Classifications

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  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
• • A—HUMAN NECESSITIES
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  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
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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
  • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
• • A—HUMAN NECESSITIES
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  • 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
  • A61K31/4965—Non-condensed pyrazines
  • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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  • 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
  • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
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  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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  • 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
  • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
  • A61K31/5375—1,4-Oxazines, e.g. morpholine
  • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
  • A61K31/5375—1,4-Oxazines, e.g. morpholine
  • A61K31/5386—1,4-Oxazines, e.g. morpholine spiro-condensed or forming part of bridged ring systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
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  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
  • A61P25/16—Anti-Parkinson drugs
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  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • 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
  • C07D471/10—Spiro-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • 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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  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • 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
  • C07D487/10—Spiro-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
  • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
  • C07D491/10—Spiro-condensed systems
  • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
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  • 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
  • C07D498/10—Spiro-condensed systems

Definitions

• Glucocerebrosidase (EC 3.2.1.45), also called ⁇ -glucocerebrosidase, ⁇ -glucosidase, D-glucosyl-N-acylsphingosine glucohydrolase, or GCase, is an enzyme having glucosylceramidase activity.
• Glucocerebrosidase is required to cleave the beta-glucosidic linkage of the chemical glucocerebroside, which is an intermediate in glycolipid metabolism.
• Glucocerebrosidase is localized in the lysosome and disabling mutations in the gene for glucocerebrosidase (GBA1) are associated with abnormal accumulation of lipids in lysosomes.
• GBA1 Genetic diseases caused by mutations in GBA1 include neurodegenerative diseases such as Gaucher's disease and Parkinson's disease. Current treatments for diseases such Type 1 Gaucher's disease are limited to enzyme replacement therapy (ERT) administered every two weeks. ERT is very expensive and not effective for neuronopathic forms of Gaucher's disease.
• the present disclosure provides compounds that are modulators of GCase. These compounds provide new compositions and methods for the treatment of diseases associated with GCase activity (e.g., neurodegenerative diseases, such as Gaucher's disease and Parkinson's disease).
• diseases associated with GCase activity e.g., neurodegenerative diseases, such as Gaucher's disease and Parkinson's disease.
• R 1 is substituted or unsubstituted heteroaryl, substituted or unsubstituted aryl, haloalkyl, or a nitrogen protecting group
• B is cycloalkyl or heterocyclyl comprising at least one nitrogen atom in its ring
• each occurrence of R 4 is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cyclo
• the compounds of Formula (I) are compounds of Formula (I-1), (I-a), (I-b), (I-g), (I-g-13), (I-k), (I-k-3), (I-k-5), (I-l), (I-l-3), (I-l-5), (I-m), (I-m-3), (I-n), (I-n’), (I-o), (I-o’), (I-p), (I-p’), (I-x), (I-x-1), (I-y), (I-z), (I-aa), (I-bb), (I-cc), (I-dd), (I-ee), (I-ff), or (I-gg):
• compositions comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable excipient.
• methods of treating a disease or disorder in a subject in need thereof comprising administering a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (I) to the subject.
• the disease or disorder is associated with glucocerebrosidase activity.
• the disease or disorder is a neurological disease or disorder.
• the neurological disease or disorder is Parkinson’s disease or Gaucher’s disease.
• kits comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
• the kits further comprise instructions for administration (e.g., human administration).
• the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer.
• Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses.
• While compounds may be depicted as racemic or as one or more diastereoisomers, enantiomers, or other isomers, all such racemic, diastereoisomer, enantiomer, or other isomer forms of that depicted are included in the present disclosure.
• a formula is a single bond where the stereochemistry of the moieties immediately attached thereto is not specified, is absent or a single bond, and or is a single or double bond.
• structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms.
• C 1-6 alkyl is intended to encompass, C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 1-6 , C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-5 , C 2-4 , C 2-3 , C 3-6 , C 3-5 , C 3-4 , C 4-6 , C 4-5 , and C 5-6 alkyl.
• aliphatic refers to alkyl, alkenyl, alkynyl, and carbocyclic groups.
• heteroaliphatic refers to heteroalkyl, heteroalkenyl, heteroalkynyl, and heterocyclic groups.
• alkyl refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 10 carbon atoms (“C 1-10 alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms (“C 1-9 alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“C 1-8 alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“C 1-7 alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“C 1-6 alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C 1-5 alkyl”).
• an alkyl group has 1 to 4 carbon atoms (“C 1-4 alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“C 1-3 alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C 1-2 alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“C 1 alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C 2-6 alkyl”).
• C 1-6 alkyl groups include methyl (C 1 ), ethyl (C 2 ), propyl (C 3 ) (e.g., n-propyl, isopropyl), butyl (C 4 ) (e.g., n-butyl, tert-butyl, sec-butyl, iso-butyl), pentyl (C 5 ) (e.g., n-pentyl, 3-pentanyl, amyl, neopentyl, 3-methyl-2-butanyl, tertiary amyl), and hexyl ( C 6 ) (e.g., n-hexyl).
• alkyl groups include n-heptyl (C 7 ), n- octyl (C 8 ), and the like. Unless otherwise specified, each instance of an alkyl group is independently unsubstituted (an “unsubstituted alkyl”) or substituted (a “substituted alkyl”) with one or more substituents (e.g., halogen, such as F).
• substituents e.g., halogen, such as F
• the alkyl group is an unsubstituted C 1-10 alkyl (such as unsubstituted C 1-6 alkyl, e.g., ⁇ CH 3 (Me), unsubstituted ethyl (Et), unsubstituted propyl (Pr, e.g., unsubstituted n-propyl (n-Pr), unsubstituted isopropyl (i-Pr)), unsubstituted butyl (Bu, e.g., unsubstituted n-butyl (n-Bu), unsubstituted tert-butyl (tert-Bu or t-Bu), unsubstituted sec-butyl (sec-Bu), unsubstituted isobutyl (i-Bu)).
• unsubstituted C 1-6 alkyl such as unsubstituted C 1-6 alkyl, e.g., ⁇ CH 3 (Me),
• the alkyl group is a substituted C 1-10 alkyl (such as substituted C 1-6 alkyl, e.g., ⁇ CF 3 , Bn).
• haloalkyl is a substituted alkyl group, wherein one or more of the hydrogen atoms are independently replaced by a halogen, e.g., fluoro, bromo, chloro, or iodo.
• the haloalkyl moiety has 1 to 8 carbon atoms (“C 1-8 haloalkyl”).
• the haloalkyl moiety has 1 to 6 carbon atoms (“C 1-6 haloalkyl”).
• the haloalkyl moiety has 1 to 4 carbon atoms (“C 1-4 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 3 carbon atoms (“C 1-3 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 2 carbon atoms (“C 1-2 haloalkyl”). Examples of haloalkyl groups include –CHF 2 , ⁇ CH 2 F, ⁇ CF 3 , ⁇ CH 2 CF 3 , ⁇ CF 2 CF 3 , ⁇ CF 2 CF 2 CF 3 , ⁇ CCl 3 , ⁇ CFCl 2 , ⁇ CF 2 Cl, and the like.
• alkoxy refers to an alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom.
• the alkoxy moiety has 1 to 8 carbon atoms (“C 1-8 alkoxy”).
• the alkoxy moiety has 1 to 6 carbon atoms (“C 1-6 alkoxy”).
• the alkoxy moiety has 1 to 4 carbon atoms (“C 1-4 alkoxy”).
• the alkoxy moiety has 1 to 3 carbon atoms (“C 1-3 alkoxy”).
• the alkoxy moiety has 1 to 2 carbon atoms (“C 1-2 alkoxy”).
• alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy and tert-butoxy.
• alkoxyalkyl is a substituted alkyl group, wherein one or more of the hydrogen atoms are independently replaced by an alkoxy group, as defined herein.
• the alkoxyalkyl moiety has 1 to 8 carbon atoms (“C 1-8 alkoxyalkyl”).
• the alkoxyalkyl moiety has 1 to 6 carbon atoms (“C 1-6 alkoxyalkyl”).
• the alkoxyalkyl moiety has 1 to 4 carbon atoms (“C 1-4 alkoxyalkyl”).
• the alkoxyalkyl moiety has 1 to 3 carbon atoms (“C 1-3 alkoxyalkyl”). In some embodiments, the alkoxyalkyl moiety has 1 to 2 carbon atoms (“C 1-2 alkoxyalkyl”).
• heteroalkyl refers to an alkyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (i.e., inserted between adjacent carbon atoms of) and/or placed at one or more terminal position(s) of the parent chain.
• a heteroalkyl group refers to a saturated group having from 1 to 20 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC 1-20 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 18 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC 1-18 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 16 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC 1-16 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 14 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC 1-14 alkyl”).
• a heteroalkyl group is a saturated group having 1 to 12 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC 1-12 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 10 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC 1-10 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC 1-8 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 6 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC 1-6 alkyl”).
• a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and 1 or 2 heteroatoms within the parent chain (“heteroC 1-4 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom within the parent chain (“heteroC 1-3 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom within the parent chain (“heteroC 1-2 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom (“heteroC 1 alkyl”).
• the heteroalkyl group defined herein is a partially unsaturated group having 1 or more heteroatoms within the parent chain and at least one unsaturated carbon, such as a carbonyl group.
• a heteroalkyl group may comprise an amide or ester functionality in its parent chain such that one or more carbon atoms are unsaturated carbonyl groups.
• each instance of a heteroalkyl group is independently unsubstituted (an “unsubstituted heteroalkyl”) or substituted (a “substituted heteroalkyl”) with one or more substituents.
• the heteroalkyl group is an unsubstituted heteroC 1-20 alkyl.
• the heteroalkyl group is an unsubstituted heteroC 1-10 alkyl. In certain embodiments, the heteroalkyl group is a substituted heteroC 1-20 alkyl. In certain embodiments, the heteroalkyl group is an unsubstituted heteroC 1-10 alkyl.
• alkenyl refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 10 carbon atoms and one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 double bonds). In some embodiments, an alkenyl group has 2 to 9 carbon atoms (“C 2-9 alkenyl”).
• an alkenyl group has 2 to 8 carbon atoms (“C 2-8 alkenyl”). In some embodiments, an alkenyl group has 2 to 7 carbon atoms (“C 2-7 alkenyl”). In some embodiments, an alkenyl group has 2 to 6 carbon atoms (“C 2-6 alkenyl”). In some embodiments, an alkenyl group has 2 to 5 carbon atoms (“C 2-5 alkenyl”). In some embodiments, an alkenyl group has 2 to 4 carbon atoms (“C 2-4 alkenyl”). In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“C 2-3 alkenyl”). In some embodiments, an alkenyl group has 2 carbon atoms (“C 2 alkenyl”).
• the one or more carbon- carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl).
• Examples of C 2-4 alkenyl groups include ethenyl (C 2 ), 1-propenyl (C 3 ), 2-propenyl (C 3 ), 1- butenyl (C 4 ), 2-butenyl (C 4 ), butadienyl (C 4 ), and the like.
• Examples of C 2-6 alkenyl groups include the aforementioned C 2-4 alkenyl groups as well as pentenyl (C 5 ), pentadienyl (C 5 ), hexenyl (C 6 ), and the like.
• alkenyl examples include heptenyl (C 7 ), octenyl (C 8 ), octatrienyl (C 8 ), and the like.
• each instance of an alkenyl group is independently unsubstituted (an “unsubstituted alkenyl”) or substituted (a “substituted alkenyl”) with one or more substituents.
• the alkenyl group is an unsubstituted C 2-10 alkenyl.
• the alkenyl group is a substituted C 2-10 alkenyl.
• heteroalkenyl refers to an alkenyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (i.e., inserted between adjacent carbon atoms of) and/or placed at one or more terminal position(s) of the parent chain.
• a heteroalkenyl group refers to a group having from 2 to 10 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC 2-10 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 9 carbon atoms at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC 2-9 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 8 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC 2-8 alkenyl”).
• a heteroalkenyl group has 2 to 7 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC 2-7 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC 2-6 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“heteroC 2-5 alkenyl”).
• a heteroalkenyl group has 2 to 4 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“heteroC 2-4 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 3 carbon atoms, at least one double bond, and 1 heteroatom within the parent chain (“heteroC 2-3 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“heteroC 2-6 alkenyl”).
• each instance of a heteroalkenyl group is independently unsubstituted (an “unsubstituted heteroalkenyl”) or substituted (a “substituted heteroalkenyl”) with one or more substituents.
• the heteroalkenyl group is an unsubstituted heteroC 2-10 alkenyl.
• the heteroalkenyl group is a substituted heteroC 2-10 alkenyl.
• alkynyl refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 10 carbon atoms and one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 triple bonds) (“C 2-10 alkynyl”). In some embodiments, an alkynyl group has 2 to 9 carbon atoms (“C 2-9 alkynyl”). In some embodiments, an alkynyl group has 2 to 8 carbon atoms (“C 2-8 alkynyl”). In some embodiments, an alkynyl group has 2 to 7 carbon atoms (“C 2- 7 alkynyl”).
• an alkynyl group has 2 to 6 carbon atoms (“C 2-6 alkynyl”). In some embodiments, an alkynyl group has 2 to 5 carbon atoms (“C 2-5 alkynyl”). In some embodiments, an alkynyl group has 2 to 4 carbon atoms (“C 2-4 alkynyl”). In some embodiments, an alkynyl group has 2 to 3 carbon atoms (“C 2-3 alkynyl”). In some embodiments, an alkynyl group has 2 carbon atoms (“C 2 alkynyl”). The one or more carbon- carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl).
• Examples of C 2-4 alkynyl groups include, without limitation, ethynyl (C 2 ), 1-propynyl (C 3 ), 2- propynyl (C 3 ), 1-butynyl (C 4 ), 2-butynyl (C 4 ), and the like.
• Examples of C 2-6 alkenyl groups include the aforementioned C 2-4 alkynyl groups as well as pentynyl (C 5 ), hexynyl (C 6 ), and the like. Additional examples of alkynyl include heptynyl (C 7 ), octynyl (C 8 ), and the like.
• each instance of an alkynyl group is independently unsubstituted (an “unsubstituted alkynyl”) or substituted (a “substituted alkynyl”) with one or more substituents.
• the alkynyl group is an unsubstituted C 2-10 alkynyl.
• the alkynyl group is a substituted C 2-10 alkynyl.
• heteroalkynyl refers to an alkynyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (i.e., inserted between adjacent carbon atoms of) and/or placed at one or more terminal position(s) of the parent chain.
• a heteroalkynyl group refers to a group having from 2 to 10 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC 2-10 alkynyl”).
• a heteroalkynyl group has 2 to 9 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC 2-9 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 8 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC 2- 8 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 7 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC 2-7 alkynyl”).
• a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC 2-6 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain (“heteroC 2-5 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 4 carbon atoms, at least one triple bond, and 1or 2 heteroatoms within the parent chain (“heteroC 2-4 alkynyl”).
• a heteroalkynyl group has 2 to 3 carbon atoms, at least one triple bond, and 1 heteroatom within the parent chain (“heteroC 2-3 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain (“heteroC 2-6 alkynyl”). Unless otherwise specified, each instance of a heteroalkynyl group is independently unsubstituted (an “unsubstituted heteroalkynyl”) or substituted (a “substituted heteroalkynyl”) with one or more substituents.
• the heteroalkynyl group is an unsubstituted heteroC 2-10 alkynyl. In certain embodiments, the heteroalkynyl group is a substituted heteroC 2-10 alkynyl.
• the term “carbocyclyl” or “carbocyclic” refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 14 ring carbon atoms (“C 3-14 carbocyclyl”) and zero heteroatoms in the non-aromatic ring system. In some embodiments, a carbocyclyl group has 3 to 10 ring carbon atoms (“C 3-10 carbocyclyl”).
• a carbocyclyl group has 3 to 8 ring carbon atoms (“C 3-8 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 7 ring carbon atoms (“C 3-7 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (“C 3-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 4 to 6 ring carbon atoms (“C 4-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 6 ring carbon atoms (“C 5-6 carbocyclyl”).
• a carbocyclyl group has 5 to 10 ring carbon atoms (“C 5-10 carbocyclyl”).
• Exemplary C 3-6 carbocyclyl groups include, without limitation, cyclopropyl (C 3 ), cyclopropenyl (C 3 ), cyclobutyl (C 4 ), cyclobutenyl (C 4 ), cyclopentyl (C 5 ), cyclopentenyl (C 5 ), cyclohexyl (C 6 ), cyclohexenyl (C 6 ), cyclohexadienyl (C 6 ), and the like.
• Exemplary C 3-8 carbocyclyl groups include, without limitation, the aforementioned C 3-6 carbocyclyl groups as well as cycloheptyl (C 7 ), cycloheptenyl (C 7 ), cycloheptadienyl (C 7 ), cycloheptatrienyl (C 7 ), cyclooctyl (C 8 ), cyclooctenyl (C 8 ), bicyclo[2.2.1]heptanyl (C 7 ), bicyclo[2.2.2]octanyl (C 8 ), and the like.
• Exemplary C 3-10 carbocyclyl groups include, without limitation, the aforementioned C 3-8 carbocyclyl groups as well as cyclononyl (C 9 ), cyclononenyl (C 9 ), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C 9 ), decahydronaphthalenyl (C 10 ), spiro[4.5]decanyl (C 10 ), and the like.
• the carbocyclyl group is either monocyclic (“monocyclic carbocyclyl”) or polycyclic (e.g., containing a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) or tricyclic system (“tricyclic carbocyclyl”)) and can be saturated or can contain one or more carbon-carbon double or triple bonds.
• Carbocyclyl also includes ring systems wherein the carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the point of attachment is on the carbocyclyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the carbocyclic ring system.
• each instance of a carbocyclyl group is independently unsubstituted (an “unsubstituted carbocyclyl”) or substituted (a “substituted carbocyclyl”) with one or more substituents.
• the carbocyclyl group is an unsubstituted C 3-14 carbocyclyl.
• the carbocyclyl group is a substituted C 3-14 carbocyclyl.
• “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 14 ring carbon atoms (“C 3-14 cycloalkyl”).
• a cycloalkyl group has 3 to 10 ring carbon atoms (“C 3-10 cycloalkyl”).
• a cycloalkyl group has 3 to 8 ring carbon atoms (“C 3-8 cycloalkyl”).
• a cycloalkyl group has 3 to 6 ring carbon atoms (“C 3-6 cycloalkyl”).
• a cycloalkyl group has 4 to 6 ring carbon atoms (“C 4-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms (“C 5-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms (“C 5-10 cycloalkyl”). Examples of C 5-6 cycloalkyl groups include cyclopentyl (C 5 ) and cyclohexyl (C 5 ).
• C 3-6 cycloalkyl groups include the aforementioned C 5-6 cycloalkyl groups as well as cyclopropyl (C 3 ) and cyclobutyl (C 4 ).
• Examples of C 3-8 cycloalkyl groups include the aforementioned C 3-6 cycloalkyl groups as well as cycloheptyl (C 7 ) and cyclooctyl (C 8 ).
• each instance of a cycloalkyl group is independently unsubstituted (an “unsubstituted cycloalkyl”) or substituted (a “substituted cycloalkyl”) with one or more substituents.
• the cycloalkyl group is an unsubstituted C 3-14 cycloalkyl. In certain embodiments, the cycloalkyl group is a substituted C 3-14 cycloalkyl.
• the term “heterocyclyl” or “heterocyclic” refers to a radical of a 3- to 14-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“3-14 membered heterocyclyl”). In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits.
• a heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or polycyclic (e.g., a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”) or tricyclic system (“tricyclic heterocyclyl”)), and can be saturated or can contain one or more carbon- carbon double or triple bonds.
• Heterocyclyl polycyclic ring systems can include one or more heteroatoms in one or both rings.
• Heterocyclyl also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system.
• each instance of heterocyclyl is independently unsubstituted (an “unsubstituted heterocyclyl”) or substituted (a “substituted heterocyclyl”) with one or more substituents.
• the heterocyclyl group is an unsubstituted 3-14 membered heterocyclyl.
• the heterocyclyl group is a substituted 3-14 membered heterocyclyl.
• a heterocyclyl group is a 5-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heterocyclyl”).
• a heterocyclyl group is a 5-8 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heterocyclyl”).
• a heterocyclyl group is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heterocyclyl”).
• the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
• the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.
• Exemplary 3-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azirdinyl, oxiranyl, and thiiranyl.
• Exemplary 4-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azetidinyl, oxetanyl, and thietanyl.
• Exemplary 5-membered heterocyclyl groups containing 1 heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione.
• Exemplary 5- membered heterocyclyl groups containing 2 heteroatoms include, without limitation, dioxolanyl, oxathiolanyl and dithiolanyl.
• Exemplary 5-membered heterocyclyl groups containing 3 heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl.
• Exemplary 6-membered heterocyclyl groups containing 1 heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl.
• Exemplary 6-membered heterocyclyl groups containing 2 heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, and dioxanyl.
• Exemplary 6-membered heterocyclyl groups containing 3 heteroatoms include, without limitation, triazinyl.
• Exemplary 7- membered heterocyclyl groups containing 1 heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl.
• Exemplary 8-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl.
• Exemplary bicyclic heterocyclyl groups include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl, decahydronaphthyridinyl, decahydro-1,8- naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole,
• aryl refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 pi electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C 6-14 aryl”).
• an aryl group has 6 ring carbon atoms (“C 6 aryl”; e.g., phenyl).
• an aryl group has 10 ring carbon atoms (“C 10 aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl).
• an aryl group has 14 ring carbon atoms (“C 14 aryl”; e.g., anthracyl).
• Aryl also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system.
• each instance of an aryl group is independently unsubstituted (an “unsubstituted aryl”) or substituted (a “substituted aryl”) with one or more substituents.
• the aryl group is an unsubstituted C 6-14 aryl.
• the aryl group is a substituted C 6-14 aryl.
• “Arylalkyl” is a subset of “alkyl” and refers to an alkyl group substituted by an aryl group, wherein the point of attachment is on the alkyl moiety.
• heteroaryl refers to a radical of a 5-14 membered monocyclic or polycyclic (e.g., bicyclic, tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 pi electrons shared in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-14 membered heteroaryl”).
• the point of attachment can be a carbon or nitrogen atom, as valency permits.
• Heteroaryl polycyclic ring systems can include one or more heteroatoms in one or both rings.
• Heteroaryl includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heteroaryl ring system. “Heteroaryl” also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused polycyclic (aryl/heteroaryl) ring system.
• a heteroaryl group is a 5-10 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heteroaryl”).
• a heteroaryl group is a 5-8 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heteroaryl”).
• a heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heteroaryl”).
• the 5- 6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
• the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each instance of a heteroaryl group is independently unsubstituted (an “unsubstituted heteroaryl”) or substituted (a “substituted heteroaryl”) with one or more substituents. In certain embodiments, the heteroaryl group is an unsubstituted 5-14 membered heteroaryl. In certain embodiments, the heteroaryl group is a substituted 5-14 membered heteroaryl.
• Exemplary 5-membered heteroaryl groups containing 1 heteroatom include, without limitation, pyrrolyl, furanyl, and thiophenyl.
• Exemplary 5-membered heteroaryl groups containing 2 heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl.
• Exemplary 5-membered heteroaryl groups containing 3 heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl.
• Exemplary 5-membered heteroaryl groups containing 4 heteroatoms include, without limitation, tetrazolyl.
• Exemplary 6-membered heteroaryl groups containing 1 heteroatom include, without limitation, pyridinyl.
• Exemplary 6-membered heteroaryl groups containing 2 heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl.
• Exemplary 6-membered heteroaryl groups containing 3 or 4 heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively.
• Exemplary 7-membered heteroaryl groups containing 1 heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl.
• Exemplary 5,6- bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl.
• Exemplary 6,6-bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.
• Exemplary tricyclic heteroaryl groups include, without limitation, phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl, and phenazinyl.
• Heteroarylalkyl is a subset of “alkyl” and refers to an alkyl group substituted by a heteroaryl group, wherein the point of attachment is on the alkyl moiety.
• the term “unsaturated bond” refers to a double or triple bond.
• the term “unsaturated” or “partially unsaturated” refers to a moiety that includes at least one double or triple bond.
• the term “saturated” refers to a moiety that does not contain a double or triple bond, i.e., the moiety only contains single bonds.
• alkylene is the divalent moiety of alkyl
• alkenylene is the divalent moiety of alkenyl
• alkynylene is the divalent moiety of alkynyl
• heteroalkylene is the divalent moiety of heteroalkyl
• heteroalkenylene is the divalent moiety of heteroalkenyl
• heteroalkynylene is the divalent moiety of heteroalkynyl
• carbocyclylene is the divalent moiety of carbocyclyl
• heterocyclylene is the divalent moiety of heterocyclyl
• arylene is the divalent moiety of aryl
• heteroarylene is the divalent moiety of heteroaryl.
• a group is optionally substituted unless expressly provided otherwise.
• the term “optionally substituted” refers to being substituted or unsubstituted.
• alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted.
• Optionally substituted refers to a group which may be substituted or unsubstituted (e.g., “substituted” or “unsubstituted” alkyl, “substituted” or “unsubstituted” alkenyl, “substituted” or “unsubstituted” alkynyl, “substituted” or “unsubstituted” heteroalkyl, “substituted” or “unsubstituted” heteroalkenyl, “substituted” or “unsubstituted” heteroalkynyl, “substituted” or “unsubstituted” carbocyclyl, “substituted” or “unsubstituted” heterocyclyl, “substituted” or “unsubstituted” aryl or “substituted” or “unsubstituted” heteroaryl group).
• substituted means that at least one hydrogen present on a group is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction.
• a “substituted” group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position.
• substituted is contemplated to include substitution with all permissible substituents of organic compounds, and includes any of the substituents described herein that results in the formation of a stable compound.
• the present disclosure contemplates any and all such combinations in order to arrive at a stable compound.
• heteroatoms such as nitrogen may have hydrogen substituents and/or any suitable substituent as described herein which satisfy the valencies of the heteroatoms and results in the formation of a stable moiety.
• the disclosure is not intended to be limited in any manner by the exemplary substituents described herein.
• halo or halogen refers to fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), or iodine (iodo, -I).
• hydroxyl refers to the group -OH.
• amino refers to the group ⁇ NH 2 .
• substituted amino by extension, refers to a monosubstituted amino, a disubstituted amino, or a trisubstituted amino. In certain embodiments, the “substituted amino” is a monosubstituted amino or a disubstituted amino group.
• trisubstituted amino refers to an amino group wherein the nitrogen atom directly attached to the parent molecule is substituted with three groups, and includes groups selected from ⁇ N(R bb ) 3 and ⁇ N(R bb ) 3 + X ⁇ , wherein R bb and X ⁇ are as defined herein.
• sulfonyl refers to a group selected from –SO 2 N(R bb ) 2 , –SO 2 R aa , and – SO 2 OR aa , wherein R aa and R bb are as defined herein.
• acyl groups include aldehydes ( ⁇ CHO), carboxylic acids ( ⁇ CO 2 H), ketones, acyl halides, esters, amides, imines, carbonates, carbamates, and ureas.
• Acyl substituents include, but are not limited to, any of the substituents described herein, that result in the formation of a stable moiety (e.g., aliphatic, alkyl, alkenyl, alkynyl, heteroaliphatic, heterocyclic, aryl, heteroaryl, acyl, oxo, imino, thiooxo, cyano, isocyano, amino, azido, nitro, hydroxyl, thiol, halo, aliphaticamino, heteroaliphaticamino, alkylamino, heteroalkylamino, arylamino, heteroarylamino, alkylaryl, arylalkyl, aliphaticoxy, heteroaliphaticoxy, alkyl
• Nitrogen atoms can be substituted or unsubstituted as valency permits, and include primary, secondary, tertiary, and quaternary nitrogen atoms.
• the substituent present on the nitrogen atom is a nitrogen protecting group (also referred to herein as an “amino protecting group”).
• Nitrogen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3 rd edition, John Wiley & Sons, 1999, incorporated herein by reference.
• Nitrogen protecting groups such as carbamate groups include, but are not limited to, methyl carbamate, ethyl carbamate, 9-fluorenylmethyl carbamate (Fmoc), 9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluoroenylmethyl carbamate, 2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methyl carbamate (DBD- Tmoc), 4-methoxyphenacyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2- trimethylsilylethyl carbamate (Teoc), 2-phenylethyl carbamate (hZ), 1-(1-adamantyl)-1- methyle
• Nitrogen protecting groups such as sulfonamide groups include, but are not limited to, p-toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6-trimethyl-4- methoxybenzenesulfonamide (Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb), 2,6- dimethyl-4-methoxybenzenesulfonamide (Pme), 2,3,5,6-tetramethyl-4- methoxybenzenesulfonamide (Mte), 4-methoxybenzenesulfonamide (Mbs), 2,4,6- trimethylbenzenesulfonamide (Mts), 2,6-dimethoxy-4-methylbenzenesulfonamide (iMds), 2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanes
• Ts p-toluenesulfonamide
• Mtr 2,
• nitrogen protecting groups include, but are not limited to, phenothiazinyl- (10)-acyl derivative, N′-p-toluenesulfonylaminoacyl derivative, N′-phenylaminothioacyl derivative, N-benzoylphenylalanyl derivative, N-acetylmethionine derivative, 4,5-diphenyl-3- oxazolin-2-one, N-phthalimide, N-dithiasuccinimide (Dts), N-2,3-diphenylmaleimide, N-2,5- dimethylpyrrole, N-1,1,4,4-tetramethyldisilylazacyclopentane adduct (STABASE), 5- substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-one, 5-substituted 1,3-dibenzyl-1,3,5- triazacyclohexan-2-one, 1-substituted 3,5-dinitro
• a nitrogen protecting group is benzyl (Bn), tert- butyloxycarbonyl (BOC), carbobenzyloxy (Cbz), 9-flurenylmethyloxycarbonyl (Fmoc), trifluoroacetyl, triphenylmethyl, acetyl (Ac), benzoyl (Bz), p-methoxybenzyl (PMB), 3,4- dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), 2,2,2-trichloroethyloxycarbonyl (Troc), triphenylmethyl (Tr), tosyl (Ts), brosyl (Bs), nosyl (Ns), mesyl (Ms), triflyl (Tf), or dansyl (Ds).
• Bn benzyl
• BOC tert- butyloxycarbonyl
• Cbz carbobenzyloxy
• Fmoc 9-flurenylmethyloxycarbony
• the substituent present on an oxygen atom is an oxygen protecting group (also referred to herein as an “hydroxyl protecting group”).
• Oxygen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3 rd edition, John Wiley & Sons, 1999, incorporated herein by reference.
• oxygen protecting groups include, but are not limited to, methyl, methoxylmethyl (MOM), 2-methoxyethyl, methylthiomethyl (MTM), t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p- methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), t-butoxymethyl, 4-pentenyloxymethyl (POM), siloxymethyl, 2- methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl, 2- (trimethylsilyl)ethoxymethyl (SEMOR), tetrahydropyranyl (THP), 3- bromotetrahydropyranyl, tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4- methoxyt
• an oxygen protecting group is silyl.
• an oxygen protecting group is t-butyldiphenylsilyl (TBDPS), t- butyldimethylsilyl (TBDMS), triisoproylsilyl (TIPS), triphenylsilyl (TPS), triethylsilyl (TES), trimethylsilyl (TMS), triisopropylsiloxymethyl (TOM), acetyl (Ac), benzoyl (Bz), allyl carbonate, 2,2,2-trichloroethyl carbonate (Troc), 2-trimethylsilylethyl carbonate, methoxymethyl (MOM), 1-ethoxyethyl (EE), 2-methyoxy-2-propyl (MOP), 2,2,2- trichloroethoxyethyl, 2-methoxyethoxymethyl (MEM), 2-trimethylsilylethoxymethyl (SEM), methylthiomethyl (MTM), te
• TDPS t
• the substituent present on a sulfur atom is a sulfur protecting group (also referred to as a “thiol protecting group”).
• a sulfur protecting group is acetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl.
• a “counterion” or “anionic counterion” is a negatively charged group associated with a positively charged group in order to maintain electronic neutrality.
• An anionic counterion may be monovalent (i.e., including one formal negative charge).
• An anionic counterion may also be multivalent (i.e., including more than one formal negative charge), such as divalent or trivalent.
• exemplary counterions include halide ions (e.g., F – , Cl – , Br – , I – ), NO 3 – , ClO 4 – , OH – , H 2 PO 4 – , HCO 3 ⁇ , HSO 4 – , sulfonate ions (e.g., methansulfonate, trifluoromethanesulfonate, p–toluenesulfonate, benzenesulfonate, 10–camphor sulfonate, naphthalene–2–sulfonate, naphthalene–1–sulfonic acid–5–sulfonate, ethan–1–sulfonic acid– 2–sulfonate, and the like), carboxylate ions (e.g.,
• Exemplary counterions which may be multivalent include CO 3 2 ⁇ , HPO4 2 ⁇ , PO 4 3 ⁇ , B 4 O 7 2 ⁇ , SO 4 2 ⁇ , S 2 O 3 2 ⁇ , carboxylate anions (e.g., tartrate, citrate, fumarate, maleate, malate, malonate, gluconate, succinate, glutarate, adipate, pimelate, suberate, azelate, sebacate, salicylate, phthalates, aspartate, glutamate, and the like), and carboranes.
• carboxylate anions e.g., tartrate, citrate, fumarate, maleate, malate, malonate, gluconate, succinate, glutarate, adipate, pimelate, suberate, azelate, sebacate, salicylate, phthalates, aspartate, glutamate, and the like
• carboranes e.g., tartrate, citrate, fumarate, maleate, mal
• a “leaving group” is an art-understood term referring to an atomic or molecular fragment that departs with a pair of electrons in heterolytic bond cleavage, wherein the molecular fragment is an anion or neutral molecule.
• a leaving group can be an atom or a group capable of being displaced by a nucleophile. See e.g., Smith, March Advanced Organic Chemistry 6th ed. (501–502).
• Suitable leaving groups include, but are not limited to, halogen alkoxycarbonyloxy, aryloxycarbonyloxy, alkanesulfonyloxy, arenesulfonyloxy, alkyl-carbonyloxy (e.g., acetoxy), arylcarbonyloxy, aryloxy, methoxy, N,O-dimethylhydroxylamino, pixyl, and haloformates.
• the leaving group is a brosylate, such as p-bromobenzenesulfonyloxy.
• the leaving group is a nosylate, such as 2-nitrobenzenesulfonyloxy. In some embodiments, the leaving group is a sulfonate-containing group. In some embodiments, the leaving group is a tosylate group. In some embodiments, the leaving group is a phosphineoxide (e.g., formed during a Mitsunobu reaction) or an internal leaving group such as an epoxide or cyclic sulfate. Other non-limiting examples of leaving groups are water, ammonia, alcohols, ether moieties, thioether moieties, zinc halides, magnesium moieties, diazonium salts, and copper moieties.
• phosphineoxide e.g., formed during a Mitsunobu reaction
• Other non-limiting examples of leaving groups are water, ammonia, alcohols, ether moieties, thioether moieties, zinc halides, magnesium moieties, diazonium salts, and copper
• Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference.
• Pharmaceutically acceptable salts of the compounds of this disclosure include those derived from suitable inorganic and organic acids and bases.
• Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid or with organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange.
• salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate
• Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N + (C 1-4 alkyl) 4 ⁇ salts.
• Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
• Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.
• solvate refers to forms of the compound, or a salt thereof, that are associated with a solvent, usually by a solvolysis reaction. This physical association may include hydrogen bonding.
• solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and the like.
• the compounds described herein may be prepared, e.g., in crystalline form, and may be solvated. Suitable solvates include pharmaceutically acceptable solvates and further include both stoichiometric solvates and non-stoichiometric solvates.
• the solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated in the crystal lattice of a crystalline solid.
• “Solvate” encompasses both solution-phase and isolatable solvates.
• Representative solvates include hydrates, ethanolates, and methanolates.
• the term “hydrate” refers to a compound that is associated with water molecules. Typically, the number of the water molecules contained in a hydrate of a compound is in a definite ratio to the number of the compound molecules in the hydrate. Therefore, a hydrate of a compound may be represented, for example, by the general formula R ⁇ x H 2 O, wherein R is the compound, and x is a number greater than 0.
• a given compound may form more than one type of hydrate, including, e.g., monohydrates (x is 1), lower hydrates (x is a number greater than 0 and smaller than 1, e.g., hemihydrates (R ⁇ 0.5 H 2 O)), and polyhydrates (x is a number greater than 1, e.g., dihydrates (R ⁇ 2 H 2 O) and hexahydrates (R ⁇ 6 H 2 O)).
• monohydrates x is 1
• lower hydrates x is a number greater than 0 and smaller than 1, e.g., hemihydrates (R ⁇ 0.5 H 2 O)
• polyhydrates x is a number greater than 1, e.g., dihydrates (R ⁇ 2 H 2 O) and hexahydrates (R ⁇ 6 H 2 O)
• tautomers or “tautomeric” refers to two or more interconvertible compounds resulting from at least one formal migration of a hydrogen atom and at least one change in valency (e.g., a single bond to a double bond, a triple bond to a single bond, or vice versa).
• the exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH. Tautomerizations (i.e., the reaction providing a tautomeric pair) may catalyzed by acid or base.
• Exemplary tautomerizations include keto-to-enol, amide-to-imide, lactam-to-lactim, enamine-to-imine, and enamine-to-(a different enamine) tautomerizations.
• isomers compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers”. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers”.
• stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers”.
• enantiomers When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible.
• An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or ( ⁇ )-isomers respectively).
• a chiral compound can exist as either individual enantiomer or as a mixture thereof.
• a mixture containing equal proportions of the enantiomers is called a “racemic mixture”.
• the term “polymorph” refers to a crystalline form of a compound (or a salt, hydrate, or solvate thereof). Many compounds can adopt a variety of different crystal forms (i.e., different polymorphs). Typically, such different crystalline forms have different X-ray diffraction patterns, infrared spectra, and/or can vary in some or all properties such as melting points, density, hardness, crystal shape, optical and electrical properties, stability, solubility, and bioavailability.
• co-crystal refers to a crystalline structure composed of at least two components.
• a co-crystal contains a compound of the present disclosure and one or more other component(s), including, but not limited to, atoms, ions, molecules, or solvent molecules.
• a co-crystal contains a compound of the present disclosure and one or more solvent molecules.
• a co- crystal contains a compound of the present disclosure and one or more acid or base.
• a co-crystal contains a compound of the present disclosure and one or more components related to said compound, including, but not limited to, an isomer, tautomer, salt, solvate, hydrate, synthetic precursor, synthetic derivative, fragment, or impurity of said compound.
• prodrugs refers to compounds that have cleavable groups that are removed, by solvolysis or under physiological conditions, to provide the compounds described herein, which are pharmaceutically active in vivo. Such examples include, but are not limited to, choline ester derivatives and the like, N-alkylmorpholine esters and the like.
• Prodrugs include acid derivatives well known to practitioners of the art, such as, for example, esters prepared by reaction of the parent acid with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a substituted or unsubstituted amine, or acid anhydrides, or mixed anhydrides.
• Simple aliphatic or aromatic esters, amides, and anhydrides derived from acidic groups pendant on the compounds described herein are particular prodrugs.
• double ester type prodrugs such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkylesters.
• C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, aryl, C 7-12 substituted aryl, and C 7-12 arylalkyl esters of the compounds described herein may be preferred.
• composition and “formulation” are used interchangeably.
• modulate means decreasing or inhibiting activity and/or increasing or augmenting activity.
• modulating glucocerebrosidase activity means decreasing or inhibiting glucocerebrosidase activity and/or increasing or augmenting glucocerebrosidase activity.
• the compounds disclosed herein may be administered to modulate glucocerebrosidase activity for example, as a chaperone or activator.
• a “subject” to which administration is contemplated refers to a human (i.e., male or female of any age group, e.g., pediatric subject (e.g., infant, child, or adolescent) or adult subject (e.g., young adult, middle-aged adult, or senior adult)) or non-human animal.
• the non-human animal is a mammal (e.g., primate (e.g., cynomolgus monkey or rhesus monkey), commercially relevant mammal (e.g., cattle, pig, horse, sheep, goat, cat, or dog), or bird (e.g., commercially relevant bird, such as chicken, duck, goose, or turkey)).
• the non-human animal is a fish, reptile, or amphibian.
• the non-human animal may be a male or female at any stage of development.
• the non-human animal may be a transgenic animal or genetically engineered animal.
• patient refers to a human subject in need of treatment of a disease.
• the subject may also be a plant.
• the plant is a land plant. In certain embodiments, the plant is a non- vascular land plant. In certain embodiments, the plant is a vascular land plant. In certain embodiments, the plant is a seed plant. In certain embodiments, the plant is a cultivated plant. In certain embodiments, the plant is a dicot. In certain embodiments, the plant is a monocot. In certain embodiments, the plant is a flowering plant. In some embodiments, the plant is a cereal plant, e.g., maize, corn, wheat, rice, oat, barley, rye, or millet. In some embodiments, the plant is a legume, e.g., a bean plant, e.g., soybean plant.
• the plant is a tree or shrub.
• biological sample refers to any sample including tissue samples (such as tissue sections and needle biopsies of a tissue); cell samples (e.g., cytological smears (such as Pap or blood smears) or samples of cells obtained by microdissection); samples of whole organisms (such as samples of yeasts or bacteria); or cell fractions, fragments or organelles (such as obtained by lysing cells and separating the components thereof by centrifugation or otherwise).
• tissue samples such as tissue sections and needle biopsies of a tissue
• cell samples e.g., cytological smears (such as Pap or blood smears) or samples of cells obtained by microdissection
• samples of whole organisms such as samples of yeasts or bacteria
• cell fractions, fragments or organelles such as obtained by lysing cells and separating the components thereof by centrifugation or otherwise.
• biological samples include blood, serum, urine, semen, fecal matter, cerebrospinal fluid, interstitial fluid, mucous, tears, sweat, pus, biopsied tissue (e.g., obtained by a surgical biopsy or needle biopsy), nipple aspirates, milk, vaginal fluid, saliva, swabs (such as buccal swabs), or any material containing biomolecules that is derived from a first biological sample.
• administered refers to implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing a compound described herein, or a composition thereof, in or on a subject.
• treatment refers to reversing, alleviating, or inhibiting the progress of a disease described herein.
• treatment may be administered after one or more signs or symptoms of the disease have developed or have been observed. Treatment may also be continued after symptoms have resolved, for example, to delay or prevent recurrence.
• condition refers to an amount sufficient to elicit the desired biological response.
• an effective amount of a compound described herein may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the condition being treated, the mode of administration, and the age and health of the subject. In certain embodiments, an effective amount is a therapeutically effective amount. In certain embodiments, an effective amount is a prophylactic treatment. In certain embodiments, an effective amount is the amount of a compound described herein in a single dose. In certain embodiments, an effective amount is the combined amounts of a compound described herein in multiple doses. [0086] A “therapeutically effective amount” of a compound described herein is an amount sufficient to provide a therapeutic benefit in the treatment of a condition or to delay or minimize one or more symptoms associated with the condition.
• a therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the condition.
• therapeutically effective amount can encompass an amount that improves overall therapy, reduces or avoids symptoms, signs, or causes of the condition, and/or enhances the therapeutic efficacy of another therapeutic agent.
• a therapeutically effective amount is an amount sufficient for GCase activation (e.g., at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 100%, at least 150%, at least 200%, at least 250%, at least 300%, or at least 500% increase in the enzymatic activity of GCase).
• a therapeutically effective amount is an amount sufficient for treating a disease or disorder (e.g., neurological disorder).
• a therapeutically effective amount is an amount sufficient for GCase activation and treating a disease or disorder (e.g., neurological disorder).
• a “prophylactically effective amount” of a compound described herein is an amount sufficient to prevent a condition, or one or more signs or symptoms associated with the condition, or prevent its recurrence.
• a prophylactically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other agents, which provides a prophylactic benefit in the prevention of the condition.
• the term “prophylactically effective amount” can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent.
• a prophylactically effective amount is an amount sufficient for GCase activation.
• a prophylactically effective amount is an amount sufficient for treating a disease or disorder (e.g., neurological disorder). In certain embodiments, a prophylactically effective amount is an amount sufficient for GCase activation and treating a disease or disorder (e.g., neurological disorder). [0088] As used herein, the term “activate” or “activation” in the context of enzymes, for example, in the context of GCase, refers to an increase in the activity of the enzyme.
• the term refers to an increase of the level of enzyme activity, e.g., GCase activity, to a level that is statistically significantly higher than an initial level, which may, for example, be a baseline level of enzyme activity (e.g., of wild-type GCase).
• the term refers to an increase in the level of enzyme activity, e.g., GCase activity, to a level that is greater than 1%, greater than 5%, greater than 10%, greater than 25%, greater than 50%, greater than 75%, greater than 100%, greater than 150%, greater than 200%, greater than 300%, greater than 400%, greater than 500%, or greater than 1000% of an initial level, which may, for example, be a baseline level of enzyme activity.
• the term “immunotherapy” refers to a therapeutic agent that promotes the treatment of disease by inducing, enhancing, or suppressing an immune response.
• Immunotherapies designed to elicit or amplify an immune response are classified as activation immunotherapies, while immunotherapies that reduce or suppress are classified as suppression immunotherapies.
• Immunotherapies are typically, but not always, biotherapeutic agents. Numerous immunotherapies are used to treat cancer. These include, but are not limited to, monoclonal antibodies, adoptive cell transfer, cytokines, chemokines, vaccines, and small molecule inhibitors.
• the terms “biologic,” “biologic drug,” and “biological product” refer to a wide range of products such as vaccines, blood and blood components, allergenics, somatic cells, gene therapy, tissues, nucleic acids, and proteins.
• Biologics may include sugars, proteins, or nucleic acids, or complex combinations of these substances, or may be living entities, such as cells and tissues. Biologics may be isolated from a variety of natural sources (e.g., human, animal, microorganism) and may be produced by biotechnological methods and other technologies.
• the term “small molecule” or “small molecule therapeutic” refers to molecules, whether naturally occurring or artificially created (e.g., via chemical synthesis) that have a relatively low molecular weight. Typically, a small molecule is an organic compound (i.e., it contains carbon).
• the small molecule may contain multiple carbon-carbon bonds, stereocenters, and other functional groups (e.g., amines, hydroxyl, carbonyls, and heterocyclic rings, etc.).
• the molecular weight of a small molecule is not more than about 1,000 g/mol, not more than about 900 g/mol, not more than about 800 g/mol, not more than about 700 g/mol, not more than about 600 g/mol, not more than about 500 g/mol, not more than about 400 g/mol, not more than about 300 g/mol, not more than about 200 g/mol, or not more than about 100 g/mol.
• the molecular weight of a small molecule is at least about 100 g/mol, at least about 200 g/mol, at least about 300 g/mol, at least about 400 g/mol, at least about 500 g/mol, at least about 600 g/mol, at least about 700 g/mol, at least about 800 g/mol, or at least about 900 g/mol, or at least about 1,000 g/mol. Combinations of the above ranges (e.g., at least about 200 g/mol and not more than about 500 g/mol) are also possible.
• the small molecule is a therapeutically active agent such as a drug (e.g., a molecule approved by the U.S.
• the small molecule may also be complexed with one or more metal atoms and/or metal ions.
• the small molecule is also referred to as a “small organometallic molecule.”
• Preferred small molecules are biologically active in that they produce a biological effect in animals, preferably mammals, more preferably humans. Small molecules include, but are not limited to, radionuclides and imaging agents.
• the small molecule is a drug.
• the drug is one that has already been deemed safe and effective for use in humans or animals by the appropriate governmental agency or regulatory body. For example, drugs approved for human use are listed by the FDA under 21 C.F.R.
• therapeutic agent refers to any substance having therapeutic properties that produce a desired, usually beneficial, effect.
• therapeutic agents may treat, ameliorate, and/or prevent disease.
• therapeutic agents, as disclosed herein may be biologics or small molecule therapeutics, or combinations thereof.
• GCase modulators are compounds of Formula (I), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, prodrugs, and pharmaceutical compositions thereof. Accordingly, the compounds are useful for the treatment and/or prevention of diseases and disorders associated with GCase activity (e.g., neurological diseases and disorders) in a subject in need thereof.
• diseases and disorders associated with GCase activity e.g., neurological diseases and disorders
• the compounds described herein interact with GCase.
• the therapeutic effect may be a result of modulation (e.g., activation), binding, and/or modification of GCase by the compounds described herein.
• the compounds may be provided for use in any composition, kit, or method described herein as a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.
• a compound of Formula (I): (I), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein: R 1 is substituted or unsubstituted heteroaryl, substituted or unsubstituted aryl, haloalkyl, or a nitrogen protecting group; G is a bond, -NR A -, –C( O)–, –SO 2 –, -O-, -OC(R 5 )(R 6 )-, or -C(R 5 )(R 6 )-; B is cycloalkyl or heterocyclyl comprising at least one nitrogen atom in its ring; each occurrence of R 4 is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted
• the compound of Formula (I) is a compound of Formula (I- 1): or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.
• the compound of Formula (I) is a compound of Formula (I- 1): or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein: R 1 is substituted or unsubstituted heteroaryl, substituted or unsubstituted aryl, or a nitrogen protecting group; G is a bond, -O-, -OC(R 5 )(R 6 )-, or -C(R 5 )(R 6 )-; B is cycloalkyl or heterocyclyl comprising at least one nitrogen atom in its ring; each occurrence of R 4 is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, or two instances of R 4 on the same carbon form with that carbon a carbonyl; Y 1 is N or CR 5 ; each occurrence of
• R 1 is substituted or unsubstituted heteroaryl, substituted or unsubstituted aryl, haloalkyl, or a nitrogen protecting group.
• R 1 is substituted or unsubstituted heteroaryl, substituted or unsubstituted aryl, or a nitrogen protecting group.
• R 1 is substituted or unsubstituted heteroaryl, or substituted or unsubstituted aryl.
• R 1 is substituted or unsubstituted heteroaryl, or a nitrogen protecting group.
• R 1 is a nitrogen protecting group.
• R 1 is substituted or unsubstituted pyridinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted oxadiazolyl, substituted or unsubstituted thiadiazolyl, substituted or unsubstituted isoxozalyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted pyridinonyl, or substituted or unsubstituted pyridazinonyl.
• R 1 is substituted or unsubstituted 6-membered heteroaryl. In certain embodiments, R 1 is substituted or unsubstituted pyridinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyrimidinyl, or substituted or unsubstituted pyridazinyl. In certain embodiments, R 1 is substituted or unsubstituted pyridinyl. In certain embodiments, R 1 is substituted or unsubstituted pyrazinyl. In certain embodiments, R 1 is substituted or unsubstituted pyrimidinyl.
• R 1 is substituted or unsubstituted pyridazinyl.
• R 1 is heteroaryl substituted with at least one instance of halogen, haloalkyl or haloalkoxy.
• R 1 is heteroaryl substituted with at least one instance of halogen or haloalkyl.
• R 1 is heteroaryl substituted with at least one instance of halogen, C 1-4 haloalkyl or C 1-4 haloalkoxy.
• R 1 is heteroaryl substituted with at least one instance of halogen or C 1-4 haloalkyl.
• R 1 is heteroaryl substituted with at least one instance of fluoro or fluoroalkyl. In certain embodiments, R 1 is heteroaryl substituted with at least one instance of fluoro or C 1-4 fluoroalkyl. In certain embodiments, R 1 is heteroaryl substituted with at least one instance of C 1-4 fluoroalkyl. [00104] In certain embodiments, R 1 is substituted or unsubstituted pyridinyl. In certain embodiments, R 1 is substituted pyridinyl. In certain embodiments, R 1 is pyridinyl substituted with at least one instance of halogen, haloalkyl or haloalkoxy.
• R 1 is pyridinyl substituted with at least one instance of halogen or haloalkyl. In certain embodiments, R 1 is pyridinyl substituted with at least one instance of halogen or C 1-4 haloalkyl or C 1-4 haloalkoxy. In certain embodiments, R 1 is pyridinyl substituted with at least one instance of halogen or C 1-4 haloalkyl. In certain embodiments, R 1 is pyridinyl substituted with at least one instance of fluoro or fluoroalkyl. In certain embodiments, R 1 is pyridinyl substituted with at least one instance of fluoro or C 1-4 fluoroalkyl.
• R 1 is heteroaryl substituted with at least one instance of haloalkyl. In certain embodiments, R 1 is heteroaryl substituted with at least one instance of C 1-4 haloalkyl. In certain embodiments, R 1 is heteroaryl substituted with at least one instance of fluoroalkyl. In certain embodiments, R 1 is heteroaryl substituted with at least one instance of C 1-4 fluoroalkyl. In certain embodiments, R 1 is heteroaryl substituted with at least one instance of trifluoromethyl, difluoromethyl, or fluoromethyl. In certain embodiments, R 1 is heteroaryl substituted with trifluoromethyl.
• R 1 is pyridinyl substituted with at least one instance of haloalkyl. In certain embodiments, R 1 is pyridinyl substituted with at least one instance of C 1- 4 haloalkyl. In certain embodiments, R 1 is pyridinyl substituted with at least one instance of fluoroalkyl. In certain embodiments, R 1 is pyridinyl substituted with at least one instance of C 1-4 fluoroalkyl. In certain embodiments, R 1 is pyridinyl substituted with at least one instance of trifluoromethyl, difluoromethyl, or fluoromethyl.
• R 1 is pyridinyl substituted with at least one instance of trifluoromethyl.
• R 1 is pyrimidinyl substituted with at least one instance of haloalkyl.
• R 1 is pyrimidinyl substituted with at least one instance of C 1-4 haloalkyl.
• R 1 is pyrimidinyl substituted with at least one instance of fluoroalkyl.
• R 1 is pyrimidinyl substituted with at least one instance of C 1-4 fluoroalkyl.
• R 1 is pyrimidinyl substituted with at least one instance of trifluoromethyl, difluoromethyl, or fluoromethyl. In certain embodiments, R 1 is pyrimidinyl substituted with at least one instance of trifluoromethyl. [00108] In certain embodiments, R 1 is substituted or unsubstituted pyrimidinyl. In certain embodiments, R 1 is substituted pyrimidinyl. In certain embodiments, R 1 is pyrimidinyl substituted with at least one instance of halogen, unubstituted alkyl, haloalkyl or haloalkoxy.
• R 1 is pyrimidinyl substituted with at least one instance of unubstituted alkyl or haloalkyl. In certain embodiments, R 1 is pyrimidinyl substituted with at least one instance of unubstituted C 1-4 alkyl or C 1-4 haloalkyl. In certain embodiments, R 1 is pyrimidinyl substituted with at least one instance of unubstituted C 1-4 alkyl or C 1-4 fluoroalkyl. In certain embodiments, R 1 is pyrimidinyl substituted with at least one instance of methyl or C 1-4 fluoroalkyl.
• R 1 is pyrimidinyl substituted with unubstituted alkyl and haloalkyl. In certain embodiments, R 1 is pyrimidinyl substituted with unubstituted C 1-4 alkyl and C 1-4 haloalkyl. In certain embodiments, R 1 is pyrimidinyl substituted with methyl and fluoroalkyl. In certain embodiments, R 1 is pyrimidinyl substituted with methyl and C 1-4 fluoroalkyl. In certain embodiments, R 1 is pyrimidinyl substituted with methyl and trifluoromethyl, difluoromethyl, or fluoromethyl.
• R 1 is pyrimidinyl substituted with methyl and trifluoromethyl.
• R 1 is substituted or unsubstituted aryl.
• R 1 is substituted or unsubstituted phenyl.
• R 1 is unsubstituted phenyl.
• R 1 is unsubstituted phenyl or phenyl substituted with at least one instance of halogen or haloalkyl.
• R 1 is phenyl substituted with at least one instance of C 1-4 haloalkyl or halogen.
• R 1 is phenyl substituted with at least one instance of fluoroalkyl or halogen. In certain embodiments, R 1 is phenyl substituted with at least one instance of C 1-4 fluoroalkyl or halogen. In certain embodiments, R 1 is phenyl substituted with at least one instance of C 1-4 fluoroalkyl or fluoro. [00111] In certain embodiments, R 1 is phenyl substituted with at least one instance of haloalkyl or alkyl. In certain embodiments, R 1 is phenyl substituted with at least one instance of C 1-4 haloalkyl or C 1-4 alkyl.
• R 1 is phenyl substituted with at least one instance of fluoroalkyl or alkyl. In certain embodiments, R 1 is phenyl substituted with at least one instance of C 1-4 fluoroalkyl or C 1-4 alkyl. [00112] In certain embodiments, R 1 is phenyl substituted with at least one instance of fluoroalkyl. In certain embodiments, R 1 is phenyl substituted with at least one instance of C 1-4 fluoroalkyl. In certain embodiments, R 1 is phenyl substituted with at least one instance of fluoroalkyl. In certain embodiments, R 1 is phenyl substituted with at least one instance of C 1-4 fluoroalkyl.
• R 1 is phenyl substituted with at least one instance of alkyl. In certain embodiments, R 1 is phenyl substituted with at least one instance of C 1-4 alkyl. In certain embodiments, R 1 is phenyl substituted with at least one instance of halogen. In certain embodiments, R 1 is phenyl substituted with at least one instance of fluoro. [00114] In certain embodiments, R 1 is , , , , ,
• R 1 is
• R 1 is
• R 1 is , , , [00117] In certain embodiments, R 1 is , , , [00118] In certain embodiments, R 1 is [00119] In certain embodiments, R 1 is , , , or . In certain embodiments, R 1 is , , or . In certain embodiments, R 1 is . In certain embodiments, R 1 is . In certain embodiments, R 1 is . In certain embodiments, R 1 is .
• R 1 is [00120] In certain embodiments, R 1 is , , , , [00121] In certain embodiments, R 1 is , , , , , , [00122] In certain embodiments, R 1 is [00123] In certain embodiments, R 1 is , or [00124] In certain embodiments, R 1 is , , , , , , , [00125] In certain embodiments, R 1 is [00126] In certain embodiments, R 1 is , , , , , [00127] In certain embodiments, R 1 is In certain embodiments, R 1 is . In certain embodiments, R 1 is . In certain embodiments, R 1 is . In certain embodiments, R 1 is . In certain embodiments, R 1 is .
• R 1 is . [00128] In certain embodiments, R 1 is [00129] In certain embodiments, R 1 is [00130] In certain embodiments, R 1 is or [00131] In certain embodiments, R 1 is or [00132] In certain embodiments, R 1 is . In certain embodiments, R 1 is In certain embodiments, R 1 is . In certain embodiments, R 1 is In c 1 ertain embodiments, R is . [00133] In certain embodiments, R 1 is . In certain embodiments, R 1 is In certain embodiments, R 1 is . In certain embodiments, R 1 is . In certain embodiments, R 1 is . [00128] In certain embodiments, R 1 is [00129] In certain embodiments, R 1 is [00130] In certain embodiments, R 1 is or [00131] In certain embodiments, R 1 is or [00132] In certain embodiments, R 1 is . In certain embodiments, R 1 is In certain embodiments, R 1 is In certain embodiments, R 1 is . In
• G is a bond, -O-, -OC(R 5 )(R 6 )-, or -C(R 5 )(R 6 )-, wherein R 5 and R 6 are each independently hydrogen, halogen, or substituted or unsubstituted alkyl. In certain embodiments, R 5 and R 6 are each independently hydrogen or substituted or unsubstituted alkyl. In certain embodiments, R 5 and R 6 are each independently hydrogen or unsubstituted alkyl. In certain embodiments, R 5 and R 6 are each independently hydrogen or unsubstituted C 1-4 alkyl. In certain embodiments, R 5 and R 6 are each hydrogen.
• G is a bond, -O-, or -C(R 5 )(R 6 )-. In certain embodiments, G is a bond, -O-, or -OC(R 5 )(R 6 )-. In certain embodiments, G is a bond or -OC(R 5 )(R 6 )-. In certain embodiments, G is a bond or -O-. In certain embodiments, G is a bond. In certain embodiments, G is -O-. In certain embodiments, G is -C(R 5 )(R 6 )-. In certain embodiments, G is -CH 2 -. In certain embodiments, G is -OC(R 5 )(R 6 )-.
• B is cycloalkyl or heterocyclyl comprising at least one nitrogen atom in its ring. [00137] In certain embodiments, B is cycloalkyl. In certain embodiments, B is C 3-8 cycloalkyl. In certain embodiments, B is C 3-7 cycloalkyl. In certain embodiments, B is C 3-6 cycloalkyl.
• B is C 4-6 cycloalkyl. In certain embodiments, B is C 4-5 cycloalkyl. In certain embodiments, B is C 5-6 cycloalkyl. In certain embodiments, B is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In certain embodiments, B is cyclobutyl, cyclopentyl, or cyclohexyl. In certain embodiments, B is cyclobutyl or cyclopentyl. In certain embodiments, B is cyclopropyl. In certain embodiments, B is cyclobutyl. In certain embodiments, B is cyclopentyl.
• B is cyclohexyl.
• B is heterocyclyl comprising at least one nitrogen atom in its ring.
• B is a 3-8 membered heterocyclyl comprising at least one nitrogen atom in its ring.
• B is a 3-8 membered heterocyclyl comprising one nitrogen atom in its ring.
• B is a 3-8 membered heterocyclyl comprising two nitrogen atoms in its ring.
• B is a 3-8 membered heterocyclyl comprising one or two nitrogen atoms in its ring.
• B is azetidinyl, pyrrolidinyl, imidazolidinyl, or piperidinyl. In certain embodiments, B is azetidinyl. In certain embodiments, B is pyrrolidinyl. In certain embodiments, B is imidazolidinyl. In certain embodiments, B is piperidinyl. [00139] In certain embodiments, B is azetidinyl, pyrrolidinyl, imidazolidinyl, piperidinyl, cyclobutyl, cyclopentyl, or cyclohexyl.
• B is azetidinyl, pyrrolidinyl, imidazolidinyl, piperidinyl, cyclobutyl, or cyclopentyl.
• -B(R 4 ) p1 - is ; wherein: Y is N or CR 5 ; k and q are each independently 0, 1, or 2; and Y is bound to G of Formula (I).
• Y is N. In certain embodiments, Y is CR 5 . In certain embodiments, Y is CH.
• k is 0. In certain embodiments, k is 1. In certain embodiments, k is 2.
• q is 0. In certain embodiments, q is 1. In certain embodiments, q is 2. In certain embodiments, k is 0; and q is 0. In certain embodiments, k is 0; and q is 1. In certain embodiments, k is 0; and q is 2. In certain embodiments, k is 1; and q is 0. In certain embodiments, k is 1; and q is 1. In certain embodiments, k is 1; and q is 2. In certain embodiments, k is 2; and q is 0. In certain embodiments, k is 2; and q is 1. In certain embodiments, k is 2; and q is 2.
• -B(R 4 ) p1 - is , , , [00144] In certain embodiments, -B(R 4 ) p1 - is [00145] In certain embodiments, -B(R 4 ) p1 - is In certain embodiments, -B(R 4 ) p1 - is . In certain embodiments, -B(R 4 ) p1 - is [00146] In certain embodiments, -B(R 4 ) p1 - is . In certain embodiments, - B(R 4 ) p1 - is .
• -B(R 4 ) p1 - is , wherein R 4 is substituted or unsubstituted alkyl. In certain embodiments, R 4 is substituted or unsubstituted C 1-4 alkyl. In certain embodiments, R 4 is unsubstituted C 1-4 alkyl or C 1-4 fluoroalkyl. In certain embodiments, -B(R 4 ) p1 - is . In certain embodiments, -B(R 4 ) p1 - is , wherein R 4 is substituted or unsubstituted alkyl or substituted or unsubstituted alkoxy.
• R 4 is substituted or unsubstituted C 1-4 alkyl or substituted or unsubstituted C 1-4 alkoxy. In certain embodiments, R 4 is unsubstituted C 1-4 alkyl, C 1-4 fluoroalkyl, unsubstituted C 1-4 alkoxy, or C 1-4 fluoroalkoxy. [00147] In certain embodiments, -B(R 4 ) p1 - is
• -B(R 4 ) p1 - is . In certain embodiments, -B(R 4 ) p1 - is . In certain embodiments, -B(R 4 ) p1 - is .
• each occurrence of R 4 is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, or two instances of R 4 on different carbons combine to form a bridged ring, or two instances of R 4 on the same carbon form with that carbon a carbonyl or a cycloalkyl; ; p1 is 0, 1, 2, 3, 4, 5, or 6; and p2 is 0, 1, 2, 3, 4, 5, or 6.
• each R 4 is independently halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted alkoxy, or two instances of R 4 on the same carbon form with that carbon a carbonyl; p1 is 0, 1, 2, 3, 4, 5, or 6; and p2 is 0, 1, 2, 3, 4, 5, or 6. [00150] In certain embodiments, each R 4 is independently substituted or unsubstituted alkyl, or two instances of R 4 on the same carbon form with that carbon a carbonyl; p1 is 0, 1, 2, 3, 4, or 5; and p2 is 0, 1, 2, 3, 4, or 5.
• R 4 is substituted or unsubstituted alkyl, or two instances of R 4 on the same carbon form with that carbon a carbonyl. In certain embodiments, R 4 is substituted or unsubstituted C 1-4 alkyl, or two instances of R 4 on the same carbon form with that carbon a carbonyl. In certain embodiments, R 4 is substituted or unsubstituted alkyl. In certain embodiments, R 4 is substituted or unsubstituted C 1-4 alkyl. In certain embodiments, R 4 is methyl, ethyl, isopropyl, benzyl, or 2,2,2-trifluoroethyl.
• R 4 is methyl, ethyl, isopropyl, benzyl, or 2,2,2-trifluoroethyl, or two instances of R 4 on the same carbon form with that carbon a carbonyl.
• R 4 is haloalkyl.
• R 4 is 2,2-difluoroethyl.
• R 4 is 4,4,4- trifluorobutyl.
• R 4 is CF 3 OCH 2 CH 2 -.
• R 4 is ethoxyethyl.
• R 4 is methyl.
• R 4 is ethyl. In certain embodiments, R 4 is isopropyl. In certain embodiments, R 4 is substituted or unsubstituted arylalkyl. In certain embodiments, R 4 is substituted or unsubstituted benzyl. In certain embodiments, R 4 is substituted or unsubstituted cycloalkylalkyl. In certain embodiments, R 4 is cyclopropylethyl. In certain embodiments, R 4 is cyclopropylmethyl. In certain embodiments, R 4 is substituted or unsubstituted cycloalkyl. In certain embodiments, R 4 is cyclobutyl.
• R 4 is substituted or unsubstituted aryl. In certain embodiments, R 4 is substituted or unsubstituted phenyl. [00152] In certain embodiments, R 4 is substituted or unsubstituted alkyl or substituted or unsubstituted alkoxy. In certain embodiments, R 4 is substituted or unsubstituted C 1-4 alkyl or substituted or unsubstituted C 1-4 alkoxy. In certain embodiments, R 4 is unsubstituted C 1-4 alkyl, C 1-4 fluoroalkyl, unsubstituted C 1-4 alkoxy, or C 1-4 fluoroalkoxy.
• R 4 is substituted or unsubstituted alkyl. In certain embodiments, R 4 is substituted or unsubstituted C 1-4 alkyl. In certain embodiments, R 4 is unsubstituted C 1-4 alkyl or C 1-4 fluoroalkyl. [00154] In certain embodiments, two instances of R 4 on different carbons combine to form a bridged ring. [00155] In certain embodiments, p1 is 0, 1, 2, 3, 4, or 5. In certain embodiments, p1 is 0, 1, 2, 3, or 4. In certain embodiments, p1 is 0, 1, 2, or 3. In certain embodiments, p1 is 0, 1, or 2. In certain embodiments, p1 is 0 or 2.
• p is 0 or 1. In certain embodiments, p1 is 1 or 2. In certain embodiments, p1 is 0. In certain embodiments, p1 is 2. In certain embodiments, p1 is 1. [00156] In certain embodiments, p2 is 0, 1, 2, 3, 4, or 5. In certain embodiments, p2 is 0, 1, 2, 3, or 4. In certain embodiments, p2 is 0, 1, 2, or 3. In certain embodiments, p2 is 0, 1, or 2. In certain embodiments, p2 is 0 or 2. In certain embodiments, p2 is 0 or 1. In certain embodiments, p2 is 1 or 2. In certain embodiments, p2 is 0. In certain embodiments, p2 is 2. In certain embodiments, p2 is 1.
• p1 is 0, and p2 is 0. m and n
• m is 0, 1, or 2; and n is 0, 1, or 2.
• m is 0.
• m is 1.
• m is 2.
• n is 0.
• n is 1.
• n is 2.
• m is 1; and n is 0. In certain embodiments, m is 1; and n is 0. In certain embodiments, m is 1; and n is 1.
• m is 1; and n is 0.
• m is 1; and n is 1.
• m is 1; and n is 2. In certain embodiments, m is 2; and n is 0. In certain embodiments, m is 2; and n is 1. In certain embodiments, m is 2; and n is 2.
• X is -O-, -NR A -, or -C(R 4 ) 2 -. In certain embodiments, X is -O- . In certain embodiments, X is -NR A -. In certain embodiments, X is -NH-. In certain embodiments, X is -C(R 4 ) 2 -. In certain embodiments, X is -CH(CH 3 )-.
• Y 1 [00161] As described herein, Y 1 is N or CR 5 , wherein R 5 is hydrogen, halogen, or substituted or unsubstituted alkyl. In certain embodiments, Y 1 is N. In certain embodiments, Y 1 is CR 5 . In certain embodiments, Y 1 is CH.
• A is or substituted or unsubstituted 5-membered heteroaryl; wherein R 2 and R 3 are each independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R 2 and R 3 together with the atoms to which they are attached form a substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 7 is hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted alkoxy; and R 8 is substituted or unsubstituted alkyl.
• A is , , , or substituted or unsubstituted 5-membered heteroaryl; wherein R 2 and R 3 are each independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R 2 and R 3 together with the atoms to which they are attached form a substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
• A is [00166] In certain embodiments, A is [00167] In certain embodiments, A is . In certain embodiments, A is [00168] In certain embodiments, A is , , or substituted or unsubstituted 5-membered heteroaryl. [00169] In certain embodiments, A is substituted or unsubstituted 5-membered heteroaryl. In certain embodiments, A is substituted or unsubstituted 5-membered heteroaryl comprising at least one nitrogen in the heteroaryl ring.
• A is substituted or unsubstituted pyrazolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted triazolyl, substituted or unsubstituted tetrazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted oxadiazolyl, substituted or unsubstituted thiazolyl, or substituted or unsubstituted thiadiazolyl.
• A is substituted or unsubstituted pyrazolyl, substituted or unsubstituted triazolyl, substituted or unsubstituted isoxazolyl, or substituted or unsubstituted thiazolyl. In certain embodiments, A is substituted or unsubstituted pyrazolyl, or substituted or unsubstituted thiazolyl. In certain embodiments, A is substituted pyrazolyl or substituted thiazolyl. In certain embodiments, A is In certain embodiments, A is . In certain embodiments, A is . In certain embodiments, A is . [00170] In certain embodiments, A is .
• A is [00172] In certain embodiments, A is [00173] In certain embodiments, A is [00174] In certain embodiments, A is [00175] In certain embodiments, A is . [00176] In certain embodiments, A is [00177] In certain embodiments, A is [00178] In certain embodiments, R 2 and R 3 are each independently hydrogen or substituted or unsubstituted heteroaryl; or R 2 and R 3 together with the atoms to which they are attached form a substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
• R 2 and R 3 are each independently hydrogen or substituted or unsubstituted heteroaryl; or R 2 and R 3 together with the atoms to which they are attached form a substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroaryl.
• R 2 is substituted or unsubstituted heteroaryl.
• R 2 is unsubstituted heteroaryl.
• R 2 is substituted or unsubstituted thiadizaolyl.
• R 2 is unsubstituted thiadizaolyl.
• R 3 is hydrogen.
• R 2 is substituted or unsubstituted heteroaryl; and R 3 is hydrogen. In certain embodiments, R 2 is unsubstituted heteroaryl; and R 3 is hydrogen. In certain embodiments, R 2 is substituted or unsubstituted thiadizaolyl; and R 3 is hydrogen. In certain embodiments, R 2 is unsubstituted thiadizaolyl; and R 3 is hydrogen. [00182] In certain embodiments, R 2 and R 3 together with the atoms to which they are attached form a substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
• R 2 and R 3 together with the atoms to which they are attached form a substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroaryl. [00183] In certain embodiments, R 2 and R 3 together with the atoms to which they are attached form a substituted or unsubstituted aryl. In certain embodiments, R 2 and R 3 together with the atoms to which they are attached form a substituted or unsubstituted phenyl. In certain embodiments, R 2 and R 3 together with the atoms to which they are attached form a substituted phenyl.
• R 2 and R 3 together with the atoms to which they are attached form an unsubstituted phenyl. [00184] In certain embodiments, R 2 and R 3 together with the atoms to which they are attached form a substituted or unsubstituted heteroaryl. In certain embodiments, R 2 and R 3 together with the atoms to which they are attached form a substituted or unsubstituted pyrrolyl or substituted or unsubstituted pyrazolyl. In certain embodiments, R 2 and R 3 together with the atoms to which they are attached form a substituted pyrrolyl or substituted pyrazolyl.
• R 2 and R 3 together with the atoms to which they are attached form a substituted pyrrolyl or substituted pyrazolyl, wherein the pyrrolyl or pyrazolyl is substituted with substituted or unsubstituted alkyl, or substituted or unsubstituted heterocyclyl.
• R 2 and R 3 together with the atoms to which they are attached form a substituted pyrrolyl or substituted pyrazolyl, wherein the pyrrolyl or pyrazolyl is substituted with substituted or unsubstituted heterocyclyl, haloalkyl, or substituted or unsubstituted heterocyclylalkyl.
• R 2 and R 3 together with the atoms to which they are attached form a substituted pyrrolyl or substituted pyrazolyl, wherein the pyrrolyl or pyrazolyl is substituted with substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, or C 1-4 haloalkyl.
• R 2 and R 3 together with the atoms to which they are attached form a substituted pyrrolyl or substituted pyrazolyl, wherein the pyrrolyl or pyrazolyl is substituted with substituted or unsubstituted heterocyclyl.
• R 2 and R 3 together with the atoms to which they are attached form a substituted pyrrolyl or substituted pyrazolyl, wherein the pyrrolyl or pyrazolyl is substituted with C 1-4 haloalkyl.
• R 2 and R 3 together with the atoms to which they are attached form a substituted pyrrolyl or substituted pyrazolyl, wherein the pyrrolyl or pyrazolyl is substituted with substituted or unsubstituted heterocyclylalkyl.
• R 2 and R 3 together with the atoms to which they are attached form a substituted or unsubstituted pyrazolyl.
• R 2 and R 3 together with the atoms to which they are attached form a substituted pyrazolyl. In certain embodiments, R 2 and R 3 together with the atoms to which they are attached form a substituted pyrazolyl, wherein the pyrazolyl is substituted with substituted or unsubstituted alkyl, or substituted or unsubstituted heterocyclyl. In certain embodiments, R 2 and R 3 together with the atoms to which they are attached form a substituted pyrazolyl, wherein the pyrazolyl is substituted with substituted or unsubstituted heterocyclyl.
• R 2 and R 3 together with the atoms to which they are attached form a substituted pyrazolyl, wherein the pyrazolyl is substituted with substituted or unsubstituted 4- 5 membered heterocyclyl. In certain embodiments, R 2 and R 3 together with the atoms to which they are attached form a substituted pyrazolyl, wherein the pyrazolyl is substituted with substituted or unsubstituted oxetanyl. In certain embodiments, R 2 and R 3 together with the atoms to which they are attached form a substituted pyrazolyl, wherein the pyrazolyl is substituted with unsubstituted alkyl or haloalkyl.
• R 2 and R 3 together with the atoms to which they are attached form a substituted pyrazolyl, wherein the pyrazolyl is substituted with unsubstituted C 1-4 alkyl or C 1-4 haloalkyl. In certain embodiments, R 2 and R 3 together with the atoms to which they are attached form a substituted pyrazolyl, wherein the pyrazolyl is substituted with unsubstituted C 1-4 alkyl. In certain embodiments, R 2 and R 3 together with the atoms to which they are attached form a substituted pyrazolyl, wherein the pyrazolyl is substituted with C 1-4 haloalkyl.
• R 2 and R 3 together with the atoms to which they are attached form a substituted or unsubstituted pyrrolyl. In certain embodiments, R 2 and R 3 together with the atoms to which they are attached form a substituted pyrrolyl. In certain embodiments, R 2 and R 3 together with the atoms to which they are attached form a substituted pyrrolyl, wherein the pyrrolyl is substituted with substituted or unsubstituted alkyl.
• R 2 and R 3 together with the atoms to which they are attached form a substituted pyrrolyl, wherein the pyrrolyl is substituted with unsubstituted alkyl or haloalkyl. In certain embodiments, R 2 and R 3 together with the atoms to which they are attached form a substituted pyrrolyl, wherein the pyrrolyl is substituted with unsubstituted C 1- 4 alkyl or C 1-4 haloalkyl. In certain embodiments, R 2 and R 3 together with the atoms to which they are attached form a substituted pyrrolyl, wherein the pyrrolyl is substituted with unsubstituted C 1-4 alkyl.
• R 2 and R 3 together with the atoms to which they are attached form a substituted pyrrolyl, wherein the pyrrolyl is substituted with C 1-4 haloalkyl. In certain embodiments, R 2 and R 3 together with the atoms to which they are attached form a substituted pyrrolyl, wherein the pyrrolyl is substituted with substituted or unsubstituted heterocyclylalkyl. In certain embodiments, R 2 and R 3 together with the atoms to which they are attached form a substituted pyrrolyl, wherein the pyrrolyl is substituted with substituted or unsubstituted oxetanylalkyl.
• R 2 and R 3 together with the atoms to which they are attached form a substituted or unsubstituted heterocyclyl. In certain embodiments, R 2 and R 3 together with the atoms to which they are attached form a substituted or unsubstituted dihydroimidazol-2-one. In certain embodiments R 2 and R 3 together with the atoms to which they are attached form wherein R a is substituted or unsubstituted alkyl or substituted or unsubstituted heterocyclyl; and R b is substituted or unsubstituted alkyl or substituted or unsubstituted heterocyclyl.
• A is ; wherein R 7 is hydrogen, unsubstituted C 1-4 alkyl, or unsubstituted C 1-4 alkoxy; X is N or CR a ; each R a is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heterocyclyl; and R b is hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted alkoxy.
• A is a a ; wherein X is N or CR ; each R is independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heterocyclyl; and R b is hydrogen, halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted alkoxy.
• R a is independently hydrogen, or substituted or unsubstituted alkyl; and R b is hydrogen, halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted alkoxy.
• R a is independently hydrogen, or substituted or unsubstituted alkyl; and R b is halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted alkoxy.
• R a is independently hydrogen, or substituted or unsubstituted alkyl; and R b is substituted or unsubstituted alkyl, or substituted or unsubstituted alkoxy.
• X is N or CH; R a is hydrogen, or substituted or unsubstituted alkyl; and R b is substituted or unsubstituted alkyl, or substituted or unsubstituted alkoxy.
• X is N; R a is hydrogen, or substituted or unsubstituted alkyl; and R b is substituted or unsubstituted alkyl, or substituted or unsubstituted alkoxy. In certain embodiments, X is N; R a is hydrogen, or substituted or unsubstituted alkyl; and R b is hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted alkoxy.
• X is N; R a is hydrogen, or substituted or unsubstituted alkyl; and R b is hydrogen, substituted or unsubstituted C 1-4 alkyl, or substituted or unsubstituted C 1-4 alkoxy.
• X is N; R a is hydrogen, or substituted or unsubstituted alkyl; and R b is substituted or unsubstituted C 1-4 alkyl, or substituted or unsubstituted C 1-4 alkoxy.
• X is N; R a is hydrogen, or substituted or unsubstituted alkyl; and R b is unsubstituted C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 haloalkoxy, or unsubstituted C 1-4 alkoxy.
• X is N; R a is hydrogen, or substituted or unsubstituted alkyl; and R b is hydrogen, unsubstituted C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 haloalkoxy, or unsubstituted C 1-4 alkoxy.
• X is CH; R a is hydrogen, or substituted or unsubstituted alkyl; and R b is substituted or unsubstituted alkyl, or substituted or unsubstituted alkoxy.
• R b is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted alkoxy.
• R b is halogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted alkoxy.
• R b is substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted alkoxy. In certain embodiments, R b is substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted alkoxy. In certain embodiments, R b is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted alkoxy.
• R b is hydrogen, substituted or unsubstituted C 1-4 alkyl, substituted or unsubstituted C3-4 cycloalkyl, or substituted or unsubstituted C 1-4 alkoxy. In certain embodiments, R b is substituted or unsubstituted C 1-4 alkyl, substituted or unsubstituted C 3-4 cycloalkyl, or substituted or unsubstituted C 1-4 alkoxy.
• R b is unsubstituted C 1-4 alkyl, C 1-4 haloalkyl, unsubstituted C3-4 cycloalkyl, unsubstituted C3-4 cycloalkylmethyl, C 1-4 haloalkoxy, or unsubstituted C 1-4 alkoxy.
• R b is hydrogen, unsubstituted C 1-4 alkyl, C 1-4 haloalkyl, unsubstituted C 3-4 cycloalkyl, unsubstituted C 3-4 cycloalkylmethyl, C 1-4 haloalkoxy, or unsubstituted C 1-4 alkoxy.
• R b is hydrogen.
• A is a wherein R is hydrogen or substituted or unsubstituted alkyl; and R b is hydrogen, halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted alkoxy.
• R a is substituted or unsubstituted alkyl or substituted or unsubstituted heterocyclyl; and R b is hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted alkoxy.
• R a is unsubstituted alkyl, haloalkyl, haloalkoxyalkyl, heterocyclyalkyl, arylalkyl, or heterocyclyl; and R b is hydrogen, unsubstituted alkyl, or unsubstituted alkoxy.
• R a is haloalkyl or unsubstituted heterocyclyl; and R b is hydrogen, unsubstituted alkyl, or unsubstituted alkoxy.
• R a is C 1-4 haloalkyl or unsubstituted 4-5 membered heterocyclyl; and R b is hydrogen, unsubstituted C 1-4 alkyl, or unsubstituted C 1-4 alkoxy.
• R a is 2,2-difluoroethyl or oxetanyl; and R b is hydrogen, -CH 3 , or -OCH 3 .
• A is a wherein R is hydrogen or substituted or unsubstituted alkyl; and R b is hydrogen, halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted alkoxy.
• A is a a wherein X is N or CR ; and each R is independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heterocyclyl. In certain embodiments, each R a is independently hydrogen, or substituted or unsubstituted alkyl. In certain embodiments, X is N or CH. In certain embodiments, X is N. In certain embodiments, X is CH. [00195] In certain embodiments, A is ; wherein R a is hydrogen, or substituted or unsubstituted alkyl.
• A is ; wherein R a is hydrogen, heterocyclylalkyl, haloalkyl, or substituted or unsubstituted 4-5 membered heterocyclyl. [00197] In certain embodiments, A is a ; wherein R is hydrogen or haloalkyl. [00198] In certain embodiments, A is a ; wherein R is hydrogen or C 1-4 haloalkyl. [00199] In certain embodiments, A is ; where a in R is hydrogen, or substituted or unsubstituted alkyl. [00200] In certain embodiments, A is ; wherein R a is hydrogen.
• A is ; wherein R a is substituted or unsubstituted alkyl. [00202] In certain embodiments, A is ; wherein R a is haloalkyl. [00203] In certain embodiments, A is ; wherein R a is C 1-4 haloalkyl. [00204] In certain embodiments, A is ; and R b is hydrogen, halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted alkoxy. In certain embodiments, R b is halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted alkoxy.
• R b is substituted or unsubstituted alkyl, or substituted or unsubstituted alkoxy. In certain embodiments, R b is hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted alkoxy. In certain embodiments, R b is hydrogen, substituted or unsubstituted C 1-4 alkyl, or substituted or unsubstituted C 1-4 alkoxy. In certain embodiments, R b is substituted or unsubstituted C 1-4 alkyl, or substituted or unsubstituted C 1-4 alkoxy.
• R b is unsubstituted C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 haloalkoxy, or unsubstituted C 1-4 alkoxy.
• R b is hydrogen, unsubstituted C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 haloalkoxy, or unsubstituted C 1-4 alkoxy.
• A is ; wherein R a is substituted or unsubstituted alkyl or substituted or unsubstituted heterocyclyl; and R b is substituted or unsubstituted alkyl or substituted or unsubstituted heterocyclyl.
• R a is unsubstituted alkyl, haloalkyl, or unsubstituted heterocyclyl; and R b is unsubstituted alkyl, haloalkyl, or unsubstituted heterocyclyl.
• R a is unsubstituted C 1-4 alkyl, C 1-4 haloalkyl, or unsubstituted 4-5 membered heterocyclyl; and R b is unsubstituted C 1-4 alkyl, C 1-4 haloalkyl, or unsubstituted 4-5 membered heterocyclyl.
• R a is C 1-4 haloalkyl or unsubstituted 4-5 membered heterocyclyl; and R b is unsubstituted C 1-4 alkyl. In certain embodiments, R a is unsubstituted C 1-4 alkyl; and R b is C 1-4 haloalkyl or unsubstituted 4-5 membered heterocyclyl.
• R a is 2,2-difluoroethyl, oxetanyl, -CH 3 , or -CH 2 CH 3 ; and R b is 2,2-difluoroethyl, oxetanyl, -CH 3 , or -CH 2 CH 3 .
• R a is 2,2- difluoroethyl or oxetanyl; and R b is -CH 3 , or -CH 2 CH 3 .
• R b is 2,2- difluoroethyl or oxetanyl; and R a is -CH 3 , or -CH 2 CH 3 .
• A is 7 ; wherein R is hydrogen, unsubstituted C 1-4 alkyl, or unsubstituted C 1-4 alkoxy; R a is substituted or unsubstituted alkyl or substituted or unsubstituted heterocyclyl; and R b is hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted alkoxy.
• R 7 is hydrogen or unsubstituted C 1-4 alkoxy; R a is substituted or unsubstituted alkyl or substituted or unsubstituted heterocyclyl; and R b is hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted alkoxy.
• A is ; wherein R a is substituted or unsubstituted alkyl or substituted or unsubstituted heterocyclyl; and R b is hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted alkoxy.
• R a is unsubstituted alkyl, haloalkyl, or heterocyclyl; and R b is hydrogen, unsubstituted alkyl, or unsubstituted alkoxy.
• R a is haloalkyl or unsubstituted heterocyclyl; and R b is hydrogen, unsubstituted alkyl, or unsubstituted alkoxy.
• R a is haloalkyl or unsubstituted heterocyclyl; and R b is hydrogen or unsubstituted alkoxy.
• R a is C 1-4 haloalkyl or unsubstituted 4-5 membered heterocyclyl; and R b is hydrogen, unsubstituted C 1-4 alkyl, or unsubstituted C 1-4 alkoxy.
• R a is C 1-4 haloalkyl or unsubstituted 4-5 membered heterocyclyl; and R b is hydrogen or unsubstituted C 1-4 alkyl.
• R a is 2,2-difluoroethyl or oxetanyl; and R b is hydrogen, -CH 3 , or -OCH 3 .
• R a is 2,2-difluoroethyl or oxetanyl; and R b is hydrogen or -CH 3 .
• A is b ; and R is hydrogen, halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted alkoxy.
• R b is halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted alkoxy.
• R b is substituted or unsubstituted alkyl, or substituted or unsubstituted alkoxy.
• R b is hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted alkoxy. In certain embodiments, R b is hydrogen, substituted or unsubstituted C 1-4 alkyl, or substituted or unsubstituted C 1-4 alkoxy. In certain embodiments, R b is substituted or unsubstituted C 1-4 alkyl, or substituted or unsubstituted C 1-4 alkoxy. In certain embodiments, R b is unsubstituted C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 haloalkoxy, or unsubstituted C 1-4 alkoxy.
• R b is hydrogen, unsubstituted C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 haloalkoxy, or unsubstituted C 1-4 alkoxy. In certain embodiments, R b is hydrogen or unsubstituted C 1-4 alkyl.
• A is ; wherein R 7 is hydrogen, unsubstituted C 1-4 alkyl, or unsubstituted C 1-4 alkoxy; R a is substituted or unsubstituted alkyl or substituted or unsubstituted heterocyclyl; and R b is substituted or unsubstituted alkyl or substituted or unsubstituted heterocyclyl.
• R 7 is hydrogen or unsubstituted C 1-4 alkoxy; R a is substituted or unsubstituted alkyl or substituted or unsubstituted heterocyclyl; and R b is substituted or unsubstituted alkyl.
• A is ; wherein R a is substituted or unsubstituted alkyl or substituted or unsubstituted heterocyclyl; and R b is substituted or unsubstituted alkyl or substituted or unsubstituted heterocyclyl.
• R a is substituted or unsubstituted alkyl or substituted or unsubstituted heterocyclyl; and R b is substituted or unsubstituted alkyl. In certain embodiments, R a is substituted or unsubstituted alkyl; and R b is substituted or unsubstituted alkyl. In certain embodiments, R a is haloalkyl or heterocyclyl; and R b is unsubstituted alkyl. In certain embodiments, R a is haloalkyl; and R b is unsubstituted alkyl.
• R a is C 1-4 haloalkyl or unsubstituted 4-5 membered heterocyclyl; and R b is unsubstituted C 1-4 alkyl. In certain embodiments, R a is C 1-4 haloalkyl; and R b is unsubstituted C 1-4 alkyl. In certain embodiments, R a is 2,2-difluoroethyl or oxetanyl; and R b is -CH 3 , or -CH 2 CH 3 . In certain embodiments, R a is 2,2-difluoroethyl; and R b is -CH 3 or -CH 2 CH 3 .
• A is ; wherein R 2 and R 3 are each independently substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In certain embodiments, A is ; wherein R 2 and R 3 are each independently substituted or unsubstituted alkyl, or substituted or unsubstituted aryl. In certain embodiments, A is ; wherein R 2 is substituted or unsubstituted alkyl, and R 3 is substituted or unsubstituted aryl.
• A is ; wherein R 2 is substituted or unsubstituted C 1-4 alkyl, and R 3 is substituted or unsubstituted phenyl. In certain embodiments, A is ; wherein R 2 is unsubstituted C 1-4 alkyl, and R 3 is unsubstituted phenyl. In certain embodiments, A is [00214] In certain embodiments, A is
• A is , ,
• A is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
• A is , [00218] In certain embodiments, A is [00219] In certain embodiments, A is [00220] In certain embodiments, A is , , [00221] In certain embodiments, A is [00222] In certain embodiments, A is [00223] In certain embodiments, A is In certain embodiments, A is , [00224] In certain embodiments, A is , , [00225] In certain embodiments, A is , , , , , [00226] In certain embodiments, A is [00227] In certain embodiments, A is [00228] In certain embodiments, A is [00229] In certain embodiments, A is .
• A is . In certain embodiments, A is . In certain embodiments, A is . In certain embodiments, A is . In certain embodiments, A is . In certain embodiments, A is . In certain embodiments, A is . In certain embodiments, A is . [00230] In certain embodiments, A is . In certain embodiments, A is . In certain embodiments, A is . [00231] In certain embodiments, A is , or . In certain embodiments, A is .
• the compound of Formula (I) is of Formula (I-a): (I-a), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 , G, R 4 , p1, p2, m, n, L, and A are as defined herein.
• the compound of Formula (I) is of Formula (I-b): (I-b), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 , G, R 4 , p1, p2, m, n, L, and A are as defined herein; Y is N or CR 5 ; R 5 is hydrogen, halogen, or substituted or unsubstituted alkyl; and k and q are each independently 0, 1, or 2. [00235] In certain embodiments, Y is N. In certain embodiments, Y is CR 5 .
• Y is CH.
• m is 0, 1, or 2; n is 0, 1, or 2; k is 0, 1, or 2; and q is 0, 1, or 2.
• m is 0. In certain embodiments, m is 1. In certain embodiments, m is 2. In certain embodiments, n is 0. In certain embodiments, n is 1. In certain embodiments, n is 2. In certain embodiments, k is 0. In certain embodiments, k is 1. In certain embodiments, k is 2. In certain embodiments, q is 0. In certain embodiments, q is 1. In certain embodiments, q is 2. [00237] In certain embodiments, m is 0; and n is 0.
• m is 0; and n is 1. In certain embodiments, m is 0; and n is 2. In certain embodiments, m is 1; and n is 0. In certain embodiments, m is 1; and n is 1. In certain embodiments, m is 1; and n is 2. In certain embodiments, m is 2; and n is 0. In certain embodiments, m is 2; and n is 1. In certain embodiments, m is 2; and n is 2. [00238] In certain embodiments, k is 0; and q is 0. In certain embodiments, k is 0; and q is 1. In certain embodiments, k is 0; and q is 2. In certain embodiments, k is 1; and q is 0.
• k is 1; and q is 1. In certain embodiments, k is 1; and q is 2. In certain embodiments, k is 2; and q is 0. In certain embodiments, k is 2; and q is 1. In certain embodiments, k is 2; and q is 2. [00239] In certain embodiments, m is 0; n is 0; k is 0; and q is 0. In certain embodiments, m is 0; n is 0; k is 1; and q is 0. In certain embodiments, m is 0; n is 0; k is 0; and q is 1. In certain embodiments, m is 0; n is 0; k is 1; and q is 1.
• m is 0; n is 0; k is 2; and q is 0. In certain embodiments, m is 0; n is 0; k is 0; and q is 2. [00240] In certain embodiments, m is 0; n is 1; k is 0; and q is 0. In certain embodiments, m is 0; n is 1; k is 1; and q is 0. In certain embodiments, m is 0; n is 1; k is 0; and q is 1. In certain embodiments, m is 0; n is 1; k is 1; and q is 1. In certain embodiments, m is 0; n is 1; k is 0; and q is 2. In certain embodiments, m is 0; n is 1; k is 0; and q is 2.
• m is 0; n is 1; k is 2; and q is 0. [00241] In certain embodiments, m is 1; n is 0; k is 0; and q is 0. In certain embodiments, m is 1; n is 0; k is 1; and q is 0. In certain embodiments, m is 1; n is 0; k is 0; and q is 1. In certain embodiments, m is 1; n is 0; k is 1; and q is 1. In certain embodiments, m is 1; n is 0; k is 0; and q is 2. In certain embodiments, m is 1; n is 0; k is 2; and q is 0.
• m is 1; n is 1; k is 0; and q is 0. In certain embodiments, m is 1; n is 1; k is 1; and q is 0. In certain embodiments, m is 1; n is 1; k is 0; and q is 1. In certain embodiments, m is 1; n is 1; k is 1; and q is 1. In certain embodiments, m is 1; n is 1; k is 0; and q is 2. In certain embodiments, m is 1; n is 1; k is 2; and q is 0. [00243] In certain embodiments, m is 0; n is 2; k is 0; and q is 0.
• m is 0; n is 2; k is 1; and q is 0. In certain embodiments, m is 0; n is 2; k is 0; and q is 1. In certain embodiments, m is 0; n is 2; k is 1; and q is 1. In certain embodiments, m is 0; n is 2; k is 0; and q is 2. In certain embodiments, m is 0; n is 2; k is 2; and q is 0. [00244] In certain embodiments, m is 2; n is 0; k is 0; and q is 0. In certain embodiments, m is 2; n is 0; k is 1; and q is 0.
• m is 2; n is 0; k is 0; and q is 1. In certain embodiments, m is 2; n is 0; k is 1; and q is 1. In certain embodiments, m is 2; n is 0; k is 0; and q is 2. In certain embodiments, m is 2; n is 0; k is 2; and q is 0.
• the compound of Formula (I) is of Formula (I-c): or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 , G, Y, R 4 , p1, p2, L, and A are as defined herein.
• the compound of Formula (I-c) is of Formula (I-c-1): (I-c-1), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 , L, and A are as defined herein.
• the compound of Formula (I-c) is of Formula (I-c-2): (I-c-2), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 , R 4 , L, and A are as defined herein.
• R 4 is substituted or unsubstituted alkyl or substituted or unsubstituted alkoxy.
• R 4 is substituted or unsubstituted C 1-4 alkyl or substituted or unsubstituted C 1-4 alkoxy.
• R 4 is unsubstituted C 1-4 alkyl, C 1-4 fluoroalkyl, unsubstituted C 1-4 alkoxy, or C 1-4 fluoroalkoxy.
• the compound of Formula (I-c) is of Formula (I-c-3): (I-c-3), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 , R 4 , L, and A are as defined herein.
• R 4 is substituted or unsubstituted alkyl.
• R 4 is substituted or unsubstituted C 1-4 alkyl. In certain embodiments, R 4 is unsubstituted C 1-4 alkyl or C 1-4 fluoroalkyl.
• the compound of Formula (I-c) is of Formula (I-c-4): (I-c-4), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 , L, and A are as defined herein.
• the compound of Formula (I-c) is of Formula (I-c-5): (I-c-5), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 , L, and A are as defined herein.
• the compound of Formula (I) is of Formula (I-d): (I-d), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 , G, Y, R 4 , p1, p2, L, and A are as defined herein.
• the compound of Formula (I-d) is of Formula (I-d-1): (I-d-1), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 , L, and A are as defined herein.
• the compound of Formula (I-d) is of Formula (I-d-2): (I-d-2), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 , L, and A are as defined herein.
• the compound of Formula (I-d) is of Formula (I-d-3): (I-d-3), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 , L, and A are as defined herein.
• the compound of Formula (I-d) is of Formula (I-d-4): (I-d-4), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 , L, and A are as defined herein.
• the compound of Formula (I-d) is of Formula (I-d-5): (I-d-5), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 , L, and A are as defined herein.
• the compound of Formula (I-d) is of Formula (I-d-6): (I-d-6), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 , L, and A are as defined herein.
• the compound of Formula (I) is of Formula (I-e): (I-e), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 , G, Y, R 4 , p1, p2, L, and A are as defined herein.
• the compound of Formula (I-e) is of Formula (I-e-1): (I-e-1), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 , L, and A are as defined herein.
• the compound of Formula (I-e) is of Formula (I-e-2): (I-e-2), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 , R 4 , L, and A are as defined herein.
• R 4 is substituted or unsubstituted alkyl or substituted or unsubstituted alkoxy.
• R 4 is substituted or unsubstituted C 1-4 alkyl or substituted or unsubstituted C 1-4 alkoxy.
• R 4 is unsubstituted C 1-4 alkyl, C 1-4 fluoroalkyl, unsubstituted C 1-4 alkoxy, or C 1-4 fluoroalkoxy.
• the compound of Formula (I-e) is of Formula (I-e-3): (I-e-3), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 , R 4 , L, and A are as defined herein.
• R 4 is substituted or unsubstituted alkyl.
• R 4 is substituted or unsubstituted C 1-4 alkyl. In certain embodiments, R 4 is unsubstituted C 1-4 alkyl or C 1-4 fluoroalkyl.
• the compound of Formula (I-e) is of Formula (I-e-4): (I-e-4), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 , L, and A are as defined herein.
• the compound of Formula (I-e) is of Formula (I-e-5): (I-e-5), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 , L, and A are as defined herein.
• the compound of Formula (I) is of Formula (I-f): (I-f), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 , G, Y, R 4 , p1, p2, L, and A are as defined herein.
• the compound of Formula (I-f) is of Formula (I-f-1): (I-f-1), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 , L, and A are as defined herein.
• the compound of Formula (I-f) is of Formula (I-f-2): (I-f-2), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 , L, and A are as defined herein.
• the compound of Formula (I-f) is of Formula (I-f-3): (I-f-3), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 , L, and A are as defined herein.
• the compound of Formula (I-f) is of Formula (I-f-4): (I-f-4), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 , L, and A are as defined herein.
• the compound of Formula (I-f) is of Formula (I-f-5): (I-f-5), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 , L, and A are as defined herein.
• the compound of Formula (I) is of Formula (I-g): (I-g), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 , G, Y, R 4 , p1, p2, L, and A are as defined herein.
• the compound of Formula (I-g) is of Formula (I-g-1): (I-g-1), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 , L, and A are as defined herein.
• the compound of Formula (I-g) is of Formula (I-g-2): (I-g-2), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 , R 4 , L, and A are as defined herein.
• R 4 is substituted or unsubstituted alkyl. In certain embodiments, R 4 is substituted or unsubstituted C 1-4 alkyl. In certain embodiments, R 4 is unsubstituted C 1-4 alkyl or C 1-4 fluoroalkyl.
• the compound of Formula (I-g) is of Formula (I-g-3): (I-g-3), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 , R 4 , L, and A are as defined herein.
• R 4 is substituted or unsubstituted alkyl or substituted or unsubstituted alkoxy.
• R 4 is substituted or unsubstituted C 1-4 alkyl or substituted or unsubstituted C 1-4 alkoxy.
• R 4 is unsubstituted C 1-4 alkyl, C 1-4 fluoroalkyl, unsubstituted C 1-4 alkoxy, or C 1-4 fluoroalkoxy.
• the compound of Formula (I-g) is of Formula (I-g-4): (I-g-4), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 , L, and A are as defined herein.
• the compound of Formula (I-g) is of Formula (I-g-5): (I-g-5), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 , L, and A are as defined herein.
• the compound of Formula (I-g) is of Formula (I-g-6): (I-g-6), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 , L, and A are as defined herein.
• the compound of Formula (I-g) is of Formula (I-g-7): (I-g-7), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 , R 4 , L, and A are as defined herein.
• R 4 is substituted or unsubstituted alkyl. In certain embodiments, R 4 is substituted or unsubstituted C 1-4 alkyl. In certain embodiments, R 4 is unsubstituted C 1-4 alkyl or C 1-4 fluoroalkyl.
• the compound of Formula (I-g) is of Formula (I-g-8): (I-g-8), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 , R 4 , L, and A are as defined herein.
• R 4 is substituted or unsubstituted alkyl or substituted or unsubstituted alkoxy.
• R 4 is substituted or unsubstituted C 1-4 alkyl or substituted or unsubstituted C 1-4 alkoxy.
• R 4 is unsubstituted C 1-4 alkyl, C 1-4 fluoroalkyl, unsubstituted C 1-4 alkoxy, or C 1-4 fluoroalkoxy.
• the compound of Formula (I-g) is of Formula (I-g-9): (I-g-9), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 , R 4 , p1, L, and A are as defined herein.
• the compound of Formula (I-g) is of Formula (I-g-10): (I-g-10), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 , L, and A are as defined herein.
• the compound of Formula (I-g) is of Formula (I-g-11): (I-g-11), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 , R 4 , L, and A are as defined herein.
• R 4 is substituted or unsubstituted alkyl or substituted or unsubstituted alkoxy.
• R 4 is substituted or unsubstituted C 1-4 alkyl or substituted or unsubstituted C 1-4 alkoxy.
• R 4 is unsubstituted C 1-4 alkyl, C 1-4 fluoroalkyl, unsubstituted C 1-4 alkoxy, or C 1-4 fluoroalkoxy.
• the compound of Formula (I-g) is of Formula (I-g-12): or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 , R 4 , L, and A are as defined herein.
• R 4 is substituted or unsubstituted alkyl.
• R 4 is substituted or unsubstituted C 1-4 alkyl. In certain embodiments, R 4 is unsubstituted C 1-4 alkyl or C 1-4 fluoroalkyl.
• the compound of Formula (I-g) is of Formula (I-g-13): (I-g-13), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 and A are as defined herein.
• the compound of Formula (I) is of Formula (I-h): (I-h), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 , G, Y, R 4 , p1, p2, L, and A are as defined herein.
• the compound of Formula (I-h) is of Formula (I-h-1): (I-h-1), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 , L, and A are as defined herein.
• the compound of Formula (I-h) is of Formula (I-h-2): (I-h-2), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 , L, and A are as defined herein.
• the compound of Formula (I-h) is of Formula (I-h-3): (I-h-3), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 , L, and A are as defined herein.
• the compound of Formula (I) is of Formula (I-i): (I-i), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 , G, Y, R 4 , p1, p2, L, and A are as defined herein.
• the compound of Formula (I-i) is of Formula (I-i-1): (I-i-1), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 , L, and A are as defined herein.
• the compound of Formula (I-i) is of Formula (I-i-2): (I-i-2), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 , L, and A are as defined herein.
• the compound of Formula (I-i) is of Formula (I-i-3): (I-i-3), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 , L, and A are as defined herein.
• the compound of Formula (I) is of Formula (I-j): (I-j), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 , G, Y, R 4 , p1, p2, L, and A are as defined herein.
• the compound of Formula (I-j) is of Formula (I-j-1): (I-j-1), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 , L, and A are as defined herein.
• the compound of Formula (I-j) is of Formula (I-j-2): (I-j-2), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 , R 4 , L, and A are as defined herein.
• R 4 is substituted or unsubstituted alkyl or substituted or unsubstituted alkoxy.
• R 4 is substituted or unsubstituted C 1-4 alkyl or substituted or unsubstituted C 1-4 alkoxy.
• R 4 is unsubstituted C 1-4 alkyl, C 1-4 fluoroalkyl, unsubstituted C 1-4 alkoxy, or C 1-4 fluoroalkoxy.
• the compound of Formula (I-j) is of Formula (I-j-3): (I-j-3), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 , R 4 , L, and A are as defined herein.
• R 4 is substituted or unsubstituted alkyl.
• R 4 is substituted or unsubstituted C 1-4 alkyl. In certain embodiments, R 4 is unsubstituted C 1-4 alkyl or C 1-4 fluoroalkyl.
• the compound of Formula (I-j) is of Formula (I-j-4): (I-j-4), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 , L, and A are as defined herein.
• the compound of Formula (I-j) is of Formula (I-j-5): (I-j-5), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 , L, and A are as defined herein.
• the compound of Formula (I-j) is of Formula (I-j-6): (I-j-6), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 , L, and A are as defined herein.
• the compound of Formula (I-j) is of Formula (I-j-7): (I-j-7), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 , R 4 , L, and A are as defined herein.
• R 4 is substituted or unsubstituted alkyl or substituted or unsubstituted alkoxy.
• R 4 is substituted or unsubstituted C 1-4 alkyl or substituted or unsubstituted C 1-4 alkoxy.
• R 4 is unsubstituted C 1-4 alkyl, C 1-4 fluoroalkyl, unsubstituted C 1-4 alkoxy, or C 1-4 fluoroalkoxy.
• the compound of Formula (I-j) is of Formula (I-j-8): (I-j-8), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 , R 4 , L, and A are as defined herein.
• R 4 is substituted or unsubstituted alkyl.
• R 4 is substituted or unsubstituted C 1-4 alkyl. In certain embodiments, R 4 is unsubstituted C 1-4 alkyl or C 1-4 fluoroalkyl.
• the compound of Formula (I-j) is of Formula (I-j-9): (I-j-9), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 , L, and A are as defined herein.
• the compound of Formula (I-j) is of Formula (I-j-10): (I-j-10), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 , R 4 , L, and A are as defined herein.
• R 4 is substituted or unsubstituted alkyl or substituted or unsubstituted alkoxy.
• R 4 is substituted or unsubstituted C 1-4 alkyl or substituted or unsubstituted C 1-4 alkoxy.
• R 4 is unsubstituted C 1-4 alkyl, C 1-4 fluoroalkyl, unsubstituted C 1-4 alkoxy, or C 1-4 fluoroalkoxy.
• the compound of Formula (I-j) is of Formula (I-j-11): or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 , R 4 , L, and A are as defined herein.
• R 4 is substituted or unsubstituted alkyl.
• R 4 is substituted or unsubstituted C 1-4 alkyl. In certain embodiments, R 4 is unsubstituted C 1-4 alkyl or C 1-4 fluoroalkyl.
• the compound of Formula (I) is of Formula (I-k): (I-k), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 , G, Y, R 4 , p1, p2, L, and A are as defined herein.
• the compound of Formula (I-k) is of Formula (I-k-1): (I-k-1), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 , R 4 , p2, L, and A are as defined herein.
• the compound of Formula (I-k) is of Formula (I-k-2): (I-k-2), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 , L, and A are as defined herein.
• the compound of Formula (I-k) is of Formula (I-k-3): (I-k-3), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 and A are as defined herein.
• the compound of Formula (I-k) is of Formula (I-k-4): (I-k-4), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 , L, and A are as defined herein.
• the compound of Formula (I-k) is of Formula (I-k-5): (I-k-5), [00326] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 and A are as defined herein.
• the compound of Formula (I) is of Formula (I- l): (I-l), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 , G, Y, R 4 , p1, p2, L, and A are as defined herein.
• the compound of Formula (I-l) is of Formula (I-l-1): (I-l-1), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 , R 4 , p2, L, and A are as defined herein.
• the compound of Formula (I-l) is of Formula (I-l-2): (I-l-2), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 , L, and A are as defined herein.
• the compound of Formula (I-l) is of Formula (I-l-3): (I-l-3), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 and A are as defined herein.
• the compound of Formula (I-l) is of Formula (I-l-4): (I-l-4), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 , L, and A are as defined herein.
• the compound of Formula (I-l) is of Formula (I-l-5): (I-l-5), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 and A are as defined herein.
• the compound of Formula (I) is of Formula (I-m): (I-m), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 , G, Y, R 4 , p1, p2, L, and A are as defined herein.
• the compound of Formula (I-m) is of Formula (I-m-1): (I-m-1), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 , R 4 , p1, L, and A are as defined herein.
• the compound of Formula (I-m) is of Formula (I-m-2): (I-m-2), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 , L, and A are as defined herein.
• the compound of Formula (I-m) is of Formula (I-m-3): (I-m-3), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 and A are as defined herein.
• the compound of Formula (I) is of Formula (I-n) or (I-n’): (I-n’), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 , G, B, R 4 , p1, p2, m, and n are as defined herein; X is N or CR a ; each R a is independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heterocyclyl; and R b is hydrogen, halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted alkoxy.
• each R a is independently hydrogen, or substituted or unsubstituted alkyl; and R b is halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted alkoxy.
• X is N or CH. In certain embodiments, X is N. In certain embodiments, X is CH. In certain embodiments, X is N or CH; R a is hydrogen or haloalkyl; and R b is halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted alkoxy.
• X is N or CH; R a is hydrogen or fluoroalkyl; and R b is halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted alkoxy.
• X is N or CH; R a is hydrogen or C 1-4 fluoroalkyl; and R b is halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted alkoxy.
• X is N; R a is hydrogen or haloalkyl; and R b is halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted alkoxy.
• X is N; R a is hydrogen or fluoroalkyl; and R b is halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted alkoxy.
• X is N; R a is hydrogen or C 1-4 fluoroalkyl; and R b is halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted alkoxy.
• X is N; R a is haloalkyl; and R b is halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted alkoxy.
• X is N; R a is fluoroalkyl; and R b is halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted alkoxy.
• X is N; R a is C 1-4 fluoroalkyl; and R b is halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted alkoxy.
• X is CH; and R a is hydrogen or substituted or unsubstituted alkyl.
• X is CH; and R a is hydrogen or haloalkyl.
• X is CH; and R a is hydrogen or fluoroalkyl. In certain embodiments, X is CH; and R a is hydrogen or C 1-4 fluoroalkyl. In certain embodiments, X is CH; and R a is hydrogen.
• the compound of Formula (I-n) is of Formula (I-n-1): (I-n-1), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 , G, B, R 4 , p1, p2, m, and n are as defined herein; X is N or CR a ; and each R a is independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heterocyclyl.
• each R a is independently hydrogen, or substituted or unsubstituted alkyl.
• X is N or CH. In certain embodiments, X is N. In certain embodiments, X is CH. In certain embodiments, X is N or CH; and R a is hydrogen or haloalkyl. In certain embodiments, X is N or CH; and R a is hydrogen or fluoroalkyl. In certain embodiments, X is N or CH; and R a is hydrogen or C 1-4 fluoroalkyl. In certain embodiments, X is N; and R a is hydrogen or haloalkyl.
• X is N; and R a is hydrogen or fluoroalkyl. In certain embodiments, X is N; and R a is hydrogen or C 1-4 fluoroalkyl. In certain embodiments, X is N; and R a is haloalkyl. In certain embodiments, X is N; and R a is fluoroalkyl. In certain embodiments, X is N; and R a is C 1-4 fluoroalkyl. In certain embodiments, X is CH; and R a is hydrogen or substituted or unsubstituted alkyl. In certain embodiments, X is CH; and R a is hydrogen or haloalkyl.
• X is CH; and R a is hydrogen or fluoroalkyl. In certain embodiments, X is CH; and R a is hydrogen or C 1-4 fluoroalkyl. In certain embodiments, X is CH; and R a is hydrogen.
• the compound of Formula (I) is of Formula (I-o) or (I-o’): or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 , G, B, R 4 , p1, p2, m, and n are as defined herein; R a is hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heterocyclyl; and R b is hydrogen, halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted alkoxy.
• the compound of Formula (I-o) is of Formula (I-o-l): (I-o-1), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 , G, B, R 4 , p1, p2, m, and n are as defined herein; and R a is hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heterocyclyl.
• R a is hydrogen, or substituted or unsubstituted alkyl.
• R a is substituted or unsubstituted alkyl or substituted or unsubstituted heterocyclyl. In certain embodiments, R a is substituted or unsubstituted alkyl. In certain embodiments, R a is haloalkyl. In certain embodiments, R a is fluoroalkyl. In certain embodiments, R a is C 1-4 fluoroalkyl. In certain embodiments, R a is 2,2- difluoroethyl, or 2,2,2-trifluoroethyl. In certain embodiments, R a is 2,2-difluoroethyl. In certain embodiments, R a is 2,2,2-trifluoroethyl.
• the compound of Formula (I) is of Formula (I-p) or (I-p’): or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 , G, B, R 4 , p1, p2, m, and n are as defined herein; and R b is hydrogen, halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted alkoxy.
• the compound of Formula (I-p) is of Formula (I-p-1): (I-p-1), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 , G, B, R 4 , p1, p2, m, and n are as defined herein.
• the compound of Formula (I) is of Formula (I-q): (I-q), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 , G, Y, R 4 , p1, p2, m, n, k, and q are as defined herein; X is N or CR a ; each R a is independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heterocyclyl; and R b is hydrogen, halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted alkoxy.
• each R a is independently hydrogen, or substituted or unsubstituted alkyl.
• X is N or CH. In certain embodiments, X is N. In certain embodiments, X is CH. In certain embodiments, X is N or CH; and R a is hydrogen or haloalkyl. In certain embodiments, X is N or CH; and R a is hydrogen or fluoroalkyl. In certain embodiments, X is N or CH; and R a is hydrogen or C 1-4 fluoroalkyl. In certain embodiments, X is N; and R a is hydrogen or haloalkyl.
• X is N; and R a is hydrogen or fluoroalkyl. In certain embodiments, X is N; and R a is hydrogen or C 1-4 fluoroalkyl. In certain embodiments, X is N; and R a is haloalkyl. In certain embodiments, X is N; and R a is fluoroalkyl. In certain embodiments, X is N; and R a is C 1-4 fluoroalkyl. In certain embodiments, X is CH; and R a is hydrogen or substituted or unsubstituted alkyl. In certain embodiments, X is CH; and R a is hydrogen or haloalkyl.
• X is CH; and R a is hydrogen or fluoroalkyl. In certain embodiments, X is CH; and R a is hydrogen or C 1-4 fluoroalkyl. In certain embodiments, X is CH; and R a is hydrogen.
• the compound of Formula (I) is of Formula (I-q-1): (I-q-1), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 , G, Y, R 4 , p1, p2, m, n, k, and q are as defined herein; X is N or CR a ; and each R a is independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heterocyclyl.
• the compound of Formula (I-q) is of Formula (I-q-2): (I-q-2), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 , G, Y, R 4 , p1, p2, m, n, k, and q are as defined herein; X is N or CR a ; and each R a is independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heterocyclyl.
• the compound of Formula (I-q) is of Formula (I-q-3): (I-q-3), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 , G, Y, R 4 , p1, p2, m, n, k, and q are as defined herein; X is N or CR a ; and each R a is independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heterocyclyl.
• the compound of Formula (I-q) is of Formula (I-q-4): (I-q-4), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 , G, Y, R 4 , p1, p2, m, n, k, and q are as defined herein; X is N or CR a ; and each R a is independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heterocyclyl.
• the compound of Formula (I-n) is of Formula (I-q-5): (I-q-5), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 , G, Y, R 4 , p1, p2, m, n, k, and q are as defined herein; X is N or CR a ; and each R a is independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heterocyclyl.
• the compound of Formula (I-q) is of Formula (I-q-6): (I-q-6), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 , G, Y, R 4 , p1, p2, m, n, k, and q are as defined herein; X is N or CR a ; and each R a is independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heterocyclyl.
• the compound of Formula (I) is of Formula (I-r): (I-r), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 , G, Y, R 4 , p1, p2, m, n, k, and q are as defined herein; R a is hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heterocyclyl; and R b is hydrogen, halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted alkoxy.
• R a is hydrogen, or substituted or unsubstituted alkyl. In certain embodiments, R a is substituted or unsubstituted alkyl or substituted or unsubstituted heterocyclyl. In certain embodiments, R a is substituted or unsubstituted alkyl. In certain embodiments, R a is haloalkyl. In certain embodiments, R a is fluoroalkyl. In certain embodiments, R a is C 1-4 fluoroalkyl. In certain embodiments, R a is 2,2- difluoroethyl, or 2,2,2-trifluoroethyl.
• R a is 2,2-difluoroethyl. In certain embodiments, R a is 2,2,2-trifluoroethyl.
• the compound of Formula (I) is of Formula (I-r-1): (I-r-1), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 , G, Y, R 4 , p1, p2, m, n, k, and q are as defined herein; and R a is hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heterocyclyl.
• the compound of Formula (I-r) is of Formula (I-r-2): (I-r-2), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 , G, Y, R 4 , p1, p2, m, n, k, and q are as defined herein; and R a is hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heterocyclyl.
• the compound of Formula (I-r) is of Formula (I-r-3): (I-r-3), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 , G, Y, R 4 , p1, p2, m, n, k, and q are as defined herein; X is N or CR a ; and R a is hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heterocyclyl.
• the compound of Formula (I-r) is of Formula (I-r-4): (I-r-4), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 , G, Y, R 4 , p1, p2, m, n, k, and q are as defined herein; X is N or CR a ; and R a is hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heterocyclyl.
• the compound of Formula (I-r) is of Formula (I-r-5): (I-r-5), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 , G, Y, R 4 , p1, p2, m, n, k, and q are as defined herein; X is N or CR a ; and R a is hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heterocyclyl.
• the compound of Formula (I-r) is of Formula (I-r-6): (I-r-6), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 , G, Y, R 4 , p1, p2, m, n, k, and q are as defined herein; X is N or CR a ; and R a is hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heterocyclyl.
• the compound of Formula (I) is of Formula (I-s): (I-s), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 , G, Y, R 4 , p1, p2, m, n, k, and q are as defined herein; and R b is hydrogen, halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted alkoxy.
• the compound of Formula (I-s) is of Formula (I-s-1): (I-s-1), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 , G, Y, R 4 , p1, p2, m, n, k, and q are as defined herein.
• the compound of Formula (I-s) is of Formula (I-s-2): (I-s-2), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 , G, Y, R 4 , p1, p2, m, n, k, and q are as defined herein.
• the compound of Formula (I-s) is of Formula (I-s-3): (I-s-3), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 , G, Y, R 4 , p1, p2, m, n, k, and q are as defined herein.
• the compound of Formula (I-s) is of Formula (I-s-4): (I-s-4), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 , G, Y, R 4 , p1, p2, m, n, k, and q are as defined herein.
• the compound of Formula (I-s) is of Formula (I-s-5): (I-s-5), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 , G, Y, R 4 , p1, p2, m, n, k, and q are as defined herein.
• the compound of Formula (I-s) is of Formula (I-s-6): (I-s-6), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 , G, Y, R 4 , p1, p2, m, n, k, and q are as defined herein.
• the compound of Formula (I) is of Formula (I-t): (I-t), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 , G, Y, R 4 , p1, p2, m, n, k, and q are as defined herein.
• the compound of Formula (I-t) is of Formula (I-t-1): (I-t-1), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 , G, Y, R 4 , p1, p2, m, n, k, and q are as defined herein.
• the compound of Formula (I-t) is of Formula (I-t-2): (I-t-2), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 , G, Y, R 4 , p1, p2, m, n, k, and q are as defined herein.
• the compound of Formula (I-t) is of Formula (I-t-3): (I-t-3), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 , G, Y, R 4 , p1, p2, m, n, k, and q are as defined herein.
• the compound of Formula (I-t) is of Formula (I-t-4): (I-t-4), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 , G, Y, R 4 , p1, p2, m, n, k, and q are as defined herein.
• the compound of Formula (I-t) is of Formula (I-t-5): (I-t-5), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 , G, Y, R 4 , p1, p2, m, n, k, and q are as defined herein.
• the compound of Formula (I) is of Formula (I-u): (I-u), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 , G, Y, R 4 , p1, p2, m, n, k, and q are as defined herein.
• the compound of Formula (I-r) is of Formula (I-u-1): (I-u-1), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 , G, Y, R 4 , p1, p2, m, n, k, and q are as defined herein.
• the compound of Formula (I-r) is of Formula (I-u-2): (I-u-2), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 , G, Y, R 4 , p1, p2, m, n, k, and q are as defined herein.
• the compound of Formula (I-u) is of Formula (I-u-3): (I-u-3), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 , G, Y, R 4 , p1, p2, m, n, k, and q are as defined herein.
• the compound of Formula (I-r) is of Formula (I-u-4): (I-u-4), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 , G, Y, R 4 , p1, p2, m, n, k, and q are as defined herein.
• the compound of Formula (I-u) is of Formula (I-u-5): (I-u-5), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 , G, Y, R 4 , p1, p2, m, n, k, and q are as defined herein.
• the compound of Formula (I) is of Formula (I-v): (I-v), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 , R 4 , L, and A are as defined herein.
• the compound of Formula (I) is of Formula (I-v-1): (I-v-1), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 , R 4 , L, and A are as defined herein.
• the compound of Formula (I) is of Formula (I-v-2): (I-v-2), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 , R 4 , L, and A are as defined herein.
• R 4 is substituted or unsubstituted alkyl or substituted or unsubstituted alkoxy.
• R 4 is substituted or unsubstituted C 1-4 alkyl or substituted or unsubstituted C 1-4 alkoxy.
• R 4 is unsubstituted C 1-4 alkyl, C 1-4 fluoroalkyl, unsubstituted C 1-4 alkoxy, or C 1-4 fluoroalkoxy.
• the compound of Formula (I) is of Formula (I-v-3): (I-v-3), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 , R 4 , L, and A are as defined herein.
• R 4 is substituted or unsubstituted alkyl.
• R 4 is substituted or unsubstituted C 1-4 alkyl. In certain embodiments, R 4 is unsubstituted C 1-4 alkyl or C 1-4 fluoroalkyl.
• the compound of Formula (I) is of Formula (I-v-4): (I-v-4), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 , R 4 , and A are as defined herein.
• the compound of Formula (I) is of Formula (I-w): or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 , R 4 , and A are as defined herein; R a is hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heterocyclyl; and R b is hydrogen, halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted alkoxy.
• R a is hydrogen, or substituted or unsubstituted alkyl. In certain embodiments, R a is substituted or unsubstituted alkyl or substituted or unsubstituted heterocyclyl. In certain embodiments, R a is substituted or unsubstituted alkyl. In certain embodiments, R a is haloalkyl. In certain embodiments, R a is fluoroalkyl. In certain embodiments, R a is C 1-4 fluoroalkyl. In certain embodiments, R a is 2,2- difluoroethyl, or 2,2,2-trifluoroethyl.
• R a is 2,2-difluoroethyl. In certain embodiments, R a is 2,2,2-trifluoroethyl.
• the compound of Formula (I-x) is of Formula (I-w-1): (I-w-1), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 , R 4 , and A are as defined herein; and R a is hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heterocyclyl.
• the compound of Formula (I) is of Formula (I-w-2): (I-w-2), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 and R 4 are as defined herein; and R b is hydrogen, halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted alkoxy.
• the compound of Formula (I-w) is of Formula (I-w-3): (I-w-3), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 and R 4 are as defined herein.
• the compound of Formula (I) is of Formula (I-x): or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 is as defined herein; R a is substituted or unsubstituted alkyl or substituted or unsubstituted heterocyclyl; and R b is hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted alkoxy.
• R a is unsubstituted alkyl, haloalkyl, or heterocyclyl; and R b is hydrogen, unsubstituted alkyl, or unsubstituted alkoxy.
• R a is haloalkyl or unsubstituted heterocyclyl; and R b is hydrogen, unsubstituted alkyl, or unsubstituted alkoxy.
• R a is haloalkyl or unsubstituted heterocyclyl; and R b is hydrogen or unsubstituted alkoxy.
• R a is C 1-4 haloalkyl or unsubstituted 4-5 membered heterocyclyl; and R b is hydrogen, unsubstituted C 1-4 alkyl, or unsubstituted C 1-4 alkoxy.
• R a is C 1-4 haloalkyl or unsubstituted 4-5 membered heterocyclyl; and R b is hydrogen or unsubstituted C 1-4 alkyl.
• R a is 2,2-difluoroethyl or oxetanyl; and R b is hydrogen, -CH 3 , or -OCH 3 .
• R a is 2,2-difluoroethyl or oxetanyl; and R b is hydrogen or -CH 3 . In certain embodiments, R a is 2,2-difluoroethyl; and R b is hydrogen.
• the compound of Formula (I-x) is of Formula (I-x-1): (I-x-1), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 is as defined herein; and R b is hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted alkoxy. In certain embodiments, R b is hydrogen, unsubstituted alkyl, or unsubstituted alkoxy. In certain embodiments, R b is hydrogen, unsubstituted alkyl, or unsubstituted alkoxy.
• R b is hydrogen or unsubstituted alkoxy. In certain embodiments, R b is hydrogen, unsubstituted C 1-4 alkyl, or unsubstituted C 1-4 alkoxy. In certain embodiments, R b is hydrogen or unsubstituted C 1-4 alkyl. In certain embodiments, R b is hydrogen, -CH 3 , or - OCH 3 . In certain embodiments, R b is hydrogen or -CH 3 . In certain embodiments, R b is hydrogen.
• the compound of Formula (I-x) is of Formula (I-x-2): (I-x-2), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 is as defined herein.
• the compound of Formula (I) is of Formula (I-y): or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 is as defined herein; and R a is substituted or unsubstituted alkyl or substituted or unsubstituted heterocyclyl; and R b is hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted alkoxy.
• R a is unsubstituted alkyl, haloalkyl, or heterocyclyl; and R b is hydrogen, unsubstituted alkyl, or unsubstituted alkoxy.
• R a is haloalkyl or unsubstituted heterocyclyl; and R b is hydrogen, unsubstituted alkyl, or unsubstituted alkoxy.
• R a is haloalkyl or unsubstituted heterocyclyl; and R b is hydrogen or unsubstituted alkoxy.
• R a is C 1-4 haloalkyl or unsubstituted 4-5 membered heterocyclyl; and R b is hydrogen, unsubstituted C 1-4 alkyl, or unsubstituted C 1-4 alkoxy.
• R a is C 1-4 haloalkyl or unsubstituted 4-5 membered heterocyclyl; and R b is hydrogen or unsubstituted C 1-4 alkyl.
• R a is 2,2-difluoroethyl or oxetanyl; and R b is hydrogen, -CH 3 , or - OCH 3 .
• R a is 2,2-difluoroethyl or oxetanyl; and R b is hydrogen or - CH 3 . In certain embodiments, R a is 2,2-difluoroethyl; and R b is hydrogen.
• the compound of Formula (I) is of Formula (I-z): or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 is as defined herein; R a is substituted or unsubstituted alkyl or substituted or unsubstituted heterocyclyl; and R b is hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted alkoxy.
• R a is unsubstituted alkyl, haloalkyl, haloalkoxyalkyl, heterocyclyalkyl, arylalkyl, or heterocyclyl; and R b is hydrogen, unsubstituted alkyl, or unsubstituted alkoxy.
• R a is haloalkyl or unsubstituted heterocyclyl; and R b is hydrogen, unsubstituted alkyl, or unsubstituted alkoxy.
• R a is C 1-4 haloalkyl or unsubstituted 4-5 membered heterocyclyl; and R b is hydrogen, unsubstituted C 1-4 alkyl, or unsubstituted C 1-4 alkoxy.
• R a is 2,2- difluoroethyl or oxetanyl; and R b is hydrogen, -CH 3 , or -OCH 3 .
• R a is 2,2-difluoroethyl; and R b is hydrogen.
• the compound of Formula (I) is of Formula (I-aa): or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 is as defined herein; R a is substituted or unsubstituted alkyl or substituted or unsubstituted heterocyclyl; and R b is hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted alkoxy.
• R a is unsubstituted alkyl, haloalkyl, haloalkoxyalkyl, heterocyclyalkyl, arylalkyl, or heterocyclyl; and R b is hydrogen, unsubstituted alkyl, or unsubstituted alkoxy.
• R a is haloalkyl or unsubstituted heterocyclyl; and R b is hydrogen, unsubstituted alkyl, or unsubstituted alkoxy.
• R a is C 1-4 haloalkyl or unsubstituted 4-5 membered heterocyclyl; and R b is hydrogen, unsubstituted C 1-4 alkyl, or unsubstituted C 1-4 alkoxy.
• R a is 2,2- difluoroethyl or oxetanyl; and R b is hydrogen, -CH 3 , or -OCH 3 .
• R a is 2,2-difluoroethyl; and R b is hydrogen.
• the compound of Formula (I) is of Formula (I-bb): (I-bb), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 is as defined herein; R a is substituted or unsubstituted alkyl or substituted or unsubstituted heterocyclyl; and R b is substituted or unsubstituted alkyl or substituted or unsubstituted heterocyclyl.
• R a is substituted or unsubstituted alkyl or substituted or unsubstituted heterocyclyl; and R b is substituted or unsubstituted alkyl. In certain embodiments, R a is substituted or unsubstituted alkyl; and R b is substituted or unsubstituted alkyl. In certain embodiments, R a is haloalkyl or heterocyclyl; and R b is unsubstituted alkyl. In certain embodiments, R a is haloalkyl; and R b is unsubstituted alkyl.
• R a is C 1- 4 haloalkyl or unsubstituted 4-5 membered heterocyclyl; and R b is unsubstituted C 1-4 alkyl. In certain embodiments, R a is C 1-4 haloalkyl; and R b is unsubstituted C 1-4 alkyl. In certain embodiments, R a is 2,2-difluoroethyl or oxetanyl; and R b is -CH 3 , or -CH 2 CH 3 . In certain embodiments, R a is 2,2-difluoroethyl; and R b is -CH 3 or -CH 2 CH 3 .
• the compound of Formula (I) is of Formula (I-cc): (I-cc), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 is as defined herein; R a is substituted or unsubstituted alkyl or substituted or unsubstituted heterocyclyl; and R b is substituted or unsubstituted alkyl or substituted or unsubstituted heterocyclyl.
• R a is substituted or unsubstituted alkyl or substituted or unsubstituted heterocyclyl; and R b is substituted or unsubstituted alkyl. In certain embodiments, R a is substituted or unsubstituted alkyl; and R b is substituted or unsubstituted alkyl. In certain embodiments, R a is haloalkyl or heterocyclyl; and R b is unsubstituted alkyl. In certain embodiments, R a is haloalkyl; and R b is unsubstituted alkyl.
• R a is C 1- 4 haloalkyl or unsubstituted 4-5 membered heterocyclyl; and R b is unsubstituted C 1-4 alkyl. In certain embodiments, R a is C 1-4 haloalkyl; and R b is unsubstituted C 1-4 alkyl. In certain embodiments, R a is 2,2-difluoroethyl or oxetanyl; and R b is -CH 3 , or -CH 2 CH 3 . In certain embodiments, R a is 2,2-difluoroethyl; and R b is -CH 3 or -CH 2 CH 3 .
• the compound of Formula (I) is of Formula (I-dd): (I-dd), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 is as defined herein; R a is substituted or unsubstituted alkyl or substituted or unsubstituted heterocyclyl; and R b is hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted alkoxy.
• R a is unsubstituted alkyl, haloalkyl, haloalkoxyalkyl, heterocyclyalkyl, arylalkyl, or heterocyclyl; and R b is hydrogen, unsubstituted alkyl, or unsubstituted alkoxy.
• R a is haloalkyl or unsubstituted heterocyclyl; and R b is hydrogen, unsubstituted alkyl, or unsubstituted alkoxy.
• R a is C 1-4 haloalkyl or unsubstituted 4-5 membered heterocyclyl; and R b is hydrogen, unsubstituted C 1-4 alkyl, or unsubstituted C 1-4 alkoxy.
• R a is 2,2- difluoroethyl or oxetanyl; and R b is hydrogen, -CH 3 , or -OCH 3 .
• R a is 2,2-difluoroethyl; and R b is hydrogen.
• the compound of Formula (I) is of Formula (I-ee): or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 is as defined herein; and R a is substituted or unsubstituted alkyl or substituted or unsubstituted heterocyclyl; and R b is hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted alkoxy.
• R a is unsubstituted alkyl, haloalkyl, or heterocyclyl; and R b is hydrogen, unsubstituted alkyl, or unsubstituted alkoxy.
• R a is haloalkyl or unsubstituted heterocyclyl; and R b is hydrogen, unsubstituted alkyl, or unsubstituted alkoxy.
• R a is haloalkyl or unsubstituted heterocyclyl; and R b is hydrogen or unsubstituted alkoxy.
• R a is C 1-4 haloalkyl or unsubstituted 4-5 membered heterocyclyl; and R b is hydrogen, unsubstituted C 1-4 alkyl, or unsubstituted C 1-4 alkoxy.
• R a is C 1-4 haloalkyl or unsubstituted 4-5 membered heterocyclyl; and R b is hydrogen or unsubstituted C 1-4 alkyl.
• R a is 2,2-difluoroethyl or oxetanyl; and R b is hydrogen, -CH 3 , or - OCH 3 .
• R a is 2,2-difluoroethyl or oxetanyl; and R b is hydrogen or - CH 3 . In certain embodiments, R a is 2,2-difluoroethyl; and R b is hydrogen. In certain embodiments, R a is oxetanyl; and R b is hydrogen.
• the compound of Formula (I) is of Formula (I-ff): (I-ff), [00403] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 is as defined herein; R a is substituted or unsubstituted alkyl or substituted or unsubstituted heterocyclyl; and R b is hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted alkoxy.
• R a is unsubstituted alkyl, haloalkyl, haloalkoxyalkyl, heterocyclyalkyl, arylalkyl, or heterocyclyl; and R b is hydrogen, unsubstituted alkyl, or unsubstituted alkoxy.
• R a is haloalkyl or unsubstituted heterocyclyl; and R b is hydrogen, unsubstituted alkyl, or unsubstituted alkoxy.
• R a is C 1-4 haloalkyl or unsubstituted 4-5 membered heterocyclyl; and R b is hydrogen, unsubstituted C 1-4 alkyl, or unsubstituted C 1-4 alkoxy.
• R a is 2,2-difluoroethyl or oxetanyl; and R b is hydrogen, -CH 3 , or -OCH 3 .
• R a is 2,2-difluoroethyl; and R b is hydrogen.
• R a is oxetanyl; and R b is -CH 3 .
• the compound of Formula (I) is of Formula (I-gg): [00405] or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof; wherein R 1 is as defined herein; and R a is substituted or unsubstituted alkyl or substituted or unsubstituted heterocyclyl; R b is hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted alkoxy.
• R a is unsubstituted alkyl, haloalkyl, or heterocyclyl; and R b is hydrogen, unsubstituted alkyl, or unsubstituted alkoxy.
• R a is haloalkyl or unsubstituted heterocyclyl; and R b is hydrogen, unsubstituted alkyl, or unsubstituted alkoxy.
• R a is haloalkyl or unsubstituted heterocyclyl; and R b is hydrogen or unsubstituted alkoxy.
• R a is C 1-4 haloalkyl or unsubstituted 4-5 membered heterocyclyl; and R b is hydrogen, unsubstituted C 1-4 alkyl, or unsubstituted C 1-4 alkoxy.
• R a is C 1-4 haloalkyl or unsubstituted 4-5 membered heterocyclyl; and R b is hydrogen or unsubstituted C 1-4 alkyl.
• R a is 2,2-difluoroethyl or oxetanyl; and R b is hydrogen, -CH 3 , or - OCH 3 .
• R a is 2,2-difluoroethyl or oxetanyl; and R b is hydrogen or - CH 3 . In certain embodiments, R a is 2,2-difluoroethyl; and R b is hydrogen. In certain embodiments, R a is oxetanyl; and R b is hydrogen. In certain embodiments, R a is 2,2- difluoroethyl; and R b is -CH 3 .
• the compound is of formula (I-g-13), (I-k-3), (I-k-5), (I-l- 5), (I-m-3): or a pharmaceutically acceptable salt thereof, wherein: R 1 is , , , , ; and A is , , , , , , [00407]
• the compound of Formula (I) is one of the compounds of Table 1, or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof: Table 1.
• the provided compounds activate GCase with an EC 50 of less than 100,000 nM, less than 50,000 nM, less than 20,000 nM, less than 10,000 nM, less than 5,000 nM, less than 2,500 nM, less than 1,000 nM, less than 900 nM, less than 800 nM, less than 700 nM, less than 600 nM, less than 500 nM, less than 400 nM, less than 300 nM, less than 200 nM, less than 100 nM, less than 90 nM, less than 80 nM, less than 70 nM, less than 60 nM, less than 50 nM, less than 40 nM, less than 30 nM, less than 20 nM, less than 10 nM, less than 5 nM, less than 4 nM, less than 3 nM, less than 2 nM, or less than 1 nM.
• compositions comprising a disclosed compound (e.g., a compound of Formula (I)), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, and optionally a pharmaceutically acceptable excipient.
• the pharmaceutical composition described herein comprises a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
• the compound of Formula (I) is provided in an effective amount in the pharmaceutical composition. In certain embodiments, the effective amount is a therapeutically effective amount.
• the effective amount is a prophylactically effective amount. In certain embodiments, the effective amount is an amount effective for treating a disease or disorder in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for treating a neurological disease or disorder in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for preventing a neurological disease or disorder in a subject in need thereof. [00411] In certain embodiments, the effective amount is an amount effective for reducing the risk of developing a disease (e.g., neurological disease or disorder) in a subject in need thereof. [00412] In certain embodiments, the effective amount is an amount effective for increasing the activity of GCase in a subject, tissue, biological sample, or cell.
• the subject being treated or administered a compound described herein is an animal.
• the animal may be of either sex and may be at any stage of development.
• the subject described herein is a human.
• the subject is a non-human animal.
• the subject is a mammal.
• the subject is a non-human mammal.
• the subject is a domesticated animal, such as a dog, cat, cow, pig, horse, sheep, or goat.
• the subject is a companion animal, such as a dog or cat.
• the subject is a livestock animal, such as a cow, pig, horse, sheep, or goat.
• the subject is a zoo animal.
• the subject is a research animal, such as a rodent (e.g., mouse, rat), dog, pig, or non-human primate.
• the animal is a genetically engineered animal.
• the animal is a transgenic animal (e.g., transgenic mice and transgenic pigs).
• the subject is a fish or reptile.
• the effective amount is an amount effective for increasing the activity of GCase by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 100%, at least about 150%, at least about 200%, at least about 250%, at least about 300%, at least about 400%, at least about 500%, or at least about 1000%.
• the effective amount is an amount effective for iincreasing the activity of GCase by a range between a percentage described in this paragraph and another percentage described in this paragraph, inclusive.
• the present disclosure provides pharmaceutical compositions comprising a compound that interacts with (e.g., activates) GCase for use in treating a GCase-related disease or disorder in a subject in need thereof.
• the present disclosure provides pharmaceutical compositions comprising a compound that interacts with (e.g., activates) GCase for use in treating a disease or disorder associated with aberrant activity of GCase in a subject in need thereof.
• the present disclosure provides pharmaceutical compositions comprising a compound that interacts with (e.g., activates) GCase for use in treating a disease or disorder associated with mutated GCase in a subject in need thereof.
• the composition is for use in treating a disease or disorder. In certain embodiments, the composition is for use in treating a neurological disease or disorder. In certain embodiments, the composition is for use in treating Gaucher’s disease or Parkinson's disease. In certain embodiments, the composition is for use in treating Gaucher’s disease. In certain embodiments, the composition is for use in treating Parkinson's disease. [00417] A compound or composition, as described herein, can be administered in combination with one or more additional pharmaceutical agents (e.g., therapeutically and/or prophylactically active agents).
• additional pharmaceutical agents e.g., therapeutically and/or prophylactically active agents.
• the compounds or compositions can be administered in combination with additional pharmaceutical agents that improve their activity (e.g., activity (e.g., potency and/or efficacy) in treating a disease in a subject in need thereof, in preventing a disease in a subject in need thereof, and/or in reducing the risk to develop a disease in a subject in need thereof), improve bioavailability, improve safety, reduce drug resistance, reduce and/or modify metabolism, inhibit excretion, and/or modify distribution in a subject or cell.
• additional pharmaceutical agents that improve their activity (e.g., activity (e.g., potency and/or efficacy) in treating a disease in a subject in need thereof, in preventing a disease in a subject in need thereof, and/or in reducing the risk to develop a disease in a subject in need thereof), improve bioavailability, improve safety, reduce drug resistance, reduce and/or modify metabolism, inhibit excretion, and/or modify distribution in a subject or cell.
• the therapy employed may achieve a desired effect for the
• a pharmaceutical composition described herein including a compound described herein and an additional pharmaceutical agent exhibit a synergistic effect that is absent in a pharmaceutical composition including one of the compound and the additional pharmaceutical agent, but not both.
• the compound or composition can be administered concurrently with, prior to, or subsequent to one or more additional pharmaceutical agents, which may be useful as, e.g., combination therapies.
• Pharmaceutical agents include therapeutically active agents.
• Pharmaceutical agents also include prophylactically active agents.
• Pharmaceutical agents include small organic molecules such as drug compounds (e.g., compounds approved for human or veterinary use by the U.S.
• the additional pharmaceutical agent is a pharmaceutical agent useful for treating and/or preventing a disease (e.g., neurological disease or disorder).
• a disease e.g., neurological disease or disorder.
• Each additional pharmaceutical agent may be administered at a dose and/or on a time schedule determined for that pharmaceutical agent.
• the additional pharmaceutical agents may also be administered together with each other and/or with the compound or composition described herein in a single dose or administered separately in different doses.
• the particular combination to employ in a regimen will take into account compatibility of the compound described herein with the additional pharmaceutical agent(s) and/or the desired therapeutic and/or prophylactic effect to be achieved. In general, it is expected that the additional pharmaceutical agent(s) in combination be utilized at levels that do not exceed the levels at which they are utilized individually. In some embodiments, the levels utilized in combination will be lower than those utilized individually. [00419]
• the compound or pharmaceutical composition is a solid.
• the compound or pharmaceutical composition is a powder. In certain embodiments, the compound or pharmaceutical composition can be dissolved in a liquid to make a solution. In certain embodiments, the compound or pharmaceutical composition is dissolved in water to make an aqueous solution. In certain embodiments, the pharmaceutical composition is a liquid for parental injection. In certain embodiments, the pharmaceutical composition is a liquid for oral administration (e.g., ingestion). In certain embodiments, the pharmaceutical composition is a liquid (e.g., aqueous solution) for intravenous injection. In certain embodiments, the pharmaceutical composition is a liquid (e.g., aqueous solution) for subcutaneous injection.
• the pharmaceutical compositions of the present dislcosure can be administered to humans and other animals orally, parenterally, intracisternally, intraperitoneally, topically, bucally, or the like, depending on the disease or condition being treated.
• a pharmaceutical composition comprising a compound of Formula (I) is administered, orally or parenterally, at dosage levels of each pharmaceutical composition sufficient to deliver from about 0.001 mg/kg to about 200 mg/kg in one or more dose administrations for one or several days (depending on the mode of administration).
• the effective amount per dose varies from about 0.001 mg/kg to about 200 mg/kg, about 0.001 mg/kg to about 100 mg/kg, about 0.01 mg/kg to about 100 mg/kg, from about 0.01 mg/kg to about 50 mg/kg, preferably from about 0.1 mg/kg to about 40 mg/kg, preferably from about 0.5 mg/kg to about 30 mg/kg, from about 0.01 mg/kg to about 10 mg/kg, from about 0.1 mg/kg to about 10 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic and/or prophylactic effect.
• the compounds described herein may be at dosage levels sufficient to deliver from about 0.001 mg/kg to about 200 mg/kg, from about 0.001 mg/kg to about 100 mg/kg, from about 0.01 mg/kg to about 100 mg/kg, from about 0.01 mg/kg to about 50 mg/kg, preferably from about 0.1 mg/kg to about 40 mg/kg, preferably from about 0.5 mg/kg to about 30 mg/kg, from about 0.01 mg/kg to about 10 mg/kg, from about 0.1 mg/kg to about 10 mg/kg, and more preferably from about 1 mg/kg to about 25 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic and/or prophylactic effect.
• the desired dosage may be delivered three times a day, two times a day, once a day, every other day, every third day, every week, every two weeks, every three weeks, or every four weeks. In certain embodiments, the desired dosage may be delivered using multiple administrations (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or more administrations).
• the composition described herein is administered at a dose that is below the dose at which the agent causes non-specific effects. [00422] In certain embodiments, the pharmaceutical composition is administered at a dose of about 0.001 mg to about 1000 mg per unit dose. In certain embodiments, the pharmaceutical composition is administered at a dose of about 0.01 mg to about 200 mg per unit dose.
• the pharmaceutical composition is administered at a dose of about 0.01 mg to about 100 mg per unit dose. In certain embodiments, pharmaceutical composition is administered at a dose of about 0.01 mg to about 50 mg per unit dose. In certain embodiments, the pharmaceutical composition is administered at a dose of about 0.01 mg to about 10 mg per unit dose. In certain embodiments, the pharmaceutical composition is administered at a dose of about 0.1 mg to about 10 mg per unit dose. [00423] Pharmaceutical compositions described herein can be prepared by any method known in the art of pharmacology.
• compositions can be prepared, packaged, and/or sold in bulk, as a single unit dose, and/or as a plurality of single unit doses.
• a “unit dose” is a discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient.
• the amount of the active ingredient is generally equal to the dosage of the active ingredient which would be administered to a subject and/or a convenient fraction of such a dosage, such as, for example, one-half or one-third of such a dosage.
• Relative amounts of the active ingredient, the pharmaceutically acceptable excipient, and/or any additional ingredients in a pharmaceutical composition of the invention will vary, depending upon the identity, size, and/or condition of the subject treated and further depending upon the route by which the composition is to be administered.
• the composition may comprise between 0.1% and 100% (w/w) active ingredient.
• compositions used in the manufacture of provided pharmaceutical compositions include inert diluents, dispersing and/or granulating agents, surface active agents and/or emulsifiers, disintegrating agents, binding agents, preservatives, buffering agents, lubricating agents, and/or oils. Excipients such as cocoa butter and suppository waxes, coloring agents, coating agents, sweetening, flavoring, and perfuming agents may also be present in the composition.
• Exemplary diluents include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, cornstarch, powdered sugar, and mixtures thereof.
• Exemplary granulating and/or dispersing agents include potato starch, corn starch, tapioca starch, sodium starch glycolate, clays, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose, and wood products, natural sponge, cation-exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked poly(vinyl-pyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethyl cellulose, cross- linked sodium carboxymethyl cellulose (croscarmellose), methylcellulose, pregelatinized starch (starch 1500), microcrystalline starch, water insoluble starch, calcium carboxymethyl cellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate, quaternary ammonium compounds, and mixtures thereof.
• crospovidone cross-linked poly(vinyl-pyrrolidone)
• sodium carboxymethyl starch sodium starch glycolate
• Exemplary surface active agents and/or emulsifiers include natural emulsifiers (e.g. acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidal clays (e.g. bentonite (aluminum silicate) and Veegum (magnesium aluminum silicate)), long chain amino acid derivatives, high molecular weight alcohols (e.g.
• natural emulsifiers e.g. acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin
• colloidal clays e.g. bentonite (aluminum silicate) and Veegum (mag
• stearyl alcohol cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol), carbomers (e.g. carboxy polymethylene, polyacrylic acid, acrylic acid polymer, and carboxyvinyl polymer), carrageenan, cellulosic derivatives (e.g. carboxymethylcellulose sodium, powdered cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose), sorbitan fatty acid esters (e.g.
• polyoxyethylene sorbitan monolaurate Tween 20
• polyoxyethylene sorbitan Tween 60
• polyoxyethylene sorbitan monooleate Tween 80
• sorbitan monopalmitate Span 40
• sorbitan monostearate Span 60
• sorbitan tristearate Span 65
• polyoxyethylene esters e.g. polyoxyethylene monostearate (Myrj 45), polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil, polyoxymethylene stearate, and Solutol
• sucrose fatty acid esters e.g.
• CremophorTM polyoxyethylene ethers, (e.g. polyoxyethylene lauryl ether (Brij 30)), poly(vinyl-pyrrolidone), diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, Pluronic F-68, Poloxamer-188, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium, and/or mixtures thereof.
• polyoxyethylene ethers e.g. polyoxyethylene lauryl ether (Brij 30)
• poly(vinyl-pyrrolidone) diethylene glycol monolaurate
• triethanolamine oleate sodium oleate
• potassium oleate ethyl oleate
• oleic acid ethyl laurate
• Exemplary binding agents include starch (e.g., cornstarch and starch paste), gelatin, sugars (e.g., sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums (e.g., acacia, sodium alginate, extract of Irish moss, panwar gum, ghatti gum, mucilage of isapol husks, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, cellulose acetate, poly(vinyl-pyrrolidone), magnesium aluminum silicate (Veegum), and larch arabogalactan), alginates, polyethylene oxide, polyethylene glycol, inorganic calcium salts, silicic acid, polymethacrylates, waxes, water, alcohol, and/or
• Exemplary preservatives include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, alcohol preservatives, acidic preservatives, and other preservatives.
• the preservative is an antioxidant.
• the preservative is a chelating agent.
• Exemplary antioxidants include alpha tocopherol, ascorbic acid, acorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite.
• Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA) and salts and hydrates thereof (e.g., sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, and the like), citric acid and salts and hydrates thereof (e.g., citric acid monohydrate), fumaric acid and salts and hydrates thereof, malic acid and salts and hydrates thereof, phosphoric acid and salts and hydrates thereof, and tartaric acid and salts and hydrates thereof.
• EDTA ethylenediaminetetraacetic acid
• salts and hydrates thereof e.g., sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, and the like
• citric acid and salts and hydrates thereof e.g., citric acid mono
• antimicrobial preservatives include benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal.
• Exemplary antifungal preservatives include butyl paraben, methyl paraben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid.
• Exemplary alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, and phenylethyl alcohol.
• Exemplary acidic preservatives include vitamin A, vitamin C, vitamin E, beta- carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid.
• Other preservatives include tocopherol, tocopherol acetate, deteroxime mesylate, cetrimide, butylated hydroxyanisol (BHA), butylated hydroxytoluened (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium bisulfite, sodium metabisulfite, potassium sulfite, potassium metabisulfite, Glydant Plus, Phenonip, methylparaben, Germall 115, Germaben II, Neolone, Kathon, and Euxyl.
• Exemplary buffering agents include citrate buffer solutions, acetate buffer solutions, phosphate buffer solutions, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium gluceptate, calcium gluconate, D- gluconic acid, calcium glycerophosphate, calcium lactate, propanoic acid, calcium levulinate, pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasic calcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, dibasic potassium phosphate, monobasic potassium phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic sodium phosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water, isotonic s
• Exemplary lubricating agents include magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behanate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, and mixtures thereof.
• Exemplary natural oils include almond, apricot kernel, avocado, babassu, bergamot, black current seed, borage, cade, camomile, canola, caraway, carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee, corn, cotton seed, emu, eucalyptus, evening primrose, fish, flaxseed, geraniol, gourd, grape seed, hazelnut, hyssop, isopropyl myristate, jojoba, kukui nut, lavandin, lavender, lemon, litsea cubeba, macademia nut, mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange, orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed, pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood, sasquana, savoury, sea
• Exemplary synthetic oils include, but are not limited to, butyl stearate, caprylic triglyceride, capric triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and mixtures thereof.
• Liquid dosage forms for oral and parenteral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs.
• the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
• inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate,
• oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
• agents of the invention are mixed with solubilizing agents such CREMOPHOR EL ® (polyethoxylated castor oil), alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers, and combinations thereof.
• CREMOPHOR EL ® polyethoxylated castor oil
• injectable preparations for example, sterile injectable aqueous or oleaginous suspensions, may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
• Sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
• acceptable vehicles and solvents that may be employed are water, Ringer’s solution, U.S.P. and isotonic sodium chloride solution.
• sterile, fixed oils are conventionally employed as a solvent or suspending medium.
• any bland fixed oil can be employed including synthetic mono- or diglycerides.
• fatty acids such as oleic acid are used in the preparation of injectables.
• Injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
• Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
• the active agent is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay
• the dosage form may also comprise buffering agents.
• Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
• the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
• embedding compositions which can be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
• the active agents can also be in micro-encapsulated form with one or more excipients as noted above.
• the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art.
• the active agent may be admixed with at least one inert diluent such as sucrose, lactose or starch.
• inert diluent such as sucrose, lactose or starch.
• Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose.
• the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
• Formulations suitable for topical administration include liquid or semi-liquid preparations such as liniments, lotions, gels, applicants, oil-in-water or water-in-oil emulsions such as creams, ointments, or pastes; or solutions or suspensions such as drops.
• Formulations for topical administration to the skin surface can be prepared by dispersing the drug with a dermatologically acceptable carrier such as a lotion, cream, ointment, or soap.
• a dermatologically acceptable carrier such as a lotion, cream, ointment, or soap.
• Useful carriers are capable of forming a film or layer over the skin to localize application and inhibit removal.
• the agent can be dispersed in a liquid tissue adhesive or other substance known to enhance adsorption to a tissue surface.
• tissue adhesive or other substance known to enhance adsorption to a tissue surface.
• tissue-coating solutions such as pectin-containing formulations can be used.
• Ophthalmic formulation, ear drops, and eye drops are also contemplated as being within the scope of this invention.
• transdermal patches which have the added advantage of providing controlled delivery of an agent to the body.
• dosage forms can be made by dissolving or dispensing the agent in the proper medium.
• Absorption enhancers can also be used to increase the flux of the agent across the skin.
• the carrier for a topical formulation can be in the form of a hydroalcoholic system (e.g., liquids and gels), an anhydrous oil or silicone based system, or an emulsion system, including, but not limited to, oil-in-water, water-in-oil, water-in-oil-in- water, and oil-in-water-in-silicone emulsions.
• a hydroalcoholic system e.g., liquids and gels
• an anhydrous oil or silicone based system emulsion system
• emulsion system including, but not limited to, oil-in-water, water-in-oil, water-in-oil-in- water, and oil-in-water-in-silicone emulsions.
• the emulsions can cover a broad range of consistencies including thin lotions (which can also be suitable for spray or aerosol delivery), creamy lotions, light creams, heavy creams, and the like.
• kits e.g., pharmaceutical packs.
• the kits provided may comprise a pharmaceutical composition or compound described herein and a container (e.g., a vial, ampule, bottle, syringe, and/or dispenser package, or other suitable container).
• a container e.g., a vial, ampule, bottle, syringe, and/or dispenser package, or other suitable container.
• provided kits may optionally further include a second container comprising a pharmaceutical excipient for dilution or suspension of a pharmaceutical composition or compound described herein.
• kits including a first container comprising a compound or pharmaceutical composition described herein.
• the kits are useful for treating a disease (e.g., neurological disease or disorder) in a subject in need thereof.
• the kits are useful for preventing a disease (e.g., neurological disease or disorder) in a subject in need thereof.
• the kits are useful for reducing the risk of developing a disease (e.g., neurological disease or disorder) in a subject in need thereof.
• the kits are useful for increasing the activity of GCase in a subject or cell.
• kits described herein further includes instructions for using the kit.
• a kit described herein may also include information as required by a regulatory agency such as the U.S. Food and Drug Administration (FDA).
• the information included in the kits is prescribing information.
• the kits and instructions provide for treating a disease (e.g., neurological disease or disorder) in a subject in need thereof.
• the kits and instructions provide for preventing a disease (e.g., neurological disease or disorder) in a subject in need thereof.
• the kits and instructions provide for reducing the risk of developing a disease (e.g., neurological disease or disorder) in a subject in need thereof.
• kits and instructions provide for increasing the activity of GCase in a subject or cell.
• a kit described herein may include one or more additional pharmaceutical agents described herein as a separate composition.
• Methods of Treatment [00452] The present disclosure provides methods for treating a disease or disorder in a subject in need thereof. In certain embodiments, the present disclosure provides methods for treating a disease or disorder associated with GCase activity. In certain embodiments, the application provides a method of treating a neurological disease or disorder. In certain embodiments, the application provides a method of treating Gaucher’s disease or Parkinson’s disease. In certain embodiments, the application provides a method of treating Gaucher’s disease. In certain embodiments, the application provides a method of treating Parkinson’s disease.
• the present disclosure provides a method of activating GCase.
• the present disclosure provides a method of increasing the activity of GCase.
• the application provides a method of activating GCase (e.g., increasing the activity of GCase) in vitro.
• the application provides a method of activating GCase (e.g., increasing the activity of GCase) in vivo.
• the application provides a method of increasing the activity of GCase in a cell.
• the application provides a method of increasing the activity of GCase in a human cell.
• the methods comprise administering to a subject in need thereof (e.g., a subject with a neurological disease or disorder) a compound that interacts with GCase, for example, a compound that is a modulator of GCase (e.g., an activator of GCase), a binder of GCase, or a compound that modifies GCase.
• a compound that is a modulator of GCase e.g., an activator of GCase
• a binder of GCase e.g., a binder of GCase
• the methods comprise administering a compound of the disclosure (e.g., a compound of Formula (I)), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug, or composition thereof, to a subject in need thereof.
• the method comprises administering a pharmaceutical composition comprising a compound of the disclosure (e.g., a compound of Formula (I)), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug, or composition thereof, to a subject in need thereof.
• Another object of the present disclosure is the use of a compound as described herein (e.g., of any formulae herein) in the manufacture of a medicament for use in the treatment of a disorder or disease described herein.
• Another object of the present disclosure is the use of a compound as described herein (e.g., of any formulae herein) for use in the treatment of a disorder or disease described herein.
• EXAMPLES [00456] In order that the invention described herein may be more fully understood, the following examples are set forth. The examples described in this application are offered to illustrate the compounds, pharmaceutical compositions, and methods provided herein and are not to be construed in any way as limiting their scope.
• the result mixture was heated to 60 °C and stirred for 2 h. Desired product could be detected by LCMS.
• the reaction mixture was diluted by EtOAc (20 mL), washed by water (2 x 15 mL) and brine (1 x 15 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated. The residue was purified with Combi-flash (40 g silico gel column), eluted with Hex:EtOAc.
• the resulting mixture was stirred for overnight at 80°C under argon atmosphere.
• the resulting mixture was diluted with EtOAc (20 mL), washed with water (2 x 15 mL) and brine (15 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure.
• Desired product could be detected by LCMS.
• the residue was purified by reverse flash chromatography with the following conditions (column, C18 gel; mobile phase, B phase: MeCN, A phase: water; 5% to 100% B gradient in 20 min; detector: UV 254/220 nm). This resulted in tert-butyl 6-(6- (hydrazinecarbonyl)pyrazin-2-yl)-2,6-diazaspiro[3.4]octane-2-carboxylate (450 mg, 90.0%) as a white solid.
• tert-butyl 4-(2-ethoxy-2-oxoethyl)-3-methyl-4- (nitromethyl)piperidine-1-carboxylate 300 mg, 41 %) as a colorless oil
• tert-butyl 5'-oxo-8-azaspiro[bicyclo[3.2.1]octane-3,3'-pyrrolidine]-8-carboxylate To the solution of tert-butyl 3-(2-ethoxy-2-oxoethyl)-3-(nitromethyl)-8- azabicyclo[3.2.1]octane-8-carboxylate (300 mg, 0.842 mmol,
• the resulted mixture was hydrogenated (30 atm) overnight at 80 °C. Desired product could be detected by LCMS.
• the reaction system was filtrated through celite and the filtrate was concentrated.
• the resulting mixture was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water, 5% to 95% gradient in 20 min; detector, UV 254/220 nm. This resulted in tert-butyl 5'-oxo-8-azaspiro[bicyclo[3.2.1]octane-3,3'- pyrrolidine]-8-carboxylate (150 mg, 54%) as a colorless oil.
• Desired product could be detected by LCMS.
• the resulting mixture was concentrated and was purified with a Combi- flash (40 g silico gel column), eluted with a gradient of DCM/MeOH to give tert-butyl 6-(4- (2-formylhydrazine-1-carbonyl)pyrimidin-2-yl)-2,6-diazaspiro[3.4]octane-2-carboxylate (300 mg, 67%) as a colorless oil.
• Desired product could be detected by LCMS.
• the resulting mixture was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water, 5% to 95% gradient in 20 min; detector, UV 254/220 nm. This resulted in 6-(2-(2-methyl-6- (trifluoromethyl)pyrimidin-4-yl)-2,6-diazaspiro[3.4]octan-6-yl)-1-(tetrahydro-2H-pyran-2- yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (170 mg, 86%) as a white solid.
• Step 1 tert-Butyl 2-[4-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[3.5]nonane-7- carboxylate:
• tert-butyl 2,7-diazaspiro[3.5]nonane-7- carboxylate 100 mg, 442 ⁇ mol, 1.0 equiv
• 2-bromo-4-(trifluoromethyl)pyridine 99.9 mg, 442 ⁇ mol, 1.0 equiv.
• Step 2 2-[4-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[3.5]nonane hydrochloride:
• Step 2 2-[4-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[3.5]nonane hydrochloride:
• Step 3 7-[1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-2-[4- (trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[3.5]nonane:
• Step 2 2- ⁇ [4-(trifluoromethyl)pyridin-3-yl]oxy ⁇ -6-azaspiro[3.5]nonane hydrochloride:
• Step 2 2- ⁇ [4-(trifluoromethyl)pyridin-3-yl]oxy ⁇ -6-azaspiro[3.5]nonane hydrochloride:
• MS m/z 287 [M+H] + .
• Step 3 6-[6-(1,3,4-thiadiazol-2-yl)pyrazin-2-yl]-2- ⁇ [2-(trifluoromethyl)pyridin-3- yl]oxy ⁇ -6-azaspiro[3.5]nonane:
• 2- ⁇ [4- (trifluoromethyl)pyridin-3-yl]oxy ⁇ -6-azaspiro[3.5]nonanehydrochloride (24.2 mg, 85 ⁇ mol, 1.0 equiv)
• 2-chloro-6-(1,3,4-thiadiazol-2-yl)pyrazine (16.8 mg, 85 ⁇ mol, 1.0 equiv.) as the starting materials to give 6-[6-(1,3,4-thiadiazol-2-yl)pyrazin-2-yl]-2- ⁇ [4- (trifluoromethyl)pyridin-3-yl]oxy ⁇ -6-azaspiro[3.5]nonane (14 mg, 37%, two isomers in
• Step 1 tert-butyl 7-[4-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[3.5]nonane-2- carboxylate:
• tert-butyl 2,7-diazaspiro[3.5]nonane-2- carboxylate 200 mg, 884 ⁇ mol, 1.0 equiv
• 2-bromo-4-(trifluoromethyl)pyridine 200 mg, 884 ⁇ mol, 1.0 equiv.
• Step 2 7-[4-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[3.5]nonane hydrochloride:
• Step 2 7-[4-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[3.5]nonane hydrochloride:
• tert-butyl 7-[4- (trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[3.5]nonane-2-carboxylate (175 mg) as the starting material to give the crude product 7-[4-(trifluoromethyl)pyridin-2-yl]-2,7- diazaspiro[3.5]nonane hydrochloride (160 mg).
• Step 3 2-[1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-7-[4- (trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[3.5]nonane:
• Step 3 2-[1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-7-[4- (trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[3.5]nonane hydrochloride (160 mg, 520 ⁇ mol, 1.0 equiv) and 6-chloro-1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazine (114 mg, 520 ⁇ mol, 1.0 equiv) as the starting materials to give 2-[1-(2,2-difluoroethyl
• Step 1 tert-butyl 2- ⁇ [2-(trifluoromethyl)308yridine-3-yl]oxy ⁇ -6- azaspiro[3.5]nonane-6-carboxylate:
• 2- (trifluoromethyl)pyridin-3-ol 67.6 mg, 414 ⁇ mol, 1 equiv.
• tert-butyl 2-hydroxy-6- azaspiro[3.5]nonane-6-carboxylate 100 mg, 414 ⁇ mol, 1.0 equiv.
• Step 2 2- ⁇ [2-(trifluoromethyl)pyridin-3-yl]oxy ⁇ -6-azaspiro[3.5]nonane hydrochloride:
• Step 2 2- ⁇ [2-(trifluoromethyl)pyridin-3-yl]oxy ⁇ -6-azaspiro[3.5]nonane hydrochloride:
• tert-butyl 2- ⁇ [2- (trifluoromethyl)pyridin-3-yl]oxy ⁇ -6-azaspiro[3.5]nonane-6-carboxylate 148 mg
• MS m/z 287 [M+H] + .
• Step 3 6-[1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-2- ⁇ [2- (trifluoromethyl)pyridin-3-yl]oxy ⁇ -6-azaspiro[3.5]nonane:
• 2- ⁇ [2-(trifluoromethyl)pyridin-3-yl]oxy ⁇ -6-azaspiro[3.5]nonane hydrochloride (18 mg, 55 ⁇ mol, 1.0 equiv) and 6-chloro-1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazine (12 mg, 55 ⁇ mol, 1.0 equiv.) as the starting materials to give 6-[1-(2,2-difluoroethyl)-1H- pyrazolo[3,4-b]pyrazin-6-yl]-2- ⁇ [2-(trifluoromethyl)pyri
• Step 2 2-[2-(trifluoromethyl)pyridin-3-yl]-2,7-diazaspiro[4.5]decane hydrochloride:
• 2-[2-(trifluoromethyl)pyridin-3-yl]-2,7-diazaspiro[4.5]decane hydrochloride followeded the general procedure B using tert-butyl 2-[2- (trifluoromethyl)pyridin-3-yl]-2,7-diazaspiro[4.5]decane-7-carboxylate (243 mg) as the starting material to give the crude product 2-[2-(trifluoromethyl)pyridin-3-yl]-2,7- diazaspiro[4.5]decane hydrochloride (200 mg).
• Step 3 7-[1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-2-[2- (trifluoromethyl)pyridin-3-yl]-2,7-diazaspiro[4.5]decane:
• 2-[2-(trifluoromethyl)pyridin-3-yl]-2,7-diazaspiro[4.5]decane hydrochloride 17.7 mg, 55 ⁇ mol, 1.0 equiv) 6-chloro-1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazine (12 mg, 55 ⁇ mol, 1.0 equiv) as the starting materials to give 7-[1-(2,2-difluoroethyl)-1H-pyrazolo[3,4- b]pyrazin-6-yl]-2-[2-(trifluoromethyl)pyr
• Step 2 2-[4-(trifluoromethyl)pyridin-2-yl]-2,8-diazaspiro[4.5]decane hydrochloride:
• 2-[4-(trifluoromethyl)pyridin-2-yl]-2,8-diazaspiro[4.5]decane hydrochloride followsed the general procedure B using tert-butyl 2-[4- (trifluoromethyl)pyridin-2-yl]-2,8-diazaspiro[4.5]decane-8-carboxylate (115 mg) as the starting material to give the crude product 2-[4-(trifluoromethyl)pyridin-2-yl]-2,8- diazaspiro[4.5]decane hydrochloride (88 mg).
• Step 3 8-[1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-2-[4- (trifluoromethyl)pyridin-2-yl]-2,8-diazaspiro[4.5]decane:
• 2-[4-(trifluoromethyl)pyridin-2-yl]-2,8-diazaspiro[4.5]decane hydrochloride (25.1 mg, 78 ⁇ mol, 1.0 equiv)
• 6-chloro-1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazine 17. mg, 78 ⁇ mol, 1.0 equiv) as the starting materials to give 8-[1-(2,2-difluoroethyl)-1H-pyrazolo[3,4- b]pyrazin-6-yl]-2-[4-(trifluor
• Step 2 7-[2-(trifluoromethyl)pyridin-3-yl]-2,7-diazaspiro[4.5]decane hydrochloride:
• Step 2 7-[2-(trifluoromethyl)pyridin-3-yl]-2,7-diazaspiro[4.5]decane hydrochloride:
• Step 3 2-[1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-7-[2- (trifluoromethyl)pyridin-3-yl]-2,7-diazaspiro[4.5]decane:
• Step 3 2-[1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-7-[2- (trifluoromethyl)pyridin-3-yl]-2,7-diazaspiro[4.5]decane hydrochloride (17.7 mg, 55 ⁇ mol, 1.0 equiv) 6-chloro-1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazine (12 mg, 55 ⁇ mol, 1.0 equiv) as the starting materials to give 2-[1-(2,2-difluoroethyl)-1H-pyrazol
• Step 2 6-[2-(trifluoromethyl)pyridin-4-yl]-2,6-diazaspiro[3.5]nonane hydrochloride:
• Step 2 6-[2-(trifluoromethyl)pyridin-4-yl]-2,6-diazaspiro[3.5]nonane hydrochloride:
• Step 3 2-[1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-6-[2- (trifluoromethyl)pyridin-4-yl]-2,6-diazaspiro[3.5]nonane:
• 6-[2-(trifluoromethyl)pyridin-4-yl]-2,6-diazaspiro[3.5]nonanehydrochloride 200 mg, 650 ⁇ mol, 1.0 equiv
• 6-chloro-1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazine 142 mg, 650 ⁇ mol, 1.0 equiv) as the starting materials to give 2-[1-(2,2-difluoroethyl)-1H- pyrazolo[3,4-b]pyrazin-6-yl]-6-[2-(trifluoromethyl
• Step 2 6-[2-(trifluoromethyl)pyridin-3-yl]-2,6-diazaspiro[3.5]nonane hydrochloride:
• Step 2 6-[2-(trifluoromethyl)pyridin-3-yl]-2,6-diazaspiro[3.5]nonane hydrochloride:
• Step 3 2-[1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-6-[2- (trifluoromethyl)pyridin-4-yl]-2,6-diazaspiro[3.5]nonane:
• 6-[2-(trifluoromethyl)pyridin-3-yl]-2,6-diazaspiro[3.5]nonane hydrochloride 17. mg, 55 ⁇ mol, 1.0 equiv
• 6-chloro-1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazine (12 mg, 55 ⁇ mol, 1.0 equiv) as the starting materials to give 2-[1-(2,2-difluoroethyl)-1H-pyrazolo[3,4- b]pyrazin-6-yl]-6-[2-(trifluoromethyl)pyri
• Step 1 tert-butyl 2-[2-(trifluoromethyl)pyridin-4-yl]-2,6-diazaspiro[3.5]nonane-6- carboxylate:
• tert-butyl 2,6-diazaspiro[3.5]nonane-6- carboxylate 50 mg, 221 ⁇ mol, 1.0 equiv
• 4-bromo-2-(trifluoromethyl)pyridine 50 mg, 221 ⁇ mol, 1.0 equiv.
• Step 2 7-[4-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[3.5]nonane hydrochloride:
• Step 2 7-[4-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[3.5]nonane hydrochloride:
• Step 3 6-[1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-2-[2- (trifluoromethyl)pyridin-4-yl]-2,6-diazaspiro[3.5]nonane:
• 2-[2-(trifluoromethyl)pyridin-4-yl]-2,6-diazaspiro[3.5]nonane hydrochloride (20 mg, 65 ⁇ mol, 1.0 equiv) and 6-chloro-1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazine (14.2 mg, 65 ⁇ mol, 1.0 equiv) as the starting materials to give 6-[1-(2,2-difluoroethyl)-1H-pyrazolo[3,4- b]pyrazin-6-yl]-2-[2-(trifluoromethyl)pyr
• Step 2 2- ⁇ [2-(trifluoromethyl)pyridin-4-yl]oxy ⁇ -6-azaspiro[3.5]nonane hydrochloride:
• 2- ⁇ [2-(trifluoromethyl)pyridin-4-yl]oxy ⁇ -6-azaspiro[3.5]nonane hydrochloride followeded the general procedure B using tert-butyl 2- ⁇ [2- (trifluoromethyl)pyridin-4-yl]oxy ⁇ -6-azaspiro[3.5]nonane-6-carboxylate (105 mg) as the starting material to give the crude product 2- ⁇ [2-(trifluoromethyl)pyridin-4-yl]oxy ⁇ -6- azaspiro[3.5]nonane hydrochloride (80 mg).
• Step 3 6-[1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-2- ⁇ [2- (trifluoromethyl)pyridin-4-yl]oxy ⁇ -6-azaspiro[3.5]nonane:
• 2- ⁇ [2-(trifluoromethyl)pyridin-4-yl]oxy ⁇ -6-azaspiro[3.5]nonane hydrochloride (22.1 mg, 68.6 ⁇ mol, 1.0 equiv)
• 6-chloro-1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazine (15 mg, 68.6 ⁇ mol, 1.0 equiv.) as the starting materials to give 6-[1-(2,2-difluoroethyl)-1H- pyrazolo[3,4-b]pyrazin-6-yl]-2- ⁇ [2-(trifluoromethyl)pyridin-4-
• Step 2 2-[1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-2,6- diazaspiro[3.5]nonane hydrochloride:
• Step 2 2-[1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-2,6- diazaspiro[3.5]nonane hydrochloride:
• Step 2 2-[1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-2,6-diazaspiro[3.5]nonane-6-carboxylate (180 mg) as the starting material to give the crude product 2-[4-(trifluoromethyl)pyridin-2- yl]-2,7-diazaspiro[3.5]nonane hydrochloride (170 mg).
• Step 3 2-[1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-6-[5- (trifluoromethyl)pyridin-2-yl]-2,6-diazaspiro[3.5]nonane:
• Step 2 8-[4-(trifluoromethyl)pyridin-2-yl]-2,8-diazaspiro[4.5]decane hydrochloride:
• Step 2 8-[4-(trifluoromethyl)pyridin-2-yl]-2,8-diazaspiro[4.5]decane hydrochloride:
• tert-butyl 8-[4- (trifluoromethyl)pyridin-2-yl]-2,8-diazaspiro[4.5]decane-2-carboxylate 130 mg
• 2-[4-(trifluoromethyl)pyridin-2-yl]-2,7- diazaspiro[3.5]nonane hydrochloride 100 mg.
• Step 3 2-[1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-8-[4- (trifluoromethyl)pyridin-2-yl]-2,8-diazaspiro[4.5]decane:
• Step 3 2-[1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-8-[4- (trifluoromethyl)pyridin-2-yl]-2,8-diazaspiro[4.5]decane hydrochloride (25 mg, 78 ⁇ mol, 1.0 equiv) and 6-chloro-1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazine (17 mg, 78 ⁇ mol, 1.0 equiv) as the starting materials to give 2-[1-(2,2-difluoroethyl)-1H
• Step 2 2-phenyl-2,6-diazaspiro[3.5]nonane hydrochloride:
• 2-phenyl-2,6-diazaspiro[3.5]nonane hydrochloride followsed the general procedure B using tert-butyl 2-phenyl-2,6-diazaspiro[3.5]nonane-6-carboxylate (200 mg) as the starting material to give the crude product 2-[4-(trifluoromethyl)pyridin-2-yl]-2,7- diazaspiro[3.5]nonane hydrochloride (180 mg).
• Step 3 6-[1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-2-phenyl-2,6- diazaspiro[3.5]nonane:
• 2-phenyl-2,6- diazaspiro[3.5]nonane hydrochloride (13.1 mg, 55 ⁇ mol, 1.0 equiv)
• 6-chloro-1-(2,2- difluoroethyl)-1H-pyrazolo[3,4-b]pyrazine (12 mg, 55 ⁇ mol, 1.0 equiv) as the starting materials to give 6-[1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-2-phenyl-2,6- diazaspiro[3.5]nonane (15 mg, 71%) as a colorless oil.
• Step 1 tert-butyl 2- ⁇ [6-(trifluoromethyl)pyridin-3-yl]oxy ⁇ -6-azaspiro[3.5]nonane- 6-carboxylate:
• 6-(trifluoromethyl)pyridin-3-ol 67.6 mg, 414 ⁇ mol, 1 equiv.
• tert-butyl 2-hydroxy-6-azaspiro[3.5]nonane-6-carboxylate 100 mg, 414 ⁇ mol, 1.0 equiv.
• Step 2 2- ⁇ [6-(trifluoromethyl)pyridin-3-yl]oxy ⁇ -6-azaspiro[3.5]nonane hydrochloride:
• 2- ⁇ [6-(trifluoromethyl)pyridin-3-yl]oxy ⁇ -6-azaspiro[3.5]nonane hydrochloride tert-butyl 2- ⁇ [6-(trifluoromethyl)pyridin-3- yl]oxy ⁇ -6-azaspiro[3.5]nonane-6-carboxylate (88 mg) as the starting material to give the crude product 2- ⁇ [6-(trifluoromethyl)pyridin-3-yl]oxy ⁇ -6-azaspiro[3.5]nonane hydrochloride (80 mg).
• Step 3 6-[1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-2- ⁇ [6- (trifluoromethyl)pyridin-3-yl]oxy ⁇ -6-azaspiro[3.5]nonane:
• 2- ⁇ [6-(trifluoromethyl)pyridin-3-yl]oxy ⁇ -6-azaspiro[3.5]nonane hydrochloride (22.1 mg, 68.6 ⁇ mol, 1.0 equiv) and 6-chloro-1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazine (15 mg, 68.6 ⁇ mol, 1.0 equiv.) as the starting materials to give 6-[1-(2,2-difluoroethyl)-1H- pyrazolo[3,4-b]pyrazin-6-yl]-2- ⁇ [6
• Step 2 2-[6-(trifluoromethyl)pyridin-2-yl]-2,6-diazaspiro[3.5]nonane hydrochloride:
• Step 2 2-[6-(trifluoromethyl)pyridin-2-yl]-2,6-diazaspiro[3.5]nonane hydrochloride:
• Step 3 6-[1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-2-[6- (trifluoromethyl)pyridin-2-yl]-2,6-diazaspiro[3.5]nonane:
• Step 2 2-(2,5-difluorophenoxy)-6-azaspiro[3.5]nonane hydrochloride:
• Step 2 2-(2,5-difluorophenoxy)-6-azaspiro[3.5]nonane hydrochloride:
• Step 3 6-[1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-2- ⁇ [6- (trifluoromethyl)pyridin-3-yl]oxy ⁇ -6-azaspiro[3.5]nonane:
• 2-(2,5-difluorophenoxy)-6-azaspiro[3.5]nonane hydrochloride (19.9 mg, 68.6 ⁇ mol, 1.0 equiv)
• 6-chloro-1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazine (15 mg, 68.6 ⁇ mol, 1.0 equiv.) as the starting materials to give 6-[1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6- yl]-2-(2,5-difluorophenoxy)
• Step 2 6-[6-(trifluoromethyl)pyridin-2-yl]-2,6-diazaspiro[3.5]nonane hydrochloride:
• 6-[6-(trifluoromethyl)pyridin-2-yl]-2,6-diazaspiro[3.5]nonane hydrochloride followsed the general procedure B using tert-butyl 6-[6- (trifluoromethyl)pyridin-2-yl]-2,6-diazaspiro[3.5]nonane-2-carboxylate (57 mg) as the starting material to give the crude product 6-[6-(trifluoromethyl)pyridin-2-yl]-2,6- diazaspiro[3.5]nonane hydrochloride (45 mg).
• Step 3 2-[1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-6-[6- (trifluoromethyl)pyridin-2-yl]-2,6-diazaspiro[3.5]nonane:
• Step 2 2-[2-(trifluoromethyl)pyridin-3-yl]-2,6-diazaspiro[3.5]nonane hydrochloride:
• 2-[2-(trifluoromethyl)pyridin-3-yl]-2,6-diazaspiro[3.5]nonane hydrochloride Followed the general procedure B using tert-butyl 2-[2- (trifluoromethyl)pyridin-3-yl]-2,6-diazaspiro[3.5]nonane-6-carboxylate (53 mg) as the starting material to give the crude product 2-[2-(trifluoromethyl)pyridin-3-yl]-2,6- diazaspiro[3.5]nonane hydrochloride (45 mg).
• Step 3 6-[1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-2-[2- (trifluoromethyl)pyridin-3-yl]-2,6-diazaspiro[3.5]nonane:
• 2-[2-(trifluoromethyl)pyridin-3-yl]-2,6-diazaspiro[3.5]nonane hydrochloride 17. mg, 55 ⁇ mol, 1.0 equiv
• 6-chloro-1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazine (12 mg, 55 ⁇ mol, 1.0 equiv) as the starting materials to give 6-[1-(2,2-difluoroethyl)-1H-pyrazolo[3,4- b]pyrazin-6-yl]-2-[2-(trifluoromethyl)pyri
• Step 2 2- ⁇ [6-(trifluoromethyl)pyridin-2-yl]oxy ⁇ -6-azaspiro[3.5]nonane hydrochloride:
• Step 2 2- ⁇ [6-(trifluoromethyl)pyridin-2-yl]oxy ⁇ -6-azaspiro[3.5]nonane hydrochloride:
• tert-butyl 2- ⁇ [6-(trifluoromethyl)pyridin-2- yl]oxy ⁇ -6-azaspiro[3.5]nonane-6-carboxylate 138 mg
• MS m/z 286 [M+H] + .
• Step 3 6-[1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-2- ⁇ [6- (trifluoromethyl)pyridin-2-yl]oxy ⁇ -6-azaspiro[3.5]nonane:
• 2- ⁇ [6-(trifluoromethyl)pyridin-2-yl]oxy ⁇ -6-azaspiro[3.5]nonane hydrochloride (22.1 mg, 68.6 ⁇ mol, 1.0 equiv) and 6-chloro-1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazine (15 mg, 68.6 ⁇ mol, 1.0 equiv.) as the starting materials to give 6-[1-(2,2-difluoroethyl)-1H- pyrazolo[3,4-b]pyrazin-6-yl]-2- ⁇ [6
• Step 2 2- ⁇ [5-(trifluoromethyl)pyridin-2-yl]oxy ⁇ -6-azaspiro[3.5]nonane hydrochloride:
• Step 2 2- ⁇ [5-(trifluoromethyl)pyridin-2-yl]oxy ⁇ -6-azaspiro[3.5]nonane hydrochloride:
• Step 3 6-[1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-2- ⁇ [5- (trifluoromethyl)pyridin-2-yl]oxy ⁇ -6-azaspiro[3.5]nonane:
• 2- ⁇ [5-(trifluoromethyl)pyridin-2-yl]oxy ⁇ -6-azaspiro[3.5]nonane hydrochloride (22.1 mg, 68.6 ⁇ mol, 1.0 equiv) and 6-chloro-1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazine (15 mg, 68.6 ⁇ mol, 1.0 equiv.) as the starting materials to give 6-[1-(2,2-difluoroethyl)-1H- pyrazolo[3,4-b]pyrazin-6-yl]-2- ⁇ [5
• Step 2 2- ⁇ [4-(trifluoromethyl)pyridin-2-yl]oxy ⁇ -6-azaspiro[3.5]nonane hydrochloride:
• Step 2 2- ⁇ [4-(trifluoromethyl)pyridin-2-yl]oxy ⁇ -6-azaspiro[3.5]nonane hydrochloride:
• Step 3 6-[1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-2- ⁇ [4- (trifluoromethyl)pyridin-2-yl]oxy ⁇ -6-azaspiro[3.5]nonane:
• 2- ⁇ [4-(trifluoromethyl)pyridin-2-yl]oxy ⁇ -6-azaspiro[3.5]nonane hydrochloride (22.1 mg, 68.6 ⁇ mol, 1.0 equiv) and 6-chloro-1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazine (15 mg, 68.6 ⁇ mol, 1.0 equiv.) as the starting materials to give 6-[1-(2,2-difluoroethyl)-1H- pyrazolo[3,4-b]pyrazine (15 mg, 68.6 ⁇ mol, 1.0 equiv.) as
• Step 2 2-(3,5-difluorophenoxy)-6-azaspiro[3.5]nonane hydrochloride:
• Step 2 2-(3,5-difluorophenoxy)-6-azaspiro[3.5]nonane hydrochloride:
• Step 3 6-[1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-2-(3,5- difluorophenoxy)-6-azaspiro[3.5]nonane:
• 2-(3,5- difluorophenoxy)-6-azaspiro[3.5]nonane hydrochloride (19.9 mg, 68.6 ⁇ mol, 1.0 equiv)
• 6-chloro-1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazine (15 mg, 68.6 ⁇ mol, 1.0 equiv.) as the starting materials to give 6-[1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-2-(3,5- difluorophenoxy)-6-azaspiro[3.5]nonan
• Step 2 tert-butyl 2- ⁇ [3-(trifluoromethyl)pyridin-2-yl]oxy ⁇ -6-azaspiro[3.5]nonane hydrochloride:
• Step 2 tert-butyl 2- ⁇ [3- (trifluoromethyl)pyridin-2-yl]oxy ⁇ -6-azaspiro[3.5]nonane hydrochloride:
• Step 3 6-[1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-2- ⁇ [3- (trifluoromethyl)pyridin-2-yl]oxy ⁇ -6-azaspiro[3.5]nonane:
• 2- ⁇ [3-(trifluoromethyl)pyridin-2-yl]oxy ⁇ -6-azaspiro[3.5]nonane hydrochloride (22.1 mg, 68.6 ⁇ mol, 1.0 equiv) and 6-chloro-1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazine (15 mg, 68.6 ⁇ mol, 1.0 equiv.) as the starting materials to give 6-[1-(2,2-difluoroethyl)-1H- pyrazolo[3,4
• Step 2 2-[6-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]decane hydrochloride:
• Step 2 2-[6-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]decane hydrochloride:
• tert-butyl 2-[6- (trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]decane-7-carboxylate 260 mg
• Step 3 7-[1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-2-[6- (trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]decane:
• Step 2 2-[3-(trifluoromethyl)pyridin-4-yl]-2,6-diazaspiro[3.5]nonane hydrochloride:
• Step 2 2-[3-(trifluoromethyl)pyridin-4-yl]-2,6-diazaspiro[3.5]nonane hydrochloride:
• Step 3 6-[1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-2-[3- (trifluoromethyl)pyridin-4-yl]-2,6-diazaspiro[3.5]nonane:
• 2-[3-(trifluoromethyl)pyridin-4-yl]-2,6-diazaspiro[3.5]nonanehydrochloride 70 mg, 227 ⁇ mol, 1.0 equiv
• 6-chloro-1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazine 50 mg, 227 ⁇ mol, 1.0 equiv) as the starting materials to give 6-[1-(2,2-difluoroethyl)-1H- pyrazolo[3,4-b
• Step 2 7-[6-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]decane hydrochloride:
• Step 2 7-[6-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]decane hydrochloride:
• tert-butyl 7-[6- (trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]decane-2-carboxylate (162 mg) as the starting material to give the crude product 7-[6-(trifluoromethyl)pyridin-2-yl]-2,7- diazaspiro[4.5]decane hydrochloride (150 mg).
• Step 3 7-[1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-2-[6- (trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]decane:
• Step 2 2-[6-(trifluoromethyl)pyridin-3-yl]-2,6-diazaspiro[3.5]nonane hydrochloride:
• Step 2 2-[6-(trifluoromethyl)pyridin-3-yl]-2,6-diazaspiro[3.5]nonane hydrochloride:
• Step 3 6-[1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-2-[6- (trifluoromethyl)pyridin-3-yl]-2,6-diazaspiro[3.5]nonane:
• Step 2 2-[1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-8-[4- (trifluoromethyl)pyridin-2-yl]-2,8-diazaspiro[4.5]decan-3-one:
• Step 2 2-[1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-8-[4- (trifluoromethyl)pyridin-2-yl]-2,8-diazaspiro[4.5]decan-3-one:
• 8-[4-(trifluoromethyl)pyridin-2-yl]-2,8-diazaspiro[4.5]decan-3-one (28.5 mg, 95 ⁇ mol, 1.0 equiv.)
• Step 2 8-[1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-2-[4- (trifluoromethyl)pyridin-2-yl]-2,8-diazaspiro[4.5]decan-3-one:
• 8-[1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-2,8- diazaspiro[4.5]decan-3-one (20 mg, 60 ⁇ mol, 1.0 equiv.) and 2-bromo-4- (trifluoromethyl)pyridine (16 mg, 71 ⁇ mol, 1.2 equiv.) as the starting materials to 8-[1-(2,2- difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-
• Step 1 8-[4-(trifluoromethyl)pyridin-2-yl]-2,8-diazaspiro[4.5]decan-1-one:
• Step 1 8-[4-(trifluoromethyl)pyridin-2-yl]-2,8-diazaspiro[4.5]decan-1-one:
• Step 2 2-[1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-8-[4- (trifluoromethyl)pyridin-2-yl]-2,8-diazaspiro[4.5]decan-3-one:
• 8-[4-(trifluoromethyl)pyridin-2-yl]-2,8-diazaspiro[4.5]decan-1-one (28.5 mg, 95 ⁇ mol, 1.0 equiv.) and 6-chloro-1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazine (25 mg, 95 ⁇ mol, 1.0 equiv.) as the starting materials to 2-[1-(2,2-difluoroethyl)-1H- pyrazolo[3,4-b]pyrazine
• Step 2 8-[1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-2-[4- (trifluoromethyl)pyridin-2-yl]-2,8-diazaspiro[4.5]decan-1-one:
• Step 2 6-[3-(trifluoromethyl)pyridin-4-yl]-2,6-diazaspiro[3.5]nonane hydrochloride:
• Step 2 6-[3-(trifluoromethyl)pyridin-4-yl]-2,6-diazaspiro[3.5]nonane hydrochloride:
• Step 3 6-[1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-2-[6- (trifluoromethyl)pyridin-3-yl]-2,6-diazaspiro[3.5]nonane:
• Step 1 tert-butyl 6-[4-(trifluoromethyl)pyridin-3-yl]-2,6-diazaspiro[3.5]nonane-2- carboxylate:
• tert-butyl 2,6-diazaspiro[3.5]nonane-6- carboxylate 50 mg, 221 ⁇ mol, 1.0 equiv
• 3-bromo-4-(trifluoromethyl)pyridine 50 mg, 221 ⁇ mol, 1.0 equiv.
• Step 2 6-[4-(trifluoromethyl)pyridin-3-yl]-2,6-diazaspiro[3.5]nonane hydrochloride:
• Step 2 6-[4-(trifluoromethyl)pyridin-3-yl]-2,6-diazaspiro[3.5]nonane hydrochloride:
• Step 3 2-[1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-6-[4- (trifluoromethyl)pyridin-3-yl]-2,6-diazaspiro[3.5]nonane:
• Step 1 tert-butyl 6-[5-(trifluoromethyl)pyridin-3-yl]-2,6-diazaspiro[3.5]nonane-2- carboxylate:
• tert-butyl 2,6-diazaspiro[3.5]nonane-6- carboxylate 50 mg, 221 ⁇ mol, 1.0 equiv
• 3-bromo-5-(trifluoromethyl)pyridine 50 mg, 221 ⁇ mol, 1.0 equiv.
• Step 2 6-[5-(trifluoromethyl)pyridin-3-yl]-2,6-diazaspiro[3.5]nonane hydrochloride:
• Step 2 6-[5-(trifluoromethyl)pyridin-3-yl]-2,6-diazaspiro[3.5]nonane hydrochloride:
• Step 3 2-[1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-6-[5- (trifluoromethyl)pyridin-3-yl]-2,6-diazaspiro[3.5]nonane:
• Step 3 2-[1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-6-[5- (trifluoromethyl)pyridin-3-yl]-2,6-diazaspiro[3.5]nonane hydrochloride (30 mg, 97.5 ⁇ mol, 1.0 equiv) and 6-chloro-1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazine (21.3 mg, 97.5 ⁇ mol, 1.0 equiv) as the starting materials to give 2-[1-(2,2-difluoroethyl)
• Step 1 tert-butyl 2-phenyl-2,7-diazaspiro[4.5]decane-7-carboxylate:
• tert-butyl 2,7-diazaspiro[4.5]decane-7-carboxylate 340 mg, 1.4 mmol, 1 equiv.
• iodobenzene 557 mg, 1.4 mmom, 1 equiv.
• Step 2 2-phenyl-2,7-diazaspiro[4.5]decane hydrochloride: Followinged the general procedure B using tert-butyl 2-phenyl-2,7-diazaspiro[4.5]decane-7-carboxylate (320 mg) as the starting material to give the crude product 2-phenyl-2,7-diazaspiro[4.5]decane hydrochloride (250 mg). MS m/z: 217 [M+H] + .
• Step 3 7-[1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-2-phenyl-2,7- diazaspiro[4.5]decane:
• 2-phenyl-2,7- diazaspiro[4.5]decane hydrochloride 14 mg, 55 ⁇ mol, 1.0 equiv
• 6-chloro-1-(2,2- difluoroethyl)-1H-pyrazolo[3,4-b]pyrazine (12 mg, 55 ⁇ mol, 1.0 equiv) as the starting materials to give 7-[1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-2-phenyl-2,7- diazaspiro[4.5]decane (10 mg, 46%) as a colorless oil.
• Step 2 7-phenyl-2,7-diazaspiro[4.5]decane hydrochloride:
• tert-butyl 7-phenyl-2,7-diazaspiro[4.5]decane-2-carboxylate 160 mg
• Step 3 2-[1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-7-phenyl-2,7- diazaspiro[4.5]decane:
• 7-phenyl-2,7- diazaspiro[4.5]decane hydrochloride 14 mg, 55 ⁇ mol, 1.0 equiv
• 6-chloro-1-(2,2- difluoroethyl)-1H-pyrazolo[3,4-b]pyrazine (12 mg, 55 ⁇ mol, 1.0 equiv) as the starting materials to give 2-[1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-7-phenyl-2,7- diazaspiro[4.5]decane (14 mg, 64%) as a colorless oil.
• Step 1 tert-butyl 2-phenyl-2,7-diazaspiro[3.5]nonane-7-carboxylate:
• tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate 320 mg, 1.4 mmol, 1 equiv.
• iodobenzene 557 mg, 1.4 mmom, 1 equiv.
• Step 2 7-phenyl-2,7-diazaspiro[3.5]nonane hydrochloride:
• tert-butyl 2-phenyl-2,7-diazaspiro[3.5]nonane-7-carboxylate 68 mg
• Step 3 7-[1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-2-phenyl-2,7- diazaspiro[3.5]nonane:
• 2-phenyl-2,7- diazaspiro[3.5]nonane hydrochloride (13.1 mg, 55 ⁇ mol, 1.0 equiv)
• 6-chloro-1-(2,2- difluoroethyl)-1H-pyrazolo[3,4-b]pyrazine (12 mg, 55 ⁇ mol, 1.0 equiv) as the starting materials to give 7-[1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-2-phenyl-2,7- diazaspiro[3.5]nonane (10.4 mg, 49%) as a colorless oil.
• Step 1 tert-butyl 7-phenyl-2,7-diazaspiro[3.5]nonane-2-carboxylate:
• tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate 320 mg, 1.4 mmol, 1 equiv.
• iodobenzene 557 mg, 1.4 mmol, 1 equiv.
• Step 2 7-phenyl-2,7-diazaspiro[3.5]nonane hydrochloride:
• tert-butyl 7-phenyl-2,7-diazaspiro[3.5]nonane-2-carboxylate 37 mg
• Step 3 2-[1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-7-phenyl-2,7- diazaspiro[3.5]nonane:
• 7-phenyl-2,7- diazaspiro[3.5]nonane hydrochloride (13.1 mg, 55 ⁇ mol, 1.0 equiv)
• 6-chloro-1-(2,2- difluoroethyl)-1H-pyrazolo[3,4-b]pyrazine (12 mg, 55 ⁇ mol, 1.0 equiv) as the starting materials to give 2-[1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-7-phenyl-2,7- diazaspiro[3.5]nonane (8 mg, 38%) as a colorless oil.
• Step 2 6-phenyl-2,6-diazaspiro[3.5]nonane hydrochloride:
• Step 2 6-phenyl-2,6-diazaspiro[3.5]nonane hydrochloride:
• tert-butyl 6-phenyl-2,6-diazaspiro[3.5]nonane-2-carboxylate 34 mg
• Step 3 2-(2-phenyl-1,3-thiazol-4-yl)-1- ⁇ 6-phenyl-2,6-diazaspiro[3.5]nonan-2- yl ⁇ ethan-1-one:
• 6-phenyl-2,6-diazaspiro[3.5]nonane hydrochloride (16.3 mg, 68.4 ⁇ mol, 1 euqiv.)
• 2-(2-phenyl-1,3-thiazol-4-yl)acetic acid (15 mg, 68.4 ⁇ mol, 1 euqiv.) as the starting materials to give 2-(2-phenyl-1,3-thiazol-4-yl)-1- ⁇ 6- phenyl-2,6-diazaspiro[3.5]nonan-2-yl ⁇ ethan-1-one (15 mg, 54%) as a white solid.
• Step 2 tert-butyl 1-oxo-2-(6-(trifluoromethyl)pyridin-2-yl)-2,8- diazaspiro[4.5]decane-8-carboxylate: A mixture of tert-butyl 1-oxo-2,8- diazaspiro[4.5]decane-8-carboxylate (300 mg, 1.180 mmol, 1 equiv), 2-fluoro-6- (trifluoromethyl)pyridine (214.21 mg, 1.298 mmol, 1.1 equiv) and Cs 2 CO 3 (768.65 mg, 2.360 mmol, 2 equiv) in DMF (5 mL) was heated at 100 °C overnight.
• Step 3 2-(6-(trifluoromethyl)pyridin-2-yl)-2,8-diazaspiro[4.5]decan-1-one hydrochloride:
• Step 3 2-(6-(trifluoromethyl)pyridin-2-yl)-2,8-diazaspiro[4.5]decan-1-one hydrochloride:
• tert-butyl 1-oxo-2-[6- (trifluoromethyl)pyridin-2-yl]-2,8-diazaspiro[4.5]decane-8-carboxylate (220 mg, 0.551 mmol, 1 equiv) as the starting material to give the crude product 2-(6- (trifluoromethyl)pyridin-2-yl)-2,8-diazaspiro[4.5]decan-1-one hydrochloride (210 mg).
• Step 4 8-(1-((2-oxaspiro[3.3]heptan-6-yl)methyl)-1H-pyrazolo[3,4-b]pyrazin-6- yl)-2-(6-(trifluoromethyl)pyridin-2-yl)-2,8-diazaspiro[4.5]decan-1-one: To a stirred solution of 1-((2-oxaspiro[3.3]heptan-6-yl)methyl)-6-chloro-1H-pyrazolo[3,4-b]pyrazine (60 mg, 0.227 mmol, 1 equiv) and 2-[6-(trifluoromethyl)pyridin-2-yl]-2,8-diazaspiro[4.5]decan-1- one hydrochloride (83.5 mg, 0.250 mmol, 1.1 equiv) in DMF (1.00 mL) was added Na 2 CO 3 (4
• Step 2 8-[1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-2-[2- (trifluoromethyl)pyridin-3-yl]-2,8-diazaspiro[4.5]decan-3-one:
• 8-[1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-2,8- diazaspiro[4.5]decan-3-one 25 mg, 74.3 ⁇ mol, 1.0 equiv
• 3-bromo-2- (trifluoromethyl)pyridine (16.8 mg, 74.3 ⁇ mol, 1.0 equiv) as the starting materials to give 8- [1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyra
• Step 2 7-[1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-2,7- diazaspiro[3.5]nonane hydrochloride:
• Step 2 7-[1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-2,7- diazaspiro[3.5]nonane hydrochloride:
• Step 2 7-[1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-2,7-diazaspiro[3.5]nonane-2-carboxylate (314 mg) as the starting material to give the 7-[1-(2,2-difluoroethyl)-1H-pyrazolo[3,4- b]pyrazin-6-yl]-2,7-diazaspiro[
• Step 3 7-[1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-2-[2- (trifluoromethyl)pyridin-3-yl]-2,7-diazaspiro[3.5]nonane:
• 7-[1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-2,7-diazaspiro[3.5]nonane hydrochloride (30 mg, 87 ⁇ mol, 1.0 equiv) and 3-fluoro-2-(trifluoromethyl)pyridine (14.4 mg, 87 ⁇ mol, 1.0 equiv) as the starting materials to give 7-[1-(2,2-difluoroethyl)-1H- pyrazolo[3,4-b]
• Step 1 tert-butyl 1-benzyl-2,4-dioxo-3-(4-(trifluoromethyl)pyridin-2-yl)-1,3,8- triazaspiro[4.5]decane-8-carboxylate: A solution of tert-butyl 2,4-dioxo-3-(4- (trifluoromethyl)pyridin-2-yl)-1,3,8-triazaspiro[4.5]decane-8-carboxylate (80 mg, 0.193 mmol, 1 equiv), benzyl chloride (26.88 mg, 0.212 mmol, 1.1 equiv) and Cs 2 CO 3 (126 mg, 0.386 mmol, 2 equiv) in DMF (1 mL) was stirred for 1.5 h at 50 °C.
• Step 2 1-benzyl-3-(4-(trifluoromethyl)pyridin-2-yl)-1,3,8-triazaspiro[4.5]decane- 2,4-dione hydrochloride:
• Step 2 1-benzyl-3-(4-(trifluoromethyl)pyridin-2-yl)-1,3,8-triazaspiro[4.5]decane- 2,4-dione hydrochloride:
• tert-butyl 1-benzyl-2,4- dioxo-3-(4-(trifluoromethyl)pyridin-2-yl)-1,3,8-triazaspiro[4.5]decane-8-carboxylate (60 mg, 0.119 mmol, 1 equiv) as the starting material to give the crude product 1-benzyl-3-(4- (trifluoromethyl)pyridin-2-yl)-1,3,8-triazaspiro[4.5]decane-2,4-dione hydrochloride (32.6 mg).
• Step 3 1-benzyl-8-(1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-3-(4- (trifluoromethyl)pyridin-2-yl)-1,3,8-triazaspiro[4.5]decane-2,4-dione: A solution of 1-benzyl- 3-(4-(trifluoromethyl)pyridin-2-yl)-1,3,8-triazaspiro[4.5]decane-2,4-dione hydrochloride (32.6 mg, 0.074 mmol, 1 equiv) and Na 2 CO 3 (15.73 mg, 0.148 mmol, 2 equiv) in DMF (1 mL) was stirred for 2 h at 100 °C.
• Step 1 tert-butyl 2,4-dioxo-1-(2,2,2-trifluoroethyl)-3-(4-(trifluoromethyl)pyridin- 2-yl)-1,3,8-triazaspiro[4.5]decane-8-carboxylate: A solution of tert-butyl 2,4-dioxo-3-(4- (trifluoromethyl)pyridin-2-yl)-1,3,8-triazaspiro[4.5]decane-8-carboxylate (80 mg, 0.193 mmol, 1 equi
• Step 2 1-(2,2,2-trifluoroethyl)-3-(4-(trifluoromethyl)pyridin-2-yl)-1,3,8- triazaspiro[4.5]decane-2,4-dione hydrochloride:
• Step 2 1-(2,2,2-trifluoroethyl)-3-(4-(trifluoromethyl)pyridin-2-yl)-1,3,8- triazaspiro[4.5]decane-2,4-dione hydrochloride:
• Step 2 1-(2,2,2-trifluoroethyl)-3-(4-(trifluoromethyl)pyridin-2-yl)-1,3,8- triazaspiro[4.5]decane-2,4-dione hydrochloride:
• Step 3 8-(1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-1-(2,2,2- trifluoroethyl)-3-(4-(trifluoromethyl)pyridin-2-yl)-1,3,8-triazaspiro[4.5]decane-2,4-dione: A solution of 1-(2,2,2-trifluoroethyl)-3-(4-(trifluoromethyl)pyridin-2-yl)-1,3,8- triazaspiro[4.5]decane-2,4-dione hydrochloride (27.2 mg, 0.063 mmol, 1 equiv), 6-chloro-1- (2,2-difluoroethyl)pyrazolo[3,4-b]pyrazine (15.17 mg, 0.069 mmol, 1.1 equiv)
• Step 1 tert-butyl 4-(((benzyloxy)carbonyl)amino)-4-((4-(trifluoromethyl)pyridin- 2-yl)carbamoyl)piperidine-1-carboxylate: A solution of 4-(((benzyloxy)carbonyl)amino)-1- (tert-butoxycarbonyl)piperidine-4-carboxylic acid (1 g, 2.643 mmol, 1 equiv), 4- (trifluoromethyl)pyridin-2-amine (0.51 g, 3.17 mmol, 1.2 equiv), TCFH (1.11 g, 3.964 mmol, 1.5 equiv) and NMI (0.65 g, 7.93 mmol, 3 equiv) in ACN (10 mL) was stirred for overnight at 60 °C.
• Step 2 tert-butyl 2,4-dioxo-3-(4-(trifluoromethyl)pyridin-2-yl)-1,3,8- triazaspiro[4.5]decane-8-carboxylate: A solution of tert-butyl 4- (((benzyloxy)carbonyl)amino)-4-((4-(trifluoromethyl)pyridin-2-yl)carbamoyl)piperidine-1- carboxylate (450 mg, 0.861 mmol, 1 equiv) in DMF (5 mL) was stirred for overnight at 120 °C.
• Step 3 tert-butyl 1-ethyl-2,4-dioxo-3-(4-(trifluoromethyl)pyridin-2-yl)-1,3,8- triazaspiro[4.5]decane-8-carboxylate: A solution of tert-butyl 2,4-dioxo-3-(4- (trifluoromethyl)pyridin-2-yl)-1,3,8-triazaspiro[4.5]decane-8-carboxylate (80 mg, 0.193 mmol, 1 equiv), iodoethane (36.13 mg, 0.232 mmol, 1.2 equiv) and Cs 2 CO 3 (125.80 mg, 0.386 mmol, 2 equiv) in DMF (2 mL) was stirred for 1.5 h at 50 °C.
• Step 4 1-ethyl-3-(4-(trifluoromethyl)pyridin-2-yl)-1,3,8-triazaspiro[4.5]decane- 2,4-dione hydrochloride:
• Step 4 1-ethyl-3-(4-(trifluoromethyl)pyridin-2-yl)-1,3,8-triazaspiro[4.5]decane- 2,4-dione hydrochloride:
• Step 5 8-(1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-1-ethyl-3-(4- (trifluoromethyl)pyridin-2-yl)-1,3,8-triazaspiro[4.5]decane-2,4-dione: A solution of 1-ethyl- 3-(4-(trifluoromethyl)pyridin-2-yl)-1,3,8-triazaspiro[4.5]decane-2,4-dione (27.6 mg, 0.073 mmol, 1 equiv), 6-chloro-1-(2,2-difluoroethyl)pyrazolo[3,4-b]pyrazine (17.56 mg, 0.080 mmol, 1.1 equiv) and Na 2 CO 3 (15.48 mg, 0.146 mmol, 2 equi
• Step 1 tert-butyl 3-oxo-2-(4-(trifluoromethyl)pyridin-2-yl)-2,8- diazaspiro[4.5]decane-8-carboxylate: To a stirred solution of tert-butyl 3-oxo-2,8- diazaspiro[4.5]decane-8-carboxylate (500 mg, 1.966 mmol, 1 equiv) and 2-fluoro-4- (trifluoromethyl)pyridine (389.47 mg, 2.359 mmol, 1.2 equiv) in DMF (10 mL) was added Cs 2 CO 3 (12
• Step 2 tert-butyl 4,4-dimethyl-3-oxo-2-(4-(trifluoromethyl)pyridin-2-yl)-2,8- diazaspiro[4.5]decane-8-carboxylate: To a stirred solution of tert-butyl 3-oxo-2-(4- (trifluoromethyl)pyridin-2-yl)-2,8-diazaspiro[4.5]decane-8-carboxylate (200 mg, 0.500 mmol, 1 equiv) in THF (3 mL) was added a solution of lithium diisopropylamide (1 M in THF, 1.1 mmol, 1.1 mL, 2.2 equiv) under nitrogen atmosphere at -40 °C dropwise.
• Step 3 4,4-dimethyl-2-[4-(trifluoromethyl)pyridin-2-yl]-2,8-diazaspiro[4.5]decan- 3-one hydrochloride:
• Step 3 4,4-dimethyl-2-[4-(trifluoromethyl)pyridin-2-yl]-2,8-diazaspiro[4.5]decan- 3-one hydrochloride:
• tert-butyl 4,4-dimethyl-3-oxo- 2-[4-(trifluoromethyl)pyridin-2-yl]-2,8-diazaspiro[4.5]decane-8-carboxylate (60 mg, 0.140 mmol, 1 equiv) as the starting material to afford crude product 4,4-dimethyl-2-[4- (trifluoromethyl)pyridin-2-yl]-2,8-diazaspiro[4.5]decan-3-one hydrochloride (40 mg) as a white solid.
• Step 4 8-(1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4,4-dimethyl-2- (4-(trifluoromethyl)pyridin-2-yl)-2,8-diazaspiro[4.5]decan-3-one: To a stirred solution of 4,4- dimethyl-2-[4-(trifluoromethyl)pyridin-2-yl]-2,8-diazaspiro[4.5]decan-3-one hydrochloride (40 mg, 0.110 mmol, 1 equiv) and 6-chloro-1-(2,2-difluoroethyl)pyrazolo[3,4-b]pyrazine (28.84 mg, 0.132 mmol, 1.2 equiv) in DMF (1 mL) was added Na 2 CO 3 (34.96 mg, 0.330 m
• Step 1 tert-butyl 1-isopropyl-2,4-dioxo-3-(4-(trifluoromethyl)pyridin-2-yl)-1,3,8- triazaspiro[4.5]decane-8-carboxylate: A solution of tert-butyl 2,4-dioxo-3-(4- (trifluoromethyl)pyridin-2-yl)-1,3,8-triazaspiro[4.5]decane-8-carboxylate (80 mg, 0.193 mmol, 1 equiv), 2-iodopropane (39.38 mg,
• Step 2 1-isopropyl-3-(4-(trifluoromethyl)pyridin-2-yl)-1,3,8- triazaspiro[4.5]decane-2,4-dione hydrocholride:
• Step 2 1-isopropyl-3-(4-(trifluoromethyl)pyridin-2-yl)-1,3,8- triazaspiro[4.5]decane-2,4-dione hydrocholride:
• Step 2 1-isopropyl-3-(4-(trifluoromethyl)pyridin-2-yl)-1,3,8-triazaspiro[4.5]decane-2,4-dione hydrocholride:
• Step 3 8-(1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-1-isopropyl-3-(4- (trifluoromethyl)pyridin-2-yl)-1,3,8-triazaspiro[4.5]decane-2,4-dione: A solution of 1- isopropyl-3-(4-(trifluoromethyl)pyridin-2-yl)-1,3,8-triazaspiro[4.5]decane-2,4-dione hydrochloride (22.0 mg, 0.056 mmol, 1 equiv) and Na 2 CO 3 (11.90 mg, 0.112 mmol, 2 equiv) in DMF (1 mL) was stirred for 2 h at 100 °C.
• Step 1 tert-butyl 4-ethyl-3-oxo-2-(4-(trifluoromethyl)pyridin-2-yl)-2,8- diazaspiro[4.5]decane-8-carboxylate: To a stirred solution of tert-butyl 3-oxo-2-(4- (trifluoromethyl)pyridin-2-yl)-2,8-diazaspiro[4.5]decane-8-carboxylate (200 mg, 0.500 mmol, 1 equiv) in THF (3 mL) was added
• Step 2 4-ethyl-2-[4-(trifluoromethyl)pyridin-2-yl]-2,8-diazaspiro[4.5]decan-3-one hydrochloride:
• Step 2 4-ethyl-2-[4-(trifluoromethyl)pyridin-2-yl]-2,8-diazaspiro[4.5]decan-3-one hydrochloride:
• Step 2 4-ethyl-2-[4-(trifluoromethyl)pyridin-2-yl]-2,8-diazaspiro[4.5]decan-3-one hydrochloride:
• Step 3 8-(1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-ethyl-2-(4- (trifluoromethyl)pyridin-2-yl)-2,8-diazaspiro[4.5]decan-3-one: To a stirred solution of 4- ethyl-2-[4-(trifluoromethyl)pyridin-2-yl]-2,8-diazaspiro[4.5]decan-3-one hydrochloride (50 mg, 0.137 mmol, 1 equiv) and 6-chloro-1-(2,2-difluoroethyl)pyrazolo[3,4-b]pyrazine (36.05 mg, 0.164 mmol, 1.2 equiv) in DMF (1 mL) was added Na 2 CO 3 (43.70 mg, 0.411
• Step 1 tert-butyl 1-( ⁇ [6-(trifluoromethyl)pyridin-2-yl]oxy ⁇ methyl)-8- azaspiro[4.5]decane-8-carboxylate:
• tert-butyl 1- (hydroxymethyl)-8-azaspiro[4.5]decane-8-carboxylate 50 mg, 221 ⁇ mol, 1.0 equiv) and 2- bromo-6-(trifluoromethyl)pyridine (41.9 mg, 221 ⁇ mol, 1.0 equiv.) as the starting materials to tert-butyl 1-( ⁇ [6-(trifluoromethyl)pyridin-2
• Step 2 1-( ⁇ [6-(trifluoromethyl)pyridin-2-yl]oxy ⁇ methyl)-8-azaspiro[4.5]decane hydrochloride:
• Step 2 1-( ⁇ [6-(trifluoromethyl)pyridin-2-yl]oxy ⁇ methyl)-8-azaspiro[4.5]decane hydrochloride:
• tert-butyl 1-( ⁇ [6- (trifluoromethyl)pyridin-2-yl]oxy ⁇ methyl)-8-azaspiro[4.5]decane-8-carboxylate (16 mg) as the starting material to give the 1-( ⁇ [6-(trifluoromethyl)pyridin-2-yl]oxy ⁇ methyl)-8- azaspiro[4.5]decane hydrochloride (16 mg).
• Step 3 8-[1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-2- ⁇ [6- (trifluoromethyl)pyridin-2-yl]oxy ⁇ -8-azaspiro[4.5]decane:
• 6-chloro-1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazine (10 mg, 46 ⁇ mol, 1.0 equiv) and 1-( ⁇ [6-(trifluoromethyl)pyridin-2-yl]oxy ⁇ methyl)-8-azaspiro[4.5]decane hydrochloride (16 mg, 46 ⁇ mol, 1.0 equiv) as the starting materials to give 8-[1-(2,2-difluoroethyl)-1H- pyrazolo[3,4-b]pyra
• Step 2 2- ⁇ [6-(trifluoromethyl)pyridin-2-yl]oxy ⁇ -8-azaspiro[4.5]decane hydrochloride:
• 2- ⁇ [6-(trifluoromethyl)pyridin-2-yl]oxy ⁇ -8-azaspiro[4.5]decane hydrochloride followsed the general procedure B using tert-butyl 2- ⁇ [6- (trifluoromethyl)pyridin-2-yl]oxy ⁇ -8-azaspiro[4.5]decane-8-carboxylate (15 mg) as the starting material to give 2- ⁇ [6-(trifluoromethyl)pyridin-2-yl]oxy ⁇ -8-azaspiro[4.5]decane hydrochloride (15 mg).
• Step 3 8-[1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-2- ⁇ [6- (trifluoromethyl)pyridin-2-yl]oxy ⁇ -8-azaspiro[4.5]decane:
• 6-chloro-1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazine (13.6 mg, 62.4 ⁇ mol, 1.0 equiv) and 2- ⁇ [6-(trifluoromethyl)pyridin-2-yl]oxy ⁇ -8-azaspiro[4.5]decane hydrochloride (15 mg, 62.4 ⁇ mol, 1.0 equiv) as the starting materials to give 8-[1-(2,2-difluoroethyl)-1H- pyrazolo[3,4-b]pyrazin-6-yl]-2- ⁇ [6-(trifluor
• Step 2 1-( ⁇ [6-(trifluoromethyl)pyridin-2-yl]oxy ⁇ methyl)-7-azaspiro[3.5]nonane hydrochloride:
• Step 2 1-( ⁇ [6-(trifluoromethyl)pyridin-2-yl]oxy ⁇ methyl)-7-azaspiro[3.5]nonane hydrochloride:
• Step 3 7-[1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1-( ⁇ [6- (trifluoromethyl)pyridin-2-yl]oxy ⁇ methyl)-7-azaspiro[3.5]nonane:
• 6-chloro-1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazine (13.6 mg, 62.4 ⁇ mol, 1.0 equiv) and 1-( ⁇ [6-(trifluoromethyl)pyridin-2-yl]oxy ⁇ methyl)-7- azaspiro[3.5]nonane hydrochloride (21 mg, 62.4 ⁇ mol, 1.0 equiv) as the starting materials to give 7-[1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1-( ⁇ [6- (trifluoro
• Step 2 1- ⁇ [6-(trifluoromethyl)pyridin-2-yl]oxy ⁇ -7-azaspiro[3.5]nonane hydrochloride:
• Step 2 1- ⁇ [6-(trifluoromethyl)pyridin-2-yl]oxy ⁇ -7-azaspiro[3.5]nonane hydrochloride:
• Step 3 7-[1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1- ⁇ [6- (trifluoromethyl)pyridin-2-yl]oxy ⁇ -7-azaspiro[3.5]nonane:
• 6-chloro-1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazine (18.3 mg, 83.6 ⁇ mol, 1.0 equiv) and 1- ⁇ [6-(trifluoromethyl)pyridin-2-yl]oxy ⁇ -7-azaspiro[3.5]nonane hydrochloride (27 mg, 93.6 ⁇ mol, 1.0 equiv) as the starting materials to give 7-[1-(2,2-difluoroethyl)-1H- pyrazolo[3,4-
• Step 2 2- ⁇ [6-(trifluoromethyl)pyridin-2-yl]oxy ⁇ -7-azaspiro[3.5]nonane hydrochloride:
• Step 2 2- ⁇ [6-(trifluoromethyl)pyridin-2-yl]oxy ⁇ -7-azaspiro[3.5]nonane hydrochloride:
• Step 3 7-[1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-2- ⁇ [6- (trifluoromethyl)pyridin-2-yl]oxy ⁇ -7-azaspiro[3.5]nonane:
• 6-chloro-1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazine 17.6 mg, 80.5 ⁇ mol, 1.0 equiv
• 2- ⁇ [6-(trifluoromethyl)pyridin-2-yl]oxy ⁇ -7-azaspiro[3.5]nonane hydrochloride 26 mg, 80.5 ⁇ mol, 1.0 equiv
• Step 2 2-( ⁇ [6-(trifluoromethyl)pyridin-2-yl]oxy ⁇ methyl)-7-azaspiro[3.5]nonane hydrochloride:
• Step 2 2-( ⁇ [6-(trifluoromethyl)pyridin-2-yl]oxy ⁇ methyl)-7-azaspiro[3.5]nonane hydrochloride:
• Step 3 7-[1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-2-( ⁇ [6- (trifluoromethyl)pyridin-2-yl]oxy ⁇ methyl)-7-azaspiro[3.5]nonane:
• 6-chloro-1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazine (18.8 mg, 86.1 ⁇ mol, 1.0 equiv) and 2-( ⁇ [6-(trifluoromethyl)pyridin-2-yl]oxy ⁇ methyl)-7- azaspiro[3.5]nonane hydrochloride (29 mg, 86.1 ⁇ mol, 1.0 equiv) as the starting materials to give 7-[1-(2,2-difluoroethyl)-1H-pyrazine (18.8 mg, 86.1 ⁇ mol, 1.0 equiv) and 2-( ⁇ [6-
• Step 3 8-[1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-2- ⁇ [2- (trifluoromethyl)pyridin-3-yl]oxy ⁇ -8-azaspiro[4.5]decane:
• 6-chloro-1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazine 17.8 mg, 81.7 ⁇ mol, 1.0 equiv
• 2- ⁇ [2-(trifluoromethyl)pyridin-3-yl]oxy ⁇ -8-azaspiro[4.5]decane hydrochloride (27.5 mg, 81.7 ⁇ mol, 1.0 equiv) as the starting materials to give 8-[1-(2,2-difluoroethyl)-1H- pyrazolo[3,4-b]pyrazin-6-yl]-2- ⁇ [2-(trifluoro
• Step 1 tert-butyl 1- ⁇ [2-(trifluoromethyl)pyridin-3-yl]oxy ⁇ -7-azaspiro[3.5]nonane- 7-carboxylate:
• tert-butyl 1-hydroxy-7- azaspiro[3.5]nonane-7-carboxylate 50 mg, 207 ⁇ mol, 1.0 equiv
• 3-fluoro-2- (trifluoromethyl)pyridine 34.2 mg, 207 ⁇ mol, 1.0 equiv.
• Step 2 1- ⁇ [2-(trifluoromethyl)pyridin-3-yl]oxy ⁇ -7-azaspiro[3.5]nonane hydrochloride:
• Step 2 1- ⁇ [2-(trifluoromethyl)pyridin-3-yl]oxy ⁇ -7-azaspiro[3.5]nonane hydrochloride:
• Step 3 7-[1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1- ⁇ [2- (trifluoromethyl)pyridin-3-yl]oxy ⁇ -7-azaspiro[3.5]nonane:
• 6-chloro-1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazine 28.4 mg, 130 ⁇ mol, 1.0 equiv
• 1- ⁇ [2-(trifluoromethyl)pyridin-3-yl]oxy ⁇ -7-azaspiro[3.5]nonane hydrochloride 42 mg, 130 ⁇ mol, 1.0 equiv) as the starting materials to give 7-[1-(2,2-difluoroethyl)-1H- pyrazolo[3,4-b]pyrazin-6-yl]-1- ⁇ [2-(trifluor
• Step 2 2- ⁇ [2-(trifluoromethyl)pyridin-3-yl]oxy ⁇ -7-azaspiro[3.5]nonane hydrochloride:
• 2- ⁇ [2-(trifluoromethyl)pyridin-3-yl]oxy ⁇ -7-azaspiro[3.5]nonane hydrochloride tert-butyl 2- ⁇ [2- (trifluoromethyl)pyridin-3-yl]oxy ⁇ -7-azaspiro[3.5]nonane-7-carboxylate (68 mg) as the starting material to give 2- ⁇ [2-(trifluoromethyl)pyridin-3-yl]oxy ⁇ -7-azaspiro[3.5]nonane hydrochloride (65 mg).
• Step 3 7-[1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-2- ⁇ [2- (trifluoromethyl)pyridin-3-yl]oxy ⁇ -7-azaspiro[3.5]nonane:
• 6-chloro-1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazine (19.6 mg, 89.8 ⁇ mol, 1.0 equiv) and 2- ⁇ [2-(trifluoromethyl)pyridin-3-yl]oxy ⁇ -7-azaspiro[3.5]nonane hydrochloride (29 mg, 89.8 ⁇ mol, 1.0 equiv) as the starting materials to give 7-[1-(2,2-difluoroethyl)-1H- pyrazolo[3,4-b]pyrazin-6-yl]-2- ⁇ [
• Step 2 2-( ⁇ [2-(trifluoromethyl)pyridin-3-yl]oxy ⁇ methyl)-7-azaspiro[3.5]nonane hydrochloride:
• Step 2 2-( ⁇ [2-(trifluoromethyl)pyridin-3-yl]oxy ⁇ methyl)-7-azaspiro[3.5]nonane hydrochloride:
• Step 3 7-[1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-2-( ⁇ [2- (trifluoromethyl)pyridin-3-yl]oxy ⁇ methyl)-7-azaspiro[3.5]nonane:
• 6-chloro-1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazine (16.2 mg, 74.2 ⁇ mol, 1.0 equiv) and 2-( ⁇ [2-(trifluoromethyl)pyridin-3-yl]oxy ⁇ methyl)-7- azaspiro[3.5]nonane hydrochloride (25 mg, 74.2 ⁇ mol, 1.0 equiv) as the starting materials to give 7-[1-(2,2-difluoroethyl)-1H-pyrazolo[
• Step 1 (4-(trifluoromethyl)pyridin-2-yl)methanol: To a stirred solution of ethyl 4- (trifluoromethyl)pyridine-2-carboxylate (300 mg, 1.37 mmol, 1 equiv) in MeOH (3 mL) was added NaBH 4 (103 mg, 2.74 mmol, 2 equiv) at 0 °C.
• Step 2 2-(chloromethyl)-4-(trifluoromethyl)pyridine: To a stirred solution of [4- (trifluoromethyl)pyridin-2-yl]methanol (100 mg, 0.565 mmol, 1 equiv) in DCM (1 mL) was added SOCl 2 (335 mg, 2.82 mmol, 5 equiv) dropwise at 0 °C. The resulting mixture was stirred for 2 h at room temperature. The resulting mixture was concentrated under reduced pressure.
• Step 3 tert-butyl 2- ⁇ [4-(trifluoromethyl)pyridin-2-yl]methyl ⁇ -2,7- diazaspiro[3.5]nonane-7-carboxylate:
• 2- (chloromethyl)-4-(trifluoromethyl)pyridine 70 mg, 0.358 mmol, 1 equiv
• tert-butyl 2,7- diazaspiro[3.5]nonane-7-carboxylate 89.0 mg, 0.394 mmol, 1.1 equiv
• Step 4 2-((4-(trifluoromethyl)pyridin-2-yl)methyl)-2,7-diazaspiro[3.5]nonane hydrochloride:
• Step 4 2-((4-(trifluoromethyl)pyridin-2-yl)methyl)-2,7-diazaspiro[3.5]nonane hydrochloride:
• tert-butyl 2- ⁇ [4- (trifluoromethyl)pyridin-2-yl]methyl ⁇ -2,7-diazaspiro[3.5]nonane-7-carboxylate 60 mg, 0.156 mmol, 1 equiv
• Step 5 1-(2,2-difluoroethyl)-6-(2-((4-(trifluoromethyl)pyridin-2-yl)methyl)-2,7- diazaspiro[3.5]nonan-7-yl)-1H-pyrazolo[3,4-b]pyrazine: To a stirred solution of 2-((4- (trifluoromethyl)pyridin-2-yl)methyl)-2,7-diazaspiro[3.5]nonane hydrochloride (60 mg, 0.186 mmol, 1 equiv) and 6-chloro-1-(2,2-difluoroethyl)pyrazolo[3,4-b]pyrazine (40.7 mg, 0.186 mmol, 1 equiv) in DMF (2 mL) was added Na 2 CO 3 (59.8 mg, 0.558 mmol, 3 equiv) at room temperature.
• the resulting mixture was stirred for 2 h at 100 °C.
• the resulting mixture was diluted with water (20 mL) and extracted with EtOAc (15 mL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated to dryness under reduced pressure.
• Step 1 tert-butyl 3-oxo-2-[2-(trifluoromethyl)pyridin-3-yl]-2,7- diazaspiro[4.5]decane-7-carboxylate:
• tert-butyl 3- oxo-2,7-diazaspiro[4.5]decane-7-carboxylate 50 mg, 197 ⁇ mol, 1.0 equiv
• 3-fluoro-2- (trifluoromethyl)pyridine 32.5 mg, 197 ⁇ mol, 1.0 equiv.
• Step 2 2-[2-(trifluoromethyl)pyridin-3-yl]-2,7-diazaspiro[4.5]decan-3-one hydrochloride:
• Step 2 2-[2-(trifluoromethyl)pyridin-3-yl]-2,7-diazaspiro[4.5]decan-3-one hydrochloride:
• Step 2 2-[2-(trifluoromethyl)pyridin-3-yl]-2,7-diazaspiro[4.5]decan-3-one hydrochloride:
• Step 3 7-[1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-2-[2- (trifluoromethyl)pyridin-3-yl]-2,7-diazaspiro[4.5]decan-3-one:
• 6-chloro-1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazine (19.5 mg, 89.4 ⁇ mol, 1.0 equiv) and 2-[2-(trifluoromethyl)pyridin-3-yl]-2,7-diazaspiro[4.5]decan-3-one hydrochloride (30 mg, 89.4 ⁇ mol, 1.0 equiv) as the starting materials to give 7-[1-(2,2- difluoroethyl)-1H-pyrazolo[3,
• Step 2 2-[2-(trifluoromethyl)pyridin-3-yl]-2,7-diazaspiro[4.5]decan-1-one hydrochloride:
• Step 2 2-[2-(trifluoromethyl)pyridin-3-yl]-2,7-diazaspiro[4.5]decan-1-one hydrochloride:
• Step 3 7-[1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-2-[2- (trifluoromethyl)pyridin-3-yl]-2,7-diazaspiro[4.5]decan-1-one:
• 6-chloro-1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazine (22.8 mg, 104 ⁇ mol, 1.0 equiv)
• 2-[2-(trifluoromethyl)pyridin-3-yl]-2,7-diazaspiro[4.5]decan-1-one hydrochloride 35 mg, 104 ⁇ mol, 1.0 equiv) as the starting materials to give 7-[1-(2,2- difluoroethyl)-1H-pyrazolo[3,4-b]
• Step 2 2-((2-(trifluoromethyl)pyridin-3-yl)methyl)-2,7-diazaspiro[3.5]nonane hydrochloride:
• Step 2 2-((2-(trifluoromethyl)pyridin-3-yl)methyl)-2,7-diazaspiro[3.5]nonane hydrochloride:
• tert- butyl 2-((2- (trifluoromethyl)pyridin-3-yl)methyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (60.0 mg, 0.156 mmol, 1.00 equiv) as the starting materials to afford the crude product 2-((2- (trifluoromethyl)pyridin-3-yl)methyl)-2,7-diazaspiro[3.5]nonane hydrochloride (50 mg).
• Step 3 1-(2,2-difluoroethyl)-6-(2-((2-(trifluoromethyl)pyridin-3-yl)methyl)-2,7- diazaspiro [3.5]nonan-7-yl)-1H-pyrazolo[3,4-b]pyrazine: To a stirred solution of 2-((2- (trifluoromethyl)pyridin-3-yl)methyl)-2,7-diazaspiro[3.5]nonane hydrochloride (50 mg, 0.156 mmol, 1.00 equiv), 6-chloro-1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazine (44.7 mg, 0.175 mmol, 1.12 equiv) and Na 2 CO 3 (55.72 mg, 0.525 mmol, 3.00 equiv) in DMF (1.00 mL) at
• Step 1 tert-butyl 2-((6-(trifluoromethyl)pyridin-2-yl)methyl)-2,7- diazaspiro[3.5]nonane-7-carboxylate:
• tert-butyl 2,7- diazaspiro[3.5]nonane-7-carboxylate 120 mg, 0.530 mmol, 1.00 equiv
• 2- (chloromethyl)-6-(trifluoromethyl)pyridine 124.43 mg, 0.636 mmol, 1.2 equiv) as the starting materials to afford tert-butyl 2-((6-(trifluoromethyl)
• Step 2 2-((6-(trifluoromethyl)pyridin-2-yl)methyl)-2,7-diazaspiro[3.5]nonane:
• Step 2 2-((6-(trifluoromethyl)pyridin-2-yl)methyl)-2,7-diazaspiro[3.5]nonane:
• tert-butyl 2-((6-(trifluoromethyl)pyridin-2- yl)methyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate 100 mg, 0.259 mmol, 1.00 equiv
• Step 3 1-(2,2-difluoroethyl)-6-(2-((6-(trifluoromethyl)pyridin-2-yl)methyl)-2,7- diaza spiro[3.5]nonan-7-yl)-1H-pyrazolo[3,4-b]pyrazine: To a stirred solution of 2-((6- (trifluoromethyl)pyridin-2-yl)methyl)-2,7-diaza spiro[3.5]nonane hydrochloride (50.0 mg, 0.155 mmol, 1.00 equiv), 6-chloro-1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazine (33.97 mg, 0.155 mmol, 1.00 equiv) and Na 2 CO 3 (49.41 mg, 0.465 mmol, 3.00 equiv) in DMF (1.00
• Step 1 tert-butyl 3-oxo-2-[6-(trifluoromethyl)pyridin-2-yl]-2,7- diazaspiro[4.5]decane-7-carboxylate:
• tert-butyl 3- oxo-2,7-diazaspiro[4.5]decane-7-carboxylate 100 mg, 393 ⁇ mol, 1.0 equiv
• 2-bromo-6- (trifluoromethyl)pyridine 88.9 mg, 393 ⁇ mol, 1.0 equiv.
• Step 2 2-[6-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]decan-3-one hydrochloride:
• Step 2 2-[6-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]decan-3-one hydrochloride:
• Step 2 2-[6-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]decan-3-one hydrochloride:
• Step 3 7-[1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-2-[6- (trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]decan-3-one:
• 6-chloro-1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazine (15 mg, 68.6 ⁇ mol, 1.0 equiv) and 2-[6-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]decan-3-one hydrochloride (23 mg, 68.6 ⁇ mol, 1.0 equiv) as the starting materials to give 7-[1-(2,2- difluoroethyl)-1H-pyrazolo[
• Step 1 tert-butyl 1-oxo-2-[6-(trifluoromethyl)pyridin-2-yl]-2,7- diazaspiro[4.5]decane-7-carboxylate:
• tert-butyl 1- oxo-2,7-diazaspiro[4.5]decane-7-carboxylate 100 mg, 393 ⁇ mol, 1.0 equiv
• 2-bromo-6- (trifluoromethyl)pyridine 88.9 mg, 393 ⁇ mol, 1.0 equiv.
• Step 2 2-[6-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]decan-1-one hydrochloride:
• Step 2 2-[6-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]decan-1-one hydrochloride:
• Step 3 7-[1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-2-[6- (trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]decan-1-one:
• 6-chloro-1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazine (15 mg, 68.6 ⁇ mol, 1.0 equiv) and 2-[6-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]decan-1-one hydrochloride (23 mg, 68.6 ⁇ mol, 1.0 equiv) as the starting materials to give 7-[1-(2,2- difluoroethyl)-1H-pyrazolo[
• Step 1 tert-butyl 3-oxo-2-[4-(trifluoromethyl)pyridin-2-yl]-2,7- diazaspiro[4.5]decane-7-carboxylate:
• tert-butyl 3-oxo-2,7-diazaspiro[4.5]decane-7-carboxylatee 100 mg, 393 ⁇ mol, 1.0 equiv
• 2-bromo-4- (trifluoromethyl)pyridine 88.9 mg, 393 ⁇ mol, 1.0 equiv.
• Step 2 2-[4-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]decan-3-one hydrochloride:
• Step 2 2-[4-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]decan-3-one hydrochloride:
• Step 2 2-[4-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]decan-3-one hydrochloride:
• Step 3 7-[1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-2-[4- (trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]decan-3-one:
• 6-chloro-1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazine (15 mg, 68.6 ⁇ mol, 1.0 equiv) and 2-[4-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]decan-3-one hydrochloride (23 mg, 68.6 ⁇ mol, 1.0 equiv) as the starting materials to give 7-[1-(2,2- difluoroethyl)-1H-pyrazolo[
• Step 1 tert-butyl 1-oxo-2-[4-(trifluoromethyl)pyridin-2-yl]-2,7- diazaspiro[4.5]decane-7-carboxylate:
• tert-butyl 1- oxo-2,7-diazaspiro[4.5]decane-7-carboxylate 100 mg, 393 ⁇ mol, 1.0 equiv
• 2-bromo-4- (trifluoromethyl)pyridine 88.9 mg, 393 ⁇ mol, 1.0 equiv.
• Step 2 2-[4-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]decan-1-one hydrochloride:
• Step 2 2-[4-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]decan-1-one hydrochloride:
• Step 3 7-[1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-2-[4- (trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]decan-1-one:
• 6-chloro-1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazine (15 mg, 68.6 ⁇ mol, 1.0 equiv) and 2-[4-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]decan-1-one hydrochloride (23 mg, 68.6 ⁇ mol, 1.0 equiv) as the starting materials to give 7-[1-(2,2- difluoroethyl)-1H-pyrazolo[
• Step 2 2-[1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-8-[6- (trifluoromethyl)pyridin-2-yl]-2,8-diazaspiro[4.5]decan-1-one:
• 6-chloro-1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazine 25 mg, 114 ⁇ mol, 1.2 equiv
• 8-[6-(trifluoromethyl)pyridin-2-yl]-2,8-diazaspiro[4.5]decan-1-one (28.5 mg, 95.3 ⁇ mol, 1.0 equiv) as the starting materials to give 2-[1-(2,2-difluoroethyl)-1H- pyrazolo[3,4-b]pyrazine
• Step 2 2-[1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-8-[6- (trifluoromethyl)pyridin-2-yl]-2,8-diazaspiro[4.5]decan-3-one:
• 6-chloro-1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazine 25 mg, 114 ⁇ mol, 1.2 equiv
• 8-[6-(trifluoromethyl)pyridin-2-yl]-2,8-diazaspiro[4.5]decan-3-one (28.5 mg, 95.3 ⁇ mol, 1.0 equiv) as the starting materials to give 2-[1-(2,2-difluoroethyl)-1H- pyrazolo[3,4-b]pyrazine
• Step 2 2-[2-(trifluoromethyl)pyridin-3-yl]-2,7-diazaspiro[3.5]nonane hydrochloride:
• 2-[2-(trifluoromethyl)pyridin-3-yl]-2,7-diazaspiro[3.5]nonane hydrochloride followeded the general procedure B using tert-butyl 2-[2- (trifluoromethyl)pyridin-3-yl]-2,7-diazaspiro[3.5]nonane-7-carboxylate (70 mg) as the starting material to give 2-[2-(trifluoromethyl)pyridin-3-yl]-2,7-diazaspiro[3.5]nonane hydrochloride (65 mg).
• Step 3 5-methyl-6-phenyl-N- ⁇ 2-[2-(trifluoromethyl)pyridin-3-yl]-2- azaspiro[3.5]nonan-7-yl ⁇ -5H-pyrrolo[2,3-b]pyrazine-7-carboxamide:
• Step 3 5-methyl-6-phenyl-N- ⁇ 2-[2-(trifluoromethyl)pyridin-3-yl]-2- azaspiro[3.5]nonan-7-yl ⁇ -5H-pyrrolo[2,3-b]pyrazine-7-carboxamide:
• Step 3 5-methyl-6-phenyl-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (16.5 mg, 65 ⁇ mol, 1.0 equiv) and 2-[2-(trifluoromethyl)pyridin-3-yl]-2,7-diazaspiro[3.5]nonane hydrochloride (20 mg, 65 ⁇ mol, 1.0 equiv) as the starting materials
• Step 2 2-[2-(trifluoromethyl)pyridin-3-yl]-2-azaspiro[3.5]nonan-7-amine hydrochloride:
• Step 2 2-[2-(trifluoromethyl)pyridin-3-yl]-2-azaspiro[3.5]nonan-7-amine hydrochloride:
• Step 3 5-methyl-6-phenyl-N- ⁇ 2-[2-(trifluoromethyl)pyridin-3-yl]-2- azaspiro[3.5]nonan-7-yl ⁇ -5H-pyrrolo[2,3-b]pyrazine-7-carboxamide:
• Step 3 5-methyl-6-phenyl-N- ⁇ 2-[2-(trifluoromethyl)pyridin-3-yl]-2- azaspiro[3.5]nonan-7-yl ⁇ -5H-pyrrolo[2,3-b]pyrazine-7-carboxamide
• Example 112 2-[1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-8-[5- (trifluoromethyl)pyridin-2-yl]-2,8-diazaspiro[4.5]decan-3-one [00748]
• General Procedure A to afford the desired product as a white solid (13 mg, 50%).
• Example 122 2-[1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-8-[5- (trifluoromethyl)pyridin-3-yl]-2,8-diazaspiro[4.5]decan-1-one [00758]
• the General Procedure A to afford the desired product as a white solid (7 mg, 22%).
• Example 125 2-[1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-7-[6- (trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[3.5]nonane [00761]
• the General Procedure A to afford the desired product as a white solid (25 mg, 80%).
• Example 126 2-[1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-7-[5- (trifluoromethyl)pyridin-3-yl]-2,7-diazaspiro[3.5]nonane [00762]
• the General Procedure A to afford the desired product as a white solid (25 mg, 80%).
• Example 127 2-[1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-7-[6- (trifluoromethyl)pyridin-3-yl]-2,7-diazaspiro[3.5]nonane [00763]
• the General Procedure A to afford the desired product as a white solid (27 mg, 81%).
• Example 128 2-[1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-7-[4- (trifluoromethyl)pyridin-3-yl]-2,7-diazaspiro[3.5]nonane [00764]
• the General Procedure A to afford the desired product as a white solid (23 mg, 74%).
• Example 129 2-[1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-7-[2- (trifluoromethyl)pyridin-3-yl]-2,7-diazaspiro[3.5]nonane [00765]
• the General Procedure A to afford the desired product as a white solid (22 mg, 71%).
• Example 133 2-[1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-6-( ⁇ [6- (trifluoromethyl)pyridin-3-yl]oxy ⁇ methyl)-2-azaspiro[3.3]heptane [00769]
• the General Procedure A to afford the desired product as a colorless oil (8 mg, 19%).

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