WO2016193812A1 - Substituted pyridines and method of use - Google Patents

Substituted pyridines and method of use Download PDF

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Publication number
WO2016193812A1
WO2016193812A1 PCT/IB2016/000821 IB2016000821W WO2016193812A1 WO 2016193812 A1 WO2016193812 A1 WO 2016193812A1 IB 2016000821 W IB2016000821 W IB 2016000821W WO 2016193812 A1 WO2016193812 A1 WO 2016193812A1
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WO
WIPO (PCT)
Prior art keywords
amino
sulfonyl
phenyl
pyridine
carboxamide
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
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PCT/IB2016/000821
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English (en)
French (fr)
Inventor
Robert J. Altenbach
Marlon D. Cowart
Tom Roger Lisette DE MUNCK
Sebastien Jean Jacques Cedric DROPSIT MONTOVERT
Gregory A. Gfesser
Hans KELGTERMANS
Sebastien Laurent Xavier MARTINA
Steven Emiel VAN DER PLAS
Xueqing Wang
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Galapagos NV
AbbVie SARL
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Galapagos NV
AbbVie SARL
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Filing date
Publication date
Priority to JP2017562678A priority Critical patent/JP2018516932A/ja
Priority to CR20170595A priority patent/CR20170595A/es
Priority to RU2017146661A priority patent/RU2017146661A/ru
Priority to KR1020177037457A priority patent/KR20180029204A/ko
Priority to BR112017026132A priority patent/BR112017026132A2/pt
Priority to MX2017015591A priority patent/MX2017015591A/es
Priority to CN201680043914.3A priority patent/CN107922338A/zh
Priority to EP16736610.3A priority patent/EP3303294A1/en
Priority to AU2016272702A priority patent/AU2016272702A1/en
Priority to CA2988046A priority patent/CA2988046A1/en
Application filed by Galapagos NV, AbbVie SARL filed Critical Galapagos NV
Publication of WO2016193812A1 publication Critical patent/WO2016193812A1/en
Priority to IL256032A priority patent/IL256032A/en
Priority to PH12017502201A priority patent/PH12017502201A1/en
Anticipated expiration legal-status Critical
Priority to CONC2017/0012566A priority patent/CO2017012566A2/es
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/443—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring

Definitions

  • the invention relates to substituted pyridine compounds that are modulators of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein, useful in treating diseases and conditions mediated and modulated by CFTR.
  • CFTR Cystic Fibrosis Transmembrane Conductance Regulator
  • the invention also relates to compositions containing compounds of the invention, processes for their preparation, and methods of treatment using them.
  • ABC transporters are a family of homologous membrane transporter proteins regulating the transport of a wide variety of pharmacological agents (for example drugs, xenobiotics, anions, etc.) that bind and use cellular adenosine triphosphate (ATP) for their specific activities. Some of these transporters were found to defend malignant cancer cells against pharmacological agents (for example drugs, xenobiotics, anions, etc.) that bind and use cellular adenosine triphosphate (ATP) for their specific activities. Some of these transporters were found to defend malignant cancer cells against pharmacological agents (for example drugs, xenobiotics, anions, etc.) that bind and use cellular adenosine triphosphate (ATP) for their specific activities. Some of these transporters were found to defend malignant cancer cells against pharmacological agents (for example drugs, xenobiotics, anions, etc.) that bind and use cellular adenosine triphosphate (ATP) for their specific activities
  • chemotherapeutic agents acting as multidrug resistance proteins (like the MDR1-P glycoprotein, or the multidrug resistance protein, MRP 1). So far, 48 ABC transporters, grouped into 7 families based on their sequence identity and function, have been identified.
  • ABC transporters provide protection against harmful environmental compounds by regulating a variety of important physiological roles within the body, and therefore represent important potential drug targets for the treatment of diseases associated with transporter defects, outwards cell drug transport, and other diseases in which modulation of ABC transporter activity may be beneficial.
  • CFTR The cAMP/ATP-mediated anion channel, CFTR, is one member of the ABC transporter family commonly associated with diseases, which is expressed in a variety of cell types, including absorptive and secretory epithelia cells, where it regulates anion flux across the membrane, as well as the activity of other ion channels and proteins.
  • the activity of CFTR in epithelial cells is essential for the maintenance of electrolyte transport throughout the body, 1 ABV12212USO1 including respiratory and digestive tissue (Quinton, P.M., 1990. Cystic fibrosis: a disease in electrolyte transport. FASEB J.4, 2709–2717).
  • CFTR comprises about 1480 amino acids that encode a protein made up of a tandem repeat of transmembrane domains, each containing six transmembrane helices and a nucleotide binding domain.
  • the pair of transmembrane domains is linked by a large, polar, regulatory (R)-domain with multiple phosphorylation sites that regulate channel activity and cellular trafficking.
  • Cystic fibrosis is caused by a defect in this gene which induces mutations in CFTR. Cystic fibrosis is the most common fatal genetic disease in humans, and affects ⁇ 0.04% of white individuals (Bobadilla, J.L., Macek, M., Jr, Fine, J.P., Farrell, P.M., 2002. Cystic fibrosis: a worldwide analysis of CFTR mutations--correlation with incidence data and application to screening. Hum. Mutat.19, 575–606.
  • CF patients Beyond respiratory disease, CF patients also suffer from gastrointestinal problems and pancreatic insufficiency that result in death if left untreated. Furthermore, female subjects with cystic fibrosis suffer from decreased fertility, whilst males with cystic fibrosis are infertile.
  • ⁇ F508-CFTR the most common CF mutation (present in at least 1 allele in ⁇ 90% of CF patients) and occurring in approximately 70% of the cases of cystic fibrosis, contains a single amino acid deletion of phenylalanine 508. This deletion prevents the nascent protein from folding correctly, which protein in turn cannot exit the endoplasmic reticulum (ER) and traffic to the plasma membrane, and then is rapidly degraded. As a result, the number of channels present in the membrane is far less than in cells expressing wild-type CFTR. In addition to impaired trafficking, the mutation results in defective channel gating.
  • CFTR activity modulation may be beneficial for other diseases not directly caused by mutations in CFTR, such as, for example, chronic obstructive pulmonary disease (COPD), dry eye disease, and Sjogren's Syndrome.
  • COPD chronic obstructive pulmonary disease
  • COPD dry eye disease
  • Sjogren's Syndrome a chronic obstructive pulmonary disease
  • COPD is characterized by a progressive and non-reversible airflow limitation, which is due to mucus hypersecretion, bronchiolitis, and emphysema.
  • a potential treatment of mucus hypersecretion and impaired mucociliary clearance that is common in COPD could consist in using activators of mutant or wild-type CFTR.
  • the anion secretion increase across CFTR may facilitate fluid transport into the airway surface liquid to hydrate the mucus and
  • ABV12212USO1 optimize periciliary fluid viscosity.
  • the resulting enhanced mucociliary clearance would help in reducing the symptoms associated with COPD.
  • Dry eye disease is characterized by a decrease in tear production and abnormal tear film lipid, protein and mucin profiles. Many factors may cause dry eye disease, some of which include age, arthritis, Lasik eye surgery, chemical/thermal burns, medications, allergies, and diseases, such as cystic fibrosis and Sjogrens's syndrome. Increasing anion secretion via CFTR could enhance fluid transport from the corneal endothelial cells and secretory glands surrounding the eye, and eventually improve corneal hydration, thus helping to alleviate dry eye disease associated symptoms.
  • Sjogrens's syndrome is an autoimmune disease where the immune system harms moisture-producing glands throughout the body, including the eye, mouth, skin, respiratory tissue, liver, vagina, and gut.
  • the ensuing symptoms include, dry eye, mouth, and vagina, as well as lung disease.
  • Sjogrens's syndrome is also associated with rheumatoid arthritis, systemic lupus, systemic sclerosis, and polymypositis/dermatomyositis.
  • the cause of the disease is believed to lie in defective protein trafficking, for which treatment options are limited.
  • modulation of CFTR activity may help hydrating the various organs and help to elevate the associated symptoms.
  • the defective protein trafficking induced by the ⁇ F508-CFTR has been shown to be the underlying basis for a wide range of other diseases, in particular diseases where the defective functioning of the endoplasmic reticulum (ER) may either prevent the CFTR protein to exit the cell, and/or the misfolded protein is degraded (Morello, J.-P., Bouvier, M., Petäjä-Repo, U.E., Bichet, D.G., 2000. Pharmacological chaperones: a new twist on receptor folding. Trends Pharmacol. Sci.21, 466–469. doi:10.1016/S0165-6147(00)01575-3; Shastry, B.S., 2003. Neurodegenerative disorders of protein aggregation. Neurochem. Int.43, 1–7.
  • a number of genetic diseases are associated with a defective ER processing equivalent to the defect observed with CFTR in CF such as glycanosis CDG type 1, hereditary emphysema ( ⁇ -l-antitrypsin (PiZ variant)), congenital hyperthyroidism, osteogenesis imperfecta (Type I, II, or IV procollagen), hereditary hypofibrinogenemia (fibrinogen), ACT deficiency ( ⁇ -l- antichymotrypsin), diabetes insipidus (DI), neurophyseal DI (vasopvessin hormoneN2-receptor), 4 ABV12212USO1 neprogenic DI (aquaporin II), Charcot-Marie Tooth syndrome (peripheral myelin protein 22), Perlizaeus-Merzbacher disease, neurodegenerative diseases such as Alzheimer's disease (APP and presenilins), Parkinson's disease, amyotrophic lateral sclerosis, progressive supran
  • anion secretion reduction by CFTR modulators may be beneficial for the treatment of secretory diarrheas, in which epithelial water transport is dramatically increased as a result of secretagogue activated chloride transport.
  • the mechanism involves elevation of cAMP and stimulation of CFTR.
  • the present invention discloses compounds that may act as CFTR modulators for the treatment of cystic fibrosis.
  • the present invention also provides methods for the preparation of these compounds, pharmaceutical compositions comprising these compounds and methods for the treatment of cystic fibrosis by administering the compounds of the invention.
  • phenoxy optionally substituted with one or more independently selected R 5 groups; or phenyl optionally substituted with one or more independently selected R 5 groups;
  • 4-6 membered monocyclic heterocycle comprising 1 or 2 heteroatoms independently selected from the group consisting of O, S, and N;
  • N-linked 4-6 membered monocyclic heterocycle comprising 1, 2, or 3 heteroatoms
  • N-linked 4-6 membered monocyclic heterocycle comprising 1, 2, or 3 heteroatoms
  • C 1-4 alkyl optionally substituted with one or more independently selected -OH, halo, or C 1-4 alkoxy;
  • 4-6 membered monocyclic heterocycle comprising 1 or 2 heteroatoms independently selected from the group consisting of N, O, and S, wherein the monocyclic heterocycle is optionally substituted with one or more independently selected -OH;
  • ABV12212USO1 5-6 membered monocyclic heteroaryl comprising 1, 2, or 3 heteroatoms independently selected from the group consisting of O, S, and N, wherein the monocyclic heteroaryl is optionally substituted with one or more independently selected R 5 groups; or
  • C 1-4 alkyl optionally substituted with one or more independently selected halo or–OH; or C 1-4 alkoxy optionally substituted with one or more independently selected halo;
  • 4-6 membered monocyclic heterocycle comprising 1 or 2 heteroatoms independently selected from the group consisting of O, S, and N, wherein the monocyclic heterocycle is optionally substituted with one or more
  • 4-6 membered monocyclic heterocycle comprising 1 or 2 heteroatoms independently selected from the group consisting of O, S, and N, fused to a phenyl ring, wherein the monocyclic heterocycle and the phenyl are optionally substituted with one or more independently selected R 5 groups;
  • 5-11 membered spirocyclic heterocycle comprising 1 or 2 heteroatoms independently selected from the group consisting of O, S, and N, wherein the spirocyclic heterocycle is optionally substituted with one or more independently selected R 5 groups; 5-6 membered monocyclic heteroaryl comprising 1, 2, or 3 heteroatoms independently
  • R 2 and R 3 together with the nitrogen atom to which they are attached form 8 ABV12212USO1 an azetidine or a pyrrolidine ring, wherein the azetidine and the pyrrolidine are optionally substituted with one or more independently selected R 9 groups; or
  • a 7-11 membered spirocyclic heterocycle comprising one or more heteroatoms independently selected from the group consisting of N, O, and S; wherein the spirocyclic heterocycle is optionally substituted with one or more independently selected R 5 groups; each R 4 is independently selected from the group consisting of:
  • each R 5 is independently selected from the group consisting of:
  • R 6 is H, C 1-4 alkyl, or C 3-7 cycloalkyl wherein the C 3-7 cycloalkyl is optionally substituted with one or more independently selected R 5 groups;
  • each R 9 is independently selected from the group consisting of:
  • each R 10a and R 10b is independently selected from the group consisting of H and C 1-4 alkyl;
  • each R 11a and R 11b is independently selected from the group consisting of
  • R 12a and R 12b are independently selected from the group consisting of
  • R 13 is independently C 1-4 alkyl optionally substituted with one or more independently selected –OH;
  • compositions comprising a compound of the invention, and a pharmaceutical carrier.
  • Such compositions can be
  • compositions may additionally comprise further therapeutically active ingredients suitable for use in combination with the compounds of the invention.
  • further therapeutically active ingredient is an agent for the treatment of cystic fibrosis.
  • the compounds of the invention useful in the pharmaceutical compositions and treatment methods disclosed herein, are pharmaceutically acceptable as prepared and used.
  • Yet another aspect of the invention relates to a method for treating, or preventing conditions and disorders related to Cystic Fibrosis Transmembrane Conductance Regulator activity in mammals. More particularly, the method is useful for treating or preventing conditions and disorders related to cystic fibrosis, Sjögren's syndrome, pancreatic insufficiency, chronic obstructive lung disease, or chronic obstructive airway disease. Accordingly, the compounds and compositions of the invention are useful as a medicament for treating or preventing Cystic Fibrosis Transmembrane Conductance Regulator modulated disease.
  • compositions comprising the compounds, methods for making the compounds, and methods for treating or preventing conditions and disorders by administering the compounds are further described herein.
  • the compounds of the invention are provided for use in the treatment of cystic fibrosis.
  • the compounds of the invention are provided for use in the treatment of cystic fibrosis caused by class I, II, III, IV, and/or VI mutations.
  • the present invention also provides pharmaceutical compositions comprising a compound of the invention, and a suitable pharmaceutical carrier for use in medicine.
  • the pharmaceutical composition is for use in the treatment of cystic fibrosis.
  • compositions comprising such compounds and methods for treating conditions and disorders using such compounds and compositions are also included.
  • variable(s) may contain one or more variable(s) that occur more than one time in any substituent or in the formulae herein. Definition of a variable on each occurrence is independent of its definition at another occurrence. Further, combinations of substituents are permissible only if such combinations result in stable compounds. Stable compounds are compounds which can be isolated from a reaction mixture.
  • alkoxy as used herein means an alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom.
  • Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, and hexyloxy.
  • the number of carbon atoms in an alkoxy moiety is indicated by the prefix“C x - y ”, wherein x is the minimum and y is the maximum number of carbon atoms in the substituent.
  • “C 1 - 6 alkoxy” means an alkoxy substituent containing from 1 to 6 carbon atoms and“C 1 - 4 alkoxy” means an alkoxy substituent containing from 1 to 4 carbon atoms.
  • “alkyl” as used herein means a saturated, straight or branched hydrocarbon chain radical. In some instances, the number of carbon atoms in an alkyl moiety is indicated by the prefix“C x - y ”, wherein x is the minimum and y is the maximum number of carbon atoms in the substituent.
  • “C 1 - 6 alkyl” means an alkyl substituent containing from 1 to 6 carbon atoms
  • “C 1 - 4 alkyl” means an alkyl substituent containing from 1 to 4 carbon atoms.
  • alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 1-methylbutyl, 2- methylbutyl, 3-methylbutyl, 3,3-dimethylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2- dimethylpropyl, 1-methylpropyl, 2-methylpropyl, 1-ethylpropyl, and 1,2,2-trimethylpropyl.
  • C 3-7 cycloalkyl as used herein, means cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl, each of which is optionally substituted unless otherwise indicated.
  • C 3-6 cycloalkyl as used herein, means cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, each of which is optionally substituted unless otherwise indicated.
  • C 4-6 cycloalkyl as used herein, means cyclobutyl, cyclopentyl, and cyclohexyl, each of which is optionally substituted unless otherwise indicated.
  • halo or“halogen” as used herein, means chloro (Cl), bromo (Br), iodo (I), and fluoro (F).
  • 3- and 4-Membered monocyclic heterocycle have one carbon ring atom replaced by a heteroatom selected from the group consisting of O, N, and S.
  • 5-, 6-, 7-, and 8-Membered monocyclic heterocycle may have one, two, or three carbon ring atoms replaced by heteroatoms selected from the group consisting of O, N, and S.
  • Examples of five- membered monocyclic heterocycle include those containing in the ring: 1 O; 1 S; 1 N; 2 N; 3 N; 1 S and 1 N; 1 S, and 2 N; 1 O and 1 N; or 1 O and 2 N.
  • Non-limiting examples of 5-membered monocyclic heterocyclic groups include 1,3-dioxolanyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, imidazolidinyl, oxazolidinyl, imidazolinyl, isoxazolidinyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, thiazolinyl, and thiazolidinyl.
  • Examples of six-membered monocyclic heterocyclic include those containing in the ring: 1 O; 2 O; 1 S; 2 S; 1 N; 2 N; 3 N; 1 S, 1 O, and 1 N; 1 S and 1 N; 1 S and 2 N; 1 S and 1 O; 1 S and 2 13 ABV12212USO1 O; 1 O and 1 N; and 1 O and 2 N.
  • 6-membered monocyclic heterocyclic groups include tetrahydropyranyl, dihydropyranyl, 1,4-dioxanyl, 1,4-dithianyl, hexahydropyrimidine, morpholinyl, piperazinyl, piperidinyl, 1,2,3,6-tetrahydropyridinyl, tetrahydrothiopyranyl, thiomorpholinyl, thioxanyl, and trithianyl.
  • monocyclic heterocycles include, but are not limited to, azetidinyl, azepanyl, aziridinyl, diazepanyl, 1,4-dioxanyl, 1,3- dioxolanyl, 1,3-dithiolanyl, 1,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, oxetanyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyr
  • 4-6 membered monocyclic heterocycle or“4-6 membered monocyclic heterocyclic” as used herein, means a 4-, 5-, or 6-membered monocyclic heterocycle as defined herein above.
  • Non-limiting examples of 4-6 membered monocyclic heterocycle include azetidinyl, oxetanyl, 1,3-dioxolanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, 1,4- dioxanyl, piperazinyl, piperidinyl, thiomorpholinyl, and morpholinyl.
  • 3-6 membered monocyclic heterocycle or“3-6 membered monocyclic heterocyclic” as used herein, means a 3-, 4-, 5-, or 6-membered monocyclic heterocycle as defined herein above.
  • Non-limiting examples of 3-6 membered monocyclic heterocycle include aziridinyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperazinyl, piperidinyl, thiomorpholinyl, and morpholinyl.
  • the term“5- 11 membered spiro heterocycle” as used herein, means a 3-6 membered monocyclic heterocycle wherein two substituents on the same carbon atom of the 3-6 membered monocyclic heterocycle ring together with said carbon atom form a second ring system; wherein the second ring system is a C 3-6 cycloalkyl or a 3-6 membered monocyclic heterocycle.
  • Examples of 5-11 membered spiro heterocycle include, but not limited to, 1-oxaspiro[4.4]non-3- yl, and 1-oxaspiro[4.5]decan-3-yl.
  • 7- 11 membered spiro heterocycle means a 4-6 membered monocyclic heterocycle wherein two substituents on the same carbon atom of the 4-6 membered monocyclic heterocycle ring together with said carbon atom form a second ring system; wherein the second ring system is a C 4-6 cycloalkyl or a 4-6 membered monocyclic heterocycle.
  • 7-11 membered spiro heterocycles are 6-oxa-2-azaspiro[3.5]nonyl, 6-oxa- 2-azaspiro[3.4]octyl, and 2-oxa-6-azaspiro[3.3]heptyl.
  • the nitrogen atoms within the heterocycle rings may optionally be oxidized or may optionally be quaternized.
  • the term“5-6 membered monocyclic heteroaryl” as used herein, means a five- or six- membered monocyclic aromatic ring structure wherein one or more of the ring carbon atoms are replaced with heteroatom(s) independently selected from the group consisting of O, N, and S.
  • the five-membered ring contains two double bonds.
  • the 5 membered ring may also contain one heteroatom selected from the group consisting of O and S; or may contain one, two, three, or four nitrogen atoms and optionally one oxygen or one sulfur atom.
  • the 6-membered ring contains three double bonds and one, two, three or four nitrogen atoms.
  • 5-6 membered monocyclic heteroaryl include, but are not limited to, furanyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, 1,3-oxazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, 1,3-thiazolyl, thienyl, triazolyl, and triazinyl.
  • the 5-6 membered monocyclic heteroaryls including exemplary rings, are optionally substituted unless otherwise indicated, and are connected to the parent molecular moiety through any substitutable carbon atom or any substitutable nitrogen atom contained within the ring systems.
  • the nitrogen atom in the heteroaryl rings may optionally be oxidized and may optionally be quaternized.
  • phenoxy as used herein means a phenyl appended to the parent molecular moiety through an oxygen atom.
  • heteroatom as used herein, means a nitrogen (N), oxygen (O), or sulfur (S).
  • radioactive atoms refers to a compound of the invention in which at least one of the atoms is a radioactive atom or radioactive isotope, wherein the radioactive atom or isotope spontaneously emits gamma rays or energetic particles, for example alpha particles or beta particles, or positrons.
  • radioactive atoms include, but are not limited to, 3 H (tritium), 14 C, 11 C, 15 O, 18 F, 35 S, 123 I, and 125 I.
  • a non-hydrogen radical is in the place of hydrogen radical of any substitutable atom of the moiety.
  • a substituted heterocycle moiety is a heterocycle moiety in which at least one non-hydrogen radical is in the place of a hydrogen radical on the heterocycle. It should be recognized that if there are more than one substitution on a moiety, each non-hydrogen radical may be identical or different (unless otherwise stated).
  • a moiety is described as being“optionally substituted,” the moiety may be either (1) not substituted or (2) substituted. If a moiety is described as being optionally substituted with up to a particular number of non-hydrogen radicals, that moiety may be either (1) not substituted; or (2) substituted by up to that particular number of non-hydrogen radicals or by up to the maximum number of substitutable positions on the moiety, whichever is less. Thus, for example, if a moiety is described as a heteroaryl optionally substituted with up to 3 non-hydrogen radicals, then any heteroaryl with less than 3 substitutable positions would be optionally substituted by up to only as many non-hydrogen radicals as the heteroaryl has substitutable positions.
  • tetrazolyl (which has only one substitutable position) would be optionally substituted with up to one non-hydrogen radical.
  • an amino nitrogen is described as being optionally substituted with up to 2 non-hydrogen radicals, then a primary amino nitrogen will be optionally substituted with up to 2 non-hydrogen radicals, whereas a secondary amino nitrogen will be optionally substituted with up to only 1 non-hydrogen radical.
  • substituted with one or more refers to one to four substituents. In one embodiment it refers to one to three substituents. In further embodiments it refers to one or two substituents. In a yet further embodiment it refers to one substituent.
  • “treat”,“treating”, and“treatment” refer to a method of alleviating or abrogating a disease and/or its attendant symptoms. In certain embodiments,“treat,”“treating,” and“treatment” refer to ameliorating at least one physical parameter, which may not be discernible by the subject. In yet another embodiment,“treat”,“treating”, and“treatment” refer to modulating the disease or disorder, either physically (for example, stabilization of a discernible symptom), physiologically (for example, stabilization of a physical parameter), or both. In a further embodiment,“treat”,“treating”, and“treatment” refer to slowing the progression of the disease or disorder.
  • “prevent”,“preventing”, and“prevention” refer to a method of preventing the onset of a disease and/or its attendant symptoms or barring a subject from acquiring a disease.
  • “prevent”,“preventing” and“prevention” also include delaying the onset of a disease and/or its attendant symptoms and reducing a subject's risk of acquiring or developing a disease or disorder.
  • the phrase“therapeutically effective amount” means an amount of a compound, or a pharmaceutically acceptable salt thereof, sufficient to prevent the development of, or to alleviate to some extent, one or more of the symptoms of the condition or disorder being treated when administered alone or in conjunction with another therapeutic agent for treatment in a particular subject or subject population.
  • The“therapeutically effective amount” may vary depending on the compound, the disease and its severity, and the age, weight, health, etc., of the subject to be treated. For example in a human or other mammal, a therapeutically effective amount may be determined experimentally in a laboratory or clinical setting, or may be the amount required by the guidelines of the United States Food and Drug Administration, or equivalent foreign agency, for the particular disease and subject being treated.
  • subject is defined herein to refer to animals such as mammals, including, but not limited to, primates (e.g., humans), cows, sheep, goats, pigs, horses, dogs, cats, rabbits, rats, mice and the like. In preferred embodiments, the subject is a human.
  • primates e.g., humans
  • cows e.g., humans
  • sheep cows
  • goats pigs
  • horses dogs
  • cats rabbits, rats, mice and the like.
  • rabbits rats
  • mice mice and the like.
  • the subject is a human.
  • human human
  • patient and“subject” are used interchangeably herein.
  • Class I mutation(s) refers to mutations which interfere with protein synthesis. They result in the introduction of a premature signal of termination of translation (stop codon) in the mRNA. The truncated CFTR proteins are unstable and rapidly degraded, so, the net effect is that there is no protein at the apical membrane.
  • Class I mutation(s) refers to p.Gly542X (G542X), W1282X, c.489+1G>T (621+1G>T), or c.579+1G>T
  • Class I mutation(s) refers to G542X; or W1282X mutations.
  • Class II mutation(s) refers to mutations which affect protein maturation. These lead to the production of a CFTR protein that cannot be correctly folded and/or trafficked to its site of function on the apical membrane.
  • Class II mutation(s) refers to p.Phe508del (F508del), p.Ile507del, or p.Asn1303Lys (N1303K) mutations. More particularly, Class II mutation(s) refers to F508del or N1303K mutations. 17 ABV12212USO1
  • “Class III mutation(s)” refers to mutations which alter the regulation of the CFTR channel.
  • Class III mutation(s) refers to p.Gly551Asp (G551D), G551S, R553G; G1349D; S1251N, G178R, S549N mutations. More particularly, Class III mutation(s) refers to G551D, R553G, G1349D, S1251N, G178R, or S549N mutations.
  • Class IV mutation(s) refers to mutations which affect chloride conductance.
  • the CFTR protein is correctly trafficked to the cell membrane but generates reduced chloride flow or a“gating defect” (most are missense mutations located within the membrane-spanning domain).
  • Class IV mutation(s) refers to p.Arg117His
  • Class V mutation(s) refers to mutations which reduce the level of normally functioning CFTR at the apical membrane or result in a“conductance defect” (for example partially aberrant splicing mutations or inefficient trafficking missense mutations).
  • Class V mutation(s) refers to c.1210-12T[5] (5T allele), c.S3140-26A>G (3272- 26A>G), c.3850-2477C>T (3849+10kbC>T) mutations.
  • Class VI mutation(s) refers to mutations which decrease the stability of the CFTR which is present or which affect the regulation of other channels, resulting in inherent instability of the CFTR protein. In effect, although functional, the CFTR protein is unstable at the cell surface and it is rapidly removed and degraded by cell machinery.
  • Class VI mutation(s) refers to Rescued F508del, 120del23, N287Y, 4326dellTC, or 4279insA mutations. More particularly, Class VI mutation(s) refers to Rescued F508del mutations.
  • phenoxy optionally substituted with one or more independently selected R 5 groups; or phenyl optionally substituted with one or more independently selected R 5 groups;
  • 4-6 membered monocyclic heterocycle comprising 1 or 2 heteroatoms independently selected from the group consisting of O, S, and N;
  • N-linked 4-6 membered monocyclic heterocycle comprising 1, 2, or 3 heteroatoms
  • N-linked 4-6 membered monocyclic heterocycle comprising 1, 2, or 3 heteroatoms
  • 4-6 membered monocyclic heterocycle comprising 1 or 2 heteroatoms independently selected from the group consisting of N, O, and S, wherein the monocyclic heterocycle is optionally substituted with one or more independently selected R 5 groups;
  • C 1-4 alkyl optionally substituted with one or more independently selected -OH, halo, or C 1-4 alkoxy;
  • 4-6 membered monocyclic heterocycle comprising 1 or 2 heteroatoms independently selected from the group consisting of N, O, and S, wherein the monocyclic heterocycle is optionally substituted with one or more independently selected -OH;
  • C 1-4 alkyl optionally substituted with one or more independently selected halo; 5-6 membered monocyclic heteroaryl comprising 1, 2, or 3 heteroatoms independently selected from the group consisting of O, S, and N, wherein the monocyclic heteroaryl is optionally substituted with one or more independently selected R 5 groups; or
  • C 1-4 alkyl optionally substituted with one or more independently selected halo or–OH; or C 1-4 alkoxy optionally substituted with one or more independently selected halo;
  • 4-6 membered monocyclic heterocycle comprising 1 or 2 heteroatoms independently selected from the group consisting of O, S, and N, wherein the monocyclic heterocycle is optionally substituted with one or more
  • 4-6 membered monocyclic heterocycle comprising 1 or 2 heteroatoms independently selected from the group consisting of O, S, and N, fused to a phenyl ring, wherein the monocyclic heterocycle and the phenyl are optionally substituted with one or more independently selected R 5 groups;
  • 5-11 membered spirocyclic heterocycle comprising 1 or 2 heteroatoms independently selected from the group consisting of O, S, and N, wherein the spirocyclic heterocycle is optionally substituted with one or more independently selected R 5 groups; 5-6 membered monocyclic heteroaryl comprising 1, 2, or 3 heteroatoms independently
  • azetidine or a pyrrolidine ring wherein the azetidine and the pyrrolidine are optionally substituted with one or more independently selected R 9 groups;
  • a 7-11 membered spirocyclic heterocycle comprising one or more heteroatoms independently selected from the group consisting of N, O, and S; wherein the spirocyclic heterocycle is optionally substituted with one or more independently selected R 5 groups; each R 4 is independently selected from the group consisting of:
  • ABV12212USO1 C 1-4 alkyl optionally substituted with one or more independently selected halo;
  • each R 5 is independently selected from the group consisting of:
  • R 6 is H, C 1-4 alkyl, or C 3-7 cycloalkyl wherein the C 3-7 cycloalkyl is optionally substituted with one or more independently selected R 5 groups;
  • C 1-4 alkyl optionally substituted with one or more independently selected halo; or C 1-4 alkoxy optionally substituted with one or more independently selected halo; C 1-4 alkoxy optionally substituted with one or more independently selected halo; or 4-6 membered monocyclic heterocycle comprising 1 or 2 heteroatoms independently selected from the group consisting of O, S, and N; wherein the monocyclic heterocycle is optionally substituted with one or more independently selected R 5 groups;
  • each R 8a and R 8b is independently selected from the group consisting of
  • each R 9 is independently selected from the group consisting of:
  • each R 10a and R 10b is independently selected from the group consisting of H and C 1-4 alkyl;
  • each R 11a and R 11b is independently selected from the group consisting of
  • R 12a and R 12b are independently selected from the group consisting of
  • R 13 is independently C 1-4 alkyl optionally substituted with one or more independently selected –OH;
  • R 1 is 23 ABV12212USO1 phenyl optionally substituted with one or more independently selected R 4 groups;
  • N-linked 4-6 membered monocyclic heterocycle comprising 1, 2, or 3 heteroatoms
  • N-linked 4-6 membered monocyclic heterocycle comprising 1, 2, or 3 heteroatoms
  • C 1-4 alkyl optionally substituted with one or more independently selected -OH, halo, or C 1-4 alkoxy
  • 24 ABV12212USO1 4-6 membered monocyclic heterocycle comprising 1 or 2 heteroatoms independently selected from the group consisting of N, O, and S, wherein the monocyclic heterocycle is optionally substituted with one or more independently selected -OH;
  • C 1-4 alkyl optionally substituted with one or more independently selected halo; 5-6 membered monocyclic heteroaryl comprising 1, 2, or 3 heteroatoms independently selected from the group consisting of O, S, and N, wherein the monocyclic heteroaryl is optionally substituted with one or more independently selected R 5 groups; or
  • 4-6 membered monocyclic heterocycle comprising 1 or 2 heteroatoms independently selected from the group consisting of O, S, and N, wherein the monocyclic heterocycle is optionally substituted with one or more
  • 4-6 membered monocyclic heterocycle comprising 1 or 2 heteroatoms independently selected from the group consisting of O, S, and N, fused to a phenyl ring, wherein the monocyclic heterocycle and the phenyl are optionally substituted with one or more independently selected R 5 groups; or
  • ABV12212USO1 5-11 membered spirocyclic heterocycle comprising 1 or 2 heteroatoms independently selected from the group consisting of O, S, and N, wherein the spirocyclic heterocycle is optionally substituted with one or more independently selected R 5 groups; and R 3 is H; or
  • azetidine or a pyrrolidine ring wherein the azetidine and the pyrrolidine are optionally substituted with one or more independently selected R 9 groups;
  • a 7-11 membered spirocyclic heterocycle comprising one or more heteroatoms independently selected from the group consisting of N, O, and S; wherein the spirocyclic heterocycle is optionally substituted with one or more independently selected R 5 groups; each R 4 is independently selected from the group consisting of :
  • each R 5 is independently selected from the group consisting of:
  • R 6 is H, C 1-4 alkyl, or C 3-7 cycloalkyl wherein the C 3-7 cycloalkyl is optionally substituted with one or more independently selected R 5 groups;
  • C 1-4 alkyl optionally substituted with one or more independently selected halo; or C 1-4 alkoxy optionally substituted with one or more independently selected halo; C 1-4 alkoxy optionally substituted with one or more independently selected halo; or 4-6 membered monocyclic heterocycle comprising 1 or 2 heteroatoms independently selected from the group consisting of O, S and N; wherein the monocyclic
  • ABV12212USO1 heterocycle is optionally substituted with one or more independently selected R 5 groups;
  • R 8a and R 8b are independently selected from the group consisting of
  • each R 9 is independently selected from the group consisting of:
  • 4-6 membered monocyclic heterocycle comprising 1 or 2 heteroatoms independently selected from the group consisting of O, S, and N, wherein the monocyclic heterocycle is optionally substituted with one or more independently selected R 5 groups; and R 10a and R 10b are independently selected from the group consisting of H and C 1-4 alkyl.
  • R 1 is phenyl optionally substituted with one or more independently selected R 4 groups.
  • R 1 is phenyl optionally substituted with one, two, or three independently selected R 4 groups.
  • R 1 is phenyl which is unsubstituted.
  • R 1 is phenyl substituted with one or two independently selected R 4 groups.
  • R 1 is phenyl substituted with one R 4 group.
  • each R 4 is independently selected from the group consisting of fluoro, C 1-4 alkyl optionally substituted with 1, 2, or 3 fluoro; and C 1-4 alkoxy optionally substituted with 1, 2, or 3 fluoro.
  • each R 4 is independently selected from the group consisting of C 1-4 alkyl optionally substituted with 1, 2, or 3 fluoro; and C 1-4 alkoxy optionally substituted with 1, 2, or 3 fluoro.
  • R 4 are F, CH 3 , -CH(CH 3 ) 2 , t-Bu, CF 3 , -OCH 3 ,–OCH(CH 3 ) 2 , and -OCF 3 .
  • Particular examples of R 4 are F, CF 3 , and -OCF 3 .
  • R 4 is F.
  • R 4 is CF 3 .
  • R 4 is -OCF 3 .
  • R 4A is H, F, CH 3 , -CH(CH 3 ) 2 , t-Bu, CF 3 , -OCH 3 , -O-CH(CH 3 ) 2 , or -OCF 3
  • R 4B is F or–OCF 3
  • X, R 2 , and R 3 are as defined in the Summary and embodiments herein below.
  • R 4A is H, F, CH 3 , -CH(CH 3 ) 2 , t-Bu, CF 3 , -OCH 3 , -O-CH(CH 3 ) 2 , or -OCF 3
  • each R 4B is independently F or–OCF 3
  • X, R 2 , and R 3 are as defined in the Summary and embodiments herein below.
  • n is 0 or 1. In certain embodiments, n is 0. In certain embodiments, n is 1.
  • R 4A is H, -CH(CH 3 ) 2 , -O-CH(CH 3 ) 2 , t-Bu, CH 3 , -OCH 3 , F, CF 3 , or -OCF 3 .
  • R 4A is H, F, CF 3 , or -OCF 3 .
  • R 4A is F, CF 3 , or -OCF 3 .
  • 28 ABV12212USO1 In certain embodiments of Formula I-a, n is 0 or 1, R 4A is F, CF 3 or -OCF 3 , and R 4B is F.
  • R 4A is F.
  • n is 0 and R 4A is F.
  • n is 0 and R 4A is H.
  • R 1 is N-linked 4-6 membered monocyclic heterocycle comprising 1, 2, or 3 heteroatoms independently selected from the group consisting of N, O, and S, wherein the monocyclic heterocycle is optionally substituted with 1, 2, or 3 independently selected R 5 groups.
  • R 1 is N-linked 4-6 membered monocyclic heterocycle comprising 1 or 2 heteroatoms independently selected from the group consisting of N and O, wherein the monocyclic heterocycle is optionally substituted with 1, 2, or 3
  • each R 5 is independently selected from the group consisting of F, CH 3 , t-Bu, CF 3 , -OCH 3 , and -OCF 3 . In some such embodiments, each R 5 is independently selected from the group consisting of F, CH 3 , t-Bu, CF 3 , -OCH 3 , -CH 2 OH, and -OCF 3 .
  • R 1 is azetidinyl, pyrrolidinyl, morpholinyl, or piperidinyl, each of which is optionally substituted with 1 or 2 independently selected R 5 groups.
  • each R 5 is independently selected from the group consisting of F, CH 3 , t-Bu, CF 3 , -OCH 3 , and -OCF 3 .
  • R 1 is piperidinyl, which is optionally substituted with 1 or 2 independently selected R 5 groups.
  • each R 5 is
  • R 1 is piperidinyl substituted with two fluoro groups. In some such embodiments, R 1 is piperidinyl substituted with one fluoro group. In some such embodiments, R 1 is piperidinyl substituted with one methyl group. In some such embodiments, R 1 is piperidinyl substituted with two methyl groups. In some such embodiments, R 1 is piperidinyl substituted with one CF 3 , group. In some such embodiments, R 1 is piperidinyl substituted with one–OCH 3 , group. In some such embodiments, R 1 is piperidinyl substituted with one–OCF 3 , group. In some such embodiments, R 1 is piperidinyl substituted with one t-Bu group.
  • R 1 is N-linked 4-6 membered monocyclic heterocycle comprising 1, 2, or 3 heteroatoms independently selected from the group consisting 29 ABV12212USO1 of N, O, and S, fused to a phenyl, wherein the monocyclic heterocycle and the phenyl are optionally substituted with 1, 2, or 3 independently selected R 5 groups.
  • monocyclic heterocycle and the phenyl are optionally substituted with 1, 2, or 3 independently selected R 5 groups.
  • R 1 is 3,4-dihydro-2H-benzo[b][1,4]oxazinyl, optionally substituted with 1, 2, or 3 independently selected R 5 groups. In some such embodiments, R 1 is unsubstituted 3,4-dihydro- 2H-benzo[b][1,4]oxazinyl.
  • R 1 is C 1-4 alkyl optionally substituted with one or more independently selected–OH, C 1-4 alkoxy, or 4-6 membered monocyclic heterocycle comprising 1 or 2 heteroatoms independently selected from the group consisting of O, S, and N.
  • R 1 is C 1-4 alkyl which is unsubstituted.
  • R 1 is C 1-4 alkyl which is substituted with–OH.
  • R 1 is C 1-4 alkyl which is substituted with C 1-4 alkoxy.
  • R 1 is C 1-4 alkyl which is substituted with4-6 membered monocyclic heterocycle comprising 1 or 2 heteroatoms independently selected from the group consisting of O, S, and N.
  • R 1 is CH 2 CH 3 .
  • R 1 is CH 2 CH 2 OH.
  • R 1 is -CH(CH 3 ) 2 .
  • R 1 is CH 2 CH 2 OCH 3 .
  • R 1 is C 1 alkyl substituted with tetrahydrofuran.
  • R 1 is C 3-7 cycloalkyl optionally substituted with one or more independently selected R 5 groups.
  • R 1 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • R 1 is cyclopentyl.
  • R 1 is -NR 6 R 7 .
  • R 1 is -NR 6 R 7 ;
  • R 6 is H, CH 3 , or cyclopropyl; wherein the cyclopropyl is optionally substituted with 1 or 2 independently selected R 5 groups; and
  • R 1 is -NR 6 R 7 ;
  • R 6 is H, CH 3 , cyclobutyl or cyclopropyl; wherein the cyclobutyl and cyclopropyl are optionally substituted with 1 or 2 independently selected R 5 groups; and R 7 is
  • R 7 is C 1-4 alkyl substituted with one phenyl wherein the phenyl is optionally substituted with 1, 2, or 3 independently selected CF 3 , fluoro, or C 1-4 alkoxy.
  • X is H; halo; C 1-4 alkyl optionally substituted with one or more independently selected halo; C 1-4 alkoxy optionally substituted with one or more independently selected–OH, C 1-4 alkoxy, or–NR 11A R 11B ; -NR 12A R 12B ; optionally substituted cyclopropyl; optionally substituted phenoxy; or optionally substituted phenyl.
  • X is H, halo, optionally substituted cyclopropyl, or optionally substituted phenyl. 31 ABV12212USO1 [0097] In certain embodiments of Formula I, X is H, halo, or unsubstituted cyclopropyl.
  • X is H.
  • X is bromo, -NR 12A R 12B , alkoxy, cyclopropyl, phenoxy, or phenyl; wherein the cyclopropyl, phenoxy, and phenyl are optionally substituted with 1, 2, or 3 independently selected R 5 groups, and the C 1-4 alkoxy is optionally substituted with one or more independently selected–OH, C 1-4 alkoxy, or–NR 11A R 11B .
  • the cyclopropyl is unsubstituted.
  • the phenyl and phenoxy are substituted with F.
  • X is bromo, cyclopropyl, or phenyl; wherein the cyclopropyl and the phenyl are optionally substituted with 1, 2, or 3 independently selected R 5 groups.
  • the cyclopropyl is unsubstituted.
  • X is bromo
  • X is cyclopropyl, or phenyl; wherein the cyclopropyl and the phenyl are optionally substituted with 1, 2, or 3 independently selected R 5 groups. In some such embodiments, the cyclopropyl is unsubstituted.
  • X is cyclopropyl, phenoxy, or phenyl; wherein the cyclopropyl, phenoxy, and phenyl are optionally substituted with 1, 2, or 3 independently selected R 5 groups.
  • the cyclopropyl is unsubstituted.
  • X is unsubstituted cyclopropyl or phenyl substituted with one fluoro.
  • X is unsubstituted cyclopropyl, phenyl substituted with one fluoro, or phenoxy substituted with one fluoro.
  • X is unsubstituted cyclopropyl.
  • X is phenyl substituted with one fluoro.
  • X is phenoxy substituted with one fluoro.
  • X is C 1-4 alkoxy optionally substituted with one or more independently selected–OH, C 1-4 alkoxy, or–NR 11A R 11B .
  • R 11A and R 11B are H or C 1-4 alkyl.
  • R 11A and R 11B are both CH 3 .
  • X is C 1-4 alkoxy which is unsubstituted. In some such embodiments of Formula I, X is -OCH 3 . 32 ABV12212USO1 [00111] In certain embodiments of Formula I, X is C 1-4 alkoxy which is substituted with C 1-4 alkoxy. In some such embodiments of Formula I, X is -OCH 2 CH 2 OCH 3 .
  • X is C 1-4 alkoxy which is substituted with– NR 11A R 11B .
  • R 11A and R 11B are H or C 1-4 alkyl.
  • R 11A and R 11B are both CH 3 .
  • X is -NR 12A R 12B .
  • R 12A and R 12B are H, C 1-4 alkyl, or C 3-7 cycloalkyl.
  • R 12A and R 12B are both CH 3 .
  • R 12A is H and R 12B is cyclopropyl.
  • R 2 and R 3 are H.
  • R 2 is C 1-6 alkyl optionally substituted with 1, 2, or 3 independently selected
  • 4-6 membered monocyclic heterocycle comprising 1 or 2 heteroatoms independently selected from the group consisting of N, O, and S, wherein the monocyclic heterocycle is optionally substituted with 1, 2, or 3 independently selected -OH;
  • ABV12212USO1 phenyl optionally substituted with 1, 2, or 3 independently selected R 5 groups.
  • R 2 is C 1-6 alkyl optionally substituted with one or more independently selected
  • C 1-4 alkyl optionally substituted with one or more independently selected -OH, fluoro, or C 1-4 alkoxy;
  • 4-6 membered monocyclic heterocycle comprising 1 or 2 heteroatoms independently selected from the group consisting of N, O, and S, wherein the monocyclic heterocycle is optionally substituted with one or more independently selected -OH;
  • ABV12212USO1 5-6 membered monocyclic heteroaryl comprising 1, 2, or 3 heteroatoms independently selected from the group consisting of O, S, and N, wherein the monocyclic heteroaryl is optionally substituted with one or more independently selected R 5 groups; or
  • phenyl optionally substituted with one or more independently selected R 5 groups.
  • R 2 is C 3-6 alkyl substituted with one or two–OH, and optionally further substituted with 1, 2, or 3 fluoro; or optionally further substituted with one C 1-4 alkoxy optionally substituted with
  • R 2 is C 2-6 alkyl substituted with one or two–OH, and optionally further substituted with 1, 2, or 3 fluoro; or optionally further substituted with one C 1-4 alkoxy optionally substituted with
  • R 2 is C 3-6 alkyl substituted with one–OH, and optionally further substituted with 1, 2, or 3 fluoro or optionally further substituted with one C 1-4 alkoxy wherein the C 1-4 alkoxy is optionally substituted with one cyclopropyl or 1, 2, or 3 fluoro.
  • the optional substituents are independently selected from the group consisting of CF 3 , -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH(CH 3 ) 2 , -OC(CH 3 ) 3 , -OCH(CH 3 ) 2 , -OCH 2 CF 3 , and–OCH 2 -cyclopropyl.
  • the optional substituents are independently selected from the group consisting of F, -OCH 3 , -OCH 2 CH 3 ,
  • R 2 is C 3-6 alkyl substituted with one–OH, and optionally further substituted with 1, 2, or 3 fluoro or optionally further substituted with one C 1-4 alkoxy wherein the C 1-4 alkoxy is optionally substituted with 1, 2, or 3 fluoro.
  • 35 ABV12212USO1 In certain embodiments, R 2 is C 3-5 alkyl substituted with one–OH, and optionally further substituted with 1, 2, or 3 fluoro.
  • R 2 is C 3-4 alkyl substituted with one–OH and 3 fluoro.
  • R 2 is C 3-5 alkyl substituted with one -OH.
  • R 2 is C 4-5 alkyl substituted with one -OH.
  • R 2 is C 3 alkyl substituted with one -OH.
  • R 2 is
  • R A is H or CH 3 .
  • R B , R C , and R D are H;
  • R B , R C , and R D are fluoro;
  • R B and R C are H, and R D is C 1-4 alkoxy, -OCH 2 -cyclopropyl, or -OCH 2 CF 3 .
  • R A is H.
  • R A is H, and R B , R C , and R D are fluoro; or R B and R C are H, and R D is–OCH 3 , -OCH 2 CH 3 , -OCH(CH 3 ) 2 ,–OC(CH 3 ) 3 , -OCH 2 -cyclopropyl, or -OCH 2 CF 3 .
  • R A is H, and R B , R C , and R D are fluoro; or R B and R C are H, and R D is -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 OCH 2 CH 3 ,
  • R A is H
  • R B , R C , and R D are fluoro
  • R A is H
  • R B and R C are H
  • R D is–OCH 3 , -OCH 2 CH 3 , -OCH(CH 3 ) 2 ,–OC(CH 3 ) 3 , -OCH 2 -cyclopropyl, or -OCH 2 CF 3 .
  • R A is H
  • R B and R C are H
  • R D is -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 OCH 2 CH 3 , -OCH 2 CH 2 OCH 3 , -OCH 2 CH(CH 3 ) 2 , -OC(CH 3 ) 3 ,
  • R 2 is C 1-6 alkyl substituted with one substituent wherein the substituent is:
  • C 1-4 alkyl optionally substituted with 1, 2, or 3 independently selected -OH, fluoro, or C 1-4 alkoxy;
  • 4-6 membered monocyclic heterocycle comprising 1 or 2 heteroatoms independently selected from the group consisting of N, O, and S, wherein the monocyclic heterocycle is optionally substituted with 1, 2, or 3 independently selected -OH;
  • 5-6 membered monocyclic heteroaryl comprising 1, 2, or 3 heteroatoms independently selected from the group consisting of O, S, and N, wherein the monocyclic heteroaryl is optionally substituted with 1, 2, or 3 independently selected R 5 groups.
  • R 2 is C 1-6 alkyl substituted with one
  • R 8a and R 8b are independently selected from the group consisting of H; C 1-4 alkyl; and cyclopropyl.
  • R 2 is C 1-4 alkyl substituted with one C 3-5 cycloalkyl which is optionally substituted with 1, 2, or 3 independently selected–OH; fluoro; C 1-4 alkoxy optionally substituted with 1, 2, or 3 fluoro; or C 1-4 alkyl optionally substituted with 1, 2, or 3 independently selected -OH, fluoro, or C 1-4 alkoxy.
  • R 2 is -CH 2 -cyclopropyl wherein the cyclopropyl is optionally substituted with one–OH.
  • R 2 is -CH 2 -cyclopropyl wherein the cyclopropyl is optionally substituted with 1, 2, or 37 ABV12212USO1 3 independently selected -OH, fluoro, -CH 2 OH, or C 1-4 alkoxy.
  • R 2 is -CH 2 -cyclobutyl wherein the cyclobutyl is optionally substituted with 1, 2, or 3 independently selected fluoro,-OH, CH 2 OH, or CH 2 OCH 2 CH 3 .
  • R 2 is -CH 2 CH 2 -cyclopropyl wherein the cyclopropyl is optionally substituted with CH 3 .
  • R 2 is C 1-4 alkyl substituted with one 4-6 membered monocyclic heterocycle comprising 1 or 2 heteroatoms independently selected from the group consisting of N and O, wherein the monocyclic heterocycle is optionally substituted.
  • the monocyclic heterocycle is tetrahydrofuranyl, 1,3-dioxolanyl,
  • the monocyclic heterocycle is tetrahydrofuranyl.
  • the monocyclic heterocycles, including the exemplary rings are optionally substituted with 1, 2, or 3 independently selected -OH; fluoro; C 1-4 alkoxy optionally substituted with 1, 2, or 3 fluoro; or C 1-4 alkyl optionally substituted with 1, 2, or 3 fluoro.
  • R 2 is C 1-4 alkyl substituted with one 5-6 membered monocyclic heteroaryl comprising 1, 2, or 3 heteroatoms independently selected from the group consisting of O, S, and N, wherein the monocyclic heteroaryl is optionally substituted with 1, 2, or 3 independently selected R 5 groups.
  • the monocyclic heteroaryl is furanyl, optionally substituted with 1, 2, or 3 independently selected R 5 groups.
  • the monocyclic heteroaryl is furanyl or pyrimidinyl, wherein the furanyl and pyrimidinyl are optionally substituted with 1, 2, or 3 independently selected R 5 groups.
  • R 2 is C 3-6 cycloalkyl optionally substituted with 1, 2, or 3 independently selected–OH; fluoro; C 1-4 alkyl optionally substituted with 1, 2, or 3 fluoro; or C 1-4 alkoxy optionally substituted with 1, 2, or 3 fluoro.
  • R 2 is cyclobutyl, cyclopentyl, or cyclohexyl, each of which is optionally substituted.
  • the C 3-6 cycloalkyl, including the exemplary rings are optionally substituted with 1 or 2 independently selected fluoro, CH 3 , CF 3 , -OH, or -OCH 3 .
  • the C 3-6 cycloalkyl, including the exemplary rings are substituted with one–OH.
  • R 2 is C 3-6 cycloalkyl optionally substituted with 1, 2, or 3 independently selected -OH; fluoro; C 1-4 alkyl optionally substituted with -OH or 1, 2, or 38 ABV12212USO1 3 fluoro; or C 1-4 alkoxy optionally substituted with 1, 2, or 3 fluoro.
  • R 2 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of which is optionally substituted.
  • the C 3-6 cycloalkyl, including the exemplary rings are optionally substituted with 1 or 2 substituents independently selected fluoro, CH 2 OH, CH 3 , CF 3 , -OH, or -OCH 3 .
  • the C 3-6 cycloalkyl, including the exemplary rings are substituted with one -OH.
  • R 2 is 4-6 membered monocyclic heterocycle comprising 1 or 2 heteroatoms independently selected from the group consisting of O, S, and N, wherein the monocyclic heterocycle is optionally substituted with 1, 2, or 3 independently selected–OH; fluoro; C 1-4 alkyl optionally substituted with 1, 2, or 3 fluoro; or C 1-4 alkoxy optionally substituted with 1, 2, or 3 fluoro.
  • R 2 is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, or piperidinyl; each of which is optionally
  • R 2 is optionally substituted tetrahydrofuranyl or tetrahydropyranyl.
  • the monocyclic ring, including the exemplary rings are optionally substituted with 1 or 2 independently selected fluoro, CH 3 , CF 3 , -OH, or -OCH 3 .
  • the monocyclic rings, including the exemplary rings are substituted with one -OH.
  • R 2 is 4-6 membered monocyclic heterocycle comprising 1 or 2 heteroatoms independently selected from the group consisting of O, S, and N, fused to a phenyl ring, wherein the monocyclic heterocycle and the phenyl are optionally substituted with 1, 2, or 3 independently selected R 5 groups.
  • R 2 is optionally substituted chromanyl.
  • R 2 is 5-11 membered spirocyclic heterocycle comprising 1 or 2 heteroatoms independently selected from the group consisting of O, S, and N, wherein the spirocyclic heterocycle is optionally substituted with 1, 2, or 3 independently selected R 5 groups.
  • R 2 is optionally substituted 1-oxaspiro[4.4]non-3-yl or optionally substituted 1-oxaspiro[4.5]decan-3-yl.
  • R 2 and R 3 together with the nitrogen atom to which they are attached form an azetidine or a pyrrolidine ring, wherein the azetidine and the pyrrolidine are optionally substituted with 1, 2, or 3 independently selected R 9 groups.
  • R 2 and R 3 together with the nitrogen atom to which they are attached form an azetidine ring which is optionally substituted with 1, 2, or 3 independently selected R 9 groups.
  • R 2 and R 3 together with the nitrogen atom to which they are attached form an azetidine ring which is substituted with 1 or 2 R 9 groups; and each R 9 is independently selected from the group consisting of–OH, fluoro, -CN, CF 3 , optionally substituted cyclopropyl, C 1 - 4 alkyl optionally substituted with one–OH or one C 1-4 alkoxy; and C 1-4 alkoxy optionally substituted with 1, 2, or 3 fluoro.
  • R 2 and R 3 together with the nitrogen atom to which they are attached form an azetidine ring which is substituted with 1 or 2 R 9 groups; and each R 9 is independently selected from the group consisting of–OH, fluoro, -CN, CF 3 , unsubstituted cyclopropyl, CH 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 , -C(CH 3 ) 2 OH, -CH 2 OH, -CH 2 OCH 3 ,–OCH 3 , -OCHF 2 , and–OCH 2 CHF 2 .
  • R 2 and R 3 together with the nitrogen atom to which they are attached form an azetidine ring which is substituted with one–OH, and optionally further substituted with one substituent selected from the group consisting of fluoro, -CH 3 , -CH(CH 3 ) 2 , CF 3 , and unsubstituted cyclopropyl.
  • R 2 and R 3 together with the nitrogen atom to which they are attached form a pyrrolidine ring which is optionally substituted with 1, 2, or 3 independently selected R 9 groups.
  • each R 9 is independently selected from the group consisting of–OH, fluoro, CF 3 , optionally substituted cyclopropyl, C 1 - 4 alkyl optionally substituted with one–OH or one C 1-4 alkoxy; and C 1-4 alkoxy optionally substituted with 1, 2, or 3 fluoro.
  • each R 9 is independently selected from the group consisting of–OH, fluoro, and C 1-4 alkyl optionally substituted with one–OH.
  • each R 9 is independently selected from the group consisting of -OH, fluoro, CF 3 , optionally substituted cyclopropyl, C 1 - 4 alkyl optionally substituted with one -OH or one C 1-4 alkoxy; C 1-4 alkoxy optionally substituted with 1, 2, or 3 fluoro; or 4-6 membered monocyclic heterocycle comprising 1 or 2 heteroatoms independently selected from the group consisting of O, S, and N, wherein the monocyclic heterocycle is optionally substituted with one or more independently selected R 5 groups.
  • each R 9 is independently selected from the group consisting of -OH, fluoro, C 1-4 alkyl optionally substituted with one -OH; and morpholinyl.
  • R 2 and R 3 together with the nitrogen atom to which they are attached form a 7-11 membered spirocyclic heterocycle comprising 1 or 2 heteroatoms independently selected from the group consisting of N and O; wherein the spirocyclic
  • heterocycle is optionally substituted with 1, 2, or 3 independently selected R 5 groups.
  • R 2 and R 3 together with the nitrogen atom to which they are attached, is 2- oxa-6-azaspiro[3.3]heptyl, 6-oxa-2-azaspiro[3.4]octyl, or 6-oxa-2-azaspiro[3.5]nonyl; each of which is optionally substituted with 1, 2, or 3 independently selected R 5 groups.
  • R 1 is phenyl optionally substituted with one, two, or three independently selected R 4 groups;
  • R 2 is C 1-6 alkyl optionally substituted with 1, 2, or 3 independently selected
  • 4-6 membered monocyclic heterocycle comprising 1 or 2 heteroatoms independently selected from the group consisting of N, O, and S, wherein the monocyclic heterocycle is optionally substituted with 1, 2, or 3 independently selected -OH;
  • phenyl optionally substituted with 1, 2, or 3 independently selected R 5 groups.
  • the invention is directed to compounds of Formula I wherein
  • R 1 is phenyl optionally substituted with one, two, or three independently selected R 4 groups;
  • R 2 is C 3-6 alkyl substituted with one or two–OH, and optionally further substituted with 1, 2, or 3 fluoro; or optionally further substituted with one C 1-4 alkoxy which is optionally substituted with
  • the invention is directed to compounds of Formula I wherein
  • R 1 is phenyl optionally substituted with one, two, or three independently selected R 4 groups;
  • R 2 is C 1-6 alkyl substituted with one substituent wherein the substituent is
  • C 1-4 alkyl optionally substituted with 1, 2, or 3 independently selected -OH, fluoro, or C 1-4 alkoxy;
  • 4-6 membered monocyclic heterocycle comprising 1 or 2 heteroatoms independently selected from the group consisting of N, O, and S, wherein the monocyclic heterocycle is optionally substituted with 1, 2, or 3 independently selected -OH;
  • 5-6 membered monocyclic heteroaryl comprising 1, 2, or 3 heteroatoms independently selected from the group consisting of O, S, and N, wherein the monocyclic heteroaryl is optionally substituted with 1, 2, or 3 independently selected R 5 groups.
  • the invention is directed to compounds of Formula I wherein
  • R 1 is phenyl optionally substituted with one, two, or three independently selected R 4 groups;
  • ABV12212USO1 R 2 is C 3-6 cycloalkyl optionally substituted with 1, 2, or 3 independently selected–OH; fluoro;
  • C 1-4 alkyl optionally substituted with 1, 2, or 3 fluoro; or C 1-4 alkoxy optionally substituted with 1, 2, or 3 fluoro.
  • the invention is directed to compounds of Formula I wherein
  • R 1 is phenyl optionally substituted with one, two, or three independently selected R 4 groups;
  • R 2 is 4-6 membered monocyclic heterocycle comprising 1 or 2 heteroatoms independently selected from the group consisting of O, S, and N, wherein the monocyclic heterocycle is optionally substituted with 1, 2, or 3 independently selected–OH; fluoro; C 1-4 alkyl optionally substituted with 1, 2, or 3 fluoro; or C 1-4 alkoxy optionally substituted with 1, 2, or 3 fluoro.
  • the invention is directed to compounds of Formula I wherein
  • R 1 is phenyl optionally substituted with one, two, or three independently selected R 4 groups;
  • R 2 and R 3 together with the nitrogen atom to which they are attached form an azetidine or a pyrrolidine ring, wherein the azetidine and the pyrrolidine are optionally substituted with 1, 2, or 3 independently selected R 9 groups.
  • the invention is directed to compounds of Formula I wherein
  • R 1 is N-linked 4-6 membered monocyclic heterocycle comprising 1, 2, or 3 heteroatoms
  • R 2 is C 3-6 alkyl substituted with one–OH and optionally further substituted with 1, 2, or 3 fluoro; or optionally further substituted with one C 1-4 alkoxy wherein the C 1-4 alkoxy is optionally substituted with 1, 2, or 3 fluoro.
  • the invention is directed to compounds of Formula I wherein
  • R 1 is -NR 6 R 7 ;
  • R 2 is C 3-6 alkyl substituted with one–OH and optionally further substituted with 1, 2, or 3 fluoro; or optionally further substituted with one C 1-4 alkoxy wherein the C 1-4 alkoxy is optionally substituted with 1, 2, or 3 fluoro.
  • the invention is directed to compounds of Formula I-a wherein X is H; 44 ABV12212USO1 n is 0, 1, or 2;
  • R 4A is H, F, CH 3 , -CH(CH 3 ) 2 , t-Bu, CF 3 , -OCH 3 , -O-CH(CH 3 ) 2 , or -OCF 3 ;
  • R 4B is F or–OCF 3 .
  • the invention is directed to compounds of Formula I-a wherein X is H;
  • n 0, 1, or 2;
  • R 4A is H, F, CH 3 , -CH(CH 3 ) 2 , t-Bu, CF 3 , -OCH 3 , -O-CH(CH 3 ) 2 , or -OCF 3 ;
  • each R 4B is independently F or -OCF 3 .
  • the invention is directed to compounds of Formula I-a wherein n is 0 or 1;
  • R 4A is F, CF 3 , or -OCF 3 ;
  • R 4B is F.
  • the invention is directed to compounds of Formula I-a wherein X is H;
  • n 0 or 1
  • R 4A is F, CF 3 , or -OCF 3 ;
  • R 4B is F.
  • the invention is directed to compounds of Formula I-a wherein X is cyclopropyl or phenyl, each optionally substituted with 1, 2, or 3 independently selected R 5 groups;
  • n 0 or 1
  • R 4A is F, CF 3 , or -OCF 3 ;
  • R 4B is F.
  • the invention is directed to compounds of Formula I-a wherein n is 0, 1, or 2;
  • R 4A is H, F, CH 3 , -CH(CH 3 ) 2 , t-Bu, CF 3 , -OCH 3 , -O-CH(CH 3 ) 2 , or -OCF 3 ;
  • R 4B is F or–OCF 3 ;
  • R 2 is C 3-6 alkyl substituted with one or two–OH, and optionally further substituted with 1, 2, or 3 fluoro; or optionally further substituted with one C 1-4 alkoxy which is optionally substituted with
  • the invention is directed to compounds of Formula I-a wherein n is 0, 1, or 2;
  • R 4A is H, F, CH 3 , -CH(CH 3 ) 2 , t-Bu, CF 3 , -OCH 3 , -O-CH(CH 3 ) 2 , or -OCF 3 ;
  • each R 4B is independently F or -OCF 3 ;
  • R 2 is C 3-6 alkyl substituted with one or two -OH, and optionally further substituted with 1, 2, or 3 fluoro; or optionally further substituted with one C 1-4 alkoxy which is optionally substituted with
  • the invention is directed to compounds of Formula I-a wherein X is H;
  • n 0, 1, or 2;
  • R 4A is H, F, CH 3 , -CH(CH 3 ) 2 , t-Bu, CF 3 , -OCH 3 , -O-CH(CH 3 ) 2 , or -OCF 3 ;
  • R 4B is F or–OCF 3 ;
  • R 2 is C 3-6 alkyl substituted with one or two–OH, and optionally further substituted with 1, 2, or 3 fluoro; or optionally further substituted with one C 1-4 alkoxy which is optionally substituted with
  • the invention is directed to compounds of Formula I-a wherein X is H;
  • n 0, 1, or 2;
  • R 4A is H, F, CH 3 , -CH(CH 3 ) 2 , t-Bu, CF 3 , -OCH 3 , -O-CH(CH 3 ) 2 , or -OCF 3 ;
  • each R 4B is independently F or -OCF 3 ; and 46 ABV12212USO1 R 2 is C 3-6 alkyl substituted with one or two -OH, and optionally further substituted with 1, 2, or 3 fluoro; or optionally further substituted with one C 1-4 alkoxy which is optionally substituted with
  • the invention is directed to compounds of Formula I-a wherein n is 0, 1, or 2;
  • R 4A is H, F, CH 3 , -CH(CH 3 ) 2 , t-Bu, CF 3 , -OCH 3 , -O-CH(CH 3 ) 2 , or -OCF 3 ;
  • R 4B is F or–OCF 3 ;
  • R 2 is C 3-6 alkyl substituted with one–OH, and optionally further substituted with 1, 2, or 3 fluoro or optionally further substituted with one C 1-4 alkoxy wherein the C 1-4 alkoxy is optionally substituted with one cyclopropyl or 1, 2, or 3 fluoro.
  • the invention is directed to compounds of Formula I-a wherein n is 0, 1, or 2;
  • R 4A is H, F, CH 3 , -CH(CH 3 ) 2 , t-Bu, CF 3 , -OCH 3 , -O-CH(CH 3 ) 2 , or -OCF 3 ;
  • each R 4B is independently F or–OCF 3 ;
  • R 2 is C 3-6 alkyl substituted with one -OH, and optionally further substituted with 1, 2, or 3 fluoro or optionally further substituted with one C 1-4 alkoxy wherein the C 1-4 alkoxy is optionally substituted with one cyclopropyl or 1, 2, or 3 fluoro.
  • the invention is directed to compounds of Formula I-a wherein X is H;
  • n 0, 1, or 2;
  • R 4A is H, F, CH 3 , -CH(CH 3 ) 2 , t-Bu, CF 3 , -OCH 3 , -O-CH(CH 3 ) 2 , or -OCF 3 ;
  • R 4B is F or–OCF 3 ;
  • R 2 is C 3-6 alkyl substituted with one–OH, and optionally further substituted with 1, 2, or 3 fluoro or optionally further substituted with one C 1-4 alkoxy wherein the C 1-4 alkoxy is optionally substituted with one cyclopropyl or 1, 2, or 3 fluoro.
  • the invention is directed to compounds of Formula I-a wherein X is H; 47 ABV12212USO1 n is 0, 1, or 2;
  • R 4A is H, F, CH 3 , -CH(CH 3 ) 2 , t-Bu, CF 3 , -OCH 3 , -O-CH(CH 3 ) 2 , or -OCF 3 ;
  • each R 4B is independently F or -OCF 3 ;
  • R 2 is C 3-6 alkyl substituted with one -OH, and optionally further substituted with 1, 2, or 3 fluoro or optionally further substituted with one C 1-4 alkoxy wherein the C 1-4 alkoxy is optionally substituted with one cyclopropyl or 1, 2, or 3 fluoro.
  • the invention is directed to compounds of Formula I-a wherein X is unsubstituted cyclopropyl;
  • n 0, 1, or 2;
  • R 4A is H, F, CH 3 , -CH(CH 3 ) 2 , t-Bu, CF 3 , -OCH 3 , -O-CH(CH 3 ) 2 , or -OCF 3 ;
  • R 4B is F or–OCF 3 ;
  • R 2 is C 3-6 alkyl substituted with one–OH, and optionally further substituted with 1, 2, or 3 fluoro.
  • the invention is directed to compounds of Formula I-a wherein X is unsubstituted cyclopropyl;
  • n 0, 1, or 2;
  • R 4A is H, F, CH 3 , -CH(CH 3 ) 2 , t-Bu, CF 3 , -OCH 3 , -O-CH(CH 3 ) 2 , or -OCF 3 ;
  • each R 4B is independently F or -OCF 3 ;
  • R 2 is C 3-6 alkyl substituted with one -OH, and optionally further substituted with 1, 2, or 3 fluoro.
  • the invention is directed to compounds of Formula I-a wherein X is phenyl substituted with one fluoro;
  • n 0, 1, or 2;
  • R 4A is H, F, CH 3 , -CH(CH 3 ) 2 , t-Bu, CF 3 , -OCH 3 , -O-CH(CH 3 ) 2 , or -OCF 3 ;
  • R 4B is F or–OCF 3 ;
  • R 2 is C 3-6 alkyl substituted with one–OH, and optionally further substituted with 1, 2, or 3 fluoro.
  • the invention is directed to compounds of Formula I-a wherein X is phenyl substituted with one fluoro;
  • n 0, 1, or 2;
  • R 4A is H, F, CH 3 , -CH(CH 3 ) 2 , t-Bu, CF 3 , -OCH 3 , -O-CH(CH 3 ) 2 , or -OCF 3 ; 48 ABV12212USO1 each R 4B is independently F or -OCF 3 ; and
  • R 2 is C 3-6 alkyl substituted with one -OH, and optionally further substituted with 1, 2, or 3 fluoro.
  • the invention is directed to compounds of Formula I-a wherein n is 0, 1, or 2;
  • R 4A is H, F, CH 3 , -CH(CH 3 ) 2 , t-Bu, CF 3 , -OCH 3 , -O-CH(CH 3 ) 2 , or -OCF 3 ;
  • R 4B is F or–OCF 3 ;
  • the invention is directed to compounds of Formula I-a wherein n is 0, 1, or 2;
  • R 4A is H, F, CH 3 , -CH(CH 3 ) 2 , t-Bu, CF 3 , -OCH 3 , -O-CH(CH 3 ) 2 , or -OCF 3 ;
  • each R 4B is independently F or -OCF 3 ;
  • the invention is directed to compounds of Formula I-a wherein X is H;
  • n 0, 1, or 2;
  • R 4A is H, F, CH 3 , -CH(CH 3 ) 2 , t-Bu, CF 3 , -OCH 3 , -O-CH(CH 3 ) 2 , or -OCF 3 ;
  • R 4B is F or–OCF 3 ;
  • the invention is directed to compounds of Formula I-a wherein X is H;
  • n 0, 1, or 2;
  • 49 ABV12212USO1 R 4A is H, F, CH 3 , -CH(CH 3 ) 2 , t-Bu, CF 3 , -OCH 3 , -O-CH(CH 3 ) 2 , or -OCF 3 ;
  • each R 4B is independently F or -OCF 3 ;
  • the invention is directed to compounds of Formula I-a wherein n is 0, 1, or 2;
  • R 4A is H, F, CH 3 , -CH(CH 3 ) 2 , t-Bu, CF 3 , -OCH 3 , -O-CH(CH 3 ) 2 , or -OCF 3 ;
  • R 4B is F or–OCF 3 ;
  • R 2 is C 3-6 cycloalkyl optionally substituted with 1 or 2 independently selected fluoro, CH 3 , CF 3 , -OH, or -OCH 3 .
  • the invention is directed to compounds of Formula I-a wherein n is 0, 1, or 2;
  • R 4A is H, F, CH 3 , -CH(CH 3 ) 2 , t-Bu, CF 3 , -OCH 3 , -O-CH(CH 3 ) 2 , or -OCF 3 ;
  • each R 4B is independently F or -OCF 3 ;
  • R 2 is C 3-6 cycloalkyl optionally substituted with 1 or 2 independently selected fluoro, CH 3 , CF 3 , -OH, or -OCH 3 .
  • the invention is directed to compounds of Formula I-a wherein n is 0, 1, or 2;
  • R 4A is H, F, CH 3 , -CH(CH 3 ) 2 , t-Bu, CF 3 , -OCH 3 , -O-CH(CH 3 ) 2 , or -OCF 3 ;
  • each R 4B is independently F or -OCF 3 ;
  • R 2 is C 3-6 cycloalkyl optionally substituted with 1 or 2 independently selected fluoro, CH 2 OH, CF 3 , -OH, or -OCH 3 .
  • the invention is directed to compounds of Formula I-a wherein X is H;
  • n 0, 1, or 2;
  • R 4A is H, F, CH 3 , -CH(CH 3 ) 2 , t-Bu, CF 3 , -OCH 3 , -O-CH(CH 3 ) 2 , or -OCF 3 ;
  • R 4B is F or–OCF 3 ;
  • R 2 is C 3-6 cycloalkyl optionally substituted with 1 or 2 independently selected fluoro, CH 3 , CF 3 , -OH, or -OCH 3 .
  • 50 ABV12212USO1 [00187] In one embodiment, the invention is directed to compounds of Formula I-a wherein X is H;
  • n 0, 1, or 2;
  • R 4A is H, F, CH 3 , -CH(CH 3 ) 2 , t-Bu, CF 3 , -OCH 3 , -O-CH(CH 3 ) 2 , or -OCF 3 ;
  • each R 4B is independently F or -OCF 3 ;
  • R 2 is C 3-6 cycloalkyl optionally substituted with 1 or 2 independently selected fluoro, CH 3 , CF 3 , -OH, or -OCH 3 .
  • the invention is directed to compounds of Formula I-a wherein n is 0, 1, or 2;
  • R 4A is H, F, CH 3 , -CH(CH 3 ) 2 , t-Bu, CF 3 , -OCH 3 , -O-CH(CH 3 ) 2 , or -OCF 3 ;
  • R 4B is F or–OCF 3 ; and R 2 is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, or piperidinyl; each of which is optionally substituted with 1 or 2 independently selected fluoro, CH 3 , CF 3 , -OH, or -OCH 3 .
  • the invention is directed to compounds of Formula I-a wherein n is 0, 1, or 2;
  • R 4A is H, F, CH 3 , -CH(CH 3 ) 2 , t-Bu, CF 3 , -OCH 3 , -O-CH(CH 3 ) 2 , or -OCF 3 ;
  • each R 4B is independently F or -OCF 3 ;
  • R 2 is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, or pyrrolidinyl; each of which is optionally substituted with 1 or 2 independently selected CH 3 , CF 3 , or -OH.
  • the invention is directed to compounds of Formula I-a wherein X is H;
  • n 0, 1, or 2;
  • R 4A is H, F, CH 3 , -CH(CH 3 ) 2 , t-Bu, CF 3 , -OCH 3 , -O-CH(CH 3 ) 2 , or -OCF 3 ;
  • R 4B is F or–OCF 3 ;
  • R 2 is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, or piperidinyl; each of which is optionally substituted with 1 or 2 independently selected fluoro, CH 3 , CF 3 , -OH, or -OCH 3 .
  • the invention is directed to compounds of Formula I-a wherein X is H;
  • n 0, 1, or 2;
  • R 4A is H, F, CH 3 , -CH(CH 3 ) 2 , t-Bu, CF 3 , -OCH 3 , -O-CH(CH 3 ) 2 , or -OCF 3 ; 51 ABV12212USO1 each R 4B is individually F or -OCF 3 ; and
  • R 2 is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, or piperidinyl; each of which is optionally substituted with 1 or 2 independently selected fluoro, CH 3 , CF 3 , -OH, or -OCH 3 .
  • the invention is directed to compounds of Formula I-a wherein n is 0, 1, or 2;
  • R 4A is H, F, CH 3 , -CH(CH 3 ) 2 , t-Bu, CF 3 , -OCH 3 , -O-CH(CH 3 ) 2 , or -OCF 3 ;
  • R 4B is F or–OCF 3 ;
  • R 2 and R 3 together with the nitrogen atom to which they are attached form an azetidine ring which is optionally substituted with 1, 2, or 3 independently selected R 9 groups.
  • the invention is directed to compounds of Formula I-a wherein n is 0, 1, or 2;
  • R 4A is H, F, CH 3 , -CH(CH 3 ) 2 , t-Bu, CF 3 , -OCH 3 , -O-CH(CH 3 ) 2 , or -OCF 3 ;
  • each R 4B is independently F or -OCF 3 ;
  • R 2 and R 3 together with the nitrogen atom to which they are attached form an azetidine ring which is optionally substituted with 1, 2, or 3 independently selected R 9 groups.
  • the invention is directed to compounds of Formula I-a wherein X is H;
  • n 0, 1, or 2;
  • R 4A is H, F, CH 3 , -CH(CH 3 ) 2 , t-Bu, CF 3 , -OCH 3 , -O-CH(CH 3 ) 2 , or -OCF 3 ;
  • R 4B is F or–OCF 3 ;
  • R 2 and R 3 together with the nitrogen atom to which they are attached form an azetidine ring which is substituted with one–OH, and optionally further substituted with one substituent selected from the group consisting of fluoro, -CH 3 , -CH(CH 3 ) 2 , CF 3 , and unsubstituted cyclopropyl.
  • the invention is directed to compounds of Formula I-a wherein X is H;
  • n 0, 1, or 2;
  • R 4A is H, F, CH 3 , -CH(CH 3 ) 2 , t-Bu, CF 3 , -OCH 3 , -O-CH(CH 3 ) 2 , or -OCF 3 ;
  • each R 4B is independently F or -OCF 3 ;
  • ABV12212USO1 R 2 and R 3 together with the nitrogen atom to which they are attached form an azetidine ring which is substituted with one -OH, and optionally further substituted with one substituent selected from the group consisting of fluoro, -CH 3 , -CH(CH 3 ) 2 , CF 3 , and unsubstituted cyclopropyl.
  • the invention is directed to compounds of Formula I-a wherein n is 0, 1, or 2;
  • R 4A is H, F, CH 3 , -CH(CH 3 ) 2 , t-Bu, CF 3 , -OCH 3 , -O-CH(CH 3 ) 2 , or -OCF 3 ;
  • R 4B is F or–OCF 3 ;
  • R A is H or CH 3 ;
  • R B , R C , and R D are H;
  • R B , R C , and R D are fluoro;
  • R B and R C are H, and R D is C 1-4 alkoxy, -OCH 2 -cyclopropyl, or -OCH 2 CF 3 .
  • the invention is directed to compounds of Formula I-a wherein n is 0, 1, or 2;
  • R 4A is H, F, CH 3 , -CH(CH 3 ) 2 , t-Bu, CF 3 , -OCH 3 , -O-CH(CH 3 ) 2 , or -OCF 3 ;
  • each R 4B is independently F or–OCF 3 ;
  • R A is H or CH 3 ;
  • R B , R C , and R D are each independently H or fluoro; or
  • R B and R C are H, and R D is C 1-4 alkoxy, -OCH 2 -cyclopropyl, or -OCH 2 CF 3 .
  • the invention is directed to compounds of Formula I-a wherein X is H; 53 ABV12212USO1 n is 0, 1, or 2;
  • R 4A is H, F, CH 3 , -CH(CH 3 ) 2 , t-Bu, CF 3 , -OCH 3 , -O-CH(CH 3 ) 2 , or -OCF 3 ;
  • R 4B is F or–OCF 3 ;
  • R A is H or CH 3 ;
  • R B , R C , and R D are H;
  • R B , R C , and R D are fluoro;
  • R B and R C are H, and R D is C 1-4 alkoxy, -OCH 2 -cyclopropyl, or -OCH 2 CF 3 .
  • the invention is directed to compounds of Formula I-a wherein X is H;
  • n 0, 1, or 2;
  • R 4A is H, F, CH 3 , -CH(CH 3 ) 2 , t-Bu, CF 3 , -OCH 3 , -O-CH(CH 3 ) 2 , or -OCF 3 ;
  • each R 4B is independently F or -OCF 3 ;
  • R A is H or CH 3 ;
  • R B , R C , and R D are each independently H or fluoro; or
  • R B and R C are H, and R D is C 1-4 alkoxy, -OCH 2 -cyclopropyl, or -OCH 2 CF 3 .
  • the invention is directed to compounds of Formula I-a wherein n is 0 or 1;
  • R 4A is F, CF 3 , or -OCF 3 ;
  • R A is H
  • R B , R C , and R D are fluoro;
  • R B and R C are H, and R D is -OCH 3 , -OCH 2 CH 3 , -OCH(CH 3 ) 2 ,–OC(CH 3 ) 3 ,
  • the invention is directed to compounds of Formula I-a wherein X is H;
  • n 0 or 1
  • R 4A is F, CF 3 , or -OCF 3 ;
  • R A is H
  • R B , R C , and R D are fluoro;
  • R B and R C are H, and R D is -OCH 3 , -OCH 2 CH 3 , -OCH(CH 3 ) 2 ,–OC(CH 3 ) 3 ,
  • the invention is directed to compounds of Formula I-a wherein X is H;
  • n 0;
  • R 4A is F
  • R A is H
  • R B , R C , and R D are fluoro;
  • R B and R C are H, and R D is -OCH 3 , -OCH 2 CH 3 , -OCH(CH 3 ) 2 ,–OC(CH 3 ) 3 ,
  • Exemplary compounds of Formula I include, but are not limited to:
  • ABV12212USO1 (3-amino-5- ⁇ [2-(trifluoromethoxy)phenyl]sulfonyl ⁇ pyridin-2-yl)(3-hydroxyazetidin-1- yl)methanone;
  • ABV12212USO1 (3-amino-5- ⁇ [4-(trifluoromethyl)phenyl]sulfonyl ⁇ pyridin-2-yl)(3-hydroxy-3- methylazetidin-1-yl)methanone;
  • ABV12212USO1 (3-amino-5- ⁇ [4-(trifluoromethoxy)phenyl]sulfonyl ⁇ pyridin-2-yl)(6-oxa-2- azaspiro[3.5]non-2-yl)methanone;
  • ABV12212USO1 3-amino-5- ⁇ [(2S)-2-methylpyrrolidin-1-yl]sulfonyl ⁇ -N-(3,3,3-trifluoro-2- hydroxypropyl)pyridine-2-carboxamide;
  • ABV12212USO1 3-amino-5- ⁇ methyl[4-(trifluoromethyl)benzyl]sulfamoyl ⁇ -N-(3,3,3-trifluoro-2- hydroxypropyl)pyridine-2-carboxamide;

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