WO2014085489A1 - Inhibitor of apoptosis protein (iap) antagonists - Google Patents

Inhibitor of apoptosis protein (iap) antagonists Download PDF

Info

Publication number
WO2014085489A1
WO2014085489A1 PCT/US2013/072064 US2013072064W WO2014085489A1 WO 2014085489 A1 WO2014085489 A1 WO 2014085489A1 US 2013072064 W US2013072064 W US 2013072064W WO 2014085489 A1 WO2014085489 A1 WO 2014085489A1
Authority
WO
WIPO (PCT)
Prior art keywords
substituted
unsubstituted
alkyl
formula
heteroaryl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2013/072064
Other languages
English (en)
French (fr)
Inventor
Nicholas David Peter COSFORD
Mitchell Dennis VAMOS
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sanford Burnham Prebys Medical Discovery Institute
Original Assignee
Sanford Burnham Prebys Medical Discovery Institute
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Sanford Burnham Prebys Medical Discovery Institute filed Critical Sanford Burnham Prebys Medical Discovery Institute
Priority to US14/648,435 priority Critical patent/US9546174B2/en
Priority to EP13859485.8A priority patent/EP2925764B1/en
Priority to JP2015545193A priority patent/JP6382831B2/ja
Priority to CA2896577A priority patent/CA2896577C/en
Publication of WO2014085489A1 publication Critical patent/WO2014085489A1/en
Anticipated expiration legal-status Critical
Priority to US15/363,935 priority patent/US10047119B2/en
Priority to US16/031,837 priority patent/US10544188B2/en
Priority to US16/740,240 priority patent/US11111270B2/en
Priority to US17/389,171 priority patent/US11912786B2/en
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0802—Tripeptides with the first amino acid being neutral
    • C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
    • C07K5/0806—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atoms, i.e. Gly, Ala
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/04—Drugs for disorders of the muscular or neuromuscular system for myasthenia gravis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/02—Nutrients, e.g. vitamins, minerals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/14—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/06—Antianaemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • 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
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/10—Spiro-condensed systems
    • 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
    • A61K38/00—Medicinal preparations containing peptides
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

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 proteins (IAPs).
  • 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.
  • W 1 is O, S, N-R A , or C(R 8a )(R 8b );
  • W 2 is O, S, N-R A , or C(R 8c )(R 8d ); provided that W 1 and W 2 are not both O, or both S;
  • R 1 is H, Ci-C 6 alkyl, C 3 -C 6 cycloalkyl, -Ci-C 6 alkyl-(substituted or unsubstituted C 3 -C 6 cycloalkyl), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -Ci-Cealkyl- (substituted or unsubstituted aryl), or -Ci-C 6 alkyl-(substituted or unsubstituted heteroaryl); when X 1 is O, N-R A , S, S(O), or S(0) 2 , then X 2 is C(R 2a R 2b );
  • X 1 is CR 2c R 2d and X 2 is CR 2a R 2b , and R 2c and R 2a together form a bond;
  • X 1 and X 2 are independently selected from C and N, and are members of a fused substituted or unsubstituted saturated or partially saturated 3-10 membered cycloalkyl ring, a fused substituted or unsubstituted saturated or partially saturated 3-10 membered heterocycloalkyl ring, a fused substituted or unsubstituted 5-10 membered aryl ring, or a fused substituted or unsubstituted 5-10 membered heteroaryl ring;
  • R A is H, C r C 6 alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
  • R 2a , R 2b , R 2c , R 2d are independently selected from H, substituted or unsubstituted C r C 6 alkyl, substituted or unsubstituted Ci-Ceheteroalkyl, substituted or unsubstituted C3-C 6 cycloalkyl, substituted or unsubstituted C 2 -C 5 heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -Ci-C 6 alkyl-(substituted or unsubstituted C3- C 6 cycloalkyl), -Ci-C 6 alkyl-(substituted or unsubstituted C 2 -C 5 heterocycloalkyl), -Ci-C 6 alkyl- (substituted or unsubstituted aryl), -Ci-C 6 alkyl-(substituted or unsubstit
  • R B is substituted or unsubstituted CpCealkyl, substituted or unsubstituted C3-C 6 cycloalkyl,
  • R D and R E are independently selected from H, substituted or unsubstituted Ci-C 6 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 2 -C 5 heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -Ci-C 6 alkyl- (substituted or unsubstituted C 3 -C 6 cycloalkyl), -Ci-C 6 alkyl-(substituted or unsubstituted C 2 - C 5 heterocycloalkyl), -Ci-C 6 alkyl-(substituted or unsubstituted aryl), or -C r C 6 alkyl- (substituted or unsubstituted heteroaryl);
  • n 0, 1 or 2;
  • R 3 is C r C 3 alkyl, or Ci-C 3 fluoroalkyl
  • R 4 is -NHR 5 , -N(R 5 ) 2 , -N + (R 5 ) 3 or -OR 5 ;
  • each R 5 is independently selected from H, C r C 3 alkyl, Ci-C 3 haloalkyl, C r C 3 heteroalkyl and -C r C 3 alkyl-(C 3 -C 5 cycloalkyl); R 3 and R 5 together with the atoms to which they are attached form a substituted or unsubstituted 5-7 membered ring;
  • R 3 is bonded to a nitrogen atom of U to form a substituted or unsubstituted 5-7 membered ring;
  • each R 7 is independently selected from C r C 6 alkyl, Ci-C 6 haloalkyl, C r C 6 heteroalkyl, a
  • substituted or unsubstituted C 3 -Ci 0 cycloalkyl a substituted or unsubstituted C 2 - Cioheterocycloalkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, -Ci-C 6 alkyl-(substituted or unsubstituted C 3 -Ci 0 cycloalkyl), -Ci-C 6 alkyl- (substituted or unsubstituted C 2 -Cioheterocycloalkyl, -Ci-C 6 alkyl-(substituted or unsubstituted aryl), -Ci-C 6 alkyl-(substituted or unsubstituted heteroaryl), -(CH 2 ) p -CH(substituted or unsubstituted aryl) 2 , -(CH 2 )
  • p 0, 1 or 2;
  • R 8a , R 8b , R 8c , and R 8d are independently selected from H, C r C 6 alkyl, C r C 6 fluoroalkyl, C r C 6 alkoxy, Ci-C 6 heteroalkyl, and substituted or unsubstituted aryl;
  • R 8a and R 8d are as defined above, and R 8b and R 8c together form a bond;
  • R 8a and R 8d are as defined above, and R 8b and R 8c together with the atoms to which they are
  • R 8c and R 8d are as defined above, and R 8a and R 8b together with the atoms to which they are attached form a substituted or unsubstituted saturated, or partially saturated 3 -7 membered spirocycle or heterospirocycle comprising 1 -3 heteroatoms selected from S, O and N;
  • R 8a and R 8b are as defined above, and R 8c and R 8d together with the atoms to which they are
  • W 2 is O, S, or C(R 8c )(R 8d );
  • R 1 is H, or C r C 6 alkyl
  • X 1 is O, N-R A , S, S(O), or S(0) 2 ;
  • R A is H, C r C 6 alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
  • R B is substituted or unsubstituted Ci-C 6 alkyl, -Ci-C 6 alkyl-(substituted or unsubstituted C 3 -
  • R D and R E are independently selected from H, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted C3-C 6 cycloalkyl, substituted or unsubstituted C 2 -C 5 heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -Ci-Cealkyl- (substituted or unsubstituted C 3 -C 6 cycloalkyl), -Ci-C 6 alkyl
  • R 3 is C r C 3 alkyl, or C r C 3 fluoroalkyl
  • each R 5 is independently selected from H, C r C 3 alkyl, C r C 3 haloalkyl, C r C 3 heteroalkyl and -C r C 3 alkyl-(C 3 -C 5 cycloalkyl);
  • each R 7 is independently selected from C r C 6 alkyl, Ci-C 6 haloalkyl, C r C 6 heteroalkyl, a
  • substituted or unsubstituted C 3 -Ci 0 cycloalkyl a substituted or unsubstituted C 2 - Cioheterocycloalkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, -Ci-C 6 alkyl-(substituted or unsubstituted C 3 -Ci 0 cycloalkyl), -Ci-C 6 alkyl- (substituted or unsubstituted C 2 -Cioheterocycloalkyl, -Ci-C 6 alkyl-(substituted or unsubstituted aryl), -Ci-C 6 alkyl-(substituted or unsubstituted heteroaryl), -(CH 2 ) p -CH(substituted or unsubstituted aryl) 2 , -(CH 2 )
  • p 0, 1 or 2;
  • R 8a and R 8b are independently selected from H, C r C 6 alkyl, and Ci-C 6 fluoroalkyl;
  • R 8c and R 8d are independently selected from H, C r C 6 alkyl, and Ci-C 6 fluoroalkyl;
  • X 1 when X 1 is O, then X 2 is selected from CR 2c R 2d and N-R A , and X 3 is CR 2a R 2b ;
  • X 1 is CH 2
  • X 2 is selected from O, N-R A , S, S(O), and S(0) 2
  • X 3 is CR 2a R 2b ;
  • X 1 is CR 2e R 2f and X 2 is CR 2c R 2d , and R 2e and R 2c together form a bond, and X 3 is CR 2a R 2b ;
  • X 1 and X 2 are independently selected from C and N, and are members of a fused substituted or unsubstituted saturated or partially saturated 3-10 membered cycloalkyl ring, a fused substituted or unsubstituted saturated or partially saturated 3-10 membered heterocycloalkyl ring, a fused substituted or unsubstituted 5-10 membered aryl ring, or a fused substituted or unsubstituted 5-10 membered heteroaryl ring, and X 3 is CR 2a R 2b ;
  • X 2 and X 3 are independently selected from C and N, and are members of a fused substituted or unsubstituted saturated or partially saturated 3-10 membered cycloalkyl ring, a fused substituted or unsubstituted saturated or partially saturated 3-10 membered heterocycloalkyl ring, a fused substituted or unsubstituted 5-10 membered aryl ring, or a fused substituted or unsubstituted 5-10 membered heteroaryl ring, and X 1 is CR 2e R 2f ;
  • R A is H, Ci-C 6 alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
  • W 1 is O, S, N-R A , or C(R 8a )(R 8b );
  • W 2 is O, S, N-R A , or C(R 8c )(R 8d ); provided that W 1 and W 2 are not both O, or both S;
  • R 2a , R 2b , R 2c , R 2d R 2e , and R 2f are independently selected from H, substituted or unsubstituted C r C 6 alkyl, substituted or unsubstituted Ci-C 6 heteroalkyl, substituted or unsubstituted C 3 - C 6 cycloalkyl, substituted or unsubstituted C 2 -C 5 heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -Ci-C 6 alkyl-(substituted or unsubstituted C 3 - C 6 cycloalkyl), -Ci-C 6 alkyl-(substituted or unsubstituted C 2 -C 5 heterocycloalkyl), -C r C 6 alkyl- (substituted or unsubstituted aryl), -Ci-C 6 alkyl-(sub
  • R B is substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted C3-C 6 cycloalkyl,
  • R D and R E are independently selected from H, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted C3-C 6 cycloalkyl, substituted or unsubstituted C 2 -C 5 heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -Ci-C 6 alkyl- (substituted or unsubstituted C 3 -C 6 cycloalkyl), -Ci-C 6 alkyl-(substituted or unsubstituted C 2 - C 5 heterocycloalkyl), -Ci-C 6 alkyl-(substituted or unsubstituted aryl), or -C r C 6 alkyl- (substituted or unsubstituted heteroaryl);
  • n 0, 1 or 2;
  • R 3 is C r C 3 alkyl, or C r C 3 fluoroalkyl
  • R 4 is -NHR 5 , -N(R 5 ) 2 , -N + (R 5 ) 3 or -OR 5 ;
  • each R 5 is independently selected from H, Ci-C 3 alkyl, Ci-C 3 haloalkyl, Ci-C 3 heteroalkyl and -Cp C 3 alkyl-(C 3 -C 5 cycloalkyl);
  • R 3 and R 5 together with the atoms to which they are attached form a substituted or unsubstituted 5-7 membered ring;
  • R 3 is bonded to a nitrogen atom of U to form a substituted or unsubstituted 5-7 membered ring;
  • each R 7 is independently selected from Ci-C 6 alkyl, Ci-C 6 haloalkyl, Ci-C 6 heteroalkyl, a
  • substituted or unsubstituted C 3 -Ci 0 cycloalkyl a substituted or unsubstituted C 2 - Cioheterocycloalkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, -Ci-C 6 alkyl-(substituted or unsubstituted C 3 -Ci 0 cycloalkyl), -Ci-C 6 alkyl- (substituted or unsubstituted C 2 -Ci 0 heterocycloalkyl, -Ci-C 6 alkyl-(substituted or unsubstituted aryl), -Ci-C 6 alkyl-(substituted or unsubstituted heteroaryl), -(CH 2 ) p -CH(substituted or unsubstituted aryl) 2 , -(CH 2 ) p
  • p 0, 1 or 2;
  • R 8a , R 8b , R 8c , and R 8d are independently selected from H, C C 6 alkyl, Ci-C 6 fluoroalkyl, C C 6 alkoxy, Ci-Ceheteroalkyl, and substituted or unsubstituted aryl;
  • R 8a and R 8d are as defined above, and R 8b and R 8c together form a bond;
  • R 8a and R 8d are as defined above, and R 8b and R 8c together with the atoms to which they are
  • R 8c and R 8d are as defined above, and R 8a and R 8b together with the atoms to which they are
  • R 8a and R 8b are as defined above, and R 8c and R 8d together with the atoms to which they are
  • W 2 is O, S, or C(R 8c )(R 8d );
  • R 1 is H, or C r C 6 alkyl
  • X 1 is O, N-R A , S, S(O), or S(0) 2 ;
  • R A is H, Ci-C 6 alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
  • R B is substituted or unsubstituted CpCealkyl, -Ci-C 6 alkyl-(substituted or unsubstituted C 3 -
  • C 6 cycloalkyl C 6 cycloalkyl
  • -Ci-C 6 alkyl-(substituted or unsubstituted heteroaryl) or - NR D R E ;
  • R D and R E are independently selected from H, substituted or unsubstituted CpCealkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 2 -C 5 heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -Ci-C 6 alkyl- (substituted or unsubstituted C 3 -C 6 cycloalkyl), -Ci-C 6 alkyl-(substituted or unsubstituted C 2 - C 5 heterocycloalkyl), -Ci-C 6 alkyl-(substituted or unsubstituted aryl), or -Ci-C 6 alkyl- (substituted or unsubstituted heteroaryl);
  • R 3 is Ci-C 3 alkyl, or C C 3 fluoroalkyl; each R 5 is independently selected from H, Ci-C 3 alkyl, Ci-C 3 haloalkyl, Ci-C 3 heteroalkyl and -Cp C 3 alkyl-(C 3 -C 5 cycloalkyl);
  • each R 7 is independently selected from Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Ceheteroalkyl, a
  • substituted or unsubstituted C 3 -Ci 0 cycloalkyl a substituted or unsubstituted C 2 - Cioheterocycloalkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, -Ci-C 6 alkyl-(substituted or unsubstituted C 3 -Ci 0 cycloalkyl), -Ci-C 6 alkyl- (substituted or unsubstituted C 2 -Ci 0 heterocycloalkyl, -Ci-C 6 alkyl-(substituted or unsubstituted aryl), -Ci-C 6 alkyl-(substituted or unsubstituted heteroaryl), -(CH 2 ) p -CH(substituted or unsubstituted aryl) 2 , -(CH 2 ) p
  • p 0, 1 or 2;
  • R 8a and R 8b are independently selected from H, Ci-Cealkyl, and Ci-Cefluoroalkyl;
  • R 8c and R 8d are independently selected from H, Ci-Cealkyl, and Ci-Cefluoroalkyl;
  • R 1 is H, Ci-Cealkyl, C3-C 6 cycloalkyl, -Ci-C 6 alkyl-(substituted or unsubstituted C3-C 6 cycloalkyl), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -Ci-Cealkyl- (substituted or unsubstituted aryl), -Ci-C 6 alkyl-(substituted or unsubstituted heteroaryl); when X 1 is selected from N-R A , S, S(O) and S(0) 2 , then X 2 is CR 2c R 2d , and X 3 is CR 2a R 2b ;
  • X 1 when X 1 is O, then X 2 is selected from CR 2c R 2d and N-R A , and X 3 is CR 2a R 2b ;
  • X 1 is CH 2
  • X 2 is selected from O, N-R A , S, S(O), and S(0) 2
  • X 3 is CR 2a R 2b ;
  • X 1 is CR 2e R 2f and X 2 is CR 2c R 2d , and R 2e and R 2c together form a bond, and X 3 is CR 2a R 2b ;
  • X 1 and X 2 are independently selected from C and N, and are members of a fused substituted or unsubstituted saturated or partially saturated 3-10 membered cycloalkyl ring, a fused substituted or unsubstituted saturated or partially saturated 3-10 membered heterocycloalkyl ring, a fused substituted or unsubstituted 5-10 membered aryl ring, or a fused substituted or unsubstituted 5-10 membered heteroaryl ring, and X 3 is CR 2a R 2b ;
  • X 2 and X 3 are independently selected from C and N, and are members of a fused substituted or unsubstituted saturated or partially saturated 3-10 membered cycloalkyl ring, a fused substituted or unsubstituted saturated or partially saturated 3-10 membered heterocycloalkyl ring, a fused substituted or unsubstituted 5-10 membered aryl ring, or a fused substituted or unsubstituted 5-10 membered heteroaryl ring, and X 1 is CR 2e R 2f ;
  • R A is H, Ci-C 6 alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
  • W 1 is O, S, N-R A , or C(R 8a )(R 8b );
  • W 2 is O, S, N-R A , or C(R 8c )(R 8d ); provided that W 1 and W 2 are not both O, or both S;
  • R 2a , R 2b , R 2c , R 2d R 2e , and R 2f are independently selected from H, substituted or unsubstituted C r C 6 alkyl, substituted or unsubstituted Ci-C 6 heteroalkyl, substituted or unsubstituted C 3 - C 6 cycloalkyl, substituted or unsubstituted C 2 -C 5 heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -Ci-C 6 alkyl-(substituted or unsubstituted C 3 - Cecycloalkyl), -Ci-C 6 alkyl-(substituted or unsubstituted C 2 -C 5 heterocycloalkyl), -Ci-Cealkyl- (substituted or unsubstituted aryl), -Ci-C 6 alkyl-(substit
  • R B is substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted C3-C 6 cycloalkyl,
  • R D and R E are independently selected from H, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 2 -C 5 heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -Ci-C 6 alkyl- (substituted or unsubstituted C 3 -C 6 cycloalkyl), -Ci-C 6 alkyl-(substituted or unsubstituted C 2 - C 5 heterocycloalkyl), -Ci-C 6 alkyl-(substituted or unsubstituted aryl), or -C r C 6 alkyl- (substituted or unsubstituted heteroaryl);
  • n 0, 1 or 2;
  • R 3 is C r C 3 alkyl, or C r C 3 fluoroalkyl
  • R 4 is -NHR 5 , -N(R 5 ) 2 , -N + (R 5 ) 3 or -OR 5 ;
  • each R 5 is independently selected from H, Ci-C 3 alkyl, Ci-C 3 haloalkyl, Ci-C 3 heteroalkyl and -Cp C 3 alkyl-(C 3 -C 5 cycloalkyl);
  • R 3 and R 5 together with the atoms to which they are attached form a substituted or unsubstituted 5-7 membered ring;
  • R 3 is bonded to a nitrogen atom of U to form a substituted or unsubstituted 5-7 membered ring;
  • each R 7 is independently selected from C r C 6 alkyl, Ci-C 6 haloalkyl, C r C 6 heteroalkyl, a
  • substituted or unsubstituted C 3 -Ci 0 cycloalkyl a substituted or unsubstituted C 2 - Cioheterocycloalkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, -Ci-C 6 alkyl-(substituted or unsubstituted C 3 -Ci 0 cycloalkyl), -C r C 6 alkyl- (substituted or unsubstituted C 2 -Ci 0 heterocycloalkyl, -Ci-C 6 alkyl-(substituted or unsubstituted aryl), -Ci-C 6 alkyl-(substituted or unsubstituted heteroaryl), -(CH 2 ) p -CH(substituted or unsubstituted aryl) 2 , -(CH 2 ) p
  • R 8a , R 8b , R 8c , and R 8d are independently selected from H, C C 6 alkyl, Ci-C 6 fluoroalkyl, C C 6 alkoxy, Ci-Ceheteroalkyl, and substituted or unsubstituted aryl;
  • R 8a and R 8d are as defined above, and R 8b and R 8c together form a bond;
  • R 8a and R 8d are as defined above, and R 8b and R 8c together with the atoms to which they are
  • R 8c and R 8d are as defined above, and R 8a and R 8b together with the atoms to which they are
  • R 8a and R 8b are as defined above, and R 8c and R 8d together with the atoms to which they are
  • W 2 is O, S, or C(R 8c )(R 8d );
  • R 1 is H, or Ci-Qalkyl
  • X 1 is O, N-R A , S, S(O), or S(0) 2 ;
  • R A is H, Ci-C 6 alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
  • R B is substituted or unsubstituted Ci-C 6 alkyl, -Ci-C 6 alkyl-(substituted or unsubstituted C 3 -
  • R D and R E are independently selected from H, substituted or unsubstituted Ci-C 6 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 2 -C 5 heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -Ci-Cealkyl- (substituted or unsubstituted C3-C 6 cycloalkyl), -Ci-C 6 alkyl-(substituted or unsubstituted C 2 - C 5 heterocycloalkyl), -Ci-C 6 alkyl-(substituted or unsubstituted aryl), or -Ci-C 6 alkyl- (substituted or unsubstituted heteroaryl);
  • R 3 is C r C 3 alkyl, or Ci-C 3 fluoroalkyl
  • each R 5 is independently selected from H, Ci-C 3 alkyl, Ci-C 3 haloalkyl, Ci-C 3 heteroalkyl and -Cp C 3 alkyl-(C 3 -C 5 cycloalkyl);
  • each R 7 is independently selected from Ci-C 6 alkyl, Ci-C 6 haloalkyl, Ci-C 6 heteroalkyl, a
  • Cioheterocycloalkyl a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, -Ci-C 6 alkyl-(substituted or unsubstituted C 3 -Ci 0 cycloalkyl), -C r C 6 alkyl-
  • p 0, 1 or 2;
  • R 8a and R 8b are independently selected from H, C r C 6 alkyl, and Ci-C 6 fluoroalkyl;
  • R 8c and R 8d are independently selected from H, C r C 6 alkyl, and Ci-C 6 fluoroalkyl;
  • R 1 is H, C r C 6 alkyl, C 3 -C 6 cycloalkyl, -Ci-C 6 alkyl-(substituted or unsubstituted C 3 -C 6 cycloalkyl), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -Ci-C 6 alkyl- (substituted or unsubstituted aryl), -Ci-C 6 alkyl-(substituted or unsubstituted heteroaryl); when X 1 is selected from N-R A , S, S(O) and S(0) 2 , then X 2 is CR 2c R 2d , and X 3 is CR 2a R 2b ;
  • X 1 when X 1 is O, then X 2 is selected from CR 2c R 2d and N-R A , and X 3 is CR 2a R 2b ;
  • X 1 is CH 2
  • X 2 is selected from O, N-R A , S, S(O), and S(0) 2
  • X 3 is CR 2a R 2b ;
  • X 1 is CR 2e R 2f and X 2 is CR 2c R 2d , and R 2e and R 2c together form a bond, and X 3 is CR 2a R 2b ;
  • X 1 and X 2 are independently selected from C and N, and are members of a fused substituted or unsubstituted saturated or partially saturated 3-10 membered cycloalkyl ring, a fused substituted or unsubstituted saturated or partially saturated 3-10 membered heterocycloalkyl ring, a fused substituted or unsubstituted 5-10 membered aryl ring, or a fused substituted or unsubstituted 5-10 membered heteroaryl ring, and X 3 is CR 2a R 2b ;
  • X 2 and X 3 are independently selected from C and N, and are members of a fused substituted or unsubstituted saturated or partially saturated 3-10 membered cycloalkyl ring, a fused substituted or unsubstituted saturated or partially saturated 3-10 membered heterocycloalkyl ring, a fused substituted or unsubstituted 5-10 membered aryl ring, or a fused substituted or unsubstituted 5-10 membered heteroaryl ring, and X 1 is CR 2e R 2f ;
  • W 1 is O, S, N-R A , or C(R 8a )(R 8b );
  • W 2 is O, S, N-R A , or C(R 8c )(R 8d );
  • W 3 is O, S, N-R A , or C(R 8e )(R 8f ); provided that the ring comprising W 1 , W 2 and W 3 does not comprise two adjacent oxygen atoms or sulfur atoms;
  • R A is H, C r C 6 alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
  • R 1 is H, C r C 6 alkyl, C 3 -C 6 cycloalkyl, -Ci-C 6 alkyl-(substituted or unsubstituted C 3 -C 6 cycloalkyl), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -Ci-C 6 alkyl- (substituted or unsubstituted aryl), -Ci-C 6 alkyl-(substituted or unsubstituted heteroaryl);
  • R 2a , R 2b , R 2c , R 2d R 2e , and R 2f are independently selected from H, substituted or unsubstituted C r C 6 alkyl, substituted or unsubstituted Ci-C 6 heteroalkyl, substituted or unsubstituted C 3 - Cecycloalkyl, substituted or unsubstituted C 2 -C 5 heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -Ci-C 6 alkyl-(substituted or unsubstituted C 3 - C 6 cycloalkyl), -Ci-C 6 alkyl-(substituted or unsubstituted C 2 -C 5 heterocycloalkyl), -Ci-C 6 alkyl- (substituted or unsubstituted aryl), -Ci-C 6 alkyl-(substit
  • R B is substituted or unsubstituted Ci-C 6 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl,
  • R D and R E are independently selected from H, substituted or unsubstituted Ci-C 6 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 2 -C 5 heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -Ci-C 6 alkyl- (substituted or unsubstituted C 3 -C 6 cycloalkyl), -Ci-C 6 alkyl-(substituted or unsubstituted C 2 - C 5 heterocycloalkyl), -Ci-C 6 alkyl-(substituted or unsubstituted aryl), or -C r C 6 alkyl- (substituted or unsubstituted heteroaryl);
  • n 0, 1 or 2;
  • R 3 is C r C 3 alkyl, or Ci-C 3 fluoroalkyl
  • R 4 is -NHR 5 , -N(R 5 ) 2 , -N + (R 5 ) 3 or -OR 5 ;
  • each R 5 is independently selected from H, Ci-C 3 alkyl, Ci-C 3 haloalkyl, Ci-C 3 heteroalkyl and -Cp C 3 alkyl-(C 3 -C 5 cycloalkyl);
  • R 3 and R 5 together with the atoms to which they are attached form a substituted or unsubstituted 5-7 membered ring;
  • R 3 is bonded to a nitrogen atom of U to form a substituted or unsubstituted 5-7 membered ring;
  • each R 7 is independently selected from C r C 6 alkyl, Ci-C 6 haloalkyl, C r C 6 heteroalkyl, a
  • substituted or unsubstituted C 3 -Ci 0 cycloalkyl a substituted or unsubstituted C 2 - Cioheterocycloalkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, -Ci-C 6 alkyl-(substituted or unsubstituted C 3 -Ci 0 cycloalkyl), -Ci-C 6 alkyl- (substituted or unsubstituted C 2 -Cioheterocycloalkyl, -Ci-C 6 alkyl-(substituted or unsubstituted aryl), -Ci-C 6 alkyl-(substituted or unsubstituted heteroaryl), -(CH 2 ) p -CH(substituted or unsubstituted aryl) 2 , -(CH 2 )
  • p 0, 1 or 2;
  • R 8a , R 8b , R 8c , R 8d , R 8e and R 8f are independently selected from H, C r C 6 alkyl, C r C 6 fluoroalkyl, Ci-C 6 alkoxy, Ci-C 6 heteroalkyl, and substituted or unsubstituted aryl;
  • R 8a , R 8d , R 8e and R 8f are as defined above, and R 8b and R 8c together form a bond;
  • R 8a , R 8b , R 8d , and R 8f are as defined above, and R 8c and R 8e together form a bond;
  • R 8a , R 8d , R 8e and R 8f are as defined above, and R 8b and R 8c together with the atoms to which they are attached form a substituted or unsubstituted fused 5-7 membered saturated, or partially saturated carbocyclic ring or heterocyclic ring comprising 1 -3 heteroatoms selected from S, O and N, a substituted or unsubstituted fused 5-10 membered aryl ring, or a substituted or unsubstituted fused 5-10 membered heteroaryl ring comprising 1 -3 heteroatoms selected from S, O and N;
  • R 8a , R 8b , R 8d , and R 8f are as defined above, and R 8c and R 8e together with the atoms to which they are attached form a substituted or unsubstituted fused 5-7 membered saturated, or partially saturated carbocyclic ring or heterocyclic ring comprising 1 -3 heteroatoms selected from S, O and N, a substituted or unsubstituted fused 5-10 membered aryl ring, or a substituted or unsubstituted fused 5-10 membered heteroaryl ring comprising 1 -3 heteroatoms selected from S, O and N;
  • R 8c , R 8d , R 8e and R 8f are as defined above, and R 8a and R 8b together with the atoms to which they are attached form a substituted or unsubstituted saturated, or partially saturated 3-7 membered spirocycle or heterospirocycle comprising 1 -3 heteroatoms selected from S, O and N;
  • R 8a , R 8b , R 8e and R 8f are as defined above, and R 8c and R 8d together with the atoms to which they are attached form a substituted or unsubstituted saturated, or partially saturated 3-7 membered spirocycle or heterospirocycle comprising 1 -3 heteroatoms selected from S, O and N;
  • R 8a , R 8b , R 8c , and R 8d are as defined above, and R 8e and R 8f together with the atoms to which they are attached form a substituted or unsubstituted saturated, or partially saturated 3-7 membered spirocycle or heterospirocycle comprising 1 -3 heteroatoms selected from S, O and N;
  • W 3 is O, S, or C(R 8e )(R 8f );
  • R 1 is H, or Ci-Qalkyl
  • X 1 is O, N-R A , S, S(O), or S(0) 2 ;
  • R A is H, Ci-Cealkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
  • R 2a and R 2b are independently selected from H, substituted or unsubstituted CpCealkyl, and -
  • R is substituted or unsubstituted Ci-C 6 alkyl, -Ci-C 6 alkyl-(substituted or unsubstituted C 3 -
  • C 6 cycloalkyl C 6 cycloalkyl
  • -Ci-C 6 alkyl-(substituted or unsubstituted heteroaryl) or - NR D R E ;
  • R D and R E are independently selected from H, substituted or unsubstituted Ci-C 6 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 2 -C 5 heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -Ci-C 6 alkyl- (substituted or unsubstituted C 3 -C 6 cycloalkyl), -Ci-C 6 alkyl-(substituted or unsubstituted C 2 - C 5 heterocycloalkyl), -Ci-C 6 alkyl-(substituted or unsubstituted aryl), or -Ci-C 6 alkyl- (substituted or unsubstituted heteroaryl);
  • R 3 is CrQalkyl, or C r C 3 fluoroalkyl
  • each R 5 is independently selected from H, C r C 3 alkyl, C r C 3 haloalkyl, C r C 3 heteroalkyl and -C r C 3 alkyl-(C 3 -C 5 cycloalkyl); each R 7 is independently selected from Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Ceheteroalkyl, a substituted or unsubstituted C3-Ciocycloalkyl, a substituted or unsubstituted C 2 - Cioheterocycloalkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, -Ci-C 6 alkyl-(substituted or unsubstituted C 3 -Ci 0 cycloalkyl), -Ci-C 6 alkyl- (substituted or unsubstituted C 2 -Ci 0 heterocyclo
  • p 0, 1 or 2;
  • R 8a and R 8b are independently selected from H, Ci-Cealkyl and Ci-Cefluoroalkyl;
  • R 8e and R 8f are independently selected from H, Ci-Cealkyl and Ci-Cefluoroalkyl;
  • R 1 is H, Ci-Cealkyl, C3-C 6 cycloalkyl, -Ci-C 6 alkyl-(substituted or unsubstituted C3-C 6 cycloalkyl), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -Ci-Cealkyl- (substituted or unsubstituted aryl), -Ci-C 6 alkyl-(substituted or unsubstituted heteroaryl); when X 1 is selected from N-R A , S, S(O) and S(0) 2 , then X 2 is CR 2c R 2d , and X 3 is CR 2a R 2b ;
  • X 1 when X 1 is O, then X 2 is selected from CR 2c R 2d and N-R A , and X 3 is CR 2a R 2b ;
  • X 1 is CH 2
  • X 2 is selected from O, N-R A , S, S(O), and S(0) 2
  • X 3 is CR 2a R 2b ;
  • X 1 is CR 2e R 2f and X 2 is CR 2c R 2d , and R 2e and R 2c together form a bond, and X 3 is CR 2a R 2b ;
  • X 1 and X 2 are independently selected from C and N, and are members of a fused substituted or unsubstituted saturated or partially saturated 3-10 membered cycloalkyl ring, a fused substituted or unsubstituted saturated or partially saturated 3-10 membered heterocycloalkyl ring, a fused substituted or unsubstituted 5-10 membered aryl ring, or a fused substituted or unsubstituted 5-10 membered heteroaryl ring, and X 3 is CR 2a R 2b ;
  • X 2 and X 3 are independently selected from C and N, and are members of a fused substituted or unsubstituted saturated or partially saturated 3-10 membered cycloalkyl ring, a fused substituted or unsubstituted saturated or partially saturated 3-10 membered heterocycloalkyl ring, a fused substituted or unsubstituted 5-10 membered aryl ring, or a fused substituted or unsubstituted 5-10 membered heteroaryl ring, and X 1 is CR 2e R 2f ;
  • R A is H, Ci-C 6 alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
  • W 1 is O, S, N-R A , or C(R 8a )(R 8b );
  • W 2 is O, S, N-R A , or C(R 8c )(R 8d );
  • W 3 is O, S, N-R A , or C(R 8e )(R 8f ); provided that the ring comprising W 1 , W 2 and W 3 does not comprise two adjacent oxygen atoms or sulfur atoms;
  • R 2a , R 2b , R 2c , R 2d R 2e , and R 2f are independently selected from H, substituted or unsubstituted C r C 6 alkyl, substituted or unsubstituted Ci-C 6 heteroalkyl, substituted or unsubstituted C 3 - Cecycloalkyl, substituted or unsubstituted C 2 -C 5 heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -Ci-C 6 alkyl-(substituted or unsubstituted C3- Cecycloalkyl), -Ci-C 6 alkyl-(substituted or unsubstituted C 2 -C 5 heterocycloalkyl), -Ci-Cealkyl- (substituted or unsubstituted aryl), -Ci-C 6 alkyl-(substituted or
  • R B is substituted or unsubstituted Ci-C 6 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl,
  • R D and R E are independently selected from H, substituted or unsubstituted Ci-C 6 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 2 -C 5 heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -Ci-C 6 alkyl- (substituted or unsubstituted C 3 -C 6 cycloalkyl), -Ci-C 6 alkyl-(substituted or unsubstituted C 2 - C 5 heterocycloalkyl), -Ci-C 6 alkyl-(substituted or unsubstituted aryl), or -C r C 6 alkyl- (substituted or unsubstituted heteroaryl);
  • n 0, 1 or 2;
  • R 3 is C r C 3 alkyl, or Ci-C 3 fluoroalkyl
  • R 4 is -NHR 5 , -N(R 5 ) 2 , -N + (R 5 ) 3 or -OR 5 ;
  • each R 5 is independently selected from H, Ci-C 3 alkyl, Ci-C 3 haloalkyl, Ci-C 3 heteroalkyl and -Cp C 3 alkyl-(C 3 -C 5 cycloalkyl);
  • R 3 and R 5 together with the atoms to which they are attached form a substituted or unsubstituted 5-7 membered ring;
  • R 3 is bonded to a nitrogen atom of U to form a substituted or unsubstituted 5-7 membered ring;
  • each R 7 is independently selected from C r C 6 alkyl, Ci-C 6 haloalkyl, C r C 6 heteroalkyl, a
  • substituted or unsubstituted C 3 -Ci 0 cycloalkyl a substituted or unsubstituted C 2 - Cioheterocycloalkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, -Ci-C 6 alkyl-(substituted or unsubstituted C 3 -Ci 0 cycloalkyl), -Ci-C 6 alkyl- (substituted or unsubstituted C 2 -Cioheterocycloalkyl, -Ci-C 6 alkyl-(substituted or unsubstituted aryl), -Ci-C 6 alkyl-(substituted or unsubstituted heteroaryl), -(CH 2 ) p -CH(substituted or unsubstituted aryl) 2 , -(CH 2 )
  • p 0, 1 or 2;
  • R 8a , R 8b , R 8c , R 8d , R 8e and R 8f are independently selected from H, C r C 6 alkyl, C r C 6 fluoroalkyl, C r C 6 alkoxy, Ci-C 6 heteroalkyl, and substituted or unsubstituted aryl;
  • R 8a , R 8d , R 8e and R 8f are as defined above, and R 8b and R 8c together form a bond;
  • R 8a , R 8b , R 8d , and R 8f are as defined above, and R 8c and R 8e together form a bond;
  • R 8a , R 8d , R 8e and R 8f are as defined above, and R 8b and R 8c together with the atoms to which they are attached form a substituted or unsubstituted fused 5-7 membered saturated, or partially saturated carbocyclic ring or heterocyclic ring comprising 1 -3 heteroatoms selected from S, O and N, a substituted or unsubstituted fused 5-10 membered aryl ring, or a substituted or unsubstituted fused 5-10 membered heteroaryl ring comprising 1 -3 heteroatoms selected from S, O and N;
  • R 8a , R 8b , R 8d , and R 8f are as defined above, and R 8c and R 8e together with the atoms to which they are attached form a substituted or unsubstituted fused 5-7 membered saturated, or partially saturated carbocyclic ring or heterocyclic ring comprising 1 -3 heteroatoms selected from S, O and N, a substituted or unsubstituted fused 5-10 membered aryl ring, or a substituted or unsubstituted fused 5-10 membered heteroaryl ring comprising 1 -3 heteroatoms selected from S, O and N;
  • R 8c , R 8d , R 8e and R 8f are as defined above, and R 8a and R 8b together with the atoms to which they are attached form a substituted or unsubstituted saturated, or partially saturated 3-7 membered spirocycle or heterospirocycle comprising 1 -3 heteroatoms selected from S, O and N;
  • R 8a , R 8b , R 8e and R 8f are as defined above, and R 8c and R 8d together with the atoms to which they are attached form a substituted or unsubstituted saturated, or partially saturated 3-7 membered spirocycle or heterospirocycle comprising 1 -3 heteroatoms selected from S, O and N;
  • R 8a , R 8b , R 8c , and R 8d are as defined above, and R 8e and R 8f together with the atoms to which they are attached form a substituted or unsubstituted saturated, or partially saturated 3-7 membered spirocycle or heterospirocycle comprising 1 -3 heteroatoms selected from S, O and N;
  • W 3 is O, S, or C(R 8e )(R 8f );
  • R 1 is H, or C r C 6 alkyl
  • X 1 is O, N-R A , S, S(O), or S(0) 2 ;
  • R A is H, Ci-C 6 alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
  • R 2a and R 2b are independently selected from H, substituted or unsubstituted CpCealkyl, and -
  • R is substituted or unsubstituted CpCealkyl, -Ci-C 6 alkyl-(substituted or unsubstituted C 3 -
  • Cecycloalkyl Cecycloalkyl
  • -Ci-Cealkyl- substituted or unsubstituted aryl
  • - NR D R E NR D R E ;
  • R D and R E are independently selected from H, substituted or unsubstituted CpCealkyl, substituted or unsubstituted C3-C 6 cycloalkyl, substituted or unsubstituted C 2 -C 5 heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -Ci-C 6 alkyl- (substituted or unsubstituted C 3 -C 6 cycloalkyl), -Ci-C 6 alkyl-(substituted or unsubstituted C 2 - C 5 heterocycloalkyl), -Ci-C 6 alkyl-(substituted or unsubstituted aryl), or -Ci-C 6 alkyl- (substituted or unsubstituted heteroaryl);
  • R 3 is C r C 3 alkyl, or Ci-C 3 fluoroalkyl; each R 5 is independently selected from H, Ci-C 3 alkyl, Ci-C 3 haloalkyl, Ci-C 3 heteroalkyl and -Cp C 3 alkyl-(C 3 -C 5 cycloalkyl);
  • each R 7 is independently selected from Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Ceheteroalkyl, a
  • substituted or unsubstituted C 3 -Ci 0 cycloalkyl a substituted or unsubstituted C 2 - Cioheterocycloalkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, -Ci-C 6 alkyl-(substituted or unsubstituted C 3 -Ci 0 cycloalkyl), -Ci-C 6 alkyl- (substituted or unsubstituted C 2 -Ci 0 heterocycloalkyl, -Ci-C 6 alkyl-(substituted or unsubstituted aryl), -Ci-C 6 alkyl-(substituted or unsubstituted heteroaryl), -(CH 2 ) p -CH(substituted or unsubstituted aryl) 2 , -(CH 2 ) p
  • p 0, 1 or 2;
  • R 8a and R 8b are independently selected from H, Ci-Cealkyl, and Ci-Cefluoroalkyl;
  • R 8e and R 8f are independently selected from H, Ci-Cealkyl, and Ci-Cefluoroalkyl;
  • compositions comprising compounds of Formula A, Formula B, Formula C, Formula D, Formula E, Formula F, or Formula G, for treatment of cancer, inflammatory diseases and/or autoimmune diseases in an individual in need thereof.
  • compositions comprising compounds of Formula A, Formula B, Formula C, Formula D, Formula E, Formula F, or Formula G, for inhibition of the activity of inhibitor of apoptosis proteins (IAPs) in an individual in need thereof.
  • IAPs apoptosis proteins
  • Figure 1 exemplifies the effects of compounds 16c, 17a, 17b, and 17c on MDA-MB-231 breast cancer cell survival.
  • IAP apoptosis pathway
  • the members of the IAP family are functionally and structurally related proteins, which inhibit apoptosis.
  • IAPs share a Baculovirus IAP Repeat domain, each having one to three copies. Eight members of the IAP family have currently been identified, in both baculovirus and humans.
  • XIAP Five human members of the IAP family include: XIAP, c-IAPl (also, BIRC2), C-IAP2 (also, BIRC3), NAIP, and survivin.
  • 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 IAPs 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 is a mitochondrial protein that negatively regulates apoptosis or programmed cell death.
  • SMAC binds to IAP, which prevents IAP from binding to, and deactivating caspases.
  • caspases promotes apoptosis by activating caspases.
  • the compounds described herein are nonpeptidic SMAC mimetics and induce apoptosis (e.g., in cancer cells).
  • the compounds described herein are IAP antagonists.
  • IAPs not only regulate caspases and apoptosis, but also modulate
  • IAP 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 PR s and mediate activation of nuclear factor-kappa B (NF- ⁇ ) transcription factors as well as the MAP kinases p38 and J K. Accordingly, the compounds described herein are also useful in treatment of non-neoplastic diseases and/or inflammatory diseases and/or autoimmune diseases.
  • Amino refers to the -NH 2 radical.
  • Niro refers to the -N0 2 radical.
  • Alkyl refers to a straight or branched hydrocarbon chain radical, having from one to thirty carbon atoms, and which is attached to the rest of the molecule by a single bond. Alkyls comprising any number of carbon atoms from 1 to 30 are included. An alkyl comprising up to 30 carbon atoms is refered to as a Ci-C 30 alkyl, likewise, for example, an alkyl comprising up to 12 carbon atoms is a C 1 -C 12 alkyl. Alkyls (and other moieties defined herein) comprising other numbers of carbon atoms are represented similarily.
  • Alkyl groups include, but are not limited to, Ci-C 30 alkyl, Q-C 20 alkyl, C 1 -C15 alkyl, CpCio alkyl, C r C 8 alkyl, C r C 6 alkyl, C r C 4 alkyl, C r C 3 alkyl, C r C 2 alkyl, C 2 -C 8 alkyl, C 3 -C 8 alkyl and C 4 -C 8 alkyl.
  • alkyl groups include, but are not limited to, methyl, ethyl, ⁇ -propyl, 1 -methylethyl (z ' o-propyl), n-butyl, z ' -butyl, -butyl, n-pentyl, 1 , 1 -dimethylethyl (i-butyl), 3-methylhexyl, 2-methylhexyl, and the like.
  • an alkyl group may be optionally substituted as described below.
  • Alkylene or “alkylene chain” refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group.
  • 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 as described below.
  • Heteroalkylene refers to an alkyl radical as described above where one or more carbon atoms of the alkyl is replaced with a O, N or S atom.
  • Heteroalkylene or “heteroalkylene chain” refers to a straight or branched divalent heteroalkyl chain linking the rest of the molecule to a radical group. Unless stated otherwise specifically in the specification, the heteroalkyl or heteroalkylene group may be optionally substituted as described below.
  • heteroalkyl groups include, but are not limited to -OCH 2 CH 2 OMe, -OCH 2 CH 2 OCH 2 CH 2 NH 2 , or -OCH 2 CH 2 OCH 2 CH 2 OCH 2 CH 2 N(Me) 2 .
  • heteroalkylene groups include, but are not limited to -OCH 2 CH 2 0-, - OCH 2 CH 2 OCH 2 CH 2 0-, or -OCH 2 CH 2 OCH 2 CH 2 OCH 2 CH 2 0-.
  • Alkylamino refers to a radical of the formula -NHR a or -NR a R a where each R a is,
  • an alkyl radical as defined above. Unless stated otherwise specifically in the specification, an alkylamino group may be optionally substituted as described below.
  • 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 or bridged ring systems.
  • Aryl radicals include, but are not limited to, aryl radicals derived from the hydrocarbon ring systems of aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, a -indacene, -indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene.
  • Carboxy refers to -C0 2 H.
  • carboxy moieties may be replaced with a "carboxylic acid bioisostere", which refers to a functional group or moiety that exhibits similar physical and/or chemical properties as a carboxylic acid moiety.
  • a carboxylic acid bioisostere has similar biological properties to that of a carboxylic acid group.
  • a compound with a carboxylic acid moiety can have the carboxylic acid moiety exchanged with a carboxylic acid bioisostere and have similar physical and/or biological properties when compared to the carboxylic acid-containing compound.
  • a carboxylic acid bioisostere would ionize at physiological pH to roughly the same extent as a carboxylic acid group.
  • bioisosteres of a carboxylic acid include, but are not
  • Cycloalkyl refers to a stable, non-aromatic, monocyclic or polycyclic carbocyclic ring, which may include fused or bridged ring systems, which is saturated or unsaturated, and attached to the rest of the molecule by a single bond.
  • Representative cycloalkyls include, but are not limited to, cycloaklyls having from three to fifteen carbon atoms, from three to ten carbon atoms, from three to eight carbon atoms, from three to six carbon atoms, from three to five carbon atoms, or three to four carbon atoms.
  • Monocyclic cyclcoalkyl radicals include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • Polycyclic radicals include, for example, adamantyl, norbornyl, decalinyl, and 7,7-dimethyl-bicyclo[2.2.1]heptanyl.
  • a cycloalkyl group may be optionally substituted.
  • Illustrative examples of cycloalkyl groups include, but are not limited to, the following moieties: and the like.
  • fused refers to any ring structure described herein which is fused to an existing ring structure.
  • the fused ring is a heterocyclyl ring or a heteroaryl ring
  • any carbon atom on the existing ring structure which becomes part of the fused heterocyclyl ring or the fused heteroaryl ring may be replaced with a nitrogen atom.
  • Halo or "halogen” refers to bromo, chloro, fluoro or iodo.
  • Haloalkyl refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl,
  • haloalkyl group may be optionally substituted.
  • Perhalo or “perfluoro” refers to a moiety in which each hydrogen atom has been replaced by a halo atom or fluorine atom, respectively.
  • Heterocyclyl or “heterocyclic ring” or “hetercycloalkyl” refers to a stable 3- to 24-membered non-aromatic 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.
  • the heterocyclyl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heterocyclyl radical may be optionally oxidized; the nitrogen atom may be optionally quatemized; and the heterocyclyl radical may be partially or fully saturated.
  • Examples of such heterocyclyl radicals include, but are not limited to, dioxolanyl, thienyl[l,3]dithianyl, decahydroisoquinolyl, imidazolinyl,
  • heterocyclyl group may be optionally substituted.
  • heterocycloalkyl groups also referred to as non-
  • heterocycloalkyl also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides and the oligosaccharides. Unless otherwise noted, heterocycloalkyls have from 2 to 10 carbons in the ring. It is understood that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including the heteroatoms) that make up the heterocycloalkyl (i.e. skeletal atoms of the heterocycloalkyl ring). Unless stated otherwise specifically in the specification, a heterocycloalkyl group may be optionally substituted.
  • 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 or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heteroaryl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized.
  • Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[£][l,4]dioxepinyl, 1 ,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl,
  • substituted means any of the above groups (i.e., alkyl, alkylene, alkoxy, alkoxyalkyl, alkylcarbonyl, alkyloxycarbonyl,alkylamino, amidyl, amidinylalkyl, amidinylalkylcarbonyl, aminoalkyl, aryl, aralkyl, arylcarbonyl, aryloxycarbonyl, aralkylcarbonyl, aralkyloxycarbonyl, aryloxy, cycloalkyl, cycloalkylalkyl, cycloalkylcarbonyl, cycloalkylalkylcarbonyl, cycloalkylalkylcarbonyl, cycloalkyloxycarbonyl, guanidinylalkyl,
  • guanidinylalkylcarbonyl, haloalkyl, heterocyclyl and/or heteroaryl may be further functionalized wherein at least one hydrogen atom is replaced by a bond to a non-hydrogen atom substituent.
  • a substituted group may include one or more substituents selected from: oxo, -CO 2 H, nitrile, nitro, hydroxyl, thiooxy, alkyl, alkylene, alkoxy, alkoxyalkyl, alkylcarbonyl, alkyloxycarbonyl, aryl, aralkyl, arylcarbonyl, aryloxycarbonyl, aralkylcarbonyl, aralkyloxycarbonyl, aryloxy, cycloalkyl, cycloalkylalkyl, cycloalkylcarbonyl, cycloalkylalkylcarbonyl, cycloalkyloxycarbonyl, heterocyclyl, heteroary
  • dialkylarylsilyl groups alkyldiarylsilyl groups, triarylsilyl groups, perfluoroalkyl or perfluoroalkoxy, for example, trifluoromethyl or trifluoromethoxy.
  • Substituted also means any of the above groups in which one or more hydrogen atoms are replaced by a higher-order bond (e.g. , a double- or triple-bond) to a heteroatom such as oxygen in oxo, carbonyl, carboxyl, and ester groups; and nitrogen in groups such as imines, oximes, hydrazones, and nitriles.
  • R g and R h are the same or different and independently hydrogen, alkyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N- heteroaryl and/or heteroarylalkyl.
  • each of the foregoing substituents may also be optionally substituted with one or more of the above substituents.
  • any of the above groups may be substituted to include one or more internal oxygen or sulfur atoms.
  • an alkyl group may be substituted with one or more internal oxygen atoms to form an ether or polyether group. Similarily, an alkyl group may be substituted with one or more internal sulfur atoms to form a thioether, disulfide, etc. Amidyl moieties may be substituted with up to 2 halo atoms, while other groups above may be substituted with one or more halo atoms. With the exception of alkyl groups, all other groups may also be substituted with amino or monoalklyamino. With the exception of alkyl and alkylcarbonyl groups, all other groups may also be substituted with guanidinyl or amidynyl. Optional substitutents for any of the above groups also include arylphosphoryl, for example -R a P(Ar) 3 wherein R a is an alkylene and Ar is aryl moiety, for example phenyl.
  • 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.
  • 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).
  • a "tautomer” refers to a proton shift from one atom of a molecule to another atom of the same molecule.
  • the compounds presented herein may exist as tautomers. 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. Some examples of tautomeric interconversions include:
  • Formula A includes compounds of Formula A-I, Formula A-II, Formula A-III-1, Formula A-III-2, Formula A-III-3, Formula A-IV, Formula A-V-l, Formula A-V-2, Formula A-V-3, Formula A-VI-1, Formula A-VI-2, Formula A-VI-3, Formula A-VII-1, Formula A-VII-2, Formula A-VII- 3, Formula A- VIII, Formula A-IX-1, Formula A-IX-2, Formula A-X, Formula A-XI, Formula A-XII, Formula A-XIII, Formula A-XIV, Formula A-XV-1, Formula A-XV-2, Formula A-XV-3, Formula A- XV-4, Formula A-XVI-1, Formula A-XVI-2, Formula A-XVII, Formula A-XVIII, Formula A-XIX, Formula A-XX, and Formula A-XXI.
  • W 1 is O, S, N-R A , or C(R 8a )(R 8b );
  • W 2 is O, S, N-R A , or C(R 8c )(R 8d ); provided that W 1 and W 2 are not both O, or both S;
  • R 1 is H, C r C 6 alkyl, C 3 -C 6 cycloalkyl, -Ci-C 6 alkyl-(substituted or unsubstituted C 3 -C 6 cycloalkyl), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -Ci-C 6 alkyl- (substituted or unsubstituted aryl), -Ci-C 6 alkyl-(substituted or unsubstituted heteroaryl); when X 1 is O, N-R A , S, S(O), or S(0) 2 , then X 2 is C(R 2a R 2b );
  • X 1 is CR 2c R 2d and X 2 is CR 2a R 2b , and R 2c and R 2a together form a bond;
  • X 1 and X 2 are independently selected from C and N, and are members of a fused substituted or unsubstituted saturated or partially saturated 3-10 membered cycloalkyl ring, a fused substituted or unsubstituted saturated or partially saturated 3-10 membered heterocycloalkyl ring, a fused substituted or unsubstituted 5-10 membered aryl ring, or a fused substituted or unsubstituted 5-10 membered heteroaryl ring;
  • R A is H, C r C 6 alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
  • R 2a , R 2b , R 2c , R 2d are independently selected from H, substituted or unsubstituted Ci-C 6 alkyl, substituted or unsubstituted Ci-Ceheteroalkyl, substituted or unsubstituted C3-C 6 cycloalkyl, substituted or unsubstituted C 2 -C 5 heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -Ci-C 6 alkyl-(substituted or unsubstituted C 3 - C 6 cycloalkyl), -Ci-C 6 alkyl-(substituted or unsubstituted C 2 -C 5 heterocycloalkyl), -Ci-C 6 alkyl- (substituted or unsubstituted aryl), -Ci-C 6 alkyl-(substituted or unsubstit
  • R B is substituted or unsubstituted Ci-C 6 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl,
  • R D and R E are independently selected from H, substituted or unsubstituted Ci-C 6 alkyl, substituted or unsubstituted C3-C 6 cycloalkyl, substituted or unsubstituted C 2 -C 5 heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -Ci-Cealkyl- (substituted or unsubstituted C3-C 6 cycloalkyl), -Ci-C 6 alkyl-(substituted or unsubstituted C 2 - C 5 heterocycloalkyl), -Ci-C 6 alkyl-(substituted or unsubstituted aryl), or -Ci-C 6 alkyl- (substituted or unsubstituted heteroaryl);
  • n 0, 1 or 2;
  • R 3 is C r C 3 alkyl, or Ci-C 3 fluoroalkyl
  • R 4 is -NHR 5 , -N(R 5 ) 2 , -N + (R 5 ) 3 or -OR 5 ;
  • each R 5 is independently selected from H, C r C 3 alkyl, C r C 3 haloalkyl, C r C 3 heteroalkyl and -C r C 3 alkyl-(C 3 -C 5 cycloalkyl);
  • R 3 and R 5 together with the atoms to which they are attached form a substituted or unsubstituted 5-7 membered ring;
  • R 3 is bonded to a nitrogen atom of U to form a substituted or unsubstituted 5-7 membered ring;
  • each R 7 is independently selected from Ci-C 6 alkyl, Ci-C 6 haloalkyl, Ci-C 6 heteroalkyl, a
  • substituted or unsubstituted C 3 -Ci 0 cycloalkyl a substituted or unsubstituted C 2 - Cioheterocycloalkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, -Ci-C 6 alkyl-(substituted or unsubstituted C 3 -Ciocycloalkyl), -Ci-C 6 alkyl- (substituted or unsubstituted C2-Cioheterocycloalkyl, -Ci-C 6 alkyl-(substituted or unsubstituted aryl), -Ci-C 6 alkyl-(substituted or unsubstituted heteroaryl), -(CH 2 ) p -CH(substituted or unsubstituted aryl) 2 , -(CH 2 ) p -CH
  • p 0, 1 or 2;
  • R 8a , R 8b , R 8c , and R 8d are independently selected from H, C r C 6 alkyl, C r C 6 fluoroalkyl, C r C 6 alkoxy, Ci-C 6 heteroalkyl, and substituted or unsubstituted aryl;
  • R 8a and R 8d are as defined above, and R 8b and R 8c together form a bond;
  • R 8a and R 8d are as defined above, and R 8b and R 8c together with the atoms to which they are
  • R 8c and R 8d are as defined above, and R 8a and R 8b together with the atoms to which they are
  • R 8a and R 8b are as defined above, and R 8c and R 8d together with the atoms to which they are
  • R 3 is Ci-C 3 alkyl.
  • R 4 is-NHR 5 , -N(R 5 ) 2 , or -N + (R 5 ) 3 ;
  • each R 5 is independently selected from H, Ci-C 3 alkyl, and -Ci-C 3 alkyl-(C3-C 5 cycloalkyl).
  • R 3 is C r C 3 alkyl
  • R 4 is-NHR 5 , -N(R 5 ) 2 , or -N + (R 5 ) 3 ;
  • each R 5 is independently selected from H, C r C 3 alkyl, and -Ci-C 3 alkyl-(C 3 -C 5 cycloalkyl).
  • q 1 , 2 or 3.
  • q 1 , 2 or 3.
  • ring A is a fused substituted or unsubstituted saturated or partially saturated 3-10 membered cycloalkyl ring, substituted or unsubstituted saturated or partially saturated 3-10 membered heterocycloalkyl ring, substituted or unsubstituted 5-10 membered aryl ring, or substituted or unsubstituted 5-10 membered heteroaryl ring.
  • ring A is selected from indolyl, and phenyl.
  • R a and R are independently selected from H and
  • Ci-C 3 alkyl Ci-C 3 alkyl
  • R 8b and R 8c together with the atoms to which they are attached form a substituted or unsubstituted fused 5-7 membered saturated, or partially saturated carbocyclic ring or heterocyclic ring comprising 1 -3 heteroatoms selected from S, O and ⁇ , a substituted or unsubstituted fused 5-10 membered aryl ring, or a substituted or unsubstituted fused 5-10 membered heteroaryl ring comprising 1 -3 heteroatoms selected from S, O and ⁇ .
  • ring B is an aryl or heteroaryl ring.
  • ring B is an aryl. In some embodiments, ring B is phenyl. In some embodiments, ring B is a heteroaryl ring. In some embodiments, ring B is a monocyclic heteroaryl ring or a bicyclic heteroaryl ring. In some embodiments, ring B is a monocyclic heteroaryl ring. In some embodiments, ring B is a bicyclic heteroaryl ring. In some embodiments, ring B is selected from phenyl, pyridinyl and thiophenyl. In some embodiments, ring B is selected from pyridinyl and thiophenyl.
  • R 8a and R 8b together with the atoms to which they are attached form a substituted or unsubstituted saturated or partially saturated 3-7 membered spirocycle or heterospirocycle comprising 1 -3 heteroatoms selected from S, O and N; or R 8c and R 8d together with the atoms to which they are attached form a substituted or
  • W 2 is O, S, or C(R 8c )(R 8d );
  • R 1 is H, or C r C 6 alkyl
  • X 1 is O, N-R A , S, S(O), or S(0) 2 ;
  • R A is H, C r C 6 alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
  • R B is substituted or unsubstituted Ci-C 6 alkyl, -Ci-C 6 alkyl-(substituted or unsubstituted C 3 -
  • R D and R E are independently selected from H, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted C3-C 6 cycloalkyl, substituted or unsubstituted C2-C 5 heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -Ci-Cealkyl- (substituted or unsubstituted C3-C 6 cycloalkyl), -Ci-C 6 alkyl-(substituted or unsubstituted C 2 - C 5 heterocycloalkyl), -Ci-C 6 alkyl-(substituted or unsubstituted aryl), or -Ci-C 6 alkyl- (substituted or unsubstituted heteroaryl);
  • R 3 is C r C 3 alkyl, or Ci-C 3 fluoroalkyl
  • each R 5 is independently selected from H, C r C 3 alkyl, Ci-C 3 haloalkyl, C r C 3 heteroalkyl and -C r C 3 alkyl-(C 3 -C 5 cycloalkyl);
  • each R 7 is independently selected from C r C 6 alkyl, Ci-C 6 haloalkyl, C r C 6 heteroalkyl, a
  • substituted or unsubstituted C 3 -Ci 0 cycloalkyl a substituted or unsubstituted C 2 - Cioheterocycloalkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, -Ci-C 6 alkyl-(substituted or unsubstituted C 3 -Ci 0 cycloalkyl), -C r C 6 alkyl- (substituted or unsubstituted C 2 -Ci 0 heterocycloalkyl, -Ci-C 6 alkyl-(substituted or unsubstituted aryl), -Ci-C 6 alkyl-(substituted or unsubstituted heteroaryl), -(CH 2 ) p -CH(substituted or unsubstituted aryl) 2 , -(CH 2 ) p
  • p 0, 1 or 2;
  • R 8a and R 8b are independently selected from H, C r C 6 alkyl, and Ci-C 6 fluoroalkyl;
  • R 8c and R 8d are independently selected from H, C r C 6 alkyl, and Ci-C 6 fluoroalkyl;
  • R B is substituted or unsubstituted CpCealkyl, -Ci-C 6 alkyl-(substituted or unsubstituted C 3 - C 6 cycloalkyl), -Ci-C 6 alkyl-(substituted or unsubstituted C 2 -C 5 heterocycloalkyl), -Ci-C 6 alkyl- (substituted or unsubstituted aryl), or -Ci-C 6 alkyl-(substituted or unsubstituted heteroaryl).
  • R 2a , R 2b , R 2c , R 2d are independently selected from H, and C r C 3 alkyl.
  • R 6 is substituted or unsubstituted C 2 -Cioheterocycloalkyl, or substituted or unsubstituted
  • R 6 is a substituted or unsubstituted C 2 -Cioheterocycloalkyl.
  • R 6 is a substituted or unsubstituted heteroaryl.
  • each R 7 is independently selected from a substituted or unsubstituted C 3 -Ci 0 cycloalkyl, a
  • substituted or unsubstituted C 2 -Ci 0 heterocycloalkyl a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, -Ci-C 6 alkyl-(substituted or unsubstituted C 3 - Ciocycloalkyl), -Ci-C 6 alkyl-(substituted or unsubstituted C 2 -Ci 0 heterocycloalkyl, -Ci-C 6 alkyl- (substituted or unsubstituted aryl), -Ci-C 6 alkyl-(substituted or unsubstituted heteroaryl), - (CH 2 ) p -CH(substituted or unsubstituted aryl) 2; -(CH 2 ) p -CH(substituted or unsubstituted heteroaryl) 2 , -(CH 2 )
  • R 7 is independently selected from a substituted or unsubstituted C 3 -Ciocycloalkyl, a substituted or unsubstituted C 2 -Cioheterocycloalkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, and -(CH 2 ) p -CH(substituted or unsubstituted aryl) 2 .
  • R is H
  • X 1 is O
  • R 2a , R 2b are independently selected from H, and C r C 3 alkyl;
  • R , R , R , R are independently selected from H and C C 3 alkyl.
  • acemate or stereoisomer thereof selected from:
  • a pharmaceutical composition comprising a compound of Formula A described above or below, or pharmaceutically acceptable salt, N-oxide, racemate or stereoisomer thereof, and a pharmaceutically acceptable carrier.
  • Formula B - Seven-Five ring systems
  • Formula B includes compounds of Formula B-I, Formula B-II, Formula B-III-1 , Formula B-III-2, Formula B-III-3, Formula B-IV, Formula B-V-l , Formula B-V-2, Formula B-V-3, Formula B-VI-1 , Formula B-VI-2, Formula B-VI-3, Formula B-VII-1 , Formula B-VII-2, Formula B-VII- 3, Formula B-VIII-1 , Formula B-VIII-2, Formula B-VIII-3, Formula B-IX-1 , Formula B-IX-2, Formula B-X, Formula B-XI-1 , Formula B-XI-2, Formula B-XII, Formula B-XIII, Formula B-XIV, Formula B- XV, Formula B-XVI-1 , Formula B-XVI-2, Formula B-XVI-3, Formula B-XVI-4, Formula B-XVII-1 , Formula B-XVII-2, Formula B-XVIII, Formula B-XIX, Formula B-X, Formula B-XI
  • R 1 is H, Ci-Cealkyl, C3-C 6 cycloalkyl, -Ci-C 6 alkyl-(substituted or unsubstituted C3-C 6 cycloalkyl), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -Ci-Cealkyl- (substituted or unsubstituted aryl), -Ci-C 6 alkyl-(substituted or unsubstituted heteroaryl); when X 1 is selected from N-R A , S, S(O) and S(0) 2 , then X 2 is CR 2c R 2d , and X 3 is CR 2a R 2b ;
  • X 1 when X 1 is O, then X 2 is selected from CR 2c R 2d and N-R A , and X 3 is CR 2a R 2b ;
  • X 1 is CH 2
  • X 2 is selected from O, N-R A , S, S(O), and S(0) 2
  • X 3 is CR 2a R 2b ;
  • X 1 is CR 2e R 2f and X 2 is CR 2c R 2d , and R 2e and R 2c together form a bond, and X 3 is CR 2a R 2b ;
  • X 1 and X 2 are independently selected from C and N, and are members of a fused substituted or unsubstituted saturated or partially saturated 3-10 membered cycloalkyl ring, a fused substituted or unsubstituted saturated or partially saturated 3-10 membered heterocycloalkyl ring, a fused substituted or unsubstituted 5-10 membered aryl ring, or a fused substituted or unsubstituted 5-10 membered heteroaryl ring, and X 3 is CR 2a R 2b ;
  • X 2 and X 3 are independently selected from C and N, and are members of a fused substituted or unsubstituted saturated or partially saturated 3-10 membered cycloalkyl ring, a fused substituted or unsubstituted saturated or partially saturated 3-10 membered heterocycloalkyl ring, a fused substituted or unsubstituted 5-10 membered aryl ring, or a fused substituted or unsubstituted 5-10 membered heteroaryl ring, and X 1 is CR 2e R 2f ;
  • R A is H, Ci-C 6 alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
  • W 1 is O, S, N-R A , or C(R 8a )(R 8b );
  • W 2 is O, S, N-R A , or C(R 8c )(R 8d ); provided that W 1 and W 2 are not both O, or both S;
  • R 2a , R 2b , R 2c , R 2d R 2e , and R 2f are independently selected from H, substituted or unsubstituted C Cealkyl, substituted or unsubstituted Ci-Ceheteroalkyl, substituted or unsubstituted C3- Cecycloalkyl, substituted or unsubstituted C 2 -C 5 heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -Ci-C 6 alkyl-(substituted or unsubstituted C 3 - C 6 cycloalkyl), -Ci-C 6 alkyl-(substituted or unsubstituted C 2 -C 5 heterocycloalkyl), -C r C 6 alkyl- (substituted or unsubstituted aryl), -Ci-C 6 alkyl-(substituted
  • R B is substituted or unsubstituted Ci-C 6 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl,
  • R D and R E are independently selected from H, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted C3-C 6 cycloalkyl, substituted or unsubstituted C 2 -C 5 heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -Ci-Cealkyl- (substituted or unsubstituted C3-C 6 cycloalkyl), -Ci-C 6 alkyl-(substituted or unsubstituted C 2 - C 5 heterocycloalkyl), -Ci-C 6 alkyl-(substituted or unsubstituted aryl), or -C r C 6 alkyl- (substituted or unsubstituted heteroaryl); m is 0, 1 or 2;
  • R 3 is C r C 3 alkyl, or C r C 3 fluoroalkyl
  • R 4 is -NHR 5 , -N(R 5 ) 2 , -N + (R 5 ) 3 or -OR 5 ;
  • each R 5 is independently selected from H, C r C 3 alkyl, C r C 3 haloalkyl, C r C 3 heteroalkyl and -C r C 3 alkyl-(C 3 -C 5 cycloalkyl);
  • R 3 and R 5 together with the atoms to which they are attached form a substituted or unsubstituted 5-7 membered ring;
  • R 3 is bonded to a nitrogen atom of U to form a substituted or unsubstituted 5-7 membered ring;
  • each R 7 is independently selected from Ci-C 6 alkyl, Ci-C 6 haloalkyl, Ci-C 6 heteroalkyl, a
  • substituted or unsubstituted C 3 -Ciocycloalkyl a substituted or unsubstituted C 2 - Cioheterocycloalkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, -Ci-C 6 alkyl-(substituted or unsubstituted C 3 -Ci 0 cycloalkyl), -Ci-C 6 alkyl- (substituted or unsubstituted C 2 -Ci 0 heterocycloalkyl, -Ci-C 6 alkyl-(substituted or unsubstituted aryl), -Ci-C 6 alkyl-(substituted or unsubstituted heteroaryl), -(CH 2 ) p -CH(substituted or unsubstituted aryl) 2 , -(CH 2 ) p -
  • p 0, 1 or 2;
  • R 8a , R 8b , R 8c , and R 8d are independently selected from H, C C 6 alkyl, Ci-C 6 fluoroalkyl, C C 6 alkoxy, Ci-Ceheteroalkyl, and substituted or unsubstituted aryl;
  • R 8a and R 8d are as defined above, and R 8b and R 8c together form a bond;
  • R 8a and R 8d are as defined above, and R 8b and R 8c together with the atoms to which they are
  • R 8c and R 8d are as defined above, and R 8a and R 8b together with the atoms to which they are
  • R 8a and R 8b are as defined above, and R 8c and R 8d together with the atoms to which they are
  • R 3 is Ci-Qalkyl.
  • R 4 is-NHR 5 , -N(R 5 ) 2 , or -N + (R 5 ) 3 ;
  • each R 5 is independently selected from H, C r C 3 alkyl, and -Ci-C 3 alkyl-(C 3 -C 5 cycloalkyl).
  • R 3 is d-Qalkyl
  • R 4 is-NHR 5 , -N(R 5 ) 2 , or -N + (R 5 ) 3 ;
  • each R 5 is independently selected from H, Ci-C 3 alkyl, and -Ci-C 3 alkyl-(C 3 -C 5 cycloalkyl).
  • q 1, 2 or 3.
  • q 1, 2 or 3.
  • X 1 is selected from N-R A , S, S(O) and S(0) 2 ;
  • X 2 is CH 2 .
  • X 1 is CH 2 ;
  • X 2 is selected from O, N-R A , S, S(O), and S(0) 2 .
  • Formula B-IX-1 Formula B-IX-2
  • pharmaceutically acceptable salt, N-oxide, racemate or stereoisomer thereof is one group of compounds having the structure of Formula B-X:
  • ring A is a fused substituted or unsubstituted saturated or partially saturated 3-10 membered cycloalkyl ring, substituted or unsubstituted saturated or partially saturated 3-10 membered heterocycloalkyl ring, substituted or unsubstituted 5-10 membered aryl ring, or substituted or unsubstituted 5-10 membered heteroaryl ring.
  • ring A is selected from indolyl and phenyl.
  • Formula B-XII [00139] Within such a group of compounds are compounds wherein R a and R are independently selected from H and Ci-Csalkyl.
  • X 1 is O, S or S(0) 2 , and X 2 is CH 2;
  • X 1 and X 2 are C and are members of a fused substituted or unsubstituted a fused substituted or unsubstituted 5-10 membered aryl ring, or a fused substituted or unsubstituted 5-10 membered heteroaryl ring;
  • R 8b and R 8c together with the atoms to which they are attached form a substituted or unsubstituted fused 5-7 membered saturated, or partially saturated carbocyclic ring or heterocyclic ring comprising 1 -3 heteroatoms selected from S, O and N, a substituted or unsubstituted fused 5-10 membered aryl ring, or a substituted or unsubstituted fused 5-10 membered heteroaryl ring comprising 1 -3 heteroatoms selected from S, O and N.
  • ring B is an aryl or heteroaryl ring.
  • ring B is an aryl. In some embodiments, ring B is phenyl. In some embodiments, ring B is a heteroaryl ring. In some embodiments, ring B is a monocyclic heteroaryl ring or a bicyclic heteroaryl ring. In some embodiments, ring B is a monocyclic heteroaryl ring. In some embodiments, ring B is a bicyclic heteroaryl ring. In some embodiments, ring B is selected from phenyl, pyridinyl and thiophenyl. In some embodiments, ring B is selected from pyridinyl and thiophenyl.
  • R 8a and R 8b together with the atoms to which they are attached form a substituted or unsubstituted saturated, or partially saturated 3-7 membered spirocycle or heterospirocycle comprising 1 -3 heteroatoms selected from S, O and N or R 8c and R 8d together with the atoms to which they are attached form a substituted or
  • W 2 is O, S, or C(R 8c )(R 8d );
  • R 1 is H, or C r C 6 alkyl
  • X 1 is O, N-R A , S, S(O), or S(0) 2 ;
  • R A is H, Ci-C 6 alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
  • R 2a and R 2b are independently selected from H, substituted or unsubstituted CpCealkyl, and -
  • R is substituted or unsubstituted CpCealkyl, -Ci-C 6 alkyl-(substituted or unsubstituted C 3 -
  • Cecycloalkyl Cecycloalkyl
  • -Ci-Cealkyl- substituted or unsubstituted aryl
  • - NR D R E NR D R E ;
  • R D and R E are independently selected from H, substituted or unsubstituted CpCealkyl, substituted or unsubstituted C3-C 6 cycloalkyl, substituted or unsubstituted C 2 -C 5 heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -Ci-C 6 alkyl- (substituted or unsubstituted C 3 -C 6 cycloalkyl), -Ci-C 6 alkyl-(substituted or unsubstituted C 2 - C 5 heterocycloalkyl), -Ci-C 6 alkyl-(substituted or unsubstituted aryl), or -Ci-Cealkyl- (substituted or unsubstituted heteroaryl);
  • R 3 is C r C 3 alkyl, or Ci-C 3 fluoroalkyl; each R 5 is independently selected from H, d-C 3 alkyl, Ci-C 3 haloalkyl, Ci-C 3 heteroalkyl and -Cp C 3 alkyl-(C 3 -C 5 cycloalkyl);
  • each R 7 is independently selected from Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Ceheteroalkyl, a
  • substituted or unsubstituted C 3 -Ci 0 cycloalkyl a substituted or unsubstituted C 2 - Cioheterocycloalkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, -Ci-C 6 alkyl-(substituted or unsubstituted C 3 -Ci 0 cycloalkyl), -Ci-C 6 alkyl- (substituted or unsubstituted C 2 -Ci 0 heterocycloalkyl, -Ci-C 6 alkyl-(substituted or unsubstituted aryl), -Ci-C 6 alkyl-(substituted or unsubstituted heteroaryl), -(CH 2 ) p -CH(substituted or unsubstituted aryl) 2 , -(CH 2 ) p
  • p 0, 1 or 2;
  • R 8a and R 8b are independently selected from H, Ci-Cealkyl, and Ci-Cefluoroalkyl;
  • R 8c and R 8d are independently selected from H, Ci-Cealkyl, and Ci-Cefluoroalkyl;
  • R 2a , R 2b R 2c , R 2d , R 2e , andR 2f are independently H or Ci-C 3 alkyl.
  • R 6 is substituted or unsubstituted C 2 -Ci 0 heterocycloalkyl, or substituted or unsubstituted
  • R 6 is a substituted or unsubstituted C 2 -Cioheterocycloalkyl.
  • R 6 is a substituted or unsubstituted heteroaryl.
  • each R 7 is independently selected from a substituted or unsubstituted C 3 -Ci 0 cycloalkyl, a
  • substituted or unsubstituted C 2 -Ci 0 heterocycloalkyl a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, -Ci-C 6 alkyl-(substituted or unsubstituted C 3 - Ciocycloalkyl), -Ci-C 6 alkyl-(substituted or unsubstituted C 2 -Cioheterocycloalkyl, -Ci-Cealkyl- (substituted or unsubstituted aryl), -Ci-C 6 alkyl-(substituted or unsubstituted heteroaryl), - (CH 2 ) p -CH(substituted or unsubstituted aryl) 2 -(CH 2 ) p -CH(substituted or unsubstituted heteroaryl) 2 , -(CH 2 )
  • R 7 is independently selected from a substituted or unsubstituted C 3 -Ci 0 cycloalkyl, a substituted or unsubstituted C 2 -Ci 0 heterocycloalkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, and -(CH 2 ) p -CH(substituted or unsubstituted aryl) 2 .
  • W 2 is C(R 8c )(R 8d );
  • R 1 is H
  • R 2 a , R 2b are independently selected fromH, and C r C 3 alkyl;
  • R 8a , R 8b , R 8c , R 8d are independently selected from H and C C 3 alkyl.
  • a compound of Formula B described above or below, or pharmaceutically acceptable salt, N-oxide, racemate or stereoisomer thereof, is
  • compositions comprising a compound of Formula B described above, or pharmaceutically acceptable salt, N-oxide, racemate or stereoisomer thereof, and a pharmaceutically acceptable carrier.
  • Formula C includes compounds of Formula C-I, Formula C-II, Formula C-III-1, Formula C-III-2, Formula C-III-3, Formula C-IV, Formula C-V-l, Formula C-V-2, Formula C-V-3, Formula C-VI-1, Formula C-VI-2, Formula C-VI-3, Formula C-VII-1, Formula C-VII-2, Formula C-VII- 3, Formula C-VIII-1, Formula C-VIII-2, Formula C-VIII-3, Formula C-IX-1, Formula C-IX-2, Formula C-X-1, Formula C-X-2, Formula C-XI, Formula C-XII, Formula C-XIII, Formula C-XIV, Formula C-XV- 1, Formula C-XV-2, Formula C-XV-3, Formula C-XV-4, Formula C-XVI-1, Formula C-XVI-2, Formula C-XVII, Formula C-XVIII, Formula C-XIX, Formula C-XX, and Formula C-XXI.
  • R 1 is H, C r C 6 alkyl, C 3 -C 6 cycloalkyl, -Ci-C 6 alkyl-(substituted or unsubstituted C 3 -C 6 cycloalkyl), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -Ci-C 6 alkyl- (substituted or unsubstituted aryl), -Ci-C 6 alkyl-(substituted or unsubstituted heteroaryl); when X 1 is selected from N-R A , S, S(O) and S(0) 2 , then X 2 is CR 2c R 2d , and X 3 is CR 2a R 2b ;
  • X 1 when X 1 is O, then X 2 is selected from CR 2c R 2d and N-R A , and X 3 is CR 2a R 2b ;
  • X 1 is CH 2
  • X 2 is selected from O, N-R A , S, S(O), and S(0) 2
  • X 3 is CR 2a R 2b ;
  • X 1 is CR 2e R 2f and X 2 is CR 2c R 2d , and R 2e and R 2c together form a bond, and X 3 is CR 2a R 2b ;
  • X 1 and X 2 are independently selected from C and N, and are members of a fused substituted or unsubstituted saturated or partially saturated 3-10 membered cycloalkyl ring, a fused substituted or unsubstituted saturated or partially saturated 3-10 membered heterocycloalkyl ring, a fused substituted or unsubstituted 5-10 membered aryl ring, or a fused substituted or unsubstituted 5-10 membered heteroaryl ring;
  • X 3 is CR 2a R 2b ;
  • X 2 and X 3 are independently selected from C and N, and are members of a fused substituted or unsubstituted saturated or partially saturated 3-10 membered cycloalkyl ring, a fused substituted or unsubstituted saturated or partially saturated 3-10 membered heterocycloalkyl ring, a fused substituted or unsubstituted 5-10 membered aryl ring, or a fused substituted or unsubstituted 5-10 membered heteroaryl ring, and X 1 is CR 2e R 2f ;
  • R A is H, Ci-Cealkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
  • W 1 is O, S, N-R A , or C(R 8a )(R 8b );
  • W 2 is O, S, N-R A , or C(R 8c )(R 8d ); provided that W 1 and W 2 are not both O, or both S;
  • R 2a , R 2b , R 2c , R 2d R 2e , and R 2f are independently selected from H, substituted or unsubstituted C Cealkyl, substituted or unsubstituted CpCeheteroalkyl, substituted or unsubstituted C3- Cecycloalkyl, substituted or unsubstituted C 2 -C 5 heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -Ci-C 6 alkyl-(substituted or unsubstituted C3- C 6 cycloalkyl), -Ci-C 6 alkyl-(substituted or unsubstituted C 2 -C 5 heterocycloalkyl), -Ci-C 6 alkyl- (substituted or unsubstituted aryl), -Ci-C 6 alkyl-(substituted or
  • R B is substituted or unsubstituted Ci-C 6 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl,
  • R D and R E are independently selected from H, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted C3-C 6 cycloalkyl, substituted or unsubstituted C 2 -C 5 heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -Ci-Cealkyl- (substituted or unsubstituted C3-C 6 cycloalkyl), -Ci-C 6 alkyl-(substituted or unsubstituted C 2 - C 5 heterocycloalkyl), -Ci-C 6 alkyl-(substituted or unsubstituted aryl), or -Ci-Cealkyl- (substituted or unsubstituted heteroaryl);
  • R 3 is C r C 3 alkyl, or Ci-C 3 fluoroalkyl
  • R 4 is -NHR 5 , -N(R 5 ) 2 , -N + (R 5 ) 3 or -OR 5 ;
  • each R 5 is independently selected from H, C r C 3 alkyl, C r C 3 haloalkyl, C r C 3 heteroalkyl and -C r C 3 alkyl-(C 3 -C 5 cycloalkyl);
  • R 3 and R 5 together with the atoms to which they are attached form a substituted or unsubstituted 5-7 membered ring;
  • R 3 is bonded to a nitrogen atom of U to form a substituted or unsubstituted 5-7 membered ring;
  • each R 7 is independently selected from Ci-C 6 alkyl, Ci-C 6 haloalkyl, Ci-C 6 heteroalkyl, a
  • p 0, 1 or 2;
  • R 8a , R 8b , R 8c , and R 8d are independently selected from H, C r C 6 alkyl, C r C 6 fluoroalkyl, C r C 6 alkoxy, Ci-Ceheteroalkyl, and substituted or unsubstituted aryl;
  • R 8a and R 8d are as defined above, and R 8b and R 8c together form a bond;
  • R 8a and R 8d are as defined above, and R 8b and R 8c together with the atoms to which they are
  • R 8c and R 8d are as defined above, and R 8a and R 8b together with the atoms to which they are
  • R 8a and R 8b are as defined above, and R 8c and R 8d together with the atoms to which they are
  • R 3 is d-Qalkyl.
  • R 4 is-NHR 5 , -N(R 5 ) 2 , or -N + (R 5 ) 3 ;
  • each R 5 is independently selected from H, C r C 3 alkyl, and -Ci-C 3 alkyl-(C 3 -C 5 cycloalkyl).
  • R 3 is Ci-Qalkyl
  • R 4 is-NHR 5 , -N(R 5 ) 2 , or -N + (R 5 ) 3 ;
  • each R 5 is independently selected from H, Ci-C 3 alkyl, and -Ci-C 3 alkyl-(C 3 -C 5 cycloalkyl).
  • q 1, 2 or 3.
  • X 1 is selected from N-R A , S, S(O) and S(0) 2 ;
  • X 2 is CH 2 .
  • X 1 is CH 2 ; and X 2 is selected from O, N-R A , S, S(O), and S(0) 2 .
  • ring A is a fused substituted or unsubstituted saturated or partially saturated 3-10
  • cycloalkyl ring substituted or unsubstituted saturated or partially saturated 3-10 membered heterocycloalkyl ring, substituted or unsubstituted 5-10 membered aryl ring, or substituted or unsubstituted 5-10 membered heteroaryl ring.
  • ring A is selected from indolyl and phenyl.
  • R 2a , R 2b R 2c , R 2d , R 2e , and R 2f are independently H or C 1 -C3 alkyl; and R 1 is H or methyl.
  • R 1 is H.
  • R 8b and R 8c together with the atoms to which they are attached form a substituted or unsubstituted fused 5-7 membered saturated, or partially saturated carbocyclic ring or heterocyclic ring comprising 1 -3 heteroatoms selected from S, O and N, a substituted or unsubstituted fused 5-10 membered aryl ring, or a substituted or unsubstituted fused 5-10 membered heteroaryl ring comprising 1 -3 heteroatoms selected from S, O and N.
  • ring B is an aryl or heteroaryl ring.
  • ring B is an aryl. In some embodiments, ring B is phenyl. In some embodiments, ring B is a heteroaryl ring. In some embodiments, ring B is a monocyclic heteroaryl ring or a bicyclic heteroaryl ring. In some embodiments, ring B is a monocyclic heteroaryl ring. In some embodiments, ring B is a bicyclic heteroaryl ring. In some embodiments, ring B is selected from phenyl, pyridinyl and thiophenyl. In some embodiments, ring B is selected from pyridinyl and thiophenyl.
  • R 8a and R 8b together with the atoms to which they are attached form a substituted or unsubstituted saturated, or partially saturated 3-7 membered spirocycle or heterospirocycle comprising 1 -3 heteroatoms selected from S, O and N; or R 8c and R 8d together with the atoms to which they are attached form a substituted or unsubstituted saturated, or partially saturated 3-7 membered spirocycle or heterospirocycle comprising 1 -3 heteroatoms selected from S, O and N.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Diabetes (AREA)
  • Immunology (AREA)
  • Hematology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Ophthalmology & Optometry (AREA)
  • Neurology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Dermatology (AREA)
  • Urology & Nephrology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Obesity (AREA)
  • Endocrinology (AREA)
  • Cardiology (AREA)
  • Rheumatology (AREA)
  • Biophysics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Molecular Biology (AREA)
  • Genetics & Genomics (AREA)
  • Biochemistry (AREA)
  • Biomedical Technology (AREA)
  • Vascular Medicine (AREA)
  • Neurosurgery (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Emergency Medicine (AREA)
  • Oncology (AREA)
PCT/US2013/072064 2012-11-30 2013-11-26 Inhibitor of apoptosis protein (iap) antagonists Ceased WO2014085489A1 (en)

Priority Applications (8)

Application Number Priority Date Filing Date Title
US14/648,435 US9546174B2 (en) 2012-11-30 2013-11-26 Inhibitor of apoptosis protein (IAP) antagonists
EP13859485.8A EP2925764B1 (en) 2012-11-30 2013-11-26 Inhibitor of apoptosis protein (iap) antagonists
JP2015545193A JP6382831B2 (ja) 2012-11-30 2013-11-26 アポトーシス阻害タンパク質（ｉａｐ）のアンタゴニスト
CA2896577A CA2896577C (en) 2012-11-30 2013-11-26 Inhibitor of apoptosis protein (iap) antagonists
US15/363,935 US10047119B2 (en) 2012-11-30 2016-11-29 Inhibitor of apoptosis protein (IAP) antagonists
US16/031,837 US10544188B2 (en) 2012-11-30 2018-07-10 Inhibitor of apoptosis protein (IAP) antagonists
US16/740,240 US11111270B2 (en) 2012-11-30 2020-01-10 Inhibitor of apoptosis protein (IAP) antagonists
US17/389,171 US11912786B2 (en) 2012-11-30 2021-07-29 Inhibitor of apoptosis protein (IAP) antagonists

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201261731794P 2012-11-30 2012-11-30
US61/731,794 2012-11-30

Related Child Applications (2)

Application Number Title Priority Date Filing Date
US14/648,435 A-371-Of-International US9546174B2 (en) 2012-11-30 2013-11-26 Inhibitor of apoptosis protein (IAP) antagonists
US15/363,935 Continuation US10047119B2 (en) 2012-11-30 2016-11-29 Inhibitor of apoptosis protein (IAP) antagonists

Publications (1)

Publication Number Publication Date
WO2014085489A1 true WO2014085489A1 (en) 2014-06-05

Family

ID=50828427

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2013/072064 Ceased WO2014085489A1 (en) 2012-11-30 2013-11-26 Inhibitor of apoptosis protein (iap) antagonists

Country Status (5)

Country Link
US (5) US9546174B2 (enExample)
EP (1) EP2925764B1 (enExample)
JP (2) JP6382831B2 (enExample)
CA (1) CA2896577C (enExample)
WO (1) WO2014085489A1 (enExample)

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015187998A2 (en) 2014-06-04 2015-12-10 Sanford-Burnham Medical Research Institute Use of inhibitor of apoptosis protein (iap) antagonists in hiv therapy
WO2016079527A1 (en) 2014-11-19 2016-05-26 Tetralogic Birinapant Uk Ltd Combination therapy
WO2016097773A1 (en) 2014-12-19 2016-06-23 Children's Cancer Institute Therapeutic iap antagonists for treating proliferative disorders
US9546174B2 (en) 2012-11-30 2017-01-17 Sanford-Burnham Medical Research Institute Inhibitor of apoptosis protein (IAP) antagonists
CN110028508A (zh) * 2019-05-16 2019-07-19 南京华威医药科技集团有限公司 一种抗肿瘤的重氮双环类细胞凋亡蛋白抑制剂
US10441654B2 (en) 2014-01-24 2019-10-15 Children's Hospital Of Eastern Ontario Research Institute Inc. SMC combination therapy for the treatment of cancer
WO2020148447A1 (en) 2019-01-17 2020-07-23 Debiopharm International S.A. Combination product for the treatment of cancer
US10870663B2 (en) 2018-11-30 2020-12-22 Glaxosmithkline Intellectual Property Development Limited Compounds useful in HIV therapy
WO2021058794A1 (en) 2019-09-25 2021-04-01 Debiopharm International S.A. Dosing regimens for treatment of patients with locally advanced squamous cell carcinoma
WO2021222614A1 (en) * 2020-04-30 2021-11-04 Sanford Burnham Prebys Medical Discovery Institute Inhibitor of apoptosis (iap) protein antagonists
WO2023081290A1 (en) * 2021-11-04 2023-05-11 Sanford Burnham Prebys Medical Discovery Institute Inhibitor of apoptosis (iap) protein antagonists
RU2806030C2 (ru) * 2018-11-30 2023-10-25 Глаксосмиткляйн Интеллекуал Проперти Дивелопмент Лимитед Соединения, пригодные для терапии против вич
WO2024121395A1 (en) * 2022-12-09 2024-06-13 Debiopharm International Sa Iap inhibitors, methods of making the same and uses thereof

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
PL3458101T3 (pl) 2016-05-20 2021-05-31 F. Hoffmann-La Roche Ag Koniugaty PROTAC-przeciwciało i sposoby ich stosowania
WO2020110056A1 (en) * 2018-11-30 2020-06-04 Glaxosmithkline Intellectual Property Development Limited Compounds useful in hiv therapy
US20230011378A1 (en) 2019-08-08 2023-01-12 Institute For Cancer Research D/B/A The Research Institute Of Fox Chase Cancer Center Combination Therapy For Treatment Of Cancer
JP7659553B2 (ja) * 2019-11-08 2025-04-09 サンフォード バーンハム プレビス メディカル ディスカバリー インスティテュート アポトーシス阻害（ｉａｐ）タンパク質アンタゴニスト
WO2023056069A1 (en) 2021-09-30 2023-04-06 Angiex, Inc. Degrader-antibody conjugates and methods of using same
WO2025090605A1 (en) * 2023-10-24 2025-05-01 University Of Houston System Combination of iap inhibitors and cellular kinase inhibitors, such as ponatinib, for use in the treatment of cancer or pulmonary diseases, such as copd, cystic fibrosis, pulmonary fibrosis and covid-19

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4107288A (en) 1974-09-18 1978-08-15 Pharmaceutical Society Of Victoria Injectable compositions, nanoparticles useful therein, and process of manufacturing same
US5145684A (en) 1991-01-25 1992-09-08 Sterling Drug Inc. Surface modified drug nanoparticles
US20100190668A1 (en) 2009-01-29 2010-07-29 Takeshi Hishinuma Grease Composition and Process for Producing the Same
US20110046189A1 (en) 2008-04-11 2011-02-24 The Regents Of The University Of Michigan Heteroaryl-substituted bicyclic smac mimetics and the uses thereof

Family Cites Families (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5455242A (en) 1991-09-27 1995-10-03 Merrell Dow Pharmaceuticals Inc. Carboxyalkyl tricyclic derivatives useful as inhibitors of enkephalinase and ace
US5457196A (en) 1991-09-27 1995-10-10 Merrell Dow Pharmaceuticals Inc. 2-substituted indane-2-carboxyalkyl derivatives useful as inhibitors of enkephalinase and ACE
NZ256589A (en) 1992-10-30 1996-05-28 Merrell Dow Pharma Condensed azepine analogues and medicaments (where a is c, o or s and b is o or s)
US5508272A (en) 1993-06-15 1996-04-16 Bristol-Myers Squibb Company Compounds containing a fused bicycle ring and processes therefor
FR2803594B1 (fr) * 2000-01-11 2002-07-19 Centre Nat Rech Scient Oligomeres de mimes contraints non peptidiques de dipeptides ou de tripeptides, et leurs utilisations
EP1718300A4 (en) * 2004-01-16 2008-05-14 Univ Michigan CONFORMATIVELY IMPROVED SMAC MIMETIKA AND ITS USES
WO2006014361A1 (en) 2004-07-02 2006-02-09 Genentech, Inc. Inhibitors of iap
US7674787B2 (en) 2004-07-09 2010-03-09 The Regents Of The University Of Michigan Conformationally constrained Smac mimetics and the uses thereof
US20100190688A1 (en) * 2004-07-12 2010-07-29 Bin Chao Tetrapeptide analogs
CA2610396A1 (en) * 2005-06-08 2006-12-14 Novartis Ag Organic compounds
WO2007101347A1 (en) 2006-03-07 2007-09-13 Aegera Therapeutics Inc. Bir domain binding compounds
WO2008124129A2 (en) 2007-04-09 2008-10-16 University Of Massachusetts Treating hiv with a m-csf effector kinase inhibitor like imatinib
BRPI0810522B8 (pt) 2007-04-13 2021-05-25 Univ Michigan Regents compostos miméticos diazo bicíclicos de smac, composição farmacêutica e kit compreendendo ditos compostos e uso dos mesmos para o tratamento de câncer
WO2010120476A2 (en) * 2009-04-01 2010-10-21 Amylin Pharmaceuticals, Inc. N-terminus conformationally constrained glp-1 receptor agonist compounds
US9346852B2 (en) 2011-03-14 2016-05-24 Bristol-Myers Scuibb Company Substituted adipic acid amides and uses thereof
WO2013182662A1 (en) 2012-06-06 2013-12-12 Bionor Immuno As Vaccine
JP6382831B2 (ja) 2012-11-30 2018-08-29 サンフォード−バーンハム メディカル リサーチ インスティテュート アポトーシス阻害タンパク質（ｉａｐ）のアンタゴニスト
US10300074B2 (en) 2014-06-04 2019-05-28 Sanford Burnham Prebys Medical Discovery Institute Use of inhibitor of apoptosis protein (IAP) antagonists in HIV therapy

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4107288A (en) 1974-09-18 1978-08-15 Pharmaceutical Society Of Victoria Injectable compositions, nanoparticles useful therein, and process of manufacturing same
US5145684A (en) 1991-01-25 1992-09-08 Sterling Drug Inc. Surface modified drug nanoparticles
US20110046189A1 (en) 2008-04-11 2011-02-24 The Regents Of The University Of Michigan Heteroaryl-substituted bicyclic smac mimetics and the uses thereof
US20100190668A1 (en) 2009-01-29 2010-07-29 Takeshi Hishinuma Grease Composition and Process for Producing the Same

Non-Patent Citations (12)

* Cited by examiner, † Cited by third party
Title
"Fieser and Fieser's Reagents for Organic Synthesis", vol. 1-40, 1991, JOHN WILEY AND SONS
"Larock's Comprehensive Organic Transformations", vol. 1-5, 1989, ELSEVIER SCIENCE PUBLISHERS
BIN ZHANG ET AL., J. MED. CHEM., vol. 51, no. 23, 2008, pages 7352 - 7355
CAREYSUNDBERG: "Remington's Pharmaceutical Sciences", vol. A, B, 2000, MACK PUBLISHING COMPANY
CLARIDGE, T. ET AL.: "Synthesis and Analysis of Leu-Enkephalin Analogues Containing Reverse Turn Peptidomimetics", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 6, no. 4, 1996, pages 485 - 490, XP004135062 *
GILLEY, C. B.BULLER, M. J.KOBAYASHI, Y., ORG. LETT., vol. 9, 2007, pages 3631
GREENEWUTS: "Protective Groups in Organic Synthesis", 1999, JOHN WILEY & SONS
HYVL, J.SROGL, J., EUR. J. ORG. CHEM., 2010, pages 2849 - 2851
KOCIENSKI: "Protective Groups", 1994, THIEME VERLAG
MITCHELL VAMOS ET AL., ACS CHEM BIOL., vol. 8, no. 4, 2013, pages 725 - 732
See also references of EP2925764A4
SLOMCZYNSKA, U. ET AL.: "Electrochemical Cyclization of Dipeptides To Form Novel Bicyclic, Reverse-Turn Peptidomimetics. 2. Synthesis and Conformational Analysis of 6,5-Bicyclic Systems", JOURNAL OF ORGANIC CHEMISTRY, vol. 61, 1996, pages 1198 - 1204, XP002008591 *

Cited By (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11912786B2 (en) 2012-11-30 2024-02-27 Sanford Burnham Prebys Medical Discovery Institute Inhibitor of apoptosis protein (IAP) antagonists
US11111270B2 (en) 2012-11-30 2021-09-07 Sanford Burnham Prebys Medical Discovery Institute Inhibitor of apoptosis protein (IAP) antagonists
US10544188B2 (en) 2012-11-30 2020-01-28 Sanford Burnham Prebys Medical Discovery Institute Inhibitor of apoptosis protein (IAP) antagonists
US9546174B2 (en) 2012-11-30 2017-01-17 Sanford-Burnham Medical Research Institute Inhibitor of apoptosis protein (IAP) antagonists
US10047119B2 (en) 2012-11-30 2018-08-14 Sanford-Burnham Medical Research Institute Inhibitor of apoptosis protein (IAP) antagonists
US10441654B2 (en) 2014-01-24 2019-10-15 Children's Hospital Of Eastern Ontario Research Institute Inc. SMC combination therapy for the treatment of cancer
US10864217B2 (en) 2014-06-04 2020-12-15 Sanford Burnham Prebys Medical Discovery Institute Use of inhibitor of apoptosis protein (IAP) antagonists in HIV therapy
US10300074B2 (en) 2014-06-04 2019-05-28 Sanford Burnham Prebys Medical Discovery Institute Use of inhibitor of apoptosis protein (IAP) antagonists in HIV therapy
WO2015187998A3 (en) * 2014-06-04 2016-02-04 Sanford-Burnham Medical Research Institute Use of inhibitor of apoptosis protein (iap) antagonists in hiv therapy
WO2015187998A2 (en) 2014-06-04 2015-12-10 Sanford-Burnham Medical Research Institute Use of inhibitor of apoptosis protein (iap) antagonists in hiv therapy
WO2016079527A1 (en) 2014-11-19 2016-05-26 Tetralogic Birinapant Uk Ltd Combination therapy
WO2016097773A1 (en) 2014-12-19 2016-06-23 Children's Cancer Institute Therapeutic iap antagonists for treating proliferative disorders
US11492361B2 (en) 2018-11-30 2022-11-08 Glaxosmithkline Intellectual Property Development Limited Compounds useful in HIV therapy
US10870663B2 (en) 2018-11-30 2020-12-22 Glaxosmithkline Intellectual Property Development Limited Compounds useful in HIV therapy
US11873310B2 (en) 2018-11-30 2024-01-16 Glaxosmithkline Intellectual Property Development Limited Compounds useful in HIV therapy
RU2806030C2 (ru) * 2018-11-30 2023-10-25 Глаксосмиткляйн Интеллекуал Проперти Дивелопмент Лимитед Соединения, пригодные для терапии против вич
WO2020148447A1 (en) 2019-01-17 2020-07-23 Debiopharm International S.A. Combination product for the treatment of cancer
CN110028508B (zh) * 2019-05-16 2021-05-28 南京华威医药科技集团有限公司 一种抗肿瘤的重氮双环类细胞凋亡蛋白抑制剂
CN110028508A (zh) * 2019-05-16 2019-07-19 南京华威医药科技集团有限公司 一种抗肿瘤的重氮双环类细胞凋亡蛋白抑制剂
WO2020228478A1 (zh) * 2019-05-16 2020-11-19 南京华威医药科技集团有限公司 一种抗肿瘤的重氮双环类细胞凋亡蛋白抑制剂
WO2021058794A1 (en) 2019-09-25 2021-04-01 Debiopharm International S.A. Dosing regimens for treatment of patients with locally advanced squamous cell carcinoma
WO2021222614A1 (en) * 2020-04-30 2021-11-04 Sanford Burnham Prebys Medical Discovery Institute Inhibitor of apoptosis (iap) protein antagonists
WO2023081290A1 (en) * 2021-11-04 2023-05-11 Sanford Burnham Prebys Medical Discovery Institute Inhibitor of apoptosis (iap) protein antagonists
WO2024121395A1 (en) * 2022-12-09 2024-06-13 Debiopharm International Sa Iap inhibitors, methods of making the same and uses thereof

Also Published As

Publication number Publication date
JP6382831B2 (ja) 2018-08-29
JP2016501223A (ja) 2016-01-18
JP2018162256A (ja) 2018-10-18
US20190135861A1 (en) 2019-05-09
US20150307499A1 (en) 2015-10-29
CA2896577C (en) 2024-01-23
EP2925764A4 (en) 2016-08-03
EP2925764A1 (en) 2015-10-07
US9546174B2 (en) 2017-01-17
US11111270B2 (en) 2021-09-07
EP2925764B1 (en) 2023-03-01
US11912786B2 (en) 2024-02-27
US20170081362A1 (en) 2017-03-23
US10047119B2 (en) 2018-08-14
US10544188B2 (en) 2020-01-28
US20200317731A1 (en) 2020-10-08
US20220119444A1 (en) 2022-04-21
CA2896577A1 (en) 2014-06-05

Similar Documents

Publication Publication Date Title
US11912786B2 (en) Inhibitor of apoptosis protein (IAP) antagonists
US9676778B2 (en) Substituted pyrrolo[2,3-b]pyrazines as JAK3 inhibitors
ES2883450T3 (es) Inhibidores de histona metiltransferasa
EP3541811A1 (en) Inhibitors of bruton's tyrosine kinase
JP7659553B2 (ja) アポトーシス阻害（ｉａｐ）タンパク質アンタゴニスト
AU2021212770A1 (en) Strad-binding agents and uses thereof
US20230295181A1 (en) Inhibitor of apoptosis (iap) protein antagonists
WO2020028525A1 (en) Sumo inhibitor compounds and uses thereof
WO2022197734A1 (en) Bicyclic heteroaryl boronate derivatives as ectonucleotide pyrophosphatase phosphodiesterase 1 inhibitors
WO2025117697A1 (en) 7-aza bicyclic heteroaryl derivatives as ectonucleotide pyrophosphatase phosphodiesterase 1 inhibitors
WO2023081290A1 (en) Inhibitor of apoptosis (iap) protein antagonists

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 13859485

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 2896577

Country of ref document: CA

ENP Entry into the national phase

Ref document number: 2015545193

Country of ref document: JP

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 14648435

Country of ref document: US

NENP Non-entry into the national phase

Ref country code: DE

WWE Wipo information: entry into national phase

Ref document number: 2013859485

Country of ref document: EP