Classifications

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  • 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
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  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
  • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
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  • 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
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  • 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
  • A61K31/4436—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a heterocyclic ring having sulfur 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
  • A61K31/495—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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • 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
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  • 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
  • C07D405/06—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 carbon chain containing only aliphatic carbon atoms
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  • 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
  • C07D405/14—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 three or more hetero rings
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  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
  • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
  • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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  • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
  • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
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  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems
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  • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
  • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
  • C07D487/04—Ortho-condensed systems
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  • 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
  • C07D491/04—Ortho-condensed systems
  • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
  • C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered
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  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
  • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
  • C07D493/04—Ortho-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
  • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
  • C07D495/04—Ortho-condensed systems
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  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
  • C07D498/04—Ortho-condensed systems
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  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
  • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
  • C07D513/04—Ortho-condensed systems
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  • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
  • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
  • C07F9/02—Phosphorus compounds
  • C07F9/28—Phosphorus compounds with one or more P—C bonds
  • C07F9/535—Organo-phosphoranes
  • C07F9/5352—Phosphoranes containing the structure P=C-
• • C—CHEMISTRY; METALLURGY
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  • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
  • C07F9/02—Phosphorus compounds
  • C07F9/28—Phosphorus compounds with one or more P—C bonds
  • C07F9/54—Quaternary phosphonium compounds
  • C07F9/5442—Aromatic phosphonium compounds (P-C aromatic linkage)
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  • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
  • C07F9/02—Phosphorus compounds
  • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
  • C07F9/655—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms
  • C07F9/6552—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a six-membered ring
  • C07F9/65522—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a six-membered ring condensed with carbocyclic rings or carbocyclic ring systems
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  • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
  • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
  • C07F9/02—Phosphorus compounds
  • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
  • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
  • C07F9/65586—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system at least one of the hetero rings does not contain nitrogen as ring hetero atom

Definitions

• Small ubiquitin-like modifier is a member of the ubiquitin-like protein (Ubl) family that is covalently conjugated to cellular proteins in a manner similar to Ub-conjugation (Kerscher, O., Felberbaum, R., and Hochstrasser, M. 2006. Modification of proteins by ubiquitin and ubiquitin-like proteins. Annu Rev Cell Dev Biol. 22: 159-80). Mammalian cells express three major isoforms: SUMO l , SUM02 and SUM03.
• SUM02 and SUM03 share -95% amino acid sequence homology but have -45% sequence homology with SUMO l (Kamitani, T., Kito, K., Nguyen, H. P., Fukuda-Kamitani, T., and Yeh, E. T. 1998. Characterization of a second member of the sentrin family of ubiquitin-like proteins. J Biol Chem. 273( 18): 1 1349-53).
• SUMO proteins can be conjugated to a single lysine residue of a protein (monosumoylation) or to a second SUMO protein that is already conjugated to a protein forming a SUMO chain (polysumoylation).
• SUM02/3 can form such chains because they possess internal consensus SUMO modification sites (Tatham, M. H., Jaffray, E., Vaughan, O. A., Desterro, J. M., Botting, C. H., Naismith, J. H., Hay, R. T. 2001.
• Polymeric chains of SUMO-2 and SUM 0-3 are conjugated to protein substrates by SAE1/SAE2 and Ubc9. J Biol Chem. 276(38):35368-74).
• An additional isoform, SUM04 is found in kidney, lymph node and spleen cells, but it is not known whether SUM04 can be conjugated to cellular proteins.
• SAE SUMO-activating enzyme
• SAE 1 SUMO-activating enzyme subunit 1
• SAE2 UAA2
• SAE like other El activating enzymes, uses ATP to adenylate the C-terminal glycine residue of SUMO.
• a thioester intermediate is then formed between the C-terminal glycine of SUMO and a cysteine residue in SAE2.
• SUMO is transferred from the El to the cysteine residue of the SUMO conjugating enzyme (E2), UBC9.
• Ubc9 is currently the only known conjugating enzyme for SUMO and functions with SUMOl , SUM02 and SUM03 proteins.
• SUMO proteins are then conjugated to the target protein, either directly or in conjunction with an E3 ligase, through isopeptide bond formation with the epsilon amino group of a lysine side chain on a target protein.
• E3 ligases including PIAS (protein inhibitor of activated signal transducer and activator of transcription protein) proteins and Ran-binding protein 2 (RanBP2), and polycomb 2 (Pc2), have been identified (Johnson, E. S., and Gupta, A. A. 2001.
• the nucleoporin RanBP2 has SUMOl E3 ligase activity.
• the polycomb protein Pc2 is a SUMO E3. Cell. 1 13(1): 127- 37).
• SUMO ubiquitin's mysterious cousin. Nat Rev Mol Cell Biol. 2(3):202-10.
• SENPs de-sumoylating enzymes
• SAE-initiated SUMO-conjugation plays a major role in regulating diverse cellular processes, including cell cycle regulation, transcriptional regulation, cellular protein targeting, maintenance of genome integrity, chromosome segregation, and protein stability (Hay, R. T. 2005. SUMO: a history of modification. Mol Cell. 18( 1): 1 -12; Gill, G. 2004. SUMO and ubiquitin in the nucleus: different functions, similar mechanisms? Genes Dev. 18(17):2046-59).
• SUMO- conjugation causes changes in the subcellular localization of RanGAPl by targeting it to the nuclear pore complex (Mahajan, R., Delphin, C., Guan, T., Gerace, L., and Melchior, F. 1997. A small ubiquitin-related polypeptide involved in targeting RanGAPl to nuclear pore complex protein RanBP2. Cell. 88(1):97- 1070). Sumoylation counteracts ubiquitination and subsequently blocks the degradation of ⁇ ⁇ , thereby negatively regulating NF- ⁇ activation (Desterro, J. M., Rodriguez, M. S., Hay, R. T. 1998. SUMO- 1 modification of IkappaB alpha inhibits NF-kappaB activation.
• SAE inhibitors may also be applicable for the treatment of other diseases and conditions outside of oncology.
• SUMO modifies proteins that play important roles in neurodegenerative diseases (Steffan, J. S., Agrawal, N., Pallos, J., Rockabrand, E., Trotman, L. C, Slepko, N., Hies, K., Lukacsovich, T., Zhu, Y. Z., Cattaneo, E., Pandolfi, P. P., Thompson, L. M., Marsh, J. L. 2004. SUMO modification of Huntington and Huntington's disease pathology. Science. 304(5667): 100-4); Dorval, V., and Fraser, P.
• Y is -O-, -CH , or -N(H)-;
• R A is hydrogen, fluoro, -NH 2 , or hydroxyl
• R A ' is hydrogen or fluoro, provided that when R is -NH 2 or hydroxyl, R A ' is hydrogen;
• R B is hydrogen or, together with the oxygen to which it is attached, forms a prodrug
• R C is hydrogen or C alkyl
• R D is hydrogen, halogen, -CF 3 , or C,. 4 alkyl
• X is C(H), C(F), or N;
• X 2 is S or O
• X 3 is C(R X3 ) or N;
• R x is hydrogen, methyl, or halogen;
• Z x is hydrogen, halogen, cyano, R z3 , -S-R z3 , -S(0)-R z3 , or -S(0) 2 -R z3 ;
• R z3 is an optionally substituted phenyl, an optionally substituted 5- to 7-membered cycloaliphatic, an optionally substituted 5- to 7-membered heterocyclyl, or an optionally substituted Ci-4 aliphatic;
• Z] is not hydrogen, halogen, methyl, or cyano if 3 ⁇ 4 is hydrogen or methyl
• (a) 3 ⁇ 4 is a ring system having an optionally substituted 5- to 7-membered heterocyclyl with 1 -2 heteroatoms or an optionally substituted 5- to 7-membered cycloaliphatic fused to
• (b) 3 ⁇ 4 is L-R e wherein L is -L r , -V r L 2 -, or -L
• L is a C] -3 alkylene chain wherein 1 or 2 saturated carbon atoms are optionally substituted by (R f )(R fl ) and in which there are optionally one or two degrees of unsaturation;
• each R f is independently hydrogen; hydroxyl; -N(R h )(R h '); d. 4 aliphatic optionally substituted with hydroxyl, -OCH 3 , or cyclopropyl ; -0-C
• deliberately 4 aliphatic optionally substituted with hydroxyl, -OCH 3 , or cyclopropyl ; or, together with R fl and the carbon atom to which they are attached, form CH 2 , or a 3- to 6-membered carbocycle or 4- to 6-membered heterocycle comprising a heteroatom chosen from N (which may be protonated or C,. alkylated), O, or S, the heteroatom optionally located immediately adjacent to the quaternary carbon of the heterocycle;
• R h and R h ' are each independently hydrogen or Q.4 alkyl
• V is -S-, -0-, -S(O)-, -S(0) 2 -, -C(O)- or -N(R g )-;
• L2 is a Co-2 alkylene chain wherein one saturated carbon atom is optionally substituted by (R f )(R f ');
• R g is hydrogen or C 4 alkyl
• R e is hydrogen, hydroxyl, halogen, -CF 3 , or an optionally substituted C,. 4 aliphatic,
• R e is a ring chosen from optionally substituted 6-membered aryl, optionally substituted 5-to 6-membered heteroaryl, optionally substituted 3- to 7-membered cycloaliphatic, or optionally substituted 4- to 7-membered heterocyclyl, which is optionally fused to a second optionally substituted 6-membered aryl, optionally substituted 5-to 6-membered heteroaryl, optionally substituted 3- to 7-membered cycloaliphatic, or optionally substituted 4- to 7-membered heterocyclyl;
• Zj is hydrogen
• FIG. 1 is an XRPD pattern of compound I-257b Form 1 .
• FIG. 2 is an XRPD pattern of compound I-263a Form 1.
• FIG. 3 is an XRPD pattern of compound I-256b Form 1 .
• FIG. 4 shows a differential scanning calorimetry (DSC) thermogram for I-263a Form 1 .
• FIG. 5 shows a thermogravimetric analysis (TGA) thermogram for I-263a Form 1 .
• FIG. 6 shows a raman pattern for I-263a Form 1 including data in the region of 500 cm “ ' to 3000 cm " ' .
• FIG. 7 shows a raman pattern for I-263a Form 1 including data in the region of 200 cm “ ' to 1600 cm “ 1 .
• FIG. 8 shows a differential scanning calorimetry (DSC) thermogram for I-257b Form 1 .
• FIG. 9 shows a thermogravimetric analysis (TGA) thermogram for I-257b Form 1 .
• FIG. 10 shows a raman pattern for I-257b Form 1 including data in the region of 500 cm “ ' to 3000 cm " ' .
• FIG. 1 1 shows a raman pattern for I-257b Form 1 including data in the region of 200 cm “1 to 1600 cm " ' .
• FIG. 12 shows a differential scanning calorimetry (DSC) thermogram for I-256b Form 1 .
• FIG. 13 shows a thermogravimetric analysis (TGA) thermogram for I-256b Form 1 .
• FIG. 14 is an XRPD pattern of compound I-263a Form 2.
• FIG. 15 is an XRPD pattern of compound I-263a Form 3.
• FIG. 16 shows a thermogravimetric analysis (TGA) thermogram for I-263a Form 3.
• FIG. 17 shows a differential scanning calorimetry (DSC) thermogram for I-263a Form 3.
• Chemical entities of the present disclosure include those described generally for formula (/), above, and are further illustrated by the classes, subclasses, and species disclosed herein. It will be appreciated that preferred subsets described for each variable herein can be used for any of the structural subsets as well. As used herein, the following definitions shall apply unless otherwise indicated.
• chemical entities of the present disclosure may be optionally substituted with one or more substituents, such as are disclosed generally above, or as exemplified by particular classes, subclasses, and species disclosed herein.
• substituents such as are disclosed generally above, or as exemplified by particular classes, subclasses, and species disclosed herein.
• phrase “optionally substituted” is used interchangeably with the phrase “substituted or unsubstituted.”
• substituted whether preceded by the term “optionally” or not, means that a hydrogen radical of the designated moiety is replaced with the radical of a specified substituent, provided that the substitution results in a stable or chemically feasible chemical entity.
• substituted when used in reference to a designated atom, means that attached to the atom is a hydrogen radical, which hydrogen atom can be replaced with the radical of a suitable substituent.
• an "optionally substituted” group may have a substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by this disclosure are, for instance, those that result in the formation of stable or chemically feasible chemical entities.
• a stable chemical entity or chemically feasible chemical entity is one in which the chemical structure is not substantially altered when kept at a temperature from about -80°C to about +40°C, in the absence of moisture or other chemically reactive conditions, for at least a week, or a chemical entity which maintains its integrity long enough to be useful for therapeutic or prophylactic administration to a patient.
• substituents refers to a number of substituents that equals from one to the maximum number of substituents possible based on the number of available bonding sites, provided that the above conditions of stability and chemical feasibility are met.
• the term "independently selected” means that the same or different values may be selected for multiple instances of a given variable in a single chemical entity.
• a 3-7-membered saturated, partially unsaturated, or aromatic monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10- membered partially unsaturated, or aromatic bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur includes cycloaliphatic, heterocyclic, aryl and heteroaryl rings.
• aromatic includes aryl and heteroaryl groups as described generally below and herein.
• aliphatic or "aliphatic group,” as used herein, means an optionally substituted straight-chain or branched C M2 hydrocarbon, or a cyclic Ci_ 12 hydrocarbon which is completely saturated or which contains one or more units of unsaturation, but which is not aromatic (also referred to herein as “carbocycle,” “cycloaliphatic,” “cycloalkyl,” or “cycloalkenyl”).
• suitable aliphatic groups include optionally substituted linear, branched or cyclic alkyl, alkenyl, alkynyl groups and hybrids thereof, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl, or (cycloalkyl)alkenyl.
• aliphatic groups have 1-12, 1-10, 1-8, 1-6, 1-5, 1-4, 1-3, or 1-2 carbon atoms.
• alkyl used alone or as part of a larger moiety, refers to an optionally substituted straight or branched chain saturated hydrocarbon group having 1 -12, 1-10, 1-8, 1-6, 1-5,
• alkenyl used alone or as part of a larger moiety, refers to an optionally substituted straight or branched chain hydrocarbon group having at least one double bond and having
• alkynyl used alone or as part of a larger moiety, refers to an optionally substituted straight or branched chain hydrocarbon group having at least one triple bond and having 2- 12, 2- 10, 2-8, 2-6, 2-5, 2-4, or 2-3 carbon atoms.
• cycloaliphatic refers to an optionally substituted saturated or partially unsaturated cyclic aliphatic ring system having from 3 to about 14 ring carbon atoms.
• the cycloaliphatic group is an optionally substituted monocyclic hydrocarbon having 3- 8 or 3-6 ring carbon atoms.
• Cycloaliphatic groups include, without limitation, optionally substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl, cyclooctenyl, or cyclooctadienyl.
• cycloaliphatic also include optionally substituted bridged or fused bicyclic rings having 6- 12, 6-10, or 6-8 ring carbon atoms, wherein any individual ring in the bicyclic system has 3-8 ring carbon atoms.
• cycloalkyl refers to an optionally substituted saturated ring system of about 3 to about 10 ring carbon atoms.
• exemplary monocyclic cycloalkyl rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
• cycloalkenyl refers to an optionally substituted non-aromatic monocyclic or multicyclic ring system containing at least one carbon-carbon double bond and having about 3 to about 10 carbon atoms.
• exemplary monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl, and cycloheptenyl.
• haloaliphatic refers to an aliphatic, alkyl, alkenyl or alkoxy group, as the case may be, which is substituted with one or more halogen atoms.
• halogen or halo means F, CI, Br, or I.
• fluoroaliphatic refers to a haloaliphatic wherein the halogen is fluoro, including perfluorinated aliphatic groups.
• fluoroaliphatic groups include, without limitation, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, 1 , 1 ,2-trifluoroethyl, 1 ,2,2- trifluoroethyl, and pentafluoroethyl.
• heteroatom refers to one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4- dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR + (as in N-substituted pyrrolidinyl)).
• aryl and “ar-,” used alone or as part of a larger moiety e.g., "aralkyl,” “aralkoxy,” or “aryloxyalkyl,” refer to an optionally substituted C ⁇ u aromatic hydrocarbon moiety comprising one to three aromatic rings.
• the aryl group is a C 6 _
• Aryl groups include, without limitation, optionally substituted phenyl, naphthyl, or anthracenyl.
• aryl and “ar-,” as used herein, also include groups in which an aryl ring is fused to one or more cycloaliphatic rings to form an optionally substituted cyclic structure such as a tetrahydronaphthyl, indenyl, or indanyl ring.
• aryl may be used interchangeably with the terms “aryl group,” “aryl ring,” and “aromatic ring.”
• an "aralkyl” or “arylalkyl” group comprises an aryl group covalently attached to an alkyl group, either of which independently is optionally substituted.
• the aralkyl group is C 6 _io aryl Ci_ 6 alkyl, including, without limitation, benzyl, phenethyl, and naphfhylmethyl.
• heteroaryl and “heteroar-,” used alone or as part of a larger moiety, e.g., “heteroaralkyl,” or “heteroaralkoxy,” refer to groups having 5 to 14 ring atoms, such as 5, 6, 9, or 10 ring atoms; having 6, 10, or 14 pi electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms.
• a heteroaryl group may be mono-, bi-, tri-, or polycyclic, for instance mono-, bi-, or tricyclic, such as mono- or bicyclic.
• heteroatom refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen.
• a nitrogen atom of a heteroaryl may be a basic nitrogen atom and may also be optionally oxidized to the corresponding N-oxide.
• heteroaryl When a heteroaryl is substituted by a hydroxy group, it also includes its corresponding tautomer.
• heteroaryl and “heteroar-,” as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocycloaliphatic rings.
• heteroaryl groups include thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, pteridinyl, indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl
• heteroaryl may be used interchangeably with the terms “heteroaryl ring,” “heteroaryl group,” or “heteroaromatic,” any of which terms include rings that are optionally substituted.
• heteroarylkyl refers to an alkyl group substituted by a heteroaryl, wherein the alkyl and heteroaryl portions independently are optionally substituted.
• heterocycle As used herein, the terms “heterocycle,” “heterocyclyl,” “heterocyclic radical,” and “heterocyclic ring” are used interchangeably and refer to a stable 3- to 8-membered monocyclic or 7- 10-membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, for instance one to four, heteroatoms, as defined above.
• nitrogen includes a substituted nitrogen.
• the nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR + (as in N-substituted pyrrolidinyl).
• a heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted.
• saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and thiamorpholinyl.
• a heterocyclyl group may be mono-, bi-, tri-, or polycyclic, for instanct mono-, bi-, or tricyclic, and such as mono- or bicyclic.
• heterocyclylalkyl refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted.
• a heterocyclic ring also includes groups in which the heterocyclic ring is fused to one or more aryl rings.
• partially unsaturated refers to a ring moiety that includes at least one double or triple bond between ring atoms.
• the term “partially unsaturated” is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aromatic (e.g., aryl or heteroaryl) moieties, as herein defined.
• alkylene refers to a bivalent alkyl group.
• An "alkylene chain” is a polymethylene group, i.e., -(CH 2 ) n -, wherein n is a positive integer, such as from 1 to 6, from 1 to 5, from 1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3.
• An optionally substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms is optionally replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group and also include those described in the specification herein. It will be appreciated that two substituents of the alkylene group may be taken together to form a ring system. In certain embodiments, two substituents can be taken together to form a 3-7-membered ring. The substituents can be on the same or different atoms.
• An alkylene chain also can be optionally interrupted by a functional group.
• An alkylene chain is "interrupted" by a functional group when an internal methylene unit is interrupted by the functional group. Examples of suitable "interrupting functional groups" are described in the specification and claims herein, and include double and/or triple bonds between carbons in the alkylene chain.
• An aryl (including aralkyl, aralkoxy, aryloxyalkyl and the like) or heteroaryl (including heteroaralkyl and heteroarylalkoxy and the like) group may contain one or more substituents and thus may be "optionally substituted.”
• An aliphatic or heteroaliphatic group, or a non-aromatic carbocyclic or heterocyclic ring may contain one or more substituents and thus may be "optionally substituted.”
• a ring nitrogen atom of a heteroaryl or non-aromatic heterocyclic ring also may be oxidized to form the corresponding N-hydroxy or N-oxide chemical entity.
• a nonlimiting example of such a heteroaryl having an oxidized ring nitrogen atom is N-oxidopyridyl.
• Exemplary rings that are formed when two independent occurrences of R + (or any other variable similarly defined in the specification and claims herein), are taken together with their intervening atom(s) include, but are not limited to the following: a) two independent occurrences of R + (or any other variable similarly defined in the specification or claims herein) that are bound to the same atom and are taken together with that atom to form a ring, for example, N(R + ) 2 , where both occurrences of R + are taken together with the nitrogen atom to form a piperidin- l -yl, piperazin- l -yl, or morpholin-4-yl group; and b) two independent occurrences of R + (or any other variable similarly defined in the specification or claims herein) that are bound to different atoms and are taken together with both of those atoms to form a ring, for example where a phenyl group is substituted with two , these two occurrences of R + are taken together with the oxygen
• structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present chemical entities are within the scope of the present disclosure. Unless otherwise stated, all tautomeric forms of the chemical entities disclosed herein are within the scope of the present disclosure.
• structures depicted herein are also meant to include chemical entities that differ only in the presence of one or more isotopically enriched atoms.
• chemical entities having the present structures where there is a replacement of hydrogen by deuterium or tritium, or a replacement of a carbon by a l3 C- or 14 C-enriched carbon are within the scope of this disclosure.
• Such chemical entities are useful, as a nonlimiting example, as analytical tools or probes in biological assays.
• the present disclosure encompasses one enantiomer of inhibitor free from the corresponding optical isomer, a racemic mixture of the inhibitor, and mixtures enriched in one enantiomer relative to its corresponding optical isomer.
• the mixture contains, for example, an enantiomeric excess of at least 50%, 75%, 90%, 95%, 99%, or 99.5%.
• the enantiomers of the present disclosure may be resolved by methods known to those skilled in the art, for example by formation of diastereoisomeric salts which may be separated, for example, by crystallization; formation of diastereoisomeric derivatives or complexes which may be separated, for example, by crystallization, gas-liquid or liquid chromatography; selective reaction of one enantiomer with an enantiomer-specific reagent, for example enzymatic esterification; or gas- liquid or liquid chromatography in a chiral environment, for example on a chiral support for example silica with a bound chiral ligand or in the presence of a chiral solvent.
• enantiomers may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer into the other by asymmetric transformation.
• the present disclosure encompasses a diastereomer free of other diastereomers, a pair of diastereomers free from other diasteromeric pairs, mixtures of diasteromers, mixtures of diasteromeric pairs, mixtures of diasteromers in which one diastereomer is enriched relative to the other diastereomer(s) and mixtures of diasteromeric pairs in which one diastereomeric pair is enriched relative to the other diastereomeric pair(s).
• the mixture is enriched in one diastereomer or diastereomeric pair(s) relative to the other diastereomers or diastereomeric pair(s), the mixture is enriched with the depicted or referenced diastereomer or diastereomeric pair(s) relative to other diastereomers or diastereomeric pair(s) for the chemical entity, for example, by a molar excess of at least 50%, 75%, 90%, 95%, 99% or 99.5%.
• the diastereoisomeric pairs may be separated by methods known to those skilled in the art, for example chromatography or crystallization and the individual enantiomers within each pair may be separated as described above. Specific procedures for chromatographically separating diastereomeric pairs of precursors used in the preparation of chemical entities disclosed herein are provided the examples herein.
• chemical entity I-la [( lR,2R,3S,4R)-4- ⁇ [5-( ⁇ 4-[( 1 S)- 1 -(6-bromopyridin-2-yl)- 1 -hydroxyethyl]-2- thienyl ⁇ carbonyl)pyrimidin-4-yl]amino ⁇ -2,3-dihydroxycyclopentyl]methyl sulfamate or
• chemical entity I-l [( l R,2R,3S,4R)-4- ⁇ [5-( ⁇ 4-[( l S)- l -(6-bromopyridin-2-yl)- l - hydroxyethyl]-2-thienyl ⁇ carbonyl)pyrimidin-4-yl]amino ⁇ -2, 3-dihydroxycyclopentyl] methyl sulfamate and [(lR,2R,3S,4R)-4- ⁇ [5-( ⁇ 4-[( l R)- l -(6-bromopyridin-2-yl)- ] -hydroxyethyl]-2- thienyl ⁇ carbonyl)pyrimidin-4-yl]amino ⁇ -2,3
• R a , R a ', R b , X b X 2 , X3, R d , Z and 3 ⁇ 4 have the values described herein and stereochemical configurations depicted at asterisked positions indicate absolute stereochemistry.
• R , R ', R , Xi , X 2 , X3, Z ⁇ , and Z 2 have the values described herein and stereochemical configurations depicted at asterisked positions indicate absolute stereochemistry.
• the chemical entity of formula (/) is represented by formula (H-a) or (II-b)
• R a , R a ', R b , X 2 , X3, Z l s and Z? have the values described herein and stereochemical configurations depicted at asterisked positions indicate absolute stereochemistry.
• the chemical entity of formula (I) is represented by formula (II-a) wherein R a , R a ', R b , X 2 , X3, Zi, and Z 2 have the values described herein and stereochemical configurations depicted at asterisked positions indicate absolute stereochemistry.
• the chemical entity of formula (/) is represented by formula (Il-b) wherein R ⁇ R ', R b , X 2 , X3, Z, , and Z 2 have the values described herein and stereochemical configurations depicted at asterisked positions indicate absolute stereochemistry.
• the chemical entity of formula (7) is represented by formula (IH-a) or (Ill-b
• R a , R a ', R b , Z ⁇ , and Z 2 have the values described herein and stereochemical configurations depicted at asterisked positions indicate absolute stereochemistry.
• the chemical entity of formula (I) is represented by formula (III-a) wherein R a , R a ', R b , Zj , and Z2 have the values described herein and stereochemical configurations depicted at asterisked positions indicate absolute stereochemistry.
• the chemical entity of formula (I) is represented by formula (IH-b) wherein R a , R a ', R b , Z and Z? have the values described herein and stereochemical configurations depicted at asterisked positions indicate absolute stereochemistry.
• the chemical entity of formula (I) is represented by formula (IV-a) or (IV-b):
• R b , Z 1 ; and Z2 have the values described herein and stereochemical configurations depicted at asterisked positions indicate absolute stereochemistry.
• the chemical entity of formula (I) is represented by formula (IV-a) wherein R b , Z 1 ; and Z? have the values described herein and stereochemical configurations depicted at asterisked positions indicate absolute stereochemistry.
• the chemical entity of formula (I) is represented by formula (IV-b) wherein R b , Z) , and have the values described herein and stereochemical configurations depicted at asterisked positions indicate absolute stereochemistry.
• X 5 , m, and Ring A have the values described herein and stereochemical configurations depicted at asterisked positions indicate absolute stereochemistry.
• the chemical entity of formula (/) is represented by formula (V-a) or (V-b):
• the chemical entity of formula (7) is represented by formula V-a) wherein R b , Z,, R k , X 4 , X 5 , m, and Ring A have the values described herein and stereochemical configurations depicted at asterisked positions indicate absolute stereochemistry.
• the chemical entity of formula (I) is represented by formula (V-b) wherein R b , Z, R , X4, X5, m, and Ring A have the values described herein and stereochemical configurations depicted at asterisked positions indicate absolute stereochemistry.
• Y, R a , R a ', R b , R c , X, , X 2 , X 3 , R d , Z, , R k , X 4 , X_, m, X 6 , R j , and R m have the values described herein and stereochemical configurations depicted at asterisked positions indicate absolute stereochemistry.
• the chemical entity of formula ( ⁇ ) is represented by formula (Vl-a) or (VI-b):
• R a , R a ', R , X Z, , R k , X 4 , X 5 , m, X 6 , X 6 ', R j , and R m have the values described herein and stereochemical configurations depicted at asterisked positions indicate absolute stereochemistry.
• the chemical entity of formula (/) is represented by formula (VI- ⁇ ) wherein R a , R a ', R b , Xi, Zj, R k , X 4 , X 5 , m, X 6 , X 6 ', R and R m have the values described herein and stereochemical configurations depicted at asterisked positions indicate absolute stereochemistry.
• the chemical entity of formula (/) is represented by formula (Vl-b) wherein R a , R a ', R b , Xi, Zi , R k , X 4 , X 5 , m, X 6 , X 6 ⁇ R J , and R m have the values described herein and stereochemical configurations depicted at asterisked positions indicate absolute stereochemistry.
• R ⁇ R a ', R , R c , Xi , R d , Z t , Xi, X 3 , L, and R e have the values described herein and stereochemical configurations depicted at asterisked positions indicate absolute stereochemistry.
• the chemical entity of formula (I) is represented by formula (VII- a) or (VH-b):
• R b , Z, , L, and R e have the values described herein and stereochemical configurations depicted at asterisked positions indicate absolute stereochemistry.
• the chemical entity of formula (7) is represented by formula (VH-a) wherein R b , Z, , L, and R e have the values described herein and stereochemical configurations depicted at asterisked positions indicate absolute stereochemistry.
• the chemical entity of formula ( ⁇ ) is represented by formula (VH-b) wherein R b , Z L, and R e have the values described herein and stereochemical configurations depicted at asterisked positions indicate absolute stereochemistry.
• the chemical entity of formula (/) is represented by formula (VHI).
• the chemical entity of formula (I) is represented by formula (VIII- d) or (Vlll-b):
• Y, R a , R a ', R b , X, , R c , R d , Z, , R f , R f* , E 5 , E 6 , R e6 , R e7 , and R e8 have the values described herein and stereochemical configurations depicted at asterisked positions indicate absolute stereochemistry.
• the chemical entity of formula (I) is represented by formula (VIII-a) wherein Y, R a , R a ', R b , Xi, R c , R d , Z, , R f , R f ', E 5 , E 6 , R e6 , R e7 , and R e8 have the values described herein and stereochemical configurations depicted at asterisked positions indicate absolute stereochemistry.
• the chemical entity of formula (I) is represented by formula VlH-b) wherein Y, R ⁇ R a ', R b , X R c , R d , Z, , R f , R f ', E 5) E 6 , R e6 , R e7 , and R eS have the values described herein and stereochemical configurations depicted at asterisked positions indicate absolute stereochemistry.
• R a , R a ', R b , X 2 , X 3 , Z, , R f , R f ', R e5 , E 6 , R e6 , R e7 , and R e8 have the values described herein and stereochemical configurations depicted at asterisked positions indicate absolute stereochemistry.
• R ⁇ R a ', R b , Z, , R f , R f ', R e5 , E 6 , R e6 , R e7 , and R e8 have the values described herein and stereochemical configurations depicted at asterisked positions indicate absolute stereochemistry.
• the chemical entity of formula (I) is represented by formula (IX-a) wherein R a , R a ', R b , Z, , R r , R f ', R e5 , E 6 , R e6 , R e7 , and R e8 have the values described herein and stereochemical configurations depicted at asterisked positions indicate absolute stereochemistry.
• the chemical entity of formula (I) is represented by formula ⁇ IX-b) wherein R a , R a ', R b , Z
• Y is -0-, -CH 2 -, or -N(H)-. In some embodiments, Y is -0-. In some embodiments, Y is -CH 2 -. In some embodiments, Y is -N(H)-.
• R a is hydrogen, fluoro, -NH 2 , or -OH. In some embodiments, R a is hydrogen, fluoro or -OH. In some embodiments, R a is hydrogen or -OH. In some embodiments, R a is hydrogen. In some embodiments, R a is -OH.
• R a ' is hydrogen or fluoro; provided that when R a is -NH 2 or -OH, R a ' is hydrogen. In some embodiments, R a ' is hydrogen.
• R a is hydrogen and R a ' is hydrogen. In some embodiments, R a is fluoro and R a ' is fluoro. In some embodiments, R a is -NH 2 and R a ' is hydrogen. In some embodiments, R a is hydrogen and R a ' is fluoro. In some embodiments, R a is -OH and R a ' is hydrogen. In some embodiments, R a is fluoro or hydrogen and R a ' is fluoro.
• R c is hydrogen or C]_ 4 alkyl. In some embodiments, R c is hydrogen or methyl. In some embodiments, R c is hydrogen. [0083] In some embodiments, R D is hydrogen, halogen, -CF 3 , or Ci_ 4 alkyl. In some embodiments, R D is hydrogen, fluoro, chloro, or methyl. In some embodiments, R D is hydrogen.
• Xi is C(H), C(F) or N. In some embodiments, Xi is C(H) or N. In some embodiments, X] is C(H). In some embodiments, Xj is N.
• X 2 is S or O. In some embodiments, X 2 is S. In some embodiments, X 2 is O.
• X 3 is C(R X3 ) or N, wherein R X3 has the values described herein. In some embodiments, X 3 is C(R 3 ), wherein R 3 has the values described herein. In some embodiments, X 3 is N. In some embodiments, X 3 is C(H).
• R" is hydrogen, methyl, or halogen.
• R X3 is hydrogen, methyl, fluoro, or chloro.
• R X3 is hydrogen or methyl.
• R XJ is hydrogen.
• Z is hydrogen, halogen, cyano, R Z3 , -S-R Z3 , -S(0)-R Z3 , or -S(0) 2 - R Z3 , wherein R Z3 has the values described herein, and wherein Zj is not hydrogen, halogen, methyl, or cyano if Z 2 is hydrogen or methyl.
• Z is hydrogen; halogen; cyano; phenyl optionally substituted with one or more independently selected halogens; 5- to 7-membered cycloaliphatic or heterocyclyl optionally fused to a 6-membered aryl, wherein the 5- to 7-membered cycloaliphatic or heterocyclyl optionally fused to a 6-membered aryl is optionally substituted with one or more independently selected halogens; C fluoroaliphatic; or a Q.
• each R Z3 independently has the values described herein; and wherein Zi is not hydrogen, halogen, methyl, or cyano if Z> is hydrogen or methyl.
• Z is phenyl, halophenyl, or 5- to 7- membered cycloaliphatic or heterocyclyl optionally fused to a 6-membered aryl, wherein the 5- to 7- membered cycloaliphatic or heterocyclyl optionally fused to a 6-membered aryl is optionally substituted with one or more halogen.
• Zi is a C aliphatic group (i) substituted with one or more phenyl, halophenyl, 5- or 6-membered cycloaliphatic or heterocyclyl, and (ii) optionally substituted with one or more hydroxyl, -OCM aliphatic, halogen, C aliphatic, acetyl, -OCH 3 , -CH 2 OCH 3 , cyano, -N(R Z5 ) 2 , -CH 2 NH 2 , -C0 2 H, or -CF 3 , wherein each R Z5 independently has the values described herein.
• Zi is hydrogen; halogen; cyano; or C aliphatic optionally substituted with one or more hydroxyl, CM alkoxy, -N(R Z5 ) 2 , or phenyl optionally substituted with one more independently selected halogens wherein each R" independently has the values described herein; wherein Zi is not hydrogen, halogen, methyl, or cyano if Z? is hydrogen or methyl.
• Zi is hydrogen, chloro, or methyl, and Z 2 is not hydrogen or methyl.
• Z ⁇ is hydrogen, and 3 ⁇ 4 is not hydrogen or methyl.
• Z : is chloro, and 3 ⁇ 4 is not hydrogen or methyl.
• Zj is methyl, and 3 ⁇ 4 is not hydrogen or methyl.
• R z3 is an optionally substituted phenyl, an optionally substituted 5- to 7-membered cycloaliphatic, an optionally substituted 5- to 7-membered heterocyclyl, or an optionally substituted C,_ 4 aliphatic.
• R z3 is a phenyl, 5- to 7-membered cycloaliphatic, 5- to 7-membered heterocyclyl, or Ci_ 4 aliphatic, any of which are optionally substituted with n occurrences of R 2 , wherein n and R 2 have the values described herein.
• R z3 is a phenyl, 5- to 7-membered cycloaliphatic, 5- to 7-membered heterocyclyl, or C,_ 4 aliphatic, any of which may be substituted with one or more independently selected R z4 , wherein each R 24 independently has the values described herein.
• R z3 is a phenyl, 5- to 7- membered cycloaliphatic, 5- to 7-membered heterocyclyl, or Ci_ 4 aliphatic, any of which are optionally substituted with one to three independently selected R z4 , wherein each R z4 independently has the values described herein.
• R z3 is a phenyl, 5- to 7-membered cycloaliphatic, 5- to 7-membered heterocyclyl, or C)_ aliphatic, any of which may be substituted with one to two independently selected R z4 , wherein each R 7'4 independently has the values described herein.
• R z3 is a phenyl, 5- to 7-membered cycloaliphatic, 5- to 7-membered heterocyclyl, or C,_ 4 aliphatic, any of which may be substituted with one R z4 , wherein R z4 has the values described herein.
• R z3 is a phenyl, 5- to 7-membered cycloaliphatic, or Ci.4 aliphatic, any of which may be substituted with one to three R z4 , wherein each R z4 independently has the values described herein.
• R z3 is a phenyl, 5- to 7-membered cycloaliphatic, or C 1 .4 aliphatic, any of which may be substituted with one R z4 , wherein R z4 has the values described herein.
• each occurrence of R z4 is independently hydroxyl, halogen, cyano, C, relieve4 aliphatic, C,. 4 fluoroaliphatic, C,. 4 alkoxy, C fluoroalkoxy, -N(R z5 ) 2 , -C(0)R z6 , -C(0) 2 R z5 , 5- or 6-membered cycloaliphatic or heterocyclyl, or a phenyl optionally substituted with one or more independently selected halogens, wherein each R" independently has the values described herein and R z6 has the values described herein.
• each occurrence of R z4 is independently halogen, cyano, C 1 .4 aliphatic, or C,_ 4 fluoroaliphatic.
• each occurence of R z4 is independently chloro, bromo, fluoro, iodo, methyl, ethyl, propyl, tert-butyl, methoxy, ethoxy, isopropoxy, tert-butoxy, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, trifluoromethylthio, dimethylamino, diethylamino, ethyne, cyclopropyl, or phenyl.
• each occurrence of R z4 is independently chloro, bromo, fluoro, iodo, methyl, ethyl, difluoromethoxy, trifluoromethoxy, ethyne, cyclopropyl, or phenyl. In some embodiments, each occurence of R z4 is independently chloro, bromo, fluoro, methyl, ethyl, or trifluoromethyl. In some embodiments, each occurrence of R z4 is independently chloro, bromo, iodo, or methyl.
• each R z5 is independently hydrogen or Q_ 4 alkyl. In some embodiments, each R z5 is independently hydrogen or methyl. In some embodiments, R z5 is hydrogen. In some embodiments, R" is methyl. In some embodiments, each R" is independently methyl or ethyl.
• R z6 is C,. 4 alkyl. In some embodiments, R z6 is methyl. In some embodiments, R z6 is methyl or ethyl.
• (a) 3 ⁇ 4 is a ring system having an optionally substituted 5- to 7- membered heterocyclyl with 1-2 heteroatoms or an optionally substituted 5- to 7-membered cycloaliphatic fused to
• (a) 3 ⁇ 4 is a ring system having a 5- to 7-membered heterocyclyl with 1-2 heteroatoms or a 5- to 7-membered cycloaliphatic fused to
• ring system is optionally substituted by n occurrences of R 2 , wherein n and R 2 have the values described herein;
• R e is either:
• R e is not hydrogen if R f and R fl are present and form a ring
• Lj is a Ci_3 alkylene chain wherein 1 or 2 saturated carbon atoms are optionally substituted by (R f )(R f ') and in which there are optionally one or two degrees of unsaturation;
• V is -S-, -0-, -S(O)-, -S(0) 2 -, -C(O)- or -N(R S )-, wherein R s has the values described herein;
• L2 is a Co- 2 alkylene chain wherein one saturated carbon atom is optionally substituted by
• (a) 3 ⁇ 4 is a ring system having a 5- to 7-membered heterocyclyl with 1-2 heteroatoms or a 5- to 7-membered cycloaliphatic fused to
• ring system is optionally substituted by 1-3 independent occurrences of halogen, hydroxyl, cyano, Ci_ aliphatic, Cj. 4 fluoroaliphatic, Ci_ 4 alkoxy, fluoroalkoxy, -S-Ci.
• each occurrence of R 7 is independently hydrogen or Ci_ 4 alkyl
• each occurrence of R zS is independently Ci_ 4 alkyl
• T 2 is a Ci_C 2 alkylene chain
• R z9 is cyano, -N0 2 , -N(R z7 ) 2 , -OR z7 , -C(0)R z8 , -C(0) 2 R z7 , or -C(0)N(R z7 ) 2 ;
• R e is hydrogen, hydroxyl, halogen, -CF 3 , or Ci_ 4 aliphatic optionally substituted with one or more hydroxyl, halogen, or C ⁇ _ 4 aliphatic,
• R e is not hydrogen if R f and R f ' are present and form a ring
• R e is a ring chosen from 6-membered aryl, 5-to 6-membered heteroaryl, 3- to 7-membered cycloaliphatic, or 4- to 7-membered heterocyclyl, which is optionally fused to a second 6-membered aryl, 5-to 6-membered heteroaryl, 3- to 7-membered cycloaliphatic, or 4- to 7-membered heterocyclyl, R e being optionally substituted by 1-3 independent occurrences of halogen, hydroxyl, cyano, C,_ 4 aliphatic, Q. 4 fluoroaliphatic, C,. 4 alkoxy, C
• each occurrence of R z7 is independently hydrogen or C]_ 4 alkyl; each occurrence of R z is independently C,_ 4 alkyl;
• T 2 is a C I.CT alkylene chain
• R z9 is cyano, -N0 2 , -N(R z7 ) 2 , -OR z7 , -C(0)R z8 , -C(0) 2 R z7 , or -C(0)N(R z7 ) 2 .
• Z 2 is a ring system having a 5- to 7-membered heterocyclyl with 1-2 heteroatoms or a 5- to 7-membered cycloaliphatic fused to
• ring system is optionally substituted by n occurrences of R 2 , wherein n and R 2 have the values described herein.
• 3 ⁇ 4 is a ring system having a 5- to 7-membered heterocyclyl with 1-2 heteroatoms or a 5- to 7-membered cycloaliphatic fused to
• ring system is optionally substituted by 1 -3 independent occurrences of halogen, hydroxyl, cyano, Ci_ 4 aliphatic, Ci_ 4 fluoroaliphatic, Ci. 4 alkoxy, C, 4 fluoroalkoxy, -S-C
• each R z7 independently has the values described herein and R z8 , T 2 , and R z9 have the values described herein.
• 3 ⁇ 4 is a ring system having a 5- to 7-membered heterocyclyl with 1 -2 heteroatoms or a 5- to 7-membered cycloaliphatic fused to a 5-membered heteroaryl or a 6- membered aryl or heteroaryl to form a bicyclic group; wherein the ring system is optionally substituted by 1-3 independent occurrences of halogen, hydroxyl, cyano, Ci_ 4 aliphatic, Ci_ 4 fluoroaliphatic, C,_ 4 alkoxy, C fluoroalkoxy, -S-Ci_ 4 aliphatic, -S-Ci_ 4 fluoroaliphatic, -N(R z7 ) 2 , - C(0)R z8 , -S(0)R zS , -S(0) 2 R z8 , -C(0) 2 R z7 , -C(0)N(R z7 ) 2 , --
• 3 ⁇ 4 is a 6-membered heterocyclyl, the heterocyclyl containing 1 N or O atom, fused to a 6-membered aryl or heteroaryl ring to form a bicyclic group, wherein the ring system is optionally substituted by 1-3 independent occurrences of halogen, hydroxyl, cyano, Ci_ 4 aliphatic, Ci_ 4 fluoroaliphatic, C M alkoxy, Ci_ 4 fluoroalkoxy, -S-C,_ 4 aliphatic, -S-C,.
• R z7 is hydrogen or Ci- alkyl. In some embodiments, R z7 is hydrogen or methyl. In some embodiments, R z7 is hydrogen. In some embodiments, R z7 is methyl. In some embodiments, R z7 is methyl or ethyl.
• R z8 is Ci_ 4 alkyl. In some embodiments, R z8 is methyl. In some embodiments, R zS is methyl or ethyl.
• T 2 is an optionally substituted C
• T 2 is a Ci_C 2 alkylene chain optionally substituted with 0-3 independent occurrences of R t2 , wherein R' 2 has the values described herein.
• T 2 is a Q. 2 alkylene chain.
• T 2 is -CH 2 -CH 2 -.
• T 2 is -C(CH 3 ) 2 -.
• T 2 is -CH 2 -.
• each occurrence of R t2 is independently C,_ 4 alkyl. In some embodiments, each occurrence of R 12 is independently methyl or ethyl. In some embodiments, R 12 is methyl.
• R z9 is cyano, -N(R z7 ) 2 , -OR z7 , -C(0)R z8 , -C(0) 2 R z7 , or - C(0)N(R z7 ) 2 , wherein R z7 and R z8 have the values described herein.
• R k is hydrogen or methyl. In some embodiments, R k is deuterium. In some embodiments, R k is hydrogen.
• X 4 is S, O, or N(R n4 ), wherein R" 4 has the values described herein. In some embodiments, X4 is O or N(R" 4 ), wherein R n4 has the values described herein. In some embodiments, X 4 is N(R n4 ), wherein R" 4 has the values described herein. In some embodiments, X 4 is O or N(H). In some embodiments, X 4 is O. In some embodiments, X 4 is N(H).
• R" 4 is hydrogen or C
• X 5 is O, C(O), or C(R x5 )(R x5 '), wherein R x5 and R x5, have the values described herein.
• X 5 is O.
• X 5 is C(R :, )(R : ").
• X 5 is CD 2 .
• X 5 is O, C(O), or C(R x3 )(R x5 '), wherein X 5 is not O if t is N(R" 4 ) or S.
• X 5 is CH 2 .
• R" is hydrogen, halogen, hydroxyl, or C,. 4 alkyl, or R" and R x5 ', taken together with the carbon atom to which they are attached, form a spirocychc 3-6 membered carbocycle or a spirocychc 4-6 membered heterocycle comprising one heteroatom chosen from O, N, or S.
• R x5 is hydrogen, fluoro, hydroxyl, or Ci_ 4 alkyl, or R x5 and R x: ", taken together with the carbon atom to which they are attached, form a spirocychc 3-6 membered carbocycle or a spirocyclic 4-6 membered heterocycle comprising one heteroatom chosen from O, N, or S.
• R x5 is hydrogen, fluoro, hydroxyl, or d- 4 alkyl.
• R x5 is hydrogen, fluoro, chloro, hydroxyl, or methyl.
• R" 5 is hydrogen or methyl.
• R xS is hydrogen.
• R x5 is hydrogen, halogen or C 1 -4 alkyl, or R° and R x5 ', taken together with the carbon atom to which they are attached, form a spirocyclic 3-6 membered carbocycle or a spirocyclic 4-6 membered heterocycle comprising one heteroatom chosen from O, N, or S, wherein R x5 ' is not halogen if R n is hydroxyl.
• R x5 ' is hydrogen, fluoro, or Ci_4 alkyl, or R x5 and R x5 ', taken together with the carbon atom to which they are attached, form a spirocyclic 3-6 membered carbocycle or a spirocyclic 4-6 membered heterocycle comprising one heteroatom chosen from O, N, or S, wherein R x3 ' is not halogen if R x5 is hydroxyl.
• R 5, is hydrogen, fluoro, or C M alky], wherein R 5 ' is not fluoro if R" is hydroxyl.
• R"' is hydrogen, fluoro, chloro, or methyl, wherein R x3 ' is not fluoro if R x5 is hydroxyl.
• R x5 ' is hydrogen.
• R x5 is hydrogen, halogen, hydroxy], or Q. 4 alkyl and R x5 ' is hydrogen.
• R 3 is hydrogen, fluoro, chloro, hydroxyl, or methyl and R x5 ' is hydrogen.
• R 3 is hydrogen or methyl and R"' is hydrogen.
• R 3 is hydrogen and R 3 ' is hydrogen.
• R x5 is fluoro and R x5 ' is fluoro.
• R ' ° is methyl and R"' is methyl.
• R x1 and R"' taken together with the carbon atom to which they are attached, a spirocyclic 3-6 membered carbocycle or a spirocyclic 4-6 membered heterocycle comprising one heteroatom chosen from O, N, or S.
• R x5 and R°' taken together with the carbon atom to which they are attached, form a spirocyclic 3-6 membered carbocycle.
• R x5 and R x5 ' are independently hydrogen or fluoro; or, together with the carbon to which they are attached, form a cyclopropyl ring.
• Ring A is a fused 5-membered heteroaryl or 6-membered aryl or heteroary], and is optionally substituted with 1-3 independent occurrences of halogen, hydroxy], cyano, CM aliphatic, C fluoroaliphatic, C M alkoxy, C fluoroalkoxy, -S-CM aliphatic, -S-C fluoroaliphatic, -N(R z7 ) 2 , -C(0)R z8 , -S(0)R zS , -S(0) 2 R z8 , -C(0) 2 R z7 , -C(0)N(R z7 ) 2 , -S(0) 2 N(R z7 ) 2 , - OC(0)N(R z7 ) 2 , -N(R z7 )C(0)R zS , -N(R z7 )S0 2 R zS , -N(R zS , -N
• Ring A is a fused 6-membered aryl or heteroaryl having one heteroatom and is optionally substituted with 1 -3 independent occurrences of halogen, hydroxyl, cyano, Q _ 4 aliphatic, C M fluoroaliphatic, C alkoxy, C M fluoroalkoxy, -S-C M aliphatic, -S-C,. 4 fluoroaliphatic, -N(R z7 ) 2 , -C(0)R z8 .
• Ring A is a fused 5-membered heteroaryl or 6-membered aryl or heteroaryl, and is optionally substituted with 1 -3 independent occurrences of chloro, bromo, fluoro, iodo, methyl, ethyl, propyl, isopropyl, tert-butyl, methoxy, ethoxy, isopropoxy, tert-butoxy, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, trifluoromethylthio, dimethylamino, diethylamino, cyano, ethyne, cyclopropyl, or phenyl.
• Ring A is a fused 6-membered aryl or heteroaryl, and is optionally substituted with 1-3 independent occurrences of chloro, bromo, fluoro, iodo, methyl, ethyl, propyl, isopropyl, tert-butyl, methoxy, ethoxy, isopropoxy, tert-butoxy, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, trifluoromethylthio, dimethylamino, diethylamino, cyano,ethyne, cyclopropyl, or phenyl.
• Ring A is a fused phenyl or pyridyl, and is optionally substituted with 1-3 independent occurrences of chloro, bromo, fluoro, iodo, methyl, ethyl, propyl, isopropyl, tert-butyl, methoxy, ethoxy, isopropoxy, tert-butoxy, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, trifluoromethylthio, dimethylamino, diethylamino, cyano, ethyne, cyclopropyl, or phenyl.
• Ring A is a fused 6-membered aryl or heteroaryl, and is optionally substituted with 1-3 independent occurrences of chloro, bromo, fluoro, iodo, methyl, ethyl, propyl, isopropyl, tert-butyl, methoxy, ethoxy, isopropoxy, tert-butoxy, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, trifluoromethylthio, dimethylamino, cyano, diethylamino, ethyne, cyclopropyl, or phenyl.
• Z 2 is
• 3 ⁇ 4 is (a- iii), wherein X 4 , X 5 , X 6 , X 6 ', R m , and R j have the values described herein.
• 3 ⁇ 4 is (a-iv), wherein X4, X5, X 3 ⁇ 4 , X(,', R m , and R J have the values described herein. [00120]
• Z 2
• 3 ⁇ 4, X 5 , X 6 , X 7 , X 8 , and R 1 have the values described herein.
• 3 ⁇ 4> is (a- v), wherein X4, X 5 , X 6 , X 7 , X 8 , and R j have the values described herein.
• 3 ⁇ 4 is (a-vi), wherein X 4 , X 5 , X 6 , X 7 , Xg, and R s have the values described herein.
• X 7 is O or S.
• X 8 is S or N(H).
• 3 ⁇ 4 is
• 3 ⁇ 4 is (a-vii), wherein X4, X 5 , R m , and R J have the values described herein. In some embodiments, 3 ⁇ 4 is (a-viii), wherein X 5 and R j have the values described herein. In some embodiments, 3 ⁇ 4 is (a-ix), wherein X 5 and R J have the values described herein. In some embodiments, Z 2 is (a-x), wherein X 5 and R J have the values described herein. In some embodiments, 3 ⁇ 4 is (a-xi), wherein X 5 and R j have the values described herein. In some embodiments, 3 ⁇ 4 is (a-xii), wherein X 4 , R m , and R J have the values described herein. In some embodiments, 3 ⁇ 4 is (a-xii), wherein X 4 , R m , and R J have the values described herein. In some embodiments, 3 ⁇ 4 is (a-xii), wherein X 4 , R
• X 6 is N or C(R 6 ), wherein R x6 has the values described herein. In some embodiments, X 6 is N or C(H). In some embodiments, X 6 is N. In some embodiments, X 6 is C(R 6 ), wherein R x6 has the values described herein. In some embodiments, X 6 is C(H).
• R 6 is hydrogen, halogen, hydroxyl, cyano, C aliphatic, C,_ 4 fluoroaliphatic, C,. 4 alkoxy, C 4 fluoroalkoxy, -N(R z7 ) 2 , -C(0) 2 R z7 , -C(0)N(R z7 ) 2 , -S(0) 2 N(R z7 ) 2 , - CH 2 -OR z7 , -CH 2 NR z7 , a 3- to 6-membered cycloaliphatic, or a 4- to 6-membered heterocyclyl, wherein each R z7 independently has the values described herein.
• R x6 is hydrogen, chloro, bromo, fluoro, iodo, methyl, ethyl, propyl, tert-butyl, methoxy, ethoxy, isopropoxy, tert-butoxy, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, trifluoromethylthio, dimethylamino, diethylamino, ethyne, or cyclopropyl.
• R 6 is hydrogen, chloro, fluoro, bromo, iodo, methyl, ethyl, isopropyl, cyano, cyclopropyl, CF 3 , -OCH 3 , -OCH 2 CH 3 , or - C ⁇ CH.
• R x6 is hydrogen, fluoro, chloro, bromo, iodo, or methyl.
• R 6 is hydrogen, fluoro, chloro, or methyl.
• R x6 is hydrogen, fluoro, or chloro. In some embodiments, R x6 is hydrogen.
• X 6 ' is N or C(R x6 '), wherein R x6 ' has the values described herein. In some embodiments, X 6 ' is N or C(R 6 ), wherein R x6 has the values described herein. In some embodiments, X 6 ' is N or C(H). In some embodiments, X 6 ' is N. In some embodiments, X 6 ' is C(R x6 '), wherein R x6 ' has the values described herein. In some embodiments, X 6 ' is C(H).
• R x6 ' is hydrogen, halogen, hydroxyl, cyano, Ci_ 4 aliphatic, C
• R x6 is hydrogen, chloro, bromo, fluoro, iodo, methyl, ethyl, propyl, tert-butyl, methoxy, ethoxy, isopropoxy, tert-butoxy, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, trifluoromethylthio, dimethylamino, diethylamino, ethyne, or cyclopropyl.
• R x ' is hydrogen, chloro, fluoro, bromo, iodo, methyl, ethyl, isopropyl, cyano, cyclopropyl, CF 3 , -OCH 3 , -OCH 2 CH 3 , or - C ⁇ CH.
• R x6 is hydrogen, fluoro, chloro, bromo, iodo, or methyl.
• R x6 ' is hydrogen, fluoro, chloro, bromo, iodo, or methyl.
• R x6 ' is hydrogen, fluoro, chloro, or methyl.
• R x6 ' is hydrogen, fluoro, or chloro.
• R x6, is hydrogen.
• R j is hydrogen, halogen, hydroxyl, cyano, Cj. 4 aliphatic, C M fluoroaliphatic, C,. 4 alkoxy, C fluoroalkoxy, -N(R z7 ) 2 , -C(0) 2 R z7 , -C(0)N(R z7 ) 2 , -S(0) 2 N(R z7 ) 2 , - CH 2 -OR z7 , -CH 2 NR Z? , a 3- to 6-membered cycloaliphatic, or a 4- to 6-menibered heterocyclyl, wherein each R z7 independently has the values described herein.
• R j is hydrogen, chloro, bromo, fluoro, iodo, methyl, ethyl, propyl, tert-butyl, methoxy, ethoxy, isopropoxy, tert-butoxy, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, trifluoromethylthio, dimethylamino, diethylamino, ethyne, or cyclopropyl.
• R J is hydrogen, chloro, fluoro, bromo, iodo, methyl, ethyl, isopropyl, cyano, cyclopropyl, CF 3 , -OCH 3 , -OCH 2 CH 3 , or - C ⁇ CH.
• R J is methyl, ethyl, isopropyl, hydrogen, fluoro, chloro, bromo, cyclopropyl, -C ⁇ CH or -CF 3 .
• R J is hydrogen, fluoro, chloro, bromo, iodo, or methyl.
• R j is hydrogen, fluoro, chloro, or methyl.
• R' is fluoro, chloro, or methyl.
• R J is hydrogen, fluoro, or chloro.
• R j is hydrogen.
• R j is fluoro or chloro.
• R j is methyl.
• R J is fluoro.
• R J is chloro.
• R m is hydrogen, halogen, hydroxyl, cyano, Ci_ 4 aliphatic, Ci_ 4 fluoroaliphatic, C,. 4 alkoxy, C fluoroalkoxy, -N(R z7 ) 2 , -C(0) 2 R z7 , -C(0)N(R z7 ) 2 , -S(0) 2 N(R z7 ) 2 , - CH 2 -OR z7 , -CH 2 NR z7 , a 3- to 6-membered cycloaliphatic, or a 4- to 6-membered heterocyclyl, wherein each R z7 independently has the values described herein.
• R m is hydrogen, chloro, bromo, fluoro, iodo, methyl, ethyl, propyl, tert-butyl, methoxy, ethoxy, isopropoxy, tert-butoxy, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, trifluoromethylthio, dimethylamino, diethylamino, ethyne, or cyclopropyl.
• R m is hydrogen, fluoro, chloro, fluoro, bromo, iodo, methyl, ethyl, isopropyl, cyano, cyclopropyl, CF 3 , -OCH 3 , -OCH 2 CH , or -C ⁇ CH.
• R m is hydrogen, fluoro, chloro, bromo, iodo, or methyl.
• R m is hydrogen, fluoro, chloro, or methyl.
• R m is hydrogen, fluoro, or chloro.
• R m is hydrogen.
• each R x6 , R x6 ', R s and R m is independently hydrogen, halogen, hydroxyl, cyano, aliphatic, C,_ 4 fluoroaliphatic, C]. 4 alkoxy, Ci- fluoroalkoxy, -N(R z7 ) 2 , - C(0) 2 R z7 , -C(0)N(R z7 ) 2 , -S(0) 2 N(R z7 ) 2 , -CH 2 -OR z7 , -CH 2 NR z7 , 3- to 6-membered cycloaliphatic, or a 4- to 6-membered heterocyclyl, wherein each R z?
• each of R x6 , R x6 ', R j and R m is independently hydrogen, chloro, fluoro, bromo, iodo, methyl, ethyl, isopropyl, cyano, cyclopropyl, CF 3 , -OCH 3 , -OCH 2 CH 3 , or -C ⁇ CH; wherein at least one of R x6 , R x7 , R j and R m is hydrogen.
• each R 6 , R x6 ', R' and R m is independently hydrogen, halogen, hydroxyl, cyano, Ci_ 4 aliphatic, C,. 4 fluoroaliphatic, C alkoxy, C fluoroalkoxy, -N(R z7 ) 2 , -C(0) 2 R z7 , -C(0)N(R z7 ) 2 , - S(0) 2 N(R z7 ) 2 , -CH 2 -OR z7 , -CH 2 NR z7 , 3- to 6-membered cycloaliphatic, or a 4- to 6-membered heterocyclyl, wherein each R z7 independently has the values described herein and at least one of R x6 , R x6 ', R j and R m is hydrogen.
• each of R x6 , R x6 ', R J , and R m is independently hydrogen, chloro, iluoro, bromo, iodo, methyl, ethyl, isopropyl, cyano, cyclopropyl, CF 3 , -OCH 3 , - OCH 2 CH 3 , or -OCH; wherein at least two of R x6 , R x7 , R j and R m are hydrogen.
• each R x6 , R x6 ', R 1 and R m is independently hydrogen, halogen, hydroxyl, cyano, C)_ aliphatic, C fluoroaliphatic, C alkoxy, C fluoroalkoxy, -N(R z7 ) 2 , -C(0) 2 R z7 , -C(0)N(R z7 ) 2 , - S(0) 2 N(R z7 ) 2 , -CH 2 -OR z7 , -CH 2 NR z7 , 3- to 6-membered cycloaliphatic, or a 4- to 6-membered heterocyclyl, wherein each R z7 independently has the values described herein and at least one of R 6 , R x6 ', R j and R m is hydrogen.
• each of R 6 , R x6 ', R and R m is independently hydrogen, chloro, fluoro, bromo, iodo, methyl, ethyl, isopropyl, cyano, cyclopropyl, CF 3 , -OCH 3 , - OCH 2 CH 3 , or -C ⁇ CH; wherein at least two of R x6 , R x7 , R j and R m are hydrogen.
• R 6 is hydrogen; R 6 ' is hydrogen; and R j and R m are independently hydrogen, halogen, hydroxyl, cyano, C 1 .4 aliphatic, C ⁇ 4 fluoroaliphatic, C 1 .4 alkoxy, C 1 .4 fluoroalkoxy, -N(R z7 ) 2 , -C(0) 2 R z7 , -C(0)N(R z7 ) 2 , -S(0) 2 N(R z7 ) 2 , -CH 2 -OR z7 , -CH 2 NR z7 , 3- to 6-membered cycloaliphatic, or a 4- to 6-membered heterocyclyl, wherein each R z7 independently has the values described herein.
• R 6 is hydrogen; R 6 ' is hydrogen; and R j and R m are independently hydrogen, chloro, fluoro, bromo, iodo, methyl, ethyl, isopropyl, cyano, cyclopropyl, CF 3 , -OCH 3 , -OCH 2 CH 3 , or -C ⁇ CH.
• R x6 is hydrogen; R x6 ' is hydrogen; R m is hydrogen; and R j is methyl, ethyl, isopropyl, hydrogen, fluoro, chloro, bromo, cyclopropyl, -C ⁇ CH or -CF 3 .
• R 6 is hydrogen; R 6 ' is hydrogen; R m is hydrogen; and R j is hydrogen, fluoro, chloro, or methyl.
• m is 0-2. In some embodiments, m is 1 -2. In some embodiments, m is 0- 1. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2.
• 3 ⁇ 4 is L-R e .
• L is -L r , -V,-L 2 -, or wherein L, , V I ; and L2 have the values described herein.
• L is -CH(OH)- or - C(OH)(CH 3 )-. In some embodiments, L is -CH(NH 2 )- or -C(CH 3 )(NH 2 )-. In some embodiments, L is - CH(OH)- or -CH(NH 2 )-. In some embodiments, L is -C(CH 3 )(OH)- or -C(CH 3 )(NH 2 )-. In some
• L is «* ⁇ . ⁇ or ⁇ . ⁇ ⁇ ⁇ some embodiments, L is -CH 2 -. In some embodiments, L is -CH(OH)-. In some embodiments, L is -C(OH)(CH 3 )-. In some embodiments, L is -CH(NH 2 )-. In some embodiments, L is -C(CH 3 )(NH 2 )-. In some embodiments, L is -CH 2 -CH 2 -. In
• L is ⁇ . In some embodiments, L is
• L is a C
• L is - C(R f )(R f ')-, wherein R f and R f ' have the values described herein.
• is -CH?-.
• Li is * ,
• each R f is independently hydrogen; hydroxyl; -N(R h )(R h '); d. 4 aliphatic optionally substituted with hydroxyl, -OCH 3 , or cyclopropyl; -O-C 1 .
• each R f is independently hydrogen, hydroxyl, N(R h )(R h '), -OCH 3 , cyclopropyl, or C aliphatic optionally substituted with hydroxyl or -OCH 3 , wherein R h and R h ' have the values described herein, or, together with the carbon atom to which they are attached, R f and R fl form a 4- to 6-membered heterocycle comprising a heteroatom chosen from N (which may be protonated or C]_ 4 alkylated), O, or S, the heteroatom optionally located immediately adjacent to the quaternary carbon of the heterocycle.
• each R f is independently hydrogen, hydroxyl, N(R h )(R hl ), - OCH 3 , cyclopropyl, or C aliphatic optionally substit together with
• each R f is independently hydrogen, hydroxyl
• each R f is independently hydrogen, C
• each R fl is independently hydrogen, cyclopropyl, or Q.
• aliphatic optionally substituted with hydroxyl or -OCH 3 or, together with the carbon atom to which they are attached, R f and R f ' form a 4- to 6-membered heterocycle comprising a heteroatom chosen from N (which may be protonated or C alkylated), O, or S, the heteroatom optionally located immediately adjacent to the quaternary carbon of the heterocycle; or, together with the carbon atom to which they are attached, R f
• each R FL is independently hydrogen, cyclopropyl, or C,. 4 alkyl optionally substituted with hydroxyl or -OCH 3 .
• each R F ' is independently hydrogen, CM alkyl, or cyclopropyl.
• each R FL is independently hydrogen, methyl, ethyl, or isopropyl.
• each R F ' is independently hydrogen or methyl.
• each R F ' is independently hydrogen or methyl.
• each R F ' is hydrogen.
• each R F is independently hydrogen, hydroxyl, N(R H )(R H '), -OCH 3 , cyclopropyl, or . 4 aliphatic optionally substituted with hydroxyl or -OCH 3 ; and each R F ' is independently hydrogen, cyclopropyl, or CM aliphatic optionally substituted with hydroxyl or -OCH 3 , wherein at least one of R F and R F ' comprises at least one heteroatom; or, together with the carbon atom to which they are attached, R F and R F ' form a 4- to 6-membered heterocycle comprising a heteroatom chosen from N (which may be protonated or C,.
• R f and R f ' form , ,or 3 ⁇ 4 ⁇ ⁇ f wherein
• X 9 has the values described herein. In some emdodiments, together with the carbon atom to which
• each R f is independently hydrogen, hydroxyl, N(R h )(R h '), C
• each R f and R f ' is independently hydrogen, methyl, ethyl, or isopropyl.
• each R f and R f ' is independently hydrogen or methyl.
• R h and R h ' are each independently hydrogen or C, 4 alkyl. In some embodiments, R h and R h ' are each independently hydrogen or methyl. In some embodiments, R h and R hl are each hydrogen. In some embodiments, R h is hydrogen or Ci_ alkyl. In some embodiments, R h is hydrogen or methyl. In some embodiments, R h is hydrogen. In some embodiments, R b is hydrogen or Ci_ alkyl and R 1 " is hydrogen. In some embodiments, R h is hydrogen or methyl and R h ' is hydrogen. In some embodiments, R h is methyl and R hl is methyl.
• X 9 is O, N(R h ), or S, wherein R h has the values described herein. In some embodiments, X 9 is O, N(H), N(CH 3 ), or S. In some embodiments, X 9 is O. In some embodiments, X 9 is N(H). In some embodiments, X 9 is N(CH 3 ). In some embodiments, X 9 is S.
• V is -S-, -0-, -S(O)-, -S(0) 2 -, -C(O)- or -N(R )-, wherein R s has the values described herein.
• V is -C(O)- or -N(R S )-, wherein R s has the values described herein.
• V ⁇ is -S-, -S(O)-, or -S(0) 2 -.
• is -O-
• R g is hydrogen or Ci_ alkyl.
• R s is hydrogen, methyl, ethyl, or isopropyl.
• R s is hydrogen or methyl.
• R g is hydrogen.
• R s is methyl.
• > is a C 0 .2 alkylene chain wherein one saturated carbon atom is optionally substituted by (R f )(R f '), wherein R f and R f ' have the values described herein.
• L 2 is -C(R f )(R f ')-.
• L> is -CH 2 -.
• L? is - CH 2 -CH 2 -.
• L 2 is absent.
• R e is either (i) hydrogen, hydroxyl, halogen, -CF 3 , or an optionally substituted C ( _ 4 aliphatic, with the proviso that R e is not hydrogen if R f and R f ' are present and form a ring; OR (ii) R e is a ring chosen from optionally substituted 6-membered aryl, optionally substituted 5-to 6-membered heteroaryl, optionally substituted 3- to 7-membered cycloaliphatic, or optionally substituted 4- to 7-membered heterocyclyl, which is optionally fused to a second optionally substituted 6-membered aryl, optionally substituted 5-to 6-membered heteroaryl, optionally substituted 3- to 7-membered cycloaliphatic, or optionally substituted 4- to 7-membered heterocyclyl.
• R e is hydrogen, hydroxyl, halogen, -CF 3 , or C
• R e is hydroxyl, halogen, -CF 3 , or Ci_ 4 alkyl optionally substituted with one or more hydroxyl, halogen, or d. 4 alkyl.
• R e is an optionally substituted ring chosen from 3- to 7-membered cycloaliphatic or 4- to 7-membered heterocyclyl, which is optionally fused to a second 6-membered aryl, 5- to 6-membered heteroaryl, 3- to 7-membered cycloaliphatic, or 4- to 7-membered heterocyclyl, which is optionally substituted.
• R e is a ring chosen from 3- to 7- membered cycloaliphatic or 4- to 7-membered heterocyclyl, which is optionally fused to a second 6- membered aryl, 5- to 6-membered heteroaryl, 3- to 7-membered cycloaliphatic, or 4- to 7-membered heterocyclyl, wherein the R e ring or rings are optionally substituted by n occurrences of R 2 , wherein n and R 2 have the values described herein.
• R is a ring chosen from 3- to 7-membered cycloaliphatic or 4- to 7-membered heterocyclyl, which is optionally fused to a second 6-membered aryl, 5- to 6-membered heteroaryl, 3- to 7-membered cycloaliphatic, or 4- to 7-membered heterocyclyl, wherein the R e ring or rings are optionally substituted by 1 -3 independent occurrences of halogen, hydroxyl, cyano, C
• R e is a 5- to 7-membered cycloaliphatic ring or a 5- to 7- membered heterocyclyl having only one heteroatom, wherein the ring is optionally substituted. In some embodiments, R e is a 5- to 7-membered cycloaliphatic ring or a 5- to 7-membered heterocyclyl having only one heteroatom, wherein the ring is optionally substituted by n occurrences of R 2 , wherein n and R 2 have the values described herein.
• R e is a 5- to 7-membered cycloaliphatic ring or a 5- to 7-membered heterocyclyl having only one heteroatom, wherein the ring is optionally substituted by 1-3 independent occurrences of halogen, hydroxyl, cyano, C,_ 4 aliphatic, C
• R e is
• R e is (b-i) wherein Ej , R el , and R el ' have the values described herein.
• R e is (b-ii) wherein E] has the values described herein.
• R e is (b-iii) wherein E 2 has the values described herein and dashes indicate single or double bonds.
• R e is (b-iv) wherein E 3 , R el , R el ', and R e2 have the values described herein and dashes indicate single or double bonds. In some embodiments, R e is (b-v) wherein E 3 ', R el , R l ', and R e2 have the values described herein. In some embodiments, R e is (b-vi) wherein R el , R el ', and R e2 have the values described herein. In some embodiments, E, is N or C(H). In some embodiments, E 2 is O, S, or CH 2 .
• E 3 is O, S, N(R e3 ), or C(H)(R e3 ), wherein R e3 has the values described herein.
• E 3 ' is O, N(R e3 ) or C(H)(R e3 ), wherein R e3 has the values described herein.
• R l and R el ' are each
• R e2 is hydrogen or methyl.
• R e3 is hydrogen or methyl.
• R e is a 6-membered aryl or 5-to 6-membered heteroaryl, which is optionally fused to a second 6-membered aryl, 5-to 6-membered heteroaryl, 3- to 7-membered cycloaliphatic, or 4- to 7-membered heterocyclyl, wherein the R e ring or rings are optionally substituted.
• R e is a 6-membered aryl or 5-to 6-membered heteroaryl, which is optionally fused to a second 6-membered aryl, 5-to 6-membered heteroaryl, 3- to 7-membered cycloaliphatic, or 4- to 7-membered heterocyclyl, wherein the R e ring or rings are optionally substituted with n occurrences of R 2 , wherein n and R 2 have the values described herein.
• R e is a 6-membered aryl or 5-to 6-membered heteroaryl, which is optionally fused to a second 6-membered aryl, 5-to 6-membered heteroaryl, 3- to 7-membered cycloaliphatic, or 4- to 7- membered heterocyclyl, wherein the R e ring or rings are optionally substituted with 1 -3 independent occurrences of halogen, hydroxy!, cyano, C1.4 aliphatic, Ci_ 4 fluoroaliphatic, CM alkoxy, C
• R e is a 6-membered aryl or 5-to 6-membered heteroaryl, which is optionally substituted with 1 -3 independent occurrences of chloro, fluoro, bromo, iodo, methyl, ethyl, cyano, cyclopropyl, CF 3 , -OCH 3 , -OCH 2 CH 3 , or -C ⁇ CH.
• R e is
• R e is (b-vii), wherein E 4 and R e4 have the values described herein. In some embodiments, R e is (b-viii), wherein E 5 , E 6 , and R e4 have the values described herein. In some embodiments, R e is
• E 5 , E 6 , R e6 , R 7 , and R e8 have the values described herein.
• E 4 is S, O, or N(R n4 ), wherein R" 4 has the values described herein. In some embodiments, E 4 is S or O. In some embodiments, E 4 is S. In some embodiments, E 4 is O.
• R e4 is hydrogen, methyl, chloro, fluoro, bromo, iodo, cyano, or - CF 3 . In some embodiments, R e4 is hydrogen, methyl, chloro, fluoro, cyano, or -CF 3 . In some embodiments, R e4 is hydrogen, methyl, chloro, or fluoro. In some embodiments, R e4 is hydrogen or methyl. In some embodiments, R e4 is hydrogen.
• E 5 is N or C(R"), wherein R e:> has the values described herein. In some embodiments, E 5 is C(R e:> ), wherein R" has the values described herein. In some embodiments, E 5 is N or C(H). In some embodiments, E 5 is C(H). In some embodiments, E 5 is N.
• R e5 is hydrogen, halogen, methyl, -SCH 3 , -OCH 3 , -CF 3 , -OCF 3 , - OCF 2 H, or -C ⁇ CH.
• R" is hydrogen, halogen, methyl, -OCH 3 , -CF 3 , or -C ⁇ CH.
• R" is hydrogen or halogen.
• R" is hydrogen, fluoro, or chloro.
• R e5 is hydrogen, methyl, fluoro, or chloro. In some embodiments, R e5 is hydrogen.
• E 6 is N or C(H). In some embodiments, E 6 is N. In some embodiments, E 6 is C(H).
• R e6 is hydrogen, halogen, methyl, -SCH 3 , -OCH 3 , -CF 3 , -OCF 3 , - OCF 2 H, or -C ⁇ CH. In some embodiments, R e6 is hydrogen, halogen, methyl, -OCH 3 , -CF 3 , or -C ⁇ CH. In some embodiments, R e6 is hydrogen or halogen. In some embodiments, R e6 is hydrogen, fluoro, or chloro. In some embodiments, R e6 is hydrogen, methyl, fluoro, or chloro. In some embodiments, R e6 is hydrogen.
• R e7 is hydrogen, halogen, methyl, -SCH 3 , -OCH 3 , -CF 3 , -OCF 3 , - OCF 2 H, or -C ⁇ CH. In some embodiments, R e7 is hydrogen, halogen, methyl, -OCH 3 , -CF 3 , or -C ⁇ CH. In some embodiments, R e7 is hydrogen or halogen. In some embodiments, R e7 is hydrogen, fluoro, or chloro. In some embodiments, R e7 is hydrogen, methyl, fluoro, or chloro. In some embodiments, R e7 is hydrogen.
• R eS is hydrogen, halogen, methyl, -SCH 3 , -OCH 3 , -CF 3 , -OCF 3 , - OCF 2 H, or -C ⁇ CH.
• R e8 is hydrogen, halogen, methyl, -OCH 3 , -CF 3 , or -C ⁇ CH.
• R e8 is hydrogen or halogen.
• R e8 is hydrogen, fluoro, or chloro.
• R e is hydrogen, methyl, fluoro, or chloro.
• R e is hydrogen.
• each of R e5 , R e6 , R e7 , and R e8 is independently hydrogen, halogen, methyl, -OCH 3 , -CF 3 , or -C ⁇ CH; wherein at least one of R", R e6 , R e7 , and R eS is hydrogen.
• each of R e5 , R e6 , R e7 , and R e8 is independently hydrogen, halogen, methyl, -OCH 3 , -CF 3 , or -C ⁇ CH; wherein at least two of R e5 , R e6 , R e7 , and R eS are hydrogen.
• R e6 is hydrogen, fluoro, or chloro
• R e7 is hydrogen, fluoro, or chloro
• R eS is hydrogen, halogen, methyl, -OCH 3 , or cyano
• at least one of R e6 , R e7 , and R eS is hydrogen.
• R e6 is hydrogen, fluoro, or chloro
• R e7 is hydrogen, fluoro, or chloro
• R e8 is hydrogen, halogen, methyl, -OCH 3 , or cyano; wherein at least two of R e6 , R e7 , and R e8 are hydrogen.
• R R is furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, phenyl, naphthyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, indolizinyl, imidazopyridyl, indolyl, isoindolyl, indazolyl, benzimidazolyl, benzthiazolyl, benzothienyl, benzofuranyl, benzoxazolyl, benzodioxolyl, benzthiadiazolyl, 2,3-dihydrobenzofuranyl, 4H-furo[3,2-b]pyrrolyl
• R R is furanyl, thienyl, phenyl, naphthyl, pyridyl, benzothienyl, benzofuranyl, cyclohexyl, or cyclohexenyl.
• 3 ⁇ 4 is hydrogen. In some embodiments, 3 ⁇ 4 is chloro and Z ⁇ is not hydrogen, halogen, methyl, or cyano.
• R b is hydrogen or, together with the oxygen to which it is attached, forms a prodrug.
• R b is hydrogen or -C(0)-R bx , wherein R b has the values described herein.
• R b is hydrogen.
• R b is -C(0)-R bx , wherein R b has the values described herein.
• R bx is C,_ 4 alkyl, -CH(R y )-NH 2 , pyrrolidinyl, or -L b -OP0 3 H 2 , wherein L b and R by have the values described herein.
• R bx is -CH(R by )-NH 2 wherein R by has the values described herein.
• R x is -L b -OP0 3 H 2 , wherein L b has the values described herein.
• R bx is C 1 .4 alkyl.
• R y is C
• R by is C]. 4 alkyl optionally substituted with hydroxyl, phenyl, carboxyl, amino, or - C(0)NH 2 .
• R by is Ci -4 alkyl.
• R by is methyl, ethyl, isopropyl, propyl, butyl, or isobutyl.
• R by is methyl, ethyl, isopropyl, or isobutyl. In some embodiments, R by is methyl. In some embodiments, R by is ethyl. In some embodiments, R y is isopropyl. In some embodiments, R by is isobutyl.
• L b is a bivalent linker chosen from C l alkylene or -(CH 2 ) consultr phenylene-(CH 2 ) n2 - where n l is 0 or 1 and n2 is 1 or 2.
• L b is C : . 4 alkylene.
• L b is C]. 4 methylene.
• L b is ethylene.
• L b is -(CH 2 ) n i -phenyl ene-(CH 2 ) n 2- where n l is 0 or 1 and n2 is 1 or 2.
• L is -phenylene-(CH 2 ) n2 - where n2 is 1 or 2.
• L b is -CH 2 - phenylene-(CH 2 ) n2 - where n2 is 1 or 2.
• L b is -(CH 2 ) n i-phenylene-CH 2 - where n l is 0 or 1.
• L b is -(CH 2 ) relieve r phenylene-(CH 2 ) n2 - where n l is 0 or 1 and n2 is 2.
• At least one, at least two, at least three, at least four, at least five, at least six, or all of the following is/are true: Y is -0-; R a is hydroxyl; R a ' is hydrogen; R c is hydrogen; Xi is N; R d is hydrogen; or X 3 is C(H). In some embodiments, at least one, at least two, at least three, at least four, at least five, at least six, or all of the following is/are true: Y is -0-; R a is hydrogen; R a ' is hydrogen; R c is hydrogen; Xi is N; R d is hydrogen; or X 3 is C(H).
• n is 1 -5. In some embodiments, n is 1 -4. In some embodiments, n is 1-3. In some embodiments, n is 1 -2. In some embodiments, n is 1.
• each occurrence of R 2 is independently -R 2 ⁇ -T 3 -R 2d , -T 3 -R 2a , or - V 2 -T 3 -R 2d , wherein R 2a , T 3 , R 2d , V 2 and T 3 have the values described herein.
• each occurrence of R 2 is independently -R 2a or T 3 -R a , wherein R 2a and T 3 have the values described herein.
• each occurrence of R 2 is independently -R 2 , wherein R 2a has the values described herein.
• each occurrence of R 2 is independently halogen, -R 2c , -N(R 2b ) 2 , -OR 2b , -SR 2c , d-6 aliphatic or C,. 6 fluoroaliphatic, wherein R 2b and R 2c have the values described herein.
• each occurrence of R 2a is independently halogen, -CN, -N0 2 , -R 2c , -N(R 2b ) 2 , -OR 2b , -SR 2c , -S(0)R 2c , -S(0) 2 R 2c , -C(0)R b , -C(0)OR b , -C(0)N(R 2b ) 2 , -S(0) 2 N(R 2b ) 2 , -OC(0)N(R 2b ) 2 , -N(R 2e )C(0)R 2b , -N(R 2e )S0 2 R 2c , -N(R 2e )C(0)OR 2b , -N(R 2e )C(0)N(R 2b ) 2 , - N(R 2e )S0 2 N(R 2b ) 2 , or -Si(R 2c ) 3 , or a
• each occurrence of R 2b is independently hydrogen or a group selected from C,_ 6 aliphatic, Ci_ 6 haloaliphatic, 3- to 10-membered cycloaliphatic, 4- to 10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two occurrences of R 2b , taken together with a nitrogen atom to which they are bound, form a 4- to -7-membered heterocyclyl having 0-1 additional heteroatoms selected from nitrogen, oxygen, and sulfur.
• each occurrence of R 2c is independently a group selected from C,_ C 6 aliphatic, Q.Q haloaliphatic, 3- to 10-membered cycloaliphatic, 4- to 10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl having 1 -5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
• each occurrence of R 2d is independently hydrogen or a group selected from 3- to 10-membered cycloaliphatic, 4- to 10-membered heterocyclyl having 1 -5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
• each occurrence of R 2e is independently hydrogen or a Ci_ 6 aliphatic group.
• each occurrence of V 2 is independently -N(R )-, -0-, -S-, -S(O)-, -S(0) 2 -, -C(O)-, -C(0)0-, -C(0)N(R 2e )-, -S(0) 2 N(R 2e )-, -OC(0)N(R 2e )-, -N(R 2e )C(0)-, -N(R 2e )S0 2 -, - N(R 2e )C(0)0-, -N(R 2e )C(0)N(R e )-, -N(R 2e )S0 2 N(R 2e )-, -OC(O)-, or -C(0)N(R 2e )-0-, wherein R 2e has the values described herein.
• each occurrence of T 3 is a C ⁇ 6 alkylene chain wherein the alkylene chain optionally is interrupted by -N(R 4 )-, -0-, -S-, -S(O)-, -S(0) 2 -, -C(O)-, -C(0)0-, -C(0)N(R 4 )-, - S(0) 2 N(R 4 )-, -OC(0)N(R 4 )-, -N(R 4 )C(0)-, -N(R 4 )SO r , -N(R 4 )C(0)0-, -N(R 4 )C(0)N(R 4 )-, - N(R 4 )S(0) 2 N(R 4 )-, -OC(O)-, or -C(0)N(R 4 )-0- or wherein T 3 or a portion thereof optionally forms part of a 3- to 7-membered cycloaliphatic or 4- to 7-membere
• R a is hydrogen and R a ' is hydrogen;
• R a is hydrogen and R a ' is fluoro;
• R a is fluoro and R a ' is fluoro; or
• R a is OH and R a ' is hydrogen;
• Z is hydrogen, halogen, cyano, R z3 , -S-R z3 , -S(0)-R z3 , or -S(0) 2 -R z3 ;
• R z3 is a phenyl, 5- to 7-membered cycloaliphatic, 5- to 7-membered heterocyclyl, or Ci_ 4 aliphatic, any of which may be substituted with one or more independently selected R z4 ;
• R z4 is hydroxyl, halogen, cyano, CM aliphatic, C fluoroaliphatic, d_ 4 alkoxy, Q_ 4 fluoroalkoxy, -
• N(R") 2 , -C(0)R z6 . -C(0) 2 R z5 5- or 6-membered cycloaliphatic or heterocyclyl, or a phenyl optionally substituted with one or more independently selected halogens;
• each R" is independently hydrogen or C 4 alkyl ;
• R z6 is C,. 4 alkyl
• X 4 is O or N(R n4 );
• R n4 is hydrogen or CM alkyl
• X 6 is N or C(R x6 );
• each of R x6 , R x6 ', R j and R m is independently hydrogen, halogen, hydroxyl, cyano, C aliphatic, C fluoroaliphatic, C M alkoxy, C,. 4 fluoroalkoxy, -N(R z7 ) 2 , -C(0) 2 R z7 , -C(0)N(R z7 ) 2 , -S(0) 2 N(R z7 ) 2 , - CH 2 -OR z7 , -CH 2 NR z7 , a 3- to 6-membered cycloaliphatic, or a 4- to 6-membered heterocyclyl, wherein at least one of R x6 , R x6 ', R j and R m is hydrogen; and
• each R z7 is independently hydrogen or C alkyl.
• is hydrogen, halogen, cyano, or Ci_ 4 aliphatic optionally substituted with one or more hydroxyl, Q. 4 alkoxy, -N(R z5 ) 2 , or phenyl optionally substituted with one more independently selected halogens;
• X 4 is O or N(H);
• X 6 is N or C(H);
• R x6 ' is hydrogen
• R m is hydrogen, fluoro or chloro
• R j is methyl, ethyl, isopropyl, hydrogen, fluoro, chloro, bromo, cyclopropyl, -C ⁇ CH or -CF 3 .
• the chemical entity of formula (/) is:
• the chemical entity of formula (/) is:
• R a is hydrogen and R a ' is hydrogen;
• R a is hydrogen and R ' is fluoro;
• R a is fluoro and R a ' is fluoro; or
• R a is OH and R a ' is hydrogen;
• Z is hydrogen, halogen, cyano, R z3 , -S-R z3 , -S(0)-R z3 , or -S(0) 2 -R z3 ;
• R z3 is a phenyl, 5- to 7-membered cycloaliphatic, 5- to 7-membered heterocyclyl, or CM aliphatic, any of which may be substituted with one or more independently selected R z4 ;
• R z4 is hydroxyl, halogen, cyano, CM aliphatic, Ci_ 4 fluoroaliphatic, C alkoxy, Ci_ 4 fluoroalkoxy, -
• each R z5 is independently hydrogen or C alkyl
• R z6 is C M alkyl
• X 4 is O or N(R" 4 );
• R" 4 is hydrogen or Q. 4 alkyl
• X 6 is N or C(R x6 );
• each of R x6 , R x6 ', R j and R m is independently hydrogen, halogen, hydroxyl, cyano, CM aliphatic, C M fluoroaliphatic, C,. 4 alkoxy, C,.
• each R z7 is independently hydrogen or C 1 .4 alkyl.
• Zi is hydrogen, halogen, cyano, or C ] -4 aliphatic optionally substituted with one or more hydroxyl, Q. 4 alkoxy, -N(R") 2 , or phenyl optionally substituted with one more independently selected halogens;
• X 4 is O or N(H);
• X 6 is N or C(H);
• R x6 ' is hydrogen
• R m is hydrogen, fluoro or chloro
• R* is methyl, ethyl, isopropyl, hydrogen, fluoro, chloro, bromo, cyclopropyl, -C ⁇ CH or -CF 3 .

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