WO2024251212A1 - Composés d'isoindolinone et de dihydropyrrolopridinone et leurs utilisations - Google Patents

Composés d'isoindolinone et de dihydropyrrolopridinone et leurs utilisations Download PDF

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WO2024251212A1
WO2024251212A1 PCT/CN2024/097833 CN2024097833W WO2024251212A1 WO 2024251212 A1 WO2024251212 A1 WO 2024251212A1 CN 2024097833 W CN2024097833 W CN 2024097833W WO 2024251212 A1 WO2024251212 A1 WO 2024251212A1
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alkyl
haloalkyl
hydroxyalkyl
aminoalkyl
cycloalkyl
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Sridhar NARAYAN
Paul R. August
Peng YUE
Jinxing LI
Mary MCMAHON
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Revir Therapeutics Inc
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Revir Therapeutics Inc
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Priority to EP24818743.7A priority Critical patent/EP4724441A1/fr
Priority to CN202480038288.3A priority patent/CN121335899A/zh
Publication of WO2024251212A1 publication Critical patent/WO2024251212A1/fr
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    • 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
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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
    • 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
    • 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
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    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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    • 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
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
    • C07D451/06—Oxygen atoms
    • 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
    • C07D471/04—Ortho-condensed systems
    • 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
    • C07D471/08—Bridged systems
    • 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
    • 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
    • C07D487/08—Bridged 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
    • C07D487/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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

Definitions

  • Huntington's disease is a progressive, autosomal dominant neurodegenerative disorder of the brain, having symptoms characterized by involuntary movements, cognitive impairment, and mental deterioration. Death, typically caused by pneumonia or coronary artery disease, usually occurs 13 to 15 years after the onset of symptoms. The prevalence of HD is between three and seven individuals per 100,000 in populations of western European descent. In North America, an estimated 30,000 people have HD, while an additional 200,000 people are at risk of inheriting the disease from an affected parent.
  • the disease is caused by an expansion of uninterrupted trinucleotide CAG repeats in the “mutant” huntingtin (Htt) gene, leading to production of HTT (Htt protein) with an expanded poly-glutamine (polyQ) stretch, also known as a “CAG repeat” sequence.
  • Htt huntingtin
  • polyQ poly-glutamine
  • ring C is 4 to 10-membered heterocycloalkyl or 4 to 10-membered heterocycloalkenylene;
  • each R 1 is independently hydrogen, halogen, -CN, -NO 2 , -OH, -OR a , -SH, -SR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 aminoalkyl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, or aminoalkyl is optionally substituted with 1 to 4 substituents independently selected from R e ; or
  • R 1 two R 1 are taken together to form a bond, a C 1 -C 3 alkylene or C 1 -C 3 heteroalkylene, wherein the alkylene or heteroalkylene is optionally substituted with 1 to 4 substituents independently selected from R e ; or
  • R 1 two R 1 are taken together to form a C 3 -C 6 cycloalkyl or 4 to 6-membered heterocycloalkyl, each of which is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • each R 2 is independently hydrogen, halogen, -OH, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 aminoalkyl; or
  • X is absent, -CH 2 -, -O-, -OCH 2 -, -S-, or -NR 3 -;
  • R 3 is hydrogen, C 1 -C 3 alkyl, C 1 -C 3 hydroxyalkyl, C 1 -C 3 haloalkyl, or C 3 -C 6 cycloalkyl;
  • each A is independently N or CR 4 , wherein at least two of A are N;
  • each R 4 is independently hydrogen, halogen, -CN, -NO 2 , -OH, -OR a , -SH, -SR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 aminoalkyl;
  • R 3 and one of R 4 are taken together to form a 5 or 6-membered heterocycloalkylene or 5 or 6-membered heteroarylene;
  • B is N or CR 5 ;
  • D is N or CR 6 ;
  • E is N or CR 7 ;
  • F is N or CR 8 ;
  • R 5 , R 6 , R 7 or R 8 is C 2 -C 6 alkene, C 3 -C 6 cycloalkyl, 4 to 6 membered heterocycloalkyl, 5 to 10-membered heteroaryl, or -O- (C 1 -C 6 alkylene) -5 to 10-membered heteroaryl, wherein the alkene, cycloalkyl, heterocycloalkyl and heteroaryl is optionally substituted with 1 to 4 substituents selected from R e ;
  • each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • R c and R d are each independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • p is an integer from 1-9.
  • ring C is 4 to 10-membered heterocycloalkyl or 4 to 10-membered heterocycloalkenylene;
  • each R 1 is independently hydrogen, halogen, -CN, -NO 2 , -OH, -OR a , -SH, -SR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 aminoalkyl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, or aminoalkyl is optionally substituted with 1 to 4 substituents independently selected from R e ; or
  • R 1 two R 1 are taken together to form a bond, a C 1 -C 3 alkylene or C 1 -C 3 heteroalkylene, wherein the alkylene or heteroalkylene is optionally substituted with 1 to 4 substituents independently selected from R e ; or
  • R 1 two R 1 are taken together to form a C 3 -C 6 cycloalkyl or 4 to 6-membered heterocycloalkyl, each of which is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • each R 2 is independently hydrogen, halogen, -OH, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 aminoalkyl; or
  • X is absent, -CH 2 -, -O-, -S-, or -NR 3 -;
  • R 3 is hydrogen, C 1 -C 3 alkyl, C 1 -C 3 hydroxyalkyl, C 1 -C 3 haloalkyl, or C 3 -C 6 cycloalkyl;
  • each A is independently N or CR 4 , wherein at least two of A are N;
  • each R 4 is independently hydrogen, halogen, -CN, -NO 2 , -OH, -OR a , -SH, -SR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 aminoalkyl;
  • B is N or CR 5 ;
  • D is N or CR 6 ;
  • E is N or CR 7 ;
  • F is N or CR 8 ;
  • each R 10 is independently halogen, -CN, -NO 2 , -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 3 -C 6 cycloalkyl, or 4 to 6-membered heterocycloalkyl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, heteroalkyl, cycloalkyl and heterocycloalkyl is optionally substituted with 1 to 4-substituents independently selected from R e ; or
  • each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • R c and R d are each independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • p is an integer from 1-9.
  • composition comprising a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof; and a pharmaceutically acceptable excipient.
  • Also disclosed herein is a method of treating a neurodegenerative disease or disorder in a patient in need thereof, the method comprising administering to the patient a compound disclosed herein or a pharmaceutically acceptable salt or solvate thereof.
  • the neurodegenerative disease or disorder is selected from Alzheimer’s disease, amyotrophic lateral sclerosis, Huntington’s disease (HD) , Parkinson’s disease, Prion disease, and spinocerebellar ataxias. In some embodiments, the neurodegenerative disease or disorder is Huntington’s disease (HD) .
  • Carboxyl refers to -COOH.
  • Cyano refers to -CN.
  • Alkyl refers to a straight-chain, or branched-chain saturated hydrocarbon monoradical having from one to about ten carbon atoms, more preferably one to six carbon atoms. Examples include, but are not limited to methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2, 2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2, 2-dimethyl-1-butyl, 3, 3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopent
  • a numerical range such as “C 1 -C 6 alkyl” or “C 1-6 alkyl” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated.
  • the alkyl is a C 1-10 alkyl.
  • the alkyl is a C 1 - 6 alkyl.
  • the alkyl is a C 1-5 alkyl.
  • the alkyl is a C 1-4 alkyl.
  • the alkyl is a C 1-3 alkyl.
  • an alkyl group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • the alkyl is optionally substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH 2 , or -NO 2 .
  • the alkyl is optionally substituted with halogen, -CN, -OH, or -OMe.
  • the alkyl is optionally substituted with halogen.
  • Alkenyl refers to a straight-chain, or branched-chain hydrocarbon monoradical having one or more carbon-carbon double-bonds and having from two to about ten carbon atoms, more preferably two to about six carbon atoms.
  • a numerical range such as “C 2 -C 6 alkenyl” or “C 2-6 alkenyl” means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkenyl” where no numerical range is designated.
  • an alkenyl group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • the alkenyl is optionally substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH 2 , or -NO 2 .
  • the alkenyl is optionally substituted with halogen, -CN, -OH, or -OMe.
  • the alkenyl is optionally substituted with halogen.
  • Alkynyl refers to a straight-chain or branched-chain hydrocarbon monoradical having one or more carbon-carbon triple-bonds and having from two to about ten carbon atoms, more preferably from two to about six carbon atoms. Examples include, but are not limited to ethynyl, 2-propynyl, 2-butynyl, 1, 3-butadiynyl and the like.
  • a numerical range such as “C 2 -C 6 alkynyl” or “C 2-6 alkynyl” means that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkynyl” where no numerical range is designated.
  • an alkynyl group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • the alkynyl is optionally substituted with oxo, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH 2 , or -NO 2 .
  • the alkynyl is optionally substituted with halogen, -CN, -OH, or -OMe.
  • the alkynyl is optionally substituted with halogen.
  • Alkylene refers to a straight or branched divalent hydrocarbon chain. Unless stated otherwise specifically in the specification, an alkylene group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkylene is optionally substituted with oxo, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH 2 , or -NO 2 . In some embodiments, the alkylene is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkylene is optionally substituted with halogen.
  • Alkoxy refers to a radical of the formula -OR a where R a is an alkyl radical as defined. Unless stated otherwise specifically in the specification, an alkoxy group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkoxy is optionally substituted with halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH 2 , or -NO 2 . In some embodiments, the alkoxy is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkoxy is optionally substituted with halogen.
  • Aryl refers to a radical derived from an aromatic monocyclic or aromatic multicyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom.
  • the aromatic monocyclic or aromatic multicyclic hydrocarbon ring system can contain only hydrogen and carbon and from five to eighteen carbon atoms, where at least one of the rings in the ring system is aromatic, i.e., it contains a cyclic, delocalized (4n+2) ⁇ –electron system in accordance with the Hückel theory.
  • the ring system from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin and naphthalene.
  • the aryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the aryl is bonded through an aromatic ring atom) or bridged ring systems.
  • the aryl is a 6-to 10-membered aryl.
  • the aryl is a 6-membered aryl (phenyl) .
  • Aryl radicals include, but are not limited to, aryl radicals derived from the hydrocarbon ring systems of anthrylene, naphthylene, phenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene.
  • an aryl may be optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • the aryl is optionally substituted with halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
  • the aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe. In some embodiments, the aryl is optionally substituted with halogen.
  • Carbocycle refers to a saturated, unsaturated, or aromatic rings in which each atom of the ring is carbon. Carbocycle may include 3-to 10-membered monocyclic rings, 6-to 12-membered bicyclic rings, and 6-to 12-membered bridged rings. Each ring of a bicyclic carbocycle may be selected from saturated, unsaturated, and aromatic rings. An aromatic ring, e.g., phenyl, may be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene. Any combination of saturated, unsaturated, and aromatic bicyclic rings, as valence permits, are included in the definition of carbocyclic.
  • Exemplary carbocycles include cyclopentyl, cyclohexyl, cyclohexenyl, adamantyl, phenyl, indanyl, and naphthyl. Unless stated otherwise specifically in the specification, a carbocycle may be optionally substituted.
  • Cycloalkyl refers to a partially or fully saturated, monocyclic, or polycyclic carbocyclic ring, which may include fused (when fused with an aryl or a heteroaryl ring, the cycloalkyl is bonded through a non-aromatic ring atom) , spiro, or bridged ring systems. In some embodiments, the cycloalkyl is fully saturated.
  • Representative cycloalkyls include, but are not limited to, cycloalkyls having from three to fifteen carbon atoms (e.g., C 3 -C 15 fully saturated cycloalkyl or C 3 -C 15 cycloalkenyl) , from three to ten carbon atoms (e.g., C 3 -C 10 fully saturated cycloalkyl or C 3 -C 10 cycloalkenyl) , from three to eight carbon atoms (e.g., C 3 -C 8 fully saturated cycloalkyl or C 3 -C 8 cycloalkenyl) , from three to six carbon atoms (e.g., C 3 -C 6 fully saturated cycloalkyl or C 3 -C 6 cycloalkenyl) , from three to five carbon atoms (e.g., C 3 -C 5 fully saturated cycloalkyl or C 3 -C 5 cycloalkenyl) , or three to four
  • the cycloalkyl is a 3-to 10-membered fully saturated cycloalkyl or a 3-to 10-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 3-to 6-membered fully saturated cycloalkyl or a 3-to 6-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 5-to 6-membered fully saturated cycloalkyl or a 5-to 6-membered cycloalkenyl.
  • Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • Polycyclic cycloalkyls include, for example, adamantyl, norbornyl, decalinyl, bicyclo [3.3.0] octane, bicyclo [4.3.0] nonane, cis-decalin, trans-decalin, bicyclo [2.1.1] hexane, bicyclo [2.2.1] heptane, bicyclo [2.2.2] octane, bicyclo [3.2.2] nonane, and bicyclo [3.3.2] decane, and 7, 7-dimethyl-bicyclo [2.2.1] heptanyl.
  • Partially saturated cycloalkyls include, for example cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.
  • a cycloalkyl is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
  • a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe.
  • the cycloalkyl is optionally substituted with halogen.
  • Cycloalkenyl refers to an unsaturated non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which includes fused or bridged ring systems, preferably having from three to twelve carbon atoms and comprising at least one double bond.
  • a cycloalkenyl comprises three to ten carbon atoms.
  • a cycloalkenyl comprises five to seven carbon atoms.
  • the cycloalkenyl may be attached to the rest of the molecule by a single bond. Examples of monocyclic cycloalkenyls includes, e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.
  • Halo or “halogen” refers to bromo, chloro, fluoro or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro.
  • haloalkyl or “haloalkane” refers to an alkyl radical, as defined above, that is substituted by one or more halogen radicals, for example, trifluoromethyl, dichloromethyl, bromomethyl, 2, 2, 2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like.
  • the alkyl part of the fluoroalkyl radical is optionally further substituted.
  • halogen substituted alkanes examples include halomethane (e.g., chloromethane, bromomethane, fluoromethane, iodomethane) , di-and trihalomethane (e.g., trichloromethane, tribromomethane, trifluoromethane, triiodomethane) , 1-haloethane, 2-haloethane, 1, 2-dihaloethane, 1-halopropane, 2-halopropane, 3-halopropane, 1, 2-dihalopropane, 1, 3-dihalopropane, 2, 3-dihalopropane, 1, 2, 3-trihalopropane, and any other suitable combinations of alkanes (or substituted alkanes) and halogens (e.g., Cl, Br, F, I, etc. ) .
  • halogen substituted alkanes e.g., Cl, Br, F, I, etc.
  • Fluoroalkyl refers to an alkyl radical, as defined above, that is substituted by one or more fluoro radicals, for example, trifluoromethyl, difluoromethyl, fluoromethyl, 2, 2, 2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like.
  • “Hydroxyalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more hydroxyls. In some embodiments, the alkyl is substituted with one hydroxyl. In some embodiments, the alkyl is substituted with one, two, or three hydroxyls. Hydroxyalkyl include, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl is hydroxymethyl.
  • Aminoalkyl refers to an alkyl radical, as defined above, that is substituted by one or more amines. In some embodiments, the alkyl is substituted with one amine. In some embodiments, the alkyl is substituted with one, two, or three amines. Aminoalkyl include, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl is aminomethyl.
  • Heteroalkyl refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g., -NH-, -N (alkyl) -) , sulfur, phosphorus, or combinations thereof.
  • a heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl.
  • a heteroalkyl is a C 1 -C 6 heteroalkyl wherein the heteroalkyl is comprised of 1 to 6 carbon atoms and one or more atoms other than carbon, e.g., oxygen, nitrogen (e.g.
  • heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl.
  • heteroalkyl are, for example, -CH 2 OCH 3 , -CH 2 CH 2 OCH 3 , -CH 2 CH 2 OCH 2 CH 2 OCH 3 , -CH (CH 3 ) OCH 3 , -CH 2 NHCH 3 , -CH 2 N (CH 3 ) 2 , -CH 2 CH 2 NHCH 3 , or -CH 2 CH 2 N (CH 3 ) 2 .
  • a heteroalkyl is optionally substituted for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
  • a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe. In some embodiments, the heteroalkyl is optionally substituted with halogen.
  • Heterocycloalkyl refers to a 3-to 24-membered partially or fully saturated ring radical comprising 2 to 23 carbon atoms and from one to 8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, silicon, and sulfur. In some embodiments, the heterocycloalkyl is fully saturated. In some embodiments, the heterocycloalkyl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heterocycloalkyl comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heterocycloalkyl comprises one to three nitrogens. In some embodiments, the heterocycloalkyl comprises one or two nitrogens.
  • the heterocycloalkyl comprises one nitrogen. In some embodiments, the heterocycloalkyl comprises one nitrogen and one oxygen.
  • the heterocycloalkyl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with an aryl or a heteroaryl ring, the heterocycloalkyl is bonded through a non-aromatic ring atom) , spiro, or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heterocycloalkyl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized.
  • heterocycloalkyls include, but are not limited to, heterocycloalkyls having from two to fifteen carbon atoms (e.g., C 2 -C 15 fully saturated heterocycloalkyl or C 2 -C 15 heterocycloalkenyl) , from two to ten carbon atoms (e.g., C 2 -C 10 fully saturated heterocycloalkyl or C 2 -C 10 heterocycloalkenyl) , from two to eight carbon atoms (e.g., C 2 -C 8 fully saturated heterocycloalkyl or C 2 -C 8 heterocycloalkenyl) , from two to seven carbon atoms (e.g., C 2 -C 7 fully saturated heterocycloalkyl or C 2 -C 7 heterocycloalkenyl) , from two to six carbon atoms (e.g., C 2 -C 6 fully saturated heterocycloalkyl or C 2 -C 6 heterocycloalkenyl) , from two to five carbon
  • heterocycloalkyl radicals include, but are not limited to, aziridinyl, azetidinyl, oxetanyl, dioxolanyl, thienyl [1, 3] dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl
  • heterocycloalkyl also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides, and the oligosaccharides.
  • heterocycloalkyls have from 2 to 10 carbons in the ring. It is understood that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including the heteroatoms) that make up the heterocycloalkyl (i.e. skeletal atoms of the heterocycloalkyl ring) .
  • the heterocycloalkyl is a 3-to 8-membered fully saturated heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3-to 7-membered fully saturated heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3-to 6-membered fully saturated heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 4-to 6-membered fully saturated heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 5-to 6-membered fully saturated heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3-to 8-membered heterocycloalkenyl.
  • the heterocycloalkyl is a 3-to 7-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3-to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 4-to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 5-to 6-membered heterocycloalkenyl.
  • a heterocycloalkyl may be optionally substituted as described below, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • the heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
  • the heterocycloalkyl is optionally substituted with halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe. In some embodiments, the heterocycloalkyl is optionally substituted with halogen.
  • Heteroaryl refers to a 5-to 14-membered ring system radical comprising one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, and sulfur, and at least one aromatic ring.
  • the heteroaryl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur.
  • the heteroaryl comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen.
  • the heteroaryl comprises one to three nitrogens.
  • the heteroaryl comprises one or two nitrogens.
  • the heteroaryl comprises one nitrogen.
  • the heteroaryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the heteroaryl is bonded through an aromatic ring atom) or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heteroaryl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized.
  • the heteroaryl is a 5-to 10-membered heteroaryl.
  • the heteroaryl is a 5-to 6-membered heteroaryl.
  • the heteroaryl is a 6-membered heteroaryl.
  • the heteroaryl is a 5-membered heteroaryl.
  • examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo [b] [1, 4] dioxepinyl, 1, 4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl) , benzotriazolyl, benzo [4, 6] imidazo [1, 2-a] pyridinyl, carbazolyl, cinnolinyl,
  • a heteroaryl may be optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • the heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
  • the heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe. In some embodiments, the heteroaryl is optionally substituted with halogen.
  • substituted refers to moieties having substituents replacing a hydrogen on one or more carbons or substitutable heteroatoms, e.g., NH, of the structure. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, i.e., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc.
  • substituted refers to moieties having substituents replacing two hydrogen atoms on the same carbon atom, such as substituting the two hydrogen atoms on a single carbon with an oxo, imino or thioxo group.
  • substituted is contemplated to include all permissible substituents of organic compounds.
  • the permissible substituents include acyclic and cyclic, branched, and unbranched, carbocyclic, and heterocyclic, aromatic, and non-aromatic substituents of organic compounds.
  • the permissible substituents can be one or more and the same or different for appropriate organic compounds.
  • the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms.
  • one or more when referring to an optional substituent means that the subject group is optionally substituted with one, two, three, or four substituents. In some embodiments, the subject group is optionally substituted with one, two, or three substituents. In some embodiments, the subject group is optionally substituted with one or two substituents. In some embodiments, the subject group is optionally substituted with one substituent. In some embodiments, the subject group is optionally substituted with two substituents.
  • salt or “pharmaceutically acceptable salt” refers to salts derived from a variety of organic and inorganic counter ions well known in the art.
  • Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids.
  • Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
  • Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.
  • Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.
  • Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like.
  • Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine.
  • the pharmaceutically acceptable base addition salt is chosen from ammonium, potassium, sodium, calcium, and magnesium salts.
  • parenteral administration and “administered parenterally” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.
  • phrases “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • phrases “pharmaceutically acceptable excipient” or “pharmaceutically acceptable carrier” as used herein means a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
  • materials which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide;
  • an “effective amount” or “therapeutically effective amount” refers to an amount of a compound administered to a mammalian subject, either as a single dose or as part of a series of doses, which is effective to produce a desired therapeutic effect.
  • treat, ” “treating” or “treatment, ” as used herein, include alleviating, abating, or ameliorating at least one symptom of a disease or condition, preventing additional symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition.
  • Described herein are compounds, or a pharmaceutically acceptable salts or solvates thereof useful in the treatment of neurodegenerative disorders.
  • the disclosure provides a compound represented by Formula (I” ) , or a pharmaceutically acceptable salt or solvate thereof:
  • ring C is 4 to 10-membered heterocycloalkyl or 4 to 10-membered heterocycloalkenylene;
  • each R 1 is independently hydrogen, halogen, -CN, -NO 2 , -OH, -OR a , -SH, -SR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 aminoalkyl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, or aminoalkyl is optionally substituted with 1 to 4 substituents independently selected from R e ; or
  • R 1 two R 1 are taken together to form a bond, C 1 -C 3 alkylene, or C 1 -C 3 heteroalkylene, wherein the alkylene or heteroalkylene is optionally substituted with 1 to 4 substituents independently selected from R e ; or
  • R 1 two R 1 are taken together to form a C 3 -C 6 cycloalkyl or 4 to 6-membered heterocycloalkyl, each of which is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • each R 2 is independently hydrogen, halogen, -OH, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 aminoalkyl; or
  • X is absent, -CH 2 -, -O-, -OCH 2 -, or -NR 3 -;
  • R 3 is hydrogen, C 1 -C 3 alkyl, C 1 -C 3 hydroxyalkyl, C 1 -C 3 haloalkyl, or C 3 -C 6 cycloalkyl;
  • each A is independently N or CR 4 , wherein at least two of A are N;
  • each R 4 is independently hydrogen, halogen, -CN, -NO 2 , -OH, -OR a , -SH, -SR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 aminoalkyl;
  • R 3 and one of R 4 are taken together to form a 5 or 6-membered heterocycloalkylene or 5 or 6-membered heteroarylene;
  • B is N or CR 5 ;
  • D is N or CR 6 ;
  • E is N or CR 7 ;
  • F is N or CR 8 ;
  • R 5 , R 6 , R 7 or R 8 is C 2 -C 6 alkene, C 3 -C 6 cycloalkyl, 4 to 6 membered heterocycloalkyl, 5 to 10-membered heteroaryl, or -O- (C 1 -C 6 alkylene) -5 to 10-membered heteroaryl, wherein the alkene, cycloalkyl, heterocycloalkyl and heteroaryl is optionally substituted with 1 to 4 substituents selected from R e ;
  • each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • R c and R d are each independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • p is an integer from 1-9.
  • the disclosure provides a compound represented by Formula (I’ ) , or a pharmaceutically acceptable salt or solvate thereof:
  • ring C is 4 to 10-membered heterocycloalkyl or 4 to 10-membered heterocycloalkenylene;
  • each R 1 is independently hydrogen, halogen, -CN, -NO 2 , -OH, -OR a , -SH, -SR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 aminoalkyl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, or aminoalkyl is optionally substituted with 1 to 4 substituents independently selected from R e ; or
  • R 1 two R 1 are taken together to form a bond, C 1 -C 3 alkylene or C 1 -C 3 heteroalkylene, wherein the alkylene or heteroalkylene is optionally substituted with 1 to 4 substituents independently selected from R e ; or
  • R 1 two R 1 are taken together to form a C 3 -C 6 cycloalkyl or 4 to 6-membered heterocycloalkyl, each of which is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • each R 2 is independently hydrogen, halogen, -OH, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 aminoalkyl; or
  • X is absent, -CH 2 -, -O-, -S-, or -NR 3 -;
  • R 3 is hydrogen, C 1 -C 3 alkyl, C 1 -C 3 hydroxyalkyl, C 1 -C 3 haloalkyl, or C 3 -C 6 cycloalkyl;
  • each A is independently N or CR 4 , wherein at least two of A are N;
  • each R 4 is independently hydrogen, halogen, -CN, -NO 2 , -OH, -OR a , -SH, -SR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 aminoalkyl;
  • B is N or CR 5 ;
  • D is N or CR 6 ;
  • E is N or CR 7 ;
  • F is N or CR 8 ;
  • each R 10 is independently halogen, -CN, -NO 2 , -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 3 -C 6 cycloalkyl, or 4 to 6-membered heterocycloalkyl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, heteroalkyl, cycloalkyl and heterocycloalkyl is optionally substituted with 1 to 4-substituents independently selected from R e ; or
  • each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • R c and R d are each independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • p is an integer from 1-9.
  • each R 2 is independently hydrogen, halogen, -OH, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 aminoalkyl. In some embodiments of Formula (I” ) , (I’ ) , or (I) , each R 2 is independently halogen.
  • each R 2 is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 aminoalkyl. In some embodiments of Formula (I” ) , (I’ ) , or (I) , each R 2 is independently C 1 -C 6 alkyl. In some embodiments of Formula (I” ) , (I’ ) , or (I) , each R 2 is independently C 1 -C 6 haloalkyl.
  • each R 2 is independently C 1 -C 6 hydroxyalkyl. In some embodiments of Formula (I” ) , (I’ ) , or (I) , each R 2 is independently C 1 -C 6 aminoalkyl. In some embodiments of Formula (I”) , (I’ ) , or (I) , each R 2 is independently -OH. In some embodiments of Formula (I” ) , (I’ ) , or (I) , each R 2 is independently hydrogen.
  • D is CR 6 . In some embodiments of Formula (I”) , (I’ ) , or (I) , D is N.
  • R 6 is a 5 to 8-membered heteroaryl optionally substituted with 1 to 4 substituents independently selected from R 10 ; and R 7 is hydrogen, halogen, -OH, -OR a , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • R 6 is a 5 to 8-membered heteroaryl optionally substituted with 1 to 4 substituents independently selected from R 10 ; and R 7 is hydrogen, halogen, or C 1 -C 6 alkyl.
  • R 6 is a 5 to 8-membered heteroaryl optionally substituted with 1 to 4 substituents independently selected from R 10 ; and R 7 is hydrogen.
  • R 7 is a 5 to 8-membered heteroaryl optionally substituted with 1 to 4 substituents independently selected from R 10 ; and R 6 is hydrogen, halogen, -OH, -OR a , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • R 7 is a 5 to 8-membered heteroaryl optionally substituted with 1 to 4 substituents independently selected from R 10 ; and R 6 is hydrogen, halogen, or C 1 -C 6 alkyl.
  • R 7 is a 5 to 8-membered heteroaryl optionally substituted with 1 to 4 substituents independently selected from R 10 ; and R 6 is hydrogen.
  • ring C is a 4 to 10-membered heterocycloalkenylene. In some embodiments of Formula (I” ) , (I’ ) , or (I) , ring C is a 4 to 8-membered heterocycloalkenylene. In some embodiments of Formula (I” ) , (I’ ) , or (I) , ring C is a 4 to 6-membered heterocycloalkenylene. In some embodiments of Formula (I” ) , (I’ ) , or (I) , ring C is a 6-membered heterocycloalkenylene.
  • ring C is a 7-membered heterocycloalkenylene. In some embodiments of Formula (I” ) , (I’ ) , or (I) , ring C is a 8-membered heterocycloalkenylene.
  • ring C is a is a 4 to 10-membered heterocycloalkyl. In some embodiments of Formula (I” ) , (I’ ) , or (I) , ring C is a is a 4 to 8-membered heterocycloalkyl. In some embodiments of Formula (I” ) , (I’ ) , or (I) , ring C is a is a 4 to 6-membered heterocycloalkyl. In some embodiments of Formula (I” ) , (I’ ) , or (I) , ring C is a 4-membered heterocycloalkyl.
  • ring C is a 5-membered heterocycloalkyl. In some embodiments of Formula (I” ) , (I’ ) , or (I) , ring C is a 6-membered heterocycloalkyl. In some embodiments of Formula (I” ) , (I’ ) , or (I) , ring C is a 7-membered heterocycloalkyl. In some embodiments of Formula (I” ) , (I’ ) , or (I) , ring C is a 8-membered heterocycloalkyl.
  • ring C is piperidine, piperazine, or morpholine. In some embodiments of Formula (I” ) , (I’ ) , or (I) , ring C is piperidine. In some embodiments of Formula (I”) , (I’ ) , or (I) , ring C is piperazine. In some embodiments of Formula (I” ) , (I’ ) , or (I) , ring C is morpholine.
  • Z is CH or N
  • each R 1 is independently hydrogen, halogen, -CN, -NO 2 , -OH, -OR a , -SH, -SR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 aminoalkyl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, or aminoalkyl is optionally substituted with 1 to 4 substituents independently selected from R e ; or
  • R 1 two R 1 are taken together to form a bond, C 1 -C 3 alkylene, or C 1 -C 3 heteroalkylene, wherein the alkylene or heteroalkylene is optionally substituted with 1 to 4 substituents independently selected from R e ; or
  • R 1 two R 1 are taken together to form a C 3 -C 6 cycloalkyl or 4 to 6-membered heterocycloalkyl, each of which is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • R 9 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, or 4 to 6-membered heterocycloalkyl, wherein each alkyl, haloalkyl, cycloalkyl and heterocycloalkyl is independently substituted with 1 to 4 substituents selected from R e ;
  • each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • R c and R d are each independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 4 substituents independently selected from R e ; and
  • each R 1 is independently hydrogen, halogen, -CN, -NO 2 , -OH, -OR a , -SH, -SR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 aminoalkyl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, or aminoalkyl is optionally substituted with 1 to 4 substituents independently selected from R e ; or
  • R 1 two R 1 are taken together to form a bond, C 1 -C 3 alkylene, or C 1 -C 3 heteroalkylene, wherein the alkylene or heteroalkylene is optionally substituted with 1 to 4 substituents independently selected from R e ; or
  • R 1 two R 1 are taken together to form a C 3 -C 6 cycloalkyl or 4 to 6-membered heterocycloalkyl, each of which is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • R 9 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, or 4 to 6-membered heterocycloalkyl, wherein each alkyl, haloalkyl, cycloalkyl and heterocycloalkyl is independently substituted with 1 to 4 substituents selected from R e ;
  • each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • R c and R d are each independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 4 substituents independently selected from R e ; and
  • each R 1 is independently hydrogen, halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, or aminoalkyl is optionally substituted with 1 to 4 substituents independently selected from R e ; or
  • R 1 two R 1 are taken together to form a C 1 -C 3 alkylene or C 1 -C 3 heteroalkylene, wherein the alkylene or heteroalkylene is optionally substituted with 1 to 4 substituents independently selected from R e ; or
  • R 9 is hydrogen
  • each R 1 is independently hydrogen or C 1 -C 6 alkyl
  • R 9 is hydrogen
  • the disclosure provides a compound represented by Formula (II’ ) , or a pharmaceutically acceptable salt or solvate thereof:
  • ring G is a 5 to 10-membered heteroaryl
  • each R 1 is independently hydrogen, halogen, -CN, -NO 2 , -OH, -OR a , -SH, -SR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 aminoalkyl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, or aminoalkyl is optionally substituted with 1 to 4 substituents independently selected from R e ; or
  • R 1 two R 1 are taken together to form a bond, C 1 -C 3 alkylene, or C 1 -C 3 heteroalkylene, wherein the alkylene or heteroalkylene is optionally substituted with 1 to 4 substituents independently selected from R e ; or
  • R 1 two R 1 are taken together to form a C 3 -C 6 cycloalkyl or 4 to 6-membered heterocycloalkyl, each of which is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • X is bond, -CH 2 -, -O-, -S-, or -NR 3 -, wherein
  • R 3 is hydrogen, C 1 -C 3 alkyl, C 1 -C 3 hydroxyalkyl, C 1 -C 3 haloalkyl, or C 3 -C 6 cycloalkyl;
  • Z is CH or N, when X is -O-, -S-, or -NR 3 -, then Z is CH;
  • each A is independently N or CR 4 , wherein at least two of A are N;
  • each R 4 is independently hydrogen, halogen, -CN, -NO 2 , -OH, -OR a , -SH, -SR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 aminoalkyl;
  • B is N or CR 5 ;
  • E is N or CR 7 ;
  • F is N or CR 8 ;
  • R 9 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, or 4 to 6-membered heterocycloalkyl, wherein each alkyl, haloalkyl, cycloalkyl and heterocycloalkyl is independently substituted with 1 to 4 substituents selected from R e ;
  • each R 10 is independently halogen, -CN, -NO 2 , -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 aminoalkyl, C 3 -C 6 cycloalkyl, or 4 to 6-membered heterocycloalkyl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, heteroalkyl, cycloalkyl and heterocycloalkyl is optionally substituted with 1 to 4-substituents independently selected from R e ; or
  • each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • R c and R d are each independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • q 0, 1, 2, or 3.
  • Formula (I” ) , (I’ ) , or (II’ ) two of A are N. In some embodiments of Formula (I” ) , (I’ ) , or (II’ ) , three of A are N. In some embodiments of Formula (I” ) , (I’ ) , or (II’ ) , each A is N. In some embodiments of Formula (I” ) , (I’ ) , (I) , (II) , or (II’ ) , is
  • the disclosure provides a compound represented by Formula (III’ ) , or a pharmaceutically acceptable salt or solvate thereof:
  • ring G is a 5 to 10-membered heteroaryl
  • each R 1 is independently hydrogen, halogen, -CN, -NO 2 , -OH, -OR a , -SH, -SR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 aminoalkyl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, or aminoalkyl is optionally substituted with 1 to 4 substituents independently selected from R e ; or
  • R 1 two R 1 are taken together to form a bond, C 1 -C 3 alkylene, or C 1 -C 3 heteroalkylene, wherein the alkylene or heteroalkylene is optionally substituted with 1 to 4 substituents independently selected from R e ; or
  • R 1 two R 1 are taken together to form a C 3 -C 6 cycloalkyl or 4 to 6-membered heterocycloalkyl, each of which is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • X is -CH 2 -, -O-, -S-, or -NR 3 -;
  • R 3 is hydrogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 hydroxyalkyl, or C 3 -C 6 cycloalkyl;
  • A is N or CH
  • B is N or CR 5 ;
  • E is N or CR 7 ;
  • F is N or CR 8 ;
  • R 9 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, or 4 to 6-membered heterocycloalkyl, wherein each alkyl, haloalkyl, cycloalkyl and heterocycloalkyl is independently substituted with 1 to 4 substituents selected from R e ;
  • each R 10 is independently halogen, -CN, -NO 2 , -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 aminoalkyl, C 3 -C 6 cycloalkyl, or 4 to 6-membered heterocycloalkyl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, heteroalkyl, cycloalkyl and heterocycloalkyl is optionally substituted with 1 to 4-substituents independently selected from R e ; or
  • each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • R c and R d are each independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • q 0, 1, 2, or 3.
  • R 9 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, or 4 to 6-membered heterocycloalkyl, wherein each alkyl, haloalkyl, cycloalkyl and heterocycloalkyl is independently substituted with 1 to 4 substituents selected from R e .
  • R 9 is hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of Formula (II) , (II’ ) , (III) , or (III’ ) , R 9 is hydrogen or C 1 -C 6 alkyl. In some embodiments of Formula (II) , (II’ ) , (III) , or (III’ ) , R 9 is C 1 -C 6 haloalkyl.
  • R 9 is C 1 -C 6 alkyl. In some embodiments of Formula (II) , (II’ ) , (III) , or (III’ ) , R 9 is hydrogen.
  • two R 1 are taken together to form a bond, C 1 -C 3 alkylene or C 1 -C 3 heteroalkylene, wherein the alkylene or heteroalkylene is optionally substituted with 1 to 4 substituents independently selected from R e .
  • two R 1 are taken together to form a bond.
  • two R 1 are taken together to form a C 1 -C 3 alkylene.
  • two R 1 are taken together to form or a C 1 -C 3 heteroalkylene.
  • the compound of Formula (III’ ) has the structure of Formula (IIIa’ ) , or a pharmaceutically acceptable salt or solvate thereof:
  • Y is C 1 -C 3 alkylene
  • ring G is a 5 to 10-membered heteroaryl
  • each R 1 is independently hydrogen, halogen, -CN, -NO 2 , -OH, -OR a , -SH, -SR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 aminoalkyl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, or aminoalkyl is optionally substituted with 1 to 4 substituents independently selected from R e ; or
  • X is -CH 2 -, -O-, or -NR 3 -, wherein
  • R 3 is hydrogen, C 1 -C 3 alkyl, C 1 -C 3 hydroxyalkyl, C 1 -C 3 haloalkyl, or C 3 -C 6 cycloalkyl;
  • A is N or CH
  • B is N or CR 5 ;
  • E is N or CR 7 ;
  • F is N or CR 8 ;
  • each R 10 is independently halogen, -CN, -NO 2 , -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 aminoalkyl, C 3 -C 6 cycloalkyl, or 4 to 6-membered heterocycloalkyl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, heteroalkyl, cycloalkyl and heterocycloalkyl is optionally substituted with 1 to 4-substituents independently selected from R e ; or
  • each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • R c and R d are each independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • q 0, 1, 2, or 3.
  • Y is -CH 2 CH 2 CH 2 -. In some embodiments of Formula (IIIa’ ) , Y is -CH 2 CH 2 -. In some embodiments of Formula (IIIa’ ) , Y is -CH 2 -.
  • the compound of Formula (III’ ) has the structure of Formula (IIIb’ ) , or a pharmaceutically acceptable salt or solvate thereof:
  • ring G is a 5 to 10-membered heteroaryl
  • each R 1 is independently hydrogen, halogen, -CN, -NO 2 , -OH, -OR a , -SH, -SR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 aminoalkyl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, or aminoalkyl is optionally substituted with 1 to 4 substituents independently selected from R e ; or
  • R 1 two R 1 are taken together to form a C 3 -C 6 cycloalkyl or 4 to 6-membered heterocycloalkyl, each of which is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • X is -CH 2 -, -O-, -S-, or -NR 3 -, wherein
  • R 3 is hydrogen, C 1 -C 3 alkyl, C 1 -C 3 hydroxyalkyl, C 1 -C 3 haloalkyl, or C 3 -C 6 cycloalkyl;
  • A is N or CH
  • B is N or CR 5 ;
  • E is N or CR 7 ;
  • F is N or CR 8 ;
  • each R 10 is independently halogen, -CN, -NO 2 , -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 aminoalkyl, C 3 -C 6 cycloalkyl, or 4 to 6-membered heterocycloalkyl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, heteroalkyl, cycloalkyl and heterocycloalkyl is optionally substituted with 1 to 4-substituents independently selected from R e ; or
  • each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • R c and R d are each independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • q 0, 1, 2, or 3.
  • Formula (II’ ) when X is -O-, -S-, or -NR 3 -, then Z is CH. In some embodiments of Formula (II) or (II’ ) , when X is bond, then Z is CH or N. In some embodiments of Formula (II) or (II’ ) , when X is bond, then Z is N. In some embodiments of Formula (II) or (II’ ) , when X is -CH 2 -, then Z is CH or N. In some embodiments of Formula (II) or (II’ ) , when X is -CH 2 -, then Z is CH. In some embodiments of Formula (II) or (II’ ) , when X is -CH 2 -, then Z is N. In some embodiments of Formula (II) or (II’ ) , when X is -CH 2 -, then Z is N.
  • X is -O-, -S-, or -NR 3 -.
  • X is -O-or -NR 3 -.
  • X is -S-.
  • X is -O-.
  • X is -NR 3 -.
  • X is -NH-.
  • X is -NCH 3 -.
  • X is -CH 2 . In some embodiments of Formula (I” ) , X is -OCH 2 -.
  • X is absent.
  • R 3 is hydrogen, C 1 -C 3 alkyl, or C 1 -C 3 hydroxyalkyl. In some embodiments of Formula (I” ) , (I’ ) , (II’ ) , (IIIa’ ) , or (IIIb) , R 3 is C 3 -C 6 cycloaalkyl.
  • R 3 is cyclopropyl or cyclobutyl. In some embodiments of Formula (I” ) , (I’ ) , (II’ ) , (III’ ) , (IIIa’ ) , or (IIIb’ ) , R 3 is cyclopropyl.
  • R 3 is hydrogen or C 1 -C 3 alkyl. In some embodiments of Formula (I” ) , (I’ ) , (I) , (II) , (II’ ) , (III) , (III’ ) , (IIIa) , (IIIa’ ) , (IIIb) , or (IIIb’ ) , R 3 is C 1 -C 3 hydroxyalkyl.
  • R 3 is C 1 -C 3 haloalkyl. In some embodiments of Formula (I” ) , (I’ ) , (I) , (II) , (II’ ) , (III) , (III’ ) , (IIIa) , (IIIa’ ) , (IIIb) , or (IIIb’ ) , R 3 is C 1 -C 3 alkyl.
  • R 3 is hydrogen or methyl. In some embodiments of Formula (I” ) , (I’ ) , (I) , (II) , (II’ ) , (III) , (III’ ) , (IIIa) , (IIIa’ ) , (IIIb) , or (IIIb’ ) , R 3 is methyl.
  • R 3 is hydrogen.
  • the disclosure provides a compound represented by Formula (IV’ ) , or a pharmaceutically acceptable salt or solvate thereof:
  • ring G is a 5 to 10-membered heteroaryl
  • each R 1 is independently hydrogen, halogen, -CN, -NO 2 , -OH, -OR a , -SH, -SR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 aminoalkyl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, or aminoalkyl is optionally substituted with 1 to 4 substituents independently selected from R e ; or
  • R 1 two R 1 are taken together to form a bond, C 1 -C 3 alkylene, or C 1 -C 3 heteroalkylene, wherein the alkylene or heteroalkylene is optionally substituted with 1 to 4 substituents independently selected from R e ; or
  • R 1 two R 1 are taken together to form a C 3 -C 6 cycloalkyl or 4 to 6-membered heterocycloalkyl, each of which is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • Z is CH or N
  • A is N or CH
  • B is N or CR 5 ;
  • E is N or CR 7 ;
  • F is N or CR 8 ;
  • R 9 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, or 4 to 6-membered heterocycloalkyl, wherein each alkyl, haloalkyl, cycloalkyl and heterocycloalkyl is independently substituted with 1 to 4 substituents selected from R e ;
  • each R 10 is independently halogen, -CN, -NO 2 , -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 aminoalkyl, C 3 -C 6 cycloalkyl, or 4 to 6-membered heterocycloalkyl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, heteroalkyl, cycloalkyl and heterocycloalkyl is optionally substituted with 1 to 4-substituents independently selected from R e ; or
  • each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • R c and R d are each independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • q 0, 1, 2, or 3.
  • Z is N. In some embodiments of Formula (II) , (II’ ) , (IV) , or (IV’ ) , Z is CH.
  • At least one of A is N.
  • each A is N.
  • each A is independently CR 4 .
  • each A is independently N or CH.
  • each A is CH.
  • E is CR 7 .
  • F is CR 8 .
  • each R 1 is independently hydrogen, halogen, -CN, -NO 2 , -OH, -OR a , -SH, -SR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 aminoalkyl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, or aminoalkyl is optionally substituted with 1 to 4 substituents independently selected from R e .
  • each R 1 is independently hydrogen, halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, or aminoalkyl is optionally substituted with 1 to 4 substituents independently selected from R e .
  • each R 1 is independently hydrogen, halogen, or C 1 -C 6 alkyl.
  • each R 1 is independently C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • each R 1 is independently -CH 3 , -CH 2 CH 3 , -CH (CH 3 ) 2 , -CF 3 , or -CHF 2 .
  • each R 1 is independently hydrogen, -CH 3 , -CH 2 CH 3 , or -CH (CH 3 ) 2 .
  • each R 1 is independently halogen.
  • each R 1 is independently Cl, Br, or F.
  • each R 1 is independently F.
  • each R 1 is independently hydrogen.
  • two R 1 are taken together to form a C 3 -C 6 cycloalkyl.
  • two R 1 are taken together to form a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • two R 1 are taken together to form a cyclopropyl.
  • two R 1 are taken together to form a cyclobutyl.
  • two R 1 are taken together to form a cyclopentyl.
  • two R 1 are taken together to form a cyclohexyl.
  • each R 4 is independently hydrogen, halogen, -CN, -NO 2 , -OH, -OR a , -SH, -SR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 aminoalkyl.
  • each R 4 is independently hydrogen, halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 aminoalkyl.
  • each R 4 is independently hydrogen, halogen, -OH, -OR a , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 hydroxyalkyl.
  • each R 4 is independently hydrogen, halogen, or C 1 -C 6 alkyl.
  • each R 4 is independently halogen. In some embodiments of Formula (I” ) , (I’ ) , (I) , (II) , or (II’ ) , each R 4 is independently C 1 -C 6 alkyl. In some embodiments of Formula (I” ) , (I’ ) , (I) , (II) , or (II’ ) , each R 4 is independently hydrogen.
  • R 3 and one of R 4 are taken together to form a 5 or 6-membered heterocycloalkylene or 5 or 6-membered heteroarylene.
  • R 5 , R 6 , R 7 or R 8 are independently hydrogen, halogen, -CN, -NO 2 , C 1 -C 6 alkyl, C 2 -C 6 alkene, C 2 -C 6 alkyne, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, 4 to 6-membered heterocycloalkyl, or 5 to 10-membered heteroaryl.
  • R 5 , R 6 , R 7 or R 8 are independently hydrogen, halogen, -CN, C 3 -C 6 cycloalkyl, or 5 to 10-membered heteroaryl.
  • R 5 is 5 to 10-membered heteroaryl
  • R 6 , R 7 and R 8 are independently hydrogen, halogen, -CN, -NO 2 , C 1 -C 6 alkyl, C 2 -C 6 alkene, C 2 -C 6 alkyne, or C 1 -C 6 haloalkyl.
  • R 6 is 5 to 10-membered heteroaryl; and R 5 , R 7 and R 8 are independently hydrogen, halogen, -CN, -NO 2 , C 1 -C 6 alkyl, C 2 -C 6 alkene, C 2 -C 6 alkyne, or C 1 -C 6 haloalkyl.
  • R 7 is 5 to 10-membered heteroaryl; and R 5 , R 6 and R 8 are independently hydrogen, halogen, -CN, -NO 2 , C 1 -C 6 alkyl, C 2 -C 6 alkene, C 2 -C 6 alkyne, or C 1 -C 6 haloalkyl.
  • R 8 is 5 to 10-membered heteroaryl; and R 5 , R 6 and R 7 are independently hydrogen, halogen, -CN, -NO 2 , C 1 -C 6 alkyl, C 2 -C 6 alkene, C 2 -C 6 alkyne, or C 1 -C 6 haloalkyl.
  • B is CR 5 , wherein R 5 is C 2 -C 6 alkene, C 3 -C 6 cycloalkyl, 4 to 6-membered heterocycloalkyl, or 5 to 10-membered heteroaryl, wherein the alkene, cycloalkyl, heterocycloalkyl and heteroaryl is optionally substituted with 1 to 4 substituents selected from R e ; and F is N.
  • D is CR 6 , wherein R 6 is C 2 -C 6 alkene, C 3 -C 6 cycloalkyl, 4 to 6-membered heterocycloalkyl, or 5 to 10-membered heteroaryl, wherein the alkene, cycloalkyl, heterocycloalkyl and heteroaryl is optionally substituted with 1 to 4 substituents selected from R e ; and E is N.
  • D is CR 6 , wherein R 6 is C 2 -C 6 alkene, C 3 -C 6 cycloalkyl, 4 to 6-membered heterocycloalkyl, or 5 to 10-membered heteroaryl, wherein the alkene, cycloalkyl, heterocycloalkyl and heteroaryl is optionally substituted with 1 to 4 substituents selected from R e ; and F is N.
  • D is CR 6 , wherein R 6 is C 2 -C 6 alkene, C 3 -C 6 cycloalkyl, 4 to 6-membered heterocycloalkyl, or 5 to 10-membered heteroaryl, wherein the alkene, cycloalkyl, heterocycloalkyl and heteroaryl is optionally substituted with 1 to 4 substituents selected from R e ; B is N; and F is N.
  • D is CR 6 , wherein R 6 is C 2 -C 6 alkene, C 3 -C 6 cycloalkyl, 4 to 6-membered heterocycloalkyl, or 5 to 10-membered heteroaryl, wherein the alkene, cycloalkyl, heterocycloalkyl and heteroaryl is optionally substituted with 1 to 4 substituents selected from R e ; E is N; and F is N.
  • F is CR 8 , wherein R 8 is C 2 -C 6 alkene, C 3 -C 6 cycloalkyl, 4 to 6-membered heterocycloalkyl, or 5 to 10-membered heteroaryl, wherein the alkene, cycloalkyl, heterocycloalkyl and heteroaryl is optionally substituted with 1 to 4 substituents selected from R e ; and E is N.
  • R 5 is hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 aminoalkyl.
  • R 5 C 1 -C 6 alkyl In some embodiments of Formula (I”) , (I’ ) , (I) , (II) , (II’ ) , (III) , (III’ ) , (IIIa) , (IIIa’ ) , (IIIb) , (IIIb’ ) , (IV) , or (IV’ ) , R 5 C 1 -C 6 alkyl.
  • R 5 is C 1 -C 6 haloalkyl.
  • R 5 is halogen or hydrogen.
  • R 5 is halogen.
  • R 5 is hydrogen.
  • R 5 is fluorine.
  • R 5 is chlorine.
  • R 6 is hydrogen, halogen, -CN, -NO 2 , -OH, -OR a , -SH, -SR a , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 aminoalkyl; wherein each of the alkyl, haloalkyl, and hydroxyalkyl, and aminoalkyl is optionally substituted with 1 to 4 substituents independently selected from R e .
  • R 6 is hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 aminoalkyl.
  • R 6 is C 1 -C 6 alkyl.
  • R 6 is C 1 -C 6 haloalkyl.
  • R 6 is C 1 -C 6 hydroxyalkyl.
  • R 6 is halogen or hydrogen.
  • R 6 is halogen.
  • R 6 is hydrogen.
  • R 7 is hydrogen, halogen, -CN, -NO 2 , -OH, -OR a , -SH, -SR a , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 aminoalkyl; wherein each of the alkyl, haloalkyl, and hydroxyalkyl, and aminoalkyl is optionally substituted with 1 to 4 substituents independently selected from R e .
  • R 7 is hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 aminoalkyl.
  • R 7 is C 1 -C 6 alkyl.
  • R 7 is C 1 -C 6 haloalkyl.
  • R 7 is C 1 -C 6 hydroxyalkyl.
  • R 7 is halogen or hydrogen.
  • R 7 is halogen.
  • R 7 is hydrogen.
  • R 7 is flourine.
  • R 7 is chlorine.
  • R 7 is hydroxyl. In some embodiments of Formula (I’ ) , (I) , (II) , (III) , (IIIa) , (IIIb) , (IIIb’ ) , (IV) , or (IV’ ) , R 7 is methoxy.
  • R 8 is hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 aminoalkyl.
  • R 8 is C 1 -C 6 alkyl.
  • R 8 is C 1 -C 6 haloalkyl.
  • R 8 is C 1 -C 6 hydroxyalkyl.
  • R 8 is halogen or hydrogen.
  • R 8 is halogen.
  • R 8 is hydrogen.
  • R 8 is flourine.
  • R 8 is chlorine.
  • ring G is a 5 to 6-membered heteroaryl optional substituted with 1 or 4 substituents selected from R 10 .
  • ring G is a 5-membered heteroaryl optional substituted with 1 or 2 substituents selected from R 10 .
  • ring G is pyrrole, imidazole, triazole, tetrazole, thiophene, oxazole, thiazole, or thiadiazole.
  • ring G is pyrrole, imidazole, oxazole, triazole, thiazole, or thiadiazole.
  • ring G is pyrrole, imidazole, oxazole, or thiadiazole.
  • ring G is pyrrole.
  • ring G is imidazole.
  • ring G is thiadiazole.
  • ring G is oxazole.
  • ring G is:
  • each R 10 is independently halogen, -CN, -NO 2 , -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 3 -C 6 cycloalkyl, or 4 to 6-membered heterocycloalkyl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, cycloalkyl and heterocycloalkyl is optionally substituted with 1 to 4-substituents independently selected from R e ;
  • each R 10a is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, or 4 to 6-membered heterocycloalkyl, wherein each of the alkyl, haloalkyl, cycloalkyl and heterocycloalkyl is optionally substituted with 1 to 4-substituents independently selected from R e ; and
  • q 0, 1, 2, or 3.
  • each R10 is independently halogen, -CN, -NO2, -OH, -ORa, C1 C6alkyl, C1 C6haloalkyl, C3-C6cycloalkyl, or 4 to 6-membered heterocycloalkyl; each R 10a is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, or 4 to 6-membered heterocycloalkyl; and p is 0, 1, or 2.
  • Formula (II) , (II’ ) , (III) , (III’ ) , (IIIa) , (IIIa’ ) , (IIIb) , (IIIb’ ) , (IV) , or (IV’ ) is: In some embodiments of Formula (II) , (II’ ) , (III) , (III’ ) , (IIIa) , (IIIa’ ) , (IIIb) , (IIIb’ ) , (IV) , or (IV’ ) , is: In some embodiments of Formula (II) , (II’ ) , (III) , (III’ ) , (IIIa) , (IIIa’ ) , (IIIb) , (IIIb’ ) , (IV) , or (IV’ ) , is: In some embodiments of Formula (II) , (II’ ) , (III) , (III’ ) , (III’
  • ring G is a 6-membered heteroaryl optional substituted with 1 to 4 substituents selected from R 10 .
  • ring G is pyridine, pyrimidine, or triazine.
  • ring G is pyridine.
  • ring G is:
  • each R 10 is independently halogen, -CN, -NO 2 , -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 3 -C 6 cycloalkyl, or 4 to 6-membered heterocycloalkyl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, cycloalkyl and heterocycloalkyl is optionally substituted with 1 to 4-substituents independently selected from R e ; and
  • q 0, 1, 2, or 3.
  • ring G is an 8 to 10-membered bicyclic heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S; and optional substituted with 1 to 4 substituents selected from R 10 .
  • ring G is an 8-membered bicyclic heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S; and optional substituted with 1 to 4 substituents selected from R 10 .
  • ring G is an 8-membered bicyclic heteroaryl comprising 1 to 3 heteroatoms selected from N; and optional substituted with 1 to 4 substituents selected from R 10 .
  • ring G is imidazo [1, 2-a] pyrazine, imidazo [1, 2-a] pyrimidine, pyrazolo [1, 5-a] pyridine, pyrazolo [1, 5-a] pyrimidine, or 2-methyl-2H-indazole.
  • each R 10 is independently halogen, -CN, -NO 2 , -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 3 -C 6 cycloalkyl, or 4 to 6-membered heterocycloalkyl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, cycloalkyl and heterocycloalkyl is optionally substituted with
  • each R 10 is independently -CN, -NO 2 , -OH, -OR a , or -NR c R d .
  • each R 10 is independently -OH or -OR a .
  • each R 10 is independently -OH or -OMe.
  • each R 10 is independently halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl.
  • each R 10 is independently halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl.
  • each R 10 is independently C 1 -C 6 haloalkyl.
  • each R 10 is independently -CF 3 , -CHF 2 , -CH 2 CF 3 , or -CH 2 CHF 2 .
  • each R 10 is independently -CF 3 or -CHF 2 .
  • each R 10 is independently C 1 -C 6 alkyl.
  • each R 10 is independently methyl, ethyl, isopropyl, or tert-butyl.
  • each R 10 is independently methyl. In some embodiments of Formula (I’ ) , (I) , (II) , (II’ ) , (III) , (III’ ) , (IIIa) , (IIIa’ ) , (IIIb) , (IIIb) , (IV) , or (IV’ ) , each R 10 is independently methyl. In some embodiments of Formula (I’ ) , (I) , (II) , (II’ ) , (III) , (III’ ) , (IIIa) , (IIIa’ ) , (IIIb) , (IIIb’ ) , (IV) , or (IV’ ) , each R 10 is independently halogen.
  • each R 10 is independently fluorine or chlorine.
  • each R 10 is independently fluorine.
  • each R 10 is independently chlorine.
  • each R 10 is independently -F, -Cl, -CN, methyl, ethyl, -OCH 3 , -CF 3 , -CHF 2 , or -CH 2 F.
  • each R 10 is independently -F, -Cl, methyl, -CF 3 , or -CHF 2 .
  • each R 10a is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, or 4 to 6-membered heterocycloalkyl.
  • each R 10a is independently C 3 -C 6 cycloalkyl.
  • each R 10a is independently cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • each R 10a is independently cyclopropyl. In some embodiments of Formula (II) , (II’ ) , (III) , (III’ ) , (IIIa) , (IIIa’ ) , (IIIb) , (IIIb’ ) , (IV) , or (IV’ ) , each R 10a is independently cyclopropyl. In some embodiments of Formula (II) , (II’ ) , (III) , (III’ ) , (IIIa) , (IIIa’ ) , (IIIb) , (IIIb’ ) , (IV) , or (IV’ ) , each R 10a is independently cyclopropyl.
  • each R 10a is independently 4 to 6-membered heterocycloalkyl.
  • each R 10a is independently 4-membered heterocycloalkyl.
  • each R 10a is independently 5-membered heterocycloalkyl. In some embodiments of Formula (II) , (II’ ) , (III) , (III’ ) , (IIIa) , (IIIa’ ) , (IIIb) , (IIIb’ ) , (IV) , or (IV’ ) , each R 10a is independently 6-membered heterocycloalkyl.
  • each R 10a is independently oxatanyl.
  • each R 10a is independently C 1 -C 6 haloalkyl.
  • each R 10a is independently -CF 3 , -CHF 2 , -CH 2 CF 3 , or -CH 2 CHF 2 .
  • each R 10a is independently C 1 -C 6 alkyl.
  • each R 10a is independently methyl, ethyl, isopropyl, or tert-butyl.
  • each R 10a is independently methyl. In some embodiments of Formula (II) , (II’ ) , (III) , (III’ ) , (IIIa) , (IIIa’ ) , (IIIb) , (IIIb’ ) , (IV) , or (IV’ ) , each R 10a is independently hydrogen.
  • each R 10a is independently hydrogen, methyl, ethyl, isopropyl, tert-butyl, -CD 3 , -CF 3 , CHF 2 , CH 2 F, -CH 2 CF 3 , -CH 2 SO 2 CH 3 , cyclopropyl, oxetanyl,
  • p is an integer from 1-6. In some embodiments of Formula (I’ ) , (I) , (II) , (II’ ) , (III) , (III’ ) , (IIIa) , (IIIa’ ) , (IIIb) , (IIIb’ ) , (IV) , or (IV’ ) , p is an integer from 1-6. In some embodiments of Formula (I’ ) , (I) , (II) , (II’ ) , (III) , (III’ ) , (IIIa) , (IIIa’ ) , (IIIb) , (IIIb’ ) , (IV) , or (IV’ ) , p is an integer from 1-4.
  • p is 1, 2, 3, 4, 5, 6, 7, or 8.
  • p is 1, 2, 3, 4, 5, or 6.
  • p is 1, 2, 3, or 4.
  • p is 1, 2, 3, 4, 5, or 6.
  • p is 1, 2, or 3.
  • p is 1, 2, 3, 4, 5, or 6.
  • p is 1 or 2. In some embodiments of Formula (I’ ) , (I) , (II) , (II’ ) , (III) , (III’ ) , (IIIa) , (IIIa’ ) , (IIIb) , (IIIb’ ) , (IV) , or (IV’ ) , p is 1 or 2. In some embodiments of Formula (I’ ) , (I) , (II) , (II’ ) , (III) , (III’ ) , (IIIa) , (IIIa’ ) , (IIIb) , (IIIb’ ) , (IV) , or (IV’ ) , p is 1, 2, 3, 4, 5, or 6.
  • p is 2. In some embodiments of Formula (I’ ) , (I) , (II) , (II’ ) , (III) , (IIIa) , (IIIa’ ) , (IIIb) , (IIIb’ ) , (IV) , or (IV’ ) , p is 1. In some embodiments of Formula (I’ ) , (I) , (II) , (II’ ) , (III) , (III) , (IIIa) , (IIIa’ ) , (IIIb) , (IIIb’ ) , (IV) , or (IV’ ) , p is 1.
  • q is 1, 2, or 3. In some embodiments of Formula (II) , (II’ ) , (III) , (III’ ) , (IIIa) , (IIIa’ ) , (IIIb) , (IIIb’ ) , (IV) , or (IV’ ) , q is 3.
  • q is 1 or 2. In some embodiments of Formula (II) , (II’ ) , (III) , (III’ ) , (IIIa) , (IIIa’ ) , (IIIb) , (IIIb’ ) , (IV) , or (IV’ ) , q is 2.
  • q is 1. In some embodiments of Formula (II) , (II’ ) , (III) , (III’ ) , (IIIa) , (IIIa’ ) , (IIIb) , (IIIb’ ) , (IV) , or (IV’ ) , q is 0.
  • each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 4 substituents independently selected from R e .
  • each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or cycloalkyl, heterocycloalkyl. In some embodiments of a compound disclosed herein, each R a is independently C 1 -C 6 alkyl or C 1 -C 6 haloalkyl. In some embodiments of a compound disclosed herein, each R a is independently C 1 -C 6 alkyl.
  • each R a is independently methyl, ethyl, isopropyl, tert-butyl, -OCH 3 , -CF 3 , or -CHF 2 , In some embodiments of a compound disclosed herein, each R a is independently methyl, ethyl, isopropyl or tertbutyl.
  • each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 - C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 4 substituents independently selected from R e .
  • each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or cycloalkyl, heterocycloalkyl. In some embodiments of a compound disclosed herein, each R b is independently hydrogen, C 1 -C 6 alkyl or C 1 -C 6 haloalkyl. In some embodiments of a compound disclosed herein, each R b is independently hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound disclosed herein, each R b is hydrogen. In some embodiments of a compound disclosed herein, each R b is independently C 1 -C 6 alkyl.
  • each R b is independently hydrogen, methyl, ethyl, isopropyl, tert-butyl, -OCH 3 , -CF 3 , or -CHF 2 , In some embodiments of a compound disclosed herein, each R b is independently hydrogen, methyl, ethyl, isopropyl, or tert-butyl. In some embodiments of a compound disclosed herein, each R b is independently hydrogen or methyl.
  • R c and R d are each independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 4 substituents independently selected from R e .
  • each R c and R d are independently hydrogen, C 1 -C 6 alkyl or C 1 -C 6 haloalkyl. In some embodiments of a compound disclosed herein, each R c and R d are independently hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound disclosed herein, each R c and R d are hydrogen. In some embodiments of a compound disclosed herein, each R c and R d are independently C 1 -C 6 alkyl.
  • each R c and R d are independently hydrogen methyl, ethyl, isopropyl, tert-butyl, -OCH 3 , -CF 3 , or -CHF 2 , In some embodiments of a compound disclosed herein, each R c and R d are independently hydrogen, methyl, ethyl, isopropyl, or tert-butyl. In some embodiments of a compound disclosed herein, each R c and R d are independently hydrogen or methyl. In some embodiments of a compound disclosed herein, each R c and R d are methyl.
  • each R e is independently halogen, -CN, -OH, or C 1 -C 6 alkyl.
  • each R e is independently halogen, -OH, or C 1 -C 6 alkyl.
  • each R e is independently halogen or C 1 -C 6 alkyl.
  • each R e is independently halogen.
  • each R e is independently -F, -OH, -CF 3 , -CHF 2 , -OCH 3 , or methyl.
  • each R e is independently -F, -CF 3 , -CHF 2 , or methyl.
  • each R e is methyl.
  • one or more of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 10a , R a , R b , R c , R d , and R e groups comprise deuterium at a percentage higher than the natural abundance of deuterium.
  • one or more 1 H are replaced with one or more deuteriums in one or more of the following groups R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 10a , R a , R b , R c , R d , and R e .
  • the abundance of deuterium in each of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 10a , R a , R b , R c , R d , and R e is independently at least 1%, 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%, or 100%by molar.
  • the compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof is one of the compounds in Table 1A, Table 1B, or Table 1C.
  • the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein possess one or more double bonds. The compounds presented herein include all cis, trans, syn, anti,
  • Z isomers as well as the corresponding mixtures thereof. In some situations, the compounds described herein possess one or more chiral centers and each center exists in the R configuration, or S configuration. The compounds described herein include all diastereomeric, enantiomeric, and epimeric forms as well as the corresponding mixtures thereof.
  • mixtures of enantiomers and/or diastereoisomers, resulting from a single preparative step, combination, or interconversion are useful for the applications described herein.
  • the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers and recovering the optically pure enantiomers.
  • dissociable complexes are preferred.
  • the diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc. ) and are separated by taking advantage of these dissimilarities.
  • the diastereomers are separated by chiral chromatography.
  • the compounds described herein exist in their isotopically-labeled forms.
  • the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds.
  • the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds as pharmaceutical compositions.
  • the compounds disclosed herein include isotopically-labeled compounds, which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes examples include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, and chloride, such as 2 H (D) , 3 H, 13 C, 14 C, l5 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 Cl, respectively.
  • Compounds described herein, and the pharmaceutically acceptable salts, solvates, or stereoisomers thereof which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention.
  • isotopically-labeled compounds for example those into which radioactive isotopes such as 3 H and 14 C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3 H and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability.
  • the abundance of deuterium in each of the substituents disclosed herein is independently at least 1%, 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%, or 100%by molar.
  • one or more of the substituents disclosed herein comprise deuterium at a percentage higher than the natural abundance of deuterium.
  • one or more 1 H are replaced with one or more deuteriums in one or more of the substituents disclosed herein.
  • the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.
  • the compounds described herein exist as their pharmaceutically acceptable salts.
  • the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts.
  • the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.
  • the compounds described herein possess acidic or basic groups and therefore react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt.
  • these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein, or a solvate, or stereoisomer thereof, or by separately reacting a purified compound in its free form with a suitable acid or base, and isolating the salt thus formed.
  • Examples of pharmaceutically acceptable salts include those salts prepared by reaction of the compounds described herein with a mineral, organic acid or inorganic base, such salts including, acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyn-1, 4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne-1, 6-dioate, hydroxybenzoate,
  • the compounds described herein can be prepared as pharmaceutically acceptable salts formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, including, but not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid metaphosphoric acid, and the like; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3- (4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1, 2-ethanedis
  • other acids such as oxalic, while not in themselves pharmaceutically acceptable, are employed in the preparation of salts useful as intermediates in obtaining the compounds disclosed herein, solvate, or stereoisomer thereof and their pharmaceutically acceptable acid addition salts.
  • those compounds described herein which comprise a free acid group react with a suitable base, such as the hydroxide, carbonate, bicarbonate, sulfate, of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine.
  • a suitable base such as the hydroxide, carbonate, bicarbonate, sulfate, of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine.
  • Representative salts include the alkali or alkaline earth salts, like lithium, sodium, potassium, calcium, and magnesium, and aluminum salts and the like.
  • bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N + (C 1-4 alkyl) 4 , and the like.
  • Organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like. It should be understood that the compounds described herein also include the quaternization of any basic nitrogen-containing groups they contain. In some embodiments, water or oil-soluble or dispersible products are obtained by such quaternization.
  • the compounds described herein exist as solvates.
  • the disclosure provides for methods of treating diseases by administering the compounds in the form of such solvates.
  • the disclosure provides for methods of treating diseases by administering a composition comprising the compounds in the form of such solvates.
  • Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and, in some embodiments, are formed during the process of crystallization with pharmaceutically acceptable solvents.
  • Tautomers are compounds that are interconvertible by migration of a hydrogen atom, accompanied by a switch of a single bond and adjacent double bond. In bonding arrangements where tautomerization is possible, a chemical equilibrium of the tautomers will exist. All tautomeric forms of the compounds disclosed herein are contemplated. The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH.
  • Disclosed herein is a method of treating a neurodegenerative disease or disorder in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound or a pharmaceutically acceptable salt or stereoisomer thereof, disclosed herein.
  • the neurodegenerative disease or disorder is selected from Alzheimer’s disease, amyotrophic lateral sclerosis, Huntington’s disease, Parkinson’s disease, Prion disease, and spinocerebellar ataxias.
  • the neurodegenerative disease or disorder is Alzheimer’s disease.
  • the neurodegenerative disease or disorder is amyotrophic lateral sclerosis.
  • the neurodegenerative disease or disorder is Huntington’s disease.
  • the neurodegenerative disease or disorder is Parkinson’s disease.
  • the neurodegenerative disease or disorder is Prion disease.
  • the neurodegenerative disease or disorder is a spinocerebellar ataxia.
  • compositions containing the compound (s) described herein are administered for therapeutic treatments.
  • the compositions are administered to a patient already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest at least one of the symptoms of the disease or condition. Amounts effective for this use depend on the severity and course of the disease or condition, previous therapy, the patient’s health status, weight, and response to the drugs, and the judgment of the treating physician. Therapeutically effective amounts are optionally determined by methods including, but not limited to, a dose escalation and/or dose ranging clinical trial.
  • the administration of the compounds are administered chronically, that is, for an extended period of time, including throughout the duration of the patient’s life in order to ameliorate or otherwise control or limit the symptoms of the patient’s disease or condition.
  • a maintenance dose is administered if necessary. Subsequently, in specific embodiments, the dosage, or the frequency of administration, or both, is reduced, as a function of the symptoms.
  • the amount of a given agent that corresponds to such an amount varies depending upon factors such as the particular compound, disease condition and its severity, the identity (e.g., weight, sex) of the subject or host in need of treatment, but nevertheless is determined according to the particular circumstances surrounding the case, including, e.g., the specific agent being administered, the route of administration, the condition being treated, and the subject or host being treated.
  • doses employed for adult human treatment are typically in the range of 0.01 mg-5000 mg per day.
  • the daily dosages appropriate for the compound described herein, or a pharmaceutically acceptable salt thereof are from about 0.01 to about 50 mg/kg per body weight.
  • the daily and unit dosages are altered depending on a number of variables including, but not limited to, the activity of the compound used, the disease or condition to be treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition being treated, and the judgment of the practitioner.
  • Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ophthalmic, pulmonary, transmucosal, transdermal, vaginal, otic, nasal, and topical administration.
  • parenteral delivery includes intramuscular, subcutaneous, intravenous, intramedullary injections, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injections.
  • a compound as described herein is administered in a local rather than systemic manner, for example, via injection of the compound directly into an organ, often in a depot preparation or sustained release formulation.
  • long acting formulations are administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection.
  • the drug is delivered in a targeted drug delivery system, for example, in a liposome coated with organ specific antibody.
  • the liposomes are targeted to and taken up selectively by the organ.
  • the compound as described herein is provided in the form of a rapid release formulation, in the form of an extended release formulation, or in the form of an intermediate release formulation.
  • the compounds described herein are administered to a subject in need thereof, either alone or in combination with pharmaceutically acceptable carriers, excipients, or diluents, in a pharmaceutical composition, according to standard pharmaceutical practice. In some embodiments, the compounds described herein are administered to animals.
  • compositions comprising a compound described herein, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
  • Pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable excipients that facilitate processing of the active compounds into preparations that can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen.
  • a summary of pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995) ; Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H. A.
  • the pharmaceutically acceptable excipient is selected from carriers, binders, filling agents, suspending agents, flavoring agents, sweetening agents, disintegrating agents, dispersing agents, surfactants, lubricants, colorants, diluents, solubilizers, moistening agents, plasticizers, stabilizers, penetration enhancers, wetting agents, anti-foaming agents, antioxidants, preservatives, and any combinations thereof.
  • the compounds and salts of Formulas (I) , (II) , (III) , (IIIa) , (IIIb) , and (IV) can be synthesized according to one or more illustrative schemes herein and/or techniques known in the art. Materials used herein are either commercially available or prepared by synthetic methods generally known in the art. These schemes are not limited to the compounds listed in the examples or by any particular substituents, which are employed for illustrative purposes. Although various steps are described and depicted in the synthesis schemes below, the steps in some cases may be performed in a different order than the order shown below. Numberings or R groups in each scheme do not necessarily correspond to that of the claims or other schemes or tables herein.
  • DIPEA N, N-Diisopropylethylamine
  • LAH Lithium aluminum hydride
  • PCC Pyridinium chlorochromate
  • rt or RT Room temperature, ambient, about 25 °C
  • Step 1 To a solution of 2-methylpropan-2-yl 1, 5-dimethyl-3-oxo-8-azabicyclo [3.2.1] octane-8-carboxylate (2.50 g, 9.87 mmol) in THF (30 mL) was added LiHMDS (15.8 mL, 15.8 mmol) at -65 °C. The reaction was stirred for 1.5 h and then TMSCl (1.6 mL, 12.83 mmol) was added and the reaction mixture stirring at -78 °C for another 2 h. After the reactants were consumed, the reaction was diluted with EA and H 2 O.
  • Step 2 To a solution of 2-methylpropan-2-yl 1, 5-dimethyl-3- [ (trimethylsilyl) oxy] -8-azabicyclo [3.2.1] oct-2-ene-8-carboxylate (3.0 g, 9.22 mmol) in acetonitrile (15 mL) was added Selectfluor (5.24 g, 14.8 mmol) and the reaction mixture was stirred at room temperature overnight. After the reactants were consumed, the reaction was quenched with water and then diluted with EA (100 mL) . The organic layer was collected, dried over sodium sulfate, and concentrated in vacuo.
  • Step 3 2-Methylpropan-2-yl (1R, 4S, 5S) -4-fluoro-1, 5-dimethyl-3-oxo-8-azabicyclo [3.2.1] octane-8-carboxylate (1.3 g, 4.79 mmol) was dissolved in THF (30 mL) and LiHMDS (7.67 mL, 7.67 mmol) was added at 80 °C. The reaction was stirred at -65 °C for 1.5 h, and then TMSCl (0.79 mL, 6.23 mmol) was added. The reaction mixture was stirred for another 2 h at -78 °C. After the reactants were consumed, the reaction was diluted with EA and H 2 O.
  • Step 4 To a solution of 2-methylpropan-2-yl 1, 5-dimethyl-3- [ (trimethylsilyl) oxy] -8-azabicyclo [3.2.1] oct-2-ene-8-carboxylate (1.6 g, 4.66 mmol) in acetonitrile (15 mL) was Selectfluor (1.65 g, 4.66 mmol) was added and the reaction mixture was stirred at room temperature overnight. After the reactants were consumed, the reaction was quenched with water, and diluted with EA (100 mL) . The organic layer was collected, dried over sodium sulfate, and concentrated in vacuo.
  • Step 5 2-Methylpropan-2-yl (1S, 2S, 4R, 5R) -2, 4-difluoro-5-methyl-3-oxo-8-azabicyclo [3.2.1] octane-8-carboxylate (200 mg, 0.69 mmol) was dissolved in EtOH (1-5 mL) and NaBH 4 (32 mg, 0.83 mmol) was added at 80 °C. The reaction was refluxed for 3h. After the reactants were consumed, the mixture was cooled to room temperature, quenched with water and diluted with EA (50 mL) . The mixture was washed with brine and the organic layer was collected, dried over sodium sulfate, and concentrated in vacuo.
  • Step 6 To a solution of 2-methylpropan-2-yl (1S, 2S, 4R, 5R) -2, 4-difluoro-3-hydroxy-5-methyl-8-azabicyclo [3.2.1] octane-8-carboxylate (80 mg, 0.29 mmol) in THF (6 mL) , NaH (16.5 mg, 0.41 mmol) was added and the reaction mixture was stirred for 20 min. Next 3, 6-dibromo-1, 2-diazine (85 mg, 0.35 mmol) was added and the reaction mixture was stirred at room temperature overnight. After the reactants were consumed, the mixture was cooled to room temperature, quenched with water and diluted with EA (50 mL) .
  • Step 7 To a solution of 6- (1, 3-dimethylpyrazol-4-yl) -2, 3-dihydro-1H-pyrrolo [4, 3-c] pyridin-1-one (28 mg, 0.12) in dioxane (6 mL) was added 2-methylpropan-2-yl (1R, 2R, 3s, 4S, 5S) -3- [ (6-bromo-1, 2-diazin-3-yl) oxy] -2, 4-difluoro-1, 5-dimethyl-8-azabicyclo [3.2.1] octane-8-carboxylate (55 mg, 0.12 mmol) , XantPhos Pd G4 (11.81 mg, 0.01 m-mol) and Cs 2 CO 3 (119.91 mg, 0.37 mmol) and the reaction mixture was stirred at 90 °C overnight.
  • Step 8 2-Methylpropan-2-yl 3- ( ⁇ 6- [6- (1, 3-dimethylpyrazol-4-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [4, 3-c] pyridin-2-yl] -1, 2-diazin-3-yl ⁇ oxy) -2, 4-difluoro-1, 5-dimethyl-8-azabicyclo [3.2.1] octane-8-carboxylate (15 mg, 20.53%) was dissolved in HCl (5 mL, in dioxane) . The reaction mixture was stirred at room temperature for 3 h. After the reactants were consumed, the reaction was concentrated in vacuo.
  • Step 1 To a solution of 2-methylpropan-2-yl (1S, 3S, 4S, 5R) -4-fluoro-3-hydroxy-1, 5-dimethyl-8-azabicyclo [3.2.1] octane-8-carboxylate (120 mg, 0.44 mmol) in THF (6 mL) was added NaH (15.80 mg, 0.66 mmol) . The reaction mixture was stirred for 20 min and then 3, 6-dibromo-1, 2-diazine (156.64 mg, 0.66 mmol) was added. The reaction mixture was further stirred at room temperature overnight. After the reactants were consumed, the mixture was cooled to room temperature, quenched with water and diluted with EA (50 mL) .
  • Step 2 To a solution of 3- (1, 3-dimethylpyrazol-4-yl) -6, 7-dihydro-5H-pyrrolo [4, 3-b] pyridin-5-one (23 mg, 0.10 mmol) in dioxane (6 mL) were added 2-methylpropan-2-yl (1S, 3S, 4S, 5R) -3- [ (6-bromo-1, 2-diazin-3-yl) oxy] -4-fluoro-1, 5-dimethyl-8-azabicyclo [3.2.1] octane-8-carboxylate (43.36 mg, 0.10 mmol) , XantPhos Pd G4 (9.70 mg, 0.01 mmol) and Cs 2 CO 3 (98.33 mg, 0.30 mmol) .
  • Step 3 2-Methylpropan-2-yl (1R, 2R, 5S) -3- ( ⁇ 6- [3- (1, 3-dimethylpyrazol-4-yl) -5-oxo-6, 7-dihydro-5H-pyrrolo [4, 3-b] pyridin-6-yl] -1, 2-diazin-3-yl ⁇ oxy) -2-fluoro-1, 5-dimet-hyl-8-azabicyclo [3.2.1] octane-8-carboxylate (13 mg, 0.02 mmol) was dissolved in HCl (5 mL, in dioxane) and the reaction mixture was stirred at room temperature for 3 h.
  • Step 1 To a solution of (2S) -2- ( ⁇ [ (9H-fluoren-9-ylmethyl) oxy] carbonyl ⁇ amino) -3, 3-dimethylbutanoic acid (10 g, 28.29 mmol, 1.0 eq) and methyl aminoacetate (3.0 g, 33.95 mmol, 1.2 eq) in acetonitrile (50 mL) was added DIEA (9.1 g, 70.74 mmol, 2.5 eq) and HATU (11.8 g, 31.12 mmol, 1.1 eq) , and then the reaction mixture was stirred at room temperature for 16 h.
  • Step 2 A solution of 9H-fluoren-9-ylmethyl ⁇ [ (7S) -8, 8-dimethyl-3, 6-dioxo-5-aza-2-oxanon-7-yl] amino ⁇ methanoate (5.0 g, 11.78 mmol, 1.0 eq) in acetonitrile (100 mL) was stirred room temperature for 16 h. After the reactants were consumed, the solution was concentrated in vacuo to afford 9H-fluoren-9-ylmethyl ⁇ [ (7S) -8, 8-dimethyl-3, 6-dioxo-5-aza-2-oxanon-7-yl] amino ⁇ methanoate (4.85 g, 11.43 mmol, 97.00%) as a yellow solid. MS m/z 171.2 [M+H] + .
  • Step 3 LiAlH 4 (2.14 g, 56.40 mmol, 6.0 eq) was added to a vigorous stirred solution of (3S) -3-(2-methylprop-2-yl) piperazine-2, 5-dione (1.6 g, 9.40 mmol, 1.0 eq) in THF (20 mL) in an ice bath, and the mixture was further stirred at 70 °C for 16 h. After the reactants were consumed, the mixture was poured into KOH (6N) in an ice bath. The resulting mixture was further stirred for 1 h, filtered, and the filtrate was collected.
  • Step 4 DIEA (1.13 g, 8.79 mmol, 1.46 mL, 2.5 eq) was added to a vigorous stirred solution of (2S) -2- (2-methylprop-2-yl) piperazine (0.5 g, 3.51 mmol, 1.0 eq) and 3, 6-diiodo-1, 2-diazine (1.17 g, 3.51 mmol, 1.0 eq) in n-BuOH (7 mL) at room temperature, and the mixture was stirred at 120 °C for 16 h.
  • Step 5 Pd (dppf) Cl 2 (49 mg, 0.06 mmol, 0.05 eq) was added to a vigorous stirred solution of 1-methyl-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrazole (250 mg, 1.20 mmol, 1.0 eq) , 3-bromo-6, 7-dihydro-5H-pyrrolo [4, 3-b] pyridin-5-one (256 mg, 1.20 mmol, 1.0 eq) and K 2 CO 3 (332 mg, 2.40 mmol, 2.0 eq) in dioxane (5 mL) and water (1 mL) . The mixture was stirred at 80 °C for 16 h.
  • Step 6 6- (1-Methylpyrazol-4-yl) -2, 3-dihydro-1H-pyrrolo [4, 3-c] pyridin-1-one (50 mg, 0.23 mmol, 1.0 eq) and 6-iodo-3- [ (3S) -3- (2-methylprop-2-yl) piperazin-1-yl] -1, 2-diazine (80 mg, 0.23 mmol, 1.0 eq) was dissolved in DMF (2 mL) and CuI (4 mg, 0.02 mmol, 0.10 eq) , K 2 CO 3 (97 mg, 0.70 mmol, 3.0 eq) and (1R, 2R) -cyclohexane-1, 2-diamine (2.7 mg, 0.02 mmol, 0.10 eq) was added and the reaction mixture was stirred at 100 °C for 16 h.
  • Step 1 To a 100 mL round-bottomed flask was added spiro [4-azaspiro [2.5] octane-5, 1'-cyclopropane] -7-one (500 mg, 3.31 mmol) in MeOH (5 mL) . This was followed with the addition of NaBH 4 (0.18 mL, 4.96 mmol) at 0 °C over 5 min to give an off-white suspension. The resulting mixture was stirred for 1 h at room temperature. LCMS showed the desired MS (M+H: 154.1) . The resulting mixture was cooled to 0 °C and quenched with HCl (2 M, 0.5 mL) and then concentrated in vacuo.
  • Step 2 To a solution of spiro [4-azaspiro [2.5] octane-5, 1'-cyclopropane] -7-ol (460 mg, 3.00 mmol) in THF (10 mL) was added NaH (270.20 mg, 4.50 mmol) at 0 °C and the resulting mixture was stirred for 30 min at room temperature. Next 3, 6-dibromo-1, 2-diazine (928.42 mg, 3.90 mmol) was added at 0 °C and the resulting mixture was stirred for 12 h at 60 °C.
  • Step 3 To a flask containing 3- (1, 3-dimethylpyrazol-4-yl) -6, 7-dihydro-5H-pyrrolo [4, 3-b] pyridin-5-one (40.47 mg, 0.18 mmol) in dioxane (2 mL) was added 7- [ (6-bromo-1, 2-diazin-3-yl) oxy] spiro [4-azaspiro [2.5] octane-5, 1'-cyclopropane] (50 mg, 0.16 mmol) , Cs 2 CO 3 (157.56 mg, 0.48 mmol) and 3- (1, 3-dimethyl-1H-pyrazol-4-yl) -6, 7-dihydro-5H-pyrrolo [3, 4-b] pyridin-5-one (26.11 mg, 0.02 mmol) under nitrogen.
  • Step 2 To a solution of 6-bromo-3-chloro-1, 2, 4-triazine (200 mg, 1.03 mmol) and 2, 2, 6, 6-tetramethyl-4- (methylamino) hexahydropyridine (192.71 mg, 1.13 mmol) in toluene (10 mL) was added DIEA (0.34 mL, 2.06 mmol) and the reaction mixture was stirred at 120 °C for 3 h. LCMS showed the reaction was completed.
  • Step 3 To a solution of 3- (1, 3-dimethylpyrazol-4-yl) -6, 7-dihydro-5H-pyrrolo [4, 3-b] pyridin-5-one (35 mg, 0.15 mmol) and 6-bromo-3- [methyl (2, 2, 6, 6-tetramethylhexahydropyridin-4-yl) amino] -1, 2, 4-triazine (52 mg, 0.16 mmol) in dioxane (10 mL) was added BrettPhos Pd G 4 (13.61 mg, 0.01 mmol) and Cs 2 CO 3 (146.62 mg, 0.45 mmol) . The reaction mixture was stirred at 90 °C for 16 h under N 2 .
  • Step 1 To a solution of methyl 3-amino-5-bromo-2-methylbenzoate (1.0 g, 4.10 mmol) in DCM (10 mL) was added nitrosonium tetrafluoroborate (480 mg, 4.10 mmol) portion wise at 0 °C under N 2 to obtain a yellow solution which was stirred at 0 °C for 1 h. Then oxylene (30 mL) was added the reaction mixture was refluxed at 130 °C for 3 h. Next the reaction mixture was cooled to room temperature and poured into H 2 O. The aqueous layer was extracted EA. The combined organic layers were washed with brine, dried over MgSO 4 , filtered, and concentrated. The crude mixture was purified by silica gel column chromatography with PE/EA 10/1, v/v to obtain methyl 5-bromo-3-fluoro-2-methylbenzoate (860 mg, 85%) .
  • nitrosonium tetrafluoroborate 480
  • Step 2 To the solution of 5-bromo-3-fluoro-2-methylbenzoate (860 mg, 3.5 mmol) and NBS (623 mg, 3.5 mmol) in (trifluoromethyl) benzene (10 mL) , was added AIBN (57 mg, 0.35 mmol) . The reaction mixture was stirred under N 2 at 100 °C for 16 h. Next, the reaction mixture was cooled to room temperature and poured into H 2 O. The aqueous layer was extracted EA. The combined organic layers were washed with brine, dried over MgSO 4 , filtered, and concentrated. The crude mixture was purified by silica gel column chromatography with PE/EA 10/1, v/v to obtain methyl 5-bromo-2- (bromomethyl) -3-fluorobenzoate (800 mg, 70%) .
  • Step 3 Methyl 5-bromo-2- (bromomethyl) -3-fluorobenzoate (800 mg, 2.5 mmol) was dissolved in THF (7 mL) and NH 4 OH (7 mL) was added. The reaction was stirred at room temperature for 4 h and was then filtered and concentrated under vacuum. The crude product was used directly in the next step without further purification.
  • Step 4 To the solution of 6-bromo-4-fluoroisoindolin-1-one (100 mg, 0.43 mmol) and 1, 3-dimethyl-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (96 mg, 0.43 mmol) in dioxane: H 2 O (5: 1) (2 mL : 0.4 mL) , potassium carbonate (118 mg, 0.86 mmol) and PdCl 2 (dppf) (31 mg, 0.043 mmol) were added. The reaction mixture was stirred under N 2 at 100 °C for 16 h.
  • Step 2 To a mixture of methyl 2-chloro-5-methylpyrimidine-4-carboxylate (5.0 g, 26.80 mmol) in CCl 4 (100 mL) was added NBS (6.20 g, 34.84 mmol) and AIBN (0.44 g, 2.68 mmol) at room temperature under N 2 , and the resulting mixture was stirred at 95 °C for 2 h. Next NBS (2.38 g, 13.40 mmol) was added and the mixture was stirred at 95 °C for 1 h. Then NBS (1.43 g, 8.04 mmol) was added and the mixture was stirred at 95 °C for 1 h.
  • Step 3 A mixture of methyl 5- (bromomethyl) -2-chloropyrimidine-4-carboxylate (4.0 g, 15.07 mmol) in NH 3 -dioxane (30 mL) was stirred at room temperature for 1 h. LCMS analysis showed the reaction was completed. The mixture was the filtrated and concentrated to afford 2-chloro-6, 7-dihydro-5H-pyrrolo [4, 3-d] pyrimidin-7-one (1.3 g, 50.98%) as a red solid.
  • Step 5 To a mixture of 2- (2, 4-dimethyl-1, 3-thiazol-5-yl) -6, 7-dihydro-5H-pyrrolo [4, 3-d] pyrimidin-7-one (65 mg, 0.26 mmol) , 2-methylpropan-2-yl (1R, 3s, 5S) -3- [ (6-bromo-1, 2-diazin-3-yl) oxy] -1, 5-dimethyl-8-azabicyclo [3.2.1] octane-8-carboxylate (119.70 mg, 0.29 mmol) in dioxane (20 mL) was added XantPhos Pd G4 (42.76 mg, 0.03 mmol) and Cs 2 CO 3 (257.97 mg, 0.79 mmol) at room temperature under N 2 , and the mixture was stirred at 95 °C for 16 h.
  • Step 6 To a mixture of 2-methylpropan-2-yl (1S, 3s, 5R) -3- ( ⁇ 6- [2- (2, 4-dimethyl-1, 3-thiazol-5-yl) -7-oxo-6, 7-dihydro-5H-pyrrolo [4, 3-d] pyrimidin-6-yl] -1, 2-diazin-3-yl ⁇ oxy) -1, 5-dimethyl-8-azabicyclo [3.2.1] octane-8-carboxylate (100 mg, 0.17 mmol) in DCM (10 mL) was added TFA (1 mL) at room temperature and the mixture was stirred at room temperature for 0.5 h. LCMS analysis showed the reaction was completed.
  • Step 1 To a solution of methyl 5-bromo-2-chloroisonicotinate (5 g, 20 mmol, 1.0 eq) , methylboronic acid (1.79 g, 29.8 mmol, 1.5 eq) , K 3 PO 4 (14.8 g, 69.9 mmol, 3.5 eq) , P (Cy) 3 (1.11 g, 3.97 mmol, 0.2 eq) and Pd (OAc) 2 (448 mg, 2.00 mmol, 0.1 eq) in toluene (95 mL) and H 2 O (4.5 mL) was degassed and purged with N 2 three times.
  • Step 2 2-Chloro-5-methylisonicotinate (15.0 g, 81.7 mmol, 1.0 eq) , N-bromosuccinimide (20.3 g, 113.9 mmol, 1.4 eq) and benzoyl peroxide (448.0 mg, 1.85 mmol, 0.03 eq) were combined with carbon tetrachloride (250 mL) .
  • the reaction mixture was heated to 80 °C and stirred for 3 h.
  • the reaction mixture was cooled to rt and concentrated in vacuum.
  • the obtained residue was purified by silica gel column chromatography with PE/EA to obtain methyl 5- (bromomethyl) -2-chloroisonicotinate (17.0 g, 79%) as a brown solid.
  • LC/MS (ESI) 263.9, 265.9 [M+H] + .
  • Step 3 Methyl 5- (bromomethyl) -2-chloroisonicotinate (17.0 g, 64.6 mmol, 1.0 eq) was suspended in 28 %aqueous ammonium hydroxide and the mixture was kept stirring at rt for 8 hrs. Then the mixture was filtered, and the residue was washed with water and methanol. The solid was collected, dried under vacuum and used in the next step without further purification. LC/MS (ESI) : 169.0, 171.0 [M+H] + .
  • Step 4 6-Chloro-2, 3-dihydro-1H-pyrrolo [3, 4-c] pyridin-1-one (336.0 mg, 2.0 mmol, 1.0 eq) , 2, 4-dimethyl-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) thiazole) (526.1 mg, 2.20 mmol, 1.1 eq) , aqueous potassium carbonate (2 M, 8.0 mL) and PdCl 2 (dppf) . CH 2 Cl 2 adduct (146.3 mg, 0.2 mmol, 0.1 eq) were charged to a three-neck 100 mL round bottom flask.
  • Step 5 To a round bottom flask charged with 6- (2, 4-dimethylthiazol-5-yl) -2, 3-dihydro-1H-pyrrolo [3, 4-c] pyridin-1-one (36.7 mg, 0.15 mmol, 1.0 eq) , tert-butyl (1R, 3s, 5S) -3- ( (6-bromopyridazin-3-yl) oxy) -1, 5-dimethyl-8-azabicyclo [3.2.1] octane-8-carboxylate (61.8 mg, 0.15 mmol, 1.1 eq) , Cs 2 CO 3 (148.9 mg, 0.46 mmol, 3.0 eq) , and XantPhos Pd G4 (14.2 mg, 0.015 mmol, 0.1 eq) was added 1, 4-dioxane (4 mL) .
  • reaction mixture was degassed with argon for 5 min then heated at 90 °C for 8 hrs.
  • the reaction mixture was cooled to RT and diluted with EtOAc.
  • the organic phase was washed with brine, dried over sodium sulfate, and concentrated under vacuum.
  • Step 1 Potassium hydroxide (74.8 g, 1.33 mol, 4.5 eq) in water (60 mL) was added to a vigorous stirred solution of 3-oxopentanedioic acid (82.8 g, 0.566 mol, 4.5 eq) and hexane-2, 5-dione (34.0 g, 35.0 mL, 0.298 mol, 1.0 eq) in water (120 mL) at 0 °C. After the addition, ammonium chloride (47.8 g, 0.896 mol, 3.0 eq) and sodium acetate (49.0 g, 0.596 mol, 2.0 eq) in water (200 mL) were added keeping the temperature at 5 °C.
  • the pH value was adjusted to ⁇ 9 by using solid KOH.
  • the mixture was stirred at room temperature for 4 days during which time the pH value was adjusted to ⁇ 9 by using additional solid KOH.
  • Step 2 To an ice-cold solution of l, 5-dimethyl-8-azabicyclo [3.2.1] octan-3-one (3 g, 19.6 mmol, 1.0 eq) of DCM (60 mL) was added pyridine (4.0 mL, 49.0 mmol, 2.5 eq) . Triphosgene (2.33g, 7.84 mmol, 0.4 eq) was dissolved in DCM (20mL) and added to the above solution dropwise. After 30 minutes, t-BuOH (3.78 mL, 39.2 mmol, 2.0 eq) was added and the mixture was gradually warmed to RT and stirred for 8 hrs.
  • the reaction was quenched with water and diluted with DCM (300 mL) .
  • the mixture was washed with 1N HCl (1 x 50 mL) , saturated sodium bicarbonate (1 x 50 mL) , and brine (1 x 50 mL) .
  • the organic layer was collected and dried over sodium sulfate, and then concentrated in vacuo.
  • Step 3 (1R, 5S) -1, 5-Dimethyl-3-oxo-8-azabicyclo [3.2.1] octane-8-carboxylate (2.3 g, 9.1 mmol) was dissolved in EtOH (50 mL) and the solution was heated to reflux. Sodium borohydride (336 mg, 1.0 eq) and was added the mixture was stirred for 15 min. The mixture was cooled to RT and quenched with aqueous ammonium chloride. The organic solvent was removed under vacuum and the residue was redissolved in EtOAc (100 mL) . The mixture was washed with brine, and the organic layer was collected and dried over sodium sulfate, and then concentrated in vacuo.
  • Step 4 To a solution of (1R, 3s, 5S) -3-hydroxy-1, 5-dimethyl-8-azabicyclo [3.2.1] octane-8-carboxylate (1.10g g, 4.34 mmol, 1.0 eq) in anhydrous THF (20 mL) was added NaH (60 wt %, 208 mg, 5.21 mmol, 1.2 eq) . The solution was stirred at room temperature for 30 min, then 3, 6-dibromopyridazine (1.24 g, 5.21 mmol, 1.2 eq) was added and the mixture was stirred at RT for 8 hrs.
  • Step 5 A mixture of 6- (1, 3-dimethylpyrazol-4-yl) -2, 3-dihydro-1H-pyrrolo [4, 3-c] pyridin-1-one (210 mg, 0.92 mmol) , 2-methylpropan-2-yl (1R, 3s, 5S) -3- [ (6-bromo-1, 2-diazin-3-yl) oxy] -1, 5-dimethyl-8-azabicyclo [3.2.1] octane-8-carboxylate (379.36 mg, 0.92 mmol) in dioxane (30 mL) was added Xantphos Pd G4 (149.05 mg, 0.09 mmol) , Cs 2 CO 3 (897.04 mg, 2.76 mmol) at RT under N 2 and the mixture was stirred at 95 °C for 16 h.
  • Step 6 A mixture of 2-methylpropan-2-yl (1R, 3s, 5S) -3- ( ⁇ 6- [6- (1, 3-dimethylpyrazol-4-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [4, 3-c] pyridin-2-yl] -1, 2-diazin-3-yl ⁇ oxy) -1, 5-dimethyl-8-azabicyclo [3.2.1] octane-8-carboxylate (360 mg, 0.64 mmol) in DCM (10 mL) was added HCl-dioxane (20 mL) at RT and the mixture was stirred or 1 h.
  • Step 1 A solution of pivaloyl chloride (41.96 mL, 341.03 mmol) in dry THF (50 mL) was added dropwise to a stirred and ice-cooled solution of 4-oxopentanoic acid (31.86 mL, 310.02 mmol) and triethylamine (128.92 mL, 930.07 mmol) in dry THF (300 mL) at 5 °C. The solution was stirred for 1.5 h at 5 °C, and the precipitated Et 3 N ⁇ HCl was filtered off. The solid salt was washed with THF.
  • Step 2 A solution of EtMgBr in THF (1 M, 323.14 mL, 313.14 mmol) was added dropwise over 30 min to a stirred and cooled solution of 2, 2-dimethylpropanoic 4-oxopentanoic anhydride (57 g, 284.67 mmol) in dry THF (300 mL) at -60 °C under N 2 . After the addition, the mixture was stirred for 30 min at -60 °C. Subsequently the cooling bath was removed and the mixture was stirred for an additional 1 h. The reaction was quenched with the addition of ice and NH 4 Cl solution, and was then extracted with EA.
  • Step 3 KOH (49.25 g, 877.74 mmol) in water (50 mL) was added to a vigorous stirred solution of heptane-2, 5-dione (25 g, 195.05 mmol) and 3-oxopentanedioic acid (42.30 mL, 370.60 mmol) in water (250 mL) at 0 °C.
  • NH 4 Cl (20.59 mL, 585.16 mmol) and KOAc (38.29 g, 390.11 mmol) in water (200 mL) were added at 5 °C.
  • the pH value was adjusted to ⁇ 9 by using solid KOH.
  • the mixture was stirred at room temperature for 4 days during which time the pH value was adjusted to ⁇ 9 by using additional solid KOH.
  • Step 4 To an ice-cold solution of (1S, 5R) -1-ethyl-5-methyl-8-azabicyclo [3.2.1] octan-3-one (9 g, 53.81 mmol) in DCM (80 mL) was added pyridine (10.86 mL, 134.53 mmol) . Trichloromethyl [ (trichloromethyl) oxy] methanoate (3.59 mL, 21.52 mmol) was dissolved in DCM (20 mL) and added dropwise to the reaction mixture. After 30 minutes, 2-methylpropan-2-ol (10.23 mL, 107.62 mmol) was added and the mixture was gradually warmed to RT and stirred for 8 h.
  • Step 5 2-Methylpropan-2-yl (1R) -5-ethyl-1-methyl-3-oxo-8-azabicyclo [3.2.1] octane-8-carboxylate (7.5 g, 28.05 mmol) was dissolved in EtOH (60 mL) and the solution was heated to reflux. NaBH 4 (0.31 mL, 8.42 mmol) was added and the mixture was stirred for 15 min. The mixture was cooled to RT and quenched with aqueous ammonium chloride. The organic solvent was removed under vacuum and the residue was redissolved in EA (200 mL) .
  • Step 6 To a solution of 2-methylpropan-2-yl (1R) -5-ethyl-3-hydroxy-1-methyl-8-azabicyclo [3.2.1] octane-8-carboxylate (3.7 g, 13.74 mmol) in anhydrous THF (35 mL) was added NaH (0.33 g, 13.74 mmol) . The solution was stirred at room temperature for 30 min, then 3, 6-dibromo-1, 2-diazine (3.27 g, 13.74 mmol) was added and the mixture was stirred at RT for 8 h. The reaction mixture was quenched with saturated ammonium chloride and diluted with EA (200 mL) .
  • Step 7 To a round bottom flask charged with 2-methylpropan-2-yl (1S) -3- [ (6-bromo-1, 2-diazin-3-yl) oxy] -1-ethyl-5-methyl-8-azabicyclo [3.2.1] octane-8-carboxylate (150 mg, 0.35 mmol) , 6- (1, 3-dimethylpyrazol-4-yl) -2, 3-dihydro-1H-pyrrolo [4, 3-c] pyridin-1-one (88.33 mg, 0.39 mmol) , Cs 2 CO 3 (102.23 mg, 0.31 mmol, and XantPhos Pd G4 (16.94 mg, 0.01 mmol) was added 1, 4-dioxane (4 mL) .
  • reaction mixture was degassed with argon for 5 min and then heated at 90 °C for 8 h.
  • the reaction mixture was cooled to RT and diluted with EA.
  • the organic phase was washed with brine, dried over sodium sulfate, and concentrated under vacuum.
  • Step 1 A solution of 1-ethoxy-1- [ (trimethylsilyl) oxy] cyclopropane (11.5 mL, 57.37 mmol, 1.0 eq) in MeOH (100 mL) was stirred at RT overnight. The reaction mixture was concentrated under vacuum and use directly in the next step without purification.
  • Step 2 A solution of 1-ethoxycyclopropan-1-ol (5.9 g, 57.38 mmol, 1.0 eq) and benzoic acid (1.4 g, 11.48 mmol, 0.2 eq) in toluene (6 mL) was stirred at 110 °C for 15 min. Then ethyl (triphenyl- ⁇ 5-phosphanylidene) acetate (20.0 g, 57.38 mmol, 1.0 eq) was added and the mixture was stirred at 110 °Cfor 48 hours. The reaction mixture was concentrated under vacuum. The crude product was purified by silica gel chromatography eluted with PE to give ethyl cyclopropylideneacetate (3.1 g, 42.4%) .
  • Step 3 A solution of ethyl cyclopropylideneacetate (1.7 g, 13.47 mmol, 1.0 eq) , ethyl 3-amino-3-methylbutanoate (2.3 g, 16.17 mmol, 1.2 eq) in DIEA (2.99 mL, 18.06 mmol, 1.34 eq) was stirred at 60 °C for 3 h. The reaction was monitored by TLC and LC/MS.
  • Step 4 To a solution of ethyl 3- ( (1- (2-ethoxy-2-oxoethyl) cyclopropyl) amino) -3-methylbutanoate (980 mg, 3.64 mmol, 1.0 eq) in THF (10 mL) was added t-BuOK (5.46 mL, 5.46 mmol) at 0 °C under N 2 atmosphere. The reaction mixture was stirred at 0 °C for 1 h. LC/MS showed the desired mass. The reaction mixture was poured into saturated aqueous NH 4 Cl (10 mL) . The resulting mixture was extracted with EA (2 x 20 mL) . The organic layer was dried over Na 2 SO 4 and evaporated to dryness.
  • Step 5 A solution of ethyl 7-oxospiro [4-azaspiro [2.5] octane-5, 1'-cyclopropane] -8-carboxylate (618.0 mg, 2.77 mmol, 1.0 eq) in a mixture of H 2 O (5 mL) and H 2 SO 4 (5 mL) was stirred at 120 °C for 1 h.LC/MS showed desired mass. The reaction mixture was poured into ice water. The aqueous layer was adjusted to pH over 9 and extracted with EA (3 x 20 mL) . The crude was concentrated under reduced pressure to yield 5, 5-dimethyl-4-azaspiro [2.5] octan-7-one (326.0 mg, 77.9%) . LC/MS (ESI) : 154.1 [M+H] + .
  • Step 6 To a solution of spiro [4-azaspiro [2.5] octane-5, 1'-cyclopropane] -7-one (86.0 mg, 0.57 mmol, 1.0 eq) in MeOH (5 mL) was added NaBH 4 (64.5 mg, 1.71 mmol, 3.0 eq) at 0 °C. The mixture was stirred at RT for 1 h. LC/MS showed desired mass. The reaction mixture was diluted with H 2 O and the pH was adjusted to 7. The aqueous layer was extracted with EA (2 x 10 mL) and (DCM/propan-2-ol:IPA, 10: 1) . The organic layer was dried over Na 2 SO 4 and evaporated to dryness. The crude product was use directly in the next step without further purification. LC/MS (ESI) : 156.1 [M+H] + .
  • Step 7 To a solution of 5, 5-dimethyl-4-azaspiro [2.5] octan-7-ol (106.0 mg, 0.69 mmol, 1.0 eq) in THF (5 mL) was added NaH (39.0 mg, 0.98 mmol, 1.4 eq) at 0 °C under N 2 atmosphere. The reaction mixture was stirred at 0 °C under N 2 atmosphere for 20 min. Then, 3, 6-diiodo-1, 2-diazine (252.5 mg, 0.76 mmol, 1.1 eq) was added the mixture was stirred at 60 °C overnight.
  • the reaction was cooled to RT and diluted with DMF (5 mL) and then the reaction was stirred for another 3 h at 100 °C. LC/MS showed desired mass.
  • the reaction was cooled to RT and then pouring into water.
  • the aqueous layer was extracted with EA (3 x 10 mL) .
  • the organic layer was washed with brine, dried over Na 2 SO 4 and evaporated to dryness.
  • Step 8 A solution of 7- ( (6-iodopyridazin-3-yl) oxy) -5, 5-dimethyl-4-azaspiro [2.5] octane (48.0 mg, 0.13 mmol, 1.0 eq) , 3- (1, 3-dimethylpyrazol-4-yl) -6, 7-dihydro-5H-pyrrolo [4, 3-b] pyridin-5-one (32.2 mg, 0.14 mmol, 1.05 eq) , (1R, 2R) -cyclohexane-1, 2-diamine (1.5 mg, 0.01 mmol, 0.1 eq) , CuI (2.7 mg, 0.01 mmol, 0.1 eq) , K 2 CO 3 (55.7 mg, 0.40 mmol, 3.0 eq) in DMF (3 mL) was stirred at 120 °C overnight under N 2 atmosphere.
  • Step 1 To a solution of acetone dicarboxylic acid (3.0g, 0.5mmol) in water (20mL) was added cyclopropanecarbaldehyde (2.876 g, 41 mmol) and then (2, 4-dimethoxyphenyl) methanamine (2.8 g, 20.5 mmol) was added portionwise over 10 min. The resulting reaction was stirred at room temperature for 3 days. The reaction mixture was extracted with DCM (3 x 60 mL) and the combined extracts were washed with brine, dried over anhydrous Na 2 SO 4 , and dried under vacuum to give a brown residue. The isomeric piperidones were separated by silica gel chromatography with hexane/ethyl acetate (7/1, v/v) . The desired compound (3.4 g, 54 %) was obtained as a pale yellow oil.
  • Step 3 To a mixture of 2, 6-dicyclopropyl-1- (3, 4-dimethylbenzyl) piperidin-4-ol (2.0 g, 6.03 mmol) in THF (30 mL) was added NaH (0.48 g, 12.07 mmol) at RT under N 2 and the mixture was stirred for 1 h. Then 3, 6-dibromo-1, 2-diazine (1.87 g, 7.84 mmol) was added and the mixture was stirred at 50 °C for 16 h. The mixture was quenched with MeOH and concentrated under vacuum.
  • Step 4 To a mixture of 6- (1, 3-dimethylpyrazol-4-yl) -2, 3-dihydro-1H-pyrrolo [4, 3-c] pyridin-3-one (70 mg, 0.31 mmol) and 3-bromo-6- ( ( (2S, 6S) -2, 6-dicyclopropylpiperidin-4-yl) oxy) pyridazine (149.79 mg, 0.31 mmol) in dioxane (10 mL) was added XantPhos Pd G4 (49.68 mg, 0.03 mmol) and Cs 2 CO 3 (299.77 mg, 0.92 mmol) at RT under N 2 and the mixture was stirred at 95 °C for 3h.
  • Step 5 A mixture of 2- (6- ( ( (2S, 6S) -2, 6-dicyclopropyl-1- (3, 4-dimethylbenzyl) piperidin-4-yl) oxy) pyridazin-3-yl) -6- (1, 3-dimethyl-1H-pyrazol-4-yl) -2, 3-dihydro-1H-pyrrolo
  • Step 1 4-Bromo-2, 5-dimethyl-2H-1, 2, 3-triazole (262.0 mg, 1.5 mmol, 1.5 eq) ; 4, 4, 4', 4', 5, 5, 5', 5'-octamethyl-2, 2'-bi (1, 3, 2-dioxaborolane (762 mg, 3.0 mmol, 3.0 eq) , potassium acetate (300 mg, 3.0 mmol, 3.0 eq) and PdCl 2 (dppf) were added to the CH 2 Cl 2 adduct (109.3 mg, 0.15 mmol, 0.1 eq) and the solids were degassed under N 2 .
  • Step 2 To a round bottom flask charged with 3- (2, 5-dimethyl-2H-1, 2, 3-triazol-4-yl) -6, 7-dihydro-5H-pyrrolo [3, 4-b] pyridin-5-one (37.4 mg, 0.15 mmol, 1.0 eq) , tert-butyl (1R, 3s, 5S) -3- ( (6-bromopyridazin-3-yl) oxy) -1, 5-dimethyl-8-azabicyclo [3.2.1] octane-8-carboxylate (61.8 mg, 0.15 mmol, 1.1 eq) , Cs 2 CO 3 (148.9 mg, 0.46 mmol, 3.0 eq) , and XantPhos Pd G4 (14.2 mg, 0.015 mmol, 0.1 eq) 1, 4-dioxane (4 mL) was added and the reaction mixture was degassed with argon for 5 min and then heated to 90 °
  • Step 1 4-Bromo-2, 5-dimethyl-2H-1, 2, 3-triazole (262.0 mg, 1.5 mmol, 1.5 eq) , 4, 4, 4', 4', 5, 5, 5', 5'-octamethyl-2, 2'-bi (1, 3, 2-dioxaborolane (762 mg, 3.0 mmol, 3.0 eq) , potassium acetate (300 mg, 3.0 mmol, 3.0 eq) and PdCl 2 (dppf) .
  • CH 2 Cl 2 adduct 109.3 mg, 0.15 mmol, 0.1 eq
  • Step 2 3- [1- (Trifluoromethyl) pyrazol-4-yl] -6, 7-dihydro-5H-pyrrolo [4, 3-b] pyridin-5-one (106 mg, 0.46 mmol) , 3-bromo-6- ( (2, 2, 6, 6-tetramethylpiperidin-4-yl) oxy) pyridazine (149.39 mg, 0.46 mmol) , XantPhos Pd G4 (73.95 mg, 0.05 mmol) and Cs 2 CO 3 (446.18 mg, 1.37 mmol) was dissolved in dioxane (8 mL) and the reaction mixture was stirred at 90 °C overnight.
  • Step 1 3-Bromo-6, 7-dihydro-5H-pyrrolo [3, 4-b] pyridin-5-one (213.0 mg, 1.0 mmol, 1.0 eq) , (1-ethyl-3- (trifluoromethyl) -1H-pyrazol-4-yl) boronic acid (312. mg, 1.5 mmol, 1.5 eq) , aqueous potassium carbonate (2 M, 2 mL) and PdCl 2 (dppf) .
  • CH 2 Cl 2 adduct (73.2 mg, 0.1 mmol, 0.1 eq) were charged to a three-neck 100 mL round bottom flask under nitrogen.
  • Step 2 To a round bottom flask charged with 3- (1-ethyl-3- (trifluoromethyl) -1H-pyrazol-4-yl) -6, 7-dihydro-5H-pyrrolo [3, 4-b] pyridin-5-one (44.4 mg, 0.15 mmol, 1.0 eq) , tert-butyl (1R, 3s, 5S) -3- ( (6-bromopyridazin-3-yl) oxy) -1, 5-dimethyl-8-azabicyclo [3.2.1] octane-8-carboxylate (61.8 mg, 0.15 mmol, 1.1 eq) , Cs 2 CO 3 (148.9 mg, 0.46 mmol, 3.0 eq) , and XantPhos Pd G4 (14.2 mg, 0.015 mmol, 0.1 eq) was added 1, 4-dioxane (4 mL) .
  • the reaction mixture was degassed with argon for 5 min and then heated to 90 °C for 8 h.
  • the reaction mixture was cooled to RT and diluted with EA.
  • the organic phase was washed with brine, dried over sodium sulfate, and concentrated under vacuum.
  • the crude product was purified by silica gel column chromatography with DCM/MeOH 20/1, v/v.
  • Step 1 To a solution of 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid (6.58 mL, 56.78 mmol) in 2-methylpropan-2-ol (200 mL) was added ethyl [di (prop-2-yl) ] amine (18.82 mL, 113.56 mmol) and diphenyl azidophosphonate (15.99 mL, 73.81 mmol) and the reaction mixture was stirred at 90 °C for 4 h under N 2 .
  • Step 2 To a solution of tert-butyl (3- (difluoromethyl) -1-methyl-1H-pyrazol-4-yl) carbamate (13.2 g, 53.39 mmol) in MeOH (30 mL) was added 4M HCl-MeOH (60 mL) and the reaction mixture was stirred at 25 °C overnight. Then the reaction mixture was concentrated to obtain the cured product 3- (difluoromethyl) -1-methyl-1H-pyrazol-4-amine (10.2 g) which was used in the next step without further purification. LC/MS (ESI) : 148.1 [M+H] + .
  • Step 3 To a solution of 3- (difluoromethyl) -1-methyl-1H-pyrazol-4-amine (3 g, 20.39 mmol) in acetonitrile (30 mL) was added 2-methyl-2- (nitrosooxidanyl) propane (3.67 mL, 30.59 mmol) and copper bromide (I) (1.24 mL, 40.78 mmol) and the reaction mixture was stirred at 70 °C for 1 h. The mixture was diluted with EA (50 mL*3) and H 2 O (50 mL) and then the organic layer was washed with brine (30 mL*3) , dried over sodium sulfate, and concentrated in vacuo.
  • 2-methyl-2- (nitrosooxidanyl) propane 3.67 mL, 30.59 mmol
  • copper bromide (I) (1.24 mL, 40.78 mmol
  • Step 4 4-Bromo-3- (difluoromethyl) -1-methyl-1H-pyrazole (316.5 mg, 1.5 mmol, 1.5 eq) , 4, 4, 4', 4', 5, 5, 5', 5'-octamethyl-2, 2'-bi (1, 3, 2-dioxaborolane (762 mg, 3.0 mmol, 3.0 eq) , potassium acetate (300 mg, 3.0 mmol, 3.0 eq) and PdCl 2 (dppf) .
  • CH 2 Cl 2 adduct 109.3 mg, 0.15 mmol, 0.1 eq
  • Step 5 To a round bottom flask charged with 3- (3- (difluoromethyl) -1-methyl-1H-pyrazol-4-yl) -6, 7-dihydro-5H-pyrrolo [3, 4-b] pyridin-5-one (39.4 mg, 0.15 mmol, 1.0 eq) , 6-bromo-N-methyl-N- (2,2, 6, 6-tetramethylpiperidin-4-yl) pyridazin-3-amine (61.8 mg, 0.15 mmol, 1.1 eq) , Cs 2 CO 3 (148.9 mg, 0.46 mmol, 3.0 eq) , and XantPhos Pd G4 (14.2 mg, 0.015 mmol, 0.1 eq) was added 1, 4-dioxane (4 mL) .
  • reaction mixture was degassed with argon for 5 min and then heated at 90 °C for 8 h.
  • the reaction mixture was cooled to RT and diluted with EA.
  • the organic phase was washed with brine, dried over sodium sulfate, and concentrated under vacuum.
  • Step 1 To a solution of (S) -2- ( ( ( (9H-fluoren-9-yl) methoxy) carbonyl) amino) -2-cyclopropylacetic acid (10 g, 28.29 mmol, 1.0 eq) and methyl aminoacetate (3.0 g, 33.95 mmol, 1.2 eq) in acetonitrile (50 mL) was added DIEA (9.1 g, 70.74 mmol, 2.5 eq) and HATU (11.8 g, 31.12 mmol, 1.1 eq) , and the reaction mixture was stirred at RT for 16 h.
  • Step 2 A solution of methyl (S) - (2- ( ( ( (9H-fluoren-9-yl) methoxy) carbonyl) amino) -2-cyclopropylacetyl) glycinate (5.0 g, 11.78 mmol, 1.0 eq) in acetonitrile (100 mL) was stirred RT for 16 h. After the reaction was completed, the solution was concentrated in vacuo to provided (S) -3-cyclopropylpiperazine-2, 5-dione (4.85 g, 11.43 mmol, 97.00%) as a sightly yellow solid.
  • LC/MS (ESI) 155.1 [M+H] + .
  • Step 3 LiAlH 4 (2.14 g, 56.40 mmol, 6.0 eq) was added to a vigorous stirred solution of (S) -3-cyclopropylpiperazine-2, 5-dione (1.6 g, 9.40 mmol, 1.0 eq) in THF (20 mL) in an ice bath, and then the reaction mixture was stirred at 70 °C for 16 h. After the reaction was completed, the mixture was poured into KOH (6N) and stirred in an ice bath for 1 h.
  • Step 4 DIEA (1.13 g, 8.79 mmol, 1.46 mL, 2.5 eq) was added to a vigorous stirred solution of (2S) -2- (2-methylprop-2-yl) piperazine (0.5 g, 3.51 mmol, 1.0 eq) and 3, 6-diiodo-1, 2-diazine (1.17 g, 3.51 mmol, 1.0 eq) in n-BuOH (7 mL) , and the reaction mixture was stirred at 120 °C for 16 h.
  • Step 5 Pd (dppf) Cl 2 (49 mg, 0.06 mmol, 0.05 eq) was added to a vigorous stirred solution of 1-methyl-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrazole (250 mg, 1.20 mmol, 1.0 eq) , 3-bromo-6, 7-dihydro-5H-pyrrolo [4, 3-b] pyridin-5-one (256 mg, 1.20 mmol, 1.0 eq) and K 2 CO 3 (332 mg, 2.40 mmol, 2.0 eq) in dioxane (5 mL) and water (1 mL) . The reaction mixture was stirred at 80 °C for 16 h.
  • Step 6 6- (1-Methylpyrazol-4-yl) -2, 3-dihydro-1H-pyrrolo [4, 3-c] pyridin-1-one (50 mg, 0.23 mmol, 1.0 eq) and (S) -3- (3-cyclopropylpiperazin-1-yl) -6-iodopyridazine (80 mg, 0.23 mmol, 1.0 eq) were dissolved in DMF (2 mL) , and CuI (4 mg, 0.02 mmol, 0.10 eq) , K 2 CO 3 (97 mg, 0.70 mmol, 3.0 eq) and (1R, 2R) -cyclohexane-1, 2-diamine (2.7 mg, 0.02 mmol, 0.10 eq) were added and the reaction mixture was stirred at 100 °C for 16 h.
  • Step 1 3-Bromo-6, 7-dihydro-5H-pyrrolo [3, 4-b] pyridin-5-one (213.0 mg, 1.0 mmol, 1.0 eq) , 4-methyl-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) thiazole (375 mg, 1.5 mmol, 1.5 eq) , aqueous potassium carbonate (2 M, 2 mL) and PdCl 2 (dppf) .
  • CH 2 Cl 2 adduct (73.2 mg, 0.1 mmol, 0.1 eq) were charged to a three-neck 100 mL round bottom flask under nitrogen.
  • Step 2 To a round bottom flask charged with 3- (4-methylthiazol-5-yl) -6, 7-dihydro-5H-pyrrolo [3, 4-b] pyridin-5-one (44.4 mg, 0.15 mmol, 1.0 eq) , tert-butyl (1R, 3s, 5S) -3- ( (6-bromopyridazin-3-yl) oxy) -1, 5-dimethyl-8-azabicyclo [3.2.1] octane-8-carboxylate (61.8 mg, 0.15 mmol, 1.1 eq) , Cs 2 CO 3 (148.9 mg, 0.46 mmol, 3.0 eq) , and XantPhos Pd G4 (14.2 mg, 0.015 mmol, 0.1 eq) was added 1, 4-dioxane (4 mL) .
  • the reaction mixture was degassed with argon for 5 min and was then heated to 90 °Cfor 8 h.
  • the reaction mixture was cooled RT and diluted with EA.
  • the organic phase was washed with brine, dried over sodium sulfate, and concentrated under vacuum.
  • the crude product was purified by silica gel column chromatography with DCM/MeOH 20/1, v/v, and was then dissolved HCl in dioxane (2 mL, 4.0 mol/L) .
  • the reaction mixture was stirred at RT for 1 h, and was then concentrated.
  • Step 1 To a solution of 3- ( (tert-butoxycarbonyl) amino) -3-methylbutanoic acid (12.0 g, 55.23 mmol, 1.0 eq) in THF (100 mL) was added CDI (10.75 g, 66.28 mmol, 1.20 eq) and the reaction mixture was stirred at RT for 1 h. Then added MgCl 2 (2.62 g, 43.08 mmol, 0.78 eq) and potassium 3- (tert-butoxy) -3-oxopropanoate (16.43 g, 82.85 mmol, 1.5 eq) were added and the reaction mixture was stirred at 50 °C overnight.
  • Step 2 To a solution of tert-butyl 5- ( (tert-butoxycarbonyl) amino) -5-methyl-3-oxohexanoate (5.0 g, 15.85 mmol, 1.0 eq) in DCM (10 mL) was added HCl/dioxane (5 mL) and the reaction mixture was stirred at RT for 1 h. After the reaction was completed, the reaction mixture was concentrated to give tert-butyl 5-amino-5-methyl-3-oxohexanoate (3.4 g, 99.9%) .
  • LC/MS (ESI) 216.2 [M+H] + .
  • Step 3 To a solution of tert-butyl 5-amino-5-methyl-3-oxohexanoate (3.1 g, 16.84 mmol, 1.0 eq) in DCM (18 mL) was added K 2 CO 3 (4.98 g, 36.0mmol, 2.5 eq) and cyclobutanone (5.43 mL, 70.09 mmol, 5.0 eq) and the reaction mixture was stirred at RT for 72 h. LC/MS showed desired mass. The reaction mixture was filtered and the filtrate was washed with water and brine, dried over Na 2 SO 4 and concentrated.
  • Step 4 To a solution of tert-butyl 6, 6-dimethyl-8-oxo-5-azaspiro [3.5] nonane-9-carboxylate (1200 mg, 4.49 mmol, 1.0 eq) in a mixture of H 2 O (18 mL) and H 2 SO 4 (2 mL) was added and the reaction mixture was stirred at 120 °C for 1 h. LC/MS showed desired mass. The reaction mixture was poured into ice water and the pH was adjusted to over 9. The aqueous layer was extracted with EA (3 x 20 mL) . The organic layer was dried over Na 2 SO 4 and concentrated under reduced pressure.
  • Step 5 To a solution of 6, 6-dimethyl-5-azaspiro [3.5] nonan-8-one (620 mg, 3.71 mmol, 1.0 eq) in MeOH (10 mL) was added NaBH 4 (140 mg, 3.71 mmol, 1.0 eq) at 0 °C. The reaction mixture was stirred at RT for 1 h. LC/MS showed the desired mass. The reaction mixture was the diluted with H 2 O and the pH was adjusted to around 7. The aqueous layer was extracted with EA (2 x 10 mL) and (DCM/propan-2-ol: IPA, 10: 1) . The organic layer was dried over Na 2 SO 4 and concentrated under reduced pressure.
  • Step 6 To a solution of 6, 6-dimethyl-5-azaspiro [3.5] nonan-8-ol (540.0 mg, 3.19 mmol, 1.0 eq) in THF (10 mL) was added NaH (153.13 mg, 3.83 mmol, 1.2 eq, 60%) at 0 °C under N 2 atmosphere and the reaction mixture was stirred for 20 min. Then, 3, 6-dibromo-1, 2-diazine (758.88 mg, 3.19 mmol, 1.0 eq) was added and the resulting mixture was stirred at 60 °C overnight. Next the reaction mixture was cooled to RT and the mixture was poured into water. The aqueous layer was extracted with EA (3 x 10 mL) .
  • Step 7 3-Bromo-6, 7-dihydro-5H-pyrrolo [3, 4-b] pyridin-5-one (211.0 mg, 1.0 mmol, 1.0 eq) , 1, 3-dimethyl-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (244.1 mg, 1.10 mmol, 1.1 eq) , aqueous potassium carbonate (2 M, 8 mL) and PdCl 2 (dppf) .
  • CH 2 Cl 2 adduct (73.3 mg, 0.1 mmol, 0.1 eq) were charged to a three-neck 100 mL round bottom flask under nitrogen.
  • Step 8 To a round bottom flask charged with 3- (1, 3-dimethyl-1H-pyrazol-4-yl) -6, 7-dihydro-5H-pyrrolo [3, 4-b] pyridin-5-one (34.2 mg, 0.15 mmol, 1.0 eq) , 8- ( (6-bromopyridazin-3-yl) oxy) -6, 6-dimethyl-5-azaspiro [3.5] nonane (48.9 mg, 0.15 mmol, 1.1 eq) , Cs 2 CO 3 (148.9 mg, 0.46 mmol, 3.0 eq) , and XantPhos Pd G4 (14.2 mg, 0.015 mmol, 0.1 eq) was added 1, 4-dioxane (4 mL) .
  • the reaction mixture was degassed with argon for 5 min and was then heated to 90 °C for 8 h.
  • the reaction mixture was cooled to RT and diluted with A.
  • the organic phase was washed with brine, dried over sodium sulfate, and concentrated under vacuum.
  • the crude product was purified by silica gel column chromatography with DCM/MeOH 20/1, v/v to obtain 5- (1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-4-yl) isoindolin-1-one (42.2 mg) , which was dissolved in HCl-dioxane (2 mL, 4.0 mol/L) .
  • the reaction was stirred at RT for 1 h, and was then concentrated.
  • Step 1 A solution of 2-methylpropan-2-yl 3-oxopiperazine-1-carboxylate (2.00 g, 9.99 mmol, 1.00 eq) , 3, 6-dibromo-1, 2-diazine (11.89 g, 99.90 mmol, 5.00 eq) , Cs 2 CO 3 (9.76 g, 29.97 mmol, 3.00 eq) , Pd(dba) Cl 2 (1.00 g, 1.00 mmol, 0.10 eq) and Xanphos (1.00 g, 2.00 mmol, 0.20 eq) in 1, 4-dioxane (150 mL) was stirred at 100 °C for 16 h.
  • Step 2 A mixture of 3- (2, 4-dimethyl-1, 3-thiazol-5-yl) -6, 7-dihydro-5H-pyrrolo [4, 3-b] pyridin-5-one (100 mg, 0.41 mmol, 1.0 eq) , 2-methylpropan-2-yl 4- (6-bromo-1, 2-diazin-3-yl) -3-oxopiperazine-1-carboxylate (174.75 mg, 0.49 mmol, 1.2 eq) , Cs 2 CO 3 (398.48 mg, 1.22 mmol, 3.0 eq) and XantPhos Pd G4 (66.04 mg, 0.04 mmol, 0.1 eq) in dioxane (1 mL) was stirred under N 2 at 100 °C for 3 h.
  • Step 1 3-Bromo-6, 7-dihydro-5H-pyrrolo [3, 4-b] pyridin-5-one (213.0 mg, 1.0 mmol, 1.0 eq) , 1-methyl-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (312. mg, 1.5 mmol, 1.5 eq) , aqueous potassium carbonate (2 M, 2 mL) and PdCl 2 (dppf) .
  • CH 2 Cl 2 adduct (73.2 mg, 0.1 mmol, 0.1 eq) were charged to a three-neck 100 mL round bottom flask under nitrogen.
  • Step 2 To a round bottom flask charged with 3- (1-methyl-1H-pyrazol-4-yl) -6, 7-dihydro-5H-pyrrolo [3, 4-b] pyridin-5-one (32.2 mg, 0.15 mmol, 1.0 eq) , tert-butyl (S) -4- (6-bromopyridazin-3-yl) -2-isopropylpiperazine-1-carboxylate (57.6 mg, 0.15 mmol, 1.1 eq) , Cs 2 CO 3 (148.9 mg, 0.46 mmol, 3.0 eq) , and XantPhos Pd G4 (14.2 mg, 0.015 mmol, 0.1 eq) was added 1, 4-dioxane (4 mL) .
  • the reaction mixture was degassed with argon for 5 min and was then heated at 90 °C for 8 h.
  • the reaction mixture was cooled to RT and was diluted with EA.
  • the organic phase was washed with brine, dried over sodium sulfate, and was concentrated under vacuum.
  • the crude product was purified by silica gel column chromatography with DCM/MeOH 20/1, v/v, and was then dissolved HCl in dioxane (2 mL, 4.0 mol/L) .
  • the reaction was stirred at RT for 1 h, and was then concentrated.
  • Step 2 To a solution of 6-bromo-3-chloro-1, 2, 4-triazine (200 mg, 1.03 mmol) and (1R, 5S) -N, 1, 5-trimethyl-8-azabicyclo [3.2.1] octan-3-amine (192.71 mg, 1.13 mmol) in toluene (10 mL) was added DIEA (0.34 mL, 2.06 mmol) and the reaction mixture was stirred at 120 °C for 3 h. LC/MS showed the reaction was completed.
  • Step 3 To a solution of 3- (1, 3-dimethylpyrazol-4-yl) -6, 7-dihydro-5H-pyrrolo [4, 3-b] pyridin-5-one (35 mg, 0.15 mmol) and (1R, 3S, 5S) -N- (6-bromo-1, 2, 4-triazin-3-yl) -N, 1, 5-trimethyl-8-azabicyclo [3.2.1] octan-3-amine (52 mg, 0.16 mmol) in dioxane (10 mL) was added BrettPhos Pd G4 (13.61 mg, 0.01 mmol) and Cs 2 CO 3 (146.62 mg, 0.45 mmol) ; and the reaction mixture was stirred at 90 °C for 16 h under N 2 .
  • Step 1 A solution of ethyl 5-bromo-2-methylnicotinate (3.00 g, 12.35 mmol, 1.00 eq) , benzoyl peroxide (5.98 g, 24.70 mmol, 2.00 eq) and N-bromosuccinimide (4.37 g, 24.70 mmol, 2.00 eq) in carbon tetrachloride (30 mL) was stirred at 80 °C for 16 h. After consumption of the starting material, the reaction mixture was concentrated under vacuum.
  • Step 2 A solution of ethyl 5-bromo-2- (bromomethyl) nicotinate (2.00 g, 6.23 mmol, 1.00 eq) and ammonia (1.06, 62.30 mmol, 10.0 eq) in isopropanol (10 mL) was stirred at 25 °C for 6 h. After consumption of the starting material, the reaction mixture was concentrated under vacuum.
  • Step 3 3-Bromo-6, 7-dihydro-5H-pyrrolo [3, 4-b] pyridin-5-one (1.00 g, 5.0 mmol, 1.00 eq) , 2, 4-dimethyl-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) thiazole) (1.31 g, 5.50 mmol, 1.10 eq) , aqueous potassium carbonate (2 M, 8 mL) and PdCl 2 (dppf) . CH 2 Cl 2 adduct (365.7 mg, 0.50 mmol, 0.1 eq) were charged to a three-neck 100 mL round bottom flask under nitrogen.
  • Step 4 A solution of 2, 2, 6, 6-tetramethylhexahydropyridin-4-one (10.0 g, 64.42 mmol, 1.00 eq) , cyclohexanone (18.97 g, 193.25 mmol, 3.00 eq) and NH 4 Cl (20.67 g, 386.50 mmol, 6.00 eq) in DMSO (30 mL) was stirred at 80 °C for 48 h. After consumption of the starting material, the mixture was cooled to room temperature and diluted with 100 mL of water. The aqueous layer was extracted with EA (3 x 100 mL) .
  • Step 5 To a solution of spiro [1-azaspiro [5.5] undecane-2, 1'-cyclohexane] -4-one (6.40 g, 27.19 mmol, 1.00 eq) in MeOH (65 mL) , NaBH 4 (0.51 g, 13.60 mmol, 0.50 eq) was added at 0 °C; and the reaction mixture was stirred at room temperature for 3 h. After consumption of the starting material, the reaction mixture was concentrated under vacuum.
  • Step 6 To a solution of spiro [1-azaspiro [5.5] undecane-2, 1'-cyclohexane] -4-ol (3.00 g, 12.64 mmol, 1.00 eq) in THF (30 mL) , NaH (0.76 g, 31.59 mmol, 2.50 eq) was added dropwise over 30 min at 0 °C. Next the resulting mixture was stirred under N 2 at 25 °C for 0.5 h. Then 3, 6-dibromo-1, 2-diazine (3.61 g, 15.16 mmol, 1.20 eq) was added and the reaction mixture was stirred under N 2 at 25 °C for 24 h.
  • Step 7 To a solution of 4- [ (6-bromo-1, 2-diazin-3-yl) oxy] spiro [1-azaspiro [5.5] undecane-2, 1'-cyclohexane] (0.9 g, 2.28 mmol, 1.00 eq) , 3- (1, 3-dimethylpyrazol-4-yl) -6, 7-dihydro-5H-pyrrolo [4, 3-b] pyridin-5-one (0.63 g, 2.74 mmol, 1.20 eq) and Cs 2 CO 3 (2.23 g, 6.85 mmol, 3.00 eq) in 1, 4-dioxane (15 mL) was added XPhos Pd G4 (0.20 g, 0.23 mmol, 0.10 eq) at 25 °C; and the reaction mixture was stirred under N 2 at 90 °C for 4 h.
  • Step 1 To the solution of methyl 3-amino-5-bromo-2-methylbenzoate (1.0 g, 4.10 mmol) in DCM (10 mL) , nitrosonium tetrafluoroborate, (480 mg, 4.10 mmol) was added portionwise at 0 °C under N 2 ; and the reaction mixture was stirred at 0 °C for 1 h. Then oxylene (30 mL) was added and the reaction mixture was refluxed at 130 °C for 3 h. The reaction mixture was cooled to room temperature and poured into H 2 O and the aqueous layer was extracted EA. The organic layer was washed with brine, dried over MgSO 4 , filtered, and concentrated. The crude product was purified by silica gel column chromatography with PE/EA 10/1, v/v to afford methyl 5-bromo-3-fluoro-2-methylbenzoate (860 mg, 85%) .
  • Step 2 To the solution of 5-bromo-3-fluoro-2-methylbenzoate (860 mg, 3.5 mmol) and NBS (623 mg, 3.5 mmol) in (trifluoromethyl) benzene (10 mL) , was added AIBN (57 mg, 0.35 mmol) ; and the reaction mixture was stirred under N 2 at 100 °C for 16 h. Then the reaction mixture was cooled to room temperature and was poured into H 2 O. The aqueous layer was extracted EA. The organic layer was washed with brine, dried over MgSO 4 , filtered, and concentrated. The crude product was purified by silica gel column chromatography with PE/EA 10/1, v/v to afford methyl 5-bromo-2- (bromomethyl) -3-fluorobenzoate (800 mg, 70%) .
  • Step 3 To a solution of methyl 5-bromo-2- (bromomethyl) -3-fluorobenzoate (800 mg, 2.5 mmol) in THF (7 mL) , NH 4 OH (7 mL) was added and the reaction mixture was stirred at RT for 4 h. The reaction mixture was filtered and concentrated under vacuum. The crude product was used for directly in the next step.
  • Step 4 6-Bromo-4-fluoroisoindolin-1-one (343.0 mg, 1.5 mmol, 1.5 eq) , 4, 4, 4', 4', 5, 5, 5', 5'-octamethyl-2, 2'-bi (1, 3, 2-dioxaborolane (762 mg, 3.0 mmol, 3.0 eq) , potassium acetate (300 mg, 3.0 mmol, 3.0 eq) and PdCl 2 (dppf) .
  • CH 2 Cl 2 adduct (109.3 mg, 0.15 mmol, 0.1 eq) were charged to a three-neck 100 mL round bottom flask under nitrogen.
  • Step 5 To a round bottom flask charged with 6- (2, 5-dimethyl-2H-1, 2, 3-triazol-4-yl) -4-fluoroisoindolin-1-one (36.9 mg, 0.15 mmol, 1.0 eq) , tert-butyl (1R, 3S, 5S) -3- ( (6-bromopyridazin-3-yl) oxy) -1, 5-dimethyl-8-azabicyclo [3.2.1] octane-8-carboxylate (61.8 mg, 0.15 mmol, 1.1 eq) , Cs 2 CO 3 (148.9 mg, 0.46 mmol, 3.0 eq) , and XantPhos Pd G4 (14.2 mg, 0.015 mmol, 0.1 eq) was added 1, 4-dioxane (4 mL) .
  • the reaction mixture was degassed with argon for 5 min and was then heated at 90 °Cfor 8 h.
  • the reaction mixture was cooled to RT and was then diluted with EA.
  • the organic phase was washed with brine, dried over sodium sulfate, and concentrated under vacuum.
  • the crude product was purified by silica gel column chromatography with DCM/MeOH 20/1, v/v, and was then dissolved HCl in dioxane (2 mL, 4.0 mol/L) .
  • the reaction was stirred at RT for 1 h, and was then concentrated.
  • Step 1 To a solution of (2S) -2- ( ⁇ [ (9H-fluoren-9-ylmethyl) oxy] carbonyl ⁇ amino) -3, 3-dimethylbutanoic acid (10 g, 28.29 mmol, 1.0 eq) and methyl aminoacetate (3.0 g, 33.95 mmol, 1.2 eq) in acetonitrile (50 mL) was added DIEA (9.1 g, 70.74 mmol, 2.5 eq) and HATU (11.8 g, 31.12 mmol, 1.1 eq) , and the reaction mixture was stirred at RT for 16 h.
  • Step 2 A solution of 9H-fluoren-9-ylmethyl ⁇ [ (7S) -8, 8-dimethyl-3, 6-dioxo-5-aza-2-oxanon-7-yl] amino ⁇ methanoate (5.0 g, 11.78 mmol, 1.0 eq) in acetonitrile (100 mL) was stirred RT for 16 h.
  • Step 3 LiAlH 4 (2.14 g, 56.40 mmol, 6.0 eq) was added to a vigorous stirred solution of (3S) -3-(2-methylprop-2-yl) piperazine-2, 5-dione (1.6 g, 9.40 mmol, 1.0 eq) in THF (20 mL) in an ice bath, and the resulting reaction mixture was stirred at 70 °C for 16 h. Next the mixture was poured into KOH (6N) , and the mixture was stirred in an ice bath for 1 h and was then filtered.
  • Step 4 DIEA (1.13 g, 8.79 mmol, 1.46 mL, 2.5 eq) was added to a vigorous stirred solution of (2S) -2- (2-methylprop-2-yl) piperazine (0.5 g, 3.51 mmol, 1.0 eq) and 3, 6-diiodo-1, 2-diazine (1.17 g, 3.51 mmol, 1.0 eq) in n-BuOH (7 mL) at RT, and the reaction mixture was stirred at 120 °C for 16 h.
  • Step 5 Pd (dppf) Cl 2 (49 mg, 0.06 mmol, 0.05 eq) was added to a vigorous stirred solution of 1-methyl-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrazole (250 mg, 1.20 mmol, 1.0 eq) , 3-bromo-6, 7-dihydro-5H-pyrrolo [4, 3-b] pyridin-5-one (256 mg, 1.20 mmol, 1.0 eq) and K 2 CO 3 (332 mg, 2.40 mmol, 2.0 eq) in dioxane (5 mL) and water (1 mL) and the resulting reaction mixture was stirred at 80 °Cfor 16 h.
  • 1-methyl-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrazole 250 mg, 1.20 mmol, 1.0 eq
  • Step 6 To the solution of methyl 3-amino-5-bromo-2-methylbenzoate (1.0 g, 4.10 mmol) in DCM (10 mL) , was nitrosonium tetrafluoroborate, (480 mg, 4.10 mmol) was added portionwise at 0 °C under N 2 and the resulting reaction mixture was stirred at 0 °C for 1 h. Then oxylene (30 mL) was added and the reaction mixture was refluxed at 130 °C for 3 h. The reaction mixture was cooled to room temperature and poured into H 2 O. The aqueous layer was extracted EA. The organic layer was washed with brine, dried over MgSO 4 , filtered, and concentrated. The crude product was purified by silica gel column chromatography with PE/EA 10/1, v/v to obtain methyl 5-bromo-3-fluoro-2-methylbenzoate (860 mg, 85%) .
  • Step 7 To the solution of 5-bromo-3-fluoro-2-methylbenzoate (860 mg, 3.5 mmol) and NBS (623 mg, 3.5 mmol) in (trifluoromethyl) benzene (10 mL) , was AIBN (57 mg, 0.35 mmol) was added; and the reaction mixture was stirred under N 2 at 100 °C for 16 h. The reaction mixture was then cooled to room temperature and poured into H 2 O. The aqueous layer was extracted EA. The organic layer was washed with brine, dried over MgSO 4 , filtered, and concentrated. The crude product was purified by silica gel column chromatography with PE/EA 10/1, v/v to obtain methyl 5-bromo-2- (bromomethyl) -3-fluorobenzoate (800 mg, 70%) .
  • Step 8 To a solution of methyl 5-bromo-2- (bromomethyl) -3-fluorobenzoate (800 mg, 2.5 mmol) dissolved in THF (7 mL) , NH 4 OH (7 mL) was added and the reaction was stirred at RT for 4 . The reaction mixture was filtered and concentrated under vacuum. The crude product was used directly in the next step.
  • Step 9 6-Bromo-4-fluoroisoindolin-1-one (228 mg, 1.0 mmol, 1.0 eq) , 1, 3-dimethyl-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (244.1 mg, 1.10 mmol, 1.1 eq) , aqueous potassium carbonate (2 M, 8 mL) and PdCl 2 (dppf) .
  • CH 2 Cl 2 adduct (73.3 mg, 0.1 mmol, 0.1 eq) were charged to a three-neck 100 mL round bottom flask under nitrogen.
  • Step 10 6- (1, 3-Dimethyl-1H-pyrazol-4-yl) -4-fluoroisoindolin-1-one (50 mg, 0.23 mmol, 1.0 eq) and 6-iodo-3- [ (3S) -3- (2-methylprop-2-yl) piperazin-1-yl] -1, 2-diazine (80 mg, 0.23 mmol, 1.0 eq) were dissolved in DMF (2 mL) , and CuI (4 mg, 0.02 mmol, 0.10 eq) , K 2 CO 3 (97 mg, 0.70 mmol, 3.0 eq) and (1R, 2R) -cyclohexane-1, 2-diamine (2.7 mg, 0.02 mmol, 0.10 eq) were added and the resulting reaction mixture was stirred at 100 °C for 16 h.
  • Step 1 6-Bromo-4-fluoroisoindolin-1-one (457.9 mg, 2.0 mmol, 1.0 eq) , 2, 4-dimethyl-5- (4,4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) thiazole) (526.1 mg, 2.20 mmol, 1.1 eq) , aqueous potassium carbonate (2 M, 8 mL) and PdCl 2 (dppf) . CH 2 Cl 2 adduct (146.3 mg, 0.2 mmol, 0.1 eq) were charged to a three-neck 100 mL round bottom flask under nitrogen.
  • Step 2 To a round bottom flask charged with 6- (2, 4-dimethylthiazol-5-yl) -4-fluoroisoindolin-1-one (37.4 mg, 0.15 mmol, 1.0 eq) , tert-butyl 7- (6-bromopyridazin-3-yl) -4, 7-diazaspiro [2.5] octane-4-carboxylate (55.2 mg, 0.15 mmol, 1.1 eq) , Cs 2 CO 3 (148.9 mg, 0.46 mmol, 3.0 eq) , and XantPhos Pd G4 (14.2 mg, 0.015 mmol, 0.1 eq) was added 1, 4-dioxane (4 mL) .
  • the reaction mixture was degassed with argon for 5 min and was then heated to 90 °C for 8 h.
  • the reaction mixture was cooled to RT and was then diluted with EA.
  • the organic phase was washed with brine, dried over sodium sulfate, and concentrated under vacuum.
  • the crude product was purified by silica gel column chromatography with DCM/MeOH 20/1, v/v to obtain 5- (1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-4-yl) isoindolin-1-one (42.2 mg) , which was dissolved HCl in dioxane (2 mL, 4.0 mol/L) .
  • the reaction was stirred at RT for 1 h and was then concentrated.
  • Step 1 6-Bromoisoindolin-1-one (426.0 mg, 2.0 mmol, 1.0 eq) , 1, 3-dimethyl-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (488 mg, 2.20 mmol, 1.1 eq) , aqueous potassium carbonate (2 M, 8 mL) and PdCl 2 (dppf) .
  • CH 2 Cl 2 adduct 146.3 mg, 0.2 mmol, 0.1 eq
  • Anhydrous dioxane (9 mL) was added and the reaction mixture was heated to 85 °C overnight.
  • Step 2 To a round bottom flask charged with 6- (1, 3-dimethyl-1H-pyrazol-4-yl) isoindolin-1-one (34.2 mg, 0.15 mmol, 1.0 eq) , tert-butyl (1R, 3s, 5S) -3- ( (6-bromopyridazin-3-yl) oxy) -1, 5-dimethyl-8-azabicyclo [3.2.1] octane-8-carboxylate (61.8 mg, 0.15 mmol, 1.1 eq) , Cs 2 CO 3 (148.9 mg, 0.46 mmol, 3.0 eq) , and XantPhos Pd G4 (14.2 mg, 0.015 mmol, 0.1 eq) was added 1, 4-dioxane (4 mL) .
  • the reaction mixture was degassed with argon for 5 min and was then heated to 90 °C for 8 h.
  • the reaction mixture was cooled down to RT and was then diluted with EA.
  • the organic phase was washed with brine, dried over sodium sulfate, and concentrated under vacuum.
  • the crude product was purified by silica gel column chromatography with DCM/MeOH 20/1, v/v, and was then dissolved HCl in dioxane (2 mL, 4.0 mol/L) .
  • the reaction was stirred at RT for 1 h and was then concentrated.
  • Example 28 Synthesis of 6- (1, 3-dimethyl-1H-pyrazol-4-yl) -2- (6- ( ( (1R, 3s, 5S) -1, 5-dimethyl-8-azabicyclo [3.2.1] octan-3-yl) oxy) pyridazin-3-yl) -7-fluoro-2, 3-dihydro-1H-pyrrolo [3, 4-c] pyridin-1-one (Compound No. 116)
  • Step 1 LDA (48 mL, 2.0 mol in THF) was added dropwise into a solution of 5-bromo-2-chloro-3-fluoropyridine (10 g, 47.52 mmol) in THF (200 mL) at -78 °C under N 2 and the reaction mixture was stirred at -78 °C for 2 h. The mixture was poured into the CO 2 (solid) in THF. The reaction mixture was then concentrated under vacuum. The pH value of the residue was adjusted to 3 with 2 M HCl. The resulting mixture was extracted with EA, washed with brine, dried over MgSO 4 , and concentrated under vacuum to afford the desired product (12 g, crude) as a white solid.
  • Step 2 To a solution of 5-bromo-2-chloro-3-fluoroisonicotinic acid (12 g, 51.2 mmol) and K 2 CO 3 (5.7 g, 41.7 mmol) in DMF (80 mL) , MeI (3.4 mL, 54.7 mmol) was added portionwise; and the reaction mixture was stirred at RT for 16 h. The reaction mixture was poured into H 2 O. The aqueous layer was extracted EA. The organic layer was washed with brine, dried over MgSO 4 , filtered, and concentrated. The crude product was purified by silica gel column chromatography with PE/EA 10/1, v/v to obtain methyl 5-bromo-2-chloro-3-fluoroisonicotinate (10 g, 79%) .
  • Step 3 To the solution of 5-bromo-2-chloro-3-fluoroisonicotinate (2500 mg, 9.4 mmol) and 2, 4, 6-trimethyl-1, 3, 5, 2, 4, 6-trioxatriborinane in dioxane (25 mL) , was added potassium carbonate (2600 mg, 18.8 mmol) and PdCl 2 (dppf) (500 mg, 0.94 mmol) ; and the reaction mixture was stirred under N 2 at 110 °C for 1 h. Then the mixture was cooled, filtered through a pad of Celite and the filter cake was washed with EA. The filtrate was washed with brine and the organic layer was collected, dried over sodium sulfate, and concentrated in vacuo. The crude product was purified by silica gel column chromatography with PE/EA 10/1, v/v to afford methyl 2-chloro-3-fluoro-5-methylisonicotinate (673 mg, 35.3%) .
  • Step 4 To a solution of methyl 2-chloro-3-fluoro-5-methylisonicotinate (320 mg, 1.6 mmol) and NBS (285 mg, 1.6 mmol) in CCl 4 (10 mL) , was added BPO (40 mg, 0.16 mmol) ; and the reaction mixture was stirred under N 2 at 80 °C for 16 h. The mixture was cooled to room temperature and was then poured into H 2 O. The aqueous layer was extracted EA. The organic layer was washed with brine, dried over MgSO 4 , filtered, and concentrated. The crude product was purified by silica gel column chromatography with PE/EA 5/1, v/v to afford methyl 5- (bromomethyl) -2-chloro-3-fluoroisonicotinate (356 mg, 80%) .
  • Step 5 Methyl 5- (bromomethyl) -2-chloro-3-fluoroisonicotinate (356 mg, 1.26 mmol) was dissolved in THF (5 mL) and NH 4 OH (5 mL) was added; and the reaction was stirred at RT for 3 h. The reaction mixture was filtered and concentrated under vacuum. The crude product was used directly in the next step.
  • Step 6 6-Chloro-7-fluoro-2, 3-dihydro-1H-pyrrolo [3, 4-c] pyridin-1-one (186.0 mg, 1.0 mmol, 1.0 eq) , 1, 3-dimethyl-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (312 mg, 1.5 mmol, 1.5 eq) , aqueous potassium carbonate (2 M, 2 mL) and PdCl 2 (dppf) .
  • Step 7 To a round bottom flask charged with 6- (1, 3-dimethyl-1H-pyrazol-4-yl) -7-fluoro-2, 3-dihydro-1H-pyrrolo [3, 4-c] pyridin-1-one (36.9 mg, 0.15 mmol, 1.0 eq) , tert-butyl (S) -4- (6-bromopyridazin-3-yl) -2-isopropylpiperazine-1-carboxylate (57.6 mg, 0.15 mmol, 1.1 eq) , Cs 2 CO 3 (148.9 mg, 0.46 mmol, 3.0 eq) , and XantPhos Pd G4 (14.2 mg, 0.015 mmol, 0.1 eq) was added 1, 4-dioxane (4 mL) .
  • the reaction mixture was degassed with argon for 5 min and was then heated to 90 °C for 8 h.
  • the reaction mixture was cooled to RT and was diluted with EA.
  • the organic phase was washed with brine, dried over sodium sulfate, and concentrated under vacuum.
  • the crude product was purified by silica gel column chromatography with DCM/MeOH 20/1, v/v, and was then dissolved HCl in dioxane (2 mL, 4.0 mol/L) .
  • the reaction was stirred at RT for 1 h and was then concentrated.
  • Step 1 To methyl 2-chloro-3-methylisonicotinate (5000 mg, 27.03 mmol) in TFA (50 mL) , H 2 O 2 (42.16 mL, 351.35 mmol) was added and the mixture was stirred for 4 h. The mixture was cooled to RT and quenched with aqueous Na 2 SO 3 . The mixture was concentrated under vacuum and the residue was redissolved in EA (300 mL) . The mixture was washed with brine and the organic layer was collected, dried over sodium sulfate, and concentrated in vacuo.
  • Step 2 POBr3 (6398.79 mg, 22.32 mmol) was added to the solution of 2-chloro-4- (methoxycarbonyl) -3-methylpyridine 1-oxide (3000 mg, 14.88 mmol) in toluene (30 mL) at RT and the reaction mixture was stirred at 80 °C for 4 h. The reaction mixture was cooled to RT and was quenched with aqueous Na 2 CO 3 . This mixture was extracted with EA (3 x 100 mL) and the combined extracts were dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure.
  • Step 3 Methyl 6-bromo-2-chloro-3-methylpyridine-4-carboxylate (1500 mg, 5.67 mmol) , NBS (1513.80 mg, 8.50 mmol) and AIBN (0.17 mL, 1.13 mmol) were combined with carbon tetrachloride (40 mL); and the reaction mixture was heated to 80 °C for 3 h. The reaction mixture was cooled to RT and concentrated under vacuum.
  • Step 4 Methyl 6-bromo-3- (bromomethyl) -2-chloropyridine-4-carboxylate (1150 mg, 3.35 mmol) was suspended in 28 %aqueous ammonium hydroxide and the mixture was stirred at RT for 8 h. Then the mixture was filtered, and the residue was washed with water and methanol. The solid was collected, dried under vacuum and used in the next step without further purification. LC/MS (ESI) : 246.9 [M+H] + .
  • Step 5 6-Bromo-4-chloro-2, 3-dihydro-1H-pyrrolo [4, 3-c] pyridin-1-one (550 mg, 2.22 mmol) , 2, 5-dimethyl-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1, 2, 3-triazole (545.35 mg, 2.44 mmol) , K 2 CO 3 (921.41 mg, 6.67 mmol) ) and Pd (dppf) Cl 2 (162.62 mg, 0.22 mmol) were charged into a 100 mL round bottom flask.
  • Step 6 To a round bottom flask charged with 4-chloro-6- (1, 3-dimethylpyrazol-4-yl) -2, 3-dihydro-1H-pyrrolo [4, 3-c] pyridin-1-one (120 mg, 0.46 mmol) , 2-methylpropan-2-yl (1S, 3s, 5R) -3- [ (6-iodo-1, 2-diazin-3-yl) oxy] -1, 5-dimethyl-8-azabicyclo [3.2.1] octane-8-carboxylate (230.80 mg, 0.50 mmol) , Cs 2 CO 3 (446.50 mg, 1.37 mmol) , and XantPhos Pd G4 (43.96 mg, 0.05 mmol) was added 1, 4-dioxane (4 mL) .
  • reaction mixture was degassed with argon for 5 min and was then heated to 90 °Cfor 8 h.
  • the reaction mixture was cooled to RT and then diluted with EA.
  • the organic phase was washed with brine, dried over sodium sulfate, and concentrated under vacuum.
  • Step 1 Ethyl 5-bromo-4-fluoro-2-methylbenzoate (2.60 g, 10.0 mmol, 1.0 eq) , N-bromosuccinimide (2.49 g, 14.0 mmol, 1.4 eq) and benzoyl peroxide (242. mg, 1.0 mmol, 0.1 eq) were combined with carbon tetrachloride (150 mL) . The reaction mixture was heated to 80 °C and stirred for 3 h. The reaction mixture was cooled to RT and concentrated under vacuum.
  • Step 2 Ethyl 5-bromo-2- (bromomethyl) -4-fluorobenzoate (2.61 g, 7.7 mmol, 1.0 eq) was suspended in 28 %aqueous ammonium hydroxide and the mixture was stirred at RT for 8 h. Then the mixture was filtered, and the residue was washed with water and methanol. The solid was collected, dried under vacuum and used in the next step without further purification. LC/MS (ESI) : 230.0, 232.0 [M+H] + .
  • Step 3 6-Bromo-5-fluoroisoindolin-1-one (456.0 mg, 2.0 mmol, 1.0 eq) , 1, 3-dimethyl-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (488 mg, 2.20 mmol, 1.1 eq) , aqueous potassium carbonate (2 M, 8 mL) and PdCl 2 (dppf) .
  • Step 4 To a round bottom flask charged with 6- (1, 3-dimethyl-1H-pyrazol-4-yl) isoindolin-1-one (34.2 mg, 0.15 mmol, 1.0 eq) , tert-butyl 7- (6-bromopyridazin-3-yl) -2, 7-diazaspiro [4.4] nonane-2-carboxylate (57.3 mg, 0.15 mmol, 1.1 eq) , Cs 2 CO 3 (148.9 mg, 0.46 mmol, 3.0 eq) , and XantPhos Pd G4 (14.2 mg, 0.015 mmol, 0.1 eq) was added 1, 4-dioxane (4 mL) .
  • reaction mixture was degassed with argon for 5 min and was then heated to 90 °C for 8 h.
  • the reaction mixture was cooled to RT and diluted with EA.
  • the organic phase was washed with brine, dried over sodium sulfate, and concentrated under vacuum.
  • Step 5 To a round bottom flask charged with tert-butyl 7- (6- (6- (1, 3-dimethyl-1H-pyrazol-4-yl) -5-fluoro-1-oxoisoindolin-2-yl) pyridazin-3-yl) -2, 7-diazaspiro [4.4] nonane-2-carboxylate (69 mg, 0.12 mmol, 1.0 eq) and acetaldehyde (0.3 mL, 1.52 mmol, 12.0 eq) was added MeOH (4 mL) ; and the reaction mixture was stirred at 0 °C for 1h.
  • Step 1 5-Bromoisoindolin-1-one (315 mg, 1.5 mmol, 1.5 eq) , 4, 4, 4', 4', 5, 5, 5', 5'-octamethyl-2, 2'-bi (1, 3, 2-dioxaborolane (762 mg, 3.0 mmol, 3.0 eq) , potassium acetate (300 mg, 3.0 mmol, 3.0 eq) and PdCl 2 (dppf) .
  • CH 2 Cl 2 adduct (109.3 mg, 0.15 mmol, 0.1 eq) were charged to a three-neck 100 mL round bottom flask under nitrogen and anhydrous dioxane (9 mL) was added and the mixture was heated to 90 °C.When full conversion was achieved, the reaction mixture was cooled to room temperature. Then 5-bromo-3-methyl-1, 2, 4-thiadiazole (177.3 mg, 1.0 mmol, 1.0 eq) , aqueous potassium carbonate (2 M, 2 mL) and PdCl 2 (dppf) . CH 2 Cl 2 adduct (109.3 mg, 0.15 mmol, 0.1 eq) were added and the reaction mixture was heated to 90 °C.
  • Step 2 To a round bottom flask charged with 5- (3-methyl-1, 2, 4-thiadiazol-5-yl) isoindolin-1-one (34.8 mg, 0.15 mmol, 1.0 eq) , 3-bromo-6- ( (2, 2, 6, 6-tetramethylpiperidin-4-yl) oxy) pyridazine (50.0 mg, 0.16 mmol, 1.1 eq) , Cs 2 CO 3 (148.9 mg, 0.46 mmol, 3.0 eq) , and XantPhos Pd G4 (14.2 mg, 0.015 mmol, 0.1 eq) was added 1, 4-dioxane (4 mL) .
  • the reaction mixture was degassed with argon for 5 min and was then heated to 90 °C for 8 h.
  • the reaction mixture was cooled to RT and diluted with EA.
  • the organic phase was washed with brine, dried over sodium sulfate, and concentrated under vacuum.
  • the crude product was purified by silica gel column chromatography with DCM/MeOH 20/1, v/v.
  • Step 1 Methyl 6-bromo-3-chloropyrazine-2-carboxylate (400 mg, 1.59 mmol, 1.0 eq) , (2, 5-dimethylpyrazol-3-yl) boranediol (222.52 mg, 1.59 mmol, 1.0 eq) , sodium carbonate (505.57 mg, 4.77 mmol, 3.0 eq) and PdCl 2 (dppf) .
  • Step 2 Methyl 3-chloro-6- (1, 3-dimethylpyrazol-5-yl) pyrazine-2-carboxylate (500 mg, 1.87 mmol, 1.2 eq) , 2, 4, 6-trimethyl-1, 3, 5, 2, 4, 6-trioxatriborinane (1.29 mL, 2.25 mmol, 1.0 eq) , potassium carbonate (777.31 mg, 5.62 mmol, 3.0 eq) and PdCl 2 (dppf) .
  • CH 2 Cl 2 adduct (137.05 mg, 0.19 mmol, 0.1 eq) were charged to a three-neck 100 mL round bottom flask under nitrogen.
  • Step 3 Methyl 6- (1, 3-dimethyl-1H-pyrazol-4-yl) -3-methylpyrazine-2-carboxylate (430 mg, 1.75 mmol, 1.0 eq) , N-bromosuccinimide (371.67 mg, 2.10 mmol, 1.2 eq) and benzoyl peroxide (129.17 mg, 0.79 mmol, 0.45 eq) were combined with carbon tetrachloride (10 mL) and the reaction mixture was heated to 80 °C and stirred for 16 h. The reaction mixture was cooled to RT and concentrated under vacuum.
  • Step 4 Methyl 3- (bromomethyl) -6- (1, 3-dimethylpyrazol-4-yl) pyrazine-2-carboxylate (440 mg, 1.35 mmol, 1.0 eq) was suspended in 28 %aqueous ammonium hydroxide and the mixture was stirred at RT for 8 h. The mixture was filtered, and the residue was washed with water and methanol. The solid was collected, dried under vacuum, and used in the next step without further purification. LC/MS (ESI) : 230.1 [M+H] +
  • Step 5 To a round bottom flask charged with 3- (1, 3-dimethylpyrazol-4-yl) -6, 7-dihydro-5H-pyrrolo [4, 3-b] pyrazin-5-one (40 mg, 0.17 mmol, 1.0 eq) , tert-butyl (1R, 3s, 5S) -3- ( (6-bromopyridazin-3-yl) oxy) -1, 5-dimethyl-8-azabicyclo [3.2.1] octane-8-carboxylate (71.95 mg, 0.17 mmol, 1.0 eq) , Cs 2 CO 3 (170.13 mg, 0.52 mmol, 3.0 eq) , and XantPhos Pd G4 (16.79 mg, 0.02 mmol, 0.1 eq) was added 1, 4-dioxane (4 mL) .
  • reaction mixture was degassed with argon for 5 min and was then heated to 90 °Cfor 8 h.
  • the reaction mixture was cooled to RT and diluted with EA.
  • the organic phase was washed with brine, dried over sodium sulfate, and concentrated under vacuum.

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Abstract

L'invention concerne des composés d'isoindolinone et des compositions pharmaceutiques comprenant lesdits composés. L'invention concerne en outre des méthodes de traitement de troubles neurologiques tels que la maladie de Huntington (HD).
PCT/CN2024/097833 2023-06-06 2024-06-06 Composés d'isoindolinone et de dihydropyrrolopridinone et leurs utilisations Ceased WO2024251212A1 (fr)

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CN202480038288.3A CN121335899A (zh) 2023-06-06 2024-06-06 异吲哚啉酮和二氢吡咯并吡啶酮化合物以及其用途

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102762548A (zh) * 2009-12-22 2012-10-31 沃泰克斯药物股份有限公司 磷脂酰肌醇3-激酶的异吲哚啉酮抑制剂
CN113396145A (zh) * 2018-10-15 2021-09-14 盖罗发现有限责任公司 Pfkfb3抑制剂及其用途
WO2022216947A1 (fr) * 2021-04-08 2022-10-13 Chdi Foundation, Inc. Composés d'isoindolinone et agents d'imagerie pour l'imagerie de la protéine huntingtine
WO2023081845A1 (fr) * 2021-11-05 2023-05-11 Georgiamune Llc Modulateurs d'akt3
WO2023081854A1 (fr) * 2021-11-05 2023-05-11 Georgiamune Llc Modulateurs d'akt3

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102762548A (zh) * 2009-12-22 2012-10-31 沃泰克斯药物股份有限公司 磷脂酰肌醇3-激酶的异吲哚啉酮抑制剂
CN113396145A (zh) * 2018-10-15 2021-09-14 盖罗发现有限责任公司 Pfkfb3抑制剂及其用途
WO2022216947A1 (fr) * 2021-04-08 2022-10-13 Chdi Foundation, Inc. Composés d'isoindolinone et agents d'imagerie pour l'imagerie de la protéine huntingtine
WO2023081845A1 (fr) * 2021-11-05 2023-05-11 Georgiamune Llc Modulateurs d'akt3
WO2023081854A1 (fr) * 2021-11-05 2023-05-11 Georgiamune Llc Modulateurs d'akt3

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