Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D275/00—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings
  • C07D275/04—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings condensed with carbocyclic rings or ring systems
  • C07D275/06—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings condensed with carbocyclic rings or ring systems with hetero atoms directly attached to the ring sulfur atom
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
  • C07D279/02—1,2-Thiazines; Hydrogenated 1,2-thiazines
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D281/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one sulfur atom as the only ring hetero atoms
  • C07D281/02—Seven-membered rings
  • C07D281/04—Seven-membered rings having the hetero atoms in positions 1 and 4
  • C07D281/08—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
  • C07D281/10—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems condensed with one six-membered ring
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
  • C07D285/15—Six-membered rings
  • C07D285/16—Thiadiazines; Hydrogenated thiadiazines
  • C07D285/18—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
  • C07D285/36—Seven-membered rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
  • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
  • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
  • C07D513/04—Ortho-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
  • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
  • C07D513/10—Spiro-condensed systems

Definitions

• 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).
• a compound that modulates e.g., antagonizes
• a pharmaceutically acceptable salt, and/or hydrate, and/or cocrystal, and/or drug combination of the compound e.g., for treating a condition, disease or disorder in which a decrease or increase in NLRP3 activity (e.g., an increase, e.g.
• 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 TNFa 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).
• MFS The inherited CAPS Muckle-Wells syndrome
• FCAS familial cold autoinflammatory syndrome
• NOMID neonatal onset multi-system inflammatory disease
• 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, disease
• IBD Intestinal bowel disease
• UC Ulcerative Colitis
• CD Crohn’s disease
• TNF- a tumor necrosis factor-alpha
• Anti-TNFa therapies 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 intestinal 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.
• NLRP3 inflammasome inhibitors could be an efficacious treatment option for UC, Crohn’s disease, or subsets of IBD patients.
• 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.
• inflammasome related cytokines including IL-1 b, IL-6, and IL-18
• 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)
• 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).
• TNF-R2 TNF-receptor 2
• 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 ⁇ secretion - would be expected to inhibit the mechanism leading to anti-TNF non- responsiveness, re-sensitizing the patient 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 ⁇ and TNF- ⁇ 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-1 ⁇ and TNF- ⁇ .
• 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.
• 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-TNF ⁇ agents.
• 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).
• a compound that modulates e.g., antagonizes
• a pharmaceutically acceptable salt, and/or hydrate, and/or cocrystal, and/or drug combination of the compound 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).
• provided herein is a compound of Formula AA
• compositions as well as other methods of using and making the same.
• 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.
• methods of treating a subject 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.
• inflammatory or autoimmune disease including IBD such as UC and CD
• methods for the treatment of inflammatory or autoimmune disease including IBD, such as UC and CD 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.
• 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
• 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.
• 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.
• 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.
• the treatment further includes a therapeutically effective amount of an anti-TNFa agent, in addition to the NLRP3 antagonist.
• 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.
• 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.
• 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
• one or more pharmaceutically acceptable excipients e.g., a compound described generically or specifically herein or a pharmaceutically acceptable salt thereof or compositions containing the same.
• methods for modulating e.g., agonizing, partially agonizing, antagonizing
• NLRP3 activity 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.
• methods of treatment of a disease in which NLRP3 signaling contributes to the pathology and/or symptoms and/or progression of the disease 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).
• 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 of treatment 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.
• 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
• 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.
• 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,
• the methods can further include identifying the subject.
• 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.
• API refers to an active pharmaceutical ingredient.
• an “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.
• 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.
• 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.
• 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.
• pharmaceutically acceptable salt may refer to pharmaceutically acceptable addition salts prepared from pharmaceutically acceptable non-toxic acids including inorganic and organic acids.
• 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.
• 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.
• 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
• 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.
• 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, tart
• “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.
• 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.
• 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.
• primate e.g., human
• monkey cow, pig, sheep, goat
• horse dog, cat, rabbit, rat
• patient is used interchangeably herein in reference, for example, to a mammalian subject, such as a human.
• 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.
• “treat”,“treating”, and“treatment”, in the context of treating a disease or disorder are meant to include alleviating or abrogating a disorder, disease, or condition, or one or more of the symptoms associated with the disorder, disease, or condition; or to slowing the progression, spread or worsening of a disease, disorder or condition or of one or more symptoms thereof.
• halo refers to fluoro (F), chloro (Cl), bromo (Br), or iodo (I).
• 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.
• C1-10 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.
• haloalkyl refers to an alkyl, in which one or more hydrogen atoms is/are replaced with an independently selected halo.
• alkoxy refers to an -O-alkyl radical (e.g., -OCH3).
• 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.
• 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.
• heterocyclic rings include five-membered, six- membered, and seven-membered heterocyclic rings.
• 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.
• heterocycloalkyl refers to an nonaromatic 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring, fused, or spiro system radical having 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, or S (e.g., carbon atoms and 1-3, 1-6, or 1-9 heteroatoms of N, O, or S if monocyclic, bicyclic, or tricyclic, respectively), wherein 0, 1, 2, or 3 atoms of each ring may be substituted by a substituent.
• heterocycloalkyls include five-membered, six- membered, and seven-membered heterocyclic rings.
• Examples include piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, tetrahydrofuranyl, and the like.
• aryl is intended to mean an aromatic ring radical containing 6 to 10 ring carbons. Examples include phenyl and naphthyl.
• 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.
• hydroxy refers to an OH group.
• amino refers to an NH 2 group.
• oxo refers to O.
• 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 NC(O) group of Formula AA.
• 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 YC(O) group of Formula AA.
• 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 YC(O) group of Formula AA.
• atoms making up the compounds of the present embodiments are intended to include all isotopic forms of such atoms.
• Isotopes include those atoms having the same atomic number but different mass numbers.
• isotopes of hydrogen include tritium and deuterium
• isotopes of carbon include 13 C and 14 C.
• 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 may describe and exemplify methods for separating individual components of said stereoisomer mixtures (e.g., resolving the enantiomers of a racemic mixture).
• Figure 1 Expression levels of RNA encoding NLRP3 in Crohn’s Disease patients who are responsive and non-responsive to infliximab.
• Figure 2 Expression levels of RNA encoding IL-1 ⁇ in Crohn’s Disease patients who are responsive and non-responsive to infliximab.
• Figure 3 Expression levels of RNA encoding NLRP3 in Ulcerative Colitis (UC) patients who are responsive and non-responsive to infliximab.
• Figure 4 Expression levels of RNA encoding IL-1 ⁇ in Ulcerative Colitis (UC) patients who are responsive and non-responsive to infliximab.
• Figure 5 Layout of the microplate to measure activity of compounds in the THP-1 stimulation assay.
• DETAILED DESCRIPTION In some embodiments, provided herein is a compound of Formula AA
• Y is -CR 15 R 15 - or -NR 16 -;
• ring A is: (i) a saturated or unsaturated monocyclic ring that includes from 5-8 ring atoms (inclusive of N-R 3 and S(O)); or
• ring atoms are ring heteroatoms, which are each independently selected from the group consisting of O, N, NH, NR 13 , S, S(O), and S(O)2; and
• ring atoms are ring carbon atoms, which are each independently selected from the group consisting of C, CH, CH2, C(O), CR 1 , C(R 1 )2, and CHR 1 ;
• each of the divalent group’s 1-6 ring carbon atoms is independently selected from the group consisting of CH, CH2, C(O), CR 1 , C(R 1 )2, and CHR 1 ;
• two or three adjacent ring carbon atoms of the divalent group are each independently selected from the group consisting of C, CH, and CR 1 , and are fused to a second ring that is selected from the group consisting of:
• heteroaryl including from 5-10 ring atoms, wherein from 1-4 ring atoms are each independently selected from the group consisting of N, N(R N ), O, and S, wherein the heteroaryl is optionally substituted with from 1-3 independently selected R a ;
• heterocycloalkyl including from 3-10 ring atoms, wherein from 1-3 ring atoms are each independently selected from the group consisting of N(R N ), O, and S, wherein the heterocycloalkyl is optionally substituted with from 1-4 independently selected R b ; or
• one of the divalent group’s ring carbon atoms is C and is spiro-fused to a second ring that is selected from the group consisting of:
• heterocycloalkyl including from 3-10 ring atoms, wherein from 1-3 ring atoms are each independently selected from the group consisting of N(R N ), O, and S, wherein the heterocycloalkyl is optionally substituted with from 1-4 independently selected R b ; each R 1 is independently selected from the group consisting of: 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 heterocycl
• each C1-C6 alkyl substituent and each C1-C6 alkoxy substituent on R 1 when present, is further optionally independently substituted with one to three hydroxy, C1-C6 alkoxy, halo, NR 8 R 9 , or oxo;
• OS(O2)C6-C10 aryl S(O2)C6-C10 aryl, C6-C10 aryl, OC6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, CO2H, and CONR 8 R 9 ,
• ring B is a 5-10-membered heteroaryl or a C 6 -C 10 aryl
• 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 , S(O 2 )C 1 -
• heterocycloalkyl and a C 2 -C 6 alkenyl
• C 1 -C 6 alkyl is optionally substituted with one or more hydroxy, halo, C 1 -C 6 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 atom to which each is attached form a 3- to 7-membered ring optionally containing one or more additional heteroatoms;
• R 10 is C1-C6 alkyl;
• 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;
• R 3 is selected from hydrogen, cyano, hydroxy, C1-C6 alkoxy, C1-C6 alkyl,
• 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 ;
• each occurrence of R 15 is independently selected from hydrogen and C 1 -C 6 alkyl
• R 16 is selected from hydrogen and C 1 -C 6 alkyl
• ring A is a saturated or unsaturated bicyclic or tricyclic ring that includes from 6-14 ring atoms. In some embodiments, ring A is a bicyclic or tricyclic ring that includes from 8-14 ring atoms. In certain embodiments (when ring A is a saturated or unsaturated bicyclic or tricyclic ring that includes from 6-14 (e.g., 8-14) ring atoms), (A) applies.
• ring A when ring A is a saturated or unsaturated bicyclic or tricyclic ring that includes from 6-14 (e.g., 8-14) ring atoms (e.g., when (A) applies), ring A has Formula (A1):
• ring C is selected from the group consisting of:
• heteroaryl including from 5-10 ring atoms, wherein from 1-4 ring atoms are each independently selected from the group consisting of N, N(R N ), O, and S, wherein the heteroaryl is optionally substituted with from 1-3 independently selected R a ;
• each of A 1a and A 1c is independently selected from: a bond, CH2, CHR 1 , C(R 1 )2, C(O), N, NH, NR 13 , O, S(O)2, and A 1d -A 1e -A 1f ; provided that one or more of A 1a and A 1c is other than a bond;
• each of A 1d , A 1e , and A 1f is independently a bond, CH 2 , CHR 1 , C(R 1 ) 2 , C(O), S(O) 2 , NH, NR 13 , and O, provided that from 2-3 of A 1d , A 1e , and A 1f are other than a bond,
• a 1a is selected from a bond, CH2, CHR 1 , C(R 1 )2, and A 1d -A 1e -A 1f .
• each of A 1d , A 1e , and A 1f is independently selected from a bond, CH2, CHR 1 , and C(R 1 )2.
• each of A 1d , A 1e , and A 1f can be independently selected from a bond and CH2.
• a 1a is a bond. In certain embodiments of Formula (A1), A 1a is selected from CH2, CHR 1 , and, C(R 1 )2. In certain embodiments of Formula (A1), A 1a is A 1d -A 1e -A 1f . In certain of the foregoing embodiments, one of A 1d , A 1e , and A 1f is a bond. In certain embodiments (when A 1a is A 1d -A 1e -A 1f ), one of A 1d , A 1e , and A 1f is selected from CH 2 , CHR 1 , and, C(R 1 ) 2 .
• one of A 1d , A 1e , and A 1f can be a bond; and each of the remaining A 1d , A 1e , and A 1f can be CH2.
• a 1c is selected from the group consisting of: CH2, CHR 1 , C(R 1 )2, C(O), S(O)2, and A 1d -A 1e -A 1f .
• a 1c is C(O).
• a 1c is selected from the group consisting of: CH2, CHR 1 , and C(R 1 )2.
• a 1c is A 1d -A 1e -A 1f .
• each of A 1d , A 1e , and A 1f is independently selected from a bond, C(O), NH, NR 13 , CH 2 , CHR 1 , and C(R 1 ) 2 .
• each of A 1d , A 1e , and A 1f can be independently selected from a bond, C(O), and CH 2 .
• one of A 1d , A 1e , and A 1f is C(O).
• a 1a is a bond; and A 1c is selected from CH2, CHR 1 , C(R 1 )2, C(O), and A 1d -A 1e -A 1f .
• a 1c is C(O).
• a 1c is CH 2 , CHR 1 , or C(R 1 ) 2 (e.g., A 1c is CH 2 ).
• ring A is selected from:
• ring A is: .
• a 1c is A 1d -A 1e -A 1f , wherein one of A 1d , A 1e , and A 1f is C(O) or CH 2 (e.g., A 1d is C(O); or A 1d is CH 2 ).
• each of the remaining A 1d , A 1e , and A 1f is independently selected from: a bond, NH, NR 13 , CH 2 , CHR 1 , and C(R 1 ) 2 .
• ring A is:
• ring A is selected from: r methyl)).
• ring A when ring A is selected from: s selected from CH2, CHR 1 , and C(R 1 )2 (e.g., A 1e is CH2).
• a 1f is a bond.
• a 1f is selected from CH 2 , CHR 1 , and C(R 1 ) 2 (e.g., A 1f is CH 2 ).
• a 1a is selected from CH2, CHR 1 , and, C(R 1 )2; and
• a 1c is selected from CH 1f
• a 1c is selected from is selected from the group consisting of: CH 2 , CHR 1 , C(O), and A 1d -A 1e -A 1f .
• a 1a is selected from CH 2 , CHR 1 , and, C(R 1 ) 2 ; and A 1c is selected from CH 2 , CHR 1 , C(R 1 ) 2 , C(O), and A 1d -A 1e -A 1f (e.g., when A 1c is selected from is selected from the group consisting of: CH2, CHR 1 , C(O), and A 1d -A 1e -A 1f )), A 1c is C(O).
• ring A is selected from:
• a 1a is selected from CH2, CHR 1 , and, C(R 1 )2; and A 1c is selected from CH 2 , CHR 1 , C(R 1 ) 2 , C(O), and A 1d -A 1e -A 1f (e.g., when A 1c is selected from is selected from the group consisting of: CH2, CHR 1 , C(O), and A 1d -A 1e -A 1f )), A 1c is A 1d -A 1e -A 1f . In certain of the foregoing embodiments, A 1f is a bond.
• each of A 1d and A 1e is independently selected from C(O), CH2, CHR 1 , and C(R 1 ) 2 .
• each of A 1d and A 1e is independently C(O) and CH 2 .
• ring A is:
• a 1a is A 1d -A 1e -A 1f ; and A 1c is selected from CH2, CHR 1 , C(R 1 ) 2 , C(O), and A 1d -A 1e -A 1f .
• a 1c is selected from the group consisting of: CH2, CHR 1 , C(O), and A 1d -A 1e -A 1f .
• a 1c is C(O).
• each of A 1d , A 1e , and A 1f of A 1a is independently a bond, CH 2 , CHR 1 , and C(R 1 )2.
• one of A 1d , A 1e , and A 1f is a bond.
• each of the remaining A 1d , A 1e , and A 1f is CH2.
• ring A is:
• each R 1 when present is independently selected from the group consisting of: C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C1-C6 haloalkoxy, halo, CN, C6-C10 aryl, 5- to 10-membered heteroaryl, NH2, NHC1-C6 alkyl, N(C1-C6 alkyl)2, NHCOC1-C6 alkyl, C3-C7 cycloalkyl, and 3- to 7-membered heterocycloalkyl.
• each R 1 when present is C 1 -C 6 alkyl.
• ring C is C 6-10 aryl optionally substituted with from 1-5 independently selected R a .
• ring C is C 6 aryl optionally substituted with from 1-3 (e.g., 1-2, e.g., 1) independently selected R a .
• ring C is selected from: , wherein the asterisk represents point of attachment to A 1a .
• ring C is heteroaryl including from 5-10 ring atoms, wherein from 1-4 ring atoms are each independently selected from the group consisting of N, N(R N ), O, and S, wherein the heteroaryl is optionally substituted with from 1-3 independently selected R a .
• ring C is heteroaryl including from 5-6 ring atoms, wherein from 1-4 ring atoms are each independently selected from the group consisting of N, N(R N ), O, and S, wherein the heteroaryl is optionally substituted with from 1-3 independently selected R a .
• ring C is heteroaryl including from 6 ring atoms, wherein from 1-3 (e.g., 1-2, e.g., 1 or 2) ring atoms are each independently selected from the group consisting of N, N(R N ), O, and S, wherein the heteroaryl is optionally substituted with from 1-2 independently selected R a .
• ring C is selected from: , , , , ,
• ring C is heteroaryl including from 5 ring atoms, wherein from 1-3 (e.g., 1-2, e.g., 1) ring atoms are each independently selected from the group consisting of N, N(R N ), O, and S, wherein the heteroaryl is optionally substituted with from 1-2 independently selected R a .
• ring C is thiophenyl optionally substituted with from 1-2 (e.g., 1) independently selected R a .
• ring C is selected from:
• R a e.g., substituted with 1 R a ; or unsubstituted
• ring C is heteroaryl including from 8-10 ring atoms, wherein from 1-3 (e.g., 1-2, e.g., 1 or 2) ring atoms are each independently selected from the group consisting of N, N(R N ), O, and S, wherein the heteroaryl is optionally substituted with from 1-2 independently selected R a .
• ring C is selected from:
• each R a when present is independently selected from: hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR 8 R 9 , 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, OC 6 -C 10 aryl, 5- to 10- membered heteroaryl, C 3 -C 10 cycloalkyl, 3- to 10-membered heterocycloalkyl, CO 2 H, and CONR 8 R 9 ,
• 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, C1-4 haloalkyl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C1-C6 alkoxy, oxo, NR 8 R 9 , COOC 1 -C 6 alkyl, C 6 -C 10 aryl, CO 2 H, and CONR 8 R 9 .
• one or more occurrences of R a is C1-C6 alkyl which is optionally substituted with one or more substituents each independently selected from hydroxy, halo, C 3 -C 10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C 1 -C 6 alkoxy, oxo, NR 8 R 9 , COOC1-C6 alkyl, C6-C10 aryl, CO2H, and CONR 8 R 9 .
• one or more occurrences of R a is C 1 -C 6 alkyl which is optionally substituted with one or more substituents each independently selected from hydroxy, halo, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C1-C6 alkoxy, NR 8 R 9 , COOC 1 -C 6 alkyl, C 6 -C 10 aryl, CO 2 H, and CONR 8 R 9 .
• one or more occurrences of R a is C1-C6 alkyl which is optionally substituted with one or more substituents each independently selected from halo, hydroxy and NR 8 R 9 ,
• one or more occurrences of R a is OC 6 -C 10 aryl, C 2 -C 6 alkenyl, 3- to 10-membered heterocycloalkyl, C 6 -C 10 aryl, or 5- to 10-membered heteroaryl, each of which is optionally substituted as defined in claim 66.
• one or more occurrences of R a is CN, halo, CO 2 H, CONR 8 R 9 , or COOC1-C6 alkyl.
• ring C is selected from:
• ring C is C5-8 (e.g., C5-6, e.g., C5) cycloalkyl optionally substituted with from 1-2 independently selected R b .
• ring C is heterocycloalkyl including from 5-8 (e.g., 5 or 6, (e.g., 5)) ring atoms, wherein from 1-3 (e.g., 1) ring atoms are each independently selected from the group consisting of N(R N ), O, and S, wherein the heterocycloalkyl is optionally substituted with from 1-4 independently selected R b .
• each R b is independently selected from hydroxy, halo, oxo, C1- C 6 alkyl, C 1 -C 6 alkoxy, OC 3 -C 10 cycloalkyl, NR 8 R 9 , CN, COOC 1 -C 6 alkyl, C 6 -C 10 aryl, OC 6 -C 10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, CO2H, and CONR 8 R 9 .
• each R b is independently C1-3 alkyl.
• ring A is as defined in any of the embodiments described herein; and ring C is as defined in any of the embodiments described herein.
• ring A is as defined in any one of claims 25-26 (e.g., claim 26), and ring C is as defined in any one of claims 54-56.
• ring A is as defined in any one of claims 25-26 (e.g., claim 26), and ring C is as defined in any one of claims 59-60.
• ring A is as defined in any one of claims 25-26 (e.g., claim 26), and ring C is as defined in any one of claims 61-63.
• ring A is as defined in any one of claims 25-26 (e.g., claim 26), and ring C is as defined in any one of claims 64-65.
• ring A is as defined in any one of claims 25-26 (e.g., claim 26), and ring C is as defined in any one of claims 72-74.
• ring A is as defined in any one of claims 29-35, and ring C is as defined in any one of claims 54-56.
• ring A is as defined in any one of claims 29-35, and ring C is as defined in any one of claims 59-60.
• ring A is as defined in any one of claims 29-35, and ring C is as defined in any one of claims 61-63. In some embodiments of Formula (A1), ring A is as defined in any one of claims 29-35, and ring C is as defined in any one of claims 64-65. In some embodiments of Formula (A1), ring A is as defined in any one of claims 29-35, and ring C is as defined in any one of claims 72-74. In some embodiments of Formula (A1), ring A is as defined in any one of claims 39, 44, and 51, and ring C is as defined in any one of claims 54-56.
• ring A is as defined in any one of claims 39, 44, and 51, and ring C is as defined in any one of claims 59-60. In some embodiments of Formula (A1), ring A is as defined in any one of claims 39, 44, and 51, and ring C is as defined in any one of claims 61-63. In some embodiments of Formula (A1), ring A is as defined in any one of claims 39, 44, and 51, and ring C is as defined in any one of claims 64-65. In some embodiments of Formula (A1), ring A is as defined in any one of claims 39, 44, and 51, and ring C is as defined in any one of claims 72-74. In certain embodiments (when ring A is a saturated or unsaturated bicyclic or tricyclic ring that includes from 6-14 ring atoms), (B) applies. In certain of the foregoing embodiments, ring A has Formula (A2):
• ring D is selected from the group consisting of:
• each of A 2a , A 2b , A 2c , and A 2d is independently selected from: a bond, NH, NR 13 , O, CH 2 , CH(R 1 ), C(R 1 ) 2 , C(O), and S(O) 2 ; provided that one or more of A 2a , A 2b , A 2c , and A 2d are other than a bond, and
• a 2c and A 2d are not both O or not both S(O)2; and A 2a and A 2b are not both O or not both S(O) 2 .
• a 2a is CH2,CH(R 1 ), or C(R 1 ) 2 (e.g., CH2); and A 2b is a bond.
• each of A 2a and A 2b is independently selected from the group consisting of CH 2 , CH(R 1 ), and C(R 1 ) 2 (e.g., each of A 2a and A 2b is CH 2 ).
• a 2c is C(O).
• a 2d is selected from a bond, NH, NR 13 , CH2, CH(R 1 ), and C(R 1 ) 2 . In certain embodiments (when A 2c is C(O)), A 2d is a bond. In certain embodiments (when A 2c is C(O)), A 2d is selected from CH 2 , CH(R 1 ), and C(R 1 ) 2 . In some embodiments of Formula (A2), A 2a is CH2, CH(R 1 ), or C(R 1 ) 2 (e.g., CH2); A 2b is a bond; and A 2c is C(O).
• a 2d is a bond (e.g., ring .
• a 2d is selected from CH2, CH(R 1 ), and C(R 1 ) 2 (e.g., CH2
• each of A 2a and A 2b is independently selected from the group consisting of CH 2 , CH(R 1 ), and C(R 1 ) 2b
• a 2d is a bond (e.g., ring .
• ring D is heterocycloalkyl including from 3-10 ring atoms, wherein from 1-3 ring atoms are each independently selected from the group consisting of N(R N ), O, and S, wherein the heterocycloalkyl is optionally substituted with from 1-4 independently selected R b .
• ring D is heterocycloalkyl including from 4-6 (e.g., 5) ring atoms, wherein from 1-3 (e.g., from 1-2 (e.g., 1)) ring atoms are each independently selected from the group consisting of N(R N ), O, and S, wherein the heterocycloalkyl is optionally substituted with from 1-4 independently selected R b .
• ring D is , , or each of which is optionally substituted with from 1-2 R b (e.g., unsubstituted).
• ring D is C 3-10 cycloalkyl optionally substituted with from 1-4 independently selected R b .
• ring D is C 3-6 cycloalkyl optionally substituted with from 1-2 (e.g., 1) independently selected R b .
• ring D is or .
• each R b is independently selected from hydroxy, halo, oxo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, OC 3 -C 10 cycloalkyl, NR 8 R 9 , CN, COOC 1 -C 6 alkyl, C 6 -C 10 aryl, OC6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, CO2H, and CONR 8 R 9 ,
• C 1 -C 6 alkyl, C 1 -C 6 alkoxy, 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 , COOC 1 -C 6 alkyl, C 6 -C 10 aryl, CO 2 H, and CONR 8 R 9 .
• R b is C 1 -C 6 alkyl 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 , COOC1-C6 alkyl, C6-C10 aryl, CO 2 H, and CONR 8 R 9 .
• ring A is a saturated or unsaturated monocyclic ring that includes from 5-8 ring atoms.
• ring A is a saturated monocyclic ring that includes from 5-8 ring atoms.
• ring A has Formula (A3):
• each of A 3a , A 3b , A 3c , A 3d , and A 3e is independently selected from: a bond, CH 2 , CHR 1 , C(R 1 )2, C(O), N, NH, NR 13 , O, and, S(O)2; provided that three or more of A 3a , A 3b , A 3c , A 3d , and A 3e are other than a bond, and
• a 3a and A 3b are not both O or not both S(O) 2 ;
• a 3b and A 3c are not both O or not both S(O)2;
• a 3c and A 3d are not both O or not both S(O)2;
• a 3d and A 3e are not both O or not both S(O) 2 .
• a 3a is C(O).
• a 3a is selected from the group consisting of CH 2 , CHR 1 , and C(R 1 )2.
• a 3b is selected from the group consisting of CH 2 , CHR 1 , and C(R 1 )2.
• a 3b is selected from the group consisting of NH and NR 13 .
• a 3c is selected from the group consisting of CH 2 , CHR 1 , and C(R 1 )2.
• a 3c is selected from the group consisting of NH and NR 13 .
• a 3d is a bond.
• a 3d is selected from the group consisting of CH2, CHR 1 , and C(R 1 )2 (e.g., A 3d is CH2 or CHR 1 ).
• a 3e is a bond.
• a 3e is selected from the group consisting of CH 2 , CHR 1 , and C(R 1 ) 2 (e.g., A 3e is CH 2 or CHR 1 ).
• a 3a is C(O); A 3e is a bond; and A 3d is a bond.
• each of R 3b and R 3c is selected from the group consisting of CH2, CHR 1 , and C(R 1 )2.
• each of R 3b and R 3c is CH 2 (e.g., ring .
• one of R 3b and R 3c is selected from the group consisting of CHR 1 and C(R 1 )2.
• ring A is selected from:
• a 3a is CH 2 , CHR 1 , or C(R 1 ) 2 ;
• a 3e is a bond; and
• a 3d is a bond.
• each of R 3b and R 3c is selected from the group consisting of CH 2 , CHR 1 , and C(R 1 ) 2 .
• each of R 3b and R 3c is CH 2 (e.g., ring .
• one of R 3b and R 3c is selected from the group consisting of CHR 1 and C(R 1 ) 2 .
• ring A is selected from the group consisting of:
• a 3a is C(O); A 3e is a bond; and A 3d is other than a bond.
• each of A 3b , A 3c , and A 3d is selected from the group consisting of CH 2 , CHR 1 , and C(R 1 ) 2 .
• each of A 3b , A 3c , and A 3d is CH2 (e.g., ring A is In certain other of these embodiments, one of A 3b , A 3c , and A 3d is selected from the group consisting of CHR 1 and C(R 1 )2.
• ring A is selected from:
• a 3b is NH or NR 13 .
• each of A 3c and A 3d is selected from the group consisting of CH2, CHR 1 , and C(R 1 )2.
• each of A 3c and A 3d is CH 2 .
• ring A is selected from: .
• a 3a is CH2, CHR 1 , or C(R 1 )2; A 3e is a bond; and A 3d is other than a bond.
• each of A 3b , A 3c , and A 3d is selected from the group consisting of CH 2 , CHR 1 , and C(R 1 ) 2 .
• each of A 3b , A 3c , and A 3d is CH2 (e.g., ring A is In certain other of these embodiments, one of A 3b , A 3c , and A 3d is selected from the group consisting of CHR 1 and C(R 1 ) 2 .
• ring A is selected from:
• a 3a is C(O); and A 3e is CH 2 ; and A 3d is other than a bond.
• each of A 3b and A 3d is independently selected from the group consisting of CH2, CHR 1 , and C(R 1 )2.
• each of A 3b and A 3d is CH 2 .
• a 3c is selected from NH, NR 13 , CH2, CHR 1 , and C(R 1 )2.
• ring A is selected from:
• each R 1 is independently selected from the group consisting of: 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, CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, 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,CONR 8 R 9 , S(O 2 )C 1 -C 6 alkyl, S(O)
• R 1 is C 3 -C 7 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10 aryl, or 5- to 10-membered heteroaryl, each C 1 -C 6 alkyl substituent and each C 1 -C 6 alkoxy substituent on R 1 , when present, is further optionally independently substituted with one to three hydroxy, C1-C6 alkoxy, halo, NR 8 R 9 , or oxo; and
• 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) substituents on R 1 are optionally substituted with one or more substituents independently selected from halo, C 1 -C 6 alkyl, and OC 1 -C 6 alkyl.
• R 1 is C1-C6 alkyl, optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkoxy, NR 8 R 9 , 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), NHCOC 1 -C 6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), and NHCO(3- to 7-membered heterocycloalkyl),
• 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) substituents on R 1 are optionally substituted with one or more substituents independently selected from halo, C 1 -C 6 alkyl, and OC 1 -C 6 alkyl.
• one or more occurrences of R 1 is C1-C6 alkyl, optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, NR 8 R 9 , C 6 -C 10 aryl, and 5- to 10-membered heteroaryl; wherein the C6-C10 aryl and 5- to 10-membered heteroaryl substituents on R 1 are optionally substituted with one or more substituents independently selected from halo, C1-C6 alkyl, and OC1- C 6 alkyl.
• R 1 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, C1-C6 alkyl, C1-C6 alkoxy, NR 8 R 9 , 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), and NHCO(3- to 7-membere
• each C 1 -C 6 alkyl substituent and each C 1 -C 6 alkoxy substituent on R 1 when present, is further optionally independently substituted with one to three hydroxy, C 1 -C 6 alkoxy, halo, NR 8 R 9 , or oxo;
• 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) substituents on R 1 are optionally substituted with one or more substituents independently selected from halo, C1-C6 alkyl, and OC1-C6 alkyl.
• one or more occurrences of R 1 is C 6 -C 10 aryl optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, C1-C6 alkyl, C1-C6 alkoxy, NR 8 R 9 , COOC1-C6 alkyl, and CONR 8 R 9 ;
• each C1-C6 alkyl substituent and each C1-C6 alkoxy substituent on R 1 when present, is further optionally independently substituted with one to three hydroxy, C 1 -C 6 alkoxy, halo, NR 8 R 9 , or oxo.
• one or more occurrences of R 1 is hydroxyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, 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), NHCOC 2 -C 6 alkynyl,CONR 8 R 9 , S(O 2 )C 1 -C 6 alkyl, S(O)C 1 -C 6 alkyl, or S(O 2 )NR 11 R 12 .
• the group R 1 is hydroxyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, NH 2 , NHC 1 -C 6 alkyl, N(C 1 -C 6 alkyl) 2
• R 1 is C1-C6 alkyl optionally substituted with one or more hydroxy.
• R 1 is 1-hydroxy-2-methylpropan-2-yl.
• R 1 is 2-hydroxyethyl. In some embodiments, R 1 is C 1 -C 6 alkyl.
• R 1 is methyl
• R 1 is isopropyl
• R 1 is isopropyl. In some embodiments, R 1 is C1-C6 alkyl substituted with hydroxy at the carbon directly connected to ring A.
• R 1 is 2-hydroxy-2-propyl.
• R 1 is hydroxymethyl
• R 1 is 1-hydroxyethyl.
• R 1 is 1-hydroxy-2-propyl. In some embodiments, R 1 is C1-C6 alkyl substituted with two or more hydroxy groups. In some embodiments, R 1 is C1-C6 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 C3-C7 cycloalkyl optionally substituted with one or more hydroxy. In some embodiments, R 1 is C 3 -C 7 cycloalkyl.
• R 1 is C3-C7 cycloalkyl substituted with hydroxy at the carbon directly connected to ring A.
• R 1 is 1-hydroxy-1-cyclopropyl.
• R 1 is 1-hydroxy-1-cyclobutyl.
• R 1 is 1-hydroxy-1-cyclopentyl.
• R 1 is 1-hydroxy-1-cyclohexyl.
• R 1 is 3- to 7-membered heterocycloalkyl optionally substituted with one or more hydroxy.
• R 1 is 3- to 7-membered heterocycloalkyl.
• R 1 is morpholinyl (e.g., 1-morpholinyl).
• R 1 is 1,3-dioxolan-2-yl.
• R 1 is 3- to 7-membered heterocycloalkyl optionally substituted with one or more C 1 -C 6 alkyl.
• R 1 is 1-methylpyrrolidin-2-yl.
• R 1 is 3- to 7-membered heterocycloalkyl substituted with hydroxy at the carbon directly connected to ring A.
• R 1 is C 1 -C 6 alkyl optionally substituted with one or more oxo.
• R 1 is COCH3.
• R 1 is COCH 2 CH 3 .
• 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.
• 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.
• R 1 is methoxymethyl. In some embodiments, R 1 is C 3 -C 7 cycloalkyl optionally substituted with one or more C 1 -C 6 alkoxy.
• R 1 is 3- to 7-membered heterocycloalkyl optionally substituted with one or more C1-C6 alkoxy.
• R 1 is C 1 -C 6 alkyl optionally substituted with one or more NR 8 R 9 .
• R 1 is C1-C6 alkyl substituted with NR 8 R 9 at the carbon directly connected to ring A.
• R 1 is (methylamino)methyl.
• R 1 is (dimethylamino)methyl.
• R 1 is aminomethyl
• R 1 is N-methylacetamidomethyl.
• R 1 is 1-(dimethylamino)eth-1-yl.
• R 1 is 2-(dimethylamino)prop-2-yl.
• R 1 is (2-methoxy-eth-1-yl)(methyl)aminomethyl.
• R 1 is (methyl)(acetyl)aminomethyl.
• R 1 is (methyl)(cyclopropylmethyl)aminomethyl.
• R 1 is (methyl)(2,2-difluoroeth-1-yl)aminomethyl. In some embodiments, R 1 is C3-C7 cycloalkyl optionally substituted with one or more NR 8 R 9 . In some embodiments, R 1 is 3- to 7-membered heterocycloalkyl optionally substituted with one or more NR 8 R 9 .
• R 1 is C 1 -C 6 haloalkyl optionally substituted with one or more hydroxy. In some embodiments, R 1 is C1-C6 alkoxy.
• R 1 is C 1 -C 6 haloalkoxy. 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.
• 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).
• R 1 is azetidinylmethyl (e.g., azetidin-1-ylmethyl).
• R 1 is optionally substituted azetidinylmethyl (e.g., 3-methoxyazetidin-1- ylmethyl).
• R 1 is morpholinylmethyl (e.g., morpholin-4-ylmethyl). In some embodiments, R 1 is C1-C6 alkyl optionally substituted with C6-C10 aryl, wherein the C6- C 10 aryl is further optionally substituted as defined elsewhere herein.
• R 1 is C 1 -C 6 alkyl optionally substituted with unsubstituted C 6 -C 10 aryl (e.g., benzyl). In some embodiments, R 1 is halo.
• R 1 is fluoro
• R 1 is chloro
• R 1 is CN
• R 1 is NO2.
• R 1 is COC1-C6 alkyl.
• R 1 is CO-C 6 -C 10 aryl.
• R 1 is CO(5- to 10-membered heteroaryl).
• R 1 is CO2C1-C6 alkyl.
• R 1 is CO 2 C 3 -C 8 cycloalkyl.
• R 1 is OCOC 1 -C 6 alkyl.
• R 1 is OCOC6-C10 aryl.
• R 1 is OCO(5- to 10-membered heteroaryl).
• R 1 is OCO(3- to 7-membered heterocycloalkyl).
• R 1 is C6-C10 aryl, wherein the C6-C10 aryl is optionally substituted as described elsewhere herein.
• R 1 is phenyl wherein the phenyl is substituted with C 1-6 alkyl, wherein the C1-6 alkyl is further optionally substituted (e.g., with hydroxy) as defined elsewhere herein.
• R 1 is phenyl
• R 1 is 5- to 10-membered heteroaryl.
• R 1 is pyridyl (e.g., 4-pyridyl).
• R 1 is pyrazolyl (e.g., 1-pyrazolyl).
• R 1 is NH2.
• R 1 is NHC1-C6 alkyl.
• R 1 is N(C 1 -C 6 alkyl) 2 .
• R 1 is CONR 8 R 9 .
• R 1 is SF5.
• R 1 is SC 1 -C 6 alkyl
• R 1 is S(O 2 )C 1 -C 6 alkyl.
• R 1 is S(O2)CH3.
• R 1 is S(O 2 )NR 11 R 12 .
• R 1 is S(O 2 )N(CH 3 ) 2 .
• R 1 is S(O)C1-C6 alkyl.
• R 1 is S(O)CH3.
• the group R a is S(O)CH3.
• R a is C1-C6 alkyl optionally substituted with one or more hydroxy. In some embodiments, R a is 1-hydroxy-2-methylpropan-2-yl.
• R a is 2-hydroxyethyl. In some embodiments, R a is C 1 -C 6 alkyl.
• R a is methyl
• R a is isopropyl
• R a is isopropyl. In some embodiments, R a is C1-C6 alkyl substituted with hydroxy at the carbon directly connected to ring A.
• R a is 2-hydroxy-2-propyl.
• R a is hydroxymethyl
• R a is 1-hydroxyethyl. In some embodiments, R a is 1-hydroxy-2-propyl. In some embodiments, R a is C 1 -C 6 alkyl substituted with two or more hydroxy groups.
• R a is C1-C6 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 a is 1,2-dihydroxy-prop-2-yl. In some embodiments, R a is C3-C7 cycloalkyl optionally substituted with one or more hydroxy. In some embodiments, R a is C 3 -C 7 cycloalkyl.
• R a is C 3 -C 7 cycloalkyl substituted with hydroxy at the carbon directly connected to ring A.
• R a is 1-hydroxy-1-cyclopropyl.
• R a is 1-hydroxy-1-cyclobutyl.
• R a is 1-hydroxy-1-cyclopentyl.
• R a is 1-hydroxy-1-cyclohexyl.
• R a is 3- to 7-membered heterocycloalkyl optionally substituted with one or more hydroxy.
• R a is 3- to 7-membered heterocycloalkyl.
• R a is morpholinyl (e.g., 1-morpholinyl).
• R a is 1,3-dioxolan-2-yl.
• R a is 3- to 7-membered heterocycloalkyl optionally substituted with one or more C 1 -C 6 alkyl.
• R a is 1-methylpyrrolidin-2-yl.
• R a is 3- to 7-membered heterocycloalkyl substituted with hydroxy at the carbon directly connected to ring A.
• R a is C 1 -C 6 alkyl optionally substituted with one or more oxo.
• R a is COCH3.
• R a is COCH2CH3.
• R a is C 3 -C 7 cycloalkyl optionally substituted with one or more oxo. In some embodiments, R a is 3- to 7-membered heterocycloalkyl optionally substituted with one or more oxo. In some embodiments, R a is C1-C6 alkyl optionally substituted with one or more C1-C6 alkoxy. In some embodiments, R a is 2-methoxy-2-propyl.
• R a is methoxymethyl. In some embodiments, R a is C3-C7 cycloalkyl optionally substituted with one or more C1-C6 alkoxy.
• R a is 3- to 7-membered heterocycloalkyl optionally substituted with one or more C1-C6 alkoxy.
• R a is C 1 -C 6 alkyl optionally substituted with one or more NR 8 R 9 .
• R a is C 1 -C 6 alkyl substituted with NR 8 R 9 at the carbon directly connected to ring A.
• R a is (methylamino)methyl.
• R a is (dimethylamino)methyl.
• R a is aminomethyl
• R a is N-methylacetamidomethyl.
• R a is 1-(dimethylamino)eth-1-yl.
• R a is 2-(dimethylamino)prop-2-yl.
• R a is (2-methoxy-eth-1-yl)(methyl)aminomethyl.
• R a is (methyl)(acetyl)aminomethyl.
• R a is (methyl)(cyclopropylmethyl)aminomethyl.
• R a is (methyl)(2,2-difluoroeth-1-yl)aminomethyl. In some embodiments, R a is C 3 -C 7 cycloalkyl optionally substituted with one or more NR 8 R 9 . In some embodiments, R a is 3- to 7-membered heterocycloalkyl optionally substituted with one or more NR 8 R 9 .
• R a is C 1 -C 6 haloalkyl optionally substituted with one or more hydroxy. In some embodiments, R a is C1-C6 alkoxy.
• R a is C1-C6 haloalkoxy. In some embodiments, R a 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.
• R a is pyrrolidinylmethyl (e.g., pyrrolidin-1-ylmethyl).
• R a is optionally substituted pyrrolidinylmethyl (e.g., 3,3- difluoropyrrolidin-1-ylmethyl).
• R a is azetidinylmethyl (e.g., azetidin-1-ylmethyl).
• R a is optionally substituted azetidinylmethyl (e.g., 3-methoxyazetidin-1- ylmethyl).
• R a is morpholinylmethyl (e.g., morpholin-4-ylmethyl). In some embodiments, R a is halo.
• R a is fluoro
• R a is chloro
• R a is CN
• R a is CO 2 C 1 -C 6 alkyl.
• R a is CO2C3-C8 cycloalkyl.
• R a is C6-C10 aryl.
• R a is phenyl
• R a is 5- to 10-membered heteroaryl.
• R a is pyridyl (e.g., 4-pyridyl).
• R a is pyrazolyl (e.g., 1-pyrazolyl).
• R a is NR 8 R 9 .
• R a is CONR 8 R 9 .
• o 1 or 2.
• o 1.
• o 2.
• p 0, 1, 2, or 3.
• B is a 5- to 10-membered monocyclic or bicyclic heteroaryl or a C 6 -C 10 monocyclic or bicyclic aryl, such as phenyl.
• B is a 5- to 6-membered monocyclic heteroaryl or a C6 monocyclic aryl. In some embodiments, B is a 5- to 10-membered monocyclic or bicyclic heteroaryl.
• B is a C 6 -C 10 monocyclic or bicyclic aryl.
• B is a 5-membered heteroaryl.
• B is a 7-10 membered monocyclic or bicyclic heteroaryl.
• B is phenyl substituted with 1 or 2 R 6 and optionally substituted with 1, 2, or 3 R 7 .
• B is pyridyl substituted with 1 or 2 R 6 and optionally substituted with 1, 2, or 3 R 7 .
• B is indazolyl substituted with 1 or 2 R 6 and optionally substituted with 1, 2, or 3 R 7 .
• B is pyrazolyl substituted with 1 or 2 R 6 and optionally substituted with 1 or 2 R 7 .
• B is phenyl, o is 1 or 2, and p is 0, 1, 2, or 3.
• B is phenyl, o is 1, and p is 0, 1, 2, or 3.
• B is phenyl, o is 2, and p is 0, 1, 2, or 3.
• 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 Y(CO)group of Formula AA.
• the substituted ring is the substituted ring .
• the substituted ring is the substituted ring .
• the substituted ring is the substituted ring .
• the substituted ring is the substituted ring .
• the substituted ring B is .
• the substituted ring is the substituted ring .
• the substituted ring In some embodiments, the substituted ring . In some embodiments, the substituted ring . In some embodiments, the substituted ring . In some embodiments, the substituted ring . In some embodiments, the substituted ring . In some embodiments, the substituted ring B is . In some embodiments, the substituted ring . In some embodiments, the substituted ring . In some embodiments, the substituted ring . 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 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 B is . In some embodiments, the substituted ring B is . In some embodiments, the substituted ring . In some embodiments, the substituted ring .
• 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 substitute
• the substituted ring is the substituted ring .
• the substituted ring is phenyl substituted with 1 or 2 R 6 and optionally substituted with 1 or 2 R 7 .
• 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 9
• R 7 is independently selected from C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 - C6 haloalkoxy, halo, CN, 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 C1-C6 alkyl is optionally substituted with one to two C1-C6 alkoxy.
• each R 6 and R 7 is independently selected from C1-C6 alkyl optionally substituted with hydroxy, C3-C7 cycloalkyl, C1-C6 haloalkyl, and halo.
• 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,
• 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 , SF 5 , S(O 2 )C 1 -C 6 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;
• each R 6 and R 7 is independently selected from C1- C 6 alkyl optionally substituted with hydroxy, C 3 -C 7 cycloalkyl, C 1 -C 6 haloalkyl, and halo;
• R 6 and R 7 on adjacent atoms taken together with the atoms connecting them, independently form a C4-C5 carbocyclic ring or a 5-membered heterocyclic ring containing 1 O, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from C 1 -C 6 alkyl.
• each R 6 and R 7 is independently selected from methyl, 2-hydroxy-2-propyl, cyclopropyl, trifluoromethyl, difluoromethyl, and fluoro;
• R 6 and R 7 on adjacent atoms, taken together with the atoms connecting them, independently form a C4-C5 carbocyclic ring or a 5-membered heterocyclic ring containing 1 O, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more methyl.
• B is phenyl substituted with 1 or 2 R 6 and optionally
• 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,
• 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 , SF 5 , S(O 2 )C 1 -C 6 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;
• each R 6 and R 7 is independently selected from C1-C6 alkyl optionally substituted with hydroxy, C3-C7 cycloalkyl, C1-C6 haloalkyl, and halo; or at least one pair (e.g., two pairs) of R 6 and R 7 on adjacent atoms, taken together with the atoms connecting them, independently form a C 4 -C 5 carbocyclic ring or a 5-membered heterocyclic ring containing 1 O, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from C1-C6 alkyl.
• each R 6 and R 7 is independently selected from methyl, 2-hydroxy-2-propyl, cyclopropyl, trifluoromethyl, difluoromethyl, and fluoro; or at least one pair (e.g., two pairs) of R 6 and R 7 on adjacent atoms, taken together with the atoms connecting them, independently form a C 4 -C 5 carbocyclic ring or a 5-membered heterocyclic ring containing 1 O, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more methyl.
• B is phenyl substituted with 1 or 2 R 6 and optionally
• 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,
• 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), 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 C1-C6 alkoxy;
• each R 6 and R 7 is independently selected from C1-C6 alkyl optionally substituted with hydroxy, C3-C7 cycloalkyl, C1-C6 haloalkyl, and halo;
• R 6 and R 7 on adjacent atoms taken together with the atoms connecting them, independently form a C4-C5 carbocyclic ring or a 5-membered heterocyclic ring containing 1 O, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from C 1 -C 6 alkyl.
• each R 6 and R 7 is independently selected from methyl, 2-hydroxy-2-propyl, cyclopropyl, trifluoromethyl, difluoromethyl, and fluoro;
• R 6 and R 7 on adjacent atoms taken together with the atoms connecting them, independently form a C 4 -C 5 carbocyclic ring or a 5-membered heterocyclic ring containing 1 O, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more methyl.
• B is pyridyl substituted with 1 or 2 R 6 and optionally substituted with 1 or 2 R 7 .
• 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,
• 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 , SF 5 , S(O 2 )C 1 -C 6 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;
• each R 6 and R 7 is independently selected from C 1 -C 6 alkyl optionally substituted with hydroxy, C 3 -C 7 cycloalkyl, C 1 -C 6 haloalkyl, and halo;
• R 6 and R 7 on adjacent atoms taken together with the atoms connecting them, independently form a C 4 -C 5 carbocyclic ring or a 5-membered heterocyclic ring containing 1 O, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from C1-C6 alkyl.
• each R 6 and R 7 is independently selected from methyl, 2-hydroxy-2-propyl, cyclopropyl, trifluoromethyl, difluoromethyl, and fluoro;
• R 6 and R 7 on adjacent atoms taken together with the atoms connecting them, independently form a C4-C5 carbocyclic ring or a 5-membered heterocyclic ring containing 1 O, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more methyl.
• each occurrence of R 6 and each occurrence of R 7 is a monovalent substituent as described elsewhere herein;
• R 6 and R 7 on adjacent carbon atoms taken together with the atom to which each is attached, form one or more independently selected carbocyclic or heterocyclic ring as described elsewhere herein; and each remaining occurrences of R 6 and R 7 (inclusive of pair(s) of R 6 and R 7 on adjacent atoms) is independently a monovalent substituent as described herein.
• R 6 and R 7 is independently a monovalent substituent as described herein.
• 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 , S(O 2 )C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl and 3- to 10-membered
• heterocycloalkyl and a C 2 -C 6 alkenyl
• R 6 and R 7 are each optionally substituted with one or more substituents independently selected from
• 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,
• 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, 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
• R 6 and R 7 are each optionally substituted with one or more substituents independently selected from
• heterocycloalkyl NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC 2 -C 6 alkynyl,
• 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;
• 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-C7 cycloalkyl and 3- to 7-membered heterocyclo
• 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;
• 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, 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,
• 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;
• 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;
• R 6 and R 7 are each independently selected from C 1 -C 6 alkyl, halo, CN, NO 2 , COC 1 -C 6 alkyl, 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, 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 heterocyclo
• 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- 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
• 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 , SF 5 , SC 1 -C 6 alkyl, S(O 2 )C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl and 3-
• 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;
• 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- 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;
• R 6 and R 7 are each independently selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halo, CN, NO 2 , COC 1 - C 6 alkyl, 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,
• 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 C 4 -C 8 carbocyclic ring, wherein the carbocyclic ring is optionally independently substituted with one or more hydroxy or oxo.
• R 6 and R 7 are each independently selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halo, CN, NO 2 , COC 1 - C6 alkyl, CO2C1-C6 alkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, CONR 8 R 9 , and 3- to 7- membered heterocycloalkyl,
• C 1 -C 6 alkyl and 3- to 7-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy or oxo,
• 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.
• R 6 and R 7 are each independently selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halo, CN, NO 2 , COC 1 - C6 alkyl, CO2C1-C6 alkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, CONR 8 R 9 , and 3- to 7- membered heterocycloalkyl,
• C 1 -C 6 alkyl and 3- to 7-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy or oxo,
• 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.
• the heterocyclic ring is optionally independently substituted with one or more hydroxy or oxo.
• 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,
• 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 C 4 -C 8 carbocyclic ring, wherein the carbocyclic ring is optionally independently substituted with one or more hydroxy or oxo.
• 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.
• R 6 and R 7 on adjacent atoms taken together with the atoms connecting them, independently form at least one C 4 aliphatic carbocyclic ring, wherein the carbocyclic ring is optionally independently substituted with one or more hydroxy or oxo.
• R 6 and R 7 on adjacent atoms taken together with the atoms connecting them, independently form at least one C5 aliphatic carbocyclic ring, wherein the carbocyclic ring is optionally independently substituted with one or more hydroxy or oxo.
• 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.
• the heterocyclic ring is optionally independently substituted with one or more hydroxy or oxo.
• 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 C1-C6 alkyl.
• 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.
• R 6 and R 7 on adjacent atoms taken together with the atoms connecting them, independently form at least one C6 aliphatic carbocyclic ring, wherein the carbocyclic ring is optionally independently substituted with one or more C 1 -C 6 alkyl.
• 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.
• R 6 is selected from C1-C6 alkyl, 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, 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, C 3 -C 7 cycloalkyl and 3- to 7-membered heterocyclo
• 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.
• 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 alkoxy, halo, CN, NO 2 , COC1-C6 alkyl, CO2C1-C6 alkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, CONR 8 R 9 , and 3- to 7-membered heterocycloalkyl,
• C 1 -C 6 alkyl and 3- to 7-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy or oxo,
• 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
• 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.
• 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,
• 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- 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;
• 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,
• each 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, 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;
• 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,
• C 1 -C 6 alkyl and 3- to 7-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy or oxo,
• R 6 and R 7 on adjacent atoms taken together with the atoms connecting them, independently form at least one C 4 -C 8 carbocyclic ring, wherein the carbocyclic ring is optionally independently substituted with one or more hydroxy or oxo.
• C1-C6 alkyl and 3- to 7-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy or oxo.
• substituents each independently selected from hydroxy or oxo.
• one R 6 and one R 7 are on adjacent atoms, and taken together with the atoms connecting them, form a C 4 -C 8 carbocyclic ring or a 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is unsubstituted.
• 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.
• R 6 is C 1 -C 6 alkyl.
• R 6 is isopropyl.
• R 6 is ethyl
• R 6 is methyl
• R 6 is C1-C6 alkyl substituted with one or more halo.
• R 6 is trifluoromethyl.
• R 6 is trifluoromethoxy
• R 6 is C3-C7 cycloalkyl.
• R 6 is cyclopropyl. In some embodiments, R 6 is halo.
• R 6 is chloro
• R 6 is fluoro
• R 6 is cyano
• R 6 is attached to a carbon of an aryl ring B.
• R 6 is attached to a carbon of a heteroaryl ring B.
• R 6 is attached to a nitrogen of a heteroaryl ring B.
• o 1 or 2; 2, or 3:
• At least one R 6 is C 1 -C 6 alkyl
• at least one R 7 is C 1 -C 6 alkyl optionally substituted with one or more halo.
• At least one R 6 is C 1 -C 6 alkyl and at least one R 7 is C 1 -C 6 alkyl.
• At least one R 6 is isopropyl and at least one R 7 is methyl.
• At least one R 6 is isopropyl and at least one R 7 is isopropyl.
• At least one R 6 is C 1 -C 6 alkyl
• at least one R 7 is C 1 -C 6 alkyl substituted with one or more halo.
• At least one R 6 is isopropyl and at least one R 7 is trifluoromethyl.
• 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.
• At least one R 6 is C 1 -C 6 alkyl, and at least one R 7 is halo.
• At least one R 6 is isopropyl and at least one R 7 is halo.
• At least one R 6 is isopropyl and at least one R 7 is chloro.
• At least one R 6 is isopropyl and at least one R 7 is fluoro.
• At least one R 6 is C1-C6 alkyl, and at least one R 7 is cyano.
• At least one R 6 is isopropyl and at least one R 7 is cyano.
• At least one R 6 is C 3 -C 7 cycloalkyl, and at least one R 7 is C 3 -C 7 cycloalkyl.
• At least one R 6 is cyclopropyl, and at least one R 7 is cyclopropyl.
• At least one R 6 is C3-C7 cycloalkyl, and at least one R 7 is halo.
• At least one R 6 is cyclopropyl and at least one R 7 is halo.
• At least one R 6 is cyclopropyl and at least one R 7 is chloro.
• At least one R 6 is cyclopropyl and at least one R 7 is fluoro.
• 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.
• At least one R 6 is isopropyl, and at least one R 7 is C 1 -C 6 alkoxy.
• At least one R 6 is isopropyl, and at least one R 7 is methoxy.
• 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.
• At least one R 6 is isopropyl, and at least one R 7 is trifluoromethoxy.
• 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 C1-C6 haloalkyl optionally substituted with hydroxy.
• At least one R 6 is halo, and at least one R 7 is C1-C6 haloalkoxy.
• At least one R 6 is chloro, and at least one R 7 is trifluoromethoxy.
• At least one R 6 is C1-C6 alkoxy; and at least one R 7 is halo.
• at least one R 7 is C 1 -C 6 alkyl, and at least one R 6 is C 1 -C 6 alkyl optionally substituted with one or more halo.
• At least one R 7 is isopropyl and at least one R 6 is methyl.
• At least one R 7 is C 1 -C 6 alkyl, and at least one R 6 is C 1 -C 6 alkyl substituted with one or more halo.
• At least one R 7 is isopropyl and at least one R 6 is trifluoromethyl.
• At least one R 7 is C 1 -C 6 alkyl, and at least one R 6 is C 3 -C 7 cycloalkyl. In some embodiments, at least one R 7 is isopropyl and at least one R 6 is cyclopropyl.
• At least one R 7 is C 1 -C 6 alkyl, and at least one R 6 is halo.
• At least one R 7 is isopropyl and at least one R 6 is halo.
• At least one R 7 is isopropyl and at least one R 6 is chloro.
• At least one R 7 is isopropyl and at least one R 6 is fluoro.
• At least one R 7 is C 1 -C 6 alkyl, and at least one R 6 is cyano.
• At least one R 7 is isopropyl and at least one R 6 is cyano.
• At least one R 7 is C3-C7 cycloalkyl, and at least one R 6 is C3-C7 cycloalkyl.
• At least one R 7 is cyclopropyl, and at least one R 6 is cyclopropyl.
• At least one R 7 is C 3 -C 7 cycloalkyl, and at least one R 6 is halo.
• At least one R 7 is cyclopropyl and at least one R 6 is halo.
• At least one R 7 is cyclopropyl and at least one R 6 is chloro.
• At least one R 7 is cyclopropyl and at least one R 6 is fluoro.
• 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.
• At least one R 7 is isopropyl, and at least one R 6 is C1-C6 alkoxy.
• At least one R 7 is isopropyl, and at least one R 6 is methoxy.
• 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.
• At least one R 7 is isopropyl, and at least one R 6 is trifluoromethoxy. In some embodiments, at least one R 7 is halo, and at least one R 6 is C 1 -C 6 haloalkyl optionally substituted with one or more hydroxy.
• At least one R 7 is halo, and at least one R 6 is C1-C6 haloalkoxy.
• At least one R 7 is chloro, and at least one R 6 is trifluoromethoxy.
• R 6 and R 7 are each attached to a carbon of a heteroaryl ring B.
• R 6 is attached to a carbon and R 7 is attached to a nitrogen of a heteroaryl ring B.
• R 7 is attached to a carbon and R 6 is attached to a nitrogen of a heteroaryl ring B.
• R 6 and R 7 are on adjacent atoms, and taken together with the atoms connecting them, form a C5 aliphatic carbocyclic ring.
• R 6 and R 7 are on adjacent atoms, and taken together with the atoms connecting them, form a C6 aliphatic carbocyclic ring.
• R 6 and R 7 are on adjacent atoms, and taken together with the atoms connecting them, form a C 6 aromatic carbocyclic ring.
• 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.
• 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.
• 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.
• 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,
• ring is fused to the B ring at the 2- and 3- positions relative to the bond connecting the B ring to the Y(CO)group.
• one pair of one R 6 and one R 7 are on adjacent atoms; and said pair of one R 6 and one R 7 taken together with the atoms connecting them form form a C 4 -C 8 carbocyclic ring or a 5- to 8- membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S,
• ring is fused to the B ring at the 2- and 3- positions relative to the bond connecting the B ring to the Y(CO) group.
• one pair of one R 6 and one R 7 are on adjacent atoms; and said pair of one R 6 and one R 7 taken together with the atoms connecting them form form a C 5 aliphatic carbocyclic ring.
• 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.
• 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.
• 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
• 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.
• 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
• 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.
• 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.
• 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.
• 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.
• 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.
• 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,
• 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 YC(O) 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 YC(O) group.
• 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,
• 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 YC(O) 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 YC(O) group.
• 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.
• 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.
• 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 heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S.
• 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 halo (e.g., Cl or F).
• 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.
• one R 7 is pyrazolyl and is para to the bond connecting the B ring to the YC(O) group of Formula AA.
• one R 7 is 3-pyrazolyl and is para to the bond connecting the B ring to the YC(O) group of Formula AA.
• one R 7 is 4-pyrazolyl and is para to the bond connecting the B ring to the YC(O) group of Formula AA.
• one R 7 is 5-pyrazolyl and is para to the bond connecting the B ring to the YC(O) group of Formula AA.
• one R 7 is thiazolyl and is para to the bond connecting the B ring to the YC(O) group of Formula AA.
• one R 7 is 4-thiazolyl and is para to the bond connecting the B ring to the YC(O) group of Formula AA.
• one R 7 is 5-thiazolyl and is para to the bond connecting the B ring to the YC(O) group of Formula AA. In some embodiments, one R 7 is furyl and is para to the bond connecting the B ring to the YC(O) group of Formula AA.
• one R 7 is 2-furyl and is para to the bond connecting the B ring to the YC(O) group of Formula AA.
• one R 7 is thiophenyl and is para to the bond connecting the B ring to the YC(O) group of Formula AA.
• one R 7 is 2-thiophenyl and is para to the bond connecting the B ring to the YC(O) group of Formula AA.
• one R 7 is phenyl and is para to the bond connecting the B ring to the YC(O) group of Formula AA.
• one R 7 is cycloalkenyl (e.g., cyclopentenyl, e.g., 1-cyclopentenyl) and is para to the bond connecting the B ring to the YC(O) group of Formula AA.
• cycloalkenyl e.g., cyclopentenyl, e.g., 1-cyclopentenyl
• one R 7 is phenyl optionally substituted with one or more C 1 -C 6 alkyl (e.g., methyl or propyl, e.g., 2-propyl) optionally substituted with one or more hydroxyl, NR 8 R 9 (e.g., dimethylamino), or C6-C10 aryl (e.g., phenyl, naphthyl, or methylenedioxyphenyl and is para to the bond connecting the B ring to the YC(O) group of Formula AA.
• C 1 -C 6 alkyl e.g., methyl or propyl, e.g., 2-propyl
• NR 8 R 9 e.g., dimethylamino
• C6-C10 aryl e.g., phenyl, naphthyl, or methylenedioxyphenyl and is para to the bond connecting the B ring to the YC(O) group of Formula AA.
• 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 YC(O) group of Formula AA.
• C1-C6 alkoxy e.g., methoxy
• NR 8 R 9 e.g., dimethylamino
• C 6 -C 10 aryl e.g., phenyl, naphthyl, or methylenedioxyphenyl and is para to the bond connecting the B ring to the YC(O) group of Formula AA.
• one R 7 is phenyl optionally substituted with one or more C6-C10 aryloxy (e.g., phenoxy) and is para to the bond connecting the B ring to the YC(O) group of Formula AA.
• one R 7 is phenyl optionally substituted with one or more CN and is para to the bond connecting the B ring to the YC(O) group of Formula AA.
• 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 YC(O) group of Formula AA and is para to the bond connecting the B ring to the YC(O) group of Formula AA.
• halo e.g., F, Cl
• one R 7 is phenyl optionally substituted with one or more COOC 1 -C 6 alkyl (e.g., CO2t-Bu) and is para to the bond connecting the B ring to the YC(O) group of Formula AA.
• one R 7 is phenyl optionally substituted with one or more S(O2)C1-C6 alkyl (e.g., S(O 2 )methyl) and is para to the bond connecting the B ring to the YC(O) group of Formula AA.
• 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 YC(O) group of Formula AA.
• heterocycloalkyl e.g., morpholinyl
• 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 Y(CO) groupof Formula AA.
• CONR 8 R 9 e.g., unsubstituted amido
• 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 Y(CO) groupof Formula AA and is para to the bond connecting the B ring to the Y(CO) groupof Formula AA.
• C 1 -C 6 alkyl e.g., methyl or propyl, e.g., 2-propyl
• halo e.g., F, Cl
• R 6 and R 7 are each attached to a carbon of an aryl ring B.
• R 6 and R 7 are each attached to a carbon of a heteroaryl ring B.
• R 6 is attached to a carbon and R 7 is attached to a nitrogen of a heteroaryl ring B.
• R 7 is attached to a carbon and R 6 is attached to a nitrogen of a heteroaryl ring B.
• 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 C 1 -C 6 alkoxy; C 3 -C 7 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 C1-C6
• 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(O 2 )NR 11 R 12 ; S(O)C 1 -C 6 alkyl; and S(O 2 )C 1 -C 6 alkyl.
• 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(O 2 )CH 3; and S(O 2 )NR 11 R 12 .
• 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; COCH3; COPh; 2-methoxy-2-propyl; S(O2)CH3; and
• the substituted ring each R 6 is independently selected from the group consisting of: C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 6 haloalkyl, C 1 - C6 alkoxy, C1-C6 haloalkoxy, wherein the C1-C6 alkyl, C1-C6 haloalkyl, and C3-C7 cycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, or oxo.
• 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,
• 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 , SF5, 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;
• 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,
• 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 , 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;
• 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,
• 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 , 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.
• 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,
• 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;
• 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,
• 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), 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;
• 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,
• 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;
• 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,
• 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
• 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,
• 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), 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;
• R 3 is selected from hydrogen, C 1 -C 6 alkyl, , wherein the C1-C2 alkylene group is optionally substituted with oxo.
• R 3 is hydrogen
• R 3 is C 1-3 alkyl (e.g., methyl).
• R 3 is cyano
• R 3 is hydroxy
• R 3 is C 1 -C 6 alkoxy. In some embodiments, R 3 is C 1 -C 6 alkyl.
• R 3 is methyl
• R 3 is , wherein the C1-C2 alkylene group is optionally substituted with oxo.
• R 3 is–CH 2 R 14 .
• R 3 is–C(O)R 14 .
• R 3 is–CH2CH2R 14 .
• R 3 is–CHR 14 CH 3 .
• R 3 is–CH 2 C(O)R 14 .
• R 3 is–C(O)CH2R 14 .
• R 3 is CO 2 C 1 -C 6 alkyl.
• Y is -CR 15 R 15 - (e.g., -CH2-).
• Y is -NR 16 - (e.g., -NH-).
• R 14 is -NR 16 - (e.g., -NH-).
• R 14 is hydrogen, C 1 -C 6 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 .
• R 14 is hydrogen or C 1 -C 6 alkyl.
• 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 .
• R 14 is hydrogen
• R 14 is C1-C6 alkyl.
• R 14 is methyl
• R 14 is 5- to 10-membered monocyclic or bicyclic heteroaryl optionally independently substituted with 1 or 2 R 6 .
• R 14 is C6-C10 monocyclic or bicyclic aryl optionally independently substituted with 1 or 2 R 6 .
• the sulfur in the moiety has (S) stereochemistry.
• the sulfur in the moiety has (R) stereochemistry.
• R 10 is C1-C6 alkyl.
• R 10 is methyl
• R 10 is ethyl.
• the groups R 8 and R 9 are ethyl.
• each of R 8 and R 9 at each occurrence is hydrogen
• each R 8 at each occurrence is hydrogen and each R 9 at each occurrence is C1-C6 alkyl.
• each R 8 at each occurrence is hydrogen and each R 9 at each occurrence is methyl.
• each R 8 at each occurrence is hydrogen and each R 9 at each occurrence is ethyl.
• each of R 8 and R 9 at each occurrence is methyl.
• each of R 8 and R 9 at each occurrence is ethyl.
• R 8 and R 9 taken together with the nitrogen they are attached to form a 3- membered ring.
• R 8 and R 9 taken together with the nitrogen they are attached to form a 4- membered ring.
• 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.
• R 8 and R 9 taken together with the nitrogen they are attached to form a 7- membered ring.
• R 13 is C1-C6 alkyl.
• R 13 is methyl
• R 13 is ethyl
• R 13 is C6-C10 aryl.
• R 13 is phenyl
• R 13 is 5- to 10-membered heteroaryl.
• the groups R 11 and R 12 are 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 of R 11 and R 12 at each occurrence is hydrogen
• each R 11 at each occurrence is hydrogen and each R 12 at each occurrence is C 1 -C 6 alkyl.
• each R 11 at each occurrence is hydrogen and each R 12 at each occurrence is methyl.
• each R 11 at each occurrence is hydrogen and each R 12 at each occurrence is ethyl.
• each of R 11 and R 12 at each occurrence is methyl.
• each of R 11 and R 12 at each occurrence is ethyl. In some embodiments of the compound of formula AA,
• R 6 is selected from:
• R 6 is selected from:
• R 6 is selected from:
• R 6 is selected from: isopropyl, ethyl, methyl, trifluoromethyl, trifluoromethoxy, cyclopropyl, halo, chloro, and fluoro.
• R 6 is selected from: isopropyl, ethyl, methyl, trifluoromethyl, trifluoromethoxy, cyclopropyl, halo, chloro, and fluoro.
• R 6 is selected from:
• R 6 is selected from:
• R 6 is selected from:
• R 6 is selected from: isopropyl, ethyl, methyl, trifluoromethyl, trifluoromethoxy, cyclopropyl, halo, chloro, and fluoro.
• R 6 is selected from: isopropyl, ethyl, methyl, trifluoromethyl, trifluoromethoxy, cyclopropyl, halo, chloro, and fluoro.
• R 6 is selected from:
• R 6 is selected from:
• R 6 is C 1 -C 6 alkyl, and the other R 6 is C 1 -C 6 alkyl optionally substituted with one or more halo;
• One R 6 is C1-C6 alkyl and the other R 6 is C1-C6 alkyl;
• R 6 is C 1 -C 6 alkyl, and the other R 6 is C 1 -C 6 alkyl substituted with one or more halo;
• One R 6 is C1-C6 alkyl, and the other R 6 is C3-C7 cycloalkyl;
• R 6 is C1-C6 alkyl, and the other R 6 is halo;
• R 6 is C 1 -C 6 alkyl, and the other R 6 is cyano;
• One R 6 is C3-C7 cycloalkyl, and the other R 6 is C3-C7 cycloalkyl;
• R 6 is C 3 -C 7 cycloalkyl, and the other R 6 is halo;
• R 6 is cyclopropyl and the other R 6 is halo
• R 6 is C1-C6 alkyl, and the other R 6 is C1-C6 alkoxy optionally substituted with one or more halo;
• R 6 is C 1 -C 6 alkyl, and the other R 6 is C 1 -C 6 alkoxy;
• R 6 is C1-C6 alkyl, and the other R 6 is C1-C6 alkoxy substituted with one or more halo;
• One R 6 is halo, and the other R 6 is C1-C6 haloalkyl;
• R 6 is halo, and the other R 6 is C 1 -C 6 haloalkoxy;
• R 6 is C 1 -C 6 alkoxy; and the other R 6 is halo;
• R 6 is C1-C6 alkoxy; and the other R 6 is chloro.
• the compound of formula AA is C1-C6 alkoxy; and the other R 6 is chloro.
• R 6 is isopropyl; and the other R 6 is methyl;
• R 6 is isopropyl; and the other R 6 is n-propyl;
• R 6 is isopropyl; and the other R 6 is isopropyl;
• R 6 is isopropyl; and the other R 6 is trifluoromethyl;
• R 6 is isopropyl; and the other R 6 is cyclopropyl;
• R 6 is isopropyl; and the other R 6 is chloro;
• R 6 is isopropyl; and the other R 6 is fluoro;
• R 6 is ethyl; and the other R 6 is fluoro;
• R 6 is isopropyl; and the other R 6 is cyano;
• R 6 is cyclopropyl; and the other R 6 is cyclopropyl;
• R 6 is cyclopropyl; and the other R 6 is chloro;
• R 6 is cyclopropyl; and the other R 6 is fluoro;
• R 6 is isopropyl; and the other R 6 is methoxy;
• One R 6 is isopropyl; and the other R 6 is methoxy; or One R 6 is isopropyl; and the other R 6 is trifluoromethoxy.
• the compound of formula AA is isopropyl; and the other R 6 is methoxy; or One R 6 is isopropyl; and the other R 6 is trifluoromethoxy.
• R 6 and R 7 are one of the following combinations:
• R 6 is C 1 -C 6 alkyl, and R 7 is C 1 -C 6 alkyl optionally substituted with one or more halo; R 6 is C1-C6 alkyl and R 7 is C1-C6 alkyl;
• R 6 is C1-C6 alkyl, and R 7 is C1-C6 alkyl substituted with one or more halo;
• R 6 is C 1 -C 6 alkyl, and R 7 is C 3 -C 7 cycloalkyl;
• R 6 is C1-C6 alkyl, and R 7 is halo
• R 6 is C1-C6 alkyl, and R 7 is cyano
• R 6 is C 3 -C 7 cycloalkyl, and R 7 is C 3 -C 7 cycloalkyl;
• R 6 is C3-C7 cycloalkyl, and R 7 is halo;
• R 6 is cyclopropyl and R 7 is halo
• R 6 is C 1 -C 6 alkyl, and R 7 is C 1 -C 6 alkoxy optionally substituted with one or more halo; R 6 is C 1 -C 6 alkyl, and R 7 is C 1 -C 6 alkoxy;
• R 6 is C1-C6 alkyl, and R 7 is C1-C6 alkoxy substituted with one or more halo;
• R 6 is halo, and R 7 is C 1 -C 6 haloalkyl
• R 6 is halo, and R 7 is C 1 -C 6 haloalkoxy
• R 6 is C1-C6 alkoxy; and R 7 is halo;
• R 6 is C1-C6 alkoxy; and R 7 is chloro;
• R 7 is C 1 -C 6 alkyl, and R 6 is C 1 -C 6 alkyl optionally substituted with one or more halo;
• R 7 is C1-C6 alkyl, and R 6 is C1-C6 alkyl substituted with one or more halo;
• R 7 is C1-C6 alkyl, and R 6 is C3-C7 cycloalkyl;
• R 7 is C 1 -C 6 alkyl, and R 6 is halo
• R 7 is C 1 -C 6 alkyl and R 6 is halo
• R 7 is C1-C6 alkyl, and R 6 is cyano
• R 7 is C 3 -C 7 cycloalkyl, and R 6 is C 3 -C 7 cycloalkyl;
• R 7 is C 3 -C 7 cycloalkyl, and R 6 is halo;
• R 7 is C3-C7 cycloalkyl and R 6 is halo;
• R 7 is C 1 -C 6 alkyl, and R 6 is C 1 -C 6 alkoxy optionally substituted with one or more halo; R 7 is C 1 -C 6 alkyl, and R 6 is C 1 -C 6 alkoxy;
• R 7 is C1-C6 alkyl, and R 6 is C1-C6 alkoxy substituted with one or more halo;
• R 7 is halo, and R 6 is C1-C6 haloalkyl
• R 7 is halo, and R 6 is C 1 -C 6 haloalkoxy
• R 7 is C1-C6 alkoxy; and R 6 is halo; or
• R 7 is C1-C6 alkoxy; and R 6 is chloro.
• R 6 and R 7 are one of the following combinations:
• R 6 is isopropyl; and R 7 is methyl;
• R 6 is isopropyl
• R 7 is isopropyl
• R 6 is isopropyl; and R 7 is trifluoromethyl;
• R 6 is isopropyl; and R 7 is cyclopropyl;
• R 6 is isopropyl; and R 7 is chloro;
• R 6 is isopropyl; and R 7 is fluoro;
• R 6 is ethyl; and R 7 is fluoro;
• R 6 is isopropyl; and R 7 is cyano;
• R 6 is cyclopropyl; and R 7 is cyclopropyl;
• R 6 is cyclopropyl; and R 7 is chloro;
• R 6 is cyclopropyl; and R 7 is fluoro; R 6 is isopropyl; and R 7 is methoxy;
• R 6 is isopropyl; and R 7 is trifluoromethoxy;
• R 6 is chloro; and R 7 is trifluoromethyl;
• R 6 is chloro; and R 7 is trifluoromethoxy;
• R 7 is isopropyl; and R 6 is methyl;
• R 7 is isopropyl; and R 6 is trifluoromethyl; R 7 is isopropyl; and R 6 is cyclopropyl;
• R 7 is isopropyl; and R 6 is chloro;
• R 7 is ethyl; and R 6 is fluoro;
• R 7 is isopropyl; and R 6 is cyano;
• R 7 is cyclopropyl; and R 6 is cyclopropyl;
• R 7 is cyclopropyl; and R 6 is chloro;
• R 7 is cyclopropyl; and R 6 is fluoro;
• R 7 is isopropyl; and R 6 is methoxy;
• R 7 is isopropyl; and R 6 is trifluoromethoxy;
• R 7 is chloro; and R 6 is trifluoromethyl; or
• R 7 is chloro; and R 6 is trifluoromethoxy.
• R 6 and R 7 are one of the following combinations:
• R 6 is C 1 -C 6 alkyl, and R 7 is C 1 -C 6 alkyl optionally substituted with one or more halo; R 6 is C1-C6 alkyl and R 7 is C1-C6 alkyl;
• R 6 is C1-C6 alkyl, and R 7 is C1-C6 alkyl substituted with one or more halo;
• R 6 is C 1 -C 6 alkyl, and R 7 is C 3 -C 7 cycloalkyl;
• R 6 is C1-C6 alkyl, and R 7 is halo
• R 6 is C1-C6 alkyl, and R 7 is cyano
• R 6 is C 3 -C 7 cycloalkyl, and R 7 is C 3 -C 7 cycloalkyl;
• R 6 is C3-C7 cycloalkyl, and R 7 is halo;
• R 6 is cyclopropyl and R 7 is halo
• R 6 is C 1 -C 6 alkyl, and R 7 is C 1 -C 6 alkoxy optionally substituted with one or more halo; R 6 is C 1 -C 6 alkyl, and R 7 is C 1 -C 6 alkoxy;
• R 6 is C1-C6 alkyl, and R 7 is C1-C6 alkoxy substituted with one or more halo;
• R 6 is halo, and R 7 is C 1 -C 6 haloalkyl
• R 6 is halo, and R 7 is C 1 -C 6 haloalkoxy
• R 6 is C1-C6 alkoxy; and R 7 is halo; R 6 is C1-C6 alkoxy; and R 7 is chloro;
• R 7 is C 1 -C 6 alkyl, and R 6 is C 1 -C 6 alkyl optionally substituted with one or more halo;
• R 7 is C 1 -C 6 alkyl, and R 6 is C 1 -C 6 alkyl substituted with one or more halo;
• R 7 is C1-C6 alkyl, and R 6 is C3-C7 cycloalkyl;
• R 7 is C1-C6 alkyl, and R 6 is halo
• R 7 is C 1 -C 6 alkyl and R 6 is halo
• R 7 is C1-C6 alkyl, and R 6 is cyano
• R 7 is C3-C7 cycloalkyl, and R 6 is C3-C7 cycloalkyl;
• R 7 is C 3 -C 7 cycloalkyl, and R 6 is halo;
• R 7 is C 3 -C 7 cycloalkyl and R 6 is halo
• R 7 is C1-C6 alkyl, and R 6 is C1-C6 alkoxy optionally substituted with one or more halo; R 7 is C 1 -C 6 alkyl, and R 6 is C 1 -C 6 alkoxy;
• R 7 is C 1 -C 6 alkyl, and R 6 is C 1 -C 6 alkoxy substituted with one or more halo;
• R 7 is halo, and R 6 is C1-C6 haloalkyl
• R 7 is halo, and R 6 is C1-C6 haloalkoxy
• R 7 is C 1 -C 6 alkoxy; and R 6 is halo; or
• R 7 is C1-C6 alkoxy; and R 6 is chloro.
• R 6 and R 7 are one of the following combinations:
• R 6 is isopropyl; and R 7 is methyl;
• R 6 is isopropyl
• R 7 is isopropyl
• R 6 is isopropyl; and R 7 is trifluoromethyl;
• R 6 is isopropyl; and R 7 is cyclopropyl;
• R 6 is isopropyl; and R 7 is chloro;
• R 6 is isopropyl; and R 7 is fluoro;
• R 6 is ethyl; and R 7 is fluoro;
• R 6 is isopropyl; and R 7 is cyano; R 6 is cyclopropyl; and R 7 is cyclopropyl;
• R 6 is cyclopropyl; and R 7 is chloro;
• R 6 is cyclopropyl; and R 7 is fluoro;
• R 6 is isopropyl; and R 7 is methoxy;
• R 6 is isopropyl; and R 7 is trifluoromethoxy;
• R 6 is chloro; and R 7 is trifluoromethyl;
• R 6 is chloro; and R 7 is trifluoromethoxy;
• R 7 is isopropyl; and R 6 is methyl;
• R 7 is isopropyl; and R 6 is trifluoromethyl;
• R 7 is isopropyl; and R 6 is cyclopropyl;
• R 7 is isopropyl; and R 6 is chloro;
• R 7 is ethyl; and R 6 is fluoro;
• R 7 is isopropyl; and R 6 is cyano;

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