WO2012122391A1 - Heterocyclic modulators of lipid synthesis - Google Patents

Heterocyclic modulators of lipid synthesis Download PDF

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Publication number
WO2012122391A1
WO2012122391A1 PCT/US2012/028309 US2012028309W WO2012122391A1 WO 2012122391 A1 WO2012122391 A1 WO 2012122391A1 US 2012028309 W US2012028309 W US 2012028309W WO 2012122391 A1 WO2012122391 A1 WO 2012122391A1
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WO
WIPO (PCT)
Prior art keywords
alkyl
compound
virus
cycloalkyl
methyl
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/US2012/028309
Other languages
English (en)
French (fr)
Inventor
Johan D. Oslob
Robert S. Mcdowell
Russell Johnson
Hanbiao Yang
Marc EVANCHIK
Cristiana A. Zaharia
Haiying CAI
Lily W. HU
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.)
Sagimet Biosciences Inc
Original Assignee
3V Biosciences Inc
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
Priority to BR122015005121-5A priority Critical patent/BR122015005121B1/pt
Priority to BR112013022761A priority patent/BR112013022761B8/pt
Priority to BR122015005122-3A priority patent/BR122015005122B1/pt
Priority to HRP20170500TT priority patent/HRP20170500T1/hr
Priority to ES12754969.9T priority patent/ES2624131T3/es
Priority to CN201280020832.9A priority patent/CN103561576B/zh
Priority to KR1020137026499A priority patent/KR101930106B1/ko
Priority to EP12754969.9A priority patent/EP2683244B1/en
Priority to AU2012225390A priority patent/AU2012225390B2/en
Priority to MX2013010170A priority patent/MX342287B/es
Priority to EP17153778.0A priority patent/EP3190108B1/en
Priority to KR1020187017297A priority patent/KR101968058B1/ko
Priority to DK12754969.9T priority patent/DK2683244T3/en
Priority to SI201230912A priority patent/SI2683244T1/sl
Priority to EA201391290A priority patent/EA031193B1/ru
Priority to MX2016009579A priority patent/MX369388B/es
Priority to JP2013557870A priority patent/JP5973473B2/ja
Priority to CA2829082A priority patent/CA2829082C/en
Priority to LTEP12754969.9T priority patent/LT2683244T/lt
Application filed by 3V Biosciences Inc filed Critical 3V Biosciences Inc
Priority to NZ614879A priority patent/NZ614879B2/en
Publication of WO2012122391A1 publication Critical patent/WO2012122391A1/en
Priority to IL228276A priority patent/IL228276A/en
Priority to ZA2013/06655A priority patent/ZA201306655B/en
Anticipated expiration legal-status Critical
Priority to IL247804A priority patent/IL247804B/en
Ceased legal-status Critical Current

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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
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    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
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    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
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    • 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
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    • 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
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Definitions

  • the present disclosure relates generally to heterocyclic modulators of lipid synthesis and methods of use thereof.
  • the present heterocyclic modulators of lipid synthesis can be used for the treatment of disorders characterized by disregulation in the fatty acid synthase function in a subject by modulating the fatty acid synthase pathway and/or the fatty acid synthase function.
  • Viral disease is a significant health concern that threatens large segments of human populations.
  • Some of the features related to viral infection which are of concern to health care professionals include its highly contagious nature (e.g., HIV, SARS, etc.) and high mutability.
  • Some viruses are also oncogenic (such as HPV, EBV and HBV). While viruses are structurally amongst the simplest of organisms, they are regarded to be among the most difficult to control and present a daunting challenge for antiviral drug R&D.
  • antiviral drugs widely used in patients, such as Amantadine and Oseltamivir for influenza, Acyclovir for HSV-related infections, Ganciclovir for CMV infection, and multiple agents including co-formulated drugs (Efavirenz, emtricitabine, and tonfovir disoproxil fumarate) for AIDS treatments.
  • co-formulated drugs Esfavirenz, emtricitabine, and tonfovir disoproxil fumarate
  • HCV hepatitis C virus
  • the present standard of care treatment regimen for HCV infection involves combination therapy with interferon-alpha and ribavirin, often with the addition of a direct- acting protease inhibitor (Telaprevir or Boceprevir).
  • Telaprevir or Boceprevir a direct- acting protease inhibitor
  • the treatment is cumbersome and sometimes has debilitating and severe side effects. For this reason, many patients are not treated in early stages of the disease. Additionally, some patient populations do not durably respond to treatment. New and effective methods of treating HCV infection are urgently needed.
  • the present disclosure addresses the deficiencies for antiviral and anticancer treatments by providing novel heterocyclic modulators of lipid synthesis having improved antiviral and anticancer activities.
  • A is CH or N
  • q 0, 1, 2, 3, or 4;
  • R 20 is hydrogen or C 1-6 alkyl, C 1-6 alkoxy, or–N(R 13 )(R 14 );
  • R 2 is hydrogen, halo, C 1-6 alkoxy, C 1-6 alkyl, or R 2 and R 3 taken together with the atoms to which they are attached form a 5-membered heterocyclyl;
  • R 20 , R 4 and R 11 taken together with the atoms to which they are attached join together to form a heteroaryl, or R 11 and R 12 taken together with the atoms to which they are attached join together to form a heteroaryl;
  • R 12 is hydrogen, halo, cyano, C 1-6 alkyl, C 1-6 alkoxy,–N(R 13 R 14 ), CF 3 ,–OCF 3 ,
  • heterocyclyl heteroaryl, or alkylamino
  • R 17 and R 18 are each independently hydrogen or alkyl or can optionally join together to form a bond
  • m 0 or 1.
  • X, Y, and Z are each independently CR or NR', wherein R is hydrogen or C 1-6 alkyl and R' is hydrogen, C 1-6 alkyl, or absent;
  • L and D are each independently C or N;
  • q 0, 1, 2, 3, or 4;
  • R 2 is hydrogen, halo, C 1-6 alkoxy, C 1-6 alkyl, or R 2 and R 3 taken together with the atoms to which they are attached form a 5-membered heterocyclyl;
  • R 11 is hydrogen, halo, cyano, C 1-6 alkyl, C 1-6 alkoxy,–N(R 13 R 14 ), CF 3 ,–OCF 3 ,
  • R 5 , R 6 , R 7 , R 8 , R 9 R 10 , R 13 , and R 14 are each independently hydrogen, C 1-6 alkyl
  • R 15 and R 16 are each independently hydrogen, C 1-6 alkyl, cycloalkyl, aryl,
  • heterocyclyl heteroaryl, or alkylamino
  • R 17 and R 18 are each independently hydrogen or alkyl or can optionally join together to form a bond
  • n 1 or 2;
  • X, Y, and Z are each independently CR or NR', wherein R is hydrogen or C 1-6 alkyl and R' is hydrogen, C 1-6 alkyl, or absent;
  • Q is C or N
  • R 3 is hydrogen, hydroxyl, halo, C 1-6 alkyl, C 1-6 alkoxy, or if Q is N then R 3 is absent;
  • R 11 is hydrogen, halo, cyano, C 1-6 alkyl, C 1-6 alkoxy,–N(R 13 R 14 ), CF 3 ,–OCF 3 ,
  • R 20 , R 4 and R 11 taken together with the atoms to which they are attached join together to form a heteroaryl, or R 11 and R 12 taken together with the atoms to which they are attached join together to form a heteroaryl;
  • R 20 is hydrogen or C 1-6 alkyl, C 1-6 alkoxy, or–N(R 13 )(R 14 );
  • R 5 , R 6 , R 7 , R 8 , R 9 R 10 , R 13 , and R 14 are each independently hydrogen, C 1-6 alkyl
  • R 15 and R 16 are each independently hydrogen, C 1-6 alkyl, cycloalkyl, aryl,
  • heterocyclyl heteroaryl, or alkylamino
  • R 19 is aryl, heteroaryl, cycloalkyl, or heterocyclyl
  • n 0, 1, or 2;
  • the present disclosure provides for compounds of Structures (IV- A), (IV-B), or (IV-C):
  • q 0, 1, 2, 3, or 4;
  • R 20 is hydrogen or C 1-6 alkyl, C 1-6 alkoxy, or–N(R 13 )(R 14 );
  • R 2 is hydrogen, halo, C 1-6 alkoxy, or C 1-6 alkyl
  • R 3 is hydrogen, hydroxyl, halo, C 1-6 alkyl, or C 1-6 alkoxy;
  • R 23 is hydrogen,–N(R 13 )(R 14 ), C 1-6 alkyl, C 1-6 alkoxy, is absent if L 1 is N, or R 23 and R 24 taken together with the atoms to which they are attached join together to form a heterocyclyl, heteroaryl, or cycloalkyl;
  • R 24 is hydrogen,–N(R 13 )(R 14 ), C 1-6 alkyl, C 1-6 alkoxy,–(C 1-6 alkoxy)(heterocyclyl), heterocyclyl, or R 23 and R 24 taken together with the atoms to which they are attached join together to form a heterocyclyl, heteroaryl, or cycloalkyl;
  • R 13 and R 14 are each independently hydrogen, C 1-6 alkyl, cycloalkyl, aryl,
  • R 15 and R 16 are each independently hydrogen, C 1-6 alkyl, C 1-6 alkoxy, cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl, or alkylamino.
  • L 7 is N or O, wherein R 30 is absent if L 7 is O;
  • A is CH or N
  • R 20 is hydrogen or C 1-6 alkyl, C 1-6 alkoxy, or–N(R 13 )(R 14 );
  • R 2 is hydrogen, halo, C 1-6 alkoxy, or C 1-6 alkyl
  • R 3 is halo, C 1-6 alkyl, or C 1-6 alkoxy
  • R 46 and R 47 are each independently hydrogen, C 1-6 alkyl, cycloalkyl, aryl,
  • R 48 is alkyl or is absent;
  • R 31 is hydrogen, C 1-6 alkyl, or C 1-6 alkoxy
  • R 13 and R 14 are each independently hydrogen, C 1-6 alkyl, cycloalkyl, aryl,
  • R 15 and R 16 are each independently hydrogen, C 1-6 alkyl, cycloalkyl, aryl,
  • heterocyclyl heteroaryl, hydroxyalkyl, or alkylamino
  • v 0 or 1.
  • L 13 , L 14 , L 15 , and A are each independently CH or N;
  • q 0, 1, 2, 3, or 4;
  • R 20 is hydrogen or C 1-6 alkyl, C 1-6 alkoxy, or–N(R 13 )(R 14 );
  • R 3 is halo, C 1-6 alkyl, or C 1-6 alkoxy
  • R 35 is hydrogen, C 1-6 alkyl, or C 1-6 alkoxy;
  • R 36 is hydrogen, C 1-6 alkyl, C 1-6 alkoxy,–N(R 15 R 16 ), heterocyclyl, or heteroaryl;
  • R 13 and R 14 are each independently hydrogen, C 1-6 alkyl, cycloalkyl, aryl,
  • R 15 and R 16 are each independently hydrogen, C 1-6 alkyl, C 1-6 alkoxy, cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl, or alkylamino.
  • R 1 is H, -CN, halogen, C 1 -C 4 straight or branched alkyl, -O-(C 3 -C 5 cycloalkyl),
  • each R 2 is independently H, halogen or C 1 -C 4 straight or branched alkyl
  • R 21 is cyclobutyl, azetidin-1-yl, or cyclopropyl
  • R 22 is H, halogen, or C 1 -C 2 alkyl
  • R 35 is–C(O)-R 351 , -C(O)-NHR 351 , -C(O)-O-R 351 or S(O) 2 R 351 ;
  • R 351 is C 1 -C 6 straight or branched alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl.
  • R 3 is H or halogen.
  • R 1 is–CF 3 .
  • the present disclosure provides for compounds of Structures (VIII- A), (VIII-B), or (VIII-C):
  • R 2 is hydrogen, halo, C 1-6 alkoxy, or C 1-6 alkyl
  • R 3 is hydrogen, hydroxyl, halo, C 1-6 alkyl, or C 1-6 alkoxy;
  • R 39 is hydrogen, C 1-6 alkyl, or C 1-6 alkoxy;
  • R 13 and R 14 are each independently hydrogen, C 1-6 alkyl, cycloalkyl, aryl,
  • C 3 -C 5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom; and when R 1 is not H, -CN or halogen, it is optionally substituted with one or more halogens;
  • R 24 is H, C 1 -C 4 straight or branched alkyl, -(C 1 -C 4 alkyl) t -OH ,
  • L 1 or L 2 is N;
  • R 21 is halogen, C 1 -C 4 straight or branched alkyl, C 3 -C 5 cycloalkyl wherein the C 3 -C 5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom,–S(O) u -(C 1 -C 4 straight or branched alkyl) wherein u is 0 or 2, or
  • R 3 is H or halogen.
  • R 1 is halogen,–CN or C 1 -C 2 haloalkyl.
  • both L 1 and L 2 are N.
  • R 21 is C 1 -C 2 alkyl or C 3 -C 5 cycloalkyl and R 22 is C 1 -C 2 alkyl.
  • R 21 is C 3 -C 5 cycloalkyl and R 22 is C 1 -C 2 alkyl.
  • R 24 is -(C 1 -C 2 alkyl) t -O-(C 1 -C 2 alkyl) wherein t is 0 or 1.
  • R 21 is C 3 -C 5 cycloalkyl
  • R 22 is C 1 -C 2 alkyl
  • R 24 is C 1 -C 2 alkyl.
  • R 1 is–CN.
  • R 1 is–CN, each R 2 is H, R 3 is H or F, R 21 is C 3 -C 4 cycloalkyl, R 22 is methyl, L 1 and L 2 are N, and R 24 is methoxy or ethoxy.
  • R 1 is–CN, each R 2 is H, R 3 is H or F, R 21 is C 3 -C 4 cycloalkyl, R 22 is methyl, L 1 is CH, L 2 is N, and R 24 is methyl, ethyl, hydroxymethyl, methoxymethyl, or 2-methoxyethyl.
  • R 1 is–CN, each R 2 is H, R 3 is H or F, R 21 is C 3 -C 4 cycloalkyl, R 22 is methyl, L 1 is N, L 2 is CH, and R 24 is methyl, ethyl, hydroxymethyl, methoxymethyl, or 2-methoxyethyl.
  • compounds have a structure selected from the rou consistin of:
  • R 1 is H, -CN, halogen, C 1 -C 4 straight or branched alkyl, -O-(C 3 -C 5 cycloalkyl),
  • each R 2 is independently hydrogen, halogen or C 1 -C 4 straight or branched alkyl
  • R 3 is H, -OH or halogen;
  • L 3 is C(R 60 ) 2 , O or NR 50 ;
  • each R 60 is independently H, -OH, -CN, -O t -(C 3 -C 5 cycloalkyl), -O-(C 1 -C 4 straight or branched alkyl), or -C(O)-N(R 601 ) 2 wherein:
  • t 0 or 1
  • each R 50 is independently H,–C(O)-O t -(C 1 -C 4 straight or branched alkyl),
  • the C 3 -C 5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom
  • n 1, 2 or 3;
  • n 1 or 2;
  • R 21 is H, halogen, C 1 -C 4 straight or branched alkyl, C 3 -C 5 cycloalkyl wherein the C 3 -C 5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom
  • R 22 is H, halogen, C 1 -C 2 alkyl
  • each R 26 is independently–OH, -CN, halogen, C 1 -C 4 straight or branched alkyl,
  • t 0 or 1
  • the C 3 -C 5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom
  • s 0, 1 or 2;
  • two of R 26 , R 60 , R 50 , R 501 and R 601 optionally join to form a ring wherein the two of R 26 , R 60 , R 50 , R 501 and R 601 may be two R 26 , two R 60 , two R 50 , two R 501 or two R 601 .
  • R 21 is halogen, C 1 -C 4 straight or branched alkyl or C 3 -C 5 cycloalkyl.
  • R 3 is H or F.
  • R 1 is–CN.
  • R 1 is–CF 3 .
  • n 1
  • m is 1 [0071] In some aspects of Structure (X), m is 2.
  • R 21 is C 1 -C 2 alkyl or C 3 -C 5 cycloalkyl and R 22 is C 1 - C 2 alkyl.
  • R 21 is C 3 -C 5 cycloalkyl and R 22 is C 1 -C 2 alkyl.
  • n is 2
  • m is 1
  • L 3 is -N–C(O)-O-(C 1 -C 2 alkyl).
  • L 3 is NR 50 ;
  • R 50 is C 1 -C 2 alkyl;
  • R 21 is cyclobutyl;
  • R 22 is H or methyl;
  • R 3 is H;
  • R 1 is -CN;
  • m is 2 and n is 1 or 2.
  • n is 2, m is 1, L 3 is O and s is 0.
  • R 22 is H, methyl or ethyl.
  • R 22 is methyl
  • R 22 is H.
  • R 1 is–CN, each R 2 is H, R 3 is H or F, R 21 is C 3 -C 4 cycloalkyl, R 22 is methyl, n is 2 and L 3 is NR 50 where R 50 is methyl or ethyl.
  • the compound has a structure selected from the group consisting of:
  • R 1 is H, -CN, halogen, C 1 -C 4 straight or branched alkyl, -O-(C 3 -C 5 cycloalkyl), -O-(C 1 -C 4 straight or branched alkyl) wherein:
  • the C 3 -C 5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom; and when R 1 is not H, -CN or halogen, it is optionally substituted with one or more halogens;
  • each R 2 is independently H, halogen or C 1 -C 4 straight or branched alkyl
  • R 3 is H, -OH, or halogen
  • R 21 is cyclobutyl, azetidin-1-yl, or cyclopropyl
  • R 22 is H, halogen, C 1 -C 2 alkyl
  • R 351 is C 1 -C 2 alkyl or C 2 -O-(C 1 or C 2 alkyl).
  • R 3 is H or halogen.
  • R 1 is halogen,–CN or C 1 -C 2 haloalkyl.
  • R 21 is C 3 -C 4 cycloalkyl and R 22 is C 1 -C 2 alkyl.
  • Base addition salts are formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base.
  • a metal ion e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion
  • X, Y, and Z are each independently CR or NR', wherein R is hydrogen or C 1-6 alkyl and R' is hydrogen, C 1-6 alkyl, or absent;
  • A is CH or N
  • R 2 is hydrogen, halo, C 1-6 alkoxy, C 1-6 alkyl, or R 2 and R 3 taken together with the atoms to which they are attached form a 5-membered heterocyclyl;
  • R 20 , R 4 and R 11 taken together with the atoms to which they are attached join together to form a heteroaryl, or R 11 and R 12 taken together with the atoms to which they are attached join together to form a heteroaryl;
  • R 5 , R 6 , R 7 , R 8 , R 9 R 10 , R 13 , and R 14 are each independently hydrogen, C 1-6 alkyl
  • R 17 and R 18 are each independently hydrogen or alkyl or can optionally join together to form a bond;
  • n 1 or 2;
  • m 0 or 1.
  • R 3 is F.
  • X, Y, and Z are NR'.
  • the compounds of Structure (I) have one of the following Structures (I-A) or (I-B):
  • X, Y, and Z are each independently CR or NR', wherein R is hydrogen or C 1-6 alkyl and R' is hydrogen, C 1-6 alkyl, or absent;
  • q 0, 1, 2, 3, or 4;
  • R 2 is hydrogen, halo, C 1-6 alkoxy, C 1-6 alkyl, or R 2 and R 3 taken together with the atoms to which they are attached form a 5-membered heterocyclyl
  • R 3 is hydrogen, hydroxyl, halo, C 1-6 alkyl, C 1-6 alkoxy, or R 2 and R 3 taken together with the atoms to which they are attached form a 5-membered heterocyclyl
  • R 11 is hydrogen, halo, cyano, C 1-6 alkyl, C 1-6 alkoxy,–N(R 13 R 14 ), CF 3 ,–OCF 3 ,
  • R 20 , R 4 and R 11 taken together with the atoms to which they are attached join together to form a heteroaryl, or R 11 and R 12 taken together with the atoms to which they are attached join together to form a heteroaryl;
  • R 12 is hydrogen, halo, cyano, C 1-6 alkyl, C 1-6 alkoxy,–N(R 13 R 14 ), CF 3 ,–OCF 3 ,
  • R 5 , R 6 , R 7 , R 8 , R 9 R 10 , R 13 , and R 14 are each independently hydrogen, C 1-6 alkyl
  • R 15 and R 16 are each independently hydrogen, C 1-6 alkyl, cycloalkyl, aryl,
  • heterocyclyl heteroaryl, or alkylamino
  • R 17 and R 18 are each independently hydrogen or alkyl or can optionally join together to form a bond.
  • the compounds of Structure (I) have one of the following Structures (I-C) or (I-D):
  • X, Y, and Z are each independently CR or NR', wherein R is hydrogen or C 1-6 alkyl and R' is hydrogen, C 1-6 alkyl, or absent;;
  • R 2 is hydrogen, halo, C 1-6 alkoxy, C 1-6 alkyl, or R 2 and R 3 taken together with the atoms to which they are attached form a 5-membered heterocyclyl;
  • R 3 is hydrogen, hydroxyl, halo, C 1-6 alkyl, C 1-6 alkoxy, or R 2 and R 3 taken together with the atoms to which they are attached form a 5-membered heterocyclyl;
  • R 20 is hydrogen or C 1-6 alkyl, C 1-6 alkoxy, or–N(R 13 )(R 14 );
  • R 11 is hydrogen, halo, cyano, C 1-6 alkyl, C 1-6 alkoxy,–N(R 13 R 14 ), CF 3 ,–OCF 3 ,
  • R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 are each independently H, C 1-6 alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, alkylamino, or -N(R 15 R 16 ); and
  • R 15 and R 16 are each independently H, C 1-6 alkyl, cycloalkyl, aryl, heterocyclyl,
  • heteroaryl or alkylamino.
  • the compounds of Structure (I) have one of the following Structures (I-E), (I-F), (I-G), (I-H):
  • R 2 is hydrogen, halo, C 1-6 alkoxy, C 1-6 alkyl, or R 2 and R 3 taken together with the atoms to which they are attached form a 5-membered heterocyclyl;
  • R 3 is hydrogen, hydroxyl, halo, C 1-6 alkyl, C 1-6 alkoxy, or R 2 and R 3 taken together with the atoms to which they are attached form a 5-membered heterocyclyl;
  • R 20 is hydrogen or C 1-6 alkyl, C 1-6 alkoxy, or–N(R 13 )(R 14 );
  • R 11 is hydrogen, halo, cyano, C 1-6 alkyl, C 1-6 alkoxy,–N(R 13 R 14 ), CF 3 ,–OCF 3 ,
  • R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 13 , and R 14 are each independently H, C 1-6 alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, alkylamino, or -N(R 15 R 16 ); and
  • R 15 and R 16 are each independently H, C 1-6 alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, or alkylamino.
  • the compounds of Structure (I) have one of the following Structures(I-I), (I-J), or (I-K):
  • X and Y are each independently CR or NR', wherein R is H or C 1-6 alkyl and R' is H, C 1-6 alkyl, or absent;
  • q 0, 1, 2, 3, or 4;
  • R 20 is hydrogen or C 1-6 alkyl, C 1-6 alkoxy, or–N(R 13 )(R 14 );
  • R 2 is hydrogen, halo, C 1-6 alkoxy, C 1-6 alkyl, or R 2 and R 3 taken together with the atoms to which they are attached form a 5-membered heterocyclyl;
  • R 3 is hydrogen, hydroxyl, halo, C 1-6 alkyl, C 1-6 alkoxy, or R 2 and R 3 taken together with the atoms to which they are attached form a 5-membered heterocyclyl;
  • R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 are each independently H, C 1-6 alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, alkylamino, or -N(R 15 R 16 ); and
  • R 15 and R 16 are each independently H, C 1-6 alkyl, cycloalkyl, aryl, heterocyclyl,
  • heteroaryl or alkylamino.
  • the compounds of Structure (I) have one of the following Structures(I-L) or (I-M):
  • R 15 and R 16 are each independently H, C 1-6 alkyl, cycloalkyl, aryl, heterocyclyl,
  • the compounds of Structure (I) have one of the following Structures (I-N) or (I-O):
  • the compounds of Structure (I) have the following Structure (I- P):
  • R 2 is hydrogen, halo, C 1-6 alkoxy, C 1-6 alkyl, or R 2 and R 3 taken together with the atoms to which they are attached form a 5-membered heterocyclyl;
  • R 3 is hydrogen, hydroxyl, halo, C 1-6 alkyl, C 1-6 alkoxy, or R 2 and R 3 taken together with the atoms to which they are attached form a 5-membered heterocyclyl;
  • R 20 is hydrogen or C 1-6 alkyl, C 1-6 alkoxy, or–N(R 13 )(R 14 );
  • R 11 is hydrogen, halo, cyano, C 1-6 alkyl, C 1-6 alkoxy,–N(R 13 R 14 ), CF 3 ,–OCF 3 ,
  • R 20 , R 4 and R 11 taken together with the atoms to which they are attached join together to form a heteroaryl, or R 11 and R 12 taken together with the atoms to which they are attached join together to form a heteroaryl;
  • R 12 is hydrogen, halo, cyano, C 1-6 alkyl, C 1-6 alkoxy,–N(R 13 R 14 ), CF 3 ,–OCF 3 ,
  • R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 13 , and R 14 are each independently H, C 1-6 alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, alkylamino, or -N(R 15 R 16 ); and
  • heteroaryl or alkylamino.
  • the compounds of Structure (I) have one of the following Structures (I-Q), (I-R), or (I-S):
  • X, Y, and Z are each independently CR or NR', wherein R is H or C 1-6 alkyl and R' is H, C 1-6 alkyl, or absent;
  • q 0, 1, 2, 3, or 4;
  • R 20 is hydrogen or C 1-6 alkyl, C 1-6 alkoxy, or–N(R 13 )(R 14 );
  • R 2 is hydrogen, halo, C 1-6 alkoxy, C 1-6 alkyl, or R 2 and R 3 taken together with the atoms to which they are attached form a 5-membered heterocyclyl;
  • R 3 is hydrogen, hydroxyl, halo, C 1-6 alkyl, C 1-6 alkoxy, or R 2 and R 3 taken together with the atoms to which they are attached form a 5-membered heterocyclyl;
  • R 11 is hydrogen, halo, cyano, C 1-6 alkyl, C 1-6 alkoxy,–N(R 13 R 14 ), CF 3 ,–OCF 3 ,
  • R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 13 , and R 14 are each independently H, C 1-6 alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, alkylamino, or -N(R 15 R 16 ); and
  • the compounds of Structure (I) have the following Structure (I- U):
  • the compounds of Structure (I) have one of the following Structures (I-V):
  • L and D are each independently C or N;
  • R 3 is hydrogen, hydroxyl, halo, C 1-6 alkyl, C 1-6 alkoxy, or R 2 and R 3 taken together with the atoms to which they are attached form a 5-membered heterocyclyl;
  • R 11 is hydrogen, halo, cyano, C 1-6 alkyl, C 1-6 alkoxy,–N(R 13 R 14 ), CF 3 ,–OCF 3 ,
  • R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 13 , and R 14 are each independently H, C 1-6 alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, alkylamino, or -N(R 15 R 16 );
  • R 15 and R 16 are each independently H, C 1-6 alkyl, cycloalkyl, aryl, heterocyclyl,
  • heteroaryl or alkylamino
  • R 17 and R 18 are each independently hydrogen or alkyl or can optionally join together to form a bond
  • n 1 or 2;
  • m 0 or 1.
  • the compounds of Structure (II) have the following Structure (II-A):
  • X, Y, and Z are each independently CR or NR', wherein R is H or C 1-6 alkyl and R' is H, C 1-6 alkyl, or absent;
  • R 2 is hydrogen, halo, C 1-6 alkoxy, C 1-6 alkyl, or R 2 and R 3 taken together with the atoms to which they are attached form a 5-membered heterocyclyl;
  • R 3 is hydrogen, hydroxyl, halo, C 1-6 alkyl, C 1-6 alkoxy, or R 2 and R 3 taken together with the atoms to which they are attached form a 5-membered heterocyclyl;
  • R 20 is hydrogen or C 1-6 alkyl, C 1-6 alkoxy, or–N(R 13 )(R 14 );
  • R 11 is hydrogen, halo, cyano, C 1-6 alkyl, C 1-6 alkoxy,–N(R 13 R 14 ), CF 3 ,–OCF 3 ,–
  • R 15 and R 16 are each independently H, C 1-6 alkyl, cycloalkyl, aryl, heterocyclyl,
  • heteroaryl or alkylamino.
  • the compounds of Structure (II) have the following Structure (II-B):
  • X and Y are each independently CR or NR', wherein R is H or C 1-6 alkyl and R' is H, C 1-6 alkyl, or absent;
  • R 2 is hydrogen, halo, C 1-6 alkoxy, C 1-6 alkyl, or R 2 and R 3 taken together with the atoms to which they are attached form a 5-membered heterocyclyl;
  • R 3 is hydrogen, hydroxyl, halo, C 1-6 alkyl, C 1-6 alkoxy, or R 2 and R 3 taken together with the atoms to which they are attached form a 5-membered heterocyclyl;
  • R 20 is hydrogen or C 1-6 alkyl, C 1-6 alkoxy, or–N(R 13 )(R 14 );
  • R 11 is hydrogen, halo, cyano, C 1-6 alkyl, C 1-6 alkoxy,–N(R 13 R 14 ), CF 3 ,–OCF 3 ,
  • R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 are each independently H, C 1-6 alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, alkylamino, or -N(R 15 R 16 ); and
  • R 15 and R 16 are each independently H, C 1-6 alkyl, cycloalkyl, aryl, heterocyclyl,
  • the compounds of Structure (II) have one of the following Structures (II-C), (II-D), or (II-E):
  • X and Y are each independently CR or NR', wherein R is H or C 1-6 alkyl and R' is H, C 1-6 alkyl, or absent;
  • R 2 is hydrogen, halo, C 1-6 alkoxy, C 1-6 alkyl, or R 2 and R 3 taken together with the atoms to which they are attached form a 5-membered heterocyclyl;
  • R 3 is hydrogen, hydroxyl, halo, C 1-6 alkyl, C 1-6 alkoxy, or R 2 and R 3 taken together with the atoms to which they are attached form a 5-membered heterocyclyl;
  • R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 are each independently H, C 1-6 alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, alkylamino, or -N(R 15 R 16 ); and
  • R 15 and R 16 are each independently H, C 1-6 alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, or alkylamino.
  • X, Y, and Z are each independently CR or NR', wherein R is H or C 1-6 alkyl and R' is H, C 1-6 alkyl, or absent;
  • Q is C or N
  • R 3 is hydrogen, hydroxyl, halo, C 1-6 alkyl, C 1-6 alkoxy, or if Q is N R 3 is absent;
  • R 20 is hydrogen or C 1-6 alkyl, C 1-6 alkoxy, or–N(R 13 )(R 14 );
  • R 11 is hydrogen, halo, cyano, C 1-6 alkyl, C 1-6 alkoxy,–N(R 13 R 14 ), CF 3 ,–OCF 3 ,
  • R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 13 , and R 14 are each independently H, C 1-6 alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, alkylamino, or -N(R 15 R 16 ); R 15 and R 16 are each independently H, C 1-6 alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, or alkylamino;
  • R 19 is aryl, heteroaryl, cycloalkyl, or heterocyclyl
  • n 0, 1, or 2;
  • m 0 or 1.
  • the compounds of Structure (III) have one of the following Structures (III-A), (III-B), or (III-C):
  • R 3 is hydrogen, hydroxyl, halo, C 1-6 alkyl, or C 1-6 alkoxy;
  • R 11 is hydrogen, halo, cyano, C 1-6 alkyl, C 1-6 alkoxy,–N(R 13 R 14 ), CF 3 ,–OCF 3 ,–
  • R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 are each independently H, C 1-6 alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, alkylamino, or -N(R 15 R 16 ); and
  • R 15 and R 16 are each independently H, C 1-6 alkyl, cycloalkyl, aryl, heterocyclyl,
  • the compounds of Structure (III) have one of the following Structures (III-D), (III-E), or (III-F):
  • the compounds of Structure (IV) have one of the following Structures (IV-A), (IV-B), or (IV-C):
  • L 1 , L 2 , L 3 , L 4 , and A are each independently CH or N;
  • q 0, 1, 2, 3, or 4;
  • R 3 is hydrogen, hydroxyl, halo, C 1-6 alkyl, or C 1-6 alkoxy;
  • R 23 is hydrogen,–N(R 13 )(R 14 ), C 1-6 alkyl, C 1-6 alkoxy, is absent if L 1 is N, or R 23 and R 24 taken together with the atoms to which they are attached join together to form a heterocyclyl, heteroaryl, or cycloalkyl;
  • R 24 is hydrogen,–N(R 13 )(R 14 ), C 1-6 alkyl, C 1-6 alkoxy,–(C 1-6 alkoxy)(heterocyclyl), heterocyclyl, or R 23 and R 24 taken together with the atoms to which they are attached join together to form a heterocyclyl, heteroaryl, or cycloalkyl;
  • R 13 and R 14 are each independently hydrogen, C 1-6 alkyl, cycloalkyl, aryl,
  • R 15 and R 16 are each independently hydrogen, C 1-6 alkyl, C 1-6 alkoxy, cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl, or alkylamino.
  • the compounds of Structure (IV) have one of the following Structures (IV-D) and (IV-E):
  • R 20 is hydrogen or C 1-6 alkyl, C 1-6 alkoxy, or–N(R 13 )(R 14 );
  • R 2 is hydrogen, halo, C 1-6 alkoxy, or C 1-6 alkyl
  • R 13 and R 14 are each independently hydrogen, C 1-6 alkyl, cycloalkyl, aryl,
  • L 6 is CH or N
  • R 1 is cyano
  • R 2 is hydrogen or halo; R 2 is hydrogen.
  • R 3 is hydrogen
  • R 21 and R 22 are each independently hydrogen or C 1-6 alkyl.
  • R 21 and R 22 are each independently C 1-6 alkyl.
  • R 25 is hydrogen
  • L 2 is N.
  • L 1 is CH.
  • L 3 is CH.
  • L 4 is CH.
  • A is N.
  • R 26 is heterocyclyl
  • R 24 is–N(R 13 )(R 14 ).
  • L 5 and L 6 are each independently N. In certain aspects of Structure (IV), s is 1.
  • the compounds of Structure (IV) have one of the following Structures (IV-H), (IV-I), (IV-J), (IV-K), (IV-L), (IV-M), (IV-N), or (IV-O): .
  • L 7 is N or O, wherein R 30 is absent if L 7 is O;
  • A is CH or N
  • R 20 is hydrogen or C 1-6 alkyl, C 1-6 alkoxy, or–N(R 13 )(R 14 );
  • R 3 is halo, C 1-6 alkyl, or C 1-6 alkoxy
  • R 31 is hydrogen, C 1-6 alkyl, or C 1-6 alkoxy
  • heterocyclyl heteroaryl, hydroxyalkyl, or alkylamino
  • v 0 or 1.
  • the compounds of Structure (V) have one of the following Structures (V-A), (V-B), (V-C), or (V-D):
  • q 0, 1, 2, 3, or 4;
  • R 20 is hydrogen or C 1-6 alkyl, C 1-6 alkoxy, or–N(R 13 )(R 14 );
  • R 2 is hydrogen, halo, C 1-6 alkoxy, or C 1-6 alkyl
  • R 3 is halo, C 1-6 alkyl, or C 1-6 alkoxy;
  • R 46 and R 47 are each independently hydrogen, C 1-6 alkyl, cycloalkyl, aryl,
  • R 31 is hydrogen, C 1-6 alkyl, or C 1-6 alkoxy
  • R 15 and R 16 are each independently hydrogen, C 1-6 alkyl, cycloalkyl, aryl,
  • L 8 , L 9 , and L 10 are each independently CH 2 , NH, or O;
  • L 11 and L 12 are each independently CH or N;
  • A is CH.
  • R 2 is hydrogen or halo.
  • R 3 is fluorine
  • R 21 and R 22 are each independently hydrogen or C 1-6 alkyl.
  • R 30 is hydrogen
  • L 8 is O.
  • L 9 is O.
  • the compounds of Structure (VI) have one of the following Structures (VI-A) or (VI-B):
  • q 0, 1, 2, 3, or 4;
  • R 3 is halo, C 1-6 alkyl, or C 1-6 alkoxy
  • the compounds of Structure (VI) have one of the following Structures (VI-C) or (VI-D):
  • q 0, 1, 2, 3, or 4;
  • R 20 is hydrogen or C 1-6 alkyl, C 1-6 alkoxy, or–N(R 13 )(R 14 );
  • R 2 is hydrogen, halo, C 1-6 alkoxy, or C 1-6 alkyl
  • R 3 is halo, C 1-6 alkyl, or C 1-6 alkoxy
  • R 35 is hydrogen, C 1-6 alkyl, or C 1-6 alkoxy
  • R 36 is hydrogen, C 1-6 alkyl, C 1-6 alkoxy,–N(R 15 R 16 ), heterocyclyl, or heteroaryl;
  • R 13 and R 14 are each independently hydrogen, C 1-6 alkyl, cycloalkyl, aryl,
  • R 15 and R 16 are each independently hydrogen, C 1-6 alkyl, C 1-6 alkoxy, cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl, or alkylamino;
  • R 37 and R 38 are each independently hydrogen, C 1-6 alkyl, C 1-6 alkoxy, hydroxyalkyl, heteroaryl, heterocyclyl, or R 37 and R 38 taken together with the atoms to which they are attached join together to form a heteroaryl or heterocyclyl.
  • R 2 is hydrogen or halo.
  • R 2 is hydrogen
  • R 3 is fluorine
  • R 21 and R 22 are each independently hydrogen or C 1-6 alkyl.
  • R 21 and R 22 are each independently C 1-6 alkyl.
  • R 35 is hydrogen
  • R 34 is thienyl, pyrryl, furyl, pyridyl, pyrimidyl, pyrazinyl, pyrazolyl, oxazolyl, isoxazolyl, imidazolyl, thiazolyl, pyranyl, tetrazolyl, pyrrolyl, pyrrolinyl, pyridazinyl, triazolyl, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl, oxadiazolyl, benzoxazolyl, benzoxadiazolyl, thiadiazolyl, benzothiazolyl, or
  • L 13 is N.
  • A is CH.
  • R 1 is H, -CN, halogen, C 1 -C 4 straight or branched alkyl, -O-(C 3 -C 5 cycloalkyl),
  • R 21 is cyclobutyl and R 22 is
  • R 1 is–CN.
  • R 351 is (R)-3-tetrahydrofuranyl or (S)-3- tetrahydrofuranyl.
  • L 16 is C or N, wherein R 41 is absent if L 16 is N;
  • R 1 is cyano
  • L 17 is N.
  • the compounds of Structure (VII) have one of the following Structures (VII-C) or (VII-D):
  • R 13 and R 14 are each independently hydrogen, C 1-6 alkyl, cycloalkyl, aryl,
  • heterocyclyl heteroaryl, hydroxyalkyl, or alkylamino.
  • R 21 and R 22 are each independently hydrogen or C 1-6 alkyl.
  • R 21 and R 22 are each independently C 1-6 alkyl.
  • R 39 is hydrogen
  • L 19 is N.
  • A is N.
  • the compounds of Structure (VIII) have the following Structure (VIII-D):
  • C 3 -C 5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom; and when R 1 is not H, -CN or halogen, it is optionally substituted with one or more halogens;
  • each R 2 is independently hydrogen, halogen or C 1 -C 4 straight or branched alkyl;
  • R 3 is H, -OH, or halogen;
  • R 21 is H, halogen, C 1 -C 4 straight or branched alkyl, C 3 -C 5 cycloalkyl wherein the C 3 - C 5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom;
  • R 22 is H, halogen, or C 1 -C 2 alkyl
  • R 24 is H, C 1 -C 4 straight or branched alkyl, -(C 1 -C 4 alkyl) t -OH ,
  • t is 0 or 1;
  • the C 3 -C 5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom;
  • L 1 is CR 23 or N;
  • L 1 or L 2 is N;
  • R 23 is H or C 1 -C 4 straight or branched alkyl.
  • R 24 is C 1 -C 4 straight or branched alkyl
  • R 21 is halogen, C 1 -C 4 straight or branched alkyl, C 3 -C 5 cycloalkyl wherein the C 3 -C 5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom,–S(O) u -(C 1 -C 4 straight or branched alkyl) wherein u is 0 or 2, or
  • R 3 is H or halogen.
  • R 1 is halogen,–CN or C 1 -C 2 haloalkyl.
  • both L 1 and L 2 are N.
  • R 21 is C 1 -C 2 alkyl or C 3 -C 5 cycloalkyl and R 22 is C 1 -C 2 alkyl.
  • R 21 is C 3 -C 5 cycloalkyl and R 22 is C 1 -C 2 alkyl.
  • R 24 is -(C 1 -C 2 alkyl) t -O-(C 1 -C 2 alkyl) wherein t is 0 or 1.
  • R 21 is C 3 -C 5 cycloalkyl
  • R 22 is C 1 -C 2 alkyl
  • R 24 is C 1 -C 2 alkyl.
  • R 21 is cyclobutyl
  • R 3 is H or F.
  • R 1 is–CN.
  • R 1 is–CF 3 .
  • R 22 is H, methyl or ethyl.
  • R 22 is H.
  • R 22 is methyl
  • R 1 is–CN
  • each R 2 is hydrogen
  • R 3 is H or F
  • R 21 is C 3 -C 4 cycloalkyl
  • R 22 is methyl
  • L 1 and L 2 are N
  • R 24 is methyl, ethyl
  • R 1 is–CN
  • each R 2 is H
  • R 3 is H or F
  • R 21 is C 3 -C 4 cycloalkyl
  • R 22 is methyl
  • L 1 and L 2 are N
  • R 24 is methoxy or ethoxy.
  • R 1 is–CN, each R 2 is H, R 3 is H or F, R 21 is C 3 -C 4 cycloalkyl, R 22 is methyl, L 1 is CH, L 2 is N, and R 24 is methyl, ethyl, hydroxymethyl, methoxymethyl, or 2-methoxyethyl.
  • R 1 is–CN
  • each R 2 is H
  • R 3 is H or F
  • R 21 is C 3 -C 4 cycloalkyl
  • R 22 is methyl
  • L 1 is N
  • L 2 is CH
  • R 24 is methyl, ethyl, hydroxymethyl, methoxymethyl, or 2-methoxyethyl.
  • compounds have a structure selected from the group consisting of:
  • R 1 is H, -CN, halogen, C 1 -C 4 straight or branched alkyl, -O-(C 3 -C 5 cycloalkyl),
  • the C 3 -C 5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom; and when R 1 is not H, -CN or halogen, it is optionally substituted with one or more halogens;
  • each R 2 is independently hydrogen, halogen or C 1 -C 4 straight or branched alkyl
  • R 3 is H, -OH or halogen
  • L 3 is C(R 60 ) 2 , O or NR 50 ;
  • each R 60 is independently H, -OH, -CN, -O t -(C 3 -C 5 cycloalkyl), -O-(C 1 -C 4 straight or branched alkyl), or -C(O)-N(R 601 ) 2 wherein:
  • t 0 or 1
  • the C 3 -C 5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom
  • each R 50 is independently H,–C(O)-O t -(C 1 -C 4 straight or branched alkyl),
  • t 0 or 1
  • the C 3 -C 5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom
  • n 1, 2 or 3;
  • n 1 or 2;
  • R 21 is H, halogen, C 1 -C 4 straight or branched alkyl, C 3 -C 5 cycloalkyl wherein the C 3 -C 5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom
  • R 22 is H, halogen, C 1 -C 2 alkyl
  • each R 26 is independently–OH, -CN, halogen, C 1 -C 4 straight or branched alkyl,
  • t 0 or 1
  • the C 3 -C 5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom
  • s 0, 1 or 2;
  • each R 601 and R 501 is independently H or C 1 -C 4 straight or branched alkyl
  • two of R 26 , R 60 , R 50 , R 501 and R 601 optionally join to form a ring wherein the two of R 26 , R 60 , R 50 , R 501 and R 601 may be two R 26 , two R 60 , two R 50 , two R 501 or two R 601 .
  • R 21 is halogen, C 1 -C 4 straight or branched alkyl or C 3 -C 5 cycloalkyl.
  • R 3 is H or halogen.
  • R 1 is–CN or C 1 -C 2 haloalkyl.
  • R 3 is H or F.
  • R 1 is–CN.
  • R 1 is–CF 3 .
  • n 1
  • n is 2.
  • R 21 is C 1 -C 2 alkyl or C 3 -C 5 cycloalkyl and R 22 is C 1 -C 2 alkyl.
  • R 21 is C 3 -C 5 cycloalkyl and R 22 is C 1 -C 2 alkyl.
  • n is 2
  • m is 1
  • L 3 is -N–C(O)-O-(C 1 -C 2 alkyl).
  • L 3 is NR 50 ;
  • R 50 is C 1 -C 2 alkyl;
  • R 21 is cyclobutyl;
  • R 22 is H or methyl;
  • R 3 is H;
  • R 1 is -CN;
  • m is 2 and n is 1 or 2.
  • n is 2, m is 1, L 3 is O and s is 0.
  • R 22 is H, methyl or ethyl.
  • R 22 is methyl
  • R 22 is H.
  • R 1 is–CN, each R 2 is H, R 3 is H or F, R 21 is C 3 -C 4 cycloalkyl, R 22 is methyl, n is 2 and L 3 is NR 50 where R 50 is methyl or ethyl.
  • R 1 is–CN, each R 2 is H, R 3 is H or F, R 21 is C 3 -C 4 cycloalkyl, R 22 is methyl, n is 2 and L 3 is O.
  • the compound has a structure selected from the group consisting of:
  • R 1 is H, -CN, halogen, C 1 -C 4 straight or branched alkyl, -O-(C 3 -C 5 cycloalkyl),
  • the C 3 -C 5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom; and when R 1 is not H, -CN or halogen, it is optionally substituted with one or more
  • each R 2 is independently H, halogen or C 1 -C 4 straight or branched alkyl
  • R 3 is H, -OH, or halogen
  • R 21 is cyclobutyl, azetidin-1-yl, or cyclopropyl
  • R 22 is H, halogen, C 1 -C 2 alkyl
  • R 351 is C 1 -C 2 alkyl or C 2 -O-(C 1 or C 2 alkyl).
  • R 3 is H or halogen.
  • R 1 is halogen,–CN or C 1 -C 2 haloalkyl.
  • R 21 is C 3 -C 4 cycloalkyl and R 22 is C 1 -C 2 alkyl.
  • R 21 is cyclobutyl and R 22 is C 1 -C 2 alkyl.
  • R 21 is cyclobutyl
  • R 3 is H or F.
  • R 1 is–CN. [0332] In some aspects of Structure (XI), R 1 is–CF 3 .
  • R 22 is H, methyl or ethyl.
  • R 22 is H.
  • R 22 is methyl
  • R 1 is–CN, each R 2 is H, R 3 is H or F, R 21 is cyclobutyl, R 22 is methyl and R 351 is methyl or ethyl.
  • the compound has a structure selected from the group consisting of:
  • the present disclosure provides compounds having any one of the structures found in Table 1. According to the present disclosure, the compounds of Table 1 are inhibitors of fatty acid synthase.
  • R" is hydrogen or alkyl

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DK12754969.9T DK2683244T3 (en) 2011-03-08 2012-03-08 Heterocyclic modulators of lipid synthesis
BR122015005122-3A BR122015005122B1 (pt) 2011-03-08 2012-03-08 Compostos moduladores heterocíclicos de síntese de lipídios, composição farmacêutica que compreende os mesmos, bem como usos dos ditos compostos para tratar uma infecção viral, uma condição que tem como uma característica a desregulação de uma função de ácido graxo sintase e câncer
HRP20170500TT HRP20170500T1 (hr) 2011-03-08 2012-03-08 Heterociklički modulatori sinteze lipida
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CN201280020832.9A CN103561576B (zh) 2011-03-08 2012-03-08 脂质合成的杂环调节剂
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EP12754969.9A EP2683244B1 (en) 2011-03-08 2012-03-08 Heterocyclic modulators of lipid synthesis
AU2012225390A AU2012225390B2 (en) 2011-03-08 2012-03-08 Heterocyclic modulators of lipid synthesis
MX2013010170A MX342287B (es) 2011-03-08 2012-03-08 Moduladores heterociclicos de sintesis lipidica.
EP17153778.0A EP3190108B1 (en) 2011-03-08 2012-03-08 Heterocyclic modulators of lipid synthesis
EA201391290A EA031193B1 (ru) 2011-03-08 2012-03-08 Гетероциклические модуляторы синтеза липидов
BR122015005121-5A BR122015005121B1 (pt) 2011-03-08 2012-03-08 Compostos moduladores heterocíclicos de síntese de lipídios, composição farmacêutica que compreende os mesmos, bem como usos dos ditos compostos para tratar uma infecção viral, uma condição que tem como uma característica a desregulação de uma função de ácido graxo sintase e câncer
SI201230912A SI2683244T1 (sl) 2011-03-08 2012-03-08 Heterociklični modulatorji sinteze lipidov
KR1020187017297A KR101968058B1 (ko) 2011-03-08 2012-03-08 지질 합성의 헤테로사이클릭 조절자
MX2016009579A MX369388B (es) 2011-03-08 2012-03-08 Moduladores heterociclicos de sintesis lipidica.
JP2013557870A JP5973473B2 (ja) 2011-03-08 2012-03-08 脂質合成の複素環式モジュレーター
CA2829082A CA2829082C (en) 2011-03-08 2012-03-08 Heterocyclic modulators of lipid synthesis
LTEP12754969.9T LT2683244T (lt) 2011-03-08 2012-03-08 Lipidų sintezės heterocikliniai moduliatoriai
BR112013022761A BR112013022761B8 (pt) 2011-03-08 2012-03-08 Compostos moduladores heterocíclicos de síntese de lipídios, suas composições e usos
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BR122015005121B1 (pt) 2022-01-25
CA2829082C (en) 2019-07-23
CN105001225B (zh) 2018-04-06
JP5973473B2 (ja) 2016-08-23
KR101968058B1 (ko) 2019-04-10
HUE032459T2 (en) 2017-09-28
HK1216310A1 (zh) 2016-11-04
EA031193B1 (ru) 2018-11-30
JP2016074742A (ja) 2016-05-12
MX369388B (es) 2019-11-07
BR122015005122A2 (pt) 2020-09-24
MX2013010170A (es) 2014-03-12
ZA201306655B (en) 2018-12-19
EP2683244A4 (en) 2014-10-01
EP3190108A1 (en) 2017-07-12
EA201391290A1 (ru) 2014-05-30
JP2016074741A (ja) 2016-05-12
EP3190108B1 (en) 2021-05-19
LT2683244T (lt) 2017-04-10
KR20140025375A (ko) 2014-03-04
SI2683244T1 (sl) 2017-05-31
BR112013022761A2 (pt) 2020-09-01
AU2012225390A1 (en) 2013-05-02
JP2014510727A (ja) 2014-05-01
PL2683244T3 (pl) 2017-08-31
AU2012225390B2 (en) 2015-11-12
CN103561576B (zh) 2015-07-22
MX342287B (es) 2016-09-23
NZ614879A (en) 2015-08-28
CN105001225A (zh) 2015-10-28
BR122015005121A2 (pt) 2020-09-24
PT2683244T (pt) 2017-05-08
IL247804B (en) 2018-11-29

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