WO2021222614A1 - Inhibitor of apoptosis (iap) protein antagonists - Google Patents

Inhibitor of apoptosis (iap) protein antagonists Download PDF

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WO2021222614A1
WO2021222614A1 PCT/US2021/029957 US2021029957W WO2021222614A1 WO 2021222614 A1 WO2021222614 A1 WO 2021222614A1 US 2021029957 W US2021029957 W US 2021029957W WO 2021222614 A1 WO2021222614 A1 WO 2021222614A1
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compound
solvate
pharmaceutically acceptable
acceptable salt
optionally substituted
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PCT/US2021/029957
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French (fr)
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Nicholas David Peter Cosford
Dominik HEIMANN
Peter TERIETE
Sumit Kumar CHANDA
Lars PACHE
Laurent Jean Stephane DE BACKER
Nicole BATA
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Sanford Burnham Prebys Medical Discovery Institute
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Priority to EP21797523.4A priority Critical patent/EP4143198A4/en
Priority to US17/997,461 priority patent/US20230295181A1/en
Priority to AU2021265826A priority patent/AU2021265826A1/en
Priority to CA3179329A priority patent/CA3179329A1/en
Publication of WO2021222614A1 publication Critical patent/WO2021222614A1/en

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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/475—Quinolines; Isoquinolines having an indole ring, e.g. yohimbine, reserpine, strychnine, vinblastine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/554—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one sulfur as ring hetero atoms, e.g. clothiapine, diltiazem
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D487/12—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 three hetero rings
    • C07D487/14—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
    • C07D487/22—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 four or more hetero rings
    • 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
    • C07D498/12—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 three hetero rings
    • C07D498/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • Described herein are compounds that modulate the activity of certain proteins involved in apoptotic pathways, or signaling pathways associated with inflammation and/or autoimmune diseases and/or cell division and/or angiogenesis.
  • the compounds described herein are antagonists of inhibitor of apoptosis (IAP) proteins.
  • the compounds described herein are antagonists of melanoma inhibitor of apoptosis protein (ML-IAP).
  • the compounds described herein are selective ML-IAP antagonists.
  • the compounds described herein are useful for the treatment of certain types of cancers as described herein.
  • the compounds, pharmaceutical compositions, and methods described herein are effective in the treatment of lung cancer.
  • the compounds, compositions, and methods described herein are effective in the treatment of chemo-resistant cancers.
  • the compounds described herein are pan -IAP antagonists.
  • the compounds described herein are useful for the treatment of cancer, inflammatory diseases, and/or autoimmune diseases as described herein.
  • R 1 is hydrogen, G-Galkyl. G-Gcycloalkyl. Ci-Cealkyl-iG-Cecycloalkyl), G-Galkyl-(phenyl). or G-Galkyl-(5- to 6-membered heteroaryl); wherein the G-Galkyl. G-Gcycloalkyl. phenyl, or 5- to 6-membered heteroaryl is optionally substituted with 1, 2, or 3 R 9 ;
  • X is NR A , O, S, S(O), or S(0) 2 ;
  • R A is hydrogen, Ci-Cealkyl, C(0)-(Ci-C 6 alkyl), C(0)-(C 3 -C 6 cycloalkyl), C(0)-(phenyl), or C(O)- (5- to 6-membered heteroaryl); wherein each CrG, alkyl. G-Gcycloalkyl. phenyl, or 5- to 6- membered heteroaryl is optionally substituted with 1, 2, or 3 R 9 ; or X is C and taken together with R 2a , R 2b , and the carbon atom to which they are attached, forms a phenyl or 5- to 10-membered heteroaryl ring, optionally substituted with 1, 2, or 3 R 9 ;
  • R 2a , R 2b , R 3a , and R 3b are each independently hydrogen, G-Galkyl.
  • G-Galkynyl. C3-Ciocycloalkyl, 3- to 10-membered heterocycloalkyl, G-Goaryl. or 5- to 10-membered heteroaryl; wherein each G-Galkyl.
  • G-Galkynyl is optionally substituted with 1 or 2 G-Ciocycloalkyl, 3- to 10-membered heterocycloalkyl, G-Goaryl. or 5- to 10-membered heteroaryl rings; wherein each G-Galkyl.
  • G-Ghaloalkyl Ci-Ce alkoxy, Ci-Ceheteroalkyl, G-Galkcnyl.
  • G-Galkynyl C3-Ciocycloalkyl, 3- to 10-membered heterocycloalkyl, G-Goaryl.
  • 5- to 10-membered heteroaryl is optionally substituted with 1, 2, or 3 R 9 ; or R 2a and R 2b together with the carbon atom to which they are attached form a carbonyl; or R 2a and R 3a , and optionally R 2b and R 3b , together with the carbon atoms to which they are attached form a G-Gcycloalkyl.
  • 5- to 10-membered heterocycloalkyl, G-Goaryl. or 5- to 10- membered heteroaryl ring wherein each G-Gcycloalkyl. 5- to 10-membered heterocycloalkyl, G-Goaryl. or 5- to 10-membered heteroaryl ring is optionally substituted with 1, 2, or 3 R 9 ;
  • R 4a and R 4b are each independently hydrogen, halogen, G-Galkyl.
  • G-Ghaloalkyl. G-G alkoxy.
  • G-Galkenyl G-Galkynyl.
  • G-Galkenyl Ci- Ghaloalkyl, C i -Co alkoxy, G-Gheteroalkyl.
  • G-Galkynyl is optionally substituted with 1 or 2 G-Ciocycloalkyl, 3- to 10-membered heterocycloalkyl, G-Goaryl. or 5- to 10-membered heteroaryl; wherein each G-Galkyl. G-Ghaloalkyl. G-G alkoxy. Ci- Gheteroalkyl, G-Galkenyl. G-Galkynyl. G-Ciocycloalkyl, 3- to 10-membered heterocycloalkyl, G-Goaryl.
  • R 5 is NHR 8 ,NHS(0) 2 R 8 , OR 8 , SR 8 , S(0) 2 R 8 , or S(0) 2 NHR 8 ; or R 5 , R 4a , and R 4b , together with the carbon atom to which they are attached, form a Ce-Cioaryl or 5- to 10-membered heteroaryl ring; wherein the Ce-Cioaryl or 5- to 10-membered heteroaryl ring is optionally substituted with 1, 2, or 3 R 9 ;
  • R 6a is hydrogen, halogen, -U, or -G;
  • R 6b is halogen, -U, or -G;
  • Ci-U is CrCi, alkyl.
  • Ci-Cdialoalkyl Ci-Cealkoxy, CVG, heteroalkyl. CVG, alkenyl. or G-Galkynyl: wherein each CVGalkyl.
  • G-Ghaloalkyl Ci-Galkoxy, G-Gheteroalkyl, G-Galkcnyl. or G-Galkynyl is optionally substituted with 1, 2, or 3 R 9 and/or 1 or 2 -G;
  • -G is C3-Ciocycloalkyl, 3- to 10-membered heterocycloalkyl, G-Goaryl, or 5- to 10-membered heteroaryl; wherein each C3-Ciocycloalkyl, 3- to 10-membered heterocycloalkyl, G-Goaryl, or 5- to 10-membered heteroaryl is optionally substituted with 1, 2, or 3 R 9 ; or R 6a and R 6b together with the carbon atom to which they are attached form a saturated or partially saturated 3- to 7-membered cycloalkyl or a saturated or partially saturated 3- to 7- membered heterocycloalkyl; wherein the cycloalkyl or heterocycloalkyl is optionally substituted with 1, 2, or 3 R 9 ;
  • R 7a is hydrogen, halogen, Ci-C4alkyl, or G-Ghaloalkyl
  • R 7 *’ is hydrogen, halogen, Ci-C4alkyl, or Ci-C4haloalkyl; or R 7a and R 7b together with the carbon atom to which they are attached form a saturated or partially saturated 3- to 7-membered cycloalkyl or a saturated or partially saturated 3- to 7- membered heterocycloalkyl; wherein the cycloalkyl or heterocycloalkyl is optionally substituted with 1, 2, or 3 R 9 ; or R 6b and R 715 together with the carbon atoms to which they are attached form a C3-Ciocycloalkyl or 3- to 10-membered heterocycloalkyl ring; wherein each C3-Ciocycloalkyl or 3- to 10- membered heterocycloalkyl ring is optionally substituted with 1, 2, or 3 R 9 ; or R 6a , R 6b , R 7a , and R 7b together with the carbon atoms to which they are attached form a 5 - to 10- member
  • R 8 is Z, CVGalkyl. (Ci-Galkylene)-Z, (Ci-Gheteroalkylene)-Z, (C 2 -Galkenylene)-Z, CH(Z) 2 , CH 2 CH(Z) 2 , CH(C I -C , alkyl )Z. or C(0)Z; wherein each alkyl, alkylene, heteroalkylene, or alkenylene is optionally substituted with 1, 2, or 3 R 9 ;
  • Z is C3-Ciocycloalkyl, 3- to 10-membered heterocycloalkyl, G-Goaryl, or 5- to 10-membered heteroaryl; wherein each C3-Ciocycloalkyl, 3- to 10-membered heterocycloalkyl, G-Goaryl, and 5- to 10-membered heteroaryl is optionally substituted with 1, 2, or 3 R 9 ; each R 9 is independently halogen, G-Galkyl, G-Galkenyl, G-Galkynyl, G-Ghaloalkyl, G- C4alkoxy, Ci-C4haloalkoxy, Ci-C4heteroalkyl, -C(0)H, -C(0)0H, -CN, C3-Ciocycloalkyl, 3- to 10-membered heterocycloalkyl, G-Goaryl, 5- to 10-membered heteroaryl, -C(0)(G- C 4 alkyl), -C(0)0(Ci-G
  • R 1 is hydrogen, CrG, alkyl.
  • G-Gcycloalkyl. phenyl, or 5- to 6-membered heteroaryl is optionally substituted with 1, 2, or 3 R 9 ;
  • X is NR A , O, S, S(O), or S(0) 2 ;
  • R A is hydrogen, G-Galkyl, C(0)-(G-Galkyl), C(0)-(G-Gcycloalkyl), C(0)-(phenyl), or C(O)- (5- to 6-membered heteroaryl); wherein each G-Galkyl.
  • G-Gcycloalkyl. phenyl, or 5- to 6- membered heteroaryl is optionally substituted with 1, 2, or 3 R 9 ; or
  • X is C and taken together with R 2a , R 2b , and the carbon atom to which they are attached, forms a phenyl or 5- to 10-membered heteroaryl ring, optionally substituted with 1, 2, or 3 R 9 ;
  • R 2a , R 2b , R 3a , and R 3b are each independently hydrogen, Ci-G, alkyl.
  • G-Galkynyl. C3-Ciocycloalkyl, 3- to 10-membered heterocycloalkyl, G,-Cioaryl. or 5- to 10-membered heteroaryl; wherein each G-Galkyl.
  • G-Galkynyl is optionally substituted with 1 or 2 C3-Ciocycloalkyl, 3- to 10-membered heterocycloalkyl, G-Goaryl. or 5- to 10-membered heteroaryl rings; wherein each G-Galkyl.
  • G-Galkynyl C3-Ciocycloalkyl, 3- to 10-membered heterocycloalkyl, G-Goaryl.
  • 5- to 10-membered heteroaryl is optionally substituted with 1, 2, or 3 R 9 ; or R 2a and R 2b together with the carbon atom to which they are attached form a carbonyl; or R 2a and R 3a , and optionally R 2b and R 3b , together with the carbon atoms to which they are attached form a G-Gcycloalkyl.
  • 5- to 10-membered heterocycloalkyl, G-Goaryl. or 5- to 10- membered heteroaryl ring wherein each G-Gcycloalkyl. 5- to 10-membered heterocycloalkyl, G-Goaryl. or 5- to 10-membered heteroaryl ring is optionally substituted with 1, 2, or 3 R 9 ;
  • R 4a and R 4b are each independently hydrogen, halogen, G-Galkyl.
  • G-Ghaloalkyl. G-G alkoxy.
  • G-Galkenyl G-Galkynyl.
  • G- Ghaloalkyl C i -Co alkoxy, Ci-Cohctcroalkyl.
  • G-Galkynyl is optionally substituted with 1 or 2 C 3 -Gocycloalkyl, 3- to 10-membered heterocycloalkyl, G-Goaryl. or 5- to 10-membered heteroaryl; wherein each G-Galkyl.
  • R 5 is NHR 8 ,NHS(0) 2 R 8 , OR 8 , SR 8 , S(0) 2 R 8 , or S(0) 2 NHR 8 ; or R 5 , R 4a , and R 4b , together with the carbon atom to which they are attached, form a G-Goaryl or 5- to 10-membered heteroaryl ring; wherein the G-Goaryl or 5- to 10-membered heteroaryl ring is optionally substituted with 1, 2, or 3 R 9 ;
  • R 6a is hydrogen, halogen, -U a , or -G;
  • R 6b is halogen, -U b , or -G; -U a is C -G, alkyl. G-Ghaloalkyl. Ci-Cealkoxy, G-Gheteroalkyl. G-Galkenyl. or G-Galkynyl: wherein each CrG, alkyl. G-Ghaloalkyl. Ci-Cealkoxy, G-Gheteroalkyl. G-Galkenyl. or G-Galkynyl is optionally substituted with 1, 2, or 3 R 9 and/or 1 or 2 -G;
  • -U b is G-Galkyl.
  • -G is C 3 -Gocycloalkyl, 3- to 10-membered heterocycloalkyl, G-Goaryl. or 5- to 10-membered heteroaryl; wherein each C 3 -Gocycloalkyl, 3- to 10-membered heterocycloalkyl, Ce-Goaryl, or 5- to 10-membered heteroaryl is optionally substituted with 1, 2, or 3 R 9 ;
  • R 7a is hydrogen, halogen, Ci-C4alkyl, or Ci-C t haloalkyl
  • R 715 is hydrogen, halogen, Ci-C4alkyl, or Ci-C4haloalkyl
  • R 8 is Z, G-Galkyl. (Ci-C 6 alkylene)-Z, (Ci-C 6 heteroalkylene)-Z, (C2-Galkenylene)-Z, CH(Z)2, CH2CH(Z)2, CH(G-Galkyl)Z. or C(0)Z; wherein each alkyl, alkylene, heteroalkylene, or alkenylene is optionally substituted with 1, 2, or 3 R 9 ;
  • Z is C 3 -Gocycloalkyl, 3- to 10-membered heterocycloalkyl, Ce-Goaryl, 5- to 10-membered heteroaryl; wherein each C 3 -Gocycloalkyl, 3- to 10-membered heterocycloalkyl, Ce-Goaryl, 5- to 10-membered heteroaryl is optionally substituted with 1, 2, or 3 R 9 ; each R 9 is independently halogen, Ci-C4alkyl, C2-Galkenyl, C2-Galkynyl, Ci-C4haloalkyl, Ci- C4alkoxy, Ci-C4haloalkoxy, Ci-C4heteroalkyl, -C(0)H, -C(0)0H, -CN, C3-Ciocycloalkyl, 3- to 10-membered heterocycloalkyl, Ce-Goaryl, 5- to 10-membered heteroaryl, -C(0)(Ci- C 4 alkyl), -C(0)0(Ci-C 4
  • R 1 is hydrogen, G-Galkyl. G-Gcycloalkyl. Ci-Cealkyl-iG-Cecycloalkyl), Ci-Cealkyl-(phenyl), or G-Galkyl-(5- to 6-membered heteroaryl); wherein the Ci-G, alkyl. G-Gcycloalkyl. phenyl, or 5- to 6-membered heteroaryl is optionally substituted with 1, 2, or 3 R 9 ;
  • X is NR A , O, S, S(O), or S(0) 2 ;
  • R A is hydrogen, Ci-C 6 alkyl, C(0)-(Ci-C 6 alkyl), C(0)-(G-C 6 cycloalkyl), C(0)-(phenyl), or C(O)- (5- to 6-membered heteroaryl); wherein each G-Galkyl.
  • G-Gcycloalkyl. phenyl, or 5- to 6- membered heteroaryl is optionally substituted with 1, 2, or 3 R 9 ; or
  • X is C and taken together with R 2a , R 2b , and the carbon atom to which they are attached, forms a phenyl or 5- to 10-membered heteroaryl ring, optionally substituted with 1, 2, or 3 R 9 ;
  • R 2a , R 2b , R 3a , and R 3b are each independently hydrogen, G-Galkyl.
  • G-Ghaloalkyl. Ci-Ce alkoxy, Ci-Ceheteroalkyl, G-Galkcnyl.
  • G-Galkynyl. C3-Ciocycloalkyl, 3- to 10-membered heterocycloalkyl, G-Goaryl. or 5- to 10-membered heteroaryl; wherein each G-Galkyl.
  • Ci- Cehaloalkyl, Ci-Ce alkoxy, Ci-Ceheteroalkyl, G-Galkenyl, or G-Galkynyl is optionally substituted with 1 or 2 G-Ciocycloalkyl, 3- to 10-membered heterocycloalkyl, G-Goaryl. or 5- to 10-membered heteroaryl rings; wherein each G-Galkyl.
  • G-Ghaloalkyl G-G alkoxy.
  • G-Galkcnyl G-Galkynyl.
  • C3-Ciocycloalkyl, 3- to 10-membered heterocycloalkyl, Ce-Cioaryl, or 5- to 10-membered heteroaryl is optionally substituted with 1, 2, or 3 R 9 ; or R 2a and R 2b together with the carbon atom to which they are attached form a carbonyl; or R 2a and R 3a , and optionally R 2b and R 3b , together with the carbon atoms to which they are attached form a G-Gcycloalkyl.
  • R 4a and R 4b are each independently hydrogen, halogen, G-Galkyl.
  • G-Ghaloalkyl. G-G alkoxy.
  • G-Galkenyl G-Galkynyl.
  • G-Galkenyl Ci- Ghaloalkyl, C i -Co alkoxy, G-Gheteroalkyl.
  • G-Galkynyl is optionally substituted with 1 or 2 C3-Ciocycloalkyl, 3- to 10-membered heterocycloalkyl, Ce-Goaryl, or 5- to 10-membered heteroaryl; wherein each Ci-G, alkyl. Ci-G,haloalkyl. G-G > alkoxy. Ci- Ceheteroalkyl, G-G, alkenyl. G-Galkynyl.
  • C 3 -Gocycloalkyl, 3- to 10-membered heterocycloalkyl, Ce-Goaryl, or 5- to 10-membered heteroaryl is optionally substituted with 1, 2, or 3 R 9 ; or R 4a and R 4b together with the carbon atom to which they are attached form a carbonyl; or R 4a and R 4b together with the carbon atom to which they are attached form a C 3 -Gocycloalkyl or 3- to 10-membered heterocycloalkyl ring; wherein the C 3 -Gocycloalkyl or 3- to 10- membered heterocycloalkyl ring is optionally substituted with 1, 2, or 3 R 9 ;
  • R 5 is NHR 8 ,NHS(0) 2 R 8 , OR 8 , SR 8 , S(0) 2 R 8 , or S(0) 2 NHR 8 ; or R 5 , R 4a , and R 4b , together with the carbon atom to which they are attached, form a G-Goaryl or 5- to 10-membered heteroaryl ring; wherein the G-Goaryl or 5- to 10-membered heteroaryl ring is optionally substituted with 1, 2, or 3 R 9 ;
  • R 6a is hydrogen, halogen, -U, or -G;
  • R 6b is halogen, -U, or -G;
  • -U is G-G, alkyl.
  • G-G alkoxy.
  • G-G heteroalkyl.
  • G-G alkenyl. or G-Galkynyl: wherein each G-G, alkyl.
  • Ci-Ceheteroalkyl, G-G, alkenyl. or G-Galkynyl is optionally substituted with 1, 2, or 3 R 9 and/or 1 or 2 -G;
  • -G is C 3 -Gocycloalkyl, 3- to 10-membered heterocycloalkyl, Ce-Goaryl, or 5- to 10-membered heteroaryl; wherein each C 3 -Gocycloalkyl, 3- to 10-membered heterocycloalkyl, Ce-Goaryl, or 5- to 10-membered heteroaryl is optionally substituted with 1, 2, or 3 R 9 ; or R 6a and R 6b together with the carbon atom to which they are attached form a saturated or partially saturated 3- to 7-membered cycloalkyl or a saturated or partially saturated 3- to 7- membered heterocycloalkyl; wherein the cycloalkyl or heterocycloalkyl is optionally substituted with 1, 2, or 3 R 9 ;
  • R 7a is hydrogen, halogen, Ci-C4alkyl, or Ci-C haloalkyl
  • R 715 is hydrogen, halogen, Ci-C4alkyl, or Ci-C4haloalkyl; or R 7a and R 7b together with the carbon atom to which they are attached form a saturated or partially saturated 3- to 7-membered cycloalkyl or a saturated or partially saturated 3- to 7- membered heterocycloalkyl; wherein the cycloalkyl or heterocycloalkyl is optionally substituted with 1, 2, or 3 R 9 ; or R 6b and R 7 *’ together with the carbon atoms to which they are attached form a C 3 -Gocycloalkyl or 3- to 10-membered heterocycloalkyl ring; wherein each C 3 -Gocycloalkyl or 3- to 10- membered heterocycloalkyl ring is optionally substituted with 1, 2, or 3 R 9 ; or R 6a , R 6b , R 7a , and R 7b together with the carbon atoms to which they are attached form a 5 - to 10- membered
  • Z is C3-C9cycloalkyl, 3- to 10-membered heterocycloalkyl, G-Goaryl, 5- to 10-membered heteroaryl; wherein each G-Gcycloalkyl, 3- to 10-membered heterocycloalkyl, G,-Cioaryl.
  • 5- to 10-membered heteroaryl is optionally substituted with 1, 2, or 3 R 9 ; or Z is a substituted Gocycloalkyl substituted with 1, 2, or 3 R 9 ; and each R 9 is independently halogen, G-Galkyl, G-Galkenyl, G-Galkynyl, Ci-C4haloalkyl, G- C4alkoxy, G-Ghaloalkoxy, Ci-C4heteroalkyl, -C(0)H, -C(0)0H, -CN, G-Gocycloalkyl, 3- to 10-membered heterocycloalkyl, G-Goaryl, 5- to 10-membered heteroaryl, -C(0)(G- C 4 alkyl), -C(0)0(Ci-Galkyl), -C(0)NH 2 , -C(0)NH(Ci-Galkyl), -C(0)N(Ci-C 4 alkyl) 2 , -NH 2 , -NH(Ci-
  • FIG. 1 illustrates the sensitizing effect of a selective ML-IAP antagonist (Compound A) on lung cancer cells.
  • FIG. 2 illustrates the effects of gene ablation on cancer cell viability.
  • FIG. 3 illustrates IAP antagonists effect on reversing HIV-1 latency.
  • ML-IAP melanoma inhibitor of apoptosis protein
  • ML-IAP potent, selective antagonists of melanoma inhibitor of apoptosis protein
  • ML-IAP is a viable therapeutic target for treating conditions such as lung cancer.
  • studies of ML-IAP have primarily utilized genetic silencing or knock-down mutants in order to study the effects of this protein on cancer progression.
  • the current lack of selective antagonists of ML-IAP has stifled the ability to research and treat conditions wherein ML-IAP is overexpressed or hyperactive, such as may be the case in many cancers.
  • Cancer is a persistent and growing cause of death throughout the world. Based on the GLOBOCAN 2012 estimates, about 14.1 million cancer cases and 8.2 million cancer deaths are estimated to have occurred in 2012 worldwide. Lung cancer has the highest incidence rate of all cancers and is the leading cause of cancer-induced mortality in all populations worldwide. With a mortality rate of more than double that of any other cancer lung cancer is among the deadliest cancers.
  • Apoptosis a form of programmed cell death, is often dysregulated in malignant cells, and the evasion of apoptosis is a hallmark of cancer.
  • cancer cells As cancer cells divide and proliferate, normal control of cell death is impaired and tumor formation occurs. Disruption of normal cell death processes is a hallmark of cancer leading to escape of tumorigenic cells from apoptotic stimuli as well as substantially increased resistance to chemotherapies and radiation therapies. Cancer cells often display aberrant upregulation of pathways which inhibit apoptosis, allowing the cancer cells to proliferate.
  • One such pathway which is upregulated in cancer cells is the inhibitor of apoptosis (IAP) pathway.
  • the IAP protein family is involved in blocking and attenuating programmed cell death pathways, predominantly through modulation of the caspase cascade.
  • the members of the IAP family are functionally and structurally related proteins that inhibit apoptosis. Proteins are ascribed to the IAP family if they possess a Baculovirus Inhibitor of apoptosis protein Repeat (BIR) domain.
  • BIR Baculovirus Inhibitor of apoptosis protein Repeat
  • IAPs have been identified as potential therapeutic targets for the treatment of cancer.
  • ML-IAP stands out as a particularly viable target. This is supported by studies on ML- IAP’s function within the apoptotic signaling network as well as its role as a biomarker for disease prognosis.
  • ML-IAP has been identified as an attractive target in lung cancer. Inhibition of ML-IAP in this malignancy leads to a substantial reduction in tumor growth as well as sensitization to traditional standard of care (SOC) therapies.
  • ML-IAP is upregulated in various cancers and is believed to underlie the resistance of many malignant cells to chemotherapeutics. Ablation or antagonism of ML-IAP is therefore an attractive therapeutic strategy for the treatment of cancer.
  • novel, selective ML-IAP antagonists as disclosed herein may be particularly advantageous in the treatment of treatment- resistant cancers.
  • ML-IAP also known as Livin or KIAP
  • the ML-IAP BIR domain is also responsible for apoptosis inhibition, and small molecule antagonists have significant potential for development as therapeutic agents.
  • the RING domain of ML-IAP has been shown to function as an E3 ligase, facilitating the ubiquitination and subsequent degradation of itself and, more importantly, the natural caspase antagonist that modulates apoptotic signaling - the second mitochondria-derived activator of caspases (SMAC).
  • SMAC is a mitochondrial protein that negatively regulates apoptosis, also known as programmed cell death.
  • SMAC When a cell is primed for apoptosis by the final execution step of caspase activation, SMAC binds to IAPs, preventing IAPs from binding to and deactivating caspases. Thus, SMAC promotes apoptosis by activating caspases.
  • ML-IAP inhibits a direct increase of SMAC and a re -sensitization of cells to apoptotic stimuli.
  • protein and mRNA levels of ML-IAP are low to undetectable in most adult tissues but are highly expressed in a number of cancers such as melanoma and lung cancer.
  • ML-IAP maps to chromosome 20ql3, a region frequently implicated in the mutagenic etiology of lung cancers.
  • ML-IAP levels have been shown to be highly relevant as a prognostic biomarker in lung cancer and other cancers. As expected, high ML-IAP expression results in a poor outcome whilst lower levels are more favorable.
  • IAP proteins are found in many types of human cancer and are associated with chemoresistance, disease progression and poor prognosis.
  • the IAP pathway When the IAP pathway is upregulated, the IAP proteins bind to and prevent initiator and effector caspases from cleaving downstream cellular proteins. The proteolytic action of caspases is required to allow the cell death cascade to progress normally.
  • provided herein are compounds that bind and inhibit the upregulated ML-IAP.
  • the compounds provided herein in some embodiments, bind to ML-IAP and prevent it from suppressing caspase action, thereby allowing the cell death cascade to progress normally.
  • compounds described herein are able to inhibit the action of ML-IAP, thereby inducing apoptosis in cells.
  • the antagonists of ML-IAP offer additional utility as adjuvant therapies in the treatment of cancer.
  • a tumor that may otherwise avoid apoptosis in response to standard of care (SOC) chemotherapy, immunotherapy, radiation therapy, etc., will often become responsive or sensitized to those therapies following treatment with an ML-IAP antagonist.
  • SOC standard of care
  • these compounds may derive additional benefit from use in a combination therapy with other known cancer agents.
  • the compounds described herein are nonpeptidic second mitochondria- derived activator of caspase (SMAC) mimetics and induce apoptosis (e.g., in cancer cells).
  • SMAC caspase
  • the compounds described herein are ML-IAP antagonists.
  • the compounds described herein are ML-IAP antagonists with selectivity for ML-IAP over other members of the IAP family.
  • ML-IAP Almost all studies on ML-IAP to date have been based on gene ablation studies using RNA interference, because no selective ML-IAP antagonists were available.
  • selective ML-IAP antagonists are generated utilizing a rational design approach mimicking the SMAC-IAP interaction.
  • potent and highly selective inhibitors of ML-IAP in vitro are potent and highly selective inhibitors of ML-IAP in vitro.
  • a compound disclosed herein blocks resistance to chemotherapeutics in whole cells, halts tumor cell proliferation, and is non-toxic in normal cells.
  • a compound, composition, or method of treatment disclosed herein facilitates a subject’s ability to overcome resistance to current first-line therapies.
  • a compound or method of treatment disclosed herein reduces the burden that chemotherapy and radiotherapy exerts on the patient by sensitizing the cancer to much lower doses of SOC therapies.
  • elevated levels of ML-IAP in bronchial aspiration and other tumor sampling methods are identified as valuable prognostic markers of disease staging and progression.
  • compounds disclosed herein are useful for the further characterization of the role of ML-IAP as a biomarker in lung cancer.
  • IAP apoptosis pathway
  • BIR baculovirus IAP repeat
  • XIAP inhibits apoptosis by binding to and inhibiting the activity of caspase-9, caspase-3 and caspase 7.
  • IAP proteins are found in many types of human cancer and are associated with chemoresistance, disease progression and poor prognosis.
  • the IAP pathway is upregulated, the IAP proteins bind to and prevent initiator and effector caspases from cleaving downstream cellular proteins.
  • the proteolytic action of caspases is required to allow the cell death cascade to progress normally. Accordingly, provided herein are compounds that bind the upregulated IAP proteins.
  • the compounds provided herein in some embodiments, bind to IAP proteins and prevent them from suppressing caspase action, thereby allowing the cell death cascade to progress normally.
  • provided herein are compounds that inhibit the action of IAP proteins, thereby inducing apoptosis in cells.
  • SMAC SMAC is a mitochondrial protein that negatively regulates apoptosis, also known as programmed cell death.
  • SMAC binds to IAP, which prevents IAP from binding to, and deactivating caspases.
  • SMAC promotes apoptosis by activating caspases.
  • the compounds described herein are nonpeptidic second mitochondria- derived activator of caspase (SMAC) mimetics and induce apoptosis (e.g., in cancer cells).
  • the compounds described herein are IAP antagonists.
  • IAP proteins not only regulate caspases and apoptosis, but also modulate inflammatory signaling and immunity, mitogenic kinase signaling, proliferation and mitosis, as well as cell invasion and metastasis.
  • Inhibitor of apoptosis (IAP) proteins have emerged as regulators of innate immune signaling downstream of Pattern Recognition Receptors (PRRs) such as Toll-like receptor 4 (TLR4), Nucleotide-Binding Oligomerization Domain 1 (NODI) and NOD2 receptors, and Retinoic Acid-Inducible Gene (RIG)-I Receptor.
  • PRRs Pattern Recognition Receptors
  • TLR4 Toll-like receptor 4
  • NODI Nucleotide-Binding Oligomerization Domain 1
  • NOD2 Nucleotide-Binding Oligomerization Domain 1
  • RAG Retinoic Acid-Inducible Gene
  • Cellular Inhibitor of Apoptosis Protein- 1 (cIAPl; also Baculoviral IAP Repeat Containing 2 or BIRC2), Cellular Inhibitor of Apoptosis Protein-2 (cIAP2; also, Baculoviral IAP Repeat Containing 3 or BIRC3), and X-linked Inhibitor of Apoptosis (XIAP) facilitate ubiquitin -dependent signaling activated by these PRRs and mediate activation of nuclear factor-kappa B (NF-KB) transcription factors as well as the MAP kinases p38 and JNK. Accordingly, the compounds described herein are also useful in the treatment of non-neoplastic diseases and/or inflammatory diseases and/or autoimmune diseases.
  • antiretroviral therapy only targets actively replicating HIV and not the dormant, replication competent HIV that resides in certain types of cells. These dormant HIV viruses can reactivate and trigger new rounds of viral replication upon discontinuation of antiretroviral therapy.
  • a strategy for improving HIV treatment is to also target the dormant, replication competent HIV virus residing in latently infected cells, which are cells that are infected with HIV but are not actively producing HIV. These latently infected cells are not undergoing active virus replication and the viral genome has been integrated into the host DNA in such a manner that the virus DNA is indistinguishable from the host’s DNA. Latently infected cells are not recognized by the immune system and are not susceptible to antiretroviral therapy (ART).
  • the dormant virus and latently infected cells can remain hidden and persist indefinitely.
  • One approach for targeting latently infected cells is to develop new therapeutic agents or drugs that can reverse latency in infected cells by inducing active HIV replication. Once the dormant HIV virus is “awakened”, the infected cells become susceptible to immune system clearance or the effects of additional treatments such as killer agents to eliminate infected cells. Concurrent treatment with antiretroviral drugs will prevent the spread of the reactivated virus and suppress new rounds of HIV infection.
  • the combination of therapeutic agents that can reverse the latency of HIV-infected cells and drugs to eradicate the awakened HIV virus is termed the “shock and kill” or “kick and kill” approach.
  • IAP inhibition has been implicated in the reversal of HIV latency.
  • the IAP antagonists may be used alone or in combination with other therapeutic agents, such as those that are used to treat HIV.
  • other therapeutic agents that could be used in combination with IAP antagonists include therapeutic agents that activate HIV transcription in latently infected cells, therapeutic agents that inhibit active HIV replication, or any combination thereof.
  • the additional therapeutic agents that inhibit active HIV replication include antiretroviral therapy drugs.
  • the pharmaceutical compositions are described comprising IAP antagonists, alone or in combination with one or more additional therapeutics agents that are useful for the treatment of HIV in a mammal.
  • the mammal is a human.
  • Alkyl refers to an optionally substituted straight-chain, or optionally substituted branched- chain saturated hydrocarbon monoradical having from one to about ten carbon atoms, or from 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-l-butyl, 2-ethyl- 1 -but
  • alkyl means that the alkyl group consists 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 Ci-Cio alkyl, a C1-C9 alkyl, a Ci-Cs alkyl, a C1-C7 alkyl, a C 1 -G, alkyl, a C1-C5 alkyl, a C1-C4 alkyl, a C 1 -C 3 alkyl, a C 1 -C 2 alkyl, or a Ci alkyl.
  • an alkyl group is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • the alkyl is optionally substituted with oxo, halogen, -CN, -CF 3 , -OH, -OMe, -NH2, or - NO 2 .
  • the alkyl is optionally substituted with oxo, halogen, -CN, -CF 3 , -OH, or -OMe.
  • the alkyl is optionally substituted with halogen.
  • Alkenyl refers to an optionally substituted straight-chain, or optionally substituted 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.
  • C2-C6 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.
  • the alkenyl is a C 2 -C 10 alkenyl, a C 2 -C 9 alkenyl, a C 2 -C 8 alkenyl, a C 2 -C 7 alkenyl, a C 2 -C 6 alkenyl, a C 2 -C 5 alkenyl, a C 2 -C 4 alkenyl, a C 2 -C 3 alkenyl, or a C 2 alkenyl.
  • an alkenyl group is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • an alkenyl is optionally substituted with oxo, halogen, -CN, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
  • an alkenyl is optionally substituted with oxo, halogen, -CN, -CF 3 , -OH, or -OMe.
  • the alkenyl is optionally substituted with halogen.
  • Alkynyl refers to an optionally substituted straight-chain or optionally substituted 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.
  • C2-C6 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.
  • the alkynyl is a C 2 -C 10 alkynyl, a C 2 -C 9 alkynyl, a C 2 -C 8 alkynyl, a C 2 -C 7 alkynyl, a C 2 -C 6 alkynyl, a C 2 -C 5 alkynyl, a C 2 -C 4 alkynyl, a C 2 -C 3 alkynyl, or a C 2 alkynyl.
  • an alkynyl group is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • an alkynyl is optionally substituted with oxo, halogen, -CN, -CF 3 , -OH, -OMe, -NH2, or -NO 2 .
  • an alkynyl is optionally substituted with oxo, halogen, -CN, -CF3, -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, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an alkylene is optionally substituted with oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, an alkylene is optionally substituted with oxo, halogen, -CN, -CF3, -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, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an alkoxy is optionally substituted with oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, an alkoxy is optionally substituted with oxo, halogen, -CN, -CF3, -OH, or -OMe. In some embodiments, the alkoxy is optionally substituted with halogen.
  • 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. Hydroxyalkyl include, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the hydroxyalkyl is aminomethyl.
  • Aryl refers to a radical derived from a hydrocarbon ring system comprising hydrogen, 6 to 30 carbon atoms and at least one aromatic ring.
  • 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.
  • 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.
  • the aryl is phenyl.
  • an aryl may be optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • an aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2.
  • an aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the aryl is optionally substituted with halogen.
  • Cycloalkyl refers to a stable, 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) or bridged ring systems.
  • Representative cycloalkyls include, but are not limited to, cycloalkyls having from three to fifteen carbon atoms (C3- Ci5 cycloalkyl), from three to ten carbon atoms (C3-C10 cycloalkyl), from three to eight carbon atoms (C3-C8 cycloalkyl), from three to six carbon atoms (C3-C6 cycloalkyl), from three to five carbon atoms (C3-C5 cycloalkyl), or three to four carbon atoms (C3-C4 cycloalkyl).
  • the cycloalkyl is a 3 - to 6-membered cycloalkyl.
  • the cycloalkyl is a 5 - to 6- membered cycloalkyl.
  • Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • Polycyclic cycloalkyls or carbocycles include, for example, adamantyl, norbomyl, 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.
  • Some examples of partially saturated bicyclic cycloalkyls include, by way of non limiting example, include tetrahydronaphthalene, dihydronaphthalene, indane, indene, and dihydroanthracene.
  • a cycloalkyl 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 cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2.
  • a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, - CN, -CF3, -OH, or -OMe. In some embodiments, the cycloalkyl is optionally substituted with halogen.
  • “Deuteroalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more deuterium atoms. In some embodiments, the alkyl is substituted with one deuterium atom. In some embodiments, the alkyl is substituted with one, two, or three deuterium atoms.
  • the alkyl is substituted with one, two, three, four, five, or six deuterium atoms.
  • Deuteroalkyl includes, for example, CD 3 , CH 2 D, CHD 2 , CH 2 CD 3 , CD 2 CD 3 , CHDCD3, CH 2 CH 2 D, or CH 2 CHD 2 .
  • the deuteroalkyl is CD3.
  • Haloalkyl refers to an alkyl radical, as defined above, that is substituted by one or more halogen atoms. In some embodiments, the alkyl is substituted with one, two, or three halogen atoms. In some embodiments, the alkyl is substituted with one, two, three, four, five, or six halogen halogens.
  • Haloalkyl includes, for example, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like. In some embodiments, the haloalkyl is trifluoromethyl.
  • Halo or “halogen” refers to bromo, chloro, fluoro or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro.
  • 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, or combinations thereof. In some instances, a heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl.
  • a heteroalkyl is a C i-G, heteroalkyl wherein the heteroalkyl is comprised of 1 to 5 carbon atoms and one or more atoms other than carbon, e.g., oxygen, nitrogen, sulfur, or combinations thereof.
  • a carbon atom or heteroatom is optionally oxidized (e.g, -C(0)0CH 2 -, -CH 2 S(0) 2 NHCH 2 -, -NHC(0)NHCH 2 , -CH 2 NHC(0)CH 2 ).
  • heteroalkyl examples include, for example, -CFhOCFF, -CFhCFhOCFF, - CH 2 CH 2 OCH 2 CH 2 OCH3, or -Gr[(G3 ⁇ 4)OG3 ⁇ 4.
  • 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 -N0 2 .
  • a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe.
  • the heteroalkyl is optionally substituted with halogen.
  • 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.
  • Heterocycloalkyl refers to a stable 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 and sulfur. In some embodiments, the heterocycloalkyl comprises 1 or 2 heteroatoms selected from nitrogen and 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) 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 quatemized.
  • heterocycloalkyls include, but are not limited to, heterocycloalkyls having from two to fifteen carbon atoms (C 2 -Ci 5 heterocycloalkyl), from two to ten carbon atoms (C 2 -Cio heterocycloalkyl), from two to eight carbon atoms (G-G heterocycloalkyl), from two to six carbon atoms (C 2 -G, heterocycloalkyl), from two to five carbon atoms (G-G heterocycloalkyl), or two to four carbon atoms (G-G heterocycloalkyl).
  • the heterocycloalkyl is a 3 - to 6-membered heterocycloalkyl.
  • the cycloalkyl is a 5- to 6-membered heterocycloalkyl.
  • heterocycloalkyl radicals include, but are not limited to, aziridinyl, azetidinyl, dioxolanyl, thienyl[l,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,
  • heterocycloalkyl also includes all ring forms of the carbohydrates, including but not limited to, the monosaccharides, the disaccharides and the oligosaccharides. 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).
  • a heterocycloalkyl 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 heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2.
  • a heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, - CF3, -OH, or -OMe. In some embodiments, the heterocycloalkyl is optionally substituted with halogen.
  • 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, 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 i-G, heteroalkyl.
  • 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, -CF3, -OH, -OMe, -NH2, or -NO2.
  • a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroalkyl is optionally substituted with halogen.
  • Heteroaryl refers to a 5- to 14-membered ring system radical comprising hydrogen atoms, 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 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 quatemized.
  • the heteroaryl is a 5 - to 10-membered heteroaryl. In some embodiments, the heteroaryl is a 5 - to 6- membered heteroaryl. Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][l,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[
  • a heteroaryl is optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • a heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2.
  • a heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroaryl is optionally substituted with halogen.
  • an “effective amount” or “therapeutically effective amount” refers to an amount of a compound administered to a subject (e.g. a mammal, such as a human), either as a single dose or as part of a series of doses, which is effective to produce a desired therapeutic effect.
  • “Therapy” may include any medical intervention to cure, remedy, treat, reverse, halt, delay, or otherwise modulate the effects of a disease or condition.
  • therapies include surgery, radiation, chemotherapy, immunotherapy, blood transfusion, tissue or organ grafting, transplantation.
  • Therapies may comprise small molecules, peptides, peptidomimetics, macromolecules, antibodies, proteins, genetic material (e.g., DNA, RNA, or fragments thereof).
  • Therapies may treat side-effects of a disease or condition, such as inflammation, pain, infection, weight loss/weight gain, depression, anxiety, loss of appetite, sleep loss, nausea, etc.
  • therapies may be prophylactic, i.e. therapies that prevent, anticipate, slow, or delay the onset of a disease or condition.
  • Treatment of a subject includes any type of intervention used in an attempt to alter the natural course of the subject.
  • treatment includes administration of a pharmaceutical composition, subsequent to the initiation of a pathologic event or contact with an etiologic agent and includes stabilization of the condition (e.g., condition does not worsen, e.g., cancer does not metastasize and the like) or alleviation of the condition (e.g., reduction in tumor size, remission of cancer, absence of symptoms of autoimmune disease and the like).
  • treatment also includes prophylactic treatment (e.g., administration of a composition described herein when an individual is suspected to be suffering from a condition described herein).
  • prophylactic treatment e.g., administration of a composition described herein when an individual is suspected to be suffering from a condition described herein.
  • a compound disclosed herein binds to ML-IAP and modulates its function.
  • the ML-IAP modulator is an inhibitor.
  • an inhibitor is an antagonist (e.g., a partial antagonist, a full antagonist, an inverse agonist).
  • the modulator binds at the BIR domain and inhibits SMAC binding.
  • the modulator binds to an allosteric site.
  • the modulator interferes with, blocks, prevents, or reduces a protein-protein interaction.
  • the modulator interferes with, blocks, prevents, or reduces a ligand (e.g., a peptide) from binding.
  • a ML-IAP antagonist inhibits the ability of SMAC or a fragment thereof from binding to ML-IAP. In some embodiments, the ML-IAP antagonist inhibits a peptide (e.g., SMAC) from binding to a BIR domain. In some embodiments, a compound disclosed herein occupies a ML-IAP BIR domain. In some embodiments, a compound disclosed herein is highly selective for ML-IAP over other IAPs and/or other BIR domains (e.g, XIAP BIR1/2, XIAP BIR3, cIAPl BIR2, cIAPl BIR3, cIAP2 BIR2, cIAP2 BIR3).
  • a compound disclosed herein is 10-fold selective for ML-IAP BIR over another BIR domain. In some embodiments, a compound disclosed herein is 10-fold selective for ML-IAP over all other BIR domains. In some embodiments, a compound disclosed herein exhibits selectivity for ML-IAP BIR over other BIR domains with a selectivity ratio of 2, 5, 10, 20, 50, 100, 1000, or more.
  • the ML-IAP antagonist mimics certain features of an endogenous peptide or protein. In some embodiments, the ML-IAP antagonist is conformationally constrained. [0054] In some embodiments, selectivity for ML-IAP over another IAP (e.g., XIAP) results in enhanced anti -cancer effects. In some embodiments, selectivity for ML-IAP over another IAP (e.g., XIAP) results in enhanced effects against lung cancers. In some embodiments, selectivity for ML-IAP over another IAP (e.g., XIAP) results in enhanced induction of cell death in certain cancer cell lines.
  • IAP e.g., XIAP
  • ML-IAP selectivity over another IAP is 50-fold or greater. In some embodiments, ML-IAP selectivity results in an enhanced safety profde (e.g., reduced risk or severity of complications resulting from treatment).
  • a compound or composition as described herein is synergistic with another form of cancer therapy.
  • ML-IAP inhibition decreases the effective dose (e.g., EC50, IC50, ED50) needed for another form of therapy to exert anti -cancer effects. In some embodiments, ML-IAP inhibition slows, delays, or reverses tumor development. In some embodiments, the therapeutic window is increased compared to treatment in the absence of an ML-IAP antagonist. In some embodiments, a previously untreatable tumor becomes responsive to SOC therapy.
  • Some embodiments of the present disclosure relate to compounds or pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, having the structure of Formula (A-I): wherein,
  • R 1 is hydrogen, CrG, alkyl.
  • G-Gcycloalkyl G-Galkyl-(G-Gcycloalkyl), G-Galkyl-(phenyl), or G-Galkyl-(5- to 6-membered heteroaryl); wherein the G-Galkyl.
  • G-Gcycloalkyl. phenyl, or 5- to 6-membered heteroaryl is optionally substituted with 1, 2, or 3 R 9 ;
  • X is NR A , O, S, S(O), or S(0) 2 ;
  • R A is hydrogen, G-Galkyl, C(0)-(G-Galkyl), C(0)-(G-Gcyeloalkyl), C(0)-(phenyl), or C(0)-(5- to 6-membered heteroaryl); wherein each G-Galkyl.
  • G-Gcycloalkyl. phenyl, or 5- to 6- membered heteroaryl is optionally substituted with 1, 2, or 3 R 9 ; or
  • X is C and taken together with R 2a , R 2b , and the carbon atom to which they are attached, forms a phenyl or 5- to 10-membered heteroaryl ring, optionally substituted with 1, 2, or 3 R 9 ;
  • R 2a , R 2b , R 3a , and R 3b are each independently hydrogen, G-Galkyl.
  • G-Ghaloalkyl G-G alkoxy, G- Gheteroalkyl, G-Galkcnyl.
  • G-Galkynyl C3-Ciocycloalkyl, 3- to 10-membered heterocycloalkyl, G-Goaryl, or 5- to 10-membered heteroaryl; wherein each G-Galkyl.
  • G-Galkynyl is optionally substituted with 1 or 2 G-Gocycloalkyl, 3- to 10-membered heterocycloalkyl, G-Goaryl. or 5- to 10-membered heteroaryl rings; wherein each G-Galkyl.
  • G-Ghaloalkyl G-G alkoxy.
  • G- Gheteroalkyl G-Galkenyl.
  • G-Galkynyl is optionally substituted with 1 or 2 G-Gocycloalkyl, 3- to 10-membered heterocycloalkyl, G-Goaryl. or 5- to 10-membered heteroaryl rings; wherein each G-Galkyl.
  • G-Ghaloalkyl G-G alkoxy.
  • G- Gheteroalkyl G-Galkenyl.
  • G-Galkynyl G-Galkynyl.
  • C3-Ciocycloalkyl, 3- to 10-membered heterocycloalkyl, G-Goaryl, or 5- to 10-membered heteroaryl is optionally substituted with 1, 2, or 3 R 9 ; or R 2a and R 2b together with the carbon atom to which they are attached form a carbonyl; or R 2a and R 3a , and optionally R 2b and R 3b , together with the carbon atoms to which they are attached form a G-Gcycloalkyl.
  • R 4a and R 4b are each independently hydrogen, halogen, CrG, alkyl.
  • G- Ghaloalkyl C i -G, alkoxy, G-G, heteroalkyl.
  • G-G alkenyl.
  • G-Galkynyl is optionally substituted with 1 or 2 C3-Ciocycloalkyl, 3- to 10-membered heterocycloalkyl, G-Goaryl. or 5- to 10-membered heteroaryl; wherein each G-Galkyl.
  • G-Ghaloalkyl G-Ce alkoxy, G- Ceheteroalkyl, G-G, alkenyl.
  • G-Galkynyl. C3-Ciocycloalkyl, 3- to 10-membered heterocycloalkyl, G-Goaryl.
  • R 5 is NHR 8 ,NHS(0) 2 R 8 , OR 8 , SR 8 , S(0) 2 R 8 , or S(0) 2 NHR 8 ; or R 5 , R 4a , and R 4b , together with the carbon atom to which they are attached, form a G-Goaryl or 5- to 10-membered heteroaryl ring; wherein the G-Goaryl or 5- to 10-membered heteroaryl ring is optionally substituted with 1, 2, or 3 R 9 ;
  • R 6a is hydrogen, halogen, -U, or -G;
  • R 6b is halogen, -U, or -G;
  • -U is Ci -C o alkyl.
  • G-Galkenyl. or G- Galkynyl is optionally substituted with 1, 2, or 3 R 9 and/or 1 or 2 -G;
  • -G is G-Gocycloalkyl, 3- to 10-membered heterocycloalkyl, G-Goaryl. or 5- to 10-membered heteroaryl; wherein each G-Gocycloalkyl, 3- to 10-membered heterocycloalkyl, G-Goaryl. or 5- to 10-membered heteroaryl is optionally substituted with 1, 2, or 3 R 9 ; or R 6a and R 6b together with the carbon atom to which they are attached form a saturated or partially saturated 3- to 7-membered cycloalkyl or a saturated or partially saturated 3- to 7-membered heterocycloalkyl; wherein the cycloalkyl or heterocycloalkyl is optionally substituted with 1, 2, or 3 R 9 ;
  • R 7a is hydrogen, halogen, G-Galkyl, or G-Ghaloalkyl
  • R 7b is hydrogen, halogen, G-Galkyl, or G-Ghaloalkyl; or R 7a and R 7b together with the carbon atom to which they are attached form a saturated or partially saturated 3- to 7-membered cycloalkyl or a saturated or partially saturated 3- to 7-membered heterocycloalkyl; wherein the cycloalkyl or heterocycloalkyl is optionally substituted with 1, 2, or
  • R 6b and R 7b together with the carbon atoms to which they are attached form a C3-Ciocycloalkyl or 3- to 10-membered heterocycloalkyl ring; wherein each C3-Ciocycloalkyl or 3- to 10-membered heterocycloalkyl ring is optionally substituted with 1, 2, or 3 R 9 ; or R 6a , R 6b , R 7a , and R 7b together with the carbon atoms to which they are attached form a 5 - to 10- membered heteroaryl ring optionally substituted with 1, 2, or 3 R 9 ;
  • R 8 is Z, Cri-G, alkyl. (G-Galkylene)-Z, (G-Gheteroalkylene)-Z, (G-Galkenylene)-Z, CH(Z)2, CH2CH(Z)2, CH(G-Galkyl)Z. or C(0)Z; wherein each alkyl, alkylene, heteroalkylene, or alkenylene is optionally substituted with 1, 2, or 3 R 9 ;
  • Z is G-Ciocycloalkyl, 3- to 10-membered heterocycloalkyl, G- oaryl. or 5- to 10-membered heteroaryl; wherein each G-Ciocycloalkyl, 3- to 10-membered heterocycloalkyl, G- oaryl.
  • each R 9 is independently halogen, Ci-C4alkyl, G-C4alkenyl, G-C4alkynyl, Ci-C4haloalkyl, Ci- C4alkoxy, Ci-C4haloalkoxy, Ci-C4heteroalkyl, -C(0)H, -C(0)0H, -CN, G-Ciocycloalkyl, 3- to 10-membered heterocycloalkyl, G- oaryl.
  • R 5 , R 4a and R 4b together with the carbon atom to which they are attached form a G-Goaryl or 5- to 10-membered heteroaryl ring; wherein the G-Goaryl or 5- to 10- membered heteroaryl ring is optionally substituted with 1, 2, or 3 R 9 .
  • R 5 , R 4a and R 4b together with the carbon atom to which they are attached form a 5 - to 10-membered heteroaryl ring, optionally substituted with 1, 2, or 3 R 9 .
  • R 5 , R 4a and R 4b together with the carbon atom to which they are attached form a 9- or 10-membered heteroaryl ring, optionally substituted with 1, 2, or 3 R 9 .
  • R 5 , R 4a and R 4b together with the carbon atom to which they are attached form a 10-membered heteroaryl ring.
  • R 5 , R 4a and R 4b together with the carbon atom to which they are attached form a quinoline, isoquinoline, quinoxaline, quinazoline, quinolizine, naphthyridine.
  • R 5 , R 4a and R 4b together with the carbon atom to which they are attached form a 9-membered heteroaryl ring.
  • R 5 , R 4a and R 4b together with the carbon atom to which they are attached form a 2,3-dihydrobenzo[d]oxazole, benzo[d]oxazole, oxazolo[4,5-b]pyridine, lH-benzo[d]imidazole, benzo[d]thiazole, benzofuran, indole, aza-indole, lH-imidazo[4,5-b]pyridine, indolizine, imidazo[l,2- a]pyridine, or an isomer thereof, optionally substituted with 1, 2, or 3 R 9 .
  • R 5 , R 4a and R 4b together with the carbon atom to which they are attached form a benzo[d]oxazole, optionally substituted with 1, 2, or 3 R 9 .
  • the Ce-Cioaryl or 5- to 10-membered heteroaryl ring is unsubstituted.
  • R 5 is NHR 8 , NHS(0) 2 R 8 , OR 8 , SR 8 , S(0) 2 R 8 , or S(0) 2 NHR 8 .
  • R 5 is NHR 8 , NHS(0) 2 R 8 , OR 8 , or S(0) 2 NHR 8 .
  • R 5 is NHR 8 , NHS(0) 2 R 8 , or OR 8 .
  • R 5 is OR 8 .
  • R 5 is NHR 8 , or NHS(0) 2 R 8 .
  • R 5 is NHS(0) 2 R 8 .
  • R 5 is NHR 8 .
  • a compound of Formula (A -I) has one of the following formulae:
  • a compound of Formula (A -I) has the structure of Formula (A-II):
  • R 4a is H. In some embodiments, R 4a is H and R 4b is halogen or haloalkyl. In some embodiments, R 4b is CHF 2 or CF 3 . In some embodiments, R 4a is H and R 4b is difluoromethyl or trifluoromethyl. In some embodiments, R 4b is difluoromethyl or trifluoromethyl and R 5 is OR 8 . In some embodiments, R 4a and R 4b are both H.
  • R 4a and R 4b together with the carbon atom to which they are attached form a C3-Ciocycloalkyl or 3- to 10-membered heterocycloalkyl ring, wherein either of the cycloalkyl or heterocycloalkyl ring is optionally substituted with 1, 2, or 3 R 9 .
  • R 4a and R 4b together with the carbon atom to which they are attached form a G-Gcycloalkyl. optionally substituted with 1, 2, or 3 R 9 .
  • R 4a and R 4b together with the carbon atom to which they are attached form a C3-C5cycloalkyl, optionally substituted with 1, 2, or 3 R 9 .
  • R 4a and R 4b together with the carbon atom to which they are attached form a cyclopropyl, cyclobutyl, or cyclopentyl ring, optionally substituted with 1, 2, or 3 R 9 .
  • R 4a and R 4b together with the carbon atom to which they are attached form a cyclopropyl, cyclobutyl, or cyclopentyl ring and R 5 is -OR 8 or -NHR 8 .
  • R 4a and R 4b are each independently halogen, Ci-G, alkyl. G-Ghaloalkyl. C i -G, alkoxy, or G-Gheteroalkyl and R 5 is NHR 8 .
  • R 4a and R 4b together with the carbon atom to which they are attached form a carbonyl. In some embodiments, R 4a and R 4b together with the carbon atom to which they are attached form a carbonyl and R 5 is OR 8 or NHR 8 . In some embodiments, R 4a and R 4b together with the carbon atom to which they are attached form a carbonyl and R 5 is NHR 8 .
  • R 1 is hydrogen, G-Galkyl. G-Gcycloalkyl. G-Galkyl-(G- Gcycloalkyl). wherein each alkyl is optionally substituted with 1, 2, or 3 R 9 .
  • R 1 is phenethyl.
  • R 1 is hydrogen, methyl, trifluoromethyl, difluoromethyl, fluoromethyl, ethyl, propyl, isopropyl, cyclopropyl, methylenecyclopropyl, or cyclobutyl.
  • R 1 is phenethyl.
  • R 1 is hydrogen, methyl, trifluoromethyl, difluoromethyl, fluoromethyl, or ethyl.
  • R 1 is hydrogen or methyl. In some embodiments, R 1 is hydrogen.
  • a compound of Formula (A-I) has the structure of Formula (A-III):
  • R 2a and R 2b are each independently hydrogen, G-Galkyl. Ci- Ghaloalkyl, C i -G, alkoxy, G-Gheteroalkyl. G-Galkenyl. G-Galkynyl. wherein each alkyl, haloalkyl, alkoxy, heteroalkyl, alkenyl, or alkynyl is optionally substituted with 1, 2, or 3 R 9 .
  • R 2a and R 2b are each independently G-Gocycloalkyl, 3- to 10-membered heterocycloalkyl, G-Goaryl.
  • R 2a and R 2b are each independently hydrogen, G-Galkyl. G-Ghaloalkyl. C i -G, alkoxy, G- Gheteroalkyl. wherein each alkyl, haloalkyl, alkoxy, or heteroalkyl is optionally substituted with 1 or 2 G-Gcycloalkyl. 3- to 6-membered heterocycloalkyl, phenyl, or 5- or 6-membered heteroaryl.
  • R 2a is H and R 2b is Ci-G, alkyl or Ci-Ceheteroalkyl, wherein each alkyl or heteroalkyl is optionally substituted with a phenyl, or 5- or 6-membered heteroaryl.
  • R 2a is hydrogen.
  • R 2a and R 2b are each hydrogen.
  • R 2a and R 3a , and optionally R 2b and R 3b , together with the carbon atoms to which they are attached form a G-Gcycloalkyl.
  • 5- to 10-membered heterocycloalkyl, G-Goaryl. or 5- to 10-membered heteroaryl ring wherein each G-Gcycloalkyl. 5- to 10-membered heterocycloalkyl, G-Goaryl. or 5- to 10-membered heteroaryl ring is optionally substituted with 1, 2, or 3 R 9 ;
  • R 2a and R 2b together with the atom to which they are attached form a carbonyl. In some embodiments, R 2a and R 2b together with the atom to which they are attached form a carbonyl and X is NH. In some embodiments, R 2a and R 2b together with the atom to which they are attached form a carbonyl and X is O.
  • R 3a and R 3b are each independently hydrogen, G-Galkyl. Ci- Ghaloalkyl, G-Galkoxy. G-Gheteroalkyl. G-Galkcnyl. G-Galkynyl. G-Ciocycloalkyl, 3- to 10- membered heterocycloalkyl, G-Goaryl. or 5- to 10-membered heteroaryl, any of which is optionally substituted with 1, 2, or 3 R 9 . In some embodiments, R 3a and R 3b are each independently hydrogen, G-Galkyl. G-Ghaloalkyl. C i -C o alkoxy, Ci-C o hctcroalkyl.
  • R 3a and R 3b are each independently hydrogen, methyl, trifluoromethyl, difluoromethyl, ethyl, propyl, isopropyl, cyclopropyl, benzyl, phenethyl, or isobutyl.
  • R 3a and R 3b are each methyl.
  • R 3a is hydrogen.
  • R 3a and R 3b are each hydrogen.
  • R 2a and R 3a together with the carbon atoms to which they are attached, form a G-Gcycloalkyl. or 5- to 10-membered heterocycloalkyl.
  • R 2a and R 3a together with the carbon atoms to which they are attached, form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxirane, oxetane, tetrahydrofuran, tetrahydropyran, dioxane, aziridine, azetidine, pyrrolidine, piperidine, or morpholine, each of which is optionally substituted with 1 R 9 .
  • R 2a and R 3a together with the carbon atoms to which they are attached, form a cyclopropyl, cyclohexyl, dioxane, piperidine, or morpholine, each of which is optionally substituted with 1 R 9 .
  • R 2a and R 3a together with the carbon atoms to which they are attached form a G-Gcycloalkyl. optionally substituted with 1, 2, or 3 R 9 .
  • R 2a and R 3a together with the carbon atoms to which they are attached, form a cyclopropyl or cyclohexyl, either of which is optionally substituted with 1, 2, or 3 R 9 .
  • R 2a and R 3a together with the carbon atoms to which they are attached, form a cyclohexyl.
  • X is NR A , O, S, S(O), or S(0) 2 .
  • X is O.
  • X is S or S(0) 2 .
  • X is S.
  • X is S(0) 2 .
  • X is NR A .
  • R A is CrG, alkyl. C(0)-(CrG, alkyl) or C(O)- (G-Cecycloalkyl), wherein each alkyl or cycloalkyl is optionally substituted with 1, 2, or 3 R 9 .
  • R A is hydrogen, methyl, ethyl, C(0)CH 3 , C(0)cyclopropyl, or C(0)cyclohexyl, wherein each cyclopropyl or cyclohexyl is optionally substituted with 1 or 2 R 9 .
  • R A is hydrogen, methyl, or C(0)C13 ⁇ 4.
  • R A is hydrogen.
  • a compound of Formula (A-I) a compound has the structure of Formula (A-IV-a), (A-IV-b), (A-IV-c), or (A-IV-d):
  • a compound of Formula (A-I) has the structure of Formula (A-V-a), (A-V-b), (A-V-c), or (A-V-d):
  • a compound of Formula (A -I) has the structure of Formula (A-VI-a), (A-VI-b), (A-VI-c), or (A-VI-d):
  • X is C and taken together with R 2a , R 2b , and the carbon atom to which they are attached, forms a phenyl or 5- to 10-membered heteroaryl ring, optionally substituted with 1, 2, or 3 R 9 .
  • X is C and taken together with R 2a , R 2b , and the carbon atom to which they are attached, forms a phenyl ring, optionally substituted with 1, 2, or 3 R 9 .
  • X is C and taken together with R 2a , R 2b , and the carbon atom to which they are attached, forms a 5- to 10-membered heteroaryl ring, optionally substituted with 1, 2, or 3 R 9 .
  • X is C and taken together with R 2a , R 2b , and the carbon atom to which they are attached, forms a 5-membered heteroaryl ring, optionally substituted with 1, 2, or 3 R 9 .
  • X is C and taken together with R 2a , R 2b , and the carbon atom to which they are attached, forms a 9- or 10-membered heteroaryl ring, optionally substituted with 1, 2, or 3 R 9 .
  • X is C and taken together with R 2a , R 2b , and the carbon atom to which they are attached, forms a pyrrole, pyrazole, imidazole, indole, or azaindole ring, optionally substituted with 1, 2, or 3 R 9 .
  • a compound of Formula (A-I) has the structure of one of the following:
  • R 6a , R 6b , R 7a , and R 7b together with the carbon atoms to which they are attached form a 5 - to 10-membered heteroaryl ring optionally substituted with 1, 2, or 3 R 9 .
  • R 6a , R 6b , R 7a , and R 715 together with the carbon atoms to which they are attached form a furan, pyrrole, imidazole, pyrazole, triazole, pyridine, pyrimidine, pyridazine, pyrazine, thiophene, oxazole, thiazole, isoxazole, isothiazole, oxepin, azepine, thiepine, triazine, or tetrazine, any of which being optionally substituted with 1, 2, or 3 R 9 .
  • R 6a , R 6b , R 7a , and R 7b together with the carbon atoms to which they are attached form a furan, pyrrole, imidazole, pyrazole, pyridine, pyrimidine, pyridazine, pyrazine, any of which being optionally substituted with 1, 2, or 3 R 9 .
  • R 6a , R 6b , R 7a , and R 7b together with the carbon atoms to which they are attached form a furan, pyrrole, pyridine, pyrimidine, pyridazine, pyrazine, any of which being optionally substituted with 1, 2, or 3 R 9 .
  • R 6a , R 6b , R 7a , and R 7b together with the carbon atoms to which they are attached form a pyridine ring.
  • R 6b and R 7b together with the carbon atoms to which they are attached form a C3-Ciocycloalkyl or 3- to 10-membered heterocycloalkyl ring; wherein each C3-Ciocycloalkyl or 3- to 10-membered heterocycloalkyl ring is optionally substituted with 1, 2, or 3 R 9 .
  • R 6b and R 715 together with the carbon atoms to which they are attached form a G-Gcycloalkyl or 3- to 6- membered heterocycloalkyl ring; wherein each G-Gcycloalkyl or 3- to 6-membered heterocycloalkyl ring is optionally substituted with 1, 2, or 3 R 9 .
  • R 6b and R 7b together with the carbon atoms to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxirane, aziridine, oxetane, azetidine, oxolane, pyrrolidine, thiolane, oxazolidine, imidazolidine, thiazolidine, isoxazolidine, pyrazolidine, isothiazolidine, dioxolane, dithiolane, oxane, piperidine, thiolane, morpholine, piperazine, thiazine, or dioxane ring, wherein each ring is optionally substituted with 1, 2, or 3 R 9 .
  • R 6b and R 715 together with the carbon atoms to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxolane, oxane, dioxane, morpholine, pyrrolidine, or piperidine ring.
  • R 7a and R 7b together with the carbon atom to which they are attached form a saturated or partially saturated 3- to 5-membered cycloalkyl or a saturated or partially saturated 3- to 5- membered heterocycloalkyl; wherein the cycloalkyl or heterocycloalkyl is optionally substituted with
  • R 7a and R 7b together with the carbon atom to which they are attached form a cyclopropyl, cyclobutyl, cyclopropenyl, cyclobutenyl, oxirane, aziridine, oxetane, azetidine, cyclopentyl, or cyclopentenyl ring, wherein each ring is optionally substituted with 1, 2, or 3 R 9 .
  • R 7a and R 715 together with the carbon atom to which they are attached form a cyclopropyl ring, optionally substituted with 1, 2, or 3 R 9 .
  • R 7a and R 7b are each independently hydrogen, halogen, Ci-C4alkyl, or Ci-Cdialoalkyl. In some embodiments of a compound of Formula (A-I), R 7a and R 7b are each independently hydrogen, fluoro, methyl, ethyl, difluoromethyl, or trifluoromethyl. In some embodiments of a compound of Formula (A-I), R 7a and R 715 are each independently hydrogen, methyl, or ethyl. In some embodiments, R 7a and R 715 are both hydrogen.
  • R 6a and R 6b together with the carbon atom to which they are attached form a saturated or partially saturated 3- to 7-membered cycloalkyl ring optionally substituted with 1, 2, or 3 R 9 .
  • R 6a and R 6b together with the carbon atom to which they are attached form a cyclopropyl, cyclobutyl, cyclopropenyl, cyclobutenyl, oxirane, aziridine, oxetane, azetidine, or cyclopentyl, or cyclopentenyl ring, wherein each ring is optionally substituted with 1, 2, or 3 R 9 .
  • R 6a and R 6b together with the carbon atom to which they are attached form a saturated or partially saturated 3- to 5-membered cycloalkyl ring, optionally substituted with 1,
  • R 6a is hydrogen. In some embodiments of a compound of Formula (A-I), R 6a is hydrogen and R 6b is halogen, CrG, alkyl. G- Ghaloalkyl. G-G, alkenyl. or G-Galkynyl: wherein each G-Galkyl. G-G,haloalkyl. G-Galkenyl. or G-Galkynyl is optionally substituted with 1, 2, or 3 R 9 and/or 1 or 2, G. In some embodiments of a compound of Formula (A-I), R 6b is halogen, G-Galkyl. G-Ghaloalkyl.
  • G-Galkenyl. or C2- Galkynyl wherein each G-Galkyl. G-G,haloalkyl. G-Galkenyl. or G-Galkynyl is optionally substituted with 1, 2, or 3 R 9 and/or 1 or 2, G.
  • R 6b is G-Galkyl. Ci-Cehaloalkyl, G-G, alkenyl. or C2-Galkynyl.
  • each alkyl, haloalkyl, alkenyl, or alkynyl is optionally substituted with a phenyl or 5- or 6-membered heteroaryl ring, wherein each phenyl or heteroaryl ring is optionally substituted with 1, 2, or 3 R 9 .
  • R 6b is methyl, ethyl, or propyl, wherein the methyl, ethyl, or propyl is optionally substituted with G, and wherein G is a phenyl ring further substituted with 1, 2, or 3 R 9 .
  • R 6b is ethyl, optionally substituted with phenyl, tolyl, phenolyl, fluorophenyl, chlorophenyl, anilinyl, methoxyphenyl, dimethylphenyl, difluorophenyl, dichlorophenyl, dihydroxyphenyl, dimethoxyphenyl, fluoromethoxyphenyl, or naphthyl.
  • R 6b is Ci- Ci, alkyl. Ci-Cehaloalkyl, C2-G, alkenyl or G-Galkynyl.
  • each alkyl, haloalkyl, alkenyl, or alkynyl is optionally substituted with a G-Gcycloalkyl or 3- to 6-membered heterocycloalkyl ring, wherein each cycloalkyl or heterocyclalkyl ring is optionally substituted with 1, 2, or 3 R 9 .
  • R 6b is methyl, ethyl, 2-propenyl, isopropyl, or phenethyl.
  • R 6b is methyl.
  • R 6b is ethyl.
  • R 6b is 2-propenyl.
  • R 6b is isopropyl.
  • R 6b is phenethyl.
  • R 6a and R 6b are each independently halogen, G-Galkyl.
  • G-Ghaloalkyl. C2-Galkenyl, or C2-Galkynyl; wherein each G-Galkyl.
  • Ci- C haloalkyl.
  • G-Galkenyl. or C2-Galkynyl is optionally substituted with 1, 2, or 3 R 9 and/or 1 or 2,
  • R 6a and R 6b are each independently halogen, C2-Galkyl, G-Ghaloalkyl.
  • G-Galkenyl. or G-Galkynyl wherein each G-Galkyl.
  • G-Galkenyl. or C2- Galkynyl is optionally substituted with 1, 2, or 3 R 9 and/or 1 or 2, G.
  • R 6a and R 6b are each independently G-Galkyl.
  • R 6a and R 6b are each independently methyl, ethyl, or propyl, optionally substituted with G, wherein G is a phenyl ring further substituted with 1, 2, or 3 R 9 .
  • R 6a and R 6b are each independently ethyl, optionally substituted with phenyl, tolyl, phenolyl, fluorophenyl, chlorophenyl, anilinyl, methoxyphenyl, dimethylphenyl, difluorophenyl, dichlorophenyl, dihydroxyphenyl, dimethoxyphenyl, fluoromethoxyphenyl, or naphthyl.
  • R 6a and R 6b are each independently G-Galkyl. G-Ghaloalkyl. C2-Galkenyl, or C2- Ci, alkynyl.
  • R 6a and R 6b are each independently methyl, ethyl, 2-propenyl, isopropyl, or phenethyl. In some embodiments, R 6a and R 6b are each independently ethyl, 2-propenyl, isopropyl, or phenethyl. In some embodiments of a compound of Formula (A-I), R 6a and R 6b are methyl provided that when R 6a and R 6b are both methyl, then R 8 is not some embodiments of a compound of Formula (A-I),
  • R 6a and R 6b are methyl. In some embodiments, R 6a and R 6b are ethyl. In some embodiments, R 6a and R 6b are 2-propenyl. In some embodiments, R 6a and R 6b are isopropyl. In some embodiments, R 6a and R 6b are phenethyl.
  • R 8 is Z, G-Galkyl. (G-Galkylene)- Z, (G-Gheteroalkylene)-Z, (G-Galkenylene)-Z, CH(Z)2, CH2CH(Z)2, CH(G-Galkyl)Z. or C(0)Z; wherein each alkyl, alkylene, heteroalkylene, or alkenylene is optionally substituted with 1, 2, or 3 R 9 .
  • R 8 is Z, G-Galkyl. CH(Z)2, or C(0)Z.
  • R 8 is Z, G-Galkyl, CH(Z)2, or C(0)Z, wherein Z is G-Ciocycloalkyl, 3- to 10-membered heterocycloalkyl, G- oaryl. or 5- to 10-membered heteroaryl.
  • R 8 is Z or CH(Z)2.
  • R 8 is Z.
  • R 8 is CH(Z)2.
  • Z is G- Gocycloalkyl, 3- to 10-membered heterocycloalkyl, G-Goaryl. or 5- to 10-membered heteroaryl; wherein each G-Gocycloalkyl, 3- to 10-membered heterocycloalkyl, G-Goaryl. and 5- to 10- membered heteroaryl is optionally substituted with 1, 2, or 3 R 9 .
  • Z is G-Goaryl or 5- to 10-membered heteroaryl, wherein each aryl or heteroaryl is optionally substituted with 1, 2, or 3 R 9 .
  • Z is G-Gocycloalkyl or 3- to 10-membered heterocycloalkyl; wherein each G-Gocycloalkyl and 3- to 10- membered heterocycloalkyl is optionally substituted with 1, 2, or 3 R 9 .
  • Z is G-Gocycloalkyl optionally substituted with 1, 2, or 3 R 9 .
  • Z is phenyl or naphthyl, optionally substituted with 1, 2, or 3 R 9 .
  • Z is pyridine, pyrimidine, pyridazine, pyrazine, quinoline, naphthyridine, quinoxaline, quinolizine, benzofuran, benzoxazole, or benzothiophene.
  • Z is tetrahydronaphthalene, tetrahydroquinoline, tetrahydroisoquinoline, chroman, thiochroman, indane, indoline, dihydrobenzofuran, or dihydrobenzothiophene .
  • R 8 is:
  • R 8 is:
  • R 8 is:
  • R 8 is:
  • R 8 is:
  • R 8 is:
  • R 8 is:
  • R 8 is: [0092] In some embodiments of a compound of Formula (A -I), R 8 is:
  • each R 9 is independently halogen, Ci-C4alkyl, C2-C4alkenyl, C2- C4alkynyl, Ci-C4haloalkyl, Ci-C4alkoxy, Ci-C4haloalkoxy, Ci-C4heteroalkyl, -C(0)H, -C(0)OH, -CN, C3-Ciocycloalkyl, 3- to 10-membered heterocycloalkyl, G,-Cioaryl.
  • each R 9 is independently halogen, Ci-C4alkyl, C2- C4alkenyl, C2-C4alkynyl, Ci-C4haloalkyl, Ci-C4alkoxy, Ci-C4haloalkoxy, Ci-C4heteroalkyl, -C(0)H, - C(0)OH, -CN, C3-Ciocycloalkyl, 3- to 10-membered heterocycloalkyl, Ce-Goaryl, 5- to 10-membered heteroaryl, -OH, -0(Ci-C 4 alkyl), or -0(Ci-C 4 haloalkyl).
  • each R 9 is independently halogen, Ci-C4alkyl, -C(0)OH, -0(Ci-C 4 alkyl), -0(Ci-C 4 haloalkyl), or 5- to 10- membered heteroaryl. In some embodiments, each R 9 is each independently -C(0)OH, -0(CH 3 ), - OiGrhGrhF), or pyrimidine.
  • R 1 is hydrogen, CrG, alkyl. G-Gcycloalkyl. G-CealkyHG-Cecycloalkyl), G-Galkyl-(phenyl). or G-G,alkyl-(5- to 6-membered heteroaryl); wherein the G-Galkyl. CVG, cycloalkyl. phenyl, or 5- to 6-membered heteroaryl is optionally substituted with 1, 2, or 3 R 9 ;
  • X is NR A , O, S, S(O), or S(0) 2 ;
  • R A is hydrogen, Ci-Cealkyl, C(0)-(Ci-C 6 alkyl), C(0)-(G-C 6 cycloalkyl), C(0)-(phenyl), or C(0)-(5- to 6-membered heteroaryl); wherein each G-Galkyl.
  • G-Gcycloalkyl is hydrogen, Ci-Cealkyl, C(0)-(Ci-C 6 alkyl), C(0)-(G-C 6 cycloalkyl), C(0)-(phenyl), or C(0)-(5- to 6-membered heteroaryl); wherein each G-Galkyl.
  • G-Gcycloalkyl is hydrogen, Ci-Cealkyl, C(0)-(Ci-C 6 alkyl), C(0)-(G-C 6 cycloalkyl), C(0)-(phenyl), or C(0)-(5- to 6-membered heteroaryl
  • phenyl, or 5- to 6- membered heteroaryl is optionally substituted with 1, 2, or 3 R 9 ; or X is C and taken together with R 2a , R 2b , and the carbon atom to which they are attached, forms a phenyl or 5- to 10-membered heteroaryl ring, optionally substituted with 1, 2, or 3 R 9 ;
  • R 2a , R 2b , R 3a , and R 3b are each independently hydrogen, Ci-G, alkyl.
  • G-Galkynyl is optionally substituted with 1 or 2 G-Ciocycloalkyl, 3- to 10-membered heterocycloalkyl, G-Goaryl. or 5- to 10-membered heteroaryl rings; wherein each G-Galkyl.
  • G-Ghaloalkyl Ci-Ce alkoxy, G- Ceheteroalkyl, G-Galkenyl. G-Galkynyl.
  • G-Ciocycloalkyl, 3- to 10-membered heterocycloalkyl, Ce-Cioaryl, or 5- to 10-membered heteroaryl is optionally substituted with 1, 2, or 3 R 9 ; or R 2a and R 2b together with the carbon atom to which they are attached form a carbonyl; or R 2a and R 3a , and optionally R 2b and R 3b , together with the carbon atoms to which they are attached form a G-Gcycloalkyl.
  • R 4a and R 4b are each independently hydrogen, halogen, G-Galkyl.
  • G-Galkynyl is optionally substituted with 1 or 2 G-Ciocycloalkyl, 3- to 10-membered heterocycloalkyl, G-Goaryl. or 5- to 10-membered heteroaryl; wherein each G-Galkyl. G-Ghaloalkyl. G-G alkoxy. Ci- Gheteroalkyl, G-Galkenyl. G-Galkynyl. G-Ciocycloalkyl, 3- to 10-membered heterocycloalkyl, G-Goaryl.
  • R 5 is NHR 8 ,NHS(0) 2 R 8 , OR 8 , SR 8 , S(0) 2 R 8 , or S(0) 2 NHR 8 ; or R 5 , R 4a , and R 4b , together with the carbon atom to which they are attached, form a G-Goaryl or 5- to 10-membered heteroaryl ring; wherein the G-Goaryl or 5- to 10-membered heteroaryl ring is optionally substituted with 1, 2, or 3 R 9 ;
  • R 6a is hydrogen, halogen, -U a , or -G
  • R 6b is halogen, -U b , or -G
  • -U a is C -G, alkyl.
  • G-Ghaloalkyl. Ci-Cealkoxy, G-Gheteroalkyl.
  • G-Ghaloalkyl. Ci-Cealkoxy, G-Gheteroalkyl.
  • G-Galkcnyl. or C2- Galkynyl is optionally substituted with 1, 2, or 3 R 9 and/or 1 or 2 -G;
  • -U b is G-Galkyl.
  • G-Ghaloalkyl. Ci-Cealkoxy, Ci-Ceheteroalkyl, C2-Galkenyl, or C2- Galkynyl is optionally substituted with 1, 2, or 3 R 9 and/or 1 or 2 -G;
  • -G is C 3 -Gocycloalkyl, 3- to 10-membered heterocycloalkyl, Ce-Goaryl, or 5- to 10-membered heteroaryl; wherein each C3-Ciocycloalkyl, 3- to 10-membered heterocycloalkyl, Ce-Goaryl, or 5- to 10-membered heteroaryl is optionally substituted with 1, 2, or 3 R 9 ;
  • R 7a is hydrogen, halogen, Ci-C4alkyl, or Ci-C t haloalkyl
  • R 715 is hydrogen, halogen, Ci-C4alkyl, or Ci-C4haloalkyl
  • R 8 is Z, G-Galkyl. (Ci-C 6 alkylene)-Z, (Ci-C 6 heteroalkylene)-Z, (C2-Galkenylene)-Z, CH(Z)2, CH2CH(Z)2, CH(G-Galkyl)Z. or C(0)Z; wherein each alkyl, alkylene, heteroalkylene, or alkenylene is optionally substituted with 1, 2, or 3 R 9 ;
  • Z is C 3 -Gocycloalkyl, 3- to 10-membered heterocycloalkyl, Ce-Goaryl, 5- to 10-membered heteroaryl; wherein each C 3 -Gocycloalkyl, 3- to 10-membered heterocycloalkyl, Ce-Goaryl, 5- to 10-membered heteroaryl is optionally substituted with 1, 2, or 3 R 9 ; each R 9 is independently halogen, Ci-C4alkyl, C2-Galkenyl, C2-Galkynyl, Ci-C4haloalkyl, Ci- C4alkoxy, Ci-C4haloalkoxy, Ci-C4heteroalkyl, -C(0)H, -C(0)0H, -CN, C3-Ciocycloalkyl, 3- to 10-membered heterocycloalkyl, Ce-Goaryl, 5- to 10-membered heteroaryl, -C(0)(Ci-C 4 alkyl), - C(0)0(Ci-C 4
  • R 5 , R 4a and R 4b together with the carbon atom to which they are attached form a Ce-Goaryl or 5- to 10-membered heteroaryl ring; wherein the Ce-Goaryl or 5- to 10- membered heteroaryl ring is optionally substituted with 1, 2, or 3 R 9 .
  • R 5 , R 4a and R 4b together with the carbon atom to which they are attached form a 5- to 10-membered heteroaryl ring, optionally substituted with 1, 2, or 3 R 9 .
  • R 5 , R 4a and R 4b together with the carbon atom to which they are attached form a 9- or 10-membered heteroaryl ring, optionally substituted with 1, 2, or 3 R 9 .
  • R 5 , R 4a and R 4b together with the carbon atom to which they are attached form a 10-membered heteroaryl ring.
  • R 5 , R 4a and R 4b together with the carbon atom to which they are attached form a quinoline, isoquinoline, quinoxaline, quinazoline, quinolizine, naphthyridine.
  • R 5 , R 4a and R 4b together with the carbon atom to which they are attached form a 9-membered heteroaryl ring.
  • R 5 , R 4a and R 4b together with the carbon atom to which they are attached form a 2,3-dihydrobenzo[d]oxazole, benzo[d]oxazole, oxazolo[4,5-b]pyridine, lH-benzo[d]imidazole, benzo[d]thiazole, benzofuran, indole, aza-indole, lH-imidazo[4,5-b]pyridine, indolizine, imidazo[l,2- a]pyridine, or an isomer thereof, optionally substituted with 1, 2, or 3 R 9 .
  • R 5 , R 4a and R 4b together with the carbon atom to which they are attached form a benzo[d]oxazole, optionally substituted with 1, 2, or 3 R 9 .
  • the Ce-Cioaryl or 5- to 10-membered heteroaryl ring is unsubstituted.
  • R 5 is NHR 8 , NHS(0) 2 R 8 , OR 8 , SR 8 , S(0) 2 R 8 , or S(0) 2 NHR 8 .
  • R 5 is NHR 8 , NHS(0) 2 R 8 , OR 8 , or S(0) 2 NHR 8 .
  • R 5 is NHR 8 , NHS(0) 2 R 8 , or OR 8 .
  • R 5 is OR 8 .
  • R 5 is NHR 8 , or NHS(0) 2 R 8 .
  • R 5 is NHS(0) 2 R 8 .
  • R 5 is NHR 8 .
  • a compound of Formula (B-I) has any one of the following formulae:
  • a compound of Formula (B-I) has the structure of Formula (B-II):
  • R 4a is H. In some embodiments, R 4a is H and R 4b is halogen or haloalkyl. In some embodiments, R 4b is CHF 2 or CF 3 . In some embodiments, R 4a is H and R 4b is difluoromethyl or trifluoromethyl. In some embodiments, R 4b is difluoromethyl or trifluoromethyl and R 5 is OR 8 . In some embodiments, R 4a and R 4b are both H.
  • R 4a and R 4b together with the carbon atom to which they are attached form a C3-Ciocycloalkyl or 3- to 10-membered heterocycloalkyl ring, wherein either of the cycloalkyl or heterocycloalkyl ring is optionally substituted with 1, 2, or 3 R 9 .
  • R 4a and R 4b together with the carbon atom to which they are attached form a G-Gcycloalkyl. optionally substituted with 1, 2, or 3 R 9 .
  • R 4a and R 4b together with the carbon atom to which they are attached form a C3-C5cycloalkyl, optionally substituted with 1, 2, or 3 R 9 .
  • R 4a and R 4b together with the carbon atom to which they are attached form a cyclopropyl, cyclobutyl, or cyclopentyl ring, optionally substituted with 1, 2, or 3 R 9 .
  • R 4a and R 4b together with the carbon atom to which they are attached form a cyclopropyl, cyclobutyl, or cyclopentyl ring and R 5 is -OR 8 or -NHR 8 .
  • R 4a and R 4b are each independently halogen, Ci-G, alkyl. G-Ghaloalkyl. C i -G, alkoxy, or G-Gheteroalkyl and R 5 is NHR 8 .
  • R 4a and R 4b together with the carbon atom to which they are attached form a carbonyl. In some embodiments, R 4a and R 4b together with the carbon atom to which they are attached form a carbonyl and R 5 is OR 8 or NHR 8 . In some embodiments, R 4a and R 4b together with the carbon atom to which they are attached form a carbonyl and R 5 is NHR 8 .
  • R 1 is hydrogen, G-Galkyl. G-Gcycloalkyl. G-Galkyl-(G- Gcycloalkyl). wherein each alkyl is optionally substituted with 1, 2, or 3 R 9 .
  • R 1 is phenethyl.
  • R 1 is hydrogen, methyl, trifluoromethyl, difluoromethyl, fluoromethyl, ethyl, propyl, isopropyl, cyclopropyl, methylenecyclopropyl, or cyclobutyl.
  • R 1 is phenethyl.
  • R 1 is hydrogen, methyl, trifluoromethyl, difluoromethyl, fluoromethyl, or ethyl.
  • R 1 is hydrogen or methyl. In some embodiments, R 1 is hydrogen.
  • a compound of Formula (B-I) has the structure of Formula (B-III):
  • R 2a and R 2b are each independently hydrogen, G-Galkyl. Ci- Ghaloalkyl. C i -G, alkoxy, G-Gheteroalkyl. G-Galkenyl. G-Galkynyl. wherein each alkyl, haloalkyl, alkoxy, heteroalkyl, alkenyl, or alkynyl is optionally substituted with 1, 2, or 3 R 9 .
  • R 2a and R 2b are each independently G-Gocycloalkyl, 3- to 10-membered heterocycloalkyl, G-Goaryl.
  • R 2a and R 2b are each independently hydrogen, CrG, alkyl. G-G, haloalkyl. Ci-Ce alkoxy, G- Ceheteroalkyl, wherein each alkyl, haloalkyl, alkoxy, or heteroalkyl is optionally substituted with 1 or 2 G-Gcycloalkyl. 3- to 6-membered heterocycloalkyl, phenyl, or 5- or 6-membered heteroaryl.
  • R 2a is H and R 2b is G-Galkyl or G-Gheteroalkyl. wherein each alkyl or heteroalkyl is optionally substituted with a phenyl, or 5- or 6-membered heteroaryl.
  • R 2a is hydrogen.
  • R 2a and R 2b are each hydrogen.
  • R 2a and R 3a , and optionally R 2b and R 3b , together with the carbon atoms to which they are attached form a G-Gcycloalkyl.
  • 5- to 10-membered heterocycloalkyl, G-Goaryl. or 5- to 10-membered heteroaryl ring wherein each G-Gcycloalkyl. 5- to 10-membered heterocycloalkyl, G-Goaryl. or 5- to 10-membered heteroaryl ring is optionally substituted with 1, 2, or 3 R 9 ;
  • R 2a and R 2b together with the atom to which they are attached form a carbonyl. In some embodiments, R 2a and R 2b together with the atom to which they are attached form a carbonyl and X is NH. In some embodiments, R 2a and R 2b together with the atom to which they are attached form a carbonyl and X is O.
  • R 3a and R 3b are each independently hydrogen, G-Galkyl.
  • G- G haloalkyl.
  • G-Galkynyl. C3-Ciocycloalkyl, 3- to 10- membered heterocycloalkyl, G-Goaryl. or 5- to 10-membered heteroaryl, any of which is optionally substituted with 1, 2, or 3 R 9 .
  • R 3a and R 3b are each independently hydrogen, G-Galkyl.
  • G-Ghaloalkyl. C i -Co alkoxy, Ci-Cohctcroalkyl.
  • R 3a and R 3b are each independently hydrogen, methyl, trifluoromethyl, difluoromethyl, ethyl, propyl, isopropyl, cyclopropyl, benzyl, phenethyl, or isobutyl.
  • R 3a and R 3b are each methyl.
  • R 3a is hydrogen.
  • R 3a and R 3b are each hydrogen.
  • R 2a and R 3a together with the carbon atoms to which they are attached, form a G-Gcycloalkyl. or 5- to 10-membered heterocycloalkyl.
  • R 2a and R 3a together with the carbon atoms to which they are attached, form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxirane, oxetane, tetrahydrofuran, tetrahydropyran, dioxane, aziridine, azetidine, pyrrolidine, piperidine, or morpholine, each of which is optionally substituted with 1 R 9 .
  • R 2a and R 3a together with the carbon atoms to which they are attached, form a cyclopropyl, cyclohexyl, dioxane, piperidine, or morpholine, each of which is optionally substituted with 1 R 9 .
  • R 2a and R 3a together with the carbon atoms to which they are attached form a G-Gcycloalkyl. optionally substituted with 1, 2, or 3 R 9 .
  • R 2a and R 3a together with the carbon atoms to which they are attached, form a cyclopropyl or cyclohexyl, either of which is optionally substituted with 1, 2, or 3 R 9 .
  • R 2a and R 3a together with the carbon atoms to which they are attached, form a cyclohexyl.
  • X is NR A , O, S, S(O), or S(0) 2 .
  • X is O.
  • X is S or S(0) 2 .
  • X is S.
  • X is S(0) 2 .
  • X is NR A .
  • R A is Ci-G, alkyl. C(0)-(G-Galkyl). or C(0)-(G-C 6 cycloalkyl), wherein each alkyl or cycloalkyl is optionally substituted with 1, 2, or 3 R 9 .
  • R A is hydrogen, methyl, ethyl, C(0)CH 3 , C(0)cyclopropyl, or C(0)cyclohexyl, wherein each cyclopropyl or cyclohexyl is optionally substituted with 1 or 2 R 9 .
  • R A is hydrogen, methyl, or C(0)C13 ⁇ 4.
  • R A is hydrogen.
  • a compound of Formula (B-I) a compound has the structure of Formula (B-IV- a), (B-IV-b), (B-IV-c), or (B-IV-d):
  • a compound has the structure of Formula (B-V-a) or (B-V-b): [00111] In some embodiments of a compound of Formula (B-I), a compound has the structure of Formula (B-VI-a), (B-VI-b), (B-VI-c), or (B-VI-d):
  • a compound of Formula (B-I) has the structure of Formula (B-VII-a), (B-VII-b), (B-VII-c), or (B-VII-d):
  • X is C and taken together with R 2a , R 2b , and the carbon atom to which they are attached, forms a phenyl or 5- to 10-membered heteroaryl ring, optionally substituted with 1, 2, or 3 R 9 .
  • X is C and taken together with R 2a , R 2b , and the carbon atom to which they are attached, forms a phenyl ring, optionally substituted with 1, 2, or 3 R 9 .
  • X is C and taken together with R 2a , R 2b , and the carbon atom to which they are attached, forms a 5- to 10-membered heteroaryl ring, optionally substituted with 1, 2, or 3 R 9 .
  • X is C and taken together with R 2a , R 2b , and the carbon atom to which they are attached, forms a 5-membered heteroaryl ring, optionally substituted with 1, 2, or 3 R 9 .
  • X is C and taken together with R 2a , R 2b , and the carbon atom to which they are attached, forms a 9- or 10-membered heteroaryl ring, optionally substituted with 1, 2, or 3 R 9 .
  • X is C and taken together with R 2a , R 2b , and the carbon atom to which they are attached, forms a pyrrole, pyrazole, imidazole, indole, or azaindole ring, optionally substituted with 1, 2, or 3 R 9 .
  • a compound as disclosed herein has the structure of one of the following:
  • R 7a and R 7b are each independently hydrogen, halogen, Ci-C4alkyl, or Ci-Cdialoalkyl. In some embodiments, R 7a and R 7b arc each independently hydrogen, fluoro, methyl, ethyl, difluoromethyl, or trifluoromethyl. In some embodiments, R 7a and R 7b are each independently hydrogen, methyl, or ethyl. In some embodiments, R 7a and R 7b are both hydrogen.
  • R 6a is hydrogen. In some embodiments of a compound of Formula (B-I), R 6a is hydrogen and R 6b is halogen, Ci-G, alkyl. G- G, haloalkyl. G-G, alkenyl. or G-Galkynyl: wherein each G-Galkyl. G-G, haloalkyl. G-G, alkenyl or G-Galkynyl is optionally substituted with 1, 2, or 3 R 9 and/or 1 or 2, G. In some embodiments of a compound of Formula (B-I), R 6b is halogen, G-Galkyl. G-G,haloalkyl.
  • G-G alkenyl. or C2- G, alkynyl: wherein each G-Galkyl.
  • G-G, alkenyl. or G-Galkynyl is optionally substituted with 1, 2, or 3 R 9 and/or 1 or 2, G.
  • R 6b is G-Galkyl. Ci-Cehaloalkyl, G-G, alkenyl. or C2-G,alkynyl.
  • each alkyl, haloalkyl, alkenyl, or alkynyl is optionally substituted with a phenyl or 5- or 6-membered heteroaryl ring, wherein each phenyl or heteroaryl ring is optionally substituted with 1, 2, or 3 R 9 .
  • R 6b is methyl, ethyl, or propyl, optionally substituted with G, wherein G is a phenyl ring further substituted with 1, 2, or 3 R 9 .
  • R 6b is ethyl, optionally substituted with phenyl, tolyl, phenolyl, fluorophenyl, chlorophenyl, anilinyl, methoxyphenyl, dimethylphenyl, difluorophenyl, dichlorophenyl, dihydroxyphenyl, dimethoxyphenyl, fluoromethoxyphenyl, or naphthyl.
  • R 6b is G-Galkyl.
  • G-G haloalkyl.
  • G-G alkenyl. or G-Galkynyl.
  • each alkyl, haloalkyl, alkenyl, or alkynyl is optionally substituted with a C3- Cecycloalkyl or 3- to 6-membered heterocycloalkyl ring, wherein each cycloalkyl or heterocyclalkyl ring is optionally substituted with 1, 2, or 3 R 9 .
  • R 6b is methyl, ethyl, 2-propenyl, isopropyl, or phenethyl.
  • R 6b is methyl, ethyl, 2-propenyl, isopropyl, or phenethyl, and the carbon to which it is attached has the (S) stereochemical configuration.
  • R 6b is methyl, ethyl, 2-propenyl, isopropyl, or phenethyl, and the carbon to which it is attached has the (R) stereochemical configuration.
  • R 6b is methyl.
  • R 6b is ethyl.
  • R 6b is 2-propenyl.
  • R 6b is isopropyl.
  • R 6b is phenethyl.
  • R 6a and R 6b are each independently halogen, G-Galkyl.
  • G-Galkenyl. or G-Galkynyl is optionally substituted with 1, 2, or 3 R 9 and/or 1 or 2,
  • R 6a and R 6b are each independently G- Galkyl, G-Ghaloalkyl. G-Galkenyl. or G-Galkynyl. wherein each alkyl, haloalkyl, alkenyl, or alkynyl is optionally substituted with a phenyl or 5- or 6-membered heteroaryl ring, wherein each phenyl or heteroaryl ring is optionally substituted with 1, 2, or 3 R 9 .
  • R 6a and R 6b are each independently ethyl or propyl, optionally substituted with G, wherein G is a phenyl ring further substituted with 1, 2, or 3 R 9 .
  • R 6a and R 6b are each independently ethyl, optionally substituted with phenyl, tolyl, phenolyl, fluorophenyl, chlorophenyl, anilinyl, methoxyphenyl, dimethylphenyl, difluorophenyl, dichlorophenyl, dihydroxyphenyl, dimethoxyphenyl, fluoromethoxyphenyl, or naphthyl.
  • R 6a and R 6b are each independently G-Galkyl. G-Ghaloalkyl. G-Galkenyl. or G-Galkynyl.
  • R 6a and R 6b are each independently ethyl, 2-propenyl, isopropyl, or phenethyl. In some embodiments, R 6a and R 6b are ethyl. In some embodiments, R 6a and R 6b are 2-propenyl.
  • R 6a and R 6b are isopropyl. In some embodiments, R 6a and R 6b are phenethyl.
  • R 6a is halogen, G-Galkyl. G-Ghaloalkyl. G-Galkenyl. or G-Galkynyl: wherein each G-Galkyl. G-Ghaloalkyl. G- Galkcnyl. or G-Galkynyl is optionally substituted with 1, 2, or 3 R 9 and/or 1 or 2 G; and R 6b is methyl. In some embodiments of a compound of Formula (B-I), R 6a is G-Galkyl.
  • G-Ghaloalkyl G- Galkcnyl. or G-Galkynyl. wherein each alkyl, haloalkyl, alkenyl, or alkynyl is optionally substituted with a phenyl or 5- or 6-membered heteroaryl ring, wherein each phenyl or heteroaryl ring is optionally substituted with 1, 2, or 3 R 9 ; and R 6b is methyl.
  • R 6a is ethyl or propyl, optionally substituted with G, wherein G is a phenyl ring further substituted with 1, 2, or 3 R 9 ; and R 6b is methyl.
  • R 6a is ethyl, optionally substituted with phenyl, tolyl, phenolyl, fluorophenyl, chlorophenyl, anilinyl, methoxyphenyl, dimethylphenyl, difluorophenyl, dichlorophenyl, dihydroxyphenyl, dimethoxyphenyl, fluoromethoxyphenyl, or naphthyl; and R 6b is methyl.
  • R 6a is G-Galkyl. Ci-Cehaloalkyl, G-Galkenyl. or G-Galkynyl.
  • each alkyl, haloalkyl, alkenyl, or alkynyl is optionally substituted with a G-Gcycloalkyl or 3- to 6-membered heterocycloalkyl ring, wherein each cycloalkyl or heterocyclalkyl ring is optionally substituted with 1, 2, or 3 R 9 ; and R 6b is methyl.
  • R 6a is ethyl, 2-propenyl, isopropyl, or phenethyl
  • R 6b is methyl.
  • R 8 is Z, G-Galkyl. (G-Galkylene)- Z, (Ci-C 6 heteroalkylene)-Z, (C2-C6alkenylene)-Z, CH(Z)2, CH2CH(Z)2, CH(Ci-Cealkyl)Z, or C(0)Z; wherein each alkyl, alkylene, heteroalkylene, or alkenylene is optionally substituted with 1, 2, or 3 R 9 .
  • R 8 is Z, G-Galkyl. CH(Z)2, or C(0)Z.
  • R 8 is Z, G-Galkyl. CH(Z)2, or C(0)Z, wherein Z is G-Ciocycloalkyl, 3- to 10-membered heterocycloalkyl, G-Goaryl. or 5- to 10-membered heteroaryl.
  • R 8 is Z or CH(Z)2.
  • R 8 is Z.
  • R 8 is CH(Z)2.
  • Z is G- Ciocycloalkyl, 3- to 10-membered heterocycloalkyl, G-Goaryl. or 5- to 10-membered heteroaryl; wherein each C3-Ciocycloalkyl, 3- to 10-membered heterocycloalkyl, G-Goaryl. and 5- to 10- membered heteroaryl is optionally substituted with 1, 2, or 3 R 9 .
  • Z is G-Goaryl or 5- to 10-membered heteroaryl, wherein each aryl or heteroaryl is optionally substituted with 1, 2, or 3 R 9 .
  • Z is C3-Ciocycloalkyl or 3- to 10-membered heterocycloalkyl; wherein each C3-Ciocycloalkyl and 3- to 10- membered heterocycloalkyl is optionally substituted with 1, 2, or 3 R 9 .
  • Z is C3-Ciocycloalkyl optionally substituted with 1, 2, or 3 R 9 .
  • Z is phenyl or naphthyl, optionally substituted with 1, 2, or 3 R 9 .
  • Z is pyridine, pyrimidine, pyridazine, pyrazine, quinoline, naphthyridine, quinoxaline, quinolizine, benzofuran, benzoxazole, or benzothiophene.
  • Z is tetrahydronaphthalene, tetrahydroquinoline, tetrahydroisoquinoline, chroman, thiochroman, indane, indoline, dihydrobenzofuran, or dihydrobenzothiophene.
  • R 8 is:
  • R 8 is:
  • R 8 is:
  • R 8 is:
  • R 8 is:
  • R 8 is:
  • each R 9 is independently halogen, G-Galkyl, G-Galkenyl, G- C 4 alkynyl, Ci-C 4 haloalkyl, Ci-C 4 alkoxy, Ci-C 4 haloalkoxy, G-Gheteroalkyl, -C(0)H, -C(0)OH, -CN C3-Ciocycloalkyl, 3- to 10-membered heterocycloalkyl, G-Goaryl, 5- to 10-membered heteroaryl, - N(Ci-Galkyl) 2 , -OH, -O(G-Galkyl), -0(Ci-C 4 haloalkyl), -0(Ci-C 4 alkylene)-(5- to 10-membered heteroaryl), -O(G-Goaryl), -SH, S(0) 2 0H, -S(0) 2 (Ci-C 4 alkyl), -S(0) 2 NH 2
  • each R 9 is independently halogen, G-Galkyl, G- Galkenyl, C 2 -C 4 alkynyl, Ci-C 4 haloalkyl, G-Galkoxy, Ci-C 4 haloalkoxy, Ci-C 4 heteroalkyl, -C(0)H, - C(0)OH, -CN, C3-Ciocycloalkyl, 3- to 10-membered heterocycloalkyl, G-Goaryl. 5- to 10-membered heteroaryl, -OH, -0(Ci-C 4 alkyl), or -0(Ci-C 4 haloalkyl).
  • each R 9 is independently halogen, G-Galkyl, -C(0)OH, -O(G-Galkyl), -0(Ci-C 4 haloalkyl), or 5- to 10- membered heteroaryl. In some embodiments, each R 9 is each independently -C(0)OH, -0(CH 3 ), - 0(CH 2 CH 2 F), or pyrimidine.
  • R 1 is hydrogen, CrG, alkyl.
  • G-Gcycloalkyl. phenyl, or 5- to 6-membered heteroaryl is optionally substituted with 1, 2, or 3 R 9 ;
  • X is NR A , O, S, S(O), or S(0) 2 ;
  • R A is hydrogen, G-C 6 alkyl, C(0)-(G-C 6 alkyl), C(0)-(C 3 -C 6 cycloalkyl), C(0)-(phenyl), or C(0)-(5- to 6-membered heteroaryl); wherein each Ci-G, alkyl. G-Gcycloalkyl. phenyl, or 5- to 6- membered heteroaryl is optionally substituted with 1, 2, or 3 R 9 ; or X is C and taken together with R 2a , R 2b , and the carbon atom to which they are attached, forms a phenyl or 5- to 10-membered heteroaryl ring, optionally substituted with 1, 2, or 3 R 9 ;
  • R 2a , R 2b , R 3a , and R 3b are each independently hydrogen, Ci-G, alkyl.
  • G-Galkynyl. C3-Ciocycloalkyl, 3- to 10-membered heterocycloalkyl, Ce-Goaryl, or 5- to 10-membered heteroaryl; wherein each G-Galkyl.
  • G-Galkynyl is optionally substituted with 1 or 2 C3-Ciocycloalkyl, 3- to 10-membered heterocycloalkyl, G-Goaryl. or 5- to 10-membered heteroaryl rings; wherein each G-Galkyl. G-G,haloalkyl. G-Ce alkoxy, G- Ceheteroalkyl, G-G, alkenyl. G-Galkynyl. C3-Ciocycloalkyl, 3- to 10-membered heterocycloalkyl, G-Goaryl.
  • 5- to 10-membered heteroaryl is optionally substituted with 1, 2, or 3 R 9 ; or R 2a and R 2b together with the carbon atom to which they are attached form a carbonyl; or R 2a and R 3a , and optionally R 2b and R 3b , together with the carbon atoms to which they are attached form a G-Gcycloalkyl.
  • 5- to 10-membered heterocycloalkyl, G-Goaryl. or 5- to 10-membered heteroaryl ring wherein each G-Gcycloalkyl. 5- to 10-membered heterocycloalkyl, G-Goaryl. or 5- to 10-membered heteroaryl ring is optionally substituted with 1, 2, or 3 R 9 ;
  • R 4a and R 4b are each independently hydrogen, halogen, G-Galkyl.
  • G-Ghaloalkyl. G-G alkoxy.
  • G-G alkenyl.
  • G-Gocycloalkyl 3- to 10-membered heterocycloalkyl, G-Goaryl. or 5- to 10-membered heteroaryl; wherein each G-Galkyl.
  • G- Ghaloalkyl C i -Co alkoxy, Ci-Cohctcroalkyl.
  • G-Galkynyl is optionally substituted with 1 or 2 G-Gocycloalkyl, 3- to 10-membered heterocycloalkyl, G-Goaryl. or 5- to 10-membered heteroaryl; wherein each G-Galkyl.
  • G-G haloalkyl.
  • G-G alkoxy.
  • G-G alkenyl.
  • G-Galkynyl. C3-Ciocycloalkyl, 3- to 10-membered heterocycloalkyl, G-Goaryl.
  • R 5 is NHR 8 ,NHS(0) 2 R 8 , OR 8 , SR 8 , S(0) 2 R 8 , or S(0) 2 NHR 8 ; or R 5 , R 4a , and R 4b , together with the carbon atom to which they are attached, form a G-Goaryl or 5- to 10-membered heteroaryl ring; wherein the G-Goaryl or 5- to 10-membered heteroaryl ring is optionally substituted with 1, 2, or 3 R 9 ; R 6a is hydrogen, halogen, -U, or -G;
  • R 6b is halogen, -U, or -G;
  • Ci-Cehaloalkyl, Ci-Cealkoxy, Ci-Ceheteroalkyl, G-G, alkenyl. or C2- Galkynyl is optionally substituted with 1, 2, or 3 R 9 and/or 1 or 2 -G;
  • -G is C3-Ciocycloalkyl, 3- to 10-membered heterocycloalkyl, Ce-Cioaryl, or 5- to 10-membered heteroaryl; wherein each C3-Ciocycloalkyl, 3- to 10-membered heterocycloalkyl, Ce-Cioaryl, or 5- to 10-membered heteroaryl is optionally substituted with 1, 2, or 3 R 9 ; or R 6a and R 6b together with the carbon atom to which they are attached form a saturated or partially saturated 3- to 7-membered cycloalkyl or a saturated or partially saturated 3- to 7-membered heterocycloalkyl; wherein the cycloalkyl or heterocycloalkyl is optionally substituted with 1, 2, or 3 R 9 ;
  • R 7a is hydrogen, halogen, Ci-C4alkyl, or Ci-C4haloalkyl
  • R 715 is hydrogen, halogen, Ci-C4alkyl, or Ci-C4haloalkyl; or R 7a and R 7b together with the carbon atom to which they are attached form a saturated or partially saturated 3- to 7-membered cycloalkyl or a saturated or partially saturated 3- to 7-membered heterocycloalkyl; wherein the cycloalkyl or heterocycloalkyl is optionally substituted with 1, 2, or
  • R 6b and R 715 together with the carbon atoms to which they are attached form a C3-Ciocycloalkyl or 3- to 10-membered heterocycloalkyl ring; wherein each C3-Ciocycloalkyl or 3- to 10-membered heterocycloalkyl ring is optionally substituted with 1, 2, or 3 R 9 ; or R 6a , R 6b , R 7a , and R 7b together with the carbon atoms to which they are attached form a 5 - to 10- membered heteroaryl ring optionally substituted with 1, 2, or 3 R 9 ;
  • R 8 is Z, C2-G, alkyl. (Ci-C 6 alkylene)-Z, (Ci-C 6 heteroalkylene)-Z, (C2-Galkenylene)-Z, CH(Z)2, CH2CH(Z)2, CH(G -G, alkyl )Z. or C(0)Z; wherein each alkyl, alkylene, heteroalkylene, or alkenylene is optionally substituted with 1, 2, or 3 R 9 ;
  • Z is C3-C9cycloalkyl, 3- to 10-membered heterocycloalkyl, G-Goaryl. 5- to 10-membered heteroaryl; wherein each C3-C9cycloalkyl, 3 - to 10-membered heterocycloalkyl, G-Goaryl.
  • 5- to 10- membered heteroaryl is optionally substituted with 1, 2, or 3 R 9 ; or Z is a substituted Ciocycloalkyl substituted with 1, 2, or 3 R 9 ; and each R 9 is independently halogen, Ci-C4alkyl, C2-C4alkenyl, C2-C4alkynyl, Ci-C4haloalkyl, Ci- C4alkoxy, Ci-C4haloalkoxy, Ci-C4heteroalkyl, -C(0)H, -C(0)0H, -CN, C3-Ciocycloalkyl, 3- to 10-membered heterocycloalkyl, G-Goaryl.
  • R 5 , R 4a and R 4b together with the carbon atom to which they are attached form a Ce-Cioaryl or 5- to 10-membered heteroaryl ring; wherein the Ce-Cioaryl or 5- to 10- membered heteroaryl ring is optionally substituted with 1, 2, or 3 R 9 .
  • R 5 , R 4a and R 4b together with the carbon atom to which they are attached form a 5- to 10-membered heteroaryl ring, optionally substituted with 1, 2, or 3 R 9 .
  • R 5 , R 4a and R 4b together with the carbon atom to which they are attached form a 9- or 10-membered heteroaryl ring, optionally substituted with 1, 2, or 3 R 9 .
  • R 5 , R 4a and R 4b together with the carbon atom to which they are attached form a 10-membered heteroaryl ring.
  • R 5 , R 4a and R 4b together with the carbon atom to which they are attached form a quinoline, isoquinoline, quinoxaline, quinazoline, quinolizine, naphthyridine.
  • R 5 , R 4a and R 4b together with the carbon atom to which they are attached form a 9-membered heteroaryl ring.
  • R 5 , R 4a and R 4b together with the carbon atom to which they are attached form a 2,3-dihydrobenzo[d]oxazole, benzo[d]oxazole, oxazolo[4,5-b]pyridine, lH-benzo[d]imidazole, benzo[d]thiazole, benzofuran, indole, aza-indole, lH-imidazo[4,5-b]pyridine, indolizine, imidazo[l,2- a]pyridine, or an isomer thereof, optionally substituted with 1, 2, or 3 R 9 .
  • R 5 , R 4a and R 4b together with the carbon atom to which they are attached form a benzo[d]oxazole, optionally substituted with 1, 2, or 3 R 9 .
  • the Ce-Cioaryl or 5- to 10-membered heteroaryl ring is unsubstituted.
  • R 5 is NHR 8 , NHS(0) 2 R 8 , OR 8 , SR 8 , S(0) 2 R 8 , or S(0) 2 NHR 8 .
  • R 5 is NHR 8 , NHS(0) 2 R 8 , OR 8 , or S(0) 2 NHR 8 .
  • R 5 is NHR 8 , NHS(0) 2 R 8 , or OR 8 .
  • R 5 is OR 8 .
  • R 5 is NHR 8 , or NHS(0) 2 R 8 .
  • R 5 is NHS(0) 2 R 8 .
  • R 5 is NHR 8 .
  • a compound of Formula (C-I) has the structure of one of the following:
  • a compound of Formula (C-I) has the structure of Formula (C-II):
  • R 4a is H. In some embodiments, R 4a is H and R 4b is halogen or haloalkyl. In some embodiments, R 4b is CHF 2 or CF 3 . In some embodiments, R 4a is H and R 4b is difluoromethyl or trifluoromethyl. In some embodiments, R 4b is difluoromethyl or trifluoromethyl and R 5 is OR 8 . In some embodiments, R 4a and R 4b are both H.
  • R 4a and R 4b together with the carbon atom to which they are attached form a C3-Ciocycloalkyl or 3- to 10-membered heterocycloalkyl ring, wherein either of the cycloalkyl or heterocycloalkyl ring is optionally substituted with 1, 2, or 3 R 9 .
  • R 4a and R 4b together with the carbon atom to which they are attached form a G-Gcycloalkyl. optionally substituted with 1, 2, or 3 R 9 .
  • R 4a and R 4b together with the carbon atom to which they are attached form a C3-C5cycloalkyl, optionally substituted with 1, 2, or 3 R 9 .
  • R 4a and R 4b together with the carbon atom to which they are attached form a cyclopropyl, cyclobutyl, or cyclopentyl ring, optionally substituted with 1, 2, or 3 R 9 .
  • R 4a and R 4b together with the carbon atom to which they are attached form a cyclopropyl, cyclobutyl, or cyclopentyl ring and R 5 is -OR 8 or -NHR 8 .
  • R 4a and R 4b are each independently halogen, Ci-G, alkyl. G-Ghaloalkyl.
  • R 4a and R 4b together with the carbon atom to which they are attached form a carbonyl.
  • R 4a and R 4b together with the carbon atom to which they are attached form a carbonyl and R 5 is OR 8 or NHR 8 .
  • R 4a and R 4b together with the carbon atom to which they are attached form a carbonyl and R 5 is NHR 8 .
  • R 1 is hydrogen, G-Galkyl. G-Gcycloalkyl. G-Galkyl-(G- Gcycloalkyl). wherein each alkyl is optionally substituted with 1, 2, or 3 R 9 .
  • R 1 is phenethyl.
  • R 1 is hydrogen, methyl, trifluoromethyl, difluoromethyl, fluoromethyl, ethyl, propyl, isopropyl, cyclopropyl, methylenecyclopropyl, or cyclobutyl.
  • R 1 is phenethyl.
  • R 1 is hydrogen, methyl, trifluoromethyl, difluoromethyl, fluoromethyl, or ethyl.
  • R 1 is hydrogen or methyl. In some embodiments, R 1 is hydrogen.
  • a compound of Formula (C-I) has the structure of Formula (C-III):
  • R 2a and R 2b are each independently hydrogen, CrG, alkyl. G- Cehaloalkyl, G-G alkoxy, G-G, heteroalkyl. G-G, alkenyl. G-Galkynyl. wherein each alkyl, haloalkyl, alkoxy, heteroalkyl, alkenyl, or alkynyl is optionally substituted with 1, 2, or 3 R 9 .
  • R 2a and R 2b are each independently C3-Ciocycloalkyl, 3- to 10-membered heterocycloalkyl, G,-Cioaryl.
  • R 2a and R 2b are each independently hydrogen, G-Galkyl. G-G, haloalkyl. G-G alkoxy, G- Gheteroalkyl, wherein each alkyl, haloalkyl, alkoxy, or heteroalkyl is optionally substituted with 1 or 2 G-Gcycloalkyl. 3- to 6-membered heterocycloalkyl, phenyl, or 5- or 6-membered heteroaryl.
  • R 2a is H and R 2b is G-Galkyl or G-Gheteroalkyl. wherein each alkyl or heteroalkyl is optionally substituted with a phenyl, or 5- or 6-membered heteroaryl.
  • R 2a is hydrogen.
  • R 2a and R 2b are each hydrogen. [00136]
  • R 2a and R 3a , and optionally R 2b and R 3b , together with the carbon atoms to which they are attached form a G-Gcycloalkyl.
  • R 2a and R 2b together with the atom to which they are attached form a carbonyl. In some embodiments, R 2a and R 2b together with the atom to which they are attached form a carbonyl and X is NH. In some embodiments, R 2a and R 2b together with the atom to which they are attached form a carbonyl and X is O.
  • R 3a and R 3b are each independently hydrogen, G-Galkyl. Ci- Ghaloalkyl. G-Galkoxy. G-Ghctcroalkyl. G-Galkcnyl. G-Galkynyl. G-Ciocycloalkyl, 3- to 10- membered heterocycloalkyl, G-Goaryl. or 5- to 10-membered heteroaryl, any of which is optionally substituted with 1, 2, or 3 R 9 . In some embodiments, R 3a and R 3b are each independently hydrogen, G-Galkyl. G-Ghaloalkyl.
  • R 3a and R 3b are each independently hydrogen, methyl, trifluoromethyl, difluoromethyl, ethyl, propyl, isopropyl, cyclopropyl, benzyl, phenethyl, or isobutyl.
  • R 3a and R 3b are each methyl.
  • R 3a is hydrogen.
  • R 3a and R 3b are each hydrogen.
  • R 2a and R 3a together with the carbon atoms to which they are attached, form a G-Gcycloalkyl. or 5- to 10-membered heterocycloalkyl.
  • R 2a and R 3a together with the carbon atoms to which they are attached, form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxirane, oxetane, tetrahydrofuran, tetrahydropyran, dioxane, aziridine, azetidine, pyrrolidine, piperidine, or morpholine, each of which is optionally substituted with 1 R 9 .
  • R 2a and R 3a together with the carbon atoms to which they are attached, form a cyclopropyl, cyclohexyl, dioxane, piperidine, or morpholine, each of which is optionally substituted with 1 R 9 .
  • R 2a and R 3a together with the carbon atoms to which they are attached form a G-Gcycloalkyl.
  • R 2a and R 3a together with the carbon atoms to which they are attached form a G-Gcycloalkyl. optionally substituted with 1, 2, or 3 R 9 .
  • R 2a and R 3a together with the carbon atoms to which they are attached, form a cyclopropyl or cyclohexyl, either of which is optionally substituted with 1, 2, or 3 R 9 .
  • R 2a and R 3a together with the carbon atoms to which they are attached, form a cyclohexyl.
  • X is NR A , O, S, S(O), or S(0) 2 .
  • X is O.
  • X is S or S(0) 2 .
  • X is S.
  • X is S(0) 2 .
  • X is NR A .
  • R A is G-Galkyl. C(0)-(G-Galkyl). or C(0)-(G-C 6 cycloalkyl), wherein each alkyl or cycloalkyl is optionally substituted with 1, 2, or 3 R 9 .
  • R A is hydrogen, methyl, ethyl, C(0)CH 3 , C(0)cyclopropyl, or C(0)cyclohexyl, wherein each cyclopropyl or cyclohexyl is optionally substituted with 1 or 2 R 9 .
  • R A is hydrogen, methyl, or C(0)CI3 ⁇ 4.
  • R A is hydrogen.
  • a compound of Formula (C-I) a compound has the structure of Formula (C-IV- a), (C-IV-b), (C-IV-c), or (C-IV-d):
  • a compound of Formula (C-I) has the structure of Formula (C-V-a), (C-V-b), (C-V-c), or (C-V-d):
  • a compound of Formula (C-I) has the structure of Formula (C-VI-a), (C-VI-b), (C-VI-c), or (C-VI-d):
  • X is C and taken together with R 2a , R 2b , and the carbon atom to which they are attached, forms a phenyl or 5- to 10-membered heteroaryl ring, optionally substituted with 1, 2, or 3 R 9 .
  • X is C and taken together with R 2a , R 2b , and the carbon atom to which they are attached, forms a phenyl ring, optionally substituted with 1, 2, or 3 R 9 .
  • X is C and taken together with R 2a , R 2b , and the carbon atom to which they are attached, forms a 5- to 10-membered heteroaryl ring, optionally substituted with 1, 2, or 3 R 9 .
  • X is C and taken together with R 2a , R 2b , and the carbon atom to which they are attached, forms a 5-membered heteroaryl ring, optionally substituted with 1, 2, or 3 R 9 .
  • X is C and taken together with R 2a , R 2b , and the carbon atom to which they are attached, forms a 9- or 10-membered heteroaryl ring, optionally substituted with 1, 2, or 3 R 9 .
  • X is C and taken together with R 2a , R 2b , and the carbon atom to which they are attached, forms a pyrrole, pyrazole, imidazole, indole, or azaindole ring, optionally substituted with 1, 2, or 3 R 9 .
  • a compound as disclosed herein has the structure of one of the following:
  • R 6a , R 6b , R 7a , and R 7b together with the carbon atoms to which they are attached form a 5 - to 10-membered heteroaryl ring optionally substituted with 1, 2, or 3 R 9 .
  • R 6a , R 6b , R 7a , and R 715 together with the carbon atoms to which they are attached form a furan, pyrrole, pyridine, pyrimidine, pyridazine, pyrazine, any of which being optionally substituted with 1, 2, or 3 R 9 .
  • R 6a , R 6b , R 7a , and R 715 together with the carbon atoms to which they are attached form a pyridine ring.
  • R 6b and R 715 together with the carbon atoms to which they are attached form a C3-Ciocycloalkyl or 3- to 10-membered heterocycloalkyl ring; wherein each C3-Ciocycloalkyl or 3- to 10-membered heterocycloalkyl ring is optionally substituted with 1, 2, or 3 R 9 .
  • R 6b and R 7b together with the carbon atoms to which they are attached form a G-Gcycloalkyl or 3- to 6- membered heterocycloalkyl ring; wherein each G-Gcycloalkyl or 3- to 6-membered heterocycloalkyl ring is optionally substituted with 1, 2, or 3 R 9 .
  • R 6b and R 7b together with the carbon atoms to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxirane, aziridine, oxetane, azetidine, oxolane, pyrrolidine, thiolane, oxazolidine, imidazolidine, thiazolidine, isoxazolidine, pyrazolidine, isothiazolidine, dioxolane, dithiolane, oxane, piperidine, thiolane, morpholine, piperazine, thiazine, or dioxane ring, wherein each ring is optionally substituted with 1, 2, or 3 R 9 .
  • R 6b and R 7b together with the carbon atoms to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxolane, oxane, dioxane, morpholine, pyrrolidine, or piperidine ring.
  • R 7a and R 7b together with the carbon atom to which they are attached form a saturated or partially saturated 3- to 7-membered cycloalkyl or a saturated or partially saturated 3- to 7-membered heterocycloalkyl; wherein the cycloalkyl or heterocycloalkyl is optionally substituted with 1, 2, or 3 R 9 .
  • R 7a and R 715 together with the carbon atom to which they are attached form a saturated or partially saturated 3- to 5-membered cycloalkyl or a saturated or partially saturated 3- to 5- membered heterocycloalkyl; wherein the cycloalkyl or heterocycloalkyl is optionally substituted with 1, 2, or 3 R 9 .
  • R 7a and R 715 together with the carbon atom to which they are attached form a cyclopropyl, cyclobutyl, cyclopropenyl, cyclobutenyl, oxirane, aziridine, oxetane, azetidine, or cyclopentyl, or cyclopentenyl ring, wherein each ring is optionally substituted with 1, 2, or 3 R 9 .
  • ; ’ together with the carbon atom to which they are attached form a cyclopropyl ring, optionally substituted with 1, 2, or 3 R 9 .
  • ; ’ are each independently hydrogen, halogen, Ci-C4alkyl, or Ci-C4haloalkyl.
  • R 7a and R 715 are each independently hydrogen, fluoro, methyl, ethyl, difluoromethyl, or trifluoromethyl.
  • R 7a and R 715 are each independently hydrogen, methyl, or ethyl.
  • R 7a and R 715 are each hydrogen.
  • R 6a and R 6b together with the carbon atom to which they are attached form a saturated or partially saturated 3- to 7-membered cycloalkyl ring optionally substituted with 1, 2, or 3 R 9 .
  • R 6a and R 6b together with the carbon atom to which they are attached form a cyclopropyl, cyclobutyl, cyclopropenyl, cyclobutenyl, oxirane, aziridine, oxetane, azetidine, or cyclopentyl, or cyclopentenyl ring, wherein each ring is optionally substituted with 1, 2, or 3 R 9 .
  • R 6a and R 6b together with the carbon atom to which they are attached form a saturated or partially saturated 3- to 5-membered cycloalkyl ring, optionally substituted with 1, 2, or 3 R 9 .
  • R 6a is hydrogen. In some embodiments, R 6a is hydrogen and R 6b is halogen, Ci-G, alkyl. Ci-G,haloalkyl. G-Cealkenyl, or G-Galkynyl: wherein each G-Galkyl. G- Ghaloalkyl. C2-Cealkenyl, or G-Galkynyl is optionally substituted with 1, 2, or 3 R 9 and/or 1 or 2,
  • R 6b is halogen, G-Galkyl.
  • G-Ghaloalkyl C2-Cealkenyl, or G-Galkynyl: wherein each G-Galkyl.
  • G-Ghaloalkyl C2-Cealkenyl, or G-Galkynyl is optionally substituted with
  • R 6b is G-Galkyl. G-Ghaloalkyl. G-Galkenyl. or G-Galkynyl. wherein each alkyl, haloalkyl, alkenyl, or alkynyl is optionally substituted with a phenyl or 5- or 6-membered heteroaryl ring, wherein each phenyl or heteroaryl ring is optionally substituted with 1, 2, or 3 R 9 .
  • R 6b is methyl, ethyl, or propyl, wherein the methyl, ethyl, or propyl is optionally substituted with G, and wherein G is a phenyl ring further substituted with 1, 2, or 3 R 9 .
  • R 6b is ethyl, optionally substituted with phenyl, tolyl, phenolyl, fluorophenyl, chlorophenyl, anilinyl, methoxyphenyl, dimethylphenyl, difluorophenyl, dichlorophenyl, dihydroxyphenyl, dimethoxyphenyl, fluoromethoxyphenyl, or naphthyl.
  • R 6b is G-Galkyl. G-Ghaloalkyl. G-Galkenyl. or G-Galkynyl. wherein each alkyl, haloalkyl, alkenyl, or alkynyl is optionally substituted with a G-Gcycloalkyl or 3- to 6-membered heterocycloalkyl ring, wherein each cycloalkyl or heterocyclalkyl ring is optionally substituted with 1,
  • R 6b is methyl, ethyl, 2-propenyl, isopropyl, or phenethyl. In some embodiments, R 6b is methyl. In some embodiments, R 6b is ethyl. In some embodiments, R 6b is 2- propenyl. In some embodiments, R 6b is isopropyl. In some embodiments, R 6b is phenethyl.
  • R 6a and R 6b are each independently halogen, G-Galkyl.
  • G-Ghaloalkyl G-Galkenyl. or G-Galkynyl: wherein each G-Galkyl.
  • G- Ghaloalkyl C -G, alkenyl or G-Galkynyl is optionally substituted with 1, 2, or 3 R 9 and/or 1 or 2,
  • R 6a and R 6b are each independently halogen, G-Galkyl.
  • Ci- Cehaloalkyl, CN-Ci, alkenyl or G-Galkynyl is optionally substituted with 1, 2, or 3 R 9 and/or 1 or 2,
  • R 6a and R 6b are each independently Ci- Galkyl. Ci-Cehaloalkyl, CN-Ci, alkenyl or G-Galkynyl. wherein each alkyl, haloalkyl, alkenyl, or alkynyl is optionally substituted with a phenyl or 5- or 6-membered heteroaryl ring, wherein each phenyl or heteroaryl ring is optionally substituted with 1, 2, or 3 R 9 .
  • R 6a and R 6b are each independently methyl, ethyl, or propyl, optionally substituted with G, wherein G is a phenyl ring further substituted with 1, 2, or 3 R 9 .
  • R 6a and R 6b are each independently ethyl, optionally substituted with phenyl, tolyl, phenolyl, fluorophenyl, chlorophenyl, anilinyl, methoxyphenyl, dimethylphenyl, difluorophenyl, dichlorophenyl, dihydroxyphenyl, dimethoxyphenyl, fluoromethoxyphenyl, or naphthyl.
  • R 6a and R 6b are each independently G-Galkyl. Ci- C , haloalkyl. CN-Ci, alkenyl or G-Galkynyl. wherein each alkyl, haloalkyl, alkenyl, or alkynyl is optionally substituted with a G-Gcycloalkyl or 3- to 6-membered heterocycloalkyl ring, wherein each cycloalkyl or heterocyclalkyl ring is optionally substituted with 1, 2, or 3 R 9 .
  • R 6a and R 6b are each independently methyl, ethyl, 2- propenyl, isopropyl, or phenethyl. In some embodiments, R 6a and R 6b are each independently ethyl, 2- propenyl, isopropyl, or phenethyl. In some embodiments of a compound of Formula (C-I), R 6a and R 6b are methyl. In some embodiments, R 6a and R 6b are ethyl. In some embodiments, R 6a and R 6b are 2- propenyl. In some embodiments, R 6a and R 6b are isopropyl. In some embodiments, R 6a and R 6b are phenethyl.
  • R 8 is Z, G-Galkyl. (Ci-C 6 alkylene)-Z, (Ci-C 6 heteroalkylene)-Z, (C2- C 6 alkenylene)-Z, CH(Z)2, ⁇ 1 ⁇ 4 ⁇ I(Z)2, CH(G-Galkyl)Z. or C(0)Z; wherein each alkyl, alkylene, heteroalkylene, or alkenylene is optionally substituted with 1, 2, or 3 R 9 .
  • R 8 is Z, G-Galkyl. CH(Z)2, or C(0)Z.
  • R 8 is Z, C2- Galkyl.
  • R 8 is Z or CH(Z)2. In some embodiments, R 8 is Z. In some embodiments, R 8 is CH(Z)2. In some embodiments of a compound of Formula (C-I), Z is C3-C9cycloalkyl, 3- to 10-membered heterocycloalkyl, G-Goaryl.
  • Z is G-Goaryl or 5- to 10-membered heteroaryl, wherein each aryl or heteroaryl is optionally substituted with 1, 2, or 3 R 9 .
  • Z is C3-C9cycloalkyl or 3- to 10-membered heterocycloalkyl; wherein each C3-C9cycloalkyl and 3- to 10- membered heterocycloalkyl is optionally substituted with 1, 2, or 3 R 9 .
  • Z is Ciocycloalkyl substituted with 1, 2, or 3 R 9 .
  • Z is phenyl or naphthyl, optionally substituted with 1, 2, or 3 R 9 .
  • Z is pyridine, pyrimidine, pyridazine, pyrazine, quinoline, naphthyridine, quinoxaline, quinolizine, benzofuran, benzoxazole, or benzothiophene.
  • Z is tetrahydroquinoline, tetrahydroisoquinoline, chroman, thiochroman, indane, indoline, dihydrobenzofuran, or dihydrobenzothiophene .
  • R 8 is:
  • R 8 is:
  • R 8 is:
  • R 8 is:
  • R 8 is:
  • R 8 is:
  • each R 9 is independently halogen, Ci-C4alkyl, C2-C4alkenyl, C2- C4alkynyl, Ci-C4haloalkyl, Ci-C4alkoxy, Ci-C4haloalkoxy, Ci-C4heteroalkyl, -C(0)H, -C(0)OH, -CN, C3-Ciocycloalkyl, 3- to 10-membered heterocycloalkyl, Ce-Cioaryl, 5- to 10-membered heteroaryl, - N(Ci-C4alkyl)2, -OH, -0(Ci-C 4 alkyl), -0(Ci-C 4 haloalkyl), -0(Ci-C 4 alkylene)-(5- to 10-membered heteroaryl), -O(C 6 -Ci 0 aryl), -SH, S(0) 2 OH, -S(0) 2 (Ci-C 4 alky
  • each R 9 is independently halogen, Ci-C4alkyl, C2- C4alkenyl, C2-C4alkynyl, Ci-C4haloalkyl, Ci-C4alkoxy, Ci-C4haloalkoxy, Ci-C4heteroalkyl, -C(0)H, - C(0)OH, -CN, C3-Ciocycloalkyl, 3- to 10-membered heterocycloalkyl, Ce-Cioaryl, 5- to 10-membered heteroaryl, -OH, -0(Ci-C 4 alkyl), or -0(Ci-C 4 haloalkyl).
  • each R 9 is independently halogen, Ci-C4alkyl, -C(0)OH, -0(Ci-C 4 alkyl), -0(Ci-C 4 haloalkyl), or 5- to 10- membered heteroaryl. In some embodiments, each R 9 is each independently -C(0)OH, -0(CH 3 ), - OiQrhQrhF), or pyrimidine. [00159] In some embodiments, a compound of the present disclosure has the structure:
  • a compound of the present disclosure has the structure: [00163] In some embodiments, a compound of the present disclosure has the structure:
  • a compound of the present disclosure has the structure: [00167] In some embodiments, a compound of the present disclosure has the structure:
  • a compound of the present disclosure has the structure:
  • a compound of the present disclosure has the structure:
  • a compound of the present disclosure has the structure:
  • a compound described herein has the form of any one of the structures found in Table A.
  • Various stereoisomers e.g., enantiomers, diastereomers
  • a compound disclosed herein may be a mixture of stereoisomers.
  • a compound may be a pure isomer.
  • a compound is a mixture of enantiomers.
  • a compound is a mixture of diastereomers.
  • a compound disclosed herein exists as a mixture of various stereoisomers, wherein one or more chiral centers are unresolved or unseparated. In some embodiments, each chiral center is known. In some embodiments, a subset of the total number of chiral centers have known stereochemistry. In some embodiments, a compound may be racemized or contain a mixture of racemates.
  • 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, or preferably, by separation/resolution techniques based upon differences in solubility.
  • the optically pure enantiomer is then recovered, along with the resolving agent.
  • one isomer binds a target with higher affinity than another.
  • a mixture of isomers is preferable.
  • a compound described herein with unknown or undisclosed stereochemistry is a mixture of enantiomers or diastereomers.
  • an isomer disclosed as an (R) enantiomer may contain some portion of the (S) isomer as well.
  • a compound disclosed as an (R) isomer may contain up to 0.01%, 0.1%, 0.5%, 1%, 2%, 3%, 5%, 10%, 20%, 30%, 40%, 49% of the (S) isomer.
  • a compound disclosed as an (S) isomer may contain any amount previously described of the (R) isomer as well.
  • a compound is isomerically pure.
  • a compound disclosed as a mixture of isomers may contain a given isomer in up to 99.9%, 99%, 98%, 97%, 95%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10%, 5%, 3%, 2%, 1%, 0.5%, or 0.1% abundance relative to alternate isomers present in the mixture.
  • 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 that can be incorporated into compounds described herein, or a solvate, or stereoisomer thereof, include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, and chloride, such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 0, 17 0, 31 P, 32 P, 35 S, 18 F, and 36 C1, 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 disclosure.
  • 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. Further, substitution with heavy isotopes such as deuterium, i.e., 2 H, produces certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half- life or reduced dosage requirements.
  • the isotopically labeled compound or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is prepared by any suitable method.
  • the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, biolumine scent 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 therefor 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 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, benzene sulfonate, bisulfate, bisulfite, bromide, butyrate, butyn-l,4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, formate, fiimarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne-l,6-di
  • 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 -toluene sulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methane sulfonic acid, ethanesulfonic acid
  • those compounds described herein which comprise a free acid group react with a suitable base, such as the hydroxide, carbonate, bicarbonate, or 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, or 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 I-4 alkyl)4, and the like.
  • Representative 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 quatemization of any basic nitrogen-containing groups they contain. In some embodiments, water or oil-soluble or dispersible products are obtained by such quatemization.
  • the compounds described herein exist as solvates.
  • the disclosure provides for methods of treating diseases by administering such solvates.
  • the disclosure further provides for methods of treating diseases by administering such solvates as pharmaceutical compositions.
  • 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 such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein can be conveniently prepared or formed during the processes described herein. In addition, the compounds provided herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.
  • 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.
  • the synthesis of compounds described herein are accomplished using means described in the chemical literature, using the methods described herein, or by a combination thereof.
  • solvents, temperatures and other reaction conditions presented herein may vary.
  • the starting materials and reagents used for the synthesis of the compounds described herein are synthesized or are obtained from commercial sources, such as, but not limited to, Sigma-Aldrich, FischerScientific (Fischer Chemicals), and AcrosOrganics.
  • the compounds described herein, and other related compounds having different substituents are synthesized using techniques and materials described herein as well as those that are recognized in the field, such as described, for example, in Fieser and Fieser’s Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd’s Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), Larock’s Comprehensive Organic Transformations (VCH Publishers Inc., 1989), March, Advanced Organic Chemistry 4 th Ed., (Wiley 1992); Carey and Sundberg, Advanced Organic Chemistry 4 th Ed., Vols.
  • a synthetic route as outlined in Scheme 1 provides access compounds as described in Formula A-I, B-I, or C-I, in a highly efficient 3-step process.
  • An initial Ugi 4-component reaction (4CR) enables efficient access to the fused 7-/5-membered scaffold as described herein.
  • TFE 2,2,2,-trifluoroethanol
  • step b The primary amines of la and lb undergo a coupling reaction in step b with Boc-N-Me-Ala-OH to give a 1:1 mixture of diastereomers lc and Id, which are optionally purified by chromatography or other suitable methods. In some instances, purification is carried out using flash chromatography on silica gel. A final TFA deprotection (step c) gives the final compounds le and If. In some instances, overall yield for the four-step process involving a single purification step is 36-60%.
  • the scheme as described extends to various alternatively-substituted aldehydes, carboxylic acids, or isocyanides, facilitating the synthesis of a broad range of compounds as disclosed herein.
  • scaffolds featuring additional fused ring systems as described within Formula (A-I) or (C-I) can be accessed using an appropriately substituted carboxylic acid and/or aldehyde.
  • Examples of some fused ring systems contemplated in the present disclosure include those indicated in Scheme 2. Following a 4CR similar to that previously described in Scheme 1, followed by subsequent TFA deprotection/cyclization, a diastereomeric pair of compounds as indicated by intermediate 2 can be accessed.
  • step a an appropriate carboxylic acid, aldehyde, isocyanide, and ammonia are stirred in TFE while heating under microwave irradiation (e.g., at 80 °C for 20 min).
  • the intermediate (not shown) is treated with TFA to facilitate Boc deprotection and cyclization to achieve intermediate 2.
  • the primary amine can be substituted and deprotected to achieve a compound as described within Formula (A-I) or (C-I).
  • the microwave reaction conditions can be replaced with continuous flow conditions, which mimics the efficient heating dynamics of microwave technology.
  • the first two steps (step a) can be performed in series without the need for purification.
  • steps b and c as outlined in Scheme 1 can be executed to give final compounds as disclosed within Formula (A-I) or (C-I).
  • Scheme 4 details additional methods for functionalization of the region of the scaffold indicated in grey.
  • the N-acylindole 6 is easily converted to the methyl ester 12 in basic methanol, from which the titanium-mediated Kulinkovich reaction can be used to access cyclopropyl alcohols.
  • Formation of the sulfonate 13 followed by treatment with MgBr2 affords the allyl bromide 14, which is a versatile intermediate. From here, a variety of different types of nucleophiles (alcohols, amines, thiols) are applied to access new chemical space. Tsuji-Trost conditions may also be employed for further activation of the allyl bromide with catalytic palladium.
  • nitrile 16 is achieved from aldehyde 8 using mild conditions (Scheme 4), and nitriles such as 16 are very reactive under Kulinkovich conditions (nitrile>ester>amide) to yield the cyclopropylamine. Subsequent treatment with a variety of potential electrophiles (alkyl halides, aryl halides, sulfonyl halides, acyl halides) gives derivatives 17. In order to perform the Kulinkovich reaction from a carboxamide, a modified strategy is adopted. Protection of amide 18 (made similarly to Scheme 5, but with Cbz instead of Boc) with the MTM group, followed by cyclopropylamine formation gives 19. Several deprotection reactions and a coupling with the alanine derivative provides new analogs such as 20 where the carboxamide carbonyl is replaced by a cyclopropyl group.
  • the 2-substituted indole derivative 23 can be synthesized by Fischer indole synthesis of ketone 21 with various phenylhydrazines 22.
  • Isomer 24 may also form, but the silyl group helps direct enol formation to give preference to isomer 23. In either case, the silyl group cleaves under the acidic reaction conditions. Based on chemistry for a similarly activated acyl group, N-acylindole 6 undergoes displacement with the silyl Grignard reagent to give the ketone 21.
  • benzoxazole 28 and benzothiazole 29 can be accessed from aldehyde 8, a more efficient route via intermediate 27 by use of o-bromophenyl isocyanides 25 in the Ugi multicomponent reaction (Scheme 7). A copper-mediated coupling to form the benzoxazoles 28 and benzothiazole s 29 is then accomplished, giving the desired carboxamide isosteres.
  • the compounds of this invention will be administered in a therapeutically effective amount by any of the accepted modes of administration for agents that serve similar utilities.
  • Therapeutically effective amounts of compound of Formula I, II, or III may range from about 0.01 to about 500 mg per kg patient body weight per day, which can be administered in single or multiple doses.
  • the dosage level will be about 0.1 to about 250 mg/kg per day; more preferably about 0.5 to about 100 mg/kg per day.
  • a suitable dosage level may be about 0.01 to about 250 mg/kg per day, about 0.05 to about 100 mg/kg per day, or about 0.1 to about 50 mg/kg per day. Within this range the dosage can be about 0.05 to about 0.5, about 0.5 to about 5 or about 5 to about 50 mg/kg per day.
  • compositions are preferably provided in the form of tablets containing about 1.0 to about 1000 milligrams of the active ingredient, particularly about 1.0, 5.0, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900, and 1000 milligrams of the active ingredient.
  • the actual amount of the compound of this invention, i.e., the active ingredient will depend upon numerous factors such as the severity of the disease to be treated, the age and relative health of the subject, the potency of the compound being utilized, the route and form of administration, and other factors.
  • compositions will be administered as pharmaceutical compositions by any one of the following routes: oral, systemic (e.g., intranasal, suppository, intrapulmonary), or parenteral (e.g., intramuscular, intravenous, intrathecal, or intraperitoneal) administration.
  • routes e.g., oral, systemic (e.g., intranasal, suppository, intrapulmonary), or parenteral (e.g., intramuscular, intravenous, intrathecal, or intraperitoneal) administration.
  • parenteral e.g., intramuscular, intravenous, intrathecal, or intraperitoneal
  • compositions can take the form of tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols, liposomes, exosomes, nanoparticles, or any other appropriate compositions.
  • formulations depend on various factors such as the mode of drug administration (e.g., for oral administration, formulations in the form of tablets, pills or capsules are preferred) and the bioavailability of the drug substance.
  • pharmaceutical formulations have been developed especially for drugs that show poor bioavailability based upon the principle that bioavailability can be increased by increasing the surface area i.e., decreasing particle size.
  • U.S. Pat. No. 4,107,288 describes a pharmaceutical formulation having particles in the size range from 10 to 1,000 nm in which the active material is supported on a crosslinked matrix of macromolecules.
  • 5,145,684 describes the production of a pharmaceutical formulation in which the drug substance is pulverized to nanoparticles (average particle size of 400 nm) in the presence of a surface modifier and then dispersed in a liquid medium to give a pharmaceutical formulation that exhibits remarkably high bioavailability.
  • a pharmaceutical composition of the present disclosure comprises any one of the compounds as described herein, or pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition of the present disclosure comprises any one of the compounds of Formula (A-I), (B-I), or (C-I), or pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, and a pharmaceutically acceptable carrier.
  • the compositions are comprised of in general, a compound of Formula (A-I), (B-I), or (C-I) in combination with at least one pharmaceutically acceptable excipient.
  • Acceptable excipients are non-toxic, aid administration, and do not adversely affect the therapeutic benefit of the compound of Formula (A-I), (B-I), or (C-I).
  • excipient may be any solid, liquid, semi-solid or, in the case of an aerosol composition, gaseous excipient that is generally available to one of skill in the art.
  • Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk and the like.
  • Liquid and semisolid excipients may be selected from glycerol, propylene glycol, water, ethanol and various oils, including those of petroleum, animal, vegetable or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc.
  • Preferred liquid carriers, particularly for injectable solutions include water, saline, aqueous dextrose, and glycols.
  • Compressed gases may be used to disperse a compound of this invention in aerosol form.
  • Inert gases suitable for this purpose are nitrogen, carbon dioxide, etc.
  • the level of the compound in a formulation can vary within the full range employed by those skilled in the art.
  • the formulation will contain, on a weight percent (wt %) basis, from about 0.01-99.99 wt % of a compound of Formula (A-I), (B-I), or (C-I) based on the total formulation, with the balance being one or more suitable pharmaceutical excipients.
  • the compound is present at a level of about 1-80 wt %.
  • the compounds of the present invention may be used in combination with one or more other drugs in the treatment of diseases or conditions for which compounds of the present invention or the other drugs may have utility, where the combination of the drugs together are safer or more effective than either drug alone.
  • Such other drug(s) may be administered, by a route and in an amount commonly used therefore, contemporaneously or sequentially with a compound of the present invention.
  • a pharmaceutical composition in unit dosage form containing such other drugs and the compound of the present invention is preferred.
  • the combination therapy may also include therapies in which the compound of the present invention and one or more other drugs are administered on different overlapping schedules. It is also contemplated that when used in combination with one or more other active ingredients, the compounds of the present invention and the other active ingredients may be used in lower doses than when each is used singly.
  • the pharmaceutical compositions of the present invention also include those that contain one or more other active ingredients, in addition to a compound of the present invention.
  • the above combinations include combinations of a compound of the present invention not only with one other active compound, but also with two or more other active compounds.
  • compounds of the present invention may be used in combination with other drugs that are used in the prevention, treatment, control, amelioration, or reduction of risk of the diseases or conditions for which compounds of the present invention are useful. Such other drugs may be administered, by a route and in an amount commonly used therefore, contemporaneously or sequentially with a compound of the present invention.
  • compositions of the present invention When a compound of the present invention is used contemporaneously with one or more other drugs, a pharmaceutical composition containing such other drugs in addition to the compound of the present invention is preferred. Accordingly, the pharmaceutical compositions of the present invention also include those that also contain one or more other active ingredients, in addition to a compound of the present invention.
  • the weight ratio of the compound of the present invention to the second active ingredient may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used.
  • the administration of a compound described herein is optionally given continuously; alternatively, the dose of drug being administered is temporarily reduced or temporarily suspended for a certain length of time (i.e., a “drug holiday”).
  • the length of the drug holiday optionally varies between 2 days and 1 year, including by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days, or 365 days.
  • the dose reduction during a drug holiday includes from 10%-100%, including, by way of example only, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%.
  • a maintenance dose is administered if necessary. Subsequently, the dosage or the frequency of administration, or both, is reduced, as a function of the symptoms, to a level at which the improved disease, disorder or condition is retained. In some embodiments, patients require intermittent treatment on a long-term basis upon any recurrence of symptoms.
  • ML-IAP melanoma inhibitor of apoptosis proteins
  • the ML-IAP antagonist is selective for ML-IAP over other inhibitor of apoptosis proteins (IAPs).
  • IAPs inhibitor of apoptosis proteins
  • the ML-IAP antagonist is at least 5 -fold selective for ML-IAP over other IAPs.
  • the ML-IAP antagonist is at least 10-fold selective for ML-IAP over other IAPs.
  • the ML-IAP antagonist is at least 20-fold selective for ML-IAP over other IAPs. In some embodiments of a method of treating cancer, the ML-IAP antagonist is at least 30-fold selective for ML-IAP over other IAPs. In some embodiments of a method of treating cancer, the ML- IAP antagonist is at least 50-fold selective for ML-IAP over other IAPs. In some embodiments of a method of treating cancer, the ML-IAP antagonist is at least 100-fold selective for ML-IAP over other IAPs. In some embodiments of a method of treating cancer, the ML-IAP antagonist is at least 200- fold selective for ML-IAP over other IAPs.
  • the ML-IAP antagonist is at least 5 -fold selective for ML-IAP BIR domain over XIAP BIR2/3 domains. In some embodiments of a method of treating cancer, the ML-IAP antagonist is at least 10-fold selective for ML-IAP BIR domain over XIAP BIR2/3 domains. In some embodiments of a method of treating cancer, the ML-IAP antagonist is at least 20-fold selective for ML-IAP BIR domain over XIAP BIR2/3 domains. In some embodiments of a method of treating cancer, the ML-IAP antagonist is at least 50-fold selective for ML-IAP BIR domain over XIAP BIR2/3 domains. In some embodiments of a method of treating cancer, the ML-IAP antagonist is at least 100-fold selective for ML-IAP BIR domain over XIAP BIR2/3 domains.
  • described herein are methods for treating a disease or condition associated with the overexpression of ML-IAP in an individual, comprising administering a therapeutically effective amount of a compound described herein, or pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, to the individual.
  • described herein are methods for treating a disease or condition associated with the overexpression of ML-IAP in an individual, comprising administering a therapeutically effective amount of a compound of Formula (A -I), (B-I), or (C-I), or pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, to the individual.
  • the disease or condition is cancer. In some embodiments, the disease or condition is cancer.
  • described herein are methods of inhibiting melanoma inhibitor of apoptosis protein (ML-IAP) with a compound as described herein. In some embodiments, described herein are methods of inhibiting melanoma inhibitor of apoptosis protein (ML-IAP) with a compound of Formula (A-I), (B-I), or (C-I).
  • described herein are methods of treating cancer in an individual in need thereof comprising administering a therapeutically effective amount of a compound as described herein, or pharmaceutically acceptable salt, X'-oxidc. racemate, or stereoisomer thereof, to the individual.
  • methods of treating cancer in an individual in need thereof comprising administering a therapeutically effective amount of a compound of Formula (A-I), (B-I), or (C-I), or pharmaceutically acceptable salt, X'-oxidc. racemate, or stereoisomer thereof, to the individual.
  • the cancer is a lung cancer.
  • the cancer is chemo-resistant, refractory, or relapsed.
  • the cancer is chemo-resistant.
  • the cancer is resistant to platinum -based chemotherapy.
  • the cancer is resistant to chemotherapy, targeted therapy, immunotherapy, adjuvant therapy, or anti-angiogenesis therapy.
  • the cancer is resistant to carboplatin, cisplatin, docetaxel, gemcitabine, nab-paclitaxel, paclitaxel, pemetrexed, vinorelbine, bevacizumab, ramucirumab, afatinib, dacomitinib, erlotinib, gefitinib, necitumumab, osimertinib, atezolizumab, durvalumab, nivolumab, or pembrolizumab.
  • the cancer is resistant to carboplatin or cisplatin.
  • the cancer is resistant to paclitaxel or nab-paclitaxel.
  • the cancer is sensitized to radiation therapy, chemotherapy, targeted therapy, immunotherapy, adjuvant therapy, or anti-angiogenesis therapy.
  • the cancer is sensitized to radiation therapy.
  • the cancer is sensitized to chemotherapy.
  • the cancer is sensitized to targeted therapy.
  • the cancer is sensitized to immunotherapy.
  • the cancer is sensitized to adjuvant therapy.
  • the cancer is sensitized to anti-angiogenesis therapy.
  • the cancer is hypersensitized to chemotherapy.
  • chemo-resistance is reduced. In some embodiments, chemo-resistance is negated.
  • the cancer is sensitized to carboplatin, cisplatin, docetaxel, gemcitabine, nab-paclitaxel, paclitaxel, pemetrexed, vinorelbine, bevacizumab, ramucirumab, afatinib, dacomitinib, erlotinib, gefitinib, necitumumab, osimertinib, atezolizumab, durvalumab, nivolumab, or pembrolizumab.
  • the cancer is sensitized to carboplatin or cisplatin.
  • the cancer is sensitized to paclitaxel or nab-paclitaxel.
  • the cancer is non-small cell lung cancer, adenocarcinoma, squamous cell carcinoma, adenosquamous carcinoma, sarcomatoid carcinoma, large cell carcinoma, or small cell lung cancer.
  • the cancer is non-small cell lung cancer.
  • the cancer is adenocarcinoma.
  • the cancer is squamous cell carcinoma.
  • the cancer is adenosquamous carcinoma.
  • the cancer is sarcomatoid carcinoma.
  • the cancer is large cell carcinoma.
  • the cancer is small cell lung cancer.
  • the non-small cell lung cancer is chemo-resistant.
  • the adenocarcinoma is chemo-resistant. In some embodiments, the squamous cell carcinoma is chemo-resistant. In some embodiments, the adenosquamous carcinoma is chemo-resistant. In some embodiments, the sarcomatoid carcinoma is chemo-resistant. In some embodiments, the large cell carcinoma is chemo-resistant. In some embodiments, the small cell lung cancer is chemo-resistant.
  • a method as described herein comprises administering an additional therapeutic agent. In some embodiments, a method as described herein comprises administering at least two additional therapeutic agents.
  • the additional therapeutic agent is surgery, radiation therapy, chemotherapy, targeted therapy, immunotherapy, adjuvant therapy, anti angiogenesis therapy, or pain therapy.
  • the additional therapeutic agent is chemotherapy, targeted therapy, immunotherapy, adjuvant therapy, or anti-angiogenesis therapy.
  • the additional therapeutic agent is surgery.
  • the additional therapeutic agent is radiation therapy.
  • the additional therapeutic agent is chemotherapy.
  • the additional therapeutic agent is targeted therapy.
  • the additional therapeutic agent is immunotherapy.
  • the additional therapeutic agent is adjuvant therapy. In some embodiments, the additional therapeutic agent is anti-angiogenesis therapy. In some embodiments, the additional therapeutic agent is pain therapy.
  • a method of treating Human Immunodeficiency Vims (HIV) in a mammal comprising administering a therapeutically effective amount of a compound disclosed herein, or pharmaceutically acceptable salt, A'-oxidc. racemate, or stereoisomer thereof, to the individual.
  • HIV Human Immunodeficiency Vims
  • a method of reversing a latency of Human Immunodeficiency Vims (HIV) in a mammal comprising administering a therapeutically effective amount of a compound disclosed herein, or pharmaceutically acceptable salt, A'-oxidc. racemate, or stereoisomer thereof, to the individual.
  • the latency of HIV is reversed without activation of T cells.
  • the method further comprises administering an additional latency reversal agent, a killer agent, CarT, immunotherapy, neutralizing antibodies, or other agents.
  • the additional latency reversal agent is a histone deacetylase inhibitor (HDACi), a bromodomain and extra terminal domain inhibitors (BETi), or a Protein Kinase C (PKC) agonist.
  • the additional therapeutic agent is carboplatin, cisplatin, docetaxel, gemcitabine, nab-paclitaxel, paclitaxel, pemetrexed, vinorelbine, bevacizumab, ramucirumab, afatinib, dacomitinib, erlotinib, gefitinib, necitumumab, osimertinib, atezolizumab, durvalumab, nivolumab, or pembrolizumab.
  • the additional therapeutic agent is carboplatin, cisplatin, docetaxel, gemcitabine, nab-paclitaxel, paclitaxel, or bevacizumab. In some embodiments, the additional therapeutic agent is carboplatin, cisplatin, or paclitaxel. In some embodiments, the additional therapeutic agent is carboplatin. In some embodiments, the additional therapeutic agent is cisplatin. In some embodiments, the additional therapeutic agent is gemcitabine. In some embodiments, the additional therapeutic agent is bevacizumab. In some embodiments, the additional therapeutic agent is vinorelbine.
  • a pharmaceutical composition of the present disclosure comprises a selective melanoma inhibitor of apoptosis protein (ML-IAP) antagonist, at least one additional therapeutic agent used to treat cancer, and at least one excipient or carrier.
  • the pharmaceutical composition comprises at least two additional therapeutic agents used to treat cancer.
  • the pharmaceutical composition comprises at least three additional therapeutic agents used to treat cancer.
  • the additional therapeutic agents used to treat cancer is chemotherapy, targeted therapy, immunotherapy, adjuvant therapy, or anti-angiogenesis therapy.
  • the additional therapeutic agents used to treat cancer is carboplatin, cisplatin, docetaxel, gemcitabine, nab-paclitaxel, paclitaxel, pemetrexed, vinorelbine, bevacizumab, ramucirumab, afatinib, dacomitinib, erlotinib, gefitinib, necitumumab, osimertinib, atezolizumab, durvalumab, nivolumab, or pembrolizumab.
  • a compound described herein is administered in combination with a second anti -cancer agent.
  • anti -cancer agents for use in combination with a compound of Formula (A-I), (B-I), or (C-I) include inhibitors of mitogen-activated protein kinase signaling, e.g., U0126, PD98059, PD184352, PD0325901, ARRY-142886, SB239063, SP600125, BAY 43-9006, wortmannin, or LY294002; Syk inhibitors; mTOR inhibitors; and antibodies (e.g., rituxan).
  • mitogen-activated protein kinase signaling e.g., U0126, PD98059, PD184352, PD0325901, ARRY-142886, SB239063, SP600125, BAY 43-9006, wortmannin, or LY294002
  • Syk inhibitors e.g., mTOR inhibitors
  • mTOR inhibitors e.g., rituxan
  • anti-cancer agents that can be employed in combination with a compound of Formula (A-I), (B-I), or (C-I) include Adriamycin, Dactinomycin, Bleomycin, Vinblastine, Cisplatin, acivicin; aclarubicin; acodazole hydrochloride; acronine; adozelesin; aldesleukin; altretamine; ambomycin; ametantrone acetate; aminoglutethimide; amsacrine; anastrozole; anthramycin; asparaginase; asperlin; azacitidine; azetepa; azotomycin; batimastat; benzodepa; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate; bizelesin; bleomycin sulfate; brequinar sodium; bropirimine; busulfan; cactinomycin; ca
  • anti-cancer agents that can be employed in combination with a compound of Formula (A-I), (B-I), or (C-I) include: 20-epi-l, 25 dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TK antagonists; altretamine; ambamustine; amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; andrographolide; angiogenesis inhibitors; antagonist D; antagonist G; antarelix; anti- dorsalizing morphogenetic protein- 1; antiandrogen, prostatic carcinoma; antiestrogen; antineoplaston; antisense oligonucleotides; aphidicolin glycinate; apoptosis gene
  • anticancer agents that can be employed in combination with a compound of Formula (A-I), (B-I), or (C-I) include alkylating agents, antimetabolites, natural products, or hormones, e.g., nitrogen mustards (e.g., mechloroethamine, cyclophosphamide, chlorambucil, etc.), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine, lomusitne, etc.), ortriazenes (decarbazine, etc.).
  • nitrogen mustards e.g., mechloroethamine, cyclophosphamide, chlorambucil, etc.
  • alkyl sulfonates e.g., busulfan
  • nitrosoureas e.g., carmustine, lomusitne, etc.
  • ortriazenes decarbazine, etc.
  • antimetabolites include but are not limited to folic acid analog (e.g., methotrexate), or pyrimidine analogs (e.g., Cytarabine), purine analogs (e.g., mercaptopurine, thioguanine, pentostatin).
  • folic acid analog e.g., methotrexate
  • pyrimidine analogs e.g., Cytarabine
  • purine analogs e.g., mercaptopurine, thioguanine, pentostatin.
  • Examples of natural products useful in combination with a compound of Formula (A-I), (B-I), or (C-I) include but are not limited to vinca alkaloids (e.g., vinblastin, vincristine), epipodophyllotoxins (e.g., etoposide), antibiotics (e.g., daunorubicin, doxorubicin, bleomycin), enzymes (e.g., L-asparaginase), or biological response modifiers (e.g., interferon alpha).
  • vinca alkaloids e.g., vinblastin, vincristine
  • epipodophyllotoxins e.g., etoposide
  • antibiotics e.g., daunorubicin, doxorubicin, bleomycin
  • enzymes e.g., L-asparaginase
  • biological response modifiers e.g., interferon alpha
  • alkylating agents that can be employed in combination a compound of Formula (A-I), (B-I), or (C-I) include, but are not limited to, nitrogen mustards (e.g., mechloroethamine, cyclophosphamide, chlorambucil, melphalan, etc.), ethylenimine and methylmelamines (e.g., hexamethlymelamine, thiotepa), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine, lomusitne, semustine, streptozocin, etc.), ortriazenes (decarbazine, etc.).
  • nitrogen mustards e.g., mechloroethamine, cyclophosphamide, chlorambucil, melphalan, etc.
  • ethylenimine and methylmelamines e.g., hexameth
  • antimetabolites include, but are not limited to folic acid analog (e.g., methotrexate), or pyrimidine analogs (e.g., fluorouracil, floxuridine, Cytarabine), purine analogs (e.g., mercaptopurine, thioguanine, pentostatin.
  • folic acid analog e.g., methotrexate
  • pyrimidine analogs e.g., fluorouracil, floxuridine, Cytarabine
  • purine analogs e.g., mercaptopurine, thioguanine, pentostatin.
  • hormones and antagonists useful in combination a compound of Formula (A-I), (B-I), or (C-I) include, but are not limited to, adrenocorticosteroids (e.g., prednisone), progestins (e.g., hydroxyprogesterone caproate, megestrol acetate, medroxyprogesterone acetate), estrogens (e.g., diethlystilbestrol, ethinyl estradiol), antiestrogen (e.g., tamoxifen), androgens (e.g., testosterone propionate, fluoxymesterone), antiandrogen (e.g., flutamide), gonadotropin releasing hormone analog (e.g., leuprolide).
  • adrenocorticosteroids e.g., prednisone
  • progestins e.g., hydroxyprogesterone caproate, megestrol acetate, medr
  • platinum coordination complexes e.g., cisplatin, carboblatin
  • anthracenedione e.g., mitoxantrone
  • substituted urea e.g., hydroxyurea
  • methyl hydrazine derivative e.g., procarbazine
  • adrenocortical suppressant e.g., mitotane, aminoglutethimide
  • Examples of anti -cancer agents which act by arresting cells in the G2-M phases due to stabilized microtubules and which can be used in combination with an irreversible EGFR tyrosine kinase inhibitor compound include without limitation the following marketed drugs and drugs in development: Erbulozole (also known as R-55104), Dolastatin 10 (also known as DLS-10 and NSC- 376128), Mivobulin isethionate (also known as CI-980), Vincristine, NSC-639829, Discodermolide (also known as NVP-XX-A-296), ABT-751 (Abbott, also known as E-7010), Altorhyrtins (such as Altorhyrtin A and Altorhyrtin C), Spongistatins (such as Spongistatin 1, Spongistatin 2, Spongistatin 3, Spongistatin 4, Spongistatin 5, Spongistatin 6, Spongistatin 7, Spong
  • a compound described herein e.g., a compound of Formula (A-I), (B-I), or (C- I)
  • TRAIL TNF-alpha and/or TNF-related apoptosis-inducing ligand (TRAIL).
  • TRAIL shows homology to other members of the TNF-alpha family of proteins.
  • a compound described herein e.g., a compound of Formula (A-I), (B-I), or (C-I)
  • a TNF-alpha modulator and/or a TNF-alpha analogue e.g., lenalidomide, revlimid, CC-5013; CC-4047, ACTIMID. Thalidomide and the like.
  • a compound described herein e.g., a compound of Formula (A-I), (B-I), or (C-I)
  • an adjuvant, hormone therapy, immunotherapy or any combination thereof is administered in combination with an adjuvant, hormone therapy, immunotherapy or any combination thereof.
  • a compound described herein is administered in combination with antiretroviral therapy (ART).
  • antiretroviral therapy (ART) for use in combination with a compound of Formula (A-I), (B-I), or (C-I) include Combivir, Kaletra, Aluvia, Trizivir, Epzicom, Kivexa, Triomune, Duovir-N, Truvada, Atripla, Complera, Eviplera, Stribild, Triumeq, Evotaz, Prezcobix, Rezolsta, Dutrebis, Genvoya, Odefsey, Descovy, Juluca, Symfi, Symfi Lo, Biktarvy, Cimduo, Symtuza, Delstrigo, and Dovato.
  • a compound described herein is administered in combination with a latency reversal agent (LRA) with or without antiretroviral therapy (ART).
  • latency reversal agent (LRA) for use in combination with a compound of Formula (A-I), (B-I), or (C-I) include histone deacetylase inhibitors (HDACi), bromodomain and extra terminal domain inhibitors (BETi), Protein Kinase C (PKC) agonists, activators of positive transcription elongation factor b (P-TEFb), Toll-like receptor (TLR) agonists, immune checkpoint inhibitors, tetraethylthiuram disulfide (Disulfiram), benzotriazole derivatives, quinolines, cytokines, methyltransferase inhibitors, and methylation inhibitors.
  • HDACi histone deacetylase inhibitors
  • BETi bromodomain and extra terminal domain inhibitors
  • PKC Protein Kinase C
  • a compound described herein is administered in combination with a killer agent, CarT, immunotherapy, neutralizing antibodies, or other agents. Additional latency reversal agents can be found in Stoszko et ah, Curr Opin Virol. 2019 Jul 16; 38:37-53 which is hereby incorporated by reference for such disclosures.
  • Reactions conducted under microwave irradiation were performed in a CEM Discover microwave reactor using either CEM 10 mL reaction vessels or a ChemGlass heavy wall pressure vessel (100 mL, 38 mm* 190 mm). Reaction progress was monitored by reverse-phase HPLC and/or thin-layer chromatography (TLC). Liquid chromatography-mass spectrometry was performed using either Waters or Shimadzu 2010EV LCMS instruments using water and acetonitrile or methanol doped with 0.1% formic acid. TLC was performed using silica gel 60 F254 pre-coated plates (0.25 mm).
  • Flash chromatography was performed using silica gel (32-63 pm particle size) or aluminum oxide (activated, basic, -150 mesh size). Automated chromatographic purification was carried out using pre-packed silica or C18 cartridges (from RediSep and Luknova) and eluted using an ISCO Companion system. Reverse phase purifications were conducted using water and acetonitrile or methanol doped with 0.1% formic acid. All final product compounds were purified using one of these two chromatographic methods. Purity and characterization of compounds was established by a combination of TLC, liquid chromatography-mass spectroscopy (LC-MS) and Nuclear Magnetic Resonance (NMR) analytical techniques. 3 ⁇ 4 and 13 C NMR spectra were obtained on a Joel 400 spectrometer at 400 MHz and 101 MHz, respectively. Chemical shifts are reported in d (ppm) and were internally referenced to deuterated solvent signals.
  • LC-MS liquid chromatography-mass spectroscopy
  • NMR
  • HPLC-MS analyses were performed on a Waters ACQUITY UPLC with SQ mass detector and PDA c ' / . detector.
  • the column used was a Phenomenex Kinetex Cl 8 column (1.7um, 2.1 x 50 mm).
  • the mobile phase consisted of eluent A (water, 0.05% TFA) and eluent B (CTLCN, 0.05% TFA), and the elution proceeded at 0.5 mL/min.
  • the initial conditions were 90% A, then 90% A to 10% A linearly decreased within 1.75 min, then from 10% A to 90% A within 0.25 min.
  • the total run time is 2 minutes.
  • the resultant liquid was poured in a 5% citric acid (300 mL, aqueous solution) and extracted with ethyl acetate (3*100 mL). The combined organic layers were washed with a 1 : 1 mixture of saturated solution of sodium bicarbonate: brine (2*100 mL), dried over sodium sulfate anhydrous, filtered and concentrated to afford 15 g (97% yield) of a dark red oil.
  • a sealed mixture of the oil and 10% Pd/C (2g) in methanol (100 mL) flushed with nitrogen was placed under hydrogen atmosphere in a parr hydrogenator and stirred for 18 hours at 20PSI. The mixture was then filtered through celite and concentrated.
  • the crude intermediate was solubilized in ethyl formate (>10 eq, 30 mL) and refluxed at 80°C for 40 hours. It was concentrated to dryness and solubilized in a mixture of dichloromethane (150 mL) and triethylamine (55 mL, 6.0 eq). Phosphoryl trichloride (9 ml, 1.5 eq) was added at 0°C. The mixture was stirred at 0°C for 30 min then at 23°C for 3 hours. The mixture was poured carefully in saturated aqueous sodium bicarbonate (700mL), which was extracted with DCM (3*300 mL), dried over sodium sulfate anhydrous, filtered and concentrated.
  • the mixture was diluted with diethyl ether (lOOmL) and brine (100 mL). It was warmed up to 23°C and stirred vigorously for lh. The organic phase was separated, and the aqueous phase was extracted with dichloromethane (3* 100 mL). The combined organic layers were washed with brine, dried over sodium sulfate anhydrous, filtered through a plug of silica gel and concentrated. The crude was purified by flash column chromatography over silica gel (0-100% dichloromethane in pentane): 2.00 g (45% yield) of a colorless liquid.
  • (2S)-2-((tert-butoxycarbonyl)amino)-2-((lS)-2-hydroxycyclohexyl)acetic acid (X-8).
  • (2S)-2-((tert-butoxycarbonyl)amino)-2-(2-hydroxycyclohexyl)acetic acid (l.Oeq)
  • 4-dimethylaminopyridine (0.1 eq) in tetrahydrofuran at 0°C was added di-/ert-butyl dicarbonate (1.1 eq). The mixture was stirred for 10 minutes at 0°C then warmed up to 20°C for 16 hours.
  • the mixture was quenched with a saturated solution of sodium bicarbonate (100 mL) and extracted with ethyl acetate (3*100 mL). The combined organic layers were dried over sodium sulfate anhydrous, fdtered and concentrated.
  • the crude was solubilized in a mixture of tetrahydrof iran: water (3: 1, 40 mL) and sodium hydroxide was added (0.6g, 5 eq). The mixture was stirred vigorously for 3 hours at 40°C.
  • the mixture was quenched with 0.5M HC1 (150 mL) and extracted with ethyl acetate (3* 100 mL). The combined organic layers were dried over sodium sulfate anhydrous, fdtered and concentrated.
  • tert-Butyl (IS, 2R)-2 -hydroxy-2, 3-dihydro-lH-inden-l-ylcarbamate (2.50 g, 10.0 mmol, 1.00 eq.) was dissolved in dry DML (20.0 mL) and the solution was cooled down to 0 °C.
  • Propargyl bromide in toluene (80%, 1.34 mL, 12.0 mmol, 1.20 eq.) was added.
  • the resulting solution was treated in portions with powdered KOH (1.15 g, 420.6 mmol, 2.05 eq.) and stirring was continued at 0 °C.
  • oxalyl chloride (2.0 eq) was solubilized in dry DCM then cooled down to -78°C.
  • DMSO 4.0 eq was added dropwise and the reaction was stirred for 10 min (at -78°C).
  • a solution of the alcohol (1.0 eq) in DCM was added dropwise and stirred for 15min at -78°C.
  • triethylamine (4.5 eq) was added at -78°C and the mixture was stirred for 15 min at -78C.
  • the first undesired isomer as a yellow solid, 214 mg (14%).
  • R f 0.47 (50 % ethyl acetate in hexanes).
  • the second desired isomer as a yellow solid, 254 mg (17%).
  • Rf 0.20 (50 % ethyl acetate in hexanes).
  • the mixture was stirred at 0°C for 30 min. the cold bath was removed and it was stirred at 23°C for 18 hours.
  • the mixture was quenched with saturated aqueous sodium bicarbonate (100 mL) and extracted with ethyl acetate (3* 100 mL). The organic layers were combined, washed with brine, dried over sodium sulfate anhydrous, fdtered and concentrated.
  • the intermediate (1.0 eq, 1.3 mmol, 750 mg) was solubilized in methanol (3.0mL) and 4M HC1 in 1,4-Dioxane (3.0mL) was added. The Mixture was stirred at 40°C for 4 hours.
  • Example 12, 14, 13, and 15 Synthesis of (4S,9aS)-8,8-diallyl-4-((S)-2- (methylamino)propanamido)-5-oxo-N-((R)-l,2,3,4-tetrahydronaphthalen-l- yl)octahydropyrrolo[2,l-b][l,3]oxazepine-7-carboxamide hydrochloride (12, 14).
  • Example 19, 21, and 20 Synthesis of (4S)-8,8-diethyl-4-((S)-2- (methylamino)propanamido)-5-oxo-N-((R)-l,2,3,4-tetrahydronaphthalen-l- yl)octahydropyrrolo[2,l-b][l,3]oxazepine-7-carboxamide hydrochloride (19, 21).
  • Example 22, 23, 24, 25, and 26 Synthesis of (4S,9aS)-4-((S)-2-(methylamino)propanamido)-5- oxo-8, 8-diphenethyl-N-((R)-l, 2,3, 4-tetrahydronaphthalen-l-yl)octahydropyrrolo[2,l- b] [l,3]oxazepine-7-carboxamide hydrochloride
  • Example 28, 29, 31, 27, 30, and 32 Synthesis of (4S,9aS)-8,8-diallyl-4-((S)-2- (methylamino)propanamido)-5-oxo-N-((R)-l,2,3,4-tetrahydronaphthalen-l- yl)octahydropyrrolo[2,l-b][l,3]thiazepine-7-carboxamide hydrochloride (28, 29, 31).
  • Example 40, 41, 42, and 43 Synthesis of 4S,9aS)-8,8-diisopropyl-4-((S)-2- (methylamino)propanamido)-5-oxo-N-((R)-l,2,3,4-tetrahydronaphthalen-l- yl)octahydropyrrolo[2,l-b] [l,3]thiazepine-7-carboxamide hydrochloride (40,41,42,43)
  • Example 45, 47, 44, and 46 Synthesis of (4S,9aS)-4-((S)-2-(methylamino)propanamido)- 5-oxo-8,8-diphenethyl-N-((R)-l,2,3,4-tetrahydronaphthalen-l-yl)octahydropyrrolo[2,l- b][l,3]thiazepine-7-carboxamide hydrochloride (45, 47) and (4S,9aS)-4-((S)-2- (methylamino)propanamido)-5-oxo-8,8-phenethyl-N-((R)-l,2,3,4-tetrahydronaphthalen-l- yl)octahydropyrrolo[2,l-b][l,3]thiazepine-7-carboxamide hydrochloride (44, 46).
  • Example 48, 49, 50, 51, 52, and 53 Synthesis of (4S)-8,8-diallyl-N-benzhydryl-4-((S)-2- (methylamino)propanamido)-5-oxooctahydropyrrolo[2,l-b][l,3]oxazepine-7-carboxamide hydrochloride (48,49,50,51,52) and (4S)-8,8-allyl-N-benzhydryl-4-((S)-2- (methylamino)propanamido)-5-oxooctahydropyrrolo[2,l-b][l,3]oxazepine-7-carboxamide hydrochloride (53)
  • Example 56 and 57 Synthesis of (S)-N-((4S,7S,9aS)-8,8-dimethyl-5-oxo-7-((((R)-l,2,3,4- tetrahydronaphthalen-l-yl)amino)methyl)octahydropyrrolo[2,l-b] [l,3]oxazepin-4-yl)-2- (methylamino)propanamide dihydrochloride (56,57)
  • Example 64, 65, and 66 Synthesis of (lS,9S)-2,2-dimethyl-9-((S)-2- (methylamino)propanamido)-10-oxo-N-((R)-l,2,3,4-tetrahydronaphthalen-l- yl)dodecahydrobenzo[f]pyrrolo[2,l-b][l,3]oxazepine-l-carboxamide hydrochloride (64) and (lS,9S)-2,2-methyl-9-((S)-2-(methylamino)propanamido)-10-oxo-N-((R)-l,2,3,4- tetrahydronaphthalen-l-yl)dodecahydrobenzo[f]pyrrolo[2,l-b][l,3]oxazepine-l-carboxamide hydrochloride (65, 66).
  • Example 70 and 71 Synthesis of (4S,7S,9aS)-N-isopentyl-8,8-dimethyl-4-((S)-2- (methylamino)propanamido)-5-oxooctahydropyrrolo[2,l-b][l,3]oxazepine-7-carboxamide hydrochloride (70, 71)
  • Example 75 and 76 Synthesis of rac-(4R)-8,8-dimethyl-4-((R)-2-(methylamino)propanamido)-5- oxo-2-((phenylthio)methyl)-N-((S)-l,2,3,4-tetrahydronaphthalen-l-yl)octahydropyrrolo[2,l- b][l,3]oxazepine-7-carboxamide hydrochloride (75, 76).
  • N-methylmorpholine (4.20 mmol, 0.462 mL), HOBT (0.236 g, 1.540 mmol) and N-(tert- butoxycarbonyl)-N-methyl-L-alanine (0.313 g, 1.540 mmol) in THF (14 mL) at 0°C was added EDC.HC1 (0.282 g, 1.470 mmol). The mixture was stirred at 0°C for 30 min then warmed to 35°C for 18 hours. The mixture was diluted with water (100 mL) and 0.1M HC1 (10 mL). It was extracted with ethyl acetate (3* 100 mL).
  • Example 78 Synthesis of (4S,7S,9aS)-N-((lS,2R)-2-(2-fluoroethoxy)-2,3-dihydro-lH-inden-l- yl)-8,8-dimethyl-4-((S)-2-(methylamino)propanamido)-5-oxooctahydropyrrolo[2,l- b] [l,3]thiazepine-7-carboxamide hydrochloride
  • Example 80 Synthesis of (4'S,7'S,9a'S)-4'-((S)-2-(methylamino)propanamido)-5'-oxo-N-((R)- l,2,3,4-tetrahydronaphthalen-l-yl)hexahydro-7'H-spiro[cyclopentane-l,8'-pyrrolo[2,l- b] [l,3]thiazepine]-7'-carboxamide hydrochloride
  • Example 81 Synthesis of (4'S)-4'-((S)-2-(methylamino)propanamido)-5'-oxo-N-((R)-l,2,3,4- tetrahydronaphthalen-l-yl)-2',3',4',5',9',9a'-hexahydro-7'H-spiro[cyclopentane-l,8'-pyrrolo[2,l- b] [l,3]oxazepin]-3-ene-7'-carboxamide hydrochloride [00369]
  • Example 82 Synthesis of (4'S)-4'-((S)-2-(methylamino)propanamido)-5'-oxo-N-((R)-l,2,3,4- tetrahydronaphthalen-l-yl)hexahydro-7'H-spiro[cyclopentane-l,8'-pyrrolo[2,l- b] [l,3]oxazepine]-7'-carboxamide hydrochloride
  • Example 83 Synthesis of (2S)-l- ⁇ [(4S,7S,9aS)-8,8-Dimethyl-5-oxo-7- ⁇ [(lS,2R)-2-(prop-2-yn-l- yloxy)-2,3-dihydro-lH-inden-l-yl]carbamoyl ⁇ octahydropyrrolo[2,l-b][l,3]thiazepin-4- yl]amino ⁇ -N-methyl-l-oxopropan-2-ammonium chloride
  • SKOV-3 cancer cell lines were treated with a test compound, either as a pure enantiomer or a mixture of stereoisomers, at a concentration of 10 mM.
  • Cell viability was evaluated following treatment with a compound as disclosed in Table B . Viability of cancer cells following treatment is indicated according to the following legend:
  • Example B Evaluation of Sensitization of Cancer Cells to Standard of Care Treatment
  • ML-IAP is upregulated in many tumors and is believed to underlie chemoresistance due to its ability to inhibit apoptosis in cancer cells.
  • H460 lung cancer cells are treated with a standard of care treatment (e.g., vinorelbine) alone or in combination with a selective ML-IAP antagonist.
  • a standard of care treatment e.g., vinorelbine
  • FIG. 1 confirm this sensitizing effect in lung cancer cells with the clinically relevant anti -cancer agent vinorelbine (FIG. 1).
  • the leftward shift in the dose dependent response (DDR) curve indicates a resensitization of lung cancer cells to the anti -cancer agent.
  • TNF induction is absent following treatment with a compound described herein in breast cancer MDA-MB-231 cells. This effect provides a substantial advantage clinically as it avoids an inappropriate inflammatory response.
  • multi-well plate format FP assays based on the ability of SMAC peptides to bind the BIR domains of several IAPs are used to generate IC50 and Ki values for analogues.
  • the FP assays utilize plasmid constructs encoding various full length IAPs or fragments for expression as either GST or His6-fiision proteins in bacteria.
  • Compounds are evaluated for activity against several members of the IAP family, including the BIR domains of XIAP, cIAP 1 and cIAP2 in order to generate selectivity profiles of the compounds disclosed herein. These assays also enable the identification and characterization of potency profiles of ML-IAP binding.
  • Example D Cell-Based Assays for ML-IAP Inhibitors & Combination Therapies
  • Example D Cell-Based Assays for ML-IAP Inhibitors & Combination Therapies
  • Compounds active in the FP assays are tested in several lung cancer cell lines including all those within the NCI 60 panel for community -wide data relevance. Compounds are evaluated for the capacity to induce apoptosis and to sensitize tumor cells to apoptosis induced by lung cancer relevant chemotherapeutic drugs irrespective of mechanism.
  • lung cancer SOC is often platinum- based chemotherapy (e.g. Carboplatin or Cisplatin) and a DNA damaging agent or mitotic tubule inhibitor.
  • Various cancer cell lines are tested with these combinations in the presence and absence of ML-IAP inhibition. These in cellulo recapitulations of clinical regimens yield valuable potency and dosing information relevant to xenograft models.
  • Candidate compounds are tested in 384-well plates for effects on cell viability in the presence or absence of an appropriate conventional anticancer drug.
  • Cell viability is indirectly monitored in the first instance using CellTiterGlo (Promega Corp., Madison, WI) (Table D).
  • CellTiterGlo Promega Corp., Madison, WI
  • the induction of caspase activity is assessed utilizing the CaspaseGlo Assay system (Promega Corp., Madison, WI) (Table E).
  • Cell viability is monitored 1 to 3 days after addition of compounds and conventional drugs.
  • a concentration of cytotoxic anticancer drug is chosen that shows only marginal activity.
  • a compound of any of the formulae as disclosed herein is evaluated in combination with said anticancer drug to determine which ML-IAP antagonist can sensitize most efficaciously.
  • Select candidate compounds are tested in 14 point drug dose response (DDR) curves in a 384-well format in order to establish potency in combination with decreasing concentrations of lung cancer relevant drug regimens.
  • checker-board titrations of a conventional drug and the candidate molecules are performed to search for synergy (using ISOBOLOGRAM analysis).
  • Compounds and combinations as described herein are also tested for cytotoxicity against normal human cells (e.g. primary fibroblasts, lymphocytes, hepatocytes, epithelial and endothelial cells) using known methods.
  • Example E Evaluation of Selectivity for ML-IAP in an Orthogonal Biochemical/Biophysical Assay
  • ITC isothermal calorimetry
  • Example F Pharmacokinetic Evaluation Using in vitro Absorption, Distribution, Metabolism, Excretion and Toxicity (ADME/T) and in vivo Pharmacokinetic (PK) Assays
  • ADME/T and physicochemical profding assays are employed to optimize the drug like properties of analogues and to aid in the selection of compounds for further development.
  • Aqueous solubility data are determined at pH 5.0, 6.2 and pH 7.4 with UV detection. Compounds with aqueous solubility >10pg/mL are selected and advanced for further PK evaluation. Free plasma concentrations are determined using rapid equilibrium dialysis, which is the most quantitative method for determining levels of plasma protein binding.
  • Membrane permeability data are determined using a parallel artificial membrane permeability assay (PAMPA).
  • PAMPA membrane permeability assay
  • This in vitro method assesses the passive diffusion of compounds across a layer of specialized mixtures of phospholipids that mimic (a) the gut epithelium, and (b) brain capillary endothelial cells, the primary barrier to absorption into the brain.
  • Metabolic stability in human, mouse, and rat microsomes are also used to evaluate compounds described herein for drug-like properties. For microsomal assays, compounds are incubated in the presence of 1 mg/mF microsomes; the metabolites are quantitated using FC/MS methods.
  • Cytochrome P450 (CYP450) isoform (CYP1A2, 2C9, 2D6, and 3A4) inhibition is determined in human liver microsomes. Inhibition of product formation for compound substrates is detected by luminescence using the isoform specific P450-glo assay (Promega, Madison, WI) over 10 concentrations of inhibitor and assessed at one time point (previously determined to be in the linear range for time and protein concentration). The IC50 is analyzed by a four parameter logistic fit. Appropriate positive control inhibitors are used for each enzyme. Mechanism-based inhibition will be investigated where warranted using the established method.
  • PK studies are performed in vivo in mice for compounds as described herein. Standard formulations are evaluated, including hydroxypropyl methylcellulose, carboxymethylcellulose, and polyethylene glycol.
  • compounds are administered via indwelling catheters in jugular vein and samples collected from the carotid artery. These experiments provide basic pharmacokinetic parameters including peak plasma concentration (Cmax), bioavailability (%F), exposure (AUC), half-life (tl/2), clearance (CF), volume of distribution (Vd), and brain levels.
  • Cmax peak plasma concentration
  • bioavailability %F
  • AUC exposure
  • tl/2 half-life
  • CF volume of distribution
  • Vd volume of distribution
  • brain levels To measure bioavailability, a compound as described herein is administered to three animals/group, both orally (10 mg/kg) and intravenously (1 mg/kg).
  • Intraperitoneally administration is also assessed in order to determine both brain and plasma levels of compounds.
  • the compounds described herein were tested in vivo in mice to measure PK plasma exposure as shown in Table F.
  • the PK plasma values are indicated according to the following legend:
  • a compound as described herein is tested in mouse xenograft models of lung cancer to determine in vivo efficacy.
  • a suitable lung cancer cell line as well as a potent apoptosis inducing agent exhibiting synergy with the compounds described herein is used for a first-pass xenograft study to determine appropriate dosing ranges in vivo.
  • the dosing parameters are applied to a parallel xenograft study utilizing a suitable patient-derived lung cancer sample (Mayo Clinic, Rochester, MN).
  • a dosing regimen is selected that will maintain inhibition of ML-IAP in tumor cells by using two approaches: immunoblotting for SMAC levels, which are modulated through the E3 ligase activity of ML-IAP and measurement of activation of the apoptotic pathway through an apoptosis specific assay.
  • This method enables one to (a) determine the compound levels in blood that correlates with inhibition of ML-IAP in tumors, as well as (b) determine what level of inhibition is required for a significant reduction of tumor growth in vivo.
  • Compounds are tested in mice bearing xenografts of lung cancer cells as described above.
  • Tumor xenografts are established in a group of 16 nude mice [4 test groups of 4 animals: (Group 1) Control; (Groups 2-4) ML-IAP antagonist at three dosing ranges (IC50, 10x IC50 and maximum tolerated dose, respectively) based on PK data obtained as described previously].
  • the NCI60 panel viability data suggests that no significant single agent toxicity is to be expected, however a more detailed assessment is prudent and necessary. Studies are initiated when tumors grow to approximately 0.25 mm 3 , a size that is visible on the flank, but small enough so that the tumor does not contain a substantial necrotic core. The time point of the blood draw is based on the data from ADME/T and PK assays as described previously. Compound levels in the tumor are determined after final dosing and the animals are sacrificed.
  • Example G2 Evaluation of Efficacy in Relevant Mouse Tumorigenic (Xenograft) Models of Ovarian Cancer
  • a compound as described herein is tested in mouse xenograft models of ovarian cancer to determine in vivo efficacy.
  • a suitable ovarian cancer cell line as well as a potent apoptosis inducing agent exhibiting synergy with the compounds described herein is used for a first-pass xenograft study to determine appropriate dosing ranges in vivo.
  • the dosing parameters are applied to a parallel xenograft study utilizing a suitable patient-derived ovarian cancer sample.
  • a dosing regimen is selected that will maintain inhibition of ML-IAP in tumor cells by using two approaches: immunoblotting for SMAC levels, which are modulated through the E3 ligase activity of ML-IAP and measurement of activation of the apoptotic pathway through an apoptosis specific assay.
  • This method enables one to (a) determine the compound levels in blood that correlates with inhibition of ML-IAP in tumors, as well as (b) determine what level of inhibition is required for a significant reduction of tumor growth in vivo.
  • Compounds are tested in mice bearing xenografts of ovarian cancer cells as described above.
  • Tumor xenografts are established in a group of 16 nude mice [4 test groups of 4 animals: (Group 1) Control; (Groups 2-4) ML-IAP antagonist at three dosing ranges (IC50, lOx IC50 and maximum tolerated dose, respectively) based on PK data obtained as described previously].
  • the NCI60 panel viability data suggests that no significant single agent toxicity is to be expected, however a more detailed assessment is prudent and necessary.
  • Studies are initiated when tumors grow to approximately 0.25 mm 3 , a size that is visible on the flank, but small enough so that the tumor does not contain a substantial necrotic core. The time point of the blood draw is based on the data from ADME/T and PK assays as described previously. Compound levels in the tumor are determined after final dosing and the animals are sacrificed.
  • Example G3 Evaluation of Efficacy in Relevant Mouse Tumorigenic (Xenograft) Models of Triple-Negative Breast Cancer
  • a compound as described herein is tested in mouse xenograft models of triple -negative breast cancer to determine in vivo efficacy.
  • a suitable triple -negative breast cancer cell line as well as a potent apoptosis inducing agent exhibiting synergy with the compounds described herein is used for a first-pass xenograft study to determine appropriate dosing ranges in vivo.
  • the dosing parameters are applied to a parallel xenograft study utilizing a suitable patient-derived triple-negative breast cancer sample.
  • a dosing regimen is selected that will maintain inhibition of ML-IAP in tumor cells by using two approaches: immunoblotting for SMAC levels, which are modulated through the E3 ligase activity of ML-IAP and measurement of activation of the apoptotic pathway through an apoptosis specific assay.
  • This method enables one to (a) determine the compound levels in blood that correlates with inhibition of ML-IAP in tumors, as well as (b) determine what level of inhibition is required for a significant reduction of tumor growth in vivo.
  • Compounds are tested in mice bearing xenografts of triple-negative breast cancer cells as described above.
  • Tumor xenografts are established in a group of 16 nude mice [4 test groups of 4 animals: (Group 1) Control; (Groups 2-4) ML-IAP antagonist at three dosing ranges (IC50, lOx IC50 and maximum tolerated dose, respectively) based on PK data obtained as described previously].
  • the NCI60 panel viability data suggests that no significant single agent toxicity is to be expected, however a more detailed assessment is prudent and necessary.
  • Studies are initiated when tumors grow to approximately 0.25 mm 3 , a size that is visible on the flank, but small enough so that the tumor does not contain a substantial necrotic core. The time point of the blood draw is based on the data from ADME/T and PK assays as described previously. Compound levels in the tumor are determined after final dosing and the animals are sacrificed.
  • mice Four mice are used per dose for analysis by the TUNEL assay and immunoblotting for SMAC as well as ML-IAP levels. Animals are sacrificed 12 hours after treatment and the tumor resected on ice. The TUNEL assay is regarded as the “gold standard” in apoptosis detection and is performed as described in the scientific literature. Utilization of the TUNEL assay is well established for the determination of apoptosis levels in tissues. Resected tumor tissue is analyzed and the observed level of induction of apoptosis is correlated to SMAC levels and a reduction in tumor growth.
  • Example I Quantifying SMAC levels in tumor xenografts

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Abstract

Provided herein are compounds that modulate the activity of melanoma inhibitor of apoptosis (ML-IAP) protein, compositions comprising the compounds, and methods of using the compounds and compositions comprising the compounds.

Description

INHIBITOR OF APOPTOSIS PROTEIN (IAP) ANTAGONISTS
CROSS-REFERENCE TO RELATED APPLICATION [0001] This application claims the benefit of U.S. Provisional Application No. 63/018,464 filed on April 30, 2020, which is hereby incorporated by reference in its entirety.
STATEMENT AS TO FEDERALLY SPONSORED RESEARCH [0002] This invention was made with government support under contract number R01 CA 195227 awarded by the National Institutes of Health and National Cancer Institute, and R01AI124843 awarded by the National Institutes of Health and National Institute of Allergy and Infectious Diseases. The government has certain rights in the invention.
SUMMARY OF THE INVENTION
[0003] Described herein are compounds that modulate the activity of certain proteins involved in apoptotic pathways, or signaling pathways associated with inflammation and/or autoimmune diseases and/or cell division and/or angiogenesis. In some embodiments, the compounds described herein are antagonists of inhibitor of apoptosis (IAP) proteins. In some embodiments, the compounds described herein are antagonists of melanoma inhibitor of apoptosis protein (ML-IAP). In some embodiments, the compounds described herein are selective ML-IAP antagonists. In some embodiments, the compounds described herein are useful for the treatment of certain types of cancers as described herein. In some embodiments, the compounds, pharmaceutical compositions, and methods described herein are effective in the treatment of lung cancer. In some embodiments, the compounds, compositions, and methods described herein are effective in the treatment of chemo-resistant cancers. [0004] In some embodiments, the compounds described herein are pan -IAP antagonists. In some embodiments, the compounds described herein are useful for the treatment of cancer, inflammatory diseases, and/or autoimmune diseases as described herein.
[0005] In one aspect, provided herein are compounds having the structure of Formula (A-I), or a pharmaceutically acceptable salt, A'-oxidc. solvate, diastereomeric mixture, or individual enantiomers, or stereoisomer thereof:
Figure imgf000003_0001
wherein,
R1 is hydrogen, G-Galkyl. G-Gcycloalkyl. Ci-Cealkyl-iG-Cecycloalkyl), G-Galkyl-(phenyl). or G-Galkyl-(5- to 6-membered heteroaryl); wherein the G-Galkyl. G-Gcycloalkyl. phenyl, or 5- to 6-membered heteroaryl is optionally substituted with 1, 2, or 3 R9;
X is NRA, O, S, S(O), or S(0)2;
RA is hydrogen, Ci-Cealkyl, C(0)-(Ci-C6alkyl), C(0)-(C3-C6cycloalkyl), C(0)-(phenyl), or C(O)- (5- to 6-membered heteroaryl); wherein each CrG, alkyl. G-Gcycloalkyl. phenyl, or 5- to 6- membered heteroaryl is optionally substituted with 1, 2, or 3 R9; or X is C and taken together with R2a, R2b, and the carbon atom to which they are attached, forms a phenyl or 5- to 10-membered heteroaryl ring, optionally substituted with 1, 2, or 3 R9;
R2a, R2b, R3a, and R3b are each independently hydrogen, G-Galkyl. Ci-Cehaloalkyl, Ci-Ce alkoxy, Ci-Ceheteroalkyl, G-Galkcnyl. G-Galkynyl. C3-Ciocycloalkyl, 3- to 10-membered heterocycloalkyl, G-Goaryl. or 5- to 10-membered heteroaryl; wherein each G-Galkyl. Ci- Cehaloalkyl, Ci-Ce alkoxy, Ci-Ceheteroalkyl, G-Galkcnyl. or G-Galkynyl is optionally substituted with 1 or 2 G-Ciocycloalkyl, 3- to 10-membered heterocycloalkyl, G-Goaryl. or 5- to 10-membered heteroaryl rings; wherein each G-Galkyl. G-Ghaloalkyl. Ci-Ce alkoxy, Ci-Ceheteroalkyl, G-Galkcnyl. G-Galkynyl. C3-Ciocycloalkyl, 3- to 10-membered heterocycloalkyl, G-Goaryl. or 5- to 10-membered heteroaryl is optionally substituted with 1, 2, or 3 R9; or R2a and R2b together with the carbon atom to which they are attached form a carbonyl; or R2a and R3a, and optionally R2b and R3b, together with the carbon atoms to which they are attached form a G-Gcycloalkyl. 5- to 10-membered heterocycloalkyl, G-Goaryl. or 5- to 10- membered heteroaryl ring; wherein each G-Gcycloalkyl. 5- to 10-membered heterocycloalkyl, G-Goaryl. or 5- to 10-membered heteroaryl ring is optionally substituted with 1, 2, or 3 R9;
R4aand R4b are each independently hydrogen, halogen, G-Galkyl. G-Ghaloalkyl. G-G alkoxy. G-Gheteroalkyl. G-Galkenyl. G-Galkynyl. G-Ciocycloalkyl, 3- to 10-membered heterocycloalkyl, G-Goaryl. or 5- to 10-membered heteroaryl; wherein each G-Galkyl. Ci- Ghaloalkyl, C i -Co alkoxy, G-Gheteroalkyl. G-Galkenyl. or G-Galkynyl is optionally substituted with 1 or 2 G-Ciocycloalkyl, 3- to 10-membered heterocycloalkyl, G-Goaryl. or 5- to 10-membered heteroaryl; wherein each G-Galkyl. G-Ghaloalkyl. G-G alkoxy. Ci- Gheteroalkyl, G-Galkenyl. G-Galkynyl. G-Ciocycloalkyl, 3- to 10-membered heterocycloalkyl, G-Goaryl. or 5- to 10-membered heteroaryl is optionally substituted with 1, 2, or 3 R9; or R4a and R4b together with the carbon atom to which they are attached form a carbonyl; or R4a and R4b together with the carbon atom to which they are attached form a C3-Ciocycloalkyl or 3- to 10-membered heterocycloalkyl ring; wherein the C3-Ciocycloalkyl or 3- to 10- membered heterocycloalkyl ring is optionally substituted with 1, 2, or 3 R9;
R5 is NHR8,NHS(0)2R8, OR8, SR8, S(0)2R8, or S(0)2NHR8; or R5, R4a, and R4b, together with the carbon atom to which they are attached, form a Ce-Cioaryl or 5- to 10-membered heteroaryl ring; wherein the Ce-Cioaryl or 5- to 10-membered heteroaryl ring is optionally substituted with 1, 2, or 3 R9;
R6a is hydrogen, halogen, -U, or -G;
R6b is halogen, -U, or -G;
-U is CrCi, alkyl. Ci-Cdialoalkyl. Ci-Cealkoxy, CVG, heteroalkyl. CVG, alkenyl. or G-Galkynyl: wherein each CVGalkyl. G-Ghaloalkyl. Ci-Galkoxy, G-Gheteroalkyl, G-Galkcnyl. or G-Galkynyl is optionally substituted with 1, 2, or 3 R9 and/or 1 or 2 -G;
-G is C3-Ciocycloalkyl, 3- to 10-membered heterocycloalkyl, G-Goaryl, or 5- to 10-membered heteroaryl; wherein each C3-Ciocycloalkyl, 3- to 10-membered heterocycloalkyl, G-Goaryl, or 5- to 10-membered heteroaryl is optionally substituted with 1, 2, or 3 R9; or R6a and R6b together with the carbon atom to which they are attached form a saturated or partially saturated 3- to 7-membered cycloalkyl or a saturated or partially saturated 3- to 7- membered heterocycloalkyl; wherein the cycloalkyl or heterocycloalkyl is optionally substituted with 1, 2, or 3 R9;
R7a is hydrogen, halogen, Ci-C4alkyl, or G-Ghaloalkyl;
R7*’ is hydrogen, halogen, Ci-C4alkyl, or Ci-C4haloalkyl; or R7a and R7b together with the carbon atom to which they are attached form a saturated or partially saturated 3- to 7-membered cycloalkyl or a saturated or partially saturated 3- to 7- membered heterocycloalkyl; wherein the cycloalkyl or heterocycloalkyl is optionally substituted with 1, 2, or 3 R9; or R6b and R715 together with the carbon atoms to which they are attached form a C3-Ciocycloalkyl or 3- to 10-membered heterocycloalkyl ring; wherein each C3-Ciocycloalkyl or 3- to 10- membered heterocycloalkyl ring is optionally substituted with 1, 2, or 3 R9; or R6a, R6b, R7a, and R7b together with the carbon atoms to which they are attached form a 5 - to 10- membered heteroaryl ring optionally substituted with 1, 2, or 3 R9;
R8 is Z, CVGalkyl. (Ci-Galkylene)-Z, (Ci-Gheteroalkylene)-Z, (C2-Galkenylene)-Z, CH(Z)2, CH2CH(Z)2, CH(CI-C , alkyl )Z. or C(0)Z; wherein each alkyl, alkylene, heteroalkylene, or alkenylene is optionally substituted with 1, 2, or 3 R9;
Z is C3-Ciocycloalkyl, 3- to 10-membered heterocycloalkyl, G-Goaryl, or 5- to 10-membered heteroaryl; wherein each C3-Ciocycloalkyl, 3- to 10-membered heterocycloalkyl, G-Goaryl, and 5- to 10-membered heteroaryl is optionally substituted with 1, 2, or 3 R9; each R9 is independently halogen, G-Galkyl, G-Galkenyl, G-Galkynyl, G-Ghaloalkyl, G- C4alkoxy, Ci-C4haloalkoxy, Ci-C4heteroalkyl, -C(0)H, -C(0)0H, -CN, C3-Ciocycloalkyl, 3- to 10-membered heterocycloalkyl, G-Goaryl, 5- to 10-membered heteroaryl, -C(0)(G- C4alkyl), -C(0)0(Ci-Galkyl), -C(0)NH2, -C(0)NH(Ci-Galkyl), -C(0)N(Ci-C4alkyl)2, -NH2, -NH(Ci-C4alkyl), -N(G-Galkyl)2, -NH(C2-C4alkylene)-OH, -NH(G-Galkylene)-0-(G- C4alkyl), -OH, -O(G-Galkyl), -O(Ci-Ghalolkyl), -0(G-Galkylene)-NH2, -0(G- C4alkylene)-NH-(Ci-C4alkyl), -0(G-Galkylene)-N-(G-Galkyl)2, -O(G-Galkylene)- C(0)0H, -0(Ci-C4alkylene)-C(0)0-(Ci-Galkyl), -O(G-Galkenyl), -0(G-Galkylene)-(G- Cioaryl), -0(Ci-C4alkylene)-(5- to 10-membered heteroaryl), -O(G-Goaryl), -SH, S(0)20H, - S(0)2(Ci-Galkyl), -S(0)2NH2, -S(0)2NH(Ci-Galkyl), or -S(0)2N(Ci-Galkyl)2; or two R9 together with the atoms to which they are attached form a G-Gocycloalkyl or a 3- to 10- membered heterocycloalkyl ring; and provided that when R6a and R6b are both G¾ or when R6a and R6b together with the carbon atom to which they are attached form an unsubstituted cyclopentyl or unsubstituted cyclopentenyl, then R8 is not
Figure imgf000006_0001
[0006] In another aspect, provided herein are compounds having the structure of Formula (B-I), or a pharmaceutically acceptable salt, A'-oxide. solvate, diastereomeric mixture, or individual enantiomers, or stereoisomer thereof :
Figure imgf000006_0002
Formula (B-I) wherein,
R1 is hydrogen, CrG, alkyl. G-Gcycloalkyl. G-Galkyl-(G-Gcycloalkyl), G-Galkyl-(phenyl), or Ci-C ,alkyl-(5- to 6-membered heteroaryl); wherein the G-Galkyl. G-Gcycloalkyl. phenyl, or 5- to 6-membered heteroaryl is optionally substituted with 1, 2, or 3 R9;
X is NRA, O, S, S(O), or S(0)2;
RA is hydrogen, G-Galkyl, C(0)-(G-Galkyl), C(0)-(G-Gcycloalkyl), C(0)-(phenyl), or C(O)- (5- to 6-membered heteroaryl); wherein each G-Galkyl. G-Gcycloalkyl. phenyl, or 5- to 6- membered heteroaryl is optionally substituted with 1, 2, or 3 R9; or X is C and taken together with R2a, R2b, and the carbon atom to which they are attached, forms a phenyl or 5- to 10-membered heteroaryl ring, optionally substituted with 1, 2, or 3 R9;
R2a, R2b, R3a, and R3b are each independently hydrogen, Ci-G, alkyl. Ci-Cehaloalkyl, Ci-Ce alkoxy, Ci-Ceheteroalkyl, G-Galkenyl. G-Galkynyl. C3-Ciocycloalkyl, 3- to 10-membered heterocycloalkyl, G,-Cioaryl. or 5- to 10-membered heteroaryl; wherein each G-Galkyl. G- Cehaloalkyl, Ci-Ce alkoxy, Ci-Ceheteroalkyl, G-Galkenyl. or G-Galkynyl is optionally substituted with 1 or 2 C3-Ciocycloalkyl, 3- to 10-membered heterocycloalkyl, G-Goaryl. or 5- to 10-membered heteroaryl rings; wherein each G-Galkyl. Ci-Cehaloalkyl, Ci-Ce alkoxy, Ci-Ceheteroalkyl, G-Galkenyl. G-Galkynyl. C3-Ciocycloalkyl, 3- to 10-membered heterocycloalkyl, G-Goaryl. or 5- to 10-membered heteroaryl is optionally substituted with 1, 2, or 3 R9; or R2a and R2b together with the carbon atom to which they are attached form a carbonyl; or R2a and R3a, and optionally R2b and R3b, together with the carbon atoms to which they are attached form a G-Gcycloalkyl. 5- to 10-membered heterocycloalkyl, G-Goaryl. or 5- to 10- membered heteroaryl ring; wherein each G-Gcycloalkyl. 5- to 10-membered heterocycloalkyl, G-Goaryl. or 5- to 10-membered heteroaryl ring is optionally substituted with 1, 2, or 3 R9;
R4aand R4b are each independently hydrogen, halogen, G-Galkyl. G-Ghaloalkyl. G-G alkoxy. G-Gheteroalkyl. G-Galkenyl. G-Galkynyl. C3-Ciocycloalkyl, 3- to 10-membered heterocycloalkyl, Ce-Goaryl, or 5- to 10-membered heteroaryl; wherein each G-Galkyl. G- Ghaloalkyl. C i -Co alkoxy, Ci-Cohctcroalkyl. G-Galkenyl. or G-Galkynyl is optionally substituted with 1 or 2 C3-Gocycloalkyl, 3- to 10-membered heterocycloalkyl, G-Goaryl. or 5- to 10-membered heteroaryl; wherein each G-Galkyl. G-Ghaloalkyl, G-G alkoxy, G- Gheteroalkyl, G-Galkenyl. G-Galkynyl. G-Gocycloalkyl, 3- to 10-membered heterocycloalkyl, G-Goaryl. or 5- to 10-membered heteroaryl is optionally substituted with 1, 2, or 3 R9; or R4a and R4b together with the carbon atom to which they are attached form a carbonyl; or R4a and R4b together with the carbon atom to which they are attached form a G-Gocycloalkyl or 3- to 10-membered heterocycloalkyl ring; wherein the G-Gocycloalkyl or 3- to 10- membered heterocycloalkyl ring is optionally substituted with 1, 2, or 3 R9;
R5 is NHR8,NHS(0)2R8, OR8, SR8, S(0)2R8, or S(0)2NHR8; or R5, R4a, and R4b, together with the carbon atom to which they are attached, form a G-Goaryl or 5- to 10-membered heteroaryl ring; wherein the G-Goaryl or 5- to 10-membered heteroaryl ring is optionally substituted with 1, 2, or 3 R9;
R6a is hydrogen, halogen, -Ua, or -G;
R6b is halogen, -Ub, or -G; -Ua is C -G, alkyl. G-Ghaloalkyl. Ci-Cealkoxy, G-Gheteroalkyl. G-Galkenyl. or G-Galkynyl: wherein each CrG, alkyl. G-Ghaloalkyl. Ci-Cealkoxy, G-Gheteroalkyl. G-Galkenyl. or G-Galkynyl is optionally substituted with 1, 2, or 3 R9 and/or 1 or 2 -G;
-Ub is G-Galkyl. G-Ghaloalkyl. Ci-Cealkoxy, Ci-Ceheteroalkyl, G-Galkenyl. or G-Galkynyl: wherein each G-Galkyl. G-Ghaloalkyl. Ci-Cealkoxy, Ci-Ceheteroalkyl, G-Galkenyl. or G-Galkynyl is optionally substituted with 1, 2, or 3 R9 and/or 1 or 2 -G;
-G is C3-Gocycloalkyl, 3- to 10-membered heterocycloalkyl, G-Goaryl. or 5- to 10-membered heteroaryl; wherein each C3-Gocycloalkyl, 3- to 10-membered heterocycloalkyl, Ce-Goaryl, or 5- to 10-membered heteroaryl is optionally substituted with 1, 2, or 3 R9;
R7a is hydrogen, halogen, Ci-C4alkyl, or Ci-Cthaloalkyl;
R715 is hydrogen, halogen, Ci-C4alkyl, or Ci-C4haloalkyl;
R8 is Z, G-Galkyl. (Ci-C6alkylene)-Z, (Ci-C6heteroalkylene)-Z, (C2-Galkenylene)-Z, CH(Z)2, CH2CH(Z)2, CH(G-Galkyl)Z. or C(0)Z; wherein each alkyl, alkylene, heteroalkylene, or alkenylene is optionally substituted with 1, 2, or 3 R9;
Z is C3-Gocycloalkyl, 3- to 10-membered heterocycloalkyl, Ce-Goaryl, 5- to 10-membered heteroaryl; wherein each C3-Gocycloalkyl, 3- to 10-membered heterocycloalkyl, Ce-Goaryl, 5- to 10-membered heteroaryl is optionally substituted with 1, 2, or 3 R9; each R9 is independently halogen, Ci-C4alkyl, C2-Galkenyl, C2-Galkynyl, Ci-C4haloalkyl, Ci- C4alkoxy, Ci-C4haloalkoxy, Ci-C4heteroalkyl, -C(0)H, -C(0)0H, -CN, C3-Ciocycloalkyl, 3- to 10-membered heterocycloalkyl, Ce-Goaryl, 5- to 10-membered heteroaryl, -C(0)(Ci- C4alkyl), -C(0)0(Ci-C4alkyl), -C(0)NH2, -C(0)NH(Ci-C4alkyl), -C(0)N(Ci-C4alkyl)2, -NH2, -NH(Ci-C4alkyl), -N(Ci-C4alkyl)2, -NH(C2-C4alkylene)-OH, -NH(C2-Galkylene)-0-(Ci- C4alkyl), -OH, -0(Ci-C4alkyl), -0(Ci-C4haloalkyl), -0(C2-Galkylene)-NH2, -0(C2- C4alkylene)-NH-(Ci-C4alkyl), -0(C2-Galkylene)-N-(Ci-C4alkyl)2, -0(Ci-C4alkylene)- C(0)0H, -0(Ci-C4alkylene)-C(0)0-(Ci-C4alkyl), -0(C2-Galkenyl), -0(Ci-C4alkylene)-(C6- Cioaryl), -0(Ci-C4alkylene)-(5- to 10-membered heteroaryl), -O(Ce-Cioaryl), -SH, S(0)20H, - S(0)2(Ci-C4alkyl), -S(0)2NH2, -S(0)2NH(Ci-C4alkyl), or -S(0)2N(Ci-C4alkyl)2; or two R9 together with the atoms to which they are attached form a C3-Gocycloalkyl or a 3- to 10- membered heterocycloalkyl ring.
[0007] In another aspect, provided herein are compounds having the structure of Formula (C-I), or a pharmaceutically acceptable salt, /V-oxide, solvate, diastereomeric mixture, or individual enantiomers, or stereoisomer thereof:
Figure imgf000009_0001
Formula (C-I) wherein,
R1 is hydrogen, G-Galkyl. G-Gcycloalkyl. Ci-Cealkyl-iG-Cecycloalkyl), Ci-Cealkyl-(phenyl), or G-Galkyl-(5- to 6-membered heteroaryl); wherein the Ci-G, alkyl. G-Gcycloalkyl. phenyl, or 5- to 6-membered heteroaryl is optionally substituted with 1, 2, or 3 R9;
X is NRA, O, S, S(O), or S(0)2;
RA is hydrogen, Ci-C6alkyl, C(0)-(Ci-C6alkyl), C(0)-(G-C6cycloalkyl), C(0)-(phenyl), or C(O)- (5- to 6-membered heteroaryl); wherein each G-Galkyl. G-Gcycloalkyl. phenyl, or 5- to 6- membered heteroaryl is optionally substituted with 1, 2, or 3 R9; or X is C and taken together with R2a, R2b, and the carbon atom to which they are attached, forms a phenyl or 5- to 10-membered heteroaryl ring, optionally substituted with 1, 2, or 3 R9;
R2a, R2b, R3a, and R3b are each independently hydrogen, G-Galkyl. G-Ghaloalkyl. Ci-Ce alkoxy, Ci-Ceheteroalkyl, G-Galkcnyl. G-Galkynyl. C3-Ciocycloalkyl, 3- to 10-membered heterocycloalkyl, G-Goaryl. or 5- to 10-membered heteroaryl; wherein each G-Galkyl. Ci- Cehaloalkyl, Ci-Ce alkoxy, Ci-Ceheteroalkyl, G-Galkenyl, or G-Galkynyl is optionally substituted with 1 or 2 G-Ciocycloalkyl, 3- to 10-membered heterocycloalkyl, G-Goaryl. or 5- to 10-membered heteroaryl rings; wherein each G-Galkyl. G-Ghaloalkyl. G-G alkoxy. G-Gheteroalkyl. G-Galkcnyl. G-Galkynyl. C3-Ciocycloalkyl, 3- to 10-membered heterocycloalkyl, Ce-Cioaryl, or 5- to 10-membered heteroaryl is optionally substituted with 1, 2, or 3 R9; or R2a and R2b together with the carbon atom to which they are attached form a carbonyl; or R2a and R3a, and optionally R2b and R3b, together with the carbon atoms to which they are attached form a G-Gcycloalkyl. 5- to 10-membered heterocycloalkyl, G-Goaryl. or 5- to 10- membered heteroaryl ring; wherein each G-Gcycloalkyl. 5- to 10-membered heterocycloalkyl, G-Goaryl. or 5- to 10-membered heteroaryl ring is optionally substituted with 1, 2, or 3 R9;
R4aand R4b are each independently hydrogen, halogen, G-Galkyl. G-Ghaloalkyl. G-G alkoxy. G-Gheteroalkyl. G-Galkenyl. G-Galkynyl. G-Ciocycloalkyl, 3- to 10-membered heterocycloalkyl, G-Goaryl. or 5- to 10-membered heteroaryl; wherein each G-Galkyl. Ci- Ghaloalkyl, C i -Co alkoxy, G-Gheteroalkyl. G-Galkenyl. or G-Galkynyl is optionally substituted with 1 or 2 C3-Ciocycloalkyl, 3- to 10-membered heterocycloalkyl, Ce-Goaryl, or 5- to 10-membered heteroaryl; wherein each Ci-G, alkyl. Ci-G,haloalkyl. G-G> alkoxy. Ci- Ceheteroalkyl, G-G, alkenyl. G-Galkynyl. C3-Gocycloalkyl, 3- to 10-membered heterocycloalkyl, Ce-Goaryl, or 5- to 10-membered heteroaryl is optionally substituted with 1, 2, or 3 R9; or R4a and R4b together with the carbon atom to which they are attached form a carbonyl; or R4a and R4b together with the carbon atom to which they are attached form a C3-Gocycloalkyl or 3- to 10-membered heterocycloalkyl ring; wherein the C3-Gocycloalkyl or 3- to 10- membered heterocycloalkyl ring is optionally substituted with 1, 2, or 3 R9;
R5 is NHR8,NHS(0)2R8, OR8, SR8, S(0)2R8, or S(0)2NHR8; or R5, R4a, and R4b, together with the carbon atom to which they are attached, form a G-Goaryl or 5- to 10-membered heteroaryl ring; wherein the G-Goaryl or 5- to 10-membered heteroaryl ring is optionally substituted with 1, 2, or 3 R9;
R6a is hydrogen, halogen, -U, or -G;
R6b is halogen, -U, or -G;
-U is G-G, alkyl. G-Ghaloalkyl. G-G, alkoxy. G-G, heteroalkyl. G-G, alkenyl. or G-Galkynyl: wherein each G-G, alkyl. Ci-Cehaloalkyl, G-G, alkoxy. Ci-Ceheteroalkyl, G-G, alkenyl. or G-Galkynyl is optionally substituted with 1, 2, or 3 R9 and/or 1 or 2 -G;
-G is C3-Gocycloalkyl, 3- to 10-membered heterocycloalkyl, Ce-Goaryl, or 5- to 10-membered heteroaryl; wherein each C3-Gocycloalkyl, 3- to 10-membered heterocycloalkyl, Ce-Goaryl, or 5- to 10-membered heteroaryl is optionally substituted with 1, 2, or 3 R9; or R6a and R6b together with the carbon atom to which they are attached form a saturated or partially saturated 3- to 7-membered cycloalkyl or a saturated or partially saturated 3- to 7- membered heterocycloalkyl; wherein the cycloalkyl or heterocycloalkyl is optionally substituted with 1, 2, or 3 R9;
R7a is hydrogen, halogen, Ci-C4alkyl, or Ci-C haloalkyl;
R715 is hydrogen, halogen, Ci-C4alkyl, or Ci-C4haloalkyl; or R7a and R7b together with the carbon atom to which they are attached form a saturated or partially saturated 3- to 7-membered cycloalkyl or a saturated or partially saturated 3- to 7- membered heterocycloalkyl; wherein the cycloalkyl or heterocycloalkyl is optionally substituted with 1, 2, or 3 R9; or R6b and R7*’ together with the carbon atoms to which they are attached form a C3-Gocycloalkyl or 3- to 10-membered heterocycloalkyl ring; wherein each C3-Gocycloalkyl or 3- to 10- membered heterocycloalkyl ring is optionally substituted with 1, 2, or 3 R9; or R6a, R6b, R7a, and R7b together with the carbon atoms to which they are attached form a 5 - to 10- membered heteroaryl ring optionally substituted with 1, 2, or 3 R9; R8 is Z, C -G, alkyl. (G-Galkylcnc)-Z. (G-Gheteroalkylene)-Z, (G-Galkcnylcnc)-Z. CH(Z)2, CH2CH(Z)2, CH(G-Galkyl)Z. or C(0)Z; wherein each alkyl, alkylene, heteroalkylene, or alkenylene is optionally substituted with 1, 2, or 3 R9;
Z is C3-C9cycloalkyl, 3- to 10-membered heterocycloalkyl, G-Goaryl, 5- to 10-membered heteroaryl; wherein each G-Gcycloalkyl, 3- to 10-membered heterocycloalkyl, G,-Cioaryl. 5- to 10-membered heteroaryl is optionally substituted with 1, 2, or 3 R9; or Z is a substituted Gocycloalkyl substituted with 1, 2, or 3 R9; and each R9 is independently halogen, G-Galkyl, G-Galkenyl, G-Galkynyl, Ci-C4haloalkyl, G- C4alkoxy, G-Ghaloalkoxy, Ci-C4heteroalkyl, -C(0)H, -C(0)0H, -CN, G-Gocycloalkyl, 3- to 10-membered heterocycloalkyl, G-Goaryl, 5- to 10-membered heteroaryl, -C(0)(G- C4alkyl), -C(0)0(Ci-Galkyl), -C(0)NH2, -C(0)NH(Ci-Galkyl), -C(0)N(Ci-C4alkyl)2, -NH2, -NH(Ci-C4alkyl), -N(G-Galkyl)2, -NH(C2-C4alkylene)-OH, -NH(G-Galkylene)-0-(G- C4alkyl), -OH, -O(G-Galkyl), -O(Ci-Ghaloalkyl), -0(C2-C4alkylene)-NH2, -0(G- C4alkylene)-NH-(Ci-C4alkyl), -0(G-Galkylene)-N-(G-Galkyl)2, -O(G-Galkylene)- C(0)0H, -0(Ci-C4alkylene)-C(0)0-(Ci-Galkyl), -O(G-Galkenyl), -0(G-Galkylene)-(G- Cioaryl), -0(Ci-C4alkylene)-(5- to 10-membered heteroaryl), -O(G-Goaryl), -SH, S(0)20H, - S(0)2(Ci-Galkyl), -S(0)2NH2, -S(0)2NH(Ci-Galkyl), or -S(0)2N(Ci-Galkyl)2; or two R9 together with the atoms to which they are attached form a G-Gocycloalkyl or a 3- to 10- membered heterocycloalkyl ring.
BRIEF DESCRIPTION OF THE DRAWINGS [0008] FIG. 1 illustrates the sensitizing effect of a selective ML-IAP antagonist (Compound A) on lung cancer cells.
[0009] FIG. 2 illustrates the effects of gene ablation on cancer cell viability.
[0010] FIG. 3 illustrates IAP antagonists effect on reversing HIV-1 latency.
DETAILED DESCRIPTION OF THE INVENTION [0011] Provided herein are compounds of utility in the treatment of cancer, among other medical conditions. Compounds of the present disclosure may be, in many cases, potent, selective antagonists of melanoma inhibitor of apoptosis protein (ML-IAP). As discussed herein, ML-IAP is a viable therapeutic target for treating conditions such as lung cancer. To date, studies of ML-IAP have primarily utilized genetic silencing or knock-down mutants in order to study the effects of this protein on cancer progression. The current lack of selective antagonists of ML-IAP has stifled the ability to research and treat conditions wherein ML-IAP is overexpressed or hyperactive, such as may be the case in many cancers. By advancing the development of selective ML-IAP antagonists such as those disclosed herein, the survival of cancer patients including lung cancer patients will be increased. [0012] Cancer is a persistent and growing cause of death throughout the world. Based on the GLOBOCAN 2012 estimates, about 14.1 million cancer cases and 8.2 million cancer deaths are estimated to have occurred in 2012 worldwide. Lung cancer has the highest incidence rate of all cancers and is the leading cause of cancer-induced mortality in all populations worldwide. With a mortality rate of more than double that of any other cancer lung cancer is among the deadliest cancers. [0013] Apoptosis, a form of programmed cell death, is often dysregulated in malignant cells, and the evasion of apoptosis is a hallmark of cancer. As cancer cells divide and proliferate, normal control of cell death is impaired and tumor formation occurs. Disruption of normal cell death processes is a hallmark of cancer leading to escape of tumorigenic cells from apoptotic stimuli as well as substantially increased resistance to chemotherapies and radiation therapies. Cancer cells often display aberrant upregulation of pathways which inhibit apoptosis, allowing the cancer cells to proliferate. One such pathway which is upregulated in cancer cells is the inhibitor of apoptosis (IAP) pathway.
[0014] The IAP protein family is involved in blocking and attenuating programmed cell death pathways, predominantly through modulation of the caspase cascade. The members of the IAP family are functionally and structurally related proteins that inhibit apoptosis. Proteins are ascribed to the IAP family if they possess a Baculovirus Inhibitor of apoptosis protein Repeat (BIR) domain. IAPs have been identified as potential therapeutic targets for the treatment of cancer. One member of the IAP family, ML-IAP, stands out as a particularly viable target. This is supported by studies on ML- IAP’s function within the apoptotic signaling network as well as its role as a biomarker for disease prognosis. Furthermore, ML-IAP has been identified as an attractive target in lung cancer. Inhibition of ML-IAP in this malignancy leads to a substantial reduction in tumor growth as well as sensitization to traditional standard of care (SOC) therapies.
[0015] ML-IAP is upregulated in various cancers and is believed to underlie the resistance of many malignant cells to chemotherapeutics. Ablation or antagonism of ML-IAP is therefore an attractive therapeutic strategy for the treatment of cancer. In certain instances, novel, selective ML-IAP antagonists as disclosed herein may be particularly advantageous in the treatment of treatment- resistant cancers.
[0016] ML-IAP, also known as Livin or KIAP, was first identified as a member of the IAP protein family due to its single BIR domain. The ML-IAP BIR domain is also responsible for apoptosis inhibition, and small molecule antagonists have significant potential for development as therapeutic agents. The RING domain of ML-IAP has been shown to function as an E3 ligase, facilitating the ubiquitination and subsequent degradation of itself and, more importantly, the natural caspase antagonist that modulates apoptotic signaling - the second mitochondria-derived activator of caspases (SMAC). SMAC is a mitochondrial protein that negatively regulates apoptosis, also known as programmed cell death. When a cell is primed for apoptosis by the final execution step of caspase activation, SMAC binds to IAPs, preventing IAPs from binding to and deactivating caspases. Thus, SMAC promotes apoptosis by activating caspases.
[0017] Thus, inhibition of ML-IAP leads to a direct increase of SMAC and a re -sensitization of cells to apoptotic stimuli. Importantly, both protein and mRNA levels of ML-IAP are low to undetectable in most adult tissues but are highly expressed in a number of cancers such as melanoma and lung cancer. ML-IAP maps to chromosome 20ql3, a region frequently implicated in the mutagenic etiology of lung cancers. ML-IAP levels have been shown to be highly relevant as a prognostic biomarker in lung cancer and other cancers. As expected, high ML-IAP expression results in a poor outcome whilst lower levels are more favorable. There exists considerable therapeutic potential of ML-IAP inhibition to treat cancer. A wealth of data has been reported in cellular contexts as well as xenograft studies. In some instances, gene ablation of ML-IAP in a xenograft model of lung cancer results in substantial benefit. However, study of the effect of ML-IAP and its blockade has been limited by the absence of safe, selective, and efficacious antagonists of ML-IAP.
[0018] Alterations in IAP proteins are found in many types of human cancer and are associated with chemoresistance, disease progression and poor prognosis. When the IAP pathway is upregulated, the IAP proteins bind to and prevent initiator and effector caspases from cleaving downstream cellular proteins. The proteolytic action of caspases is required to allow the cell death cascade to progress normally. Accordingly, provided herein are compounds that bind and inhibit the upregulated ML-IAP. The compounds provided herein, in some embodiments, bind to ML-IAP and prevent it from suppressing caspase action, thereby allowing the cell death cascade to progress normally.
Functionally, compounds described herein are able to inhibit the action of ML-IAP, thereby inducing apoptosis in cells. In addition to facilitating or stimulating cell dead pathways through direct action, the antagonists of ML-IAP offer additional utility as adjuvant therapies in the treatment of cancer. As an example, a tumor that may otherwise avoid apoptosis in response to standard of care (SOC) chemotherapy, immunotherapy, radiation therapy, etc., will often become responsive or sensitized to those therapies following treatment with an ML-IAP antagonist. As such, these compounds may derive additional benefit from use in a combination therapy with other known cancer agents.
[0019] In some embodiments, the compounds described herein are nonpeptidic second mitochondria- derived activator of caspase (SMAC) mimetics and induce apoptosis (e.g., in cancer cells). In some embodiments, the compounds described herein are ML-IAP antagonists. In certain preferred embodiments, the compounds described herein are ML-IAP antagonists with selectivity for ML-IAP over other members of the IAP family.
[0020] Almost all studies on ML-IAP to date have been based on gene ablation studies using RNA interference, because no selective ML-IAP antagonists were available. Disclosed herein are various highly potent and selective ML-IAP antagonists. In some embodiments, selective ML-IAP antagonists are generated utilizing a rational design approach mimicking the SMAC-IAP interaction. In some embodiments disclosed herein are potent and highly selective inhibitors of ML-IAP in vitro. In some embodiments, a compound disclosed herein blocks resistance to chemotherapeutics in whole cells, halts tumor cell proliferation, and is non-toxic in normal cells.
[0021] In some embodiments, disclosed herein are treatments for lung cancer. In some embodiments, a compound, composition, or method of treatment disclosed herein facilitates a subject’s ability to overcome resistance to current first-line therapies. In some embodiments, a compound or method of treatment disclosed herein reduces the burden that chemotherapy and radiotherapy exerts on the patient by sensitizing the cancer to much lower doses of SOC therapies. In some embodiments, elevated levels of ML-IAP in bronchial aspiration and other tumor sampling methods are identified as valuable prognostic markers of disease staging and progression. In some embodiments, compounds disclosed herein are useful for the further characterization of the role of ML-IAP as a biomarker in lung cancer.
[0022] Aberrant and uncontrolled cell growth due to apoptosis suppression is a hallmark of cancer cells. Cancer cells often display aberrant upregulation of pathways which inhibit apoptosis, allowing the cancer cells to proliferate. One such pathway which is upregulated in cancer cells is the inhibitor of apoptosis (IAP) pathway. The members of the IAP family are functionally and structurally related proteins, which inhibit apoptosis. IAPs share a baculovirus IAP repeat (BIR) domain, each having one to three copies. Eight members of the IAP protein family have currently been identified, in both baculovirus and humans. Five human members of the IAP protein family include: XIAP, cIAPl (also, BIRC2), cIAP2 (also, BIRC3), NAIP, and survivin. In certain instances, XIAP inhibits apoptosis by binding to and inhibiting the activity of caspase-9, caspase-3 and caspase 7.
[0023] Alterations in IAP proteins are found in many types of human cancer and are associated with chemoresistance, disease progression and poor prognosis. When the IAP pathway is upregulated, the IAP proteins bind to and prevent initiator and effector caspases from cleaving downstream cellular proteins.
[0024] The proteolytic action of caspases is required to allow the cell death cascade to progress normally. Accordingly, provided herein are compounds that bind the upregulated IAP proteins. The compounds provided herein, in some embodiments, bind to IAP proteins and prevent them from suppressing caspase action, thereby allowing the cell death cascade to progress normally. In other words, provided herein are compounds that inhibit the action of IAP proteins, thereby inducing apoptosis in cells.
[0025] One protein implicated in binding with IAPs is SMAC. SMAC is a mitochondrial protein that negatively regulates apoptosis, also known as programmed cell death. When a cell is primed for apoptosis by the final execution step of caspase activation, SMAC binds to IAP, which prevents IAP from binding to, and deactivating caspases. Thus, SMAC promotes apoptosis by activating caspases. [0026] In some embodiments, the compounds described herein are nonpeptidic second mitochondria- derived activator of caspase (SMAC) mimetics and induce apoptosis (e.g., in cancer cells). In some embodiments, the compounds described herein are IAP antagonists.
[0027] In certain instances, IAP proteins not only regulate caspases and apoptosis, but also modulate inflammatory signaling and immunity, mitogenic kinase signaling, proliferation and mitosis, as well as cell invasion and metastasis. Inhibitor of apoptosis (IAP) proteins have emerged as regulators of innate immune signaling downstream of Pattern Recognition Receptors (PRRs) such as Toll-like receptor 4 (TLR4), Nucleotide-Binding Oligomerization Domain 1 (NODI) and NOD2 receptors, and Retinoic Acid-Inducible Gene (RIG)-I Receptor. In certain instances, Cellular Inhibitor of Apoptosis Protein- 1 (cIAPl; also Baculoviral IAP Repeat Containing 2 or BIRC2), Cellular Inhibitor of Apoptosis Protein-2 (cIAP2; also, Baculoviral IAP Repeat Containing 3 or BIRC3), and X-linked Inhibitor of Apoptosis (XIAP) facilitate ubiquitin -dependent signaling activated by these PRRs and mediate activation of nuclear factor-kappa B (NF-KB) transcription factors as well as the MAP kinases p38 and JNK. Accordingly, the compounds described herein are also useful in the treatment of non-neoplastic diseases and/or inflammatory diseases and/or autoimmune diseases.
[0028] Recent advances in combinatorial antiretroviral therapy (ART) have allowed individuals infected with human immunodeficiency virus (HIV) to live long and otherwise normal lives.
However, antiretroviral therapy only targets actively replicating HIV and not the dormant, replication competent HIV that resides in certain types of cells. These dormant HIV viruses can reactivate and trigger new rounds of viral replication upon discontinuation of antiretroviral therapy. In addition to targeting actively replicating HIV, a strategy for improving HIV treatment is to also target the dormant, replication competent HIV virus residing in latently infected cells, which are cells that are infected with HIV but are not actively producing HIV. These latently infected cells are not undergoing active virus replication and the viral genome has been integrated into the host DNA in such a manner that the virus DNA is indistinguishable from the host’s DNA. Latently infected cells are not recognized by the immune system and are not susceptible to antiretroviral therapy (ART).
Thus, the dormant virus and latently infected cells can remain hidden and persist indefinitely. One approach for targeting latently infected cells is to develop new therapeutic agents or drugs that can reverse latency in infected cells by inducing active HIV replication. Once the dormant HIV virus is “awakened”, the infected cells become susceptible to immune system clearance or the effects of additional treatments such as killer agents to eliminate infected cells. Concurrent treatment with antiretroviral drugs will prevent the spread of the reactivated virus and suppress new rounds of HIV infection. The combination of therapeutic agents that can reverse the latency of HIV-infected cells and drugs to eradicate the awakened HIV virus is termed the “shock and kill” or “kick and kill” approach. IAP inhibition has been implicated in the reversal of HIV latency. The IAP antagonists may be used alone or in combination with other therapeutic agents, such as those that are used to treat HIV. In some embodiments, other therapeutic agents that could be used in combination with IAP antagonists include therapeutic agents that activate HIV transcription in latently infected cells, therapeutic agents that inhibit active HIV replication, or any combination thereof. In some embodiments, the additional therapeutic agents that inhibit active HIV replication include antiretroviral therapy drugs. In some embodiments, the pharmaceutical compositions are described comprising IAP antagonists, alone or in combination with one or more additional therapeutics agents that are useful for the treatment of HIV in a mammal. In some embodiments, the mammal is a human.
Definitions
[0029] As used herein and in the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “an agent” includes a plurality of such agents, and reference to “the cell” includes reference to one or more cells (or to a plurality of cells) and equivalents thereof known to those skilled in the art, and so forth. When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulae, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included. The term “about” when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range, in some instances, will vary between 1% and 15% of the stated number or numerical range.
The term “comprising” (and related terms such as “comprise” or “comprises” or “having” or “including”) is not intended to exclude that in other certain embodiments, for example, an embodiment of any composition of matter, composition, method, or process, or the like, described herein, “consist of’ or “consist essentially of’ the described features.
[0030] As used in the specification and appended claims, unless specified to the contrary, the following terms have the meaning indicated below.
[0031] “Oxo” refers to =0.
[0032] “Alkyl” refers to an optionally substituted straight-chain, or optionally substituted branched- chain saturated hydrocarbon monoradical having from one to about ten carbon atoms, or from 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-l-butyl, 2-ethyl- 1 -butyl, n- butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl and hexyl, and longer alkyl groups, such as heptyl, octyl, and the like. Whenever it appears herein, a numerical range such as “Ci- G, alkyl” means that the alkyl group consists 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. In some embodiments, the alkyl is a Ci-Cio alkyl, a C1-C9 alkyl, a Ci-Cs alkyl, a C1-C7 alkyl, a C 1 -G, alkyl, a C1-C5 alkyl, a C1-C4 alkyl, a C1-C3 alkyl, a C1-C2 alkyl, or a Ci alkyl. Unless stated otherwise specifically in the specification, an alkyl group is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkyl is optionally substituted with oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2, or - NO2. In some embodiments, the alkyl is optionally substituted with oxo, halogen, -CN, -CF3, -OH, or -OMe. In some embodiments, the alkyl is optionally substituted with halogen.
[0033] “Alkenyl” refers to an optionally substituted straight-chain, or optionally substituted 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. The group may be in either the cis or trans conformation about the double bond(s), and should be understood to include both isomers. Examples include, but are not limited to, ethenyl (-CH=CH2), 1- propenyl (-CH2CH=CH2), isopropenyl [-C(CH3)=CH2], butenyl, 1,3-butadienyl and the like. Whenever it appears herein, a numerical range such as “C2-C6 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. In some embodiments, the alkenyl is a C2-C10 alkenyl, a C2-C9 alkenyl, a C2-C8 alkenyl, a C2-C7 alkenyl, a C2-C6 alkenyl, a C2-C5 alkenyl, a C2-C4 alkenyl, a C2-C3 alkenyl, or a C2 alkenyl. Unless stated otherwise specifically in the specification, an alkenyl group is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an alkenyl is optionally substituted with oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, an alkenyl is optionally substituted with oxo, halogen, -CN, -CF3, -OH, or -OMe. In some embodiments, the alkenyl is optionally substituted with halogen.
[0034] “Alkynyl” refers to an optionally substituted straight-chain or optionally substituted 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. Whenever it appears herein, a numerical range such as “C2-C6 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. In some embodiments, the alkynyl is a C2-C10 alkynyl, a C2-C9 alkynyl, a C2-C8 alkynyl, a C2-C7 alkynyl, a C2-C6 alkynyl, a C2-C5 alkynyl, a C2-C4 alkynyl, a C2-C3 alkynyl, or a C2 alkynyl. Unless stated otherwise specifically in the specification, an alkynyl group is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an alkynyl is optionally substituted with oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, an alkynyl is optionally substituted with oxo, halogen, -CN, -CF3, -OH, or -OMe. In some embodiments, the alkynyl is optionally substituted with halogen.
[0035] “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, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an alkylene is optionally substituted with oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, an alkylene is optionally substituted with oxo, halogen, -CN, -CF3, -OH, or -OMe. In some embodiments, the alkylene is optionally substituted with halogen.
[0036] “Alkoxy” refers to a radical of the formula -ORa where Ra 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, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an alkoxy is optionally substituted with oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, an alkoxy is optionally substituted with oxo, halogen, -CN, -CF3, -OH, or -OMe. In some embodiments, the alkoxy is optionally substituted with halogen.
[0037] “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. Hydroxyalkyl include, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the hydroxyalkyl is aminomethyl.
[0038] “Aryl” refers to a radical derived from a hydrocarbon ring system comprising hydrogen, 6 to 30 carbon atoms and at least one aromatic ring. 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. In some embodiments, the aryl is a 6- to 10-membered aryl. In some embodiments, the aryl is a 6- membered aryl. 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. In some embodiments, the aryl is phenyl. Unless stated otherwise specifically in the specification, an aryl may be optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, an aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the aryl is optionally substituted with halogen. [0039] “Cycloalkyl” refers to a stable, 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) or bridged ring systems. Representative cycloalkyls include, but are not limited to, cycloalkyls having from three to fifteen carbon atoms (C3- Ci5 cycloalkyl), from three to ten carbon atoms (C3-C10 cycloalkyl), from three to eight carbon atoms (C3-C8 cycloalkyl), from three to six carbon atoms (C3-C6 cycloalkyl), from three to five carbon atoms (C3-C5 cycloalkyl), or three to four carbon atoms (C3-C4 cycloalkyl). In some embodiments, the cycloalkyl is a 3 - to 6-membered cycloalkyl. In some embodiments, the cycloalkyl is a 5 - to 6- membered cycloalkyl. Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyls or carbocycles include, for example, adamantyl, norbomyl, 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. Some examples of partially saturated bicyclic cycloalkyls include, by way of non limiting example, include tetrahydronaphthalene, dihydronaphthalene, indane, indene, and dihydroanthracene. Unless stated otherwise specifically in the specification, a cycloalkyl is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, - CN, -CF3, -OH, or -OMe. In some embodiments, the cycloalkyl is optionally substituted with halogen. [0040] “Deuteroalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more deuterium atoms. In some embodiments, the alkyl is substituted with one deuterium atom. In some embodiments, the alkyl is substituted with one, two, or three deuterium atoms. In some embodiments, the alkyl is substituted with one, two, three, four, five, or six deuterium atoms. Deuteroalkyl includes, for example, CD3, CH2D, CHD2, CH2CD3, CD2CD3, CHDCD3, CH2CH2D, or CH2CHD2. In some embodiments, the deuteroalkyl is CD3.
[0041] “Haloalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more halogen atoms. In some embodiments, the alkyl is substituted with one, two, or three halogen atoms. In some embodiments, the alkyl is substituted with one, two, three, four, five, or six halogen halogens. Haloalkyl includes, for example, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like. In some embodiments, the haloalkyl is trifluoromethyl.
[0042] “Halo” or “halogen” refers to bromo, chloro, fluoro or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro. [0043] “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, or combinations thereof. In some instances, a heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. In one aspect, a heteroalkyl is a C i-G, heteroalkyl wherein the heteroalkyl is comprised of 1 to 5 carbon atoms and one or more atoms other than carbon, e.g., oxygen, nitrogen, sulfur, or combinations thereof. In some instances, a carbon atom or heteroatom is optionally oxidized (e.g, -C(0)0CH2-, -CH2S(0)2NHCH2-, -NHC(0)NHCH2, -CH2NHC(0)CH2). Further examples of such heteroalkyl are, for example, -CFhOCFF, -CFhCFhOCFF, - CH2CH2OCH2CH2OCH3, or -Gr[(G¾)OG¾. Unless stated otherwise specifically in the specification, 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.
In some embodiments, a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, - CF3, -OH, -OMe, -NH2, or -N02. In some embodiments, a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroalkyl is optionally substituted with halogen.
[0044] “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.
[0045] “Heterocycloalkyl” refers to a stable 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 and sulfur. In some embodiments, the heterocycloalkyl comprises 1 or 2 heteroatoms selected from nitrogen and oxygen. Unless stated otherwise specifically in the specification, 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) 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 quatemized. Representative heterocycloalkyls include, but are not limited to, heterocycloalkyls having from two to fifteen carbon atoms (C2-Ci5 heterocycloalkyl), from two to ten carbon atoms (C2-Cio heterocycloalkyl), from two to eight carbon atoms (G-G heterocycloalkyl), from two to six carbon atoms (C2-G, heterocycloalkyl), from two to five carbon atoms (G-G heterocycloalkyl), or two to four carbon atoms (G-G heterocycloalkyl). In some embodiments, the heterocycloalkyl is a 3 - to 6-membered heterocycloalkyl. In some embodiments, the cycloalkyl is a 5- to 6-membered heterocycloalkyl. Examples of such heterocycloalkyl radicals include, but are not limited to, aziridinyl, azetidinyl, dioxolanyl, thienyl[l,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, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, 1,3-dihydroisobenzofuran-l-yl, 3 -oxo- 1,3- dihydroisobenzofuran-l-yl, methyl-2-oxo-l,3-dioxol-4-yl, and 2-oxo-l,3-dioxol-4-yl. The term heterocycloalkyl also includes all ring forms of the carbohydrates, including but not limited to, the monosaccharides, the disaccharides and the oligosaccharides. 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). Unless stated otherwise specifically in the specification, a heterocycloalkyl is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, a heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, a heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, - CF3, -OH, or -OMe. In some embodiments, the heterocycloalkyl is optionally substituted with halogen.
[0046] “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, or combinations thereof. A heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. In one aspect, a heteroalkyl is a C i-G, heteroalkyl. Unless stated otherwise specifically in the specification, 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. In some embodiments, a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroalkyl is optionally substituted with halogen.
[0047] “Heteroaryl” refers to a 5- to 14-membered ring system radical comprising hydrogen atoms, 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 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 quatemized. In some embodiments, the heteroaryl is a 5 - to 10-membered heteroaryl. In some embodiments, the heteroaryl is a 5 - to 6- membered heteroaryl. Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][l,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[l,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1 -phenyl- lH-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless stated otherwise specifically in the specification, a heteroaryl is optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, a heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, a heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroaryl is optionally substituted with halogen.
[0048] An “effective amount” or “therapeutically effective amount” refers to an amount of a compound administered to a subject (e.g. a mammal, such as a human), either as a single dose or as part of a series of doses, which is effective to produce a desired therapeutic effect.
[0049] “Therapy” may include any medical intervention to cure, remedy, treat, reverse, halt, delay, or otherwise modulate the effects of a disease or condition. Examples of therapies, by way of non limiting example, include surgery, radiation, chemotherapy, immunotherapy, blood transfusion, tissue or organ grafting, transplantation. Therapies may comprise small molecules, peptides, peptidomimetics, macromolecules, antibodies, proteins, genetic material (e.g., DNA, RNA, or fragments thereof). Therapies may treat side-effects of a disease or condition, such as inflammation, pain, infection, weight loss/weight gain, depression, anxiety, loss of appetite, sleep loss, nausea, etc. Therapies may be prophylactic, i.e. therapies that prevent, anticipate, slow, or delay the onset of a disease or condition.
[0050] “Treatment” of a subject (e.g. a mammal, such as a human) includes any type of intervention used in an attempt to alter the natural course of the subject. In some embodiments, treatment includes administration of a pharmaceutical composition, subsequent to the initiation of a pathologic event or contact with an etiologic agent and includes stabilization of the condition (e.g., condition does not worsen, e.g., cancer does not metastasize and the like) or alleviation of the condition (e.g., reduction in tumor size, remission of cancer, absence of symptoms of autoimmune disease and the like). In other embodiments, treatment also includes prophylactic treatment (e.g., administration of a composition described herein when an individual is suspected to be suffering from a condition described herein). [0051] As used herein, “subject”, “individual” and “patient” are used interchangeably. None of the terms imply that a medical professional is required for the administration of the compounds disclosed herein.
ML-IAP Antagonists
[0052] In some embodiments, a compound disclosed herein binds to ML-IAP and modulates its function. In some embodiments, the ML-IAP modulator is an inhibitor. In some embodiments, an inhibitor is an antagonist (e.g., a partial antagonist, a full antagonist, an inverse agonist). In some embodiments, the modulator binds at the BIR domain and inhibits SMAC binding. In some embodiments, the modulator binds to an allosteric site. In some embodiments, the modulator interferes with, blocks, prevents, or reduces a protein-protein interaction. In some embodiments, the modulator interferes with, blocks, prevents, or reduces a ligand (e.g., a peptide) from binding. In some embodiments, a ML-IAP antagonist inhibits the ability of SMAC or a fragment thereof from binding to ML-IAP. In some embodiments, the ML-IAP antagonist inhibits a peptide (e.g., SMAC) from binding to a BIR domain. In some embodiments, a compound disclosed herein occupies a ML-IAP BIR domain. In some embodiments, a compound disclosed herein is highly selective for ML-IAP over other IAPs and/or other BIR domains (e.g, XIAP BIR1/2, XIAP BIR3, cIAPl BIR2, cIAPl BIR3, cIAP2 BIR2, cIAP2 BIR3). In some embodiments, a compound disclosed herein is 10-fold selective for ML-IAP BIR over another BIR domain. In some embodiments, a compound disclosed herein is 10-fold selective for ML-IAP over all other BIR domains. In some embodiments, a compound disclosed herein exhibits selectivity for ML-IAP BIR over other BIR domains with a selectivity ratio of 2, 5, 10, 20, 50, 100, 1000, or more.
[0053] In some embodiments, the ML-IAP antagonist mimics certain features of an endogenous peptide or protein. In some embodiments, the ML-IAP antagonist is conformationally constrained. [0054] In some embodiments, selectivity for ML-IAP over another IAP (e.g., XIAP) results in enhanced anti -cancer effects. In some embodiments, selectivity for ML-IAP over another IAP (e.g., XIAP) results in enhanced effects against lung cancers. In some embodiments, selectivity for ML-IAP over another IAP (e.g., XIAP) results in enhanced induction of cell death in certain cancer cell lines.
In some embodiments, ML-IAP selectivity over another IAP (e.g., XIAP) is 50-fold or greater. In some embodiments, ML-IAP selectivity results in an enhanced safety profde (e.g., reduced risk or severity of complications resulting from treatment). In some embodiments, a compound or composition as described herein is synergistic with another form of cancer therapy. In some embodiments, ML-IAP inhibition decreases the effective dose (e.g., EC50, IC50, ED50) needed for another form of therapy to exert anti -cancer effects. In some embodiments, ML-IAP inhibition slows, delays, or reverses tumor development. In some embodiments, the therapeutic window is increased compared to treatment in the absence of an ML-IAP antagonist. In some embodiments, a previously untreatable tumor becomes responsive to SOC therapy. Compounds
[0055] Some embodiments of the present disclosure relate to compounds or pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, having the structure of Formula (A-I):
Figure imgf000024_0001
wherein,
R1 is hydrogen, CrG, alkyl. G-Gcycloalkyl. G-Galkyl-(G-Gcycloalkyl), G-Galkyl-(phenyl), or G-Galkyl-(5- to 6-membered heteroaryl); wherein the G-Galkyl. G-Gcycloalkyl. phenyl, or 5- to 6-membered heteroaryl is optionally substituted with 1, 2, or 3 R9;
X is NRA, O, S, S(O), or S(0)2;
RA is hydrogen, G-Galkyl, C(0)-(G-Galkyl), C(0)-(G-Gcyeloalkyl), C(0)-(phenyl), or C(0)-(5- to 6-membered heteroaryl); wherein each G-Galkyl. G-Gcycloalkyl. phenyl, or 5- to 6- membered heteroaryl is optionally substituted with 1, 2, or 3 R9; or X is C and taken together with R2a, R2b, and the carbon atom to which they are attached, forms a phenyl or 5- to 10-membered heteroaryl ring, optionally substituted with 1, 2, or 3 R9;
R2a, R2b, R3a, and R3b are each independently hydrogen, G-Galkyl. G-Ghaloalkyl. G-G alkoxy, G- Gheteroalkyl, G-Galkcnyl. G-Galkynyl. C3-Ciocycloalkyl, 3- to 10-membered heterocycloalkyl, G-Goaryl, or 5- to 10-membered heteroaryl; wherein each G-Galkyl. G- Ghaloalkyl, G-G alkoxy, G-Gheteroalkyl, G-Galkcnyl. or G-Galkynyl is optionally substituted with 1 or 2 G-Gocycloalkyl, 3- to 10-membered heterocycloalkyl, G-Goaryl. or 5- to 10-membered heteroaryl rings; wherein each G-Galkyl. G-Ghaloalkyl. G-G alkoxy. G- Gheteroalkyl, G-Galkenyl. G-Galkynyl. C3-Ciocycloalkyl, 3- to 10-membered heterocycloalkyl, G-Goaryl, or 5- to 10-membered heteroaryl is optionally substituted with 1, 2, or 3 R9; or R2a and R2b together with the carbon atom to which they are attached form a carbonyl; or R2a and R3a, and optionally R2b and R3b, together with the carbon atoms to which they are attached form a G-Gcycloalkyl. 5- to 10-membered heterocycloalkyl, G-Goaryl. or 5- to 10-membered heteroaryl ring; wherein each G-Gcycloalkyl. 5- to 10-membered heterocycloalkyl, G-Goaryl. or 5- to 10-membered heteroaryl ring is optionally substituted with 1, 2, or 3 R9; R4aand R4b are each independently hydrogen, halogen, CrG, alkyl. Ci-Cehaloalkyl, G-G, alkoxy. Ci- Ceheteroalkyl, G-G, alkenyl. G-Galkynyl. C3-Ciocycloalkyl, 3- to 10-membered heterocycloalkyl, Ce-Goaryl, or 5- to 10-membered heteroaryl; wherein each CrG, alkyl. G- Ghaloalkyl. C i -G, alkoxy, G-G, heteroalkyl. G-G, alkenyl. or G-Galkynyl is optionally substituted with 1 or 2 C3-Ciocycloalkyl, 3- to 10-membered heterocycloalkyl, G-Goaryl. or 5- to 10-membered heteroaryl; wherein each G-Galkyl. G-Ghaloalkyl. G-Ce alkoxy, G- Ceheteroalkyl, G-G, alkenyl. G-Galkynyl. C3-Ciocycloalkyl, 3- to 10-membered heterocycloalkyl, G-Goaryl. or 5- to 10-membered heteroaryl is optionally substituted with 1, 2, or 3 R9; or R4a and R4b together with the carbon atom to which they are attached form a carbonyl; or R4a and R4b together with the carbon atom to which they are attached form a G-Gocycloalkyl or 3- to 10-membered heterocycloalkyl ring; wherein the C3-Gocycloalkyl or 3- to 10-membered heterocycloalkyl ring is optionally substituted with 1, 2, or 3 R9;
R5 is NHR8,NHS(0)2R8, OR8, SR8, S(0)2R8, or S(0)2NHR8; or R5, R4a, and R4b, together with the carbon atom to which they are attached, form a G-Goaryl or 5- to 10-membered heteroaryl ring; wherein the G-Goaryl or 5- to 10-membered heteroaryl ring is optionally substituted with 1, 2, or 3 R9;
R6a is hydrogen, halogen, -U, or -G;
R6b is halogen, -U, or -G;
-U is Ci -Coalkyl. G-Ghaloalkyl, G-Galkoxy. G-Gheteroalkyl. G-Galkenyl. or G-Galkynyl: wherein each G-Galkyl. G-Ghaloalkyl. G-Galkoxy. G-Gheteroalkyl. G-Galkenyl. or G- Galkynyl is optionally substituted with 1, 2, or 3 R9 and/or 1 or 2 -G;
-G is G-Gocycloalkyl, 3- to 10-membered heterocycloalkyl, G-Goaryl. or 5- to 10-membered heteroaryl; wherein each G-Gocycloalkyl, 3- to 10-membered heterocycloalkyl, G-Goaryl. or 5- to 10-membered heteroaryl is optionally substituted with 1, 2, or 3 R9; or R6a and R6b together with the carbon atom to which they are attached form a saturated or partially saturated 3- to 7-membered cycloalkyl or a saturated or partially saturated 3- to 7-membered heterocycloalkyl; wherein the cycloalkyl or heterocycloalkyl is optionally substituted with 1, 2, or 3 R9;
R7a is hydrogen, halogen, G-Galkyl, or G-Ghaloalkyl;
R7b is hydrogen, halogen, G-Galkyl, or G-Ghaloalkyl; or R7a and R7b together with the carbon atom to which they are attached form a saturated or partially saturated 3- to 7-membered cycloalkyl or a saturated or partially saturated 3- to 7-membered heterocycloalkyl; wherein the cycloalkyl or heterocycloalkyl is optionally substituted with 1, 2, or
3 R9; or R6b and R7b together with the carbon atoms to which they are attached form a C3-Ciocycloalkyl or 3- to 10-membered heterocycloalkyl ring; wherein each C3-Ciocycloalkyl or 3- to 10-membered heterocycloalkyl ring is optionally substituted with 1, 2, or 3 R9; or R6a, R6b, R7a, and R7b together with the carbon atoms to which they are attached form a 5 - to 10- membered heteroaryl ring optionally substituted with 1, 2, or 3 R9;
R8 is Z, Cri-G, alkyl. (G-Galkylene)-Z, (G-Gheteroalkylene)-Z, (G-Galkenylene)-Z, CH(Z)2, CH2CH(Z)2, CH(G-Galkyl)Z. or C(0)Z; wherein each alkyl, alkylene, heteroalkylene, or alkenylene is optionally substituted with 1, 2, or 3 R9;
Z is G-Ciocycloalkyl, 3- to 10-membered heterocycloalkyl, G- oaryl. or 5- to 10-membered heteroaryl; wherein each G-Ciocycloalkyl, 3- to 10-membered heterocycloalkyl, G- oaryl. and 5- to 10-membered heteroaryl is optionally substituted with 1, 2, or 3 R9; each R9 is independently halogen, Ci-C4alkyl, G-C4alkenyl, G-C4alkynyl, Ci-C4haloalkyl, Ci- C4alkoxy, Ci-C4haloalkoxy, Ci-C4heteroalkyl, -C(0)H, -C(0)0H, -CN, G-Ciocycloalkyl, 3- to 10-membered heterocycloalkyl, G- oaryl. 5- to 10-membered heteroaryl, -C(0)(G-Galkyl), - C(0)0(G-Galkyl), -C(0)NH2, -C(0)NH(Ci-C4alkyl), -C(0)N(Ci-Galkyl)2, -NH2, -NH(G- C4alkyl), -N(Ci-C4alkyl)2, -NH(C2-C4alkylene)-OH, -NH(C2-C4alkylene)-0-(Ci-C4alkyl), -OH, - O(G-Galkyl), -0(Ci-C4haloalkyl), -0(C2-C4alkylene)-NH2, -0(G-Galkylene)-NH-(G-Galkyl), -0(G-Galkylene)-N-(Ci-C4alkyl)2, -0(Ci-Galkylene)-C(0)0H, -0(G-Galkylene)-C(0)0-(G- C4alkyl), -O(G-Galkenyl), -0(G-Galkylene)-(G-Goaryl), -0(Ci-Galkylene)-(5- to 10- membered heteroaryl), -O(G-Goaryl), -SH, S(0)20H, -S(0)2(Ci-C4alkyl), -S(0)2NH2, - S(0)2NH(Ci-C4alkyl), or -S(0)2N(Ci-C4alkyl)2; or two R9 together with the atoms to which they are attached form a G-Gocycloalkyl or a 3 - to 10-membered heterocycloalkyl ring; and provided that when R6a and R6b are both G¾ or when R6a and R6b together with the carbon atom to which they are attached form an unsubstituted cyclopentyl or unsubstituted cyclopentenyl, then R8
Figure imgf000026_0001
[0056] In some embodiments, R5, R4a and R4b together with the carbon atom to which they are attached form a G-Goaryl or 5- to 10-membered heteroaryl ring; wherein the G-Goaryl or 5- to 10- membered heteroaryl ring is optionally substituted with 1, 2, or 3 R9. In some embodiments, R5, R4a and R4b together with the carbon atom to which they are attached form a 5 - to 10-membered heteroaryl ring, optionally substituted with 1, 2, or 3 R9. In some embodiments, R5, R4a and R4b together with the carbon atom to which they are attached form a 9- or 10-membered heteroaryl ring, optionally substituted with 1, 2, or 3 R9. In some embodiments, R5, R4a and R4b together with the carbon atom to which they are attached form a 10-membered heteroaryl ring. In some embodiments, R5, R4a and R4b together with the carbon atom to which they are attached form a quinoline, isoquinoline, quinoxaline, quinazoline, quinolizine, naphthyridine. In some embodiments, R5, R4a and R4b together with the carbon atom to which they are attached form a 9-membered heteroaryl ring. In some embodiments, R5, R4a and R4b together with the carbon atom to which they are attached form a 2,3-dihydrobenzo[d]oxazole, benzo[d]oxazole, oxazolo[4,5-b]pyridine, lH-benzo[d]imidazole, benzo[d]thiazole, benzofuran, indole, aza-indole, lH-imidazo[4,5-b]pyridine, indolizine, imidazo[l,2- a]pyridine, or an isomer thereof, optionally substituted with 1, 2, or 3 R9. In some embodiments, R5, R4a and R4b together with the carbon atom to which they are attached form a benzo[d]oxazole, optionally substituted with 1, 2, or 3 R9. In some embodiments, the Ce-Cioaryl or 5- to 10-membered heteroaryl ring is unsubstituted.
[0057] In some embodiments, R5 is NHR8, NHS(0)2R8, OR8, SR8, S(0)2R8, or S(0)2NHR8. In some embodiments, R5 is NHR8, NHS(0)2R8, OR8, or S(0)2NHR8. In some embodiments, R5 is NHR8, NHS(0)2R8, or OR8. In some embodiments, R5 is OR8. In some embodiments, R5 is NHR8, or NHS(0)2R8. In some embodiments, R5is NHS(0)2R8. In some embodiments, R5 is NHR8.
[0058] In some embodiments of a compound of Formula (A -I), a compound has one of the following formulae:
Figure imgf000027_0001
[0059] In some embodiments of a compound of Formula (A -I), a compound has the structure of Formula (A-II):
Figure imgf000027_0002
Formula (A-II).
[0060] In some embodiments, R4a is H. In some embodiments, R4a is H and R4b is halogen or haloalkyl. In some embodiments, R4b is CHF2 or CF3. In some embodiments, R4a is H and R4b is difluoromethyl or trifluoromethyl. In some embodiments, R4b is difluoromethyl or trifluoromethyl and R5 is OR8. In some embodiments, R4a and R4b are both H.
[0061] In some embodiments, R4a and R4b together with the carbon atom to which they are attached form a C3-Ciocycloalkyl or 3- to 10-membered heterocycloalkyl ring, wherein either of the cycloalkyl or heterocycloalkyl ring is optionally substituted with 1, 2, or 3 R9. In some embodiments, R4a and R4b together with the carbon atom to which they are attached form a G-Gcycloalkyl. optionally substituted with 1, 2, or 3 R9. In some embodiments, R4a and R4b together with the carbon atom to which they are attached form a C3-C5cycloalkyl, optionally substituted with 1, 2, or 3 R9. In some embodiments, R4a and R4b together with the carbon atom to which they are attached form a cyclopropyl, cyclobutyl, or cyclopentyl ring, optionally substituted with 1, 2, or 3 R9. In some embodiments, R4a and R4b together with the carbon atom to which they are attached form a cyclopropyl, cyclobutyl, or cyclopentyl ring and R5 is -OR8 or -NHR8. In some embodiments, R4a and R4b are each independently halogen, Ci-G, alkyl. G-Ghaloalkyl. C i -G, alkoxy, or G-Gheteroalkyl and R5 is NHR8.
[0062] In some embodiments, R4a and R4b together with the carbon atom to which they are attached form a carbonyl. In some embodiments, R4a and R4b together with the carbon atom to which they are attached form a carbonyl and R5 is OR8 or NHR8. In some embodiments, R4a and R4b together with the carbon atom to which they are attached form a carbonyl and R5 is NHR8.
[0063] In some embodiments, R1 is hydrogen, G-Galkyl. G-Gcycloalkyl. G-Galkyl-(G- Gcycloalkyl). wherein each alkyl is optionally substituted with 1, 2, or 3 R9. In some embodiments, R1 is phenethyl. In some embodiments, R1 is hydrogen, methyl, trifluoromethyl, difluoromethyl, fluoromethyl, ethyl, propyl, isopropyl, cyclopropyl, methylenecyclopropyl, or cyclobutyl. In some embodiments, R1 is phenethyl. In some embodiments, R1 is hydrogen, methyl, trifluoromethyl, difluoromethyl, fluoromethyl, or ethyl. In some embodiments, R1 is hydrogen or methyl. In some embodiments, R1 is hydrogen.
[0064] In some embodiments of a compound of Formula (A-I), a compound has the structure of Formula (A-III):
Figure imgf000028_0001
Formula (A-III).
[0065] In some embodiments, R2a and R2b are each independently hydrogen, G-Galkyl. Ci- Ghaloalkyl, C i -G, alkoxy, G-Gheteroalkyl. G-Galkenyl. G-Galkynyl. wherein each alkyl, haloalkyl, alkoxy, heteroalkyl, alkenyl, or alkynyl is optionally substituted with 1, 2, or 3 R9. In some embodiments, R2a and R2b are each independently G-Gocycloalkyl, 3- to 10-membered heterocycloalkyl, G-Goaryl. or 5- to 10-membered heteroaryl, wherein each cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with 1, 2, or 3 R9. In some embodiments, R2a and R2b are each independently hydrogen, G-Galkyl. G-Ghaloalkyl. C i -G, alkoxy, G- Gheteroalkyl. wherein each alkyl, haloalkyl, alkoxy, or heteroalkyl is optionally substituted with 1 or 2 G-Gcycloalkyl. 3- to 6-membered heterocycloalkyl, phenyl, or 5- or 6-membered heteroaryl. In some embodiments, R2a is H and R2b is Ci-G, alkyl or Ci-Ceheteroalkyl, wherein each alkyl or heteroalkyl is optionally substituted with a phenyl, or 5- or 6-membered heteroaryl. In some embodiments,
Figure imgf000029_0001
some embodiments, R2a is hydrogen. In some embodiments, R2a and R2b are each hydrogen.
[0066] In some embodiments, R2a and R3a, and optionally R2b and R3b, together with the carbon atoms to which they are attached form a G-Gcycloalkyl. 5- to 10-membered heterocycloalkyl, G-Goaryl. or 5- to 10-membered heteroaryl ring; wherein each G-Gcycloalkyl. 5- to 10-membered heterocycloalkyl, G-Goaryl. or 5- to 10-membered heteroaryl ring is optionally substituted with 1, 2, or 3 R9;
[0067] In some embodiments, R2a and R2b together with the atom to which they are attached form a carbonyl. In some embodiments, R2a and R2b together with the atom to which they are attached form a carbonyl and X is NH. In some embodiments, R2a and R2b together with the atom to which they are attached form a carbonyl and X is O.
[0068] In some embodiments, R3a and R3b are each independently hydrogen, G-Galkyl. Ci- Ghaloalkyl, G-Galkoxy. G-Gheteroalkyl. G-Galkcnyl. G-Galkynyl. G-Ciocycloalkyl, 3- to 10- membered heterocycloalkyl, G-Goaryl. or 5- to 10-membered heteroaryl, any of which is optionally substituted with 1, 2, or 3 R9. In some embodiments, R3a and R3b are each independently hydrogen, G-Galkyl. G-Ghaloalkyl. C i -Co alkoxy, Ci-Cohctcroalkyl. G-Galkcnyl. or G-Galkynyl. wherein each alkyl, haloalkyl, alkoxy, heteroalkyl, alkenyl, or alkynyl is optionally substituted with a cyclopropyl, phenyl, or 5- or 6-membered heteroaryl. In some embodiments, R3a and R3b are each independently hydrogen, methyl, trifluoromethyl, difluoromethyl, ethyl, propyl, isopropyl, cyclopropyl, benzyl, phenethyl, or isobutyl. In some embodiments, R3a and R3b are each methyl. In some embodiments, R3a is hydrogen. In some embodiments, R3a and R3b are each hydrogen.
[0069] In some embodiments, R2a and R3a, together with the carbon atoms to which they are attached, form a G-Gcycloalkyl. or 5- to 10-membered heterocycloalkyl. In some embodiments, R2a and R3a, together with the carbon atoms to which they are attached, form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxirane, oxetane, tetrahydrofuran, tetrahydropyran, dioxane, aziridine, azetidine, pyrrolidine, piperidine, or morpholine, each of which is optionally substituted with 1 R9. In some embodiments, R2a and R3a, together with the carbon atoms to which they are attached, form a cyclopropyl, cyclohexyl, dioxane, piperidine, or morpholine, each of which is optionally substituted with 1 R9. In some embodiments, R2a and R3a together with the carbon atoms to which they are attached form a G-Gcycloalkyl. optionally substituted with 1, 2, or 3 R9. In some embodiments, R2a and R3a, together with the carbon atoms to which they are attached, form a cyclopropyl or cyclohexyl, either of which is optionally substituted with 1, 2, or 3 R9. In some embodiments, R2a and R3a, together with the carbon atoms to which they are attached, form a cyclohexyl.
[0070] In some embodiments, X is NRA, O, S, S(O), or S(0)2. In some embodiments, X is O. some embodiments, X is S or S(0)2. In some embodiments, X is S. In some embodiments, X is S(0)2. In some embodiments, X is NRA. In some embodiments, RA is CrG, alkyl. C(0)-(CrG, alkyl) or C(O)- (G-Cecycloalkyl), wherein each alkyl or cycloalkyl is optionally substituted with 1, 2, or 3 R9. In some embodiments, RA is hydrogen, methyl, ethyl, C(0)CH3, C(0)cyclopropyl, or C(0)cyclohexyl, wherein each cyclopropyl or cyclohexyl is optionally substituted with 1 or 2 R9. In some embodiments, RA is hydrogen, methyl, or C(0)C1¾. In some embodiments, RA is hydrogen. In some embodiments of a compound of Formula (A-I), a compound has the structure of Formula (A-IV-a), (A-IV-b), (A-IV-c), or (A-IV-d):
Figure imgf000030_0001
Formula (A-IV-c) or Formula (A-IV-d).
[0071] In some embodiments of a compound of Formula (A-I), a compound has the structure of Formula (A-V-a), (A-V-b), (A-V-c), or (A-V-d):
Figure imgf000030_0002
Figure imgf000031_0001
Formula (A-V-c) or Formula (A-V-d).
[0072] In some embodiments of a compound of Formula (A -I), a compound has the structure of Formula (A-VI-a), (A-VI-b), (A-VI-c), or (A-VI-d):
Figure imgf000031_0002
Formula (A-VI-c) or Formula (A-VI-d).
[0073] In some embodiments, X is C and taken together with R2a, R2b, and the carbon atom to which they are attached, forms a phenyl or 5- to 10-membered heteroaryl ring, optionally substituted with 1, 2, or 3 R9. In some embodiments, X is C and taken together with R2a, R2b, and the carbon atom to which they are attached, forms a phenyl ring, optionally substituted with 1, 2, or 3 R9. In some embodiments, X is C and taken together with R2a, R2b, and the carbon atom to which they are attached, forms a 5- to 10-membered heteroaryl ring, optionally substituted with 1, 2, or 3 R9. In some embodiments, X is C and taken together with R2a, R2b, and the carbon atom to which they are attached, forms a 5-membered heteroaryl ring, optionally substituted with 1, 2, or 3 R9. In some embodiments, X is C and taken together with R2a, R2b, and the carbon atom to which they are attached, forms a 9- or 10-membered heteroaryl ring, optionally substituted with 1, 2, or 3 R9. In some embodiments, X is C and taken together with R2a, R2b, and the carbon atom to which they are attached, forms a pyrrole, pyrazole, imidazole, indole, or azaindole ring, optionally substituted with 1, 2, or 3 R9. In some embodiments of a compound of Formula (A-I), a compound has the structure of one of the following:
Figure imgf000032_0001
[0074] In some embodiments of a compound of Formula (A -I), R6a, R6b, R7a, and R7b together with the carbon atoms to which they are attached form a 5 - to 10-membered heteroaryl ring optionally substituted with 1, 2, or 3 R9. In some embodiments of a compound of Formula (A-I), R6a, R6b, R7a, and R715 together with the carbon atoms to which they are attached form a furan, pyrrole, imidazole, pyrazole, triazole, pyridine, pyrimidine, pyridazine, pyrazine, thiophene, oxazole, thiazole, isoxazole, isothiazole, oxepin, azepine, thiepine, triazine, or tetrazine, any of which being optionally substituted with 1, 2, or 3 R9. In some embodiments of a compound of Formula (A-I), R6a, R6b, R7a, and R7b together with the carbon atoms to which they are attached form a furan, pyrrole, imidazole, pyrazole, pyridine, pyrimidine, pyridazine, pyrazine, any of which being optionally substituted with 1, 2, or 3 R9. In some embodiments of a compound of Formula (A-I), R6a, R6b, R7a, and R7b together with the carbon atoms to which they are attached form a furan, pyrrole, pyridine, pyrimidine, pyridazine, pyrazine, any of which being optionally substituted with 1, 2, or 3 R9. In some embodiments of a compound of Formula (A-I), R6a, R6b, R7a, and R7b together with the carbon atoms to which they are attached form a pyridine ring.
[0075] In some embodiments of a compound of Formula (A-I), R6b and R7b together with the carbon atoms to which they are attached form a C3-Ciocycloalkyl or 3- to 10-membered heterocycloalkyl ring; wherein each C3-Ciocycloalkyl or 3- to 10-membered heterocycloalkyl ring is optionally substituted with 1, 2, or 3 R9. In some embodiments of a compound of Formula (A-I), R6b and R715 together with the carbon atoms to which they are attached form a G-Gcycloalkyl or 3- to 6- membered heterocycloalkyl ring; wherein each G-Gcycloalkyl or 3- to 6-membered heterocycloalkyl ring is optionally substituted with 1, 2, or 3 R9. In some embodiments of a compound of Formula (A- I), R6b and R7b together with the carbon atoms to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxirane, aziridine, oxetane, azetidine, oxolane, pyrrolidine, thiolane, oxazolidine, imidazolidine, thiazolidine, isoxazolidine, pyrazolidine, isothiazolidine, dioxolane, dithiolane, oxane, piperidine, thiolane, morpholine, piperazine, thiazine, or dioxane ring, wherein each ring is optionally substituted with 1, 2, or 3 R9. In some embodiments of a compound of Formula (A-I), R6b and R715 together with the carbon atoms to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxolane, oxane, dioxane, morpholine, pyrrolidine, or piperidine ring. [0076] In some embodiments of a compound of Formula (A -I), R7a and R7|;’ together with the carbon atom to which they are attached form a saturated or partially saturated 3- to 7-membered cycloalkyl or a saturated or partially saturated 3- to 7-membered heterocycloalkyl; wherein the cycloalkyl or heterocycloalkyl is optionally substituted with 1, 2, or 3 R9. In some embodiments of a compound of Formula (A-I), R7a and R7b together with the carbon atom to which they are attached form a saturated or partially saturated 3- to 5-membered cycloalkyl or a saturated or partially saturated 3- to 5- membered heterocycloalkyl; wherein the cycloalkyl or heterocycloalkyl is optionally substituted with
1, 2, or 3 R9. In some embodiments of a compound of Formula (A-I), R7a and R7b together with the carbon atom to which they are attached form a cyclopropyl, cyclobutyl, cyclopropenyl, cyclobutenyl, oxirane, aziridine, oxetane, azetidine, cyclopentyl, or cyclopentenyl ring, wherein each ring is optionally substituted with 1, 2, or 3 R9. In some embodiments of a compound of Formula (A-I), R7a and R715 together with the carbon atom to which they are attached form a cyclopropyl ring, optionally substituted with 1, 2, or 3 R9. In some embodiments of a compound of Formula (A-I), R7a and R7b are each independently hydrogen, halogen, Ci-C4alkyl, or Ci-Cdialoalkyl. In some embodiments of a compound of Formula (A-I), R7a and R7bare each independently hydrogen, fluoro, methyl, ethyl, difluoromethyl, or trifluoromethyl. In some embodiments of a compound of Formula (A-I), R7a and R715 are each independently hydrogen, methyl, or ethyl. In some embodiments, R7a and R715 are both hydrogen.
[0077] In some embodiments of a compound of Formula (A-I), R6a and R6b together with the carbon atom to which they are attached form a saturated or partially saturated 3- to 7-membered cycloalkyl ring optionally substituted with 1, 2, or 3 R9. In some embodiments of a compound of Formula (A-I), R6a and R6b together with the carbon atom to which they are attached form a cyclopropyl, cyclobutyl, cyclopropenyl, cyclobutenyl, oxirane, aziridine, oxetane, azetidine, or cyclopentyl, or cyclopentenyl ring, wherein each ring is optionally substituted with 1, 2, or 3 R9. In some embodiments of a compound of Formula (A-I), R6a and R6b together with the carbon atom to which they are attached form a saturated or partially saturated 3- to 5-membered cycloalkyl ring, optionally substituted with 1,
2, or 3 R9.
[0078] In some embodiments of a compound of Formula (A-I), R6ais hydrogen. In some embodiments of a compound of Formula (A-I), R6ais hydrogen and R6b is halogen, CrG, alkyl. G- Ghaloalkyl. G-G, alkenyl. or G-Galkynyl: wherein each G-Galkyl. G-G,haloalkyl. G-Galkenyl. or G-Galkynyl is optionally substituted with 1, 2, or 3 R9 and/or 1 or 2, G. In some embodiments of a compound of Formula (A-I), R6b is halogen, G-Galkyl. G-Ghaloalkyl. G-Galkenyl. or C2- Galkynyl: wherein each G-Galkyl. G-G,haloalkyl. G-Galkenyl. or G-Galkynyl is optionally substituted with 1, 2, or 3 R9 and/or 1 or 2, G. In some embodiments of a compound of Formula (A-I), R6b is G-Galkyl. Ci-Cehaloalkyl, G-G, alkenyl. or C2-Galkynyl. wherein each alkyl, haloalkyl, alkenyl, or alkynyl is optionally substituted with a phenyl or 5- or 6-membered heteroaryl ring, wherein each phenyl or heteroaryl ring is optionally substituted with 1, 2, or 3 R9. In some embodiments of a compound of Formula (A-I), R6b is methyl, ethyl, or propyl, wherein the methyl, ethyl, or propyl is optionally substituted with G, and wherein G is a phenyl ring further substituted with 1, 2, or 3 R9. In some embodiments of a compound of Formula (A-I), R6b is ethyl, optionally substituted with phenyl, tolyl, phenolyl, fluorophenyl, chlorophenyl, anilinyl, methoxyphenyl, dimethylphenyl, difluorophenyl, dichlorophenyl, dihydroxyphenyl, dimethoxyphenyl, fluoromethoxyphenyl, or naphthyl. In some embodiments of a compound of Formula (A-I), R6b is Ci- Ci, alkyl. Ci-Cehaloalkyl, C2-G, alkenyl or G-Galkynyl. wherein each alkyl, haloalkyl, alkenyl, or alkynyl is optionally substituted with a G-Gcycloalkyl or 3- to 6-membered heterocycloalkyl ring, wherein each cycloalkyl or heterocyclalkyl ring is optionally substituted with 1, 2, or 3 R9. In some embodiments of a compound of Formula (A-I), R6b is methyl, ethyl, 2-propenyl, isopropyl, or phenethyl. In some embodiments of a compound of Formula (A-I), R6b is methyl. In some embodiments, R6b is ethyl. In some embodiments, R6b is 2-propenyl. In some embodiments, R6b is isopropyl. In some embodiments, R6b is phenethyl.
[0079] In some embodiments of a compound of Formula (A-I), R6a and R6b are each independently halogen, G-Galkyl. G-Ghaloalkyl. C2-Galkenyl, or C2-Galkynyl; wherein each G-Galkyl. Ci- C , haloalkyl. G-Galkenyl. or C2-Galkynyl is optionally substituted with 1, 2, or 3 R9 and/or 1 or 2,
G. In some embodiments, R6a and R6b are each independently halogen, C2-Galkyl, G-Ghaloalkyl. G-Galkenyl. or G-Galkynyl: wherein each G-Galkyl. G-Ghaloalkyl. G-Galkenyl. or C2- Galkynyl is optionally substituted with 1, 2, or 3 R9 and/or 1 or 2, G. In some embodiments of a compound of Formula (A-I), R6a and R6b are each independently G-Galkyl. G-Ghaloalkyl. C2- Galkenyl. or G-Galkynyl. wherein each alkyl, haloalkyl, alkenyl, or alkynyl is optionally substituted with a phenyl or 5- or 6-membered heteroaryl ring, wherein each phenyl or heteroaryl ring is optionally substituted with 1, 2, or 3 R9. In some embodiments of a compound of Formula (A-I), R6a and R6b are each independently methyl, ethyl, or propyl, optionally substituted with G, wherein G is a phenyl ring further substituted with 1, 2, or 3 R9. In some embodiments, R6a and R6b are each independently ethyl, optionally substituted with phenyl, tolyl, phenolyl, fluorophenyl, chlorophenyl, anilinyl, methoxyphenyl, dimethylphenyl, difluorophenyl, dichlorophenyl, dihydroxyphenyl, dimethoxyphenyl, fluoromethoxyphenyl, or naphthyl. In some embodiments of a compound of Formula (A-I), R6a and R6b are each independently G-Galkyl. G-Ghaloalkyl. C2-Galkenyl, or C2- Ci, alkynyl. wherein each alkyl, haloalkyl, alkenyl, or alkynyl is optionally substituted with a C3- Cecycloalkyl or 3- to 6-membered heterocycloalkyl ring, wherein each cycloalkyl or heterocyclalkyl ring is optionally substituted with 1, 2, or 3 R9. In some embodiments of a compound of Formula (A- I), R6a and R6b are each independently methyl, ethyl, 2-propenyl, isopropyl, or phenethyl. In some embodiments, R6a and R6b are each independently ethyl, 2-propenyl, isopropyl, or phenethyl. In some embodiments of a compound of Formula (A-I), R6a and R6b are methyl provided that when R6aand R6b are both methyl, then R8 is not
Figure imgf000035_0001
some embodiments of a compound of Formula (A-I),
R6a and R6b are methyl. In some embodiments, R6a and R6b are ethyl. In some embodiments, R6a and R6b are 2-propenyl. In some embodiments, R6a and R6b are isopropyl. In some embodiments, R6a and R6b are phenethyl.
[0080] In some embodiments of a compound of Formula (A -I), R8 is Z, G-Galkyl. (G-Galkylene)- Z, (G-Gheteroalkylene)-Z, (G-Galkenylene)-Z, CH(Z)2, CH2CH(Z)2, CH(G-Galkyl)Z. or C(0)Z; wherein each alkyl, alkylene, heteroalkylene, or alkenylene is optionally substituted with 1, 2, or 3 R9. In some embodiments of a compound of Formula (A -I), R8 is Z, G-Galkyl. CH(Z)2, or C(0)Z. In some embodiments of a compound of Formula (A -I), R8 is Z, G-Galkyl, CH(Z)2, or C(0)Z, wherein Z is G-Ciocycloalkyl, 3- to 10-membered heterocycloalkyl, G- oaryl. or 5- to 10-membered heteroaryl. In some embodiments of a compound of Formula (A -I), R8is Z or CH(Z)2. In some embodiments of a compound of Formula (A-I), R8 is Z. In some embodiments of a compound of Formula (A-I), R8is CH(Z)2. In some embodiments of a compound of Formula (A-I), Z is G- Gocycloalkyl, 3- to 10-membered heterocycloalkyl, G-Goaryl. or 5- to 10-membered heteroaryl; wherein each G-Gocycloalkyl, 3- to 10-membered heterocycloalkyl, G-Goaryl. and 5- to 10- membered heteroaryl is optionally substituted with 1, 2, or 3 R9. In some embodiments of a compound of Formula (A-I), Z is G-Goaryl or 5- to 10-membered heteroaryl, wherein each aryl or heteroaryl is optionally substituted with 1, 2, or 3 R9. In some embodiments of a compound of Formula (A-I), Z is G-Gocycloalkyl or 3- to 10-membered heterocycloalkyl; wherein each G-Gocycloalkyl and 3- to 10- membered heterocycloalkyl is optionally substituted with 1, 2, or 3 R9. In some embodiments of a compound of Formula (A-I), Z is G-Gocycloalkyl optionally substituted with 1, 2, or 3 R9. In some embodiments of a compound of Formula (A-I), Z is phenyl or naphthyl, optionally substituted with 1, 2, or 3 R9. In some embodiments of a compound of Formula (A-I), Z is pyridine, pyrimidine, pyridazine, pyrazine, quinoline, naphthyridine, quinoxaline, quinolizine, benzofuran, benzoxazole, or benzothiophene. In some embodiments, Z is tetrahydronaphthalene, tetrahydroquinoline, tetrahydroisoquinoline, chroman, thiochroman, indane, indoline, dihydrobenzofuran, or dihydrobenzothiophene .
[0081] In some embodiments of a compound of Formula (A-I), R8 is:
Figure imgf000036_0001
[0082] In some embodiments of a compound of Formula (A -I), R8 is:
Figure imgf000037_0001
[0083] In some embodiments of a compound of Formula (A -I), R8 is:
Figure imgf000037_0002
[0085] In some embodiments of a compound of Formula (A -I), R8 is:
Figure imgf000037_0003
[0086] In some embodiments of a compound of Formula (A -I), R8 is:
Figure imgf000038_0001
Figure imgf000039_0001
[0088] In some embodiments of a compound of Formula (A -I), R8 is:
Figure imgf000039_0002
[0089] In some embodiments of a compound of Formula (A -I), R8 is:
Figure imgf000039_0003
[0091] In some embodiments of a compound of Formula (A -I), R8 is:
Figure imgf000039_0004
[0092] In some embodiments of a compound of Formula (A -I), R8 is:
Figure imgf000040_0001
[0093] In some embodiments, each R9 is independently halogen, Ci-C4alkyl, C2-C4alkenyl, C2- C4alkynyl, Ci-C4haloalkyl, Ci-C4alkoxy, Ci-C4haloalkoxy, Ci-C4heteroalkyl, -C(0)H, -C(0)OH, -CN, C3-Ciocycloalkyl, 3- to 10-membered heterocycloalkyl, G,-Cioaryl. 5- to 10-membered heteroaryl, - N(Ci-C4alkyl)2, -OH, -0(Ci-C4alkyl), -0(Ci-C4haloalkyl), -0(Ci-C4alkylene)-(5- to 10-membered heteroaryl), -0(C6-Goaryl), -SH, S(0)2OH, -S(0)2(Ci-C4alkyl), -S(0)2NH2, -S(0)2NH(Ci-C4alkyl), or -S(0)2N(Ci-C4alkyl)2. In some embodiments, each R9 is independently halogen, Ci-C4alkyl, C2- C4alkenyl, C2-C4alkynyl, Ci-C4haloalkyl, Ci-C4alkoxy, Ci-C4haloalkoxy, Ci-C4heteroalkyl, -C(0)H, - C(0)OH, -CN, C3-Ciocycloalkyl, 3- to 10-membered heterocycloalkyl, Ce-Goaryl, 5- to 10-membered heteroaryl, -OH, -0(Ci-C4alkyl), or -0(Ci-C4haloalkyl). In some embodiments, each R9 is independently halogen, Ci-C4alkyl, -C(0)OH, -0(Ci-C4alkyl), -0(Ci-C4haloalkyl), or 5- to 10- membered heteroaryl. In some embodiments, each R9 is each independently -C(0)OH, -0(CH3), - OiGrhGrhF), or pyrimidine.
[0094] Also disclosed herein is a compound or pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, having the structure of Formula (B-I):
Figure imgf000040_0002
wherein,
R1 is hydrogen, CrG, alkyl. G-Gcycloalkyl. G-CealkyHG-Cecycloalkyl), G-Galkyl-(phenyl). or G-G,alkyl-(5- to 6-membered heteroaryl); wherein the G-Galkyl. CVG, cycloalkyl. phenyl, or 5- to 6-membered heteroaryl is optionally substituted with 1, 2, or 3 R9;
X is NRA, O, S, S(O), or S(0)2; RA is hydrogen, Ci-Cealkyl, C(0)-(Ci-C6alkyl), C(0)-(G-C6cycloalkyl), C(0)-(phenyl), or C(0)-(5- to 6-membered heteroaryl); wherein each G-Galkyl. G-Gcycloalkyl. phenyl, or 5- to 6- membered heteroaryl is optionally substituted with 1, 2, or 3 R9; or X is C and taken together with R2a, R2b, and the carbon atom to which they are attached, forms a phenyl or 5- to 10-membered heteroaryl ring, optionally substituted with 1, 2, or 3 R9;
R2a, R2b, R3a, and R3b are each independently hydrogen, Ci-G, alkyl. Ci-Cehaloalkyl, Ci-Ce alkoxy, Ci- Ceheteroalkyl, G-Galkenyl. G-Galkynyl. C3-Ciocycloalkyl, 3- to 10-membered heterocycloalkyl, G-Goaryl. or 5- to 10-membered heteroaryl; wherein each G-Galkyl. Ci- Cehaloalkyl, Ci-Ce alkoxy, Ci-Ceheteroalkyl, G-Galkenyl. or G-Galkynyl is optionally substituted with 1 or 2 G-Ciocycloalkyl, 3- to 10-membered heterocycloalkyl, G-Goaryl. or 5- to 10-membered heteroaryl rings; wherein each G-Galkyl. G-Ghaloalkyl. Ci-Ce alkoxy, G- Ceheteroalkyl, G-Galkenyl. G-Galkynyl. G-Ciocycloalkyl, 3- to 10-membered heterocycloalkyl, Ce-Cioaryl, or 5- to 10-membered heteroaryl is optionally substituted with 1, 2, or 3 R9; or R2a and R2b together with the carbon atom to which they are attached form a carbonyl; or R2a and R3a, and optionally R2b and R3b, together with the carbon atoms to which they are attached form a G-Gcycloalkyl. 5- to 10-membered heterocycloalkyl, G-Goaryl. or 5- to 10-membered heteroaryl ring; wherein each G-Gcycloalkyl. 5- to 10-membered heterocycloalkyl, G-Goaryl. or 5- to 10-membered heteroaryl ring is optionally substituted with 1, 2, or 3 R9;
R4aand R4b are each independently hydrogen, halogen, G-Galkyl. G-Ghaloalkyl. G-G alkoxy. Ci- Gheteroalkyl, G-Galkenyl. G-Galkynyl. G-Ciocycloalkyl, 3- to 10-membered heterocycloalkyl, G-Goaryl. or 5- to 10-membered heteroaryl; wherein each G-Galkyl. Ci- Ghaloalkyl, C i -Co alkoxy, Ci-Cohctcroalkyl. G-Galkenyl. or G-Galkynyl is optionally substituted with 1 or 2 G-Ciocycloalkyl, 3- to 10-membered heterocycloalkyl, G-Goaryl. or 5- to 10-membered heteroaryl; wherein each G-Galkyl. G-Ghaloalkyl. G-G alkoxy. Ci- Gheteroalkyl, G-Galkenyl. G-Galkynyl. G-Ciocycloalkyl, 3- to 10-membered heterocycloalkyl, G-Goaryl. or 5- to 10-membered heteroaryl is optionally substituted with 1, 2, or 3 R9; or R4a and R4b together with the carbon atom to which they are attached form a carbonyl; or R4a and R4b together with the carbon atom to which they are attached form a G-Ciocycloalkyl or 3- to 10-membered heterocycloalkyl ring; wherein the G-Ciocycloalkyl or 3- to 10-membered heterocycloalkyl ring is optionally substituted with 1, 2, or 3 R9;
R5 is NHR8,NHS(0)2R8, OR8, SR8, S(0)2R8, or S(0)2NHR8; or R5, R4a, and R4b, together with the carbon atom to which they are attached, form a G-Goaryl or 5- to 10-membered heteroaryl ring; wherein the G-Goaryl or 5- to 10-membered heteroaryl ring is optionally substituted with 1, 2, or 3 R9;
R6a is hydrogen, halogen, -Ua, or -G; R6b is halogen, -Ub, or -G;
-Ua is C -G, alkyl. G-Ghaloalkyl. Ci-Cealkoxy, G-Gheteroalkyl. G-Galkcnyl. or G-Galkynyl: wherein each CrG, alkyl. G-Ghaloalkyl. Ci-Cealkoxy, G-Gheteroalkyl. G-Galkcnyl. or C2- Galkynyl is optionally substituted with 1, 2, or 3 R9 and/or 1 or 2 -G;
-Ub is G-Galkyl. G-Ghaloalkyl. Ci-Cealkoxy, Ci-Ceheteroalkyl, G-Galkcnyl. or C2-Galkynyl; wherein each G-Galkyl. G-Ghaloalkyl. Ci-Cealkoxy, Ci-Ceheteroalkyl, C2-Galkenyl, or C2- Galkynyl is optionally substituted with 1, 2, or 3 R9 and/or 1 or 2 -G;
-G is C3-Gocycloalkyl, 3- to 10-membered heterocycloalkyl, Ce-Goaryl, or 5- to 10-membered heteroaryl; wherein each C3-Ciocycloalkyl, 3- to 10-membered heterocycloalkyl, Ce-Goaryl, or 5- to 10-membered heteroaryl is optionally substituted with 1, 2, or 3 R9;
R7a is hydrogen, halogen, Ci-C4alkyl, or Ci-Cthaloalkyl;
R715 is hydrogen, halogen, Ci-C4alkyl, or Ci-C4haloalkyl;
R8 is Z, G-Galkyl. (Ci-C6alkylene)-Z, (Ci-C6heteroalkylene)-Z, (C2-Galkenylene)-Z, CH(Z)2, CH2CH(Z)2, CH(G-Galkyl)Z. or C(0)Z; wherein each alkyl, alkylene, heteroalkylene, or alkenylene is optionally substituted with 1, 2, or 3 R9;
Z is C3-Gocycloalkyl, 3- to 10-membered heterocycloalkyl, Ce-Goaryl, 5- to 10-membered heteroaryl; wherein each C3-Gocycloalkyl, 3- to 10-membered heterocycloalkyl, Ce-Goaryl, 5- to 10-membered heteroaryl is optionally substituted with 1, 2, or 3 R9; each R9 is independently halogen, Ci-C4alkyl, C2-Galkenyl, C2-Galkynyl, Ci-C4haloalkyl, Ci- C4alkoxy, Ci-C4haloalkoxy, Ci-C4heteroalkyl, -C(0)H, -C(0)0H, -CN, C3-Ciocycloalkyl, 3- to 10-membered heterocycloalkyl, Ce-Goaryl, 5- to 10-membered heteroaryl, -C(0)(Ci-C4alkyl), - C(0)0(Ci-C4alkyl), -C(0)NH2, -C(0)NH(Ci-C4alkyl), -C(0)N(Ci-C4alkyl)2, -NH2, -NH(Ci- C4alkyl), -N(Ci-C4alkyl)2, -NH(C2-C4alkylene)-OH, -NH(C2-C4alkylene)-0-(Ci-C4alkyl), -OH, - 0(Ci-C4alkyl), -0(Ci-C4haloalkyl), -0(C2-Galkylene)-NH2, -0(C2-C4alkylene)-NH-(Ci-C4alkyl), -0(C2-Galkylene)-N-(Ci-C4alkyl)2, -0(Ci-C4alkylene)-C(0)0H, -0(Ci-C4alkylene)-C(0)0-(Ci- C4alkyl), -0(C2-C4alkenyl), -0(Ci-C4alkylene)-(C6-Goaryl), -0(Ci-C4alkylene)-(5- to 10- membered heteroaryl), -O(Ce-Goaryl), -SH, S(0)20H, -S(0)2(G-C4alkyl), -S(0)2NH2, - S(0)2NH(Ci-C4alkyl), or -S(0)2N(Ci-C4alkyl)2; or two R9 together with the atoms to which they are attached form a C3-Gocycloalkyl or a 3- to 10-membered heterocycloalkyl ring.
[0095] In some embodiments, R5, R4a and R4b together with the carbon atom to which they are attached form a Ce-Goaryl or 5- to 10-membered heteroaryl ring; wherein the Ce-Goaryl or 5- to 10- membered heteroaryl ring is optionally substituted with 1, 2, or 3 R9. In some embodiments, R5, R4a and R4b together with the carbon atom to which they are attached form a 5- to 10-membered heteroaryl ring, optionally substituted with 1, 2, or 3 R9. In some embodiments, R5, R4a and R4b together with the carbon atom to which they are attached form a 9- or 10-membered heteroaryl ring, optionally substituted with 1, 2, or 3 R9. In some embodiments, R5, R4a and R4b together with the carbon atom to which they are attached form a 10-membered heteroaryl ring. In some embodiments, R5, R4a and R4b together with the carbon atom to which they are attached form a quinoline, isoquinoline, quinoxaline, quinazoline, quinolizine, naphthyridine. In some embodiments, R5, R4a and R4b together with the carbon atom to which they are attached form a 9-membered heteroaryl ring. In some embodiments, R5, R4a and R4b together with the carbon atom to which they are attached form a 2,3-dihydrobenzo[d]oxazole, benzo[d]oxazole, oxazolo[4,5-b]pyridine, lH-benzo[d]imidazole, benzo[d]thiazole, benzofuran, indole, aza-indole, lH-imidazo[4,5-b]pyridine, indolizine, imidazo[l,2- a]pyridine, or an isomer thereof, optionally substituted with 1, 2, or 3 R9. In some embodiments, R5, R4a and R4b together with the carbon atom to which they are attached form a benzo[d]oxazole, optionally substituted with 1, 2, or 3 R9. In some embodiments, the Ce-Cioaryl or 5- to 10-membered heteroaryl ring is unsubstituted.
[0096] In some embodiments, R5 is NHR8, NHS(0)2R8, OR8, SR8, S(0)2R8, or S(0)2NHR8. In some embodiments, R5 is NHR8, NHS(0)2R8, OR8, or S(0)2NHR8. In some embodiments, R5 is NHR8, NHS(0)2R8, or OR8. In some embodiments, R5 is OR8. In some embodiments, R5 is NHR8, or NHS(0)2R8. In some embodiments, R5is NHS(0)2R8. In some embodiments, R5 is NHR8.
[0097] In some embodiments of a compound of Formula (B-I), a compound has any one of the following formulae:
Figure imgf000043_0001
[0098] In some embodiments of a compound of Formula (B-I), a compound has the structure of Formula (B-II):
Figure imgf000043_0002
Formula (B-II).
[0099] In some embodiments, R4a is H. In some embodiments, R4a is H and R4b is halogen or haloalkyl. In some embodiments, R4b is CHF2 or CF3. In some embodiments, R4a is H and R4b is difluoromethyl or trifluoromethyl. In some embodiments, R4b is difluoromethyl or trifluoromethyl and R5 is OR8. In some embodiments, R4a and R4b are both H. [00100] In some embodiments, R4a and R4b together with the carbon atom to which they are attached form a C3-Ciocycloalkyl or 3- to 10-membered heterocycloalkyl ring, wherein either of the cycloalkyl or heterocycloalkyl ring is optionally substituted with 1, 2, or 3 R9. In some embodiments, R4a and R4b together with the carbon atom to which they are attached form a G-Gcycloalkyl. optionally substituted with 1, 2, or 3 R9. In some embodiments, R4a and R4b together with the carbon atom to which they are attached form a C3-C5cycloalkyl, optionally substituted with 1, 2, or 3 R9. In some embodiments, R4a and R4b together with the carbon atom to which they are attached form a cyclopropyl, cyclobutyl, or cyclopentyl ring, optionally substituted with 1, 2, or 3 R9. In some embodiments, R4a and R4b together with the carbon atom to which they are attached form a cyclopropyl, cyclobutyl, or cyclopentyl ring and R5 is -OR8 or -NHR8. In some embodiments, R4a and R4b are each independently halogen, Ci-G, alkyl. G-Ghaloalkyl. C i -G, alkoxy, or G-Gheteroalkyl and R5 is NHR8.
[00101] In some embodiments, R4a and R4b together with the carbon atom to which they are attached form a carbonyl. In some embodiments, R4a and R4b together with the carbon atom to which they are attached form a carbonyl and R5 is OR8 or NHR8. In some embodiments, R4a and R4b together with the carbon atom to which they are attached form a carbonyl and R5 is NHR8.
[00102] In some embodiments, R1 is hydrogen, G-Galkyl. G-Gcycloalkyl. G-Galkyl-(G- Gcycloalkyl). wherein each alkyl is optionally substituted with 1, 2, or 3 R9. In some embodiments, R1 is phenethyl. In some embodiments, R1 is hydrogen, methyl, trifluoromethyl, difluoromethyl, fluoromethyl, ethyl, propyl, isopropyl, cyclopropyl, methylenecyclopropyl, or cyclobutyl. In some embodiments, R1 is phenethyl. In some embodiments, R1 is hydrogen, methyl, trifluoromethyl, difluoromethyl, fluoromethyl, or ethyl. In some embodiments, R1 is hydrogen or methyl. In some embodiments, R1 is hydrogen.
[00103] In some embodiments of a compound of Formula (B-I), a compound has the structure of Formula (B-III):
Figure imgf000044_0001
Formula (B-III).
[00104] In some embodiments, R2a and R2b are each independently hydrogen, G-Galkyl. Ci- Ghaloalkyl. C i -G, alkoxy, G-Gheteroalkyl. G-Galkenyl. G-Galkynyl. wherein each alkyl, haloalkyl, alkoxy, heteroalkyl, alkenyl, or alkynyl is optionally substituted with 1, 2, or 3 R9. In some embodiments, R2a and R2b are each independently G-Gocycloalkyl, 3- to 10-membered heterocycloalkyl, G-Goaryl. or 5- to 10-membered heteroaryl, wherein each cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with 1, 2, or 3 R9. In some embodiments, R2a and R2b are each independently hydrogen, CrG, alkyl. G-G, haloalkyl. Ci-Ce alkoxy, G- Ceheteroalkyl, wherein each alkyl, haloalkyl, alkoxy, or heteroalkyl is optionally substituted with 1 or 2 G-Gcycloalkyl. 3- to 6-membered heterocycloalkyl, phenyl, or 5- or 6-membered heteroaryl. In some embodiments, R2a is H and R2b is G-Galkyl or G-Gheteroalkyl. wherein each alkyl or heteroalkyl is optionally substituted with a phenyl, or 5- or 6-membered heteroaryl. In some embodiments,
Figure imgf000045_0001
some embodiments, R2a is hydrogen. In some embodiments, R2a and R2b are each hydrogen.
[00105] In some embodiments, R2a and R3a, and optionally R2band R3b, together with the carbon atoms to which they are attached form a G-Gcycloalkyl. 5- to 10-membered heterocycloalkyl, G-Goaryl. or 5- to 10-membered heteroaryl ring; wherein each G-Gcycloalkyl. 5- to 10-membered heterocycloalkyl, G-Goaryl. or 5- to 10-membered heteroaryl ring is optionally substituted with 1, 2, or 3 R9;
[00106] In some embodiments, R2a and R2b together with the atom to which they are attached form a carbonyl. In some embodiments, R2a and R2b together with the atom to which they are attached form a carbonyl and X is NH. In some embodiments, R2a and R2b together with the atom to which they are attached form a carbonyl and X is O.
[00107] In some embodiments, R3a and R3b are each independently hydrogen, G-Galkyl. G- G, haloalkyl. G- alkoxy. G-Gheteroalkyl. G-Galkenyl. G-Galkynyl. C3-Ciocycloalkyl, 3- to 10- membered heterocycloalkyl, G-Goaryl. or 5- to 10-membered heteroaryl, any of which is optionally substituted with 1, 2, or 3 R9. In some embodiments, R3a and R3b are each independently hydrogen, G-Galkyl. G-Ghaloalkyl. C i -Co alkoxy, Ci-Cohctcroalkyl. G-G, alkenyl. or G-Galkynyl. wherein each alkyl, haloalkyl, alkoxy, heteroalkyl, alkenyl, or alkynyl is optionally substituted with a cyclopropyl, phenyl, or 5- or 6-membered heteroaryl. In some embodiments, R3a and R3b are each independently hydrogen, methyl, trifluoromethyl, difluoromethyl, ethyl, propyl, isopropyl, cyclopropyl, benzyl, phenethyl, or isobutyl. In some embodiments, R3a and R3b are each methyl. In some embodiments, R3a is hydrogen. In some embodiments, R3a and R3b are each hydrogen.
[00108] In some embodiments, R2a and R3a, together with the carbon atoms to which they are attached, form a G-Gcycloalkyl. or 5- to 10-membered heterocycloalkyl. In some embodiments, R2a and R3a, together with the carbon atoms to which they are attached, form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxirane, oxetane, tetrahydrofuran, tetrahydropyran, dioxane, aziridine, azetidine, pyrrolidine, piperidine, or morpholine, each of which is optionally substituted with 1 R9. In some embodiments, R2a and R3a, together with the carbon atoms to which they are attached, form a cyclopropyl, cyclohexyl, dioxane, piperidine, or morpholine, each of which is optionally substituted with 1 R9. In some embodiments, R2a and R3a together with the carbon atoms to which they are attached form a G-Gcycloalkyl. optionally substituted with 1, 2, or 3 R9. In some embodiments, R2a and R3a, together with the carbon atoms to which they are attached, form a cyclopropyl or cyclohexyl, either of which is optionally substituted with 1, 2, or 3 R9. In some embodiments, R2a and R3a, together with the carbon atoms to which they are attached, form a cyclohexyl.
[00109] In some embodiments, X is NRA, O, S, S(O), or S(0)2. In some embodiments, X is O. In some embodiments, X is S or S(0)2. In some embodiments, X is S. In some embodiments, X is S(0)2. In some embodiments, X is NRA. In some embodiments, RA is Ci-G, alkyl. C(0)-(G-Galkyl). or C(0)-(G-C6cycloalkyl), wherein each alkyl or cycloalkyl is optionally substituted with 1, 2, or 3 R9. In some embodiments, RA is hydrogen, methyl, ethyl, C(0)CH3, C(0)cyclopropyl, or C(0)cyclohexyl, wherein each cyclopropyl or cyclohexyl is optionally substituted with 1 or 2 R9. In some embodiments, RA is hydrogen, methyl, or C(0)C1¾. In some embodiments, RA is hydrogen. In some embodiments of a compound of Formula (B-I), a compound has the structure of Formula (B-IV- a), (B-IV-b), (B-IV-c), or (B-IV-d):
Figure imgf000046_0001
Formula (B-IV-c) or Formula (B-IV-d).
[00110] In some embodiments of a compound of Formula (B-I), a compound has the structure of Formula (B-V-a) or (B-V-b):
Figure imgf000046_0002
[00111] In some embodiments of a compound of Formula (B-I), a compound has the structure of Formula (B-VI-a), (B-VI-b), (B-VI-c), or (B-VI-d):
Figure imgf000047_0001
Formula (B-VI-c) or Formula (B-VI-d).
[00112] In some embodiments of a compound of Formula (B-I), a compound has the structure of Formula (B-VII-a), (B-VII-b), (B-VII-c), or (B-VII-d):
Figure imgf000047_0002
Formula (B-VII-c) or Formula (B-VII-d).
[00113] In some embodiments, X is C and taken together with R2a, R2b, and the carbon atom to which they are attached, forms a phenyl or 5- to 10-membered heteroaryl ring, optionally substituted with 1, 2, or 3 R9. In some embodiments, X is C and taken together with R2a, R2b, and the carbon atom to which they are attached, forms a phenyl ring, optionally substituted with 1, 2, or 3 R9. In some embodiments, X is C and taken together with R2a, R2b, and the carbon atom to which they are attached, forms a 5- to 10-membered heteroaryl ring, optionally substituted with 1, 2, or 3 R9. In some embodiments, X is C and taken together with R2a, R2b, and the carbon atom to which they are attached, forms a 5-membered heteroaryl ring, optionally substituted with 1, 2, or 3 R9. In some embodiments, X is C and taken together with R2a, R2b, and the carbon atom to which they are attached, forms a 9- or 10-membered heteroaryl ring, optionally substituted with 1, 2, or 3 R9. In some embodiments, X is C and taken together with R2a, R2b, and the carbon atom to which they are attached, forms a pyrrole, pyrazole, imidazole, indole, or azaindole ring, optionally substituted with 1, 2, or 3 R9. In some embodiments, a compound as disclosed herein has the structure of one of the following:
Figure imgf000048_0001
[00114] In some embodiments, R7a and R7b are each independently hydrogen, halogen, Ci-C4alkyl, or Ci-Cdialoalkyl. In some embodiments, R7a and R7b arc each independently hydrogen, fluoro, methyl, ethyl, difluoromethyl, or trifluoromethyl. In some embodiments, R7a and R7b are each independently hydrogen, methyl, or ethyl. In some embodiments, R7a and R7b are both hydrogen.
[00115] In some embodiments of a compound of Formula (B-I), R6ais hydrogen. In some embodiments of a compound of Formula (B-I), R6ais hydrogen and R6b is halogen, Ci-G, alkyl. G- G, haloalkyl. G-G, alkenyl. or G-Galkynyl: wherein each G-Galkyl. G-G, haloalkyl. G-G, alkenyl or G-Galkynyl is optionally substituted with 1, 2, or 3 R9 and/or 1 or 2, G. In some embodiments of a compound of Formula (B-I), R6b is halogen, G-Galkyl. G-G,haloalkyl. G-G, alkenyl. or C2- G, alkynyl: wherein each G-Galkyl. G-G,haloalkyl. G-G, alkenyl. or G-Galkynyl is optionally substituted with 1, 2, or 3 R9 and/or 1 or 2, G. In some embodiments of a compound of Formula (B-I), R6b is G-Galkyl. Ci-Cehaloalkyl, G-G, alkenyl. or C2-G,alkynyl. wherein each alkyl, haloalkyl, alkenyl, or alkynyl is optionally substituted with a phenyl or 5- or 6-membered heteroaryl ring, wherein each phenyl or heteroaryl ring is optionally substituted with 1, 2, or 3 R9. In some embodiments of a compound of Formula (B-I), R6b is methyl, ethyl, or propyl, optionally substituted with G, wherein G is a phenyl ring further substituted with 1, 2, or 3 R9. In some embodiments of a compound of Formula (B-I), R6b is ethyl, optionally substituted with phenyl, tolyl, phenolyl, fluorophenyl, chlorophenyl, anilinyl, methoxyphenyl, dimethylphenyl, difluorophenyl, dichlorophenyl, dihydroxyphenyl, dimethoxyphenyl, fluoromethoxyphenyl, or naphthyl. In some embodiments of a compound of Formula (B-I), R6b is G-Galkyl. G-G, haloalkyl. G-G, alkenyl. or G-Galkynyl. wherein each alkyl, haloalkyl, alkenyl, or alkynyl is optionally substituted with a C3- Cecycloalkyl or 3- to 6-membered heterocycloalkyl ring, wherein each cycloalkyl or heterocyclalkyl ring is optionally substituted with 1, 2, or 3 R9. In some embodiments of a compound of Formula (B- I), R6b is methyl, ethyl, 2-propenyl, isopropyl, or phenethyl. In some embodiments of a compound of Formula (B-I), R6b is methyl, ethyl, 2-propenyl, isopropyl, or phenethyl, and the carbon to which it is attached has the (S) stereochemical configuration. In some embodiments of a compound of Formula (B-I), R6b is methyl, ethyl, 2-propenyl, isopropyl, or phenethyl, and the carbon to which it is attached has the (R) stereochemical configuration. In some embodiments of a compound of Formula (B-I), R6b is methyl. In some embodiments, R6b is ethyl. In some embodiments, R6b is 2-propenyl. In some embodiments, R6b is isopropyl. In some embodiments, R6b is phenethyl.
[00116] In some embodiments of a compound of Formula (B-I), R6a and R6b are each independently halogen, G-Galkyl. G-G,haloalkyl. G-Galkenyl. or G-Galkynyl: wherein each G-Galkyl. Ci- Ghaloalkyl. G-Galkenyl. or G-Galkynyl is optionally substituted with 1, 2, or 3 R9 and/or 1 or 2,
G. In some embodiments of a compound of Formula (B-I), R6a and R6b are each independently G- Galkyl, G-Ghaloalkyl. G-Galkenyl. or G-Galkynyl. wherein each alkyl, haloalkyl, alkenyl, or alkynyl is optionally substituted with a phenyl or 5- or 6-membered heteroaryl ring, wherein each phenyl or heteroaryl ring is optionally substituted with 1, 2, or 3 R9. In some embodiments of a compound of Formula (B-I), R6a and R6b are each independently ethyl or propyl, optionally substituted with G, wherein G is a phenyl ring further substituted with 1, 2, or 3 R9. In some embodiments of a compound of Formula (B-I), R6a and R6b are each independently ethyl, optionally substituted with phenyl, tolyl, phenolyl, fluorophenyl, chlorophenyl, anilinyl, methoxyphenyl, dimethylphenyl, difluorophenyl, dichlorophenyl, dihydroxyphenyl, dimethoxyphenyl, fluoromethoxyphenyl, or naphthyl. In some embodiments of a compound of Formula (B-I), R6a and R6b are each independently G-Galkyl. G-Ghaloalkyl. G-Galkenyl. or G-Galkynyl. wherein each alkyl, haloalkyl, alkenyl, or alkynyl is optionally substituted with a G-Gcycloalkyl or 3- to 6-membered heterocycloalkyl ring, wherein each cycloalkyl or heterocyclalkyl ring is optionally substituted with 1, 2, or 3 R9. In some embodiments of a compound of Formula (B-I), R6a and R6b are each independently ethyl, 2-propenyl, isopropyl, or phenethyl. In some embodiments, R6a and R6b are ethyl. In some embodiments, R6a and R6b are 2-propenyl. In some embodiments, R6a and R6b are isopropyl. In some embodiments, R6a and R6b are phenethyl. In some embodiments of a compound of Formula (B-I), R6ais halogen, G-Galkyl. G-Ghaloalkyl. G-Galkenyl. or G-Galkynyl: wherein each G-Galkyl. G-Ghaloalkyl. G- Galkcnyl. or G-Galkynyl is optionally substituted with 1, 2, or 3 R9 and/or 1 or 2 G; and R6b is methyl. In some embodiments of a compound of Formula (B-I), R6a is G-Galkyl. G-Ghaloalkyl. G- Galkcnyl. or G-Galkynyl. wherein each alkyl, haloalkyl, alkenyl, or alkynyl is optionally substituted with a phenyl or 5- or 6-membered heteroaryl ring, wherein each phenyl or heteroaryl ring is optionally substituted with 1, 2, or 3 R9; and R6b is methyl. In some embodiments of a compound of Formula (B-I), R6a is ethyl or propyl, optionally substituted with G, wherein G is a phenyl ring further substituted with 1, 2, or 3 R9; and R6b is methyl. In some embodiments of a compound of Formula (B- I), R6a is ethyl, optionally substituted with phenyl, tolyl, phenolyl, fluorophenyl, chlorophenyl, anilinyl, methoxyphenyl, dimethylphenyl, difluorophenyl, dichlorophenyl, dihydroxyphenyl, dimethoxyphenyl, fluoromethoxyphenyl, or naphthyl; and R6b is methyl. In some embodiments of a compound of Formula (B-I), R6a is G-Galkyl. Ci-Cehaloalkyl, G-Galkenyl. or G-Galkynyl. wherein each alkyl, haloalkyl, alkenyl, or alkynyl is optionally substituted with a G-Gcycloalkyl or 3- to 6-membered heterocycloalkyl ring, wherein each cycloalkyl or heterocyclalkyl ring is optionally substituted with 1, 2, or 3 R9; and R6b is methyl. In some embodiments of a compound of Formula (B- I), R6a is ethyl, 2-propenyl, isopropyl, or phenethyl, and R6b is methyl.
[00117] In some embodiments of a compound of Formula (B-I), R8 is Z, G-Galkyl. (G-Galkylene)- Z, (Ci-C6heteroalkylene)-Z, (C2-C6alkenylene)-Z, CH(Z)2, CH2CH(Z)2, CH(Ci-Cealkyl)Z, or C(0)Z; wherein each alkyl, alkylene, heteroalkylene, or alkenylene is optionally substituted with 1, 2, or 3 R9. In some embodiments of a compound of Formula (B-I), R8 is Z, G-Galkyl. CH(Z)2, or C(0)Z. In some embodiments of a compound of Formula (B-I), R8 is Z, G-Galkyl. CH(Z)2, or C(0)Z, wherein Z is G-Ciocycloalkyl, 3- to 10-membered heterocycloalkyl, G-Goaryl. or 5- to 10-membered heteroaryl. In some embodiments of a compound of Formula (B-I), R8is Z or CH(Z)2. In some embodiments of a compound of Formula (B-I), R8 is Z. In some embodiments of a compound of Formula (B-I), R8is CH(Z)2. In some embodiments of a compound of Formula (B-I), Z is G- Ciocycloalkyl, 3- to 10-membered heterocycloalkyl, G-Goaryl. or 5- to 10-membered heteroaryl; wherein each C3-Ciocycloalkyl, 3- to 10-membered heterocycloalkyl, G-Goaryl. and 5- to 10- membered heteroaryl is optionally substituted with 1, 2, or 3 R9. In some embodiments of a compound of Formula (B-I), Z is G-Goaryl or 5- to 10-membered heteroaryl, wherein each aryl or heteroaryl is optionally substituted with 1, 2, or 3 R9. In some embodiments of a compound of Formula (B-I), Z is C3-Ciocycloalkyl or 3- to 10-membered heterocycloalkyl; wherein each C3-Ciocycloalkyl and 3- to 10- membered heterocycloalkyl is optionally substituted with 1, 2, or 3 R9. In some embodiments of a compound of Formula (B-I), Z is C3-Ciocycloalkyl optionally substituted with 1, 2, or 3 R9. In some embodiments of a compound of Formula (B-I), Z is phenyl or naphthyl, optionally substituted with 1, 2, or 3 R9. In some embodiments of a compound of Formula (B-I), Z is pyridine, pyrimidine, pyridazine, pyrazine, quinoline, naphthyridine, quinoxaline, quinolizine, benzofuran, benzoxazole, or benzothiophene. In some embodiments of a compound of Formula (B-I), Z is tetrahydronaphthalene, tetrahydroquinoline, tetrahydroisoquinoline, chroman, thiochroman, indane, indoline, dihydrobenzofuran, or dihydrobenzothiophene.
[00118] In some embodiments of a compound of Formula (B-I), R8 is:
Figure imgf000051_0001
[00119] In some embodiments of a compound of Formula (B-I), R8 is:
Figure imgf000052_0001
In some embodiments of a compound of Formula (B-I), R8 is:
Figure imgf000052_0002
[00121] In some embodiments of a compound of Formula (B-I), R8 is:
Figure imgf000052_0003
[00122] In some embodiments of a compound of Formula (B-I), R8 is:
Figure imgf000053_0001
[00123] In some embodiments of a compound of Formula (B-I), R8 is:
Figure imgf000053_0002
[00124] In some embodiments, each R9 is independently halogen, G-Galkyl, G-Galkenyl, G- C4alkynyl, Ci-C4haloalkyl, Ci-C4alkoxy, Ci-C4haloalkoxy, G-Gheteroalkyl, -C(0)H, -C(0)OH, -CN C3-Ciocycloalkyl, 3- to 10-membered heterocycloalkyl, G-Goaryl, 5- to 10-membered heteroaryl, - N(Ci-Galkyl)2, -OH, -O(G-Galkyl), -0(Ci-C4haloalkyl), -0(Ci-C4alkylene)-(5- to 10-membered heteroaryl), -O(G-Goaryl), -SH, S(0)20H, -S(0)2(Ci-C4alkyl), -S(0)2NH2, -S(0)2NH(Ci-C4alkyl), or
-S(0)2N(G-Galkyl)2. In some embodiments, each R9 is independently halogen, G-Galkyl, G- Galkenyl, C2-C4alkynyl, Ci-C4haloalkyl, G-Galkoxy, Ci-C4haloalkoxy, Ci-C4heteroalkyl, -C(0)H, - C(0)OH, -CN, C3-Ciocycloalkyl, 3- to 10-membered heterocycloalkyl, G-Goaryl. 5- to 10-membered heteroaryl, -OH, -0(Ci-C4alkyl), or -0(Ci-C4haloalkyl). In some embodiments, each R9 is independently halogen, G-Galkyl, -C(0)OH, -O(G-Galkyl), -0(Ci-C4haloalkyl), or 5- to 10- membered heteroaryl. In some embodiments, each R9 is each independently -C(0)OH, -0(CH3), - 0(CH2CH2F), or pyrimidine.
[00125] Also disclosed herein is a compound or pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, having the structure of Formula (C-I):
Figure imgf000053_0003
Formula (C-I) wherein,
R1 is hydrogen, CrG, alkyl. G-Gcycloalkyl. G-Galkyl-(G-Gcycloalkyl), G-Galkyl-(phenyl). or G-Galkyl-(5- to 6-membered heteroaryl); wherein the Ci-G, alkyl. G-Gcycloalkyl. phenyl, or 5- to 6-membered heteroaryl is optionally substituted with 1, 2, or 3 R9; X is NRA, O, S, S(O), or S(0)2;
RA is hydrogen, G-C6alkyl, C(0)-(G-C6alkyl), C(0)-(C3-C6cycloalkyl), C(0)-(phenyl), or C(0)-(5- to 6-membered heteroaryl); wherein each Ci-G, alkyl. G-Gcycloalkyl. phenyl, or 5- to 6- membered heteroaryl is optionally substituted with 1, 2, or 3 R9; or X is C and taken together with R2a, R2b, and the carbon atom to which they are attached, forms a phenyl or 5- to 10-membered heteroaryl ring, optionally substituted with 1, 2, or 3 R9;
R2a, R2b, R3a, and R3b are each independently hydrogen, Ci-G, alkyl. G-Cehaloalkyl, Ci-Ce alkoxy, G- Ceheteroalkyl, G-Galkenyl. G-Galkynyl. C3-Ciocycloalkyl, 3- to 10-membered heterocycloalkyl, Ce-Goaryl, or 5- to 10-membered heteroaryl; wherein each G-Galkyl. G- Cehaloalkyl, Ci-Ce alkoxy, G-Ceheteroalkyl, G-G, alkenyl. or G-Galkynyl is optionally substituted with 1 or 2 C3-Ciocycloalkyl, 3- to 10-membered heterocycloalkyl, G-Goaryl. or 5- to 10-membered heteroaryl rings; wherein each G-Galkyl. G-G,haloalkyl. G-Ce alkoxy, G- Ceheteroalkyl, G-G, alkenyl. G-Galkynyl. C3-Ciocycloalkyl, 3- to 10-membered heterocycloalkyl, G-Goaryl. or 5- to 10-membered heteroaryl is optionally substituted with 1, 2, or 3 R9; or R2a and R2b together with the carbon atom to which they are attached form a carbonyl; or R2a and R3a, and optionally R2b and R3b, together with the carbon atoms to which they are attached form a G-Gcycloalkyl. 5- to 10-membered heterocycloalkyl, G-Goaryl. or 5- to 10-membered heteroaryl ring; wherein each G-Gcycloalkyl. 5- to 10-membered heterocycloalkyl, G-Goaryl. or 5- to 10-membered heteroaryl ring is optionally substituted with 1, 2, or 3 R9;
R4aand R4b are each independently hydrogen, halogen, G-Galkyl. G-Ghaloalkyl. G-G alkoxy. G- Gheteroalkyl. G-G, alkenyl. G-Galkynyl. G-Gocycloalkyl, 3- to 10-membered heterocycloalkyl, G-Goaryl. or 5- to 10-membered heteroaryl; wherein each G-Galkyl. G- Ghaloalkyl. C i -Co alkoxy, Ci-Cohctcroalkyl. G-Galkenyl. or G-Galkynyl is optionally substituted with 1 or 2 G-Gocycloalkyl, 3- to 10-membered heterocycloalkyl, G-Goaryl. or 5- to 10-membered heteroaryl; wherein each G-Galkyl. G-G,haloalkyl. G-G alkoxy. G- Gheteroalkyl. G-G, alkenyl. G-Galkynyl. C3-Ciocycloalkyl, 3- to 10-membered heterocycloalkyl, G-Goaryl. or 5- to 10-membered heteroaryl is optionally substituted with 1, 2, or 3 R9; or R4a and R4b together with the carbon atom to which they are attached form a carbonyl; or R4a and R4b together with the carbon atom to which they are attached form a G-Gocycloalkyl or 3- to 10-membered heterocycloalkyl ring; wherein the C3-Gocycloalkyl or 3- to 10-membered heterocycloalkyl ring is optionally substituted with 1, 2, or 3 R9;
R5 is NHR8,NHS(0)2R8, OR8, SR8, S(0)2R8, or S(0)2NHR8; or R5, R4a, and R4b, together with the carbon atom to which they are attached, form a G-Goaryl or 5- to 10-membered heteroaryl ring; wherein the G-Goaryl or 5- to 10-membered heteroaryl ring is optionally substituted with 1, 2, or 3 R9; R6a is hydrogen, halogen, -U, or -G;
R6b is halogen, -U, or -G;
-U is G-G, alkyl. Ci-Cehaloalkyl, Ci-Cealkoxy, Ci-Ceheteroalkyl, G-Galkenyl. or C2-G,alkynyl: wherein each G-G, alkyl. Ci-Cehaloalkyl, Ci-Cealkoxy, Ci-Ceheteroalkyl, G-G, alkenyl. or C2- Galkynyl is optionally substituted with 1, 2, or 3 R9 and/or 1 or 2 -G;
-G is C3-Ciocycloalkyl, 3- to 10-membered heterocycloalkyl, Ce-Cioaryl, or 5- to 10-membered heteroaryl; wherein each C3-Ciocycloalkyl, 3- to 10-membered heterocycloalkyl, Ce-Cioaryl, or 5- to 10-membered heteroaryl is optionally substituted with 1, 2, or 3 R9; or R6a and R6b together with the carbon atom to which they are attached form a saturated or partially saturated 3- to 7-membered cycloalkyl or a saturated or partially saturated 3- to 7-membered heterocycloalkyl; wherein the cycloalkyl or heterocycloalkyl is optionally substituted with 1, 2, or 3 R9;
R7a is hydrogen, halogen, Ci-C4alkyl, or Ci-C4haloalkyl;
R715 is hydrogen, halogen, Ci-C4alkyl, or Ci-C4haloalkyl; or R7a and R7b together with the carbon atom to which they are attached form a saturated or partially saturated 3- to 7-membered cycloalkyl or a saturated or partially saturated 3- to 7-membered heterocycloalkyl; wherein the cycloalkyl or heterocycloalkyl is optionally substituted with 1, 2, or
3 R9; or R6b and R715 together with the carbon atoms to which they are attached form a C3-Ciocycloalkyl or 3- to 10-membered heterocycloalkyl ring; wherein each C3-Ciocycloalkyl or 3- to 10-membered heterocycloalkyl ring is optionally substituted with 1, 2, or 3 R9; or R6a, R6b, R7a, and R7b together with the carbon atoms to which they are attached form a 5 - to 10- membered heteroaryl ring optionally substituted with 1, 2, or 3 R9;
R8 is Z, C2-G, alkyl. (Ci-C6alkylene)-Z, (Ci-C6heteroalkylene)-Z, (C2-Galkenylene)-Z, CH(Z)2, CH2CH(Z)2, CH(G -G, alkyl )Z. or C(0)Z; wherein each alkyl, alkylene, heteroalkylene, or alkenylene is optionally substituted with 1, 2, or 3 R9;
Z is C3-C9cycloalkyl, 3- to 10-membered heterocycloalkyl, G-Goaryl. 5- to 10-membered heteroaryl; wherein each C3-C9cycloalkyl, 3 - to 10-membered heterocycloalkyl, G-Goaryl. 5- to 10- membered heteroaryl is optionally substituted with 1, 2, or 3 R9; or Z is a substituted Ciocycloalkyl substituted with 1, 2, or 3 R9; and each R9 is independently halogen, Ci-C4alkyl, C2-C4alkenyl, C2-C4alkynyl, Ci-C4haloalkyl, Ci- C4alkoxy, Ci-C4haloalkoxy, Ci-C4heteroalkyl, -C(0)H, -C(0)0H, -CN, C3-Ciocycloalkyl, 3- to 10-membered heterocycloalkyl, G-Goaryl. 5- to 10-membered heteroaryl, -C(0)(Ci-C4alkyl), - C(0)0(Ci-C4alkyl), -C(0)NH2, -C(0)NH(Ci-C4alkyl), -C(0)N(Ci-C4alkyl)2, -NH2, -NH(Ci- C4alkyl), -N(Ci-C4alkyl)2, -NH(C2-C4alkylene)-OH, -NH(C2-C4alkylene)-0-(Ci-C4alkyl), -OH, - 0(Ci-C4alkyl), -0(Ci-C4haloalkyl), -0(C2-C4alkylene)-NH2, -0(C2-C4alkylene)-NH-(Ci-C4alkyl), -0(C2-C4alkylene)-N-(Ci-C4alkyl)2, -0(Ci-C4alkylene)-C(0)0H, -0(Ci-C4alkylene)-C(0)0-(Ci- C4alkyl), -0(C2-C4alkenyl), -0(Ci-C4alkylene)-(C6-Cioaryl), -0(Ci-C4alkylene)-(5- to 10- membered heteroaryl), -0(G,-Cioaryl). -SH, S(0)20H, -S(0)2(Ci-C4alkyl), -S(0)2NH2, - S(0)2NH(Ci-C4alkyl), or -S(0)2N(Ci-C4alkyl)2; or two R9 together with the atoms to which they are attached form a C3-Ciocycloalkyl or a 3- to 10-membered heterocycloalkyl ring.
[00126] In some embodiments, R5, R4a and R4b together with the carbon atom to which they are attached form a Ce-Cioaryl or 5- to 10-membered heteroaryl ring; wherein the Ce-Cioaryl or 5- to 10- membered heteroaryl ring is optionally substituted with 1, 2, or 3 R9. In some embodiments, R5, R4a and R4b together with the carbon atom to which they are attached form a 5- to 10-membered heteroaryl ring, optionally substituted with 1, 2, or 3 R9. In some embodiments, R5, R4a and R4b together with the carbon atom to which they are attached form a 9- or 10-membered heteroaryl ring, optionally substituted with 1, 2, or 3 R9. In some embodiments, R5, R4a and R4b together with the carbon atom to which they are attached form a 10-membered heteroaryl ring. In some embodiments, R5, R4a and R4b together with the carbon atom to which they are attached form a quinoline, isoquinoline, quinoxaline, quinazoline, quinolizine, naphthyridine. In some embodiments, R5, R4a and R4b together with the carbon atom to which they are attached form a 9-membered heteroaryl ring. In some embodiments, R5, R4a and R4b together with the carbon atom to which they are attached form a 2,3-dihydrobenzo[d]oxazole, benzo[d]oxazole, oxazolo[4,5-b]pyridine, lH-benzo[d]imidazole, benzo[d]thiazole, benzofuran, indole, aza-indole, lH-imidazo[4,5-b]pyridine, indolizine, imidazo[l,2- a]pyridine, or an isomer thereof, optionally substituted with 1, 2, or 3 R9. In some embodiments, R5, R4a and R4b together with the carbon atom to which they are attached form a benzo[d]oxazole, optionally substituted with 1, 2, or 3 R9. In some embodiments, the Ce-Cioaryl or 5- to 10-membered heteroaryl ring is unsubstituted.
[00127] In some embodiments, R5 is NHR8, NHS(0)2R8, OR8, SR8, S(0)2R8, or S(0)2NHR8. In some embodiments, R5 is NHR8, NHS(0)2R8, OR8, or S(0)2NHR8. In some embodiments, R5 is NHR8, NHS(0)2R8, or OR8. In some embodiments, R5 is OR8. In some embodiments, R5 is NHR8, or NHS(0)2R8. In some embodiments, R5is NHS(0)2R8. In some embodiments, R5 is NHR8.
[00128] In some embodiments of a compound of Formula (C-I), a compound has the structure of one of the following:
Figure imgf000057_0002
[00129] In some embodiments of a compound of Formula (C-I), a compound has the structure of Formula (C-II):
Figure imgf000057_0001
Formula (C-II).
[00130] In some embodiments, R4a is H. In some embodiments, R4a is H and R4b is halogen or haloalkyl. In some embodiments, R4b is CHF2 or CF3. In some embodiments, R4a is H and R4b is difluoromethyl or trifluoromethyl. In some embodiments, R4b is difluoromethyl or trifluoromethyl and R5 is OR8. In some embodiments, R4a and R4b are both H.
[00131] In some embodiments, R4a and R4b together with the carbon atom to which they are attached form a C3-Ciocycloalkyl or 3- to 10-membered heterocycloalkyl ring, wherein either of the cycloalkyl or heterocycloalkyl ring is optionally substituted with 1, 2, or 3 R9. In some embodiments, R4a and R4b together with the carbon atom to which they are attached form a G-Gcycloalkyl. optionally substituted with 1, 2, or 3 R9. In some embodiments, R4a and R4b together with the carbon atom to which they are attached form a C3-C5cycloalkyl, optionally substituted with 1, 2, or 3 R9. In some embodiments, R4a and R4b together with the carbon atom to which they are attached form a cyclopropyl, cyclobutyl, or cyclopentyl ring, optionally substituted with 1, 2, or 3 R9. In some embodiments, R4a and R4b together with the carbon atom to which they are attached form a cyclopropyl, cyclobutyl, or cyclopentyl ring and R5 is -OR8 or -NHR8. In some embodiments, R4a and R4b are each independently halogen, Ci-G, alkyl. G-Ghaloalkyl. C 1 -G, alkoxy, or G-Gheteroalkyl and R5 is NHR8. [00132] In some embodiments, R4a and R4b together with the carbon atom to which they are attached form a carbonyl. In some embodiments, R4a and R4b together with the carbon atom to which they are attached form a carbonyl and R5 is OR8 or NHR8. In some embodiments, R4a and R4b together with the carbon atom to which they are attached form a carbonyl and R5 is NHR8.
[00133] In some embodiments, R1 is hydrogen, G-Galkyl. G-Gcycloalkyl. G-Galkyl-(G- Gcycloalkyl). wherein each alkyl is optionally substituted with 1, 2, or 3 R9. In some embodiments, R1 is phenethyl. In some embodiments, R1 is hydrogen, methyl, trifluoromethyl, difluoromethyl, fluoromethyl, ethyl, propyl, isopropyl, cyclopropyl, methylenecyclopropyl, or cyclobutyl. In some embodiments, R1 is phenethyl. In some embodiments, R1 is hydrogen, methyl, trifluoromethyl, difluoromethyl, fluoromethyl, or ethyl. In some embodiments, R1 is hydrogen or methyl. In some embodiments, R1 is hydrogen.
[00134] In some embodiments of a compound of Formula (C-I), a compound has the structure of Formula (C-III):
Figure imgf000058_0001
Formula (C-III).
[00135] In some embodiments, R2a and R2b are each independently hydrogen, CrG, alkyl. G- Cehaloalkyl, G-G alkoxy, G-G, heteroalkyl. G-G, alkenyl. G-Galkynyl. wherein each alkyl, haloalkyl, alkoxy, heteroalkyl, alkenyl, or alkynyl is optionally substituted with 1, 2, or 3 R9. In some embodiments, R2a and R2b are each independently C3-Ciocycloalkyl, 3- to 10-membered heterocycloalkyl, G,-Cioaryl. or 5- to 10-membered heteroaryl, wherein each cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with 1, 2, or 3 R9. In some embodiments, R2a and R2b are each independently hydrogen, G-Galkyl. G-G, haloalkyl. G-G alkoxy, G- Gheteroalkyl, wherein each alkyl, haloalkyl, alkoxy, or heteroalkyl is optionally substituted with 1 or 2 G-Gcycloalkyl. 3- to 6-membered heterocycloalkyl, phenyl, or 5- or 6-membered heteroaryl. In some embodiments, R2a is H and R2b is G-Galkyl or G-Gheteroalkyl. wherein each alkyl or heteroalkyl is optionally substituted with a phenyl, or 5- or 6-membered heteroaryl. In some embodiments,
Figure imgf000058_0002
some embodiments, R2a is hydrogen. In some embodiments, R2a and R2b are each hydrogen. [00136] In some embodiments, R2a and R3a, and optionally R2band R3b, together with the carbon atoms to which they are attached form a G-Gcycloalkyl. 5- to 10-membered heterocycloalkyl, Ce-Cioaryl, or 5- to 10-membered heteroaryl ring; wherein each G-Gcycloalkyl. 5- to 10-membered heterocycloalkyl, G-Goaryl. or 5- to 10-membered heteroaryl ring is optionally substituted with 1, 2, or 3 R9;
[00137] In some embodiments, R2a and R2b together with the atom to which they are attached form a carbonyl. In some embodiments, R2a and R2b together with the atom to which they are attached form a carbonyl and X is NH. In some embodiments, R2a and R2b together with the atom to which they are attached form a carbonyl and X is O.
[00138] In some embodiments, R3a and R3b are each independently hydrogen, G-Galkyl. Ci- Ghaloalkyl. G-Galkoxy. G-Ghctcroalkyl. G-Galkcnyl. G-Galkynyl. G-Ciocycloalkyl, 3- to 10- membered heterocycloalkyl, G-Goaryl. or 5- to 10-membered heteroaryl, any of which is optionally substituted with 1, 2, or 3 R9. In some embodiments, R3a and R3b are each independently hydrogen, G-Galkyl. G-Ghaloalkyl. Ci-Ce alkoxy, Ci-Ceheteroalkyl, G-Galkcnyl. or G-Galkynyl. wherein each alkyl, haloalkyl, alkoxy, heteroalkyl, alkenyl, or alkynyl is optionally substituted with a cyclopropyl, phenyl, or 5- or 6-membered heteroaryl. In some embodiments, R3a and R3b are each independently hydrogen, methyl, trifluoromethyl, difluoromethyl, ethyl, propyl, isopropyl, cyclopropyl, benzyl, phenethyl, or isobutyl. In some embodiments, R3a and R3b are each methyl. In some embodiments, R3a is hydrogen. In some embodiments, R3a and R3b are each hydrogen.
[00139] In some embodiments, R2a and R3a, together with the carbon atoms to which they are attached, form a G-Gcycloalkyl. or 5- to 10-membered heterocycloalkyl. In some embodiments, R2a and R3a, together with the carbon atoms to which they are attached, form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxirane, oxetane, tetrahydrofuran, tetrahydropyran, dioxane, aziridine, azetidine, pyrrolidine, piperidine, or morpholine, each of which is optionally substituted with 1 R9. In some embodiments, R2a and R3a, together with the carbon atoms to which they are attached, form a cyclopropyl, cyclohexyl, dioxane, piperidine, or morpholine, each of which is optionally substituted with 1 R9. In some embodiments, R2a and R3a together with the carbon atoms to which they are attached form a G-Gcycloalkyl. In some embodiments, R2a and R3a together with the carbon atoms to which they are attached form a G-Gcycloalkyl. optionally substituted with 1, 2, or 3 R9. In some embodiments, R2a and R3a, together with the carbon atoms to which they are attached, form a cyclopropyl or cyclohexyl, either of which is optionally substituted with 1, 2, or 3 R9. In some embodiments, R2a and R3a, together with the carbon atoms to which they are attached, form a cyclohexyl.
[00140] In some embodiments, X is NRA, O, S, S(O), or S(0)2. In some embodiments, X is O. In some embodiments, X is S or S(0)2. In some embodiments, X is S. In some embodiments, X is S(0)2. In some embodiments, X is NRA. In some embodiments, RA is G-Galkyl. C(0)-(G-Galkyl). or C(0)-(G-C6cycloalkyl), wherein each alkyl or cycloalkyl is optionally substituted with 1, 2, or 3 R9. In some embodiments, RA is hydrogen, methyl, ethyl, C(0)CH3, C(0)cyclopropyl, or C(0)cyclohexyl, wherein each cyclopropyl or cyclohexyl is optionally substituted with 1 or 2 R9. In some embodiments, RA is hydrogen, methyl, or C(0)CI¾. In some embodiments, RA is hydrogen. In some embodiments of a compound of Formula (C-I), a compound has the structure of Formula (C-IV- a), (C-IV-b), (C-IV-c), or (C-IV-d):
Figure imgf000060_0001
Formula (C-IV-c) or Formula (C-IV-d).
[00141] In some embodiments of a compound of Formula (C-I), a compound has the structure of Formula (C-V-a), (C-V-b), (C-V-c), or (C-V-d):
Figure imgf000060_0002
Formula (C-V-c) or Formula (C-V-d).
[00142] In some embodiments of a compound of Formula (C-I), a compound has the structure of Formula (C-VI-a), (C-VI-b), (C-VI-c), or (C-VI-d):
Figure imgf000061_0001
Formula (C-VI-c) or Formula (C-VI-d).
[00143] In some embodiments, X is C and taken together with R2a, R2b, and the carbon atom to which they are attached, forms a phenyl or 5- to 10-membered heteroaryl ring, optionally substituted with 1, 2, or 3 R9. In some embodiments, X is C and taken together with R2a, R2b, and the carbon atom to which they are attached, forms a phenyl ring, optionally substituted with 1, 2, or 3 R9. In some embodiments, X is C and taken together with R2a, R2b, and the carbon atom to which they are attached, forms a 5- to 10-membered heteroaryl ring, optionally substituted with 1, 2, or 3 R9. In some embodiments, X is C and taken together with R2a, R2b, and the carbon atom to which they are attached, forms a 5-membered heteroaryl ring, optionally substituted with 1, 2, or 3 R9. In some embodiments, X is C and taken together with R2a, R2b, and the carbon atom to which they are attached, forms a 9- or 10-membered heteroaryl ring, optionally substituted with 1, 2, or 3 R9. In some embodiments, X is C and taken together with R2a, R2b, and the carbon atom to which they are attached, forms a pyrrole, pyrazole, imidazole, indole, or azaindole ring, optionally substituted with 1, 2, or 3 R9. In some embodiments, a compound as disclosed herein has the structure of one of the following:
Figure imgf000061_0002
[00144] In some embodiments of a compound of Formula (C-I), R6a, R6b, R7a, and R7b together with the carbon atoms to which they are attached form a 5 - to 10-membered heteroaryl ring optionally substituted with 1, 2, or 3 R9. In some embodiments of a compound of Formula (C-I), R6a, R6b, R7a, and R7|;’ together with the carbon atoms to which they are attached form a furan, pyrrole, imidazole, pyrazole, triazole, pyridine, pyrimidine, pyridazine, pyrazine, thiophene, oxazole, thiazole, isoxazole, isothiazole, oxepin, azepine, thiepine, triazine, or tetrazine, any of which being optionally substituted with 1, 2, or 3 R9. In some embodiments of a compound of Formula (C-I), R6a, R6b, R7a, and R7|;’ together with the carbon atoms to which they are attached form a furan, pyrrole, imidazole, pyrazole, pyridine, pyrimidine, pyridazine, pyrazine, any of which being optionally substituted with 1, 2, or 3 R9. In some embodiments of a compound of Formula (C-I), R6a, R6b, R7a, and R715 together with the carbon atoms to which they are attached form a furan, pyrrole, pyridine, pyrimidine, pyridazine, pyrazine, any of which being optionally substituted with 1, 2, or 3 R9. In some embodiments of a compound of Formula (C-I), R6a, R6b, R7a, and R715 together with the carbon atoms to which they are attached form a pyridine ring.
[00145] In some embodiments of a compound of Formula (C-I), R6b and R715 together with the carbon atoms to which they are attached form a C3-Ciocycloalkyl or 3- to 10-membered heterocycloalkyl ring; wherein each C3-Ciocycloalkyl or 3- to 10-membered heterocycloalkyl ring is optionally substituted with 1, 2, or 3 R9. In some embodiments of a compound of Formula (C-I), R6band R7b together with the carbon atoms to which they are attached form a G-Gcycloalkyl or 3- to 6- membered heterocycloalkyl ring; wherein each G-Gcycloalkyl or 3- to 6-membered heterocycloalkyl ring is optionally substituted with 1, 2, or 3 R9. In some embodiments of a compound of Formula (C- I), R6b and R7b together with the carbon atoms to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxirane, aziridine, oxetane, azetidine, oxolane, pyrrolidine, thiolane, oxazolidine, imidazolidine, thiazolidine, isoxazolidine, pyrazolidine, isothiazolidine, dioxolane, dithiolane, oxane, piperidine, thiolane, morpholine, piperazine, thiazine, or dioxane ring, wherein each ring is optionally substituted with 1, 2, or 3 R9. In some embodiments of a compound of Formula (C-I), R6b and R7b together with the carbon atoms to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxolane, oxane, dioxane, morpholine, pyrrolidine, or piperidine ring.
[00146] In some embodiments of a compound of Formula (C-I), R7a and R7b together with the carbon atom to which they are attached form a saturated or partially saturated 3- to 7-membered cycloalkyl or a saturated or partially saturated 3- to 7-membered heterocycloalkyl; wherein the cycloalkyl or heterocycloalkyl is optionally substituted with 1, 2, or 3 R9. In some embodiments of a compound of Formula (C-I), R7a and R715 together with the carbon atom to which they are attached form a saturated or partially saturated 3- to 5-membered cycloalkyl or a saturated or partially saturated 3- to 5- membered heterocycloalkyl; wherein the cycloalkyl or heterocycloalkyl is optionally substituted with 1, 2, or 3 R9. In some embodiments of a compound of Formula (C-I), R7a and R715 together with the carbon atom to which they are attached form a cyclopropyl, cyclobutyl, cyclopropenyl, cyclobutenyl, oxirane, aziridine, oxetane, azetidine, or cyclopentyl, or cyclopentenyl ring, wherein each ring is optionally substituted with 1, 2, or 3 R9. In some embodiments of a compound of Formula (C-I), R7a and R7|;’ together with the carbon atom to which they are attached form a cyclopropyl ring, optionally substituted with 1, 2, or 3 R9. In some embodiments of a compound of Formula (C-I), R7a and R7|;’ are each independently hydrogen, halogen, Ci-C4alkyl, or Ci-C4haloalkyl. In some embodiments of a compound of Formula (C-I), R7a and R715 are each independently hydrogen, fluoro, methyl, ethyl, difluoromethyl, or trifluoromethyl. In some embodiments of a compound of Formula (C-I), R7a and R715 are each independently hydrogen, methyl, or ethyl. In some embodiments of a compound of Formula (C-I), R7a and R715 are each hydrogen.
[00147] In some embodiments of a compound of Formula (C-I), R6a and R6b together with the carbon atom to which they are attached form a saturated or partially saturated 3- to 7-membered cycloalkyl ring optionally substituted with 1, 2, or 3 R9. In some embodiments of a compound of Formula (C-I), R6a and R6b together with the carbon atom to which they are attached form a cyclopropyl, cyclobutyl, cyclopropenyl, cyclobutenyl, oxirane, aziridine, oxetane, azetidine, or cyclopentyl, or cyclopentenyl ring, wherein each ring is optionally substituted with 1, 2, or 3 R9. In some embodiments of a compound of Formula (C-I), R6a and R6b together with the carbon atom to which they are attached form a saturated or partially saturated 3- to 5-membered cycloalkyl ring, optionally substituted with 1, 2, or 3 R9.
[00148] In some embodiments, R6ais hydrogen. In some embodiments, R6ais hydrogen and R6b is halogen, Ci-G, alkyl. Ci-G,haloalkyl. G-Cealkenyl, or G-Galkynyl: wherein each G-Galkyl. G- Ghaloalkyl. C2-Cealkenyl, or G-Galkynyl is optionally substituted with 1, 2, or 3 R9 and/or 1 or 2,
G. In some embodiments, R6b is halogen, G-Galkyl. G-Ghaloalkyl. C2-Cealkenyl, or G-Galkynyl: wherein each G-Galkyl. G-Ghaloalkyl. C2-Cealkenyl, or G-Galkynyl is optionally substituted with
1, 2, or 3 R9 and/or 1 or 2, G. In some embodiments, R6b is G-Galkyl. G-Ghaloalkyl. G-Galkenyl. or G-Galkynyl. wherein each alkyl, haloalkyl, alkenyl, or alkynyl is optionally substituted with a phenyl or 5- or 6-membered heteroaryl ring, wherein each phenyl or heteroaryl ring is optionally substituted with 1, 2, or 3 R9. In some embodiments, R6b is methyl, ethyl, or propyl, wherein the methyl, ethyl, or propyl is optionally substituted with G, and wherein G is a phenyl ring further substituted with 1, 2, or 3 R9. In some embodiments, R6b is ethyl, optionally substituted with phenyl, tolyl, phenolyl, fluorophenyl, chlorophenyl, anilinyl, methoxyphenyl, dimethylphenyl, difluorophenyl, dichlorophenyl, dihydroxyphenyl, dimethoxyphenyl, fluoromethoxyphenyl, or naphthyl. In some embodiments, R6b is G-Galkyl. G-Ghaloalkyl. G-Galkenyl. or G-Galkynyl. wherein each alkyl, haloalkyl, alkenyl, or alkynyl is optionally substituted with a G-Gcycloalkyl or 3- to 6-membered heterocycloalkyl ring, wherein each cycloalkyl or heterocyclalkyl ring is optionally substituted with 1,
2, or 3 R9. In some embodiments, R6b is methyl, ethyl, 2-propenyl, isopropyl, or phenethyl. In some embodiments, R6b is methyl. In some embodiments, R6b is ethyl. In some embodiments, R6b is 2- propenyl. In some embodiments, R6b is isopropyl. In some embodiments, R6b is phenethyl.
[00149] In some embodiments of a compound of Formula (C-I), R6a and R6b are each independently halogen, G-Galkyl. G-Ghaloalkyl. G-Galkenyl. or G-Galkynyl: wherein each G-Galkyl. G- Ghaloalkyl. C -G, alkenyl or G-Galkynyl is optionally substituted with 1, 2, or 3 R9 and/or 1 or 2,
G. In some embodiments of a compound of Formula (C-I), R6a and R6b are each independently halogen, G-Galkyl. G -Ghaloalkyl. G-Galkcnyl. or CN-Ci.alkynyl: wherein each G-Galkyl. Ci- Cehaloalkyl, CN-Ci, alkenyl or G-Galkynyl is optionally substituted with 1, 2, or 3 R9 and/or 1 or 2,
G. In some embodiments of a compound of Formula (C-I), R6a and R6b are each independently Ci- Galkyl. Ci-Cehaloalkyl, CN-Ci, alkenyl or G-Galkynyl. wherein each alkyl, haloalkyl, alkenyl, or alkynyl is optionally substituted with a phenyl or 5- or 6-membered heteroaryl ring, wherein each phenyl or heteroaryl ring is optionally substituted with 1, 2, or 3 R9. In some embodiments of a compound of Formula (C-I), R6a and R6b are each independently methyl, ethyl, or propyl, optionally substituted with G, wherein G is a phenyl ring further substituted with 1, 2, or 3 R9. In some embodiments, R6a and R6b are each independently ethyl, optionally substituted with phenyl, tolyl, phenolyl, fluorophenyl, chlorophenyl, anilinyl, methoxyphenyl, dimethylphenyl, difluorophenyl, dichlorophenyl, dihydroxyphenyl, dimethoxyphenyl, fluoromethoxyphenyl, or naphthyl. In some embodiments of a compound of Formula (C-I), R6a and R6b are each independently G-Galkyl. Ci- C , haloalkyl. CN-Ci, alkenyl or G-Galkynyl. wherein each alkyl, haloalkyl, alkenyl, or alkynyl is optionally substituted with a G-Gcycloalkyl or 3- to 6-membered heterocycloalkyl ring, wherein each cycloalkyl or heterocyclalkyl ring is optionally substituted with 1, 2, or 3 R9. In some embodiments of a compound of Formula (C-I), R6a and R6b are each independently methyl, ethyl, 2- propenyl, isopropyl, or phenethyl. In some embodiments, R6a and R6b are each independently ethyl, 2- propenyl, isopropyl, or phenethyl. In some embodiments of a compound of Formula (C-I), R6a and R6b are methyl. In some embodiments, R6a and R6b are ethyl. In some embodiments, R6a and R6b are 2- propenyl. In some embodiments, R6a and R6b are isopropyl. In some embodiments, R6a and R6b are phenethyl.
[00150] In some embodiments, R8 is Z, G-Galkyl. (Ci-C6alkylene)-Z, (Ci-C6heteroalkylene)-Z, (C2- C6alkenylene)-Z, CH(Z)2, ϋ¼ϋI(Z)2, CH(G-Galkyl)Z. or C(0)Z; wherein each alkyl, alkylene, heteroalkylene, or alkenylene is optionally substituted with 1, 2, or 3 R9. In some embodiments, R8 is Z, G-Galkyl. CH(Z)2, or C(0)Z. In some embodiments of a compound of Formula (C-I), R8 is Z, C2- Galkyl. CH(Z)2, or C(0)Z, wherein Z is C3-C9cycloalkyl, 3- to 10-membered heterocycloalkyl, G- Cioaryl, or 5- to 10-membered heteroaryl. In some embodiments, R8is Z or CH(Z)2. In some embodiments, R8is Z. In some embodiments, R8is CH(Z)2. In some embodiments of a compound of Formula (C-I), Z is C3-C9cycloalkyl, 3- to 10-membered heterocycloalkyl, G-Goaryl. or 5- to 10- membered heteroaryl; wherein each C3-C9cycloalkyl, 3- to 10-membered heterocycloalkyl, G- Cioaryl, and 5- to 10-membered heteroaryl is optionally substituted with 1, 2, or 3 R9. In some embodiments, Z is G-Goaryl or 5- to 10-membered heteroaryl, wherein each aryl or heteroaryl is optionally substituted with 1, 2, or 3 R9. In some embodiments of a compound of Formula (C-I), Z is C3-C9cycloalkyl or 3- to 10-membered heterocycloalkyl; wherein each C3-C9cycloalkyl and 3- to 10- membered heterocycloalkyl is optionally substituted with 1, 2, or 3 R9. In some embodiments of a compound of Formula (C-I), Z is Ciocycloalkyl substituted with 1, 2, or 3 R9. In some embodiments, Z is phenyl or naphthyl, optionally substituted with 1, 2, or 3 R9. In some embodiments, Z is pyridine, pyrimidine, pyridazine, pyrazine, quinoline, naphthyridine, quinoxaline, quinolizine, benzofuran, benzoxazole, or benzothiophene. In some embodiments, Z is tetrahydroquinoline, tetrahydroisoquinoline, chroman, thiochroman, indane, indoline, dihydrobenzofuran, or dihydrobenzothiophene .
[00151] In some embodiments of a compound of Formula (C-I), R8 is:
Figure imgf000065_0001
Figure imgf000066_0001
[00152] In some embodiments of a compound of Formula (C-I), R8 is:
Figure imgf000066_0002
[00154] In some embodiments of a compound of Formula (C-I), R8 is:
Figure imgf000066_0003
[00155] In some embodiments of a compound of Formula (C-I), R8 is:
Figure imgf000067_0001
[00156] In some embodiments of a compound of Formula (C-I), R8 is:
Figure imgf000067_0002
[00157] In some embodiments of a compound of Formula (C-I), R8 is:
Figure imgf000067_0003
[00158] In some embodiments, each R9 is independently halogen, Ci-C4alkyl, C2-C4alkenyl, C2- C4alkynyl, Ci-C4haloalkyl, Ci-C4alkoxy, Ci-C4haloalkoxy, Ci-C4heteroalkyl, -C(0)H, -C(0)OH, -CN, C3-Ciocycloalkyl, 3- to 10-membered heterocycloalkyl, Ce-Cioaryl, 5- to 10-membered heteroaryl, - N(Ci-C4alkyl)2, -OH, -0(Ci-C4alkyl), -0(Ci-C4haloalkyl), -0(Ci-C4alkylene)-(5- to 10-membered heteroaryl), -O(C6-Ci0aryl), -SH, S(0)2OH, -S(0)2(Ci-C4alkyl), -S(0)2NH2, -S(0)2NH(Ci-C4alkyl), or -S(0)2N(Ci-C4alkyl)2. In some embodiments, each R9 is independently halogen, Ci-C4alkyl, C2- C4alkenyl, C2-C4alkynyl, Ci-C4haloalkyl, Ci-C4alkoxy, Ci-C4haloalkoxy, Ci-C4heteroalkyl, -C(0)H, - C(0)OH, -CN, C3-Ciocycloalkyl, 3- to 10-membered heterocycloalkyl, Ce-Cioaryl, 5- to 10-membered heteroaryl, -OH, -0(Ci-C4alkyl), or -0(Ci-C4haloalkyl). In some embodiments, each R9 is independently halogen, Ci-C4alkyl, -C(0)OH, -0(Ci-C4alkyl), -0(Ci-C4haloalkyl), or 5- to 10- membered heteroaryl. In some embodiments, each R9 is each independently -C(0)OH, -0(CH3), - OiQrhQrhF), or pyrimidine. [00159] In some embodiments, a compound of the present disclosure has the structure:
Figure imgf000068_0001
[00161] In some embodiments, a compound of the present disclosure has the structure:
Figure imgf000068_0002
[00163] In some embodiments, a compound of the present disclosure has the structure:
Figure imgf000069_0001
[00165] In some embodiments, a compound of the present disclosure has the structure:
Figure imgf000069_0002
[00167] In some embodiments, a compound of the present disclosure has the structure:
Figure imgf000070_0003
[00169] In some embodiments, a compound of the present disclosure has the structure:
Figure imgf000070_0001
[00170] In some embodiments, a compound of the present disclosure has the structure:
Figure imgf000070_0002
[00171] In some embodiments, a compound of the present disclosure has the structure:
Figure imgf000071_0001
[00172] In some embodiments, a compound described herein has the form of any one of the structures found in Table A. Various stereoisomers (e.g., enantiomers, diastereomers) exist for many of the compounds disclosed. All of the possible stereoisomers are contemplated within the context of the present disclosure. In some embodiments, a compound disclosed herein may be a mixture of stereoisomers. In some embodiments, a compound may be a pure isomer. In some embodiments, a compound is a mixture of enantiomers. In some embodiments, a compound is a mixture of diastereomers. In some embodiments, a compound disclosed herein exists as a mixture of various stereoisomers, wherein one or more chiral centers are unresolved or unseparated. In some embodiments, each chiral center is known. In some embodiments, a subset of the total number of chiral centers have known stereochemistry. In some embodiments, a compound may be racemized or contain a mixture of racemates.
Table A
Figure imgf000071_0002
Figure imgf000072_0001
Figure imgf000073_0001
Figure imgf000074_0001
Figure imgf000075_0001
Figure imgf000076_0001
Figure imgf000077_0001
Figure imgf000078_0001
Figure imgf000079_0001
Figure imgf000080_0001
Figure imgf000081_0001
Figure imgf000082_0001
Figure imgf000083_0001
Figure imgf000084_0001
Figure imgf000085_0001
Figure imgf000086_0001
Figure imgf000087_0002
Figure imgf000087_0001
[00173] Any combination of the groups described above or below for the various variables is contemplated herein. Throughout the specification, groups and substituents thereof are chosen by one skilled in the field to provide stable moieties and compounds.
Further Forms of Compounds Disclosed Herein
Isomers/Stereoisomers
[00174] In some embodiments, 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, entgegen (E), and zusammen (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. In additional embodiments of the compounds and methods provided herein, mixtures of enantiomers and/or diastereoisomers, resulting from a single preparative step, combination, or interconversion are useful for the applications described herein. In some embodiments, 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. In some embodiments, dissociable complexes are preferred. In some embodiments, the diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and are separated by taking advantage of these dissimilarities. In some embodiments, the diastereomers are separated by chiral chromatography, or preferably, by separation/resolution techniques based upon differences in solubility. In some embodiments, the optically pure enantiomer is then recovered, along with the resolving agent.
[00175] In some embodiments, one isomer binds a target with higher affinity than another. In some embodiments, a mixture of isomers is preferable. In some embodiments, a compound described herein with unknown or undisclosed stereochemistry is a mixture of enantiomers or diastereomers. In some embodiments, an isomer disclosed as an (R) enantiomer may contain some portion of the (S) isomer as well. In some embodiments, a compound disclosed as an (R) isomer may contain up to 0.01%, 0.1%, 0.5%, 1%, 2%, 3%, 5%, 10%, 20%, 30%, 40%, 49% of the (S) isomer. In the preceding example, either isomer is interchangeable, e.g., a compound disclosed as an (S) isomer may contain any amount previously described of the (R) isomer as well. In some embodiments, a compound is isomerically pure. In some embodiments, a compound disclosed as a mixture of isomers may contain a given isomer in up to 99.9%, 99%, 98%, 97%, 95%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10%, 5%, 3%, 2%, 1%, 0.5%, or 0.1% abundance relative to alternate isomers present in the mixture.
Labeled compounds
[00176] In some embodiments, the compounds described herein exist in their isotopically -labeled forms. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds as pharmaceutical compositions. Thus, in some embodiments, 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. Examples of isotopes that can be incorporated into compounds described herein, or a solvate, or stereoisomer thereof, include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, and chloride, such as 2H, 3H, 13C, 14C, 15N, 180, 170, 31P, 32P, 35S, 18F, and 36C1, 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 disclosure. Certain isotopically -labeled compounds, for example those into which radioactive isotopes such as 3H and 14C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3H and carbon-14, i.e., 14C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavy isotopes such as deuterium, i.e., 2H, produces certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half- life or reduced dosage requirements. In some embodiments, the isotopically labeled compound or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is prepared by any suitable method. [00177] In some embodiments, the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, biolumine scent labels, or chemiluminescent labels.
Pharmaceutically acceptable salts
[00178] In some embodiments, the compounds described herein exist as their pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.
[00179] In some embodiments, the compounds described herein possess acidic or basic groups and therefor react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein, or by separately reacting a purified compound in its free form with a suitable acid or base, and isolating the salt thus formed. [00180] 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, benzene sulfonate, bisulfate, bisulfite, bromide, butyrate, butyn-l,4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, formate, fiimarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne-l,6-dioate, hydroxybenzoate, g-hydroxybutyrate, hydrochloride, hydrobromide, hydroiodide, 2- hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, monohydrogenphosphate, 1 - napthalenesulfonate, 2-napthalenesulfonate, nicotinate, nitrate, palmoate, pectinate, persulfate, 3- phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate, thiocyanate, tosylateundeconate, and xylenesulfonate. [00181] Further, 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 -toluene sulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methane sulfonic acid, ethanesulfonic acid, 1,2- ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzene sulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo-[2.2.2]oct-2-ene-l-carboxylic acid, glucoheptonic acid, 4,4’-methylenebis-(3- hydroxy-2-ene-l -carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and muconic acid.
[00182] In some embodiments, those compounds described herein which comprise a free acid group react with a suitable base, such as the hydroxide, carbonate, bicarbonate, or 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. Illustrative examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N+(CI-4 alkyl)4, and the like.
[00183] Representative 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 quatemization of any basic nitrogen-containing groups they contain. In some embodiments, water or oil-soluble or dispersible products are obtained by such quatemization.
Solvates
[00184] In some embodiments, the compounds described herein exist as solvates. The disclosure provides for methods of treating diseases by administering such solvates. The disclosure further provides for methods of treating diseases by administering such solvates as pharmaceutical compositions.
[00185] 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 such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein can be conveniently prepared or formed during the processes described herein. In addition, the compounds provided herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.
Tautomers
[00186] In some situations, compounds exist as tautomers. The compounds described herein include all possible tautomers within the formulas described herein. 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.
Synthesis of Compounds
[00187] In some embodiments, the synthesis of compounds described herein are accomplished using means described in the chemical literature, using the methods described herein, or by a combination thereof. In addition, solvents, temperatures and other reaction conditions presented herein may vary. [00188] In other embodiments, the starting materials and reagents used for the synthesis of the compounds described herein are synthesized or are obtained from commercial sources, such as, but not limited to, Sigma-Aldrich, FischerScientific (Fischer Chemicals), and AcrosOrganics.
[00189] In further embodiments, the compounds described herein, and other related compounds having different substituents are synthesized using techniques and materials described herein as well as those that are recognized in the field, such as described, for example, in Fieser and Fieser’s Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd’s Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), Larock’s Comprehensive Organic Transformations (VCH Publishers Inc., 1989), March, Advanced Organic Chemistry 4th Ed., (Wiley 1992); Carey and Sundberg, Advanced Organic Chemistry 4th Ed., Vols. A and B (Plenum 2000, 2001), and Green and Wuts, Protective Groups in Organic Synthesis 3rd Ed., (Wiley 1999) (all of which are incorporated by reference for such disclosure). General methods for the preparation of compounds as disclosed herein may be derived from reactions and the reactions may be modified by the use of appropriate reagents and conditions, for the introduction of the various moieties found in the formulae as provided herein. As a guide the following synthetic methods may be utilized.
[00190] A synthetic route as outlined in Scheme 1 provides access compounds as described in Formula A-I, B-I, or C-I, in a highly efficient 3-step process. An initial Ugi 4-component reaction (4CR) enables efficient access to the fused 7-/5-membered scaffold as described herein. By stirring the carboxylic acid, aldehyde, isocyanide, and ammonia in 2,2,2,-trifluoroethanol (TFE) under microwave irradiation at 80 °C for 20 min, an intermediate product (not shown) is produced as a mixture of diastereomers. Subsequent treatment with trifluoroacetic acid (TFA) induces a reaction cascade resulting in Boc-deprotection and formation of the bicyclic ring structure shown in intermediates la and lb. These combined transformations comprise step a in Scheme 1 below. The diastereomeric pair la and lb are then separated by chromatography or other suitable methods (e.g., recrystallization), or are carried forward as a mixture of stereoisomers. In some instances, it is advantageous to carry forward with a crude mixture containing la and lb without purification. The primary amines of la and lb undergo a coupling reaction in step b with Boc-N-Me-Ala-OH to give a 1:1 mixture of diastereomers lc and Id, which are optionally purified by chromatography or other suitable methods. In some instances, purification is carried out using flash chromatography on silica gel. A final TFA deprotection (step c) gives the final compounds le and If. In some instances, overall yield for the four-step process involving a single purification step is 36-60%. The scheme as described extends to various alternatively-substituted aldehydes, carboxylic acids, or isocyanides, facilitating the synthesis of a broad range of compounds as disclosed herein.
Scheme 1
Figure imgf000092_0001
Conditions: (a) 1 eq carboxylic acid, 1.05 eq aldehyde, 1 eq isocyanide in TFE, pW heating at 80 °C, 20 min; then 8-10 eq TFA, DCM, 32 °C; (b) Boc-N-Me-Ala-OH, HOBT, EDC, NMM, THF; (c) 8 eq TFA, DCM, 23 °C.
[00191] In addition to the scaffolds outlined in Scheme 1, scaffolds featuring additional fused ring systems as described within Formula (A-I) or (C-I) can be accessed using an appropriately substituted carboxylic acid and/or aldehyde. Examples of some fused ring systems contemplated in the present disclosure, by way of non-limiting example, include those indicated in Scheme 2. Following a 4CR similar to that previously described in Scheme 1, followed by subsequent TFA deprotection/cyclization, a diastereomeric pair of compounds as indicated by intermediate 2 can be accessed. In step a, an appropriate carboxylic acid, aldehyde, isocyanide, and ammonia are stirred in TFE while heating under microwave irradiation (e.g., at 80 °C for 20 min). Following the 4CR, the intermediate (not shown) is treated with TFA to facilitate Boc deprotection and cyclization to achieve intermediate 2. In subsequent steps, as outlined in Scheme 1, the primary amine can be substituted and deprotected to achieve a compound as described within Formula (A-I) or (C-I). In many cases, the microwave reaction conditions can be replaced with continuous flow conditions, which mimics the efficient heating dynamics of microwave technology. For example, the first two steps (step a) can be performed in series without the need for purification. After collection of the intermediate 2 and a switch of solvent to THF, steps b and c as outlined in Scheme 1 can be executed to give final compounds as disclosed within Formula (A-I) or (C-I).
Scheme 2
Figure imgf000093_0001
Conditions: (a) 1 eq carboxylic acid, 1.05 eq aldehyde, 1 eq isocyanide in TFE, pW heating at 80 °C, 20 min; then 8-10 eq TFA, DCM, 32 °C
[00192] It will be understood that the reactions shown in Schemes 1-3 above are illustrative and are also applicable to synthesis of compounds of Formula II and III, and such disclosure is contemplated within the scope of embodiments described herein. Synthesis of compounds of Formula I, II, and III are also shown in further detail in the Chemistry Examples section.
[00193] Highlighted in Scheme 3 are synthetic routes to compounds featuring various amide isosteres. Using the valuable N-acylindole 6 allows the incorporation of a variety of functional groups at the region indicated in grey (Scheme 3). The utility of 6 stems from its reactivity, which is similar to an ester and allows for hydride reduction to either the alcohol (using excess NaBH4) or aldehyde 8 (using 1 equivalent of NaBH4). Alkylation of the fully reduced alcohol provides access to ether derivatives 7. Chemistry has also been developed for the trifluoromethylation of carbonyls similar to 8 to construct CF3-containing ether 9. The ^-stereochemistry at the CF3 -containing stereocenter would be predicted based on the Felkin-Anh model. Reductive amination of aldehyde 8 affords the useful amine 10, from which a library of sulfonamides 11 are prepared. Scheme 3
Figure imgf000094_0001
[00194] Scheme 4 details additional methods for functionalization of the region of the scaffold indicated in grey. The N-acylindole 6 is easily converted to the methyl ester 12 in basic methanol, from which the titanium-mediated Kulinkovich reaction can be used to access cyclopropyl alcohols. Formation of the sulfonate 13 followed by treatment with MgBr2 affords the allyl bromide 14, which is a versatile intermediate. From here, a variety of different types of nucleophiles (alcohols, amines, thiols) are applied to access new chemical space. Tsuji-Trost conditions may also be employed for further activation of the allyl bromide with catalytic palladium. Synthesis of the nitrile 16 is achieved from aldehyde 8 using mild conditions (Scheme 4), and nitriles such as 16 are very reactive under Kulinkovich conditions (nitrile>ester>amide) to yield the cyclopropylamine. Subsequent treatment with a variety of potential electrophiles (alkyl halides, aryl halides, sulfonyl halides, acyl halides) gives derivatives 17. In order to perform the Kulinkovich reaction from a carboxamide, a modified strategy is adopted. Protection of amide 18 (made similarly to Scheme 5, but with Cbz instead of Boc) with the MTM group, followed by cyclopropylamine formation gives 19. Several deprotection reactions and a coupling with the alanine derivative provides new analogs such as 20 where the carboxamide carbonyl is replaced by a cyclopropyl group.
Scheme 4
Figure imgf000095_0001
[00195] In Scheme 6, the 2-substituted indole derivative 23 can be synthesized by Fischer indole synthesis of ketone 21 with various phenylhydrazines 22. Isomer 24 may also form, but the silyl group helps direct enol formation to give preference to isomer 23. In either case, the silyl group cleaves under the acidic reaction conditions. Based on chemistry for a similarly activated acyl group, N-acylindole 6 undergoes displacement with the silyl Grignard reagent to give the ketone 21. Scheme 6
Figure imgf000096_0001
[00196] Although benzoxazole 28 and benzothiazole 29 can be accessed from aldehyde 8, a more efficient route via intermediate 27 by use of o-bromophenyl isocyanides 25 in the Ugi multicomponent reaction (Scheme 7). A copper-mediated coupling to form the benzoxazoles 28 and benzothiazole s 29 is then accomplished, giving the desired carboxamide isosteres.
Scheme 7
Figure imgf000096_0002
Administration and Pharmaceutical Composition
[00197] In general, the compounds of this invention will be administered in a therapeutically effective amount by any of the accepted modes of administration for agents that serve similar utilities. Therapeutically effective amounts of compound of Formula I, II, or III may range from about 0.01 to about 500 mg per kg patient body weight per day, which can be administered in single or multiple doses. Preferably, the dosage level will be about 0.1 to about 250 mg/kg per day; more preferably about 0.5 to about 100 mg/kg per day. A suitable dosage level may be about 0.01 to about 250 mg/kg per day, about 0.05 to about 100 mg/kg per day, or about 0.1 to about 50 mg/kg per day. Within this range the dosage can be about 0.05 to about 0.5, about 0.5 to about 5 or about 5 to about 50 mg/kg per day. For oral administration, the compositions are preferably provided in the form of tablets containing about 1.0 to about 1000 milligrams of the active ingredient, particularly about 1.0, 5.0, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900, and 1000 milligrams of the active ingredient. The actual amount of the compound of this invention, i.e., the active ingredient, will depend upon numerous factors such as the severity of the disease to be treated, the age and relative health of the subject, the potency of the compound being utilized, the route and form of administration, and other factors.
[00198] In general, compounds of this invention will be administered as pharmaceutical compositions by any one of the following routes: oral, systemic (e.g., intranasal, suppository, intrapulmonary), or parenteral (e.g., intramuscular, intravenous, intrathecal, or intraperitoneal) administration. The preferred manner of administration is oral using a convenient daily dosage regimen, which can be adjusted according to the degree of affliction. Compositions can take the form of tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols, liposomes, exosomes, nanoparticles, or any other appropriate compositions.
[00199] The choice of formulation depends on various factors such as the mode of drug administration (e.g., for oral administration, formulations in the form of tablets, pills or capsules are preferred) and the bioavailability of the drug substance. Recently, pharmaceutical formulations have been developed especially for drugs that show poor bioavailability based upon the principle that bioavailability can be increased by increasing the surface area i.e., decreasing particle size. For example, U.S. Pat. No. 4,107,288 describes a pharmaceutical formulation having particles in the size range from 10 to 1,000 nm in which the active material is supported on a crosslinked matrix of macromolecules. U.S. Pat. No. 5,145,684 describes the production of a pharmaceutical formulation in which the drug substance is pulverized to nanoparticles (average particle size of 400 nm) in the presence of a surface modifier and then dispersed in a liquid medium to give a pharmaceutical formulation that exhibits remarkably high bioavailability.
[00200] In some embodiments, a pharmaceutical composition of the present disclosure comprises any one of the compounds as described herein, or pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, and a pharmaceutically acceptable carrier. In some embodiments, a pharmaceutical composition of the present disclosure comprises any one of the compounds of Formula (A-I), (B-I), or (C-I), or pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, and a pharmaceutically acceptable carrier. [00201] The compositions are comprised of in general, a compound of Formula (A-I), (B-I), or (C-I) in combination with at least one pharmaceutically acceptable excipient. Acceptable excipients are non-toxic, aid administration, and do not adversely affect the therapeutic benefit of the compound of Formula (A-I), (B-I), or (C-I). Such excipient may be any solid, liquid, semi-solid or, in the case of an aerosol composition, gaseous excipient that is generally available to one of skill in the art.
[00202] Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk and the like. Liquid and semisolid excipients may be selected from glycerol, propylene glycol, water, ethanol and various oils, including those of petroleum, animal, vegetable or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc. Preferred liquid carriers, particularly for injectable solutions, include water, saline, aqueous dextrose, and glycols. [00203] Compressed gases may be used to disperse a compound of this invention in aerosol form.
Inert gases suitable for this purpose are nitrogen, carbon dioxide, etc.
[00204] Other suitable pharmaceutical excipients and their formulations are described in Remington's Pharmaceutical Sciences, edited by E. W. Martin (Mack Publishing Company, 20th ed., 2000).
[00205] The level of the compound in a formulation can vary within the full range employed by those skilled in the art. Typically, the formulation will contain, on a weight percent (wt %) basis, from about 0.01-99.99 wt % of a compound of Formula (A-I), (B-I), or (C-I) based on the total formulation, with the balance being one or more suitable pharmaceutical excipients. Preferably, the compound is present at a level of about 1-80 wt %.
[00206] The compounds of the present invention may be used in combination with one or more other drugs in the treatment of diseases or conditions for which compounds of the present invention or the other drugs may have utility, where the combination of the drugs together are safer or more effective than either drug alone. Such other drug(s) may be administered, by a route and in an amount commonly used therefore, contemporaneously or sequentially with a compound of the present invention. When a compound of the present invention is used contemporaneously with one or more other drugs, a pharmaceutical composition in unit dosage form containing such other drugs and the compound of the present invention is preferred. However, the combination therapy may also include therapies in which the compound of the present invention and one or more other drugs are administered on different overlapping schedules. It is also contemplated that when used in combination with one or more other active ingredients, the compounds of the present invention and the other active ingredients may be used in lower doses than when each is used singly.
[00207] Accordingly, the pharmaceutical compositions of the present invention also include those that contain one or more other active ingredients, in addition to a compound of the present invention. [00208] The above combinations include combinations of a compound of the present invention not only with one other active compound, but also with two or more other active compounds. Likewise, compounds of the present invention may be used in combination with other drugs that are used in the prevention, treatment, control, amelioration, or reduction of risk of the diseases or conditions for which compounds of the present invention are useful. Such other drugs may be administered, by a route and in an amount commonly used therefore, contemporaneously or sequentially with a compound of the present invention. When a compound of the present invention is used contemporaneously with one or more other drugs, a pharmaceutical composition containing such other drugs in addition to the compound of the present invention is preferred. Accordingly, the pharmaceutical compositions of the present invention also include those that also contain one or more other active ingredients, in addition to a compound of the present invention. The weight ratio of the compound of the present invention to the second active ingredient may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used.
[00209] In the case wherein the patient’s status does improve, upon the doctor’s discretion the administration of a compound described herein is optionally given continuously; alternatively, the dose of drug being administered is temporarily reduced or temporarily suspended for a certain length of time (i.e., a “drug holiday”). The length of the drug holiday optionally varies between 2 days and 1 year, including by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days, or 365 days. The dose reduction during a drug holiday includes from 10%-100%, including, by way of example only, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%.
[00210] Once improvement of the patient's conditions has occurred, a maintenance dose is administered if necessary. Subsequently, the dosage or the frequency of administration, or both, is reduced, as a function of the symptoms, to a level at which the improved disease, disorder or condition is retained. In some embodiments, patients require intermittent treatment on a long-term basis upon any recurrence of symptoms.
Methods of Use
[00211] In some embodiments, described herein are methods of treating cancer in an individual in need thereof comprising administering a therapeutically effective amount of a melanoma inhibitor of apoptosis proteins (ML-IAP) antagonist. In some embodiments of a method of treating cancer, the ML-IAP antagonist is selective for ML-IAP over other inhibitor of apoptosis proteins (IAPs). In some embodiments of a method of treating cancer, the ML-IAP antagonist is at least 5 -fold selective for ML-IAP over other IAPs. In some embodiments of a method of treating cancer, the ML-IAP antagonist is at least 10-fold selective for ML-IAP over other IAPs. In some embodiments of a method of treating cancer, the ML-IAP antagonist is at least 20-fold selective for ML-IAP over other IAPs. In some embodiments of a method of treating cancer, the ML-IAP antagonist is at least 30-fold selective for ML-IAP over other IAPs. In some embodiments of a method of treating cancer, the ML- IAP antagonist is at least 50-fold selective for ML-IAP over other IAPs. In some embodiments of a method of treating cancer, the ML-IAP antagonist is at least 100-fold selective for ML-IAP over other IAPs. In some embodiments of a method of treating cancer, the ML-IAP antagonist is at least 200- fold selective for ML-IAP over other IAPs.
[00212] In some embodiments of a method of treating cancer, the ML-IAP antagonist is at least 5 -fold selective for ML-IAP BIR domain over XIAP BIR2/3 domains. In some embodiments of a method of treating cancer, the ML-IAP antagonist is at least 10-fold selective for ML-IAP BIR domain over XIAP BIR2/3 domains. In some embodiments of a method of treating cancer, the ML-IAP antagonist is at least 20-fold selective for ML-IAP BIR domain over XIAP BIR2/3 domains. In some embodiments of a method of treating cancer, the ML-IAP antagonist is at least 50-fold selective for ML-IAP BIR domain over XIAP BIR2/3 domains. In some embodiments of a method of treating cancer, the ML-IAP antagonist is at least 100-fold selective for ML-IAP BIR domain over XIAP BIR2/3 domains.
[00213] In some embodiments, described herein are methods for treating a disease or condition associated with the overexpression of ML-IAP in an individual, comprising administering a therapeutically effective amount of a compound described herein, or pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, to the individual. In some embodiments, described herein are methods for treating a disease or condition associated with the overexpression of ML-IAP in an individual, comprising administering a therapeutically effective amount of a compound of Formula (A -I), (B-I), or (C-I), or pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, to the individual. In some embodiments, the disease or condition is cancer. In some embodiments, the disease or condition is cancer.
[00214] In some embodiments, described herein are methods of inhibiting melanoma inhibitor of apoptosis protein (ML-IAP) with a compound as described herein. In some embodiments, described herein are methods of inhibiting melanoma inhibitor of apoptosis protein (ML-IAP) with a compound of Formula (A-I), (B-I), or (C-I).
[00215] In some embodiments, described herein are methods of treating cancer in an individual in need thereof comprising administering a therapeutically effective amount of a compound as described herein, or pharmaceutically acceptable salt, X'-oxidc. racemate, or stereoisomer thereof, to the individual. In some embodiments, described herein are methods of treating cancer in an individual in need thereof comprising administering a therapeutically effective amount of a compound of Formula (A-I), (B-I), or (C-I), or pharmaceutically acceptable salt, X'-oxidc. racemate, or stereoisomer thereof, to the individual.
[00216] In some embodiments of any one of the methods described herein, the cancer is a lung cancer. In some embodiments, the cancer is chemo-resistant, refractory, or relapsed. In some embodiments, the cancer is chemo-resistant. In some embodiments, the cancer is resistant to platinum -based chemotherapy. In some embodiments, the cancer is resistant to chemotherapy, targeted therapy, immunotherapy, adjuvant therapy, or anti-angiogenesis therapy. In some embodiments, the cancer is resistant to carboplatin, cisplatin, docetaxel, gemcitabine, nab-paclitaxel, paclitaxel, pemetrexed, vinorelbine, bevacizumab, ramucirumab, afatinib, dacomitinib, erlotinib, gefitinib, necitumumab, osimertinib, atezolizumab, durvalumab, nivolumab, or pembrolizumab. In some embodiments, the cancer is resistant to carboplatin or cisplatin. In some embodiments, the cancer is resistant to paclitaxel or nab-paclitaxel.
[00217] In some embodiments, the cancer is sensitized to radiation therapy, chemotherapy, targeted therapy, immunotherapy, adjuvant therapy, or anti-angiogenesis therapy. In some embodiments, the cancer is sensitized to radiation therapy. In some embodiments, the cancer is sensitized to chemotherapy. In some embodiments, the cancer is sensitized to targeted therapy. In some embodiments, the cancer is sensitized to immunotherapy. In some embodiments, the cancer is sensitized to adjuvant therapy. In some embodiments, the cancer is sensitized to anti-angiogenesis therapy. In some embodiments, the cancer is hypersensitized to chemotherapy. In some embodiments, chemo-resistance is reduced. In some embodiments, chemo-resistance is negated. In some embodiments, the cancer is sensitized to carboplatin, cisplatin, docetaxel, gemcitabine, nab-paclitaxel, paclitaxel, pemetrexed, vinorelbine, bevacizumab, ramucirumab, afatinib, dacomitinib, erlotinib, gefitinib, necitumumab, osimertinib, atezolizumab, durvalumab, nivolumab, or pembrolizumab. In some embodiments, the cancer is sensitized to carboplatin or cisplatin. In some embodiments, the cancer is sensitized to paclitaxel or nab-paclitaxel.
[00218] In some embodiments, the cancer is non-small cell lung cancer, adenocarcinoma, squamous cell carcinoma, adenosquamous carcinoma, sarcomatoid carcinoma, large cell carcinoma, or small cell lung cancer. In some embodiments, the cancer is non-small cell lung cancer. In some embodiments, the cancer is adenocarcinoma. In some embodiments, the cancer is squamous cell carcinoma. In some embodiments, the cancer is adenosquamous carcinoma. In some embodiments, the cancer is sarcomatoid carcinoma. In some embodiments, the cancer is large cell carcinoma. In some embodiments, the cancer is small cell lung cancer. In some embodiments, the non-small cell lung cancer is chemo-resistant. In some embodiments, the adenocarcinoma is chemo-resistant. In some embodiments, the squamous cell carcinoma is chemo-resistant. In some embodiments, the adenosquamous carcinoma is chemo-resistant. In some embodiments, the sarcomatoid carcinoma is chemo-resistant. In some embodiments, the large cell carcinoma is chemo-resistant. In some embodiments, the small cell lung cancer is chemo-resistant.
[00219] In some embodiments, a method as described herein comprises administering an additional therapeutic agent. In some embodiments, a method as described herein comprises administering at least two additional therapeutic agents. In some embodiments, the additional therapeutic agent is surgery, radiation therapy, chemotherapy, targeted therapy, immunotherapy, adjuvant therapy, anti angiogenesis therapy, or pain therapy. In some embodiments, the additional therapeutic agent is chemotherapy, targeted therapy, immunotherapy, adjuvant therapy, or anti-angiogenesis therapy. In some embodiments, the additional therapeutic agent is surgery. In some embodiments, the additional therapeutic agent is radiation therapy. In some embodiments, the additional therapeutic agent is chemotherapy. In some embodiments, the additional therapeutic agent is targeted therapy. In some embodiments, the additional therapeutic agent is immunotherapy. In some embodiments, the additional therapeutic agent is adjuvant therapy. In some embodiments, the additional therapeutic agent is anti-angiogenesis therapy. In some embodiments, the additional therapeutic agent is pain therapy. [00220] Also disclosed is a method of treating Human Immunodeficiency Vims (HIV) in a mammal comprising administering a therapeutically effective amount of a compound disclosed herein, or pharmaceutically acceptable salt, A'-oxidc. racemate, or stereoisomer thereof, to the individual. [00221] Also disclosed is a method of reversing a latency of Human Immunodeficiency Vims (HIV) in a mammal comprising administering a therapeutically effective amount of a compound disclosed herein, or pharmaceutically acceptable salt, A'-oxidc. racemate, or stereoisomer thereof, to the individual. In some embodiments of a method of reversing a latency of Human Immunodeficiency Vims (HIV), the latency of HIV is reversed without activation of T cells. In some embodiments of a method of reversing a latency of Human Immunodeficiency Vims (HIV), the method further comprises administering an additional latency reversal agent, a killer agent, CarT, immunotherapy, neutralizing antibodies, or other agents. In some embodiments of a method of reversing a latency of Human Immunodeficiency Vims (HIV), the additional latency reversal agent is a histone deacetylase inhibitor (HDACi), a bromodomain and extra terminal domain inhibitors (BETi), or a Protein Kinase C (PKC) agonist.
Combination therapy
[00222] In some embodiments, the additional therapeutic agent is carboplatin, cisplatin, docetaxel, gemcitabine, nab-paclitaxel, paclitaxel, pemetrexed, vinorelbine, bevacizumab, ramucirumab, afatinib, dacomitinib, erlotinib, gefitinib, necitumumab, osimertinib, atezolizumab, durvalumab, nivolumab, or pembrolizumab. In some embodiments, the additional therapeutic agent is carboplatin, cisplatin, docetaxel, gemcitabine, nab-paclitaxel, paclitaxel, or bevacizumab. In some embodiments, the additional therapeutic agent is carboplatin, cisplatin, or paclitaxel. In some embodiments, the additional therapeutic agent is carboplatin. In some embodiments, the additional therapeutic agent is cisplatin. In some embodiments, the additional therapeutic agent is gemcitabine. In some embodiments, the additional therapeutic agent is bevacizumab. In some embodiments, the additional therapeutic agent is vinorelbine.
[00223] In some embodiments, a pharmaceutical composition of the present disclosure comprises a selective melanoma inhibitor of apoptosis protein (ML-IAP) antagonist, at least one additional therapeutic agent used to treat cancer, and at least one excipient or carrier. In some embodiments, the pharmaceutical composition comprises at least two additional therapeutic agents used to treat cancer. In some embodiments, the pharmaceutical composition comprises at least three additional therapeutic agents used to treat cancer. In some embodiments, the additional therapeutic agents used to treat cancer is chemotherapy, targeted therapy, immunotherapy, adjuvant therapy, or anti-angiogenesis therapy. In some embodiments, the additional therapeutic agents used to treat cancer is carboplatin, cisplatin, docetaxel, gemcitabine, nab-paclitaxel, paclitaxel, pemetrexed, vinorelbine, bevacizumab, ramucirumab, afatinib, dacomitinib, erlotinib, gefitinib, necitumumab, osimertinib, atezolizumab, durvalumab, nivolumab, or pembrolizumab. [00224] In some cases, a compound described herein is administered in combination with a second anti -cancer agent. Examples of anti -cancer agents for use in combination with a compound of Formula (A-I), (B-I), or (C-I) include inhibitors of mitogen-activated protein kinase signaling, e.g., U0126, PD98059, PD184352, PD0325901, ARRY-142886, SB239063, SP600125, BAY 43-9006, wortmannin, or LY294002; Syk inhibitors; mTOR inhibitors; and antibodies (e.g., rituxan).
[00225] Other anti -cancer agents that can be employed in combination with a compound of Formula (A-I), (B-I), or (C-I) include Adriamycin, Dactinomycin, Bleomycin, Vinblastine, Cisplatin, acivicin; aclarubicin; acodazole hydrochloride; acronine; adozelesin; aldesleukin; altretamine; ambomycin; ametantrone acetate; aminoglutethimide; amsacrine; anastrozole; anthramycin; asparaginase; asperlin; azacitidine; azetepa; azotomycin; batimastat; benzodepa; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate; bizelesin; bleomycin sulfate; brequinar sodium; bropirimine; busulfan; cactinomycin; calusterone; caracemide; carbetimer; carboplatin; carmustine; carubicin hydrochloride; carzelesin; cedefmgol; chlorambucil; cirolemycin; cladribine; crisnatol mesylate; cyclophosphamide; cytarabine; dacarbazine; daunorubicin hydrochloride; decitabine; dexormaplatin; dezaguanine; dezaguanine mesylate; diaziquone; doxorubicin; doxorubicin hydrochloride; droloxifene; droloxifene citrate; dromostanolone propionate; duazomycin; edatrexate; eflomithine hydrochloride; elsamitrucin; enloplatin; enpromate; epipropidine; epirubicin hydrochloride; erbulozole; esorubicin hydrochloride; estramustine; estramustine phosphate sodium; etanidazole; etoposide; etoposide phosphate; etoprine; fadrozole hydrochloride; fazarabine; fenretinide; floxuridine; fludarabine phosphate; fluorouracil; flurocitabine; fosquidone; fostriecin sodium; gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubicin hydrochloride; ifosfamide; ilmofosine; interleukin II (including recombinant interleukin II, or rIF2), interferon alfa-2a; interferon alfa-2b; interferon alfa-nl; interferon alfa-n3; interferon beta- la; interferon gamma- 1 b; iproplatin; irinotecan hydrochloride; lanreotide acetate; letrozole; leuprolide acetate; liarozole hydrochloride; lometrexol sodium; lomustine; losoxantrone hydrochloride; masoprocol; maytansine; mechlorethamine hydrochloride; megestrol acetate; melengestrol acetate; melphalan; menogaril; mercaptopurine; methotrexate; methotrexate sodium; metoprine; meturedepa; mitindomide; mitocarcin; mitocromin; mitogillin; mitomalcin; mitomycin; mitosper; mitotane; mitoxantrone hydrochloride; mycophenolic acid; nocodazole; nogalamycin; ormaplatin; oxisuran; pegaspargase; peliomycin; pentamustine; peplomycin sulfate; perfosfamide; pipobroman; piposulfan; piroxantrone hydrochloride; plicamycin; plomestane; porfimer sodium; porfiromycin; prednimustine; procarbazine hydrochloride; puromycin; puromycin hydrochloride; pyrazofurin; riboprine; rogletimide; safmgol; safmgol hydrochloride; semustine; simtrazene; sparfbsate sodium; sparsomycin; spirogermanium hydrochloride; spiromustine; spiroplatin; streptonigrin; streptozocin; sulofenur; talisomycin; tecogalan sodium; tegafur; teloxantrone hydrochloride; temoporfm; teniposide; teroxirone; testolactone; thiamiprine; thioguanine; thiotepa; tiazofurin; tirapazamine; toremifene citrate; trestolone acetate; triciribine phosphate; trimetrexate; trimetrexate glucuronate; triptorelin; tubulozole hydrochloride; uracil mustard; uredepa; vapreotide; verteporfm; vinblastine sulfate; vincristine sulfate; vindesine; vindesine sulfate; vinepidine sulfate; vinglycinate sulfate; vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate; vinzolidine sulfate; vorozole; zeniplatin; zinostatin; zorubicin hydrochloride.
[00226] Other anti -cancer agents that can be employed in combination with a compound of Formula (A-I), (B-I), or (C-I) include: 20-epi-l, 25 dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TK antagonists; altretamine; ambamustine; amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; andrographolide; angiogenesis inhibitors; antagonist D; antagonist G; antarelix; anti- dorsalizing morphogenetic protein- 1; antiandrogen, prostatic carcinoma; antiestrogen; antineoplaston; antisense oligonucleotides; aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA; arginine deaminase; asulacrine; atamestane; atrimustine; axinastatin 1; axinastatin 2; axinastatin 3; azasetron; azatoxin; azatyrosine; baccatin III derivatives; balanol; batimastat; BCR/ABL antagonists; benzochlorins; benzoylstaurosporine; beta lactam derivatives; beta-alethine; betaclamycin B; betulinic acid; bFGF inhibitor; bicalutamide; bisantrene; bisaziridinylspermine; bisnafide; bistratene A; bizelesin; breflate; bropirimine; budotitane; buthionine sulfoximine; calcipotriol; calphostin C; camptothecin derivatives; canarypox IL-2; capecitabine; carboxamide-amino-triazole; carboxyamidotriazole; CaRest M3; CARN 700; cartilage derived inhibitor; carzelesin; casein kinase inhibitors (ICOS); castanospermine; cecropin B; cetrorelix; chlorlns; chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin; cladribine; clomifene analogues; clotrimazole; collismycin A; collismycin B; combretastatin A4; combretastatin analogue; conagenin; crambescidin 816; crisnatol; cryptophycin 8; cryptophycin A derivatives; curacin A; cyclopentanthraquinones; cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor; cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin; dexamethasone; dexifosfamide; dexrazoxane; dexverapamil; diaziquone; didemnin B; didox; diethylnorspermine; dihydro -5 -azacytidine; 9- dioxamycin; diphenyl spiromustine; docosanol; dolasetron; doxifluridine; droloxifene; dronabinol; duocarmycin SA; ebselen; ecomustine; edelfosine; edrecolomab; eflomithine; elemene; emitefur; epirubicin; epristeride; estramustine analogue; estrogen agonists; estrogen antagonists; etanidazole; etoposide phosphate; exemestane; fadrozole; fazarabine; fenretinide; fdgrastim; finasteride; flavopiridol; flezelastine; fluasterone; fludarabine; fluorodaunorunicin hydrochloride; forfenimex; formestane; fostriecin; fotemustine; gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix; gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfam; heregulin; hexamethylene bisacetamide; hypericin; ibandronic acid; idarubicin; idoxifene; idramantone; ilmofosine; ilomastat; imidazoacridones; imiquimod; immunostimulant peptides; insulin-like growth factor-1 receptor inhibitor; interferon agonists; interferons; interleukins; iobenguane; iododoxorubicin; ipomeanol, 4-; iroplact; irsogladine; isobengazole; isohomohalicondrin B; itasetron; jasplakinolide; kahalalide F; lamellarin-N triacetate; lanreotide; leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole; leukemia inhibiting factor; leukocyte alpha interferon; leuprolide+estrogen+progesterone; leuprorelin; levamisole; liarozole; linear polyamine analogue; lipophilic disaccharide peptide; lipophilic platinum compounds; lissoclinamide 7; lobaplatin; lombricine; lometrexol; lonidamine; losoxantrone; lovastatin; loxoribine; lurtotecan; lutetium texaphyrin; lysofylline; lytic peptides; maitansine; mannostatin A; marimastat; masoprocol; maspin; matrilysin inhibitors; matrix metalloproteinase inhibitors; menogaril; merbarone; meterelin; methioninase; metoclopramide; MIF inhibitor; mifepristone; miltefosine; mirimostim; mismatched double stranded RNA; mitoguazone; mitolactol; mitomycin analogues; mitonafide; mitotoxin fibroblast growth factor-saporin; mitoxantrone; mofarotene; molgramostim; monoclonal antibody, human chorionic gonadotrophin; monophosphoryl lipid A+myobacterium cell wall sk; mopidamol; multiple drug resistance gene inhibitor; multiple tumor suppressor 1 -based therapy; mustard anticancer agent; mycaperoxide B; mycobacterial cell wall extract; myriaporone; N-acetyldinaline; N-substituted benzamides; nafarelin; nagrestip; naloxone+pentazocine; napavin; naphterpin; nartograstim; nedaplatin; nemorubicin; neridronic acid; neutral endopeptidase; nilutamide; nisamycin; nitric oxide modulators; nitroxide antioxidant; nitrullyn; 06-benzylguanine; octreotide; okicenone; oligonucleotides; onapristone; ondansetron; ondansetron; oracin; oral cytokine inducer; ormaplatin; osaterone; oxaliplatin; oxaunomycin; palauamine; palmitoylrhizoxin; pamidronic acid; panaxytriol; panomifene; parabactin; pazelliptine; pegaspargase; peldesine; pentosan polysulfate sodium; pentostatin; pentrozole; perflubron; perfbsfamide; perillyl alcohol; phenazinomycin; phenylacetate; phosphatase inhibitors; picibanil; pilocarpine hydrochloride; pirarubicin; piritrexim; placetin A; placetin B; plasminogen activator inhibitor; platinum complex; platinum compounds; platinum -triamine complex; porfimer sodium; porfiromycin; prednisone; propyl bis-acridone; prostaglandin J2; proteasome inhibitors; protein A- based immune modulator; protein kinase C inhibitor; protein kinase C inhibitors, microalgal; protein tyrosine phosphatase inhibitors; purine nucleoside phosphorylase inhibitors; purpurins; pyrazoloacridine; pyridoxylated hemoglobin polyoxyethylerie conjugate; raf antagonists; raltitrexed; ramosetron; ras famesyl protein transferase inhibitors; ras inhibitors; ras-GAP inhibitor; retelliptine demethylated; rhenium Re 186 etidronate; rhizoxin; ribozymes; Rn retinamide; rogletimide; rohitukine; romurtide; roquinimex; rubiginone Bl; ruboxyl; safmgol; saintopin; SarCNU; sarcophytol A; sargramostim; Sdi 1 mimetics; semustine; senescence derived 1; sense oligonucleotides; signal transduction inhibitors; signal transduction modulators; single chain antigen-binding protein; sizofuran; sobuzoxane; sodium borocaptate; sodium phenylacetate; solverol; somatomedin binding protein; sonermin; sparfbsic acid; spicamycin D; spiromustine; splenopentin; spongistatin 1; squalamine; stem cell inhibitor; stem-cell division inhibitors; stipiamide; stromelysin inhibitors; sulfmosine; superactive vasoactive intestinal peptide antagonist; suradista; suramin; swainsonine; synthetic glycosaminoglycans; tallimustine; tamoxifen methiodide; tauromustine; tazarotene; tecogalan sodium; tegafur; tellurapyrylium; telomerase inhibitors; temoporfm; temozolomide; teniposide; tetrachlorodecaoxide; tetrazomine; thaliblastine; thiocoraline; thrombopoietin; thrombopoietin mimetic; thymalfasin; thymopoietin receptor agonist; thymotrinan; thyroid stimulating hormone; tin ethyl etiopurpurin; tirapazamine; titanocene bichloride; topsentin; toremifene; totipotent stem cell factor; translation inhibitors; tretinoin; triacetyluridine; triciribine; trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinase inhibitors; tyrphostins; UBC inhibitors; ubenimex; urogenital sinus-derived growth inhibitory factor; urokinase receptor antagonists; vapreotide; variolin B; vector system, erythrocyte gene therapy; velaresol; veramine; verdins; verteporfm; vinorelbine; vinxaltine; vitaxin; vorozole; zanoterone; zeniplatin; zilascorb; and zinostatin stimalamer.
[00227] Yet other anticancer agents that can be employed in combination with a compound of Formula (A-I), (B-I), or (C-I) include alkylating agents, antimetabolites, natural products, or hormones, e.g., nitrogen mustards (e.g., mechloroethamine, cyclophosphamide, chlorambucil, etc.), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine, lomusitne, etc.), ortriazenes (decarbazine, etc.). Examples of antimetabolites include but are not limited to folic acid analog (e.g., methotrexate), or pyrimidine analogs (e.g., Cytarabine), purine analogs (e.g., mercaptopurine, thioguanine, pentostatin).
[00228] Examples of natural products useful in combination with a compound of Formula (A-I), (B-I), or (C-I) include but are not limited to vinca alkaloids (e.g., vinblastin, vincristine), epipodophyllotoxins (e.g., etoposide), antibiotics (e.g., daunorubicin, doxorubicin, bleomycin), enzymes (e.g., L-asparaginase), or biological response modifiers (e.g., interferon alpha).
[00229] Examples of alkylating agents that can be employed in combination a compound of Formula (A-I), (B-I), or (C-I) include, but are not limited to, nitrogen mustards (e.g., mechloroethamine, cyclophosphamide, chlorambucil, melphalan, etc.), ethylenimine and methylmelamines (e.g., hexamethlymelamine, thiotepa), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine, lomusitne, semustine, streptozocin, etc.), ortriazenes (decarbazine, etc.). Examples of antimetabolites include, but are not limited to folic acid analog (e.g., methotrexate), or pyrimidine analogs (e.g., fluorouracil, floxuridine, Cytarabine), purine analogs (e.g., mercaptopurine, thioguanine, pentostatin. [00230] Examples of hormones and antagonists useful in combination a compound of Formula (A-I), (B-I), or (C-I) include, but are not limited to, adrenocorticosteroids (e.g., prednisone), progestins (e.g., hydroxyprogesterone caproate, megestrol acetate, medroxyprogesterone acetate), estrogens (e.g., diethlystilbestrol, ethinyl estradiol), antiestrogen (e.g., tamoxifen), androgens (e.g., testosterone propionate, fluoxymesterone), antiandrogen (e.g., flutamide), gonadotropin releasing hormone analog (e.g., leuprolide). Other agents that can be used in the methods and compositions described herein for the treatment or prevention of cancer include platinum coordination complexes (e.g., cisplatin, carboblatin), anthracenedione (e.g., mitoxantrone), substituted urea (e.g., hydroxyurea), methyl hydrazine derivative (e.g., procarbazine), adrenocortical suppressant (e.g., mitotane, aminoglutethimide) .
[00231] Examples of anti -cancer agents which act by arresting cells in the G2-M phases due to stabilized microtubules and which can be used in combination with an irreversible EGFR tyrosine kinase inhibitor compound include without limitation the following marketed drugs and drugs in development: Erbulozole (also known as R-55104), Dolastatin 10 (also known as DLS-10 and NSC- 376128), Mivobulin isethionate (also known as CI-980), Vincristine, NSC-639829, Discodermolide (also known as NVP-XX-A-296), ABT-751 (Abbott, also known as E-7010), Altorhyrtins (such as Altorhyrtin A and Altorhyrtin C), Spongistatins (such as Spongistatin 1, Spongistatin 2, Spongistatin 3, Spongistatin 4, Spongistatin 5, Spongistatin 6, Spongistatin 7, Spongistatin 8, and Spongistatin 9), Cemadotin hydrochloride (also known as LU-103793 and NSC-D-669356), Epothilones (such as Epothilone A, Epothilone B, Epothilone C (also known as desoxyepothilone A or dEpoA), Epothilone D (also referred to as KOS-862, dEpoB, and desoxyepothilone B), Epothilone E, Epothilone F, Epothilone B N-oxide, Epothilone A N-oxide, 16-aza-epothilone B, 21-aminoepothilone B (also known as BMS-310705), 21-hydroxyepothilone D (also known as Desoxyepothilone F and dEpoF), 26-fluoroepothilone), Auristatin PE (also known as NSC-654663), Soblidotin (also known as TZT- 1027), LS-4559-P (Pharmacia, also known as LS-4577), LS-4578 (Pharmacia, also known as LS-477- P), LS-4477 (Pharmacia), LS-4559 (Pharmacia), RPR-112378 (Aventis), Vincristine sulfate, DZ-3358 (Daiichi), FR-182877 (Fujisawa, also known as WS-9885B), GS-164 (Takeda), GS-198 (Takeda), KAR-2 (Hungarian Academy of Sciences), BSF-223651 (BASF, also known as ILX-651 and LU- 223651), SAH-49960 (Lilly/Novartis), SDZ-268970 (Lilly/Novartis), AM-97 (Armad/Kyowa Hakko), AM-132 (Armad), AM-138 (Armad/Kyowa Hakko), IDN-5005 (Indena), Cryptophycin 52 (also known as LY-355703), AC-7739 (Ajinomoto, also known as AVE-8063A and CS-39.HC1), AC-7700 (Ajinomoto, also known as AVE-8062, AVE-8062A, CS-39-L-Ser.HCl, and RPR-258062A), Vitilevuamide, Tubulysin A, Canadensol, Centaureidin (also known as NSC-106969), T-138067 (Tularik, also known as T-67, TL-138067 and TI-138067), COBRA-1 (Parker Hughes Institute, also known as DDE-261 and WHI-261), H10 (Kansas State University), H16 (Kansas State University), Oncocidin A1 (also known as BTO-956 and DIME), DDE-313 (Parker Hughes Institute), Fijianolide B. Laulimalide, SPA-2 (Parker Hughes Institute), SPA-1 (Parker Hughes Institute, also known as SPIKET-P), 3-IAABU (Cytoskeleton/Mt. Sinai School of Medicine, also known as MF-569), Narcosine (also known as NSC-5366), Nascapine, D-24851 (Asta Medica), A-105972 (Abbott), Hemiasterlin, 3-BAABU (Cytoskeleton/Mt. Sinai School of Medicine, also known as MF-191), TMPN (Arizona State University), Vanadocene acetylacetonate, T-138026 (Tularik), Monsatrol, Inanocine (also known as NSC-698666), 3-1AABE (Cytoskeleton/Mt. Sinai School of Medicine), A- 204197 (Abbott), T-607 (Tuiarik, also known as T-900607), RPR-115781 (Aventis), Eleutherobins (such as Desmethyleleutherobin, Desaetyleleutherobin, Isoeleutherobin A, and Z-Eleutherobin), Caribaeoside, Caribaeolin, Halichondrin B, D-64131 (Asta Medica), D-68144 (Asta Medica), Diazonamide A, A-293620 (Abbott), NPI-2350 (Nereus), Taccalonolide A, TUB-245 (Aventis), A- 259754 (Abbott), Diozostatin, (-)-Phenylahistin (also known as NSCL-96F037), D-68838 (Asta Medica), D-68836 (Asta Medica), Myoseverin B, D-43411 (Zentaris, also known as D-81862), A- 289099 (Abbott), A-318315 (Abbott), HTI-286 (also known as SPA-110, trifluoroacetate salt) (Wyeth), D-82317 (Zentaris), D-82318 (Zentaris), SC-12983 (NCI), Resverastatin phosphate sodium, BPR-OY-007 (National Health Research Institutes), and SSR-250411 (Sanofi).
[00232] In some cases, a compound described herein (e.g., a compound of Formula (A-I), (B-I), or (C- I)) is administered in combination with TNF-alpha and/or TNF-related apoptosis-inducing ligand (TRAIL). TRAIL shows homology to other members of the TNF-alpha family of proteins. In some cases, a compound described herein (e.g., a compound of Formula (A-I), (B-I), or (C-I)) is administered in combination with a TNF-alpha modulator and/or a TNF-alpha analogue (e.g., lenalidomide, revlimid, CC-5013; CC-4047, ACTIMID. Thalidomide and the like). In some cases, a compound described herein (e.g., a compound of Formula (A-I), (B-I), or (C-I)) is administered in combination with an adjuvant, hormone therapy, immunotherapy or any combination thereof.
[00233] In some cases, a compound described herein is administered in combination with antiretroviral therapy (ART). Examples of antiretroviral therapy (ART) for use in combination with a compound of Formula (A-I), (B-I), or (C-I) include Combivir, Kaletra, Aluvia, Trizivir, Epzicom, Kivexa, Triomune, Duovir-N, Truvada, Atripla, Complera, Eviplera, Stribild, Triumeq, Evotaz, Prezcobix, Rezolsta, Dutrebis, Genvoya, Odefsey, Descovy, Juluca, Symfi, Symfi Lo, Biktarvy, Cimduo, Symtuza, Delstrigo, and Dovato.
[00234] In some cases, a compound described herein is administered in combination with a latency reversal agent (LRA) with or without antiretroviral therapy (ART). Examples of latency reversal agent (LRA) for use in combination with a compound of Formula (A-I), (B-I), or (C-I) include histone deacetylase inhibitors (HDACi), bromodomain and extra terminal domain inhibitors (BETi), Protein Kinase C (PKC) agonists, activators of positive transcription elongation factor b (P-TEFb), Toll-like receptor (TLR) agonists, immune checkpoint inhibitors, tetraethylthiuram disulfide (Disulfiram), benzotriazole derivatives, quinolines, cytokines, methyltransferase inhibitors, and methylation inhibitors.
[00235] In some cases, a compound described herein is administered in combination with a killer agent, CarT, immunotherapy, neutralizing antibodies, or other agents. Additional latency reversal agents can be found in Stoszko et ah, Curr Opin Virol. 2019 Jul 16; 38:37-53 which is hereby incorporated by reference for such disclosures.
EXAMPLES
Chemical Synthesis
[00236] Reactions conducted under microwave irradiation were performed in a CEM Discover microwave reactor using either CEM 10 mL reaction vessels or a ChemGlass heavy wall pressure vessel (100 mL, 38 mm* 190 mm). Reaction progress was monitored by reverse-phase HPLC and/or thin-layer chromatography (TLC). Liquid chromatography-mass spectrometry was performed using either Waters or Shimadzu 2010EV LCMS instruments using water and acetonitrile or methanol doped with 0.1% formic acid. TLC was performed using silica gel 60 F254 pre-coated plates (0.25 mm). Flash chromatography was performed using silica gel (32-63 pm particle size) or aluminum oxide (activated, basic, -150 mesh size). Automated chromatographic purification was carried out using pre-packed silica or C18 cartridges (from RediSep and Luknova) and eluted using an ISCO Companion system. Reverse phase purifications were conducted using water and acetonitrile or methanol doped with 0.1% formic acid. All final product compounds were purified using one of these two chromatographic methods. Purity and characterization of compounds was established by a combination of TLC, liquid chromatography-mass spectroscopy (LC-MS) and Nuclear Magnetic Resonance (NMR) analytical techniques. ¾ and 13C NMR spectra were obtained on a Joel 400 spectrometer at 400 MHz and 101 MHz, respectively. Chemical shifts are reported in d (ppm) and were internally referenced to deuterated solvent signals.
LC-MS Conditions
[00237] HPLC-MS analyses were performed on a Waters ACQUITY UPLC with SQ mass detector and PDA c' /. detector. The column used was a Phenomenex Kinetex Cl 8 column (1.7um, 2.1 x 50 mm). The mobile phase consisted of eluent A (water, 0.05% TFA) and eluent B (CTLCN, 0.05% TFA), and the elution proceeded at 0.5 mL/min. The initial conditions were 90% A, then 90% A to 10% A linearly decreased within 1.75 min, then from 10% A to 90% A within 0.25 min. The total run time is 2 minutes.
General Isocyanide Synthesis
Synthesis of (R)-N-(l,2,3,4-tetrahydronaphthalen-l-yl)formamide (X-l)
Figure imgf000109_0001
[00238] (R)-N-(l,2,3,4-tetrahydronaphthalen-l-yl)formamide (X-l). A solution of (R)-l, 2,3,4- tetrahydronaphthalen-1 -amine (67.9 mmol, 10 g, l.Oeq) in ethyl formate ( >10 eq, 100 mL) was refluxed at 80°C for 40 hours. The mixture was concentrated to dryness and solubilized in a mixture of dichloromethane (100 mL) and triethylamine (50 mL, 5.0 eq). Phosphoryl trichloride (10 ml, 106 mmol, 1.6 eq) was added at 0°C. The mixture was stirred at 0°C for 30 min then at 23°C for 3 hours. The mixture was poured carefully in saturated aqueous sodium bicarbonate (700mL), extracted with dichloromethane (3*300 mL), dried over sodium sulfate anhydrous, filtered and concentrated. The crude product was purified on silica gel chromatography (2-20% ethyl acetate in hexanes). Yield 7.2 g (67%) of an orange liquid. TLC-Rf = 0.57 (15% ethyl acetate in hexanes). ¾ NMR (400 MHz, CDC13) d 7.47 - 7.39 (m, 1H), 7.28 - 7.19 (m, 2H), 7.15 - 7.09 (m, 1H), 4.83 (t, 1H), 2.87 (dt, 1H), 2.76 (dt, 1H), 2.21 - 2.11 (m, 2H), 2.11 - 1.99 (m, 1H), 1.89 - 1.76 (m, 1H). Synthesis of (isocyanomethylene)dibenzene (X-2)
Figure imgf000110_0001
[00239] (isocyanomethylene)dibenzene (X-2). Follow synthesis of X-l. lOg of an orange solid 95% yield. Rf = 0.75 (15% ethyl acetate in hexanes). Ή NMR (400 MHz, CDC13) d 7.40 - 7.32 (m, 10H), 5.91 (s, 1H).
Synthesis of l-(2,2-dimethoxyethyl)-2-isocyanobenzene (X-3)
Figure imgf000110_0002
[00240] l-(2,2-dimethoxyethyl)-2-isocyanobenzene (X-3). To a solution of nitrotoluene (10g, 1.0 eq) in dimethylformamide (160mL, 0.5M) was added dimethylformamide diethylacetal (12.2 mL, 1.2 eq) and pyrrolidine (7.24mL, 1.2 eq). The yellow reaction mixture was then stirred at 80°C for 5 days.
The mixture turned red. Water (500mL) was added to the cooled reaction mixture at 23°C and extracted with ethyl acetate (1* lOOmL) and dichloromethane (2*200mL). The combined organic layers were washed with water (1* lOOmL) and brine (1* lOOmL), dried over sodium sulfate anhydrous, filtered and concentrated. To the resulting oil (16.0 g, 1.0 eq) in methanol (160mL, 0.5 M) was slowly added chlorotrimethylsilane (13.98mL, 1.5 eq). The mixture was heated to 75°C for 18 hours. The solvents were removed under vacuum. The resultant liquid was poured in a 5% citric acid (300 mL, aqueous solution) and extracted with ethyl acetate (3*100 mL). The combined organic layers were washed with a 1 : 1 mixture of saturated solution of sodium bicarbonate: brine (2*100 mL), dried over sodium sulfate anhydrous, filtered and concentrated to afford 15 g (97% yield) of a dark red oil. A sealed mixture of the oil and 10% Pd/C (2g) in methanol (100 mL) flushed with nitrogen was placed under hydrogen atmosphere in a parr hydrogenator and stirred for 18 hours at 20PSI. The mixture was then filtered through celite and concentrated. The crude intermediate was solubilized in ethyl formate (>10 eq, 30 mL) and refluxed at 80°C for 40 hours. It was concentrated to dryness and solubilized in a mixture of dichloromethane (150 mL) and triethylamine (55 mL, 6.0 eq). Phosphoryl trichloride (9 ml, 1.5 eq) was added at 0°C. The mixture was stirred at 0°C for 30 min then at 23°C for 3 hours. The mixture was poured carefully in saturated aqueous sodium bicarbonate (700mL), which was extracted with DCM (3*300 mL), dried over sodium sulfate anhydrous, filtered and concentrated. The crude was purified by column chromatography over silica gel (0-50% Dichloromethane in hexanes). 8.6 g of a stinky dark red oil (62% yield). TLC-Rf : 0.82 (30% ethyl acetate in hexanes). General Synthesis of Aldehyde
Synthesis of 2-allyl-2-(2,2-dimethoxyethyl)pent-4-enenitrile (X-4a)
Figure imgf000111_0001
[00241] 2-allyl-2-(2,2-dimethoxyethyl)pent-4-enenitrile (X-4a). To a stirred solution of 4,4- dimethoxybutanenitrile (4.0g, 1.0 eq) in THF (60mL, 0.5M) at -78°C was slowly added 2.0M lithium diisoproprylamide (32.5mL, 2.2 eq). After 30 min, iodomethane (4.83mL, 2.5eq) was added slowly at -78°C. The mixture was stirred at -78°C for lh then stirred at r.t. for 18 hours. The mixture was carefully poured in a saturated aqueous solution of ammonium chloride (300mL) and was extracted with DCM (3*200 mL), dried over sodium sulfate anhydrous, filtered and concentrated. The crude intermediate was purified by flash column chromatography over silica gel (20-100% dichloromethane in hexanes). 2.78 g (57%) of a slightly yellow liquid. Rf = 0.42 (15% ethyl acetate in hexanes). ¾ NMR (400 MHz, CDC13) d 4.60 (t, 1H), 3.36 (s, 6H), 1.82 (d, 2H), 1.39 (s, 6H). LC-MS m/z: 157.70 (calcd: 158.12 [M+H]+).
Synthesis of l-(2,2-dimethoxyethyl)cyclopent-3-ene-l-carbonitrile (X-4b)
Figure imgf000111_0002
[00242] l-(2,2-dimethoxyethyl)cyclopent-3-ene-l-carbonitrile (X-4b). A nitrogen degassed solution of Grubbs 1 or Grubbs II (0.05 eq) in benzene (50mL) was heated to 90°C for 20 min. To the hot solution was added the crude 2-allyl-2-(2,2-dimethoxyethyl)pent-4-enenitrile (1 eq, 5g, 23.89 mmol, synthesized following procedure X-4a using bromo-allyl) and the mixture was stirred under reflux for 14 hours. 0.05 eq of Grubbs catalyst was added again and the mixture stirred under reflux for a further 24 hours. The mixture was concentrated, and the product was purified by flash column chromatography over silica gel (0-20% ethyl acetate in hexanes). It afforded a colorless liquid (2.01g, 46% yield). ¾ NMR (400 MHz, CDCL) d 5.68 (s, 2H), 4.63 (t, 1H), 3.38 (s, 6H), 2.89 (d, 2H), 2.60 (d, 2H), 1.98 (d, 2H). LC-MS m/z: 181.75 (calcd: 182.12 [M+H]+).
Synthesis of 4,4-dimethoxy-2,2-dimethylbutanal (X-5a)
Figure imgf000111_0003
[00243]4,4-dimethoxy-2,2-dimethylbutanal (X-5a). The intermediate X-3a (2.78g, 1.0 eq) was solubilized in DCM (50mL) and cooled down to -78°C. 25% diisobytylaluminium hydride in hexanes (1.1 eq, 14 mL) was added and the mixture was stirred at -78°C for lh, then at 0°C for 1 hour. It was quenched with 20 mL of a saturated aqueous ammonium chloride and 30mL of a saturated aqueous solution of Rochelle salt. The mixture was diluted with diethyl ether (lOOmL) and brine (100 mL). It was warmed up to 23°C and stirred vigorously for lh. The organic phase was separated, and the aqueous phase was extracted with dichloromethane (3* 100 mL). The combined organic layers were washed with brine, dried over sodium sulfate anhydrous, filtered through a plug of silica gel and concentrated. The crude was purified by flash column chromatography over silica gel (0-100% dichloromethane in pentane): 2.00 g (45% yield) of a colorless liquid. Rf = 0.39 (15% ethyl acetate in hexanes1H NMR (400 MHz, CDCL) d 9.38 (s, 1H), 4.34 (t, 1H), 3.29 (s, 6H), 1.84 (d, 2H), 1.06 (s, 6H).
Synthesis of 2-allyl-2-(2,2-dimethoxyethyl)pent-4-enal (X-5b)
Figure imgf000112_0001
[00244] 2-allyl-2-(2,2-dimethoxyethyl)pent-4-enal (X-5b). Followed the same procedure as X-4a and X-5a using bromo allyl. 90% yield. Also contains mono alkylated X-3c (<10%). The crude mixture of mono and bis alkylated was used in the next step without further purification. NMR of nitrile intermediate: Ή NMR (400 MHz, CDC13) d 5.84 (ddt, 2H), 5.24 (dd, 2H), 5.20 (dd, 2H), 4.63 (t, 1H), 3.37 (s, 6H), 2.39 (dd, 4H), 1.84 (d, 2H). NMR of aldehyde X-5b: 1HNMR (400 MHz, CDCI3) d 9.61 (d, 1H), 5.78 - 5.66 (m, 1H), 5.14 - 5.05 (m, 3H), 4.41 (t, 1H), 3.32 (d, 3H), 3.31 (d, 3H), 2.57 - 2.47 (m, 1H), 2.47 - 2.31 (m, 2H), 2.27 - 2.16 (m, 1H), 2.05 - 1.95 (m, 1H), 1.90 - 1.82 (m, 1H), 1.79 - 1.70 (m, 1H). 13C NMR (400 MHz, CDC13) d 203.88, 134.66, 117.88, 103.23, 53.89, 47.32, 33.53, 31.98. LC-MS m/z: 213.80 (calcd:213.15 [M+H]+).
Synthesis of 2,2-diethyl-4,4-dimethoxybutanal (X-5c)
Figure imgf000112_0002
[00245] 2,2-diethyl-4,4-dimethoxybutanal (X-5c). Followed the same procedure as X-4a and X-5a using iodoethane. 70% yield. Intermediate nitrile : ¾ NMR (400 MHz, CDCI3) d 4.57 (t, 1H), 3.36 (s, 6H), 1.83 (d, 2H), 1.66 (tdt, 4H), 1.01 (t, 6H). NMR of aldehyde X-5c: Ή NMR (400 MHz, CDCI3) d 9.35 (s, 1H), 4.32 (t, 1H), 3.30 (s, 6H), 1.83 (d, 2H), 1.62 (dq, 2H), 1.45 (dq, 2H), 0.79 (t, 6H). LC- MS m/z: 156.60 (calcd: 157.12 [M-OMe]+).
Synthesis of 2,2-diisopropyl-4,4-dimethoxybutanal (X-5d)
Figure imgf000112_0003
[00246] 2,2-diisopropyl-4,4-dimethoxybutanal (X-5d). Followed the same procedure as X-4a and X-5a using 2-iodopropane. <10% yield. NMR of intermediate nitrile: Ή NMR (400 MHz, CDCI3) d 4.52 (t, 1H), 3.39 (s, 6H), 1.99 (hept, 2H), 1.74 (d, 2H), 1.08 (d, 6H), 0.99 (d, 6H). NMR of aldehyde X-5d H NMR (400 MHz, CDCL) d 9.55 (s, 1H), 4.57 (t, 1H), 3.29 (s, 6H), 2.12 - 2.02 (m, 2H), 1.89 - 1.83 (m, 2H), 0.91 (dd, 12H).
Synthesis of 4,4-dimethoxy-2,2-diphenethylbutanal (X-5e)
Figure imgf000113_0001
[00247] 4,4-dimethoxy-2,2-diphenethylbutanal (X-5e). Followed the same procedure as X-4a and X-5a using (2-iodoethyl)benzene. The mixture of mono and bis alkylated was used in the next step without further purification (880 mg, 54%). NMR of Nitrile intermediate: Ή NMR (400 MHz, CDCI3) d 7.34 - 7.29 (m, 4H), 7.25 - 7.18 (m, 6H), 4.66 (t, 1H), 3.40 (s, 6H), 2.83 - 2.76 (m, 4H), 2.04 (d, 2H), 2.03 - 1.97 (m, 4H). NMR of aldehyde X-5e: ¾ NMR (400 MHz, CDC13) d 9.46 (s, 1H), 7.35 - 7.12 (m, 52H), 4.43 (t, 1H), 3.29 (s, 6H), 2.59 - 2.53 (m, 4H), 1.87 - 1.78 (m, 6H). LC- MS m/z: 341.95 (calcd: 341.21 [M+H]+).
Synthesis of l-(2,2-dimethoxyethyl)cyclopent-3-ene-l-carbaldehyde (X-5f)
Figure imgf000113_0002
[00248] l-(2,2-dimethoxyethyl)cyclopent-3-ene-l-carbaldehyde (X-5f). Followed the synthesis of X-5a using X-4b. 2.0g, 98% yield. ¾ NMR (400 MHz, CDC13) d 9.42 (s, 1H), 5.61 (s, 2H), 4.30 (t, 1H), 3.30 (s, 6H), 2.75 (d, 2H), 2.25 (d, 2H), 2.08 (d, 2H). LC-MS m/z: 185.80 (calcd: 185.12 [M+H]+).
Synthesis of 4-(dimethoxymethyl)nicotinaldehyde (X-5g)
Figure imgf000113_0003
[00249] 4-(dimethoxymethyl)nicotinaldehyde (X-5g). P-toluenesulfonic acid (2.5 g, 1.2 eq) was added to a stirred solution of 3-bromopyridine-4-carboxyaldehyde (2.0 g, l.Oeq) in 80 mL methanol and the mixture was heated to 75°C. The orange mixture turned red. After 4 hours the mixture was cooled to 23°C and concentrated. 100 mL of saturated sodium bicarbonate was added to the crude and it was extracted with ethyl acetate (3*100 mL).The combined organic layers were washed with water(lOOmL), brine (100 mL), dried over sodium sulfate anhydrous, filtered, concentrated and purified by column chromatography over silica gel using 0-50% ethyl acetate in hexanes. It afforded 3-bromo-4-(dimethoxymethyl)pyridine [L5g, 61% yield, TLC-Rf=0.3 in 15% ethyl acetate in hexanes, ¾ NMR (400 MHz, CDCL) d 8.72 (s, 1H), 8.53 (d, 1H), 7.52 (d, 1H), 5.50 (s, 1H), 3.38 (s, 6H)]. N-butyllithium was added dropwise to a solution of the latter in dry tetrahydrofuran (100 mL) at
- I l l - -75°C. The mixture turned deep orange. The mixture was stirred for lh then dimethylformamide (2.7mL, 4.0 eq) was added dropwise. The mixture was removed from the cold bath and let warmed up to 23 °C for 5 hours. It was quenched with a saturated solution of ammonium chloride (100 mL) then neutralized with saturated sodium bicarbonate (100 mL) and extracted with ethyl acetate (3*100 mL). The combined organic layers were washed with brine (2* 100 mL), dried over sodium sulfate anhydrous, filtered, concentrated and purified by column chromatography over silica gel (480 mg, 30% yield, TLC-Rf: 0.25 in 25% ethyl acetate in hexanes). ¾ NMR (400 MHz, CDCL) d 10.43 (s, 1H), 9.06 (s, 1H), 8.81 (d, 1H), 7.62 (d, 1H), 5.91 (s, 1H), 3.40 (s, 6H). LC-MS m/z: 181.75 (calcd: 182.08 [M+H]+).
Synthesis of (S)-2-((tert-butoxycarbonyl)amino)-3-(4-methoxyphenyl)propanoic acid (X-6)
Figure imgf000114_0001
[00250] (S)-2-((tert-butoxycarbonyl)amino)-3-(4-methoxyphenyl)propanoic acid (X-6). A mixture of (tert-butoxycarbonyl)-L-tyrosine (17.77 mmol, l.Oeq), iodomethane (5 ml, 80 mmol, 4.5 eq) and potassium carbonate (37.3 mmol, 2.5 eq) was refluxed in acetone for 18 h. Then the mixture was concentrated, diluted with water at pH 2 and extracted with ethyl acetate. The combined organic layers were washed with a saturated solution of sodium bicarbonate, dried over anhydrous sodium sulfate, filtered and concentrated. It afforded 6.4 g of crude intermediate. This crude (6.4 g, 1.0 eq) was solubilized in methanol (50mL) and 2M NaOH (45mL, 5 eq) was added. The mixture was stirred at 40°C for 3 hours. The mixture was acidified to pH 2 with 0.5M HC1 and extracted with ethyl acetate (3* 20 mL). The combined organic layers were dried over sodium sulfate anhydrous, filtered and concentrated. The crude oil was purified by flash column chromatography over silica gel to afford a colorless oil (5.1 g, 97% yield) that solidifies in the fridge at 5°C. ¾ NMR (400 MHz, CDCL) d 7.089 (d, J=8.24, 2H), 6.824 (d, J=8.70, 2H), 5.04-4.97 (bm, 1H), 4.58-4.50 (bm, 1H), 3.772 (s, 3H), 3.115 (dd, J= 13.97, 5.50, 1H), 3.015 (dd, J=13.97, 5.50, 1H), 1.409 (s, 9H). LC-MS m/z: 317.85 (calcd: 318.13 [M+Na]+).
Synthesis of (S)-2-((tert-butoxycarbonyl)amino)-3-(3-methoxyphenyl)propanoic acid (X-7)
Figure imgf000114_0002
[00251] (S)-2-((tert-butoxycarbonyl)amino)-3-(3-methoxyphenyl)propanoic acid (X-7). Followed the procedure of X-6 using 3-hydroxy-L-phenylalanine. Obtained 600 mg (quantitative yield). Ή NMR (400 MHz, CDCL) d 7.192 (t, J=7.56, 1H), 6.80-6.74 (m, 3H), 5.10-5.02 (bm, 1H), 4.61-4.53 (bm, 1H), 3.762 (s, 3H), 3.151(dd, J=13.69, 5.50, 1H), 3.034 (dd, J=13.78, 6.33, 1H), 1.403 (s, 9H). LC-MS m/z: 317.85 (calcd: 318.13 [M+Na]+).
Synthesis of (2S)-2-((tert-butoxycarbonyl)amino)-2-((lS)-2-hydroxycyclohexyl)acetic acid (X-8)
Figure imgf000115_0001
[00252] (2S)-2-((tert-butoxycarbonyl)amino)-2-((lS)-2-hydroxycyclohexyl)acetic acid (X-8). To a mixture of (2S)-2-((tert-butoxycarbonyl)amino)-2-(2-hydroxycyclohexyl)acetic acid (l.Oeq), which was synthesized following the patent literature: US20100048545A1, and 4-dimethylaminopyridine (0.1 eq) in tetrahydrofuran at 0°C was added di-/ert-butyl dicarbonate (1.1 eq). The mixture was stirred for 10 minutes at 0°C then warmed up to 20°C for 16 hours. The mixture was then concentrated, solubilized in methanol and sodium hydroxide was added (2M, 5 eq). The mixture was heated to 40°C for 3h. The reaction mixture was diluted with water (200 mL) then acidified to pH 2-3 with HC1 1M and extracted with ethyl acetate. The organics are combined, washed with saturated citric acid solution, dried over sodium sulfate anhydrous, filtered and concentrated. Crude: 370 mg. LC-MS m/z: 272.00 (calcd: 272.15 [M-H]-). ‘HNMR (400 MHz, CDCh) d 5.39 (d, 1H), 4.82 (dd, 1H), 4.43 (s, 1H), 4.03 (s, 1H), 3.53 (s, 1H), 3.23 (td, 1H), 2.02 (t, 3H), 1.92 - 1.56 (m, 7H), 1.50 - 1.42 (m, 18H), 1.40 - 1.13 (m, 6H), 1.13 - 0.96 (m, 1H).
Synthesis of (2S)-2-(((benzyloxy)carbonyl)amino)-4-hydroxy-5-(phenylthio)pentanoic acid (X-9)
Figure imgf000115_0002
[00253] (2S)-2-(((benzyloxy)carbonyl)amino)-4-hydroxy-5-(phenylthio)pentanoic acid (X-9). To a stirred solution of potassium tert-butoxide (2.0 eq) in tetrahydrofuran (100 mL), was added trimethylsulfoxonium iodide (2.0 eq, 1.76 lg). The mixture was refluxed for 2 hours then cooled down to 0°C. A second mixture of I,G-carbonyldiimidazole (1.0 eq, 649mg) and Z-L-Asp(OH)-OMe (1.0 eq, 1.293g) was heated in tetrahydrofuran (0.1M) for lh at 40°C. The second mixture was cooled down to 0°C before adding it to the first mixture at 0°C. The mixture was stirred at 0°C for lh then warmed up to 23 °C for 1 hour. The reaction was quenched brine (200 mL) and extracted with ethyl acetate (3*100 mL). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate anhydrous and concentrated to afford 1.6 g of crude intermediate. The crude (450 mg, l.Oeq) was solubilized in acetonitrile (3 mL) and benzenethiol (139 mg, 1.0 eq). The reaction mixture was stirred at this temperature for 24h then was concentrated. The crude was solubilized in methanol tetrahydrofuran (20mL,l: 1) at 0°C was added sodium borohydride (0.6 eq-1 eq). The mixture was stirred at 0°C for 30 min then warmed up to r.t for 2 hours. The mixture was quenched with a saturated solution of sodium bicarbonate (100 mL) and extracted with ethyl acetate (3*100 mL). The combined organic layers were dried over sodium sulfate anhydrous, fdtered and concentrated. The crude was solubilized in a mixture of tetrahydrof iran: water (3: 1, 40 mL) and sodium hydroxide was added (0.6g, 5 eq). The mixture was stirred vigorously for 3 hours at 40°C. The mixture was quenched with 0.5M HC1 (150 mL) and extracted with ethyl acetate (3* 100 mL). The combined organic layers were dried over sodium sulfate anhydrous, fdtered and concentrated. The crude was used in the next step without further purification. LC-MS m/z: 375.80 (calc'd 376.12 [M+H]+). Tf NMR (400 MHz, CDCL) d 7.16 - 7.05 (m, 7H), 7.05 - 6.98 (m, 2H), 6.98 - 6.92 (m, 1H), 6.27 (s, 1H), 5.00 (d, 1H), 4.73 (d, 1H), 4.17 (s, 1H), 3.76 (s, 1H), 2.90 (d, 1H), 2.76 (d, 1H), 1.92 (s, 1H), 1.71 (s, 1H). 13C NMR (400 MHz, CDCL) d 179.37, 157.50, 136.44, 136.41, 129.08, 128.97, 128.50, 127.98, 125.87, 68.09, 66.93, 54.29, 41.09, 40.30.
Amine Formation
Synthesis of (R)-thiochroman-4-aminium chloride (X-10)
Figure imgf000116_0001
[00254] (R)-thiochroman-4-aminium chloride (X-10). A mixture of the thiochromanone (10g, 60.9 mmol, 1.0 eq), (R)-2-methylpropane-2-sulfinamide (7.38 g, 60.9 mmol, 1.0 eq) and titanium tetraethoxide (27.8g,1.0eq) was stirred under nitrogen at 70°C for 30 min .The mixture, cooled to r.t., was diluted with ethyl acetate (250 mL) and lOmL of brine. The mixture was stirred vigorously for 10 min. The mixture was filtered through celite and the filter cake was washed with ethyl acetate (300 mL). The solvents were removed under vacuum and the crude was solubilized in THF (0.3M) containing 2% water and cooled down to -50°C. Sodium borohydride (3.0eq, 4.2 g) was added (3.0 eq) and the mixture was stirred at -50°C for lh then at 23°C for 2 hours. The solvents were removed under vacuum and the crude was purified by column chromatography (15-75% ethyl acetate in hexanes, the R enantiomer is the first to elute) to afford the pure (R)-2-methyl-N-((R)-thiochroman-4- yl)propane-2-sulfinamide [12g, 72%yield, Ή NMR (400 MHz, CDCL) d 7.32 (d, 1H), 7.16 - 7.08 (m, 2H), 7.07 - 7.01 (m, 1H), 4.61 (q, 1H), 3.26 (td, 1H), 3.18 (s, 1H), 2.80 (dt, 1H), 2.49 - 2.37 (m, 1H), 2.07 - 1.94 (m, 1H), 1.21 (s, 9H), 13C NMR (400 MHz, CDCL) d 133.76, 132.69, 131.45,
128.50, 126.85, 124.75, 55.66, 50.99, 28.25, 22.70, 21.18] and the pure (R)-2-methyl-N-((S)- thiochroman-4-yl)propane-2-sulfinamide [3g, 18% yield, ¾ NMR (400 MHz, CDCL) d 7.31 (ddt, 1H), 7.15 - 7.08 (m, 2H), 7.05 - 7.00 (m, 1H), 4.51 (ddd, 1H), 3.53 (d, 1H), 3.16 (ddd, 1H), 3.03 - 2.95 (m, 1H), 2.44 (dtd, 1H), 2.35 (ddt, 1H), 1.22 (s, 9H). The pure (R)-2-methyl-N-((R)- thiochroman-4-yl)propane-2-sulfinamide (2g, 1 eq) was then solubilized in dioxane (1M) and 4 M HC1 in dioxane (10 eq) was added slowly. The mixture was stirred for 14 hours at 23°C. Diethyl ether (to reach 0.1M) was added and the precipitate was fdtrated, washed with diethyl ether (30 mL), collected and lyophilized in dioxane. 0.5g (40% yield, white powder). Ή NMR (400 MHz, CD3OD) d
7.35 (ddd, 1H), 7.25 (ddd, 1H), 7.20 - 7.16 (m, 1H), 7.14 (td, 1H), 4.56 (t, 1H), 3.19 (ddd, 1H), 3.04
(ddd, 1H), 2.53 - 2.44 (m, 1H), 2.38 - 2.28 (m, 1H). 13C NMR (101 MHz, CD3OD) d 135.19, 131.29, 130.43, 128.77, 128.21, 125.64, 27.74, 21.90. LC-MS m/z: 163.80 (calcd: 164.05 [M-H]+).
Synthesis of (R)-chroman-4-aminium chloride (X-ll)
Figure imgf000117_0001
[00255] (R)-chroman-4-aminium chloride (X-ll). followed the synthesis ofX-10 1.6g (16% yield, tan powder). ¾ NMR (400 MHz, CD3OD) d 7.38 (ddt, 1H), 7.29 (dddd, 1H), 7.00 (td, 1H), 6.89 (dd, 1H), 4.57 (t, 1H), 4.34 - 4.23 (m, 2H), 2.44 - 2.34 (m, 1H), 2.23 - 2.13 (m, 1H). 13C NMR (101 MHz, CD3OD) d 156.51, 131.83, 130.09, 122.16, 118.94, 118.84, 62.75, 46.00, 27.97. LC-MS m/z: 147.70 (calcd: 148.08 [M-H]+).
Synthesis of 2-(pyrimidin-2-yl)aniline (X-12)
Figure imgf000117_0002
[00256] 2-(pyrimidin-2-yl)aniline (X-12). 2-Aminophenylboronic acid pinacol ester (1.5g, 1.0 eq.), 2-bromopyrimidine (2.2g, 2.0 eq), potassium carbonate (2.84g, 3 eq) and Pd(dppf) (280 mg, 0.05eq.) were mixed in DME/water (lOmL/lmL) and refluxed for 20h. lOOmL of 1M NaOH was added. It was extracted with DCM (3*30 mL), dried over sodium sulfate anhydrous, fdtered through celite and concentrated. The product was purified by reverse phase silica gel (1,1 g, orange powder, 94 % yield.). ¾ NMR (400 MHz, CDC13): d 8.78 (d, 2H), 8.44 (ddd, 1H), 7.24 (ddd, 1H), 7.10 (t, 1H), 6.78 (ddd, 1H), 6.74 (ddd, 1H), 6.26 (s, 2H). 13C NMR (101 MHz, CDCI3): d 166.29, 156.40, 148.81, 132.01, 130.97, 118.88, 117.50, 117.39, 117.15. LC-MS m/z: 172.10 (calcd: 172.09 [M+H]+). Synthesis of (lX,2f?)-2-(Prop-2-yn-l-yloxy)-2,3-dihydro-l /-inden-l-ammonium chloride (X-13)
Figure imgf000117_0003
[00257] (IX, 2f?)-2-(Prop-2-yn-l-yloxy)-2, 3-dihydro- lLf-inden-l-ammonium chloride (X-13).
Under N2 atmosphere, tert-Butyl (IS, 2R)-2 -hydroxy-2, 3-dihydro-lH-inden-l-ylcarbamate (2.50 g, 10.0 mmol, 1.00 eq.) was dissolved in dry DML (20.0 mL) and the solution was cooled down to 0 °C. Propargyl bromide in toluene (80%, 1.34 mL, 12.0 mmol, 1.20 eq.) was added. The resulting solution was treated in portions with powdered KOH (1.15 g, 420.6 mmol, 2.05 eq.) and stirring was continued at 0 °C. After 1.5 h, water (40 mL) was added and the resulting mixture was extracted with ethyl acetate (4 x 40 mL). The combined organic layers were washed with water (2 x 40 mL) and brine (20 mL), dried over sodium sulfate anhydrous and concentrated. The residue was purified by flash column chromatography over silica gel (hexanes/ethyl acetate). It afforded tert-Butyl [(lS,2R)-2- (prop-2-yn-l-yloxy)-2,3-dihydro-lH-inden-l-yl]carbamate as a colorless solid, yield 2.29 g (79%).
Rf = 0.60 (25% ethyl acetate in hexanes). ¾ NMR (400 MHz, CDCh) d 7.35 - 7.30 (m, 1H), 7.25 - 7.19 (m, 3H), 5.27 - 5.03 (m, 2H), 4.48 (dq, 1H), 4.22 (dd, 2H), 3.09 (dd, 1H), 3.02 (dd, 1H), 2.43 (t, 1H), 1.51 (s, 9H). 13C NMR (101 MHz, CDCh) d 156.27, 141.77, 139.43, 128.14, 127.21, 125.11, 124.51, 80.06, 79.74, 79.66, 74.65, 57.41, 57.17, 36.32, 28.56. LC-MS: m/z = 287.90 (calcd. 288.16 [M+H]+). Tert-Butyl [(lS,2R)-2-(prop-2-yn-l-yloxy)-2,3-dihydro-lH-inden-l-yl]carbamate (100 mg, 0.348 mmol, 1.00 eq.) was treated with HC1 in Dioxane (4 M, 2.61 mL, 30.0 eq.) at 20°C After 2 h, all volatiles were removed under reduced pressure, the residue was transferred on a fritted funnel and washed with Et20. The remaining product was dried under reduced pressure. It afforded X-13 as a colorless solid, 71 mg (91%). ¾ NMR (400 MHz, DMSO-D6) d 8.61 (s, 3H), 7.60 (d, 1H), 7.36 - 7.25 (m, 3H), 4.71 (s, 1H), 4.51 (q, 1H), 4.39 - 4.29 (m, 2H), 3.55 (t, 1H), 3.20 - 3.07 (m, 2H). 13C NMR (101 MHz, DMSO-D6) d 140.64, 137.06, 129.24, 126.87, 125.50, 125.15, 80.15, 78.34, 77.79, 57.08, 55.17, 35.80. LC-MS: m/z = 188.05 (calcd. 188.11 [M+H+]).
Synthesis of (lS,2R)-2-(2-Fluoroethoxy)-2,3-dihydro-lH-inden-l-ammonium chloride (X-14)
Figure imgf000118_0001
[00258] (IS, 2R)-2-(2-Fluoroethoxy)-2,3-dihydro-lH-inden-l-ammonium chloride (X-14). Follow same procedure as X-13 using 2-fluoroethyl 4-methylbenzenesulfonate (315 mg, 1.44 mmol, 1.20 eq). It afforded the intermediate tert-butyl [(lS,2R)-2-(2-fluoroethoxy)-2,3-dihydro-lH-inden-l- yl]carbamate as a colorless solid, 250 mg (70%). Rf = 0.41 (25 % ethyl acetate in hexanes). ¾ NMR (400 MHz, CDCh) d 7.35 - 7.31 (m, 1H), 7.22 (d, 3H), 5.29 - 5.02 (m, 2H), 4.52 (dt, 2H), 4.33 - 4.28 (m, 1H), 3.78 (ddd, 2H), 3.04 (d, 2H), 1.50 (s, 9H). LC-MS: m/z = 295.95 (calcd. 296.17 [M+H+]). It afforded X-14 as a colorless solid, 123 mg (68%). ¾ NMR (400 MHz, DMSO- ) d 8.62 (s, 3H),
7.62 (d, 1H), 7.36 - 7.26 (m, 3H), 4.70 (t, 1H), 4.66 - 4.50 (m, 2H), 4.45 - 4.39 (m, 1H), 3.90 - 3.78 (m, 2H), 3.15 - 3.03 (m, 2H). 13C NMR (101 MHz, DMSO-th) d 140.81, 137.17, 129.18, 126.82, 125.56, 125.17, 83.85, 82.20, 79.19, 69.19, 69.01, 55.12, 35.98. LC-MS: m/z = 195.90 (calcd. 196.11 [M+H+]).
Synthesis of tert-butyl ((S)-l-(((4S,7S,9aS)-7-(lH-indole-l-carbonyl)-8,8-dimethyl-5- oxooctahydropyrrolo[2,l-b][l,3]oxazepin-4-yl)amino)-l-oxopropan-2-yl)(methyl)carbamate (X- 15)
Figure imgf000119_0001
[00259] tert-butyl ((S)-l-(((4S,7S,9aS)-7-(lH-indole-l-carbonyl)-8,8-dimethyl-5- oxooctahydropyrrolo[2,l-b][l,3]oxazepin-4-yl)amino)-l-oxopropan-2-yl)(methyl)carbamate (X- 15). Follow synthesis of X-l using Boc-HSer-OH and X-3. The crude product was purified by flash column chromatography over silica gel to afford the pure diastereoisomer (second eluting isomer). ¾ NMR (400 MHz, CD3OD) d 8.524 (d, J=8.24, 1H), 7.547 (d, J=8.24, 1H), 7.527 (d, J=3.66, 1H), 7.320 (td, J=8.46, 1.37, 1H), 7.259 (td, J=6.64, 1.37, 1H), 7.206 (broad singlet, 1H), 6.676 (d, J=3.66, 1H), 5.338 (t, J=6.41, 1H), 4.985 (s, 1H), 4.739 (q, J=7.33, 1H), 4.278 (dt, J=12.36, 3.21, 1H), 4.03- 3.93 (m, 1H), 2.729 (s, 3H), 2.272 (dd, J=13.74, 6.41, 1H), 2.209 (dd, J=13.51, 6.87, 1H), 1.964 (d, J=5.50, 1H), 1.944 (d, J=5.50, 1H), 1.395 (s, 9H), 1.301(d, J=7.33, 3H), 1.209 (s, 3H), 0.970 (s, 3H). 13C NMR (101 MHz, CD3OD) d 171.303, 171.179, 169.129, 135.786, 130.485, 125.356, 124.555, 124.164, 120.903, 117.042, 110.034, 89.162, 80.782, 70.827, 68.081, 53.236, 52.921, 50.624, 46.200, 40.488, 40.202, 32.460, 30.420, 29.314, 28.351, 23.526, 13.944. LC-MS m/z: 527.05 (calcd. 527.29 [M+H]+).
Synthesis of (4S,7S,9aS)-4-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamido)-8,8- dimethyl-5-oxooctahydropyrrolo[2,l-b] [l,3]oxazepine-7-carboxylic acid (X-16)
Figure imgf000119_0002
(4S,7S,9aS)-4-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamido)-8,8-dimethyl-5- oxooctahydropyrrolo[2,l-b][l,3]oxazepine-7-carboxylic acid (X-16). To a solution of X-15 (250 mg, 0.475 mmol) in methanol (1M) was added 2M aqueous NaOH (to reach a 1M NaOH concentration). The mixture is stirred at 40°C for 3-6 hours. The mixture was concentrated to dryness and purified by reverse phase silica gel. 89.1 mg (62 % yield). LC-MS m/z: 428.00 (calcd. 428.24 [M+H]+). ¾ NMR (400 MHz, CDC13) d 7.31 (s, 1H), 5.23 (t, 1H), 4.73 (q, 1H), 4.22 - 4.13 (m, 2H), 3.99 - 3.88 (m, 1H), 2.80 (s, 3H), 2.19 - 2.12 (m, 1H), 2.02 (dd, 1H), 1.95 (dd, 2H), 1.46 (s, 9H), 1.35 (d, 3H), 1.19 — 1.12 (m, 6H). Synthesis of tert-butyl ((S)-l-(((4S,7S,9aS)-7-formyl-8,8-dimethyl-5- oxooctahydropyrrolo[2,l-b][l,3]oxazepin-4-yl)amino)-l-oxopropan-2-yl)(methyl)carbamate (X- 17)
Figure imgf000120_0001
[00260] tert-butyl ((S)-l-(((4S,7S,9aS)-7-formyl-8,8-dimethyl-5-oxooctahydropyrrolo[2,l- b][l,3]oxazepin-4-yl)amino)-l-oxopropan-2-yl)(methyl)carbamate (X-17). To a solution of X-15 (1.0 eq, 500mg ) in tetrahydrofuran at -20°C was added sodium borohydride (2 eq). The mixture was stirred at -20°C for 30 min then at 23 °C for 18 hours. The mixture was quenched with water and sodium bicarbonate. It was extracted with ethyl acetate. The combined organic layers were washed with water, dried over sodium sulfate anhydrous, filtered and concentrated to afford the alcohol intermediate (176 mg, 46% yield, 13C NMR (101 MHz, CD3OD) d 172.13, 171.96, 88.71, 69.95,
68.01, 60.59, 52.50, 45.16, 37.88, 32.43, 29.72, 28.11, 27.30, 21.58). oxalyl chloride (2.0 eq) was solubilized in dry DCM then cooled down to -78°C. DMSO (4.0 eq) was added dropwise and the reaction was stirred for 10 min (at -78°C). A solution of the alcohol (1.0 eq) in DCM was added dropwise and stirred for 15min at -78°C. triethylamine (4.5 eq) was added at -78°C and the mixture was stirred for 15 min at -78C. The mixture was warmed up to 0°C and stirred for a further lOmin. after completion (monitored by LCMS), ethyl acetate was added to the mixture. The organic phase was washed with Brine, dried over sodium sulfate, filtered and concentrated. 555B: 125.2 mg (31%). LC-MS m/z: 412.00 (calcd. 412.24 [M+H]+).
Synthesis of (4A',7A',9aAT)-4-({(2AT)-2-[(/e/7-Butoxycarbonyl)(methyl)amino]propanoyl}amino)-8,8- dimethyl-5-oxooctahydropyrrolo[2,l-/>] [l,3]thiazepine-7-carboxylic acid (X-18)
Figure imgf000120_0002
[00261] (4AV7A',9aAT)-4-({(2AT)-2-[(/e/7-Butoxycarbonyl)(methyl)amino]propanoyl}amino)-8,8- dimethyl-5-oxooctahydropyrrolo[2,l-Z>][l,3]thiazepine-7-carboxylic acid (X-18). Followed the same procedure as X-16 using A-(tcrt-biitoxycarbonyl)-S'-trityl-L-homocystcinc instead of the homoserine. Before deprotection of the indole-convertible isocyanide, it afforded 2 isomers: the first undesired isomer as a yellow solid, 214 mg (14%). Rf = 0.47 (50 % ethyl acetate in hexanes). The second desired isomer as a yellow solid, 254 mg (17%). Rf = 0.20 (50 % ethyl acetate in hexanes). ‘HNMR (400 MHz, CDCfi) d 8.57 (d, 1H), 7.59 - 7.55 (m, 2H), 7.37 - 7.27 (m, 3H), 6.70 (d, 1H), 5.26 (t, 1H), 5.09 (s, 1H), 4.71 (s), 4.61 (dd, 1H), 3.30 (ddd, 1H), 2.90 (ddd, 1H), 2.75 (s, 3H), 2.33 - 2.25 (m, 3H), 1.96 (q, 1H), 1.43 (s, 9H), 1.33 (d, 3H), 1.26 - 1.24 (m, 5H), 1.02 (s, 3H). LC-MS: m/z = 565.26 (calcd. 565.25 [M+Na+]). It was dissolved in methanol (3.0 mL) and aq. NaOH solution (1 M, 1.20 mL, 1.20 mmol, 5.00 eq.) was added. After the resulting mixture was stirred for 5 h at 32 °C, the methanol was removed in vacuo. NaOH solution (1 M, 30 mL) and brine (10 mL) were added and washed with ethyl acetate (3* 10 mL). The aqueous layer was acidified with HC1 solution (3 M) to pH 2 and extracted with CH2CI2 (3*20 mL). The combined CH2CI2 layers were dried over sodium sulfate anhydrous and concentrated in vacuo. The residue was purified by fc (cyclohexane/ethyl acetate with 1% HCOOH). It afforded X-18 as a colorless solid, 56 mg (53%).
Rf = 0.52 (hexanes/ethyl acetate/formic acid 3:7:0.2, Ceric Ammonium Molybdate stain). *HNMR (400 MHz, CDCL) d 7.38 (s, 1H), 5.19 (t, 1H), 4.60 (q, 1H), 4.23 (d, 1H), 3.25 (ddd, 1H), 2.91 - 2.77 (m, 4H), 2.35 - 2.21 (m, 2H), 2.02 (dd, 1H), 1.93 (q, 1H), 1.46 (d, 9H), 1.35 (d, 3H), 1.21 (d, 3H), 1.17 (d, 3H). LC-MS m/z : 444.10 (calcd. 444.22 [M+H+]).
Synthesis of (4'S,7'S,9a'S)-4'-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamido)-5'-oxo- 2',3',4',5',9',9a'-hexahydro-7'H-spiro[cyclopentane-l,8'-pyrrolo[2,l-b] [l,3]thiazepin]-3-ene-7'- carboxylic acid (X-19)
Figure imgf000121_0001
[00262] (4'S,7'S,9a'S)-4'-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamido)-5'-oxo- 2',3',4',5',9',9a'-hexahydro-7'H-spiro[cyclopentane-l,8'-pyrrolo[2,l-b] [l,3]thiazepin]-3-ene-7'- carboxylic acid. Follow synthesis of X-18 using X-5f . before the removal of the convertible isocyanide, it afforded two isomers. The first non-desired isomer as a brown solid, yield 37 mg (10%). Rf = 0.33 (40% ethyl acetate in hexanes). The second desired isomer tert-butyl N-[(1S)-1- {[(4'S,7'S,9'aS)-7'-(lH-indole-l-carbonyl)-5'-oxo-3',4',5',7',9',9'a-hexahydro-2H-spiro[cyclopentane- l,8'-pyrrolo[2,l-b][l,3]thiazepin]-3-en-4'-yl]carbamoyl}ethyl]-N-methylcarbamate as a brown solid, yield 86 mg (22%). Rf = 0.21 (40% ethyl acetate in hexanes). ¾ NMR (400 MHz, CDCL) d 8.56 (d, 1H), 7.61 (d, 1H), 7.57 (d, 1H), 7.38 - 7.27 (m, 3H), 6.66 (t, 1H), 5.75 - 5.69 (m, 1H), 5.65 - 5.60 (m, 1H), 5.26 - 5.20 (m, 2H), 4.78 - 4.53 (m, 2H), 3.30 (dd, 1H), 2.93 - 2.85 (m, 1H), 2.76 (s, 3H), 2.63 - 2.50 (m, 2H), 2.42 (s, 2H), 2.33 - 2.18 (m, 3H), 1.95 (q, 1H), 1.44 (s, 9H), 1.34 (d, 3H). LC-MS: m/z = 567.25 (calcd. 567.26 [M+H+]).
[00263] The desired isomer (86 mg, 0.152 mmol, 1.00 eq.) was dissolved in methanol (1.84 mL) and aq. NaOH (1 M, 456 pL, 0.456 mmol, 3.00 eq.) was added. After the resulting mixture was stirred for 2 days at 40 °C, the methanol was removed in vacuo. Et20 (10 mL) was added and washed with NaOH solution (1 M, 3 x 10 mL). After the combined NaOH layers were extracted with Et20 (2 x 10 mL), the aqueous layer was acidified with cone. HC1 to pH Land extracted with CH2CI2 (3 x 10 mL) and EtOAc (2 x 10 mL). The combined org. layers were dried (Na2S04> and concentrated in vacuo. The residue was purified by fc (hexanes/ethyl acetate with 0.2% formic acid). It afforded (4'S,7'S,9'aS)-4'-(2-{[(tert-butoxy)carbonyl](methyl)amino}acetamido)-5'-oxo-3',4',5',7',9',9'a- hexahydro-2H-spiro[cyclopentane-l,8'-pyrrolo[2,l-b][l,3]thiazepin]-3-ene-7'-carboxylic acid as a colorless solid, yield 48 mg (68%). Rf = 0.46 (hexanes/ethyl acetate/formic acid 5:5:0.1, CAM stain). ¾ NMR (400 MHz, CDC13) d 7.40 (d, 1H), 5.74 - 5.68 (m, 1H), 5.66 - 5.60 (m, 1H), 5.19 (t, 1H), 4.63 (t, 2H), 4.46 (s, 1H), 3.25 (t, 1H), 2.85 - 2.76 (m, 4H), 2.73 (d, 1H), 2.50 - 2.42 (m, 1H), 2.36 - 2.22 (m, 4H), 2.20 - 2.11 (m, 1H), 1.93 (q, 1H), 1.45 (s, 9H), 1.34 (d, 3H). LC-MS m/z : 468.30 (calcd. 468.59 [M+H+]).
Synthesis of (4S, 9aS)-8,8-dimethyl-4-((S)-2-(methylamino)propanamido)-5-oxo-N-((R)-l, 2,3,4- tetrahydronaphthalen-l-yl)octahydropyrrolo[2,l-b][l,3]thiazepine-7-carboxamide hydrochloride (Compound A)
Figure imgf000122_0001
[00264] In a sealed round bottom flask, X-l (1.64 g, 1.0 eq) was added to a mixture of N-(tert- butoxycarbonyl)-S-trityl-L-homocysteine ( 5.0 g, 10.5 mmol, 1.0 eq), X-5a (1.8 g, 1.05 eq) and 7N ammonia (in methanol, 3.14 mL, 2.1 eq) in methanol ( 20mL, 0.5M) at 0°C. The mixture was stirred at 40°C for 17-41 hours. The mixture was concentrated and solubilized in a 2M HC1 in dioxane solution (50mL, 10 eq). The mixture was stirred for 2-4 hours at 40°C. The mixture was concentrated and quenched with saturated aqueous solution of sodium carbonate (300mL). It was extracted with ethyl acetate (3*200mL). The combined organic layers were washed with a solution of sodium bicarbonate (2*200mL), dried over sodium sulfate anhydrous, fdtered and concentrated to afford a crude oil. It was solubilized in tetrahydrofuran (0.5M) and cooled down to 0°C. To the solution was added Boc-N-Me -Alanine (l.Oeq), NMM (3.5 eq), HOBT (1.1 eq) then EDC.HC1 (1.05 eq). The mixture was stirred at 0°C for 30 min. the cold bath was removed and it was stirred at 23°C for 18 hours. The mixture was quenched with saturated aqueous sodium bicarbonate (100 mL) and extracted with ethyl acetate (3* 100 mL). The organic layers were combined, washed with brine, dried over sodium sulfate anhydrous, fdtered and concentrated. The intermediate (1.0 eq, 1.3 mmol, 750 mg) was solubilized in methanol (3.0mL) and 4M HC1 in 1,4-Dioxane (3.0mL) was added. The Mixture was stirred at 40°C for 4 hours. The mixture was concentrated and purified by reverse phase HPLC (10-70% acetonitrile in water), then lyophilized from a water-dioxane mixture to afford the product as a powder. 559 mg, 8 %, pink powder. ¾ NMR (400 MHz, CD3OD) d 8.76 (d), 8.20 (d, 1H), 7.30 (d, 1H), 7.18 - 7.05 (m, 3H), 5.42 (t, 1H), 5.09 (q, 1H), 4.74 (d, 1H), 4.15 (s, 1H), 3.92 (q, 1H), 3.29 - 3.19 (m, 1H), 2.95 - 2.87 (m, 1H), 2.84 - 2.74 (m, 2H), 2.68 (s, 3H), 2.34 - 2.21 (m, 2H), 2.08 - 1.74 (m, 6H), 1.55 (d, 3H), 1.16 (s, 3H), 1.14 (s, 3H). 13C NMR (101 MHz, CD3OD) d 172.32, 171.43, 169.24, 138.57, 137.39, 130.09, 129.79, 128.31, 127.11, 73.34, 61.87, 58.36, 54.47, 48.93, 47.33, 40.89, 33.65, 32.06, 31.81, 31.30, 30.10, 28.67, 23.90, 21.32, 16.26.
Example 1: Synthesis of (4S,7S,9aS)-8,8-dimethyl-4-((S)-2-(methylamino)propanamido)-5-oxo- N-((R)-l,2,3,4-tetrahydronaphthalen-l-yl)octahydropyrrolo[2,l-b][l,3]thiazepine-7- carboxamide 1,1-dioxide hydrochloride
Figure imgf000123_0001
[00265] Followed the synthesis of compound A until after the Boc-Alanine coupling to get tert-butyl ((2S)-l-(((4S)-8,8-dimethyl-5-oxo-7-(((R)-l,2,3,4-tetrahydronaphthalen-l- yl)carbamoyl)octahydropyrrolo[2, 1 -b] [ 1 ,3]thiazepin-4-yl)amino)- 1 -oxopropan-2- yl)(methyl)carbamate. This intermediate (1.0 eq, 0.4mmol, 247 mg) in DCM (5mL) at 0°C, was treated with MCPBA (2.0eq). The mixture was stirred at 0°C for 2 hours then concentrated and purified by flash column chromatography (50-100% ethyl acetate in hexanes). It was treated with aqueous HC1 3.0M (200 pL, 5eq) at 40°C for 3 hours then concentrated to afford 123 mg of 1. Example 2 and 3: Synthesis of (3R, 6S,12bR)-2,2-dimethyl-6-((S)-2- (methylamino)propanamido)-5-oxo-N-((R)-l,2,3,4-tetrahydronaphthalen-l-yl)- l,2,3,5,6,7,12,12b-octahydropyrrolo[l',2':l,2]azepino[3,4-b]indole-3-carboxamide hydrochloride and (3S, 6S,12bR)-2,2-dimethyl-6-((S)-2-(methylamino)propanamido)-5-oxo-N-((R)-l,2,3,4- tetrahydronaphthalen-l-yl)-l,2,3,5,6,7,12,12b-octahydropyrrolo[l',2':l,2]azepino[3,4-b]indole- 3-carboxamide hydrochloride
Figure imgf000123_0002
[00266] Followed the synthesis of Compound A using Boc-Trp-OH. Two isomers were separated: compound 2 (51.3 mg, 8% yield), compound 3 (34.1 mg, 10% yield). LCMS m/z: 542.20 (calcd. 542.30 [M+H]+).
[00267] Compound 2: ‘HNMR (400 MHz, CD3OD) d 7.38 - 7.33 (m, 2H), 7.31 - 6.87 (m, 13H), 5.76 - 5.65 (m, 1H), 5.27 (dd, 1H), 5.10 (p, 2H), 4.20 (s, 1H), 4.08 (q, 1H), 3.92 - 3.50 (m, 3H), 3.35 (s), 3.29 (dt, 1H), 2.96 (ddd, 1H), 2.73 (s, 3H), 2.01 - 1.72 (m, 9H), 1.57 (dd, 4H), 1.26 (d, 12H), 1.19 (d, 4H), 0.91 (s, 3H). 13C NMR (101 MHz, CD3OD) d 196.03, 171.73, 169.39, 138.86, 138.78, 137.42, 136.46, 134.67, 130.24, 130.12, 129.98, 129.63, 128.38, 128.18, 127.07, 127.02, 122.79, 120.26, 118.49, 112.18, 107.91, 72.63, 68.31, 58.39, 55.90, 52.64, 45.57, 42.27, 41.49, 40.36, 31.90, 31.20, 30.71, 30.46, 30.27, 30.21, 30.02, 29.77, 29.45, 29.22, 29.11, 24.75, 24.46, 24.21, 21.13, 20.72, 16.45. [00268] Compound 3: ¾ NMR (400 MHz, CD3OD) d 7.40 - 7.33 (m, 2H), 7.26 (dt, 1H), 7.23 - 6.99 (m, 8H), 6.86 (dd, 1H), 5.50 (dd, 1H), 5.16 (ddd, 1H), 4.27 (d, 1H), 4.08 - 3.97 (m, 1H), 3.70 - 3.58 (m, 1H), 3.30 - 3.22 (m, 1H), 3.05 (t, 1H), 2.71 (d, 4H), 2.60 - 2.37 (m, 5H), 1.65 - 1.59 (m, 5H), 1.28 - 1.26 (m, 4H), 1.20 (d, 3H). 13C NMR (101 MHz, CD3OD) d 172.10, 171.35, 169.69, 138.14, 137.08, 136.79, 133.90, 129.96, 129.57, 128.93, 128.15, 126.98, 122.80, 120.20, 118.48, 112.28, 108.19, 101.15, 72.22, 58.38, 54.98, 52.44, 44.66, 40.87, 31.87, 30.93, 30.45, 30.26, 29.71, 28.37, 28.23, 24.22, 24.11, 20.80, 16.36.
Example 4: Synthesis of (4S)-4-((S)-2-(methylamino)propanamido)-5-oxo-N-((R)-l,2,3,4- tetrahydronaphthalen-l-yl)-2,3,4,5,7,llb-hexahydropyrido[4',3':3,4]pyrrolo[2,l- b] [l,3]oxazepine-7-carboxamide dihydrochloride
Figure imgf000124_0001
[00269] Followed the synthesis of compound A using Boc-HSer-OH and X-5g. 27 mg (5 % yield). LC-MS m/z: 239.10 (calcd. 239.63 [M+H]2+). ¾ NMR (400 MHz, CD3OD) d 8.76 - 8.63 (m, 2H), 7.65 (d, 1H), 7.37 (dd, 1H), 7.24 - 7.07 (m, 4H), 6.86 - 6.59 (m, 1H), 5.82 - 5.58 (m, 1H), 5.14 - 5.02 (m, 1H), 4.61 - 4.25 (m, 1H), 3.76 - 3.57 (m, 1H), 2.82 (dd, 3H), 2.62 (dd, 3H), 2.07 - 1.90 (m, 4H), 1.82 (ddd, 2H), 1.63 - 1.47 (m, 4H). 13C NMR (101 MHz, CD3OD) d 173.27, 172.57, 169.96, 169.73, 150.79, 150.74, 150.70, 150.64, 150.43, 144.99, 144.82, 138.65, 137.28, 137.14, 133.19, 133.10, 130.35, 130.10, 130.05, 129.68, 129.66, 128.38, 128.31, 127.17, 127.15, 121.00, 120.90, 85.51, 85.46, 65.25, 64.76, 57.73, 57.00, 32.73, 32.48, 31.39, 31.31, 30.19, 30.16, 21.64, 21.52, 17.60, 16.46. Example 5: Synthesis of (6S,llbR)-N-benzhydryl-9-methoxy-2,2-dimethyl-6-((S)-2- (methylamino)propanamido)-5-oxo-2,3,5,6,7,llb-hexahydro-lH-benzo[c]pyrrolo[l,2-a]azepine- 3-carboxamide
Figure imgf000125_0001
[00270] Follow synthesis of compound A using X-7 and X-2. 14 mg (10% yield), LC-MS m/z: 569.60 (calcd. 569.30[M+H]+). ¾ NMR (400 MHz, CD3OD) d 8.97 (d), 7.40 - 7.18 (m, 12H), 6.80 (dd, 1H), 6.74 (d, 1H), 6.27 - 6.21 (m, 1H), 5.44 (dd, 1H), 5.11 (dd, 1H), 4.27 (s, 1H), 3.77 (s, 3H), 3.74 (d,
1H), 3.39 (dd, 1H), 3.09 (dd, 1H), 2.65 (s, 3H), 2.55 (dd, 1H), 2.41 (dd, 1H), 2.00 (dq), 1.49 (d, 3H), 1.02 (s, 3H), 0.99 (s, 3H). 13C NMR (101 MHz, CD3OD) d 172.11, 172.00, 170.24, 160.28, 143.12, 142.78, 138.66, 131.01, 129.61, 129.32, 129.31, 129.26, 128.68, 128.56, 128.51, 128.11, 118.19, 117.44, 112.56, 72.66, 59.61, 58.63, 58.22, 55.70, 52.75, 43.17, 40.59, 37.48, 32.14, 29.18, 24.34, 16.71.
Example 6 and 33: (6S,llbR)-N-benzhydryl-10-methoxy-2,2-dimethyl-6-((S)-2- (methylamino)propanamido)-5-oxo-2,3,5,6,7,llb-hexahydro-lH-benzo[c]pyrrolo[l,2-a]azepine- 3-carboxamide hydrochloride
Figure imgf000125_0002
[00271] (6S,llbR)-N-benzhydryl-10-methoxy-2,2-dimethyl-6-((S)-2-
(methylamino)propanamido)-5-oxo-2,3,5,6,7,llb-hexahydro-lH-benzo[c]pyrrolo[l,2-a]azepine- 3-carboxamide hydrochloride (6). Followed the synthesis of compound A using X-6 and X-2. Two isomers isolated: compound 6 (20 mg), compound 33 (10 mg). LC-MS m/z: 569.25 (calcd. 569.3[M+H]+).
[00272] Compound 6: ¾ NMR (400 MHz, CD3OD) d 8.44 (s, 2H), 8.06 (p), 7.38 - 7.07 (m, 17H), 6.88 (d, 1H), 6.80 (dt, 2H), 5.96 (ddt, 1H), 5.47 - 5.46 (m, 1H), 5.12 (dd), 5.07 (dd, 1H), 4.71 (d), 4.67 (d, 1H), 3.72 - 3.70 (m, 3H), 3.70 - 3.69 (m, 1H), 3.12 - 3.04 (m, 1H), 2.83 (ddd, 1H), 2.56 - 2.51 (m), 2.35 (d, 1H), 2.28 (d, 1H), 1.41 (ddd, 3H), 1.31 - 1.12 (m, 2H), 1.02 (d, 1H), 0.91 (d, 1H), 0.87 (d, 1H), 0.79 (d, 1H). 13C NMR (101 MHz, CD3OD) d 174.36, 173.83, 170.41, 169.81, 169.57, 160.18, 160.09, 140.56, 140.54, 139.83, 139.82, 131.52, 131.44, 130.37, 130.02, 129.81, 129.70, 129.59, 129.57, 129.54, 128.99, 128.97, 125.49, 125.45, 118.83, 118.76, 114.93, 114.84, 61.76, 61.72, 59.62, 59.58, 58.58, 58.52, 56.16, 55.95, 55.69, 55.66, 36.65, 36.51, 31.95, 31.92, 26.63, 26.60, 20.55,
20.44, 16.77, 16.74.
[00273] Compound 33: ¾ NMR (400 MHz, CD3OD) d 8.50 (s, 1H), 7.40 - 7.09 (m, 14H), 6.92 - 6.67 (m, 2H), 6.26 - 6.07 (m, 1H), 5.60 (t), 5.50 - 5.48 (m), 5.37 (d), 5.20 - 5.02 (m, 1H), 4.37 (s), 4.32 (s), 4.28 (s), 4.20 (s), 3.79 - 3.68 (m, 4H), 3.45 - 3.40 (m, 1H), 3.22 (t), 3.19 - 2.94 (m, 1H), 2.90 - 2.68 (m, 1H), 2.48 (d), 2.38 - 2.25 (m, 2H), 2.24 - 2.11 (m), 2.09 - 1.88 (m, 1H), 1.42 (dd,
2H), 1.34 - 1.24 (m, 3H), 1.14 - 0.81 (m, 5H). 13C NMR (101 MHz, CD3OD) d 174.18, 173.97, 173.28, 172.88, 172.02, 171.99, 171.22, 160.45, 160.11, 160.08, 160.05, 143.11, 143.08, 143.00,
142.84, 142.82, 142.81, 142.77, 142.72, 131.77, 131.58, 131.47, 131.43, 131.30, 130.49, 130.27,
129.97, 129.66, 129.62, 129.61, 129.57, 129.50, 129.46, 129.44, 129.31, 129.30, 129.28, 129.08,
128.73, 128.63, 128.61, 128.56, 128.53, 128.51, 128.45, 128.35, 128.08, 128.01, 115.29, 114.93,
114.86, 114.79, 91.50, 90.57, 90.37, 71.81, 71.71, 71.52, 71.36, 58.65, 58.50, 58.37, 58.30, 58.23, 58.18, 55.74, 55.66, 55.62, 55.46, 54.92, 54.56, 54.30, 53.65, 53.49, 53.33, 45.32, 45.20, 43.47, 42.82,
41.45, 41.39, 41.06, 40.54, 40.41, 39.61, 38.62, 38.28, 38.06, 31.97, 31.91, 29.89, 29.74, 29.66, 24.97,
24.86, 24.57, 16.93, 16.82, 16.71.
Example 8 and 9: Synthesis of (6S,llbR)-9-methoxy-2,2-dimethyl-6-((S)-2- (methylamino)propanamido)-5-oxo-N-((R)-l,2,3,4-tetrahydronaphthalen-l-yl)-2,3,5,6,7,llb- hexahydro-lH-benzo[c]pyrrolo[l,2-a]azepine-3-carboxamide hydrochloride
Figure imgf000126_0001
[00274] Followed the synthesis of compound A using X-7. Two isomers were isolated: Compound 8 (17 mg, yellow solid, 25% yield), Compound 9 (47.2 mg, yellow solid, 50% yield). LC-MS m/z: 533.20 (calcd. 533.3[M+H]+).
[00275] Compound 8: ¾ NMR (400 MHz, CD3OD) d 8.56 (d), 8.45 (d), 7.33 (d, 1H), 7.29 - 7.19 (m, 1H), 7.19 - 7.03 (m, 3H), 6.81 (d, 1H), 6.75 (s, 1H), 5.45 (t, 1H), 5.16 - 5.03 (m, 2H), 4.12 (s, 1H), 3.87 - 3.80 (m, 1H), 3.78 (d, 3H), 3.44 (dd, 1H), 3.04 (dd, 1H), 2.90 - 2.73 (m, 2H), 2.70 (s, 3H), 2.58 (dd, 1H), 2.42 (dd, 1H), 2.05 - 1.85 (m, 3H), 1.86 - 1.72 (m, 1H), 1.51 (d, 3H), 1.21 (s, 3H), 1.08 (s, 3H). 13C NMR (101 MHz, CD3OD) d 171.97, 171.61, 169.42, 160.44, 138.90, 138.88, 137.55, 130.98, 130.17, 129.99, 128.46, 128.20, 127.06, 117.44, 112.55, 73.20, 59.56, 58.48, 55.76, 53.24, 43.70, 40.22, 37.12, 31.93, 31.14, 30.27, 29.12, 24.59, 21.08, 16.37. [00276] Compound 9: ‘HNMR (400 MHz, CD3OD) d 8.19 (d), 7.34 - 7.00 (m, 7H), 6.99 - 6.90 (m, 1H), 6.80 - 6.75 (m, 1H), 6.74 (s, 1H), 6.29 - 6.24 (m, 1H), 5.35 (dd, 1H), 5.11 - 5.05 (m, 1H), 4.98 - 4.93 (m, 1H), 4.32 (s, 1H), 4.04 (dd, 1H), 3.89 - 3.81 (m, 2H), 3.80 - 3.75 (m, 5H), 3.44 (d, 1H), 3.40 - 3.33 (m, 1H), 3.17 - 3.10 (m, 2H), 2.90 (s, 2H), 2.76 - 2.68 (m, 5H), 2.57 (t, 1H), 2.31 (dd, 1H),
2.01 - 1.87 (m, 2H), 1.76 (td, 3H), 1.59 - 1.54 (m, 3H), 1.26 (d, 3H), 1.22 - 1.18 (m, 3H). 13C NMR (101 MHz, CD3OD) d 172.23, 172.14, 171.75, 169.60, 160.31, 159.62, 138.42, 138.40, 137.39,
137.36, 131.10, 130.86, 130.75, 130.52, 129.96, 129.61, 128.75, 128.15, 127.08, 116.93, 113.10, 107.67, 107.65, 103.50, 72.62, 72.58, 65.10, 58.54, 58.46, 55.74, 54.57, 52.34, 45.38, 43.91, 39.97, 36.61, 31.87, 31.22, 30.06, 28.24, 24.30, 21.38, 16.25.
Example 10 and 11: Synthesis of (6S,llbR)-10-methoxy-2,2-dimethyl-6-((S)-2- (methylamino)propanamido)-5-oxo-N-((R)-l,2,3,4-tetrahydronaphthalen-l-yl)-2,3,5,6,7,llb- hexahydro-lH-benzo[c]pyrrolo[l,2-a]azepine-3-carboxamide hydrochloride
Figure imgf000127_0001
[00277] Followed the synthesis of compound A using X-6. Two isomers were isolated: Compound 11 (5.8 mg, 5% yield), Compound 10 (9.9 mg, 10% yield). LC-MS m/z: 533.65 (calcd. 533.3[M+H]+). [00278] Compound 11: ¾ NMR (400 MHz, CD3OD) d 7.29 - 7.23 (m, 2H), 7.21 - 7.12 (m, 3H), 7.03 - 6.96 (m, 1H), 6.88 - 6.81 (m, 2H), 5.75 - 5.65 (m, 2H), 5.15 (dd, J = 7.9, 1.2 Hz, 1H), 4.75 (d, J = 1.2 Hz, 1H), 3.77 - 3.72 (m, 3H), 3.58 - 3.46 (m, 1H), 3.39 - 3.33 (m, 1H), 2.92 - 2.73 (m, 3H), 2.27 (s, 3H), 2.11 - 1.91 (m, 2H), 1.89 - 1.75 (m, 2H), 1.38 (d, J = 6.7 Hz, 3H), 1.07 (s, 3H), 1.01 (s, 3H). 13C NMR (101 MHz, CD3OD) d 174.47, 169.94, 160.11, 140.16, 134.98, 131.45, 130.53, 130.41, 128.60, 128.54, 127.52, 124.86, 119.67, 114.85, 59.47, 58.88, 56.08, 55.67, 53.75, 38.31, 36.76,
30.24, 30.12, 26.52, 22.42, 20.73, 17.27.
[00279] Compound 10: ¾ NMR (400 MHz, CD3OD) d 7.30 - 7.20 (m, 3H), 7.20 - 7.05 (m, 5H), 7.01 - 6.94 (m, 1H), 6.89 - 6.80 (m, 3H), 5.77 (dd, J = 8.0, 1.1 Hz, 1H), 5.75 - 5.67 (m, 1H), 5.04 (dd, J = 8.0, 1.1 Hz, 1H), 5.01 - 4.95 (m, 1H), 4.63 (d, J = 1.1 Hz, 1H), 3.81 - 3.72 (m, 6H), 3.15 (dd, J =
13.7, 6.5 Hz, 1H), 2.94 - 2.72 (m, 5H), 2.42 (s, 3H), 2.09 - 1.93 (m, 3H), 1.93 - 1.72 (m, 3H), 1.50 (d, J = 6.6 Hz, 3H), 0.95 (s, 3H), 0.92 (s, 3H). 13C NMR (101 MHz, CD3OD) d 173.71, 169.60,
169.49, 160.19, 139.85, 135.48, 131.57, 130.48, 130.05, 128.58, 128.32, 127.51, 127.23, 125.17,
118.50, 114.95, 59.83, 58.49, 56.01, 55.70, 53.78, 39.01, 36.34, 31.84, 30.28, 29.54, 26.86, 22.74, 20.77, 16.60. [00280] Example 12, 14, 13, and 15: Synthesis of (4S,9aS)-8,8-diallyl-4-((S)-2- (methylamino)propanamido)-5-oxo-N-((R)-l,2,3,4-tetrahydronaphthalen-l- yl)octahydropyrrolo[2,l-b][l,3]oxazepine-7-carboxamide hydrochloride (12, 14). [00281] (4S,9aS)-8,8-allyl-4-((S)-2-(methylamino)propanamido)-5-oxo-N-((R)-l,2,3,4- tetrahydronaphthalen-l-yl)octahydropyrrolo[2,l-b][l,3]oxazepine-7-carboxamide hydrochloride (13, 15)
Figure imgf000128_0001
[00282] Followed the synthesis of A using Boc-HSer-OH and X-5b. The monoalkylated compound 13 and compound 15 were side-products coming from unpurified X-5b. Four isomers separated or enriched: Compound 12 (11 mg), Compound 13 (4.0 mg, mono-allyl), Compound 14 (11.2 mg), Compound 15 (19.6 mg of mono-allyl). LC-MS m/z: 509.20 (calcd. 509.3[M+H]+), mono-alkylated: 469.15 (calcd. 469.3[M+H]+).
[00283] Compound 12: ¾ NMR (400 MHz, CD3OD) d 8.49 (d), 8.08 (d), 7.45 (s), 7.29 (d), 7.19 - 6.95 (m, 4H), 5.96 - 5.72 (m, 2H), 5.41 (d, 1H), 5.16 - 4.98 (m, 5H), 4.36 (d, 1H), 4.22 - 4.05 (m, 1H), 3.95 (d, 2H), 2.78 (q, 2H), 2.67 (s, 3H), 2.54 (dd,), 2.45 - 2.21 (m, 3H), 2.18 - 2.06 (m, 2H), 2.05 - 1.67 (m, 9H), 1.56 (d, 3H). 13C NMR (101 MHz, CD3OD) d 172.65, 171.89, 171.76, 169.15, 138.79, 138.42, 137.43, 137.32, 135.18, 135.08, 135.00, 134.66, 130.11, 130.07, 129.99, 129.86, 129.70, 129.31, 128.33, 128.13, 127.10, 126.98, 119.59, 119.28, 118.84, 118.61, 90.84, 90.24, 71.61, 71.39, 70.34, 69.09, 58.45, 54.67, 54.07, 46.53, 46.33, 44.08, 43.86, 42.85, 42.29, 41.98, 40.11, 39.63, 34.56, 33.18, 32.22, 32.16, 31.15, 31.08, 30.22, 30.06, 21.29, 21.18, 16.49, 16.46.
[00284] Compound 14: ¾ NMR (400 MHz, CD3OD) d 8.08 (d, J = 8.3 Hz, 1H), 7.29 (d, J = 7.1 Hz, 1H), 7.13 (dq, J = 14.0, 7.5 Hz, 3H), 5.94 - 5.76 (m, 2H), 5.42 (t, J = 6.6 Hz, 1H), 5.16 - 5.04 (m,
5H), 4.32 (d, J = 1.8 Hz, 1H), 4.10 (d, J = 12.2 Hz, 1H), 4.01 - 3.87 (m, 2H), 2.88 - 2.72 (m, 2H),
2.68 (s, 3H), 2.40 - 2.25 (m, 2H), 2.17 - 2.05 (m, 4H), 2.01 - 1.93 (m, 4H), 1.91 - 1.74 (m, 5H), 1.58 (d, J = 5.8 Hz, 3H). 13C NMR (101 MHz, CD3OD) d 171.90, 171.50, 169.55, 138.45, 137.45, 135.02, 134.67, 130.12, 129.72, 128.34, 127.11, 119.58, 118.85, 90.21, 71.32, 69.10, 69.07, 58.42, 54.03, 49.64, 49.43, 49.21, 49.00, 48.79, 48.57, 48.36, 46.55, 43.86, 42.84, 40.13, 33.12, 31.96, 31.15, 30.05, 21.28, 16.38.
[00285] Compound 15: mixture of 3 isomers. ¾ NMR (400 MHz, CD3OD) d 8.38 (d), 8.25 (d), 8.11 (d), 7.48 - 7.40 (m), 7.30 (d), 7.23 - 7.02 (m, 4H), 5.90 - 5.74 (m, 1H), 5.46 - 5.33 (m, 1H), 5.15 - 4.99 (m, 3H), 4.48 (d, 1H), 4.13 (d, 1H), 4.05 - 3.86 (m, 2H), 2.87 - 2.72 (m, 2H), 2.68 (s, 3H), 2.56 - 2.28 (m, 2H), 2.17 - 2.05 (m, 2H), 2.02 - 1.71 (m, 8H), 1.65 - 1.47 (m, 3H). 13C NMR (101 MHz, CD3OD) d 172.32, 172.04, 171.70, 169.63, 169.56, 169.21, 138.74, 138.49, 138.47, 137.69, 137.66, 137.54, 137.50, 137.40, 137.37, 137.32, 137.25, 136.76, 130.09, 130.07, 129.92, 129.85, 129.70, 128.29, 128.19, 128.16, 127.10, 127.05, 127.00, 117.62, 116.99, 116.88, 90.74, 90.45, 90.22, 71.32, 71.25, 67.45, 67.40, 65.20, 65.16, 64.94, 64.90, 58.41, 58.37, 54.24, 54.20, 54.15, 49.85, 41.49, 39.39,
39.35, 39.19, 39.15, 38.90, 37.95, 35.55, 35.44, 34.23, 33.44, 33.08, 31.91, 31.53, 31.51, 31.31, 31.29,
31.17, 31.15, 30.20, 30.09, 21.68, 21.36, 21.15, 16.45, 16.43, 16.40.
[00286] Examples 35-39: Synthesis of (4S,9aS)-8,8-diethyl-4-((S)-2-(methylamino)propanamido)- 5-oxo-N-((R)-l,2,3,4-tetrahydronaphthalen-l-yl)octahydropyrrolo[2,l-b][l,3]thiazepine-7- carboxamide hydrochloride (35, 37, 38, 39).
[00287] (4S, 9aS)-8,8-ethyl-4-((S)-2-(methylamino)propanamido)-5-oxo-N-((R)-l, 2,3,4- tetrahydronaphthalen-l-yl)octahydropyrrolo[2,l-b][l,3]thiazepine-7-carboxamide hydrochloride (36)
Figure imgf000129_0001
[00288] Followed the synthesis of A using X-5c. The monoalkylated compound 36 was a side-product coming from unpurified X-5c. Five isomers were separated or enriched with difficulty: (Compound 35, 10.4mg), (Compound 36, 2.1 mg, mono-alkylated), (Compound 37, 3.0 mg), (Compound 38, 17.6 mg), (Compound 39, 1.0 mg). LC-MS m/z: 501.55 (calcd. 501.30[M+H]+), mono-alkylated LC-MS m/z: 473.45 (calcd. 473.3[M+H]+).
[00289] Compound 35: ¾ NMR (400 MHz, CD3OD) d 8.62 (d), 8.52 - 8.39 (m, 2H), 7.33 - 7.26 (m), 7.20 - 7.03 (m, 4H), 5.48 (q, 1H), 5.40 - 5.33 (m), 5.07 - 4.99 (m, 1H), 4.79 (dd), 4.72 (dd, J = 11.0, 1.9 Hz, 1H), 4.41 - 4.35 (m, 1H), 3.94 - 3.82 (m, 1H), 3.29 - 3.22 (m, 1H), 2.93 - 2.68 (m, 4H), 2.63 (d, 3H), 2.25 (ddt, 1H), 2.06 - 1.56 (m, 11H), 1.50 (d, 1H), 1.45 (d, 2H), 1.41 - 1.26 (m, 1H), 0.95 - 0.84 (m, 7H). 13C NMR (101 MHz, CD3OD) d 172.64, 172.55, 171.92, 169.49, 138.86, 137.42,
130.11, 129.94, 128.14, 127.01, 71.88, 63.40, 58.44, 55.17, 47.63, 44.81, 34.78, 33.17, 31.93, 30.99, 30.25, 29.98, 26.58, 21.17, 16.63, 9.22, 8.52, 8.49.
[00290] Compound 36 (mixture of at least 3 isomers (mono alkylated)): Ή NMR (400 MHz, CD3OD) d 8.40 (d,), 8.20 (d), 8.15 (d), 7.49 - 7.41 (m), 7.32 - 7.26 (m), 7.20 - 7.04 (m, 4H), 5.57 - 5.44 (m, 1H), 5.34 (t), 5.15 - 5.01 (m, 1H), 4.72 (dd), 4.55 (dd, 1H), 4.17 (d), 4.07 (d), 3.94 - 3.85 (m, 1H), 2.95 - 2.72 (m, 4H), 2.69 - 2.64 (m, 3H), 2.36 - 2.09 (m, 3H), 2.06 - 1.72 (m, 7H), 1.72 - 1.58 (m, 1H), 1.58 - 1.44 (m, 3H), 1.43 - 1.21 (m, 1H), 1.05 - 0.81 (m, 4H). [00291] Compound 37 (mixture of mono and bis alkylate): Ή NMR (400 MHz, CD3OD) d 8.36 (s), 7.94 (d), 7.27 (d, 1H), 7.19 - 7.00 (m, 3H), 5.38 - 5.24 (m, 1H), 5.03 (d, 1H), 4.56 - 4.47 (m), 4.35 (s), 4.32 - 4.24 (m, 1H), 3.94 - 3.79 (m, 1H), 2.99 - 2.68 (m, 3H), 2.66 - 2.59 (m, 2H), 2.59 - 1.19 (m, 15H), 1.03 - 0.78 (m, 6H). 13C NMR (101 MHz, CD3OD) d 171.35, 170.00, 138.61, 137.38, 130.06, 129.96, 129.68, 128.43, 128.26, 127.11, 127.05, 72.24, 70.89, 62.01, 54.88, 49.71, 48.01, 43.94, 32.19, 32.07, 31.93, 31.69, 31.36, 30.13, 28.36, 26.15, 21.51, 9.17, 9.12, 8.42, 8.35.
[00292] Compound 38 (complex mixture of isomers mono and bis alkylated): ¾ NMR (400 MHz, CD3OD) d 8.40 (s, 1H), 7.33 - 7.21 (m, 1H), 7.16 - 7.01 (m, 4H), 5.48 - 5.30 (m, 1H), 5.09 - 4.97 (m, 1H), 4.74 - 4.58 (m, 1H), 4.39 - 4.26 (m, 1H), 3.92 - 3.83 (m, 1H), 3.27 - 3.17 (m, 1H), 2.90 - 2.35 (m, 9H), 2.27 - 2.18 (m, 1H), 2.10 - 1.21 (m, 16H), 0.96 - 0.78 (m, 7H). 13C NMR (101 MHz, CD3OD) d 171.34, 171.21, 171.07, 170.59, 170.18, 170.02, 168.43, 168.19, 167.89, 167.57, 163.55, 137.53, 137.49, 137.24, 136.13, 136.00, 135.81, 128.97, 128.93, 128.79, 128.59, 128.49, 128.38, 127.20, 127.02, 126.82, 125.86, 125.80, 125.69, 125.67, 70.55, 70.14, 69.72, 62.06, 60.27, 59.94, 57.08, 57.04, 57.01, 54.08, 53.86, 53.10, 53.05, 48.41, 47.63, 46.53, 46.37, 46.34, 46.29, 43.52, 43.36, 43.11, 35.67, 33.44, 32.38, 31.85, 31.45, 30.99, 30.89, 30.54, 30.35, 30.05, 29.92, 29.69, 29.52, 28.94, 28.77, 28.67, 27.51, 27.20, 25.54, 25.27, 25.11, 20.00, 19.89, 19.77, 15.27, 15.23, 15.05, 8.02, 7.93, 7.86, 7.81, 7.31, 7.25, 7.21, 7.08.
[00293] Compound 39: mixture of three isomers bis-alkylated. Ή NMR (400 MHz, CD3OD) d 8.50 (s, 1H), 7.30 - 7.24 (m, 1H), 7.20 - 7.05 (m, 4H), 5.49 - 5.33 (m, 1H), 5.12 - 5.00 (m, 1H), 4.74 -
4.62 (m, 1H), 4.38 - 4.30 (m, 1H), 3.71 (q, 1H), 3.50 - 3.47 (m), 3.15 - 3.12 (m), 2.91 - 2.68 (m, 4H),
2.63 - 2.55 (m, 3H), 2.42 (dd, 1H), 2.24 (d, 1H), 2.04 - 1.75 (m, 7H), 1.73 - 1.58 (m, 2H), 1.51 - 1.27 (m, 6H), 0.96 - 0.82 (m, 7H).
[00294] Example 19, 21, and 20: Synthesis of (4S)-8,8-diethyl-4-((S)-2- (methylamino)propanamido)-5-oxo-N-((R)-l,2,3,4-tetrahydronaphthalen-l- yl)octahydropyrrolo[2,l-b][l,3]oxazepine-7-carboxamide hydrochloride (19, 21).
[00295] (4S)-8,8-ethyl-4-((S)-2-(methylamino)propanamido)-5-oxo-N-((R)-l,2,3,4- tetrahydronaphthalen-l-yl)octahydropyrrolo[2,l-b][l,3]oxazepine-7-carboxamide hydrochloride (20).
Figure imgf000130_0001
[00296] Followed the synthesis of compound A using Boc-HSer-OH and X-5c. The monoalkylated compound 20 is a side-product coming from unpurified X-5c. Three isomers isolated: Compound 19 (8.6 mg), Compound 20 (2.4 mg mono), Compound 21 (40.8 mg). LC-MS m/z: 485.20 (calcd. 485.3[M+H]+), mono LC-MS m/z: 457.10 (calcd. 457.3[M+H]+).
[00297] Compound 19: ¾ NMR (400 MHz, CD3OD) d 7.49 - 7.43 (m, 1H), 7.20 - 7.05 (m, 4H), 6.00 (d), 5.78 - 5.69 (m), 5.57 (t), 5.47 - 5.32 (m, 1H), 5.15 - 4.93 (m, 1H), 4.79 (dd), 4.46 - 3.88 (m, 3H), 2.91 - 2.69 (m, 2H), 2.68 (d, 1H), 2.38 - 2.20 (m, 1H), 2.01 - 1.70 (m, 6H), 1.69 - 1.51 (m, 3H), 1.50
- 1.31 (m, 2H), 1.31 - 1.28 (m, 1H), 1.00 - 0.82 (m, 6H). 13C NMR (101 MHz, CD3OD) d 172.70,
172.14, 172.08, 171.89, 171.87, 170.16, 169.57, 169.17, 166.89, 142.54, 140.07, 138.95, 138.83,
138.49, 137.50, 137.48, 137.08, 134.97, 130.63, 130.23, 130.17, 130.14, 130.09, 130.00, 129.90,
129.75, 129.35, 128.75, 128.59, 128.35, 128.13, 127.83, 127.24, 127.10, 126.98, 113.22, 91.24, 91.00,
90.23, 71.52, 71.25, 70.88, 70.74, 69.41, 58.41, 58.39, 56.62, 54.76, 54.71, 54.19, 54.01, 47.28, 47.19, 44.36, 44.13, 44.08, 42.01, 34.50, 33.12, 32.14, 31.78, 31.24, 31.16, 31.11, 30.85, 30.25, 30.20, 30.17, 30.10, 29.36, 29.05, 28.67, 27.43, 26.67, 26.56, 26.40, 24.21, 22.47, 21.35, 21.20, 20.81, 20.61, 16.38, 9.28, 9.19, 9.03, 8.62, 8.53, 8.49.
[00298] Compound 20: ¾ NMR (400 MHz, CD3OD) d 8.03 (d, J = 8.4 Hz, 1H), 7.29 - 7.21 (m, 1H), 7.16 - 7.02 (m, 3H), 5.41 (t, J = 6.6 Hz, 1H), 5.11 - 5.00 (m, 1H), 4.83 (s, 5H), 4.22 (s, 1H), 4.10 - 4.02 (m, 1H), 3.99 - 3.87 (m, 2H), 2.85 - 2.68 (m, 2H), 2.66 (s, 2H), 2.01 (s, 2H), 1.99 - 1.73 (m,
7H), 1.66 - 1.58 (m, 1H), 1.56 (d, J = 7.0, 0.8 Hz, 3H), 1.45 - 1.37 (m, 2H), 1.36 - 1.26 (m, 1H), 0.92
- 0.78 (m, 6H). 13C NMR (101 MHz, CD3OD) d 170.75, 170.56, 168.28, 137.16, 136.20, 128.80, 128.43, 127.01, 125.81, 88.88, 69.94, 68.09, 57.08, 52.67, 47.66, 45.88, 42.82, 31.79, 30.55, 29.92, 28.78, 28.06, 25.35, 20.03, 15.12, 7.78, 7.28.
Example 22, 23, 24, 25, and 26: Synthesis of (4S,9aS)-4-((S)-2-(methylamino)propanamido)-5- oxo-8, 8-diphenethyl-N-((R)-l, 2,3, 4-tetrahydronaphthalen-l-yl)octahydropyrrolo[2,l- b] [l,3]oxazepine-7-carboxamide hydrochloride
Figure imgf000131_0001
[00299] Followed the synthesis of compound A using Boc-HSer-OH and X-5e. Five isomers separated or enriched: Compound 22 (21.6 mg), Compound 23 (17.5 mg), Compound 24 (10.4 mg), Compound 25 (9.0 mg), Compound 26 (12.6 mg). LC-MS m/z:637.25 (calcd. 637.3[M+H]+).
[00300] Compound 22: 2 isomers. ¾ NMR (400 MHz, CD3OD) d 8.61 (d), 8.13 (d), 7.36 - 6.98 (m, 13H), 6.82 (d), 6.70 - 6.64 (m), 5.54 - 5.43 (m, 1H), 5.14 - 4.93 (m, 2H), 4.59 - 4.44 (m, 1H), 4.29 - 4.10 (m, 1H), 4.03 - 3.90 (m, 2H), 2.85 - 2.70 (m, 4H), 2.68 (dd, 3H), 2.65 - 2.40 (m, 2H), 2.21 - 1.63 (m, 11H), 1.63 - 1.53 (m, 3H). 13C NMR (101 MHz, CD3OD) d 172.79, 172.17, 171.73, 171.56, 169.62, 169.18, 143.69, 143.62, 143.46, 143.24, 138.68, 138.40, 137.43, 137.16, 130.11, 130.10, 130.07, 129.99, 129.94, 129.65, 129.51, 129.42, 129.39, 129.35, 129.32, 129.30, 129.27, 128.34, 128.01, 127.14, 127.05, 127.03, 126.99, 126.88, 91.02, 90.16, 71.55, 71.29, 70.89, 69.82, 58.39,
54.83, 54.72, 54.04, 46.89, 45.36, 44.84, 40.08, 40.03, 38.09, 37.51, 34.59, 33.05, 31.98, 31.81, 31.80, 31.78, 31.64, 31.47, 31.19, 31.09, 30.19, 30.02, 21.06, 20.98, 16.39, 16.36.
[00301] Compound 23: 1HNMR (400 MHz, DMSO-d6) d 8.25 - 8.12 (m, 2H), 7.36 - 7.12 (m, 13H), 7.12 - 7.01 (m, 2H), 5.60 - 5.48 (m, 1H), 4.99 - 4.70 (m, 2H), 4.34 (s, 1H), 4.04 (d, J = 12.6 Hz, 1H), 3.88 (t, J = 12.1 Hz, 1H), 2.99 (q, J = 6.8 Hz, 1H), 2.79 - 2.57 (m, 6H), 2.36 (dd, J = 13.4, 6.5 Hz,
1H), 2.25 (s, 3H), 2.08 (s, 2H), 2.02 - 1.43 (m, 13H), 1.14 (d, J = 6.9 Hz, 3H). 13C NMR (101 MHz, DMSO-D6) d 173.56, 170.87, 168.58, 142.39, 142.17, 137.04, 136.95, 128.80, 128.49, 128.45,
128.36, 128.27, 128.24, 128.11, 126.90, 125.80, 125.77, 118.15, 88.14, 69.48, 67.60, 59.37, 51.47, 46.38, 44.89, 43.00, 38.04, 35.65, 34.36, 32.51, 30.16, 29.73, 29.63, 28.62, 19.38, 18.93.
[00302] Compound 24: ¾ NMR (400 MHz, CD3OD) d 7.86 (d, J = 5.0 Hz, 1H), 7.36 - 6.94 (m,
17H), 6.85 - 6.76 (m), 5.49 (q), 5.12 - 5.02 (m, 1H), 5.02 - 4.95 (m), 4.59 - 4.45 (m, 1H), 2.85 - 2.44 (m, 9H), 2.35 (dt, 1H), 2.04 - 2.02 (m, 3H), 2.02 - 1.57 (m, 11H), 1.31 - 1.24 (m, 1H). 13C NMR (101 MHz, CD3OD) d 176.43, 173.37, 173.30, 172.61, 171.53, 171.14, 170.90, 143.69, 143.59, 143.57, 138.75, 138.38, 137.41, 137.25, 137.12, 130.12, 130.10, 130.09, 130.02, 129.81, 129.57, 129.51, 129.47, 129.44, 129.42, 129.40, 129.37, 129.35, 129.33, 129.32, 129.25, 128.34, 128.24, 128.23, 127.19, 127.13, 127.10, 127.05, 127.02, 127.00, 126.97, 126.91, 118.14, 90.16, 82.97, 71.37, 69.72, 60.34, 53.47, 46.92, 44.85, 42.13, 42.06, 39.98, 38.69, 38.08, 37.50, 34.42, 33.49, 33.12, 32.91, 32.00, 31.90, 31.82, 31.48, 31.20, 31.09, 31.08, 30.15, 30.03, 21.10, 21.04, 20.83, 19.22.
[00303] Compound 25: ¾ NMR (400 MHz, CD3OD) d 7.37 - 7.10 (m, 15H), 7.02 (dd, J = 4.6, 1.2 Hz, 2H), 6.82 (d, J = 7.8 Hz, 1H), 6.66 (dt, J = 8.2, 4.2 Hz, 1H), 5.53 - 5.41 (m, 1H), 5.12 - 4.90 (m, 3H), 4.52 (s, 1H), 4.25 - 4.09 (m, 1H), 4.02 - 3.88 (m, 2H), 2.85 - 2.70 (m, 6H), 2.68 (s, 4H), 2.65 -
2.55 (m, 2H), 2.46 (dd, J = 13.7, 7.0 Hz, 1H), 2.21 - 2.07 (m, 3H), 2.03 (s, 2H), 2.02 - 1.69 (m, 12H),
1.56 (d, J = 7.0 Hz, 3H). 13C NMR (101 MHz, CD3OD) d 172.81, 171.74, 169.17, 143.71, 143.63, 138.69, 137.16, 130.11, 130.00, 129.95, 129.70, 129.65, 129.61, 129.53, 129.50, 129.42, 129.36, 129.32, 129.27, 128.02, 127.15, 127.06, 126.99, 126.89, 91.06, 71.56, 70.91, 58.42, 54.76, 46.92,
46.83, 45.37, 40.08, 38.11, 34.60, 31.99, 31.77, 31.66, 31.19, 30.19, 20.97, 16.32.
[00304] Example 28, 29, 31, 27, 30, and 32: Synthesis of (4S,9aS)-8,8-diallyl-4-((S)-2- (methylamino)propanamido)-5-oxo-N-((R)-l,2,3,4-tetrahydronaphthalen-l- yl)octahydropyrrolo[2,l-b][l,3]thiazepine-7-carboxamide hydrochloride (28, 29, 31).
[00305] (4S, 9aS)-8,8-allyl-4-((S)-2-(methylamino)propanamido)-5-oxo-N-((R)-l, 2,3,4- tetrahydronaphthalen-l-yl)octahydropyrrolo[2,l-b][l,3]thiazepine-7-carboxamide hydrochloride (27, 30, 32)
Figure imgf000133_0001
[00306] Follow synthesis of compound A using X-5b. The monoalkylated compound 27, compound 30 and compound 32 were side-products coming from unpurified X-5b. 6 isomers were separated: Compound 27 (1.3 mg, mono-allyl), Compound 28 (2.4mg), Compound 29 (4.6 mg), Compound 30 (2.4 mg mono), Compound 31 (3.0 mg), Compound 32 (5.0 mg mono). LC-MS m/z: 525.50 (calcd. 525.29[M+H]+), mono LC-MS m/z: 485.05 (calcd. 485.26[M+H]+).
[00307] Compound 27: ¾ NMR (400 MHz, CD3OD) d 8.47 (s, 1H), 7.42 - 7.36 (m, 1H), 7.17 - 6.99 (m, 4H), 5.90 - 5.72 (m, 2H), 5.45 (dd, J = 7.8, 4.0 Hz, 1H), 5.15 - 4.99 (m, 5H), 4.80 - 4.71 (m, 2H), 4.14 (d, J = 6.4 Hz, 1H), 3.68 (q, J = 7.2 Hz, 2H), 3.12 - 3.01 (m, 1H), 2.75 (dd, J = 16.9, 9.7 Hz, 5H), 2.59 - 2.53 (m, 4H), 2.36 - 1.69 (m, 15H), 1.46 (dd, J = 7.0, 1.8 Hz, 3H), 1.43 - 1.34 (m, 1H).
[00308] Compound 28: ¾ NMR (400 MHz, CD3OD) d 8.49 (s, 1H), 7.29 (dd, J = 6.5, 2.0 Hz, 1H), 7.20 - 7.05 (m, 5H), 5.96 - 5.77 (m, 3H), 5.38 (dd, 1H), 5.20 - 5.04 (m, 7H), 4.70 (dd, 1H), 4.41 (s, 1H), 4.27 (s), 3.74 (q, 1H), 2.90 - 2.72 (m, 5H), 2.60 (s, 3H), 2.57 (s, 1H), 2.46 - 2.34 (m, 3H), 2.29 - 1.74 (m, 15H), 1.53 - 1.44 (m, 4H). 13C NMR (101 MHz, CD3OD) d 172.35, 171.18, 138.57, 135.01, 134.61, 130.13, 129.81, 128.38, 127.13, 119.78, 118.96, 70.57, 61.81, 58.74, 54.31, 47.22, 46.91, 44.15, 42.13, 39.88, 33.55, 32.28, 31.17, 30.06, 27.65, 21.28, 16.80.
[00309] Compound 29: ¾ NMR (400 MHz, CD3OD) d 8.51 (s, 1H), 7.34 - 7.26 (m), 7.18 - 7.03 (m, 4H), 5.98 - 5.77 (m, 2H), 5.56 - 5.34 (m, 1H), 5.21 - 5.00 (m, 5H), 4.72 (dd, 1H), 4.44 (d, 1H), 3.68 (q, 1H), 2.98 - 2.63 (m, 5H), 2.62 - 2.53 (m, 3H), 2.50 - 2.32 (m, 2H), 2.32 - 1.70 (m, 10H), 1.47 (t, 1H), 1.40 (d, 2H). 13C NMR (101 MHz, CD3OD) d 172.69, 171.56, 170.99, 138.88, 137.28, 135.12, 134.66, 130.12, 129.99, 128.18, 127.03, 119.69, 118.79, 78.96, 71.44, 63.33, 58.93, 55.03, 46.82, 44.42, 42.85, 39.71, 34.77, 33.18, 32.56, 30.98, 30.24, 21.13, 17.23.
[00310] Compound 30: ¾ NMR (400 MHz, CD3OD) d 8.51 (s, 1H), 7.46 - 7.38 (m, 1H), 7.20 - 7.03 (m, 6H), 5.83 (ddt, 2H), 5.53 - 5.43 (m, 2H), 5.16 - 5.00 (m, 6H), 4.83 - 4.75 (m, 2H), 4.53 (d), 4.17 (d, 1H), 3.67 (q, J = 6.8, 6.4 Hz, 2H), 2.95 - 2.67 (m, 7H), 2.65 - 2.51 (m, 7H), 2.50 - 1.73 (m, 20H), 1.47 (d, 3H), 1.39 (d, 1H). 13C NMR (101 MHz, CD3OD) d 171.99, 171.78, 138.80, 138.51, 137.66, 137.59, 136.67, 130.00, 128.26, 127.09, 117.83, 88.30, 68.26, 62.63, 58.92, 53.80, 41.99, 39.41,
37.67, 31.59, 31.51, 30.19, 21.58, 17.13.
[00311] Compound 31: ¾ NMR (400 MHz, CD3OD) d 8.54 - 8.38 (m, 1H), 8.05 - 7.96 (m), 7.28 (dd, 1H), 7.19 - 7.04 (m, 3H), 7.01 - 6.92 (m), 6.86 - 6.82 (m), 5.96 - 5.78 (m, 2H), 5.46 - 5.32 (m, 1H), 5.18 - 5.03 (m, 5H), 4.70 (d, 1H), 4.41 (s, 1H), 3.76 (d, 1H), 3.49 - 3.44 (m, 1H), 2.91 - 2.71 (m, 4H), 2.61 (s, 3H), 2.41 (dd, 2H), 2.24 (d, 1H), 2.17 (d, 2H), 2.10 (dd, 1H), 2.04 - 1.72 (m, 7H), 1.50 (d, 3H). 13C NMR (101 MHz, CD3OD) d 172.33, 171.17, 138.56, 137.29, 135.00, 134.61, 130.13, 129.80, 128.77, 128.38, 127.12, 119.78, 118.96, 117.13, 70.58, 61.81, 58.69, 54.33, 47.22, 44.16, 42.13, 39.88, 33.53, 32.29, 32.22, 31.17, 30.07, 21.28, 16.72.
[00312] Compound 32: ¾ NMR (400 MHz, CD3OD) d 8.48 (s, 2H), 7.44 - 7.22 (m, 1H), 7.22 - 6.99 (m, 8H), 5.91 - 5.68 (m, 2H), 5.55 - 5.40 (m, 1H), 5.15 - 4.97 (m, 6H), 4.79 - 4.43 (m, 3H), 4.23 -
4.11 (m, 1H), 3.75 - 3.59 (m, 3H), 2.98 - 1.66 (m, 38H), 1.51 - 1.33 (m, 6H).
Example 40, 41, 42, and 43: Synthesis of 4S,9aS)-8,8-diisopropyl-4-((S)-2- (methylamino)propanamido)-5-oxo-N-((R)-l,2,3,4-tetrahydronaphthalen-l- yl)octahydropyrrolo[2,l-b] [l,3]thiazepine-7-carboxamide hydrochloride (40,41,42,43)
Figure imgf000134_0001
[00313] (Followed the synthesis of compound A using X-5d. Four isomers separated: Compound 40 (3.5 mg), Compound 41 (6.3 mg), Compound 42 (2.0 mg), Compound 43 (2.3 mg). LC-MS m/z: 529.55 (calcd. 529.32[M+H]+).
[00314] Compound 40: ¾ NMR (400 MHz, CD3OD) d 8.44 (s, 2H), 8.03 (d, 1H), 7.31 (d), 7.21 - 7.05 (m, 6H), 5.36 (t, 1H), 5.31 - 5.25 (m), 5.11 - 4.99 (m, 2H), 4.61 (s), 4.57 (dd, 1H), 4.40 (s, 1H), 4.26 (dd,), 3.84 (q, J = 6.9 Hz, 1H), 3.45 - 3.35 (m, 1H), 2.92 - 2.70 (m, 4H), 2.65 - 2.62 (m, 1H), 2.61 (s, 3H), 2.53 (dt, 1H), 2.32 - 2.21 (m, 1H), 2.10 - 1.71 (m, 13H), 1.50 (t, 1H), 1.46 (d, 3H), 1.10 - 0.89 (m, 19H). 13C NMR (101 MHz, CD3OD) d 172.14, 172.06, 171.86, 171.81, 171.70, 138.80, 137.27, 137.23, 130.37, 130.20, 130.06, 129.83, 128.49, 128.29, 127.08, 127.04, 72.02, 71.99, 70.67, 61.22, 58.38, 57.74, 53.94, 41.21, 34.56, 34.48, 32.13, 30.78, 30.10, 29.42, 27.66, 21.08, 21.01, 20.87, 20.73, 20.66, 20.42, 20.18, 16.96.
[00315] Compound 41: ¾ NMR (400 MHz, CD3OD) d 8.47 (s, 1H), 8.20 (d, J = 8.1 Hz, 1H), 7.30 - 7.25 (m, 1H), 7.20 - 7.06 (m, 3H), 5.37 (t, J = 8.2 Hz, 1H), 5.10 - 4.99 (m, 1H), 4.66 (dd, J = 11.2,
1.7 Hz, 1H), 4.51 (s, 1H), 3.79 (q, J = 7.0 Hz, 1H), 2.85 - 2.71 (m, 3H), 2.68 - 2.62 (m, 1H), 2.62 (s, 3H), 2.26 - 2.18 (m, 1H), 2.10 - 1.77 (m, 9H), 1.50 (d, J = 7.0 Hz, 3H), 1.07 (d, J = 6.9 Hz, 3H), 1.03 (d, J = 6.9 Hz, 3H), 0.99 (d, J = 6.9 Hz, 3H), 0.96 (d, J = 6.9 Hz, 3H). 13C NMR (101 MHz, CD3OD) d 172.09, 171.65, 170.17, 138.58, 137.14, 130.11, 129.99, 128.38, 127.08, 70.48, 63.18, 58.55, 54.34, 54.20, 49.71, 41.28, 34.38, 34.32, 33.33, 32.40, 32.06, 30.89, 30.07, 21.22, 20.87, 20.62, 20.26, 20.04, 16.57.
[00316] Compound 42: ¾ NMR (400 MHz, CD3OD) d 8.52 (s, 1H), 8.20 (d), 7.87 (d, 1H), 7.28 (d), 7.22 - 7.05 (m, 4H), 5.46 (t, 1H), 5.37 (t), 5.02 (d, 1H), 4.63 (dd, 1H), 4.51 (d, 1H), 3.60 (dq, 1H), 3.49 _ 3.47 (m), 2.79 (dt3H), 2.70 - 2.60 (m, 2H), 2.57 (d, 2H), 2.52 (d, 1H), 2.10 - 1.74 (m, 9H), 1.42 (td, 3H), 1.20 - 0.88 (m, 14H).
[00317] Compound 43: ¾ NMR (400 MHz, CD3OD) d 8.58 (d), 8.47 (s, 1H), 8.20 (d), 7.39 (d), 7.28 (d), 7.20 - 7.04 (m, 4H), 5.50 - 5.34 (m, 1H), 5.19 (dd), 5.10 - 4.96 (m, 1H), 4.79 - 4.73 (m, 1H),
4.69 - 4.59 (m, 1H), 4.50 (d), 3.85 - 3.67 (m, 1H), 3.50 - 3.46 (m), 3.15 - 3.11 (m), 3.00 (s), 2.90 -
2.70 (m, 5H), 2.65 - 2.56 (m, 3H), 2.36 - 2.16 (m, 3H), 2.09 - 1.68 (m, 10H), 1.51 - 1.35 (m, 3H), 1.23 - 0.85 (m, 21H).
[00318] Example 45, 47, 44, and 46: Synthesis of (4S,9aS)-4-((S)-2-(methylamino)propanamido)- 5-oxo-8,8-diphenethyl-N-((R)-l,2,3,4-tetrahydronaphthalen-l-yl)octahydropyrrolo[2,l- b][l,3]thiazepine-7-carboxamide hydrochloride (45, 47) and (4S,9aS)-4-((S)-2- (methylamino)propanamido)-5-oxo-8,8-phenethyl-N-((R)-l,2,3,4-tetrahydronaphthalen-l- yl)octahydropyrrolo[2,l-b][l,3]thiazepine-7-carboxamide hydrochloride (44, 46).
Figure imgf000135_0001
[00319] Followed the synthesis of compound A using X-5e. The monoalkylated compound 44 and compound 46 were side-products coming from unpurified X-5e. Four isomers were separated: Compound 44 (25 mg, mono), Compound 45 (7.8 mg), Compound 46 (2 mg, mono), Compound 47 (17.2 mg). LC-MS m/z: 653.90 (calcd. 653.35 [M+H]+), Mono :549.05 (calcd. 549.30 [M+H]+). [00320] Compound 44: ¾ NMR (400 MHz, CD3OD) d 8.44 (s, 1H), 7.35 - 6.97 (m, 16H), 5.57 - 5.36 (m, 1H), 5.10 - 4.95 (m, 1H), 4.79 - 4.65 (m, 1H), 4.60 - 4.51 (m, 1H), 3.91 - 3.83 (m, 1H), 3.29 - 3.19 (m, 1H), 2.92 - 2.52 (m, 12H), 2.36 - 1.61 (m, 13H), 1.56 - 1.45 (m, 3H). 13C NMR (101 MHz, CD3OD) d 172.75, 172.60, 172.50, 171.56, 171.30, 171.22, 169.76, 168.95, 143.51, 143.43, 143.24, 138.73, 138.51, 137.27, 137.15, 130.11, 129.95, 129.64, 129.60, 129.54, 129.52, 129.46,
129.37, 129.33, 129.29, 129.24, 129.17, 128.36, 128.03, 127.13, 127.07, 126.97, 72.03, 71.38, 63.45,
61.62, 61.41, 58.42, 58.39, 55.17, 54.44, 47.53, 47.27, 45.02, 40.59, 39.20, 37.28, 34.76, 33.49, 33.16, 32.22, 31.90, 31.85, 31.52, 31.45, 31.08, 30.19, 30.02, 21.21, 21.08, 20.99, 16.55, 16.38.
[00321] Compound 45: ¾ NMR (400 MHz, CD3OD) d 8.45 (s, 1H), 7.36 - 6.81 (m, 15H), 5.60 - 5.41 (m, 1H), 5.11 - 4.93 (m, 1H), 4.82 - 4.64 (m, 1H), 4.57 - 4.50 (m, 1H), 3.92 - 3.78 (m, 1H), 3.29 - 3.19 (m, 1H), 2.94 - 2.53 (m, 12H), 2.36 - 1.61 (m, 12H), 1.55 - 1.44 (m, 3H). 13C NMR (101 MHz, CD3OD) d 172.79, 172.65, 172.53, 171.59, 171.24, 171.11, 170.15, 170.04, 169.06, 143.53, 143.51, 143.45, 143.42, 143.27, 143.16, 138.79, 138.74, 138.53, 137.28, 137.14, 136.99, 130.24,
130.12, 129.96, 129.87, 129.65, 129.60, 129.54, 129.52, 129.45, 129.39, 129.37, 129.34, 129.30, 129.17, 128.42, 128.36, 128.05, 127.15, 127.13, 127.09, 127.07, 127.01, 126.97, 71.75, 71.39, 61.65,
61.43, 58.57, 58.52, 54.44, 47.55, 47.41, 47.29, 45.03, 39.22, 37.30, 33.53, 32.23, 32.17, 31.98, 31.91, 31.46, 31.09, 30.03, 21.09, 20.94, 16.63, 16.49.
[00322] Compound 46: ¾ NMR (400 MHz, CD3OD) d 8.45 (s, 1H), 7.40 - 6.95 (m, 9H), 5.59 - 5.43 (m), 5.36 - 5.26 (m), 5.11 - 4.99 (m, 1H), 4.70 - 4.49 (m, 1H), 4.09 (d), 3.78 (dd, 1H), 2.94 - 2.64 (m, 7H), 2.65 - 2.58 (m, 3H), 2.54 (d, 1H), 2.23 (d, 3H), 2.03 - 1.61 (m, 7H), 1.53 - 1.40 (m, 3H). [00323] Compound 47: ¾ NMR (400 MHz, CD3OD) d 8.46 (s, 1H), 7.37 - 6.98 (m, 16H), 6.85 (d, 1H), 6.76 - 6.66 (m, 1H), 5.53 (dd, 1H), 5.45 (dd), 5.07 (t), 4.98 (t, 1H), 4.79 - 4.70 (m, 1H), 4.56 (s, 1H), 4.53 (s), 3.89 - 3.81 (m, 1H), 2.93 - 2.65 (m, 9H), 2.64 (d, 3H), 2.61 - 2.53 (m, 1H), 2.37 - 2.22 (m, 2H), 2.18 - 1.59 (m, 12H), 1.55 - 1.44 (m, 3H). 13C NMR (101 MHz, CD3OD) d 172.63, 172.52, 171.57, 171.23, 169.93, 169.61, 169.16, 143.51, 143.44, 143.41, 143.25, 138.74, 138.52, 137.27, 137.15, 130.11, 130.03, 129.95, 129.71, 129.65, 129.54, 129.52, 129.37, 129.33, 129.30, 129.17, 128.36, 128.04, 127.13, 127.09, 127.07, 126.97, 72.03, 71.38, 63.46, 61.63, 58.50, 58.45, 55.17,
54.44, 54.11, 47.54, 47.28, 45.75, 45.02, 40.59, 39.21, 37.86, 37.28, 34.77, 33.51, 33.17, 32.23, 31.97, 31.93, 31.90, 31.52, 31.45, 31.08, 30.19, 30.02, 21.09, 20.99, 16.63, 16.45.
[00324] Example 48, 49, 50, 51, 52, and 53: Synthesis of (4S)-8,8-diallyl-N-benzhydryl-4-((S)-2- (methylamino)propanamido)-5-oxooctahydropyrrolo[2,l-b][l,3]oxazepine-7-carboxamide hydrochloride (48,49,50,51,52) and (4S)-8,8-allyl-N-benzhydryl-4-((S)-2- (methylamino)propanamido)-5-oxooctahydropyrrolo[2,l-b][l,3]oxazepine-7-carboxamide hydrochloride (53)
Figure imgf000136_0001
[00325] Followed the synthesis of compound A using X-5b and X-2. The monoalkylated compound 53 was a side-products coming from unpurified X-5b. 6 isomers were separated: Compound 48 (3.1 mg), Compound 49 (20.0 mg), Compound 50 (1.1 mg), Compound 51 (2.3 mg), Compound 52 (8 mg), Compound 53 (22.8 mg, mono). LC-MS m/z: 545.10 (calcd. 545.3 [M+H]+), mono-allyl: 505.45 (calcd. 505.3 [M+H]+).
[00326] Compound 48: ¾ NMR (400 MHz, CD3OD) d 8.49 (s), 7.38 - 7.19 (m, 11H), 6.16 (s, 1H), 5.96 - 5.83 (m, 1H), 5.78 - 5.65 (m, 1H), 5.39 (d, J = 7.0 Hz, 1H), 5.14 - 5.04 (m, 2H), 4.98 - 4.89 (m, 3H), 4.56 (s, 1H), 4.17 (dt, J = 12.6, 3.2 Hz, 1H), 4.00 - 3.89 (m, 1H), 3.75 (q, J = 6.9 Hz, 1H), 2.61 (s, 3H), 2.54 (dd, J = 14.4, 6.9 Hz, 1H), 2.37 - 2.25 (m, 2H), 2.23 - 2.11 (m, 1H), 2.08 - 1.76 (m, 5H), 1.50 (d, J = 7.0 Hz, 3H), 1.39 - 1.25 (m, 3H). 13C NMR (101 MHz, CD3OD) d 172.78, 172.07, 170.97, 142.70, 142.57, 135.11, 134.98, 129.56, 129.43, 129.25, 128.70, 128.57, 128.09, 119.25, 118.47, 90.93, 71.59, 70.08, 58.99, 58.45, 54.60, 46.62, 43.86, 42.20, 39.20, 34.59, 32.48, 17.17. [00327] Compound 49: ‘HNMR (400 MHz, CD3OD) d 8.51 (s), 8.39 (d), 7.40 - 7.19 (m, 11H), 6.19 - 6.11 (m, 1H), 5.96 - 5.65 (m, 2H), 5.54 - 5.36 (m, 1H), 5.17 - 4.91 (m, 6H), 4.48 (d, 1H), 4.21 - 4.05 (m, 1H), 3.97 (dtd, 1H), 3.84 (dq, 1H), 2.63 (s, 3H), 2.60 - 1.63 (m, 9H), 1.53 (dd, 3H). 13C NMR (101 MHz, CD3OD) d 172.70, 172.05, 171.53, 171.45, 170.51, 170.26, 142.81, 142.79, 142.77,
142.69, 142.55, 135.09, 134.98, 134.80, 134.58, 129.78, 129.66, 129.55, 129.41, 129.25, 128.72,
128.69, 128.64, 128.54, 128.38, 128.09, 119.69, 119.26, 118.79, 118.46, 90.89, 90.18, 71.58, 71.39, 70.06, 68.98, 68.95, 58.72, 58.69, 58.62, 58.58, 58.42, 54.63, 53.74, 47.02, 46.59, 44.06, 43.86, 42.88, 42.19, 39.97, 39.18, 34.53, 32.91, 32.17, 32.09, 16.88, 16.74.
[00328] Compound 50: ¾ NMR (400 MHz, CD3OD) d 8.49 (s, 1H), 7.36 - 7.16 (m, 11H), 6.11 (s, 1H), 5.85 - 5.64 (m, 2H), 5.48 (t, J = 6.5 Hz, 1H), 5.13 - 4.86 (m, 5H), 4.38 (s, 1H), 4.09 - 4.01 (m, 1H), 3.97 (td, J = 12.7, 12.2, 2.3 Hz, 1H), 3.56 (q, J = 6.9 Hz, 1H), 2.51 (s, 3H), 2.35 (dd, J = 14.0, 7.0 Hz, 1H), 2.18 (dd, J = 14.0, 7.0 Hz, 1H), 2.10 (d, J = 7.3 Hz, 2H), 1.98 (dd, J = 14.1, 6.0 Hz, 1H), 1.85
- 1.71 (m, 2H), 1.71 - 1.53 (m, 1H), 1.42 (d, J = 6.9 Hz, 3H), 1.29 (d, J = 16.1 Hz, 2H).
[00329] Compound 51: ¾ NMR (400 MHz, CD3OD) d 8.52 (s, 1H), 7.39 - 7.19 (m, 11H), 6.15 (d, J = 11.4 Hz, 1H), 5.90 (ddt, 1H), 5.83 - 5.66 (m, 1H), 5.50 (t), 5.40 (d, 1H), 5.15 - 4.91 (m, 4H), 4.56 (s, 1H), 4.41 (s), 4.16 (dt, 1H), 4.12 - 4.05 (m), 4.03 - 3.90 (m, 1H), 3.59 (q, 1H), 2.54 (d, 3H), 2.42 - 2.26 (m, 2H), 2.25 - 2.10 (m, 2H), 2.04 - 1.64 (m, 5H), 1.47 - 1.41 (m, 3H), 1.31 (d, J = 15.7 Hz,
1H). 13C NMR (101 MHz, CD3OD) d 172.88, 172.19, 172.07, 142.69, 142.56, 135.11, 134.99, 134.82, 134.61, 129.78, 129.66, 129.56, 129.43, 129.25, 128.70, 128.57, 128.40, 128.09, 119.26, 118.46, 90.92, 90.21, 71.60, 70.07, 68.97, 59.45, 59.22, 58.64, 58.45, 54.47, 49.64, 49.43, 49.21, 49.00, 48.79,
48.57, 48.36, 47.03, 46.62, 43.86, 42.90, 42.21, 39.20, 34.62, 33.07, 17.78.
[00330] Compound 52: ¾ NMR (400 MHz, CD3OD) d 8.53 (s, 1H), 7.40 - 7.19 (m, 11H), 6.13 (s, 1H), 5.89 - 5.64 (m, 3H), 5.50 (t, 1H), 5.21 - 4.91 (m, 7H), 4.59 (s), 4.41 (s, 1H), 4.12 - 3.94 (m,
2H), 3.55 - 3.46 (m, 1H), 2.50 (s, 3H), 2.44 - 1.96 (m, 9H), 1.89 - 1.55 (m, 4H), 1.42 (d, 3H), 1.31 (d, 2H), 0.90 (t, 1H).
[00331] Compound 53: 3isomers: ‘HNMR (400 MHz, CD3OD) d 8.41 (d), 7.42 - 7.14 (m, 13H), 6.18
- 6.12 (m, 1H), 5.79 - 5.63 (m, 1H), 5.50 - 5.37 (m, 1H), 5.07 - 4.94 (m, 2H), 4.61 (dd, 1H), 4.20 -
3.87 (m, 3H), 2.68 - 2.64 (m, 3H), 2.61 - 1.63 (m, 8H), 1.60 - 1.53 (m, 3H). 13C NMR (101 MHz, CD3OD) d 172.32, 172.25, 172.13, 171.77, 171.69, 171.16, 169.83, 169.81, 169.56, 143.02, 142.87, 142.84, 142.83, 142.72, 142.61, 137.11, 137.05, 136.61, 129.79, 129.76, 129.73, 129.61, 129.58,
129.57, 129.45, 129.39, 129.36, 129.33, 129.31, 128.82, 128.73, 128.69, 128.63, 128.61, 128.59,
128.58, 128.56, 128.44, 128.36, 128.31, 128.14, 117.69, 116.91, 116.81, 90.66, 90.47, 90.29, 71.37,
71.32, 71.24, 67.20, 64.92, 64.83, 58.54, 58.45, 58.42, 58.39, 58.27, 54.28, 54.09, 53.91, 41.60, 39.66, 39.56, 39.15, 39.01, 38.28, 35.39, 35.13, 34.16, 33.34, 32.90, 31.89, 31.86, 16.55, 16.50, 16.49. Example 54: Synthesis of (6S)-N-benzhydryl-2,2-dimethyl-6-((S)-2-
(methylamino)propanamido)-5-oxo-l,2,3,5,6,7,12,12b-octahydropyrrolo[l',2':l,2]azepino[3,4- b]indole-3-carboxamide hydrochloride
Figure imgf000138_0001
[00332] Followed the synthesis of compound A using Boc-Trp-OH and X-2. 18.4 mg. LC-MS m/z: 578.55 (calcd. 578.3 [M+H]+).
[00333] ‘HNMR (400 MHz, DMSO-d6) d 10.93 (s, 1H), 8.99 (d, J = 8.5 Hz, 1H), 8.59 (d, J = 7.3 Hz, 1H), 8.28 (s, 1H), 7.38 - 7.21 (m, 15H), 7.11 - 7.04 (m, 1H), 7.02 - 6.94 (m, 1H), 6.14 (d, J = 8.5 Hz, 1H), 5.67 (d, J = 8.6 Hz, 1H), 5.08 (ddd, J = 12.6, 7.3, 3.7 Hz, 1H), 4.32 (s, 1H), 3.33 (q, J = 6.8 Hz, 1H), 3.18 - 3.10 (m, 1H), 2.77 (ddd, J = 15.2, 12.5, 2.4 Hz, 1H), 2.37 (s, 3H), 1.26 (d, J = 6.9 Hz, 3H), 0.90 (s, 3H), 0.79 (s, 3H). 13C NMR (101 MHz, DMSO-D6) d 172.05, 170.47, 169.56, 164.54, 142.33, 142.30, 134.74, 134.68, 128.44, 128.27, 128.15, 127.91, 127.34, 127.20, 126.94, 121.33, 118.94, 117.58, 111.29, 106.47, 70.22, 58.41, 56.00, 54.19, 50.15, 40.65, 40.02, 33.41, 28.42, 28.27, 23.77, 18.04.
Example 55: Synthesis of (4S,7S)-8,8-dimethyl-4-((S)-2-(methylamino)propanamido)-5-oxo-N- (2-(pyrimidin-2-yl)phenyl)octahydropyrrolo[2,l-b][l,3]oxazepine-7-carboxamide hydrochloride
Figure imgf000138_0002
[00334] To a mixture of X-16 (70 mg, 1.0 eq.), X-12 (l.Oeq), N-methylmorpholine (4.0eq.) and HOBT.H2O (1.1 eq.) in THF (5mL) at 0°C, was added EDC.HC1 (1.05 eq.). The reaction mixture was stirred at 0°C for 30 min then at 30°C for 24h. it was quenched with a saturated solution of sodium bicarbonate (30 mL) and extracted with ethyl acetate (3*20 mL). The combined organic layers were washed with brine (3*20 mL), dried over sodium sulfate anhydrous, filtered and concentrated. It afforded 20 mg of crude intermediate. The crude intermediate was solubilized in 4M HC1 in 1,4- dioxane (l.OmL). The mixture was stirred at 40°C for 1 hours. The mixture was concentrated and purified by reverse phase HPLC (10-70% acetonitrile in water). 4.4 mg. LC-MS m/z: 481.00 (calcd. 481.2 [M+H]+). [00335] ‘HNMR (400 MHz, CD3OD) d 8.95 (dd, J = 4.9, 2.2 Hz, 2H), 8.53 (ddt, J = 18.3, 8.5, 3.2 Hz, 2H), 7.52 - 7.45 (m, 1H), 7.45 - 7.40 (m, 1H), 7.29 - 7.19 (m, 2H), 5.48 (t, J = 5.8 Hz, 1H), 4.25 (d, J = 21.7 Hz, 2H), 4.10 - 3.94 (m, 2H), 3.74 - 3.55 (m, 3H), 3.36 - 3.34 (m, 1H), 2.97 (s, 1H), 2.57 - 2.50 (m, 4H), 1.55 - 1.50 (m, 1H), 1.49 - 1.45 (m, 1H), 1.43 (d, J = 6.9 Hz, 3H), 1.29 (s, 2H), 1.26 (s, 3H), 1.10 (s, 3H).
Example 56 and 57: Synthesis of (S)-N-((4S,7S,9aS)-8,8-dimethyl-5-oxo-7-((((R)-l,2,3,4- tetrahydronaphthalen-l-yl)amino)methyl)octahydropyrrolo[2,l-b] [l,3]oxazepin-4-yl)-2- (methylamino)propanamide dihydrochloride (56,57)
Figure imgf000139_0001
[00336] To a mixture of X-17 (l.Oeq, 123 mg) and (R)-l,2,3,4-tetrahydronaphthalen-l-amine (1.1 eq) in THF (0.2M) was added sodium cyanotrihydroborate (1.5 eq) at r.t. and the mixture was stirred for 3 hours. Water (3 mL) was added and the solvents were removed under vacuum. The crude intermediate was solubilized in dioxane (3.0mL) and 4M HCI in 1,4-dioxane (3.0mL) was added. The mixture was stirred at 40°C for 4 hours. The mixture was concentrated and purified by reverse phase HPLC (10- 70% acetonitrile in water).
[00337] Compound 57: 39.6 mg (40% yield). LC-MS m/z: 443.05 (calcd. 443.2 [M+H]+). ‘HNMR (400 MHz, CD3OD) d 7.61 - 7.56 (m), 7.51 - 7.42 (m, 1H), 7.37 - 7.19 (m, 4H), 5.41 (dd), 5.00 (dd), 4.59 (q, 1H), 4.55 - 4.50 (m), 4.13 (ddd), 4.06 (q), 3.97 (td), 3.79 (d), 3.70 - 3.61 (m, 1H), 3.61 - 3.53 (m), 2.97 (dt, 1H), 2.85 (ddd, 2H), 2.73 - 2.67 (m, 1H), 2.26 - 1.81 (m, 7H), 1.66 (dd, 1H), 1.46 (s, 1H), 1.45 (s, 2H), 1.43 (s, 1H), 1.17 (d, 2H). 13C NMR (101 MHz, CD3OD) d 176.44, 169.87, 139.76, 139.71, 139.13, 132.89, 131.82, 131.57, 131.21, 131.10, 130.91, 130.70, 130.49, 130.45, 130.38, 129.93, 129.56, 127.69, 127.66, 127.57, 90.92, 73.53, 71.41, 67.21, 58.29, 57.63, 54.33, 54.25, 54.21, 50.20, 49.85, 49.39, 48.29, 46.45, 43.81, 40.53, 33.07, 31.91, 29.68, 29.49, 28.97, 27.09, 26.14, 26.11, 23.01, 19.89, 19.85, 19.53, 19.38, 18.95, 18.74, 18.70, 16.77.
Example 58 and 59: Synthesis of (4S)-N-benzhydryl-8,8-diethyl-4-((S)-2-
(methylamino)propanamido)-5-oxooctahydropyrrolo[2,l-b][l,3]oxazepine-7-carboxamide hydrochloride
Figure imgf000140_0001
[00338] Followed the synthesis of compound A using Boc-HSer-OH, X-5c and X-2. It afforded two isomers: Compound 58 (28.9 mg), Compound 59 (78.3 mg). LC-MS m/z: 521.55 (calcd. 521.3 [M+H]+).
[00339] Compound 58: ¾ NMR (400 MHz, CD3OD) d 9.13 (d), 8.47 - 8.34 (m, 1H), 7.37 - 7.19 (m, 14H), 6.17 (d, 1H), 5.51 (t), 5.37 (d, 1H), 4.47 (s, 1H), 4.34 (s), 4.20 - 4.06 (m, 1H), 3.99 - 3.86 (m, 2H), 2.66 (s, 4H), 2.40 (dd), 2.22 (dd, 1H), 2.03 - 1.74 (m, 5H), 1.56 - 1.51 (m, 3H), 1.46 - 1.34 (m, 2H), 1.18 - 1.06 (m, 1H), 0.87 (t, 3H), 0.80 - 0.74 (m, 1H), 0.71 (t, 3H). 13C NMR (101 MHz, CD3OD) d 172.64, 172.39, 172.16, 171.85, 169.85, 169.52, 142.82, 142.58, 129.75, 129.60, 129.55, 129.44, 129.21, 128.67, 128.65, 128.56, 128.47, 128.36, 128.08, 128.04, 90.99, 90.16, 71.52, 71.33, 70.53, 69.32, 58.65, 58.56, 58.44, 58.38, 58.32, 54.70, 53.76, 47.63, 47.36, 44.25, 43.97, 34.51, 32.88, 31.88, 31.86, 29.39, 29.13, 26.55, 26.08, 16.56, 16.51, 9.10, 8.88, 8.55.
[00340] Compound 59: ¾ NMR (400 MHz, CD3OD) d 8.40 - 8.31 (m, 1H), 7.37 - 7.19 (m, 12H), 6.16 - 6.10 (m, 1H), 5.50 (t, J = 6.6 Hz, 1H), 4.92 (d, J = 2.4 Hz, 1H), 4.33 (s, 1H), 4.12 - 4.04 (m, 1H), 4.03 - 3.94 (m, 1H), 3.90 (q, J = 7.0 Hz, 1H), 2.66 (s, 3H), 2.40 (dd, J = 13.8, 6.9 Hz, 1H), 1.93 (dd, J = 13.9, 6.2 Hz, 1H), 1.82 - 1.76 (m, 1H), 1.75 - 1.63 (m, 1H), 1.59 - 1.54 (m, 3H), 1.50 - 1.38 (m, 3H), 1.13 (dq, J = 14.6, 7.4 Hz, 1H), 0.86 (t, J = 7.4 Hz, 3H), 0.77 (t, J = 7.5 Hz, 3H). 13C NMR (101 MHz, CD3OD) d 172.16, 171.86, 171.78, 169.80, 142.92, 142.82, 129.76, 129.61, 129.21,
128.69, 128.67, 128.48, 128.36, 90.18, 71.33, 69.34, 69.31, 58.68, 58.58, 58.42, 53.79, 47.65, 44.26, 32.90, 31.85, 29.40, 26.57, 16.48, 8.87, 8.54.
Example 60 and 61: Synthesis of (4S)-N-benzhydryl-8,8-diisopropyl-4-((S)-2-
(methylamino)propanamido)-5-oxooctahydropyrrolo[2,l-b][l,3]oxazepine-7-carboxamide hydrochloride
Figure imgf000140_0002
[00341] Followed the synthesis of compound A using Boc-HSer-OH, X-5d and X-2. It afforded 2 Isomers: Compound 60 (4.7 mg), Compound 61 (7.7 mg). LC-MS m/z: 549.20 (calcd. 549.34 [M+H]+). [00342] Compound 60: ¾ NMR (400 MHz, CD3OD) d 8.49 (s, 1H), 7.38 - 7.16 (m, 13H), 6.22 - 6.11 (m, 1H), 5.35 (d, 1H), 4.81 (dd, 1H), 4.15 (dt, 1H), 3.97 - 3.88 (m, 1H), 3.79 (q, 1H), 2.62 (s, 2H), 2.47 - 2.36 (m, 1H), 2.28 - 2.13 (m, 2H), 1.99 - 1.81 (m, 3H), 1.74 - 1.63 (m, 1H), 1.54 - 1.44 (m, 3H), 1.09 (ddd, 6H), 1.03 - 0.83 (m, 10H), 0.82 - 0.70 (m, 3H). 13C NMR (101 MHz, CD3OD) d 173.04, 172.34, 170.56, 169.57, 142.77, 142.60, 129.69, 129.67, 129.65, 129.59, 129.42, 129.27, 129.14, 128.77, 128.66, 128.63, 128.61, 128.58, 128.47, 128.41, 128.28, 127.93, 91.27, 71.46, 70.80, 58.85, 58.53, 54.86, 53.06, 41.79, 35.54, 34.50, 33.52, 32.33, 21.71, 21.21, 20.98, 20.25, 17.09. [00343] Compound 61: ¾ NMR (400 MHz, CD3OD) d 8.46 (s, 1H), 8.33 (d), 7.38 - 7.19 (m, 11H), 6.13 - 6.07 (m, 1H), 5.47 (dd, 1H), 4.50 (s, 1H), 4.06 - 3.96 (m, 2H), 3.82 (q, 1H), 2.63 (s, 3H), 2.62 - 2.58 (m, 1H), 2.04 - 1.90 (m, 2H), 1.80 - 1.70 (m, 2H), 1.67 - 1.56 (m, 1H), 1.56 - 1.51 (m, 3H), 0.98 - 0.86 (m, 13H). 13C NMR (101 MHz, CD3OD) d 172.43, 172.36, 171.41, 170.32, 169.22, 142.91, 142.87, 142.70, 142.67, 129.75, 129.62, 128.72, 128.66, 128.52, 128.40, 90.92, 71.22, 69.70, 58.84, 58.74, 58.53, 54.17, 53.71, 41.15, 34.94, 34.03, 32.72, 32.01, 20.51, 20.39, 20.25, 16.67. Example 62 and 63: Synthesis of (4S)-N-benzhydryl-4-((S)-2-(methylamino)propanamido)-5- oxo-8,8-diphenethyloctahydropyrrolo[2,l-b][l,3]oxazepine-7-carboxamide hydrochloride
Figure imgf000141_0001
[00344] Followed the synthesis of compound A using Boc-HSer-OH, X-5e and X-2. It afforded two isomers: Compound 62 (17.0 mg), Compound 63 (25.3 mg). LC-MS m/z: 673.90 (calcd. 673.4 [M+H]+).
[00345] Compound 62: ¾ NMR (400 MHz, DMSO-d6) d 9.09 (d, J = 8.5 Hz, 1H), 8.35 (d, J = 7.2 Hz, 1H), 8.24 (s, 1H), 7.33 - 7.14 (m, 18H), 7.14 - 7.09 (m, 4H), 6.99 - 6.93 (m, 2H), 6.09 (d, J = 8.4 Hz, 1H), 5.49 (d, J = 7.0 Hz, 1H), 4.78 (q, J = 7.2 Hz, 1H), 4.61 (s, 1H), 4.03 (dt, J = 12.4, 3.2 Hz, 1H), 3.94 - 3.85 (m, 1H), 3.20 (q, J = 6.8 Hz, 1H), 2.78 (td, J = 12.9, 6.6 Hz, 1H), 2.68 - 2.57 (m, 2H),
2.42 (td, J = 13.0, 4.6 Hz, 1H), 2.33 (s, 3H), 2.30 - 2.22 (m, 1H), 2.05 - 1.82 (m, 4H), 1.81 - 1.68 (m, 3H), 1.37 - 1.24 (m, 2H), 1.22 (d, J = 6.9 Hz, 3H). 13C NMR (101 MHz, DMSO-D6) d 172.27, 171.30, 168.98, 164.02, 142.48, 142.04, 141.79, 128.47, 128.41, 128.39, 128.35, 128.34, 128.25, 128.23, 128.19, 128.13, 128.08, 128.01, 127.70, 127.48, 127.14, 127.11, 126.93, 126.84, 125.73, 125.62, 88.74, 69.71, 68.71, 58.77, 55.79, 52.04, 44.98, 43.56, 38.64, 35.04, 33.56, 33.48, 30.21, 30.01, 18.36. [00346] Compound 63: ¾ NMR (400 MHz, DMSO-d6) d 9.09 (d), 8.65 (d,), 8.35 - 8.25 (m, 2H), 7.35 - 7.14 (m, 24H), 7.14 - 7.10 (m, 1H), 7.01 - 6.92 (m, 3H), 6.06 (d, 1H), 5.61 (t, J = 6.6 Hz, 1H), 5.49 (d), 4.86 (ddd, 1H), 4.47 (s, 1H), 4.04 (dt, 1H), 3.95 - 3.83 (m, 1H), 3.20 - 3.12 (m, 1H), 2.79 (td, 4H), 2.41 (ddd, 2H), 2.33 (s, 1H), 2.28 (s, 3H), 2.05 - 1.83 (m, 2H), 1.80 - 1.59 (m, 5H), 1.58 - 1.45 (m, 1H), 1.44 - 1.25 (m, 1H), 1.21 (d, 1H), 1.18 (d, 3H). 13C NMR (101 MHz, DMSO-D6) d 172.48, 172.41, 171.33, 170.76, 168.99, 168.75, 164.34, 142.48, 142.34, 142.09, 142.05, 142.02, 141.79, 128.47, 128.41, 128.39, 128.36, 128.34, 128.25, 128.19, 128.13, 128.09, 128.09, 128.01, 128.01, 127.70, 127.49, 127.15, 127.12, 125.79, 125.62, 88.13, 69.50, 67.56, 58.58, 56.41, 51.50, 45.18, 44.99, 43.05, 38.08, 35.74, 33.70, 33.53, 32.18, 30.13, 29.77, 18.48, 18.27.
[00347] Example 64, 65, and 66: Synthesis of (lS,9S)-2,2-dimethyl-9-((S)-2- (methylamino)propanamido)-10-oxo-N-((R)-l,2,3,4-tetrahydronaphthalen-l- yl)dodecahydrobenzo[f]pyrrolo[2,l-b][l,3]oxazepine-l-carboxamide hydrochloride (64) and (lS,9S)-2,2-methyl-9-((S)-2-(methylamino)propanamido)-10-oxo-N-((R)-l,2,3,4- tetrahydronaphthalen-l-yl)dodecahydrobenzo[f]pyrrolo[2,l-b][l,3]oxazepine-l-carboxamide hydrochloride (65, 66).
Figure imgf000142_0001
[00348] Followed the synthesis of compound A using X-8. It afforded three isomers: Compound 64 (6.0 mg mono), Compound 65 (21.5 mg), Compound 66 (12.8 mg). LC-MS m/z: 511.15 (calcd. 511.4[M+H]+), mono: 497.10 (calcd. 497.3[M+H]+).
[00349] Compound 64 (mixture of isomers): *HNMR (400 MHz, DMSO-de) d 9.33 - 8.94 (m, 2H), 8.87 (d), 8.80 (d), 8.70 (d), 8.59 (d), 8.26 - 8.16 (m), 8.11 (s), 8.04 - 7.93 (m), 7.47 (d), 7.25 - 6.96 (m, 4H), 5.85 - 5.74 (m), 5.62 - 5.42 (m, 1H), 5.02 - 4.76 (m, 2H), 4.55 - 4.49 (m), 4.28 - 3.62 (m, 3H), 3.55 - 3.42 (m, 1H), 3.12 (d), 2.76 - 2.58 (m, 2H), 2.45 - 2.38 (m, 3H), 2.26 - 1.98 (m, 1H), 1.90 - 1.49 (m, 10H), 1.49 - 1.28 (m, 5H), 1.28 - 1.03 (m, 4H), 1.03 - 0.70 (m, 6H). 13C NMR (101 MHz, DMSO-D6) d 170.87, 170.47, 170.38, 170.16, 170.04, 169.99, 169.27, 168.93, 168.86, 168.84, 168.82, 168.78, 168.70, 168.69, 168.33, 137.88, 137.76, 137.55, 137.51, 137.43, 137.39, 137.38, 129.33, 129.28, 129.25, 129.20, 129.09, 128.98, 128.94, 128.62, 127.72, 127.44, 127.41, 127.16, 127.12, 126.37, 126.36, 126.26, 126.20, 88.29, 87.76, 87.45, 87.44, 84.26, 83.84, 78.44, 78.33, 70.31, 70.09, 70.06, 69.66, 69.63, 61.05, 60.41, 56.77, 56.45, 56.42, 56.19, 55.43, 55.33, 47.28, 47.18, 47.02,
46.96, 46.93, 46.88, 46.75, 46.19, 46.18, 46.15, 46.14, 45.11, 44.13, 43.88, 42.93, 39.24, 39.09, 38.97,
38.40, 33.43, 31.46, 31.36, 31.22, 31.17, 30.59, 30.52, 30.38, 30.21, 30.20, 30.18, 29.47, 29.29, 29.15,
28.92, 27.46, 27.33, 25.84, 25.40, 24.91, 24.29, 24.22, 24.09, 21.23, 20.64, 20.34, 20.33, 20.20, 20.08,
16.71, 16.59, 16.53, 16.50, 16.44. Example 67 and 68: Synthesis of (S)-N-((4S,7S,9aS)-8, 8-dimethyl- 5-oxo-7-((((R)-thiochroman-4- yl)amino)methyl)octahydropyrrolo[2,l-b][l,3]oxazepin-4-yl)-2-(methylamino)propanamide dihydrochloride
Figure imgf000143_0001
[00350] Followed the synthesis of compound 56 using X-10. It afforded two isomers: Compound 67 (2.5 mg, 15% yield), Compound 68 (2.3mg, 14% yield). LC-MS m/z: 461.00 (calcd. 461.2 [M+H]+). [00351] Compound 67: ¾ NMR (400 MHz, CD3OD) d 7.49 (dd, J = 7.7, 1.4 Hz, 1H), 7.35 - 7.29 (m, 1H), 7.24 (dd, J = 8.0, 1.4 Hz, 1H), 7.17 (td, J = 7.4, 1.4 Hz, 1H), 5.38 (dd, J = 6.9, 3.6 Hz, 1H), 4.99 - 4.90 (m, 1H), 4.64 (t, J = 3.9 Hz, 1H), 4.12 - 4.04 (m, 1H), 4.00 (q, J = 6.9 Hz, 1H), 3.93 (td, J = 12.3, 2.2 Hz, 1H), 3.80 (d, J = 9.5 Hz, 1H), 3.59 (d, J = 13.2 Hz, 1H), 3.25 (dd, J = 12.8, 3.6 Hz, 1H), 3.17 - 3.06 (m, 2H), 2.76 (dq, J = 14.8, 3.9 Hz, 1H), 2.70 (s, 3H), 2.35 - 2.23 (m, 1H), 2.15 (dd, J = 13.7, 6.8 Hz, 1H), 1.98 - 1.76 (m, 3H), 1.64 (d, J = 7.0 Hz, 3H), 1.17 (s, 3H), 1.16 (s, 3H). 13C NMR (101 MHz, CD3OD) d 176.38, 169.90, 135.96, 133.19, 131.37, 128.73, 127.64, 125.81, 90.85, 71.33, 66.78, 58.30, 56.70, 54.12, 46.32, 40.46, 32.90, 31.86, 27.20, 25.57, 22.97, 21.82, 16.76.
[00352] Compound 68: ¾ NMR (400 MHz, CD3OD) d 8.40 (s, 1H), 7.33 (dd, J = 7.7, 1.5 Hz, 1H), 7.26 - 7.18 (m, 1H), 7.15 (dd, J = 8.0, 1.5 Hz, 1H), 7.09 (td, J = 7.4, 1.5 Hz, 1H), 5.35 (dd, J = 7.0, 5.0 Hz, 1H), 4.92 (d, J = 2.4 Hz, 1H), 4.18 (d, J = 3.9 Hz, 1H), 4.08 - 4.00 (m, 1H), 3.93 (dd, J = 12.0, 2.5 Hz, 1H), 3.88 (q, J = 7.0 Hz, 1H), 3.80 (dd, J = 8.3, 2.4 Hz, 1H), 3.25 (dd, J = 12.6, 3.8 Hz, 1H), 3.02 (dt, J = 12.8, 4.5 Hz, 1H), 2.90 (dd, J = 12.5, 8.3 Hz, 1H), 2.66 (s, 3H), 2.52 (dq, J = 13.4, 4.3 Hz,
1H), 2.18 - 2.07 (m, 2H), 1.94 - 1.75 (m, 3H), 1.57 (d, J = 7.0 Hz, 3H), 1.11 (s, 3H), 1.08 (s, 3H). 13C NMR (101 MHz, CD3OD) d 174.92, 170.37, 135.12, 132.43, 130.07, 128.22, 125.21, 90.48, 71.24, 67.17, 58.55, 56.43, 53.98, 46.30, 40.09, 33.37, 32.05, 28.26, 26.86, 22.98, 22.19, 16.83.
Example 69: Synthesis of (4S,7S,9aS)-8,8-dimethyl-4-((S)-2-(methylamino)propanamido)-5-oxo- N-((R)-thiochroman-4-yl)octahydropyrrolo[2,l-b][l,3]oxazepine-7-carboxamide hydrochloride
Figure imgf000143_0002
[00353] Followed the synthesis of compound 55 using X-10. 15 mg (70% yield). LC-MS m/z: 475.40 (calcd. 475.3 [M+H]+). ¾NME (400 MHz, CD3OD) d 8.51 (s, 1H), 7.31 - 7.24 (m, 1H), 7.17 - 6.94 (m, 3H), 5.45 - 5.39 (m, 1H), 5.10 - 5.04 (m, 1H), 4.08 (dd, J = 3.7, 2.6 Hz, 2H), 3.92 (tt, J = 12.1,
2.4 Hz, 1H), 3.80 - 3.69 (m, 1H), 3.08 - 2.95 (m, 2H), 2.62 (s, 1H), 2.58 (s, 2H), 2.34 - 2.23 (m, 1H), 2.18 (dd, J = 13.4, 6.6 Hz, 1H), 2.13 - 1.98 (m, 2H), 1.97 - 1.87 (m, 1H), 1.87 - 1.75 (m, 1H), 1.49 (d, J = 7.0 Hz, 2H), 1.45 (d, J = 7.0 Hz, 1H), 1.09 (d, J = 5.6 Hz, 6H). 13C NMR (101 MHz, CD3OD) d 171.14, 171.01, 170.10, 170.09, 169.70, 169.56, 133.47, 133.43, 132.74, 132.69, 129.96, 129.88, 127.71, 127.69, 126.27, 126.25, 124.08, 124.05, 89.08, 70.35, 70.29, 69.99, 69.97, 57.46, 57.43,
52.78, 52.67, 46.95, 46.90, 45.66, 45.64, 38.85, 38.80, 31.93, 31.56, 31.07, 30.98, 28.42, 28.34, 28.01, 28.00, 22.91, 22.55, 22.52, 15.65, 15.58.
Example 70 and 71: Synthesis of (4S,7S,9aS)-N-isopentyl-8,8-dimethyl-4-((S)-2- (methylamino)propanamido)-5-oxooctahydropyrrolo[2,l-b][l,3]oxazepine-7-carboxamide hydrochloride (70, 71)
Figure imgf000144_0001
[00354] Followed the synthesis of compound 55 using 3-methylbutan-l-amine. It afforded 12 mg (60% yield). LC-MS m/z: 397.05 (calcd. 397.3 [M+H]+).
[00355] Compound 70: ¾ NMR (400 MHz, CD3OD) d 5.49 - 5.43 (m, 1H), 4.24 - 4.16 (m, 1H), 4.04 - 3.93 (m, 2H), 3.71 (s, 1H), 3.29 - 3.15 (m, 2H), 2.60 (d, J = 12.4 Hz, 3H), 2.21 (dd, J = 13.1, 6.9 Hz, 1H), 2.10 - 1.96 (m, 2H), 1.89 - 1.79 (m, 1H), 1.70 - 1.58 (m, 1H), 1.51 - 1.36 (m, 5H), 1.12 (s, 3H), 1.06 (s, 3H), 0.97 - 0.87 (m, 7H). 13C NMR (101 MHz, CD3OD) d 172.36, 172.27, 172.19,
90.47, 71.84, 71.77, 71.38, 58.71, 54.15, 54.02, 49.64, 49.43, 49.21, 49.00, 48.79, 48.57, 48.36, 46.87, 46.84, 40.07, 40.04, 39.34, 38.65, 38.63, 33.21, 32.89, 32.35, 32.19, 29.33, 26.84, 24.08, 22.78, 22.75, 22.74, 16.83.).
Example 72: Synthesis of (2S)-N-((4S,9aS)-7-(benzo[d]oxazol-2-yl)-8,8-dimethyl-5- oxooctahydropyrrolo[2,l-b][l,3]oxazepin-4-yl)-2-(methylamino)propanamide hydrochloride
Figure imgf000144_0002
[00356] A mixture of ((benzyloxy)carbonyl)-L-homoserine (7.80 mmol) (2.00 g , leq), l-(2,2- dimethoxyethyl)-2-isocyanobenzene (7.80 mmol, 1.50 g), ammonia (1.115 ml, 7.80 mmol) and 4,4- dimethoxy-2,2-dimethylbutanal (7.80 mmol, 1.25 g) in 2,2,2-trifluoroethanol (8 mL) was heated at 80°C under microwave irradiation. The mixture was then concentrated, diluted with 20 mL of dioxane and treated with HC1 (4M in dioxane, 20mL). It was concentrated again and diluted in methanol (50 mL) then sodium hydroxide (30 mL, 2M aqueous) was added. The mixture was stirred at 50°C for 5 hours. The reaction was quenched with 2M HC1 (60 mL) and extracted with ethyl acetate ( 3* 100 mL). the combined organic layers were washed with 0.1M HC1 (1* lOOmL), brine (2* 100 mL), dried over sodium sulfate anhydrous, fdtered and concentrated to afford 3 g of crude (4S,9aS)-4- (((benzyloxy)carbonyl)amino)-8,8-dimethyl-5-oxooctahydropyrrolo[2,l-b][l,3]oxazepine-7- carboxylic acid. To a solution of this acid (200 mg, 0.531 mmol, 1.0 eq) and DMF ( 1 drop, catalytic) in DCM (3 mL) at 0°C was added oxalyl chloride (56uL, 1.2 eq). The mixture was stirred at 40°C for 1 hour then 2-bromoaniline (183 mg, 1.063 mmol, 2.0 eq) was added followed by triethylamine (74ul, 2.0 eq). The mixture was stirred at 23 °C for 3 hours brine (50 mL) was added to the reaction mixture and the product was extracted with DCM (3*20 mL). The organic layers were dried over sodium sulfate anhydrous, filtered, concentrated and purified by column chromatography to afford: 209 mg (75% yield) of benzyl ((4S,9aS)-7-((2-bromophenyl)carbamoyl)-8,8-dimethyl-5- oxooctahydropyrrolo[2,l-b][l,3]oxazepin-4-yl)carbamate.
[00357] A mixture of the latter (200 mg, 0.377 mmol, 1.0 eq), cesium carbonate (67.9 mg, 1.131 mmol, 3.0 eq), 1,10-phenanthroline (13.59 mg, 0.075 mmol, 0.2 eq) and copper(I) iodide (7.18 mg, 0.038 mmol, 0.1 eq) in DME (2 mL) was heated in a microwave reactor at 120°C for 30 min. The mixture was filtered through celite and the pad was washed with ethanol. The filtrate was concentrated to afford the crude intermediate: 260 mg. LC-MS mz: 450.00 (calcd. 450.2 [M+H]+). It was diluted in ethanol (5 mL) and 10%Pd/C (30 mg) was added. The mixture was purged with nitrogen then put under hydrogen atmosphere and stirred for 2 hours at 23 °C. The reaction mixture was filtered through celite and concentrated. LC-MS m/z: 316.0 (calcd. 316.2 [M+H]+). To a solution of N-(tert-butoxycarbonyl)-N-methyl-L-alanine (153 mg, 0.755 mmol, 2.0 eq) in DCM (0.4M) was added oxalyl chloride (2.0 eq) followed by a drop of DMF. The mixture was stirred at 35°C for 30 min. The mixture was concentrated to dryness and the residue was solubilized in DCM (0.4M). To this solution, the crude tert-butyl ((2S)-l-(((4S,9aS)-7-(benzo[d]oxazol-2-yl)-8,8-dimethyl-5- oxooctahydropyrrolo[2, 1 -b] [ 1 ,3]oxazepin-4-yl)amino)- 1 -oxopropan-2-yl)(methyl)carbamate ( 1.0 eq, 189 mg) in DCM (0.5M) was added dropwise followed by diisopropyethylamine (4.0 eq, 260uL)).
The mixture was stirred at 35°C for 2 hours then concentrated to dryness. LC-MS m/z: 400.90 (calcd. 401.3 [M+H]+). To the crude in dioxane (2mL) was added 4.0M HC1 in dioxane (2mL). The mixture was stirred at 40°C for 2 hours. The mixture was concentrated and purified by reverse phase silica gel. 50 mg (35 % yield) LC-MS m/z: 401.0 (calcd. 401.3 [M+H]+).
[00358] Tf NMR (400 MHz, CD3OD) d 8.42 (s, 1H), 7.63 - 7.56 (m, 2H), 7.38 - 7.34 (m, 2H), 5.61 (d, J = 6.8 Hz, 1H), 5.01 - 4.94 (m, 2H), 4.25 - 4.17 (m, 1H), 4.01 (ddd, J = 14.0, 10.3, 2.0 Hz, 1H), 3.81 (q, J = 7.0 Hz, 1H), 2.59 (s, 3H), 2.44 (dd, J = 13.8, 6.9 Hz, 1H), 2.07 - 1.80 (m, 4H), 1.45 (s, 3H), 1.41 (d, J = 7.0 Hz, 3H), 1.25 (d, J = 3.7 Hz, 1H), 0.85 (d, J = 1.9 Hz, 1H), 0.78 (s, 3H). 13C NMR (101 MHz, CD3OD) d 171.59, 168.32, 165.44, 150.46, 140.11, 125.31, 124.71, 119.17, 110.64, 89.96, 70.34, 66.12, 57.02, 53.34, 45.17, 40.76, 32.87, 30.46, 28.33, 22.88, 15.01.
Example 73: Synthesis of (S)-N-((4S,7S,9aS)-7-((((R)-chroman-4-yl)amino)methyl)-8,8-dimethyl- 5-oxooctahydropyrrolo[2,l-b][l,3]oxazepin-4-yl)-2-(methylamino)propanamide dihydrochloride
Figure imgf000146_0001
[00359] Followed the synthesis of compound 56 using X-ll. 3.2mg (20 % yield). LC-MS m/z: 445.00 (calcd. 445.3 [M+H]+). ¾ NMR (400 MHz, CD3OD) d 8.25 (s, 1H), 7.50 - 7.44 (m, 1H), 7.37 - 7.22 (m, 1H), 7.00 - 6.93 (m, 1H), 6.90 - 6.84 (m, 1H), 5.41 - 5.27 (m, 1H), 4.97 (dd, J = 11.8, 1.9 Hz, 1H), 4.56 - 4.49 (m, 1H), 4.36 - 4.20 (m, 2H), 4.11 (dddd, J = 12.8, 6.5, 3.8, 2.8 Hz, 1H), 4.00 - 3.86 (m, 2H), 3.79 - 3.71 (m, 1H), 3.66 - 3.53 (m, 1H), 3.19 (dd, J = 13.3, 9.2 Hz, 1H), 2.69 - 2.61 (m, 4H), 2.41 - 2.31 (m, 1H), 2.19 - 1.74 (m, 5H), 1.61 (d, J = 7.0 Hz, 2H), 1.57 - 1.53 (m, 1H), 1.19 - 1.09 (m, 5H), 1.07 - 0.95 (m, 2H). 13C NMR (101 MHz, CD3OD) d 177.78, 171.46, 158.23, 133.65, 132.36, 123.63, 123.50, 120.50, 119.52, 92.43, 91.54, 72.88, 72.70, 70.89, 68.86, 64.29, 59.85, 55.73, 55.58, 54.78, 47.90, 41.99, 40.63, 35.01, 34.61, 33.34, 28.63, 27.16, 24.41, 18.16, 17.87.
Example 74: Synthesis of (4S,7S,9aS)-N-((R)-chroman-4-yl)-8,8-dimethyl-4-((S)-2-
(methylamino)propanamido)-5-oxooctahydropyrrolo[2,l-b][l,3]oxazepine-7-carboxamide hydrochloride
Figure imgf000146_0002
[00360] Followed the synthesis of 55 using X-ll. It afforded 15 mg (65%). LC-MS m/z: 459.10 (calcd. 459.3 [M+H]+). ¾ NMR (400 MHz, CD3OD) d 8.30 (dd, J = 16.7, 7.9 Hz, 1H), 7.27 - 7.21 (m, 1H), 7.13 - 7.08 (m, 1H), 6.87 - 6.79 (m, 1H), 6.77 - 6.71 (m, 1H), 5.43 - 5.36 (m, 1H), 5.12 - 5.03 (m, 1H), 4.85 - 4.81 (m, 1H), 4.26 - 4.06 (m, 4H), 4.04 (s, 1H), 3.97 - 3.81 (m, 2H), 2.66 (s, 1H), 2.63 (s, 2H), 2.21 - 1.91 (m, 6H), 1.86 - 1.73 (m, 1H), 1.53 (d, J = 6.9 Hz, 2H), 1.48 (d, J = 6.9 Hz, 1H), 1.09 (d, J = 4.4 Hz, 6H). 13C NMR (101 MHz, CD3OD) d 173.44, 172.92, 171.17, 157.66, 131.75, 131.25, 124.61, 122.81, 119.09, 91.69, 72.75, 72.51, 65.74, 59.69, 55.37, 48.23, 46.14, 41.28, 34.41, 33.06, 31.49, 30.48, 25.45, 17.74. Example 75 and 76: Synthesis of rac-(4R)-8,8-dimethyl-4-((R)-2-(methylamino)propanamido)-5- oxo-2-((phenylthio)methyl)-N-((S)-l,2,3,4-tetrahydronaphthalen-l-yl)octahydropyrrolo[2,l- b][l,3]oxazepine-7-carboxamide hydrochloride (75, 76).
Figure imgf000147_0001
[00361] To a mixture of 4,4-dimethoxy-2,2-dimethylbutanal (0.493 g, 3.08 mmol), ammonia (7M in methanol, 0.600 ml, 4.20 mmol), X-9 (1.051 g, 2.8 mmol) in methanol at 0°C was added X-l (0.484 g, 3.08 mmol). The mixture was stirred at 0°C for 10 min then at 40°C for 24 hours. The mixture was concentrated, solubilized in dioxane (7 mL) and treated with HC1 (4M in dioxane, 7mL). The mixture was stirred at 40°C for 1 hour. The mixture was quenched with a saturated aqueous solution of sodium bicarbonate (200 mL) and extracted with ethyl acetate (2*100 mL). The combined organic layers were washed with 0.5 M aqueous HC1 (100 mL), brine (2* 100 mL), dried over sodium sulfate anhydrous, filtered and concentrated. The crude (1.4 mmol, 879mg) in tetrahydrofuran (3 mL) at 0°C, was treated with TBAF (5 eq, 1M in THF, 7mmol). The mixture was then heated to 72°C for 24 h. 5mL of water was then added and the mixture was stirred for 30 min. The mixture was then cooled down to 23 °C and diluted with a saturated aqueous solution of sodium bicarbonate (50 mL). It was extracted with ethyl acetate (3*50 mL). The combined organic layers were washed with brine (2*50mL), dried over sodium sulfate anhydrous, filtered and concentrated. To a mixture of latter crude, N-methylmorpholine (4.20 mmol, 0.462 mL), HOBT (0.236 g, 1.540 mmol) and N-(tert- butoxycarbonyl)-N-methyl-L-alanine (0.313 g, 1.540 mmol) in THF (14 mL) at 0°C was added EDC.HC1 (0.282 g, 1.470 mmol). The mixture was stirred at 0°C for 30 min then warmed to 35°C for 18 hours. The mixture was diluted with water (100 mL) and 0.1M HC1 (10 mL). It was extracted with ethyl acetate (3* 100 mL). The combined organic layers were washed with a saturated solution of sodium bicarbonate (1* lOOmL), washed with brine (1* lOOmL), dried over sodium sulfate anhydrous, filtered through a plug of silica gel (the plug was washed with 200 mL of ethyl acetate) and concentrated. The crude was used in the next step without further purification. To a solution of the crude (950 mg, 1.4 mmol) in dioxane (5 mL) was added 4M HC1 in dioxane (10 eq). The mixture was stirred at 40°C for 2 hours. The mixture was then concentrated to dryness. It afforded 400 mg of crude product. The product was purified by Dionex (15-50 % acetonitrile in water). It afforded two fractions. Compound 75 (187 mg), Compound 76 (210 mg) overall yield of 25%. LC-MS m/z: 579.40 (calcd. 579.30 [M+H]+). [00362] Compound 75: ¾ NMR (400 MHz, DMSO-d6) d 8.17 (d, J = 6.8 Hz, 1H), 7.99 (d, J = 8.3 Hz, 1H), 7.33 - 7.23 (m, 5H), 7.20 - 7.02 (m, 7H), 5.48 (t, J = 6.4 Hz, 1H), 4.92 - 4.85 (m, 1H), 4.77 (ddd, J = 11.8, 6.9, 2.0 Hz, 1H), 4.00 - 3.93 (m, 2H), 3.52 (s, 1H), 3.00 - 2.87 (m, 4H), 2.68 (d, J =
7.9 Hz, 2H), 2.19 (s, 3H), 2.06 - 1.99 (m, 2H), 1.80 (dt, J = 12.5, 6.2 Hz, 3H), 1.70 - 1.63 (m, 2H), 1.47 (dt, J = 13.5, 11.3 Hz, 1H), 1.09 (d, J = 6.9 Hz, 3H), 0.97 (s, 3H), 0.96 (s, 3H). 13C NMR (101 MHz, DMSO-D6) d 174.04, 170.85, 168.92, 137.59, 137.48, 136.71, 129.54, 129.26, 129.15, 129.13, 127.39, 126.40, 87.88, 79.15, 69.91, 66.88, 59.82, 50.90, 47.13, 45.85, 40.96, 38.93, 38.36, 37.04, 34.81, 30.28, 29.21, 29.02, 24.08, 20.19, 19.43.
[00363] Compound 76: ¾ NMR (400 MHz, DMSO-d6) d 8.15 (d, J = 6.8 Hz, 1H), 8.11 (d, J = 8.6 Hz, 1H), 7.38 - 7.19 (m, 5H), 7.19 - 6.94 (m, 7H), 5.48 (t, J = 6.6 Hz, 1H), 4.89 (q, J = 7.1 Hz, 1H), 4.80 - 4.70 (m, 1H), 4.11 - 3.91 (m, 3H), 3.08 (qd, J = 14.0, 5.7 Hz, 2H), 3.01 - 2.91 (m, 1H), 2.66 (dq, J = 10.7, 6.4, 4.5 Hz, 3H), 2.20 (dd, J = 4.3, 0.9 Hz, 3H), 2.10 - 2.00 (m, 1H), 1.94 (d, J = 13.6 Hz, 1H), 1.87 - 1.48 (m, 8H), 1.12 (s, 2H), 1.09 (dd, J = 6.7, 3.5 Hz, 3H), 0.98 - 0.92 (m, 4H). 13C NMR (101 MHz, DMSO-D6) d 173.82, 171.20, 169.23, 137.73, 137.58, 137.10, 129.52, 129.42, 129.20, 128.87, 128.72, 127.15, 126.17, 88.43, 79.63, 71.36, 59.88, 51.07, 46.98, 45.95, 40.96, 39.16, 38.39, 34.89, 30.68, 30.32, 29.33, 24.84, 20.62, 19.39.
Example 77: Synthesis of (R)-4-((4S,7S,9aS)-8,8-dimethyl-4-((S)-2-(methylamino)propanamido)- 5-oxooctahydropyrrolo[2,l-b][l,3]thiazepine-7-carboxamido)-4-phenylbutanoic acid hydrochloride
Figure imgf000148_0001
[00364] Under nitrogen atmosphere, A-Ethyl-/V-(propan-2-yl)propan-2 -amine (153 pL, 0.879 mmol, 3.00 eq.) and COMU® (157 mg, 0.366 mmol, 1.25 eq.) were added to a solution of X-18 (130 mg, 0.293 mmol, 1.00 eq.) dissolved in dry THF (2.4 mL) and stirred at rt. After 45 minutes, (lR)-4- methoxy-4-oxo-l-phenylbutan-l -ammonium chloride (80 mg, 0.352 mmol, 1.20 eq.) was added and stirring was continued for 22 h. Upon completion, ethyl acetate (30 mU) was added and washed with 1M NaOH (2* 10 mU), 1M HC1 (2* 10 mU), water (10 mU) and brine (10 mU), dried over sodium sulfate anhydrous and concentrated in vacuo. The resulting residue was purified by flash column chromatography (hexanes/ethyl acetate). It afforded methyl (4R)-4-{[(4S,7S,9aS)-4-[(2S)-2-{[(tert- butoxy)carbonyl] (methyl)amino } propanamido] - 8 , 8-dimethyl- 5 -oxo-octahydropyrrolo [2,1- b][l,3]thiazepin-7-yl]formamido}-4-phenylbutanoate as a colorless solid, 123 mg (68%). Rf = 0.30 (70%ethyl acetate in hexanes, Ceric Ammonium Molybdate stain). ¾ NMR (400 MHz, CD3OD) d 8.15 (d, J = 8.4 Hz, 1H), 7.39 - 7.31 (m, 4H), 7.28 - 7.22 (m, 1H), 5.46 (d, J = 8.7 Hz, 1H), 4.95 - 4.89 (m, 1H), 4.67 - 4.61 (m, 1H), 4.20 (s, 1H), 3.65 (s, 3H), 3.35 - 3.31 (m, 1H), 2.91 (ddd, J = 14.5, 4.9, 2.5 Hz, 1H), 2.85 (s, 3H), 2.37 (td, J = 7.2, 1.4 Hz, 2H), 2.33 - 2.20 (m, 2H), 2.15 - 2.02 (m, 2H), 1.98 - 1.82 (m, 2H), 1.47 (s, 9H), 1.37 (d, J = 7.2 Hz, 3H), 1.13 (s, 3H), 1.00 (s, 3H).. 13C NMR (101 MHz, CD3OD): d (ppm)= 174.91, 173.24, 172.79, 171.84, 143.26, 129.66, 128.46, 127.65, 81.82, 73.44, 61.87, 54.36, 54.14, 52.20, 47.10, 40.88, 33.74, 32.34, 31.74, 31.10, 28.78, 28.66, 23.80, 14.47. LC-MS m/z: 619.30 (calcd. 619.32 [M+H+]). Lithium hydroxide solution (1 M, 250 pL. 0.250 mmol, 2.00 eq.) was added to the intermediate (77 mg, 0.125 mmol, 1.00 eq.) dissolved in THF (250 pL) at rt. The resulting emulsion was stirred at 40 °C for 16 h. Upon completion, ethyl acetate (30 mL) was added and washed with 1M HC1 (10 mL), water (10 mL), brine (10 mL), dried over sodium sulfate anhydrous and concentrated in vacuo. The resulting residue was purified by flash column chromatography (hexanes/ethyl acetate/formic acid 0.2%). It afforded (4R)-4-{[(4S,7S,9aS)-4-[(2S)- 2- { [(tert-butoxy)carbonyl](methyl)amino}propanamido]-8,8-dimethyl-5-oxo-octahydropyrrolo[2, 1- b][l,3]thiazepin-7-yl]formamido}-4-phenylbutanoic acid as a colorless oil, yield 53 mg (70%). Rf = 0.56 (hexanes/ethyl acetate/formic acid 1:9:0.1, Ceric Ammonium Molybdate stain). *HNMR (400 MHz, CD3OD) d 8.14 (d,), 7.38 - 7.28 (m, 4H), 7.26 - 7.20 (m, 1H), 5.44 (t), 4.93 - 4.89 (m, 1H), 4.63 (d), 4.18 (s, 1H), 3.34 - 3.29 (m, 1H), 2.92 - 2.85 (m, 1H), 2.83 (s, 3H), 2.32 (td, 2H), 2.29 -
2.25 (m, 1H), 2.25 - 2.19 (m, 1H), 2.12 - 2.00 (m, 2H), 1.94 - 1.81 (m, 2H), 1.45 (s, 9H), 1.35 (d, 3H), 1.11 (s, 3H), 0.99 (s, 3H). 13C NMR (101 MHz, CD3OD) d 176.40, 173.26, 172.80, 143.41, 129.64, 128.41, 127.61, 73.47, 61.87, 54.41, 54.14, 47.12, 40.88, 33.77, 32.33, 31.83, 31.11, 28.80, 28.67, 23.82, 14.46. LC-MS m/z: 605.25 (calcd. 605.30 [M+H+]). It (53 mg, 0.00873 mmol, 1.00 eq.) was treated with HC1 in dioxane (4 M, 873 pL, 3.49 mmol, 40.0 eq.) at rt. After 2 h, all volatiles were removed under reduced pressure, the residue was transferred on a fritted funnel and washed with Et20 (3 x 1.5 mL). The remaining product was dried under reduced pressure. It afforded (R)-4- ((4S,7S,9aS)-8,8-dimethyl-4-((S)-2-(methylamino)propanamido)-5-oxooctahydropyrrolo[2,l- b][l,3]thiazepine-7-carboxamido)-4-phenylbutanoic acid hydrochloride as a colorless solid, yield
24 mg (51%). ¾ NMR (400 MHz, CDOD3): d (ppm) = 8.15 (d, J = 8.5 Hz, 1H), 7.39 - 7.20 (m, 5H), 5.46 (t, J = 7.7 Hz, 1H), 4.91 (s, 3H), 4.75 (d, J = 10.5 Hz, 1H), 4.18 (s, 1H), 3.96 - 3.85 (m, 1H), 3.33 (s, 2H), 2.94 (d, J = 14.7 Hz, 1H), 2.67 (s, 3H), 2.41 - 2.21 (m, 4H), 2.15 - 1.95 (m, 3H), 1.87 (dd, J = 13.1, 9.2 Hz, 1H), 1.54 (d, J = 6.9 Hz, 3H), 1.14 (s, 3H), 0.99 (s, 3H). 13C NMR (101 MHz, CDOD3) d 173.60, 171.04, 170.41, 167.95, 141.89, 128.34, 127.17, 126.35, 72.15, 60.47, 57.01, 53.15, 53.06, 45.87, 39.57, 32.22, 31.44, 30.94, 30.48, 30.42, 27.45, 22.48, 14.95. LC-MS: m/z = 505.10 (calcd.
505.25 [M+H+]).
Example 78: Synthesis of (4S,7S,9aS)-N-((lS,2R)-2-(2-fluoroethoxy)-2,3-dihydro-lH-inden-l- yl)-8,8-dimethyl-4-((S)-2-(methylamino)propanamido)-5-oxooctahydropyrrolo[2,l- b] [l,3]thiazepine-7-carboxamide hydrochloride
Figure imgf000150_0001
[00365] Followed the procedure of 55 using X-18 and X-14. It afforded (4S,7S,9aS)-N-((lS,2R)-2-(2- fluoroethoxy)-2,3-dihydro-lH-inden-l-yl)-8,8-dimethyl-4-((S)-2-(methylamino)propanamido)-5- oxooctahydropyrrolo[2,l-b][l,3]thiazepine-7-carboxamide hydrochloride as a colorless solid, yield 42 mg (47%). ¾ NMR (400 MHz, CD3OD) d 8.71 (d), 7.96 (d, 1H), 7.34 (d, 1H), 7.27 - 7.17 (m, 3H), 5.52 - 5.42 (m, 2H), 4.75 (d, 1H), 4.62 - 4.55 (m, 1H), 4.46 (d, 1H), 4.36 (q, 1H), 4.25 (s, 1H), 3.94 (q, 1H), 3.80 (t, 1H), 3.74 - 3.71 (m, 1H), 3.31 - 3.27 (m, 1H), 3.11 (d, 2H), 2.91 (d, 1H), 2.68 (s, 3H), 2.37 - 2.22 (m, 2H), 2.08 (q, 1H), 1.81 (dd, 1H), 1.56 (d3H), 1.18 - 1.10 (m, 6H). 13C NMR (101 MHz, CD3OD) d 171.11, 170.81, 168.01, 141.05, 139.81, 128.06, 126.66, 124.81, 124.25, 83.73, 82.06, 80.86, 72.18, 68.99, 68.80, 60.47, 57.00, 55.49, 53.15, 45.88, 39.54, 36.08, 32.01, 31.04, 30.49, 27.48, 22.68, 15.01. LC-MS: m/z = 521.15 (calcd. 521.26 [M+H+]).
Example 79: Synthesis of (4S,7S,9aS)-8,8-dimethyl-4-((S)-2-(methylamino)butanamido)-5-oxo- N-((R)-l,2,3,4-tetrahydronaphthalen-l-yl)octahydropyrrolo[2,l-b][l,3]thiazepine-7- carboxamide hydrochloride
Figure imgf000150_0002
[00366] Followed the synthesis of X-18 using (2S)-2-{[(tert- butoxy)carbonyl](methyl)amino} butanoic acid to afford (4S,7S,9aS)-4-[(2S)-2-{[(tert- butoxy)carbonyl] (methyl)amino } butanamido] -8,8 -dimethyl-5 -oxo-octahydropyrrolo [2,1- b][l,3]thiazepine-7-carboxylic acid as a colorless gum, yield 134 mg (69%). Rf = 0.33 (hexanes/ethyl acetate/formic acid 4:6:0.1, CAM stain). ¾ NMR (400 MHz, CDC13) d 7.38 (d, J = 36.3 Hz, 1H),
5.21 (t, J = 7.0 Hz, 1H), 4.67 - 4.49 (m, 1H), 4.25 (s, 1H), 3.24 (t, J = 12.9 Hz, 1H), 2.87 - 2.79 (m, 1H), 2.77 (s, 3H), 2.32 - 2.21 (m, 2H), 2.03 - 1.87 (m, 3H), 1.66 (s, 1H), 1.47 (s, 9H), 1.20 (s, 3H), 1.17 (s, 3H), 0.88 (t, J = 7.4 Hz, 3H). 13C NMR (101 MHz, CDCI3) d 173.75, 171.06, 156.87, 80.73, 70.33, 61.36, 53.06, 46.34, 39.88, 33.24, 31.77, 30.27, 28.62, 28.46, 23.84, 21.44, 10.67. LC-MS: m/z = 458.20 (calcd. 458.23 [M+H+]).
[00367] Under nitrogen atmosphere, /V-Ethyl-/V-(propan-2-yl)propan-2 -amine (76 pL, 0.437 mmol, 2.50 eq.) and COMU® (97 mg, 0.227 mmol, 1.30 eq.) were added to a solution of (4S,7S,9aS)-4- [(2S)-2-{[(tert-Butoxy)carbonyl](methyl)amino}butanamido]-8,8-dimethyl-5-oxo- octahydropyrrolo[2,l-b][l,3]thiazepine-7-carboxylic acid (80 mg, 0.175 mmol, 1.00 eq.) in dry THF (1.7 mL) at 0 °C. After the reaction mixture was stirred for 30 min at 0 °C, (//)-(-)- 1 2.3.4-tctrahydro- 1-naphthylamine (39 pL, 0.262 mmol, 1.50 eq.) was added and stirring was continued for 24 h at rt. Afterwards, all volatiles were removed under reduced pressure, the residue was dissolved in ethyl acetate (30 mL), washed with sat. NaHCCL solution (2* 10 mL), 1M HC1 (2* 10 mL), water (10 mL) and brine (10 mL), dried (l^SCL) and concentrated in vacuo. The residue was purified by flash column chromatography (hexanes/ethyl acetate). It afforded tert-butyl N-[(lS)-l-{[(4S,7S,9aS)-8,8- dimethyl-5 -oxo-7- { [( 1 R)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl] carbamoyl } -octahydropyrrolo [2,1- b][l,3]thiazepin-4-yl]carbamoyl}propyl]-N-methylcarbamate as a colorless resin, yield 81 mg (79%). Rf = 0.30 (hexanes/ethyl acetate 5:5, Cerium(IV) sulfate stain). 1HNMR (400 MHz, CDCL) d 1H NMR (400 MHz, CDC13) d 7.28 - 7.22 (m, 1H), 7.14 (d, J = 3.9 Hz, 2H), 7.11 - 7.04 (m, 1H), 6.96 (d, J = 17.3 Hz, 1H), 5.22 - 5.09 (m, 2H), 4.55 - 4.48 (m, 1H), 4.24 (s, 1H), 3.27 (t, J = 14.0 Hz, 1H), 2.85 - 2.69 (m, 6H), 2.33 - 2.21 (m, 2H), 1.94 - 1.61 (m, 8H), 1.48 (s, 9H), 1.23 (s, 3H), 1.10 (s, 3H), 0.89 (t, J = 6.1 Hz, 3H). 13C NMR (101 MHz, CDCL) d 170.83, 170.06, 168.57, 137.36, 136.49, 129.19, 128.88, 127.32, 126.28, 80.52, 72.44, 60.90, 52.93, 47.56, 46.14, 39.87, 33.60, 31.92, 30.15, 29.22, 28.88, 28.43, 23.54, 19.92, 10.69. LC-MS: m/z = 587.30 (calcd. 587.33 [M+H+]). Tert-butyl N- [(lS)-l-{[(4S,7S,9aS)-8,8-dimethyl-5-oxo-7-{[(lR)-l,2,3,4-tetrahydronaphthalen-l-yl]carbamoyl}- octahydropyrrolo[2,l-b][l,3]thiazepin-4-yl]carbamoyl}propyl]-N-methylcarbamate (65 mg,
0.111 mmol, 1.00 eq.) was treated with HC1 in dioxane (4 M, 1.11 mL, 4.45 mmol, 40.0 eq.) at rt. After 2 h, all volatiles were removed under reduced pressure, the residue was transferred on a fritted funnel and washed with Et20 (3 x 1.5 mL). The remaining product was dried under reduced pressure. It afforded 79 as a colorless solid, yield 42 mg (72%). ¾ NMR (400 MHz, CD3OD) d 8.83 (d), 8.18 (d, 1H), 7.31 (d, 1H), 7.19 - 7.05 (m, 3H), 5.42 (t, 1H), 5.09 (d, 1H), 4.77 (d, 1H), 4.16 (s, 1H), 3.83 (d, 1H), 3.24 (d, 1H), 2.92 (d, 1H), 2.86 - 2.76 (m, 2H), 2.67 (s, 3H), 2.36 - 2.21 (m, 2H), 2.05 - 1.77 (m, 9H), 1.20 - 1.11 (m, 6H), 1.06 (t, 3H).13C NMR (101 MHz, CD3OD) d 172.12, 171.55, 167.96, 138.54, 137.45, 130.07, 129.81, 128.30, 127.10, 73.39, 63.76, 61.86, 54.53, 47.39, 40.86, 33.72,
32.35, 32.06, 31.33, 30.10, 28.70, 24.84, 23.93, 21.33, 9.17. LC-MS: m/z = 487.55 (calcd. 487.27 for C26H39N403S+ [M+H+]).
Example 80: Synthesis of (4'S,7'S,9a'S)-4'-((S)-2-(methylamino)propanamido)-5'-oxo-N-((R)- l,2,3,4-tetrahydronaphthalen-l-yl)hexahydro-7'H-spiro[cyclopentane-l,8'-pyrrolo[2,l- b] [l,3]thiazepine]-7'-carboxamide hydrochloride
Figure imgf000152_0001
[00368] Under N2 atmosphere, /V-Ethyl-/V-(propan-2-yl)propan-2 -amine (78 pL, 0.447 mmol,
3.00 eq.) and COMU® (83 mg, 0.194 mmol, 1.30 eq.) were added to a solution of carboxylic acid X- 19 (70 mg, 0.149 mmol, 1.00 eq.) in dry THF (1.2 mL). After the reaction mixture was stirred for 30 min, (//)-(-)- 1 2.3.4-tctrahydro- 1 -naphthylamine (33 pL, 0.224 mmol, 1.50 eq.) was added and stirring was continued for 24 h at rt. Afterwards, all volatiles were removed under reduced pressure, the residue was dissolved in ethyl acetate (30 mL), washed with sat. NaHCCL solution (2 x 10 mL), HCI solution (1 M, 2 x 10 mL), water (10 mL) and brine (10 mL), the organic layer was dried (Na2SC>4) and concentrated in vacuo. The crude was solubilized in methanol and palladium over carbon (10%w/w, 100 mg) was added. The mixture was put under hydrogen atmosphere and stirred for 24 hours. It was concentrated and the residue was purified by flash column chromatography (hexanes/ethyl acetate). It afforded tert-butyl N-[(lS)-l-{[(4'S,7'S,9'aS)-5'-oxo-7'-{[(lR)-l, 2,3,4- tetrahydronaphthalen- 1 -yl] carbamoyl } -hexahydro-2H-spiro [cyclopentane - 1 , 8 '-pyrrolo [2,1- b][l,3]thiazepin]-4'-yl]carbamoyl}ethyl]-N-methylcarbamate as a colorless resin, yield 34 mg (39%). Rf = 0.48 (hexanes/ethyl acetate 6:4, Cerium(IV) sulfate stain). Ή NMR (400 MHz, CDCL) d 1.34 (d, J= 7.1 Hz, 3H), 1.47 (s, 9H), 1.49 - 1.88 (m, 12H), 2.00 - 2.07 (m, 2H), 2.25 - 2.37 (m, 2H), 2.70 - 2.85 (m, 6H), 3.26 (t, J= 13.9 Hz, 1H), 4.31 (s, 1H), 4.52 (dd, J= 10.8/6.1 Hz, 1H), 4.70 (s, broad, 1H), 5.04 - 5.11 (m, 1H), 5.19 (q, J= 6.0/4.7 Hz, 1H), 7.00 (d, J= 8.0 Hz, 1H), 7.05 - 7.17 (m, 3H), 7.23 - 7.28 (m, 1H), 7.39 (s, 1H). 13C NMR (101 MHz, CDCL) d 14.0, 20.1, 23.8, 24.3, 28.4, 29.2,
Figure imgf000152_0002
168.6, 170.7, 171.0. LC-MS: m/z = 599.25 (calcd. 599.33 [M+H+]). It was treated with 4M HCI (10 eq) at 40°C for 2 hours then concentrated under vacuo to afford 80. LC-MS m/z: 499.15 (calcd.
499.27 [M+H+]).
Example 81: Synthesis of (4'S)-4'-((S)-2-(methylamino)propanamido)-5'-oxo-N-((R)-l,2,3,4- tetrahydronaphthalen-l-yl)-2',3',4',5',9',9a'-hexahydro-7'H-spiro[cyclopentane-l,8'-pyrrolo[2,l- b] [l,3]oxazepin]-3-ene-7'-carboxamide hydrochloride
Figure imgf000152_0003
[00369] Followed the synthesis of compound A using X-5f. LC-MS m/z: 481.75 (calcd. 481.3 [M+H]+). ‘HNMR (400 MHz, CD3OD) d 7.30 - 7.24 (m, 1H), 7.16 - 7.01 (m, 4H), 5.72 - 5.58 (m, 2H), 5.46 - 5.39 (m, 1H), 5.06 (td, J = 5.5, 4.9, 3.0 Hz, 1H), 4.89 (ddd, J = 11.8, 6.7, 2.0 Hz, 1H), 4.25 (s, 1H), 4.15 - 4.06 (m, 1H), 3.99 - 3.92 (m, 2H), 2.85 - 2.68 (m, 3H), 2.66 (s, 4H), 2.43 - 1.69 (m, 14H), 1.60 - 1.49 (m, 4H). 13C NMR (101 MHz, CD3OD) d 170.70, 170.26, 168.28, 137.15, 136.26, 129.31, 128.77, 128.35, 128.26, 126.98, 125.83, 88.89, 70.06, 69.13, 57.09, 52.84, 49.18, 48.59,
46.40, 44.76, 38.98, 31.93, 30.58, 30.06, 28.81, 20.16, 15.16.
Example 82: Synthesis of (4'S)-4'-((S)-2-(methylamino)propanamido)-5'-oxo-N-((R)-l,2,3,4- tetrahydronaphthalen-l-yl)hexahydro-7'H-spiro[cyclopentane-l,8'-pyrrolo[2,l- b] [l,3]oxazepine]-7'-carboxamide hydrochloride
Figure imgf000153_0001
[00370] Followed the synthesis of compound 81 until it afforded the intermediate boc-protected: tert- butyl methyl((2S)- 1 -oxo- 1 -(((4'S)-5'-oxo-7'-(((R)- 1 ,2,3,4-tetrahydronaphthalen- 1 - yl)carbamoyl)hexahydro-7H-spiro[cyclopentane- 1 ,8'-pyrrolo[2, 1 -b] [ 1 ,3]oxazepin] -4'- yl)amino)propan-2-yl)carbamate. This intermediate (200 mg) was solubilized in methanol (5ml) and Palladium over carbon (30mg, 10%W/W, wet) was added. The mixture was flushed with nitrogen before being put under hydrogen atmosphere. The mixture was stirred under hydrogen atmosphere for 3-6 hours, filtered over celite. The celite plug was washed with methanol and the filtrate was concentrated the crude was treated with HC1 (lOeq, 4M in dioxane) for 2 hours at 30°C than concentrated and purified by reverse phase silica gel C18. LC-MS m/z: 483.50 (calcd. 483.3 [M+H]+). ‘HNMR (400 MHz, CD3OD) d 7.29 - 7.23 (m, 1H), 7.17 - 7.01 (m, 4H), 5.40 (t, 1H), 5.06 (t, 1H), 4.86 (dd, 1H), 4.14 (s, 1H), 4.13 - 4.06 (m, 1H), 3.98 - 3.87 (m, 2H), 2.87 - 2.68 (m, 3H), 2.66 (d, 3H), 2.29 - 2.21 (m, 1H), 2.12 - 2.02 (m, 1H), 2.02 - 1.92 (m, 2H), 1.89 - 1.67 (m, 10H), 1.54 (dd, 6H). 13C NMR (101 MHz, CD3OD) d 170.61, 170.56, 168.26, 137.16, 136.20, 128.75, 128.40, 126.97, 125.79, 89.04, 69.98, 68.78, 57.09, 52.80, 50.23, 48.55, 43.42, 39.20, 32.82, 31.84, 30.53, 30.08, 28.79, 23.36, 23.12, 20.10, 15.10.
Example 83: Synthesis of (2S)-l-{[(4S,7S,9aS)-8,8-Dimethyl-5-oxo-7-{[(lS,2R)-2-(prop-2-yn-l- yloxy)-2,3-dihydro-lH-inden-l-yl]carbamoyl}octahydropyrrolo[2,l-b][l,3]thiazepin-4- yl]amino}-N-methyl-l-oxopropan-2-ammonium chloride
Figure imgf000154_0001
[00371] Followed the procedure of compound 55 using X-18 and X-13. It afforded (2S)-1- {[(4S,7S,9aS)-8,8-Dimethyl-5-oxo-7-{[(lS,2R)-2-(prop-2-yn-l-yloxy)-2,3-dihydro-lH-inden-l- yl]carbamoyl}octahydropyrrolo[2,l-b][l,3]thiazepin-4-yl]amino}-N-methyl-l-oxopropan-2- ammonium chloride as a colorless solid, yield 51 mg (50%). ¾ NMR (400 MHz, CD3OD) d 8.00 (d, 1H), 7.32 (d, 1H), 7.26 - 7.17 (m, 3H), 5.52 - 5.40 (m, 2H), 4.75 (dd, 1H), 4.52 (td, 1H), 4.28 - 4.21 (m, 2H), 4.16 (dd, 1H), 3.94 (q, 1H), 3.37 - 3.28 (m, 4H), 3.16 (dd, 1H), 3.09 (dd, 1H), 2.96 - 2.87 (m, 2H), 2.68 (s, 3H), 2.34 (dd, 1H), 2.30 - 2.21 (m, 1H), 2.20 - 2.07 (m, 1H), 1.81 (dd, 1H), 1.55 (d, 3H), 1.19 - 1.12 (m, 6H). 13C NMR (101 MHz, CD3OD) d 172.36, 172.09, 169.23, 142.27, 140.97,
129.34, 127.99, 126.08, 125.45, 80.60, 80.40, 76.36, 73.57, 68.08, 61.68, 58.27, 57.57, 56.63, 54.40, 49.64, 49.43, 49.21, 49.00, 48.78, 48.58, 48.36, 47.23, 40.77, 37.18, 33.44, 32.38, 31.80, 28.90, 24.14,
16.34.
Example A
[00372] SKOV-3 cancer cell lines were treated with a test compound, either as a pure enantiomer or a mixture of stereoisomers, at a concentration of 10 mM. Cell viability was evaluated following treatment with a compound as disclosed in Table B . Viability of cancer cells following treatment is indicated according to the following legend:
A = 0-25% viability B = 26-50% viability C = >50% viability
Table B
Figure imgf000155_0001
Example B: Evaluation of Sensitization of Cancer Cells to Standard of Care Treatment [00373] As discussed herein, ML-IAP is upregulated in many tumors and is believed to underlie chemoresistance due to its ability to inhibit apoptosis in cancer cells. In order to assess the role of ML-IAP antagonists in cancer treatment, H460 lung cancer cells are treated with a standard of care treatment (e.g., vinorelbine) alone or in combination with a selective ML-IAP antagonist. Early data suggests that inhibition of ML-IAP should lead to increased sensitivity to chemotherapeutic agents inducing apoptosis. Data presented in FIG. 1 confirm this sensitizing effect in lung cancer cells with the clinically relevant anti -cancer agent vinorelbine (FIG. 1). The leftward shift in the dose dependent response (DDR) curve indicates a resensitization of lung cancer cells to the anti -cancer agent. Furthermore, TNF induction is absent following treatment with a compound described herein in breast cancer MDA-MB-231 cells. This effect provides a substantial advantage clinically as it avoids an inappropriate inflammatory response.
Example C: Fluorescence Polarization (FP) Assays
[00374] Compounds of the present disclosure were evaluated for potency and selectivity in a fluorescence polarization (FP) assay that measures inhibition of SMAC peptide binding to ML-IAP.
To measure SMAC peptide binding, multi-well plate format FP assays based on the ability of SMAC peptides to bind the BIR domains of several IAPs are used to generate IC50 and Ki values for analogues. The FP assays utilize plasmid constructs encoding various full length IAPs or fragments for expression as either GST or His6-fiision proteins in bacteria. Compounds are evaluated for activity against several members of the IAP family, including the BIR domains of XIAP, cIAP 1 and cIAP2 in order to generate selectivity profiles of the compounds disclosed herein. These assays also enable the identification and characterization of potency profiles of ML-IAP binding.
[00375] The activity of the compounds disclosed herein were tested against XIAP-BIR3 as shown in Table C. Activity of the compounds are indicated according to the following legend:
A = <1 nM B = 1-10 nM C = 10-100 nM D = > 100 nM
Table C
Figure imgf000156_0001
Example D: Cell-Based Assays for ML-IAP Inhibitors & Combination Therapies Example D: Cell-Based Assays for ML-IAP Inhibitors & Combination Therapies [00376] Compounds active in the FP assays are tested in several lung cancer cell lines including all those within the NCI 60 panel for community -wide data relevance. Compounds are evaluated for the capacity to induce apoptosis and to sensitize tumor cells to apoptosis induced by lung cancer relevant chemotherapeutic drugs irrespective of mechanism. For example, lung cancer SOC is often platinum- based chemotherapy (e.g. Carboplatin or Cisplatin) and a DNA damaging agent or mitotic tubule inhibitor. Various cancer cell lines are tested with these combinations in the presence and absence of ML-IAP inhibition. These in cellulo recapitulations of clinical regimens yield valuable potency and dosing information relevant to xenograft models.
[00377] Candidate compounds are tested in 384-well plates for effects on cell viability in the presence or absence of an appropriate conventional anticancer drug. Cell viability is indirectly monitored in the first instance using CellTiterGlo (Promega Corp., Madison, WI) (Table D). To determine if cell death is apoptotic, the induction of caspase activity is assessed utilizing the CaspaseGlo Assay system (Promega Corp., Madison, WI) (Table E). Cell viability is monitored 1 to 3 days after addition of compounds and conventional drugs. For drug combination studies, a concentration of cytotoxic anticancer drug is chosen that shows only marginal activity. A compound of any of the formulae as disclosed herein is evaluated in combination with said anticancer drug to determine which ML-IAP antagonist can sensitize most efficaciously. Select candidate compounds are tested in 14 point drug dose response (DDR) curves in a 384-well format in order to establish potency in combination with decreasing concentrations of lung cancer relevant drug regimens. Furthermore, checker-board titrations of a conventional drug and the candidate molecules are performed to search for synergy (using ISOBOLOGRAM analysis). Compounds and combinations as described herein are also tested for cytotoxicity against normal human cells (e.g. primary fibroblasts, lymphocytes, hepatocytes, epithelial and endothelial cells) using known methods.
[00378] In addition to efficacy testing the compounds described herein with lung cancer SOC chemotherapeutics, potential “off label” agents are also identified that are effective once inhibition of apoptosis is eliminated by a compound as described herein. Multiple lung cancer cells are screened against an Oncology Dose Library (ODL) of 120 FDA-approved anti -cancer and experimental agents alone and in combination with a compound described herein. Hits from this assay are tested in a 14- point drug dose response (DDR) analysis as described previously.
[00379] Cell viability was evaluated following treatment with a compound as disclosed in Table D. Viability of cancer cells following treatment is indicated according to the following legend:
A = <1 nM B = 1-10 nM C = 10-100 nM D = 100-1000 nM E = >1000 nM
Table D
Figure imgf000157_0001
Figure imgf000158_0001
[00380] The induction of caspase activities was tested with a compound as disclosed in Table E. The activities are indicated according to the following legend:
A = <1 nM B = 1-10 nM C = 10-100 nM D = > 100 nM
Table E
Figure imgf000158_0002
Example E: Evaluation of Selectivity for ML-IAP in an Orthogonal Biochemical/Biophysical Assay
[00381] An isothermal calorimetry (ITC) assay is utilized to probe compound binding to ML-IAP and selectivity against the BIR domains of other IAPs. ITC is the gold standard against which other techniques are compared. ITC, however, is not only able to measure binding affinities but also the magnitude of different thermodynamic forces that determine the binding energy. Since different chemical functionalities contribute differently to the binding forces, the knowledge acquired by ITC also provides precise guidelines for optimization of drug candidates.
Example F: Pharmacokinetic Evaluation Using in vitro Absorption, Distribution, Metabolism, Excretion and Toxicity (ADME/T) and in vivo Pharmacokinetic (PK) Assays [00382] In vitro ADME/T and physicochemical profding assays are employed to optimize the drug like properties of analogues and to aid in the selection of compounds for further development. Aqueous solubility data are determined at pH 5.0, 6.2 and pH 7.4 with UV detection. Compounds with aqueous solubility >10pg/mL are selected and advanced for further PK evaluation. Free plasma concentrations are determined using rapid equilibrium dialysis, which is the most quantitative method for determining levels of plasma protein binding. Membrane permeability data are determined using a parallel artificial membrane permeability assay (PAMPA). This in vitro method assesses the passive diffusion of compounds across a layer of specialized mixtures of phospholipids that mimic (a) the gut epithelium, and (b) brain capillary endothelial cells, the primary barrier to absorption into the brain. [00383] Metabolic stability in human, mouse, and rat microsomes are also used to evaluate compounds described herein for drug-like properties. For microsomal assays, compounds are incubated in the presence of 1 mg/mF microsomes; the metabolites are quantitated using FC/MS methods. Cytochrome P450 (CYP450) isoform (CYP1A2, 2C9, 2D6, and 3A4) inhibition is determined in human liver microsomes. Inhibition of product formation for compound substrates is detected by luminescence using the isoform specific P450-glo assay (Promega, Madison, WI) over 10 concentrations of inhibitor and assessed at one time point (previously determined to be in the linear range for time and protein concentration). The IC50 is analyzed by a four parameter logistic fit. Appropriate positive control inhibitors are used for each enzyme. Mechanism-based inhibition will be investigated where warranted using the established method.
[00384] Pharmacokinetic (PK) studies are performed in vivo in mice for compounds as described herein. Standard formulations are evaluated, including hydroxypropyl methylcellulose, carboxymethylcellulose, and polyethylene glycol. For intravenous studies, compounds are administered via indwelling catheters in jugular vein and samples collected from the carotid artery. These experiments provide basic pharmacokinetic parameters including peak plasma concentration (Cmax), bioavailability (%F), exposure (AUC), half-life (tl/2), clearance (CF), volume of distribution (Vd), and brain levels. To measure bioavailability, a compound as described herein is administered to three animals/group, both orally (10 mg/kg) and intravenously (1 mg/kg). Intraperitoneally administration is also assessed in order to determine both brain and plasma levels of compounds. [00385] The compounds described herein were tested in vivo in mice to measure PK plasma exposure as shown in Table F. The PK plasma values are indicated according to the following legend:
7 = <100 nM ii = 100-500 nM iii = 500-1000 nM iv = >1000 nM Table F
Figure imgf000160_0001
Example Gl: Evaluation of Efficacy in Relevant Mouse Tumorigenic (Xenograft) Models of Lung Cancer
[00386] A compound as described herein is tested in mouse xenograft models of lung cancer to determine in vivo efficacy. A suitable lung cancer cell line as well as a potent apoptosis inducing agent exhibiting synergy with the compounds described herein is used for a first-pass xenograft study to determine appropriate dosing ranges in vivo. The dosing parameters are applied to a parallel xenograft study utilizing a suitable patient-derived lung cancer sample (Mayo Clinic, Rochester, MN). [00387] A dosing regimen is selected that will maintain inhibition of ML-IAP in tumor cells by using two approaches: immunoblotting for SMAC levels, which are modulated through the E3 ligase activity of ML-IAP and measurement of activation of the apoptotic pathway through an apoptosis specific assay. This method enables one to (a) determine the compound levels in blood that correlates with inhibition of ML-IAP in tumors, as well as (b) determine what level of inhibition is required for a significant reduction of tumor growth in vivo. Compounds are tested in mice bearing xenografts of lung cancer cells as described above. Tumor xenografts are established in a group of 16 nude mice [4 test groups of 4 animals: (Group 1) Control; (Groups 2-4) ML-IAP antagonist at three dosing ranges (IC50, 10x IC50 and maximum tolerated dose, respectively) based on PK data obtained as described previously]. The NCI60 panel viability data suggests that no significant single agent toxicity is to be expected, however a more detailed assessment is prudent and necessary. Studies are initiated when tumors grow to approximately 0.25 mm3, a size that is visible on the flank, but small enough so that the tumor does not contain a substantial necrotic core. The time point of the blood draw is based on the data from ADME/T and PK assays as described previously. Compound levels in the tumor are determined after final dosing and the animals are sacrificed.
Example G2: Evaluation of Efficacy in Relevant Mouse Tumorigenic (Xenograft) Models of Ovarian Cancer
[00388] A compound as described herein is tested in mouse xenograft models of ovarian cancer to determine in vivo efficacy. A suitable ovarian cancer cell line as well as a potent apoptosis inducing agent exhibiting synergy with the compounds described herein is used for a first-pass xenograft study to determine appropriate dosing ranges in vivo. The dosing parameters are applied to a parallel xenograft study utilizing a suitable patient-derived ovarian cancer sample.
[00389] A dosing regimen is selected that will maintain inhibition of ML-IAP in tumor cells by using two approaches: immunoblotting for SMAC levels, which are modulated through the E3 ligase activity of ML-IAP and measurement of activation of the apoptotic pathway through an apoptosis specific assay. This method enables one to (a) determine the compound levels in blood that correlates with inhibition of ML-IAP in tumors, as well as (b) determine what level of inhibition is required for a significant reduction of tumor growth in vivo. Compounds are tested in mice bearing xenografts of ovarian cancer cells as described above. Tumor xenografts are established in a group of 16 nude mice [4 test groups of 4 animals: (Group 1) Control; (Groups 2-4) ML-IAP antagonist at three dosing ranges (IC50, lOx IC50 and maximum tolerated dose, respectively) based on PK data obtained as described previously]. The NCI60 panel viability data suggests that no significant single agent toxicity is to be expected, however a more detailed assessment is prudent and necessary. Studies are initiated when tumors grow to approximately 0.25 mm3, a size that is visible on the flank, but small enough so that the tumor does not contain a substantial necrotic core. The time point of the blood draw is based on the data from ADME/T and PK assays as described previously. Compound levels in the tumor are determined after final dosing and the animals are sacrificed.
Example G3: Evaluation of Efficacy in Relevant Mouse Tumorigenic (Xenograft) Models of Triple-Negative Breast Cancer
[00390] A compound as described herein is tested in mouse xenograft models of triple -negative breast cancer to determine in vivo efficacy. A suitable triple -negative breast cancer cell line as well as a potent apoptosis inducing agent exhibiting synergy with the compounds described herein is used for a first-pass xenograft study to determine appropriate dosing ranges in vivo. The dosing parameters are applied to a parallel xenograft study utilizing a suitable patient-derived triple-negative breast cancer sample.
[00391] A dosing regimen is selected that will maintain inhibition of ML-IAP in tumor cells by using two approaches: immunoblotting for SMAC levels, which are modulated through the E3 ligase activity of ML-IAP and measurement of activation of the apoptotic pathway through an apoptosis specific assay. This method enables one to (a) determine the compound levels in blood that correlates with inhibition of ML-IAP in tumors, as well as (b) determine what level of inhibition is required for a significant reduction of tumor growth in vivo. Compounds are tested in mice bearing xenografts of triple-negative breast cancer cells as described above. Tumor xenografts are established in a group of 16 nude mice [4 test groups of 4 animals: (Group 1) Control; (Groups 2-4) ML-IAP antagonist at three dosing ranges (IC50, lOx IC50 and maximum tolerated dose, respectively) based on PK data obtained as described previously]. The NCI60 panel viability data suggests that no significant single agent toxicity is to be expected, however a more detailed assessment is prudent and necessary. Studies are initiated when tumors grow to approximately 0.25 mm3, a size that is visible on the flank, but small enough so that the tumor does not contain a substantial necrotic core. The time point of the blood draw is based on the data from ADME/T and PK assays as described previously. Compound levels in the tumor are determined after final dosing and the animals are sacrificed.
Example H: Assessing Levels of Apoptosis
[00392] Four mice are used per dose for analysis by the TUNEL assay and immunoblotting for SMAC as well as ML-IAP levels. Animals are sacrificed 12 hours after treatment and the tumor resected on ice. The TUNEL assay is regarded as the “gold standard” in apoptosis detection and is performed as described in the scientific literature. Utilization of the TUNEL assay is well established for the determination of apoptosis levels in tissues. Resected tumor tissue is analyzed and the observed level of induction of apoptosis is correlated to SMAC levels and a reduction in tumor growth.
Example I: Quantifying SMAC levels in tumor xenografts
[00393] The homogenate is further lysed with detergent and analyzed by SDS-PAGE/Westem- blotting, allowing visualization of SMAC levels in the tumor tissue. This analysis shows at what level the inhibition of ML-IAP in vivo exhibits a pronounced effect on SMAC degradation through ubiquitination by the E3 ligase domain of ML-IAP.
Example J: Monitoring Potential Toxicides
[00394] The collected blood samples are further analyzed for levels of the liver enzymes alanine transaminase (ALT) and aspartate transaminase (AST) as a preliminary assessment of possible liver damage; levels are identified and compared to the control group utilizing ELISA based assays.
Example Kl: Evaluation of Efficacy in Xenograft Models of Human Lung Cancer [00395] The antitumor effects of selected compounds described herein are measured in orthotopic xenograft models using human lung cancer cell lines as well as a suitable patient-derived lung cancer sample. The study has four arms: control, test compound alone, treatment with a SOC therapy, and the combination of test compound and SOC therapy. Furthermore, two arms are used for the patient- derived xenograft (PDX) study, one arm for control and one arm with the physician recommended SOC for the original tumor. Power calculations are performed based on published results on xenograft growth for comparable lung cancer lines, which indicate that a group size of 8 animals is required to provide a robust statistical chance of detecting a reduction in tumor growth of 60%. Due to variance known to exist in in vivo studies, 10 animals are initially included in each arm. Animals are randomly divided into each cohort representing one study arm. Lung cancer cells (l x 106) are injected into the dorsal region of BALB/c athymic nude mice. Tumors are allowed to grow to a size of approximately 100 mm3 (which is a point just after which they are palpable) before the combination treatment is initiated. This ensures that the tumor has begun to grow in all animals that will be administered compound, and also reduces the statistical variability in measuring tumor growth. Moreover, by initiating dosing after substantial tumor growth in vivo, this better mimics the human clinical condition and aids in the assessment of tumor regression with statistical certainty. Each animal is treated with test compound or vehicle for approximately 2-3 weeks, at which time untreated xenografts typically grow to a size of 200 to 300 mm3. Tumor volumes are measured three times a week at orthogonal angles to calculate tumor volumes, which are then used to calculate tumor doubling time. Differences in tumor growth are considered significant if a p-value of less than 0.05 is observed with Students’ t-test between test and control groups.
[00396] To monitor compound levels, blood samples are drawn once each week on half of the cohort (4-5 animals per group) at an appropriate time after dosing; blood levels are assessed during the treatment period. To detect toxicity (e.g., liver toxicity) related to the testing regimen, the collected blood samples are analyzed for ALT and AST levels as a preliminary assessment of possible liver damage. Levels identified are compared to the control group utilizing ELISA based assays.
Example K2: Evaluation of Efficacy in Xenograft Models of Human Ovarian Cancer [00397] The antitumor effects of selected compounds described herein are measured in orthotopic xenograft models using human ovarian cancer cell lines as well as a suitable patient-derived ovarian cancer sample. The study has four arms: control, test compound alone, treatment with a SOC therapy, and the combination of test compound and SOC therapy furthermore, two arms are used for the patient-derived xenograft (PDX) study, one arm for control and one arm with the physician recommended SOC for the original tumor. Power calculations are performed based on published results on xenograft growth for comparable ovarian cancer lines, which indicate that a group size of 8 animals is required to provide a robust statistical chance of detecting a reduction in tumor growth of 60%. Due to variance known to exist in in vivo studies, 10 animals are initially included in each arm. Animals are randomly divided into each cohort representing one study arm. Ovarian cancer cells (1 x 106) are injected into the dorsal region of BALB/c athymic nude mice. Tumors are allowed to grow to a size of approximately 100 mm3 (which is a point just after which they are palpable) before the combination treatment is initiated. This ensures that the tumor has begun to grow in all animals that will be administered compound, and also reduces the statistical variability in measuring tumor growth. Moreover, by initiating dosing after substantial tumor growth in vivo, this better mimics the human clinical condition and aids in the assessment of tumor regression with statistical certainty. Each animal is treated with test compound or vehicle for approximately 2-3 weeks, at which time untreated xenografts typically grow to a size of 200 to 300 mm3. Tumor volumes are measured three times a week at orthogonal angles to calculate tumor volumes, which are then used to calculate tumor doubling time. Differences in tumor growth are considered significant if a p-value of less than 0.05 is observed with Students’ t-test between test and control groups. [00398] To monitor compound levels, blood samples are drawn once each week on half of the cohort (4-5 animals per group) at an appropriate time after dosing; blood levels are assessed during the treatment period. To detect toxicity (e.g., liver toxicity) related to the testing regimen, the collected blood samples are analyzed for ALT and AST levels as a preliminary assessment of possible liver damage. Levels identified are compared to the control group utilizing ELISA based assays.
Example K3: Evaluation of Efficacy in Xenograft Models of Human Triple-Negative Breast Cancer
[00399] The antitumor effects of selected compounds described herein are measured in orthotopic xenograft models using human triple-negative breast cancer cell lines as well as a suitable patient- derived triple-negative breast cancer sample. The study has four arms: control, test compound alone, treatment with a SOC therapy, and the combination of test compound and SOC therapy. Furthermore, two arms are used for the patient-derived xenograft (PDX) study, one arm for control and one arm with the physician recommended SOC for the original tumor. Power calculations are performed based on published results on xenograft growth for comparable triple -negative breast cancer lines, which indicate that a group size of 8 animals is required to provide a robust statistical chance of detecting a reduction in tumor growth of 60%. Due to variance known to exist in in vivo studies, 10 animals are initially included in each arm. Animals are randomly divided into each cohort representing one study arm. Triple-negative breast cancer cells (1 x 106) are injected into the dorsal region of BALB/c athymic nude mice. Tumors are allowed to grow to a size of approximately 100 mm3 (which is a point just after which they are palpable) before the combination treatment is initiated. This ensures that the tumor has begun to grow in all animals that will be administered compound, and also reduces the statistical variability in measuring tumor growth. Moreover, by initiating dosing after substantial tumor growth in vivo, this better mimics the human clinical condition and aids in the assessment of tumor regression with statistical certainty. Each animal is treated with test compound or vehicle for approximately 2-3 weeks, at which time untreated xenografts typically grow to a size of 200 to 300 mm3. Tumor volumes are measured three times a week at orthogonal angles to calculate tumor volumes, which are then used to calculate tumor-doubling time. Differences in tumor growth are considered significant if a p-value of less than 0.05 is observed with Students’ t-test between test and control groups.
[00400] To monitor compound levels, blood samples are drawn once each week on half of the cohort (4-5 animals per group) at an appropriate time after dosing; blood levels are assessed during the treatment period. To detect toxicity (e.g., liver toxicity) related to the testing regimen, the collected blood samples are analyzed for ALT and AST levels as a preliminary assessment of possible liver damage. Levels identified are compared to the control group utilizing ELISA based assays. Example L Validation of ML-IAP as a Target
[00401] Several studies have presented evidence suggesting ML-IAP may be a viable target for combatting various forms of cancer. In an example, one such study found that siRNAs that ablate ML-IAP expression results in potent anti -tumor activity in models of human lung cancer. These findings are confirmed herein with a separate gene ablation study, wherein each member of the BIRC family is evaluated for its effects on cell viability of lung cancer cells. Ablation of expression of BIRC7, the gene for ML-IAP, shows a pronounced effect on cell viability of adenocarcinoma (A549) and non-small cell lung cancer (H460) cells (FIG. 2). Knock-down of BIRCl-4, BIRC6 or BIRC8 offers little to no impact on cell viability. BIRC5 (also known as survivin) shows a significant impact on cancer cell viability as well. However, in contrast to ML-IAP, survivin continues to play a physiological role even after development, making it a liability as a therapeutic target. These data show ML-IAP is a viable target in lung cancer cells and due to its lower liability compared to a similarly effective IAP (survivin), ML-IAP is validated as a therapeutic target in the treatment of cancer.
Example M: IAP Antagonists reverses HIV-1 Latency
[00402] It has previously been demonstrated that latency reversal of HIV- 1 can be promoted in in vitro and ex vivo systems through pharmacological manipulation of the non -canonical NF-kB pathway using the Smac mimetic compounds. SMAC mimetics modestly induced HIV-1 latency ex vivo in CD4+ T cells from ART-suppressed aviremic HIV-infected patients as a single agent. The activities of IAP antagonists in the latency infected Jurkat cell line 2D10 was examined (FIG. 3). Compounds for dose response assays, adjusted for equal DMSO concentrations, were spotted in 384- well plates and 2D 10 cells were added to each well. After 48 h, GFP expression was analyzed. Latency reversal was assessed by measuring GFP expression by flow cytometry.
[00403] While preferred embodiments of the present technology have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.

Claims

Figure imgf000166_0001
1 A compound or pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, having the structure of Formula (A-I):
Figure imgf000166_0002
Formula (A-I) wherein,
R1 is hydrogen, G-Galkyl. G-Gcycloalkyl. G-Galkyl-(G-Gcycloalkyl), G-Galkyl- (phenyl), or G-Galkyl-(5- to 6-membered heteroaryl); wherein the G-Galkyl. G- Gcycloalkyl. phenyl, or 5- to 6-membered heteroaryl is optionally substituted with 1, 2, or 3 R9;
X is NRA, O, S, S(O), or S(0)2;
RA is hydrogen, G-Galkyl. C(0)-(G-Galkyl). C(0)-(G-Gcyeloalkyl), C(0)-(phenyl), or C(0)-(5- to 6-membered heteroaryl); wherein each G-Galkyl. G-Gcycloalkyl. phenyl, or 5- to 6-membered heteroaryl is optionally substituted with 1, 2, or 3 R9; or X is C and taken together with R2a, R2b, and the carbon atom to which they are attached, forms a phenyl or 5- to 10-membered heteroaryl ring, optionally substituted with 1, 2, or
R2a. R2b, R3a, and R3b are each independently hydrogen, Ci-G, alkyl. G-Cehaloalkyl, Ci-Ce alkoxy, G-Ceheteroalkyl, G-Galkcnyl. G-Galkynyl. C3-Ciocycloalkyl, 3- to 10- membered heterocycloalkyl, Ce-Goaryl, or 5- to 10-membered heteroaryl; wherein each G-Galkyl. Ci-G,haloalkyl. Ci-Ce alkoxy, G-Ceheteroalkyl, G-Galkcnyl. or C2- Galkynyl is optionally substituted with 1 or 2 G-Gocycloalkyl, 3- to 10-membered heterocycloalkyl, G-Goaryl. or 5- to 10-membered heteroaryl rings; wherein each G- G, alkyl. G-Cehaloalkyl, C 1 -G> alkoxy, G-Ceheteroalkyl, G-Galkcnyl. G-Galkynyl. G- Ciocycloalkyl, 3- to 10-membered heterocycloalkyl, G-Goaryl. or 5- to 10-membered heteroaryl is optionally substituted with 1, 2, or 3 R9; or R2a and R2b together with the carbon atom to which they are attached form a carbonyl; or R2a and R3a, and optionally R2b and R3b, together with the carbon atoms to which they are attached form a G-Gcycloalkyl. 5- to 10-membered heterocycloalkyl, G-Goaryl. or 5- to 10-membered heteroaryl ring; wherein each G-Gcycloalkyl. 5- to 10-membered heterocycloalkyl, Ce-Goaryl, or 5- to 10-membered heteroaryl ring is optionally substituted with 1, 2, or 3 R9;
R4aand R4b are each independently hydrogen, halogen, CrG, alkyl. Ci-Cehaloalkyl, Ci-Ce alkoxy, Ci-Ceheteroalkyl, G-Galkcnyl. G-Galkynyl. C3-Ciocycloalkyl, 3- to 10- membered heterocycloalkyl, G,-Cioaryl. or 5- to 10-membered heteroaryl; wherein each G-Galkyl. Ci-Cehaloalkyl, Ci-Ce alkoxy, Ci-Ceheteroalkyl, G-Galkcnyl. or C2- Galkynyl is optionally substituted with 1 or 2 C3-Ciocycloalkyl, 3- to 10-membered heterocycloalkyl, G-Goaryl. or 5- to 10-membered heteroaryl; wherein each G-G, alkyl. Ci-Cehaloalkyl, G-Ce alkoxy, Ci-Ceheteroalkyl, G-Galkcnyl. G-Galkynyl. G- Ciocycloalkyl, 3- to 10-membered heterocycloalkyl, Ce-Goaryl, or 5- to 10-membered heteroaryl is optionally substituted with 1, 2, or 3 R9; or R4a and R4b together with the carbon atom to which they are attached form a carbonyl; or R4a and R4b together with the carbon atom to which they are attached form a G-
Gocycloalkyl or 3- to 10-membered heterocycloalkyl ring; wherein the G-Gocycloalkyl or 3- to 10-membered heterocycloalkyl ring is optionally substituted with 1, 2, or 3 R9; R5 is NHR8,NHS(0)2R8, OR8, SR8, S(0)2R8, or S(0)2NHR8; or R5, R4a, and R4b, together with the carbon atom to which they are attached, form a G- Goaryl or 5- to 10-membered heteroaryl ring; wherein the G-Goaryl or 5- to 10- membered heteroaryl ring is optionally substituted with 1, 2, or 3 R9;
R6a is hydrogen, halogen, -U, or -G;
R6b is halogen, -U, or -G;
-U is G-G, alkyl. G-Ghaloalkyl. G-Galkoxy. G-Ghctcroalkyl. C2-C6alkenyl, or C2-
Galkynyl: wherein each G-Galkyl. Ci-Cehaloalkyl, G-Galkoxy. Ci-Ceheteroalkyl, C2- G, alkenyl. or C2-C6alkynyl is optionally substituted with 1, 2, or 3 R9 and/or 1 or 2 -G;
-G is C3-Gocycloalkyl, 3- to 10-membered heterocycloalkyl, Ce-Goaryl, or 5- to 10- membered heteroaryl; wherein each C3-Gocycloalkyl, 3- to 10-membered heterocycloalkyl, Ce-Goaryl, or 5- to 10-membered heteroaryl is optionally substituted with 1, 2, or 3 R9; or R6a and R6b together with the carbon atom to which they are attached form a saturated or partially saturated 3- to 7-membered cycloalkyl or a saturated or partially saturated 3- to 7-membered heterocycloalkyl; wherein the cycloalkyl or heterocycloalkyl is optionally substituted with 1, 2, or 3 R9;
R7a is hydrogen, halogen, Ci-C4alkyl, or Ci-C haloalkyl;
R7*’ is hydrogen, halogen, Ci-C4alkyl, or Ci-C4haloalkyl; or R7a and R7b together with the carbon atom to which they are attached form a saturated or partially saturated 3- to 7-membered cycloalkyl or a saturated or partially saturated 3- to 7-membered heterocycloalkyl; wherein the cycloalkyl or heterocycloalkyl is optionally substituted with 1, 2, or 3 R9; or R6b and R715 together with the carbon atoms to which they are attached form a C3-
Ciocycloalkyl or 3- to 10-membered heterocycloalkyl ring; wherein each C3-Ciocycloalkyl or 3- to 10-membered heterocycloalkyl ring is optionally substituted with 1, 2, or 3 R9; or R6a, R6b, R7a, and R7b together with the carbon atoms to which they are attached form a 5 - to 10-membered heteroaryl ring optionally substituted with 1, 2, or 3 R9;
R8 is Z, G-G, alkyl. (Ci-C6alkylene)-Z, (Ci-C6heteroalkylene)-Z, (C2-C6alkenylene)-Z,
CH(Z)2, CH2CH(Z)2, CH(Ci-G,alkyl)Z. or C(0)Z; wherein each alkyl, alkylene, heteroalkylene, or alkenylene is optionally substituted with 1, 2, or 3 R9;
Z is C3-Ciocycloalkyl, 3- to 10-membered heterocycloalkyl, Ce-Goaryl, or 5- to 10-membered heteroaryl; wherein each C3-Ciocycloalkyl, 3- to 10-membered heterocycloalkyl, G- Cioaryl, and 5- to 10-membered heteroaryl is optionally substituted with 1, 2, or 3 R9; each R9 is independently halogen, G-C4alkyl, C2-C4alkenyl, C2-Galkynyl, G-Ghaloalkyl, G-C4alkoxy, Ci-C4haloalkoxy, Ci-C4heteroalkyl, -C(0)H, -C(0)0H, -CN, G- Ciocycloalkyl, 3- to 10-membered heterocycloalkyl, G-Goaryl. 5- to 10-membered heteroaryl, -C(0)(Ci-C4alkyl), -C(0)0(Ci-C4alkyl), -C(0)NH2, -C(0)NH(Ci-Galkyl), - C(0)N(G-C4alkyl)2, -NH2, -NH(Ci-C4alkyl), -N(Ci-C4alkyl)2, -NH(C2-C4alkylene)-OH, - NH(C2-Galkylene)-0-(Ci-C4alkyl), -OH, -0(Ci-C4alkyl), -0(G-C4halolkyl), -0(C2- C4alkylene)-NH2, -0(C2-Galkylene)-NH-(Ci-Galkyl), -0(C2-Galkylene)-N-(G- C4alkyl)2, -0(Ci-Galkylene)-C(0)0H, -0(Ci-Galkylene)-C(0)0-(Ci-C4alkyl), -0(C2- C4alkenyl), -0(G-Galkylene)-(C6-Goaryl), -0(Ci-C4alkylene)-(5- to 10-membered heteroaryl), -0(C6-Goaryl), -SH, S(0)20H, -S(0)2(Ci-Galkyl), -S(0)2NH2, -S(0)2NH(G- C4alkyl), or -S(0)2N(G-Galkyl)2; or two R9 together with the atoms to which they are attached form a C3-Gocycloalkyl or a 3- to 10-membered heterocycloalkyl ring; and provided that when R6a and R6b are both G¾ or when R6a and R6b together with the carbon atom to which they are attached form an unsubstituted cyclopentyl or unsubstituted
Figure imgf000168_0001
2. The compound of claim 1, or pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, wherein R5, R4a and R4b together with the carbon atom to which they are attached form a G-Goaryl or 5- to 10-membered heteroaryl ring; wherein the G-Goaryl or 5- to 10-membered heteroaryl ring is optionally substituted with 1, 2, or 3 R9.
3. The compound of claim 1 or 2, or pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, wherein R5, R4a and R4b together with the carbon atom to which they are attached form a 9-membered heteroaryl ring.
4. The compound of claim 1, or pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, wherein R5 is NHR8.
5. The compound of claim 1 or 4, or pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, having the structure of Formula (A-II):
Figure imgf000169_0001
Formula (A-II).
6. The compound of claim 1 or 4 or 5, or pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, wherein R4a and R4b are both H.
7. The compound of any one of claims 1 or 4 or 5, or pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, wherein R4a and R4b together with the carbon atom to which they are attached form a carbonyl.
8. The compound of any one of claims 1-7, or pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, wherein R1 is hydrogen.
9. The compound of any one of claims 1 or 4 or 5 or 7 or 8, or pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, having the structure of Formula (A -III):
Figure imgf000169_0002
Formula (A-III).
10. The compound of any one of claims 1-9, or pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, wherein R2a and R2b are each hydrogen.
11. The compound of any one of claims 1 -9, or pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, wherein R2a and R2b together with the atom to which they are attached form a carbonyl.
12. The compound of any one of claims 1-11, or pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, wherein R3a and R3b are each hydrogen.
13. The compound of any one of claims 1-9, or pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, wherein R2a and R3a together with the carbon atoms to which they are attached form a CVG, cycloalkyl.
14. The compound of any one of claims 1-13, pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, wherein X is O.
15. The compound of any one of claims 1-13, or pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, wherein X is S or S(0)2.
16. The compound of any one of claims 1-13, or pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, wherein X is S.
17. The compound of any one of claims 1-13, or pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, wherein X is S(0)2.
18. The compound of any one of claims 1-13, or pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, wherein X is NRA.
19. The compound of any one of claims 1-13, or pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, wherein X is C and taken together with R2a, R2b, and the carbon atom to which they are attached, forms a phenyl or 5- to 10- membered heteroaryl ring, optionally substituted with 1, 2, or 3 R9.
20. The compound of any one of claims 1-19, or pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, having the structure of Formula (A-IV-a), (A-IV-b), (A-IV-c), or (A-IV-d):
Figure imgf000170_0001
21. The compound of any one of claims 1 -20, or pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, wherein R6a, R6b, R7a, and R7b together with the carbon atoms to which they are attached form a 5 - to 10-membered heteroaryl ring optionally substituted with 1, 2, or 3 R9.
22. The compound of any one of claims 1-21, or pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, wherein R6a, R6b, R7a, and R715 together with the carbon atoms to which they are attached form a pyridine ring.
23. The compound of any one of claims 1 -20, or pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, wherein R7a and R715 are each hydrogen.
24. The compound of any one of claims 1-20, or pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, wherein R6a and R6b together with the carbon atom to which they are attached form a saturated or partially saturated 3- to 7- membered cycloalkyl ring optionally substituted with 1, 2, or 3 R9.
25. The compound of any one of claims 1 -20 or 24, or pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, wherein R6a and R6b together with the carbon atom to which they are attached form a saturated or partially saturated 3- to 5- membered cycloalkyl ring.
26. The compound of any one of claims 1-20, or pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, wherein R6a is hydrogen.
27. The compound of any one of claims 1-20 or 26, or pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, wherein R6b is halogen, Ci-
G, alkyl. G-G,haloalkyl. G-Galkenyl. or G-Galkynyl: wherein each G-Galkyl. Ci- Ghaloalkyl. G-Galkenyl. or G-Galkynyl is optionally substituted with 1, 2, or 3 R9 and/or 1 or 2, G.
28. The compound of any one of claims 1-20 or 26 or 27, or pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof wherein R6b is methyl, ethyl, 2-propenyl, isopropyl, orphenethyl.
29. The compound of any one of claims 1-20 or 26-28, or pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, wherein R6b is methyl.
30. The compound of any one of claims 1-20, or pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, wherein R6a and R6b are each independently halogen, G-Galkyl. G-Ghaloalkyl. G-Galkenyl. or G-Galkynyl: wherein each G-Galkyl. G-Ghaloalkyl. G-Galkenyl. or G-Galkynyl is optionally substituted with 1, 2, or 3 R9 and/or 1 or 2 G.
31. The compound of any one of claims 1-20, or pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, wherein R6a and R6b are each independently halogen, G-G, alkyl. G-G,haloalkyl. G-Galkcnyl. or G-Galkynyl: wherein each G-Galkyl. G-Ghaloalkyl. G-Galkcnyl. or G-Galkynyl is optionally substituted with 1, 2, or 3 R9 and/or 1 or 2 G.
32. The compound of any one of claims 1-20, or pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof wherein R6a and R6b are each independently methyl, ethyl, 2-propenyl, isopropyl, or phenethyl.
33. The compound of any one of claims 1 -20, or pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof wherein R6a and R6b are each independently ethyl, 2-propenyl, isopropyl, or phenethyl.
34. The compound of any one of claims 1 -20, or pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, wherein R6aand R6b are methyl.
35. The compound of any one of claims 1-34, or pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, wherein R8 is Z or CH(Z)2.
36. The compound of any one of claims 1-35, or pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, wherein R8 is Z.
37. The compound of any one of claims 1-36, or pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, wherein Z is C3-Ciocycloalkyl or 3- to 10-membered heterocycloalkyl; wherein each G-Ciocycloalkyl and 3- to 10-membered heterocycloalkyl is optionally substituted with 1, 2, or 3 R9.
38. The compound of any one of claims 1-37, or pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, wherein Z is C3-Ciocycloalkyl optionally substituted with 1, 2, or 3 R9.
39. The compound of any one of claims 1-38, or pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, wherein R8is:
Figure imgf000172_0001
The compound of any one of claims 1-38, or pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, wherein R8is:
Figure imgf000173_0001
41. The compound of any one of claims 1-38, or pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, wherein R8is:
Figure imgf000173_0002
42. The compound of any one of claims 1-38, or pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, wherein R8is:
Figure imgf000173_0003
43. A compound or pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, having the structure of Formula (B-I):
Figure imgf000173_0004
wherein,
R1 is hydrogen, CrG, alkyl. G-Gcycloalkyl. G-Cealkyl-IG-Cecycloalkyl), G-Cealkyl- (phenyl), or G-Galkyl-(5- to 6-membered heteroaryl); wherein the G-Galkyl. C3- Cecycloalkyl, phenyl, or 5- to 6-membered heteroaryl is optionally substituted with 1, 2, or 3 R9;
X is NRA, O, S, S(O), or S(0)2;
RA is hydrogen, G-Galkyl. C(0)-(G-Galkyl). C(0)-(G-C6cycloalkyl), C(0)-(phenyl), or C(0)-(5- to 6-membered heteroaryl); wherein each G-Galkyl. G-Gcycloalkyl. phenyl, or 5- to 6-membered heteroaryl is optionally substituted with 1, 2, or 3 R9; or X is C and taken together with R2a, R2b, and the carbon atom to which they are attached, forms a phenyl or 5- to 10-membered heteroaryl ring, optionally substituted with 1, 2, or 3 R9;
R2a, R2b, R3a, and R3b are each independently hydrogen, G-Galkyl. G-G,haloalkyl. C 1 -G, alkoxy, G-Gheteroalkyl. G-Cealkenyl, G-Cealkynyl, C3-Ciocycloalkyl, 3- to 10- membered heterocycloalkyl, Ce-Goaryl, or 5- to 10-membered heteroaryl; wherein each G-Galkyl. G-Ghaloalkyl. C 1 -G, alkoxy, G-Gheteroalkyl. G-Galkenyl. or G- Cealkynyl is optionally substituted with 1 or 2 G-Gocycloalkyl, 3- to 10-membered heterocycloalkyl, G-Goaryl. or 5- to 10-membered heteroaryl rings; wherein each G- Galkyl. G-Cehaloalkyl, C 1 -G, alkoxy, G-Gheteroalkyl. G-Galkenyl. G-Galkynyl. C3- Ciocycloalkyl, 3- to 10-membered heterocycloalkyl, G-Goaryl. or 5- to 10-membered heteroaryl is optionally substituted with 1, 2, or 3 R9; or R2a and R2b together with the carbon atom to which they are attached form a carbonyl; or R2a and R3a, and optionally R2b and R3b, together with the carbon atoms to which they are attached form a G-Gcycloalkyl. 5- to 10-membered heterocycloalkyl, G-Goaryl. or 5- to 10-membered heteroaryl ring; wherein each G-Gcycloalkyl. 5- to 10-membered heterocycloalkyl, G-Goaryl. or 5- to 10-membered heteroaryl ring is optionally substituted with 1, 2, or 3 R9;
R4aand R4b are each independently hydrogen, halogen, G-Galkyl. G-Ghaloalkyl. C 1 -Co alkoxy, G-Gheteroalkyl. G-Galkenyl. G-Galkynyl. G-Gocycloalkyl, 3- to 10- membered heterocycloalkyl, G-Goaryl. or 5- to 10-membered heteroaryl; wherein each Ci -Coalkyl. G-Ghaloalkyl. C 1 -C alkoxy, G-Gheteroalkyl. G-Galkenyl. or G- Cealkynyl is optionally substituted with 1 or 2 G-Gocycloalkyl, 3- to 10-membered heterocycloalkyl, G-Goaryl. or 5- to 10-membered heteroaryl; wherein each G-Galkyl. G-Cohaloalkyl, C 1 -Co alkoxy, G-Gheteroalkyl. G-Galkenyl. G-Galkynyl. G- Ciocycloalkyl, 3- to 10-membered heterocycloalkyl, G-Goaryl. or 5- to 10-membered heteroaryl is optionally substituted with 1, 2, or 3 R9; or R4a and R4b together with the carbon atom to which they are attached form a carbonyl; or R4a and R4b together with the carbon atom to which they are attached form a C3-
Ciocycloalkyl or 3- to 10-membered heterocycloalkyl ring; wherein the C3-Ciocycloalkyl or 3- to 10-membered heterocycloalkyl ring is optionally substituted with 1, 2, or 3 R9;
R5 is NHR8,NHS(0)2R8, OR8, SR8, S(0)2R8, or S(0)2NHR8; or R5, R4a, and R4b, together with the carbon atom to which they are attached, form a G- Cioaryl or 5- to 10-membered heteroaryl ring; wherein the G- oaryl or 5- to 10- membered heteroaryl ring is optionally substituted with 1, 2, or 3 R9;
R6a is hydrogen, halogen, -Ua, or -G;
R6b is halogen, -Ub, or -G;
-Ua is G-Galkyl. Ci-Cehaloalkyl, Ci-Cealkoxy, Ci-Ceheteroalkyl, G-Galkcnyl. or C2-
Galkynyl: wherein each G-Galkyl. Ci-Cehaloalkyl, Ci-Cealkoxy, Ci-Ceheteroalkyl, C2- Galkcnyl. or G-Galkynyl is optionally substituted with 1, 2, or 3 R9 and/or 1 or 2 -G;
-Ub is G-Galkyl. Ci-Cehaloalkyl, Ci-Cealkoxy, Ci-Ceheteroalkyl, G-Galkcnyl. or C2-
Galkynyl: wherein each G-Galkyl. Ci-Cehaloalkyl, Ci-Cealkoxy, Ci-Ceheteroalkyl, C2- Galkcnyl. or G-Galkynyl is optionally substituted with 1, 2, or 3 R9 and/or 1 or 2 -G;
-G is C3-Ciocycloalkyl, 3- to 10-membered heterocycloalkyl, G-Goaryl. or 5- to 10- membered heteroaryl; wherein each C3-Ciocycloalkyl, 3- to 10-membered heterocycloalkyl, G-Goaryl. or 5- to 10-membered heteroaryl is optionally substituted with 1, 2, or 3 R9;
R7a is hydrogen, halogen, Ci-C4alkyl, or Ci-C4haloalkyl;
R715 is hydrogen, halogen, Ci-C4alkyl, or Ci-C4haloalkyl;
R8 is Z, G-Galkyl. (Ci-C6alkylene)-Z, (Ci-C6heteroalkylene)-Z, (C2-C6alkenylene)-Z, CH(Z)2, CH2CH(Z)2, CH(Ci-C,alkyl)Z. or C(0)Z; wherein each alkyl, alkylene, heteroalkylene, or alkenylene is optionally substituted with 1, 2, or 3 R9;
Z is C3-Ciocycloalkyl, 3- to 10-membered heterocycloalkyl, C(,- oaryl. 5- to 10-membered heteroaryl; wherein each C3-Ciocycloalkyl, 3- to 10-membered heterocycloalkyl, C(,- Cioaryl, 5- to 10-membered heteroaryl is optionally substituted with 1, 2, or 3 R9; each R9 is independently halogen, Ci-C4alkyl, C2-C4alkenyl, C2-C4alkynyl, Ci-C4haloalkyl, Ci-C4alkoxy, Ci-C4haloalkoxy, Ci-C4heteroalkyl, -C(0)H, -C(0)0H, -CN, C3- Ciocycloalkyl, 3- to 10-membered heterocycloalkyl, C(,- oaryl. 5- to 10-membered heteroaryl, -C(0)(Ci-C4alkyl), -C(0)0(Ci-C4alkyl), -C(0)NH2, -C(0)NH(Ci-C4alkyl), - C(0)N(Ci-C4alkyl)2, -NH2, -NH(Ci-C4alkyl), -N(Ci-C4alkyl)2, -NH(C2-C4alkylene)-OH, - NH(C2-C4alkylene)-0-(Ci-C4alkyl), -OH, -0(Ci-C4alkyl), -0(Ci-C4haloalkyl), -0(C2- C4alkylene)-NH2, -0(C2-C4alkylene)-NH-(Ci-C4alkyl), -0(C2-C4alkylene)-N-(Ci- C4alkyl)2, -0(Ci-C4alkylene)-C(0)0H, -0(Ci-C4alkylene)-C(0)0-(Ci-C4alkyl), -0(C2- C4alkenyl), -0(Ci-C4alkylene)-(C6-Cioaryl), -0(Ci-C4alkylene)-(5- to 10-membered heteroaryl), -O(C6-Ci0aryl), -SH, S(0)20H, -S(0)2(Ci-C4alkyl), -S(0)2NH2, -S(0)2NH(Ci- C4alkyl), or -S(0)2N(Ci-C4alkyl)2; or two R9 together with the atoms to which they are attached form a C3-Ciocycloalkyl or a 3- to 10-membered heterocycloalkyl ring.
44. The compound of claim 43, or pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, wherein R5, R4a and R4b together with the carbon atom to which they are attached form a G,-Cioaryl or 5- to 10-membered heteroaryl ring; wherein the Ce-Cioaryl or 5- to 10-membered heteroaryl ring is optionally substituted with 1, 2, or 3 R9.
45. The compound of claim 43 or 44, or pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, wherein R5, R4a and R4b together with the carbon atom to which they are attached form a 9-membered heteroaryl ring.
46. The compound of claim 43, or pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, wherein R5 is NHR8.
47. The compound of any one of claims 43 or 46, or pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, having the structure of Formula (B-P):
Figure imgf000176_0001
Formula (B-II).
48. The compound of claim 43 or 46 or 47, or pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, wherein R4a and R4b are both H.
49. The compound of any one of claims 43 or 46 or 47, or pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, wherein R4a and R4b together with the carbon atom to which they are attached form a carbonyl.
50. The compound of any one of claims 43-49, or pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, wherein R1 is hydrogen.
51. The compound of any one of claims 43 or 46 or 47 or 49 or 50, or pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, having the structure of Formula (B-III):
Figure imgf000177_0001
Formula (B-III).
52. The compound of any one of claims 43-51, or pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, wherein R2a and R2b are each hydrogen.
53. The compound of any one of claims 43-52, or pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, wherein R2a and R2b together with the atom to which they are attached form a carbonyl.
54. The compound of any one of claims 43-53, or pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, wherein R3a and R3b are each hydrogen.
55. The compound of any one of claims 43-53, or pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, wherein R2a and R3a together with the carbon atoms to which they are attached form a CVG, cycloalkyl.
56. The compound of any one of claims 43-55, pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, wherein X is O.
57. The compound of any one of claims 43-55, or pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, wherein X is S or S(0)2.
58. The compound of any one of claims 43-55, or pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, wherein X is S.
59. The compound of any one of claims 43-55, or pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, wherein X is S(0)2.
60. The compound of any one of claims 43-55, or pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, wherein X is NRA.
61. The compound of any one of claims 43-55, or pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, wherein X is C and taken together with R2a, R2b, and the carbon atom to which they are attached, forms a phenyl or 5- to 10- membered heteroaryl ring, optionally substituted with 1, 2, or 3 R9.
62. The compound of any one of claims 43-61, or pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, having the structure of Formula (B-IV-a), (B-IV-b), (B-IV-c), or (B-IV-d):
Figure imgf000178_0001
Formula (B-IV-c) Formula (B-IV-d).
63. The compound of any one of claims 43-62, or pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, wherein R7a and R7|;’ are each H.
64. The compound of any one of claims 43-63, or pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, having the structure of Formula (B-V-a) or (B-V-b):
Figure imgf000178_0002
Formula (B-V-a) Formula (B-V-b).
65. The compound of any one of claims 43-64, or pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, wherein R6a is hydrogen.
66. The compound of any one of claims 43-65, or pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, wherein R6b is halogen, Ci- G, alkyl. G-G,haloalkyl. G-Galkenyl. or G-Galkynyl: wherein each G-Galkyl. Ci- Ghaloalkyl. G-Galkenyl. or G-Galkynyl is optionally substituted with 1, 2, or 3 R9 and/or 1 or 2 G.
67. The compound of any one of claims 43-66, or pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof wherein R6b is methyl, ethyl, 2- propenyl, isopropyl, or phenethyl.
68. The compound of any one of claims 43-67, or pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, wherein R6b is methyl.
69. The compound of any one of claims 43-64, or pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, wherein R6a and R6b are each independently halogen, G-Galkyl. G-G,haloalkyl. G-Galkenyl. or G-Galkynyl: wherein each G-Galkyl. Ci-Cehaloalkyl, G-Galkenyl. or G-Galkynyl is optionally substituted with 1, 2, or 3 R9 and/or 1 or 2, G.
70. The compound of any one of claims 43-64 or 69, or pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof wherein R6a and R6b are each independently ethyl, 2-propenyl, isopropyl, or phenethyl.
71. The compound of any one of claims 43 -64, or pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, wherein R6a is halogen, G-Galkyl. G-Ghaloalkyl. G-Galkenyl. or G-Galkynyl: wherein each G-Galkyl. G-Ghaloalkyl. G- Galkenyl. or G-Galkynyl is optionally substituted with 1, 2, or 3 R9 and/or 1 or 2 G; and R6b is methyl.
72. The compound of any one of claims 43-64 or 71, or pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof wherein R6a is ethyl, 2-propenyl, isopropyl, or phenethyl, and R6b is methyl.
73. The compound of any one of claims 43-72, or pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, wherein R8 is Z or CH(Z)2.
74. The compound of any one of claims 43-73, or pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, wherein R8 is Z.
75. The compound of any one of claims 43-74, or pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, wherein Z is C3-Gocycloalkyl or 3- to 10-membered heterocycloalkyl; wherein each C3-Gocycloalkyl and 3- to 10-membered heterocycloalkyl is optionally substituted with 1, 2, or 3 R9.
76. The compound of any one of claims 43-75, or pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, wherein Z is C3-Gocycloalkyl optionally substituted with 1, 2, or 3 R9.
77. The compound of any one of claims 43-76, or pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, wherein R8is:
Figure imgf000180_0001
79. The compound of any one of claims 43-78, or pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, wherein R8 is:
Figure imgf000180_0002
80. A compound or pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, having the structure of Formula (C-I):
Figure imgf000180_0003
wherein,
R1 is hydrogen, CrG, alkyl. G-Gcycloalkyl. G-CealkyHG-Cecycloalkyl), G-Cealkyl- (phenyl), or G-Galkyl-(5- to 6-membered heteroaryl); wherein the G-Galkyl. G- Gcycloalkyl, phenyl, or 5- to 6-membered heteroaryl is optionally substituted with 1, 2, or 3 R9;
X is NRA, O, S, S(O), or S(0)2;
RA is hydrogen, Ci-G, alkyl. C(0)-(G-Galkvl). C(0)-(G-Gcyeloalkyl), C(0)-(phenyl), or C(0)-(5- to 6-membered heteroaryl); wherein each CrG, alkyl. G-Gcycloalkyl. phenyl, or 5- to 6-membered heteroaryl is optionally substituted with 1, 2, or 3 R9; or X is C and taken together with R2a, R2b, and the carbon atom to which they are attached, forms a phenyl or 5- to 10-membered heteroaryl ring, optionally substituted with 1, 2, or 3 R9;
R2a, R2b, R3a, and R3b are each independently hydrogen, G-Galkyl. G-Ghaloalkyl, G-G alkoxy, G-Gheteroalkyl. G-Galkcnyl. G-Galkynyl, C3-Ciocycloalkyl, 3- to 10- membered heterocycloalkyl, G-Goaryl, or 5- to 10-membered heteroaryl; wherein each G-Galkyl. G-Ghaloalkyl. G-G alkoxy, G-Gheteroalkyl. G-Galkenyl. or G- Galkynyl is optionally substituted with 1 or 2 G-Gocycloalkyl, 3- to 10-membered heterocycloalkyl, G-Goaryl. or 5- to 10-membered heteroaryl rings; wherein each G- Galkyl. G-Ghaloalkyl, C i -G, alkoxy, G-Gheteroalkyl. G-Galkenyl. G-Galkynyl. G- Ciocycloalkyl, 3- to 10-membered heterocycloalkyl, G-Goaryl, or 5- to 10-membered heteroaryl is optionally substituted with 1, 2, or 3 R9; or R2a and R2b together with the carbon atom to which they are attached form a carbonyl; or R2a and R3a, and optionally R2b and R3b, together with the carbon atoms to which they are attached form a G-Gcycloalkyl. 5- to 10-membered heterocycloalkyl, G-Goaryl. or 5- to 10-membered heteroaryl ring; wherein each G-Gcycloalkyl. 5- to 10-membered heterocycloalkyl, G-Goaryl, or 5- to 10-membered heteroaryl ring is optionally substituted with 1, 2, or 3 R9;
R4aand R4b are each independently hydrogen, halogen, G-Galkyl. G-Ghaloalkyl. C 1 -G, alkoxy, G-Gheteroalkyl. G-Galkenyl. G-Galkynyl. G-Gocycloalkyl, 3- to 10- membered heterocycloalkyl, G-Goaryl. or 5- to 10-membered heteroaryl; wherein each Ci -Coalkyl. G-Ghaloalkyl. C 1 -C alkoxy, G-Gheteroalkyl. G-Galkenyl. or G- Cealkynyl is optionally substituted with 1 or 2 G-Gocycloalkyl, 3- to 10-membered heterocycloalkyl, G-Goaryl. or 5- to 10-membered heteroaryl; wherein each G-Galkyl. G-Ghaloalkyl. C 1 -Co alkoxy, G-Gheteroalkyl. G-Galkenyl. G-Galkynyl. G- Ciocycloalkyl, 3- to 10-membered heterocycloalkyl, G-Goaryl. or 5- to 10-membered heteroaryl is optionally substituted with 1, 2, or 3 R9; or R4a and R4b together with the carbon atom to which they are attached form a carbonyl; or R4a and R4b together with the carbon atom to which they are attached form a G-
Gocycloalkyl or 3- to 10-membered heterocycloalkyl ring; wherein the G-Gocycloalkyl or 3- to 10-membered heterocycloalkyl ring is optionally substituted with 1, 2, or 3 R9; R5 is NHR8,NHS(0)2R8, OR8, SR8, S(0)2R8, or S(0)2NHR8; or R5, R4a, and R4b, together with the carbon atom to which they are attached, form a G- Cioaryl or 5- to 10-membered heteroaryl ring; wherein the G- oaryl or 5- to 10- membered heteroaryl ring is optionally substituted with 1, 2, or 3 R9;
R6a is hydrogen, halogen, -U, or -G;
R6b is halogen, -U, or -G;
-U is G-Galkyl. G-Ghaloalkyl. Ci-Cealkoxy, Ci-Ceheteroalkyl, G-Galkcnyl. or C2-
Galkynyl: wherein each G-Galkyl. Ci-Cehaloalkyl, Ci-Cealkoxy, Ci-Ceheteroalkyl, C2- Galkcnyl. or G-Galkynyl is optionally substituted with 1, 2, or 3 R9 and/or 1 or 2 -G;
-G is C3-Ciocycloalkyl, 3- to 10-membered heterocycloalkyl, G-Goaryl. or 5- to 10- membered heteroaryl; wherein each C3-Ciocycloalkyl, 3- to 10-membered heterocycloalkyl, G-Goaryl. or 5- to 10-membered heteroaryl is optionally substituted with 1, 2, or 3 R9; or R6a and R6b together with the carbon atom to which they are attached form a saturated or partially saturated 3- to 7-membered cycloalkyl or a saturated or partially saturated 3- to 7-membered heterocycloalkyl; wherein the cycloalkyl or heterocycloalkyl is optionally substituted with 1, 2, or 3 R9;
R7a is hydrogen, halogen, Ci-C4alkyl, or Ci-Cthaloalkyl;
R715 is hydrogen, halogen, Ci-C4alkyl, or Ci-C4haloalkyl; or R7a and R7b together with the carbon atom to which they are attached form a saturated or partially saturated 3- to 7-membered cycloalkyl or a saturated or partially saturated 3- to 7-membered heterocycloalkyl; wherein the cycloalkyl or heterocycloalkyl is optionally substituted with 1, 2, or 3 R9; or R6b and R715 together with the carbon atoms to which they are attached form a C3-
Ciocycloalkyl or 3- to 10-membered heterocycloalkyl ring; wherein each C3-Ciocycloalkyl or 3- to 10-membered heterocycloalkyl ring is optionally substituted with 1, 2, or 3 R9; or R6a, R6b, R7a, and R7b together with the carbon atoms to which they are attached form a 5 - to 10-membered heteroaryl ring optionally substituted with 1, 2, or 3 R9;
R8 is Z, G-Galkyl. (Ci-C6alkylene)-Z, (Ci-C6heteroalkylene)-Z, (C2-C6alkenylene)-Z,
CH(Z)2, CH2CH(Z)2, CH(Ci-Ci,alkyl)Z. or C(0)Z; wherein each alkyl, alkylene, heteroalkylene, or alkenylene is optionally substituted with 1, 2, or 3 R9;
Z is C3-C9cycloalkyl, 3- to 10-membered heterocycloalkyl, G-Goaryl. 5- to 10-membered heteroaryl; wherein each C3-C9cycloalkyl, 3- to 10-membered heterocycloalkyl, G- Cioaryl, 5- to 10-membered heteroaryl is optionally substituted with 1, 2, or 3 R9; or Z is a substituted Ciocycloalkyl substituted with 1, 2, or 3 R9; and each R9 is independently halogen, Ci-C4alkyl, C2-C4alkenyl, C2-C4alkynyl, Ci-C4haloalkyl, Ci-C4alkoxy, Ci-C4haloalkoxy, Ci-C4heteroalkyl, -C(0)H, -C(0)0H, -CN, C3- Ciocycloalkyl, 3- to 10-membered heterocycloalkyl, Ce-Cioaryl, 5- to 10-membered heteroaryl, -C(0)(Ci-C4alkyl), -C(0)0(Ci-C4alkyl), -C(0)NH2, -C(0)NH(Ci-C4alkyl), - C(0)N(Ci-C4alkyl)2, -NH2, -NH(Ci-C4alkyl), -N(Ci-C4alkyl)2, -NH(C2-C4alkylene)-OH, -NH(C2-C4alkylene)-0-(Ci-C4alkyl), -OH, -0(Ci-C4alkyl), -0(Ci-C4haloalkyl), -0(C2- C4alkylene)-NH2, -0(C2-C4alkylene)-NH-(Ci-C4alkyl), -0(C2-C4alkylene)-N-(Ci- C4alkyl)2, -0(Ci-C4alkylene)-C(0)OH, -0(Ci-C4alkylene)-C(0)0-(Ci-C4alkyl), -0(C2- C4alkenyl), -0(Ci-C4alkylene)-(C6-Cioaryl), -0(Ci-C4alkylene)-(5- to 10-membered heteroaryl), -O(C6-Ci0aryl), -SH, S(0)2OH, -S(0)2(Ci-C4alkyl), -S(0)2NH2, - S(0)2NH(Ci-C4alkyl), or -S(0)2N(Ci-C4alkyl)2; or two R9 together with the atoms to which they are attached form a C3-Ciocycloalkyl or a 3- to 10-membered heterocycloalkyl ring.
81. The compound of claim 80, or pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, wherein R5, R4a and R4b together with the carbon atom to which they are attached form a G,-Cioaryl or 5- to 10-membered heteroaryl ring; wherein the Ce-Cioaryl or 5- to 10-membered heteroaryl ring is optionally substituted with 1, 2, or 3 R9.
82. The compound of claim 80 or 81, or pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, wherein R5, R4a and R4b together with the carbon atom to which they are attached form a 9-membered heteroaryl ring.
83. The compound of claim 80, or pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, wherein R5 is NHR8.
84. The compound of any one of claims 80 or 83, or pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, having the structure of Formula
(C-II):
Figure imgf000183_0001
Formula (C-II).
85. The compound of claim 80 or 83 or 84, or pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, wherein R4a and R4b are both H.
86. The compound of any one of claims 80 or 83 or 84, or pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, wherein R4a and R4b together with the carbon atom to which they are attached form a carbonyl.
87. The compound of any one of claims 80-86, or pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, wherein R1 is hydrogen.
88. The compound of any one of claims 80 or 83 or 84 or 86 or 87, or pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, having the structure of Formula (C-III):
Figure imgf000184_0001
Formula (C-III).
89. The compound of any one of claims 80-88, or pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, wherein R2a and R2b are each hydrogen.
90. The compound of any one of claims 80-88, or pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, wherein R2a and R2b together with the atom to which they are attached form a carbonyl.
91. The compound of any one of claims 80-90, or pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, wherein R3a and R3b are each hydrogen.
92. The compound of any one of claims 80-90, or pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, wherein R2a and R3a together with the carbon atoms to which they are attached form a CVG, cycloalkyl.
93. The compound of any one of claims 80-92, pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, wherein X is O.
94. The compound of any one of claims 80-92, or pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, wherein X is S or S(0)2.
95. The compound of any one of claims 80-92, or pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, wherein X is S.
96. The compound of any one of claims 80-92, or pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, wherein X is S(0)2.
97. The compound of any one of claims 80-92, or pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, wherein X is NRA.
98. The compound of any one of claims 80-92, or pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, wherein X is C and taken together with R2a, R2b, and the carbon atom to which they are attached, forms a phenyl or 5- to 10- membered heteroaryl ring, optionally substituted with 1, 2, or 3 R9.
99. The compound of any one of claims 80-98, or pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, having the structure of Formula (C-IV-a), (C-IV-b), (C-IV-c), or (C-IV-d):
Figure imgf000185_0001
Formula (C-IV-c) Formula (C-IV-d).
100. The compound of any one of claims 80-99, or pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, wherein R6a, R6b, R7a, and R715 together with the carbon atoms to which they are attached form a 5 - to 10-membered heteroaryl ring optionally substituted with 1, 2, or 3 R9.
101. The compound of any one of claims 80-100, or pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, wherein R6a, R6b, R7a, and R715 together with the carbon atoms to which they are attached form a pyridine ring.
102. The compound of any one of claims 80-101, or pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, wherein R7a and R715 are each hydrogen.
103. The compound of any one of claims 80-99, or pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, wherein R6a and R6b together with the carbon atom to which they are attached form a saturated or partially saturated 3- to 7- membered cycloalkyl ring optionally substituted with 1, 2, or 3 R9.
104. The compound of any one of claims 80-99 or 103, or pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, wherein R6a and R6b together with the carbon atom to which they are attached form a saturated or partially saturated 3- to 5-membered cycloalkyl ring.
105. The compound of any one of claims 80-99, or pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, wherein R6a is hydrogen.
106. The compound of any one of claims 80-99 or 105, or pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, wherein R6b is halogen, CrG, alkyl. Ci-G,haloalkyl. G-Galkenyl, or G-Galkynyl: wherein each G-Galkyl. G- Ghaloalkyl. G-Galkenyl. or G-Galkynyl is optionally substituted with 1, 2, or 3 R9 and/or 1 or 2, G.
107. The compound of any one of claims 80-99 or 105 or 106, or pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof wherein R6b is methyl, ethyl, 2-propenyl, isopropyl, orphenethyl.
108. The compound of any one of claims 80-99 or 105-107, or pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, wherein R6b is methyl.
109. The compound of any one of claims 80-99, or pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, wherein R6a and R6b are each independently halogen, G-Galkyl. G-Ghaloalkyl. G-Galkenyl. or G-Galkynyl: wherein each G-Galkyl. G-G,haloalkyl. G-Galkenyl. or G-Galkynyl is optionally substituted with 1, 2, or 3 R9 and/or 1 or 2 G.
110. The compound of any one of claims 80-99, or pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, wherein R6a and R6b are each independently halogen, C2-Galkyl, G-Ghaloalkyl. G-Galkenyl. or C2-Galkynyl: wherein each G-Galkyl. Ci-Cehaloalkyl, G-G, alkenyl. or C2-Galkynyl is optionally substituted with 1, 2, or 3 R9 and/or 1 or 2 G.
111. The compound of any one of claims 80-99, or pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof wherein R6a and R6b are each independently methyl, ethyl, 2-propenyl, isopropyl, or phenethyl.
112. The compound of any one of claims 80-99, or pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof wherein R6a and R6b are each independently ethyl, 2-propenyl, isopropyl, or phenethyl.
113. The compound of any one of claims 80-99, or pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, wherein R6aand R6b are methyl.
114. The compound of any one of claims 80-113, or pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, wherein R8 is Z or CH(Z)2.
115. The compound of any one of claims 80-114, or pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, wherein R8 is Z.
116. The compound of any one of claims 80-115, or pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, wherein Z is C3-C9cycloalkyl or 3- to 10-membered heterocycloalkyl; wherein each C3-Cgcycloalkyl and 3- to 10-membered heterocycloalkyl is optionally substituted with 1, 2, or 3 R9.
117. The compound of any one of claims 80-115, or pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, wherein Z is Ciocycloalkyl substituted with 1, 2, or 3 R9.
118. The compound of any one of claims 80-117, or pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, wherein R8is:
Figure imgf000187_0001
119. The compound of any one of claims 80-118, or pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, wherein R8is:
Figure imgf000187_0002
120 The compound of any one of claims 1 or 43 or 80, or pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, having the structure:
Figure imgf000189_0001
Figure imgf000190_0001
121. A compound or pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, having the structure:
Figure imgf000191_0001
122. A pharmaceutical composition comprising a compound of any one of claims 1-121, or pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, and a pharmaceutically acceptable carrier.
123. A pharmaceutical composition comprising a selective melanoma inhibitor of apoptosis protein (ML-IAP) antagonist, at least one additional therapeutic agent used to treat cancer, and at least one excipient or carrier.
124. A method of treating cancer in an individual in need thereof comprising administering a therapeutically effective amount of a melanoma inhibitor of apoptosis proteins (ML-IAP) antagonist.
125. The method of claim 124, wherein the ML-IAP antagonist is selective for ML-IAP over other inhibitors of apoptosis proteins (IAPs).
126. A method for treating a disease or condition associated with the overexpression of ML-IAP in an individual, comprising administering a therapeutically effective amount of a compound of any one of claims 1-121, or pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, to the individual.
127. The method of claim 126, wherein the disease or condition is cancer.
128. A method of inhibiting melanoma inhibitor of apoptosis protein (ML-IAP) with a compound of any one of claims 1-121.
129. A method of treating cancer in an individual in need thereof comprising administering a therapeutically effective amount of a compound of any one of claims 1-121, or pharmaceutically acceptable salt, A-oxidc. racemate, or stereoisomer thereof, to the individual.
130. The method of any one of claims 124 or 125 or 127-129, wherein the cancer is a lung cancer.
131. The method of any one of claims 124 or 125 or 127-130, wherein the cancer is chemo- resistant.
132. The method of any one of claims 124 or 125 or 127-131, wherein the cancer is sensitized to chemotherapy.
133. The method of any one of claims 124 or 125 or 127-132, wherein the cancer is non-small cell lung cancer, adenocarcinoma, squamous cell carcinoma, adenosquamous carcinoma, sarcomatoid carcinoma, large cell carcinoma, or small cell lung cancer.
134. The method of any one of claims 124 or 125 or 127-133, wherein the cancer is non-small cell lung cancer.
135. The method of claim 133 or 134, wherein the non-small cell lung cancer is chemo-resistant.
136. The method of any one of claims 124-135 further comprising administering an additional therapeutic agent.
137. The method of claim 136, wherein the additional therapeutic agent is surgery, radiation therapy, chemotherapy, targeted therapy, immunotherapy, adjuvant therapy, anti-angiogenesis therapy, or pain therapy.
138. The method of claim 136 or 137, wherein the additional therapeutic agent is carboplatin, cisplatin, docetaxel, gemcitabine, nab-paclitaxel, paclitaxel, pemetrexed, vinorelbine, bevacizumab, ramucirumab, afatinib, dacomitinib, erlotinib, gefitinib, necitumumab, osimertinib, atezolizumab, durvalumab, nivolumab, pembrolizumab.
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