, or encapsulating material. In one embodiment, each component is“ pharmaceutically acceptable” in the sense of being compatible with the other ingredients of a pharmaceutical formulation, and suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit/risk ratio. See, e.g., Remington: The Science and Practice of Pharmacy, 21st ed.; Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 6th ed.; Rowe et al., Eds.; The Pharmaceutical Press and the American Pharmaceutical Association: 2009; Handbook of Pharmaceutical Additives, 3rd ed.; Ash and Ash Eds.; Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, 2nd ed.; Gibson Ed.; CRC Press LLC: Boca Raton, FL, 2009.

The term“pharmaceutically acceptable salt” may refer to pharmaceutically acceptable addition salts prepared from pharmaceutically acceptable non-toxic acids including inorganic and organic acids. In certain instances, pharmaceutically acceptable salts are obtained by reacting a compound described herein, with acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p- toluenesulfonic acid, salicylic acid and the like. The term“pharmaceutically acceptable salt” may also refer to pharmaceutically acceptable addition salts prepared by reacting a compound having an acidic group with a base to form a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, and salts with amino acids such as arginine, lysine, and the like, or by other methods previously determined. The pharmacologically acceptable salt s not specifically limited as far as it can be used in medicaments. Examples of a salt that the compounds described hereinform with a base include the following: salts thereof with inorganic bases such as sodium, potassium, magnesium, calcium, and aluminum; salts thereof with organic bases such as methylamine, ethylamine and ethanolamine; salts thereof with basic amino acids such as lysine and ornithine; and ammonium salt. The salts may be acid addition salts, which are specifically exemplified by acid addition salts with the following: mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid:organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, and ethanesulfonic acid; acidic amino acids such as aspartic acid and glutamic acid.

The term“pharmaceutical composition” refers to a mixture of a compound described herein with other chemical components (referred to collectively herein as“excipients”), such as carriers, stabilizers, diluents, dispersing agents, suspending agents, and/or thickening agents. The pharmaceutical composition facilitates administration of the compound to an organism. Multiple techniques of administering a compound exist in the art including, but not limited to: rectal, oral, intravenous, aerosol, parenteral, ophthalmic, pulmonary, and topical administration.

As used herein, the term“prevent”,“preventing” or "prevention" in connection to a disease or disorder refers to the prophylactic treatment of a subject who is at risk of developing a condition (e.g., specific disease or disorder or clinical symptom thereof) resulting in a decrease in the probability that the subject will develop the condition.

The term“subject” refers to an animal, including, but not limited to, a primate (e.g., human), monkey, cow, pig, sheep, goat, horse, dog, cat, rabbit, rat, or mouse. The terms “subject” and“patient” are used interchangeably herein in reference, for example, to a mammalian subject, such as a human. The terms“treat,”“treating,” and“treatment,” in the context of treating a disease or disorder, are meant to include alleviating or abrogating a disorder, disease, or condition, or one or more of the symptoms associated with the disorder, disease, or condition; or to slowing the progression, spread or worsening of a disease, disorder or condition or of one or more symptoms thereof.

The terms“hydrogen” and“H” are used interchangeably herein.

The term "halo" refers to fluoro (F), chloro (Cl), bromo (Br), or iodo (I).

The term "alkyl" refers to a hydrocarbon chain that may be a straight chain or branched chain, saturated or unsaturated, containing the indicated number of carbon atoms. For example, C _1-10 indicates that the group may have from 1 to 10 (inclusive) carbon atoms in it. Non- limiting examples include methyl, ethyl, iso-propyl, tert-butyl, n-hexyl.

The term "haloalkyl" refers to an alkyl, in which one or more hydrogen atoms is/are replaced with an independently selected halo.

The term "alkoxy" refers to an -O-alkyl radical (e.g., -OCH3).

The term "carbocyclic ring" as used herein includes an aromatic or nonaromatic cyclic hydrocarbon group having 3 to 10 carbons, such as 3 to 8 carbons, such as 3 to 7 carbons, which may be optionally substituted. Examples of carbocyclic rings include five-membered, six-membered, and seven-membered carbocyclic rings.

The term“heterocyclic ring” refers to an aromatic or nonaromatic 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system having 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, or S (e.g., carbon atoms and 1-3, 1-6, or 1-9 heteroatoms of N, O, or S if monocyclic, bicyclic, or tricyclic, respectively), wherein 0, 1, 2, or 3 atoms of each ring may be substituted by a substituent. Examples of heterocyclic rings include five- membered, six-membered, and seven-membered heterocyclic rings.

The term "cycloalkyl" as used herein includes an nonaromatic cyclic, bicylic, fused, or spiro hydrocarbon radical having 3 to 10 carbons, such as 3 to 8 carbons, such as 3 to 7 carbons, wherein the cycloalkyl group which may be optionally substituted. Examples of cycloalkyls include five-membered, six-membered, and seven-membered rings. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl.

The term“heterocycloalkyl” refers to an nonaromatic 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring, fused, or spiro system radical having 1- 3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, or S (e.g., carbon atoms and 1-3, 1-6, or 1-9 heteroatoms of N, O, or S if monocyclic, bicyclic, or tricyclic, respectively), wherein 0, 1, 2, or 3 atoms of each ring may be substituted by a substituent. Examples of heterocycloalkyls include five- membered, six-membered, and seven-membered heterocyclic rings. Examples include piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, tetrahydrofuranyl, and the like.

The term "aryl" is intended to mean an aromatic ring radical containing 6 to 10 ring carbons. Examples include phenyl and naphthyl.

The term "heteroaryl" is intended to mean an aromatic ring system containing 5 to 14 aromatic ring atoms that may be a single ring, two fused rings or three fused rings wherein at least one aromatic ring atom is a heteroatom selected from, but not limited to, the group consisting of O, S and N. Examples include furanyl, thienyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl and the like. Examples also include carbazolyl, quinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, triazinyl, indolyl, isoindolyl, indazolyl, indolizinyl, purinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl. phenazinyl, phenothiazinyl, phenoxazinyl, benzoxazolyl, benzothiazolyl, 1H-benzimidazolyl, imidazopyridinyl, benzothienyl, benzofuranyl, isobenzofuran and the like.

The term“hydroxy” refers to an OH group.

The term“amino” refers to an NH2 group.

The term“oxo” refers to O. By way of example, substitution of a CH2 a group with oxo gives a C=O group.

As used herein, the terms“the ring A” or“A” are used interchangeably to denote formula AA, wherein the bond that is shown as being broken by the wavy line connects A to Z in Formula AA.

As used herein, the terms“the ring B” or“B” are used interchangeably to denote formula AA wherein the bond that is shown as being broken by the wavy line connects B to Y in Formula AA. As used herein, the term“the optionally substituted ring A” is used to denote

formula AA, wherein the bond that is shown as being broken by the wavy connects A to Z in Formula AA.

As used herein, the term“the substituted ring B” is used to denote formula AA, wherein the bond that is shown as being broken by the wavy line connects B to Y in Formula AA.

As used herein, the recitation“S(O2)”, alone or as part of a larger recitation, refers to

the group . In addition, atoms making up the compounds of the present embodiments are intended to include all isotopic forms of such atoms. Isotopes, as used herein, include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include ¹³ C and ¹⁴ C.

The scope of the compounds disclosed herein includes tautomeric form of the compounds. Thus, by way of example, a compound that is represented as containing the moiety

is also intended to include the tautomeric form containing the moiety addition, by way of example, a compound that is represented as containing the moiety

is also intended to include the tautomeric form containing the moiety . Non-limiting exemplified compounds of the formulae described herein include a stereogenic sulfur atom and optionally one or more stereogenic carbon atoms. This disclosure provides examples of stereoisomer mixtures (e.g., racemic mixture of enantiomers; mixture of diastereomers). This disclosure also describes and exemplifies methods for separating individual components of said stereoisomer mixtures (e.g., resolving the enantiomers of a racemic mixture). In cases of compounds containing only a stereogenic sulfur atom, resolved enantiomers are graphically depicted using one of the two following formats: formulas A/B (hashed and solid wedge three-dimensional representation); and formula C (“flat structures with *-labelled stereogenic sulfur).

In reaction schemes showing resolution of a racemic mixture, Formulas A/B and C are intended only to convey that the constituent enantiomers were resolved in enantiopure pure form (about 98% ee or greater). The schemes that show resolution products using the formula A/B format are not intended to disclose or imply any correlation between absolute configuration and order of elution. Some of the compounds shown in the tables below are graphically represented using the formula A/B format.

The details of one or more embodiments of the invention are set forth in the accompanying drawings and the description below. Other features and advantages of the invention will be apparent from the description and drawings, and from the claims. DESCRIPTION OF THE DRAWINGS

Figure 1: Expression levels of RNA encoding NLRP3 in Crohn’s Disease patients who are responsive and non-responsive to infliximab.

Figure 2: Expression levels of RNA encoding IL-1b in Crohn’s Disease patients who are responsive and non-responsive to infliximab.

Figure 3: Expression levels of RNA encoding NLRP3 in Ulcerative Colitis (UC) patients who are responsive and non-responsive to infliximab.

Figure 4: Expression levels of RNA encoding IL-1b in Ulcerative Colitis (UC) patients who are responsive and non-responsive to infliximab. DETAILED DESCRIPTION In some embodiments, provided herein is a compound of Formula AA

wherein

R is:–Z-Q, or NR’R’’;

Q is:

wherein ring A is selected from the group consisting of 5- to 10-membered heteroaryl, C ₆ -C ₁₀ aryl, C3-C10 cycloalkyl, and 3-10-membered heterocycloalkyl; or

(ii) H Z is:

(i) C1-C8 alkylene having from 1-8 carbon atoms independently selected from the group consisting of CH ₂ , CH, C, CR ¹⁶ , CR ¹⁷ , CHR ¹⁶ , CHR ¹⁷ , CR ¹⁶ R ¹⁶ , CR ¹⁷ R ¹⁷ , CR ¹⁶ R ¹⁷ , and C(O);

(ii) 3-10-membered heterocycloalkylene optionally substituted by one or more R ¹ and/or R ² ; or

(iii) C ₃ -C ₁₀ cycloalkyl optionally substituted by one or more R ¹ and/or R ² ; R’ and R’’ are each independently selected from:

(i) Q; or

(ii)–Z’’-Q, wherein Z’’ is C1-C8 alkylene having from 1-8 carbon atoms independently selected from the group consisting of CH2, CH, C, CR ¹⁶ , CR ¹⁷ , CHR ¹⁶ , CHR ¹⁷ , CR ¹⁶ R ¹⁶ , CR ¹⁷ R ¹⁷ , CR ¹⁶ R ¹⁷ , and C(O);

or alternatively, wherein R’ and R’’ are taken together with the N to which they are attached to form a 5-10-membered heterocycloalkyl ring optionally substituted with one or more R ¹ and/or R ² ; represents a single or double bond; wherein one of the following apply:

(i) When X is NHR ³ , a single bond is present between X and S, a double bond is present between S and N, and Y is selected from NH and CR ⁴ R ⁵ ; or

(ii) When X is O, a double bond is present between X and S, a single bond is present between S and N, the N that is bonded to S is further substituted with an H, and Y is CR ⁴ R ⁵ ; B is selected from the group consisting of 5-membered heteroaryl, 7-10 membered heteroaryl, and C ₆ -C ₁₀ aryl; m = 0, 1, or 2;

n = 0, 1, or 2; R ¹ and R ² are each independently selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, halo, CN, NO2, CO2H, COC ₁ -C ₆ alkyl, CO-C ₆ -C ₁₀ aryl; CO(5- to 10- membered heteroaryl); CO ₂ C ₁ -C ₆ alkyl, CO ₂ C ₃ -C ₈ cycloalkyl, OCOC ₁ -C ₆ alkyl, OCOC ₆ -C ₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, NH2, NHC ₁ -C ₆ alkyl, N(C ₁ -C ₆ alkyl)2, NHCOC ₁ -C ₆ alkyl, NHCOC ₆ -C ₁₀ aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC ₂ -C ₆ alkynyl, NHCOOCC ₁ -C ₆ alkyl, NH-(C=NR ¹³ )NR ¹¹ R ¹² , CONR ⁸ R ⁹ , SC ₁ -C ₆ alkyl, S(O2)C ₁ -C ₆ alkyl, S(O)C ₁ -C ₆ alkyl, S(O2)NR ¹¹ R ¹² , C3-C7 cycloalkyl and 3- to 7-membered heterocycloalkyl,

wherein the C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₃ -C ₇ cycloalkyl and 3- to 7-membered

heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC ₁ -C ₆ alkyl, CONR ⁸ R ⁹ , 3- to 7-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, OCOC ₁ -C ₆ alkyl, OCOC ₆ -C ₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC ₁ -C ₆ alkyl, NHCOC ₆ -C ₁₀ aryl, NHCO(5- to 10- membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), and NHCOC ₂ -C ₆ alkynyl;

wherein each C ₁ -C ₆ alkyl substituent and each C ₁ -C ₆ alkoxy substituent of the R ¹ or R ² C ₃ -C ₇ cycloalkyl or of the R ¹ or R ² 3- to 7-membered heterocycloalkyl is further optionally independently substituted with one to three hydroxy, halo, NR ⁸ R ⁹ , or oxo; wherein the 3- to 7-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, NHCOC ₆ -C ₁₀ aryl, NHCO(5- to 10-membered heteroaryl) and NHCO(3- to 7-membered heterocycloalkyl) are optionally substituted with one or more substituents independently selected from halo, C ₁ -C ₆ alkyl, and OC ₁ -C ₆ alkyl;

or one pair of R ¹ and R ² on adjacent atoms, taken together with the atoms connecting them, independently form at least one C ₄ -C ₈ carbocyclic ring or at least one 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, halo, oxo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC ₁ -C ₆ alkyl, C ₆ -C ₁₀ aryl, and CONR ⁸ R ⁹ wherein the C ₁ -C ₆ alkyl and C ₁ -C ₆ alkoxy are optionally substituted with hydroxy, halo, oxo, NR ⁸ R ⁹ , =NR ¹⁰ , COOC ₁ - C6 alkyl, C ₆ -C ₁₀ aryl, and CONR ⁸ R ⁹ ; R ¹⁶ and R ¹⁷ are each independently selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, halo, CN, NO2, CO2H, COC ₁ -C ₆ alkyl, CO-C ₆ -C ₁₀ aryl; CO(5- to 10- membered heteroaryl); CO2C ₁ -C ₆ alkyl, CO2C3-C8 cycloalkyl, OCOC ₁ -C ₆ alkyl, OCOC ₆ -C ₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NH ₂ , NHC ₁ -C ₆ alkyl, N(C ₁ -C ₆ alkyl) ₂ , NHCOC ₁ -C ₆ alkyl, NHCOC ₆ -C ₁₀ aryl, NHCO(5- to 10- membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC2-C6 alkynyl, NHCOOCC ₁ -C ₆ alkyl, NH-(C=NR ¹³ )NR ¹¹ R ¹² , CONR ⁸ R ⁹ , SC ₁ -C ₆ alkyl, S(O ₂ )C ₁ -C ₆ alkyl, S(O)C ₁ -C ₆ alkyl, and S(O ₂ )NR ¹¹ R ¹² ,

wherein the C ₁ -C ₆ alkyl and C ₁ -C ₆ haloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC ₁ -C ₆ alkyl, CONR ⁸ R ⁹ , OCOC ₁ -C ₆ alkyl, OCOC ₆ -C ₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC1- C6 alkyl, NHCOC ₆ -C ₁₀ aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7- membered heterocycloalkyl), and NHCOC ₂ -C ₆ alkynyl;

R ³ is selected from hydrogen, hydroxy, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkyl,

wherein the C ₁ -C ₆ alkylene group is optionally substituted by oxo; each of R ⁴ and R ⁵ is independently selected from hydrogen and C ₁ -C ₆ alkyl; o = 1 or 2;

p = 0, 1, 2, or 3; R ⁶ and R ⁷ are each independently selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, halo, CN, NO2, COC ₁ -C ₆ alkyl, CO2C ₁ -C ₆ alkyl, CO2C3-C8 cycloalkyl, OCOC ₁ -C ₆ alkyl, OCOC ₆ -C ₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7- membered heterocycloalkyl), C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, NH ₂ , NHC ₁ -C ₆ alkyl, N(C ₁ -C ₆ alkyl)2, CONR ⁸ R ⁹ , SF5, S(O2)C ₁ -C ₆ alkyl, C3-C10 cycloalkyl and 3- to 10- membered heterocycloalkyl, and a C ₂ -C ₆ alkenyl,

wherein R ⁶ and R ⁷ are each optionally substituted with one or more substituents

independently selected from hydroxy, halo, CN, oxo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC ₁ -C ₆ alkyl, CONR ⁸ R ⁹ , 3- to 7-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, OCOC ₁ -C ₆ alkyl, OCOC ₆ -C ₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC ₁ -C ₆ alkyl, NHCOC ₆ -C ₁₀ aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC ₂ -C ₆ alkynyl, C ₆ -C ₁₀ aryloxy, and S(O ₂ )C ₁ -C ₆ alkyl; and wherein the C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy that R ⁶ or R ⁷ is substituted with is optionally substituted with one or more hydroxyl, C ₆ -C ₁₀ aryl or NR ⁸ R ⁹ , or wherein R ⁶ or R ⁷ is optionally fused to a five- to–seven- membered carbocyclic ring or heterocyclic ring containing one or two heteroatoms independently selected from oxygen, sulfur and nitrogen;

wherein the 3- to 7-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, NHCOC ₆ -C ₁₀ aryl, NHCO(5- to 10-membered heteroaryl) and NHCO(3- to 7-membered heterocycloalkyl) are optionally substituted with one or more substituents independently selected from halo, C ₁ -C ₆ alkyl, and OC ₁ -C ₆ alkyl;

or at least one pair of R ⁶ and R ⁷ on adjacent atoms, taken together with the atoms connecting them, independently form at least one C ₄ -C ₈ carbocyclic ring or at least one 5- to 8- membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy,

hydroxymethyl, halo, oxo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, NR ⁸ R ⁹ , CH ₂ NR ⁸ R ⁹ , =NR ¹⁰ , COOC ₁ -C ₆ alkyl, C ₆ -C ₁₀ aryl, and CONR ⁸ R ⁹ ; each of R ⁸ and R ⁹ at each occurrence is independently selected from hydrogen, C ₁ -C ₆ alkyl, alkyl, S(O2)NR ¹¹ R ¹² , COR ¹³ , CO2R ¹³ and CONR ¹¹ R ¹² ;

wherein the C ₁ -C ₆ alkyl is optionally substituted with one or more hydroxy, halo, C ₁ -C ₆ alkoxy, C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, C ₃ -C ₇ cycloalkyl or 3- to 7-membered heterocycloalkyl; or R ⁸ and R ⁹ taken together with the nitrogen they are attached to form a 3- to 7-membered ring optionally containing one or more heteroatoms in addition to the nitrogen they are attached to; R ¹⁰ is C ₁ -C ₆ alkyl; each of R ¹¹ and R ¹² at each occurrence is independently selected from hydrogen and C ₁ -C ₆ alkyl; R ¹³ is C ₁ -C ₆ alkyl, C ₆ -C ₁₀ aryl, or 5- to 10-membered heteroaryl; R ¹⁴ is hydrogen, hydroxy, C ₁ -C ₆ alkyl, NR ⁸ R ⁹ , 5- to 10-membered monocyclic or bicyclic heteroaryl, or C ₆ -C ₁₀ monocyclic or bicyclic aryl, wherein each C ₁ -C ₆ alkyl, aryl or heteroaryl is optionally independently substituted with 1 or 2 R ⁶ , each R ¹⁵ at each occurrence are each independently selected from the group consisting of C ₁ - C6 alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, CN, COC ₁ -C ₆ alkyl, CO-C ₆ -C ₁₀ aryl; CO(5- to 10-membered heteroaryl); CO ₂ C ₁ -C ₆ alkyl, CO ₂ C ₃ -C ₈ cycloalkyl, OCOC ₁ -C ₆ alkyl, OCOC ₆ -C ₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, NH2, NHC ₁ -C ₆ alkyl, N(C ₁ -C ₆ alkyl)2, NHCOC ₁ -C ₆ alkyl, NHCOC ₆ -C ₁₀ aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC ₂ -C ₆ alkynyl, NHCOOCC ₁ -C ₆ alkyl, NH-(C=NR ¹³ )NR ¹¹ R ¹² , CONR ⁸ R ⁹ , SC ₁ -C ₆ alkyl, S(O2)C ₁ -C ₆ alkyl, S(O)C ₁ -C ₆ alkyl, S(O2)NR ¹¹ R ¹² , C3-C7 cycloalkyl and 3- to 7-membered heterocycloalkyl,

wherein the C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₃ -C ₇ cycloalkyl, and 3- to 7-membered

heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC ₁ -C ₆ alkyl, CONR ⁸ R ⁹ , 3- to 7-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, OCOC ₁ -C ₆ alkyl, OCOC ₆ -C ₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC ₁ -C ₆ alkyl, NHCOC ₆ -C ₁₀ aryl, NHCO(5- to 10- membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), and NHCOC ₂ -C ₆ alkynyl;

wherein each C ₁ -C ₆ alkyl substituent and each C ₁ -C ₆ alkoxy substituent of the R ¹⁵ C3- C7 cycloalkyl or of the R ¹⁵ 3- to 7-membered heterocycloalkyl is further optionally independently substituted with one to three hydroxy, halo, NR ⁸ R ⁹ , or oxo;

wherein the 3- to 7-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, NHCOC ₆ -C ₁₀ aryl, NHCO(5- to 10-membered heteroaryl) and NHCO(3- to 7-membered heterocycloalkyl) are optionally substituted with one or more substituents independently selected from halo, C ₁ -C ₆ alkyl, and OC ₁ -C ₆ alkyl; with the proviso that the compound of Formula AA is not the following structure:

or a pharmaceutically acceptable salt thereof. In some embodiments of Formula AA, R is–Z-Q. In some embodiments of Formula AA, R is NR’R’’. In some embodiments of Formula AA, R is NR’R’’, and R’ and R’’ are each independently selected from–Z’’-H, wherein Z’’ is C ₁ -C ₈ alkylene having from 1-8 carbon atoms independently selected from the group consisting of CH2, CH, C, CR ¹⁶ , CR ¹⁷ , CHR ¹⁶ , CHR ¹⁷ , CR ¹⁶ R ¹⁶ , CR ¹⁷ R ¹⁷ , CR ¹⁶ R ¹⁷ , and C(O). In some embodiments of Formula AA, R is NR’R’’, and R’ and R’’ are taken together with the N to which they are attached to form a 5-10-membered heterocycloalkyl ring optionally substituted with one or more R ¹ and/or R ² ; In some embodiments of Formula AA, X is NHR ³ , a single bond is present between X and S, and a double bond is present between S and N; and the compound of Formula AA is a compound of Formula AA-1, Formula AA-2, or Formula AA-3:

wherein Z’ is:

(i) C ₂ -C ₈ alkylene having from 2-8 carbon atoms independently selected from the group consisting of CH ₂ , CH, C, CR ¹⁶ , CR ¹⁷ , CHR ¹⁶ , CHR ¹⁷ , CR ¹⁶ R ¹⁶ , CR ¹⁷ R ¹⁷ , CR ¹⁶ R ¹⁷ , and C(O);

(ii) CHR ¹⁶ , CHR ¹⁷ , CR ¹⁶ R ¹⁶ , CR ¹⁷ R ¹⁷ , CR ¹⁶ R ¹⁷ , or C(O);

(ii) 3-10-membered heterocycloalkylene optionally substituted by one or more R ¹ and/or R ² ; or

(iii) C3-C10 cycloalkyl optionally substituted by one or more R ¹ and/or R ² ; and wherein when

(i) Formula AA is Formula AA-2,

(ii) ring A is phenyl,

(iii) the sum of m and n is 1, and

(iv) whichever of R ¹ and R ² that is present is CN;

then the position of the phenyl group that is para to the point of the phenyl group’s connection to the sulfur of the S(O)(NHR ³ )=N moiety is substituted with hydrogen. In some embodiments the variables shown in the formulae herein are as follows: Formula AA: In some embodiments, the compound is a compound of Formula AA-1: .

In some embodiments, the compound is a compound of Formula AA-2:

.

In some embodiments, the compound is a compound of Formula AA-3: The variable R In some embodiments, R is–Z-Q. The variables Z and Z’ The variable Z

In some embodiments, Z is

(i) C1-C8 alkylene having from 1-8 carbon atoms independently selected from the group consisting of CH2, CH, C, CR ¹⁶ , CR ¹⁷ , CHR ¹⁶ , CHR ¹⁷ , CR ¹⁶ R ¹⁶ , CR ¹⁷ R ¹⁷ , CR ¹⁶ R ¹⁷ , and C(O);

(ii) 3-10-membered heterocycloalkylene optionally substituted by one or more R ¹ and/or R ² ; or

(iii) C ₃ -C ₁₀ cycloalkyl optionally substituted by one or more R ¹ and/or R ² . In some embodiments, Z is

(i) C ₁ -C ₈ alkylene having from 1-8 carbon atoms independently selected from the group consisting of CH ₂ , CH, C, CR ¹⁶ , CR ¹⁷ , CHR ¹⁶ , CHR ¹⁷ , CR ¹⁶ R ¹⁶ , CR ¹⁷ R ¹⁷ , CR ¹⁶ R ¹⁷ , and C(O); or

(ii) 3-10-membered heterocycloalkylene optionally substituted by one or more R ¹ and/or R ² . In some embodiments, Z is

(i) C ₁ -C ₈ alkylene having from 1-8 carbon atoms independently selected from the group consisting of CH ₂ , CH, C, CR ¹⁶ , CR ¹⁷ , CHR ¹⁶ , CHR ¹⁷ , CR ¹⁶ R ¹⁶ , CR ¹⁷ R ¹⁷ , CR ¹⁶ R ¹⁷ , and C(O); or

(iii) C ₃ -C ₁₀ cycloalkyl optionally substituted by one or more R ¹ and/or R ² ; In some embodiments, Z is (ii) 3-10-membered heterocycloalkylene optionally substituted by one or more R ¹ and/or R ² ; or

(iii) C ₃ -C ₁₀ cycloalkyl optionally substituted by one or more R ¹ and/or R ² ; In some embodiments, Z is (i) C1-C8 alkylene having from 1-8 carbon atoms independently selected from the group consisting of CH ₂ , CH, C, CR ¹⁶ , CR ¹⁷ , CHR ¹⁶ , CHR ¹⁷ , CR ¹⁶ R ¹⁶ , CR ¹⁷ R ¹⁷ , CR ¹⁶ R ¹⁷ , and C(O).

In some embodiments, Z is C1-6 alkylene having from 1-6 carbon atoms independently selected from the group consisting of CH ₂ , CH, C, CR ¹⁶ , CR ¹⁷ , CHR ¹⁶ , CHR ¹⁷ , CR ¹⁶ R ¹⁶ , CR ¹⁷ R ¹⁷ , CR ¹⁶ R ¹⁷ , and C(O).

In some embodiments, Z is C1-2 alkylene having from 1-2 carbon atoms independently selected from the group consisting of CH ₂ , CHR ¹⁶ , CHR ¹⁷ , CR ¹⁶ R ¹⁶ , CR ¹⁷ R ¹⁷ , CR ¹⁶ R ¹⁷ , and C(O).

In some embodiments, Z is C1 alkylene having 1 carbon atom selected from the group consisting of CH2, CHR ¹⁶ , CHR ¹⁷ , CR ¹⁶ R ¹⁶ , CR ¹⁷ R ¹⁷ , CR ¹⁶ R ¹⁷ , and C(O).

In some embodiments (when Z is C ₁ -C ₈ alkylene having from 1-8 carbon atoms

independently selected from the group consisting of CH2, CH, C, CR ¹⁶ , CR ¹⁷ , CHR ¹⁶ , CHR ¹⁷ , CR ¹⁶ R ¹⁶ , CR ¹⁷ R ¹⁷ , CR ¹⁶ R ¹⁷ , and C(O)), the alkylene is CH2.

In some embodiments (when Z is C ₁ -C ₈ alkylene having from 1-8 carbon atoms

independently selected from the group consisting of CH2, CH, C, CR ¹⁶ , CR ¹⁷ , CHR ¹⁶ , CHR ¹⁷ , CR ¹⁶ R ¹⁶ , CR ¹⁷ R ¹⁷ , CR ¹⁶ R ¹⁷ , and C(O)), the alkylene comprises C(O).

In some embodiments (when Z is C ₁ -C ₈ alkylene having from 1-8 carbon atoms

independently selected from the group consisting of CH ₂ , CH, C, CR ¹⁶ , CR ¹⁷ , CHR ¹⁶ , CHR ¹⁷ , CR ¹⁶ R ¹⁶ , CR ¹⁷ R ¹⁷ , CR ¹⁶ R ¹⁷ , and C(O)), the alkylene is C(O).

In some embodiments (when Z is C ₁ -C ₈ alkylene having from 1-8 carbon atoms

independently selected from the group consisting of CH ₂ , CH, C, CR ¹⁶ , CR ¹⁷ , CHR ¹⁶ , CHR ¹⁷ , CR ¹⁶ R ¹⁶ , CR ¹⁷ R ¹⁷ , CR ¹⁶ R ¹⁷ , and C(O)), the alkylene is 1-methyl-1-propyl.

In some embodiments (when Z is C1-C8 alkylene having from 1-8 carbon atoms

independently selected from the group consisting of CH ₂ , CH, C, CR ¹⁶ , CR ¹⁷ , CHR ¹⁶ , CHR ¹⁷ , CR ¹⁶ R ¹⁶ , CR ¹⁷ R ¹⁷ , CR ¹⁶ R ¹⁷ , and C(O)), the alkylene is 2-methyl-1-propyl.

In some embodiments (when Z is C1-C8 alkylene having from 1-8 carbon atoms

independently selected from the group consisting of CH ₂ , CH, C, CR ¹⁶ , CR ¹⁷ , CHR ¹⁶ , CHR ¹⁷ , CR ¹⁶ R ¹⁶ , CR ¹⁷ R ¹⁷ , CR ¹⁶ R ¹⁷ , and C(O)), the alkylene is 2,2-dimethyl-1-propyl. In some embodiments (when Z is C1-C8 alkylene having from 1-8 carbon atoms independently selected from the group consisting of CH ₂ , CH, C, CR ¹⁶ , CR ¹⁷ , CHR ¹⁶ , CHR ¹⁷ , CR ¹⁶ R ¹⁶ , CR ¹⁷ R ¹⁷ , CR ¹⁶ R ¹⁷ , and C(O)), the alkylene is ethyl.

In some embodiments (when Z is C1-C8 alkylene having from 1-8 carbon atoms

independently selected from the group consisting of CH2, CH, C, CR ¹⁶ , CR ¹⁷ , CHR ¹⁶ , CHR ¹⁷ , CR ¹⁶ R ¹⁶ , CR ¹⁷ R ¹⁷ , CR ¹⁶ R ¹⁷ , and C(O)), the alkylene is n-propyl.

In some embodiments (when Z is C1-C8 alkylene having from 1-8 carbon atoms

independently selected from the group consisting of CH2, CH, C, CR ¹⁶ , CR ¹⁷ , CHR ¹⁶ , CHR ¹⁷ , CR ¹⁶ R ¹⁶ , CR ¹⁷ R ¹⁷ , CR ¹⁶ R ¹⁷ , and C(O)), the alkylene is n-butyl.

In some embodiments (when Z is C ₁ -C ₈ alkylene having from 1-8 carbon atoms

independently selected from the group consisting of CH2, CH, C, CR ¹⁶ , CR ¹⁷ , CHR ¹⁶ , CHR ¹⁷ , CR ¹⁶ R ¹⁶ , CR ¹⁷ R ¹⁷ , CR ¹⁶ R ¹⁷ , and C(O)), the alkylene is branched.

In some embodiments (when Z is C ₁ -C ₈ alkylene having from 1-8 carbon atoms

independently selected from the group consisting of CH2, CH, C, CR ¹⁶ , CR ¹⁷ , CHR ¹⁶ , CHR ¹⁷ , CR ¹⁶ R ¹⁶ , CR ¹⁷ R ¹⁷ , CR ¹⁶ R ¹⁷ , and C(O)), the alkylene is linear.

In some embodiments, Z is (ii) 3-10-membered heterocycloalkylene optionally substituted by one or more R ¹ and/or R ² .

In some embodiments, Z is a 5-6-membered heterocycloalkylene optionally substituted by one or more R ¹ and/or R ² .

In some embodiments, Z is a 5-membered heterocycloalkylene optionally substituted by one or more R ¹ and/or R ² .

In some embodiments, Z is a 6-membered heterocycloalkylene optionally substituted by one or more R ¹ and/or R ² .

In some embodiments, Z is pyrrolidinylene (e.g., 3-pyrrolidinylene) optionally substituted by one or more R ¹ and/or R ² .

In some embodiments, Z is piperidinylene (e.g., 4-piperidinylene) optionally substituted by one or more R ¹ and/or R ² .

In some embodiments, Z is (iii) C3-C10 cycloalkyl optionally substituted by one or more R ¹ and/or R ² .

In some embodiments, Z is cyclohexyl optionally substituted by one or more R ¹ and/or R ² In some embodiments, Z is cyclopentyl optionally substituted by one or more R ¹ and/or R ² . In some embodiments, Z is cyclobutyl optionally substituted by one or more R ¹ and/or R ² . In some embodiments, Z is cyclopropyl optionally substituted by one or more R ¹ and/or R ² . The variable Z’ (applicable to Formula AA-1) In some embodiments, Z’ is (i) C ₂ -C ₆ alkylene having from 2-6 carbon atoms independently selected from the group consisting of CH2, CH, C, CR ¹⁶ , CR ¹⁷ , CHR ¹⁶ , CHR ¹⁷ , CR ¹⁶ R ¹⁶ , CR ¹⁷ R ¹⁷ , CR ¹⁶ R ¹⁷ , and C(O).

In some embodiments, Z’ is C ₂ -C ₄ alkylene having from 2-4 carbon atoms independently selected from the group consisting of CH2, CH, C, CR ¹⁶ , CR ¹⁷ , CHR ¹⁶ , CHR ¹⁷ , CR ¹⁶ R ¹⁶ , CR ¹⁷ R ¹⁷ , CR ¹⁶ R ¹⁷ , and C(O).

In some embodiments, Z’ is C ₂ alkylene having 2 carbon atoms independently selected from the group consisting of CH ₂ , CHR ¹⁶ , CHR ¹⁷ , CR ¹⁶ R ¹⁶ , CR ¹⁷ R ¹⁷ , CR ¹⁶ R ¹⁷ , and C(O).

In some embodiments (when Z’ is (i) C2-C6 alkylene having from 2-6 carbon atoms independently selected from the group consisting of CH ₂ , CH, C, CR ¹⁶ , CR ¹⁷ , CHR ¹⁶ , CHR ¹⁷ , CR ¹⁶ R ¹⁶ , CR ¹⁷ R ¹⁷ , CR ¹⁶ R ¹⁷ , and C(O)), the alkylene comprises C(O).

In some embodiments (when Z’ is (i) C2-C6 alkylene having from 2-6 carbon atoms independently selected from the group consisting of CH2, CH, C, CR ¹⁶ , CR ¹⁷ , CHR ¹⁶ , CHR ¹⁷ , CR ¹⁶ R ¹⁶ , CR ¹⁷ R ¹⁷ , CR ¹⁶ R ¹⁷ , and C(O)), alkylene is C(O).

In some embodiments (when Z’ is (i) C2-C6 alkylene having from 2-6 carbon atoms independently selected from the group consisting of CH2, CH, C, CR ¹⁶ , CR ¹⁷ , CHR ¹⁶ , CHR ¹⁷ , CR ¹⁶ R ¹⁶ , CR ¹⁷ R ¹⁷ , CR ¹⁶ R ¹⁷ , and C(O)), the alkylene is 1-methyl-1-propyl.

In some embodiments (when Z’ is (i) C2-C6 alkylene having from 2-6 carbon atoms independently selected from the group consisting of CH2, CH, C, CR ¹⁶ , CR ¹⁷ , CHR ¹⁶ , CHR ¹⁷ , CR ¹⁶ R ¹⁶ , CR ¹⁷ R ¹⁷ , CR ¹⁶ R ¹⁷ , and C(O)), the alkylene is 2-methyl-1-propyl.

In some embodiments (when Z’ is (i) C ₂ -C ₆ alkylene having from 2-6 carbon atoms independently selected from the group consisting of CH2, CH, C, CR ¹⁶ , CR ¹⁷ , CHR ¹⁶ , CHR ¹⁷ , CR ¹⁶ R ¹⁶ , CR ¹⁷ R ¹⁷ , CR ¹⁶ R ¹⁷ , and C(O)), the alkylene is 2,2-dimethyl-1-propyl.

In some embodiments (when Z’ is (i) C ₂ -C ₆ alkylene having from 2-6 carbon atoms independently selected from the group consisting of CH2, CH, C, CR ¹⁶ , CR ¹⁷ , CHR ¹⁶ , CHR ¹⁷ , CR ¹⁶ R ¹⁶ , CR ¹⁷ R ¹⁷ , CR ¹⁶ R ¹⁷ , and C(O)), the alkylene is ethyl.

In some embodiments (when Z’ is (i) C ₂ -C ₆ alkylene having from 2-6 carbon atoms independently selected from the group consisting of CH2, CH, C, CR ¹⁶ , CR ¹⁷ , CHR ¹⁶ , CHR ¹⁷ , CR ¹⁶ R ¹⁶ , CR ¹⁷ R ¹⁷ , CR ¹⁶ R ¹⁷ , and C(O)), the alkylene is n-propyl.

In some embodiments (when Z’ is (i) C ₂ -C ₆ alkylene having from 2-6 carbon atoms independently selected from the group consisting of CH ₂ , CH, C, CR ¹⁶ , CR ¹⁷ , CHR ¹⁶ , CHR ¹⁷ , CR ¹⁶ R ¹⁶ , CR ¹⁷ R ¹⁷ , CR ¹⁶ R ¹⁷ , and C(O)), the alkylene is n-butyl. In some embodiments (when Z’ is (i) C2-C6 alkylene having from 2-6 carbon atoms independently selected from the group consisting of CH ₂ , CH, C, CR ¹⁶ , CR ¹⁷ , CHR ¹⁶ , CHR ¹⁷ , CR ¹⁶ R ¹⁶ , CR ¹⁷ R ¹⁷ , CR ¹⁶ R ¹⁷ , and C(O)), the alkylene is branched.

In some embodiments (when Z’ is (i) C2-C6 alkylene having from 2-6 carbon atoms independently selected from the group consisting of CH2, CH, C, CR ¹⁶ , CR ¹⁷ , CHR ¹⁶ , CHR ¹⁷ , CR ¹⁶ R ¹⁶ , CR ¹⁷ R ¹⁷ , CR ¹⁶ R ¹⁷ , and C(O)), the alkylene is linear.

In some embodiments (when Z’ is (i) C2-C6 alkylene having from 2-6 carbon atoms independently selected from the group consisting of CH2, CH, C, CR ¹⁶ , CR ¹⁷ , CHR ¹⁶ , CHR ¹⁷ , CR ¹⁶ R ¹⁶ , CR ¹⁷ R ¹⁷ , CR ¹⁶ R ¹⁷ , and C(O)), Z’ is (ii) 3-10-membered heterocycloalkylene optionally substituted by one or more R ¹ and/or R ² .

In some embodiments (when Z’ is (i) C2-C6 alkylene having from 2-6 carbon atoms independently selected from the group consisting of CH ₂ , CH, C, CR ¹⁶ , CR ¹⁷ , CHR ¹⁶ , CHR ¹⁷ , CR ¹⁶ R ¹⁶ , CR ¹⁷ R ¹⁷ , CR ¹⁶ R ¹⁷ , and C(O)), Z’ is a 5-6-membered heterocycloalkylene optionally substituted by one or more R ¹ and/or R ² .

In some embodiments (when Z’ is (i) C2-C6 alkylene having from 2-6 carbon atoms independently selected from the group consisting of CH ₂ , CH, C, CR ¹⁶ , CR ¹⁷ , CHR ¹⁶ , CHR ¹⁷ , CR ¹⁶ R ¹⁶ , CR ¹⁷ R ¹⁷ , CR ¹⁶ R ¹⁷ , and C(O)), Z’ is a 5-membered heterocycloalkylene optionally substituted by one or more R ¹ and/or R ² .

In some embodiments (when Z’ is (i) C ₂ -C ₆ alkylene having from 2-6 carbon atoms independently selected from the group consisting of CH2, CH, C, CR ¹⁶ , CR ¹⁷ , CHR ¹⁶ , CHR ¹⁷ , CR ¹⁶ R ¹⁶ , CR ¹⁷ R ¹⁷ , CR ¹⁶ R ¹⁷ , and C(O)), Z’ is a 6-membered heterocycloalkylene optionally substituted by one or more R ¹ and/or R ² .

In some embodiments (when Z’ is (i) C ₂ -C ₆ alkylene having from 2-6 carbon atoms independently selected from the group consisting of CH2, CH, C, CR ¹⁶ , CR ¹⁷ , CHR ¹⁶ , CHR ¹⁷ , CR ¹⁶ R ¹⁶ , CR ¹⁷ R ¹⁷ , CR ¹⁶ R ¹⁷ , and C(O)), Z’ is pyrrolidinylene (e.g., 3-pyrrolidinylene) optionally substituted by one or more R ¹ and/or R ² .

In some embodiments (when Z’ is (i) C2-C6 alkylene having from 2-6 carbon atoms independently selected from the group consisting of CH2, CH, C, CR ¹⁶ , CR ¹⁷ , CHR ¹⁶ , CHR ¹⁷ , CR ¹⁶ R ¹⁶ , CR ¹⁷ R ¹⁷ , CR ¹⁶ R ¹⁷ , and C(O)), Z’ is piperidinylene (e.g., 4-piperidinylene) optionally substituted by one or more R ¹ and/or R ² .

In some embodiments (when Z’ is (i) C2-C6 alkylene having from 2-6 carbon atoms independently selected from the group consisting of CH ₂ , CH, C, CR ¹⁶ , CR ¹⁷ , CHR ¹⁶ , CHR ¹⁷ , CR ¹⁶ R ¹⁶ , CR ¹⁷ R ¹⁷ , CR ¹⁶ R ¹⁷ , and C(O)), Z’ is (iii) C ₃ -C ₁₀ cycloalkyl optionally substituted by one or more R ¹ and/or R ² . In some embodiments (when Z’ is (i) C2-C6 alkylene having from 2-6 carbon atoms independently selected from the group consisting of CH ₂ , CH, C, CR ¹⁶ , CR ¹⁷ , CHR ¹⁶ , CHR ¹⁷ , CR ¹⁶ R ¹⁶ , CR ¹⁷ R ¹⁷ , CR ¹⁶ R ¹⁷ , and C(O)), Z’ is cyclohexyl optionally substituted by one or more R ¹ and/or R ²

In some embodiments (when Z’ is (i) C2-C6 alkylene having from 2-6 carbon atoms independently selected from the group consisting of CH ₂ , CH, C, CR ¹⁶ , CR ¹⁷ , CHR ¹⁶ , CHR ¹⁷ , CR ¹⁶ R ¹⁶ , CR ¹⁷ R ¹⁷ , CR ¹⁶ R ¹⁷ , and C(O)), Z’ is cyclopentyl optionally substituted by one or more R ¹ and/or R ² .

In some embodiments (when Z’ is (i) C ₂ -C ₆ alkylene having from 2-6 carbon atoms independently selected from the group consisting of CH ₂ , CH, C, CR ¹⁶ , CR ¹⁷ , CHR ¹⁶ , CHR ¹⁷ , CR ¹⁶ R ¹⁶ , CR ¹⁷ R ¹⁷ , CR ¹⁶ R ¹⁷ , and C(O)), Z’ is cyclobutyl optionally substituted by one or more R ¹ and/or R ² .

In some embodiments (when Z’ is (i) C ₂ -C ₆ alkylene having from 2-6 carbon atoms independently selected from the group consisting of CH2, CH, C, CR ¹⁶ , CR ¹⁷ , CHR ¹⁶ , CHR ¹⁷ , CR ¹⁶ R ¹⁶ , CR ¹⁷ R ¹⁷ , CR ¹⁶ R ¹⁷ , and C(O)), Z’ is cyclopropyl optionally substituted by one or more R ¹ and/or R ² . The variable Q In some embodiments, Q is:

( _{optionally substituted ring A); or}

In some embodiments, _{(optionally substituted ring A).}

In some embodiments, Q is H. The variables X and Y In some embodiments, X is NHR ³ , a single bond is present between X and S, and a double bond is present between S and N. It is understood that embodiments where X is NHR ³ , a single bond is present between X and S, and a double bond is present between S and N also cover the tautomeric form where X is NR ³ , a double bond is present between X and S, a single bond is present between S and N, and a hydrogen is bonded to the N that is single-bonded to the S. In some embodiments (when X is NHR ³ , a single bond is present between X and S, and a double bond is present between S and N), Y is NH. In some embodiments (when X is NHR ³ , a single bond is present between X and S, and a double bond is present between S and N), Y is CR ⁴ R ⁵ . In some embodiments, X is O, a double bond is present between X and S, a single bond is present between S and N, the N that is bonded to S is further substituted with an H, and Y is CR ⁴ R ⁵ . The variables m and n

In some embodiments m=0, 1, or 2.

In some embodiments m=0 or 1.

In some embodiments m=1 or 2.

In some embodiments m=0 or 2.

In some embodiments m=0.

In some embodiments m=1.

In some embodiments m=2.

In some embodiments n=0, 1, or 2.

In some embodiments n=0 or 1.

In some embodiments n=1 or 2.

In some embodiments n=0 or 2.

In some embodiments n=0.

In some embodiments n=1.

In some embodiments n=2.

In some embodiments, m=0 and n=0. In some embodiments, m=1 and n=0.

In some embodiments, m=1 and n=1. The Ring A and substitutions on the ring A

In some embodiments, A is selected from the group consisting of: 5- to 10-membered heteroaryl, C ₆ -C ₁₀ aryl, C ₃ -C ₁₀ cycloalkyl, and 3-10-membered heterocycloalkyl.

In some embodiments, A is selected from the group consisting of 5- to 10-membered heteroaryl, C ₆ -C ₁₀ aryl, and 3-10-membered heterocycloalkyl.

In some embodiments, A is selected from the group consisting of 5- to 10-membered heteroaryl.

In some embodiments, A is selected from the group consisting of C ₆ -C ₁₀ aryl.

In some embodiments, A is selected from the group consisting of 3-10-membered heterocycloalkyl.

In some embodiments, A is a 5- to 10-membered (e.g., 5- to 6-membered) heteroaryl or a C6- C10 (e.g., C6) aryl.

In some embodiments, A is a 5- to 10-membered (e.g., 5- to 6-membered) heteroaryl.

In some embodiments, A is a 5-membered heteroaryl containing a sulfur and optionally one or more nitrogens.

In some embodiments, A is a C ₆ -C ₁₀ aryl. In some embodiments, A is thiophenyl (e.g., 3-thiophenyl).

In some embodiments, A is thiazolyl (e.g., 5-thiazolyl).

In some embodiments, A is pyrazolyl (e.g., 4-pyrazolyl).

In some embodiments, A is isoxazolyl (e.g., 5-isoxazolyl).

In some embodiments, A is phenyl.

In some embodiments, A is pyrrolidinyl (e.g., 2-pyrrolidinyl or 3-pyrrolidinyl).

In some embodiments, A is piperidinyl (e.g., 3-piperidinyl or 4-piperidinyl).

In some embodiments, A is azetidinyl (e.g., 2-azetidinyl).

In some embodiments, A is morpholinyl (e.g., 2-morpholinyl).

In some embodiments, A is pyrrolidinyl (e.g., 2-pyrrolidinyl or 3-pyrrolidinyl). In some embodiments, A is phenyl optionally substituted with 1 or 2 R ¹ and optionally substituted with 1 or 2 R ² . In some embodiments, A is naphthyl optionally substituted with 1 or 2 R ¹ and optionally substituted with 1 or 2 R ² .

In some embodiments, A is furanyl optionally substituted with 1 or 2 R ¹ and optionally substituted with 1 R ² .

In some embodiments, A is furanyl optionally substituted with 1 R ¹ and optionally substituted with 1 or 2 R ² .

In some embodiments, A is thiophenyl optionally substituted with 1 or 2 R ¹ and optionally substituted with 1 or 2 R ² .

In some embodiments, A is oxazolyl optionally substituted with 1 or 2 R ¹ and optionally substituted with 1 or 2 R ² .

In some embodiments, A is thiazolyl optionally substituted with 1 or 2 R ¹ and optionally substituted with 1 or 2 R ² .

In some embodiments, A is oxazolyl optionally substituted with 2 R ¹ or optionally substituted with 2 R ² .

In some embodiments, A is thiazolyl optionally substituted with 2 R ¹ or optionally

substituted with 2 R ² .

In some embodiments, A is pyrazolyl optionally substituted with 1 or 2 R ¹ and optionally substituted with 1 or 2 R ² .

In some embodiments, A is pyrazolyl optionally substituted with 1 R ¹ and optionally substituted with 1 or 2 R ² .

In some embodiments, A is pyrazolyl optionally substituted with 1 or 2 R ¹ and optionally substituted with 1 R ² .

In some embodiments, A is pyridyl optionally substituted with 1 or 2 R ¹ and optionally substituted with 1 or 2 R ² .

In some embodiments, A is indazolyl optionally substituted with 1 or 2 R ¹ and optionally substituted with 1 or 2 R ² .

In some embodiments, A is phenyl substituted with 1 R ¹ and optionally substituted with 1 R ² . In some embodiments, A is naphthyl substituted with 1 R ¹ and optionally substituted with 1 R ² .

In some embodiments, A is furanyl substituted with 1 R ¹ and optionally substituted with 1 R ² . In some embodiments, A is thiophenyl substituted with 1 R ¹ and optionally substituted with 1 R ² .

In some embodiments, A is oxazolyl substituted with 1 R ¹ and optionally substituted with 1 R ² . In some embodiments, A is thiazolyl substituted with 1 R ¹ and optionally substituted with 1 R ² .

In some embodiments, A is pyrazolyl substituted with 1 R ¹ and optionally substituted with 1 R ² .

In some embodiments, A is pyridyl substituted with 1 R ¹ and optionally substituted with 1 R ² . In some embodiments, A is indazolyl optionally substituted with 1 R ¹ and optionally substituted with 1 R ² .

In some embodiments, A is phenyl substituted with 1 R ¹ and substituted with 1 R ² .

In some embodiments, A is furanyl substituted with 1 R ¹ and substituted with 1 R ² .

In some embodiments, A is thiophenyl substituted with 1 R ¹ and substituted with 1 R ² .

In some embodiments, A is oxazolyl substituted with 1 R ¹ and substituted with 1 R ² .

In some embodiments, A is thiazolyl substituted with 1 R ¹ and substituted with 1 R ² .

In some embodiments, A is pyrazolyl substituted with 1 R ¹ and substituted with 1 R ² .

In some embodiments, A is pyridyl substituted with 1 R ¹ and substituted with 1 R ² .

In some embodiments, A is pyrrolidinyl (e.g., 2-pyrrolidinyl or 3-pyrrolidinyl) substituted with 1 R ¹ .

In some embodiments, A is piperidinyl (e.g., 3-piperidinyl or 4-piperidinyl) substituted with 1 R ¹ .

In some embodiments, A is azetidinyl (e.g., 2-azetidinyl) substituted with 1 R ¹ .

In some embodiments, A is morpholinyl (e.g., 2-morpholinyl) substituted with 1 R ¹ .

In some embodiments, A is pyrrolidinyl (e.g., 2-pyrrolidinyl or 3-pyrrolidinyl) substituted with 1 R ¹ and substituted with 1 R ² .

In some embodiments, A is piperidinyl (e.g., 3-piperidinyl or 4-piperidinyl) substituted with 1 R ¹ and substituted with 1 R ² .

In some embodiments, A is azetidinyl (e.g., 2-azetidinyl) substituted with 1 R ¹ and substituted with 1 R ² .

In some embodiments, A is morpholinyl (e.g., 2-morpholinyl) substituted with 1 R ¹ and substituted with 1 R ² . In some embodiments, A is phenyl, m is 0 or 1, and n is 0, 1, or 2.

In some embodiments, A is furanyl, m is 0 or 1, and n is 0, 1, or 2.

In some embodiments, A is thiophenyl, m is 0 or 1, and n is 0, 1, or 2.

In some embodiments, A is oxazolyl, m is 0 or 1, and n is 0, 1, or 2.

In some embodiments, A is thiazolyl, m is 0 or 1, and n is 0, 1, or 2. In some embodiments, A is pyrazolyl, m is 0 or 1, and n is 0, 1, or 2.

In some embodiments, A is pyridyl, m is 0 or 1, and n is 0, 1, or 2.

In some embodiments, A is indazolyl, m is 0 or 1, and n is 0, 1, or 2.

In some embodiments, A is phenyl, m is 0, and n is 0 or 1.

In some embodiments, A is furanyl, m is 0, and n is 0 or 1.

In some embodiments, A is thiophenyl, m is 0, and n is 0 or 1.

In some embodiments, A is oxazolyl, m is 0, and n is 0 or 1.

In some embodiments, A is thiazolyl, m is 0, and n is 0 or 1.

In some embodiments, A is pyrazolyl, m is 0, and n is 0 or 1.

In some embodiments, A is pyridyl, m is 0, and n is 0 or 1.

In some embodiments, A is pyrrolidinyl (e.g., 2-pyrrolidinyl or 3-pyrrolidinyl), m is 0, and n is 0 or 1.

In some embodiments, A is piperidinyl (e.g., 3-piperidinyl or 4-piperidinyl), m is 0, and n is 0 or 1.

In some embodiments, A is azetidinyl (e.g., 2-azetidinyl), m is 0, and n is 0 or 1.

In some embodiments, A is morpholinyl (e.g., 2-morpholinyl), m is 0, and n is 0 or 1.

In some embodiments, A is norbornanyl.

In some embodiments, A is one of the rings disclosed hereinbelow optionally substituted as disclosed hereinbelow, wherein in each case the bond that is shown as being broken by the wavy line connects A to the Z variable in Formula AA.

In some embodiments, the optionally substituted ring A is . In some embodiments, the optionally substituted ring A is . In some embodiments, the optionally substituted ring A is . In some embodiments, the optionally substituted ring A is . In some embodiments, the optionally substituted ring A is . In some embodiments, the optionally substituted ring A is . In some embodiments, the optionally substituted ring _. In some embodiments, the optionally substituted ring A is . In some embodiments, the optionally substituted ring A is .

R ¹

In some embodiments, the optionally substituted ring A is . In some embodiments, the optionally substituted ring _. In some embodiments, the optionally substituted ring A is . In some embodiments, the optionally substituted ring A is . In some embodiments, the optionally substituted ring . In some embodiments, the optionally substituted ring A is . In some embodiments, the optionally substituted ring A is .

In some embodiments, the optionally substituted ring A is . In some embodiments, the optionally substituted ring . In some embodiments, the optionally substituted ring . In some embodiments, the optionally substituted ring A is . In some embodiments, the optionally substituted ring . In some embodiments, the optionally substituted ring . In some embodiments, the optionally substituted ring A is . In some embodiments, the optionally substituted ring A is . In some embodiments, the optionally substituted ring A is . In some embodiments, the optionally substituted ring A is . In some embodiments, the optionally substituted ring A is

In some embodiments, the optionally substituted ring A is

In some embodiments, the optionally substituted ring A is

In some embodiments, the optionally substituted ring A is

In some embodiments, the optionally substituted ring A is . In some embodiments, the optionally substituted ring A is

In some embodiments, the optionally substituted ring A is

In some embodiments, the optionally substituted ring

In some embodiments, the optionally substituted ring A is

In some embodiments, the optionally substituted ring A is

In some embodiments, the optionally substituted ring A

In some embodiments, the optionally substituted ring A is

In some embodiments, the optionally substituted ring A is . In some embodiments, the optionally substituted ring A is . In some embodiments, the optionally substituted ring A is . In some embodiments, the optionally substituted ring . In some embodiments, the optionally substituted ring . In some embodiments, the optionally substituted ring A is . In some embodiments, the optionally substituted ring . In some embodiments, the optionally substituted ring A is . In some embodiments, the optionally substituted ring A is . In some embodiments, the optionally substituted ring A is . In some embodiments, the optionally substituted ring A is . In some embodiments, the optionally substituted ring A is . In some embodiments, the optionally substituted ring . In some embodiments, the optionally substituted ring . In some embodiments, the optionally substituted ring . In some embodiments, the optionally substituted ring . In some embodiments, the optionally substituted ring . In some embodiments, the optionally substituted ring . In some embodiments, the optionally substituted ring . In some embodiments, the optionally substituted ring . In some embodiments, the optionally substituted ring A is . In some embodiments, the optionally substituted ring A is . In some embodiments, the optionally substituted ring . In some embodiments, the optionally substituted ring . In some embodiments, the optionally substituted ring . In some embodiments, the optionally substituted ring A is . In some embodiments, the optionally substituted ring . In some embodiments, the optionally substituted ring A is . In some embodiments, the optionally substituted ring A is . In some embodiments, the optionally substituted ring . In some embodiments, the optionally substituted ring A is . In some embodiments, the optionally substituted ring . In some embodiments, the optionally substituted ring . In some embodiments, the optionally substituted ring A is . In some embodiments, the optionally substituted ring . In some embodiments, the optionally substituted ring . In some embodiments, the optionally substituted ring .

In some embodiments, the optionally substituted ring A is . In some embodiments, the optionally substituted ring A is . In some embodiments, the optionally substituted ring . In some embodiments, the optionally substituted ring . In some embodiments, the optionally substituted ring A is .

In some embodiments, the optionally substituted ring A is . In some embodiments, the optionally substituted ring A is . In some embodiments, the optionally substituted ring . In some embodiments, the optionally substituted ring . In some embodiments, the optionally substituted ring A is . In some embodiments, the optionally substituted ring . In some embodiments, the optionally substituted ring A is . In some embodiments, the optionally substituted ring .

In some embodiments, the optionally substituted ring A is . In some embodiments, the optionally substituted ring A is . In some embodiments, the optionally substituted ring . In some embodiments, the optionally substituted ring . In some embodiments, the optionally substituted ring .

In some embodiments, the optionally substituted ring .

In some embodiments, the optionally substituted ring A is .

In some embodiments, the optionally substituted ring .

In some embodiments, the optionally substituted ring A is .

In some embodiments, the optionally substituted ring .

In some embodiments, the optionally substituted ring A is The groups R ¹ and R ²

In some embodiments,

R ¹ and R ² are each independently selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, halo, CN, NO2, COC ₁ -C ₆ alkyl, CO-C ₆ -C ₁₀ aryl, CO(5- to 10-membered heteroaryl), CO ₂ C ₁ -C ₆ alkyl, CO ₂ C ₃ -C ₈ cycloalkyl, OCOC ₁ -C ₆ alkyl, OCOC ₆ -C ₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, NH2, NHC ₁ -C ₆ alkyl, N(C ₁ -C ₆ alkyl)2, CONR ⁸ R ⁹ , SF5, SC ₁ -C ₆ alkyl, S(O2)C ₁ -C ₆ alkyl, S(O2)NR ¹¹ R ¹² , S(O)C ₁ -C ₆ alkyl, C3-C7 cycloalkyl and 3- to 7- membered heterocycloalkyl,

wherein the C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C3-C7 cycloalkyl and 3- to 7-membered

heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC ₁ -C ₆ alkyl, CONR ⁸ R ⁹ , 3- to 7-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, OCOC ₁ -C ₆ alkyl, OCOC ₆ -C ₁₀ aryl, OCO(5- to 10-membered heteroaryl), and OCO(3- to 7-membered heterocycloalkyl);

wherein each C ₁ -C ₆ alkyl substituent and each C ₁ -C ₆ alkoxy substituent of the R ¹ or R ² C3-C7 cycloalkyl or of the R ¹ or R ² 3- to 7-membered heterocycloalkyl is further optionally independently substituted with one to three hydroxy, halo, NR ⁸ R ⁹ , or oxo; wherein the 3- to 7-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents independently selected from halo, C ₁ -C ₆ alkyl, and OC ₁ -C ₆ alkyl;

or at least one pair of R ¹ and R ² on adjacent atoms, taken together with the atoms connecting them, independently form at least one C4-C8 carbocyclic ring or at least one 5- to-8- membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, halo, oxo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC ₁ -C ₆ alkyl, C ₆ -C ₁₀ aryl, and CONR ⁸ R ⁹ ; In some embodiments,

R ¹ and R ² are each independently selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, halo, CN, NO ₂ , COC ₁ -C ₆ alkyl, CO-C ₆ -C ₁₀ aryl; CO(5- to 10-membered heteroaryl); CO2C ₁ -C ₆ alkyl, CO2C3-C8 cycloalkyl, OCOC ₁ -C ₆ alkyl, OCOC ₆ -C ₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, NH ₂ , NHC ₁ -C ₆ alkyl, N(C ₁ -C ₆ alkyl) ₂ , CONR ⁸ R ⁹ , SF ₅ , SC ₁ -C ₆ alkyl, S(O ₂ )C ₁ -C ₆ alkyl, S(O ₂ )NR ¹¹ R ¹² , S(O)C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl and 3- to 7- membered heterocycloalkyl,

wherein the C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₃ -C ₇ cycloalkyl and 3- to 7-membered

heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC ₁ -C ₆ alkyl, CONR ⁸ R ⁹ , 3- to 7-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, OCOC ₁ -C ₆ alkyl, OCOC ₆ -C ₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC ₁ -C ₆ alkyl, NHCOC ₆ -C ₁₀ aryl, NHCO(5- to 10- membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), and NHCOC2-C6 alkynyl; wherein each C ₁ -C ₆ alkyl substituent and each C ₁ -C ₆ alkoxy substituent of the R ¹ or R ² C ₃ -C ₇ cycloalkyl or of the R ¹ or R ² 3- to 7-membered heterocycloalkyl is further optionally independently substituted with one to three hydroxy, halo, NR ⁸ R ⁹ , or oxo; wherein the 3- to 7-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, NHCOC ₆ -C ₁₀ aryl, NHCO(5- to 10-membered heteroaryl) and NHCO(3- to 7-membered heterocycloalkyl) are optionally substituted with one or more substituents independently selected from halo, C ₁ -C ₆ alkyl, and OC ₁ -C ₆ alkyl;

or at least one pair of R ¹ and R ² on adjacent atoms, taken together with the atoms connecting them, independently form at least one C ₄ -C ₈ carbocyclic ring or at least one 5- to 8- membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, halo, oxo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC ₁ -C ₆ alkyl, C ₆ -C ₁₀ aryl, and CONR ⁸ R ⁹ ; In some embodiments,

R ¹ and R ² are each independently selected from C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, halo, CN, NO2, COC ₁ -C ₆ alkyl, CO-C ₆ -C ₁₀ aryl, CO(5- to 10-membered heteroaryl), CO2C ₁ -C ₆ alkyl, CO2C3-C8 cycloalkyl, OCOC ₁ -C ₆ alkyl, OCOC ₆ -C ₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, NH2, NHC ₁ -C ₆ alkyl, N(C ₁ -C ₆ alkyl)2, CONR ⁸ R ⁹ , SF5, SC ₁ -C ₆ alkyl, S(O2)C ₁ -C ₆ alkyl, S(O2)NR ¹¹ R ¹² , S(O)C ₁ -C ₆ alkyl, C3-C7 cycloalkyl and 3- to 7- membered heterocycloalkyl,

wherein the C ₃ -C ₇ cycloalkyl, C ₁ -C ₆ haloalkyl, and 3- to 7-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC ₁ -C ₆ alkyl, CONR ⁸ R ⁹ , 3- to 7-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, OCOC ₁ -C ₆ alkyl, OCOC ₆ -C ₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7- membered heterocycloalkyl), NHCOC ₁ -C ₆ alkyl, NHCOC ₆ -C ₁₀ aryl, NHCO(5- to 10- membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), and NHCOC ₂ -C ₆ alkynyl;

wherein each C ₁ -C ₆ alkyl substituent and each C ₁ -C ₆ alkoxy substituent of the R ¹ or R ² C ₃ -C ₇ cycloalkyl or of the R ¹ or R ² 3- to 7-membered heterocycloalkyl is further optionally independently substituted with one to three hydroxy, halo, NR ⁸ R ⁹ , or oxo; wherein the 3- to 7-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, NHCOC ₆ -C ₁₀ aryl, NHCO(5- to 10-membered heteroaryl) and NHCO(3- to 7-membered heterocycloalkyl) are optionally substituted with one or more substituents independently selected from halo, C ₁ -C ₆ alkyl, and OC ₁ -C ₆ alkyl;

or at least one pair of R ¹ and R ² on adjacent atoms, taken together with the atoms connecting them, independently form at least one C ₄ -C ₈ carbocyclic ring or at least one 5- to 8- membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, halo, oxo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC ₁ -C ₆ alkyl, C ₆ -C ₁₀ aryl, and CONR ⁸ R ⁹ . In some embodiments,

R ¹ and R ² are each independently selected from C ₁ -C ₆ alkyl, halo, CN, NO ₂ , COC ₁ -C ₆ alkyl, CO-C ₆ -C ₁₀ aryl, CO(5- to 10-membered heteroaryl), CO2C ₁ -C ₆ alkyl, OCOC ₁ -C ₆ alkyl, OCOC ₆ -C ₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered

heterocycloalkyl), C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, NH ₂ , NHC ₁ -C ₆ alkyl, N(C ₁ -C ₆ alkyl)2, CONR ⁸ R ⁹ , SF5, SC ₁ -C ₆ alkyl, S(O2)C ₁ -C ₆ alkyl, S(O2)NR ¹¹ R ¹² , S(O)C ₁ -C ₆ alkyl, C3- C7 cycloalkyl and 3- to 7-membered heterocycloalkyl,

wherein the C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₃ -C ₇ cycloalkyl and 3- to 7-membered

heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC ₁ -C ₆ alkyl, CONR ⁸ R ⁹ , 3- to 7-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, OCOC ₁ -C ₆ alkyl, OCOC ₆ -C ₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC ₁ -C ₆ alkyl, NHCOC ₆ -C ₁₀ aryl, NHCO(5- to 10- membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), and NHCOC ₂ -C ₆ alkynyl;

wherein each C ₁ -C ₆ alkyl substituent and each C ₁ -C ₆ alkoxy substituent of the R ¹ or R ² C3-C7 cycloalkyl or of the R ¹ or R ² 3- to 7-membered heterocycloalkyl is further optionally independently substituted with one to three hydroxy, halo, NR ⁸ R ⁹ , or oxo; wherein the 3- to 7-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, NHCOC ₆ -C ₁₀ aryl, NHCO(5- to 10-membered heteroaryl) and NHCO(3- to 7-membered heterocycloalkyl) are optionally substituted with one or more substituents independently selected from halo, C ₁ -C ₆ alkyl, and OC ₁ -C ₆ alkyl; or at least one pair of R ¹ and R ² on adjacent atoms, taken together with the atoms connecting them, independently form at least one C ₄ -C ₈ carbocyclic ring or at least one 5- to 8- membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, halo, oxo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC ₁ -C ₆ alkyl, C ₆ -C ₁₀ aryl, and CONR ⁸ R ⁹ . In some embodiments,

R ¹ and R ² are each independently selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, halo, CN, NO ₂ , COC ₁ -C ₆ alkyl, CO-C ₆ -C ₁₀ aryl, CO(5- to 10-membered heteroaryl), CO2C ₁ -C ₆ alkyl, CO2C3-C8 cycloalkyl, OCOC ₁ -C ₆ alkyl, OCOC ₆ -C ₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, NH ₂ , NHC ₁ -C ₆ alkyl, N(C ₁ -C ₆ alkyl) ₂ , CONR ⁸ R ⁹ , SF ₅ , SC ₁ -C ₆ alkyl, S(O2)C ₁ -C ₆ alkyl, S(O2)NR ¹¹ R ¹² , S(O)C ₁ -C ₆ alkyl, C3-C7 cycloalkyl and 3- to 7- membered heterocycloalkyl,

wherein the C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₃ -C ₇ cycloalkyl and 3- to 7-membered

heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC ₁ -C ₆ alkyl, CONR ⁸ R ⁹ , 3- to 7-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, OCOC ₁ -C ₆ alkyl, OCOC ₆ -C ₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC ₁ -C ₆ alkyl, NHCOC ₆ -C ₁₀ aryl, NHCO(5- to 10- membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), and NHCOC ₂ -C ₆ alkynyl;

wherein each C ₁ -C ₆ alkyl substituent and each C ₁ -C ₆ alkoxy substituent of the R ¹ or R ² C ₃ -C ₇ cycloalkyl or of the R ¹ or R ² 3- to 7-membered heterocycloalkyl is further optionally independently substituted with one to three hydroxy, halo, or oxo;

wherein the 3- to 7-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, NHCO C ₆ -C ₁₀ aryl, NHCO(5- to 10-membered heteroaryl) and NHCO(3- to 7-membered heterocycloalkyl) are optionally substituted with one or more substituents independently selected from halo, C ₁ -C ₆ alkyl, and O C ₁ -C ₆ alkyl;

or at least one pair of R ¹ and R ² on adjacent atoms, taken together with the atoms connecting them, independently form at least one C ₄ -C ₈ carbocyclic ring or at least one 5- to-8- membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, halo, oxo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC ₁ -C ₆ alkyl, C ₆ -C ₁₀ aryl, and CONR ⁸ R ⁹ . In some embodiments,

R ¹ and R ² are each independently selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, halo, CN, NO ₂ , COC ₁ -C ₆ alkyl, CO-C ₆ -C ₁₀ aryl, CO(5- to 10-membered heteroaryl), CO2C ₁ -C ₆ alkyl, CO2C3-C8 cycloalkyl, OCOC ₁ -C ₆ alkyl, OCOC ₆ -C ₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, NH ₂ , NHC ₁ -C ₆ alkyl, N(C ₁ -C ₆ alkyl) ₂ , CONR ⁸ R ⁹ , SF ₅ , SC ₁ -C ₆ alkyl, S(O ₂ )C ₁ -C ₆ alkyl, S(O ₂ )NR ¹¹ R ¹² , S(O)C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl and 3- to 7- membered heterocycloalkyl,

wherein the C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₃ -C ₇ cycloalkyl and 3- to 7-membered

heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC ₁ -C ₆ alkyl, CONR ⁸ R ⁹ , 3- to 7-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, OCOC ₁ -C ₆ alkyl, OCOC ₆ -C ₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC ₁ -C ₆ alkyl, NHCOC ₆ -C ₁₀ aryl, NHCO(5- to 10- membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), and NHCOC2-C6 alkynyl;

wherein the 3- to 7-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, NHCOC ₆ -C ₁₀ aryl, NHCO(5- to 10-membered heteroaryl) and NHCO(3- to 7-membered heterocycloalkyl) are optionally substituted with one or more substituents independently selected from halo, C ₁ -C ₆ alkyl, and OC ₁ -C ₆ alkyl. In some embodiments,

R ¹ and R ² are each independently selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, halo, CN, NO2, COC ₁ -C ₆ alkyl, CO-C ₆ -C ₁₀ aryl, CO(5- to 10-membered heteroaryl), CO2C ₁ -C ₆ alkyl, CO2C3-C8 cycloalkyl, OCOC ₁ -C ₆ alkyl, OCOC ₆ -C ₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, NH2, NHC ₁ -C ₆ alkyl, N(C ₁ -C ₆ alkyl)2, CONR ⁸ R ⁹ , SF5, SC ₁ -C ₆ alkyl, S(O2)C ₁ -C ₆ alkyl, S(O2)NR ¹¹ R ¹² , S(O)C ₁ -C ₆ alkyl, C3-C7 cycloalkyl and 3- to 7- membered heterocycloalkyl,

wherein the C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₃ -C ₇ cycloalkyl and 3- to 7-membered

heterocycloalkyl are each unsubstituted; or at least one pair of R ¹ and R ² on adjacent atoms, taken together with the atoms connecting them, independently form at least one C ₄ -C ₈ carbocyclic ring or at least one 5- to-8- membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, halo, oxo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC ₁ -C ₆ alkyl, C ₆ -C ₁₀ aryl, and CONR ⁸ R ⁹ . In some embodiments,

R ¹ and R ² are each independently selected C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halo, CN, CO ₂ H, COC ₁ -C ₆ alkyl, CO ₂ C ₁ -C ₆ alkyl, C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, NH ₂ , NHC ₁ -C ₆ alkyl, N(C ₁ -C ₆ alkyl)2, NHCOC ₁ -C ₆ alkyl, CONR ⁸ R ⁹ , SC ₁ -C ₆ alkyl, S(O2)C ₁ -C ₆ alkyl, S(O)C ₁ -C ₆ alkyl, S(O ₂ )NR ¹¹ R ¹² , C ₃ -C ₇ cycloalkyl, and 3- to 7-membered heterocycloalkyl, wherein the C ₁ -C ₆ alkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C ₁ -C ₆ alkoxy, and NR ⁸ R ⁹ . In some embodiments,

R ¹ and R ² are each independently selected from C ₁ -C ₆ alkyl, halo, CN, COC ₁ -C ₆ alkyl, CO2C ₁ -C ₆ alkyl, C ₆ -C ₁₀ aryl, S(O)C ₁ -C ₆ alkyl, 5- to 10-membered heteroaryl, and 3- to 7- membered heterocycloalkyl,

wherein the C ₁ -C ₆ alkyl and 3- to 7-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy and oxo. In some embodiments, m=1; n=0; and

R ¹ is selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, halo, CN, NO ₂ , COC ₁ -C ₆ alkyl, CO-C ₆ -C ₁₀ aryl, CO(5- to 10-membered heteroaryl), CO ₂ C ₁ -C ₆ alkyl, CO ₂ C ₃ -C ₈ cycloalkyl, OCOC ₁ -C ₆ alkyl, OCOC ₆ -C ₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, NH2, NHC ₁ -C ₆ alkyl, N(C ₁ -C ₆ alkyl)2, CONR ⁸ R ⁹ , SF5, SC ₁ -C ₆ alkyl, S(O2)C ₁ -C ₆ alkyl, S(O ₂ )NR ¹¹ R ¹² , S(O)C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl and 3- to 7-membered

heterocycloalkyl,

wherein the C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C3-C7 cycloalkyl and 3- to 7-membered

heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC ₁ -C ₆ alkyl, CONR ⁸ R ⁹ , 3- to 7-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, OCOC ₁ -C ₆ alkyl, OCOC ₆ -C ₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC ₁ -C ₆ alkyl, NHCOC ₆ -C ₁₀ aryl, NHCO(5- to 10- membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), and NHCOC ₂ -C ₆ alkynyl;

wherein the 3- to 7-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, NHCOC ₆ -C ₁₀ aryl, NHCO(5- to 10-membered heteroaryl) and NHCO(3- to 7-membered heterocycloalkyl) are optionally substituted with one or more substituents independently selected from halo, C ₁ -C ₆ alkyl, and OC ₁ -C ₆ alkyl. In some embodiments , m=1; n=0; and,

R ¹ is selected from C ₁ -C ₆ alkyl, halo, CN, COC ₁ -C ₆ alkyl, CO2C ₁ -C ₆ alkyl, C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, S(O)C ₁ -C ₆ alkyl, and 3- to 7-membered heterocycloalkyl, wherein the C ₁ -C ₆ alkyl and 3- to 7-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy and oxo. In some embodiments, m=1; n=1; and

R ¹ and R ² are each independently selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, halo, CN, NO2, COC ₁ -C ₆ alkyl, CO-C ₆ -C ₁₀ aryl, CO(5- to 10-membered heteroaryl), CO ₂ C ₁ -C ₆ alkyl, CO ₂ C ₃ -C ₈ cycloalkyl, OCOC ₁ -C ₆ alkyl, OCOC ₆ -C ₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, NH2, NHC ₁ -C ₆ alkyl, N(C ₁ -C ₆ alkyl)2, CONR ⁸ R ⁹ , SF5, SC ₁ -C ₆ alkyl, S(O ₂ )C ₁ -C ₆ alkyl, S(O ₂ )NR ¹¹ R ¹² , S(O)C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl and 3- to 7- membered heterocycloalkyl,

wherein the C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C3-C7 cycloalkyl and 3- to 7-membered

heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC ₁ -C ₆ alkyl, CONR ⁸ R ⁹ , 3- to 7-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, OCOC ₁ -C ₆ alkyl, OCOC ₆ -C ₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC ₁ -C ₆ alkyl, NHCOC ₆ -C ₁₀ aryl, NHCO(5- to 10- membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), and NHCOC2-C6 alkynyl;

wherein the 3- to 7-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, NHCOC ₆ -C ₁₀ aryl, NHCO(5- to 10-membered heteroaryl) and NHCO(3- to 7-membered heterocycloalkyl) are optionally substituted with one or more substituents independently selected from halo, C ₁ -C ₆ alkyl, and OC ₁ -C ₆ alkyl. In some embodiments , m=1; n=1; and,

R ¹ and R ² are each independently selected from C ₁ -C ₆ alkyl, halo, CN, COC ₁ -C ₆ alkyl, CO ₂ C ₁ -C ₆ alkyl, C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, S(O)C ₁ -C ₆ alkyl, and 3- to 7- membered heterocycloalkyl,

wherein the C ₁ -C ₆ alkyl and 3- to 7-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy and oxo. In some embodiments, m=1; n=1; and

R ¹ and R ² are on adjacent atoms, and taken together with the atoms connecting them, form a C ₄ -C ₈ carbocyclic ring or a 5- to-8-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, halo, oxo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC ₁ -C ₆ alkyl, C ₆ -C ₁₀ aryl, and CONR ⁸ R ⁹ . In some embodiments, m=1; n=1; and

R ¹ and R ² are on adjacent atoms, and taken together with the atoms connecting them, form a C6 carbocyclic ring or a 5-to-6-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, halo, oxo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC ₁ -C ₆ alkyl, C ₆ -C ₁₀ aryl, and CONR ⁸ R ⁹ . In some embodiments, m=1; n=1; and R ¹ and R ² are on adjacent atoms, and taken together with the atoms connecting them, form a C ₅ carbocyclic ring or a 5- to-6-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, halo, oxo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, COOC ₁ -C ₆ alkyl, C ₆ -C ₁₀ aryl, and CONR ⁸ R ⁹ . In some embodiments, m=1; n=1; and

R ¹ and R ² are on adjacent atoms, and taken together with the atoms connecting them, form a C4-C8 carbocyclic ring or a 5- to 8-membered heterocyclic ring containing 1 or 2

heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is unsubstituted. In some embodiments, R ¹ and R ² are each independently selected from methyl, ethyl, isopropyl, 2-hydroxy-2-propyl, dimethylamino, aminomethyl, methylaminomethyl, dimethylaminomethyl, methoxycarbonyl, and carboxyl. Particular embodiments wherein ring A is substituted with one R ¹ (i.e., m=1 and n=0) and/or wherein the 3-10-membered heterocycloalkylene or C ₃ -C ₁₀ cycloalkyl of Z is substituted with one R ¹ :

In some embodiments, R ¹ is C ₁ -C ₆ alkyl optionally substituted with one or more hydroxy. In some embodiments, R ¹ is 1-hydroxy-2-methylpropan-2-yl.

In some embodiments, R ¹ is 2-hydroxyethyl. In some embodiments, R ¹ is C ₁ -C ₆ alkyl.

In some embodiments, R ¹ is methyl.

In some embodiments, R ¹ is isopropyl.

In some embodiments, R ¹ is isopropyl.

In some embodiments, R ¹ is C ₁ -C ₆ alkyl substituted with hydroxy at the carbon directly connected to ring A.

In some embodiments, R ¹ is 2-hydroxy-2-propyl.

In some embodiments, R ¹ is hydroxymethyl.

In some embodiments, R ¹ is 1-hydroxyethyl.

In some embodiments, R ¹ is 1-hydroxy-2-propyl. In some embodiments, R ¹ is C ₁ -C ₆ alkyl substituted with two or more hydroxy groups.

In some embodiments, R ¹ is C ₁ -C ₆ alkyl substituted with two or more hydroxy groups, wherein one of the two or more hydroxy groups is bonded to the carbon directly connected to ring A.

In some embodiments, R ¹ is 1,2-dihydroxy-prop-2-yl. In some embodiments, R ¹ is C ₃ -C ₇ cycloalkyl optionally substituted with one or more hydroxy.

In some embodiments, R ¹ is C3-C7 cycloalkyl.

In some embodiments, R ¹ is C3-C7 cycloalkyl substituted with hydroxy at the carbon directly connected to ring A.

In some embodiments, R ¹ is 1-hydroxy-1-cyclopropyl.

In some embodiments, R ¹ is 1-hydroxy-1-cyclobutyl.

In some embodiments, R ¹ is 1-hydroxy-1-cyclopentyl.

In some embodiments, R ¹ is 1-hydroxy-1-cyclohexyl.

In some embodiments, R ¹ is 3- to 7-membered heterocycloalkyl optionally substituted with one or more hydroxy.

In some embodiments, R ¹ is 3- to 7-membered heterocycloalkyl.

In some embodiments, R ¹ is morpholinyl (e.g., 1-morpholinyl).

In some embodiments, R ¹ is 1,3-dioxolan-2-yl.

In some embodiments, R ¹ is 3- to 7-membered heterocycloalkyl optionally substituted with one or more C ₁ -C ₆ alkyl.

In some embodiments, R ¹ is 1-methylpyrrolidin-2-yl.

In some embodiments, R ¹ is 3- to 7-membered heterocycloalkyl substituted with hydroxy at the carbon directly connected to ring A.

In some embodiments, R ¹ is C ₁ -C ₆ alkyl optionally substituted with one or more oxo.

In some embodiments, R ¹ is COCH ₃ .

In some embodiments, R ¹ is COCH ₂ CH ₃ .

In some embodiments, R ¹ is C3-C7 cycloalkyl optionally substituted with one or more oxo. In some embodiments, R ¹ is 3- to 7-membered heterocycloalkyl optionally substituted with one or more oxo.

In some embodiments, R ¹ is C ₁ -C ₆ alkyl optionally substituted with one or more C ₁ -C ₆ alkoxy.

In some embodiments, R ¹ is 2-methoxy-2-propyl.

In some embodiments, R ¹ is methoxymethyl. In some embodiments, R ¹ is C ₃ -C ₇ cycloalkyl optionally substituted with one or more C ₁ -C ₆ alkoxy. In some embodiments, R ¹ is 3- to 7-membered heterocycloalkyl optionally substituted with one or more C ₁ -C ₆ alkoxy.

In some embodiments, R ¹ is C ₁ -C ₆ alkyl optionally substituted with one or more NR ⁸ R ⁹ . In some embodiments, R ¹ is C ₁ -C ₆ alkyl substituted with NR ⁸ R ⁹ at the carbon directly connected to ring A.

In some embodiments, R ¹ is (methylamino)methyl.

In some embodiments, R ¹ is (dimethylamino)methyl.

In some embodiments, R ¹ is aminomethyl.

In some embodiments, R ¹ is N-methylacetamidomethyl.

In some embodiments, R ¹ is 1-(dimethylamino)eth-1-yl.

In some embodiments, R ¹ is 2-(dimethylamino)prop-2-yl.

In some embodiments, R ¹ is (2-methoxy-eth-1-yl)(methyl)aminomethyl.

In some embodiments, R ¹ is (methyl)(acetyl)aminomethyl.

In some embodiments, R ¹ is (methyl)(cyclopropylmethyl)aminomethyl.

In some embodiments, R ¹ is (methyl)(2,2-difluoroeth-1-yl)aminomethyl. In some embodiments, R ¹ is C3-C7 cycloalkyl optionally substituted with one or more NR ⁸ R ⁹ . In some embodiments, R ¹ is 3- to 7-membered heterocycloalkyl optionally substituted with one or more NR ⁸ R ⁹ .

In some embodiments, R ¹ is C ₁ -C ₆ haloalkyl optionally substituted with one or more hydroxy.

In some embodiments, R ¹ is C ₁ -C ₆ alkoxy.

In some embodiments, R ¹ is C ₁ -C ₆ haloalkoxy. In some embodiments, R ¹ is C ₁ -C ₆ alkyl optionally substituted with 3- to 7-membered heterocycloalkyl, wherein the 3- to 7-membered heterocycloalkyl is further optionally substituted as defined elsewhere herein.

In some embodiments, R ¹ is pyrrolidinylmethyl (e.g., pyrrolidin-1-ylmethyl).

In some embodiments, R ¹ is optionally substituted pyrrolidinylmethyl (e.g., 3,3- difluoropyrrolidin-1-ylmethyl).

In some embodiments, R ¹ is azetidinylmethyl (e.g., azetidin-1-ylmethyl).

In some embodiments, R ¹ is optionally substituted azetidinylmethyl (e.g., 3-methoxyazetidin- 1-ylmethyl).

In some embodiments, R ¹ is morpholinylmethyl (e.g., morpholin-4-ylmethyl). In some embodiments, R ¹ is halo.

In some embodiments, R ¹ is fluoro.

In some embodiments, R ¹ is chloro.

In some embodiments, R ¹ is CN.

In some embodiments, R ¹ is NO _2.

In some embodiments, R ¹ is COC ₁ -C ₆ alkyl.

In some embodiments, R ¹ is CO-C ₆ -C ₁₀ aryl.

In some embodiments, R ¹ is CO(5- to 10-membered heteroaryl).

In some embodiments, R ¹ is CO ₂ C ₁ -C ₆ alkyl.

In some embodiments, R ¹ is CO2C3-C8 cycloalkyl.

In some embodiments, R ¹ is OCOC ₁ -C ₆ alkyl.

In some embodiments, R ¹ is OCOC ₆ -C ₁₀ aryl.

In some embodiments, R ¹ is OCO(5- to 10-membered heteroaryl). In some embodiments, R ¹ is OCO(3- to 7-membered heterocycloalkyl). In some embodiments, R ¹ is C ₆ -C ₁₀ aryl.

In some embodiments, R ¹ is phenyl.

In some embodiments, R ¹ is 5- to 10-membered heteroaryl.

In some embodiments, R ¹ is pyridyl (e.g., 4-pyridyl).

In some embodiments, R ¹ is pyrazolyl (e.g., 1-pyrazolyl).

In some embodiments, R ¹ is NH2.

In some embodiments, R ¹ is NHC ₁ -C ₆ alkyl.

In some embodiments, R ¹ is N(C ₁ -C ₆ alkyl) ₂ .

In some embodiments, R ¹ is CONR ⁸ R ⁹ .

In some embodiments, R ¹ is SF ₅ .

In some embodiments, R ¹ is SC ₁ -C ₆ alkyl,

In some embodiments, R ¹ is S(O2)C ₁ -C ₆ alkyl.

In some embodiments, R ¹ is S(O2)CH3.

In some embodiments, R ¹ is S(O ₂ )NR ¹¹ R ¹² .

In some embodiments, R ¹ is S(O2)N(CH3)2.

In some embodiments, R ¹ is S(O)C ₁ -C ₆ alkyl.

In some embodiments, R ¹ is S(O)CH ₃ .

In some embodiments, R ¹ is attached to a carbon of an aryl ring A. In some embodiments, R ¹ is attached to a carbon of a heteroaryl ring A. In some embodiments, R ¹ is attached to a nitrogen of a heteroaryl ring A. Particular embodiments wherein ring A is substituted with one R ¹ and one R ² m=1 and

and/or wherein the 3-10-membered heterocycloalkylene or C3-C10 cycloalkyl of Z is substituted with one R ¹ and one R ² :

In some embodiments, R ¹ is C ₁ -C ₆ alkyl optionally substituted with one or more hydroxy, and R ² is C ₁ -C ₆ alkyl optionally substituted with one or more hydroxy.

In some embodiments, R ¹ is 1-hydroxy-2-methylpropan-2-yl, and R ² is methyl.

In some embodiments, R ¹ is 2-hydroxy-2-propyl and R ² is methyl.

In some embodiments, R ¹ is 2-hydroxy-2-propyl and R ² is isopropyl.

In some embodiments, R ¹ is 2-hydroxy-2-propyl and R ² is 2-hydroxy-2-propyl.

In some embodiments, R ¹ is 2-hydroxy-2-propyl and R ² is 1-hydroxyethyl.

In some embodiments, R ¹ is hydroxymethyl and R ² is methyl.

In some embodiments, R ¹ is 1-hydroxyethyl and R ² is methyl.

In some embodiments, R ¹ is 2-hydroxyethyl and R ² is methyl.

In some embodiments, R ¹ is 1-hydroxy-2-propyl and R ² is methyl.

In some embodiments, R ¹ is C ₁ -C ₆ alkyl optionally substituted with one or more hydroxy, and R ² is C ₆ -C ₁₀ aryl.

In some embodiments, R ¹ is 2-hydroxy-2-propyl and R ² is phenyl.

In some embodiments, R ¹ is C ₁ -C ₆ alkyl optionally substituted with one or more hydroxy, and R ² is 5- to 10-membered heteroaryl.

In some embodiments, R ¹ is 2-hydroxy-2-propyl and R ² is pyridyl.

In some embodiments, R ¹ is 2-hydroxy-2-propyl and R ² is pyrazolyl.

In some embodiments, R ¹ is C ₁ -C ₆ alkyl optionally substituted with one or more hydroxy, and R ² is SF ₅ .

In some embodiments, R ¹ is C ₁ -C ₆ alkyl optionally substituted with one or more hydroxy, and R ² is SC ₁ -C ₆ alkyl,

In some embodiments, R ¹ is C ₁ -C ₆ alkyl optionally substituted with one or more hydroxy, and R ² is S(O ₂ )C ₁ -C ₆ alkyl.

In some embodiments, R ¹ is C ₁ -C ₆ alkyl optionally substituted with one or more hydroxy, and R ² is S(O2)CH3.

In some embodiments, R ¹ is C ₁ -C ₆ alkyl optionally substituted with one or more hydroxy, and R ² is halo.

In some embodiments, R ¹ is 2-hydroxy-2-propyl and R ² is chloro. In some embodiments, R ¹ is 2-hydroxy-2-propyl and R ² is fluoro.

In some embodiments, R ¹ is C ₃ -C ₇ cycloalkyl optionally substituted with one or more hydroxy, and R ² is C ₁ -C ₆ alkyl.

In some embodiments, R ¹ is 1-hydroxy-1-cyclopropyl, and R ² is methyl.

In some embodiments, R ¹ is 1-hydroxy-1-cyclobutyl, and R ² is methyl.

In some embodiments, R ¹ is 1-hydroxy-1-cyclopentyl, and R ² is methyl.

In some embodiments, R ¹ is 1-hydroxy-1-cyclohexyl, and R ² is methyl.

In some embodiments, R ¹ is 3- to 7-membered heterocycloalkyl optionally substituted with one or more hydroxy, and R ² is C ₁ -C ₆ alkyl.

In some embodiments, R ¹ is morpholinyl, and R ² is methyl.

In some embodiments, R ¹ is 1,3-dioxolan-2-yl, and R ² is methyl.

In some embodiments, R ¹ is 3- to 7-membered heterocycloalkyl optionally substituted with one or more hydroxy, and R ² is halo.

In some embodiments, R ¹ is 1,3-dioxolan-2-yl, and R ² is fluoro.

In some embodiments, R ¹ is 1,3-dioxolan-2-yl, and R ² is chloro.

In some embodiments, R ¹ is C ₁ -C ₆ alkyl optionally substituted with one or more oxo, and R ² is methyl.

In some embodiments, R ¹ is COCH3, and R ² is methyl.

In some embodiments, R ¹ is C ₁ -C ₆ alkyl optionally substituted with one or more C ₁ -C ₆ alkoxy, and R ² is C ₁ -C ₆ alkyl.

In some embodiments, R ¹ is 2-methoxy-2-propyl, and R ² is methyl.

In some embodiments, R ¹ is C ₁ -C ₆ alkyl optionally substituted with one or more NR ⁸ R ⁹ , and R ² is C ₁ -C ₆ alkyl.

In some embodiments, R ¹ is (dimethylamino)methyl, and R ² is methyl. In some embodiments, R ¹ is C ₁ -C ₆ alkyl optionally substituted with one or more NR ⁸ R ⁹ , and R ² is halo.

In some embodiments, R ¹ is (dimethylamino)methyl, and R ² is fluoro.

In some embodiments, R ¹ is (dimethylamino)methyl, and R ² is fluoro.

In some embodiments, R ¹ is (methylamino)methyl, and R ² is fluoro.

In some embodiments, R ¹ is aminomethyl, and R ² is fluoro.

In some embodiments, R ¹ is C ₁ -C ₆ alkyl, and R ² is C ₁ -C ₆ alkyl.

In some embodiments, R ¹ is methyl, and R ² is methyl. In some embodiments, R ² is 1-hydroxy-2-methylpropan-2-yl, and R ¹ is methyl. In some embodiments, R ² is 2-hydroxy-2-propyl and R ¹ is methyl.

In some embodiments, R ² is 2-hydroxy-2-propyl and R ¹ is isopropyl.

In some embodiments, R ² is 2-hydroxy-2-propyl and R ¹ is 1-hydroxyethyl.

In some embodiments, R ² is hydroxymethyl and R ¹ is methyl.

In some embodiments, R ² is 1-hydroxyethyl and R ¹ is methyl.

In some embodiments, R ² is 2-hydroxyethyl and R ¹ is methyl.

In some embodiments, R ² is 1-hydroxy-2-propyl and R ¹ is methyl.

In some embodiments, R ² is C ₁ -C ₆ alkyl optionally substituted with one or more hydroxy, and R ¹ is C ₆ -C ₁₀ aryl.

In some embodiments, R ² is 2-hydroxy-2-propyl and R ¹ is phenyl.

In some embodiments, R ² is C ₁ -C ₆ alkyl optionally substituted with one or more hydroxy, and R ¹ is 5- to 10-membered heteroaryl.

In some embodiments, R ² is 2-hydroxy-2-propyl and R ¹ is pyridyl.

In some embodiments, R ² is 2-hydroxy-2-propyl and R ¹ is pyrazolyl.

In some embodiments, R ² is C ₁ -C ₆ alkyl optionally substituted with one or more hydroxy, and R ¹ is SF5.

In some embodiments, R ² is C ₁ -C ₆ alkyl optionally substituted with one or more hydroxy, and R ¹ is SC ₁ -C ₆ alkyl.

In some embodiments, R ² is C ₁ -C ₆ alkyl optionally substituted with one or more hydroxy, and R ¹ is S(O2)C ₁ -C ₆ alkyl.

In some embodiments, R ² is C ₁ -C ₆ alkyl optionally substituted with one or more hydroxy, and R ¹ is S(O ₂ )CH ₃ .

In some embodiments, R ² is C ₁ -C ₆ alkyl optionally substituted with one or more hydroxy, and R ¹ is halo.

In some embodiments, R ² is 2-hydroxy-2-propyl and R ¹ is chloro.

In some embodiments, R ² is 2-hydroxy-2-propyl and R ¹ is fluoro.

In some embodiments, R ² is C3-C7 cycloalkyl optionally substituted with one or more hydroxy, and R ¹ is C ₁ -C ₆ alkyl.

In some embodiments, R ² is 1-hydroxy-1-cyclopropyl, and R ¹ is methyl.

In some embodiments, R ² is 1-hydroxy-1-cyclobutyl, and R ¹ is methyl.

In some embodiments, R ² is 1-hydroxy-1-cyclopentyl, and R ¹ is methyl.

In some embodiments, R ² is 1-hydroxy-1-cyclohexyl, and R ¹ is methyl. In some embodiments, R ² is 3- to 7-membered heterocycloalkyl optionally substituted with one or more hydroxy, and R ¹ is C ₁ -C ₆ alkyl.

In some embodiments, R ² is morpholinyl, and R ¹ is methyl.

In some embodiments, R ² is 1,3-dioxolan-2-yl, and R ¹ is methyl.

In some embodiments, R ² is 3- to 7-membered heterocycloalkyl optionally substituted with one or more hydroxy, and R ¹ is halo.

In some embodiments, R ² is 1,3-dioxolan-2-yl, and R ¹ is fluoro.

In some embodiments, R ² is 1,3-dioxolan-2-yl, and R ¹ is chloro.

In some embodiments, R ² is C ₁ -C ₆ alkyl optionally substituted with one or more oxo, and R ¹ is methyl.

In some embodiments, R ² is COCH3, and R ¹ is methyl.

In some embodiments, R ² is C ₁ -C ₆ alkyl optionally substituted with one or more C ₁ -C ₆ alkoxy, and R ¹ is C ₁ -C ₆ alkyl.

In some embodiments, R ² is 2-methoxy-2-propyl, and R ¹ is methyl.

In some embodiments, R ² is C ₁ -C ₆ alkyl optionally substituted with one or more NR ⁸ R ⁹ , and R ¹ is C ₁ -C ₆ alkyl.

In some embodiments, R ² is (dimethylamino)methyl, and R ¹ is methyl.

In some embodiments, R ² is C ₁ -C ₆ alkyl optionally substituted with one or more NR ⁸ R ⁹ , and R ¹ is halo.

In some embodiments, R ² is (dimethylamino)methyl, and R ¹ is fluoro.

In some embodiments, R ² is (methylamino)methyl, and R ¹ is fluoro.

In some embodiments, R ² is aminomethyl, and R ¹ is fluoro. In some embodiments, R ² is C ₁ -C ₆ alkoxy, and R ¹ is C ₁ -C ₆ alkyl optionally substituted with one or more NR ⁸ R ⁹ .

In some embodiments, R ² is methoxy, and R ¹ is (dimethylamino)methyl. In some embodiments, R ¹ and R ² are each attached to a carbon of an aryl ring A.

In some embodiments, R ¹ and R ² are each attached to a carbon of a heteroaryl ring A.

In some embodiments, R ¹ is attached to a carbon and R ² is attached to a nitrogen of a heteroaryl ring A.

In some embodiments, R ² is attached to a carbon and R ¹ is attached to a nitrogen of a heteroaryl ring A. In some embodiments, R ¹ and R ² are on adjacent atoms, and taken together with the atoms connecting them, form a C ₅ carbocyclic ring optionally substituted with one or more substituents independently selected from hydroxy, halo, oxo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC ₁ -C ₆ alkyl, C ₆ -C ₁₀ aryl, and CONR ⁸ R ⁹ .

In some embodiments, R ¹ and R ² are on adjacent atoms, and taken together with the atoms connecting them, form a C ₅ aliphatic carbocyclic ring.

In some embodiments, R ¹ and R ² are on adjacent atoms, and taken together with the atoms connecting them, form a C6 carbocyclic ring optionally substituted with one or more substituents independently selected from hydroxy, halo, oxo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC ₁ -C ₆ alkyl, C ₆ -C ₁₀ aryl, and CONR ⁸ R ⁹ .

In some embodiments, R ¹ and R ² are on adjacent atoms, and taken together with the atoms connecting them, form a C ₆ aliphatic carbocyclic ring.

In some embodiments, R ¹ and R ² are on adjacent atoms, and taken together with the atoms connecting them, form a C6 aromatic carbocyclic ring.

In some embodiments, R ¹ and R ² are on adjacent atoms, and taken together with the atoms connecting them, form a 5-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, optionally substituted with one or more substituents independently selected from hydroxy, halo, oxo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC ₁ -C ₆ alkyl, C ₆ -C ₁₀ aryl, and CONR ⁸ R ⁹ .

In some embodiments, R ¹ and R ² are on adjacent atoms, and taken together with the atoms connecting them, form a 5-membered aliphatic heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S.

In some embodiments, R ¹ and R ² are on adjacent atoms, and taken together with the atoms connecting them, form a 5-membered heteroaromatic ring containing 1 or 2 heteroatoms independently selected from O, N, and S.

In some embodiments, R ¹ and R ² are on adjacent atoms, and taken together with the atoms connecting them, form a 6-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, optionally substituted with one or more substituents independently selected from hydroxy, halo, oxo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC ₁ -C ₆ alkyl, C ₆ -C ₁₀ aryl, and CONR ⁸ R ⁹ .

In some embodiments, R ¹ and R ² are on adjacent atoms, and taken together with the atoms connecting them, form a 6-membered aliphatic heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S. In some embodiments, R ¹ and R ² are on adjacent atoms, and taken together with the atoms connecting them, form a 6-membered heteroaromatic ring containing 1 or 2 heteroatoms independently selected from O, N, and S.

In some embodiments, R ¹ and R ² are different.

In some embodiments, R ¹ and R ² are different, and R ² comprises a carbonyl group.

In some embodiments, R ¹ and R ² are different, and R ² comprises 1 or 2 (e.g., 1) nitrogen atoms.

In some embodiments, R ¹ and R ² are different, and R ² comprises 1 or 2 (e.g., 1) oxygen atoms.

In some embodiments, R ¹ and R ² are different, and R ² comprises a sulfur atom.

In some embodiments, R ² and R ¹ are different, and R ² comprises a carbonyl group.

In some embodiments, R ² and R ¹ are different, and R ² comprises 1 or 2 (e.g., 1) nitrogen atoms.

In some embodiments, R ² and R ¹ are different, and R ² comprises 1 or 2 (e.g., 1) oxygen atoms.

In some embodiments, R ² and R ¹ are different, and R ² comprises a sulfur atom.

In some embodiments, R ¹ and R ² are the same.

In some embodiments, R ¹ is para or meta to R ² .

In some embodiments, R ¹ is para or ortho to R ² .

In some embodiments, R ¹ is ortho or meta to R ² .In some embodiments, R ¹ is para to R ² . In some embodiments, R ¹ is meta to R ² .

In some embodiments, R ¹ is ortho to R ² . The groups R ¹⁶ and R ¹⁷ In some embodiments, R ¹⁶ and R ¹⁷ are each independently selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, halo, CN, NO ₂ , CO ₂ H, COC ₁ -C ₆ alkyl, CO-C ₆ - C10 aryl; CO(5- to 10-membered heteroaryl); CO2C ₁ -C ₆ alkyl, CO2C3-C8 cycloalkyl, OCOC1- C ₆ alkyl, OCOC ₆ -C ₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NH ₂ , NHC ₁ -C ₆ alkyl, N(C ₁ -C ₆ alkyl) ₂ , NHCOC ₁ -C ₆ alkyl, NHCOC ₆ -C ₁₀ aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC2-C6 alkynyl, NHCOOCC ₁ -C ₆ alkyl, NH-(C=NR ¹³ )NR ¹¹ R ¹² , CONR ⁸ R ⁹ , SC ₁ -C ₆ alkyl, S(O ₂ )C ₁ -C ₆ alkyl, S(O)C ₁ -C ₆ alkyl, and S(O ₂ )NR ¹¹ R ¹² , wherein the C ₁ -C ₆ alkyl and C ₁ -C ₆ haloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC ₁ -C ₆ alkyl, CONR ⁸ R ⁹ , OCOC ₁ -C ₆ alkyl, OCOC ₆ -C ₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC ₁ -C ₆ alkyl, NHCOC ₆ -C ₁₀ aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), and NHCOC ₂ -C ₆ alkynyl. In some embodiments, R ¹⁶ and R ¹⁷ are each independently selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, halo, CN, CO ₂ H, COC ₁ -C ₆ alkyl, CO-C ₆ -C ₁₀ aryl; CO(5- to 10- membered heteroaryl); CO ₂ C ₁ -C ₆ alkyl, OCOC ₁ -C ₆ alkyl, NH ₂ , NHC ₁ -C ₆ alkyl, N(C ₁ -C ₆ alkyl)2, NHCOC ₁ -C ₆ alkyl, NHCOC ₆ -C ₁₀ aryl, NHCOC2-C6 alkynyl, NHCOOCC ₁ -C ₆ alkyl, NH-(C=NR ¹³ )NR ¹¹ R ¹² , CONR ⁸ R ⁹ , SC ₁ -C ₆ alkyl, S(O2)C ₁ -C ₆ alkyl, S(O)C ₁ -C ₆ alkyl, and S(O ₂ )NR ¹¹ R ¹² ,

wherein the C ₁ -C ₆ alkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C ₁ -C ₆ alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC ₁ -C ₆ alkyl, CONR ⁸ R ⁹ , OCOC ₁ -C ₆ alkyl, NHCOC ₁ -C ₆ alkyl, NHCOC ₆ -C ₁₀ aryl, and NHCOC ₂ -C ₆ alkynyl. In some embodiments, R ¹⁶ and R ¹⁷ are each independently selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halo, CN, CO ₂ H, COC ₁ -C ₆ alkyl, CO ₂ C ₁ -C ₆ alkyl, NH ₂ , NHC ₁ -C ₆ alkyl, N(C ₁ -C ₆ alkyl)2, NHCOC ₁ -C ₆ alkyl, CONR ⁸ R ⁹ , SC ₁ -C ₆ alkyl, S(O2)C ₁ -C ₆ alkyl, S(O)C ₁ -C ₆ alkyl, and S(O ₂ )NR ¹¹ R ¹² ,

wherein the C ₁ -C ₆ alkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C ₁ -C ₆ alkoxy, NR ⁸ R ⁹ ,

CONR ⁸ R ⁹ , and NHCOC ₁ -C ₆ alkyl. In some embodiments, R ¹⁶ and R ¹⁷ are each independently selected from C ₁ -C ₆ alkoxy, halo, CN, COC ₁ -C ₆ alkyl, CO2C ₁ -C ₆ alkyl, NH2, NHC ₁ -C ₆ alkyl, N(C ₁ -C ₆ alkyl)2, NHCOC ₁ -C ₆ alkyl, CONR ⁸ R ⁹ , SC ₁ -C ₆ alkyl, S(O ₂ )C ₁ -C ₆ alkyl, S(O)C ₁ -C ₆ alkyl, and S(O ₂ )NR ¹¹ R ¹² . In some embodiments, R ¹⁶ and R ¹⁷ are each independently selected from C ₁ -C ₆ alkoxy, halo, CN, COC ₁ -C ₆ alkyl, CO2C ₁ -C ₆ alkyl, N(C ₁ -C ₆ alkyl)2, CONR ⁸ R ⁹ , S(O2)C ₁ -C ₆ alkyl, S(O)C1- C ₆ alkyl, and S(O ₂ )NR ¹¹ R ¹² . In some embodiments, R ¹⁶ and R ¹⁷ are each independently selected from C ₁ -C ₆ alkoxy, halo, CN, COC ₁ -C ₆ alkyl, CO ₂ C ₁ -C ₆ alkyl, N(C ₁ -C ₆ alkyl) ₂ , CONR ⁸ R ⁹ , S(O ₂ )C ₁ -C ₆ alkyl, S(O)C ₁ - C ₆ alkyl, and S(O ₂ )NR ¹¹ R ¹² . In some embodiments, R ¹⁶ and R ¹⁷ are each independently selected from N(C ₁ -C ₆ alkyl)2. The variables o and p

In some embodiments, o=1 or 2.

In some embodiments, o=1.

In some embodiments, o=2.

In some embodiments, p=0, 1, 2, or 3.

In some embodiments, p=0.

In some embodiments, p=1.

In some embodiments, p=2.

In some embodiments, o=1 and p=0.

In some embodiments, o=2 and p=0.

In some embodiments, o=1 and p=1.

In some embodiments, o=1 and p=2.

In some embodiments, o=2 and p=1.

In some embodiments, o=2 and p=2.

In some embodiments, o=2 and p=3. The ring B and substitutions on the ring B

In some embodiments, B is a 5- to 10-membered monocyclic or bicyclic heteroaryl or a C6- C10 monocyclic or bicyclic aryl, such as phenyl.

In some embodiments, B is a 5- to 6-membered monocyclic heteroaryl or a C ₆ monocyclic aryl.

In some embodiments, B is a 5- to 10-membered monocyclic or bicyclic heteroaryl.

In some embodiments, B is a C ₆ -C ₁₀ monocyclic or bicyclic aryl.

In some embodiments, B is a 5-membered heteroaryl.

In some embodiments, B is a 7-10 membered monocyclic or bicyclic heteroaryl.

In some embodiments, B is phenyl substituted with 1 or 2 R ⁶ and optionally substituted with 1, 2, or 3 R ⁷ . In some embodiments, B is pyridyl substituted with 1 or 2 R ⁶ and optionally substituted with 1, 2, or 3 R ⁷ .

In some embodiments, B is indazolyl substituted with 1 or 2 R ⁶ and optionally substituted with 1, 2, or 3 R ⁷ .

In some embodiments, B is pyrazolyl substituted with 1 or 2 R ⁶ and optionally substituted with 1 or 2 R ⁷ .

In some embodiments, B is phenyl, o is 1 or 2, and p is 0, 1, 2, or 3.

In some embodiments, B is phenyl, o is 1, and p is 0, 1, 2, or 3.

In some embodiments, B is phenyl, o is 2, and p is 0, 1, 2, or 3. In some embodiments, B is one of the rings disclosed hereinbelow, substituted as disclosed hereinbelow, wherein in each case the bond that is shown as being broken by the wavy line connects B to the NH(CO)group of Formula AA.

In some embodiments, the substituted ring .

In some embodiments, the substituted ring .

In some embodiments, the substituted ring .

In some embodiments, the substituted ring .

In some embodiments, the substituted ring B is .

In some embodiments, the substituted ring . In some embodiments, the substituted ring .

In some embodiments, the substituted ring B is . In some embodiments, the substituted ring . In some embodiments, the substituted ring . In some embodiments, the substituted ring . In some embodiments, the substituted ring . In some embodiments, the substituted ring B is . In some embodiments, the substituted ring . In some embodiments, the substituted ring . In some embodiments, the substituted ring . In some embodiments, the substituted ring . In some embodiments, the substituted ring . In some embodiments, the substituted ring .

In some embodiments, the substituted ring B is .

In some embodiments, the substituted ring .

In some embodiments, the substituted ring .

In some embodiments, the substituted ring B is . In some embodiments, the substituted ring . In some embodiments, the substituted ring . In some embodiments, the substituted ring . In some embodiments, the substituted ring . In some embodiments, the substituted ring . In some embodiments, the substituted ring . In some embodiments, the substituted ring . In some embodiments, the substituted ring . In some embodiments, the substituted ring . In some embodiments, the substituted ring . In some embodiments, the substituted ring . In some embodiments, the substituted ring . In some embodiments, the substituted ring . In some embodiments, the substituted ring . In some embodiments, the substituted ring . In some embodiments, the substituted ring . In some embodiments, the substituted ring . In some embodiments, the substituted ring . In some embodiments, the substituted ring . In some embodiments, the substituted ring . In some embodiments, the substituted ring . In some embodiments, the substituted ring . In some embodiments, the substituted ring . In some embodiments, the substituted ring . In some embodiments, the substituted ring . In some embodiments, the substituted ring . In some embodiments, the substituted ring .

In some embodiments, the substituted ring B is selected from the group consisting of:

.

The groups R ⁶ and R ⁷

In some embodiments of any of the formulas disclosed herein, at least one R ⁶ is ortho to the bond connecting the B ring to the Y group of Formula AA. In some embodiments,

R ⁶ and R ⁷ are each independently selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, halo, CN, NO2, COC ₁ -C ₆ alkyl, CO2C ₁ -C ₆ alkyl, CO2C3-C8 cycloalkyl, OCOC ₁ -C ₆ alkyl, OCOC ₆ -C ₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7- membered heterocycloalkyl), C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, NH2, NHC ₁ -C ₆ alkyl, N(C ₁ -C ₆ alkyl)2, CONR ⁸ R ⁹ , SF5, S(O2)C ₁ -C ₆ alkyl, C3-C10 cycloalkyl and 3- to 10- membered heterocycloalkyl, and a C ₂ -C ₆ alkenyl,

wherein R ⁶ and R ⁷ are each optionally substituted with one or more substituents

independently selected from

hydroxy, halo, CN, oxo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC ₁ -C ₆ alkyl, CONR ⁸ R ⁹ , 3- to 7-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, OCOC ₁ -C ₆ alkyl, OCOC ₆ -C ₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7- membered heterocycloalkyl), NHCOC ₁ -C ₆ alkyl, NHCOC ₆ -C ₁₀ aryl, NHCO(5- to 10- membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC ₂ -C ₆ alkynyl, C ₆ -C ₁₀ aryloxy, and S(O ₂ )C ₁ -C ₆ alkyl; and wherein the C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy that R ⁶ or R ⁷ is substituted with is optionally substituted with one or more hydroxyl, C ₆ -C ₁₀ aryl or NR ⁸ R ⁹ , or wherein R ⁶ or R ⁷ is optionally fused to a five- to–seven-membered carbocyclic ring or heterocyclic ring containing one or two heteroatoms independently selected from oxygen, sulfur and nitrogen;

wherein the 3- to 7-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, NHCOC ₆ -C ₁₀ aryl, NHCO(5- to 10-membered heteroaryl) and NHCO(3- to 7-membered heterocycloalkyl) are optionally substituted with one or more substituents independently selected from halo, C ₁ -C ₆ alkyl, and OC ₁ -C ₆ alkyl;

or at least one pair of R ⁶ and R ⁷ on adjacent atoms, taken together with the atoms connecting them, independently form at least one C ₄ -C ₈ carbocyclic ring or at least one 5-to 8- membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy,

hydroxymethyl, halo, oxo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, NR ⁸ R ⁹ , CH2NR ⁸ R ⁹ , =NR ¹⁰ , COOC ₁ -C ₆ alkyl, C ₆ -C ₁₀ aryl, and CONR ⁸ R ⁹ . In some embodiments,

R ⁶ and R ⁷ are each independently selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, halo, CN, NO ₂ , COC ₁ -C ₆ alkyl, CO ₂ C ₁ -C ₆ alkyl, CO ₂ C ₃ -C ₈ cycloalkyl, OCOC ₁ -C ₆ alkyl, OCOC ₆ -C ₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7- membered heterocycloalkyl), C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, NH2, NHC ₁ -C ₆ alkyl, N(C ₁ -C ₆ alkyl) ₂ , CONR ⁸ R ⁹ , SF ₅ , S(O ₂ )C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl and 3- to 10- membered heterocycloalkyl, and a C ₂ -C ₆ alkenyl,

wherein R ⁶ and R ⁷ are each optionally substituted with one or more substituents

independently selected from

hydroxy, halo, CN, oxo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC ₁ -C ₆ alkyl, CONR ⁸ R ⁹ , 3- to 7-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, OCOC ₁ -C ₆ alkyl, OCOC ₆ -C ₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7- membered heterocycloalkyl), NHCOC ₁ -C ₆ alkyl, NHCOC ₆ -C ₁₀ aryl, NHCO(5- to 10- membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC ₂ -C ₆ alkynyl, C ₆ -C ₁₀ aryloxy, and S(O2)C ₁ -C ₆ alkyl; and wherein the C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy that R ⁶ or R ⁷ is substituted with is optionally substituted with one or more hydroxyl, C ₆ -C ₁₀ aryl or NR ⁸ R ⁹ , or wherein R ⁶ or R ⁷ is optionally fused to a five- to–seven-membered carbocyclic ring or heterocyclic ring containing one or two heteroatoms independently selected from oxygen, sulfur and nitrogen;

wherein the 3- to 7-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, NHCOC ₆ -C ₁₀ aryl, NHCO(5- to 10-membered heteroaryl) and NHCO(3- to 7-membered heterocycloalkyl) are optionally substituted with one or more substituents independently selected from halo, C ₁ -C ₆ alkyl, and OC ₁ -C ₆ alkyl;

or at least one pair of R ⁶ and R ⁷ on adjacent atoms, taken together with the atoms connecting them, independently form at least one C4-C6 aliphatic carbocyclic ring or at least one 5-to 6- membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy,

hydroxymethyl, halo, oxo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, NR ⁸ R ⁹ , CH2NR ⁸ R ⁹ , =NR ¹⁰ , COOC ₁ -C ₆ alkyl, C ₆ -C ₁₀ aryl, and CONR ⁸ R ⁹ . In some embodiments,

R ⁶ and R ⁷ are each independently selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, halo, CN, NO2, COC ₁ -C ₆ alkyl, CO2C ₁ -C ₆ alkyl, CO2C3-C8 cycloalkyl, OCOC ₁ -C ₆ alkyl, OCOC ₆ -C ₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7- membered heterocycloalkyl), C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, NH ₂ , NHC ₁ -C ₆ alkyl, N(C ₁ -C ₆ alkyl) ₂ , CONR ⁸ R ⁹ , SF ₅ , SC ₁ -C ₆ alkyl, S(O ₂ )C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl and 3- to 7-membered heterocycloalkyl,

wherein the C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₃ -C ₇ cycloalkyl and 3- to 7-membered

heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC ₁ -C ₆ alkyl, CONR ⁸ R ⁹ , 3- to 7-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, OCOC ₁ -C ₆ alkyl, OCOC ₆ -C ₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC ₁ -C ₆ alkyl, NHCOC ₆ -C ₁₀ aryl, NHCO(5- to 10- membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), and NHCOC2-C6 alkynyl;

wherein the 3- to 7-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, NHCOC ₆ -C ₁₀ aryl, NHCO(5- to 10-membered heteroaryl) and NHCO(3- to 7-membered heterocycloalkyl) are optionally substituted with one or more substituents independently selected from halo, C ₁ -C ₆ alkyl, and OC ₁ -C ₆ alkyl;

or at least one pair of R ⁶ and R ⁷ on adjacent atoms, taken together with the atoms connecting them, independently form at least one C4-C8 carbocyclic ring or at least one 5- to 8- membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy,

hydroxymethyl, halo, oxo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, NR ⁸ R ⁹ , CH2NR ⁸ R ⁹ , =NR ¹⁰ , COOC ₁ -C ₆ alkyl, C ₆ -C ₁₀ aryl, and CONR ⁸ R ⁹ . In some embodiments,

R ⁶ and R ⁷ are each independently selected from C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, halo, CN, NO ₂ , COC ₁ -C ₆ alkyl, CO ₂ C ₁ -C ₆ alkyl, CO ₂ C ₃ -C ₈ cycloalkyl, OCOC ₁ - C6 alkyl, OCOC ₆ -C ₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, NH2, NHC ₁ -C ₆ alkyl, N(C ₁ -C ₆ alkyl) ₂ , CONR ⁸ R ⁹ , SF ₅ , SC ₁ -C ₆ alkyl, S(O ₂ )C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl and 3- to 7- membered heterocycloalkyl,

wherein the C3-C7 cycloalkyl, C ₁ -C ₆ haloalkyl, and 3- to 7-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC ₁ -C ₆ alkyl, CONR ⁸ R ⁹ , 3- to 7-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, OCOC ₁ -C ₆ alkyl, OCOC ₆ -C ₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7- membered heterocycloalkyl), NHCOC ₁ -C ₆ alkyl, NHCOC ₆ -C ₁₀ aryl, NHCO(5- to 10- membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), and NHCOC2-C6 alkynyl;

wherein the 3- to 7-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, NHCOC ₆ -C ₁₀ aryl, NHCO(5- to 10-membered heteroaryl) and NHCO(3- to 7-membered heterocycloalkyl) are optionally substituted with one or more substituents independently selected from halo, C ₁ -C ₆ alkyl, and OC ₁ -C ₆ alkyl;

or at least one pair of R ⁶ and R ⁷ on adjacent atoms, taken together with the atoms connecting them, independently form at least one C4-C8 carbocyclic ring or at least one 5- to 8- membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, NR ⁸ R ⁹ , CH2NR ⁸ R ⁹ , =NR ¹⁰ , COOC ₁ -C ₆ alkyl, C ₆ -C ₁₀ aryl, and CONR ⁸ R ⁹ . In some embodiments,

R ⁶ and R ⁷ are each independently selected from C ₁ -C ₆ alkyl, halo, CN, NO2, COC ₁ -C ₆ alkyl, CO ₂ C ₁ -C ₆ alkyl, OCOC ₁ -C ₆ alkyl, OCOC ₆ -C ₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, NH2, NHC ₁ -C ₆ alkyl, N(C ₁ -C ₆ alkyl)2, CONR ⁸ R ⁹ , SF5, SC ₁ -C ₆ alkyl, S(O2)C ₁ -C ₆ alkyl, C3-C7 cycloalkyl and 3- to 7-membered heterocycloalkyl,

wherein the C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl and 3- to 7-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC ₁ -C ₆ alkyl, CONR ⁸ R ⁹ , 3- to 7-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, OCOC ₁ -C ₆ alkyl, OCOC ₆ -C ₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7- membered heterocycloalkyl), NHCOC ₁ -C ₆ alkyl, NHCOC ₆ -C ₁₀ aryl, NHCO(5- to 10- membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), and NHCOC ₂ -C ₆ alkynyl;

wherein the 3- to 7-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, NHCOC ₆ -C ₁₀ aryl, NHCO(5- to 10-membered heteroaryl) and NHCO(3- to 7-membered heterocycloalkyl) are optionally substituted with one or more substituents independently selected from halo, C ₁ -C ₆ alkyl, and OC ₁ -C ₆ alkyl;

or at least one pair of R ⁶ and R ⁷ on adjacent atoms, taken together with the atoms connecting them, independently form at least one C ₄ -C ₈ carbocyclic ring or at least one 5- to 8- membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy,

hydroxymethyl, halo, oxo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, NR ⁸ R ⁹ , CH2NR ⁸ R ⁹ , =NR ¹⁰ , COOC ₁ -C ₆ alkyl, C ₆ -C ₁₀ aryl, and CONR ⁸ R ⁹ . In some embodiments,

R ⁶ and R ⁷ are each independently selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, halo, CN, NO ₂ , COC ₁ -C ₆ alkyl, CO ₂ C ₁ -C ₆ alkyl, CO ₂ C ₃ -C ₈ cycloalkyl, OCOC ₁ -C ₆ alkyl, OCOC ₆ -C ₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7- membered heterocycloalkyl), C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, NH2, NHC ₁ -C ₆ alkyl, N(C ₁ -C ₆ alkyl)2, CONR ⁸ R ⁹ , SF5, SC ₁ -C ₆ alkyl, S(O2)C ₁ -C ₆ alkyl, C3-C7 cycloalkyl and 3- to 7-membered heterocycloalkyl,

wherein the C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₃ -C ₇ cycloalkyl, and 3- to 7-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC ₁ -C ₆ alkyl, CONR ⁸ R ⁹ , 3- to 7-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, OCOC ₁ -C ₆ alkyl, OCOC ₆ -C ₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC ₁ -C ₆ alkyl, NHCOC ₆ -C ₁₀ aryl, NHCO(5- to 10- membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), and NHCOC ₂ -C ₆ alkynyl;

wherein the 3- to 7-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, NHCOC ₆ -C ₁₀ aryl, NHCO(5- to 10-membered heteroaryl) and NHCO(3- to 7-membered heterocycloalkyl) are unsubstituted;

or at least one pair of R ⁶ and R ⁷ on adjacent atoms, taken together with the atoms connecting them, independently form at least one C4-C8 carbocyclic ring or at least one 5- to 8- membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy,

hydroxymethyl, halo, oxo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, NR ⁸ R ⁹ , CH ₂ NR ⁸ R ⁹ , =NR ¹⁰ , COOC ₁ -C ₆ alkyl, C ₆ -C ₁₀ aryl, and CONR ⁸ R ⁹ . In some embodiments,

R ⁶ and R ⁷ are each independently selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, halo, CN, NO2, COC ₁ -C ₆ alkyl, CO2C ₁ -C ₆ alkyl, CO2C3-C8 cycloalkyl, OCOC ₁ -C ₆ alkyl, OCOC ₆ -C ₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7- membered heterocycloalkyl), C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, NH ₂ , NHC ₁ -C ₆ alkyl, N(C ₁ -C ₆ alkyl)2, CONR ⁸ R ⁹ , SF5, SC ₁ -C ₆ alkyl, S(O2)C ₁ -C ₆ alkyl, C3-C7 cycloalkyl and 3- to 7-membered heterocycloalkyl,

wherein the C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl and 3- to 7-membered heterocycloalkyl are each unsubstituted;

or at least one pair of R ⁶ and R ⁷ on adjacent atoms, taken together with the atoms connecting them, independently form at least one C ₄ -C ₈ carbocyclic ring or at least one 5- to 8- membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, NR ⁸ R ⁹ , CH ₂ NR ⁸ R ⁹ , =NR ¹⁰ , COOC ₁ -C ₆ alkyl, C ₆ -C ₁₀ aryl, and CONR ⁸ R ⁹ . In some embodiments,

R ⁶ is independently selected from C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, halo, CN, C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, CO-C ₁ -C ₆ alkyl; CONR ⁸ R ⁹ , and 4- to 6-membered heterocycloalkyl,

wherein the C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₃ -C ₇ cycloalkyl and 4- to 6-membered

heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC ₁ -C ₆ alkyl, CONR ⁸ R ⁹ , 4- to 6-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, OCOC ₁ -C ₆ alkyl, OCOC ₆ -C ₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC ₁ -C ₆ alkyl, NHCOC ₆ -C ₁₀ aryl, NHCO(5- to 10- membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC2-C6 alkynyl;

and R ⁷ is independently selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, C1- C6 haloalkoxy, halo, CN, COC ₁ -C ₆ alkyl, CO2C ₁ -C ₆ alkyl, CO2C3-C6 cycloalkyl, OCOC ₁ -C ₆ alkyl, OCOC ₆ -C ₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, CONR ⁸ R ⁹ , SF5, S(O2)C ₁ -C ₆ alkyl, C3-C7 cycloalkyl and 4- to 6-membered heterocycloalkyl, wherein the C ₁ -C ₆ alkyl is optionally substituted with one to two C ₁ -C ₆ alkoxy;

or R ⁶ and R ⁷ , taken together with the atoms connecting them, independently form C ₄ -C ₇ carbocyclic ring or at least one 5-to-7-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, halo, oxo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC ₁ -C ₆ alkyl, C ₆ -C ₁₀ aryl, and CONR ⁸ R ⁹ .

In some embodiments,

R ⁶ and R ⁷ are each independently selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halo, CN, NO2, COC ₁ -C ₆ alkyl, CO2C ₁ -C ₆ alkyl, C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, CONR ⁸ R ⁹ , and 3- to 7-membered heterocycloalkyl,

wherein the C ₁ -C ₆ alkyl and 3- to 7-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy or oxo, or at least one pair of R ⁶ and R ⁷ on adjacent atoms, taken together with the atoms connecting them, independently form at least one C ₄ -C ₈ carbocyclic ring, wherein the carbocyclic ring is optionally independently substituted with one or more hydroxy or oxo. In some embodiments,

R ⁶ and R ⁷ are each independently selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halo, CN, NO ₂ , COC ₁ -C ₆ alkyl, CO2C ₁ -C ₆ alkyl, C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, CONR ⁸ R ⁹ , and 3- to 7-membered heterocycloalkyl,

wherein the C ₁ -C ₆ alkyl and 3- to 7-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy or oxo,

or at least one pair of R ⁶ and R ⁷ on adjacent atoms, taken together with the atoms connecting them, independently form at least one C ₄ -C ₆ aliphatic carbocyclic ring, wherein the carbocyclic ring is optionally independently substituted with one or more hydroxy or oxo. In some embodiments,

R ⁶ and R ⁷ are each independently selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halo, CN, NO ₂ , COC ₁ -C ₆ alkyl, CO2C ₁ -C ₆ alkyl, C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, CONR ⁸ R ⁹ , and 3- to 7-membered heterocycloalkyl,

wherein the C ₁ -C ₆ alkyl and 3- to 7-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy or oxo,

or at least one pair of R ⁶ and R ⁷ on adjacent atoms, taken together with the atoms connecting them, independently form at least one 5-to 8-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein the heterocyclic ring is optionally independently substituted with one or more hydroxy or oxo. In some embodiments,

R ⁶ and R ⁷ are each independently selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halo, CN, NO2, COC ₁ -C ₆ alkyl, CO2C ₁ -C ₆ alkyl, C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, CONR ⁸ R ⁹ , and 3- to 7-membered heterocycloalkyl,

wherein the C ₁ -C ₆ alkyl and 3- to 7-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy or oxo,

or at least one pair of R ⁶ and R ⁷ on adjacent atoms, taken together with the atoms connecting them, independently form at least one C ₄ -C ₈ carbocyclic ring, wherein the carbocyclic ring is optionally independently substituted with one or more hydroxy or oxo. In some embodiments,

at least one pair of R ⁶ and R ⁷ on adjacent atoms, taken together with the atoms connecting them, independently form at least one C4-C6 aliphatic carbocyclic ring, wherein the carbocyclic ring is optionally independently substituted with one or more hydroxy or oxo. In some embodiments,

at least one pair of R ⁶ and R ⁷ on adjacent atoms, taken together with the atoms connecting them, independently form at least one C ₄ aliphatic carbocyclic ring, wherein the carbocyclic ring is optionally independently substituted with one or more hydroxy or oxo. In some embodiments,

at least one pair of R ⁶ and R ⁷ on adjacent atoms, taken together with the atoms connecting them, independently form at least one C5 aliphatic carbocyclic ring, wherein the carbocyclic ring is optionally independently substituted with one or more hydroxy or oxo. In some embodiments,

at least one pair of R ⁶ and R ⁷ on adjacent atoms, taken together with the atoms connecting them, independently form at least one C ₆ aliphatic carbocyclic ring, wherein the carbocyclic ring is optionally independently substituted with one or more hydroxy or oxo.

In some embodiments,

at least one pair of R ⁶ and R ⁷ on adjacent atoms, taken together with the atoms connecting them, independently form at least one 5-to 6-membered heterocyclic ring containing 1 heteroatom independently selected from O, N, and S, wherein the heterocyclic ring is optionally independently substituted with one or more hydroxy or oxo. In some embodiments,

at least one pair of R ⁶ and R ⁷ on adjacent atoms, taken together with the atoms connecting them, independently form at least one 5-membered heterocyclic ring containing 1 heteroatom independently selected from O, N, and S, wherein the heterocyclic ring is optionally independently substituted with one or more hydroxy or oxo. In some embodiments, at least one pair of R ⁶ and R ⁷ on adjacent atoms, taken together with the atoms connecting them, independently form at least one 6-membered heterocyclic ring containing 1 heteroatom independently selected from O, N, and S, wherein the heterocyclic ring is optionally independently substituted with one or more hydroxy or oxo. In some embodiments,

at least one pair of R ⁶ and R ⁷ on adjacent atoms, taken together with the atoms connecting them, independently form at least one C4 aliphatic carbocyclic ring, wherein the carbocyclic ring is optionally independently substituted with one or more C ₁ -C ₆ alkyl. In some embodiments,

at least one pair of R ⁶ and R ⁷ on adjacent atoms, taken together with the atoms connecting them, independently form at least one C ₅ aliphatic carbocyclic ring, wherein the carbocyclic ring is optionally independently substituted with one or more C ₁ -C ₆ alkyl. In some embodiments,

at least one pair of R ⁶ and R ⁷ on adjacent atoms, taken together with the atoms connecting them, independently form at least one C6 aliphatic carbocyclic ring, wherein the carbocyclic ring is optionally independently substituted with one or more C ₁ -C ₆ alkyl. In some embodiments,

at least one pair of R ⁶ and R ⁷ on adjacent atoms, taken together with the atoms connecting them, independently form at least one 5-to 6-membered heterocyclic ring containing 1 heteroatom independently selected from O, N, and S, wherein the heterocyclic ring is optionally independently substituted with one or more C ₁ -C ₆ alkyl. In some embodiments,

at least one pair of R ⁶ and R ⁷ on adjacent atoms, taken together with the atoms connecting them, independently form at least one 5-membered heterocyclic ring containing 1 heteroatom independently selected from O, N, and S, wherein the heterocyclic ring is optionally independently substituted with one or more C ₁ -C ₆ alkyl. In some embodiments, at least one pair of R ⁶ and R ⁷ on adjacent atoms, taken together with the atoms connecting them, independently form at least one 6-membered heterocyclic ring containing 1 heteroatom independently selected from O, N, and S, wherein the heterocyclic ring is optionally independently substituted with one or more C ₁ -C ₆ alkyl. In some embodiments, o=1; p=0; and

R ⁶ is selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, halo, CN, NO2, COC ₁ -C ₆ alkyl, CO2C ₁ -C ₆ alkyl, CO2C3-C8 cycloalkyl, OCOC ₁ -C ₆ alkyl, OCOC ₆ -C ₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, NH ₂ , NHC ₁ -C ₆ alkyl, N(C ₁ -C ₆ alkyl) ₂ , CONR ⁸ R ⁹ , SF ₅ , SC ₁ -C ₆ alkyl, S(O2)C ₁ -C ₆ alkyl, C3-C7 cycloalkyl and 3- to 7-membered heterocycloalkyl, wherein the C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₃ -C ₇ cycloalkyl and 3- to 7-membered

heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC ₁ -C ₆ alkyl, CONR ⁸ R ⁹ , 3- to 7-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, OCOC ₁ -C ₆ alkyl, OCOC ₆ -C ₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC ₁ -C ₆ alkyl, NHCOC ₆ -C ₁₀ aryl, NHCO(5- to 10- membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), and NHCOC2-C6 alkynyl;

wherein the 3- to 7-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, NHCOC ₆ -C ₁₀ aryl, NHCO(5- to 10-membered heteroaryl) and NHCO(3- to 7-membered heterocycloalkyl) are optionally substituted with one or more substituents independently selected from halo, C ₁ -C ₆ alkyl, and OC ₁ -C ₆ alkyl. In some embodiments, o=1; p=1; and

R ⁶ and R ⁷ are each independently selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halo, CN, NO ₂ , COC ₁ -C ₆ alkyl, CO2C ₁ -C ₆ alkyl, C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, CONR ⁸ R ⁹ , and 3- to 7-membered heterocycloalkyl,

wherein the C ₁ -C ₆ alkyl and 3- to 7-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy or oxo,

or at least one pair of R ⁶ and R ⁷ on adjacent atoms, taken together with the atoms connecting them, independently form at least one C ₄ -C ₈ carbocyclic ring, wherein the carbocyclic ring is optionally independently substituted with one or more hydroxy or oxo. In some embodiments, o=1 or 2; p=1, 2, or 3; and

R ⁶ and R ⁷ are each independently selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, halo, CN, NO ₂ , COC ₁ -C ₆ alkyl, CO ₂ C ₁ -C ₆ alkyl, CO ₂ C ₃ -C ₈ cycloalkyl, OCOC ₁ -C ₆ alkyl, OCOC ₆ -C ₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7- membered heterocycloalkyl), C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, NH2, NHC ₁ -C ₆ alkyl, N(C ₁ -C ₆ alkyl) ₂ , CONR ⁸ R ⁹ , SF ₅ , SC ₁ -C ₆ alkyl, S(O ₂ )C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl and 3- to 7-membered heterocycloalkyl,

wherein the C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C3-C7 cycloalkyl, and 3- to 7-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC ₁ -C ₆ alkyl, CONR ⁸ R ⁹ , 3- to 7-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, OCOC ₁ -C ₆ alkyl, OCOC ₆ -C ₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC ₁ -C ₆ alkyl, NHCOC ₆ -C ₁₀ aryl, NHCO(5- to 10- membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), and NHCOC2-C6 alkynyl;

wherein the 3- to 7-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, NHCOC ₆ -C ₁₀ aryl, NHCO(5- to 10-membered heteroaryl) and NHCO(3- to 7-membered heterocycloalkyl) are optionally substituted with one or more substituents independently selected from halo, C ₁ -C ₆ alkyl, and OC ₁ -C ₆ alkyl. In some embodiments, o=2; p=1; and

each R ⁶ is independently selected from C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, halo, CN, C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, CO-C ₁ -C ₆ alkyl; CONR ⁸ R ⁹ , and 4- to 6-membered heterocycloalkyl,

wherein the C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₃ -C ₇ cycloalkyl and 4- to 6-membered

heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC ₁ -C ₆ alkyl, CONR ⁸ R ⁹ , 4- to 6-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, OCOC ₁ -C ₆ alkyl, OCOC ₆ -C ₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC ₁ -C ₆ alkyl, NHCOC ₆ -C ₁₀ aryl, NHCO(5- to 10- membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC2-C6 alkynyl;

and R ⁷ is independently selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, C ₁ - C6 haloalkoxy, halo, CN, COC ₁ -C ₆ alkyl, CO2C ₁ -C ₆ alkyl, CO2C3-C6 cycloalkyl, OCOC ₁ -C ₆ alkyl, OCOC ₆ -C ₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, CONR ⁸ R ⁹ , SF ₅ , S(O ₂ )C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl and 4- to 6-membered heterocycloalkyl, wherein the C ₁ -C ₆ alkyl is optionally substituted with one to two C ₁ -C ₆ alkoxy;

or R ⁶ and R ⁷ , taken together with the atoms connecting them, independently form C4-C7 carbocyclic ring or at least one 5-to-7-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, halo, oxo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC ₁ -C ₆ alkyl, C ₆ -C ₁₀ aryl, and CONR ⁸ R ⁹ . In some embodiments, o=2; p=2 or 3; and

each R ⁶ is independently selected from C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, halo, CN, C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, CO-C ₁ -C ₆ alkyl; CONR ⁸ R ⁹ , and 4- to 6-membered heterocycloalkyl,

wherein the C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₃ -C ₇ cycloalkyl and 4- to 6-membered

heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC ₁ -C ₆ alkyl, CONR ⁸ R ⁹ , 4- to 6-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, OCOC ₁ -C ₆ alkyl, OCOC ₆ -C ₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC ₁ -C ₆ alkyl, NHCOC ₆ -C ₁₀ aryl, NHCO(5- to 10- membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC ₂ -C ₆ alkynyl;

wherein each R ⁷ is independently selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, halo, CN, COC ₁ -C ₆ alkyl, CO ₂ C ₁ -C ₆ alkyl, CO ₂ C ₃ -C ₆ cycloalkyl, OCOC ₁ -C ₆ alkyl, OCOC ₆ -C ₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, CONR ⁸ R ⁹ , SF5, S(O2)C ₁ -C ₆ alkyl, C3-C7 cycloalkyl and 4- to 6-membered

heterocycloalkyl, wherein the C ₁ -C ₆ alkyl is optionally substituted with one to two C ₁ - C6 alkoxy;

or at least one pair of R ⁶ and R ⁷ on adjacent atoms, taken together with the atoms connecting them, independently form at least one C ₄ -C ₇ (e.g., C ₄ -C ₆ ) carbocyclic ring (e.g., aliphatic carbocyclic ring) or at least one 5-to-7-membered (e.g., 5-to-6-membered) heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, NR ⁸ R ⁹ , CH ₂ NR ⁸ R ⁹ , =NR ¹⁰ , COOC ₁ -C ₆ alkyl, C ₆ -C ₁₀ aryl, and CONR ⁸ R ⁹ . In some embodiments, o=1 or 2; p=1, 2, or 3; and

R ⁶ and R ⁷ are each independently selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halo, CN, NO ₂ , COC ₁ -C ₆ alkyl, CO2C ₁ -C ₆ alkyl, C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, CONR ⁸ R ⁹ , and 3- to 7-membered heterocycloalkyl,

wherein the C ₁ -C ₆ alkyl and 3- to 7-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy or oxo,

or at least one pair of R ⁶ and R ⁷ on adjacent atoms, taken together with the atoms connecting them, independently form at least one C ₄ -C ₈ carbocyclic ring, wherein the carbocyclic ring is optionally independently substituted with one or more hydroxy or oxo. In some embodiments, o=1 or 2; p=1, 2, or 3; and

R ⁶ and R ⁷ are each independently selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halo, CN, NO ₂ , COC ₁ -C ₆ alkyl, CO2C ₁ -C ₆ alkyl, C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, CONR ⁸ R ⁹ , and 3- to 7-membered heterocycloalkyl,

wherein the C ₁ -C ₆ alkyl and 3- to 7-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy or oxo. In some embodiments, o=1 or 2; p=1, 2, or 3; and

one R ⁶ and one R ⁷ are on adjacent atoms, and taken together with the atoms connecting them, form a C4-C8 carbocyclic ring or a 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, halo, oxo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC ₁ -C ₆ alkyl, C ₆ -C ₁₀ aryl, and CONR ⁸ R ⁹ . In some embodiments, o=1 or 2; p=1, 2, or 3; and

one R ⁶ and one R ⁷ are on adjacent atoms, and taken together with the atoms connecting them, form a C ₆ carbocyclic ring or a 5-to-6-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, halo, oxo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC ₁ -C ₆ alkyl, C ₆ -C ₁₀ aryl, and CONR ⁸ R ⁹ . In some embodiments, o=1 or 2; p=1, 2, or 3; and

one R ⁶ and one R ⁷ are on adjacent atoms, and taken together with the atoms connecting them, form a C ₄ -C ₈ carbocyclic ring or a 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is unsubstituted. In some embodiments, o=2; p=2 or 3; and

two pairs, each of one R ⁶ and one R ⁷ , are on adjacent atoms, and each pair of one R ⁶ and one R ⁷ taken together with the atoms connecting them independently form a C ₄ -C ₈ carbocyclic ring or a 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein each carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, halo, oxo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC ₁ -C ₆ alkyl, C ₆ -C ₁₀ aryl, and CONR ⁸ R ⁹ . In some embodiments, o=2; p=2 or 3; and

two pairs, each of one R ⁶ and one R ⁷ , are on adjacent atoms, and each pair of one R ⁶ and one R ⁷ taken together with the atoms connecting them independently form a C6 carbocyclic ring or a 5-to-6-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally

independently substituted with one or more substituents independently selected from hydroxy, halo, oxo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC ₁ -C ₆ alkyl, C ₆ -C ₁₀ aryl, and CONR ⁸ R ⁹ . In some embodiments, o=2; p=2 or 3; and

two pairs, each of one R ⁶ and one R ⁷ , are on adjacent atoms, and each pair of one R ⁶ and one R ⁷ taken together with the atoms connecting them independently form a C5 carbocyclic ring, wherein the carbocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, halo, oxo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC ₁ -C ₆ alkyl, C ₆ -C ₁₀ aryl, and CONR ⁸ R ⁹ . In some embodiments, o=2; p=2 or 3; and

two pairs, each of one R ⁶ and one R ⁷ , are on adjacent atoms, and each pair of one R ⁶ and one R ⁷ taken together with the atoms connecting them independently form a C ₄ carbocyclic ring, wherein the carbocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, halo, oxo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC ₁ -C ₆ alkyl, C ₆ -C ₁₀ aryl, and CONR ⁸ R ⁹ . In some embodiments, o=2; p=2 or 3; and

two pairs, each of one R ⁶ and one R ⁷ , are on adjacent atoms, one pair of one R ⁶ and one R ⁷ taken together with the atoms connecting them independently form a C ₄ carbocyclic ring, and the other pair of one R ⁶ and one R ⁷ taken together with the atoms connecting them

independently form a C ₅ carbocyclic ring, wherein each of C ₄ and C ₅ carbocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, halo, oxo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC ₁ -C ₆ alkyl, C ₆ -C ₁₀ aryl, and CONR ⁸ R ⁹ . In some embodiments, o=2; p=2 or 3; and

two pairs, each of one R ⁶ and one R ⁷ , are on adjacent atoms, one pair of one R ⁶ and one R ⁷ taken together with the atoms connecting them independently form a C ₅ carbocyclic ring, and the other pair of one R ⁶ and one R ⁷ taken together with the atoms connecting them

independently form a 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S (e.g., a 5-membered heteorocyclic ring, e.g., 5- membered heterocyclic ring containing 1 heteroatom), wherein each of carbocyclic and heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, halo, oxo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC ₁ -C ₆ alkyl, C ₆ -C ₁₀ aryl, and CONR ⁸ R ⁹ . In some embodiments, o=2; p=2 or 3; and

two pairs, each of one R ⁶ and one R ⁷ , are on adjacent atoms, and each pair of one R ⁶ and one R ⁷ taken together with the atoms connecting them independently form a C4-C8 carbocyclic ring or a 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is unsubstituted. Particular embodiments wherein o=1; p=0: In some embodiments, R ⁶ is C ₁ -C ₆ alkyl.

In some embodiments, R ⁶ is isopropyl.

In some embodiments, R ⁶ is ethyl.

In some embodiments, R ⁶ is methyl.

In some embodiments, R ⁶ is C ₁ -C ₆ alkyl substituted with one or more halo.

In some embodiments, R ⁶ is trifluoromethyl.

In some embodiments, R ⁶ is trifluoromethoxy.

In some embodiments, R ⁶ is C3-C7 cycloalkyl.

In some embodiments, R ⁶ is cyclopropyl.

In some embodiments, R ⁶ is halo.

In some embodiments, R ⁶ is chloro.

In some embodiments, R ⁶ is fluoro.

In some embodiments, R ⁶ is cyano.

In some embodiments, R ⁶ is attached to a carbon of an aryl ring B.

In some embodiments, R ⁶ is attached to a carbon of a heteroaryl ring B.

In some embodiments, R ⁶ is attached to a nitrogen of a heteroaryl ring B. Particular embodiments wherein o=1 or 2; 2, or 3:

In some embodiments, at least one R ⁶ is C ₁ -C ₆ alkyl, and at least one R ⁷ is C ₁ -C ₆ alkyl optionally substituted with one or more halo.

In some embodiments, at least one R ⁶ is C ₁ -C ₆ alkyl and at least one R ⁷ is C ₁ -C ₆ alkyl.

In some embodiments, at least one R ⁶ is isopropyl and at least one R ⁷ is methyl.

In some embodiments, at least one R ⁶ is isopropyl and at least one R ⁷ is isopropyl.

In some embodiments, o=1; p=1; R ⁶ is isopropyl; and R ⁷ is isopropyl.

In some embodiments, at least one R ⁶ is C ₁ -C ₆ alkyl, and at least one R ⁷ is C ₁ -C ₆ alkyl substituted with one or more halo.

In some embodiments, at least one R ⁶ is isopropyl and at least one R ⁷ is trifluoromethyl. In some embodiments, at least one R ⁶ is C ₁ -C ₆ alkyl, and at least one R ⁷ is C3-C7 cycloalkyl. In some embodiments, at least one R ⁶ is isopropyl and at least one R ⁷ is cyclopropyl.

In some embodiments, o=1; p=1; R ⁶ is isopropyl; and R ⁷ is cyclopropyl.

In some embodiments, at least one R ⁶ is C ₁ -C ₆ alkyl, and at least one R ⁷ is halo.

In some embodiments, at least one R ⁶ is isopropyl and at least one R ⁷ is halo.

In some embodiments, at least one R ⁶ is isopropyl and at least one R ⁷ is chloro.

In some embodiments, at least one R ⁶ is isopropyl and at least one R ⁷ is fluoro. In some embodiments, o=1; p=1; R ⁶ is isopropyl; and R ⁷ is chloro.

In some embodiments, o=2; p=1; at least one R ⁶ is isopropyl; and R ⁷ is chloro.

In some embodiments, o=1; p=1; R ⁶ is isopropyl; and R ⁷ is fluoro.

In some embodiments, o=2; p=1; at least one R ⁶ is isopropyl; and R ⁷ is fluoro.

In some embodiments, o=2; p=2; at least one R ⁶ is isopropyl; and at least one R ⁷ is fluoro. In some embodiments, o=2; p=2; at least one R ⁶ is isopropyl; one R ⁷ is fluoro; and the other R ⁷ is cyano.

In some embodiments, o=2; p=3; at least one R ⁶ is isopropyl; two R ⁷ are fluoro; and one R ⁷ is chloro.

In some embodiments, o=2; p=1; at least one R ⁶ is ethyl; and R ⁷ is fluoro.

In some embodiments, o=2; p=1; one R ⁶ is isopropyl; the other R ⁶ is trifluoromethyl; and R ⁷ is chloro.

In some embodiments, at least one R ⁶ is C ₁ -C ₆ alkyl, and at least one R ⁷ is cyano.

In some embodiments, at least one R ⁶ is isopropyl and at least one R ⁷ is cyano.

In some embodiments, o=1; p=1; R ⁶ is isopropyl; and R ⁷ is cyano.

In some embodiments, o=2; p=1; at least one R ⁶ is isopropyl; and R ⁷ is cyano.

In some embodiments, at least one R ⁶ is C3-C7 cycloalkyl, and at least one R ⁷ is C3-C7 cycloalkyl.

In some embodiments, at least one R ⁶ is cyclopropyl, and at least one R ⁷ is cyclopropyl. In some embodiments, at least one R ⁶ is C3-C7 cycloalkyl, and at least one R ⁷ is halo.

In some embodiments, at least one R ⁶ is cyclopropyl and at least one R ⁷ is halo.

In some embodiments, at least one R ⁶ is cyclopropyl and at least one R ⁷ is chloro.

In some embodiments, at least one R ⁶ is cyclopropyl and at least one R ⁷ is fluoro.

In some embodiments, o=1; p=1; R ⁶ is cyclopropyl; and R ⁷ is chloro.

In some embodiments, o=1; p=1; R ⁶ is cyclopropyl; and R ⁷ is fluoro.

In some embodiments, at least one R ⁶ is C ₁ -C ₆ alkyl, and at least one R ⁷ is C ₁ -C ₆ alkoxy optionally substituted with one or more halo.

In some embodiments, at least one R ⁶ is isopropyl, and at least one R ⁷ is C ₁ -C ₆ alkoxy.

In some embodiments, at least one R ⁶ is isopropyl, and at least one R ⁷ is methoxy.

In some embodiments, o=1; p=1; R ⁶ is isopropyl, and R ⁷ is methoxy.

In some embodiments, o=2; p=1; at least one R ⁶ is isopropyl, and R ⁷ is methoxy.

In some embodiments, at least one R ⁶ is C ₁ -C ₆ alkyl, and at least one R ⁷ is C ₁ -C ₆ alkoxy substituted with one or more halo.

In some embodiments, at least one R ⁶ is isopropyl, and at least one R ⁷ is trifluoromethoxy. In some embodiments, at least one R ⁶ is isopropyl, and at least one R ⁷ is difluoromethoxy. In some embodiments, at least one R ⁶ is halo, and at least one R ⁷ is C ₁ -C ₆ haloalkyl optionally substituted with hydroxy.

In some embodiments, o=1; p=1; R ⁶ is chloro, and R ⁷ is trifluoromethyl.

In some embodiments, at least one R ⁶ is halo, and at least one R ⁷ is C ₁ -C ₆ haloalkoxy.

In some embodiments, at least one R ⁶ is chloro, and at least one R ⁷ is trifluoromethoxy. In some embodiments, o=1; p=1; R ⁶ is chloro, and R ⁷ is trifluoromethoxy.

In some embodiments, at least one R ⁶ is C ₁ -C ₆ alkoxy; and at least one R ⁷ is halo.

In some embodiments, o=1; p=2; R ⁶ is C ₁ -C ₆ alkoxy; and at least one R ⁷ is chloro. In some embodiments, at least one R ⁷ is C ₁ -C ₆ alkyl, and at least one R ⁶ is C ₁ -C ₆ alkyl optionally substituted with one or more halo.

In some embodiments, at least one R ⁷ is isopropyl and at least one R ⁶ is methyl.

In some embodiments, at least one R ⁷ is C ₁ -C ₆ alkyl, and at least one R ⁶ is C ₁ -C ₆ alkyl substituted with one or more halo.

In some embodiments, at least one R ⁷ is isopropyl and at least one R ⁶ is trifluoromethyl. In some embodiments, at least one R ⁷ is C ₁ -C ₆ alkyl, and at least one R ⁶ is C3-C7 cycloalkyl. In some embodiments, at least one R ⁷ is isopropyl and at least one R ⁶ is cyclopropyl.

In some embodiments, o=1; p=1; R ⁷ is isopropyl; and R ⁶ is cyclopropyl.

In some embodiments, at least one R ⁷ is C ₁ -C ₆ alkyl, and at least one R ⁶ is halo.

In some embodiments, at least one R ⁷ is isopropyl and at least one R ⁶ is halo.

In some embodiments, at least one R ⁷ is isopropyl and at least one R ⁶ is chloro.

In some embodiments, at least one R ⁷ is isopropyl and at least one R ⁶ is fluoro.

In some embodiments, o=1; p=1; R ⁷ is isopropyl; and R ⁶ is chloro.

In some embodiments, o=2; p=1; R ⁷ is isopropyl; and at least one R ⁶ is chloro.

In some embodiments, o=1; p=1; R ⁷ is isopropyl; and R ⁶ is fluoro.

In some embodiments, o=2; p=1; R ⁷ is isopropyl; and at least one R ⁶ is fluoro.

In some embodiments, o=2; p=2; R ⁷ is isopropyl; and at least one R ⁶ is fluoro.

In some embodiments, o=2; p=2; at least one R ⁷ is isopropyl; one R ⁶ is fluoro; and the other R ⁶ is cyano.

In some embodiments, o=2; p=1; R ⁷ is ethyl; and at least one R ⁶ is fluoro.

In some embodiments, o=1; p=2; one R ⁷ is isopropyl; the other R ⁷ is trifluoromethyl; and R ⁶ is chloro.

In some embodiments, at least one R ⁷ is C ₁ -C ₆ alkyl, and at least one R ⁶ is cyano. In some embodiments, at least one R ⁷ is isopropyl and at least one R ⁶ is cyano.

In some embodiments, o=1; p=1; R ⁷ is isopropyl; and R ⁶ is cyano.

In some embodiments, o=2; p=1; R ⁷ is isopropyl; and at least one R ⁶ is cyano.

In some embodiments, at least one R ⁷ is C3-C7 cycloalkyl, and at least one R ⁶ is C3-C7 cycloalkyl.

In some embodiments, at least one R ⁷ is cyclopropyl, and at least one R ⁶ is cyclopropyl. In some embodiments, at least one R ⁷ is C3-C7 cycloalkyl, and at least one R ⁶ is halo. In some embodiments, at least one R ⁷ is cyclopropyl and at least one R ⁶ is halo.

In some embodiments, at least one R ⁷ is cyclopropyl and at least one R ⁶ is chloro.

In some embodiments, at least one R ⁷ is cyclopropyl and at least one R ⁶ is fluoro.

In some embodiments, o=1; p=1; R ⁷ is cyclopropyl; and R ⁶ is chloro.

In some embodiments, o=1; p=1; R ⁷ is cyclopropyl; and R ⁶ is fluoro.

In some embodiments, at least one R ⁷ is C ₁ -C ₆ alkyl, and at least one R ⁶ is C ₁ -C ₆ alkoxy optionally substituted with one or more halo.

In some embodiments, at least one R ⁷ is isopropyl, and at least one R ⁶ is C ₁ -C ₆ alkoxy. In some embodiments, at least one R ⁷ is isopropyl, and at least one R ⁶ is methoxy.

In some embodiments, o=1; p=1; R ⁷ is isopropyl, and R ⁶ is methoxy.

In some embodiments, o=2; p=1; R ⁷ is isopropyl, and at least one R ⁶ is methoxy.

In some embodiments, at least one R ⁷ is C ₁ -C ₆ alkyl, and at least one R ⁶ is C ₁ -C ₆ alkoxy substituted with one or more halo.

In some embodiments, at least one R ⁷ is isopropyl, and at least one R ⁶ is trifluoromethoxy. In some embodiments, at least one R ⁷ is halo, and at least one R ⁶ is C ₁ -C ₆ haloalkyl optionally substituted with one or more hydroxy.

In some embodiments, o=1; p=1; R ⁷ is chloro, and R ⁶ is trifluoromethyl.

In some embodiments, at least one R ⁷ is halo, and at least one R ⁶ is C ₁ -C ₆ haloalkoxy. In some embodiments, at least one R ⁷ is chloro, and at least one R ⁶ is trifluoromethoxy. In some embodiments, o=1; p=1; R ⁷ is chloro, and R ⁶ is trifluoromethoxy.

In some embodiments, at least one R ⁷ is C ₁ -C ₆ alkoxy; and at least one R ⁶ is halo.

In some embodiments, o=1; p=2; at least one R ⁷ is C ₁ -C ₆ alkoxy; and R ⁶ is chloro. In some embodiments, R ⁶ and R ⁷ are each attached to a carbon of an aryl ring B.

In some embodiments, R ⁶ and R ⁷ are each attached to a carbon of a heteroaryl ring B. In some embodiments, R ⁶ is attached to a carbon and R ⁷ is attached to a nitrogen of a heteroaryl ring B. In some embodiments, R ⁷ is attached to a carbon and R ⁶ is attached to a nitrogen of a heteroaryl ring B. In some embodiments, one R ⁶ and one R ⁷ are on adjacent atoms, and taken together with the atoms connecting them, form a C5 carbocyclic ring optionally substituted with one or more substituents independently selected from hydroxy, halo, oxo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC ₁ -C ₆ alkyl, C ₆ -C ₁₀ aryl, and CONR ⁸ R ⁹ .

In some embodiments, R ⁶ and R ⁷ are on adjacent atoms, and taken together with the atoms connecting them, form a C ₅ aliphatic carbocyclic ring.

In some embodiments, R ⁶ and R ⁷ are on adjacent atoms, and taken together with the atoms connecting them, form a C6 carbocyclic ring optionally substituted with one or more substituents independently selected from hydroxy, halo, oxo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC ₁ -C ₆ alkyl, C ₆ -C ₁₀ aryl, and CONR ⁸ R ⁹ .

In some embodiments, R ⁶ and R ⁷ are on adjacent atoms, and taken together with the atoms connecting them, form a C6 aliphatic carbocyclic ring.

In some embodiments, R ⁶ and R ⁷ are on adjacent atoms, and taken together with the atoms connecting them, form a C ₆ aromatic carbocyclic ring.

In some embodiments, R ⁶ and R ⁷ are on adjacent atoms, and taken together with the atoms connecting them, form a 5-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, optionally substituted with one or more substituents independently selected from hydroxy, halo, oxo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC ₁ -C ₆ alkyl, C ₆ -C ₁₀ aryl, and CONR ⁸ R ⁹ .

In some embodiments, R ⁶ and R ⁷ are on adjacent atoms, and taken together with the atoms connecting them, form a 5-membered aliphatic heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S.

In some embodiments, R ⁶ and R ⁷ are on adjacent atoms, and taken together with the atoms connecting them, form a 5-membered heteroaromatic ring containing 1 or 2 heteroatoms independently selected from O, N, and S.

In some embodiments, R ⁶ and R ⁷ are on adjacent atoms, and taken together with the atoms connecting them, form a 6-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, optionally substituted with one or more substituents independently selected from hydroxy, halo, oxo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC ₁ -C ₆ alkyl, C ₆ -C ₁₀ aryl, and CONR ⁸ R ⁹ . In some embodiments, R ⁶ and R ⁷ are on adjacent atoms, and taken together with the atoms connecting them, form a 6-membered aliphatic heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S.

In some embodiments, R ⁶ and R ⁷ are on adjacent atoms, and taken together with the atoms connecting them, form a 6-membered heteroaromatic ring containing 1 or 2 heteroatoms independently selected from O, N, and S.

In some embodiments, one R ⁶ and one R ⁷ are on adjacent atoms, and taken together with the atoms connecting them, form a C4-C8 carbocyclic ring or a 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S,

wherein the ring is fused to the B ring at the 2- and 3- positions relative to the bond connecting the B ring to the NH(CO)group. In some embodiments, o=1; p=2; and

one pair of one R ⁶ and one R ⁷ , are on adjacent atoms; and said pair of one R ⁶ and one R ⁷ taken together with the atoms connecting them form form a C4-C8 carbocyclic ring or a 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S,

wherein the ring is fused to the B ring at the 2- and 3- positions relative to the bond connecting the B ring to the NH(CO) group. In some embodiments, o=1; p=2; and

one pair of one R ⁶ and one R ⁷ , are on adjacent atoms; and said pair of one R ⁶ and one R ⁷ taken together with the atoms connecting them form form a C ₄ -C ₈ carbocyclic ring optionally independently substituted with one or more substituents independently selected from hydroxy, halo, oxo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC ₁ -C ₆ alkyl, C ₆ -C ₁₀ aryl, and CONR ⁸ R ⁹ .

In some embodiments, o=1; p=2; and

one pair of one R ⁶ and one R ⁷ , are on adjacent atoms; and said pair of one R ⁶ and one R ⁷ taken together with the atoms connecting them form form a C ₅ carbocyclic ring optionally independently substituted with one or more substituents independently selected from hydroxy, halo, oxo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC ₁ -C ₆ alkyl, C ₆ -C ₁₀ aryl, and CONR ⁸ R ⁹ .

In some embodiments, o=1; p=2; and one pair of one R ⁶ and one R ⁷ , are on adjacent atoms; and said pair of one R ⁶ and one R ⁷ taken together with the atoms connecting them form form a C ₅ aliphatic carbocyclic ring. In some embodiments, o=2; p=2; and

one pair of one R ⁶ and one R ⁷ , are on adjacent atoms; and said pair of one R ⁶ and one R ⁷ taken together with the atoms connecting them form form a C ₄ -C ₈ carbocyclic ring optionally independently substituted with one or more substituents independently selected from hydroxy, halo, oxo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC ₁ -C ₆ alkyl, C ₆ -C ₁₀ aryl, and CONR ⁸ R ⁹ .

In some embodiments, o=2; p=2; and

one pair of one R ⁶ and one R ⁷ , are on adjacent atoms; and said pair of one R ⁶ and one R ⁷ taken together with the atoms connecting them form form a C ₅ carbocyclic ring optionally independently substituted with one or more substituents independently selected from hydroxy, halo, oxo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC ₁ -C ₆ alkyl, C ₆ -C ₁₀ aryl, and CONR ⁸ R ⁹ .

In some embodiments, o=1; p=2; and

one pair of one R ⁶ and one R ⁷ , are on adjacent atoms; and said pair of one R ⁶ and one R ⁷ taken together with the atoms connecting them form form a C5 aliphatic carbocyclic ring. In some embodiments, o=2; p=2 or 3; and

two pairs, each of one R ⁶ and one R ⁷ , are on adjacent atoms; one pair of one R ⁶ and one R ⁷ taken together with the atoms connecting them form a C ₄ carbocyclic ring optionally independently substituted with one or more substituents independently selected from hydroxy, halo, oxo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC ₁ -C ₆ alkyl, C ₆ -C ₁₀ aryl, and CONR ⁸ R ⁹ ; and the other pair of one R ⁶ and one R ⁷ taken together with the atoms connecting them form a C ₅ carbocyclic ring optionally independently substituted with one or more substituents independently selected from hydroxy, halo, oxo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC ₁ -C ₆ alkyl, C ₆ -C ₁₀ aryl, and CONR ⁸ R ⁹ .

In some embodiments, o=2; p=2 or 3; and

two pairs, each of one R ⁶ and one R ⁷ , are on adjacent atoms; one pair of one R ⁶ and one R ⁷ taken together with the atoms connecting them form a C4 aliphatic carbocyclic ring and the other pair of one R ⁶ and one R ⁷ taken together with the atoms connecting them form a C ₅ aliphatic carbocyclic ring. In some embodiments, o=2; p=2 or 3; and

two pairs, each of one R ⁶ and one R ⁷ , are on adjacent atoms, and each pair of one R ⁶ and one R ⁷ taken together with the atoms connecting them form a C ₅ carbocyclic ring optionally independently substituted with one or more substituents independently selected from hydroxy, halo, oxo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC ₁ -C ₆ alkyl, C ₆ -C ₁₀ aryl, and CONR ⁸ R ⁹ .

In some embodiments, o=2; p=2 or 3; and

two pairs, each of one R ⁶ and one R ⁷ , are on adjacent atoms, and each pair of one R ⁶ and one R ⁷ taken together with the atoms connecting them form a C ₅ aliphatic carbocyclic ring.

In some embodiments, o=2; p=2 or 3; and

two pairs, each of one R ⁶ and one R ⁷ , are on adjacent atoms, and each pair of one R ⁶ and one R ⁷ taken together with the atoms connecting them form a C ₆ carbocyclic ring optionally independently substituted with one or more substituents independently selected from hydroxy, halo, oxo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC ₁ -C ₆ alkyl, C ₆ -C ₁₀ aryl, and CONR ⁸ R ⁹ .

In some embodiments, o=2; p=2 or 3; and

two pairs, each of one R ⁶ and one R ⁷ , are on adjacent atoms, and each pair of one R ⁶ and one R ⁷ taken together with the atoms connecting them form a C6 aliphatic carbocyclic ring.

In some embodiments, o=2; p=2 or 3; and

two pairs, each of one R ⁶ and one R ⁷ , are on adjacent atoms, and each pair of one R ⁶ and one R ⁷ taken together with the atoms connecting them form a C6 aromatic carbocyclic ring.

In some embodiments, o=2; p=2 or 3; and

two pairs, each of one R ⁶ and one R ⁷ , are on adjacent atoms, and each pair of one R ⁶ and one R ⁷ taken together with the atoms connecting them form a 5-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, optionally substituted with one or more substituents independently selected from hydroxy, halo, oxo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC ₁ -C ₆ alkyl, C ₆ -C ₁₀ aryl, and CONR ⁸ R ⁹ .

In some embodiments, o=2; p=2 or 3; and

two pairs, each of one R ⁶ and one R ⁷ , are on adjacent atoms, and each pair of one R ⁶ and one R ⁷ taken together with the atoms connecting them form a 5-membered aliphatic heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S.

In some embodiments, o=2; p=2 or 3; and two pairs, each of one R ⁶ and one R ⁷ , are on adjacent atoms, and each pair of one R ⁶ and one R ⁷ taken together with the atoms connecting them form a 5-membered heteroaromatic ring containing 1 or 2 heteroatoms independently selected from O, N, and S.

In some embodiments, o=2; p=2 or 3; and

two pairs, each of one R ⁶ and one R ⁷ , are on adjacent atoms, and each pair of one R ⁶ and one R ⁷ taken together with the atoms connecting them form a 6-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, optionally substituted with one or more substituents independently selected from hydroxy, halo, oxo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC ₁ -C ₆ alkyl, C ₆ -C ₁₀ aryl, and CONR ⁸ R ⁹ .

In some embodiments, o=2; p=2 or 3; and

two pairs, each of one R ⁶ and one R ⁷ , are on adjacent atoms, and each pair of one R ⁶ and one R ⁷ taken together with the atoms connecting them form a 6-membered aliphatic heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S.

In some embodiments, o=2; p=2 or 3; and

two pairs, each of one R ⁶ and one R ⁷ , are on adjacent atoms, and each pair of one R ⁶ and one R ⁷ taken together with the atoms connecting them form a 6-membered heteroaromatic ring containing 1 or 2 heteroatoms independently selected from O, N, and S. In some embodiments, o=2; p=2 or 3; and

two pairs, each of one R ⁶ and one R ⁷ , are on adjacent atoms; one pair of one R ⁶ and one R ⁷ taken together with the atoms connecting them form a C4-8 carbocyclic ring optionally independently substituted with one or more substituents independently selected from hydroxy, halo, oxo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC ₁ -C ₆ alkyl, C ₆ -C ₁₀ aryl, and CONR ⁸ R ⁹ ; and the other pair of one R ⁶ and one R ⁷ taken together with the atoms connecting them form a 5- to 8-mebered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, optionally substituted with one or more substituents independently selected from hydroxy, halo, oxo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC ₁ -C ₆ alkyl, C ₆ -C ₁₀ aryl, and CONR ⁸ R ⁹ .

In some embodiments, o=2; p=2 or 3; and

two pairs, each of one R ⁶ and one R ⁷ , are on adjacent atoms; one pair of one R ⁶ and one R ⁷ taken together with the atoms connecting them form a C5 aliphatic carbocyclic ring and the other pair of one R ⁶ and one R ⁷ taken together with the atoms connecting them form a 5- membered aliphatic heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S. In some embodiments, o=2; p=2 or 3; and

two pairs, each of one R ⁶ and one R ⁷ , are on adjacent atoms; one pair of one R ⁶ and one R ⁷ taken together with the atoms connecting them form a C5 carbocyclic ring optionally independently substituted with one or more substituents independently selected from hydroxy, halo, oxo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC ₁ -C ₆ alkyl, C ₆ -C ₁₀ aryl, and CONR ⁸ R ⁹ ; and the other pair of one R ⁶ and one R ⁷ taken together with the atoms connecting them form a 6-mebered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, optionally substituted with one or more substituents independently selected from hydroxy, halo, oxo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC ₁ -C ₆ alkyl, C ₆ -C ₁₀ aryl, and CONR ⁸ R ⁹ .

In some embodiments, o=2; p=2 or 3; and

two pairs, each of one R ⁶ and one R ⁷ , are on adjacent atoms; one pair of one R ⁶ and one R ⁷ taken together with the atoms connecting them form a C5 aliphatic carbocyclic ring and the other pair of one R ⁶ and one R ⁷ taken together with the atoms connecting them form a 5- membered aliphatic heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S. In some embodiments, o=2; p=2 or 3; and

two pairs, each of one R ⁶ and one R ⁷ , are on adjacent atoms, and each pair of one R ⁶ and one R ⁷ taken together with the atoms connecting them independently form a C4-C8 carbocyclic ring or a 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S,

wherein one of the two rings is fused to the B ring at the 2- and 3- positions relative to the bond connecting the B ring to the NH(CO) group, and the other of the two rings is fused to the B ring at the 5- and 6- positions relative to the bond connecting the B ring to the NH(CO) group.

In some embodiments, o=2; p=2 or 3; and

two pairs, each of one R ⁶ and one R ⁷ , are on adjacent atoms, and each pair of one R ⁶ and one R ⁷ taken together with the atoms connecting them independently form a C4-C8 carbocyclic ring or a 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S,

wherein one of the two rings is fused to the B ring at the 2- and 3- positions relative to the bond connecting the B ring to the NH(CO) group, and the other of the two rings is fused to the B ring at the 4- and 5- positions relative to the bond connecting the B ring to the NH(CO) group.

In some embodiments, o=2; p=2; and

two pairs, each of one R ⁶ and one R ⁷ , are on adjacent atoms, and each pair of one R ⁶ and one R ⁷ taken together with the atoms connecting them form a C5 aliphatic carbocyclic ring.

In some embodiments, o=2; p=2; and

two pairs, each of one R ⁶ and one R ⁷ , are on adjacent atoms, one pair of one R ⁶ and one R ⁷ taken together with the atoms connecting them form a C4 aliphatic carbocyclic ring, and the other pair of one R ⁶ and one R ⁷ taken together with the atoms connecting them form a C ₅ aliphatic carbocyclic ring.

In some embodiments, o=2; p=2; and

two pairs, each of one R ⁶ and one R ⁷ , are on adjacent atoms, and each pair of one R ⁶ and one R ⁷ taken together with the atoms connecting them form a C ₄ aliphatic carbocyclic ring.

In some embodiments, o=2; p=2; and

two pairs, each of one R ⁶ and one R ⁷ , are on adjacent atoms, one pair of one R ⁶ and one R ⁷ taken together with the atoms connecting them form a C ₅ aliphatic carbocyclic ring, and the other pair of one R ⁶ and one R ⁷ taken together with the atoms connecting them form a 5- membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S. In some embodiments, o=2; p=3; and

two pairs, each of one R ⁶ and one R ⁷ , are on adjacent atoms, and each pair of one R ⁶ and one R ⁷ taken together with the atoms connecting them form a C ₅ aliphatic carbocyclic ring; and one R ⁷ is halo (e.g., Cl or F).

In some embodiments, o=2; p=3; and

two pairs, each of one R ⁶ and one R ⁷ , are on adjacent atoms, and each pair of one R ⁶ and one R ⁷ taken together with the atoms connecting them form a C5 aliphatic carbocyclic ring; and one R ⁷ is CN.

In some embodiments, one R ⁷ is pyrazolyl and is para to the bond connecting the B ring to the NH(CO) group of Formula AA.

In some embodiments, one R ⁷ is 3-pyrazolyl and is para to the bond connecting the B ring to the NH(CO) group of Formula AA.

In some embodiments, one R ⁷ is 4-pyrazolyl and is para to the bond connecting the B ring to the NH(CO) group of Formula AA. In some embodiments, one R ⁷ is 5-pyrazolyl and is para to the bond connecting the B ring to the NH(CO) group of Formula AA.

In some embodiments, one R ⁷ is thiazolyl and is para to the bond connecting the B ring to the NH(CO) group of Formula AA.

In some embodiments, one R ⁷ is 4-thiazolyl and is para to the bond connecting the B ring to the NH(CO) group of Formula AA.

In some embodiments, one R ⁷ is 5-thiazolyl and is para to the bond connecting the B ring to the NH(CO) group of Formula AA.

In some embodiments, one R ⁷ is furyl and is para to the bond connecting the B ring to the NH(CO) group of Formula AA.

In some embodiments, one R ⁷ is 2-furyl and is para to the bond connecting the B ring to the NH(CO) group of Formula AA.

In some embodiments, one R ⁷ is thiophenyl and is para to the bond connecting the B ring to the NH(CO) group of Formula AA.

In some embodiments, one R ⁷ is 2-thiophenyl and is para to the bond connecting the B ring to the NH(CO) group of Formula AA.

In some embodiments, one R ⁷ is phenyl and is para to the bond connecting the B ring to the NH(CO) group of Formula AA.

In some embodiments, one R ⁷ is cycloalkenyl (e.g., cyclopentenyl, e.g., 1-cyclopentenyl) and is para to the bond connecting the B ring to the NH(CO) group of Formula AA.

In some embodiments, one R ⁷ is phenyl optionally substituted with one or more C ₁ -C ₆ alkyl (e.g., methyl or propyl, e.g., 2-propyl) optionally substituted with one or more hydroxyl, NR ⁸ R ⁹ (e.g., dimethylamino), or C ₆ -C ₁₀ aryl (e.g., phenyl, naphthyl, or

methylenedioxyphenyl and is para to the bond connecting the B ring to the NH(CO) group of Formula AA.

In some embodiments, one R ⁷ is phenyl optionally substituted with one or more C ₁ -C ₆ alkoxy (e.g., methoxy) optionally substituted with one or more hydroxyl, NR ⁸ R ⁹ (e.g.,

dimethylamino), or C ₆ -C ₁₀ aryl (e.g., phenyl, naphthyl, or methylenedioxyphenyl and is para to the bond connecting the B ring to the NH(CO) group of Formula AA.

In some embodiments, one R ⁷ is phenyl optionally substituted with one or more C ₆ -C ₁₀ aryloxy (e.g., phenoxy) and is para to the bond connecting the B ring to the NH(CO) group of Formula AA.

In some embodiments, one R ⁷ is phenyl optionally substituted with one or more CN and is para to the bond connecting the B ring to the NH(CO) group of Formula AA. In some embodiments, one R ⁷ is phenyl optionally substituted with one or more halo (e.g., F, Cl) and is para to the bond connecting the B ring to the NH(CO) group of Formula AA and is para to the bond connecting the B ring to the NH(CO) group of Formula AA.

In some embodiments, one R ⁷ is phenyl optionally substituted with one or more COOC ₁ -C ₆ alkyl (e.g., CO2t-Bu) and is para to the bond connecting the B ring to the NH(CO) group of Formula AA.

In some embodiments, one R ⁷ is phenyl optionally substituted with one or more S(O2)C ₁ -C ₆ alkyl (e.g., S(O2)methyl) and is para to the bond connecting the B ring to the NH(CO) group of Formula AA.

In some embodiments, one R ⁷ is phenyl optionally substituted with one or more 3- to 7- membered heterocycloalkyl (e.g., morpholinyl) and is para to the bond connecting the B ring to the NH(CO) group of Formula AA.

In some embodiments, one R ⁷ is phenyl optionally substituted with one or more CONR ⁸ R ⁹ (e.g., unsubstituted amido) and is para to the bond connecting the B ring to the NH(CO) group of Formula AA.

In some embodiments, one R ⁷ is phenyl optionally substituted with one or more C ₁ -C ₆ alkyl (e.g., methyl or propyl, e.g., 2-propyl) and with one or more halo (e.g., F, Cl) and is para to the bond connecting the B ring to the NH(CO) group of Formula AA and is para to the bond connecting the B ring to the NH(CO) group of Formula AA. In some embodiments, R ⁶ and R ⁷ are each attached to a carbon of an aryl ring B.

In some embodiments, R ⁶ and R ⁷ are each attached to a carbon of a heteroaryl ring B.

In some embodiments, R ⁶ is attached to a carbon and R ⁷ is attached to a nitrogen of a heteroaryl ring B.

In some embodiments, R ⁷ is attached to a carbon and R ⁶ is attached to a nitrogen of a heteroaryl ring B.

In some embodiments, the substituted ring each R ⁶ is

independently selected from the group consisting of: C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, halo, CN, C ₆ -C ₁₀ aryl, 5- to 10- membered heteroaryl, CO-C ₁ -C ₆ alkyl; CONR ⁸ R ⁹ , and 4- to 6-membered heterocycloalkyl, wherein the C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C3-C7 cycloalkyl and 4- to 6-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC ₁ -C ₆ alkyl, CONR ⁸ R ⁹ , 4- to 6-membered heterocycloalkyl, C6- C10 aryl, 5- to 10-membered heteroaryl, OCOC ₁ -C ₆ alkyl, OCOC ₆ -C ₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC ₁ -C ₆ alkyl, NHCOC ₆ -C ₁₀ aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6- membered heterocycloalkyl), and NHCOC2-C6 alkynyl.

In some embodiments, the substituted ring each R ⁶ is

independently selected from the group consisting of: C ₁ -C ₆ alkyl, C3-C7 cycloalkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, wherein the C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, and C ₃ -C ₇ cycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, or oxo.

In some embodiments, the substituted ring , wherein each R ⁶ is independently selected from C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, halo, CN, C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, CO- C ₁ -C ₆ alkyl; CONR ⁸ R ⁹ , and 4- to 6-membered heterocycloalkyl,

wherein the C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₃ -C ₇ cycloalkyl and 4- to 6-membered

heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC ₁ -C ₆ alkyl, CONR ⁸ R ⁹ , 4- to 6-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, OCOC ₁ -C ₆ alkyl, OCOC ₆ -C ₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC ₁ -C ₆ alkyl, NHCOC ₆ -C ₁₀ aryl, NHCO(5- to 10- membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC ₂ -C ₆ alkynyl;

wherein R ⁷ is independently selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, halo, CN, COC ₁ -C ₆ alkyl, CO ₂ C ₁ -C ₆ alkyl, CO ₂ C ₃ -C ₆ cycloalkyl, OCOC ₁ -C ₆ alkyl, OCOC ₆ -C ₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, CONR ⁸ R ⁹ , SF ₅ , S(O ₂ )C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl and 4- to 6-membered heterocycloalkyl, wherein the C ₁ -C ₆ alkyl is optionally substituted with one to two C ₁ -C ₆ alkoxy;

or R ⁶ and R ⁷ , taken together with the atoms connecting them, independently form C4-C7 carbocyclic ring or at least one 5-to-7-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, halo, oxo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC ₁ -C ₆ alkyl, C ₆ -C ₁₀ aryl, and CONR ⁸ R ⁹ .

In certain of these embodiments,

the R ⁶ and R ⁷ on adjacent atoms, taken together with the atoms connecting them, independently form a C ₄ -C ₈ carbocyclic ring optionally substituted with one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C ₁ -C ₆ alkyl, C ₁ - C6 alkoxy, NR ⁸ R ⁹ , CH2NR ⁸ R ⁹ , =NR ¹⁰ , COOC ₁ -C ₆ alkyl, C ₆ -C ₁₀ aryl, and CONR ⁸ R ⁹ ; and the other R ⁶ is C ₆ -C ₁₀ aryl or 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more substituents each independently selected from: hydroxy, halo, CN, oxo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC ₁ -C ₆ alkyl, CONR ⁸ R ⁹ , 4- to 6- membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, OCOC ₁ -C ₆ alkyl, OCOC ₆ -C ₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC ₁ -C ₆ alkyl, NHCOC ₆ -C ₁₀ aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC2-C6 alkynyl.

In certain of these embodiments, the R ⁶ and R ⁷ on adjacent atoms, taken together with the atoms connecting them, independently form a C _5-6 carbocyclic ring; and the other R ⁶ is 5- to 6-membered heteroaryl optionally substituted with one or more substituents each independently selected from: hydroxy, halo, C ₁ -C ₆ alkoxy, CN, and C ₁ -C ₆ alkyl.

For example, the R ⁶ and R ⁷ on adjacent atoms, taken together with the atoms connecting them, independently form a C5 carbocyclic ring; and the other R ⁶ is pyridyl (e.g., 4-pyridyl) optionally substituted with one or more substituents each independently selected from: CN, OMe, isopropyl, and ethyl.

As a non-limiting example of the foregoing embodiments, substituted ring B is: .

In some embodiments, the substituted ring , wherein each R ⁶ is independently selected from C ₁ -C ₆ alkyl, C3-C7 cycloalkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆

haloalkoxy, halo, CN, C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, CO-C ₁ -C ₆ alkyl;

CONR ⁸ R ⁹ , and 4- to 6-membered heterocycloalkyl,

wherein the C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C3-C7 cycloalkyl and 4- to 6-membered

heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC ₁ -C ₆ alkyl, CONR ⁸ R ⁹ , 4- to 6-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, OCOC ₁ -C ₆ alkyl, OCOC ₆ -C ₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC ₁ -C ₆ alkyl, NHCOC ₆ -C ₁₀ aryl, NHCO(5- to 10- membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC2-C6 alkynyl;

wherein R ⁷ is independently selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, halo, CN, COC ₁ -C ₆ alkyl, CO2C ₁ -C ₆ alkyl, CO2C3-C6 cycloalkyl, OCOC ₁ -C ₆ alkyl, OCOC ₆ -C ₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, CONR ⁸ R ⁹ , SF ₅ , S(O ₂ )C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl and 4- to 6-membered heterocycloalkyl, wherein the C ₁ -C ₆ alkyl is optionally substituted with one to two C ₁ -C ₆ alkoxy;

or R ⁶ and R ⁷ , taken together with the atoms connecting them, independently form C ₄ -C ₇ carbocyclic ring or at least one 5-to-7-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, halo, oxo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC ₁ -C ₆ alkyl, C ₆ -C ₁₀ aryl, and CONR ⁸ R ⁹ . In some embodiments, the substituted ring , wherein each R ⁶ is independently selected from C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, halo, CN, C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, CO- C ₁ -C ₆ alkyl; CONR ⁸ R ⁹ , and 4- to 6-membered heterocycloalkyl,

wherein the C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₃ -C ₇ cycloalkyl and 4- to 6-membered

heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC ₁ -C ₆ alkyl, CONR ⁸ R ⁹ , 4- to 6-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, OCOC ₁ -C ₆ alkyl, OCOC ₆ -C ₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC ₁ -C ₆ alkyl, NHCOC ₆ -C ₁₀ aryl, NHCO(5- to 10- membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC2-C6 alkynyl;

wherein R ⁷ is independently selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, halo, CN, COC ₁ -C ₆ alkyl, CO2C ₁ -C ₆ alkyl, CO2C3-C6 cycloalkyl, OCOC ₁ -C ₆ alkyl, OCOC ₆ -C ₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, CONR ⁸ R ⁹ , SF5, S(O2)C ₁ -C ₆ alkyl, C3-C7 cycloalkyl and 4- to 6-membered heterocycloalkyl, wherein the C ₁ -C ₆ alkyl is optionally substituted with one to two C ₁ -C ₆ alkoxy.

In certain embodiments (when the substituted ring one R ⁶ is C ₁ -C ₆ alkyl; and the other R ⁶ is C ₆ -C ₁₀ aryl or 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more substituents each independently selected from: hydroxy, halo, CN, oxo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC ₁ -C ₆ alkyl, CONR ⁸ R ⁹ , 4- to 6-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, OCOC ₁ -C ₆ alkyl, OCOC ₆ -C ₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6- membered heterocycloalkyl), NHCOC ₁ -C ₆ alkyl, NHCOC ₆ -C ₁₀ aryl, NHCO(5- to 10- membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC2-C6 alkynyl.

In certain of these embodiments, one R ⁶ is C ₁ -C ₆ alkyl; and the other R ⁶ is C ₆ -C ₁₀ aryl or 5- to 10-membered heteroaryl optionally substituted with a substituent selected from halo, CN, C ₁ -C ₆ alkyl, and C ₁ -C ₆ alkoxy. For example, R ⁶ is 5-6 (e.g., 6) membered heteroaryl (e.g., pyridinyl (e.g., pyridin-4-yl), pyrimidinyl, or thiazolyl) optionally substituted with a substituent selected from hydroxyl, halo, CN, C ₁ -C ₆ alkyl, and C ₁ -C ₆ alkoxy.

As a non-limiting example of the foregoing embodiments, substituted ring B is selected from:

In some embodiments, the substituted ring , wherein each R ⁶ is independently selected from C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, halo, CN, C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, CO- C ₁ -C ₆ alkyl; CONR ⁸ R ⁹ , and 4- to 6-membered heterocycloalkyl,

wherein the C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₃ -C ₇ cycloalkyl and 4- to 6-membered

heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC ₁ -C ₆ alkyl, CONR ⁸ R ⁹ , 4- to 6-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, OCOC ₁ -C ₆ alkyl, OCOC ₆ -C ₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC ₁ -C ₆ alkyl, NHCOC ₆ -C ₁₀ aryl, NHCO(5- to 10- membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC2-C6 alkynyl;

wherein each R ⁷ is independently selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, halo, CN, COC ₁ -C ₆ alkyl, CO2C ₁ -C ₆ alkyl, CO2C3-C6 cycloalkyl, OCOC ₁ -C ₆ alkyl, OCOC ₆ -C ₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, CONR ⁸ R ⁹ , SF5, S(O2)C ₁ -C ₆ alkyl, C3-C7 cycloalkyl and 4- to 6-membered

heterocycloalkyl, wherein the C ₁ -C ₆ alkyl is optionally substituted with one to two C1- C ₆ alkoxy; or at least one pair of R ⁶ and R ⁷ on adjacent atoms, taken together with the atoms connecting them, independently form at least one C ₄ -C ₇ carbocyclic ring or at least one 5-to-7-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, halo, oxo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC ₁ -C ₆ alkyl, C ₆ -C ₁₀ aryl, and CONR ⁸ R ⁹ .

In some embodiments, the substituted ring , wherein each R ⁶ is independently selected from C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, halo, CN, C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, CO- C ₁ -C ₆ alkyl; CONR ⁸ R ⁹ , and 4- to 6-membered heterocycloalkyl,

wherein the C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₃ -C ₇ cycloalkyl and 4- to 6-membered

heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC ₁ -C ₆ alkyl, CONR ⁸ R ⁹ , 4- to 6-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, OCOC ₁ -C ₆ alkyl, OCOC ₆ -C ₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC ₁ -C ₆ alkyl, NHCOC ₆ -C ₁₀ aryl, NHCO(5- to 10- membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC2-C6 alkynyl;

wherein each R ⁷ is independently selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, halo, CN, COC ₁ -C ₆ alkyl, CO2C ₁ -C ₆ alkyl, CO2C3-C6 cycloalkyl, OCOC ₁ -C ₆ alkyl, OCOC ₆ -C ₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, CONR ⁸ R ⁹ , SF5, S(O2)C ₁ -C ₆ alkyl, C3-C7 cycloalkyl and 4- to 6-membered

heterocycloalkyl, wherein the C ₁ -C ₆ alkyl is optionally substituted with one to two C ₁ - C ₆ alkoxy;

or at least one pair of R ⁶ and R ⁷ on adjacent atoms, taken together with the atoms connecting them, independently form at least one C4-C7 carbocyclic ring or at least one 5-to-7-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, halo, oxo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC ₁ -C ₆ alkyl, C ₆ -C ₁₀ aryl, and CONR ⁸ R ⁹ .

In some embodiments, the substituted ring , wherein each R ⁶ is independently selected from C ₁ -C ₆ alkyl, C3-C7 cycloalkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, halo, CN, C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, CO- C ₁ -C ₆ alkyl; CONR ⁸ R ⁹ , and 4- to 6-membered heterocycloalkyl,

wherein the C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₃ -C ₇ cycloalkyl and 4- to 6-membered

heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC ₁ -C ₆ alkyl, CONR ⁸ R ⁹ , 4- to 6-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, OCOC ₁ -C ₆ alkyl, OCOC ₆ -C ₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC ₁ -C ₆ alkyl, NHCOC ₆ -C ₁₀ aryl, NHCO(5- to 10- membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC ₂ -C ₆ alkynyl;

wherein each R ⁷ is independently selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, halo, CN, COC ₁ -C ₆ alkyl, CO ₂ C ₁ -C ₆ alkyl, CO ₂ C ₃ -C ₆ cycloalkyl, OCOC ₁ -C ₆ alkyl, OCOC ₆ -C ₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, CONR ⁸ R ⁹ , SF ₅ , S(O ₂ )C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl and 4- to 6-membered

heterocycloalkyl, wherein the C ₁ -C ₆ alkyl is optionally substituted with one to two C ₁ - C6 alkoxy;

or at least one pair of R ⁶ and R ⁷ on adjacent atoms, taken together with the atoms connecting them, independently form at least one C ₄ -C ₇ carbocyclic ring or at least one 5-to-7-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, halo, oxo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC ₁ -C ₆ alkyl, C ₆ -C ₁₀ aryl, and CONR ⁸ R ⁹ . In some embodiments, the substituted ring , wherein each R ⁶ is independently selected from C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, halo, CN, C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, CO- C ₁ -C ₆ alkyl; CONR ⁸ R ⁹ , and 4- to 6-membered heterocycloalkyl,

wherein the C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₃ -C ₇ cycloalkyl and 4- to 6-membered

heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC ₁ -C ₆ alkyl, CONR ⁸ R ⁹ , 4- to 6-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, OCOC ₁ -C ₆ alkyl, OCOC ₆ -C ₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC ₁ -C ₆ alkyl, NHCOC ₆ -C ₁₀ aryl, NHCO(5- to 10- membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC2-C6 alkynyl;

wherein each R ⁷ is independently selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, halo, CN, COC ₁ -C ₆ alkyl, CO2C ₁ -C ₆ alkyl, CO2C3-C6 cycloalkyl, OCOC ₁ -C ₆ alkyl, OCOC ₆ -C ₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, CONR ⁸ R ⁹ , SF5, S(O2)C ₁ -C ₆ alkyl, C3-C7 cycloalkyl and 4- to 6-membered

heterocycloalkyl, wherein the C ₁ -C ₆ alkyl is optionally substituted with one to two C ₁ - C ₆ alkoxy;

or R ⁶ and R ⁷ , taken together with the atoms connecting them, independently form a C ₄ -C ₇ carbocyclic ring or at least one 5-to-7-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, halo, oxo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC ₁ -C ₆ alkyl, C ₆ -C ₁₀ aryl, and CONR ⁸ R ⁹ .

In certain of these embodiments,

the R ⁶ and R ⁷ on adjacent atoms, taken together with the atoms connecting them, independently form a C ₄ -C ₈ carbocyclic ring optionally substituted with one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C ₁ -C ₆ alkyl, C ₁ - C6 alkoxy, NR ⁸ R ⁹ , CH2NR ⁸ R ⁹ , =NR ¹⁰ , COOC ₁ -C ₆ alkyl, C ₆ -C ₁₀ aryl, and CONR ⁸ R ⁹ ; the other R ⁶ is C ₆ -C ₁₀ aryl or 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more substituents each independently selected from: hydroxy, halo, CN, oxo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC ₁ -C ₆ alkyl, CONR ⁸ R ⁹ , 4- to 6- membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, OCOC ₁ -C ₆ alkyl, OCOC ₆ -C ₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC ₁ -C ₆ alkyl, NHCOC ₆ -C ₁₀ aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC2-C6 alkynyl; and

the other R ⁷ is selected from C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, halo, and CN.

In certain of these embodiments, the R ⁶ and R ⁷ on adjacent atoms, taken together with the atoms connecting them, independently form a C _5-6 carbocyclic ring; the other R ⁶ is 5- to 6- membered heteroaryl optionally substituted with one or more substituents each independently selected from: hydroxy, halo, C ₁ -C ₆ alkoxy, CN, and C ₁ -C ₆ alkyl; and the other R ⁷ is halo.

For example, the R ⁶ and R ⁷ on adjacent atoms, taken together with the atoms connecting them, independently form a C5 carbocyclic ring; the other R ⁶ is pyridyl (e.g., 4-pyridyl) optionally substituted with one or more substituents each independently selected from: CN, OMe, isopropyl, and ethyl; and the other R ⁷ is F.

As non-limiting examples of the foregoing embodiments, substituted ring B is:

In certain of these embodiments,

the R ⁶ and R ⁷ on adjacent atoms, taken together with the atoms connecting them, independently form a C ₄ -C ₈ carbocyclic ring optionally substituted with one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C ₁ -C ₆ alkyl, C1- C6 alkoxy, NR ⁸ R ⁹ , CH2NR ⁸ R ⁹ , =NR ¹⁰ , COOC ₁ -C ₆ alkyl, C ₆ -C ₁₀ aryl, and CONR ⁸ R ⁹ ;

the other R ⁶ is C ₆ -C ₁₀ aryl or 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more substituents each independently selected from: hydroxy, halo, CN, oxo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC ₁ -C ₆ alkyl, CONR ⁸ R ⁹ , 4- to 6- membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, OCOC ₁ -C ₆ alkyl, OCOC ₆ -C ₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC ₁ -C ₆ alkyl, NHCOC ₆ -C ₁₀ aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC2-C6 alkynyl; and the other R ⁷ is selected from C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, halo, and CN.

In certain of these embodiments, the R ⁶ and R ⁷ on adjacent atoms, taken together with the atoms connecting them, independently form a C _5-6 carbocyclic ring; the other R ⁶ is 5- to 6- membered heteroaryl optionally substituted with one or more substituents each independently selected from: hydroxy, halo, C ₁ -C ₆ alkoxy, CN, and C ₁ -C ₆ alkyl; and the other R ⁷ is halo.

For example, the R ⁶ and R ⁷ on adjacent atoms, taken together with the atoms connecting them, independently form a C5 carbocyclic ring; the other R ⁶ is pyridyl (e.g., 4-pyridyl) optionally substituted with one or more substituents each independently selected from: CN, OMe, isopropyl, and ethyl; and the other R ⁷ is F.

As non-limiting examples of the foregoing embodiments, substituted ring B is:

In some embodiments, the substituted ring , wherein each R ⁶ is independently selected from C ₁ -C ₆ alkyl, C3-C7 cycloalkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, halo, CN, C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, CO- C ₁ -C ₆ alkyl; CONR ⁸ R ⁹ , and 4- to 6-membered heterocycloalkyl,

wherein the C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C3-C7 cycloalkyl and 4- to 6-membered

heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC ₁ -C ₆ alkyl, CONR ⁸ R ⁹ , 4- to 6-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, OCOC ₁ -C ₆ alkyl, OCOC ₆ -C ₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC ₁ -C ₆ alkyl, NHCOC ₆ -C ₁₀ aryl, NHCO(5- to 10- membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC ₂ -C ₆ alkynyl;

wherein each R ⁷ is independently selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, halo, CN, COC ₁ -C ₆ alkyl, CO ₂ C ₁ -C ₆ alkyl, CO ₂ C ₃ -C ₆ cycloalkyl, OCOC ₁ -C ₆ alkyl, OCOC ₆ -C ₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, CONR ⁸ R ⁹ , SF ₅ , S(O ₂ )C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl and 4- to 6-membered

heterocycloalkyl, wherein the C ₁ -C ₆ alkyl is optionally substituted with one to two C1- C6 alkoxy;

or at least one pair of R ⁶ and R ⁷ on adjacent atoms, taken together with the atoms connecting them, independently form at least one C4-C7 carbocyclic ring or at least one 5-to-7-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, NR ⁸ R ⁹ , CH ₂ NR ⁸ R ⁹ , =NR ¹⁰ , COOC ₁ -C ₆ alkyl, C ₆ -C ₁₀ aryl, and CONR ⁸ R ⁹ . The group R ³

In some embodiments, R ³ is selected from hydrogen, C ₁ -C ₆ alkyl, and , wherein the C ₁ -C ₂ alkylene group is optionally substituted with oxo.

In some embodiments, R ³ is hydrogen.

In some embodiments, R ³ is hydroxy.

In some embodiments, R ³ is C ₁ -C ₆ alkoxy.

In some embodiments, R ³ is C ₁ -C ₆ alkyl.

In some embodiments, R ³ is methyl.

In some embodiments, R ³ is , wherein the C1-C2 alkylene group is optionally substituted with oxo.

In some embodiments, R ³ is–CH ₂ R ¹⁴ .

In some embodiments, R ³ is–C(O)R ¹⁴ .

In some embodiments, R ³ is–CH2CH2R ¹⁴ .

In some embodiments, R ³ is–CHR ¹⁴ CH ₃ .

In some embodiments, R ³ is–CH2C(O)R ¹⁴ .

In some embodiments, R ³ is–C(O)CH2R ¹⁴ . In some embodiments, R ³ is CO2C ₁ -C ₆ alkyl. The group R ¹⁴

In some embodiments, R ¹⁴ is hydrogen, C ₁ -C ₆ alkyl, 5- to 10-membered monocyclic or bicyclic heteroaryl or C ₆ -C ₁₀ monocyclic or bicyclic aryl , wherein each C ₁ -C ₆ alkyl, aryl or heteroaryl is optionally independently substituted with 1 or 2 R ⁶ .

In some embodiments, R ¹⁴ is hydrogen or C ₁ -C ₆ alkyl.

In some embodiments, R ¹⁴ is hydrogen, 5- to 10-membered monocyclic or bicyclic heteroaryl or C ₆ -C ₁₀ monocyclic or bicyclic aryl, wherein each C ₁ -C ₆ alkyl, aryl or heteroaryl is optionally independently substituted with 1 or 2 R ⁶ .

In some embodiments, R ¹⁴ is hydrogen.

In some embodiments, R ¹⁴ is NR ⁸ R ⁹ .

In some embodiments, R ¹⁴ is C ₁ -C ₆ alkyl.

In some embodiments, R ¹⁴ is methyl.

In some embodiments, R ¹⁴ is 5- to 10-membered monocyclic or bicyclic heteroaryl optionally independently substituted with 1 or 2 R ⁶ .

In some embodiments, R ¹⁴ is C ₆ -C ₁₀ monocyclic or bicyclic aryl optionally independently substituted with 1 or 2 R ⁶ . The moiety S(X)(O)N (S(=O)(NHR ³ )=N-)

In some embodiments, the compound is enantioenriched at the sulfur in the moiety S(X)(O)N (e.g., S(=O)(NHR ³ )=N-).

In certain embodiments (when the compound is enantioenriched at the sulfur in the moiety S(X)(O)N (e.g., S(=O)(NHR ³ )=N-)), the ee is greater than about 60% (e.g., greater than about 70%, greater than about 80%, greater than about 90%, greater than about 95%, greater than about 98%, or greater than about 99).

In some embodiments, the sulfur in the moiety S(X)(O)N (e.g., S(=O)(NHR ³ )=N-) has (S) stereochemistry.

In some embodiments, the sulfur in the moiety S(X)(O)N (e.g., S(=O)(NHR ³ )=N-) has (R) stereochemistry. The group R ¹⁰

In some embodiments, R ¹⁰ is C ₁ -C ₆ alkyl.

In some embodiments, R ¹⁰ is methyl. In some embodiments, R ¹⁰ is ethyl. The groups R ⁸ and R ⁹

In some embodiments, each of R ⁸ and R ⁹ at each occurrence is independently selected from hydrogen, C ₁ -C ₆ alkyl, (C=NR ¹³ )NR ¹¹ R ¹² , S(O2)C ₁ -C ₆ alkyl, S(O2)NR ¹¹ R ¹² , COR ¹³ , CO2R ¹³ and CONR ¹¹ R ¹² ; wherein the C ₁ -C ₆ alkyl is optionally substituted with one or more hydroxy, halo, C ₁ -C ₆ alkoxy, C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, C3-C7 cycloalkyl or 3- to 7- membered heterocycloalkyl; or R ⁸ and R ⁹ taken together with the nitrogen they are attached to form a 3- to 7-membered ring optionally containing one or more heteroatoms in addition to the nitrogen they are attached to.

In some embodiments, each of R ⁸ and R ⁹ at each occurrence is independently selected from hydrogen, C ₁ -C ₆ alkyl, (C=NR ¹³ )NR ¹¹ R ¹² , S(O ₂ )C ₁ -C ₆ alkyl, S(O ₂ )NR ¹¹ R ¹² , COR ¹³ , CO ₂ R ¹³ and CONR ¹¹ R ¹² ; wherein the C ₁ -C ₆ alkyl is optionally substituted with one or more hydroxy, halo, C ₁ -C ₆ alkoxy, C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, C3-C7 cycloalkyl or 3- to 7- membered heterocycloalkyl; or R ⁸ and R ⁹ taken together with the nitrogen they are attached to form a 3- to 7-membered ring optionally containing one or more heteroatoms in addition to the nitrogen they are attached to.