COMPOUNDS AND COMPOSITIONS FOR TREATING CONDITIONS ASSOCIATED WITH NLRP ACTIVITY TECHNICAL FIELD 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) contributes to the pathology and/or symptoms and/or progression of the condition, disease or disorder in a subject (e.g., a human). This disclosure also features compositions as well as other methods of using and making the same.

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.

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-1 b, 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-1 b 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-1 b 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-1 b, either spontaneously or when stimulated by LPS, and this IL-1 b 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-1 b 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-1 b, 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-1 b 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-1 b 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-1 b, which can be inhibited by the addition of an NLRP3 antagonist. NLRP3 inflammasome antagonists - in part by blocking IL- 1 b 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-1 b 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

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

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.

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 pharmaceutically 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.

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.

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. As used herein, the term“treat”,“treating" or "treatment" of any disease or disorder refers in one embodiment to ameliorating the disease or disorder (i.e. slowing or arresting or reducing the development of the disease or at least one of the clinical symptoms or pathological features thereof). In another embodiment“treat”, "treating" or "treatment" refers to alleviating or ameliorating at least one physical parameter or pathological features of the disease, e.g. including those, which may not be discernible by the subject. In yet another embodiment,“treat”,

"treating" or "treatment" refers to modulating the disease or disorder, either physically, (e.g. stabilization of at least one discernible or non-discernible symptom), physiologically (e.g.

stabilization of a physical parameter) or both. In yet another embodiment,“treat”, "treating" or "treatment" refers to preventing or delaying the onset or development or progression of the disease or disorder, or of at least one symptoms or pathological features associated thereof. In yet another embodiment,“treat”, "treating" or "treatment" refers to preventing or delaying progression of the disease to a more advanced stage or a more serious condition.

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 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., -OCH ₃ ).

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. Each ring of a bicyclic or tricyclic heterocyclic ring is selected from saturated, unsaturated, and aromatic (carbocyclic aromatic and heteroaromatic) rings. 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 a 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic fused or spiro ring system radical wherein at least one of the rings in the ring system (1) is nonaromatic and (2) includes 1-3 heteroatoms. When the ring system is bicyclic, 1-6 heteroatom ring members are present; and when the ring system is tricyclic, 1-9 heteroatom ring members are present. The ring heteroatoms are selected from O, N, and S (e.g., the ring system includes carbon atoms and 1-3, 1-6, or 1-9 heteroatoms selected from N, O, and 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, seven-membered, eight-membered, and ten-membered rings. Examples include piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, tetrahydrofuranyl, (3aR,6aS)-hexahydro-1H- thieno[3,4-d]imidazole, 1,2,3,4-tetrahydroisoquinoline, 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 NH ₂ group.

The term“oxo” refers to O. By way of example, substitution of a CH ₂ 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 the S(O)(NHR ³ )=N moiety of 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 the NH(CO) group of 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 line connects A to the S(O)(NHR ³ )=N moiety of 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 the NH(CO) group of Formula AA.

As used herein, the recitation“S(O ₂ )”, 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).

Formula C

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. However, with the exception of compounds 181a and 181b, the depicted stereochemistry shown for each of the tabulated compounds drawn in the formula A/B format is a tentative assignment and based, by analogy, on the absolute stereochemistry assigned to compounds 181b (see, e.g., FIGS.1 and 2).

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 DRAWINGS FIG.1 depicts ball-and-stick representations of two crystallographically independent molecules of compound 181a in the asymmetrical unit.

FIG.2 depicts ball-and-stick representations of two crystallographically independent molecules of compound 181b in the asymmetrical unit.

FIG.3 depicts the layout of the microplate used in an hTHP-1 assay.

FIG.4: Expression levels of RNA encoding NLRP3 in Crohn’s Disease patients who are responsive and non-responsive to infliximab.

FIG.5: Expression levels of RNA encoding IL-1 ^ in Crohn’s Disease patients who are responsive and non-responsive to infliximab.

FIG.6: Expression levels of RNA encoding NLRP3 in Ulcerative Colitis (UC) patients who are responsive and non-responsive to infliximab.

FIG.7: Expression levels of RNA encoding IL-1 ^ 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:

Formula AA wherein

m = 0, 1, or 2;

n = 0, 1, or 2;

o = 1 or 2;

p = 0, 1, 2, or 3,

wherein

A is a 5- to 10-membered monocyclic or bicyclic heteroaryl or a C ₆ -C ₁₀ monocyclic or bicyclic aryl;

B is a 5-membered heteroaryl, a 7-10 membered monocyclic or bicyclic heteroaryl, or a C ₆ -C ₁₀ monocyclic or bicyclic aryl; wherein at least one R ⁶ is ortho to the bond connecting the B ring to the NH(CO) group of Formula AA;

R ¹ and R ² are each independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, CN, NO2, CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, OCOC1-C6 alkyl, OCOC ₆ -C ₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C6-C10 aryl, 5- to 10-membered heteroaryl, NR ⁸ R ⁹ , C(O)R ¹³ , CONR ⁸ R ⁹ , SF5, SC1-C6 alkyl, S(O2)C1-C6 alkyl, S(O)C1-C6 alkyl, S(O2)NR ¹¹ R ¹² , C3-C7 cycloalkyl, and 3- to 7-membered heterocycloalkyl,

wherein the C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, 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, R ¹⁵ , C ₁ -C ₆ haloalkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC ₁ -C ₆ alkyl, CONR ⁸ R ⁹ , 3- to 7- membered heterocycloalkyl, C3-C7 cycloalkyl, C6-C10 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 C1-C6 alkyl substituent and each C1-C6 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, -O(C ₀ -C ₃ alkylene)C ₆ -C ₁₀ aryl, halo, NR ⁸ R ⁹ , or oxo; wherein the 3- to 7-membered heterocycloalkyl, C6-C10 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 one pair of R ¹ and R ² on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C ₄ -C ₁₂ carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring containing 1-3 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxy, OC ₃ -C ₁₀ cycloalkyl, NR ⁸ R ⁹ , =NR ¹⁰ , CN, COOC1-C6 alkyl, OS(O2)C6-C10 aryl, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C ₃ -C ₁₀ cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR ⁸ R ⁹ ,

wherein the C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, S(O ₂ )C ₆ -C ₁₀ aryl, C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₁ -C ₆ alkoxy, oxo, NR ⁸ R ⁹ , =NR ¹⁰ , COOC ₁ -C ₆ alkyl, C6-C10 aryl, and CONR ⁸ R ⁹ ; 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, C1-C6 haloalkoxy, halo, CN, NO2, COC1-C6 alkyl, CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, OCOC1- C6 alkyl, OCOC6-C10 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 ₁₀ cycloalkyl, 3- to 10-membered heterocycloalkyl, and C2-C6 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 , COOC1-C6 alkyl, CONR ⁸ R ⁹ , 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C ₆ -C ₁₀ aryloxy, and S(O ₂ )C ₁ -C ₆ alkyl; and wherein the C ₁ -C ₆ alkyl or C1-C6 alkoxy that R ⁶ or R ⁷ is substituted with is optionally substituted with one or more hydroxyl, C6-C10 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 are optionally substituted with one or more substituents independently selected from halo, C1-C6 alkyl, and OC1-C6 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 , COOC1-C6 alkyl, C6-C10 aryl, and CONR ⁸ R ⁹ ; R ¹⁰ is C ₁ -C ₆ alkyl; each of R ⁸ and R ⁹ at each occurrence is independently selected from hydrogen, C1-C6 alkyl, C ₃ -C ₇ cycloalkyl, C ₂ -C ₆ alkenyl, (C=NR ¹³ )NR ¹¹ R ¹² , S(O ₂ )C ₁ -C ₆ alkyl, S(O ₂ )NR ¹¹ R ¹² , COR ¹³ , CO2R ¹³ and CONR ¹¹ R ¹² ; wherein the C1-C6 alkyl is optionally substituted with one or more hydroxy, halo, C1-C6 alkoxy, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C7 cycloalkyl, 3- to 7-membered heterocycloalkyl, or NR ¹¹ R ¹² ;

or R ⁸ and R ⁹ taken together with the nitrogen they are attached to form a 3- to 10-membered monocyclic or bicyclic ring optionally containing one or more heteroatoms in addition to the nitrogen they are attached to, wherein the ring is optionally substituted with one or more substituents independently selected from halo, C _1- C ₆ alkyl, C _1- C ₆ haloalkyl, C ₁ -C ₆ alkoxy, oxo, N(C1-C6 alkyl)2, NH2, NH(C1-C6 alkyl), and hydroxy; R ¹³ is C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, or–(Z ¹ -Z ² ) _a1 -Z ³ ; each of R ¹¹ and R ¹² at each occurrence is independently selected from hydrogen, C1-C6 alkyl, and–(Z ¹ -Z ² ) _a1 -Z ³ ;

a1 is 0-10 (e.g., 0-4); each Z ¹ is independently C1-C6 alkylene optionally substituted with one or more substituents independently selected from oxo, halo, and hydroxy;

each Z ² is independently a bond, NH, N(C ₁ -C ₆ alkyl), -O-, -S-, or 5-10 membered heteroarylene;

Z ³ is independently C6-C10 aryl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 5- to 10- membered heteroaryl, or 3- to 10-membered heterocycloalkyl, each of which is optionally substituted with one or more substituents independently selected from halo, C1-C6 alkyl, C1-6 haloalkyl, C1-C6 alkoxy, oxo, N(C1-C6 alkyl)2, NH2, NH(C1-C6 alkyl), and hydroxy; R ³ is selected from hydrogen, cyano, hydroxy, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkyl, and , wherein the C1-C2 alkylene group is optionally substituted by oxo; R ¹⁴ is hydrogen, C ₁ -C ₆ alkyl, 5- to 10-membered monocyclic or bicyclic heteroaryl or C ₆ - C10 monocyclic or bicyclic aryl , wherein each C1-C6 alkyl, aryl or heteroaryl is optionally independently substituted with 1 or 2 R ⁶ ,

R ¹⁵ is–(Z ⁴ -Z ⁵ ) _a2 -Z ⁶ ;

a2 is an integer selected from 1-10 (e.g., 1-5);

each Z ⁴ is independently selected from–O-, -S-, -NH-, and–N(C1-C3 alkyl)-;

provided that the Z ⁴ group directly attached to R ¹ or R ² is–O- or–S-;

each Z ⁵ is independently C1-C6 alkylene optionally substituted with one or more substituents independently selected from oxo, halo, and hydroxy; and

Z ⁶ is OH, OC ₁ -C ₆ alkyl, NH ₂ , NH(C ₁ -C ₆ alkyl), N(C ₁ -C ₆ alkyl) ₂ , NHC(O)(C ₁ -C ₆ alkyl), NHC(O)(C ₁ -C ₆ alkoxy), or an optionally substituted group selected from the group consisting of:

C6-C10 aryl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocycloalkyl, each of which is optionally substituted with one or more substituents independently selected from halo, C ₁ -C ₆ alkyl, C _1-6 haloalkyl, C ₁ -C ₆ alkoxy, oxo, N(C1-C6 alkyl)2, NH2, NH(C1-C6 alkyl), and hydroxy;

or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein is a compound of Formula AA:

wherein

m = 0, 1, or 2;

n = 0, 1, or 2;

o = 1 or 2;

p = 0, 1, 2, or 3,

wherein

A is a 5- to 10-membered monocyclic or bicyclic heteroaryl or a C6-C10 monocyclic or bicyclic aryl;

B is a 5-membered heteroaryl, a 7-10 membered monocyclic or bicyclic heteroaryl, or a C6-C10 monocyclic or bicyclic aryl; wherein at least one R ⁶ is ortho to the bond connecting the B ring to the NH(CO) group of Formula AA;

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 , CO ₂ C ₁ -C ₆ alkyl, CO ₂ C ₃ -C ₈ cycloalkyl, OCOC ₁ -C ₆ alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, NR ⁸ R ⁹ , C(O)R ¹³ , CONR ⁸ R ⁹ , SF ₅ , SC ₁ -C ₆ alkyl, S(O ₂ )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 C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, 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, C1-C6 alkyl, C1-C6 alkoxy, R ¹⁵ , C1-C6 haloalkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC1-C6 alkyl, CONR ⁸ R ⁹ , 3- to 7- membered heterocycloalkyl, C ₃ -C ₇ cycloalkyl, 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 C1-C6 alkyl substituent and each C1-C6 alkoxy substituent of the R ¹ or R ² C3- 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, -O(C ₀ -C ₃ alkylene)C ₆ -C ₁₀ aryl, halo, NR ⁸ R ⁹ , or oxo;

wherein the 3- to 7-membered heterocycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents independently selected from halo, C1-C6 alkyl, and OC1-C6 alkyl; or one pair of R ¹ and R ² on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C ₄ -C ₁₂ carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring containing 1-3 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR ⁸ R ⁹ , =NR ¹⁰ , CN, COOC1-C6 alkyl, OS(O2)C6-C10 aryl, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C ₃ -C ₁₀ cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR ⁸ R ⁹ ,

wherein the C1-C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR ⁸ R ⁹ , =NR ¹⁰ , COOC1-C6 alkyl, C6-C10 aryl, and CONR ⁸ R ⁹ ; 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, C1-C6 haloalkoxy, halo, CN, NO2, COC1-C6 alkyl, CO2C1-C6 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), 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, SC1-C6 alkyl, S(O2)C1-C6 alkyl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and C2-C6 alkenyl,

wherein R ⁶ and R ⁷ are each optionally substituted with one or more substituents independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC1-C6 alkyl, CONR ⁸ R ⁹ , 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), 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, C6-C10 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, C6-C10 aryl, 5- to 10-membered heteroaryl are optionally substituted with one or more substituents independently selected from halo, C1-C6 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, C1-C6 alkyl, C1-C6 alkoxy, NR ⁸ R ⁹ , CH2NR ⁸ R ⁹ , =NR ¹⁰ , COOC1-C6 alkyl, C6-C10 aryl, and CONR ⁸ R ⁹ ; R ¹⁰ is C1-C6 alkyl; each of R ⁸ and R ⁹ at each occurrence is independently selected from hydrogen, C ₁ -C ₆ alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, (C=NR ¹³ )NR ¹¹ R ¹² , S(O2)C1-C6 alkyl, S(O2)NR ¹¹ R ¹² , COR ¹³ , CO2R ¹³ and CONR ¹¹ R ¹² ; wherein the C1-C6 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, 3- to 7-membered heterocycloalkyl, or NR ¹¹ R ¹² ;

or R ⁸ and R ⁹ taken together with the nitrogen they are attached to form a 3- to 10-membered monocyclic or bicyclic ring optionally containing one or more heteroatoms in addition to the nitrogen they are attached to, wherein the ring is optionally substituted with one or more substituents independently selected from halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, oxo, N(C1-C6 alkyl)2, NH2, NH(C1-C6 alkyl), and hydroxy; R ¹³ is C1-C6 alkyl, C1-C6 haloalkyl, or–(Z ¹ -Z ² )a1-Z ³ ; each of R ¹¹ and R ¹² at each occurrence is independently selected from hydrogen, C1-C6 alkyl, and–(Z ¹ -Z ² ) _a1 -Z ³ ;

a1 is 0-10 (e.g., 0-4);

each Z ¹ is independently C1-C6 alkylene optionally substituted with one or more substituents independently selected from oxo, halo, and hydroxy;

each Z ² is independently a bond, NH, N(C ₁ -C ₆ alkyl), -O-, -S-, or 5-10 membered heteroarylene;

Z ³ is independently C6-C10 aryl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 5- to 10- membered heteroaryl, or 3- to 10-membered heterocycloalkyl, each of which is optionally substituted with one or more substituents independently selected from halo, C ₁ -C ₆ alkyl, C _1-6 haloalkyl, C1-C6 alkoxy, oxo, N(C1-C6 alkyl)2, NH2, NH(C1-C6 alkyl), and hydroxy; R ³ is selected from hydrogen and C ₁ -C ₆ alkyl; R ¹⁴ is hydrogen, C1-C6 alkyl, 5- to 10-membered monocyclic or bicyclic heteroaryl or C6- 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 ,

R ¹⁵ is–(Z ⁴ -Z ⁵ )a2-Z ⁶ ;

a2 is an integer selected from 1-10 (e.g., 1-5);

each Z ⁴ is independently selected from–O-, -S-, -NH-, and–N(C1-C3 alkyl)-;

provided that the Z ⁴ group directly attached to R ¹ or R ² is–O- or–S-;

each Z ⁵ is independently C ₁ -C ₆ alkylene optionally substituted with one or more substituents independently selected from oxo, halo, and hydroxy; and

Z ⁶ is OH, OC1-C6 alkyl, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, NHC(O)(C1-C6 alkyl), NHC(O)(C ₁ -C ₆ alkoxy), or an optionally substituted group selected from the group consisting of:

C _6- C ₁₀ aryl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocycloalkyl, each of which is optionally substituted with one or more substituents independently selected from halo, C1-C6 alkyl, C1-6 haloalkyl, C1-C6 alkoxy, oxo, N(C ₁ -C ₆ alkyl) ₂ , NH ₂ , NH(C ₁ -C ₆ alkyl), and hydroxy;

or a pharmaceutically acceptable salt thereof;

provided that the compound is other than:

In some embodiments, the compound of Formula AA is other than one of the following compounds:

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

Formula AA wherein

m = 0, 1, or 2;

n = 0, 1, or 2;

o = 1 or 2;

p = 0, 1, 2, or 3,

wherein

A is a 5- to 10-membered monocyclic or bicyclic heteroaryl or a C6-C10 monocyclic or bicyclic aryl;

B is a 5-membered heteroaryl, a 7-10 membered monocyclic or bicyclic heteroaryl, or a C ₆ -C ₁₀ monocyclic or bicyclic aryl;

wherein at least one R ⁶ is ortho to the bond connecting the B ring to the NH(CO) group of Formula AA; R ¹ and R ² are each independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, CN, NO2, COC1-C6 alkyl, CO-C6-C10 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), C6-C10 aryl, 5- to 10- membered heteroaryl, NH2, NHC1-C6 alkyl, N(C1-C6 alkyl)2, NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC2-C6 alkynyl, NHCOOCC1-C6 alkyl, NH-(C=NR ¹³ )NR ¹¹ R ¹² , CONR ⁸ R ⁹ , SF5, SC1-C6 alkyl, S(O2)C1-C6 alkyl, S(O)C1-C6 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 alkoxy, C ₁ -C ₆ haloalkyl, C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, 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, R ¹⁵ , C ₁ -C ₆ haloalkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC ₁ -C ₆ alkyl, CONR ⁸ R ⁹ , 3- to 7- membered heterocycloalkyl, C3-C7 cycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 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 C1-C6 alkyl substituent and each C1-C6 alkoxy substituent of the R ¹ or R ² C3- 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, -O(C ₀ -C ₃ alkylene)C ₆ -C ₁₀ aryl, halo, NR ⁸ R ⁹ , or oxo;

wherein the 3- to 7-membered heterocycloalkyl, C6-C10 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, C1-C6 alkyl, and OC1-C6 alkyl; or one pair of R ¹ and R ² on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C4-C12 carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring containing 1-3 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR ⁸ R ⁹ , =NR ¹⁰ , CN, COOC ₁ -C ₆ alkyl, OS(O ₂ )C ₆ -C ₁₀ aryl, S(O ₂ )C ₆ -C ₁₀ aryl, C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR ⁸ R ⁹ ,

wherein the C1-C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C ₃ -C ₁₀ cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR ⁸ R ⁹ , =NR ¹⁰ , COOC1-C6 alkyl, C ₆ -C ₁₀ aryl, and CONR ⁸ R ⁹ ; R ⁶ and R ⁷ are each independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 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), C6-C10 aryl, 5- to 10-membered heteroaryl, NH2, NHC1-C6 alkyl, N(C1-C6 alkyl)2, CONR ⁸ R ⁹ , SF5, SC1-C6 alkyl, S(O2)C1-C6 alkyl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and 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, C1-C6 alkyl, C1-C6 alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC1-C6 alkyl, CONR ⁸ R ⁹ , 3- to 7-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(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), NHCOC2-C6 alkynyl, C6-C10 aryloxy, and S(O2)C1-C6 alkyl; and wherein the C1-C6 alkyl or C1-C6 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-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, C1-C6 alkyl, C1-C6 alkoxy, NR ⁸ R ⁹ , CH2NR ⁸ R ⁹ , =NR ¹⁰ , COOC1-C6 alkyl, C6-C10 aryl, and CONR ⁸ R ⁹ ; R ¹⁰ is C1-C6 alkyl; each of R ⁸ and R ⁹ at each occurrence is independently selected from hydrogen, C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl, C ₂ -C ₆ alkenyl, (C=NR ¹³ )NR ¹¹ R ¹² , S(O ₂ )C ₁ -C ₆ alkyl, S(O ₂ )NR ¹¹ R ¹² , COR ¹³ , CO2R ¹³ and CONR ¹¹ R ¹² ; wherein the C1-C6 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, 3- to 7-membered heterocycloalkyl, or NR ¹¹ R ¹² ; 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 ¹³ is C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₆ -C ₁₀ aryl, or 5- to 10-membered heteroaryl;

each of R ¹¹ and R ¹² at each occurrence is independently selected from hydrogen and C1-C6 alkyl; R ³ is selected from hydrogen, cyano, hydroxy, C1-C6 alkoxy, C1-C6 alkyl, and

, wherein the C ₁ -C ₂ alkylene group is optionally substituted by oxo;

R ¹⁴ is hydrogen, C ₁ -C ₆ alkyl, 5- to 10-membered monocyclic or bicyclic heteroaryl or C ₆ - C10 monocyclic or bicyclic aryl , wherein each C1-C6 alkyl, aryl or heteroaryl is optionally independently substituted with 1 or 2 R ⁶ ,

R ¹⁵ is–(Z ⁴ -Z ⁵ ) _a2 -Z ⁶ ;

a2 is an integer selected from 1-10 (e.g., 1-5);

each Z ⁴ is independently selected from–O-, -S-, -NH-, and–N(C1-C3 alkyl)-;

provided that the Z ⁴ group directly attached to R ¹ or R ² is–O- or–S-;

each Z ⁵ is independently C1-C6 alkylene optionally substituted with one or more substituents independently selected from oxo, halo, and hydroxy; and

Z ⁶ is OH, OC ₁ -C ₆ alkyl, NH ₂ , NH(C ₁ -C ₆ alkyl), N(C ₁ -C ₆ alkyl) ₂ , NHC(O)(C ₁ -C ₆ alkyl), NHC(O)(C ₁ -C ₆ alkoxy), or an optionally substituted group selected from the group consisting of:

C6-C10 aryl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocycloalkyl, each of which is optionally substituted with one or more substituents independently selected from halo, C ₁ -C ₆ alkyl, C _1-6 haloalkyl, C ₁ -C ₆ alkoxy, oxo, N(C1-C6 alkyl)2, NH2, NH(C1-C6 alkyl), and hydroxy;

or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein is a compound of Formula AA:

wherein m = 0, 1, or 2;

n = 0, 1, or 2;

o = 1 or 2;

p = 0, 1, 2, or 3,

wherein

A is a 5- to 10-membered monocyclic or bicyclic heteroaryl or a C ₆ -C ₁₀ monocyclic or bicyclic aryl;

B is a 5-membered heteroaryl, a 7-10 membered monocyclic or bicyclic heteroaryl, or a C ₆ -C ₁₀ monocyclic or bicyclic aryl;

wherein at least one R ⁶ is ortho to the bond connecting the B ring to the NH(CO) group of Formula AA; 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, C1-C6 haloalkoxy, halo, CN, NO2, COC1-C6 alkyl, CO-C6-C10 aryl, CO(5- to 10-membered heteroaryl); CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C ₆ -C ₁₀ aryl, 5- to 10- membered heteroaryl, NH2, NHC1-C6 alkyl, N(C1-C6 alkyl)2, NHCOC1-C6 alkyl, NHCOC6-C10 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 , SF ₅ , SC ₁ -C ₆ alkyl, S(O2)C1-C6 alkyl, S(O)C1-C6 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 alkoxy, C ₁ -C ₆ haloalkyl, C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, 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, C1-C6 alkyl, C ₁ -C ₆ alkoxy, R ¹⁵ , C ₁ -C ₆ haloalkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC ₁ -C ₆ alkyl, CONR ⁸ R ⁹ , 3- to 7- membered heterocycloalkyl, C ₃ -C ₇ cycloalkyl, C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), and NHCOC ₂ -C ₆ alkynyl;

wherein each C1-C6 alkyl substituent and each C1-C6 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, -O(C0-C3 alkylene)C6-C10 aryl, halo, NR ⁸ R ⁹ , or oxo;

wherein the 3- to 7-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, NHCOC6-C10 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 one monocyclic or bicyclic C ₄ -C ₁₂ carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring containing 1-3 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxy, OC ₃ -C ₁₀ cycloalkyl, NR ⁸ R ⁹ , =NR ¹⁰ , CN, COOC1-C6 alkyl, OS(O2)C6-C10 aryl, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR ⁸ R ⁹ ,

wherein the C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, S(O ₂ )C ₆ -C ₁₀ aryl, C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₁ -C ₆ alkoxy, oxo, NR ⁸ R ⁹ , =NR ¹⁰ , COOC ₁ -C ₆ alkyl, C6-C10 aryl, and CONR ⁸ R ⁹ ; 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 - C6 alkyl, OCOC6-C10 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 ₁₀ cycloalkyl, 3- to 10-membered heterocycloalkyl, and C2-C6 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 , COOC1-C6 alkyl, CONR ⁸ R ⁹ , 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 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, C6-C10 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, C6-C10 aryl, 5- to 10-membered heteroaryl, NHCOC6-C10 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, C1-C6 alkyl, C1-C6 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 ; R ¹⁰ is C1-C6 alkyl; each of R ⁸ and R ⁹ at each occurrence is independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, (C=NR ¹³ )NR ¹¹ R ¹² , S(O2)C1-C6 alkyl, S(O2)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, C ₃ -C ₇ cycloalkyl, 3- to 7-membered heterocycloalkyl, or NR ¹¹ R ¹² ; 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 ¹³ is C1-C6 alkyl, C1-C6 haloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl;

each of R ¹¹ and R ¹² at each occurrence is independently selected from hydrogen and C1-C6 alkyl; R ³ is selected from hydrogen and C1-C6 alkyl; and R ¹⁴ is hydrogen, C1-C6 alkyl, 5- to 10-membered monocyclic or bicyclic heteroaryl or C6- 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 ,

R ¹⁵ is–(Z ⁴ -Z ⁵ )a2-Z ⁶ ;

a2 is an integer selected from 1-10 (e.g., 1-5);

each Z ⁴ is independently selected from–O-, -S-, -NH-, and–N(C ₁ -C ₃ alkyl)-;

provided that the Z ⁴ group directly attached to R ¹ or R ² is–O- or–S-;

each Z ⁵ is independently C1-C6 alkylene optionally substituted with one or more substituents independently selected from oxo, halo, and hydroxy; and

Z ⁶ is OH, OC ₁ -C ₆ alkyl, NH ₂ , NH(C ₁ -C ₆ alkyl), N(C ₁ -C ₆ alkyl) ₂ , NHC(O)(C ₁ -C ₆ alkyl), NHC(O)(C1-C6 alkoxy), or an optionally substituted group selected from the group consisting of:

C _6- C ₁₀ aryl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocycloalkyl, each of which is optionally substituted with one or more substituents independently selected from halo, C1-C6 alkyl, C1-6 haloalkyl, C1-C6 alkoxy, oxo, N(C1-C6 alkyl)2, NH2, NH(C1-C6 alkyl), and hydroxy;

or a pharmaceutically acceptable salt thereof;

provided that the compound is other than:

In some embodiments, the compound of Formula AA is other than one of the following compounds:

,

F

F O

F F

O

O ^H

F

F

O

^{OH H}

^O

^{H N H H}

N _N

F

F

^H

F

F

F F

F

F _{HO HO} ^S HO

F

F F

O S

O O

S O

Cl O

^{H H}

F

N HO

H

HO N

OH ^H N

HO

HO

OH OH ^{H H} N H ^O

^{HO N H} N

^HO N

N H ^{O N} N ^H2N

S _N ^H N

H

H ₂ N ^H

N

HO N

HO N

HO _N

_H3C

H ₃ C _N

N ^{H2N H2N}

S _N ^H S _N S _N ^H S _N C ^l _HO

_OH O H ₂ N O

S ^H2N

N ^H F F

F O _H

_{HO OH}

^NC

^HO

O ^H _O ^NH ₂

_O ^NH ₂ ^N

F _{F F F O} ^NH ₂

F F ^H HO

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

wherein

m = 0, 1, or 2;

n = 0, 1, or 2;

o = 1 or 2;

p = 0, 1, 2, or 3,

wherein

A is a 5- to 10-membered monocyclic or bicyclic heteroaryl or a C6-C10 monocyclic or bicyclic aryl;

B is a 5-membered heteroaryl, a 7-10 membered monocyclic or bicyclic heteroaryl, or a C6-C10 monocyclic or bicyclic aryl;

wherein

at least one R ⁶ is ortho to the bond connecting the B ring to the NH(CO) group of Formula AA;

R ¹ and R ² are each independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 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); CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, OCOC1-C6 alkyl, OCOC6-C10 aryl,

OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C6-C10 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, NHCOC ₆ - C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC2-C6 alkynyl, NHCOOCC1-C6 alkyl, NH-(C=NR ¹³ )NR ¹¹ R ¹² , CONR ⁸ R ⁹ , SF5, SC1-C6 alkyl, S(O ₂ )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, 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, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), and NHCOC ₂ -C ₆ alkynyl; wherein each C1-C6 alkyl substituent and each C1-C6 alkoxy substituent of the R ¹ or R ² C3- 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, C6-C10 aryl, 5- to 10-membered heteroaryl, NHCOC6-C10 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, C1-C6 alkyl, and OC1-C6 alkyl; or one pair of R ¹ and R ² on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C ₄ -C ₁₂ carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring containing 1-3 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR ⁸ R ⁹ , =NR ¹⁰ , CN, COOC1-C6 alkyl, OS(O2)C6-C10 aryl, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C ₃ -C ₁₀ cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR ⁸ R ⁹ , wherein the C ₁ -C ₆ alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C1-C6 alkoxy, oxo, NR ⁸ R ⁹ , =NR ¹⁰ , COOC1-C6 alkyl, C6-C10 aryl, and CONR ⁸ R ⁹ ; 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 - C6 alkyl, OCOC6-C10 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 ₁₀ cycloalkyl, 3- to 10-membered heterocycloalkyl, and C2-C6 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, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 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, C6-C10 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, C6-C10 aryl, 5- to 10-membered heteroaryl, NHCOC6-C10 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, C1-C6 alkyl, C1-C6 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 ⁴ and R ⁵ is independently selected from hydrogen and C1-C6 alkyl;

R ¹⁰ is C ₁ -C ₆ alkyl;

each of R ⁸ and R ⁹ at each occurrence is independently selected from hydrogen, C1-C6 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 ¹³ is C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₆ -C ₁₀ aryl, or 5- to 10-membered heteroaryl;

each of R ¹¹ and R ¹² at each occurrence is independently selected from hydrogen and C1-C6 alkyl; R ³ is selected from hydrogen, cyano, hydroxy, C1-C6 alkoxy, C1-C6 alkyl, , wherein the C ₁ -C ₂ alkylene group is optionally substituted by oxo; and

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 C1-C6 alkyl, aryl or heteroaryl is optionally independently substituted with 1 or 2 R ⁶ ,

or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein is a compound of Formula AA

Formula AA

wherein

m = 0, 1, or 2;

n = 0, 1, or 2;

o = 1 or 2;

p = 0, 1, 2, or 3;

wherein

A is a 5-10-membered heteroaryl or a C ₆ -C ₁₀ aryl;

B is a 5-10-membered heteroaryl or a C ₆ -C ₁₀ aryl;

wherein

at least one R ⁶ is ortho to the bond connecting the B ring to the NR ³ (CO) group of Formula AA; 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 - C6 haloalkoxy, halo, CN, NO2, COC1-C6 alkyl, CO-C6-C10 aryl, CO-(5- to 10-membered heteroaryl), CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, OCOC1-C6 alkyl, OCOC6-C10 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 , 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, NHCOOC ₁ -C ₆ alkyl, NH-(C=NR ¹³ )NR ¹¹ R ¹² , 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 C1-C6 alkyl, C1-C6 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, C1-C6 alkyl, C1-C6 alkoxy, COOC1-C6 alkyl, NR ⁸ R ⁹ , CONR ⁸ R ⁹ , 3- to 7-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), and 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, or oxo;

wherein the 3- to 7-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl, of the R ¹ or R ² C ₁ -C ₆ alkyl, the R ¹ or R ² C ₁ -C ₆ haloalkyl, the R ¹ or R ² C ₃ -C ₇ cycloalkyl, or the R ¹ or R ² 3- to 7-membered heterocycloalkyl are optionally substituted with one or more substituents independently selected from halo, C1-C6 alkyl, oxo, and OC1- 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, C1-C6 alkyl, C1-C6 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, COOC ₁ -C ₆ alkyl, C ₆ -C ₁₀ aryl, and CONR ⁸ R ⁹ ; R ⁶ and R ⁷ are each independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1- 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, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C6-C10 aryl, 5- to 10-membered heteroaryl, NH2, NHC1-C6 alkyl, N(C1-C6 alkyl)2, CONR ⁸ R ⁹ , SF5, SC1-C6 alkyl, S(O2)C1-C6 alkyl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and 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, C1-C6 alkyl, C1-C6 alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC1-C6 alkyl, CONR ⁸ R ⁹ , 3- to 7-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(3- to 7-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC2-C6 alkynyl, C6-C10 aryloxy, and S(O2)C1- 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, halo, 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, NHCOC6-C10 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 4-to 8-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, NR ²⁰ , 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, C1-C6 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 ⁴ and R ⁵ is independently selected from hydrogen and C ₁ -C ₆ alkyl; R ¹⁰ is C ₁ -C ₆ alkyl;

each of R ⁸ and R ⁹ at each occurrence is independently selected from hydrogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C2-C6 alkynyl, (C=NR ¹³ )NR ¹¹ R ¹² , S(O2)C1-C6 alkyl, S(O2)NR ¹¹ R ¹² , COR ¹³ , CO2R ¹³ and CONR ¹¹ R ¹² ; wherein the C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is optionally substituted with one or more hydroxy, halo, oxo, C ₁ -C ₆ alkoxy, C ₂ -C ₆ alkynyl, CO ₂ R ¹³ , 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;

R ¹³ is C ₁ -C ₆ alkyl, C ₆ -C ₁₀ aryl, or 5- to 10-membered heteroaryl;

each of R ¹¹ and R ¹² at each occurrence is independently selected from hydrogen and C1-C6 alkyl; each R ³ is independently selected from hydrogen, cyano, hydroxy, C1-C6 alkoxy, C1-C6 alkyl,

CO2C1-C6 alkyl, and , wherein the C1-C2 alkylene group is optionally substituted with oxo; and

R ¹⁴ is hydrogen, C ₁ -C ₆ alkyl, 5-10-membered monocyclic or bicyclic heteroaryl or C ₆ -C ₁₀ monocyclic or bicyclic aryl, wherein each C1-C6 alkyl, aryl or heteroaryl is optionally independently substituted with 1, 2, or 3 R ⁶ ;

or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein is a compound of Formula AA

wherein

m = 0, 1, or 2;

n = 0, 1, or 2;

o = 1 or 2;

p = 0, 1, 2, or 3;

wherein

A is a 5-10-membered heteroaryl or a C6-C10 aryl;

B is a 5-10-membered heteroaryl or a C6-C10 aryl;

wherein

at least one R ⁶ is ortho to the bond connecting the B ring to the NR ³ (CO) group of Formula AA; R ¹ and R ² are each independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1- 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), C6-C10 aryl, 5- to 10- membered heteroaryl, NH2, NHC1-C6 alkyl, N(C1-C6 alkyl)2, NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC2-C6 alkynyl, NHCOOC1-C6 alkyl, NH-(C=NR ¹³ )NR ¹¹ R ¹² , CONR ⁸ R ⁹ , SF5, SC1-C6 alkyl, S(O2)C1-C6 alkyl, S(O2)NR ¹¹ R ¹² , S(O)C1-C6 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, COOC ₁ -C ₆ alkyl, NR ⁸ R ⁹ , CONR ⁸ R ⁹ , 3- to 7-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), and OCO(3- to 7- membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), and NHCOC ₂ -C ₆ alkynyl;

wherein each C1-C6 alkyl substituent and each C1-C6 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, or oxo;

wherein the 3- to 7-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl, of the R ¹ or R ² C1-C6 alkyl, the R ¹ or R ² C1-C6 haloalkyl, the R ¹ or R ² C3-C7 cycloalkyl, or the R ¹ or R ² 3- to 7-membered heterocycloalkyl are optionally substituted with one or more substituents independently selected from halo, C ₁ -C ₆ alkyl, oxo, and OC ₁ - C6 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 , COOC1-C6 alkyl, C6-C10 aryl, and CONR ⁸ R ⁹ , wherein the C1-C6 alkyl and C1-C6 alkoxy are optionally substituted with hydroxy, halo, oxo, COOC1-C6 alkyl, C6-C10 aryl, and CONR ⁸ R ⁹ ; 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, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C6-C10 aryl, 5- to 10-membered heteroaryl, NH2, NHC1-C6 alkyl, N(C1-C6 alkyl) ₂ , CONR ⁸ R ⁹ , SF ₅ , SC ₁ -C ₆ alkyl, S(O ₂ )C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, 3- to 10-membered heterocycloalkyl, and C2-C6 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, OCOC1-C6 alkyl, OCOC6-C10 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 - C6 alkyl; and wherein the C1-C6 alkyl or C1-C6 alkoxy that R ⁶ or R ⁷ is substituted with is optionally substituted with one or more hydroxyl, halo, C6-C10 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, C6-C10 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, C1-C6 alkyl, and OC1-C6 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 , COOC1-C6 alkyl, C6-C10 aryl, and CONR ⁸ R ⁹ ; R ¹⁰ is C ₁ -C ₆ alkyl;

each of R ⁸ and R ⁹ at each occurrence is independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, (C=NR ¹³ )NR ¹¹ R ¹² , S(O2)C1-C6 alkyl, S(O2)NR ¹¹ R ¹² , COR ¹³ , CO2R ¹³ and CONR ¹¹ R ¹² ; wherein the C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is optionally substituted with one or more hydroxy, halo, oxo, C ₁ -C ₆ alkoxy, C ₂ -C ₆ alkynyl, CO ₂ R ¹³ , 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 ¹³ is C ₁ -C ₆ alkyl, C ₆ -C ₁₀ aryl, or 5- to 10-membered heteroaryl;

each of R ¹¹ and R ¹² at each occurrence is independently selected from hydrogen and C1-C6 alkyl; each R ³ is independently selected from hydrogen, cyano, hydroxy, C1-C6 alkoxy, C1-C6 alkyl,

CO2C1-C6 alkyl, and , wherein the C1-C2 alkylene group is optionally substituted with oxo; and

R ¹⁴ is hydrogen, C ₁ -C ₆ alkyl, 5-10-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, 2, or 3 R ⁶ ;

or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein is a compound of Formula AA

wherein

m = 0, 1, or 2;

n = 0, 1, or 2;

o = 1 or 2;

p = 0, 1, 2, or 3;

wherein

A is a 5-10-membered heteroaryl or a C6-C10 aryl; B is a 5-10-membered heteroaryl or a C6-C10 aryl;

wherein

at least one R ⁶ is ortho to the bond connecting the B ring to the NR ³ (CO) group of Formula AA; R ¹ and R ² are each independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1- C6 haloalkoxy, halo, CN, NO2, COC1-C6 alkyl, CO-C6-C10 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), C6-C10 aryl, 5- to 10- membered heteroaryl, NH2, NHC1-C6 alkyl, N(C1-C6 alkyl)2, NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC ₂ -C ₆ alkynyl, NHCOOC ₁ -C ₆ alkyl, NH-(C=NR ¹³ )NR ¹¹ R ¹² , CONR ⁸ R ⁹ , SF ₅ , SC ₁ -C ₆ alkyl, S(O2)C1-C6 alkyl, S(O2)NR ¹¹ R ¹² , S(O)C1-C6 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, C1-C6 alkyl, C1-C6 alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC1-C6 alkyl, CONR ⁸ R ⁹ , 3- to 7-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), and OCO(3- to 7- membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), and NHCOC ₂ -C ₆ alkynyl;;

wherein each C1-C6 alkyl substituent and each C1-C6 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, NHCOC6-C10 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 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, C1-C6 alkyl, C1-C6 alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC1-C6 alkyl, C6-C10 aryl, and CONR ⁸ R ⁹ , wherein the C1-C6 alkyl and C1-C6 alkoxy are optionally substituted with hydroxy, halo, oxo, NR ⁸ R ⁹ , =NR ¹⁰ , COOC ₁ -C ₆ alkyl, C ₆ - C ₁₀ aryl, and CONR ⁸ R ⁹ ; R ⁶ and R ⁷ are each independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1- 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, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C6-C10 aryl, 5- to 10-membered heteroaryl, NH2, NHC1-C6 alkyl, N(C1-C6 alkyl) ₂ , CONR ⁸ R ⁹ , SF ₅ , SC ₁ -C ₆ alkyl, S(O ₂ )C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, 3- to 10-membered heterocycloalkyl, and 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, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7- membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 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)C1-C6 alkyl; and wherein the C1-C6 alkyl or C1-C6 alkoxy that R ⁶ or R ⁷ is substituted with is optionally substituted with one or more hydroxyl, halo, C6-C10 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 and optionally substituted with halo;

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, C1-C6 alkyl, C1-C6 alkoxy, NR ⁸ R ⁹ , CH2NR ⁸ R ⁹ , =NR ¹⁰ , COOC1-C6 alkyl, C6-C10 aryl, and CONR ⁸ R ⁹ ; R ¹⁰ is C ₁ -C ₆ alkyl;

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)C1-C6 alkyl, S(O2)NR ¹¹ R ¹² , COR ¹³ , CO2R ¹³ and CONR ¹¹ R ¹² ; wherein the C1-C6 alkyl is optionally substituted with one or more hydroxy, halo, C1-C6 alkoxy, C6-C10 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 ¹³ is C ₁ -C ₆ alkyl, C ₆ -C ₁₀ aryl, or 5- to 10-membered heteroaryl;

each of R ¹¹ and R ¹² at each occurrence is independently selected from hydrogen and C ₁ -C ₆ alkyl; R ³ is selected from hydrogen, cyano, hydroxy, C1-C6 alkoxy, C1-C6 alkyl, CO2C1-C6 alkyl, and , wherein the C ₁ -C ₂ alkylene group is optionally substituted with oxo; and R ¹⁴ is hydrogen, C1-C6 alkyl, 5-10-membered monocyclic or bicyclic heteroaryl or C6-C10 monocyclic or bicyclic aryl, wherein each C1-C6 alkyl, aryl or heteroaryl is optionally independently substituted with 1, 2, or 3 R ⁶ ;

or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein is a compound of Formula AA

Formula AA

wherein

m = 0, 1, or 2;

n = 0, 1, or 2;

o = 1 or 2;

p = 0, 1, 2, or 3; wherein

A is a 5- to 10-membered monocyclic or bicyclic heteroaryl or a C ₆ -C ₁₀ monocyclic or bicyclic aryl;

B is a 5- to 10-membered monocyclic or bicyclic heteroaryl or a C6-C10 monocyclic or bicyclic aryl;

wherein

at least one R ⁶ is ortho to the bond connecting the B ring to the NR ³ (CO) group of Formula AA; R ¹ and R ² are each independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1- 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), C6-C10 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, NHCOC ₆ -C ₁₀ aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC2-C6 alkynyl, NHCOOCC1-C6 alkyl, NH-(C=NR ¹³ )NR ¹¹ R ¹² , CONR ⁸ R ⁹ , SF5, SC1-C6 alkyl, S(O2)C1-C6 alkyl, S(O2)NR ¹¹ R ¹² , S(O)C1-C6 alkyl, C3-C7 cycloalkyl and 3- to 7-membered heterocycloalkyl,

wherein the C1-C6 alkyl, C1-C6 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, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 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 C1-C6 alkyl substituent and each C1-C6 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, C6-C10 aryl, 5- to 10-membered heteroaryl, NHCOC6-C10 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, C1-C6 alkyl, and OC1-C6 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, C1-C6 alkyl, C1-C6 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 , COOC1-C6 alkyl, C6- C10 aryl, and CONR ⁸ R ⁹ ; 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 - C6 haloalkoxy, halo, CN, NO2, COC1-C6 alkyl, CO2C1-C6 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), 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, SC1-C6 alkyl, S(O2)C1-C6 alkyl, C3-C10 cycloalkyl and 3- to 10- membered heterocycloalkyl, and C2-C6 alkenyl,

wherein R ⁶ and R ⁷ are each optionally substituted with one or more substituents independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC1-C6 alkyl, CONR ⁸ R ⁹ , 3- to 7-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(3- to 7- membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC2-C6 alkynyl, C6-C10 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, NHCOC6-C10 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, C1-C6 alkoxy, NR ⁸ R ⁹ , CH2NR ⁸ R ⁹ , =NR ¹⁰ , COOC1-C6 alkyl, C6-C10 aryl, and CONR ⁸ R ⁹ ; R ¹⁰ is C ₁ -C ₆ alkyl;

each of R ⁸ and R ⁹ at each occurrence is independently selected from hydrogen, C1-C6 alkyl, (C=NR ¹³ )NR ¹¹ R ¹² , S(O2)C1-C6 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 ¹³ is C ₁ -C ₆ alkyl, C ₆ -C ₁₀ aryl, or 5- to 10-membered heteroaryl;

each of R ¹¹ and R ¹² at each occurrence is independently selected from hydrogen and C1-C6 alkyl; and

R ³ is selected from hydrogen, cyano, hydroxy, C1-C6 alkoxy, C1-C6 alkyl,

, wherein the C1-C2 alkylene group is optionally substituted with oxo;

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 C1-C6 alkyl, aryl or heteroaryl is optionally

independently substituted with 1 or 2 R ⁶ ;

or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein is a compound of Formula AA

Formula AA wherein

m = 0, 1, or 2;

n = 0, 1, or 2;

o = 1 or 2;

p = 0, 1, 2, or 3,

wherein

A is a 5- to 10-membered monocyclic or bicyclic heteroaryl or a C6-C10 monocyclic or bicyclic aryl;

B is a 5- to 10-membered monocyclic or bicyclic heteroaryl or a C ₆ -C ₁₀ monocyclic or bicyclic aryl;

wherein

at least one R ⁶ is ortho to the bond connecting the B ring to the NH(CO) group of Formula AA; R ¹ and R ² are each independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1- C6 haloalkoxy, halo, CN, NO2, COC1-C6 alkyl, CO-C6-C10 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), C6-C10 aryl, 5- to 10- membered heteroaryl, NH2, NHC1-C6 alkyl, N(C1-C6 alkyl)2, NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC2-C6 alkynyl, NHCOOCC1-C6 alkyl, NH-(C=NR ¹³ )NR ¹¹ R ¹² , CONR ⁸ R ⁹ , SF5, SC1-C6 alkyl, S(O2)C1-C6 alkyl, S(O)C1-C6 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, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7- membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), and NHCOC ₂ -C ₆ alkynyl; wherein each C1-C6 alkyl substituent and each C1-C6 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, C6-C10 aryl, 5- to 10-membered heteroaryl, NHCOC6-C10 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, C1-C6 alkyl, and OC1-C6 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 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 , COOC1-C6 alkyl, C6- C10 aryl, and CONR ⁸ R ⁹ ; R ⁶ and R ⁷ are each independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1- C6 haloalkoxy, halo, CN, NO2, COC1-C6 alkyl, CO2C1-C6 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), C6-C10 aryl, 5- to 10-membered heteroaryl, NH2, NHC1-C6 alkyl, N(C1-C6 alkyl)2, CONR ⁸ R ⁹ , SF5, S(O2)C1-C6 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, C1-C6 alkyl, C1-C6 alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC1-C6 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), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC2-C6 alkynyl, C6-C10 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, C6-C10 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, NHCOC6-C10 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, C1-C6 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 ⁴ and R ⁵ is independently selected from hydrogen and C1-C6 alkyl;

R ¹⁰ is C1-C6 alkyl;

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 C1-C6 alkyl is optionally substituted with one or more hydroxy, halo, C1-C6 alkoxy, C6-C10 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 ¹³ is C ₁ -C ₆ alkyl, C ₆ -C ₁₀ aryl, or 5- to 10-membered heteroaryl;

each of R ¹¹ and R ¹² at each occurrence is independently selected from hydrogen and C ₁ -C ₆ alkyl;

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

, wherein the C1-C2 alkylene group is optionally substituted by oxo;

R ¹⁴ is hydrogen, C1-C6 alkyl, 5- to 10-membered monocyclic or bicyclic heteroaryl or C6-C10 monocyclic or bicyclic aryl , wherein each C ₁ -C ₆ alkyl, aryl or heteroaryl is optionally independently substituted with 1 or 2 R ⁶ ; with the proviso that the compound of Formula AA is not a compound selected from the group consisting of:

;

or a pharmaceutically acceptable salt thereof.

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

m = 0, 1, or 2;

n = 0, 1, or 2;

o = 1 or 2;

p = 0, 1, 2, or 3,

wherein

A is a 5- to 10-membered monocyclic or bicyclic heteroaryl or a C6-C10 monocyclic or bicyclic aryl;

B is a 5-membered heteroaryl, a 7-10 membered monocyclic or bicyclic heteroaryl, or a C ₆ -C ₁₀ monocyclic or bicyclic aryl;

wherein

at least one R ⁶ is ortho to the bond connecting the B ring to the NH(CO) group of Formula AA; 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 - C6 haloalkoxy, halo, CN, NO2, COC1-C6 alkyl, CO-C6-C10 aryl; CO(5- to 10-membered heteroaryl); CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C ₆ -C ₁₀ aryl, 5- to 10- membered heteroaryl, NH2, NHC1-C6 alkyl, N(C1-C6 alkyl)2, NHCOC1-C6 alkyl, NHCOC6-C10 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 , SF ₅ , SC ₁ -C ₆ alkyl, S(O2)C1-C6 alkyl, S(O)C1-C6 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, C1-C6 alkyl, C1-C6 alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC1-C6 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), NHCOC1-C6 alkyl, NHCOC6-C10 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 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, C6-C10 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, C1-C6 alkyl, and OC1-C6 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 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 , COOC1-C6 alkyl, C6- C ₁₀ aryl, and CONR ⁸ R ⁹ ; R ⁶ and R ⁷ are each independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1- C6 haloalkoxy, halo, CN, NO2, COC1-C6 alkyl, CO2C1-C6 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), C6-C10 aryl, 5- to 10-membered heteroaryl, NH2, NHC1-C6 alkyl, N(C1-C6 alkyl)2, CONR ⁸ R ⁹ , SF5, S(O2)C1-C6 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, C1-C6 alkyl, C1-C6 alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC1-C6 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), NHCOC1-C6 alkyl, NHCOC6-C10 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, C6-C10 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, C6-C10 aryl, 5- to 10-membered heteroaryl, NHCOC6-C10 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, C1-C6 alkyl, C1-C6 alkoxy, NR ⁸ R ⁹ , CH2NR ⁸ R ⁹ , =NR ¹⁰ , COOC1-C6 alkyl, C6-C10 aryl, and CONR ⁸ R ⁹ ; each of R ⁴ and R ⁵ is independently selected from hydrogen and C ₁ -C ₆ alkyl;

R ¹⁰ is C1-C6 alkyl;

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 C1-C6 alkyl is optionally substituted with one or more hydroxy, halo, C1-C6 alkoxy, C6-C10 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; R ¹³ is C1-C6 alkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl;

each of R ¹¹ and R ¹² at each occurrence is independently selected from hydrogen and C ₁ -C ₆ alkyl;

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

, wherein the C ₁ -C ₂ alkylene group is optionally substituted by oxo; and

R ¹⁴ is hydrogen, C1-C6 alkyl, 5- to 10-membered monocyclic or bicyclic heteroaryl or C6-C10 monocyclic or bicyclic aryl , wherein each C1-C6 alkyl, aryl or heteroaryl is optionally independently substituted with 1 or 2 R ⁶ ;

or a pharmaceutically acceptable salt thereof. In certain of any of the foregoing embodiments, R ³ is H or methyl, wherein the compound is other than: In some embodiments, provided herein is a compound of Formula AA:

wherein the moiety is as defined for (AA-1), (AA-2), (AA-3), or (AA-4) below:

(AA-1):

A is a 5- to 10-membered monocyclic or bicyclic heteroaryl or a C ₇ -C ₁₀ bicyclic aryl; m = 0, 1, or 2; and

n = 0, 1, or 2; (AA-2):

A is phenyl;

m = 0, 1, or 2; and

n = 0, 1, or 2, provided that m + n = 0, 2, 3, or 4; (AA-3):

B is a 5-membered heteroaryl, a 7-10 membered monocyclic or bicyclic heteroaryl, or a C ₆ -C ₁₀ monocyclic or bicyclic aryl; wherein at least one R ⁶ is ortho to the bond connecting the B ring to the NH(CO) group of Formula AA;

o = 1 or 2;

p = 0, 1, 2, or 3; when (AA-1), (AA-2), or (AA-3) applies,

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, C1-C6 haloalkoxy, halo, CN, NO2, CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, NR ⁸ R ⁹ , C(O)R ¹³ , CONR ⁸ R ⁹ , SF ₅ , SC ₁ -C ₆ alkyl, S(O2)C1-C6 alkyl, S(O)C1-C6 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 alkoxy, C ₁ -C ₆ haloalkyl, C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, 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, C1-C6 alkyl, C ₁ -C ₆ alkoxy, R ¹⁵ , C ₁ -C ₆ haloalkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC ₁ -C ₆ alkyl, CONR ⁸ R ⁹ , 3- to 7- membered heterocycloalkyl, C ₃ -C ₇ cycloalkyl, C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), and OCO(3- to 7- membered heterocycloalkyl); wherein each C1-C6 alkyl substituent and each C1-C6 alkoxy substituent of the R ¹ or R ² C3- 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, -O(C ₀ -C ₃ alkylene)C ₆ -C ₁₀ aryl, halo, NR ⁸ R ⁹ , or oxo;

wherein the 3- to 7-membered heterocycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents independently selected from halo, C1-C6 alkyl, and OC1-C6 alkyl;

or one pair of R ¹ and R ² on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C ₄ -C ₁₂ carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring containing 1-3 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxy, OC ₃ -C ₁₀ cycloalkyl, NR ⁸ R ⁹ , =NR ¹⁰ , CN, COOC1-C6 alkyl, OS(O2)C6-C10 aryl, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR ⁸ R ⁹ ,

wherein the C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, S(O ₂ )C ₆ -C ₁₀ aryl, C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₁ -C ₆ alkoxy, oxo, NR ⁸ R ⁹ , =NR ¹⁰ , COOC ₁ -C ₆ alkyl, C6-C10 aryl, and CONR ⁸ R ⁹ ; OR

when (AA-4) applies, R ¹ ’ is selected from the group consisting of:

methyl; C2-C6 alkyl; C1-C6 haloalkyl; C1-C6 alkoxy; C1-C6 haloalkoxy; halo; CN; NO2; 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; NR ⁸ R ⁹ ; C(O)R ¹³ ; CONR ⁸ R ⁹ ; SF5; SC1-C6 alkyl; S(O2)C1-C6 alkyl, S(O)C1-C6 alkyl; S(O2)NR ¹¹ R ¹² ; C3-C7 cycloalkyl; and 3- to 7-membered heterocycloalkyl,

wherein when R ¹ ’ is methyl, R ¹ ’ is substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, R ¹⁵ , C1-C6 haloalkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC1-C6 alkyl, CONR ⁸ R ⁹ , 3- to 7-membered heterocycloalkyl, C3- C7 cycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), and OCO(3- to 7-membered heterocycloalkyl); and

when R ¹ ’ is selected from the group consisting of C ₂ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C7 cycloalkyl and 3- to 7-membered heterocycloalkyl, R ¹ ’ 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, R ¹⁵ , C ₁ -C ₆ haloalkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC1-C6 alkyl, CONR ⁸ R ⁹ , 3- to 7-membered heterocycloalkyl, C3-C7 cycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 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’ C ₃ -C ₇ cycloalkyl or of the R ^1’ 3- to 7-membered heterocycloalkyl is further optionally independently substituted with one to three hydroxy, halo, -O(C ₀ -C ₃ alkylene)C ₆ -C ₁₀ aryl, 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, C1-C6 alkyl, and OC1-C6 alkyl; R ⁶ and R ⁷ are each independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, CN, NO2, COC1-C6 alkyl, CO2C1-C6 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), C6-C10 aryl, 5- to 10-membered heteroaryl, NH2, NHC1-C6 alkyl, N(C1-C6 alkyl)2, CONR ⁸ R ⁹ , SF5, SC1-C6 alkyl, S(O2)C1-C6 alkyl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and 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, C1-C6 alkyl, C1-C6 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), C6-C10 aryloxy, and S(O2)C1-C6 alkyl; and wherein the C1-C6 alkyl or C1-C6 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, C6-C10 aryl, 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 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, C1-C6 alkyl, C1-C6 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 ; R ¹⁰ is C1-C6 alkyl; each of R ⁸ and R ⁹ at each occurrence is independently selected from hydrogen, C ₁ -C ₆ alkyl, C3-C7 cycloalkyl, C2-C6 alkenyl, (C=NR ¹³ )NR ¹¹ R ¹² , S(O2)C1-C6 alkyl, S(O2)NR ¹¹ R ¹² , COR ¹³ , CO2R ¹³ and CONR ¹¹ R ¹² ; wherein the C1-C6 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, 3- to 7-membered heterocycloalkyl, or NR ¹¹ R ¹² ;

or R ⁸ and R ⁹ taken together with the nitrogen they are attached to form a 3- to 10-membered monocyclic or bicyclic ring optionally containing one or more heteroatoms in addition to the nitrogen they are attached to, wherein the ring is optionally substituted with one or more substituents independently selected from halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, oxo, N(C ₁ -C ₆ alkyl) ₂ , NH ₂ , NH(C ₁ -C ₆ alkyl), and hydroxy; R ¹³ is C1-C6 alkyl, C1-C6 haloalkyl, or–(Z ¹ -Z ² )a1-Z ³ ; each of R ¹¹ and R ¹² at each occurrence is independently selected from hydrogen, C ₁ -C ₆ alkyl, and–(Z ¹ -Z ² )a1-Z ³ ;

a1 is 0-10 (e.g., 0-4);

each Z ¹ is independently C ₁ -C ₆ alkylene optionally substituted with one or more substituents independently selected from oxo, halo, and hydroxy; each Z ² is independently a bond, NH, N(C1-C6 alkyl), -O-, -S-, or 5-10 membered heteroarylene;

Z ³ is independently C _6- C ₁₀ aryl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, 5- to 10- membered heteroaryl, or 3- to 10-membered heterocycloalkyl, each of which is optionally substituted with one or more substituents independently selected from halo, C1-C6 alkyl, C1-6 haloalkyl, C ₁ -C ₆ alkoxy, oxo, N(C ₁ -C ₆ alkyl) ₂ , NH ₂ , NH(C ₁ -C ₆ alkyl), and hydroxy;

R ³ is selected from hydrogen and C1-C6 alkyl (e.g., R ³ is selected from hydrogen and methyl);

R ¹⁵ is–(Z ⁴ -Z ⁵ ) _a2 -Z ⁶ ;

a2 is an integer selected from 1-10 (e.g., 1-5);

each Z ⁴ is independently selected from–O-, -S-, -NH-, and–N(C1-C3 alkyl)-;

provided that the Z ⁴ group directly attached to R ¹ or R ² is–O- or–S-;

each Z ⁵ is independently C ₁ -C ₆ alkylene optionally substituted with one or more substituents independently selected from oxo, halo, and hydroxy; and

Z ⁶ is OH, OC1-C6 alkyl, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, NHC(O)(C1-C6 alkyl), NHC(O)(C ₁ -C ₆ alkoxy), or an optionally substituted group selected from the group consisting of:

C6-C10 aryl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocycloalkyl, each of which is optionally substituted with one or more substituents independently selected from halo, C ₁ -C ₆ alkyl, C _1-6 haloalkyl, C ₁ -C ₆ alkoxy, oxo, N(C1-C6 alkyl)2, NH2, NH(C1-C6 alkyl), and hydroxy;

or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein is a compound of Formula AA

Formula AA wherein the moiety is as defined for (AA-1), (AA-2), (AA-3), or (AA-4) below:

(AA-1):

A is a 5- to 10-membered monocyclic or bicyclic heteroaryl or a C7-C10 bicyclic aryl; m = 0, 1, or 2; and

n = 0, 1, or 2; (AA-2):

A is phenyl;

m = 0, 1, or 2; and

n = 0, 1, or 2, provided that m + n = 0, 2, 3, or 4; (AA-3):

B is a 5-membered heteroaryl, a 7-10 membered monocyclic or bicyclic heteroaryl, or a C6-C10 monocyclic or bicyclic aryl; wherein at least one R ⁶ is ortho to the bond connecting the B ring to the NH(CO) group of Formula AA;

o = 1 or 2;

p = 0, 1, 2, or 3; when (AA-1), (AA-2), or (AA-3) apply,

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, C1-C6 haloalkoxy, halo, CN, NO2, COC1-C6 alkyl, CO-C6-C10 aryl, CO(5- to 10-membered heteroaryl); CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C ₆ -C ₁₀ aryl, 5- to 10- membered heteroaryl, NH2, NHC1-C6 alkyl, N(C1-C6 alkyl)2, NHCOC1-C6 alkyl, NHCOC6-C10 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 , SF ₅ , SC ₁ -C ₆ alkyl, S(O ₂ )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, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl, C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, 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, C1-C6 alkyl, C1-C6 alkoxy, R ¹⁵ , C1-C6 haloalkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC1-C6 alkyl, CONR ⁸ R ⁹ , 3- to 7- membered heterocycloalkyl, C ₃ -C ₇ cycloalkyl, C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), and NHCOC ₂ -C ₆ alkynyl;

wherein each C1-C6 alkyl substituent and each C1-C6 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, -O(C ₀ -C ₃ alkylene)C ₆ -C ₁₀ aryl, halo, NR ⁸ R ⁹ , or oxo;

wherein the 3- to 7-membered heterocycloalkyl, C6-C10 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, C1-C6 alkyl, and OC1-C6 alkyl; or one pair of R ¹ and R ² on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C4-C12 carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring containing 1-3 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxy, OC ₃ -C ₁₀ cycloalkyl, NR ⁸ R ⁹ , =NR ¹⁰ , CN, COOC1-C6 alkyl, OS(O2)C6-C10 aryl, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR ⁸ R ⁹ ,

wherein the C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, S(O ₂ )C ₆ -C ₁₀ aryl, C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₁ -C ₆ alkoxy, oxo, NR ⁸ R ⁹ , =NR ¹⁰ , COOC ₁ -C ₆ alkyl, C ₆ -C ₁₀ aryl, and CONR ⁸ R ⁹ ; OR

when (AA-4) applies, R ¹ ’ is selected from the group consisting of:

methyl; C2-C6 alkyl; C1-C6 haloalkyl; C1-C6 alkoxy; C1-C6 haloalkoxy; halo; CN; NO2; COC1-C6 alkyl; CO-C6-C10 aryl; CO(5- to 10-membered heteroaryl); CO2C1-C6 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); C6-C10 aryl; 5- to 10-membered heteroaryl; NH2; NHC1-C6 alkyl; N(C1-C6 alkyl)2; NHCOC1-C6 alkyl; NHCOC6-C10 aryl; NHCO(5- to 10-membered heteroaryl); NHCO(3- to 7-membered heterocycloalkyl); NHCOC ₂ -C ₆ alkynyl; NHCOOC ₁ -C ₆ alkyl; NH- (C=NR ¹³ )NR ¹¹ R ¹² ; CONR ⁸ R ⁹ ; SF5; SC1-C6 alkyl; S(O2)C1-C6 alkyl; S(O)C1-C6 alkyl; S(O2)NR ¹¹ R ¹² ; C3-C7 cycloalkyl; and 3- to 7-membered heterocycloalkyl,

wherein when R ¹ ’ is methyl, R ¹ ’ is substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, R ¹⁵ , C ₁ -C ₆ haloalkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC1-C6 alkyl, CONR ⁸ R ⁹ , 3- to 7-membered heterocycloalkyl, C3- C ₇ cycloalkyl, 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 when R ¹ ’ is selected from the group consisting of C2-C6 alkyl, C1-C6 alkoxy, C1- C6 haloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C7 cycloalkyl, and 3- to 7-membered heterocycloalkyl, R ¹ ’ is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, R ¹⁵ , C1-C6 haloalkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC1-C6 alkyl, CONR ⁸ R ⁹ , 3- to 7-membered heterocycloalkyl, C3-C7 cycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 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 C1-C6 alkyl substituent and each C1-C6 alkoxy substituent of the R ^1’ C3-C7 cycloalkyl or of the R ¹ ’ 3- to 7-membered heterocycloalkyl is further optionally independently substituted with one to three hydroxy, -O(C0-C3 alkylene)C6-C10 aryl, halo, NR ⁸ R ⁹ , or oxo;

wherein the 3- to 7-membered heterocycloalkyl, C6-C10 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, C1-C6 alkyl, and OC1-C6 alkyl;

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 - C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C6-C10 aryl, 5- to 10-membered heteroaryl, NH2, NHC1-C6 alkyl, N(C1-C6 alkyl) ₂ , CONR ⁸ R ⁹ , SF ₅ , SC ₁ -C ₆ alkyl, S(O ₂ )C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, 3- to 10-membered heterocycloalkyl, and C2-C6 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 , COOC1-C6 alkyl, CONR ⁸ R ⁹ , 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 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)C1-C6 alkyl; and wherein the C1-C6 alkyl or C1-C6 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, C6-C10 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, C1-C6 alkyl, and OC1-C6 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, C1-C6 alkyl, C1-C6 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 ; R ¹⁰ is C1-C6 alkyl; each of R ⁸ and R ⁹ at each occurrence is independently selected from hydrogen, C ₁ -C ₆ alkyl, C3-C7 cycloalkyl, C2-C6 alkenyl, (C=NR ¹³ )NR ¹¹ R ¹² , S(O2)C1-C6 alkyl, S(O2)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, C ₃ -C ₇ cycloalkyl, 3- to 7-membered heterocycloalkyl, or NR ¹¹ R ¹² ; 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 ¹³ is C1-C6 alkyl, C1-C6 haloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl;

each of R ¹¹ and R ¹² at each occurrence is independently selected from hydrogen and C1-C6 alkyl; R ³ is selected from hydrogen and C1-C6 alkyl (e.g., R ³ is selected from hydrogen and methyl);

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 ;

a2 is an integer selected from 1-10 (e.g., 1-5);

each Z ⁴ is independently selected from–O-, -S-, -NH-, and–N(C1-C3 alkyl)-;

provided that the Z ⁴ group directly attached to R ¹ or R ² is–O- or–S-;

each Z ⁵ is independently C ₁ -C ₆ alkylene optionally substituted with one or more substituents independently selected from oxo, halo, and hydroxy; and Z ⁶ is OH, OC1-C6 alkyl, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, NHC(O)(C1-C6 alkyl), NHC(O)(C ₁ -C ₆ alkoxy), or an optionally substituted group selected from the group consisting of:

C _6- C ₁₀ aryl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocycloalkyl, each of which is optionally substituted with one or more substituents independently selected from halo, C1-C6 alkyl, C1-6 haloalkyl, C1-C6 alkoxy, oxo, N(C ₁ -C ₆ alkyl) ₂ , NH ₂ , NH(C ₁ -C ₆ alkyl), and hydroxy;

or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein is a compound of Formula AA

Formula AA wherein

m = 1 or 2;

n = 1 or 2;

o = 1 or 2;

p = 0, 1, 2, or 3,

wherein

A is a 5- to 10-membered monocyclic or bicyclic heteroaryl or a C ₆ -C ₁₀ monocyclic or bicyclic aryl;

B is a 5-membered heteroaryl, a 7-10 membered monocyclic or bicyclic heteroaryl, or a C ₆ -C ₁₀ monocyclic or bicyclic aryl; wherein at least one R ⁶ is ortho to the bond connecting the B ring to the NH(CO) group of Formula AA; one pair of R ¹ and R ² are on adjacent atoms, and taken together with the atoms connecting them, independently form one monocyclic or bicyclic C ₄ -C ₁₂ carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring containing 1-3 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxy, OC ₃ -C ₁₀ cycloalkyl, NR ⁸ R ⁹ , =NR ¹⁰ , CN, COOC1-C6 alkyl, OS(O2)C6-C10 aryl, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10- membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR ⁸ R ⁹ , wherein the C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, S(O ₂ )C ₆ -C ₁₀ aryl, C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₁ -C ₆ alkoxy, oxo, NR ⁸ R ⁹ , =NR ¹⁰ , COOC ₁ -C ₆ alkyl, C ₆ -C ₁₀ aryl, and CONR ⁸ R ⁹ ; each of R ¹ and R ² that are not taken together with the atoms connecting them to form at least one ring 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, NO2, CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C6-C10 aryl, 5- to 10-membered heteroaryl, NR ⁸ R ⁹ , C(O)R ¹³ , CONR ⁸ R ⁹ , SF ₅ , SC ₁ -C ₆ alkyl, S(O ₂ )C ₁ -C ₆ alkyl, S(O)C1-C6 alkyl, S(O2)NR ¹¹ R ¹² , C3-C7 cycloalkyl, and 3- to 7-membered heterocycloalkyl,

wherein the C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, 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, C1-C6 alkyl, C1-C6 alkoxy, R ¹⁵ , C1-C6 haloalkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC1-C6 alkyl, CONR ⁸ R ⁹ , 3- to 7- membered heterocycloalkyl, C ₃ -C ₇ cycloalkyl, 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 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, -O(C0-C3 alkylene)C6-C10 aryl, 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, C1-C6 alkyl, and OC1-C6 alkyl; 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 - C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C6-C10 aryl, 5- to 10-membered heteroaryl, NH2, NHC1-C6 alkyl, N(C1-C6 alkyl) ₂ , CONR ⁸ R ⁹ , SF ₅ , SC ₁ -C ₆ alkyl, S(O ₂ )C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, 3- to 10-membered heterocycloalkyl, and C2-C6 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, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), 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, C6-C10 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, C6-C10 aryl, 5- to 10-membered heteroaryl are optionally substituted with one or more substituents independently selected from halo, C1-C6 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, C1-C6 alkyl, C1-C6 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 ; R ¹⁰ is C1-C6 alkyl; each of R ⁸ and R ⁹ at each occurrence is independently selected from hydrogen, C ₁ -C ₆ alkyl, C3-C7 cycloalkyl, C2-C6 alkenyl, (C=NR ¹³ )NR ¹¹ R ¹² , S(O2)C1-C6 alkyl, S(O2)NR ¹¹ R ¹² , COR ¹³ , CO2R ¹³ and CONR ¹¹ R ¹² ; wherein the C1-C6 alkyl is optionally substituted with one or more hydroxy, halo, C1-C6 alkoxy, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C7 cycloalkyl, 3- to 7-membered heterocycloalkyl, or NR ¹¹ R ¹² ;

or R ⁸ and R ⁹ taken together with the nitrogen they are attached to form a 3- to 10-membered monocyclic or bicyclic ring optionally containing one or more heteroatoms in addition to the nitrogen they are attached to, wherein the ring is optionally substituted with one or more substituents independently selected from halo, C _1- C ₆ alkyl, C _1- C ₆ haloalkyl, C ₁ -C ₆ alkoxy, oxo, N(C1-C6 alkyl)2, NH2, NH(C1-C6 alkyl), and hydroxy; R ¹³ is C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, or–(Z ¹ -Z ² ) _a1 -Z ³ ; each of R ¹¹ and R ¹² at each occurrence is independently selected from hydrogen, C1-C6 alkyl, and–(Z ¹ -Z ² ) _a1 -Z ³ ;

a1 is 0-10 (e.g., 0-4);

each Z ¹ is independently C1-C6 alkylene optionally substituted with one or more substituents independently selected from oxo, halo, and hydroxy;

each Z ² is independently a bond, NH, N(C ₁ -C ₆ alkyl), -O-, -S-, or 5-10 membered heteroarylene;

Z ³ is independently C6-C10 aryl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 5- to 10- membered heteroaryl, or 3- to 10-membered heterocycloalkyl, each of which is optionally substituted with one or more substituents independently selected from halo, C1-C6 alkyl, C1-6 haloalkyl, C1-C6 alkoxy, oxo, N(C1-C6 alkyl)2, NH2, NH(C1-C6 alkyl), and hydroxy;

R ³ is selected from hydrogen, cyano, hydroxy, C1-C6 alkoxy, C1-C6 alkyl, and , wherein the C ₁ -C ₂ alkylene group is optionally substituted by oxo;

R ¹⁴ is hydrogen, C ₁ -C ₆ alkyl, 5- to 10-membered monocyclic or bicyclic heteroaryl or C ₆ - C10 monocyclic or bicyclic aryl , wherein each C1-C6 alkyl, aryl or heteroaryl is optionally independently substituted with 1 or 2 R ⁶ ,

R ¹⁵ is–(Z ⁴ -Z ⁵ ) _a2 -Z ⁶ ; a2 is an integer selected from 1-10 (e.g., 1-5);

each Z ⁴ is independently selected from–O-, -S-, -NH-, and–N(C ₁ -C ₃ alkyl)-;

provided that the Z ⁴ group directly attached to R ¹ or R ² is–O- or–S-;

each Z ⁵ is independently C1-C6 alkylene optionally substituted with one or more substituents independently selected from oxo, halo, and hydroxy; and

Z ⁶ is OH, OC ₁ -C ₆ alkyl, NH ₂ , NH(C ₁ -C ₆ alkyl), N(C ₁ -C ₆ alkyl) ₂ , NHC(O)(C ₁ -C ₆ alkyl), NHC(O)(C1-C6 alkoxy), or an optionally substituted group selected from the group consisting of:

C6-C10 aryl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocycloalkyl, each of which is optionally substituted with one or more substituents independently selected from halo, C ₁ -C ₆ alkyl, C _1-6 haloalkyl, C ₁ -C ₆ alkoxy, oxo, N(C1-C6 alkyl)2, NH2, NH(C1-C6 alkyl), and hydroxy;

or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein is a compound of Formula AA

Formula AA wherein

m = 1 or 2;

n = 1 or 2;

o = 1 or 2;

p = 0, 1, 2, or 3,

wherein

A is a 5- to 10-membered monocyclic or bicyclic heteroaryl or a C6-C10 monocyclic or bicyclic aryl; B is a 5-membered heteroaryl, a 7-10 membered monocyclic or bicyclic heteroaryl, or a C ₆ -C ₁₀ monocyclic or bicyclic aryl; wherein at least one R ⁶ is ortho to the bond connecting the B ring to the NH(CO) group of Formula AA; one pair of R ¹ and R ² are on adjacent atoms, and taken together with the atoms connecting them, independently form one monocyclic or bicyclic C ₄ -C ₁₂ carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring containing 1-3 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxy, OC ₃ -C ₁₀ cycloalkyl, NR ⁸ R ⁹ , =NR ¹⁰ , CN, COOC1-C6 alkyl, OS(O2)C6-C10 aryl, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10- membered heteroaryl, C ₃ -C ₁₀ cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR ⁸ R ⁹ , wherein the C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, S(O ₂ )C ₆ -C ₁₀ aryl, C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₁ -C ₆ alkoxy, oxo, NR ⁸ R ⁹ , =NR ¹⁰ , COOC ₁ -C ₆ alkyl, C6-C10 aryl, and CONR ⁸ R ⁹ ; each of R ¹ and R ² that are not taken together with the atoms connecting them to form at least one ring is independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, CN, NO2, CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, NR ⁸ R ⁹ , C(O)R ¹³ , CONR ⁸ R ⁹ , SF ₅ , SC ₁ -C ₆ alkyl, S(O ₂ )C ₁ -C ₆ alkyl, S(O)C1-C6 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 alkoxy, C ₁ -C ₆ haloalkyl, C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, 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, C1-C6 alkyl, C1-C6 alkoxy, R ¹⁵ , C1-C6 haloalkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC1-C6 alkyl, CONR ⁸ R ⁹ , 3- to 7- membered heterocycloalkyl, C ₃ -C ₇ cycloalkyl, C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), and OCO(3- to 7- membered heterocycloalkyl); wherein each C1-C6 alkyl substituent and each C1-C6 alkoxy substituent of the R ¹ or R ² C3- 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, -O(C ₀ -C ₃ alkylene)C ₆ -C ₁₀ aryl, halo, NR ⁸ R ⁹ , or oxo;

wherein the 3- to 7-membered heterocycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents independently selected from halo, C1-C6 alkyl, and OC1-C6 alkyl; 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 - C6 alkyl, OCOC6-C10 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 ₁₀ cycloalkyl, 3- to 10-membered heterocycloalkyl, and C2-C6 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 , COOC1-C6 alkyl, CONR ⁸ R ⁹ , 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C ₆ -C ₁₀ aryloxy, and S(O ₂ )C ₁ -C ₆ alkyl; and wherein the C ₁ -C ₆ alkyl or C1-C6 alkoxy that R ⁶ or R ⁷ is substituted with is optionally substituted with one or more hydroxyl, C6-C10 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, C6-C10 aryl, 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 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, C1-C6 alkyl, C1-C6 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 ; R ¹⁰ is C1-C6 alkyl; each of R ⁸ and R ⁹ at each occurrence is independently selected from hydrogen, C ₁ -C ₆ alkyl, C3-C7 cycloalkyl, C2-C6 alkenyl, (C=NR ¹³ )NR ¹¹ R ¹² , S(O2)C1-C6 alkyl, S(O2)NR ¹¹ R ¹² , COR ¹³ , CO2R ¹³ and CONR ¹¹ R ¹² ; wherein the C1-C6 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, 3- to 7-membered heterocycloalkyl, or NR ¹¹ R ¹² ;

or R ⁸ and R ⁹ taken together with the nitrogen they are attached to form a 3- to 10-membered monocyclic or bicyclic ring optionally containing one or more heteroatoms in addition to the nitrogen they are attached to, wherein the ring is optionally substituted with one or more substituents independently selected from halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, oxo, N(C1-C6 alkyl)2, NH2, NH(C1-C6 alkyl), and hydroxy; R ¹³ is C1-C6 alkyl, C1-C6 haloalkyl, or–(Z ¹ -Z ² )a1-Z ³ ; each of R ¹¹ and R ¹² at each occurrence is independently selected from hydrogen, C ₁ -C ₆ alkyl, and–(Z ¹ -Z ² )a1-Z ³ ;

a1 is 0-10 (e.g., 0-4);

each Z ¹ is independently C ₁ -C ₆ alkylene optionally substituted with one or more substituents independently selected from oxo, halo, and hydroxy;

each Z ² is independently a bond, NH, N(C1-C6 alkyl), -O-, -S-, or 5-10 membered heteroarylene;

Z ³ is independently C _6- C ₁₀ aryl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, 5- to 10- membered heteroaryl, or 3- to 10-membered heterocycloalkyl, each of which is optionally substituted with one or more substituents independently selected from halo, C1-C6 alkyl, C1-6 haloalkyl, C ₁ -C ₆ alkoxy, oxo, N(C ₁ -C ₆ alkyl) ₂ , NH ₂ , NH(C ₁ -C ₆ alkyl), and hydroxy; R ³ is selected from hydrogen and C1-C6 alkyl (e.g., R ³ is selected from hydrogen and methyl);

R ¹⁴ is hydrogen, C ₁ -C ₆ alkyl, 5- to 10-membered monocyclic or bicyclic heteroaryl or C ₆ - C10 monocyclic or bicyclic aryl , wherein each C1-C6 alkyl, aryl or heteroaryl is optionally independently substituted with 1 or 2 R ⁶ ,

R ¹⁵ is–(Z ⁴ -Z ⁵ ) _a2 -Z ⁶ ;

a2 is an integer selected from 1-10 (e.g., 1-5);

each Z ⁴ is independently selected from–O-, -S-, -NH-, and–N(C1-C3 alkyl)-;

provided that the Z ⁴ group directly attached to R ¹ or R ² is–O- or–S-;

each Z ⁵ is independently C ₁ -C ₆ alkylene optionally substituted with one or more substituents independently selected from oxo, halo, and hydroxy; and

Z ⁶ is OH, OC ₁ -C ₆ alkyl, NH ₂ , NH(C ₁ -C ₆ alkyl), N(C ₁ -C ₆ alkyl) ₂ , NHC(O)(C ₁ -C ₆ alkyl), NHC(O)(C ₁ -C ₆ alkoxy), or an optionally substituted group selected from the group consisting of:

C6-C10 aryl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocycloalkyl, each of which is optionally substituted with one or more substituents independently selected from halo, C ₁ -C ₆ alkyl, C _1-6 haloalkyl, C ₁ -C ₆ alkoxy, oxo, N(C1-C6 alkyl)2, NH2, NH(C1-C6 alkyl), and hydroxy;

or a pharmaceutically acceptable salt thereof.

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

Formula AA

wherein

m = 1 or 2;

n = 1 or 2;

o = 1 or 2; p = 0, 1, 2, or 3,

wherein

A is a 5- to 10-membered monocyclic or bicyclic heteroaryl or a C ₆ -C ₁₀ monocyclic or bicyclic aryl;

B is a 5-membered heteroaryl, a 7-10 membered monocyclic or bicyclic heteroaryl, or a C ₆ -C ₁₀ monocyclic or bicyclic aryl;

wherein at least one R ⁶ is ortho to the bond connecting the B ring to the NH(CO) group of Formula AA; one pair of R ¹ and R ² are on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C4-C12 carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring containing 1-3 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR ⁸ R ⁹ , =NR ¹⁰ , CN, COOC ₁ -C ₆ alkyl, OS(O ₂ )C ₆ -C ₁₀ aryl, S(O ₂ )C ₆ -C ₁₀ aryl, C ₆ -C ₁₀ aryl, 5- to 10- membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR ⁸ R ⁹ , wherein the C1-C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C ₃ -C ₁₀ cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR ⁸ R ⁹ , =NR ¹⁰ , COOC1-C6 alkyl, C ₆ -C ₁₀ aryl, and CONR ⁸ R ⁹ ; each of R ¹ and R ² that are not taken together with the atoms connecting them to form at least one ring 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, NO ₂ , COC ₁ -C ₆ alkyl, CO-C ₆ -C ₁₀ aryl, CO(5- to 10-membered heteroaryl); CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10- membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C6-C10 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, NHCOC ₆ -C ₁₀ aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC2-C6 alkynyl, NHCOOCC1-C6 alkyl, NH-(C=NR ¹³ )NR ¹¹ R ¹² , CONR ⁸ R ⁹ , SF5, SC1-C6 alkyl, S(O2)C1-C6 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, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl, C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, 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, C1-C6 alkyl, C ₁ -C ₆ alkoxy, R ¹⁵ , C ₁ -C ₆ haloalkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC ₁ -C ₆ alkyl, CONR ⁸ R ⁹ , 3- to 7- membered heterocycloalkyl, C3-C7 cycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 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 C1-C6 alkyl substituent and each C1-C6 alkoxy substituent of the R ¹ or R ² C3- 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, -O(C ₀ -C ₃ alkylene)C ₆ -C ₁₀ aryl, halo, NR ⁸ R ⁹ , or oxo;

wherein the 3- to 7-membered heterocycloalkyl, C6-C10 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, C1-C6 alkyl, and OC1-C6 alkyl; R ⁶ and R ⁷ are each independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, CN, NO2, COC1-C6 alkyl, CO2C1-C6 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), 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, SC1-C6 alkyl, S(O2)C1-C6 alkyl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and 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, C1-C6 alkyl, C1-C6 alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC1-C6 alkyl, CONR ⁸ R ⁹ , 3- to 7-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(3- to 7-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC2-C6 alkynyl, C6-C10 aryloxy, and S(O2)C1-C6 alkyl; and wherein the C1-C6 alkyl or C1-C6 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, C6-C10 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, C1-C6 alkyl, and OC1-C6 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 , COOC1-C6 alkyl, C6-C10 aryl, and CONR ⁸ R ⁹ ; R ¹⁰ is C ₁ -C ₆ alkyl; each of R ⁸ and R ⁹ at each occurrence is independently selected from hydrogen, C1-C6 alkyl, C ₃ -C ₇ cycloalkyl, C ₂ -C ₆ alkenyl, (C=NR ¹³ )NR ¹¹ R ¹² , S(O ₂ )C ₁ -C ₆ alkyl, S(O ₂ )NR ¹¹ R ¹² , COR ¹³ , CO2R ¹³ and CONR ¹¹ R ¹² ; wherein the C1-C6 alkyl is optionally substituted with one or more hydroxy, halo, C1-C6 alkoxy, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C7 cycloalkyl, 3- to 7-membered heterocycloalkyl, or NR ¹¹ R ¹² ; 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 ¹³ is C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₆ -C ₁₀ aryl, or 5- to 10-membered heteroaryl;

each of R ¹¹ and R ¹² at each occurrence is independently selected from hydrogen and C ₁ -C ₆ alkyl; R ³ is selected from hydrogen, cyano, hydroxy, C1-C6 alkoxy, C1-C6 alkyl, and , wherein the C ₁ -C ₂ alkylene group is optionally substituted by oxo; R ¹⁴ is hydrogen, C1-C6 alkyl, 5- to 10-membered monocyclic or bicyclic heteroaryl or C6- 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 ,

R ¹⁵ is–(Z ⁴ -Z ⁵ )a2-Z ⁶ ;

a2 is an integer selected from 1-10 (e.g., 1-5);

each Z ⁴ is independently selected from–O-, -S-, -NH-, and–N(C ₁ -C ₃ alkyl)-;

provided that the Z ⁴ group directly attached to R ¹ or R ² is–O- or–S-;

each Z ⁵ is independently C1-C6 alkylene optionally substituted with one or more substituents independently selected from oxo, halo, and hydroxy; and

Z ⁶ is OH, OC ₁ -C ₆ alkyl, NH ₂ , NH(C ₁ -C ₆ alkyl), N(C ₁ -C ₆ alkyl) ₂ , NHC(O)(C ₁ -C ₆ alkyl), NHC(O)(C1-C6 alkoxy), or an optionally substituted group selected from the group consisting of:

C _6- C ₁₀ aryl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocycloalkyl, each of which is optionally substituted with one or more substituents independently selected from halo, C1-C6 alkyl, C1-6 haloalkyl, C1-C6 alkoxy, oxo, N(C1-C6 alkyl)2, NH2, NH(C1-C6 alkyl), and hydroxy;

or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein is a compound of Formula AA

Formula AA

wherein

m = 1 or 2;

n = 1 or 2;

o = 1 or 2;

p = 0, 1, 2, or 3,

wherein A is a 5- to 10-membered monocyclic or bicyclic heteroaryl or a C6-C10 monocyclic or bicyclic aryl;

B is a 5-membered heteroaryl, a 7-10 membered monocyclic or bicyclic heteroaryl, or a C6-C10 monocyclic or bicyclic aryl;

wherein at least one R ⁶ is ortho to the bond connecting the B ring to the NH(CO) group of Formula AA; one pair of R ¹ and R ² are on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C ₄ -C ₁₂ carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring containing 1-3 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxy, OC ₃ -C ₁₀ cycloalkyl, NR ⁸ R ⁹ , =NR ¹⁰ , CN, COOC1-C6 alkyl, OS(O2)C6-C10 aryl, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10- membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR ⁸ R ⁹ , wherein the C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, S(O ₂ )C ₆ -C ₁₀ aryl, C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₁ -C ₆ alkoxy, oxo, NR ⁸ R ⁹ , =NR ¹⁰ , COOC ₁ -C ₆ alkyl, C6-C10 aryl, and CONR ⁸ R ⁹ ; each of R ¹ and R ² that are not taken together with the atoms connecting them to form at least one ring 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, NO2, COC1-C6 alkyl, CO-C6-C10 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, NHC1-C6 alkyl, N(C1-C6 alkyl)2, NHCOC1-C6 alkyl, NHCOC6-C10 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 , SF ₅ , SC ₁ -C ₆ alkyl, S(O ₂ )C ₁ -C ₆ alkyl, S(O)C1-C6 alkyl, S(O2)NR ¹¹ R ¹² , C3-C7 cycloalkyl, and 3- to 7-membered heterocycloalkyl, wherein the C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, 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, C1-C6 alkoxy, R ¹⁵ , C1-C6 haloalkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC1-C6 alkyl, CONR ⁸ R ⁹ , 3- to 7- membered heterocycloalkyl, C3-C7 cycloalkyl, 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(3- to 7-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 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, -O(C0-C3 alkylene)C6-C10 aryl, halo, NR ⁸ R ⁹ , or oxo;

wherein the 3- to 7-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, NHCOC6-C10 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; R ⁶ and R ⁷ are each independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 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, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C6-C10 aryl, 5- to 10-membered heteroaryl, NH2, NHC1-C6 alkyl, N(C1-C6 alkyl) ₂ , CONR ⁸ R ⁹ , SF ₅ , SC ₁ -C ₆ alkyl, S(O ₂ )C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, 3- to 10-membered heterocycloalkyl, and 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, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 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)C1-C6 alkyl; and wherein the C1-C6 alkyl or C1-C6 alkoxy that R ⁶ or R ⁷ is substituted with is optionally substituted with one or more hydroxyl, C6-C10 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, NHCOC6-C10 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, C1-C6 alkyl, C1-C6 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 ; R ¹⁰ is C1-C6 alkyl; each of R ⁸ and R ⁹ at each occurrence is independently selected from hydrogen, C ₁ -C ₆ alkyl, C3-C7 cycloalkyl, C2-C6 alkenyl, (C=NR ¹³ )NR ¹¹ R ¹² , S(O2)C1-C6 alkyl, S(O2)NR ¹¹ R ¹² , COR ¹³ , CO2R ¹³ and CONR ¹¹ R ¹² ; wherein the C1-C6 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, 3- to 7-membered heterocycloalkyl, or NR ¹¹ R ¹² ; 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 ¹³ is C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₆ -C ₁₀ aryl, or 5- to 10-membered heteroaryl;

each of R ¹¹ and R ¹² at each occurrence is independently selected from hydrogen and C1-C6 alkyl; R ³ is selected from hydrogen and C ₁ -C ₆ alkyl (e.g., R ³ is selected from hydrogen and methyl);

R ¹⁴ is hydrogen, C1-C6 alkyl, 5- to 10-membered monocyclic or bicyclic heteroaryl or C6- 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 ,

R ¹⁵ is–(Z ⁴ -Z ⁵ )a2-Z ⁶ ; a2 is an integer selected from 1-10 (e.g., 1-5);

each Z ⁴ is independently selected from–O-, -S-, -NH-, and–N(C ₁ -C ₃ alkyl)-;

provided that the Z ⁴ group directly attached to R ¹ or R ² is–O- or–S-;

each Z ⁵ is independently C1-C6 alkylene optionally substituted with one or more substituents independently selected from oxo, halo, and hydroxy; and

Z ⁶ is OH, OC ₁ -C ₆ alkyl, NH ₂ , NH(C ₁ -C ₆ alkyl), N(C ₁ -C ₆ alkyl) ₂ , NHC(O)(C ₁ -C ₆ alkyl), NHC(O)(C1-C6 alkoxy), or an optionally substituted group selected from the group consisting of:

C6-C10 aryl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocycloalkyl, each of which is optionally substituted with one or more substituents independently selected from halo, C ₁ -C ₆ alkyl, C _1-6 haloalkyl, C ₁ -C ₆ alkoxy, oxo, N(C1-C6 alkyl)2, NH2, NH(C1-C6 alkyl), and hydroxy;

or a pharmaceutically acceptable salt thereof.

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

Formula AA

wherein

m = 1 or 2;

n = 1 or 2;

o = 1 or 2;

p = 0, 1, 2, or 3,

wherein

A is a 5- to 10-membered monocyclic or bicyclic heteroaryl or a C6-C10 monocyclic or bicyclic aryl;

B is a 5-membered heteroaryl, a 7-10 membered monocyclic or bicyclic heteroaryl, or a C6-C10 monocyclic or bicyclic aryl; wherein at least one R ⁶ is ortho to the bond connecting the B ring to the NH(CO) group of Formula AA; one pair of R ¹ and R ² are on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C4-C12 carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring containing 1-3 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxy, OC ₃ -C ₁₀ cycloalkyl, NR ⁸ R ⁹ , =NR ¹⁰ , CN, COOC ₁ -C ₆ alkyl, OS(O ₂ )C ₆ -C ₁₀ aryl, S(O ₂ )C ₆ -C ₁₀ aryl, C ₆ -C ₁₀ aryl, 5- to 10- membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR ⁸ R ⁹ , wherein the C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, S(O ₂ )C ₆ -C ₁₀ aryl, C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, C ₃ -C ₁₀ cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR ⁸ R ⁹ , =NR ¹⁰ , COOC1-C6 alkyl, C ₆ -C ₁₀ aryl, and CONR ⁸ R ⁹ ; each of R ¹ and R ² that are not taken together with the atoms connecting them to form at least one ring 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, NO2, COC1-C6 alkyl, CO-C6-C10 aryl, CO(5- to 10-membered heteroaryl); CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, OCOC1-C6 alkyl, OCOC6-C10 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 , 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 , SF ₅ , SC ₁ -C ₆ alkyl, S(O ₂ )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 C1-C6 alkyl, C1-C6 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, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 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 - 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, NHCOC6-C10 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; R ⁶ and R ⁷ are each independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 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), C6-C10 aryl, 5- to 10-membered heteroaryl, NH2, NHC1-C6 alkyl, N(C1-C6 alkyl)2, CONR ⁸ R ⁹ , SF5, SC1-C6 alkyl, S(O2)C1-C6 alkyl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and 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, C1-C6 alkyl, C1-C6 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, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 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, C6-C10 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, C6-C10 aryl, 5- to 10-membered heteroaryl, NHCOC6-C10 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, C1-C6 alkyl, and OC1-C6 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, C1-C6 alkyl, C1-C6 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 ⁴ and R ⁵ is independently selected from hydrogen and C1-C6 alkyl;

R ¹⁰ is C ₁ -C ₆ alkyl; each of R ⁸ and R ⁹ at each occurrence is independently selected from hydrogen, C1-C6 alkyl, ( 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; R ¹³ is C1-C6 alkyl, C1-C6 haloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl;

each of R ¹¹ and R ¹² at each occurrence is independently selected from hydrogen and C1-C6 alkyl; R ³ is selected from hydrogen, cyano, hydroxy, C1-C6 alkoxy, C1-C6 alkyl, and , wherein the C1-C2 alkylene group is optionally substituted by oxo; and

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 ,

or a pharmaceutically acceptable salt thereof. In certain of any of the foregoing embodiments, it is provided that the compound is not selected from the group consisting of: , ,

, , , , , , , , , , , , , , , , , , , , ,

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula AA is other than one of the following compounds:

_HO

^H

_N

F

F

F

HO

F

F

F N H ^HO

^{H O} N

_N

O O

HO

F ^{H N H} F

F

F

F H _O

F

F O H ₂ N O

S ^{(S) H}

F

F _HO

HO O H ₂ N O

S ^(S)

S F F

O S O

O S O

Cl

OH OH

O

F N HO H

N

HO ^{O NH} _{2 O}

H S ^* HO

HO

N H

^HO

N ^{OH F} _HO ^{N H} O

H _{N N}

( ^R) S F ^H2N

N ^H H N

^HO N

N H ^O N H

N

HO N

HO

N

N CH

H ₃

2 ^{N H} O ^H HO _N

_H3

H ₃ N

C ^l _HO

_OH

F F

F O _H

_H

_OH

F ^H ₂ ^N _O

O ^H2N

F S S _N ^H O _N ^NC

^HO

^HO

_O ^NH ₂ O

S ^H

HO

^N F

OH F ^NH2

O _F O OH F

_{F F} O

N F

F

N ^H OH _O ²

H ₂ N ^H S ^N _N H ^O

HO HO

O

S * NH ₂ H ^H

2N _{N N}

O

In some embodiments the variables shown in the formulae herein are as follows:

The moiety

In some embodiments, the defined for (AA-1):

A is a 5- to 10-membered monocyclic or bicyclic heteroaryl or a C ₇ -C ₁₀ bicyclic aryl; m = 0, 1, or 2; and

n = 0, 1, or 2.

In some embodiments, the defined for (AA-2):

A is phenyl;

m = 0, 1, or 2; and

n = 0, 1, or 2, provided that m + n = 0, 2, 3, or 4.

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 a 5- to 10-membered (e.g., 5- to 6-membered) monocyclic or bicyclic heteroaryl or a C6-C10 (e.g., C6) monocyclic or bicyclic aryl, such as phenyl.

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

In some embodiments, A is a 5-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 6-membered heteroaryl.

In some embodiments, A is a C6-C10 monocyclic or bicyclic aryl.

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 imidazolyl optionally substituted with 1 or 2 R ¹ and optionally substituted with 1 or 2 R ² .

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

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

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

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

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

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

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

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

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

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

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

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

In some embodiments, A is triazinyl substituted with 1 R ¹ and 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 pyridazinyl 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 pyridazinyl, 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 thiazolyl, m is 1, and n is 1.

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

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

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

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

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

In some embodiments, A is isoxazolyl, m is 1, and n is 1.

In some embodiments, A is isothiazolyl, m is 1, and n is 1..

In some embodiments, A is triazolyl (e.g., 1,2,3-triazolyl or 1,2,4-triazolyl), m is 1, and n is 1. In some embodiments, A is pyridinyl, m is 1 or 2, and n is 1 or 2.

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

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

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

In some embodiments, A is triazinyl, m is 1, and n is 1.

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 S(O)(NR ³ R ³ )=N moiety of 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 A is . In some embodiments, the optionally substituted ring A is .

R ² In some embodiments, the optionally substituted ring A is . R ² _R ¹ N

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 A is ^R2 . In some embodiments, the optionally substituted ring A is ^R2 .

In some embodiments, the optionally substituted ring A is ^R2 . 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 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 .

R ² 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 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 ^{R 2} . 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 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 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

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 . 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 .

N N

In some embodiments, the optionally substituted ring A is ^R1 .

N N

In some embodiments, the optionally substituted ring A is ^R1 . 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 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 In some embodiments, the optionally substituted ring R ²

N N

R ¹ _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

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 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 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

In some embodiments, the optionally substituted ring A is . In some embodiments, the optionally substituted ring A is selected from the group consisting of:

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

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

,

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

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

In some embodiments, when ring A is phenyl, then R ¹ and R ² are each independently selected from C3 alkyl, C5-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, F, I, CN, NO2, COC2-C6 alkyl, CO-C6-C10 aryl, CO(5- to 10-membered heteroaryl), CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, OCOC ₂ -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(C1-C6 alkyl)2, NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC2-C6 alkynyl, NHCOOCC1-C6 alkyl, NH- (C=NR ¹³ )NR ¹¹ R ¹² , 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, C3-C7 cycloalkyl, and 3- to 7-membered heterocycloalkyl, wherein the C1-C6 alkyl, C1-C6 haloalkyl, C3-C7 cycloalkyl and 3- to 7-membered heterocycloalkyl are 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, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 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 C1-C6 alkyl substituent and each C1-C6 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, C6-C10 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, C1-C6 alkyl, and OC1-C6 alkyl;

or one pair of R ¹ and R ² on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C ₄ or C ₆ -C ₁₂ carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring containing 1-3 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR ⁸ R ⁹ , =NR ¹⁰ , CN, COOC1-C6 alkyl, OS(O2)C6-C10 aryl, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C ₃ -C ₁₀ cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR ⁸ R ⁹ , wherein the C1-C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10- membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₁ -C ₆ alkoxy, oxo, 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 C3 alkyl, C5-C6 alkyl, C1- C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, F, I, CN, NO2, COC2-C6 alkyl, CO-C6-C10 aryl, CO(5- to 10-membered heteroaryl), CO ₂ C ₁ -C ₆ alkyl, CO ₂ C ₃ -C ₈ cycloalkyl, OCOC ₂ -C ₆ alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered

heterocycloalkyl), C6-C10 aryl, 5- to 10-membered heteroaryl, NH2, NHC1-C6 alkyl, N(C1-C6 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 , SF5, SC1-C6 alkyl, S(O2)C1-C6 alkyl, S(O2)NR ¹¹ R ¹² , S(O)C1-C6 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 are optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC1-C6 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), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), and NHCOC ₂ -C ₆ alkynyl;

wherein each C1-C6 alkyl substituent and each C1-C6 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, NHCOC6-C10 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 one monocyclic or bicyclic C4 or C6-C12 carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring containing 1-3 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR ⁸ R ⁹ , =NR ¹⁰ , CN, COOC ₁ -C ₆ alkyl, OS(O ₂ )C ₆ -C ₁₀ aryl, S(O ₂ )C ₆ -C ₁₀ aryl, C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, C ₃ -C ₁₀ cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR ⁸ R ⁹ , wherein the C1-C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10- membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C ₁ -C ₆ alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR ⁸ R ⁹ , =NR ¹⁰ , COOC1-C6 alkyl, C6-C10 aryl, and CONR ⁸ R ⁹ .

In some embodiments of the compound of Formula AA, when ring A is pyridyl, then 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, COC1-C6 alkyl, CO-C6-C10 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, NHC2-C6 alkyl, N(C1-C6 alkyl)2, NHCOC1-C6 alkyl, NHCOC6-C10 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 , SF ₅ , SC ₁ -C ₆ alkyl, S(O2)C1-C6 alkyl, S(O2)NR ¹¹ R ¹² , S(O)C1-C6 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 optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC1-C6 alkyl, CONR ⁸ R ⁹ , 3- to 5-membered heterocycloalkyl, 5-membered heteroaryl, 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, NHCOC6-C10 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, NHCOC6-C10 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 one monocyclic or bicyclic C4-C12 carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring containing 1-3 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR ⁸ R ⁹ , =NR ¹⁰ , CN, COOC ₁ -C ₆ alkyl, OS(O ₂ )C ₆ -C ₁₀ aryl, S(O ₂ )C ₆ -C ₁₀ aryl, C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, C ₃ -C ₁₀ cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR ⁸ R ⁹ , wherein the C1-C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR ⁸ R ⁹ , =NR ¹⁰ , COOC1-C6 alkyl, C6-C10 aryl, and CONR ⁸ R ⁹ .

In some embodiments of the compound of Formula AA, R ¹ and R ² are each independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, CN, NO2, COC1-C6 alkyl, CO-C6-C10 aryl, CO(5- to 10-membered heteroaryl), CO2C1-C6 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), C6-C10 aryl, 5- to 10-membered heteroaryl, NH2, NHC2-C6 alkyl, N(C1-C6 alkyl)2, NHCOC1-C6 alkyl, NHCOC6-C10 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 , 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, 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 optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC1-C6 alkyl, CONR ⁸ R ⁹ , 3- to 5-membered heterocycloalkyl, 5-membered heteroaryl, OCOC1-C6 alkyl, OCOC ₆ -C ₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered

heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), and NHCOC2-C6 alkynyl; wherein each C1-C6 alkyl substituent and each C1-C6 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, C6-C10 aryl, 5- to 10-membered heteroaryl, NHCOC6-C10 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, C1-C6 alkyl, and OC1-C6 alkyl;

or one pair of R ¹ and R ² on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C ₄ -C ₁₂ carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring containing 1-3 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxy, OC ₃ -C ₁₀ cycloalkyl, NR ⁸ R ⁹ , =NR ¹⁰ , CN, COOC1-C6 alkyl, OS(O2)C6-C10 aryl, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR ⁸ R ⁹ , wherein the C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, S(O ₂ )C ₆ -C ₁₀ aryl, C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, C ₃ -C ₁₀ cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₁ -C ₆ alkoxy, oxo, NR ⁸ R ⁹ , =NR ¹⁰ , COOC ₁ -C ₆ alkyl, C ₆ -C ₁₀ aryl, and CONR ⁸ R ⁹ . The groups R ¹ and R ²

In some embodiments,

R ¹ and R ² are each independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1- 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), C6-C10 aryl, 5- to 10- membered heteroaryl, NH2, NHC1-C6 alkyl, N(C1-C6 alkyl)2, CONR ⁸ R ⁹ , SF5, SC1-C6 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 C1-C6 alkyl, C1-C6 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, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), and OCO(3- to 7-membered heterocycloalkyl);

wherein each C1-C6 alkyl substituent and each C1-C6 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, C1-C6 alkyl, C1-C6 alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC1-C6 alkyl, C6-C10 aryl, and CONR ⁸ R ⁹ ; In some embodiments,

R ¹ and R ² are each independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1- 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), C6-C10 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 C1-C6 alkyl, C1-C6 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, C1-C6 alkyl, C1-C6 alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC1-C6 alkyl, CONR ⁸ R ⁹ , 3- to 7- membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 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 C1-C6 alkyl substituent and each C1-C6 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, C6-C10 aryl, 5- to 10-membered heteroaryl, NHCOC6-C10 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, C1-C6 alkyl, C1-C6 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, COC1-C6 alkyl, CO-C6-C10 aryl, CO(5- to 10-membered heteroaryl), CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, OCOC1-C6 alkyl, OCOC6-C10 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(O2)NR ¹¹ R ¹² , S(O)C1-C6 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, C1-C6 alkyl, C1-C6 alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC1-C6 alkyl, CONR ⁸ R ⁹ , 3- to 7- membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC ₆ -C ₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7- membered heterocycloalkyl), and NHCOC2-C6 alkynyl; wherein each C1-C6 alkyl substituent and each C1-C6 alkoxy substituent of the R ¹ or R ² C3- 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, C6-C10 aryl, 5- to 10-membered heteroaryl, NHCOC6-C10 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, C1-C6 alkyl, and OC1-C6 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- C6-C10 aryl, CO(5- to 10-membered heteroaryl), CO2C1-C6 alkyl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C6-C10 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)C1-C6 alkyl, S(O2)NR ¹¹ R ¹² , S(O)C1-C6 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, C1-C6 alkyl, C1-C6 alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC1-C6 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), NHCOC1-C6 alkyl, NHCOC6-C10 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 - 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, C6-C10 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, C1-C6 alkyl, and OC1-C6 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 - C6 haloalkoxy, halo, CN, NO2, COC1-C6 alkyl, CO-C6-C10 aryl, CO(5- to 10-membered heteroaryl), CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C ₆ -C ₁₀ aryl, 5- to 10- membered heteroaryl, NH2, NHC1-C6 alkyl, N(C1-C6 alkyl)2, CONR ⁸ R ⁹ , SF5, SC1-C6 alkyl, S(O2)C1-C6 alkyl, S(O2)NR ¹¹ R ¹² , S(O)C1-C6 alkyl, C3-C7 cycloalkyl and 3- to 7-membered heterocycloalkyl,

wherein the C1-C6 alkyl, C1-C6 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, OCOC6-C10 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 C1-C6 alkyl substituent and each C1-C6 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, or oxo;

wherein the 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, NHCOC6-C10 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 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, C1-C6 alkyl, C1-C6 alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC1-C6 alkyl, C6-C10 aryl, and CONR ⁸ R ⁹ .

In some embodiments,

R ¹ and R ² are each independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1- C ₆ haloalkoxy, halo, CN, NO ₂ , COC ₁ -C ₆ alkyl, CO-C ₆ -C ₁₀ aryl, CO(5- to 10-membered heteroaryl), CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C6-C10 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, C1-C6 alkyl, C1-C6 alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC1-C6 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), NHCOC1-C6 alkyl, NHCOC6-C10 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, NHCOC6-C10 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 C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1- 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), C6-C10 aryl, 5- to 10- membered heteroaryl, NH2, NHC1-C6 alkyl, N(C1-C6 alkyl)2, CONR ⁸ R ⁹ , SF5, SC1-C6 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 C1-C6 alkyl, C1-C6 haloalkyl, C3-C7 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 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, C1-C6 alkyl, C1-C6 alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC1-C6 alkyl, C6-C10 aryl, and CONR ⁸ R ⁹ ; In some embodiments,

R ¹ and R ² are each independently selected from C1-C6 alkyl, halo, CN, COC1-C6 alkyl, CO2C1-C6 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 C1-C6 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, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C6-C10 aryl, 5- to 10-membered heteroaryl, NH2, NHC1-C6 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, C3-C7 cycloalkyl and 3- to 7-membered heterocycloalkyl, wherein the C1-C6 alkyl, C1-C6 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, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 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, C6-C10 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, C1-C6 alkyl, and OC1-C6 alkyl. In some embodiments , m=1; n=0; and,

R ¹ is selected from C1-C6 alkyl, halo, CN, COC1-C6 alkyl, CO2C1-C6 alkyl, C6-C10 aryl, 5- to 10- membered heteroaryl, S(O)C1-C6 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 C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1- C6 haloalkoxy, halo, CN, NO2, COC1-C6 alkyl, CO-C6-C10 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, NHC1-C6 alkyl, N(C1-C6 alkyl)2, CONR ⁸ R ⁹ , SF5, SC1-C6 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 C1-C6 alkyl, C1-C6 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, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 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, NHCOC6-C10 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, C6-C10 aryl, 5- to 10-membered heteroaryl, S(O)C1-C6 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 - 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, C1-C6 alkyl, C1-C6 alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC1-C6 alkyl, C6-C10 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, C1-C6 alkyl, C1-C6 alkoxy, COOC1-C6 alkyl, C6-C10 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 ₄ - 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, it is provided that:

(1) one or more of R ¹ or R ² , when present, is selected from NR ^8’ R ^9’ , C(O)NR ^8’ R ^9’ , S(O)2NR ^11’ R ^12’ , C(O)R ^13’ , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C3-C7 cycloalkyl, 3- to 7- membered heterocycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl,

wherein each of the C ₃ -C ₇ cycloalkyl, and 3- to 7-membered heterocycloalkyl is substituted with NR ^8’ R ^9’ , C(O)NR ^8’ R ^9’ , R ^15’ , C1-C6 haloalkoxy, or C3-C7 cycloalkyl;

wherein each of the C1-C6 alkyl and C1-C6 haloalkyl is substituted with NR ^8’ R ^9’ , C(O)NR ^8’ R ^9’ , R ¹⁵ , C ₁ -C ₆ haloalkoxy, or C ₃ -C ₇ cycloalkyl;

and

each of the C1-C6 alkoxy, C6-C10 aryl and 5- to 10-membered heteroaryl is substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, R ¹⁵ , C ₁ -C ₆ haloalkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC ₁ -C ₆ alkyl, CONR ⁸ R ⁹ , 3- to 7- membered heterocycloalkyl, C3-C7 cycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), and OCO(3- to 7- membered heterocycloalkyl);

or (2) one pair of R ¹ and R ² on adjacent atoms, taken together with the atoms connecting them, independently form one ring that is selected from:

(a) C ₄ -C ₈ carbocyclic ring or 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 independently substituted with one or more substituents each independently selected from from C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, OC ₃ -C ₁₀ cycloalkyl, CN, OS(O ₂ )C ₆ -C ₁₀ aryl, S(O ₂ )C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl, wherein the S(O2)C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10- membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C1-C6 alkoxy, oxo, NR ⁸ R ⁹ , =NR ¹⁰ , COOC1-C6 alkyl, C6-C10 aryl, and CONR ⁸ R ⁹ ;

(b) C ₄ -C ₈ carbocyclic ring or 5- to-8-membered heterocyclic ring containing 3 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, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR ⁸ R ⁹ , =NR ¹⁰ , CN, COOC ₁ -C ₆ alkyl, OS(O ₂ )C ₆ -C ₁₀ aryl, S(O ₂ )C ₆ -C ₁₀ aryl, C ₆ -C ₁₀ aryl, 5- to 10- membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR ⁸ R ⁹ , wherein the C1-C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C ₃ -C ₁₀ cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR ⁸ R ⁹ , =NR ¹⁰ , COOC1-C6 alkyl, C ₆ -C ₁₀ aryl, and CONR ⁸ R ⁹ ; and

(c) monocyclic or bicyclic C ₉ -C ₁₂ carbocyclic ring or monocyclic or bicyclic 9- to 12- membered heterocyclic ring containing 1-3 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 ₂ -C ₆ alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR ⁸ R ⁹ , =NR ¹⁰ , CN, COOC1-C6 alkyl, OS(O2)C6-C10 aryl, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR ⁸ R ⁹ , wherein the C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C ₁ -C ₆ alkoxy, oxo, 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, C3-C7 cycloalkyl, C2-C6 alkenyl, (C=NR ¹³ )NR ¹¹ R ¹² , S(O2)C1-C6 alkyl, S(O2)NR ¹¹ R ¹² , COR ¹³ , CO2R ¹³ and CONR ¹¹ R ¹² ; wherein the C1-C6 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, 3- to 7-membered heterocycloalkyl, or NR ¹¹ R ¹² ;

or R ^8’ and R ^9’ taken together with the nitrogen they are attached to form a 3- to 10- membered monocyclic or bicyclic ring optionally containing one or more heteroatoms in addition to the nitrogen they are attached to, wherein the ring is optionally substituted with one or more substituents independently selected from halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, oxo, N(C ₁ -C ₆ alkyl) ₂ , NH ₂ , NH(C ₁ -C ₆ alkyl), and hydroxy;

provided that:

(1) one or more occurrences of R ^8’ or R ^9’ is C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, (C=NR ^13’ )NR ^11’ R ^12’ , S(O2)NR ^11’ R ^12’ , C(O)R ^13’ , CO2R ^13’ and CONR ^11’ R ^12’ ; wherein the C1-C6 alkyl is substituted with NR ¹¹ R ¹² ; or

(2) one or more pairs of R ^8’ and R ^9’ attached to the same nitrogen taken together with the nitrogen they are attached to form:

(a) a 8- to 10-membered monocyclic or bicyclic ring optionally containing one or more heteroatoms in addition to the nitrogen they are attached to, wherein the ring is optionally substituted with one or more substituents independently selected from halo, C1-C6 alkyl, C1-C6 haloalkyl, C ₁ -C ₆ alkoxy, oxo, N(C ₁ -C ₆ alkyl) ₂ , NH ₂ , NH(C ₁ -C ₆ alkyl), and hydroxy; or

(b) a 3- to 7-membered monocyclic or bicyclic ring optionally containing one or more heteroatoms in addition to the nitrogen they are attached to, wherein the ring is substituted with one or more substituents independently selected from halo, C _1- C ₆ alkyl, C _1- C ₆ haloalkyl, C ₁ -C ₆ alkoxy, oxo, N(C ₁ -C ₆ alkyl) ₂ , NH ₂ , NH(C ₁ -C ₆ alkyl), and hydroxy;

each of R ^11’ and R ^12’ at each occurrence is independently selected from hydrogen, C1-C6 alkyl, and–(Z ¹ -Z ² )a1-Z ³ , provided that one or more occurrences of R ^11’ and R ^12’ is–(Z ¹ -Z ² )a1-Z ³ ;

R ^13’ is–(Z ¹ -Z ² ) _a1 -Z ^3’ , wherein

when a1 is 0, Z ^3’ is independently C6-10 aryl, C3-C10 cycloalkyl, 5- to 10-membered heteroaryl, 3- to 10-membered heterocycloalkyl, C2-C6 alkenyl, or C2-C6 alkynyl, each of which is substituted with one or more substituents independently selected from halo, C1-C6 alkyl, C1-6 haloalkyl, C ₁ -C ₆ alkoxy, oxo, N(C ₁ -C ₆ alkyl) ₂ , NH ₂ , NH(C ₁ -C ₆ alkyl), and hydroxy;

when a1 is 1-10 (e.g., 1-4), Z ^3’ is an independently selected Z ³ ;

R ¹⁵ ’ is–(Z ⁴ -Z ⁵ )a2’-Z ⁶ ;

a2’ is an integer selected from 2-10 (e.g., 2-5);

each Z ⁴ is independently selected from–O-, -S-, -NH-, and–N(C ₁ -C ₃ alkyl)-;

provided that the Z ⁴ group directly attached to R ¹ or R ² is–O- or–S-;

each Z ⁵ is independently C1-C6 alkylene optionally substituted with one or more substituents independently selected from oxo, halo, and hydroxy; and

Z ⁶ is OH, OC ₁ -C ₆ alkyl, NH ₂ , NH(C ₁ -C ₆ alkyl), N(C ₁ -C ₆ alkyl) ₂ , NHC(O)(C ₁ -C ₆ alkyl), NHC(O)(C1-C6 alkoxy), or an optionally substituted group selected from the group consisting of:

C _6- C ₁₀ aryl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocycloalkyl, each of which is optionally substituted with one or more substituents independently selected from halo, C1-C6 alkyl, C1-6 haloalkyl, C1-C6 alkoxy, oxo, N(C1-C6 alkyl)2, NH2, NH(C1-C6 alkyl), and hydroxyl. In some embodiments, R ¹ ’ is selected from the group consisting of:

methyl substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, R ¹⁵ , C ₁ -C ₆ haloalkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC1-C6 alkyl, CONR ⁸ R ⁹ , 3- to 7-membered heterocycloalkyl, C3-C7 cycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), and OCO(3- to 7-membered heterocycloalkyl);

C ₂ -C ₆ alkyl; C ₁ -C ₆ haloalkyl; C ₁ -C ₆ alkoxy; C ₁ -C ₆ haloalkoxy; halo; CN; NO ₂ ; CO ₂ C ₁ -C ₆ alkyl; CO2C3-C8 cycloalkyl; OCOC1-C6 alkyl; OCOC6-C10 aryl; OCO(5- to 10-membered heteroaryl); OCO(3- to 7-membered heterocycloalkyl); C ₆ -C ₁₀ aryl; 5- to 10-membered heteroaryl; NR ⁸ R ⁹ ; C(O)R ¹³ ; CONR ⁸ R ⁹ ; SF ₅ ; SC ₁ -C ₆ alkyl; S(O ₂ )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 C2-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, 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, C1-C6 alkyl, C1-C6 alkoxy, R ¹⁵ , C1-C6 haloalkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC1-C6 alkyl, CONR ⁸ R ⁹ , 3- to 7- membered heterocycloalkyl, C3-C7 cycloalkyl, C6-C10 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); and

wherein each C1-C6 alkyl substituent and each C1-C6 alkoxy substituent of the R ^1’ C3-C7 cycloalkyl or of the R ^1’ 3- to 7-membered heterocycloalkyl is further optionally independently substituted with one to three hydroxy, halo, -O(C ₀ -C ₃ alkylene)C ₆ -C ₁₀ aryl, NR ⁸ R ⁹ , or oxo;

wherein the 3- to 7-membered heterocycloalkyl, C6-C10 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. In some embodiments, one pair of R ¹ and R ² is on adjacent atoms, and taken together with the atoms connecting them, independently form one monocyclic or bicyclic C ₄ -C ₁₂ carbocyclic ring (e.g., C ₅ or C ₆ carbocyclic ring) or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring containing 1-3 (e.g., 1-2, e.g., 2) heteroatoms independently selected from O, N, and S (e.g., tetrahydropyridine, dihydrofuran, or dihydropyran), wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C1-C6 alkyl (e.g., methyl), C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy (e.g., methoxy, ethoxy, isopropoxyl), OC3-C10 cycloalkyl, NR ⁸ R ⁹ , =NR ¹⁰ , CN, COOC1-C6 alkyl, S(O ₂ )C ₆ -C ₁₀ aryl, C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, C ₃ -C ₁₀ cycloalkyl, 3- to 10- membered heterocycloalkyl (e.g., azetidinyl or oxetanyl), and CONR ⁸ R ⁹ , wherein the C1-C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo (e.g., fluoro), C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR ⁸ R ⁹ (e.g., amino, methylamino, or dimethylamino), =NR ¹⁰ , COOC ₁ -C ₆ alkyl, C ₆ -C ₁₀ aryl, and CONR ⁸ R ⁹ . In some embodiments, one pair of R ¹ and R ² is on adjacent atoms, and taken together with the atoms connecting them, independently form one monocyclic or bicyclic C5-C6 carbocyclic ring,

wherein the carbocyclic is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, methyl, isopropoxyl, azetidinyl, oxetanyl, wherein the methyl, isopropoxyl, azetidinyl, and oxetanyl are optionally substituted with one or more substituents each independently selected from hydroxy, fluoro, amino, methylamino, and dimethylamino; or

one pair of R ¹ and R ² on adjacent atoms taken together forms a moiety selected from:

each of which is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, methyl, isopropoxyl, azetidinyl, oxetanyl, wherein the methyl, isopropoxyl, azetidinyl, and oxetanyl are optionally substituted with one or more substituents each independently selected from hydroxy, fluoro, amino, methylamino, and dimethylamino. In some embodiments, one pair of R ¹ and R ² is on adjacent atoms, and taken together with the atoms connecting them, independently form at least one bicyclic spirocyclic C ₄ -C ₁₂ carbocyclic ring, wherein the carbocyclic ring is optionally substituted with one or more substituents each independently selected from hydroxy, halo, oxo, methyl, isopropoxyl, azetidinyl, oxetanyl, wherein the methyl, isopropoxyl, azetidinyl, and oxetanyl are optionally substituted with one or more substituents each independently selected from hydroxy, fluoro, amino, methylamino, and dimethylamino.

In some embodiments, one pair of R ¹ and R ² is on adjacent atoms, and taken together with the atoms connecting them, independently form at least one bicyclic spirocyclic 5- to-12- membered heterocyclic ring containing 1-3 heteroatoms independently selected from O, N, and S, wherein the carbocyclic or heterocyclic ring is optionally substituted with one or more substituents each independently selected from hydroxy, halo, oxo, methyl, isopropoxyl, azetidinyl, oxetanyl, wherein the methyl, isopropoxyl, azetidinyl, and oxetanyl are optionally substituted with one or more substituents each independently selected from hydroxy, fluoro, amino, methylamino, and dimethylamino. In some embodiments, each of R ¹ and R ² , when present, is independently selected from the group consisting of C ₁ -C ₆ alkyl optionally substituted with one or more hydroxy, halo, oxo, C ₁ -C ₆ alkoxy, 3- to 7-membered heterocycloalkyl optionally substituted with halo, C ₃ -C ₇ cycloalkyl, R ¹⁵ , C1-C6 haloalkoxy, C6-C10 aryl optionally substituted with OC1-C6 alkyl, or NR ⁸ R ⁹ ; C3-C7 cycloalkyl optionally substituted with one or more hydroxy, halo, oxo, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkyl, or NR ⁸ R ⁹ wherein the C ₁ -C ₆ salkoxy or C ₁ -C ₆ alkyl is further optionally substituted with one to three hydroxy, halo, NR ⁸ R ⁹ , or oxo; 3- to 7-membered heterocycloalkyl optionally substituted with one or more hydroxy, halo, oxo, C1-C6 alkyl, or NR ⁸ R ⁹ wherein the C1-C6 alkoxy or C1-C6 alkyl is further optionally substituted with one to three hydroxy, halo, NR ⁸ R ⁹ , or oxo; C ₁ -C ₆ haloalkyl; C1-C6 alkoxy; C1-C6 haloalkoxy; halo; CN; CO-C1-C6 alkyl; CO-C6-C10 aryl; CO(5- to 10- membered heteroaryl); CO2C1-C6 alkyl; CO2C3-C8 cycloalkyl; OCOC1-C6 alkyl; OCOC6-C10 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 ; S(O2)NR ¹¹ R ¹² ; S(O)C1-C6 alkyl; and S(O2)C1-C6 alkyl.

In certain embodiments, R ¹ is selected from the group consisting of 1-hydroxy-2- methylpropan-2-yl; methyl; isopropyl; isobutyl; difluoromethyl; 2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl; 2-hydroxyethyl; 1-hydroxy-2-propyl; 1,2-dihydroxy-2-propyl; 1,2,3-trihydroxy-2-propyl; 1-amino-2-hydroxy-prop-2-yl; 1-acetamido-2-hydroxy-prop-2-yl; 1- (tert-butoxycarbonyl)amino-2-hydroxy-prop-2-yl; 1-(2-hydroxyethoxy)-2-hydroxy-2-propyl; 1- (2-benzyloxyethoxy)-2-hydroxy-2-propyl; 1-(2-methoxyethoxy)-2-hydroxy-2-propyl; 1-hydroxy- 1-cyclopropyl; 1-hydroxy-1-cyclobutyl; 1-hydroxy-1-cyclopentyl; 1-hydroxy-1-cyclohexyl; morpholinyl; pyrrolidinyl; 1,3-dioxolan-2-yl; COCH ₃ ; COCH ₂ CH ₃ ; difluoromethoxy; 2-methoxy- 2-propyl; (methylamino)methyl; (2,2-difluoroeth-1-yl)(methyl)aminomethyl; (2,2,2-trifluoroeth- 1-yl)(methyl)aminomethyl; (dimethylamino)methyl; 1-(dimethylamino)ethyl; 2- ((methyl)aminomethyl)-prop-2-yl; 2-((methyl)amino)-prop-2-yl; (methyl)(cyclopropylmethyl)aminomethyl; (methyl)(2-(dimethylamino)eth-1-yl)aminomethyl; (cyclobutyl)(methyl)aminomethyl; 1-(cyclobutyl)amino-eth-1-yl; isopropylaminomethyl; (cyclobutyl)aminomethyl; cycloheptylaminomethyl; tetrahydropyranylaminomethyl; sec- butylaminomethyl; ethylaminomethyl; allylaminomethyl; (2,2-difluoroeth-1-yl)aminomethyl; (2- methoxy-eth-1-yl)aminomethyl; (2-methoxy-eth-1-yl)(methyl)aminomethyl; 2-fluoro-1- dimethylamino-eth-1-yl; 1-dimethylamino-2,2-difluoroeth-1-yl; 1-dimethylamino-2,2,2- trifluoroeth-1-yl; 1-dimethylamino-2,2,2-trimethyleth-1-yl; dimethylamino(cyclopropyl)methyl; methoxymethyl; isopropyl(methyl)amino; fluoro; chloro; phenyl; pyridyl; pyrazolyl; azetidinyl; 5- methyl-oxazolidin-2-one-5-yl; S(O2)CH3; S(O2)NR ¹¹ R ¹² ; (3,3-difluoropyrrolidin-1-yl)methyl; 1- (difluoromethoxyl)eth-1-yl; azetidinylmethyl; 1-((methyl)aminomethyl)-cycloprop-1-yl; 4- methoxybenzyl; 4-methyl-piperazin-1-yl; morpholinylmethyl; and cyclopentyl.

In certain of any of the foregoing embodiments, R ² is selected from the group consisting of fluoro, chloro, cyano, methyl; methoxy; ethoxy; isopropyl; 1-hydroxy-2-methylpropan-2-yl; 2- hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl; 2-hydroxyethyl; 1-hydroxy-2-propyl; 1- hydroxy-1-cyclopropyl; COCH ₃ ; COPh; 2-methoxy-2-propyl; methoxymethyl; (dimethylamino)methyl; S(O2)CH3; and S(O2)NR ¹¹ R ¹² . In some embodiments, one or more R ¹ when present is independently a C ₁ -C ₆ alkyl substituted with one or more hydroxy.

In certain of these embodiments, one or more R ¹ is independently selected from 1-hydroxy- 2-methylpropan-2-yl; 2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl; 2-hydroxyethyl; 1- hydroxy-2-propyl; 1,2-dihydroxy-2-propyl; and 1,2,3-trihydroxy-2-propyl.

In some embodiments, one or more R ¹ when present is independently a C1-C6 alkyl substituted with one or more hydroxy and further substituted with one or more (e.g., one) NR ⁸ R ⁹ .

In certain of these embodiments, one or more R ¹ is independently selected from 1-amino- 2-hydroxy-prop-2-yl; 1-acetamido-2-hydroxy-prop-2-yl; and 1-(tert-butoxycarbonyl)amino-2- hydroxy-prop-2-yl.

In some embodiments, one or more R ¹ when present is independently a C ₁ -C ₆ alkyl substituted with one or more hydroxy and further substituted with one or more (e.g., one) R ¹⁵ .

In certain of these embodiments (e.g., a2 = 1 or 2), one or more R ¹ is independently selected from 1-(2-hydroxyethoxy)-2-hydroxy-2-propyl; 1-(2-benzyloxyethoxy)-2-hydroxy-2-propyl; and 1-(2-methoxyethoxy)-2-hydroxy-2-propyl.

In certain of these embodiments (e.g., a2 = 1), one or more R ¹ is independently selected from 1-(2-hydroxyethoxy)-2-hydroxy-2-propyl and 1-(2-methoxyethoxy)-2-hydroxy-2-propyl.

In certain embodiments (e.g., a2 = 1), one or more R ¹ is independently selected from: In certain embodiments (e.g., a2 > 1), one or more R ¹ is .

In some embodiments, one or more R ¹ is independently C1-C6 alkyl substituted with one or more (e.g., one) NR ⁸ R ⁹ and further optionally substituted with one or more halo.

In certain of these embodiments, one or more R ¹ is independently selected from: (methylamino)methyl; (2,2-difluoroeth-1-yl)(methyl)aminomethyl; (2,2,2-trifluoroeth-1- yl)(methyl)aminomethyl; (dimethylamino)methyl; 1-(dimethylamino)ethyl; 2- ((methyl)aminomethyl)-prop-2-yl; 2-((methyl)amino)-prop-2-yl; (methyl)(cyclopropylmethyl)aminomethyl; (methyl)(2-(dimethylamino)eth-1-yl)aminomethyl; (cyclobutyl)(methyl)aminomethyl; 1-(cyclobutyl)amino-eth-1-yl; isopropylaminomethyl; (cyclobutyl)aminomethyl; cycloheptylaminomethyl; tetrahydropyranylaminomethyl; sec- butylaminomethyl; ethylaminomethyl; allylaminomethyl; (2,2-difluoroeth-1-yl)aminomethyl; (2- methoxy-eth-1-yl)aminomethyl; (2-methoxy-eth-1-yl)(methyl)aminomethyl; 2-fluoro-1- dimethylamino-eth-1-yl; 1-dimethylamino-2,2-difluoroeth-1-yl; 1-dimethylamino-2,2,2- trifluoroeth-1-yl; 1-dimethylamino-2,2,2-trimethyleth-1-yl; and dimethylamino(cyclopropyl)methyl (e.g., one or more R ¹ is dimethylaminomethyl or methylaminomethyl). In some embodiments, one or more R ¹ is C ₁ -C ₆ alkyl that is optionally substituted with one or more halo. In certain of these embodiments, one or more R ¹ is C2-C6 alkyl that is optionally substituted with one or more halo. As non-limiting examples, R ¹ is ethyl or difluoromethyl.

In certain of any of the foregoing embodiments of R ¹ , one or more R ² is independently selected from C1-C6 alkyl, C1-C6 alkyl optionally substituted with one or more hydroxy, C1-C6 alkyl optionally substituted with one or more C1-C6 alkoxy, and halo. Particular embodiments wherein m=1 and n=0 or when (AA-3) applies:

In some embodiments, R ¹ is C1-C6 alkyl optionally substituted with one or more hydroxy.

In certain of these embodiments, R ¹ is independently selected from 1-hydroxy-2-methylpropan-2- yl; 2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl; 2-hydroxyethyl; 1-hydroxy-2-propyl; 1,2-dihydroxy-2-propyl; and 1,2,3-trihydroxy-2-propyl. In some embodiments, R ¹ is 1-hydroxy-2-methylpropan-2-yl.

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 2-hydroxyethyl.

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

In some embodiments, R ¹ is 1,2,3-trihydroxy-2-propyl. In some embodiments, R ¹ is C ₁ -C ₆ alkyl.

In some embodiments, R ¹ is isobutyl.

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 C1-C6 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 a C1-C6 alkyl substituted with one or more hydroxy and further substituted with one or more (e.g., one) NR ⁸ R ⁹ .

In certain of these embodiments, R ¹ is independently selected from 1-amino-2-hydroxy-prop-2-yl; 1-acetamido-2-hydroxy-prop-2-yl; and 1-(tert-butoxycarbonyl)amino-2-hydroxy-prop-2-yl. In some embodiments, R ¹ is 1-amino-2-hydroxy-prop-2-yl. In some embodiments, R ¹ is 1-acetamido-2-hydroxy-prop-2-yl.

In some embodiments, R ¹ is 1-(tert-butoxycarbonyl)amino-2-hydroxy-prop-2-yl. In some embodiments, R ¹ is independently a C1-C6 alkyl substituted with one or more hydroxy and further substituted with one or more (e.g., one) R ¹⁵ .

In certain of these embodiments, a2 is 1 in R ¹⁵ .

In certain of the foregoing embodiments, one or more R ¹ is independently selected from 1-(2- hydroxyethoxy)-2-hydroxy-2-propyl; 1-(2-benzyloxyethoxy)-2-hydroxy-2-propyl; and 1-(2- methoxyethoxy)-2-hydroxy-2-propyl.

. In certain embodiments when R ¹ is independently a C ₁ -C ₆ alkyl substituted with one or more hydroxy and further substituted with one or more (e.g., one) R ¹⁵ , a2 is > 1. In certain of these embodiments, R ¹ is: . In some embodiments, R ¹ is C ₁ -C ₆ alkyl optionally substituted with one or more R ¹⁵ . In some embodiments, R ¹ is C3-C7 cycloalkyl optionally substituted with one or more hydroxy. In some embodiments, R ¹ is C ₃ -C ₇ cycloalkyl (e.g., cyclopropyl or cyclopentyl).

In some embodiments, R ¹ is C3-C7 cycloalkyl optionally substituted with one or more C1-C6 alkyl wherein said C1-C6 alkyl is further optionally substituted as described elsewhere herein. In some embodiments, R ¹ is 1-((methyl)aminomethyl)-cycloprop-1-yl. In some embodiments, R ¹ is C ₃ -C ₇ 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 azetidinyl.

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 C1-C6 alkyl optionally substituted with one or more oxo.

In some embodiments, R ¹ is COCH3.

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 C1-C6 alkyl optionally substituted with one or more C1-C6 haloalkoxy.

In some embodiments, R ¹ is 1-(difluoromethoxyl)eth-1-yl. In some embodiments, R ¹ is C3-C7 cycloalkyl optionally substituted with one or more C1-C6 alkoxy.

In some embodiments, R ¹ is 3- to 7-membered heterocycloalkyl optionally substituted with one or more C1-C6 alkoxy. In some embodiments, R ¹ is 3- to 7-membered heterocycloalkyl optionally substituted with one or more oxo and further optionally substituted with one or more C1-C6 alkyl.

In some embodiments, R ¹ is 5-methyl-oxazolidin-2-one-5-yl. 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 C1-C6 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 (2,2,2-trifluoroeth-1-yl)(methyl)aminomethyl.

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

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

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

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

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

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

In some embodiments, R ¹ is 2-fluoro-1-dimethylamino-eth-1-yl.

In some embodiments, R ¹ is 1-dimethylamino-2,2-difluoroeth-1-yl. In some embodiments, R ¹ is 1-dimethylamino-2,2,2-trifluoroeth-1-yl.

In some embodiments, R ¹ is 1-dimethylamino-2,2,2-trimethyleth-1-yl.

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

In some embodiments, R ¹ is isopropylaminomethyl.

In some embodiments, R ¹ is (cyclobutyl)aminomethyl.

In some embodiments, R ¹ is cycloheptylaminomethyl.

In some embodiments, R ¹ is tetrahydropyranylaminomethyl.

In some embodiments, R ¹ is sec-butylaminomethyl.

In some embodiments, R ¹ is ethylaminomethyl.

In some embodiments, R ¹ is allylaminomethyl.

In some embodiments, R ¹ is 2,2-difluoroeth-1-yl)aminomethyl.

In some embodiments, R ¹ is (2-methoxy-eth-1-yl)aminomethyl. In some embodiments, R ¹ is C1-C6 alkyl substituted with NR ⁸ R ⁹ , wherein said C1-C6 alkyl is further optionally substituted as described elsewhere herein.

In some embodiments, R ¹ is dimethylamino(cyclopropyl)methyl. 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 C1-C6 haloalkyl optionally substituted with one or more hydroxy. In some embodiments, R ¹ is C ₁ -C ₆ alkoxy that is optionally substituted as defined elsewhere herein.

In some embodiments, R ¹ is C1-C6 alkoxy.

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

In some embodiments, R ¹ is difluoromethoxy. In some embodiments, R ¹ is C1-C6 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 4-methyl-piperazin-1-yl. In some embodiments, R ¹ is 3- to 7-membered heterocycloalkyl optionally substituted with one or more hydroxy. In certain of these embodiments, R ¹ is further optionally substituted with one or more C1-C6 alkyl, wherein each of said C1-C6 alkyl is further optionally substituted as defined

anywhere herein. As a non-limiting example, In some embodiments, R ¹ is 3- to 7-membered heterocycloalkyl optionally substituted with one or more substituents independently selected from hydroxy and R ¹⁵ . In certain of these embodiments, R ¹ is further optionally substituted with one or more C ₁ -C ₆ alkyl, wherein each of said C ₁ -C ₆ alkyl is further optionally substituted as defined anywhere herein. As a non-limiting

example, R ¹ is .

In some embodiments, R ¹ is C1-C6 alkyl optionally substituted with one or more C6-C10 aryl, wherein said aryl is further optionally substituted as described elsewhere herein.

In some embodiments, R ¹ is 4-methoxybenzyl.

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 COC1-C6 alkyl.

In some embodiments, R ¹ is CO-C6-C10 aryl.

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

In some embodiments, R ¹ is CO2C1-C6 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(C1-C6 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)C1-C6 alkyl.

In some embodiments, R ¹ is S(O ₂ )CH ₃ .

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)C1-C6 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 m=1 and n=1:

In some embodiments, R ¹ is C1-C6 alkyl optionally substituted with one or more hydroxy, and R ² is C1-C6 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 C1-C6 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 C1-C6 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 C1-C6 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(O2)C1-C6 alkyl.

In some embodiments, R ¹ is C1-C6 alkyl optionally substituted with one or more hydroxy, and R ² is S(O ₂ )CH ₃ .

In some embodiments, R ¹ is C1-C6 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 1,2-dihydroxy-2-propyl and R ² is fluoro.

In some embodiments, R ¹ is 1,2-dihydroxy-2-propyl and R ² is chloro. In some embodiments, R ¹ is C ₁ -C ₆ alkyl optionally substituted with one or more hydroxy, and R ² is C1-C6 alkyl optionally substituted with one or more C1-C6 alkoxy.

In some embodiments, R ¹ is 2-hydroxy-2-propyl and R ² is methoxymethyl. In some embodiments, R ¹ is C ₃ -C ₇ cycloalkyl optionally substituted with one or more hydroxy, and R ² is C1-C6 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 C1-C6 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 C1-C6 alkyl optionally substituted with one or more oxo, and R ² is methyl.

In some embodiments, R ¹ is COCH ₃ , and R ² is methyl.

In some embodiments, R ¹ is C1-C6 alkyl optionally substituted with one or more C1-C6 alkoxy, and R ² is C1-C6 alkyl.

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

In some embodiments, R ¹ is C1-C6 alkyl optionally substituted with one or more NR ⁸ R ⁹ , and R ² is C1-C6 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 ¹ is C ₁ -C ₆ alkyl substituted with one or more hydroxy; and R ² is C ₁ -C ₆ alkyl substituted with one or more hydroxy. In certain of the foregoing embodiments, R ¹ or R ² is further optionally substituted as defined elsewhere herein (e.g., R ¹ or R ² is further optionally substituted with one R ¹⁵ ).

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

In some embodiments, R ¹ is 1,3-dihydroxy-2-methyl-2-propyl; and R ² is hydroxymethyl.

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

In some embodiments, R ¹ is 2-hydroxyeth-1-yl; and R ² is hydroxymethyl.

In some embodiments, R ¹ is 1,2-dihydroxy-3-propyl; and R ² is hydroxymethyl.

In some embodiments, R ¹ is 1,2,3-trihydroxy-2-propyl; and R ² is hydroxymethyl.

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

In some embodiments, R ¹ is 1,2-dihydroxy-2-propyl; and R ² is hydroxymethyl. In some embodiments, R ¹

and R ² is hydroxymethyl. In some embodiments, R ² is C1-C6 alkyl substituted with one or more hydroxy; and R ¹ is hydroxymethyl.

In some embodiments, R ² is 1,3-dihydroxy-2-methyl-2-propyl; and R ¹ is hydroxymethyl. In some embodiments, R ² is 2-hydroxymethyl-2-propyl; and R ¹ is hydroxymethyl. In some embodiments, R ² is 2-hydroxyeth-1-yl; and R ¹ is hydroxymethyl.

In some embodiments, R ² is 1,2-dihydroxy-3-propyl; and R ¹ is hydroxymethyl.

In some embodiments, R ² is 1,2,3-trihydroxy-2-propyl; and R ¹ is hydroxymethyl.

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

In some embodiments, R ² is 1,2-dihydroxy-2-propyl; and R ¹ is hydroxymethyl. In some embodiments, R ²

and R ¹ is hydroxymethyl. 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 C1-C6 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 C1-C6 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 SF ₅ .

In some embodiments, R ² is C1-C6 alkyl optionally substituted with one or more hydroxy, and R ¹ is SC1-C6 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)C1-C6 alkyl. In some embodiments, R ² is C1-C6 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 1,2-dihydroxy-2-propyl and R ¹ is fluoro.

In some embodiments, R ² is 1,2-dihydroxy-2-propyl and R ¹ is chloro. In some embodiments, R ¹ is C ₁ -C ₆ alkyl optionally substituted with one or more hydroxy, and R ² is C1-C6 alkyl optionally substituted with one or more C1-C6 alkoxy.

In some embodiments, R ¹ is 2-hydroxy-2-propyl and R ² is methoxymethyl. In some embodiments, R ² is C3-C7 cycloalkyl optionally substituted with one or more hydroxy, and R ¹ is C1-C6 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 C1-C6 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 C1-C6 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 C1-C6 alkyl optionally substituted with one or more C1-C6 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 C1-C6 alkyl optionally substituted with one or more NR ⁸ R ⁹ , and R ¹ is C1-C6 alkyl.

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

In some embodiments, R ² is C1-C6 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 , COOC1-C6 alkyl, C6-C10 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, C1-C6 alkyl, C1-C6 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 C6 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 C ₆ 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 , COOC1-C6 alkyl, C6-C10 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, C1-C6 alkyl, C1-C6 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 . Particular embodiments of R ^1’ when (AA-4) applies:

In some embodiments, R ^1’ is C2-C6 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 1,2-dihydroxy-2-propyl.

In some embodiments, R ^1’ is 1,2,3-trihydroxy-2-propyl. In some embodiments, R ^1’ is C2-C6 alkyl.

In some embodiments, R ^1’ is isobutyl.

In some embodiments, R ^1’ is isopropyl. In some embodiments, R ^1’ is C ₂ -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 1-hydroxyethyl.

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

In some embodiments, R ^1’ is C ₂ -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 a C2-C6 alkyl substituted with one or more hydroxy and further substituted with one or more (e.g., one) NR ⁸ R ⁹ .

In certain of these embodiments, R ^1’ is independently selected from 1-amino-2-hydroxy-prop-2- yl; 1-acetamido-2-hydroxy-prop-2-yl; and 1-(tert-butoxycarbonyl)amino-2-hydroxy-prop-2-yl. In some embodiments, R ^1’ is 1-amino-2-hydroxy-prop-2-yl.

In some embodiments, R ^1’ is 1-acetamido-2-hydroxy-prop-2-yl.

In some embodiments, R ^1’ is 1-(tert-butoxycarbonyl)amino-2-hydroxy-prop-2-yl. In some embodiments, R ^1’ is independently a C2-C6 alkyl substituted with one or more hydroxy and further substituted with one or more (e.g., one) R ¹⁵ .

In certain of these embodiments, a2 is 1 in R ¹⁵ .

In certain of the foregoing embodiments, one or more R ^1’ is independently selected from 1-(2- hydroxyethoxy)-2-hydroxy-2-propyl; 1-(2-benzyloxyethoxy)-2-hydroxy-2-propyl; and 1-(2- methoxyethoxy)-2-hydroxy-2-propyl.

. In certain embodiments when R ^1’ is independently a C ₂ -C ₆ alkyl substituted with one or more hydroxy and further substituted with one or more (e.g., one) R ¹⁵ , a2 is > 1. In certain of these embodiments, R ^1’ is: . In some embodiments, R ^1’ is C3-C7 cycloalkyl optionally substituted with one or more hydroxy. In some embodiments, R ^1’ is C ₃ -C ₇ cycloalkyl (e.g., cyclopropyl or cyclopentyl).

In some embodiments, R ^1’ is C ₃ -C ₇ cycloalkyl optionally substituted with one or more C ₁ -C ₆ alkyl wherein said C1-C6 alkyl is further optionally substituted as described elsewhere herein. In some embodiments, R ^1’ is 1-((methyl)aminomethyl)-cycloprop-1-yl. In some embodiments, R ^1’ is C ₃ -C ₇ 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 azetidinyl.

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 C2-C6 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 C ₃ -C ₇ 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 C2-C6 alkyl optionally substituted with one or more C1-C6 alkoxy. In some embodiments, R ^1’ is 2-methoxy-2-propyl. In some embodiments, R ^1’ is methyl substituted with one or more C1-C6 alkoxy.

In some embodiments, R ^1’ is methoxymethyl. In some embodiments, R ^1’ is C ₂ -C ₆ alkyl optionally substituted with one or more C ₁ -C ₆ haloalkoxy.

In some embodiments, R ^1’ is 1-(difluoromethoxyl)eth-1-yl. In some embodiments, R ^1’ is C3-C7 cycloalkyl optionally substituted with one or more C1-C6 alkoxy.

In some embodiments, R ^1’ is 3- to 7-membered heterocycloalkyl optionally substituted with one or more C1-C6 alkoxy. In some embodiments, R ^1’ is methyl substituted with one or more (e.g., 1) NR ⁸ R ⁹ .

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 (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 (2,2,2-trifluoroeth-1-yl)(methyl)aminomethyl.

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

In some embodiments, R ^1’ is (cyclobutyl)(methyl)aminomethyl.

In some embodiments, R ^1’ is (2-methoxy-eth-1-yl)(methyl)aminomethyl. In some embodiments, R ^1’ is methyl substituted with NR ⁸ R ⁹ , wherein said C ₁ -C ₆ alkyl is further optionally substituted as described elsewhere herein.

In some embodiments, R ^1’ is dimethylamino(cyclopropyl)methyl. In some embodiments, R ^1’ is C ₂ -C ₆ alkyl substituted with NR ⁸ R ⁹ , wherein said C ₂ -C ₆ alkyl is further optionally substituted as described elsewhere herein.

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

In some embodiments, R ^1’ is C2-C6 alkyl substituted with NR ⁸ R ⁹ at the carbon directly connected to ring A.

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-((methyl)aminomethyl)-prop-2-yl.

In some embodiments, R ^1’ is 2-((methyl)amino)-prop-2-yl.

In some embodiments, R ^1’ is 2-fluoro-1-dimethylamino-eth-1-yl.

In some embodiments, R ^1’ is 1-dimethylamino-2,2-difluoroeth-1-yl.

In some embodiments, R ^1’ is 1-dimethylamino-2,2,2-trifluoroeth-1-yl.

In some embodiments, R ^1’ is 1-dimethylamino-2,2,2-trimethyleth-1-yl.

In some embodiments, R ^1’ is (cyclobutyl)(methyl)aminomethyl.

In some embodiments, R ^1’ is isopropylaminomethyl.

In some embodiments, R ^1’ is (cyclobutyl)aminomethyl.

In some embodiments, R ^1’ is cycloheptylaminomethyl.

In some embodiments, R ^1’ is tetrahydropyranylaminomethyl.

In some embodiments, R ^1’ is sec-butylaminomethyl.

In some embodiments, R ^1’ is ethylaminomethyl.

In some embodiments, R ^1’ is allylaminomethyl.

In some embodiments, R ^1’ is 2,2-difluoroeth-1-yl)aminomethyl.

In some embodiments, R ^1’ is (2-methoxy-eth-1-yl)aminomethyl. In some embodiments, R ^1’ is C ₃ -C ₇ 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 C1-C6 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 C1-C6 haloalkoxy.

In some embodiments, R ^1’ is difluoromethoxy. In some embodiments, R ^1’ is C ₂ -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 methyl 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 4-methyl-piperazin-1-yl. In some embodiments, R ^1’ is C ₂ -C ₆ alkyl optionally substituted with one or more C ₆ -C ₁₀ aryl, wherein said aryl is further optionally substituted as described elsewhere herein. In some embodiments, R ^1’ is methyl substituted with C ₆ -C ₁₀ aryl, wherein said aryl is further optionally substituted as described elsewhere herein.

In some embodiments, R ^1’ is 4-methoxybenzyl. 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 COC1-C6 alkyl.

In some embodiments, R ^1’ is CO-C6-C10 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)C1-C6 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)C1-C6 alkyl. In some embodiments, R ^1’ is S(O)CH3.

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. In some embodiments of any of the formulae herein, each of R ¹ and R ² is independently selected from the group consisting of C1-C6 alkyl optionally substituted with one or more hydroxy, halo, oxo, or C1-C6 alkoxy; C3-C7 cycloalkyl optionally substituted with one or more hydroxy, halo, oxo, C ₁ -C ₆ alkoxy, or C ₁ -C ₆ alkyl; wherein the C ₁ -C ₆ alkoxy or C ₁ -C ₆ alkyl is further optionally substituted with one to three hydroxy, halo, NR ⁸ R ⁹ , or oxo; 3- to 7-membered heterocycloalkyl optionally substituted with one or more hydroxy, halo, oxo, or C1-C6 alkyl wherein the C ₁ -C ₆ alkoxy or C ₁ -C ₆ alkyl is further optionally substituted with one to three hydroxy, halo, or oxo; C ₁ -C ₆ haloalkyl; C ₁ -C ₆ alkoxy; C ₁ -C ₆ haloalkoxy; halo; CN; CO-C ₁ -C ₆ alkyl; CO- C6-C10 aryl; CO(5- to 10-membered heteroaryl); CO2C1-C6 alkyl; CO2C3-C8 cycloalkyl; OCOC1- C6 alkyl; OCOC6-C10 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)NR ¹¹ R ¹² ; S(O)C1-C6 alkyl; and S(O2)C1-C6 alkyl. In some embodiments of any of the formulae herein, R ¹ is selected from the group consisting of 1-hydroxy-2-methylpropan-2-yl; methyl; isopropyl; 2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl; 2-hydroxyethyl; 1-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl; 1-hydroxy-1-cyclobutyl; 1-hydroxy-1-cyclopentyl; 1-hydroxy-1-cyclohexyl; morpholinyl; 1,3- dioxolan-2-yl; COCH ₃ ; COCH ₂ CH ₃ ; 2-methoxy-2-propyl; fluoro; chloro; phenyl; pyridyl; pyrazolyl; S(O2)CH3; and S(O2)NR ¹¹ R ¹² . In some embodiments, R ² is selected from the group consisting of fluoro, chloro, cyano, methyl; methoxy; ethoxy; isopropyl; 1-hydroxy-2-methylpropan-2-yl; 2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl; 2-hydroxyethyl; 1-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl; COCH ₃ ; COPh; 2-methoxy-2-propyl; S(O ₂ )CH _3; and S(O ₂ )NR ¹¹ R ¹² . In some embodiments, one pair of R ¹ and R ² is on adjacent atoms, and taken together with the atoms connecting them, independently form at least one bicyclic spirocyclic 5- to-12- membered heterocyclic ring containing 1-3 heteroatoms independently selected from O, N, and S, wherein the carbocyclic or heterocyclic ring is optionally substituted with one or more substituents each independently selected from hydroxy, halo, oxo, methyl, isopropoxyl, azetidinyl, oxetanyl, wherein the methyl, isopropoxyl, azetidinyl, and oxetanyl are optionally substituted with one or more substituents each independently selected from hydroxy, fluoro, amino, methylamino, and dimethylamino. In some embodiments, the optionally substituted ring A is selected from the group consisting of a 5-membered heteroaryl comprising 2 or more heteroatoms, a 5-membered heteroaryl comprising 1 heteroatom or heteroatomic group selected from N, NH, and NR ¹ , and a 5-membered heteroaryl comprising 1 heteroatom selected from O and S, wherein the heteroatom is not bonded to the position of the heteroaryl that is bonded to the S(O)(NHR ³ )=N moiety; m is 1; n is 1; R ¹ and R ² are on adjacent atoms, and taken together with the atoms connecting them, independently form one monocyclic or bicyclic C ₄ -C ₁₂ carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring containing 1-3 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR ⁸ R ⁹ , =NR ¹⁰ , CN, COOC1-C6 alkyl, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR ⁸ R ⁹ , wherein the C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, S(O ₂ )C ₆ -C ₁₀ aryl, C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, C ₃ -C ₁₀ cycloalkyl, and 3- to 10- membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₁ -C ₆ alkoxy, oxo, 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 optionally substituted ring A is a pyrazolyl; m is 1; n is 1; R ¹ and R ² are on adjacent atoms, and taken together with the atoms connecting them, independently form one monocyclic or bicyclic C4-C12 carbocyclic ring or one monocyclic or bicyclic 5- to-12- membered heterocyclic ring containing 1-3 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxy, OC ₃ -C ₁₀ cycloalkyl, NR ⁸ R ⁹ , =NR ¹⁰ , CN, COOC ₁ -C ₆ alkyl, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10- membered heterocycloalkyl, and CONR ⁸ R ⁹ , wherein the C1-C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, C ₃ -C ₁₀ cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, 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 optionally substituted ring A is an imidazolyl; m is 1; n is 1; R ¹ and R ² are on adjacent atoms, and taken together with the atoms connecting them, independently form one monocyclic or bicyclic C ₄ -C ₁₂ carbocyclic ring or one monocyclic or bicyclic 5- to-12- membered heterocyclic ring containing 1-3 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR ⁸ R ⁹ , =NR ¹⁰ , CN, COOC1-C6 alkyl, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10- membered heterocycloalkyl, and CONR ⁸ R ⁹ , wherein the C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, S(O ₂ )C ₆ -C ₁₀ aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₁ -C ₆ alkoxy, oxo, 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 optionally substituted ring A is a thiophenyl; m is 1; n is 1; R ¹ and R ² are on adjacent atoms, and taken together with the atoms connecting them, independently form one monocyclic or bicyclic C4-C12 carbocyclic ring or one monocyclic or bicyclic 5- to-12- membered heterocyclic ring containing 1-3 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR ⁸ R ⁹ , =NR ¹⁰ , CN, COOC1-C6 alkyl, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10- membered heterocycloalkyl, and CONR ⁸ R ⁹ , wherein the C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, S(O ₂ )C ₆ -C ₁₀ aryl, C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, C ₃ -C ₁₀ cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, 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 optionally substituted ring A is a thiazolyl; m is 1; n is 1; R ¹ and R ² are on adjacent atoms, and taken together with the atoms connecting them, independently form one monocyclic or bicyclic C ₄ -C ₁₂ carbocyclic ring or one monocyclic or bicyclic 5- to-12- membered heterocyclic ring containing 1-3 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR ⁸ R ⁹ , =NR ¹⁰ , CN, COOC1-C6 alkyl, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10- membered heterocycloalkyl, and CONR ⁸ R ⁹ , wherein the C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, S(O ₂ )C ₆ -C ₁₀ aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₁ -C ₆ alkoxy, oxo, NR ⁸ R ⁹ , =NR ¹⁰ , COOC1-C6 alkyl, C6-C10 aryl, and CONR ⁸ R ⁹ .

In some embodiments, the optionally substituted ring wherein Z ⁴ is selected from the group consisting of–CH ₂ -,–C(O)-, and NH; Z ⁵ is selected from the group consisting of O, NH, N-CH3, and–CH2-.

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 C6-C10 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 . 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 B is . 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 B is . In some embodiments, the substituted ring B is .

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

In some embodiments, the substituted ring B is . 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 The groups R ⁶ and R ⁷

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 - C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C6-C10 aryl, 5- to 10-membered heteroaryl, NH2, NHC1-C6 alkyl, N(C1-C6 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 C2-C6 alkenyl,

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

hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC1-C6 alkyl, CONR ⁸ R ⁹ , 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC ₆ -C ₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 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, C6-C10 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, C6-C10 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, C1-C6 alkyl, and OC1-C6 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, C1-C6 alkoxy, NR ⁸ R ⁹ , CH2NR ⁸ R ⁹ , =NR ¹⁰ , COOC1-C6 alkyl, C6-C10 aryl, and CONR ⁸ R ⁹ . In some embodiments,

R ⁶ and R ⁷ are each independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1- C6 haloalkoxy, halo, CN, NO2, COC1-C6 alkyl, CO2C1-C6 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), 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)C1-C6 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, C1-C6 alkyl, C1-C6 alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC1-C6 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, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 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, C6-C10 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, C6-C10 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, C1-C6 alkyl, and OC1-C6 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 ₆ 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, C1-C6 alkyl, C1-C6 alkoxy, NR ⁸ R ⁹ , CH2NR ⁸ R ⁹ , =NR ¹⁰ , COOC1-C6 alkyl, C6-C10 aryl, and CONR ⁸ R ⁹ . In some embodiments,

R ⁶ and R ⁷ are each independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1- 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), C6-C10 aryl, 5- to 10-membered heteroaryl, NH2, NHC1-C6 alkyl, N(C1-C6 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 C1-C6 alkyl, C1-C6 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, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7- membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 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, NHCOC6-C10 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, C1-C6 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 C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 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, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C6-C10 aryl, 5- to 10-membered heteroaryl, NH2, NHC1-C6 alkyl, N(C1-C6 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, C1-C6 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, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 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, C6-C10 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, C1-C6 alkyl, and OC1-C6 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, C1-C6 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, halo, CN, NO ₂ , 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), C6-C10 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 C1-C6 alkyl, 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, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 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 NHCOC2-C6 alkynyl;

wherein the 3- to 7-membered heterocycloalkyl, C6-C10 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, C1-C6 alkyl, and OC1-C6 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, C1-C6 alkoxy, NR ⁸ R ⁹ , CH2NR ⁸ R ⁹ , =NR ¹⁰ , COOC1-C6 alkyl, C6-C10 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 - C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C6-C10 aryl, 5- to 10-membered heteroaryl, NH2, NHC1-C6 alkyl, N(C1-C6 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 C1-C6 alkyl, C1-C6 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, 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(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, C6-C10 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 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 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 - C6 haloalkoxy, halo, CN, NO2, COC1-C6 alkyl, CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, OCOC1- C6 alkyl, OCOC6-C10 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, SC1-C6 alkyl, S(O2)C1-C6 alkyl, C3-C7 cycloalkyl and 3- to 7-membered heterocycloalkyl, wherein the C1-C6 alkyl, C3-C7 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 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, C1-C6 alkyl, C1-C6 alkoxy, NR ⁸ R ⁹ , CH2NR ⁸ R ⁹ , =NR ¹⁰ , COOC1-C6 alkyl, C6-C10 aryl, and CONR ⁸ R ⁹ . In some embodiments,

R ⁶ is independently selected from C1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 haloalkyl, C1-C6 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 C1-C6 alkyl, C1-C6 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, OCOC1-C6 alkyl, OCOC6-C10 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 C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 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), C6-C10 aryl, 5- to 10-membered heteroaryl, CONR ⁸ R ⁹ , SF5, S(O2)C1- 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, C1-C6 alkyl, C1-C6 alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC1-C6 alkyl, C6-C10 aryl, and CONR ⁸ R ⁹ . In some embodiments,

R ⁶ and R ⁷ are each independently selected from C1-C6 alkyl, C1-C6 alkoxy, halo, CN, NO2, COC ₁ -C ₆ alkyl, CO ₂ C 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 C1-C6 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 C4-C8 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 C1-C6 alkyl, C1-C6 alkoxy, halo, CN, NO2, COC ₁ -C ₆ alkyl, CO ₂ C 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 C1-C6 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 C4-C6 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 C1-C6 alkyl, C1-C6 alkoxy, halo, CN, NO2, COC ₁ -C ₆ alkyl, CO ₂ C 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 C1-C6 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 C1-C6 alkyl, C1-C6 alkoxy, halo, CN, NO2, COC ₁ -C ₆ alkyl, CO ₂ C 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 C1-C6 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 C4-C8 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- 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 C4 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 ₅ 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 C1-C6 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 C1-C6 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 C1-C6 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, COC1-C6 alkyl, CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C6-C10 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 C1-C6 alkyl, C1-C6 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, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 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, C6-C10 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, C1-C6 alkyl, and OC1-C6 alkyl. In some embodiments, o=1; p=1; and

R ⁶ and R ⁷ are each independently selected from C1-C6 alkyl, C1-C6 alkoxy, halo, CN, NO2, COC1-C6 alkyl, CO2C1-C6 alkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, CONR ⁸ R ⁹ , and 3- to 7-membered heterocycloalkyl,

wherein the C1-C6 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 C4-C8 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 C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1- 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), C6-C10 aryl, 5- to 10-membered heteroaryl, NH2, NHC1-C6 alkyl, N(C1-C6 alkyl)2, CONR ⁸ R ⁹ , SF5, SC1-C6 alkyl, S(O2)C1-C6 alkyl, C3-C7 cycloalkyl and 3- to 7-membered heterocycloalkyl,

wherein the C1-C6 alkyl, C1-C6 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, C1-C6 alkyl, C1-C6 alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC1-C6 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), NHCOC1-C6 alkyl, NHCOC6-C10 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, NHCOC6-C10 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 C1-C6 alkyl, C1-C6 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, C1-C6 alkyl, C1-C6 alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC1-C6 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), NHCOC1-C6 alkyl, NHCOC6-C10 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 -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, OCOC6-C10 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 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, C1-C6 alkyl, C1-C6 alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC1-C6 alkyl, C6-C10 aryl, and CONR ⁸ R ⁹ . In some embodiments, o=2; p=2 or 3; and

each R ⁶ is independently selected from C1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 haloalkyl, C1-C6 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 C1-C6 alkyl, C1-C6 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;

wherein each R ⁷ is independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 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, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C6-C10 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 C1-C6 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 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, C1-C6 alkyl, C1-C6 alkoxy, NR ⁸ R ⁹ , CH2NR ⁸ R ⁹ , =NR ¹⁰ , COOC1-C6 alkyl, C6-C10 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 C1-C6 alkyl, C1-C6 alkoxy, halo, CN, NO2, COC ₁ -C ₆ alkyl, CO ₂ C 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 C1-C6 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 C4-C8 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 C1-C6 alkyl, C1-C6 alkoxy, halo, CN, NO2, COC ₁ -C ₆ alkyl, CO ₂ C 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 C1-C6 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 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, 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 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, C1-C6 alkyl, C1-C6 alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC1-C6 alkyl, C6-C10 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 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, 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, C1-C6 alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC1-C6 alkyl, C6-C10 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, C1-C6 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 ₅ carbocyclic ring, wherein the carbocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C1-C6 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, C1-C6 alkyl, C1-C6 alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC1-C6 alkyl, C6-C10 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 C5 carbocyclic ring, wherein each of C4 and C5 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 C5 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 C ₃ -C ₇ 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 C1-C6 alkyl, and at least one R ⁷ is C1-C6 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 C ₃ -C ₇ 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 C1-C6 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 C1-C6 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 C1-C6 alkyl, and at least one R ⁷ is C1-C6 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 C1-C6 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 C1-C6 alkyl, and at least one R ⁷ is C1-C6 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 C1-C6 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 C1-C6 alkyl, and at least one R ⁶ is C1-C6 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 C1-C6 alkyl, and at least one R ⁶ is C1-C6 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 C1-C6 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 C1-C6 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 C1-C6 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 C1-C6 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 C1-C6 alkoxy; and at least one R ⁶ is halo.

In some embodiments, o=1; p=2; at least one R ⁷ is C1-C6 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, C1-C6 alkyl, C1-C6 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, C1-C6 alkyl, C1-C6 alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC1-C6 alkyl, C6-C10 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, C1-C6 alkyl, C1-C6 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 NR ³ (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 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 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; 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 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 C5 carbocyclic ring optionally independently substituted with one or more substituents independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC1-C6 alkyl, C6-C10 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, C1-C6 alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC1-C6 alkyl, C6-C10 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, C1-C6 alkyl, C1-C6 alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC1-C6 alkyl, C6-C10 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 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 .

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 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, 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, C1-C6 alkyl, C1-C6 alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC1-C6 alkyl, C6-C10 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 , COOC1-C6 alkyl, C6-C10 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, C1-C6 alkyl, C1-C6 alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC1-C6 alkyl, C6-C10 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 C _4-8 carbocyclic ring optionally independently substituted with one or more substituents independently selected from hydroxy, halo, oxo, C ₁ -C ₆ alkyl, C1-C6 alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC1-C6 alkyl, C6-C10 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, C1-C6 alkyl, C1-C6 alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC1-C6 alkyl, C6-C10 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, C1-C6 alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC1-C6 alkyl, C6-C10 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 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 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 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 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 NR ³ (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 NR ³ (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 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, one pair of one R ⁶ and one R ⁷ taken together with the atoms connecting them form a C ₄ 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 C4 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 NR ³ (CO) group of Formula AA.

In some embodiments, one R ⁷ is phenyl optionally substituted with one or more C1-C6 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 C1-C6 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 COOC1-C6 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)C1-C6 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) groupof 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) groupof Formula AA and is para to the bond connecting the B ring to the NH(CO) groupof 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, R ⁶ and R ⁷ are each independently selected from a C2-C6 alkyl, C2-C6 haloalkyl, C ₂ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, I, CN, NO ₂ , COC ₁ -C ₆ alkyl, CO ₂ C ₁ -C ₆ alkyl, CO ₂ C ₃ - C8 cycloalkyl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C6-C10 aryl, 5- to 10-membered heteroaryl, NH2, NHC1-C6 alkyl, N(C1-C6 alkyl)2, CONR ⁸ R ⁹ , SF5, SC1-C6 alkyl, S(O2)C1-C6 alkyl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl, and 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, C1-C6 alkyl, C1-C6 alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC1-C6 alkyl, CONR ⁸ R ⁹ , 3- to 7-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(3- to 7- membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC2-C6 alkynyl, C6-C10 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, NHCOC6-C10 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 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, C1-C6 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 a C ₂ -C ₆ alkyl, C ₂ -C ₆ haloalkyl, C2-C6 alkoxy, C1-C6 haloalkoxy, I, CN, NO2, COC1-C6 alkyl, CO2C1-C6 alkyl, CO2C3- 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, NH ₂ , NHC ₁ -C ₆ alkyl, N(C1-C6 alkyl)2, CONR ⁸ R ⁹ , SF5, SC1-C6 alkyl, S(O2)C1-C6 alkyl, C3-C10 cycloalkyl and 3- to 10-membered heterocycloalkyl, and C2-C6 alkenyl,

wherein R ⁶ and R ⁷ are each optionally substituted with one or more substituents independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC1-C6 alkyl, CONR ⁸ R ⁹ , 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 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)C1-C6 alkyl; and wherein the C1-C6 alkyl or C1-C6 alkoxy that R ⁶ or R ⁷ is substituted with is optionally substituted with one or more hydroxyl, C6-C10 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, C6-C10 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, C1-C6 alkyl, and OC1-C6 alkyl;

or 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 and/or heteroatomic groups independently selected from O, NH, NR ¹³ , S, S(O), and S(O)2, wherein the selected heteroatoms and/or heteroatomic groups are cumulative with the nitrogen atoms present in ring B, and wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 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 a C2-C6 alkyl, C2- C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, I, 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), C6-C10 aryl, 5- to 10-membered heteroaryl, NH2, NHC1-C6 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 ₁₀ cycloalkyl and 3- to 10- membered heterocycloalkyl, and 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, C1-C6 alkyl, C1-C6 alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC1-C6 alkyl, CONR ⁸ R ⁹ , 3- to 7-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7- membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC2-C6 alkynyl, C6-C10 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, NHCOC6-C10 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 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 and/or heteroatomic groups independently selected from O, NH, NR ¹³ , S, S(O), and S(O) ₂ , wherein the selected heteroatoms and/or heteroatomic groups are cumulative with the nitrogen atoms present in ring B, and 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 , COOC1-C6 alkyl, C6-C10 aryl, and CONR ⁸ R ⁹ .

In some embodiments, R ⁶ and R ⁷ are each independently selected from a C2-C6 alkyl, C2-C6 haloalkyl, C ₂ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, I, CN, NO ₂ , COC ₁ -C ₆ alkyl, CO ₂ C ₁ -C ₆ alkyl, CO ₂ C ₃ - C8 cycloalkyl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C6-C10 aryl, 5- to 10-membered heteroaryl, NH2, NHC1-C6 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 ₁₀ cycloalkyl and 3- to 10-membered heterocycloalkyl, and 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, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7- membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 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)C1-C6 alkyl; and wherein the C1-C6 alkyl or C1-C6 alkoxy that R ⁶ or R ⁷ is substituted with is optionally substituted with one or more hydroxyl, C6-C10 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, NHCOC6-C10 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 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 and/or heteroatomic groups independently selected from O, NH, NR ¹³ , S, S(O), and S(O) ₂ , wherein the selected heteroatoms and/or heteroatomic groups are cumulative with the nitrogen atoms present in ring B, and 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 , COOC1-C6 alkyl, C6-C10 aryl, and CONR ⁸ R ⁹ .

In some embodiments,

In some embodiments,

In some embodiments,

In certain embodiments (when

each R ⁶ is independently selected from C1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, CN, C6-C10 aryl, 5- to 10-membered heteroaryl, CO-C1-C6 alkyl; CONR ⁸ R ⁹ , and 4- to 6-membered heterocycloalkyl,

wherein the C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, C ₃ - C7 cycloalkyl and 4- to 6-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 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, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 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 C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1- 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), C6-C10 aryl, 5- to 10-membered heteroaryl, CONR ⁸ R ⁹ , SF5, S(O2)C1-C6 alkyl, C3-C7 cycloalkyl and 4- to 6-membered heterocycloalkyl, wherein the C1-C6 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, C1-C6 alkyl, C1-C6 alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC1-C6 alkyl, C6-C10 aryl, and CONR ⁸ R ⁹ .

In some embodiments, B is

In certain of these embodiments, each R ⁶ is independently selected from C1-C6 alkyl, C3- C7 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, CN, C6-C10 aryl, 5- to 10- membered heteroaryl, CO-C ₁ -C ₆ alkyl; CONR ⁸ R ⁹ , and 4- to 6-membered heterocycloalkyl,

wherein the C1-C6 alkyl, C1-C6 haloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, 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, C1-C6 alkyl, C1-C6 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), NHCOC1-C6 alkyl, NHCOC6-C10 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 C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1- C6 haloalkoxy, halo, CN, COC1-C6 alkyl, CO2C1-C6 alkyl, CO2C3-C6 cycloalkyl, OCOC1-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, 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 C1-C6 alkyl is optionally substituted with one to two C ₁ -C ₆ alkoxy.

In certain of these embodiments, the other R ⁶ is C ₁ -C ₆ alkyl. For example, each R ⁶ is

isopropyl (i.e., the substituted ring B is

In certain other embodiments (when the substituted ring B is one R ⁶ is C1- C6 alkyl; and the other R ⁶ is C6-C10 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, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 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 C1-C6 alkyl; and the other R ⁶ is C6-C10 aryl or 5- to 10-membered heteroaryl optionally substituted with a substituent selected from halo, CN, C ₁ - C6 alkyl, and C1-C6 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:

(e.g., R ⁷ is halo (e.g.,

fluoro)).

In some embodiments, B is

In certain of these embodiments, one R ⁶ is C1-C6 alkyl; and the other R ⁶ is C6-C10 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 , COOC1-C6 alkyl, CONR ⁸ R ⁹ , 4- to 6-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 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 - C6 alkyl, and C1-C6 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.

In certain of the foregoing embodiments, each R ⁷ is independently halo or cyano, As a non-limiting example of the foregoing embodiments, substituted ring B is:

In some embodiments, B is

In some embodiments, B is

In certain embodiments (when B is each R ⁶ is independently selected from C1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 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 C1-C6 alkyl, C1-C6 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;

wherein each R ⁷ is independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 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, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C6-C10 aryl, 5- to 10-membered heteroaryl, CONR ⁸ R ⁹ , SF5, S(O2)C1-C6 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 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, C1-C6 alkyl, C1-C6 alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC ₁ -C ₆ alkyl, C ₆ -C ₁₀ aryl, and CONR ⁸ R ⁹ .

In certain embodiments (when B is ; or B is 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-C7 carbocyclic ring or a 5- to 7- 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, C1-C6 alkyl, C1-C6 alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC1-C6 alkyl, C6-C10 aryl, and CONR ⁸ R ⁹ .

In certain of the foregoing embodiments, one pair of R ⁶ and R ⁷ taken together with the atoms connecting them independently form a C ₅ carbocyclic ring, wherein the carbocyclic ring is optionally substituted with one or more substituents independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC1-C6 alkyl, C6-C10 aryl, and CONR ⁸ R ⁹ .

In certain of these embodiments (when one pair of R ⁶ and R ⁷ taken together with the atoms connecting them independently form a C5 carbocyclic ring, wherein the carbocyclic ring is 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 ), the other pair of R ⁶ and R ⁷ taken together with the atoms connecting them independently form a C5 carbocyclic ring, wherein the carbocyclic ring is optionally substituted with one or more substituents independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC ₁ -C ₆ alkyl, C ₆ -C ₁₀ aryl, and CONR ⁸ R ⁹ .

As non-limiting examples of the foregoing embodiments (when B is the

substituted ring B is:

As a non-limiting example of the foregoing embodiments (when B is the

substituted ring B is:

In certain of these embodiments (when o=2 and p=2 (e.g., B is or B is

); and one pair of R ⁶ and R ⁷ taken together with the atoms connecting them independently form a C ₅ carbocyclic ring, wherein the carbocyclic ring is optionally substituted with one or more substituents independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC ₁ -C ₆ alkyl, C ₆ -C ₁₀ aryl, and CONR ⁸ R ⁹ ), the other pair of R ⁶ and R ⁷ taken together with the atoms connecting them independently form a C ₄ or C _6-7 (e.g., C ₄ ) carbocyclic ring, wherein the carbocyclic ring is 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 , COOC1-C6 alkyl, C6-C10 aryl, and CONR ⁸ R ⁹ .

As a non-limiting example, the substituted ring B is:

In certain of these embodiments (when o=2 and p=2 (e.g., B is or B is one pair of R ⁶ and R ⁷ taken together with the atoms connecting them

independently form a C ₄ carbocyclic ring, wherein the carbocyclic ring is optionally substituted with one or more substituents independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C1- C6 alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC1-C6 alkyl, C6-C10 aryl, and CONR ⁸ R ⁹ . In certain of these embodiments, the other pair of R ⁶ and R ⁷ taken together with the atoms connecting them independently form a C4 carbocyclic ring, wherein the carbocyclic ring is 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 (when the substituted ring B is ; 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, C6-C10 aryl, 5- to 10-membered heteroaryl, CO-C1-C6 alkyl; CONR ⁸ R ⁹ , and 4- to 6-membered heterocycloalkyl, wherein the C1-C6 alkyl, C1-C6 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, OCOC1-C6 alkyl, OCOC6-C10 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 C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 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), C6-C10 aryl, 5- to 10-membered heteroaryl, CONR ⁸ R ⁹ , SF5, S(O2)C1-C6 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 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, C1-C6 alkyl, C1-C6 alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC ₁ -C ₆ alkyl, C ₆ -C ₁₀ aryl, and CONR ⁸ R ⁹ ),

one pair of R ⁶ and R ⁷ on adjacent atoms, taken together with the atoms connecting them, independently form one C4-C7 carbocyclic ring or 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, C1-C6 alkyl, C1-C6 alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC ₁ -C ₆ alkyl, C ₆ -C ₁₀ aryl, and CONR ⁸ R ⁹ ; and each of the remaining R ⁶ and R ⁷ is independently selected from C ₁ -C ₆ alkyl and C ₃ -C ₇ cycloalkyl.

In certain of these embodiments, one pair of R ⁶ and R ⁷ on adjacent atoms, taken together with the atoms connecting them, independently form one C4-C7 (e.g., C5) carbocyclic ring; and each of the remaining R ⁶ and R ⁷ is independently selected from C ₁ -C ₆ alkyl and C ₃ -C ₇ cycloalkyl. As a non-limiting example of the foregoing embodiments, the substituted ring B is .

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

In some embodiments, B is

In certain of these embodiments, 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-C1-C6 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, C1-C6 alkyl, C1-C6 alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC1-C6 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), NHCOC1-C6 alkyl, NHCOC6-C10 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, CO ₂ C ₁ -C ₆ alkyl, CO ₂ C ₃ -C ₆ cycloalkyl, OCOC ₁ -C ₆ alkyl, OCOC6-C10 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 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, C1-C6 alkyl, C1-C6 alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC1-C6 alkyl, C6-C10 aryl, and CONR ⁸ R ⁹ .

In some embodiments, .

In certain of these embodiments, each R ⁶ is independently selected from C ₁ -C ₆ alkyl, C ₃ - C7 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, CN, C6-C10 aryl, 5- to 10- membered heteroaryl, CO-C1-C6 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, C1-C6 alkyl, C1-C6 alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC1-C6 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), NHCOC1-C6 alkyl, NHCOC6-C10 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 ₂ -C ₆ alkenyl, C ₁ -C ₆ haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, CN, COC1-C6 alkyl, CO2C1-C6 alkyl, CO2C3-C6 cycloalkyl, OCOC1-C6 alkyl, OCOC6-C10 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 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 , COOC1-C6 alkyl, C6-C10 aryl, and CONR ⁸ R ⁹ . In certain of the foregoing embodiments, 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 ₇ carbocyclic ring or a 5- to 7-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 , COOC1-C6 alkyl, C6-C10 aryl, and CONR ⁸ R ⁹ .

In certain of these embodiments, one pair of R ⁶ and R ⁷ taken together with the atoms connecting them independently form a C ₅ carbocyclic ring, wherein the carbocyclic ring is optionally substituted with one or more substituents independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC1-C6 alkyl, C6-C10 aryl, and CONR ⁸ R ⁹ .

In certain of the foregoing embodiments, the other pair of R ⁶ and R ⁷ taken together with the atoms connecting them independently form a C ₅ carbocyclic ring, wherein the carbocyclic ring is optionally substituted with one or more substituents independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC1-C6 alkyl, C6-C10 aryl, and CONR ⁸ R ⁹ .

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

.

For example, R ⁷ is selected from each R ⁷ is independently selected from C1-C6 alkyl, C2- C6 alkenyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, and CN.

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

In certain of the foregoing embodiments, each R ⁶ is independently selected from C ₁ -C ₆ alkyl, C3-C7 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, CN, C6-C10 aryl, 5- to 10-membered heteroaryl, CO-C ₁ -C ₆ alkyl, CONR ⁸ R ⁹ , and 4- to 6-membered heterocycloalkyl, wherein each of the C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₃ -C ₇ cycloalkyl, 4- to 6-membered heterocycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1- 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), NHCOC1-C6 alkyl, NHCOC6- C10 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 C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1- C6 haloalkoxy, halo, CN, COC1-C6 alkyl, CO2C1-C6 alkyl, CO2C3-C6 cycloalkyl, OCOC1-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, 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 each of the C1-C6 alkyl is optionally substituted with C ₁ -C ₆ alkoxy;

or R ⁶ and R ⁷ on adjacent atoms, taken together with the atoms connecting them, independently form C4-C7 carbocyclic ring or 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, C1-C6 alkyl, C1-C6 alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC1-C6 alkyl, C6-C10 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 C4-C7 (e.g., C4 or C5) carbocyclic ring or 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 , COOC1-C6 alkyl, C6-C10 aryl, and CONR ⁸ R ⁹ . For example, the R ⁶ and R ⁷ on adjacent atoms, taken together with the atoms connecting them, independently form C ₄ -C ₇ (e.g., C ₅ ) carbocyclic ring. For example, the substituted ring B is

In certain embodiments (when the substituted ring B is selected from: and

; and the R ⁶ and R ⁷ on adjacent atoms, taken together with the atoms connecting them, independently form C4-C7 (e.g., C4 or C5) carbocyclic ring or 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, C1-C6 alkyl, C1-C6 alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC ₁ -C ₆ alkyl, C ₆ -C ₁₀ aryl, and CONR ⁸ R ⁹ ):

the remaining 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, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6- membered heterocycloalkyl), and NHCOC ₂ -C ₆ alkynyl.

In certain of these embodiments, the remaining R ⁶ is C6-C10 aryl or 5- to 10-membered heteroaryl optionally substituted with a substituent selected from halo, CN, C1-C6 alkyl, and C1- C ₆ alkoxy. For example, R ⁶ is 5-6 membered heteroaryl (e.g., pyridinyl (e.g., pyridin-4-yl), pyrimidinyl, or thiazolyl) optionally substituted with a substituent selected from halo, CN, C1-C6 alkyl, and C ₁ -C ₆ alkoxy.

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

.

In certain of the foregoing embodiments, each R ⁶ is independently selected from C1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, CN, C6-C10 aryl, 5- to 10-membered heteroaryl, CO-C ₁ -C ₆ alkyl, CONR ⁸ R ⁹ , and 4- to 6-membered heterocycloalkyl, wherein each of the C1-C6 alkyl, C1-C6 haloalkyl, C3-C7 cycloalkyl, 4- to 6-membered heterocycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl 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 - C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 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 C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1- 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, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C6-C10 aryl, 5- to 10-membered heteroaryl, CONR ⁸ R ⁹ , SF5, S(O2)C1-C6 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 one pair R ⁶ and R ⁷ on adjacent atoms, taken together with the atoms connecting them, independently form C ₄ -C ₇ carbocyclic ring or 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, C1-C6 alkyl, C1-C6 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, one pair R ⁶ and R ⁷ on adjacent atoms, taken together with the atoms connecting them, independently form C4-C7 (e.g., C4 or C5) carbocyclic ring or 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 . For example, the R ⁶ and R ⁷ on adjacent atoms, taken together with the atoms connecting them, independently form C4-C7 (e.g.,

C ₅ ) carbocyclic ring. For example, the substituted ring B is :

In certain embodiments (when the substituted ring B is selected from: and ; and one pair of R ⁶ and R ⁷ on adjacent atoms, taken together with the atoms connecting them, independently form C4-C7 (e.g., C4 or C5) carbocyclic ring or 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, C1-C6 alkyl, C1-C6 alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC1-C6 alkyl, C6-C10 aryl, and CONR ⁸ R ⁹ ):

the remaining 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, C1-C6 alkyl, C1-C6 alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC1-C6 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), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6- membered heterocycloalkyl), and NHCOC ₂ -C ₆ alkynyl.

In certain of these embodiments, the remaining R ⁶ is C ₆ -C ₁₀ aryl or 5- to 10-membered heteroaryl optionally substituted with a substituent selected from halo, CN, C1-C6 alkyl, and C1- C6 alkoxy. For example, R ⁶ is 5-6 membered heteroaryl (e.g., pyridinyl (e.g., pyridin-4-yl), pyrimidinyl, or thiazolyl) optionally substituted with a substituent selected from halo, CN, C ₁ -C ₆ alkyl, and C1-C6 alkoxy. As a non-limiting example of the foregoing embodiments, substituted ring B is selected from:

(e.g., R ⁷ is halo (e.g., fluoro)).

The group R ³ In some embodiments, R ³ is hydrogen or C ₁ -C ₆ alkyl.

In certain of these embodiments, R ³ is hydrogen or methyl.

In some embodiments, R ³ is other than cyano.

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 cyano.

In some embodiments, R ³ is hydroxy.

In some embodiments, R ³ is C1-C6 alkoxy.In some embodiments, R ³ is C1-C6 alkyl.

In some embodiments, R ³ is methyl.

In some embodiments, R ³ is wherein the C ₁ -C ₂ alkylene group is optionally substituted with oxo.

In some embodiments, R ³ is–CH2R ¹⁴ .

In some embodiments, R ³ is–C(O)R ¹⁴ .

In some embodiments, R ³ is–CH ₂ CH ₂ R ¹⁴ .

In some embodiments, R ³ is–CHR ¹⁴ CH3.

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 CO ₂ C 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 C6-C10 monocyclic or bicyclic aryl, wherein each C1-C6 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 C1-C6 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 C6-C10 monocyclic or bicyclic aryl optionally independently substituted with 1 or 2 R ⁶ . The moiety S(=O)(NHR ³ )=N- In some embodiments, the sulfur in the moiety S(=O)(NHR ³ )=N- has (S) stereochemistry.

In some embodiments, the sulfur in the moiety 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(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, C1-C6 alkoxy, C6-C10 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, C1-C6 alkoxy, C6-C10 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 hydrogen,

In some embodiments, each R ⁸ at each occurrence is hydrogen and each R ⁹ at each occurrence is C1-C6 alkyl.

In some embodiments, each R ⁸ at each occurrence is hydrogen and each R ⁹ at each occurrence is methyl.

In some embodiments, each R ⁸ at each occurrence is hydrogen and each R ⁹ at each occurrence is ethyl.

In some embodiments, each of R ⁸ and R ⁹ at each occurrence is methyl.

In some embodiments, each of R ⁸ and R ⁹ at each occurrence is ethyl.

In some embodiments, R ⁸ and R ⁹ taken together with the nitrogen they are attached to form a 3- membered ring.

In some embodiments, R ⁸ and R ⁹ taken together with the nitrogen they are attached to form a 4- membered ring.

In some embodiments, R ⁸ and R ⁹ taken together with the nitrogen they are attached to form a 5- membered ring. In some embodiments, R ⁸ and R ⁹ taken together with the nitrogen they are attached to form a 6- membered ring optionally containing one or more oxygen atoms in addition to the nitrogen they are attached to.

In some embodiments, R ⁸ and R ⁹ taken together with the nitrogen they are attached to form a 6- membered ring optionally containing one or more nitrogen atoms in addition to the nitrogen they are attached to.

In some embodiments, R ⁸ and R ⁹ taken together with the nitrogen they are attached to form a 7- membered ring. In some embodiments, one of R ⁸ and R ⁹ is C(O)R ¹³ ; R ¹³ is–(Z ¹ -Z ² ) _a1 -Z ³ ; and a1 is 0.

In certain of these embodiments, the other one of R ⁸ and R ⁹ is hydrogen.

As a non-limiting example of the foregoing embodiments, NR ⁸ R ⁹ is selected from the group consisting of: NHCOC ₆ -C ₁₀ aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7- membered heterocycloalkyl), and NHCOC2-C6 alkynyl. In some embodiments, one of R ⁸ and R ⁹ is C(O)R ¹³ ; R ¹³ is C ₁ -C ₆ alkyl. In certain embodiments, NR ⁸ R ⁹ is selected from the group consisting of: NH2, NHC1-C6 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, and NHCOOC1-C6 alkyl.

The group R ¹³

In some embodiments, R ¹³ is C1-C6 alkyl.

In some embodiments, R ¹³ is methyl.

In some embodiments, R ¹³ is ethyl.

In some embodiments, R ¹³ is–(Z ¹ -Z ² )a1-Z ³ .

In certain of these embodiments, a1 is 0. In certain embodiments, Z ³ is C6-C10 aryl or 5- to 10- membered heteroaryl.

In some embodiments, R ¹³ is C6-C10 aryl.

In some embodiments, R ¹³ is phenyl. In some embodiments, R ¹³ is 5- to 10-membered heteroaryl. The groups R ¹¹ and R ¹²

In some embodiments, each of R ¹¹ and R ¹² at each occurrence is independently selected from hydrogen and C1-C6 alkyl.

In some embodiments, each of R ¹¹ and R ¹² at each occurrence is hydrogen,

In some embodiments, each R ¹¹ at each occurrence is hydrogen and each R ¹² at each occurrence is C1-C6 alkyl.

In some embodiments, each R ¹¹ at each occurrence is hydrogen and each R ¹² at each occurrence is methyl.

In some embodiments, each R ¹¹ at each occurrence is hydrogen and each R ¹² at each occurrence is ethyl.

In some embodiments, each of R ¹¹ and R ¹² at each occurrence is methyl.

In some embodiments, each of R ¹¹ and R ¹² at each occurrence is ethyl. The group R ¹⁵

In some embodiments, R ¹⁵ is–(Z ⁴ -Z ⁵ )a2-Z ⁶ .

In certain embodiments, a2 is 1-5.

In certain embodiments, the Z ⁴ group directly attached to R ¹ or R ² is–O-.

In certain embodiments, each Z ⁴ is independently–O- or–NH-, provided that the Z ⁴ group directly attached to R ¹ or R ² is–O-.

In certain embodiments, each Z ⁴ is–O-.

In certain embodiments, each Z ⁵ is independently C ₂ -C ₆ alkylene optionally substituted with one or more substituents independently selected from oxo, halo, and hydroxyl. In certain these embodiments, each Z ⁵ is independently C ₂ -C ₄ (e.g., C ₂ -C ₃ (e.g., C ₂ or C ₃ )) alkylene.

In certain embodiments, Z ⁶ is OH.

In certain embodiments, Z ⁶ is NHC(O)(C1-C6 alkoxy).

In certain embodiments, Z ⁶ is C6-C10 aryl.

In certain embodiments, Z ⁶ is C ₁ -C ₆ alkoxy. In certain embodiments of R ¹⁵ , a2=1; and Z ⁴ is O. In certain of these embodiments, Z ⁵ is C2-C4 (e.g., C ₂ -C ₃ (e.g., C ₂ or C ₃ )) alkylene. In certain of the foregoing embodiments, Z ⁶ is selected from OH, NHC(O)(C1-C6 alkoxy), and C ₁ -C ₆ alkoxy. As non-limiting examples, R ¹⁵ is selected from:

In certain embodiments of R ¹⁵ , a2=1; and each Z ⁴ is O. In certain of these embodiments, Z ⁵ is C2-C4 (e.g., C2-C3 (e.g., C2 or C3)) alkylene. In certain of the foregoing embodiments, Z ⁶ is selected from OH, NHC(O)(C1-C6 alkoxy), and C ₁ -C ₆ alkoxy. In certain other of the foregoing embodiments, Z ⁶ is C6-C10 aryl (e.g., R ¹⁵ is

In certain embodiments of R ¹⁵ , a2 ³2 (e.g., a2 is 3 or 4); each Z ⁴ is O; and each Z ⁵ is ethylene. In certain of these embodiments Z ⁶ is OH. In certain other embodiments, Z ⁶ is NHC(O)(C1-C6 alkoxy) (e.g., Boc). As a non-limiting example, R ¹⁵ is:

In some embodiments of the compound of formula AA, the substituted ring A is

and R ¹ is selected from:

C ₁ -C ₆ alkyl optionally substituted with one or more hydroxy; C ₃ -C ₇ cycloalkyl optionally substituted with one or more hydroxy; 3- to 7-membered heterocycloalkyl optionally substituted with one or more hydroxy; C1-C6 alkyl substituted with one or more oxo; C3-C7 cycloalkyl substituted with one or more oxo; C ₁ -C ₆ alkyl substituted with one or more C ₁ -C ₆ alkoxy; C ₃ -C ₇ cycloalkyl substituted with one or more C ₁ -C ₆ alkoxy; C ₁ -C ₆ haloalkyl; C ₁ -C ₆ alkoxy; C ₁ -C ₆ haloalkoxy; halo; CN; NO2; COC1-C6 alkyl; CO-C6-C10 aryl; CO(5- to 10-membered heteroaryl); CO2C1-C6 alkyl; CO2C3-C8 cycloalkyl; OCOC1-C6 alkyl; OCOC6-C10 aryl; OCO(5- to 10- membered heteroaryl); OCO(3- to 7-membered heterocycloalkyl); C ₆ -C ₁₀ aryl; 5- to 10- membered heteroaryl; NH2; NHC1-C6 alkyl; N(C1-C6 alkyl)2; CONR ⁸ R ⁹ ; SF5; and S(O2)C1-C6 alkyl.

In some embodiments of the compound of formula AA, the substituted ring A is ;

and R ¹ is selected from:

1-hydroxy-2-methylpropan-2-yl; methyl; isopropyl; 2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl; 2-hydroxyethyl; 1-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl; 1- hydroxy-1-cyclobutyl; 1-hydroxy-1-cyclopentyl; 1-hydroxy-1-cyclohexyl; morpholinyl; 1,3-dioxolan-2-yl; COCH3; COCH2CH3; 2-methoxy-2-propyl; (dimethylamino)methyl; 1-(dimethylamino)ethyl; fluoro; chloro; phenyl; pyridyl; pyrazolyl; and S(O ₂ )CH ₃ . In some embodiments of the compound of formula AA,

the substituted ring A is

and R ¹ is selected from:

C1-C6 alkyl optionally substituted with one or more hydroxy; C3-C7 cycloalkyl optionally substituted with one or more hydroxy; 3- to 7-membered heterocycloalkyl optionally substituted with one or more hydroxy; C ₁ -C ₆ alkyl substituted with one or more oxo; C ₃ - C7 cycloalkyl substituted with one or more oxo; C1-C6 alkyl substituted with one or more C1-C6 alkoxy; C3-C7 cycloalkyl substituted with one or more C1-C6 alkoxy; C1-C6 alkyl substituted with one or more NR ⁸ R ⁹ ; 3- to 7-membered heterocycloalkyl substituted with one or more NR ⁸ R ⁹ ; C ₁ -C ₆ haloalkyl; C ₁ -C ₆ alkoxy; C ₁ -C ₆ haloalkoxy; halo; CN; NO ₂ ; COC1-C6 alkyl; CO-C6-C10 aryl; CO(5- to 10-membered heteroaryl); CO2C1-C6 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; NHC1-C6 alkyl; N(C1-C6 alkyl)2; CONR ⁸ R ⁹ ; SF5; and S(O2)C1-C6 alkyl. In some embodiments of the compound of formula AA, the substituted ring A is

and R ¹ is selected from:

1-hydroxy-2-methylpropan-2-yl; methyl; isopropyl; 2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl; 2-hydroxyethyl; 1-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl; 1- hydroxy-1-cyclobutyl; 1-hydroxy-1-cyclopentyl; 1-hydroxy-1-cyclohexyl; morpholinyl; 1,3-dioxolan-2-yl; COCH ₃ ; COCH ₂ CH ₃ ; 2-methoxy-2-propyl; (dimethylamino)methyl; 1-(dimethylamino)ethyl; fluoro; chloro; phenyl; pyridyl; pyrazolyl; and S(O ₂ )CH ₃ . In some embodiments of the compound of formula AA, the substituted ring A is

and R ¹ is selected from:

C1-C6 alkyl optionally substituted with one or more hydroxy; C3-C7 cycloalkyl optionally substituted with one or more hydroxy; 3- to 7-membered heterocycloalkyl optionally substituted with one or more hydroxy; C ₁ -C ₆ alkyl substituted with one or more oxo; C ₃ - C7 cycloalkyl substituted with one or more oxo; C1-C6 alkyl substituted with one or more C1-C6 alkoxy; C3-C7 cycloalkyl substituted with one or more C1-C6 alkoxy; C1-C6 alkyl substituted with one or more NR ⁸ R ⁹ ; 3- to 7-membered heterocycloalkyl substituted with one or more NR ⁸ R ⁹ ; C1-C6 haloalkyl; C1-C6 alkoxy; C1-C6 haloalkoxy; halo; CN; NO2; COC1-C6 alkyl; CO-C6-C10 aryl; CO(5- to 10-membered heteroaryl); CO2C1-C6 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; NHC1-C6 alkyl; N(C1-C6 alkyl)2; CONR ⁸ R ⁹ ; SF5; and S(O2)C1-C6 alkyl. In some embodiments of the compound of formula AA, the substituted ring A is

and R ¹ is selected from:

1-hydroxy-2-methylpropan-2-yl; methyl; isopropyl; 2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl; 2-hydroxyethyl; 1-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl; 1- hydroxy-1-cyclobutyl; 1-hydroxy-1-cyclopentyl; 1-hydroxy-1-cyclohexyl; morpholinyl; 1,3-dioxolan-2-yl; COCH ₃ ; COCH ₂ CH ₃ ; 2-methoxy-2-propyl; (dimethylamino)methyl; 1-(dimethylamino)ethyl; fluoro; chloro; phenyl; pyridyl; pyrazolyl; and S(O ₂ )CH ₃ . In some embodiments of the compound of formula AA, the substituted ring

and R ¹ is selected from:

C1-C6 alkyl optionally substituted with one or more hydroxy; C3-C7 cycloalkyl optionally substituted with one or more hydroxy; 3- to 7-membered heterocycloalkyl optionally substituted with one or more hydroxy; C1-C6 alkyl substituted with one or more oxo; C3- C7 cycloalkyl substituted with one or more oxo; C1-C6 alkyl substituted with one or more C ₁ -C ₆ alkoxy; C ₃ -C ₇ cycloalkyl substituted with one or more C ₁ -C ₆ alkoxy; C ₁ -C ₆ alkyl substituted with one or more NR ⁸ R ⁹ ; 3- to 7-membered heterocycloalkyl substituted with one or more NR ⁸ R ⁹ ; C1-C6 haloalkyl; C1-C6 alkoxy; C1-C6 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); C6-C10 aryl; 5- to 10-membered heteroaryl; NH2; NHC1-C6 alkyl; N(C1-C6 alkyl)2; CONR ⁸ R ⁹ ; SF5; and S(O2)C1-C6 alkyl. In some embodiments of the compound of formula AA, the substituted ring

and R ¹ is selected from:

1-hydroxy-2-methylpropan-2-yl; methyl; isopropyl; 2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl; 2-hydroxyethyl; 1-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl; 1- hydroxy-1-cyclobutyl; 1-hydroxy-1-cyclopentyl; 1-hydroxy-1-cyclohexyl; morpholinyl; 1,3-dioxolan-2-yl; COCH ₃ ; COCH ₂ CH ₃ ; 2-methoxy-2-propyl; (dimethylamino)methyl; 1-(dimethylamino)ethyl; fluoro; chloro; phenyl; pyridyl; pyrazolyl; and S(O2)CH3. In some embodiments of the compound of formula AA, the substituted ring A is

and R ¹ is selected from:

C1-C6 alkyl optionally substituted with one or more hydroxy; C3-C7 cycloalkyl optionally substituted with one or more hydroxy; 3- to 7-membered heterocycloalkyl optionally substituted with one or more hydroxy; C ₁ -C ₆ alkyl substituted with one or more oxo; C ₃ - C7 cycloalkyl substituted with one or more oxo; C1-C6 alkyl substituted with one or more C1-C6 alkoxy; C3-C7 cycloalkyl substituted with one or more C1-C6 alkoxy; C1-C6 alkyl substituted with one or more NR ⁸ R ⁹ ; 3- to 7-membered heterocycloalkyl substituted with one or more NR ⁸ R ⁹ ; C1-C6 haloalkyl; C1-C6 alkoxy; C1-C6 haloalkoxy; halo; CN; NO2; COC1-C6 alkyl; CO-C6-C10 aryl; CO(5- to 10-membered heteroaryl); CO2C1-C6 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; NHC1-C6 alkyl; N(C1-C6 alkyl)2; CONR ⁸ R ⁹ ; SF5; and S(O2)C1-C6 alkyl. In some embodiments of the compound of formula AA, the substituted ring A is

and R ¹ is selected from:

1-hydroxy-2-methylpropan-2-yl; methyl; isopropyl; 2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl; 2-hydroxyethyl; 1-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl; 1- hydroxy-1-cyclobutyl; 1-hydroxy-1-cyclopentyl; 1-hydroxy-1-cyclohexyl; morpholinyl; 1,3-dioxolan-2-yl; COCH ₃ ; COCH ₂ CH ₃ ; 2-methoxy-2-propyl; (dimethylamino)methyl; 1-(dimethylamino)ethyl; fluoro; chloro; phenyl; pyridyl; pyrazolyl; and S(O ₂ )CH ₃ . In some embodiments of the compound of formula AA, the substituted ring A is

and R ¹ is selected from:

C ₁ -C ₆ alkyl optionally substituted with one or more hydroxy; C ₃ -C ₇ cycloalkyl optionally substituted with one or more hydroxy; 3- to 7-membered heterocycloalkyl optionally substituted with one or more hydroxy; C1-C6 alkyl substituted with one or more oxo; C3- C ₇ cycloalkyl substituted with one or more oxo; C ₁ -C ₆ alkyl substituted with one or more C ₁ -C ₆ alkoxy; C ₃ -C ₇ cycloalkyl substituted with one or more C ₁ -C ₆ alkoxy; C ₁ -C ₆ alkyl substituted with one or more NR ⁸ R ⁹ ; 3- to 7-membered heterocycloalkyl substituted with one or more NR ⁸ R ⁹ ; C1-C6 haloalkyl; C1-C6 alkoxy; C1-C6 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; CO2C3-C8 cycloalkyl; OCOC1-C6 alkyl; OCOC6-C10 aryl; OCO(5- to 10-membered heteroaryl); OCO(3- to 7-membered heterocycloalkyl); C6-C10 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 ; and S(O ₂ )C ₁ -C ₆ alkyl. In some embodiments of the compound of formula AA, the substituted ring A is

and R ¹ is selected from:

1-hydroxy-2-methylpropan-2-yl; methyl; isopropyl; 2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl; 2-hydroxyethyl; 1-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl; 1- hydroxy-1-cyclobutyl; 1-hydroxy-1-cyclopentyl; 1-hydroxy-1-cyclohexyl; morpholinyl; 1,3-dioxolan-2-yl; COCH3; COCH2CH3; 2-methoxy-2-propyl; (dimethylamino)methyl; 1-(dimethylamino)ethyl; fluoro; chloro; phenyl; pyridyl; pyrazolyl; and S(O2)CH3. In some embodiments of the compound of formula AA, the substituted ring A is

and R ¹ is selected from:

C1-C6 alkyl optionally substituted with one or more hydroxy; C3-C7 cycloalkyl optionally substituted with one or more hydroxy; 3- to 7-membered heterocycloalkyl optionally substituted with one or more hydroxy; C ₁ -C ₆ alkyl substituted with one or more oxo; C ₃ - C7 cycloalkyl substituted with one or more oxo; C1-C6 alkyl substituted with one or more C1-C6 alkoxy; C3-C7 cycloalkyl substituted with one or more C1-C6 alkoxy; C1-C6 alkyl substituted with one or more NR ⁸ R ⁹ ; 3- to 7-membered heterocycloalkyl substituted with one or more NR ⁸ R ⁹ ; C1-C6 haloalkyl; C1-C6 alkoxy; C1-C6 haloalkoxy; halo; CN; NO2; COC1-C6 alkyl; CO-C6-C10 aryl; CO(5- to 10-membered heteroaryl); CO2C1-C6 alkyl; CO2C3-C8 cycloalkyl; OCOC1-C6 alkyl; OCOC6-C10 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 ; and S(O ₂ )C ₁ -C ₆ alkyl. In some embodiments of the compound of formula AA, the substituted ring A is

and R ¹ is selected from:

1-hydroxy-2-methylpropan-2-yl; methyl; isopropyl; 2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl; 2-hydroxyethyl; 1-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl; 1- hydroxy-1-cyclobutyl; 1-hydroxy-1-cyclopentyl; 1-hydroxy-1-cyclohexyl; morpholinyl; 1,3-dioxolan-2-yl; COCH3; COCH2CH3; 2-methoxy-2-propyl; (dimethylamino)methyl; 1-(dimethylamino)ethyl; fluoro; chloro; phenyl; pyridyl; pyrazolyl; and S(O ₂ )CH ₃ . In some embodiments of the compound of formula AA,

the substituted ring A is

and R ¹ is selected from:

C ₁ -C ₆ alkyl optionally substituted with one or more hydroxy; C ₃ -C ₇ cycloalkyl optionally substituted with one or more hydroxy; 3- to 7-membered heterocycloalkyl optionally substituted with one or more hydroxy; C ₁ -C ₆ alkyl substituted with one or more oxo; C ₃ - C ₇ cycloalkyl substituted with one or more oxo; C ₁ -C ₆ alkyl substituted with one or more C1-C6 alkoxy; C3-C7 cycloalkyl substituted with one or more C1-C6 alkoxy; C1-C6 alkyl substituted with one or more NR ⁸ R ⁹ ; 3- to 7-membered heterocycloalkyl substituted with one or more NR ⁸ R ⁹ ; C ₁ -C ₆ haloalkyl; C ₁ -C ₆ alkoxy; C ₁ -C ₆ haloalkoxy; halo; CN; NO ₂ ; COC1-C6 alkyl; CO-C6-C10 aryl; CO(5- to 10-membered heteroaryl); CO2C1-C6 alkyl; CO2C3-C8 cycloalkyl; OCOC1-C6 alkyl; OCOC6-C10 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 ; and S(O ₂ )C ₁ -C ₆ alkyl. In some embodiments of the compound of formula AA, the substituted ring A is

and R ¹ is selected from:

1-hydroxy-2-methylpropan-2-yl; methyl; isopropyl; 2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl; 2-hydroxyethyl; 1-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl; 1- hydroxy-1-cyclobutyl; 1-hydroxy-1-cyclopentyl; 1-hydroxy-1-cyclohexyl; morpholinyl; 1,3-dioxolan-2-yl; COCH ₃ ; COCH ₂ CH ₃ ; 2-methoxy-2-propyl; (dimethylamino)methyl; 1-(dimethylamino)ethyl; fluoro; chloro; phenyl; pyridyl; pyrazolyl; and S(O ₂ )CH ₃ . In some embodiments of the compound of formula AA, the substituted ring A is

and R ¹ is selected from:

C ₁ -C ₆ alkyl optionally substituted with one or more hydroxy; C ₃ -C ₇ cycloalkyl optionally substituted with one or more hydroxy; 3- to 7-membered heterocycloalkyl optionally substituted with one or more hydroxy; C1-C6 alkyl substituted with one or more oxo; C3- C ₇ cycloalkyl substituted with one or more oxo; C ₁ -C ₆ alkyl substituted with one or more C ₁ -C ₆ alkoxy; C ₃ -C ₇ cycloalkyl substituted with one or more C ₁ -C ₆ alkoxy; C ₁ -C ₆ alkyl substituted with one or more NR ⁸ R ⁹ ; 3- to 7-membered heterocycloalkyl substituted with one or more NR ⁸ R ⁹ ; 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; CO2C3-C8 cycloalkyl; OCOC1-C6 alkyl; OCOC6-C10 aryl; OCO(5- to 10-membered heteroaryl); OCO(3- to 7-membered heterocycloalkyl); C6-C10 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 ; and S(O ₂ )C ₁ -C ₆ alkyl. In some embodiments of the compound of formula AA, the substituted ring A is

and R ¹ is selected from:

1-hydroxy-2-methylpropan-2-yl; methyl; isopropyl; 2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl; 2-hydroxyethyl; 1-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl; 1- hydroxy-1-cyclobutyl; 1-hydroxy-1-cyclopentyl; 1-hydroxy-1-cyclohexyl; morpholinyl; 1,3-dioxolan-2-yl; COCH ₃ ; COCH ₂ CH ₃ ; 2-methoxy-2-propyl; (dimethylamino)methyl; 1-(dimethylamino)ethyl; fluoro; chloro; phenyl; pyridyl; pyrazolyl; and S(O ₂ )CH ₃ . In some embodiments of the compound of formula AA, the substituted ring A is

and R ¹ is selected from:

C ₁ -C ₆ alkyl optionally substituted with one or more hydroxy; C ₃ -C ₇ cycloalkyl optionally substituted with one or more hydroxy; 3- to 7-membered heterocycloalkyl optionally substituted with one or more hydroxy; C1-C6 alkyl substituted with one or more oxo; C3- C ₇ cycloalkyl substituted with one or more oxo; C ₁ -C ₆ alkyl substituted with one or more C ₁ -C ₆ alkoxy; C ₃ -C ₇ cycloalkyl substituted with one or more C ₁ -C ₆ alkoxy; C ₁ -C ₆ alkyl substituted with one or more NR ⁸ R ⁹ ; 3- to 7-membered heterocycloalkyl substituted with one or more NR ⁸ R ⁹ ; C1-C6 haloalkyl; C1-C6 alkoxy; C1-C6 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; CO2C3-C8 cycloalkyl; OCOC1-C6 alkyl; OCOC6-C10 aryl; OCO(5- to 10-membered heteroaryl); OCO(3- to 7-membered heterocycloalkyl); C6-C10 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 ; and S(O ₂ )C ₁ -C ₆ alkyl. In some embodiments of the compound of formula AA, the substituted ring A is

and R ¹ is selected from:

1-hydroxy-2-methylpropan-2-yl; methyl; isopropyl; 2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl; 2-hydroxyethyl; 1-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl; 1- hydroxy-1-cyclobutyl; 1-hydroxy-1-cyclopentyl; 1-hydroxy-1-cyclohexyl; morpholinyl; 1,3-dioxolan-2-yl; COCH3; COCH2CH3; 2-methoxy-2-propyl; (dimethylamino)methyl; 1-(dimethylamino)ethyl; fluoro; chloro; phenyl; pyridyl; pyrazolyl; and S(O2)CH3. In some embodiments of the compound of formula AA, the substituted ring A is

and R ¹ is selected from:

C1-C6 alkyl optionally substituted with one or more hydroxy; C3-C7 cycloalkyl optionally substituted with one or more hydroxy; 3- to 7-membered heterocycloalkyl optionally substituted with one or more hydroxy; C ₁ -C ₆ alkyl substituted with one or more oxo; C ₃ - C7 cycloalkyl substituted with one or more oxo; C1-C6 alkyl substituted with one or more C1-C6 alkoxy; C3-C7 cycloalkyl substituted with one or more C1-C6 alkoxy; C1-C6 alkyl substituted with one or more NR ⁸ R ⁹ ; 3- to 7-membered heterocycloalkyl substituted with one or more NR ⁸ R ⁹ ; C1-C6 haloalkyl; C1-C6 alkoxy; C1-C6 haloalkoxy; halo; CN; NO2; COC1-C6 alkyl; CO-C6-C10 aryl; CO(5- to 10-membered heteroaryl); CO2C1-C6 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; NHC1-C6 alkyl; N(C1-C6 alkyl)2; CONR ⁸ R ⁹ ; SF5; and S(O2)C1-C6 alkyl. In some embodiments of the compound of formula AA, the substituted ring A is

and R ¹ is selected from:

1-hydroxy-2-methylpropan-2-yl; methyl; isopropyl; 2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl; 2-hydroxyethyl; 1-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl; 1- hydroxy-1-cyclobutyl; 1-hydroxy-1-cyclopentyl; 1-hydroxy-1-cyclohexyl; morpholinyl; 1,3-dioxolan-2-yl; COCH ₃ ; COCH ₂ CH ₃ ; 2-methoxy-2-propyl; (dimethylamino)methyl; 1-(dimethylamino)ethyl; fluoro; chloro; phenyl; pyridyl; pyrazolyl; and S(O ₂ )CH ₃ . In some embodiments of the compound of formula AA,

the substituted ring A is

and R ¹ is selected from:

C ₁ -C ₆ alkyl optionally substituted with one or more hydroxy; C ₃ -C ₇ cycloalkyl optionally substituted with one or more hydroxy; 3- to 7-membered heterocycloalkyl optionally substituted with one or more hydroxy; C1-C6 alkyl substituted with one or more oxo; C3- C ₇ cycloalkyl substituted with one or more oxo; C ₁ -C ₆ alkyl substituted with one or more C ₁ -C ₆ alkoxy; C ₃ -C ₇ cycloalkyl substituted with one or more C ₁ -C ₆ alkoxy; C ₁ -C ₆ alkyl substituted with one or more NR ⁸ R ⁹ ; 3- to 7-membered heterocycloalkyl substituted with one or more NR ⁸ R ⁹ ; C1-C6 haloalkyl; C1-C6 alkoxy; C1-C6 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; CO2C3-C8 cycloalkyl; OCOC1-C6 alkyl; OCOC6-C10 aryl; OCO(5- to 10-membered heteroaryl); OCO(3- to 7-membered heterocycloalkyl); C6-C10 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 ; and S(O ₂ )C ₁ -C ₆ alkyl. In some embodiments of the compound of formula AA,

the substituted ring A is

and R ¹ is selected from:

1-hydroxy-2-methylpropan-2-yl; methyl; isopropyl; 2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl; 2-hydroxyethyl; 1-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl; 1- hydroxy-1-cyclobutyl; 1-hydroxy-1-cyclopentyl; 1-hydroxy-1-cyclohexyl; morpholinyl; 1,3-dioxolan-2-yl; COCH3; COCH2CH3; 2-methoxy-2-propyl; (dimethylamino)methyl; 1-(dimethylamino)ethyl; fluoro; chloro; phenyl; pyridyl; pyrazolyl; and S(O2)CH3. In some embodiments of the compound of formula AA,

the substituted ring A is

and R ¹ is selected from:

C1-C6 alkyl optionally substituted with one or more hydroxy; C3-C7 cycloalkyl optionally substituted with one or more hydroxy; 3- to 7-membered heterocycloalkyl optionally substituted with one or more hydroxy; C ₁ -C ₆ alkyl substituted with one or more oxo; C ₃ - C7 cycloalkyl substituted with one or more oxo; C1-C6 alkyl substituted with one or more C1-C6 alkoxy; C3-C7 cycloalkyl substituted with one or more C1-C6 alkoxy; C1-C6 alkyl substituted with one or more NR ⁸ R ⁹ ; 3- to 7-membered heterocycloalkyl substituted with one or more NR ⁸ R ⁹ ; C1-C6 haloalkyl; C1-C6 alkoxy; C1-C6 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); C6-C10 aryl; 5- to 10-membered heteroaryl; NH2; NHC1-C6 alkyl; N(C1-C6 alkyl)2; CONR ⁸ R ⁹ ; SF5; and S(O2)C1-C6 alkyl. In some embodiments of the compound of formula AA,

the substituted ring

and R ¹ is selected from:

1-hydroxy-2-methylpropan-2-yl; methyl; isopropyl; 2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl; 2-hydroxyethyl; 1-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl; 1- hydroxy-1-cyclobutyl; 1-hydroxy-1-cyclopentyl; 1-hydroxy-1-cyclohexyl; morpholinyl; 1,3-dioxolan-2-yl; COCH3; COCH2CH3; 2-methoxy-2-propyl; (dimethylamino)methyl; 1-(dimethylamino)ethyl; fluoro; chloro; phenyl; pyridyl; pyrazolyl; and S(O2)CH3. In some embodiments of the compound of formula AA,

the substituted ring

and R ¹ is selected from:

C1-C6 alkyl optionally substituted with one or more hydroxy; C3-C7 cycloalkyl optionally substituted with one or more hydroxy; 3- to 7-membered heterocycloalkyl optionally substituted with one or more hydroxy; C ₁ -C ₆ alkyl substituted with one or more oxo; C ₃ - C ₇ cycloalkyl substituted with one or more oxo; C ₁ -C ₆ alkyl substituted with one or more C1-C6 alkoxy; C3-C7 cycloalkyl substituted with one or more C1-C6 alkoxy; C1-C6 alkyl substituted with one or more NR ⁸ R ⁹ ; 3- to 7-membered heterocycloalkyl substituted with one or more NR ⁸ R ⁹ ; C ₁ -C ₆ haloalkyl; C ₁ -C ₆ alkoxy; C ₁ -C ₆ haloalkoxy; halo; CN; NO ₂ ; COC1-C6 alkyl; CO-C6-C10 aryl; CO(5- to 10-membered heteroaryl); CO2C1-C6 alkyl; CO2C3-C8 cycloalkyl; OCOC1-C6 alkyl; OCOC6-C10 aryl; OCO(5- to 10-membered heteroaryl); OCO(3- to 7-membered heterocycloalkyl); C6-C10 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 ; and S(O ₂ )C ₁ -C ₆ alkyl. In some embodiments of the compound of formula AA,

the substituted ring A is

and R ¹ is selected from:

1-hydroxy-2-methylpropan-2-yl; methyl; isopropyl; 2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl; 2-hydroxyethyl; 1-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl; 1- hydroxy-1-cyclobutyl; 1-hydroxy-1-cyclopentyl; 1-hydroxy-1-cyclohexyl; morpholinyl; 1,3-dioxolan-2-yl; COCH ₃ ; COCH ₂ CH ₃ ; 2-methoxy-2-propyl; (dimethylamino)methyl; 1-(dimethylamino)ethyl; fluoro; chloro; phenyl; pyridyl; pyrazolyl; and S(O2)CH3. In some embodiments of the compound of formula AA,

the substituted ring A is

and R ¹ is selected from:

C ₁ -C ₆ alkyl optionally substituted with one or more hydroxy; C ₃ -C ₇ cycloalkyl optionally substituted with one or more hydroxy; 3- to 7-membered heterocycloalkyl optionally substituted with one or more hydroxy; C1-C6 alkyl substituted with one or more oxo; C3- C7 cycloalkyl substituted with one or more oxo; C1-C6 alkyl substituted with one or more C ₁ -C ₆ alkoxy; C ₃ -C ₇ cycloalkyl substituted with one or more C ₁ -C ₆ alkoxy; C ₁ -C ₆ alkyl substituted with one or more NR ⁸ R ⁹ ; 3- to 7-membered heterocycloalkyl substituted with one or more NR ⁸ R ⁹ ; C1-C6 haloalkyl; C1-C6 alkoxy; C1-C6 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); C6-C10 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 ; and S(O ₂ )C ₁ -C ₆ alkyl. In some embodiments of the compound of formula AA, the substituted ring A is

and R ¹ is selected from:

1-hydroxy-2-methylpropan-2-yl; methyl; isopropyl; 2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl; 2-hydroxyethyl; 1-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl; 1- hydroxy-1-cyclobutyl; 1-hydroxy-1-cyclopentyl; 1-hydroxy-1-cyclohexyl; morpholinyl; 1,3-dioxolan-2-yl; COCH ₃ ; COCH ₂ CH ₃ ; 2-methoxy-2-propyl; (dimethylamino)methyl; 1-(dimethylamino)ethyl; fluoro; chloro; phenyl; pyridyl; pyrazolyl; and S(O ₂ )CH ₃ .

the substituted ring A is

and R ¹ is selected from:

C ₁ -C ₆ alkyl optionally substituted with one or more hydroxy; C ₃ -C ₇ cycloalkyl optionally substituted with one or more hydroxy; 3- to 7-membered heterocycloalkyl optionally substituted with one or more hydroxy; C ₁ -C ₆ alkyl substituted with one or more oxo; C ₃ - C ₇ cycloalkyl substituted with one or more oxo; C ₁ -C ₆ alkyl substituted with one or more C1-C6 alkoxy; C3-C7 cycloalkyl substituted with one or more C1-C6 alkoxy; C1-C6 alkyl substituted with one or more NR ⁸ R ⁹ ; 3- to 7-membered heterocycloalkyl substituted with one or more NR ⁸ R ⁹ ; C ₁ -C ₆ haloalkyl; C ₁ -C ₆ alkoxy; C ₁ -C ₆ haloalkoxy; halo; CN; NO ₂ ; COC1-C6 alkyl; CO-C6-C10 aryl; CO(5- to 10-membered heteroaryl); CO2C1-C6 alkyl; CO2C3-C8 cycloalkyl; OCOC1-C6 alkyl; OCOC6-C10 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 ; and S(O ₂ )C ₁ -C ₆ alkyl. In some embodiments of the compound of formula AA,

the substituted ring A is

and R ¹ is selected from:

1-hydroxy-2-methylpropan-2-yl; methyl; isopropyl; 2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl; 2-hydroxyethyl; 1-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl; 1- hydroxy-1-cyclobutyl; 1-hydroxy-1-cyclopentyl; 1-hydroxy-1-cyclohexyl; morpholinyl; 1,3-dioxolan-2-yl; COCH3; COCH2CH3; 2-methoxy-2-propyl; (dimethylamino)methyl; 1-(dimethylamino)ethyl; fluoro; chloro; phenyl; pyridyl; pyrazolyl; and S(O2)CH3. In some embodiments of the compound of formula AA,

the substituted ring A is

and R ¹ is selected from:

C ₁ -C ₆ alkyl optionally substituted with one or more hydroxy; C ₃ -C ₇ cycloalkyl optionally substituted with one or more hydroxy; 3- to 7-membered heterocycloalkyl optionally substituted with one or more hydroxy; C1-C6 alkyl substituted with one or more oxo; C3- C ₇ cycloalkyl substituted with one or more oxo; C ₁ -C ₆ alkyl substituted with one or more C1-C6 alkoxy; C3-C7 cycloalkyl substituted with one or more C1-C6 alkoxy; C1-C6 alkyl substituted with one or more NR ⁸ R ⁹ ; 3- to 7-membered heterocycloalkyl substituted with one or more NR ⁸ R ⁹ ; 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; CO2C3-C8 cycloalkyl; OCOC1-C6 alkyl; OCOC6-C10 aryl; OCO(5- to 10-membered heteroaryl); OCO(3- to 7-membered heterocycloalkyl); C6-C10 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 ; and S(O ₂ )C ₁ -C ₆ alkyl. In some embodiments of the compound of formula AA,

the substituted ring A is

and R ¹ is selected from:

1-hydroxy-2-methylpropan-2-yl; methyl; isopropyl; 2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl; 2-hydroxyethyl; 1-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl; 1- hydroxy-1-cyclobutyl; 1-hydroxy-1-cyclopentyl; 1-hydroxy-1-cyclohexyl; morpholinyl; 1,3-dioxolan-2-yl; COCH3; COCH2CH3; 2-methoxy-2-propyl; (dimethylamino)methyl; 1-(dimethylamino)ethyl; fluoro; chloro; phenyl; pyridyl; pyrazolyl; and S(O ₂ )CH ₃ . In some embodiments of the compound of formula AA,

the substituted ring A is

and R ¹ is selected from:

C ₁ -C ₆ alkyl optionally substituted with one or more hydroxy; C ₃ -C ₇ cycloalkyl optionally substituted with one or more hydroxy; 3- to 7-membered heterocycloalkyl optionally substituted with one or more hydroxy; C1-C6 alkyl substituted with one or more oxo; C3- C ₇ cycloalkyl substituted with one or more oxo; C ₁ -C ₆ alkyl substituted with one or more C1-C6 alkoxy; C3-C7 cycloalkyl substituted with one or more C1-C6 alkoxy; C1-C6 alkyl substituted with one or more NR ⁸ R ⁹ ; 3- to 7-membered heterocycloalkyl substituted with one or more NR ⁸ R ⁹ ; C ₁ -C ₆ haloalkyl; C ₁ -C ₆ alkoxy; C ₁ -C ₆ haloalkoxy; halo; CN; NO ₂ ; COC1-C6 alkyl; CO-C6-C10 aryl; CO(5- to 10-membered heteroaryl); CO2C1-C6 alkyl; CO2C3-C8 cycloalkyl; OCOC1-C6 alkyl; OCOC6-C10 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 ; and S(O ₂ )C ₁ -C ₆ alkyl. In some embodiments of the compound of formula AA,

the substituted ring A is

and R ¹ is selected from:

1-hydroxy-2-methylpropan-2-yl; methyl; isopropyl; 2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl; 2-hydroxyethyl; 1-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl; 1- hydroxy-1-cyclobutyl; 1-hydroxy-1-cyclopentyl; 1-hydroxy-1-cyclohexyl; morpholinyl; 1,3-dioxolan-2-yl; COCH ₃ ; COCH ₂ CH ₃ ; 2-methoxy-2-propyl; (dimethylamino)methyl; 1-(dimethylamino)ethyl; fluoro; chloro; phenyl; pyridyl; pyrazolyl; and S(O2)CH3. In some embodiments of the compound of formula AA, the substituted ring A is

and R ¹ is selected from:

C1-C6 alkyl optionally substituted with one or more hydroxy; C3-C7 cycloalkyl optionally substituted with one or more hydroxy; 3- to 7-membered heterocycloalkyl optionally substituted with one or more hydroxy; C ₁ -C ₆ alkyl substituted with one or more oxo; C ₃ - C7 cycloalkyl substituted with one or more oxo; C1-C6 alkyl substituted with one or more C1-C6 alkoxy; C3-C7 cycloalkyl substituted with one or more C1-C6 alkoxy; C1-C6 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 - C6 alkyl; OCOC6-C10 aryl; OCO(5- to 10-membered heteroaryl); OCO(3- to 7-membered heterocycloalkyl); C6-C10 aryl; 5- to 10-membered heteroaryl; NH2; NHC1-C6 alkyl; N(C ₁ -C ₆ alkyl) ₂ ; CONR ⁸ R ⁹ ; SF ₅ ; C ₁ -C ₆ alkyl substituted with one or more NR ⁸ R ⁹ ; and S(O2)C1-C6 alkyl.

the substituted ring A is

and R ¹ is selected from:

1-hydroxy-2-methylpropan-2-yl; methyl; isopropyl; 2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl; 2-hydroxyethyl; 1-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl; 1- hydroxy-1-cyclobutyl; 1-hydroxy-1-cyclopentyl; 1-hydroxy-1-cyclohexyl; morpholinyl; (dimethylamino)methyl; 1,3-dioxolan-2-yl; COCH3; COCH2CH3; 2-methoxy-2-propyl; fluoro; chloro; phenyl; pyridyl; pyrazolyl; and S(O ₂ )CH ₃ .

the substituted ring A is

and R ¹ is selected from:

C1-C6 alkyl optionally substituted with one or more hydroxy; C3-C7 cycloalkyl optionally substituted with one or more hydroxy; 3- to 7-membered heterocycloalkyl optionally substituted with one or more hydroxy; C ₁ -C ₆ alkyl substituted with one or more oxo; C ₃ - C7 cycloalkyl substituted with one or more oxo; C1-C6 alkyl substituted with one or more C ₁ -C ₆ alkoxy; C ₃ -C ₇ cycloalkyl substituted with one or more C ₁ -C ₆ alkoxy; 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); CO2C1-C6 alkyl; CO2C3-C8 cycloalkyl; OCOC1- C6 alkyl; OCOC6-C10 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(C1-C6 alkyl)2; CONR ⁸ R ⁹ ; SF5; C1-C6 alkyl substituted with one or more NR ⁸ R ⁹ ; and S(O2)C1-C6 alkyl.

the substituted ring A is

and R ¹ is selected from:

1-hydroxy-2-methylpropan-2-yl; methyl; isopropyl; 2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl; 2-hydroxyethyl; 1-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl; 1- hydroxy-1-cyclobutyl; 1-hydroxy-1-cyclopentyl; 1-hydroxy-1-cyclohexyl; morpholinyl; 1,3-dioxolan-2-yl; COCH3; COCH2CH3; 2-methoxy-2-propyl; fluoro; chloro; phenyl; pyridyl; pyrazolyl; (dimethylamino)methyl; and S(O ₂ )CH ₃ . In some embodiments of the compound of formula AA,

the substituted ring A is

and R ¹ and R ² are one of the following combinations:

R ¹ is C1-C6 alkyl optionally substituted with one or more hydroxy, and R ² is C1-C6 alkyl optionally substituted with one or more hydroxy;

R ¹ is C ₁ -C ₆ alkyl optionally substituted with one or more hydroxy, and R ² is C ₆ -C ₁₀ aryl; R ¹ is C1-C6 alkyl optionally substituted with one or more hydroxy, and R ² is 5- to 10- membered heteroaryl;

R ¹ is C ₁ -C ₆ alkyl optionally substituted with one or more hydroxy, and R ² is SF ₅ ;

R ¹ is C1-C6 alkyl optionally substituted with one or more hydroxy, and R ² is S(O2)C1-C6 alkyl; R ¹ is C1-C6 alkyl optionally substituted with one or more hydroxy, and R ² is halo;

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

R ¹ is 3- to 7-membered heterocycloalkyl optionally substituted with one or more hydroxy, and R ² is C1-C6 alkyl;

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

R ¹ is C1-C6 alkyl optionally substituted with one or more oxo, and R ² is methyl;

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;

R ¹ is C1-C6 alkyl optionally substituted with one or more NR ⁸ R ⁹ , and R ² is C1-C6 alkyl; R ¹ is C ₁ -C ₆ alkyl optionally substituted with one or more NR ⁸ R ⁹ , and R ² is halo;

R ² is C ₁ -C ₆ alkyl optionally substituted with one or more hydroxy, and R ¹ is C ₆ -C ₁₀ aryl; R ² is C1-C6 alkyl optionally substituted with one or more hydroxy, and R ¹ is 5- to 10- membered heteroaryl;

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

R ² is C1-C6 alkyl optionally substituted with one or more hydroxy, and R ¹ is S(O2)C1-C6 alkyl;

R ² is C ₁ -C ₆ alkyl optionally substituted with one or more hydroxy, and R ¹ is halo;

R ² is C3-C7 cycloalkyl optionally substituted with one or more hydroxy, and R ¹ is C1-C6 alkyl;

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

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

R ² is C ₁ -C ₆ alkyl optionally substituted with one or more oxo, and R ¹ is methyl;

R ² is C1-C6 alkyl optionally substituted with one or more C1-C6 alkoxy, and R ¹ is C1-C6 alkyl;

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; R ² is C1-C6 alkyl optionally substituted with one or more NR ⁸ R ⁹ , and R ¹ is halo. In some embodiments of the compound of formula AA,

and R ¹ and R ² are one of the following combinations:

R ¹ is 1-hydroxy-2-methylpropan-2-yl, and R ² is methyl; R ¹ is 2-hydroxy-2-propyl and R ² is methyl;

R ¹ is 2-hydroxy-2-propyl and R ² is isopropyl;

R ¹ is 2-hydroxy-2-propyl and R ² is 2-hydroxy-2-propyl; R ¹ is 2-hydroxy-2-propyl and R ² is 1-hydroxyethyl; R ¹ is hydroxymethyl and R ² is methyl;

R ¹ is 1-hydroxyethyl and R ² is methyl;

R ¹ is 2-hydroxyethyl and R ² is methyl;

R ¹ is 1-hydroxy-2-propyl and R ² is methyl;

R ¹ is 2-hydroxy-2-propyl and R ² is phenyl;

R ¹ is 2-hydroxy-2-propyl and R ² is pyridyl;

R ¹ is 2-hydroxy-2-propyl and R ² is pyrazolyl;

R ¹ is 2-hydroxy-2-propyl, and R ² is S(O ₂ )CH ₃ ;

R ¹ is 2-hydroxy-2-propyl and R ² is chloro;

R ¹ is 2-hydroxy-2-propyl and R ² is fluoro;

R ¹ is 1-hydroxy-1-cyclopropyl, and R ² is methyl;

R ¹ is 1-hydroxy-1-cyclobutyl, and R ² is methyl;

R ¹ is 1-hydroxy-1-cyclopentyl, and R ² is methyl;

R ¹ is 1-hydroxy-1-cyclohexyl, and R ² is methyl;

R ¹ is morpholinyl, and R ² is methyl;

R ¹ is 1,3-dioxolan-2-yl, and R ² is methyl;

R ¹ is 1,3-dioxolan-2-yl, and R ² is fluoro;

R ¹ is 1,3-dioxolan-2-yl, and R ² is chloro;

R ¹ is COCH3, and R ² is methyl;

R ¹ is 2-methoxy-2-propyl, and R ² is methyl; R ² is (dimethylamino)methyl, and R ¹ is methyl.

R ² is 1-hydroxy-2-methylpropan-2-yl, and R ¹ is methyl;

R ² is 2-hydroxy-2-propyl and R ¹ is methyl;

R ² is 2-hydroxy-2-propyl and R ¹ is isopropyl;

R ² is 2-hydroxy-2-propyl and R ¹ is 1-hydroxyethyl;

R ² is hydroxymethyl and R ¹ is methyl;

R ² is 1-hydroxyethyl and R ¹ is methyl;

R ² is 2-hydroxyethyl and R ¹ is methyl;

R ² is 1-hydroxy-2-propyl and R ¹ is methyl;

R ² is 2-hydroxy-2-propyl and R ¹ is phenyl;

R ² is C1-C6 alkyl optionally substituted with one or more hydroxy, and R ¹ is 5- to 10- membered heteroaryl;

R ² is 2-hydroxy-2-propyl and R ¹ is pyridyl;

R ² is 2-hydroxy-2-propyl and R ¹ is pyrazolyl;

R ² is C1-C6 alkyl optionally substituted with one or more hydroxy, and R ¹ is S(O2)CH3; R ² is 2-hydroxy-2-propyl and R ¹ is chloro;

R ² is 2-hydroxy-2-propyl and R ¹ is fluoro;

R ² is C3-C7 cycloalkyl optionally substituted with one or more hydroxy, and R ¹ is C1-C6 alkyl;

R ² is 1-hydroxy-1-cyclopropyl, and R ¹ is methyl;

R ² is 1-hydroxy-1-cyclobutyl, and R ¹ is methyl;

R ² is 1-hydroxy-1-cyclopentyl, and R ¹ is methyl;

R ² is 1-hydroxy-1-cyclohexyl, and R ¹ is methyl;

R ² is morpholinyl, and R ¹ is methyl;

R ² is 1,3-dioxolan-2-yl, and R ¹ is methyl;

R ² is 1,3-dioxolan-2-yl, and R ¹ is fluoro;

R ² is 1,3-dioxolan-2-yl, and R ¹ is chloro;

R ² is C1-C6 alkyl optionally substituted with one or more oxo, and R ¹ is methyl;

R ² is COCH ₃ , and R ¹ is methyl; or

R ² is 2-methoxy-2-propyl, and R ¹ is methyl. In some embodiments, of the compound of formula AA,

the substituted ring

and R ¹ and R ² are one of the following combinations:

R ¹ is C1-C6 alkyl optionally substituted with one or more hydroxy, and R ² is C1-C6 alkyl optionally substituted with one or more hydroxy;

R ¹ is C ₁ -C ₆ alkyl optionally substituted with one or more hydroxy, and R ² is C ₆ -C ₁₀ aryl; R ¹ is C ₁ -C ₆ alkyl optionally substituted with one or more hydroxy, and R ² is 5- to 10- membered heteroaryl;

R ¹ is C1-C6 alkyl optionally substituted with one or more hydroxy, and R ² is SF5;

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;

R ¹ is C1-C6 alkyl optionally substituted with one or more hydroxy, and R ² is halo;

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

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

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

R ¹ is C1-C6 alkyl optionally substituted with one or more oxo, and R ² is methyl;

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;

R ¹ is C1-C6 alkyl optionally substituted with one or more NR ⁸ R ⁹ , and R ² is C1-C6 alkyl; R ¹ is C ₁ -C ₆ alkyl optionally substituted with one or more NR ⁸ R ⁹ , and R ² is halo;

R ² is C1-C6 alkyl optionally substituted with one or more hydroxy, and R ¹ is C6-C10 aryl; R ² is C1-C6 alkyl optionally substituted with one or more hydroxy, and R ¹ is 5- to 10- membered heteroaryl;

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

R ² is C1-C6 alkyl optionally substituted with one or more hydroxy, and R ¹ is S(O2)C1-C6 alkyl; R ² is C1-C6 alkyl optionally substituted with one or more hydroxy, and R ¹ is halo; R ² is C ₃ -C ₇ cycloalkyl optionally substituted with one or more hydroxy, and R ¹ is C ₁ -C ₆ alkyl;

R ² is 3- to 7-membered heterocycloalkyl optionally substituted with one or more hydroxy, and R ¹ is C1-C6 alkyl;

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

R ² is C1-C6 alkyl optionally substituted with one or more oxo, and R ¹ is methyl;

or

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. R ² is C1-C6 alkyl optionally substituted with one or more NR ⁸ R ⁹ , and R ¹ is C1-C6 alkyl;

or

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, of the compound of formula AA,

and R ¹ and R ² are one of the following combinations:

R ¹ is 1-hydroxy-2-methylpropan-2-yl, and R ² is methyl;

R ¹ is 2-hydroxy-2-propyl and R ² is methyl;

R ¹ is 2-hydroxy-2-propyl and R ² is isopropyl;

R ¹ is 2-hydroxy-2-propyl and R ² is 2-hydroxy-2-propyl;

R ¹ is 2-hydroxy-2-propyl and R ² is 1-hydroxyethyl;

R ¹ is hydroxymethyl and R ² is methyl;

R ¹ is 1-hydroxyethyl and R ² is methyl;

R ¹ is 2-hydroxyethyl and R ² is methyl;

R ¹ is 1-hydroxy-2-propyl and R ² is methyl;

R ¹ is 2-hydroxy-2-propyl and R ² is phenyl;

R ¹ is 2-hydroxy-2-propyl and R ² is pyridyl;

R ¹ is 2-hydroxy-2-propyl and R ² is pyrazolyl; R ¹ is 2-hydroxy-2-propyl, and R ² is S(O2)CH3;

R ¹ is 2-hydroxy-2-propyl and R ² is chloro;

R ¹ is 2-hydroxy-2-propyl and R ² is fluoro;

R ¹ is 1-hydroxy-1-cyclopropyl, and R ² is methyl;

R ¹ is 1-hydroxy-1-cyclobutyl, and R ² is methyl;

R ¹ is 1-hydroxy-1-cyclopentyl, and R ² is methyl;

R ¹ is 1-hydroxy-1-cyclohexyl, and R ² is methyl;

R ¹ is morpholinyl, and R ² is methyl;

R ¹ is 1,3-dioxolan-2-yl, and R ² is methyl;

R ¹ is 1,3-dioxolan-2-yl, and R ² is fluoro;

R ¹ is 1,3-dioxolan-2-yl, and R ² is chloro;

R ¹ is COCH ₃ , and R ² is methyl;

R ¹ is 2-methoxy-2-propyl, and R ² is methyl;

R ¹ is (dimethylamino)methyl, and R ² is methyl.

R ² is 1-hydroxy-2-methylpropan-2-yl, and R ¹ is methyl;

R ² is 2-hydroxy-2-propyl and R ¹ is methyl;

R ² is 2-hydroxy-2-propyl and R ¹ is isopropyl;

R ² is 2-hydroxy-2-propyl and R ¹ is 1-hydroxyethyl;

R ² is hydroxymethyl and R ¹ is methyl;

R ² is 1-hydroxyethyl and R ¹ is methyl;

R ² is 2-hydroxyethyl and R ¹ is methyl;

R ² is 1-hydroxy-2-propyl and R ¹ is methyl;

R ² is 2-hydroxy-2-propyl and R ¹ is phenyl;

R ² is C1-C6 alkyl optionally substituted with one or more hydroxy, and R ¹ is 5- to 10- membered heteroaryl;

R ² is 2-hydroxy-2-propyl and R ¹ is pyridyl;

R ² is 2-hydroxy-2-propyl and R ¹ is pyrazolyl;

R ² is C1-C6 alkyl optionally substituted with one or more hydroxy, and R ¹ is S(O2)CH3; R ² is 2-hydroxy-2-propyl and R ¹ is chloro;

R ² is 2-hydroxy-2-propyl and R ¹ is fluoro; R ² is C3-C7 cycloalkyl optionally substituted with one or more hydroxy, and R ¹ is C1-C6 alkyl;

R ² is 1-hydroxy-1-cyclopropyl, and R ¹ is methyl;

R ² is 1-hydroxy-1-cyclobutyl, and R ¹ is methyl;

R ² is 1-hydroxy-1-cyclopentyl, and R ¹ is methyl;

R ² is 1-hydroxy-1-cyclohexyl, and R ¹ is methyl;

R ² is morpholinyl, and R ¹ is methyl;

R ² is 1,3-dioxolan-2-yl, and R ¹ is methyl;

R ² is 1,3-dioxolan-2-yl, and R ¹ is fluoro;

R ² is 1,3-dioxolan-2-yl, and R ¹ is chloro;

R ² is C1-C6 alkyl optionally substituted with one or more oxo, and R ¹ is methyl;

R ² is (dimethylamino)methyl, and R ¹ is methyl;

R ² is COCH ₃ , and R ¹ is methyl; or

R ² is 2-methoxy-2-propyl, and R ¹ is methyl.

In some embodiments, of the compound of formula AA,

the substituted ring

and R ¹ and R ² are one of the following combinations:

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;

R ¹ is C1-C6 alkyl optionally substituted with one or more hydroxy, and R ² is C6-C10 aryl; R ¹ is C ₁ -C ₆ alkyl optionally substituted with one or more hydroxy, and R ² is 5- to 10- membered heteroaryl;

R ¹ is C1-C6 alkyl optionally substituted with one or more hydroxy, and R ² is SF5;

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;

R ¹ is C1-C6 alkyl optionally substituted with one or more hydroxy, and R ² is halo; R ¹ is C3-C7 cycloalkyl optionally substituted with one or more hydroxy, and R ² is C1-C6 alkyl;

R ¹ is 3- to 7-membered heterocycloalkyl optionally substituted with one or more hydroxy, and R ² is C1-C6 alkyl;

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

R ¹ is C1-C6 alkyl optionally substituted with one or more oxo, and R ² is methyl;

R ¹ is C1-C6 alkyl optionally substituted with one or more C1-C6 alkoxy, and R ² is C1-C6 alkyl;

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;

R ¹ is C1-C6 alkyl optionally substituted with one or more NR ⁸ R ⁹ , and R ² is halo;

R ² is C ₁ -C ₆ alkyl optionally substituted with one or more hydroxy, and R ¹ is C ₆ -C ₁₀ aryl; R ² is C ₁ -C ₆ alkyl optionally substituted with one or more hydroxy, and R ¹ is 5- to 10- membered heteroaryl;

R ² is C1-C6 alkyl optionally substituted with one or more hydroxy, and R ¹ is SF5.

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

R ² is C1-C6 alkyl optionally substituted with one or more hydroxy, and R ¹ is halo;

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

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

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

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;

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

R ² is C1-C6 alkyl optionally substituted with one or more oxo, and R ¹ is methyl; or

R ² is C1-C6 alkyl optionally substituted with one or more C1-C6 alkoxy, and R ¹ is C1-C6 alkyl. In some embodiments, of the compound of formula AA, the substituted ring

and R ¹ and R ² are one of the following combinations:

R ¹ is 1-hydroxy-2-methylpropan-2-yl, and R ² is methyl; R ¹ is 2-hydroxy-2-propyl and R ² is methyl;

R ¹ is 2-hydroxy-2-propyl and R ² is isopropyl;

R ¹ is 2-hydroxy-2-propyl and R ² is 2-hydroxy-2-propyl; R ¹ is 2-hydroxy-2-propyl and R ² is 1-hydroxyethyl; R ¹ is hydroxymethyl and R ² is methyl;

R ¹ is 1-hydroxyethyl and R ² is methyl;

R ¹ is 2-hydroxyethyl and R ² is methyl;

R ¹ is 1-hydroxy-2-propyl and R ² is methyl;

R ¹ is 2-hydroxy-2-propyl and R ² is phenyl;

R ¹ is 2-hydroxy-2-propyl and R ² is pyridyl;

R ¹ is 2-hydroxy-2-propyl and R ² is pyrazolyl;

R ¹ is 2-hydroxy-2-propyl, and R ² is S(O2)CH3;

R ¹ is 2-hydroxy-2-propyl and R ² is chloro;

R ¹ is 2-hydroxy-2-propyl and R ² is fluoro;

R ¹ is 1-hydroxy-1-cyclopropyl, and R ² is methyl;

R ¹ is 1-hydroxy-1-cyclobutyl, and R ² is methyl;

R ¹ is 1-hydroxy-1-cyclopentyl, and R ² is methyl;

R ¹ is 1-hydroxy-1-cyclohexyl, and R ² is methyl;

R ¹ is morpholinyl, and R ² is methyl;

R ¹ is 1,3-dioxolan-2-yl, and R ² is methyl;

R ¹ is 1,3-dioxolan-2-yl, and R ² is fluoro;

R ¹ is 1,3-dioxolan-2-yl, and R ² is chloro;

R ¹ is COCH ²

3, and R is methyl;

R ¹ is 2-methoxy-2-propyl, and R ² is methyl;

R ¹ is (dimethylamino)methyl, and R ² is methyl;

R ² is 1-hydroxy-2-methylpropan-2-yl, and R ¹ is methyl; R ² is 2-hydroxy-2-propyl and R ¹ is methyl;

R ² is 2-hydroxy-2-propyl and R ¹ is isopropyl;

R ² is 2-hydroxy-2-propyl and R ¹ is 1-hydroxyethyl;

R ² is hydroxymethyl and R ¹ is methyl;

R ² is 1-hydroxyethyl and R ¹ is methyl;

R ² is 2-hydroxyethyl and R ¹ is methyl;

R ² is 1-hydroxy-2-propyl and R ¹ is methyl;

R ² is 2-hydroxy-2-propyl and R ¹ is phenyl;

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

R ² is 2-hydroxy-2-propyl and R ¹ is pyridyl;

R ² is 2-hydroxy-2-propyl and R ¹ is pyrazolyl;

R ² is C ₁ -C ₆ alkyl optionally substituted with one or more hydroxy, and R ¹ is S(O ₂ )CH ₃ ; R ² is 2-hydroxy-2-propyl and R ¹ is chloro;

R ² is 2-hydroxy-2-propyl and R ¹ is fluoro;

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

R ² is 1-hydroxy-1-cyclopropyl, and R ¹ is methyl;

R ² is 1-hydroxy-1-cyclobutyl, and R ¹ is methyl;

R ² is 1-hydroxy-1-cyclopentyl, and R ¹ is methyl;

R ² is 1-hydroxy-1-cyclohexyl, and R ¹ is methyl;

R ² is morpholinyl, and R ¹ is methyl;

R ² is 1,3-dioxolan-2-yl, and R ¹ is methyl;

R ² is 1,3-dioxolan-2-yl, and R ¹ is fluoro;

R ² is 1,3-dioxolan-2-yl, and R ¹ is chloro;

R ² is C ₁ -C ₆ alkyl optionally substituted with one or more oxo, and R ¹ is methyl;

R ² is (dimethylamino)methyl, and R ¹ is methyl;

R ² is COCH3, and R ¹ is methyl; or

R ² is 2-methoxy-2-propyl, and R ¹ is methyl.

`

In some embodiments, of the compound of formula AA, the substituted ring

and R ¹ and R ² are one of the following combinations:

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;

R ¹ is C1-C6 alkyl optionally substituted with one or more hydroxy, and R ² is C6-C10 aryl; R ¹ is C ₁ -C ₆ alkyl optionally substituted with one or more hydroxy, and R ² is 5- to 10- membered heteroaryl;

R ¹ is C1-C6 alkyl optionally substituted with one or more hydroxy, and R ² is SF5;

R ¹ is C1-C6 alkyl optionally substituted with one or more hydroxy, and R ² is S(O2)C1-C6 alkyl;

R ¹ is C1-C6 alkyl optionally substituted with one or more hydroxy, and R ² is halo;

R ¹ is C3-C7 cycloalkyl optionally substituted with one or more hydroxy, and R ² is C1-C6 alkyl;

R ¹ is 3- to 7-membered heterocycloalkyl optionally substituted with one or more hydroxy, and R ² is C1-C6 alkyl;

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

R ¹ is C1-C6 alkyl optionally substituted with one or more oxo, and R ² is methyl;

R ¹ is C1-C6 alkyl optionally substituted with one or more C1-C6 alkoxy, and R ² is C1-C6 alkyl;

R ¹ is C1-C6 alkyl optionally substituted with one or more NR ⁸ R ⁹ , and R ² is C1-C6 alkyl; R ¹ is C1-C6 alkyl optionally substituted with one or more NR ⁸ R ⁹ , and R ² is halo;

R ² is C ₁ -C ₆ alkyl optionally substituted with one or more hydroxy, and R ¹ is C ₆ -C ₁₀ aryl; R ² is C1-C6 alkyl optionally substituted with one or more hydroxy, and R ¹ is 5- to 10- membered heteroaryl;

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

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

R ² is C ₁ -C ₆ alkyl optionally substituted with one or more hydroxy, and R ¹ is halo; R ² is C3-C7 cycloalkyl optionally substituted with one or more hydroxy, and R ¹ is C1-C6 alkyl;

R ² is 3- to 7-membered heterocycloalkyl optionally substituted with one or more hydroxy, and R ¹ is C1-C6 alkyl;

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

R ² is C1-C6 alkyl optionally substituted with one or more NR ⁸ R ⁹ , and R ¹ is C1-C6 alkyl;

R ² is C1-C6 alkyl optionally substituted with one or more NR ⁸ R ⁹ , and R ¹ is halo;

R ² is C ₁ -C ₆ alkyl optionally substituted with one or more oxo, and R ¹ is methyl; or

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, of the compound of formula AA,

the substituted ring

and R ¹ and R ² are one of the following combinations:

R ¹ is 1-hydroxy-2-methylpropan-2-yl, and R ² is methyl;

R ¹ is 2-hydroxy-2-propyl and R ² is methyl;

R ¹ is 2-hydroxy-2-propyl and R ² is isopropyl;

R ¹ is 2-hydroxy-2-propyl and R ² is 2-hydroxy-2-propyl;

R ¹ is 2-hydroxy-2-propyl and R ² is 1-hydroxyethyl;

R ¹ is hydroxymethyl and R ² is methyl;

R ¹ is 1-hydroxyethyl and R ² is methyl;

R ¹ is 2-hydroxyethyl and R ² is methyl;

R ¹ is 1-hydroxy-2-propyl and R ² is methyl;

R ¹ is 2-hydroxy-2-propyl and R ² is phenyl;

R ¹ is 2-hydroxy-2-propyl and R ² is pyridyl;

R ¹ is 2-hydroxy-2-propyl and R ² is pyrazolyl;

R ¹ is 2-hydroxy-2-propyl, and R ² is S(O ₂ )CH ₃ ;

R ¹ is 2-hydroxy-2-propyl and R ² is chloro;

R ¹ is 2-hydroxy-2-propyl and R ² is fluoro; R ¹ is 1-hydroxy-1-cyclopropyl, and R ² is methyl;

R ¹ is 1-hydroxy-1-cyclobutyl, and R ² is methyl;

R ¹ is 1-hydroxy-1-cyclopentyl, and R ² is methyl;

R ¹ is 1-hydroxy-1-cyclohexyl, and R ² is methyl;

R ¹ is morpholinyl, and R ² is methyl;

R ¹ is 1,3-dioxolan-2-yl, and R ² is methyl;

R ¹ is 1,3-dioxolan-2-yl, and R ² is fluoro;

R ¹ is 1,3-dioxolan-2-yl, and R ² is chloro;

R ¹ is COCH ₃ , and R ² is methyl;

R ¹ is 2-methoxy-2-propyl, and R ² is methyl;

R ¹ is (dimethylamino)methyl, and R ² is methyl.

R ² is 1-hydroxy-2-methylpropan-2-yl, and R ¹ is methyl;

R ² is 2-hydroxy-2-propyl and R ¹ is methyl;

R ² is 2-hydroxy-2-propyl and R ¹ is isopropyl;

R ² is 2-hydroxy-2-propyl and R ¹ is 1-hydroxyethyl;

R ² is hydroxymethyl and R ¹ is methyl;

R ² is 1-hydroxyethyl and R ¹ is methyl;

R ² is 2-hydroxyethyl and R ¹ is methyl;

R ² is 1-hydroxy-2-propyl and R ¹ is methyl;

R ² is 2-hydroxy-2-propyl and R ¹ is phenyl;

R ² is C1-C6 alkyl optionally substituted with one or more hydroxy, and R ¹ is 5- to 10- membered heteroaryl;

R ² is 2-hydroxy-2-propyl and R ¹ is pyridyl;

R ² is 2-hydroxy-2-propyl and R ¹ is pyrazolyl;

R ² is C ₁ -C ₆ alkyl optionally substituted with one or more hydroxy, and R ¹ is S(O ₂ )CH ₃ ; R ² is 2-hydroxy-2-propyl and R ¹ is chloro;

R ² is 2-hydroxy-2-propyl and R ¹ is fluoro;

R ² is C3-C7 cycloalkyl optionally substituted with one or more hydroxy, and R ¹ is C1-C6 alkyl;

R ² is 1-hydroxy-1-cyclopropyl, and R ¹ is methyl;

R ² is 1-hydroxy-1-cyclobutyl, and R ¹ is methyl; R ² is 1-hydroxy-1-cyclopentyl, and R ¹ is methyl;

R ² is 1-hydroxy-1-cyclohexyl, and R ¹ is methyl;

R ² is morpholinyl, and R ¹ is methyl;

R ² is 1,3-dioxolan-2-yl, and R ¹ is methyl;

R ² is 1,3-dioxolan-2-yl, and R ¹ is fluoro;

R ² is 1,3-dioxolan-2-yl, and R ¹ is chloro;

R ² is C1-C6 alkyl optionally substituted with one or more oxo, and R ¹ is methyl;

R ² is (dimethylamino)methyl, and R ¹ is methyl;

R ² is COCH ₃ , and R ¹ is methyl; or

R ² is 2-methoxy-2-propyl, and R ¹ is methyl. In some embodiments, of the compound of formula AA,

the substituted ring

and R ¹ and R ² are one of the following combinations:

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;

R ¹ is C1-C6 alkyl optionally substituted with one or more hydroxy, and R ² is C6-C10 aryl; R ¹ is C ₁ -C ₆ alkyl optionally substituted with one or more hydroxy, and R ² is 5- to 10- membered heteroaryl;

R ¹ is C1-C6 alkyl optionally substituted with one or more hydroxy, and R ² is SF5;

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;

R ¹ is C1-C6 alkyl optionally substituted with one or more hydroxy, and R ² is halo;

R ¹ is C3-C7 cycloalkyl optionally substituted with one or more hydroxy, and R ² is C1-C6 alkyl;

R ¹ is 3- to 7-membered heterocycloalkyl optionally substituted with one or more hydroxy, and R ² is C1-C6 alkyl;

R ¹ is 3- to 7-membered heterocycloalkyl optionally substituted with one or more hydroxy, and R ² is halo; R ¹ is C1-C6 alkyl optionally substituted with one or more oxo, and R ² is methyl; 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;

R ¹ is C1-C6 alkyl optionally substituted with one or more NR ⁸ R ⁹ , and R ² is C1-C6 alkyl;

R ¹ is C1-C6 alkyl optionally substituted with one or more NR ⁸ R ⁹ , and R ² is halo;

R ² is C ₁ -C ₆ alkyl optionally substituted with one or more hydroxy, and R ¹ is C ₆ -C ₁₀ aryl; R ² is C1-C6 alkyl optionally substituted with one or more hydroxy, and R ¹ is 5- to 10- membered heteroaryl;

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

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

R ² is C ₁ -C ₆ alkyl optionally substituted with one or more hydroxy, and R ¹ is halo;

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

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

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

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;

R ² is C1-C6 alkyl optionally substituted with one or more NR ⁸ R ⁹ , and R ¹ is halo;

R ² is C1-C6 alkyl optionally substituted with one or more oxo, and R ¹ is methyl; or

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, of the compound of formula AA,

the substituted ring

and R ¹ and R ² are one of the following combinations:

R ¹ is 1-hydroxy-2-methylpropan-2-yl, and R ² is methyl;

R ¹ is 2-hydroxy-2-propyl and R ² is methyl;

R ¹ is 2-hydroxy-2-propyl and R ² is isopropyl; R ¹ is 2-hydroxy-2-propyl and R ² is 2-hydroxy-2-propyl; R ¹ is 2-hydroxy-2-propyl and R ² is 1-hydroxyethyl; R ¹ is hydroxymethyl and R ² is methyl;

R ¹ is 1-hydroxyethyl and R ² is methyl;

R ¹ is 2-hydroxyethyl and R ² is methyl;

R ¹ is 1-hydroxy-2-propyl and R ² is methyl;

R ¹ is 2-hydroxy-2-propyl and R ² is phenyl;

R ¹ is 2-hydroxy-2-propyl and R ² is pyridyl;

R ¹ is 2-hydroxy-2-propyl and R ² is pyrazolyl;

R ¹ is 2-hydroxy-2-propyl, and R ² is S(O ₂ )CH ₃ ;

R ¹ is 2-hydroxy-2-propyl and R ² is chloro;

R ¹ is 2-hydroxy-2-propyl and R ² is fluoro;

R ¹ is 1-hydroxy-1-cyclopropyl, and R ² is methyl;

R ¹ is 1-hydroxy-1-cyclobutyl, and R ² is methyl;

R ¹ is 1-hydroxy-1-cyclopentyl, and R ² is methyl;

R ¹ is 1-hydroxy-1-cyclohexyl, and R ² is methyl;

R ¹ is morpholinyl, and R ² is methyl;

R ¹ is 1,3-dioxolan-2-yl, and R ² is methyl;

R ¹ is 1,3-dioxolan-2-yl, and R ² is fluoro;

R ¹ is 1,3-dioxolan-2-yl, and R ² is chloro;

R ¹ is COCH3, and R ² is methyl;

R ¹ is 2-methoxy-2-propyl, and R ² is methyl;

R ¹ is (dimethylamino)methyl, and R ² is methyl.

R ² is 1-hydroxy-2-methylpropan-2-yl, and R ¹ is methyl; R ² is 2-hydroxy-2-propyl and R ¹ is methyl;

R ² is 2-hydroxy-2-propyl and R ¹ is isopropyl;

R ² is 2-hydroxy-2-propyl and R ¹ is 1-hydroxyethyl; R ² is hydroxymethyl and R ¹ is methyl;

R ² is 1-hydroxyethyl and R ¹ is methyl;

R ² is 2-hydroxyethyl and R ¹ is methyl;

R ² is 1-hydroxy-2-propyl and R ¹ is methyl; R ² is 2-hydroxy-2-propyl and R ¹ is phenyl;

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

R ² is 2-hydroxy-2-propyl and R ¹ is pyridyl;

R ² is 2-hydroxy-2-propyl and R ¹ is pyrazolyl;

R ² is C ₁ -C ₆ alkyl optionally substituted with one or more hydroxy, and R ¹ is S(O ₂ )CH ₃ ; R ² is 2-hydroxy-2-propyl and R ¹ is chloro;

R ² is 2-hydroxy-2-propyl and R ¹ is fluoro;

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

R ² is 1-hydroxy-1-cyclopropyl, and R ¹ is methyl;

R ² is 1-hydroxy-1-cyclobutyl, and R ¹ is methyl;

R ² is 1-hydroxy-1-cyclopentyl, and R ¹ is methyl;

R ² is 1-hydroxy-1-cyclohexyl, and R ¹ is methyl;

R ² is morpholinyl, and R ¹ is methyl;

R ² is 1,3-dioxolan-2-yl, and R ¹ is methyl;

R ² is 1,3-dioxolan-2-yl, and R ¹ is fluoro;

R ² is 1,3-dioxolan-2-yl, and R ¹ is chloro;

R ² is C ₁ -C ₆ alkyl optionally substituted with one or more oxo, and R ¹ is methyl;

R ² is (dimethylamino)methyl, and R ¹ is methyl;

R ² is COCH3, and R ¹ is methyl; or

R ² is 2-methoxy-2-propyl, and R ¹ is methyl. In some embodiments, of the compound of formula AA,

the substituted ring

and R ¹ and R ² are one of the following combinations:

R ¹ is C1-C6 alkyl optionally substituted with one or more hydroxy, and R ² is C1-C6 alkyl optionally substituted with one or more hydroxy;

R ¹ is C1-C6 alkyl optionally substituted with one or more hydroxy, and R ² is C6-C10 aryl; R ¹ is C1-C6 alkyl optionally substituted with one or more hydroxy, and R ² is 5- to 10- membered heteroaryl;

R ¹ is C ₁ -C ₆ alkyl optionally substituted with one or more hydroxy, and R ² is SF ₅ ;

R ¹ is C1-C6 alkyl optionally substituted with one or more hydroxy, and R ² is S(O2)C1-C6 alkyl;

R ¹ is C ₁ -C ₆ alkyl optionally substituted with one or more hydroxy, and R ² is halo;

R ¹ is C3-C7 cycloalkyl optionally substituted with one or more hydroxy, and R ² is C1-C6 alkyl;

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

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

R ¹ is C ₁ -C ₆ alkyl optionally substituted with one or more oxo, and R ² is methyl;

R ¹ is C1-C6 alkyl optionally substituted with one or more C1-C6 alkoxy, and R ² is C1-C6 alkyl;

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; R ¹ is C1-C6 alkyl optionally substituted with one or more NR ⁸ R ⁹ , and R ² is halo;

R ² is C1-C6 alkyl optionally substituted with one or more hydroxy, and R ¹ is C6-C10 aryl; R ² is C ₁ -C ₆ alkyl optionally substituted with one or more hydroxy, and R ¹ is 5- to 10- membered heteroaryl;

R ² is C1-C6 alkyl optionally substituted with one or more hydroxy, and R ¹ is SF5.

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

R ² is C1-C6 alkyl optionally substituted with one or more hydroxy, and R ¹ is halo;

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

R ² is 3- to 7-membered heterocycloalkyl optionally substituted with one or more hydroxy, and R ¹ is C1-C6 alkyl;

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

R ² is C1-C6 alkyl optionally substituted with one or more NR ⁸ R ⁹ , and R ¹ is C1-C6 alkyl; R ² is C1-C6 alkyl optionally substituted with one or more NR ⁸ R ⁹ , and R ¹ is halo; R ² is C ₁ -C ₆ alkyl optionally substituted with one or more oxo, and R ¹ is methyl; or

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, of the compound of formula AA,

the substituted ring

and R ¹ and R ² are one of the following combinations:

R ¹ is 1-hydroxy-2-methylpropan-2-yl, and R ² is methyl;

R ¹ is 2-hydroxy-2-propyl and R ² is methyl;

R ¹ is 2-hydroxy-2-propyl and R ² is isopropyl;

R ¹ is 2-hydroxy-2-propyl and R ² is 2-hydroxy-2-propyl;

R ¹ is 2-hydroxy-2-propyl and R ² is 1-hydroxyethyl;

R ¹ is hydroxymethyl and R ² is methyl;

R ¹ is 1-hydroxyethyl and R ² is methyl;

R ¹ is 2-hydroxyethyl and R ² is methyl;

R ¹ is 1-hydroxy-2-propyl and R ² is methyl;

R ¹ is 2-hydroxy-2-propyl and R ² is phenyl;

R ¹ is 2-hydroxy-2-propyl and R ² is pyridyl;

R ¹ is 2-hydroxy-2-propyl and R ² is pyrazolyl;

R ¹ is 2-hydroxy-2-propyl, and R ² is S(O2)CH3;

R ¹ is 2-hydroxy-2-propyl and R ² is chloro;

R ¹ is 2-hydroxy-2-propyl and R ² is fluoro;

R ¹ is 1-hydroxy-1-cyclopropyl, and R ² is methyl;

R ¹ is 1-hydroxy-1-cyclobutyl, and R ² is methyl;

R ¹ is 1-hydroxy-1-cyclopentyl, and R ² is methyl;

R ¹ is 1-hydroxy-1-cyclohexyl, and R ² is methyl;

R ¹ is morpholinyl, and R ² is methyl;

R ¹ is 1,3-dioxolan-2-yl, and R ² is methyl;

R ¹ is 1,3-dioxolan-2-yl, and R ² is fluoro; R ¹ is 1,3-dioxolan-2-yl, and R ² is chloro;

R ¹ is COCH ₃ , and R ² is methyl;

R ¹ is 2-methoxy-2-propyl, and R ² is methyl;

R ¹ is (dimethylamino)methyl, and R ² is methyl.

R ² is 1-hydroxy-2-methylpropan-2-yl, and R ¹ is methyl;

R ² is 2-hydroxy-2-propyl and R ¹ is methyl;

R ² is 2-hydroxy-2-propyl and R ¹ is isopropyl;

R ² is 2-hydroxy-2-propyl and R ¹ is 1-hydroxyethyl;

R ² is hydroxymethyl and R ¹ is methyl;

R ² is 1-hydroxyethyl and R ¹ is methyl;

R ² is 2-hydroxyethyl and R ¹ is methyl;

R ² is 1-hydroxy-2-propyl and R ¹ is methyl;

R ² is 2-hydroxy-2-propyl and R ¹ is phenyl;

R ² is C1-C6 alkyl optionally substituted with one or more hydroxy, and R ¹ is 5- to 10- membered heteroaryl;

R ² is 2-hydroxy-2-propyl and R ¹ is pyridyl;

R ² is 2-hydroxy-2-propyl and R ¹ is pyrazolyl;

R ² is C1-C6 alkyl optionally substituted with one or more hydroxy, and R ¹ is

S(O ₂ )CH ₃ ;

R ² is 2-hydroxy-2-propyl and R ¹ is chloro;

R ² is 2-hydroxy-2-propyl and R ¹ is fluoro;

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

R ² is 1-hydroxy-1-cyclopropyl, and R ¹ is methyl;

R ² is 1-hydroxy-1-cyclobutyl, and R ¹ is methyl;

R ² is 1-hydroxy-1-cyclopentyl, and R ¹ is methyl;

R ² is 1-hydroxy-1-cyclohexyl, and R ¹ is methyl;

R ² is morpholinyl, and R ¹ is methyl;

R ² is 1,3-dioxolan-2-yl, and R ¹ is methyl;

R ² is 1,3-dioxolan-2-yl, and R ¹ is fluoro;

R ² is 1,3-dioxolan-2-yl, and R ¹ is chloro; R ² is C1-C6 alkyl optionally substituted with one or more oxo, and R ¹ is methyl; R ² is (dimethylamino)methyl, and R ¹ is methyl;

R ² is COCH ₃ , and R ¹ is methyl; or

R ² is 2-methoxy-2-propyl, and R ¹ is methyl. In some embodiments, of the compound of formula AA,

the substituted ring

and R ¹ and R ² are one of the following combinations:

R ¹ is C1-C6 alkyl optionally substituted with one or more hydroxy, and R ² is C1-C6 alkyl optionally substituted with one or more hydroxy;

R ¹ is C1-C6 alkyl optionally substituted with one or more hydroxy, and R ² is C6-C10 aryl; R ¹ is C1-C6 alkyl optionally substituted with one or more hydroxy, and R ² is 5- to 10- membered heteroaryl;

R ¹ is C1-C6 alkyl optionally substituted with one or more hydroxy, and R ² is SF5;

R ¹ is C1-C6 alkyl optionally substituted with one or more hydroxy, and R ² is S(O2)C1-C6 alkyl;

R ¹ is C ₁ -C ₆ alkyl optionally substituted with one or more hydroxy, and R ² is halo;

R ¹ is C3-C7 cycloalkyl optionally substituted with one or more hydroxy, and R ² is C1-C6 alkyl;

R ¹ is 3- to 7-membered heterocycloalkyl optionally substituted with one or more hydroxy, and R ² is C1-C6 alkyl;

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

R ¹ is C1-C6 alkyl optionally substituted with one or more oxo, and R ² is methyl;

R ¹ is C1-C6 alkyl optionally substituted with one or more C1-C6 alkoxy, and R ² is C1-C6 alkyl;

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; R ¹ is C1-C6 alkyl optionally substituted with one or more NR ⁸ R ⁹ , and R ² is halo;

R ² is C ₁ -C ₆ alkyl optionally substituted with one or more hydroxy, and R ¹ is C ₆ -C ₁₀ aryl; R ² is C1-C6 alkyl optionally substituted with one or more hydroxy, and R ¹ is 5- to 10- membered heteroaryl;

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

R ² is C1-C6 alkyl optionally substituted with one or more hydroxy, and R ¹ is S(O2)C1-C6 alkyl;

R ² is C ₁ -C ₆ alkyl optionally substituted with one or more hydroxy, and R ¹ is halo;

R ² is C3-C7 cycloalkyl optionally substituted with one or more hydroxy, and R ¹ is C1-C6 alkyl;

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

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

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;

R ² is C1-C6 alkyl optionally substituted with one or more NR ⁸ R ⁹ , and R ¹ is halo;

R ² is C1-C6 alkyl optionally substituted with one or more oxo, and R ¹ is methyl; or

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, of the compound of formula AA,

and R ¹ and R ² are one of the following combinations:

R ¹ is 1-hydroxy-2-methylpropan-2-yl, and R ² is methyl;

R ¹ is 2-hydroxy-2-propyl and R ² is methyl;

R ¹ is 2-hydroxy-2-propyl and R ² is isopropyl;

R ¹ is 2-hydroxy-2-propyl and R ² is 2-hydroxy-2-propyl;

R ¹ is 2-hydroxy-2-propyl and R ² is 1-hydroxyethyl;

R ¹ is hydroxymethyl and R ² is methyl;

R ¹ is 1-hydroxyethyl and R ² is methyl;

R ¹ is 2-hydroxyethyl and R ² is methyl;

R ¹ is 1-hydroxy-2-propyl and R ² is methyl; R ¹ is 2-hydroxy-2-propyl and R ² is phenyl;

R ¹ is 2-hydroxy-2-propyl and R ² is pyridyl;

R ¹ is 2-hydroxy-2-propyl and R ² is pyrazolyl;

R ¹ is 2-hydroxy-2-propyl, and R ² is S(O2)CH3;

R ¹ is 2-hydroxy-2-propyl and R ² is chloro;

R ¹ is 2-hydroxy-2-propyl and R ² is fluoro;

R ¹ is 1-hydroxy-1-cyclopropyl, and R ² is methyl;

R ¹ is 1-hydroxy-1-cyclobutyl, and R ² is methyl;

R ¹ is 1-hydroxy-1-cyclopentyl, and R ² is methyl;

R ¹ is 1-hydroxy-1-cyclohexyl, and R ² is methyl;

R ¹ is morpholinyl, and R ² is methyl;

R ¹ is 1,3-dioxolan-2-yl, and R ² is methyl;

R ¹ is 1,3-dioxolan-2-yl, and R ² is fluoro;

R ¹ is 1,3-dioxolan-2-yl, and R ² is chloro;

R ¹ is COCH3, and R ² is methyl;

R ¹ is 2-methoxy-2-propyl, and R ² is methyl;

R ¹ is (dimethylamino)methyl, and R ² is methyl.

R ² is 1-hydroxy-2-methylpropan-2-yl, and R ¹ is methyl;

R ² is 2-hydroxy-2-propyl and R ¹ is methyl;

R ² is 2-hydroxy-2-propyl and R ¹ is isopropyl;

R ² is 2-hydroxy-2-propyl and R ¹ is 1-hydroxyethyl;

R ² is hydroxymethyl and R ¹ is methyl;

R ² is 1-hydroxyethyl and R ¹ is methyl;

R ² is 2-hydroxyethyl and R ¹ is methyl;

R ² is 1-hydroxy-2-propyl and R ¹ is methyl;

R ² is 2-hydroxy-2-propyl and R ¹ is phenyl;

R ² is C1-C6 alkyl optionally substituted with one or more hydroxy, and R ¹ is 5- to 10- membered heteroaryl;

R ² is 2-hydroxy-2-propyl and R ¹ is pyridyl;

R ² is 2-hydroxy-2-propyl and R ¹ is pyrazolyl;

R ² is C1-C6 alkyl optionally substituted with one or more hydroxy, and R ¹ is S(O2)CH3; R ² is 2-hydroxy-2-propyl and R ¹ is chloro;

R ² is 2-hydroxy-2-propyl and R ¹ is fluoro;

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

R ² is 1-hydroxy-1-cyclopropyl, and R ¹ is methyl;

R ² is 1-hydroxy-1-cyclobutyl, and R ¹ is methyl;

R ² is 1-hydroxy-1-cyclopentyl, and R ¹ is methyl;

R ² is 1-hydroxy-1-cyclohexyl, and R ¹ is methyl;

R ² is morpholinyl, and R ¹ is methyl;

R ² is 1,3-dioxolan-2-yl, and R ¹ is methyl;

R ² is 1,3-dioxolan-2-yl, and R ¹ is fluoro;

R ² is 1,3-dioxolan-2-yl, and R ¹ is chloro;

R ² is C ₁ -C ₆ alkyl optionally substituted with one or more oxo, and R ¹ is methyl;

R ² is (dimethylamino)methyl, and R ¹ is methyl;

R ² is COCH3, and R ¹ is methyl; or

R ² is 2-methoxy-2-propyl, and R ¹ is methyl. In some embodiments, of the compound of formula AA,

and R ¹ and R ² are one of the following combinations:

R ¹ is C1-C6 alkyl optionally substituted with one or more hydroxy, and R ² is C1-C6 alkyl optionally substituted with one or more hydroxy;

R ¹ is C ₁ -C ₆ alkyl optionally substituted with one or more hydroxy, and R ² is C ₆ -C ₁₀ aryl; R ¹ is C1-C6 alkyl optionally substituted with one or more hydroxy, and R ² is 5- to 10- membered heteroaryl;

R ¹ is C ₁ -C ₆ alkyl optionally substituted with one or more hydroxy, and R ² is SF ₅ ;

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;

R ¹ is C ₁ -C ₆ alkyl optionally substituted with one or more hydroxy, and R ² is halo; R ¹ is C3-C7 cycloalkyl optionally substituted with one or more hydroxy, and R ² is C1-C6 alkyl;

R ¹ is 3- to 7-membered heterocycloalkyl optionally substituted with one or more hydroxy, and R ² is C1-C6 alkyl;

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

R ¹ is C1-C6 alkyl optionally substituted with one or more oxo, and R ² is methyl;

R ¹ is C1-C6 alkyl optionally substituted with one or more C1-C6 alkoxy, and R ² is C1-C6 alkyl;

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;

R ¹ is C1-C6 alkyl optionally substituted with one or more NR ⁸ R ⁹ , and R ² is halo;

R ² is C ₁ -C ₆ alkyl optionally substituted with one or more hydroxy, and R ¹ is C ₆ -C ₁₀ aryl; R ² is C ₁ -C ₆ alkyl optionally substituted with one or more hydroxy, and R ¹ is 5- to 10- membered heteroaryl;

R ² is C1-C6 alkyl optionally substituted with one or more hydroxy, and R ¹ is SF5.

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

R ² is C1-C6 alkyl optionally substituted with one or more hydroxy, and R ¹ is halo;

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

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

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

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;

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

R ² is C1-C6 alkyl optionally substituted with one or more oxo, and R ¹ is methyl; or

R ² is C1-C6 alkyl optionally substituted with one or more C1-C6 alkoxy, and R ¹ is C1-C6 alkyl. In some embodiments, of the compound of formula AA, the substituted ring

and R ¹ and R ² are one of the following combinations:

R ¹ is 1-hydroxy-2-methylpropan-2-yl, and R ² is methyl; R ¹ is 2-hydroxy-2-propyl and R ² is methyl;

R ¹ is 2-hydroxy-2-propyl and R ² is isopropyl;

R ¹ is 2-hydroxy-2-propyl and R ² is 2-hydroxy-2-propyl; R ¹ is 2-hydroxy-2-propyl and R ² is 1-hydroxyethyl; R ¹ is hydroxymethyl and R ² is methyl;

R ¹ is 1-hydroxyethyl and R ² is methyl;

R ¹ is 2-hydroxyethyl and R ² is methyl;

R ¹ is 1-hydroxy-2-propyl and R ² is methyl;

R ¹ is 2-hydroxy-2-propyl and R ² is phenyl;

R ¹ is 2-hydroxy-2-propyl and R ² is pyridyl;

R ¹ is 2-hydroxy-2-propyl and R ² is pyrazolyl;

R ¹ is 2-hydroxy-2-propyl, and R ² is S(O2)CH3;

R ¹ is 2-hydroxy-2-propyl and R ² is chloro;

R ¹ is 2-hydroxy-2-propyl and R ² is fluoro;

R ¹ is 1-hydroxy-1-cyclopropyl, and R ² is methyl;

R ¹ is 1-hydroxy-1-cyclobutyl, and R ² is methyl;

R ¹ is 1-hydroxy-1-cyclopentyl, and R ² is methyl;

R ¹ is 1-hydroxy-1-cyclohexyl, and R ² is methyl;

R ¹ is morpholinyl, and R ² is methyl;

R ¹ is 1,3-dioxolan-2-yl, and R ² is methyl;

R ¹ is 1,3-dioxolan-2-yl, and R ² is fluoro;

R ¹ is 1,3-dioxolan-2-yl, and R ² is chloro;

R ¹ is COCH ²

3, and R is methyl;

R ¹ is 2-methoxy-2-propyl, and R ² is methyl;

R ¹ is (dimethylamino)methyl, and R ² is methyl.

R ² is 1-hydroxy-2-methylpropan-2-yl, and R ¹ is methyl; R ² is 2-hydroxy-2-propyl and R ¹ is methyl;

R ² is 2-hydroxy-2-propyl and R ¹ is isopropyl;

R ² is 2-hydroxy-2-propyl and R ¹ is 1-hydroxyethyl;

R ² is hydroxymethyl and R ¹ is methyl;

R ² is 1-hydroxyethyl and R ¹ is methyl;

R ² is 2-hydroxyethyl and R ¹ is methyl;

R ² is 1-hydroxy-2-propyl and R ¹ is methyl;

R ² is 2-hydroxy-2-propyl and R ¹ is phenyl;

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

R ² is 2-hydroxy-2-propyl and R ¹ is pyridyl;

R ² is 2-hydroxy-2-propyl and R ¹ is pyrazolyl;

R ² is C ₁ -C ₆ alkyl optionally substituted with one or more hydroxy, and R ¹ is S(O ₂ )CH ₃ ; R ² is 2-hydroxy-2-propyl and R ¹ is chloro;

R ² is 2-hydroxy-2-propyl and R ¹ is fluoro;

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

R ² is 1-hydroxy-1-cyclopropyl, and R ¹ is methyl;

R ² is 1-hydroxy-1-cyclobutyl, and R ¹ is methyl;

R ² is 1-hydroxy-1-cyclopentyl, and R ¹ is methyl;

R ² is 1-hydroxy-1-cyclohexyl, and R ¹ is methyl;

R ² is morpholinyl, and R ¹ is methyl;

R ² is 1,3-dioxolan-2-yl, and R ¹ is methyl;

R ² is 1,3-dioxolan-2-yl, and R ¹ is fluoro;

R ² is 1,3-dioxolan-2-yl, and R ¹ is chloro;

R ² is C ₁ -C ₆ alkyl optionally substituted with one or more oxo, and R ¹ is methyl;

R ² is (dimethylamino)methyl, and R ¹ is methyl;

R ² is COCH3, and R ¹ is methyl; or

R ² is 2-methoxy-2-propyl, and R ¹ is methyl. In some embodiments, of the compound of formula AA, the substituted ring

and R ¹ and R ² are one of the following combinations:

R ¹ is 1-hydroxy-2-methylpropan-2-yl, and R ² is methyl; R ¹ is 2-hydroxy-2-propyl and R ² is methyl;

R ¹ is 2-hydroxy-2-propyl and R ² is isopropyl;

R ¹ is 2-hydroxy-2-propyl and R ² is 2-hydroxy-2-propyl; R ¹ is 2-hydroxy-2-propyl and R ² is 1-hydroxyethyl; R ¹ is hydroxymethyl and R ² is methyl;

R ¹ is 1-hydroxyethyl and R ² is methyl;

R ¹ is 2-hydroxyethyl and R ² is methyl;

R ¹ is 1-hydroxy-2-propyl and R ² is methyl;

R ¹ is 2-hydroxy-2-propyl and R ² is phenyl;

R ¹ is 2-hydroxy-2-propyl and R ² is pyridyl;

R ¹ is 2-hydroxy-2-propyl and R ² is pyrazolyl;

R ¹ is 2-hydroxy-2-propyl, and R ² is S(O2)CH3;

R ¹ is 2-hydroxy-2-propyl and R ² is chloro;

R ¹ is 2-hydroxy-2-propyl and R ² is fluoro;

R ¹ is 1-hydroxy-1-cyclopropyl, and R ² is methyl;

R ¹ is 1-hydroxy-1-cyclobutyl, and R ² is methyl;

R ¹ is 1-hydroxy-1-cyclopentyl, and R ² is methyl;

R ¹ is 1-hydroxy-1-cyclohexyl, and R ² is methyl;

R ¹ is morpholinyl, and R ² is methyl;

R ¹ is 1,3-dioxolan-2-yl, and R ² is methyl;

R ¹ is 1,3-dioxolan-2-yl, and R ² is fluoro;

R ¹ is 1,3-dioxolan-2-yl, and R ² is chloro;

R ¹ is COCH ²

3, and R is methyl;

R ¹ is 2-methoxy-2-propyl, and R ² is methyl;

R ¹ is (dimethylamino)methyl, and R ² is methyl.

R ² is 1-hydroxy-2-methylpropan-2-yl, and R ¹ is methyl; R ² is 2-hydroxy-2-propyl and R ¹ is methyl;

R ² is 2-hydroxy-2-propyl and R ¹ is isopropyl;

R ² is 2-hydroxy-2-propyl and R ¹ is 1-hydroxyethyl;

R ² is hydroxymethyl and R ¹ is methyl;

R ² is 1-hydroxyethyl and R ¹ is methyl;

R ² is 2-hydroxyethyl and R ¹ is methyl;

R ² is 1-hydroxy-2-propyl and R ¹ is methyl;

R ² is 2-hydroxy-2-propyl and R ¹ is phenyl;

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

R ² is 2-hydroxy-2-propyl and R ¹ is pyridyl;

R ² is 2-hydroxy-2-propyl and R ¹ is pyrazolyl;

R ² is C ₁ -C ₆ alkyl optionally substituted with one or more hydroxy, and R ¹ is S(O ₂ )CH ₃ ; R ² is 2-hydroxy-2-propyl and R ¹ is chloro;

R ² is 2-hydroxy-2-propyl and R ¹ is fluoro;

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

R ² is 1-hydroxy-1-cyclopropyl, and R ¹ is methyl;

R ² is 1-hydroxy-1-cyclobutyl, and R ¹ is methyl;

R ² is 1-hydroxy-1-cyclopentyl, and R ¹ is methyl;

R ² is 1-hydroxy-1-cyclohexyl, and R ¹ is methyl;

R ² is morpholinyl, and R ¹ is methyl;

R ² is 1,3-dioxolan-2-yl, and R ¹ is methyl;

R ² is 1,3-dioxolan-2-yl, and R ¹ is fluoro;

R ² is 1,3-dioxolan-2-yl, and R ¹ is chloro;

R ² is C ₁ -C ₆ alkyl optionally substituted with one or more oxo, and R ¹ is methyl;

R ² is (dimethylamino)methyl, and R ¹ is methyl;

R ² is COCH3, and R ¹ is methyl; or

R ² is 2-methoxy-2-propyl, and R ¹ is methyl. In some embodiments, of the compound of formula AA,

and R ¹ and R ² are one of the following combinations:

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;

R ¹ is C1-C6 alkyl optionally substituted with one or more hydroxy, and R ² is C6-C10 aryl; R ¹ is C ₁ -C ₆ alkyl optionally substituted with one or more hydroxy, and R ² is 5- to 10- membered heteroaryl;

R ¹ is C1-C6 alkyl optionally substituted with one or more hydroxy, and R ² is SF5;

R ¹ is C1-C6 alkyl optionally substituted with one or more hydroxy, and R ² is S(O2)C1-C6 alkyl;

R ¹ is C1-C6 alkyl optionally substituted with one or more hydroxy, and R ² is halo;

R ¹ is C3-C7 cycloalkyl optionally substituted with one or more hydroxy, and R ² is C1-C6 alkyl;

R ¹ is 3- to 7-membered heterocycloalkyl optionally substituted with one or more hydroxy, and R ² is C1-C6 alkyl;

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

R ¹ is C1-C6 alkyl optionally substituted with one or more oxo, and R ² is methyl;

R ¹ is C1-C6 alkyl optionally substituted with one or more C1-C6 alkoxy, and R ² is C1-C6 alkyl;

R ¹ is C1-C6 alkyl optionally substituted with one or more NR ⁸ R ⁹ , and R ² is C1-C6 alkyl; R ¹ is C1-C6 alkyl optionally substituted with one or more NR ⁸ R ⁹ , and R ² is halo;

R ² is C ₁ -C ₆ alkyl optionally substituted with one or more hydroxy, and R ¹ is C ₆ -C ₁₀ aryl; R ² is C1-C6 alkyl optionally substituted with one or more hydroxy, and R ¹ is 5- to 10- membered heteroaryl;

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

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

R ² is C ₁ -C ₆ alkyl optionally substituted with one or more hydroxy, and R ¹ is halo; R ² is C3-C7 cycloalkyl optionally substituted with one or more hydroxy, and R ¹ is C1-C6 alkyl;

R ² is 3- to 7-membered heterocycloalkyl optionally substituted with one or more hydroxy, and R ¹ is C1-C6 alkyl;

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

R ² is C1-C6 alkyl optionally substituted with one or more NR ⁸ R ⁹ , and R ¹ is C1-C6 alkyl;

R ² is C1-C6 alkyl optionally substituted with one or more NR ⁸ R ⁹ , and R ¹ is halo;

R ² is C ₁ -C ₆ alkyl optionally substituted with one or more oxo, and R ¹ is methyl; or

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, of the compound of formula AA,

and R ¹ and R ² are one of the following combinations:

R ¹ is 1-hydroxy-2-methylpropan-2-yl, and R ² is methyl;

R ¹ is 2-hydroxy-2-propyl and R ² is methyl;

R ¹ is 2-hydroxy-2-propyl and R ² is isopropyl;

R ¹ is 2-hydroxy-2-propyl and R ² is 2-hydroxy-2-propyl;

R ¹ is 2-hydroxy-2-propyl and R ² is 1-hydroxyethyl;

R ¹ is hydroxymethyl and R ² is methyl;

R ¹ is 1-hydroxyethyl and R ² is methyl;

R ¹ is 2-hydroxyethyl and R ² is methyl;

R ¹ is 1-hydroxy-2-propyl and R ² is methyl;

R ¹ is 2-hydroxy-2-propyl and R ² is phenyl;

R ¹ is 2-hydroxy-2-propyl and R ² is pyridyl;

R ¹ is 2-hydroxy-2-propyl and R ² is pyrazolyl;

R ¹ is 2-hydroxy-2-propyl, and R ² is S(O ₂ )CH ₃ ;

R ¹ is 2-hydroxy-2-propyl and R ² is chloro;

R ¹ is 2-hydroxy-2-propyl and R ² is fluoro; R ¹ is 1-hydroxy-1-cyclopropyl, and R ² is methyl;

R ¹ is 1-hydroxy-1-cyclobutyl, and R ² is methyl;

R ¹ is 1-hydroxy-1-cyclopentyl, and R ² is methyl;

R ¹ is 1-hydroxy-1-cyclohexyl, and R ² is methyl;

R ¹ is morpholinyl, and R ² is methyl;

R ¹ is 1,3-dioxolan-2-yl, and R ² is methyl;

R ¹ is 1,3-dioxolan-2-yl, and R ² is fluoro;

R ¹ is 1,3-dioxolan-2-yl, and R ² is chloro;

R ¹ is COCH ₃ , and R ² is methyl;

R ¹ is 2-methoxy-2-propyl, and R ² is methyl;

R ¹ is (dimethylamino)methyl, and R ² is methyl.

R ² is 1-hydroxy-2-methylpropan-2-yl, and R ¹ is methyl;

R ² is 2-hydroxy-2-propyl and R ¹ is methyl;

R ² is 2-hydroxy-2-propyl and R ¹ is isopropyl;

R ² is 2-hydroxy-2-propyl and R ¹ is 1-hydroxyethyl;

R ² is hydroxymethyl and R ¹ is methyl;

R ² is 1-hydroxyethyl and R ¹ is methyl;

R ² is 2-hydroxyethyl and R ¹ is methyl;

R ² is 1-hydroxy-2-propyl and R ¹ is methyl;

R ² is 2-hydroxy-2-propyl and R ¹ is phenyl;

R ² is C1-C6 alkyl optionally substituted with one or more hydroxy, and R ¹ is 5- to 10- membered heteroaryl;

R ² is 2-hydroxy-2-propyl and R ¹ is pyridyl;

R ² is 2-hydroxy-2-propyl and R ¹ is pyrazolyl;

R ² is C ₁ -C ₆ alkyl optionally substituted with one or more hydroxy, and R ¹ is S(O ₂ )CH ₃ ; R ² is 2-hydroxy-2-propyl and R ¹ is chloro;

R ² is 2-hydroxy-2-propyl and R ¹ is fluoro;

R ² is C3-C7 cycloalkyl optionally substituted with one or more hydroxy, and R ¹ is C1-C6 alkyl;

R ² is 1-hydroxy-1-cyclopropyl, and R ¹ is methyl;

R ² is 1-hydroxy-1-cyclobutyl, and R ¹ is methyl; R ² is 1-hydroxy-1-cyclopentyl, and R ¹ is methyl;

R ² is 1-hydroxy-1-cyclohexyl, and R ¹ is methyl;

R ² is morpholinyl, and R ¹ is methyl;

R ² is 1,3-dioxolan-2-yl, and R ¹ is methyl;

R ² is 1,3-dioxolan-2-yl, and R ¹ is fluoro;

R ² is 1,3-dioxolan-2-yl, and R ¹ is chloro;

R ² is C1-C6 alkyl optionally substituted with one or more oxo, and R ¹ is methyl;

R ² is (dimethylamino)methyl, and R ¹ is methyl;

R ² is COCH ₃ , and R ¹ is methyl; or

R ² is 2-methoxy-2-propyl, and R ¹ is methyl. In some embodiments, of the compound of formula AA,

and R ¹ and R ² are one of the following combinations:

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;

R ¹ is C1-C6 alkyl optionally substituted with one or more hydroxy, and R ² is C6-C10 aryl; R ¹ is C ₁ -C ₆ alkyl optionally substituted with one or more hydroxy, and R ² is 5- to 10- membered heteroaryl;

R ¹ is C1-C6 alkyl optionally substituted with one or more hydroxy, and R ² is SF5;

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;

R ¹ is C1-C6 alkyl optionally substituted with one or more hydroxy, and R ² is halo;

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

R ¹ is 3- to 7-membered heterocycloalkyl optionally substituted with one or more hydroxy, and R ² is C1-C6 alkyl;

R ¹ is 3- to 7-membered heterocycloalkyl optionally substituted with one or more hydroxy, and R ² is halo; R ¹ is C1-C6 alkyl optionally substituted with one or more oxo, and R ² is methyl; 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;

R ¹ is C1-C6 alkyl optionally substituted with one or more NR ⁸ R ⁹ , and R ² is C1-C6 alkyl;

R ¹ is C1-C6 alkyl optionally substituted with one or more NR ⁸ R ⁹ , and R ² is halo;

R ² is C ₁ -C ₆ alkyl optionally substituted with one or more hydroxy, and R ¹ is C ₆ -C ₁₀ aryl; R ² is C1-C6 alkyl optionally substituted with one or more hydroxy, and R ¹ is 5- to 10- membered heteroaryl;

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

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

R ² is C ₁ -C ₆ alkyl optionally substituted with one or more hydroxy, and R ¹ is halo;

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

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

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

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;

R ² is C1-C6 alkyl optionally substituted with one or more NR ⁸ R ⁹ , and R ¹ is halo;

R ² is C1-C6 alkyl optionally substituted with one or more oxo, and R ¹ is methyl; or

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, of the compound of formula AA,

and R ¹ and R ² are one of the following combinations:

R ¹ is 1-hydroxy-2-methylpropan-2-yl, and R ² is methyl;

R ¹ is 2-hydroxy-2-propyl and R ² is methyl;

R ¹ is 2-hydroxy-2-propyl and R ² is isopropyl; R ¹ is 2-hydroxy-2-propyl and R ² is 2-hydroxy-2-propyl; R ¹ is 2-hydroxy-2-propyl and R ² is 1-hydroxyethyl; R ¹ is hydroxymethyl and R ² is methyl;

R ¹ is 1-hydroxyethyl and R ² is methyl;

R ¹ is 2-hydroxyethyl and R ² is methyl;

R ¹ is 1-hydroxy-2-propyl and R ² is methyl;

R ¹ is 2-hydroxy-2-propyl and R ² is phenyl;

R ¹ is 2-hydroxy-2-propyl and R ² is pyridyl;

R ¹ is 2-hydroxy-2-propyl and R ² is pyrazolyl;

R ¹ is 2-hydroxy-2-propyl, and R ² is S(O ₂ )CH ₃ ;

R ¹ is 2-hydroxy-2-propyl and R ² is chloro;

R ¹ is 2-hydroxy-2-propyl and R ² is fluoro;

R ¹ is 1-hydroxy-1-cyclopropyl, and R ² is methyl;

R ¹ is 1-hydroxy-1-cyclobutyl, and R ² is methyl;

R ¹ is 1-hydroxy-1-cyclopentyl, and R ² is methyl;

R ¹ is 1-hydroxy-1-cyclohexyl, and R ² is methyl;

R ¹ is morpholinyl, and R ² is methyl;

R ¹ is 1,3-dioxolan-2-yl, and R ² is methyl;

R ¹ is 1,3-dioxolan-2-yl, and R ² is fluoro;

R ¹ is 1,3-dioxolan-2-yl, and R ² is chloro;

R ¹ is COCH3, and R ² is methyl;

R ¹ is 2-methoxy-2-propyl, and R ² is methyl;

R ¹ is (dimethylamino)methyl, and R ² is methyl.

R ² is 1-hydroxy-2-methylpropan-2-yl, and R ¹ is methyl; R ² is 2-hydroxy-2-propyl and R ¹ is methyl;

R ² is 2-hydroxy-2-propyl and R ¹ is isopropyl;

R ² is 2-hydroxy-2-propyl and R ¹ is 1-hydroxyethyl; R ² is hydroxymethyl and R ¹ is methyl;

R ² is 1-hydroxyethyl and R ¹ is methyl;

R ² is 2-hydroxyethyl and R ¹ is methyl;

R ² is 1-hydroxy-2-propyl and R ¹ is methyl; R ² is 2-hydroxy-2-propyl and R ¹ is phenyl;

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

R ² is 2-hydroxy-2-propyl and R ¹ is pyridyl;

R ² is 2-hydroxy-2-propyl and R ¹ is pyrazolyl;

R ² is C ₁ -C ₆ alkyl optionally substituted with one or more hydroxy, and R ¹ is S(O ₂ )CH ₃ ; R ² is 2-hydroxy-2-propyl and R ¹ is chloro;

R ² is 2-hydroxy-2-propyl and R ¹ is fluoro;

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

R ² is 1-hydroxy-1-cyclopropyl, and R ¹ is methyl;

R ² is 1-hydroxy-1-cyclobutyl, and R ¹ is methyl;

R ² is 1-hydroxy-1-cyclopentyl, and R ¹ is methyl;

R ² is 1-hydroxy-1-cyclohexyl, and R ¹ is methyl;

R ² is morpholinyl, and R ¹ is methyl;

R ² is 1,3-dioxolan-2-yl, and R ¹ is methyl;

R ² is 1,3-dioxolan-2-yl, and R ¹ is fluoro;

R ² is 1,3-dioxolan-2-yl, and R ¹ is chloro;

R ² is C ₁ -C ₆ alkyl optionally substituted with one or more oxo, and R ¹ is methyl;

R ² is (dimethylamino)methyl, and R ¹ is methyl;

R ² is COCH3, and R ¹ is methyl; or

R ² is 2-methoxy-2-propyl, and R ¹ is methyl. In some embodiments, of the compound of formula AA,

and R ¹ and R ² are one of the following combinations:

R ¹ is C1-C6 alkyl optionally substituted with one or more hydroxy, and R ² is C1-C6 alkyl optionally substituted with one or more hydroxy;

R ¹ is C ₁ -C ₆ alkyl optionally substituted with one or more hydroxy, and R ² is C ₆ -C ₁₀ aryl; R ¹ is C1-C6 alkyl optionally substituted with one or more hydroxy, and R ² is 5- to 10- membered heteroaryl;

R ¹ is C ₁ -C ₆ alkyl optionally substituted with one or more hydroxy, and R ² is SF ₅ ;

R ¹ is C1-C6 alkyl optionally substituted with one or more hydroxy, and R ² is S(O2)C1-C6 alkyl;

R ¹ is C ₁ -C ₆ alkyl optionally substituted with one or more hydroxy, and R ² is halo;

R ¹ is C3-C7 cycloalkyl optionally substituted with one or more hydroxy, and R ² is C1-C6 alkyl;

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

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

R ¹ is C ₁ -C ₆ alkyl optionally substituted with one or more oxo, and R ² is methyl;

R ¹ is C1-C6 alkyl optionally substituted with one or more C1-C6 alkoxy, and R ² is C1-C6 alkyl;

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; R ¹ is C1-C6 alkyl optionally substituted with one or more NR ⁸ R ⁹ , and R ² is halo;

R ² is C1-C6 alkyl optionally substituted with one or more hydroxy, and R ¹ is C6-C10 aryl; R ² is C ₁ -C ₆ alkyl optionally substituted with one or more hydroxy, and R ¹ is 5- to 10- membered heteroaryl;

R ² is C1-C6 alkyl optionally substituted with one or more hydroxy, and R ¹ is SF5.

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

R ² is C1-C6 alkyl optionally substituted with one or more hydroxy, and R ¹ is halo;

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

R ² is 3- to 7-membered heterocycloalkyl optionally substituted with one or more hydroxy, and R ¹ is C1-C6 alkyl;

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

R ² is C1-C6 alkyl optionally substituted with one or more NR ⁸ R ⁹ , and R ¹ is C1-C6 alkyl; R ² is C1-C6 alkyl optionally substituted with one or more NR ⁸ R ⁹ , and R ¹ is halo; R ² is C ₁ -C ₆ alkyl optionally substituted with one or more oxo, and R ¹ is methyl; or

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, of the compound of formula AA,

and R ¹ and R ² are one of the following combinations:

R ¹ is 1-hydroxy-2-methylpropan-2-yl, and R ² is methyl;

R ¹ is 2-hydroxy-2-propyl and R ² is methyl;

R ¹ is 2-hydroxy-2-propyl and R ² is isopropyl;

R ¹ is 2-hydroxy-2-propyl and R ² is 2-hydroxy-2-propyl;

R ¹ is 2-hydroxy-2-propyl and R ² is 1-hydroxyethyl;

R ¹ is hydroxymethyl and R ² is methyl;

R ¹ is 1-hydroxyethyl and R ² is methyl;

R ¹ is 2-hydroxyethyl and R ² is methyl;

R ¹ is 1-hydroxy-2-propyl and R ² is methyl;

R ¹ is 2-hydroxy-2-propyl and R ² is phenyl;

R ¹ is 2-hydroxy-2-propyl and R ² is pyridyl;

R ¹ is 2-hydroxy-2-propyl and R ² is pyrazolyl;

R ¹ is 2-hydroxy-2-propyl, and R ² is S(O2)CH3;

R ¹ is 2-hydroxy-2-propyl and R ² is chloro;

R ¹ is 2-hydroxy-2-propyl and R ² is fluoro;

R ¹ is 1-hydroxy-1-cyclopropyl, and R ² is methyl;

R ¹ is 1-hydroxy-1-cyclobutyl, and R ² is methyl;

R ¹ is 1-hydroxy-1-cyclopentyl, and R ² is methyl;

R ¹ is 1-hydroxy-1-cyclohexyl, and R ² is methyl;

R ¹ is morpholinyl, and R ² is methyl;

R ¹ is 1,3-dioxolan-2-yl, and R ² is methyl;

R ¹ is 1,3-dioxolan-2-yl, and R ² is fluoro;

R ¹ is 1,3-dioxolan-2-yl, and R ² is chloro; R ¹ is COCH3, and R ² is methyl;

R ¹ is 2-methoxy-2-propyl, and R ² is methyl;

R ¹ is (dimethylamino)methyl, and R ² is methyl.

R ² is 1-hydroxy-2-methylpropan-2-yl, and R ¹ is methyl;

R ² is 2-hydroxy-2-propyl and R ¹ is methyl;

R ² is 2-hydroxy-2-propyl and R ¹ is isopropyl;

R ² is 2-hydroxy-2-propyl and R ¹ is 1-hydroxyethyl;

R ² is hydroxymethyl and R ¹ is methyl;

R ² is 1-hydroxyethyl and R ¹ is methyl;

R ² is 2-hydroxyethyl and R ¹ is methyl;

R ² is 1-hydroxy-2-propyl and R ¹ is methyl;

R ² is 2-hydroxy-2-propyl and R ¹ is phenyl;

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

R ² is 2-hydroxy-2-propyl and R ¹ is pyridyl;

R ² is 2-hydroxy-2-propyl and R ¹ is pyrazolyl;

R ² is C1-C6 alkyl optionally substituted with one or more hydroxy, and R ¹ is S(O2)CH3; R ² is 2-hydroxy-2-propyl and R ¹ is chloro;

R ² is 2-hydroxy-2-propyl and R ¹ is fluoro;

R ² is C3-C7 cycloalkyl optionally substituted with one or more hydroxy, and R ¹ is C1-C6 alkyl;

R ² is 1-hydroxy-1-cyclopropyl, and R ¹ is methyl;

R ² is 1-hydroxy-1-cyclobutyl, and R ¹ is methyl;

R ² is 1-hydroxy-1-cyclopentyl, and R ¹ is methyl;

R ² is 1-hydroxy-1-cyclohexyl, and R ¹ is methyl;

R ² is morpholinyl, and R ¹ is methyl;

R ² is 1,3-dioxolan-2-yl, and R ¹ is methyl;

R ² is 1,3-dioxolan-2-yl, and R ¹ is fluoro;

R ² is 1,3-dioxolan-2-yl, and R ¹ is chloro;

R ² is C1-C6 alkyl optionally substituted with one or more oxo, and R ¹ is methyl;

R ² is (dimethylamino)methyl, and R ¹ is methyl; R ² is COCH3, and R ¹ is methyl; or

R ² is 2-methoxy-2-propyl, and R ¹ is methyl. In some embodiments, of the compound of formula AA,

and R ¹ and R ² are one of the following combinations:

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;

R ¹ is C1-C6 alkyl optionally substituted with one or more hydroxy, and R ² is C6-C10 aryl; R ¹ is C ₁ -C ₆ alkyl optionally substituted with one or more hydroxy, and R ² is 5- to 10- membered heteroaryl;

R ¹ is C1-C6 alkyl optionally substituted with one or more hydroxy, and R ² is SF5;

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;

R ¹ is C1-C6 alkyl optionally substituted with one or more hydroxy, and R ² is halo;

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

R ¹ is 3- to 7-membered heterocycloalkyl optionally substituted with one or more hydroxy, and R ² is C1-C6 alkyl;

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

R ¹ is C1-C6 alkyl optionally substituted with one or more oxo, and R ² is methyl;

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;

R ¹ is C1-C6 alkyl optionally substituted with one or more NR ⁸ R ⁹ , and R ² is C1-C6 alkyl; R ¹ is C ₁ -C ₆ alkyl optionally substituted with one or more NR ⁸ R ⁹ , and R ² is halo;

R ² is C ₁ -C ₆ alkyl optionally substituted with one or more hydroxy, and R ¹ is C ₆ -C ₁₀ aryl; R ² is C1-C6 alkyl optionally substituted with one or more hydroxy, and R ¹ is 5- to 10- membered heteroaryl; R ² is C1-C6 alkyl optionally substituted with one or more hydroxy, and R ¹ is SF5.

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

R ² is C1-C6 alkyl optionally substituted with one or more hydroxy, and R ¹ is halo;

R ² is C3-C7 cycloalkyl optionally substituted with one or more hydroxy, and R ¹ is C1-C6 alkyl;

R ² is 3- to 7-membered heterocycloalkyl optionally substituted with one or more hydroxy, and R ¹ is C1-C6 alkyl;

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

R ² is C1-C6 alkyl optionally substituted with one or more NR ⁸ R ⁹ , and R ¹ is C1-C6 alkyl; R ² is C ₁ -C ₆ alkyl optionally substituted with one or more NR ⁸ R ⁹ , and R ¹ is halo;

R ² is C ₁ -C ₆ alkyl optionally substituted with one or more oxo, and R ¹ is methyl; or R ² is C1-C6 alkyl optionally substituted with one or more C1-C6 alkoxy, and R ¹ is C1-C6 alkyl.

In some embodiments, of the compound of formula AA,

and R ¹ and R ² are one of the following combinations:

R ¹ is 1-hydroxy-2-methylpropan-2-yl, and R ² is methyl;

R ¹ is 2-hydroxy-2-propyl and R ² is methyl;

R ¹ is 2-hydroxy-2-propyl and R ² is isopropyl;

R ¹ is 2-hydroxy-2-propyl and R ² is 2-hydroxy-2-propyl;

R ¹ is 2-hydroxy-2-propyl and R ² is 1-hydroxyethyl;

R ¹ is hydroxymethyl and R ² is methyl;

R ¹ is 1-hydroxyethyl and R ² is methyl;

R ¹ is 2-hydroxyethyl and R ² is methyl;

R ¹ is 1-hydroxy-2-propyl and R ² is methyl; R ¹ is 2-hydroxy-2-propyl and R ² is phenyl;

R ¹ is 2-hydroxy-2-propyl and R ² is pyridyl;

R ¹ is 2-hydroxy-2-propyl and R ² is pyrazolyl;

R ¹ is 2-hydroxy-2-propyl, and R ² is S(O2)CH3;

R ¹ is 2-hydroxy-2-propyl and R ² is chloro;

R ¹ is 2-hydroxy-2-propyl and R ² is fluoro;

R ¹ is 1-hydroxy-1-cyclopropyl, and R ² is methyl;

R ¹ is 1-hydroxy-1-cyclobutyl, and R ² is methyl;

R ¹ is 1-hydroxy-1-cyclopentyl, and R ² is methyl;

R ¹ is 1-hydroxy-1-cyclohexyl, and R ² is methyl;

R ¹ is morpholinyl, and R ² is methyl;

R ¹ is 1,3-dioxolan-2-yl, and R ² is methyl;

R ¹ is 1,3-dioxolan-2-yl, and R ² is fluoro;

R ¹ is 1,3-dioxolan-2-yl, and R ² is chloro;

R ¹ is COCH3, and R ² is methyl;

R ¹ is 2-methoxy-2-propyl, and R ² is methyl;

R ¹ is (dimethylamino)methyl, and R ² is methyl.

R ² is 1-hydroxy-2-methylpropan-2-yl, and R ¹ is methyl;

R ² is 2-hydroxy-2-propyl and R ¹ is methyl;

R ² is 2-hydroxy-2-propyl and R ¹ is isopropyl;

R ² is 2-hydroxy-2-propyl and R ¹ is 1-hydroxyethyl;

R ² is hydroxymethyl and R ¹ is methyl;

R ² is 1-hydroxyethyl and R ¹ is methyl;

R ² is 2-hydroxyethyl and R ¹ is methyl;

R ² is 1-hydroxy-2-propyl and R ¹ is methyl;

R ² is 2-hydroxy-2-propyl and R ¹ is phenyl;

R ² is C1-C6 alkyl optionally substituted with one or more hydroxy, and R ¹ is 5- to 10- membered heteroaryl;

R ² is 2-hydroxy-2-propyl and R ¹ is pyridyl;

R ² is 2-hydroxy-2-propyl and R ¹ is pyrazolyl;

R ² is C1-C6 alkyl optionally substituted with one or more hydroxy, and R ¹ is S(O2)CH3; R ² is 2-hydroxy-2-propyl and R ¹ is chloro;

R ² is 2-hydroxy-2-propyl and R ¹ is fluoro;

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

R ² is 1-hydroxy-1-cyclopropyl, and R ¹ is methyl;

R ² is 1-hydroxy-1-cyclobutyl, and R ¹ is methyl;

R ² is 1-hydroxy-1-cyclopentyl, and R ¹ is methyl;

R ² is 1-hydroxy-1-cyclohexyl, and R ¹ is methyl;

R ² is morpholinyl, and R ¹ is methyl;

R ² is 1,3-dioxolan-2-yl, and R ¹ is methyl;

R ² is 1,3-dioxolan-2-yl, and R ¹ is fluoro;

R ² is 1,3-dioxolan-2-yl, and R ¹ is chloro;

R ² is (dimethylamino)methyl, and R ¹ is methyl;

R ² is C1-C6 alkyl optionally substituted with one or more oxo, and R ¹ is methyl; or R ² is COCH3, and R ¹ is methyl. In some embodiments, of the compound of formula AA,

the substituted ring

and R ¹ and R ² are one of the following combinations:

R ¹ is C1-C6 alkyl optionally substituted with one or more hydroxy, and R ² is C1-C6 alkyl optionally substituted with one or more hydroxy;

R ¹ is C1-C6 alkyl optionally substituted with one or more hydroxy, and R ² is C6-C10 aryl; R ¹ is C1-C6 alkyl optionally substituted with one or more hydroxy, and R ² is 5- to 10- membered heteroaryl;

R ¹ is C ₁ -C ₆ alkyl optionally substituted with one or more hydroxy, and R ² is SF ₅ ;

R ¹ is C1-C6 alkyl optionally substituted with one or more hydroxy, and R ² is S(O2)C1-C6 alkyl;

R ¹ is C ₁ -C ₆ alkyl optionally substituted with one or more hydroxy, and R ² is halo; R ¹ is C3-C7 cycloalkyl optionally substituted with one or more hydroxy, and R ² is C1-C6 alkyl;

R ¹ is 3- to 7-membered heterocycloalkyl optionally substituted with one or more hydroxy, and R ² is C1-C6 alkyl;

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

R ¹ is C1-C6 alkyl optionally substituted with one or more oxo, and R ² is methyl;

R ¹ is C1-C6 alkyl optionally substituted with one or more C1-C6 alkoxy, and R ² is C1-C6 alkyl;

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; R ¹ is C1-C6 alkyl optionally substituted with one or more NR ⁸ R ⁹ , and R ² is halo;

R ² is C ₁ -C ₆ alkyl optionally substituted with one or more hydroxy, and R ¹ is C ₆ -C ₁₀ aryl; R ² is C ₁ -C ₆ alkyl optionally substituted with one or more hydroxy, and R ¹ is 5- to 10- membered heteroaryl;

R ² is C1-C6 alkyl optionally substituted with one or more hydroxy, and R ¹ is SF5.

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

R ² is C1-C6 alkyl optionally substituted with one or more hydroxy, and R ¹ is halo;

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

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

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

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

R ² is C1-C6 alkyl optionally substituted with one or more oxo, and R ¹ is methyl; or R ² is C1-C6 alkyl optionally substituted with one or more C1-C6 alkoxy, and R ¹ is C1-C6 alkyl. In some embodiments, of the compound of formula AA, the substituted ring

and R ¹ and R ² are one of the following combinations:

R ¹ is 1-hydroxy-2-methylpropan-2-yl, and R ² is methyl;

R ¹ is 2-hydroxy-2-propyl and R ² is methyl;

R ¹ is 2-hydroxy-2-propyl and R ² is isopropyl;

R ¹ is 2-hydroxy-2-propyl and R ² is 2-hydroxy-2-propyl;

R ¹ is 2-hydroxy-2-propyl and R ² is 1-hydroxyethyl;

R ¹ is hydroxymethyl and R ² is methyl;

R ¹ is 1-hydroxyethyl and R ² is methyl;

R ¹ is 2-hydroxyethyl and R ² is methyl;

R ¹ is 1-hydroxy-2-propyl and R ² is methyl;

R ¹ is 2-hydroxy-2-propyl and R ² is phenyl;

R ¹ is 2-hydroxy-2-propyl and R ² is pyridyl;

R ¹ is 2-hydroxy-2-propyl and R ² is pyrazolyl;

R ¹ is 2-hydroxy-2-propyl, and R ² is S(O ₂ )CH ₃ ;

R ¹ is 2-hydroxy-2-propyl and R ² is chloro;

R ¹ is 2-hydroxy-2-propyl and R ² is fluoro;

R ¹ is 1-hydroxy-1-cyclopropyl, and R ² is methyl;

R ¹ is 1-hydroxy-1-cyclobutyl, and R ² is methyl;

R ¹ is 1-hydroxy-1-cyclopentyl, and R ² is methyl;

R ¹ is 1-hydroxy-1-cyclohexyl, and R ² is methyl;

R ¹ is morpholinyl, and R ² is methyl;

R ¹ is 1,3-dioxolan-2-yl, and R ² is methyl;

R ¹ is 1,3-dioxolan-2-yl, and R ² is fluoro;

R ¹ is 1,3-dioxolan-2-yl, and R ² is chloro;

R ¹ is COCH3, and R ² is methyl;

R ¹ is 2-methoxy-2-propyl, and R ² is methyl;

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; R ¹ is C1-C6 alkyl optionally substituted with one or more NR ⁸ R ⁹ , and R ² is halo; R ² is 1-hydroxy-2-methylpropan-2-yl, and R ¹ is methyl;

R ² is 2-hydroxy-2-propyl and R ¹ is methyl;

R ² is 2-hydroxy-2-propyl and R ¹ is isopropyl;

R ² is 2-hydroxy-2-propyl and R ¹ is 1-hydroxyethyl;

R ² is hydroxymethyl and R ¹ is methyl;

R ² is 1-hydroxyethyl and R ¹ is methyl;

R ² is 2-hydroxyethyl and R ¹ is methyl;

R ² is 1-hydroxy-2-propyl and R ¹ is methyl;

R ² is 2-hydroxy-2-propyl and R ¹ is phenyl;

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

R ² is 2-hydroxy-2-propyl and R ¹ is pyridyl;

R ² is 2-hydroxy-2-propyl and R ¹ is pyrazolyl;

R ² is C1-C6 alkyl optionally substituted with one or more hydroxy, and R ¹ is S(O2)CH3; R ² is 2-hydroxy-2-propyl and R ¹ is chloro;

R ² is 2-hydroxy-2-propyl and R ¹ is fluoro;

R ² is C3-C7 cycloalkyl optionally substituted with one or more hydroxy, and R ¹ is C1-C6 alkyl;

R ² is 1-hydroxy-1-cyclopropyl, and R ¹ is methyl;

R ² is 1-hydroxy-1-cyclobutyl, and R ¹ is methyl;

R ² is 1-hydroxy-1-cyclopentyl, and R ¹ is methyl;

R ² is 1-hydroxy-1-cyclohexyl, and R ¹ is methyl;

R ² is morpholinyl, and R ¹ is methyl;

R ² is 1,3-dioxolan-2-yl, and R ¹ is methyl;

R ² is 1,3-dioxolan-2-yl, and R ¹ is fluoro;

R ² is 1,3-dioxolan-2-yl, and R ¹ is chloro;

R ² is C1-C6 alkyl optionally substituted with one or more oxo, and R ¹ is methyl;

R ² is C1-C6 alkyl optionally substituted with one or more NR ⁸ R ⁹ , and R ¹ is C1-C6 alkyl; R ² is C ₁ -C ₆ alkyl optionally substituted with one or more NR ⁸ R ⁹ , and R ¹ is halo;

R ² is COCH3, and R ¹ is methyl; or

R ² is 2-methoxy-2-propyl, and R ¹ is methyl. In some embodiments, of the compound of formula AA,

the substituted ring

and R ¹ and R ² are one of the following combinations:

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;

R ¹ is C1-C6 alkyl optionally substituted with one or more hydroxy, and R ² is C6-C10 aryl; R ¹ is C ₁ -C ₆ alkyl optionally substituted with one or more hydroxy, and R ² is 5- to 10- membered heteroaryl;

R ¹ is C1-C6 alkyl optionally substituted with one or more hydroxy, and R ² is SF5;

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;

R ¹ is C1-C6 alkyl optionally substituted with one or more hydroxy, and R ² is halo;

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

R ¹ is 3- to 7-membered heterocycloalkyl optionally substituted with one or more hydroxy, and R ² is C1-C6 alkyl;

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

R ¹ is C1-C6 alkyl optionally substituted with one or more oxo, and R ² is methyl;

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;

R ¹ is C1-C6 alkyl optionally substituted with one or more NR ⁸ R ⁹ , and R ² is C1-C6 alkyl; R ¹ is C ₁ -C ₆ alkyl optionally substituted with one or more NR ⁸ R ⁹ , and R ² is halo;

R ² is C ₁ -C ₆ alkyl optionally substituted with one or more hydroxy, and R ¹ is C ₆ -C ₁₀ aryl; R ² is C1-C6 alkyl optionally substituted with one or more hydroxy, and R ¹ is 5- to 10- membered heteroaryl;

R ² is C ₁ -C ₆ alkyl optionally substituted with one or more hydroxy, and R ¹ is SF ₅ . R ² is C1-C6 alkyl optionally substituted with one or more hydroxy, and R ¹ is S(O2)C1-C6 alkyl;

R ² is C ₁ -C ₆ alkyl optionally substituted with one or more hydroxy, and R ¹ is halo;

R ² is C3-C7 cycloalkyl optionally substituted with one or more hydroxy, and R ¹ is C1-C6 alkyl;

R ² is 3- to 7-membered heterocycloalkyl optionally substituted with one or more hydroxy, and R ¹ is C1-C6 alkyl;

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

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; R ² is C1-C6 alkyl optionally substituted with one or more NR ⁸ R ⁹ , and R ¹ is halo;

R ² is C ₁ -C ₆ alkyl optionally substituted with one or more oxo, and R ¹ is methyl; or 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, of the compound of formula AA,

the substituted ring

and R ¹ and R ² are one of the following combinations:

R ¹ is 1-hydroxy-2-methylpropan-2-yl, and R ² is methyl;

R ¹ is 2-hydroxy-2-propyl and R ² is methyl;

R ¹ is 2-hydroxy-2-propyl and R ² is isopropyl;

R ¹ is 2-hydroxy-2-propyl and R ² is 2-hydroxy-2-propyl;

R ¹ is 2-hydroxy-2-propyl and R ² is 1-hydroxyethyl;

R ¹ is hydroxymethyl and R ² is methyl;

R ¹ is 1-hydroxyethyl and R ² is methyl;

R ¹ is 2-hydroxyethyl and R ² is methyl;

R ¹ is 1-hydroxy-2-propyl and R ² is methyl;

R ¹ is 2-hydroxy-2-propyl and R ² is phenyl; R ¹ is 2-hydroxy-2-propyl and R ² is pyridyl;

R ¹ is 2-hydroxy-2-propyl and R ² is pyrazolyl;

R ¹ is 2-hydroxy-2-propyl, and R ² is S(O ₂ )CH ₃ ;

R ¹ is 2-hydroxy-2-propyl and R ² is chloro;

R ¹ is 2-hydroxy-2-propyl and R ² is fluoro;

R ¹ is 1-hydroxy-1-cyclopropyl, and R ² is methyl;

R ¹ is 1-hydroxy-1-cyclobutyl, and R ² is methyl;

R ¹ is 1-hydroxy-1-cyclopentyl, and R ² is methyl;

R ¹ is 1-hydroxy-1-cyclohexyl, and R ² is methyl;

R ¹ is morpholinyl, and R ² is methyl;

R ¹ is 1,3-dioxolan-2-yl, and R ² is methyl;

R ¹ is 1,3-dioxolan-2-yl, and R ² is fluoro;

R ¹ is 1,3-dioxolan-2-yl, and R ² is chloro;

R ¹ is COCH3, and R ² is methyl;

R ¹ is 2-methoxy-2-propyl, and R ² is methyl;

R ¹ is (dimethylamino)methyl, and R ² is methyl.

R ² is 1-hydroxy-2-methylpropan-2-yl, and R ¹ is methyl;

R ² is 2-hydroxy-2-propyl and R ¹ is methyl;

R ² is 2-hydroxy-2-propyl and R ¹ is isopropyl;

R ² is 2-hydroxy-2-propyl and R ¹ is 1-hydroxyethyl;

R ² is hydroxymethyl and R ¹ is methyl;

R ² is 1-hydroxyethyl and R ¹ is methyl;

R ² is 2-hydroxyethyl and R ¹ is methyl;

R ² is 1-hydroxy-2-propyl and R ¹ is methyl;

R ² is 2-hydroxy-2-propyl and R ¹ is phenyl;

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

R ² is 2-hydroxy-2-propyl and R ¹ is pyridyl;

R ² is 2-hydroxy-2-propyl and R ¹ is pyrazolyl;

R ² is C1-C6 alkyl optionally substituted with one or more hydroxy, and R ¹ is S(O2)CH3; R ² is 2-hydroxy-2-propyl and R ¹ is chloro; R ² is 2-hydroxy-2-propyl and R ¹ is fluoro;

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

R ² is 1-hydroxy-1-cyclopropyl, and R ¹ is methyl;

R ² is 1-hydroxy-1-cyclobutyl, and R ¹ is methyl;

R ² is 1-hydroxy-1-cyclopentyl, and R ¹ is methyl;

R ² is 1-hydroxy-1-cyclohexyl, and R ¹ is methyl;

R ² is morpholinyl, and R ¹ is methyl;

R ² is 1,3-dioxolan-2-yl, and R ¹ is methyl;

R ² is 1,3-dioxolan-2-yl, and R ¹ is fluoro;

R ² is 1,3-dioxolan-2-yl, and R ¹ is chloro;

R ² is C ₁ -C ₆ alkyl optionally substituted with one or more oxo, and R ¹ is methyl;

R ² is (dimethylamino)methyl, and R ¹ is methyl;

R ² is COCH3, and R ¹ is methyl; or

R ² is 2-methoxy-2-propyl, and R ¹ is methyl.

In some embodiments, the optionally substituted ring

adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C4-C12 carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring that includes from 1-3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR ¹³ , S, S(O), and S(O)2, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxy, OC ₃ -C ₁₀ cycloalkyl, NR ⁸ R ⁹ , =NR ¹⁰ , CN, COOC1-C6 alkyl, OS(O2)C6-C10 aryl, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR ⁸ R ⁹ , wherein the C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, S(O ₂ )C ₆ -C ₁₀ aryl, C ₆ -C ₁₀ aryl, 5- to 10- membered heteroaryl, C ₃ -C ₁₀ cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, 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 optionally substituted ring

adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C4-C12 carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring that includes from 1-3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR ¹³ , S, S(O), and S(O) ₂ , and wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3- C ₁₀ cycloalkyl, NR ⁸ R ⁹ , =NR ¹⁰ , CN, COOC ₁ -C ₆ alkyl, OS(O ₂ )C ₆ -C ₁₀ aryl, S(O ₂ )C ₆ -C ₁₀ aryl, C ₆ - C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR ⁸ R ⁹ , wherein the C1-C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10- membered heteroaryl, C ₃ -C ₁₀ cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, 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 optionally substituted ring

adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C4-C12 carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring that includes from 1-3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR ¹³ , S, S(O), and S(O) ₂ , and wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxy, OC ₃ - C ₁₀ cycloalkyl, NR ⁸ R ⁹ , =NR ¹⁰ , CN, COOC ₁ -C ₆ alkyl, OS(O ₂ )C ₆ -C ₁₀ aryl, S(O ₂ )C ₆ -C ₁₀ aryl, C ₆ - C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR ⁸ R ⁹ , wherein the C1-C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10- membered heteroaryl, C ₃ -C ₁₀ cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₁ -C ₆ alkoxy, oxo, 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 optionally substituted ring

adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C ₄ -C ₁₂ carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring that includes from 1-3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR ¹³ , S, S(O), and S(O)2, and wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxy, OC ₃ - C10 cycloalkyl, NR ⁸ R ⁹ , =NR ¹⁰ , CN, COOC1-C6 alkyl, OS(O2)C6-C10 aryl, S(O2)C6-C10 aryl, C6- C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR ⁸ R ⁹ , wherein the C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, S(O ₂ )C ₆ -C ₁₀ aryl, C ₆ -C ₁₀ aryl, 5- to 10- membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₁ -C ₆ alkoxy, oxo, 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 optionally substituted ring

adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C ₄ -C ₁₂ carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring that includes from 1-3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR ¹³ , S, S(O), and S(O)2, and wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxy, OC ₃ - C10 cycloalkyl, NR ⁸ R ⁹ , =NR ¹⁰ , CN, COOC1-C6 alkyl, OS(O2)C6-C10 aryl, S(O2)C6-C10 aryl, C6- C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR ⁸ R ⁹ , wherein the C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, S(O ₂ )C ₆ -C ₁₀ aryl, C ₆ -C ₁₀ aryl, 5- to 10- membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₁ -C ₆ alkoxy, oxo, NR ⁸ R ⁹ , =NR ¹⁰ , COOC1-C6 alkyl, C6-C10 aryl, and CONR ⁸ R ⁹ .

In some embodiments, the optionally substituted ring

adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C ₄ -C ₁₂ carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring that includes from 1-3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR ¹³ , S, S(O), and S(O)2, and wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3- C10 cycloalkyl, NR ⁸ R ⁹ , =NR ¹⁰ , CN, COOC1-C6 alkyl, OS(O2)C6-C10 aryl, S(O2)C6-C10 aryl, C6- C ₁₀ aryl, 5- to 10-membered heteroaryl, C ₃ -C ₁₀ cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR ⁸ R ⁹ , wherein the C1-C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10- membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₁ -C ₆ alkoxy, oxo, NR ⁸ R ⁹ , =NR ¹⁰ , COOC1-C6 alkyl, C6-C10 aryl, and CONR ⁸ R ⁹ .

In some embodiments, the optionally substituted ring

adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C ₄ -C ₁₂ carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring that includes from 1-3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR ¹³ , S, S(O), and S(O) ₂ , and wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3- C10 cycloalkyl, NR ⁸ R ⁹ , =NR ¹⁰ , CN, COOC1-C6 alkyl, OS(O2)C6-C10 aryl, S(O2)C6-C10 aryl, C6- C ₁₀ aryl, 5- to 10-membered heteroaryl, C ₃ -C ₁₀ cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR ⁸ R ⁹ , wherein the C1-C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10- membered heteroaryl, C ₃ -C ₁₀ cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C ₁ -C ₆ alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR ⁸ R ⁹ , =NR ¹⁰ , COOC1-C6 alkyl, C6-C10 aryl, and CONR ⁸ R ⁹ .

In some embodiments, the optionally

adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C4-C12 carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring that includes from 0-2 heteroatoms and/heteroatomic groups independently selected from O, NH, NR ¹³ , S, S(O), and S(O) ₂ (in addition to the nitrogen atom attached to R ¹ ), and wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxy, OC ₃ -C ₁₀ cycloalkyl, NR ⁸ R ⁹ , =NR ¹⁰ , CN, COOC ₁ -C ₆ alkyl, OS(O2)C6-C10 aryl, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR ⁸ R ⁹ , wherein the C1-C6 alkyl, C1-C6 alkoxy, S(O ₂ )C ₆ -C ₁₀ aryl, C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, C ₃ -C ₁₀ cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR ⁸ R ⁹ , =NR ¹⁰ , COOC1-C6 alkyl, C6-C10 aryl, and CONR ⁸ R ⁹ .

In some embodiments, the optionally substituted ring

adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C4-C12 carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring that includes from 1-3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR ¹³ , S, S(O), and S(O) ₂ , and wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3- C ₁₀ cycloalkyl, NR ⁸ R ⁹ , =NR ¹⁰ , CN, COOC ₁ -C ₆ alkyl, OS(O ₂ )C ₆ -C ₁₀ aryl, S(O ₂ )C ₆ -C ₁₀ aryl, C ₆ - C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR ⁸ R ⁹ , wherein the C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, S(O ₂ )C ₆ -C ₁₀ aryl, C ₆ -C ₁₀ aryl, 5- to 10- membered heteroaryl, C ₃ -C ₁₀ cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, 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 optionally substituted ring

adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C4-C12 carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring that includes from 1-3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR ¹³ , S, S(O), and S(O)2, and wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxy, OC ₃ - C10 cycloalkyl, NR ⁸ R ⁹ , =NR ¹⁰ , CN, COOC1-C6 alkyl, OS(O2)C6-C10 aryl, S(O2)C6-C10 aryl, C6- C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR ⁸ R ⁹ , wherein the C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, S(O ₂ )C ₆ -C ₁₀ aryl, C ₆ -C ₁₀ aryl, 5- to 10- membered heteroaryl, C ₃ -C ₁₀ cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, 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 optionally substituted

adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C ₄ -C ₁₂ carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring that includes from 0-2 heteroatoms and/heteroatomic groups independently selected from O, NH, NR ¹³ , S, S(O), and S(O)2 (in addition to the nitrogen atom attached to R ² ), and wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR ⁸ R ⁹ , =NR ¹⁰ , CN, COOC1-C6 alkyl, OS(O ₂ )C ₆ -C ₁₀ aryl, S(O ₂ )C ₆ -C ₁₀ aryl, C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, C ₃ -C ₁₀ cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR ⁸ R ⁹ , wherein the C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C1-C6 alkoxy, oxo, NR ⁸ R ⁹ , =NR ¹⁰ , COOC1-C6 alkyl, C6-C10 aryl, and CONR ⁸ R ⁹ .

R ² In some embodiments, the optionally substituted ring A is _{; R} ¹ _{and R} ² _on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C ₄ -C ₁₂ carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring that includes from 0-2 heteroatoms and/heteroatomic groups independently selected from O, NH, NR ¹³ , S, S(O), and S(O)2 (in addition to the nitrogen attached to R ² ), and wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR ⁸ R ⁹ , =NR ¹⁰ , CN, COOC1-C6 alkyl, OS(O ₂ )C ₆ -C ₁₀ aryl, S(O ₂ )C ₆ -C ₁₀ aryl, C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, C ₃ -C ₁₀ cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR ⁸ R ⁹ , wherein the C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C1-C6 alkoxy, oxo, NR ⁸ R ⁹ , =NR ¹⁰ , COOC1-C6 alkyl, C6-C10 aryl, and CONR ⁸ R ⁹ .

In some embodiments, the optionally substituted ring

adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C ₄ -C ₁₂ carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring that includes from 1-3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR ¹³ , S, S(O), and S(O)2, and wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3- C ₁₀ cycloalkyl, NR ⁸ R ⁹ , =NR ¹⁰ , CN, COOC ₁ -C ₆ alkyl, OS(O ₂ )C ₆ -C ₁₀ aryl, S(O ₂ )C ₆ -C ₁₀ aryl, C ₆ - C ₁₀ aryl, 5- to 10-membered heteroaryl, C ₃ -C ₁₀ cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR ⁸ R ⁹ , wherein the C1-C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10- membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C ₁ -C ₆ alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR ⁸ R ⁹ , =NR ¹⁰ , COOC1-C6 alkyl, C6-C10 aryl, and CONR ⁸ R ⁹ .

In some embodiments, the optionally substituted ring _{; one pair of R} ¹ _and R ² on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C ₄ -C ₁₂ carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring that includes from 1-3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR ¹³ , S, S(O), and S(O)2, and wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxy, OC ₃ - C10 cycloalkyl, NR ⁸ R ⁹ , =NR ¹⁰ , CN, COOC1-C6 alkyl, OS(O2)C6-C10 aryl, S(O2)C6-C10 aryl, C6- C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR ⁸ R ⁹ , wherein the C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, S(O ₂ )C ₆ -C ₁₀ aryl, C ₆ -C ₁₀ aryl, 5- to 10- membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₁ -C ₆ alkoxy, oxo, NR ⁸ R ⁹ , =NR ¹⁰ , COOC1-C6 alkyl, C6-C10 aryl, and CONR ⁸ R ⁹ .

In some embodiments, the optionally substituted ring

adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C4-C12 carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring that includes from 1-3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR ¹³ , S, S(O), and S(O)2, and wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxy, OC ₃ - C10 cycloalkyl, NR ⁸ R ⁹ , =NR ¹⁰ , CN, COOC1-C6 alkyl, OS(O2)C6-C10 aryl, S(O2)C6-C10 aryl, C6- C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR ⁸ R ⁹ , wherein the C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, S(O ₂ )C ₆ -C ₁₀ aryl, C ₆ -C ₁₀ aryl, 5- to 10- membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₁ -C ₆ alkoxy, oxo, 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 optionally substituted ring _{; one pair of R} ¹ _and R ² on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C4-C12 carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring that includes from 1-3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR ¹³ , S, S(O), and S(O)2, and wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxy, OC ₃ - C10 cycloalkyl, NR ⁸ R ⁹ , =NR ¹⁰ , CN, COOC1-C6 alkyl, OS(O2)C6-C10 aryl, S(O2)C6-C10 aryl, C6- C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR ⁸ R ⁹ , wherein the C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, S(O ₂ )C ₆ -C ₁₀ aryl, C ₆ -C ₁₀ aryl, 5- to 10- membered heteroaryl, C ₃ -C ₁₀ cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, 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 optionally substituted ring

adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C4-C12 carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring that includes from 1-3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR ¹³ , S, S(O), and S(O) ₂ , wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR ⁸ R ⁹ , =NR ¹⁰ , CN, COOC ₁ -C ₆ alkyl, OS(O ₂ )C ₆ -C ₁₀ aryl, S(O ₂ )C ₆ -C ₁₀ aryl, C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR ⁸ R ⁹ , wherein the C1-C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10- membered heteroaryl, C ₃ -C ₁₀ cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C ₁ -C ₆ alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, 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 optionally substituted ring one pair of R ¹ and R ² on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C4-C12 carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring wherein a) when each of the adjacent atoms is a carbon atom, then the heterocyclic ring includes from 1-3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR ¹³ , S, S(O), and S(O)2; and b) when one of the adjacent atoms is a nitrogen atom, then the heterocyclic ring includes from 0-2 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR ¹³ , S, S(O), and S(O) ₂ (in addition to the aforementioned nitrogen atom attached to R ¹ ), and wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxy, OC ₃ -C ₁₀ cycloalkyl, NR ⁸ R ⁹ , =NR ¹⁰ , CN, COOC1-C6 alkyl, OS(O2)C6-C10 aryl, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10- membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR ⁸ R ⁹ , wherein the C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, S(O ₂ )C ₆ -C ₁₀ aryl, C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, C ₃ -C ₁₀ cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR ⁸ R ⁹ , =NR ¹⁰ , COOC1-C6 alkyl, C ₆ -C ₁₀ aryl, and CONR ⁸ R ⁹ .

In some embodiments, the optionally substituted ring _{; one pair of R} ¹ _and R ² on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C4-C12 carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring that includes from 1-3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR ¹³ , S, S(O), and S(O) ₂ , and wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3- C ₁₀ cycloalkyl, NR ⁸ R ⁹ , =NR ¹⁰ , CN, COOC ₁ -C ₆ alkyl, OS(O ₂ )C ₆ -C ₁₀ aryl, S(O ₂ )C ₆ -C ₁₀ aryl, C ₆ - C ₁₀ aryl, 5- to 10-membered heteroaryl, C ₃ -C ₁₀ cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR ⁸ R ⁹ , wherein the C1-C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10- membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C ₁ -C ₆ alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR ⁸ R ⁹ , =NR ¹⁰ , COOC1-C6 alkyl, C6-C10 aryl, and CONR ⁸ R ⁹ .

In some embodiments, the optionally substituted ring

adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C ₄ -C ₁₂ carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring that includes from 0-2 heteroatoms and/heteroatomic groups independently selected from O, NH, NR ¹³ , S, S(O), and S(O) ₂ (in addition to the nitrogen atom attached to R ¹ ), and wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR ⁸ R ⁹ , =NR ¹⁰ , CN, COOC1-C6 alkyl, OS(O ₂ )C ₆ -C ₁₀ aryl, S(O ₂ )C ₆ -C ₁₀ aryl, C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, C ₃ -C ₁₀ cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR ⁸ R ⁹ , wherein the C1-C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C1-C6 alkoxy, oxo, NR ⁸ R ⁹ , =NR ¹⁰ , COOC1-C6 alkyl, C6-C10 aryl, and CONR ⁸ R ⁹ .

In some embodiments, the optionally substituted ring

adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C4-C12 carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring that includes from 1-3 heteroatoms and/heteroatomic groups independently selected from O, NH, NR ¹³ , S, S(O), and S(O)2, and wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxy, OC ₃ - C10 cycloalkyl, NR ⁸ R ⁹ , =NR ¹⁰ , CN, COOC1-C6 alkyl, OS(O2)C6-C10 aryl, S(O2)C6-C10 aryl, C6- C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR ⁸ R ⁹ , wherein the C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, S(O ₂ )C ₆ -C ₁₀ aryl, C ₆ -C ₁₀ aryl, 5- to 10- membered heteroaryl, C ₃ -C ₁₀ cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, 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 optionally substituted ring one pair of R ¹ and R ² on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C4-C12 carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring wherein a) when each of the adjacent atoms is a carbon atom, then the heterocyclic ring includes from 1-3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR ¹³ , S, S(O), and S(O)2; and b) when one of the adjacent atoms is a nitrogen atom, then the heterocyclic ring includes from 0-2 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR ¹³ , S, S(O), and S(O) ₂ (in addition to the aforementioned nitrogen atom attached to R ² ), and wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxy, OC ₃ -C ₁₀ cycloalkyl, NR ⁸ R ⁹ , =NR ¹⁰ , CN, COOC1-C6 alkyl, OS(O2)C6-C10 aryl, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10- membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR ⁸ R ⁹ , wherein the C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, S(O ₂ )C ₆ -C ₁₀ aryl, C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₁ -C ₆ alkoxy, oxo, 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 optionally substituted ring one pair of R ¹ and R ² on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C ₄ -C ₁₂ carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring that includes from 0-2 heteroatoms and/heteroatomic groups independently selected from O, NH, NR ¹³ , S, S(O), and S(O)2 (in addition to the nitrogen atom(s) attached to R ² ), and wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR ⁸ R ⁹ , =NR ¹⁰ , CN, COOC1-C6 alkyl, OS(O2)C6-C10 aryl, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR ⁸ R ⁹ , wherein the C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C1-C6 alkoxy, oxo, NR ⁸ R ⁹ , =NR ¹⁰ , COOC1-C6 alkyl, C6-C10 aryl, and CONR ⁸ R ⁹ .

In some embodiments of the compound of formula AA,

the substituted ring and R ⁶ is selected from:

C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl substituted with one or more halo, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkoxy substituted with one or more halo, C ₃ -C ₇ cycloalkyl, halo, and cyano. In some embodiments of the compound of formula AA,

the substituted ring

and R ⁶ is selected from:

isopropyl, ethyl, methyl, trifluoromethyl, trifluoromethoxy, cyclopropyl, halo, chloro, and fluoro.

In some embodiments of the compound of formula AA,

the substituted ring

and R ⁶ is selected from:

C1-C6 alkyl, C1-C6 alkyl substituted with one or more halo, C1-C6 alkoxy, C1-C6 alkoxy substituted with one or more halo, C ₃ -C ₇ cycloalkyl, halo, and cyano. In some embodiments of the compound of formula AA,

the substituted ring

and R ⁶ is selected from:

isopropyl, ethyl, methyl, trifluoromethyl, trifluoromethoxy, cyclopropyl, halo, chloro, and fluoro. In some embodiments of the compound of formula AA, the substituted ring

and R ⁶ is selected from:

C1-C6 alkyl, C1-C6 alkyl substituted with one or more halo, C1-C6 alkoxy, C1-C6 alkoxy substituted with one or more halo, C3-C7 cycloalkyl, halo, and cyano. In some embodiments of the compound of formula AA,

the substituted ring

and R ⁶ is selected from:

isopropyl, ethyl, methyl, trifluoromethyl, trifluoromethoxy, cyclopropyl, halo, chloro, and fluoro. In some embodiments of the compound of formula AA,

the substituted ring

and R ⁶ is selected from:

C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl substituted with one or more halo, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkoxy substituted with one or more halo, C3-C7 cycloalkyl, halo, and cyano. In some embodiments of the compound of formula AA,

the substituted ring

and R ⁶ is selected from:

isopropyl, ethyl, methyl, trifluoromethyl, trifluoromethoxy, cyclopropyl, halo, chloro, and fluoro. In some embodiments of the compound of formula AA, the substituted ring

and R ⁶ is selected from:

C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl substituted with one or more halo, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkoxy substituted with one or more halo, C3-C7 cycloalkyl, halo, and cyano. In some embodiments of the compound of formula AA,

the substituted ring

and R ⁶ is selected from:

isopropyl, ethyl, methyl, trifluoromethyl, trifluoromethoxy, cyclopropyl, halo, chloro, and fluoro.

In some embodiments, the substituted ring each R ⁶ is independently selected from the group consisting of: C1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 haloalkyl, C1-C6 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, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 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: C1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 haloalkyl, C1-C6 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 C1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 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 C1-C6 alkyl, C1-C6 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;

wherein R ⁷ is independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 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, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7- membered heterocycloalkyl), C6-C10 aryl, 5- to 10-membered heteroaryl, CONR ⁸ R ⁹ , SF5, 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, the substituted ring , wherein each R ⁶ is independently selected from C1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 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 C1-C6 alkyl, C1-C6 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, OCOC1-C6 alkyl, OCOC6-C10 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 C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 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), C6-C10 aryl, 5- to 10-membered heteroaryl, CONR ⁸ R ⁹ , SF5, S(O2)C1-C6 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 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, C1-C6 alkyl, C1-C6 alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC1-C6 alkyl, C6-C10 aryl, and CONR ⁸ R ⁹ . In some embodiments, the substituted ring , wherein each R ⁶ is independently selected from C1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C ₁ -C ₆ haloalkoxy, halo, CN, C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, CO-C ₁ - C6 alkyl; CONR ⁸ R ⁹ , and 4- to 6-membered heterocycloalkyl,

wherein the C1-C6 alkyl, C1-C6 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, OCOC1-C6 alkyl, OCOC6-C10 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 C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 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, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7- membered heterocycloalkyl), C6-C10 aryl, 5- to 10-membered heteroaryl, CONR ⁸ R ⁹ , SF5, 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.

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, C1-C6 haloalkoxy, halo, CN, C6-C10 aryl, 5- to 10-membered heteroaryl, CO-C1- C6 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, C1-C6 alkyl, C1-C6 alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC1-C6 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), NHCOC1-C6 alkyl, NHCOC6-C10 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, C1-C6 haloalkoxy, halo, CN, COC1-C6 alkyl, CO2C1-C6 alkyl, CO2C3-C6 cycloalkyl, OCOC1-C6 alkyl, OCOC6-C10 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)C1-C6 alkyl, C3-C7 cycloalkyl and 4- to 6-membered

heterocycloalkyl, wherein the C1-C6 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, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC1-C6 alkyl, C6-C10 aryl, and CONR ⁸ R ⁹ .

In some embodiments, the substituted ring , wherein each R ⁶ is independently selected from C1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, CN, C6-C10 aryl, 5- to 10-membered heteroaryl, CO-C1- C ₆ alkyl; CONR ⁸ R ⁹ , and 4- to 6-membered heterocycloalkyl,

wherein the C1-C6 alkyl, C1-C6 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, OCOC1-C6 alkyl, OCOC6-C10 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 C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 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, OCOC1-C6 alkyl, OCOC6-C10 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 C1-C6 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, halo, oxo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC1-C6 alkyl, C6-C10 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 - C6 alkyl; CONR ⁸ R ⁹ , and 4- to 6-membered heterocycloalkyl,

wherein the C1-C6 alkyl, C1-C6 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, C1-C6 alkyl, C1-C6 alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC1-C6 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), NHCOC1-C6 alkyl, NHCOC6-C10 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, CO ₂ C ₁ -C ₆ alkyl, CO ₂ C ₃ -C ₆ cycloalkyl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C6-C10 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 C1-C6 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, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC1-C6 alkyl, C6-C10 aryl, and CONR ⁸ R ⁹ .

In some embodiments, the substituted ring , wherein each R ⁶ is independently selected from C1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C ₁ -C ₆ haloalkoxy, halo, CN, C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, CO-C ₁ - C6 alkyl; CONR ⁸ R ⁹ , and 4- to 6-membered heterocycloalkyl,

wherein the C1-C6 alkyl, C1-C6 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, C1-C6 alkyl, C1-C6 alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC1-C6 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;

wherein each R ⁷ is independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 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, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C6-C10 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 C1-C6 alkyl is optionally substituted with one to two C1-C6 alkoxy; or R ⁶ and R ⁷ , taken together with the atoms connecting them, independently form a 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, C1-C6 alkyl, C1-C6 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 - C6 alkyl; CONR ⁸ R ⁹ , and 4- to 6-membered heterocycloalkyl,

wherein the C1-C6 alkyl, C1-C6 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, C1-C6 alkyl, C1-C6 alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC1-C6 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), NHCOC1-C6 alkyl, NHCOC6-C10 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, CO ₂ C ₁ -C ₆ alkyl, CO ₂ C ₃ -C ₆ cycloalkyl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C6-C10 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 C1-C6 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 . In some embodiments, of the compound of formula AA,

the substituted ring

and the two R ⁶ are one of the following combinations:

(i) One R ⁶ is C1-C6 alkyl, and the other R ⁶ is C1-C6 alkyl optionally substituted with one or more halo;

(ii) One R ⁶ is C ₁ -C ₆ alkyl and the other R ⁶ is C ₁ -C ₆ alkyl;

(iii) One R ⁶ is C1-C6 alkyl, and the other R ⁶ is C1-C6 alkyl substituted with one or more halo; (iv) One R ⁶ is C1-C6 alkyl, and the other R ⁶ is C3-C7 cycloalkyl;

(v) One R ⁶ is C ₁ -C ₆ alkyl, and the other R ⁶ is halo;

(vi) One R ⁶ is C1-C6 alkyl, and the other R ⁶ is cyano;

(vii) One R ⁶ is C3-C7 cycloalkyl, and the other R ⁶ is C3-C7 cycloalkyl;

(viii) One R ⁶ is C ₃ -C ₇ cycloalkyl, and the other R ⁶ is halo;

(ix) One R ⁶ is cyclopropyl and the other R ⁶ is halo;

(x) One R ⁶ is C1-C6 alkyl, and the other R ⁶ is C1-C6 alkoxy optionally substituted with one or more halo;

(xi) One R ⁶ is C ₁ -C ₆ alkyl, and the other R ⁶ is C ₁ -C ₆ alkoxy;

(xii) One R ⁶ is C1-C6 alkyl, and the other R ⁶ is C1-C6 alkoxy substituted with one or more halo;

(xiii) One R ⁶ is halo, and the other R ⁶ is C ₁ -C ₆ haloalkyl;

(xiv) One R ⁶ is halo, and the other R ⁶ is C1-C6 haloalkoxy;

(xv) One R ⁶ is C1-C6 alkoxy; and the other R ⁶ is halo;

(xvi) One R ⁶ is C ₁ -C ₆ alkoxy; and the other R ⁶ is chloro. In some embodiments, of the compound of formula AA, the substituted ring

and the two R ⁶ are one of the following combinations:

(i) One R ⁶ is isopropyl; and the other R ⁶ is methyl;

(ii) One R ⁶ is isopropyl; and the other R ⁶ is n-propyl;

(iii) One R ⁶ is isopropyl; and the other R ⁶ is isopropyl;

(iv) One R ⁶ is isopropyl; and the other R ⁶ is trifluoromethyl;

(v) One R ⁶ is isopropyl; and the other R ⁶ is cyclopropyl;

(vi) One R ⁶ is isopropyl; and the other R ⁶ is chloro;

(vii) One R ⁶ is isopropyl; and the other R ⁶ is fluoro;

(viii) One R ⁶ is ethyl; and the other R ⁶ is fluoro;

(ix) One R ⁶ is isopropyl; and the other R ⁶ is cyano;

(x) One R ⁶ is cyclopropyl; and the other R ⁶ is cyclopropyl;

(xi) One R ⁶ is cyclopropyl; and the other R ⁶ is chloro;

(xii) One R ⁶ is cyclopropyl; and the other R ⁶ is fluoro;

(xiii) One R ⁶ is isopropyl; and the other R ⁶ is methoxy;

(xiv) One R ⁶ is isopropyl; and the other R ⁶ is methoxy; or

(xv) One R ⁶ is isopropyl; and the other R ⁶ is trifluoromethoxy. In some embodiments, of the compound of formula AA,

the substituted ring

and R ⁶ and R ⁷ are one of the following combinations:

(i) R ⁶ is C1-C6 alkyl, and R ⁷ is C1-C6 alkyl optionally substituted with one or more halo; (ii) R ⁶ is C1-C6 alkyl and R ⁷ is C1-C6 alkyl;

(iii)R ⁶ is C ₁ -C ₆ alkyl, and R ⁷ is C ₁ -C ₆ alkyl substituted with one or more halo;

(iv) R ⁶ is C1-C6 alkyl, and R ⁷ is C3-C7 cycloalkyl;

(v) R ⁶ is C1-C6 alkyl, and R ⁷ is halo;

(vi) R ⁶ is C ₁ -C ₆ alkyl, and R ⁷ is cyano; (vii) R ⁶ is C3-C7 cycloalkyl, and R ⁷ is C3-C7 cycloalkyl;

(viii) R ⁶ is C ₃ -C ₇ cycloalkyl, and R ⁷ is halo;

(ix) R ⁶ is cyclopropyl and R ⁷ is halo;

(x) R ⁶ is C1-C6 alkyl, and R ⁷ is C1-C6 alkoxy optionally substituted with one or more halo; (xi) R ⁶ is C1-C6 alkyl, and R ⁷ is C1-C6 alkoxy;

(xii) R ⁶ is C ₁ -C ₆ alkyl, and R ⁷ is C ₁ -C ₆ alkoxy substituted with one or more halo; (xiii) R ⁶ is halo, and R ⁷ is C1-C6 haloalkyl;

(xiv) R ⁶ is halo, and R ⁷ is C1-C6 haloalkoxy;

(xv) R ⁶ is C ₁ -C ₆ alkoxy; and R ⁷ is halo;

(xvi) R ⁶ is C ₁ -C ₆ alkoxy; and R ⁷ is chloro;

(xvii) R ⁷ is C1-C6 alkyl, and R ⁶ is C1-C6 alkyl optionally substituted with one or more halo;

(xviii) R ⁷ is C ₁ -C ₆ alkyl, and R ⁶ is C ₁ -C ₆ alkyl substituted with one or more halo;

(xix) R ⁷ is C1-C6 alkyl, and R ⁶ is C3-C7 cycloalkyl;

(xx) R ⁷ is C1-C6 alkyl, and R ⁶ is halo;

(xxi) R ⁷ is C ₁ -C ₆ alkyl and R ⁶ is halo;

(xxii) R ⁷ is C1-C6 alkyl, and R ⁶ is cyano;

(xxiii) R ⁷ is C3-C7 cycloalkyl, and R ⁶ is C3-C7 cycloalkyl;

(xxiv) R ⁷ is C ₃ -C ₇ cycloalkyl, and R ⁶ is halo;

(xxv) R ⁷ is C3-C7 cycloalkyl and R ⁶ is halo;

(xxvi) R ⁷ is C1-C6 alkyl, and R ⁶ is C1-C6 alkoxy optionally substituted with one or more halo;

(xxvii) R ⁷ is C ₁ -C ₆ alkyl, and R ⁶ is C ₁ -C ₆ alkoxy;

(xxviii) R ⁷ is C1-C6 alkyl, and R ⁶ is C1-C6 alkoxy substituted with one or more halo; (xxix) R ⁷ is halo, and R ⁶ is C ₁ -C ₆ haloalkyl;

(xxx) R ⁷ is halo, and R ⁶ is C ₁ -C ₆ haloalkoxy;

(xxxi) R ⁷ is C1-C6 alkoxy; and R ⁶ is halo; or

(xxxii) R ⁷ is C1-C6 alkoxy; and R ⁶ is chloro.

In some embodiments, of the compound of formula AA, the substituted ring

and R ⁶ and R ⁷ are one of the following combinations:

(i) R ⁶ is isopropyl; and R ⁷ is methyl;

(ii) R ⁶ is isopropyl; and R ⁷ is isopropyl;

(iii)R ⁶ is isopropyl; and R ⁷ is trifluoromethyl;

(iv) R ⁶ is isopropyl; and R ⁷ is cyclopropyl;

(v) R ⁶ is isopropyl; and R ⁷ is chloro;

(vi) R ⁶ is isopropyl; and R ⁷ is fluoro;

(vii) R ⁶ is ethyl; and R ⁷ is fluoro;

(viii) R ⁶ is isopropyl; and R ⁷ is cyano;

(ix) R ⁶ is cyclopropyl; and R ⁷ is cyclopropyl;

(x) R ⁶ is cyclopropyl; and R ⁷ is chloro;

(xi) R ⁶ is cyclopropyl; and R ⁷ is fluoro; R ⁶ is isopropyl; and R ⁷ is methoxy; (xii) R ⁶ is isopropyl; and R ⁷ is trifluoromethoxy;

(xiii) R ⁶ is chloro; and R ⁷ is trifluoromethyl;

(xiv) R ⁶ is chloro; and R ⁷ is trifluoromethoxy;

(xv) R ⁷ is isopropyl; and R ⁶ is methyl;

(xvi) R ⁷ is isopropyl; and R ⁶ is trifluoromethyl;

(xvii) R ⁷ is isopropyl; and R ⁶ is cyclopropyl;

(xviii) R ⁷ is isopropyl; and R ⁶ is chloro;

(xix) R ⁷ is ethyl; and R ⁶ is fluoro;

(xx) R ⁷ is isopropyl; and R ⁶ is cyano;

(xxi) R ⁷ is cyclopropyl; and R ⁶ is cyclopropyl;

(xxii) R ⁷ is cyclopropyl; and R ⁶ is chloro;

(xxiii) R ⁷ is cyclopropyl; and R ⁶ is fluoro;

(xxiv) R ⁷ is isopropyl; and R ⁶ is methoxy;

(xxv) R ⁷ is isopropyl; and R ⁶ is trifluoromethoxy;

(xxvi) R ⁷ is chloro; and R ⁶ is trifluoromethyl; or

(xxvii) R ⁷ is chloro; and R ⁶ is trifluoromethoxy. In some embodiments, of the compound of formula AA,

the substituted ring

and R ⁶ and R ⁷ are one of the following combinations:

(i) R ⁶ is C ₁ -C ₆ alkyl, and R ⁷ is C ₁ -C ₆ alkyl optionally substituted with one or more halo; (ii) R ⁶ is C ₁ -C ₆ alkyl and R ⁷ is C ₁ -C ₆ alkyl;

(iii)R ⁶ is C1-C6 alkyl, and R ⁷ is C1-C6 alkyl substituted with one or more halo;

(iv) R ⁶ is C1-C6 alkyl, and R ⁷ is C3-C7 cycloalkyl;

(v) R ⁶ is C ₁ -C ₆ alkyl, and R ⁷ is halo;

(vi) R ⁶ is C1-C6 alkyl, and R ⁷ is cyano;

(vii) R ⁶ is C3-C7 cycloalkyl, and R ⁷ is C3-C7 cycloalkyl;

(viii) R ⁶ is C ₃ -C ₇ cycloalkyl, and R ⁷ is halo;

(ix) R ⁶ is cyclopropyl and R ⁷ is halo;

(x) R ⁶ is C1-C6 alkyl, and R ⁷ is C1-C6 alkoxy optionally substituted with one or more halo; (xi) R ⁶ is C ₁ -C ₆ alkyl, and R ⁷ is C ₁ -C ₆ alkoxy;

(xii) R ⁶ is C ₁ -C ₆ alkyl, and R ⁷ is C ₁ -C ₆ alkoxy substituted with one or more halo; (xiii) R ⁶ is halo, and R ⁷ is C1-C6 haloalkyl;

(xiv) R ⁶ is halo, and R ⁷ is C1-C6 haloalkoxy;

(xv) R ⁶ is C ₁ -C ₆ alkoxy; and R ⁷ is halo;

(xvi) R ⁶ is C1-C6 alkoxy; and R ⁷ is chloro;

(xvii) R ⁷ is C1-C6 alkyl, and R ⁶ is C1-C6 alkyl optionally substituted with one or more halo;

(xviii) R ⁷ is C1-C6 alkyl, and R ⁶ is C1-C6 alkyl substituted with one or more halo; (xix) R ⁷ is C1-C6 alkyl, and R ⁶ is C3-C7 cycloalkyl;

(xx) R ⁷ is C ₁ -C ₆ alkyl, and R ⁶ is halo;

(xxi) R ⁷ is C ₁ -C ₆ alkyl and R ⁶ is halo;

(xxii) R ⁷ is C1-C6 alkyl, and R ⁶ is cyano;

(xxiii) R ⁷ is C3-C7 cycloalkyl, and R ⁶ is C3-C7 cycloalkyl;

(xxiv) R ⁷ is C ₃ -C ₇ cycloalkyl, and R ⁶ is halo;

(xxv) R ⁷ is C3-C7 cycloalkyl and R ⁶ is halo; (xxvi) R ⁷ is C1-C6 alkyl, and R ⁶ is C1-C6 alkoxy optionally substituted with one or more halo;

(xxvii) R ⁷ is C ₁ -C ₆ alkyl, and R ⁶ is C ₁ -C ₆ alkoxy;

(xxviii) R ⁷ is C1-C6 alkyl, and R ⁶ is C1-C6 alkoxy substituted with one or more halo; (xxix) R ⁷ is halo, and R ⁶ is C1-C6 haloalkyl;

(xxx) R ⁷ is halo, and R ⁶ is C ₁ -C ₆ haloalkoxy;

(xxxi) R ⁷ is C1-C6 alkoxy; and R ⁶ is halo; or

(xxxii) R ⁷ is C1-C6 alkoxy; and R ⁶ is chloro.

In some embodiments, of the compound of formula AA,

the substituted ring

and R ⁶ and R ⁷ are one of the following combinations:

(i) R ⁶ is isopropyl; and R ⁷ is methyl;

(ii) R ⁶ is isopropyl; and R ⁷ is isopropyl;

(iii)R ⁶ is isopropyl; and R ⁷ is trifluoromethyl;

(iv) R ⁶ is isopropyl; and R ⁷ is cyclopropyl;

(v) R ⁶ is isopropyl; and R ⁷ is chloro;

(vi) R ⁶ is isopropyl; and R ⁷ is fluoro;

(vii) R ⁶ is ethyl; and R ⁷ is fluoro;

(viii) R ⁶ is isopropyl; and R ⁷ is cyano;

(ix) R ⁶ is cyclopropyl; and R ⁷ is cyclopropyl;

(x) R ⁶ is cyclopropyl; and R ⁷ is chloro;

(xi) R ⁶ is cyclopropyl; and R ⁷ is fluoro;

(xii) R ⁶ is isopropyl; and R ⁷ is methoxy;

(xiii) R ⁶ is isopropyl; and R ⁷ is trifluoromethoxy;

(xiv) R ⁶ is chloro; and R ⁷ is trifluoromethyl;

(xv) R ⁶ is chloro; and R ⁷ is trifluoromethoxy;

(xvi) R ⁷ is isopropyl; and R ⁶ is methyl;

(xvii) R ⁷ is isopropyl; and R ⁶ is trifluoromethyl;

(xviii) R ⁷ is isopropyl; and R ⁶ is cyclopropyl; (xix) R ⁷ is isopropyl; and R ⁶ is chloro;

(xx) R ⁷ is ethyl; and R ⁶ is fluoro;

(xxi) R ⁷ is isopropyl; and R ⁶ is cyano;

(xxii) R ⁷ is cyclopropyl; and R ⁶ is cyclopropyl;

(xxiii) R ⁷ is cyclopropyl; and R ⁶ is chloro;

(xxiv) R ⁷ is cyclopropyl; and R ⁶ is fluoro;

(xxv) R ⁷ is isopropyl; and R ⁶ is methoxy;

(xxvi) R ⁷ is isopropyl; and R ⁶ is trifluoromethoxy;

(xxvii) R ⁷ is chloro; and R ⁶ is trifluoromethyl; or

(xxviii) R ⁷ is chloro; and R ⁶ is trifluoromethoxy. In some embodiments, of the compound of formula AA,

the substituted ring

and R ⁶ and R ⁷ are one of the following combinations:

(i) R ⁶ is C ₁ -C ₆ alkyl, and R ⁷ is C ₁ -C ₆ alkyl optionally substituted with one or more halo; (ii) R ⁶ is C1-C6 alkyl and R ⁷ is C1-C6 alkyl;

(iii)R ⁶ is C1-C6 alkyl, and R ⁷ is C1-C6 alkyl substituted with one or more halo;

(iv) R ⁶ is C ₁ -C ₆ alkyl, and R ⁷ is C ₃ -C ₇ cycloalkyl;

(v) R ⁶ is C1-C6 alkyl, and R ⁷ is halo;

(vi) R ⁶ is C1-C6 alkyl, and R ⁷ is cyano;

(vii) R ⁶ is C ₃ -C ₇ cycloalkyl, and R ⁷ is C ₃ -C ₇ cycloalkyl;

(viii) R ⁶ is C ₃ -C ₇ cycloalkyl, and R ⁷ is halo;

(ix) R ⁶ is cyclopropyl and R ⁷ is halo;

(x) R ⁶ is C1-C6 alkyl, and R ⁷ is C1-C6 alkoxy optionally substituted with one or more halo; (xi) R ⁶ is C ₁ -C ₆ alkyl, and R ⁷ is C ₁ -C ₆ alkoxy;

(xii) R ⁶ is C1-C6 alkyl, and R ⁷ is C1-C6 alkoxy substituted with one or more halo; (xiii) R ⁶ is halo, and R ⁷ is C1-C6 haloalkyl;

(xiv) R ⁶ is halo, and R ⁷ is C ₁ -C ₆ haloalkoxy;

(xv) R ⁶ is C1-C6 alkoxy; and R ⁷ is halo; (xvi) R ⁶ is C1-C6 alkoxy; and R ⁷ is chloro;

(xvii) R ⁷ is C ₁ -C ₆ alkyl, and R ⁶ is C ₁ -C ₆ alkyl optionally substituted with one or more halo;

(xviii) R ⁷ is C1-C6 alkyl, and R ⁶ is C1-C6 alkyl substituted with one or more halo;

(xix) R ⁷ is C1-C6 alkyl, and R ⁶ is C3-C7 cycloalkyl;

(xx) R ⁷ is C ₁ -C ₆ alkyl, and R ⁶ is halo;

(xxi) R ⁷ is C1-C6 alkyl and R ⁶ is halo;

(xxii) R ⁷ is C1-C6 alkyl, and R ⁶ is cyano;

(xxiii) R ⁷ is C ₃ -C ₇ cycloalkyl, and R ⁶ is C ₃ -C ₇ cycloalkyl;

(xxiv) R ⁷ is C ₃ -C ₇ cycloalkyl, and R ⁶ is halo;

(xxv) R ⁷ is C3-C7 cycloalkyl and R ⁶ is halo;

(xxvi) R ⁷ is C ₁ -C ₆ alkyl, and R ⁶ is C ₁ -C ₆ alkoxy optionally substituted with one or more halo;

(xxvii) R ⁷ is C1-C6 alkyl, and R ⁶ is C1-C6 alkoxy;

(xxviii) R ⁷ is C1-C6 alkyl, and R ⁶ is C1-C6 alkoxy substituted with one or more halo; (xxix) R ⁷ is halo, and R ⁶ is C ₁ -C ₆ haloalkyl;

(xxx) R ⁷ is halo, and R ⁶ is C1-C6 haloalkoxy;

(xxxi) R ⁷ is C1-C6 alkoxy; and R ⁶ is halo; or

(xxxii) R ⁷ is C ₁ -C ₆ alkoxy; and R ⁶ is chloro;

(xxxiii) R ⁶ and R ⁷ on adjacent atoms taken together with the atoms connecting them form a C4-C6 aliphatic carbocyclic ring optionally substituted with one or more hydroxy, oxo, or C ₁ -C ₆ alkyl; or

(xxxiv) R ⁶ and R ⁷ on adjacent atoms taken together with the atoms connecting them form a 5-to-6-membered heterocyclic ring containing 1 heteroatom independently selected from O, N, and S, wherein the heterocyclic ring optionally substituted with one or more hydroxy, oxo, or C ₁ -C ₆ alkyl.. In some embodiments, of the compound of formula AA,

the substituted ring and R ⁶ and R ⁷ are one of the following combinations:

(i) R ⁶ is isopropyl; and R ⁷ is methyl;

(ii) R ⁶ is isopropyl; and R ⁷ is isopropyl;

(iii)R ⁶ is isopropyl; and R ⁷ is trifluoromethyl;

(iv) R ⁶ is isopropyl; and R ⁷ is cyclopropyl;

(v) R ⁶ is isopropyl; and R ⁷ is chloro;

(vi) R ⁶ is isopropyl; and R ⁷ is fluoro;

(vii) R ⁶ is ethyl; and R ⁷ is fluoro;

(viii) R ⁶ is isopropyl; and R ⁷ is cyano;

(ix) R ⁶ is cyclopropyl; and R ⁷ is cyclopropyl;

(x) R ⁶ is cyclopropyl; and R ⁷ is chloro;

(xi) R ⁶ is cyclopropyl; and R ⁷ is fluoro;

(xii) R ⁶ is isopropyl; and R ⁷ is methoxy;

(xiii) R ⁶ is isopropyl; and R ⁷ is trifluoromethoxy;

(xiv) R ⁶ is chloro; and R ⁷ is trifluoromethyl;

(xv) R ⁶ is chloro; and R ⁷ is trifluoromethoxy;

(xvi) R ⁷ is isopropyl; and R ⁶ is methyl;

(xvii) R ⁷ is isopropyl; and R ⁶ is trifluoromethyl;

(xviii) R ⁷ is isopropyl; and R ⁶ is cyclopropyl;

(xix) R ⁷ is isopropyl; and R ⁶ is chloro;

(xx) R ⁷ is ethyl; and R ⁶ is fluoro;

(xxi) R ⁷ is isopropyl; and R ⁶ is cyano;

(xxii) R ⁷ is cyclopropyl; and R ⁶ is cyclopropyl;

(xxiii) R ⁷ is cyclopropyl; and R ⁶ is chloro;

(xxiv) R ⁷ is cyclopropyl; and R ⁶ is fluoro;

(xxv) R ⁷ is isopropyl; and R ⁶ is methoxy;

(xxvi) R ⁷ is isopropyl; and R ⁶ is trifluoromethoxy;

(xxvii) R ⁷ is chloro; and R ⁶ is trifluoromethyl;

(xxviii) R ⁷ is chloro; and R ⁶ is trifluoromethoxy;

(xxix) R ⁶ and R ⁷ on adjacent atoms taken together with the atoms connecting them form a C4 aliphatic carbocyclic ring; (xxx) R ⁶ and R ⁷ on adjacent atoms taken together with the atoms connecting them form a C ₅ aliphatic carbocyclic ring;

(xxxi) R ⁶ and R ⁷ on adjacent atoms taken together with the atoms connecting them form a C6 aliphatic carbocyclic ring;

(xxxii) R ⁶ and R ⁷ on adjacent atoms taken together with the atoms connecting them form a 5-membered heterocyclic ring containing 1 heteroatoms independently selected from O, N, and S;

(xxxiii) R ⁶ and R ⁷ on adjacent atoms taken together with the atoms connecting them form a 6-membered heterocyclic ring containing 1 heteroatoms independently selected from O, N, and S; or

(xxxiv) R ⁶ and R ⁷ on adjacent atoms taken together with the atoms connecting them form a C ₅ aliphatic carbocyclic ring. In some embodiments, of the compound of formula AA,

the substituted ring

and R ⁶ and R ⁷ are one of the following combinations:

(i) R ⁶ is C1-C6 alkyl, and R ⁷ is C1-C6 alkyl optionally substituted with one or more halo; (ii) R ⁶ is C1-C6 alkyl and R ⁷ is C1-C6 alkyl;

(iii)R ⁶ is C ₁ -C ₆ alkyl, and R ⁷ is C ₁ -C ₆ alkyl substituted with one or more halo;

(iv) R ⁶ is C1-C6 alkyl, and R ⁷ is C3-C7 cycloalkyl;

(v) R ⁶ is C1-C6 alkyl, and R ⁷ is halo;

(vi) R ⁶ is C ₁ -C ₆ alkyl, and R ⁷ is cyano;

(vii) R ⁶ is C3-C7 cycloalkyl, and R ⁷ is C3-C7 cycloalkyl;

(viii) R ⁶ is C3-C7 cycloalkyl, and R ⁷ is halo;

(ix) R ⁶ is cyclopropyl and R ⁷ is halo;

(x) R ⁶ is C ₁ -C ₆ alkyl, and R ⁷ is C ₁ -C ₆ alkoxy optionally substituted with one or more halo; (xi) R ⁶ is C1-C6 alkyl, and R ⁷ is C1-C6 alkoxy;

(xii) R ⁶ is C1-C6 alkyl, and R ⁷ is C1-C6 alkoxy substituted with one or more halo;

(xiii) R ⁶ is halo, and R ⁷ is C ₁ -C ₆ haloalkyl; (xiv) R ⁶ is halo, and R ⁷ is C1-C6 haloalkoxy;

(xv) R ⁶ is C ₁ -C ₆ alkoxy; and R ⁷ is halo;

(xvi) R ⁶ is C ₁ -C ₆ alkoxy; and R ⁷ is chloro;

(xvii) R ⁷ is C1-C6 alkyl, and R ⁶ is C1-C6 alkyl optionally substituted with one or more halo;

(xviii) R ⁷ is C ₁ -C ₆ alkyl, and R ⁶ is C ₁ -C ₆ alkyl substituted with one or more halo;

(xix) R ⁷ is C1-C6 alkyl, and R ⁶ is C3-C7 cycloalkyl;

(xx) R ⁷ is C1-C6 alkyl, and R ⁶ is halo;

(xxi) R ⁷ is C ₁ -C ₆ alkyl and R ⁶ is halo;

(xxii) R ⁷ is C ₁ -C ₆ alkyl, and R ⁶ is cyano;

(xxiii) R ⁷ is C3-C7 cycloalkyl, and R ⁶ is C3-C7 cycloalkyl;

(xxiv) R ⁷ is C ₃ -C ₇ cycloalkyl, and R ⁶ is halo;

(xxv) R ⁷ is C ₃ -C ₇ cycloalkyl and R ⁶ is halo;

(xxvi) R ⁷ is C1-C6 alkyl, and R ⁶ is C1-C6 alkoxy optionally substituted with one or more halo;

(xxvii) R ⁷ is C ₁ -C ₆ alkyl, and R ⁶ is C ₁ -C ₆ alkoxy;

(xxviii) R ⁷ is C1-C6 alkyl, and R ⁶ is C1-C6 alkoxy substituted with one or more halo; (xxix) R ⁷ is halo, and R ⁶ is C1-C6 haloalkyl;

(xxx) R ⁷ is halo, and R ⁶ is C ₁ -C ₆ haloalkoxy;

(xxxi) R ⁷ is C1-C6 alkoxy; and R ⁶ is halo; or

(xxxii) R ⁷ is C1-C6 alkoxy; and R ⁶ is chloro.

In some embodiments, of the compound of formula AA,

the substituted ring

and R ⁶ and R ⁷ are one of the following combinations:

(i) R ⁶ is C1-C6 alkyl, and R ⁷ is C1-C6 alkyl optionally substituted with one or more halo; (ii) R ⁶ is C ₁ -C ₆ alkyl and R ⁷ is C ₁ -C ₆ alkyl;

(iii)R ⁶ is C1-C6 alkyl, and R ⁷ is C1-C6 alkyl substituted with one or more halo;

(iv) R ⁶ is C1-C6 alkyl, and R ⁷ is C3-C7 cycloalkyl; (v) R ⁶ is C1-C6 alkyl, and R ⁷ is halo;

(vi) R ⁶ is C ₁ -C ₆ alkyl, and R ⁷ is cyano;

(vii) R ⁶ is C ₃ -C ₇ cycloalkyl, and R ⁷ is C ₃ -C ₇ cycloalkyl;

(viii) R ⁶ is C3-C7 cycloalkyl, and R ⁷ is halo;

(ix) R ⁶ is cyclopropyl and R ⁷ is halo;

(x) R ⁶ is C ₁ -C ₆ alkyl, and R ⁷ is C ₁ -C ₆ alkoxy optionally substituted with one or more halo;

(xi) R ⁶ is C1-C6 alkyl, and R ⁷ is C1-C6 alkoxy;

(xii) R ⁶ is C ₁ -C ₆ alkyl, and R ⁷ is C ₁ -C ₆ alkoxy substituted with one or more halo; (xiii) R ⁶ is halo, and R ⁷ is C ₁ -C ₆ haloalkyl;

(xiv) R ⁶ is halo, and R ⁷ is C1-C6 haloalkoxy;

(xv) R ⁶ is C ₁ -C ₆ alkoxy; and R ⁷ is halo;

(xvi) R ⁶ is C ₁ -C ₆ alkoxy; and R ⁷ is chloro;

(xvii) R ⁷ is C1-C6 alkyl, and R ⁶ is C1-C6 alkyl optionally substituted with one or more halo;

(xviii) R ⁷ is C ₁ -C ₆ alkyl, and R ⁶ is C ₁ -C ₆ alkyl substituted with one or more halo;

(xix) R ⁷ is C1-C6 alkyl, and R ⁶ is C3-C7 cycloalkyl;

(xx) R ⁷ is C1-C6 alkyl, and R ⁶ is halo;

(xxi) R ⁷ is C ₁ -C ₆ alkyl and R ⁶ is halo;

(xxii) R ⁷ is C1-C6 alkyl, and R ⁶ is cyano;

(xxiii) R ⁷ is C3-C7 cycloalkyl, and R ⁶ is C3-C7 cycloalkyl;

(xxiv) R ⁷ is C ₃ -C ₇ cycloalkyl, and R ⁶ is halo;

(xxv) R ⁷ is C ₃ -C ₇ cycloalkyl and R ⁶ is halo;

(xxvi) R ⁷ is C1-C6 alkyl, and R ⁶ is C1-C6 alkoxy optionally substituted with one or more halo;

(xxvii) R ⁷ is C ₁ -C ₆ alkyl, and R ⁶ is C ₁ -C ₆ alkoxy;

(xxviii)R ⁷ is C1-C6 alkyl, and R ⁶ is C1-C6 alkoxy substituted with one or more halo; (xxix) R ⁷ is halo, and R ⁶ is C1-C6 haloalkyl;

(xxx) R ⁷ is halo, and R ⁶ is C ₁ -C ₆ haloalkoxy;

(xxxi) R ⁷ is C1-C6 alkoxy; and R ⁶ is halo;

(xxxii) R ⁷ is C1-C6 alkoxy; and R ⁶ is chloro; (xxxiii)R ⁶ and R ⁷ on adjacent atoms taken together with the atoms connecting them form a C _4- C ₆ aliphatic carbocyclic ring optionally substituted with one or more hydroxy, oxo, or C ₁ -C ₆ alkyl; or

(xxxiv) R ⁶ and R ⁷ on adjacent atoms taken together with the atoms connecting them form a 5-to-6-membered heterocyclic ring containing 1 heteroatom independently selected from O, N, and S, wherein the heterocyclic ring optionally substituted with one or more hydroxy, oxo, or C1-C6 alkyl. In some embodiments, of the compound of formula AA,

the substituted ring

and R ⁶ and R ⁷ are one of the following combinations:

(i) R ⁶ is isopropyl; and R ⁷ is methyl;

(ii) R ⁶ is isopropyl; and R ⁷ is isopropyl;

(iii)R ⁶ is isopropyl; and R ⁷ is trifluoromethyl;

(iv) R ⁶ is isopropyl; and R ⁷ is cyclopropyl;

(v) R ⁶ is isopropyl; and R ⁷ is chloro;

(vi) R ⁶ is isopropyl; and R ⁷ is fluoro;

(vii) R ⁶ is ethyl; and R ⁷ is fluoro;

(viii) R ⁶ is isopropyl; and R ⁷ is cyano;

(ix) R ⁶ is cyclopropyl; and R ⁷ is cyclopropyl;

(x) R ⁶ is cyclopropyl; and R ⁷ is chloro;

(xi) R ⁶ is cyclopropyl; and R ⁷ is fluoro;

(xii) R ⁶ is isopropyl; and R ⁷ is methoxy;

(xiii) R ⁶ is isopropyl; and R ⁷ is trifluoromethoxy;

(xiv) R ⁶ is chloro; and R ⁷ is trifluoromethyl;

(xv) R ⁶ is chloro; and R ⁷ is trifluoromethoxy;

(xvi) R ⁷ is isopropyl; and R ⁶ is methyl;

(xvii) R ⁷ is isopropyl; and R ⁶ is trifluoromethyl;

(xviii) R ⁷ is isopropyl; and R ⁶ is cyclopropyl; (xix) R ⁷ is isopropyl; and R ⁶ is chloro;

(xx) R ⁷ is ethyl; and R ⁶ is fluoro;

(xxi) R ⁷ is isopropyl; and R ⁶ is cyano;

(xxii) R ⁷ is cyclopropyl; and R ⁶ is cyclopropyl;

(xxiii) R ⁷ is cyclopropyl; and R ⁶ is chloro;

(xxiv) R ⁷ is cyclopropyl; and R ⁶ is fluoro;

(xxv) R ⁷ is isopropyl; and R ⁶ is methoxy;

(xxvi) R ⁷ is isopropyl; and R ⁶ is trifluoromethoxy;

(xxvii) R ⁷ is chloro; and R ⁶ is trifluoromethyl;

(xxviii)R ⁷ is chloro; and R ⁶ is trifluoromethoxy;

(xxix) R ⁶ and R ⁷ on adjacent atoms taken together with the atoms connecting them form a C ₄ aliphatic carbocyclic ring;

(xxx) R ⁶ and R ⁷ on adjacent atoms taken together with the atoms connecting them form a C5 aliphatic carbocyclic ring;

(xxxi) R ⁶ and R ⁷ on adjacent atoms taken together with the atoms connecting them form a C ₆ aliphatic carbocyclic ring;

(xxxii) R ⁶ and R ⁷ on adjacent atoms taken together with the atoms connecting them form a 5-membered heterocyclic ring containing 1 heteroatoms independently selected from O, N, and S;

(xxxiii)R ⁶ and R ⁷ on adjacent atoms taken together with the atoms connecting them form a 6-membered heterocyclic ring containing 1 heteroatoms independently selected from O, N, and S; or

(xxxiv) R ⁶ and R ⁷ on adjacent atoms taken together with the atoms connecting them form a C5 aliphatic carbocyclic ring. In some embodiments, of the compound of formula AA,

the substituted ring

and R ⁶ and R ⁷ are one of the following combinations: (i) R ⁶ is isopropyl; and R ⁷ is methyl;

(ii) R ⁶ is isopropyl; and R ⁷ is isopropyl;

(iii)R ⁶ is isopropyl; and R ⁷ is trifluoromethyl;

(iv) R ⁶ is isopropyl; and R ⁷ is cyclopropyl;

(v) R ⁶ is isopropyl; and R ⁷ is chloro;

(vi) R ⁶ is isopropyl; and R ⁷ is fluoro;

(vii) R ⁶ is ethyl; and R ⁷ is fluoro;

(viii) R ⁶ is isopropyl; and R ⁷ is cyano;

(ix) R ⁶ is cyclopropyl; and R ⁷ is cyclopropyl;

(x) R ⁶ is cyclopropyl; and R ⁷ is chloro;

(xi) R ⁶ is cyclopropyl; and R ⁷ is fluoro;

(xii) R ⁶ is isopropyl; and R ⁷ is methoxy;

(xiii) R ⁶ is isopropyl; and R ⁷ is trifluoromethoxy; (xiv) R ⁶ is chloro; and R ⁷ is trifluoromethyl; (xv) R ⁶ is chloro; and R ⁷ is trifluoromethoxy; (xvi) R ⁷ is isopropyl; and R ⁶ is methyl;

(xvii) R ⁷ is isopropyl; and R ⁶ is trifluoromethyl; (xviii) R ⁷ is isopropyl; and R ⁶ is cyclopropyl; (xix) R ⁷ is isopropyl; and R ⁶ is chloro;

(xx) R ⁷ is ethyl; and R ⁶ is fluoro;

(xxi) R ⁷ is isopropyl; and R ⁶ is cyano;

(xxii) R ⁷ is cyclopropyl; and R ⁶ is cyclopropyl; (xxiii) R ⁷ is cyclopropyl; and R ⁶ is chloro;

(xxiv) R ⁷ is cyclopropyl; and R ⁶ is fluoro;

(xxv) R ⁷ is isopropyl; and R ⁶ is methoxy;

(xxvi) R ⁷ is isopropyl; and R ⁶ is trifluoromethoxy; (xxvii) R ⁷ is chloro; and R ⁶ is trifluoromethyl; or (xxviii) R ⁷ is chloro; and R ⁶ is trifluoromethoxy. In some embodiments, of the compound of formula AA, the substituted ring

and R ⁶ and R ⁷ are one of the following combinations:

(i) each R ⁶ is independently C1-C6 alkyl, and R ⁷ is C1-C6 alkyl optionally substituted with one or more halo;

(ii) each R ⁶ is independently C ₁ -C ₆ alkyl and R ⁷ is C ₁ -C ₆ alkyl;

(iii)each R ⁶ is independently C1-C6 alkyl, and R ⁷ is C1-C6 alkyl substituted with one or more halo;

(iv) each R ⁶ is independently C ₁ -C ₆ alkyl, and R ⁷ is C ₃ -C ₇ cycloalkyl;

(v) each R ⁶ is independently C ₁ -C ₆ alkyl, and R ⁷ is halo;

(vi) each R ⁶ is independently C1-C6 alkyl, and R ⁷ is cyano;

(vii) each R ⁶ is independently C3-C7 cycloalkyl, and R ⁷ is C3-C7 cycloalkyl;

(viii) each R ⁶ is independently C ₃ -C ₇ cycloalkyl, and R ⁷ is halo;

(ix) each R ⁶ is independently cyclopropyl and R ⁷ is halo;

(x) each R ⁶ is independently C1-C6 alkyl, and R ⁷ is C1-C6 alkoxy optionally substituted with one or more halo;

(xi) each R ⁶ is independently C1-C6 alkyl, and R ⁷ is C1-C6 alkoxy;

(xii) each R ⁶ is independently C1-C6 alkyl, and R ⁷ is C1-C6 alkoxy substituted with one or more halo;

(xiii) each R ⁶ is independently halo, and R ⁷ is C ₁ -C ₆ haloalkyl;

(xiv) each R ⁶ is independently halo, and R ⁷ is C1-C6 haloalkoxy;

(xv) each R ⁶ is independently C1-C6 alkoxy; and R ⁷ is halo;

(xvi) each R ⁶ is independently C ₁ -C ₆ alkoxy; and R ⁷ is chloro;

(xvii) R ⁷ is C1-C6 alkyl, and each R ⁶ is independently C1-C6 alkyl optionally substituted with one or more halo;

(xviii) R ⁷ is C ₁ -C ₆ alkyl, and each R ⁶ is independently C ₁ -C ₆ alkyl substituted with one or more halo;

(xix) R ⁷ is C1-C6 alkyl, and each R ⁶ is independently C3-C7 cycloalkyl;

(xx) R ⁷ is C ₁ -C ₆ alkyl, and each R ⁶ is independently halo; (xxi) R ⁷ is C1-C6 alkyl and each R ⁶ is independently halo;

(xxii) R ⁷ is C ₁ -C ₆ alkyl, and R ⁶ is cyano;

(xxiii) R ⁷ is C ₃ -C ₇ cycloalkyl, and each R ⁶ is independently C ₃ -C ₇ cycloalkyl;

(xxiv) R ⁷ is C3-C7 cycloalkyl, and each R ⁶ is independently halo;

(xxv) R ⁷ is C3-C7 cycloalkyl and each R ⁶ is independently halo;

(xxvi) R ⁷ is C ₁ -C ₆ alkyl, and each R ⁶ is independently C ₁ -C ₆ alkoxy optionally

substituted with one or more halo;

(xxvii) R ⁷ is C1-C6 alkyl, and each R ⁶ is independently C1-C6 alkoxy;

(xxviii) R ⁷ is C ₁ -C ₆ alkyl, and each R ⁶ is independently C ₁ -C ₆ alkoxy substituted with one or more halo;

(xxix) R ⁷ is halo, and each R ⁶ is independently C1-C6 haloalkyl;

(xxx) R ⁷ is halo, and each R ⁶ is independently C ₁ -C ₆ haloalkoxy;

(xxxi) R ⁷ is C ₁ -C ₆ alkoxy; and each R ⁶ is independently halo;

(xxxii) R ⁷ is C1-C6 alkoxy; and R ⁶ is chloro;

(xxxiii) R ⁶ and R ⁷ on adjacent atoms taken together with the atoms connecting them form a C ₅ aliphatic carbocyclic ring;

(xxxiv) R ⁶ and R ⁷ on adjacent atoms taken together with the atoms connecting them form a C4-C6 aliphatic carbocyclic ring optionally substituted with one or more hydroxy, oxo, or C ₁ -C ₆ alkyl; and one R ⁶ is halo or cyano; or

(xxxv) R ⁶ and R ⁷ on adjacent atoms taken together with the atoms connecting them form a 5-to-6-membered heterocyclic ring containing 1 heteroatom independently selected from O, N, and S, wherein the heterocyclic ring optionally substituted with one or more hydroxy, oxo, or C ₁ -C ₆ alkyl; and one R ⁶ is halo or cyano. In some embodiments, of the compound of formula AA,

the substituted ring

and R ⁶ and R ⁷ are one of the following combinations:

(i) each R ⁶ is isopropyl; and R ⁷ is methyl; (ii) each R ⁶ is isopropyl; and R ⁷ is isopropyl;

(iii)each R ⁶ is isopropyl; and R ⁷ is trifluoromethyl;

(iv) each R ⁶ is isopropyl; and R ⁷ is cyclopropyl;

(v) each R ⁶ is isopropyl; and R ⁷ is chloro;

(vi) each R ⁶ is isopropyl; and R ⁷ is fluoro;

(vii) each R ⁶ is ethyl; and R ⁷ is fluoro;

(viii) each R ⁶ is isopropyl; and R ⁷ is cyano;

(ix) each R ⁶ is cyclopropyl; and R ⁷ is cyclopropyl;

(x) each R ⁶ is cyclopropyl; and R ⁷ is chloro;

(xi) each R ⁶ is cyclopropyl; and R ⁷ is fluoro;

(xii) each R ⁶ is isopropyl; and R ⁷ is methoxy;

(xiii) each R ⁶ is isopropyl; and R ⁷ is trifluoromethoxy;

(xiv) each R ⁶ is chloro; and R ⁷ is trifluoromethyl;

(xv) each R ⁶ is chloro; and R ⁷ is trifluoromethoxy;

(xvi) R ⁷ is isopropyl; and each R ⁶ is methyl;

(xvii) R ⁷ is isopropyl; and each R ⁶ is trifluoromethyl;

(xviii) R ⁷ is isopropyl; and each R ⁶ is cyclopropyl;

(xix) R ⁷ is isopropyl; and each R ⁶ is chloro;

(xx) R ⁷ is ethyl; and each R ⁶ is fluoro;

(xxi) R ⁷ is isopropyl; and each R ⁶ is cyano;

(xxii) R ⁷ is cyclopropyl; and each R ⁶ is cyclopropyl;

(xxiii) R ⁷ is cyclopropyl; and each R ⁶ is chloro;

(xxiv) R ⁷ is cyclopropyl; and each R ⁶ is fluoro;

(xxv) R ⁷ is isopropyl; and each R ⁶ is methoxy;

(xxvi) R ⁷ is isopropyl; and each R ⁶ is trifluoromethoxy;

(xxvii) R ⁷ is chloro; and each R ⁶ is trifluoromethyl;

(xxviii) R ⁷ is chloro; and each R ⁶ is trifluoromethoxy;

(xxix) one R ⁶ is isopropyl; the other R ⁶ is trifluoromethyl; and R ⁷ is chloro;

(xxx) R ⁶ and R ⁷ on adjacent atoms taken together with the atoms connecting them form a C4 aliphatic carbocyclic ring; and one R ⁶ is fluoro, chloro, or cyano; (xxxi) R ⁶ and R ⁷ on adjacent atoms taken together with the atoms connecting them form a C ₅ aliphatic carbocyclic ring; and one R ⁶ is fluoro, chloro, or cyano;

(xxxii) R ⁶ and R ⁷ on adjacent atoms taken together with the atoms connecting them form a C6 aliphatic carbocyclic ring; and one R ⁶ is fluoro, chloro, or cyano;

(xxxiii) R ⁶ and R ⁷ on adjacent atoms taken together with the atoms connecting them form a 5-membered heterocyclic ring containing 1 heteroatoms independently selected from O, N, and S; and one R ⁶ is fluoro, chloro, or cyano; or

(xxxiv) R ⁶ and R ⁷ on adjacent atoms taken together with the atoms connecting them form a 6-membered heterocyclic ring containing 1 heteroatoms independently selected from O, N, and S; and one R ⁶ is fluoro, chloro, or cyano. In some embodiments, of the compound of formula AA,

the substituted ring

and R ⁶ and R ⁷ are one of the following combinations:

(i) each R ⁶ is independently C1-C6 alkyl, and R ⁷ is C1-C6 alkyl optionally substituted with one or more halo;

(ii) each R ⁶ is independently C ₁ -C ₆ alkyl and R ⁷ is C ₁ -C ₆ alkyl;

(iii)each R ⁶ is independently C ₁ -C ₆ alkyl, and R ⁷ is C ₁ -C ₆ alkyl substituted with one or more halo;

(iv) each R ⁶ is independently C1-C6 alkyl, and R ⁷ is C3-C7 cycloalkyl;

(v) each R ⁶ is independently C ₁ -C ₆ alkyl, and R ⁷ is halo;

(vi) each R ⁶ is independently C1-C6 alkyl, and R ⁷ is cyano;

(vii) each R ⁶ is independently C3-C7 cycloalkyl, and R ⁷ is C3-C7 cycloalkyl;

(viii) each R ⁶ is independently C ₃ -C ₇ cycloalkyl, and R ⁷ is halo;

(ix) each R ⁶ is independently cyclopropyl and R ⁷ is halo;

(x) each R ⁶ is independently C1-C6 alkyl, and R ⁷ is C1-C6 alkoxy optionally substituted with one or more halo;

(xi) each R ⁶ is independently C ₁ -C ₆ alkyl, and R ⁷ is C ₁ -C ₆ alkoxy; (xii) each R ⁶ is independently C1-C6 alkyl, and R ⁷ is C1-C6 alkoxy substituted with one or more halo;

(xiii) each R ⁶ is independently halo, and R ⁷ is C ₁ -C ₆ haloalkyl;

(xiv) each R ⁶ is independently halo, and R ⁷ is C1-C6 haloalkoxy;

(xv) each R ⁶ is independently C1-C6 alkoxy; and R ⁷ is halo;

(xvi) each R ⁶ is independently C ₁ -C ₆ alkoxy; and R ⁷ is chloro;

(xvii) R ⁷ is C1-C6 alkyl, and each R ⁶ is independently C1-C6 alkyl optionally substituted with one or more halo;

(xviii) R ⁷ is C ₁ -C ₆ alkyl, and each R ⁶ is independently C ₁ -C ₆ alkyl substituted with one or more halo;

(xix) R ⁷ is C1-C6 alkyl, and each R ⁶ is independently C3-C7 cycloalkyl;

(xx) R ⁷ is C ₁ -C ₆ alkyl, and each R ⁶ is independently halo;

(xxi) R ⁷ is C ₁ -C ₆ alkyl and each R ⁶ is independently halo;

(xxii) R ⁷ is C1-C6 alkyl, and R ⁶ is cyano;

(xxiii) R ⁷ is C3-C7 cycloalkyl, and each R ⁶ is independently C3-C7 cycloalkyl;

(xxiv) R ⁷ is C ₃ -C ₇ cycloalkyl, and each R ⁶ is independently halo;

(xxv) R ⁷ is C3-C7 cycloalkyl and each R ⁶ is independently halo;

(xxvi) R ⁷ is C1-C6 alkyl, and each R ⁶ is independently C1-C6 alkoxy optionally

substituted with one or more halo;

(xxvii) R ⁷ is C1-C6 alkyl, and each R ⁶ is independently C1-C6 alkoxy;

(xxviii) R ⁷ is C1-C6 alkyl, and each R ⁶ is independently C1-C6 alkoxy substituted with one or more halo;

(xxix) R ⁷ is halo, and each R ⁶ is independently C ₁ -C ₆ haloalkyl;

(xxx) R ⁷ is halo, and each R ⁶ is independently C1-C6 haloalkoxy;

(xxxi) R ⁷ is C ₁ -C ₆ alkoxy; and each R ⁶ is independently halo; or

(xxxii) R ⁷ is C ₁ -C ₆ alkoxy; and R ⁶ is chloro.

In some embodiments, of the compound of formula AA,

and R ⁶ and R ⁷ are one of the following combinations:

(i) each R ⁶ is isopropyl; and R ⁷ is methyl;

(ii) each R ⁶ is isopropyl; and R ⁷ is isopropyl;

(iii)each R ⁶ is isopropyl; and R ⁷ is trifluoromethyl;

(iv) each R ⁶ is isopropyl; and R ⁷ is cyclopropyl;

(v) each R ⁶ is isopropyl; and R ⁷ is chloro;

(vi) each R ⁶ is isopropyl; and R ⁷ is fluoro;

(vii) each R ⁶ is ethyl; and R ⁷ is fluoro;

(viii) each R ⁶ is isopropyl; and R ⁷ is cyano;

(ix) each R ⁶ is cyclopropyl; and R ⁷ is cyclopropyl;

(x) each R ⁶ is cyclopropyl; and R ⁷ is chloro;

(xi) each R ⁶ is cyclopropyl; and R ⁷ is fluoro;

(xii) each R ⁶ is isopropyl; and R ⁷ is methoxy;

(xiii) each R ⁶ is isopropyl; and R ⁷ is trifluoromethoxy;

(xiv) each R ⁶ is chloro; and R ⁷ is trifluoromethyl;

(xv) each R ⁶ is chloro; and R ⁷ is trifluoromethoxy;

(xvi) R ⁷ is isopropyl; and each R ⁶ is methyl;

(xvii) R ⁷ is isopropyl; and each R ⁶ is trifluoromethyl;

(xviii) R ⁷ is isopropyl; and each R ⁶ is cyclopropyl;

(xix) R ⁷ is isopropyl; and each R ⁶ is chloro;

(xx) R ⁷ is ethyl; and each R ⁶ is fluoro;

(xxi) R ⁷ is isopropyl; and each R ⁶ is cyano;

(xxii) R ⁷ is cyclopropyl; and each R ⁶ is cyclopropyl;

(xxiii) R ⁷ is cyclopropyl; and each R ⁶ is chloro;

(xxiv) R ⁷ is cyclopropyl; and each R ⁶ is fluoro;

(xxv) R ⁷ is isopropyl; and each R ⁶ is methoxy;

(xxvi) R ⁷ is isopropyl; and each R ⁶ is trifluoromethoxy;

(xxvii) R ⁷ is chloro; and each R ⁶ is trifluoromethyl;

(xxviii) R ⁷ is chloro; and each R ⁶ is trifluoromethoxy; or

(xxix) one R ⁶ is isopropyl; the other R ⁶ is trifluoromethyl; and R ⁷ is chloro. In some embodiments, of the compound of formula AA,

the substituted ring

and R ⁶ and R ⁷ are one of the following combinations:

(i) R ⁶ is C1-C6 alkyl, and each R ⁷ is independently C1-C6 alkyl optionally substituted with one or more halo;

(ii) R ⁶ is C ₁ -C ₆ alkyl and each R ⁷ is independently C ₁ -C ₆ alkyl;

(iii)R ⁶ is C ₁ -C ₆ alkyl, and each R ⁷ is independently C ₁ -C ₆ alkyl substituted with one or more halo;

(iv) R ⁶ is C1-C6 alkyl, and each R ⁷ is independently C3-C7 cycloalkyl;

(v) R ⁶ is C ₁ -C ₆ alkyl, and each R ⁷ is independently halo;

(vi) R ⁶ is C1-C6 alkyl, and R ⁷ is cyano;

(vii) R ⁶ is C3-C7 cycloalkyl, and each R ⁷ is independently C3-C7 cycloalkyl;

(viii) R ⁶ is C ₃ -C ₇ cycloalkyl, and each R ⁷ is independently halo;

(ix) R ⁶ is cyclopropyl and each R ⁷ is independently halo;

(x) R ⁶ is C1-C6 alkyl, and each R ⁷ is independently C1-C6 alkoxy optionally substituted with one or more halo;

(xi) R ⁶ is C ₁ -C ₆ alkyl, and each R ⁷ is independently C ₁ -C ₆ alkoxy;

(xii) R ⁶ is C1-C6 alkyl, and each R ⁷ is independently C1-C6 alkoxy substituted with one or more halo;

(xiii) R ⁶ is halo, and each R ⁷ is independently C ₁ -C ₆ haloalkyl;

(xiv) R ⁶ is halo, and each R ⁷ is independently C1-C6 haloalkoxy;

(xv) R ⁶ is C1-C6 alkoxy; and each R ⁷ is independently halo;

(xvi) R ⁶ is C ₁ -C ₆ alkoxy; and R ⁷ is chloro;

(xvii) each R ⁷ is independently C1-C6 alkyl, and R ⁶ is C1-C6 alkyl optionally substituted with one or more halo;

(xviii) each R ⁷ is independently C ₁ -C ₆ alkyl, and R ⁶ is C ₁ -C ₆ alkyl substituted with one or more halo;

(xix) each R ⁷ is independently C1-C6 alkyl, and R ⁶ is C3-C7 cycloalkyl;

(xx) each R ⁷ is independently C ₁ -C ₆ alkyl, and R ⁶ is halo; (xxi) each R ⁷ is independently C1-C6 alkyl and R ⁶ is halo;

(xxii) each R ⁷ is independently C ₁ -C ₆ alkyl, and R ⁶ is cyano;

(xxiii) each R ⁷ is independently C ₃ -C ₇ cycloalkyl, and R ⁶ is C ₃ -C ₇ cycloalkyl.

(xxiv) each R ⁷ is independently C3-C7 cycloalkyl, and R ⁶ is halo;

(xxv) each R ⁷ is independently C3-C7 cycloalkyl and R ⁶ is halo;

(xxvi) each R ⁷ is independently C ₁ -C ₆ alkyl, and R ⁶ is C ₁ -C ₆ alkoxy optionally

substituted with one or more halo;

(xxvii) each R ⁷ is independently C1-C6 alkyl, and R ⁶ is C1-C6 alkoxy;

(xxviii) each R ⁷ is independently C ₁ -C ₆ alkyl, and R ⁶ is C ₁ -C ₆ alkoxy substituted with one or more halo;

(xxix) each R ⁷ is independently halo, and R ⁶ is C1-C6 haloalkyl;

(xxx) each R ⁷ is independently halo, and R ⁶ is C ₁ -C ₆ haloalkoxy;

(xxxi) each R ⁷ is independently C ₁ -C ₆ alkoxy; and R ⁶ is halo;

(xxxii) each R ⁷ is independently C1-C6 alkoxy; and R ⁶ is chloro;

(xxxiii) R ⁶ and R ⁷ on adjacent atoms taken together with the atoms connecting them form a C ₅ aliphatic carbocyclic ring;

(xxxiv) R ⁶ and R ⁷ on adjacent atoms taken together with the atoms connecting them form a C4-C6 aliphatic carbocyclic ring optionally substituted with one or more hydroxy, oxo, or C ₁ -C ₆ alkyl; or

(xxxv) R ⁶ and R ⁷ on adjacent atoms taken together with the atoms connecting them form a 5-to-6-membered heterocyclic ring containing 1 heteroatom independently selected from O, N, and S, wherein the heterocyclic ring optionally substituted with one or more hydroxy, oxo, or C ₁ -C ₆ alkyl.

In some embodiments, of the compound of formula AA,

the substituted ring

and R ⁶ and R ⁷ are one of the following combinations: (i) R ⁶ is isopropyl; and each R ⁷ is methyl;

(ii) R ⁶ is isopropyl; and each R ⁷ is isopropyl;

(iii)R ⁶ is isopropyl; and each R ⁷ is trifluoromethyl;

(iv) R ⁶ is isopropyl; and each R ⁷ is cyclopropyl;

(v) R ⁶ is isopropyl; and each R ⁷ is chloro;

(vi) R ⁶ is isopropyl; and each R ⁷ is fluoro;

(vii) R ⁶ is ethyl; and each R ⁷ is fluoro;

(viii) R ⁶ is isopropyl; and each R ⁷ is cyano;

(ix) R ⁶ is cyclopropyl; and each R ⁷ is cyclopropyl;

(x) R ⁶ is cyclopropyl; and each R ⁷ is chloro;

(xi) R ⁶ is cyclopropyl; and each R ⁷ is fluoro;

(xii) R ⁶ is isopropyl; and R ⁷ is methoxy;

(xiii) R ⁶ is isopropyl; and each R ⁷ is trifluoromethoxy;

(xiv) R ⁶ is chloro; and each R ⁷ is trifluoromethyl;

(xv) R ⁶ is chloro; and each R ⁷ is trifluoromethoxy;

(xvi) each R ⁷ is isopropyl; and R ⁶ is methyl;

(xvii) each R ⁷ is isopropyl; and R ⁶ is trifluoromethyl;

(xviii) each R ⁷ is isopropyl; and R ⁶ is cyclopropyl;

(xix) each R ⁷ is isopropyl; and R ⁶ is chloro;

(xx) each R ⁷ is ethyl; and R ⁶ is fluoro;

(xxi) each R ⁷ is isopropyl; and R ⁶ is cyano;

(xxii) each R ⁷ is cyclopropyl; and R ⁶ is cyclopropyl;

(xxiii) each R ⁷ is cyclopropyl; and R ⁶ is chloro;

(xxiv) each R ⁷ is cyclopropyl; and R ⁶ is fluoro;

(xxv) each R ⁷ is isopropyl; and R ⁶ is methoxy;

(xxvi) each R ⁷ is isopropyl; and R ⁶ is trifluoromethoxy;

(xxvii) each R ⁷ is chloro; and R ⁶ is trifluoromethyl;

(xxviii) each R ⁷ is chloro; and R ⁶ is trifluoromethoxy;

(xxix) R ⁶ and R ⁷ on adjacent atoms taken together with the atoms connecting them form a C5 aliphatic carbocyclic ring; and one R ⁷ is fluoro, chloro, or cyano; (xxx) R ⁶ and R ⁷ on adjacent atoms taken together with the atoms connecting them form a C ₄ aliphatic carbocyclic ring; and one R ⁷ is fluoro, chloro, or cyano;

(xxxi) R ⁶ and R ⁷ on adjacent atoms taken together with the atoms connecting them form a C6 aliphatic carbocyclic ring; and one R ⁷ is fluoro, chloro, or cyano;

(xxxii) R ⁶ and R ⁷ on adjacent atoms taken together with the atoms connecting them form a 5-membered heterocyclic ring containing 1 heteroatoms independently selected from O, N, and S; and one R ⁷ is fluoro, chloro, or cyano; or

(xxxiii) R ⁶ and R ⁷ on adjacent atoms taken together with the atoms connecting them form a 6-membered heterocyclic ring containing 1 heteroatoms independently selected from O, N, and S; and one R ⁷ is fluoro, chloro, or cyano. In some embodiments, of the compound of formula AA,

and R ⁶ and R ⁷ are one of the following combinations:

(i) R ⁶ is C1-C6 alkyl, and each R ⁷ is independently C1-C6 alkyl optionally substituted with one or more halo;

(ii) R ⁶ is C ₁ -C ₆ alkyl and each R ⁷ is independently C ₁ -C ₆ alkyl;

(iii) R ⁶ is C1-C6 alkyl, and each R ⁷ is independently C1-C6 alkyl substituted with one or more halo;

(iv) R ⁶ is C ₁ -C ₆ alkyl, and each R ⁷ is independently C ₃ -C ₇ cycloalkyl;

(v) R ⁶ is C1-C6 alkyl, and each R ⁷ is independently halo;

(vi) R ⁶ is C1-C6 alkyl, and R ⁷ is cyano;

(vii) R ⁶ is C ₃ -C ₇ cycloalkyl, and each R ⁷ is independently C ₃ -C ₇ cycloalkyl;

(viii) R ⁶ is C ₃ -C ₇ cycloalkyl, and each R ⁷ is independently halo;

(ix) R ⁶ is cyclopropyl and each R ⁷ is independently halo;

(x) R ⁶ is C1-C6 alkyl, and each R ⁷ is independently C1-C6 alkoxy optionally substituted with one or more halo;

(xi) R ⁶ is C1-C6 alkyl, and each R ⁷ is independently C1-C6 alkoxy; (xii) R ⁶ is C1-C6 alkyl, and each R ⁷ is independently C1-C6 alkoxy substituted with one or more halo;

(xiii) R ⁶ is halo, and each R ⁷ is independently C ₁ -C ₆ haloalkyl;

(xiv) R ⁶ is halo, and each R ⁷ is independently C1-C6 haloalkoxy;

(xv) R ⁶ is C1-C6 alkoxy; and each R ⁷ is independently halo;

(xvi) R ⁶ is C ₁ -C ₆ alkoxy; and R ⁷ is chloro;

(xvii) each R ⁷ is independently C1-C6 alkyl, and R ⁶ is C1-C6 alkyl optionally substituted with one or more halo;

(xviii) each R ⁷ is independently C ₁ -C ₆ alkyl, and R ⁶ is C ₁ -C ₆ alkyl substituted with one or more halo;

(xix) each R ⁷ is independently C1-C6 alkyl, and R ⁶ is C3-C7 cycloalkyl;

(xx) each R ⁷ is independently C ₁ -C ₆ alkyl, and R ⁶ is halo;

(xxi) each R ⁷ is independently C ₁ -C ₆ alkyl and R ⁶ is halo;

(xxii) each R ⁷ is independently C1-C6 alkyl, and R ⁶ is cyano;

(xxiii) each R ⁷ is independently C3-C7 cycloalkyl, and R ⁶ is C3-C7 cycloalkyl;

(xxiv) each R ⁷ is independently C ₃ -C ₇ cycloalkyl, and R ⁶ is halo;

(xxv) each R ⁷ is independently C3-C7 cycloalkyl and R ⁶ is halo;

(xxvi) each R ⁷ is independently C1-C6 alkyl, and R ⁶ is C1-C6 alkoxy optionally substituted with one or more halo;

(xxvii) each R ⁷ is independently C1-C6 alkyl, and R ⁶ is C1-C6 alkoxy;

(xxviii)each R ⁷ is independently C1-C6 alkyl, and R ⁶ is C1-C6 alkoxy substituted with one or more halo;

(xxix) each R ⁷ is independently halo, and R ⁶ is C ₁ -C ₆ haloalkyl;

(xxx) each R ⁷ is independently halo, and R ⁶ is C1-C6 haloalkoxy;

(xxxi) each R ⁷ is independently C ₁ -C ₆ alkoxy; and R ⁶ is halo;

(xxxii) each R ⁶ is independently C ₁ -C ₆ alkoxy; and R ⁶ is chloro;

(xxxiii)R ⁶ and R ⁷ on adjacent atoms taken together with the atoms connecting them form a C5 aliphatic carbocyclic ring;

(xxxiv) R ⁶ and R ⁷ on adjacent atoms taken together with the atoms connecting them form a C4-C6 aliphatic carbocyclic ring optionally substituted with one or more hydroxy, oxo, or C1-C6 alkyl; or (xxxiv) R ⁶ and R ⁷ on adjacent atoms taken together with the atoms connecting them form a 5-to-6-membered heterocyclic ring containing 1 heteroatom independently selected from O, N, and S, wherein the heterocyclic ring optionally substituted with one or more hydroxy, oxo, or C1-C6 alkyl.

In some embodiments, of the compound of formula AA,

and R ⁶ and R ⁷ are one of the following combinations:

(i) R ⁶ is isopropyl; and each R ⁷ is methyl;

(ii) R ⁶ is isopropyl; and each R ⁷ is isopropyl;

(iii) R ⁶ is isopropyl; and each R ⁷ is trifluoromethyl;

(iv) R ⁶ is isopropyl; and each R ⁷ is cyclopropyl;

(v) R ⁶ is isopropyl; and each R ⁷ is chloro;

(vi) R ⁶ is isopropyl; and each R ⁷ is fluoro;

(vii) R ⁶ is ethyl; and each R ⁷ is fluoro;

(viii) R ⁶ is isopropyl; and each R ⁷ is cyano;

(ix) R ⁶ is cyclopropyl; and each R ⁷ is cyclopropyl;

(x) R ⁶ is cyclopropyl; and each R ⁷ is chloro;

(xi) R ⁶ is cyclopropyl; and each R ⁷ is fluoro;

(xii) R ⁶ is isopropyl; and each R ⁷ is methoxy;

(xiii) R ⁶ is isopropyl; and each R ⁷ is trifluoromethoxy;

(xiv) R ⁶ is chloro; and each R ⁷ is trifluoromethyl;

(xv) R ⁶ is chloro; and each R ⁷ is trifluoromethoxy;

(xvi) each R ⁷ is isopropyl; and R ⁶ is methyl;

(xvii) each R ⁷ is isopropyl; and R ⁶ is trifluoromethyl;

(xviii) each R ⁷ is isopropyl; and R ⁶ is cyclopropyl;

(xix) each R ⁷ is isopropyl; and R ⁶ is chloro;

(xx) each R ⁷ is ethyl; and R ⁶ is fluoro; (xxi) each R ⁷ is isopropyl; and R ⁶ is cyano;

(xxii) each R ⁷ is cyclopropyl; and R ⁶ is cyclopropyl;

(xxiii) each R ⁷ is cyclopropyl; and R ⁶ is chloro;

(xxiv) each R ⁷ is cyclopropyl; and R ⁶ is fluoro;

(xxv) each R ⁷ is isopropyl; and R ⁶ is methoxy;

(xxvi) each R ⁷ is isopropyl; and R ⁶ is trifluoromethoxy;

(xxvii) each R ⁷ is chloro; and R ⁶ is trifluoromethyl;

(xxviii)each R ⁷ is chloro; and R ⁶ is trifluoromethoxy;

(xxix) R ⁶ and R ⁷ on adjacent atoms taken together with the atoms connecting them form a C ₅ aliphatic carbocyclic ring; and one R ⁷ is fluoro, chloro, or cyano;

(xxx) R ⁶ and R ⁷ on adjacent atoms taken together with the atoms connecting them form a C ₄ aliphatic carbocyclic ring; and one R ⁷ is fluoro, chloro, or cyano;

(xxxi) R ⁶ and R ⁷ on adjacent atoms taken together with the atoms connecting them form a C6 aliphatic carbocyclic ring; and one R ⁷ is fluoro, chloro, or cyano;

(xxxii) R ⁶ and R ⁷ on adjacent atoms taken together with the atoms connecting them form a 5- membered heterocyclic ring containing 1 heteroatoms independently selected from O, N, and S; and one R ⁷ is fluoro, chloro, or cyano; or

(xxxiii)R ⁶ and R ⁷ on adjacent atoms taken together with the atoms connecting them form a 6- membered heterocyclic ring containing 1 heteroatoms independently selected from O, N, and S; and one R ⁷ is fluoro, chloro, or cyano. In some embodiments, of the compound of formula AA,

and R ⁶ and R ⁷ are one of the following combinations:

(i) each R ⁶ is independently C1-C6 alkyl, and R ⁷ is C1-C6 alkyl optionally substituted with one or more halo;

(ii) each R ⁶ is independently C ₁ -C ₆ alkyl and R ⁷ is C ₁ -C ₆ alkyl;

(iii)each R ⁶ is independently C1-C6 alkyl, and R ⁷ is C1-C6 alkyl substituted with one or more halo; (iv) each R ⁶ is independently C1-C6 alkyl, and R ⁷ is C3-C7 cycloalkyl;

(v) each R ⁶ is independently C ₁ -C ₆ alkyl, and R ⁷ is halo;

(vi) each R ⁶ is independently C ₁ -C ₆ alkyl, and R ⁷ is cyano;

(vii) each R ⁶ is independently C3-C7 cycloalkyl, and R ⁷ is C3-C7 cycloalkyl;

(viii) each R ⁶ is independently C3-C7 cycloalkyl, and R ⁷ is halo;

(ix) each R ⁶ is independently cyclopropyl and R ⁷ is halo;

(x) each R ⁶ is independently C1-C6 alkyl, and R ⁷ is C1-C6 alkoxy optionally substituted with one or more halo;

(xi) each R ⁶ is independently C ₁ -C ₆ alkyl, and R ⁷ is C ₁ -C ₆ alkoxy;

(xii) each R ⁶ is independently C ₁ -C ₆ alkyl, and R ⁷ is C ₁ -C ₆ alkoxy substituted with one or more halo;

(xiii) each R ⁶ is independently halo, and R ⁷ is C ₁ -C ₆ haloalkyl;

(xiv) each R ⁶ is independently halo, and R ⁷ is C ₁ -C ₆ haloalkoxy;

(xv) each R ⁶ is independently C1-C6 alkoxy; and R ⁷ is halo;

(xvi) each R ⁶ is independently C1-C6 alkoxy; and R ⁷ is chloro;

(xvii) R ⁷ is C ₁ -C ₆ alkyl, and each R ⁶ is independently C ₁ -C ₆ alkyl optionally substituted with one or more halo;

(xviii) R ⁷ is C1-C6 alkyl, and each R ⁶ is independently C1-C6 alkyl substituted with one or more halo;

(xix) R ⁷ is C1-C6 alkyl, and each R ⁶ is independently C3-C7 cycloalkyl;

(xx) R ⁷ is C1-C6 alkyl, and each R ⁶ is independently halo;

(xxi) R ⁷ is C ₁ -C ₆ alkyl and each R ⁶ is independently halo;

(xxii) R ⁷ is C ₁ -C ₆ alkyl, and R ⁶ is cyano;

(xxiii) R ⁷ is C3-C7 cycloalkyl, and each R ⁶ is independently C3-C7 cycloalkyl;

(xxiv) R ⁷ is C ₃ -C ₇ cycloalkyl, and each R ⁶ is independently halo;

(xxv) R ⁷ is C ₃ -C ₇ cycloalkyl and each R ⁶ is independently halo;

(xxvi) R ⁷ is C1-C6 alkyl, and each R ⁶ is independently C1-C6 alkoxy optionally

substituted with one or more halo;

(xxvii) R ⁷ is C ₁ -C ₆ alkyl, and each R ⁶ is independently C ₁ -C ₆ alkoxy;

(xxviii) R ⁷ is C1-C6 alkyl, and each R ⁶ is independently C1-C6 alkoxy substituted with one or more halo; (xxix) R ⁷ is halo, and each R ⁶ is independently C1-C6 haloalkyl; (xxx) R ⁷ is halo, and each R ⁶ is independently C ₁ -C ₆ haloalkoxy; (xxxi) R ⁷ is C ₁ -C ₆ alkoxy; and each R ⁶ is independently halo; or (xxxii) R ⁷ is C1-C6 alkoxy; and R ⁶ is chloro. In some embodiments, of the compound of formula AA,

and R ⁶ and R ⁷ are one of the following combinations:

(i) each R ⁶ is isopropyl; and R ⁷ is methyl;

(ii) each R ⁶ is isopropyl; and R ⁷ is isopropyl;

(iii)each R ⁶ is isopropyl; and R ⁷ is trifluoromethyl;

(iv) each R ⁶ is isopropyl; and R ⁷ is cyclopropyl;

(v) each R ⁶ is isopropyl; and R ⁷ is chloro;

(vi) each R ⁶ is isopropyl; and R ⁷ is fluoro;

(vii) each R ⁶ is ethyl; and R ⁷ is fluoro;

(viii) each R ⁶ is isopropyl; and R ⁷ is cyano;

(ix) each R ⁶ is cyclopropyl; and R ⁷ is cyclopropyl;

(x) each R ⁶ is cyclopropyl; and R ⁷ is chloro;

(xi) each R ⁶ is cyclopropyl; and R ⁷ is fluoro;

(xii) each R ⁶ is isopropyl; and R ⁷ is methoxy;

(xiii) each R ⁶ is isopropyl; and R ⁷ is trifluoromethoxy;

(xiv) each R ⁶ is chloro; and R ⁷ is trifluoromethyl;

(xv) each R ⁶ is chloro; and R ⁷ is trifluoromethoxy;

(xvi) R ⁷ is isopropyl; and each R ⁶ is methyl;

(xvii) R ⁷ is isopropyl; and each R ⁶ is trifluoromethyl;

(xviii) R ⁷ is isopropyl; and each R ⁶ is cyclopropyl;

(xix) R ⁷ is isopropyl; and each R ⁶ is chloro;

(xx) R ⁷ is ethyl; and each R ⁶ is fluoro; (xxi) R ⁷ is isopropyl; and each R ⁶ is cyano;

(xxii) R ⁷ is cyclopropyl; and each R ⁶ is cyclopropyl;

(xxiii) R ⁷ is cyclopropyl; and each R ⁶ is chloro;

(xxiv) R ⁷ is cyclopropyl; and each R ⁶ is fluoro;

(xxv) R ⁷ is isopropyl; and each R ⁶ is methoxy;

(xxvi) R ⁷ is isopropyl; and each R ⁶ is trifluoromethoxy;

(xxvii) R ⁷ is chloro; and each R ⁶ is trifluoromethyl;

(xxviii) R ⁷ is chloro; and each R ⁶ is trifluoromethoxy; or

(xxix) one R ⁶ is isopropyl; the other R ⁶ is trifluoromethyl; and R ⁷ is chloro. In some embodiments, of the compound of formula AA,

and R ⁶ and R ⁷ are one of the following combinations:

(i) R ⁶ is C1-C6 alkyl, and each R ⁷ is independently C1-C6 alkyl optionally substituted with one or more halo;

(ii) R ⁶ is C1-C6 alkyl and each R ⁷ is independently C1-C6 alkyl;

(iii)R ⁶ is C1-C6 alkyl, and each R ⁷ is independently C1-C6 alkyl substituted with one or more halo;

(iv) R ⁶ is C ₁ -C ₆ alkyl, and each R ⁷ is independently C ₃ -C ₇ cycloalkyl;

(v) R ⁶ is C1-C6 alkyl, and each R ⁷ is independently halo;

(vi) R ⁶ is C1-C6 alkyl, and R ⁷ is cyano;

(vii) R ⁶ is C ₃ -C ₇ cycloalkyl, and each R ⁷ is independently C ₃ -C ₇ cycloalkyl;

(viii) R ⁶ is C3-C7 cycloalkyl, and each R ⁷ is independently halo;

(ix) R ⁶ is cyclopropyl and each R ⁷ is independently halo;

(x) R ⁶ is C ₁ -C ₆ alkyl, and each R ⁷ is independently C ₁ -C ₆ alkoxy optionally substituted with one or more halo;

(xi) R ⁶ is C1-C6 alkyl, and each R ⁷ is independently C1-C6 alkoxy;

(xii) R ⁶ is C ₁ -C ₆ alkyl, and each R ⁷ is independently C ₁ -C ₆ alkoxy substituted with one or more halo;

(xiii) R ⁶ is halo, and each R ⁷ is independently C1-C6 haloalkyl; (xiv) R ⁶ is halo, and each R ⁷ is independently C1-C6 haloalkoxy;

(xv) R ⁶ is C ₁ -C ₆ alkoxy; and each R ⁷ is independently halo;

(xvi) R ⁶ is C ₁ -C ₆ alkoxy; and R ⁷ is chloro;

(xvii) each R ⁷ is independently C1-C6 alkyl, and R ⁶ is C1-C6 alkyl optionally substituted with one or more halo;

(xviii) each R ⁷ is independently C ₁ -C ₆ alkyl, and R ⁶ is C ₁ -C ₆ alkyl substituted with one or more halo;

(xix) each R ⁷ is independently C1-C6 alkyl, and R ⁶ is C3-C7 cycloalkyl;

(xx) each R ⁷ is independently C ₁ -C ₆ alkyl, and R ⁶ is halo;

(xxi) each R ⁷ is independently C ₁ -C ₆ alkyl and R ⁶ is halo;

(xxii) each R ⁷ is independently C1-C6 alkyl, and R ⁶ is cyano;

(xxiii) each R ⁷ is independently C ₃ -C ₇ cycloalkyl, and R ⁶ is C ₃ -C ₇ cycloalkyl;

(xxiv) each R ⁷ is independently C ₃ -C ₇ cycloalkyl, and R ⁶ is halo;

(xxv) each R ⁷ is independently C3-C7 cycloalkyl and R ⁶ is halo;

(xxvi) each R ⁷ is independently C1-C6 alkyl, and R ⁶ is C1-C6 alkoxy optionally

substituted with one or more halo;

(xxvii) each R ⁷ is independently C1-C6 alkyl, and R ⁶ is C1-C6 alkoxy;

(xxviii) each R ⁷ is independently C1-C6 alkyl, and R ⁶ is C1-C6 alkoxy substituted with one or more halo;

(xxix) each R ⁷ is independently halo, and R ⁶ is C1-C6 haloalkyl;

(xxx) each R ⁷ is independently halo, and R ⁶ is C1-C6 haloalkoxy;

(xxxi) each R ⁷ is independently C ₁ -C ₆ alkoxy; and R ⁶ is halo; or

(xxxii) each R ⁷ is independently C ₁ -C ₆ alkoxy; and R ⁶ is chloro. In some embodiments, of the compound of formula AA,

the substituted ring

and R ⁶ and R ⁷ are one of the following combinations:

(i) R ⁶ is isopropyl; and each R ⁷ is methyl;

(ii) R ⁶ is isopropyl; and each R ⁷ is isopropyl; (iii)R ⁶ is isopropyl; and each R ⁷ is trifluoromethyl;

(iv) R ⁶ is isopropyl; and each R ⁷ is cyclopropyl;

(v) R ⁶ is isopropyl; and each R ⁷ is chloro;

(vi) R ⁶ is isopropyl; and each R ⁷ is fluoro;

(vii) R ⁶ is ethyl; and each R ⁷ is fluoro;

(viii) R ⁶ is isopropyl; and each R ⁷ is cyano;

(ix) R ⁶ is cyclopropyl; and each R ⁷ is cyclopropyl;

(x) R ⁶ is cyclopropyl; and each R ⁷ is chloro;

(xi) R ⁶ is cyclopropyl; and each R ⁷ is fluoro;

(xii) R ⁶ is isopropyl; and each R ⁷ is methoxy;

(xiii) ;R ⁶ is isopropyl; and each R ⁷ is trifluoromethoxy; (xiv) R ⁶ is chloro; and each R ⁷ is trifluoromethyl; (xv) R ⁶ is chloro; and each R ⁷ is trifluoromethoxy; (xvi) each R ⁷ is isopropyl; and R ⁶ is methyl;

(xvii) each R ⁷ is isopropyl; and R ⁶ is trifluoromethyl; (xviii) each R ⁷ is isopropyl; and R ⁶ is cyclopropyl; (xix) each R ⁷ is isopropyl; and R ⁶ is chloro;

(xx) each R ⁷ is ethyl; and R ⁶ is fluoro;

(xxi) each R ⁷ is isopropyl; and R ⁶ is cyano;

(xxii) each R ⁷ is cyclopropyl; and R ⁶ is cyclopropyl; (xxiii) each R ⁷ is cyclopropyl; and R ⁶ is chloro;

(xxiv) each R ⁷ is cyclopropyl; and R ⁶ is fluoro;

(xxv) each R ⁷ is isopropyl; and R ⁶ is methoxy;

(xxvi) each R ⁷ is isopropyl; and R ⁶ is trifluoromethoxy; (xxvii) each R ⁷ is chloro; and R ⁶ is trifluoromethyl; or (xxviii) each R ⁷ is chloro; and R ⁶ is trifluoromethoxy. In some embodiments, of the compound of formula AA,

and R ⁶ and R ⁷ are one of the following combinations:

(i) each R ⁶ is independently C ₁ -C ₆ alkyl, and each R ⁷ is independently C ₁ -C ₆ alkyl optionally substituted with one or more halo;

(ii) each R ⁶ is independently C1-C6 alkyl and each R ⁷ is independently C1-C6 alkyl;;

(iii)each R ⁶ is independently C1-C6 alkyl, and each R ⁷ is independently C1-C6 alkyl

substituted with one or more halo;

(iv) each R ⁶ is independently C1-C6 alkyl, and each R ⁷ is independently C3-C7 cycloalkyl; (v) each R ⁶ is independently C1-C6 alkyl, and each R ⁷ is independently halo;

(vi) each R ⁶ is independently C ₁ -C ₆ alkyl, and R ⁷ is cyano;

(vii) each R ⁶ is independently C ₃ -C ₇ cycloalkyl, and each R ⁷ is independently C ₃ -C ₇ cycloalkyl;

(viii) each R ⁶ is independently C ₃ -C ₇ cycloalkyl, and each R ⁷ is independently halo; (ix) each R ⁶ is independently cyclopropyl and each R ⁷ is independently halo;

(x) each R ⁶ is independently C1-C6 alkyl, and each R ⁷ is independently C1-C6 alkoxy

optionally substituted with one or more halo;

(xi) each R ⁶ is independently C ₁ -C ₆ alkyl, and each R ⁷ is independently C ₁ -C ₆ alkoxy;

(xii) each R ⁶ is independently C1-C6 alkyl, and each R ⁷ is independently C1-C6 alkoxy substituted with one or more halo;

(xiii) each R ⁶ is independently halo, and each R ⁷ is independently C ₁ -C ₆ haloalkyl; (xiv) each R ⁶ is independently halo, and each R ⁷ is independently C1-C6 haloalkoxy; (xv) each R ⁶ is independently C1-C6 alkoxy; and each R ⁷ is independently halo;

(xvi) each R ⁶ is independently C ₁ -C ₆ alkoxy; and R ⁷ is chloro;

(xvii) each R ⁷ is independently C ₁ -C ₆ alkyl, and each R ⁶ is independently C ₁ -C ₆ alkyl optionally substituted with one or more halo;

(xviii) each R ⁷ is independently C ₁ -C ₆ alkyl, and each R ⁶ is independently C ₁ -C ₆ alkyl substituted with one or more halo;

(xix) each R ⁷ is independently C1-C6 alkyl, and each R ⁶ is independently C3-C7

cycloalkyl;

(xx) each R ⁷ is independently C ₁ -C ₆ alkyl, and each R ⁶ is independently halo;

(xxi) each R ⁷ is independently C1-C6 alkyl and each R ⁶ is independently halo;

(xxii) each R ⁷ is independently C1-C6 alkyl, and R ⁶ is cyano; (xxiii) each R ⁷ is independently C3-C7 cycloalkyl, and each R ⁶ is independently C3-C7 cycloalkyl

(xxiv) each R ⁷ is independently C ₃ -C ₇ cycloalkyl, and each R ⁶ is independently halo; (xxv) each R ⁷ is independently C3-C7 cycloalkyl and each R ⁶ is independently halo; (xxvi) each R ⁷ is independently C1-C6 alkyl, and each R ⁶ is independently C1-C6 alkoxy optionally substituted with one or more halo;

(xxvii) each R ⁷ is independently C1-C6 alkyl, and each R ⁶ is independently C1-C6 alkoxy; (xxviii) each R ⁷ is independently C1-C6 alkyl, and each R ⁶ is independently C1-C6 alkoxy substituted with one or more halo;

(xxix) each R ⁷ is independently halo, and each R ⁶ is independently C ₁ -C ₆ haloalkyl; (xxx) each R ⁷ is independently halo, and each R ⁶ is independently C1-C6 haloalkoxy; (xxxi) each R ⁷ is independently C ₁ -C ₆ alkoxy; and each R ⁶ is independently halo;

(xxxii) each R ⁷ is independently C ₁ -C ₆ alkoxy; and R ⁶ is chloro;

(xxxiii) 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 C4-C8 aliphatic carbocyclic ring;

(xxxiv) 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 C4-C6 aliphatic carbocyclic ring optionally substituted with one or more hydroxy, oxo, or C ₁ -C ₆ alkyl; (xxxv) two pairs, each of one R ⁶ and one R ⁷ , are on adjacent atoms, and one pair of one R ⁶ and one R ⁷ taken together with the atoms connecting them form a C4-C6 aliphatic carbocyclic ring optionally substituted with one or more hydroxy, oxo, or C ₁ -C ₆ alkyl, and the other pair of one R ⁶ and one R ⁷ taken together with the atoms connecting them form a 5-to-6-membered heterocyclic ring containing 1 heteroatom independently selected from O, N, and S, wherein the heterocyclic ring is optionally substituted with one or more hydroxy, oxo, or C ₁ -C ₆ alkyl; or

(xxxvi) 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-to-6-membered heterocyclic ring containing 1 heteroatom independently selected from O, N, and S, wherein the heterocyclic ring optionally substituted with one or more hydroxy, oxo, or C1-C6 alkyl. In some embodiments, of the compound of formula AA,

and R ⁶ and R ⁷ are one of the following combinations:

(i) each R ⁶ is isopropyl; and each R ⁷ is methyl;

(ii) each R ⁶ is isopropyl; and each R ⁷ is isopropyl;

(iii)each R ⁶ is isopropyl; and each R ⁷ is trifluoromethyl;

(iv) each R ⁶ is isopropyl; and each R ⁷ is cyclopropyl;

(v) each R ⁶ is isopropyl; and each R ⁷ is chloro;

(vi) each R ⁶ is isopropyl; and each R ⁷ is fluoro;

(vii) each R ⁶ is ethyl; and each R ⁷ is fluoro;

(viii) each R ⁶ is isopropyl; and each R ⁷ is cyano;

(ix) each R ⁶ is cyclopropyl; and each R ⁷ is cyclopropyl;

(x) each R ⁶ is cyclopropyl; and each R ⁷ is chloro;

(xi) each R ⁶ is cyclopropyl; and each R ⁷ is fluoro;

(xii) each R ⁶ is isopropyl; and each R ⁷ is methoxy;

(xiii) each R ⁶ is isopropyl; and each R ⁷ is trifluoromethoxy; (xiv) each R ⁶ is chloro; and each R ⁷ is trifluoromethyl; (xv) each R ⁶ is chloro; and each R ⁷ is trifluoromethoxy; (xvi) each R ⁷ is isopropyl; and each R ⁶ is methyl;

(xvii) each R ⁷ is isopropyl; and each R ⁶ is trifluoromethyl; (xviii) each R ⁷ is isopropyl; and each R ⁶ is cyclopropyl; (xix) each R ⁷ is isopropyl; and each R ⁶ is chloro;

(xx) each R ⁷ is ethyl; and each R ⁶ is fluoro;

(xxi) each R ⁷ is isopropyl; and each R ⁶ is cyano;

(xxii) each R ⁷ is cyclopropyl; and each R ⁶ is cyclopropyl; (xxiii) each R ⁷ is cyclopropyl; and each R ⁶ is chloro;

(xxiv) each R ⁷ is cyclopropyl; and each R ⁶ is fluoro; (xxv) each R ⁷ is isopropyl; and each R ⁶ is methoxy;

(xxvi) each R ⁷ is isopropyl; and each R ⁶ is trifluoromethoxy;

(xxvii) each R ⁷ is chloro; and each R ⁶ is trifluoromethyl;

(xxviii) each R ⁷ is chloro; and each R ⁶ is trifluoromethoxy;

(xxix) one R ⁶ is isopropyl; the other R ⁶ is trifluoromethyl; and each R ⁷ is chloro;

(xxx) each R ⁶ is isopropyl; one R ⁷ is fluoro; and the other R ⁷ is cyano;

(xxxi) 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;

(xxxii) 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 C4 aliphatic carbocyclic ring optionally substituted with one or more hydroxy, oxo, or methyl;

(xxxiii) 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 optionally substituted with one or more hydroxy, oxo, or methyl;

(xxxiv) 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 optionally substituted with one or more hydroxy, oxo, or methyl;

(xxxv) 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 heteroatom independently selected from O, N, and S, wherein the heterocyclic ring is optionally substituted with one or more hydroxy, oxo, or methyl;

(xxxvi) 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 heteroatom independently selected from O, N, and S, wherein the heterocyclic ring is optionally substituted with one or more hydroxy, oxo, or methyl; or

(xxxvii) 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 5-membered heterocyclic ring containing 1 heteroatom independently selected from O, N, and S, wherein the heterocyclic ring is optionally substituted with one or more hydroxy, oxo, or methyl, 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 optionally substituted with one or more hydroxy, oxo, or methyl . In some embodiments, of the compound of formula AA,

and R ⁶ and R ⁷ are one of the following combinations:

(i) each R ⁶ is independently C1-C6 alkyl, and each R ⁷ is independently C1-C6 alkyl

optionally substituted with one or more halo;

(ii) each R ⁶ is independently C ₁ -C ₆ alkyl and each R ⁷ is independently C ₁ -C ₆ alkyl;

(iii) each R ⁶ is independently C1-C6 alkyl, and each R ⁷ is independently C1-C6 alkyl

substituted with one or more halo;

(iv) each R ⁶ is independently C ₁ -C ₆ alkyl, and each R ⁷ is independently C ₃ -C ₇ cycloalkyl; (v) each R ⁶ is independently C ₁ -C ₆ alkyl, and each R ⁷ is independently halo;

(vi) each R ⁶ is independently C1-C6 alkyl, and R ⁷ is cyano;

(vii) each R ⁶ is independently C3-C7 cycloalkyl, and each R ⁷ is independently C3-C7

cycloalkyl;

(viii) each R ⁶ is independently C3-C7 cycloalkyl, and each R ⁷ is independently halo;

(ix) each R ⁶ is independently cyclopropyl and each R ⁷ is independently halo;

(x) each R ⁶ is independently C ₁ -C ₆ alkyl, and each R ⁷ is independently C ₁ -C ₆ alkoxy optionally substituted with one or more halo;

(xi) each R ⁶ is independently C1-C6 alkyl, and each R ⁷ is independently C1-C6 alkoxy; (xii) each R ⁶ is independently C ₁ -C ₆ alkyl, and each R ⁷ is independently C ₁ -C ₆ alkoxy substituted with one or more halo;

(xiii) each R ⁶ is independently halo, and each R ⁷ is independently C1-C6 haloalkyl;

(xiv) each R ⁶ is independently halo, and each R ⁷ is independently C1-C6 haloalkoxy;

(xv) each R ⁶ is independently C ₁ -C ₆ alkoxy; and each R ⁷ is independently halo; (xvi) each R ⁶ is independently C1-C6 alkoxy; and R ⁷ is chloro;

(xvii) each R ⁷ is independently C ₁ -C ₆ alkyl, and each R ⁶ is independently C ₁ -C ₆ alkyl

optionally substituted with one or more halo;

(xviii) each R ⁷ is independently C1-C6 alkyl, and each R ⁶ is independently C1-C6 alkyl

substituted with one or more halo;

(xix) each R ⁷ is independently C ₁ -C ₆ alkyl, and each R ⁶ is independently C ₃ -C ₇ cycloalkyl; (xx) each R ⁷ is independently C1-C6 alkyl, and each R ⁶ is independently halo;

(xxi) each R ⁷ is independently C1-C6 alkyl and each R ⁶ is independently halo;

(xxii) each R ⁷ is independently C ₁ -C ₆ alkyl, and R ⁶ is cyano;

(xxiii) each R ⁷ is independently C ₃ -C ₇ cycloalkyl, and each R ⁶ is independently C ₃ -C ₇

cycloalkyl;

(xxiv) each R ⁷ is independently C ₃ -C ₇ cycloalkyl, and each R ⁶ is independently halo;

(xxv) each R ⁷ is independently C ₃ -C ₇ cycloalkyl and each R ⁶ is independently halo;

(xxvi) each R ⁷ is independently C1-C6 alkyl, and each R ⁶ is independently C1-C6 alkoxy optionally substituted with one or more halo;

(xxvii) each R ⁷ is independently C ₁ -C ₆ alkyl, and each R ⁶ is independently C ₁ -C ₆ alkoxy; (xxviii)each R ⁷ is independently C1-C6 alkyl, and each R ⁶ is independently C1-C6 alkoxy substituted with one or more halo;

(xxix) each R ⁷ is independently halo, and each R ⁶ is independently C ₁ -C ₆ haloalkyl;

(xxx) each R ⁷ is independently halo, and each R ⁶ is independently C1-C6 haloalkoxy;

(xxxi) each R ⁷ is independently C1-C6 alkoxy; and each R ⁶ is independently halo;

(xxxii) each R ⁷ is independently C ₁ -C ₆ alkoxy; and R ⁶ is chloro;

(xxxiii) 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 C4-C8 aliphatic carbocyclic ring;

(xxxiv) two pairs, each of one R ⁶ and one R ⁷ on adjacent atoms taken together with the atoms connecting them form a C4-C6 aliphatic carbocyclic ring optionally substituted with one or more hydroxy, oxo, or C1-C6 alkyl; or

(xxxv) two pairs, each of one R ⁶ and one R ⁷ on adjacent atoms taken together with the atoms connecting them form a 5-to-6-membered heterocyclic ring containing 1 heteroatom independently selected from O, N, and S, wherein the heterocyclic ring optionally substituted with one or more hydroxy, oxo, or C ₁ -C ₆ alkyl. In some embodiments, of the compound of formula AA,

the substituted ring B is

and R ⁶ and R ⁷ are one of the following combinations:

(i) each R ⁶ is isopropyl; and each R ⁷ is methyl;

(ii) each R ⁶ is isopropyl; and each R ⁷ is isopropyl;

(iii) each R ⁶ is isopropyl; and each R ⁷ is trifluoromethyl;

(iv) each R ⁶ is isopropyl; and each R ⁷ is cyclopropyl;

(v) each R ⁶ is isopropyl; and each R ⁷ is chloro;

(vi) each R ⁶ is isopropyl; and each R ⁷ is fluoro;

(vii) each R ⁶ is ethyl; and each R ⁷ is fluoro;

(viii) each R ⁶ is isopropyl; and each R ⁷ is cyano;

(ix) each R ⁶ is cyclopropyl; and each R ⁷ is cyclopropyl;

(x) each R ⁶ is cyclopropyl; and each R ⁷ is chloro;

(xi) each R ⁶ is cyclopropyl; and each R ⁷ is fluoro;

(xii) each R ⁶ is isopropyl; and each R ⁷ is methoxy;

(xiii) each R ⁶ is isopropyl; and each R ⁷ is trifluoromethoxy;

(xiv) each R ⁶ is chloro; and each R ⁷ is trifluoromethyl;

(xv) each R ⁶ is chloro; and each R ⁷ is trifluoromethoxy;

(xvi) each R ⁷ is isopropyl; and each R ⁶ is methyl;

(xvii) each R ⁷ is isopropyl; and each R ⁶ is trifluoromethyl;

(xviii) each R ⁷ is isopropyl; and each R ⁶ is cyclopropyl;

(xix) each R ⁷ is isopropyl; and each R ⁶ is chloro;

(xx) each R ⁷ is ethyl; and each R ⁶ is fluoro;

(xxi) each R ⁷ is isopropyl; and each R ⁶ is cyano;

(xxii) each R ⁷ is cyclopropyl; and each R ⁶ is cyclopropyl; (xxiii) each R ⁷ is cyclopropyl; and each R ⁶ is chloro;

(xxiv) each R ⁷ is cyclopropyl; and each R ⁶ is fluoro;

(xxv) each R ⁷ is isopropyl; and each R ⁶ is methoxy;

(xxvi) each R ⁷ is isopropyl; and each R ⁶ is trifluoromethoxy;

(xxvii) each R ⁷ is chloro; and each R ⁶ is trifluoromethyl;

(xxviii)each R ⁷ is chloro; and each R ⁶ is trifluoromethoxy;

(xxix) one R ⁶ is isopropyl; the other R ⁶ is trifluoromethyl; and each R ⁷ is chloro;

(xxx) each R ⁶ is isopropyl; one R ⁷ is fluoro; and the other R ⁷ is cyano; or

(xxxi) two pairs, each of one R ⁶ and one R ⁷ on adjacent atoms taken together with the atoms connecting them form a C ₄ aliphatic carbocyclic ring optionally substituted with one or more hydroxy, oxo, or methyl;

(xxxii) two pairs, each of one R ⁶ and one R ⁷ on adjacent atoms taken together with the atoms connecting them form a C ₅ aliphatic carbocyclic ring optionally substituted with one or more hydroxy, oxo, or methyl;

(xxxiii)two pairs, each of one R ⁶ and one R ⁷ on adjacent atoms taken together with the atoms connecting them form a C ₆ aliphatic carbocyclic ring optionally substituted with one or more hydroxy, oxo, or methyl;

(xxxiv) two pairs, each of one R ⁶ and one R ⁷ on adjacent atoms taken together with the atoms connecting them form a 5-membered heterocyclic ring containing 1 heteroatom independently selected from O, N, and S, wherein the heterocyclic ring is optionally substituted with one or more hydroxy, oxo, or methyl;

(xxxv) two pairs, each of one R ⁶ and one R ⁷ on adjacent atoms taken together with the atoms connecting them form a 6-membered heterocyclic ring containing 1 heteroatom independently selected from O, N, and S, wherein the heterocyclic ring is optionally substituted with one or more hydroxy, oxo, or methyl; or

(xxxvi) 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, of the compound of formula AA,

and R ⁶ and R ⁷ are one of the following combinations:

(i) each R ⁶ is independently C1-C6 alkyl, and each R ⁷ is independently C1-C6 alkyl

optionally substituted with one or more halo;

(ii) each R ⁶ is independently C ₁ -C ₆ alkyl and each R ⁷ is independently C ₁ -C ₆ alkyl;

(iii)each R ⁶ is independently C1-C6 alkyl, and each R ⁷ is independently C1-C6 alkyl

substituted with one or more halo;

(iv) each R ⁶ is independently C ₁ -C ₆ alkyl, and each R ⁷ is independently C ₃ -C ₇ cycloalkyl; (v) each R ⁶ is independently C ₁ -C ₆ alkyl, and each R ⁷ is independently halo;

(vi) each R ⁶ is independently C1-C6 alkyl, and R ⁷ is cyano;

(vii) each R ⁶ is independently C3-C7 cycloalkyl, and each R ⁷ is independently C3-C7 cycloalkyl;

(viii) each R ⁶ is independently C3-C7 cycloalkyl, and each R ⁷ is independently halo; (ix) each R ⁶ is independently cyclopropyl and each R ⁷ is independently halo;

(x) each R ⁶ is independently C ₁ -C ₆ alkyl, and each R ⁷ is independently C ₁ -C ₆ alkoxy

optionally substituted with one or more halo;

(xi) each R ⁶ is independently C1-C6 alkyl, and each R ⁷ is independently C1-C6 alkoxy;

(xii) each R ⁶ is independently C ₁ -C ₆ alkyl, and each R ⁷ is independently C ₁ -C ₆ alkoxy substituted with one or more halo;

(xiii) each R ⁶ is independently halo, and each R ⁷ is independently C1-C6 haloalkyl; (xiv) each R ⁶ is independently halo, and each R ⁷ is independently C1-C6 haloalkoxy; (xv) each R ⁶ is independently C ₁ -C ₆ alkoxy; and each R ⁷ is independently halo; (xvi) each R ⁶ is independently C1-C6 alkoxy; and R ⁷ is chloro;

(xvii) each R ⁷ is independently C1-C6 alkyl, and each R ⁶ is independently C1-C6 alkyl optionally substituted with one or more halo;

(xviii) each R ⁷ is independently C1-C6 alkyl, and each R ⁶ is independently C1-C6 alkyl substituted with one or more halo; (xix) each R ⁷ is independently C1-C6 alkyl, and each R ⁶ is independently C3-C7 cycloalkyl;

(xx) each R ⁷ is independently C ₁ -C ₆ alkyl, and each R ⁶ is independently halo;

(xxi) each R ⁷ is independently C1-C6 alkyl and each R ⁶ is independently halo;

(xxii) each R ⁷ is independently C1-C6 alkyl, and R ⁶ is cyano;

(xxiii) each R ⁷ is independently C ₃ -C ₇ cycloalkyl, and each R ⁶ is independently C ₃ -C ₇ cycloalkyl;

(xxiv) each R ⁷ is independently C3-C7 cycloalkyl, and each R ⁶ is independently halo; (xxv) each R ⁷ is independently C ₃ -C ₇ cycloalkyl and each R ⁶ is independently halo; (xxvi) each R ⁷ is independently C ₁ -C ₆ alkyl, and each R ⁶ is independently C ₁ -C ₆ alkoxy optionally substituted with one or more halo;

(xxvii) each R ⁷ is independently C ₁ -C ₆ alkyl, and each R ⁶ is independently C ₁ -C ₆

alkoxy;

(xxviii) each R ⁷ is independently C1-C6 alkyl, and each R ⁶ is independently C1-C6 alkoxy substituted with one or more halo;

(xxix) each R ⁷ is independently halo, and each R ⁶ is independently C ₁ -C ₆ haloalkyl; (xxx) each R ⁷ is independently halo, and each R ⁶ is independently C1-C6 haloalkoxy; (xxxi) each R ⁷ is independently C1-C6 alkoxy; and each R ⁶ is independently halo; or (xxxii) each R ⁷ is independently C ₁ -C ₆ alkoxy; and R ⁶ is chloro. In some embodiments of the compound of formula AA,

and R ⁶ and R ⁷ are one of the following combinations:

(i) each R ⁶ is isopropyl; and each R ⁷ is methyl;

(ii) each R ⁶ is isopropyl; and each R ⁷ is isopropyl;

(iii)each R ⁶ is isopropyl; and each R ⁷ is trifluoromethyl;

(iv) each R ⁶ is isopropyl; and each R ⁷ is cyclopropyl;

(v) each R ⁶ is isopropyl; and each R ⁷ is chloro;

(vi) each R ⁶ is isopropyl; and each R ⁷ is fluoro; (vii) each R ⁶ is ethyl; and each R ⁷ is fluoro;

(viii) each R ⁶ is isopropyl; and each R ⁷ is cyano;

(ix) each R ⁶ is cyclopropyl; and each R ⁷ is cyclopropyl;

(x) each R ⁶ is cyclopropyl; and each R ⁷ is chloro;

(xi) each R ⁶ is cyclopropyl; and each R ⁷ is fluoro;

(xii) each R ⁶ is isopropyl; and each R ⁷ is methoxy;

(xiii) each R ⁶ is isopropyl; and each R ⁷ is trifluoromethoxy;

(xiv) each R ⁶ is chloro; and each R ⁷ is trifluoromethyl;

(xv) each R ⁶ is chloro; and each R ⁷ is trifluoromethoxy;

(xvi) each R ⁷ is isopropyl; and each R ⁶ is methyl;

(xvii) each R ⁷ is isopropyl; and each R ⁶ is trifluoromethyl;

(xviii) each R ⁷ is isopropyl; and each R ⁶ is cyclopropyl;

(xix) each R ⁷ is isopropyl; and each R ⁶ is chloro;

(xx) each R ⁷ is ethyl; and each R ⁶ is fluoro;

(xxi) each R ⁷ is isopropyl; and each R ⁶ is cyano;

(xxii) each R ⁷ is cyclopropyl; and each R ⁶ is cyclopropyl;

(xxiii) each R ⁷ is cyclopropyl; and each R ⁶ is chloro;

(xxiv) each R ⁷ is cyclopropyl; and each R ⁶ is fluoro;

(xxv) each R ⁷ is isopropyl; and each R ⁶ is methoxy;

(xxvi) each R ⁷ is isopropyl; and each R ⁶ is trifluoromethoxy;

(xxvii) each R ⁷ is chloro; and each R ⁶ is trifluoromethyl;

(xxviii) each R ⁷ is chloro; and each R ⁶ is trifluoromethoxy;

(xxix) one R ⁶ is isopropyl; the other R ⁶ is trifluoromethyl; and R ⁷ is chloro; or (xxx) R ⁶ is isopropyl; one R ⁷ is fluoro; and the other R ⁷ is cyano.

In some embodiments, of the compound of formula AA,

the substituted ring and R ⁶ and R ⁷ are one of the following combinations:

each R ⁶ is independently C ₁ -C ₆ alkyl, and each R ⁷ is independently C ₁ -C ₆ alkyl optionally substituted with one or more halo;

each R ⁶ is independently C1-C6 alkyl and each R ⁷ is independently C1-C6 alkyl;

each R ⁶ is independently C1-C6 alkyl, and each R ⁷ is independently C1-C6 alkyl substituted with one or more halo;

each R ⁶ is independently C1-C6 alkyl, and each R ⁷ is independently C3-C7 cycloalkyl;

each R ⁶ is independently C1-C6 alkyl, and each R ⁷ is independently halo;

each R ⁶ is independently C ₁ -C ₆ alkyl, and each R ⁷ is cyano;

each R ⁶ is independently C ₃ -C ₇ cycloalkyl, and each R ⁷ is independently C ₃ -C ₇ cycloalkyl; each R ⁶ is independently C3-C7 cycloalkyl, and each R ⁷ is independently halo;

each R ⁶ is independently cyclopropyl and each R ⁷ is independently halo;

each R ⁶ is independently C ₁ -C ₆ alkyl, and each R ⁷ is independently C ₁ -C ₆ alkoxy optionally substituted with one or more halo;

each R ⁶ is independently C1-C6 alkyl, and each R ⁷ is independently C1-C6 alkoxy;

each R ⁶ is independently C ₁ -C ₆ alkyl, and each R ⁷ is independently C ₁ -C ₆ alkoxy substituted with one or more halo;

each R ⁶ is independently halo, and each R ⁷ is independently C1-C6 haloalkyl;

each R ⁶ is independently halo, and each R ⁷ is independently C ₁ -C ₆ haloalkoxy;

each R ⁶ is independently C1-C6 alkoxy; and each R ⁷ is independently halo;

each R ⁶ is independently C1-C6 alkoxy; and each R ⁷ is chloro;

each R ⁷ is independently C ₁ -C ₆ alkyl, and each R ⁶ is independently C ₁ -C ₆ alkyl optionally substituted with one or more halo;

each R ⁷ is independently C1-C6 alkyl, and each R ⁶ is independently C1-C6 alkyl substituted with one or more halo;

each R ⁷ is independently C ₁ -C ₆ alkyl, and each R ⁶ is independently C ₃ -C ₇ cycloalkyl;

each R ⁷ is independently C1-C6 alkyl, and each R ⁶ is independently halo;

each R ⁷ is independently C1-C6 alkyl and each R ⁶ is independently halo;

each R ⁷ is independently C ₁ -C ₆ alkyl, and each R ⁶ is cyano;

each R ⁷ is independently C3-C7 cycloalkyl, and each R ⁶ is independently C3-C7 cycloalkyl; each R ⁷ is independently C3-C7 cycloalkyl, and each R ⁶ is independently halo; each R ⁷ is independently C3-C7 cycloalkyl and each R ⁶ is independently halo; each R ⁷ is independently C ₁ -C ₆ alkyl, and each R ⁶ is independently C ₁ -C ₆ alkoxy optionally substituted with one or more halo;

each R ⁷ is independently C1-C6 alkyl, and each R ⁶ is independently C1-C6 alkoxy;

each R ⁷ is independently C1-C6 alkyl, and each R ⁶ is independently C1-C6 alkoxy substituted with one or more halo;

each R ⁷ is independently halo, and each R ⁶ is independently C1-C6 haloalkyl;

each R ⁷ is independently halo, and each R ⁶ is independently C1-C6 haloalkoxy;

each R ⁷ is independently C ₁ -C ₆ alkoxy; and each R ⁶ is independently halo;

each R ⁷ is independently C ₁ -C ₆ alkoxy; and each R ⁶ is chloro;

R ⁶ and R ⁷ on adjacent atoms taken together with the atoms connecting them form a C4-C6 aliphatic carbocyclic ring optionally substituted with one or more hydroxy, oxo, or C ₁ -C ₆ alkyl; and one R ⁶ is halo or cyano; or

R ⁶ and R ⁷ on adjacent atoms taken together with the atoms connecting them form a 5-to-6- membered heterocyclic ring containing 1 heteroatom independently selected from O, N, and S, wherein the heterocyclic ring optionally substituted with one or more hydroxy, oxo, or C ₁ - C6 alkyl; and one R ⁶ is halo or cyano. In some embodiments, of the compound of formula AA,

the substituted ring B is

and R ⁶ and R ⁷ are one of the following combinations:

each R ⁶ is isopropyl; and each R ⁷ is methyl;

each R ⁶ is isopropyl; and each R ⁷ is isopropyl;

each R ⁶ is isopropyl; and each R ⁷ is trifluoromethyl;

each R ⁶ is isopropyl; and each R ⁷ is cyclopropyl;

each R ⁶ is isopropyl; and each R ⁷ is chloro;

each R ⁶ is isopropyl; and each R ⁷ is fluoro;

each R ⁶ is ethyl; and each R ⁷ is fluoro; each R ⁶ is isopropyl; and each R ⁷ is cyano;

each R ⁶ is cyclopropyl; and each R ⁷ is cyclopropyl;

each R ⁶ is cyclopropyl; and each R ⁷ is chloro;

each R ⁶ is cyclopropyl; and each R ⁷ is fluoro;

each R ⁶ is isopropyl; and each R ⁷ is methoxy;

each R ⁶ is isopropyl; and each R ⁷ is trifluoromethoxy;

each R ⁶ is chloro; and each R ⁷ is trifluoromethyl;

each R ⁶ is chloro; and each R ⁷ is trifluoromethoxy;

each R ⁷ is isopropyl; and each R ⁶ is methyl;

each R ⁷ is isopropyl; and each R ⁶ is trifluoromethyl;

each R ⁷ is isopropyl; and each R ⁶ is cyclopropyl;

each R ⁷ is isopropyl; and each R ⁶ is chloro;

each R ⁷ is ethyl; and each R ⁶ is fluoro;

each R ⁷ is isopropyl; and each R ⁶ is cyano;

each R ⁷ is cyclopropyl; and each R ⁶ is cyclopropyl;

each R ⁷ is cyclopropyl; and each R ⁶ is chloro;

each R ⁷ is cyclopropyl; and each R ⁶ is fluoro;

each R ⁷ is isopropyl; and each R ⁶ is methoxy;

each R ⁷ is isopropyl; and each R ⁶ is trifluoromethoxy;

each R ⁷ is chloro; and each R ⁶ is trifluoromethyl;

each R ⁷ is chloro; and each R ⁶ is trifluoromethoxy;

one R ⁶ is isopropyl; the other R ⁶ is trifluoromethyl; and each R ⁷ is chloro;

each R ⁶ is isopropyl; one R ⁷ is fluoro; and the other R ⁷ is cyano;

R ⁶ and R ⁷ on adjacent atoms taken together with the atoms connecting them form a C4 aliphatic carbocyclic ring; and one R ⁶ is chloro, fluoro, or cyano;

R ⁶ and R ⁷ on adjacent atoms taken together with the atoms connecting them form a C ₅ aliphatic carbocyclic ring; and one R ⁶ is chloro, fluoro, or cyano;

R ⁶ and R ⁷ on adjacent atoms taken together with the atoms connecting them form a C6 aliphatic carbocyclic ring; and one R ⁶ is chloro, fluoro, or cyano; R ⁶ and R ⁷ on adjacent atoms taken together with the atoms connecting them form a 5- membered heterocyclic ring containing 1 heteroatoms independently selected from O, N, and S; and one R ⁶ is chloro, fluoro, or cyano;

R ⁶ and R ⁷ on adjacent atoms taken together with the atoms connecting them form a 6- membered heterocyclic ring containing 1 heteroatoms independently selected from O, N, and S; and one R ⁶ is chloro, fluoro, or cyano; or

R ⁶ and R ⁷ on adjacent atoms taken together with the atoms connecting them form a C5 aliphatic carbocyclic ring; and one R ⁶ is chloro, fluoro, or cyano. In some embodiments, of the compound of formula AA,

and R ⁶ and R ⁷ are one of the following combinations:

(i) each R ⁶ is independently C1-C6 alkyl, and each R ⁷ is independently C1-C6 alkyl optionally substituted with one or more halo;

(ii) each R ⁶ is independently C1-C6 alkyl and each R ⁷ is independently C1-C6 alkyl;

(iii)each R ⁶ is independently C1-C6 alkyl, and each R ⁷ is independently C1-C6 alkyl

substituted with one or more halo;

(iv) each R ⁶ is independently C ₁ -C ₆ alkyl, and each R ⁷ is independently C ₃ -C ₇ cycloalkyl; (v) each R ⁶ is independently C1-C6 alkyl, and each R ⁷ is independently halo;

(vi) each R ⁶ is independently C1-C6 alkyl, and R ⁷ is cyano;

(vii) each R ⁶ is independently C ₃ -C ₇ cycloalkyl, and each R ⁷ is independently C ₃ -C ₇ cycloalkyl;

(viii) each R ⁶ is independently C3-C7 cycloalkyl, and each R ⁷ is independently halo; (ix) each R ⁶ is independently cyclopropyl and each R ⁷ is independently halo;

(x) each R ⁶ is independently C1-C6 alkyl, and each R ⁷ is independently C1-C6 alkoxy

optionally substituted with one or more halo;

(xi) each R ⁶ is independently C ₁ -C ₆ alkyl, and each R ⁷ is independently C ₁ -C ₆ alkoxy; (xii) each R ⁶ is independently C1-C6 alkyl, and each R ⁷ is independently C1-C6 alkoxy substituted with one or more halo;

(xiii) each R ⁶ is independently halo, and each R ⁷ is independently C ₁ -C ₆ haloalkyl; (xiv) each R ⁶ is independently halo, and each R ⁷ is independently C1-C6 haloalkoxy; (xv) each R ⁶ is independently C1-C6 alkoxy; and each R ⁷ is independently halo;

(xvi) each R ⁶ is independently C ₁ -C ₆ alkoxy; and R ⁷ is chloro;

(xvii) each R ⁷ is independently C1-C6 alkyl, and each R ⁶ is independently C1-C6 alkyl optionally substituted with one or more halo;

(xviii) each R ⁷ is independently C ₁ -C ₆ alkyl, and each R ⁶ is independently C ₁ -C ₆ alkyl substituted with one or more halo;

(xix) each R ⁷ is independently C1-C6 alkyl, and each R ⁶ is independently C3-C7

cycloalkyl;

(xx) each R ⁷ is independently C ₁ -C ₆ alkyl, and each R ⁶ is independently halo;

(xxi) each R ⁷ is independently C1-C6 alkyl and each R ⁶ is independently halo;

(xxii) each R ⁷ is independently C1-C6 alkyl, and R ⁶ is cyano;

(xxiii) each R ⁷ is independently C ₃ -C ₇ cycloalkyl, and each R ⁶ is independently C ₃ -C ₇ cycloalkyl;

(xxiv) each R ⁷ is independently C3-C7 cycloalkyl, and each R ⁶ is independently halo; (xxv) each R ⁷ is independently C ₃ -C ₇ cycloalkyl and each R ⁶ is independently halo; (xxvi) each R ⁷ is independently C1-C6 alkyl, and each R ⁶ is independently C1-C6 alkoxy optionally substituted with one or more halo;

(xxvii) each R ⁷ is independently C ₁ -C ₆ alkyl, and each R ⁶ is independently C ₁ -C ₆ alkoxy; (xxviii) each R ⁷ is independently C ₁ -C ₆ alkyl, and each R ⁶ is independently C ₁ -C ₆ alkoxy substituted with one or more halo;

(xxix) each R ⁷ is independently halo, and each R ⁶ is independently C ₁ -C ₆ haloalkyl; (xxx) each R ⁷ is independently halo, and each R ⁶ is independently C ₁ -C ₆ haloalkoxy; (xxxi) each R ⁷ is independently C1-C6 alkoxy; and each R ⁶ is independently halo; or (xxxii) each R ⁷ is independently C1-C6 alkoxy; and R ⁶ is chloro.

In some embodiments, of the compound of formula AA,

and R ⁶ and R ⁷ are one of the following combinations:

(i) each R ⁶ is isopropyl; and each R ⁷ is methyl;

(ii) each R ⁶ is isopropyl; and each R ⁷ is isopropyl;

(iii)each R ⁶ is isopropyl; and each R ⁷ is trifluoromethyl;

(iv) each R ⁶ is isopropyl; and each R ⁷ is cyclopropyl;

(v) each R ⁶ is isopropyl; and each R ⁷ is chloro;

(vi) each R ⁶ is isopropyl; and each R ⁷ is fluoro;

(vii) each R ⁶ is ethyl; and each R ⁷ is fluoro;

(viii) each R ⁶ is isopropyl; and each R ⁷ is cyano;

(ix) each R ⁶ is cyclopropyl; and each R ⁷ is cyclopropyl;

(x) each R ⁶ is cyclopropyl; and each R ⁷ is chloro;

(xi) each R ⁶ is cyclopropyl; and each R ⁷ is fluoro;

(xii) each R ⁶ is isopropyl; and each R ⁷ is methoxy;

(xiii) each R ⁶ is isopropyl; and each R ⁷ is trifluoromethoxy; (xiv) each R ⁶ is chloro; and each R ⁷ is trifluoromethyl; (xv) each R ⁶ is chloro; and each R ⁷ is trifluoromethoxy; (xvi) each R ⁷ is isopropyl; and each R ⁶ is methyl;

(xvii) each R ⁷ is isopropyl; and each R ⁶ is trifluoromethyl; (xviii) each R ⁷ is isopropyl; and each R ⁶ is cyclopropyl; (xix) each R ⁷ is isopropyl; and each R ⁶ is chloro;

(xx) each R ⁷ is ethyl; and each R ⁶ is fluoro;

(xxi) each R ⁷ is isopropyl; and each R ⁶ is cyano;

(xxii) each R ⁷ is cyclopropyl; and each R ⁶ is cyclopropyl; (xxiii) each R ⁷ is cyclopropyl; and each R ⁶ is chloro;

(xxiv) each R ⁷ is cyclopropyl; and each R ⁶ is fluoro;

(xxv) each R ⁷ is isopropyl; and each R ⁶ is methoxy;

(xxvi) each R ⁷ is isopropyl; and each R ⁶ is trifluoromethoxy; (xxvii) each R ⁷ is chloro; and each R ⁶ is trifluoromethyl;

(xxviii) each R ⁷ is chloro; and each R ⁶ is trifluoromethoxy;

(xxix) one R ⁶ is isopropyl; the other R ⁶ is trifluoromethyl; and each R ⁷ is chloro; or (xxx) each R ⁶ is isopropyl; one R ⁷ is fluoro; and the other R ⁷ is cyano. In some embodiments, of the compound of formula AA,

and R ⁶ and R ⁷ are one of the following combinations:

(i) each R ⁶ is independently C1-C6 alkyl, and each R ⁷ is independently C1-C6 alkyl optionally substituted with one or more halo;

(ii) each R ⁶ is independently C1-C6 alkyl and each R ⁷ is independently C1-C6 alkyl;

(iii)each R ⁶ is independently C1-C6 alkyl, and each R ⁷ is independently C1-C6 alkyl

substituted with one or more halo;

(iv) each R ⁶ is independently C ₁ -C ₆ alkyl, and each R ⁷ is independently C ₃ -C ₇ cycloalkyl; (v) each R ⁶ is independently C1-C6 alkyl, and each R ⁷ is independently halo;

(vi) each R ⁶ is independently C1-C6 alkyl, and R ⁷ is cyano;

(vii) each R ⁶ is independently C ₃ -C ₇ cycloalkyl, and each R ⁷ is independently C ₃ -C ₇ cycloalkyl;

(viii) each R ⁶ is independently C3-C7 cycloalkyl, and each R ⁷ is independently halo; (ix) each R ⁶ is independently cyclopropyl and each R ⁷ is independently halo;

(x) each R ⁶ is independently C1-C6 alkyl, and each R ⁷ is independently C1-C6 alkoxy

optionally substituted with one or more halo;

(xi) each R ⁶ is independently C ₁ -C ₆ alkyl, and each R ⁷ is independently C ₁ -C ₆ alkoxy;

(xii) each R ⁶ is independently C ₁ -C ₆ alkyl, and each R ⁷ is independently C ₁ -C ₆ alkoxy substituted with one or more halo;

(xiii) each R ⁶ is independently halo, and each R ⁷ is independently C1-C6 haloalkyl; (xiv) each R ⁶ is independently halo, and each R ⁷ is independently C ₁ -C ₆ haloalkoxy; (xv) each R ⁶ is independently C1-C6 alkoxy; and each R ⁷ is independently halo;

(xvi) each R ⁶ is independently C1-C6 alkoxy; and R ⁷ is chloro; (xvii) each R ⁷ is independently C1-C6 alkyl, and each R ⁶ is independently C1-C6 alkyl optionally substituted with one or more halo;

(xviii) each R ⁷ is independently C ₁ -C ₆ alkyl, and each R ⁶ is independently C ₁ -C ₆ alkyl substituted with one or more halo;

(xix) each R ⁷ is independently C1-C6 alkyl, and each R ⁶ is independently C3-C7

cycloalkyl;

(xx) each R ⁷ is independently C1-C6 alkyl, and each R ⁶ is independently halo;

(xxi) each R ⁷ is independently C1-C6 alkyl and each R ⁶ is independently halo;

(xxii) each R ⁷ is independently C ₁ -C ₆ alkyl, and R ⁶ is cyano;

(xxiii) each R ⁷ is independently C ₃ -C ₇ cycloalkyl, and each R ⁶ is independently C ₃ -C ₇ cycloalkyl;

(xxiv) each R ⁷ is independently C ₃ -C ₇ cycloalkyl, and each R ⁶ is independently halo; (xxv) each R ⁷ is independently C ₃ -C ₇ cycloalkyl and each R ⁶ is independently halo; (xxvi) each R ⁷ is independently C1-C6 alkyl, and each R ⁶ is independently C1-C6 alkoxy optionally substituted with one or more halo;

(xxvii) each R ⁷ is independently C ₁ -C ₆ alkyl, and each R ⁶ is independently C ₁ -C ₆ alkoxy; (xxviii) each R ⁷ is independently C1-C6 alkyl, and each R ⁶ is independently C1-C6 alkoxy substituted with one or more halo;

(xxix) each R ⁷ is independently halo, and each R ⁶ is independently C ₁ -C ₆ haloalkyl; (xxx) each R ⁷ is independently halo, and each R ⁶ is independently C1-C6 haloalkoxy; (xxxi) each R ⁷ is independently C1-C6 alkoxy; and each R ⁶ is independently halo;

(xxxvi) each R ⁷ is independently C ₁ -C ₆ alkoxy; and R ⁶ is chloro;

(xxxvii) 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 C4-C6 aliphatic carbocyclic ring optionally substituted with one or more hydroxy, oxo, or C ₁ -C ₆ alkyl; (xxxii) 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-to-6-membered heterocyclic ring containing 1 heteroatom independently selected from O, N, and S, wherein the heterocyclic ring optionally substituted with one or more hydroxy, oxo, or C1-C6 alkyl; or (xxxiii) 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- C ₆ aliphatic carbocyclic ring optionally substituted with one or more hydroxy, oxo, or C ₁ -C ₆ alkyl, and the other pair of one R ⁶ and one R ⁷ taken together with the atoms connecting them form a 5-to-6-membered heterocyclic ring containing 1 heteroatom independently selected from O, N, and S, wherein the heterocyclic ring optionally substituted with one or more hydroxy, oxo, or C1-C6 alkyl. In some embodiments, of the compound of formula AA,

and R ⁶ and R ⁷ are one of the following combinations:

(i) each R ⁶ is isopropyl; and each R ⁷ is methyl;

(ii) each R ⁶ is isopropyl; and each R ⁷ is isopropyl;

(iii)each R ⁶ is isopropyl; and each R ⁷ is trifluoromethyl;

(iv) each R ⁶ is isopropyl; and each R ⁷ is cyclopropyl;

(v) each R ⁶ is isopropyl; and each R ⁷ is chloro;

(vi) each R ⁶ is isopropyl; and each R ⁷ is fluoro;

(vii) each R ⁶ is ethyl; and each R ⁷ is fluoro;

(viii) each R ⁶ is isopropyl; and each R ⁷ is cyano;

(ix) each R ⁶ is cyclopropyl; and each R ⁷ is cyclopropyl;

(x) each R ⁶ is cyclopropyl; and each R ⁷ is chloro;

(xi) each R ⁶ is cyclopropyl; and each R ⁷ is fluoro;

(xii) each R ⁶ is isopropyl; and each R ⁷ is methoxy;

(xiii) each R ⁶ is isopropyl; and each R ⁷ is trifluoromethoxy;

(xiv) each R ⁶ is chloro; and each R ⁷ is trifluoromethyl;

(xv) each R ⁶ is chloro; and each R ⁷ is trifluoromethoxy;

(xvi) each R ⁷ is isopropyl; and each R ⁶ is methyl;

(xvii) each R ⁷ is isopropyl; and each R ⁶ is trifluoromethyl;

(xviii) each R ⁷ is isopropyl; and each R ⁶ is cyclopropyl; (xix) each R ⁷ is isopropyl; and each R ⁶ is chloro;

(xx) each R ⁷ is ethyl; and each R ⁶ is fluoro;

(xxi) each R ⁷ is isopropyl; and each R ⁶ is cyano;

(xxii) each R ⁷ is cyclopropyl; and each R ⁶ is cyclopropyl;

(xxiii) each R ⁷ is cyclopropyl; and each R ⁶ is chloro;

(xxiv) each R ⁷ is cyclopropyl; and each R ⁶ is fluoro;

(xxv) each R ⁷ is isopropyl; and each R ⁶ is methoxy;

(xxvi) each R ⁷ is isopropyl; and each R ⁶ is trifluoromethoxy;

(xxvii) R ⁷ is chloro; and each R ⁶ is trifluoromethyl;

(xxviii) R ⁷ is chloro; and each R ⁶ is trifluoromethoxy;

(xxix) one R ⁶ is isopropyl; the other R ⁶ is trifluoromethyl; and R ⁷ is chloro;

(xxx) R ⁶ is isopropyl; one R ⁷ is fluoro; and the other R ⁷ is cyano; 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;

(xxxi) 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 optionally substituted with one or more hydroxy, oxo, or methyl;

(xxxii) 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 optionally substituted with one or more hydroxy, oxo, or methyl;

(xxxiii) 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 aliphatic carbocyclic ring optionally substituted with one or more hydroxy, oxo, or methyl;

(xxxiv) 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 heteroatom independently selected from O, N, and S, wherein the heterocyclic ring is optionally substituted with one or more hydroxy, oxo, or methyl

(xxxv) 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 heteroatom independently selected from O, N, and S, wherein the heterocyclic ring is optionally substituted with one or more hydroxy, oxo, or methyl; or

(xxxvi) 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 5-membered heterocyclic ring containing 1 heteroatom independently selected from O, N, and S, wherein the heterocyclic ring is optionally substituted with one or more hydroxy, oxo, or methyl, and the other pair of one R ⁶ and one R ⁷ taken together with the atoms connecting them form a C5 aliphatic carbocyclic ring optionally substituted with one or more hydroxy, oxo, or methyl .

In some embodiments, of the compound of formula AA,

and R ⁶ and R ⁷ are one of the following combinations:

(i) each R ⁶ is independently C ₁ -C ₆ alkyl, and R ⁷ is C ₁ -C ₆ alkyl optionally substituted with one or more halo;

(ii) each R ⁶ is independently C1-C6 alkyl and R ⁷ is C1-C6 alkyl;

(iii)each R ⁶ is independently C1-C6 alkyl, and R ⁷ is C1-C6 alkyl substituted with one or more halo;

(iv) each R ⁶ is independently C1-C6 alkyl, and R ⁷ is C3-C7 cycloalkyl;

(v) each R ⁶ is independently C1-C6 alkyl, and R ⁷ is halo;

(vi) each R ⁶ is independently C ₁ -C ₆ alkyl, and R ⁷ is cyano;

(vii) each R ⁶ is independently C3-C7 cycloalkyl, and R ⁷ is C3-C7 cycloalkyl;

(viii) each R ⁶ is independently C3-C7 cycloalkyl, and R ⁷ is halo;

(ix) each R ⁶ is independently cyclopropyl and R ⁷ is halo;

(x) each R ⁶ is independently C ₁ -C ₆ alkyl, and R ⁷ is C ₁ -C ₆ alkoxy optionally substituted with one or more halo;

(xi) each R ⁶ is independently C1-C6 alkyl, and R ⁷ is C1-C6 alkoxy; (xii) each R ⁶ is independently C1-C6 alkyl, and R ⁷ is C1-C6 alkoxy substituted with one or more halo;

(xiii) each R ⁶ is independently halo, and R ⁷ is C ₁ -C ₆ haloalkyl;

(xiv) each R ⁶ is independently halo, and R ⁷ is C1-C6 haloalkoxy;

(xv) each R ⁶ is independently C1-C6 alkoxy; and R ⁷ is halo;

(xvi) each R ⁶ is independently C ₁ -C ₆ alkoxy; and R ⁷ is chloro;

(xvii) R ⁷ is C1-C6 alkyl, and each R ⁶ is independently C1-C6 alkyl optionally substituted with one or more halo;

(xviii) R ⁷ is C ₁ -C ₆ alkyl, and each R ⁶ is independently C ₁ -C ₆ alkyl substituted with one or more halo;

(xix) R ⁷ is C1-C6 alkyl, and each R ⁶ is independently C3-C7 cycloalkyl;

(xx) R ⁷ is C ₁ -C ₆ alkyl, and each R ⁶ is independently halo;

(xxi) R ⁷ is C ₁ -C ₆ alkyl and each R ⁶ is independently halo;

(xxii) R ⁷ is C1-C6 alkyl, and R ⁶ is cyano;

(xxiii) R ⁷ is C3-C7 cycloalkyl, and each R ⁶ is independently C3-C7 cycloalkyl;

(xxiv) R ⁷ is C ₃ -C ₇ cycloalkyl, and each R ⁶ is independently halo;

(xxv) R ⁷ is C3-C7 cycloalkyl and each R ⁶ is independently halo;

(xxvi) R ⁷ is C1-C6 alkyl, and each R ⁶ is independently C1-C6 alkoxy optionally

substituted with one or more halo;

(xxvii) R ⁷ is C1-C6 alkyl, and each R ⁶ is independently C1-C6 alkoxy;

(xxviii) R ⁷ is C1-C6 alkyl, and each R ⁶ is independently C1-C6 alkoxy substituted with one or more halo;

(xxix) R ⁷ is halo, and each R ⁶ is independently C ₁ -C ₆ haloalkyl;

(xxx) R ⁷ is halo, and each R ⁶ is independently C1-C6 haloalkoxy;

(xxxi) R ⁷ is C ₁ -C ₆ alkoxy; and each R ⁶ is independently halo;

(xxxii) R ⁷ is C ₁ -C ₆ alkoxy; and R ⁶ is chloro;

(xxxiii) 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 C4-C8 aliphatic carbocyclic ring; and one R ⁷ is halo; (xxxiv) 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 -C ₈ aliphatic carbocyclic ring; and one R ⁷ is cyano;

(xxxv) 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 C4-C6 aliphatic carbocyclic ring optionally substituted with one or more hydroxy, oxo, or C ₁ -C ₆ alkyl; and one R ⁷ is halo or cyano;

(xxxvi) 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-to-6-membered heterocyclic ring containing 1 heteroatom independently selected from O, N, and S, wherein the heterocyclic ring optionally substituted with one or more hydroxy, oxo, or C ₁ -C ₆ alkyl; and one R ⁷ is halo or cyano; or

(xxxvii) 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-C6 aliphatic carbocyclic ring optionally substituted with one or more hydroxy, oxo, or C1-C6 alkyl, and the other pair of one R ⁶ and one R ⁷ taken together with the atoms connecting them form a 5-to-6-membered heterocyclic ring containing 1 heteroatom independently selected from O, N, and S, wherein the heterocyclic ring optionally substituted with one or more hydroxy, oxo, or C ₁ -C ₆ alkyl; and one R ⁷ is halo or cyano. In some embodiments, of the compound of formula AA,

and R ⁶ and R ⁷ are one of the following combinations:

(i) each R ⁶ is isopropyl; and each R ⁷ is methyl;

(ii) each R ⁶ is isopropyl; and each R ⁷ is isopropyl;

(iii)each R ⁶ is isopropyl; and each R ⁷ is trifluoromethyl;

(iv) each R ⁶ is isopropyl; and each R ⁷ is cyclopropyl;

(v) each R ⁶ is isopropyl; and each R ⁷ is chloro; (vi) each R ⁶ is isopropyl; and each R ⁷ is fluoro;

(vii) each R ⁶ is ethyl; and each R ⁷ is fluoro;

(viii) each R ⁶ is isopropyl; and each R ⁷ is cyano;

(ix) each R ⁶ is cyclopropyl; and each R ⁷ is cyclopropyl;

(x) each R ⁶ is cyclopropyl; and each R ⁷ is chloro;

(xi) each R ⁶ is cyclopropyl; and each R ⁷ is fluoro;

(xii) each R ⁶ is isopropyl; and each R ⁷ is methoxy;

(xiii) each R ⁶ is isopropyl; and each R ⁷ is trifluoromethoxy;

(xiv) each R ⁶ is chloro; and each R ⁷ is trifluoromethyl;

(xv) each R ⁶ is chloro; and each R ⁷ is trifluoromethoxy;

(xvi) each R ⁷ is isopropyl; and each R ⁶ is methyl;

(xvii) each R ⁷ is isopropyl; and each R ⁶ is trifluoromethyl;

(xviii) each R ⁷ is isopropyl; and each R ⁶ is cyclopropyl;

(xix) each R ⁷ is isopropyl; and each R ⁶ is chloro;

(xx) each R ⁷ is ethyl; and each R ⁶ is fluoro;

(xxi) each R ⁷ is isopropyl; and each R ⁶ is cyano;

(xxii) each R ⁷ is cyclopropyl; and each R ⁶ is cyclopropyl;

(xxiii) each R ⁷ is cyclopropyl; and each R ⁶ is chloro;

(xxiv) each R ⁷ is cyclopropyl; and each R ⁶ is fluoro;

(xxv) each R ⁷ is isopropyl; and each R ⁶ is methoxy;

(xxvi) each R ⁷ is isopropyl; and each R ⁶ is trifluoromethoxy;

(xxvii) each R ⁷ is chloro; and each R ⁶ is trifluoromethyl;

(xxviii) each R ⁷ is chloro; and each R ⁶ is trifluoromethoxy;

(xxix) each R ⁶ is isopropyl; two R ⁷ are fluoro; and one R ⁷ is chloro;

(xxx) 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 chloro;

(xxxi) 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 fluoro; (xxxii) 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 optionally substituted with one or more hydroxy, oxo, or methyl; and one R ⁷ is fluoro or chloro;

(xxxiii) 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 optionally substituted with one or more hydroxy, oxo, or methyl; and one R ⁷ is fluoro or chloro;

(xxxiv) 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 aliphatic carbocyclic ring optionally substituted with one or more hydroxy, oxo, or methyl; and one R ⁷ is fluoro or chloro;

(xxxv) 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 heteroatom independently selected from O, N, and S, wherein the heterocyclic ring is optionally substituted with one or more hydroxy, oxo, or methyl; and one R ⁷ is fluoro or chloro;

(xxxvi) 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 heteroatom independently selected from O, N, and S, wherein the heterocyclic ring is optionally substituted with one or more hydroxy, oxo, or methyl; and one R ⁷ is fluoro or chloro; or

(xxxvii) 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 5-membered heterocyclic ring containing 1 heteroatom independently selected from O, N, and S, wherein the heterocyclic ring is optionally substituted with one or more hydroxy, oxo, or methyl, and the other pair of one R ⁶ and one R ⁷ taken together with the atoms connecting them form a C5 aliphatic carbocyclic ring optionally substituted with one or more hydroxy, oxo, or methyl ; and one R ⁷ is fluoro or chloro. Non-Limiting Combinations In some embodiments, when ring A is phenyl, then R ¹ and R ² are each independently selected from C ₃ alkyl, C ₅ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, F, I, CN, NO ₂ , COC ₂ -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, OCOC2-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C6-C10 aryl, 5- to 10-membered heteroaryl, NH2, NHC1-C6 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, NHCOOCC1-C6 alkyl, NH- (C=NR ¹³ )NR ¹¹ R ¹² , CONR ⁸ R ⁹ , SF5, SC1-C6 alkyl, S(O2)C1-C6 alkyl, S(O2)NR ¹¹ R ¹² , S(O)C1-C6 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 are optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C1-C6 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), NHCOC1-C6 alkyl, NHCOC6- C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), and NHCOC ₂ -C ₆ alkynyl;

wherein each C1-C6 alkyl substituent and each C1-C6 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, C6-C10 aryl, 5- to 10-membered heteroaryl, NHCOC6-C10 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 one monocyclic or bicyclic C ₄ or C ₆ -C ₁₂ carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring containing 1-3 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxy, OC ₃ -C ₁₀ cycloalkyl, NR ⁸ R ⁹ , =NR ¹⁰ , CN, COOC1-C6 alkyl, OS(O2)C6-C10 aryl, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10- membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR ⁸ R ⁹ , wherein the C1-C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C ₃ -C ₁₀ cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR ⁸ R ⁹ , =NR ¹⁰ , COOC1-C6 alkyl, C6-C10 aryl, and CONR ⁸ R ⁹ ; and

R ⁶ and R ⁷ are each independently selected from a C ₂ -C ₆ alkyl, C ₂ -C ₆ haloalkyl, C ₂ -C ₆ alkoxy, C ₁ - C6 haloalkoxy, I, CN, NO2, COC1-C6 alkyl, CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, OCOC1-C6 alkyl, OCOC6-C10 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 ₁₀ cycloalkyl and 3- to 10-membered heterocycloalkyl, and C2-C6 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, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 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), NHCOC2-C6 alkynyl, C6-C10 aryloxy, and S(O2)C1- C6 alkyl; and wherein the C1-C6 alkyl or C1-C6 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 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 and/or heteroatomic groups independently selected from O, NH, NR ¹³ , S, S(O), and S(O) ₂ , wherein the selected heteroatoms and/or heteroatomic groups are cumulative with the nitrogen atoms present in ring B, and wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 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 ¹ and R ² are each independently selected from C3 alkyl, C5-C6 alkyl, C1- C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, F, I, CN, NO2, COC2-C6 alkyl, CO-C6-C10 aryl, CO(5- to 10-membered heteroaryl), CO ₂ C ₁ -C ₆ alkyl, CO ₂ C ₃ -C ₈ cycloalkyl, OCOC ₂ -C ₆ alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C6-C10 aryl, 5- to 10-membered heteroaryl, NH2, NHC1-C6 alkyl, N(C1-C6 alkyl)2, NHCOC1-C6 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 , SF5, SC1-C6 alkyl, S(O2)C1-C6 alkyl, S(O2)NR ¹¹ R ¹² , S(O)C1-C6 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 optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC1-C6 alkyl, CONR ⁸ R ⁹ , 3- to 7-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(3- to 7-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), and NHCOC ₂ -C ₆ alkynyl;

wherein each C1-C6 alkyl substituent and each C1-C6 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, NHCOC6-C10 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 one monocyclic or bicyclic C4 or C6-C12 carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring containing 1-3 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR ⁸ R ⁹ , =NR ¹⁰ , CN, COOC ₁ -C ₆ alkyl, OS(O ₂ )C ₆ -C ₁₀ aryl, S(O ₂ )C ₆ -C ₁₀ aryl, C ₆ -C ₁₀ aryl, 5- to 10- membered heteroaryl, C ₃ -C ₁₀ cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR ⁸ R ⁹ , wherein the C1-C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR ⁸ R ⁹ , =NR ¹⁰ , COOC1-C6 alkyl, C6-C10 aryl, and CONR ⁸ R ⁹ ; and

R ⁶ and R ⁷ are each independently selected from a C ₂ -C ₆ alkyl, C ₂ -C ₆ haloalkyl, C ₂ -C ₆ alkoxy, C ₁ - C ₆ haloalkoxy, I, 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, OCOC6-C10 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 ₁₀ cycloalkyl and 3- to 10-membered heterocycloalkyl, and C2-C6 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, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 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), NHCOC2-C6 alkynyl, C6-C10 aryloxy, and S(O2)C1- C6 alkyl; and wherein the C1-C6 alkyl or C1-C6 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, C1-C6 alkyl, and OC1-C6 alkyl;

or 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 and/or heteroatomic groups independently selected from O, NH, NR ¹³ , S, S(O), and S(O)2, wherein the selected heteroatoms and/or heteroatomic groups are cumulative with the nitrogen atoms present in ring B, and wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR ⁸ R ⁹ , CH2NR ⁸ R ⁹ , =NR ¹⁰ , COOC1-C6 alkyl, C6-C10 aryl, and CONR ⁸ R ⁹ . In some embodiments of the compound of Formula AA, when ring A is pyridyl, then R ¹ and R ² are each independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 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), C6-C10 aryl, 5- to 10-membered heteroaryl, NH ₂ , NHC ₂ -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, NHCOOCC1-C6 alkyl, NH-(C=NR ¹³ )NR ¹¹ R ¹² , CONR ⁸ R ⁹ , SF5, SC1-C6 alkyl, S(O2)C1-C6 alkyl, S(O2)NR ¹¹ R ¹² , S(O)C1-C6 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 optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC1-C6 alkyl, CONR ⁸ R ⁹ , 3- to 5-membered heterocycloalkyl, 5-membered heteroaryl, OCOC ₁ -C ₆ alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 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 - 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, NHCOC6-C10 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 one monocyclic or bicyclic C4-C12 carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring containing 1-3 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR ⁸ R ⁹ , =NR ¹⁰ , CN, COOC1-C6 alkyl, OS(O2)C6-C10 aryl, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C ₃ -C ₁₀ cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR ⁸ R ⁹ , wherein the C ₁ -C ₆ alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₁ -C ₆ alkoxy, oxo, NR ⁸ R ⁹ , =NR ¹⁰ , COOC ₁ -C ₆ alkyl, C ₆ -C ₁₀ aryl, and CONR ⁸ R ⁹ ; and R ⁶ and R ⁷ are each independently selected from a C2-C6 alkyl, C2-C6 haloalkyl, C2-C6 alkoxy, C1- C ₆ haloalkoxy, I, 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), C6-C10 aryl, 5- to 10-membered heteroaryl, NH2, NHC1-C6 alkyl, N(C1-C6 alkyl)2, CONR ⁸ R ⁹ , SF5, SC1-C6 alkyl, S(O2)C1-C6 alkyl, C3-C10 cycloalkyl and 3- to 10-membered heterocycloalkyl, and 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, C1-C6 alkyl, C1-C6 alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC1-C6 alkyl, CONR ⁸ R ⁹ , 3- to 7-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 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, C6-C10 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, C6-C10 aryl, 5- to 10-membered heteroaryl, NHCOC6-C10 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, C1-C6 alkyl, and OC1-C6 alkyl; or 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 and/or heteroatomic groups independently selected from O, NH, NR ¹³ , S, S(O), and S(O)2, wherein the selected heteroatoms and/or heteroatomic groups are cumulative with the nitrogen atoms present in ring B, and wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR ⁸ R ⁹ , CH2NR ⁸ R ⁹ , =NR ¹⁰ , COOC1-C6 alkyl, C6-C10 aryl, and CONR ⁸ R ⁹ . In some embodiments of the compound of Formula AA, R ¹ and R ² are each independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, CN, NO2, COC1-C6 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), C6-C10 aryl, 5- to 10-membered heteroaryl, NH2, NHC2-C6 alkyl, N(C1-C6 alkyl)2, NHCOC1-C6 alkyl, NHCOC6-C10 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 , SF5, SC1-C6 alkyl, S(O2)C1-C6 alkyl, S(O2)NR ¹¹ R ¹² , S(O)C1-C6 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 optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC1-C6 alkyl, CONR ⁸ R ⁹ , 3- to 5-membered heterocycloalkyl, 5-membered heteroaryl, 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, NHCOC6-C10 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 - 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, NHCOC6-C10 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 one monocyclic or bicyclic C4-C12 carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring containing 1-3 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR ⁸ R ⁹ , =NR ¹⁰ , CN, COOC ₁ -C ₆ alkyl, OS(O ₂ )C ₆ -C ₁₀ aryl, S(O ₂ )C ₆ -C ₁₀ aryl, C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, C ₃ -C ₁₀ cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR ⁸ R ⁹ , wherein the C ₁ -C ₆ alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C1-C6 alkoxy, oxo, NR ⁸ R ⁹ , =NR ¹⁰ , COOC1-C6 alkyl, C6-C10 aryl, and CONR ⁸ R ⁹ ; and R ⁶ and R ⁷ are each independently selected from a C2-C6 alkyl, C2-C6 haloalkyl, C2-C6 alkoxy, C1- C ₆ haloalkoxy, I, 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, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C6-C10 aryl, 5- to 10-membered heteroaryl, NH2, NHC1-C6 alkyl, N(C1-C6 alkyl) ₂ , CONR ⁸ R ⁹ , SF ₅ , SC ₁ -C ₆ alkyl, S(O ₂ )C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl and 3- to 10-membered heterocycloalkyl, and C2-C6 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, OCOC1-C6 alkyl, OCOC6-C10 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 - C6 alkyl; and wherein the C1-C6 alkyl or C1-C6 alkoxy that R ⁶ or R ⁷ is substituted with is optionally substituted with one or more hydroxyl, C6-C10 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, C6-C10 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, C1-C6 alkyl, and OC1-C6 alkyl;

or 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 and/or heteroatomic groups independently selected from O, NH, NR ¹³ , S, S(O), and S(O)2, wherein the selected heteroatoms and/or heteroatomic groups are cumulative with the nitrogen atoms present in ring B, and wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 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 ¹ and R ² are each independently selected from C3 alkyl, C5-C6 alkyl, C1- C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, F, I, CN, NO2, COC2-C6 alkyl, CO-C6-C10 aryl, CO(5- to 10-membered heteroaryl), CO ₂ C ₁ -C ₆ alkyl, CO ₂ C ₃ -C ₈ cycloalkyl, OCOC ₂ -C ₆ alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C6-C10 aryl, 5- to 10-membered heteroaryl, NH2, NHC2-C6 alkyl, N(C1-C6 alkyl)2, NHCOC1-C6 alkyl, NHCOC ₆ -C ₁₀ aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC2-C6 alkynyl, NHCOOCC1-C6 alkyl, NH-(C=NR ¹³ )NR ¹¹ R ¹² , CONR ⁸ R ⁹ , SF5, SC1-C6 alkyl, S(O2)C1-C6 alkyl, S(O2)NR ¹¹ R ¹² , S(O)C1-C6 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 optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 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), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), and NHCOC ₂ -C ₆ alkynyl; wherein each C1-C6 alkyl substituent and each C1-C6 alkoxy substituent of the R ¹ or R ² C3- 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, C6-C10 aryl, 5- to 10-membered heteroaryl, NHCOC6-C10 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, C1-C6 alkyl, and OC1-C6 alkyl;

or one pair of R ¹ and R ² on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C ₄ or C ₆ -C ₁₂ carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring containing 1-3 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxy, OC ₃ -C ₁₀ cycloalkyl, NR ⁸ R ⁹ , =NR ¹⁰ , CN, COOC1-C6 alkyl, OS(O2)C6-C10 aryl, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10- membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR ⁸ R ⁹ , wherein the C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, S(O ₂ )C ₆ -C ₁₀ aryl, C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₁ -C ₆ alkoxy, oxo, NR ⁸ R ⁹ , =NR ¹⁰ , COOC ₁ -C ₆ alkyl, C6-C10 aryl, and CONR ⁸ R ⁹ ; and

R ⁶ and R ⁷ are each independently selected from a C2-C6 alkyl, C2-C6 haloalkyl, C2-C6 alkoxy, C1- C ₆ haloalkoxy, I, 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), C6-C10 aryl, 5- to 10-membered heteroaryl, NH2, NHC1-C6 alkyl, N(C1-C6 alkyl) ₂ , CONR ⁸ R ⁹ , SF ₅ , SC ₁ -C ₆ alkyl, S(O ₂ )C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl and 3- to 10-membered heterocycloalkyl, and 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, C1-C6 alkyl, C1-C6 alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC1-C6 alkyl, CONR ⁸ R ⁹ , 3- to 5-membered heterocycloalkyl, 5-membered heteroaryl, OCOC ₁ -C ₆ alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7- membered heterocycloalkyl), NHCOC2-C6 alkynyl, C6-C10 aryloxy, and S(O2)C1-C6 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, NHCOC6-C10 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 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 and/or heteroatomic groups independently selected from O, NH, NR ¹³ , S, S(O), and S(O) ₂ , wherein the selected heteroatoms and/or heteroatomic groups are cumulative with the nitrogen atoms present in ring B, and 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 , COOC1-C6 alkyl, C6-C10 aryl, and CONR ⁸ R ⁹ . [Combination 1]

In some embodiments, the optionally substituted ring A is , wherein R ^x is selected from the group consisting of H and C1-C6 alkyl (e.g., methyl); Z ¹ is selected from the group consisting of O, NH, and -CH2- optionally substituted with 1-2 R ²⁰ ; Z ² is selected from the group consisting of NH and -CH ₂ - optionally substituted with 1-2 R ²⁰ ; Z ³ is selected from the group consisting of -CH2- optionally substituted with 1-2 R ²⁰ , -CH2CH2- optionally substituted with 1-2 R ²⁰ , and -CH2CH2CH2- optionally substituted with 1-2 R ²⁰ ; R ²⁰ is selected from the group consisting of hydroxy, halo (e.g., fluoro), oxo, C ₁ -C ₆ alkyl (e.g., methyl or ethyl) optionally substituted with one R ²¹ , C1-C6 alkoxy (e.g., methoxy, ethoxy, or isopropoxy) optionally substituted with one R ²¹ , NR ⁸ R ⁹ , 3- to 10-membered heterocycloalkyl (e.g., azetidinyl or pyrrolidinyl) optionally substituted with one R ²¹ , or one pair of R ²⁰ on the same atom, taken together with the atom connecting them, independently forms a monocyclic C3-C4 carbocyclic ring or a monocyclic 3- to 4-membered heterocyclic ring containing 1 O atom optionally substituted with OS(O) ₂ Ph; R ²¹ is selected from the group consisting of halo (e.g., fluoro), NR ⁸ R ⁹ , C ₂ -C ₆ alkynyl (e.g., ethynyl), and C1-C6 alkoxy (e.g., methoxy); R ⁸ and R ⁹ at each occurrence is independently selected from hydrogen, C1-C6 alkyl (e.g., methyl or ethyl), COR ¹³ , and CO2R ¹³ ; R ¹³ is selected from the group consisting of: C ₁ -C ₆ alkyl (e.g., methyl or t-butyl) and C ₁ -C ₆ haloalkyl (e.g., trifluoromethyl); and

wherein 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-C7 carbocyclic ring or a 5- to 7-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, C1-C6 alkyl, C1-C6 alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC1-C6 alkyl, C6-C10 aryl, and CONR ⁸ R ⁹ ; and

the remaining R ⁷ that is not taken with a R ⁶ on adjacent atoms to form a C ₄ -C ₇ carbocyclic ring or a 5- to 7-membered heterocyclic ring is independently selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, CN, COC1-C6 alkyl, CO2C1-C6 alkyl, CO2C3-C6 cycloalkyl, OCOC1-C6 alkyl, OCOC6-C10 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(O2)C1-C6 alkyl, C3-C7 cycloalkyl and 4- to 6-membered heterocycloalkyl, wherein the C1-C6 alkyl is optionally substituted with one to two C1-C6 alkoxy.

[Combination 2] In some embodiments, the optionally substituted ring wherein Z ⁴ is selected from the group consisting of–CH ₂ -,–C(O)-, and NH; Z ⁵ is selected from the group consisting of O, NH, N-CH3, and–CH2-; and

the substituted ring B is selected from:

wherein

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-C7 carbocyclic ring or a 5- to 7-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, C1-C6 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 remaining R ⁷ that is not taken with a R ⁶ on adjacent atoms to form a C ₄ -C ₇ carbocyclic ring or a 5- to 7-membered heterocyclic ring is independently selected from C1-C6 alkyl, C1-C6 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), C6-C10 aryl, 5- to 10-membered heteroaryl, CONR ⁸ R ⁹ , SF5, S(O2)C1-C6 alkyl, C3-C7 cycloalkyl and 4- to 6-membered heterocycloalkyl, wherein the C1-C6 alkyl is optionally substituted with one to two C ₁ -C ₆ alkoxy. In some embodiments of [Combination 1] and [Combination 2], the substituted ring B

In some embodiments of [Combination 1] and [Combination 2], the substituted ring B

In some embodiments of [Combination 1] and [Combination 2], one pair of R ⁶ and R ⁷ taken together with the atoms connecting them independently form a C5 carbocyclic ring, wherein the carbocyclic ring is optionally substituted with one or more substituents independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC1-C6 alkyl, C6-C10 aryl, and CONR ⁸ R ⁹ .

In certain of these embodiments, the other pair of R ⁶ and R ⁷ taken together with the atoms connecting them independently form a C ₅ carbocyclic ring, wherein the carbocyclic ring is optionally substituted with one or more substituents independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC1-C6 alkyl, C6-C10 aryl, and CONR ⁸ R ⁹ .

As non-limiting examples of the foregoing embodiments, the substituted ring B is

selected from:

As further non-limiting examples, the substituted ring B is

In certain embodiments of [Combination 1] and [Combination 2] (when one pair of R ⁶ and R ⁷ taken together with the atoms connecting them independently form a C5 carbocyclic ring, wherein the carbocyclic ring is 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 - C10 aryl, and CONR ⁸ R ⁹ ), the other pair of R ⁶ and R ⁷ taken together with the atoms connecting them independently form a C4 carbocyclic ring, wherein the carbocyclic ring is 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 (e.g., the

substituted ring B is: In some embodiments of [Combination 1] and [Combination 2], one pair of R ⁶ and R ⁷ taken together with the atoms connecting them independently form a C ₄ carbocyclic ring, wherein the carbocyclic ring is optionally substituted with one or more substituents independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC1-C6 alkyl, C6-C10 aryl, and CONR ⁸ R ⁹ .

In certain of these embodiments, the other pair of R ⁶ and R ⁷ taken together with the atoms connecting them independently form a C4 carbocyclic ring, wherein the carbocyclic ring is 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 (e.g.,

the substituted ring B is:

Additional Features of the Embodiments Herein In some embodiments of the compound of Formula AA (e.g., Formula AA-1, Formula AA-2, Formula AA-3, Formula AA-4, or Formula AA-5), R ⁶ is not CN.

In some embodiments, the compound of Formula AA is not a compound selected from the group consisting of:

In some embodiments, the compound of Formula AA is not a compound selected from the group consisting of:

. In some embodiments the compound of any of the formulae herein is not a compound disclosed in EP 0173498, which is incorporated herein by reference in its entirety.

In some embodiments the compound of any of the formulae herein is not a compound disclosed in US 4666506, which is incorporated herein by reference in its entirety.

In some embodiments, the compound of any of the formulae herein is not a compound disclosed in WO 2018225018, which is incorporated herein by reference in its entirety.

In some embodiments, the compound of any one of the formulae herein is not a compound disclosed in IN 201721020305, which is incorporated herein by reference in its entirety. In some embodiments, the compound of Formula AA is not selected from the group consisting of:

, _,

, , . It is understood that the combination of variables in the formulae herein is such that the compounds are stable. In some embodiments, provided herein is a compound that is selected from the group consisting of the compounds in Table 1: Table 1

01’ _148a H ₂ N

O ^O

F 104 150

F F F

F 106 151a

Cl

107 152a

F

108 153a

109 154a

N

F 10a 157

N 112 158

N ^{N N} N 13a 159a ^{O NH}

N

N 16a 161a ^H O

N N N

N 120 165 N N

N 21a 167

22a 168

124 170

25b 171

N 129 172a H ₂ N

N N N N 30a 173b

N N

N 31b 176 ^{H N}

^F

^Cl 34a 177a

H ^{35b 178b} HN _O

H N H _H 137 180

F H

H 38b 181b

141 183a

^{43b 185a NH2}

45a H ₂ N ^{187 NH2}

88b 189a

189

90b HN 220b

92 ^O _NH 223b

93a 226

95 229

5bb 232

97 235

01 239

03 243

05a 246

06a 249

07a 252

7aa 255

09 258

12 261

13 264

16 267

F

and pharmaceutically acceptable salts thereof. In some embodiments, provided herein is a compound that is selected from the group consisting of the compounds in the following table: ^{03 NH} 339

07 340a

09 341a

13 343b

15a 347

17 351

18 354 

9ba 357

20b O 359a

22 361b

3ba 364b

26 367a

28a 371b

30a 374a

32b 376

34 378

34b 380a

36 O 382a

37b 384a

and pharmaceutically acceptable salts thereof. In some embodiments, provided herein is a compound that is selected from the group consisting of the compounds in the following table: 01 409a

02

03

04

C _N 4a 411a4

05 06

07 413a

08

09

In some embodiments, provided herein is a compound that is selected from the group consisting of the compounds in the following table: 1 1 A18-3 O 2

3

4

5 5 A18-7 6 6

7 7

8 8

9 9

0 10 A19-61

2

3

4

5 15 A20-56 A

7 A

8 A

9 A

0 A1-6 A21-41

2

3

4

5 A2-5 B1-36

7

8

9

0 A3-4 B2-5 1 2

3

4

5 A4-3 B3-66

7

8

9

0 A5-2 B5-21

2

3

4

5 A5-7 B6-36

7

8

9

0 A6-6 B7-5 1 2

3

4

5

6 A7-6 B9-27

8

9

0

1 A8-5 B10-32

3

4

5 A9-3 B11-36

7

8 9

0 A10-2 B12-5 1 2

3

4

5 A10-7 B13-66

7

8

9 A11-5 B14-6 0

1

2

3

4 A12-4 B16-25

6

7

8 A13-2 B17-29

0

1

2

3 A13-7 B18-34

5

6

7 A14-5 C1-68

9

0

1 A15-3 C3-62

3

4

5 A15-7 C5-6 6

7

8

9

0 A16-6 D2-2 1 2

3

4

5 A17-5 D4-6

6

7

8

In some embodiments, provided herein is a compound that is selected from the group consisting of the compounds in Table 1C below: Table 1C d ^Structure Cmpd # Structure

a

b

b

a

a

b

and pharmaceutically acceptable salts thereof. In some embodiments, provided herein is a compound that is selected from the group consisting of the compounds in Table 1D below: T l 1D

m

#

00 01a 1026a0

00

0

0

00

03a 1028a0

00 0 0 00

05a00000000 07b 1030c00

0

0

00

0

0

010 1032 1 1 01

1

1

012 1033a1

1

01

1 1

014 1034b1

1

01

1 1

016 1036b 1 1 01

1

1

018 10381

1

01

1

1

020 10402

2

02

2

2

022 10422

2

02

2

23b 1043b 02

2

2

04

4

45b024 4 25a 1025b

02

2

and pharmaceutically acceptable salts thereof. In some embodiments, provided herein is a compound that is selected from the group consisting of the compounds in Table 1E below: Table 1E

m 0

2 1103

4

and pharmaceutically acceptable salts thereof. In one embodiment, provided herein is a pharmaceutical composition comprising any NLRP3 antagonist species defined here (for example, a compound or example of Tables 1, 1A, 1C, 1D, 1E, 16, 17, 18, 19, B1, B2, B3 and B4), and an anti-TNF ^ agent disclosed herein.

Preferably wherein the anti-TNF ^ ^agent is Infliximab, Etanercept, Certolizumab pegol,

Golimumab or Adalimumab, more preferably wherein the anti-TNF ^ ^agent is Adalimumab ^ In one embodiment, provided herein is a pharmaceutical combination of a compound of any NLRP3 antagonist species defined here (for example, a compound or example of Tables 1, 1A, 1C, 1D, 1E, 16, 17, 18, 19, B1, B2, B3 and B4), and an anti-TNF ^ ^agent Preferably wherein the anti-TNF ^ ^agent is Infliximab, Etanercept, Certolizumab pegol, Golimumab or Adalimumab, more preferably wherein the anti-TNF ^ ^agent is Adalimumab ^ Pharmaceutical Compositions and Administration

General

In some embodiments, a chemical entity (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 thereof) is administered as a pharmaceutical composition that includes the chemical entity and one or more pharmaceutically acceptable excipients, and optionally one or more additional therapeutic agents as described herein.

In some embodiments, the chemical entities can be administered in combination with one or more conventional pharmaceutical excipients. Pharmaceutically acceptable excipients include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as d-a-tocopherol polyethylene glycol 1000 succinate, surfactants used in pharmaceutical dosage forms such as Tweens, poloxamers or other similar polymeric delivery matrices, serum proteins, such as human serum albumin, buffer substances such as phosphates, tris, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium-chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, and wool fat. Cyclodextrins such as a-, ^, and g-cyclodextrin, or chemically modified derivatives such as hydroxyalkylcyclodextrins, including 2- and 3-hydroxypropyl-b-cyclodextrins, or other solubilized derivatives can also be used to enhance delivery of compounds described herein. Dosage forms or compositions containing a chemical entity as described herein in the range of 0.005% to 100% with the balance made up from non-toxic excipient may be prepared. The contemplated compositions may contain 0.001%-100% of a chemical entity provided herein, in one embodiment 0.1-95%, in another embodiment 75-85%, in a further embodiment 20-80%. Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington: The Science and Practice of Pharmacy, 22 ^nd Edition (Pharmaceutical Press, London, UK.2012).

In some embodiments, an NLRP3 antagonist and/or an anti-TNFa agent disclosed herein is administered as a pharmaceutical composition that includes the NLRP3 antagonist and/or anti- TNFa agent and one or more pharmaceutically acceptable excipients, and optionally one or more additional therapeutic agents as described herein. Preferably the pharmaceutical composition that includes an NLRP3 antagonist and an anti-TNFa agent.

Preferably the above pharmaceutical composition embodiments comprise an NLRP3 antagonist disclosed herein. More preferably the above pharmaceutical composition

embodiments comprise an NLRP3 antagonist and an anti-TNFa agent disclosed herein. Routes of Administration and Composition Components

In some embodiments, the chemical entities described herein or a pharmaceutical composition thereof can be administered to subject in need thereof by any accepted route of administration. Acceptable routes of administration include, but are not limited to, buccal, cutaneous, endocervical, endosinusial, endotracheal, enteral, epidural, interstitial, intra-abdominal, intra-arterial, intrabronchial, intrabursal, intracerebral, intracisternal, intracoronary, intradermal, intraductal, intraduodenal, intradural, intraepidermal, intraesophageal, intragastric, intragingival, intraileal, intralymphatic, intramedullary, intrameningeal, intramuscular, intraovarian, intraperitoneal, intraprostatic, intrapulmonary, intrasinal, intraspinal, intrasynovial, intratesticular, intrathecal, intratubular, intratumoral, intrauterine, intravascular, intravenous, nasal, nasogastric, oral, parenteral, percutaneous, peridural, rectal, respiratory (inhalation), subcutaneous, sublingual, submucosal, topical, transdermal, transmucosal, transtracheal, ureteral, urethral and vaginal. In certain embodiments, a preferred route of administration is parenteral (e.g., intratumoral).

Compositions can be formulated for parenteral administration, e.g., formulated for injection via the intravenous, intramuscular, sub-cutaneous, or even intraperitoneal routes. Typically, such compositions can be prepared as injectables, either as liquid solutions or suspensions; solid forms suitable for use to prepare solutions or suspensions upon the addition of a liquid prior to injection can also be prepared; and the preparations can also be emulsified. The preparation of such formulations will be known to those of skill in the art in light of the present disclosure.

The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions; formulations including sesame oil, peanut oil, or aqueous propylene glycol; and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases the form must be sterile and must be fluid to the extent that it may be easily injected. It also should be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi.

The carrier also can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils. The proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion, and by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.

Sterile injectable solutions are prepared by incorporating the active compounds in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum-drying and freeze-drying techniques, which yield a powder of the active ingredient, plus any additional desired ingredient from a previously sterile-filtered solution thereof.

Intratumoral injections are discussed, e.g., in Lammers, et al.,“Effect of Intratumoral Injection on the Biodistribution and the Therapeutic Potential of HPMA Copolymer-Based Drug Delivery Systems” Neoplasia.2006, 10, 788–795.

In certain embodiments, the chemical entities described herein or a pharmaceutical composition thereof are suitable for local, topical administration to the digestive or GI tract, e.g., rectal administration. Rectal compositions include, without limitation, enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppositories, and enemas (e.g., retention enemas).

Pharmacologically acceptable excipients usable in the rectal composition as a gel, cream, enema, or rectal suppository, include, without limitation, any one or more of cocoa butter glycerides, synthetic polymers such as polyvinylpyrrolidone, PEG (like PEG ointments), glycerine, glycerinated gelatin, hydrogenated vegetable oils, poloxamers, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol Vaseline, anhydrous lanolin, shark liver oil, sodium saccharinate, menthol, sweet almond oil, sorbitol, sodium benzoate, anoxid SBN, vanilla essential oil, aerosol, parabens in phenoxyethanol, sodium methyl p-oxybenzoate, sodium propyl p-oxybenzoate, diethylamine, carbomers, carbopol, methyloxybenzoate, macrogol cetostearyl ether, cocoyl caprylocaprate, isopropyl alcohol, propylene glycol, liquid paraffin, xanthan gum, carboxy-metabisulfite, sodium edetate, sodium benzoate, potassium metabisulfite, grapefruit seed extract, methyl sulfonyl methane (MSM) , lactic acid, glycine, vitamins, such as vitamin A and E and potassium acetate.

In certain embodiments, suppositories can be prepared by mixing the chemical entities described herein with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum and release the active compound. In other embodiments, compositions for rectal administration are in the form of an enema.

In other embodiments, the compounds described herein or a pharmaceutical composition thereof are suitable for local delivery to the digestive or GI tract by way of oral administration (e.g., solid or liquid dosage forms.).

Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the chemical entity is mixed with one or more pharmaceutically acceptable excipients, such as sodium citrate or dicalcium phosphate and/or: a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

In one embodiment, the compositions will take the form of a unit dosage form such as a pill or tablet and thus the composition may contain, along with a chemical entity provided herein, a diluent such as lactose, sucrose, dicalcium phosphate, or the like; a lubricant such as magnesium stearate or the like; and a binder such as starch, gum acacia, polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives or the like. In another solid dosage form, a powder, marume, solution or suspension (e.g., in propylene carbonate, vegetable oils, PEG’s, poloxamer 124 or triglycerides) is encapsulated in a capsule (gelatin or cellulose base capsule). Unit dosage forms in which one or more chemical entities provided herein or additional active agents are physically separated are also contemplated; e.g., capsules with granules (or tablets in a capsule) of each drug; two-layer tablets; two-compartment gel caps, etc. Enteric coated or delayed release oral dosage forms are also contemplated.

Other physiologically acceptable compounds include wetting agents, emulsifying agents, dispersing agents or preservatives that are particularly useful for preventing the growth or action of microorganisms. Various preservatives are well known and include, for example, phenol and ascorbic acid.

In certain embodiments the excipients are sterile and generally free of undesirable matter. These compositions can be sterilized by conventional, well-known sterilization techniques. For various oral dosage form excipients such as tablets and capsules sterility is not required. The USP/NF standard is usually sufficient.

In certain embodiments, solid oral dosage forms can further include one or more components that chemically and/or structurally predispose the composition for delivery of the chemical entity to the stomach or the lower GI; e.g., the ascending colon and/or transverse colon and/or distal colon and/or small bowel. Exemplary formulation techniques are described in, e.g., Filipski, K.J., et al., Current Topics in Medicinal Chemistry, 2013, 13, 776-802, which is incorporated herein by reference in its entirety.

Examples include upper-GI targeting techniques, e.g., Accordion Pill (Intec Pharma), floating capsules, and materials capable of adhering to mucosal walls.

Other examples include lower-GI targeting techniques. For targeting various regions in the intestinal tract, several enteric/pH-responsive coatings and excipients are available. These materials are typically polymers that are designed to dissolve or erode at specific pH ranges, selected based upon the GI region of desired drug release. These materials also function to protect acid labile drugs from gastric fluid or limit exposure in cases where the active ingredient may be irritating to the upper GI (e.g., hydroxypropyl methylcellulose phthalate series, Coateric (polyvinyl acetate phthalate), cellulose acetate phthalate, hydroxypropyl methylcellulose acetate succinate, Eudragit series (methacrylic acid–methyl methacrylate copolymers), and Marcoat). Other techniques include dosage forms that respond to local flora in the GI tract, Pressure-controlled colon delivery capsule, and Pulsincap.

Ocular compositions can include, without limitation, one or more of any of the following: viscogens (e.g., Carboxymethylcellulose, Glycerin, Polyvinylpyrrolidone, Polyethylene glycol); Stabilizers (e.g., Pluronic (triblock copolymers), Cyclodextrins); Preservatives (e.g., Benzalkonium chloride, ETDA, SofZia (boric acid, propylene glycol, sorbitol, and zinc chloride; Alcon Laboratories, Inc.), Purite (stabilized oxychloro complex; Allergan, Inc.)).

Topical compositions can include ointments and creams. Ointments are semisolid preparations that are typically based on petrolatum or other petroleum derivatives. Creams containing the selected active agent are typically viscous liquid or semisolid emulsions, often either oil-in-water or water-in-oil. Cream bases are typically water-washable, and contain an oil phase, an emulsifier and an aqueous phase. The oil phase, also sometimes called the“internal” phase, is generally comprised of petrolatum and a fatty alcohol such as cetyl or stearyl alcohol; the aqueous phase usually, although not necessarily, exceeds the oil phase in volume, and generally contains a humectant. The emulsifier in a cream formulation is generally a nonionic, anionic, cationic or amphoteric surfactant. As with other carriers or vehicles, an ointment base should be inert, stable, nonirritating and non-sensitizing.

In any of the foregoing embodiments, pharmaceutical compositions described herein can include one or more one or more of the following: lipids, interbilayer crosslinked multilamellar vesicles, biodegradeable poly(D,L-lactic-co-glycolic acid) [PLGA]-based or poly anhydride-based nanoparticles or microparticles, and nanoporous particle-supported lipid bilayers.

In one embodiment, provided herein is a pharmaceutical composition comprising any NLRP3 antagonist species defined here (for example, a compound or example of Tables 1, 1C, 1D, 1E, B1, B2, B3, and B4), and an anti-TNF ^ agent disclosed herein. Preferably wherein the anti-TNF ^ ^agent is Infliximab, Etanercept, Certolizumab pegol, Golimumab or Adalimumab, more preferably wherein the anti-TNF ^ ^agent is Adalimumab ^

In one embodiment, provided herein is a pharmaceutical combination of a compound of any NLRP3 antagonist species defined here (for example, a compound or example of Tables 1, 1C, 1D, 1E, B1, B2, B3, and B4), and an anti-TNF ^ ^agent Preferably wherein the anti- TNF ^ ^agent is Infliximab, Etanercept, Certolizumab pegol, Golimumab or Adalimumab, more preferably wherein the anti-TNF ^ ^agent is Adalimumab ^ Enema Formulations

In some embodiments, enema formulations containing the chemical entities described herein are provided in "ready-to-use" form. In some embodiments, enema formulations containing the chemical entities described herein are provided in one or more kits or packs. In certain embodiments, the kit or pack includes two or more separately contained/packaged components, e.g. two components, which when mixed together, provide the desired formulation (e.g., as a suspension). In certain of these embodiments, the two component system includes a first component and a second component, in which: (i) the first component (e.g., contained in a sachet) includes the chemical entity (as described anywhere herein) and optionally one or more pharmaceutically acceptable excipients (e.g., together formulated as a solid preparation, e.g., together formulated as a wet granulated solid preparation); and (ii) the second component (e.g., contained in a vial or bottle) includes one or more liquids and optionally one or more other pharmaceutically acceptable excipients together forming a liquid carrier. Prior to use (e.g., immediately prior to use), the contents of (i) and (ii) are combined to form the desired enema formulation, e.g., as a suspension. In other embodiments, each of component (i) and (ii) is provided in its own separate kit or pack.

In some embodiments, each of the one or more liquids is water, or a physiologically acceptable solvent, or a mixture of water and one or more physiologically acceptable solvents. Typical such solvents include, without limitation, glycerol, ethylene glycol, propylene glycol, polyethylene glycol and polypropylene glycol. In certain embodiments, each of the one or more liquids is water. In other embodiments, each of the one or more liquids is an oil, e.g. natural and/or synthetic oils that are commonly used in pharmaceutical preparations.

Further pharmaceutical excipients and carriers that may be used in the pharmaceutical products herein described are listed in various handbooks (e.g. D. E. Bugay and W. P. Findlay (Eds) Pharmaceutical excipients (Marcel Dekker, New York, 1999), E-M Hoepfner, A. Reng and P. C. Schmidt (Eds) Fiedler Encyclopedia of Excipients for Pharmaceuticals, Cosmetics and Related Areas (Edition Cantor, Munich, 2002) and H. P. Fielder (Ed) Lexikon der Hilfsstoffe für Pharmazie, Kosmetik and angrenzende Gebiete (Edition Cantor Aulendorf, 1989)).

In some embodiments, each of the one or more pharmaceutically acceptable excipients can be independently selelcted from thickeners, viscosity enhancing agents, bulking agents, mucoadhesive agents, penetration enhanceers, buffers, preservatives, diluents, binders, lubricants, glidants, disintegrants, fillers, solubilizing agents, pH modifying agents, preservatives, stabilizing agents, anti-oxidants, wetting or emulsifying agents, suspending agents, pigments, colorants, isotonic agents, chelating agents, emulsifiers, and diagnostic agents. In certain embodiments, each of the one or more pharmaceutically acceptable excipients can be independently selelcted from thickeners, viscosity enhancing agents, mucoadhesive agents, buffers, preservatives, diluents, binders, lubricants, glidants, disintegrants, and fillers.

In certain embodiments, each of the one or more pharmaceutically acceptable excipients can be independently selelcted from thickeners, viscosity enhancing agents, bulking agents, mucoadhesive agents, buffers, preservatives, and fillers.

In certain embodiments, each of the one or more pharmaceutically acceptable excipients can be independently selelcted from diluents, binders, lubricants, glidants, and disintegrants.

Examples of thickeners, viscosity enhancing agents, and mucoadhesive agents include without limitation: gums, e.g. xanthan gum, guar gum, locust bean gum, tragacanth gums, karaya gum, ghatti gum, cholla gum, psyllium seed gum and gum arabic; poly(carboxylic acid-containing) based polymers, such as poly (acrylic, maleic, itaconic, citraconic, hydroxyethyl methacrylic or methacrylic) acid which have strong hydrogen-bonding groups, or derivatives thereof such as salts and esters; cellulose derivatives, such as methyl cellulose, ethyl cellulose, methylethyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxyethyl ethyl cellulose, carboxymethyl cellulose, hydroxypropylmethyl cellulose or cellulose esters or ethers or derivatives or salts thereof; clays such as manomorillonite clays, e.g. Veegun, attapulgite clay; polysaccharides such as dextran, pectin, amylopectin, agar, mannan or polygalactonic acid or starches such as hydroxypropyl starch or carboxymethyl starch; polypeptides such as casein, gluten, gelatin, fibrin glue; chitosan, e.g. lactate or glutamate or carboxymethyl chitin; glycosaminoglycans such as hyaluronic acid; metals or water soluble salts of alginic acid such as sodium alginate or magnesium alginate; schleroglucan; adhesives containing bismuth oxide or aluminium oxide; atherocollagen; polyvinyl polymers such as carboxyvinyl polymers; polyvinylpyrrolidone (povidone); polyvinyl alcohol; polyvinyl acetates, polyvinylmethyl ethers, polyvinyl chlorides, polyvinylidenes, and/or the like; polycarboxylated vinyl polymers such as polyacrylic acid as mentioned above; polysiloxanes; polyethers; polyethylene oxides and glycols; polyalkoxys and polyacrylamides and derivatives and salts thereof. Preferred examples can include cellulose derivatives, such as methyl cellulose, ethyl cellulose, methylethyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxyethyl ethyl cellulose, carboxymethyl cellulose, hydroxypropylmethyl cellulose or cellulose esters or ethers or derivatives or salts thereof (e.g., methyl cellulose); and polyvinyl polymers such as polyvinylpyrrolidone (povidone).

Examples of preservatives include without limitation: benzalkonium chloride, benzoxonium chloride, benzethonium chloride, cetrimide, sepazonium chloride, cetylpyridinium chloride, domiphen bromide (Bradosol®), thiomersal, phenylmercuric nitrate, phenylmercuric acetate, phenylmercuric borate, methylparaben, propylparaben, chlorobutanol, benzyl alcohol, phenyl ethyl alcohol, chlorohexidine, polyhexamethylene biguanide, sodium perborate, imidazolidinyl urea, sorbic acid, Purite®), Polyquart®), and sodium perborate tetrahydrate and the like.

In certain embodiments, the preservative is a paraben, or a pharmaceutically acceptable salt thereof. In some embodiments, the paraben is an alkyl substituted 4-hydroxybenzoate, or a pharmaceutically acceptable salt or ester thereof. In certain embodiments, the alkyl is a C1-C4 alkyl. In certain embodiments, the preservative is methyl 4-hydroxybenzoate (methylparaben), or a pharmaceutically acceptable salt or ester thereof, propyl 4-hydroxybenzoate (propylparaben), or a pharmaceutically acceptable salt or ester thereof, or a combination thereof.

Examples of buffers include without limitation: phosphate buffer system (sodium dihydrogen phospahate dehydrate, disodium phosphate dodecahydrate, bibasic sodium phosphate, anhydrous monobasic sodium phosphate), bicarbonate buffer system, and bisulfate buffer system.

Examples of disintegrants include, without limitation: carmellose calcium, low substituted hydroxypropyl cellulose (L-HPC), carmellose, croscarmellose sodium, partially pregelatinized starch, dry starch, carboxymethyl starch sodium, crospovidone, polysorbate 80 (polyoxyethylenesorbitan oleate), starch, sodium starch glycolate, hydroxypropyl cellulose pregelatinized starch, clays, cellulose, alginine, gums or cross linked polymers, such as cross- linked PVP (Polyplasdone XL from GAF Chemical Corp). In certain embodiments, the disintegrant is crospovidone.

Examples of glidants and lubricants (aggregation inhibitors) include without limitation: talc, magnesium stearate, calcium stearate, colloidal silica, stearic acid, aqueous silicon dioxide, synthetic magnesium silicate, fine granulated silicon oxide, starch, sodium laurylsulfate, boric acid, magnesium oxide, waxes, hydrogenated oil, polyethylene glycol, sodium benzoate, stearic acid glycerol behenate, polyethylene glycol, and mineral oil. In certain embodiments, the glidant/lubricant is magnesium stearate, talc, and/or colloidal silica; e.g., magnesium stearate and/or talc.

Examples of diluents, also referred to as“fillers” or“bulking agents” include without limitation: dicalcium phosphate dihydrate, calcium sulfate, lactose (e.g., lactose monohydrate), sucrose, mannitol, sorbitol, cellulose, microcrystalline cellulose, kaolin, sodium chloride, dry starch, hydrolyzed starches, pregelatinized starch, silicone dioxide, titanium oxide, magnesium aluminum silicate and powdered sugar. In certain embodiments, the diluent is lactose (e.g., lactose monohydrate).

Examples of binders include without limitation: starch, pregelatinized starch, gelatin, sugars (including sucrose, glucose, dxtrose, lactose and sorbitol), polyethylene glycol, waxes, natural and synthetic gums such as acacia tragacanth, sodium alginate cellulose, including hydroxypropylmethylcellulose, hydroxypropylcellulose, ethylcellulose, and veegum, and synthetic polymers such as acrylic acid and methacrylic acid copolymers, methacrylic acid copolymers, methyl methacrylate copolymers, aminoalkyl methacrylate copolymers, polyacrylic acid/polymethacrylic acid and polyvinylpyrrolidone (povidone). In certain embodiments, the binder is polyvinylpyrrolidone (povidone). In some embodiments, enema formulations containing the chemical entities described herein include water and one or more (e.g., all) of the following excipients:

^ One or more (e.g., one, two, or three) thickeners, viscosity enhancing agents, binders, and/or mucoadhesive agents (e.g., cellulose or cellulose esters or ethers or derivatives or salts thereof (e.g., methyl cellulose); and polyvinyl polymers such as polyvinylpyrrolidone (povidone);

^ One or more (e.g., one or two; e.g., two) preservatives, such as a paraben, e.g., methyl 4-hydroxybenzoate (methylparaben), or a pharmaceutically acceptable salt or ester thereof, propyl 4-hydroxybenzoate (propylparaben), or a pharmaceutically acceptable salt or ester thereof, or a combination thereof;

^ One or more (e.g., one or two; e.g., two) buffers, such as phosphate buffer system (e.g., sodium dihydrogen phospahate dehydrate, disodium phosphate dodecahydrate); ^ One or more (e.g., one or two, e.g., two) glidants and/or lubricants, such as magnesium stearate and/or talc;

^ One or more (e.g., one or two; e.g., one) disintegrants, such as crospovidone; and ^ One or more (e.g., one or two; e.g., one) diluents, such as lactose (e.g., lactose monohydrate).

In certain of these embodiments, the chemical entity is a compound of Formula AA, or a pharmaceutically acceptable salt and/or hydrate and/or cocrystal thereof.

In certain embodiments, enema formulations containing the chemical entities described herein include water, methyl cellulose, povidone, methylparaben, propylparaben, sodium dihydrogen phospahate dehydrate, disodium phosphate dodecahydrate, crospovidone, lactose monohydrate, magnesium stearate, and talc. In certain of these embodiments, the chemical entity is a compound of Formula AA, or a pharmaceutically acceptable salt and/or hydrate and/or cocrystal thereof. In certain embodiments, enema formulations containing the chemical entities described herein are provided in one or more kits or packs. In certain embodiments, the kit or pack includes two separately contained/packaged components, which when mixed together, provide the desired formulation (e.g., as a suspension). In certain of these embodiments, the two component system includes a first component and a second component, in which: (i) the first component (e.g., contained in a sachet) includes the chemical entity (as described anywhere herein) and one or more pharmaceutically acceptable excipients (e.g., together formulated as a solid preparation, e.g., together formulated as a wet granulated solid preparation); and (ii) the second component (e.g., contained in a vial or bottle) includes one or more liquids and one or more one or more other pharmaceutically acceptable excipients together forming a liquid carrier. In other embodiments, each of component (i) and (ii) is provided in its own separate kit or pack.

In certain of these embodiments, component (i) includes the chemical entitiy (e.g., a compound of Formula AA, or a pharmaceutically acceptable salt and/or hydrate and/or cocrystal thereof; e.g., a compound of Formula AA) and one or more (e.g., all) of the following excipients:

(a) One or more (e.g., one) binders (e.g., a polyvinyl polymer, such as polyvinylpyrrolidone (povidone); (b) One or more (e.g., one or two, e.g., two) glidants and/or lubricants, such as magnesium stearate and/or talc;

(c) One or more (e.g., one or two; e.g., one) disintegrants, such as crospovidone; and (d) One or more (e.g., one or two; e.g., one) diluents, such as lactose (e.g., lactose monohydrate).

In certain embodiments, component (i) includes from about 40 weight percent to about 80 weight percent (e.g., from about 50 weight percent to about 70 weight percent, from about 55 weight percent to about 70 weight percent; from about 60 weight percent to about 65 weight percent; e.g., about 62.1 weight percent) of the chemical entity (e.g., a compound of Formula AA, or a pharmaceutically acceptable salt and/or hydrate and/or cocrystal thereof).

In certain embodiments, component (i) includes from about 0.5 weight percent to about 5 weight percent (e.g., from about 1.5 weight percent to about 4.5 weight percent, from about 2 weight percent to about 3.5 weight percent; e.g., about 2.76 weight percent) of the binder (e.g., povidone).

In certain embodiments, component (i) includes from about 0.5 weight percent to about 5 weight percent (e.g., from about 0.5 weight percent to about 3 weight percent, from about 1 weight percent to about 3 weight percent; about 2 weight percent e.g., about 1.9 weight percent) of the disintegrant (e.g., crospovidone).

In certain embodiments, component (i) includes from about 10 weight percent to about 50 weight percent (e.g., from about 20 weight percent to about 40 weight percent, from about 25 weight percent to about 35 weight percent; e.g., about 31.03 weight percent) of the diluent (e.g., lactose, e.g., lactose monohydrate).

In certain embodiments, component (i) includes from about 0.05 weight percent to about 5 weight percent (e.g., from about 0.05 weight percent to about 3 weight percent) of the glidants and/or lubricants.

In certain embodiments (e.g., when component (i) includes one or more lubricants, such as magnesium stearate), component (i) includes from about 0.05 weight percent to about 1 weight percent (e.g., from about 0.05 weight percent to about 1 weight percent; from about 0.1 weight percent to about 1 weight percent; from about 0.1 weight percent to about 0.5 weight percent; e.g., about 0.27 weight percent) of the lubricant (e.g., magnesium stearate). In certain embodiments (when component (i) includes one or more lubricants, such as talc), component (i) includesfrom about 0.5 weight percent to about 5 weight percent (e.g., from about 0.5 weight percent to about 3 weight percent, from about 1 weight percent to about 3 weight percent; from about 1.5 weight percent to about 2.5 weight percent; from about 1.8 weight percent to about 2.2 weight percent; about 1.93 weight percent) of the lubricant (e.g., talc).

In certain of these embodiments, each of (a), (b), (c), and (d) above is present.

In certain embodiments, component (i) includes the ingredients and amounts as shown in Table A.

Table A

In certain embodiments, component (i) includes the ingredients and amounts as shown in Table B.

Table B

In certain embodiments, component (i) is formulated as a wet granulated solid preparation. In certain of these embodiments an internal phase of ingredients (the chemical entity, disintegrant, and diluent) are combined and mixed in a high-shear granulator. A binder (e.g., povidone) is dissolved in water to form a granulating solution. This solution is added to the Inner Phase mixture resulting in the development of granules. While not wishing to be bound by theory, granule development is believed to be facilitated by the interaction of the polymeric binder with the materials of the internal phase. Once the granulation is formed and dried, an external phase (e.g., one or more lubricants - not an intrinsic component of the dried granulation), is added to the dry granulation. It is believed that lubrication of the granulation is important to the flowability of the granulation, in particular for packaging. In certain of the foregoing embodiments, component (ii) includes water and one or more (e.g., all) of the following excipients:

(a’) One or more (e.g., one, two; e.g., two) thickeners, viscosity enhancing agents, binders, and/or mucoadhesive agents (e.g., cellulose or cellulose esters or ethers or derivatives or salts thereof (e.g., methyl cellulose); and polyvinyl polymers such as polyvinylpyrrolidone (povidone);

(b’) One or more (e.g., one or two; e.g., two) preservatives, such as a paraben, e.g., methyl 4-hydroxybenzoate (methylparaben), or a pharmaceutically acceptable salt or ester thereof, propyl 4-hydroxybenzoate (propylparaben), or a pharmaceutically acceptable salt or ester thereof, or a combination thereof; and

(c’) One or more (e.g., one or two; e.g., two) buffers, such as phosphate buffer system (e.g., sodium dihydrogen phospahate dihydrate, disodium phosphate dodecahydrate); In certain of the foregoing embodiments, component (ii) includes water and one or more (e.g., all) of the following excipients:

(a’’) a first thickener, viscosity enhancing agent, binder, and/or mucoadhesive agent (e.g., a cellulose or cellulose ester or ether or derivative or salt thereof (e.g., methyl cellulose)); (a’’’) a second thickener, viscosity enhancing agent, binder, and/or mucoadhesive agent (e.g., a polyvinyl polymer, such as polyvinylpyrrolidone (povidone));

(b’’) a first preservative, such as a paraben, e.g., propyl 4-hydroxybenzoate (propylparaben), or a pharmaceutically acceptable salt or ester thereof;

(b’’) a second preservative, such as a paraben, e.g., methyl 4-hydroxybenzoate (methylparaben), or a pharmaceutically acceptable salt or ester thereof,

(c’’) a first buffer, such as phosphate buffer system (e.g., disodium phosphate dodecahydrate);

(c’’’) a second buffer, such as phosphate buffer system (e.g., sodium dihydrogen phospahate dehydrate),

In certain embodiments, component (ii) includes from about 0.05 weight percent to about 5 weight percent (e.g., from about 0.05 weight percent to about 3 weight percent, from about 0.1 weight percent to about 3 weight percent; e.g., about 1.4 weight percent) of (a’’). In certain embodiments, component (ii) includes from about 0.05 weight percent to about 5 weight percent (e.g., from about 0.05 weight percent to about 3 weight percent, from about 0.1 weight percent to about 2 weight percent; e.g., about 1.0 weight percent) of (a’’’).

In certain embodiments, component (ii) includes from about 0.005 weight percent to about 0.1 weight percent (e.g., from about 0.005 weight percent to about 0.05 weight percent; e.g., about 0.02 weight percent) of (b’’).

In certain embodiments, component (ii) includes from about 0.05 weight percent to about 1 weight percent (e.g., from about 0.05 weight percent to about 0.5 weight percent; e.g., about 0.20 weight percent) of (b’’’).

In certain embodiments, component (ii) includes from about 0.05 weight percent to about 1 weight percent (e.g., from about 0.05 weight percent to about 0.5 weight percent; e.g., about 0.15 weight percent) of (c’’).

In certain embodiments, component (ii) includes from about 0.005 weight percent to about 0.5 weight percent (e.g., from about 0.005 weight percent to about 0.3 weight percent; e.g., about 0.15 weight percent) of (c’’’).

In certain of these embodiments, each of (a’’) - (c’’’) is present.

In certain embodiments, component (ii) includes water (up to 100%) and the ingredients and amounts as shown in Table C.

Table C

In certain embodiments, component (ii) includes water (up to 100%) and the ingredients and amounts as shown in Table D. Table D

Ready-to-use" enemas are generally be provided in a "single-use" sealed disposable container of plastic or glass. Those formed of a polymeric material preferably have sufficient flexibility for ease of use by an unassisted patient. Typical plastic containers can be made of polyethylene. These containers may comprise a tip for direct introduction into the rectum. Such containers may also comprise a tube between the container and the tip. The tip is preferably provided with a protective shield which is removed before use. Optionally the tip has a lubricant to improve patient compliance.

In some embodiments, the enema formulation (e.g., suspension) is poured into a bottle for delivery after it has been prepared in a separate container. In certain embodiments, the bottle is a plastic bottle (e.g., flexible to allow for delivery by squeezing the bottle), which can be a polyethylene bottle (e.g., white in color). In some embodiments, the bottle is a single chamber bottle, which contains the suspension or solution. In other embodiments, the bottle is a multichamber bottle, where each chamber contains a separate mixture or solution. In still other embodiments, the bottle can further include a tip or rectal cannula for direct introduction into the rectum. Dosages

The dosages may be varied depending on the requirement of the patient, the severity of the condition being treating and the particular compound being employed. Determination of the proper dosage for a particular situation can be determined by one skilled in the medical arts. The total daily dosage may be divided and administered in portions throughout the day or by means providing continuous delivery.

In some embodiments, the compounds described herein are administered at a dosage of from about 0.001 mg/Kg to about 500 mg/Kg (e.g., from about 0.001 mg/Kg to about 200 mg/Kg; from about 0.01 mg/Kg to about 200 mg/Kg; from about 0.01 mg/Kg to about 150 mg/Kg; from about 0.01 mg/Kg to about 100 mg/Kg; from about 0.01 mg/Kg to about 50 mg/Kg; from about 0.01 mg/Kg to about 10 mg/Kg; from about 0.01 mg/Kg to about 5 mg/Kg; from about 0.01 mg/Kg to about 1 mg/Kg; from about 0.01 mg/Kg to about 0.5 mg/Kg; from about 0.01 mg/Kg to about 0.1 mg/Kg; from about 0. 1 mg/Kg to about 200 mg/Kg; from about 0. 1 mg/Kg to about 150 mg/Kg; from about 0.1 mg/Kg to about 100 mg/Kg; from about 0.1 mg/Kg to about 50 mg/Kg; from about 0.1 mg/Kg to about 10 mg/Kg; from about 0.1 mg/Kg to about 5 mg/Kg; from about 0.1 mg/Kg to about 1 mg/Kg; from about 0.1 mg/Kg to about 0.5 mg/Kg).

In some embodiments, enema formulations include from about 0.5 mg to about 2500 mg (e.g., from about 0.5 mg to about 2000 mg, from about 0.5 mg to about 1000 mg, from about 0.5 mg to about 750 mg, from about 0.5 mg to about 600 mg, from about 0.5 mg to about 500 mg, from about 0.5 mg to about 400 mg, from about 0.5 mg to about 300 mg, from about 0.5 mg to about 200 mg; e.g., from about 5 mg to about 2500 mg, from about 5 mg to about 2000 mg, from about 5 mg to about 1000 mg; from about 5 mg to about 750 mg; from about 5 mg to about 600 mg; from about 5 mg to about 500 mg; from about 5 mg to about 400 mg; from about 5 mg to about 300 mg; from about 5 mg to about 200 mg; e.g., from about 50 mg to about 2000 mg, from about 50 mg to about 1000 mg, from about 50 mg to about 750 mg, from about 50 mg to about 600 mg, from about 50 mg to about 500 mg, from about 50 mg to about 400 mg, from about 50 mg to about 300 mg, from about 50 mg to about 200 mg; e.g., from about 100 mg to about 2500 mg, from about 100 mg to about 2000 mg, from about 100 mg to about 1000 mg, from about 100 mg to about 750 mg, from about 100 mg to about 700 mg, from about 100 mg to about 600 mg, from about 100 mg to about 500 mg, from about 100 mg to about 400 mg, from about 100 mg to about 300 mg, from about 100 mg to about 200 mg; e.g., from about 150 mg to about 2500 mg, from about 150 mg to about 2000 mg, from about 150 mg to about 1000 mg, from about 150 mg to about 750 mg, from about 150 mg to about 700 mg, from about 150 mg to about 600 mg, from about 150 mg to about 500 mg, from about 150 mg to about 400 mg, from about 150 mg to about 300 mg, from about 150 mg to about 200 mg; e.g., from about 150 mg to about 500 mg; e.g., from about 300 mg to about 2500 mg, from about 300 mg to about 2000 mg, from about 300 mg to about 1000 mg, from about 300 mg to about 750 mg, from about 300 mg to about 700 mg, from about 300 mg to about 600 mg; e.g., from about 400 mg to about 2500 mg, from about 400 mg to about 2000 mg, from about 400 mg to about 1000 mg, from about 400 mg to about 750 mg, from about 400 mg to about 700 mg, from about 400 mg to about 600 from about 400 mg to about 500 mg; e.g., 150 mg or 450 mg) of the chemical entity in from about 1 mL to about 3000 mL (e.g., from about 1 mL to about 2000 mL, from about 1 mL to about 1000 mL, from about 1 mL to about 500 mL, from about 1 mL to about 250 mL, from about 1 mL to about 100 mL, from about 10 mL to about 1000 mL, from about 10 mL to about 500 mL, from about 10 mL to about 250 mL, from about 10 mL to about 100 mL, from about 30 mL to about 90 mL, from about 40 mL to about 80 mL; from about 50 mL to about 70 mL; e.g., about 1 mL, about 5 mL, about 10 mL, about 15 mL, about 20 mL, about 25 mL, about 30 mL, about 35 mL, about 40 mL, about 45 mL,about 50 mL, about 55 mL, about 60 mL, about 65 mL, about 70 mL, about 75 mL, about 100 mL, about 250 mL, or about 500 mL, or about 1000 mL, or about 2000mL, or about 3000 mL; e.g., 60 mL) of liquid carrier.

In certain embodiments, enema formulations include from about 50 mg to about 250 mg (e.g., from about 100 mg to about 200; e.g., about 150 mg) of the chemical entity in from about 10 mL to about 100 mL (e.g., from about 20 mL to about 100 mL, from about 30 mL to about 90 mL, from about 40 mL to about 80 mL; from about 50 mL to about 70 mL) of liquid carrier. In certain embodiments, enema formulations include about 150 mg of the chemical entity in about 60 mL of the liquid carrier. In certain of these embodiments, the chemical entity is a compound of Formula AA, or a pharmaceutically acceptable salt and/or hydrate and/or cocrystal thereof. For example, enema formulations can include about 150 mg of a compound of Formula AA in about 60 mL of the liquid carrier.

In certain embodiments, enema formulations include from about 350 mg to about 550 mg (e.g., from about 400 mg to about 500; e.g., about 450 mg) of the chemical entity in from about 10 mL to about 100 mL (e.g., from about 20 mL to about 100 mL, from about 30 mL to about 90 mL, from about 40 mL to about 80 mL; from about 50 mL to about 70 mL) of liquid carrier. In certain embodiments, enema formulations include about 450 mg of the chemical entity in about 60 mL of the liquid carrier. In certain of these embodiments, the chemical entity is a compound of Formula AA, or a pharmaceutically acceptable salt and/or hydrate and/or cocrystal thereof. For example, enema formulations can include about 450 mg of a compound of Formula AA in about 60 mL of the liquid carrier.

In some embodiments, enema formulations include from about from about 0.01 mg/mL to about 50 mg/mL (e.g., from about 0.01 mg/mL to about 25 mg/mL; from about 0.01 mg/mL to about 10 mg/mL; from about 0.01 mg/mL to about 5 mg/mL; from about 0.1 mg/mL to about 50 mg/mL; from about 0.01 mg/mL to about 25 mg/mL; from about 0.1 mg/mL to about 10 mg/mL; from about 0.1 mg/mL to about 5 mg/mL; from about 1 mg/mL to about 10 mg/mL; from about 1 mg/mL to about 5 mg/mL; from about 5 mg/mL to about 10 mg/mL; e.g., about 2.5 mg/mL or about 7.5 mg/mL) of the chemical entity in liquid carrier. In certain of these embodiments, the chemical entity is a compound of Formula AA, or a pharmaceutically acceptable salt and/or hydrate and/or cocrystal thereof. For example, enema formulations can include about 2.5 mg/mL or about 7.5 mg/mL of a compound of Formula AA in liquid carrier. Regimens

The foregoing dosages can be administered on a daily basis (e.g., as a single dose or as two or more divided doses) or non-daily basis (e.g., every other day, every two days, every three days, once weekly, twice weeks, once every two weeks, once a month).

In some embodiments, the period of administration of a compound described herein is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more. In a further embodiment, a period of during which administration is stopped is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 1 1 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 1 1 months, 12 months, or more. In an embodiment, a therapeutic compound is administered to an individual for a period of time followed by a separate period of time. In another embodiment, a therapeutic compound is administered for a first period and a second period following the first period, with administration stopped during the second period, followed by a third period where administration of the therapeutic compound is started and then a fourth period following the third period where administration is stopped. In an aspect of this embodiment, the period of administration of a therapeutic compound followed by a period where administration is stopped is repeated for a determined or undetermined period of time. In a further embodiment, a period of administration is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more. In a further embodiment, a period of during which administration is stopped is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more. Methods of Treatment

In some embodiments, methods for treating a subject having condition, disease or disorder in which a decrease or increase in NLRP3 activity (e.g., an increase, e.g., NLRP3 signaling) contributes to the pathology and/or symptoms and/or progression of the condition, disease or disorder are provided, comprising administering to a subject 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).

Indications

In some embodiments, the condition, disease or disorder is selected from: inappropriate host responses to infectious diseases where active infection exists at any body site, such as septic shock, disseminated intravascular coagulation, and/or adult respiratory distress syndrome; acute or chronic inflammation due to antigen, antibody and/or complement deposition; inflammatory conditions including arthritis, cholangitis, colitis, encephalitis, endocarditis, glomerulonephritis, hepatitis, myocarditis, pancreatitis, pericarditis, reperfusion injury and vasculitis, immune-based diseases such as acute and delayed hypersensitivity, graft rejection, and graft-versus-host disease; auto-immune diseases including Type 1 diabetes mellitus and multiple sclerosis. For example, the condition, disease or disorder may be an inflammatory disorder such as rheumatoid arthritis, osteoarthritis, septic shock, COPD and periodontal disease.

In some embodiments, the condition, disease or disorder is an autoimmune diseases. Non- limiting examples include rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, inflammatory bowel diseases (IBDs) comprising Crohn disease (CD) and ulcerative colitis (UC), which are chronic inflammatory conditions with polygenic susceptibility. In certain embodiments, the condition is an inflammatory bowel disease. In certain embodiments, the condition is Crohn’s disease, autoimmune colitis, iatrogenic autoimmune colitis, ulcerative colitis, colitis induced by one or more chemotherapeutic agents, colitis induced by treatment with adoptive cell therapy, colitis associated by one or more alloimmune diseases (such as graft-vs-host disease, e.g., acute graft vs. host disease and chronic graft vs. host disease), radiation enteritis, collagenous colitis, lymphocytic colitis, microscopic colitis, and radiation enteritis. In certain of these embodiments, the condition is alloimmune disease (such as graft-vs-host disease, e.g., acute graft vs. host disease and chronic graft vs. host disease), celiac disease, irritable bowel syndrome, rheumatoid arthritis, lupus, scleroderma, psoriasis, cutaneous T-cell lymphoma, uveitis, and mucositis (e.g., oral mucositis, esophageal mucositis or intestinal mucositis).

In some embodiments, the condition, disease or disorder is selected from major adverse cardiovascular events such as carbiovascular death, non-fatal myocardial infarction and non-fatal stroke in patients with a prior hear attack and inflammatory atherosclerosis (see for example, NCT01327846).

In some embodiments, the condition, disease or disorder is selected from 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 some embodiments, the condition, disease or disorder is a cardiovascular indication. In some embodiments, the condition, disease or disorder is myocardial infraction. In some embodiments, the condition, disease or disorder is stroke. In some embodiments, the condition, disease or disorder is obesity.

In some embodiments, the condition, disease or disorder is Type 2 Diabetes.

In some embodiments, the condition, disease or disorder is NASH.

In some embodiments, the condition, disease or disorder is Alzheimer’s disease.

In some embodiments, the condition, disease or disorder is gout.

In some embodiments, the condition, disease or disorder is SLE.

In some embodiments, the condition, disease or disorder is rheumatoid arthritis.

In some embodiments, the condition, disease or disorder is IBD.

In some embodiments, the condition, disease or disorder is multiple sclerosis.

In some embodiments, the condition, disease or disorder is COPD.

In some embodiments, the condition, disease or disorder is asthma.

In some embodiments, the condition, disease or disorder is scleroderma.

In some embodiments, the condition, disease or disorder is pulmonary fibrosis.

In some embodiments, the condition, disease or disorder is age related macular degeneration (AMD).

In some embodiments, the condition, disease or disorder is cystic fibrosis.

In some embodiments, the condition, disease or disorder is Muckle Wells syndrome. In some embodiments, the condition, disease or disorder is familial cold autoinflammatory syndrome (FCAS).

In some embodiments, the condition, disease or disorder is chronic neurologic cutaneous and articular syndrome.

In some embodiments, the condition, disease or disorder is selected from: myelodysplastic syndromes (MDS); non-small cell lung cancer, such as non-small cell lung cancer in patients carrying mutation or overexpression of NLRP3; acute lymphoblastic leukemia (ALL), such as ALL in patients resistant to glucocorticoids treatment; Langerhan’s cell histiocytosis (LCH); multiple myeloma; promyelocytic leukemia; acute myeloid leukemia (AML) chronic myeloid leukemia (CML); gastric cancer; and lung cancer metastasis.

In some embodiments, the condition, disease or disorder is selected from: myelodysplastic syndromes (MDS); non-small cell lung cancer, such as non-small cell lung cancer in patients carrying mutation or overexpression of NLRP3; acute lymphoblastic leukemia (ALL), such as ALL in patients resistant to glucocorticoids treatment; Langerhan’s cell histiocytosis (LCH); multiple myeloma; promyelocytic leukemia; gastric cancer; and lung cancer metastasis.

In some embodiments, the indication is MDS.

In some embodiments, the indication is non-small lung cancer in patients carrying mutation or overexpression of NLRP3.

In some embodiments, the indication is ALL in patients resistant to glucocorticoids treatment.

In some embodiments, the indication is LCH.

In some embodiments, the indication is multiple myeloma.

In some embodiments, the indication is promyelocytic leukemia.

In some embodiments, the indication is gastric cancer.

In some embodiments, the indication is lung cancer metastasis.

Combination therapy

This disclosure contemplates both monotherapy regimens as well as combination therapy regimens.

In some embodiments, the methods described herein can further include administering one or more additional therapies (e.g., one or more additional therapeutic agents and/or one or more therapeutic regimens) in combination with administration of the compounds described herein.

In certain embodiments, the second therapeutic agent or regimen is administered to the subject prior to contacting with or administering the chemical entity (e.g., about one hour prior, or about 6 hours prior, or about 12 hours prior, or about 24 hours prior, or about 48 hours prior, or about 1 week prior, or about 1 month prior).

In other embodiments, the second therapeutic agent or regimen is administered to the subject at about the same time as contacting with or administering the chemical entity. By way of example, the second therapeutic agent or regimen and the chemical entity are provided to the subject simultaneously in the same dosage form. As another example, the second therapeutic agent or regimen and the chemical entity are provided to the subject concurrently in separate dosage forms.

In still other embodiments, the second therapeutic agent or regimen is administered to the subject after contacting with or administering the chemical entity (e.g., about one hour after, or about 6 hours after, or about 12 hours after, or about 24 hours after, or about 48 hours after, or about 1 week after, or about 1 month after). Patient Selection

In some embodiments, the methods described herein further include the step of identifying a subject (e.g., a patient) in need of treatment for an indication related to NLRP3 activity, such as an indication related to NLRP3 polymorphism.

In some embodiments, the methods described herein further include the step of identifying a subject (e.g., a patient) in need of treatment for an indication related to NLRP3 activity, such as an indication related to NLRP3 where polymorphism is a gain of function

In some embodiments, the methods described herein further include the step of identifying a subject (e.g., a patient) in need of treatment for an indication related to NLRP3 activity, such as an indication related to NLRP3 polymorphism found in CAPS syndromes.

In some embodiments, the methods described herein further include the step of identifying a subject (e.g., a patient) in need of treatment for an indication related to NLRP3 activity, such as an indication related NLRP3 polymorphism where the polymorphism is VAR_014104 (R262W) In some embodiments, the methods described herein further include the step of identifying a subject (e.g., a patient) in need of treatment for an indication related to NLRP3 activity, such as an indication related NLRP3 polymorphism where the polymorphism is a natural variant reported in http://www.uniprot.org/uniprot/Q96P20. In some embodiments, the methods described herein further include the step of identifying a subject (e.g., a patient) in need of treatment for an indication related to NLRP3 activity, such as an indication related to point mutation of NLRP3 signaling. Anti-TNFa Agents

The term“anti-TNFa agent” refers to an agent which directly or indirectly blocks, down- regulates, impairs, inhibits, impairs, or reduces TNFa activity and/or expression. In some embodiments, an anti-TNFa agent is an antibody or an antigen-binding fragment thereof, a fusion protein, a soluble TNFa receptor (a soluble tumor necrosis factor receptor superfamily member 1A (TNFR1) or a soluble tumor necrosis factor receptor superfamily 1B (TNFR2)), an inhibitory nucleic acid, or a small molecule TNFa antagonist. In some embodiments, the inhibitory nucleic acid is a ribozyme, small hairpin RNA, a small interfering RNA, an antisense nucleic acid, or an aptamer.

Exemplary anti-TNFa agents that directly block, down-regulate, impair, inhibit, or reduce TNFa activity and/or expression can, e.g., inhibit or decrease the expression level of TNFa or a receptor of TNFa (TNFR1 or TNFR2) in a cell (e.g., a cell obtained from a subject, a

mammalian cell), or inhibit or reduce binding of TNFa to its receptor (TNFR1 and/or TNFR2) and/or. Non-limiting examples of anti-TNFa agents that directly block, down-regulate, impair, inhibit, or reduce TNFa activity and/or expression include an antibody or fragment thereof, a fusion protein, a soluble TNFa receptor (e.g., a soluble TNFR1 or soluble TNFR2), inhibitory nucleic acids (e.g., any of the examples of inhibitory nucleic acids described herein), and a small molecule TNFa antagonist.

Exemplary anti-TNFa agents that can indirectly block, down-regulate, impair, inhibitreduce TNFa activity and/or expression can, e.g., inhibit or decrease the level of downstream signaling of a TNFa receptor (e.g., TNFR1 or TNFR2) in a mammalian cell (e.g., decrease the level and/or activity of one or more of the following signaling proteins: AP-1, mitogen-activated protein kinase kinase kinase 5 (ASK1), inhibitor of nuclear factor kappa B (IKK), mitogen-activated protein kinase 8 (JNK), mitogen-activated protein kinase (MAPK), MEKK 1/4, MEKK 4/7, MEKK 3/6, nuclear factor kappa B (NF-kB), mitogen-activated protein kinase kinase kinase 14 (NIK), receptor interacting serine/threonine kinase 1 (RIP), TNFRSF1A associated via death domain (TRADD), and TNF receptor associated factor 2 (TRAF2), in a cell), and/or decrease the level of TNFa-induced gene expression in a mammalian cell (e.g., decrease the transcription of genes regulated by, e.g., one or more transcription factors selected from the group of activating transcription factor 2 (ATF2), c-Jun, and NF-kB). A description of downstream signaling of a TNFa receptor is provided in Wajant et al., Cell Death Differentiation 10:45-65, 2003 (incorporated herein by reference). For example, such indirect anti-TNFa agents can be an inhibitory nucleic acid that targets (decreases the expression) a signaling component downstream of a TNFa-induced gene (e.g., any TNFa-induced gene known in the art), a TNFa receptor (e.g., any one or more of the signaling components downstream of a TNFa receptor described herein or known in the art), or a transcription factor selected from the group of NF-kB, c-Jun, and ATF2. In other examples, such indirect anti-TNFa agents can be a small molecule inhibitor of a protein encoded by a TNFa-induced gene (e.g., any protein encoded by a TNFa-induced gene known in the art), a small molecule inhibitor of a signaling component downstream of a TNFa receptor (e.g., any of the signaling components downstream of a TNFa receptor described herein or known in the art), and a small molecule inhibitor of a transcription factor selected from the group of ATF2, c-Jun, and NF-kB.

In other embodiments, anti-TNFa agents that can indirectly block, down-regulate, impair, or reduce one or more components in a cell (e.g., acell obtained from a subject, a mammalian cell) that are involved in the signaling pathway that results in TNFa mRNA transcription, TNFa mRNA stabilization, and TNFa mRNA translation (e.g., one or more components selected from the group of CD14, c-Jun, ERK1/2, IKK, IkB, interleukin 1 receptor associated kinase 1 (IRAK), JNK, lipopolysaccharide binding protein (LBP), MEK1/2, MEK3/6, MEK4/7, MK2, MyD88,  NF-kB, NIK, PKR, p38, AKT serine/threonine kinase 1 (rac), raf kinase (raf), ras, TRAF6, TTP). For example, such indirect anti-TNFa agents can be an inhibitory nucleic acid that targets (decreases the expression) of a component in a mammalian cell that is involved in the signaling pathway that results in TNFa mRNA transcription, TNFa mRNA stabilization, and TNFa mRNA translation (e.g., a component selected from the group of CD14, c-Jun, ERK1/2, IKK, IkB, IRAK, JNK, LBP, MEK1/2, MEK3/6, MEK4/7, MK2, MyD88, NF-kB, NIK, IRAK, lipopolysaccharide binding protein (LBP), PKR, p38, rac, raf, ras, TRAF6, TTP). In other examples, an indirect anti-TNFa agents is a small molecule inhibitor of a component in a mammalian cell that is involved in the signaling pathway that results in TNFa mRNA

transcription, TNFa mRNA stabilization, and TNFa mRNA translation (e.g., a component selected from the group of CD14, c-Jun, ERK1/2, IKK, IkB, IRAK, JNK, lipopolysaccharide binding protein (LBP), MEK1/2, MEK3/6, MEK4/7, MK2, MyD88, NF-kB, NIK, IRAK, lipopolysaccharide binding protein (LBP), PKR, p38, rac, raf, ras, TRAF6, TTP). Antibodies In some embodiments, the anti-TNFa agent is an antibody or an antigen-binding fragment thereof (e.g., a Fab or a scFv). In some embodiments, an antibody or antigen-binding fragment of an antibody described herein can bind specifically to TNFa. In some embodiments, an antibody or antigen-binding fragment described herein binds specifically to any one of TNFa, TNFR1, or TNFR2. In some embodiments, an antibody or antigen-binding fragment of an antibody described herein can bind specifically to a TNFa receptor (TNFR1 or TNFR2).

In some embodiments, the antibody can be a humanized antibody, a chimeric antibody, a multivalent antibody, or a fragment thereof. In some embodiments, an antibody can be a scFv- Fc, a VHH domain, a VNAR domain, a (scFv)2, a minibody, or a BiTE.

In some embodiments, an antibody can be a crossmab, a diabody, a scDiabody, a scDiabody-CH3, a Diabody-CH3, a DutaMab, a DT-IgG, a diabody-Fc, a scDiabody-HAS, a charge pair antibody, a Fab-arm exchange antibody, a SEEDbody, a Triomab, a LUZ-Y, a Fcab, a kl-body, an orthogonal Fab, a DVD-IgG, an IgG(H)-scFv, a scFv-(H)IgG, an IgG(L)-scFv, a scFv-(L)-IgG, an IgG (L,H)-Fc, an IgG(H)-V, a V(H)-IgG, an IgG(L)-V, a V(L)-IgG, an KIH IgG-scFab, a 2scFv-IgG, an IgG-2scFv, a scFv4-Ig, a Zybody, a DVI-IgG, a nanobody, a nanobody-HSA, a DVD-Ig, a dual-affinity re-targeting antibody (DART), a triomab, a kih IgG with a common LC, an ortho-Fab IgG, a 2-in-1-IgG, IgG-ScFv, scFv2-Fc, a bi-nanobody, tanden antibody, a DART-Fc, a scFv-HAS-scFv, a DAF (two-in-one or four-in-one), a DNL-Fab3, knobs-in-holes common LC, knobs-in-holes assembly, a TandAb, a Triple Body, a miniantibody, a minibody, a TriBi minibody, a scFv-CH3 KIH, a Fab-scFv, a scFv-CH-CL-scFv, a F(ab')2- scFV2, a scFv-KIH, a Fab-scFv-Fc, a tetravalent HCAb, a scDiabody-Fc, a tandem scFv-Fc, an intrabody, a dock and lock bispecific antibody, an ImmTAC, a HSAbody, a tandem scFv, an IgG-IgG, a Cov-X-Body, and a scFv1-PEG-scFv2.

Non-limiting examples of an antigen-binding fragment of an antibody include an Fv fragment, a Fab fragment, a F(ab')2 fragment, and a Fab' fragment. Additional examples of an antigen-binding fragment of an antibody is an antigen-binding fragment of an antigen-binding fragment of an IgA (e.g., an antigen-binding fragment of IgA1 or IgA2) (e.g., an antigen-binding fragment of a human or humanized IgA, e.g., a human or humanized IgA1 or IgA2); an antigen- binding fragment of an IgD (e.g., an antigen-binding fragment of a human or humanized IgD); an antigen-binding fragment of an IgE (e.g., an antigen-binding fragment of a human or humanized IgE); an IgG (e.g., an antigen-binding fragment of IgG1, IgG2, IgG3, or IgG4) (e.g., an antigen- binding fragment of a human or humanized IgG, e.g., human or humanized IgG1, IgG2, IgG3, or IgG4); or an antigen-binding fragment of an IgM (e.g., an antigen-binding fragment of a human or humanized IgM). Non-limiting examples of anti-TNFa agents that are antibodies that specifically bind to TNFa are described in Ben-Horin et al., Autoimmunity Rev.13(1):24-30, 2014; Bongartz et al., JAMA 295(19):2275-2285, 2006; Butler et al., Eur. Cytokine Network 6(4):225-230, 1994; Cohen et al., Canadian J. Gastroenterol. Hepatol.15(6):376-384, 2001; Elliott et al., Lancet 1994; 344: 1125-1127, 1994; Feldmann et al., Ann. Rev. Immunol.19(1):163-196, 2001; Rankin et al., Br. J. Rheumatol.2:334-342, 1995; Knight et al., Molecular Immunol.30(16):1443-1453, 1993; Lorenz et al., J. Immunol.156(4):1646-1653, 1996; Hinshaw et al., Circulatory Shock 30(3):279-292, 1990; Ordas et al., Clin. Pharmacol. Therapeutics 91(4):635-646, 2012;

Feldman, Nature Reviews Immunol.2(5):364-371, 2002; Taylor et al., Nature Reviews

Rheumatol.5(10):578-582, 2009; Garces et al., Annals Rheumatic Dis.72(12):1947-1955, 2013; Palladino et al., Nature Rev. Drug Discovery 2(9):736-746, 2003; Sandborn et al., Inflammatory Bowel Diseases 5(2):119-133, 1999; Atzeni et al., Autoimmunity Reviews 12(7):703-708, 2013; Maini et al., Immunol. Rev.144(1):195-223, 1995; Wanner et al., Shock 11(6):391-395, 1999; and U.S. Patent Nos.6,090,382; 6,258,562; and 6,509,015).

In certain embodiments, the anti-TNFa agent can include or is golimumab

(golimumabTM), adalimumab (Humira™), infliximab (Remicade™), CDP571, CDP 870, or certolizumab pegol (Cimzia™). In certain embodiments, the anti-TNFa agent can be a TNFa inhibitor biosimilar. Examples of approved and late-phase TNFa inhibitor biosimilars include, but are not limited to, infliximab biosimilars such as Flixabi™ (SB2) from Samsung Bioepis, Inflectra® (CT-P13) from Celltrion/Pfizer, GS071 from Aprogen, Remsima™, PF-06438179 from Pfizer/Sandoz, NI-071 from Nichi-Iko Pharmaceutical Co., and ABP 710 from Amgen; adalimumab biosimilars such as Amgevita® (ABP 501) from Amgen and Exemptia™ from Zydus Cadila, BMO-2 or MYL-1401-A from Biocon/Mylan, CHS-1420 from Coherus, FKB327 from Kyowa Kirin, and BI 695501 from Boehringer Ingelheim;Solymbic®, SB5 from Samsung Bioepis, GP-2017 from Sandoz, ONS-3010 from Oncobiologics, M923 from Momenta, PF- 06410293 from Pfizer, and etanercept biosimilars such as Erelzi™ from Sandoz/Novartis, Brenzys™ (SB4) from Samsung Bioepis, GP2015 from Sandoz, TuNEX® from Mycenax, LBEC0101 from LG Life, and CHS-0214 from Coherus.

In some embodiments of any of the methods described herein, the anti-TNFa agent is selected from the group consisting of: adalimumab, certolizumab, etanercept, golimumab, infliximabm, CDP571, and CDP 870. In some embodiments, any of the antibodies or antigen-binding fragments described herein has a dissociation constant (K _D ) of less than 1 x 10 ^-5 M (e.g., less than 0.5 x 10 ^-5 M, less than 1 x 10 ^-6 M, less than 0.5 x 10 ^-6 M, less than 1 x 10 ^-7 M, less than 0.5 x 10 ^-7 M, less than 1 x 10 ^-8 M, less than 0.5 x 10 ^-8 M, less than 1 x 10 ^-9 M, less than 0.5 x 10 ^-9 M, less than 1 x 10 ^-10 M, less than 0.5 x 10 ^-10 M, less than 1 x 10 ^-11 M, less than 0.5 x 10 ^-11 M, or less than 1 x 10 ^-12 M), e.g., as measured in phosphate buffered saline using surface plasmon resonance (SPR).

In some embodiments, any of the antibodies or antigen-binding fragments described herein has a KD of about 1 x 10 ^-12 M to about 1 x 10 ^-5 M, about 0.5 x 10 ^-5 M, about 1 x 10 ^-6 M, about 0.5 x 10 ^-6 M, about 1 x 10 ^-7 M, about 0.5 x 10 ^-7 M, about 1 x 10 ^-8 M, about 0.5 x 10 ^-8 M, about 1 x 10 ^-9 M, about 0.5 x 10 ^-9 M, about 1 x 10 ^-10 M, about 0.5 x 10 ^-10 M, about 1 x 10 ^-11 M, or about 0.5 x 10 ^-11 M (inclusive); about 0.5 x 10 ^-11 M to about 1 x 10 ^-5 M, about 0.5 x 10 ^-5 M, about 1 x 10 ^-6 M, about 0.5 x 10 ^-6 M, about 1 x 10 ^-7 M, about 0.5 x 10 ^-7 M, about 1 x 10 ^-8 M, about 0.5 x 10 ^-8 M, about 1 x 10 ^-9 M, about 0.5 x 10 ^-9 M, about 1 x 10 ^-10 M, about 0.5 x 10 ^-10 M, or about 1 x 10 ^-11 M (inclusive); about 1 x 10 ^-11 M to about 1 x 10 ^-5 M, about 0.5 x 10 ^-5 M, about 1 x 10 ^-6 M, about 0.5 x 10 ^-6 M, about 1 x 10 ^-7 M, about 0.5 x 10 ^-7 M, about 1 x 10 ^-8 M, about 0.5 x 10 ^-8 M, about 1 x 10 ^-9 M, about 0.5 x 10 ^-9 M, about 1 x 10 ^-10 M, or about 0.5 x 10 ^-10 M (inclusive); about 0.5 x 10 ^-10 M to about 1 x 10 ^-5 M, about 0.5 x 10 ^-5 M, about 1 x 10 ^-6 M, about 0.5 x 10 ^-6 M, about 1 x 10 ^-7 M, about 0.5 x 10 ^-7 M, about 1 x 10 ^-8 M, about 0.5 x 10 ^-8 M, about 1 x 10 ^-9 M, about 0.5 x 10 ^-9 M, or about 1 x 10 ^-10 M (inclusive); about 1 x 10 ^-10 M to about 1 x 10 ^-5 M, about 0.5 x 10 ^-5 M, about 1 x 10 ^-6 M, about 0.5 x 10 ^-6 M, about 1 x 10 ^-7 M, about 0.5 x 10 ^-7 M, about 1 x 10 ^-8 M, about 0.5 x 10 ^-8 M, about 1 x 10 ^-9 M, or about 0.5 x 10 ^-9 M (inclusive); about 0.5 x 10 ^-9 M to about 1 x 10 ^-5 M, about 0.5 x 10 ^-5 M, about 1 x 10 ^-6 M, about 0.5 x 10 ^-6 M, about 1 x 10 ^-7 M, about 0.5 x 10 ^-7 M, about 1 x 10 ^-8 M, about 0.5 x 10 ^-8 M, or about 1 x 10 ^-9 M (inclusive); about 1 x 10 ^-9 M to about 1 x 10 ^-5 M, about 0.5 x 10 ^-5 M, about 1 x 10 ^-6 M, about 0.5 x 10 ^-6 M, about 1 x 10 ^-7 M, about 0.5 x 10 ^-7 M, about 1 x 10 ^-8 M, or about 0.5 x 10 ^-8 M (inclusive); about 0.5 x 10 ^-8 M to about 1 x 10 ^-5 M, about 0.5 x 10 ^-5 M, about 1 x 10 ^-6 M, about 0.5 x 10 ^-6 M, about 1 x 10 ^-7 M, about 0.5 x 10 ^-7 M, or about 1 x 10 ^-8 M (inclusive); about 1 x 10 ^-8 M to about 1 x 10 ^-5 M, about 0.5 x 10 ^-5 M, about 1 x 10 ^-6 M, about 0.5 x 10 ^-6 M, about 1 x 10 ^-7 M, or about 0.5 x 10 ^-7 M (inclusive); about 0.5 x 10 ^-7 M to about 1 x 10 ^-5 M, about 0.5 x 10 ^-5 M, about 1 x 10 ^-6 M, about 0.5 x 10 ^-6 M, or about 1 x 10 ^-7 M (inclusive); about 1 x 10 ^-7 M to about 1 x 10 ^-5 M, about 0.5 x 10 ^-5 M, about 1 x 10 ^-6 M, or about 0.5 x 10 ^-6 M (inclusive); about 0.5 x 10 ^-6 M to about 1 x 10 ^-5 M, about 0.5 x 10 ^-5 M, or about 1 x 10 ^-6 M (inclusive); about 1 x 10 ^-6 M to about 1 x 10 ^-5 M or about 0.5 x 10 ^-5 M (inclusive); or about 0.5 x 10 ^-5 M to about 1 x 10 ^-5 M (inclusive), e.g., as measured in phosphate buffered saline using surface plasmon resonance (SPR).

In some embodiments, any of the antibodies or antigen-binding fragments described herein has a Koff of about 1 x 10 ^-6 s ^-1 to about 1 x 10 ^-3 s ^-1 , about 0.5 x 10 ^-3 s ^-1 , about 1 x 10 ^-4 s ^-1 , about 0.5 x 10 ^-4 s ^-1 , about 1 x 10 ^-5 s ^-1 , or about 0.5 x 10 ^-5 s ^-1 (inclusive); about 0.5 x 10 ^-5 s ^-1 to about 1 x 10 ^-3 s ^-1 , about 0.5 x 10 ^-3 s ^-1 , about 1 x 10 ^-4 s ^-1 , about 0.5 x 10 ^-4 s ^-1 , or about 1 x 10 ^-5 s ^-1 (inclusive); about 1 x 10 ^-5 s ^-1 to about 1 x 10 ^-3 s ^-1 , about 0.5 x 10 ^-3 s ^-1 , about 1 x 10 ^-4 s ^-1 , or about 0.5 x 10 ^-4 s ^-1 (inclusive); about 0.5 x 10 ^-4 s ^-1 to about 1 x 10 ^-3 s ^-1 , about 0.5 x 10 ^-3 s ^-1 , or about 1 x 10 ^-4 s ^-1 (inclusive); about 1 x 10 ^-4 s ^-1 to about 1 x 10 ^-3 s ^-1 , or about 0.5 x 10 ^-3 s ^-1 (inclusive); or about 0.5 x 10 ^-5 s ^-1 to about 1 x 10 ^-3 s ^-1 (inclusive), e.g., as measured in phosphate buffered saline using surface plasmon resonance (SPR).

In some embodiments, any of the antibodies or antigen-binding fragments described herein has a Kon of about 1 x 10 ² M ^-1 s ^-1 to about 1 x 10 ⁶ M ^-1 s ^-1 , about 0.5 x 10 ⁶ M ^-1 s ^-1 , about 1 x 10 ⁵ M ^-1 s ^-1 , about 0.5 x 10 ⁵ M ^-1 s ^-1 , about 1 x 10 ⁴ M ^-1 s ^-1 , about 0.5 x 10 ⁴ M ^-1 s ^-1 , about 1 x 10 ³ M ^-1 s ^-1 , or about 0.5 x 10 ³ M ^-1 s ^-1 (inclusive); about 0.5 x 10 ³ M ^-1 s ^-1 to about 1 x 10 ⁶ M ^-1 s ^-1 , about 0.5 x 10 ⁶ M ^-1 s ^-1 , about 1 x 10 ⁵ M ^-1 s ^-1 , about 0.5 x 10 ⁵ M ^-1 s ^-1 , about 1 x 10 ⁴ M ^-1 s ^-1 , about 0.5 x 10 ⁴ M ^-1 s ^-1 , or about 1 x 10 ³ M ^-1 s ^-1 (inclusive); about 1 x 10 ³ M ^-1 s ^-1 to about 1 x 10 ⁶ M ^-1 s ^-1 , about 0.5 x 10 ⁶ M ^-1 s ^-1 , about 1 x 10 ⁵ M ^-1 s ^-1 , about 0.5 x 10 ⁵ M ^-1 s ^-1 , about 1 x 10 ⁴ M ^-1 s ^-1 , or about 0.5 x 10 ⁴ M ^-1 s ^-1 (inclusive); about 0.5 x 10 ⁴ M ^-1 s ^-1 to about 1 x 10 ⁶ M ^-1 s ^-1 , about 0.5 x 10 ⁶ M ^-1 s ^-1 , about 1 x 10 ⁵ M ^-1 s ^-1 , about 0.5 x 10 ⁵ M ^-1 s ^-1 , or about 1 x 10 ⁴ M ^-1 s ^-1 (inclusive); about 1 x 10 ⁴ M ^-1 s ^-1 to about 1 x 10 ⁶ M ^-1 s ^-1 , about 0.5 x 10 ⁶ M ^-1 s ^-1 , about 1 x 10 ⁵ M ^-1 s ^-1 , or about 0.5 x 10 ⁵ M ^-1 s ^-1 (inclusive); about 0.5 x 10 ⁵ M ^-1 s ^-1 to about 1 x 10 ⁶ M ^-1 s ^-1 , about 0.5 x 10 ⁶ M ^-1 s ^-1 , or about 1 x 10 ⁵ M ^-1 s ^-1 (inclusive); about 1 x 10 ⁵ M ^-1 s ^-1 to about 1 x 10 ⁶ M ^-1 s ^-1 , or about 0.5 x 10 ⁶ M ^-1 s ^-1

(inclusive); or about 0.5 x 10 ⁶ M ^-1 s ^-1 to about 1 x 10 ⁶ M ^-1 s ^-1 (inclusive), e.g., as measured in phosphate buffered saline using surface plasmon resonance (SPR). Fusion Proteins In some embodiments, the anti-TNFa agent is a fusion protein (e.g., an extracellular domain of a TNFR fused to a partner peptide, e.g., an Fc region of an immunoglobulin, e.g., human IgG) (see, e.g., Deeg et al., Leukemia 16(2):162, 2002; Peppel et al., J. Exp. Med.

174(6):1483-1489, 1991) or a soluble TNFR (e.g., TNFR1 or TNFR2) that binds specifically to TNFa. In some embodiments, the anti-TNFa agent includes or is a soluble TNFa receptor (e.g., Bjornberg et al., Lymphokine Cytokine Res.13(3):203-211, 1994; Kozak et al., Am. J. Physiol. Reg. Integrative Comparative Physiol.269(1):R23-R29, 1995; Tsao et al., Eur Respir J.

14(3):490-495, 1999; Watt et al., J Leukoc Biol.66(6):1005-1013, 1999; Mohler et al., J.

Immunol.151(3):1548-1561, 1993; Nophar et al., EMBO J.9(10):3269, 1990; Piguet et al., Eur. Respiratory J.7(3):515-518, 1994; and Gray et al., Proc. Natl. Acad. Sci. U.S.A.87(19):7380- 7384, 1990). In some embodiments, the anti-TNFa agent includes or is etanercept (Enbrel ^TM ) (see, e.g., WO 91/03553 and WO 09/406,476, incorporated by reference herein). In some embodiments, the anti-TNFa agent inhibitor includes or is r-TBP-I (e.g., Gradstein et al., J.

Acquir. Immune Defic. Syndr.26(2): 111-117, 2001).

Inhibitory Nucleic Acids An antisense nucleic acid molecule can be fully or partially complementary to all or part of a non-coding region of the coding strand of a nucleotide sequence encoding an AP-1, ASK1, CD14, c-jun, ERK1/2, IkB, IKK, IRAK, JNK, LBP, MAPK, MEK1/2, MEKK1/4, MEKK4/7, MEKK 3/6, MK2, MyD88, NF-kB, NIK, p38, PKR, rac, ras, raf, RIP, TNFa, TNFR1, TNFR2, TRADD, TRAF2, TRAF6, or TTP protein. Non-coding regions (5' and 3' untranslated regions) are the 5' and 3' sequences that flank the coding region in a gene and are not translated into amino acids.

Based upon the sequences disclosed herein, one of skill in the art can easily choose and synthesize any of a number of appropriate antisense nucleic acids to target a nucleic acid encoding an AP-1, ASK1, CD14, c-jun, ERK1/2, IkB, IKK, IRAK, JNK, LBP, MAPK, MEK1/2, MEKK1/4, MEKK4/7, MEKK 3/6, MK2, MyD88, NF-kB, NIK, p38, PKR, rac, ras, raf, RIP, TNFa, TNFR1, TNFR2, TRADD, TRAF2, TRAF6, or TTP protein described herein. Antisense nucleic acids targeting a nucleic acid encoding an AP-1, ASK1, CD14, c-jun, ERK1/2, IkB, IKK, IRAK, JNK, LBP, MAPK, MEK1/2, MEKK1/4, MEKK4/7, MEKK 3/6, MK2, MyD88, NF-kB, NIK, p38, PKR, rac, ras, raf, RIP, TNFa, TNFR1, TNFR2, TRADD, TRAF2, TRAF6, or TTP protein can be designed using the software available at the Integrated DNA Technologies website.

An antisense nucleic acid can be, for example, about 5, 10, 15, 18, 20, 22, 24, 25, 26, 28, 30, 32, 35, 36, 38, 40, 42, 44, 45, 46, 48, or 50 nucleotides or more in length. An antisense oligonucleotide can be constructed using enzymatic ligation reactions and chemical synthesis using procedures known in the art. For example, an antisense nucleic acid can be chemically synthesized using variously modified nucleotides or naturally occurring nucleotides designed to increase the physical stability of the duplex formed between the antisense and sense nucleic acids, e.g., phosphorothioate derivatives and acridine substituted nucleotides or to increase the biological stability of the molecules.

Examples of modified nucleotides which can be used to generate an antisense nucleic acid include 1-methylguanine, 1-methylinosine, 2,2-dimethylguanine, 2-methyladenine, 2- methylguanine, 3-methylcytosine, 2-methylthio-N6-isopentenyladenine, uracil-5-oxyacetic acid (v), wybutoxosine, pseudouracil, queosine, 2-thiocytosine, 5-fluorouracil, 5-bromouracil, 5- chlorouracil, 5-iodouracil, hypoxanthine, xanthine, 4-acetylcytosine, 5-(carboxyhydroxylmethyl) uracil, 5-carboxymethylaminomethyl-2-thiouridine, 5-carboxymethylaminomethyluracil, dihydrouracil, beta-D-galactosylqueosine, inosine, N6-isopentenyladenine, 5-methylcytosine, N6-adenine, 7-methylguanine, 5-methylaminomethyluracil, 5-methoxyaminomethyl-2-thiouracil, beta-D-mannosylqueosine, 5'-methoxycarboxymethyluracil, 5-methoxyuracil, 5-methyl-2- thiouracil, 2-thiouracil, 4-thiouracil, 5-methyluracil, uracil-5-oxyacetic acid methylester, uracil- 5-oxyacetic acid (v), 5-methyl-2-thiouracil, 3-(3-amino-3-N-2-carboxypropyl) uracil, (acp3)w, and 2,6-diaminopurine. Alternatively, the antisense nucleic acid can be produced biologically using an expression vector into which a nucleic acid has been subcloned in an antisense orientation (i.e., RNA transcribed from the inserted nucleic acid will be of an antisense orientation to a target nucleic acid of interest).

The antisense nucleic acid molecules described herein can be prepared in vitro and administered to a subject, e.g., a human subject. Alternatively, they can be generated in situ such that they hybridize with or bind to cellular mRNA and/or genomic DNA encoding an AP-1, ASK1, CD14, c-jun, ERK1/2, IkB, IKK, IRAK, JNK, LBP, MAPK, MEK1/2, MEKK1/4, MEKK4/7, MEKK 3/6, MK2, MyD88, NF-kB, NIK, p38, PKR, rac, ras, raf, RIP, TNFa, TNFR1, TNFR2, TRADD, TRAF2, TRAF6, or TTP protein to thereby inhibit expression, e.g., by inhibiting transcription and/or translation. The hybridization can be by conventional nucleotide complementarities to form a stable duplex, or, for example, in the case of an antisense nucleic acid molecule that binds to DNA duplexes, through specific interactions in the major groove of the double helix. The antisense nucleic acid molecules can be delivered to a mammalian cell using a vector (e.g., an adenovirus vector, a lentivirus, or a retrovirus).

An antisense nucleic acid can be an a-anomeric nucleic acid molecule. An a-anomeric nucleic acid molecule forms specific double-stranded hybrids with complementary RNA in which, contrary to the usual, b-units, the strands run parallel to each other (Gaultier et al., Nucleic Acids Res.15:6625-6641, 1987). The antisense nucleic acid can also comprise a chimeric RNA-DNA analog (Inoue et al., FEBS Lett.215:327-330, 1987) or a 2'-O- methylribonucleotide (Inoue et al., Nucleic Acids Res.15:6131-6148, 1987).

Another example of an inhibitory nucleic acid is a ribozyme that has specificity for a nucleic acid encoding an AP-1, ASK1, CD14, c-jun, ERK1/2, IkB, IKK, IRAK, JNK, LBP, MAPK, MEK1/2, MEKK1/4, MEKK4/7, MEKK 3/6, MK2, MyD88, NF-kB, NIK, p38, PKR, rac, ras, raf, RIP, TNFa, TNFR1, TNFR2, TRADD, TRAF2, TRAF6, or TTP mRNA, e.g., specificity for any one of the sequences presented in Table E). Ribozymes are catalytic RNA molecules with ribonuclease activity that are capable of cleaving a single-stranded nucleic acid, such as an mRNA, to which they have a complementary region. Thus, ribozymes (e.g., hammerhead ribozymes (described in Haselhoff and Gerlach, Nature 334:585-591, 1988)) can be used to catalytically cleave mRNA transcripts to thereby inhibit translation of the protein encoded by the mRNA. An AP-1, ASK1, CD14, c-jun, ERK1/2, IkB, IKK, IRAK, JNK, LBP, MAPK, MEK1/2, MEKK1/4, MEKK4/7, MEKK 3/6, MK2, MyD88, NF-kB, NIK, p38, PKR, rac, ras, raf, RIP, TNFa, TNFR1, TNFR2, TRADD, TRAF2, TRAF6, or TTP mRNA can be used to select a catalytic RNA having a specific ribonuclease activity from a pool of RNA molecules. See, e.g., Bartel et al., Science 261:1411-1418, 1993.

Alternatively, a ribozyme having specificity for an AP-1, ASK1, CD14, c-jun, ERK1/2, IkB, IKK, IRAK, JNK, LBP, MAPK, MEK1/2, MEKK1/4, MEKK4/7, MEKK 3/6, MK2, MyD88, NF-kB, NIK, p38, PKR, rac, ras, raf, RIP, TNFa, TNFR1, TNFR2, TRADD, TRAF2, TRAF6, or TTP mRNA can be designed based upon the nucleotide sequence of any of the AP-1, ASK1, CD14, c-jun, ERK1/2, IkB, IKK, IRAK, JNK, LBP, MAPK, MEK1/2, MEKK1/4, MEKK4/7, MEKK 3/6, MK2, MyD88, NF-kB, NIK, p38, PKR, rac, ras, raf, RIP, TNFa, TNFR1, TNFR2, TRADD, TRAF2, TRAF6, or TTP mRNA sequences disclosed herein (e.g., in Table E). For example, a derivative of a Tetrahymena L-19 IVS RNA can be constructed in which the nucleotide sequence of the active site is complementary to the nucleotide sequence to be cleaved in an AP-1, ASK1, CD14, c-jun, ERK1/2, IkB, IKK, IRAK, JNK, LBP, MAPK, MEK1/2, MEKK1/4, MEKK4/7, MEKK 3/6, MK2, MyD88, NF-kB, NIK, p38, PKR, rac, ras, raf, RIP, TNFa, TNFR1, TNFR2, TRADD, TRAF2, TRAF6, or TTP mRNA (see, e.g., U.S. Patent. Nos.4,987,071 and 5,116,742).

An inhibitory nucleic acid can also be a nucleic acid molecule that forms triple helical structures. For example, expression of an AP-1, ASK1, CD14, c-jun, ERK1/2, IkB, IKK, IRAK, JNK, LBP, MAPK, MEK1/2, MEKK1/4, MEKK4/7, MEKK 3/6, MK2, MyD88, NF-kB, NIK, p38, PKR, rac, ras, raf, RIP, TNFa, TNFR1, TNFR2, TRADD, TRAF2, TRAF6, or TTP polypeptide can be inhibited by targeting nucleotide sequences complementary to the regulatory region of the gene encoding the AP-1, ASK1, CD14, c-jun, ERK1/2, IkB, IKK, IRAK, JNK, LBP, MAPK, MEK1/2, MEKK1/4, MEKK4/7, MEKK 3/6, MK2, MyD88, NF-kB, NIK, p38, PKR, rac, ras, raf, RIP, TNFa, TNFR1, TNFR2, TRADD, TRAF2, TRAF6, or TTP polypeptide (e.g., the promoter and/or enhancer, e.g., a sequence that is at least 1 kb, 2 kb, 3 kb, 4 kb, or 5 kb upstream of the transcription initiation start state) to form triple helical structures that prevent transcription of the gene in target cells. See generally Maher, Bioassays 14(12):807-15, 1992; Helene, Anticancer Drug Des.6(6):569-84, 1991; and Helene, Ann. N.Y. Acad. Sci.660:27-36, 1992.

In various embodiments, inhibitory nucleic acids can be modified at the sugar moiety, the base moiety, or phosphate backbone to improve, e.g., the solubility, stability, or hybridization, of the molecule. For example, the deoxyribose phosphate backbone of the nucleic acids can be modified to generate peptide nucleic acids (see, e.g., Hyrup et al., Bioorganic Medicinal Chem. 4(1):5-23, 1996). Peptide nucleic acids (PNAs) are nucleic acid mimics, e.g., DNA mimics, in which the deoxyribose phosphate backbone is replaced by a pseudopeptide backbone and only the four natural nucleobases are retained. The neutral backbone of PNAs allows for specific hybridization to RNA and DNA under conditions of low ionic strength. PNA oligomers can be synthesized using standard solid phase peptide synthesis protocols (see, e.g., Perry-O'Keefe et al., Proc. Natl. Acad. Sci. U.S.A.93:14670-675, 1996). PNAs can be used as antisense or antigene agents for sequence-specific modulation of gene expression by, e.g., inducing transcription or translation arrest or inhibiting replication.

An antisense nucleic acid molecule can be fully or partially complementary to all or part of a non-coding region of the coding strand of a nucleotide sequence encoding an AP-1, ASK1, CD14, c-jun, ERK1/2, IkB, IKK, IRAK, JNK, LBP, MAPK, MEK1/2, MEKK1/4, MEKK4/7, MEKK 3/6, MK2, MyD88, NF-kB, NIK, p38, PKR, rac, ras, raf, RIP, TNFa, TNFR1, TNFR2, TRADD, TRAF2, TRAF6, or TTP protein. Non-coding regions (5' and 3' untranslated regions) are the 5' and 3' sequences that flank the coding region in a gene and are not translated into amino acids.

Based upon the sequences disclosed herein, one of skill in the art can easily choose and synthesize any of a number of appropriate antisense nucleic acids to target a nucleic acid encoding an AP-1, ASK1, CD14, c-jun, ERK1/2, IkB, IKK, IRAK, JNK, LBP, MAPK, MEK1/2, MEKK1/4, MEKK4/7, MEKK 3/6, MK2, MyD88, NF-kB, NIK, p38, PKR, rac, ras, raf, RIP, TNFa, TNFR1, TNFR2, TRADD, TRAF2, TRAF6, or TTP protein described herein. Antisense nucleic acids targeting a nucleic acid encoding an AP-1, ASK1, CD14, c-jun, ERK1/2, IkB, IKK, IRAK, JNK, LBP, MAPK, MEK1/2, MEKK1/4, MEKK4/7, MEKK 3/6, MK2, MyD88, NF-kB, NIK, p38, PKR, rac, ras, raf, RIP, TNFa, TNFR1, TNFR2, TRADD, TRAF2, TRAF6, or TTP protein can be designed using the software available at the Integrated DNA Technologies website.

An antisense nucleic acid can be, for example, about 5, 10, 15, 18, 20, 22, 24, 25, 26, 28, 30, 32, 35, 36, 38, 40, 42, 44, 45, 46, 48, or 50 nucleotides or more in length. An antisense oligonucleotide can be constructed using enzymatic ligation reactions and chemical synthesis using procedures known in the art. For example, an antisense nucleic acid can be chemically synthesized using variously modified nucleotides or naturally occurring nucleotides designed to increase the physical stability of the duplex formed between the antisense and sense nucleic acids, e.g., phosphorothioate derivatives and acridine substituted nucleotides or to increase the biological stability of the molecules.

Examples of modified nucleotides which can be used to generate an antisense nucleic acid include 1-methylguanine, 1-methylinosine, 2,2-dimethylguanine, 2-methyladenine, 2- methylguanine, 3-methylcytosine, 2-methylthio-N6-isopentenyladenine, uracil-5-oxyacetic acid (v), wybutoxosine, pseudouracil, queosine, 2-thiocytosine, 5-fluorouracil, 5-bromouracil, 5- chlorouracil, 5-iodouracil, hypoxanthine, xanthine, 4-acetylcytosine, 5-(carboxyhydroxylmethyl) uracil, 5-carboxymethylaminomethyl-2-thiouridine, 5-carboxymethylaminomethyluracil, dihydrouracil, beta-D-galactosylqueosine, inosine, N6-isopentenyladenine, 5-methylcytosine, N6-adenine, 7-methylguanine, 5-methylaminomethyluracil, 5-methoxyaminomethyl-2-thiouracil, beta-D-mannosylqueosine, 5'-methoxycarboxymethyluracil, 5-methoxyuracil, 5-methyl-2- thiouracil, 2-thiouracil, 4-thiouracil, 5-methyluracil, uracil-5-oxyacetic acid methylester, uracil- 5-oxyacetic acid (v), 5-methyl-2-thiouracil, 3-(3-amino-3-N-2-carboxypropyl) uracil, (acp3)w, and 2,6-diaminopurine. Alternatively, the antisense nucleic acid can be produced biologically using an expression vector into which a nucleic acid has been subcloned in an antisense orientation (i.e., RNA transcribed from the inserted nucleic acid will be of an antisense orientation to a target nucleic acid of interest).

The antisense nucleic acid molecules described herein can be prepared in vitro and administered to a subject, e.g., a human subject. Alternatively, they can be generated in situ such that they hybridize with or bind to cellular mRNA and/or genomic DNA encoding an AP-1, ASK1, CD14, c-jun, ERK1/2, IkB, IKK, IRAK, JNK, LBP, MAPK, MEK1/2, MEKK1/4, MEKK4/7, MEKK 3/6, MK2, MyD88, NF-kB, NIK, p38, PKR, rac, ras, raf, RIP, TNFa, TNFR1, TNFR2, TRADD, TRAF2, TRAF6, or TTP protein to thereby inhibit expression, e.g., by inhibiting transcription and/or translation. The hybridization can be by conventional nucleotide complementarities to form a stable duplex, or, for example, in the case of an antisense nucleic acid molecule that binds to DNA duplexes, through specific interactions in the major groove of the double helix. The antisense nucleic acid molecules can be delivered to a mammalian cell using a vector (e.g., an adenovirus vector, a lentivirus, or a retrovirus).

An antisense nucleic acid can be an a-anomeric nucleic acid molecule. An a-anomeric nucleic acid molecule forms specific double-stranded hybrids with complementary RNA in which, contrary to the usual, b-units, the strands run parallel to each other (Gaultier et al., Nucleic Acids Res.15:6625-6641, 1987). The antisense nucleic acid can also comprise a chimeric RNA-DNA analog (Inoue et al., FEBS Lett.215:327-330, 1987) or a 2'-O- methylribonucleotide (Inoue et al., Nucleic Acids Res.15:6131-6148, 1987).

Another example of an inhibitory nucleic acid is a ribozyme that has specificity for a nucleic acid encoding an AP-1, ASK1, CD14, c-jun, ERK1/2, IkB, IKK, IRAK, JNK, LBP, MAPK, MEK1/2, MEKK1/4, MEKK4/7, MEKK 3/6, MK2, MyD88, NF-kB, NIK, p38, PKR, rac, ras, raf, RIP, TNFa, TNFR1, TNFR2, TRADD, TRAF2, TRAF6, or TTP mRNA, e.g., specificity for any one of the sequences presented in Table E). Ribozymes are catalytic RNA molecules with ribonuclease activity that are capable of cleaving a single-stranded nucleic acid, such as an mRNA, to which they have a complementary region. Thus, ribozymes (e.g., hammerhead ribozymes (described in Haselhoff and Gerlach, Nature 334:585-591, 1988)) can be used to catalytically cleave mRNA transcripts to thereby inhibit translation of the protein encoded by the mRNA. An AP-1, ASK1, CD14, c-jun, ERK1/2, IkB, IKK, IRAK, JNK, LBP, MAPK, MEK1/2, MEKK1/4, MEKK4/7, MEKK 3/6, MK2, MyD88, NF-kB, NIK, p38, PKR, rac, ras, raf, RIP, TNFa, TNFR1, TNFR2, TRADD, TRAF2, TRAF6, or TTP mRNA can be used to select a catalytic RNA having a specific ribonuclease activity from a pool of RNA molecules. See, e.g., Bartel et al., Science 261:1411-1418, 1993.

Alternatively, a ribozyme having specificity for an AP-1, ASK1, CD14, c-jun, ERK1/2, IkB, IKK, IRAK, JNK, LBP, MAPK, MEK1/2, MEKK1/4, MEKK4/7, MEKK 3/6, MK2, MyD88, NF-kB, NIK, p38, PKR, rac, ras, raf, RIP, TNFa, TNFR1, TNFR2, TRADD, TRAF2, TRAF6, or TTP mRNA can be designed based upon the nucleotide sequence of any of the AP-1, ASK1, CD14, c-jun, ERK1/2, IkB, IKK, IRAK, JNK, LBP, MAPK, MEK1/2, MEKK1/4, MEKK4/7, MEKK 3/6, MK2, MyD88, NF-kB, NIK, p38, PKR, rac, ras, raf, RIP, TNFa, TNFR1, TNFR2, TRADD, TRAF2, TRAF6, or TTP mRNA sequences disclosed herein (e.g., in Table E). For example, a derivative of a Tetrahymena L-19 IVS RNA can be constructed in which the nucleotide sequence of the active site is complementary to the nucleotide sequence to be cleaved in an AP-1, ASK1, CD14, c-jun, ERK1/2, IkB, IKK, IRAK, JNK, LBP, MAPK, MEK1/2, MEKK1/4, MEKK4/7, MEKK 3/6, MK2, MyD88, NF-kB, NIK, p38, PKR, rac, ras, raf, RIP, TNFa, TNFR1, TNFR2, TRADD, TRAF2, TRAF6, or TTP mRNA (see, e.g., U.S. Patent. Nos.4,987,071 and 5,116,742).

An inhibitory nucleic acid can also be a nucleic acid molecule that forms triple helical structures. For example, expression of an AP-1, ASK1, CD14, c-jun, ERK1/2, IkB, IKK, IRAK, JNK, LBP, MAPK, MEK1/2, MEKK1/4, MEKK4/7, MEKK 3/6, MK2, MyD88, NF-kB, NIK, p38, PKR, rac, ras, raf, RIP, TNFa, TNFR1, TNFR2, TRADD, TRAF2, TRAF6, or TTP polypeptide can be inhibited by targeting nucleotide sequences complementary to the regulatory region of the gene encoding the AP-1, ASK1, CD14, c-jun, ERK1/2, IkB, IKK, IRAK, JNK, LBP, MAPK, MEK1/2, MEKK1/4, MEKK4/7, MEKK 3/6, MK2, MyD88, NF-kB, NIK, p38, PKR, rac, ras, raf, RIP, TNFa, TNFR1, TNFR2, TRADD, TRAF2, TRAF6, or TTP polypeptide (e.g., the promoter and/or enhancer, e.g., a sequence that is at least 1 kb, 2 kb, 3 kb, 4 kb, or 5 kb upstream of the transcription initiation start state) to form triple helical structures that prevent transcription of the gene in target cells. See generally Maher, Bioassays 14(12):807-15, 1992; Helene, Anticancer Drug Des.6(6):569-84, 1991; and Helene, Ann. N.Y. Acad. Sci.660:27-36, 1992.

In various embodiments, inhibitory nucleic acids can be modified at the sugar moiety, the base moiety, or phosphate backbone to improve, e.g., the solubility, stability, or hybridization, of the molecule. For example, the deoxyribose phosphate backbone of the nucleic acids can be modified to generate peptide nucleic acids (see, e.g., Hyrup et al., Bioorganic Medicinal Chem. 4(1):5-23, 1996). Peptide nucleic acids (PNAs) are nucleic acid mimics, e.g., DNA mimics, in which the deoxyribose phosphate backbone is replaced by a pseudopeptide backbone and only the four natural nucleobases are retained. The neutral backbone of PNAs allows for specific hybridization to RNA and DNA under conditions of low ionic strength. PNA oligomers can be synthesized using standard solid phase peptide synthesis protocols (see, e.g., Perry-O'Keefe et al., Proc. Natl. Acad. Sci. U.S.A.93:14670-675, 1996). PNAs can be used as antisense or antigene agents for sequence-specific modulation of gene expression by, e.g., inducing transcription or translation arrest or inhibiting replication.

Inhibitory nucleic acids that can decrease the expression of AP-1, ASK1, CD14, c‐jun,  ERK1/2, IkB, IKK, IRAK, JNK, LBP, MAPK, MEK1/2, MEKK1/4, MEKK4/7, MEKK 3/6, MK2, MyD88, NF-kB, NIK, p38, PKR, rac, ras, raf, RIP, TNFa, TNFR1, TNFR2, TRADD, TRAF2, TRAF6, or TTP mRNA expression in a mammalian cell include antisense nucleic acid molecules, i.e., nucleic acid molecules whose nucleotide sequence is fully or partially

complementary to all or part of a AP-1, ASK1, CD14, c-jun, ERK1/2, IkB, IKK, IRAK, JNK, LBP, MAPK, MEK1/2, MEKK1/4, MEKK4/7, MEKK 3/6, MK2, MyD88, NF-kB, NIK, p38, PKR, rac, ras, raf, RIP, TNFa, TNFR1, TNFR2, TRADD, TRAF2, TRAF6, or TTP mRNA (e.g., fully or partially complementary to all or a part of any one of the sequences presented in Table E). Table E.

Small Molecules In some embodiments, the anti-TNFa agent is a small molecule. In some embodiments, the small molecule is a tumor necrosis factor-converting enzyme (TACE) inhibitor (e.g., Moss et al., Nature Clinical Practice Rheumatology 4: 300-309, 2008). In some embodiments, the anti- TNFa agent is C87 (Ma et al., J. Biol. Chem.289(18):12457-66, 2014). In some embodiments, the small molecule is LMP-420 (e.g., Haraguchi et al., AIDS Res. Ther.3:8, 2006). In some embodiments, the TACE inhibitor is TMI-005 and BMS-561392. Additional examples of small molecule inhibitors are described in, e.g., He et al., Science 310(5750):1022-1025, 2005.

In some examples, the anti-TNFa agent is a small molecule that inhibits the activity of one of AP-1, ASK1, IKK, JNK, MAPK, MEKK 1/4, MEKK4/7, MEKK 3/6, NIK, TRADD, RIP, NF-kB, and TRADD in a cell (e.g., in a cell obtained from a subject, a mammalian cell).

In some examples, the anti-TNFa agent is a small molecule that inhibits the activity of one of CD14, MyD88 (see, e.g., Olson et al., Scientific Reports 5:14246, 2015), ras (e.g., Baker et al., Nature 497:577-578, 2013), raf (e.g., vemurafenib (PLX4032, RG7204), sorafenib tosylate, PLX-4720, dabrafenib (GSK2118436), GDC-0879, RAF265 (CHIR-265), AZ 628, NVP-BHG712, SB590885, ZM 336372, sorafenib, GW5074, TAK-632, CEP-32496, encorafenib (LGX818), CCT196969, LY3009120, RO5126766 (CH5126766), PLX7904, and MLN2480). In some examples, the anti-TNFa agent TNFa inhibitor is a small molecule that inhibits the activity of one of MK2 (PF 3644022 and PHA 767491), JNK (e.g., AEG 3482, BI 78D3, CEP 1347, c-JUN peptide, IQ 1S, JIP-1 (153-163), SP600125, SU 3327, and TCS JNK6o), c-jun (e.g., AEG 3482, BI 78D3, CEP 1347, c-JUN peptide, IQ 1S, JIP-1 (153-163), SP600125, SU 3327, and TCS JNK6o), MEK3/6 (e.g., Akinleye et al., J. Hematol. Oncol.6:27, 2013), p38 (e.g., AL 8697, AMG 548, BIRB 796, CMPD-1, DBM 1285 dihydrochloride, EO 1428, JX 401, ML 3403, Org 48762-0, PH 797804, RWJ 67657, SB 202190, SB 203580, SB 239063, SB 706504, SCIO 469, SKF 86002, SX 011, TA 01, TA 02, TAK 715, VX 702, and VX 745), PKR (e.g., 2-aminopurine or CAS 608512-97-6), TTP (e.g., CAS 329907-28-0), MEK1/2 (e.g., Facciorusso et al., Expert Review Gastroentrol. Hepatol.9:993-1003, 2015), ERK1/2 (e.g., Mandal et al., Oncogene 35:2547-2561, 2016), NIK (e.g., Mortier et al., Bioorg. Med. Chem. Lett.20:4515-4520, 2010), IKK (e.g., Reilly et al., Nature Med.19:313-321, 2013), IkB (e.g., Suzuki et al., Expert. Opin. Invest. Drugs 20:395-405, 2011), NF-kB (e.g., Gupta et al., Biochim. Biophys. Acta 1799(10-12):775-787, 2010), rac (e.g., U.S. Patent No.9,278,956), MEK4/7, IRAK (Chaudhary et al., J. Med. Chem.58(1):96-110, 2015), LBP (see, e.g., U.S. Patent No. 5,705,398), and TRAF6 (e.g., 3-[(2,5-Dimethylphenyl)amino]-1-phenyl-2-propen-1-one). In some embodiments of any of the methods described herein, the inhibitory nucleic acid can be about 10 nucleotides to about 50 nucleotides (e.g., about 10 nucleotides to about 45 nucleotides, about 10 nucleotides to about 40 nucleotides, about 10 nucleotides to about 35 nucleotides, about 10 nucleotides to about 30 nucleotides, about 10 nucleotides to about 28 nucleotides, about 10 nucleotides to about 26 nucleotides, about 10 nucleotides to about 25 nucleotides, about 10 nucleotides to about 24 nucleotides, about 10 nucleotides to about 22 nucleotides, about 10 nucleotides to about 20 nucleotides, about 10 nucleotides to about 18 nucleotides, about 10 nucleotides to about 16 nucleotides, about 10 nucleotides to about 14 nucleotides, about 10 nucleotides to about 12 nucleotides, about 12 nucleotides to about 50 nucleotides, about 12 nucleotides to about 45 nucleotides, about 12 nucleotides to about 40 nucleotides, about 12 nucleotides to about 35 nucleotides, about 12 nucleotides to about 30 nucleotides, about 12 nucleotides to about 28 nucleotides, about 12 nucleotides to about 26 nucleotides, about 12 nucleotides to about 25 nucleotides, about 12 nucleotides to about 24 nucleotides, about 12 nucleotides to about 22 nucleotides, about 12 nucleotides to about 20 nucleotides, about 12 nucleotides to about 18 nucleotides, about 12 nucleotides to about 16 nucleotides, about 12 nucleotides to about 14 nucleotides, about 15 nucleotides to about 50 nucleotides, about 15nucleotides to about 45 nucleotides, about 15nucleotides to about 40 nucleotides, about 15nucleotides to about 35 nucleotides, about 15 nucleotides to about 30 nucleotides, about 15nucleotides to about 28 nucleotides, about 15nucleotides to about 26 nucleotides, about 15nucleotides to about 25 nucleotides, about 15nucleotides to about 24 nucleotides, about 15nucleotides to about 22 nucleotides, about 15nucleotides to about 20 nucleotides, about 15nucleotides to about 18 nucleotides, about 15nucleotides to about 16 nucleotides, about 16 nucleotides to about 50 nucleotides, about 16 nucleotides to about 45 nucleotides, about 16 nucleotides to about 40 nucleotides, about 16 nucleotides to about 35 nucleotides, about 16 nucleotides to about 30 nucleotides, about 16 nucleotides to about 28 nucleotides, about 16 nucleotides to about 26 nucleotides, about 16 nucleotides to about 25 nucleotides, about 16 nucleotides to about 24 nucleotides, about 16 nucleotides to about 22 nucleotides, about 16 nucleotides to about 20 nucleotides, about 16 nucleotides to about 18 nucleotides, about 18 nucleotides to about 20 nucleotides, about 20 nucleotides to about 50 nucleotides, about 20 nucleotides to about 45 nucleotides, about 20 nucleotides to about 40 nucleotides, about 20 nucleotides to about 35 nucleotides, about 20 nucleotides to about 30 nucleotides, about 20 nucleotides to about 28 nucleotides, about 20 nucleotides to about 26 nucleotides, about 20 nucleotides to about 25 nucleotides, about 20 nucleotides to about 24 nucleotides, about 20 nucleotides to about 22 nucleotides, about 24 nucleotides to about 50 nucleotides, about 24 nucleotides to about 45 nucleotides, about 24 nucleotides to about 40 nucleotides, about 24 nucleotides to about 35 nucleotides, about 24 nucleotides to about 30 nucleotides, about 24 nucleotides to about 28 nucleotides, about 24 nucleotides to about 26 nucleotides, about 24 nucleotides to about 25 nucleotides, about 26 nucleotides to about 50 nucleotides, about 26 nucleotides to about 45 nucleotides, about 26 nucleotides to about 40 nucleotides, about 26 nucleotides to about 35 nucleotides, about 26 nucleotides to about 30 nucleotides, about 26 nucleotides to about 28 nucleotides, about 28 nucleotides to about 50 nucleotides, about 28 nucleotides to about 45 nucleotides, about 28 nucleotides to about 40 nucleotides, about 28 nucleotides to about 35 nucleotides, about 28 nucleotides to about 30 nucleotides, about 30 nucleotides to about 50 nucleotides, about 30 nucleotides to about 45 nucleotides, about 30 nucleotides to about 40 nucleotides, about 30 nucleotides to about 38 nucleotides, about 30 nucleotides to about 36 nucleotides, about 30 nucleotides to about 34 nucleotides, about 30 nucleotides to about 32 nucleotides, about 32 nucleotides to about 50 nucleotides, about 32 nucleotides to about 45 nucleotides, about 32 nucleotides to about 40 nucleotides, about 32 nucleotides to about 35 nucleotides, about 35 nucleotides to about 50 nucleotides, about 35 nucleotides to about 45 nucleotides, about 35 nucleotides to about 40 nucleotides, about 40 nucleotides to about 50 nucleotides, about 40 nucleotides to about 45 nucleotides, about 42 nucleotides to about 50 nucleotides, about 42 nucleotides to about 45 nucleotides, or about 45 nucleotides to about 50 nucleotides) in length. One skilled in the art will appreciate that inhibitory nucleic acids may comprises at least one modified nucleic acid at either the 5’ or 3’ end of DNA or RNA.

In some embodiments, the inhibitory nucleic acid can be formulated in a liposome, a micelle (e.g., a mixed micelle), a nanoemulsion, or a microemulsion, a solid nanoparticle, or a nanoparticle (e.g., a nanoparticle including one or more synthetic polymers). Additional exemplary structural features of inhibitory nucleic acids and formulations of inhibitory nucleic acids are described in US 2016/0090598.

In some embodiments, the inhibitory nucleic acid (e.g., any of the inhibitory nucleic acid described herein) can include a sterile saline solution (e.g., phosphate-buffered saline (PBS)). In some embodiments, the inhibitory nucleic acid (e.g., any of the inhibitory nucleic acid described herein) can include a tissue-specific delivery molecule (e.g., a tissue-specific antibody).

In one embodiment, provided herein is a combination of a compound of any preceding embodiment, for use in the treatment or the prevention of a condition mediated by TNF- ^, in a patient in need thereof, wherein the compound is administered to said patient at a therapeutically effective amount. Preferably, the subject is resistant to treatment with an anti-TNFa agent. Preferably, the condition is a gut disease or disorder.

In one embodiment, provided herein is a pharmaceutical composition of comprising a compound of any preceding embodiment, and an anti-TNF ^ agent disclosed herein. Preferably wherein the anti-TNF ^ ^agent is Infliximab, Etanercept, Certolizumab pegol, Golimumab or Adalimumab, more preferably wherein the anti-TNF ^ ^agent is Adalimumab ^

In one embodiment, provided herein is a pharmaceutical combination of a compound of any preceding embodiment, and an anti-TNF ^ ^agent Preferably wherein the anti-TNF ^ ^agent is Infliximab, Etanercept, Certolizumab pegol, Golimumab or Adalimumab, more preferably wherein the anti-TNF ^ ^agent is Adalimumab ^ In one embodiment, the present invention relates to an NLRP3 antagonist for use in the treatment or the prevention of a condition mediated by TNF- ^, in particular a gut disease or disorder, in a patient in need thereof, wherein the NLRP3 antagonist is administered to said patient at a therapeutically effective amount.

In one embodiment, the present invention relates to an NLRP3 antagonist for use in the treatment or the prevention of a condition, in particular a gut disease or disorder, in a patient in need thereof wherein the NLRP3 antagonist is administered to said patient at a therapeutically effective amount.

In one embodiment, the present invention relates to an NLRP3 antagonist for use in the treatment, stabilization or lessening the severity or progression of gut disease or disorder, in a patient in need thereof wherein the NLRP3 antagonist is administered to said patient at a therapeutically effective amount.

In one embodiment, the present invention relates to an NLRP3 antagonist for use in the slowing, arresting, or reducing the development of a gut disease or disorder, in a patient in need thereof wherein the NLRP3 antagonist is administered to said patient at a therapeutically effective amount.

In one embodiment, the present invention relates to an NLRP3 antagonist for use according to above listed embodiments wherein the NLRP3 antagonist is a gut-targeted NLRP3 antagonist.

In one embodiment, the present invention relates ton NLRP3 antagonist for use according to any of the above embodiments, wherein the gut disease is IBD.

In one embodiment, the present invention relates to an NLRP3 antagonist for use according to any of the above embodiments, wherein the gut disease is US or CD.

In one embodiment, the present invention relates to a method for the treatment or the prevention of a condition mediated by TNF- ^, in particular a gut disease or disorder, in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a gut-targeted NLRP3 antagonist.

In one embodiment, the present invention relates to a method for the treatment or the prevention of a condition, in particular a gut disease or disorder, in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a gut-targeted NLRP3 antagonist. In one embodiment, the present invention relates to a method for the treatment, stabilization or lessening the severity or progression of gut disease or disorder, in a patient in need thereof comprising administering to said patient a therapeutically effective amount of a gut- targeted NLRP3 antagonist.

In one embodiment, the present invention relates to a method for slowing, arresting, or reducing the development of a gut disease or disorder, in a patient in need thereof comprising administering to said patient a therapeutically effective amount of a gut-targeted NLRP3 antagonist.

In one embodiment, the present invention relates to a method according to any of the above embodiments, wherein the gut disease is IBD.

In one embodiment, the present invention relates to a method according to any of the above embodiments x to xx, wherein the gut disease is UC or CD.

In one embodiment, the present invention relates to a method for the treatment or the prevention of a condition mediated by TNF- ^, in particular a gut disease or disorder, in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a gut-targeted NLRP3 antagonist. Compound Preparation and Biological Assays

As can be appreciated by the skilled artisan, methods of synthesizing the compounds of the formulae herein will be evident to those of ordinary skill in the art. Synthetic chemistry transformations and protecting group methodologies (protection and deprotection) useful in synthesizing the compounds described herein are known in the art and include, for example, those such as described in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T. W. Greene and RGM. Wuts, Protective Groups in Organic Synthesis, 2d. Ed., John Wiley and Sons (1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995), and subsequent editions thereof. Preparative Examples The following abbreviations have the indicated meanings: ACN = acetonitrile

BTC = trichloromethyl chloroformate

Boc = t-butyloxy carbonyl

Davephos = 2-Dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl

DCM = dichloromethane

DEA = diethylamine

DMF = N,N-dimethylformamide

DMSO = dimethyl sulfoxide

DIEA = N,N-diisopropylethylamine

DPPA = diphenylphosphoryl azide

dppf = 1,1'-Bis(diphenylphosphino)ferrocene

EtOH = ethanol

HATU = 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyri dinium 3-oxid hexafluorophosphate

Hex = hexane

HPLC = high performance liquid chromatography

LC-MS = liquid chromatography– mass spectrometry

LiHMDS = lithium bis(trimethylsilyl)amide

LDA = lithium diisopropylamide

M = mol/L

Me = methyl

MeOH = methanol

MSA = methanesulfonic acid

NBS = N-bromosuccinimide

NCS = N-chlorosuccinimide

NMR = nuclear magnetic resonance

Pd(dppf)Cl ₂ = dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium

Ph = phenyl

PPh ₃ Cl ₂ = dichlorotriphenylphosphorane

Py = pyridine

RT = room temperature

Rt = Retention time

R _f = Retardation factor

Sat. = saturated

TBAF = tetrabutylammonium fluoride TBS = tert-butyldimethylsilyl

TBSCl = tert-butyldimethylsilyl chloride

TBDPSCl = tert-butyldiphenylsilyl chloride

TEA = triethylamine

TFA = trifluoroacetic acid

THF = tetrahydrofuran

TLC = thin layer chromatography

TsOH = 4-methylbenzenesulfonic acid

UV = ultraviolet

Burgess reagent = (Methoxycarbonylsulfamoyl)triethylammonium hydroxide inner salt DIAD = Diisopropylazodicarboxylate

DIBAL-H = Diisobutylaluminum hydride

DPPA = Diphenylphosphoryl azide

LAH = Lithium aluminum hydride

NFSI = N-fluoro benzene sulfonamide

NMO = 4-Methylmorpholine N-oxide

Pd(dtbpf)Cl2= [1,1'-Bis(di-tert-butylphosphino)ferrocene]dichloropalladium (II) Ruphos = 2-Dicyclohexylphosphino-2,6-diisopropoxy-1,1-biphenyl

SEM-Cl = 2-(Trimethylsilyl)ethoxymethyl chloride

TsCl = 4-Methylbenzenesulfonyl chloride

TPAP = Tetrapropylammonium perruthenate

General

The progress of reactions was often monitored by TLC or LC-MS. The identity of the products was often confirmed by LC-MS. The LC-MS was recorded using one of the following methods. Method A: Shim-pack XR-ODS, C18, 3x50 mm, 2.5 um column, 1.0 uL injection, 1.5 mL/min flow rate, 90-900 amu scan range, 190-400 nm UV range, 5-100% (1.1 min), 100% (0.6 min) gradient with ACN (0.05% TFA) and water (0.05% TFA), 2 minute total run time. Method B: Kinetex EVO, C18, 3x50 mm, 2.2 um column, 1.0 uL injection, 1.5 mL/min flow rate, 90-900 amu scan range, 190-400 nm UV range, 10-95% (1.1 min), 95% (0.6 min) gradient with ACN and water (0.5% NH4HCO3 ), 2 minute total run time. Method C: Shim-pack XR-ODS, C18, 3x50 mm, 2.5 um column, 1.0 uL injection, 1.5 mL/min flow rate, 90-900 amu scan range, 190-400 nm UV range, 5-100% (2.1 min), 100% (0.6 min) gradient with ACN (0.05% TFA) and water (0.05% TFA), 3 minute total run time. Method D: Kinetex EVO, C18, 3x50 mm, 2.2 um column, 1.0 uL injection, 1.5 mL/min flow rate, 90-900 amu scan range, 190-400 nm UV range, 10-95% (2.1 min), 95% (0.6 min) gradient with ACN and water (0.5% NH4HCO3 ), 3 minute total run time. Method F: Phenomenex, CH0-7644, Onyx Monolithic C18, 50 x 4.6 mm, 10.0 uL injection, 1.5 mL/min flow rate, 100-1500 amu scan range, 220 and 254 nm UV detection, 5% with ACN (0.1% TFA) to 100% water (0.1% TFA) over 9.5 min, with a stay at 100% (ACN, 0.1% TFA) for 1 min, then equilibration to 5% (ACN, 0.1% TFA) over 1.5 min. The final targets were purified by Prep-HPLC. The Prep-HPLC was carried out using the following method. Method E: Prep-HPLC: Column, XBridge Shield RP18 OBD (19x250 mm, 10 um); mobile phase, Water (10mmol/L NH4HCO3) and ACN, UV detection 254/210 nm. Method G: Prep-HPLC: Higgins Analytical Proto 200, C18 Column, 250 x 20 mm, 10 um; mobile phase, Water (0.1% TFA) and ACN (0.1% TFA), UV detection 254/210 nm. NMR was recorded on BRUKER NMR 300.03 MHz, DUL-C-H, ULTRASHIELD ^TM 300, AVANCE II 300 B-ACS ^TM 120 or BRUKER NMR 400.13 MHz, BBFO, ULTRASHIELD ^TM 400, AVANCE III 400, B-ACS ^TM 120 or BRUKER AC 250 NMR instrument with TMS as reference measured in ppm (part per million). Racemic compounds of this invention can be resolved to give individual enantiomers using a variety of known methods. For example, chiral stationary phases can used and the elution conditions can include normal phase or super-critical fluid with or without acidic or basic additives. Enantiomerically pure acids or bases can be used to form diatereomeric salts with the racemic compounds whereby pure enantiomers can be obtained by fractional crystallization. The racemates can also be derivatized with enantiomerically pure auxiliary reagents to form diastereomeric mixtures that can be separated. The auxiliary is then removed to give pure enantiomers. Schemes for the preparation of final targets: Schemes 1-3 below illustrate several conditions used for coupling of sulfonimidamide 1 or 5 and isocyanate 2 to afford aminocarbonyl sulfonimidamide 4 via 3 or 6 after deprotection. As used in the schemes, rings“A” and“B” may be substituted as disclosed herein. Scheme 1:

Scheme 2:

Scheme 4 below illustrates the coupling between sulfonimidamide 7 and isocyanate 2 to provide sulfonimidamide 8.

Scheme 5 below illustrates the conversion of carboxylic acid 9 through Curtius rearrangement to isocyanate 2 via acyl azide 10, whereupon coupling between 2 and sulfonimidamide 5 affords aminocarbonyl sulfonimidamide 4.

Scheme of final targets: Schemes below illustrate several conditions used for coupling of sulfonimidamide and isocyanate to afford aminocarbonyl sulfonimidamide.

Scheme of final targets: Schemes below illustrate several conditions used for coupling of sulfonimidamide and isocyanate or isocyanate equivalents to afford aminocarbonyl sulfonimidamide.

Schemes for the preparation of Sulfonimidamide Intermediates 1-29:

Schemes below illustrate the preparation of sulfonamide intermediates.

N'-(tert-butyldimethylsilyl)-4-(2-hydroxypropan-2-yl)-5-meth ylfuran-2-sulfonimidamide Step 1: Methyl 5-(chlorosulfonyl)-2-methylfuran-3-carboxylate Into a 500-mL 3-necked round-bottom flask was placed methyl 2-methylfuran-3-carboxylate (7 g, 50 mmol) in CHCl3 (200 mL). This was followed by the addition of chlorosulfonic acid (11.6 g, 100 mmol) dropwise with stirring at -10 ^o C. The reaction mixture was stirred for 48 h at RT, after which the system was cooled to -10 ^o C. Then to the above was added phosphorus pentachloride (22.9 g, 110 mmol). The resulting solution was stirred for 0.5 h at 50 ^o C and then was quenched by pouring onto 200 mL of water/ice. The resulting mixture was extracted with 3x200 mL of DCM. The organic layers were combined and dried over anhydrous Na2SO4, and then concentrated under vacuum. This resulted in 7.5 g (crude, 63%) of the title compound as light brown oil. The crude product was used in the next step. Step 2: Methyl 2-methyl-5-sulfamoylfuran-3-carboxylate

Into a 250-mL round-bottom flask was placed a solution of methyl 5-(chlorosulfonyl)-2- methylfuran-3-carboxylate (7.5 g, crude) in DCM (75 mL). To the above was added a saturated solution of ammonia in DCM (50 mL). The resulting solution was stirred for 3 h at RT and then was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with a gradient of ethyl acetate/petroleum ether (1:4 to 1:2). This resulted in 5.0 g (46% over two steps) of the title compound as a light yellow solid. MS-ESI: 218.0 (M-1). Step 3: 4-(2-Hydroxypropan-2-yl)-5-methylfuran-2-sulfonamide

Into a 250-mL 3-necked round-bottom flask purged with and maintained under nitrogen was placed a solution of methyl 2-methyl-5-sulfamoylfuran-3-carboxylate (3.7 g, 16.9 mmol) in THF (100 mL). This was followed by the addition of MeMgBr (3 M in THF, 25 mL) dropwise with stirring at -10 ^o C. The resulting mixture was stirred for 10 h at RT and then was quenched by the addition of 50 mL of NH4Cl (sat.). The resulting solution was extracted with 3x50 mL of ethyl acetate. The organic layers were combined and dried over anhydrous Na2SO4, then concentrated under vacuum. The residue was applied onto a silica gel column and eluted with a gradient of ethyl acetate/petroleum ether (1:3 to 1:1). This resulted in 2.6 g (75%) of the title compound as a light yellow solid. MS-ESI: 218.0 (M-1). Step 4: N-(tert-butyldimethylsilyl)-4-(2-hydroxypropan-2-yl)-5-methy lfuran-2-sulfonamide Into a 250-mL round-bottom flask purged with and maintained under nitrogen was placed 4-(2- hydroxypropan-2-yl)-5-methylfuran-2-sulfonamide (1.0 g, 4.56 mmol), DCM (100 mL), 1H- imidazole (612 mg, 9.12 mmol), and TBSCl (3.4 g, 22.6 mmol). The resulting solution was stirred for 14 h at RT and then was diluted with 100 mL of water. The resulting mixture was extracted with 3x50 mL of DCM and the organic layers were combined and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with a gradient of ethyl acetate/petroleum ether (1:10 to 1:3). This resulted in 1.4 g (92%) of the title compound as a white solid. MS-ESI: 332.0 (M-1). Step 5: N'-(tert-butyldimethylsilyl)-4-(2-hydroxypropan-2-yl)-5-meth ylfuran-2- sulfonimidamide

Into a 250-mL 3-necked round-bottom flask purged with and maintained under nitrogen was placed PPh3Cl2 (3.0 g, 10.2 mmol) in CHCl3 (100 mL). This was followed by the addition of TEA (2.06 g, 20.4 mmol) dropwise with stirring at RT. After stirred at 0 ^o C for 10 min, to the above was added a solution of N-(tert-butyldimethylsilyl)-4-(2-hydroxypropan-2-yl)-5-methy lfuran-2- sulfonamide (2.3 g, 6.8 mmol) in CHCl3 (10 mL) dropwise with stirring at 0 ^o C. The resulting solution was allowed to react for 30 min at 0 ^o C. To the mixture was added a saturated solution of ammonia in DCM (10 mL) at 0 ^o C. The resulting solution was stirred for 2 h at RT. The reaction was then quenched by the addition of 100 mL of water. The resulting solution was extracted with 3x50 mL of DCM and the organic layers combined and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with a gradient of ethyl acetate/petroleum ether (1:10 to 1:3). This resulted in 0.80 g (52.8%) of the title compound as a light yellow solid. MS- ESI: 333.0 (M+1). Scheme 7A:

TBS

N _NH

N'-(tert-butyldimethylsi yl)thiazole-2-sulfonimidamide

Step 1: Methyl 2-mercaptothia zole-5-carboxylate

Into a 250-mL round-bottom flask was placed methyl 2-bromothiazole-5-carboxylate (10 g, 45 mmol), EtOH (100 mL), and sodium hydrogensulfide (5 g, 89 mmol). The resulting solution was stirred for 2 h at 80 ^o C and then was cooled to 0 ^o C with a water/ice bath. The pH value of the solution was adjusted to 3 with aq. HCl (1 N). The solids were collected by filtration. This resulted in 6 g (76%) of the title compound as a light yellow solid. MS-ESI: 176.0 (M+1).

Step 2: Methyl 2-(chlorosulfonyl)thiazole-5-carboxylate

Into a 250-mL round-bottom flask was placed methyl 2-mercaptothiazole-5-carboxylate (6 g, 34 mmol) and acetic acid (60 mL). This was followed by the addition of sodium hypochlorite (60 mL,

8%-10% wt.) in portions at 0 ^o C. The resulting solution was stirred for 1 h at RT and then was diluted with 100 mL of water. The solution was extracted with 3x50 mL of DCM. The organic layers were combined and dried over anhydrous Na ₂ SO ₄ , then concentrated under vacuum. This resulted in 5 g (crude, 60%) of the title compound as yellow oil. The crude product was used in the next step.

Step 3-6 used similar procedure for converting compound 12 to Intermediate 1 shown in Scheme

6 to afford Intermediate 2. MS-ESI: 336.1 (M+1). Scheme 7B:

S Intermediate 2

N'-(tert-butyldimethylsilyl)-5-(2-hydroxypropan-2-yl)thiazol e-2-sulfonimidamide

Step 1: Methyl 2-mercaptothiazole-5-carboxylate

Into a 2-L round-bottom flask was placed methyl 2-bromothiazole-5-carboxylate (100 g, 450 mmol), EtOH (1000 mL), sodium hydrogensulfide (50 g, 890 mmol). The resulting solution was stirred for 2 h at 80 ^o C and then was cooled to 0 ^o C with a water/ice bath. The pH value of the solution was adjusted to 3 with hydrogen chloride (1 N). The solids were collected by filtration. This resulted in 63.2 g (80%) of the title compound as a light yellow solid. MS-ESI: 176.0 (M+1). Step 2: Methyl 2-(chlorosulfonyl)thiazole-5-carboxylate

Into a 1-L round-bottom flask was placed methyl 2-mercaptothiazole-5-carboxylate (30 g, 170 mmol) and acetic acid (300 mL). This was followed by the addition of sodium hypochlorite (300 mL, 8%-10% wt.) in portions at 0 ^o C. The resulting solution was stirred for 2 h at RT and then was diluted with 500 mL of water. The solution was extracted with 3x300 mL of DCM and the combined organic layers were washed with 2x300 mL of brine and dried over anhydrous Na ₂ SO ₄ . The crude product as a yellow solution in DCM was used in the next step.

Step 3: Methyl 2-sulfamoylthiazole-5-carboxylate

Into a 2-L round-bottom flask was placed methyl 2-(chlorosulfonyl)thiazole-5-carboxylate as a crude solution in DCM (900 mL). To the solution was introduced NH ₃ (g) below 0 ^o C for 20 minutes. The resulting solution was stirred for 1 h at RT and then concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:5 to 1:3). This resulted in 23 g (75%, 2 steps) of the title compound as a white solid. MS-ESI: 223.0 (M+1).

Step 4: 5-(2-Hydroxypropan-2-yl)thiazole-2-sulfonamide

Into a 500-mL round-bottom flask purged with and maintained under nitrogen was placed a solution of methyl 2-sulfamoylthiazole-5-carboxylate (15 g, 67.5 mmol) in THF (150 mL). This was followed by the addition of MeMgBr/THF (3 M, 90 mL) dropwise with stirring at 0 ^o C. The resulting solution was stirred for 14 h at RT and then was quenched by the addition of 100 mL of NH ₄ Cl (sat.). The resulting solution was extracted with 3x150 mL of DCM. The organic layers were combined and dried over anhydrous Na ₂ SO ₄ , then concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:5 to 1:3). This resulted in 11.5 g (78%) of the title compound as a white solid. MS-ESI: 223.0 (M+1), 221.0 (M-1) in positive and negative ion mode, respectively.

Step 5: N-(tert-butyldimethylsilyl)-5-(2-hydroxypropan-2-yl)thiazole -2-sulfonamide

Into a 250-mL 3-necked round-bottom flask purged with and maintained under nitrogen was placed a solution of 5-(2-hydroxypropan-2-yl)thiazole-2-sulfonamide (5 g, 22.5 mmol) in THF (100 mL). Then to the above was added NaH (60% wt, 1.8 g, 45.0 mmol) in portions in an ice/water bath. After stirring for 20 minutes in a water/ice bath, this was followed by the addition of a solution of TBSCl (4.1 g, 27.2 mmol) in THF (10 mL) dropwise with stirring at 0 ^o C. The resulting solution was stirred for 4 h at RT. The reaction was quenched with sat. NH4Cl (100 mL). The resulting solution was extracted with 3 x 100 mL of ethyl acetate and the combined organic layers were dried over Na2SO4 and concentrated under vacuum. The crude solid was washed with ethyl acetate/hexane (1:5) (2x100 mL). This resulted in 6.81 g (90%) of the title compound as a yellow solid. MS-ESI: 337.1 (M+1), 335.1 (M-1) in positive and negative ion mode, respectively.

Step 6: N'-(tert-butyldimethylsilyl)-5-(2-hydroxypropan-2-yl)thiazol e-2-sulfonimidamide Into a 100-mL 3-necked round-bottom flask purged with and maintained under nitrogen was placed a solution of PPh3Cl2 (3 g, 9.0 mmol) in CHCl3 (100 mL). This was followed by the addition of DIEA (1.54 g, 11.9 mmol) dropwise with stirring at RT. The resulting solution was stirred for 10 min at RT. This was followed by the addition of a solution of N-(tert-butyldimethylsilyl)-5-(2- hydroxypropan-2-yl)thiazole-2-sulfonamide (2.0 g, 5.9 mmol) in CHCl3 (30 mL) dropwise with stirring in an ice/water bath. The resulting solution was stirred for 30 min in an ice/water bath. To the above was introduced NH3 (g) below 0 ^o C for 15 minutes. The resulting solution was stirred for 20 minutes at RT. The solids were filtered out and the filtrate was concentrated and the residue was dissolved in 300 mL of ethyl acetate. The solution was washed with brine (2x100 mL), dried over Na2SO4 and concentrated under vacuum. The crude solid was washed with CHCl3 (100 mL). Then the filtrate was concentrated under vacuum and the residue was further purified by a silica gel column with ethyl acetate/petroleum ether (1:10 to 1:3). The original washed solid and solid from silica gel purification were combined. This resulted in 1.2 g (60%) of the title compound as a white solid. MS-ESI: 336.1 (M+1). ¹ H-NMR (300 MHz, DMSO-d6) d 7.66 (s, 1H), 7.12 (s, 2H), 5.78 (s, 1H), 1.51 (s, 6H), 0.86 (s, 9H), 0.02 (s, 3H), 0.01 (s, 3H). Table 2. The Intermediate in the following Table was prepared using the similar procedures for converting compound 16 to Intermediate 2 shown in Scheme 7B starting from ethyl 5-bromo-4- methylthiazole-2-carboxylate.

Scheme 8:

N'-(tert-butyldimethylsilyl)-4-(2-hydroxypropan-2-yl)-5-meth ylthiophene-2-sulfonimidamide Steps 1-3 used similar procedures for converting compound 11 to compound 14 shown in Scheme 6 to afford compound 25 from compound 22. MS-ESI: 234.0 (M-1).

Steps 4-5 used similar procedure for converting compound 20 to Intermediate 2 shown in Scheme 7B to afford Intermediate 4 from compound 25. MS-ESI: 349.1 (M+1). Table 3. The Intermediate in the following Table was prepared using similar procedure as shown in Scheme 8 above for converting compound 22 to Intermediate 4 starting from the appropriate materials.

Scheme 9:

N'-(tert-butyldimethylsilyl)-2-fluoro-4-(2-hydroxypropan-2-y l)benzenesulfonimidamide Step 1: Methyl 4-(chlorosulfonyl)-3-fluorobenzoate

Into a 1 L round-bottom flask was placed a solution of methyl 4-amino-3-fluorobenzoate (10 g, 59.1 mmol) in aq. HCl (6 N, 200 mL). This was followed by the addition of a solution of NaNO2 (6.1 g, 88.8 mmol) in water (20 mL) dropwise with stirring at 0 ^o C. The resulting solution was stirred for 30 min at 0 ^o C. The above mixture was added to a saturated solution of SO2 in AcOH (200 mL) dropwise with stirring at 0 ^o C. Then to the above was added CuCl2 (8.0 g, 59.6 mmol). The resulting solution was stirred for 1 h at RT and was then quenched by the addition of 200 mL of water. The resulting solution was extracted with 3x200 mL of DCM. The organic layers were combined, dried over anhydrous Na2SO4 and concentrated under vacuum. This resulted in 10 g (67%) of the title compound as yellow oil. The product was used in the next step without further purification.

Step 2: Methyl 3-fluoro-4-sulfamoylbenzoate

Into a 1000 mL round bottom flask was placed a solution of methyl 4-(chlorosulfonyl)-3- fluorobenzoate solution (10 g, 39.5 mmol) in DCM (50 mL). This was followed by the addition of a saturated solution of ammonia in DCM (500 mL) in portions with stirring at 0 ^o C. The resulting solution was stirred for 1 h at 0 ^o C. The resulting solution was concentrated and the residue was purified with SiO2-gel column and diluted with ethyl acetate/ petroleum ether (1:2 to 1:1). This resulted in 8.28 g (90%) of the title compound as yellow solid. MS-ESI: 232.1 (M-1).

Step 3: 2-Fluoro-4-(2-hydroxypropan-2-yl)benzenesulfonamide

Into a 1 L 3-necked round-bottom flask was placed a solution of methyl 3-fluoro-4- sulfamoylbenzoate (8.28 g 35.5 mmol) in THF (500 mL). This was followed by the addition of MeMgBr/THF (3 M, 60 mL) dropwise with stirring at 0 ^o C. The resulting solution was stirred overnight at RT and then was quenched by the addition of 100 mL of sat. NH4Cl. The resulting solution was extracted with 3x200 mL of ethyl acetate and the combined organic layers were concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:2 to 1:1). This resulted 7.45 g (89.9%) of the title compound as a white solid. MS-ESI: 233.1 (M+1).

Step 4: N-(tert-butyldimethylsilyl)-2-fluoro-4-(2-hydroxypropan-2-yl )benzenesulfonamide Into a 500 mL round bottom flask was placed a solution of 2-fluoro-4-(2-hydroxypropan-2- yl)benzenesulfonamide (7.45 g 31.9 mmol) in THF (200 mL). This was followed by the addition of NaH (60% wt, 1.91 g, 79.6 mmol). The mixture was stirred at 0 ^o C for 0.5 h. This was followed by the addition of the solution of TBSCl (7.19 g, 47.9 mmol) in THF (50 mL) dropwise. The resulting solution was stirred at RT overnight. The reaction was quenched with ice-water (100 mL); the resulting solution was extracted with EtOAc (3x200 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was purified with SiO2-gel column and eluted with ethyl acetate/petroleum ether (1:5 to 1:2). This resulted 10 g (90%)of the title compound as a white solid. MS-ESI: 348.1 (M+1).

Step 5: N'-(tert-butyldimethylsilyl)-2-fluoro-4-(2-hydroxypropan-2- yl)benzenesulfonimidamide

Into a 1 L 3-necked round-bottom flask purged with and maintained under nitrogen was placed a solution of PPh3Cl2 (19.2 g, 57.6 mmol) in CHCl3 (100 mL). This was followed by the addition of DIEA (7.4 g, 57.6 mmol) dropwise with stirring at 0 ^o C. After stirred at 0 ^o C for 10 min, to the above was added a solution of N'-(tert-butyldimethylsilyl)-2-fluoro-4-(2-hydroxypropan-2- yl)benzenesulfonimidamide (10 g, 28.8 mmol) in CHCl3 (100 mL) dropwise with stirring at 0 ^o C. The resulting solution was allowed to react for 30 min at 0 ^o C. To the mixture was added a saturated solution of ammonia in DCM (500 mL) at 0 ^o C. The resulting solution was stirred for 2 h at RT. The solids were filtered out, and the filtrate was dilute with 100 mL of water. The resulting solution was extracted with 3x200 mL of DCM and the combined organic layers were dried over anhydrous Na2SO4 concentrated under vacuum. The residue was applied onto a silica gel column and eluted with a gradient of ethyl acetate/petroleum ether (1:10 to 1:3). This resulted in 5 g (50%) of the title compound as a light yellow solid. MS-ESI: 347.2 (M+1). Table 4. The Intermediates in the following Table were prepared using similar procedure as shown in Scheme 9 above for converting compound 27 to Intermediate 11 starting from the appropriate materials.

Table 5. The Intermediate in the following Table was prepared using similar procedure as shown in Scheme 9 above for converting compound 28 to Intermediate 11 starting from methyl 4- (chlorosulfonyl)benzoate.

Scheme 10:

N'-(tert-butyldimethylsilyl)-1-isopropyl-1H-pyrazole-3-sulfo nimidamide Step 1: 1-Isopropyl-3-nitro-1H-pyrazole

Into a 250-mL round-bottom flask was placed a solution of 3-nitro-1H-pyrazole (10 g, 88.4 mmol) in DMF (100 mL). This was followed by the addition of NaH (60% wt., 3.9 g, 97.5 mmol) in portions at 0 ^o C. The resulting solution was stirred for 0.5 h at 0 ^o C. This was followed by the addition of 2-bromopropane (14.1 g, 114.6 mmol) dropwise with stirring at 0 ^o C in 10 min. The resulting solution was stirred for 16 h at RT and then was quenched by the addition of 100 mL of water. The resulting solution was extracted with 3x100 mL of ethyl acetate. The organic layers were combined and dried over anhydrous Na2SO4, then concentrated under vacuum. The residue was applied onto a silica gel column and eluted with a gradient of ethyl acetate/petroleum ether (1:5 to 1:3). This resulted in 11.8 g (86%) of the title compound as yellow oil. MS-ESI: 156.1 (M+1).

Step 2: 3-Amino-1-(propan-2-yl)-1H-pyrazole

Into a 250-mL round-bottom flask was placed a solution of 1-isopropyl-3-nitro-1H-pyrazole (10.8 g, 69.6 mmol) in MeOH (100 mL). Then Pd/C (10% wt., 1.5 g) was added. The flask was evacuated and flushed three times with hydrogen. The mixture was stirred for 24 h at RT under an atmosphere of hydrogen. The solids were filtered out. The resulting filtrate was concentrated under vacuum. This resulted in 7.27 g (83%) of the title compound as yellow oil. MS-ESI: 126.1 (M+1). Steps 3-4 used similar procedures for converting compound 27 to compound 29 shown in Scheme 9 to afford compound 50 from compound 48. MS-ESI: 188.0 (M-1).

Steps 5-6 were using the similar procedures for converting compound 30 to Intermediate 11 shown in Scheme 9 to afford Intermediate 18 from compound 50. MS-ESI: 303.2 (M+1). Table 6. The Intermediate in the following Table was prepared using similar procedure as shown in Scheme 10 above for converting compound 48 to Intermediate 18 starting from the appropriate materials.

Scheme 11:

N'-(tert-butyldimethylsilyl)-4-((dimethylamino)methyl)benzen esulfonimidamide

Step 1: 4-Nitrobenzoyl chloride

Into a 500-mL round-bottom flask was placed 4-nitrobenzoic acid (20 g, 120 mmol), DCM (200 mL), and DMF (0.2 mL). This was followed by the addition of oxalyl chloride (15 mL, 177.1 mmol) dropwise with stirring at 0 ^o C. The resulting solution was stirred for 4 h at RT and then was concentrated under vacuum. This resulted in 22 g (crude) of the title compound as yellow oil. The crude product was used in the next step.

Step 2: N,N-dimethyl-4-nitrobenzamide

Into a 500-mL round-bottom flask was placed dimethylamine hydrochloride (6.5 g, 79.7 mmol), DCM (200 mL), and TEA (50 mL). This was followed by the addition of 4-nitrobenzoyl chloride (22 g, 119 mmol) dropwise with stirring at 0 ^o C. The resulting solution was stirred for 6 h at RT and then was concentrated under vacuum. The resulting mixture was washed with 2x50 mL of water. The solids were collected by filtration. This resulted in 16 g (69% over two steps) of the title compound as a white solid. MS-ESI: 195.1 (M+1).

Step 3: 4-Amino-N,N-dimethylbenzamide Into a 250-mL round-bottom flask was placed N,N-dimethyl-4-nitrobenzamide (16 g, 82.4 mmol), MeOH (100 mL). Then Pd/C (10% wt., 1 g) was added. The flask was evacuated and flushed three times with hydrogen. The resulting solution was stirred for 12 h at RT under an atmosphere of hydrogen. The solids were filtered out. The resulting filtrate was concentrated under vacuum. This resulted in 13 g (96%) of the title compound as a white solid. MS-ESI: 165.1 (M+1).

Steps 4-5 used similar procedures for converting compound 27 to compound 29 shown in Scheme 9 to afford compound 43 from compound 41. MS-ESI: 229.1 (M+1).

Step 6: 4-((Dimethylamino)methyl)benzenesulfonamide

Into a 100-mL round-bottom flask purged with and maintained under nitrogen was placed a solution of N,N-dimethyl-4-sulfamoylbenzamide (1.8 g, 7.9 mmol) in THF (50 mL). This was followed by the addition of 9-BBN (5.8 g) in portions at 0 ^o C. The resulting solution was stirred for 12 h at 70 ^o C and then was quenched by the addition of 20 mL of water/ice. The resulting solution was extracted with 3x100 mL of ethyl acetate and the organic layers were combined. The resulting mixture was washed with 200 mL of water and then the organic layer was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with a gradient of DCM/MeOH (20:1 to 15:1). This resulted in 1 g (59%) of the title compound as a white solid. MS- ESI: 215.1 (M+1).

Steps 7-8 were using the similar procedures for converting compound 30 to Intermediate 11 shown in Scheme 9 to afford Intermediate 23 from compound 44. MS-ESI: 328.2 (M+1). Scheme 12:

Intermediate 24

N'-(tert-butyldimethylsilyl)-3-((dimethylamino)methyl)benzen esulfonimidamide

Step 1: 3-amino-N,N-dimethylbenzamide

Into a 1000-mL round-bottom flask was placed dimethylamine as a hydrochloride salt (16.3 g, 200 mmol) in DCM (500 mL), DIEA (25.83 mg, 200 mmol). To the above was added 3-aminobenzoic acid (13.7 g, 100 mmol), HATU (57 g, 150 mmol). The resulting solution was stirred for 1 h at RT. The reaction was then quenched by the addition of 500 mL of NH4Cl (aq.). The resulting solution was extracted with 3x500 ml of ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate and concentrated. The residue was applied onto a silica gel column and eluted with a gradient of DCM/methanol (50:1 to 20:1). This resulted in 13.14 g (80%) of the title compound as a yellow solid. MS-ESI: 165.1 (M+1).

Steps 2-6 used the similar procedures for converting compound 41 to Intermediate 23 shown in Scheme 11 to afford Intermediate 24 from compound 47. MS-ESI: 328.2 (M+1).

Intermediate 25

N'-(tert-butyldimethylsilyl)-4-((dimethylamino)methyl)-2-flu orobenzenesulfonimidamide Steps 1-5 used similar procedures for converting compound 38 to compound 43 shown in Scheme 11 to afford compound 57. MS-ESI: 247.0 (M+1).

Step 6: 4-((Dimethylamino)methyl)-2-fluorobenzenesulfonamide

Into a 1-L round-bottom flask was placed a solution of 3-fluoro-N,N-dimethyl-4- sulfamoylbenzamide (19.3 g, 78.4 mmol) in THF (200 mL). This was followed by the addition of LiAlH4 (8.8 g, 231.9 mmol) in portions at 0 ^o C. The resulting solution was stirred for 12 h at RT and then was quenched by the addition of 10 mL of water. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with a gradient of ethyl acetate/petroleum ether (6:1 to 8:1). This resulted in 7.0 g (38%) of the title compound as a white solid. MS-ESI: 233.1 (M+1).

Steps 7-8 used similar procedures for converting compound 44 to Intermediate 23 shown in Scheme 11 to afford Intermediate 25. MS-ESI: 346.2 (M+1). Scheme 14:

S

Br S S

N ^aBH ₄ ^{, EtOH} S

Br Dess-Martin, DCM ^Br MeMgBr/THF

O Br

N

TBD

TB

2 T

Ste MeM

NH ₂ St

^TBS

Intermediate 26 Intermediate 26 2

H ^{O S}

N'-(tert-butyldimethylsilyl)-4-(2-hydroxypropan-2-yl)thiazol e-2-sulfonimidamide

Step 1: (2-Bromothiazol-4-yl)methanol

Into a 500-mL round-bottom flask was placed a solution of ethyl 2-bromothiazole-4-carboxylate

(14 g, 59.3 mmol), EtOH (200 mL). This was followed by the addition of NaBH ₄ (2.3 g, 60.5 mmol) in portions at 0 ^o C. The resulting solution was stirred for 3 h at RT and then was quenched by the addition of 100 mL of water. The resulting solution was extracted with 2x200 mL of DCM.

The organic layers were combined, dried over anhydrous Na ₂ SO ₄ and then concentrated under vacuum. This resulted in 10.0 g (87%) of the title compound as colorless oil. MS-ESI: 195.9, 193.9

(M+1).

Step 2: 2-Bromothiazole-4-carbaldehyde

Into a 250-mL round-bottom flask was placed a solution of (2-bromothiazol-4-yl)methanol (10.0 g, 51.5 mmol) in DCM (100 mL). To the solution was added Dess-Martin reagent (24.0 g, 56.6 mmol). The resulting solution was stirred for 2 h at RT and then was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with a gradient of ethyl acetate/petroleum ether (1:50 to 1:20). This resulted in 8.0 g (81%) of the title compound as yellow oil. MS-ESI: 193.9, 191.9 (M+1).

Step 3: 1-(2-Bromothiazol-4-yl)ethanol

Into a 250-mL 3-necked round-bottom flask purged with and maintained under nitrogen was placed a solution of 2-bromothiazole-4-carbaldehyde (8 g, 41.7 mmol) in THF (100 mL). This was followed by the addition of MeMgBr (3 M in THF, 15 mL) dropwise with stirring at 0 ^o C. The resulting solution was stirred for 2 h at RT and then was quenched by the addition of 100 mL of NH4Cl (sat.). The resulting solution was extracted with 3x100 mL of DCM and the combined organic layers were concentrated under vacuum. The residue was applied onto a silica gel column and eluted with a gradient of ethyl acetate/petroleum ether (1:10 to 1:5). This resulted in 6.0 g (69%) of the title compound as brown oil. MS-ESI: 209.9, 207.9 (M+1).

Step 4: 2-Bromo-4-(1-(tert-butyldiphenylsilyloxy)ethyl)thiazole

Into a 250-mL round-bottom flask was placed a solution of 1-(2-bromothiazol-4-yl)ethanol (6.0 g, 28.8 mmol) and 1H-imidazole (4.0 g, 58.8 mmol) in DMF (50 mL). To the solution was added TBDPSCl (8.7 g, 31.6 mmol). The resulting solution was stirred for 12 h at RT and then was diluted with 100 mL of water. The resulting solution was extracted with 3x100 mL of DCM and the combined organic layers were concentrated under vacuum. The residue was applied onto a silica gel column and eluted with a gradient of ethyl acetate/petroleum ether (1:100 to 1:50). This resulted in 10.0 g (78%) of the title compound as light yellow oil. MS-ESI: 448.1, 446.1 (M+1). Step 5: 4-(1-(Tert-butyldiphenylsilyloxy)ethyl)thiazole-2-sulfonyl chloride

Into a 250-mL 3-necked round-bottom flask purged with and maintained under nitrogen was placed a solution of 2-bromo-4-(1-(tert-butyldiphenylsilyloxy)ethyl)thiazole (10.0 g, 22.4 mmol) in THF (100 mL). This was followed by the addition of n-BuLi (2.5 M in THF, 11 mL) dropwise with stirring at -78 ^o C. The resulting solution was stirred for 30 min at -78 ^o C. To the above SO2 gas was introduced. The reaction was warmed to RT and stirred for 30 min and then was concentrated under vacuum. The residue was dissolved in DCM (100 mL) and then NCS (3.6 g, 26.9 mmol) was added. The resulting solution was stirred for 30 min at RT and then was concentrated under vacuum. This resulted in 8.0 g (crude, 77%) of the title compound as a white solid. The crude product was used in the next step.

Step 6: N-tert-butyl-4-(1-(tert-butyldiphenylsilyloxy)ethyl)thiazole -2-sulfonamide

Into a 100-mL round-bottom flask purged with and maintained under nitrogen was placed a solution of 4-(1-(tert-butyldiphenylsilyloxy)ethyl)thiazole-2-sulfonyl chloride (8.0 g, 17.2 mmol) in DCM (50 mL). To the solution were added TEA (3.5 g, 34.6 mmol) and 2-methylpropan-2- amine (1.9 g, 26.0 mmol). The resulting solution was stirred for 2 h at RT and then was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with a gradient of ethyl acetate/petroleum ether (1:15 to 1:5). This resulted in 8.0 g (71%, 2 steps) of the title compound as brown oil. MS-ESI: 503.2 (M+1).

Step 7: N-tert-butyl-4-(1-hydroxyethyl)thiazole-2-sulfonamide

Into a 250-mL round-bottom flask was placed a solution of N-tert-butyl-4-(1-(tert- butyldiphenylsilyloxy)ethyl)thiazole-2-sulfonamide (8.0 g, 15.9 mmol) in THF (100 mL). To the solution was added TBAF (9.6 g, 292.5 mmol). The resulting solution was stirred for 2 h at RT and then was diluted with 100 mL of water. The resulting solution was extracted with 3x100 mL of DCM and the combined organic layers were concentrated under vacuum. The residue was applied onto a silica gel column and eluted with a gradient of ethyl acetate/petroleum ether (1:10 to 1:3). This resulted in 4.0 g (95%) of the title compound as light yellow oil. MS-ESI: 265.1 (M+1).

Step 8: 4-Acetyl-N-tert-butylthiazole-2-sulfonamide

Into a 100-mL round-bottom flask was placed a solution of N-tert-butyl-4-(1- hydroxyethyl)thiazole-2-sulfonamide (4.0 g, 15.1 mmol) in DCM (50 mL). To the solution was added Dess-Martin reagent (7.1 g, 16.6 mmol). The resulting solution was stirred for 2 h at RT and then was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with a gradient of ethyl acetate/petroleum ether (1:10 to 1:3). This resulted in 3.5 g (88%) of the title compound as light yellow oil. MS-ESI: 363.0 (M+1).

Step 9: 4-Acetylthiazole-2-sulfonamide

Into a 100-mL round-bottom flask was placed a solution of 4-acetyl-N-tert-butylthiazole-2- sulfonamide (3.5 g, 13.3 mmol) in DCM (5 mL). To the solution was added TFA (20 mL). The resulting solution was stirred for 14 h at 40 ^o C and then was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with a gradient of ethyl acetate/petroleum ether (1:10 to 1:3). This resulted in 2.5 g (91%) of the title compound as a gray solid. MS-ESI: 207.0 (M+1).

Steps 10-12 used similar procedures for converting compound 29 to Intermediate 11 shown in Scheme 9 to afford Intermediate 26 from compound 69. MS-ESI: 336.1 (M+1).

Scheme 15A:

N'-(tert-butyldimethylsilyl)-2-(2-hydroxypropan-2-yl)thiazol e-5-sulfonimidamide

Step 1: 1-(Thiazol-2-yl)ethanol

Into a 500-mL round-bottom flask was placed 1-(thiazol-2-yl)ethanone (20 g, 157 mmol), EtOH (200 mL). This was followed by the addition of NaBH ₄ (3 g, 81.3 mmol) in portions at 0 ^o C. The resulting solution was stirred for 2 h at RT and then was quenched by the addition of 10 mL of NH ₄ Cl (sat.). The resulting solution was diluted with 200 mL of water and extracted with 2x200 mL of DCM. The organic layers were combined and dried over anhydrous Na ₂ SO ₄ , then concentrated under vacuum. This resulted in 20 g (98%) of the title compound as light yellow oil. MS-ESI: 130.0 (M+1).

Step 2: 2-(1-(Tert-butyldiphenylsilyloxy)ethyl)thiazole

Into a 500-mL round-bottom flask was placed 1-(thiazol-2-yl)ethanol (20 g, 154.8 mmol), DMF (150 mL), 1H-imidazole (20.5 g, 301 mmol). This was followed by the addition of TBDPSCl (46 g, 167 mmol) dropwise with stirring at 0 ^o C. The resulting solution was stirred for 2 h at RT and then was diluted with 300 mL of water. The resulting solution was extracted with 3x200 mL of DCM. The organic layers were combined and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with a gradient of ethyl acetate/petroleum ether (1:100 to 1:80). This resulted in 55 g (97%) of the title compound as colorless oil. MS-ESI: 368.1 (M+1).

Step 3: 2-(1-(Tert-butyldiphenylsilyloxy)ethyl)thiazole-5-sulfonyl chloride

Into a 500-mL 3-necked round-bottom flask purged with and maintained under nitrogen was placed a solution of 2-(1-(tert-butyldiphenylsilyloxy)ethyl)thiazole (30 g, 81.6 mmol) in THF (200 mL). This was followed by the addition of n-BuLi (2.5 M in THF, 35.2 mL) dropwise with stirring at -78 ^o C. The resulting solution was stirred for 0.5 h at -78 ^o C and then SO2 was introduced into the above reaction mixture. The reaction was slowly warmed to RT and then NCS (12.8 g, 95.86 mmol) was added. The resulting solution was stirred for 1 h at RT. The solids were filtered out. The resulting filtrate was concentrated under vacuum. This resulted in 30 g (crude, 79%) of the title compound as brown oil. The crude product was used in the next step.

Step 4: N-tert-butyl-2-(1-(tert-butyldiphenylsilyloxy)ethyl)thiazole -5-sulfonamide

Into a 500-mL round-bottom flask was placed 2-(1-(tert-butyldiphenylsilyloxy)ethyl)thiazole-5- sulfonyl chloride (crude, 30 g, 64.37 mmol), DCM (200 mL), TEA (13 g, 128.47 mmol). This was followed by the addition of 2-methylpropan-2-amine (5.6 g, 76.6 mmol) dropwise with stirring at 0 ^o C. The resulting solution was stirred for 2 h at RT and then was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with a gradient of ethyl acetate/petroleum ether (1:30 to 1:20). This resulted in 25 g (61% over two steps) of the title compound as brown oil. MS-ESI: 503.2 (M+1).

Step 5: N-tert-butyl-2-(1-hydroxyethyl)thiazole-5-sulfonamide

Into a 500-mL round-bottom flask was placed N-tert-butyl-2-(1-(tert- butyldiphenylsilyloxy)ethyl)thiazole- 5-sulfonamide (25 g, 49.7 mmol), THF (200 mL), TBAF (30 g, 99.67 mmol). The resulting solution was stirred for 2 h at RT and then was diluted with 200 mL of water. The resulting solution was extracted with 3x200 mL of DCM. The organic layers were combined and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with a gradient of ethyl acetate/petroleum ether (1:20 to 1:10). This resulted in 12 g (91%) of the title compound as light yellow oil. MS-ESI: 265.1 (M+1).

Step 6: 2-Acetyl-N-tert-butylthiazole-5-sulfonamide

Into a 500-mL round-bottom flask was placed N-tert-butyl-2-(1-hydroxyethyl)thiazole-5- sulfonamide (12 g, 45.4 mmol), DCM (200 mL). To this solution was added Dess-Martin reagent (20 g, 47.2 mmol) in portions at RT. The resulting solution was stirred for 2 h at RT and then was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with a gradient of ethyl acetate/petroleum ether (1:20 to 1:10). This resulted in 9 g (76%) of the title compound as a light yellow solid. MS-ESI: 263.0 (M+1).

Step 7: 2-Acetylthiazole-5-sulfonamide

Into a 100-mL round-bottom flask was placed 2-acetyl-N-tert-butylthiazole-5-sulfonamide (7 g,

26.7 mmol), TFA (20 mL). The resulting solution was stirred for 14 h at 70 ^o C and then was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with a gradient of ethyl acetate/petroleum ether (1:5 to 1:3). This resulted in 5 g (91%) of the title compound as a yellow solid. MS-ESI: 207.0 (M+1).

Step 8: 2-(2-Hydroxypropan-2-yl)thiazole-5-sulfonamide

Into a 500-mL 3-necked round-bottom flask purged with and maintained under nitrogen was placed 2-acetylthiazole-5-sulfonamide (5 g, 24.3 mmol), THF (100 mL). This was followed by the addition of MeMgBr (3 M in THF, 8.1 mL, 24.3 mmol) dropwise with stirring at 0 ^o C. The resulting solution was stirred for 14 h at RT and then was quenched by the addition of 100 mL of NH4Cl

(sat.). The resulting solution was extracted with 2x150 mL of DCM. The organic layers were combined and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with a gradient of ethyl acetate/petroleum ether (1:5 to 1:3). This resulted in 2.9 g (54%) of the title compound as a light yellow solid. MS-ESI: 223.0 (M+1).

Steps 9-10 used similar procedures for converting compound 14 to Intermediate 1 shown in

Scheme 6 to afford Intermediate 27 from compound 80. MS-ESI: 336.1 (M+1).

Sc

O OH

( N'-(tert-butyldime thylsilyl)-2-(2-hydroxypropan-2-yl)thiazole-5-sulfonimidamid e

Step 1: 2-(2-Methyl-1,3-dioxolan-2-yl)thiazole

Into a 500-mL round-bottom flask was placed a solution of 1-(thiazol-2-yl)ethanone (20 g, 157.0 mmol) in toluene (300 mL) and ethane-1,2-diol (19.5 g, 314 mmol). To the solution was added TsOH (2.7 g, 15.7 mmol). The resulting solution was refluxed overnight and water was separated from the solution during the reflux. The resulting solution was diluted with 200 mL of water and extracted with 2x100 mL of ethyl acetate. The organic layers were combined, dried over anhydrous Na2SO4, and then concentrated under vacuum. This resulted in 26.6 g (99%) of the title compound as light yellow oil. MS-ESI: 172.0 (M+1).

Step 2: 2-(2-Methyl-1,3-dioxolan-2-yl)thiazole-5-sulfonamide

Into a 500-mL 3-necked round-bottom flask purged with and maintained under nitrogen was placed a solution of 2-(2-methyl-1,3-dioxolan-2-yl)thiazole (14 g, 81.6 mmol) in THF (200 mL). This was followed by the addition of n-BuLi (2.5 M in THF, 35.2 mL, 88.0 mmol) dropwise with stirring at -78 ^o C. The resulting solution was stirred for 0.5 h at -78 ^o C and then SO2 was introduced into the above reaction mixture. The reaction was slowly warmed to RT and then NCS (12.8 g, 95.86 mmol) was added. The resulting solution was stirred for 1 h at RT. The solids were filtered out. The resulting filtrate was concentrated under vacuum and then was diluted in DCM (160 mL). To the above was added a saturated solution of ammonia in DCM (300 mL). The resulting solution was stirred for 3 h at RT and then was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with a gradient of ethyl acetate/petroleum ether (1:20 to 1:5). This resulted in 12.5 g (61%) of the title compound as a yellow solid. MS-ESI: 251.0 (M+1).

Step 3: 2-Acetylthiazole-5-sulfonamide

Into a 250-mL round-bottom flask was placed a solution of 2-(2-methyl-1,3-dioxolan-2- yl)thiazole-5-sulfonamide (12.5 g, 50.0 mmol) in THF (125 mL). To the above was added aq. HCl (4 N, 50.0 mL). The resulting solution was stirred for 6 h at 70 ^o C. The resulting solution was diluted with 100 mL of water and extracted with 2x200 mL of ethyl acetate. The organic layers were combined, dried over anhydrous Na2SO4, then concentrated under vacuum. The residue was applied onto a silica gel column and eluted with a gradient of ethyl acetate/petroleum ether (1:2 to 1:1). This resulted in 9.3 g (90%) of the title compound as a yellow solid. MS-ESI: 207.0 (M+1). Steps 4-6 used the same procedures for converting compound 19 to Intermediate 2 shown in Scheme 7B to afford Intermediate 27 from compound 84. MS-ESI: 336.1 (M+1).

N'-(tert-butoxycarbonyl)-2-(2-hydroxypropan-2-yl)thiazole-5- sulfonimidamide

Step 1: 2-(Thiazol-2-yl)propan-2-ol

Into a 10-L 4-necked round-bottom flask purged with and maintained under nitrogen was placed a solution of 1-(thiazol-2-yl)ethanone (200 g, 1.6 mol) in THF (4 L). This was followed by the addition of MeMgBr (3 M in THF, 942 mL) dropwise with stirring at 0°C. The mixture was stirred at 0°C for 2 h. After warmed the mixture to RT, the solution was stirred for an additional 16 h. Then the reaction was quenched by the addition of 3 L of NH ₄ Cl (sat.). The resulting solution was extracted with 3x1 L of ethyl acetate. The organic layers were combined, dried over anhydrous Na ₂ SO ₄ , then concentrated under vacuum. The residue was applied onto a silica gel column and eluted with a gradient of ethyl acetate/petroleum ether (1:3 to 1:1). This resulted in 210 g (93%) of the title compound as a brown oil. MS-ESI: 144.0 (M+1).

Step 2: Lithium 2-(2-hydroxypropan-2-yl)thiazole-5-sulfinate

Into a 10-L 4-necked round-bottom flask purged with and maintained under nitrogen was placed a solution of 2-(thiazol-2-yl)propan-2-ol (50 g, 349.0 mmol) in THF (1.5 L). This was followed by the addition of n-BuLi (2.5 M in hexane, 350 mL) dropwise with stirring at -78°C. The mixture was stirred at -78°C for 1 h. Then SO ₂ was bubbled into the mixture for 15 min below -30°C. The mixture was stirred for an additional 1 h at RT and then was concentrated under vacuum. This resulted in 87 g (crude) of the title compound as a light yellow solid. The crude product was used directly in the next step. Step 3: Methyl 2-(2-hydroxypropan-2-yl)thiazole-5-sulfinate

Into a 2-L 3-necked round-bottom flask, lithium 2-(2-hydroxypropan-2-yl)thiazole-5-sulfinate (87 g, crude) was dissolved in anhydrous MeOH (500 mL). Then SOCl2 (43 g, 360 mmol) was added to the mixture dropwise with stirring at 0 ^o C. The mixture was stirred overnight at RT and then was concentrated under vacuum. The residue was diluted with 500 mL of ethyl acetate. The resulting solution was washed with 2x200 mL of water and 2x200 mL of brine. The solution was dried over anhydrous Na2SO4, then concentrated under vacuum. This resulted in 72 g (crude) of the title compound as light yellow oil. The crude product was used directly in the next step.

Step 4: 2-(2-Hydroxypropan-2-yl)thiazole-5-sulfinamide

Into a 10-L 4-necked round-bottom flask purged with and maintained under nitrogen was placed a solution of methyl 2-(2-hydroxypropan-2-yl)thiazole-5-sulfinate (72 g, 326 mmol) in THF (500 mL). Then to the above NH3 (0.5 M in THF, 2.0 L) was added. After cooling to -78°C, LiHMDS (1 M in THF, 2.0 L) was added to the mixture dropwise with stirring. Then the mixture was stirred at -78°C for 2 h. The reaction was quenched by the addition of 500 mL of NH4Cl (sat.). The resulting solution was extracted with 3x300 mL of ethyl acetate. The organic layers were combined, dried over anhydrous Na2SO4, then concentrated under vacuum. This resulted in 32 g (crude) of the title compound as brown oil. The crude product was used directly in the next step. Step 5: Tert-butyl 2-(2-hydroxypropan-2-yl)thiazol-5-ylsulfinylcarbamate

Into a 1-L 3-necked round-bottom flask purged with and maintained under nitrogen was placed a solution of 2-(2-hydroxypropan-2-yl)thiazole-5-sulfinamide (32 g, crude) in THF (300 mL). This was followed by the addition of LDA (2 M in THF, 116 mL) dropwise with string at 0°C. The mixture was stirred at 0°C for 1 h, then (Boc)2O (33.8 g, 155 mmol) was added in portions at 0°C. The mixture was warmed to RT and stirred for an additional 2 h. The reaction was quenched with 200 mL of ice-water (200 mL), and the pH value of the solution was adjusted to 6 with HCOOH. The resulting solution was extracted with 3x200 mL of ethyl acetate. The organic layers were combined, dried over anhydrous Na2SO4, then concentrated under vacuum. The residue was applied onto a silica gel column and eluted with a gradient of ethyl acetate/petroleum ether (1:2 to 1:1). This resulted in 19 g (18%, 4 steps) of the title compound as a white solid.

Step 6: N-(tert-butyldimethylsilyl)-2-(2-hydroxypropan-2-yl)thiazole -5-sulfonimidamide Into a 1-L 3-necked round-bottom flask purged with and maintained under nitrogen, tert-butyl 2- (2-hydroxypropan-2-yl)thiazol-5-ylsulfinylcarbamate (19 g, 62 mmol) was dissolved in fresh distilled ACN (200 mL). Then to the above solution was added NCS (9.8 g, 74 mmol) in portions. The mixture was stirred for 1 h at RT and then NH3 was bubbled in the mixture for 15 min. The mixture was stirred at RT for 2 h and then was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with a gradient of ethyl acetate/petroleum ether (1:2 to 1:1). This resulted in 13 g (65%) of the title compound as a white solid.

4-(2-Hydroxypropan-2-yl)-N'-methylthiophene-2-sulfonimidamid e

Step 1 used the procedures for converting compound 15 to Intermediate 1 shown in Scheme 6 to afford compound 93 by substituting ammonia with methylamine. MS-ESI: 349.1 (M+1).

Step 2: 4-(2-Hydroxypropan-2-yl)-N'-methylthiophene-2-sulfonimidamid e

Into a 25-mL round-bottom flask purged with under nitrogen was placed a solution of N'-(tert- butyldimethylsilyl)-4-(2-hydroxypropan-2-yl)-N-methylthiophe ne-2-sulfonimidamide (500 mg, 1.43 mmol) in DCM (10 mL). To the solution was added HF/Py (70% wt., 200 mg). The resulting solution was stirred for 2 h at RT. The pH value of the solution was adjusted to 8 with aq. Na ₂ CO ₃ (5 % wt.). The resulting solution was extracted with 3x10 mL of ethyl acetate. The organic layers were combined, dried over anhydrous Na ₂ SO ₄ , then concentrated under vacuum. This resulted in 300 mg (89%) of the title compound as brown oil. MS-ESI: 235.0 (M+1).

Schemes for the preparation of isocyanate intermediates 30-58:

Schemes below illustrate the synthesis of isocyanates.

Step 1: 4-Fluoro-2,6-bis(prop-1-en-2-yl)aniline

Into a 500-mL round-bottom flask purged with and maintained under nitrogen was placed 2,6- dibromo-4-fluoroaniline (15 g, 55.8 mmol), dioxane (150 mL), water (15 mL), Cs2CO3 (55 g, 169 mmol), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (25 g, 149 mmol), and Pd(dppf)Cl2 (4 g, 5.47 mmol). The resulting solution was stirred for 15 h at 100 ^o C and then was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with a gradient of ethyl acetate/petroleum ether (1: 10 to 1:8). This resulted in 9.2 g (86%) of the title compound as brown oil. MS-ESI: 192.1 (M+1).

Step 2: 4-Fluoro-2,6-bis(propan-2-yl)aniline

Into a 500-mL round-bottom flask was placed 4-fluoro-2,6-bis(prop-1-en-2-yl)aniline (9.2 g, 48.1 mmol), and MeOH (200 mL). Then Pd/C (10% wt., 900 mg) was added. The flask was evacuated and flushed three times with hydrogen. The resulting solution was stirred for 12 h at RT under an atmosphere of hydrogen. The solids were filtered out. The resulting filtrate was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with a gradient of ethyl acetate/petroleum ether (1:10 to 1:8). This resulted in 7.2 g (77%) of the title compound as brown oil. MS-ESI: 196.1 (M+1).

Step 1: 4-Amino-3,5-dibromo-2-fluorobenzonitrile

Into a 1-L round-bottom flask was placed 4-amino-2-fluorobenzonitrile (25 g, 184 mmol), ACN (500 mL), and NBS (81.7 g, 459 mmol). The resulting solution was stirred overnight at 75 ^o C and then was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with a gradient of ethyl acetate/petroleum ether (1:100 to 1:98). This resulted in 50 g (93%) of the title compound as brown oil. MS-ESI: 294.9/292.9/296.9 (M+1).

Steps 2-3 used similar procedures for converting compound 94 to Intermediate 30 shown in Scheme 18 to afford Intermediate 31 from compound 97. MS-ESI: 221.1 (M+1).

4-(Difluoromethoxy)-2,6-diisopropylbenzenamine

Step 1: 2,6-Dibromo-4-(difluoromethoxy)benzenamine

Into a 100-mL round-bottom flask was placed 4-(difluoromethoxy)benzenamine (3 g, 18.9 mmol), ACN (30 mL), and NBS (7.7 g, 43.3 mmol). The resulting solution was stirred overnight at RT and then was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with a gradient of ethyl acetate/petroleum ether (1:30 to 1:20). This resulted in 2.9 g (48%) of the title compound as brown oil. MS-ESI: 317.9/315.9/319.9 (M+1).

Steps 2-3 used similar procedures for converting compound 94 to Intermediate 30 shown in Scheme 18 to afford Intermediate 32 from compound 100”. MS-ESI: 244.1 (M+1).

4-(Difluoromethoxy)-2-ethyl-6-isopropylbenzenamine

Step 1: 2-Bromo-4-(difluoromethoxy)benzenamine

Into a 250-mL round-bottom flask purged with and maintained under nitrogen was placed 4- (difluoromethoxy)benzenamine (10 g, 62.8 mmol), ACN (100 mL), and NBS (5.59 g, 31.4 mmol). The resulting solution was stirred for 1 h RT and then was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with a gradient of ethyl acetate/petroleum ether (1:20 to 1:10). This resulted in 7.9 g (53%) of the title compound as red oil. MS-ESI: 238.0/240.0 (M+1).

Step 2: 4-(Difluoromethoxy)-2-(prop-1-en-2-yl)benzenamine

Into a 250-mL round-bottom flask purged with and maintained under nitrogen was placed 2- bromo-4-(difluoromethoxy)benzenamine (7.9 g, 33.2 mmol), dioxane (100 mL), water (10 mL), Cs2CO3 (32.46 g, 99.63 mmol), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (8.36 g, 49.8 mmol), and Pd(dppf)Cl2 (1.21 g, 1.65 mmol). The resulting solution was stirred overnight at 90 ^o C. The solids were filtered out. The filtrate was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with a gradient of ethyl acetate/petroleum ether (1:30 to 1:20). This resulted in 5.3 g (80%) of the title compound as a yellow solid. MS-ESI: 200.1 (M+1).

Step 3: 4-(Difluoromethoxy)-2-isopropylbenzenamine

Into a 250-mL round-bottom flask was placed 4-(difluoromethoxy)-2-(prop-1-en-2- yl)benzenamine (5.3 g, 26.6 mmol) in MeOH (100 mL). Then Pd/C (10% wt., 500 mg) was added. The flask was evacuated and filled three times with hydrogen. The resulting solution was stirred for 3 h at RT under hydrogen. The solids were filtered out. The resulting filtrate was concentrated under vacuum. This resulted in 5.15 g (96%) of the title compound as red oil. MS-ESI: 202.1 (M+1).

Step 4: 2-Bromo-4-(difluoromethoxy)-6-isopropylbenzenamine

Into a 500-mL round-bottom flask was placed 4-(difluoromethoxy)-2-isopropylbenzenamine (5.15 g, 25.6 mmol), CHCl3 (200 mL), Fe turnings (500 mg), and Br2 (4.45 g, 27.9 mmol). The resulting mixture was stirred overnight at 70 ^o C and then was quenched by the addition of 200 mL of water. The resulting solution was extracted with 3x100 mL of DCM and the organic layers combined and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with a gradient of ethyl acetate/petroleum ether (1:30 to 1:20). This resulted in 6.98 g (97%) of the title compound as dark red oil. MS-ESI: 280.0/282.0 (M+1).

Step 5: 4-(Difluoromethoxy)-2-isopropyl-6-vinylbenzenamine

Into a 250-mL round-bottom flask purged with and maintained under nitrogen was placed 2- bromo-4-(difluoromethoxy)-6-isopropylbenzenamine (3 g, 10.7 mmol), dioxane (100 mL), water (10 mL), Cs2CO3 (10.47 g, 32.13 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (2.47 g, 16.0 mmol), and Pd(dppf)Cl2 (784 mg, 1.07 mmol). The resulting solution was stirred overnight at 90 ^o C and then was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with a gradient of ethyl acetate/petroleum ether (1:30 to 1:20). This resulted in 2.3 g (94%) of the title compound as dark green oil. MS-ESI: 228.1 (M+1).

Step 6: 4-(Difluoromethoxy)-2-ethyl-6-isopropylbenzenamine

Into a 250-mL round-bottom flask was placed 4-(difluoromethoxy)-2-isopropyl-6- vinylbenzenamine (2.3 g, 10.1 mmol), MeOH (100 mL). Then Pd/C (10% wt., 200 mg) was added. The flask was evacuated and filled three times with hydrogen. The resulting solution was stirred overnight at RT under hydrogen. The solids were filtered out. The filtrate was concentrated under vacuum. This resulted in 2.2 g (95%) of the title compound as red oil. MS-ESI: 230.1 (M+1). Table 7. The Intermediate 34 in the following Table was prepared from compound 105’’ using similar procedure as shown in Scheme 21 above for converting compound 105’’ to 106’’. Int t s ] ⁺ Int 1

Intermediate 35

4-Amino-5-cyclopropyl-2-fluoro-3-isopropylbenzonitrile

Step 1: 4-Amino-5-bromo-2-fluorobenzonitrile

Into a 250-mL round-bottom flask was placed a solution of 4-amino-2-fluorobenzonitrile (9 g, 66.1 mmol) in ACN (120 mL). Then NBS (12.4 g, 69.7 mmol) was added. The resulting solution was stirred overnight at 80 ^o C and then was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with a gradient of ethyl acetate/petroleum ether (1:20 to 1:10). This resulted in 10.9 g (77%) of the title compound as a yellow solid. MS-ESI: 215.0/217.0 (M+1). ¹ H NMR (300 MHz, DMSO-d6) d 7.89 (d, J = 6.0 Hz, 1H), 6.69 (br s, 2H), 6.63 (d, J = 12.0 Hz, 1H). Step 2: 4-Amino-5-cyclopropyl-2-fluorobenzonitrile

Into a 250-mL round-bottom flask purged with and maintained under nitrogen was placed a solution of 4-amino-5-bromo-2-fluorobenzonitrile (6.37 g, 29.6 mmol) in dioxane (70 mL) and water (10 mL). To the solution were added Cs2CO3 (9.7 g, 29.8 mmol), cyclopropylboronic acid (3.8 g, 44.2 mmol) and Pd(dppf)Cl2 (1.08 g, 1.48 mmol). The resulting solution was stirred overnight at 90 ^o C and then was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with a gradient of ethyl acetate/petroleum ether (1:10 to 1:5). This resulted in 5.03 g (96%) of the title compound as a yellow solid. MS-ESI: 177.1 (M+1).

Step 3: 4-Amino-3-bromo-5-cyclopropyl-2-fluorobenzonitrile

Into a 250-mL round-bottom flask was placed a solution of 4-amino-5-cyclopropyl-2- fluorobenzonitrile (5.03 g, 28.7 mmol) in ACN (50 mL). To the solution was added NBS (5.6 g, 31.5 mmol). The resulting solution was stirred overnight at 80 ^o C and then was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with a gradient of ethyl acetate/petroleum ether (1:10 to 1:5). This resulted in 6.972 g (96%) of the title compound as a yellow solid. MS-ESI: 255.0/257.0 (M+1).

Step 4: 4-Amino-5-cyclopropyl-2-fluoro-3-(prop-1-en-2-yl)benzonitril e

Into a 250-mL round-bottom flask purged with and maintained under nitrogen was placed a solution of 4-amino-3-bromo-5-cyclopropyl-2-fluorobenzonitrile (6.972 g, 27.33 mmol) in dioxane (120 mL) and water (20 mL). To the solution were added 4,4,5,5-tetramethyl-2-(prop-1- en-2-yl)-1,3,2-dioxaborolane (6.9 g, 41.00 mmol), Cs2CO3 (13.4 g, 41.00 mmol) and Pd(dppf)Cl2 (0.4 g, 0.55 mmol). The resulting solution was stirred overnight at 80 ^o C and then was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with a gradient of ethyl acetate/petroleum ether (1:10 to 1:5). This resulted in 4.73 g (80%) of the title compound as a yellow solid. MS-ESI: 217.1 (M+1).

Step 5: 4-Amino-5-cyclopropyl-2-fluoro-3-isopropylbenzonitrile

Into a 250-mL round-bottom flask was placed a solution of 4-amino-5-cyclopropyl-2-fluoro-3- (prop-1-en-2-yl)benzonitrile (4.73 g, 21.97 mmol), MeOH (100 mL). To the solution was added AcOH (0.5 mL). Then Pd/C (10% wt., 500 mg) was added. The flask was evacuated and filled three times with hydrogen. The resulting solution was stirred for 4 h at 40 ^o C under an atmosphere of hydrogen. The solids were filtered out. The filtrate was concentrated under vacuum. This resulted in 4.71 g (99%) of the title compound as a light yellow solid. MS-ESI: 219.1 (M+1). Scheme 23:

8-Fluoro-1,2,3,5,6,7-hexahydro-s-indacen-4-amine

Step 1: 3-Chloro-1-(2,3-dihydro-1H-inden-5-yl)propan-1-one

Into a 3-L round-bottom flask was placed a solution of AlCl3 (111 g, 834 mmol) in DCM (1200 mL). This was followed by the addition of a solution of 2,3-dihydro-1H-indene (90 g, 762 mmol) and 3-chloropropanoyl chloride (96.3 g, 759 mmol) in DCM (300 mL) dropwise with stirring at - 10 ^o C in 30 min. The resulting solution was stirred for 16 h at RT. Then the reaction mixture was added dropwise to cold HCl (3 N, 1200 mL) over 45 min at -10 ^o C. The resulting solution was extracted with 3x600 mL of DCM and the organic layers were combined, dried over anhydrous Na2SO4, then concentrated under vacuum. This resulted in 160.5 g (crude) of the title compound as a yellow solid. The crude product was used in the next step.

Step 2: 1,2,3,5,6,7-Hexahydro-s-indacen-1-one

Into a 1-L round-bottom flask was placed a solution of 3-chloro-1-(2,3-dihydro-1H-inden-5- yl)propan-1-one (160.5 g, 759 mmol) in conc. H2SO4 (900 mL). The resulting solution was stirred for 16 h at 55 ^o C and then was quenched by adding the reaction mixture carefully to 4500 mL of water/ice. The solids were collected by filtration and dried over infrared lamp for 24 h. The crude mixture was purified by chromatography and eluted with ethyl acetate/petroleum ether (1:100). This resulted in 10 g (7.6%) of 1,6,7,8-tetrahydro-as-indacen-3(2H)–one (compound 113”a) and 112.2 g (85%) of the title compound (compound 113”) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) d 7.44 (s, 1H), 7.39 (s, 1H), 3.13– 2.79 (m, 8H), 2.70– 2.55 (m, 2H), 2.20– 1.90 (m, 2H). ¹ H NMR (400 MHz, DMSO-d6) d 7.49 (d, J = 7.7 Hz, 1H), 7.31 (d, J = 7.7 Hz, 1H), 3.19– 2.98 (m, 4H), 2.93– 2.80 (m, 3H), 2.68– 2.54 (m, 2H), 2.15– 1.95 (m, 2H).

Step 3: 4-nitro-2,3,6,7-tetrahydro-s-indacen-1(5H)-one (114) (Major) and 8-nitro-2,3,6,7- tetrahydro-s-indacen-1(5H)-one (115) (Minor)

Into a 1-L round-bottom flask was placed a solution of 1,2,3,5,6,7-hexahydro-s-indacen-1-one (80 g, 464.5 mmol) in H2SO4 (500 mL). Then HNO3 (58.5 g, 929 mmol) was added dropwise over 1h at 0 ^o C. The resulting solution was stirred for 1 hr at 0 ^o C. The reaction mixture was slowly added to a mixture of water/ice (1000 mL) and DCM (500 mL) with ice bath cooling. The organic layer was collected, dried over Na2SO4 and concentrated under vacuum. This resulted in 90 g (90%) of the mixture of 4-nitro-2,3,6,7-hexahydro-s-indacen-1-one and 8-nitro-2,3,6,7-tetrahydro-s- indacen-1(5H)-one as a yellow solid.

Step 4: 1,2,3,5,6,7-hexahydro-s-indacen-4-amine

Into a 1-L round-bottom flask was placed a solution of the mixture of 4-nitro-1,2,3,5,6,7- hexahydro-s-indacen-1-one and 8-nitro-2,3,6,7-tetrahydro-s-indacen-1(5H)-one (21.7 g, 100 mmol) in MeOH (300 mL). To the solution was added MSA (11.5 g, 120 mmol). Then Pd(OH)2/C (20% wt, 5.5 g) was added. The flask was evacuated and filled three times with hydrogen. The resulting mixture was stirred for 16 h at RT under hydrogen (50 psi). The solids were filtered out and washed with methanol. The methanol filtrate and wash was diluted with water (500 mL) and the pH was adjusted to 10.6 with 2N NaOH. The resulting slurry was filtered and the crude solids were recrystallized from methanol/water (9:1) with heating. This resulted in 13.7 g (79%) of the title compound as an off-white solid.

Step 5: 8-Nitro-1,2,3,5,6,7-hexahydro-s-indacen-4-amine

Into a 500-mL round-bottom flask was placed 1,2,3,5,6,7-hexahydro-s-indacen-4-amine (8 g, 46.2 mmol), EtOH (200 mL), and 2,3,5,6-tetrabromo-4-methyl-4-nitrocyclohexa-2,5-dienone (21.6 g, 46.1 mmol). The resulting solution was stirred for 12 h at RT and then was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with a gradient of ethyl acetate/petroleum ether (1:50 to 1:30). This resulted in 5 g (50%) of the title compound as a yellow solid. MS-ESI: 219.1 (M+1).

Step 6: 4-Fluoro-8-nitro-1,2,3,5,6,7-hexahydro-s-indacene

Into a 100-mL round-bottom flask was placed 8-nitro-1,2,3,5,6,7-hexahydro-s-indacen-4-amine (5 g, 22.9 mmol) and HF/Py (70% wt., 20 mL). This was followed by the addition of 3-methylbutyl nitrite (3 g, 25.6 mmol) dropwise with stirring at 0 ^o C. The resulting solution was stirred for 2 h at RT and then was diluted with 50 mL of water. The resulting solution was extracted with 3x50 mL of DCM. The organic layers were combined and dried over anhydrous Na2SO4, then concentrated under vacuum. This resulted in 4 g (crude, 79%) of the title compound as brown oil.

Step 7: 8-Fluoro-1,2,3,5,6,7-hexahydro-s-indacen-4-amine

Into a 100-mL round-bottom flask was placed 4-fluoro-8-nitro-1,2,3,5,6,7-hexahydro-s-indacene (4 g, 18.1 mmol) in MeOH (50 mL). Then Pd/C (10% wt., 0.5 g) was added. The flask was evacuated and filled three times with hydrogen. The resulting mixture was stirred for 12 h at RT under an atmosphere of hydrogen. The solids were filtered out and the filtrate was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with a gradient of ethyl acetate/petroleum ether (1:10 to 1:5). This resulted in 2 g (46%, 2 steps) of the title compound as a white solid. MS-ESI: 192.1 (M+1). Scheme 24:

Intermediate 37

1 _{-methyl-1,2,3,5,6,7-hexahydro-s-indacen-4-amine} Step 1: 4-nitro-2,3,6,7-tetrahydro-s-indacen-1(5H)-one

Into a 1-L round-bottom flask was placed a solution of 1,2,3,5,6,7-hexahydro-s-indacen-1-one (40 g, 232 mmol) in H ₂ SO ₄ (250 mL). Then HNO ₃ (29 g, 464 mmol) was added dropwise over 1 h at 0 ^o C. The resulting solution was stirred for 1 hr at 0 ^o C. The reaction mixture was slowly added to a mixture of water/ice (500 mL) and DCM (250 mL) with ice bath cooling. The organic layer was collected, dried over anhydrous Na ₂ SO ₄ and concentrated under vacuum. The crude product was purified by silica gel column with a gradient of ethyl acetate and petroleum ether (1:50 to 1:1). This resulted in minor product 5 g (10%) of the title compound and major product 30 g (60%) of 8-nitro-2,3,6,7-tetrahydro-s-indacen-1(5H)-one both as a yellow solid.

Step 2: 1-methylene-4-nitro-1,2,3,5,6,7-hexahydro-s-indacene

Into a 250-mL round-bottom flask was placed a solution of methyltriphenylphosphanium bromide (16.4 g, 46.04 mmol) and t-BuOK (5.2 g, 46.0 mmol) in THF (150 mL) at 0 ^o C. The resulting solution was stirred for 30 min at 0 ^o C. Then the solution of 4-nitro-1,2,3,5,6,7-hexahydro-s- indacen-1-one (5 g, 23.0 mmol) in THF (10 mL) was added dropwise to the reaction mixture at 0 ^o C. The resulting solution was stirred overnight at RT. The resulting mixture was concentrated. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:10). This resulted in 2.6 g (52%) of the title compound as a green solid.

Step 3: 1-methyl-1,2,3,5,6,7-hexahydro-s-indacen-4-amine

Into a 100-mL round-bottom flask was placed a solution of 1-methylidene-4-nitro-1,2,3,5,6,7- hexahydro-s-indacene (2.6 g, 12.1 mmol) in MeOH (20 mL), Pd/C (10% wt, 300 mg) was added. The flask was evacuated and filled three times with hydrogen. then H ₂ (g) was introduced in with a balloon. The resulting solution was stirred for 2 h at RT. The Pd/C catalyst was filtered out. The filtrate was concentrated. This resulted in 2 g of the title compound as red oil. Table 8. Intermediate 38 in the following Table was prepared from Compound 114’’ using similar procedure as shown in Scheme 24 above for converting compound 115’’ to intermediate 37.

Scheme 25:

8-Chloro-1,2,3,5,6,7-hexahydro-s-indacen-4-amine

Step 1: 8-Chloro-1,2,3,5,6,7-hexahydro-s-indacen-4-amine

Into a 50-mL round-bottom flask was placed a solution of 1,2,3,5,6,7-hexahydro-s-indacen-4- amine (1.73 g, 9.99 mmol) in DMF (10 mL). To the solution was added NCS (1.47 g, 11.0 mmol). The resulting solution was stirred overnight at RT and then was diluted with 30 mL of DCM. The resulting mixture was washed with 3x10 mL of water and the organic layer was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with a gradient of ethyl acetate/petroleum ether (1:20 to 1:10). This resulted in 1.88 g (91%) of the title compound as a yellow solid. MS-ESI: 208.1/210.1 (M+1). Scheme 26:

8-Amino-1,2,3,5,6,7-hexahydro-s-indacene-4-carbonitrile

Step 1: 8-Bromo-1,2,3,5,6,7-hexahydro-s-indacen-4-amine

Into a 100-mL round-bottom flask was placed a solution of 1,2,3,5,6,7-hexahydro-s-indacen-4- amine (2.6 g, 15.0 mmol) in DMF (30 mL). To the solution was added NBS (2.9 g, 16.3 mmol). The resulting solution was stirred for 12 h at RT and then was diluted with 80 mL of ethyl acetate. The resulting mixture was washed with 3x20 mL of water and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with a gradient of ethyl acetate/petroleum ether (1:30 to 1:20). This resulted in 3.0 g (79%) of the title compound as a brown solid. MS-ESI: 252.0, 254.0 (M+1).

Step 2: 8-Amino-1,2,3,5,6,7-hexahydro-s-indacene-4-carbonitrile

Into a 50-mL round-bottom flask purged with and maintained under nitrogen was placed a solution of 8-bromo-1,2,3,5,6,7-hexahydro-s-indacen-4-amine (725 mg, 2.88 mmol) in DMF (10 mL). To the solution were added t-BuOK (330 mg, 2.90 mmol), CuCN (386 mg, 4.32 mmol), and Pd(dppf)Cl2 (424 mg, 0.58 mmol). The resulting solution was stirred for 12 h at 120 ^o C and then was diluted with 20 mL of water. The resulting solution was extracted with 3x20 mL ethyl acetate. The organic layers were combined, dried over anhydrous Na2SO4, then concentrated under vacuum. The residue was applied onto a silica gel column and eluted with a gradient of ethyl acetate/petroleum ether (1:60 to 1:40). This resulted in 192 mg (34%) of the title compound as a yellow solid. MS-ESI: 199.1 (M+1). Scheme 27:

m no , sopropy enzon r e

Step 1: 4-Amino-3,5-diisopropylbenzonitrile

Into a 100-mL round-bottom flask purged with and maintained under nitrogen was placed a solution of 4-bromo-2,6-diisopropylbenzenamine (5.1 g, 19.9 mmol) in DMF (30 mL). To the solution were added Zn(CN) ₂ (2.80 g, 23.9 mmol), Pd(dppf)Cl ₂ (732 mg, 1.00 mmol) and t-BuOK

(3.36 g, 29.9 mmol). The resulting mixture was stirred for 16 h at 120 ^o C and then was diluted with

30 mL of water. The solution was extracted with 3x30 mL of ethyl acetate and the combined organic layers were concentrated under vacuum. The residue was applied onto a silica gel column and eluted with a gradiente of ethyl acetate/petroleum ether (1:30 to 1:20). This resulted in 3.2 g

(80%) of the title compound as a yellow solid. MS-ESI: 203.1 (M+1). Sc

OH

8-(Difluoromethoxy)-1, hexahydro-s-indacen-4-amine

Step 1: 1,2,3,5,6,7-Hexahydro-s-indacene

Into a 1-L round-bottom flask was placed a solution of 1,2,3,5,6,7-hexahydro-s-indacen-1-one (37.2 g, 216 mmol) and MSA (42 g, 437.5 mmol) in MeOH (300 mL). Then Pd(OH)2/C (20% wt, 8 g) was added. The flask was evacuated and filled three times with hydrogen. The resulting solution was stirred for 16 h at RT under an atmosphere of hydrogen. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with a gradient of ethyl acetate/petroleum ether (1:150 to 1:100). This resulted in 27.1 g (79%) of the title compound as a white solid.

Step 2: 4-Bromo-1,2,3,5,6,7-hexahydro-s-indacene

Into a 500-mL 3-necked round-bottom flask purged with and maintained under nitrogen was placed a solution of 1,2,3,5,6,7-hexahydro-s-indacene (15 g, 94.8 mmol) in CCl4 (200 mL). Then I2 (1.2 g, 4.72 mmol) was added. This was followed by the addition of a solution of Br2 (16 g, 100 mmol) in CCl4 (50 mL) dropwise with stirring at 0 ^o C in 10 min. The resulting solution was stirred for 2 h at 0 ^o C. The reaction was then quenched by the addition of 150 mL of NH4Cl (sat.). The resulting solution was extracted with 3x150 mL of DCM and the combined organic layers were dried over anhydrous Na2SO4 and concentrated under vacuum. The crude product was purified by silica gel column with a gradient of ethyl acetate/hexane (1:500 to 1:100). This resulted in 19 g (85%) of the title compound as yellow oil. ¹ H NMR (300 MHz, DMSO-d6) d 7.02 (s, 1H), 2.95- 2.75 (m, 8H), 2.03-2.01 (m, 4H)

Step 3: 1,2,3,5,6,7-Hexahydro-s-indacen-4-ol

Into a 500-mL 3-necked round-bottom flask purged with and maintained under nitrogen was placed a solution of 4-bromo-1,2,3,5,6,7-hexahydro-s-indacene (5 g, 21.08 mmol) in THF (150 mL). This was followed by the addition of n-BuLi (2.5 M in hexane, 10 mL) dropwise with stirring at -78 ^o C. The resulting solution was stirred for 30 min at -78 ^o C. Then to the above was added trimethyl borate (2.6 g, 25.30 mmol) dropwise with stirring at -78 ^o C. The reaction was warmed to RT slowly and then was stirred for 1 h at RT. Then to the mixture was added AcOH (2.0 mL, 33.20 mmol) and H2O2 (1.0 mL, 28.88 mmol) dropwise with stirring at RT. The resulting solution was stirred for 2 h at RT and then was quenched by the addition of 200 mL of NH4Cl (sat.). The resulting solution was extracted with 3x200 mL of DCM. The organic layers were combined and dried over anhydrous Na2SO4, then concentrated under vacuum. The residue was applied onto a silica gel column and eluted with a gradient of ethyl acetate/petroleum ether (1:7 to 1:5). This resulted in 1.9 g (52%) of the title compound as an off-white solid. MS-ESI: 175.1 (M+1).

Step 4: 8-Nitro-1,2,3,5,6,7-hexahydro-s-indacen-4-ol

Into a 250-mL round-bottom flask purged with and maintained under nitrogen was placed a solution of 1,2,3,5,6,7-hexahydro-s-indacen-4-ol (1.9 g, 10.9 mmol) in EtOH (100 mL). To the solution was added 2,3,5,6-tetrabromo-4-methyl-4-nitrocyclohexa-2,5-dienone (6.1 g, 13.1 mmol). The resulting solution was stirred overnight at RT and then was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with a gradient of ethyl acetate/petroleum ether (1:5 to 1:3). This resulted in 1.1 g (46%) of the title compound as a light yellow solid. MS-ESI: 218.1 (M-1).

Step 5: 4-(Difluoromethoxy)-8-nitro-1,2,3,5,6,7-hexahydro-s-indacene

Into a 100-mL round-bottom flask purged with and maintained under nitrogen was placed a solution of 8-nitro-1,2,3,5,6,7-hexahydro-s-indacen-4-ol (1.1 g, 5.0 mmol) in DMF (20 mL) and water (2 mL). To the solution were added K2CO3 (1.4 g, 10.0 mmol) and sodium 2-chloro-2,2- difluoroacetate (1.5 g, 10.0 mmol). The resulting solution was stirred for 1 h at 120 ^o C and then was diluted with 20 mL of water. The pH value of the solution was adjusted to 7 with aq. HCl (1 N). The resulting solution was extracted with 3x20 mL of DCM. The organic layers were combined and dried over anhydrous Na2SO4, then concentrated under vacuum. The residue was applied onto a silica gel column and eluted with a gradient of ethyl acetate/petroleum ether (1:2 to 1:3). This resulted in 0.55 g (41%) of the title compound as a light yellow solid. MS-ESI: 270.1 (M+1). Step 6: 8-(Difluoromethoxy)-1,2,3,5,6,7-hexahydro-s-indacen-4-amine

Into a 100-mL round-bottom flask was placed a solution of 4-(difluoromethoxy)-8-nitro- 1,2,3,5,6,7-hexahydro-s-indacene (550 mg, 2.0 mmol) in MeOH (10 mL). Then Pd/C (10% wt., 100 mg) was added. The flask was evacuated and filled three times with hydrogen. The resulting solution was stirred for 12 h at RT under an atmosphere of hydrogen. The solids were filtered out. The resulting filtrate was concentrated under vacuum. This resulted in 460 mg (94%) of the title compound as a light yellow solid. MS-ESI: 240.1 (M+1). Scheme 29:

3-Fluoro-2,6-diisopropylbenzenamine

Step 1: 2,6-Dibromo-4-chloro-3-fluoroaniline

Into a 500-mL round-bottom flask was placed 4-chloro-3-fluoroaniline (5.08 g, 34.9 mmol), ACN (200 mL), and NBS (18.69 g, 105.0 mmol). The resulting solution was stirred for 12 h at RT and then was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with a gradient of ethyl acetate/petroleum ether (1:200 to 1:100). This resulted in 9.7 g (92%) of the title compound as a light yellow solid. MS-ESI: 303.8/305.8/301.8 (M+1).

Step 2: 4-Chloro-3-fluoro-2,6-bis(prop-1-en-2-yl)aniline

Into a 500-mL round-bottom flask purged with and maintained under nitrogen was placed a solution of 2,6-dibromo-4-chloro-3-fluoroaniline (9.03 g, 29.8 mmol) in 1,4-dioxane (200 mL) and water (20 mL). To the solution were added 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2- dioxaborolane (15.12 g, 89.98 mmol), Cs ₂ CO ₃ (29.34 g, 90.1 mmol) and Pd(dppf)Cl ₂ (2.20 g, 3.0 mmol). The resulting solution was stirred for 12 h at 90 ^o C and then was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with a gradient of ethyl acetate/petroleum ether (1:30 to 1:20). This resulted in 4.3 g (64%) of the title compound as yellow oil. MS-ESI: 226.1, 228.1 (M+1).

Step 3: 3-Fluoro-2,6-bis(propan-2-yl)aniline

Into a 100-mL round-bottom flask was placed a solution of 4-chloro-3-fluoro-2,6-bis(prop-1-en- 2-yl)aniline (1 g, 4.4 mmol) in MeOH (15 mL). Then Pd/C(10% wt., 100 mg) was added. The flask was evacuated and filled three times with hydrogen. The resulting solution was stirred for 3 h at RT under an atmosphere of hydrogen. The solids were filtered out. The resulting filtrate was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with a gradient of ethyl acetate/petroleum ether (1:5 to 1:3). This resulted in 700 mg (81%) of the title compound as light yellow oil. MS-ESI: 196.1 (M+1). Scheme 30:

1 ^{30'' Intermediate 44} Intermediate 44

4-Isocyanato-1,2,3,5,6,7-hexahydro-s-indacene

Step 1: 4-Isocyanato-1,2,3,5,6,7-hexahydro-s-indacene

Into a 50-mL round-bottom flask purged with and maintained under nitrogen was placed 1,2,3,5,6,7-hexahydro-s-indacen-4-amine (64 mg, 0.4 mmol), THF (5 mL) and BTC (37 mg, 0.1 mmol). The resulting solution was stirred for 2 h at 65 ^o C and then was concentrated under vacuum. This resulted in 75 mg (crude) of the title compound as light brown oil. The crude product was used directly in the next step.

Table 9. The Intermediates in the following Table were prepared using similar procedure as shown in Scheme 30 above for converting compound 130’’ to Intermediate 44.

The following schemes illustrate additional general methods for the synthesis of compounds of Formula AA: Scheme 31: Sche

Scheme 33A: Sche

Scheme 34:

Scheme for the preparation of Sulfonimidamide Intermediates: Schemes below illustrate the preparation of sulfonimidamide intermediates 59-88 and 112-113. Scheme 36:

N'-(tert-butyldimethylsilyl)-5-(2-hydroxypropan-2-yl)-1-phen yl-1H-pyrazole-3-sulfonimidamide Step 1: Ethyl 3-nitro-1-phenyl-1H-pyrazole-5-carboxylate

Into a 250-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed ethyl 3-nitro-1H-pyrazole-5-carboxylate (5.0 g, 27.0 mmol), THF (150 mL), phenylboronic acid (6.6 g, 54.1 mmol), Cu(OAc)2 (7.38 g, 40.6 mmol), and pyridine (8.54 g, 108 mmol). The resulting solution was stirred overnight at RT. The resulting mixture was concentrated under vacuum. The residue was eluted from a silica gel column with ethyl acetate/petroleum ether (1:1). This resulted in 3.1 g (44%) of the title compound as an off-white solid. MS-ESI: 262 (M+1). Step 2: Ethyl 3-amino-1-phenyl-1H-pyrazole-5-carboxylate

Into a 100-mL round-bottom flask, was placed ethyl 3-nitro-1-phenyl-1H-pyrazole-5-carboxylate (3.92 g, 15.0 mmol), MeOH (50 mL), and Pd/C (wet 10%wt., 400 mg). The flask was evacuated and filled three times with hydrogen. The resulting solution was stirred overnight at RT. The solids were filtered out. The resulting mixture was concentrated under vacuum. This resulted in 2.8 g (81%) of the title compound as a light yellow solid. MS-ESI: 232 (M+1).

Step 3: Ethyl 3-(chlorosulfonyl)-1-phenyl-1H-pyrazole-5-carboxylate

Into a 100-mL round-bottom flask, was placed ethyl 3-amino-1-phenyl-1H-pyrazole-5- carboxylate (1.8 g, 7.78 mmol), HCl (cc.6.0 mol/L, 15 mL). This was followed by the addition of a solution of NaNO2 (646 mg, 9.36 mmol) in water (2.0 mL) dropwise with stirring at -10℃. The resulting solution was stirred for 30 min at -10℃. The above mixture was added to a saturated solution of SO2 in AcOH (20 mL) dropwise with stirring at 0℃. Then to the above was added CuCl2 (1.05 g, 7.81 mmol). The resulting solution was stirred for 1 h at RT. The reaction was then quenched by the addition of 30 mL of water. The resulting solution was extracted with 3x30 mL of DCM and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 2.2 g (90%) of the title compound as a light yellow solid.

Step 4: Ethyl 1-phenyl-3-sulfamoyl-1H-pyrazole-5-carboxylate

Into a 100-mL round-bottom flask, was placed a solution of ethyl 3-(chlorosulfonyl)-1-phenyl-1H- pyrazole-5-carboxylate (2.2 g, 6.99 mmol) in DCM (10 mL). Then to the above was introduced NH3 gas bubbled at 0℃ for 10 min. The resulting solution was stirred for 2 h at RT. The resulting mixture was concentrated under vacuum. The residue was eluted from a silica gel column with ethyl acetate/petroleum ether (1:1). This resulted in 1.07 g (52%) of the title compound as a light yellow solid. MS-ESI: 296 (M+1).

Step 5: 5-(2-Hydroxypropan-2-yl)-1-phenyl-1H-pyrazole-3-sulfonamide

Into a 100-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of ethyl 1-phenyl-3-sulfamoyl-1H-pyrazole-5-carboxylate (1.65 g, 5.59 mmol) in THF (30 mL). This was followed by the addition of MeMgBr/THF (3.0 M, 18.6 mL) dropwise with stirring at 0℃. The resulting solution was stirred overnight at RT. The reaction was then quenched by the addition of 30 mL of NH ₄ Cl (sat.). The resulting solution was extracted with 3x30 mL of DCM and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was eluted from a silica gel column with ethyl acetate/petroleum ether (2:1). This resulted in 1.35 g (86%) of the title compound as a yellow solid. MS-ESI: 282 (M+1). Step 6: N-(tert-butyldimethylsilyl)-5-(2-hydroxypropan-2-yl)-1-pheny l-1H-pyrazole-3- sulfonamide

Into a 100-mL round-bottom flask, was placed 5-(2-hydroxypropan-2-yl)-1-phenyl-1H-pyrazole- 3- sulfonamide (500 mg, 1.78 mmol), THF (10 mL). This was followed by the addition of sodium hydride (60% wt. oil dispersion, 86 mg, 3.58 mmol) in portions at 0℃. Then to the above was added TBSCl (538 mg, 3.57 mmol). The resulting solution was stirred for 2 h at RT. The reaction was then quenched by the addition of 10 mL of water. The resulting solution was extracted with 3x10 mL of DCM. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was eluted from a silica gel column with ethyl acetate/petroleum ether (1:2). This resulted in 660 mg (94%) of the title compound as a light yellow solid. MS-ESI: 396 (M+1).

Step 7: N'-(tert-butyldimethylsilyl)-5-(2-hydroxypropan-2-yl)-1-phen yl-1H-pyrazole-3- sulfonimidamide

Into a 100-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed the solution of PPh ₃ Cl ₂ (1.67 g, 5.01 mmol) in chloroform (30 mL). This was followed by the addition of DIEA (1.29 g, 9.98 mmol) dropwise with stirring at RT. The resulting solution was stirred for 10 min at RT and the reaction system was cooled to 0℃. To this was added a solution of N-(tert-butyldimethylsilyl)-5-(2-hydroxypropan-2-yl)-1-pheny l-1H-pyrazole- 3-sulfonamide (660 mg, 1.67 mmol) in chloroform (3.0 mL) dropwise with stirring at 0℃. The resulting solution was stirred for 30 min at 0℃. To the mixture was added introduced NH3 gas bubble for 15 min at 0℃. The resulting solution was stirred for 2 h at RT. The resulting solution was diluted with 30 mL of water. The resulting solution was extracted with 3x30 mL of DCM and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was eluted from a silica gel column with ethyl acetate/petroleum ether (1:1). This resulted in 530 mg (81%) of the title compound as a light yellow solid. MS-ESI: 395 (M+1). Scheme 37:

N'-(tert-butyldimethylsilyl)-4-(2-hydroxypropan-2-yl)-5-meth ylthiazole-2-sulfonimidamide Steps 1-6 used similar procedures for converting compound 16 to intermediate 2 shown in Scheme 7B to afford intermediate 60 from compound 151’’. MS-ESI: 350 (M+1). Scheme 38:

Intermediate 61

O N O S NH

O ₂ N-methyl-N-(4-sulfamoylbenzyl)acetamide

Intermediate 62

N-(4-(N'-(tert-butyldimethylsilyl)sulfamidimidoyl)benzyl)-N- methylacetamide

Step 1: N-benzyl-N-methylacetamide

Into a 1.0 L round-bottom flask were added benzyl(methyl)amine (10 g, 82.5 mmol) and DCM (500 mL) at 0℃. To this stirred solution were added DIEA (21.3 g, 165 mmol) and acetyl chloride (9.72 g, 124 mmol) in portions at 0℃. The resulting mixture was stirred for 4 h at RT. The resulting mixture was concentrated under reduced pressure. The residue was eluted from a silica gel column with ethyl acetate/petroleum ether (1:1) to afford the title compound (13 g, 96.5%) as a yellow oil. MS-ESI: 164 (M+1).

Step 2: 4-((N-methylacetamido)methyl)benzenesulfonyl chloride

Into a 250 mL round-bottom flask were added N-benzyl-N-methylacetamide (3.0 g, 18.4 mmol,) and DCM (6.0 mL) at 0℃. To this stirred solution were added ClSO2OH (6.0 mL) in one portion at 0℃. The resulting mixture was stirred for 3 h at RT. The reaction was quenched by the addition of water/ice (150 mL) at 0℃. The resulting solution was extracted with 3x150 mL of DCM and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product of the title compound (2.2 g, 45.7%)) was used in the next step directly without further purification.

Step 3: N-methyl-N-(4-sulfamoylbenzyl)acetamide

Into a 250 mL round-bottom flask were added 4-[(N-methylacetamido)methyl]benzene-1-sulfonyl chloride (2.2 g, 8.41 mmol) and DCM (3.0 mL) at 0℃. To this stirred solution were added NH ₃ (g) in DCM (40 mL) dropwise at 0℃. The resulting mixture was stirred overnight at RT. The resulting mixture was concentrated under reduced pressure. The residue was eluted from a silica gel column with ethyl acetate/petroleum ether (1:1) to afford the minor compound 159B (122 mg, 6.1%) and the title compound (1.9 g, 93.3%) both as white solids. MS-ESI: 243 (M+1).

Step 4-6 used similar procedures for converting compound 148’’ to intermediate 59 shown in Scheme 36 to afford intermediate 62 from intermediate 61. MS-ESI: 356 (M+1). Table 10. Intermediate 62B in the following Table was prepared using the similar procedures for converting compound 157’’ to Intermediate 62 shown in Scheme 38 from compound 159”B which was separated from step 3 in Scheme 38. The Intermediate 63 was prepared using similar procedures for converting compound 157” to Intermediate 62 shown in Scheme 38 from appropriate starting materials.

Intermediate Structure IUPAC Name Exact ss H] ⁺ nter 6 nter ⁹ Scheme 39:

Intermediate 64

4-((Methylamino)methyl)benzenesulfonamide Intermediate 65

N-(4-(N'-(tert-butyldimethylsilyl)sulfamimidoyl)benzyl)-N-me thylpent-4-ynamide

Step 1: 4-((Methylamino)methyl)benzenesulfonamide

Into a 500-mL sealed tube, was placed N-methyl-N-[(4-sulfamoylphenyl)methyl]acetamide (5.0 g), hydrogen chloride (200 mL, 12 M). The resulting solution was stirred for 16 h at 100℃ in an oil bath. The resulting mixture was concentrated. This resulted in 5.0 g of the title compound as an off-white crude solid. MS-ESI: 201 (M+1)

Step 2: N-methyl-N-(4-sulfamoylbenzyl)pent-4-ynamide

Into a 250 mL round-bottom flask was placed 4-((methylamino)methyl)benzenesulfonamide (4.0 g, 20 mmol) in DMF (40 mL ). To this stirred solution was added HATU (6.33 g,16.7 mmol), DIEA (5.16 g, 40 mmol) and pent-4-ynoic acid (2.16 g, 22 mmol). Then the mixture was stirred overnight RT. The resulting solution was diluted with 40 mL of water. The resulting solution was extracted with 3x50 mL of ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was eluted from a silica gel column with ethyl acetate/petroleum ether (1:1). This resulted in 2.97 g (53%) of the title compound as a light yellow solid. MS-ESI: 281 (M+1).

Steps 3-5 used similar procedures for converting Intermediate 61 to Intermediate 62 shown in Scheme 38 to afford Intermediate 65 from compound 163’’. MS-ESI: 394 (M+1). Scheme 40A:

Tert-butyl 4-( (tert-butyldimethylsilyl)sulfamimidoyl)benzyl(methyl)carbama te

Intermediate 67

N'-( hexahydro-s-indacen-4-yl)carbamoyl)-4-

((methylamino)methyl)benzenesulfonimidamide

Step 1: Tert-butyl methyl(4-sulfamoylbenzyl)carbamate

Into a 250-mL round-bottom flask, was placed 4-[(methylamino)methyl]benzene-1-sulfonamide (5.0 g, 25 mmol) in DCM (100 mL). To this stirred solution was added di-tert-butyl dicarbonate (6.0 g, 27.5 mmol). The resulting solution was stirred for 5 h at RT. The resulting mixture was concentrated. The residue was eluted from a silica gel column with ethyl acetate/petroleum ether (1:1). This resulted in 5.0 g (66.7 %) of the title compound as a light yellow solid. MS-ESI: 301 (M+1).

Steps 2-4 used similar procedures for converting compound 148’’ to intermediate 59 shown in Scheme 36 to afford Intermediate 66 from compound 166’’. MS-ESI: 414 (M+1). Step 5: Tert-butyl(4-(N-(tert-butyldimethylsilyl)-N'-((1,2,3,5,6,7-h exahydro-s-indacen-4- yl)carbamoyl)-sulfamidimidoyl)benzyl)(methyl)carbamate

Into a 50-mL round-bottom flask, was placed tert-butyl (4-(N'-(tert- butyldimethylsilyl)sulfamidimidoyl)benzyl)(methyl)carbamate (500 mg, 1.21 mmol) in THF (15 mL). To this stirred solution was added 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (343 mg, 1.81 mmol) and NaH (60%wt. oil dispersion, 96.8 mg, 2.42 mmol). The resulting solution was stirred for 3 h at RT. The reaction was quenched by the addition of MeOH (10 mL). This resulted in 500 mg (67.5%) of the title compound as a white crude solid. MS-ESI: 613 (M+1). Step 6: N'-(1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoyl)-4- ((methylamino)methyl)benzenesulfonimidamide

Into a 50-mL round-bottom flask was placed tert-butyl N-[(4-[[(tert-butyldimethylsilyl)amino] ([[(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl]imino])ox o- ^ ⁶ -sulfanyl]phenyl)methyl]-N- methylcarbamate (90 mg) and HCl in dioxane (4 M, 5.0 mL). The resulting solution was stirred for 16 h at RT. The resulting mixture was concentrated. The crude product was purified by Prep- HPLC with the following conditions: Column, Sunfire Prep C18 OBD,10 um,19*250 mm; mobile phase A: water (0.05% TFA) and B: ACN (20% to 50% gradient of B over 17 min); Detector, UV 220/254 nm. This resulted in 30 mg of the title compound as a white solid. MS-ESI: 399 (M+1).

Scheme 42:

N'-(tert-butyldimethylsilyl)-6-(2-hydroxypropan-2-yl)-2-meth ylpyridine-3-sulfonimidamide Step 1: ethyl 5-amino-6-methylpicolinate

Into a 50-mL seal tube was placed methyl 6-bromo-2-methylpyridin-3-amine (500 mg, 2.67 mmol) in MeOH (15 mL) and Pd(OAc) ₂ (120 mg, 0.53 mmol), dppf (444 mg, 0.80 mmol), TEA (809 mg, 8.01 mmol). The seal tube was evacuated and flushed three times with CO. The resulting solution was stirred for 5 h at 100℃ under 10 atm of CO. Then the solution was concentrated under vacuum. The residue was eluted from a silica gel column with ethyl acetate/petroleum ether (1:1). This resulted in 351 mg (79.2 %) of the title compound as a light yellow solid. MS-ESI: 167 (M+1). Steps 2-4 used similar procedures for converting compound 27 to Intermediate 30 shown in Scheme 9 to afford compound 176’’ from compound 173’’. MS-ESI: 231 (M+1).

Steps 5-6 used similar procedures for converting compound 148’’ to intermediate 59 shown in Scheme 36 to afford Intermediate 70 from compound 176’’. MS-ESI: 344 (M+1). Table 11. The Intermediates in the following Table were prepared using the similar procedures for converting compound 172’’ to Intermediate 70 shown in Scheme 42 from appropriate starting materials. Intermediate Structure IUPAC Name Exact Mass # [M+H] ⁺ nter

Scheme 43:

^S

N'-(tert-butyldimethylsilyl)-4-(2-methoxypropan-2-yl)benzene sulfonimidamide Step 1: 1-Bromo-4-(2-methoxypropan-2-yl)benzene

Into a 250-mL round-bottom flask, was placed a solution of 2-(4-bromophenyl)propan-2-ol (10 g, 46.5 mmol) in THF (50 mL). To this stirred solution was added NaH (60% wt. oil dispersion, 5.19 g, 93 mmol) at 0℃. The resulting solution was stirred for 30 min at 0℃. To this stirred solution was added MeI (6.60 g, 46.5 mmol) dropwise with stirring at 0℃. The resulting solution was allowed to react for an additional 15 h at RT. The resulting solution was quenched with 40 mL of water. The resulting solution was extracted with 3x50 mL of ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was eluted from a silica gel column with ethyl acetate/petroleum ether (15/85). This resulted in 8.5 g (50.3%) of the title compound as a yellow solid.

Step 2: 4-(2-Methoxypropan-2-yl)benzenesulfinic acid

Into a 250-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 1-bromo-4-(2-methoxypropan-2-yl)benzene (5.0 g, 21.8 mmol) in THF (50 mL). To this stirred solution was added n-BuLi (13 mL, 32.7 mmol, 2.5 M) dropwise with stirring at -78℃. The resulting solution was stirred for 30 min at -78℃. SO ₂ (g) was introduced into the stirring solution at -78℃. The resulting solution was allowed to react for an additional 60 min at RT. The resulting mixture was concentrated. This resulted in 6.0 g (crude) of the title compound as a yellow solid. MS-ESI: 213 (M-1)

Step 3: 4-(2-Methoxypropan-2-yl)benzenesulfonyl chloride

Into a 50-mL round-bottom flask, was placed 4-(2-methoxypropan-2-yl)benzene-1-sulfinic acid (4.9 g, 22.9 mmol) in THF (50 mL). To this stirred solution was added NCS (4.58 g, 34.3 mmol). The resulting solution was stirred for 30 min at 0℃. The mixture was allowed to react for an additional 60 min at RT. NH3 (g) was introduced into the reaction solution. The resulting solution was allowed to react for an additional 120 min at RT. The resulting mixture was concentrated. The residue was eluted from a silica gel column with ethyl acetate/petroleum ether (1/4). This resulted in 4.3 g (82 %) of the title compound as a yellow solid.

Step 4: 4-(2-Methoxypropan-2-yl)benzenesulfonamide

Into a 250-mL round-bottom flask was placed 4-(2-methoxypropan-2-yl)benzene-1-sulfonyl chloride (4.3 g, 17.3 mmol) in DCM (50 mL). NH3 (g) was introduced into the reaction solution at 0℃. The resulting solution was stirred for 180 min at RT. The resulting mixture was concentrated. The residue was eluted from a silica gel column with ethyl acetate/petroleum ether (1/3). This resulted in 3.9 g (98.5%) of the title compound as a yellow solid. MS-ESI: 230 (M+1). Step 5: N-(tert-butyldimethylsilyl)-4-(2-methoxypropan-2-yl)benzenes ulfonamide

Into a 100-mL round-bottom flask, was placed a solution of 4-(2-methoxypropan-2-yl)benzene-1- sulfonamide (4.0 g, 17.5 mmol) in THF (40 mL). To this stirred solution was added NaH (1.4 g, 34.9 mmol, 60%wt. oil dispersion) and TBSCl (3.16 g, 21 mmol) at 0℃. The resulting solution was allowed to react with stirring for 15 h at RT. The resulting solution was quenched with 40 mL of water. The resulting solution was extracted with 3x50 mL of ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was eluted from a silica gel column with ethyl acetate/petroleum ether (30/70). This resulted in 2.3 g (38.4%) of the title compound as a yellow solid. MS-ESI: 344 (M+1)

Step 6: N'-(tert-butyldimethylsilyl)-4-(2-methoxypropan-2-yl)benzene sulfonimidamide

Into a 500-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed the solution of PPh3Cl2 (12.4 g, 37.3 mmol) in chloroform (150 mL). This was followed by the addition of DIEA (9.63 g, 74.5 mmol) dropwise with stirring at RT. The resulting solution was stirred for 10 min at RT and the reaction system was cooled to 0℃. To this was added a solution of N-(tert-butyldimethylsilyl)-4-(2-methoxypropan-2-yl)benzene- 1- sulfonamide (3.2 g, 9.31 mmol) in chloroform (30 mL) dropwise with stirring at 0℃. The resulting solution was stirred for 30 min at 0℃. To the mixture was introduced NH ₃ gas bubble for 15 min at 0℃. The resulting solution was stirred for 2 h at RT. The resulting solution was diluted with 100 mL of water. The resulting solution was extracted with 3x200 mL of DCM and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was eluted from a silica gel column with ethyl acetate/petroleum ether (36/64). This resulted in 1.4 g (36.5%) of the title compound as a yellow solid. MS-ESI: 343 (M+1) Scheme 44:

N N

N'-(tert-butyldimethylsilyl)-5-((dimethylamino)methyl)pyridi ne-2-sulfonimidamide

Step 1: (6-Bromopyridin-3-yl)-N,N-dimethylmethanamine

Into a 500-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of n itrogen, were placed Ti(OEt)4 (12.3 g, 53.8 mmol) and dimethylamine (4.85 g, 108 mmol) in Me OH (50 mL) at RT. To a stirred solutionwas added 6-bromopyridine-3-carbaldehyde (5.0 g, 26. 9 mmol) in MeOH (30 mL) dropwise at 0℃. Then the reaction solution was stirred at RT for 3h. NaBH4 (1.02 g, 26.9 mmol) was added to the mixture and the resulting solution was stirred over night at RT. The reaction was quenched by the addition of water/ice (30mL) at 0℃. The resultin g mixture was concentrated under reduced pressure. Then the resulting mixture extracted with et hyl acetate (3 x 50mL) and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was eluted from a silica gel column with ethyl aceta te/petroleum ether (5:1) to afford the title compound (3.5 g, 60.5%) as a yellow oil. MS-ESI: 216 /218 (M+1).

Steps 2-6 used similar procedures for converting compound 179’’ to Intermediate 72 shown in Scheme 43 to afford Intermediate 73 from compound 185. MS-ESI: 329 (M+1). Table 12. The Intermediates in the following Table were prepared using the similar procedures for converting compound 184’’ to Intermediate 73 shown in Scheme 44 from appropriate starting materials. Inte act ass H] ⁺ nter ²⁹

Scheme 45:

H _2N S

N T ^BS N'-(tert-butyldimethylsilyl)-1-methyl-1H-indazole-5-sulfonim idamide Steps 1-6 used similar procedures for converting compound 179’’ to Intermediate 72 shown in Scheme 43 to afford Intermediate 75 from compound 190’’. MS-ESI: 325 (M+1). Scheme 46:

O ^TBS

N'-(tert-butyldimethylsilyl)-4-(2-(dimethylamino)propan-2-yl )benzenesulfonimidamide Step 1: 4-(Prop-1-en-2-yl)benzenesulfonamide

Into a 250-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 4-bromobenzene-1-sulfonamide (5.0 g, 21.2 mmol) in dioxane (100 mL) and H2O (15 mL). To this stirred solution was added 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2- dioxaborolane (14.2 g, 84.7 mmol), Pd(dppf)Cl2 (4.65 g, 6.35 mmol) and Cs2CO3 (13.8 g, 42.4 mmol). The resulting solution was stirred for 15 h at 100 ℃. The resulting mixture was concentrated under reduced pressure. The residue was eluted from a silica gel column with ethyl acetate/petroleum ether (40/60). This resulted in 3.6 g (86.2%) of the title compound as a yellow solid. MS-ESI: 198 (M+1). Step 2: 2-Chloro-N-(2-(4-sulfamoylphenyl)propan-2-yl)acetamide

Into a 1.0-L round-bottom flask, was placed 4-(prop-1-en-2-yl)benzene-1-sulfonamide (5.0 g, 25.4 mmol) in H ₂ SO ₄ (50 mL) and AcOH (250 mL). To the stirred solution was added 2- chloroacetonitrile (38.3 g, 507 mmol). The resulting solution was stirred for 30 min at 0℃. The resulting solution was allowed to react for an additional 15 h at RT. The pH value of the solution was adjusted to 7 with Na ₂ CO ₃ (5.0 M). Then the resulting mixture was extracted with ethyl acetate (3 x 200mL) and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was eluted from a silica gel column with ethyl acetate/petroleum ether (2/3). This resulted in 4.2 g (57%) of the title compound as yellow oil. MS-ESI: 291 (M+1).

Step 3: 4-(2-Aminopropan-2-yl)benzenesulfonamide

Into a 250-mL round-bottom flask, was placed 2-chloro-N-[2-(4-sulfamoylphenyl)propan-2- yl]acetamide (4.2 g, 14.5 mmol) in CH ₃ COOH (15 mL) and ethanol (75 mL). To this stirred solution was added thiourea (1.32 g, 17.3mmol). The resulting solution was stirred for 16 h at 85℃. The resulting mixture was washed with 100 ml of H ₂ O and extracted with 3x250 mL of ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 2.3 g (54.3%) of the title compound as a yellow solid. MS-ESI: 215 (M+1).

Step 4: 4-(2-(Dimethylamino)propan-2-yl)benzenesulfonamide

Into a 250-mL round-bottom flask, was placed 4-(2-aminopropan-2-yl)benzene-1-sulfonamide (2.14 g, 9.99 mmol) in MeOH (50 mL). To this stirred solution was added HCHO (37%wt., 599 mg, 20 mmol) and NaBH3CN (1.86 g, 30 mmol). The resulting solution was stirred for 120 min at RT. The resulting mixture was diluted with 100 mL of water and extracted with 3x250 mL of ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum The residue was eluted from a silica gel column with ethyl acetate/petroleum ether (30/70). This resulted in 1.0 g (41.3%) of the title compound as a yellow solid. MS-ESI: 243 (M+1).

Steps 5-7 used similar procedures for converting compound 148’’ to intermediate 59 shown in Scheme 36 to afford Intermediate 76 from compound 200. MS-ESI: 356 (M+1). Scheme 47:

_O

N'-(tert yldimethylsilyl)-4-(1-(dimethylamino)ethyl)benzenesulfonimid amide

Step 1: (E)-4-(1-((tert-butylsulfinyl)imino)ethyl)benzenesulfonamide

Into a 250-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was added 2-methylpropane-2-sulfinamide (3.04g, 25.1 mmol) in THF (50 mL). To this stirred solution was added Ti(OEt)4 (11.5 g, 50.2 mmol) and 4-acetylbenzene-1-sulfonamide (5.0 g, 25.1 mmol) in portions at RT. The resulting mixture was stirred for overnight at 70℃ under nitrogen atmosphere. The reaction was quenched with Water (20 mL) at 0℃. The resulting mixture was extracted with ethyl acetate (3 x 30 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with ethyl acetate/petroleum ether (1:1) to afford the title compound (5.0 g,75.8%) as a yellow solid. MS-ESI: 303 (M+1). Step 2: 4-(1-((Tert-butylsulfinyl)amino)ethyl)benzenesulfonamide

Into a 500 mL round-bottom flask were added 4-[(1E)-1-[(2-methylpropane-2- sulfinyl)imino]ethyl]benzene -1-sulfonamide (4.65 g, 15.4 mmol) in THF (200 mL) at RT. To this stirred solution was added NaBH ₄ (1.16 g, 30.8 mmol) in portions at 0℃ under nitrogen atmosphere. The resulting mixture was stirred for 4 h at RT under nitrogen atmosphere. The reaction was quenched by the addition of HCl (2M, 50 mL) at 0℃. The resulting mixture was extracted with ethyl acetate (3 x 50mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford the title compound (4.5 g, 96.1%) as a white solid. MS-ESI: 305 (M+1).

Step 3: 4-(1-Aminoethyl)benzenesulfonamide

Into a 250 mL round-bottom flask were added 4-[1-[(2-methylpropane-2- sulfinyl)amino]ethyl]benzene-1 -sulfonamide (4.4 g, 14.5 mmol) and MeOH (50 mL) at room temperature. To this stirred solution was added HCl (gas) in 1,4-dioxane (8.0 mL, 26.3 mmol) in one portions at RT. The resulting mixture was stirred overnight at RT. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse flash chromatography with the following conditions (column, C18 silica gel; mobile phase, MeCN in water, 10% to 50% gradient in 10 min; detector, UV 254 nm.) to afford the title compound (2.6 g, 89.7%) as a white solid. MS-ESI: 201 (M+1).

Step 4: 4-(1-(Dimethylamino)ethyl)benzenesulfonamide

Into a 250 mL round-bottom flask was added 4-(1-aminoethyl)benzene-1-sulfonamide (2.0 g, 9.99 mmol) and MeOH (60 mL) at RT. To this stirred solution was added HCHO (37%wt., 1.61 g, 53.6 mmol) and NaBH ₃ CN (1.25 g, 20 mmol) in portions at RT. The resulting mixture was stirred overnight at RT. The reaction solution was diluted with 100 mL of water and extracted with 3x100 mL of ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was eluted from a silica gel column with ethyl acetate/petroleum ether. The residue was purified by silica gel column chromatography, eluted with ethyl acetate/petroleum ether (1:2) to afford the title compound (1.5 g, 65.8%) as a white solid. MS-ESI: 229 (M+1).

Steps 5-7 used similar procedures for converting compound 148’’ to intermediate 59 shown in Scheme 36 to afford Intermediate 77 from compound 207’’. MS-ESI: 342 (M+1). Scheme 48:

Intermediate 78

4-(2-Hydroxypropan-2-yl)-N,N-dimethylthiophene-2-sulfonimida mide Step 1: N'-(tert-butyldimethylsilyl)-4-(2-hydroxypropan-2-yl)-N,N-di methylthiophene-2- sulfonimidamide

Into a 50-mL 3-necked round-bottom flask, was placed N-(tert-butyldimethylsilyl)-4-(2- hydroxypropan-2-yl) thiophene-2-sulfonoimidamide (300 mg, 0.90 mmol) in THF (3.0 mL). To the solution were added NaH (60%wt. oil dispersion, 53.8 mg, 1.35 mmol) at -10℃ in ethanol/ice bath. To the solution were added iodomethane (0.50 mL) dropwise with stirring at 0℃ in 30 min. The resulting solution was stirred for 30 min at RT. The reaction was then quenched by the addition of NH4Cl(aq.). The resulting solution was extracted with 3x20 mL of ethyl acetate and the organic layers combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was eluted from a silica gel column with ethyl acetate/petroleum ether (1:5). This resulted in 252 mg (77.5%) of the title compound as a white solid. MS-ESI: 363 (M+1).

Step 2: N'-(tert-butyldimethylsilyl)-4-(2-hydroxypropan-2-yl)-N,N-di methylthiophene-2- sulfonimidamide

Into a 50-mL round-bottom flask, was placed N-(tert-butyldimethylsilyl)-4-(2-hydroxypropan-2- yl)-N,N -dimethylthiophene-2-sulfonoimidamide (200 mg, 0.55 mmol) in THF (10 mL). To the solution was added HF/Py (70%wt., 0.10 mL) dropwise with stirring at RT. The resulting solution was stirred for 60 min at RT. The resulting mixture was concentrated under vacuum. The resulting solution was extracted with ethyl acetate (3x10mL), the organic layers combined and dried over anhydrous sodium sulfate. The residue was eluted from a silica gel column with ethyl acetate. This resulted in 127 mg (92.7%) of the title compound as a white solid. MS-ESI: 249 (M+1). Scheme 49:

Intermediate 79

H

2-(2-Hydroxypropan-2-yl)-N-methylthiazole-5-sulfonimidamide Step 1: Tert-butyl (chloro(2-(2-hydroxypropan-2-yl)thiazol-5-yl)(oxo)- ^ ⁶ - sulfaneylidene)carbamate

Into a 1.0-L round-bottom flask, was placed tert-butyl N-[[2-(2-hydroxypropan-2-yl)-1,3-thiazol- 5-yl] sulfinyl]carbamate (100 g, 326 mmol) in ACN (500 mL). To the stirred solution was added NCS (65.4 g, 490 mmol). The resulting solution was stirred for 2 h at RT. The resulted solution was concentrated. This resulted in 120 g (crude) of the title compound as yellow oil. MS-ESI: 341/343 (M+1).

Step 2: Tert-butyl((2-(2-hydroxypropan-2-yl)thiazol-5-yl)(methylamin o)(oxo)- ^ ⁶ - sulfaneylidene) carbamate

Into a 250-mL round-bottom flask, was placed tert-butyl (chloro(2-(2-hydroxypropan-2- yl)thiazol-5-yl)(oxo)- ^ ⁶ -sulfaneylidene)carbamate (10 g, 29.3 mmol) in THF (100 mL). To the stirred solution was added CH ₃ NH ₂ (1.82 g, 58.6 mmol). The resulting solution was stirred for 2 h at RT. The resulted solution was concentrated. The residue was eluted from a silica gel column with ethyl acetate/ petroleum ether (1:1). This resulted in 6.1 g (62%) of the title compound as a yellow solid. MS-ESI: 336 (M+1).

Step 3: 2-(2-Hydroxypropan-2-yl)-N'-methylthiazole-5-sulfonimidamide

Into a 100-mL round-bottom flask, was placed tert-butyl((2-(2-hydroxypropan-2-yl)thiazol-5- yl)(methylamino)(oxo)- ^ ⁶ -sulfaneylidene) carbamate (3.0 g, 8.94 mmol) in HCl (gas) in 1,4- dioxane (8 mL, 26.3 mmol) in one portion at RT. The resulting solution was stirred for 60 min at RT. The resulting mixture was concentrated under vacuum. This resulted in 2.10 g (crude) of the title compound as a yellow solid. MS-ESI: 236 (M+1). Scheme 50A:

₂

O

Tert-butyl (amino(2-(2-methoxypropan-2-yl)thiazol-5-yl)(oxo) - ⁶ -sulfaneylidene)carbamate Step 1: Methyl 2-(2-methoxypropan-2-yl)thiazole-5-sulfinate

Into a 1-L round-bottom flask, was placed a solution of methyl 2-(2-hydroxypropan-2-yl)-1,3- thiazole-5-sulfinate (40 g, 181 mmol) in THF (500 mL). To this stirred solution was added NaH (60% wt. oil dispersion, 7.95 g, 199 mmol) in three portions at 0℃ in an ice/ethanol bath. To this reaction solution was added MeI (51.3 g, 362 mmol) dropwise with stirring at 0℃ in an ice/ethanol bath. The resulting solution was stirred for 3 h at RT. The reaction was then quenched by the addition of water (50 mL ) at 0℃. The resulting solution was extracted with 3x300 mL of ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 32 g (75.3%) of the title compound as a white solid. MS-ESI: 236 (M+1).

Step 2: 2-(2-Methoxypropan-2-yl)thiazole-5-sulfinamide

Into a 1-L 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of methyl 2-(2-methoxypropan-2-yl)-1,3-thiazole-5-sulfinate (20 g, 85 mmol) in THF (500 mL). This was followed by the addition of KHMDS (500 mL, 1.0 mole, 2 M) dropwise with stirring at -78℃ in a liquid nitrogen/ethanol bath. The resulting solution was stirred for 3 h at -78℃ in a liquid nitrogen/ethanol bath. The reaction was quenched by the addition of water (50 mL). The resulting solution was extracted with 3x300 mL of ethyl acetate dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was eluted from a silica gel column with ethyl acetate/petroleum ether (1:3). This resulted in 14 g (74.8%) of the title compound as a white solid. MS-ESI: 221.0 (M+1).

Step 3: Tert-butyl ((2-(2-methoxypropan-2-yl)thiazol-5-yl)sulfinyl)carbamate

Into a 500-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 2-(2-methoxypropan-2-yl)-1,3-thiazole-5-sulfinamide (10 g, 45.4 mmol) in THF (250 mL). To this stirred solution was added NaH (60%wt. oil dispersion, 3.63 g, 90.8 mmol) in three times at 0℃ in an ice/ethanol bath. To this solution was added Boc2O (9.91 g, 45.4 mmol) in portions at 0℃ in an ice/ethanol bath. The resulting solution was stirred for 3 h at RT. The reaction was then quenched by the addition of water (50 mL). The resulting solution was extracted with 3x300 mL of ethyl acetate concentrated under vacuum. This resulted in 12 g (82.5%) of the title compound as a white solid. MS-ESI: 321.1 (M+1).

Step 4: Tert-butyl (chloro(2-(2-methoxypropan-2-yl)thiazol-5-yl)(oxo)- ^ ⁶ - sulfaneylidene)carbamate

Into a 500-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of tert-butyl N-[[2-(2-methoxypropan-2-yl)-1,3-thiazol-5- yl]sulfinyl]carbamate (11 g, 34.3 mmol) in THF (200 mL). NCS (13.8 g, 103 mmol) was added to the reaction solution in one portion at RT. The resulting solution was stirred for 3 h at RT. This reaction solution was used to the next step directly without further purification. Step 5: Tert-butyl (amino(2-(2-methoxypropan-2-yl)thiazol-5-yl)(oxo)- ^ ⁶ - sulfaneylidene)carbamate

Into a 500-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of tert-butyl N-[[2-(2-methoxypropan-2-yl)-1,3-thiazol-5- yl]sulfinyl]carbamate (9.0 g, 28.9mmol) in THF (200 mL). To the mixture was added introduced NH3 gas bubble for 15 min at 0℃. The resulting solution was stirred for 1 h at RT. The resulting mixture was concentrated. The residue was eluted from a silica gel column with ethyl acetate/petroleum ether (1:1). This resulted in 7g (72.3%) of the title compound as a white solid. MS-ESI: 336.1 (M+1). Scheme 51:

NH ₂

N'-(tert-butyldimethylsilyl)-6-isobutylpyridine-3-sulfonimid amide Steps 1-2 used similar procedures for converting compound 27 to Intermediate 29 shown in Scheme 9 to afford compound 219’’ from compound 217’’. MS-ESI: 238 (M+1). Step 3: 6-(2-Methylprop-1-enyl)pyridine-3-sulfonamide

Into a 500 mL round-bottom flash were added 6-bromopyridine-3-sulfonamide (5.5 g, 23.2 mmol) and dioxane (150 mL) and water (15 mL) at RT. To this solution was added Pd(dppf)Cl ₂ (1.7 g, 2.32 mmol), Cs2CO3 (15.1 g, 46.4 mmol) and 4,4,5,5-tetramethyl-2-(2-methylprop-1-en-1-yl)- 1,3,2-dioxaborolane (8.45 g, 46.4mmol) in one portion at RT under nitrogen atmosphere. The resulting mixture was stirred overnight at 100℃ under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (1:1) to afford title compound (4.0 g, 81.2%) as a light yellow oil. MS-ESI: 213 (M+1).

Step 4: 6-Isobutylpyridine-3-sulfonamide

Into a 250mL 3-necked round-bottom flask was added 6-(2-methylprop-1-en-1-yl)pyridine-3- sulfonamide (4 g, 18.8 mmol) and MeOH (100 mL) at RT under nitrogen atmosphere. To this stirred solution was added Pd/C (wet 10% wt., 900 mg). The flask was evacuated and filled three times with hydrogen. The resulting mixture was stirred overnight at RT under hydrogen atmosphere. The resulting mixture was filtered; the filter cake was washed with MeOH (3x20 mL). The filtrate was concentrated under reduced pressure. The crude product of the title compound (3.8 g) was used to the next step directly without further purification. MS-ESI: 215 (M+1).

Steps 5-7 used similar procedures for converting compound 148’’ to intermediate 59 shown in Scheme 36 to afford intermediate 81 from compound 221’’. MS-ESI: 328 (M+1). Table 13. The Intermediates in the following Table were prepared using the similar procedures for converting compound 217’’ to Intermediate 81 shown in Scheme 51 from appropriate starting materials.

Scheme 52:

N-(tert-butyldimethylsilyl)-4-((tert-butyldimethylsilyloxy)m ethyl)benzenesulfonimidamide

Example 233 (Compound 342)

N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4- (hydroxymethyl)benzenesulfonimidamide

Step 1: 4-(Hydroxymethyl)benzenesulfonamide

Into a 100-mL round-bottom flask, was placed 4-sulfamoylbenzoic acid (1.0 g, 4.97 mmol) in THF (15 mL). This was followed by the addition of BH ₃ -THF (14.3 mL, 149 mmol) dropwise with stirring at 0℃ in an ice/ethanol bath. The resulting solution was stirred for 12 h at RT. The reaction was then quenched by the addition of HCl (50 mL, 2 M) dropwise in an ice bath and stirred for 1h at RT. The mixture was extracted with 8x50 mL of ethyl acetate. The organic layers were combined and concentrated. This resulted in 800 mg (86%) of the title compound as a yellow solid. MS-ESI: 188 (M+1).

Steps 2-3 used similar procedures for converting compound 148’’ to Intermediate 59 shown in Scheme 36 to afford Intermediate 83 from compound 225’’. MS-ESI: 415 (M+1).Steps 4-5 used similar procedures for converting compound 166’’ to Intermediate 67 shown in Scheme 40A to afford compound Example 233 from Intermediate 83. MS-ESI: 386 (M+1). Intermediate 84

O S NH ₂

B

4-(Bromomethyl)-N'-(1,2,3,5,6,7-h exa y ro-s- n acen- -y carbamoyl)benzenesulfonimidamide Step 6: 4-(Bromomethyl)-N'-(1,2,3,5,6,7-hexahydro-s-indacen-4- ylcarbamoyl)benzenesulfonimidamide

Into a 250-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 1-[amino[4-(hydroxymethyl)phenyl]oxo- ^ ⁶ -sulfanylidene]-3-(1,2,3,5,6,7-hexahydro- s-indacen-4-yl)urea (1.0 g, 2.59 mmol) in THF (50 mL). To the stirred solution was added PBr ₃ (702 mg, 2.59 mmol) in portions. The resulting solution was stirred for 3 h at RT. The solids were collected by filtration. This resulted in 500 mg (43%) of the title compound as a white solid. MS- ESI: 449/411 (M+1).

Scheme 53:

Intermediate 85 N

N TBS N'-(tert-butyldimethylsilyl)-2-me isoquinoline-6-sulfonimidamide Step 1: 6-Bromo-2-methyl-1,2,3,4-tetrahydroisoquinoline

Into a 250-mL round-bottom flask, was placed 6-bromo-1,2,3,4-tetrahydroisoquinoline (6.0 g, 28.3 mmol) in MeOH (100 mL) under N ₂ . To the stirred solution was added HCHO (1.02 g, 34 mmol) in portions at RT. The resulting solution was stirred for 4 h, then NaBH3CN (3.56 g, 56.6 mmol) was added in portions at RT. The resulting solution was stirred overnight at RT. The reaction was then quenched by the addition of water (100 mL) and extracted with 3x150 mL ethyl acetate. The organic layers were combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was eluted from a silica gel column with acetate/petroleum ether (1:1). This resulted in 5 g (78.2%) of the title compound as a white solid. MS-ESI: 226/228 (M+1).

teps 2-5 used similar procedures for converting compound 185’’ to Intermediate 173’’ shown in Scheme 44 to afford Intermediate 85 from compound 229. MS-ESI: 238 (M+1). Scheme 54:

Intermediate 86

N'-(tert-butyldimethylsilyl)-2-methyl-1, tetrahydroisoquinoline-7-sulfonimidamide

Step 1: 1-(3,4-Dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethanone

Into a 250-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 1,2,3,4-tetrahydroisoquinoline (8.0 g, 60.1 mmol) and 2,2,2-trifluoroacetic anhydride (25.2 g, 120mmol). The resulting solution was stirred for 12 h at RT. The reaction was then quenched by the addition of 100 mL of water/ice. The resulting solution was extracted with 3x100 mL of ethyl acetate and the organic layers were combined and dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 10 g (72.6%) of the title compound as a yellow solid. MS-ESI: 230 (M+1).

Steps 2-3 used similar procedures for converting compound 158’’ to Intermediate 61 shown in Scheme 38 to afford compound 236’’ from compound 234’’. MS-ESI: 309 (M+1).

Step 4: 1,2,3,4-Tetrahydroisoquinoline-7-sulfonamide

Into a 100-mL round-bottom flask, was placed 2-(2,2,2-trifluoroacetyl)-1,2,3,4– tetrahydroisoquinoline -7-sulfonamide (8.0 g, 26 mmol) in ethanol (12 mL) and H2O (60 mL). To the stirred solution was added KOH (7.28 g, 123 mmol) in one portion at RT. The resulting solution was stirred for 12 h at RT. The resulting mixture was concentrated. The crude product was applied onto a silica gel column with DCM/MeOH (10:1). This resulted in 5.0 g (90.8%) of the title compound as a light yellow solid.

Step 5 used similar procedures for converting compound 228’’ to compound 229’’ shown in Scheme 53 to afford compound 238’’ from compound 237’’. MS-ESI: 227 (M+1).

Steps 6-7 used similar procedures for converting compound 148’’ to intermediate 59 shown in Scheme 36 to afford intermediate 86 from compound 238’’. MS-ESI: 340 (M+1). Scheme 55:

N'-(tert-butyldimethylsilyl)-2-methyl-1,2,3,4-tetrahydroisoq uinoline-7-sulfonimidamide Step 1: 4-((Dimethylamino)methyl)-2-methoxybenzenesulfonamide

Into a 50-mL round-bottom flask, was placed 4-[(dimethylamino)methyl]-2-fluorobenzene-1- sulfonamide (1 g, 4.31 mmol) and DMF (10 mL, 0.14 mmol). Then to the above was added sodium methoxide (2.16 g, 40 mmol). The resulting solution was stirred for 12 h at RT. The reaction was then quenched by the addition of 5.0 mL of water. The residue was eluted from a C18 column with ACN:H ₂ O (3:7). This resulted in 800 mg (76.1%) of the title compound as a yellow solid. MS- ESI: 245 (M+1).

Steps 2-3 used similar procedures for converting compound 148’’ to intermediate 59 shown in Scheme 36 to afford intermediate 87 from compound 240’’. MS-ESI: 358 (M+1). Scheme 56:

N'-(tert-butyldimethylsilyl)-5-((dimethylamino)methyl)-3-flu orothiophene-2-sulfonimidamide Step 1: (4-Fluorothiophen-2-yl)methanol

Into a 1000-mL round-bottom flask, was placed methyl 4-fluorothiophene-2-carboxylate (10 g, 62.4 mmol) in ethanol (300 mL). Then to the above solution was added NaBH4 (4.62 g, 125 mmol) in portions at 0℃ in an ice/ethanol bath. The resulting solution was stirred for 30 min at 0℃ and then the reaction solution was allowed to react for an additional 16 h at RT. The reaction was then quenched by the addition of 50 mL of water. Then the mixture was concentrated and extracted with 3x100mL of ethyl acetate and the organic layers were combined and dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 6.4 g (77.6%) of the title compound as white oil. MS-ESI: 133 (M+1)

Step 2: 2-(Bromomethyl)-4-fluorothiophene

Into a 250-mL round-bottom flask, was placed (4-fluorothiophen-2-yl)methanol (8.5 g, 64.3 mmol) in DCM (70 mL). To the stirred solution was added PBr ₃ (19.2 g, 70.8 mmol) dropwise at 0℃ in an ice/ethanol bath. The resulting solution was stirred for 30 min at 0℃. The resulting solution was allowed to react for an additional 12 h at RT. The reaction was then quenched by the addition of 50 mL of water. Then the mixture was concentrated and extracted with 3x100mL of ethyl acetate and the organic layers were combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was eluted from a silica gel column with ethyl acetate/petroleum ether (15/85). This resulted in 7.0 g (55.8%) of the title compound as yellow oil. MS-ESI: 194/196 (M+1).

Step 3: 1-(4-Fluorothiophen-2-yl)-N,N-dimethylmethanamine

Into a 250-mL round-bottom flask, was placed 2-(bromomethyl)-4-fluorothiophene (7.4 g, 37.9 mmol) in CHCl3 (50 mL). To the above solution was added butoxytributyl-l4-azane sulfate (6.76 g, 19 mmol) and DMA (37 mL, 425 mmol) with stirring at RT. The resulting solution was stirred for 2h at 60℃. The reaction was then quenched by the addition of 50 mL of water. Then the mixture was concentrated and extracted with 3x100mL of ethyl acetate and the organic layers were combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was eluted from a silica gel column with ethyl acetate/petroleum ether (17/83). This resulted in 6.0 g (99.5%) of the title compound as a yellow solid. MS-ESI: 160 (M+1).

Step 4: Lithium 5-((dimethylamino)methyl)-3-fluorothiophene-2-sulfinate

Into a 500-mL 3-necked round-bottom flask purged with and maintained under nitrogen, was placed a solution of [(4-fluorothiophen-2-yl)methyl]dimethylamine (6.2 g, 38.9 mmol) in THF (60 mL). This was followed by the addition of n-BuLi/THF (18.7 mL, 2.5 M) dropwise with stirring at -78℃ in a liquid nitrogen/ethanol bath. The resulting solution was stirred for 30 min at -78℃. To the above SO ₂ (g) was introduced into the reaction solution at -78℃. The resulting solution was allowed to react for an additional 2 h at RT. The resulting mixture was concentrated. This resulted in 10 g (crude) of the title compound as a yellow solid. MS-ESI: 222 (M-1).

Step 5: 5-((Dimethylamino)methyl)-3-fluorothiophene-2-sulfonyl chloride

Into a 500-mL round-bottom flask, was placed a solution of 5-[(dimethylamino)methyl]-3- fluorothiophene -2-sulfinic acid (10 g, 44.8 mmol) in THF (100 mL). To the above solution was added NCS (7.18 g, 53.8 mmol). The resulting solution was stirred for 30 min at 0℃ and then allowed to react for an additional 2h at RT. This reaction was used for next step without purification. Step 6: 5-((Dimethylamino)methyl)-3-fluorothiophene-2-sulfonamide

Into a 500-mL round-bottom flask, was placed a solution of 5-[(dimethylamino)methyl]-3- fluorothiophene -2-sulfonyl chloride (10 g, 38.8 mmol) in THF (100 mL). To the above NH ₃ (g) was introduced at RT. The resulting solution was stirred for 30 min at RT. The resulting mixture was concentrated. The residue was eluted from a silica gel column with ethyl acetate/petroleum ether (60/40). This resulted in 2.1 g (22.7%) of the title compound as yellow oil. MS-ESI: 239 (M+1).

Step 7: N-(tert-butyldimethylsilyl)-5-((dimethylamino)methyl)-3-fluo rothiophene-2- sulfonamide

Into a 100-mL round-bottom flask, was placed a solution of 5-[(dimethylamino)methyl]-3- fluorothiophene -2-sulfonamide (1.8 g, 7.55 mmol) in THF (30 mL) under N2. To the above solution was added NaH (60%wt. oil dispersion, 640mg, 15 mmol) with stirring at 0℃. The resulting solution was stirred for 5 min at 0℃. This was followed by the addition of TBSCl (1.37 g, 9.09 mmol) at 0℃. The resulting solution was allowed to react for an additional 15 h at RT. The reaction was then quenched by the addition of 20 mL of water. Then the mixture was concentrated and extracted with 3x100mL of ethyl acetate and the organic layers were combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was eluted from a silica gel column with ethyl acetate/petroleum ether (1:1). This resulted in 2.0 g (75.2%) of the title compound as yellow oil. MS-ESI: 353 (M+1).

Step 8: N-(tert-butyldimethylsilyl)-5-((dimethylamino)methyl)-3-fluo rothiophene-2- sulfonimidoyl chloride

Into a 500-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed a solution of PPh ₃ Cl ₂ (29.5 g, 88.7 mmol) in CHCl ₃ (50 mL). To the above solution was added DIEA (17.2 g, 133 mmol) dropwise in an ice/water bath. The solution was stirred at RT for 20 minutes. This was followed by the addition of N-(tert-butyldimethylsilyl)-5- [(dimethylamino)methyl]-3-fluorothiophene- 2-sulfonamide (15.7 g, 44.4 mmol) in CHCl ₃ (30 mL) at 0℃. The resulting solution was allowed to react for an additional 30 min at 0℃. Then the reaction solution was used for next step without purification.

Step 9: N'-(tert-butyldimethylsilyl)-5-((dimethylamino)methyl)-3-flu orothiophene-2- sulfonimidamide

Into a 500-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed [(tert-butyldimethylsilyl)imino](chloro)[5-[(dimethylamino)m ethyl]-3- fluorothiophen-2-yl]- ^ ⁶ -sulfanone (16.5 g, 44.4 mmol) in CHCl ₃ (80 mL). To the above NH ₃ (g) was introduced at 0℃ for 15min. The resulting solution was stirred for 15 min at 0℃ and then allowed to react for an additional 15 h at RT. The resulting mixture was concentrated. The residue was eluted from a silica gel column with ethyl acetate/ petroleum ether (60/40). This resulted in 5.8 g (37.2 %) of the title compound as a yellow solid. MS-ESI: 352(M+1). Scheme 68: Intermediate 112

N'-(tert-butyldimethylsilyl)-2-(2-hydroxypropan-2-yl)thiazol e-5-sulfonimidamide Step 1: 2-(2-Hydroxypropan-2-yl)thiazole-5-sulfonimidamide

Into a 250-mL round-bottom flask, was placed a solution of tert-butyl 2-(2-hydroxypropan- 2-yl)thiazole-5-sulfonimidoylcarbamate (3.21 g, 10 mmol) in HCl/dioxane (4 M, 50 mL). The resulting solution was stirred for 1 h at RT. The solution was concentrated to give the title compound (3.2 g, crude, yellow oil). MS-ESI: 222 (M+1).

Step 2: N'-(tert-butyldimethylsilyl)-2-(2-hydroxypropan-2-yl)thiazol e-5-sulfonimidamide Into a 250-mL round-bottom flask, was placed 2-(2-hydroxypropan-2-yl)thiazole-5- sulfonimidamide (3.2 g crude, 10 mmol) in THF (100 mL), DIEA (3.87 g, 30 mmol) was added in at RT. Then TBSCl (3.0 g, 20 mmol) was added to the solution in portions. The resulting solution was stirred for 16 h at RT. The solution was concentrated and the crude product was purified by silica gel column with ethyl acetate/ petroleum ether (1:1) to give the title compound (2.3 g, yield 70%, yellow solid). MS-ESI: 336 (M+1). Scheme 69:

Intermediate 113

O N S N S NH ₂

HO

2-(2-Hydroxypropan-2-yl)-N-methylthiazole-5-sulfonimidamide Step 1: Tert-butyl (chloro(2-(2-hydroxypropan-2-yl)thiazol-5-yl)(oxo)- ^ ⁶ - sulfaneylidene)carbamate

Into a 1-L round-bottom flask, was placed tert-butyl N-[[2-(2-hydroxypropan-2-yl)-1,3-thiazol-5- yl]sulfinyl]carbamate (100 g, 326 mmol) in ACN (500 mL). To the stirred solution was added NCS (65.4 g, 49 mmol). The resulting solution was stirred for 2 h at RT. The resulted solution was concentrated. This resulted in 120 g crude title compound as yellow oil.

Step 2: Tert-((2-(2-hydroxypropan-2-yl)thiazol-5-yl)(methylamino)(ox o)- ^ ⁶ - sulfaneylidene)carbamate

Into a 250-mL round-bottom flask, was placed tert-butyl N-[chloro[2-(2-hydroxypropan-2-yl)-1,3- thiazol-5- yl]oxo- ^ ⁶ -sulfanylidene]carbamate (10 g, 29.3 mmol) in THF (100 mL). To the stirred solution was added CH ₃ NH ₂ (1.82 g, 58.6 mmol). The resulting solution was stirred for 2 h at RT. The resulted solution was concentrated. The residue was eluted from silica gel with ethyl acetate/ petroleum ether (1:1). This resulted in 6.1 g (62%) of the title compound as a yellow solid. MS- ESI: 336 (M+1). Step 3: 2-(2-Hydroxypropan-2-yl)-N'-methylthiazole-5-sulfonimidamide

Into a 100-mL round-bottom flask, was placed tert-butyl((2-(2-hydroxypropan-2-yl)thiazol-5-yl) (methylamino)(oxo)- ^ ⁶ -sulfaneylidene)carbamate (3.0 g, 8.94 mmol) in HCl (gas) in 1,4-dioxane (8.0 mL, 26.3 mmol) in one portion at RT. The resulting solution was stirred for 60 min at RT. The resulting mixture was concentrated under vacuum. This resulted in 2.10 g crude title compound as a yellow solid. MS-ESI: 236 (M+1). The schemes below illustrate the synthesis of Intermediates 89-96, 101-104, 114-117A, and

118’’-126’’, which are isocyanate and precursors thereof as well as other intermediates: Scheme 57:

Intermediate 89

7-Nitro-6-vinyl-1H-indazole

Step 1: 7-Nitro-1H-indazol-6-ol

Into a 25-mL round-bottom flask, was placed 1H-indazol-6-ol (500 mg, 3.73 mmol). This was followed by the addition of H2SO4 (5.0 mL) in several batches at 0℃. To this was added KNO3 (377 mg, 3.73 mmol) in portions at 0℃. The resulting solution was stirred for 30 min at 0℃ in a water/ice bath. The reaction was then quenched by the addition of 50 mL of water/ice. The solids were collected by filtration. This resulted in 350 mg (52.4%) of the title compound as a brown solid. MS-ESI: 180 (M+1).

Step 2: 7-Nitro-1H-indazol-6-yl trifluoromethanesulfonate

Into a 50-mL round-bottom flask, was placed 7-nitro-1H-indazol-6-ol (350 mg, 1.95 mmol) in DCM (10 mL), TEA (593 mg, 5.86 mmol), Tf ₂ O (717 mg, 2.54 mmol). The resulting solution was stirred for 16 h at RT. The resulting solution was diluted with 20 mL of H2O. The resulting solution was extracted with 3x20 mL of ethyl acetate dried over anhydrous sodium sulfate and concentrated. The residue was eluted from a silica gel column with ethyl acetate/petroleum ether (1:3). This resulted in 80 mg (13.2%) of the title compound as a yellow solid. MS-ESI: 312 (M+1). Step 3: 7-Nitro-6-vinyl-1H-indazole

Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 7-nitro-1H-indazol-6-yl trifluoromethanesulfonate (100 mg, 0.32 mmol) in dioxane (10 mL) and H2O (2.0 mL), Cs2CO3 (209 mg, 0.64 mmol), 2-ethenyl-4,4,5,5-tetramethyl-1,3,2- dioxaborolane (59.4 mg, 0.39 mmol), Pd(dppf)Cl2 (23.5 mg, 0.030 mmol). The resulting solution was stirred for 16 h at 90℃. in an oil bath. Then the mixture was concentrated under vacuum. The residue was eluted from a silica gel column with ethyl acetate/petroleum ether (1:3). This resulted in 50 mg (82.6%) of the title compound as a yellow solid. MS-ESI: 190 (M+1). Intermediate 90

Step 4: 6-Ethyl-1H-indazol-7-amine

Into a 50-mL round-bottom flask, was placed 6-ethenyl-7-nitro-1H-indazole (50 mg) in MeOH (10 mL), and Pd/C (10% wt., 5.0 mg). The flask was evacuated and flushed three times with hydrogen. The resulting solution was stirred for 12 h at RT under an atmosphere of hydrogen. The Pd/C catalysts were filtered out, the filtrate was concentrated under vacuum. This resulted in 44 mg of the title compound as a yellow solid. MS-ESI: 162 (M+1). Scheme 58:

6- e

Step 1: 2-Methyl-7-nitro-6-vinyl-2H-indazole

Into a 50-mL round-bottom flask, was placed 6-ethenyl-7-nitro-1H-indazole (380 mg, 2.01 mmol) in acetone (20 mL), KOH (225 mg, 4.02 mmol). This was followed by the addition of MeI (342 mg, 2.41 mmol) dropwise with stirring. The resulting solution was stirred for 1 h at 0℃ in a water/ice bath. The resulting solution was diluted with 20 mL of H ₂ O. The resulting solution was extracted with 3x30 ml of ethyl acetate dried over anhydrous sodium sulfate and concentrated. The residue was eluted from a silica gel column with ethyl acetate/petroleum ether (1:1). This resulted in 210 mg (51.5%) of 254’’ as a yellow solid and 180 mg (44%) of 255’’ as a yellow solid. MS- ESI: 208 (M+1).

Step 2: 6-Ethyl-2-methyl-2H-indazol-7-amine

Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of N2, was placed 6-ethenyl-1-methyl-7-nitro-1H-indazole (210 mg, 1.03 mmol) in MeOH (15 mL) and Pd/C (10% wt., 50 mg). The flask was evacuated and flushed three times with hydrogen. The resulting solution was stirred for 12 h at RT under an atmosphere of hydrogen. The Pd/C catalysts were filtered out, and the filtrate was concentrated under vacuum. This resulted in 160 mg (88.4%) of the title compound as a yellow solid. MS-ESI:176 (M+1). Table 14. The Intermediates in the following Table were prepared using the similar procedures for converting compound 254’’ to Intermediate 91 shown in Scheme 58 from 255’’. Intermediate Structure IUPAC Name Exact Mass # [M+H] ⁺ te Scheme 59:

H ^{O O} B Li DMF O _malo ^P _ni ^y _c ^, _{acid Pd/C,H2} (COCl) ₂ , DCM

4 Br 2 -phos

B

2,4,5,6-Tetrahydro-1H-cyclobuta[f]inden-3-amine Step 1: Bicyclo[4.2.0]octa-1(6),2,4-triene-3-carbaldehyde

Into a 500-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 3-bromobicyclo[4.2.0]octa-1(6),2,4-triene (70 g, 382 mmol) in THF (300 mL). This was followed by the addition of n-BuLi (184 mL, 459 mmol) dropwise with stirring at about -70℃. After addition, the reaction mixture was stirred at this temperature for 30 min. To this solution was added DMF (36.3 g, 497 mmol) dropwise with stirring at -70℃. The resulting solution was stirred for 30 min at -70℃ in a liquid nitrogen bath. The reaction was slowly warmed to RT and then quenched by the addition of 100 mL of water. The resulting solution was extracted with 3x200 ml of DCM. The organic layers combined and dried over anhydrous Na ₂ SO ₄ , and then the organic layers was concentrated. This resulted in 50 g (98.9%) of the title compound as light yellow oil. MS-ESI: 133 (M+1). Step 2: (Z)-3-(bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)acrylic acid

Into a 250-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed bicyclo[4.2.0]octa-1(6),2,4-triene-3-carbaldehyde (1.7 g, 12.9 mmol) in pyridine (20 mL), propanedioic acid (1.99 g, 19.2 mmol) and piperidine (110 mg, 1.29 mmol). The resulting solution was stirred for overnight at 90℃. in an oil bath. The resulting mixture was concentrated. This resulted in 2.1 g (93.7%) of the title compound as a solid. MS-ESI: 173 (M-1). Step 3: 3-(Bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)propanoic acid

Into a 250-mL round-bottom flask, was placed 2-(Z or E)-3-[bicyclo[4.2.0]octa-1(6),2,4-trien-3- yl]prop -2-enoic acid (2.1 g, 12.1 mmol) and Pd/C (10% wt., 200 mg). The flask was evacuated and flushed three times with hydrogen. The resulting solution was stirred for 12 h at RT under an atmosphere of hydrogen. The Pd/C catalysts were filtered out, the filtrate was concentrated under vacuum. This resulted in 2.1 g (98.9%) of the title compound as a solid. MS-ESI: 175 (M-1). Step 4: 3-(Bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)propanoyl chloride

Into a 250-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 3-[bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl]propanoic acid (10 g, 56.8 mmol) in DCM (100 mL). This was followed by the addition of oxalyl chloride (7.2 g, 56.8 mmol) dropwise with stirring at 0℃. The resulting solution was stirred for 2 h at 0℃ in a water/ice bath. The resulting mixture was concentrated. This resulted in 10 g (90.5%) of the title compound as light yellow oil. Step 5: 1,2,5,6-Tetrahydro-4H-cyclobuta[f]inden-4-one

Into a 100-mL round-bottom flask, was placed 3-[bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl]propanoyl chloride (5.0 g, 25.7 mmol) in DCM (50 mL). This was followed by the addition of AlCl3 (3.4 g, 25.7 mmol) in portions at 0℃. for 10 min. The resulting solution was stirred for 1 h at 0℃ in a water/ice bath. The reaction was then quenched by the addition of 100 mL of water. The resulting solution was extracted with 2x50 mL of DCM. The organic layers combined and dried over anhydrous Na ₂ SO ₄ , then concentrated. The residue was eluted from a silica gel column with ethyl acetate/petroleum ether (1:20 to 1:15). This resulted in 3.5 g (86.1%) of the title compound as a white solid. ¹ H NMR (300 MHz, CDCl3) d 7.45 (s, 1H), 7.17 (s, 1H), 3.22 (m, 4H), 3.18– 3.00 (m, 2H), 2.73– 2.63 (m, 2H). Step 6: 2,4,5,6-Tetrahydro-1H-cyclobuta[f]indene

Into a 500-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 1,2,5,6-tetrahydrocyclobuta[f]inden-4-one (20 g, 126 mmol) in THF (200 mL). This was followed by the addition of BH3-Me2S (25.3 mL, 253 mmol, 10 M) dropwise at 0℃ in an ice bath. The resulting solution was stirred for 14 h at 70℃ in an oil bath. The reaction was then quenched by the addition of 20 mL of MeOH. The resulting mixture was concentrated. The residue was eluted from a silica gel column with ethyl acetate/petroleum ether (1:100 to 1:50). This resulted in 15 g (82.3%) of the title compound as colorless oil. ¹ H NMR (300 MHz, CDCl3) d 6.95 (s, 2H), 3.10 (s, 4H), 2.88 (t, J = 7.4 Hz, 4H), 2.03 (p, J = 7.4 Hz, 2H). Step 7: 3-Iodo-2,4,5,6-tetrahydro-1H-cyclobuta[f]indene

Into a 500-mL round-bottom flask, was placed acetic acid (100 mL), 2,4,5,6-tetrahydro-1H- cyclobuta[f]indene (15 g, 104 mmol) and NIS (35.1 g, 156 mmol). The resulting solution was stirred for 3 h at 50℃ in an oil bath. The resulting solution was diluted with 200 mL of water. The mixture was extracted with 3x100 mL of DCM. The organic layers combined and dried over anhydrous Na ₂ SO ₄ , then concentrated. The residue was eluted from a silica gel column with ethyl acetate/petroleum ether (1:100 to 1:80). This resulted in 5.0 g (17.8%) of the title compound as yellow oil. Step 8: Tert-butyl (2,4,5,6-tetrahydro-1H-cyclobuta[f]inden-3-yl)carbamate:

Into a 250-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 3-iodo-2,4,5,6-tetrahydro-1H-cyclobuta[f]indene (5.0 g, 18.5 mmol) in toluene (100 mL), tert-butyl carbamate (6.5 g, 55.5 mmol), X-phos (900 mg, 1.85 mmol), Pd2(dba)3 (800 mg, 0.93 mmol) , t-BuOK (6.2 g, 55.5 mmol). The resulting solution was stirred for 14 h at 100℃ in an oil bath. The resulting mixture was concentrated. The residue was eluted from a silica gel column with ethyl acetate/petroleum ether (1:50 to 1:20). This resulted in 3.0 g (83.3%) of the title compound as a white solid. MS-ESI: 260 (M+1).

1H NMR (300 MHz, CDCl3) d 6.72 (s, 1H), 6.13 (br, 1H), 3.26 (d, J = 4.5 Hz, 2H), 3.01 (d, J = 4.5 Hz, 2H), 2.90 (t, J = 7.4 Hz, 2H), 2.75 (t, J = 7.4 Hz, 2H), 2.06 (p, J = 7.4 Hz, 2H), 1.52 (s, 9H). Step 9: 2,4,5,6-Tetrahydro-1H-cyclobuta[f]inden-3-amine

Into a 100-mL round-bottom flask, was placed tert-butyl2,4,5,6-tetrahydro-1H-cyclobuta[f]inden- 3-ylcarbamate (3.0 g, 11.6 mmol) in DCM (20 mL), 2,2,2-trifluoroacetic acid (5.0 mL). The resulting solution was stirred for 2 h at RT. The resulting solution was diluted with 50 mL of water. The pH value of the solution was adjusted to 10 with sat. aqueous Na2CO3. The resulting solution was extracted with 3x20 mL of DCM. The organic layers combined and dried over anhydrous Na2SO4, then concentrated. This resulted in 1.5 g (81.4%) of the title compound as a yellow solid. MS-ESI: 160 (M+1). Scheme 60:

Intermediate 94

amine

Step 1: 8-Nitro-2,3,5,6-tetrahydro-7H-indeno[5,6-b]furan-7-one

Into a 100-mL round-bottom flask, was placed 2H,3H,5H,6H,7H-indeno[5,6-b]furan-7-one (4 g, 23 mmol,) in H ₂ SO ₄ (20 mL). This was followed by the addition of HNO ₃ (2.13 g, 23 mmol, 68%) dropwise with stirring at 0℃ in an ice/ethanol bath. The resulting solution was stirred for 1 h at 0℃. The reaction was then quenched by the addition of 200 mL of water/ice. The solids were collected by filtration. This resulted in 4.0 g (79.5%) of the title compound as a light brown solid. MS-ESI: 220 (M+1). Step 2: 3,5,6,7-Tetrahydro-2H-indeno[5,6-b]furan-8-amine

Into a 100-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 8-nitro-2H,3H,5H,6H,7H-indeno[5,6-b]furan-7-one (4.0 g, 18.3 mmol) in MeOH (50 mL), TsOH (1.0 mL), Pd(OH)2/C (20%wt., 1 g). The flask was evacuated and flushed three times with hydrogen. The resulting solution was stirred for 16 h at RT under an atmosphere of hydrogen. The solids were filtered out. The resulting mixture was concentrated. The residue was dissolved in 50 mL of EA. The resulting mixture was washed with 2x50 ml of NaHCO3 and 3 x40 ml of H ₂ O. The mixture was dried over anhydrous sodium sulfate. The residue was eluted from a silica gel column with ethyl acetate/petroleum ether (1:9). This resulted in 1.1 g (34.4%) of the title compound as a yellow solid. MS-ESI: 176 (M+1). Step 3: 4-Bromo-3,5,6,7-tetrahydro-2H-indeno[5,6-b]furan-8-amine

Into a 50-mL round-bottom flask, was placed 2H,3H,5H,6H,7H-indeno[5,6-b]furan-8-amine (1.1 g, 6.28 mmol) in ACN (30 mL) and NBS (1.34 g , 7.53 mmol). The resulting solution was stirred for 2 h at RT. The resulting mixture was concentrated. The residue was eluted from a silica gel column with ethyl acetate/petroleum ether (1:8). This resulted in 83 mg (52 %) of the title compound as a yellow solid. MS-ESI: 254 (M+1). Step 4: 4-Bromo-3,5,6,7-tetrahydro-2H-indeno[5,6-b]furan

Into a 50-mL round-bottom flask, was placed 4-bromo-2H,3H,5H,6H,7H-indeno[5,6-b]furan-8- amine (500 mg, 1.97 mmol) in ethanol (15 mL) and acetic acid (3.0 mL, 0.050 mmol). To the above solution was added NaNO ₂ (1.36 g, 19.7 mmol) in H ₂ O (3 mL) dropwise at 0℃. The resulting solution was stirred for 2 h at RT. The resulting solution was diluted with 30 mL of H2O. The resulting solution was extracted with 3x30 ml of ethyl acetate dried over anhydrous sodium sulfate and concentrated. The residue was eluted from a silica gel column with ethyl acetate/petroleum ether (1:10). This resulted in 100 mg (21.3%) of the title compound as a yellow solid. MS-ESI: 239 (M+1). Step 5: Tert-butyl (3,5,6,7-tetrahydro-2H-indeno[5,6-b]furan-4-yl)carbamate

Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 4-bromo-2H,3H,5H,6H,7H-indeno[5,6-b]furan (120 mg, 0.50 mmol) in toluene (15 mL), t-BuOK (282 mg, 2.51 mmol), tert-butyl carbamate (588 mg, 5.02 mmol), Xphos (47.8 mg, 0.10 mmol), and Pd2(dba)3CHCl3 (104 mg, 0.10 mmol). The resulting solution was stirred for 16 h at 100℃ in an oil bath. The resulting mixture was concentrated. The residue was eluted from a silica gel column with ethyl acetate/petroleum ether (1:5). This resulted in 80 mg (57.9%) of the title compound as a yellow solid. MS-ESI: 276 (M+1). Step 6: 3,5,6,7-Tetrahydro-2H-indeno[5,6-b]furan-4-amine

Into a 50-mL round-bottom flask, was placed tert-butyl N-[2H,3H,5H,6H,7H-indeno[5,6-b]furan- 4-yl] carbamate (80 mg, 0.29 mmol) in DCM (8 mL) and TFA (3.0 mL, 0.030 mmol). The resulting solution was stirred for 2 h at room temperature. The resulting mixture was concentrated. The residue was dissolved in 15 mL of DCM. The resulting mixture was washed with 2 x15 ml of NaOH (aq.). The organic layer was dried with Na ₂ SO ₄ and then concentrated. This resulted in 50 mg (98.2%) of the title compound as a yellow solid. MS-ESI: 176(M+1). Scheme 61:

Tricyclo[6.2.0.0 ^3,6 ]deca-1,3 -trien-2-amine Step 1: 2,2'-(1,4-Phenylene)bis(ethan-1-ol)

Into a 1.0-L round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 2-[4-(carboxymethyl)phenyl]acetic acid (40 g, 200 mmol) in THF (500 mL). This was followed by the addition of BH ₃ -Me ₂ S (60 mL, 600 mmol, 10 M) dropwise with stirring at 0℃. The resulting solution was stirred for 24 h at RT. The reaction was then quenched by the addition of 200 mL of water. The resulting solution was extracted with 2x150 mL of ethyl acetate. The organic layers combined and dried over anhydrous Na2SO4, then concentrated. The residue was eluted from a silica gel column with ethyl acetate/petroleum ether (1:10 to 1:3). This resulted in 28 g (81.8%) of the title compound as brown oil. MS-ESI: 167 (M+1).

Step 2: 1,4-Bis(2-bromoethyl)benzene

Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 2-[4-(2-hydroxyethyl)phenyl]ethan-1-ol (28 g, 168 mmol) in aq. HBr (300 mL, 40%wt.). The resulting solution was stirred for 5 h at 100℃ in an oil bath. The resulting solution was diluted with 500 mL of water. The resulting solution was extracted with 3x200 mL of DCM. The organic layers combined, then concentrated. This resulted in 40 g (81.4%) of the title compound as a white solid. MS-ESI: 291, 293, 295 (M+1).

Step 3: 1,4-Dibromo-2,5-bis(2-bromoethyl)benzene

Into a 500-mL round-bottom flask, was placed 1,4-bis(2-bromoethyl)benzene (30 g, 103 mmol) in trichloromethane (200 mL). To the above solution was added I2 (0.78 g, 3.08 mmol), iron powder (0.75 g, 13.4 mmol), Br ₂ (41 g, 257 mmol). The resulting solution was stirred for 24 h at RT. The reaction was then quenched by the addition of aqueous Na2SO3. The resulting solution was extracted with 3x200 mL DCM and the organic layers was combined and dried over anhydrous Na ₂ SO ₄ then concentrated. This resulted in 40 g (86.6%) of the title compound as a white solid. MS-ESI: 449/451/453 (M+1).

Step 4: Tricyclo[6.2.0.0 ^3,6 ]deca-1,3(6),7-triene

Into a 1000-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 1,4-dibromo-2,5-bis(2-bromoethyl)benzene (40 g, 88.9 mmol) in THF (400 mL). This was followed by the addition of n-BuLi (74.7 mL, 187 mmol, 2.5 M) dropwise with stirring at - 78℃ in a liquid nitrogen bath. The resulting solution was stirred for 30 min at -78℃. The reaction was then quenched by the addition of aqueous NH4Cl (300 ml) and extracted with 2x200 mL of DCMDCM and the organic layers was combined and dried over anhydrous Na2SO4 then concentrated. This resulted in 8.0 g (69.1%) of the title compound as a light yellow solid.

Step 5: 2-Iodotricyclo[6.2.0.0 ^3,6 ]deca-1,3(6),7-triene

Into a 250-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed tricyclo[6.2.0.0 ^3,6 ]deca-1,3(6),7-triene (8 g, 61.45 mmol) in acetic acid (50 mL) and NIS (20.7 g, 92.2 mmol). The resulting solution was stirred for 3 h at 50℃ in an oil bath. The resulting solution was diluted with 100 mL of water. The reaction was then quenched by the addition of aqueous Na ₂ SO ₃ . The resulting solution was extracted with 3x50 mL of DCM and the organic layers was combined and dried over anhydrous Na2SO4 then concentrated. The residue was eluted from a silica gel column with ethyl acetate/petroleum ether (1:100). This resulted in 2.5 g (18.2%) of the title compound as a white solid. Step 6: Tert-butyl tricyclo[6.2.0.0 ^3,6 ]deca-1,3(6),7-trien-2-ylcarbamate

Into a 250-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 2-iodotricyclo[6.2.0.0 ^3,6 ]deca-1,3(6),7-triene (2.5 g, 9.76 mmol) in toluene (50 mL). To the stirred solution was added tert-butyl carbamate (3.43 g, 29.3 mmol), Pd2(dba)3 (447 mg, 0.49 mmol), Xphos (466 mg, 0.98 mmol), and t-BuOK (3.29g, 29.3 mmol). The resulting solution was stirred for 14 h at 100℃ in an oil bath. The resulting mixture was concentrated. The residue was eluted from a silica gel column with ethyl acetate/petroleum ether (1:50 to 1:30). This resulted in 1.5 g (62.6%) of the title compound as a light yellow solid. MS-ESI: 246 (M+1).

Step 7: Tricyclo[6.2.0.0 ^3,6 ]deca-1,3(6),7-trien-2-amine

Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed tert-butyl N-[tricyclo[6.2.0.0 ^3,6 ]deca-1,3(6),7-trien-2-yl]carbamate (1.5 g, 6.1 mmol) in DCM (20 mL) and 2,2,2-trifluoroacetic acid (4.0 mL). The resulting solution was stirred for 2 h at RT. The resulting mixture was concentrated. This resulted in 800 mg (90.1%) of the title compound as a brown solid. MS-ESI: 146 (M+1). Scheme 62A:

3-Amino-2,4-diisopropylbenzonitrile Step 1: 3-Amino-2,4-dibromo-6-chlorobenzonitrile

Into a 500-mL round-bottom flask, was placed 5-amino-2-chlorobenzonitrile (10 g, 65.8 mmol), ACN (200 mL) and NBS (17.6 g, 98.7 mmol). The resulting solution was stirred for 14 h at RT. The resulting mixture was concentrated. The residue was eluted from a silica gel column with ethyl acetate/petroleum ether (1:15 to 1:5). This resulted in 18 g of the title compound as a yellow solid. MS-ESI: 310, 312 (M+1).

Step 2: 3-Amino-6-chloro-2,4-di(prop-1-en-2-yl)benzonitrile

Into a 500-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 3-amino-2,4-dibromo-6-chlorobenzonitrile (15 g, 48 mmol) in dioxane (200 mL) and H2O (20 mL), 2-(tetramethyl-1,3,2-dioxaborolan-2-yl)prop-2-en-1-ylium (17.6 g, 106 mmol), Cs ₂ CO ₃ (47 g, 144 mmol), and Pd(dppf)Cl ₂ (1.5 g, 4.8 mmol). The resulting solution was stirred for 14 h at 100℃ in an oil bath. The resulting mixture was concentrated. The residue was eluted from a silica gel column with ethyl acetate/ petroleum ether (1:0 to 1:25). This resulted in 10 g of the title compound as brown oil. MS-ESI: 233 (M+1).

Step 3: 3-Amino-2,4-diisopropylbenzonitrile

Into a 500-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 3-amino-6-chloro-2,4-bis(prop-1-en-2-yl)benzonitrile (10 g, 43 mmol) in MeOH (50 mL). Then Pd/C (10% wt., 2.0 g) was added. The flask was evacuated and flushed three times with hydrogen. The resulting solution was stirred for 16 h at RT under an atmosphere of hydrogen. The solids were filtered out. The resulting filtrate was concentrated under vacuum. This resulted in 8.0 g of the title compound as brown oil. MS-ESI: 203 (M+1). Scheme 65:

8-Amino-1,2,3,5,6,7-hexahydro-s-indacen-1-ol

Step 1: 8-Amino-3,5,6,7-tetrahydro-s-indacen-1(2H)-one

Into a 250-mL round-bottom flask purged and maintained with an inert atmosphere of hydrogen, was placed a solution of 8-nitro-1,2,3,5,6,7-hexahydro-s-indacen-1-one (700 mg, 3.22 mmol) in MeOH (10 mL), and Pd/C (10% wt., 100 mg). The flask was evacuated and flushed three times with hydrogen. The resulting solution was stirred for 2 h at RT under an atmosphere of hydrogen. The Pd/C catalysts were filtered out, and the filtrate was concentrated under vacuum. This resulted in 550 mg (91.2%) of the title compound as a yellow oil. MS-ESI: 188 (M+1).

Step 2: 8-Amino-1,2,3,5,6,7-hexahydro-s-indacen-1-ol

Into a 100 mL round-bottom flask, was placed a solution of 8-amino-3,5,6,7-tetrahydro-s-indacen- 1 (2H)-one (2.0 g, 10.7 mmol ) in ethanol. To this solution was added NaBH4(1.9 g, 50 mmol) with stirring in portions at 0℃ in an ice bath. The resulting solution was stirred for 16 h at RT. The reaction was quenched by water (10 mL). The resulting solution was extracted with 3x50 mL of ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate, and then concentrated under vacuum. This resulted in 1.5 g of the title compound as a yellow solid. MS-ESI: 189 (M+1). Scheme 66:

Intermediate 103

4-Amino-1,2,3,5,6,7-hexahydro-s-indacen-1-ol Step 1: 4-Amino-3,5,6,7-tetrahydro-s-indacen-1(2H)-one

Into a 250-mL round-bottom flask purged and maintained with an inert atmosphere of hydrogen, was placed a solution of 4-nitro-1,2,3,5,6,7-hexahydro-s-indacen-1-one (3.0 g, 13.8 mmol) in MeOH (30 mL), and Pd/C (10% wt., 500 mg). The flask was evacuated and flushed three times with hydrogen. The resulting solution was stirred for 4 h at RT under an atmosphere of hydrogen. The Pd/C catalysts were filtered out, the filtrate was concentrated under vacuum. The residue was eluted from a silica gel column with DCM/MeOH (10:1). This resulted in 2.2 g (85.1%) of the title compound as a white solid. MS-ESI: 187 (M+1).

Step 2: 4-Amino-1,2,3,5,6,7-hexahydro-s-indacen-1-ol

Into a 100-mL round-bottom flask, was placed a solution of 8-amino-3,5,6,7-tetrahydro-s-indacen- 1(2H)-one (2.0 g, 10.7 mmol) in ethanol (20 mL) and NaBH4 (1.9 g, 50 mmol). The resulting solution was stirred for 16h at RT. The reaction was quenched with water. The resulting solution was extracted with 3x50 mL of ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate. The mixture was concentrated under vacuum. This resulted in 1.36 g of the title compound as a yellow solid. MS-ESI: 190 (M+1). Scheme 67:

Intermediate 104

3-(3-(But-3-ynyl)-3H-diazirin-3-yl)propanoic acid

Step 1: Methyl 3-oxohept-6-ynoate

Into a 2000-mL 3-neck round-bottom flask purged with and maintained under nitrogen, was placed methyl 3-oxobutanoate (20 g, 172 mmol) in THF (200 mL). To the above solution was added LDA (200 mL, 400 mmol, 2 M) dropwise at -20℃ in a dry ice bath. Then reaction was allowed to react at -20℃ for 30 min. Then 3-bromoprop-1-yne (20.5 g, 172 mmol) was added to the reaction solution in portions at -20℃. The resulting solution was stirred for 3 h at -20℃ in a dry ice bath. The reaction was then quenched by the addition of 500 mL of NH ₄ Cl solution. The pH value of the solution was adjusted to 3 with HCl (aq). The resulting solution was extracted with 3x200 ml of ethyl acetate and the organic layers was combined and dried over anhydrous Na ₂ SO ₄ , then concentrated. This resulted in the title compound (2.0 g, 7.53%) as white oil.

Step 2: Methyl 2-(2-(but-3-ynyl)-1,3-dioxolan-2-yl)acetate

Into a 500-mL round-bottom flask, was placed methyl 3-oxohept-6-ynoate (20 g, 130 mmol) in toluene (200 mL), ethane-1,2-diol (40.2 g, 649 mmol) and TsOH (2.23 g, 13 mmol). The resulting solution was stirred for 6 h at 120℃ in an oil bath. The resulting solution was diluted with 200 mL of Et ₂ O. The resulting mixture was washed with 3 x100 ml of NaHCO ₃ and 3x100 ml of saturated NaCl solution. The mixture was dried over anhydrous sodium sulfate and concentrated. This resulted in the title compound (20 g, 77.9%) as yellow oil.

Step 3: 2-(2-(But-3-ynyl)-1,3-dioxolan-2-yl)ethanol

Into a 1.0-L 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed methyl 2-[2-(but-3-yn-1-yl)-1,3-dioxolan-2-yl]acetate (90 g, 454 mmol) in THF (300mL). To this above solution was added LiAlH ₄ (17.9 g, 472 mmol) in portions with stirring at 0℃ in an ice/ethanol bath. The resulting solution was stirred for 6 h at RT. The reaction was then quenched by the addition of water/ice. The solids were filtered out. The resulting filtrate was concentrated under vacuum. This resulted in the title compound (80 g crude) and used in the next step directly. MS-ESI: 169 (M-1). Step 4: 1-Hydroxyhept-6-yn-3-one

Into a 3.0-L 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 2-[2-(but-3-yn-1-yl)-1,3-dioxolan-2-yl]ethan-1-ol (80 g, 470 mmol) in THF (1.0L) and HCl (500 mL). The resulting solution was stirred for 16 h at RT. The resulting solution was diluted with 1.0L of water. The mixture was extracted with 3 x1.0L of ethyl acetate and the organic layer was combined and dried over anhydrous sodium sulfate. The solids were filtered out. The resulting filtrate was concentrated under vacuum. The residue was eluted from a silica gel column with DCM/petroleum ether (1:1). This resulted in 20 g of the title compound as a white solid. MS-ESI: 125 (M-1).

Step 5: 2-(3-(But-3-ynyl)diaziridin-3-yl)ethanol

Into a 500-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 1-hydroxyhept-6-yn-3-one (20 g, 159 mmol) in DCM (250 mL). To the above solution was introduced NH ₃ (g) for 15 min at -40℃ in a liquid nitrogen/ethanol bath. The resulting solution was stirred for 1 h at -40℃ and then allowed to react for 16h at RT. The resulting mixture was concentrated. This resulted in 18 g (crude) of the title compound as a white solid. MS-ESI: 141 (M+1).

Step 6: 2-(3-(But-3-ynyl)-3H-diazirin-3-yl)ethanol

Into a 500-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 2-[3-(but-3-yn-1-yl)diaziridin-3-yl]ethan-1-ol (14.4 g, 114 mmol) in DCM (200 mL), TEA (34.6g, 342 mmol), I ₂ (58 g, 228 mmol). The resulting solution was stirred for 4 h at RT. The reaction was then quenched by the addition of Na2S2O3. The resulting mixture was quenched with 100 mL of water. The resulting solution was extracted with 3x300 mL of DCM and the organic layers combined and dried over anhydrous sodium sulfate. The solids were filtered out. The resulting mixture was concentrated. This resulted in 6.0 g (38%) of the title compound as a white solid. MS-ESI: 139 (M+1).

Step 7: 3-(But-3-ynyl)-3-(2-iodoethyl)-3H-diazirine

Into a 250-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 2-[3-(but-3-yn-1-yl)-3H-diazirin-3-yl]ethan-1-ol (5.0 g, 36.2 mmol) in THF (20 mL), imidazole (3.7 g, 54.3 mmol), I2 (9.18 g, 36.2 mmol), PPh3 (14.2 g, 54.3 mmol). The resulting solution was stirred for 16 h at RT. The reaction was then quenched by the addition of 20 mL of saturated Na2S2O3 solution. The resulting solution was extracted with 3x50 mL of DCM dried over anhydrous sodium sulfate. The solids were filtered out. The resulting mixture was concentrated. This resulted in 5.0 g (crude) of the title compound as a yellow solid. MS-ESI: 248 (M+1).

Step 8: 3-(3-(But-3-ynyl)-3H-diazirin-3-yl)propanenitrile

Into a 500-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 3-(but-3-yn-1-yl)-3-(2-iodoethyl)-3H-diazirine (5.0 g, 20.2 mmol) in DMF (250 mL), KCN (2.62 g, 40.3mmol). The resulting solution was stirred for 16 h at 60℃ in an oil bath. The reaction was then quenched by the addition of 20 mL of FeSO4 solution. The resulting solution was extracted with 3x50 ml of ethyl acetate dried over anhydrous sodium sulfate. The solids were filtered out. The resulting mixture was concentrated. This resulted in 2.0 g (crude) of the title compound as a solid. MS-ESI: 148 (M+1).

Step 9: 3-(3-(But-3-ynyl)-3H-diazirin-3-yl)propanoic acid

Into a 100-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 3-[3-(but-3-yn-1-yl)-3H-diazirin-3-yl]propanenitrile (1.0 g, 3.40 mmol) in MeOH (40 mL), NaOH (272 mg, 6.79 mmol). The resulting solution was stirred for 16 h at 90℃ in an oil bath. The resulting solution was concentrated. The residue was eluted from a silica gel column with ethyl acetate/ petroleum ether (1:1). This resulted in 400 mg crude (26.6%) of the title compound as yellow oil. MS-ESI: 167 (M+1). Scheme 70:

Intermediate 114

3 _{,5-Diisopropyl-1-phenyl-1H-pyrazol-4-amine}

Step 1: 3,5-Diisopropyl-1-phenyl-1H-pyrazole

Into a 100-mL round-bottom flask, was placed 2-propanol (50 mL), phenylhydrazine (3.81 g, 35.2 mmol) and 2,6-dimethylheptane-3,5-dione (5.0 g, 32.0 mmol). The resulting solution was stirred overnight at 85℃ in an oil bath. The resulting mixture was concentrated. The residue was dissolved in 100 mL of ethyl acetate. The resulting mixture was washed with 50 mL of H2O. The mixture was dried over anhydrous sodium sulfate and then concentrated. This resulted in 6.9 g (94%) of the title compound as a light yellow oil. MS-ESI: 229 (M+1).

Step 2: 3,5-Diisopropyl-4-nitro-1-phenyl-1H-pyrazole

Into a 100-mL round-bottom flask, was placed 1-phenyl-3,5-bis(propan-2-yl)-1H-pyrazole (6.9 g, 30 mmol) in Ac ₂ O (50 mL). This was followed by the addition of HNO ₃ (4.07 mL, 91 mmol) dropwise with stirring at 0℃ in 10 min. The resulting solution was stirred for overnight at RT. The residue was dissolved in 150 mL of ethyl acetate. The resulting mixture was washed with 2x100 mL of H2O. The mixture was dried over anhydrous sodium sulfate and then concentrated. This resulted in 3.7 g (44.8%) of the title compound as yellow oil. MS-ESI: 274 (M+1).

Step 3: 3,5-Diisopropyl-1-phenyl-1H-pyrazol-4-amine

Into a 250-mL round-bottom flask, was placed 4-nitro-1-phenyl-3,5-bis(propan-2-yl)-1H-pyrazole (3.7 g, 13.5 mmol) in MeOH (100 mL), to the stirred solution was added Pd/C (10%wt., 400 mg). The flask was evacuated and flushed three times with hydrogen. The resulting solution was stirred overnight at RT under an atmosphere of hydrogen. The Pd/C catalysts were filtered out, the filtrate was concentrated under vacuum. This resulted in 2.7 g (82%) of the title compound as a light yellow oil. MS-ESI: 244 (M+1).

1 _{,2,3,6,7,8-Hexahydro-as-indacen-4-amine}

Step 1: 4-Nitro-1,6,7,8-tetrahydro-as-indacen-3(2H)-one (308) and 5-nitro-1,6,7,8- tetrahydro-as-indacen-3(2H)-one (309’’)

Into a 250-mL round-bottom flask was placed a solution of 1,6,7,8-tetrahydro-as-indacen-3(2H)– one (Cpd 307’’ was isolated from 113’’ in Scheme 23 by chromatography) (9.8 g, 46.5 mmol) in H2SO4 (50 mL). Then HNO3 (5.85 g, 92.9 mmol) was added dropwise over 10 min at 0℃. The resulting solution was stirred for 1 h at 0℃. The reaction mixture was slowly added to a mixture of water/ice (100 mL) and DCM (50 mL) with ice bath cooling. The organic layer was collected, dried over Na ₂ SO ₄ and concentrated under vacuum. This resulted in 11 g (89%) of a mixture of cpd 308’’ and cpd 309’’ as a yellow solid. The mixture was monitored by TLC (ethyl acetate/ petroleum ether = 1/10, Rf = 0.4),

Step 2: 1,2,3,6,7,8-hexahydro-as-indacen-4-amine (116)

Into a 100-mL round-bottom flask was placed a solution of the mixture of 4-nitro-1,6,7,8- tetrahydro-as-indacen-3(2H)-one and 5-nitro-1,6,7,8-tetrahydro-as-indacen-3(2H)-one (2.17 g, 10 mmol) in MeOH (30 mL). To the solution was added MSA (1.15 g, 12 mmol). Then Pd(OH)2/C (20%wt., 550 mg) was added. The flask was evacuated and filled three times with hydrogen. The resulting mixture was stirred for 16 h at RT under hydrogen (50 psi). The solids were filtered out and washed with MeOH. The MeOH filtrate and wash was diluted with water (50 mL) and the pH was adjusted to 10.6 with 2 N NaOH. The resulting mixture was filtered and the crude solids were recrystallized from MeOH/water (9:1) with heating. This resulted in 1.38 g (80%) of the title compound as an off-white solid. MS-ESI: 174 (M+1). Scheme 73: O O O

Br ^{LiAlD AlCl} Br O D D _C

D

^con

^D

I

1 _{,2,3,5,6,7-Hexahydro-s-indacen-3,3,5,5-d4-4-amine}

Step 1: 5-Bromo-2,3-dihydro-1H-indene-1,1-d ₂

Into a 250-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of LiAlD ₄ (1.57 g, 37 mmol) in Et ₂ O (150 mL). This was followed by the addition of AlCl ₃ (10.1 g, 76 mmol) in portions at 0℃ in 5 min. To this was added 5- bromo-2,3-dihydro-1H-inden-1-one (4.0 g, 19 mmol) in portions at 0℃ in 5 min. The resulting solution was stirred for 4 h at RT. The reaction mixture was cooled to 0℃ with a water/ice bath.

The reaction was then quenched by careful addition of 10 mL of water. The solids were filtered out. The resulting solution was extracted with 3x100 mL of ethyl acetate and concentrated under vacuum. This resulted in 3.5 g (93%) of the title compound as brown oil. MS-ESI: 199/201 (M+1). Step 2: Tert-butyl (E)-3-(2,3-dihydro-1H-inden-5-yl-1,1-d ₂ )acrylate

Into a 250-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 5-bromo-2,3-dihydro-1H-indene-1,1-d ₂ (7.0 g, 35 mmol) in DMF (80 mL), to the stirred solution was added tris(4-methylphenyl)phosphane (1.07 g, 3.52 mmol), tert- butyl prop-2-enoate (4.0 mL), triethylamine (5.0 mL) and Pd(OAc)2 (395 mg, 1.76 mmol). The resulting solution was stirred overnight at 100℃ in an oil bath. The resulting mixture was concentrated under vacuum. The resulting solution was extracted with 3x50 mL of ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate. The residue was eluted from a silica gel column with DCM/petroleum ether (1:1). This resulted in 5.7 g (66%) of the title compound as light yellow oil. MS-ESI: 247 (M+1).

Step 3: Tert-butyl 3-(2,3-dihydro-1H-inden-5-yl-1,1-d ₂ )propanoate

Into a 100-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of tert-butyl (E)-3-(2,3-dihydro-1H-inden-5-yl-1,1-d2)acrylate (5.8 g, 24 mmol) in MeOH (40 mL), to the stirred solution was added Pd/C (580 mg, 10% wt.). The flask was evacuated and flushed three times with hydrogen. The resulting solution was stirred for 1h at RT under an atmosphere of hydrogen. The Pd/C catalysts were filtered out, the filtrate was concentrated under vacuum. This resulted in 5.7 g (98%) of the title compound as colorless oil. MS-ESI: 249 (M+1).

Step 4: 3-(2,3-Dihydro-1H-inden-5-yl-1,1-d ₂ )propanoic acid

Into a 100-mL round-bottom flask, was placed a solution of tert-butyl 3-(2,3-dihydro-1H-inden-5- yl-1,1-d ₂ )propanoate (4.3 g, 17.3 mmol) in DCM (50 mL), to the stirred solution was added CF3COOH (5.5 mL, 74 mmol). The resulting solution was stirred for overnight at RT. The resulting mixture was concentrated under vacuum. This resulted in 3.1 g (93%) of the title compound as an off-white solid. MS-ESI: 191 (M-1).

Step 5: 3-(2,3-Dihydro-1H-inden-5-yl-1,1-d ₂ )propanoyl chloride

Into a 100-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 3-(2,3-dihydro-1H-inden-5-yl-1,1-d2)propanoic acid (9.0 g, 41.7 mmol) in DCM (40 mL). This was followed by the addition of oxalic dichloride (8.0 mL) at 0℃. To this was added DMF (0.5 mL) at 0℃. The resulting solution was stirred for 3 h at RT. The resulting mixture was concentrated under vacuum. This resulted in 4.0 g (41%) of the title compound as brown oil. Step 6: 3,5,6,7-Tetrahydro-s-indacen-1(2H)-one-7,7-d ₂

Into a 100-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 3-(2,3-dihydro-1H-inden-5-yl-1,1-d ₂ )propanoyl chloride (3.9 g, 18 mmol) in DCE (40 mL). This was followed by the addition of AlCl3 (3.3 g, 25 mmol) in portions at 0℃ in 2 min. The resulting solution was stirred for 1 h at RT. The reaction was then quenched by the addition of 200 mL of water/ice. The resulting solution was extracted with 3x50 mL of DCM and the organic layers combined and dried over anhydrous sodium sulfate. The residue was eluted from a silica gel column with ethyl acetate/petroleum ether (2:100). This resulted in 1.5 g (46%) of the title compound as an off-white solid. MS-ESI: 175 (M+1).

Step 7: 8-Nitro-3,5,6,7-tetrahydro-s-indacen-1(2H)-one-7,7-d ₂ (Cpd 318’’, major) and 4- Nitro-3,5,6,7-tetrahydro-s-indacen-1(2H)-one-7,7-d ₂ (Cpd 317’’, minor)

Into a 25-mL round-bottom flask, was placed 3,5,6,7-tetrahydro-s-indacen-1(2H)-one-7,7-d ₂ (120 g). This was followed by the addition of H2SO4 (8.0 mL) at 0℃. To this was added HNO3 (2.0 mL) at 0℃ in 2 min. To the mixture was added H ₂ SO ₄ (2.0 mL) at 0℃ in 2 min. The resulting solution was stirred for 1 h at 0℃. The reaction was then quenched by the addition of water/ice. The resulting solution was extracted with 3x50 mL of ethyl acetate dried in an oven under reduced pressure. The residue was separated on silica gel eluted with ethyl acetate/petroleum ether (3:100). This resulted in 870 mg of cpd 318’’ and 290 mg of cpd 317’’, both as yellow solids. Cpd 317’’: ¹ H NMR (300 MHz, CDCl3) d 7.83 (s, 1H), 3.55– 3.45 (m, 2H), 3.42 (t, J = 7.6 Hz, 2H), 2.84– 2.74 (m, 2H), 2.22 (t, J = 7.6 Hz, 2H). Cpd 318”: ¹ H NMR (300 MHz, CDCl3) d 7.46 (s, 1H), 3.20 – 3.00 (m, 4H), 2.83– 2.73 (m, 2H), 2.20 (t, J = 7.5 Hz, 2H).

Step 8: 8-Amino-3,5,6,7-tetrahydro-s-indacen-1(2H)-one-7,7-d ₂

Into a 250-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 8-nitro-3,5,6,7-tetrahydro-s-indacen-1(2H)-one-7,7-d ₂ (870 mg) in MeOH (100 mL), to the stirred solution was added Pd/C (87 mg, 10%wt.). The flask was evacuated and flushed three times with hydrogen. The resulting solution was stirred for 1h at RT under an atmosphere of hydrogen. The Pd/C catalysts were filtered out, the filtrate was concentrated under vacuum. This resulted in 700 mg of the title compound as a yellow solid. MS-ESI: 190 (M+1). Step 9: 1,2,3,5,6,7-Hexahydro-s-indacen-3,3,5,5-d ₄ -4-amine

Into a 250-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of LiAlD ₄ (160 mg, 3.8 mmol) in Et ₂ O (40 mL). This was followed by the addition of AlCl3 (634 mg, 4.8 mmol) in portions at 0℃ in 2 min. To this solution was added 8- amino-3,5,6,7-tetrahydro-s-indacen-1(2H)-one-7,7-d ₂ (600 mg, 3.17 mmol) at 0℃. The resulting solution was stirred for 4 h at RT. The reaction was then quenched by the addition of 10 mL of water. The resulting solution was diluted with 20 mL of EtOAc. The solids were filtered out. The resulting solution was extracted with 3x50 mL of ethyl acetate dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was eluted from a silica gel column with ethyl acetate/petroleum ether (5:1). This resulted in 470 mg (78%) of the Intermediate 117 as a yellow solid. MS-ESI: 178 (M+1).

Intermediate 117A

1 _{,2,3,5,6,7-hexahydro-s-indacen-1,1,7,7-d4-4-amine}

Intermediate 117A was prepared starting from compound 317” and using the same procedure as shown in scheme 73 above for converting compound 318” to intermediate 117. MS-ESI: 178 (M+1). Table 15. The Intermediates in the following Table were prepared using similar procedure as shown in Scheme 30 above for converting compound 130’’ to Intermediate 44.

Schemes below the synthesis of sulfonimidamide Intermediates 118-123. Scheme 74:

N-(tert-butyldimethylsilyl)-6-isopropylpyridine-3-sulfonimid amide Steps 1-4 used similar procedures for converting compound 245’’ to Intermediate 88 shown in Scheme 56 to afford Intermediate 118 from compound 322’’. MS-ESI: 314 (M+1).

Scheme 75:

Intermediate 119

Step 1: 4-Amino-3-fluoro-N-methylbenzamide

Into a 500 mL round-bottom flask were added 4-amino-3-fluorobenzoic acid (15 g, 97 mmol) and DMF (100 mL) at RT. To the stirred solution was added HATU (74 mg, 0.19 mmol) and DIEA (25 mg, 0.19 mmol) at 0℃. To the above mixture was added MeNH ₂ /THF (2M, 97 mL, 194 mmol) in one portion at 0℃. The resulting mixture was stirred for additional 2 h at RT. The resulting mixture was extracted with EtOAc (3x100 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was eluted from silica gel column with petroleum ether /EtOAc (1:1) to afford the title compound (16 g, 98%) as yellow oil. MS-ESI: 169 (M+1).

Steps 2-3 used similar procedures for converting compound 27 to Intermediate 29 shown in Scheme 9 to afford compound 329’’ from compound 327’’. MS-ESI: 233 (M+1).

Step 4: 2-Fluoro-4-((methylamino)methyl)benzenesulfonamide

Into a 250-mL round-bottom flask were placed 3-fluoro-N-methyl-4-sulfamoylbenzamide (1.2 g) in THF (40 mL) at 0℃. To the stirred solution was added LiAlH ₄ (543 mg, 14 mmol) in portions at 0℃ under nitrogen atmosphere. The resulting mixture was stirred overnight at 70℃. The reaction was quenched with water (2 mL). The resulting mixture was filtered, the filter cake was washed with EtOAc (3x10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (EtOAc/MeOH = 25:1) to afford the title compound (800 mg, 77%) as a white solid. MS-ESI: 219 (M+1).

Step 5: Tert-butyl (3-fluoro-4-sulfamoylbenzyl)(methyl)carbamate

Into a 100-mL round-bottom flask were placed 2-fluoro-4-[(methylamino)methyl]benzene-1- sulfonamide (800 mg, 3.7 mmol) in THF (20 mL) at 0℃. To a stirred solution was added (Boc)2O (1.5 g, 6.89 mmol) in portions at 0℃. The resulting mixture was stirred for 2 h at RT and concentrated under reduced pressure. The residue was purified by Prep- TLC (PE/EtOAc 1:1) to afford the title compound (900 mg, 77%) as a white solid. MS-ESI: 319 (M+1).

Steps 6-7 used similar procedures for converting compound 248’’ to Intermediate 88 shown in Scheme 56 to afford Intermediate 119 from compound 331’’. MS-ESI: 432 (M+1). Scheme 76:

N'-(tert-butyldimethylsilyl)-4-((dimethylamino)methyl)-3-flu orobenzenesulfonimidamide Step 1: 1-(2-Fluoro-4-nitrophenyl)-N,N-dimethylmethanamine

Into a 250-mL round-bottom flask, was placed a solution of 1-(bromomethyl)-2-fluoro-4- nitrobenzene (8.0 g, 34 mmol) in MeOH (50 mL). This was followed by the addition of dimethylamine (2 M, 21 mL) dropwise with stirring at 0℃ in 5 min. The resulting solution was stirred for 4 h at RT. The resulting mixture was concentrated under vacuum. This resulted in 7.0 g crude title compound as yellow oil. MS-ESI: 199 (M+1).

Step 2: 4-((Dimethylamino)methyl)-3-fluoroaniline

Into a 100-mL round-bottom flask, was placed the solution of [(2-fluoro-4- nitrophenyl)methyl]dimethylamine (7.0 g, 35 mmol) in AcOH (20 mL), to the stirred solution was added iron powder (10 g, 179 mmol). The resulting solution was stirred for 16 h at RT. The solids were filtered out. The resulting filtrate was concentrated under vacuum. The residue was eluted from a silica gel column with DCM/MeOH (9:1). This resulted in 6.5 g crude title compound as yellow oil. MS-ESI: 169 (M+1).

Steps 3-4 used similar procedures for converting compound 145’’ to compound 147’’ shown in Scheme 36 to afford compound 337’’ from compound 335’’. MS-ESI: 233 (M+1).

Steps 5-6 used similar procedures for converting compound 148’’ to Intermediate 59 shown in Scheme 36 to afford Intermediate 120 from compound 337’’. MS-ESI: 233 (M+1). Scheme 77:

Intermediate 121

N'-(tert-butyldimethylsilyl)-4-isopropylthiophene-2-sulfonim idamide Steps 1-2 used similar procedures for converting compound 158’’ to intermediate 61 shown in Scheme 38 to afford compound 341’’ from compound 339’’. MS-ESI: 221 (M+1).

Step 3 used similar procedures for converting compound 147’’ to compound 148’’ shown in Scheme 36 to afford compound 342’’ from compound 341’’. MS-ESI: 221 (M+1).

Step 4: 4-Isopropylthiophene-2-sulfonamide

Into a 250-mL round-bottom flask, was placed the solution of 4-(2-hydroxypropan-2-yl)thiophene- 2-sulfonamide (1.5 g, 6.79 mmol) in DCM (20 mL). To the stirred solution was added TFA (3.9 g, 34 mmol) and Et3SiH (2.32 g, 20 mmol). The result solution was stirred overnight at RT. The mixture was concentrated under vacuum. The residue was eluted from silica gel column with a gradient of ethyl acetate/petroleum ether (1:5 to 1:3). This resulted in 1.1 g (79%) of the title compound as a light yellow solid. MS-ESI: 206 (M+1).

Steps 5-6 used similar procedures for converting compound 148’’ to Intermediate 59 shown in Scheme 36 to afford Intermediate 121 from compound 344’’. MS-ESI: 319 (M+1).

N-(tert-butyldimethylsilyl)-4-(1-methylpyrrolidin-2-yl)benze nesulfonimidamide

Step 1: 2-(4-Bromophenyl)-1-methylpyrrolidine

Into a 100-mL round-bottom flask, was placed 2-(4-bromophenyl)pyrrolidine (3.0 g, 13.3 mmol) in HCHO (3.23 g, 37% wt.), to the stirred solution was added NaBH ₃ CN (2.5 g, 40 mmol). The resulting solution was stirred for 12 h at RT and concentrated under vacuum. The residue was eluted from a silica gel column with ethyl acetate/petroleum ether (1:1). This resulted in 2.8 g (88%) of the title compound as a light yellow solid. MS-ESI: 240/242 (M+1). Steps 2-6 used similar procedures for converting compound 245’’ to Intermediate 88 shown in Scheme 56 to afford Intermediate 122’’ from compound 347’’. MS-ESI: 354 (M+1). Scheme 79:

Intermediate 123

N-(tert-butyldimethylsilyl)-2-(2-methyl-1,3-dioxolan-2-yl)th iazole-5-sulfonimidamide Step 1: 2-(2-Methyl-1,3-dioxolan-2-yl)thiazole

Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 1-(1,3-thiazol-2-yl)ethan-1-one (27 g, 212 mmol) in toluene (300 mL), to the stirred solution was added TsOH (2.0 g, 11.6 mmol) and ethane-1,2-diol (40 g, 644 mmol). The resulting solution was stirred for 14 h at 110℃ in an oil bath. The resulting mixture was concentrated under vacuum. The residue was eluted from a silica gel column with ethyl acetate/petroleum ether (1:20 to 1:10). This resulted in 36 g (99%) of the title compound as brown oil. MS-ESI: 172 (M+1).

Steps 2-5 used similar procedures for converting compound 245’’ to Intermediate 88 shown in Scheme 56 to afford Intermediate 123 from compound 353’’. MS-ESI: 363 (M+1). Scheme 80:

N'-(tert-butyldimethylsilyl)-5-((dimethylamino)methyl)-3-flu oropyridine-2-sulfonimidamide Step 1: 6-Chloro-5-fluoro-N,N-dimethylnicotinamide

To a stirred solution of 6-chloro-5-fluoronicotinic acid (10 g, 49.5 mmol) in THF (150 mL) in a 250-mL round-bottom flask under nitrogen was added HATU (28.2 g, 74.3 mmol), DIEA (12.8 g, 99 mmol) and dimethylamine in THF (2 M, 75 mL, 149 mmol) at RT. The resulting solution was stirred for 16 h at RT. The reaction was quenched with water (400 mL). The resulting solution was extracted with 3x400 mL of EtOAc and the organic layers combined and dried over Na ₂ SO ₄ and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:1). This resulted in 8.0 g (80%) of the title compound as a white solid. MS-ESI: 203/205 (M+1).

Step 2: 6-(Benzylthio)-5-fluoro-N,N-dimethylnicotinamide

To a stirred solution of 6-chloro-5-fluoro-N,N-dimethylnicotinamide (8.0 g, 39.4 mmol) in dioxane (160 mL) in a 100-mL round-bottom flask under nitrogen was added

phenylmethanethiol (9.76 g, 78.8 mmol) and t-BuOK (8.84 g, 78.8 mmol). The resulting solution was stirred for 16 h at 80 ^° C. The resulting mixture was quenched with water (400 mL) and extracted with 3x500 mL of EtOAc. The organic layer was combined and dried over anhydrous Na2SO4. The solids were filtered out. The resulting filtrate was concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:1). This resulted in 6.0 g (52%) of the title compound as yellow oil. MS-ESI: 291 (M+1).

Step 3: 1-(6-(Benzylthio)-5-fluoropyridin-3-yl)-N,N-dimethylmethanam ine

To a stirred solution of 6-(benzylthio)-5-fluoro-N,N-dimethylnicotinamide (6.0 g, 20.7 mmol) in THF (100 mL) in a 250-mL round-bottom flask under nitrogen was added BH ₃ in THF (1 M, 104 mmol, 104 mL) dropwise at 0 ^° C. The resulting solution was stirred for 16 h at RT. The reaction was quenched with MeOH (100 mL). The resulting mixture was concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:1). This resulted in 4.4 g (77.1%) of the title compound as a white solid. MS-ESI: 277 (M+1).

Step 4: 5-((Dimethylamino)methyl)-3-fluoropyridine-2-sulfonyl chloride

To a stirred solution of 1-(6-(benzylthio)-5-fluoropyridin-3-yl)-N,N-dimethylmethanam ine (4.4 g, 15.9 mmol) in DCM (30 mL), AcOH (15 mL) and H ₂ O (15 mL) in a 250-mL 3-necked round- bottom flask under nitrogen was introduced Cl2 gas bubbled at 0 ^° C for 30 min. Then the resulting solution was stirred for another 30 min at 0 ^° C. The resulting mixture diluted with water (100 mL) and extracted with 3x100 mL DCM. The organic layers were combined and washed with brine (100 mL), then dried over anhydrous Na2SO4. This resulted in the title compound in DCM solution which was used for next step directly.

Step 5: 5-((Dimethylamino)methyl)-3-fluoropyridine-2-sulfonamide

To a stirred solution of 5-((dimethylamino)methyl)-3-fluoropyridine-2-sulfonyl chloride (crude) in DCM (300 mL) was introduced NH3 gas bubbled for 30 min at 0 ^° C. The resulting solution was stirred for 2 h at RT. The resulting mixture was concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:1). This resulted in 1.56 g (42% over two steps) of the title compound as a white solid. MS-ESI: 234 (M+1).

Step 6: N-(tert-butyldimethylsilyl)-5-((dimethylamino)methyl)-3-fluo ropyridine-2- sulfonamide

To a stirred solution of 5-((dimethylamino)methyl)-3-fluoropyridine-2-sulfonamide (233 mg, 1.0 mmol) in THF (10 mL) in a 50-mL round-bottom flask under nitrogen was added NaH (60% dispersion in mineral oil, 120 mg, 3.0 mmol) at 0 ^° C, to this was added TBSCl (227 mg, 1.50 mmol) at 0 ^° C. The resulting solution was stirred for 2 h at RT. The resulting mixture was quenched with 10 mL of water. The resulting solution was extracted with 3x10 mL of EtOAc and dried over anhydrous Na ₂ SO ₄ . The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:1). This resulted in 200 mg (57.5%) of the title compound as a yellow solid. MS-ESI: 348 (M+1).

Step 7: N'-(tert-butyldimethylsilyl)-5-((dimethylamino)methyl)-3-flu oropyridine-2- sulfonimidamide

To a stirred solution of PPh3Cl2 (383 mg, 1.15 mmol) in CHCl3 (10 mL) in a 100-mL 3-necked round-bottom flask under nitrogen was added DIEA (371 mg, 2.88 mmol) dropwise with stirring at 0 ^° C. The resulting solution was stirred for 10 min at RT. To this was added a solution of N- (tert-butyldimethylsilyl)-5-((dimethylamino)methyl)-3-fluoro pyridine-2-sulfonamide (200 mg, 0.58 mmol) in CHCl ₃ (10 mL) dropwise with stirring at 0 ^° C. The resulting solution was allowed to react, with stirring, for an additional 30 min while the temperature was maintained at 0 ^° C in a water/ice bath. To the above NH3(g) was bubbled for 10 min at 0 ^° C. The resulting solution was allowed to react, with stirring, for an additional 30 min at RT. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:1). This resulted in 150 mg (75.0%) of the title compound as an off- white solid. MS-ESI: 347 (M+1).

Scheme 81:

Intermediate 125

2-(4- butyldimethylsilyl)sulfamidimidoyl)phenyl)-N,2-dimethylpropa namide

Step 1: 2-Methyl-2-(4-sulfamoylphenyl)propanoic acid

To a stirred solution of ethyl 2-methyl-2-(4-sulfamoylphenyl) propanoate (5.42 g, 20.0 mmol) in MeOH (60 mL) in a 250-mL round-bottom flask was added the solution of NaOH (8.0 g, 200 mmol) in water (40 mL) dropwise at RT. The resulting solution was stirred for 2 h at 55 ^° C and the organic solvent was removed under vacuum. The pH value of the solution was adjusted to 1- 2 with HCl (2 M). The resulting solution was extracted with 3x200 mL of DCM and the organic layers were combined and dried over Na ₂ SO ₄ , concentrated under vacuum. This resulted in 3.90 g (80.2%) of the title compound as a light yellow solid. MS-ESI: 242 (M-1)

Step 2: N,2-dimethyl-2-(4-sulfamoylphenyl)propanamide

To a stirred solution of 2-methyl-2-(4-sulfamoylphenyl)propanoic acid (2.43 g, 10.0 mmol) in THF (60 mL) in a 250-mL round-bottom flask under nitrogen was added CDI (1.94 g, 12.0 mmol) in portions at RT. The resulting solution was stirred for 30 min at RT. Then the reaction was stirred for 30 min at 60 ^° C. Methanamine in THF (2 M) (40 mL, 80.0 mmol) was added dropwise at RT. The resulting solution was stirred for 16 h at RT. The reaction was then quenched by the addition of 90 mL of water. The resulting solution was extracted with 3x120 mL of DCM and the organic layers were combined and dried over anhydrous Na2SO4. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:1).This resulted in 1.80 g (70.3%) of the title compound as yellow solid. MS-ESI: 257 (M+1).

Steps 3-4 used similar procedures for converting compound 362” to intermediate 124 shown in Scheme 80 to afford intermediate 125 from compound 366”. MS-ESI: 370 (M+1).

Scheme 82: O O O O

B _r ^S OH OH O

O O ^{S n-BuLi O} _S O _{1. NCS} ^S _S ^O

NH ₂

Intermediate 126

N'-(t yldimethylsilyl)-2-(5-hydroxy-2,2-dimethyl-1,3-dioxan-5-yl)t hiazole-5- sulfonimidamide

Step 1: 2,2-Dimethyl-5-(thiazol-2-yl)-1,3-dioxan-5-ol

To a stirred solution of 2-bromothiazole (4.89 g, 30.0 mmol) in THF (200 mL) in a 500-mL 3- necked round-bottom flask under nitrogen was added n-BuLi/hexane (2.5 M, 12 mL, 30.0 mmol) dropwise with stirring at -78 ^° C. The resulting solution was stirred for 30 min at -78 ^° C. Then 2,2- dimethyl-1,3-dioxan-5-one (3.90 g, 30.0 mmol) in THF (10 mL) was added dropwise at -70 ^° C.

The resulting solution was allowed to react, with stirring, for an additional 30 min at RT. The

resulting mixture was quenched with 20 mL of MeOH and concentrated under reduced pressure.

The residue was eluted from silica gel with EtOAc/PE (1/10). This resulted in 3.20 g (49.6%) of

the title compound as a yellow solid. MS-ESI: 216 (M+1).

Step 2: Lithium 2-(5-hydroxy-2,2-dimethyl-1,3-dioxan-5-yl)thiazole-5-sulfina te

To a stirred solution of 2,2-dimethyl-5-(thiazol-2-yl)-1,3-dioxan-5-ol (2.15 g, 10.0 mmol) in

THF (100 mL) in a 250-mL 3-necked round-bottom flask under nitrogen was n-BuLi/hexane (2.5

M, 4.0 mL, 10.0 mmol) dropwise with stirring at -70 ^° C. The resulting solution was stirred for 60

min at -70 ^° C. Then SO ₂ (g) was bubbled to the solution at -50 ^° C for 10 min. The resulting solution was allowed to react, with stirring, for an additional 30 min at 20 ^° C. The resulting

mixture was concentrated under reduced pressure. This resulted in 2.5 g (crude) of the title

compound as an off-white solid. MS-ESI: 278 (M-1).

Step 3: 2-(5-hydroxy-2,2-dimethyl-1,3-dioxan-5-yl)thiazole-5-sulfona mide

To a stirred solution of lithium 2-(5-hydroxy-2,2-dimethyl-1,3-dioxan-5-yl)thiazole-5-sulfina te

(2.5 g, crude) in DCM (100 mL) in a 250-mL round-bottom flask was added NCS (2.67 g, 20.0

mmol) in small portions at RT. The resulting solution was stirred for 2 h at RT.

The resulting solution was diluted with 50 mL of water, then extracted with 3x50 mL of DCM

and the organic layers were combined and dried over anhydrous Na ₂ SO ₄ . Then NH ₃ (g) was

bubbled into reaction mixture for 10 min at 0 ^° C. The resulting solution was stirred for 2 h at RT.

The resulting mixture was concentrated under vacuum. The residue was eluted from silica gel

with EtOAc/PE (1/3). This resulted in 1.80 g (61.2% over two steps) of the title compound as a

yellow solid. MS-ESI: 293 (M-1).

Step 4-5 used similar procedures for converting compound 362” to intermediate 124 shown in

Scheme 80 to afford intermediate 126 from compound 371”. MS-ESI: 408 (M+1).

Scheme 83: N _H2 S HO O O

N _a

4-(Azetidin-1-ylmethyl)-N'-(tert-butyldimethylsilyl)-2-fluor obenzenesulfonimidamide Step 1: (4-Amino-3-fluorophenyl)(azetidin-1-yl)methanone

To a stirred solution of 4-amino-3-fluorobenzoic acid (5.0 g, 32.3 mmol) in DMF (50 mL) in a 250 mL round-bottom flask was added DIEA (8.33 g, 64.6 mmol) and HATU (24.5 g, 64.6 mmol) at 0 ^° C. This was followed by the addition of azetidine (3.68 g, 64.6 mmol) in DMF (10 mL) dropwise with stirring at 0 ^° C. The resulting mixture was stirred for 16 h at RT. The reaction was then quenched by the addition of water (100 mL). The resulting mixture was extracted with EtOAc (5 x 100 mL). The organic layers were combined and dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1/2) to afford the title compound (5.71 g, 91.2%) as a light yellow solid. MS-ESI: 195 (M+1).

Step 2: 4-(Azetidine-1-carbonyl)-2-fluorobenzenesulfonamide

To a stirred solution of (4-amino-3-fluorophenyl)(azetidin-1-yl)methanone (3.88 g, 20.0 mmol) in HCl (6 M, 30 mL) in a 250-mL 3-necked round-bottom flask under nitrogen was added a solution of NaNO2 (1.66 g, 24.0 mmol) in H2O (5 mL) dropwise with stirring at 0 ^° C, the solution was stirred for 30 min, this solution was assigned as solution A. Then CuCl2 (1.34 g, 10.0 mmol) was added to a 250-mL single necked round-bottom flask with AcOH (40 mL) as the solvent. Then SO2 (g) was bubbled to the reaction mixture with stirring at RT for 20 min, this solution was assigned as solution B. To the solution B was added solution A dropwise with stirring at 0 ^° C. The resulting solution was stirred for 2 h at RT. The reaction mixture was diluted with 100 mL of water, extracted with 3x100 mL of DCM and the organic layers were combined and dried over anhydrous Na2SO4. To the crude DCM solution (~300 mL) was bubbled NH3 (g) with stirring at 0 ^° C for 10 min. The resulting solution was stirred for 2 h at RT. The solution was concentrated under vacuum. The crude product was eluted from silica gel with EtOAc/PE (1:1). This resulted in 2.61 g (50.6%) of the title compound as yellow oil. MS-ESI: 257 (M-1).

Step 3: 4-(Azetidin-1-ylmethyl)-2-fluorobenzenesulfonamide

To a stirred solution of 4-(azetidine-1-carbonyl)-2-fluorobenzenesulfonamide (1.0 g, 3.88 mmol) in THF (20 mL) was added LiAlH4 (441 mg, 11.6 mmol) in portions at 0 ^° C. The resulting mixture was stirred for 16 h at 70 ^° C. The reaction was quenched with 10 g of solid

Na ₂ SO ^.

410H ₂ O at 0 ^° C. The resulting mixture was filtered and the filter cake was washed with EtOAc (2 x 50 mL). The filtrate was concentrated under reduced pressure. The residue was

eluted from silica gel with EtOAc/PE (1:1) to afford the title compound (613 mg, 64.8%) as a

light yellow solid. MS-ESI: 245 (M+1).

Steps 4-5 used similar procedures for converting compound 362” to intermediate 124 shown in

Scheme 80 to afford intermediate 127 from compound 376”. MS-ESI: 358 (M+1).

Scheme 84:

TBS O ^{O O} N _{H2 NH2} ^O

S _NH S O F

Br

"

P ^P

TF d

Tert-butyl 3-(3-fluoro-4-(N'-((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)sulfamidimidoyl)phenyl) -pyrrolidine-1-carboxylate

Step 1: Tert-butyl 3-(3-fluoro-4-sulfamoylphenyl)-2,5-dihydro-1H-pyrrole-1-carb oxylate To a stirred solution of 4-bromo-2-fluorobenzenesulfonamide (20.0 g, 78.7 mmol) in 1,4- dioxane/H ₂ O (5:1) (200 mL) in a 250-mL 3-necked round-bottom flask under nitrogen was added tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro- 1H -pyrrole-1- carboxylate (27.9 g, 94.4 mmol) then K2CO3 (21.8 g, 157 mmol) and Pd(dppf)Cl2 (11.5 g, 15.7 mmol) were added to the solution at RT. The resulting solution was stirred for 16 h at 90 ^° C. The insoluble matter was filtered out and the filtrate was concentrated under reduced pressure. The residue was eluted from silica gel with EtOAc/PE (1/3) to give the title compound (7.32 g, 27.2%) as white solid. MS-ESI: 343 (M+1).

Step 2: Tert-butyl 3-(3-fluoro-4-sulfamoylphenyl)pyrrolidine-1-carboxylate

To a stirred solution of tert-butyl 3-(3-fluoro-4-sulfamoylphenyl)-2,5-dihydro-1H-pyrrole-1- carboxylate (7.30 g, 21.3 mmol) in MeOH (200 mL) in a 500 mL round-bottom flask under nitrogen was added Pd/C (10% wt.1.0 g) in portions. The flask was evacuated and refilled three times with hydrogen. The resulting solution was stirred for 2 h at RT under atmosphere of hydrogen with a balloon. The solid was filtered out. The resulting mixture was concentrated under reduced pressure. The residue was eluted from silica gel with EtOAc/PE (1:2) to give the title compound (6.30 g, 86.0%) as white solid. MS-ESI: 345 (M+1).

Steps 3-5 used similar procedures for converting compound 362” to intermediate 124 shown in Scheme 80 to afford compound 383” from compound 380”. MS-ESI: 458 (M+1).

Step 6: Tert-Butyl 3-(4-(N-(tert-butyldimethylsilyl)-N'-((1,2,3,5,6,7-hexahydro -s-indacen-4- yl) carbamoyl)sulfamidimidoyl)-3-fluorophenyl)pyrrolidine-1-carb oxylate

To a stirred solution of tert-butyl 3-(4-(N'-(tert-butyldimethylsilyl)sulfamidimidoyl)-3- fluorophenyl)- pyrrolidine-1-carboxylate (5.2 g, 11.3 mmol) in THF (100 mL) in a 100-mL 3- necked round-bottom purged with and maintained under nitrogen was added NaH (60% dispersion in mineral oil, 820 mg, 34 mmol) in portions at 0 ^° C. The reaction mixture was stirred for 15 min at RT.4-isocyanato-1,2,3,5,6,7-hexahydro- s-indacene (2.7 g, 13.6 mmol) in THF (10 mL) was added dropwise to the solution at 0 ^° C. The resulting solution was stirred for 60 min at RT. The resulting mixture was quenched with 5 mL of water, then concentrated under reduced pressure. The residue was eluted from silica gel with EtOAc/PE (1:6) to give title compound (5.1 g, 69%) as white solid. MS-ESI: 657 (M+1). Step 7: Tert-Butyl 3-(3-fluoro-4-(N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)car bamoyl) sulfamidimidoyl)phenyl)pyrrolidine-1-carboxylate

To a stirred solution of tert-butyl 3-(4-(N-(tert-butyldimethylsilyl)-N'- ((1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)sulfamidimidoyl)-3-fluorophenyl)pyrro lidine-1 -carboxylate (5.1 g, 7.8 mmol) in DCM (100 mL) in a 500 mL round-bottom flask was added TFA (5 mL) dropwise at 0 ^° C. The resulting solution was stirred for 60 min at RT. The resulting mixture was concentrated under reduced pressure. The residue was eluted from silica gel with EtOAc/PE (1:8) to give the title compound (1.2 g, 35 %) as white solid. MS-ESI: 543 (M+1).

Intermediate 128A and 128B

Intermediate 128A and 128B (stereochemistry not assigned) (R)- and (S)-Tert-butyl 3-(3-fluoro-4-(N'-((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)sulfamidimidoyl) -phenyl)pyrrolidine-1-carboxylate Step 8: Tert-butyl 3-(3-fluoro-4-((R)-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl )carbamoyl) sulfamidimidoyl)phenyl)pyrrolidine-1-carboxylate and tert-butyl 3-(3-fluoro-4-((S)-N'- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamidimi doyl)phenyl)pyrrolidine-1- carboxylate

Tert-Butyl 3-(3-fluoro-4-(N'-((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)sulfamidimidoyl)phenyl) pyrrolidine-1-carboxylate (1.2 g) was resolved by Prep chiral SFC with the following conditions: Column: (R,R)Whelk, 21.1*250 mm, 5 um; Mobile Phase A: CO2, Mobile Phase B: MeOH; Flow rate: 40 mL/min; Gradient: 40% B; 220 nm;

Rt ₁ :7.14 min (Intermediate 128A, 480 mg, 98%de); Rt ₂ :10.3 min (Intermediate 128B, 500 mg, 98%de) both as an off white solid. MS-ESI: 543 (M+1).

Scheme 85: TBS O

TBS TBS O F

5 Br

NaH O ₁₀ S

H _2N

O S H _N TBS

Tert-butyl 2-(4-(N'-(tert-butyldimethylsilyl)sulfamidimidoyl)phenyl)aze tidine-1-carboxylate

Step 1: Tert-butyl (1-(4-bromophenyl)-3-hydroxypropyl)carbamate

To a stirred solution of 3-amino-3-(4-bromophenyl)propan-1-ol (6.90 g, 30.0 mmol) in THF (100 mL) in a 250-mL round-bottom flask under nitrogen was added NaH (60% dispersion in mineral oil, 1.80 g, 45.0 mmol) in portions at 0 ^° C. The resulting solution was stirred for 20 min at RT.

This was followed by the addition of (Boc)2O (9.81 g, 45.0 mmol) in THF (10 mL) dropwise

with stirring at 0 ^° C. The resulting solution was stirred for 16 h at RT. The reaction was then quenched by the addition of 50 mL of water. The resulting solution was extracted with 3x100 mL of EtOAc. The organic layers were combined and dried over anhydrous Na ₂ SO ₄ and concentrated under vacuum. The crude product was eluted from silica gel with EtOAc/PE (1:4). This resulted in 8.43 g (85.2%) of the title compound as a yellow solid. MS-ESI: 330/332 (M+1). Step 2: Tert-butyl (1-(4-bromophenyl)-3-((tert-butyldimethylsilyl)oxy)propyl)ca rbamate To a stirred solution of tert-butyl (1-(4-bromophenyl)-3-hydroxypropyl)carbamate (6.60 g, 20.0 mmol) in THF (100 mL) in a 250-mL round-bottom flask under nitrogen was added NaH (60% dispersion in mineral oil, 1.20 g, 30.0 mmol) in portions at 0 ^° C. The resulting solution was stirred for 20 min at RT. This was followed by the addition of TBSCl (4.53 g, 30.0 mmol) in THF (10 mL) dropwise with stirring at 0 ^° C. The resulting solution was stirred for 2 h at RT. The reaction was then quenched by the addition of 50 mL of water. The resulting solution was extracted with 3x100 mL EtOAc. The organic layers were combined and dried over anhydrous Na ₂ SO ₄ and concentrated under vacuum. The crude product was eluted from silica gel with EtOAc/PE (1:5). This resulted in 7.81 g (87.9%) of the title compound as a yellow solid. MS- ESI: 444/446 (M+1).

Steps 3-4 used similar procedures for converting compound 369” to compound 371” shown in Scheme 82 to afford compound 389” from compound 387”. MS-ESI: 445 (M+1).

Step 5: Tert-butyl (3-hydroxy-1-(4-sulfamoylphenyl)propyl)carbamate

To a stirred solution of tert-butyl (3-((tert-butyldimethylsilyl)oxy)-1 -(4- sulfamoylphenyl)propyl)carbamate (1.50 g, 3.37 mmol) in THF (30 mL) in a 100-mL round- bottom flask was added TBAF (1.76 g, 6.74 mmol) in several batches at RT. The resulting solution was stirred for 30 min at RT. The reaction was then quenched by the addition of 50 mL of water. The resulting solution was extracted with 3x150 mL of EtOAc and the organic layers were combined and dried over Na2SO4 and concentrated under reduced pressure. The residue was eluted from silica gel with DCM/MeOH (20/1). This resulted in 896 mg (80.6%) of the title compound as a yellow solid. MS-ESI: 331 (M+1).

Step 6: 3-((Tert-butoxycarbonyl)amino)-3-(4-sulfamoylphenyl)propyl methanesulfonate To a stirred solution of tert-butyl (3-hydroxy-1-(4-sulfamoylphenyl)propyl) carbamate (660 mg, 2.00 mmol) in DCM (20 mL) in a 100-mL round-bottom flask under nitrogen was added TEA (404 mg, 4.00 mmol) at RT, then methanesulfonyl chloride (230 mg, 2.00 mmol) dropwise at 0 ^° C. The resulting solution was stirred for 4 h at 0 ^° C. The reaction was then quenched by the addition of 10 mL of water/ice. The resulting solution was extracted with 3x150 mL of EtOAc and the organic layers were combined and dried over anhydrous Na2SO4 and concentrated. To the residue was added 10 mL of EtOAc/PE (1:5) and the turbid solution was sonicated for 5 min. The product was collected by filtration. This resulted in 635 mg (77.8%) of the title compound as a white solid. MS-ESI: 409 (M+1).

Step 7: 3-amino-3-(4-sulfamoylphenyl)propyl methanesulfonate

To a stirred solution of 3-((tert-butoxycarbonyl)amino)-3-(4-sulfamoylphenyl)propyl methanesulfonate (635 mg, 1.56 mmol) in DCM (15 ml) in a 100-mL round-bottom flask was added TFA (5 ml) dropwise at RT. The resulting solution was stirred for 16 h at RT. The resulting mixture was concentrated under vacuum. The crude product was used in the next step directly without further purification. This resulted in 500 mg (crude) of the title compound as yellow oil. MS-ESI: 309 (M+1).

Step 8: 4-(Azetidin-2-yl)benzenesulfonamide

To a stirred solution of 3-amino-3-(4-sulfamoylphenyl)propyl methanesulfonate (500 mg, crude) in 2-methyl-2-propanol (20 mL) in a 100-mL round-bottom flask. The pH value of the solution was adjusted to 12 with NaOH (4 M). The resulting solution was stirred for 4 h at 60 ^° C. The resulting solution was extracted with 3x50 mL of EtOAc and the organic layers were combined and dried over anhydrous Na2SO4 and concentrated. The product was used in the next step directly without further purification. This resulted in 800 mg (crude) of the title compound as yellow oil. MS-ESI: 213 (M+1).

Step 9: Tert-butyl 2-(4-sulfamoylphenyl)azetidine-1-carboxylate

To a stirred solution of 4-(azetidin-2-yl)benzenesulfonamide (800 mg, crude) in THF (10 mL) in a 50-mL round-bottom flask was added TEA (253 mg, 2.50 mmol), this was followed by the addition of (Boc) ₂ O (545 mg, 2.50 mmol) in THF (5 mL) dropwise at RT. The resulting solution was stirred for 2 h at RT. The reaction was then quenched by the addition of 10 mL of water. The resulting solution was extracted with 3x30 mL of EtOAc and the organic layers were combined and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:1). This resulted in 200 mg (41% over three steps) of the title compound as a yellow solid. MS-ESI: 313 (M+1).

Steps 10-11 used similar procedures for converting compound 362” to intermediate 124 shown in Scheme 80 to afford intermediate 129 from compound 394”. MS-ESI: 426 (M+1).

Scheme 86:

1-(4-(N'-( butyldimethylsilyl)sulfamidimidoyl)-3-fluorophenyl)-N-methyl cyclopropane-1- carboxamide

Step 1: Methyl 2-(4-bromo-3-fluorophenyl)acetate

To a stirred solution of 2-(4-bromo-3-fluorophenyl)acetic acid (10.0 g, 42.9 mmol) in MeOH (200 mL) in a 500-mL round-bottom flask under nitrogen was added SOCl ₂ (10.2 g, 85.8 mmol) dropwise at 0 ^° C over 30 min. The resulting solution was stirred for 16 h at RT. The resulting solution was concentrated under vacuum. The crude product was eluted from silica gel with EtOAc/PE (1:1). This resulted in 10.0 g (94.3%) of the title compound as an orange solid. MS- ESI: 247/249 (M+1).

Step 2: Methyl 1-(4-bromo-3-fluorophenyl)cyclopropane-1-carboxylate

To a stirred solution of methyl 2-(4-bromo-3-fluorophenyl)acetate (10.0 g, 40.5 mmol) in DMF (200 mL) in a 500-mL round-bottom flask under nitrogen. This was followed by the addition of NaH (60% dispersion in mineral oil, 4.88 g, 122 mmol) in portions at 0 ^° C. To this was added 1,2-dibromoethane (11.4 g, 60.7 mmol) dropwise at 0 ^° C. The resulting solution was stirred for 3 days at RT. The reaction was then quenched with 50 mL of water. The resulting solution was extracted with EtOAc (3x100 mL). The organic layers were combined and washed with brine (300 mL), then dried over anhydrous Na ₂ SO ₄ and concentrated under vacuum. The crude product was eluted from silica gel with EtOAc/PE (1:1). This resulted in 5.0 g (45.2%) of the title compound as a yellow solid.

Steps 3-4 used similar procedures for converting compound 364” to compound 366” shown in Scheme 81 to afford compound 400” from compound 398”. MS-ESI: 272/274 (M+1).

Steps 5-9 used similar procedures for converting compound 369” to intermediate 126 shown in Scheme 82 to afford intermediate 130 from compound 400”. MS-ESI: 386 (M+1).

Scheme 87:

Intermediate 131

N'-( butyldimethylsilyl)-6-(2-hydroxypropan-2-yl)pyridine-3-sulfo nimidamide Step 1 used similar procedures for converting compound 374” to compound 375” shown in Scheme 83 to afford compound 406” from compound 405”. MS-ESI: 217 (M+1).

Step 2: 6-(2-Hydroxypropan-2-yl)pyridine-3-sulfonamide

To a stirred solution of methyl 5-sulfamoylpicolinate (4.80 g, 22.2 mmol) in THF (300 mL) in a 500-mL 3-necked round-bottom flask under nitrogen was added MeMgBr/THF (3 M, 74 mL, 222 mmol) dropwise at 0 ^° C. The resulting solution was stirred for 16 h at RT. The reaction was then quenched with 50 mL of NH4Cl (aq). The resulting solution was extracted with 3x100 ml of EtOAc and the organic layers were combined and dried over Na ₂ SO ₄ and concentrated under vacuum. The residue was eluted from silica gel with DCM/MeOH (60:1). This resulted in 2.46 g (51.3%) of the title compound as a light yellow solid. MS-ESI: 215 (M-1).

Steps 3-4 used similar procedures for converting compound 362” to intermediate 124 shown in Scheme 80 to afford intermediate 131 from compound 407”. MS-ESI: 330 (M+1).

Table 30. The Intermediate 132 was prepared using similar procedures for converting compound 405” to Intermediate 131 shown in Scheme 87 from appropriate starting materials.

Scheme 88:

N'-(tert-butyldimethylsilyl)-5-(2-hydroxypropan-2-yl)-1-( 4-methoxybenzyl)-1H-pyrazole-3- sulfonimidamide

Step 1: Methyl 1-(4-methoxybenzyl)-3-nitro-1H-pyrazole-5-carboxylate

To a stirred solution of methyl 3-nitro-1H-pyrazole-5-carboxylate (8.0 g, 46.8 mmol) in DMF (70 mL) in a 250 mL round-bottom flask was added TEA (26.8 g, 187 mmol) and 4- methoxybenzyl chloride (14.64 g, 93.5 mmol) dropwise at RT, the solution was stirred for 16 h at RT. The resulting mixture was quenched with 100 mL of water and extracted with EtOAc (3 x 300 mL). The combined organic layers were washed with brine (300 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in a mixture of the title compound and methyl 1-(4-methoxybenzyl)-5-nitro-1H-pyrazole-3- carboxylate (~6:1) (11.3 g, 82.9%) as a light yellow oil. MS-ESI: 292 (M+1).

Step 2: Methyl 3-amino-1-(4-methoxybenzyl)-1H-pyrazole-5-carboxylate

To a stirred solution of the mixture methyl 2-[(4-methoxyphenyl)methyl]-5-nitropyrazole-3- carboxylate and methyl 1-(4-methoxybenzyl)-5-nitro-1H-pyrazole-3-carboxylate (11.3 g, 38.8 mmol) in MeOH (500 mL) in a 1000 mL round-bottom flask under nitrogen was added Pt/C (5% wt., 1.50 g) in portions. The flask was evacuated and flushed 3 times with hydrogen. The solution was stirred for 16 h at RT under hydrogen atmosphere with a balloon. The resulting mixture was filtered, the filter cake was washed with MeOH (3x50 mL). The filtrate was concentrated under reduced pressure. The crude product was eluted from silica gel with

EtOAc/PE (1:3). This resulted in the title compound (7.1 g, 70.1%) as a light yellow solid. MS- ESI: 262 (M+1).

Steps 3-7 used similar procedures for converting compound 405” to Intermediate 131 shown in Scheme 87 to afford Intermediate 133 from compound 411”. MS-ESI: 439 (M+1).

Scheme 89:

N'-(tert-butyldimethylsilyl)-2-(2-hydroxypropan-2-yl)-4-(met hoxymethyl)thiazole-5- sulfonimidamide

Step 1: (2-Bromothiazol-4-yl) MeOH

To a stirred solution of methyl 2-bromothiazole-4-carboxylate (10.0 g, 45.0 mmol) in EtOH (150 mL) in a 250-mL round-bottom flask was added NaBH4 (3.42 g, 90.0 mmol) in portions at RT. The resulting solution was stirred for 3 h at RT. The reaction was then quenched by the addition of 200 mL of water. The resulting solution was extracted with 3x300 ml of EtOAc and concentrated. The crude product was eluted from silica gel with EtOAc/PE (1:5). This resulted in 8.0 g (91.6%) of the title compound as yellow oil. MS-ESI: 196/194 (M+1).

Step 2: 2-Bromo-4-(methoxymethyl)thiazole

To a stirred solution of (2-bromothiazol-4-yl)methanol (8.0 g, 41.2 mmol) in THF (100 mL) in a 250-mL round-bottom flask under nitrogen was added NaH (60% dispersion in mineral oil, 1.65 g, 82.4 mmol) in portions at 0 ^° C. The resulting solution was stirred for 20 min at RT. This was followed by the addition of CH3I (6.43 g, 45.3 mmol) dropwise with stirring at 0 ^° C. The resulting solution was stirred for 16 h at RT. The reaction was then quenched with 200 mL of water. The resulting solution was extracted with 3x200 ml of EtOAc and the organic layers combined and concentrated under vacuum. The residue was eluted from silica gel with

EtOAc/PE (1:30). This resulted in 7.0 g (81.7%) of the title compound as a light yellow solid. MS-ESI: 210/208 (M+1).

Step 3: 2-(4-(Methoxymethyl)thiazol-2-yl)propan-2-ol

To a stirred solution of 2-bromo-4-(methoxymethyl)thiazole (7.0 g, 33.6 mmol) in THF (70 mL) a 250-mL 3-necked round-bottom flask under nitrogen was added n-BuLi/hexane (2.5 M, 14.8 mL, 37.0 mmol) dropwise at -78 ^° C over 30 min. To this was added acetone (2.15 g, 37.0 mmol) dropwise with stirring at -78 ^° C. The resulting solution was stirred for 50 min at RT. The reaction was then quenched by the addition of 80 mL of water/ice. The resulting solution was extracted with 3x80 mL of EtOAc. The resulting mixture was washed with 2 x50 mL of water. The mixture was dried over anhydrous Na2SO4. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1/5). This resulted in 3.20 g (50.8%) of the title compound as yellow oil. MS-ESI: 250 (M-1).

Steps 4-7 used similar procedures for converting compound 369” to intermediate 126 shown in Scheme 82 to afford intermediate 134 from compound 419”. MS-ESI: 380 (M+1).

Scheme 90:

N'-(tert ldimethylsilyl)-4-(1-(dimethylamino)-2,2-difluoroethyl)benze nesulfonimidamide Step 1: 1-(4-Bromophenyl)-2,2-difluoroethan-1-one

To a stirred solution of 1,4-dibromobenzene (10.0 g, 42.4 mmol) in THF (300 mL) a 500-mL 3- necked round-bottom flask under nitrogen was added n-BuLi/hexane (2.5 M, 18.6 mL, 46.6 mmol) dropwise at -70 ^° C. The resulting solution was stirred for 30 min at -70 ^° C. Then to this was added ethyl ethyl 2,2-difluoroacetate (15.7 g, 127 mmol) in THF (20 mL) dropwise at -70 ^° C. The resulting solution was stirred for 30 min at -70 ^° C. The reaction was then quenched by the addition of 200 mL of water. The resulting solution was extracted with 3x200 mL of DCM and the combined organic layers dried over Na ₂ SO _4, then concentrated under reduced pressure. This resulted in 6.0 g (crude) of the title compound as a yellow oil. MS-ESI: 235/237 (M+1). Step 2: 1-(4-Bromophenyl)-2,2-difluoroethan-1-ol

To a stirred solution of 1-(4-bromophenyl)-2,2-difluoroethan-1-one (6.0 g, crude) in ethanol (40 mL) in a 50-mL round-bottom flask under nitrogen was added NaBH4 (3.22 g, 84.8 mmol) in portions at 0 ^° C. The resulting solution was stirred for 1 h at RT. The reaction was then quenched by the addition of 50 mL of water. The resulting solution was extracted with 3x20 mL of DCM, the combined organic layers were dried over Na ₂ SO ₄ and then concentrated under reduced pressure. The residue was eluted from silica gel with EtOAc/PE (1/5). This resulted in 5 g (49.8% over two steps) of the title compound as brown oil. MS-ESI: 237/239 (M+1).

Step 3: 1-(4-Bromophenyl)-2,2-difluoroethyl methanesulfonate

To a stirred solution of 1-(4-bromophenyl)-2,2-difluoroethan-1-ol (4.74 g, 20.0 mmol) in DCM (100 mL) in a 250-mL round-bottom flask was added TEA (6.06 g, 60.0 mmol) at RT. This was followed by the addition of methanesulfonyl chloride (3.45 g, 30.0 mmol) dropwise with stirring at 0 ^° C. The resulting solution was stirred for 30 min at RT. The reaction was then quenched by the addition of 100 mL of water. The resulting solution was extracted with 3x100 mL of DCM, the combined organic layers were dried over Na ₂ SO ₄ and then concentrated under vacuum. This resulted in 5.53 g (87.7%) of the title compound as brown oil. MS-ESI: 315/317 (M+1).

Step 4: 1-(4-Bromophenyl)-2,2-difluoro-N,N-dimethylethan-1-amine

To a stirred solution of 1-(4-bromophenyl)-2,2-difluoroethyl methanesulfonate (5.53 g, 17.6 mmol) in THF (100 mL) in a 250-mL round-bottom flask was added dimethylamine in THF (2 M, 352 mL, 704 mmol) dropwise at 0 ^° C. The resulting solution was stirred for 14 h at 60 ^° C in an oil bath. The resulting mixture was concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:1). This resulted in 3.96 g (85.2%) of the title compound as brown oil. MS-ESI: 264/266 (M+1).

Steps 5-8 used similar procedures for converting compound 369” to Intermediate 126 shown in Scheme 82 to afford Intermediate 135 from compound 427”. MS-ESI: 378 (M+1).

Scheme 91:

O

O O O O NH ₂

O

B _r HO

H ₂ N TBS

te 136

N'-(tert yldimethylsilyl)-4-(2-hydroxypropan-2-yl)-5-phenylthiophene- 2-sulfonimidamide

Step 1: Methyl 2-bromo-5-(chlorosulfonyl)thiophene-3-carboxylate

To a stirred solution of methyl 2-bromothiophene-3-carboxylate (4.42 g, 20.0 mmol) in CHCl3

(100 mL) in a 250-mL round-bottom flask was added HSO ₃ Cl (7.02 g, 60.0 mmol) dropwise at 0

°C. The resulting solution was stirred for 16 h at RT. This was followed by the addition of PCl ₅

(12.5 g, 60.0 mmol) in several batches at 0 ^° C. The resulting solution was stirred for 3 h at 60 ^° C

in an oil bath. The reaction mixture was poured into 200 mL of water/ice slowly. The resulting

solution was extracted with 3x100 mL of DCM, the combined organic layers dried over Na ₂ SO ₄

then concentrated under vacuum. This resulted in 4.50 g (crude) of the title compound as light

yellow oil.

Step 2: Methyl 2-bromo-5-sulfamoylthiophene-3-carboxylate

To a stirred solution of methyl 2-bromo-5-(chlorosulfonyl)thiophene-3-carboxylate (4.50 g,

crude) in DCM (100 mL) in a 250-mL round-bottom flask. Then NH3 (g) was introduced to the

reaction mixture with stirring at 0 ^° C for 10 min. The resulting solution was stirred for 2 h at 25

°C, the mixture was concentrated under vacuum. The crude product was eluted from silica gel with EtOAc/PE (1:1). This resulted in 3.04 g (50.6%) of the title compound as yellow solid. MS- ESI: 300/298 (M-1).

Step 3: Methyl 2-phenyl-5-sulfamoylthiophene-3-carboxylate

To a stirred solution of methyl 2-bromo-5-sulfamoylthiophene-3-carboxylate (3.0 g, 10.0 mmol) in dioxane (100 mL)/H2O (10 mL) in a 500-mL 3-necked round-bottom flask under nitrogen was added Cs ₂ CO ₃ (8.15 g, 25.0 mmol). Then phenylboronic acid (3.05 g, 25.0 mmol), Xphos (477 mg, 1.0 mmol) and Pd(dppf)Cl2 (732 mg, 1.0 mmol) were added at RT. The resulting solution was stirred for 16 h at 80 ^° C in an oil bath. The insoluble was filtered out and the filtrate was concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:3). This resulted in 1.81 g (61.1%) of the title compound as yellow oil. MS-ESI: 296 (M-1).

Steps 4-7 used similar procedures for converting compound 406” to intermediate 131 shown in Scheme 87 to afford intermediate 136 from compound 434”. MS-ESI: 411 (M+1).

Scheme 92:

N'-(te - utyldimethylsilyl)-4-(1-(dimethylamino)-2-fluoroethyl)benzen esulfonimidamide Step 1: 2-Amino-2-(4-bromophenyl)ethan-1-ol

To a stirred solution of 2-amino-2-(4-bromophenyl)acetic acid (5.0 g, 21.7 mmol) in THF (200 mL) in a 500-mL 3-necked round-bottom flask under nitrogen was added BH ₃ /THF (1M, 108 mmol, 108 mL) dropwise at 0 ^° C in an ice bath. The resulting solution was stirred for 16 h at 50 ^° C in an oil bath. The reaction was then quenched by the addition of 50 mL of MeOH. The resulting mixture was concentrated under vacuum. The residue was eluted from silica gel with DCM/MeOH (10:1). This resulted in 2.67 g (56.9%) of the title compound as yellow oil. MS- ESI: 216/218 (M+1).

Step 2: 2-(4-Bromophenyl)-2-(dimethylamino)ethan-1-ol

To a stirred solution of 2-amino-2-(4-bromophenyl)ethan-1-ol (2.67 g, 12.4 mmol) in HCOOH (10 mL) in a 100-mL round-bottom flask under nitrogen was added (HCHO)n (1.12 g, 37.2 mmol) at 0 ^° C. The resulting solution was stirred for 2 h at 85 ^° C in an oil bath. The pH value of the solution was adjusted to 10 with Na ₂ CO ₃ (5 M). The resulting solution was extracted with 3x100 mL of EtOAc, the combine organic layers was dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:3). This resulted in 2.37 g (78.3%) of the title compound as a yellow solid. MS-ESI: 244/246 (M+1). Step 3: 1-(4-Bromophenyl)-2-fluoro-N,N-dimethylethan-1-amine

To a stirred solution of 2-(4-bromophenyl)-2-(dimethylamino)ethan-1-ol (1.22 g, 5.00 mmol) in DCM (20 mL) in a 100-mL 3-necked round-bottom flask under nitrogen was added DAST (4.03 g, 25.0 mmol) dropwise at 0 ^° C. The resulting solution was stirred for 16 h at RT. The reaction was then quenched by the addition of 10 mL of water/ice. The pH value of the solution was adjusted to 9 with NaHCO ₃ (6 M). Then the mixture was extracted with EtOAc (3x50 mL) and the organic layers were combined and dried over anhydrous Na ₂ SO _4, then concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:1). This resulted in 925 mg (75.2%) of the title compound as brown oil. MS-ESI: 246/248 (M+1).

Step 4: Lithium 4-(1-(dimethylamino)-2-fluoroethyl)benzenesulfinate

To a stirred solution of 1-(4-bromophenyl)-2-fluoro-N,N-dimethylethan-1-amine (738 mg, 3.00 mmol) in THF (30 mL) in a 100-mL 3-necked round-bottom flask under nitrogen was added n- BuLi/hexane(2.5 M, 2.40 mL, 6.0 mmol) dropwise at -78 ^° C. The resulting solution was stirred for 30 min at -78 ^° C. Then SO2 (g) was bubbled into the reaction solution for 15 min below 0 ^° C. The resulting solution was allowed to react, with stirring, for an additional 1 h at RT. The reaction was concentrated under vacuum and for next step without purification. MS-ESI: 232 (M+1).

Step 5: 4-(1-(Dimethylamino)-2-fluoroethyl)benzenesulfonamide

To a stirted solution of Lithium 4-(1-(dimethylamino)-2-fluoroethyl)benzenesulfinate (693 mg, crude) in DCM (40 mL) in a 100-mL round-bottom flask was added DCDMH (1.18 g, 6.00 mmol) at RT. Then the reaction solution was stirred for 2 h at RT. Then NH3 (g) was bubbled into the solution for 10 min at 0 ^° C. The resulting solution was allowed to react, with stirring, for an additional 1 h at RT. The resulting mixture was concentrated under vacuum. The residue was eluted from silica gel with DCM/MeOH (1:10). This resulted in 163 mg (22.1% over two steps) of the title compound as yellow oil. MS-ESI: 247 (M+1).

Steps 6-8 used similar procedures for converting compound 362” to intermediate 124 shown in Scheme 80 to afford intermediate 137 from compound 443”. MS-ESI: 360 (M+1).

Scheme 93:

Intermediate 138

N'-(tert-butyldimethylsilyl)-5-fluoro-2-isopropylpyridine-4- sulfonimidamide Steps 1-3 used similar procedures for converting compound 369” to compound 371” shown in Scheme 82 to afford compound 449” from compound 446”. MS-ESI: 211/213 (M+1).

To a stirred solution of 2-chloro-5-fluoropyridine-4-sulfonamide (1.27 g, 6.00 mmol) in H ₂ O (15 mL) and dioxane (60 mL) in a 100-mL 3-necked round-bottom flask under nitrogen was added 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (3.02 g, 18.0 mmol). Then Cs2CO3 (3.91 g, 12.0 mmol) and Pd(dppf)Cl ₂ (439 mg, 0.600 mmol) were added. The resulting solution was stirred for 12 h at 80 ^° C in an oil bath. The resulted mixture was concentrated under vacuum. The resulting solution was diluted with 50 mL of H2O. The resulting solution was extracted with 3x100 mL of DCM, the combined organic layers was dried over anhydrous Na ₂ SO ₄ and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:9). This resulted in 1.18 g (90.8%) of the title compound as a dark yellow solid. MS-ESI: 217 (M+1). Step 5: 5-Fluoro-2-isopropylpyridine-4-sulfonamide

To a stirred solution of 5-fluoro-2-(prop-1-en-2-yl)pyridine-4-sulfonamide (1.18 g, 5.46 mmol) in isopropyl alcohol (50 mL) in a 100-mL round-bottom flask under nitrogen was added Pd/C (10%wt., 200 mg), the flask was evacuated and flushed with hydrogen 3 times. The resulting solution was stirred for 3 h at RT under hydrogen with a balloon. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:9). This resulted in 1.07 g (89.9%) of the title compound as yellow oil. MS- ESI: 219 (M+1).

Steps 6-8 used similar procedures for converting compound 362” to intermediate 124 shown in Scheme 80 to afford intermediate 138 from compound 451”. MS-ESI: 332 (M+1).

Scheme 94: O

N Cl HO

NH ₂ NH ^TBS

S ^te

3 ⁹

N'-(tert-butyldimethylsilyl)-2-(2-hydroxypropan-2-yl)thiazol e-4-sulfonimidamide

Step 1: 2-(4-(Benzylthio) thiazol-2-yl)propan-2-ol

To a stirred solution of 2-(4-bromothiazol-2-yl)propan-2-ol (8.0 g, 36.0 mmol) in 1,2- dimethoxyethane (100 mL) in a 100-mL 3-necked round-bottom flask under nitrogen was added

Na ₂ CO ₃ (11.4 g, 108 mmol). Then phenylmethanethiol (22.3 g, 180 mmol) and XPhos Pd G2

(3.20 g, 3.60 mmol) were added. The resulting solution was stirred for 16 h at 80 ^° C in an oil

bath. The insoluble was filtered out and the filtrate was concentrated under vacuum. The residue

was eluted from silica gel with EtOAc/hexane (1:5). This resulted in 4.99 g (52.3%) of the title

compound as a yellow solid. MS-ESI: 266 (M+1).

Step 2: 2-(2-Hydroxypropan-2-yl) thiazole-4-sulfonyl chloride

To a stirred solution of 2-(4-(benzylthio) thiazol-2-yl)propan-2-ol (500 mg, 1.89 mmol) in

MeCN (40 mL), H ₂ O (2 mL), AcOH (0.75 mL) in a 100-mL round-bottom flask was added

DCDMH (1.12 g, 5.67 mmol) in MeCN (10 mL) dropwise with stirring at 0 ^° C. The resulting

solution was stirred for 3 h at RT. The resulting mixture was diluted with 30 mL of water. The

resulting solution was extracted with 3x30 mL of EtOAc, the combined organic layers was dried over anhydrous Na2SO4 and concentrated under vacuum. This resulted in 400 mg (crude) of the title compound as a yellow solid.

Step 3: 2-(2-Hydroxypropan-2-yl) thiazole-4-sulfonamide

To a stirred solution of 2-(2-hydroxypropan-2-yl) thiazole-4-sulfonyl chloride (400 mg, crude) in DCM (30 mL) in a 100-mL round-bottom flask bubbled NH3 (g) at 0 ^° C for 10 min. The resulting solution was stirred for 20 min at RT. The resulting mixture was concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:1). This resulted in 150 mg (35.7% for Steps 2&3) of the title compound as a yellow solid. MS-ESI: 221 (M-1).

Steps 4-5 used similar procedures for converting compound 362” to intermediate 124 shown in Scheme 80 to afford intermediate 139 from compound 457”. MS-ESI: 336 (M+1).

Scheme 95:

N-(tert-butyldimethylsilyl)-6-methyl-4,5,6,7-tetrahydrothien o[2,3-c]pyridine-2-sulfonimidamide Step 1: 6-Methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine

To a stirred solution of 4,5,6,7-tetrahydrothieno[2,3-c]pyridine

hydrochloride (1.76 g, 10.0 mmol) in THF (100 mL) in a 250-mL round-bottom flask under nitrogen was added NaH (60% dispersion in mineral oil, 800 mg, 20.0 mmol) in portions at 0 ^° C. The resulting solution was stirred for 20 min at RT. This was followed by the addition of CH ₃ I (4.26 g, 30.0 mmol) dropwise with stirring at 0 ^° C. The resulting solution was stirred for 16 h at RT. The reaction was then quenched by the addition of water (100 mL). The resulting solution was extracted with 3x100 ml of EtOAc and the organic layers combined and dried over Na ₂ SO ₄ , then concentrated under vacuum. The residue was eluted from silica gel with DCM/MeOH (18:1). This resulted in 1.25 g (81.7%) of the title compound as a light yellow solid. MS-ESI: 154 (M+1).

Steps 2-6 used similar procedures for converting compound 369” to intermediate 126 shown in Scheme 82 to afford intermediate 140 from compound 460”. MS-ESI: 346 (M+1).

Scheme 96:

N butyldimethylsilyl)-4-(difluoromethoxy)benzenesulfonimidamid e

Step 1: 4-(Difluoromethoxy)benzenesulfonamide

To a stirred solution of 4-(difluoromethoxy)benzenesulfonyl chloride (2.43 g, 10.0 mmol) in THF (100 mL) in a 250-mL round-bottom flask was bubbled NH ₃ (g) for 10 min with stirring at 0 ^° C. The resulting solution was stirred for 2 h at RT and concentrated under vacuum. The crude product was eluted from silica gel with EtOAc/PE (1:1). This resulted in 1.93 g (86.5%) of the title compound as yellow oil. MS-ESI: 222 (M-1).

Steps 2-4 used similar procedures for converting compound 362” to intermediate 124 shown in Scheme 80 to afford intermediate 141 from compound 466”. MS-ESI: 337 (M+1). Scheme 97:

Tert-butyl ((5-(N'-(tert-butyldimethylsilyl)sulfamidimidoyl)-4-fluoroth iophen-2- yl)methyl)(methyl)carbamate

Step 1: (4-Fluorothiophen-2-yl)methanol

To a stirred solution of methyl 4-fluorothiophene-2-carboxylate (10.0 g, 62.5 mmol) in THF (200 mL) in a 500-mL round-bottom flask under nitrogen was added LiAlH ₄ (4.75 g, 125 mmol) in portions at 0 ^° C. The resulting solution was stirred for 16 h at RT. The reaction was then quenched with 100 mL of water/ice. The insoluble was filtered out and the filtrate was extracted with EtOAc (3x200 mL). The organic layers were combined and dried over anhydrous Na ₂ SO ₄ and concentrated under vacuum. The crude product was eluted from silica gel with EtOAc/PE (1:1). This resulted in 7.0 g (84.8%) of the title compound as a yellow solid. MS-ESI: 133 (M+1).

Step 2: 2-(Bromomethyl)-4-fluorothiophene

To a stirred solution of (4-fluorothiophen-2-yl)methanol (7.0 g, 53.0 mmol) in DCM (150 mL) in a 500-mL round-bottom flask was added PBr ₃ (17.2 g, 63.6 mmol) dropwise at 0 ^° C. The resulting solution was stirred for 3 h at RT. The reaction was then quenched by the addition of 60 mL of water. The resulting solution was extracted with DCM (3x50 mL). The organic layers were combined and dried over anhydrous Na ₂ SO ₄ and concentrated under vacuum. The crude product was eluted from silica gel with EtOAc/PE (1:5). This resulted in 8.0 g (77.4%) of the title compound as a yellow solid.

Step 3: 1-(4-Fluorothiophen-2-yl)-N-methylmethanamine

To a stirred solution of 2-(bromomethyl)-4-fluorothiophene (8.00 g, 41.0 mmol) in THF (100 mL) in a 250-mL round-bottom flask was added methanamine in THF (2 M, 41 mL, 82.0 mmol) at RT. The resulting solution was stirred for 16 h at RT. The reaction was then quenched with 50 mL of water. The resulting solution was extracted with EtOAc (3x100 mL). The organic layers were combined and dried over anhydrous Na2SO4 and concentrated under vacuum. The crude product was eluted from silica gel with EtOAc/PE (1:1). This resulted in 4.0 g (67.3%) of the title compound as a yellow solid. MS-ESI: 146 (M+1).

Step 4: Tert-butyl ((4-fluorothiophen-2-yl)methyl)(methyl)carbamate

To a stirred solution of 1-(4-fluorothiophen-2-yl)-N-methylmethanamine (4.0 g, 27.6 mmol) in THF (40 mL) in a 100-mL round-bottom flask under nitrogen was added NaH (60% dispersion in mineral oil, 1.66 g, 41.4 mmol) in portions at 0 ^° C. The resulting solution was stirred for 20 min at RT. This was followed by the addition of (Boc)2O (9.03 g, 41.4 mmol) in THF (5 mL) dropwise with stirring at 0 ^° C. The resulting solution was stirred for 16 h at RT. The reaction was then quenched with 10 mL of water. The resulting solution was extracted with EtOAc. The organic layers were combined and dried over anhydrous Na2SO4 and concentrated under vacuum. The crude product was eluted from silica gel with EtOAc/PE (1:3). This resulted in 5.0 g (74.0%) of the title compound as a yellow solid. MS-ESI: 246 (M+1).

Steps 5-8 used similar procedures for converting compound 369” to intermediate 126 shown in Scheme 82 to afford intermediate 142 from compound 470”. MS-ESI: 438 (M+1).

Scheme 98:

Tert-butyl 2-(4-( (tert-butyldimethylsilyl)sulfamidimidoyl)phenyl)pyrrolidine- 1-carboxylate

Step 1: 2,2,2-Trifluoro-1-(2-phenylpyrrolidin-1-yl)ethan-1-one

To a stirred solution of 2-phenylpyrrolidine (16.5 g, 112 mmol) in DCM (200 mL) in a 500-mL round-bottom flask under nitrogen was added TEA (22.6 g, 224 mmol) followed by TFAA (16.0 mL) dropwise at 0 ^° C. The resulting solution was stirred for 2 h at RT. The reaction was then quenched with 100 mL of water. The resulting solution was extracted with 3x200 mL of DCM. The organic layers were combined and dried over anhydrous Na2SO4 and concentrated under vacuum. The crude product was eluted from silica gel with EtOAc/PE (1:4). This resulted in 20.0 g (73.5%) of the title compound as yellow oil. MS-ESI: 244 (M+1).

Step 2: 4-(1-(2,2,2-trifluoroacetyl)pyrrolidin-2-yl)benzenesulfonyl chloride

To a stirred solution of 2,2,2-trifluoro-1-(2-phenylpyrrolidin-1-yl)ethan-1-one (4.86 g, 20.0 mmol) in CHCl ₃ (100 mL) in a 250-mL round-bottom flask was added HSO ₃ Cl (7.02 g, 60.0 mmol) dropwise at 0 ^° C. The resulting solution was stirred for 16 h at RT. This was followed by the addition of PCl5 (12.5 g, 60.0 mmol) in several batches at 0 ^° C. The resulting solution was stirred for 3 h at 60 ^° C in an oil bath. The reaction mixture was poured into 200 mL of water/ice slowly. The resulting solution was extracted with 3x100 mL of DCM. The organic layers were combined and dried over anhydrous Na ₂ SO ₄ and concentrated under vacuum. This resulted in 5.10 g (crude) of the title compound as light yellow oil.

Step 3: 4-(1-(2,2,2-Trifluoroacetyl)pyrrolidin-2-yl)benzenesulfonami de

To a stirred solution of 4-(1-(2,2,2-trifluoroacetyl)pyrrolidin-2-yl)benzenesulfonyl chloride (5.10 g, crude) in DCM (100 mL) in a 250-mL round-bottom flask. Then NH ₃ (g) was introduced into the reaction solution with stirring at 0 ^° C for 10 min. The resulting solution was stirred for 2 h at RT and concentrated under vacuum. The crude product was eluted from silica gel with

EtOAc/PE (1:1). This resulted in 3.26 g (50.6%, over two steps) of the title compound as a yellow solid. MS-ESI: 321 (M-1).

Step 4: 4-(Pyrrolidin-2-yl)benzenesulfonamide

To a stirred solution of 4-(1-(2,2,2-trifluoroacetyl)pyrrolidin-2-yl)benzenesulfonami de (3.22 g, 10.0 mmol) in MeOH (30 mL) in a 250-mL round-bottom flask under nitrogen was added K ₂ CO ₃ (4.14 g, 30.0 mmol). The resulting solution was stirred for 16 h at RT. The solids were filtered out and the filter cake was washed with 3x100 mL of EtOAc, the filtrate and the wash were combined and concentrated under vacuum. The crude product was eluted from silica gel with EtOAc/PE (1:1). This resulted in 1.86 g (82.1%) of the title compound as yellow oil. MS-ESI: 227 (M+1).

Step 5: Tert-butyl 2-(4-sulfamoylphenyl)pyrrolidine-1-carboxylate

To a stirred solution of 4-(pyrrolidin-2-yl)benzenesulfonamide (1.13 g, 5.0 mmol) in DCM (30 mL) in a 250-mL round-bottom flask under nitrogen was added NaHCO3 (840 mg, 10.0 mmol) and Boc ₂ O (1.20 g, 5.50 mmol) in portions at RT. The resulting solution was stirred for 2 h at RT. The reaction was then quenched by the addition of water. The resulting solution was extracted with 3x50 mL of DCM and the organic layers combined and concentrated under vacuum. The crude product was eluted from silica gel with EtOAc/PE (1:1). This resulted in 1.24 g (76.3%) of the title compound as yellow oil. MS-ESI: 327 (M+1).

Steps 6-7 used similar procedures for converting compound 362” to intermediate 124 shown in Scheme 80 to afford intermediate 143 from compound 479”. MS-ESI: 440 (M+1).

Scheme 99:

N'-(tert-butyldimethylsilyl)-6-cyclopentylpyridine-3-sulfoni midamide Steps 1-2 used similar procedures for converting compound 374” to compound 375” shown in Scheme 83 to afford compound 219 from compound 217. MS-ESI: 239/237 (M+1).

Step 3: 6-Cyclopentylpyridine-3-sulfonamide

To a stirred solution of 6-bromopyridine-3-sulfonamide (2.00 g, 8.44 mmol) in THF (20 mL) in a 250-mL round-bottom flask under nitrogen were added Pd(dppf)Cl2 (309mg, 0.422 mmol). Then CuI (161 mg, 0.844 mmol) was added and cyclopentylzinc(II) bromide (1M in THF, 34.0 mL) dropwise at RT under nitrogen. The resulting mixture was stirred overnight at 80 ^° C under nitrogen. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EtOAc/PE (1:2) to afford the title compound (1.70 g, 89.2%) as a yellow solid. MS-ESI: 225 (M-1).

Steps 4-5 used similar procedures for converting compound 362” to intermediate 124 shown in Scheme 80 to afford intermediate 144 from compound 481”. MS-ESI: 340 (M+1).

Scheme 100:

Tert-butyl (2-(4-(N'-(tert-butyldiphenylsilyl)sulfamidimidoyl)-3-fluoro phen l pan-2-

yl)(methyl)carbamate

Step 1: 2-Fluoro-4-(prop-1-en-2-yl)benzenesulfonamide

To a stirred solution of 4-bromo-2-fluorobenzenesulfonamide (10.2 g, 40.0 mmol) in dioxane (300 mL) and H2O (30 mL) in a 500-mL round-bottom flask under nitrogen was added Cs2CO3 (32.6 g, 100 mmol). Then 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (16.8 g, 100 mmol) and Pd(dppf)Cl2 (1.46 g, 2.00 mmol) were added. The resulting solution was stirred for 16 h at 90 ^° C in an oil bath. The resulting mixture was concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:2). This resulted in 6.09 g (70.8%) of the title compound as yellow oil. MS-ESI: 216 (M+1).

Step 2: 2-Chloro-N-(2-(3-fluoro-4-sulfamoylphenyl)propan-2-yl)acetam ide

To a stirred solution of 2-fluoro-4-(prop-1-en-2-yl)benzenesulfonamide (6.02 g, 28.0 mmol) in AcOH (150 mL) in a 500-mL round-bottom flask under nitrogen was added 2-chloroacetonitrile (21.0 g, 280 mmol), then H2SO4 (30 mL) was added dropwise at 0 ^° C. The resulting solution was stirred for 12 h at RT. The resulting solution was poured into 200 mL of water/ice. The pH value of the solution was adjusted to 7 with NaOH (6 M). The resulting solution was extracted with 3x300 mL of EtOAc. The organic layers were combined and dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was eluted from silica gel with DCM/MeOH (10:1). This resulted in 4.42 g (51.1%) of the title compound as a yellow solid. MS-ESI: 309 (M+1).

Step 3: 4-(2-Aminopropan-2-yl)-2-fluorobenzenesulfonamide

To a stirred solution of 2-chloro-N-(2-(3-fluoro-4-sulfamoylphenyl)propan-2-yl)acetam ide (4.02 g, 13.0 mmol) in EtOH (80 mL) and AcOH (16 mL) in a 250-mL round-bottom flask under nitrogen was added thiourea (1.19 g, 15.6 mmol). The resulting solution was stirred for 12 h at 80 ^° C. The resulting mixture was concentrated and diluted with 200 mL of water. The resulting solution was extracted with 2x200 mL of EtOAc. The organic layers were combined and dried over anhydrous Na2SO4 and concentrated under vacuum. This resulted in 3.01 g (99.7%) of the title compound as a yellow solid. MS-ESI: 233 (M+1).

Step 4: Tert-butyl (2-(3-fluoro-4-sulfamoylphenyl)propan-2-yl)carbamate

To a stirred solution of 4-(2-aminopropan-2-yl)-2-fluorobenzenesulfonamide (3.01 g, 13.0 mmol) in THF (50 mL) in a 100-mL round-bottom flask under nitrogen was added TEA (2.63 g, 26.0 mmol), followed by the addition of (Boc) ₂ O (4.25 g, 19.5 mmol) in THF (10 mL) dropwise at 0 ^° C. The resulting solution was stirred for 12 h at RT. The resulting solution was diluted with 100 mL of water. The resulting solution was extracted with 3x100 mL of EtOAc. The organic layers were combined and dried over anhydrous Na ₂ SO ₄ and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:1). This resulted in 2.81 g (65.2%) of the title compound as yellow oil. MS-ESI: 333 (M+1).

Step 5: Tert-butyl (2-(4-(N-(tert-butyldiphenylsilyl)sulfamoyl)-3-fluorophenyl) propan-2- yl)carbamate

To a stirred solution of tert-butyl (2-(3-fluoro-4-sulfamoylphenyl)propan-2-yl)carbamate (2.80 g, 8.43 mmol) in THF (100 mL) in a 250-mL round-bottom flask under nitrogen was added NaH (60% oil dispersion, 506 mg, 12.6 mmol) in portions at 0 ^° C. The resulting solution was stirred for 20 min at RT. This was followed by the addition of TBDPSCl (2.78 g, 10.1 mmol) in THF (5 mL) dropwise with stirring at 0 ^° C. The resulting solution was stirred for 12 h at RT. The reaction was then quenched by the addition of 200 mL of water. The resulting solution was extracted with 3x200 mL of EtOAc. The organic layers were combined and dried over anhydrous Na ₂ SO ₄ and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:5). This resulted in 3.0 g (62.4%) of the title compound as a yellow solid. MS-ESI: 571 (M+1).

Step 6: Tert-butyl(2-(4-(N-(tert-butyldiphenylsilyl)sulfamoyl)-3-flu orophenyl)propan-2- yl)(methyl)carbamate

To a stirred solution of tert-butyl (2-(4-(N-(tert-butyldiphenylsilyl)sulfamoyl)-3- fluorophenyl)propan-2-yl)carbamate (2.90 g, 5.08 mmol) in THF (100 mL) in a 250-mL round- bottom flask under nitrogen was added NaH (60% oil dispersion, 406 mg, 10.2 mmol) in portions at 0 ^° C. The resulting solution was stirred for 20 min at RT. This was followed by the addition of CH3I (866 mg, 6.10 mmol) dropwise with stirring at 0 ^° C. The resulting solution was stirred for 12 h at RT. The reaction was then quenched by the addition of 100 mL of water. The resulting solution was extracted with 3x100 mL of EtOAc and the combined organic layer concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:5). This resulted in 2.0 g (67.3%) of the title compound as a yellow solid. MS-ESI: 585 (M+1).

Step 7: Tert-butyl(2-(4-(N'-(tert-butyldiphenylsilyl)sulfamidimidoyl )-3- fluorophenyl)propan-2-yl) -(methyl)carbamate

To a stirred solution of PPh3Cl2 (1.33 g, 4.0 mmol) in CHCl3 (20 mL) in a 250-mL 3-necked round-bottom flask under nitrogen was added DIEA (1.29 g, 10.0 mmol) dropwise at 0 ^° C. The resulting solution was stirred for 10 min at RT. To this was added a solution of tert-butyl(2-(4- (N-(tert-butyldiphenylsilyl)sulfamoyl)-3-fluorophenyl)propan -2-yl)(methyl) carbamate (1.17 g, 2.00 mmol) in CHCl ₃ (20 mL) dropwise with stirring at 0 ^° C. The resulting solution was allowed to react, with stirring, for an additional 30 min while the temperature was maintained at 0 ^° C in a water/ice bath. To the above NH3 (g) was bubbled for 15 min at 0 ^° C. The resulting solution was allowed to react, with stirring, for an additional 30 min at RT. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:3). This resulted in 703 mg (60.2%) of the title compound as an off- white solid. MS-ESI: 584 (M+1).

Scheme 101: Br

( ¹⁾ Mg _{(HCHO)n, HCOOH} n-BuLi, -78 ^o C O NCS, RT ^NC _Br Br Br S

tep 4

N

N'-(tert -(cyclopropyl(dimethylamino)methyl)benzenesulfonimidamide

Step 1: (4-Bromophenyl)(cyclopropyl)methanamine

To a stirred solution of 4-bromobenzonitrile (10.0 g, 54.9 mmol) in THF (200 mL) in a 1000-mL 3-necked round-bottom flask under nitrogen was added cyclopropyl magnesium bromide (1 M in THF, 165 mL, 165 mmol) dropwise at 0 ^° C in 20 min. The resulting solution was stirred for 5 h at 0 ^° C. To this was added MeOH (200 mL) at 0 ^° C in 5 min. To the mixture was added NaBH ₄

(10.4 g, 275 mmol), in portions at 0 ^° C over 10 min. The resulting solution was allowed to react, with stirring, for an additional 16 h at RT. The reaction was then quenched by the addition of 10 mL of water. The solids were filtered out. The resulting mixture was concentrated under vacuum.

The residue was eluted from silica gel with DCM/MeOH (20:1). This resulted in 9.79 g (78.9%) of the title compound as yellow oil. MS-ESI: 226/228 (M+1).

Step 2: 1-(4-Bromophenyl)-1-cyclopropyl-N,N-dimethylmethanamine

To a stirred solution of (4-bromophenyl)(cyclopropyl)methanamine (5.29 g, 23.4 mmol) in DCE (50 mL) in a 250-mL round-bottom flask under nitrogen was added HCOOH (10.8 g, 234 mmol) dropwise at RT. To this was added (HCHO)n (3.54 g, 39.3 mmol) at RT. The resulting solution was stirred for 1 h at 80 ^° C. The reaction was then quenched by the addition of 150 mL of water. The resulting solution was extracted with 3x200 mL of DCM. The organic layers were combined and dried over anhydrous Na ₂ SO ₄ . The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (2:1). This resulted in 3.30 g (55.4%) of the title compound as a white solid. MS-ESI: 254/256 (M+1). Steps 3-7 used similar procedures for converting compound 369” to Intermediate 126 shown in Scheme 82 to afford intermediate 146 from compound 492”. MS-ESI: 368 (M+1).

Table 31. Intermediate 147 was prepared using similar procedures for converting compound 490” to Intermediate 146 shown in Scheme 101 from appropriate starting materials.

Scheme 102:

butyldimethylsilyl)-6-(difluoromethyl)pyridine-3-sulfonimida mide Step 1: 5-Bromo-2-(difluoromethyl)pyridine

To a stirred solution of 5-bromopicolinaldehyde (1.86 g, 10.0 mmol) in THF (50 mL) in a 250- mL round-bottom flask was added DAST (3.22 g, 20.0 mmol) dropwise at 0 ^° C. The resulting solution was stirred for 6 h at RT. The reaction was then poured into 100 mL of water/ice. The resulting solution was extracted with 3x200 mL of EtOAc and the organic layers combined and dried over anhydrous Na ₂ SO ₄ and concentrated under vacuum. This resulted in 2.10 g (crude) of the title compound as yellow oil. MS-ESI: 208/210 (M+1).

Steps 2-5 used similar procedures for converting compound 369” to intermediate 126 shown in Scheme 82 to afford intermediate 148 from compound 498”. MS-ESI: 322 (M+1).

Scheme 103

Intermediate 103

tert-butyl (R)-((4-formylphenyl)(3-(1,2,3,5,6,7-hexahydro-s-indacen-4-y l)ureido)(oxo)- ^ ⁶ - sulfanylidene)carbamate

Step 1: ((4-bromobenzyl)oxy)(tert-butyl)dimethylsilane

Into a 500-mL round bottom flask was placed 4-bromobenzyl alcohol (15 g, 80.2 mmol), imidazole (12.01 g, 176.44 mmol) in DCM (270 mL). TBSCl (13.08 g, 84.21 mmol) was added in one portion and the mixture stirred overnight at RT. MeOH (10 mL) was added and the reaction mixture was stirred for 30 min. The mixture was transferred to a separatory funnel, washed with water (2 x 100 mL) and aq. NaHCO3 (100 mL). The organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure affording the title compound (23.75 g, 98%) as a pale yellow oil. The crude product was used in the next step.

Step 2: (4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)magnesium bromide

Magnesium turnings (888 mg, 35.6 mmol) were suspended in a flame-dried 100-mL round bottom flask. Dry THF (10 mL) was added. A solution of ((4-bromobenzyl)oxy)(tert-butyl)dimethylsilane (10 g, 33.19 mmol) in 30 mL THF was prepared and was added to the Mg-containing flask via dropping funnel. The mixture was refluxed for 2 h then cooled to RT and left to settle overnight. The Grignard solution was titrated against a known quantity of menthol and a catalytic amount of 1,10-phenanthroline in THF. Final titer (average of two titrations) was 0.51 M.

Step 3: (S)-4-(((tert-butyldimethylsilyl)oxy)methyl)benzenesulfinami de

In a 100 mL round bottom flask, a solution of (4-(((tert-butyldimethylsilyl)oxy)methyl) phenyl)magnesium bromide (prepared using the procedure described in the step above; 0.86 M in THF, 27 mL, 23 mmol) was diluted with THF (71 mL) and cooled to -46 ^o C (acetonitrile-dry ice bath). The resulting milky suspension was added via cannula to a solution of (2R,3aS,8aR)-3- (mesitylsulfonyl)-3,3a,8,8a-tetrahydroindeno- [1,2-d][1,2,3]oxathiazole 2-oxide (5.88 g, 15.58 mmol; prepared using the procedure detailed in Org. Synth.2006, 83, 131) in THF (68 mL) keeping the internal temperature of the mixture below -42 ^o C. After addition, the reaction mixture was stirred at -46 ^o C for 1 hour. LiHMDS (1 M in toluene, 46.7 mL, 46.7 mmol) was added and the reaction mixture was warmed-up to 0 ^o C and stirred for 1 h. A saturated solution of NaHCO3 (50 mL) was added and the mixture stirred for 15 min. EtOAc (150 mL) and half-saturated brine (50 mL) were added and the organic layer was separated. The aqueous layer was extracted with EtOAc (2x100 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography with an isocratic mixture of 6% (10% NH ₄ OH in MeOH) in chloroform affording 2.3 g of the title compound (75%) as an off-white solid. MS-ESI: 286.1 (M+1).

Step 4: tert-butyl (S)-((4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)sulfiny l)carbamate In a 500-mL round bottom flask was dissolved (S)-4-(((tert-butyldimethylsilyl)oxy)methyl) benzenesulfinamide (12.0 g, 42.03 mmol) in THF (350 ml). n-BuLi (2.5 M in THF, 35.2 ml, 88.3 mmol) was then added at -78 °C . The mixture was stirred at the same temperature for 10 min. A solution of di-tert-butyl carbonate (9.63 g, 44.13 mmol) in THF (21 mL) was added in one portion and the reaction mixture warmed up to 0 °C with stirring. The solution was stirred at 0 °C for 1 h. Formic acid (98%, 4.5 mL, 88.3 mmol) was added, the reaction mixture was stirred 10 min and then diluted with EtOAc (350 mL). Half-saturated brine (100 mL) was added and the phases were separated. The aqueous phase was extracted with EtOAc (2x200 mL). The organic phases were combined, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude was purified by flash chromatography using a gradient of 5-10 % MeOH in DCM affording 12.3 g of the title compound (76 %) as a transparent syrup. MS-ESI: 286.0 (M-Boc).

Step 5: tert-butyl (S)-(amino(4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)(o xo)- ^ ⁶ - sulfanylidene)- carbamate

To a cooled (-10 ^o C) solution of tert-butyl (S)-((4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl) sulfinyl)carbamate (12.20 g, 31.9 mmol) in THF (50 ml) in a 100-mL round bottom flask was added TCCA (2.52 g, 10.84 mmol, 0.34 eq) in portions. Internal temperature was kept below -5 ^o C. The mixture was stirred at 0 ^o C for 60 min, followed by 1 h at RT. Concentrated ammonium hydroxide (14 M, 34.2 mL) was added dropwise and the reaction left to warm to RT overnight. The reaction mixture was diluted with ethyl acetate (400 mL) and washed the organic phase with half-saturated brine (100 mL). The aqueous phase was extracted with EtOAc (300 ml) and the combined organic phases were dried (Na ₂ SO ₄ ), evaporated and the crude was purified by flash chromatography using a gradient of 5-50% EtOAc in hexanes to afford 10 g of the title compound (78%) as a light brown syrup. MS-ESI: 423.1 (M+Na).

Step 6: tert-butyl (R)-((3-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)ureido)(4- (hydroxymethyl)phenyl) (oxo)- ^ ⁶ -sulfanylidene)carbamate

To a 0 °C (ice bath) solution of tert-butyl (S)-(amino(4-(((tert-butyldimethylsilyl)oxy)methyl) phenyl)(oxo)- ^ ⁶ -sulfanylidene)carbamate (9.77 g, 24.39 mmol) in THF (244 ml) was added dropwise potassium tert-butoxide (1 M in THF, 25.6 ml, 25.6 mmol) keeping the internal temperature below -2.2 °C. The reaction mixture was stirred for 1 hour at 0°C. A solution of 4- isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (5.1 g, 25.61 mmol) in THF (66 mL) was added dropwise and the mixture stirred at RT for 1 h, then formic acid was added (1 mL, 25.61 mmol) and the solution stirred for 10 min. The reaction mixture was diluted with EtOAc (300 mL) and washed with half-saturated brine (100 mL). The aqueous phase was extracted with EtOAc (250 mL) and the combined organic phases were dried over anhydrous Na ₂ SO ₄ , and concentrated under reduced pressure affording the crude TBS ether (13.95 g).

The TBS ether was dissolved in MeOH (211 mL), cooled to 0°C and aqueous HCl (2 M, 280 mL, 558.67 mmol) was added and the reaction mixture was stirred 2 hours at 0°C. The crude mixture was diluted with EtOAc (400 mL), transferred to a separatory funnel and washed with water (100 mL). A white solid precipitated out of solution and the heterogeneous mixture was filtered. The solid was washed with water (100 mL) and EtOAc (100 mL), and dried overnight at low pressure affording 5.96 g of the title compound (53 % over two steps) as a white solid. MS-ESI: 486.3 (M+1).

Step 7: tert-butyl (R)-((4-formylphenyl)(3-(1,2,3,5,6,7-hexahydro-s-indacen-4- yl)ureido)(oxo)- ^ ⁶ - sulfanylidene)carbamate

In a flame-dried 500-mL round bottom flask, MnO ₂ (12 g, 143 mmol) was suspended in dry toluene (250 mL) under an argon atmosphere. The solvent was removed under reduced pressure at 50 °C, then the flask was kept at high vacuum pump for 1 h. A solution of tert-butyl (R)-((3-(1,2,3,5,6,7- hexahydro-s- indacen-4-yl)ureido)(4-(hydroxymethyl)phenyl)(oxo)- ^ ⁶ -sulfanylidene)carbamate (1.5 g, 3.089 mmol) in dry THF (130 mL) was added to the flask containing the MnO2 under an argon atmosphere. The resulting mixture was vigorously stirred at RT for 3 h. The mixture was filtered through a Celite pad which was washed with MeOH (150 mL) and the filtrate and wash were concentrated under reduced pressure at 30 °C, resulting in isolation of 1.22 g of the title compound as a pale yellow solid (82%). MS-ESI: 484.4 (M+1).

Scheme 104:

Tert-butyl (2-(4-(N'-(tert-butyldimethylsilyl)sulfamidimidoyl)phenyl)pr opan-2- yl)(methyl)carbamate

Step 1: Tert-butyl (2-(4-bromophenyl)propan-2-yl)carbamate

To a stirred solution of 2-(4-bromophenyl)propan-2-amine (5.0 g, 23.4 mmol) in DCM (60 mL) in a 250-mL round-bottom flask was added TEA (4.73 g, 46.8 mmol), followed by the addition of (Boc) ₂ O (8.94 g, 41.0 mmol) in DCM (10 mL) dropwise at 0 ^° C. The resulting solution was stirred for 15 h at RT. The solution was concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (3/7). This resulted in 6.81 g (92.7%) of the title compound as a yellow solid. MS-ESI: 314/316 (M+1).

Step 2: Tert-butyl (2-(4-bromophenyl)propan-2-yl)(methyl)carbamate To a stirred solution of tert-butyl (2-(4-bromophenyl)propan-2-yl)carbamate (3.14 g, 10.0 mmol) in THF (100 mL) in a 250-mL round-bottom flask under nitrogen was added NaH (60% oil dispersion, 800 mg, 20.0 mmol) in portions at 0 ^° C. The resulting solution was stirred for 20 min at RT. This was followed by the addition of CH3I (4.26 g, 30.0 mmol) dropwise with stirring at 0 ^° C The resulting solution was allowed to react, with stirring, for an additional 16 h at RT. The reaction was then quenched by the addition of 100 mL of water. The resulting solution was extracted with 3x100 mL of EtOAc and the organic layers were combined then dried over anhydrous magnesium sulfate and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1/4). This resulted in 2.47 g (75.2%) of the title compound as a yellow solid. MS-ESI: 328/330 (M+1).

Steps 3-7 used similar procedures for converting compound 369” to intermediate 126 shown in Scheme 82 to afford intermediate 150 from compound 515”. MS-ESI: 442 (M+1).

Scheme 105:

N'-(tert-butyldimethylsilyl)-4-

trifluoroethyl)amino)methyl)benzenesulfonimidamide

Step 1: N-(4-bromobenzyl)-2,2,2-trifluoro-N-methylethan-1-amine To a stirred solution of 1-(4-bromophenyl)-N-methylmethanamine (3.90 g, 19.5 mmol) in DCM (200 mL) in a 500-mL round-bottom flask under nitrogen was added TFA (6.67 g, 58.5 mmol) and PhSiH ₃ (4.21 g, 39.0 mmol) at RT. The resulting solution was stirred for 12 h at 40 ^° C in an oil bath. The reaction mixture was cooled to 0 ^° C with a water/ice bath. The pH value of the solution was adjusted to 7 with NaOH (1 M). The resulting solution was extracted with 3x200 mL of DCM, the combined organic layers were dried over anhydrous Na ₂ SO ₄ and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:10). This resulted in 3.80 g (69.1%) of the title compound as yellow oil. MS-ESI: 282 (M+1).

Steps 2-5 used similar procedures for converting compound 369” to intermediate 126 shown in Scheme 82 to afford intermediate 151 from compound 521”. MS-ESI: 396 (M+1).

Table 32. Intermediate 152 was prepared using similar procedures for converting compound

520” to Intermediate 151 shown in Scheme 105 from appropriate starting materials.

I t

] n

Scheme 106:

Intermediate 153

N'-(tert-butyldimethylsilyl)benzenesulfonimidamide

Steps 1-2 used similar procedures for converting compound 362” to intermediate 124 shown in Scheme 80 to afford intermediate 153 from compound 525”. MS-ESI: 271 (M+1).

Scheme 107:

3-Formyl-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl )benzenesulfonimidamide Step 1: 3-(Hydroxymethyl)benzenesulfonamide

To a stirred solution of 3-sulfamoylbenzoic acid (10 g, 49.7 mmol) in THF (200 mL) in a 1000 mL 3-necked round-bottom flask under nitrogen was added BH ₃ -THF (1 M, 198 mL, 198 mmol) dropwise at 0 ^° C in an ice bath. The resulting solution was stirred for 30 min at 0 ^° C and then allowed to react, with stirring, for an additional 4 h at RT. The reaction was then quenched by the addition of 200 mL of MeOH. The resulting solution was concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:1). This resulted in 8.8 g (94.6%) of the title compound as yellow oil. MS-ESI: 186 (M-1). Step 2: 3-(((Tert-butyldimethylsilyl)oxy)methyl)benzenesulfonamide

To a stirred solution of 3-(hydroxymethyl)benzenesulfonamide (5.0 g, 26.7 mmol) in THF (50 mL) in a 250-mL round-bottom flask under nitrogen was added NaH (60% oil dispersion, 1.28 g, 53.4 mmol) and TBSCl (6.04 g, 40.1 mmol) in portions at 0 ^° C in a water/ice bath. The resulting solution was stirred for 12 h at RT. The reaction was then quenched by the addition of 100 mL of water/ice. The resulting solution was extracted with 3x150 mL of EtOAc and the organic layers were combined and dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (2:1). This resulted in 5.8 g (72%) of the title compound as a white solid. MS-ESI: 302 (M+1).

Steps 3-5 used similar procedures for converting compound 362” to intermediate 124 shown in Scheme 80 to afford compound 532” from compound 529”. MS-ESI: 415 (M+1).

Step 6: N-(tert-butyldimethylsilyl)-3-(((tert-butyldimethylsilyl)oxy )methyl)-N'-((1,2,3,5,6,7- hexahydro -s-indacen-4-yl)carbamoyl)benzenesulfonimidamide

To a stirred solution of N'-(tert-butyldimethylsilyl)-3-(((tert- butyldimethylsilyl)oxy)methyl)benzene- sulfonimidamide (2.0 g, 4.82 mmol) in THF (20 mL) in a 100-mL 3-necked round-bottom flask under nitrogen was added NaH (60% oil dispersion, 0.23 g, 9.64 mmol) in portions at 0 ^° C. The resulting solution was stirred for 15 min at 0 ^° C in a water/ice bath. Then to the stirred solution was added 4-isocyanato-1,2,3,5,6,7-hexahydro-s- indacene (0.96 g, 4.82 mmol) in THF (5 mL) dropwise at 0 ^° C. The resulting solution was stirred for 2 h at RT. The reaction was then quenched by the addition of 15 mL of water/ice. The resulting solution was extracted with 3x50 mL of EtOAc and the organic layers were combined and dried over anhydrous Na ₂ SO ₄ and concentrated under vacuum. This resulted in 2.25 g (75.9%) of the title compound as a white solid. MS-ESI: 614 (M+1).

Step 7: N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-3- (hydroxymethyl)benzenesulfonimidamide

To a stirred solution of N-(tert-butyldimethylsilyl)-3-(((tert-butyldimethylsilyl)oxy )methyl)-N'- ((1,2,3,5,6,7- hexahydro-s-indacen-4-yl) carbamoyl)benzenesulfonimidamide (500 mg, 0.81 mmol) in THF (10 mL) in a 100-mL round-bottom flask under nitrogen was added HCl in 1,4- dioxane (4 M, 10.0 mL, 40.0 mmol) dropwise at 0 ^° C. The resulting solution was stirred for 2 h at RT. The resulting mixture was concentrated under vacuum. The residue was eluted from silica gel with DCM/MeOH (10/1). This resulted in 125 mg (39.8%) of the title compound as a white solid. MS-ESI: 386 (M+1).

Step 8: 3-Formyl-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)benzenesulfonimidamide

To a stirred solution of N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-3- (hydroxymethyl)benzene- sulfonimidamide (120 mg, 0.31 mmol) in THF (10 mL) in a 50-mL round-bottom flask under nitrogen was added MnO2 (541 mg, 6.23 mmol) at RT. The resulting solution was stirred for 12 h at RT. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was eluted from silica gel with DCM/MeOH (10:1). This resulted in 80 mg (67.0%) of the title compound as a white solid. MS-ESI: 384 (M+1). Scheme 108:

N'-( butyldimethylsilyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazi ne-3-sulfonimidamide Step 1: 6,7-Dihydro-5H-pyrazolo[5,1-b][1,3]oxazine

To a stirred solution of 1,2-dihydro-3H-pyrazol-3-one (42 g, 500 mmol) in DMF (500 mL) in a 1 L 3-neck flask was added K2CO3 (138 g, 1.0 mol) in portions and 1,3-dibromopropane (111 g, 550 mmol) was added dropwise at RT. The resulting mixture was stirred for 16 h at 130 ^° C under nitrogen. The insoluble was filtered out, the filtrate was poured into 1500 mL of water, extracted with 3x500 mL of EtOAc. The organic layers combined and dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was eluted from silica gel with PE/EtOAc (20:1) to afford 24.8 g (40%) the title compound as a yellow solid. MS-ESI: 125 (M+1).

Step 2: 6,7-Dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonyl chloride

To a stirred solution of 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine (24 g, 194 mmol) in chlorosulfonic acid (143 mL) in a 1000-mL 3-necked round-bottom flask under nitrogen. The resulting solution was stirred for 16 h at 80 ^° C under nitrogen. The reaction mixture was poured into 1500 mL of water/ice very slowly, extracted with 3x500 mL of EtOAc. The organic layers were combined and dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was washed with 300 mL of PE. This resulted in the title compound (28.1 g, 65.0%) as a yellow solid. MS-ESI: 223/225 (M+1).

Step 3: 6,7-Dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonamide

To a stirred solution of ammonia (30%wt., 100 mL) in a 1000-mL 3-necked round-bottom flask under nitrogen was added 6,7-dihydro-5H-pyrazolo[5,1-b][1,3] oxazine-3-sulfonyl chloride (28 g, 126 mmol) in THF (100 mL) dropwise at RT. The resulting solution was stirred for 16 h at 60 ^° C under nitrogen. The organic solvent was removed by centration under reduced pressure and then extracted with 3x500 mL of EtOAc. The organic layers were combined and dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was eluted from gel column with PE/EtOAc (1:1). This resulted in 16.9 g (66%) of the title compound as a light yellow solid. MS-ESI: 202 (M-1).

Steps 4-6 used similar procedures for converting compound 362” to intermediate 124 shown in Scheme 80 to afford intermediate 155 from compound 538”. MS-ESI: 317 (M+1).

Scheme 109:

(6R)-N'-(tert-butyldiphenylsilyl)-6-((tert-butyldiphenylsily l)oxy)-6,7-dihydro-5H-pyrazolo[5,1- b][1,3]oxazine-3-sulfonimidamide

Step 1: 1,2-Dihydropyrazol-5-one

To a 5 L 4-neck flask containing a solution of methyl (E)-3-methoxyacrylate (2000 g, 17.2 mol) in MeOH (2.0 L) was added hydrazine hydrate (921 g, 18.4 mol) dropwise at RT under nitrogen. The resulting mixture was stirred for 90 min at 60 ^° C under nitrogen. The resulting mixture was concentrated under reduced pressure. This resulted in the title compound (1467 g, 68%wt, yield 69%) as an off-white solid. MS-ESI: 85 (M+1).

Step 2: 2-Acetyl-1,2-dihydropyrazol-5-one

To a 10 L 4-neck flask containing a solution of 1,2-dihydropyrazol-5-one (1467 g, 68%wt, 11.9 mol) in pyridine (6.0 L) was added Ac2O (1214 g, 11.9 mol) at RT under nitrogen. The resulting mixture was stirred for 1.5 h at 95 ^° C under nitrogen. The resulting mixture was concentrated under reduced pressure. The residue was slurry with MeOH (1x3000 mL). The resulting mixture was filtered, the filter cake was washed with MeOH (1x500 mL). The filter cake was dried under reduced pressure. This resulted in the title compound (1630 g, 78%wt， 85%) as an off-white solid. MS-ESI: 127 (M+1). ¹ H NMR (400 MHz, DMSO-d ₆ ) d 8.12 (d, J = 3.0 Hz, 1H), 6.00 (d, J = 3.0 Hz, 1H), 2.48 (s, 3H), 2.44 (s, 1H).

Step 3: (R)-2-acetyl-1-(oxiran-2-ylmethyl)-1,2-dihydropyrazol-5-one

To a 10 L 4-neck flask containing a solution of 2-acetyl-1,2-dihydropyrazol-5-one (400 g, 78%wt，3.17 mol) and R-glycidol (246 g, 3.33 mol) in THF (4.0 L), to the stirred solution was added PPh3 (915 g, 3.49 mol). To the above mixture was added TMAD (705 g, 3488 mmol) in portions at 0 ^° C. The resulting mixture was stirred for additional 1 h at RT. The resulting mixture was quenched with 1x4.0 L of water. The aqueous layer was extracted with EtOAc (3x1.0 L). The organic layers were combined and washes with brine (1 L), dried over Na ₂ SO ₄ and concentrated under reduced pressure. The crude was slurry in PE/EtOAc (10:1) (16 L) for 4 h. The resulting mixture was filtered. The filter cake was washed with PE/EtOAc (10:1) (1x1000 mL). The filtrate was concentrated under reduced pressure. This resulted in the title compound (470 g, 84%wt, 87%) as an off-white solid. MS-ESI: 183 (M+1). ¹ H NMR (400 MHz, DMSO- d6) d 8.27 (d, J = 3.0 Hz, 1H), 6.27 (d, J = 3.0 Hz, 1H), 4.56 (dd, J = 11.8, 2.7 Hz, 1H), 4.02 (dd, J = 11.8, 6.8 Hz, 1H), 3.40-3.34 (m, 1H), 2.86 (dd, J = 5.1, 4.3 Hz, 1H), 2.74 (dd, J = 5.1, 2.6 Hz, 1H), 2.54 (s, 3H).

Step 4: (R)-2-acetyl-1-(3-chloro-2-hydroxypropyl)-1,2-dihydropyrazol -5-one

To a 10 L 3-neck flask was placed a solution of (R)-2-acetyl-1-(oxiran-2-ylmethyl)-1,2- dihydropyrazol -5-one (500 g, 84%wt, 2.74 mol) in THF (2.5 L), to the stirred solution was added AcOH (494 g, 8233 mmol) dropwise and LiCl (186 g, 4391 mmol) in portions at 0 ^° C under nitrogen. The resulting mixture was stirred for 16 h at RT under nitrogen. The reaction was quenched with water at RT. The aqueous layer was extracted with EtOAc (3x3.0 L). The organic layers were combined and washed with 2x3.0 L of sat. NaHCO3 and 5.0 L of brine. The organic layer was dried over Na ₂ SO ₄ and concentrated under reduced pressure. This resulted in the title compound (552 g, 82%wt, yield 90%) as an off-white solid. MS-ESI: 219 (M+1). ¹ H NMR (400 MHz, CDCl3) d 8.10 (d, J = 3.0 Hz, 1H), 6.02 (d, J = 3.0 Hz, 1H), 4.44 (d, J = 5.0 Hz, 2H), 4.29- 4.23 (m, 1H), 3.81- 3.67 (m, 2H), 2.61 (s, 3H).

Step 5: (R)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-ol To a 10 L 3-neck flask was placed a solution of (R)-2-acetyl-1-(3-chloro-2-hydroxypropyl)-1,2- dihydropyrazol-5-one (500 g, 82%wt, 2.29 mol) in DMF (5.0 L), to the stirred solution was added K ₂ CO ₃ (948 g, 6.86 mol) under nitrogen. The resulting mixture was stirred for 16 h at 135 ^° C under nitrogen and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM/MeOH (20:1) to afford (152 g, yield 58%) of the title compound as an off-white solid. MS-ESI: 141 (M+1). ¹ H NMR (400 MHz, MeOH-d ₄ ) d 7.11 (d, J = 2.1 Hz, 1H), 5.31 (d, J = 2.1 Hz, 1H), 4.19– 4.12 (m, 1H), 4.12– 3.98 (m, 3H), 3.90 – 3.81 (m, 1H).

Step 6: (R)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-yl acetate

To a stirred solution of (R)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-ol (55.0 g, 392 mmol) in MeCN (825 mL) in a 2-L 3-necked round-bottom flask under nitrogen was added pyridine (93.1 g, 1.18 mol) and DMAP (4.79 g, 39.2 mmol). This was followed by the addition of acetyl chloride (43.1 g, 549 mmol) dropwise with stirring at 0 ^° C. The resulting solution was stirred for 2 h at RT. LCMS showed reaction was completed. The resulting mixture was concentrated directly. The residue was eluted from silica gel with EtOAc/PE (1:4). This resulted in 58 g (81%) of the title compound as a light yellow solid. MS-ESI: 183 (M+1). ¹ H NMR (400 MHz, CDCl ₃ ) d 7.39 (d, J = 2.0 Hz, 1H), 5.57 (d, J = 2.0 Hz, 1H), 5.45-5.36 (m, 1H), 4.49-4.41 (m, 1H), 4.40- 4.27 (m, 2H), 4.24 (dd, J = 12.1, 1.5 Hz, 1H), 2.14 (s, 3H).

Step 7: (R)-6-acetoxy-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-s ulfonic acid

To a stirred solution of (R)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-yl acetate (58.0 g, 318 mmol) in DCM (120 mL) in a 2-L 3-necked round-bottom flask under nitrogen.was added chlorosulfonic acid (81.3 g, 700 mmol) dropwise at 0 ^° C. The resulting solution was stirred for 12 h at RT. LCMS showed the conversion was completed. The reaction mixture was used directly in the next step. MS-ESI: 263 (M+1).

Step 8: (R)-3-(chlorosulfonyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]ox azin-6-yl acetate

To a stirred solution of (R)-6-acetoxy-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-s ulfonic acid in DCM (crude from step 7) in a 2-L 3-necked round-bottom flask under nitrogen was added pyridine (55.1 g, 696 mmol) dropwise at 0 °C. To this was added PCl5 (144 g, 696 mmol) in portions at 0 ^° C. The resulting solution was stirred for 2 h at RT. The reaction was then quenched by the addition of 1 L of water/ice. The resulting solution was extracted with 3x300 mL of EtOAc. The resulting mixture was washed with 2 x500 ml of NaHCO ₃ and 1 x500 mL of H ₂ O. The resulting mixture was washed with 1x500 mL of NaCl (aq.). The mixture was dried over anhydrous Na2SO4 and concentrated under vacuum. This resulted in 76 g (crude) of the title compound as a light yellow solid. MS-ESI: 281/283 (M+1).

Step 9: (R)-6-hydroxy-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-s ulfonamide

To a stirred solution of NH3 in THF (1M, 730 ml) in a 3-L round-bottom flask was added (R)-3- (chloro- sulfonyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3] oxazin-6-yl acetate (73.0 g) in several batches. The flask was then filled with NH ₃ (balloon). The resulting solution was stirred overnight at 40 ^° C in an oil bath. After reaction completed, the solids were filtered out. The filtrate was concentrated. The residue was diluted with NH3 (7 M in MeOH, 730 mL). The resulting solution was stirred for 2h at RT. LC showed the reaction was complete. The MeOH solution was concentrated under reduced pressure to a final volume of about 100 mL. Et ₂ O (360 ml) was charged to the resulting solution and kept stirring for 30 min. The mixture was filtered, and the cake washed with Et2O (100 mL). The white solid was dried under vacuum. This resulted in 37 g (53% for 3 steps) of the title compound as a white solid. MS-ESI: 220 (M+1). ¹ H NMR (300 MHz, DMSO-d6) d 7.48 (s, 1H), 7.06 (s, 2H), 5.64 (d, J = 2.3 Hz, 1H), 4.30 (s, 3H), 4.30– 4.18 (m, 1H), 4.00– 3.90 (m, 1H).

Step 10: (R)-N-(tert-butyldiphenylsilyl)-6-((tert-butyldiphenylsilyl) oxy)-6,7-dihydro-5H- pyrazolo[5,1-b] -[1,3]oxazine-3-sulfonamide

To a stirred solution of (R)-6-hydroxy-6,7-dihydro-5H-pyrazolo[5,1-b][1,3] oxazine-3- sulfonamide (500 mg, 2.28 mmol) in DMF (20 mL) in a 50-mL round-bottom flask was added DBU (2.08 g, 13.7 mmol) and TBDPSCl (5.02 g, 18.2 mmol) at 0 ^° C. The resulting solution was stirred for 2 h at RT and then diluted with 30 mL of H2O. The resulting solution was extracted with 3x100 mL of EtOAc. The combined organic layers were dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was eluted from silica gel with EtOAc/PE (1:1). This resulted in 530 mg (33.3%) of the title compound as a solid. MS-ESI: 696 (M+1).

Step 11: (6R)-N'-(tert-butyldiphenylsilyl)-6-((tert-butyldiphenylsily l)oxy)-6,7-dihydro-5H- pyrazolo [5,1-b][1,3]oxazine-3-sulfonimidamide To a stirred solution of PPh3Cl2 (759 mg, 2.28 mmol) in DCE (30 mL) in a 100-mL 3-necked round-bottom flask under nitrogen was added DIEA (492 mg, 3.81 mmol) at 0 ^° C. The resulting solution was stirred for 10 min at RT. Then (R)-N-(tert-butyldiphenylsilyl)-6-((tert- butyldiphenylsilyl)oxy)-6,7-dihydro-5H- pyrazolo[5,1-b][1,3] oxazine-3-sulfonamide (530 mg, 0.76 mmol) in CHCl3 (10 mL) was added at 0 ^° C. The resulting solution was stirred for 30 min at 0 ^° C. Then NH ₃ (g) was bubbled to the reaction mixture for 15 min at 0 ^° C. The resulting solution was stirred for 2 h at RT. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:1). This resulted in 400 mg (75.6%) of the title compound as a white solid. MS-ESI: 695 (M+1).

Scheme 110:

(6R)-N'-(tert-butyldimethylsilyl)-6-methoxy-6,7-dihydro-5H-p yrazolo[5,1-b][1,3]oxazine-3- sulfonimidamide

Step 1: (R)-6-methoxy-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine

To a stirred solution of (R)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-ol (40 g, 285 mmol) in DMF (400 mL) in a 1 L 4-neck round-bottom flask was added NaH (60% oil dispersion, 13.7 g, 342 mmol) in portions at 0 °C. The resulting mixture was stirred for 1 h at RT. To the above mixture was added MeI (48.7 g, 343 mmol) dropwise at RT. The resulting mixture was stirred for additional 2 h at RT. The reaction was quenched with AcOH (3.66 g, 57.1 mmol) at 0 ^° C and concentrated under reduced pressure. The residue was eluted from silica gel with

PE/EtOAc (1:2) to afford the title compound (34.6 g, 79%) as a light yellow solid. MS-ESI: 155 (M+1).

Steps 2-4 used similar procedures for converting compound 547” to compound 550” shown in Scheme 109 to afford intermediate 159 from compound 562”. MS-ESI: 232 (M-1).

Steps 5-6 used similar procedures for converting compound 362” to intermediate 124 shown in Scheme 80 to afford intermediate 157 from compound 555”. MS-ESI: 347 (M+1).

Scheme 111:

Intermediate 158

Tert-butyl ( -3-(N'-(tert-butyldimethylsilyl)sulfamidimidoyl)-6,7-dihydro -5H-pyrazolo[5,1- b][1,3]oxazin-6-yl) )carbamate

Steps 1-5 used similar procedures for converting compound 541” to compound 546” shown in Scheme 109 to afford compound 559” from compound 541”. MS-ESI: 141 (M+1).

Step 6: (S)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-yl methanesulfonate

To a stirred solution of (S)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-ol (40 g, 285 mmol) in pyridine (280 mL) in a 500 mL 3-neck flask under nitrogen was added MsCl (39 g, 343 mmol) dropwise at RT. The resulting mixture was stirred for 30 min at RT. The resulting mixture was concentrated under reduced pressure. The crude was diluted with 500 mL of water. The resulting mixture was extracted with EtOAc (3 x 300 mL). The combined organic layers were washed with water (3x200 mL) and brine 1x100 mL, dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure. This resulted in the title compound (57 g, 92%) as an off-white solid. MS-ESI: 219 (M+1).

Step 7: (R)-6-azido-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine

To a stirred solution of (S)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-yl methanesulfonate (46 g, 211 mmol) in DMF (313 mL) in a 1 L 3-neck flask under nitrogen was added NaN3 (21 g, 316 mmol) at RT. The resulting mixture was stirred for 6 h at 80 ^° C. LCMS showed reaction was complete. This was used directly in the next step. MS-ESI: 166 (M+1).

Step 8: (R)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-amine

To a stirred solution of (R)-6-azido-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine in DMF from the last step was added MeOH (313 mL) followed by Pd/C (10%wt., 10 g) under nitrogen. The mixture was hydrogenated at RT for 5 h under hydrogen atmosphere using a hydrogen balloon. LCMS showed reaction was complete. The mixture was filtered through a pad of Celite and concentrated under reduced pressure to remove low boiling solvent. This resulted in the title compound in DMF solution which was used directly in the next step. MS-ESI: 140 (M+1). Step 9: Tert-butyl (R)-(6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-yl)carbamat e To a stirred solution of (R)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-amine in DMF from the last step was added MeOH (313 mL) followed by TEA (50 g, 496 mmol) and di-tert-butyl dicarbonate (79 g, 364 mmol) at RT under nitrogen. The resulting mixture was stirred for 16 h at RT. The resulting mixture was quenched with 500 mL of water. The resulting mixture was extracted with EtOAc (3 x 300 mL). The combined organic layers were washed with H ₂ O (2x600 mL) and brine (1x600 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in the title compound (45.9 g, 91%, for 3 steps) as an off-white solid. MS-ESI: 240 (M+1).

Step 10: Tert-butyl (R)-(3-bromo-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6- yl)carbamate

To a stirred solution of tert-butyl (R)-(6,7-dihydro-5H-pyrazolo[5,1-b][1,3] oxazin-6- yl)carbamate (140 g, 585 mmol) in MeCN (2.1 L) in a 3 L 3-neck flask under nitrogen was added NBS (115 g, 644 mmol) at 0 ^° C. The resulting mixture was stirred for 2 h at RT. The resulting mixture was diluted with 2000 mL of water. The resulting mixture was extracted with EtOAc (3 x 800 mL). The combined organic layers were washed with brine (1x800 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in the title compound (167 g, 90%) as an off-white solid. MS-ESI: 318/320 (M+1). Step 11: Tert-butyl (R)-(3-bromo-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6- yl)(methyl)carbamate

To a stirred solution of tert-butyl(R)-(3-bromo-6,7-dihydro-5H-pyrazolo -[5,1-b][1,3]oxazin-6- yl)carbamate (170 g, 534 mmol) in DMF (1.19 L) in a 3 L 3-neck flask under nitrogen was added sodium hydride (60% oil dispersion, 26 g, 650 mmol) in portions at 0 °C. The mixture was stirred for 1 h at 0 ^° C. Then MeI (379 g, 2.67 mol) was added and the mixture was allowed to warm to RT and stirred for 2 h. The reaction mixture was quenched by water and extracted with EtOAc (3*800 mL), the organic layers were washed with H ₂ O (3x500 mL) and brine (1x800 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (8:1) to afford the title compound (153 g, 86%) as an off-white solid. MS-ESI: 332/334 (M+1). Step 12: Tert-butyl(R)-(3-(benzylthio)-6,7-dihydro-5H-pyrazolo[5,1-b] [1,3]oxazin-6- yl)(methyl) carbamate

To a stirred solution of tert-butyl(R)-(3-bromo-6,7-dihydro-5H-pyrazolo -[5,1-b][1,3] oxazin-6- yl)(methyl)carbamate (130 g, 391 mmol) in THF (1.3 L) in a 3 L 3-neck flask under nitrogen was added n-BuLi (188 mL, 470 mmol, 2.5 mol/L) dropwise at -78 ^° C. The resulting mixture was stirred for 1 h at -78 ^° C. To the above mixture was added bis(phenylmethyl) disulfide (145 g, 587 mmol) in THF (300 mL) dropwise at -78 ^° C. The resulting mixture was stirred for additional 2 h at RT. The reaction was quenched by the addition of sat. NH4Cl (aq.) (500 mL) at RT. The resulting mixture was extracted with EtOAc (3 x 500 mL). The combined organic layers were washed with brine (1x800 mL), dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column

chromatography, eluted with PE/EtOAc (6:1) to afford the title compound (106 g, 72%) as an off-white solid. MS-ESI: 376 (M+1).

Step 13: Tert-butyl (R)-(3-(chlorosulfonyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]o xazin-6- yl)(methyl) carbamate

To a stirred solution of tert-butyl (R)-(3-(benzylthio)-6,7-dihydro-5H-pyrazolo[5,1- b][1,3]oxazin-6-yl)- (methyl) carbamate (110 g, 293 mmol) in AcOH (3.67 L)/H2O (1.83 L) in a 10 L 3-neck flask under nitrogen was added NCS (155 g, 1.17 mol) in portions at 0 ^° C . The resulting mixture was stirred for 1 h at RT. The reaction was quenched with water/ice at RT. The resulting mixture was extracted with MTBE (3 x 1 L). The combined organic layers were washed with water (2 x 1.0 L), NaHCO3 ( L) and brine (1x1 L), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in the title compound (80 g, crude ) as a yellow solid. MS-ESI: 374 (M+Na).

Step 14: Tert-butyl (R)-methyl(3-sulfamoyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]ox azin-6- yl)carbamate

To a stirred solution of tert-butyl (R)-(3-(chlorosulfonyl)-6,7-dihydro-5H-pyrazolo[5,1- b][1,3]oxazin- 6-yl)(methyl) carbamate (80 g, 227 mmol) in NH3 in THF (1 M, 800 mL, 800 mmol) in a 2 L 3-neck flask under nitrogen. The flask was then filled with NH3 (balloon). The resulting mixture was stirred for overnight at 60 ^° C. The reaction mixture was quenched by water and extracted with MTBE (3*800 mL), the organic layers were washed with H2O (3x500 mL) and brine (1x800 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The precipitated solid was slurry with MTBE (1x100 mL). This resulted in the title compound (36 g, for 2 steps) as an off-white solid. MS-ESI: 333 (M+1). Steps 15-16 used similar procedures for converting compound 362” to intermediate 124 shown in Scheme 80 to afford intermediate 158 from compound 568. MS-ESI: 446 (M+1).

Scheme 112:

N'-( butyldimethylsilyl)-5-(2-hydroxypropan-2-yl)pyridine-3-sulfo nimidamide Step 1 used similar procedures for converting compound 406” to compound 407” shown in Scheme 87 to afford compound 571” from compound 570”. MS-ESI: 215/217 (M+1).

Steps 2-7 used similar procedures for converting compound 369” to intermediate 126 shown in Scheme 82 to afford intermediate 159 from compound 571”. MS-ESI: 330 (M+1).

Scheme 113:

(tert-butyldimethylsilyl)-2-(1-((tert-butyldimethylsilyl)oxy )-2-hydroxypropan-2-yl)thiazole-5- sulfonimidamide

Step 1 used similar procedures for converting compound 406” to compound 407” shown in Scheme 87 to afford compound 87 from compound 577”. MS-ESI: 144 (M+1).

Steps 2-3 used similar procedures for converting compound 369” to compound 371” shown in Scheme 82 to afford compound 85 from compound 87. MS-ESI: 223 (M+1).

Step 4: 2-(Prop-1-en-2-yl)thiazole-5-sulfonamide

To a stirred solution of 2-(2-hydroxypropan-2-yl)thiazole-5-sulfonamide (50 g, 225 mmol,) in trifluoromethanesulfonoperoxoic acid (60 mL) in a 1-L round-bottom flask under nitrogen was added TFA (60 mL). The resulting solution was stirred for 16 h at 50 ^° C in an oil bath. The pH value of the solution was adjusted to 8 with NaOH (3 %wt.) solution. The resulting solution was extracted with 3x500 mL of DCM and the organic layers were combined and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:2). This resulted in 10 g (21%) of the title compound as an off-white solid. MS-ESI: 205 (M+1).

Step 5: 2-(1,2-Dihydroxypropan-2-yl)thiazole-5-sulfonamide Into a 500-mL round-bottom flask, was placed 2-(prop-1-en-2-yl)thiazole-5-sulfonamide (10 g, 49 mmol) in t-BuOH (40 mL) and acetone (40 mL), to the stirred solution was added NMO (11.5 g, 97.9 mmol) and the resulting solution was stirred for 15 min at RT. Then to this was added a solution of OsO4 (1.24 g, 4.9 mmol) in H2O (60 mL) at RT. The resulting solution was stirred overnight at RT. The reaction was then quenched by the addition of the saturation solution of Na ₂ S ₂ O ₃ (50 mL). The resulting solution was extracted with EtOAc (3x100 mL). The organic layers were combined and dried over anhydrous Na2SO4 and concentrated under vacuum. The crude product was eluted from silica gel with MeOH/DCM (7:100). This resulted in 5 g (43%) of the title compound as yellow oil. MS-ESI: 239 (M+1).

Steps 6-9 used similar procedures for converting compound 362” to intermediate 124 shown in Scheme 80 to afford intermediate 160 from compound 579”. MS-ESI: 466 (M+1).

Table 33. The Intermediate 161 was prepared using similar procedures for converting compound 577” to Intermediate 160 shown in Scheme 113 from appropriate starting materials. +

Scheme 114:

Intermediate 162 N'-(tert-butyldimethylsilyl)-5-(((tert-butyldimethylsilyl)ox y)methyl)-1-isopropyl-1H-pyrazole-3- sulfonimidamide

Steps 1-3 used similar procedures for converting compound 410” to compound 413” shown in Scheme 88 to afford compound 586” from compound 583”. MS-ESI: 262 (M+1).

Step 4 used similar procedures for converting compound 416” to compound 417” shown in Scheme 89 to afford compound 587” from compound 586”. MS-ESI: 220 (M+1).

Steps 5-6 used similar procedures for converting compound 362” to intermediate 124 shown in Scheme 80 to afford intermediate 167 from compound 594”. MS-ESI: 447 (M+1).

Scheme 115:

N-(tert-butyldiphenylsilyl)-4-(1- uoromethoxy)ethyl)benzenesulfonimidamide Step 1 used similar procedures for converting intermediate 550” to compound 551” shown in Scheme 109 to afford compound 590” from compound 589”. MS-ESI: 438 (M+1).

Step 2: N-(tert-butyldiphenylsilyl)-4-(1-hydroxyethyl)benzenesulfona mide

To a stirred solution of 4-acetyl-N-(tert-butyldiphenylsilyl)benzenesulfonamide (12 g, 27.5 mmol) in MeOH (100 mL) in a 500-mL round-bottom flask under nitrogen was added NaBH ₄ (2.09 g, 54.9 mmol). The resulting solution was stirred for 2 h at RT. The reaction was then quenched by the addition of 200 mL of water. The resulting solution was extracted with 3x200 mL of EtOAc and the organic layers were combined and concentrated under vacuum. This resulted in 8.0 g of the title compound as a yellow solid. MS-ESI: 440 (M+1).

Step 3: N-(tert-butyldiphenylsilyl)-4-(1-(difluoromethoxy)ethyl)benz enesulfonamide

To a stirred solution of N-(tert-butyldiphenylsilyl)-4-(1-hydroxyethyl)benzenesulfona mide (3.5 g, 7.97 mmol) in DCM (50 mL) and H ₂ O (50 mL) in a 250-mL round-bottom flask under nitrogen was added KOAc (3.12 g, 31.9 mmol) and (bromodifluoromethyl)trimethylsilane (6.47 g, 3.24 mmol). The resulting solution was stirred for 24 h at RT. The resulting solution was extracted with 3x100 mL of DCM and the organic layers were combined and concentrated under vacuum. The residue was eluted from silica gel column with PE/EtOAc (3:1) to afford the title compound (2.81 g, yield 72%) as an off-white solid MS-ESI: 490 (M+1).

Step 4 used similar procedures for converting compound 362” to Intermediate 124 shown in Scheme 80 to afford Intermediate 163 from compound 592”. MS-ESI: 489 (M+1).

Scheme 116:

6-Cyclopropyl-5-methyl-2,3-dihydro-1H-inden-4-amine

Step 1: 6-Bromo-2,3-dihydro-1H-inden-5-amine

To a stirred solution of 2,3-dihydro-1H-inden-5-amine (5.0 g, 37.5 mmol) in MeCN (300 mL) in a 500-mL round-bottom flask under nitrogen was added a solution of NBS (6.68 g, 37.5 mmol) in MeCN/THF (1:1) (50 mL) dropwise at 0 ^° C. The resulting solution was stirred for 1 h at 0 ^° C in a water/ice bath. The reaction was then quenched by the addition of 100 mL of sat. NaHCO ₃ (aq). The resulting solution was extracted with 3x100 mL of EtOAc and the organic layers were combined and concentrated under vacuum. The residue was eluted from silica gel with

EtOAc/PE (1:20). This resulted in 7.0 g (87.9%) of the title compound as purple oil. MS-ESI: 212/214 (M+1).

Step 2: 6-Bromo-4-nitro-2,3-dihydro-1H-inden-5-amine

To a stirred solution of 6-bromo-2,3-dihydro-1H-inden-5-amine (1.92 g, 9.05 mmol) in cc. H2SO4 (10 mL) in a 50-mL round-bottom flask was added KNO3 (1.1 g, 10.9 mmol) at 0 ^° C. The resulting solution was stirred for 16 h at RT. The resulting solution was poured into 100 mL of water/ice slowly. The pH value of the solution was adjusted to 8 with sat. NaHCO ₃ (aq.). The resulting solution was extracted with 3x100 mL of EtOAc. The combined organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was eluted from silica gel with EtOAc/PE (1:5). This resulted in 980 mg (42.1%) of the title compound as a red solid. MS-ESI: 256/258 (M+1).

Step 3: 6-Cyclopropyl-4-nitro-2,3-dihydro-1H-inden-5-amine

To a stirred solution of 6-bromo-4-nitro-2,3-dihydro-1H-inden-5-amine (0.98 g, 3.81 mmol) in toluene (50 mL) and H2O (7 mL) in a 100-mL round-bottom flask under nitrogen was added cyclopropylboronic acid (0.49 g, 5.70 mmol). Then Pd(dppf)Cl2 (278 mg, 0.38 mmol), SPhos (156 mg, 0.381 mmo) and Cs ₂ CO ₃ (2.48 g, 7.62 mmol) were added. The resulting solution was stirred for 16 h at 80 ^° C under nitrogen. The insoluble was filtered out, the filter cake was washed with 200 mL of EtOAc. The filtrate was concentrated under reduced pressure. The residue was eluted from silica gel with EtOAc/PE (1:3). This resulted in 946 mg (95.2%) of the title compound as a red solid. MS-ESI: 219 (M+1).

Step 4: 5-Bromo-6-cyclopropyl-4-nitro-2,3-dihydro-1H-indene

To a stirred solution of 6-cyclopropyl-4-nitro-2,3-dihydro-1H-inden-5-amine (946 mg, 4.33 mmol) in MeCN (50 mL) in a 100-mL round-bottom flask under nitrogen was added tert-butyl nitrite (670 mg, 6.50 mmol) dropwise at 0 ^° C, CuBr (746 mg, 5.20 mmol) was added in portions at 0 ^° C. The resulting solution was stirred for 3 h at 60 ^° C. The resulting mixture was

concentrated under vacuum. The residue was eluted from a silica gel with EtOAc/PE (1:10). This resulted in 750 mg (61.3%) of the title compound as red oil. ¹ H NMR (400 MHz, DMSO-d6) d 7.18 (s, 1H), 3.00-2.80 (m, 4H), 2.20-2.00 (m, 3H), 1.10-0.95 (m, 2H), 0.80-0.65 (m, 2H).

Step 5: 6-Cyclopropyl-5-methyl-4-nitro-2,3-dihydro-1H-indene

To a stirred solution of 5-bromo-6-cyclopropyl-4-nitro-2,3-dihydro-1H-indene (700 mg, 2.48 mmol) in toluene (42 mL) and H2O (7 mL) in a 100-mL round-bottom flask under nitrogen was added 2,4,4,5,5-penta- methyl-1,3,2-dioxaborolane (528 mg, 3.72 mmol). Then Cs ₂ CO ₃ (1.62 g, 4.96 mmol), Pd(dppf)Cl ₂ (181 mg, 0.25 mmol) and SPhos (101 mg, 0.25 mmol) were added. The resulting solution was stirred for 16 h at 80 ^° C under nitrogen. The resulting mixture was concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:3). This resulted in 265 mg (49.2%) of the title compound as dark yellow oil. ¹ H NMR (400 MHz, DMSO-d6) d 7.16 (s, 1H), 2.96–2.80 (m, 4H), 2.32 (s, 3H), 2.10–1.98 (m, 2H), 1.98–1.85 (m, 1H), 1.01–0.89 (m, 2H), 0.68–0.59 (m, 2H).

Step 6: 6-Cyclopropyl-5-methyl-2,3-dihydro-1H-inden-4-amine

To a stirred solution of 6-cyclopropyl-5-methyl-4-nitro-2,3-dihydro-1H-indene (265 mg, 1.22 mmol) in MeOH (25 mL) in a 100-mL round-bottom flask under nitrogen was added Pd/C (10% wt., 50 mg), the flask was evacuated and flushed with hydrogen 3 times. The resulting solution was stirred for 16 h at RT under hydrogen with a balloon. The solids were filtered out. The resulting mixture was concentrated under vacuum. This resulted in 187 mg (81.9%) of the title compound as dark yellow oil. MS-ESI: 188 (M+1).

Scheme 117:

Intermediate 165

4-Amino- tetrahydro-as-indacen-1(2H)-one

Step 1: 1-(2,3-Dihydro-1H-inden-4-yl)prop-2-en-1-ol

To a stirred solution of 2,3-dihydro-1H-indene-4-carbaldehyde (4.0 g, 27.4 mmol) in THF (50 mL) in a 100-mL round-bottom flask under nitrogen was added bromo(ethenyl)magnesium (27.4 mL, 27.4 mmol, 1.0 M in THF) dropwise at 0 ^° C. The resulting solution was stirred for 2 h at RT. The reaction was then quenched by the addition of 100 mL of water/ice. The resulting solution was extracted with 3x50 mL of DCM and the organic layers were combined then concentrated under vacuum. This resulted in 3.5 g (73.4%) of the title compound as brown oil. MS-ESI: 175 (M+1).

Step 2: 1-(2,3-Dihydro-1H-inden-4-yl)prop-2-en-1-one

To a stirred solution of 1-(2,3-dihydro-1H-inden-4-yl)prop-2-en-1-ol (3.50 g, 20.1 mmol) in DCM (50 mL) in a 100-mL round-bottom flask under nitrogen was added Dess-Martin (8.52 g, 20.1 mmol) in portions at 0 ^° C. The resulting solution was stirred for 1 h at RT. The resulting mixture was quenched by addition of sat. Na ₂ S ₂ O ₃ . The mixture was extracted with 3x200 mL EtOAc and the organic layers were combined and dried over anhydrous Na ₂ SO ₄ and

concentrated under vacuum. The residue was eluted from a silica gel with EtOAc/PE (1:50 to 1:30). This resulted in 3 g (86.7%) of the title compound as a yellow solid. MS-ESI: 173 (M+1). Step 3: 3,6,7,8-Tetrahydro-as-indacen-1(2H)-one

To a stirred solution of sulfuric acid (30 mL) in a 100-mL round-bottom flask under nitrogen was added a solution of 1-(2,3-dihydro-1H-inden-4-yl)prop-2-en-1-ol (3.0 g, 17.4 mmol) in DCM (5 mL) dropwise at 0 ^° C. The resulting solution was stirred for 3 h at 50 ^° C in an oil bath. The resulting solution was poured into 200 mL of water/ice slowly. The resulting solution was extracted with 3x200 mL of DCM and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:30 to 1:10). This resulted in 1.0 g (33.3%) of the title compound as a yellow solid. MS-ESI: 173 (M+1).

Step 4: 4-Nitro-3,6,7,8-tetrahydro-as-indacen-1(2H)-one

To a stirred solution of sulfuric acid (5.00 mL) in a 100-mL round-bottom flask under nitrogen was added 3,6,7,8-tetrahydro-as-indacen-1(2H)-one (500 mg, 2.9 mmol) in portions at 0 ^° C. To this was added nitric acid (365 mg, 5.8 mmol) dropwise with stirring at 0 ^° C. The resulting solution was stirred for 1 h at 0 ^° C in a water/ice bath. The resulting solution was poured into 20 mL of water/ice slowly. The resulting solution was extracted with 3x20 mL of DCM

concentrated under vacuum. This resulted in 400 mg (63%) of the title compound as a brown solid. MS-ESI: 218 (M+1).

Step 5: 4-Amino-3,6,7,8-tetrahydro-as-indacen-1(2H)-one To a stirred solution of 4-nitro-3,6,7,8-tetrahydro-as-indacen-1(2H)-one (400 mg, 1.84 mmol) in MeOH (20 mL) in a 100-mL round-bottom flask under nitrogen was added Pd/C (10% wt., 100 mg), the flask was evacuated and flushed with hydrogen 3 times. The resulting solution was stirred for 16 h at RT under hydrogen with a balloon. The solids were collected by filtration. The resulting mixture was concentrated under vacuum. This resulted in 300 mg (87%) of the title compound as a brown solid. MS-ESI: 188 (M+1).

Scheme 118:

8-Allyl-1,2,3,5,6,7-hexahydro-s-indacen-4-amine

Step 1: 8-Iodo-1,2,3,5,6,7-hexahydro-s-indacen-4-amine

To a stirred solution of 1,2,3,5,6,7-hexahydro-s-indacen-4-amine (2.01 g, 12 mmol) in N,N- dimethylformamide (10 mL) in a 50-mL round-bottom flask was added NIS (2.97 g, 13.2 mmol). The resulting solution was stirred for 3 h at RT. The resulting solution was diluted with 100 mL of EtOAc. The resulting mixture was washed with 100 mL of brine. The resulting mixture was concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:20). This resulted in 2.84 g (79%) of the title compound as an orange solid. MS-ESI: 300 (M+1).

Step 2: 8-Allyl-1,2,3,5,6,7-hexahydro-s-indacen-4-amine

To a stirred solution of 8-iodo-1,2,3,5,6,7-hexahydro-s-indacen-4-amine (460 mg, 1.54 mmol) and PPh ₃ (202 mg, 0.77 mmol) in DMF(15 mL) in 50 mL round-bottom flask under nitrogen was added Pd(pph3)2Cl2 (216 mg, 0.31 mmol) and tributyl(prop-2-en-1-yl)stannane (432 mg, 1.3 mmol) at RT. The resulting mixture was stirred for 16 h at 120 ^° C under nitrogen. The resulting mixture was diluted with water (40 mL) and extracted with EtOAc (3 x 80 mL). The combined organic layers were washed with brine (40 mL), dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was eluted from silica gel with EtOAc/PE (1:2) to afford the title compound (200 mg, 61%) as a brown solid. MS-ESI: 214 (M+1).

Scheme 119:

6-Isopropyl-2,3-dihydro-1H-inden-5-amine

Step 1: 6-Bromo-2,3-dihydro-1H-inden-5-amine

To a stirred solution of 2,3-dihydro-1H-inden-5-amine (5 g, 37.5 mmol) in MeCN (300 mL) in a 500-mL round-bottom flask was added a solution of NBS (6.68 g, 37.5 mmol) in MeCN/THF (1:1, 40 mL) dropwise at 0 ^° C. The resulting solution was stirred for 2 h at 0 ^° C in a water/ice bath. The reaction was then quenched by the addition of 100 mL of sat. NaHCO ₃ (aq). The resulting solution was extracted with 3x100 mL of EtOAc and the organic phase was combined and dried over anhydrous Na2SO4, then concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:20). This resulted in 7.2 g (90%) of the title compound as purple oil. MS-ESI: 212 (M+1).

Step 2: 6-(Prop-1-en-2-yl)-2,3-dihydro-1H-inden-5-amine

To a stirred solution of 6-bromo-2,3-dihydro-1H-inden-5-amine (7.5 g, 35.4 mmol) in 1,4- dioxane (100 mL) and H ₂ O (10 mL) in a 250-mL round-bottom flask under nitrogen was added Cs2CO3 (23.1 g, 70.8 mmol). Then 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2 -dioxaborolane (8.9 g, 53.1 mmol) and Pd(dppf)Cl ₂ (2.6 g, 3.54 mmol) were added. The resulting solution was stirred for 16 h at 80 ^° C. The reaction was then quenched by the addition of 200 mL of water. The solids were filtered out. The resulting solution was extracted with 3x300 mL of EtOAc and the organic layers were combined and dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:3). This resulted in 5.8 g (94.8%) of the title compound as yellow oil. MS-ESI: 174 (M+1).

Step 3: 6-Isopropyl-2,3-dihydro-1H-inden-5-amine

To a stirred solution of 6-(prop-1-en-2-yl)-2,3-dihydro-1H-inden-5-amine (5.8 g, 33.5 mmol) in MeOH (100 mL) in a 250-mL round-bottom flask under nitrogen was added Pd/C (10% wt., 0.58 g). The flask was evacuated and flushed with hydrogen 3 times. The resulting solution was stirred for 16 h at RT under hydrogen with a balloon. The solids were filtered out. The resulting mixture was concentrated under vacuum. This resulted in 5.77 g (98.3%) of the title compound as yellow oil. MS-ESI: 176 (M+1).

Scheme 120:

Tert-butyl (S)-(amino(3-fluoro-5-(2-hydroxypropan-2-yl)thiophen-2-yl)(o xo)- ^ ⁶ - sulfaneylidene)carbamate

Step 1: 2-(4-Fluorothiophen-2-yl)propan-2-ol

To a 250 mL 3-neck flask placed a solution of methyl 4-fluorothiophene-2-carboxylate (5.5 g, 34.3 mmol) in THF (55 mL) was added MeMgBr (1M in THF) (86 mL, 86 mmol) dropwise at 0 ^° C under nitrogen. The resulting solution was stirred for 3 h at 0 ^° C under nitrogen. LC showed reaction is completed. The resulting mixture was quenched with cold sat. aq. NH ₄ Cl (100 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (2 x 50 mL). The organic layer was dried over by anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was re-crystallized from PE/EtOAc (100:1) to afford (4.0 g, 72%) of the title compound as a light yellow solid. GCMS: 160 [M]. ¹ H NMR (400 MHz, DMSO-d6) d 6.91 (d, J = 1.7 Hz, 1H), 6.84 (d, J = 1.7 Hz, 1H), 5.52 (s, 1H), 1.47 (s, 6H).

Step 2: (1S,2R)-1-((2,4,6-trimethylphenyl)sulfonamido)-2,3-dihydro-1 H-inden-2-yl (S)-3- fluoro-5-(2-hydroxypropan-2-yl)thiophene-2-sulfinate

To a 100 mL 3-neck flask placed a solution of 2-(4-fluorothiophen-2-yl)propan-2-ol (2.0 g, 12.5mmol) in THF (30 mL) was added LDA (2 M in hexane, 12.5 mL, 25 mmol) dropwise at -78 ^° C over 1 min under nitrogen. The resulting solution was stirred for 30 min at -78 ^° C, this solution was assigned as A. The solution of (2R,3aS,8aR)-3-(mesitylsulfonyl)-3,3a,8,8a- tetrahydroindeno[1,2-d][1,2,3] oxathiazole 2-oxide (4.7 g, 12.5 mmol) in THF (10 mL) was transferred into the solution A, while the internal temperature of the resulting solution was kept below -65 ^° C under nitrogen. The resulting solution was stirred for 30 min at -70 ^° C under nitrogen. LC showed the reaction to be complete. The resulting mixture was quenched with cool sat. aq. NH ₄ Cl (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (2 x 50 mL). The organic layer was dried over by anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was re- crystallized from PE/EtOAc (10:1) to afford (2.6 g, 38%, de=100%) of the title compound as a white solid. MS-ESI: 560 [M+Na] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) d 8.19 (d, J = 9.7 Hz, 1H), 7.27– 7.17 (m, 2H), 7.18– 7.12 (m, 1H), 7.04 (s, 2H), 7.01 (s, 1H), 6.92 (d, J = 7.4 Hz, 1H), 5.86 (s, 1H), 4.98– 4.89 (m, 1H), 4.80 (dd, J = 9.6, 5.1 Hz, 1H), 3.22 (dd, J = 16.7, 4.8 Hz, 1H), 3.08 (dd, J = 16.7, 2.2 Hz, 1H), 2.61 (s, 6H), 2.28 (s, 3H), 1.49 (s, 3H), 1.48 (s, 3H).

Step 3: (S)-3-fluoro-5-(2-hydroxypropan-2-yl)thiophene-2-sulfinamide

The solution of (1S,2R)-1-((2,4,6-trimethylphenyl)sulfonamido)-2,3-dihydro-1 H-inden-2-yl-(S)- 3-fluoro-5 -(2-hydroxypropan-2-yl)thiophene-2-sulfinate (1.5 g, 2.79 mmol) in THF (9 mL) was added in one portion to a stirred 50 mL of 3-neck flask placed a solution of NaHMDS (2M in THF) (5.6 ml, 11.2 mmol) in THF (15 mL) at -10 ^° C under nitrogen. The resulting solution was stirred for 1 h at -10 ^° C under nitrogen. LC showed the reaction to be complete. The resulting mixture was quenched with AcOH (704 mg, 11.7 mmol) and MeOH (1.5 mL) below 0 ^° C. The resulting mixture was diluted with water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (2 x 50 mL). The organic layer was dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure. The crude product was re-crystallized from PE/EtOAc (3:1) to afford (452 mg, 72%, ee=85.4%) of the title compound as a white solid. MS-ESI: 224 (M+1). ¹ H NMR (400 MHz, DMSO-d6) d 6.92 (s, 1H), 6.61 (s, 2H), 5.70 (s, 1H), 1.46 (s, 3H), 1.45 (s, 3H).

Step 4: Tert-butyl (S)-((3-fluoro-5-(2-hydroxypropan-2-yl)thiophen-2-yl)sulfiny l)carbamate To a 25 mL 3-neck flask was added (S)-3-fluoro-5-(2-hydroxypropan-2-yl)thiophene-2- sulfinamide (200 mg, 0.62 mmol, ee=85.4%), this was followed by the addition of 3.0 mL of dry THF under nitrogen. The reaction mixture was cooled to 0 ^° C and KOtBu (120 mg, 0.74 mmol) was added (internal temperature was controlled below 0 ^° C). The solution was stirred for 30 min then the Boc2O (195 mg, 0.62 mmol) in 1.0 mL of THF was added. The ice bath was removed and the reaction mixture was stirred at RT for 1 h. LC showed the reaction to be complete. The resulting mixture was quenched with aq. NH ₄ Cl (25 mL) and extracted with EtOAc (3 x 5 mL). The combined organic layers were washed with brine (2 x 5 mL). The organic layer was dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure. The crude product was re-crystallized from PE/EtOAc (5:1) to afford (49 mg, 17%, ee=97.4%) of the title compound as a white solid. MS-ESI: 386 [M+Na+MeCN] ⁺ , ¹ H NMR (300 MHz, DMSO-d6) d 10.96 (s, 1H), 7.03 (s, 1H), 5.85 (s, 1H), 1.50 (s, 3H), 1.48 (s, 3H), 1.46 (s, 9H). Step 5: Tert-butyl (S)-(amino(3-fluoro-5-(2-hydroxypropan-2-yl)thiophen-2-yl)(o xo)- ^ ⁶ - sulfaneylidene) carbamate To a 10 mL 3-neck flask was added tert-butyl (S)-((3-fluoro-5-(2-hydroxypropan-2- yl)thiophen-2-yl) sulfinyl)carbamate (15 mg, 0.046 mmol, ee=97.4%), this was followed by the addition of dry THF (0.3 mL) under nitrogen. The reaction mixture was cooled to 0 ^° C and TCCA (3.8 mg, 0.016 mmol) was added portion-wise to avoid any exotherm and extensive over- chlorination. The reaction was stirred at 0 ^° C for 1 h. This solution was assigned as A. The solution A was cooled to -50 ^° C and the solution of NH ₃ (7 M in MeOH) was added dropwise via syringe. The reaction was stirred at -50 ^° C for 1h. LC showed the reaction to be complete. After filtration, the filtrate was purified by Prep-HPLC to afford (3.0 mg, 19% , ee=97.9%) of the title compound as a white solid. MS-ESI: 339 (M+1). ¹ H NMR (400 MHz, MeOH-d ₄ ) d 6.81 (s, 1H), 1.58 (s, 6H), 1.39 (s, 9H).

Scheme 121:

6-Cyclopropyl-4-isocyanato-5-methyl-2,3-dihydro-1H-indene To a stirred solution of 6-cyclopropyl-5-methyl-2,3-dihydro-1H-inden-4-amine (187 mg, 1.0 mmol) in THF (30 mL) in a 100-mL round-bottom flask under nitrogen was added TEA (101 mg, 1.0 mmol) and triphosgene (148 mg, 0.5.0 mmol). The resulting solution was stirred for 2 h at 70 ^° C in an oil bath. The resulting mixture was concentrated under vacuum. This resulted in 213 mg (crude) of the title compound as yellow oil. This was used in the next step without further purification. Table 34. The Intermediates in the following Table were prepared using the similar procedures for converting Intermediate 164 to Intermediate 169 shown in Scheme 121.

Scheme 122:

2,2,2-Trichloroethyl (8-cyano-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamate To a stirred solution of 8-amino-1,2,3,5,6,7-hexahydro-s-indacene-4-carbonitrile (700 mg, 3.54 mmol) in THF (10 mL) in a 100-mL round-bottom flask was added DIEA (912 mg, 7.07 mmol) and 2,2,2-trichloroethyl chloroformate (1.49 g, 7.07 mmol). The resulting solution was stirred for 12 h at RT. The reaction was then quenched by the addition of 20 mL of water. The resulting solution was extracted with 3x30 mL of EtOAc and the organic layers combined and dried over anhydrous Na ₂ SO ₄ and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:3). This resulted in 1.1 g (83.3%) of the title compound as yellow solid. MS-ESI: 373/375/377 (M+1).

Table 34. The Intermediates in the following Table were prepared using the similar procedures for converting Intermediate 40 to Intermediate 173 shown in Scheme 122.

Scheme 123:

Tert-butyl ((5- ' (tert-butyldimethylsilyl)sulfamidimidoyl)thiophen-3- yl)methyl)(methyl)carbamate

Steps 1-2 used similar procedures for converting compound 431” to compound 433” shown in Scheme 91 to afford compound 615” from compound 613”. MS-ESI: 219 (M-1).

Steps 3-6 used similar procedures for converting compound 242 to compound 470” shown in Scheme 97 to afford intermediate 619” from compound 615”. MS-ESI: 307 (M+1).

Steps 7-9 used similar procedures for converting compound 362” to intermediate 124 shown in Scheme 80 to afford intermediate 176 from compound 619”. MS-ESI: 420 (M+1).

Scheme 124:

Intermediate 177

N'-(tert-butyldimethylsilyl)-6,7-dihydro-4H-thieno -c]pyran-2-sulfonimidamide

Step 1: 6,7-Dihydro-4H-thieno[3,2-c]pyran

To a stirred solution of 2-(thiophen-2-yl)ethan-1-ol (10 g, 78 mmol) in ACN (400 mL) in a 1-L round-bottom flask under nitrogen was added paraformaldehyde (3.02 g, 34 mmol) at RT, followed by the addition of InCl ₃ (863 mg, 3.9 mmol) in portions at 0 ^° C. The resulting solution was stirred for 2 h at 70 ^° C. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:10). This resulted in 6.0 g (55%) of the title compound as brown oil. MS-ESI: 141 (M+1).

Step 2: 6,7-Dihydro-4H-thieno[3,2-c]pyran-2-sulfonyl chloride

To a stirred solution of 6,7-dihydro-4H-thieno[3,2-c]pyran (2.0 g, 14 mmol) in DCE (100 mL) under nitrogen was added N,N-dimethylformamide sulfur trioxide complex (SO3-DMF complex) (2.62 g, 17 mmol) dropwise at RT. The resulting solution was stirred for 1 h at RT. Then to the stirred solution was added SOCl ₂ (2.04 g, 17 mmol) dropwise at 0 ^° C. The resulting solution was stirred for 4 h at 50 ^° C. The reaction solution was quenched with ice/water (20 mL). The resulting mixture was extracted with EtOAc (4x100 mL). The organic layers were combined and concentrated under vacuum. This resulted in 2.1 g (crude) of the title compound as a yellow solid.

Step 3: 6,7-Dihydro-4H-thieno[3,2-c]pyran-2-sulfonamide To stirred solution of 6,7-dihydro-4H-thieno[3,2-c]pyran-2-sulfonyl chloride (2.1 g, crude from last step) in DCM (100 mL) was introduced NH ₃ gas bubbled for 15 min at 0 ^° C. The resulting solution was stirred overnight at RT. The reaction solution was concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:1). This resulted in 800 mg (25.6% over two steps) of the title compound as a yellow solid. MS-ESI: 218 (M-1).

Steps 4-5 used similar procedures for converting compound 362” to intermediate 124 shown in Scheme 80 to afford intermediate 177 from compound 625”. MS-ESI: 333 (M+1).

Scheme 125:

2 _{-(( -azido-2-hydroxypropan-2-yl)-N'-((1,2,3,5,6,7-hexahydro-s-in dacen-4-} yl)carbamoyl)thiazole-5-sulfonimidamide

Step 1: (R) and (S)-2-(1,2-dihydroxypropan-2-yl)thiazole-5-sulfonamide

Compound 586” (10 g) was resolved by Prep-Chiral-HPLC with the following conditions: CHIRALPAK AD, 5*25 cm, 5 um; Mobile Phase A: CO ₂ , Mobile Phase B: MeOH(2 mM NH ₃ - MeOH); Flow rate: 200 mL/min; Gradient:40% B; 220 nm; Rt1: 3.5 (Compound 586”A); Rt2: 5.6 (Compound 586”B). This resulted in 4.1 g (99%ee) of Compound 586”A and 4.0 g (98%ee) of Compound 586”B both as a white solid. MS-ESI: 237 (M-1).

Step 2: (R)-2-hydroxy-2-(5-sulfamoylthiazol-2-yl)propyl 4-methylbenzenesulfonate

To a stirred solution of (R)-2-(1,2-dihydroxypropan-2-yl)thiazole-5-sulfonamide (4.0 g, 17 mmol) in pyridine (40 mL) in a 250-mL round-bottom flask under nitrogen was added 4- methylbenzenesulfonyl chloride (4.8 g, 25 mmol) in portions at 0 ^° C. The resulting solution was stirred overnight at RT. The resulting mixture was quenched with HCl (1 M, 40 mL). The resulting mixture was extracted with 3x40 mL ethyl acetate. The combined organic layer was dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under vacuum. The residue was eluted from silica gel with PE/EtOAc (1:1). This resulted in 5.2 g (79%) of the title compound as a yellow solid. MS-ESI: 391 (M-1).

Sep 3: (R)-2-(1-azido-2-hydroxypropan-2-yl)thiazole-5-sulfonamide

To a stirred solution of (R)-2-hydroxy-2-(5-sulfamoylthiazol-2-yl)propyl 4- methylbenzenesulfonate (3.2 g, 8.2 mmol) in EtOH (40 mL) in a 250-mL round-bottom flask under nitrogen was added NH4Cl (2.18 g, 41 mmol) at RT, followed by the addition of NaN3(1.3 g, 20 mmol) in portions at 0 ^° C carefully. The resulting solution was stirred overnight at 80 ^° C. The resulting mixture was diluted with water (30 mL). The resulting mixture was extracted with 3x30 mL ethyl acetate. The combined organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was eluted from silica gel with PE/EtOAc (1:1). This resulted in 2.1 g (98%) of the title compound as a yellow solid. MS-ESI: 264 (M+1).

Steps 4-5 used similar procedures for converting compound 362” to intermediate 124 shown in Scheme 80 to afford compound 630” from compound 628”. MS-ESI: 377 (M+1).

Step 6: 2-((R)-1-azido-2-hydroxypropan-2-yl)-N-(tert-butyldimethylsi lyl)-N'-((1,2,3,5,6,7- hexahydro-s- indacen-4-yl)carbamoyl)thiazole-5-sulfonimidamide

To a stirred solution of 2-((R)-1-azido-2-hydroxypropan-2-yl)-N'-(tert- butyldimethylsilyl)thiazole-5- sulfonimidamide (1.7 g, 4.5 mmol) in THF (10 mL) in a 100-mL round-bottom flask under nitrogen was added NaH (60% wt. dispersion in mineral oil, 540 mg, 13.5 mmol) in portions at 0 ^° C. The resulting solution was stirred for 5 min at 0 ^° C. To the above solution was added 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (900 mg, 4.5 mmol) in small portions at 0 ^° C. The resulting mixture was stirred for 1 h at RT. The reaction was quenched with water/ice (10 mL) at 0 ^° C. The resulting mixture was extracted with ethyl acetate (3 x 15 mL). The combined organic layer was dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure. This resulted in 3.0 g (crude) of the title compound as yellow oil. MS-ESI: 576 (M+1).

Step 7: 2-((R)-1-azido-2-hydroxypropan-2-yl)-N'-((1,2,3,5,6,7-hexahy dro-s-indacen-4- yl)carbamoyl) thiazole-5-sulfonimidamide

To a stirred solution of 2-((R)-1-azido-2-hydroxypropan-2-yl)-N-(tert-butyldimethylsi lyl)-N'- ((1,2,3,5,6,7- hexahydro-s-indacen-4-yl)carbamoyl)thiazole-5-sulfonimidamid e (3.0 g, crude) in THF (20 mL) in a 100-mL round-bottom flask was added HF-pyridine (2.0 mL) dropwise at ^° C. The resulting solution was stirred for 1 h at RT. The resulting mixture was concentrated under vacuum. The residue was eluted from silica gel with DCM/MeOH (10:1). This resulted in 1.6 g (76.8% over two steps) of the title compound as a yellow solid. MS-ESI: 462 (M+1).

Scheme 126:

2 _{-( -1-(2-(benzyloxy)ethoxy)-2-hydroxypropan-2-yl)-N-(tert-butyl dimethylsilyl)thiazole-5-} sulfonimidamide

Step 1: (R)-2-(1-(2-(benzyloxy)ethoxy)-2-hydroxypropan-2-yl)thiazole -5-sulfonamide To a stirred solution of 2-(benzyloxy)ethan-1-ol (3.88 g, 25.5 mmol) in THF (30 mL) in a 100- mL round-bottom flask under nitrogen was added NaH (60% wt. dispersion in mineral oil, 2.04 g, 51 mmol) in portions at 0 ^° C. The resulting mixture was stirred for 30 min at 0 ^° C. (R)-2- hydroxy-2-(5-sulfamoyl- thiazol-2-yl)propyl 4-methylbenzenesulfonate (2.0 g, 5.1 mmol) in THF (10 mL) was added to the solution dropwise at 0 ^° C. The resulting solution was stirred for 32 h at 35 ^° C. The reaction was quenched with ice/water (100 mL) at 0 ^° C. The resulting mixture was extracted with ethyl acetate (3 x 200 mL). The combined organic layers were washed with brine (2x200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was

concentrated under reduced pressure. The residue was eluted from silica gel with PE/EtOAc (1:2). This resulted in 1.8 g (95%) of the title compound as a yellow solid. MS-ESI: 371 (M-1). Steps 2-4 used similar procedures for converting compound 362” to intermediate 124 shown in Scheme 80 to afford intermediate 179” from compound 632”. MS-ESI: 486 (M+1).

Table 35. The Intermediate 180 was prepared using similar procedures for converting compound 627” to Intermediate 179 shown in Scheme 126 from appropriate starting materials.

Scheme 127:

I _{ntermediate 181} N-(tert-butyldimethylsilyl)-3-(N'-(tert-butyldimethylsilyl)s ulfamidimidoyl)-N- methylbenzenesulfonamide

Step 1: N ₁ ,N ₃ -bis(tert-butyldimethylsilyl)-N1-methylbenzene-1,3-dis ulfonamide

To a stirred solution of N-methylbenzene-1,3-disulfonamide (220 mg, 0.88 mmol) in THF (6 mL) in a 25-mL round-bottom flask under nitrogen was added NaH (60% wt. dispersion in mineral oil, 211 mg, 5.28 mmol) in portions at 0 ^° C. The resulting solution was stirred for 20 min at RT. To the solution was added TBSCl (397 mg, 2.64 mmol) in portions at 0 ^° C. The resulting solution was stirred overnight at RT. The reaction solution was quenched with 10 mL water. The mixture was extracted with 3x20 mL ethyl acetate. The organic layer was dried with anhydrous Na ₂ SO ₄ and concentrated under vacuum. The residue was eluted from silica gel with PE/EtOAc (1:2). This resulted in 400 mg (95%) of the title compound as yellow oil. MS-ESI: 479 (M+1).

Steps 2-4 used similar procedures for converting compound 363” to intermediate 124 shown in Scheme 80 to afford intermediate 181 from compound 636”. MS-ESI: 478 (M+1).

Table 36. The Intermediate 146 was prepared using similar procedures for converting compound 459” to Intermediate 139 shown in Scheme 95 from appropriate starting materials. ] ⁺

Scheme for the preparation of Key Intermediates: Schemes below illustrate the preparation of key intermediates.

Scheme 128:

Tert-butyl 2-(N'-(tert-butyldimethylsilyl)sulfamidimidoyl)-6,7-dihydrot hieno[3,2-c]pyridine- 5(4H)-carboxylate

Step 1: Tert-butyl 2-sulfamoyl-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxyla te

To a stirred solution of 4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-sulfonamide hydrochloride (1.0 g, 4.58 mmol, an intermediate to Intermediate 182) in THF (20 mL) in a 100-mL round-bottom flask were added TEA (1.39 g, 13.7 mmol) at RT, followed by the addition of Boc2O (1.0 g, 4.58 mmol) in portions at RT. The reaction mixture was stirred for 2 h at RT and then was

concentrated under vacuum. The residue was eluted from silica gel with EtOAc (100%). This resulted in 1.0 g (69%) of the title compound as a light yellow solid. MS-ESI: 319 (M+1).

Step 2: Tert-butyl 2-(N-(tert-butyldimethylsilyl)sulfamoyl)-6,7-dihydrothieno[3 ,2- c]pyridine-5(4H)- carboxylate

To a stirred solution of tert-butyl 2-sulfamoyl-6,7-dihydrothieno[3,2-c]pyridine-5(4H)- carboxylate (500 mg, 1.57 mmol) in THF (15 mL) in a 100-mL round-bottom flask under nitrogen was added NaH (60% wt. dispersion in mineral oil, 126 mg, 3.14 mmol) in portions at 0 ^° C. The resulting mixture was stirred for 10 min at RT, followed by the addition of TBSCl (473 mg, 3.14 mmol) in portions at 0 ^° C. The reaction mixture was stirred for 2 h at RT. The reaction was quenched with water (10 mL) at 0 ^° C. The mixture was extracted with EtOAc (3x20 mL) and the organic layers were combined. The organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum. This resulted in 723 mg (crude) of the title compound as light yellow liquid. MS-ESI: 433 (M+1).

Step 3: Tert-butyl 2-(N-(tert-butyldimethylsilyl)sulfamidimidoyl)-6,7-dihydroth ieno[3,2- c]pyridine-5 (4H)-carboxylate

To a stirred mixture of PPh ₃ Cl ₂ (693 mg, 2.08 mmol) in CHCl ₃ (10 mL) a 100-mL 3-necked round-bottom flask under nitrogen was added DIEA (537 mg, 4.16 mmol) dropwise at 0 ^° C. The reaction mixture was stirred for 15 min at 0 ^° C. To the above mixture was added tert-butyl 2-(N- (tert-butyldimethylsilyl)sulfamoyl) -6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxylate (723 mg, crude) in CHCl3 (5.0 mL) dropwise over 5 min at 0 ^° C. The reaction mixture was stirred for additional 30 min at 0 ^° C. NH3 (gas) was bubbled into the above mixture for 15 min at 0 ^° C. The reaction mixture was stirred overnight at RT. The reaction mixture was filtered, the filter cake was washed with DCM (10 mL). The filtrate and wash were combined and concentrated under reduced pressure. The residue was eluted from silica gel with EtOAc (100%). This resulted in 300 mg (44%, over two steps) of the title compound as a light yellow solid. MS-ESI: 432 (M+1). Scheme 129:

N'-(tert-butyldimethylsilyl)-4-(((tert-butyldimethylsilyl )oxy)methyl)-2-(5-hydroxy-2,2-dimethyl- 1 dioxan-5-yl)thiazole-5-sulfonimidamide

Step 1: 2-Bromo-4-(((tert-butyldimethylsilyl)oxy)methyl)thiazole

To a stirred solution of (2-bromothiazol-4-yl)methanol (13 g, 67 mmol) in THF (150 mL) in a 250-mL round-bottom flask under nitrogen was added NaH (60% wt. dispersion in mineral oil, 8.0 g, 201 mmol) in portions at 0 ^° C in an ice/water bath. The reaction mixture was stirred for 10 min at RT. Then to the above mixture was added TBSCl (30.3 g, 201 mmol) in portions at 0 ^° C. The reaction mixture was stirred for 2 h at RT. The reaction was quenched with 200 mL of water. The mixture was extracted with 3x300 mL of EtOAc and the organic layers were combined, dried over anhydrous Na ₂ SO ₄ , and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:30). This resulted in 15 g (73%) of the title compound as yellow oil. MS-ESI: 308/310 (M+1). Step 2: 5-(4-(((Tert-butyldimethylsilyl)oxy)methyl)thiazol-2-yl)-2,2 -dimethyl-1,3-dioxan-5- ol

To a stirred solution of 2-bromo-4-(((tert-butyldimethylsilyl)oxy)methyl)thiazole (1.4 g, 4.55 mmol) in THF (30 mL) in a 100-mL 3-necked round-bottom flask under nitrogen was added n- BuLi in hexane (2.5 M, 1.8 mL, 4.55 mmol) dropwise at -78 ^° C. The reaction solution was stirred for 30 min at -78 ^° C. Then to the solution was added 2,2-dimethyl-1,3-dioxan-5-one (621 mg, 4.78 mmol) in THF (5 mL) dropwise at -78 ^° C. The reaction mixture was stirred for 1 h at -78 ^° C. The reaction was quenched with H2O (20 mL) at 0 ^° C. The resulting mixture was extracted with EtOAc (3x30 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na ₂ SO ₄ and concentrated under vacuum. The residue was purified by prep-TLC (PE/EtOAc 10:1). This resulted in 1.1 g (67%) of the title compound as brown oil. MS-ESI: 360 (M+1).

Step 3: 4-(((Tert-butyldimethylsilyl)oxy)methyl)-2-(5-hydroxy-2,2-di methyl-1,3-dioxan-5- yl)thiazole-5- sulfinic acid, lithium salt

To a stirred solution of 5-(4-(((tert-butyldimethylsilyl)oxy)methyl)thiazol-2-yl)-2,2 -dimethyl- 1,3-dioxan-5-ol (1.1 g, 3.06 mmol) in THF (30 mL) in a 100-mL 3-necked round-bottom flask under nitrogen was added n-BuLi in hexane (2.5 M, 2.7 mL, 6.73 mmol) dropwise at -78 ^° C. The reaction solution was stirred for 30 min at -78 ^° C. Then SO ₂ (g) was bubbled to the solution at - 50 ^° C for 20 min. The reaction mixture was allowed to react with stirring for an additional 2 h at RT. The mixture was concentrated directly under vacuum. This resulted in 1.5 g (crude) of the title compound as a yellow solid. MS-ESI: 422 (M-1).

Step 4: 4-(((Tert-butyldimethylsilyl)oxy)methyl)-2-(5-hydroxy-2,2-di methyl-1,3-dioxan-5- yl)thiazole-5- sulfonyl chloride

To a stirred solution of 4-(((tert-butyldimethylsilyl)oxy)methyl)-2-(5-hydroxy-2,2-di methyl-1,3- dioxan-5-yl) thiazole-5-sulfinic acid, lithium salt (1.5 g, crude) in THF (20 mL) in a 100-mL round-bottom flask was added NCS (610 mg, 4.59 mmol) in portions at 0 ^° C. The reaction mixture was stirred for 2 h at 0 ^° C. To the reaction solution was added NH3 in THF (0.5 M, 50 mL) in portions at 0 ^° C. The reaction mixture was stirred for 2 h at 0 ^° C. The mixture was concentrated under vacuum. The residue was purified by prep-TLC (PE/EtOAc 7:1). This resulted in 685 mg (51%, over two steps) of the title compound as a brown solid. MS-ESI: 439 (M+1).

Steps 5-6 used similar procedures for converting compound 639” to Intermediate 183 shown in Scheme 128 to afford Intermediate 184 from compound 644”. MS-ESI: 552 (M+1).

Scheme 130:

5-(Azetidin-1-ylmethyl)-N'-(tert-butyldimethylsilyl)-3-fluor othiophene-2-sulfonimidamide Step 1: 1-((4-Fluorothiophen-2-yl)methyl)azetidine

To a stirred solution of 2-(bromomethyl)-4-fluorothiophene (2.4 g, 12.4 mmol) in THF (25 mL) in a 100-mL round-bottom flask under nitrogen were added azetidine (1.06 g, 18.6 mmol) and TEA (2.49 g, 25 mmol) in portions at RT. The reaction solution was stirred for 2 h at RT. The reaction solution was concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:1). This resulted in 2.0 g (94%) of the title compound as yellow oil. MS-ESI: 172 (M+1).

Steps 2-4 used similar procedures for converting compound 642” to Intermediate 184 shown in Scheme 129 to afford Intermediate 185 from compound 646”. MS-ESI: 364 (M+1). Scheme 131:

Tert yl ((5-(N'-(tert-butyldimethylsilyl)sulfamidimidoyl)-4-fluoroth iophen-2- yl)methyl)(cyclobutyl)carbamate

Step 1: N-((4-fluorothiophen-2-yl)methyl)cyclobutanamine

To a stirred solution of 2-(bromomethyl)-4-fluorothiophene (4.5 g, 23 mmol) in EtOH (100 mL) in a 250-mL round-bottom flask under nitrogen were added cyclobutanamine (2.0 g, 28 mmol) at 0 ^° C, followed by the addition of NaOH (1.5 g, 38 mmol) in portions at 0 ^° C. The reaction mixture was stirred overnight at RT. The reaction mixture was concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:3). This resulted in 3.5 g (82%) of the title compound as a yellow solid. MS-ESI: 186 (M+1).

Step 2: Tert-butyl cyclobutyl((4-fluorothiophen-2-yl)methyl)carbamate

To stirred solution of N-((4-fluorothiophen-2-yl)methyl)cyclobutanamine (3.5 g, 19 mmol) in DCM (50 mL) in a 250-mL round-bottom flask under nitrogen were added Et3N (5.4 mL, 38 mmol) at RT, followed by the addition of Boc ₂ O (5.0 g, 23 mmol) at RT. The reaction mixture was stirred for 3 h at RT. The reaction was quenched with 100 mL of water. The mixture was extracted with 3x100 mL of DCM and the organic layers were combined and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (5:1). This resulted in 4.6 g (85%) of the title compound as a yellow solid. MS-ESI: 286 (M+1).

Steps 3-6 used similar procedures for converting compound 642” to Intermediate 184 shown in Scheme 129 to afford Intermediate 186 from compound 650”. MS-ESI: 478 (M+1).

Scheme 132:

Tert-butyl ((5-(N'-(tert-butyldimethylsilyl)sulfamidimidoyl)thiophen-2- yl)(cyclopropyl)methyl) )carbamate

Step 1: 5-Bromo-N-(tert-butyl)thiophene-2-sulfonamide

To a stirred solution of 5-bromothiophene-2-sulfonyl chloride (20 g, 77 mmol) in DCM (200 mL) in a 1-L round-bottom flask were added 2-methylpropan-2-amine (8.43 g, 116 mmol) at RT, followed by the addition of TEA (15.6 g, 154 mmol) at RT. The reaction mixture was stirred overnight at RT and then was quenched with 10 mL of water. The mixture was extracted with 3x150 mL of DCM and the organic layers were combined and dried over anhydrous Na2SO4 and concentrated under vacuum. This resulted in 20.1 g (88%) of the title compound as a red solid. MS-ESI: 298/300 (M+1).

Step 2: N-(tert-butyl)-5-(cyclopropanecarbonyl)thiophene-2-sulfonami de

To a stirred solution of 5-bromo-N-(tert-butyl)thiophene-2-sulfonamide (20 g, 67 mmol) in THF (500 mL) in a 1-L 3-necked round-bottom flask under nitrogen was added n-BuLi in hexane (2.5 M, 67 mL, 168 mmol) dropwise at -78 ^° C. The reaction solution was stirred for 1 h at -78 ^° C. To the reaction solution was added N-methoxy-N-methylcyclopropanecarboxamide (35 g, 270 mmol) in THF (20 mL) dropwise at -78 ^° C. Then the reaction mixture was stirred for 1 h at -78 ^° C. The reaction was quenched with 20 mL of MeOH. The mixture was concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (21%). This resulted in 7.1 g (37%) of the title compound as a white solid. MS-ESI: 288 (M+1).

Step 3: N-(tert-butyl)-5-(cyclopropyl(hydroxy)methyl)thiophene-2-sul fonamide

To a stirred solution of N-(tert-butyl)-5-(cyclopropanecarbonyl)thiophene-2-sulfonami de (2.0 g, 6.96 mmol) in MeOH (40 mL) in a 100-mL round-bottom flask under nitrogen was added NaBH ₄ (529 mg, 14 mmol) at 0 ^° C. The reaction mixture was stirred for 2 h at RT. The reaction was quenched with 10 mL of water. The mixture was extracted with 3x100 mL of EtOAc and the organic layers were combined. The organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated under vacuum. This resulted in 1.8 g (89%) of the title compound as yellow oil. MS-ESI: 290 (M+1).

Step 4: N-(tert-butyl)-5-(cyclopropyl(1,3-dioxoisoindolin-2-yl)methy l)thiophene-2- sulfonamide To a stirred solution of N-(tert-butyl)-5-(cyclopropyl(hydroxy)methyl)thiophene-2-sul fonamide (1.2 g, 4.15 mmol) in THF (24 mL) in a 100-mL round-bottom flask under nitrogen were added isoindoline-1,3-dione (610 mg, 4.15 mmol) and PPh ₃ (1.63 g, 6.22 mmol) at RT. To the stirred mixture was added DIAD (1.26 g, 6.22 mmol) dropwise at 0 ^° C. The reaction mixture was stirred overnight at RT. The mixture was concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:6). This resulted in 1.7 g (98%) of the title compound as a yellow solid. MS-ESI: 419 (M+1).

Step 5: 5-(Amino(cyclopropyl)methyl)-N-(tert-butyl)thiophene-2-sulfo namide

To a stirred solution of N-(tert-butyl)-5-(cyclopropyl(1,3-dioxoisoindolin-2-yl)methy l)thiophene- 2- sulfonamide (200 mg, 0.48 mmol) in EtOH (10 mL) in a 50-mL round-bottom flask was added NH2NH2.H2O (80%wt., 180 mg, 2.88 mmol). The reaction solution was stirred for 3 h at 80 ^° C. The reaction solution was concentrated under vacuum. The residue was dissolved in 10 mL of DCM. The solids were filtered out and the filtrate was concentrated under vacuum. This resulted in 100 mg (73%) of the title compound as yellow oil. MS-ESI: 289 (M+1).

yl)(cyclopropyl)methyl)carbamate

To a stirred solution of 5-(amino(cyclopropyl)methyl)-N-(tert-butyl)thiophene-2-sulfo namide (100 mg, 0.35 mmol) in DCM (10 mL) in a 50-mL round-bottom flask were added TEA (70 mg, 0.69 mmol) at RT, followed by the addition of Boc ₂ O (151 mg, 0.69 mmol) at RT. The reaction solution was stirred overnight at 40 ^° C. The reaction solution was diluted with H2O (10 mL). The mixture was extracted with 3x20 mL of DCM and the organic layers were combined. The organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1/3). This resulted in 100 mg (74%) of the title compound as yellow oil. MS-ESI: 389 (M+1).

Step 7: N-(tert-butyl)-5-(cyclopropyl(methylamino)methyl)thiophene-2 -sulfonamide

To a stirred solution of tert-butyl ((5-(N-(tert-butyl)sulfamoyl)thiophen-2- yl)(cyclopropyl)methyl)carbamate (100 mg, 0.26 mmol) in THF (10 mL) in a 50-mL round- bottom flask under nitrogen was added LiAlH4 (30 mg, 0.78 mmol) at 0 ^° C. The reaction mixture was stirred for 2 h at 80 ^° C. The reaction was quenched with 5.0 mL of water. The reaction mixture was concentrated under vacuum. The residue was dissolved in 10 mL of MeOH. The solids were filtered and the filtrate was concentrated under vacuum. This resulted in 74 mg (94%) of the title compound as off-white oil. MS-ESI: 303 (M+1).

Step 8: 5-(Cyclopropyl(methylamino)methyl)thiophene-2-sulfonamide

A solution of N-(tert-butyl)-5-(cyclopropyl(methylamino)methyl)thiophene-2 -sulfonamide (74 mg, 0.24 mmol) in HCl in 1,4-dioxane (4 M, 5.0 mL, 2.0 mmol) in a 50-mL round-bottom flask was stirred overnight at RT. The reaction mixture was concentrated under vacuum. The residue was eluted from silica gel with DCM/MeOH (10:1). This resulted in 53 mg (89%) of the title compound as yellow oil. MS-ESI: 247 (M+1).

Step 9: Tert-butyl (cyclopropyl(5-sulfamoylthiophen-2-yl)methyl)(methyl)carbama te

To a stirred solution of 5-(cyclopropyl(methylamino)methyl)thiophene-2-sulfonamide (53 mg, 0.21 mmol) in DCM (8 mL) in a 25-mL round-bottom flask was added TEA (43 mg, 0.43 mmol) at RT, followed by the addition of Boc ₂ O (69 mg, 0.32 mmol) at RT. The reaction solution was stirred overnight at 40 ^° C. The reaction was diluted with H2O (8 mL). The mixture was extracted with 3x8 mL of DCM and the organic layers combined and dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1/3). This resulted in 51 mg (70%) of the title compound as yellow oil. MS-ESI: 347 (M+1).

Steps 10-11 used similar procedures for converting compound 639” to Intermediate 183 shown in Scheme 128 to afford Intermediate 187 from compound 663”. MS-ESI: 460 (M+1).

Step 12: Tert-butyl (S) and (R)-(cyclopropyl(5-sulfamoylthiophen-2- yl)methyl)(methyl)carbamate

Tert-butyl (cyclopropyl(5-sulfamoylthiophen-2-yl)methyl)(methyl)carbama te (663”, 1.0 g) was resolved by Chiral-Prep-HPLC using the following conditions: Column CHIRALPAK IG, 2*25 cm, 5 um; Mobile Phase A: Hex (8 mM NH ^.

3MeOH), Mobile Phase B: EtOH; Flow rate: 20 mL/min; Gradient: 20 B to 20 B over 17 min; UV 254/220 nm; Rt ₁ : 8.479 (663”F); Rt ₂ : 10.122 (663”S); Injection Volumn:0.5 ml; Number of runs:39. This resulted in 417 mg (98% ee) of 663”F and 407 mg (99% ee) of 663”S both as yellow solid. MS-ESI: 347 (M+1). The stereochemistry of 663”F and 663”S were assigned arbitrarily for registration purpose. Table 54 The Intermediates in the following table were prepared using the similar procedures for converting compound 633” to Intermediate 187 shown in Scheme 132 starting from 663”F or 663”S.

Scheme 133:

Intermediate 188

Step 1: 1-((Tert-butyldimethylsilyl)oxy)-2-(4-(((tert-butyldimethyls ilyl)oxy)methyl)thiazol- 2-yl)propan -2-ol

To a stirred solution of 2-bromo-4-(((tert-butyldimethylsilyl)oxy)methyl)thiazole (300 mg, 0.97 mmol) in THF (10 mL) in a 50-mL 3-necked round-bottom flask under nitrogen was added n-BuLi in hexane (2.5 M, 0.4 mL, 0.97 mmol) dropwise at -78 ^° C. The reaction solution was stirred for 30 min at -78 ^° C. To the solution was added 1-((tert- butyldimethylsilyl)oxy)propan-2-one (183 mg, 0.97 mmol) at -78 ^° C over 10 min. The reaction mixture was stirred for 12 h at RT. The reaction was quenched with 10 mL of H ₂ O (10 mL). The mixture was extracted with 3x20 mL of DCM and the organic layers were combined and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:10). This resulted in 250 mg (62%) of the title compound as yellow oil. MS-ESI: 418 (M+1).

Steps 2-6 used similar procedures for converting compound 642” to Intermediate 184 shown in Scheme 129 to afford Intermediate 188 from compound 665”. MS-ESI: 610 (M+1).

Step 7: (S) and (R)-2-(1-((tert-butyldimethylsilyl)oxy)-2-hydroxypropan-2-yl )-4-(((tert- butyldimethylsilyl)oxy)methyl)thiazole-5-sulfonamide

2-(1-((Tert-butyldimethylsilyl)oxy)-2-hydroxypropan-2-yl) -4-(((tert- butyldimethylsilyl)oxy)methyl)thiazole-5-sulfonamide (668”, 1.0 g) was resolved by Prep-SFC using the following conditions: Column: Lux Cellulose-4, 5*25 cm, 5 um; Mobile Phase A: CO ₂ , Mobile Phase B: MeOH; Flow rate: 150 mL/min; Gradient: 25% B; 220 nm; Rt ₁ : 3.81 min. (668”A); Rt2: 4.88 min. (668”B); Injection Volume: 1.5 ml; number of runs: 40. This resulted in 420 mg (98%ee) of 668”A and 428 mg (99%ee) of 668”B both as yellow solid. MS-ESI: 497 (M+1).

Table 55 The intermediates in the following table were prepared using the similar procedures for converting compound 668” to Intermediate 188 shown in Scheme 133 starting from 668”A or 668”B. ntermediate Structure IUPAC Name Exact

- n n

Scheme 134:

N'-(tert-butyldimethylsilyl)-5-methoxy-4,5,6,7-tetrahydroben zo[c]thiophene-1-sulfonimidamide Step 1: 4,5,6,7-Tetrahydrobenzo[c]thiophen-5-ol

To a stirred solution of 6,7-dihydrobenzo[c]thiophen-5(4H)-one (3.7 g, 24 mmol) in MeOH (100 mL) in a 250-mL round-bottom flask under nitrogen was added NaBH4 (1.09 g, 29 mmol) in portions at 0 ^° C. The resulting mixture was stirred for 5 h at RT. The reaction was quenched with H ₂ O (5.0 mL). The mixture was extracted with 3x50 mL of DCM and the organic layers were combined, dried over anhydrous Na2SO4, and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:40). This resulted in 3.0 g (80%) of the title compound as yellow oil. MS-ESI: 155 (M+1).

Step 2: 5-Methoxy-4,5,6,7-tetrahydrobenzo[c]thiophene

To a stirred solution of 4,5,6,7-tetrahydrobenzo[c]thiophen-5-ol (3.0 g, 19.5 mmol) in THF (30 mL) in a 100-mL round-bottom flask was added NaH (60% wt. dispersion in mineral oil, 1.95 g, 49 mmol) at 0 ^° C. The reaction mixture was stirred for 10 min at RT, followed by the addition of CH3I (4.15 g, 29.2 mmol) dropwsie at RT. The reaction mixture was stirred for 5 h at RT. The reaction was then quenched with H2O (30 mL). The mixture was extracted with 3x50 mL of DCM and the organic layers were combined, dried over anhydrous Na ₂ SO ₄ , and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:80). This resulted in 3.0 g (91%) of the title compound as yellow oil. MS-ESI: 169 (M+1).

regioiosmer

To a stirred solution of 5-methoxy-4,5,6,7-tetrahydrobenzo[c]thiophene (3.0 g, 18 mmol) in CHCl3 (30 mL) in a 100-mL 3-necked round-bottom flask was added ClSO3H (2.49 g, 21 mmol) dropwise at -10 ^° C. The reaction mixture was stirred for 48 h at RT. Then to the above mixture was added PCl5 (7.36 g, 35.7 mmol) at -10 ^° C. The reaction mixture was stirred for 3 h at 50 ^° C and then poured into 200 mL of water/ice. The mixture was extracted with 3x200 mL of DCM. The organic layers were combined, dried over anhydrous Na ₂ SO ₄ , and then concentrated under vacuum. This resulted in 1.5 g (crude) of the title compound as light brown oil. This crude product was used in the next step.

Step 4: 5-Methoxy-4,5,6,7-tetrahydrobenzo[c]thiophene-1-sulfonamide and 6-methoxy- 4,5,6,7- tetrahydrobenzo[c]thiophene-1-sulfonamide and its regio-isomer

To a stirred solution of 5-methoxy-4,5,6,7-tetrahydrobenzo[c]thiophene-1-sulfonyl chloride from Step 3 above (1.5 g, crude) in DCM (50 mL) in a 250-mL round-bottom flask was bubbled NH ₃ (g) for 15 min at 0 ^° C. The reaction mixture was stirred for 3 h at RT and concentrated under vacuum. The residue was eluted from silica gel with a gradient of EtOAc/PE (1:4 to 1:2). This resulted in 650 mg (15% over two steps) of 674”F and 620 mg (14%) of 674”S, both as a yellow solid. MS-ESI: 248 (M+1). The regiochemistry of 674”F and 674”S were assigned based on NMR including COSY and NOESY.

Compound 674”F: ¹ H NMR (300 MHz, DMSO-d ₆ ) d 7.46 (br s, 2H), 7.34 (s, 1H), 3.75-3.55 (m, 1H), 3.26 (s, 3H), 2.99-2.80 (m, 3H), 2.71 (dd, J = 16.3, 5.9 Hz, 1H), 1.95-1.75 (m, 2H).

NOESY: Ar-H 7.34 (s, 1H) correlated with ring-methylene 2.71 (dd, J = 16.3, 5.9 Hz, 1H), exchangeable proton NH ₂ correlated with ring-methylene 2.99-2.80 (m, 3H).

Compound 674”S: ¹ H NMR (300 MHz, DMSO-d6) d 7.50 (br s, 2H), 7.32 (s, 1H), 3.85-3.55 (m, 1H), 3.30 (s, 3H), 3.08 (dd, J = 17.8, 4.7 Hz, 1H), 2.92 (dd, J = 17.7, 5.9 Hz, 1H), 2.80-2.55 (m, 2H), 1.90-1.75 (m, 2H).

NOESY: Ar-H 7.32 (s, 1H) correlated with ring-methylene 2.80-2.55 (m, 2H), exchangeable proton NH2 correlated with ring-methylene 3.08 (dd, J = 17.8, 4.7 Hz, 1H) and 2.92 (dd, J = 17.7, 5.9 Hz, 1H).

Steps 5-6 used similar procedures for converting compound 639” to Intermediate 183 shown in Scheme 128 to afford Intermediate 189F from compound 674”F. MS-ESI: 361 (M+1).

Table 56 The Intermediates in the following table were prepared using the similar procedures for converting compound 674”F to Intermediate 189F shown in Scheme 134 starting from 674”S.

Scheme 135

5-((S)-1-(2-(benzyloxy)ethoxy)-2-hydroxypropan-2-yl)-N'-( tert-butyldimethylsilyl)thiophene-2- sulfonimidamide

Steps 1-2 used similar procedures for converting compound 672” to compound 674” shown in Scheme 134 to afford compound 678” from compound 676”. MS-ESI: 220 (M-1).

Step 3: 5-(2-Hydroxypropan-2-yl)thiophene-2-sulfonamide

To a stirred solution of methyl 5-sulfamoylthiophene-2-carboxylate (1.0 g, 4.52 mmol) in THF (40 mL) in a 100-mL 3-necked round-bottom flask under nitrogen was added CH ₃ MgBr in THF (3.0 M, 7.5 mL, 22.6 mmol) dropwise at 0 ^° C. The reaction mixture was stirred overnight at RT, quenched with sat. NH4Cl (40 mL) at 0 ^° C, and then extracted with EtOAc (3x40 mL). The organic layers were combined, dried over anhydrous Na ₂ SO ₄ , and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:2). This resulted in 500 mg (50%) of the title compound as a yellow solid. MS-ESI: 222 (M+1). Step 4: 5-(Prop-1-en-2-yl)thiophene-2-sulfonamide

To a stirred solution of 5-(2-hydroxypropan-2-yl)thiophene-2-sulfonamide (500 mg, 2.25 mmol) in THF (20 mL) in a 100-mL round-bottom flask under nitrogen was added Burgess reagent (1.15 g, 4.5 mmol) in portions at RT. The reaction mixture was stirred overnight at RT. The reaction mixture was quenched with H2O (10 mL) and extracted with EtOAc (3x20 mL). The organic layers were dried over anhydrous Na ₂ SO ₄ and concentrated under vacuum. The residue was purified by prep-TLC (PE/EtOAc=1:2). This resulted in 420 mg (91.5%) of the title compound as a white solid. MS-ESI: 204 (M+1).

Step 5: 5-(1,2-Dihydroxypropan-2-yl)thiophene-2-sulfonamide

To a stirred solution of 5-(prop-1-en-2-yl)thiophene-2-sulfonamide (420 mg, 2.06 mmol) in t- BuOH (4.0 mL) and acetone (4.0 mL) in a 50-mL round-bottom flask was added NMO (483 mg, 4.12 mmol) and the reaction solution was stirred for 15 min at RT. Then to this was added a solution of OsO ₄ (53 mg, 0.21 mmol) in H ₂ O (3.0 mL) dropwise at RT. The reaction mixture was stirred overnight at RT. The reaction was quenched with sat. aq. Na2S2O3 (5.0 mL). The mixture was extracted with 3x10 mL EtOAc. The organic layers were combined and dried over anhydrous Na ₂ SO ₄ and concentrated under vacuum. The crude product was eluted from silica gel with MeOH/DCM (7:100). This resulted in 245 mg (50%) of the title compound as yellow oil. MS-ESI: 238 (M+1).

Step 6: (S) and (R)-5-(1,2-dihydroxypropan-2-yl)thiophene-2-sulfonamide

5-(1,2-Dihydroxypropan-2-yl)thiophene-2-sulfonamide (681”, 245 mg) was resolved by Prep- Chiral HPLC using the following conditions: CHIRALPAK AD-H SFC, 5*25 cm, 5 um; Mobile Phase A: CO ₂ , Mobile Phase B: MeOH:ACN=1:1 (2 mM NH ₃ -MeOH); Flow rate: 150 mL/min; Gradient: 50% B; 220 nm; Rt ₁ : 4.1 min (681”F); Rt ₂ : 7.4 min (681”S). This resulted in 100 mg (99%ee) of 681”F and 110 mg (98%ee) of 681”S, both as yellow oil. Absolute stereochemistry of both were unconfirmed. MS-ESI: 236 (M-1).

Step 7: (S)-2-hydroxy-2-(5-sulfamoylthiophen-2-yl)propyl 4-methylbenzenesulfonate

To a stirred solution of (S)-5-(1,2-dihydroxypropan-2-yl)thiophene-2-sulfonamide (681”F, 100 mg, 0.42 mmol) in pyridine (8.0 mL) in a 50-mL round-bottom flask was added TsCl (239 mg, 1.26 mmol) at RT. The reaction mixture was stirred for 16 h at RT, diluted with 20 mL of H ₂ O, and then extracted with 3x20 mL of EtOAc. The organic layers were combined and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:10). This resulted in 125 mg (76%) of the title compound as yellow oil. MS-ESI: 392 (M+1).

Step 8: (S)-5-(1-(2-(benzyloxy)ethoxy)-2-hydroxypropan-2-yl)thiophen e-2-sulfonamide To a stirred solution of 2-(benzyloxy)ethan-1-ol (243 mg, 1.6 mmol) in THF(10 mL) in a 50-mL round-bottom flask under nitrogen was added NaH (60% wt. dispersion in mineral oil, 128 mg, 3.2 mmol) at 0 ^° C. The reaction mixture was stirred for 30 min at 0 ^° C, followed by the addition of (S)-2-hydroxy-2-(5-sulfamoylthiophen-2-yl)propyl 4-methylbenzenesulfonate (125 mg, 0.32 mmol) at 0 ^° C. The reaction mixture was stirred for 32 h at 35 ^° C. The reaction was quenched with H ₂ O (10 mL) at 0 ^° C. The mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (2x10 mL) and dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was eluted from silica gel with PE/EtOAc (1:2). This resulted in 113 mg (95%) of the title compound as yellow oil. MS-ESI: 372 (M+1).

Steps 9-10 used similar procedures for converting compound 639” to Intermediate 183 shown in Scheme 128 to afford Intermediate 190 from compound 683”F. MS-ESI: 485 (M+1).

Table 57 The intermediates in the following table were prepared using the similar procedures for converting compound 681”F to Intermediate 190 shown in Scheme 135 starting from 586”B.

Scheme 136:

Intermediate 192

Tert-butyl (1-(4-(N'-(tert-butyldimethylsilyl)sulfamidimidoyl)-3- fluorophenyl)ethyl)(cyclobutyl)carbamate

Steps 1-2 used similar procedures for converting compound 654” to compound 656” shown in Scheme 132 to afford compound 687” from compound 685”. MS-ESI: 274 (M+1).

Step 3: N-(tert-butyl)-4-(1-(cyclobutylamino)ethyl)-2-fluorobenzenes ulfonamide

To a stirred solution 4-acetyl-N-tert-butyl-2-fluorobenzenesulfonamide (3.6 g, 13 mmol) in DCM (100 mL) in a 250-mL round-bottom flask under nitrogen were added cyclobutylamine (1.87 g, 26 mmol) at RT, followed by the addition of HCOOH (1.33 g, 29 mmol) dropwsie at RT. The reaction solution was stirred overnight at RT. To the above solution was added

NaBH(OAc) ₃ (5.86 g, 28 mmol) in portions at RT. The reaction mixture was stirred for additional 2 days at 35 ^° C. The mixture was adjusted to pH 9 with NaOH (2 M). The mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was purified by prep-TLC (PE/EtOAc 2:1). This resulted in 1.5 g (35%) of the title compound as a yellow solid. MS-ESI: 329 (M+1).

Step 4: 4-(1-(Cyclobutylamino)ethyl)-2-fluorobenzenesulfonamide

To a stirred solution of N-(tert-butyl)-4-(1-(cyclobutylamino)ethyl)-2-fluorobenzenes ulfonamide (1.5 g, 4.57 mmol) in DCM (20 mL) in a 250-mL round-bottom flask was added BCl ₃ in DCM (1 M, 20 mL, 20 mmol) dropwise at 0 ^° C. The reaction solution was stirred for 2 h at RT. The residue was adjusted to pH 9 with NaOH (2 M). The mixture was extracted with EtOAc (3x80 mL). The combined organic layers were dried over anhydrous Na ₂ SO ₄ and concentrated under vacuum. This resulted in 1.2 g (crude) of the title compound as yellow oil. MS-ESI: 273 (M+1). Steps 5-7 used similar procedures for converting compound 662” to Intermediate 187 shown in Scheme 132 to afford Intermediate 192 from compound 689”. MS-ESI: 486 (M+1).

Scheme 137:

Intermediate 193

N'-(tert-butyldimethylsilyl)-4-((cyclobutyl(methyl)amino)met hyl)-2- fluorobenzenesulfonimidamide

Step 1: 4-(N-(tert-butyl)sulfamoyl)-3-fluorobenzoic acid

To a stirred solution of 4-bromo-N-tert-butyl-2-fluorobenzenesulfonamide (7.7 g, 25 mmol) in THF (40 mL) in a 100-mL 3-necked round-bottom flask under nitrogen was added n-BuLi in hexane (2.5 M, 20 mL, 50 mmol) dropwise at -78 ^° C. The reaction solution was stirred for 30 min at -78 ^° C. CO2 (g) was bubbled into the above solution for 20 min at -30 ^° C. The reaction mixture was stirred for additional 3 h at RT. The pH value of the solution was adjusted to 10 with NaOH (1 M). The mixture was extracted with 3x30 mL of DCM. The pH value of the solution was adjusted to 3 with HCl (1 M). The mixture was extracted with 3x100 mL of EtOAc. The organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum. This resulted in 5.0 g (74%) of the title compound as a yellow solid. MS-ESI: 274 (M-1).

Step 2: 4-(N-(tert-butyl)sulfamoyl)-N-cyclobutyl-3-fluoro-N-methylbe nzamide

To a stirred solution of 4-(N-(tert-butyl)sulfamoyl)-3-fluorobenzoic acid (4.9 g, 18 mmol) in DCM (50 mL) in a 250-mL round-bottom flask were added N-methylcyclobutanamine (1.83 g, 21.6 mmol), HATU (8.8 g, 23 mmol) and TEA (5.4 g, 53 mmol). The reaction mixture was stirred overnight at RT. The reaction was quenched with H2O (50 mL). The mixture was extracted with DCM (3x80 mL). The organic layers were dried over anhydrous Na ₂ SO ₄ and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (2/3). This resulted in 2.58 g (42%) of the title compound as a yellow solid. MS-ESI: 343 (M+1).

Step 3 used similar procedures for converting compound 688” to compound 689” shown in Scheme 136 to afford compound 694” from compound 693”. MS-ESI: 287 (M+1).

Step 4: 4-((Cyclobutyl(methyl)amino)methyl)-2-fluorobenzenesulfonami de

To a stirred solution of N-cyclobutyl-3-fluoro-N-methyl-4-sulfamoylbenzamide (2.2 g, 7.7 mmol) in THF (30 mL) in a 100-mL round-bottom flask under nitrogen was added BH ₃ -THF (1 M, 15 mL, 15 mmol) at 0 ^° C. The reaction mixture was stirred for 30 min at 0 ^° C. The reaction mixture was stirred overnight at RT. The reaction was quenched with aq. HCl (2 M, 50 mL) at 0 ^° C. The reaction mixture was stirred for 10 min at RT. The pH value of the solution was adjusted to 9 with NaOH (5 M). The mixture was extracted with 3x50 mL of EtOAc and the organic layers were combined. The organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum. This resulted in 1.74 g (83%) of the title compound as a yellow solid. MS-ESI: 273 (M+1).

Steps 5-6 used similar procedures for converting compound 639” to Intermediate 183 shown in Scheme 128 to afford Intermediate 193 from compound 695”. MS-ESI: 386 (M+1).

Scheme 138:

Intermediate 194

N-(tert-butyldimethylsilyl)-5-((dimethylamino)methyl)thiophe ne-2-sulfonimidamide Step 1 used similar procedures for converting compound 654” to compound 655” shown in Scheme 132 to afford compound 698” from compound 697”. MS-ESI: 297/299 (M+1).

Step 2: N-(tert-butyl)-5-((dimethylamino)methyl)thiophene-2-sulfonam ide

To a stirred solution of 5-bromo-N-(tert-butyl)thiophene-2-sulfonamide (1.15 g, 3.86 mmol) in dioxane (30 mL) and H ₂ O (3.0 mL) in a 100-mL round-bottom flask under nitrogen were added N,N-dimethyl-1-(trifluoro-l4-boraneyl)methanamine, potassium salt (764 mg, 4.63 mmol) and Cs2CO3 (3.77 g, 11.7 mmol) in portions at RT. Then Ruphos (360 mg, 0.77 mmol) and Pd(AcO)2 (173 mg, 0.77 mmol) were added to the mixture. The reaction mixture was stirred overnight at 100 ^° C. The solids were filtered out and the filtrate was concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (2/1). This resulted in 120 mg (11%) of the title compound as yellow oil. MS-ESI: 277 (M+1).

Step 3 used similar procedures for converting compound 688” to compound 689” shown in Scheme 136 to afford compound 700” from compound 699”. MS-ESI: 221 (M+1).

Steps 4-5 used similar procedures for converting compound 639” to Intermediate 183 shown in Scheme 128 to afford Intermediate 194 from compound 700”. MS-ESI: 334 (M+1).

Scheme 139

Tert-butyl ( -2-(5-(N-(tert-butyldimethylsilyl)sulfamidimidoyl)thiophen-2 -yl)pyrrolidine-1- carboxylate

Step 1: Tert-butyl (4-(5-(N-(tert-butyl)sulfamoyl)thiophen-2-yl)-4-oxobutyl)car bamate To a stirred solution of 5-bromo-N-(tert-butyl)thiophene-2-sulfonamide (5.0 g, 16.8 mmol) in THF (50 mL) in a 250-mL 3-necked round-bottom flask under nitrogen was added n-BuLi in hexane (2.5 M, 13 mL, 32.5 mmol) dropwise at -78 ^° C. The reaction mixture was stirred for 1 h at -78 ^° C. Then to the mixture was added tert-butyl 2-oxopyrrolidine-1-carboxylate (6.21 g, 33.6 mmol) at -78 ^° C. The reaction mixture was stirred for 2 h at RT and then quenched with H2O (50 mL). The mixture was extracted with EtOAc (3x100 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:1). This resulted in 1.8 g (27%) of the title compound as a yellow solid. MS-ESI: 405 (M+1).

Step 2: N-(tert-butyl)-5-(3,4-dihydro-2H-pyrrol-5-yl)thiophene-2-sul fonamide

A solution of tert-butyl (4-(5-(N-(tert-butyl)sulfamoyl)thiophen-2-yl)-4-oxobutyl)car bamate (1.8 g, 4.45 mmol) in formic acid (20 mL) in a 100-mL round-bottom flask under nitrogen was stirred for 12 h at RT. The pH value of the solution was adjusted to 9 with sat.Na ₂ CO ₃ (aq). The mixture was extracted with EtOAc (3x100 mL) and the organic layers were combined. The organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was eluted from silica gel with DCM/MeOH (10:1). This resulted in 1.0 g (78%) of the title compound as a yellow solid. MS-ESI: 287 (M+1).

Step 3: 5-(3,4-Dihydro-2H-pyrrol-5-yl)thiophene-2-sulfonamide

To a stirred solution of N-(tert-butyl)-5-(3,4-dihydro-2H-pyrrol-5- yl)thiophene-2-sulfonamide (1.0 g, 3.49 mmol) in DCM (10 mL) in a 100-mL round-bottom flask was added BCl ₃ in DCM (1 M, 10 mL, 10 mmol) dropwise at 0 ^° C. The reaction mixture was stirred for 2 h at RT. The reaction was quenched with 10 mL of MeOH. The mixture was concentrated under vacuum. The residue was eluted from silica gel with DCM/MeOH (10:1). This resulted in 600 mg (75%) of the title compound as a yellow solid. MS-ESI: 231 (M+1). Step 4: 5-(Pyrrolidin-2-yl)thiophene-2-sulfonamide

To a stirred solution of 5-(3,4-dihydro-2H-pyrrol-5-yl)thiophene-2-sulfonamide (600 mg, 2.6 mmol) in MeOH (10 mL) in a 50-mL round-bottom flask under nitrogen was added NaBH ₄ (197 mg, 5.21 mmol) in portions at 0 ^° C. The reaction mixture was stirred for 2 h at RT. The reaction mixture was diluted with 10 mL of water. The mixture was extracted with 3x50 mL of EtOAc and the organic

layers were combined. The organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated under vacuum. This resulted in 500 mg (83%) of the title compound as yellow oil. MS-ESI: 233 (M+1). Step 5 used similar procedures for converting compound 662” to compound 663” shown in

Scheme 132 to afford compound 706” from compound 705”. MS-ESI: 331 (M-1).

Step 6: Tert-butyl (S)-2-(5-sulfamoylthiophen-2-yl)pyrrolidine-1-carboxylate and tert-butyl (R)-2- (5-sulfamoylthiophen-2-yl)pyrrolidine-1-carboxylate

Tert-butyl 2-(5-sulfamoylthiophen-2-yl)pyrrolidine-1-carboxylate (706”, 600 mg) was resolved by Prep-SFC using the following conditions: Column, CHIRALPAK AD-H SFC, 5*25 cm, 5 um; Mobile Phase A: CO2, Mobile Phase B: MeOH (2 mM NH3-MeOH); Flow rate: 200

mL/min; Gradient: 24% B; UV 254 nm; Rt1: 3.5 min (706”F); Rt2: 5.6 min (706”S). This

resulted in 250 mg (98%ee) of 706”F and 240 mg (99%ee) of 706”S, both as a yellow solid.

Absolute stereochemistry of both enantiomers were assigned arbitrarily. MS-ESI: 333 (M+1).

Steps 7-8 used similar procedures for converting compound 639” to Intermediate 183 shown in Scheme 128 to afford Intermediate 195F from compound 706”F. MS-ESI: 446 (M+1).

Table 58 The intermediates in the following table were prepared using the similar procedures for converting compound 706”F to Intermediate 195F shown in Scheme 139 starting from 706”S. t s ]- Scheme 140:

yl)thiazole-5-sulfonimidamide

Step 1: Diethyl 2-(thiazol-2-yl)malonate

To a stirred solution of ethyl 2-(1,3-thiazol-2-yl)acetate (5.0 g, 29 mmol) in THF (20 mL) in a 100-mL 3-necked round-bottom flask under nitrogen was added NaH (60% wt. dispersion in mineral oil, 2.34 g, 58 mmol) in portions at 0 ^° C. The reaction mixture was stirred for 30 min at 0 ^° C. Then diethyl carbonate (50 mL) was added to the above mixture. The reaction mixture was stirred for 10 h at 65 ^° C. The reaction was quenched with 50 mL of water and extracted with 3x50 mL of EtOAc. The organic layers were combined, dried over anhydrous Na2SO4, and concentrated under vacuum. This resulted in 7.59 g (crude) of the title compound as a light yellow solid. MS-ESI: 244 (M+1).

Step 2: Diethyl 2-methyl-2-(thiazol-2-yl)malonate

To a stirred solution of diethyl 2-(thiazol-2-yl)malonate (2.0 g, 8.22 mmol) in THF (30 mL) in a 250-mL 3-necked round-bottom flask under nitrogen were added DBU (2.5 g, 16 mmol) at RT, followed by the addition of CH3I (4.67 g, 33 mmol) dropwise at 0 ^° C. The reaction mixture was stirred for 2 h at RT and then quenched with 20 mL of water/ice. The mixture was extracted with 3x50 mL of EtOAc and the organic layers were combined, dried over anhydrous Na ₂ SO ₄ , and concentrated under vacuum. The crude product was purified by TLC with EtOAc/PE (1/2). This resulted in 1.1 g (52%) of the title compound as light yellow oil. MS-ESI: 258 (M+1).

Step 3: 2-Methyl-2-(thiazol-2-yl)propane-1,3-diol

To a stirred solution of diethyl 2-methyl-2-(thiazol-2-yl)malonate (1.1 g, 4.23 mmol) in THF (25 mL) in a 250-mL 3-necked round-bottom flask under nitrogen was added DIBAL-H in hexane (1 M, 25 mL, 25 mmol) in portions at 0 ^° C in an ice/water bath over 10 min. The reaction mixture was stirred for 2 h at RT. The reaction was then quenched with 20 mL of MeOH. The mixture was concentrated under vacuum. The crude product was purified by RP-HPLC with ACN/H2O (9/1). This resulted in 384 mg (60%) of the title compound as light yellow oil. MS-ESI: 174 (M+1).

Step 4: 2-(2,2,3,3,6,9,9,10,10-Nonamethyl-4,8-dioxa-3,9-disilaundeca n-6-yl)thiazole

To a stirred solution of 2-methyl-2-(thiazol-2-yl)propane-1,3-diol (384 mg, 2.22 mmol) in THF (10 mL) in a 50-mL round-bottom flask under nitrogen was added NaH (60%wt. dispersion in mineral oil, 532 mg, 13.3 mmol) in portions at 0 ^° C in an ice/water bath. The reaction mixture was stirred for 10 min at 0 ^° C. To the above mixture was added TBSCl (3.34 g, 22 mmol) in portions at 0 ^° C. The reaction mixture was stirred for 4 h at RT. The reaction was quenched with 20 mL of water/ice. The mixture was extracted with 3x50 mL of EtOAc and the organic layers were combined, dried over anhydrous Na2SO4, and concentrated under vacuum. This resulted in 846 mg (crude) of the title compound as light yellow oil. MS-ESI: 402 (M+1).

Steps 5-8 used similar procedures for converting compound 642” to Intermediate 184 shown in Scheme 129 to afford Intermediate 196 from compound 712”. MS-ESI: 594 (M+1).

Scheme 141:

Intermediate 197

N'-(tert-butyldimethylsilyl)-2-(1-((tert-butyldimethylsily )-2-methylpropan-2-yl)thiazole-5-

sulfonimidamide

Step 1: Ethyl 2-methyl-2-(thiazol-2-yl)propanoate

To a stirred solution of ethyl 2-(thiazol-2-yl)acetate (2.5 g, 14.6 mmol) in THF (30 mL) in a 100- mL round-bottom flask under nitrogen was added NaH (60% wt. dispersion in mineral, 3.5 g, 87.6 mmol) in portions at 0 ^° C. The reaction mixture was stirred for 10 min at RT. Then to the above was added CH ₃ I (21 g, 146 mmol) dropwise at 0 ^° C. The reaction mixture was stirred overnight at RT. The reaction was quenched with ice/water at 0 ^° C. The mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (2x30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:10). This resulted in 1.1 g (38%) of the title compound as a yellow solid. MS-ESI: 200 (M+1).

Step 2: 2-Methyl-2-(thiazol-2-yl)propan-1-ol To a stirred solution of ethyl 2-methyl-2-(thiazol-2-yl)propanoate (1.3 g, 6.5 mmol) in THF (15 mL) in a 50-mL round-bottom flask was added NaBH ₄ (1.48 g, 39 mmol) in portions at 0 ^° C. The reaction mixture was stirred for 2 h at 0 ^° C. The reaction was quenched with ice/water at 0 ^° C. The mixture was extracted with 3x50 mL of EtOAc. The organic layers were combined, dried over anhydrous Na2SO4, and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:3). This resulted in 600 mg (58%) of the title compound as a yellow solid. MS-ESI: 158 (M+1).

Steps 3-7 used similar procedures for converting compound 711” to Intermediate 196 shown in Scheme 140 to afford Intermediate 197 from compound 718”. MS-ESI: 464 (M+1).

Scheme 142:

Intermediate 198

N'-(tert-butyldimethylsilyl)-5-phenylthiophene-2-sulfonimida mide Step 1: 5-Phenylthiophene-2-sulfonamide

To a stirred solution of 5-bromothiophene-2-sulfonamide (500 mg, 2.07 mmol) in dioxane (20 mL) and H2O (2.0 mL) in a 50 mL 3-necked round-bottom flask under nitrogen were added phenylboronic acid (504 mg, 4.13 mmol), Pd(dppf)Cl ₂ (151 mg, 0.21 mmol) and Cs ₂ CO ₃ (1.35 g, 4.13 mmol) at RT. The reaction mixture was stirred overnight at 100 ^° C. The reaction was diluted with H2O (20 mL) and the mixture was extracted with 3x20 mL of EtOAc. The combined organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was eluted from silica gel with PE/EtOAc (5:1). This resulted in 450 mg (91 %) as a white solid. MS-ESI: 238 (M-1).

Steps 2-3 used similar procedures for converting compound 639” to Intermediate 183 shown in Scheme 128 to afford Intermediate 198 from compound 724. MS-ESI: 353 (M+1).

Scheme 143:

Intermediate 199

N-(tert-butyldimethylsilyl)-5-(2-hydroxyphenyl)thiophene-2-s ulfonimidamide Steps 1-2 used similar procedures for converting compound 639” to Intermediate 183 shown in Scheme 128 to afford compound 727” from compound 723”. MS-ESI: 355/357 (M+1).

Step 3 used similar procedures for converting compound 723” to compound 724” shown in

Scheme 142 to afford Intermediate 199 from compound 727”. MS-ESI: 369 (M+1).

Table 59 The intermediates in the following table were prepared using the similar procedures for converting compound 723” to Intermediate 199 shown in Scheme 143. s # [M-H]- n Scheme 144:

N'-(tert-butyldimethylsily utyldimethylsilyl)oxy)methyl)-5-(2-hydroxypropan-2- yl)thiazole-2-sulfonimidamide

Step 1: Ethyl 2-mercaptothiazole-4-carboxylate

To a stirred solution of ethyl 2-bromothiazole-4-carboxylate (100 g, 424 mmol) in EtOH (1.0 L) in a 2000-mL round-bottom flask was added NaSH (119 g, 2.12 mol) in portions at RT. The reaction mixture was stirred for 3 h at 85 ^° C and then concentrated under vacuum. The residue was dissolved in 500 mL of H2O. The pH value of the solution was adjusted to 3 with HCl (1 M). The solids were collected by filtration. This resulted in 80 g (99.8%) of the title compound as a yellow solid. MS-ESI: 190 (M+1).

Step 2: Ethyl 2-(chlorosulfonyl)thiazole-4-carboxylate To a stirred solution of ethyl 2-mercaptothiazole-4-carboxylate (80 g, 421 mmol) in HCl (12 M, 800 mL) and AcOH (800 mL) in a 5000-mL round-bottom flask was added NaClO in H ₂ O (13%wt., 1.2 L, 1.78 mol) dropwise at 0 ^° C. The reaction mixture was stirred for 2 h at 0 ^° C. The residue was dissolved in 1.6 L of H2O. The mixture was extracted with 2x2.0 L of DCM. The organic layers were dried over anhydrous Na2SO4 and concentrated under vacuum. This resulted in 36 g (crude) of the title compound as yellow oil.

Step 3: Ethyl 2-sulfamoylthiazole-4-carboxylate

To a stirred solution of ethyl 2-(chlorosulfonyl)thiazole-4-carboxylate (36 g, crude) in DCM (500 mL) in a 1.0-L round-bottom flask was introduced NH ₃ (g) bubbled for 20 min at 0 ^° C. The reaction mixture was stirred for 1 h at 0 ^° C. The mixture was concentrated under vacuum. The residue was eluted from silica gel with DCM/MeOH (10:1). This resulted in 18 g (18%, over two steps) of the title compound as a white solid. MS-ESI: 235 (M-1).

Step 4: 4-(Hydroxymethyl)thiazole-2-sulfonamide

To a stirred solution of ethyl 2-sulfamoylthiazole-4-carboxylate (12 g, 51 mmol) in EtOH (500 mL) in a 1-L round-bottom flask under nitrogen was added NaBH4 (15.5 g, 408 mmol) in portions at 0 ^° C. The reaction mixture was stirred for 4 h at 0 ^° C. The reaction was quenched with 100 mL of water/ice. The reaction mixture was concentrated under vacuum. The pH value of the mixture was adjusted to 5 with HCl (6 M). The mixture was concentrated under vacuum. The solids were dissolved with MeOH (200 mL). The residue was eluted from silica gel with EtOAc (100%). This resulted in 8.0 g (81%) of the title compound as a white solid. MS-ESI: 193 (M-1). Step 5: N-(tert-butyldimethylsilyl)-4-(((tert-butyldimethylsilyl)oxy )methyl)thiazole-2- sulfonamide

To a stirred solution of 4-(hydroxymethyl)thiazole-2-sulfonamide (4.6 g, 24 mmol) in THF (100 mL) in a 250-mL round-bottom flask under nitrogen was added NaH (60% wt. dispersion in mineral oil, 7.68 g, 192 mmol) in several batches at 0 ^° C. The mixture was stirred for 10 min at RT, followed by the addition of TBSCl (10.8 g, 72 mmol) in portions at 0 ^° C. The reaction mixture was stirred for 1 h at RT. The reaction was quenched with ice/water (100 mL). The mixture was extracted with EtOAc (3x100 mL). The organic layers were dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:3). This resulted in 4.5 g (45%) of the title compound as yellow oil. MS-ESI: 421 (M-1). Step 6: N-(tert-butyldimethylsilyl)-4-(((tert-butyldimethylsilyl)oxy )methyl)-5-(2- hydroxypropan-2-yl) thiazole-2-sulfonamide

To a stirred solution of N-(tert-butyldimethylsilyl)-4-(((tert- butyldimethylsilyl)oxy)methyl)thiazole-2- sulfonamide (3.0 g, 7.1 mmol) in THF (20 mL) in a 100-mL 3-necked round-bottom flask under nitrogen was added n-BuLi in hexane (2.5 M, 5.7 mL, 14.2 mmol) dropwise at -78 ^° C. The reaction solution was stirred for 1 h at -78 ^° C. Then to this solution was added acetone (4.2 g, 71 mmol) at -78 ^° C. The reaction mixture was stirred for 1 h at -78 ^° C. The reaction was quenched with 20 mL of water/ice. The mixture was extracted with 3x100 mL of EtOAc. The organic layers was dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (10:1). This resulted in 1.48 g (43%) of the title compound as yellow oil. MS-ESI: 481 (M+1).

Step 7 used similar procedures for converting compound 640” to Intermediate 183 shown in Scheme 128 to afford Intermediate 201 from compound 734”. MS-ESI: 480 (M+1).

Scheme 145:

Intermediate 202

N'-(tert-butyldimethylsilyl)-1-ethyl-1H-pyrazole-3-sulfonimi damide Step 1: 1-Ethyl-3-nitro-1H-pyrazole To a stirred solution of 3-nitro-1H-pyrazole (20 g, 177 mmol) in DMF (100 mL) in a 250-mL round-bottom flask were added K ₂ CO ₃ (49 g, 354 mmol) in portions at RT, followed by the addition of iodoethane (55 g, 354 mmol) dropwise at RT. The reaction mixture was stirred for 16 h at 80 ^° C in an oil bath. The reaction mixture was diluted with 200 mL of H2O. The mixture was extracted with 3x200 mL of EtOAc and the organic layers were combined and dried over anhydrous Na ₂ SO ₄ . The mixture was concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:4). This resulted in 22.6 g (91%) of the title compound as yellow oil. MS-ESI: 142 (M+1). ¹ H NMR (400 MHz, DMSO-d6) d 8.06 (d, J = 2.5 Hz, 1H), 7.04 (d, J = 2.5 Hz, 1H), 4.27 (q, J = 7.3 Hz, 2H), 1.42 (t, J = 7.3 Hz, 3H).

Step 2: 1-Ethyl-1H-pyrazol-3-amine

To a stirred solution of 1-ethyl-3-nitro-1H-pyrazole (22 g, 156 mmol) in MeOH (100 mL) in a 250-mL round-bottom flask under nitrogen was added Pd/C (10% wt., 2.2 g) in portions at 0 ^° C. The flask was evacuated and refilled three times with hydrogen. The reaction mixture was stirred overnight at RT under atmosphere of hydrogen with a balloon. The solids were filtered out. The filtrate was concentrated under vacuum. This resulted in 13.8 g (80%) of the title compound as yellow oil. MS-ESI: 112 (M+1).

Step 3: 1-Ethyl-1H-pyrazole-3-sulfonamide

To a stirred solution of 1-ethyl-1H-pyrazol-3-amine (3.4 g, 31 mmol,) in HCl (6 M, 20 mL) in a 100-mL round-bottom flask was added NaNO ₂ (2.53 g, 37 mmol) in H ₂ O (5.0 mL) dropwise slowly at 0 ^° C over 25 min. The reaction solution was stirred for 40 min at 0 ^° C, this solution was assigned as solution A. Then CuCl ₂ (8.23 g, 61 mmol) was added to a 250-mL single necked round-bottom flask with AcOH (100 mL) as the solvent, SO ₂ (g) was bubbled to the mixture with stirring at 0 ^° C for 20 min, this mixture was assigned as solution B. To the mixture B was added solution A dropwise with stirring at 0 ^° C. The reaction mixture was stirred for additional 2 h at 0 ^° C. The reaction mixture was diluted with 100 mL of H ₂ O. The mixture was extracted with 3x150 mL of DCM. The organic layers were dried over anhydrous Na ₂ SO ₄ and concentrated under vacuum. The residue was dissolved in 30 mL of DCM and NH3 (g) was bubbled for 15 min at 0 ^° C. The reaction was stirred for 2 h at RT. The reaction mixture was concentrated under vacuum. The residue was eluted from silica gel with PE/EtOAc (3:1). This resulted in 1.75 g (33%) of the title compound as a yellow solid. MS-ESI: 174 (M-1). Steps 4-5 used similar procedures for converting compound 639” to Intermediate 183 shown in Scheme 128 to afford Intermediate 202 from compound 738”. MS-ESI: 289 (M+1).

Scheme 146:

Intermediate 203

N'-(tert-butyldimethylsilyl)-5-(2-hydroxypropan-2-yl)-1-isop ropyl-1H-pyrazole-3- sulfonimidamide

Steps 1-2 used similar procedures for converting compound 735” to compound 737” shown in Scheme 145 to afford compound 742” from compound 740”. Compound 742" (5 g) and Compound 742"BP (0.5 g) were separated from silica gel eluted with PE/EtOAc (5:1). MS-ESI: 184 (M+1). The regiochemistry of 742” and 742”BP were assigned based on NMR including NOESY. Compound 742": ¹ H NMR (300 MHz, DMSO-d6) d 5.93 (s, 1H), 5.33-5.10 (m, 1H), 4.83 (s, 2H), 3.77 (s, 3H), 1.31 (d, J = 6.3 Hz, 6H).

NOESY: exchangeable protons NH ₂ 4.83 (s, 2H) has no correlation with i-Pr’s CH at 5.33-5.10 (m, 1H) and O-CH33.77 (s, 3H) has correlation with i-Pr’s CH3 at 1.31 (d, J = 6.3 Hz, 6H). Compound 742"BP: ¹ H NMR (300 MHz, DMSO-d6) d 5.72 (s, 1H), 5.35 (s, 2H), 4.59-4.32 (m, 1H), 3.71 (s, 3H), 1.30 (d, J = 6.6 Hz, 6H).

NOESY: exchangeable protons NH25.35 (s, 2H) has correlation with i-Pr’s CH at 4.59-4.32 (m, 1H) and O-CH33.71 (s, 3H) has no correlation with i-Pr’s CH3 at 1.30 (d, J = 6.6 Hz, 6H).

Steps 3-4 used similar procedures for converting compound 737” to compound 738” shown in Scheme 145 to afford compound 744” from compound 742”. MS-ESI: 246 (M-1).

Step 5: 5-(2-Hydroxypropan-2-yl)-1-isopropyl-1H-pyrazole-3-sulfonami de

To a stirred solution of methyl 1-isopropyl-3-sulfamoyl-1H-pyrazole-5-carboxylate (430 mg, 1.74 mmol) in THF (50 mL) in a 100-mL 3-necked round-bottom flask under nitrogen was added MeMgBr in THF (3.0 M, 3.5 mL, 10 mmol) at 0 ^° C. The reaction mixture was stirred for 16 h at RT. The reaction mixture was quenched with water/ice at 0 ^° C. The pH value of the solution was adjusted to 6 with HCl (6 M). The reaction mixture was extracted with 3x50 mL of EtOAc. The combined organic layers were dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (3:1). This resulted in 400 mg (93%) of the title compound as a yellow solid. MS-ESI: 246 (M-1).

Steps 6-7 used similar procedures for converting compound 639” to Intermediate 183 shown in Scheme 128 to afford Intermediate 203 from compound 745”. MS-ESI: 361 (M+1).

Scheme 147:

Intermediate 204

N'-(tert-butyldimethylsilyl)-6-(2-hydroxypropan-2-yl)pyridin e-2-sulfonimidamide

Step 1: Methyl 6-sulfamoylpicolinate

To a stirred solution of 6-bromopyridine-2-sulfonamide (5.0 g, 21 mmol) in MeOH (200 mL) in 500 mL-sealed tube under nitrogen were added Pd(dppf)Cl ₂ (1.54 g, 2.1 mmol), Pd(PPh ₃ ) ₄ (2.44 g, 2.1 mmol) and TEA (11 g, 105 mmol) at RT. Then the sealed tube was evacuated and refilled three times with CO. The reaction mixture was stirred overnight at 80 ^° C under CO atmosphere (10 atm). The reaction mixture was concentrated under vacuum. The residue was eluted from silica gel with PE/EtOAc (1:2). This resulted in 1.8 g (39%) of the title compound as a light yellow solid. MS-ESI: 215 (M-1).

Steps 2-4 used similar procedures for converting compound 744 to Intermediate 203 shown in Scheme 146 to afford Intermediate 204 from compound 748”. MS-ESI: 330 (M+1).

Scheme 148:

2-Fluoro-N'-( hexahydro-s-indacen-4-yl)carbamoyl)-4-(1-methyl-2,5-dihydro- 1H-

pyrrol-3-yl)benzenesulfonimidamide

Steps 1-3 used similar procedures for converting compound 639” to Intermediate 183 shown in Scheme 128 to afford compound 753” from compound 483”. MS-ESI: 367/369 (M+1).

Step 4: 4-Bromo-N-(tert-butyldimethylsilyl)-2-fluoro-N'-((1,2,3,5,6, 7-hexahydro-s-indacen-

To a stirred solution of 4-bromo-N'-(tert-butyldimethylsilyl)-2-fluorobenzenesulfonim idamide (3.0 g, 8.2 mmol) in THF (50 mL) in a 250-mL round-bottom flask under nitrogen was added NaH (60% wt. dispersion in mineral oil, 1.0 g, 25 mmol) in portions at 0 ^° C. The reaction mixture was stirred for 10 min at RT. Then to the mixture was added 4-isocyanato-1,2,3,5,6,7- hexahydro-s-indacene (1.95 g, 9.8 mmol) in portions at 0 ^° C. The reaction mixture was stirred for 1 h at RT. The reaction mixture was quenched with H ₂ O (50 mL) and then extracted with EtOAc (3x100 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was eluted from silica gel column with EtOAc/PE (1:5). This resulted in 2.8 g (61%) of the title compound as a white solid. MS-ESI: 566/568 (M+1).

Step 5: 4-Bromo-2-fluoro-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)c arbamoyl)

benzenesulfonimidamide

To a stirred solution of 4-bromo-N-(tert-butyldimethylsilyl)-2-fluoro-N'-((1,2,3,5,6, 7-hexahydro- s-indacen -4-yl)carbamoyl)benzenesulfonimidamide (2.8 g, 4.94 mmol) in DCM (100 mL) in a 250-mL round-bottom flask was added TFA (56 mg, 0.49 mmol) at RT. The reaction mixture was stirred for 1 h at RT and then concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:8). This resulted in 1.9 g (85%) of the title compound as a yellow solid. MS-ESI: 452/454 (M+1).

Step 6: 2-Fluoro-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl )-4-(1-methyl-2,5- dihydro-1H- pyrrol-3-yl)benzenesulfonimidamide

To a stirred solution of 4-bromo-2-fluoro-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)c arbamoyl) benzenesulfonimidamide (1.9 g, 4.2 mmol) in dioxane (90 mL) and H2O (10 mL) in a 250-mL round-bottom flask under nitrogen were added K ₃ PO ₄ (1.78 g, 8.4 mmol), Pd(dtbpf)Cl ₂ (274 mg, 0.42 mmol) and 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5 -dihydro-1H- pyrrole (966 mg, 4.62 mmol) at RT. The reaction mixture was stirred for 5 h at 60 ^° C and then concentrated under vacuum. The resulted was dissolved in 100 mL H ₂ O and extracted with EtOAc (3x100 mL). The combined organic layers were dried over Na2SO4 and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:1). This resulted in 100 mg (5.3%) of the title compound as a yellow solid. MS-ESI: 455 (M+1).

Scheme 149:

N'-(tert-butyldimethylsilyl)-4-(1-(dimethylamino)-2-methylpr opan-2- yl)benzenesulfonimidamide

Step 1: 2-Methyl-2-(4-sulfamoylphenyl)propanoic acid

To a stirred solution of ethyl 2-methyl-2-(4-sulfamoylphenyl)propanoate (7.0 g, 26 mmol) in MeOH (140 mL) and H ₂ O (93 mL) in a 500-mL round-bottom flask was added NaOH (10 g, 258 mmol) at 0 ^° C. The reaction mixture was stirred for 90 min at 55 ^° C in an oil bath. The pH value of the mixture was adjusted to 2-3 with HCl (2 M). To the mixture was added additional 200 mL of MeOH. The solids were filtered out. The filtrate was concentrated under vacuum. This resulted in 5.0 g (80%) of the title compound as a white crude solid. MS-ESI: 242 (M-1).

Step 2: N,N,2-trimethyl-2-(4-sulfamoylphenyl)propanamide

To a stirred solution of 2-methyl-2-(4-sulfamoylphenyl)propanoic acid (3.0 g, 12 mmol) in THF (150 mL) in a 250-mL round-bottom flask were added HATU (6.8 g, 18 mmol), DIEA (3.19 g, 25 mmol) and dimethylamine (4.44 g, 99 mmol) at RT. The reaction solution was stirred for 12 h at RT. The resulting solution was concentrated under vacuum. The residue was eluted from silica gel with DCM/MeOH (30:1). This resulted in 2.5 g (75%) of the title compound as a white solid. MS-ESI: 269 (M-1).

Step 3: 4-(1-(Dimethylamino)-2-methylpropan-2-yl)benzenesulfonamide To a stirred solution of N,N,2-trimethyl-2-(4-sulfamoylphenyl)propanamide (2.5 g, 9.25 mmol) in THF (30 mL) in a 250-mL 3-necked round-bottom flask under nitrogen was added DIBAL-H in hexane (1 M, 46 mL, 46.2 mmol) at -10 ^° C. The reaction mixture was stirred for 12 h at RT. The reaction was quenched with 15 mL of MeOH. The reaction mixture was concentrated under vacuum. The residue was diluted with 200 mL of HCl (2 M). The mixture was extracted with 3x200 mL of EtOAc. The combined organic layers were dried over anhydrous Na ₂ SO ₄ and concentrated under vacuum. The residue was eluted from silica gel with DCM/MeOH (10:1). This resulted in 1.50 g (63%) of the title compound as a yellow solid. MS-ESI: 255 (M-1). Steps 4-5 used similar procedures for converting compound 639” to Intermediate 183 shown in Scheme 128 to afford Intermediate 206 from compound 759”. MS-ESI: 370 (M+1).

Scheme 150:

N'-(tert-butyldimethylsilyl)-3-fluoro-5-isopropylpyridine-2- sulfonimidamide Step 1: 2-(Benzylthio)-5-bromo-3-fluoropyridine To a stirred solution of 5-bromo-2,3-difluoropyridine (20 g, 103 mmol) in dioxane (80 mL) in a 500-mL round-bottom flask under nitrogen were added t-BuOK (11.6 g, 103 mmol) in portions at 0 ^° C, followed by phenylmethanethiol (12.8 g, 103 mmol) in portions at RT. The reaction mixture was stirred overnight at 75 ^° C and then quenched with H2O (200 mL). The mixture was extracted with EtOAc (3x200 mL). The organic layers were dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:1). This resulted in 18 g (59%) of the title compound as colorless oil. MS-ESI: 298/300 (M+1).

Step 2: 2-(Benzylthio)-3-fluoro-5-(prop-1-en-2-yl)pyridine

To a stirred solution of 2-(benzylthio)-5-bromo-3-fluoropyridine (18 g, 48 mmol) in dioxane (300 mL) and H ₂ O (60 mL) in a 1-L round-bottom flask under nitrogen were added Cs ₂ CO ₃ (47 g, 145 mmol) and Pd(dppf)Cl2 (5.3 g, 7.2 mmol). Then to the above mixture was added 4,4,5,5- tetramethyl-2-(prop-1-en-2-yl) -1,3,2-dioxaborolane (24 g, 145 mmol) at RT. The reaction mixture was stirred overnight at 90 ^° C. The reaction mixture was extracted with 4x300 mL of EtOAc and the organic layers combined and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:2). This resulted in 10 g (80%) of the title compound as brown oil. MS-ESI: 260 (M+1).

Step 3: 2-(Benzylthio)-3-fluoro-5-isopropylpyridine

To a stirred solution of 2-(benzylthio)-3-fluoro-5-(prop-1-en-2-yl)pyridine (10 g, 39 mmol) in MeOH (20 mL) in a 300-mL sealed tube under nitrogen were added AcOH (1.0 mL) and Pd/C (10%wt., 2.1 g) at RT. The sealed tube was evacuated and refilled three times with hydrogen. The resulting mixture was stirred for 24 h at 40 ^° C under atmosphere of hydrogen with a balloon. The solids were filtered out. The filtrate was concentrated under vacuum. This resulted in 5.0 g (49%) of the title compound as brown oil. MS-ESI: 262 (M+1).

Step 4: 3-Fluoro-5-isopropylpyridine-2-sulfonamide

To a stirred solution of 2-(benzylthio)-3-fluoro-5-isopropylpyridine (500 mg, 1.9 mmol) in DCM (20 mL) and AcOH (20.00 mL) and H ₂ O (20 mL) in a 250-mL 3-necked round-bottom flask was introduced Cl2 bubbled for 30 min at 0 ^° C. The mixture was extracted with DCM (3x40 mL). The combined organic layers were washed with brine (3x100 mL). The organic layer was dried over anhydrous Na ₂ SO ₄ . Then the solids were filtered out, NH ₃ (g) was bubbled into the filtrate for 20 min at 0 ^° C. The reaction mixture was stirred overnight at RT. The mixture was concentrated under vacuum. The residue was eluted from silica gel with EtOAc (100%). This resulted in 50 mg (12%) of the title compound as yellow oil. MS-ESI: 217 (M-1).

Steps 5-6 used similar procedures for converting compound 639” to Intermediate 183 shown in Scheme 128 to afford Intermediate 207 from compound 765”. MS-ESI: 332 (M+1).

Scheme 151:

N'-(tert-butyldimethylsilyl)-2-fluoro-4-(1-methylpiperidin-3 -yl)benzenesulfonimidamide Steps 1-2 used similar procedures for converting compound 762” to compound 764” shown in Scheme 150 to afford compound 769” from compound 767”. MS-ESI: 357 (M-1).

Step 3: 2-Fluoro-4-(piperidin-3-yl)benzenesulfonamide

To a stirred solution of tert-butyl 3-(3-fluoro-4-sulfamoylphenyl)piperidine-1-carboxylate (500 mg, 1.4 mmol) in DCM (5.0 mL) in a 25-mL round-bottom flask was added HCl in dioxane (4 M, 3.5 mL, 14 mmol) dropwise at RT. The reaction mixture was stirred for 2 h at RT and then diluted with 5.0 mL of water. The mixture was extracted with 3x10 mL of DCM. The organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated under vacuum. This resulted in 400 mg (crude) of the title compound as a yellow solid. MS-ESI: 257 (M-1).

Step 4: 2-Fluoro-4-(1-methylpiperidin-3-yl)benzenesulfonamide

To a stirred solution of 2-fluoro-4-(piperidin-3-yl)benzenesulfonamide (400 mg, crude) in MeOH (5.0 mL) in a 25-mL round-bottom flask under nitrogen was added HCHO (269 mg, 8.4 mmol) in portions at RT. The resulting solution was stirred overnight at RT. Then to the solution was added NaBH ₃ CN (173 mg, 2.8 mmol) at RT. The reaction mixture was stirred for 2 h at RT. The mixture was concentrated under vacuum. The reaction was quenched with H ₂ O (10 mL). The mixture was extracted with EtOAc (3x20 mL). The organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated under vacuum. The residue was eluted from silica gel with

DCM/MeOH (10:1). This resulted in 300 mg (79%) of the title compound as a yellow solid. MS- ESI: 271 (M-1).

Steps 5-6 used similar procedures for converting compound 639” to Intermediate 183 shown in Scheme 128 to afford Intermediate 208 from compound 771”. MS-ESI: 386 (M+1).

Scheme 152:

Intermediate 209 N'-(tert-butyldimethylsilyl)-3-fluoro-5-methyl-4,5,6,7-tetra hydrothieno[3,2-c]pyridine-2- sulfonimidamide

Steps 1-2 used similar procedures for converting compound 642” to compound 644” shown in Scheme 129 to afford compound 775” from compound 773”. MS-ESI: 375 (M+1).

Step 3: Tert-butyl 2-(N-(tert-butyl)sulfamoyl)-3-fluoro-6,7-dihydrothieno[3,2-c ]pyridine- 5(4H)- carboxylate

To a stirred solution of tert-butyl 2-(N-(tert-butyl)sulfamoyl)-6,7-dihydrothieno[3,2-c]pyridine - 5(4H)- carboxylate (4.0 g, 10.7 mmol) in THF (40 mL) in a 250-mL 3-necked round-bottom flask under nitrogen was added n-BuLi in hexane (2.5 M, 13 mL, 32 mmol) dropwise at -78 ^° C. The reaction mixture was stirred for 30 min at -78 ^° C. Then to the reaction solution was added NFSI (6.74 g, 21.4 mmol) in THF (10 mL) dropwise at -78 ^° C. The reaction mixture was stirred for 2 h at RT and then quenched with H ₂ O (40 mL). The mixture was extracted with EtOAc (3x100 mL) and the organic layers were combined, dried over anhydrous Na2SO4, and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:1). This resulted in 1.7 g (41%) of the title compound as yellow oil. MS-ESI: 392 (M+1).

Step 4: N-(tert-butyl)-3-fluoro-4,5,6,7-tetrahydrothieno[3,2-c]pyrid ine-2-sulfonamide To a stirred solution of tert-butyl 2-(N-(tert-butyl)sulfamoyl)-3-fluoro-6,7-dihydrothieno[3,2- c]pyridine -5(4H)-carboxylate (300 mg, 0.76 mmol) in DCM (5.0 mL) in a 25-mL round-bottom flask was added HCl in dioxane (4 M, 0.75 mL) dropwise at RT. The reaction mixture was stirred for 1 h at RT. The reaction mixture was concentrated under vacuum. This resulted in 200 mg (89%) of the title compound as yellow oil. MS-ESI: 293 (M+1).

Step 5: N-(tert-butyl)-3-fluoro-5-methyl-4,5,6,7-tetrahydrothieno[3, 2-c]pyridine-2- sulfonamide

To a stirred solution of N-(tert-butyl)-3-fluoro-4,5,6,7-tetrahydrothieno[3,2-c]pyrid ine-2- sulfonamide (200 mg, 0.68 mmol) in MeOH (2.0 mL) in a 25-mL round-bottom flask under nitrogen was added HCHO (31 mg, 1.03 mmol) in portions. The reaction mixture was stirred for 1 h at RT. To above mixture was added NaBH ₃ CN (64 mg, 1.03 mmol) in portions at RT. The reaction mixture was stirred for 2 h at RT. The reaction mixture was concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:1). This resulted in 200 mg (95%) of the title compound as yellow oil. MS-ESI: 307 (M+1).

Step 6 used similar procedures for converting compound 703” to compound 704” shown in Scheme 139 to afford compound 779” from compound 778”. MS-ESI: 249 (M-1).

Steps 7-8 used similar procedures for converting compound 639” to Intermediate 183 shown in Scheme 128 to afford Intermediate 209 from compound 779”. MS-ESI: 364 (M+1).

Scheme 153:

T ^BS _N

Tert-butyl 2-(N-(tert-butyldimethylsilyl)sulfamidimidoyl)-3-fluoro-6,7- dihydrothieno[3,2- c]pyridine-5(4H)-carboxylate

Steps 1-4 used similar procedures for converting compound 688” to Intermediate 192 shown in Scheme 136 to afford Intermediate 210 from compound 776”. MS-ESI: 450 (M+1).

Scheme 154:

N-(tert-butyldimethylsilyl)-5,6-dimethyl-5,6-dihydro-4H-thie no[3,4-c]pyrrole-1- sulfonimidamide

Step 1: Methyl 4-(1-acetamidovinyl)thiophene-3-carboxylate

To a stirred solution of methyl 4-bromothiophene-3-carboxylate (10 g, 45 mmol) in DMF (100 mL) in a 250-mL round-bottom flask under nitrogen were added tris(2- methoxyphenyl)phosphine (3.19 g, 9.05 mmol) and N-vinylacetamide (2.24 g, 226 mmol) at RT. To the above mixture were added Pd(AcO) ₂ (1.02 g, 4.5 mmol) and TEA (6.0 mL, 43 mmol) at RT. Then the reaction mixture was stirred overnight at 80 ^° C. The reaction mixture was quenched with H2O (100 mL). The mixture was extracted with EtOAc (3x200 mL) and the organic layers were combined. The organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated under vacuum. The residue was eluted from silica gel with PE/EtOAc (1:1). This resulted in 6.0 g (60%) of the title compound as yellow liquid. MS-ESI: 226 (M+1).

Step 2: Methyl 4-(1-acetamidoethyl)thiophene-3-carboxylate To a stirred solution of methyl 4-(1-acetamidovinyl)thiophene-3-carboxylate (5.0 g, 22 mmol) in MeOH (100 mL) in a 250-mL round-bottom flask under nitrogen was added Pd/C (10% wt., 500 mg) in portions at 0 ^° C. The flask was evacuated and refilled three times with hydrogen. The reaction mixture was stirred for 2 days at RT under atmosphere of hydrogen with a balloon. The reaction mixture was filtered and the filter cake was washed with MeOH (3x10 mL). The filtrate was concentrated under reduced pressure. The residue was eluted from silica gel with PE/EtOAc (1:1). This resulted in 3.3 g (66%) of the title compound as a yellow solid. MS-ESI: 228 (M+1). Step 3: 4-(1-Acetamidoethyl)thiophene-3-carboxylic acid

A solution of methyl 4-(1-acetamidoethyl)thiophene-3-carboxylate (3.2 g, 14 mmol) in HCl (2 M, 30 mL) in a 100-mL round-bottom flask under nitrogen was stirred overnight at 100 ^° C. The resulting mixture was concentrated under vacuum. This resulted in 3.0 g (crude) of the title compound as a brown solid. MS-ESI: 212 (M-1).

Step 4: 6-Methyl-5,6-dihydro-4H-thieno[3,4-c]pyrrol-4-one

To a stirred solution of 4-(1-acetamidoethyl)thiophene-3-carboxylic acid (3.0 g, crude) in DCM (200 mL) were added HATU (8.02 g, 21 mmol) and TEA (4.27 g, 42 mmol) in portions at RT. The reaction mixture was stirred overnight at RT. The reaction mixture was concentrated under vacuum. The residue was eluted from silica gel with PE/EtOAc (1:1). This resulted in 1.9 g (88%, over two steps) of the title compound as a light yellow solid. MS-ESI: 154 (M+1).

Step 5 used similar procedures for converting compound 770” to compound 771” shown in Scheme 151 to afford compound 789” from compound 788”. MS-ESI: 168 (M+1).

Steps 6-7 used similar procedures for converting compound 672” to compound 674” shown in Scheme 134 to afford compound 791” from compound 789”. MS-ESI: 245 (M-1).

Step 8: 5,6-Dimethyl-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-sulfonami de

To a stirred solution of 5,6-dimethyl-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-sul fonamide (486 mg, 1.97 mmol) in THF (5.0 mL) under nitrogen was added LiAlH ₄ (225 mg, 5.91 mmol) in portions at 0 ^° C. The reaction mixture was stirred overnight at 70 ^° C. The reaction mixture was quenched with H2O (0.3 mL) and aq. NaOH (25% wt., 0.3 mL) at 0 ^° C. The mixture was concentrated under vacuum. The residue was eluted from silica gel with DCM/MeOH (12:1). This resulted in 300 mg (65%) of the title compound as yellow oil. MS-ESI: 231 (M-1). Steps 9-10 used similar procedures for converting compound 639” to Intermediate 183 shown in Scheme 128 to afford Intermediate 211 from compound 792”. MS-ESI: 346 (M+1).

Scheme 155:

Intermediate 212

N'-(tert-butyldimethylsilyl)-3-fluoro-6,7-dihydro-4H-thieno[ 3,2-c]pyran-2-sulfonimidamide Step 1: 4-Fluorothiophene-2-carbaldehyde

To a stirred solution of (4-fluorothiophen-2-yl)methanol (7.5 g, 56.8 mmol) in DCM (300 mL) in a 1 L round-bottom flask under nitrogen was added Dess-Martin reagent (48 g, 113 mmol) in portions at 0 ^° C. The reaction mixture was stirred for 1 h at RT and then quenched with sat. aq. Na2S2O3 (200 mL). The mixture was extracted with DCM (3x200 mL) and the organic layer combined. The organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was eluted from silica gel with PE/EtOAc (1:1). This resulted in 6.75 g (91%) of the title compound as yellow oil. MS-ESI: 131 (M+1).

Step 2: (E)-4-fluoro-2-(2-methoxyvinyl)thiophene

To a stirred solution of 4-fluorothiophene-2-carbaldehyde (5.0 g, 38.4 mmol) in THF (300 mL) in a 1 L round-bottom flask under nitrogen were added (methoxymethyl)triphenylphosphanium chloride (20 g, 58 mmol) in portions at 0 ^° C, followed by the addition of t-BuOK (6.47 g, 58 mmol) in portions at 0 ^° C. The reaction mixture was stirred for 4 h at 15 ^° C, quenched with H2O (200 mL), and extracted with EtOAc (3x200 mL). The combined organic layers were dried over anhydrous Na ₂ SO ₄ and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:9). This resulted in 5.0 g (82%) of the title compound as brown oil. MS-ESI: 159 (M+1).

Step 3: 2-(4-Fluorothiophen-2-yl)acetaldehyde

To a stirred solution of (E)-4-fluoro-2-(2-methoxyvinyl)thiophene (5.0 g, 32 mmol) in dioxane (36 mL) in a 250 mL round-bottom flask was added aq. HCl (4 M, 36 mL) at 0 ^° C. The reaction mixture was stirred for 4 h at 15 ^° C. The mixture was extracted with EtOAc (3x100 mL) and the organic layers were combined and concentrated under vacuum. This resulted in 1.5 g (33%) of the title compound as brown oil. MS-ESI: 145 (M+1).

Step 4 used similar procedures for converting compound 731” to compound 732” shown in Scheme 144 to afford compound 797” from compound 796”. MS-ESI: 147 (M+1).

Step 5: 3-Fluoro-6,7-dihydro-4H-thieno[3,2-c]pyran

To a stirred solution of 2-(4-fluorothiophen-2-yl)ethan-1-ol (300 mg, 2.05 mmol) in ACN (30 mL) in a 100-mL round-bottom flask were added InCl ₃ (902 mg, 4.1 mmol) at RT, followed by the addition of paraformaldehyde (131 mg, 4.1 mmol) in portions at RT. The reaction mixture was stirred overnight at 70 ^° C. The reaction mixture was quenched with H2O (30 mL) and extracted with EtOAc (3x50 mL). The combined organic layers were combined and dried over anhydrous Na ₂ SO ₄ and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (8:92). This resulted in 240 mg (74%) of the title compound as colorless oil. MS-ESI: 159 (M+1).

Step 6: 3-Fluoro-6,7-dihydro-4H-thieno[3,2-c]pyran-2-sulfonyl chloride To a stirred solution of 3-fluoro-6,7-dihydro-4H-thieno[3,2-c]pyran (300 mg, 1.9 mmol) in 1,2- dichloroethane (50 mL) in a 100-mL round-bottom flask was added sulfur trioxide DMF complex (349 mg, 2.28 mmol) in portions at RT. The reaction mixture was stirred for 30 min at RT. To above mixture was added SOCl2 (271 mg, 2.3 mmol) dropwise at 0 ^° C. The reaction mixture was stirred overnight at 50 ^° C and then concentrated under vacuum. This resulted in 260 mg (crude) of the title compound as a yellow solid.

Step 7: 3-Fluoro-6,7-dihydro-4H-thieno[3,2-c]pyran-2-sulfonamide

To a stirred solution of 3-fluoro-6,7-dihydro-4H-thieno[3,2-c]pyran-2-sulfonyl chloride (260 mg, crude) in DCM (10 mL) in a 50-mL round-bottom flask was introduced NH ₃ (g) bubbled for 10 min at 0 ^° C. The reaction mixture was stirred for 2 h at 15 ^° C. The reaction mixture was quenched with H2O (10 mL). The mixture was extracted with DCM (3x10 mL) and the organic layers were combined and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:2). This resulted in 200 mg (44%, over two steps) of the title compound as a yellow solid. MS-ESI: 236 (M-1).

Steps 8-9 used similar procedures for converting compound 639” to Intermediate 183 shown in Scheme 128 to afford Intermediate 212 from compound 800”. MS-ESI: 351 (M+1).

Scheme 156:

Intermediate 213

N'-(tert-butyldimethylsilyl)-1-(difluoromethyl)-4-fluoro-1H- pyrazole-3-sulfonimidamide Step 1: 4-Fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole

To a stirred solution of 4-fluoro-1H-pyrazole (10 g, 116 mmol) in DMF (100 mL) under nitrogen was added NaH (60% wt., dispersion in mineral oil, 10.7 g, 267 mmol) at 0 ^° C over 10 min. The reaction mixture was stirred for 30 min at 10 ^° C. To this mixture was added SEM-Cl (45 g, 267 mmol) dropwise at 0 ^° C over 10 min. The reaction mixture was stirred overnight at 7 ^° C. The reaction was quenched with 100 mL of water, extracted with 3x100 mL of EtOAc. The organic layers were combined, washed with 5x100 mL of brine, dried over anhydrous Na2SO4, and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:100). This resulted in 27.4 g (crude) of the title compound as a light yellow liquid. MS-ESI: 217 (M+1). Steps 2-3 used similar procedures for converting compound 719” to compound 720” shown in Scheme 141 to afford compound 805” from compound 803”.

Step 4: N,N-dibenzyl-4-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1 H-pyrazole-5- sulfonamide

To a stirred solution of 4-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5- sulfonyl chloride (20.4 g, 65 mmol) in DCM (200 mL) was added Et ₃ N (8.85 g, 87 mmol) dropwise with stirring at 0 ^° C over 5 min. To this mixture was added dibenzylamine (17 g, 84 mmol) dropwise with stirring at 0 ^° C over 5 min. The reaction mixture was stirred for 1 h at 8 ^° C. The reaction was quenched with 300 mL of water. The mixture was extracted with 3x300 mL of DCM and the organic layers were combined. The organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:19). This resulted in 22.5 g (73%) of the title compound as light yellow oil. MS-ESI: 346 (M+1).

Step 5: N,N-dibenzyl-4-fluoro-1-(hydroxymethyl)-1H-pyrazole-5-sulfon amide To a stirred solution of N,N-dibenzyl-4-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1 H- pyrazole-5- sulfonamide (22.5 g, 47.3 mmol) in DCM (25 mL) was added TFA (25 mL) dropwise at RT. The reaction mixture was stirred overnight at RT and then concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:4). This resulted in 15 g (84%) of the title compound as yellow oil. MS-ESI: 376 (M+1).

Step 6: N,N-dibenzyl-4-fluoro-1H-pyrazole-5-sulfonamide

To a stirred solution of N,N-dibenzyl-4-fluoro-1-(hydroxymethyl)-1H-pyrazole-5-sulfon amide (15 g, 40 mmol) in dioxane (50 mL) was added NH ^.

3H2O (30% wt., 50 mL) dropwise at RT. The reaction mixture was stirred for 3 h at RT and then concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:1). This resulted in 12 g (87%) of the title compound as a white solid. MS-ESI: 346 (M+1).

Step 7: N,N-dibenzyl-1-(difluoromethyl)-4-fluoro-1H-pyrazole-3-sulfo namide

To a stirred solution of N,N-dibenzyl-4-fluoro-1H-pyrazole-5-sulfonamide (6.6 g, 19 mmol) in DMF (100 mL) were added Cs2CO3 (18.7 g, 57 mmol) in portions at RT, followed by the addition of sodium 2-chloro-2,2-difluoroacetate (4.38 g, 29 mmol) in portions at RT. The reaction mixture was stirred for 3 h at 110 ^° C. The reaction mixture was quenched with 100 mL of water/ice at 0 ^° C. The mixture was extracted with 3x100 mL of EtOAc and the organic layers were combined. The organic layer was washed with 5x100 ml of brine, dried over anhydrous Na ₂ SO ₄ , and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:5). This resulted in 2.98 g (39%) of the title compound as a white solid. MS-ESI: 396 (M+1). Step 8: 1-(Difluoromethyl)-4-fluoro-1H-pyrazole-3-sulfonamide

To a stirred solution of N,N-dibenzyl-1-(difluoromethyl)-4-fluoro-1H-pyrazole-3-sulfo namide (2.97 g, 7.5 mmol) in DCM (30 mL) was added cc.H ₂ SO ₄ (98% wt., 30 mL) dropwise at 0 ^° C. The reaction mixture was stirred for 90 min at RT. The reaction mixture was quenched with 20 mL of water/ice. The pH value of the solution was adjusted to 7 with NaOH (5 M). The mixture was extracted with EtOAc (3x100 mL). The organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated under vacuum. The residue was eluted from silica gel with DCM/MeOH (15:1). This resulted in 1.31 g (81%) of the title compound as a white solid. MS-ESI: 214 (M-1). Steps 9-10 used similar procedures for converting compound 639” to Intermediate 183 shown in Scheme 128 to afford Intermediate 213 from compound 810”. MS-ESI: 329 (M+1).

Scheme 157:

Tert-butyl 2-(N'-(tert-butyldimethylsilyl)sulfamidimidoyl)-4-(difluorom ethyl)-6,7- dihydrothieno[3,2-c]pyridine-5(4H)-carboxylate

Step 1: 4-(Difluoromethyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine

To a stirred solution of 2-(thiophen-2-yl)ethan-1-amine (5.00 g, 39.3 mmol) in HCl (6 M, 40 mL) and water (40 mL) was added 1-ethoxy-2,2-difluoroethan-1-ol (5.45 g, 43.2 mmol) dropwise at RT. The reaction mixture was stirred for 12 h at RT and then diluted with 30 mL of water. The pH value of the solution was adjusted to 7 with NaOH (2 M). The resulting solution was extracted with 3x200 mL of EtOAc; the combined organic layers were dried over anhydrous Na ₂ SO ₄ and concentrated under vacuum. This resulted in 3 g (40.3%) of the title compound as yellow oil. MS-ESI: 190 (M+1).

Step 2: Tert-butyl 4-(difluoromethyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-ca rboxylate To a stirred solution of 4-(difluoromethyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (2.00 g, 10.6 mmol) in DCM (20 mL) was added TEA (2.14 g, 21.2 mmol) at RT, followed by the addition of (Boc)2O (3.46 g, 15.9 mmol) in 10 mL DCM dropwise at RT. The resulting solution was stirred for 2 h at RT. The reaction was quenched with water 30 mL, and then extracted with EtOAc (3x50 mL). The combined organic layers were dried over anhydrous Na ₂ SO ₄ and concentrated under vacuum. The residue was eluted from a silica gel column with EtOAc/PE (1:10). This resulted in 2.20 g (71.9%) of the title compound as yellow oil. MS-ESI: 290 (M+1).

Step 3: Tert-butyl 4-(difluoromethyl)-2-sulfamoyl-6,7-dihydrothieno[3,2-c]pyrid ine-5(4H)- carboxylate

To a stirred solution of tert-butyl 4-(difluoromethyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)- carboxylate (2.20 g, 7.60 mmol) in THF (20 mL) under nitrogen was added n-BuLi (2.5 M in hexane, 6.1 mL, 15.2 mmol) dropwise at -78 ^° C and stirred for 30 min at -78 ^° C. To the above solution was bubbled SO2 (g) for 15 min at -50 ^° C. The reaction mixture was stirred for 1 h at RT, and then concentrated under vacuum. To the above residue was added DCM (20 mL), followed by NCS (1.52 g, 11.4 mmol) in small portions at 0 ^° C. The reaction mixture was stirred for 1 h, and then NH3 (g) was bubbled for 15 min at 0 ^° C. The resulting mixture was further stirred for 2 h at RT. The reaction was quenched with water (50 mL) and extracted with DCM (3x100 mL). The combined organic layers were dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions: Column, XBridge Shield RP18 OBD, 30*150 mm, 5 um; mobile phase, Water (10 mM NH ₄ HCO ₃ +0.1%NH ^.

3H ₂ O) and ACN (35% to 40% Phase B over 7 min); Detector, UV 254 nm. This resulted in 500 mg (19.6%) of the title compound as a yellow solid. MS-ESI: 369 (M+1).

Steps 4-5 used similar procedures for converting compound 639” to Intermediate 183 shown in Scheme 128 to afford Intermediate 214 from compound 815”. MS-ESI: 482 (M+1). Step 6: (S) and (R) tert-butyl 4-(difluoromethyl)-2-sulfamoyl-6,7-dihydrothieno[3,2- c]pyridine-5(4H)-carboxylate

Compound 815’’ (120 mg) was resolved by chiral prep-HPLC using the following conditions: Column CHIRALPAK IA, 3*25 cm, 5 um; Mobile Phase A: Hex (8 mM NH ^.

3MeOH), Mobile Phase B: EtOH; Flow rate: 40 mL/min; Gradient: 30% B to 30% B over 12 min; 254/220 nm; RT1: 7.85 min (Compound 815F’’); RT2: 9.3 min (Compound 815S’’). This resulted in 25.5 mg of Compound 815F’’ and 27.0 mg of Compound 815S’’; both as white solid. MS-ESI: 369 (M+1). The stereochemistry assignments of 815F’’ and 815F’’ are arbitrary.

Table 74 The intermediates in the following table were prepared using the similar procedures for converting compound 815” to Intermediate 214 shown in Scheme 157 starting from 815F’’ and 815S’’..

Scheme 158:

Tert-butyl ((5-(N'-(tert-butyldimethylsilyl)sulfamidimidoyl)-4-fluoroth iophen-3- yl)methyl)(methyl)carbamate

Step 1: 2-Chlorothiophene-3-carbonyl chloride

To a stirred solution of 2-chlorothiophene-3-carboxylic acid (5.00 g, 30.9 mmol) in DCM (300 mL) under nitrogen was added SOCl ₂ (12.3 g, 104 mmol) dropwise at 0 ^° C. The resulting solution was stirred for 1 h at RT. The resulting mixture was concentrated under vacuum. This resulted in 5.00 g (crude) of the title compound as a yellow solid.

Step 2: 2-Chloro-N-methylthiophene-3-carboxamide To a stirred solution of methanamine (2 M in THF, 150 mL, 300 mmol) under nitrogen was added 2-chlorothiophene-3-carbonyl chloride (5.00 g, crude from last step) in THF (10 mL) dropwise at 0 ^° C. The resulting solution was stirred for 16 h at RT. The resulting mixture was concentrated under vacuum. The residue was eluted from a silica gel column with EtOAc/PE (1:1). This resulted in 3 g (55.6% over 2 steps) of the title compound as a white solid. MS-ESI: 176/178 (M+1).

Step 3: 1-(2-Chlorothiophen-3-yl)-N-methylmethanamine

To a stirred solution of 2-chloro-N-methylthiophene-3-carboxamide (3.00 g, 17.1 mmol) in THF (150 mL) under nitrogen was added BH ₃ -THF (1 M, 34.2 mL, 34.2 mmol) dropwise at 0 ^° C. The resulting solution was stirred for 16 h at RT, then quenched with 10 mL of MeOH. The resulting mixture was concentrated. The residue was eluted from a silica gel column with EtOAc/PE (1:1). This resulted in 2.0 g (72.5%) of the title compound as a white solid. MS-ESI: 162/164 (M+1). Step 4: Tert-butyl ((2-chlorothiophen-3-yl)methyl)(methyl)carbamate

To a stirred solution of 1-(2-chlorothiophen-3-yl)-N-methylmethanamine (2.00 g, 12.4 mmol) in dioxane (100 mL) and water (10 mL) under nitrogen was added NaHCO3 (3.12 g, 37.1 mmol) in portions at RT, followed by the addition of (Boc) ₂ O (4.05 g, 18.6 mmol) in dioxane (10 mL) dropwise at RT. The resulting solution was stirred for 16 h at RT. The resulting mixture was diluted with 50 ml of water, and extracted with 3x50 mL of DCM. The combined organic layers were dried over anhydrous Na ₂ SO ₄ . The resulting mixture was concentrated under vacuum. The residue was eluted from a silica gel column with EtOAc/PE (1:1). This resulted in 2.5 g (77.2%) of the title compound as a white solid. MS-ESI: 262/264 (M+1).

Step 5: Tert-butyl ((2-chloro-5-(chlorosulfonyl)thiophen-3-yl)methyl)(methyl)ca rbamate To a stirred solution of tert-butyl ((2-chlorothiophen-3-yl)methyl)(methyl)carbamate (2.50 g, 9.58 mmol) in THF (100 mL) under nitrogen was added n-BuLi (2.5 M in hexane, 9.60 mL, 24.0 mmol) dropwise at -78 ^° C, the resulting solution was stirred for 1 h at -78 ^° C. To the above solution was bubbled SO ₂ (g) at -50 ^° C for 15 min. The resulting solution was stirred for 1 h at RT. The resulting mixture was concentrated under vacuum. To the above residue was added DCM (50 mL), followed was added NCS (2.55 g, 19.2 mmol) in small portions at 0 ^° C. The resulting mixture was stirred for 2 h at RT, then concentrated under vacuum. This resulted in 3.00 g (crude) of the title compound as a yellow solid. This compound was monitored by LC-MS after adding 7 M MeOH/NH ₃ to an aliquot of the reaction mixture, MS-ESI: 341/343 (M+1). Step 6: Tert-butyl ((5-(N-(tert-butyl)sulfamoyl)-2-chlorothiophen-3- yl)methyl)(methyl)carbamate

To a stirred solution of tert-butyl ((2-chloro-5-(chlorosulfonyl)thiophen-3- yl)methyl)(methyl)carbamate (3.00 g, crude from last step) in DCM (100 mL) under nitrogen was added t-BuNH2 (1.02 g, 13.8 mmol) dropwise at 0 ^° C. The resulting solution was stirred for 16 h at RT. The resulting mixture was diluted with 100 mL of water and extracted with 3x100 mL of DCM. The combined organic layers were dried over anhydrous Na ₂ SO ₄ . The resulting mixture was concentrated under vacuum. The residue was eluted from a silica gel column with EtOAc/PE (1:1). This resulted in 1.80 g (45.3% over 2 steps) of the title compound as a white solid. MS-ESI: 397/399 (M+1).

Step 7: Tert-butyl ((5-(N-(tert-butyl)sulfamoyl)-2-chloro-4-fluorothiophen-3- yl)methyl)(methyl)carbamate

To a stirred solution of tert-butyl ((5-(N-(tert-butyl)sulfamoyl)-2-chlorothiophen-3- yl)methyl)(methyl)- carbamate (1.80 g, 4.55 mmol) in THF (100 mL) under nitrogen was added n-BuLi (2.5 M in hexane, 3.64 mL, 9.10 mmol) dropwise at -78 ^° C. The resulting solution was stirred for 1 h at -78 ^° C. NFSI (2.87 g, 9.10 mmol) in THF (15 mL) was added dropwise at -78 ^° C under nitrogen. The resulting solution was stirred for 16 h at RT. The reaction mixture was quenched with 20 mL of water, extracted with 3x100 mL of EtOAc. The combined organic layers were dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:1). This resulted in 1.2 g (63.8%) of the title compound as a white solid. MS-ESI: 415/417 (M+1).

Step 8: Tert-butyl ((5-(N-(tert-butyl)sulfamoyl)-4-fluorothiophen-3- yl)methyl)(methyl)carbamate

To a stirred solution of tert-butyl ((5-(N-(tert-butyl)sulfamoyl)-2-chloro-4-fluorothiophen-3- yl)methyl)- (methyl)carbamate (1.2 g, 2.90 mmol) in MeOH (100 mL) under nitrogen was added Pd/C (10%wt., 240 mg) in portions at RT. The flask was evacuated and flushed with hydrogen 3 times. The resulting solution was stirred 16 h at RT under hydrogen with a balloon. The Pd/C catalysts were filtered out, the filtrate was concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:1). This resulted in 700 mg (63.6%) of the title compound as a white solid. MS-ESI: 381 (M+1).

Step 9: 3-Fluoro-4-((methylamino)methyl)thiophene-2-sulfonamide

To a stirred solution of tert-butyl ((5-(N-(tert-butyl)sulfamoyl)-4-fluorothiophen-3- yl)methyl)(methyl)- carbamate (700 mg, 1.84 mmol) in DCM (10 mL) was added BCl ₃ (1M in DCM, 5 mL, 5 mmol) dropwise at 0 ^° C. The resulting solution was stirred for 16 h at RT. The reaction was then quenched by the addition of 10 mL of MeOH and concentrated under vacuum. This resulted in 450 mg (crude) of the title compound as yellow oil which was used in next step without further purification. MS-ESI: 225 (M+1).

Step 10: Tert-butyl ((4-fluoro-5-sulfamoylthiophen-3-yl)methyl)(methyl)carbamate

To a stirred solution of 3-fluoro-4-((methylamino)methyl)thiophene-2-sulfonamide (450 mg, crude from last step) in DCM (10 mL) was added TEA (362 mg, 3.58 mmol), followed by (Boc)2O (781 mg, 3.58 mmol) in DCM (5 mL) dropwise at RT. The resulting solution was stirred for 16 h at RT. The resulting solution was extracted with 3x100 mL of EtOAc and the organic layers were combined, dried over anhydrous Na ₂ SO ₄ , and concentrated under vacuum. The residue was purified by Prep-TLC (PE/EtOAc 1:1). This resulted in 500 mg (83.7% over 2 steps) of the title compound as yellow oil. MS-ESI: 325 (M+1).

Steps 11-12 used similar procedures for converting compound 639” to Intermediate 183 shown in Scheme 128 to afford Intermediate 215 from compound 827”. MS-ESI: 438 (M+1).

Scheme 159:

Tert-butyl (2-(N'-(tert-butyldimethylsilyl)sulfamidimidoyl)-4,5,6,7-tet rahydrobenzo[b]thiophen- 6-yl)(methyl)carbamate

Step 1: Ethyl (E)-4-(thiophen-3-yl)but-2-enoate

To a stirred solution of 2-(thiophen-3-yl)acetaldehyde (5.00 g, 39.7 mmol) in THF (100 mL) under nitrogen was added ethyl 2-(triphenyl- ^ ⁵ -phosphaneylidene)acetate (13.8 g, 39.7 mmol) in THF (10 mL) dropwise at 0 ^° C. The resulting solution was stirred for 3 h at RT. The resulting solution was extracted with 5x100 mL of EtOAc and the organic layers combined and dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:4). This resulted in 4.25 g (54.6%) of the title compound as yellow oil. GC-MS-EI: 196 (M).

Step 2: Ethyl 4-(thiophen-3-yl)butanoate

To a stirred solution of ethyl (E)-4-(thiophen-3-yl)but-2-enoate (3.00 g, 15.3 mmol) in MeOH (50 mL) under nitrogen was added Pd/C (10%wt., 240 mg) in portions at RT. The flask was evacuated and flushed with hydrogen 3 times. The resulting solution was stirred 16 h at RT under hydrogen with a balloon. The Pd/C catalysts were filtered out, the filtrate was concentrated under vacuum. The residue was eluted from a silica gel column with EtOAc/PE (1:4). This resulted in 2.15 g (71.0%) of the title compound as yellow oil. GC-MS-EI: 198 (M).

Step 3: 4-(Thiophen-3-yl)butanoic acid

To a stirred solution of ethyl 4-(thiophen-3-yl)butanoate (5.00 g, 25.3 mmol) in MeOH (50 mL) was added aq. NaOH (4 M, 30 mL) dropwise at 0 ^° C. The resulting mixture was stirred for 16 h at RT. The pH value of the mixture was adjusted to 5 with HCl (6 M). The mixture was extracted with EtOAc (3x300 mL). The organic layers were combined and dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was eluted from silica gel with PE/EtOAc (1:1). This resulted in (4.08 g, 95%) of the title compound as yellow oil. MS-ESI: 169 (M-1).

Step 4: 4-(Thiophen-3-yl)butanoyl chloride

To a stirred solution of 4-(thiophen-3-yl)butanoic acid (4.70 g, 27.6 mmol) in DCM (60 mL) and DMF (cat., 0.1 mL) under nitrogen was added oxalyl chloride (6.96 g, 55.2 mmol) dropwise at 0 ^° C. The resulting mixture was stirred for 2 h at RT. The resulting mixture was concentrated under vacuum. The crude product was used in next step without further purification. This compound was monitored by LC-MS after adding 7M MeOH/NH ₃ to an aliquot of the reaction mixture MS- ESI: 170 (M+1).

Step 5: 5,6-Dihydrobenzo[b]thiophen-7(4H)-one

To a stirred solution of 4-(thiophen-3-yl)butanoyl chloride (6.00 g, 31.9 mmol) in DCM (100 mL) under nitrogen was added anhydrous AlCl ₃ (8.48 g, 64.2 mmol) in portions at 0 ^° C. The resulting solution was stirred for 2 h at RT, then quenched with 300 mL of water/ice. The resulting solution was extracted with 3x300 mL of DCM and the organic layers were combined and concentrated under vacuum. This resulted in 4.2 g (86.6% over 2 steps) of the title compound as brown oil. MS-ESI: 153 (M+1).

Step 6: Methyl 7-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-6-carboxylate

To a stirred solution of 5,6-dihydrobenzo[b]thiophen-7(4H)-one (2.80 g, 18.4 mmol) in DMF (20 mL) under nitrogen was added NaH (60%wt. dispersion in mineral oil, 1.68 g, 42.0 mmol) in portions at 0 ^° C. The resulting solution was stirred for 30 min at 10 ^° C, then dimethyl carbonate (9.94 g, 110 mmol) was added dropwise at 0 ^° C. The resulting solution was stirred for 3 h at RT. The reaction was quenched with 10 mL of water. The resulting solution was extracted with 3x20 mL of EtOAc and the organic layers were combined and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:5). This resulted in 3.3 g (85.3%) of the title compound as yellow oil. ¹ H NMR (400 MHz, DMSO-d6) d 8.06 (d, J = 5.0 Hz, 1H), 7.17 (d, J = 5.0 Hz, 1H), 3.81 (dd, J = 8.8, 6.3 Hz, 1H), 3.69 (s, 3H), 3.02-2.85 (m, 2H), 2.40-2.25 (m, 2H). Step 7: Methyl 7-hydroxy-4,5,6,7-tetrahydrobenzo[b]thiophene-6-carboxylate

To a stirred solution of methyl 7-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-6-carboxylate (5.00 g, 23.8 mmol) in THF (30 mL) and MeOH (20 mL) was added NaBH4 (0.90 g, 23.7 mmol) in portions at 0 ^° C. The resulting solution was stirred for 3 h at RT. The reaction mixture was quenched with 10 mL of water, organic solvent was removed under vacuum, then the residue was extracted with EtOAc (3x20 mL). The organic layers were combined and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (3:7). This resulted in 1.8 g (35.7%) of the title compound as yellow oil. MS-ESI: 213 (M+1).

Step 8: Methyl 4,5,6,7-tetrahydrobenzo[b]thiophene-6-carboxylate

To a stirred solution of methyl 7-hydroxy-4,5,6,7-tetrahydrobenzo[b]thiophene-6-carboxylate (1.40 g, 6.60 mmol) in DCM (40 mL) was added Et ₃ SiH (1.53 g, 13.2 mmol) and BF ₃ -Et ₂ O (47%wt. in Et2O, 3.99 g, 13.2 mmol) dropwise at 0 ^° C. The resulting solution was stirred for 16 h at 0 ^° C and then quenched with sat. NaHCO ₃ (10 mL) and extracted with EtOAc (3x30 mL). The organic layers were combined, dried over anhydrous Na ₂ SO ₄ , and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (30:70). This resulted in 1.2 g (92.7%) of the title compound as nearly colorless oil. MS-ESI: 197 (M+1).

Step 9: 4,5,6,7-Tetrahydrobenzo[b]thiophene-6-carboxylic acid To a stirred solution of methyl 4,5,6,7-tetrahydrobenzo[b]thiophene-6-carboxylate (1.20 g, 6.12 mmol) in MeOH (50 mL) was added NaOH (4 M, 10 mL, 40 mmol) dropwise at RT. The resulting solution was stirred for 1 h at RT. The pH value of the mixture was adjusted to 6 with HCl (6 M) and extracted with 3x80 mL of EtOAc. The organic layers were combined, dried over anhydrous Na2SO4, and concentrated under vacuum. This resulted in 1.10 g (98.7%) of the title compound as brown oil. MS-ESI: 181 (M-1).

Step 10: Tert-butyl (4,5,6,7-tetrahydrobenzo[b]thiophen-6-yl)carbamate

To a stirred solution of 4,5,6,7-tetrahydrobenzo[b]thiophene-6-carboxylic acid (500 mg, 2.75 mmol) in toluene (20 mL) under nitrogen was added TEA (306 mg, 3.03 mmol) and t-BuOH (407 mg, 5.50 mmol) at RT. DPPA (831 mg, 3.02 mmol) in toluene (5 mL) was added dropwise at RT. The resulting solution was stirred for 16 h at 90 ^° C. The reaction mixture was

concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (5:95). This resulted in 540 mg (77.7%) of the title compound as yellow oil. MS-ESI: 254 (M+1).

Step 11: Tert-butyl methyl(4,5,6,7-tetrahydrobenzo[b]thiophen-6-yl)carbamate

To a stirred solution of tert-butyl (4,5,6,7-tetrahydrobenzo[b]thiophen-6-yl)carbamate (1.00 g, 3.95 mmol) in THF (20 mL) under nitrogen was added NaH (60%wt. dispersion in mineral oil, 395 mg, 9.87 mmol) in portions at 0 ^° C, followed by the addition of MeI (2.81 g, 19.8 mmol) dropwise at 0 ^° C. The resulting solution was stirred for 16 h at RT. The reaction mixture was quenched with 5 mL of water. The resulting solution was further diluted with 30 mL of water and extracted with 3x80 mL of EtOAc. The organic layers were combined and concentrated under vacuum. This resulted in 1.02 g (96.6%) of the title compound as yellow oil. MS-ESI: 268 (M+1).

Steps 12-15 used similar procedures for converting compound 814” to Intermediate 214 shown in Scheme 157 to afford Intermediate 216 from compound 840”. MS-ESI: 460 (M+1).

Scheme 160:

N'-(tert-butyldimethylsilyl)-5-(2,2-difluoroethyl)-4,5,6,7-t etrahydrothieno[3,2-c]pyridine-2- sulfonimidamide

Step 1: 5-(2,2-Difluoroethyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridin e

To a stirred solution of 4,5,6,7-tetrahydrothieno[3,2-c]pyridine hydrochloride (5.0 g, 28.5 mmol) in isopropyl alcohol (200 mL) was added K2CO3 (9.83 g, 71.3 mmol) in portions and 2,2- difluoroethyl trifluoromethanesulfonate (12.2 g, 57.0 mmol) dropwise at RT. The resulting solution was stirred for 3 h at 65 ^° C. The reaction was quenched with 10 mL of water and extracted with 3x150 mL of DCM. The organic layers were combined, dried over anhydrous Na ₂ SO ₄ , and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:1). This resulted in 2.7 g (46.7%) of the title compound as yellow oil. MS-ESI: 204 (M+1). ¹ H NMR (400 MHz, DMSO-d6) d 7.26 (d, J = 5.1 Hz, 1H), 6.77 (d, J = 5.1 Hz, 1H), 6.18 (tt, J = 55.8, 4.3 Hz, 1H), 3.64-3.59 (m, 2H), 2.97-2.81 (m, 4H), 2.81- 2.74 (m, 2H).

Steps 2-5 used similar procedures for converting compound 814” to Intermediate 214 shown in Scheme 157 to afford Intermediate 217 from compound 845”. MS-ESI: 396 (M+1).

Compound 847” ¹ H NMR (300 MHz, DMSO-d6) d 7.58 (s, 2H), 7.24 (s, 1H), 6.19 (tt, J = 55.8, 4.3 Hz, 1H), 3.64-3.59 (m, 2H), 3.03-2.78 (m, 6H). Scheme 161:

N'-(tert-butyldimethylsilyl)-2-(7-hydroxy-1,13-diphenyl-2 ,5,9,12-tetraoxatridecan-7-yl)thiazole- 5-sulfonimidamide

Step 1: 1,13-Diphenyl-2,5,9,12-tetraoxatridecan-7-ol

To a stirred solution of 2-(benzyloxy)ethan-1-ol (26.0 mL, 183 mmol) under nitrogen was added Na (2.20 g, 95.7 mmol) at 100 ^° C, followed by the addition of 2-(chloromethyl)oxirane (2.40 mL, 30.8 mmol) dropwise at 80 ^° C for 16 h. The reaction was quenched with MeOH (20 mL) at 0 ^° C. The resulting mixture concentrated and diluted with 20 mL of water, then extracted with EtOAc (3x20 mL). The combined organic layers were washed with brine (2x20 mL), dried over anhydrous Na ₂ SO ₄ , and concentrated under vacuum. The residue was purified by RP-HPLC using the following conditions: column, C18 silica gel; mobile phase, 10 mM NH4HCO3 in water and ACN (10% ACN to 60% gradient over 30 min); detector, UV 210 nm. This resulted in 5.60 g (50.5%) of the title compound as a dark yellow oil. ¹ H NMR (300 MHz, DMSO-d ₆ ) d 7.48- 7.12 (m, 10H), 4.75 (d, J = 5.2 Hz, 1H), 4.48 (s, 4H), 3.80-3.65 (m, 1H), 3.60-3.50 (m, 8H), 3.46-3.28 (m, 4H).

Step 2: 1,13-Diphenyl-2,5,9,12-tetraoxatridecan-7-one

To a stirred solution of 1,13-diphenyl-2,5,9,12-tetraoxatridecan-7-ol (2.70 g, 7.50 mmol) in DCM (20 mL) was added NMO (1.76 g, 15.0 mmol) and TPAP (0.527 g, 1.50 mmol) dropwise at RT. The resulting solution was stirred for 3 h at RT. The reaction was quenched with water (20 mL) and then extracted with 3x20 mL of EtOAc. The organic layers were combined, dried over anhydrous Na2SO4, and concentrated under vacuum. The residue was purified by RP-HPLC with the following conditions: column, C ₁₈ silica gel; mobile phase, 10 mM NH ₃ HCO ₃ in water and ACN (5% ACN to 55% gradient over 30 min); detector, UV 220 nm. This resulted in 800 mg (29.8%) of the title compound as light yellow oil. ¹ H NMR (400 MHz, DMSO-d6) d 7.55- 7.15 (m, 10H), 4.50 (s, 4H), 4.25 (s, 4H), 3.65-3.50 (m, 8H).

Step 3: 1,13-Diphenyl-7-(thiazol-2-yl)-2,5,9,12-tetraoxatridecan-7-o l

To a stirred solution of 2-bromothiazole (3.00 g, 18.3 mmol) in THF (30 mL) under nitrogen was added t-BuLi (1.3 M in n-pentane, 15.4 mL, 20.1 mmol) dropwise at -78 ^° C, followed by the addition of 1,13-diphenyl-2,5,9,12-tetraoxatridecan-7-one (6.55 g, 18.3 mmol) dropwise at -78 ^° C. The resulting mixture was stirred for 3 h at -78 ^° C. The reaction was quenched with water (10 mL). The resulting mixture was extracted with EtOAc (3x30 mL). The combined organic layers were washed with brine (3x20 mL), dried over anhydrous Na ₂ SO ₄ , and concentrated under vacuum. The residue was eluted from silica gel column with PE/EtOAC (1:1) to afford 3.7 g (46.7%) the title compound as a light yellow oil. MS-ESI: 444 (M+1). ¹ H NMR (300 MHz, DMSO-d ₆ ) d 7.72 (d, J = 3.2 Hz, 1H), 7.61 (d, J = 3.2 Hz, 1H), 7.38-7.20 (m, 10H), 5.96 (s, 1H), 4.43 (s, 4H), 3.85-3.69 (m, 4H), 3.62-3.39 (m, 8H).

Steps 4-7 used similar procedures for converting compound 814” to Intermediate 214 shown in Scheme 157 to afford Intermediate 218 from compound 852”. MS-ESI: 636 (M+1). Scheme 162:

5-(2-Methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-amine

Step 1: N-(2,3-dihydro-1H-inden-4-yl)pivalamide

To a stirred solution of 2,3-dihydro-1H-inden-4-amine (7.00 g, 52.6 mmol) in THF (200 mL) was added TEA (7.98 g, 78.8 mmol) at RT. This was followed by the addition of pivaloyl chloride (7.60 g, 63.1 mmol) dropwise by syringe at RT. The reaction mixture was stirred at RT for 6 h. The reaction was quenched with water (200 mL). The resulting solution was extracted with 3x200 mL of DCM, the organic layers were combined, dried over anhydrous Na2SO4, and concentrated under vacuum. The reaction mixture was eluted from silica gel with PE/EtOAC (1:10). This result in 21 g (95.0%) of the title compound as a brown solid. MS-ESI: 218 (M+1) Step 2: N-(5-bromo-2,3-dihydro-1H-inden-4-yl)pivalamide

To a stirred solution of N-(2,3-dihydro-1H-inden-4-yl)pivalamide (13.5 g, 62.1 mmol) in toluene (200 mL) was added Pd(OAc) ₂ (0.70 g, 3.11 mmol), NBS (13.3 g, 74.5 mmol) and TsOH (5.33 g, 31.0 mmol) in portions at RT. The resulting mixture was stirred under air for 16 h at RT. The reaction was then quenched with aq. NaHCO ₃ (sat., 20 mL). The resulting solution was extracted with 3x20 mL of EtOAc. The organic layers were combined, washed with brine (2x20 mL), dried over anhydrous Na2SO4, and concentrated under vacuum. The residue was eluted from a silica gel column with EtOAc/PE (1:20). This resulted in 12.0 g (65.0%) of the title compound as a light yellow solid. MS-ESI: 296/298 (M+1). ¹ H NMR (400 MHz, DMSO-d ₆ ) d 9.09 (s, 1H), 7.40 (d, J = 7.9 Hz, 1H), 7.07 (d, J = 8.0 Hz, 1H), 2.87 (t, J = 7.4 Hz, 2H), 2.70 (t, J = 7.5 Hz, 2H), 2.08-1.92 (m, 2H), 1.23 (s, 9H).

Step 3: 5-Bromo-2,3-dihydro-1H-inden-4-amine

To a stirred solution of N-(5-bromo-2,3-dihydro-1H-inden-4-yl)pivalamide (2.00 g, 6.75 mmol) in MeOH (10 mL) was added H2SO4 (conc., 10 mL) dropwise at 0 ^° C. The resulting solution was stirred for 16 h at 100 ^° C. The reaction mixture was cooled to 0 ^° C and added dropwise to 100 mL of water carefully. The pH value of the mixture was adjusted to 14 with NaOH (2 M). The resulting mixture was extracted with 3x150 mL of EtOAc, the organic layers were combined and dried over anhydrous Na2SO4. The residue was eluted from silica gel with EtOAc/PE (1:15). This resulted in 1.16 g (81.0%) of the title compound as a yellow solid. LCMS-ESI: 212 (M+1). ¹ H NMR (400 MHz, DMSO-d6) d 7.11 (d, J = 7.9 Hz, 1H), 6.41 (d, J = 7.9 Hz, 1H), 4.98 (s, 2H), 2.76 (t, J = 7.5 Hz, 2H), 2.70 (t, J = 7.4 Hz, 2H), 2.10-1.90 (m, 2H).

Step 4: 5-(2-Methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-amine

To a stirred solution of 5-bromo-2,3-dihydro-1H-inden-4-amine (1.50 g, 7.07 mmol) in dioxane (30 mL) and water (6 mL) was added K2CO3 (3.23 g, 23.3 mmol) and (2-methoxypyridin-4- yl)boronic acid (1.62 g, 10.6 mmol) in portions at RT. The mixture was degassed with nitrogen for 15 min before Pd(dppf)Cl ₂ (517 mg, 0.71 mmol) was added. The resulting mixture was stirred for 2 h at 80 ^° C under nitrogen. The resulting mixture was diluted with 150 mL of water and extracted with 3x120 mL of EtOAc, the organic layers were combined, dried over anhydrous Na ₂ SO ₄ , and concentrated under vacuum. The residue was eluted from silica gel with EtOAc /PE (1:10). This resulted in 1.37 g (62.9%) of the title compound as a light yellow solid. LCMS-ESI: 241 (M+1).

Scheme 163: Intermediate 220

4-(4-Isocyanato-2,3-dihydro-1H-inden-5-yl)-2-methoxypyridine To a stirred solution of 5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-amine (165 mg, 0.68 mmol) in THF (5 mL) under nitrogen was added BTC (102 mg, 0.34 mmol) in portions at RT. The resulting solution was stirred for 2 h at 80 ^° C. The resulting mixture was concentrated under vacuum. The crude product was used for next step without purification. This compound was monitored by LC-MS after adding MeOH to an aliquot of the reaction mixture, MS-ESI: 299 (M+1)

Schemes of Sulfonimidamide and Aniline Intermediates: Schemes 164-175 illustrate the preparations of sulfonimidamide and aniline intermediates.

Scheme 164:

Intermediate 221

N'-(tert-butyldimethylsilyl)-3-fluoro-4-(2-hydroxypropan-2-y l)thiophene-2-sulfonimidamide Step 1: N-(tert-butyl)-5-chlorothiophene-2-sulfonamide

To a stirred solution of t-BuNH ₂ (20.2 g, 276 mmol) in DCM (180 mL) under nitrogen was added TEA (42.0 g, 415 mmol), followed by the addition of 5-chlorothiophene-2-sulfonyl chloride (10.0 g, 46.3 mmol) in DCM (20 mL) dropwise at 0 ^° C. The resulting solution was stirred for 16 h at 35 ^° C. The reaction was quenched with water/ice (200 mL) and extracted with DCM (2x200 mL). The combined organic layers were dried over anhydrous Na ₂ SO ₄ and concentrated under vacuum. The residue was eluted from a silica gel column with EtOAc/PE (1:10). This resulted in 11.0 g (93.9%) of the title compound as a yellow solid. MS-ESI: 252/254 (M-1). ¹ H NMR (400 MHz, DMSO-d ₆ ) d 7.90 (s, 1H), 7.46 (d, J = 4.0 Hz, 1H), 7.21 (d, J = 4.1 Hz, 1H), 1.17 (s, 9H).

Step 2: N-(tert-butyl)-5-chloro-3-fluorothiophene-2-sulfonamide To a stirred solution of N-(tert-butyl)-5-chlorothiophene-2-sulfonamide (11.0 g, 43.5 mmol) in THF (200 mL) under nitrogen was added n-BuLi (2.5 M in hexane, 52.4 mL, 131 mmol) dropwise at -78 ^° C. The resulting solution was stirred at -78 ^° C for 1 h. To the above solution was added NFSI (41.6 g, 131 mmol) in THF (100 mL) dropwise at -78 ^° C. The resulting solution was slowly warmed to RT, and stirred at RT for another 1 h. The reaction mixture was then quenched with water/ice (250 mL) and extracted with EtOAc (3x300 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was eluted from a silica gel column with EtOAc/PE (1:20). This resulted in 6.2 g (43.3%) of the title compound as a yellow solid. MS-ESI: 270/272 (M-1).

Step 3: N-(tert-butyl)-5-chloro-3-fluoro-4-(2-hydroxypropan-2-yl)thi ophene-2-sulfonamide To a stirred solution of N-(tert-butyl)-5-chloro-3-fluorothiophene-2-sulfonamide (6.2 g, 22.8 mmol) in THF (200 mL) under nitrogen was added n-BuLi (2.5 M in hexane, 91.2 mL, 228 mmol) dropwise at -78 ^° C. The resulting solution was stirred for 50 min at -78 ^° C. To this was added acetone (53.0 g, 913 mmol) dropwise with stirring at -78 ^° C. The resulting solution was stirred for additional 1.5 h at -60 ^° C. The reaction was then quenched with water/ice (200 mL) and extracted with EtOAc (2x300 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was eluted from a silica gel column with EtOAc/PE (1:5). This resulted in 4.4 g (65.4 %) of the title compound as yellow oil. MS-ESI: 328/330 (M-1).

Step 4: N-(tert-butyl)-3-fluoro-4-(2-hydroxypropan-2-yl)thiophene-2- sulfonamide

To a stirred solution of N-(tert-butyl)-5-chloro-3-fluoro-4-(2-hydroxypropan-2-yl)thi ophene-2- sulfonamide (4.3 g, 13.1 mmol) in MeOH (80 mL) under nitrogen was added Pd/C (10% wt, 470 mg) in portions at RT. The flask was evacuated and refilled with hydrogen three times. The resulting mixture was stirred for 16 h at RT under hydrogen with a balloon. The solids were filtered out and the filtrate was concentrated under vacuum. This resulted in 3.88 g (crude) of the title compound as a white solid. MS-ESI: 294 (M-1).

Step 5: 3-Fluoro-4-(2-hydroxypropan-2-yl)thiophene-2-sulfonamide

To a stirred solution of N-(tert-butyl)-3-fluoro-4-(2-hydroxypropan-2-yl)thiophene-2- sulfonamide (3.88 g, 13.1 mmol) in DCM (78 mL) under nitrogen was added BCl ₃ (1 M in DCM, 39 mL, 39 mmol) dropwise at 0 ^° C. The resulting solution was stirred for 3 h at RT. The reaction was then quenched with water/ice (80 mL) and extracted with EtOAc (2x100 mL). The combined organic layers were dried over anhydrous Na ₂ SO ₄ and concentrated under vacuum. The residue was eluted from a silica gel column with EtOAc/PE (2:3). This resulted in 1.9 g (60.7% over 2 steps) of the title compound as yellow oil. MS-ESI: 238 (M-1).

Step 6: N-(tert-butyldimethylsilyl)-3-fluoro-4-(2-hydroxypropan-2-yl )thiophene-2- sulfonamide

To a stirred solution of 3-fluoro-4-(2-hydroxypropan-2-yl)thiophene-2-sulfonamide (1.89 g, 7.91 mmol) in THF (40 mL) under nitrogen was added NaH (60% wt., 630 mg, 15.9 mmol) in portions at 0 ^° C, followed by the addition of TBSCl (2.39 g, 15.9 mmol) in THF (5 mL) dropwise with stirring at 0 ^° C. The resulting solution was stirred for 2 h at RT. The reaction was quenched with water/ice (50 mL). The resulting solution was extracted with EtOAc (2x50 mL). The organic layers were combined and dried over anhydrous Na ₂ SO ₄ . The resulting solution was concentrated under vacuum. The residue was eluted from a silica gel column with EtOAc/PE (1:3). This resulted in 2.1 g (75.2%) of the title compound as a white solid. MS-ESI: 352 (M-1). ¹ H NMR (400 MHz, DMSO-d ₆ ) d 8.13 (s, 1H), 7.56 (d, J = 5.1 Hz, 1H), 5.38 (s, 1H), 1.43 (s, 6H), 0.89 (s, 9H), 0.16 (s, 6H).

Step 7: N'-(tert-butyldimethylsilyl)-3-fluoro-4-(2-hydroxypropan-2-y l)thiophene-2- sulfonimidamide

To a stirred solution of PPh3Cl2 (1.41 g, 4.24 mmol) in CHCl3 (15 mL) under nitrogen was added DIEA (1.83 g, 14.1 mmol) dropwise at 0 ^° C. The resulting solution was stirred for 15 min at 0 ^° C. To the above solution was added N-(tert-butyldimethylsilyl)-2-(difluoromethyl)thiazole-5- sulfonamide (1.0 g, 2.83 mmol) in CHCl ₃ (10 mL) dropwise at 0 ^° C. The resulting solution was stirred for 2 h at 0 ^° C. NH3 (g) was bubbled into the reaction solution for 10 min at 0 ^° C. Then the solution was stirred for another 30 min at RT. The solids were filtered out, the filtrate was diluted with water (20 mL). The resulting solution was extracted with DCM (3x20 mL). The organic layers were dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was eluted from a silica gel column with EtOAc/PE (1:1). This resulted in 800 mg (80.1%) of the title compound as an off-white solid. MS-ESI: 353 (M+1). Scheme 165:

I _{ntermediate 222}

N'-(tert-butyldimethylsilyl)-2-fluoro-5-(2-hydroxypropan-2-y l)benzenesulfonimidamide Step 1: Ethyl 4-fluoro-3-sulfamoylbenzoate

To a stirred solution of ethyl 3-amino-4-fluorobenzoate (500 mg, 2.73 mmol) in HCl (6 M, 5 mL) was added NaNO ₂ (226 mg, 3.28 mmol) in water (0.5 mL) dropwise at 0 ^° C. The resulting solution was stirred for 30 min at 0 ^° C, the mixture was assigned as A. SO2 (g) was bubbled in AcOH (10 mL) for 5 min at 0 ^° C, then to the solution was added CuCl (272 mg, 2.73 mmol) at 0 ^° C, this mixture was assigned as B. Mixture A was added to mixture B dropwise at 0 ^° C. The resulting mixture was stirred for 30 min at RT. The reaction mixture diluted with water (20 mL), then extracted with DCM (3x30 mL). The organic layers were combined and dried over anhydrous Na ₂ SO _4. To the above solution was bubbled NH ₃ at 0 ^° C for 3 min. The resulting mixture was stirred for 30 min at RT. The resulting mixture was concentrated under vacuum. The residue was eluted from a silica gel column with EtOAc/PE (1:3). This resulted in 500 mg (74.1%) of the title compound as a white solid. MS-ESI: 246 (M-1). Step 2: 2-Fluoro-5-(2-hydroxypropan-2-yl)benzenesulfonamide

To a stirred solution of ethyl 4-fluoro-3-sulfamoylbenzoate (500 mg, 2.02 mmol) in THF (40 mL) was added MeMgBr (3 M in THF, 5.4 mL, 16.2 mmol) dropwise at 0 ^° C. The resulting solution was stirred for 16 h at RT. The resulting mixture was quenched with 30 mL of saturated NH4Cl (aq.), extracted with 3x50 mL of EtOAc. The organic layers were combined and dried over anhydrous Na ₂ SO _4. The resulting solution was concentrated under vacuum. The residue was eluted from a silica gel column with EtOAc/PE (1:3). This resulted in 420 mg (89.2%) of the title compound as a white solid. MS-ESI: 232 (M-1).

Steps 3-4 used similar procedures for converting compound 639” to Intermediate 183 shown in Scheme 128 to afford Intermediate 222 from compound 869”. MS-ESI: 347 (M+1).

Scheme 166:

N'-(tert-butyldimethylsilyl)-3,5-bis(2-hydroxypropan-2-yl)be nzenesulfonimidamide Steps 1-2 used similar procedures for converting compound 867” to compound 868” shown in Scheme 165 to afford compound 873” from compound 871”. MS-ESI: 272 (M-1). Step 3: 3,5-Bis(2-hydroxypropan-2-yl)benzenesulfonamide

To a stirred solution of dimethyl 5-sulfamoylisophthalate (5 g, 18.3 mmol) in THF (100 mL) was added MeMgBr (3 M in THF, 120 mL, 360 mmol) dropwise at 0 ^° C. The resulting mixture was stirred for 48 h at RT. The reaction mixture was quenched with 200 mL of sat. NH4Cl (aq.), then extracted with 3x200 mL of EtOAc. The organic layers were combined and dried over anhydrous Na ₂ SO _4. The resulting solution was concentrated under vacuum. The crude product was purified by reverse column using the following conditions: Column, C18 silica gel; mobile phase, ACN and water: increasing to ACN/water from 0/100 to 90/10 over 30 min; Detector, UV 254 nm. This resulted in 2.5 g (50.0%) of the title compound as a white solid. MS-ESI: 274 (M+1).

Steps 4-5 used similar procedures for converting compound 639” to Intermediate 183 shown in Scheme 128 to afford Intermediate 223 from compound 874”. MS-ESI: 387 (M+1).

Scheme 167:

N'-(tert-butyldimethylsilyl)-3-cyano-5-(2-hydroxypropan-2-yl )benzenesulfonimidamide Steps 1-2 used similar procedures for converting compound 867” to compound 869” shown in Scheme 165 to afford compound 879” from compound 876”. MS-ESI: 292/294 (M-1). Step 4: 3-Cyano-5-(2-hydroxypropan-2-yl)benzenesulfonamide

To a stirred solution of 3-bromo-5-(2-hydroxypropan-2-yl)benzenesulfonamide (294 mg, 1.00 mmol) in DMF (5 mL) under nitrogen was added Zn(CN) ₂ (232 mg, 2.00 mmol) and Pd(PPh ₃ ) ₄ (231 mg, 0.20 mmol). The resulting mixture was stirred for 5 h at 80 ^° C. The reaction mixture was quenched with 20 mL of water, and then extracted with 3x20 ml of EtOAc. The organic layers were combined and dried over anhydrous Na ₂ SO _4. The resulting solution was concentrated under vacuum. The residue was eluted from a silica gel with EtOAc/PE (2:1). This resulted in 150 mg (62.5%) of the title compound as a yellow solid. MS-ESI: 239/240 (M-1).

Steps 5-6 used similar procedures for converting compound 639” to Intermediate 183 shown in Scheme 128 to afford Intermediate 224 from compound 880”. MS-ESI: 354 (M+1).

Scheme 168:

N'-(tert-butyldimethylsilyl)-3-(((tert-butyldimethylsilyl)ox y)methyl)-4-(2-hydroxypropan-2- yl)benzenesulfonimidamide

Steps 1-2 used similar procedures for converting compound 867” to compound 868” shown in Scheme 165 to afford compound 884” from compound 882”. MS-ESI: 212 (M-1).

Step 3: 3-(Hydroxymethyl)-4-(2-hydroxypropan-2-yl)benzenesulfonamide

To a stirred mixture of 1-oxo-1,3-dihydroisobenzofuran-5-sulfonamide (1.3 g, 6.10 mmol) and LiCl (119 mg, 2.81 mmol) in THF (40 mL) under nitrogen was added MeMgBr (3 M in THF, 40.7 mL, 122 mmol) dropwise at 0 ^° C. The resulting mixture was stirred for 16 h at RT. The reaction was quenched with 50 mL of sat. NH ₄ Cl (aq.) at 0 ^° C. The resulting mixture was extracted with 3 x 100 mL of EtOAc. The organic layers were combined and dried over anhydrous Na2SO4. The resulting solution was concentrated under vacuum. This resulted in 1.1 g (73.6%) of the title compound as red oil. MS-ESI: 246 (M+1).

Step 4: 3-(((Tert-butyldimethylsilyl)oxy)methyl)-4-(2-hydroxypropan- 2- yl)benzenesulfonamide

To a stirred solution of 3-(hydroxymethyl)-4-(2-hydroxypropan-2-yl)benzenesulfonamide (1.1 g, 4.49 mol) in DCM (40 mL) under nitrogen was added TEA (1.36 g, 13.5 mmol) and TBSCl (1.01 g, 6.74 mmol) at RT. The resulting mixture was stirred for 6 h at RT. The reaction mixture was quenched with 40 mL of water, extracted with 3 x 30 mL of DCM. The organic layers were combined and dried over anhydrous Na ₂ SO ₄ . The resulting solution was concentrated under vacuum. The residue was eluted from a silica gel column with DCM/MeOH (100:1). This resulted in 1.3 g (80.6%) of the title compound as an off-white solid. MS-ESI: 360 (M+1).

Steps 5-6 used similar procedures for converting compound 639” to Intermediate 183 shown in Scheme 128 to afford Intermediate 225 from compound 886”. MS-ESI: 473 (M+1).

Scheme 169:

Intermediate 226

N'-(tert-butyldimethylsilyl)-4-(((tert-butyldimethylsilyl)ox y)methyl)-2-(2-hydroxypropan-2- yl)thiazole-5-sulfonimidamide

Step 1: (2-Bromothiazol-4-yl)methanol

To a stirred solution of ethyl 2-bromothiazole-4-carboxylate (3.0 g, 12.8 mmol) in EtOH (30 mL) was added NaBH4 (1.0 g, 25.4 mmol) in portions at 0 ^° C. The resulting solution was stirred for 3 h at RT. The reaction was quenched with 100 mL of water at 0 ^° C. Then extracted with 3x100 ml of EtOAc, the organic layers were combined and dried over anhydrous Na ₂ SO ₄ . The resulting solution was concentrated under vacuum. This resulted in 2 g (81.0%) of the title compound as yellow oil. MS-ESI: 194/196 (M+1).

Step 2: 2-Bromo-4-(((tert-butyldimethylsilyl)oxy)methyl)thiazole

To a stirred solution of (2-bromothiazol-4-yl)methanol (2.0 g, 10.3 mmol) in THF (20 mL) under nitrogen was added NaH (60% wt., 1.2 g, 30.9 mmol) in portions at 0 ^° C. After stirring for 15 minutes at RT, a solution of TBSCl (4.7 g, 30.9 mmol) in THF (5 mL) was added dropwise at 0 ^° C. The resulting solution was stirred for 2 h at RT. The reaction was then quenched with 50 mL of water. The resulting solution was extracted with 3x100 mL of EtOAc. The organic layers were combined and dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was eluted from a silica gel column EtOAc/PE (1:30). This resulted in 2.5 g (79%) of the title compound as yellow oil. MS-ESI: 310/308 (M+1).

Step 3: 2-(4-(((Tert-butyldimethylsilyl)oxy)methyl)thiazol-2-yl)prop an-2-ol

To a stirred mixture of 2-bromo-4-(((tert-butyldimethylsilyl)oxy)methyl)thiazole (2.5 g, 8.14 mmol) in THF (30 mL) under nitrogen was added n-BuLi (2.5 M in hexane, 4.86 mL, 12.2 mmol) dropwise at -78 ^° C. After stirring for 30 min at -78 ^° C, to the above was added acetone (1.8 g, 32.4 mmol) dropwise at -78 ^° C. The resulting mixture was stirred for 1 h at RT. The resulting mixture was quenched with 50 mL of water, extracted with 3x100 ml of EtOAc. The organic layers were combined and dried over anhydrous Na2SO4. The resulting solution was concentrated under vacuum. The residue was eluted from a silica gel column with EtOAc/PE (1:10). This resulted in 2 g (85.6%) of the title compound as yellow oil. MS-ESI: 288 (M+1). Steps 4-7 used similar procedures for converting compound 665’’ to Intermediate 188 shown in Scheme 133 to afford Intermediate 226 from compound 891". MS-ESI: 480 (M+1).

Scheme 170:

3,5,6,7-Tetrahydro-2H-indeno[5,6-b]furan-8-amine

Step 1: (Z)-3-(2,3-Dihydrobenzofuran-5-yl)acrylic acid

To a stirred solution of 2,3-dihydrobenzofuran-5-carbaldehyde (25 g, 169 mmol) in pyridine (200 mL) under nitrogen was added malonic acid (21.5 g, 203 mmol) and piperidine (1.4 g, 16.44 mmol). The resulting solution was stirred for 16 h at 100 ^° C. The resulting mixture was cooled to RT, diluted with water (200 mL), and extracted with EtOAc (3x200 mL). The organic layers were combined and dried over anhydrous Na2SO4 then concentrated under vacuum. This resulted in 30 g (93.4%) of the title compound as a yellow solid. MS-ESI: 189 (M-1).

Step 2: 3-(2,3-Dihydrobenzofuran-5-yl)propanoic acid

To a stirred solution of (Z)-3-(2,3-dihydrobenzofuran-5-yl)acrylic acid (25 g, 132 mmol) in MeOH (200 mL) under nitrogen was added Pd/C (10%wt., 4 g). The flask was evacuated and refilled with hydrogen three times. The resulting solution was stirred for 16 h at RT under hydrogen with a balloon. The solids were filtered out and the filtrate was concentrated under vacuum. This resulted in 25 g (98.6%) of the title compound as a light yellow solid. MS-ESI: 191 (M-1).

Step 3: 3-(2,3-Dihydrobenzofuran-5-yl)propanoyl chloride To a stirred solution of 3-(2,3-dihydrobenzofuran-5-yl)propanoic acid (20 g, 104 mmol) in DCM (200 mL) under nitrogen was added oxalyl chloride (13.21 g, 104 mmol). The resulting solution was stirred for 2 h at RT. The resulting mixture was concentrated under vacuum. This resulted in 20 g (crude) of the title compound as a light yellow liquid which was used for next step without further purification.

Step 4: 2,3,5,6-Tetrahydro-7H-indeno[5,6-b]furan-7-one

To a stirred solution of 3-(2,3-dihydrobenzofuran-5-yl)propanoyl chloride (crude from last step) in DCM (200 mL) under nitrogen was added AlCl3 (12.7 g, 95.2 mmol) in portions at 0 ^° C. The resulting solution was stirred for 2 h at 0 ^° C. The reaction was quenched with 200 mL of water/ice, extracted with 3x200 mL of DCM. The organic layers were combined and dried over anhydrous Na2SO4. The resulting solution was concentrated under vacuum. The residue was eluted from a silica gel column with EtOAc/PE (1:3). This resulted in 10 g (54.6% over two steps) of the title compound as a yellow solid. MS-ESI: 175 (M+1).

Step 5: 8-Nitro-2,3,5,6-tetrahydro-7H-indeno[5,6-b]furan-7-one

To a stirred solution of 2,3,5,6-tetrahydro-7H-indeno[5,6-b]furan-7-one (5 g, 28.7 mmol) in conc. H ₂ SO ₄ (20 mL) was added HNO ₃ (1.99 g, 31.6 mmol) dropwise at 0 ^° C. The resulting solution was stirred for 2 h at 0 ^° C. The resulting solution was diluted with 200 mL of ice/water, extracted with 3x100 mL of DCM. The organic layers were combined and dried over anhydrous Na ₂ SO ₄ . The resulting mixture was concentrated under vacuum. This resulted in 5 g (79.6%) of the title compound as a light yellow solid. MS-ESI: 220 (M+1).

Step 6: 3,5,6,7-Tetrahydro-2H-indeno[5,6-b]furan-8-amine

To a stirred solution of 8-nitro-2,3,5,6-tetrahydro-7H-indeno[5,6-b]furan-7-one (5 g, 22.8 mmol) in MeOH (50 mL) was added methanesulfonic acid (675 mg, 7.0 mmol) and Pd(OH) ₂ /C

(20%wt., 1 g). The flask was evacuated and refilled with hydrogen three times. The resulting solution was stirred for 16 h at RT under hydrogen with a balloon. The pH value of the solution was adjusted to 9 with 1M NaOH (aq.). The solids were filtered out and the filtrate was concentrated under vacuum. This resulted in 3.50 g (87.7%) of the title compound as a yellow solid. MS-ESI: 176 (M+1).

Scheme 171:

Tert-butyl (amino(2-(2-hydroxypropan-2-yl-1,1,1,3,3,3-d ₆ )thiazol-5 l xo)- l ⁶ - sulfaneylidene)carbamate Step 1: (Methyl-d ₃ )magnesium iodide

To a stirred mixture of Mg turnings (10.0 g, 410 mmol) and iodine (10.0 mg, a small crystal) in Et ₂ O (1.3 L) under nitrogen was added CD ₃ I (50 g, 345 mmol) in Et ₂ O (100 mL) dropwise at 0 ^° C. The resulting mixture was stirred for 2 h at RT. This resulted in the title compound (crude in Et2O, ~0.25 M) as a grey solution which was used for next step without further purification. Step 2: 2-(Thiazol-2-yl)propan-1,1,1,3,3,3-d ₆ -2-ol

To a stirred solution of (methyl-d ₃ )magnesium iodide (crude 0.25 M in Et ₂ O, 1.4 L, 350 mmol) under nitrogen was added methyl thiazole-2-carboxylate (10.7 g, 74.8 mmol) in THF (150 mL) dropwise at 0 ^° C. The resulting solution was stirred for 2 h at RT. The reaction was quenched with 200 mL of water at 0 ^° C. Then extracted with 2x1 L of EtOAc, the organic layers were combined and dried over anhydrous Na2SO4. The resulting mixture was concentrated under vacuum. The residue was eluted from a silica gel column with EtOAc/PE (1:10). This resulted in 9 g (80.7%) of the title compound as a white solid. MS-ESI: 150 (M+1).

Steps 3-7 used similar procedures for converting compound 87 to Intermediate 28 shown in Scheme 16 to afford Intermediate 228 from compound 903”. MS-ESI: 328 (M+1). Scheme 172:

N'-(tert-butyldimethylsilyl)-5-(2-hydroxypropan-2-yl)-4-phen ylthiophene-2-sulfonimidamide Step 1: Methyl 3-phenylthiophene-2-carboxylate

To a stirred solution of methyl 3-bromothiophene-2-carboxylate (3.0 g, 13.6 mmol) in dioxane (40 mL) and H2O (13 mL) under nitrogen was added phenylboronic acid (1.99 g, 16.3 mmol), Na ₂ CO ₃ (2.16 g, 20.4 mmol) and Pd(PPh ₃ ) ₄ (784 mg, 0.679 mmol). The resulting mixture was stirred for 5 h at 90 ^° C. The reaction was diluted with 50 mL of water. Then extracted with 3x50 mL of EtOAc, the organic layers were combined and dried over anhydrous Na2SO4. The resulting mixture was concentrated under vacuum. The residue was eluted from silica gel column with EtOAc/PE (1/3). This resulted in 2.8 g (94.4%) of the title compound as a light yellow solid.MS-ESI: 219 (M+1).

Step 2: Methyl 3-phenyl-5-sulfamoylthiophene-2-carboxylate

To a stirred solution of methyl 3-phenylthiophene-2-carboxylate (2.8 g, 12.8 mmol) in CHCl ₃ (30 mL) under nitrogen was added chlorosulfonic acid (3.0 g, 25.6 mmol) dropwise at 0 ^° C. The solution was stirred for 2 h at RT, then PCl5 (13.2 g, 64.0 mmol) was added in portions at 70 ^° C. The resulting mixture was stirred for 3 h at 70 ^° C. The reaction mixture was slowly poured into 100 mL of ice/water. Then extracted with 3x50 mL of DCM, the organic layer were combined and dried over anhydrous Na2SO4. The resulting solution was concentrated under vacuum. The residue was dissolved in THF (50 mL), then NH3 (g) was bubbled for 5 min at 0 ^° C. The resulting mixture was stirred for 1 h at RT. The resulting mixture was concentrated under vacuum. The residue was eluted from silica gel column with EtOAc/PE (1/2). This resulted in 2.0 g (52.6%) of the title compound as a light yellow solid. MS-ESI: 296 (M-1).

Steps 3-5 used similar procedures for converting compound 868” to Intermediate 222 shown in Scheme 165 to afford Intermediate 229 from compound 910”. MS-ESI: 411 (M+1).

Scheme 173:

N-(tert-butyldimethylsilyl)-4-(isopropyl(methyl)amino)benzen esulfonimidamide

Step 1: 4-Bromo-N-isopropylaniline To a stirred solution of 4-bromoaniline (7.6 g, 44.2 mmol) in EtOH (50 mL) and H2O (50 mL) under nitrogen was added AcONa (10.9 g, 133 mmol), AcOH (40 mL) and acetone (12.8 g, 221 mmol) at 0 ^° C. The resulting mixture was stirred for 30 min at RT. To the above mixture was added NaBH4 (8.36 g, 221 mmol) in portions slowly at 0 ^° C. The resulting mixture was stirred for 2 h at 0 ^° C. The reaction was quenched with 50 mL of NaOH (2 M, aq.), extracted with 3 x 100 mL of EtOAc. The organic layers were combined and dried over anhydrous Na ₂ SO ₄ . The resulting solution was concentrated under vacuum. The residue was eluted from a silica gel column with EtOAc/PE (1:1). This resulted in 9 g (95.6%) of the title compound as a yellow solid. MS-ESI: 214/216 (M+1).

Step 2: 4-Bromo-N-isopropyl-N-methylaniline

To a stirred solution of 4-bromo-N-isopropylaniline (9 g, 42.3 mmol) in DMF (100 mL) under nitrogen was added K ₂ CO ₃ (11.7 g, 84.6 mmol), followed by the addition of MeI (30.1 g, 212 mmol) dropwise at 0 ^° C. The resulting mixture was stirred for 16 h at 80 ^° C. The reaction was quenched with 150 mL of water/ice, extracted with 3 x 100 mL of EtOAc. The organic layers were combined and dried over anhydrous Na2SO4. The resulting solution was concentrated under vacuum. The residue was eluted from a silica gel column with EtOAc/PE (1:1). This resulted in 6.18 g (64.4%) of the title compound as a yellow oil. MS-ESI: 228/230 (M+1).

Steps 3-7 used similar procedures for converting compound 642’’ to Intermediate 184 shown in Scheme 129 to afford Intermediate 230 from compound 915”. MS-ESI: 342 (M+1).

Scheme 174:

Intermediate 231

To a mixture of 2-aminocyclopent-1-ene-1-carbonitrile (5.4 g, 50 mmol) in DCE (125 mL) under nitrogen was added cyclopentanone (8.4 g, 100 mmol) at RT, followed by the addition of BF ₃ .Et ₂ O (47%wt., 100 mmol, 14.5 g) dropwise at 0 ^° C. The resulting mixture was heat to 75 ^° C for 6 h. The reaction cooled to RT, then quenched with water/ice (100 mL), extracted with DCM (2x50 mL) to remove the impurities. The aqueous phase was collected and its pH value adjusted to 14 with NaOH (6 M). A solid was precipitated and collected by filtration. The filter cake was washed with water (150 mL) then dried under infra-red light. This resulted in 7.0 g of the title compound (80%) as a light yellow solid. MS-ESI: 175 (M+1).

Scheme 175:

3,5-Diisopropylpyridin-4-amine

Step 1: 3,5-Di(prop-1-en-2-yl)pyridin-4-amine

To a stirred solution of 3,5-dibromopyridin-4-amine (5.0 g, 20 mmol) in dioxane (150 mL) and water (15 mL) under nitrogen was added 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2- dioxaborolane (10 g, 60 mmol), Cs ₂ CO ₃ (19.6 g, 60 mmol) and Pd(dppf)Cl ₂ (1.46 g, 2.0 mmol). The resulting solution was stirred for 15 h at 90 ^° C. The resulting mixture was concentrated under vacuum. The residue was eluted from a silica gel with EtOAc/PE (1:3). This resulted in 3.0 g (87%) of the title compound as light yellow oil. MS-ESI: 175 (M+1).

Step 2: 3,5-Diisopropylpyridin-4-amine

To a stirred solution of 3,5-di(prop-1-en-2-yl)pyridin-4-amine (3.0 g, 17.2 mmol) in MeOH (50 mL) under nitrogen was added Pd/C (wet.10% wt., 300 mg). The flask was evacuated and flushed three times with hydrogen. The resulting solution was stirred for 16 h at RT under hydrogen with a balloon. The Pd/C catalysts were filtered out, the filtrate was concentrated under vacuum. This resulted in 2.8 g (91%) of the title compound as a light yellow solid. MS-ESI: 178 (M+1). Reagent 1

Dichlorotriphenylphosphorane This reagent was either purchased or prepared using the following procedure:

An oven dried 40 mL vial equipped with a stir bar was capped with a rubber septum and flushed with nitrogen. At room temperature, a solution of PPh3 (0.85 g, 3.2 mmol) in anhydrous 1,2- dichloroethane (5 mL) was introduced via syringe. The reaction vessel was immersed in an ice / water bath and cooled for 5 min. A solution of hexachloroethane (0.76 g, 3.2 mmol) in anhydrous 1,2-dichloroethane (5 mL) was introduced dropwise via syringe. After the addition was complete the reaction mixture was stirred at the same temperature for an additional 5 min and then placed into a preheated block set at 80 °C. Heating was continued for 4.5 h, at which time the reaction was assumed to be complete. The light golden clear solution was cooled to ambient temperature. The reagent thus prepared was transferred via syringe in subsequent reactions without any work up or purification. The total volume of the reaction mixture was 11 mL for the molar calculations for next steps. This solution containing PPh ₃ Cl ₂ was stored under nitrogen at room temperature until used.

Reagent 2

Polymer-bound dichlorotriphenylphosphorane

Polystyrene bound PPh ₃ (0.32 g, 0.32 mmol) was suspended in anhydrous dichloroethane (6 mL) and shaked on a shaker for 5 mins. It was then filtered and the process was repeated again to swell the polymer. Filtered resin was suspended in anhydrous dichloroethane (6 mL) a third time and the whole suspension was transferred into an oven dried 40 mL vial with a stir bar via pipette. The vial was capped with a rubber septum and connected to a steady flow of nitrogen. The reaction vessel was immersed in an ice/water bath and cooled down for 10 min. A solution of hexachloroethane (0.076 g, 0.32 mmol) in anhydrous 1,2-dichloroethane (2 mL) was introduced drop wise via syringe. After the addition was complete the reaction mixture was placed in an already heated block set at 82 ^o C for 5 h. At this point the reaction is assumed to be completed. It was gradually brought to room temperature and used in the next step as is. This reagent was used at 1.5 equiv. with respect to sulfonamide in the next step.

Synthetic Examples Example 1

Example 1 ( hexahydro-s-indacen-4-ylcarbamoyl)-4-(2-hydroxypropan-2- y )-5-methylfuran-2-sulfonimidamide

Example 1 was synthesized according to the general method shown in Scheme 1, as illustrated below. Examples 2 and 3

E ^{xamples 2 and 3}

Examples 2 (181a) and 3 (181b): (S)- and (R)- N'-(1,2,3,5,6,7-hexahydro-s-indacen-4- ylcarbamoyl)-4-(2-hydroxypropan-2-yl)-5-methylfuran-2-sulfon imidamide Examples 2 and 3 were prepared through chiral separation of Example 1 as illustrated below.

E ^{xamples 2 and 3}

Step 1: N'-(tert-butyldimethylsilyl)-N-(1,2,3,5,6,7-hexahydro-s-inda cen-4-ylcarbamoyl)-4- (2-hydroxypropan-2-yl)-5-methylfuran-2-sulfonimidamide

Into a 50-mL round-bottom flask was placed N'-(tert-butyldimethylsilyl)-4-(2- hydroxypropan-2-yl)-5-methylfuran-2-sulfonimidamide (200 mg, 0.6 mmol), THF (10 mL), NaH (60% wt, 48 mg, 1.2 mmol). This was followed by the addition of a solution of 4-isocyanato- 1,2,3,5,6,7-hexahydro-s-indacene (120 mg, 0.6 mmol) in THF (1 mL) dropwise with stirring at RT. The resulting solution was stirred for 12 h at RT. The reaction was then quenched by the addition of 10 mL of NH ₄ Cl (sat.). The resulting solution was extracted with 3x10 mL of DCM and the organic layers combined and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:10 to 1:3). This resulted in 140 mg (43.8%) of the title compound as brown oil. MS-ESI: 532.0 (M-1). Step 2: N'-(1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoyl)-4-(2-hydr oxypropan-2-yl)-5- methylfuran-2-sulfonimidamide

Into a 50-mL round-bottom flask was placed N'-(tert-butyldimethylsilyl)-N-(1,2,3,5,6,7- hexahydro-s-indacen-4-ylcarbamoyl)-4-(2-hydroxypropan-2-yl)- 5-methylfuran-2- sulfonimidamide (130 g, 0.2 mmol), THF (10 mL), and TBAF (300 mg, 0.5 mmol). The resulting solution was stirred for 2 h at RT and then concentrated under vacuum. The crude product was purified by Prep-HPLC using method E eluted with a gradient of 30~60% ACN. This resulted in 82 mg (80.3%) of Example 1 as a white solid.

Example 1: MS-ESI: 418.0 (M+1). ¹ H NMR (400 MHz, DMSO-d6) d 8.39 (s, 1H), 7.57 (s, 2H), 6.87 (s, 1H), 6.85 (s, 1H), 5.04 (s, 1H), 2.79 (t, J = 7.4 Hz, 4H), 2.71– 2.63 (m, 4H), 2.42 (s, 3H), 1.94 (tt, J = 7.4 and 7.4 Hz, 4H), 1.40 (s, 6H).

Step 3: Chiral separation

The product obtained as described in the previous step (70 mg) was resolved by Chiral-Prep- HPLC using the following conditions: Column, ChiralPak ID, 2*25 cm, 5 um; mobile phase, Hex and EtOH (hold 20% EtOH over 18 min); Flow rate, 20 mL/min; Detector, UV 254/220 nm. This resulted in 26.8 mg of Example 2 (front peak, 99% ee) as a white solid and 27.7 mg (second peak, 99.3% ee) of Example 3 as a white solid.

Example 2: MS-ESI: 418.0 (M+1). ¹ H NMR (400 MHz, DMSO-d ₆ ) d 8.36 (s, 1H), 7.57 (s, 2H), 6.87 (s, 1H), 6.85 (s, 1H), 5.03 (s, 1H), 2.78 (t, J = 7.2 Hz, 4H), 2.73– 2.60 (m, 4H), 2.41 (s, 3H), 1.93 (tt, J = 7.2 and 7.2 Hz, 4H), 1.39 (s, 6H).

Example 3: MS-ESI: 418.0 (M+1). ¹ H NMR (400 MHz, DMSO-d ₆ ) d 8.39 (s, 1H), 7.58 (s, 2H), 6.87 (s, 1H), 6.85 (s, 1H), 5.03 (s, 1H), 2.78 (t, J = 7.2 Hz, 4H), 2.73– 2.60 (m, 4H), 2.41 (s, 3H), 1.93 (tt, J = 7.2 and 7.2 Hz, 4H), 1.39 (s, 6H). Single crystal X-ray crystallographic analysis was performed on compound 181a. FIG 1 shows ball and stick models of the asymmetrical unit containing two crystallographically independent molecules of compound 181a, with hydrogen atoms omitted for clarity. Table M below shows fractional atomic coordinates of compound 181a. Table M.

Single crystal X-ray crystallographic analysis was performed on compound 181b. FIG 2 shows ball and stick models of the asymmetrical unit containing two crystallographically independent molecules of compound 181b, with hydrogen atoms omitted for clarity. Table N below shows fractional atomic coordinates of compound 181b. Table N.

Example 4

E _{xample 4 (101’): N'-( hexahydro-s-indacen-4-ylcarbamoyl)-2-(2-hydroxypropan-2-}

yl)thiazole-5-sulfonimidamide Example 4 (above) was synthesized according to the general methods in Schemes 2 and 3, as illustrated in Route 1 and Route 2 below. Examples 5 and 6

Examples 5 and 6 (stereochemistry not assigned)

Examples 5 (101) and 6 (102): (S)- and (R)-N'-(1,2,3,5,6,7-hexahydro-s-indacen-4- ylcarbamoyl)-2-(2-hydroxypropan-2-yl)thiazole-5-sulfonimidam ide Examples 5 and 6 (above) were synthesized according to general methods shown in Schemes 2 and 3, as illustrated in Route 1 and Route 2 below. Example 7 Boc

Example 7 (194): Tert-butyl N-(1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoyl)-2-(2- hydroxypropan-2-yl)thiazole-5-sulfonimidoylcarbamate Example 7 was synthesized according to general method shown in Scheme 3, as illustrated in Route 2 below.

Route 1

Examples 5 and 6 (stereochemistry not assigned) Step 1: N-(tert-butyldimethylsilyl)-N'-(1,2,3,5,6,7-hexahydro-s-inda cen-4-ylcarbamoyl)-2- (2-hydroxypropan-2-yl)thiazole-5-sulfonimidamide

Into a 50-mL round-bottom flask was placed a solution of N'-(tert-butyldimethylsilyl)-2-(2- hydroxypropan-2-yl)thiazole-5-sulfonimidamide (336 mg, 1.0 mmol) in THF (10 mL). To this solution was added NaH (60% wt, 80 mg, 2.0 mmol) in portions at 0 ^o C. The solution was stirred at 0 ^o C for 15 minutes, and this was followed by the addition of a solution of 4-isocyanato- 1,2,3,5,6,7-hexahydro-s-indacene (209 mg, 1.1 mmol) in THF (5 mL) dropwise with stirring at RT. The resulting solution was stirred for 12 h at RT. The reaction was then quenched by the addition of 10 mL of NH4Cl (sat.). The resulting solution was extracted with 3x10 mL of DCM and the combined organic layers were concentrated under vacuum. This resulted in 535 mg (crude) of the title compound as a brown oil. MS-ESI: 535.0 (M+1).

Step 2: N'-(1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoyl)-2-(2-hydr oxypropan-2- yl)thiazole-5-sulfonimidamide

Into a 50-mL round-bottom flask was placed a solution of N-(tert-butyldimethylsilyl)-N'- (1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoyl)-2-(2-hydroxy propan-2-yl)thiazole-5- sulfonimidamide (535 mg, crude, 1.0 mmol) in THF (10 mL). To this solution was added HF/Py (70% wt, 143 mg, 5.0 mmol) dropwise at 0 ^o C. The solution was stirred at RT for 4 h. The reaction was then quenched by the addition of 10 mL of water. The resulting solution was extracted with 3x10 mL of ethyl acetate and the combined organic layers were concentrated under vacuum. The crude product was purified by Prep-HPLC using Method E with ACN/water (20% to 60% in 10 minutes). This resulted in 189 mg (45%, 2 steps) of Example 4 as a white solid.

Example 4: MS-ESI: 421.0 (M+1). ¹ H NMR (400 MHz, DMSO-d6) d 8.46 (br s, 1H), 8.04 (s, 1H), 7.80 (br s, 2H), 6.86 (s, 1H) 6.28 (s, 1H), 2.88– 2.71 (m, 4H), 2.71– 2.56 (m, 4H), 2.02– 1.80 (m, 4H), 1.49 (s, 6H).

Step 2: Chiral separation.

The product obtained as described in the previous step (189 mg) was resolved by Chiral-Prep- HPLC using the following conditions: Column, CHIRAL Cellulose-SB, 2*25 cm, 5 um; mobile phase, Hex (0.1%DEA) and EtOH (hold 20% EtOH over 16 min); Flow rate, 20 mL/min; Detector, UV 254/220 nm. This resulted in 70 mg of Example 5 (front peak, 99% ee 101) as a white solid and 65 mg of Example 6 (second peak, 97.5% ee 102) as a white solid. Absolute stereochemistry of these two isomers has not been assigned.

Example 5: MS-ESI: 421.0 (M+1). ¹ H NMR (400 MHz, DMSO-d6) d 8.43 (br s, 1H), 8.05 (s, 1H), 7.83 (br s, 2H), 6.87 (s, 1H) 6.29 (s, 1H), 2.82– 2.71 (m, 4H), 2.71– 2.56 (m, 4H), 2.02– 1.80 (m, 4H), 1.50 (s, 6H).

Example 6: MS-ESI: 421.0 (M+1). ¹ H NMR (400 MHz, DMSO-d6) d 8.41 (br s, 1H), 8.05 (s, 1H), 7.83 (s, 2H), 6.87 (s, 1H) 6.27 (s, 1H), 2.82– 2.71 (m, 4H), 2.71– 2.56 (m, 4H), 2.02– 1.80 (m, 4H), 1.50 (s, 6H). Route 2:

Boc

O ^NH O ^NH

E ^{xamples 5 and 6 (stereochemistry not assigned)} Step 1: Tert-butyl N-(1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoyl)-2-(2-hydro xypropan- 2-yl)thiazole-5-sulfonimidoylcarbamate

Tert-butyl (amino(2-(2-hydroxypropan-2-yl)thiazol-5-yl)(oxo)- ^ ⁶ -sulfaneylidene)carbamate (12 g, 37 mmol) was dissolved in dried THF (200 mL). To the solution was added NaH (17.7 g, 60%, 44 mmol) in portions at 0°C under nitrogen atmosphere, and then the mixture was stirred at 0°C for 0.5 h. Freshly prepared 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (7.4 g, 37 mmol) was dissolved in dried THF (50 mL) and the solution was added to the front mixture dropwise at 0°C. The mixture was stirred at RT for 1 h. The reaction was quenched with ice-water (100 mL), and the pH value of the resulting solution was adjusted to 6 with HCO ₂ H. The solution was extracted with EtOAc (3x200 mL) and the combined organic layers were dried over anhydrous Na ₂ SO ₄ and concentrated to give 17.5 g of Example 7 as a crude grey solid.

Example 7: MS-ESI: 521.0 (M+1). ¹ H NMR (300 MHz, MeOD-d ₄ ) d 8.14 (s, 1H), 6.89 (s, 1H), 3.00– 2.60 (m, 8H), 2.20– 1.90 (m, 4H), 1.51 (s, 6H), 1.37 (s, 9H). Step 2: N'-(1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoyl)-2-(2-hydr oxypropan-2- yl)thiazole-5-sulfonimidamide

The crude tert-butyl (N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(2-hy droxypropan- 2-yl)-thiazole-5-sulfonimidoyl)carbamate (crude 17.5 g) was dissolved in THF (200 mL). To the solution was added HCl (200 mL, 4M in 1,4-dioxane) at RT. The mixture was stirred at RT overnight and concentrated. The residue was purified with SiO ₂ -gel column and eluted with MeOH/DCM (5%) and further purified by reverse column with MeOH/water (50% to 80% in 50 minutes) to give 12 g of Example 4 (51%, 2 steps) as a white solid.

Example 4: MS-ESI: 421.0 (M+1). ¹ H NMR (400 MHz, DMSO-d6) d 8.46 (br s, 1H), 8.04 (s, 1H), 7.80 (br s, 2H), 6.86 (s, 1H) 6.28 (s, 1H), 2.88– 2.71 (m, 4H), 2.71– 2.56 (m, 4H), 2.02– 1.80 (m, 4H), 1.49 (s, 6H).

Step 3: Chiral separation.

The product obtained as described in the previous step (12 g) was resolved by Chiral-Prep-SFC using the following conditions: Column, CHIRALPAK IF, 2*25cm, 5um; Mobile Phase A: CO2: 60, Mobile Phase B: MeOH (2mM NH3-MeOH): 40; Flow rate: 40 mL/min; Detector, UV 220 nm. This resulted in 3.8 g of Example 6 (front peak, 99% ee 102) as a white solid and 4.6 g of Example 5 (second peak, 97.5% ee 101) as a white solid. Absolute stereochemistry of these two isomers has not been assigned.

Example 5: MS-ESI: 421.0 (M+1). ¹ H NMR (400 MHz, DMSO-d6) d 8.43 (br s, 1H), 8.05 (s, 1H), 7.83 (br s, 2H), 6.87 (s, 1H) 6.29 (s, 1H), 2.82– 2.71 (m, 4H), 2.71– 2.56 (m, 4H), 2.02– 1.80 (m, 4H), 1.50 (s, 6H).

Example 6: MS-ESI: 421.0 (M+1). ¹ H NMR (400 MHz, DMSO-d6) d 8.41 (br s, 1H), 8.05 (s, 1H), 7.83 (s, 2H), 6.87 (s, 1H) 6.27 (s, 1H), 2.82– 2.71 (m, 4H), 2.71– 2.56 (m, 4H), 2.02– 1.80 (m, 4H), 1.50 (s, 6H).

Example 8

Example 8 (270): N'-(8-fluoro-1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoyl)- 4-(2- hydroxypropan-2-yl)-N-methylthiophene-2-sulfonimidamide (Scheme 4) Example 8 was synthesized according to the general method shown in Scheme 4.

Into a 50-mL round-bottom flask purged with and maintained under nitrogen was placed a solution of 4-fluoro-8-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (110 mg, 0.51 mmol) in DCM (5 mL). To the solution were added TEA (153 mg, 1.51 mmol) and 4-(2-hydroxypropan-2-yl)-N'- methylthiophene-2-sulfonimidamide (120 mg, 0.51 mmol). The resulting solution was stirred for 14 h at RT and then was concentrated under vacuum. The crude product was purified by Prep- HPLC using method E eluted with a gradient of 30~74% ACN. This resulted in 80 mg (35%) of Example 8 as a white solid. Example 8: MS-ESI: 450.1 (M-1). ¹ H NMR (400 MHz, DMSO-d6) d 8.50 (br s, 1H), 7.64 (s, 1H), 7.59-7.50 (m, 2H), 5.23 (s, 1H), 2.84-2.69 (m, 8H), 2.50 (s, 3H), 1.99 (t, J = 7.2 Hz, 4H), 1.42 (d, J = 2.8 Hz, 6H) Example 9 (204)

N'-( dimethylpyridin-4-yl)carbamoyl)-4-methyl-5-(2-hydroxypropan- 2-yl)thiophene-2- sulfonimidamide (Scheme 5)

Step 1: 4-Azido-2,6-dimethylpyridine

To the solution of 2,6-dimethylpyridine-4-carboxylic acid (151 mg, 1.0 mmol) in dried toluene (15 mL). To the solution was added DPPA (825 mg, 3.0 mmol) and TEA (303 mg, 3.0 mmol). The mixture was stirred at 60 ^o C for 4 h. The solution was concentrated under vacuum. This gave 900 mg (crude) of the title compound as yellow oil.

Step 2 & 3: N-(tert-butyldimethylsilyl)-N'-((2,6-dimethylpyridin-4-yl)ca rbamoyl)-5-(2- hydroxypropan-2-yl)-3-methylthiophene-2-sulfonimidamide

The 4-azido-2,6-dimethylpyridine (900 mg, crude) was dissolved in THF (20 mL). To the solution was added N'-(tert-butyldimethylsilyl)-5-(2-hydroxypropan-2-yl)-3-meth ylthiophene-2- sulfonimidamide (349 mg, 1.0 mmol) and NaOH (120 mg, 3.0 mmol). The mixture was stirred at 50 ^o C for 12 h. The solution was diluted with water 20 mL, then the resulting solution was extracted with 3x20 mL of ethyl acetate. The organic layers were combined, dried over anhydrous Na2SO4, then concentrated under vacuum. This gave 500 mg (crude) of the title compound as a yellow solid. MS-ESI: 497.0 (M+1).

Step 4: N'-((2,6-dimethylpyridin-4-yl)carbamoyl)-4-methyl-5-(2-hydro xypropan-2- yl)thiophene-2-sulfonimidamide

Into a 50-mL round-bottom flask was placed a solution of N-(tert-butyldimethylsilyl)-N'- ((2,6-dimethylpyridin-4-yl)carbamoyl)-4-methyl-5-(2-hydroxyp ropan-2-yl)thiophene-2- sulfonimidamide (500 mg, crude) in THF (10 mL), to this solution was added HF/Py (70% wt, 143 mg, 5.0 mmol) dropwise at 0 ^o C. The solution was stirred at RT for 4 h. The reaction was then quenched by the addition of 10 mL of water. The resulting solution was extracted with 3x10 mL of ethyl acetate and the combined organic layers were concentrated under vacuum. The crude product was purified by Prep-HPLC using method E eluted with a gradient of ACN/water (10% to

30% in 10 minutes). This resulted in 15 mg (4%, 4 steps) of Example 9 as a white solid. MS-ESI:

383.0 (M+1). ¹ H NMR (300 MHz, DMSO-d6) d 9.31 (s, 1H), 7.53 (br s, 2H), 7.31 (s, 1H), 7.14 (s, 2H), 5.81 (s, 1H), 2.28 (s, 6H), 2.23 (s, 3H), 1.50 (s, 6H). Table 16. Examples in the following table were prepared using similar conditions as described in

Example 1 and Scheme 1 from appropriate starting materials. ass ] ⁺ 2 2 1 methylthiophene-2-sulfonimidamide O NH ₂ O

S 2-fluoro-N'-(1,2,3,5,6,7-hexahydro-s- N indacen-4-ylcarbamoyl)-4-(2- 2 -1) 2 1 2 1 -1) -1) -1)

OH sulfonimidamide OH 1

1 3

1

1 ) 1 3

2

HO methylbenzenesulfonimidamide F O NH ₂

S O 3-fluoro-N'-(8-fluoro-1,2,3,5,6,7-hexahydro- N id 4 l b l 2 1 2 2

Table 17. Examples in the following table were prepared using similar conditions as described in

Example 4 - route 1 and Scheme 2 from appropriate starting materials. m ass # ] ⁺ 33 34 35 ) 36

H fonimidamide

N O NH ₂

S O N'-(2-cyclopropyl-4-(difluoromethoxy)- N

37 6i lh l b l 4

38 )

39 )

40 )

41

42 )

43 )

44 )

45 y oypopa--y - - e y ua-- sulfonimidamide ^NH '

^{F O} _NH2

N ^H

O ₂ e ^NH O

O 2

O e ^NH ₂ O

O

Table 18. Examples in the following table were prepared using similar conditions as described in ^O

Table 19. Examples in the following table were obtained from chiral HPLC resolutions of racemic

examples described above. The chiral column and eluents are listed in the table. As a convention, the faster-eluting enantiomer is always listed first in the table followed by the slower-eluting enantiomer of the pair. The symbol * at a chiral center denotes that this chiral center has been resolved and the absolute stereochemistry at that center has not been determined. _Ex ^{Final Target} _{Structure IUPAC Name Column Eluents} LC-MS

+H] ⁺ 7 0.3

8 0.3

8 5.3

8 5.3

8 6.2

8 6.2

8 yca a oy -- -y oypopa--y - - 4.1 methylthiophene-2-sulfonimidamide 5um Hex O

OH _* ^NH

S 2 O (R)-or (S)- N

8 ' 123 6 h hd id 4 ChiralPak 20%

4.1

8 0.1

-1)

8 0.1

-1)

8 2.0

-1)

9 2.0

-1)

9 6.1

-1)

9 6.1

-1)

₉ 8.1

₉ ylcarbamoyl)-1-isopropyl-1H-pyrazole-3- .1 8.1 sulfonimidamide 5um Hex(0

%DEA) _O ^NH2

F O

S (S)-or (R)- * _N N'-(4-(difluoromethoxy)-2,6- ChiralPak 20%

9 EOH i 8.2

₉ 8.2

9 7.2

₉ 7.2

9 8.2

₁₀ 8.2

10 9.3

10 9.2

10 3.2

OH sulfonimidamide M=3:1 _O ^NH ₂ O

S (R)-or (S)- 30%

'

1 ₀ 3.1

10 6.2

₁₀₆ 6.2

10 6.1

1 ₀ 6.1

1 ₀ 4.2

1 ₁ 4.2

1 ₁ 9.1

-1)

1 ₁ 9.1

F hydroxypropan-2-yl)thiazole-5- 5um -1) OH sulfonimidamide M=1:1 ^O _NH

OH ₂ (S)-or (R)- S O

* N'-(8-cyano-1,2,3,5,6,7-hexahydro-s- ChiralPak

1 ₁ ^{122a or 122b} N

S indacen-4-lcarbamol)-4-(2- ID 2*25cm 30% IPA 443.1

-1)

₁₁ 3.1

-1)

₁₁ 5.1

-1)

₁₁ 5.1

-1)

11 3.2

11 3.2

₁₁ 6.2

₁₂ 6.2

12 6.1

₁₂ 6.1 hydroxypropan-2-yl)thiophene-2- 5um .

HO sulfonimidamide %DEA) (S)-or (R)- O ^NH ₂

F N'-(8-fluoro-1,2,3,5,6,7-hexahydro-s- ChiralPak 40%

1 ₂ ^{105a or 105b} O

S

* indacen-4-lcarbamol)-3-(2- ID 2*25cm EtOH in 432.1

₁₂ 2.1

₁₃ 8.1

-1)

₁₃ 8.1

-1)

13 5.2

13 5.2

13 1.2

13 1.2

₁₃ 9.1

-1)

₁₃ S , , 9.1

H F

N hydroxypropan-2-yl)thiazole-2- 5um (0.1%TF (M-1) HO sulfonimidamide A) in CO _{2 O} ^NH ₂ O (S)-or (R)- S N'-(4-fluoro-2,6- ChiralPak 20%

1 ₃ ^{144a or 144b} S _* ^N _F diisoro lhenlcarbamol)-5-(2- IF 2*25cm MeOH 443.2 ₁₃ 3.1 ₁₄ 0.1

-1) ₁₄ 0.1

-1) ₁₄ ^6.2 ₁₄ ^6.2 ₁₄ 4.1

-1) ₁₄ 4.1

-1) ₁₄ 4.1 yroxypropan--y)t azoe-5- 5um -1)

OH sulfonimidamide %DEA) ^O _NH2

S O (R)-or (S)- * N

1 ₄ ^{16 b 16 N} N '-(8-cyano-1,2,3,5,6,7-hexahydro-s- ChiralPak 30%

EOH i 444.1

-1)

₁₄ 4.1

-1)

₁₄ 4.1

-1)

₁₅ 2.1

-1)

₁₅ 2.1

-1)

15 8.1

-1)

₁₅ 8.1

-1)

15 1.2

15 1.2

15 HO p pyp y y , , 2.1

N S

S hydroxypropan-2-yl)thiophene-2- 5um Hex

O _{* NH} ^O

2 sulfonimidamide (R)-or (S)- N'-(4-fluoro-2,6- ChiralPak 30%

15 148b 148 ^F

H _N dii lh l b l 52 ID 2*25 EtOH i 442.1

15 4.1

-1)

₁₅ 4.1

-1)

16 3.1

16 3.1

₁₆ ^8.2

₁₆ ^8.2

₁₆ ^5.1

OH y ^O _NH2

S O

* (R)-or (S)- Chi lPk

1 ₆ ^5.1

16 ^0.2

₁₆ ^0.2

16 0.2

₁₆ 0.2

17 0.2

₁₇ 0.2

17 4.2

₁₇ 4.2

HO O hydroxypropan-2-yl)-4-methylthiophene-2- 5um Hex

F sulfonimidamide

F ^O _NH2

S O (S)-or (R)- 30%

* N 4-fluoro-N'-((8-fluoro-1,2,3,5,6,7- ChiralPak EtOH in

17 0.2

₁₇ 0.2

₁₇ 3.1

₁₇ 3.1

₁₇ 2.2

17 2.2

18 2.1

₁₈ 2.1

sulfonimidamide

F (S)-or (R)- 18 HO ^F _N N'-((4-cyano-2,6- ChiralPak 15%

173a or 173b diisoro lhenl)carbamol)-3-fluoro-5- ID 2*25cm EtOH in 467.2 18 7.2 18 8.2 18 8.2 18 9.2 18 9.2 18 3.2 18 3.2 19

6.1

(hydroxymethyl)-2-(2-hydroxypropan-2- 5um A)

CN yl)thiazole-5-sulfonimidamide

HO HO

O N H (R)-or (S)- N

19 220b 220 ^S N'-((8-cyano-1,2,3,5,6,7-hexahydro-s- ChiralPak MeOH

6.1

19 0.2

19 0.2

19 8.2

19 8.2

19 3.1

19 3.1

19 1.2

19

₂

S yroxypropan-- x(. 1.2 H ^O _O ^{N N}

H yl)benzenesulfonimidamide 5um e

%DEA) ^O _NH2

S O (R)-or (S)- N'-(8-fluoro- ₂₀ ^{106a or 106b N} _* N 1,2,3,5,6,7-hexahydro-s- ChiralPak

AD-H, 25%

9.2

20 9.2

20 4.2

₂₀ 4.2

₂₀ 8.1

-1)

₂₀ 8.1

-1)

₂₀ 8.2

₂₀ 8.2

F Example 77: MS-ESI: 421.1 (M+1). ¹ H NMR (400 MHz, DMSO-d6) d 8.41 (br s, 1H), 7.74 (br s, 2H), 7.68 (s, 1H), 6.87 (s, 1H), 5.36 (s, 1H), 3.02– 2.50 (m, 8H), 2.10– 1.80 (m, 4H), 1.48 (s, 6H).

Example 200: MS-ESI: 439.2 (M+1).1H NMR (400 MHz, DMSO-d6) d 8.38 (br, 1H), 8.02 (s, 1H), 7.75 (br, 1H), 6.27 (s, 1H), 2.81 (t, J= 7.6 Hz, 4H), 2.70 (t, J= 6.8 Hz, 4H), 2.02-1.95 (m, 4H), 1.50 (s, 6H).

Example 203: MS-ESI: 404.2 (M+1). ¹ H NMR (300 MHz, DMSO-d6) d 8.42 (br s, 1H), 7.76 (s, 1H), 7.72 (s, 2H), 7.01 (s, 1H), 6.88 (s, 1H), 5.11 (s, 1H), 2.90 - 2.72 (m, 4H), 2.72– 2.60 (m, 4H), 2.10– 1.80 (m, 4H), 1.46 (s, 6H).

Example 205: MS-ESI: 418.1 (M-1). ¹ H NMR (400 MHz, DMSO-d6) d 8.39 (br s, 1H), 7.68 (s, 2H), 7.63 (s, 1H), 7.59 (s, 1H), 6.88 (s, 1H), 5.23 (s, 1H), 2.95– 2.75 (m, 4H), 2.75– 2.60 (m, 4H), 2.05– 1.80 (m, 4H), 1.43 (s, 6H).

Example 206: MS-ESI: 438.2 (M+1). ¹ H NMR (300 MHz, DMSO-d6) d 8.41 (br s, 1H), 7.65 (s, 2H), 7.59 (s, 1H), 7.55 (s, 1H), 5.20 (s, 1H), 2.90 - 2.60 (m, 8H), 2.10– 1.80 (m, 4H), 1.39 (s, 6H). Example 208 (Compound 221)

4,5-Dichloro-N'-((4-fluoro-2,6-diisopropylphenyl)carbamoyl)t hiophene-2-sulfonimidamide

Step 1: N-(tert-butyldimethylsilyl)-4,5-dichlorothiophene-2-sulfonam ide

4,5-Dichlorothiophene-2-sulfonamide (50 mg, 0.22 mmol) was dissolved in anhydrous CH2Cl2 (2 mL). Triethylamine (0.090 mL, 0.65 mmol) and TBSCl (38 mg, 0.25 mmol) were added and the resulting mixture was stirred overnight at room temperature, or until the reaction was complete as indicated by LCMS(Method F: m/Z=424.1 [M+DMSO+H] ⁺ , retention time = 3.70 min). The reaction mixture was used in the next step as is. Step 2: N-(tert-butyldimethylsilyl)-4,5-dichlorothiophene-2-sulfonim idamide

In an oven-dried vial under nitrogen, a solution of PPh3Cl2 (143 mg, 0.44 mmol) was prepared in dichloroethane (1.5 mL). Triethylamine (0.120 mL, 0.86 mmol) was introduced in a steady stream via syringe at 0 °C. The reaction mixture was stirred at room temperature for 10 min. The reaction mixture was then cooled in an ice / water bath for 2 min and the reaction mixture of TBS protected sulfonamide (prepared in 2 mL DCM) from step 1 was introduced via syringe rapidly drop by drop (addition time < 30 seconds). The resulting mixture was stirred at 0 ^o C for 30 min, at which time anhydrous ammonia was bubbled into the reaction mixture for 45 seconds. The suspension thus formed was stirred in an ice / water bath for 30 min and then warmed to room temperature and centrifuged to remove solids. The supernatant was concentrated in vacuo and dried under high vacuum for 30 min.

Step 3: 4,5-Dichloro-N'-((4-fluoro-2,6-diisopropylphenyl)carbamoyl)t hiophene- 2- sulfonimidamide and N-(tert-butyldimethylsilyl)-4,5-dichloro- N'-((4-fluoro- 2,6-diisopropyl phenyl)carbamoyl)thiophene-2-sulfonimidamide

To the crude reaction mixture from step 2 was added anhydrous THF (1.5 mL) and the resulting solution was stirred in an ice / water bath for 5 min, at which time NaH (17 mg, 0.44 mmol) was added. After 2 min stirring, a solution of 5-fluoro-2-isocyanato-1,3-diisopropylbenzene (36.5 mg, 0.165 mmol) in THF (3 ml) was added dropwise at 0 °C. The resulting mixture was brought to room temperature and stirred for 30 min to give a mixture of crude products. LC-MS (Method F): m/Z=451.8 [M+H] ⁺ , retention time = 6.18 min; for TBS-protected product, 566.4 [M+H] ⁺ , retention time = 9.25 min. Step 4: 4,5-Dichloro-N'-((4-fluoro-2,6-diisopropylphenyl)carbamoyl)t hiophene- 2- sulfonimidamide

To the reaction mixture from step 3 was carefully added 4N HCl in dioxane (0.3 mL) and the resulting mixture was stirred at room temperature for approximately 30 min until the completion of reaction, as determined by LCMS analysis (Method F: 451.8 [M+H] ⁺ , retention time = 6.18 min). The reaction mixture was then concentrated in vacuo. DMSO (0.5 mL) was added to the residue and the resulting solution was purified on a prep-HPLC to afford the title compound. LC- MS: 451 [M+H] ⁺ . Table 20. Examples in the following table were prepared using similar procedures as described in Example 208 above starting from appropriate sulfonamides. Final Exact T _{arget #} ^{Structure IUPAC Name} Mass

H] ⁺ .05 . ^{17 .07 .28 .17 .18 .24 .17 .40 .40}

NH ₂ ^{.40 .40}

Example 221 (Compound 141)

NH O

H

N'-((1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)carb amoyl)-4-(2-hydroxypropan-2-yl)- 5-methylfuran-2-sulfonimidamide (Scheme 31)

Step 1: Phenyl (1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)carbamat e

Into a 50-mL 3-necked round-bottom flask purged and maintained with nitrogen, was placed 1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-amine (50 mg, 0.29 mmol) in THF (10 mL), to this was added NaH (60%wt. oil dispersion, 22.8 mg, 0.57 mmol) at 0℃; and then phenyl chloroformate (67.4 mg, 0.43 mmol,) in THF (2.0 mL) was added dropwise at 0℃. The resulting solution was stirred for 2 h at RT. This reaction solution was used for next step directly without any purification.

Step 2: N-(tert-butyldimethylsilyl)-N'-((1,2,3,5,6,7-hexahydrodicycl openta[b,e]pyridin-8- yl)carbamoyl) -4-(2-hydroxypropan-2-yl)-5-methylfuran-2-sulfonimidamide

Into a 50-mL 3-necked round-bottom flask purged and maintained with nitrogen, was placed N-(tert-butyldimethylsilyl)-4-(2-hydroxypropan-2-yl)-5-methy lfuran-2-sulfonoimidamide (96 mg, 0.29 mmol) in THF (10 mL). To this was added NaH (60%wt. oil dispersion, 23.2 mg, 0.58 mmol) at 0 ℃, followed by phenyl (1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8- yl)carbamate (127 mg, 0.43 mmol) crude in THF from via syringe rapidly drop by drop. The resulting mixture was stirred for 16 h at RT. The reaction was then quenched by the addition of 5.0 mL of water. The resulting solution was extracted with 4x10 ml of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was eluted from a silica gel column with ethyl acetate/petroleum ether (1;1). This resulted in 50 mg (38.4%) of the title compound as an off-white solid. MS-ESI: 533(M+1).

Step 3: N'-((1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)carb amoyl)-4-(2- hydroxypropan-2-yl) -5-methylfuran-2-sulfonimidamide

Into a 50-mL round-bottom flask, was placed N-(tert-butyldimethylsilyl)-N'-((1,2,3,5,6,7 -hexahydrodicyclopenta[b,e]pyridin-8-yl)carbamoyl)-4-(2-hydr oxypropan-2-yl)-5- methylfuran-2-sulfonimidamide (58 mg, 0.11 mmol) in THF (10 mL), to this was added TBAF (28.8 mg, 0.11 mmol). The resulting solution was stirred for 1 h at RT. The resulting mixture was concentrated under vacuum. The residue was eluted from a silica gel column with DCM/MeOH (10:1). The crude product was further purified by Prep-HPLC with the following conditions: Column: XBridge Prep OBD C18 Column 19*250 mm, 5um; Mobile Phase A: water (10 mM NH4HCO3), Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 11% B to 40% B in 7 min; UV 254/210 nm; Rt: 6 min. This resulted in 25 mg (54.87%) of Example 221 as a white solid. MS-ESI: 419 (M+1). ¹ H NMR (400 MHz, DMSO-d6, ppm) d: 8.82 (s, 1H), 7.65 (s, 2H), 6.90 (s, 1H), 5.03 (s, 1H), 2.82-2.78 (m, 4H), 2.76-2.67 (m, 4H), 2.41 (s, 3H), 2.00-1.92 (m, 4H), 1.39 (s, 6H).

Table 21. Examples in the following table were prepared using similar conditions as described in Example 221 and Scheme 31 from appropriate starting materials.

Ex t +

Example 223 (Compound 321) HO N

2-(2-Hydroxypropan-2-y H-cyclobuta[f]inden-3- yl)carbamoyl)thiazole-5-sulfonimidamide (Scheme 3A)

Examples 224 and 225 (Compound 321b and 321a)

(R)- and (S)- 2-(2-hydroxypropan-2-yl)-N'-((2,4,5,6-tetrahydro H-cyclobuta[f]inden-3-

yl)carbamoyl)thiazole-5-sulfonimidamide

Route 1:

Step 1: Tert-butyl(2-(2-hydroxypropan-2-yl)-N-((2,4,5,6-tetrahydro-1 H-cyclobuta[f]inden- 3-yl) carbamoyl)thiazole-5-sulfonimidoyl)carbamate

Into a 100-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed tert-butyl N-[amino[2-(2-hydroxypropan-2-yl)-1,3-thiazol-5-yl]oxo- ^ ⁶ - sulfanylidene]carbamate (1.39g, 4.32 mmol) in THF (50 mL). To this solution was added NaH (60%wt. oil dispersion, 518 mg, 13mmol) at 0℃, followed by the addition of 3-isocyanato- 2,4,5,6-tetrahydro-1H-cyclobuta[f]indene (800 mg, 4.32 mmol) in THF (5.0 mL) dropwise at 0℃. The resulting solution was stirred for 14 h at RT. The reaction was then quenched by the addition of 100 mL of water. The resulting solution was extracted with 3x50 mL of DCM. The organic layers combined and dried over anhydrous Na ₂ SO ₄ , then concentrated. The residue was eluted from a silica gel column with ethyl acetate/petroleum ether (1:5 to 1:1). This resulted in 2.0 g (91%) of title compound as a light yellow solid. MS-ESI: 507 (M+1).

Step 2: 2-(2-Hydroxypropan-2-yl)-N'-((2,4,5,6-tetrahydro-1H-cyclobut a[f]inden-3- yl)carbamoyl) thiazole-5-sulfonimidamide

Into a 100-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed tert-butyl(2-(2-hydroxypropan-2-yl)-N-((2,4,5,6-tetrahydro-1 H-cyclobuta[f]inden-3- yl)carbamoyl) thiazole-5-sulfonimidoyl)carbamate (2.2 g, 4.34 mmol) in dioxane (40 mL). To this was added conc. HCl (8 mL,12 M) dropwise at 0℃. The resulting solution was stirred for 14 h at RT. The resulting solution was diluted with 100 mL of water. The resulting solution was extracted with 3x50 mL of DCM. The organic layers combined and dried over anhydrous Na ₂ SO ₄ , then concentrated. The crude product was purified by HP-Flash with the following conditions: Column, C18 silica gel; mobile phase, ACN:H2O=25:75 increasing to ACN:H2O=55:45 within 25 ; Detector, UV 254 nm. This resulted in 1.5 g (85%) of Example 223. MS-ESI: 407 (M+1). ¹ H NMR (300 MHz, DMSO-d6) d 8.35 (s, 1H), 8.05 (s, 1H), 7.74 (s, 2H), 6.66 (s, 1H), 6.25 (s, 1H), 3.06– 2.94 (m, 2H), 2.93– 2.84 (m, 2H), 2.82– 2.60 (m, 4H), 2.03– 1.79 (m, 2H), 1.50 (s, 6H).

Step 3: Chiral resolution

Example 223（1.5 g) was separated with the followed condition: Column: CHIRALPAK IG, 20*250 mm, 5 um; Mobile Phase A: CO ₂ : 60, Mobile Phase B: MeOH-----Preparative: 40; Flow rate: 50 mL/min; 220 nm. The resulting solution was stirred for 20 min at 10℃. This resulted in 546 mg (99%ee, 36.4%) of Example 224 (RT1: 3.47 min) as a white solid and 595 mg (99%ee, 39.6%) of Example 225 (RT2: 5.35 min) as a white solid. The absolute stereochemistry was tentatively assigned.

Example 224: MS-ESI: 407.1 (M+1). ¹ H NMR (300 MHz, DMSO-d6) d 8.35 (s, 1H), 8.05 (s, 1H), 7.74 (s, 2H), 6.66 (s, 1H), 6.25 (s, 1H), 3.06– 2.94 (m, 2H), 2.93– 2.84 (m, 2H), 2.82– 2.60 (m, 4H), 2.03– 1.79 (m, 2H), 1.50 (s, 6H).

Example 225: MS-ESI: 407.1 (M+1). ¹ H NMR (300 MHz, DMSO-d ₆ ) d 8.35 (s, 1H), 8.05 (s, 1H), 7.74 (s, 2H), 6.66 (s, 1H), 6.25 (s, 1H), 3.06– 2.94 (m, 2H), 2.93– 2.84 (m, 2H), 2.82– 2.60 (m, 4H), 2.03– 1.79 (m, 2H), 1.50 (s, 6H). Route 2:

Step 1: Chiral resolution (R) and (S)-tert-butyl(amino(2-(2-hydroxypropan-2-yl)thiazol-5- yl)(oxo)- ^ ⁶ -sulfaneylidene)carbamate

The product10 g of Intermediate 28 was separated with the followed condition: Column: CHIRALPAK IC, 5*25 cm,5 um; Mobile Phase A:CO2 :55, Mobile Phase B: EtOH:HeX=1:1:45; Flow rate: 150 mL/min; UV 220 nm; Rt1: 5.13 (Intermediate 28A); Rt2: 5.65 (Intermediate 28B). This resulted in 3 g (99.5% ee, 60%) of 28A, and 3 g (99.0 % ee, 60%) of 28B.

Step 2: Tert-butyl (R)-(2-(2-hydroxypropan-2-yl)-N-((2,4,5,6-tetrahydro-1H- cyclobuta[f]inden-3-yl) carbamoyl)thiazole-5-sulfonimidoyl)carbamate

Into a 100-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed intermediate 28A (>99% ee, 1.67 g, 5.20 mmol) in THF (50 mL), NaH (60% wt. oil dispersion, 624 mg, 15.6 mmol) was added at 0℃, this was followed by the addition of 3- isocyanato-2,4,5,6-tetrahydro-1H-cyclobuta[f]indene (850 mg, crude) in THF (5 mL) dropwise at 0℃. The resulting solution was stirred for 14 h at RT. The reaction was then quenched by the addition of 100 mL of water. The resulting solution was extracted with 3x100 mL of DCM. The organic layers combined and dried over anhydrous Na2SO4, then concentrated. This resulted in 2.2 g (83.5%) of title compound as a light yellow solid. MS-ESI: 507 (M+1).

Step 3: (R)-2-(2-hydroxypropan-2-yl)-N'-((2,4,5,6-tetrahydro-1H- cyclobuta[f]inden-3- yl)carbamoyl) thiazole-5-sulfonimidamide

Into a 100-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed tert-butyl (S)-(2-(2-hydroxypropan-2-yl)-N-((2,4,5,6-tetrahydro-1H-cycl obuta[f] inden-3-yl)carbamoyl) thiazole-5-sulfonimidoyl)carbamate (2.2 g, 4.34 mmol) in dioxane (40 mL), to this was added conc. HCl (8 mL, 12M) dropwise at 0℃. The resulting solution was stirred for 8 h below 10℃. The resulting solution was diluted with 100 mL of water. The

resulting solution was extracted with 3x100 mL of DCM. The organic layers combined and dried over anhydrous Na2SO4, then concentrated. The crude product was purified by HP-Flash with the following conditions: Column, C18 silica gel; mobile phase, MeCN:water=25:75 increasing to MeCN:water=55:45 within 30 min; Detector, UV 210 nm. This resulted in 1.37 g (77.3%) of

Example 224 (99.4% ee) as a white solid. MS-ESI: 407 (M+1).

1H NMR (300 MHz, DMSO-d6) d 8.43 (s, 1H), 8.09 (s, 1H), 7.90 (s, 2H), 6.67 (s, 1H), 6.29 (s, 1H), 2.92 (d, J = 3.9 Hz, 2H), 2.89 (d, J = 3.9 Hz, 2H), 2.90– 2.55 (m, 4H), 2.00– 1.75 (m, 6H), 1.50 (s, 6H).

Table 22. Examples in the following table were prepared using similar conditions as described in Example 223– Route 1 and Scheme 3A from appropriate starting materials. ] ⁺

N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl-1,1,7,7- 228 25

Example 229 (Compound 307)

F ^H2N H

N H

F 2-Fluoro-N'-((8-fluoro- 1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4- hydroxybenzenesulfonimidamide (Scheme 3B) NCO O

F

Step1: N-(tert-butyldimethylsilyl)-2-fluoro-N'-(8-fluoro-1,2,3,5,6, 7-hexahydro-s-indacen-4- ylcarbamoyl)-4-methoxybenzenesulfonimidamide

Into a 50-mL round-bottom flask, was placed a solution of N-(tert-butyldimethylsilyl)-2-fluoro-4- methoxybenzene-1-sulfonoimidamide (139 mg, 0.44 mmol) in THF (5.0 mL). To this solution was added NaH (60%wt. oil dispersion, 35.2 mg, 0.44 mmol) at 0℃.This was followed by the addition of 4-fluoro-8-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (95 mg, 0.44 mmol) in THF (5 mL) dropwise at RT. The resulting solution was stirred for 1 h at RT. The reaction was then quenched by the addition of 100 mL of water. The resulting solution was extracted with 3x50 mL of ethyl acetate. The organic layers combined and dried over anhydrous Na ₂ SO ₄ , and then concentrated.

The residue was eluted from a silica gel column with ethyl acetate/petroleum ether (1:5 to 1:1).

This resulted in 120 mg (51.2%) of the title compound as yellow oil. MS-ESI: 536 (M+1).

Step 2: 2-Fluoro-N'-(8-fluoro-1,2,3,5,6,7-hexahydro-s-indacen-4-ylca rbamoyl)-4- hydroxybenzenesulfonimidamide Into a 50-mL round-bottom flask, was placed a solution of 1-[[(tert-butyldimethylsilyl)imino](2- fluoro-4- methoxybenzene)sulfinyl]-3-(8-fluoro-1,2,3,5,6,7-hexahydro-s -indacen-4-yl)urea (120 mg, 0.22 mmol) in ACN (5.0 mL), to this solution was added BBr ₃ (561 mg, 2.24 mmol) dropwise at 0℃. The resulting solution was stirred for 2 h at RT. The reaction was then quenched by the addition of 5 mL of MeOH. The resulting mixture was concentrated. The crude product (100 mg) was purified by Prep-HPLC under the following conditions: Column, XBridge Prep OBD C18, 19*250 mm, 5 um; mobile phase: water (10 mM NH4HCO3) and ACN (25% to 43% ACN gradient in 7 min); Detector, UV. This resulted in 17.7 mg (19.4%) of Example 229 as a white solid. MS- ESI: 408 (M+1). Example 230 (Compound 323)

N'-((1-hydroxy-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoy l)-2-(2-hydroxypropan-2- yl)thiazole-5-sulfonimidamide (Scheme 32)

Into a 50-mL round-bottom flask, was placed 2-(2-hydroxypropan-2-yl)-N'-((1-oxo-1,2,3,5,6,7- hexahydro-s-indacen-4-yl)carbamoyl)thiazole-5-sulfonimidamid e (100 mg, 0.23 mmol) in ethanol (10 mL). To this solution was added NaBH ₄ (17.4 mg, 0.46 mmol) in portions at 0℃. The resulting solution was stirred for 2 h at RT. The crude product (5 mL) was purified by Flash-Prep-HPLC with the following conditions: Column: XBridge Prep OBD C18 Column 30×150mm 5um; Mobile Phase A: water (10 mM NH ₄ HCO ₃ ), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 10% to 28% B in 7 min; 210/254 nm; Rt: 6.00 min. This resulted in 180 mg of the title compound (Example 230) as a solid. MS-ESI: 437.1 (M+1).

1H NMR (400 MHz, DMSO-d ₆ ) d 8.51 (br s, 1H), 8.04 (s, 1H), 7.82 (br s, 2H), 6.97 (s, 1H), 6.28 (s, 1H), 5.07 (d, J = 5.6 Hz, 1H), 5.05-4.85 (m, 1H),2.95-2.75 (m, 2H), 2.75-50 (m, 4H), 2.35- 2.15 (m, 1H), 2.00-1.80 (m, 2H), 1.80-1.60 (m, 1H), 1.51 (s, 6H). Example 231 (Compound 338)

O S NH ₂ O N'-((1,2,3,5,6,7-hexahydr o-s- ndacen- -y )carbamoy )-4-((3-methoxyazetidin-1- yl)methyl)benzenesulfonimidamide (Sch e 33A)

O Br

Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 1-[amino[4-(bromomethyl)phenyl]oxo- ^ ⁶ -sulfanylidene]-3-(1,2,3,5,6,7-hexahydro-s- indacen-4-yl)urea(50 mg, 0.11 mmol) in THF(5 mL). To this solution was added DIEA (28.4 mg, 0.22mmol) and 3-methoxyazetidine(10.5 mg, 0.12 mmol) at RT. The resulting solution was stirred for 1 h at 65℃. The resulting mixture was concentrated. The crude product was purified by Prep- HPLC with the following conditions: Column: XBridge Prep C18 OBD Column 19×100mm 5um 13nm; Mobile Phase A: water (10 mM NH4HCO3mM+0.1%NH ^.

3H2O), Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 30% to 37% B in 9.5 min; 254/210 nm; Rt: 9.62 min .This resulted in 5 mg of Example 231 as a white solid. MS-ESI: 455 (M+1). ¹ H NMR (300MHz , DMSO-d6) d: 8.27 (br s, 1H), 7.81 (d, J = 8.4 Hz, 2H), 7.45 (d, J = 8.4 Hz, 2H), 7.34 (s, 2H), 6.85 (s, 1H), 4.02-3.94 (m, 1H), 3.67 (s, 2H), 3.51-3.46 (m, 2H), 3.14(s, 3H), 2.95-2.80 (m, 2H), 2.78- 2.73 (m, 4H), 2.69-2.63 (m, 4H), 1.96-1.88 (m, 4H). Table 23. Examples in the following table were prepared using similar conditions as described in Example 231 and Scheme 33A from appropriate starting materials. Exact ^{. # Final}

T _{ar et #} ^{Structure IUPAC Name} Mass

+H] ⁺ 32 ⁴⁵⁷

33 ³⁸⁶

34 ⁴⁵⁵

35 ⁴⁷⁵

36 ⁴³⁹ 37 ⁴²⁵ 38 ⁴³⁹

39 _{((met y(prop- -yny)amno)met y)benzenesu onmdamde} ⁴³⁷

N ^O O

N _H2

S N ^NH

40 ⁴⁵³ 41 ⁴⁶³ 42 ⁴⁰⁰ 43 ³⁸⁵

Example 244 (Compound 401)

N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-((2-o xopyrrolidin-1- yl)methyl)benzenesulfonimidamide (Scheme 33B)

Into a 40-mL sealed tube purged and maintained with an inert atmosphere of nitrogen, was placed 1-[amino[4-(bromomethyl)phenyl]oxo- ^ ⁶ -sulfanylidene]-3-(1,2,3,5,6,7-hexahydro-s-indacen-4- yl)urea (200 mg, 0.45 mmol) in THF (10 mL), to this stirred solution was added DIEA (173 mg, 1.34 mmol) and pyrrolidin-2-one (114 mg, 1.34 mmol) at RT. The resulting solution was stirred for 3 h at 60 ^o C. The resulting mixture was concentrated. The crude product was purified by Prep- HPLC with the following conditions: Column, XBridge Prep OBD C18, 30x150 mm 5 um; mobile phase, water (10 mM NH ₄ HCO ₃ ) and ACN (25% to 44% ACN gradient in 7 min); Detector, UV. This resulted in 10 mg (4.95%) of Example 244 as a white solid. MS-ESI: 453 (M+1).

1H NMR (400 MHz, DMSO-d6) d: 8.26 (br s, 1H), 7.83 (d, J = 8.0 Hz, 2H), 7.40 (d, J = 8.0 Hz, 2H), 7.27 (br s, 2H), 6.85 (s, 1H), 4.43 (s, 2H), 3.26-3.22 (m, 2H), 2.78-2.74 (m, 4H), 2.65-2.61 (m, 4H), 2.30 (t, J = 8.20 Hz, 2H), 1.98-1.89 (m, 6H). Example 245 (Compound 404) N'-((1, hexahydro-s-indacen-4-yl)carbamoyl)-4-(2-hydroxypropan-2-yl) -N,N-

dimethylthiophene-2-sulfonimidamide (Scheme 4A)

Into a 50-mL 3-necked round-bottom flask, was placed a solution of 4-(2-hydroxypropan-2-yl)- N,N- dimethylthiophene-2-sulfonoimidamide (125 mg, 0.50 mmol) in THF (2.0 mL). To this was added NaH (60%wt. oil dispersion, 30.2 mg, 0.75 mmol) in several batches at 0℃ in an ice/water bath. To the mixture was added 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (110 mg, 0.55 mmol) at 0℃ in an ice/water bath. The resulting solution was stirred for 30 min at 0℃ in a water/ice bath. The reaction was then quenched by the addition of NH4Cl (aq.). The resulting solution was extracted with ethyl acetate and the organic layers combined, the organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions: X Bridge Prep C ₁₈ OBD, 19*150mm 5 um; mobile phase, water (10 mM NH4HCO3) and ACN (10% to 80% in 6 min); Detector, UV 254 nm. This resulted in 90 mg (39.9%) of Example 245 as a white powder. MS-ESI: 448.2 (M+1). ¹ H NMR (DMSO-d ₆ , 300 MHz): d 8.60 (br s, 1H), 7.71 (s, 1H), 7.58 (br s, 1H), 6.88 (s, 1H), 5.21 (s, 1H), 2.86-2.70 (m, 8H), 2.70 (s, 6H), 1.98-1.90 (m, 4H), 1.3 (s, 6H). Example 246 (Compound 331)

N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-(2-hy droxypropan-2-yl)-N- methylthiophene-2-sulfonimidamide (Scheme 4)

E ^{xample 246}

Into a 50-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 4-(2-hydroxypropan-2-yl)-N-methylthiophene-2-sulfonoimidamid e (106 mg, 0.45 mmol) in THF (4.0 mL). This was followed by the addition of NaH (60%wt. oil dispersion, 23.5 mg, 0.59 mmol) in several batches at 0℃ in a water/ice bath. To this was added a solution of 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (99.1 mg, 0.50 mmol) in THF (2.0 mL) dropwise with stirring at 0℃. The resulting solution was stirred for 30 min at 0℃ in a water/ice bath. The reaction was then quenched by the addition of water/ice. The resulting solution was extracted with ethyl acetate and the organic layers combined, the organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions: Column, X Bridge Shield RP18 OBD, 19x250 mm, 10 um; mobile phase, water (10 mM NH ₄ HCO ₃ +0.1%NH ₃ .H ₂ O) and ACN (43% to 67% ACN gradient in 6 min); Detector, UV 254 nm. This resulted in 80 mg (40.79%) of Example 246 as a white solid. MS-ESI: 434.15 (M+1). ¹ H NMR (DMSO-d6, 300 MHz): d 8.55 (br s, 1H) 7.65 (s, 1H), 7.59 (s, 1H), 7.53 (s, 1H), 6.89 (s, 1H), 5.22 (s, 1H) 2.63-2.85 (m, 8H) 2.49 (s, 3H) 2.00-1.80 (m, 4H) 1.31 (s, 6H).

Table 24. Examples in the following table were prepared using similar conditions as described in Example 246 and Scheme 4 from appropriate starting materials.

Final Exact Example

T t St t IUPAC N M ss

H] ⁺

2 5

Example 248 (Compound 405)

H ^2N

N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)(methyl)carbamoyl) -2-(2-hydroxypropan-2- yl)thiazole-5-sulfonimidamide (Scheme 34) N O

Step 1: Tert-butyl(N-((1,2,3,5,6,7-hexahydro-s-indacen -4-yl)(methyl)carbamoyl)-2- (2- hydroxypropan -2-yl)thiazole-5-sulfonimidoyl)carbamate

Into a 50-mL round-bottom flask, was placed tert-butyl N-([[(1,2,3,5,6,7-hexahydro-s-indacen-4- yl) carbamoyl]imino][2-(2-hydroxypropan-2-yl)-1,3-thiazol-5-yl]o xo- ^ ⁶ -sulfanyl)carbamate (200 mg, 0.38 mmol) in THF (10 mL), to this stirred solution was added CH ₃ I (60 mg, 0.42 mmol) dropwise at 0℃. The resulting solution was stirred for 1 d at RT. The resulting mixture was concentrated. This resulted in 100 mg (49%) of the title compound as a solid. MS-ESI: 535 (M+1). Step 2: N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)(methyl)carbamoyl) -2-(2-hydroxypropan- 2-yl) thiazole-5-sulfonimidamide

Into a 25-mL round-bottom flask, was placed tert-butyl N-([[(1,2,3,5,6,7-hexahydro-s-indacen-4- yl) (methyl)carbamoyl]imino][2-(2-hydroxypropan-2-yl)-1,3-thiazo l-5-yl]oxo- ^ ⁶ - sulfanyl)carbamate (100 mg) in HCl (4M, 10 mL). The resulting solution was stirred for 5 h at RT. The crude product was purified by Prep-HPLC with the following conditions: Column, XBridge Prep C18 OBD, 5um, 19*150 mm; mobile phase, water (10 mM NH4HCO3mM) and ACN (22% to 53% ACN gradient in 7 min); Detector, UV. This resulted in 15.7 mg of Example 248 as a solid. MS-ESI: 435 (M+1). Table 25. Example 249 was isolated as a side product from the preparation of Example 248.

Example 250 (Compound 324)

N-(N-((1, hexahydro-s-indacen-4-yl)carbamoyl)-2-(2-hydroxypropan-2-yl) thiazole-5-

sulfonimidoyl)acetamide (Scheme 35A)

Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a mixture of N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(2- hydroxypropan-2-yl)thiazole-5- sulfonimidamide (200 mg, 0.48 mmol) and TEA (96 mg, 0.96 mmol) in DCM (20 mL). To the stirred solution, Ac2O (74 mg, 0.72 mmol) was added dropwise at 0 ^o C. The resulting solution was stirred overnight. Then 80 mg of the product was obtained by Prep-HPLC with the following conditions: Column: XBridge Prep C18 OBD Column 19×150 mm 5um; Mobile Phase A: water (10 mM NH4HCO3), Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 18% B to 41% B in 7 min; 254 /210 nm; Rt: 5.05 min, this resulted in 100 mg of the Example 250 as a white solid. MS-ESI: 462.14 (M+1). ¹ H NMR (300 MHz, CD3OD-d4) d: 8.11 (s, 1H), 6.89 (s, 1H), 2.92– 2.69 (m, 8H), 2.09– 2.01 (m, 4H), 1.99 (s, 3H), 1.60 (d, J = 2.3 Hz, 6H). Example 251 (Compound 407)

methyl 4-((4- 1,2,3,5,6,7-hexahydro-s-indacen-4-

yl)carbamoyl)sulfamidimidoyl)benzyl)(methyl)amino)-4-oxobuta noate (Scheme 35)

Into a 8-mL round-bottom flask, was placed a solution of 1-[amino([4-[(methylamino)methyl]- phenyl])oxo- ^ ⁶ -sulfanylidene]-3-(1,2,3,5,6,7-hexahydro-s-indacen-4-y l)urea (100 mg, 0.25 mmol), methyl 4-chloro-4-oxobutanoate (37.8 mg, 0.25 mmol) in DMF (10 mL), to this stirred solution was added HATU (191 mg, 0.50 mmol) and DIEA (64.9 mg, 0.50 mmol). The resulting solution was stirred for 20 min at RT. The crude product was purified by Prep-HPLC with the following conditions: Column, XBridge Shield RP18 OBD, 19*250 mm,10 um; mobile phase, water (10 mM NH ₄ HCO ₃ ) and ACN (15% to 75% ACN gradient in 7 min); Detector, UV 250 nm. This resulted in 4.2 mg (3.27%) of Example 251 as a white solid. MS-ESI: 513 (M+1). ¹ H NMR (300MHz, CD3OD-d4) d: 8.02-7.94 (m, 2H), 7.49-7.41 (m, 2H), 6.89 (s, 1H), 4.68 (s, 2H), 3.68 (s, 3H), 3.04 (s, 3H), 2.85-2.80 (m, 4H), 2.75-2.60 (m, 8H), 2.03-1.97 (m, 4H).

Example 252 (Compound 410)

4-((4-(N'-(1,2,3,5,6,7-hexahydro-s-indacen-4-

Into a 50-mL round-bottom flask, was placed a solution of methyl 3-[([4-[amino([[(1,2,3,5,6,7– hexahydro-s-indacen-4-yl)carbamoyl]imino])oxo- ^ ⁶ -sulfanyl]phenyl]methyl)(methyl)- carbamoyl]propanoate (80 mg, 0.16 mmol) in THF (3.0 mL) and H2O (3.0 mL), to the stirred solution was added KOH (17.5 mg, 0.31 mmol). The resulting solution was stirred for 120 min at RT. The crude product was purified by Prep-HPLC with the following conditions: Column, XBridge Shield RP18 OBD, 19*250 mm,10 um; mobile phase, water (10 mM NH4HCO3) and ACN (15% to 75% gradient in 7 min); Detector, UV250 nm. This resulted in 39 mg (50%) of Example 252 as a white solid. MS-ESI: 499 (M+1). ¹ H-NMR (300 MHz, CD3OD-d4) d: 8.10-7.80 (m, 2H), 7.55-7.30 (m, 2H), 6.89 (s, 1H), 4.68 (s, 2H), 3.04 (s, 3H), 2.90-2.60 (m, 12H), 2.10-1.80 (m, 4H). Example 253 (Compound 408)

(E)-N-(4-(N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoy l)sulfamidimidoyl)benzyl)-N- methyloct-4-en-7-ynamide (Scheme 35)

Example 253 was prepared using similar conditions as described in Example 251 and Scheme 35 from 3-(3-(but-3-ynyl)-3H-diazirin-3-yl)propanoic acid and Intermediate 67. MS-ESI: 519 (M+1) Table 26. Examples in the following table were prepared using similar conditions as described in Example 4 - route 1 and Scheme 2 from appropriate starting materials.

Final Exact +

N-(4-(N'-((1,2,3,5,6,7-hexahydro-s-

y F ^O 3-Fluoro-N'-(1,2,3,5,6,7-hexahydro-s-

O

S NH N'-(1,2,3,5,6,7-hexahydro-s-indacen-4-

Table 27. Examples in the following table were prepared using similar conditions as described in Example 4 - route 2 and Scheme 3 from appropriate starting materials. E

+

-

Table 28. Examples in the following table were obtained from chiral HPLC resolutions of racemic examples described above. The chiral column and eluents are listed in the table. As a convention, the faster-eluting enantiomer is always listed first in the table followed by the slower-eluting enantiomer of the pair. The symbol * at a chiral center denotes that this chiral center has been resolved and the absolute stereochemistry at that center has not been determined. For mixtures contained two chiral centers and if two columns are used for separating the four diastereomers, the individual isomers are listed in the order of faster column 1/faster column 2; faster column 1/slower column 2; slower column 1/faster column 2; followed by slower column 1/slower column 2. Final

S

Ex

] ₊

29

29

29

29

30 (S) or (R) -N'-((3-fluoro-2,6- CHIRALP 30% EtOH 30

¹²

¹²

30

30

# The amount of NH ₃ in this chiral chromatographic solvent and similar solvents were adjusted by adding 2 M NH3 in methanol to the desired NH3 concentration. In this case, the resulting concentration of NH3 in methanol is 8 mM.

Example 425 (Compound 318) 1-{Amino[5-(2-hydroxypropan-2-yl)-1,3-thiazol-2-yl]oxo- sulfanylidene}-3-(8-bromo-

1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea

Step 1: 4-Bromo-1,2,3,5,6,7-hexahydro-8-isocyanato-s-indacene To a solution of 8-bromo-1,2,3,5,6,7-hexahydros-indacen-4-amine (1.5 g, 5.94 mmol) in anhydrous THF (50 mL) was added triethylamine (1.07 mL, 7.73 mmol) and triphosgene (882 mg, 2.97 mmol) at room temperature. The resulting mixture was then stirred at 60 °C for 4h. Reaction mixture was then brought to room temperature and used directly in the next step. Step 2: 1-{Amino[5-(2-hydroxypropan-2-yl)-1,3-thiazol-2-yl]oxo- ^ ⁶ -sulfanylidene}-3-(8- bromo-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea To a solution of N-(tert-butyldimethylsilyl)-5-(2-hydroxypropan-2-yl)-1,3-thi azole-2- sulfonoimidamide (400 mg, 1.2 mmol) in anhydrous THF (10 mL) was added NaH (60% wt. oil dispersioin, 96 mg, 2.4 mmol) at room temperature. After 5 min, a solution of 4-bromo-1,2,3,5,6,7- hexahydro-8-isocyanato-s-indacene (2 mL, 2 mmol, from Step 1) was added drop wise. The resulting mixture was stirred at room temperature for 20 min before quenching carefully with 4 M HCl solution in dioxane (3 mL). Saturated aqueous ammonium chloride was added and the mixture was extracted with dichloromethane (15 mL x 3). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by prep-HPLC to obtain the titled compound (280 mg, 47%). LCMS: [M+H] ⁺ = 499.3. Example 426 (Compound 313) 1-{Amino[5-(2-hydroxypropan-2-yl)-1,3-thiazol-2-yl]oxo- ^ ⁶ -sulfanylidene}-3-[7- dimethylphenyl)-2,3-dihydro-1H-inden-4-yl]urea

Step 1: N-(2,3-dihydro-1H-inden-4-yl)acetamide To a solution of 2,3-dihydro-1H-inden-4-amine (3.4 g, 26 mmol) in ethanol (45 mL) was added a solution of acetic anhydride (4.9 mL, 52 mmol) in ethanol (15 mL) dropwise at 0 °C. The resulting mixture was gradually warmed up to RT and stirred for 15 h. Solvent was removed under reduced pressure and the residue was triturated with diethyl ether to afford titled compound as off white solid (3 g, 66%). LCMS [M+H] ⁺ = 176.3. Step 2: N-(4-bromo-2,3-dihydro-1H-inden-7-yl)acetamide Into a 250-mL round-bottom flask was added N-(2,3-dihydro-1H-inden-4-yl)acetamide (3 g, 17.1 mmol) and acetic acid (45 mL). The resulting solution was cooled to 0 °C and then a solution of bromine (5.4 g, 34.2 mmol) in acetic acid (12 mL) was added dropwise with stirring over 10 min. The cooling bath was removed and the reaction mixture was stirred at RT for 1h. Water was added and the resulting precipitates of product were collected by filtration and dried under vacuum to afford titled compound as off white solid (3.9 g, 90%). LCMS [M+H] ⁺ = 254.4. Step 3: N-(2,3-dihydro-4-(3,4-dimethylphenyl)-1H-inden-7-yl)acetamid e A mixture of N-(4-bromo-2,3-dihydro-1H-inden-7-yl)acetamide (1 g, 3.9 mmol), 3,4- dimethylphenylboronic acid (700 mg, 4.68 mmol), Pd(dppf)Cl ₂ .DCM (160 mg, 0.19 mmol), sodium carbonate (900 mg, 8.58 mmol as 2 M aqueous solution) in dioxane (12 mL) was stirred at 100 °C in an oil bath for 72 h. The reaction mixture was brought to RT, water (20 mL) was added and extracted with EtOAc (15 mL x 3). The combined organic layers were washed with brine, dried over MgSO ₄ , filtered, and concentrated in vacuo. The crude product was purified by silica gel flash chromatography using 0- 30% gradient of EtOAc in hexanes to afford titled compound (880 mg, 81%). LCMS [M+H] ⁺ = 280.6. Step 4: 2,3-Dihydro-7-(3,4-dimethylphenyl)-1H-inden-4-amine A solution of N-(2,3-dihydro-4-(3,4-dimethylphenyl)-1H-inden-7-yl)acetamid e (880 mg, 3.15 mmol) in 6 N HCl (20 mL) was stirred at 100 °C for 40 h. After consumption of the starting material, the reaction mixture was cooled to 0 °C and adjusted to pH = 8 with 10 M aqueous sodium hydroxide solution. The precipitates formed were collected, washed with water and dried under vacuum to afford the titled compound (81 mg, 67%) as tan colored powder. LCMS [M+H] ⁺ = 238.3. Step 5: 1-{Amino[5-(2-hydroxypropan-2-yl)-1,3-thiazol-2-yl]oxo- ^ ⁶ -sulfanylidene}-3-[7-(3,4- dimethylphenyl)-2,3-dihydro-1H-inden-4-yl]urea To a solution of N-(tert-butyldimethylsilyl)-5-(2-hydroxypropan-2-yl)-1,3-thi azole-2- sulfonoimidamide (42 mg, 0.13 mmol) in DMF (1 mL) was added Et3N (35 uL, 0.25 mmol) and the resulting mixture was stirred at room temperature for 10 min, followed by the addition of CDI (41 mg, 0.25 mmol). The reaction mixture was further stirred at RT for 1 h, and then 2,3-dihydro- 7-(3,4-dimethylphenyl)-1H-inden-4-amine (30 mg, 0.13 mmol) was added. The resulting reaction mixture was stirred overnight at room temperature. The presence of desired product was then confirmed by LC-MS. The reaction mixture was quenched with 4 M HCl in dioxane (1 mL) and stirred for 30 min to de-protect the TBS group which indicated the formation of desired product on LCMS. The crude product was purified by preparative HPLC to provide titled compound (16.4 mg, 27%). LCMS [M+H] ⁺ = 485.49. Example 427 (Compound 314)

1-{Amino[5-(2-hydroxypropan-2-yl)-1,3-thiazol-2-yl]oxo- ^ ⁶ -sulfanylidene}-3-[8- dimethylphenyl)- hexahydro-s-indacen-4-yl]urea

Step 1: 1,2,3,5,6,7-Hexahydro-8-(3,4-dimethylphenyl)-s-indacen-4-ami ne 8-Bromo-1,2,3,5,6,7-hexahydro-s-indacen-4-amine (105 mg, 0.42 mmol), 3,4-dimethylphenyl- boronic acid (187 mg, 1.25 mmol), Pd(dppf)Cl2 (30.4 mg, 0.04 mmol) and dioxane (1.5 mL) were added to a reaction vial. Cesium carbonate (1.24 mL, 1 M in H ₂ O) was then added and the reaction mixture was stirred at 80 °C for 16 h. Reaction mixture was brought to RT and filtered through a small bed of Celite and rinsed with dioxane (5 mL). Water (5 mL) was added to the filtrates and extracted with diethyl ether (5 mL x 3). The combined organic layers were washed with brine, dried over anhydrous MgSO ₄ , filtered, and concentrated in vacuo to provide titled compound which was used in the next step without any purification. LCMS [M+H] ⁺ = 278.4. Step 2: 1-{Amino[5-(2-hydroxypropan-2-yl)-1,3-thiazol-2-yl]oxo- ^ ⁶ -sulfanylidene}-3-[8-(3,4- dimethylphenyl)-1,2,3,5,6,7-hexahydro-s-indacen-4-yl]urea The title product was obtained using similar procedure as in Step 5 Example 426. LCMS: [M+H] ⁺ = 525.42. Example 428 (Compound 309) 3-[Amino(dimethyl-1,3-thiazol-5-yl)oxo- ^ ⁶ -sulfanylidene]-1-[4-fluoro-2,6-bis(propan-2- yl)phenyl]urea

F

S

Step 1: N-(tert-butyldimethylsilyl)-2,4-dimethyl-1,3-thiazole-5-sulf onamide Dimethyl-1,3-thiazole-5-sulfonamide (41.4 mg, 0.22 mmol) was dissolved in anhydrous CH2Cl2 (2 mL). Triethylamine (0.090 mL, 0.65 mmol) and TBSCl (38 mg, 0.25 mol) were added and the resulting mixture was stirred at 50 ^o C for 18 h. Reaction mixture was brought to RT and used directly in the next step. LCMS: [M+H] ⁺ = 307.2. Step 2: N-(tert-butyldimethylsilyl)-2,4-dimethyl-1,3-thiazole-5-sulf onoimidamide Polymer bound dichlorotriphenylphosphorane reaction mixture (described for Reagent 2) was cooled in an ice/water bath under nitrogen. Triethylamine (0.1 mL, 0.72 mmol, 2.25 equiv.) was added slowly via syringe. Resulting mixture was stirred at 0 ^o C for 10 min and then the reaction mixture from Step 1 above was added dropwise via syringe. This reaction mixture was further stirred at 0 ^o C for 30 min and then a steady stream of anhydrous ammonia was bubbled into the reaction mixture for 3 min. Reaction vial was screw capped and stirred in ice/water bath for 2h. Reaction mixture was warmed up to room temperature, carefully opened and filtered to remove resin. The cloudy filtrate was centrifuged to remove any solids. Supernatant was concentrated in vacuo and dried under high vacuum for 1 h and used directly in the next step. LCMS: [M+H] ⁺ = 306.8. Step 3: 3-{[(Tert-butyldimethylsilyl)amino](dimethyl-1,3-thiazol-5-y l)oxo- ^ ⁶ -sulfanylidene}- 1-[4-fluoro-2,6-bis(propan-2-yl)phenyl]urea To the crude reaction mixture from Step 2 was added anhydrous THF (1.5 mL) and the resulting mixture was stirred in an ice/water bath for 5 min. NaH (17 mg, 0.44 mmol) was added and after 2 min of stirring a solution of isocyanate (0.165 mmol) in THF (3 ml) was added dropwise at 0 ^o C. The resulting mixture was brought to RT and stirred for 15 min to give a mixture of crude products. LCMS: [M+H] ⁺ = 527.5; for de-protected product, [M+H] ⁺ = 413.5. Step 4: 3-[amino(dimethyl-1,3-thiazol-5-yl)oxo- ^ ⁶ -sulfanylidene]-1-[4-fluoro-2,6- bis(propan-2-yl)phenyl]urea To the reaction from Step 3 was carefully added 4N HCl in dioxane (0.3 mL) and the resulting mixture was stirred at RT for 30 min or till the completion of reaction as determined by the LCMS analysis ([M+H] ⁺ = 413.5). Reaction mix was then concentrated in vacuo. DMSO (0.8 mL) was added to the residue and purified by prep-HPLC to afford titled compound (10 mg). Examples in the following table were prepared using similar procedures described in Example 428. Table 29.

Example 281 (Compound 378)

3-Fluoro-5-(2-hydroxypropan-2-yl)-N'-((2,4,5,6-tetrahydro-1H -cyclobuta[f]inden-3- yl)carbamoyl)thiophene-2-sulfonimidamide (Scheme 1)

Examples 432 (Compound 378a) and Example 433 (Compound 378b)

(R)- and (S)-3-Fluoro-5-(2-hydroxypropan-2-yl)-N'- tetrahydro-1H-cyclobuta[f]inden-3-

yl) -carbamoyl)thiophene-2-sulfonimidamide

Step 1: N-(tert-butyldimethylsilyl)-3-fluoro-5-(2-hydroxypropan-2-yl )-N'-(2,4,5,6- tetrahydro-1H -cyclobuta[f]inden-3-ylcarbamoyl)thiophene-2-sulfonimidamide

To a stirred solution of N'-(tert-butyldimethylsilyl)-3-fluoro-5-(2-hydroxypropan-2-y l)thiophene- 2 -sulfonimidamide (200 mg, 0.57 mmol) in THF (15 mL) in a 100 mL 3-necked round-bottom flask under nitrogen was added NaH (60% oil dispersion, 68 mg, 1.70 mmol) in one portion at 0 ^° C, then 3-isocyanato-2,4,5,6-tetrahydro-1H-cyclobuta[f]indene (105 mg, 0.57 mmol) in THF (2.0 mL) was added dropwise at 0 ^° C. The resulting solution was stirred for 2 h at RT. The reaction was then quenched by the addition of 10 mL of water. The resulting solution was extracted with 3x50 mL of EtOAc and the organic layers were combined and dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The crude product was purified by Prep-TLC (PE/EtOAc = 1:1). This resulted in 110 mg (36.1%) of the title compound as a yellow solid. MS-ESI: 538 (M+1). Step 2: 3-Fluoro-5-(2-hydroxypropan-2-yl)-N'-((2,4,5,6-tetrahydro-1H -cyclobuta[f]inden-3- yl) carbamoyl)thiophene-2-sulfonimidamide

To a stirred solution of N-(tert-butyldimethylsilyl)-3-fluoro-5-(2-hydroxypropan-2-yl )-N'- (2,4,5,6- tetrahydro-1H-cyclobuta[f]inden-3-ylcarbamoyl)thiophene-2-su lfonimidamide (100 mg, 0.19 mmol) in THF (15 mL) in a 50-mL round-bottom flask was added TBAF (146 mg, 0.56 mmol) in one portion at RT. The resulting solution was stirred for 2 h at RT. The resulting mixture was concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (3:2). The crude product was purified by Prep-HPLC with the following conditions: XBridge Prep C18 OBD Column, 19*150 mm*5um; mobile phase, Water (10 mM NH4HCO3+0.1%NH ^.

3H2O) and MeCN (25% to 41% Phase B over 7 min); Detector, UV 254/210 nm. This resulted in 60 mg (76.1%) of

Example 281 as a white solid. MS-ESI: 424 (M+1). ¹ H NMR (400 MHz, DMSO-d ₆ ) d 8.31 (s, 1H), 7.69 (br s, 2H), 6.95 (s, 1H), 6.66 (s, 1H), 5.86 (s, 1H), 3.05-2.93 (m, 2H), 2.93-2.85 (m, 2H), 2.83-2.63 (m, 4H), 2.00-1.80 (m, 2H), 1.47 (s, 3H), 1.46 (s, 3H).

Step 3: Chiral separation

3-Fluoro-5-(2-hydroxypropan-2-yl)-N'-(2,4,5,6-tetrahydro-1H- cyclobuta[f]inden-3- ylcarbamoyl)thiophene-2-sulfonimidamide (60 mg) was resolved by Chiral HPLC with the following conditions: Column: CHIRALPAK IG, 20*250 mm, 5 um; Mobile Phase A: Hex (8 mM NH ^.

3MeOH), Mobile Phase B: IPA; Flow rate: 20 mL/min; Gradient: 30 B to 30 B in 13 min;

220/254 nm; Rt1: 6.2 min (Example 432); Rt2: 9.46 min (Example 433). This resulted in 15 mg of Example 432 and 16 mg of Example 433, both as white solids.

Example 432: MS-ESI: 424 (M+1). ¹ H NMR (400 MHz, DMSO-d ₆ ) d 8.32 (s, 1H), 7.79 (br s, 2H), 6.97 (s, 1H), 6.67 (s, 1H), 5.88 (s, 1H), 3.05-2.93 (m, 2H), 2.93-2.85 (m, 2H), 2.83-2.63 (m, 4H), 2.00-1.80 (m, 2H), 1.48 (s, 3H), 1.47 (s, 3H).

Example 433: MS-ESI: 424 (M+1). ¹ H NMR (400 MHz, DMSO-d6) d 8.30 (s, 1H), 7.80 (s, 2H), 6.97 (s, 1H), 6.67 (s, 1H), 5.86 (s, 1H), 3.05-2.93 (m, 2H), 2.93-2.85 (m, 2H), 2.85-2.65 (m, 4H), 2.00-1.80 (m, 2H), 1.48 (s, 3H), 1.47 (s, 3H).

Table 37. Examples in the following table were prepared using similar conditions as described in Example 281 and Scheme 1 from appropriate starting materials. xact # ass

+H] ⁺ 34 35 sulfonimidamide 829 212Dihd 2 l ' 123 6

37 62 52 87 2 ¹ 18 43 N'-((8-cyano-1,2,3,5,6,7-hexahydro-s-indacen-4- 79

4-(Azetidin-2-yl)-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)benzenesulfonimidamide

(Scheme I)

Step 1: Tert-butyl 2-(4-(N-(tert-butyldimethylsilyl)-N'-((1,2,3,5,6,7-hexahydro -s-indacen-4- yl) carbamoyl)sulfamidimidoyl)phenyl)azetidine-1-carboxylate

To a stirred solution of tert-butyl 2-(4-(N-(tert- butyldimethylsilyl)sulfamidimidoyl)phenyl)azetidine-1- carboxylate (80 mg, 0.19 mmol) in THF (5 mL) in a 100 mL 3 necked round-bottom flask under nitrogen was added NaH (60% oil dispersion, 15.2 mg, 0.38 mmol) in one portion at 0 ^° C, 4-isocyanato-1,2,3,5,6,7-hexahydro-s- indacene (39.3 mg, 0.19 mmol) in THF (2 mL) was added dropwise at 0 ^° C. The resulting

solution was stirred for 2 h at RT. The reaction was then quenched by the addition of 5 mL of water. The resulting solution was extracted with 3x50 mL of EtOAc. The organic layers were combined and dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was eluted from silica gel with EtOAc/PE (1/1). This resulted in 90 mg (76.6%) of the title compound as a yellow solid. MS-ESI: 625 (M+1)

Step 2: 4-(Azetidin-2-yl)-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoylbenzenesulfonimidamide

To a stirred solution of tert-butyl 2-(4-(N-(tert-butyldimethylsilyl)-N'-((1,2,3,5,6,7-hexahydro -s- indacen-4- yl)carbamoyl)sulfamidimidoyl)phenyl)azetidine-1-carboxylate (90 mg, 0.14 mmol) in DCM (10 mL) in a 25-mL round-bottom flask was added TFA (2 mL) dropwise at 0 ^° C. The resulting solution was stirred for 10 min at 0 ^° C. The resulting mixture was concentrated under reduced pressure below 30 ^° C. The crude product was purified by Prep-HPLC with the following conditions: XBridge Prep OBD C18 Column, 30*150 mm 5 um; mobile phase, water (10 mM NH4HCO3+0.1%NH ^.

3H2O) and MeCN (20% to 40% Phase B over 7 min); Detector, UV 254/220 nm. This resulted in 6.10 mg (10.3%) of Example 444 as a white solid. MS-ESI: 411 (M+1).

Example 445 (Compound 870a)

(6R)- hexahydro-s-indacen-4-yl)carbamoyl)-6- amino)-6,7-dihydro-5H-

pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidamide (Scheme II)

Step 1: Tert-butyl (R)-3-(N-(tert-butyldimethylsilyl)-N'-(1,2,3,5,6,7-hexahydro -s-indacen-4- ylcarbamoyl)sulfamimidoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1, 3]oxazin-6- yl(methyl)carbamate To a stirred solution of tert-butyl (R)-3-(N'-(tert-butyldimethylsilyl)sulfamimidoyl)-6,7-dihydr o- 5H- pyrazolo[5,1-b][1,3]oxazin-6-yl-(methyl)carbamate (1.10 g, 3.31 mmol) in THF (50 mL) in a 100-mL 3 necked round-bottom flask under nitrogen was added NaH (60% oil dispersion, 397 mg, 9.93 mmol) in portions at 0 ^° C. The resulting solution was stirred for 20 min at RT. To this was added 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (1.32 g, 6.62 mmol) in THF (5 mL) dropwise at 0 ^° C. The resulting solution was allowed to react, with stirring, for an additional 16 h at RT. The reaction was then quenched by the addition of 20 mL of water. The resulting solution was extracted with 3x30 mL of EtOAc. The organic layers were combined and dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was eluted from silica gel with EtOAc/PE (2:3). This resulted in 556 mg (35%) of the title compound as an off-white solid. MS-ESI: 645 (M+1).

Step 2: (6R)-N'-(1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoyl)-6-(m ethylamino)-6,7- dihydro-5H- pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidamide

To a stirred solution of tert-butyl (R)-3-(N-(tert-butyldimethylsilyl)-N'- (1,2,3,5,6,7-hexahydro-s- indacen-4-ylcarbamoyl)sulfamimidoyl)-6,7-dihydro-5H-pyrazolo [5,1-b][1,3]oxazin-6- yl(methyl)carbamate (280 mg, 0.43 mmol) in DCM (10 mL) in a 50-mL round-bottom flask was added BF3.Et2O (47%wt., 289 mg, 2.0 mmol) dropwise at 0 ^° C. The resulting solution was stirred for 2 h at 0 ^° C. The reaction was then quenched by the addition of 0.5 mL of sat. NaHCO3 (aq). The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions: XBridge Prep OBD C18 Column, 30*150 mm, 5um; mobile phase, water (10 mM NH4HCO3+0.1%NH ^.

3H2O) and MeCN (10% to 33% Phase B over 7 min); Detector, UV (254/220 nm). This resulted in 80 mg (40.9%) of Example 445 as an off-white solid. MS-ESI: 431 (M+1). ¹ H NMR (400 MHz, DMSO-d ₆ ) d 8.18 (br s, 1H), 7.52 (s, 1H), 7.25 (br s, 2H), 6.86 (s, 1H), 4.40-4.32 (m, 1H), 4.32-4.19 (m, 2H), 4.00-3.90 (m, 1H), 3.25-3.10 (m, 1H), 2.78 (t, J = 7.4 Hz, 4H), 2.75– 2.60 (m, 4H), 2.35 (d, J = 2.2 Hz, 3H), 2.00– 1.88 (m, 4H).

Example 446 (Compound 846) H ₂ N ^O

4-((Dimethylamino)m y , , , y -cyclobuta[f]inden-3- ylcarbamoyl)benzenesulfonimidamide (Scheme 3)

Step 1: Tert-butyl 4-((dimethylamino)methyl)-N-(2,4,5,6-tetrahydro-1H-cyclobuta [f]inden- 3- ylcarbamoyl)phenylsulfonimidoylcarbamate

To a stirred solution of tert-butyl (amino(4-((dimethylamino)methyl)phenyl)(oxo)-l ⁶ - sulfaneylidene)carbamate (100 mg, 0.32 mmol) in THF (5.0 mL) a 100 mL 3 necked round- bottom flask under nitrogen was added NaH (60% oil dispersion, 25.6 mg, 0.64 mmol) in one portion at 0 ^° C, then 3-isocyanato-2,4,5,6-tetrahydro-1H-cyclobuta[f]indene (60 mg, 0.32 mmol) in THF (5 mL) was added dropwise at 0 ^° C. The resulting solution was stirred for 2 h at RT. The reaction was then quenched by the addition of 10 mL of water. The resulting solution was extracted with 3x100 mL of EtOAc and the organic layers were combined and dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. This resulted in 60 mg (37.7%) of the title compound as yellow oil. MS-ESI: 499 (M+1).

Step 2: 4-((Dimethylamino)methyl)-N'-((2,4,5,6-tetrahydro-1H-cyclobu ta[f]inden-3- yl)carbamoyl) benzenesulfonimidamide

To a stirred solution of tert-butyl 4-((dimethylamino)methyl)-N-(2,4,5,6 -tetrahydro-1H- cyclobuta[f]inden-3-ylcarbamoyl)phenylsulfonimidoylcarbamate (60 mg, 0.12 mmol) in THF (5 mL) in a 50-mL round-bottom flask was added HCl in 1,4-dioxane (4 M, 2.0 mL) dropwise at 0 ^° C. The resulting solution was stirred for 30 min at RT. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions: XBridge Shield RP18 OBD Column, 19*250 mm, 10 um; Mobile Phase A: water (10 mM NH4HCO3), Mobile Phase B: MeCN; Flow rate: 25 mL/min; Gradient: 46% B to 47% B in

7 min; UV 210/254 nm. This resulted in 22.8 mg (45.1%) of Example 446 as a white solid. MS- ESI: 399 (M+1). ¹ H NMR (400 MHz, MeOH-d ₄ ) d 7.98 (d, J = 8.3 Hz, 2H), 7.53 (d, J = 8.3 Hz, 2H), 6.65 (s, 1H), 3.61 (s, 2H), 3.01 (s, 2H), 2.92 (s, 2H), 2.84 (t, J = 7.4 Hz, 2H), 2.75 (t, J = 7.3 Hz, 2H), 2.29 (s, 6H), 2.06-1.90 (m, 2H).

Table 38. Examples in the following table were prepared using similar conditions as described in Example 446 and Scheme 3 from appropriate starting materials.

Cmpd # Exact ass +H] ⁺

²⁵

85 85 /457 Example 451 (Compound 853) F ^O

N _H2

S O

2-Fluoro-N'-(1,2,3,5,6,7-hex ahydros-indacen-4-ylcarbamoyl)-4-(2-(methylamino)propan-2- yl)benzenesulfonimidamideonimidamide (Scheme III)

Step 1: Tert-butyl 2-(4-(N-(tert-butyldiphenylsilyl)-N'-(1,2,3,5,6,7-hexahydro- s-indacen-4- ylcarbamoyl) sulfamimidoyl)-3-fluorophenyl)propan-2-yl(methyl)carbamate

To a stirred solution of tert-butyl 2-(4-(N'-(tert-butyldiphenylsilyl)sulfamimidoyl)-3- fluorophenyl)propan-2-yl(methyl) carbamate (400 mg, 0.69 mmol) in THF (10 mL) in a 100-mL round-bottom flask under nitrogen was added NaH (60% oil dispersion, 82.2 mg, 2.06 mmol) in portions at 0 ^° C, then 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (136 mg, 0.685 mmol) in THF (5 mL) was added dropwise at 0 ^° C. The resulting solution was stirred for 2 h at RT. The reaction was then quenched by the addition of 10 mL of water. The resulting solution was extracted with 3x30 mL of EtOAc. The organic layers were combined and dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. This resulted in 400 mg (74.6%) of the title compound as a yellow solid. MS-ESI: 783 (M+1).

Step 2: 2-Fluoro-N'-(1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoyl)- 4-(2- (methylamino)propan-2-yl) benzenesulfonimidamide

To a stirred solution of tert-butyl 2-(4-(N-(tert-butyldiphenylsilyl)-N'-(1,2,3,5,6,7-hexahydro- s- indacen- 4-ylcarbamoyl)sulfamimidoyl)-3 -fluorophenyl)propan-2-yl(methyl)carbamate (80 mg, 0.1 mmol) in dioxane (5 mL) a 25-mL round-bottom flask under nitrogen was added cc. HCl (0.09 mL, 1.02 mmol) dropwise at 0 ^° C. The resulting solution was stirred for 30 min at RT. The pH value of the solution was adjusted to 7 with sat. NaHCO3 solution. The resulting solution was extracted with 3x20 mL of EtOAc. The organic layers were combined and dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions: XBridge Prep C18 OBD Column, 198*150 mm, 5um; mobile phase, water (10 mM NH4HCO3+0.1%NH ^.

3H2O) and MeCN (28% to 49% Phase B over 7 min); Detector, UV 254 nm. This resulted in 11.8 mg (25.9%) of Example 451 as a white solid. MS-ESI: 445 (M+1). ¹ H NMR (400 MHz, DMSO-d6) d 8.30 (br s, 1H), 7.76 (dd, J = 8.0, 8.0 Hz, 1H), 7.55 (br s, 2H), 7.43 (dd, J = 12.5, 1.6 Hz, 1H), 7.39 (dd, J = 8.3, 1.8 Hz, 1H), 6.85 (s, 1H), 2.75 (t, J = 7.4 Hz, 4H), 2.62 (t, J = 7.6 Hz, 4H), 1.99 (s, 3H), 1.95-1.80 (m, 4H), 1.34 (s, 3H), 1.33 (s, 3H).

Table 39. Examples in the following table were prepared using similar conditions as described in Example 451 and Scheme III from appropriate starting materials.

Cm d # xact # ass

+H] ^{+ 50}

Example 453 (Compound 840)

5-(2-Hydroxypropan-2-yl)-N'-((3-oxo-1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)thiazole- 2 lf i id id S h IV Step 1: N-(tert-butyldimethylsilyl)-5-(2-hydroxypropan-2-yl)-N'-((3- oxo-1,2,3,5,6,7- hexahydro-s -indacen-4-yl)carbamoyl)thiazole-2-sulfonimidamide

To a stirred solution of N'-(tert-butyldimethylsilyl)-5-(2-hydroxypropan-2-yl)thiazol e-2- sulfonimidamide (1.40 g, 4.17 mmol) in THF (20 mL) in a 100 mL 3 necked round-bottom flask under nitrogen was added NaH (60% oil dispersion, 333 mg, 8.34 mmol) in portions at 0 ^° C, then 2,2,2-trichloroethyl (3-oxo-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamate (1.82 g, 5.01 mmol) in THF (10 mL) was added dropwise at 0 ^° C. The resulting solution was stirred for 2 h at RT. The reaction was then quenched by the addition of Na2SO ^.

410H2O (1.6 g, 5.0 mmol). The solids were filtered out. The resulting mixture was concentrated under vacuum. This resulted in

3.0 g (crude) of the title compound as a light yellow crude oil. MS-ESI: 549 (M+1)

Step 2: 5-(2-Hydroxypropan-2-yl)-N'-((3-oxo-1,2,3,5,6,7-hexahydro-s- indacen-4- yl)carbamoyl) thiazole-2-sulfonimidamide

To a stirred solution of N-(tert-butyldimethylsilyl)-5-(2-hydroxypropan-2-yl)-N'- ((3-oxo- 1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)thiazole-2-su lfonimidamide (1.40 g, 2.55 mmol, crude) in DCM (10 mL) in a 100-mL round-bottom flask was added HF-Pyridine (70% wt., 73 mg, 2.55 mmol). The resulting solution was stirred for 16 h at RT. The solids were filtered out. The resulting mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions: XBridge Prep OBD C18 Column, 30*150 mm, 5um; mobile phase, water (10 mM NH ₄ HCO ₃ ) and MeCN (22% to 24% Phase B over 7 min); Detector, UV 220 nm. This resulted in 540 mg (28.8% over 2 steps) of Example 453 as a white solid. MS-ESI: 435 (M+1). ¹ H NMR (400 MHz, MeOH-d4) d 7.78 (s, 1H), 7.13 (s, 1H), 3.07-3.04 (m, 2H), 2.91 (t, J = 7.3 Hz, 2H), 2.82-2.78 (m, 2H), 2.70- 2.68 (m, 2H), 2.04-2.01

(m, 2H), 1.66 (s, 6H).

Table 40. Examples in the following table were prepared using similar conditions as described in xact Structure IUPAC Name ass

[M+H] + 805

490

4 ³⁵

⁴⁴⁰

524

Example 458 (Compound 828)

N'-((8-allyl-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl) -5-(2-hydroxypropan-2-yl)-1- h l1H l 3 lf i id id Sh 2

Step 1: N'-((8-allyl-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl) -N-(tert- butyldimethylsilyl)-5- (2-hydroxypropan-2-yl)-1-phenyl-1H-pyrazole-3-sulfonimidamid e

To a stirred solution of N'-(tert-butyldimethylsilyl)-5-(2-hydroxypropan-2-yl)-1-phen yl-1H- pyrazole-3 -sulfonimidamide (82.4 mg, 0.21 mmol) in THF (5.0 mL) in a 100 mL 3 necked round- bottom flask under nitrogen was added NaH (60% oil dispersion, 25.0 mg, 0.63 mmol) in one portion at 0 ^° C. The resulting solution was stirred for 30 min at 0 ^° C. To the above mixture was added 4-allyl-8-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (50.0 mg, 0.21 mmol) at 0 ^° C. The resulting mixture was stirred for additional 4 h at RT under nitrogen atmosphere. The reaction was quenched with 5 mL of water at 0 ^° C. The resulting mixture was extracted with EtOAc (3 x 15 mL). The combined organic layers were washed with brine (2x15 mL), dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure. This resulted in 112 mg (85%) crude title compound as a yellow solid. MS-ESI: 634 (M+1).

Step 2: N'-((8-allyl-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl) -5-(2- hydroxypropan-2-yl) -1-phenyl-1H-pyrazole-3-sulfonimidamide

To a stirred solution of N'-((8-allyl-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl) -N-(tert- butyl- dimethylsilyl)-5-(2-hydroxypropan-2-yl)-1-phenyl-1H-pyrazole -3-sulfonimidamide (110 mg, 0.17 mmol) in THF (5 mL) in a 50-mL round-bottom flask was added HF/Py (70% wt., 25 mg, 0.87 mmol) at 0 ^° C. The resulting solution was stirred for 1 h at 25 ^° C. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions: Sunfire prep C18 column 30*150, 5um; Mobile Phase A: water (0.1% FA), Mobile Phase B: MeCN; Flow rate: 60 mL/min; Gradient: 53% B to 55% B in 10 min; 254/210 nm; Rt: 7.73 min; Detector, 254/210 um. This resulted in 31.7 mg (35.0%) of Example 458 as a white solid. MS-ESI: 520 (M+1). ¹ H NMR (400 MHz, DMSO-d6) d 8.31 (s, 1H), 7.53 (s, 7H), 6.72 (s, 1H), 5.90-5.65 (m, 1H), 5.46 (s, 1H), 4.98-4.88 (m, 2H), 3.23 (dt, J = 6.5, 1.7 Hz, 2H), 2.80-2.72 (m, 4H), 2.72-2.62 (m, 4H), 1.98-1.85 (m, 4H), 1.35 (s, 3H), 1.34 (s, 3H).

Table 41. Example 459 was obtained during the Pre-HPLC purification from isomerizaton of xact # ^# _{Structure IUPAC Name} Mass

[M+H] ⁺ 843 (E)-5-(2-hdrox roan-2-l)-1-henl-N'-((8-(ro-1-en-1- 20

Example 458 and Scheme 2 from appropriate starting materials.

Cmpd # Exact # ass

+H] ^{+ 53}

40 43 29 1 ⁵ 34 34 06 35 29 40 03 16 23 63 51 73 96 833 ' ¹⁷ 31 45 23 64 2 ⁴ 53 0 ^{7 27}

81 5 ^{6 27} 05 40 81 ²²

²³

2-Fluoro-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl )-4-(1- ((methylamino)methyl)cyclopropyl)benzenesulfonimidamide (Scheme V)

Step 1: 1-(4-(N-(tert-butyldimethylsilyl)-N'-((1,2,3,5,6,7-hexahydro -s-indacen-4- yl)carbamoyl) sulfamidimidoyl)-3-fluorophenyl)-N-methylcyclopropane-1-carb oxamide

To a stirred solution of 1-(4-(N'-(tert-butyldimethylsilyl)sulfamidimidoyl) -3-fluorophenyl)-N- methylcyclopropane-1-carboxamide (100 mg, 0.26 mmol) in THF (5 mL) in a 25-mL round- bottom flask was added DBU (12.5 mg, 0.52 mmol) and 4-isocyanato-1,2,3,5,6,7-hexahydro-s- indacene (51.7 mg, 0.26 mmol). The resulting solution was stirred for 16 h at RT. The resulting mixture was used in the next step directly without further purification. MS-ESI: 585 (M+1). Step 2: 1-(3-Fluoro-4-(N'-((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)sulfamidimidoyl)phenyl) -N-methylcyclopropane-1-carboxamide

To the solution from the step 1 was added HF-Pyridine (70% wt., 37 mg, 1.3 mmol). The resulting solution was stirred for 1 h at RT. The reaction was then quenched by the addition of 5 mL of water. The resulting solution was extracted with 3x15 mL of EtOAc. The organic layers were combined and dried over anhydrous Na ₂ SO ₄ and concentrated under vacuum. The crude product was eluted from silica gel with PE/EtOAc (1:3). This resulted in 73.3 mg (62.1% over 2 steps) of the title compound as a yellow solid. MS-ESI: 471 (M+1).

Step 3: 2-Fluoro-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl )-4-(1- ((methylamino)methyl) cyclopropyl)benzenesulfonimidamide

To a stirred solution of 1-(3-fluoro-4-(N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)car bamoyl)- sulfamidimidoyl)phenyl)-N-methylcyclopropane-1-carboxamide (47.1 mg, 0.10 mmol) in THF (2 mL) in a 8-mL sealed tube purged with and maintained under nitrogen was added BH ₃ -THF (1 M, 0.5 mL, 0.50 mmol) dropwise at 0 ^° C. The resulting solution was stirred for 16 h at 30 ^° C. The reaction was then quenched by the addition of 10 mL of water. The resulting solution was extracted with 3x15 mL of EtOAc. The organic layers were combined and dried over anhydrous Na ₂ SO ₄ and concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions: Sunfire prep C18 column 30*150, 5um; mobile phase, H2O/MeCN = 90:10 increasing to H ₂ O/MeCN = 10:90 within 30 min; Detector, 254 nm. This resulted in 18.3 mg (40.0%) of

Example 495 as a solid. MS-ESI: 457 (M+1).

Table 43. Examples in the following table were prepared using similar conditions as described in Example 495 and Scheme V from appropriate startin materials

Cm act ass +H] ⁺ 8

4 ¹

Example 497 (Compound 809)

5-((Dimethylamino)methyl)-3-fluoro-N'-((1,2,3,5,6,7-hexahydr o-s-indacen-4- yl)carbamoyl)pyridine-2-sulfonimidamide (Scheme VI)

Step 1-2 used similar procedures as step 1-2 shown in Example 495 to afford Example 497. MS-ESI: 432 (M+1). ¹ H NMR (400 MHz, DMSO-d6) d 8.78 (s, 1H), 8.53 (br s, 1H), 8.34 (dd, J = 10.4, 1.2 Hz, 1H), 7.78 (s, 2H), 6.86 (s, 1H), 4.62 (s, 2H), 2.81 (s, 6H), 2.81-2.70 (m, 4H), 2.70-2.50 (m, 4H), 2.00-1.80 (m, 4H)

Example 499 (Compound 909)

H

N

N'-((8 yano-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-(2-hy droxypropan-2- yl)thiazole-2-sulfonimidamide (Scheme VIII) HO HO ^H HO

C ^l _Cl O _N

C ^N Step

To a stirred solution of N'-(tert-butyldimethylsilyl)-4-(2-hydroxypropan -2-yl)thiazole-2- sulfonimidamide (485 mg, 1.44 mmol) in THF (10 mL) in a 25-mL round-bottom flask was

added HF/Py (70%wt., 206 mg, 7.2 mmol). The resulting solution was stirred for 1 h at RT. The

resulting mixture was concentrated under reduced pressure. The residue was eluted from silica

gel with DCM/MeOH (10:1). This resulted in 299 mg (93.8%) of the title compound as a yellow

solid. MS-ESI: 222 (M+1).

Step 2: N'-((8-cyano-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl) -4-(2-hydroxypropan- 2-yl) thiazole-2-sulfonimidamide To a stirred solution of 4-(2-hydroxypropan-2-yl)thiazole-2-sulfonimidamide (221 mg, 1.00

mmol) in THF (20 mL) in a 50-mL round-bottom flask under nitrogen was added NaH (60%

dispersion in mineral oil, 120 mg, 3.00 mmol) in one portion at 0 ^° C, 2,2,2-trichloroethyl (8- cyano-1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamate (374 mg, 1.00 mmol) was added to the

solution in portions at 0 ^° C. The resulting solution was stirred for 60 min at RT. The resulting

mixture was quenched with 5 mL of water then concentrated under reduced pressure. The crude

product was purified by Prep-HPLC with the following conditions: XBridge Shield RP18 OBD

Column, 19*250 mm, 10 um; mobile phase, water (10 mM NH4HCO3) and MeCN (13% to 34%

Phase B over 7 min); Detector, 254/220 nm. This resulted in 134 mg (30.1%) of Example 499 as an off-white solid. MS-ESI: 446 (M+1). ¹ H NMR (400 MHz, DMSO-d ₆ ) d 8.90 (s, 1H), 7.98 (s,

2H), 7.72 (s, 1H), 5.37 (s, 1H), 2.93 (t, J = 7.4 Hz, 4H), 2.70 (t, J = 7.7 Hz, 4H), 2.10-1.90 (m,

4H), 1.47 (s, 3H), 1.46 (s, 3H).

Example 500 (Compound 838)

2-Fluoro-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl )-4-(pyrrolidin-3- yl)benzenesulfonimidamide (Scheme IX)

Step 1: 2-Fluoro-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl )-4-(pyrrolidin-3-yl) benzenesulfonimidamide

To a stirred solution of tert-butyl 3-(3-fluoro-4-(N'-((1,2,3,5,6,7-hexahydro-s-indacen -4- yl)carbamoyl)sulfamidimidoyl)phenyl)pyrrolidine-1-carboxylat e (272 mg, 0.50 mmol) in DCM

(10 mL) in a 50-mL round-bottom flask was added BF ^.

3Et ₂ O (47%wt., 362 mg, 2.50 mmol)

dropwise at 0 ^° C. The resulting solution was stirred for 2 h at 0 ^° C. The reaction was then

quenched by the addition of 0.2 mL of sat. NaHCO3 solution. The resulting mixture was

concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions: XBridge Prep OBD C18 Column, 30*150mm, 5um; mobile phase, water (10 mM

NH4HCO3+0.1%NH ^.

3H2O) and MeCN (10% to 33% Phase B over 7 min); Detector, UV

(254/220 nm). This resulted in 90.8 mg (41.0%) of Example 500 as an off-white solid. MS-ESI:

443(M+1). ¹ H NMR (300 MHz, MeOH-d ₄ ) d 7.98 (d, J = 7.7 Hz, 1H), 7.45-7.25 (m, 2H), 6.91

(s, 1H), 3.82-3.56 (m, 3H), 3.50-3.10 (m, 2H), 2.90-2.65 (m, 8H), 2.60-2.30 (m, 2H), 2.10-1.90

(m, 4H).

Table 44. Example 501 and Example 502 in the following table were prepared using similar

conditions as described in Example 500 and Scheme IX from the corresponding chiral

Intermediate 128B and Intermediate 128A.

t

[M+H] ⁺

Example 503 (Compound 832)

N'-((1 exahydro-s-indacen-4-yl)carbamoyl)-3-

(morpholinomethyl)benzenesulfonimidamide (Scheme X)

Step 1: N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-3- (morpholinomethyl)benzene -sulfonimidamide

To a stirred solution of 3-formyl-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl )benzene- sulfonimidamide (50 mg, 0.13 mmol) in DCE (5 mL) in a 25-mL round-bottom flask under nitrogen was added morpholine (33.9 mg, 0.39 mmol) at RT. The resulting solution was stirred overnight at RT. Then NaBH(OAc)3 (55.1 mg, 0.26 mmol) was added to the mixture at 0 ^° C. The resulting solution was stirred for 12 h at RT. The resulting solution was extracted with 3x10 mL of EtOAc and the organic layers were combined and dried over anhydrous Na2SO4 and

concentrated under vacuum. The residue was eluted from silica gel with DCM/MeOH (10:1), further purified by Prep-HPLC with the following conditions: XBridge Prep OBD C18 Column, 30*150 mm, 5um; mobile phase, water (10 mM NH4HCO3+0.1%NH ^.

3H2O) and MeCN (10% to

33% Phase B over 7 min); Detector, UV (254/220 nm). This resulted in 27.9 mg (47.2%) of

Example 503 as a yellow solid. MS-ESI: 455 (M+1).

Table 45. Examples in the following table were prepared using similar conditions as described in Example 503 and Scheme X from appropriate starting materials.

Exact ass +H] ⁺ 57

6 ⁸

70

53

9 ⁹

Example 509 (Compound 868f)

(S)-N'-((1-hydroxy-1,23567-hexahydro-s-indacen-4-yl)carbamoy l)-5-(2-hydroxypropan-2- ole-2-sulfonimidamide (Scheme 32)

To a stirred solution of (S)-5-(2-hydroxypropan-2-yl)-N'-((1-oxo-1,2,3,5,6,7-hexahydr o-s- indacen-4- yl)carbamoyl)thiazole-2-sulfonimidamide (180 mg, 0.41 mmol) in EtOH (10 mL) in a 50-mL round-bottom flask was added NaBH ₄ (31.3 mg, 0.828 mmol) in portions at 0 ^° C.

The resulting solution was stirred for 2 h at RT. The reaction was then quenched with 5 mL of water. The solids were filtered out. The resulting mixture was concentrated under vacuum.

The crude product was purified by Prep-HPLC with the following conditions: XBridge Prep

C18 OBD Column, 19*150 mm 5um; mobile phase, water (10 mM NH4HCO3+0.1%

NH ^.

3H2O) and MeCN (5% to 24% Phase B over 7 min); Detector, UV 254 nm. This resulted in 130 mg (71.9%) of Example 509 as a white solid. MS-ESI: 437 (M+1). ¹ H NMR (400

MHz, DMSO-d ₆ ) d 8.49 (br s, 1H), 7.79 (s, 1H), 7.65 (br s, 2H), 6.97 (s, 1H), 5.90 (s, 1H),

5.10 (d, J = 5.6 Hz, 1H), 5.00-4.90 (m, 1H), 3.90-3.80 (m, 2H), 3.80-3.60 (m, 4H), 2.35-2.25

(m, 1H), 2.05-1.85 (m, 2H), 1.75-1.60 (m, 1H), 1.55 (s, 6H).

Table 46. Examples in the following table were prepared using similar conditions as described in Example 509 and Scheme 32 from appropriate chiral starting ketones.

t s

[M+H] ⁺ 867f (R)-N'-((3-h drox -123567-hexah dro-s-indacen-4- 437

437

437

Example 513 (Compound 839)

5-(2-hydroxypropan-2-yl)-1-phenyl-N'-( propyl-1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)-1H-pyrazole-3-sulfonimidamide (Scheme XI)

To a stirred solution of N'-((8-allyl-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl) -5- (2- hydroxypropan-2-yl)-1-phenyl-1H-pyrazole-3-sulfonimidamide (20 mg, 0.038 mmol) in MeOH (10 mL) 50 mL round-bottom flask under nitrogen was added Pd/C (10% wt., 5.0 mg), the flask was excavated and flushed with hydrogen 3 times. The resulting mixture was stirred for 16 h at RT under hydrogen with a balloon. The resulting mixture was filtered; the filter cake was washed with MeOH (3x5 mL). The filtrate and wash were concentrated under reduced pressure. The

crude product was purified by Prep-HPLC using the following conditions: XBridge Shield RP18

OBD Column 19*250 mm, 10 um; Mobile Phase A: water (10 mM NH ₄ HCO ₃ ), Mobile Phase B:

MeCN; Flow rate: 25 mL/min; Gradient: 50% B to 52% B in 10 min; 210/254 nm; Rt: 11.45

min. This resulted in Example 513 (6.5 mg, 32.4%) as a white solid. MS-ESI: 522 (M+1). ¹ H

NMR (400 MHz, MeOH-d ₄ ) d 7.60-7.48 (m, 5H), 6.87 (s, 1H), 2.84 (t, J = 7.4 Hz, 4H), 2.82- 2.70 (m, 4H), 2.57-2.48 (m, 2H), 2.08-1.96 (m, 4H), 1.60-1.45 (m, 2H), 1.45 (s, 3H), 1.44 (s,

3H), 0.95 (t, J = 7.4 Hz, 3H).

Table 47. Example 514 was obtained from Step 3 in Route 2 in Example 224.

Compound #

a ^ss ] ₊ 45

Table 48. Examples in the following table were obtained from chiral HPLC resolutions of

racemic examples described above. The chiral column and eluents are listed in the table. As a convention, the faster-eluting enantiomer is always listed first in the table followed by the

slower-eluting enantiomer of the pair. The symbol * at a chiral center denotes that this chiral center has been resolved and the absolute stereochemistry at that center has not been determined.

Assigned stereochemistry in compound names are tentative. _# ^{Cmpd #} _{Structure IUPAC Name Column Eluents} ^LC-MS

[ _M+H]+ 5 18

6 18

7 32 8 32 41

yl)benzenesulfonimidamide um) ) (S) or (R)-N'-((1,2,3,5,6,7-hexahydro- CHIRA IPA in

LPAK Hex:DCM=0 18 4

4

sulfonimidamide cm, )

um (S) or (R)-2-(2-hydroxypropan-2-yl)- Chiralpa 812a N'-((6-i r l-23-dihdr-1H- k ID-2, EtOH in

b][1,3]oxazine-3-sulfonimidamide um) ) 871a (S,6R) or (R,6R)-6-methoxy-N'- CHIRA EtOH in

2-yl)thiazole-5-sulfonimidamide cm, 5

um CHIRA 820a (R) or (S)-N'-((1,2,3,5,6,7-hexahydro- L ART

Cellulos EtOH in

opo o e y e eesu o .

amide cm; 3 FA) um CHIRA

(S) or (R)-N'-((1,2,3,5,6,7-hexahydro- LPAK

832a s-indacen-4-l)carbamol)-3- ID EtOH in

c]pyridine-2-sulfonimidamide c ,

um ) 413b (S) or (R)-N'-((1,2,3,5,6,7-hexahydro- Chiralpa k ID EtOH in

1H-pyrazole-3-sulfonimidamide cm, 5 (0.1% FA) um 873b (S) or (R)-N'-((1,2,3,5,6,7-hexahydro- Chiralpa 50% EtOH

1H-pyrazole-3-sulfonimidamide cm, 5

um CHIRA

(R) or (S)-4-(difluoromethoxy)-N'- LPAK EtOH in 841b 12 h h i 4 2*2 Hex (8 mM 422 , ,, -e ay osoqu o e-- sulfonimidamide 0mm, 5 ₃ e

um ) CHIRA 850b (S) or (R)-6-cyclopentyl-N'- L ART

Cellulos EtOH in yl)benzenesulfonimidamide ,

um ) (R) or (S)-2-fluoro-N'-((1,2,3,5,6,7- (R,R)W

853a helk EtOH in

457

457

sulfonimidamide cm, 5

um CHIRA

(S) or (R)-3-fluoro-5-(2- L ART

859a h 2 l ' 1 lll i

^.

trifluoroethyl)amino)methyl)benzenesu cm (5 NH ₃ MeOH lfonimidamide um) ) (S) or (R)-N'-((1,2,3,5,6,7-hexahydro- CHIRA

s-indacen-4-yl)carbamoyl)-4- LPAK EtOH in 861a ((meth l(222- IG 2*25 Hex (8 mM 481

sulfonimidamide cm, 5 )

um CHIRA

L ART

355a (R) or (S)-6-((dimethylamino)methyl)- Cellulos EtOH in

HN -y e eesu o a e u ;

from Ex.

502 CHIRA

H ₂ N L

838a * ^O

S _O (SR) or (RR) -2-fluoro-N'- PAK IA

411e indacen-4-yl)carbamoyl)-5-(1,2- CHIR Hex (0.1% 79 dihydroxypropan-2-yl)-3- LPAK

IG, FA) ^{O H}

F _N fluorothiophene-2-sulfonimidamide 20*250 O (mixture of two isomers) mm, 5 S N um

sulfonimidamide um;

from Ex.

634 1 ^st and

2 ^nd peak (RR) and (SR)-4-(1- CHIRA

from Ex.

639 819d

1 ^st peak

(R,R) or (S,R)-N'-((1,2,3,5,6,7- Ultimate 35% MeOH 847b

y)t azoe--su onmdamde (5 um); ) n CO ₂ from Ex.

511 1 ^st peak 868d (S,R) or (S,S)-N'-((1-hydroxy- Chiralpa

k AD 35% MeOH

yl)carbamoyl)benzenesulfonimidamide from Ex.

660 2 ^nd peak

Chiralpa

854a (R,R) or (S,R)-4- k IG EtOH in

yl)carbamoyl)benzenesulfonimidamide um;

from Ex. ) 664 ^ģ The amount of NH3 in this chiral chromatographic solvent and similar solvents were adjusted by adding 2 M NH ₃ in MeOH to the desired NH ₃ concentration. In this case, the resulting concentration of NH ₃ in MeOH is 8 mM.

Example 669 (Compound 901)

3 _{-Fluoro-5-((methylamino)m dro-1H-cyclobuta[f]inden-3-} yl)carbamoyl)thiophene-2-sulfonimidamide (Scheme XII)

Examples 670 (Compound 901a) and Examples 671 (Compound 901b)

( _{S)- and (R)- 3-Fluoro-5-((methylamino)methyl)-N'-((2,4,5,6-tetrahydro-1H- cyclobuta[f]inden-} 3-yl)carbamoyl)thiophene-2-sulfonimidamide

_{Step 1: Tert-butyl((5-(N-(tert-butyldimethylsilyl)-N'-((2,4,5,6-tetr ahydro-1H-} cyclobuta[f]inden-3-yl) carbamoyl)sulfamidimidoyl)-4-fluorothiophen-2- yl)methyl)(methyl)carbamate

To a stirred solution of tert-butyl ((5-(N'-(tert-butyldimethylsilyl)sulfamidimidoyl)-4- fluorothiophen-2-yl) methyl)(methyl)carbamate (200 mg, 0.46 mmol) in THF (5.0 mL) in a 25- mL round-bottom flask was added DBU (139 mg, 0.91 mmol) at RT, followed by the addition of 3-isocyanato-2,4,5,6-tetrahydro-1H-cyclobuta[f]indene (85 mg, 0.46 mmol) in THF (3 mL) dropwise at 0 ^° C. The resulting solution was stirred overnight at RT. The reaction was quenched with water (5 mL). The resulting solution was extracted with 3x10 mL ethyl acetate. The organic layers were combined and dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 180 mg (crude) of the title compound as a white solid. MS-ESI: 538 (M+1). Step 2: 3-Fluoro-5-((methylamino)methyl)-N'-((2,4,5,6-tetrahydro-1H- cyclobuta[f]inden-3- yl) carbamoyl)thiophene-2-sulfonimidamide

To a stirred solution of tert-butyl ((5-(N-(tert-butyldimethylsilyl)-N'-((2,4,5,6-tetrahydro-1H- cyclobuta[f] inden-3-yl)carbamoyl)sulfamidimidoyl)-4-fluorothiophen-2- yl)methyl)(methyl)carbamate (180 mg, crude) in THF (5 mL) in a 25-mL round-bottom flask was added HCl in 1,4-dioxane (4 M, 5.0 mL) dropwise at 0 ^° C. The resulting solution was stirred overnight at RT. The resulting mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions: XBridge Prep OBD C18 Column, 30*150mm 5um; mobile phase, water (10 mM NH4HCO3+0.1%NH3.H2O) and ACN (20% to 30% Phase B over 7 min); Detector, UV 254/210 nm. This resulted in 65 mg (34.8% over two steps) of Example 669 as a white solid. MS-ESI: 424 (M+1). ¹ H NMR (300 MHz, DMSO-d ₆ ) d 8.26 (br s, 1H), 6.93 (s, 1H), 6.66 (s, 1H), 3.79 (s, 2H), 3.00-2.94 (m, 2H), 2.92-2.85 (m, 2H), 2.83-2.67 (m, 4H), 2.29 (s, 3H), 1.96-1.83 (m, 2H).

Step 3: Chiral separation

Example 669 (60 mg) was resolved by Prep-Chiral-HPLC with the following conditions:

CHIRALPAK ID, 2*25cm(5 um); Mobile Phase A: Hex:DCM=3:1(10 mM NH3-MeOH), Mobile Phase B: EtOH; Flow rate: 20 mL/min; Gradient: 30% B to 30% B over 23 min;

Detector: UV 254/220 nm. Rt1: 6.2 (Example 670); Rt2: 9.46 (Example 671). This resulted in 22.1 mg (99%ee) of (Example 670) as a white solid. This resulted in 22.3 mg (99%ee) of (Example 671) as a white solid.

Example 670 MS-ESI: 424 (M+1). ¹ H NMR (400 MHz, DMSO-d ₆ ) d 8.25 (br s, 1H), 6.92 (s, 1H), 6.65 (s, 1H), 3.78 (s, 2H), 3.00-2.94 (m, 2H), 2.91-2.84 (m, 2H), 2.83-2.64 (m, 4H), 2.29 (s, 3H), 1.95-1.85 (m, 2H).

Example 671 MS-ESI: 424 (M+1). ¹ H NMR (400 MHz, DMSO-d ₆ ) d 8.28 (br s, 1H), 6.94 (s, 1H), 6.66 (s, 1H), 3.79 (s, 2H), 3.00-2.93 (m, 2H), 2.91-2.85 (m, 2H), 2.83-2.67 (m, 4H), 2.29 (s, 3H), 1.96-1.84 (m, 2H). Table 49. Examples in the following table were prepared using similar conditions as described in Example 669 and Scheme XII from appropriate starting materials.

Example 673 (Compound 922a)

2-( -1-amino-2-hydroxypropan-2-yl)-N'-((1,2,3,5,6,7-hexahydro-s- indacen-4- yl)carbamoyl)thiazole-5-sulfonimidamide (Scheme XIII)

To a stirred solution of 2-((R)-1-azido-2-hydroxypropan-2-yl)-N'-((1,2,3,5,6,7-hexahy dro-s- indacen-4-yl) carbamoyl)thiazole-5-sulfonimidamide (100 mg, 0.22 mmol) in THF (10 mL) in a 50-mL round-bottom flask under nitrogen was added LiAlH ₄ (17 mg, 0.44 mmol) at 0 ^° C. The resulting solution was stirred for 2 h at 0 ^° C. The reaction was quenched with water/ice at 0 ^° C. The resulting mixture was filtered. The filter cake was washed with water (3x5 mL). The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions: Sunfire prep C18 column, 30*150, 5 um; Mobile Phase A: Water (0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 20% B to 37% B over 7 min; Rt ₁ :4.72, UV 254/210 nm. This resulted in 8.2 mg (8.7%) of Example 673 as a white solid. MS-ESI: 436 (M+1). ¹ H NMR (400 MHz, DMSO-d ₆ ) d: 8.46 (br, s, 1H), 8.18 (s, 1H), 7.17 (br, s, 4H), 6.89 (s, 1H), 3.10-2.98 (m, 2H), 2.84-2.74 (m, 4H), 2.73-2.61 (m, 4H), 2.00-1.87 (m, 4H), 1.53 (s, 3H).

Example 674 (Compound 896)

N _{'-( hexahydro-s-indacen-4-yl)carbamoyl)-2-((R)-5-methyl-2-oxooxa zolidin-5-} yl)thiazole-5-sulfonimidamide (Scheme XIV)

To a stirred solution of 2-((R)-1-amino-2-hydroxypropan-2-yl)-N'-((1,2,3,5,6,7-hexahy dro-s- indacen-4-yl) carbamoyl)thiazole-5-sulfonimidamide (Ex.673, 80 mg, 0.18 mmol) in THF (10 mL) in a 50-mL round-bottom flask under nitrogen was added bis(trichloromethyl) carbonate (23 mg, 0.09 mmol) at 0 ^° C. The resulting mixture was stirred for 2 h at RT. The resulting mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions: XBridge Prep C18 OBD Column, 19×150 mm 5 um; Mobile Phase A: Water (10 mM NH4HCO3+0.1%NH3.H2O), Mobile Phase B: ACN; Flow rate: 25 mL/min;

Gradient: 13% B to 36% B over 7 min; Rt ₁ :6.47, UV 254/210 nm. This resulted in 3.7 mg (4.4%) of Example 674 as a white solid. MS-ESI: 462 (M+1). ¹ H NMR (400 MHz, DMSO-d ₆ ) d 8.47 (br s, 1H), 8.20 (s, 1H), 7.96 (s, 1H), 7.86 (br s, 2H), 6.88 (s, 1H), 3.79-3.71 (m, 2H), 2.83-2.74 (m, 4H), 2.72-2.60 (m, 4H), 1.99-1.87 (m, 4H), 1.79 (s, 3H).

Example 675 (Compound 894)

N-((2R)-2-(5-(N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carb amoyl)sulfamidimidoyl)thiazol-2- yl)-2-hydroxypropyl)acetamide (Scheme XV)

To a stirred solution of 2-((R)-1-amino-2-hydroxypropan-2-yl)-N'-((1,2,3,5,6,7-hexahy dro-s- indacen-4-yl) carbamoyl)thiazole-5-sulfonimidamide (100 mg, 0.23 mmol) in DCM (10 mL) in a 50-mL round-bottom flask under nitrogen was added TEA (70 mg, 0.69 mmol) at RT, followed by the addition of Ac2O (23 mg, 0.23 mmol) dropwise at 0 ^° C. The resulting solution was stirred for 1 h at RT. The resulting mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions: XBridge Prep C18 OBD Column, 19×150 mm 5 um; Mobile Phase A: Water (10 mM NH ₄ HCO ₃ +0.1%NH ₃ .H ₂ O), Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 12% B to 20% B over 10 min; Rt1: 12.43 min, Detector, UV 254/210 nm. This resulted in 5.3 mg (4.83%) of Example 675 as a white solid. MS-ESI: 478 (M+1).1H NMR (400 MHz, DMSO-d6) d 8.41 (br, s, 1H), 8.08 (s, 1H), 7.98 (br s, 1H), 7.82 (br, s, 2H), 6.88 (s, 1H), 6.52 (s, 1H), 3.60-3.47 (m, 1H), 3.31-3.25 (m, 1H), 2.85-2.73 (m, 4H), 2.72- 2.60 (m, 4H), 2.00-1.87 (m, 4H), 1.83 (s, 3H), 1.45 (s, 3H).

Example 676 (Compound 894a)

T _{ert-butyl ((2R)-2-(5-(N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-} yl)carbamoyl)sulfamidimidoyl)thiazol-2-yl)-2-hydroxypropyl)c arbamate (Scheme XVI)

To a stirred solution of 2-((R)-1-amino-2-hydroxypropan-2-yl)-N'-((1,2,3,5,6,7-hexahy dro-s- indacen-4-yl) carbamoyl)thiazole-5-sulfonimidamide (100 mg, 0.23 mmol) in DCM (10 mL) in a 50-mL round-bottom flask was added TEA (70 mg, 0.69 mmol) at RT, followed by the addition of Boc2O (50 mg, 0.23 mmol) in THF (5 mL) dropwise at 0 ^° C. The resulting solution was stirred for 1 h at RT. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions: XSelect CSH Prep C18 OBD

Column, 19*250 mm, 5 um; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 45% B to 70% B over 7 min; Rt1: 6.28 min, UV 254/210 nm. This resulted in 5.5 mg (4.47%) of Example 676 as a white solid. MS-ESI: 536 (M+1). ¹ H NMR (400 MHz, DMSO-d ₆ ) d 8.42 (br, s, 1H), 8.08 (s, 1H), 7.87 (br, s, 2H), 6.88 (s, 1H), 6.73 (br s, 1H), 6.33 (s, 1H), 3.45-3.34 (m, 1H), 3.25-3.15 (m, 1H), 2.84-2.75 (m, 4H), 2.72-2.61 (m, 4H), 1.99-1.87 (m, 4H), 1.44 (s, 3H), 1.37 (s, 9H).

Example 677 (Compound 918a)

N _{'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-( (R)-2-hydroxy-1-(2-} hydroxyethoxy)propan-2-yl)thiazole-5-sulfonimidamide (Scheme XVII)

To a stirred solution of 2-((R)-1-(2-(benzyloxy)ethoxy)-2-hydroxypropan-2-yl)-N'-((1, 2,3,5,6,7- hexahydro-s- indacen-4-yl)carbamoyl)thiazole-5-sulfonimidamide (80 mg, 0.14 mmol) in DCM (3.0 mL) in a 50-mL round-bottom flask under nitrogen was added trichloroborane (0.50 mL) dropwise at 0 ^° C. The resulting mixture was stirred for 16 h at RT. The reaction was quenched with water at 0 ^° C. The resulting mixture was extracted with DCM (3x30 mL). The combined organic layers were washed with brine (1x30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions: XBridge Prep C18 OBD Column, 19×150mm

5um; Mobile Phase A: Water(10 mM NH ₄ HCO ₃ +0.1%NH ₃ .H ₂ O), Mobile Phase B: ACN; Flow

rate: 25 mL/min; Gradient:8 B to 38 B over 7 min; Rt ₁ : 5.50; Detector, UV 254/210 nm. This

resulted in 33.3 mg (49%) of Example 677 as a white solid. MS-ESI: 480 (M+1).

1H NMR (400 MHz, DMSO-d6) d 8.42 (br s, 1H), 8.08 (s, 1H), 7.85 (br s, 2H), 6.88 (s, 1H), 6.28

(s, 1H), 4.58 (br s, 1H), 3.69-3.58 (m, 2H), 3.61-3.44 (m, 4H), 2.84-2.75 (m, 4H), 2.72-2.61 (m,

4H), 1.99-1.87 (m, 4H), 1.47 (s, 3H).

Table 50. Examples in the following table were prepared using similar conditions as described in

Example 451 and Scheme III from appropriate starting materials.

Cmpd #

E Exact ass +H] ^{+ 78}

Table 51. Examples in the following table were prepared using similar conditions as described in

Example 453 and Scheme IV from appropriate starting materials.

xact ass +H] ⁺ 90

35

40 sulfonimidamide 897

24

71 95

Table 52. Examples in the following table were obtained from chiral HPLC resolutions of

racemic examples described above. The chiral column and eluents are listed in the table. As a convention, the faster-eluting enantiomer is always listed first in the table followed by the

slower-eluting enantiomer of the pair. The symbol * at a chiral center denotes that this chiral center has been resolved and the absolute stereochemistry at that center has not been determined. Assigned stereochemistry in compound names are tentative.

E _x ^MS

+ _H]+ 6 52

6 52

6 31 e ay o eo ,-cpy e-- . c

sulfonimidamide L(5um) NH ₃ - MeOH) 20% EtOH

(S) or (R)-N'-((1,2,3,5,6,7- in

906a hexahdro-s-indacen-4- CHIRALP Hex:DCM 6 31

6 05

6 05

6 18

6 18

6 32

6 32 870c (R) or (S)- (6R)-N'-((1,2,3,5,6,7- 20% EtOH 6 31

6 31

Examples 699~709

General procedure for reductive amination

In a flame-dried 25 mL round bottom flask, a primary or secondary amine (0.41 mmol) and sodium triacetoxyborohydride (75 mg, 0.354 mmol) were added to a solution of tert-butyl (R)-((4- formylphenyl)(3-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)ureido )(oxo)- ^ ⁶ -sulfanylidene)carbamate (100 mg, 0.207 mmol) in dry DCE (6 mL) under an argon atmosphere. The flask was sealed and the resulting cloudy mixture was stirred at RT for 18h.

In cases where the reduction rate was extremely slow, additional portion of NaBH4 (15 mg, 0.41 mmol) was added to the reaction flask and the resulting mixture was stirred at RT for additional 24 h.

The reaction was quenched with NaHCO3 sat. solution (2.5 mL) and the product was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with water (5 mL) and brine (5 mL), dried over Na2SO4, filtered and concentrated under reduced pressure at 30 °C, to give the products as pale yellow solids.

General procedure for Boc-deprotection

In a 20 mL vial, the product of reductive amination (0.156 mmol) was dissolved in formic acid (0.9 mL) and the resulting solution was stirred at room temperature overnight (16 h). The solution was concentrated in vacuo at room temperature affording a pale yellow oil, which was triturated in EtOAc resulting in the formation of a white solid. The product was purified by reverse phase flash chromatography using a gradient of 70-100% CH3CN in H2O (formic acid 0.1%) generating the desired products as a white powders. Compounds were isolated as formate salts except where indicated.

Examples below were prepared from tert-butyl (R)-((4-formylphenyl)(3-(1,2,3,5,6,7-hexahydro- s-indacen-4-yl)ureido)(oxo)- ^ ⁶ -sulfanylidene)carbamate following the general procedures for reductive amination and then Boc-deprotection above.

Example 699: (R)-4-((allylamino)methyl)-N'-((1,2,3,5,6,7-hexahydro-s-inda cen-4- yl)carbamoyl)- benzenesulfonimidamide

Example 700: (R)-4-((ethylamino)methyl)-N'-((1,2,3,5,6,7-hexahydro-s-inda cen-4- yl)carbamoyl)- benzenesulfonimidamide

Example 701: (R)-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-( ((2- methoxyethyl)amino)- methyl)benzenesulfonimidamide

Example 702: (R)-4-((sec-butylamino)methyl)-N'-((1,2,3,5,6,7-hexahydro-s- indacen-4- yl)carbamoyl)- benzenesulfonimidamide

Example 703: (R)-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-( ((tetrahydro- 2H-pyran-4- yl)-amino)methyl)benzenesulfonimidamide

Example 704: (R)-4-((cycloheptylamino)methyl)-N'-((1,2,3,5,6,7-hexahydro- s-indacen-4- yl)- carbamoyl)-benzenesulfonimidamide

Example 705: (R)-4-((cyclobutylamino)methyl)-N'-((1,2,3,5,6,7-hexahydro-s -indacen-4- yl)carbamoyl)- benzenesulfonimidamide Example 706: (R)-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4- ((isopropylamino)methyl)- benzenesulfonimidamide

Example 707: (R)-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-( (4- methylpiperazin-1-yl)- methyl)benzenesulfonimidamide

Example 708: (R)-4-(((2,2-difluoroethyl)amino)methyl)-N'-((1,2,3,5,6,7-he xahydro-s- indacen-4-yl)- carbamoyl)benzenesulfonimidamide

Example 709: (R)-4-((cyclobutyl(methyl)amino)methyl)-N'-((1,2,3,5,6,7-hex ahydro-s- indacen-4-yl)- carbamoyl)benzenesulfonimidamide

Table 53: Structure and analytical data for Examples 699 to 709 am S‐ESI 69 5.3

⁷⁰ 3.3

70 3.3

⁷⁰ 1.3 .   ,  ,  . .   ,   , . .   ,  , 

1.35 (d, J = 6.6 Hz, 3H), 1.02 (t, J = 7.5 Hz,  3H). 8.43 (s, 1H), 8.05 ( br s, 2H), 7.67 (d, J = 8.1  Hz, 2H), 

6.90(s1H)4.26(s2H)4.03(ddJ=11.84.4Hz2H) ⁷⁰ 9.4

⁷⁰ 1.4

⁷⁰ 9.3

70 7.3

70 8.4

70 9.3

70 3.3 (m,  ), . .  (m,  ). Examples 710 (Compound 875a) and 711 (Compound 875b)

( _{R)- and (S)-1-(Difluoromethyl)-4-fluoro-N'-((1,2,3,5,6,7-hexahydro-s -indacen-4-yl)carbamoyl)-} 1H- pyrazole-3-sulfonimidamide

Step 1: 4-Fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole In a 1-L flask, a cold (0 °C) solution of 4-fluoro-1H-pyrazole (14.14 g, 115.0 mmol) in dry DMF (150 mL) was treated carefully portion-wise with NaH (60% in oil, 5.31 g, 132.8 mmol) over 20 min. The suspension was then treated dropwise with SEM-Cl (23.0 mL, 129.7 mmol) keeping the internal temperature below 10 °C. The suspension was left to warm to RT and stirred for 7 h. The reaction was diluted with EtOAc (500 mL) and quenched with half-saturated brine (1.4 L). The organic layer was separated and washed again with half-saturated brine (2x500 mL) and brine (300 mL). The aqueous phases were back extracted with EtOAc (2x500 mL). The organic layers were combined and dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. Purification on normal phase silica using a gradient of 100% hexanes to 30% EtOAc / hexanes gave 23.0 g of the title compound as a colorless oil (85%). MS-ESI: 217.1 (M+1). Step 2: lithium 4-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5- sulfinate In a 1-L round bottom flask, a cold (-70 °C) solution of 4-fluoro-1-((2- (trimethylsilyl)ethoxy)methyl)- 1H-pyrazole (19.98 g, 92.36 mmol) in dry THF (150 mL) was treated dropwise with n-BuLi (2.5 M in hexanes, 40.0 mL, 100.00 mmol) over 20 min by the keeping internal temperature below -65 °C. After 1 h at -70 °C, an atmosphere of SO ₂ (g) was introduced via balloon. After stirring for 20 min at -70 °C the dry-ice bath was removed, and the reaction mixture was left to warm to RT. The suspension was left to stir at RT for 30 min. The crude reaction mixture was concentrated in vacuo to provide a beige solid. The material was mixed with DCM (200 mL) and sonicated for 15 min and triturated over 5 h. The solid was collected by filtration and after drying under vacuum 24.39 g (86%) of the title compound was isolated as a beige solid. The product was used as is in the next step. Step 3: N,N-dibenzyl-4-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1 H-pyrazole-5- sulfonamide In a 100-mL round bottom flask, a cold (0 °C, ice-water bath) suspension of lithium 4-fluoro-1- ((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-sulfinate (24.4 g, 79.76 mmol) in a mixture of DCM (200 mL) and water (100 mL) was treated in two portions with NCS (11.98 g, 89.715 mmol) over 3-5 min under vigorous stirring by keeping internal temperature below 10 °C. The biphasic solution was stirred for 1 h. To the biphasic reaction mixture cooled at 0 °C, Et3N (15 mL, 107.6 mmol) was added in one portion followed by N,N-dibenzylamine (20.0 mL, 104.0 mmol). Internal temperature was kept below 7-8 °C. Then, the ice-water bath was removed and the reaction was left to warm to RT over 1h. The biphasic solution was diluted with more DCM (100 mL) and water (100 mL). The organic layer was separated and washed with water (100 mL) again. The aqueous layers were back extracted with DCM (2x100 mL). The organic layers were combined, cooled to 0 °C, and treated slowly by the addition of aq. HCl 0.5 N (120 mL, 60 mmol) over 5-10 min by keeping internal temperature below 10 °C. The organic layer was separated (500 mL) and washed with half-saturated brine (100 mL). The aqueous layers were back extracted with DCM (100 mL). The organic layers were combined, dried over Na2SO4, concentrated and purified through the use of a short silica plug, eluting with dichloromethane.31.88 g (80%) of the title compound was isolated as a colorless oil. MS-ESI: 498.2 (M+Na). Step 4: N,N-dibenzyl-4-fluoro-1H-pyrazole-5-sulfonamide In a 1000-ml round bottom flask, a cold (0 °C) solution of N,N-dibenzyl-4-fluoro-1-((2- (trimethylsilyl)- ethoxy)methyl)-1H-pyrazole-5-sulfonamide (31.76 g, 66.77 mmol) in DCM (100 mL) was treated slowly with TFA (50 mL, 653 mmol). The ice-water bath was removed and the reaction was left to warm to RT and stirred for 2 h. The reaction was concentrated in vacuo and the residue was dissolved in 1,4-dioxane (45 mL), cooled to 10 °C, and treated very slowly over 5 min with conc. NH ₄ OH (28-30%, 45 mL, 335 mmol). The mixture was stirred for 2 h at RT. The reaction mixture was diluted with water (100 mL) and brine (100 mL) and extracted with EtOAc (200 mL). The organic layer was washed with brine (100 mL). The aqueous phases were back extracted with EtOAc (150 mL). The organic layers were combined, dried over Na2SO4, filtered and concentrated in vacuo. After evaporation, a waxy gummy white solid was obtained. This crude material was purified by normal phase silica column chromatography, eluting with EtOAc / hexanes (1:2). The title compound was isolated as a white solid (17.62 g, 72%). MS-ESI: 346.1 (M+1). Step 5: N,N-dibenzyl-1-(difluoromethyl)-4-fluoro-1H-pyrazole-3-sulfo namide In a 1-L round bottom flask equipped with a condenser, a suspension of N,N-dibenzyl-4-fluoro- 1H-pyrazole-5-sulfonamide (17.49 g, 50.638 mmol), sodium chlorodifluoroacetate (9.48 g, 62.18 mmol) and Cs2CO3 (20.07 g, 61.60 mmol) in anhydrous DMF (70 mL) was heated slowly to 130 °C over 2 h. The reaction was maintained at this temperature for 16 h. The brown suspension was cooled to RT and poured into half-saturated brine (700 mL) and extracted with EtOAc (250 mL). The organic layer was washed again with half-saturated brine (300 mL) and then brine (150 mL). The aqueous phases were back extracted with EtOAc (200 mL). The organic layers were combined and dried over Na ₂ SO ₄ . After concentration, the resulting dark residue was purified by silica column chromatography, eluting with EtOAc / hexanes (1:1). After evaporation, the title compound was isolated as a brown oil (15.12g, 65%). MS-ESI: 418.1 (M+1). Step 6: 1-(difluoromethyl)-4-fluoro-1H-pyrazole-3-sulfonamide In a 1-L round bottom flask (1000 mL), finely powdered N,N-dibenzyl-1-(difluoromethyl)-4- fluoro-1H- pyrazole-3-sulfonamide (15.1 g, 32.9 mmol) was cooled to 0 °C, treated with cold conc. H ₂ SO ₄ (90 mL, 1620 mmol) and stirred at 0 °C for 60 min. The yellow suspension was added dropwise to ice and the suspension was diluted with water (1.5 L) and solid NaCl (200 g) was added. The aqueous phase was extracted with EtOAc (800 mL) and washed with brine (200 mL). The aqueous phases were back extracted with EtOAc (2x400 mL). The organic layers were combined, dried over Na ₂ SO ₄ , filtered through Celite and concentrated in vacuo. The residue was re-dissolved in EtOAc (200 mL) and decolorized using active charcoal. The solution was concentrated in vacuo. The crude was triturated with DCM (100 mL) and heptane (150 mL). After filtration and drying, the title compound was isolated (4.807 g, 66%) as a beige solid. MS- ESI: 216.1 (M+1). Step 7: N-(tert-butyldimethylsilyl)-1-(difluoromethyl)-4-fluoro-1H-p yrazole-3-sulfonamide In a 100-mL round bottom flask, a cold (0 °C) solution of 1-(difluoromethyl)-4-fluoro-1H- pyrazole-3- sulfonamide (1.015 g, 4.716 mmol) in THF (4 mL) was treated dropwise with Et3N (1.4 mL, 10 mmol) keeping internal temperature below 5 °C. After 5 min, a solution of tert- butyldimethylsilyl chloride (975 mg, 6.469 mmol) in toluene (0.9 mL) was added via a cannula by keeping internal temperature below 7 °C. The suspension was warmed to RT and heated to 70 °C for 3 h. The reaction mixture was diluted with MTBE (50 mL). The organic phase was washed twice with aq. NaHCO ₃ (2x40 mL), and brine (40 mL). The organic phase was dried over Na ₂ SO ₄ , treated with active charcoal (160 mg), filtered through Celite and concentrated in vacuo. The residue was co-evaporated with heptane. The solid obtained was triturated with heptane (45 mL) and MTBE (3 mL) overnight. After filtration and drying, the title compound was isolated as a beige solid (1.07 g, 67%). MS-ESI: 330.1 (M+1). Step 8: (R)-1-(difluoromethyl)-4-fluoro-N-((S)-1-(4-methoxyphenyl)et hyl)-1H-pyrazole-3- sulfonimidamide and (S)-1-(difluoromethyl)-4-fluoro-N-((S)-1-(4-methoxyphenyl)et hyl)- 1H-pyrazole- 3-sulfonimidamide (D-8A and D-8B) In a 25-mL round bottom flask, a cold (0 °C) solution of PPh ₃ Cl ₂ (826 mg, 2.48 mmol) in dry DCM (4 mL) was treated dropwise with Et3N (0.52 mL, 3.73 mmol). The ice water bath was removed and a suspension was obtained. The reaction was allowed to warm to RT and stirred for 10 min at this temperature. The white suspension was cooled to -70 °C and a solution of N-(tert- butyldimethylsilyl)-1-(difluoromethyl)-4-fluoro- 1H-pyrazole-3-sulfonamide (405 mg, 1.23 mmol) in DCM (2 mL) was added via a cannula by keeping internal temperature below -50 °C. The dry ice bath was removed and the reaction was allowed to warm to 0 °C. The reaction was stirred at 0 °C for 30 min. Then, the reaction mixture was cooled back to -70 °C and (S)-(-)-4- Methoxy-a-methylbenzylamine (0.55 mL, 3.72 mmol) was added dropwise by keeping internal temperature below -45 °C. After 5 min, the dry ice bath was removed and the suspension was left to warm to 0 °C. The suspension was stirred at 0 °C for 30 min and left to warm to RT for an additional stirring period of 90 min. The solvent was removed under reduced pressure to give a crude residue which was treated with a mixture of ACN (4 mL), water (2 mL) and HCOOH (0.46 mL, 12.2 mmol). The reaction was stirred at RT for 2 h. The reaction was concentrated under vacuum to remove half the volume of ACN and, after, diluted with EtOAc (50 mL), washed with 1% HCOOH in half- saturated brine (2 x 30mL), aq. NaHCO ₃ :brine (1:1) (2 x 30 mL) and brine (25 mL). The aqueous phases were back extracted with EtOAc (50 mL). The organic layers were combined and dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was dissolved in DCM / hexanes (1:1) and purified on silica gel column by eluting with a gradient of 100% hexanes to 90% EtOAc / hexanes. The title compounds were isolated as white solids (first eluting diastereomer D-8A, Rf = 0.60 (DCM/EtOAc = 1:1), 104.9 mg, 24% yield, and second eluting diastereomer D-8B, Rf = 0.51 (DCM/EtOAc = 1:1), 73 mg, 17% yield). Absolute

stereochemistry was not determined. MS-ESI: 371.1 (M+Na). Step 9: (R)-1-(difluoromethyl)-4-fluoro-N'-((1,2,3,5,6,7-hexahydro-s -indacen-4- yl)carbamoyl)-N-((S)- 1-(4-methoxyphenyl)ethyl)-1H-pyrazole-3-sulfonimidamide and (S)- 1-(difluoromethyl)-4-fluoro-N'- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-N-((S)- 1-(4-methoxyphenyl)ethyl)-1H-pyrazole-3-sulfonimidamide (I-9A and I-9B) In a 25 mL round bottom flask, a solution of 1-(difluoromethyl)-4-fluoro-N'-((1,2,3,5,6,7- hexahydro- s-indacen-4-yl)carbamoyl)-N-((S)-1-(4-methoxyphenyl)ethyl)-1 H-pyrazole-3- sulfonimidamide (diastereomer D-8A, 49.4 mg, 0.142 mmol) in EtOAc (1.5 mL) was treated with 4-isocyanato-1,2,3,5,6,7-hexahydro- s-indacene (33.5 mg, 0.168 mmol) in one portion. The reaction was stirred for 1h at RT. Then, heptane (2 mL) was added dropwise over 2-3 min and a white solid was observed. The mixture was stirred at RT for a total of 2 h. The white solid was collected by filtration and the material was washed with EtOAc / heptane (1 mL / 2 mL) and dried under high vacuum to give the title compound as diastereomer D-9A (43.4 mg, 55%) as a white solid. Similarly, 40 mg of Diastereomer B gave diastereomer D-9B (43.9 mg, 69%). MS- ESI: 548.2 (M+1).

Step 10: (S)-1-(difluoromethyl)-4-fluoro-N'-((1,2,3,5,6,7-hexahydro-s -indacen-4- yl)carbamoyl)-1H- pyrazole-3-sulfonimidamide and (R)-1-(difluoromethyl)-4-fluoro-N'- ((1,2,3,5,6,7-hexahydro-s-indacen- 4-yl)-carbamoyl)-1H-pyrazole-3-sulfonimidamide (Examples 710 and 711) In a 5-mL round bottom flask, a cold (0 °C) suspension of diastereomer D9-A (31.4 mg, 0.057 mmol) in DCM (1 mL) was treated dropwise with TFA (0.4 mL, 5.2 mmol). The resulting solution was left to warm to RT by removing the ice-water bath after 5 min. The solution was stirred at RT for 2 h. Then, the reaction mixture was added to a 50 mL flask containing heptane (20 mL) and the solution was concentrated in vacuo. The material was suspended in DCM (20 mL) and heptane (20 mL) was added and triturated overnight at RT. The white solid was collected by filtration, washed with DCM / heptane (1:1, 2x2 mL) to afford 18.6 mg (76%) of the title product (Example 710). Absolute stereochemistry was not determined. ¹ H NMR (400 MHz, DMSO): d 8.62 (d; J = 4.59 Hz; 1 H); 8.45 (br s; 1 H); 7.90 (s; 2 H); 7.83 (t; J = 58.27 Hz; 1 H); 6.86 (s; 1 H); 2.75 (t; J = 7.35 Hz; 4 H); 2.56-2.69 (m; 4 H); 1.86-1.93 (m; 4 H). MS(ESI): 414.1 (M+1). Example 711 was generated from diastereomer D-9B using the same procedure, yielding 17.6 mg (73%) of product. Absolute stereochemistry was not determined. ¹ H NMR (400 MHz, DMSO): d 8.62 (d; J = 4.57 Hz; 1 H); 8.46 (br s; 1 H); 7.90 (s; 2 H); 7.83 (t; J = 58.25 Hz; 1 H); 6.85 (s; 1 H); 2.75 (t; J = 7.32 Hz; 4 H); 2.54-2.68 (m; 4 H); 1.86-1.93 (m; 4 H). MS(ESI): 414.1 (M+1).

Example 712 (Compound 886a)

N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(2-hy droxypropan-2-yl)-N-((R)-1-(4- methoxyphenyl)ethyl)thiazole-5-sulfonimidamide

Step 1: lithium 2-(5-sulfinatothiazol-2-yl)propan-2-yl sulfite

In a flame-dried 500 mL round bottom flask, a cold (-70 °C) solution of 2-(thiazol-2-yl)propan- 2-ol (10.101 g, 70.538 mmol) in dry THF (100 mL) was treated dropwise with n-BuLi (2.5 M in hexanes, 60 mL, 150 mmol). After 1 h at -70 °C, an atmosphere of SO2 (g) was introduced for 15 min using a balloon. Then, while maintaining the SO ₂ atmosphere, the dry-ice bath was removed and the suspension was allowed to warm to RT over 30 minutes. The suspension was cooled to 0 ^o C and collected by filtration and washed with Et2O. The very fine off-white powder was dried under high vacuum to give 23.4 g (94%) of the title compound as an off-white powder. MS(ESI): 208.0 (M+1).

Step 2: 2-(2-hydroxypropan-2-yl)thiazole-5-sulfonamide In a 100 mL round bottom flask immersed in a cool water bath, a suspension of hydroxylamine- O-sulfonic acid (18.64 g, 164.8 mmol) in water (50 mL) was treated with NaOAc (9.007 g, 109.8 mmol) followed by addition of lithium 2-(5-sulfinatothiazol-2-yl)propan-2-yl sulfite (15.10 g, 55.13 mmol). The white suspension was stirred at RT for 1 h. The reaction mixture was diluted with more water and extracted with EtOAc. The organic layer was separated and washed with water and brine. The aqueous phases (pH around 1-2) were back extracted with EtOAc. The organic layers were combined and dried over Na2SO4, filtered and concentrated in vacuo. The off-white solid was triturated in CHCl3 (250 mL) for 1 h under reflux. The hot suspension was cooled to RT and the material was collected by filtration. The filtered material was dried under high vacuum to give the title compound as an off-white solid (9.11 g, 72%). MS(ESI): 223.0 (M+1).

Step 3: N-(tert-butyldimethylsilyl)-2-(2-hydroxypropan-2-yl)thiazole -5-sulfonamide

In a 100-mL round-bottom flask, a cloudy solution of 2-(2-hydroxypropan-2-yl)thiazole-5- sulfonamide (8.110 g, 36.49 mmol) in THF (30 mL) was treated with Et3N (11.5 mL, 82.5 mmol). The mixture was cooled to 0 °C and a solution of tert-butyldimethylsilyl chloride (7.55 g, 50.1 mmol) in toluene (10 mL) was added. The suspension was warmed to RT and heated to 70 °C for 3 h.

The reaction mixture was diluted with MTBE. The organic phase was washed twice with aq. NaHCO ₃ , and brine, dried over Na ₂ SO ₄ , filtered through Celite® and concentrated in vacuo. The beige solid was recrystallized by dissolving in MTBE (20-40 mL) and adding heptane (300 mL). After filtration and drying, the title compound was isolated as an off-white solid (11.35 g, 91%). MS(ESI): 337.1 (M+1).

Step 4: 2-(2-hydroxypropan-2-yl)-N-((R)-1-(4-methoxyphenyl)ethyl)thi azole-5- sulfonimidamide

In a 10 mL round-bottom flask, a suspension of PPh ₃ Cl ₂ (380 mg, 1.140 mmol) in dry CHCl ₃ (2 mL) was treated with Et ₃ N (0.25 mL, 1.79 mmol). The mixture was stirred for 10 min at RT. The white suspension was cooled to 0 °C and a solution of N-(tert-butyldimethylsilyl)-2-(2- hydroxypropan-2-yl)-thiazole-5- sulfonamide (201 mg, 0.597 mmol) in CHCl3 (1 mL) was added via a cannula; a yellow solution was immediately obtained. The reaction mixture was stirred for 20 min at 0 °C. To the reaction mixture was added (R)-(+)-4-methoxy-a-methylbenzylamine (0.175 mL, 1.185 mmol) in one portion at 0 °C. The mixture was stirred at 0 °C for 30 min and warmed slowly to RT for 3 h. After an additional 6 h of stirring at RT, extra (R)-(+)-4-Methoxy- a-methylbenzylamine (0.045 mL, 0.305 mmol) was added and stirring continued for another 16 hours.

The solvent was removed under reduced pressure to give a crude residue which was dissolved in ACN (2 mL). To the suspension was added water (1 mL) and HCOOH (0.225 mL, 5.96 mmol) and a yellow cloudy solution was obtained. The reaction was stirred at RT for 1 h. The reaction was diluted with EtOAc, washed with 1% HCOOH in half-saturated brine (2 x 50 mL), aq. NaHCO ₃ : brine (1:1) (2 x 50 mL) and brine. The aqueous phases were back extracted with EtOAc. The organic layers were combined and dried over Na ₂ SO ₄ . The title compound was isolated as a 1:1 mixture of diastereomers (212 mg, quantitative) and was brought to the next step as is. MS(ESI): 356.1 (M+1).

Step 5: N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(2-hy droxypropan-2-yl)-N- ((R)-1- (4-methoxyphenyl)ethyl)thiazole-5-sulfonimidamide (Example 712)

In a 25 mL round-bottom flask, a mixture of crude 2-(2-hydroxypropan-2-yl)-N-((R)-1-(4- methoxyphenyl)- ethyl)thiazole-5-sulfonimidamide (0.597 mmol) and 4-isocyanato-1,2,3,5,6,7- hexahydro-s-indacene (138 mg, 0.693 mmol) was dissolved in EtOAc (2 mL). The clear reaction solution was stirred at RT for 3 h. A white precipitate was observed to form after 30 min. The suspension was diluted with more EtOAc (4 mL) and collected by filtration. The white solid was washed with more EtOAc (3x), dried under high vacuum overnight giving 207 mg (61%) of the title compound as a white solid (1:1 mixture of diastereomers as measured by proton NMR). MS(ESI): 555.2 (M+1).

Example 713 (Compound 874b)

(R)-2-((S)-1,2-dihydroxypropan-2-yl)-N'-((1,2,3,5,6,7-hexahy dro-s-indacen-4- yl)carbamoyl)thiazole-5-sulfonimidamide

Step 1: (S)-2-(thiazol-2-yl)propane-1,2-diol (E-1S)

In a 1 L round-bottom flask, t-BuOH (230 mL), water (230 mL) and THF (230 mL) was added, AD-mix-beta (111.8 g, 1.4 g per mmol of propenyl thiazole), followed by methanesulfonamide (7.60 g, 79.88 mmol) and (DHQD) ₂ AQN (2.74 g, 3.195 mmol). The reaction mixture was cooled to 0 ^o C with a mechanical stirrer. Into the cooled reaction mixture was added 2-propenyl thiazole (10 g, 79.8 mmol) and stirred for approximately 1 h at this temperature and then the ice-water bath was removed and stirred at RT for 24h. The reaction mixture was diluted with H ₂ O (100 mL) and was extracted with EtOAc (3 x 400mL). The combined organic extracts were washed with H ₂ O (75 mL) and brine (100 mL), dried over Na2SO4 and concentrated to give a yellowish orange solid. The crude material was purified by column chromatography using silica gel (20% methanol in DCM) to give 9.2 g of the product with 80% ee. Crystallization from mixture of ethyl acetate (140 mL), methanol (10 mL) and hexanes (420 mL) gave 6.4 g (70%) as a white solid with 99% ee. Chiral HPLC conditions; 70% hexanes +30% ethanol (0.1% DEA), Chiralpak IF column, flow rate; 1 mL/min, run time; 15 mins, R _t = 10.3 min).

Step 2: (S)-2-(2,2,4-trimethyl-1,3-dioxolan-4-yl)thiazole (E-2S)

In a 25 mL single neck round bottom flask was charged (S)-2-(thiazol-2-yl)propane-1,2-diol (6.4 g, 40.2 mmol, ee 99%) followed by acetone (50 mL) and stirred to get a clear solution at RT. pTSA (690 mg, 4.02 mmol) was added and stirred for 20 h at 40°C. The reaction mixture then cooled to RT, diluted with ethyl acetate (150 mL) and washed with satd. NaHCO ₃ solution (20 mL). The collected organic layer was washed with brine solution (50 mL), dried over anhydrous Na2SO4 and concentrated to give a crude oil. The crude oil was purified on silica gel by eluting from 100% hexanes to 20% ethyl acetate to the title compounds as a colorless oil (4.8 g, 60%). The material was used in the next step as is.

Step 3: (S)-2-((S)-2,2,4-trimethyl-1,3-dioxolan-4-yl)thiazole-5-sulf inamide (D-3S)

This step was performed using the procedure described in Scheme 103, Step 3 from 300 mg of (S)- 2-(2,2,4-trimethyl-1,3-dioxolan-4-yl)thiazole from the Step above to yield the title compound as a white solid (130 mg, 33%). MS(ESI): 263.0 (M+1).

Step 4: tert-butyl ((S)-(2-((S)-2,2,4-trimethyl-1,3-dioxolan-4-yl)thiazol-5-yl) sulfinyl)- carbamate (D-4S)

This step was performed using the procedure described in Scheme 103, Step 4 from 100 mg of (S)-2-((S)-2,2,4-trimethyl-1,3-dioxolan-4-yl)thiazole-5-sulf inamide (D-3S) to yield the title compound as a colourless viscous oil (110 mg, 80%).

Step 5: tert-butyl ((S)-amino(oxo)(2-((S)-2,2,4-trimethyl-1,3-dioxolan-4-yl)thi azol-5-yl)- ^ ⁶ - sulfaneylidene)carbamate (D-5S)

This step was performed using the procedure described in Scheme 103, Step 5 from 110 mg of tert-butyl ((S)-(2-((S)-2,2,4-trimethyl-1,3-dioxolan-4-yl)thiazol-5-yl) sulfinyl)-carbamate (D-4S) to yield the title compound as an off-white solid (63 mg, 60%). MS(ESI): 378.1 (M+1).

Step 6: tert-butyl ((R)-(3-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)ureido)(oxo)(2 -((S)-2,2,4- trimethyl-1,3-dioxolan-4-yl)thiazol-5-yl)- ^ ⁶ -sulfaneylidene)carbamate (D-6S)

In a 10 mL round bottom flask was charged tert-butyl ((S)-amino(oxo)(2-((S)-2,2,4-trimethyl-1,3- dioxolan-4-yl)thiazol-5-yl)- ^ ⁶ -sulfaneylidene)carbamate (D-5S, 25 mg, 0.06 mmol) followed by THF (2.0 mL) and cooled to 0 ⁰ C with stirring. Charged 1 M potassium tert-butoxide solution in THF (0.070 mL) and reaction mixture was stirred for 30 min at 0 ⁰ C. The solution of 4-isocyanato- 1,2,3,5,6,7-hexahydro-s-indacene (13.2 mg in 0.5 mL THF) was added at 0 ⁰ C and then stirred for approx.1 hours at RT. The reaction mixture was quenched with 1 M formic acid in THF (0.070 mL) at 0 ⁰ C and then extracted with ethyl acetate (25 mL) and filtered through Celite. The filtrate was concentrated under reduced pressure to afford an off-white solid. The residue was purified by column chromatography using a gradient of 100% ethyl acetate to 1% methanol in ethyl acetate. The title compound (25 mg, 66%) was isolated as an off-white solid and used in the next step as is.

Step 7: (R)-2-((S)-1,2-dihydroxypropan-2-yl)-N'-((1,2,3,5,6,7-hexahy dro-s-indacen-4- yl)carbamoyl)- thiazole-5-sulfonimidamide (Example 713)

In a 10 mL round-bottom flask was charged tert-butyl ((R)-(3-(1,2,3,5,6,7-hexahydro-s-indacen- 4-yl)ureido)(oxo)(2-((S)-2,2,4-trimethyl-1,3-dioxolan-4-yl)t hiazol-5-yl)- ^ ⁶ - sulfaneylidene)carbamate (D-6S, 25 mg, 0.043 mmol) followed by anhydrous DCM (3 mL) and the reaction suspension was cooled to 0°-5°C under an argon atmosphere. TFA was slowly added (0.05 mL) and stirred for 1 hour at 0 °C. Added more TFA (0.3 mL) and reaction was stirred for additional 3 hours. Added slowly another 0.45 mL of TFA in to the reaction mixture and stirred for additional 2.5 hours at 0 ^o C. The reaction solution was concentrated under reduced pressure and repeatedly co-evaporated with acetonitrile (3 x 5 mL) and concentrated.

The residue was dissolved DMSO and purified by C18 RP-HPLC by eluting with 100% water (0.1% TFA) to 95% acetonitrile in water. After lyophilization, the title compound was isolated as a white solid (12 mg, 58%). ¹ H NMR (DMSO-d6, 400 MHz): d 8.41 (br s, 1H), 8.04 (s, 1H), 7.82 (s, 2H), 6.86 (s, 1H), 6.12 (s, 1H), 5.00 (t, J = 6.0 Hz, 1H), 3.53 (d, J = 6.1 Hz, 2H), 2.76 (t, J = 7.4 Hz, 4H), 2.66 (s, 4H), 1.92 (p, J = 7.4 Hz, 4H), 1.43 (s, 3H). MS(ESI): 437.1 (M+1).

Example 714 (Compound 874a)

(R)-2-((R)-1,2-dihydroxypropan-2-yl)-N'-((1,2,3,5,6,7-hexahy dro- indacen-4-

yl)carbamoyl)thiazole-5-sulfonimidamide This compound was prepared as illustrated in Example 713 Steps 1-7 with replacement of reagents AD-mix-beta and (DHQD) ₂ AQN in Step 1 with AD-mix-alpha and (DHQ) ₂ AQN. ¹ H NMR (400 MHz, DMSO): d 8.41 (br s, 1H), 8.05 (s, 1H), 7.82 (br s, 2H), 6.86 (s, 1H), 6.12 (s, 1H), 4.99 (t, J = 6.08 Hz, 1 H), 3.53 (d, J = 6.07 Hz; 2H), 2.76 (t; J = 7.39 Hz, 4H), 2.55-2.70 (m, 4H), 1.92 (p, J = 7.35 Hz, 4H), 1.43 (s, 3H). MS(ESI): 437.1 (M+1).

Example 715

N'-((2,4,5,6-tetrahydro-1H-cyclobuta[f]inden-3-yl)carbamoyl) -4,5,6,7-tetrahydrothieno[3,2- c]pyridine-2-sulfonimidamide (Scheme XVIII)

Examples 716 and Example 717

(S)- and (R)-N'-((2,4,5,6-tetrahydro-1H-cyclobuta[f]inden-3-yl)carbam oyl)-4,5,6,7- tetrahydrothieno[3,2-c]pyridine-2-sulfonimidamide

Step 1: Tert-butyl 2-(N-(tert-butyldimethylsilyl)-N'-((2,4,5,6-tetrahydro-1H- cyclobuta[f]inden-3-yl) carbamoyl)sulfamidimidoyl)-6,7-dihydrothieno[3,2-c]pyridine- 5(4H)-carboxylate

To a stirred solution of tert-butyl 2-(N'-(tert-butyldimethylsilyl)sulfamidimidoyl)-6,7- dihydrothieno[3,2-c] pyridine-5(4H)-carboxylate (200 mg, 0.46 mmol) in THF (6.0 mL) in a 50- mL round-bottom flask under nitrogen was added NaH (60% wt. dispersion in mineral oil, 37 mg, 0.93 mmol) in portions at 0 ^° C. The reaction mixture was stirred for 10 min at RT. Then to this was added a mixture of 3-isocyanato-2,4,5,6-tetrahydro-1H-cyclobuta[f]indene (86 mg, 0.46 mmol) in THF (2.0 mL) dropwise with stirring at 0 ^° C. The reaction mixture was stirred for 2 h at RT and then quenched with 1.0 mL of water. The resulting mixture was extracted with 3x25 mL of EtOAc and the organic layers were combined. The organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated under vacuum. The crude product was eluted from silica gel with DCM/MeOH (10:1). This resulted in 130 mg (46%) of the title compound as a light yellow solid. MS-ESI: 617 (M+1).

Step 2: N'-((2,4,5,6-tetrahydro-1H-cyclobuta[f]inden-3-yl)carbamoyl) -4,5,6,7- tetrahydrothieno[3,2-c] pyridine-2-sulfonimidamide

A solution of tert-butyl 2-(N-(tert-butyldimethylsilyl)-N'-((2,4,5,6-tetrahydro-1H- cyclobuta[f]inden-3-yl) carbamoyl)sulfamidimidoyl)-6,7-dihydrothieno[3,2-c]pyridine- 5(4H)- carboxylate (130 mg, 0.21 mmol) in HCl in dioxane (4 M, 8.0 mL) in a 25-mL round-bottom flask was stirred for 30 min at RT. The reaction mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC using the following conditions: XBridge Prep C18 OBD Column, 19×150 mm 5 um; Mobile Phase A: water (10 mM NH ₄ HCO ₃ + 0.1%NH ^.

3H ₂ O), Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 19% B to 38% B over 7 min; UV 210/254 nm; Rt1: 6.92 min. This resulted in 50 mg (59%) of Example 715 as a white solid. MS- ESI: 403 (M+1). ¹ H NMR (400 MHz, DMSO-d ₆ ) d 8.27 (s, 1H), 7.31 (s, 1H), 6.66 (s, 1H), 3.72 (s, 2H), 3.10-2.99 (m, 2H), 2.99-2.91 (m, 2H), 2.91-2.79 (m, 2H), 2.85-2.66 (m, 6H), 1.96-1.86 (m, 2H).

Step 3: Chiral separation

Example 715 (40 mg) was resolved by Prep-Chiral-HPLC with the following conditions:

CHIRALPAK IG, 2*25 cm, 5 um; Mobile Phase A: CO2, Mobile Phase B: MeOH:ACN=1:1 (2 mM NH3-MeOH); Flow rate: 45 mL/min; Gradient: 50% B; UV 220 nm; Rt1: 8.28 min. (Example 716); Rt ₂ : 11.31 min. (Example 717). This resulted in 12.8 mg (99.9%ee) of

Example 716 followed by 14.8 mg (97.5%ee) of Example 717, both as a white solid.

Example 716: MS-ESI: 403 (M+1). ¹ H NMR (400 MHz, DMSO-d6) d 8.19 (s, 1H), 7.26 (s, 1H), 6.64 (s, 1H), 3.70 (s, 2H), 3.10-3.00 (m, 2H), 3.00-2.90 (m, 2H), 2.90-2.81 (m, 2H), 2.82-2.65 (m, 6H), 1.95-1.83 (m, 2H).

Example 717: MS-ESI: 403 (M+1). ¹ H NMR (400 MHz, DMSO-d6) d 8.17 (s, 1H), 7.24 (s, 1H), 6.63 (s, 1H), 3.69 (s, 2H), 3.13-3.00 (m, 2H), 3.00-2.90 (m, 2H), 2.90-2.81 (m, 2H), 2.82-2.65 (m, 6H), 1.95-1.84 (m, 2H).

Table 60 Examples in the following table were prepared using similar conditions as described in Example 715 and Scheme XVIII from appropriate starting materials.

N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-

Example 733

N'-(( , , , , , carbamoyl)-4-(hydroxymethyl)-2-(1,2,3- trihydroxypropan-2-yl)thiazole-5-sulfonimidamide (Scheme XIX)

Step 1: N'-(tert-butyldimethylsilyl)-4-(((tert-butyldimethylsilyl)ox y)methyl)-N-((1,2,3,5,6,7- hexahydro -s-indacen-4-yl)carbamoyl)-2-(5-hydroxy-2,2-dimethyl-1,3-dio xan-5-yl)thiazole- 5-sulfonimidamide To a stirred solution of N'-(tert-butyldimethylsilyl)-4-(((tert-butyldimethylsilyl)ox y)methyl)-2- (5-hydroxy -2,2-dimethyl-1,3-dioxan-5-yl)thiazole-5-sulfonimidamide (150 mg, 0.27 mmol) in THF (10 mL) in a 50-mL round-bottom flask under nitrogen was added NaH (60% wt.

dispersion in mineral, 43.2 mg, 1.08 mmol) in portions at 0 ^° C. The resulting solution was stirred for 10 min at RT. Then to the above mixture was added 4-isocyanato-1,2,3,5,6,7-hexahydro-s- indacene (81 mg, 0.41 mmol) at RT. The resulting mixture was stirred for 4 h at RT. The reaction mixture was quenched with 2.0 mL of H2O. The mixture was concentrated under vacuum. The residue was purified by Prep-TLC (PE/EtOAc 1:1). This resulted in 110 mg (54%) of the title compound as an off-white solid. MS-ESI: 751 (M+1).

Step 2: N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-(hydr oxymethyl)-2-(1,2,3- trihydroxypropan-2-yl)thiazole-5-sulfonimidamide

To a stirred solution of N'-(tert-butyldimethylsilyl)-4-(((tert-butyldimethylsilyl)ox y)methyl)-N- ((1,2,3,5,6,7- hexahydro-s-indacen-4-yl)carbamoyl)-2-(5-hydroxy-2,2-dimethy l-1,3-dioxan-5- yl)thiazole-5-sulfonimidamide (110 mg, 0.15 mmol) in THF (12 mL) in a 50-mL round-bottom flask was added HCl in dioxane (4 M, 4 mL) dropwise at RT. The reaction solution was stirred for 2 h at RT. The reaction solution was concentrated under vacuum. The crude product was purified by Prep-HPLC using the following conditions: XBridge Prep OBD C18 Column, 30×150 mm 5 um; Mobile Phase A: water (10 mM NH4HCO3 + 0.1%NH ^.

3H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 5% B to 35% B over 7 min; UV 210/254 nm; Rt ₁ : 6.2 min. This resulted in 32 mg (46%) of Example 733 as a white solid. MS-ESI: 483 (M+1). ¹ H NMR (400 MHz, MeOH-d4) d 6.92 (s, 1H), 5.01-4.90 (m, 2H), 3.92-3.81 (m, 4H), 2.91-2.70 (m, 8H), 2.09-1.98 (m, 4H).

Table 61 Examples in the following table were prepared using similar conditions as described in Example 733 and Scheme XIX from appropriate starting materials.

Example 735

5-((Dimethylamino)methyl)-N'-( ( , ,3,5,6,7- exa ydro-s- ndacen-4-yl)carbamoyl)thiophene-2- sulfonimidamide (Scheme XX)

Step 1: N-(tert-butyldimethylsilyl)-5-((dimethylamino)methyl)-N'-((1 ,2,3,5,6,7-hexahydro-s- indacen-4- yl)carbamoyl)thiophene-2-sulfonimidamide

To a stirred solution of N-(tert-butyldimethylsilyl)-5-((dimethylamino)methyl)thiophe ne-2- sulfonimidamide (800 mg, 2.4 mmol) in THF (50 mL) in a 100-mL round-bottom flask under nitrogen was added NaH (60% wt. dispersion in mineral oil, 192 mg, 4.8 mmol) in portions at 0 ^° C. The reaction mixture was stirred for 10 min at RT. Then to the reaction mixture was added 4- isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (382 mg, 1.92 mmol) in portions at 0 ^° C. The reaction mixture was stirred for 2 h at RT and then quenched with 5.0 mL of water. The mixture was extracted with 3x150 mL of EtOAc and the organic layers were combined. The organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated under vacuum. This resulted in 950 mg (crude) of the title compound as yellow oil which was used in the next step without further purification. MS-ESI: 533 (M+1).

Step 2: 5-((Dimethylamino)methyl)-N'-((1,2,3,5,6,7-hexahydro-s-indac en-4- yl)carbamoyl)thiophene -2-sulfonimidamide

The crude product of N-(tert-butyldimethylsilyl)-5-((dimethylamino)methyl)-N'-((1 ,2,3,5,6,7- hexahydro-s- indacen-4-yl)carbamoyl)thiophene-2-sulfonimidamide (950 mg, crude)

was applied on Prep-TLC and using DCM/MeOH (10:1) to keep Rf = 0.4~0.5, then left the product on TLC overnight at RT. The TBS group was removed on TLC to give the final product which was then eluted from TLC with DCM/MeOH (10:1). The final product was further purified by Prep-HPLC using the following conditions: XSelect CSH Prep C18 OBD Column, 5 um, 19*150 mm; Mobile Phase A: water (10 mM NH ₄ HCO ₃ + 0.1%NH ^.

3H ₂ O), Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 38 B to 50 B over 7 min; UV 210/254 nm; Rt: 5.53 min. This resulted in 280 mg (28 %, over two steps) of Example 735 as a white solid. MS-ESI: 419 (M+1). ¹ H NMR (400 MHz, DMSO-d ₆ ) d 8.41 (br s, 1H), 7.82 (br s, 2H), 7.63 (d, J = 3.6 Hz, 1H), 7.49 (d, J = 4.0 Hz, 1H), 6.88 (s, 1H), 4.73 (s, 2H), 2.89-2.72 (m, 4H), 2.82 (s, 6H), 2.71- 2.61 (m, 4H), 1.98-1.87 (m, 4H).

Table 62 Examples in the following table were prepared using similar conditions as described in Example 735 and Scheme XX from appropriate starting materials.

Example 738

4-(Hydroxymethyl)-2-(2-hydroxypropan-2-yl)-N'-((3-oxo-1,2,3, 5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)thiazole-5-sulfonimidamide (Scheme XXI)

Step 1: N-(tert-butyldimethylsilyl)-4-(((tert-butyldimethylsilyl)oxy )methyl)-2-(2- hydroxypropan-2–yl)-N'-((3-oxo-1,2,3,5,6,7-hexahydro-s-ind acen-4-yl)carbamoyl)thiazole- 5-sulfonimidamide

To a stirred solution of N-(tert-butyldimethylsilyl)-4-(((tert-butyldimethylsilyl)oxy )methyl)-2-(2- hydroxypropan-2-yl)thiazole-5-sulfonimidamide (200 mg, 0.42 mmol) in THF (20 mL) in a 100- mL round-bottom flask under nitrogen was added t-BuOK (94 mg, 0.83 mmol) in portions at 0 ^° C. The reaction mixture was stirred for 10 min at RT. Then to the above mixture was added 2,2,2-trichloroethyl (3-oxo-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamate (174 mg, 0.50 mmol) at RT. The reaction mixture was stirred for 4 h at RT. The reaction mixture was diluted with 20 mL of H ₂ O. The mixture was extracted with 3x30 mL of EtOAc and the organic layers were combined. The organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum. The crude product was purified by Prep-TLC with EtOAc/PE (1/1). This resulted in 239 mg (82%) of the title compound as a light yellow solid. MS-ESI: 693 (M+1).

Step 2: 4-(Hydroxymethyl)-2-(2-hydroxypropan-2-yl)-N'-((3-oxo-1,2,3, 5,6,7-hexahydro-s- indacen-4-yl) carbamoyl)thiazole-5-sulfonimidamide

To a stirred solution of N-(tert-butyldimethylsilyl)-4-(((tert-butyldimethylsilyl)oxy )methyl)-2-(2- hydroxypropan-2-yl)-N'-((3-oxo-1,2,3,5,6,7-hexahydro-s-indac en-4-yl)carbamoyl)thiazole-5- sulfonimidamide (20 mg, 0.029 mmol) in THF (5.0 mL) in a 25-mL round-bottom flask was added HF/Py (70% wt., 0.10 mL, 3.85 mmol). The reaction solution was stirred for 2 h at RT. The reaction solution was concentrated under vacuum. The crude product was purified by Prep- HPLC using the following conditions: XBridge Prep C18 OBD Column, 19*150 mm, 5 um; mobile phase, water (10 mL NH ₄ HCO ₃ + 0.1%NH ^.

3H ₂ O) and ACN (5% Phase B up to 30% over 7 min). This resulted in 7.0 mg (52%) of Example 738 as a white solid. MS-ESI: 465 (M+1). ¹ H NMR (300 MHz, MeOH-d4) d 7.13 (s, 1H), 4.99-4.86 (m, 2H), 3.07-2.99 (m, 2H), 2.96-2.87 (m, 2H), 2.84-2.74 (m, 2H), 2.71-2.63 (m, 2H), 2.08-1.93 (m, 2H), 1.58 (s, 6H). Table 63 Examples in the following table were prepared using similar conditions as described in Example 738 and Scheme XXI from appropriate starting materials. _{Example # Structure IUPAC Name} ^{Exact Mass}

+

p

5-(2-Hydroxypropan-2-yl)-1-isopropyl-N ((3-oxo-1,2,3,5,6,7-hexahydro-s-indacen-4-

yl)carbamoyl)-1H-pyrazole-3-sulfonimidamide (Scheme XXII)

Step 1: N-(tert-butyldimethylsilyl)-5-(2-hydroxypropan-2-yl)-1-isopr opyl-N'-((3-oxo- 1,2,3,5,6,7- hexahydro-s-indacen-4-yl)carbamoyl)-1H-pyrazole-3-sulfonimid amide

To a stirred solution of N'-(tert-butyldimethylsilyl)-5-(2-hydroxypropan-2-yl)-1-isop ropyl-1H- pyrazole-3- sulfonimidamide (250 mg, 0.69 mmol) in THF (8.0 mL) in a 25-mL round-bottom flask under nitrogen were added DBU (233 mg, 1.53 mmol) and 2,2,2-trichloroethyl (3-oxo- 1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamate (251 mg, 0.69 mmol) in portions at 0 ^° C in an ice/water bath. The reaction mixture was stirred overnight at RT. The reaction mixture was diluted with H2O (8 mL). The mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (3x15 mL) and dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was eluted silica gel with PE/EtOAc (3:1). This resulted in 80 mg (20%) of the title compound as a yellow solid. MS- ESI: 574 (M+1).

Step 2: 5-(2-Hydroxypropan-2-yl)-1-isopropyl-N'-((3-oxo-1,2,3,5,6,7- hexahydro-s-indacen- 4-yl) carbamoyl)-1H-pyrazole-3-sulfonimidamide

To a stirred solution of N-(tert-butyldimethylsilyl)-5-(2-hydroxypropan-2-yl)-1-isopr opyl-N'-((3- oxo- 1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1H-pyrazole- 3-sulfonimidamide (80 mg, 0.14 mmol) in THF (5.0 mL) was added HF-Pyridine (70% wt., 0.03 mL, 1.12 mmol) at RT. The reaction mixture was stirred for 2 h at RT. The pH value of the mixture was adjusted to pH 7 with sat. NaHCO ₃ (aq.). The mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (5.0 mL) and dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure. The crude product (50 mg) was purified by Prep-HPLC using the following conditions: XBridge Prep OBD C18 Column, 30×150 mm, 5 um; Mobile Phase A: water (10 mM NH ₄ HCO ₃ + 0.1%NH ^.

3H ₂ O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 30% B to 45% B over 7 min; 254/210 nm; Rt1: 6.43 min. This resulted in 25.6 mg (40%) of Example 740 as a white solid. MS-ESI: 399 (M+1). ¹ H NMR (400 MHz, MeOH-d ₄ ) d 7.12 (s, 1H), 6.60 (s, 1H), 5.36-5.28 (m, 1H), 3.05 (t, J = 5.6 Hz, 2H), 2.94 (t, J = 7.6 Hz, 2H), 2.90-2.80 (m, 2H), 2.77-2.66 (m, 2H), 2.08-2.02 (m, 2H), 1.62 (s, 6H), 1.50 (d, J = 6.8 Hz, 3H), 1.47 (d, J = 6.8 Hz, 3H).

Example 741

2-( -1,2-dihydroxypropan-2-yl)-N'-((2,4,5,6-tetrahydro-1H-cyclob uta[f]inden-3- yl)carbamoyl)thiazole-5-sulfonimidamide (Scheme XXIII)

Step 1: N-(tert-butyldimethylsilyl)-2-((S)-1-((tert-butyldimethylsil yl)oxy)-2- hydroxypropan-2-yl)-N'- ((2,4,5,6-tetrahydro-1H-cyclobuta[f]inden-3- yl)carbamoyl)thiazole-5-sulfonimidamide

To a stirred solution of N'-(tert-butyldimethylsilyl)-2-((S)-1-((tert-butyldimethylsi lyl)oxy)-2- hydroxypropan-2-yl)thiazole-5-sulfonimidamide (500 mg, 1.07 mmol) in THF (10 mL) in a 50-mL round-bottom flask under nitrogen was added NaH (60% wt. dispersion in mineral oil, 87 mg, 2.15 mmol) in portions at 0 ^° C. The reaction mixture was stirred for 10 min at RT. To the above mixture was added trichloromethyl (2,4,5,6-tetrahydro-1H-cyclobuta[f]inden-3- yl)carbamate (359 mg, 1.07 mmol) in portions at 0 ^° C. The reaction mixture was stirred for 2 h at RT. The reaction was quenched with 10 mL of water. The mixture was extracted with 3x20 mL of EtOAc. The organic layers were dried over anhydrous Na ₂ SO ₄ and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (2:1). This resulted in 300 mg (43%) of the title compound as light brown oil. MS-ESI: 651 (M+1)

Step 2: 2-((S)-1,2-dihydroxypropan-2-yl)-N'-((2,4,5,6-tetrahydro-1H- cyclobuta[f]inden-3- yl) carbamoyl)thiazole-5-sulfonimidamide

To a stirred solution of N-(tert-butyldimethylsilyl)-2-((S)-1-((tert-butyldimethylsil yl)oxy)-2- hydroxypropan-2-yl)-N'-((2,4,5,6-tetrahydro-1H-cyclobuta[f]i nden-3-yl)carbamoyl)thiazole-5- sulfonimidamide (300 mg, 0.46 mmol) in THF (10 mL) in a 50-mL round-bottom flask was added TBAF (480 mg, 1.84 mmol) at RT. The reaction mixture was stirred for 2 h at RT. The reaction mixture was concentrated under vacuum. The residue was eluted from silica gel with EtOAc (100%). The product was further purified by Flash-Prep-HPLC using the following conditions: XSelect CSH Prep C ₁₈ OBD Column, 5 um, 19*150 mm; Mobile Phase A: water (10 mM NH ^.

4HCO3+0.1%NH3H2O), Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 25% B to 42% B over 7 min; 254/210 nm; Rt1: 5.32 min. This resulted in 130 mg (67%) of Example 741 as an off-white solid. MS-ESI: 423 (M+1). ¹ H NMR (400 MHz, DMSO-d ₆ ) d 8.42 (br s, 1H), 8.11 (s, 1H), 7.90 (br s, 2H), 6.67 (s, 1H), 6.14 (s, 1H), 5.00 (t, J = 6.0 Hz, 1H), 3.55 (d, J = 6.0 Hz, 2H), 3.05-2.95 (m, 2H), 2.95-2.85 (m, 2H), 2.82-2.60 (m, 4H), 1.95- 1.85 (m, 2H), 1.45 (s, 3H).

Table 64 Examples in the following table were prepared using similar conditions as described in Example 741 and Scheme XXIII from appropriate starting materials.

Example 743

2-((R)-1,2-dihydroxypropan-2-yl)-N'-((3-oxo-1,2,3,5,6,7-hexa hydro-s-indacen-4- yl)carbamoyl)thiazole-5-sulfonimidamide (Scheme XXIV)

Step 1: N-(tert-butyldimethylsilyl)-2-((R)-1-((tert-butyldimethylsil yl)oxy)-2- hydroxypropan-2-yl)-N'- ((3-oxo-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)thiaz ole- 5-sulfonimidamide To a stirred solution of N'-(tert-butyldimethylsilyl)-2-((R)-1-((tert-butyldimethylsi lyl)oxy)-2- hydroxypropan-2-yl)thiazole-5-sulfonimidamide (300 mg, 0.64 mmol) in THF (10 mL) in a 100- mL round-bottom flask under nitrogen was added t-BuOK (217 mg, 1.93 mmol) in portions at 0 °C. The reaction mixture was stirred for 10 min at RT. To the reaction mixture was added trichloromethyl (3-oxo-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamate (202 mg, 0.58 mmol) in portions at 0 ^° C. The reaction mixture was stirred for 16 h at RT. The reaction mixture was quenched with H2O (10 mL). The mixture was extracted with 5x20 mL of EtOAc and the organic layers were combined. The organic layer was dried with anhydrous Na2SO4 and concentrated under vacuum. This resulted in 400 mg (91%) of the title compound as a brown solid. MS-ESI: 679 (M+1).

Step 2: 2-((R)-1,2-dihydroxypropan-2-yl)-N'-((3-oxo-1,2,3,5,6,7-hexa hydro-s-indacen-4- yl)carbamoyl) thiazole-5-sulfonimidamide

To a stirred solution of N-(tert-butyldimethylsilyl)-2-((R)-1-((tert-butyldimethylsil yl)oxy)-2- hydroxypropan -2-yl)-N'-((3-oxo-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carba moyl)thiazole-5- sulfonimidamide (200 mg, 0.30 mmol) in THF (10 mL) in a 100-mL round-bottom flask was added TBAF (509 mg, 1.95 mmol) at RT. The reaction solution was stirred for 2 h at RT. The reaction mixture was diluted with H2O (10 mL). The mixture was extracted with 5x20 mL of EtOAc and the organic layers were combined. The organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated under vacuum. The residue was eluted from silica gel with

DCM:MeOH (20:1). The product was further purified by Prep-HPLC using the following conditions: XBridge Prep C18 OBD Column, 19×150 mm, 5 um; Mobile Phase A: water (10 mM NH ₄ HCO ₃ +0.1%NH ^.

3H ₂ O), Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 5% B to 30% B over 7 min; UV 254/210 nm; Rt ₁ : 5.78 min. This resulted in 80 mg (60%) of Example 743 as a white solid. MS-ESI: 451 (M+1). ¹ H NMR (400 MHz, DMSO-d6) d 9.01 (s, 1H), 8.07 (s, 1H), 7.65 (br s, 2H), 7.09 (s, 1H), 6.12 (s, 1H), 4.99 (br s, 1H), 3.54 (s, 2H), 2.96 (t, J = 5.2 Hz, 2H), 2.87 (t, J = 7.2 Hz, 2H), 2.83-2.61 (m, 4H), 1.99-1.93 (m, 2H), 1.44 (s, 3H).

Table 65 Examples in the following table were prepared using similar conditions as described in Example 743 and Scheme XXIV from appropriate starting materials.

(S)-3-(5,5-difluoro-7,9-dimethyl-5H-5l4,6l4-dipyrrolo[1,2-c: 2',1'-f][1,3,2]diazaborinin-3-yl)-N- (4-(N' hexahydro-s-indacen-4-yl)carbamoyl)sulfamidimidoyl)benzyl)-N -

methylpropanamide (Scheme XXV)

Step 1: (S)-3-(5,5-difluoro-7,9-dimethyl-5H-5l ₄ ,6l ₄ -dipyrrolo[1,2-c:2',1'- f][1,3,2]diazaborinin-3-yl)-N- (4-(N'-((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)sulfamidimidoyl)benzyl)-N-methylpropanamide

To a stirred solution of (S)-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4- ((methylamino)methyl) benzenesulfonimidamide (12 mg, 0.030 mmol) in DMF (0.50 mL) in a 25-mL round-bottom flask were added 2,5-dioxopyrrolidin-1-yl 3-(5,5-difluoro-7,9-dimethyl- 5H-5l4,6l4-dipyrrolo[1,2-c:2',1'-f][1,3,2] diazaborinin-3-yl)propanoate (11 mg, 0.027 mmol) and TEA (6.09 mg, 0.060 mmol) at RT. The reaction solution was stirred for 25 h at RT. The solution was purified by Prep-HPLC using the following conditions: XBridge Prep OBD C18 Column, 19*250 mm, 5 um; mobile phase, water (10 mM NH4HCO3+0.1%NH ^.

3H2O) and ACN (54% PhaseB up to 69% over 10 min); UV 254/210. This resulted in 5.8 mg (29%) of Example 745 as a red solid. MS-ESI: 673 (M+1). ¹ H NMR (400 MHz, MeOH-d ₄ ) d 7.95 (d, J = 8.1 Hz, 2H), 7.47-7.35 (m, 3H), 7.01-6.88 (m, 2H), 6.35-6.20 (m, 2H), 4.79-4.61 (m, 2H), 3.29-3.20 (m, 2H), 3.00 (s, 3H), 2.94-2.60 (m, 10H), 2.53 (s, 3H), 2.28 (s, 3H), 2.05-1.94 (m, 4H). Example 746 and Example 747

(S) and (R)-5-((S)-1-(2-(benzyloxy)ethoxy)-2-hydroxypropan-2-yl)-N'- ((1,2,3,5,6,7-hexahydro- s-indacen-4-yl)carbamoyl)thiophene-2-sulfonimidamide (Scheme 2)

Step 1: 5-((S)-1-(2-(benzyloxy)ethoxy)-2-hydroxypropan-2-yl)-N-(tert - butyldimethylsilyl)-N'- ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)thiophene-2 - sulfonimidamide

To a stirred solution of 5-((S)-1-(2-(benzyloxy)ethoxy)-2-hydroxypropan-2-yl)-N'-(ter t- butyldimethylsilyl) thiophene-2-sulfonimidamide (350 mg, 0.72 mmol) in THF (8 mL) in a 25-mL round-bottom flask under nitrogen was added NaH (60% wt. dispersion in mineral oil, 52 mg, 2.17 mmol) in portions 0 ^° C. The reaction mixture was stirred for 10 min at RT. To above mixture was added 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (144 mg, 0.72 mmol) in portions at 0 ^° C. The reaction mixture was stirred for 3 h at RT. The reaction was quenched with 10 mL of water/ice at 0 ^° C. The mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (3x 15 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in 469 mg (crude) of the title compound as a light yellow solid. MS-ESI: 684 (M+1). Step 2: (S) and (R)-5-((S)-1-(2-(benzyloxy)ethoxy)-2-hydroxypropan-2-yl)-N'- ((1,2,3,5,6,7- hexahydro-s-indacen-4-yl)carbamoyl)thiophene-2-sulfonimidami de

To a stirred solution of 5-((S)-1-(2-(benzyloxy)ethoxy)-2-hydroxypropan-2-yl)-N-(tert - butyldimethyl- silyl)-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)t hiophene-2- sulfonimidamide (50 mg, crude) in THF (5.0 mL) in a 25-mL round-bottom flask was added HF/Py (70%wt., 0.1 mL, 3.7 mmol). The reaction mixture was stirred for 1 h at RT. The reaction mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC using the following conditions: XSelect CSH Prep C18 OBD Column, 5 um, 19*150 mm; Mobile Phase A: water (10 mM NH4HCO3+0.1%NH ^.

3H2O), Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 30% B to 50% B over 7 min; UV, 210/254 nm; Rt1: 6.37 min. This resulted in 10 mg (25%) of Example 746 and 10 mg (25%) of Example 747, both as a white solid. MS- ESI: 570 (M+1).

Example 746 ¹ H NMR (400 MHz, MeOH-d4) d 7.77 (s, 1H), 7.65 (s, 1H), 7.37-7.25 (m, 5H), 6.92 (s, 1H), 4.54 (s, 2H), 3.67-3.49 (m, 6H), 2.91-2.79 (m, 8H), 2.10-1.98 (m, 4H), 1.52 (s, 3H). Example 747 ¹ H NMR (400 MHz, MeOH-d4) d 7.56 (d, J = 3.6 Hz, 1H), 7.40-7.25 (m, 5H), 7.00 (d, J = 4.0 Hz, 1H), 6.92 (s, 1H), 4.55 (s, 2H), 3.72-3.58 (m, 6H), 2.90-2.71 (m, 8H), 2.10- 1.95 (m, 4H), 1.60 (s, 3H).

Example 748

(S)-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-5-( (S)-2-hydroxy-1-(2- hydroxyethoxy)propan-2-yl)thiophene-2-sulfonimidamide (Scheme XVII) Step 1: (S)-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-5-( (S)-2-hydroxy-1-(2- hydroxyethoxy)propan-2-yl)thiophene-2-sulfonimidamide

To a stirred solution of (S)-5-((S)-1-(2-(benzyloxy)ethoxy)-2-hydroxypropan-2-yl)-N'- ((1,2,3,5,6,7- hexahydro-s-indacen-4-yl)carbamoyl)thiophene-2-sulfonimidami de (20 mg, 0.035 mmol) in DCM (10 mL) was added BCl ₃ in DCM (1 M, 0.1 mL, 0.1 mmol) dropwise at 0 ^° C under nitrogen atmosphere. The reaction mixture was stirred for 5 h at 0 ^° C. The reaction was quenched with water/ice at 0 ^° C. The mixture was extracted with DCM (3x10 mL). The combined organic layers were washed with brine (3 x 10 mL) and dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure. The crude product (20 mg) was purified by Prep-HPLC using the following conditions: XSelect CSH Prep C18 OBD Column, 5 um, 19*150 mm; Mobile Phase A: water (10 mM, NH ₄ HCO ₃ +0.1%NH ^.

3H ₂ O), Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 32% B to 40% B over 10 min; UV 210/254 nm; Rt1: 10.63 min. This resulted in 1.7 mg (10%) of Example 748 as a white solid. MS-ESI: 480 (M+1). ¹ H NMR (300 MHz, MeOH-d ₄ ) d 7.87 (s, 1H), 7.78 (s, 1H), 6.94 (s, 1H), 3.69-3.50 (m, 6H), 2.91-2.70 (m, 8H), 2.11-1.96 (m, 4H), 1.54 (s, 3H).

Table 66 Examples in the following table were prepared using similar conditions as described in Example 748 and Scheme XVII from Example 747 and Example 759.

Example 752

6-(Dimethylamino)-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)-4,5,6,7- tetrahydrobenzo[b]thiophene-2-sulfonimidamide (Scheme XXVI)

Step 1: Tert-butyl (2-(N-(tert-butyldimethylsilyl)-N'-((1,2,3,5,6,7-hexahydro-s -indacen-4- yl)- carbamoyl)sulfamidimidoyl)-4,5,6,7-tetrahydrobenzo[b]thiophe n-6- yl)(methyl)carbamate

To a stirred solution of tert-butyl (2-(N'-(tert-butyldimethylsilyl)sulfamidimidoyl)-4,5,6,7- tetrahydro- benzo[b]thiophen-6-yl)(methyl)carbamate (30 mg, 0.065 mmol) in THF (5 mL) under nitrogen was added NaH (60%wt dispersion in mineral oil, 5.24 mg, 0.131 mmol) in portions at 0 ^° C. The resulting mixture was stirred for 10 min at 0 ^° C, then 4-isocyanato- 1,2,3,5,6,7-hexahydro-s-indacene (20 mg, 0.098 mmol) was added in one portion at 0 ^° C. The resulting solution was stirred for 16 h at RT, then quenched with 10 mL of water. The resulting solution was extracted with 3x50 mL of EtOAc. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. This resulted in 40 mg (93.1%) of the title compound as a yellow solid. MS-ESI: 659 (M+1).

Step 2: 6-(Dimethylamino)-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)-4,5,6,7- tetrahydro- benzo[b]thiophene-2-sulfonimidamide

To a stirred solution of tert-butyl (2-(N-(tert-butyldimethylsilyl)-N'-((1,2,3,5,6,7-hexahydro-s - indacen- 4-yl)carbamoyl)sulfamidimidoyl)-4,5,6,7-tetrahydrobenzo[b]th iophen-6- yl)(methyl)carbamate (20 mg, 0.044 mmol) in THF (10 mL) under nitrogen was added LAH (8.4 mg, 0.22 mmol) in one portion at 0 ^° C. The resulting mixture was stirred for 16 h at RT. The reaction mixture was quenched with water (1 mL) and diluted with EtOAc (50 mL). The solids were filtered out and the filtrate was concentrated under vacuum. The residue was purified by Prep-HPLC using the following conditions: XBridge Shield RP18 OBD Column, 30*150 mm, 5 um; Mobile Phase A: water (10 mM NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 25% B to 55% B over 7 min; 254/220 nm. This resulted in 3.5 mg (25%) of Example 752 as white solid. MS-ESI: 459 (M+1).

Table 67 Examples in the following table were prepared using similar conditions as described in Example 1 and Scheme 1 from appropriate starting materials.

Table 68 Examples in the following table were prepared using similar conditions as described in Example 4 and Scheme 2 from appropriate starting materials.

Table 69 Examples in the following table were prepared using similar conditions as described in Example 251 and Scheme 35 from appropriate starting materials.

Table 70 Examples in the following table were prepared using similar conditions as described in Example 453 and Scheme IV from appropriate starting materials.

Table 71 Examples in the following table were prepared using similar conditions as described in Example 497 and Scheme VI from appropriate starting materials.

Table 72 Examples in the following table were prepared using similar conditions as described in Example 513 and Scheme XI from appropriate starting materials.

Table 73 Examples in the following table were prepared using similar conditions as described in Example 446 and Scheme 3 from appropriate starting materials.

Table 74 Examples in the following table were prepared using similar conditions as described in Example 451 and Scheme III from appropriate starting materials.

Table 75 Examples in the following table were obtained from chiral HPLC resolutions of racemic examples described above. The chiral column and eluents are listed in the table. As a convention, the faster-eluting enantiomer is always listed first in the table followed by the slower-eluting enantiomer of the pair. The symbol * at a chiral center denotes that this chiral center has been resolved and the absolute stereochemistry at that center has not been determined. Assigned stereochemistry in compound names are tentative. Some carbon stereocenters were assigned arbitrarily for registration purpose, such as the carbon centers for Examples 874~877.

Table 76 Examples in the following table were prepared using similar conditions as described in Example 735 and Scheme XX from appropriate starting materials.

Table 77 Examples in the following table were obtained from chiral HPLC resolutions of racemic examples described above. TheF chiral column and eluents are listed in the table. As a convention, the faster-eluting enantiomer is always listed first in the table followed by the slower-eluting enantiomer of the pair. The symbol * at a chiral center denotes that this chiral center has been resolved and the absolute stereochemistry at that center has not been determined. Assigned stereochemistry in compound names are tentative.

883 The following protocol is suitable for testing the activity of the compounds disclosed herein. Procedure 1: IL-1b production in PMA-differentiated THP-1 cells stimulated with Gramicidin.

THP-1 cells were purchased from the American Type Culture Collection and sub-cultured according to instructions from the supplier. Cells were cultured in complete RPMI 1640 (containing 10% heat inactivated FBS, penicillin (100 units/ml) and streptomycin (100 mg/ml)), and maintained in log phase prior to experimental setup. Prior to the experiment, compounds were dissolved in dimethyl sulfoxide (DMSO) to generate a 30mM stock. The compound stock was first pre-diluted in DMSO to 3, 0.34, 0.042 and 0.0083 mM intermediate concentrations and subsequently spotted using Echo550 liquid handler into an empty 384-well assay plate to achieve desired final concentration (e.g.100, 33, 11, 3.7, 1.2, 0.41, 0.14, 0.046, 0.015, 0.0051, 0.0017 mM). DMSO was backfilled in the plate to achieve a final DMSO assay concentration of 0.37%. The plate was then sealed and stored at room temperature until required.

THP-1 cells were treated with PMA (Phorbol 12-myristate 13-acetate) (20 ng/ml) for 16- 18 hours. On the day of the experiment the media was removed and adherent cells were detached with trypsin for 5 minutes. Cells were then harvested, washed with complete RPMI 1640, spun down, and resuspended in RPMI 1640 (containing 2% heat inactivated FBS, penicillin (100 units/ml) and streptomycin (100 mg/ml) . The cells were plated in the 384-well assay plate containing the spotted compounds at a density of 50,000 cells/well (final assay volume 50 µl). Cells were incubated with compounds for 1 hour and then stimulated with gramicidin (5mM) (Enzo) for 2 hours. Plates were then centrifuged at 340g for 5 min. Cell free supernatant (40µL) was collected using a 96-channel PlateMaster (Gilson) and the production of IL-1b was evaluated by HTRF (cisbio). The plates were incubated for 18 h at 4ºC and read using the preset HTRF program (donor emission at 620 nm, acceptor emission at 668 nm) of the SpectraMax i3x spectrophotometer (Molecular Devices, software SoftMax 6). A vehicle only control and a dose titration of CRID3 (100 - 0.0017 mM) were run concurrently with each experiment. Data was normalized to vehicle-treated samples (equivalent to 0% inhibition) and CRID3 at 100 µM (equivalent to 100% inhibition). Compounds exhibited a concentration-dependent inhibition of IL- 1b production in PMA-differentiated THP-1 cells.

Procedure 2: IL-1b production in PMA-differentiated THP-1 cells stimulated with Gramicidin.

THP-1 cells were purchased from the American Type Culture Collection and sub-cultured according to instructions from the supplier. Prior to experiments, cells were cultured in complete RPMI 1640 (containing 10% heat inactivated FBS, penicillin (100 units/ml) and streptomycin (100 mg/ml)), and maintained in log phase prior to experimental setup. Prior to the experiment THP-1 were treated with PMA (Phorbol 12-myristate 13-acetate) (20 ng/ml) for 16-18 hours. Compounds were dissolved in dimethyl sulfoxide (DMSO) to generate a 30mM stock. On the day of the experiment the media was removed and adherent cells were detached with trypsin for 5 minutes. Cells were then harvested, washed with complete RPMI 1640, spun down, resuspended in RPMI 1640 (containing 2% heat inactivated FBS, penicillin (100 units/ml) and streptomycin (100 mg/ml) . The cells were plated in a 384-well plate at a density of 50,000 cells/well (final assay volume 50 µl). Compounds were first dissolved in assay medium to obtain a 5x top concentration of 500µM. 10 step dilutions (1:3) were then undertaken in assay medium containing 1.67% DMSO. 5x compound solutions were added to the culture medium to achieve desired final concentration (e.g.100, 33, 11, 3.7, 1.2, 0.41, 0.14, 0.046, 0.015, 0.0051, 0.0017 mM). Final DMSO concentration was at 0.37%. Cells were incubated with compounds for 1 hour and then stimulated with gramicidin (5mM) (Enzo) for 2 hours. Plates were then centrifuged at 340g for 5 min. Cell free supernatant (40µL) was collected using a 96-channel PlateMaster (Gilson) and the production of IL-1b was evaluated by HTRF (cisbio). A vehicle only control and a dose titration of CRID3 (100 - 0.0017 mM) were run concurrently with each experiment. Data was normalized to vehicle- treated samples (equivalent to 0% inhibition) and CRID3 at 100 µM (equivalent to 100% inhibition). Compounds exhibited a concentration-dependent inhibition of IL-1b production in PMA-differentiated THP-1 cells.

Procedure 3 1. Experimental procedure 1.1 Cell Culture 1) Culture THP-1 cells in the complete RPMI-1640 medium with 10% FBS at 37 ^° C, 5% CO2. 2) Passage the cells every 3 days by inoculating 3x10 ⁵ cells per ml. 1.2 Compound Preparation Prepare the 3-fold serial dilution of the compounds with DMSO in a 384-well LDV Microplate using TECAN EVO system to generate the compound source plate with 10 concentrations. Top concentration is 30 mM. FIG.3 depicts the layout of the microplate. 1.3 Cell preparation 1) Centrifuge THP-1 cells at 350g for 5 min. 2) Re-suspend cells with complete RMPI-1640 medium, and count cells. 3) Seed cells in T225 flask, about 2.5x10 ⁷ per flask, treat cells with 20ng/ml PMA (final DMSO concentration< 1%). 4) Incubate overnight. 1.4 THP-1 Stimulation 1) Wash adherent THP-1 cells with PBS, and detach cells with 4ml trypsin for T225 flask. 2) Centrifuge cells at 350g for 5 min, re-suspend cells with RPMI-1640 containing 2% FBS and count cells with trypan blue.

3) Transfer 50 nl/well the serial dilution of test compound to 384-well plate by Echo; For the high control and first point of CRID3 (MCC950), transfer 165 nl, then backfill to make the DMSO concentration is consistent in all wells, the plate layout is as below. 4) Seed 50k cells in 40ul RPMI-1640 with 2% FBS per well in 384-well plate. 5) Incubate for 1h at 37 ^° C, 5% CO ₂ . 6) Prepare 5x gramicidin, add 10 ^l per well, the final concentration is 5 ^M, incubate for 2hrs at 37 ^° C, 5% CO2. 7) Centrifuge at 350 g for 1 min.

8) Pipet 16 ^l supernatant by apricot, and transfer into white 384 proxiplate. FIG.3 depicts the layout of the plates: HC: 100 ^M CRID3 (MCC950) + 5 ^M gramicidin LC：5 ^M Gramicidin.

1.5 IL-1b detection 1) Homogenize the 5x diluent #5 with a vortex and add 1 volume of stock solution in 4 volumes of distilled water. 2) Thaw 20x stock solution of anti-IL1b-Cryptate-antibody and anti-IL1b XL-antibody. Dilute these two antibodies to 1x with detection buffer #3. 3) Pre-mix the two ready-to-use antibody solutions just prior to use. 4) Dispense 4ul of pre-mixed Anti-IL1b antibodies working solution into all wells. 5) Seal the plate and incubate overnight at 4 ^o C. 6) Read the cell plate using EnVison and plot Readout vs. the test compound concentration to calculate the IC50. 2. Data Analysis: 1. IC ₅₀ of compounds can be calculated using the following formulas Formula for IC50 % inhibition =100-100 x [HCave-Readout / (HCave– LCave)] 2. Fit the normalized data in a dose-response manner using XLfit, and calculate the compound concentration. Tables B1, B2, and B3 show the biological activity of compounds in hTHP-1 assay containing 2% fetal bovine serum. Table B4 shows the biological activity of compounds in hTHP-1 assay containing 10% fetal bovine serum. Key: <0.008 µM =“++++++”; ³0.008 and <0.04 µM = “+++++”; ³0.04 and <0.2 µM =“++++”; ³0.2 and <1 µM =“+++”; ³1 and <5 µM =“++”; ³5 and <30 µM =“+”.

Table B1. Average IC50 of compounds in hTHP-1 assay

Table B2. 463 464 465 466 467 468 469 470 471 472 473 474 475 476 477 478 479 480 481 482 483 484 485 486 487 488 489 490 491 492 493 494 495 496 497 498 499 500 501 502 503 504 505 506 507 508 509 510 511 512 513 514 515 516 517 518 519 520 521 522 523 524 525 526 527 528 529 530 531 532 533 534 535 536 537 538

Table B3

Table B4

Study Example 1. The CARD8 gene is located within the inflammatory bowel disease (IBD) 6 linkage region on chromosome 19. CARD8 interacts with NLRP3, and Apoptosis-associated Speck-like protein to form a caspase-1 activating complex termed the NLRP3 inflammasome. The NLRP3 inflammasome mediates the production and secretion of interleukin-1 ^, by processing pro-IL-1 ^ into mature secreted IL-1 ^. In addition to its role in the inflammasome, CARD8 is also a potent inhibitor of nuclear factor NF- ^B. NF- ^B activation is essential for the production of pro-IL-1 ^. Since over-production of IL-1 ^ and dyregulation of NF- ^B are hallmarks of Crohn’s disease, CARD8 is herein considered to be a risk gene for inflammatory bowel disease. A significant association of CARD8 with Crohn’s disease was detected in two British studies with a risk effect for the minor allele of the non-synonymous single-nucleotide polymorphism (SNP) of a C allele at rs2043211. This SNP introduces a premature stop codon, resulting in the expression of a severely truncated protein. This variant CARD8 protein is unable to suppress NF- ^B activity, leading to constitutive production of pro-IL-1 ^ , which is a substrate for the NLRP3

inflammasome. It is believed that a gain-of-function mutation in an NLRP3 gene (e.g., any of the gain-of-function mutations described herein, e.g., any of the gain-of-function mutations in an NLRP3 gene described herein) combined with a loss-of-function mutation in a CARD8 gene (e.g., a C allele at rs2043211) results in the development of diseases related to increased NLRP3 inflammasome expression and/or activity. Patients having, e.g., a gain-of-function mutation in an NLRP3 gene and/or a loss-of-function mutation in a CARD8 gene are predicted to show improved therapeutic response to treatment with an NLRP3 antagonist.

A study is designed to determine: whether NLRP3 antagonists inhibit inflammasome function and inflammatory activity in cells and biopsy specimens from patients with Crohn’s disease or ulcerative colitis; and whether the specific genetic variants identify patients with Crohn’s disease or ulcerative colitis who are most likely to respond to treatment with an NLRP3 antagonist.

The secondary objectives of this study are to: determine if an NLRP3 antagonist reduces inflammasome activity in Crohn’s disease and ulcerative biopsy samples (comparing Crohn’s disease and ulcerative colitis results with control patient results); determine if an NLRP3 antagonist reduced inflammatory cytokine RNA and protein expression in Crohn’s disease and ulcerative colitis samples; determine if baseline (no ex vivo treatment) RNA levels of NLRP3, ASC, and IL-1 ^ are greater in biopsy samples from patients with anti-TNFa agent resistance status; and stratify the results according to presence of specific genetic mutations in genes encoding ATG16L1, NLRP3, and CARD8 (e.g., any of the mutations in the ATG16L1 gene, NLRP3 gene, and CARD8 gene described herein). Methods

^ Evaluation of baseline expression of NLRP3 RNA and quantify inhibition of inflammasome activity by an NLRP3 antagonist in biopsies of disease tissue from patients with Crohn’s disease and ulcerative colitis.

^ Determine if NLRP3 antagonist treatment reduces the inflammatory response in biopsies of disease from patients with Crohn’s disease based on decreased expression of inflammatory gene RNA measured with Nanostring.

^ Sequence patient DNA to detect specific genetic mutations in the ATG16L1 gene, NLRP3 gene, and CARD8 gene (e.g., any of the exemplary mutations in these genes described herein) and then stratify the results of functional assays according to the presence of these genetic mutations. Experimental Design

^ Human subjects and tissue:

Endoscopic or surgical biopsies from areas of disease in patients with Crohn’s disease and ulcerative colitis who are either anti-TNFa treatment naïve or resistant to anti-TNFa treatment; additionally biopsies from control patients (surveillance colonoscopy or inflammation-free areas from patients with colorectal cancer) are studied. ^ Ex vivo Treatment Model:

Organ or LPMC culture as determined appropriate ^ Endpoints to be measured:

Before ex vivo treatment-- NLRP3 RNA level

After ex vivo treatment- inflammasome activity (either processed IL-1 ^, processed caspase-1, or secreted IL-1 ^); RNA for inflammatory cytokines (Nanostring); viable T cell number and/or T cell apoptosis. ^ Data Analysis Plan:

^ Determine if NLRP3 antagonist treatment decreases processed IL-1 ^, processed

caspase-1 or secreted IL-1 ^, and inflammatory cytokine RNA levels.

^ Stratify response data according to treatment status at biopsy and the presence of genetic mutations in the NLRP3 gene, CARD8 gene, and ATG16L1 gene (e.g., any of the exemplary genetic mutations of these genes described herein). Study Example 2. Treatment of anti-TNF ^ resistant patients with NLRP3 antagonists

PLoS One 2009 Nov 24;4(11):e7984, describes that mucosal biopsies were obtained at endoscopy in actively inflamed mucosa from patients with Ulcerative Colitis, refractory to corticosteroids and/or immunosuppression, before and 4-6 weeks after their first infliximab (an anti-TNF ^ agent) infusion and in normal mucosa from control patients. The patients in this study were classified for response to infliximab based on endoscopic and histologic findings at 4-6 weeks after first infliximab treatment as responder or non-responder. Transcriptomic RNA expression levels of these biopsies were accessed by the inventors of the invention disclosed herein from GSE 16879, the publically available Gene Expression Omnibus

(https://www.ncbi.nlm.nih.gov/geo/geo2r/?acc=GSE16879). Expression levels of RNA encoding NLRP3 and IL-1b were determined using GEO2R (a tool available on the same website), based on probe sets 207075_at and 205067_at, respectively. It was surprisingly found that in Crohn’s disease patients that are non-responsive to the infliximab (an anti-TNF ^ agent) have higher expression of NLRP3 and IL-1 ^ RNA than responsive patients (Figs.4 and 5). Similar surprising results of higher expression of NLRP3 and IL-1 ^ RNA in UC patients that are non-responsive to infliximab (an anti-TNF ^ agent) compared to infliximab (an anti-TNF ^ agent) responsive patients (Figs.6 and 7) were found.

Said higher levels of NLRP3 and IL-1 ^ RNA expression levels in anti-TNF ^ agent non- responders, is hypothesised herein to lead to NLRP3 activation which in turns leads ot release of IL-1 ^ that induces IL-23 production, leading to said resistance to anti-TNF ^ agents. Therefore, treatment of Crohn’s and UC anti-TNF ^ non-responders with an NLRP3 antagonist would prevent this cascade, and thus prevent development of non-responsiveness to anti-TNF ^ agents. Indeed, resistance to anti-TNF ^ agents is common in other inflammatory or autoimmune diseases. Therefore, use of an NLRP3 antagonist for the treatment of inflammatory or autoimmune diseases will block the mechanism leading to non-responsiveness to anti- TNF ^^agents. Consequently, use of NLRP3 antagonists will increase the sensitivity of patients with inflammatory or autoimmune diseases to anti-TNF ^ agents, resulting in a reduced dose of anti-TNF ^ agents for the treatment of these diseases. Therefore, a combination of an NLRP3 antagonist and an anti-TNF ^ agent can be used in the treatment of diseases wherein TNF ^ is overexpressed, such as inflammatory or autoimmune diseases, to avoid such non-responsive development of patients to anti-TNF ^ agents. Preferably, this combination threatment can be used in the treatment of IBD, for example Crohn’s disease and UC.

Further, use of NLRP3 antagonists offers an alternative to anti-TNF ^ agents for the treatment of diseases wherein TNF ^ is overexpressed. Therefore, NLRP3 antagonists offers an alternative to anti-TNF ^ agents inflammatory or autoimmune diseases, such as IBD (e.g.

Crohn’s disease and UC).

Systemtic anti-TNF ^ agents are also known to increase the risk of infection. Gut restricted NLRP3 antagonists, however, offers a gut targeted treatment (i.e. non-systemic treatment), preventing such infections. Therefore, treatment of TNF ^ gut diseases, such as IBD (i.e. Crohn’s disease and UC), with gut restricted NLRP3 antagonists has the additional advantage of reducing the risk of infection compared to anti-TNF ^ agents.

Proposed Experiment:

Determine the expression of NLRP3 and caspase-1 in LPMCs and epithelial cells in patients with non-active disease, in patients with active disease, in patients with active disease resistant to corticosteroids, patients with active disease resistant to TNF-blocking agents. The expression of NLRP3 and caspase-1 in LPMCs and epithelial cells will be analyzed by

RNAScope technology. The expression of active NLRP3 signature genes will be analyzed by Nanostring technology. A pilot analysis to determine feasibility will be performed with 5 samples from control, 5 samples from active CD lesions, and 5 samples from active UC lesions. Study Example 3.

It is presented that NLRP3 antagonists reverse resistance to anti-TNF induced T cell depletion/apoptosis in biopsy samples from IBD patients whose disease is clinically considered resistant or unresponsive to anti-TNF therapy. A study is designed to determine: whether NLRP3 antagonists inhibit inflammasome function and inflammatory activity in cells and biopsy specimens from patients with Crohn’s disease or ulcerative colitis; and whether an NLRP3 antagonist will synergize with anti-TNFa therapy in patients with Crohn’s disease or ulcerative colitis.

The secondary objectives of this study are to: determine if an NLRP3 antagonist reduces inflammasome activity in Crohn’s disease and ulcerative biopsy samples (comparing Crohn’s disease and ulcerative colitis results with control patient results); determine if an NLRP3 antagonist reduced inflammatory cytokine RNA and protein expression in Crohn’s disease and ulcerative colitis samples; determine if an NLRP3 antagonist in the absence of co-treatment with anti-TNFa antibody induces T cell depletion in Crohn’s disease and ulcerative colitis biopsy samples; and determine if baseline (no ex vivo treatment) RNA levels of NLRP3, ASC, and IL- 1b are greater in biopsy samples from patients with anti-TNFa agent resistance status. Methods

^ Evaluation of baseline expression of NLRP3 RNA and quantify inhibition of inflammasome activity by an NLRP3 antagonist in biopsies of disease tissue from patients with Crohn’s disease and ulcerative colitis.

^ Determine if there is synergy between an NLRP3 antagonist and anti-TNF antibody with respect to effects on T cell depletion/apoptosis in biopsies of disease from patients with Crohn’s disease and ulcerative colitis.

^ Determine if NLRP3 antagonist treatment reduces the inflammatory response in biopsies of disease from patients with Crohn’s disease based on decreased expression of inflammatory gene RNA measured with Nanostring. Experimental Design ^ Human subjects and tissue:

Endoscopic or surgical biopsies from areas of disease in patients with Crohn’s disease and ulcerative colitis who are either anti-TNFa treatment naïve or resistant to anti-TNFa treatment; additionally biopsies from control patients (surveillance colonoscopy or inflammation-free areas from patients with colorectal cancer) are studied. ^ Ex vivo Treatment Model:

Organ or LPMC culture as determined appropriate ^ Ex vivo Treatments:

NLRP3 antagonist (2 concentrations), negative control (vehicle), positive control (caspase-1 inhibitor) each in the presence or absence of anti-TNF antibody at a concentration appropriate to distinguish differences in the T cell apoptotic between biopsies from anti-TNF resistant and anti-TNF-sensitive Crohn’s disease patients. Each treatment condition is evaluated in a minimum in duplicate samples. ^ Endpoints to be measured:

Before ex vivo treatment-- NLRP3 RNA level

After ex vivo treatment- inflammasome activity (either processed IL-1b, processed caspase-1, or secreted IL-1b); RNA for inflammatory cytokines (Nanostring); viable T cell number and/or T cell apoptosis. ^ Data Analysis Plan:

^ Determine if NLRP3 antagonist co-treatment increases T cell apoptosis/deletion in response to anti-TNF.

^ Determine if the level of NLRP3 RNA expression is greater in TNF-resistant Crohn’s disease and ulcerative colitis samples compared to anti-TNF treatment-naïve samples. ^ Determine if NLRP3 antagonist treatment decreases processed IL-1b, processed

caspase-1 or secreted IL-1b, and inflammatory cytokine RNA levels. Biological Assay - Nigericin-stimulated IL-1 ^ secretion assay in THP-1 cells Monocytic THP-1 cells (ATCC: TIB-202) were maintained according to providers’ instructions in RPMI media (RPMI/Hepes +10% fetal bovine serum + Sodium Pyruvate + 0.05 mM Beta-mercaptoethanol (1000x stock) + Pen-Strep). Cells were differentiated in bulk with 0.5 µM phorbol 12-myristate 13-acetate (PMA; Sigma # P8139) for 3 hours, media was exchanged, and cells were plated at 50,000 cells per well in a 384-well flat-bottom cell culture plates (Greiner, #781986), and allowed to differentiate overnight. Compound in a 1:3.16 serial dilution series in DMSO was added 1:100 to the cells and incubated for 1 hour. The NLRP3 inflammasome was activated with the addition of 15 µM (final concentration) Nigericin (Enzo Life Sciences, #BML-CA421-0005), and cells were incubated for 3 hours.10 µL supernatant was removed, and IL-1 ^ levels were monitored using an HTRF assay (CisBio, #62IL1PEC) according to manufacturers’ instructions. Viability and pyroptosis was monitored with the addition of PrestoBlue cell viability reagent (Life Technologies, #A13261) directly to the cell culture plate.

A number of embodiments of the invention have been described. Nevertheless, it will be understood that various modifications may be made without departing from the spirit and scope of the invention. Accordingly, other embodiments are within the scope of the following claims.