WO2019148125A1 - Srebp inhibitors comprising a 6-membered central ring - Google Patents

Srebp inhibitors comprising a 6-membered central ring Download PDF

Info

Publication number
WO2019148125A1
WO2019148125A1 PCT/US2019/015458 US2019015458W WO2019148125A1 WO 2019148125 A1 WO2019148125 A1 WO 2019148125A1 US 2019015458 W US2019015458 W US 2019015458W WO 2019148125 A1 WO2019148125 A1 WO 2019148125A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
cycloalkyl
heterocycloalkyl
compound
pharmaceutically acceptable
Prior art date
Application number
PCT/US2019/015458
Other languages
French (fr)
Inventor
Michael John Green
Barry Patrick Hart
Original Assignee
Capulus Therapeutics, Llc
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 CA3089134A priority Critical patent/CA3089134A1/en
Application filed by Capulus Therapeutics, Llc filed Critical Capulus Therapeutics, Llc
Priority to EA202091848A priority patent/EA202091848A1/en
Priority to AU2019212959A priority patent/AU2019212959A1/en
Priority to KR1020207024962A priority patent/KR20200128531A/en
Priority to CN201980023901.3A priority patent/CN112243374A/en
Priority to BR112020015375-3A priority patent/BR112020015375A2/en
Priority to EP19743447.5A priority patent/EP3746070A4/en
Priority to MX2020007956A priority patent/MX2020007956A/en
Priority to SG11202006853PA priority patent/SG11202006853PA/en
Priority to JP2020562085A priority patent/JP2021512160A/en
Publication of WO2019148125A1 publication Critical patent/WO2019148125A1/en
Priority to IL276276A priority patent/IL276276A/en
Priority to US16/940,212 priority patent/US11718628B2/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • 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
    • C07D491/056—Ortho-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4418—Non condensed pyridines; Hydrogenated derivatives thereof having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • 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
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/40—Acylated substituent nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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

Definitions

  • the present disclosure relates to compounds comprising a three-ring core, their use for inhibiting components of the sterol regulatory element binding protein (SREBP) pathway, such as SREBP or SREBP cleavage activating protein (SCAP), and their use in therapeutic methods of treating conditions and disorders.
  • SREBP sterol regulatory element binding protein
  • SCAP SREBP cleavage activating protein
  • SREBPs are membrane-bound transcription factors that regulate cholesterol, fatty acid, and triglyceride biosynthesis, and lipid uptake.
  • Fatty acids and lipids are a source of energy and important components of many biological structures, such as lipid membranes of cells.
  • SREBP-la controls a broad range of target genes that are involved in the production of fatty acids, triglycerides, phospholipids, and cholesterol.
  • SREBP-lc primarily activates genes which control fatty acid and triglyceride synthesis.
  • SREBP-2 activates genes involved in the synthesis of regulators of cholesterol metabolism, which has been demonstrated in mouse, human, and Drosophila studies.
  • SREBP SREBP cleavage activating protein
  • NASH nonalcoholic steatohepatitis
  • SREBP- lc is the major transcriptional regulator of the biosynthesis of fatty acids, and expression of this transcription factor can be stimulated by androgens and epidermal growth factor in prostate cancer cells. Overexpression of SREBP- lc may drive tumorgenicity and invasion of prostate cancer cells.
  • SREBP-2 itself is also regulated by androgens in a direct feedback circuit of androgen production.
  • prostate cancer cells have dysfunctional cholesterol homeostasis, resulting in accumulation of cholesterol and increased proliferation. This increase in cholesterol levels has been shown to be driven by regulated by increased SREBP-2 activity. SREBP-2 expression increases during disease progression, and is significantly higher after castration compared to prior.
  • Regulating components of the SREBP pathway is an important therapeutic approach for treating disorders, such as metabolic diseases and cancer.
  • disorders such as metabolic diseases and cancer.
  • compounds that can inhibit components of the SREBP pathway such as SREBPs and SCAP.
  • R 16 or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein:
  • R 1 is -C(O)OR 9 , -C(O)NR 8 R 9 , -S(O) 2 NR 8 R 9 , -NR 10 C(O)NR 8 R 9 , -NR 10 C(O)R 9 , -NR 10 S(O)2R 9 ,
  • each of R 8 , R 9 , and R 10 is independently selected from the group consisting of hydrogen, (C 1-10 )alkyl, (C 3-10 )cycloalkyl, (C 3-10 )cycloalkyl(C 1-10 )alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, (C 6-10 )aryl, (C 6-10 )aryl(C 1-10 )alkyl, heteroaryl, and heteroaryl-alkyl,
  • R 26 is (C 1-10 )alkyl, (C 3-10 )cycloalkyl, (C 3-10 )cycloalkyl(C 1-10 )alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, (C 6-10 )aryl, (C 6-10 )aryl(C 1-10 )alkyl, heteroaryl, or heteroaryl-alkyl,
  • heterocycloalkyl-alkyl (C 6-10 )aryl, (C 6-10 )aryl(C 1-10 )alkyl, heteroaryl, and heteroaryl-alkyl of R 8 , R 9 , R 10 , and R 26 is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, (C 1-10 )alkyl, (C 1-10 )haloalkyl, cyano, oxo, -OR 19 , -C(O)NR 19 R 19 , -NR 19 C(O)R 19 , -NR 19 C(O)NR 19 R 19 , -NR 19 R 19 , -S(O) 2 NR 19 R 19 , -NR 19 S(O)2R 19 , -S(O) ⁇ R 20 , -C(O)OR 19 , -C(O)R 20 , and -(OR 38 )n1sOR 19 , each R 19
  • heterocycloalkyl wherein each of the foregoing alkyl, cycloalkyl, or heterocycloalkyl moieties is independently unsubstituted or substituted with one or more halo,
  • each R 20 is independently (C 1-10 )alkyl, (C 3-10 )cycloalkyl,
  • each R 38 is independently (C 1-10 )alkylene or (C 1-10 )haloalkylene,
  • each nlS is independently an integer from 1 to S;
  • n4 is 0, l, or 2;
  • heterocycloalkyl wherein the heterocycloalkyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, cyano, oxo, (C 1-10 )alkyl, (C2-i 0 )alkenyl, (C2-i 0 )alkynyl, (C 3-10 )cycloalkyl, (C 3-10 )cycloalkyl(C 1-10 )alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, (C 6-10 )aryl, (C 6-10 )aryl(C 1-10 )alkyl, heteroaryl, heteroaryl-alkyl, -OR 23 , -C(O)NR 23 R 23 , -NR 23 C(O)R 23 , -NR 23 C(O)OR 23 , -NR 23 C(O)NR 23 R 23 , -NR 23 C(O)OR 23 , -NR 23 C(
  • heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aryl-alkyl, heteroaryl, and heteroaryl-alkyl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, oxo, alkyl, haloalkyl, -OR 31 , -C(O)NR 31 R 31 , -NR 31 C(O)R 31 , -NR 31 C(O)OR 31 , -NR 31 C(O)NR 31 R 31 , -NR 31 S(O) 2 R 31 , and -SiOVR 31 , wherein each R 31 is independently hydrogen, alkyl, or haloalkyl, and each n9 is independently 0, 1, or 2,
  • each R 23 is independently hydrogen, (C 1-10 )alkyl, (C 3-10 )cycloalkyl,
  • each R 24 is independently (C 1-10 )alkyl, (C 3-10 )cycloalkyl,
  • each R 39 is independently (C 1-10 )alkylene or (C 1-10 )haloalkylene, each nl6 is independently an integer from 1 to S; and
  • n6 is O, l, or 2;
  • R 2 and R 3 are independently selected from the group consisting of hydrogen, halo, cyano,
  • each (C 1-10 )alkyl, (C 3-10 )cycloalkyl, and (C 3- ioJcycloalkyliCMoJalkyl is
  • each R 25 is independently hydrogen (C 1-10 )alkyl, (C 3-10 )cycloalkyl,
  • each R 30 is independently (C 1-10 )alkyl, (C 3-10 )cycloalkyl, (C 3-10 )cycloalkyl(C 1-10 )alkyl, or heterocycloalkyl, wherein each of the foregoing is independently unsubstituted or substituted with one or more halo, and
  • n7 is 0, l, or 2;
  • X 1 , X 2 , X 3 and X 4 are independently CR 4 or N, wherein X 2 , X 3 and X 4 may not all be N; when at least one of X 1 , X 2 , X 3 and X 4 is N, each R 4 is independently selected from the group consisting of hydrogen, halo, cyano, (C 1-10 )alkyl, (C 3-10 )cycloalkyl,
  • heterocycloalkyl, and heterocycloalkyl-alkyl is independently unsubstituted or substituted with one or more halo, each R 27 is independently hydrogen or (C 1-10 )alkyl, (C 3-10 )cycloalkyl,
  • heterocycloalkyl wherein each of the foregoing alkyl, cycloalkyl, or heterocycloalkyl moieties is independently unsubstituted or substituted with one or more halo,
  • each R 28 is independently (C 1-10 )alkyl, (C 3-10 )cycloalkyl,
  • n8 is 0 , 1 or 2;
  • each R 4 is independently selected from the group consisting of hydrogen, halo, cyano, (C 1-10 )alkyl, (C 3-10 )cycloalkyl,
  • heterocycloalkyl, and heterocycloalkyl-alkyl is independently unsubstituted or substituted with one or more halo, each R 27 is independently hydrogen, (C 1-10 )alkyl, (C 3-10 )cycloalkyl,
  • each R 28 is independently (C1-10)alkyl, (C 3-10 )cycloalkyl,
  • n8 is 0, 1 , or 2; or
  • carbocyciyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, cyano, (C1-10)alkyl, (C 3-10 )cycloalkyl, (C 3-10 )cycloalkyl(C1-10)alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, -OR 27 , -C(O)NR 27 R 27 , -NR 2 7 C(O)R 27 , -NR 27 R 27 ,
  • heterocyclyl is unsubstituted or substituted with one or more substituents
  • halo independently selected from the group consisting of halo, cyano, (C1-10)alkyl, (C 3-10 )cycloalkyl, (C 3-10 )cycloalkyl(C1-10)alkyl, heterocycloalkyl connected by an annular carbon atom, heterocycloalkyl-alkyl, -OR 2 ', -C(O)NR 27 R 27 , -S(O)2NR 27 R 27 , ⁇ S(O)n8 R 28 , and -C(O)R 28 ,
  • each R 27 is independently hydrogen, (C1-10)alkyl, (C 3-10 )cycloalkyl,
  • each R 28 is independently (C1-10)alkyl, (C 3- ioicycloalkyl, (C 3-10 )cyeloalkylfC! -10 )alkyl, wherein each of the foregoing is independently unsubstituted or substituted with one or more halo, and n8 is 0, l, or 2;
  • R 15 and R 17 are independently hydrogen, halo, alkyl, or -OR 29 , wherein each R 29 is
  • each alkyl or cycloalkyl in R 15 or R 17 is independently unsubstituted or substituted with one or more halo;
  • R 14 is (C 1-10 )alkyl, (C 1-10 )alkenyl, (C 3-10 )cycloalkyl, (C 3-10 )cycloalkenyl,
  • R 16 is hydrogen, fluoro, (C 1-10 )alkyl, (C 3-10 )cycloalkyl, (C 3-10 )cycloalkyl(C 1-10 )alkyl,
  • heterocycloalkyl connected through an annular carbon atom, heterocycloalkyl-alkyl, -OR 5 , -C(O)NR 5 R 5 , -R 5 C(O)NR 5 R 5 , -S(O) 2 NR 5 R 5 , -S(O)n1R 6 , or -C(O)R 6 ;
  • (C 3-10 )cycloalkyl(C 1-10 )alkyl, heterocycloalkyl, heterocycloalkenyl, or heterocycloalkyl- alkyl of R 14 or R 16 is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of (C 1-10 )alkyl, cycloalkyl, heterocycloalkyl, halo, cyano, oxo, -OR 7 , -C(O)OR 7 , -C(O)NR 7 R 7 , -NR 7 C(O)R 7 , -NR 7 C(O)NR 7 R 7 , -NR 7 R 7 , -S(O) 2 NR 7 R 7 , -NR 7 S(O)2R 7 , -S(O)n2R 13 , and -C(O)R 13 ;
  • each alkyl, cycloalkyl, and heterocycloalkyl is independently unsubstituted or substituted with one or more substituents selected from the group consisting of halo, cycloalkyl, halocycloalkyl, heterocycloalkyl, haloheterocycloalkyl, and -(OR 33 )n1oOR 32 , wherein each nlO is independently an integer from 0 to 5, each R 32 is independently hydrogen, (C 1-10 )alkyl or (C 1-10 )haloalkyl, and each R 33 is independently (C 1-10 )alkylene or (C 1-10 )haloalkylene;
  • each R 5 is independently hydrogen, (C 1-10 )alkyl, or (C 3-10 )cycloalkyl; or two R 5 , together with the nitrogen atom to which they are attached, form a heterocycloalkyl; wherein each alkyl, cycloalkyl, or heterocycloalkyl is independently unsubstituted or substituted with one or more substituents selected from the group consisting of halo, cyano, oxo, alkyl, haloalkyl, -C(O)OR 34 , -C(O)NR 34 R 34 , -NR 34 C(O)R 34 , -NR 34 C(O)NR 34 R 34 , -NR 34 R 34 , -S(O) 2 NR 34 R 34 , -NR 34 S(O)2R 34 , -S(O)n11R 34 , -C(O)R 34 , and -(OR 35 )n 12 OR 34 , wherein each R 34 is independently
  • each nl2 is independently an integer from 0 to 5; and each R 35 is independently (C 1-10 )alkylene or (C 1-10 )haloalkylene;
  • each R 6 is independently (C 1-10 )alkyl or (C 3-10 )cycloalkyl, wherein each alkyl or cycloalkyl is independently unsubstituted or substituted with one or more halo;
  • each nl is independently 0, 1, or 2;
  • each R 7 is independently hydrogen, unsubstituted (C 1-10 )alkyl, or (C 1-10 )alkyl substituted with one or more halo;
  • each n2 is independently 0, 1, or 2
  • each R 13 is independently unsubstituted (C 1-10 )alkyl or (C 1-10 )alkyl substituted with one or more halo;
  • carbocyclyl or heterocyclyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, cyano, oxo, (C 1-10 )alkyl, (C 3-10 )cycloalkyl, (C 3-10 )cycloalkyl(C 1-10 )alkyl, -OR 18 , -C(O)NR 18 R 18 , -NR 18 C(O)R 18 , -NR ,8 C(O)NR ,8 R 18 , -NR 18 R 18 , -S(O)2NR ,8 R 18 , -NR 18 S(O)2R 18 , -S(O) ⁇ R 21 , -C(O)OR 18 , and -C(O)R 21 ,
  • each (C 1-10 )alkyl, (C 3-10 )cycloalkyl, and (C 3-10 )cycloalkyl(C 1-10 )alkyl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, alkyl, haloalkyl, cyano, oxo, -C(O)OR 36 , -C(O)NR 36 R 36 , -NR 36 C(O)R 36 ,
  • cycloalkyl is independently unsubstituted or substituted with one or more halo
  • each n3 is independently 0, 1, or 2.
  • the compound of Formula (X) is a compound of Formula (X-A):
  • R 1 , R 2 , R 3 , R 14 , R 15 , R 16 , R 17 , X 1 , X 2 , X 3 , and X 4 are as described for Formula (X) above.
  • the compound of Formula (X) or Formula (X-A) is a compound of Formula (X-Ai):
  • the compound of Formula (X) is a compound of Formula (X-B):
  • R 1 , R 2 , R 3 , R 14 , R 15 , R 16 , R 17 , X 1 , X 2 , X 3 , and X 4 are as described for Formula (X) above.
  • the compound of Formula (X) or Formula (X-B) is a compound of Formula (X-Bi):
  • R 1 , R 2 , R 3 , R 14 , R 15 , R 16 , R 17 , X 1 , X 2 , X 3 , and X 4 are as described for Formula (X) above.
  • R 17 is hydrogen.
  • R 1 is -C(O)NR 8 R 9 , -S(O)2NR 8 R 9 ,
  • R 10 is hydrogen.
  • R 1 is -C(O)NR 8 R 9 , and the R 8 and R 9 together with the nitrogen to which they are attached form an unsubstituted or substituted heterocycloalkyl.
  • R 2 is halo.
  • R 4 is independently selected from the group consisting of hydrogen, halo, cyano, (C 1-10 )alkyl, and -OR 27 .
  • R 3 is hydrogen.
  • R 1 is -C(O)OR 9 , -C(O)NR 8 R 9 , -S(O) 2 NR 8 R 9 , -NR 10 C(O)NR 8 R 9 , -NR 10 C(O)R 9 , -NR 10 S(O)2R 9 , -OR 26 , -SR 9 , -S(O)R 9 , -S(O)2R 9 , -NR 8 R 9 , or -NR 10 C(O)OR 9 .
  • a pharmaceutical composition which comprises a compound of Formula (X), such as a compound of Formula (X-A), (X-B), (X-Ai), or (X-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer of any of the foregoing, and a pharmaceutically acceptable excipient.
  • a compound of Formula (X) such as a compound of Formula (X-A), (X-B), (X-Ai), or (X-Bi)
  • a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer of any of the foregoing and a pharmaceutically acceptable excipient.
  • a method of inhibiting a sterol regulatory element-binding protein by contacting the SREBP or contacting an SREBP cleavage activating-protein (SCAP) with a compound of Formula (X), such as a compound of Formula (X-A), (X-B), (X-Ai), or (X-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer of any of these; or a pharmaceutical composition comprising any of the foregoing and a pharmaceutically acceptable excipient.
  • a compound of Formula (X) such as a compound of Formula (X-A), (X-B), (X-Ai), or (X-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer of any of these; or a pharmaceutical composition comprising any of the foregoing and a pharmaceutically acceptable excipient.
  • a method of inhibiting the proteolytic activation of a sterol regulatory element-binding protein by contacting an SREBP cleavage activating-protein (SCAP) with a compound of Formula (X), such as a compound of Formula (X-A), (X-B), (X-Ai), or (X-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer of any of these; or a pharmaceutical composition comprising any of the foregoing and a pharmaceutically acceptable excipient.
  • a compound of Formula (X) such as a compound of Formula (X-A), (X-B), (X-Ai), or (X-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer of any of these; or a pharmaceutical composition comprising any of the foregoing and a pharmaceutically acceptable excipient.
  • a method of treating a disorder in a subject in need thereof by administering to the subject in need thereof an effective amount of a compound of Formula (X), such as a compound of Formula (X-A), (X-B), (X-Ai), or (X-Bi), or a
  • a compound of Formula (X) such as a compound of Formula (X-A), (X-B), (X-Ai), or (X-Bi), or a
  • compound of Formula (X) such as a compound of Formula (X-A), (X-B), (X-Ai), or (X-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer of any of these, in the manufacture of a medicament for use in inhibiting a sterol regulatory element-binding protein (SREBP) in a subject in need thereof.
  • SREBP sterol regulatory element-binding protein
  • a compound of Formula (X) such as a compound of Formula (X-A), (X-B), (X-Ai), or (X-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer of any of these, in the manufacture of a medicament for use in inhibiting the proteolytic activation of a sterol regulatory element-binding protein (SREBP) in a subject in need thereof.
  • SREBP sterol regulatory element-binding protein
  • a compound of Formula (X) such as a compound of Formula (X-A), (X-B), (X-Ai), or (X-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer of any of these, in the manufacture of a medicament for use in treating a disorder in a subject in need thereof.
  • a compound of Formula (X) such as a compound of Formula (X-A), (X-B), (X-Ai), or (Z-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer of any of these, in the manufacture of a medicament for use in treating a disorder in a subject in need thereof, wherein the disorder is mediated by a sterol regulatory element-binding protein (SREBP).
  • SREBP sterol regulatory element-binding protein
  • a compound of Formula (X) such as a compound of Formula (X-A), (X-B), (X-Ai), or (Z-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer of any of these; or a pharmaceutical composition comprising any of the foregoing and a pharmaceutically acceptable excipient, for inhibiting a sterol regulatory element-binding protein (SREBP).
  • SREBP sterol regulatory element-binding protein
  • a compound of Formula (X) such as a compound of Formula (X-A), (X-B), (X-Ai), or (X-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer of any of these; or a pharmaceutical composition comprising any of the foregoing and a pharmaceutically acceptable excipient, for use in inhibiting the proteolytic activation of a sterol regulatory element-binding protein (SREBP).
  • SREBP sterol regulatory element-binding protein
  • a compound of Formula (X) such as a compound of Formula (X-A), (X-B), (X-Ai), or (X-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer of any of these; or a pharmaceutical composition comprising any of the foregoing and a pharmaceutically acceptable excipient, for treating a disorder in a subject in need thereof.
  • a compound of Formula (X) such as a compound of Formula (X-A), (X-B), (X-Ai), or (X-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer of any of these; or a pharmaceutical composition comprising any of the foregoing and a pharmaceutically acceptable excipient, for treating a disorder in a subject in need thereof, wherein the disorder is mediated by a sterol regulatory element-binding protein (SREBP).
  • SREBP sterol regulatory element-binding protein
  • the SREBP is an SREBP- 1.
  • the SREBP is SREBP-la.
  • the SREBP is SREBP- lc.
  • the SREBP is SREBP-2.
  • the disorder is Metabolic Syndrome, type 2 diabetes, obesity, fatty liver disease, insulin resistance, adiposopathy, or dyslipidemia.
  • the disorder is a hyperproliferative disorder, such as cancer.
  • the disorder is endotoxic shock, systemic inflammation, or
  • a method of treating fatty liver disease in a subject in need thereof by administering to the subject in need thereof an effective amount of a compound of Formula (X), such as a compound of Formula (X-A), (X-B), (X-Ai), or (X-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer of any of these; or a pharmaceutical composition comprising any of the foregoing and a pharmaceutically acceptable excipient.
  • a compound of Formula (X) such as a compound of Formula (X-A), (X-B), (X-Ai), or (X-Bi)
  • a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer of any of these or a pharmaceutical composition comprising any of the foregoing and a pharmaceutically acceptable excipient.
  • a compound of Formula (X) such as a compound of Formula (X-A), (X-B), (X-Ai), or (Z-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof; or a pharmaceutical composition comprising any of the foregoing and a pharmaceutically acceptable excipient, for treating fatty liver disease in a subject in need thereof.
  • a compound of Formula (X) such as a compound of Formula (X-A), (X-B), (X-Ai), or (X-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer of any of these, in the manufacture of a medicament for use in treating fatty liver disease in a subject in need thereof.
  • NASH non-alcoholic steatohepatitis
  • a compound of Formula (X) such as a compound of Formula (X-A), (X-B), (X-Ai), or (X-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer of any of these; or a pharmaceutical composition comprising any of the foregoing and a pharmaceutically acceptable excipient
  • a compound of Formula (X) such as a compound of Formula (X-A), (X-B), (X-Ai), or (X-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof; or a pharmaceutical composition comprising any of the foregoing and a pharmaceutically acceptable excipient, for treating non-alcoholic
  • NASH steatohepatitis
  • a compound of Formula (X) such as a compound of Formula (X-A), (X-B), (X-Ai), or (X-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer of any of these, in the manufacture of a medicament for use in treating non-alcoholic steatohepatitis (NASH) in a subject in need thereof.
  • NASH non-alcoholic steatohepatitis
  • a method of treating a hyperproliferative disorder in a subject in need thereof by administering to the subject in need thereof an effective amount of a compound of Formula (X), such as a compound of Formula (X-A), (X-B), (X-Ai), or (X-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer of any of these; or a pharmaceutical composition comprising any of the foregoing and a pharmaceutically acceptable excipient.
  • a compound of Formula (X) such as a compound of Formula (X-A), (X-B), (X-Ai), or (X-Bi)
  • a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer of any of these or a pharmaceutical composition comprising any of the foregoing and a pharmaceutically acceptable excipient.
  • a compound of Formula (X) such as a compound of Formula (X-A), (X-B), (X-Ai), or (X-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof; or a pharmaceutical composition comprising any of the foregoing and a pharmaceutically acceptable excipient, for treating a
  • hyperproliferative disorder in a subject in need thereof.
  • a compound of Formula (X) such as a compound of Formula (X-A), (X-B), (X-Ai), or (X-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer of any of these, in the manufacture of a medicament for use in treating a hyperproliferative disorder in a subject in need thereof.
  • FIG. 1 is a diagram depicting the procedure to evaluate the effect of compounds on differentiation and maturation of adipocytes.
  • FIG. 2 is an image of differentiated 3T3 LI cells stained with oil red-O, after being in the presence of compound Z-725 (also known as Compound 4).
  • FIG. 3 is an image of differentiated human pre-adipocyte cells stained with oil red-O, after being in the presence of compound Z-725.
  • FIG. 4 is an image of Western blot analysis of the effect compounds Z-725, Z-826, Z- 780, and Z-796 had on SREBP processing and activation in HepG2 cells. Topoisomerase I was used as a loading control. DETAILED DESCRIPTION
  • R 1 is -C(O)OR 9 , -C(O)NR 8 R 9 , -S(O) 2 NR 8 R 9 , -NR 10 C(O)NR 8 R 9 , -NR 10 C(O)R 9 , -NR 10 S(O) 2 R 9 ,
  • each of R 8 , R 9 , and R 10 is independently selected from the group consisting of hydrogen, (C 1-10 )alkyl, (C 3-10 )cycloalkyl, (C 3-10 )cycloalkyl(C 1-10 )alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, (C 6-10 )aryl, (C 6-10 )aryl(C 1-10 )alkyl, heteroaryl, and heteroaryl-alkyl,
  • R 26 is (C 1-10 )alkyl, (C 3-10 )cycloalkyl, (C 3-10 )cycloalkyl(C 1-10 )alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, (C 6-10 )aryl, (C 6-10 )aryl(C 1-10 )alkyl, heteroaryl, or heteroaryl-alkyl,
  • heterocycloalkyl-alkyl (C 6-10 )aryl, (C 6-10 )aryl(C 1-10 )alkyl, heteroaryl, and heteroaryl-alkyl of R 8 , R 9 , R 10 , and R 26 is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, (C 1-10 )alkyl, (C 1-10 )haloalkyl, cyano, oxo, -OR 19 ,
  • each R 19 is independently hydrogen, (C 1-10 )alkyl, (C 3-10 )cycloalkyl,
  • heterocycloalkyl wherein each of the foregoing alkyl, cycloalkyl, or heterocycloalkyl moieties is independently unsubstituted or substituted with one or more halo,
  • each R 20 is independently (C 1-10 )alkyl, (C 3-10 )cycloalkyl,
  • each R 38 is independently (C 1-10 )alkylene or (C 1-10 )haloalkylene,
  • each nlS is independently an integer from 1 to 5;
  • n4 is 0, l, or 2;
  • heterocycloalkyl wherein the heterocycloalkyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, cyano, oxo, (C 1-10 )alkyl, (C2-i 0 )alkenyl, (C2-i 0 )alkynyl, (C 3-10 )cycloalkyl, (C 3-10 )cycloalkyl(C 1-10 )alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, (C 6-10 )aryl, (C 6-10 )aryl(C 1-10 )alkyl, heteroaryl, heteroaryl-alkyl, -OR 23 , -C(O)NR 23 R 23 , -NR 23 C(O)R 23 , -NR 23 C(O)OR 23 , -NR 23 C(O)NR 23 R 23 , -NR 23 C(O)OR 23 , -NR 23 C(
  • heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aryl-alkyl, heteroaryl, and heteroaryl-alkyl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, oxo, alkyl, haloalkyl, -OR 31 , -C(O)NR 31 R 31 , -NR 31 C(O)R 31 , -NR 31 C(O)OR 31 , -NR 31 C(O)NR 31 R 31 , -NR 31 S(O) 2 R 31 , and -S(O)n9R 31 , wherein each R 31 is independently hydrogen, alkyl, or haloalkyl, and each n9 is independently 0, 1, or 2,
  • each R 23 is independently hydrogen, (C 1-10 )alkyl, (C 3-10 )cycloalkyl,
  • each R 24 is independently (C 1-10 )alkyl, (C 3-10 )cycloalkyl,
  • each R 39 is independently (C 1-10 )alkylene or (C 1-10 )haloalkylene,
  • each nl6 is independently an integer from 1 to 5;
  • n6 is 0, l, or 2;
  • R 3 are independently selected from the group consisting of hydrogen, halo, cyano, (C 1-10 )alkyl, (C 3-10 )cycloalkyl, (C 3-10 )cycloalkyl(C 1-10 )alkyl, -OR 25 , -C(O)NR 25 R 25 , -NR 25 C(O)R 25 , -NR 25 C(O)NR 25 R 25 , -NR 25 R 25 , -S(O) 2 NR 25 R 25 , -NR 25 S(O)2R 25 ,
  • each (C 1-10 )alkyl, (C 3-10 )cycloalkyl, and (C 3-10 )cycloalkyl(C 1-10 )alkyl is
  • each R 25 is independently hydrogen (C 1-10 )alkyl, (C 3-10 )cycloalkyl,
  • each R 30 is independently (C 1-10 )alkyl, (C 3-10 )cycloalkyl, (C 3-10 )cycloalkyl(C 1-10 )alkyl, or heterocycloalkyl, wherein each of the foregoing is independently unsubstituted or substituted with one or more halo, and
  • n7 is 0, l, or 2;
  • X 1 , X 2 , X 3 and X 4 are independently CR 4 or N, wherein X 2 , X 3 and X 4 may not all be N;
  • each R 4 is independently selected from the group consisting of hydrogen, halo, cyano, (C 1-10 )alkyl, (C 3-10 )cycloalkyl,
  • heterocycloalkyl and heterocycloalkyl-alkyl is independently
  • each R 27 is independently hydrogen or (C 1-10 )alkyl, (C 3-10 )cycloalkyl,
  • heterocycloalkyl wherein each of the foregoing alkyl, cycloalkyl, or heterocycloalkyl moieties is independently unsubstituted or substituted with one or more halo,
  • each R 28 is independently (C 1-10 )alkyl, (C 3-10 )cycloalkyl,
  • n8 is 0 , 1 or 2;
  • each R 4 is independently selected from the group
  • heterocycloalkyl and heterocycloalkyl-alkyl is independently
  • each R 27 is independently hydrogen, (C 1-10 )alkyl, (C 3-10 )cycloalkyl,
  • heterocycloalkyl wherein each of the foregoing alkyl, cycloalkyl, or heterocycloalkyl moieties is independently unsubstituted or substituted with one or more halo,
  • each R 28 is independently (C 1-10 )alkyl, (C 3-10 )cycloalkyl,
  • n8 is 0, 1, or 2;
  • carbocyclyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, cyano, (C 1-10 )alkyl, (C 3-10 )cycloalkyl, (C 3-10 )cycloalkyl(C 1-10 )alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, -OR 27 , -C(O)NR 27 R 27 , -NR 27 C(O)R 27 , -NR 7 R 27 , -S(O)2NR 7 R 27 , -NR 27 S(O)2R 27 , -8(O)n8R 2 , and -C(O)R 28 ,
  • heterocyclyl is unsubstituted or substituted with one or more substituents
  • halo independently selected from the group consisting of halo, cyano, (C 1-10 )alkyl, (C 3-10 )cycloalkyl, (C 3-10 )cycloalkyl(C 1-10 )alkyl, heterocycloalkyl connected by an annular carbon atom, heterocycloalkyl-alkyl, -OR 27 , -C(O)NR 27 R 27 , -S(O) 2 NR 27 R 27 , -S(0>*R 28 , and -C(O)R 28 ,
  • each R 27 is independently hydrogen, (C 1-10 )alkyl, (C 3-10 )cycloalkyl,
  • each R 28 is independently (C 1-10 )alkyl, (C 3-10 )cycloalkyl, (C 3-10 )cycloalkyl(C 1-10 )alkyl, wherein each of the foregoing is independently unsubstituted or substituted with one or more halo, and
  • n8 is 0, l, or 2;
  • R 15 and R 17 are independently hydrogen, halo, alkyl, or -OR 29 , wherein each R 29 is
  • each alkyl or cycloalkyl in R 15 or R 17 is independently unsubstituted or substituted with one or more halo;
  • R 14 is (C 1-10 )alkyl, (C 1-10 )alkenyl, (C 3-10 )cycloalkyl, (C 3-10 )cycloalkenyl,
  • R 16 is hydrogen, fluoro, (C 1-10 )alkyl, (C 3-10 )cycloalkyl, (C 3-10 )cycloalkyl(C 1-10 )alkyl,
  • heterocycloalkyl connected through an annular carbon atom, heterocycloalkyl-alkyl, -OR 5 , -C(O)NR 5 R 5 , -R 5 C(O)NR 5 R 5 , -S(O) 2 NR 5 R 5 , -S(O) friendshipiR 6 , or -C(O)R 6 ;
  • (C 3-10 )cycloalkyl(C 1-10 )alkyl, heterocycloalkyl, heterocycloalkenyl, or heterocycloalkyl- alkyl of R 14 or R 16 is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of (C 1-10 )alkyl, cycloalkyl, heterocycloalkyl, halo, cyano, oxo, -OR 7 , -C(O)OR 7 , -C(O)NR 7 R 7 , -NR 7 C(O)R 7 , -NR 7 C(O)NR 7 R 7 , -NR 7 R 7 , -S(O) 2 NR 7 R 7 , -NR 7 S(O)2R 7 , -S(O)n2R 13 , and -C(O)R 13 ;
  • each alkyl, cycloalkyl, and heterocycloalkyl is independently unsubstituted or substituted with one or more substituents selected from the group consisting of halo, cycloalkyl, halocycloalkyl, heterocycloalkyl, haloheterocycloalkyl, and -(OR 33 )n1oOR 32 , wherein each nlO is independently an integer from 0 to 5, each R 32 is independently hydrogen, (C 1-10 )alkyl or (C 1-10 )haloalkyl, and each R 33 is independently (C 1-10 )alkylene or (C 1-10 )haloalkylene; each R 5 is independently hydrogen, (C 1-10 )alkyl, or (C 3-10 )cycloalkyl; or two R 5 , together with the nitrogen atom to which they are attached, form a heterocycloalkyl; wherein each alkyl, cycloalkyl, or heterocycloalkyl is independently un
  • each R 34 is independently hydrogen, (C 1-10 )alkyl, or (C 1-10 )haloalkyl; each nil is
  • each nl2 is independently an integer from 0 to 5; and each R 35 is independently (C 1-10 )alkylene or (C 1-10 )haloalkylene;
  • each R 6 is independently (C 1-10 )alkyl or (C 3-10 )cycloalkyl, wherein each alkyl or cycloalkyl is independently unsubstituted or substituted with one or more halo;
  • each nl is independently 0, 1, or 2;
  • each R 7 is independently hydrogen, unsubstituted (C 1-10 )alkyl, or (C 1-10 )alkyl substituted with one or more halo;
  • each n2 is independently 0, 1, or 2
  • each R 13 is independently unsubstituted (C 1-10 )alkyl or (C 1-10 )alkyl substituted with one or more halo;
  • carbocyclyl or heterocyclyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, cyano, oxo, (C 1-10 )alkyl, (C 3-10 )cycloalkyl, (C 3-10 )cycloalkyl(C 1-10 )alkyl, -OR 18 , -C(O)NR 18 R 18 , -NR 18 C(O)R 18 , -NR 18 C(O)NR 18 R 18 , -NR 18 R 18 , -S(O) 2 NR 18 R 18 , -NR 18 S(O)2R 18 , -S(O)asR. 21 , -C(O)OR 18 , and -C(O)R 21 ,
  • each (C 1-10 )alkyl, (C 3-10 )cycloalkyl, and (C 3-10 )cycloalkyl(C 1-10 )alkyl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, alkyl, haloalkyl, cyano, oxo, -C(O)OR 36 , -C(O)NR 36 R 36 , -NR 36 C(O)R 36 ,
  • cycloalkyl is independently unsubstituted or substituted with one or more halo
  • each n3 is independently 0, 1, or 2.
  • the compound of Formula (X) is a compound of Formula (Z):
  • R 1 is -C(O)OR 9 , -C(O)NR 8 R 9 , -S(O) 2 NR 8 R 9 , -NR 10 C(O)NR 8 R 9 , -NR 10 C(O)R 9 , -NR 10 S(O)2R 9 , -OR 26 , -SR 9 , -S(O)R 9 , -S(O)2R 9 , -NR 8 R 9 , -NR 10 C(O)OR 9 , -C(O)R 26 , -NR 10 S(O) 2 NR 8 R 9 , or -C(O)NR 10 S(O)2R 9 ;
  • each of R 8 , R 9 , and R 10 is independently selected from the group consisting of hydrogen, (C 1-10 )alkyl, (C 3-10 )cycloalkyl, (C 3-10 )cycloalkyl(C 1-10 )alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, (C 6-10 )aryl, (C 6-10 )aryl(C 1-10 )alkyl, heteroaryl, and heteroaryl-alkyl
  • R 26 is (C 1-10 )alkyl, (C 3-10 )cycloalkyl, (C 3-10 )cycloalkyl(C 1-10 )alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, (C 6-10 )aryl, (C 6-10 )aryl(C 1-10 )alkyl, heteroaiyl, or heteroaryl-alkyl,
  • heterocycloalkyl-alkyl (C 6-10 )aryl, (C 6-10 )aryl(C 1-10 )alkyl, heteroaiyl, and heteroaryl-alkyl of R 8 , R 9 , R 10 , and R 26 is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, cyano, oxo, -OR 19 , -C(O)NR ,9 R 19 , -NR 19 C(O)R 19 ,
  • each R 19 is independently hydrogen, (C 1-10 )alkyl, (C 3-10 )cycloalkyl,
  • heterocycloalkyl wherein each of the foregoing alkyl, cycloalkyl, or heterocycloalkyl moieties is independently unsubstituted or substituted with one or more halo,
  • each R 20 is independently (C 1-10 )alkyl, (C 3-10 )cycloalkyl,
  • n4 is 0, l, or 2;
  • heterocycloalkyl wherein the heterocycloalkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of halo, cyano, oxo, (C 1-10 )alkyl, (C2 -10 )alkenyl, (C2 -10 )alkynyl, (C 3-10 )cycloalkyl,
  • heterocycloalkyl wherein each of the foregoing alkyl, cycloalkyl, or heterocycloalkyl moieties is independently unsubstituted or substituted with one or more halo,
  • each R 24 is independently (C 1-10 )alkyl, (C 3-10 )cycloalkyl,
  • n6 is 0, l, or 2;
  • R 2 and R 3 are independently selected from the group consisting of hydrogen, halo, cyano,
  • each (C 1-10 )alkyl, (C 3-10 )cycloalkyl, and (C 3-10 )cycloalkyl(C 1-10 )alkyl is
  • each R 25 is independently hydrogen (C 1-10 )alkyl, (C 3-10 )cycloalkyl,
  • each R 30 is independently (C 1-10 )alkyl, (C 3-10 )cycloalkyl, (C 3-10 )cycloalkyl(C 1-10 )alkyl, or heterocycloalkyl, wherein each of the foregoing is independently unsubstituted or substituted with one or more halo, and
  • n7 is 0, l, or 2;
  • X 1 , X 2 , X 3 and X 4 are independently CR 4 or N, wherein X 2 , X 3 and X 4 may not all be N;
  • each R 4 is independently selected from the group consisting of hydrogen, halo, cyano, (C 1-10 )alkyl, (C 3-10 )cycloalkyl, (C 3-10 )cycloalkyl(C 1-10 )alkyl, heterocycloalkyl connected by an annular carbon atom, heterocycloalkyl-alkyl, -OR 27 , -C(O)NR 27 R 27 , -S(O) 2 NR 27 R 27 , -S(O),*R 28 , -C(O)OR 27 , and -C(O)R 28 ,
  • heterocycloalkyl, and heterocycloalkyl-alkyl is independently unsubstituted or substituted with one or more halo, each R 27 is independently hydrogen or (C 1-10 )alkyl, (C 3-10 )cycloalkyl,
  • heterocycloalkyl wherein each of the foregoing alkyl, cycloalkyl, or heterocycloalkyl moieties is independently unsubstituted or substituted with one or more halo,
  • each R 28 is independently (C 1-10 )alkyl, (C 3-10 )cycloalkyl,
  • n8 is 0 , 1 or 2;
  • each R 4 is independently selected from the group consisting of hydrogen, halo, cyano, (C 1-10 )alkyl, (C 3-10 )cycloalkyl,
  • heterocycloalkyl, and heterocycloalkyl-alkyl is independently unsubstituted or substituted with one or more halo, each R 27 is independently hydrogen, (C 1-10 )alkyl, (C 3-10 )cycloalkyl,
  • heterocycloalkyl wherein each of the foregoing alkyl, cycloalkyl, or heterocycloalkyl moieties is independently unsubstituted or substituted with one or more halo,
  • each R 28 is independently (C 1-10 )alkyl, (C 3-10 )cycloalkyl,
  • n8 is 0, 1, or 2;
  • carbocyclyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, cyano, (C 1-10 )alkyl, (C 3-10 )cycloalkyl, (C 3-10 )cycloalkyl(C 1-10 )alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, -OR 27 , -C(O)NR 27 R 27 , -NR 27 C(O)R 27 , -NR 27 R 27 , -S(O) 2 NR 27 R 27 , -NR 27 S(O)2R 27 , -S(O) friendshipeR 28 , and -C(O)R 28 ,
  • heterocyclyl is unsubstituted or substituted with one or more substituents
  • halo independently selected from the group consisting of halo, cyano, (C 1-10 )alkyl, (C 3-10 )cycloalkyl, (C 3-10 )cycloalkyl(C 1-10 )alkyl, heterocycloalkyl connected by an annular carbon atom, heterocycloalkyl-alkyl, -OR 27 , -C(O)NR 27 R 27 , -S(O) 2 NR 27 R 27 , -S(O)n8R 28 , and -C(O)R 28 ,
  • each R 27 is independently hydrogen, (C 1-10 )alkyl, (C 3-10 )cycloalkyl,
  • each R 28 is independently (C 1-10 )alkyl, (C 3-10 )cycloalkyl, (C 3-10 )cycloalkyl(C 1-10 )alkyl, wherein each of the foregoing is independently unsubstituted or substituted with one or more halo, and
  • R 15 and R 17 are independently hydrogen, halo, alkyl, or -OR 29 , wherein each R 29 is independently hydrogen, (C 1-10 )alkyl, (C 3-10 )cycloalkyl, or (C 3-10 )cycloalkyl(C 1-10 )alkyl, and each alkyl or cycloalkyl in R 15 or R 17 , if present, is independently unsubstituted or substituted with one or more halo;
  • R 14 is (C 1-10 )alkyl, (C 1-10 )alkenyl, (C 3-10 )cycloalkyl, (C 3-10 )cycloalkenyl,
  • R 16 is hydrogen, fluoro, (C 1-10 )alkyl, (C 3-10 )cycloalkyl, (C 3-10 )cycloalkyl(C 1-10 )alkyl,
  • heterocycloalkyl connected through an annular carbon atom, heterocycloalkyl-alkyl, -OR 5 , -C(O)NR 5 R 5 , -R 5 C(O)NR 5 R 5 , -S(O) 2 NR 5 R 5 , -S(O) friendshipiR 6 , or -C(O)R 6 ;
  • R 14 or R 16 is independently unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of (C 1-10 )alkyl, halo, cyano, oxo, -OR 7 , -C(O)OR 7 , -C(O)NR 7 R 7 , -NR 7 C(O)R 7 , -NR 7 C(O)NR 7 R 7 , -NR 7 R 7 , -S(O) 2 NR 7 R 7 , -NR 7 S(O)2R 7 , -S(O)n2R 13 , and -C(O)R 13 ;
  • each R 5 is independently hydrogen, (C 1-10 )alkyl, or (C 3-10 )cycloalkyl; or two R 5 , together with the nitrogen atom to which they are attached, form a heterocycloalkyl; wherein each alkyl, cycloalkyl, or heterocycloalkyl is independently unsubstituted or substituted with one or more halo;
  • each R 6 is independently (C 1-10 )alkyl or (C 3-10 )cycloalkyl, wherein each alkyl or cycloalkyl is independently unsubstituted or substituted with one or more halo;
  • each nl is independently 0, 1, or 2;
  • each R 7 is independently hydrogen, unsubstituted (C 1-10 )alkyl, or (C 1-10 )alkyl substituted with one or more halo;
  • each n2 is independently 0, 1, or 2
  • each R 13 is independently unsubstituted (C 1-10 )alkyl or (C 1-10 )alkyl substituted with one or more halo; or R 14 and R 15 , together with the atoms to which they are attached, form a carbocyclyl or heterocyclyl,
  • carbocyclyl or heterocyclyl is unsubstituted or substituted with one or two substituents independently selected from the group consisting of halo, cyano, oxo, (C 1-10 )alkyl, (C 3-10 )cycloalkyl, (C 3-10 )cycloalkyl(C 1-10 )alkyl, -OR 18 , -C(O)NR 18 R 18 , -NR 18 C(O)R 18 , -NR ,8 C(O)NR ,8 R 18 , -NR 18 R 18 , -S(O)2NR ,8 R 18 , -NR 18 S(O)2R 18 , -S(O) friendship3R 21 , -C(O)OR 18 , and -C(O)R 21 ,
  • each R 18 is independently hydrogen, (C 1-10 )alkyl, or (C 3-10 )cycloalkyl; or two R 18 , together with the nitrogen atom to which they are attached, form a heterocycloalkyl; wherein each alkyl, cycloalkyl, or heterocycloalkyl is independently unsubstituted or substituted with one or more halo, each R 21 is independently (C 1-10 )alkyl or (C 3-10 )cycloalkyl, wherein each alkyl or
  • cycloalkyl is independently unsubstituted or substituted with one or more halo
  • each n3 is independently 0, 1, or 2.
  • the compound of Formula (Z) is a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R 1 is -C(O)OR 9 , -C(O)NR 8 R 9 , -S ⁇ aNR 8 R 9 , -NR 10 QOJNR 8 R 9 , -NR ,0 C(O)R 9 , -NR ,0 S(O)2R 9 , -OR 26 , -SR 9 , -S(O)R 9 , -S(O)2R 9 , -NR 8 R 9 , or -NR 10 C(O)OR 9 .
  • R 1 is -C(O)OR 9 , -C(O)NR 8 R 9 , -S(O) 2 NR 8 R 9 , -NR 10 C(O)NR 8 R 9 , -NR 10 C(O)R 9 , -NR 10 S(O)2R 9 , -OR 26 , -SR 9 , -S(O)R 9 , -S(O)2R 9 , -NR 8 R 9 , or -NR 10 C(O)OR 9 ,
  • each of R 8 , R 9 , and R 10 is independently selected from the group consisting of hydrogen, (C 1-10 )alkyl, (C 3-10 )cycloalkyl, (C 3-10 )cycloalkyl(C 1-10 )alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, (C 6-10 )aryl, (C 6-10 )aryl(C 1-10 )alkyl, heteroaryl, and heteroaryl-alkyl,
  • R 26 is (C 1-10 )alkyl, (C 3-10 )cycloalkyl, (C 3-10 )cycloalkyl(C 1-10 )alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, (C 6-10 )aryl, (C 6-10 )aryl(C 1-10 )alkyl, heteroaryl, or heteroaryl-alkyl,
  • heterocycloalkyl-alkyl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, cyano, oxo, -OR 19 , -C(O)NR ,9 R 19 , -NR ,9 C(O)R 19 , -NR 19 C(O)NR ,9 R 19 , -NR 19 R 19 , -S(O) 2 NR 19 R 19 , -NR ,9 S(O)2R 19 , -S(O)MR 20 , -C(O)OR 19 , and -C(O)R 20 , each R 19 is independently hydrogen, (C 1-10 )alkyl, (C 3-10 )cycloalkyl,
  • heterocycloalkyl wherein each of the foregoing alkyl, cycloalkyl, or heterocycloalkyl moieties is independently unsubstituted or substituted with one or more halo,
  • each R 20 is independently (C 1-10 )alkyl, (C 3-10 )cycloalkyl,
  • n4 is 0, 1, or 2;
  • heterocycloalkyl wherein the heterocycloalkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of halo, cyano, oxo, (C 1-10 )alkyl, (C 2 -i 0 )alkenyl, (C2-i 0 )alkynyl, (C 3-10 )cycloalkyl,
  • each R 23 is independently hydrogen, (C 1-10 )alkyl, (C 3-10 )cycloalkyl,
  • each R 24 is independently (C 1-10 )alkyl, (C 3-10 )cycloalkyl,
  • n6 is 0, l, or 2;
  • R 3 are independently selected from the group consisting of hydrogen, halo, cyano, (C 1-10 )alkyl, (C 3-10 )cycloalkyl, (C 3-10 )cycloalkyl(C 1-10 )alkyl, -OR 25 , -C(O)NR 25 R 25 , -NR 25 C(O)R 25 , -NR 25 C(O)NR 25 R 25 , -NR 25 R 25 , -S(O) 2 NR 25 R 25 , -NR 25 S(O)2R 25 ,
  • each (C 1-10 )alkyl, (C 3-10 )cycloalkyl, and (C 3-10 )cycloalkyl(C 1-10 )alkyl is
  • each R 25 is independently hydrogen (C 1-10 )alkyl, (C 3-10 )cycloalkyl,
  • each R 30 is independently (C 1-10 )alkyl, (C 3-10 )cycloalkyl, (C 3-10 )cycloalkyl(C 1-10 )alkyl, or heterocycloalkyl, wherein each of the foregoing is independently unsubstituted or substituted with one or more halo, and
  • n7 is 0, l, or 2;
  • X 1 , X 2 , X 3 and X 4 are independently CR 4 or N, wherein X 2 , X 3 and X 4 may not all be N;
  • each R 4 is independently selected from the group consisting of hydrogen, halo, cyano, (C 1-10 )alkyl, (C 3-10 )cycloalkyl,
  • heterocycloalkyl and heterocycloalkyl-alkyl is independently
  • each R 27 is independently hydrogen or (C 1-10 )alkyl, (C 3-10 )cycloalkyl,
  • heterocycloalkyl wherein each of the foregoing alkyl, cycloalkyl, or heterocycloalkyl moieties is independently unsubstituted or substituted with one or more halo,
  • each R 28 is independently (C 1-10 )alkyl, (C 3-10 )cycloalkyl,
  • n8 is 0 , 1 or 2;
  • each R 4 is independently selected from the group
  • heterocycloalkyl and heterocycloalkyl-alkyl is independently
  • each R 27 is independently hydrogen, (C 1-10 )alkyl, (C 3-10 )cycloalkyl,
  • heterocycloalkyl wherein each of the foregoing alkyl, cycloalkyl, or heterocycloalkyl moieties is independently unsubstituted or substituted with one or more halo,
  • each R 28 is independently (C 1-10 )alkyl, (C 3-10 )cycloalkyl,
  • n8 is O, l, or 2;
  • carbocyclyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, cyano, (C 1-10 )alkyl, (C 3-10 )cycloalkyl, (C 3-10 )cycloalkyl(C 1-10 )alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, -OR 27 , -C(O)NR 27 R 27 , -NR 27 C(O)R 27 , -NR 27 R 27 , -S(O)2NR 27 R 27 , -NR 27 S(O)2R 27 , -8(O)n8R 28 , and -C(O)R 28 ,
  • heterocyclyl is unsubstituted or substituted with one or more substituents
  • halo independently selected from the group consisting of halo, cyano, (C 1-10 )alkyl, (C 3-10 )cycloalkyl, (C 3-10 )cycloalkyl(C 1-10 )alkyl, heterocycloalkyl connected by an annular carbon atom, heterocycloalkyl-alkyl, -OR 27 , -C(O)NR 27 R 27 , -S(O) 2 NR 27 R 27 , -S(0>*R 28 , and -C(O)R 28 ,
  • each R 27 is independently hydrogen, (C 1-10 )alkyl, (C 3-10 )cycloalkyl,
  • each R 28 is independently (C 1-10 )alkyl, (C 3-10 )cycloalkyl, (C 3-10 )cycloalkyl(C 1-10 )alkyl, wherein each of the foregoing is independently unsubstituted or substituted with one or more halo, and
  • n8 is 0, l, or 2;
  • R 15 and R 17 are independently hydrogen, halo, alkyl, or -OR 29 , wherein each R 29 is
  • each alkyl or cycloalkyl in R 15 or R 17 is independently unsubstituted or substituted with one or more halo;
  • R 14 is (C 1-10 )alkyl, (C 1-10 )alkenyl, (C 3-10 )cycloalkyl, (C 3-10 )cycloalkenyl,
  • R 16 is hydrogen, fluoro, (C 1-10 )alkyl, (C 3-10 )cycloalkyl, (C 3-10 )cycloalkyl(C 1-10 )alkyl,
  • heterocycloalkyl connected through an annular carbon atom, heterocycloalkyl-alkyl, -OR 5 , -C(O)NR 5 R 5 , -R 5 C(O)NR 5 R 5 , -S(O) 2 NR 5 R 5 , -S(O) friendshipiR 6 , or -C(O)R 6 ;
  • R 14 or R 16 is independently unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of (C 1-10 )alkyl, halo, cyano, oxo, -OR 7 , -C(O)OR 7 , -C(O)NR 7 R 7 , -NR 7 C(O)R 7 , -NR 7 C(O)NR 7 R 7 , -NR 7 R 7 , -S(O) 2 NR 7 R 7 , -NR 7 S(O)2R 7 , -S(O)n2R 13 ,and -C(O)R 13 ;
  • each R 5 is independently hydrogen, (C 1-10 )alkyl, or (C 3-10 )cycloalkyl; or two R 5 , together with the nitrogen atom to which they are attached, form a heterocycloalkyl; wherein each alkyl, cycloalkyl, or heterocycloalkyl is independently unsubstituted or substituted with one or more halo;
  • each R 6 is independently (C 1-10 )alkyl or (C 3-10 )cycloalkyl, wherein each alkyl or cycloalkyl is independently unsubstituted or substituted with one or more halo; each nl is independently 0, 1, or 2;
  • each R 7 is independently hydrogen, unsubstituted (C 1-10 )alkyl, or (C 1-10 )alkyl substituted with one or more halo;
  • each n2 is independently 0, 1, or 2
  • each R 13 is independently unsubstituted (C 1-10 )alkyl or (C 1-10 )alkyl substituted with one or more halo;
  • carbocyclyl or heterocyclyl is unsubstituted or substituted with one or two substituents independently selected from the group consisting of halo, cyano, oxo, (C 1-10 )alkyl, (C 3-10 )cycloalkyl, (C 3-10 )cycloalkyl(C 1-10 )alkyl, -OR 18 , -C(O)NR 18 R 18 , -NR 18 C(O)R 18 , -NR 18 C(O)NR 18 R 18 , -NR 18 R 18 , -S(O) 2 NR 18 R 18 , -NR 18 S(O)2R 18 , -S(O)n3R 21 , -C(O)OR 18 , and -C(O)R 21 ,
  • each R 18 is independently hydrogen, (C 1-10 )alkyl, or (C 3-10 )cycloalkyl; or two R 18 , together with the nitrogen atom to which they are attached, form a heterocycloalkyl; wherein each alkyl, cycloalkyl, or heterocycloalkyl is independently unsubstituted or substituted with one or more halo
  • each R 21 is independently (C 1-10 )alkyl or (C 3-10 )cycloalkyl, wherein each alkyl or
  • cycloalkyl is independently unsubstituted or substituted with one or more halo
  • each n3 is independently 0, 1, or 2.
  • the compound of Formula (X) is a compound of Formula (X-A):
  • R 1 , R 2 , R 3 , R 14 , R 15 , R 16 , R 17 , X 1 , X 2 , X 3 , and X 4 are as described for Formula (X) above.
  • the compound of Formula (Z) is a compound of Formula (Z-A):
  • R 1 , R 2 , R 3 , R 14 , R 15 , R 16 , R 17 , X 1 , X 2 , X 3 , and X 4 are as described for Formula (Z) above.
  • the compound of Formula (I) is a compound of Formula (I- A):
  • the compound of Formula (X) or Formula (X- A) is a compound of Formula (X-Ai):
  • R 1 , R 2 , R 3 , R 14 , R 15 , R 16 , R 17 , X 1 , X 2 , X 3 , and X 4 are as described for Formula (X) above.
  • the compound of Formula (Z) or Formula (Z-A) is a compound of Formula (Z-Ai):
  • R 1 , R 2 , R 3 , R 14 , R 15 , R 16 , R 17 , X 1 , X 2 , X 3 , and X 4 are as described for Formula (Z) above.
  • the compound of Formula (I) or Formula (I- A) is a compound of Formula (I-Ai):
  • R 1 , R 2 , R 3 , R 14 , R 15 , R 16 , R 17 , X 1 , X 2 , X 3 , and X 4 are as described for Formula (I) above.
  • the compound of Formula (X) is a compound of Formula (X-B):
  • R 1 , R 2 , R 3 , R 14 , R 15 , R 16 , R 17 , X 1 , X 2 , X 3 , and X 4 are as described for Formula (X) above.
  • the compound of Formula (Z) is a compound of Formula (Z-B):
  • R 1 , R 2 , R 3 , R 14 , R 15 , R 16 , R 17 , X 1 , X 2 , X 3 , and X 4 are as described for Formula (Z) above.
  • the compound of Formula (I) is a compound of Formula (I-B):
  • R 1 , R 2 , R 3 , R 14 , R 15 , R 16 , R 17 , X 1 , X 2 , X 3 , and X 4 are as described for Formula (I) above.
  • the compound of Formula (X) or Formula (X-B) is a compound of Formula (X-Bi):
  • R 1 , R 2 , R 3 , R 14 , R 15 , R 16 , R 17 , X 1 , X 2 , X 3 , and X 4 are as described for Formula (X) above.
  • the compound of Formula (Z) or Formula (Z-B) is a compound of Formula (Z-Bi):
  • R 1 , R 2 , R 3 , R 14 , R 15 , R 16 , R 17 , X 1 , X 2 , X 3 , and X 4 are as described for Formula (Z) above.
  • the compound of Formula (I) or Formula (I-B) is a compound of Formula (I-Bi):
  • R 1 , R 2 , R 3 , R 14 , R 15 , R 16 , R 17 , X 1 , X 2 , X 3 , and X 4 are as described for Formula (I) above.
  • the compound of Formula (Z-A), (Z-B), (Z-Ai), or (Z-Bi) is a compound of Formula (I- A), (I-B), (I-Ai), or (I-Bi), respectively, wherein R 1 is -C(O)OR 9 , -C(O)NR 8 R 9 , -S(O) 2 NR 8 R 9 , -NR 10 C(O)NR 8 R 9 , -NR 10 C(O)R 9 , -NR 10 S(O) 2 R 9 , -OR 26 , -SR 9 , -S(O)R 9 , -S(O)2R 9 , -NR 8 R 9 , or -NR 10 C(O)OR 9 .
  • alkyl refers to an unbranched or branched saturated hydrocarbon chain. Alkyl can be used alone, or as part of another radical, such as cycloalkyl-alkyl. In some embodiments, alkyl as used herein has 1 to SO carbon atoms ((C 1-50 )alkyl), 1 to 20 carbon atoms ((C 1-20 )alkyl), 1 to 12 carbon atoms ((C 1-12 )alkyl), 1 to 10 carbon atoms ((C 1-10 )alkyl), 1 to 8 carbon atoms ((C 1-8 )alkyl), 1 to 6 carbon atoms ((C 1-6 )alkyl), or 1 to 4 carbon atoms ((C 1-4 )alkyl).
  • alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methyl pentyl.
  • alkyl residue having a specific number of carbons is named, all geometric isomers having that number of carbons may be encompassed.
  • butyl can include n-butyl, sec- butyl, isobutyl and t-butyl
  • propyl can include n-propyl and isopropyl.
  • Haloalkyl refers to an alkyl group substituted with one or more independently selected halo groups (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more).
  • Alkenyl refers to an unbranched or branched hydrocarbon chain containing at least one carbon-carbon double bond. Alkenyl can be used alone, or as part of another radical, such as cycloalkyl-alkenyl.
  • alkenyl as used herein has 1 to 50 carbon atoms ((C 1-50 )alkenyl), 1 to 20 carbon atoms ((C 1-20 )alkenyl), 1 to 12 carbon atoms ((C 1-12 )alkenyl), 1 to 10 carbon atoms ((C 1-10 )alkenyl), 1 to 8 carbon atoms ((C 1-8 )alkenyl), 1 to 6 carbon atoms ((C 1-6 )alkenyl), or 1 to 4 carbon atoms ((C 1-4 )alkenyl).
  • Alkenyl may have one, two, three, four, five, or more carbon-carbon double bonds, as valency permits. When an alkenyl residue having a specific number of carbons is named, all geometric isomers having that number of carbons may be encompassed.
  • Cycloalkyl refers to a monocyclic or polycyclic saturated
  • cycloalkyl has 3 to 50 carbon atoms ((C 3-50 )cycloalkyl), 3 to 20 carbon atoms ((C 3-20 )cycloalkyl), 3 to 12 carbon atoms ((C 3-12 )cycloalkyl), 3 to 10 carbon atoms ((C 3-10 )cycloalkyl), 3 to 8 carbon atoms ((C3 ⁇ )cycloalkyl), 3 to 6 carbon atoms ((C 3- 6 )cycloalkyl), or 3 to 5 carbon atoms ((C 3-4 )cycloalkyl).
  • Cycloalkyl includes monocyclic and polycyclic groups, such as fused bicycles and spirocycles.
  • polycyclic groups include fused bicycles, bridged cyclic groups, and spirocycles.
  • cycloalkyl groups include cyclopropyl, cycloburyl, cyclopentyl, cyclohexyl, octahydropentalenyl, octahydro-lH-indene, decahydronaphthalene, cubane, bicyclo[3.1.0]hexane, and
  • Halocycloalkyl refers to a cycloalkyl group substituted with one or more independently selected halo groups (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more).
  • Cycloalkenyl refers to a non-aromatic monocyclic or polycyclic hydrocarbon containing at least one carbon-carbon double bond.
  • cycloalkenyl has 3 to 50 carbon atoms ((C 3-50 )cycloalkenyl), 3 to 20 carbon atoms ((C 3 - 20)cycloalkenyl), 3 to 12 carbon atoms ((C 3-12 )cycloalkenyl), 3 to 10 carbon atoms ((C 3 - 10)cycloalkenyl), 3 to 8 carbon atoms ((C 3-8 )cycloalkenyl), 3 to 6 carbon atoms ((C 3 - 6 )cycloalkenyl), or 3 to 5 carbon atoms ((C 3-4 )cycloalkenyl).
  • Cycloalkenyl includes monocyclic and polycyclic groups (including fused, bridged, and spirocycles), and may have one, two, three, four, five, or more carbon-carbon double bonds, as valency permits.
  • Cycloalkyl-alkyl refers to a cycloalkyl group (as defined above) connected to an alkyl group (as defined above), wherein the alkyl group is attached to another moiety (such as the core structure of the molecule). Substituted cycloalkyl-alkyl can include one or more additional attachments to substituents at any point of the cycloalkyl or alkyl, as valency permits.
  • the cycloalkyl-alkyl may comprise any combination of cycloalkyl and alkyl groups.
  • the cycloalkyl has 3 to 50 carbon atoms ((C 3-50 )cycloalkyl-alkyl), 3 to 20 carbon atoms ((C 3-20 )cycloalkyl-alkyl), 3 to 12 carbon atoms ((C 3-12 )cycloalkyl-alkyl), 3 to 10 carbon atoms ((C 3-10 )cycloalkyl-alkyl), 3 to 8 carbon atoms ((C 3-8 )cycloalkyl-alkyl), 3 to 6 carbon atoms ((C 3-6 )cycloalkyl-alkyl), or 3 to 5 carbon atoms ((C 3-4 )cycloalkyl-alkyl).
  • the alkyl has 1 to 50 carbon atoms (cycloalkyl- (C 1-50 )alkyl), 1 to 20 carbon atoms (cycloalkyl- (C 1-20 )alkyl), 1 to 12 carbon atoms (cycloalkyl-(C 1-12 )alkyl), 1 to 10 carbon atoms (cycloalkyl- (C 1-10 )alkyl), 1 to 8 carbon atoms (cycloalkyl-(C 1-8 )alkyl), 1 to 6 carbon atoms (cycloalkyl-(C 1- e)alkyl), or 1 to 4 carbon atoms (cycloalkyl-(C 1-4 )alkyl).
  • the cycloalkyl- alkyl is a (C 3-20 )cycloalkyl(C 1-20 )alkyl, (C 3-12 )cycloalkyl(C 1-12 )alkyl, (C 3-10 )cycloalkyl(C 1-10 )alkyl, (C 3-10 )cycloalkyl(C 3-8 )alkyl, (C 3-10 )cycloalkyl(Cw)alkyl, (C 3-6 )cycloalkyl(C 3-8 )alkyl, (C 3 - 6 )cycloalkyl(C 3-6 )alkyl, or (C 3-6 )cycloalkyl(C 1-4 )alkyl.
  • Carbocyclyl refers to a monocyclic or polycyclic saturated or unsaturated
  • Carbocyclyl includes cycloalkyl, aryl, and non-aromatic unsaturated carbocyclic groups such as cycloalkenyl.
  • carbocyclyl has 3 to 50 carbon atoms ((C 3 - 5 0 )carbocyclyl), 3 to 20 carbon atoms ((C 3-20 )carbocyclyl), 3 to 12 carbon atoms ((C 3 - 12 )carbocyclyl), 3 to 10 carbon atoms ((C 1-10 )carbocyclyl), 3 to 8 carbon atoms ((C 3 - 8 )carbocyclyl), 3 to 6 carbon atoms ((C 3-6 )carbocyclyl), or 3 to 5 carbon atoms ((C 3- 4 )carbocyclyl).
  • Heterocycloalkyl refers to a saturated monocyclic or polycyclic ring containing carbon and at least one heteroatom selected from the group consisting of O, N, and S.
  • the heterocycloalkyl group may comprise 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or more ring atoms (e.g., be a 3-membered, 4-membered, 5-membered, 6-membered, 7-membered, 8-membered, 9- membered, 10-membered, 11-membered, or 12-membered heterocycloalkyl).
  • the ring atoms may be, for example, atoms of a single ring or atoms of two or more fused rings, a bridged ring, or a spirocycle.
  • Heterocycloalkyl may include groups comprising 1 to 5 ring heteroatoms, 1 to 4 heteroatoms, 1 to 3 ring heteroatoms, 1 or 2 ring heteroatoms, or 1 ring heteroatom, wherein each heteroatom is independently selected from the group consisting of N, O, and S.
  • Each ring S atom, where present, may independently be unoxidized sulfur (e.g., -S-) or a sulfur oxide, such as -S(O)-, or
  • a heterocycloalkyl has 2 to 8 ring carbon atoms and with 1 to 3 ring heteroatoms independently selected from N, O, and S.
  • Heterocycloalkyl may include, for example, saturated bridged cyclic structures comprising at least one ring heteroatom (for example, one ring with one heteroatom and a hydrocarbon bridge), and saturated spirocycles comprising at least one ring heteroatom (for example, a two-ring spirocycle with one
  • hydrocarbon ring and one ring comprising one heteroatom In some embodiments,
  • heterocycloalkyl is connected through an annular carbon atom, wherein the point of attachment of the heterocycloalkyl to another group is a ring carbon atom of the heterocycloalkyl.
  • heterocycloalkyl include, but are not limited to, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, thiazolinyl, thiazolidinyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxinyl, piperidinyl, morpholinyl, thiomorpholinyl,
  • thiomorpholinyl S-oxide thiomorpholinyl S-dioxide
  • piperazinyl azepinyl, oxepinyl, diazepinyl, and tropanyl.
  • Heterocycloalkyl refers to a heterocycloalkyl group substituted with one or more independently selected halo groups (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more).
  • Heterocycloalkenyl refers to a non-aromatic monocyclic or polycyclic ring containing carbon, at least one heteroatom selected from the group consisting of O, N, and S, and at least one double bond.
  • Each ring S atom where present, may independently be a sulfur oxide, such as -S(O)-, or -S(O)2-.
  • the heterocycloalkenyl group may comprise 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or more ring atoms (e.g., be a 3-membered, 4-membered, 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, 10- member ed, 11 -membered, or 12- membered heterocycloalkenyl).
  • Heterocycloalkenyl may include groups comprising 1 to 5 ring heteroatoms, 1 to 4 heteroatoms, 1 to 3 ring heteroatoms, 1 or 2 ring heteroatoms, or 1 ring heteroatom, wherein each heteroatom is independently selected from the group consisting of N, O, and S.
  • a heterocycloalkenyl has 2 to 8 ring carbon atoms and with 1 to 3 ring heteroatoms independently selected from N, O, and S.
  • a heterocycloalkenyl has 2 to 8 ring carbon atoms and with 1 to 3 ring heteroatoms independently selected from
  • heterocycloalkenyl is connected through an annular carbon atom, wherein the point of attachment of the heterocycloalkenyl to another group is a ring carbon atom of the
  • heterocycloalkenyl may have one, two, three, four, five, or more double bonds, as valency permits, and each double bond independently may be between two ring carbon atoms, two ring heteroatoms, or one ring carbon atom and one ring heteroatom, as valency permits.
  • Heterocyclyl refers to a saturated or unsaturated monocyclic or polycyclic ring containing carbon and at least one heteroatom selected from the group consisting of O, N, and S. Each ring S atom, where present, may independently be a sulfur oxide, such as -S(O)-, or -S(O)2-. Heterocyclyl includes heterocycloalkyl, heteroaryl, and non-aromatic unsaturated heterocyclic groups such as heterocycloalkenyl.
  • the heterocyclyl group may comprise 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or more ring atoms (e.g., be a 3-membered, 4-membered, 5-membered, 6- membered, 7-membered, 8-membered, 9-membered, 10-membered, 11 -membered, or 12- membered heterocyclyl), and may include groups comprising 1 to 5 ring heteroatoms, 1 to 4 heteroatoms, 1 to 3 ring heteroatoms, 1 or 2 ring heteroatoms, or 1 ring heteroatom, wherein each heteroatom is independently selected from the group consisting of N, O, and S.
  • heterocyclyl is connected through an annular carbon atom, wherein the point of attachment of the heterocyclyl to another group is a ring carbon atom of the heterocyclyl.
  • Heterocycloalkyl-alkyl refers to a heterocycloalkyl group (as defined above) connected to an alkyl group (as defined above), wherein the alkyl group is attached to another moiety (such as the core structure of the molecule).
  • the alkyl group may be attached to the heterocycloalkyl through an annular carbon atom of the heterocycloalkyl, or through an annular heteroatom of the heterocycloalkyl (such as through a ring N atom).
  • heterocycloalkyl-alkyl can include one or more additional attachments to substituents at any point of the heterocycloalkyl or alkyl, as valency permits.
  • the heterocycloalkyl-alkyl may comprise any combination of heterocycloalkyl and alkyl groups.
  • the heterocycloalkyl comprises 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or more ring atoms.
  • heterocycloalkyl may include groups comprising 1 to 5 ring heteroatoms, 1 to 4 heteroatoms, 1 to 3 ring heteroatoms, 1 or 2 ring heteroatoms, or 1 ring heteroatom, wherein each heteroatom is independently selected from the group consisting of N, O, and S.
  • the alkyl has 1 to 50 carbon atoms (heterocycloalkyl-(C 1-50 )alkyl), 1 to 20 carbon atoms
  • heterocycloalkyl-(C 1-20 )alkyl 1 to 12 carbon atoms (heterocycloalkyl-(C 1-12 )alkyl), 1 to 10 carbon atoms (heterocycloalkyl-(C 1-10 )alkyl), 1 to 8 carbon atoms (heterocycloalkyl-(C 1-8 )alkyl), 1 to 6 carbon atoms (heterocycloalkyl-(C 1-6 )alkyl), or 1 to 4 carbon atoms (heterocycloalkyl-(C 1- 4 )alkyl).
  • the heterocycloalkyl-alkyl is a (3-20
  • Aryl refers to a monocyclic or polycyclic radical comprising at least one aromatic hydrocarbon ring.
  • Aryl may include an aromatic hydrocarbon monocyclic or polycyclic radical.
  • Aryl may include groups with a single aromatic ring (e.g., phenyl) and multiple fused aromatic rings (e.g., naphthyl, anthryl).
  • Aryl may also include, for example, a single aromatic hydrocarbon ring fused to a non-aromatic hydrocarbon ring (e.g., 1,2,3,4- tetrahydronaphthalene), or a single aromatic hydrocarbon fused to a non-aromatic ring comprising at least one heteroatom (e.g., 1,2,3,4-tetrahydroisoquinoline).
  • aryl as used herein has from 6 to 14 annular carbon atoms ((Ce -1 - aryl), or 6 to 10 annular carbon atoms ((C 6-10 )aryl).
  • Aryl-alkyl refers to an aryl group (as defined above) connected to an alkyl group (as defined above), wherein the alkyl group is attached to another moiety (such as the core structure of the molecule). Substituted aryl-alkyl can include one or more additional attachments to substituents at any point of the aryl or alkyl, as valency permits.
  • the aryl-alkyl may comprise any combination of aryl and alkyl groups. In some embodiments, the aryl has from 6 to 14 annular carbon atoms ((C 6-14 )aryl-alkyl), or 6 to 10 annular carbon atoms ((C 6-10 )aryl-alkyl).
  • the alkyl has 1 to 50 carbon atoms (aryl-(C 1-50 )alkyl), 1 to 20 carbon atoms (aryl-(C 1-20 )alkyl), 1 to 12 carbon atoms (aryl-(C 1-12 )alkyl), 1 to 10 carbon atoms (aryl-(C 1- i 0 )alkyl), 1 to 8 carbon atoms (aryl-(C 1-8 )alkyl), 1 to 6 carbon atoms (aryl-(C 1-6 )alkyl), or 1 to 4 carbon atoms (aryl-(C 1-4 )alkyl).
  • the aryl-alkyl is a (C 6-14 )aryl(C 1- 2 0 )alkyl, (C 6-14 )aryl(C 1-12 )alkyl, (C 6-14 )aryl(C 1-10 )alkyl, (C 6-14 )aryl(C 1-8 )alkyl, (C 6-14 )aryl(C 1- 6)alkyl, (C 6-10 )aryl(C 1-10 )alkyl, (C 6-10 )aryl(C 1-8 )alkyl, (C 6-10 )aryl(C 1-6 )alkyl, or (C 6-10 )aryl(C 1- 4 )alkyl.
  • Heteroaryl refers to a monocyclic or polycyclic radical comprising at least one aromatic ring, wherein the aromatic ring comprises at least one ring heteroatom independently selected from the group consisting of N, O, and S, (e.g., pyridine, pyrazine, furan, thiophene, quinoline).
  • S e.g., pyridine, pyrazine, furan, thiophene, quinoline.
  • Each ring S atom, where present, may independently be unoxidized sulfur
  • Heteroaryl includes polycyclic systems comprising two or more aromatic rings, wherein at least one aromatic ring comprises at least one ring heteroatom selected from N, O, and S. Heteroaryl may include groups comprising 1 to 5 ring heteroatoms, 1 to 4 heteroatoms, 1 to 3 ring heteroatoms, 1 or 2 ring heteroatoms, or 1 ring heteroatom, wherein each heteroatom is independently selected from the group consisting of N,
  • a heteroaryl has 3 to 8 ring carbon atoms, with 1 to 3 ring heteroatoms independently selected from N, O, and S.
  • Heteroaryl may comprise 5, 6, 7, 8, 9, 10,
  • annular atoms e.g., be a 3-membered, 4-membered, 5-membered, 6-membered,
  • Heteroaryl may comprise, for example, 1 to 14 annular carbon atoms ((C 1-14 )heteroaryl), 1 to 10 annular carbon atoms ((C 1-10 )heteroaryl), 1 to 6 annular carbon atoms ((C 1-6 )heteroaryl), 1 to 5 annular carbon atoms ((C 1-5 )heteroaryl), or 2 to 5 annular carbon atoms ((C2-5)heteroaryl).
  • annular carbon atoms ((C 1-14 )heteroaryl)
  • 1 to 10 annular carbon atoms ((C 1-10 )heteroaryl)
  • 1 to 6 annular carbon atoms ((C 1-6 )heteroaryl)
  • 1 to 5 annular carbon atoms ((C 1-5 )heteroaryl)
  • 2 to 5 annular carbon atoms ((C2-5)heteroaryl).
  • heteroaryl is connected through an annular carbon atom, wherein the point of attachment of the heteroaryl to another group is a ring carbon atom of the heteroaryl.
  • heteroaryl groups include pyridyl, pyridazinyl, pyrimidinyl, benzothiazolyl, furanyl, and pyrazolyl.
  • Heteroaryl-alkyl refers to a heteroaryl group (as defined above) connected to an alkyl group (as defined above), wherein the alkyl group is attached to another moiety (such as the core structure of the molecule). Substituted heteroaryl-alkyl can include one or more additional attachments to substituents at any point of the heteroaryl or alkyl, as valency permits.
  • the alkyl group may be attached to the heteroaryl through an annular carbon atom of the heteroaryl, or through an annular heteroatom of the heteroaryl.
  • the heteroaryl-alkyl may comprise any combination of heteroaryl and alkyl groups.
  • the heteroaryl may have 3 to 8 ring carbon atoms, with 1 to 3 ring heteroatoms independently selected from N, O, and S.
  • Heteroaryl may comprise 5, 6, 7, 8, 9, 10, 11, 12, or more annular atoms (e.g., be a 3-membered, 4-membered, 5- membered, 6-membered, 7-membered, 8-membered, 9-membered, 10-membered, 11-membered, or 12-membered heteroaryl), wherein the annular atoms are present in one or more rings.
  • the alkyl has 1 to 50 carbon atoms (heteroaryl-(C 1-50 )alkyl), 1 to 20 carbon atoms (heteroaryl-(C 1-20 )alkyl), 1 to 12 carbon atoms (heteroaryl-(C 1-12 )alkyl), 1 to 10 carbon atoms (heteroaryl-(C 1-10 )alkyl), 1 to 8 carbon atoms (heteroaryl-(C 1-8 )alkyl), 1 to 6 carbon atoms (heteroaryl-(C 1-6 )alkyl), or 1 to 4 carbon atoms (heteroaryl-(C 1-4 )alkyl).
  • the heteroaryl-alkyl is a (C 1-14 )heteroaryl(C 1-20 )alkyl, (C 1-10 )heteroaryl(C 1-12 )alkyl, (C 1- 6 )heteroaryl(C 1-10 )alkyl, (C 1-5 )heteroaryl(C 1-8 )alkyl, (C 1- s)heteroaryl(C 1-6 )alkyl, (C 1-5 )heteroaryl (C 1-8 )alkyl, (C 1-5 )heteroaryliC 3-6 )alkyl, or (C 1-5 )heteroaryl(C 1-4 )alkyl.
  • (C 1-6 )alkyl (which may also be referred to as C1-C6 alkyl, C 1-6 alkyl, or Cl-6 alkyl) is intended to encompassC 1 , C2, C3, C4, C5, C6, C 1 -6, C 1 -5, C 1-4 , C1-3, C1-2, C2-6, C2-5, C2-4, C2-3, C 3- 6, C 3-5 , C 3- 4, C «, C4-5, and C5-6 alkyl.
  • Haldroxy refers to the radical -OH.
  • Halo refers to fluoro, chloro, bromo, or iodo radicals.
  • Cyano means the radical -CN.
  • the compound of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-Ai), (Z-B), (Z-Bi), (I), (I-A), (I-Ai), (I-B), or (I-Bi), is a solvate.
  • the solvate is a hydrate.
  • “Pharmaceutically acceptable” includes that which is useful in preparing a
  • a pharmaceutical composition that is generally safe, non-toxic and not biologically or otherwise undesirable, and includes that which is acceptable for veterinary use as well as human pharmaceutical use.
  • a pharmaceutical composition comprising a compound of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-Ai), (Z-B), (Z-Bi), (I), (I-A), (I-Ai), (I-B), or (I-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, and a pharmaceutically acceptable excipient
  • “Pharmaceutically acceptable salt” includes a salt which is generally safe, non-toxic and not biologically or otherwise undesirable, and includes that which is acceptable for veterinary use as well as human pharmaceutical use. Such salts may include acid addition salts and base addition salts.
  • Acid addition salts may be formed with inorganic acid such as, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like; or an organic acid such as, but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4- acetamidobenzoic acid, camphoric acid, camphor- 10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane- 1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluc
  • Salts derived from inorganic bases may include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts.
  • Salts derived from organic bases may include, but are not limited to, salts of primary, secondary, or tertiary amines;
  • substituted amines including naturally occurring substituted amines; cyclic amines; ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, deanol, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, benethamine, benzathine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purines, piperazine, piperidine, or N-ethylpiperidine.
  • structures depicted herein such as compounds of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-B), (Z-Ai), (Z-Bi), (I), (I-A), (I- ), (I-Ai), or (I-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, or isomer thereof, are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms.
  • the compounds herein may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds.
  • the compound is isotopically- labeled, such as an isotopically-labeled compound of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-B), (Z-Ai), (Z-Bi), (I), (I-A), (I-B), (I-Ai), or (I-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, or isomer thereof, where a fraction of one or more atoms are replaced by an isotope of the same element
  • Exemplary isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, chlorine, such as 2 H 3 H n C, 13 C, 14 C 13 N, 15 0, 17 0, 35 S, 18 F, 36 C1.
  • isotope labeled compounds may be useful in compound or substrate tissue distribution study. Incorporation of heavier isotopes such as deuterium ( 2 H) may, in some embodiments, afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life, or reduced dosage requirements.
  • the compounds disclosed herein such as compounds of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-Ai), (Z-B), (Z-Bi), (I), (I-A), (I-B), (I-Ai), or (I-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, or isotope thereof, may contain one or more asymmetric centers and thus may give rise to one or more isomers.
  • each of R 8 , R 9 , and R 10 is independently selected from the group consisting of hydrogen, (C 1-10 )alkyl, (C 3-10 )cycloalkyl, (C 3-10 )cycloalkyl(C 1-10 )alkyl, heterocycloalkyl, and heterocycloalkyl-alkyl, or R 8 and R 9 , together with the nitrogen atom to which they are attached, form a heterocycloalkyl.
  • Each (C 1-10 )alkyl, (C 3-10 )cycloalkyl, (C 3-10 )cycloalkyl(C 1-10 )alkyl, heterocycloalkyl (including a heterocycloalkyl formed by R 8 and R 9 ) and heterocycloalkyl-alkyl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, cyano, oxo, -OR 19 , -C(O)NR 19 R 19 , -NR 19 C(O)R 19 , -NR 19 C(O)NR 19 R 19 , -NR 19 R 19 , -S(O) 2 NR 19 R 19 , -NR 19 S(O)2R 19 , -S(O), ⁇ 20 , -C(O)OR 19 , and -C(O)R 20 .
  • the one or more substituents are independently selected from the group consisting of halo, -OH, -0(C 1- i 0 )alkyl, -NR 19 R 19 , and -C(O)NR 19 R 19 .
  • the halo is fluoro.
  • each R 19 is independently H or (C 1-10 )alkyl, or two R 19 , together with the nitrogen to which they are attached, form a heterocycloalkyl.
  • the halo is fluoro.
  • each R 19 is independently H or (C 1-10 )alkyl, or two R 19 , together with the nitrogen to which they are attached, form a heterocycloalkyl.
  • the halo is fluoro.
  • each R 19 is independently H or (C 1-10 )alkyl, or two R 19 , together with the nitrogen to which they are attached, form a heterocycloalkyl.
  • heterocycloalkyl is a 5-6 member ed heterocycloalkyl comprising 1 to 4 heteroatoms
  • the heterocycloalkyl of the heterocycloalkyl-alkyl is a 5-6 membered heterocycloalkyl comprising 1 to 4 heteroatoms independently selected from N, O, and S.
  • R 8 and R 9 together with the nitrogen atom to which they are attached, form a 5-6 membered heterocycloalkyl comprising 1 to 4 heteroatoms independently selected from N, O, and S.
  • each of R 8 , R 9 , and R 10 is independently selected from the group consisting of hydrogen, (C 1-10 )alkyl,
  • each R 23 is independently hydrogen or (C 1-10 )alkyl, such as (C 1-8 )alkyl, (C 1-6 )alkyl, or (C 1-4 )alkyl.
  • each R 24 is independently (C 1-10 )alkyl, such as (C 1-8 )alkyl, (C 1-6 )alkyl, or (C 1-4 )alkyl.
  • each R 25 is independently hydrogen or (C 1-10 )alkyl, such as (C 1-8 )alkyl, (C 1-6 )alkyl, or (C 1-4 )alkyl.
  • each R 30 is independently (C 1-10 )alkyl, such as (C 1-8 )alkyl, (C 1-8 )alkyl, or (C 1- 4 )alkyl.
  • each R 27 is independently hydrogen or (C 1-10 )alkyl, such as (C 1- 8 )alkyl, (C 1-6 )alkyl, or (C 1-4 )alkyl.
  • each R 28 is independently (C 1-10 )alkyl, such as (C 1-8 )alkyl, (C 1-6 )alkyl, or (C 1-4 )alkyl.
  • each R 29 is independently hydrogen or (C 1-10 )alkyl, such as (C 1-8 )alkyl, (C 1-6 )alkyl, or (C 1-4 )alkyl.
  • each R 5 is independently hydrogen or (C 1-10 )alkyl, such as (C 1-8 )alkyl, (C 1-8 )alkyl, or (C 1-4 )alkyl.
  • each R 6 is independently (C 1-10 )alkyl, such as (C 1-8 )alkyl, (C 1- e)alkyl, or (C 1- »)alkyl.
  • each R 7 is independently hydrogen or (C 1-10 )alkyl, such as (C 1-8 )alkyl, (C 1-6 )alkyl, or (C 1-4 )alkyl.
  • any of the foregoing alkyl are independently unsubstituted or substituted with one or more halo.
  • any of the foregoing alkyl are independently unsubstituted or substituted with one, two, or three halo.
  • the halo is independently fluoro or chloro.
  • R 1 is -C(O)OR 9 , -C(O)NR 8 R 9 , -S(O) 2 NR 8 R 9 , -NR 10 C(O)NR 8 R 9 , -NR 10 C(O)R 9 ,
  • R 1 is -C(O)R 26 , -NR 10 S(O)2NR 8 R 9 , or -C(O)NR 10 S(O)2R 9 .
  • R 1 is -NR 10 S(O)2NR 8 R 9 .
  • R 10 is hydrogen.
  • R 8 and R 9 are independently hydrogen or (C 1-10 )alkyl. In some embodiments, R 8 is hydrogen and R 9 is (C 1-10 )alkyl, for example isopropyl. In other embodiments, R 1 is
  • R 10 is hydrogen.
  • R 9 is hydrogen, (C 1-10 )alkyl, or (C 3-10 )cycloalkyl.
  • R 10 is hydrogen and R 9 is (C 3-10 )cycloalkyl, for example cyclopropyl.
  • R 1 is -C(O)R 26 .
  • R 26 is (C 1-10 )alkyl or (C 3-10 )cycloalkyl, wherein the alkyl or cycloalkyl is unsubstituted or substituted as described in Formula (X).
  • R 1 is -C(O)R 26 , wherein R 26 is (C 3-10 )cycloalkyl, such as cyclohexyl.
  • R 1 is:
  • R 1 is -C(O)NR 8 R 9 , -S(O)2NR 8 R 9 ,
  • R 1 is -NR 10 C(O)NR 8 R 9 .
  • R 1 is -NR ,0 C(O)OR 9 .
  • R 1 is -NR 10 S(O)2R 9 .
  • R 10 may be H.
  • R 1 is -NHC(O)NR 8 R 9 , -NHC(O)R 9 , -NHC(O)OR 9 , or -NHS(O)2R 9 .
  • R 8 and R 9 together with the nitrogen atom to which they are attached, form an unsubstituted or substituted heterocycloalkyl.
  • the heterocycloalkyl is a 5-membered or 6-membered ring.
  • R 8 and R 9 together with the nitrogen atom to which they are attached form an unsubstituted or substituted piperidinyl.
  • R 1 is -C(O)NR 8 R 9 , -SiO ⁇ NR 8 R 9 , or -NR ,0 C(O)NR 8 R 9 .
  • R 1 is -0(O)>3 ⁇ 43 ⁇ 4 9
  • R 8 and R 9 together with the nitrogen atom to which they are attached, form an unsubstituted or substituted heterocycloalkyl.
  • the heterocycloalkyl is a 4-membered to 8-membered heterocycloalkyl, which is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, oxo, -OR 23 , (C 1-10 )alkyl, -NR 23 C(O)OR 23 , -NR 23 R 23 , -C(O)OR 23 , and
  • the heterocycloalkyl is a substituted or unsubstituted ring, spirocycle, or bridged ring.
  • the heterocycloalkyl comprises, in addition to the nitrogen atom to which R 8 and R 9 are both connected, one or two additional heteroatoms selected from the group consisting of O, N, and S.
  • the heterocycloalkyl is a 5-membered or 6-membered ring, which is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, -OR 23 ,
  • each (C 1-10 )alkyl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo and -OR 31 .
  • each R 31 is independently hydrogen or alkyl.
  • the (C 1-10 )alkyl is substituted with -OH.
  • each R 23 is independently H or (C 1-10 )alkyl, or two R 23 , together with the nitrogen atom to which they are attached, form a heterocycloalkyl group.
  • R 8 and R 9 together with the nitrogen atom to which they are attached form an unsubstituted or substituted piperidinyl.
  • the piperidinyl is unsubstituted.
  • the piperidinyl is substituted with one or more substituents independently selected from the group consisting of -
  • OR 23 (C 1-10 )alkyl, -C(O)OR 23 , and -NR 23 C(O)OR 23 .
  • the piperidinyl may be substituted with one or two substituents independently selected from the group consisting of -
  • R 23 is independently H or
  • (C 1-10 )alkyl such as (C 1-8 )alkyl, (C 1-6 )alkyl, or (C 1- *)alkyl.
  • the piperidinyl is substituted with one or two substituents independently selected from the group consisting of -0(C 1-10 )alkyl, -OH, (C 1-10 )alkyl, -C(O)OH, and -NHC(O)0(C 1-10 )alkyl.
  • the piperidinyl is substituted with one or two substituents independently selected from the group consisting of -OH, methyl, ethyl, propyl, butyl, -C(O)OH, and -NHC(O)0-tert- butyl.
  • the piperidinyl is substituted with one -OH.
  • R 8 and R 9 together with the nitrogen atom to which they are attached form a 4-, 5- , 6-, 7-, or 8-membered heterocycloalkyl comprising one nitrogen ring atom, wherein the heterocycloalkyl is unsubstituted or substituted.
  • the heterocycloalkyl is substituted with one or more substituents (such as one to five) independently selected from the group consisting of halo, oxo, -OR 23 , (C 1-10 )alkyl, -C(O)OR 23 , and -NR 23 C(O)OR 23 .
  • each halo is fluoro.
  • each (C 1-10 )alkyl is independently unsubstituted or substituted with one or more -OH.
  • heterocycloalkyl is substituted with one or more substituents (such as one to five) independently selected from the group consisting of fluoro, -OH, and (C 1-10 )alkyl, wherein each (C 1-10 )alkyl is independently unsubstituted or substituted with one or more -OH.
  • substituents such as one to five
  • each (C 1-10 )alkyl is independently unsubstituted or substituted with one or more -OH.
  • (C 1-10 )alkyl is independently methyl, ethyl, propyl, or butyl, each of which is independently unsubstituted or substituted with one or two -OH.
  • R 1 may be:
  • R 1 is -C(O)NR 8 R 9
  • R 8 and R 9 are both hydrogen.
  • R 8 is hydrogen
  • R 9 is (C 1-10 )alkyl, wherein the alkyl is unsubstituted or substituted.
  • the alkyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, cyano, oxo, -OR 19 , -NR ,9 R 19 , -S(O)n4R 20 , -C(O)OR 19 , and -C(O)R 20 .
  • substituents independently selected from the group consisting of halo, cyano, oxo, -OR 19 , -NR ,9 R 19 , -S(O)n4R 20 , -C(O)OR 19 , and -C(O)R 20 .
  • the alkyl is unsubstituted or substituted with one or more substituents selected from the group consisting of -OH, -NH, and -C(O)OH.
  • R 1 is:
  • R 1 is -NR 10 C(O)NR 8 R 9 , wherein R 8 and R 9 are independently selected from the group consisting of hydrogen, (C 1-10 )alkyl, (C 3-10 )cycloalkyl, (C 3-10 )cycloalkyl(C 1-10 )alkyl, heterocycloalkyl, and heterocycloalkyl-alkyl; or R 8 and R 9 , together with the nitrogen atom to which they are attached, form a heterocycloalkyl.
  • R 8 and R 9 are independently selected from the group consisting of hydrogen, (C 1-10 )alkyl, (C 3-10 )cycloalkyl, (C 3-10 )cycloalkyl(C 1-10 )alkyl, heterocycloalkyl, and heterocycloalkyl-alkyl; or R 8 and R 9 , together with the nitrogen atom to which they are attached, form a heterocycloalkyl.
  • the heterocycloalkyl is a 5-membered or 6-membered ring.
  • R 8 and R 9 together with the nitrogen atom to which they are attached form an unsubstituted or substituted piperidinyl.
  • R 8 is hydrogen and R 9 is hydrogen, (C 1-10 )alkyl, (C 3-10 )cycloalkyl, (C 3- ioJcycloalkyliCMoJalkyl, heterocycloalkyl, or heterocycloalkyl-alkyl.
  • the heterocycloalkyl is a 5- to 7-membered heterocycloalkyl, or the heterocycloalkyl-alkyl is a (5- to 7-membered)heterocycloalkyl-(C 1-10 )alkyl.
  • the (C 1-10 )alkyl, (C 3-10 )cycloalkyl, (C 3-10 )cycloalkyl(C 1-10 )alkyl, heterocycloalkyl, or heterocycloalkyl-alkyl of R 9 , or the heterocycloalkyl formed by R 8 and R 9 may be unsubstituted or substituted, for example with one or more substituents independently selected from the group consisting of -OR 23 , (C 1-10 )alkyl, and -NR 23 C(O)OR 23 . In certain embodiments, one or two substituents are independently selected from the group consisting of -OR 23 , (C 1-10 )alkyl, and -NR 3 C(O)OR 23 .
  • R 23 is independently H or (C 1-10 )alkyl, such as (C 1-8 )alkyl, (C 1-6 )alkyl, or (C 1- *)alkyl.
  • the piperidinyl is substituted with one or two -OH or -CH3. In some embodiments, the piperidinyl is substituted with one -OH.
  • R 1 may be:
  • R 1 is -NR 10 C(O)OR 9 , wherein R 9 is hydrogen, (C 1-10 )alkyl, (C 3-10 )cycloalkyl, (C 3-10 )cycloalkyl(C 1-10 )alkyl, heterocycloalkyl, or
  • heterocycloalkyl-alkyl is a 5- to 7-membered heterocycloalkyl, or the heterocycloalkyl-alkyl is a (5- to 7-membered)heterocycloalkyl- (C 1-10 )alkyl.
  • the (C 1-10 )alkyl, (C 3-10 )cycloalkyl, (C 3-10 )cycloalkyl(C 1-10 )alkyl, heterocycloalkyl, or heterocycloalkyl-alkyl of R 9 may be unsubstituted or substituted, for example with one or more substituents independently selected from the group consisting of -OR 23 , (C 1-10 )alkyl, and -NR 23 C(O)OR 23 .
  • R 9 is substituted with one or two substituents independently selected from the group consisting of -OR 23 , (C 1-10 )alkyl, and -NR 23 C(O)OR 23 .
  • R 23 is independently H or (C 1-10 )alkyl, such as (C 1-8 )alkyl, (C 1-6 )alkyl, or (C 1-4 )alkyl.
  • the piperidinyl is substituted with one or two -OH or -CH3.
  • the piperidinyl is substituted with one -OH.
  • R 10 is hydrogen or (C 1-10 )alkyl, such as methyl, ethyl, propyl, or butyl.
  • R 1 is
  • R 1 is -S(O)2NR 8 R 9 .
  • R 8 and R 9 are independently selected from the group consisting of hydrogen, (C 3-1 ojalkyl, and
  • the alkyl, cycloalkyl, or heterocycloalkyl are independently substituted with one or more -OR 23 , halo, oxo, or -NR 19 R 19 substituents.
  • the alkyl, cycloalkyl, or heterocycloalkyl are independently substituted with one or more -OR 23 or halo substituents.
  • R 1 is -NR 10 S(O)2R 9 .
  • R 10 and R 9 are selected from the group consisting of hydrogen, (C 1-10 )alkyl, and (C 3-10 )cycloalkyl.
  • R 10 is hydrogen.
  • the alkyl, cycloalkyl, or heterocycloalkyl are independently substituted with one or more -OR 23 or halo substituents.
  • R 8 and R 9 are both hydrogen.
  • R 10 is (C 1-10 )alkyl, such as (C 1-6 )alkyl, or (C 1-4 )alkyl, such as methyl, ethyl, or propyl.
  • R 1 is:
  • R 1 is -C(O)OR 9 .
  • R 9 is hydrogen, (C 1-10 )alkyl, or (C 3-10 )cycloalkyl.
  • R 1 is -C(O)OH, or
  • R 1 is -NR 8 R 9 .
  • each R 8 and R 9 are independently hydrogen, (C 1-10 )alkyl, or (C 3-10 )cycloalkyl, wherein each alkyl and cycloalkyl is independently unsubstituted or substituted.
  • R 8 and R 9 together with the nitrogen atom to which they are attached, form a substituted or unsubstituted heterocycloalkyl.
  • the heterocycloalkyl is a 4- to 10- member ed, 4- to 8- membered, 4- to 6-membered, or 5- or 6-membered heterocycloalkyl.
  • the heterocycloalkyl comprises, in addition to the nitrogen atom to which R 8 and R 9 are attached, one or two heteroatoms independently selected from the group consisting of O, S, and N.
  • R 8 and R 9 form a 5- or 6-membered heterocycloalkyl comprising, in addition to the nitrogen to which R 8 and R 9 are attached, one O or one S ring atom.
  • the heterocycloalkyl comprises an S ring atom
  • the S is in an oxidized state and forms -SO2.
  • the heterocycloalkyl is unsubstituted.
  • the heterocycloalkyl is substituted with one or more substituents selected from the group consisting of halo, oxo, and (C 1-10 )alkyl, wherein each alkyl is independently unsubstituted or substituted with one or more substituents selected from the group consisting of halo, -OH, -0(C 1-10 )alkyl, and -0(C 1-10 )haloalkyl.
  • R 1 is:
  • R 1 is -C(O)NR 10 NR 8 R 9 .
  • R 10 is hydrogen or (C 1-10 )alkyl.
  • R 10 is hydrogen. In other embodiments, R 10 is (C 1-10 )alkyl, such as (C 1-4 )alkyl, for example methyl or ethyl. In some embodiments, each of R 8 and R 9 are independently hydrogen, (C 1-10 )alkyl, or (C 3-10 )cycloalkyl, wherein each alkyl or cycloalkyl is unsubstituted or substituted. In some embodiments, the (C 1-10 )alkyl is (C 1-8 )alkyl, or (C 1-4 )alkyl.
  • the (C 3-10 )cycloalkyl is (C 3-6 )cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • the (C 1-10 )alkyl is methyl, ethyl, or propyl (such as isopropyl or n-propyl).
  • each alkyl and cycloalkyl is independently unsubstituted or substituted with one or more substituents.
  • the substituents are selected from the group consisting of (C 1-10 )alkyl, halo, oxo, and -OR 19 .
  • each R 19 is independently hydrogen, (C 1-10 )alkyl (such as (C 1-8 )alkyl, or (C 1-4 )alkyl), or (C 1-10 )haloalkyl (such as (C 1-8 jhaloalkyl, or (C 1-4 )haloalkyl).
  • R 8 and R 9 together with the nitrogen with which they are attached form a heterocycloalkyl, which may be unsubstituted or substituted.
  • the heterocycloalkyl is a S-to 8-membered heterocycloalkyl.
  • the heterocycloalkyl comprises one to three heteroatoms, in addition to the nitrogen attached to R 8 and R 9 , selected from the group consisting of O, N, and S.
  • the heterocycloalkyl is substituted with one or more substituents selected from the group consisting of (C 1-10 )alkyl (such as (C 1-8 )alkyl, or (Chalky.), halo, and -OR 23 .
  • each (C 1-10 )alkyl is unsubstituted or substituted, for example with one or more halo or -OH, or a combination thereof.
  • each R 23 is independently hydrogen or (C 1-10 )alkyl (such as (C 1-6 )alkyl, or (C 1-4 )alkyl).
  • R 1 is:
  • any of the compounds provided herein such as a compound of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-Ai), (Z-B), (Z-Bi), (I), (I-A), (I-B), (I- Ai), or (I-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof
  • R 3 is hydrogen, (C 1-10 )alkyl, or (C 3-10 )cycloalkyl.
  • the (C 1-10 )alkyl or (C 3-10 )cycloalkyl is substituted with one or more halo.
  • the one or more halo is one, two, or three halo.
  • the one or more halo is two or three halo.
  • R 3 is hydrogen or cyclopropyl.
  • R 3 is hydrogen.
  • R 3 is methyl.
  • R 3 is halo, for example chloro or fluoro.
  • R 2 is hydrogen, halo, (C 1-10 )alkyl, (C 3-10 )cycloalkyl, or - OR 25 .
  • the (C 1-10 )alkyl or (C 3-10 )cycloalkyl is substituted with one or more halo. In some embodiments, the (C 1-10 )alkyl or (C 3-10 )cycloalkyl is substituted with one, two, or three halo. In some embodiments, the (C 1-10 )alkyl or (C 3-10 )cycloalkyl is substituted with two or three halo.
  • R 2 is chloro, fluoro, or propyl. In some embodiments, R 2 is methyl. In some embodiments, R 2 is chloro or fluoro. In certain embodiments, R 3 is hydrogen and R 2 is chloro.
  • both of R 2 and R 3 are independently halo.
  • R 2 and R 3 are independently hydrogen, halo, or (C 1-10 )alkyl, wherein the alkyl is unsubstituted or substituted with one or more halo.
  • R 2 and R 3 are independently hydrogen, halo, or unsubstituted (C 1-10 )alkyl.
  • R 2 and R 3 are independently hydrogen, chloro, or methyl.
  • R 3 is hydrogen, and R 2 is halo or (C 1-10 )alkyl, wherein the alkyl is unsubstituted or substituted with one or more halo.
  • R 3 is hydrogen, and R 2 is chloro or methyl.
  • any of the compounds provided herein such as a compound of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-Ai), (Z-B), (Z-Bi), (I), (I-A), (I-B),
  • R 25 is independently selected from the group consisting of (C 1-10 )alkyl, (C 3-10 )cycloalkyl, (C 3-10 )cycloalkyl(C 1-10 )alkyl, or
  • heterocycloalkyl or two R 25 , together with the nitrogen atom to which they are attached, form a heterocycloalkyl; wherein each of the foregoing alkyl, cycloalkyl, or heterocycloalkyl moieties is independently unsubstituted or substituted with one or more halo.
  • any of the compounds provided herein such as a compound of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-Ai), (Z-B), (Z-Bi), (I), (I-A), (I-B), (I- Ai), or (I-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, each of X 1 , X 2 , X 3 , and X 4 are CR 4 , and
  • any of the compounds provided herein such as a compound of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-Ai), (Z-B), (Z-Bi), (I), (I-A), (I-B), (I- Ai), or (I-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, each of X 2 , X 3 and X 4 are CR 4 ; X 1 is N; and
  • any of the compounds provided herein such as a compound of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-Ai), (Z-B), (Z-Bi), (I), (I-A), (I-B), (I-Ai), or (I-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, each of X 1 , X 3 and X 4 are CR 4 ; X 2 is N; and
  • any of the compounds provided herein such as a compound of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-Ai), (Z-B), (Z-Bi), (I), (I-A), (I-B), (I- Ai), or (I-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, each of X 1 , X 2 , and X 4 are CR 4 ; X 3 is N; and
  • any of the compounds provided herein such as a compound of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-Ai), (Z-B), (Z-Bi), (I), (I-A), (I-B), (I- Ai), or (I-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, each of X 1 , X 2 , and X 3 are CR 4 ; X 4 is N; and
  • any of the compounds provided herein such as a compound of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-Ai), (Z-B), (Z-Bi), (I), (I-A), (I-B), (I- Ai), or (I-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof
  • X 1 and X 4 are CR 4
  • X 2 and X 3 are N;
  • any of the compounds provided herein such as a compound of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-Ai), (Z-B), (Z-Bi), (I), (I-A), (I-B), (I- Ai), or (I-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof
  • X 1 and X 2 are CR 4
  • X 3 and X 4 are N
  • any of the compounds provided herein such as a compound of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-Ai), (Z-B), (Z-Bi), (I), (I-A), (I-B), (I- Ai), or (I-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof
  • X 2 and X 3 are CR 4
  • X 1 and X 4 are N
  • any of the compounds provided herein such as a compound of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-Ai), (Z-B), (Z-Bi), (I), (I-A), (I-B), (I- Ai), or (I-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof
  • X 3 and X 4 are CR 4
  • X 1 and X 2 are N
  • any of the compounds provided herein such as a compound of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-Ai), (Z-B), (Z-Bi), (I), (I-A), (I-B), (I- Ai), or (I-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof
  • X 1 and X 3 are CR 4
  • X 2 and X 4 are N
  • any of the compounds provided herein such as a compound of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-Ai), (Z-B), (Z-Bi), (I), (I-A), (I-B), (I- Ai), or (I-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof
  • X 2 and X 4 are CR 4
  • X 1 and X 3 are N
  • any of the compounds provided herein such as a compound of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-Ai), (Z-B), (Z-Bi), (I), (I-A), (L-B), (I- Ai), or (I-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof
  • X 3 is CR 4 ; each of X 1 , X 2 , and X 4 are N; and
  • each R 4 is independently selected from the group consisting of hydrogen, halo, cyano, (C 1-10 )alkyl, and (C 3-10 )cycloalkyl.
  • the (C 1-10 )alkyl or (C 3-10 )cycloalkyl are independently unsubstituted or substituted with one or more halo.
  • the (C 1-10 )alkyl or (C 3-10 )cycloalkyl are substituted with one, two, or three halo.
  • (C 1-10 )alkyl or (C 3-10 )cycloalkyl are substituted with two or three halo.
  • the (C 1-10 )alkyl is substituted with one or more halo.
  • the (C 1-10 )alkyl is substituted with one, two, or three halo.
  • (C 1-10 )alkyl is substituted with one halo.
  • each R 4 is independently hydrogen, fluoro, chloro, cyano, methyl, ethyl, or propyl.
  • each R 4 is
  • the (C 1-10 )alkyl or (C 3-10 )cycloalkyl are independently unsubstituted or substituted with one or more halo.
  • the (C 1-10 )alkyl or (C 3-10 )cycloalkyl are independently unsubstituted or substituted with one, two, or three halo.
  • the (C 1-10 )alkyl is substituted with one or more halo.
  • each R 27 is H or (C 1-10 )alkyl, such as (C 1-8 )alkyl, (C 1-6 )alkyl, or (C 1-4 )alkyl; or two R 27 , together with the nitrogen atom to which they are attached, form heterocycloalkyl.
  • each R 4 is independently hydrogen, fluoro, chloro, cyano, methyl, ethyl, propyl, -NH2, or -N(CH 3 )2.
  • the halo is iodo or fluoro. In certain embodiments, the halo is fluoro. In some embodiments, wherein at least one of X 2 , X 3 and X 4 is N, and an adjacent annular carbon is bonded to R 4 , the R 4 is independently hydrogen, fluoro, cyano, (C 1-10 )alkyl, or -OR 27 .
  • two R 4 on adjacent annular carbon atoms together with the carbon atoms to which they are attached form a carbocyclyl, wherein the carbocyclyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, cyano, (C 1-10 )alkyl, (C 3-10 )cycloalkyl, (C 3- ioJcycloalkyliCMoJalkyl, heterocycloalkyl, heterocycloalkyl-alkyl, -OR 27 , -C(O)NR 27 R 27 , -NR 27 C(O)R 27 , -NR 27 R 27 , -S(O) 2 NR 27 R 27 , -NR 27 S(O)2R 27 , -S(O)nsR 28 , and -C(O)R 28 .
  • substituents independently selected from the group consisting of halo, cyano, (C 1-10 )alkyl, (C
  • two R 4 on adjacent annular carbon atoms together with the carbon atoms to which they are attached may form a 5- membered or 6-membered carbocyclyl which is fused to the 6-membered ring formed by X 1 , X 2 , X 3 , and X 4 , wherein the carbocyclyl is unsubstituted or substituted.
  • the carbocyclyl is aromatic. In other embodiments, the carbocyclyl is not aromatic.
  • two R 4 on adjacent annular carbon atoms together with the carbon atoms to which they are attached form a heterocarbocyclyl, wherein the
  • heterocarbocyclyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, cyano, (C 1-10 )alkyl, (C 3-10 )cycloalkyl,
  • two R 4 on adjacent annular carbon atoms together with the carbon atoms to which they are attached may form a 5-membered or 6-membered heterocyclyl which is fused to the 6- membered ring formed by X 1 , X 2 , X 3 , and X 4 , wherein the heterocarbocyclyl is unsubstituted or substituted.
  • the heterocyclyl is aromatic. In other embodiments, the heterocyclyl is not aromatic.
  • the heterocyclyl is comprises 1 to 3 heteroatoms independently selected from the group consisting of O, N, and S.
  • the heterocyclyl is a 5- or 6-membered heterocyclyl comprising 1 to 2 heteroatoms independently selected from the group consisting of O and N.
  • each R 4 is H.
  • R 15 and R 17 are independently hydrogen, halo, or alkyl.
  • the alkyl is independently unsubstituted or substituted with one or more halo.
  • the alkyl is independently unsubstituted or substituted with one, two, or three halo. In certain embodiments, the alkyl is independently unsubstituted or substituted with two or three halo. In certain embodiments, R 15 and R 17 are independently hydrogen, fluoro, chloro, methyl, ethyl, or propyl.
  • R 14 is (C 1-10 )alkyl, (C 1-10 )alkenyl, (C 3-10 )cycloalkyl, (C 3-10 )cycloalkenyl, heterocycloalkyl connected through an annular carbon atom, or heterocycloalkenyl connected through an annular carbon atom. In certain embodiments, R 14 is (C 1-10 )alkyl, (C 1-10 )alkenyl, (C 3-10 )cycloalkyl, heterocycloalkyl, or heterocycloalkenyl connected through an annular carbon atom. In certain embodiments, R 14 is (C 1-10 )alkyl, (C 1-10 )alkenyl, (C 3-10 )cycloalkyl, heterocycloalkyl
  • R 14 is (C 1-10 )alkyl, (C 3-10 )cycloalkyl, or heterocycloalkyl connected through an annular carbon atom.
  • R 14 is (C 1- u)alkyl, (C 1-6 )alkyl, or (C 1-4 )alkyl, such as hexyl, pentyl, butyl, propyl, ethyl, or methyl, which may be unsubstituted or substituted.
  • R 14 is unsubstituted or substituted tert-butyl, or unsubstituted or substituted isopropyl.
  • R 14 is (C 1-8 )alkenyl, (C 1-6 )alkenyl, or (C 1-4 )alkenyl, wherein the alkenyl comprises one or two C-C double bonds, and wherein the alkenyl may be unsubstituted or substituted.
  • R 14 is isopropenyl.
  • R 14 is a 4-, 5-, or 6- membered heterocycloalkyl comprising one to three heteroatoms independently selected from O and N, wherein the heterocycloalkyl is connected through an annular carbon atom.
  • R 14 may be a (C 3-5 )heterocycloalkyl comprising one or two O atoms.
  • R 14 is a 5- or 6-membered heterocycloalkenyl comprising one to three
  • R 14 is (C 3-10 )cycloalkyl, for example (C 3- e)cycloalkyl, (C 3-6 )cycloalkyl, or (C «)cycloalkyl.
  • R 14 is cyclobutyl or cyclopropyl, unsubstituted or substituted with halo, -OR 7 (such as -OH or -0(C 1- i 0 )alkyl) or a combination thereof.
  • the alkyl, alkenyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl of R 14 is substituted with one or more substituents as described in Formula
  • the alkyl, alkenyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl of R 14 may be unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of (C 1-10 )alkyl, halo, -OR 7 , and -C(O)OR 7 .
  • Each R 7 may be hydrogen or (C 1-10 )alkyl, such as (C 1- s)alkyl, (C 1-8 )alkyl, or (C 1-4 )alkyl, for example hexyl, pentyl, butyl, propyl, ethyl, or methyl, wherein the alkyl is independently unsubstituted or substituted with one or more halo.
  • the alkyl, cycloalkyl, heterocycloalkyl, or heterocycloalkenyl is independently unsubstituted or substituted with one, two, or three halo.
  • the alkyl, cycloalkyl, heterocycloalkyl, or heterocycloalkenyl is substituted with two or three halo. In some embodiments, the alkyl is substituted with one, two, or three alkyl.
  • R 14 is (C 1-10 )alkyl wherein the alkyl is unsubstituted or substituted with oxo. In still other embodiments, R 14 is (C 1-10 )alkyl substituted with -NR 7 R 7 . In some embodiments, each R 7 is independently hydrogen or (C 1- i 0 )alkyl.
  • R 14 is -OR 5 , wherein R 5 is hydrogen, (C 1-10 )alkyl, or
  • R 5 is (C 1-10 )alkyl, such as (C 1-4 )alkyl or (C 1-2 )alkyl, or (C 3-10 )cycloalkyl, such as (C 3-6 )cycloalkyl, each of which may be unsubstituted or substituted with halo or -(OR 35 )n120R 34 , or a combination thereof.
  • nl2 is 0, 1, 2, or 3.
  • each R 35 is independently (C 1-10 )alkyl or (C 1-10 )haloalkyl alkyl, such as (C 1-4 )alkyl, (C 1-4 )haloalkyl, (C 1- 3)alkyl, or (C 1- 3)haloalkyl.
  • R 34 is hydrogen or (C 1-10 )alkyl, such as (C 1-4 )alkyl or (C 1- 3)alkyl.
  • nl2 is 0 or 1
  • R 35 is methyl, ethyl, or propyl
  • R 34 is hydrogen, methyl, ethyl, or propyl.
  • R 14 is:
  • R 15 is hydrogen. In other embodiments, R 15 is -OR 29 . In some embodiments, R 29 is hydrogen, (C 1-10 )alkyl, (C 1-10 )haloalkyl, (C 3-10 )cycloalkyl, or
  • R 14 and R 15 together with the atoms to which they are attached, form a Cs or Ce carbocyclyl. In other embodiments, R 14 and R 15 , together with the atoms to which they are attached, form a 5- or 6-membered heterocyclyl.
  • the heterocyclyl is a S- or 6-membered heterocyclyl comprising one to three heteroatoms independently selected from O and N, such as a C 3-5 cycloalkyl comprising one or two O atoms.
  • the heterocyclyl is a 5- or 6-membered heterocyclyl comprising one or two N atoms, or one O atom and one N atom.
  • the carbocyclyl or heterocyclyl is unsubstituted or substituted with one or two substituents independently selected from the group consisting of (C 1-10 )alkyl, (C 3-10 )cycloalkyl, or
  • (C 3-10 )cycloalkyl(C 3-10 )alkyl substituents such as (C 1-8 )alkyl, (C 1-8 )alkyl, (C 1-4 )alkyl, (C 3- 8 )cycloalkyl, (C 3-6 )cycloalkyl, (C 3- ejcycloalkyl, (C 3-8 )cycloalkyl(C 1-8 )alkyl,
  • the carbocyclyl or heterocyclyl is unsubstituted or substituted with one or two substituents independently selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, cyclopropyl, cyclobutyl, cyclopropyl-methyl, and cyclobutyl-methyl.
  • the butyl is tert-butyl.
  • the carbocyclyl or heterocyclyl is substituted with one or more halo.
  • R 16 and R 17 are both H.
  • R 16 is (C 1-10 )alkyl, such as (C 1-6 )alkyl or (C 1-4 )alkyl.
  • the alkyl is unsubstituted, while in other embodiments, the alkyl is substituted.
  • R 16 is -OR 5 .
  • R 5 is hydrogen or (C 1-10 )alkyl.
  • the alkyl is substituted with halo or -(OR 35 )n120R 34 .
  • R 17 is hydrogen.
  • R 16 is hydrogen, fluoro, (C 1-10 )alkyl, (C 3-10 )cycloalkyl,
  • heterocycloalkyl, or heterocycloalkyl-alkyl is independently unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of (C 1-10 )alkyl, halo, cyano, oxo, -OR 7 , -C(O)OR 7 , -C(O)NR 7 R 7 , -NR 7 C(O)R 7 , -NR 7 C(O)NR 7 R 7 , -NR 7 R 7 , -S(O)2NR 7 R 7 , -NR 7 S(O)2R 7 , -S(O)ii2R 13 , and -C(O)R 13 .
  • R 16 is hydrogen or fluoro. In some embodiments, R 16 is hydrogen.
  • the compound of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-Ai), (Z-B), (Z-Bi), (I), a-A), (I-B), or (I-Bi) is:
  • the compound of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-Ai), (Z-B), (Z-Bi), (I), a-A), (Z-B), or (Z-Bi) is:
  • the compound of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-Ai), (Z-B), (Z-Bi), (I), (I-A), (I-Ai), (Z-B), or (Z-Bi) is:
  • the compound of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-Ai), (I), (I-A), or (I-Ai) is:
  • the compound of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-Ai), (I), (I-A), or (I-Ai) is:
  • the compound of Formula (X), (X-A), (X-Ai), (X-B), (X- Bi), (Z), (Z-A), (Z-Ai), (I), (I-A), or (I-Ai) is:
  • compositions comprising any of the compounds disclosed herein, such as a compound of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-B), (Z-Ai), (Z-Bi), (I), (I- A), (I-B), (I-Ai), or (I-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, and a pharmaceutically acceptable excipient
  • the compounds disclosed herein such as a compound of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-Ai), (I), (I- A), or (I-Ai), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, may be prepared, for example, through the reaction routes depicted in General Schemes 1- ⁇ .
  • General Reaction Scheme I provides two routes to compound 1-5, which is an example of a compound of Formula (X), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof as described herein.
  • compound 1-1 is coupled with compound 1-2 in the presence of a palladium catalyst and base to produce compound 1-3.
  • Suitable palladium catalysts may include, for example, tetrakis(triphenylphosphine)palladium(0)
  • suitable bases may include, for example, aqueous sodium carbonate or potassium carbonate.
  • compound 1-3 is reacted with compound 1-4 in the presence of a coupling reagent and a base.
  • Suitable coupling reagents may include bis(di-tert-butyl(4-dimethylaminophenyl)phosphine) dichloropalladium(n) or [l,l'-bis(diphenylphosphino) ferrocene]dichloropalladium(II) or tetrakis(triphenylphosphine)palladium(0).
  • Suitable bases may include aqueous sodium carbonate or potassium carbonate. Either of the two coupling reactions may be carried out using a solvent, for example, dioxane or dimethoxyethane. In some embodiments, the reactions are carried out between 60 °C to 120 °C, for between 8 h to 24 h.
  • compound 1-4 is coupled with compound 1-1 to produce compound 1-6, which is next coupled with compound 1-2 to produce compound I-S. Similar coupling reagents and conditions may be used as were previously described for the first route.
  • compounds of Formula (X), (X-A), (X-Ai), (Z), (Z-A), (Z-Ai), (I), (I- A), or (I-Ai), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R 1 is -C(O)NR 8 R 9 may be prepared according to General Reaction Scheme ⁇ .
  • the reaction is carried out in a dipolar aprotic solvent, such as DMF or dioxane, and may be performed, for example, at room temperature until the reaction has gone to completion, such as for 8 h to 48 h.
  • a dipolar aprotic solvent such as DMF or dioxane
  • the compound ⁇ -l may be prepared as described in General Reaction Scheme I above, wherein R 1 is -COOH.
  • Compound ⁇ II-4 may be prepared, for example, by reacting compound ⁇ -1 with a carbamoyl chloride compound IU-2 in the presence of an organic base, such as diisopropylethyl amine or triethylamine. The reaction may be carried out in a solvent, such as dichloromethane, at room temperature for 4 h to 24 h.
  • compound III-4 may be prepared by reacting compound ⁇ -l with phenylchloroformate in dichloromethane in the presence of triethylamine for approximately 16 h at room temperature, and then treating resulting phenyl carbamate with an amine HNR 8 R 9 in tetrahydrofuran at 0 °C to room temperature for 4 h to 24 h.
  • Compound ⁇ -6 may be prepared, for example, by reacting compound ⁇ -1 with a chloroformate compound ⁇ - 5, in the presence of an organic base, such as diisopropylethyl amine or triethylamine. The reaction may be carried out in a solvent, such as dichloromethane, at room temperature for 4 h to 24 h.
  • Compound ⁇ -8 may be prepared, for example, by reacting compound ⁇ -1 with a sulfonyl halide compound ⁇ II-7 wherein X is chlorine or fluorine. This reaction may be carried out in the presence of an organic base, such as triethylamine, and in solvent such as pyridine for 4 h to 24 h at room temperature.
  • Compound ⁇ -1 may be prepared, for example, as described in General Reaction Scheme I above, wherein R 1 is -NH2.
  • kits for using the compounds disclosed herein such as compounds of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-B), (Z-Ai), (Z-Bi), (I), (I-A), (I-B), (I-Ai), or (I-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or a pharmaceutical composition comprising any of the foregoing and a pharmaceutically acceptable excipient.
  • These include methods of inhibiting a component of the SREBP pathway, such as an SREBP or SCAP; and methods of treating a disorder in a subject in need thereof.
  • the disorder is mediated by an SREBP or SCAP.
  • treat refers to any indicia of success in the amelioration of an injury, disease, disorder, pathology, or condition, including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the injury, disease, disorder, pathology, or condition more tolerable to the subject; slowing or stopping the rate of degeneration, decline, or development; slowing the progression of injury, disease, disorder, pathology, or condition; making the final point of degeneration less debilitating; improving a subject's physical or mental well-being; or relieving or causing regression of the injury, disease, disorder, pathology, or condition.
  • the treatment of symptoms can be based on objective or subjective parameters, which may include the results of a physical examination, a neuropsychiatric exam, and/or a psychiatric evaluation.
  • Certain methods and uses disclosed herein may treat cancer by, for example, decreasing the incidence of cancer, causing remission of cancer, slowing the rate of growth of cancer cells, slowing the rate of spread of cancer cells, reducing metastasis, or reducing the growth of metastatic tumors, reducing the size of one or more tumors, reducing the number of one or more tumors, or any combinations thereof.
  • a combination of an SREBP and SCAP is inhibited.
  • Such methods may include contacting an SREBP with a compound of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-B), (Z-Ai), (Z-Bi), (I), (I-A), (I-B), (I- Ai), or (1-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or a pharmaceutical composition comprising any of the forgoing and a pharmaceutically acceptable excipient
  • Such uses and methods may also include contacting SCAP with a compound of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-B), (Z-A), (Z-B), (Z-A
  • a compound of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-B), (Z-Ai), (Z-Bi), (I), (I-A), (I-B), (I-Ai), or (I-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof is administered to a subject in need thereof to inhibit a component of the SREBP pathway.
  • a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-B), (Z-Ai), (Z-Bi), (I), (I-A), (I-B), (I-Ai), or (I-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, is administered to the subject in need thereof.
  • a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof is administered to the subject in need thereof.
  • the compound or pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof is administered as a pharmaceutical composition, as described herein.
  • the component of the SREBP pathway that is inhibited by the methods and uses described herein may be an SREBP or SCAP.
  • an SREBP is inhibited.
  • the SREBP may be, for example, an SREBP-1 (such as SREBP-la or SREBP-1 c) or SREBP-2.
  • SREBP-1 such as SREBP-la or SREBP-1 c
  • SREBP-2 two or three of SREBP-la, SREBP- lc, and SREBP-2 are inhibited.
  • the component is an SREBP-1.
  • the SREBP is SREBP-1 a.
  • the component is SREBP- lc.
  • the SREBP is SREBP-2.
  • the component of the SREBP pathway is SCAP.
  • both an SREBP and SCAP are inhibited.
  • two or three of SREBP-la, SREBP-lc, and SREBP-2 are inhibited, and SCAP is inhibited.
  • Inhibition of a component of the SREBP pathway may include partial inhibition or full inhibition. Partial inhibition may include reducing the activity of a component of the SREBP pathway to a level that is still detectable. Full inhibition may include stopping all activity of a component of the SREBP pathway (such as stopping the activity of an SREBP or SCAP), or reducing the activity of a component of the SREBP pathway to a level below detection. Inhibition of a component of the SREBP pathway may be measured directly or indirectly, using any methods known in the art
  • inhibition of a component of the SREBP pathway is measured directly, for example by measuring the product of a reaction catalyzed by an SREBP pathway component.
  • Inhibition of SREBP activation may in some embodiments be demonstrated by western blotting and quantitatively assessing the levels of full- length and cleaved SREBP- 1 and/or SREBP-2 proteins from a cell line (such as a hepatic cell lines) or primary cells (such as primary hepatocytes of mouse, rat or human origin).
  • inhibition of a component of the SREBP pathway is measured indirectly, for example by measuring the level of expression of one or more genes that are regulated by SREBP.
  • the inhibition of a component of the SREBP pathway such as an SREBP or SCAP, may reduce the expression of one or more genes that are regulated by an SREBP, for example an SREBP-1 (such as SREBP-la or SREBP-lc) or SREBP-2.
  • SCAP plays a role in activating SREBPs, thus inhibiting the activity of SCAP may reduce the expression of one or more genes that are regulated by an SREBP.
  • SREBP pathway inhibition may also be determined by assessing gene transcription levels of one or more target genes of SREBP-1 and/or SREBP-2, such as one or more of ACSS2, ALDOC, CYP51A1, DHCR7, ELOVL6, FASN, FDFT1, FDPS, HMGCS1, HSD17B7, Ettl, INSIG1, LDLR, LSS, ME1, PCSK9, PMVK, RDHl 1, SC5DL, SQLE, STARD4, TM7SF2, PNPLA3, SREBFl, SREBF2, HMGCR, MVD, MVK, ACLY, MSMOl, ACACA, or ACACB.
  • ACSS2 gene transcription levels of one or more target genes of SREBP-1 and/or SREBP-2, such as one or more of ACSS2, ALDOC, CYP51A1, DHCR7, ELOVL6, FASN, FDFT1, FDPS, HMGCS1, HSD17B7, Ettl, INSIG1, LDLR
  • the transcription levels may be assessed, for example, by transcriptomic analysis, including but not limited to q-PCR. A reduction in one, two, three, four, five, or more of these genes may indicate inhibition of SREBP activation.
  • This evaluation of endogenous SREBP gene expression may be assessed in cell lines (such as hepatic cell lines) or primary cells (such as primary hepatocytes of mouse, rat, or human origin). In some
  • the gene transcription levels of PCSK9 or PNPLA3, or a combination thereof are evaluated.
  • the expression of PCSK9 is reduced. In other embodiments, the expression of PNPLA3 is reduced. In still further embodiments, both the expression of PCSK9 and PNPLA3 are reduced.
  • one or more SREBP is contacted, for example an SREBP- 1 (such as SREBP- la or SREBP- lc) or SREBP-2, or any combinations thereof.
  • SCAP is contacted. In still further embodiments, one or more of SREBP-la, SREBP-lc, SREBP-2, and SCAP is contacted. In certain embodiments, inhibition of a component of the SREBP pathway may treat a disorder mediated by an SREBP, such as the disorders as described herein.
  • expression of one or more genes as described above is reduced in a subject in need thereof.
  • Another method of indirectly detecting SREBP pathway inhibition may include:
  • the cells may then be treated with a compound, such as a compound of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-B), (Z-Ai), (Z-Bi), (I), (I- A), (I-B), (I-Ai), or (I-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof.
  • a reduction of luciferase activity reflects inhibition of SREBP activation, and non-cytotoxicity of the compound can be assessed by LDH release.
  • a pharmaceutical composition comprising a compound of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A),
  • the compound is a compound of Formula (X-A), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof.
  • the compound is a compound of Formula (X-Ai), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof.
  • the compound is a compound of Formula (X-Ai), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof.
  • the compound is a compound of
  • the compound is a compound of Formula (X-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof.
  • the compound is a compound of Formula (Z-A), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof.
  • the compound is a compound of Formula (Z-Ai), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof.
  • the compound is a compound of Formula (Z-B), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof.
  • the compound is a compound of Formula (Z-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof.
  • the compound is a compound of Formula (I-A), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof.
  • the compound is a compound of Formula (I-Ai), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof.
  • the compound is a compound of Formula (I-B), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof.
  • the compound is a compound of Formula (I-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof.
  • the disorder is mediated by an SREBP.
  • the uses and methods of treatment describe herein may use a compound of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-B), (Z-Ai), (Z-Bi), (I), (I-A), (I-B), (I-Ai), or (I-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof; or a pharmaceutical composition comprising a compound of Formula (X), (X-A), (X-Ai), (X-B), (X- Bi), (Z), (Z-A), (Z-B), (Z-Ai), (Z-Bi), (I), (I-A), (I-B), (I-Ai), or (I-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, and a pharmaceutically acceptable excipient
  • the disorder is a metabolic disorder, such as a disorder that affects lipid metabolism, cholesterol metabolism, or insulin metabolism.
  • a metabolic disorder such as a disorder that affects lipid metabolism, cholesterol metabolism, or insulin metabolism.
  • the disorder is related to lipid metabolism, cholesterol metabolism, or insulin metabolism, for example, liver disease as a result of the buildup of fat in the liver, or
  • the disorder is a liver disease, such as chronic liver disease.
  • the liver disease is mediated by a component of the SREBP pathway, such as an SREBP or SCAP.
  • the liver disease is mediated by an SREBP.
  • the liver disease is mediated by a downstream gene target of an SREBP, such as PNPLA-3.
  • the liver disease is mediated by SCAP.
  • a liver disease in a subject in need thereof comprising administering to the subject in need thereof a compound of Formula (X), (X- A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-B), (Z-Ai), (Z-Bi), (I), (I-A), (I-Ai), (I-B), or (I-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof; or a
  • the chronic liver disease may be, for example, primary alcoholic liver disease, nonalcoholic fatty liver disease (NAFLD), or nonalcoholic steatohepatitis (NASH).
  • NAFLD nonalcoholic fatty liver disease
  • NASH nonalcoholic steatohepatitis
  • the liver disease is liver fat, liver inflammation, or liver fibrosis, or a combination thereof.
  • the liver disease is non-alcoholic fatty liver disease (NAFLD).
  • NAFLD is a group of conditions that are related to fat buildup in the liver.
  • NASH Non-alcoholic steatohepatitis
  • the liver inflammation may lead to liver damage and scarring, which can be irreversible, and it can also progress to cirrhosis and liver failure.
  • NAFLD and NASH are associated with metabolic disorders such as obesity, dyslipidemia, insulin resistance, and type 2 diabetes. Other disorders associated with NAFLD and NASH include increased abdominal fat and high blood pressure.
  • NASH is mediated by a component of the SREBP pathway, such as an SREBP or SCAP.
  • NASH uses and methods of treating NASH in a subject in need thereof, comprising administering to the subject in need thereof a compound of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-B), (Z-Ai), (Z-Bi), (I), (I-A), (I-Ai), (I-B), or (I-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof; or a pharmaceutical composition comprising any of the foregoing and a pharmaceutically acceptable excipient
  • Treatment of NASH may include reduction in average liver fat content, which may be evaluated, for example, by magnetic resonance imaging (MRI), magnetic resonance elastography (MRE), ultrasound, or computerized tomography (CT); reduction of the liver enzyme alanine aminotransferase (ALT); reduction of the liver enzyme aspartate aminotransferase (ALT);
  • Treatment of NASH may be evaluated using the NAFLD activity score (NAS); or steatosis, activity, and fibrosis score (SAF); or other NASH diagnostic and/or scoring metrics (such as FIB4 or ELF).
  • NAS NAFLD activity score
  • SAF steatosis, activity, and fibrosis score
  • FIB4 FIB4 or ELF
  • liver fibrosis associated with NASH
  • uses and methods of treating a disorder in a subject in need thereof, wherein the disorder is liver fibrosis associated with NASH comprising administering to the subject in need thereof a compound of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z- A), (Z-B), (Z-Ai), (Z-Bi), (I), (I-A), (I-Ai), (I-B), or (I-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof; or a pharmaceutical composition comprising any of the foregoing and a pharmaceutically acceptable excipient
  • the liver fibrosis is mediated by SREBP.
  • Treatment of liver fibrosis may be evaluated, for example, by magnetic resonance imaging (MRI), magnetic resonance elastography (MRE), ultrasound, or computerized tomography (CT); reduction of the liver enzyme alanine aminotransferase (ALT); reduction of the liver enzyme aspartate aminotransferase (ALT); reduction of liver inflammation and/or fibrosis as evaluated through histological scoring of liver biopsy; or any combinations thereof
  • MRI magnetic resonance imaging
  • MRE magnetic resonance elastography
  • CT computerized tomography
  • ALT liver enzyme aspartate aminotransferase
  • ALT aspartate aminotransferase
  • a disorder in a subject in need thereof wherein the disorder is fatty liver disease
  • administering comprising administering to the subject in need thereof a compound of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-B), (Z- Ai), (Z-Bi), (I), (I- A), (I-Ai), (I-B), or (I-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof; or a pharmaceutical composition comprising any of the foregoing and a pharmaceutically acceptable excipient.
  • the fatty liver disease is mediated by SREBP.
  • a subject may have fatty liver disease when the fat content of the subject's liver is 5% or greater.
  • a subject with fatty liver disease has NASH, or liver fibrosis associated with NASH.
  • a subject with fatty liver disease has not been diagnosed with NASH or liver fibrosis associated with NASH.
  • Treatment of fatty liver disease may be evaluated, for example, by magnetic resonance imaging (MRI), magnetic resonance elastography (MRE), ultrasound, or computerized tomography (CT); reduction of the liver enzyme alanine aminotransferase (ALT); reduction of the liver enzyme aspartate aminotransferase (ALT); reduction of liver inflammation as evaluated through histological scoring of liver biopsy; reduction of liver fibrosis as evaluated through histological scoring of liver biopsy; reduction of liver fat content as evaluated through histological scoring of liver biopsy; or any combinations thereof.
  • MRI magnetic resonance imaging
  • MRE magnetic resonance elastography
  • CT computerized tomography
  • liver disease such as methods of treating liver fibrosis, fatty liver disease, or NASH, the subject is
  • Other metabolic disorders which may be treated with the compounds or pharmaceutical compositions described herein may include, for example, insulin resistance, hyperglycemia, diabetes mellitus, dyslipidemia, adiposopathy, obesity, and Metabolic Syndrome.
  • the metabolic disorder is mediated by a genetic factor.
  • the metabolic disorder is mediated by one or more environmental factors, such as a diet rich in fat, or a diet rich in sugar, or a combination thereof.
  • the metabolic disorder is mediated by SREBP.
  • the diabetes mellitus is type I diabetes. In certain embodiments, the diabetes mellitus is type ⁇ diabetes.
  • Diabetes also known as diabetes mellitus
  • Diabetes mellitus refers to a disease or condition that is generally characterized by metabolic defects in production and utilization of glucose which result in the failure to maintain appropriate blood sugar levels in the body.
  • the diabetes is type ⁇ diabetes, which is characterized by insulin resistance, in which insulin loses its ability to exert its biological effects across a broad range of concentrations.
  • the diabetes is mediated by a component of the SREBP pathway, such as an SREBP or SCAP.
  • Insulin resistance has been hypothesized to unify the clustering of hypertension, glucose intolerance, hyperinsulinemia, increased levels of triglyceride, decreased HDL cholesterol, and central and overall obesity.
  • “Metabolic Syndrome” refers to a similar clustering of conditions, which may include abdominal obesity, hypertension, high blood sugar, high serum triglycerides (such as elevated fasting serum triglycerides), and low HDL levels, and is associated with a risk of developing cardiovascular disease and/or type ⁇ diabetes.
  • the Metabolic Syndrome or insulin resistance is mediated by a component of the SREBP pathway, such as an SREBP or SCAP.
  • the subject is administered between about 0.01 mg/kg to about 100 mg/kg of compound of Formula (X), (X- A), ( ⁇ - ⁇ ), (X-B), (X-Bi), (Z), (Z-A), (Z-B), (Z-Ai), (Z-Bi), (I), (I-A), ( ⁇ - ⁇ ), (I-B), or (I-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, relative to the body mass of the subject
  • the metabolic disorder is dyslipidemia.
  • uses and methods of treating dyslipidemia in a subject in need thereof comprising administering to the subject in need thereof a compound of Formula (X), (X-A), (X- Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-B), (Z-Ai), (Z-Bi), (I), (I-A), (I-Ai), (I-B), or (I-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof; or a compound of Formula (X), (X-A), (X- Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-B), (Z-Ai), (Z-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof; or a
  • Dyslipidemia refers to abnormal blood plasma levels of one or more lipids or one or more lipoproteins, or any combinations thereof.
  • Dyslipidemia may include depressed levels or elevated levels of one or more lipids and/or one or more lipoproteins, or a combination of depressed and elevated levels (for example, elevated levels of one type of lipid and depressed levels of another type of lipid and/or lipoprotein).
  • Dyslipidemia may include, but is not limited to, elevated low density lipoprotein cholesterol (LDL), elevated apolipoprotein B, elevated triglycerides (TGs), elevated lipoprotein(a), elevated apolipoprotein A, reduced high density lipoprotein cholesterol (HDL), or reduced apolipoprotein Al, or any combinations thereof.
  • LDL low density lipoprotein cholesterol
  • TGs elevated triglycerides
  • HDL reduced high density lipoprotein cholesterol
  • Al reduced apolipoprotein Al
  • Dyslipidemia such as abnormal cholesterol or abnormal TG levels, is associated with an increased risk for vascular disease (such as heart attack or stroke), atherosclerosis, and coronary artery disease.
  • the dyslipidemia is hyperlipidemia.
  • Hyperlipidemia refers to the presence of an abnormally elevated level of lipids in the blood, and may include (1) hypercholesterolemia (an elevated cholesterol level); ( 2 ) hypertriglyceridemia, (an elevated triglyceride level); and (3) combined hyperlipidemia, (a combination of hypercholesterolemia and hypertriglyceridemia).
  • Dyslipidemia may arise from a combination of genetic predisposition and diet, and may be associated with being overweight, diabetes, or Metabolic Syndrome.
  • Lipid disorders may also arise as the result of certain medications (such as those used for anti-rejection regimens in people who have had organ or tissue transplants).
  • the dyslipidemia such as hyperlipidemia
  • the SREBP pathway such as an SREBP or SCAP.
  • ⁇ uses and methods of reducing cholesterol levels, modulating cholesterol metabolism, modulating cholesterol catabolism, modulating the absorption of dietary cholesterol, reversing cholesterol transport, or lowering triglycerides in a subject in need thereof, comprising administering to the subject in need thereof a compound of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-B), (Z-Ai), (Z-Bi), (I), (I-A), (I-Ai), (I-B), or (I-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof; or a pharmaceutical composition comprising any of the foregoing and a pharmaceutically acceptable excipient.
  • the subject is administered between about 0.01 mg/kg to about 100 mg/kg of compound of Formula (X), (X- A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-B), (Z-Ai), (Z-Bi), (I), (L-A), (I-Ai), (I-B), or (I-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, relative to the body mass of the subject
  • adiposopathy in a subject in need thereof, comprising administering to the subject in need thereof a compound of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-Ai), (Z-B), (Z-Bi), (I), (I-A), (I-Ai), (I-B), or (I-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof; or a pharmaceutical composition comprising any of the foregoing and a
  • the adiposopathy is associated with Metabolic Syndrome.
  • the adiposopathy is mediated by a component of the SREBP pathway, such as an SREBP or SCAP.
  • Gallstones may be associated with gallbladder inflammation, pancreas inflammation, or liver inflammation.
  • the gallstones are cholesterol gallstones, which may form when bile contains a high concentration of cholesterol and not enough bile salts.
  • the gallstones, which may include cholesterol gallstone disease is mediated by a component of the SREBP pathway, such as an SREBP or SCAP.
  • the disorder is pancreatitis.
  • the disorder is endotoxic shock, systemic inflammation, or xanthoma.
  • the disorder is atherosclerosis, coronary artery disease, angina pectoris, carotid artery disease, stroke, or cerebral arteriosclerosis.
  • any of the foregoing disorders are mediated by a component of the SREBP pathway, such as an SREBP or SCAP.
  • the subject is administered between about 0.01 mg kg to about 100 mg/kg of compound of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-Ai), (Z-B), (Z-Bi), (I), (I-A), (I-Ai), (I-B), or (I-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, relative to the body mass of the subject
  • the subject is overweight, obese, has insulin resistance, is pre-diabetic or has type ⁇ diabetes. In certain embodiments of any of the preceding embodiments, the subject has NASH.
  • the disorder is a hyperproliferative disorder.
  • uses and methods of treating a hyperproliferative disorder in a subject in need thereof comprising administering to the subject in need thereof a compound of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-Ai), (Z-B), (Z-Bi), (I), (I-A), (I-Ai), (I-B), or (I-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof; or a pharmaceutical composition comprising any of the foregoing and a compound of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-Ai), (Z-B), (Z-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof; or a pharmaceutical
  • the metabolism of fatty acids, cholesterol, and triglycerides may play a role in hyperproliferative disorders, such as cancer.
  • hyperproliferative disorders such as cancer.
  • cell metabolism shifts from catabolic to anabolic processes.
  • the tumor cells may synthesize up to 95% of the saturated and mono- unsaturated fatty acids.
  • Some cancers exhibit increased synthesis of fatty acids and other lipids (such as cholesterol), and steroids (such as androgens).
  • Elevated fatty acid synthase (FAS) expression may induce progression to S phase in cancer cells, and inhibition of FAS expression may reduce cell growth and may induce apoptosis.
  • components of the SREBP pathway may play a role in hype ⁇ oliferative disorders.
  • Hyperproliferative disorders which are disorders associated with some degree of abnormal cell proliferation, may be benign or malignant Benign hyperproliferative disorders may include pre-cancerous disorders.
  • the disorder is a benign hyperproliferative disorder.
  • the benign hyperproliferative disorder is mediated by a component of the SREBP pathway, such as an SREBP or SCAP.
  • the disorder is a malignant hyperproliferative disorder.
  • the malignant hyperproliferative disorder is mediated by a component of the SREBP pathway, such as an SREBP or SCAP.
  • the hyperproliferative disorder is breast cancer, liver cancer, ovarian cancer, pancreatic cancer, or prostate cancer.
  • a hyperproliferative disorder in a subject in need thereof between about 0.01 mg/kg to about 100 mg/kg.
  • the dose of a compound of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z- Ai), (Z-B), (Z-Bi), (I), (I- A), (I-Ai), (I-B), or (I-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, administered to a subject in need thereof according to any of the disclosed methods may vary with the particular compound or pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof; the method of administration; the particular disorder being treated; and the characteristics of the subject (such as weight, sex, and/or age).
  • the amount of the compound or pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof is a therapeutically effective amount
  • the effective amount of the compound or pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, relative to the subject's body mass may in some embodiments be between about 0.01 mg/kg to about 100 mg/kg.
  • about 0.7 mg to about 7 g daily, or about 7 mg to about 350 mg daily, or about 350 mg to about 1.75 g daily, or about 1.75 to about 7 g daily of the compound of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-Ai), (Z-B), (Z-Bi), (I), (I-A), (I-Ai), (I-B), or (I-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof is administered to a subject in need thereof.
  • the compound or pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof is administered as a pharmaceutical composition, as described herein.
  • any of the uses and methods provided herein may comprise administering to a subject in need therein a pharmaceutical composition that comprises an effective amount of a compound provided herein, such as a compound of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-Ai), (Z-B), (Z-Bi), (I), (I-A), (I-Ai), (I-B), or (I-Bi), or a corresponding amount of a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, and a compound of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-Ai), (Z-B), (Z-Bi), or a corresponding amount of a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, and a
  • the compounds of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-Ai), (Z- B), (Z-Bi), (I), (I-A), (I-Ai), (I-B), or (I-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof as provided herein, or a pharmaceutical composition comprising any of these and a pharmaceutically acceptable excipient as provided herein, may be administered to a subject via any suitable route, including, for example, intravenous, intramuscular, subcutaneous, oral, or transdermal routes.
  • the invention provides a method of treating a disorder in subject in need thereof by parenteral ly administering to the subject in need thereof an effective amount of a compound of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-Ai), (Z-B), (Z-Bi), (I), (I- A), (I-Ai), (I-B), or (I-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof as provided herein, or a pharmaceutical composition comprising an effective amount of any of the foregoing and a pharmaceutically acceptable excipient as provided herein.
  • the disorder is a hyperproliferative disorder.
  • the hyperproliferative disorder is cancer.
  • the disorder is fatty liver disease.
  • the disorder is NASH.
  • the route of administration is intravenous, intra-arterial, intramuscular, or subcutaneous. In some embodiments, the route of administration is transdermal.
  • compositions comprising a compound of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-Ai), (Z-B), (Z-Bi), (I), (I- A), (I-Ai), (I-B), or (I-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, and a pharmaceutically acceptable excipient, for the use in treating a disorder as described herein.
  • the disorder is prevented, or the onset delayed, or the development delayed.
  • the disorder is a hyperproliferative disorder.
  • the hyperproliferative disorder is cancer.
  • the disorder is fatty liver disease.
  • the disorder is NASH.
  • the composition comprises a pharmaceutical formulation which is present in a one or more unit dosage forms, for example one, two, three, four, or more unit dosage forms.
  • articles of manufacture comprising a compound of Formula (X), (X- A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-Ai), (Z-B), (Z-Bi), (I), (I- A), (I-Ai), (I-B), or (I-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or
  • Suitable packaging may include, for example, vials, vessels, ampules, bottles, jars, flexible packaging, and the like.
  • An article of manufacture may further be sterilized and/or sealed kits.
  • kits comprising a compound of Formula (X), (X-A), (X- Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-Ai), (Z-B), (Z-Bi), (I), (I-A), (I-Ai), (I-B), or (I-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or a
  • kits may be used in any of the uses and methods described herein. In some embodiments, the kit further comprises instructions.
  • the kits may be used for any one or more of the uses described herein, and, accordingly, may contain instructions for the treatment of a hyperproliferative disease (such as cancer), fatty liver disease, or NASH.
  • the kits may comprise one or more containers. Each component (if there is more than one component) may be packaged in separate containers or some components may be combined in one container where cross-reactivity and shelf life permit.
  • kits may be in unit dosage forms, bulk packages (e.g., multi-dose packages) or subunit doses.
  • kits may be provided that contain sufficient dosages of a compound of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-Ai), (Z-B), (Z-Bi), (I), (I-A), (I- Ai), (I-B), or (I-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, as disclosed herein and/or a second pharmaceutically active compound useful for a disorder detailed herein to provide effective treatment of a subject for an extended period, such as one week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 3 months, 4 months, 5 months, 7 months, 8 months, 9 months, or more.
  • Kits may also include multiple unit doses of a compound of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-Ai), (Z-B), (Z-Bi), (I), (I-A), (I- Ai), (I-B), or (I-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, and instructions for use, and be packaged in quantities sufficient for storage and use in pharmacies (e.g., hospital pharmacies or compounding pharmacies).
  • pharmacies e.g., hospital pharmacies or compounding pharmacies.
  • kits may optionally include a set of instructions, generally written instructions, although electronic storage media (e.g., magnetic diskette or optical disk) containing instructions are also acceptable, relating to the use of components) of the uses and methods as described herein.
  • the instructions included with the kit may include information as to the components and their administration to an individual.
  • Embodiment I- 1 A compound of Formula (I):
  • R 1 is -C(O)OR 9 , -C(O)NR 8 R 9 , -S(O) 2 NR 8 R 9 , -NR 10 C(O)NR 8 R 9 , -NR 10 C(O)R 9 , -NR 10 S(O)2R 9 , -OR 26 , -SR 9 , -S(O)R 9 , -S(O) 2 R 9 , -NR 8 R 9 , or -NR 10 C(O)OR 9 ,
  • each of R 8 , R 9 , and R 10 is independently selected from the group consisting of hydrogen, (C 1-10 )alkyl, (C 3-10 )cycloalkyl, (C 3-10 )cycloalkyliC 1-10 )alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, (C 6-10 )aryl, (C 6-10 )aryl(C 1-10 )alkyl, heteroaryl, and heteroaryl-alkyl,
  • R 26 is (C 1-10 )alkyl, (C 3-10 )cycloalkyl, (C 3-10 )cycloalkyl(C 1-10 )alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, (C 6-10 )aryl, (C 6-10 )aryl(C 1-10 )alkyl, heteroaryl, or heteroaryl-alkyl,
  • heterocycloalkyl-alkyl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, cyano, oxo, -OR 19 , -C(O)NR 19 R 19 , -NR 19 C(O)R 19 , -NR 19 C(O)NR 19 R 19 , -NR 19 R 19 , -S(O)2NR 19 R 19 , -NR 19 S(O)2R 19 , -S(O)D4R 2 °, -C(O)OR 19 , and -C(O)R 20 , each R 19 is independently hydrogen, (C 1-10 )alkyl, (C 3-10 )cycloalkyl,
  • heterocycloalkyl wherein each of the foregoing alkyl, cycloalkyl, or heterocycloalkyl moieties is independently unsubstituted or substituted with one or more halo,
  • each R 20 is independently (C 1-10 )alkyl, (C 3-10 )cycloalkyl,
  • n4 is 0, l, or 2;
  • heterocycloalkyl wherein the heterocycloalkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of halo, cyano, oxo, (C 1-10 )alkyl, (C2-i 0 )alkenyl, (C2-i 0 )alkynyl, (C 3-10 )cycloalkyl,
  • each R 23 is independently hydrogen, (C 1-10 )alkyl, (C 3-10 )cycloalkyl,
  • heterocycloalkyl wherein each of the foregoing alkyl, cycloalkyl, or heterocycloalkyl moieties is independently unsubstituted or substituted with one or more halo,
  • each R 24 is independently (C 1-10 )alkyl, (C 3-10 )cycloalkyl,
  • R 2 and R 3 are independently selected from the group consisting of hydrogen, halo, cyano,
  • each (C 1-10 )alkyl, (C 3-10 )cycloalkyl, and (C 3- ioJcycloalkyliCMoJalkyl is
  • each R 25 is independently hydrogen (C 1-10 )alkyl, (C 3-10 )cycloalkyl,
  • each R 30 is independently (C 1-10 )alkyl, (C 3-10 )cycloalkyl, (C 3-10 )cycloalkyl(C 1-10 )alkyl, or heterocycloalkyl, wherein each of the foregoing is independently unsubstituted or substituted with one or more halo, and
  • n7 is 0, l, or 2;
  • X 1 , X 2 , X 3 and X 4 are independently CR 4 or N, wherein X 2 , X 3 and X 4 may not all be N;
  • each R 4 is independently selected from the group consisting of hydrogen, halo, cyano, (C 1-10 )alkyl, (C 3-10 )cycloalkyl,
  • heterocycloalkyl and heterocycloalkyl-alkyl is independently
  • each R 27 is independently hydrogen or (C 1-10 )alkyl, (C 3-10 )cycloalkyl,
  • heterocycloalkyl wherein each of the foregoing alkyl, cycloalkyl, or heterocycloalkyl moieties is independently unsubstituted or substituted with one or more halo,
  • each R 28 is independently (C 1-10 )alkyl, (C 3-10 )cycloalkyl,
  • n8 is 0 , 1 or 2;
  • each R 4 is independently selected from the group consisting of hydrogen, halo, cyano, (C 1-10 )alkyl, (C 3-10 )cycloalkyl,
  • heterocycloalkyl, and heterocycloalkyl-alkyl is independently unsubstituted or substituted with one or more halo, each R 27 is independently hydrogen, (C 1-10 )alkyl, (C 3-10 )cycloalkyl,
  • heterocycloalkyl wherein each of the foregoing alkyl, cycloalkyl, or heterocycloalkyl moieties is independently unsubstituted or substituted with one or more halo,
  • each R 28 is independently (C 1-10 )alkyl, (C 3-10 )cycloalkyl,
  • n8 is O, l, or 2;
  • R 4 on adjacent annular carbon atoms together with the carbon atoms to which they are attached may form a carbocyclyl or heterocyclyl, wherein the carbocyclyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, cyano, (C 1-10 )alkyl, (C 3-10 )cycloalkyl, (C 3-10 )cycloalkyl(C 1-10 )alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, -OR 27 , -C(O)NR 27 R 27 , -NR 27 C(O)R 27 , -NR 27 R 27 , -S(O) 2 NR 27 R 27 , -NR 27 S(O)2R 27 , -S(O)uiR 28 , and -C(O)R 28 ,
  • heterocyclyl is unsubstituted or substituted with one or more substituents
  • halo independently selected from the group consisting of halo, cyano, (C 1-10 )alkyl, (C 3-10 )cycloalkyl, (C 3-10 )cycloalkyl(C 1-10 )alkyl, heterocycloalkyl connected by an annular carbon atom, heterocycloalkyl-alkyl, -OR 27 , -C(O)NR 27 R 27 , -S(O) 2 NR 27 R 27 , -S(O) friendship8R 28 , and -C(O)R 28 ,
  • each R 27 is independently hydrogen, (C 1-10 )alkyl, (C 3-10 )cycloalkyl,
  • each R 28 is independently (C 1-10 )alkyl, (C 3-10 )cycloalkyl, (C 3-10 )cycloalkyl(C 1-10 )alkyl, wherein each of the foregoing is independently unsubstituted or substituted with one or more halo, and
  • n8 is 0, l, or 2;
  • R 15 and R 17 are independently hydrogen, halo, alkyl, or -OR 29 , wherein each R 29 is
  • each alkyl or cycloalkyl in R 15 or R 17 is independently unsubstituted or substituted with one or more halo;
  • R 14 is (C 1-10 )alkyl, (C 1-10 )alkenyl, (C 3-10 )cycloalkyl, (C 3-10 )cycloalkenyl,
  • R 16 is hydrogen, fluoro, (C 1-10 )alkyl, (C 3-10 )cycloalkyl, (C 3-10 )cycloalkyl(C 1-10 )alkyl, heterocycloalkyl connected through an annular carbon atom, heterocycloalkyl-alkyl, -OR 5 , -C(O)NR 5 R 5 , -R 5 C(O)NR 5 R 5 , -S(O)2NR 5 R 5 , -S(O) friendshipiR 6 , or -C(O)R 6 ;
  • R 16 is hydrogen, fluoro, (C 1-10 )alkyl, (C 3-10 )cycloalkyl, (C 3-10 )cycloalkyl(C 1-10 )alkyl, heterocycloalkyl connected through an annular carbon atom, heterocycloalkyl-alkyl, -OR 5 , -C(O)NR 5 R 5 , -R ⁇ OJNR ⁇ l 5
  • R 14 or R 16 is independently unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of (C 1-10 )alkyl, halo, cyano, oxo, -OR 7 , -C(O)OR 7 , -C(O)NR 7 R 7 , -NR 7 C(O)R 7 , -NR 7 C(O)NR 7 R 7 , -NR 7 R 7 , -S(O) 2 NR 7 R 7 , -NR 7 S(O)2R 7 , -S(O)n2R 13 , and -C(O)R 13 ;
  • each R 5 is independently hydrogen, (C 1-10 )alkyl, or (C 3-10 )cycloalkyl; or two R 5 , together with the nitrogen atom to which they are attached, form a heterocycloalkyl; wherein each alkyl, cycloalkyl, or heterocycloalkyl is independently unsubstituted or substituted with one or more halo;
  • each R 6 is independently (C 1-10 )alkyl or (C 3-10 )cycloalkyl, wherein each alkyl or cycloalkyl is independently unsubstituted or substituted with one or more halo;
  • each nl is independently 0, 1, or 2;
  • each R 7 is independently hydrogen, unsubstituted (C 1-10 )alkyl, or (C 1-10 )alkyl substituted with one or more halo;
  • each n2 is independently 0, 1, or 2
  • each R 13 is independently unsubstituted (C 1-10 )alkyl or (C 1-10 )alkyl substituted with one or more halo;
  • carbocyclyl or heterocyclyl is unsubstituted or substituted with one or two substituents independently selected from the group consisting of halo, cyano, oxo, (C 1-10 )alkyl, (C 3-10 )cycloalkyl, (C 3-10 )cycloalkyl(C 1-10 )alkyl, -OR 18 , -C(O)NR ,8 R 18 , -NR 18 C(O)R 18 , -NR 18 C(O)NR 18 R 18 , -NR 18 R 18 , -S(O) 2 NR 18 R 18 , -NR 18 S(O)2R 18 , -S(O)asR.
  • substituents independently selected from the group consisting of halo, cyano, oxo, (C 1-10 )alkyl, (C 3-10 )cycloalkyl, (C 3-10 )cycloalkyl(C 1-10 )alkyl, -OR
  • each R 18 is independently hydrogen, (C 1-10 )alkyl, or (C 3-10 )cycloalkyl; or two R 18 , together with the nitrogen atom to which they are attached, form a heterocycloalkyl; wherein each alkyl, cycloalkyl, or heterocycloalkyl is independently unsubstituted or substituted with one or more halo; each R 21 is independently (C 1-10 )alkyl or (C 3-10 )cycloalkyl, wherein each alkyl or cycloalkyl is independently unsubstituted or substituted with one or more halo, and
  • each n3 is independently 0, 1, or 2.
  • Embodiment 1-2 The compound of Embodiment 1-1, wherein the compound is of Formula (I-A):
  • R 1 , R 2 , R 3 , R 14 , R 15 , R 16 , R 17 , X 1 , X 2 , X 3 , and X 4 are as defined for Formula (I).
  • Embodiment 1-3 The compound of Embodiment 1-1, wherein the compound is of Formula (I-B):
  • R 1 , R 2 , R 3 , R 14 , R 15 , R 16 , R 17 , X 1 , X 2 , X 3 , and X 4 are as defined for Formula (I).
  • Embodiment 1-4 The compound of any one of Embodiments I- 1 to 1-3, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R 17 is hydrogen.
  • Embodiment 1-5 The compound of any one of Embodiments I- 1 to 1-4, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R 1 is -C(O)NR 8 R 9 , -SiO ⁇ NR 8 R 9 , -NR 10 C(O)NR 8 R 9 , -NR 10 C(O)R 9 , -NR 10 C(O)OR 9 , or -NR 10 S(O)2R 9
  • Embodiment 1-6 The compound of any one of Embodiments 1-1 to 1-5, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R 1 is -NR 10 C(O)NR 8 R 9 .
  • Embodiment 1-7 The compound of any one of Embodiments I- 1 to 1-5, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R 1 is -NR 10 C(O)OR 9 .
  • Embodiment 1-8 The compound of any one of Embodiments 1-1 to 1-5, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R 1 is -NR 10 S(O)2R 9 .
  • Embodiment 1-9 The compound of any one of Embodiments I- 1 to 1-8, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R 10 is hydrogen.
  • Embodiment I- 10 The compound of any one of Embodiments 1-1 to 1-5, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R 1 is -QOJNR ⁇ . 9 , and the R 8 and R 9 together with the nitrogen to which they are attached form an unsubstituted or substituted heterocycloalkyl.
  • Embodiment 1-11 The compound of any one of Embodiments 1-1 to 1-5, or 1-10, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R 1 is -0(O) ⁇ 3 ⁇ 4 9 , and the R 8 and R 9 together with the nitrogen to which they are attached form an unsubstituted or substituted piperidinyl.
  • Embodiment 1-12 The compound of Embodiment I- 11, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein the piperidinyl is substituted with one to three substituents independently selected from the group consisting of -OR 23 , (C 1-10 )alkyl, and -NR 23 C(O)OR 23 .
  • Embodiment 1-13 The compound of any one of Embodiments 1-1 to 1-12, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R 2 is halo.
  • Embodiment 1-14 The compound of any one of Embodiments I- 1 to I- 13 , or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein one of X 1 , X 2 , X 3 , and X 4 are N.
  • Embodiment 1-15 The compound of any one of Embodiments 1-1 to 1-13, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein X 1 , X 2 , and X 4 are CR 4 , and X 3 is N.
  • Embodiment 1-16 The compound of any one of Embodiments I- 1 to I- 13 , or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein two of X ⁇ X 2 , X 3 , and X 4 are N.
  • Embodiment 1-17 The compound of any one of Embodiments 1-1 to 1-13, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein each of X 1 , X 2 , X 3 and X 4 is CR 4 .
  • Embodiment 1-18 The compound of any one of Embodiments I- 1 to I- 17, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein each R 4 is independently selected from the group consisting of hydrogen, halo, cyano, (C 1-10 )alkyl, and -OR 27
  • Embodiment I- 19 The compound of any one of Embodiments I- 1 to I- 18, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R 14 is (C 1-10 )alkyl or heterocycloalkyl connected through an annular carbon atom, wherein the alkyl or heterocycloalkyl is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of (C 1-10 )alkyl, halo, -C(O)OR 7 , and -OR 5 .
  • Embodiment 1-20 The compound of any one of Embodiments I- 1 to I- 16, 1- 18, or I- 19, wherein at least one of X 2 , X 3 and X 4 is N, and an adjacent annular carbon is bonded to R 4 , wherein the R 4 is independently hydrogen, fluoro, cyano, (C 1-10 )alkyl, or -OR 27 .
  • Embodiment 1-21 The compound of any one of Embodiments 1-1 to 1-20, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R 3 is hydrogen.
  • Embodiment 1-22 The compound of any one of Embodiments I- 1 , 1-2, or 1-4 to 1-21 , wherein the compound is of Formula (I-Ai):
  • R 1 , R 2 , R 3 , R 14 , R 15 , R 16 , R 17 , X 1 , X 2 , X 3 , and X 4 are as defined for Formula (I).
  • Embodiment 1-2 The compound of any one of Embodiments 1-1 or 1-3 to 1-21, wherein the compound is of Formula (I-Bi):
  • R 1 , R 2 , R 3 , R 14 , R 15 , R 16 , R 17 , X 1 , X 2 , X 3 , and X 4 are as defined for Formula (I).
  • Embodiment 1-24 The compound of any one of Embodiments 1-1, 1-2, 1-4 to 1-7, or 1-9 to 1-22, selected from the group consisting of:
  • Embodiment I-2S A pharmaceutical composition, comprising the compound of any one of Embodiments 1-1 to 1-24, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, and a pharmaceutically acceptable excipient
  • Embodiment 1-26 A method of inhibiting a sterol regulatory element-binding protein (SREBP), comprising contacting the SREBP or contacting an SREBP cleavage activating- protein (SCAP) with a compound of any one of Embodiments 1-1 to 1-24, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or the pharmaceutical composition of Embodiment 1-25.
  • SREBP sterol regulatory element-binding protein
  • SCAP SREBP cleavage activating- protein
  • a method of inhibiting the proteolytic activation of a sterol regulatory element-binding protein comprising contacting an SREBP cleavage activating-protein (SCAP) with a compound of any one of Embodiments 1-1 to 1-24, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or the pharmaceutical composition of Embodiment 1-25.
  • SREBP sterol regulatory element-binding protein
  • Embodiment 1-28 The method of Embodiment 1-26 or 1-27, wherein the SREBP is an SREBP-1.
  • Embodiment 1-29 The method of Embodiment 1-28, wherein the SREBP-1 is SREBP- la.
  • Embodiment 1-30 The method of Embodiment 1-28, wherein the SREBP-1 is SREBP- lc.
  • Embodiment 1-3 The method of Embodiment 1-26 or 1-27, wherein the SREBP is SREBP-2.
  • Embodiment 1-32 The method of any one of Embodiments 1-26 to 1-31 , wherein SREBP is inhibited in a subject in need thereof.
  • Embodiment 1-33 The method of any one of Embodiments 1-26 to 1-32, wherein SCAP is inhibited in a subject in need thereof.
  • Embodiment 1-34 The method of any one of Embodiments 1-26 to 1-33, wherein the expression of one or more genes selected from the group consisting of ACSS2, ALDOC, CYP51 Al, DHCR7, ELOVL6, FASN, FDFT1 , FDPS, HMGCS1, HSD17B7, ⁇ 3 ⁇ 1 , INSIG1, LDLR, LSS, ME1, PCSK9, PMVK, RDH11 , SC5DL, SQLE, STARD4, TM7SF2, PNPLA3, SREBFl, SREBF2, HMGCR, MVD, MVK, ACLY, MSMOl, ACACA, and ACACB is reduced after contacting the SREBP or SCAP with the compound, or pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or the pharmaceutical composition.
  • Embodiment 1-35 A method of treating a disorder in a subject in need thereof, comprising administering to the subject an effective amount of a compound of any one of Embodiments 1-1 to 1-24, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or the pharmaceutical composition of Embodiment 1-25.
  • Embodiment 1-36 A method of treating a disorder in a subject in need thereof, wherein the disorder is mediated by a sterol regulatory element-binding protein (SREBP), comprising administering to the subject an effective amount of a compound of any one of Embodiments 1-1 to 1-24, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or the pharmaceutical composition of Embodiment 1-25.
  • SREBP sterol regulatory element-binding protein
  • Embodiment 1-37 The method of Embodiment 1-35 or 1-36, wherein the disorder is Metabolic Syndrome, type 2 diabetes, obesity, liver disease, insulin resistance, adiposopathy, or dyslipidemia.
  • Embodiment 1-38 The method of Embodiment 1-37, wherein the dyslipidemia is hypertriglyceridemia or elevated cholesterol levels.
  • Embodiment 1-39 The method of Embodiment 1-37, wherein the liver disease is nonalcoholic steatohepatitis, liver fibrosis, or liver inflammation, or a combination thereof.
  • Embodiment 1-40 The method of Embodiment 1-35 or 1-36, wherein the disorder is a hyperproliferative disorder.
  • Embodiment 1-4 The method of Embodiment 1-40, wherein the hyperproliferative disorder is cancer.
  • Embodiment 1-42 The method of Embodiment 1-41 , wherein the cancer is breast cancer, liver cancer, ovarian cancer, pancreatic cancer, or prostate cancer.
  • Embodiment 1-43 The method of Embodiment 1-35 or 1-36, wherein the disorder is endotoxic shock, systemic inflammation, or atherosclerosis.
  • Embodiment 1-44 Use of a compound of any one of Embodiments 1-1 to 1-24, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, in the
  • Embodiment 1-45 Use of a compound of any one of Embodiments 1-1 to 1-24, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, in the
  • Embodiment 1-46 Use of a compound of any one of Embodiments 1-1 to 1-24, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, in the
  • a medicament for use in inhibiting the proteolytic activation of a sterol regulatory element-binding protein (SREBP) in a subject in need thereof.
  • SREBP sterol regulatory element-binding protein
  • Embodiment 1-47 Use of a compound of any one of Embodiments 1-1 to 1-24, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, in the
  • SREBP sterol regulatory element-binding protein
  • Embodiment 1-48 Use of a compound of any one of Embodiments 1-1 to 1-24, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or the pharmaceutical composition of Embodiment I-2S, for inhibiting a sterol regulatory element- binding protein (SREBP).
  • SREBP sterol regulatory element- binding protein
  • Embodiment 1-49 Use of a compound of any one of Embodiments 1-1 to 1-24, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or the pharmaceutical composition of Embodiment I-2S, for inhibiting an SREBP cleavage activating protein (SCAP).
  • SCAP SREBP cleavage activating protein
  • Embodiment 1-50 The use of any one of Embodiments 1-45 to 1-49, wherein the SREBP is an SREBP- 1.
  • Embodiment 1-51 The method of Embodiment 1-50, wherein the SREBP-1 is SREBP- la.
  • Embodiment 1-52 The method of Embodiment 1-50, wherein the SREBP-1 is SREBP- [0259] Embodiment 1-53. The use of any one of Embodiments 1-45 to 1-49, wherein the SREBP is SREBP-2.
  • Embodiment 1-54 The use of any one of Embodiments 1-44 to 1-53, wherein SREBP is inhibited in a subject in need thereof.
  • Embodiment 1-55 The use of any one of Embodiments 1-44 to 1-54, wherein SCAP is inhibited in a subject in need thereof.
  • Embodiment 1-56 Use of a compound of any one of Embodiments 1-1 to 1-24, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or the
  • Embodiment 1-25 for treating a disorder in a subject in need thereof.
  • Embodiment 1-57 Use of a compound of any one of Embodiments 1-1 to 1-24, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or the
  • composition of Embodiment 1-25 for treating a disorder in a subject in need thereof, wherein the disorder is mediated by a sterol regulatory element-binding protein
  • Embodiment 1-58 The use of Embodiment 1-56 or 57, wherein the disorder is
  • Metabolic Syndrome type 2 diabetes, obesity, liver disease, insulin resistance, adiposopathy, or dyslipidemia.
  • Embodiment 1-59 The use of Embodiment 1-58, wherein the dyslipidemia is hypertriglyceridemia or elevated cholesterol levels.
  • Embodiment 1-60 The use of Embodiment 1-58, wherein the liver disease is nonalcoholic steatohepatitis, liver fibrosis, or liver inflammation, or a combination thereof.
  • Embodiment 1-61 The use of Embodiment 1-56 or 1-57, wherein the disorder is a hyperproliferative disorder.
  • Embodiment 1-62 The use of Embodiment 1-61, wherein the hyperproliferative disorder is cancer.
  • Embodiment 1-63 The use of Embodiment 1-62, wherein the cancer is breast cancer, liver cancer, ovarian cancer, pancreatic cancer, or prostate cancer.
  • Embodiment 1-64 The use of Embodiment 1-56 or 1-57, wherein the disorder is endotoxic shock, systemic inflammation, or atherosclerosis.
  • Embodiment 1-65 A method of treating non-alcoholic steatohepatitis (NASH) in a subject in need thereof, comprising administering to the subject an effective amount of a compound of any one of Embodiments 1-1 to 1-24, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or the pharmaceutical composition of Embodiment 1-25.
  • NASH non-alcoholic steatohepatitis
  • Embodiment 1-66 Use of a compound of any one of Embodiments 1-1 to 1-24, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or the
  • Embodiment 1-25 for treating non-alcoholic steatohepatitis (NASH) in a subject in need thereof.
  • NASH non-alcoholic steatohepatitis
  • Embodiment 1-67 Use of a compound of any one of Embodiments 1-1 to 1-24, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or the
  • Embodiment 1-25 in the manufacture of a medicament for use in treating non-alcoholic steatohepatitis (NASH) in a subject in need thereof.
  • NASH non-alcoholic steatohepatitis
  • Embodiment 1-68 A method of treating a hyperproliferative disorder in a subject in need thereof, comprising administering to the subject an effective amount of a compound of any one of Embodiments 1-1 to 1-24, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or the pharmaceutical composition of Embodiment 1-25.
  • Embodiment 1-69 Use of a compound of any one of Embodiments 1-1 to 1-24, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or the
  • Embodiment 1-25 for treating a hyperproliferative disorder in a subject in need thereof.
  • Embodiment 1-70 Use of a compound of any one of Embodiments 1-1 to 1-24, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or the pharmaceutical composition of Embodiment I-2S, in the manufacture of a medicament for treating a hyperproliferative disorder in a subject in need thereof.
  • Embodiment 1-71 The compound of Embodiment 1-1 , selected from the group consisting of:
  • Embodiment 1-72 The compound of any one of Embodiments 1-1 to 1-3, 1-22, or 1-23, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R 1 is
  • Embodiment 1-73 The compound of any one of Embodiments 1-1 to 1-3, 1-22, or 1-23, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R 1 is
  • Embodiment 1-74 The compound of any one of Embodiments 1-1 to 1-3, 1-22, or 1-23, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R 1 is
  • Embodiment 1-75 The compound of any one of Embodiments 1-1 to 1-3, 1-22, or 1-23, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R 1 is
  • Embodiment 1-76 The compound of any one of Embodiments 1-1 to 1-3, 1-22, or 1-23, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R 14 is
  • Embodiment 1-77 A pharmaceutical composition, comprising a compound of any one of Embodiments 1-71 to 1-76, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, and a pharmaceutically acceptable excipient.
  • Embodiment II- 1 A compound of Formula (Z):
  • a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof wherein: is -C(O)OR 9 , -C(O)NR 8 R 9 , -S(O) 2 NR 8 R 9 , -NR 10 C(O)NR 8 R 9 , -NR 10 C(O)R 9 , -NR 10 S(O)2R 9 , -OR 26 , -SR 9 , -S(O)R 9 , -S(O)2R 9 , -NR 8 R 9 , -NR 10 C(O)OR 9 , -C(O)R 26 , -NR 10 S(O) 2 NR 8 R 9 , or -C(O)NR 10 S(O)2R 9 ;
  • each of R 8 , R 9 , and R 10 is independently selected from the group consisting of hydrogen, (C 1-10 )alkyl, (C 3-10 )cycloalkyl, (C 3-10 )cycloalkyl(C 1-10 )alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, (C 6-10 )aryl, (C 6-10 )aryl(C 1-10 )alkyl, heteroaryl, and heteroaryl-alkyl,
  • R 26 is (C 1-10 )alkyl, (C 3-10 )cycloalkyl, (C 3-10 )cycloalkyl(C 1-10 )alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, (C 6-10 )aryl, (C 6-10 )aryl(C 1-10 )alkyl, heteroaryl, or heteroaryl-alkyl,
  • each (C 1-10 )alkyl, (C 3-10 )cycloalkyl, (C 3-10 )cycloalkyl(C 1-10 )alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, (Cfr-i 0 )aryl, (Cfr-i 0 )aryl(C 1-10 )alkyl, heteroaryl, and heteroaryl-alkyl of R 8 , R 9 , R 10 , and R 26 is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, cyano, oxo, -OR 19 , -C(O)NR 19 R 19 , -NR 19 C(O)R 19 , -NR ,9 C(O)NR ,9 R 19 , -NR 19 R 19 , -S(O) 2 NR 19 R 19 , -NR ,9 S(O) 2 R 19 , -S(O
  • each R 19 is independently hydrogen, (C 1-10 )alkyl, (C 3-10 )cycloalkyl,
  • heterocycloalkyl wherein each of the foregoing alkyl, cycloalkyl, or heterocycloalkyl moieties is independently unsubstituted or substituted with one or more halo,
  • each R 20 is independently (C 1-10 )alkyl, (C 3-10 )cycloalkyl,
  • n4 is 0, l, or 2;
  • heterocycloalkyl wherein the heterocycloalkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of halo, cyano, oxo, (C 1-10 )alkyl, (C2-i 0 )alkenyl, (C2-i 0 )alkynyl, (C 3-10 )cycloalkyl,
  • eachR 23 is independently hydrogen, (C 1-10 )alkyl, (C 3-10 )cycloalkyl,
  • each R 24 is independently (C 1-10 )alkyl, (C 3-10 )cycloalkyl,
  • n6 is 0, 1, or 2;
  • R 3 are independently selected from the group consisting of hydrogen, halo, cyano, (C 1-10 )alkyl, (C 3-10 )cycloalkyl, (C 3-10 )cycloalkyl(C 1-10 )alkyl, -OR 25 , -C(O)NR 25 R 25 , -NR 25 C(O)R 25 , -NR 25 C(O)NR 25 R 25 , -NR 25 R 25 , -S(O) 2 NR 25 R 25 , -NR 25 S(O)2R 25 ,
  • each (C 1-10 )alkyl, (C 3-10 )cycloalkyl, and (C 3-10 )cycloalkyl(C 1-10 )alkyl is
  • each R 25 is independently hydrogen (C 1-10 )alkyl, (C 3-10 )cycloalkyl,
  • each R 30 is independently (C 1-10 )alkyl, (C 3-10 )cycloalkyl, (C 3-10 )cycloalkyl(C 1-10 )alkyl, or heterocycloalkyl, wherein each of the foregoing is independently unsubstituted or substituted with one or more halo, and
  • n7 is 0, l, or 2;
  • X 1 , X 2 , X 3 and X 4 are independently CR 4 or N, wherein X 2 , X 3 and X 4 may not all be N;
  • each R 4 is independently selected from the group consisting of hydrogen, halo, cyano, (C 1-10 )alkyl, (C 3-10 )cycloalkyl,
  • heterocycloalkyl and heterocycloalkyl-alkyl is independently
  • each R 27 is independently hydrogen or (C 1-10 )alkyl, (C 3-10 )cycloalkyl,
  • each R 28 is independently (C 1-10 )alkyl, (C 3-10 )cycloalkyl,
  • n8 is 0 , 1 or 2;
  • each R 4 is independently selected from the group consisting of hydrogen, halo, cyano, (C 1-10 )alkyl, (C 3-10 )cycloalkyl,
  • heterocycloalkyl, and heterocycloalkyl-alkyl is independently unsubstituted or substituted with one or more halo, each R 27 is independently hydrogen, (C 1-10 )alkyl, (C 3-10 )cycloalkyl,
  • heterocycloalkyl wherein each of the foregoing alkyl, cycloalkyl, or heterocycloalkyl moieties is independently unsubstituted or substituted with one or more halo,
  • each R 28 is independently (C 1-10 )alkyl, (C 3-10 )cycloalkyl,
  • n8 is 0, 1, or 2;
  • carbocyclyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, cyano, (C 1-10 )alkyl, (C 3-10 )cycloalkyl, (C 3-10 )cycloalkyl(C 1-10 )alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, -OR 27 , -C(O)NR 27 R 27 , -NR 27 C(O)R 27 , -NR 27 R 27 , -S(O) 2 NR 27 R 27 , -NR 27 S(O)2R 27 , -S(O),*R 28 , and -C(O)R 28 ,
  • heterocyclyl is unsubstituted or substituted with one or more substituents
  • halo independently selected from the group consisting of halo, cyano, (C 1-10 )alkyl, (C 3-10 )cycloalkyl, (C 3-10 )cycloalkyl(C 1-10 )alkyl, heterocycloalkyl connected by an annular carbon atom, heterocycloalkyl-alkyl, -OR 27 , -C(O)NR 27 R 27 , -S(O) 2 NR 27 R 27 , -S(O)n8R 28 , and -C(O)R 28 ,
  • each R 27 is independently hydrogen, (C 1-10 )alkyl, (C 3-10 )cycloalkyl,
  • each R 28 is independently (C 1-10 )alkyl, (C 3-10 )cycloalkyl, (C 3-10 )cycloalkyl(C 1-10 )alkyl, wherein each of the foregoing is independently unsubstituted or substituted with one or more halo, and
  • n8 is 0, l, or 2;
  • R 15 and R 17 are independently hydrogen, halo, alkyl, or -OR 29 , wherein each R 29 is
  • each alkyl or cycloalkyl in R 15 or R 17 is independently unsubstituted or substituted with one or more halo;
  • R 14 is (C 1-10 )alkyl, (C 1-10 )alkenyl, (C 3-10 )cycloalkyl, (C 3-10 )cycloalkenyl,
  • R 16 is hydrogen, fluoro, (C 1-10 )alkyl, (C 3-10 )cycloalkyl, (C 3-10 )cycloalkyl(C 1-10 )alkyl,
  • heterocycloalkyl connected through an annular carbon atom, heterocycloalkyl-alkyl, -OR 5 , -C(O)NR 5 R 5 , -R 5 C(O)NR 5 R 5 , -S(O) 2 NR 5 R 5 , -S(O)n1R 6 , or -C(O)R 6 ;
  • R 14 or R 16 is independently unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of (C 1-10 )alkyl, halo, cyano, oxo, -OR 7 , -C(O)OR 7 , -C(O)NR 7 R 7 , -NR 7 C(O)R 7 , -NR 7 C(O)NR 7 R 7 , -NR 7 R 7 , -S(O) 2 NR 7 R 7 , -NR 7 S(O)2R 7 , -S(O)n2R 13 , and -C(O)R 13 ;
  • each R 5 is independently hydrogen, (C 1-10 )alkyl, or (C 3-10 )cycloalkyl; or two R 5 , together with the nitrogen atom to which they are attached, form a heterocycloalkyl; wherein each alkyl, cycloalkyl, or heterocycloalkyl is independently unsubstituted or substituted with one or more halo;
  • each R 6 is independently (C 1-10 )alkyl or (C 3-10 )cycloalkyl, wherein each alkyl or cycloalkyl is independently unsubstituted or substituted with one or more halo;
  • each nl is independently 0, 1, or 2;
  • each R 7 is independently hydrogen, unsubstituted (C 1-10 )alkyl, or (C 1-10 )alkyl substituted with one or more halo;
  • each n2 is independently 0, 1, or 2
  • each R 13 is independently unsubstituted (C 1-10 )alkyl or (C 1-10 )alkyl substituted with one or more halo;
  • carbocyclyl or heterocyclyl is unsubstituted or substituted with one or two substituents independently selected from the group consisting of halo, cyano, oxo, (C 1-10 )alkyl, (C 3-10 )cycloalkyl, (C 3-10 )cycloalkyl(C 1-10 )alkyl, -OR 18 , -C(O)NR 18 R 18 , -NR 18 C(O)R 18 , -NR ,8 C(O)NR ,8 R 18 , -NR 18 R 18 , -S(O)2NR ,8 R 18 , -NR 18 S(O)2R 18 , -S(O) friendship3R 21 , -C(O)OR 18 , and -C(O)R 21 ,
  • each R 18 is independently hydrogen, (C 1-10 )alkyl, or (C 3-10 )cycloalkyl; or two R 18 , together with the nitrogen atom to which they are attached, form a heterocycloalkyl; wherein each alkyl, cycloalkyl, or heterocycloalkyl is independently unsubstituted or substituted with one or more halo each R 21 is independently (C 1-10 )alkyl or (C 3-10 )cycloalkyl, wherein each alkyl or cycloalkyl is independently unsubstituted or substituted with one or more halo, and
  • each n3 is independently 0, 1, or 2.
  • Embodiment II-2 The compound of Embodiment II-l , or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R 1 is -C(O)OR 9 , -C(O)NR 8 R 9 , -S(O) 2 NR 8 R 9 , -NR 10 C(O)NR 8 R 9 , -NR 10 C(O)R 9 , -NR 10 S(O) 2 R 9 , -OR 26 , -SR 9 , -S(O)R 9 , -S(O)2R 9 , -NR 8 R 9 , or -NR 10 C(O)OR 9 .
  • Embodiment II-3 The compound of Embodiment II-l or II-2, wherein the compound is of Formula (Z-A):
  • R 1 , R 2 , R 3 , R 14 , R 15 , R 16 , R 17 , X 1 , X 2 , X 3 , and X 4 are as defined for Formula (Z).
  • Embodiment II-4 The compound of Embodiment II-l or II-2, wherein the compound is of Formula (Z-B):
  • R 1 , R 2 , R 3 , R 14 , R 15 , R 16 , R 17 , X 1 , X 2 , X 3 , and X 4 are as defined for Formula (Z).

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Hematology (AREA)
  • Diabetes (AREA)
  • Obesity (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Pyridine Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

Provided herein are compounds comprising a three-ring core, such as compounds of Formula (X), Formula (X-A), Formula (X-Ai), Formula (X-B), Formula (X-Bi), Formula (Z), Formula (Z-A), Formula (Z-Ai), Formula (Z-B), Formula (Z-Bi), Formula (I), Formula (I-A), Formula (I-Ai), Formula (I-B), and Formula (I-Bi), and pharmaceutically acceptable salts, solvates, tautomers, isotopes, or isomers thereof. Also provided herein are methods of inhibiting a component of the sterol regulatory element binding protein (SREBP) pathway, such as an SREBP or SREBP cleavage activating protein (SCAP), using these compounds, or pharmaceutically acceptable salts, solvates, tautomers, isotopes, or isomers thereof. Further provided are methods of treating a disorder in a subject in need thereof, such as liver disease, non-alcoholic steatohepatitis, insulin resistance, or cancer.

Description

SREBP INHIBITORS COMPRISING A 6-MEMBERED CENTRAL RING
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of U. S. Provisional Application No. 62/623,405, filed January 29, 2018; and U.S. Provisional Application No. 62/744,397, filed October 11, 2018, the disclosures of which are hereby incorporated by reference in their entireties.
FIELD OF THE INVENTION
[0002] The present disclosure relates to compounds comprising a three-ring core, their use for inhibiting components of the sterol regulatory element binding protein (SREBP) pathway, such as SREBP or SREBP cleavage activating protein (SCAP), and their use in therapeutic methods of treating conditions and disorders.
BACKGROUND
[0003] SREBPs are membrane-bound transcription factors that regulate cholesterol, fatty acid, and triglyceride biosynthesis, and lipid uptake. Fatty acids and lipids are a source of energy and important components of many biological structures, such as lipid membranes of cells.
Cholesterol is an important component of biological processes and structures. In mammals, there are three known SREBP isoforms: SREBP-la, SREBP-lc, and SREBP-2. SREBP-la controls a broad range of target genes that are involved in the production of fatty acids, triglycerides, phospholipids, and cholesterol. SREBP-lc primarily activates genes which control fatty acid and triglyceride synthesis. SREBP-2 activates genes involved in the synthesis of regulators of cholesterol metabolism, which has been demonstrated in mouse, human, and Drosophila studies. The activity of SREBPs is regulated by SREBP cleavage activating protein (SCAP), which transports SREBP(s) from the endoplasmic reticulum to the Golgi apparatus where the SREBP(s) are proteolytically cleaved, releasing the transcription factor domain.
[0004] The pathways regulated by SREBPs and SCAP have been implicated in disorders of metabolism, such as hypertension, dyslipidemia, obesity, type 2 diabetes, insulin resistance, fatty liver, and nonalcoholic steatohepatitis (NASH). NASH, for example, is liver inflammation and hepatocyte ballooning as a result of fat building up in the liver, which can lead to liver damage, such as cirrhosis. NASH can also be associated with other metabolism disorders, such as insulin resistance and metabolic syndrome.
[0005] The metabolism of fatty acids, cholesterol, and triglycerides may also be linked to hyperproliferative disorders, such as cancer. One characteristic of the oncogenic transformation of cancer cells is the shift of metabolism from catabolic to anabolic processes. Many cancers require synthesis of fatty acids and other lipids (such as cholesterol), and steroids (such as androgens). Thus, components of the SREBP pathway may play a role in hyperproliferative disorders, such as prostate cancer. SREBP- lc is the major transcriptional regulator of the biosynthesis of fatty acids, and expression of this transcription factor can be stimulated by androgens and epidermal growth factor in prostate cancer cells. Overexpression of SREBP- lc may drive tumorgenicity and invasion of prostate cancer cells. In addition to regulating androgen synthesis, SREBP-2 itself is also regulated by androgens in a direct feedback circuit of androgen production. However, prostate cancer cells have dysfunctional cholesterol homeostasis, resulting in accumulation of cholesterol and increased proliferation. This increase in cholesterol levels has been shown to be driven by regulated by increased SREBP-2 activity. SREBP-2 expression increases during disease progression, and is significantly higher after castration compared to prior.
[0006] Regulating components of the SREBP pathway, such as SCAP or SREBPs, is an important therapeutic approach for treating disorders, such as metabolic diseases and cancer. Thus, there is a need for compounds that can inhibit components of the SREBP pathway, such as SREBPs and SCAP.
BRIEF SUMMARY [0007] In some aspects, provided herein is a compound of Formula (X):
R1 R2
R3
R15 x o1 I<ivx2
R' 14 1 J*. X3
YT
Figure imgf000004_0001
R16 or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein:
R1 is -C(O)OR9, -C(O)NR8R9, -S(O)2NR8R9, -NR10C(O)NR8R9, -NR10C(O)R9, -NR10S(O)2R9,
-OR26, -SR9, -S(O)R9, -S(O)2R9, -NR8R9, -NR10C(O)OR9, -C(O)R26, -NR10S(O)2NR8R9, - C(O)NR10S(O)2R9, or -C(O)NR10NR8R9;
wherein each of R8, R9, and R10 is independently selected from the group consisting of hydrogen, (C1-10)alkyl, (C3-10)cycloalkyl, (C3-10)cycloalkyl(C1-10)alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, (C6-10)aryl, (C6-10)aryl(C1-10)alkyl, heteroaryl, and heteroaryl-alkyl,
R26 is (C1-10)alkyl, (C3-10)cycloalkyl, (C3-10)cycloalkyl(C1-10)alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, (C6-10)aryl, (C6-10)aryl(C1-10)alkyl, heteroaryl, or heteroaryl-alkyl,
each (C1-10)alkyl, (C3-10)cycloalkyl, (C3-10)cycloalkyl(C1-10)alkyl, heterocycloalkyl,
heterocycloalkyl-alkyl, (C6-10)aryl, (C6-10)aryl(C1-10)alkyl, heteroaryl, and heteroaryl-alkyl of R8, R9, R10, and R26 is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, (C1-10)alkyl, (C1-10)haloalkyl, cyano, oxo, -OR19, -C(O)NR19R19, -NR19C(O)R19, -NR19C(O)NR19R19, -NR19R19, -S(O)2NR19R19, -NR19S(O)2R19, -S(O)^R20, -C(O)OR19, -C(O)R20, and -(OR38)n1sOR19, each R19 is independently hydrogen, (C1-10)alkyl, (C3-10)cycloalkyl,
(C3-10)cycloalkyl(C1-10)alkyl, or heterocycloalkyl; or two R19, together with the nitrogen atom to which they are attached, form a
heterocycloalkyl; wherein each of the foregoing alkyl, cycloalkyl, or heterocycloalkyl moieties is independently unsubstituted or substituted with one or more halo,
each R20 is independently (C1-10)alkyl, (C3-10)cycloalkyl,
(C3-10)cycloalkyl(C1-10)alkyl, or heterocycloalkyl, wherein each of the foregoing is independently unsubstituted or substituted with one or more halo,
each R38 is independently (C1-10)alkylene or (C1-10)haloalkylene,
each nlS is independently an integer from 1 to S; and
n4 is 0, l, or 2;
or R8 and R9, together with the nitrogen atom to which they are attached, form a
heterocycloalkyl, wherein the heterocycloalkyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, cyano, oxo, (C1-10)alkyl, (C2-i0)alkenyl, (C2-i0)alkynyl, (C3-10)cycloalkyl, (C3-10)cycloalkyl(C1-10)alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, (C6-10)aryl, (C6-10)aryl(C1-10)alkyl, heteroaryl, heteroaryl-alkyl, -OR23, -C(O)NR23R23, -NR23C(O)R23, -NR23C(O)OR23, -NR23C(O)NR23R23, -NR23R23, -S(O)2NR23R23, -NR23S(O)2R24, -S(0>*R24, -C(O)OR23, -C(O)R24, and -(OR39>,i60R23, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl,
heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aryl-alkyl, heteroaryl, and heteroaryl-alkyl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, oxo, alkyl, haloalkyl, -OR31, -C(O)NR31R31, -NR31C(O)R31, -NR31C(O)OR31, -NR31C(O)NR31R31, -NR31S(O)2R31, and -SiOVR31, wherein each R31 is independently hydrogen, alkyl, or haloalkyl, and each n9 is independently 0, 1, or 2,
each R23 is independently hydrogen, (C1-10)alkyl, (C3-10)cycloalkyl,
(C3-10)cycloalkyl(C1-10)alkyl, or heterocycloalkyl; or two R23, together with the nitrogen atom to which they are attached, form a heterocycloalkyl; wherein each of the foregoing alkyl, cycloalkyl, or heterocycloalkyl moieties is independently unsubstituted or substituted with one or more halo,
each R24 is independently (C1-10)alkyl, (C3-10)cycloalkyl,
(C3-10)cycloalkyl(C1-10)alkyl, or heterocycloalkyl, wherein each of the foregoing is independently unsubstituted or substituted with one or more halo,
each R39 is independently (C1-10)alkylene or (C1-10)haloalkylene, each nl6 is independently an integer from 1 to S; and
n6 is O, l, or 2;
R2 and R3 are independently selected from the group consisting of hydrogen, halo, cyano,
(C1-10)alkyl, (C3-10)cycloalkyl, (C3-10)cycloalkyl(C1-10)alkyl, -OR25, -C(O)NR25R25, -NR25C(O)R25, -NR25C(O)NR25R25, -NR25R25, -S(O)2NR25R25, -Μ12¾(O)Λ25,
-S(O)n7R3°, -NR25C(O)OR25R25, -C(O)OR25, and -C(O)R30,
wherein each (C1-10)alkyl, (C3-10)cycloalkyl, and (C3-ioJcycloalkyliCMoJalkyl is
independently unsubstituted or substituted with one or more halo, each R25 is independently hydrogen (C1-10)alkyl, (C3-10)cycloalkyl,
(C3-10)cycloalkyl(C1-10)alkyl, or heterocycloalkyl; or two R25, together with the nitrogen atom to which they are attached, form a heterocycloalkyl; wherein each of the foregoing alkyl, cycloalkyl, or heterocycloalkyl moieties is independently unsubstituted or substituted with one or more halo,
each R30 is independently (C1-10)alkyl, (C3-10)cycloalkyl, (C3-10)cycloalkyl(C1-10)alkyl, or heterocycloalkyl, wherein each of the foregoing is independently unsubstituted or substituted with one or more halo, and
n7 is 0, l, or 2;
X1, X2, X3 and X4 are independently CR4 or N, wherein X2, X3 and X4 may not all be N; when at least one of X1, X2, X3 and X4 is N, each R4 is independently selected from the group consisting of hydrogen, halo, cyano, (C1-10)alkyl, (C3-10)cycloalkyl,
(C3-10)cycloalkyl(C1-10)alkyl, heterocycloalkyl connected by an annular carbon atom, heterocycloalkyl-alkyl, -OR27, -C(O)NR27R27, -S(O)2NR27R27, -S(O)n8R28, -C(O)OR27, and -C(O)R28,
wherein each (C1-10)alkyl, (C3-10)cycloalkyl, (C3-10)cycloalkyl(C1-10)alkyl,
heterocycloalkyl, and heterocycloalkyl-alkyl is independently unsubstituted or substituted with one or more halo, each R27 is independently hydrogen or (C1-10)alkyl, (C3-10)cycloalkyl,
(C3-10)cycloalkyl(C1-10)alkyl, or heterocycloalkyl; or two R27, together with the nitrogen atom to which they are attached, form a
heterocycloalkyl; wherein each of the foregoing alkyl, cycloalkyl, or heterocycloalkyl moieties is independently unsubstituted or substituted with one or more halo,
each R28 is independently (C1-10)alkyl, (C3-10)cycloalkyl,
(C3-10)cycloalkyl(C1-10)alkyl, or heterocycloalkyl, wherein each of the foregoing is independently unsubstituted or substituted with one or more halo,
n8 is 0 , 1 or 2; or
when each of X1, X2, X3 and X4 is CR4, each R4 is independently selected from the group consisting of hydrogen, halo, cyano, (C1-10)alkyl, (C3-10)cycloalkyl,
(C3-10)cycloalkyl(C1-10)alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, -OR27,
-C(O)NR27R27, -NR27C(O)R27, -NR27R27, -NR27S(O)2R27, -S(O)2NR27R27, -S(O)nsR28, -C(O)OR27, and -C(O)R28,
wherein each (C1-10)alkyl, (C3-10)cycloalkyl, (C3-10)cycloalkyl(C1-10)alkyl,
heterocycloalkyl, and heterocycloalkyl-alkyl is independently unsubstituted or substituted with one or more halo, each R27 is independently hydrogen, (C1-10)alkyl, (C3-10)cycloalkyl,
(C3-10)cycloalkyl(C1-10)alkyl, or heterocycloalkyl; or two R27, together with the nitrogen atom to which they are attached, form a heterocycloalkyl; wherein each of the foregoing alkyl, cycloalkyl, or heterocycloalkyl moieties is independently unsubstituted or substituted with one or more halo,
each R28 is independently (C1-10)alkyl, (C3-10)cycloalkyl,
(C3-10)cycloalkyl(C1-10)alkyl, or heterocycloalkyl, wherein each of the foregoing is independently unsubstituted or substituted with one or more halo, and
n8 is 0, 1 , or 2; or
two R4 on adjacent annular carbon atoms together with the carbon atoms to which they are attached may form a carbocyclyl or heterocyclyl,
wherein the carbocyciyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, cyano, (C1-10)alkyl, (C3-10)cycloalkyl, (C3-10)cycloalkyl(C1-10)alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, -OR27, -C(O)NR27R27, -NR2 7C(O)R27, -NR27R27,
-S(O) 2NR27R27 -NR27S(O)2R27, -S(O)n8R28, and -C(O)R28,
or the heterocyclyl is unsubstituted or substituted with one or more substituents
independently selected from the group consisting of halo, cyano, (C1-10)alkyl, (C3-10)cycloalkyl, (C3-10)cycloalkyl(C1-10)alkyl, heterocycloalkyl connected by an annular carbon atom, heterocycloalkyl-alkyl, -OR2', -C(O)NR27R27 , -S(O)2NR27R27, ~S(O)n8 R28, and -C(O)R28,
each R27 is independently hydrogen, (C1-10)alkyl, (C3-10)cycloalkyl,
(C3-10)cycloalkyl(Cl-l0)alkyl; or two R2 7, together with the nitrogen atom to which they are attached, form a heterocycloalkyl; wherein each of the foregoing alkyl, cycloalkyl, or heterocycloalkyl moieties is independently unsubstituted or substituted with one or more halo,
each R28 is independently (C1-10)alkyl, (C3-ioicycloalkyl, (C3-10)cyeloalkylfC!-10)alkyl, wherein each of the foregoing is independently unsubstituted or substituted with one or more halo, and n8 is 0, l, or 2;
R15 and R17 are independently hydrogen, halo, alkyl, or -OR29, wherein each R29 is
independently hydrogen, (C1-10)alkyl, (C3-10)cycloalkyl, or (C3-10)cycloalkyl(C1-10)alkyl, and each alkyl or cycloalkyl in R15 or R17, if present, is independently unsubstituted or substituted with one or more halo;
R14 is (C1-10)alkyl, (C1-10)alkenyl, (C3-10)cycloalkyl, (C3-10)cycloalkenyl,
(C3-10)cycloalkyl(C1-10)alkyl, heterocycloalkyl connected through an annular carbon atom, heterocycloalkenyl connected through an annular carbon atom, heterocycloalkyl- alkyl, -OR5, -C(O)NR5R5, -R5C(O)NR5R5, -S(O)2NR5R5, -S(O)n1R6, or -C(O)R6;
R16 is hydrogen, fluoro, (C1-10)alkyl, (C3-10)cycloalkyl, (C3-10)cycloalkyl(C1-10)alkyl,
heterocycloalkyl connected through an annular carbon atom, heterocycloalkyl-alkyl, -OR5, -C(O)NR5R5, -R5C(O)NR5R5, -S(O)2NR5R5, -S(O)n1R6, or -C(O)R6;
wherein the (C1-10)alkyl, (C1-10)alkenyl, (C3-10)cycloalkyl, (C3-10)cycloalkenyl,
(C3-10)cycloalkyl(C1-10)alkyl, heterocycloalkyl, heterocycloalkenyl, or heterocycloalkyl- alkyl of R14 or R16 is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of (C1-10)alkyl, cycloalkyl, heterocycloalkyl, halo, cyano, oxo, -OR7, -C(O)OR7, -C(O)NR7R7, -NR7C(O)R7, -NR7C(O)NR7R7, -NR7R7, -S(O)2NR7R7, -NR7S(O)2R7, -S(O)n2R13, and -C(O)R13;
wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently unsubstituted or substituted with one or more substituents selected from the group consisting of halo, cycloalkyl, halocycloalkyl, heterocycloalkyl, haloheterocycloalkyl, and -(OR33)n1oOR32, wherein each nlO is independently an integer from 0 to 5, each R32 is independently hydrogen, (C1-10)alkyl or (C1-10)haloalkyl, and each R33 is independently (C1-10)alkylene or (C1-10)haloalkylene;
each R5 is independently hydrogen, (C1-10)alkyl, or (C3-10)cycloalkyl; or two R5, together with the nitrogen atom to which they are attached, form a heterocycloalkyl; wherein each alkyl, cycloalkyl, or heterocycloalkyl is independently unsubstituted or substituted with one or more substituents selected from the group consisting of halo, cyano, oxo, alkyl, haloalkyl, -C(O)OR34, -C(O)NR34R34, -NR34C(O)R34, -NR34C(O)NR34R34, -NR34R34, -S(O)2NR34R34, -NR34S(O)2R34, -S(O)n11R34, -C(O)R34, and -(OR35)n12OR34, wherein each R34 is independently hydrogen, (C1-10)alkyl, or (C1-10)haloalkyl; each nl 1 is
independently 0, 1, or 2; each nl2 is independently an integer from 0 to 5; and each R35 is independently (C1-10)alkylene or (C1-10)haloalkylene;
each R6 is independently (C1-10)alkyl or (C3-10)cycloalkyl, wherein each alkyl or cycloalkyl is independently unsubstituted or substituted with one or more halo;
each nl is independently 0, 1, or 2;
each R7 is independently hydrogen, unsubstituted (C1-10)alkyl, or (C1-10)alkyl substituted with one or more halo;
each n2 is independently 0, 1, or 2,
and each R13 is independently unsubstituted (C1-10)alkyl or (C1-10)alkyl substituted with one or more halo;
or R14 and R15, together with the atoms to which they are attached, form a carbocyclyl or
heterocyclyl,
wherein the carbocyclyl or heterocyclyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, cyano, oxo, (C1-10)alkyl, (C3-10)cycloalkyl, (C3-10)cycloalkyl(C1-10)alkyl, -OR18, -C(O)NR18R18, -NR18C(O)R18, -NR,8C(O)NR,8R18, -NR18R18, -S(O)2NR,8R18, -NR18S(O)2R18, -S(O)^R21, -C(O)OR18, and -C(O)R21,
wherein each (C1-10)alkyl, (C3-10)cycloalkyl, and (C3-10)cycloalkyl(C1-10)alkyl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, alkyl, haloalkyl, cyano, oxo, -C(O)OR36, -C(O)NR36R36, -NR36C(O)R36,
-NR36C(O)NR36R36, -NR36R36, -S(O)2NR36R36, -NR36S(O)2R36,
-S(0)n13R36, -C(O)R36, and -(OR37)n140R36, wherein each R36 is independently hydrogen, (C1-10)alkyl, or (C1-10)haloalkyl; each nl3 is independently 0, 1, or 2; each nl4 is independently an integer from 0 to 5; and each R37 is independently (C1-10)alkylene or (C1-10)haloalkylene; wherein each R18 is independently hydrogen, (C1-10)alkyl, or (C3-10)cycloalkyl; or two R18, together with the nitrogen atom to which they are attached, form a heterocycloalkyl; wherein each alkyl, cycloalkyl, or heterocycloalkyl is independently unsubstituted or substituted with one or more halo; each R21 is independently (C1-10)alkyl or (C3-10)cycloalkyl, wherein each alkyl or
cycloalkyl is independently unsubstituted or substituted with one or more halo; and
each n3 is independently 0, 1, or 2.
[0008] In some variations, the compound of Formula (X) is a compound of Formula (X-A):
Figure imgf000011_0001
or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, where R1, R2, R3, R14, R15, R16, R17, X1, X2, X3, and X4 are as described for Formula (X) above.
[0009] In other variations, the compound of Formula (X) or Formula (X-A) is a compound of Formula (X-Ai):
Figure imgf000011_0002
( ), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, where R1, R2, R3, R14, R15, R16, R17, X1, X2, X3, and X4 are as described for Formula (X) above.
[0010] In other variations, the compound of Formula (X) is a compound of Formula (X-B):
Figure imgf000012_0001
or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, where R1, R2, R3, R14, R15, R16, R17, X1, X2, X3, and X4 are as described for Formula (X) above.
[0011] In certain variations, the compound of Formula (X) or Formula (X-B) is a compound of Formula (X-Bi):
Figure imgf000012_0002
or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, where R1, R2, R3, R14, R15, R16, R17, X1, X2, X3, and X4 are as described for Formula (X) above.
[0012] In some variations of any of the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, R17 is hydrogen. In certain variations of any of the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, R1 is -C(O)NR8R9, -S(O)2NR8R9,
-NR10C(O)NR8R9, -NR10C(O)R9, -NR10C(O)OR9, or -NR10(SO)2R9. In certain of these variations, R10 is hydrogen. In some variations, R1 is -C(O)NR8R9, and the R8 and R9 together with the nitrogen to which they are attached form an unsubstituted or substituted heterocycloalkyl.
[0013] In some variations of any of the disclosed variations, R2 is halo. In certain variations, R4 is independently selected from the group consisting of hydrogen, halo, cyano, (C1-10)alkyl, and -OR27. In some variations, R3 is hydrogen.
[0014] In some embodiments of the compound of Formula (X-A), (X-B), (X-Ai), or (X-Bi), R1 is -C(O)OR9, -C(O)NR8R9, -S(O)2NR8R9, -NR10C(O)NR8R9, -NR10C(O)R9, -NR10S(O)2R9, -OR26, -SR9, -S(O)R9, -S(O)2R9, -NR8R9, or -NR10C(O)OR9.
[0015] In other aspects, provided herein is a pharmaceutical composition which comprises a compound of Formula (X), such as a compound of Formula (X-A), (X-B), (X-Ai), or (X-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer of any of the foregoing, and a pharmaceutically acceptable excipient.
[0016] In yet other aspects, provided herein is a method of inhibiting a sterol regulatory element-binding protein (SREBP) by contacting the SREBP or contacting an SREBP cleavage activating-protein (SCAP) with a compound of Formula (X), such as a compound of Formula (X-A), (X-B), (X-Ai), or (X-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer of any of these; or a pharmaceutical composition comprising any of the foregoing and a pharmaceutically acceptable excipient.
[0017] In still further aspects, provided herein is a method of inhibiting the proteolytic activation of a sterol regulatory element-binding protein (SREBP) by contacting an SREBP cleavage activating-protein (SCAP) with a compound of Formula (X), such as a compound of Formula (X-A), (X-B), (X-Ai), or (X-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer of any of these; or a pharmaceutical composition comprising any of the foregoing and a pharmaceutically acceptable excipient.
[0018] In other aspects, provided herein is a method of treating a disorder in a subject in need thereof by administering to the subject in need thereof an effective amount of a compound of Formula (X), such as a compound of Formula (X-A), (X-B), (X-Ai), or (X-Bi), or a
pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer of any of these; or a pharmaceutical composition comprising any of the foregoing and a pharmaceutically acceptable excipient.
[0019] In some aspects, provided herein is a method of treating a disorder in a subject in need thereof, wherein the disorder is mediated by a sterol regulatory element-binding protein (SREBP), by administering to the subject in need thereof an effective amount of a compound of Formula (X), such as a compound of Formula (X-A), (X-B), (X-Ai), or (X-Bi), or a
pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer of any of these; or a pharmaceutical composition comprising any of the foregoing and a pharmaceutically acceptable excipient
[0020] In further aspects, provided herein is the use of compound of Formula (X), such as a compound of Formula (X-A), (X-B), (X-Ai), or (X-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer of any of these, in the manufacture of a medicament for use in inhibiting a sterol regulatory element-binding protein (SREBP) in a subject in need thereof.
[0021] In yet other aspects, provided herein is the use of a compound of Formula (X), such as a compound of Formula (X-A), (X-B), (X-Ai), or (X-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer of any of these, in the manufacture of a medicament for use in inhibiting the proteolytic activation of a sterol regulatory element-binding protein (SREBP) in a subject in need thereof.
[0022] In some aspects, provided herein is the use of a compound of Formula (X), such as a compound of Formula (X-A), (X-B), (X-Ai), or (X-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer of any of these, in the manufacture of a medicament for use in treating a disorder in a subject in need thereof.
[0023] In other aspects, provided herein is the use of a compound of Formula (X), such as a compound of Formula (X-A), (X-B), (X-Ai), or (Z-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer of any of these, in the manufacture of a medicament for use in treating a disorder in a subject in need thereof, wherein the disorder is mediated by a sterol regulatory element-binding protein (SREBP). [0024] In still further aspects, provided herein is the use of a compound of Formula (X), such as a compound of Formula (X-A), (X-B), (X-Ai), or (Z-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer of any of these; or a pharmaceutical composition comprising any of the foregoing and a pharmaceutically acceptable excipient, for inhibiting a sterol regulatory element-binding protein (SREBP).
[0025] In still further aspects, provided herein is the use of a compound of Formula (X), such as a compound of Formula (X-A), (X-B), (X-Ai), or (X-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer of any of these; or a pharmaceutical composition comprising any of the foregoing and a pharmaceutically acceptable excipient, for use in inhibiting the proteolytic activation of a sterol regulatory element-binding protein (SREBP).
[0026] In further aspects, provided herein is the use of a compound of Formula (X), such as a compound of Formula (X-A), (X-B), (X-Ai), or (X-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer of any of these; or a pharmaceutical composition comprising any of the foregoing and a pharmaceutically acceptable excipient, for treating a disorder in a subject in need thereof.
[0027] In some aspects, provided herein is a the use of a compound of Formula (X), such as a compound of Formula (X-A), (X-B), (X-Ai), or (X-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer of any of these; or a pharmaceutical composition comprising any of the foregoing and a pharmaceutically acceptable excipient, for treating a disorder in a subject in need thereof, wherein the disorder is mediated by a sterol regulatory element-binding protein (SREBP).
[0028] In some variations of the aspects herein, the SREBP is an SREBP- 1. In certain variations, the SREBP is SREBP-la. In other variations, the SREBP is SREBP- lc. In still further embodiments, the SREBP is SREBP-2. In some variations, the disorder is Metabolic Syndrome, type 2 diabetes, obesity, fatty liver disease, insulin resistance, adiposopathy, or dyslipidemia. In other variations, the disorder is a hyperproliferative disorder, such as cancer. In still further variations, the disorder is endotoxic shock, systemic inflammation, or
atherosclerosis. [0029] In some aspects, provided herein is a method of treating fatty liver disease in a subject in need thereof, by administering to the subject in need thereof an effective amount of a compound of Formula (X), such as a compound of Formula (X-A), (X-B), (X-Ai), or (X-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer of any of these; or a pharmaceutical composition comprising any of the foregoing and a pharmaceutically acceptable excipient.
[0030] In further aspects, provided herein is the use of a compound of Formula (X), such as a compound of Formula (X-A), (X-B), (X-Ai), or (Z-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof; or a pharmaceutical composition comprising any of the foregoing and a pharmaceutically acceptable excipient, for treating fatty liver disease in a subject in need thereof.
[0031] In yet other aspects, provided herein is the use of a compound of Formula (X), such as a compound of Formula (X-A), (X-B), (X-Ai), or (X-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer of any of these, in the manufacture of a medicament for use in treating fatty liver disease in a subject in need thereof.
[0032] In some aspects, provided herein is a method of treating non-alcoholic steatohepatitis (NASH) in a subject in need thereof, by administering to the subject in need thereof an effective amount of a compound of Formula (X), such as a compound of Formula (X-A), (X-B), (X-Ai), or (X-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer of any of these; or a pharmaceutical composition comprising any of the foregoing and a pharmaceutically acceptable excipient
[0033] In further aspects, provided herein is the use of a compound of Formula (X), such as a compound of Formula (X-A), (X-B), (X-Ai), or (X-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof; or a pharmaceutical composition comprising any of the foregoing and a pharmaceutically acceptable excipient, for treating non-alcoholic
steatohepatitis (NASH) in a subject in need thereof.
[0034] In yet other aspects, provided herein is the use of a compound of Formula (X), such as a compound of Formula (X-A), (X-B), (X-Ai), or (X-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer of any of these, in the manufacture of a medicament for use in treating non-alcoholic steatohepatitis (NASH) in a subject in need thereof.
[0035] In some aspects, provided herein is a method of treating a hyperproliferative disorder in a subject in need thereof, by administering to the subject in need thereof an effective amount of a compound of Formula (X), such as a compound of Formula (X-A), (X-B), (X-Ai), or (X-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer of any of these; or a pharmaceutical composition comprising any of the foregoing and a pharmaceutically acceptable excipient.
[0036] In still further aspects, provided herein is the use of a compound of Formula (X), such as a compound of Formula (X-A), (X-B), (X-Ai), or (X-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof; or a pharmaceutical composition comprising any of the foregoing and a pharmaceutically acceptable excipient, for treating a
hyperproliferative disorder in a subject in need thereof.
[0037] In other aspects, provided herein is the use of a compound of Formula (X), such as a compound of Formula (X-A), (X-B), (X-Ai), or (X-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer of any of these, in the manufacture of a medicament for use in treating a hyperproliferative disorder in a subject in need thereof.
DESCRIPTION OF THE FIGURES
[0038] FIG. 1 is a diagram depicting the procedure to evaluate the effect of compounds on differentiation and maturation of adipocytes.
[0039] FIG. 2 is an image of differentiated 3T3 LI cells stained with oil red-O, after being in the presence of compound Z-725 (also known as Compound 4).
[0040] FIG. 3 is an image of differentiated human pre-adipocyte cells stained with oil red-O, after being in the presence of compound Z-725.
[0041] FIG. 4 is an image of Western blot analysis of the effect compounds Z-725, Z-826, Z- 780, and Z-796 had on SREBP processing and activation in HepG2 cells. Topoisomerase I was used as a loading control. DETAILED DESCRIPTION
[0042] The following description sets forth numerous exemplary configurations, methods, parameters, and the like. It should be recognized, however, that such description is not intended as a limitation on the scope of the present disclosure, but is instead provided as a description of exemplary embodiments.
I. Compounds of Formula (X)
[0043] In some aspects, provided herein are compounds of Formula (X):
Figure imgf000018_0001
or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein:
R1 is -C(O)OR9, -C(O)NR8R9, -S(O)2NR8R9, -NR10C(O)NR8R9, -NR10C(O)R9, -NR10S(O)2R9,
-OR26, -SR9, -S(O)R9, -S(O)2R9, -NR8R9, -NR10C(O)OR9, -C(O)R26, -NR10S(O)2NR8R9, - C(O)NR10S(O)^9, or -C(O)NR10NR8R9;
wherein each of R8, R9, and R10 is independently selected from the group consisting of hydrogen, (C1-10)alkyl, (C3-10)cycloalkyl, (C3-10)cycloalkyl(C1-10)alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, (C6-10)aryl, (C6-10)aryl(C1-10)alkyl, heteroaryl, and heteroaryl-alkyl,
R26 is (C1-10)alkyl, (C3-10)cycloalkyl, (C3-10)cycloalkyl(C1-10)alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, (C6-10)aryl, (C6-10)aryl(C1-10)alkyl, heteroaryl, or heteroaryl-alkyl,
each (C1-10)alkyl, (C3-10)cycloalkyl, (C3-10)cycloalkyl(C1-10)alkyl, heterocycloalkyl,
heterocycloalkyl-alkyl, (C6-10)aryl, (C6-10)aryl(C1-10)alkyl, heteroaryl, and heteroaryl-alkyl of R8, R9, R10, and R26 is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, (C1-10)alkyl, (C1-10)haloalkyl, cyano, oxo, -OR19,
-C(O)NR,9R19, -NR19C(O)R19, -NR,9C(O)NR,9R19, -NR19R19, -S(O)2NR,9R19, -NR,9S(O)2R,9, -S(O)MR20, -C(O)OR19, -C(O)R20, and -(OR38)n150R19, each R19 is independently hydrogen, (C1-10)alkyl, (C3-10)cycloalkyl,
(C3-10)cycloalkyl(C1-10)alkyl, or heterocycloalkyl; or two R19, together with the nitrogen atom to which they are attached, form a
heterocycloalkyl; wherein each of the foregoing alkyl, cycloalkyl, or heterocycloalkyl moieties is independently unsubstituted or substituted with one or more halo,
each R20 is independently (C1-10)alkyl, (C3-10)cycloalkyl,
(C3-10)cycloalkyl(C1-10)alkyl, or heterocycloalkyl, wherein each of the foregoing is independently unsubstituted or substituted with one or more halo,
each R38 is independently (C1-10)alkylene or (C1-10)haloalkylene,
each nlS is independently an integer from 1 to 5; and
n4 is 0, l, or 2;
or R8 and R9, together with the nitrogen atom to which they are attached, form a
heterocycloalkyl, wherein the heterocycloalkyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, cyano, oxo, (C1-10)alkyl, (C2-i0)alkenyl, (C2-i0)alkynyl, (C3-10)cycloalkyl, (C3-10)cycloalkyl(C1-10)alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, (C6-10)aryl, (C6-10)aryl(C1-10)alkyl, heteroaryl, heteroaryl-alkyl, -OR23, -C(O)NR23R23, -NR23C(O)R23, -NR23C(O)OR23, -NR23C(O)NR23R23, -NR23R23, -S(O)2NR23R23, -NR23S(O)2R24, -S(0>6R24, -C(O)OR23, -C(O)R24, and -(OR39)n160R23, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl,
heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aryl-alkyl, heteroaryl, and heteroaryl-alkyl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, oxo, alkyl, haloalkyl, -OR31, -C(O)NR31R31, -NR31C(O)R31, -NR31C(O)OR31, -NR31C(O)NR31R31, -NR31S(O)2R31, and -S(O)n9R31, wherein each R31 is independently hydrogen, alkyl, or haloalkyl, and each n9 is independently 0, 1, or 2,
each R23 is independently hydrogen, (C1-10)alkyl, (C3-10)cycloalkyl,
(C3-10)cycloalkyl(C1-10)alkyl, or heterocycloalkyl; or two R23, together with the nitrogen atom to which they are attached, form a heterocycloalkyl; wherein each of the foregoing alkyl, cycloalkyl, or heterocycloalkyl moieties is independently unsubstituted or substituted with one or more halo,
each R24 is independently (C1-10)alkyl, (C3-10)cycloalkyl,
(C3-10)cycloalkyl(C1-10)alkyl, or heterocycloalkyl, wherein each of the foregoing is independently unsubstituted or substituted with one or more halo,
each R39 is independently (C1-10)alkylene or (C1-10)haloalkylene,
each nl6 is independently an integer from 1 to 5; and
n6 is 0, l, or 2;
R3 are independently selected from the group consisting of hydrogen, halo, cyano, (C1-10)alkyl, (C3-10)cycloalkyl, (C3-10)cycloalkyl(C1-10)alkyl, -OR25, -C(O)NR25R25, -NR25C(O)R25, -NR25C(O)NR25R25, -NR25R25, -S(O)2NR25R25, -NR25S(O)2R25,
-S(O)n7R3°, -NR25C(O)OR25R25, -C(O)OR25, and -C(O)R30,
wherein each (C1-10)alkyl, (C3-10)cycloalkyl, and (C3-10)cycloalkyl(C1-10)alkyl is
independently unsubstituted or substituted with one or more halo,
each R25 is independently hydrogen (C1-10)alkyl, (C3-10)cycloalkyl,
(C3-10)cycloalkyl(C1-10)alkyl, or heterocycloalkyl; or two R25, together with the nitrogen atom to which they are attached, form a heterocycloalkyl; wherein each of the foregoing alkyl, cycloalkyl, or heterocycloalkyl moieties is independently unsubstituted or substituted with one or more halo, each R30 is independently (C1-10)alkyl, (C3-10)cycloalkyl, (C3-10)cycloalkyl(C1-10)alkyl, or heterocycloalkyl, wherein each of the foregoing is independently unsubstituted or substituted with one or more halo, and
n7 is 0, l, or 2;
X1, X2, X3 and X4 are independently CR4 or N, wherein X2, X3 and X4 may not all be N;
when at least one of X1, X2, X3 and X4 is N, each R4 is independently selected from the group consisting of hydrogen, halo, cyano, (C1-10)alkyl, (C3-10)cycloalkyl,
(C3-10)cycloalkyl(C1-10)alkyl, heterocycloalkyl connected by an annular carbon atom, heterocycloalkyl-alkyl, -OR27, -C(O)NR27R27, -S(O)2NR27R27, -S(O)n8R28, -C(O)OR27, and -C(O)R28,
wherein each (C1-10)alkyl, (C3-10)cycloalkyl, (C3-10)cycloalkyl(C1-10)alkyl,
heterocycloalkyl, and heterocycloalkyl-alkyl is independently
unsubstituted or substituted with one or more halo, each R27 is independently hydrogen or (C1-10)alkyl, (C3-10)cycloalkyl,
(C3-10)cycloalkyl(C1-10)alkyl, or heterocycloalkyl; or two R27, together with the nitrogen atom to which they are attached, form a
heterocycloalkyl; wherein each of the foregoing alkyl, cycloalkyl, or heterocycloalkyl moieties is independently unsubstituted or substituted with one or more halo,
each R28 is independently (C1-10)alkyl, (C3-10)cycloalkyl,
(C3-10)cycloalkyl(C1-10)alkyl, or heterocycloalkyl, wherein each of the foregoing is independently unsubstituted or substituted with one or more halo,
n8 is 0 , 1 or 2; or
when each of X1, X2, X3 and X4 is CR4, each R4 is independently selected from the group
consisting of hydrogen, halo, cyano, (C1-10)alkyl, (C3-10)cycloalkyl,
(C3-10)cycloalkyl(C1-10)alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, -OR27,
-C(O)NR27R27, -NR27C(O)R27, -NR27R27, -NR27S(O)2R27, -S(O)2NR27R27, -S(O)neR28, -C(O)OR27, and -C(O)R28, wherein each (C1-10)alkyl, (C3-10)cycloalkyl, (C3-10)cycloalkyl(C1-10)alkyl,
heterocycloalkyl, and heterocycloalkyl-alkyl is independently
unsubstituted or substituted with one or more halo, each R27 is independently hydrogen, (C1-10)alkyl, (C3-10)cycloalkyl,
(C3-10)cycloalkyl(C1-10)alkyl, or heterocycloalkyl; or two R27, together with the nitrogen atom to which they are attached, form a
heterocycloalkyl; wherein each of the foregoing alkyl, cycloalkyl, or heterocycloalkyl moieties is independently unsubstituted or substituted with one or more halo,
each R28 is independently (C1-10)alkyl, (C3-10)cycloalkyl,
(C3-10)cycloalkyl(C1-10)alkyl, or heterocycloalkyl, wherein each of the foregoing is independently unsubstituted or substituted with one or more halo, and
n8 is 0, 1, or 2; or
two R4 on adjacent annular carbon atoms together with the carbon atoms to which they are attached may form a carbocyclyl or heterocyclyl,
wherein the carbocyclyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, cyano, (C1-10)alkyl, (C3-10)cycloalkyl, (C3-10)cycloalkyl(C1-10)alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, -OR27, -C(O)NR27R27, -NR27C(O)R27, -NR 7R27, -S(O)2NR 7R27, -NR27S(O)2R27, -8(O)n8R2 , and -C(O)R28,
or the heterocyclyl is unsubstituted or substituted with one or more substituents
independently selected from the group consisting of halo, cyano, (C1-10)alkyl, (C3-10)cycloalkyl, (C3-10)cycloalkyl(C1-10)alkyl, heterocycloalkyl connected by an annular carbon atom, heterocycloalkyl-alkyl, -OR27, -C(O)NR27R27, -S(O)2NR27R27, -S(0>*R28, and -C(O)R28,
each R27 is independently hydrogen, (C1-10)alkyl, (C3-10)cycloalkyl,
(C3-10)cycloalkyl(C1-10)alkyl; or two R27, together with the nitrogen atom to which they are attached, form a heterocycloalkyl; wherein each of the foregoing alkyl, cycloalkyl, or heterocycloalkyl moieties is independently unsubstituted or substituted with one or more halo,
each R28 is independently (C1-10)alkyl, (C3-10)cycloalkyl, (C3-10)cycloalkyl(C1-10)alkyl, wherein each of the foregoing is independently unsubstituted or substituted with one or more halo, and
n8 is 0, l, or 2;
R15 and R17 are independently hydrogen, halo, alkyl, or -OR29, wherein each R29 is
independently hydrogen, (C1-10)alkyl, (C3-10)cycloalkyl, or (C3-10)cycloalkyl(C1-10)alkyl, and each alkyl or cycloalkyl in R15 or R17, if present, is independently unsubstituted or substituted with one or more halo;
R14 is (C1-10)alkyl, (C1-10)alkenyl, (C3-10)cycloalkyl, (C3-10)cycloalkenyl,
(C3-10)cycloalkyl(C1-10)alkyl, heterocycloalkyl connected through an annular carbon atom, heterocycloalkenyl connected through an annular carbon atom, heterocycloalkyl- alkyl, -OR5, -C(O)NR5R5, -R5C(O)NR5R5, -S(O)2NR5R5, -S(O)„iR6, or -C(O)R6;
R16 is hydrogen, fluoro, (C1-10)alkyl, (C3-10)cycloalkyl, (C3-10)cycloalkyl(C1-10)alkyl,
heterocycloalkyl connected through an annular carbon atom, heterocycloalkyl-alkyl, -OR5, -C(O)NR5R5, -R5C(O)NR5R5, -S(O)2NR5R5, -S(O)„iR6, or -C(O)R6;
wherein the (C1-10)alkyl, (C1-10)alkenyl, (C3-10)cycloalkyl, (C3-10)cycloalkenyl,
(C3-10)cycloalkyl(C1-10)alkyl, heterocycloalkyl, heterocycloalkenyl, or heterocycloalkyl- alkyl of R14 or R16 is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of (C1-10)alkyl, cycloalkyl, heterocycloalkyl, halo, cyano, oxo, -OR7, -C(O)OR7, -C(O)NR7R7, -NR7C(O)R7, -NR7C(O)NR7R7, -NR7R7, -S(O)2NR7R7, -NR7S(O)2R7, -S(O)n2R13, and -C(O)R13;
wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently unsubstituted or substituted with one or more substituents selected from the group consisting of halo, cycloalkyl, halocycloalkyl, heterocycloalkyl, haloheterocycloalkyl, and -(OR33)n1oOR32, wherein each nlO is independently an integer from 0 to 5, each R32 is independently hydrogen, (C1-10)alkyl or (C1-10)haloalkyl, and each R33 is independently (C1-10)alkylene or (C1-10)haloalkylene; each R5 is independently hydrogen, (C1-10)alkyl, or (C3-10)cycloalkyl; or two R5, together with the nitrogen atom to which they are attached, form a heterocycloalkyl; wherein each alkyl, cycloalkyl, or heterocycloalkyl is independently unsubstituted or substituted with one or more substituents selected from the group consisting of halo, cyano, oxo, alkyl, haloalkyl, -C(O)OR34, -C(O)NR34R34, -NR34C(O)R34, -NR34C(O)NR34R34, -NR34R34,
-S(O)2NR34R34, -NR34S(O)2R34, -S(0>mR34, -C(O)R34, and -(OR35)n120R34, wherein each R34 is independently hydrogen, (C1-10)alkyl, or (C1-10)haloalkyl; each nil is
independently 0, 1, or 2; each nl2 is independently an integer from 0 to 5; and each R35 is independently (C1-10)alkylene or (C1-10)haloalkylene;
each R6 is independently (C1-10)alkyl or (C3-10)cycloalkyl, wherein each alkyl or cycloalkyl is independently unsubstituted or substituted with one or more halo;
each nl is independently 0, 1, or 2;
each R7 is independently hydrogen, unsubstituted (C1-10)alkyl, or (C1-10)alkyl substituted with one or more halo;
each n2 is independently 0, 1, or 2,
and each R13 is independently unsubstituted (C1-10)alkyl or (C1-10)alkyl substituted with one or more halo;
or R14 and R15, together with the atoms to which they are attached, form a carbocyclyl or
heterocyclyl,
wherein the carbocyclyl or heterocyclyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, cyano, oxo, (C1-10)alkyl, (C3-10)cycloalkyl, (C3-10)cycloalkyl(C1-10)alkyl, -OR18, -C(O)NR18R18, -NR18C(O)R18, -NR18C(O)NR18R18, -NR18R18, -S(O)2NR18R18, -NR18S(O)2R18, -S(O)asR.21, -C(O)OR18, and -C(O)R21,
wherein each (C1-10)alkyl, (C3-10)cycloalkyl, and (C3-10)cycloalkyl(C1-10)alkyl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, alkyl, haloalkyl, cyano, oxo, -C(O)OR36, -C(O)NR36R36, -NR36C(O)R36,
-NR36C(O)NR36R36, -NR36R36, -S(O)2NR36R36, -NR36S(O)2R36, -S(O)n13R36, -C(O)R36, and -(OR37)n140R36, wherein each R36 is
independently hydrogen, (C1-10)alkyl, or (C1-10)haloalkyl; each nl3 is independently 0, 1, or 2; each nl4 is independently an integer from 0 to 5; and each R37 is independently (C1-10)alkylene or (C1-10)haloalkylene; wherein each R18 is independently hydrogen, (C1-10)alkyl, or (C3-10)cycloalkyl; or two R18, together with the nitrogen atom to which they are attached, form a heterocycloalkyl; wherein each alkyl, cycloalkyl, or heterocycloalkyl is independently unsubstituted or substituted with one or more halo; each R21 is independently (C1-10)alkyl or (C3-10)cycloalkyl, wherein each alkyl or
cycloalkyl is independently unsubstituted or substituted with one or more halo; and
each n3 is independently 0, 1, or 2.
[0044] In some embodiments, the compound of Formula (X) is a compound of Formula (Z):
Figure imgf000025_0001
or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein:
R1 is -C(O)OR9, -C(O)NR8R9, -S(O)2NR8R9, -NR10C(O)NR8R9, -NR10C(O)R9, -NR10S(O)2R9, -OR26, -SR9, -S(O)R9, -S(O)2R9, -NR8R9, -NR10C(O)OR9, -C(O)R26, -NR10S(O)2NR8R9, or -C(O)NR10S(O)2R9;
wherein each of R8, R9, and R10 is independently selected from the group consisting of hydrogen, (C1-10)alkyl, (C3-10)cycloalkyl, (C3-10)cycloalkyl(C1-10)alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, (C6-10)aryl, (C6-10)aryl(C1-10)alkyl, heteroaryl, and heteroaryl-alkyl, R26 is (C1-10)alkyl, (C3-10)cycloalkyl, (C3-10)cycloalkyl(C1-10)alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, (C6-10)aryl, (C6-10)aryl(C1-10)alkyl, heteroaiyl, or heteroaryl-alkyl,
each (C1-10)alkyl, (C3-10)cycloalkyl, (C3-10)cycloalkyl(C1-10)alkyl, heterocycloalkyl,
heterocycloalkyl-alkyl, (C6-10)aryl, (C6-10)aryl(C1-10)alkyl, heteroaiyl, and heteroaryl-alkyl of R8, R9, R10, and R26 is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, cyano, oxo, -OR19, -C(O)NR,9R19, -NR19C(O)R19,
-NR19C(O)NR19R19, -NR19R19, -S(O)2NR19R19, -NR19S(O)2R19, -S(O),*R20, -C(O)OR19, and -C(O)R20,
each R19 is independently hydrogen, (C1-10)alkyl, (C3-10)cycloalkyl,
(C3-10)cycloalkyl(C1-10)alkyl, or heterocycloalkyl; or two R19, together with the nitrogen atom to which they are attached, form a
heterocycloalkyl; wherein each of the foregoing alkyl, cycloalkyl, or heterocycloalkyl moieties is independently unsubstituted or substituted with one or more halo,
each R20 is independently (C1-10)alkyl, (C3-10)cycloalkyl,
(C3-10)cycloalkyl(C1-10)alkyl, or heterocycloalkyl, wherein each of the foregoing is independently unsubstituted or substituted with one or more halo, and
n4 is 0, l, or 2;
or R8 and R9, together with the nitrogen atom to which they are attached, form a
heterocycloalkyl, wherein the heterocycloalkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of halo, cyano, oxo, (C1-10)alkyl, (C2-10)alkenyl, (C2-10)alkynyl, (C3-10)cycloalkyl,
(C3-10)cycloalkyl(C1-10)alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, (C6-10)aryl, (C6-10)aryl(C1-10)alkyl, heteroaryl, heteroaryl-alkyl, -OR23, -C(O)NR23R23, -NR23C(O)R23, -NR23C(O)OR23, -NR23C(O)NR23R23, -NR23R23, -S(O)2NR23R23, -NR23S(O)2R24, -S(O)„6R24, -C(O)OR23, and -C(O)R24, wherein each R23 is independently hydrogen, (C1-10)alkyl, (C3-10)cycloalkyl, (C3-10)cycloalkyl(C1-10)alkyl, or heterocycloalkyl; or two R23, together with the nitrogen atom to which they are attached, form a
heterocycloalkyl; wherein each of the foregoing alkyl, cycloalkyl, or heterocycloalkyl moieties is independently unsubstituted or substituted with one or more halo,
each R24 is independently (C1-10)alkyl, (C3-10)cycloalkyl,
(C3-10)cycloalkyl(C1-10)alkyl, or heterocycloalkyl, wherein each of the foregoing is independently unsubstituted or substituted with one or more halo, and
n6 is 0, l, or 2;
R2 and R3 are independently selected from the group consisting of hydrogen, halo, cyano,
(C1-10)alkyl, (C3-10)cycloalkyl, (C3-10)cycloalkyl(C1-10)alkyl, -OR25, -C(O)NR25R25, -NR25C(O)R25, -NR25C(O)NR25R25, -NR25R25, -S(O)2NR25R25, -NR25S(O)2R25,
-S(O)„7R30, -NR25C(O)OR25R25, -C(O)OR25, or -C(O)R30,
wherein each (C1-10)alkyl, (C3-10)cycloalkyl, and (C3-10)cycloalkyl(C1-10)alkyl is
independently unsubstituted or substituted with one or more halo, each R25 is independently hydrogen (C1-10)alkyl, (C3-10)cycloalkyl,
(C3-10)cycloalkyl(C1-10)alkyl, or heterocycloalkyl; or two R25, together with the nitrogen atom to which they are attached, form a heterocycloalkyl; wherein each of the foregoing alkyl, cycloalkyl, or heterocycloalkyl moieties is independently unsubstituted or substituted with one or more halo,
each R30 is independently (C1-10)alkyl, (C3-10)cycloalkyl, (C3-10)cycloalkyl(C1-10)alkyl, or heterocycloalkyl, wherein each of the foregoing is independently unsubstituted or substituted with one or more halo, and
n7 is 0, l, or 2;
X1, X2, X3 and X4 are independently CR4 or N, wherein X2, X3 and X4 may not all be N;
when at least one of X1, X2, X3 and X4 is N, each R4 is independently selected from the group consisting of hydrogen, halo, cyano, (C1-10)alkyl, (C3-10)cycloalkyl, (C3-10)cycloalkyl(C1-10)alkyl, heterocycloalkyl connected by an annular carbon atom, heterocycloalkyl-alkyl, -OR27, -C(O)NR27R27, -S(O)2NR27R27, -S(O),*R28, -C(O)OR27, and -C(O)R28,
wherein each (C1-10)alkyl, (C3-10)cycloalkyl, (C3-10)cycloalkyl(C1-10)alkyl,
heterocycloalkyl, and heterocycloalkyl-alkyl is independently unsubstituted or substituted with one or more halo, each R27 is independently hydrogen or (C1-10)alkyl, (C3-10)cycloalkyl,
(C3-10)cycloalkyl(C1-10)alkyl, or heterocycloalkyl; or two R27, together with the nitrogen atom to which they are attached, form a
heterocycloalkyl; wherein each of the foregoing alkyl, cycloalkyl, or heterocycloalkyl moieties is independently unsubstituted or substituted with one or more halo,
each R28 is independently (C1-10)alkyl, (C3-10)cycloalkyl,
(C3-10)cycloalkyl(C1-10)alkyl, or heterocycloalkyl, wherein each of the foregoing is independently unsubstituted or substituted with one or more halo,
n8 is 0 , 1 or 2; or
when each of X1, X2, X3 and X4 is CR4, each R4 is independently selected from the group consisting of hydrogen, halo, cyano, (C1-10)alkyl, (C3-10)cycloalkyl,
(C3-10)cycloalkyl(C1-10)alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, -OR27,
-C(O)NR27R27, -NR27C(O)R27, -NR27R27, -NR27S(O)2R27, -S(O)2NR27R27, -S(O)nsR28, -C(O)OR27, and -C(O)R28,
wherein each (C1-10)alkyl, (C3-10)cycloalkyl, (C3-10)cycloalkyl(C1-10)alkyl,
heterocycloalkyl, and heterocycloalkyl-alkyl is independently unsubstituted or substituted with one or more halo, each R27 is independently hydrogen, (C1-10)alkyl, (C3-10)cycloalkyl,
(C3-10)cycloalkyl(C1-10)alkyl, or heterocycloalkyl; or two R27, together with the nitrogen atom to which they are attached, form a
heterocycloalkyl; wherein each of the foregoing alkyl, cycloalkyl, or heterocycloalkyl moieties is independently unsubstituted or substituted with one or more halo,
each R28 is independently (C1-10)alkyl, (C3-10)cycloalkyl,
(C3-10)cycloalkyl(C1-10)alkyl, or heterocycloalkyl, wherein each of the foregoing is independently unsubstituted or substituted with one or more halo, and
n8 is 0, 1, or 2; or
two R4 on adjacent annular carbon atoms together with the carbon atoms to which they are attached may form a carbocyclyl or heterocyclyl,
wherein the carbocyclyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, cyano, (C1-10)alkyl, (C3-10)cycloalkyl, (C3-10)cycloalkyl(C1-10)alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, -OR27, -C(O)NR27R27, -NR27C(O)R27, -NR27R27, -S(O)2NR27R27, -NR27S(O)2R27, -S(O)„eR28, and -C(O)R28,
or the heterocyclyl is unsubstituted or substituted with one or more substituents
independently selected from the group consisting of halo, cyano, (C1-10)alkyl, (C3-10)cycloalkyl, (C3-10)cycloalkyl(C1-10)alkyl, heterocycloalkyl connected by an annular carbon atom, heterocycloalkyl-alkyl, -OR27, -C(O)NR27R27, -S(O)2NR27R27, -S(O)n8R28, and -C(O)R28,
each R27 is independently hydrogen, (C1-10)alkyl, (C3-10)cycloalkyl,
(C3-10)cycloalkyl(C1-10)alkyl; or two R27, together with the nitrogen atom to which they are attached, form a heterocycloalkyl; wherein each of the foregoing alkyl, cycloalkyl, or heterocycloalkyl moieties is independently unsubstituted or substituted with one or more halo,
each R28 is independently (C1-10)alkyl, (C3-10)cycloalkyl, (C3-10)cycloalkyl(C1-10)alkyl, wherein each of the foregoing is independently unsubstituted or substituted with one or more halo, and
n8 is 0, l, or 2; R15 and R17 are independently hydrogen, halo, alkyl, or -OR29, wherein each R29 is independently hydrogen, (C1-10)alkyl, (C3-10)cycloalkyl, or (C3-10)cycloalkyl(C1-10)alkyl, and each alkyl or cycloalkyl in R15 or R17, if present, is independently unsubstituted or substituted with one or more halo;
R14 is (C1-10)alkyl, (C1-10)alkenyl, (C3-10)cycloalkyl, (C3-10)cycloalkenyl,
(C3-10)cycloalkyl(C1-10)alkyl, heterocycloalkyl connected through an annular carbon atom, heterocycloalkenyl connected through an annular carbon atom, heterocycloalkyl- alkyl, -OR5, -C(O)NR5R5, -R5C(O)NR5R5, -S(O)2NR5R5, -S(O)n1R6, or -C(O)R6;
R16 is hydrogen, fluoro, (C1-10)alkyl, (C3-10)cycloalkyl, (C3-10)cycloalkyl(C1-10)alkyl,
heterocycloalkyl connected through an annular carbon atom, heterocycloalkyl-alkyl, -OR5, -C(O)NR5R5, -R5C(O)NR5R5, -S(O)2NR5R5, -S(O)„iR6, or -C(O)R6;
the (C1-10)alkyl, (C1-10)alkenyl, (C3-10)cycloalkyl, (C3-10)cycloalkenyl,
(C3-10)cycloalkyl(C1-10)alkyl, heterocycloalkyl, heterocycloalkenyl, or heterocycloalkyl- alkyl, of R14 or R16 is independently unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of (C1-10)alkyl, halo, cyano, oxo, -OR7, -C(O)OR7, -C(O)NR7R7, -NR7C(O)R7, -NR7C(O)NR7R7, -NR7R7, -S(O)2NR7R7, -NR7S(O)2R7, -S(O)n2R13, and -C(O)R13;
each R5 is independently hydrogen, (C1-10)alkyl, or (C3-10)cycloalkyl; or two R5, together with the nitrogen atom to which they are attached, form a heterocycloalkyl; wherein each alkyl, cycloalkyl, or heterocycloalkyl is independently unsubstituted or substituted with one or more halo;
each R6 is independently (C1-10)alkyl or (C3-10)cycloalkyl, wherein each alkyl or cycloalkyl is independently unsubstituted or substituted with one or more halo;
each nl is independently 0, 1, or 2;
each R7 is independently hydrogen, unsubstituted (C1-10)alkyl, or (C1-10)alkyl substituted with one or more halo;
each n2 is independently 0, 1, or 2,
and each R13 is independently unsubstituted (C1-10)alkyl or (C1-10)alkyl substituted with one or more halo; or R14 and R15, together with the atoms to which they are attached, form a carbocyclyl or heterocyclyl,
wherein the carbocyclyl or heterocyclyl is unsubstituted or substituted with one or two substituents independently selected from the group consisting of halo, cyano, oxo, (C1-10)alkyl, (C3-10)cycloalkyl, (C3-10)cycloalkyl(C1-10)alkyl, -OR18, -C(O)NR18R18, -NR18C(O)R18, -NR,8C(O)NR,8R18, -NR18R18, -S(O)2NR,8R18, -NR18S(O)2R18, -S(O)„3R21, -C(O)OR18, and -C(O)R21,
wherein each R18 is independently hydrogen, (C1-10)alkyl, or (C3-10)cycloalkyl; or two R18, together with the nitrogen atom to which they are attached, form a heterocycloalkyl; wherein each alkyl, cycloalkyl, or heterocycloalkyl is independently unsubstituted or substituted with one or more halo, each R21 is independently (C1-10)alkyl or (C3-10)cycloalkyl, wherein each alkyl or
cycloalkyl is independently unsubstituted or substituted with one or more halo, and
each n3 is independently 0, 1, or 2.
[0045] In some embodiments, the compound of Formula (Z) is a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R1 is -C(O)OR9, -C(O)NR8R9, -S^aNR8R9, -NR10QOJNR8R9, -NR,0C(O)R9, -NR,0S(O)2R9, -OR26, -SR9, -S(O)R9, -S(O)2R9, -NR8R9, or -NR10C(O)OR9.
[0046] Thus, in some aspects, provided herein are compounds of Formula (I):
Figure imgf000031_0001
or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein: R1 is -C(O)OR9, -C(O)NR8R9, -S(O)2NR8R9, -NR10C(O)NR8R9, -NR10C(O)R9, -NR10S(O)2R9, -OR26, -SR9, -S(O)R9, -S(O)2R9, -NR8R9, or -NR10C(O)OR9,
wherein each of R8, R9, and R10 is independently selected from the group consisting of hydrogen, (C1-10)alkyl, (C3-10)cycloalkyl, (C3-10)cycloalkyl(C1-10)alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, (C6-10)aryl, (C6-10)aryl(C1-10)alkyl, heteroaryl, and heteroaryl-alkyl,
R26 is (C1-10)alkyl, (C3-10)cycloalkyl, (C3-10)cycloalkyl(C1-10)alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, (C6-10)aryl, (C6-10)aryl(C1-10)alkyl, heteroaryl, or heteroaryl-alkyl,
each (C1-10)alkyl, (C3-10)cycloalkyl, (C3-10)cycloalkyl(C1-10)alkyl, heterocycloalkyl,
heterocycloalkyl-alkyl, (C6-10)aryl, (C6-10)aryl(C1-10)alkyl, heteroaryl, and heteroaryl-alkyl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, cyano, oxo, -OR19, -C(O)NR,9R19, -NR,9C(O)R19, -NR19C(O)NR,9R19, -NR19R19, -S(O)2NR19R19, -NR,9S(O)2R19, -S(O)MR20, -C(O)OR19, and -C(O)R20, each R19 is independently hydrogen, (C1-10)alkyl, (C3-10)cycloalkyl,
(C3-10)cycloalkyl(C1-10)alkyl, or heterocycloalkyl; or two R19, together with the nitrogen atom to which they are attached, form a
heterocycloalkyl; wherein each of the foregoing alkyl, cycloalkyl, or heterocycloalkyl moieties is independently unsubstituted or substituted with one or more halo,
each R20 is independently (C1-10)alkyl, (C3-10)cycloalkyl,
(C3-10)cycloalkyl(C1-10)alkyl, or heterocycloalkyl, wherein each of the foregoing is independently unsubstituted or substituted with one or more halo, and
n4 is 0, 1, or 2;
or R8 and R9, together with the nitrogen atom to which they are attached, form a
heterocycloalkyl, wherein the heterocycloalkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of halo, cyano, oxo, (C1-10)alkyl, (C2-i0)alkenyl, (C2-i0)alkynyl, (C3-10)cycloalkyl,
(C3-10)cycloalkyl(C1-10)alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, (C6-10)aryl, (C6-10)aryl(C1.i0)alkyl, heteroaryl, heteroaryl-alkyl, -OR23, -C(O)NR23R23, -NR23C(O)R23, -NR23C(O)OR23, -NR23C(O)NR23R23, -NR23R23, -S(O)2NR23R23, -NR23S(O)2R24, -S(0>*R24, -C(O)OR23, and -C(O)R24,
wherein each R23 is independently hydrogen, (C1-10)alkyl, (C3-10)cycloalkyl,
(C3-10)cycloalkyl(C1-10)alkyl, or heterocycloalkyl; or two R23, together with the nitrogen atom to which they are attached, form a heterocycloalkyl; wherein each of the foregoing alkyl, cycloalkyl, or heterocycloalkyl moieties is independently unsubstituted or substituted with one or more halo,
each R24 is independently (C1-10)alkyl, (C3-10)cycloalkyl,
(C3-10)cycloalkyl(C1-10)alkyl, or heterocycloalkyl, wherein each of the foregoing is independently unsubstituted or substituted with one or more halo, and
n6 is 0, l, or 2;
R3 are independently selected from the group consisting of hydrogen, halo, cyano, (C1-10)alkyl, (C3-10)cycloalkyl, (C3-10)cycloalkyl(C1-10)alkyl, -OR25, -C(O)NR25R25, -NR25C(O)R25, -NR25C(O)NR25R25, -NR25R25, -S(O)2NR25R25, -NR25S(O)2R25,
-S(O)n7R30, -NR25C(O)OR25R25, -C(O)OR25, or -C(O)R30,
wherein each (C1-10)alkyl, (C3-10)cycloalkyl, and (C3-10)cycloalkyl(C1-10)alkyl is
independently unsubstituted or substituted with one or more halo,
each R25 is independently hydrogen (C1-10)alkyl, (C3-10)cycloalkyl,
(C3-10)cycloalkyl(C1-10)alkyl, or heterocycloalkyl; or two R25, together with the nitrogen atom to which they are attached, form a heterocycloalkyl; wherein each of the foregoing alkyl, cycloalkyl, or heterocycloalkyl moieties is independently unsubstituted or substituted with one or more halo, each R30 is independently (C1-10)alkyl, (C3-10)cycloalkyl, (C3-10)cycloalkyl(C1-10)alkyl, or heterocycloalkyl, wherein each of the foregoing is independently unsubstituted or substituted with one or more halo, and
n7 is 0, l, or 2;
X1, X2, X3 and X4 are independently CR4 or N, wherein X2, X3 and X4 may not all be N;
when at least one of X1, X2, X3 and X4 is N, each R4 is independently selected from the group consisting of hydrogen, halo, cyano, (C1-10)alkyl, (C3-10)cycloalkyl,
(C3-10)cycloalkyl(C1-10)alkyl, heterocycloalkyl connected by an annular carbon atom, heterocycloalkyl-alkyl, -OR27, -C(O)NR27R27, -S(O)2NR27R27, -S(O)n8R28, -C(O)OR27, and -C(O)R28,
wherein each (C1-10)alkyl, (C3-10)cycloalkyl, (C3-10)cycloalkyl(C1-10)alkyl,
heterocycloalkyl, and heterocycloalkyl-alkyl is independently
unsubstituted or substituted with one or more halo, each R27 is independently hydrogen or (C1-10)alkyl, (C3-10)cycloalkyl,
(C3-10)cycloalkyl(C1-10)alkyl, or heterocycloalkyl; or two R27, together with the nitrogen atom to which they are attached, form a
heterocycloalkyl; wherein each of the foregoing alkyl, cycloalkyl, or heterocycloalkyl moieties is independently unsubstituted or substituted with one or more halo,
each R28 is independently (C1-10)alkyl, (C3-10)cycloalkyl,
(C3-10)cycloalkyl(C1-10)alkyl, or heterocycloalkyl, wherein each of the foregoing is independently unsubstituted or substituted with one or more halo,
n8 is 0 , 1 or 2; or
when each of X1, X2, X3 and X4 is CR4, each R4 is independently selected from the group
consisting of hydrogen, halo, cyano, (C1-10)alkyl, (C3-10)cycloalkyl,
(C3-10)cycloalkyl(C1-10)alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, -OR27,
-C(O)NR27R27, -NR27C(O)R27, -NR27R27, -NR27S(O)2R27, -S(O)2NR27R27, -S(O)neR28, -C(O)OR27, and -C(O)R28, wherein each (C1-10)alkyl, (C3-10)cycloalkyl, (C3-10)cycloalkyl(C1-10)alkyl,
heterocycloalkyl, and heterocycloalkyl-alkyl is independently
unsubstituted or substituted with one or more halo, each R27 is independently hydrogen, (C1-10)alkyl, (C3-10)cycloalkyl,
(C3-10)cycloalkyl(C1-10)alkyl, or heterocycloalkyl; or two R27, together with the nitrogen atom to which they are attached, form a
heterocycloalkyl; wherein each of the foregoing alkyl, cycloalkyl, or heterocycloalkyl moieties is independently unsubstituted or substituted with one or more halo,
each R28 is independently (C1-10)alkyl, (C3-10)cycloalkyl,
(C3-10)cycloalkyl(C1-10)alkyl, or heterocycloalkyl, wherein each of the foregoing is independently unsubstituted or substituted with one or more halo, and
n8 is O, l, or 2;
two R4 on adjacent annular carbon atoms together with the carbon atoms to which they are attached may form a carbocyclyl or heterocyclyl,
wherein the carbocyclyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, cyano, (C1-10)alkyl, (C3-10)cycloalkyl, (C3-10)cycloalkyl(C1-10)alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, -OR27, -C(O)NR27R27, -NR27C(O)R27, -NR27R27, -S(O)2NR27R27, -NR27S(O)2R27, -8(O)n8R28, and -C(O)R28,
or the heterocyclyl is unsubstituted or substituted with one or more substituents
independently selected from the group consisting of halo, cyano, (C1-10)alkyl, (C3-10)cycloalkyl, (C3-10)cycloalkyl(C1-10)alkyl, heterocycloalkyl connected by an annular carbon atom, heterocycloalkyl-alkyl, -OR27, -C(O)NR27R27, -S(O)2NR27R27, -S(0>*R28, and -C(O)R28,
each R27 is independently hydrogen, (C1-10)alkyl, (C3-10)cycloalkyl,
(C3-10)cycloalkyl(C1-10)alkyl; or two R27, together with the nitrogen atom to which they are attached, form a heterocycloalkyl; wherein each of the foregoing alkyl, cycloalkyl, or heterocycloalkyl moieties is independently unsubstituted or substituted with one or more halo,
each R28 is independently (C1-10)alkyl, (C3-10)cycloalkyl, (C3-10)cycloalkyl(C1-10)alkyl, wherein each of the foregoing is independently unsubstituted or substituted with one or more halo, and
n8 is 0, l, or 2;
R15 and R17 are independently hydrogen, halo, alkyl, or -OR29, wherein each R29 is
independently hydrogen, (C1-10)alkyl, (C3-10)cycloalkyl, or (C3-10)cycloalkyl(C1-10)alkyl, and each alkyl or cycloalkyl in R15 or R17, if present, is independently unsubstituted or substituted with one or more halo;
R14 is (C1-10)alkyl, (C1-10)alkenyl, (C3-10)cycloalkyl, (C3-10)cycloalkenyl,
(C3-10)cycloalkyl(C1-10)alkyl, heterocycloalkyl connected through an annular carbon atom, heterocycloalkenyl connected through an annular carbon atom, heterocycloalkyl- alkyl, -OR5, -C(O)NR5R5, -R5C(O)NR5R5, -S(O)2NR5R5, -S(O)„iR6, or -C(O)R6;
R16 is hydrogen, fluoro, (C1-10)alkyl, (C3-10)cycloalkyl, (C3-10)cycloalkyl(C1-10)alkyl,
heterocycloalkyl connected through an annular carbon atom, heterocycloalkyl-alkyl, -OR5, -C(O)NR5R5, -R5C(O)NR5R5, -S(O)2NR5R5, -S(O)„iR6, or -C(O)R6;
the (C1-10)alkyl, (C1-10)alkenyl, (C3-10)cycloalkyl, (C3-10)cycloalkenyl,
(C3-10)cycloalkyl(C1-10)alkyl, heterocycloalkyl, heterocycloalkenyl, or heterocycloalkyl- alkyl, of R14 or R16 is independently unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of (C1-10)alkyl, halo, cyano, oxo, -OR7, -C(O)OR7, -C(O)NR7R7, -NR7C(O)R7, -NR7C(O)NR7R7, -NR7R7, -S(O)2NR7R7, -NR7S(O)2R7, -S(O)n2R13,and -C(O)R13;
each R5 is independently hydrogen, (C1-10)alkyl, or (C3-10)cycloalkyl; or two R5, together with the nitrogen atom to which they are attached, form a heterocycloalkyl; wherein each alkyl, cycloalkyl, or heterocycloalkyl is independently unsubstituted or substituted with one or more halo;
each R6 is independently (C1-10)alkyl or (C3-10)cycloalkyl, wherein each alkyl or cycloalkyl is independently unsubstituted or substituted with one or more halo; each nl is independently 0, 1, or 2;
each R7 is independently hydrogen, unsubstituted (C1-10)alkyl, or (C1-10)alkyl substituted with one or more halo;
each n2 is independently 0, 1, or 2,
and each R13 is independently unsubstituted (C1-10)alkyl or (C1-10)alkyl substituted with one or more halo;
or R14 and R15, together with the atoms to which they are attached, form a carbocyclyl or
heterocyclyl,
wherein the carbocyclyl or heterocyclyl is unsubstituted or substituted with one or two substituents independently selected from the group consisting of halo, cyano, oxo, (C1-10)alkyl, (C3-10)cycloalkyl, (C3-10)cycloalkyl(C1-10)alkyl, -OR18, -C(O)NR18R18, -NR18C(O)R18, -NR18C(O)NR18R18, -NR18R18, -S(O)2NR18R18, -NR18S(O)2R18, -S(O)n3R21, -C(O)OR18, and -C(O)R21,
wherein each R18 is independently hydrogen, (C1-10)alkyl, or (C3-10)cycloalkyl; or two R18, together with the nitrogen atom to which they are attached, form a heterocycloalkyl; wherein each alkyl, cycloalkyl, or heterocycloalkyl is independently unsubstituted or substituted with one or more halo
each R21 is independently (C1-10)alkyl or (C3-10)cycloalkyl, wherein each alkyl or
cycloalkyl is independently unsubstituted or substituted with one or more halo, and
each n3 is independently 0, 1, or 2. [0047] In some embodiments, the compound of Formula (X) is a compound of Formula (X-A):
Figure imgf000038_0001
or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, where R1, R2, R3, R14, R15, R16, R17, X1, X2, X3, and X4 are as described for Formula (X) above.
[0048] In some embodiments, the compound of Formula (Z) is a compound of Formula (Z-A):
Figure imgf000038_0002
or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, where R1, R2, R3, R14, R15, R16, R17, X1, X2, X3, and X4 are as described for Formula (Z) above.
[0049] In some embodiments, the compound of Formula (I) is a compound of Formula (I- A):
Figure imgf000038_0003
or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, where R1, R2, R3, R14, R15, R16, R17, X1, X2, X3, and X4 are as described for Formula (I) above. [0050] In some embodiments, the compound of Formula (X) or Formula (X- A) is a compound of Formula (X-Ai):
Figure imgf000039_0001
or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, where R1, R2, R3, R14, R15, R16, R17, X1, X2, X3, and X4 are as described for Formula (X) above.
[0051] In some embodiments, the compound of Formula (Z) or Formula (Z-A) is a compound of Formula (Z-Ai):
Figure imgf000039_0002
or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, where R1, R2, R3, R14, R15, R16, R17, X1, X2, X3, and X4 are as described for Formula (Z) above.
[0052] In some embodiments, the compound of Formula (I) or Formula (I- A) is a compound of Formula (I-Ai):
Figure imgf000040_0001
or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, where R1, R2, R3, R14, R15, R16, R17, X1, X2, X3, and X4 are as described for Formula (I) above.
[0053] In other embodiments, the compound of Formula (X) is a compound of Formula (X-B):
Figure imgf000040_0002
or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, where R1, R2, R3, R14, R15, R16, R17, X1, X2, X3, and X4 are as described for Formula (X) above.
[0054] In other embodiments, the compound of Formula (Z) is a compound of Formula (Z-B):
Figure imgf000040_0003
or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, where R1, R2, R3, R14, R15, R16, R17, X1, X2, X3, and X4 are as described for Formula (Z) above.
[0055] In other embodiments, the compound of Formula (I) is a compound of Formula (I-B):
Figure imgf000041_0001
or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, where R1, R2, R3, R14, R15, R16, R17, X1, X2, X3, and X4 are as described for Formula (I) above.
[0056] In certain embodiments, the compound of Formula (X) or Formula (X-B) is a compound of Formula (X-Bi):
Figure imgf000041_0002
( ),
or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, where R1, R2, R3, R14, R15, R16, R17, X1, X2, X3, and X4 are as described for Formula (X) above.
[0057] In certain embodiments, the compound of Formula (Z) or Formula (Z-B) is a compound of Formula (Z-Bi):
Figure imgf000042_0001
or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, where R1, R2, R3, R14, R15, R16, R17, X1, X2, X3, and X4 are as described for Formula (Z) above.
[0058] In certain embodiments, the compound of Formula (I) or Formula (I-B) is a compound of Formula (I-Bi):
Figure imgf000042_0002
or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, where R1, R2, R3, R14, R15, R16, R17, X1, X2, X3, and X4 are as described for Formula (I) above.
[0059] Thus, in some embodiments, the compound of Formula (Z-A), (Z-B), (Z-Ai), or (Z-Bi) is a compound of Formula (I- A), (I-B), (I-Ai), or (I-Bi), respectively, wherein R1 is -C(O)OR9, -C(O)NR8R9, -S(O)2NR8R9, -NR10C(O)NR8R9, -NR10C(O)R9, -NR10S(O)2R9, -OR26, -SR9, -S(O)R9, -S(O)2R9, -NR8R9, or -NR10C(O)OR9.
[0060] "Alkyl", as used herein, refers to an unbranched or branched saturated hydrocarbon chain. Alkyl can be used alone, or as part of another radical, such as cycloalkyl-alkyl. In some embodiments, alkyl as used herein has 1 to SO carbon atoms ((C1-50)alkyl), 1 to 20 carbon atoms ((C1-20)alkyl), 1 to 12 carbon atoms ((C1-12)alkyl), 1 to 10 carbon atoms ((C1-10)alkyl), 1 to 8 carbon atoms ((C1-8)alkyl), 1 to 6 carbon atoms ((C1-6)alkyl), or 1 to 4 carbon atoms ((C1-4)alkyl). Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methyl pentyl. When an alkyl residue having a specific number of carbons is named, all geometric isomers having that number of carbons may be encompassed. Thus, for example, "butyl" can include n-butyl, sec- butyl, isobutyl and t-butyl, and "propyl" can include n-propyl and isopropyl.
[0061] "Haloalkyl", as used herein, refers to an alkyl group substituted with one or more independently selected halo groups (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more).
[0062] " Alkenyl", as used herein, refers to an unbranched or branched hydrocarbon chain containing at least one carbon-carbon double bond. Alkenyl can be used alone, or as part of another radical, such as cycloalkyl-alkenyl. In some embodiments, alkenyl as used herein has 1 to 50 carbon atoms ((C1-50)alkenyl), 1 to 20 carbon atoms ((C1-20)alkenyl), 1 to 12 carbon atoms ((C1-12)alkenyl), 1 to 10 carbon atoms ((C1-10)alkenyl), 1 to 8 carbon atoms ((C1-8)alkenyl), 1 to 6 carbon atoms ((C1-6)alkenyl), or 1 to 4 carbon atoms ((C1-4)alkenyl). Alkenyl may have one, two, three, four, five, or more carbon-carbon double bonds, as valency permits. When an alkenyl residue having a specific number of carbons is named, all geometric isomers having that number of carbons may be encompassed.
[0063] "Cycloalkyl", as used herein, refers to a monocyclic or polycyclic saturated
hydrocarbon. In some embodiments, cycloalkyl has 3 to 50 carbon atoms ((C3-50)cycloalkyl), 3 to 20 carbon atoms ((C3-20)cycloalkyl), 3 to 12 carbon atoms ((C3-12)cycloalkyl), 3 to 10 carbon atoms ((C3-10)cycloalkyl), 3 to 8 carbon atoms ((C3^)cycloalkyl), 3 to 6 carbon atoms ((C3- 6)cycloalkyl), or 3 to 5 carbon atoms ((C3-4)cycloalkyl). Cycloalkyl includes monocyclic and polycyclic groups, such as fused bicycles and spirocycles. In some embodiments, polycyclic groups include fused bicycles, bridged cyclic groups, and spirocycles. Examples of cycloalkyl groups include cyclopropyl, cycloburyl, cyclopentyl, cyclohexyl, octahydropentalenyl, octahydro-lH-indene, decahydronaphthalene, cubane, bicyclo[3.1.0]hexane, and
bicyclo[ 1.1.1 ]pentane.
[0064] "Halocycloalkyl", as used herein, refers to a cycloalkyl group substituted with one or more independently selected halo groups (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more). [0065] "Cycloalkenyl", as used herein, refers to a non-aromatic monocyclic or polycyclic hydrocarbon containing at least one carbon-carbon double bond. In some embodiments, cycloalkenyl has 3 to 50 carbon atoms ((C3-50)cycloalkenyl), 3 to 20 carbon atoms ((C3- 20)cycloalkenyl), 3 to 12 carbon atoms ((C3-12)cycloalkenyl), 3 to 10 carbon atoms ((C3- 10)cycloalkenyl), 3 to 8 carbon atoms ((C3-8)cycloalkenyl), 3 to 6 carbon atoms ((C3- 6)cycloalkenyl), or 3 to 5 carbon atoms ((C3-4)cycloalkenyl). Cycloalkenyl includes monocyclic and polycyclic groups (including fused, bridged, and spirocycles), and may have one, two, three, four, five, or more carbon-carbon double bonds, as valency permits.
[0066] "Cycloalkyl-alkyl" refers to a cycloalkyl group (as defined above) connected to an alkyl group (as defined above), wherein the alkyl group is attached to another moiety (such as the core structure of the molecule). Substituted cycloalkyl-alkyl can include one or more additional attachments to substituents at any point of the cycloalkyl or alkyl, as valency permits. The cycloalkyl-alkyl may comprise any combination of cycloalkyl and alkyl groups. In some embodiments, the cycloalkyl has 3 to 50 carbon atoms ((C3-50)cycloalkyl-alkyl), 3 to 20 carbon atoms ((C3-20)cycloalkyl-alkyl), 3 to 12 carbon atoms ((C3-12)cycloalkyl-alkyl), 3 to 10 carbon atoms ((C3-10)cycloalkyl-alkyl), 3 to 8 carbon atoms ((C3-8)cycloalkyl-alkyl), 3 to 6 carbon atoms ((C3-6)cycloalkyl-alkyl), or 3 to 5 carbon atoms ((C3-4)cycloalkyl-alkyl). In some embodiments, the alkyl has 1 to 50 carbon atoms (cycloalkyl- (C1-50)alkyl), 1 to 20 carbon atoms (cycloalkyl- (C1-20)alkyl), 1 to 12 carbon atoms (cycloalkyl-(C1-12)alkyl), 1 to 10 carbon atoms (cycloalkyl- (C1-10)alkyl), 1 to 8 carbon atoms (cycloalkyl-(C1-8)alkyl), 1 to 6 carbon atoms (cycloalkyl-(C1- e)alkyl), or 1 to 4 carbon atoms (cycloalkyl-(C1-4)alkyl). In certain embodiments, the cycloalkyl- alkyl is a (C3-20)cycloalkyl(C1-20)alkyl, (C3-12)cycloalkyl(C1-12)alkyl, (C3-10)cycloalkyl(C1-10)alkyl, (C3-10)cycloalkyl(C3-8)alkyl, (C3-10)cycloalkyl(Cw)alkyl, (C3-6)cycloalkyl(C3-8)alkyl, (C3- 6)cycloalkyl(C3-6)alkyl, or (C3-6)cycloalkyl(C1-4)alkyl.
[0067] "Carbocyclyl" refers to a monocyclic or polycyclic saturated or unsaturated
hydrocarbon. Carbocyclyl includes cycloalkyl, aryl, and non-aromatic unsaturated carbocyclic groups such as cycloalkenyl. In some embodiments, carbocyclyl has 3 to 50 carbon atoms ((C3- 50)carbocyclyl), 3 to 20 carbon atoms ((C3-20)carbocyclyl), 3 to 12 carbon atoms ((C3- 12)carbocyclyl), 3 to 10 carbon atoms ((C1-10)carbocyclyl), 3 to 8 carbon atoms ((C3- 8)carbocyclyl), 3 to 6 carbon atoms ((C3-6)carbocyclyl), or 3 to 5 carbon atoms ((C3- 4)carbocyclyl).
[0068] "Heterocycloalkyl", as used herein, refers to a saturated monocyclic or polycyclic ring containing carbon and at least one heteroatom selected from the group consisting of O, N, and S. The heterocycloalkyl group may comprise 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or more ring atoms (e.g., be a 3-membered, 4-membered, 5-membered, 6-membered, 7-membered, 8-membered, 9- membered, 10-membered, 11-membered, or 12-membered heterocycloalkyl). The ring atoms may be, for example, atoms of a single ring or atoms of two or more fused rings, a bridged ring, or a spirocycle. Heterocycloalkyl may include groups comprising 1 to 5 ring heteroatoms, 1 to 4 heteroatoms, 1 to 3 ring heteroatoms, 1 or 2 ring heteroatoms, or 1 ring heteroatom, wherein each heteroatom is independently selected from the group consisting of N, O, and S. Each ring S atom, where present, may independently be unoxidized sulfur (e.g., -S-) or a sulfur oxide, such as -S(O)-, or
-S(O)2-. In certain examples, a heterocycloalkyl has 2 to 8 ring carbon atoms and with 1 to 3 ring heteroatoms independently selected from N, O, and S. Heterocycloalkyl may include, for example, saturated bridged cyclic structures comprising at least one ring heteroatom (for example, one ring with one heteroatom and a hydrocarbon bridge), and saturated spirocycles comprising at least one ring heteroatom (for example, a two-ring spirocycle with one
hydrocarbon ring and one ring comprising one heteroatom). In some embodiments,
heterocycloalkyl is connected through an annular carbon atom, wherein the point of attachment of the heterocycloalkyl to another group is a ring carbon atom of the heterocycloalkyl. Examples of heterocycloalkyl include, but are not limited to, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, thiazolinyl, thiazolidinyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxinyl, piperidinyl, morpholinyl, thiomorpholinyl,
thiomorpholinyl S-oxide, thiomorpholinyl S-dioxide, piperazinyl, azepinyl, oxepinyl, diazepinyl, and tropanyl.
[0069] "Haloheterocycloalkyl", as used herein, refers to a heterocycloalkyl group substituted with one or more independently selected halo groups (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more). [0070] "Heterocycloalkenyl", as used herein, refers to a non-aromatic monocyclic or polycyclic ring containing carbon, at least one heteroatom selected from the group consisting of O, N, and S, and at least one double bond. Each ring S atom, where present, may independently be a sulfur oxide, such as -S(O)-, or -S(O)2-. The heterocycloalkenyl group may comprise 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or more ring atoms (e.g., be a 3-membered, 4-membered, 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, 10- member ed, 11 -membered, or 12- membered heterocycloalkenyl). Heterocycloalkenyl may include groups comprising 1 to 5 ring heteroatoms, 1 to 4 heteroatoms, 1 to 3 ring heteroatoms, 1 or 2 ring heteroatoms, or 1 ring heteroatom, wherein each heteroatom is independently selected from the group consisting of N, O, and S. In certain examples, a heterocycloalkenyl has 2 to 8 ring carbon atoms and with 1 to 3 ring heteroatoms independently selected from N, O, and S. In some embodiments,
heterocycloalkenyl is connected through an annular carbon atom, wherein the point of attachment of the heterocycloalkenyl to another group is a ring carbon atom of the
heterocycloalkenyl. Heterocycloalkenyl may have one, two, three, four, five, or more double bonds, as valency permits, and each double bond independently may be between two ring carbon atoms, two ring heteroatoms, or one ring carbon atom and one ring heteroatom, as valency permits.
[0071] "Heterocyclyl" refers to a saturated or unsaturated monocyclic or polycyclic ring containing carbon and at least one heteroatom selected from the group consisting of O, N, and S. Each ring S atom, where present, may independently be a sulfur oxide, such as -S(O)-, or -S(O)2-. Heterocyclyl includes heterocycloalkyl, heteroaryl, and non-aromatic unsaturated heterocyclic groups such as heterocycloalkenyl. The heterocyclyl group may comprise 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or more ring atoms (e.g., be a 3-membered, 4-membered, 5-membered, 6- membered, 7-membered, 8-membered, 9-membered, 10-membered, 11 -membered, or 12- membered heterocyclyl), and may include groups comprising 1 to 5 ring heteroatoms, 1 to 4 heteroatoms, 1 to 3 ring heteroatoms, 1 or 2 ring heteroatoms, or 1 ring heteroatom, wherein each heteroatom is independently selected from the group consisting of N, O, and S. In some embodiments, heterocyclyl is connected through an annular carbon atom, wherein the point of attachment of the heterocyclyl to another group is a ring carbon atom of the heterocyclyl. [0072] "Heterocycloalkyl-alkyl" refers to a heterocycloalkyl group (as defined above) connected to an alkyl group (as defined above), wherein the alkyl group is attached to another moiety (such as the core structure of the molecule). The alkyl group may be attached to the heterocycloalkyl through an annular carbon atom of the heterocycloalkyl, or through an annular heteroatom of the heterocycloalkyl (such as through a ring N atom). Substituted
heterocycloalkyl-alkyl can include one or more additional attachments to substituents at any point of the heterocycloalkyl or alkyl, as valency permits. The heterocycloalkyl-alkyl may comprise any combination of heterocycloalkyl and alkyl groups. In some embodiments, the heterocycloalkyl comprises 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or more ring atoms. The
heterocycloalkyl may include groups comprising 1 to 5 ring heteroatoms, 1 to 4 heteroatoms, 1 to 3 ring heteroatoms, 1 or 2 ring heteroatoms, or 1 ring heteroatom, wherein each heteroatom is independently selected from the group consisting of N, O, and S. In some embodiments, the alkyl has 1 to 50 carbon atoms (heterocycloalkyl-(C1-50)alkyl), 1 to 20 carbon atoms
(heterocycloalkyl-(C1-20)alkyl), 1 to 12 carbon atoms (heterocycloalkyl-(C1-12)alkyl), 1 to 10 carbon atoms (heterocycloalkyl-(C1-10)alkyl), 1 to 8 carbon atoms (heterocycloalkyl-(C1-8)alkyl), 1 to 6 carbon atoms (heterocycloalkyl-(C1-6)alkyl), or 1 to 4 carbon atoms (heterocycloalkyl-(C1- 4)alkyl). In certain embodiments, the heterocycloalkyl-alkyl is a (3-20
membered)heterocycloalkyl(C1-20)alkyl, (3-12 membered)heterocycloalkyl(C1-12)alkyl, (3-12 membered)heterocycloalkyl(C1-10)alkyl, (3-10 membered)heterocycloalkyl(C1-8)alkyl, (3-10 membered)heterocycloalkyl(C1-6)alkyl, (3-6 membered)heterocycloalkyl(C1-8)alkyl, (3-6 membered)heterocycloalkyl(C1-6)alkyl, or (3-6 membered)heterocycloalkyl(C1-4)alkyl.
[0073] "Aryl", as used herein, refers to a monocyclic or polycyclic radical comprising at least one aromatic hydrocarbon ring. Aryl may include an aromatic hydrocarbon monocyclic or polycyclic radical. Aryl may include groups with a single aromatic ring (e.g., phenyl) and multiple fused aromatic rings (e.g., naphthyl, anthryl). Aryl may also include, for example, a single aromatic hydrocarbon ring fused to a non-aromatic hydrocarbon ring (e.g., 1,2,3,4- tetrahydronaphthalene), or a single aromatic hydrocarbon fused to a non-aromatic ring comprising at least one heteroatom (e.g., 1,2,3,4-tetrahydroisoquinoline). In some embodiments, aryl as used herein has from 6 to 14 annular carbon atoms ((Ce-1- aryl), or 6 to 10 annular carbon atoms ((C6-10)aryl). [0074] "Aryl-alkyl" refers to an aryl group (as defined above) connected to an alkyl group (as defined above), wherein the alkyl group is attached to another moiety (such as the core structure of the molecule). Substituted aryl-alkyl can include one or more additional attachments to substituents at any point of the aryl or alkyl, as valency permits. The aryl-alkyl may comprise any combination of aryl and alkyl groups. In some embodiments, the aryl has from 6 to 14 annular carbon atoms ((C6-14)aryl-alkyl), or 6 to 10 annular carbon atoms ((C6-10)aryl-alkyl). In some embodiments, the alkyl has 1 to 50 carbon atoms (aryl-(C1-50)alkyl), 1 to 20 carbon atoms (aryl-(C1-20)alkyl), 1 to 12 carbon atoms (aryl-(C1-12)alkyl), 1 to 10 carbon atoms (aryl-(C1- i0)alkyl), 1 to 8 carbon atoms (aryl-(C1-8)alkyl), 1 to 6 carbon atoms (aryl-(C1-6)alkyl), or 1 to 4 carbon atoms (aryl-(C1-4)alkyl). In certain embodiments, the aryl-alkyl is a (C6-14)aryl(C1- 20)alkyl, (C6-14)aryl(C1-12)alkyl, (C6-14)aryl(C1-10)alkyl, (C6-14)aryl(C1-8)alkyl, (C6-14)aryl(C1- 6)alkyl, (C6-10)aryl(C1-10)alkyl, (C6-10)aryl(C1-8)alkyl, (C6-10)aryl(C1-6)alkyl, or (C6-10)aryl(C1- 4)alkyl.
[0075] "Heteroaryl", as used herein, refers to a monocyclic or polycyclic radical comprising at least one aromatic ring, wherein the aromatic ring comprises at least one ring heteroatom independently selected from the group consisting of N, O, and S, (e.g., pyridine, pyrazine, furan, thiophene, quinoline). Each ring S atom, where present, may independently be unoxidized sulfur
(e.g., -S-) or a sulfur oxide, such as -S(O)-, or -S(O)2-. Heteroaryl includes polycyclic systems comprising two or more aromatic rings, wherein at least one aromatic ring comprises at least one ring heteroatom selected from N, O, and S. Heteroaryl may include groups comprising 1 to 5 ring heteroatoms, 1 to 4 heteroatoms, 1 to 3 ring heteroatoms, 1 or 2 ring heteroatoms, or 1 ring heteroatom, wherein each heteroatom is independently selected from the group consisting of N,
O, and S. In certain examples, a heteroaryl has 3 to 8 ring carbon atoms, with 1 to 3 ring heteroatoms independently selected from N, O, and S. Heteroaryl may comprise 5, 6, 7, 8, 9, 10,
11, 12, or more annular atoms (e.g., be a 3-membered, 4-membered, 5-membered, 6-membered,
7-membered, 8-membered, 9-membered, 10-membered, 11 -membered, or 12-membered heteroaryl), wherein the annular atoms are present in one or more rings. Heteroaryl may comprise, for example, 1 to 14 annular carbon atoms ((C1-14)heteroaryl), 1 to 10 annular carbon atoms ((C1-10)heteroaryl), 1 to 6 annular carbon atoms ((C1-6)heteroaryl), 1 to 5 annular carbon atoms ((C1-5)heteroaryl), or 2 to 5 annular carbon atoms ((C2-5)heteroaryl). In some
embodiments, heteroaryl is connected through an annular carbon atom, wherein the point of attachment of the heteroaryl to another group is a ring carbon atom of the heteroaryl. Examples of heteroaryl groups include pyridyl, pyridazinyl, pyrimidinyl, benzothiazolyl, furanyl, and pyrazolyl.
[0076] "Heteroaryl-alkyl" refers to a heteroaryl group (as defined above) connected to an alkyl group (as defined above), wherein the alkyl group is attached to another moiety (such as the core structure of the molecule). Substituted heteroaryl-alkyl can include one or more additional attachments to substituents at any point of the heteroaryl or alkyl, as valency permits. The alkyl group may be attached to the heteroaryl through an annular carbon atom of the heteroaryl, or through an annular heteroatom of the heteroaryl. The heteroaryl-alkyl may comprise any combination of heteroaryl and alkyl groups. The heteroaryl may have 3 to 8 ring carbon atoms, with 1 to 3 ring heteroatoms independently selected from N, O, and S. Heteroaryl may comprise 5, 6, 7, 8, 9, 10, 11, 12, or more annular atoms (e.g., be a 3-membered, 4-membered, 5- membered, 6-membered, 7-membered, 8-membered, 9-membered, 10-membered, 11-membered, or 12-membered heteroaryl), wherein the annular atoms are present in one or more rings. In some embodiments, the alkyl has 1 to 50 carbon atoms (heteroaryl-(C1-50)alkyl), 1 to 20 carbon atoms (heteroaryl-(C1-20)alkyl), 1 to 12 carbon atoms (heteroaryl-(C1-12)alkyl), 1 to 10 carbon atoms (heteroaryl-(C1-10)alkyl), 1 to 8 carbon atoms (heteroaryl-(C1-8)alkyl), 1 to 6 carbon atoms (heteroaryl-(C1-6)alkyl), or 1 to 4 carbon atoms (heteroaryl-(C1-4)alkyl). In certain embodiments, the heteroaryl-alkyl is a (C1-14)heteroaryl(C1-20)alkyl, (C1-10)heteroaryl(C1-12)alkyl, (C1- 6)heteroaryl(C1-10)alkyl, (C1-5)heteroaryl(C1-8)alkyl, (C1-s)heteroaryl(C1-6)alkyl, (C1-5)heteroaryl (C1-8)alkyl, (C1-5)heteroaryliC3-6)alkyl, or (C1-5)heteroaryl(C1-4)alkyl.
[0077] It should be understood that when a range of values is listed, it is intended to encompass each value and sub-range within the range. For example, "(C1-6)alkyl" (which may also be referred to as C1-C6 alkyl, C1-6 alkyl, or Cl-6 alkyl) is intended to encompassC1 , C2, C3, C4, C5, C6, C1-6, C1-5, C1-4, C1-3, C1-2, C2-6, C2-5, C2-4, C2-3, C3-6, C3-5, C3-4, C«, C4-5, and C5-6 alkyl.
[0078] "Hydroxy", as used herein, refers to the radical -OH.
[0079] "Halo", as used herein, refers to fluoro, chloro, bromo, or iodo radicals. [0080] "Cyano" means the radical -CN.
[0081] "Oxo", as used herein, refers to the radical =0.
[0082] "Optional" or "optionally" means that the subsequently described event or
circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not.
[0083] In some embodiments of the compound of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-Ai), (Z-B), (Z-Bi), (I), (I-A), (I-Ai), (I-B), or (I-Bi), is a solvate. In some embodiments, the solvate is a hydrate.
[0084] In some embodiments, provided is a pharmaceutically acceptable salt of a compound of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-Ai), (Z-B), (Z-Bi), (I), (I-A), (I-Ai), (I-B), or (I-Bi).
[0085] "Pharmaceutically acceptable" includes that which is useful in preparing a
pharmaceutical composition that is generally safe, non-toxic and not biologically or otherwise undesirable, and includes that which is acceptable for veterinary use as well as human pharmaceutical use. For example, provided herein is a pharmaceutical composition comprising a compound of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-Ai), (Z-B), (Z-Bi), (I), (I-A), (I-Ai), (I-B), or (I-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, and a pharmaceutically acceptable excipient
[0086] "Pharmaceutically acceptable salt" includes a salt which is generally safe, non-toxic and not biologically or otherwise undesirable, and includes that which is acceptable for veterinary use as well as human pharmaceutical use. Such salts may include acid addition salts and base addition salts. Acid addition salts may be formed with inorganic acid such as, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like; or an organic acid such as, but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4- acetamidobenzoic acid, camphoric acid, camphor- 10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane- 1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucic acid, naphthalene- 1,5-disulfonic acid, naphthalene-2-sulfonic acid, l-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid, or undecylenic acid. Salts derived from inorganic bases may include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. Salts derived from organic bases may include, but are not limited to, salts of primary, secondary, or tertiary amines;
substituted amines including naturally occurring substituted amines; cyclic amines; ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, deanol, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, benethamine, benzathine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purines, piperazine, piperidine, or N-ethylpiperidine.
[0087] In some embodiments, provided is an isotope of a compound of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-Ai), (Z-B), (Z-Bi), (I), (I-A), (I-Ai), (I-B), or (I-Bi).
[0088] Unless otherwise stated, structures depicted herein, such as compounds of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-B), (Z-Ai), (Z-Bi), (I), (I-A), (I- ), (I-Ai), or (I-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, or isomer thereof, are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. The compounds herein may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. In some embodiments, the compound is isotopically- labeled, such as an isotopically-labeled compound of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-B), (Z-Ai), (Z-Bi), (I), (I-A), (I-B), (I-Ai), or (I-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, or isomer thereof, where a fraction of one or more atoms are replaced by an isotope of the same element Exemplary isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, chlorine, such as 2H 3H nC, 13C, 14C 13N, 150, 170, 35S, 18F, 36C1. Certain isotope labeled compounds (e.g. 3H and 14C) may be useful in compound or substrate tissue distribution study. Incorporation of heavier isotopes such as deuterium (2H) may, in some embodiments, afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life, or reduced dosage requirements.
[0089] The compounds disclosed herein, such as compounds of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-Ai), (Z-B), (Z-Bi), (I), (I-A), (I-B), (I-Ai), or (I-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, or isotope thereof, may contain one or more asymmetric centers and thus may give rise to one or more isomers.
[0090] In some embodiments, provided is a tautomer of a compound of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-Ai), (Z-B), (Z-Bi), (I), (I-A), (I-Ai), (I-B), or (I-Bi).
[0091] In some embodiments of the compound of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-Ai), (Z-B), (Z-Bi), (I), (I-A), (I-Ai), (I-B), or (I-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, each of R8, R9, and R10 is independently selected from the group consisting of hydrogen, (C1-10)alkyl, (C3-10)cycloalkyl, (C3-10)cycloalkyl(C1-10)alkyl, heterocycloalkyl, and heterocycloalkyl-alkyl, or R8 and R9, together with the nitrogen atom to which they are attached, form a heterocycloalkyl. Each (C1-10)alkyl, (C3-10)cycloalkyl, (C3-10)cycloalkyl(C1-10)alkyl, heterocycloalkyl (including a heterocycloalkyl formed by R8 and R9) and heterocycloalkyl-alkyl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, cyano, oxo, -OR19, -C(O)NR19R19, -NR19C(O)R19, -NR19C(O)NR19R19, -NR19R19, -S(O)2NR19R19, -NR19S(O)2R19, -S(O),^20, -C(O)OR19, and -C(O)R20. In certain embodiments, the one or more substituents are independently selected from the group consisting of halo, -OH, -0(C1- i0)alkyl, -NR19R19, and -C(O)NR19R19. In some embodiments, the halo is fluoro. In certain embodiments, each R19 is independently H or (C1-10)alkyl, or two R19, together with the nitrogen to which they are attached, form a heterocycloalkyl. In certain embodiments, the
heterocycloalkyl is a 5-6 member ed heterocycloalkyl comprising 1 to 4 heteroatoms
independently selected from N, O, and S. In certain embodiments, the heterocycloalkyl of the heterocycloalkyl-alkyl is a 5-6 membered heterocycloalkyl comprising 1 to 4 heteroatoms independently selected from N, O, and S. In other embodiments, R8 and R9, together with the nitrogen atom to which they are attached, form a 5-6 membered heterocycloalkyl comprising 1 to 4 heteroatoms independently selected from N, O, and S. In certain embodiments, each of R8, R9, and R10 is independently selected from the group consisting of hydrogen, (C1-10)alkyl,
(C3-6)cycloalkyl, (C3-6)cycloalkyl(C1-10)alkyl, (5-6 membered) heterocycloalkyl, and (5-6 membered) heterocycloalkyl-(C1-10)alkyl, or R8 and R9, together with the nitrogen atom to which they are attached, form a 5-6 membered heterocycloalkyl comprising 1 to 4 heteroatoms independently selected from N, O, and S.
[0092] In some embodiments of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z- Ai), (Z-B), (Z-Bi), (I), (I- A), (I-Ai), (I-B), or (I-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, each R23 is independently hydrogen or (C1-10)alkyl, such as (C1-8)alkyl, (C1-6)alkyl, or (C1-4)alkyl. In other embodiments, each R24 is independently (C1-10)alkyl, such as (C1-8)alkyl, (C1-6)alkyl, or (C1-4)alkyl. In other embodiments, each R25 is independently hydrogen or (C1-10)alkyl, such as (C1-8)alkyl, (C1-6)alkyl, or (C1-4)alkyl. In further embodiments, each R30 is independently (C1-10)alkyl, such as (C1-8)alkyl, (C1-8)alkyl, or (C1- 4)alkyl. In certain embodiments, each R27 is independently hydrogen or (C1-10)alkyl, such as (C1- 8)alkyl, (C1-6)alkyl, or (C1-4)alkyl. In other embodiments, each R28 is independently (C1-10)alkyl, such as (C1-8)alkyl, (C1-6)alkyl, or (C1-4)alkyl. In some embodiments, each R29 is independently hydrogen or (C1-10)alkyl, such as (C1-8)alkyl, (C1-6)alkyl, or (C1-4)alkyl. In other embodiments, each R5 is independently hydrogen or (C1-10)alkyl, such as (C1-8)alkyl, (C1-8)alkyl, or (C1-4)alkyl. In still further embodiments, each R6 is independently (C1-10)alkyl, such as (C1-8)alkyl, (C1- e)alkyl, or (C1-»)alkyl. In other embodiments, each R7 is independently hydrogen or (C1-10)alkyl, such as (C1-8)alkyl, (C1-6)alkyl, or (C1-4)alkyl. In certain embodiments, any of the foregoing alkyl are independently unsubstituted or substituted with one or more halo. For example, in some embodiments any of the foregoing alkyl are independently unsubstituted or substituted with one, two, or three halo. In some embodiments, the halo is independently fluoro or chloro.
[0093] In some embodiments of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z- Ai), (Z-B), or (Z-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, R1 is -C(O)OR9, -C(O)NR8R9, -S(O)2NR8R9, -NR10C(O)NR8R9, -NR10C(O)R9,
-NR10S(O)2R9, -OR26, -SR9, -S(O)R9, -S(O)2R9, -NR8R9, -NR10C(O)OR9, -C(O)R26, -NR10S(O)2NR8R9, or -C(O)NR10S(O)2R9. In some embodiments, R1 is -C(O)R26, -NR10S(O)2NR8R9, or -C(O)NR10S(O)2R9.
[0094] In some embodiments of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z- Ai), (Z-B), or (Z-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, R1 is -NR10S(O)2NR8R9. In some embodiments, R10 is hydrogen. In certain
embodiments, R8 and R9 are independently hydrogen or (C1-10)alkyl. In some embodiments, R8 is hydrogen and R9 is (C1-10)alkyl, for example isopropyl. In other embodiments, R1 is
-C(O)NR,0S(O)2R9. In certain embodiments, R10 is hydrogen. In certain embodiments, R9 is hydrogen, (C1-10)alkyl, or (C3-10)cycloalkyl. In some embodiments, R10 is hydrogen and R9 is (C3-10)cycloalkyl, for example cyclopropyl. In still other embodiments, R1 is -C(O)R26. In certain of these embodiments, R26 is (C1-10)alkyl or (C3-10)cycloalkyl, wherein the alkyl or cycloalkyl is unsubstituted or substituted as described in Formula (X). In certain embodiments, R1 is -C(O)R26, wherein R26 is (C3-10)cycloalkyl, such as cyclohexyl.
[0095] Thus, in some embodiments, R1 is:
Figure imgf000054_0001
[0096] In some embodiments of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z- Ai), (Z-B), (Z-Bi), (I), (I- A), (I-Ai), (I-B), or (I-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, R1 is -C(O)NR8R9, -S(O)2NR8R9,
-NR10C(O)NR8R9, -NR10C(O)R9, -NR,0C(O)OR9, or -NR,0S(O)2R9. In some embodiments, R1 is -NR10C(O)NR8R9. In other embodiments, R1 is -NR,0C(O)OR9. In still further embodiments, R1 is -NR10S(O)2R9. In any of these embodiments, R10 may be H. Thus, in some embodiments, R1 is -NHC(O)NR8R9, -NHC(O)R9, -NHC(O)OR9, or -NHS(O)2R9.
[0097] In certain embodiments of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z- Ai), (Z-B), (Z-Bi), (I), (I- A), (I-Ai), (I-B), or (I-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, R8 and R9, together with the nitrogen atom to which they are attached, form an unsubstituted or substituted heterocycloalkyl. In certain embodiments, the heterocycloalkyl is a 5-membered or 6-membered ring. In particular embodiments, R8 and R9, together with the nitrogen atom to which they are attached form an unsubstituted or substituted piperidinyl. In some of these embodiments, R1 is -C(O)NR8R9, -SiO^NR8R9, or -NR,0C(O)NR8R9.
[0098] In certain embodiments of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-
Ai), (Z-B), (Z-Bi), (I), (I- A), (I-Ai), (I-B), or (I-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, R1 is -0(O)>¾¾9, and R8 and R9, together with the nitrogen atom to which they are attached, form an unsubstituted or substituted heterocycloalkyl.
In some embodiments, the heterocycloalkyl is a 4-membered to 8-membered heterocycloalkyl, which is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, oxo, -OR23, (C1-10)alkyl, -NR23C(O)OR23, -NR23R23, -C(O)OR23, and
-C(O)NR23R23. For example, in some embodiments the heterocycloalkyl is a substituted or unsubstituted ring, spirocycle, or bridged ring. In some embodiments, the heterocycloalkyl comprises, in addition to the nitrogen atom to which R8 and R9 are both connected, one or two additional heteroatoms selected from the group consisting of O, N, and S. In some
embodiments, the heterocycloalkyl is a 5-membered or 6-membered ring, which is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, -OR23,
(C1-10)alkyl, -NR23C(O)OR23, -NR23R23, -C(O)OR23, and -C(O)NR23R23. In some embodiments, the halo is fluoro. In certain embodiments, each (C1-10)alkyl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo and -OR31. In some embodiments, each R31 is independently hydrogen or alkyl. In some embodiments, the (C1-10)alkyl is substituted with -OH. In certain embodiments, each R23 is independently H or (C1-10)alkyl, or two R23, together with the nitrogen atom to which they are attached, form a heterocycloalkyl group. In some embodiments, R8 and R9, together with the nitrogen atom to which they are attached form an unsubstituted or substituted piperidinyl. In certain embodiments, the piperidinyl is unsubstituted. In other embodiments, the piperidinyl is substituted with one or more substituents independently selected from the group consisting of -
OR23, (C1-10)alkyl, -C(O)OR23, and -NR23C(O)OR23. For example, the piperidinyl may be substituted with one or two substituents independently selected from the group consisting of -
OR23, (C1-10)alkyl, and -NR23C(O)OR23. In some embodiments, R23 is independently H or
(C1-10)alkyl, such as (C1-8)alkyl, (C1-6)alkyl, or (C1-*)alkyl. In certain embodiments, the piperidinyl is substituted with one or two substituents independently selected from the group consisting of -0(C1-10)alkyl, -OH, (C1-10)alkyl, -C(O)OH, and -NHC(O)0(C1-10)alkyl. In some embodiments, the piperidinyl is substituted with one or two substituents independently selected from the group consisting of -OH, methyl, ethyl, propyl, butyl, -C(O)OH, and -NHC(O)0-tert- butyl. In some embodiments, the piperidinyl is substituted with one -OH. In still further embodiments, R8 and R9, together with the nitrogen atom to which they are attached form a 4-, 5- , 6-, 7-, or 8-membered heterocycloalkyl comprising one nitrogen ring atom, wherein the heterocycloalkyl is unsubstituted or substituted. In some embodiments, the heterocycloalkyl is substituted with one or more substituents (such as one to five) independently selected from the group consisting of halo, oxo, -OR23, (C1-10)alkyl, -C(O)OR23, and -NR23C(O)OR23. In some embodiments, each halo is fluoro. In some embodiments, each (C1-10)alkyl is independently unsubstituted or substituted with one or more -OH. In some embodiments the heterocycloalkyl is substituted with one or more substituents (such as one to five) independently selected from the group consisting of fluoro, -OH, and (C1-10)alkyl, wherein each (C1-10)alkyl is independently unsubstituted or substituted with one or more -OH. In still further embodiments, each
(C1-10)alkyl is independently methyl, ethyl, propyl, or butyl, each of which is independently unsubstituted or substituted with one or two -OH.
[0099] Thus, for example, R1 may be:
Figure imgf000056_0001
Figure imgf000057_0001
[0100] In other embodiments of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z- Ai), (Z-B), (Z-Bi), (I), (I- A), (I-Ai), (I-B), or (I-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, R1 is -C(O)NR8R9, and R8 and R9 are both hydrogen. In still further embodiments, R8 is hydrogen, and R9 is (C1-10)alkyl, wherein the alkyl is unsubstituted or substituted. For example, in some embodiments the alkyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, cyano, oxo, -OR19, -NR,9R19, -S(O)n4R20, -C(O)OR19, and -C(O)R20. In some
embodiments, the alkyl is unsubstituted or substituted with one or more substituents selected from the group consisting of -OH, -NH, and -C(O)OH. Thus, in certain embodiments, R1 is:
Figure imgf000058_0001
[0101] In certain embodiments of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z- Ai), (Z-B), (Z-Bi), (I), (I-A), (I-Ai), (I-B), or (I-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, R1 is -NR10C(O)NR8R9, wherein R8 and R9 are independently selected from the group consisting of hydrogen, (C1-10)alkyl, (C3-10)cycloalkyl, (C3-10)cycloalkyl(C1-10)alkyl, heterocycloalkyl, and heterocycloalkyl-alkyl; or R8 and R9, together with the nitrogen atom to which they are attached, form a heterocycloalkyl. In some
embodiments, the heterocycloalkyl is a 5-membered or 6-membered ring. In some embodiments, R8 and R9, together with the nitrogen atom to which they are attached form an unsubstituted or substituted piperidinyl. In some embodiments, R8 is hydrogen and R9 is hydrogen, (C1-10)alkyl, (C3-10)cycloalkyl, (C3-ioJcycloalkyliCMoJalkyl, heterocycloalkyl, or heterocycloalkyl-alkyl. In some embodiments, the heterocycloalkyl is a 5- to 7-membered heterocycloalkyl, or the heterocycloalkyl-alkyl is a (5- to 7-membered)heterocycloalkyl-(C1-10)alkyl. The (C1-10)alkyl, (C3-10)cycloalkyl, (C3-10)cycloalkyl(C1-10)alkyl, heterocycloalkyl, or heterocycloalkyl-alkyl of R9, or the heterocycloalkyl formed by R8 and R9, may be unsubstituted or substituted, for example with one or more substituents independently selected from the group consisting of -OR23, (C1-10)alkyl, and -NR23C(O)OR23. In certain embodiments, one or two substituents are independently selected from the group consisting of -OR23, (C1-10)alkyl, and -NR 3C(O)OR23. In some embodiments, R23 is independently H or (C1-10)alkyl, such as (C1-8)alkyl, (C1-6)alkyl, or (C1-*)alkyl. In certain embodiments, the piperidinyl is substituted with one or two -OH or -CH3. In some embodiments, the piperidinyl is substituted with one -OH.
[0102] Thus, for example, R1 may be:
Figure imgf000059_0001
[0103] In certain embodiments of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z- Ai), (Z-B), (Z-Bi), (I), (I- A), (I-Ai), (I-B), or (I-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, R1 is -NR10C(O)OR9, wherein R9 is hydrogen, (C1-10)alkyl, (C3-10)cycloalkyl, (C3-10)cycloalkyl(C1-10)alkyl, heterocycloalkyl, or
heterocycloalkyl-alkyl. In some embodiments, the heterocycloalkyl is a 5- to 7-membered heterocycloalkyl, or the heterocycloalkyl-alkyl is a (5- to 7-membered)heterocycloalkyl- (C1-10)alkyl. The (C1-10)alkyl, (C3-10)cycloalkyl, (C3-10)cycloalkyl(C1-10)alkyl, heterocycloalkyl, or heterocycloalkyl-alkyl of R9, may be unsubstituted or substituted, for example with one or more substituents independently selected from the group consisting of -OR23, (C1-10)alkyl, and -NR23C(O)OR23. In certain embodiments, R9 is substituted with one or two substituents independently selected from the group consisting of -OR23, (C1-10)alkyl, and -NR23C(O)OR23. In some embodiments, R23 is independently H or (C1-10)alkyl, such as (C1-8)alkyl, (C1-6)alkyl, or (C1-4)alkyl. In certain embodiments, the piperidinyl is substituted with one or two -OH or -CH3. In some embodiments, the piperidinyl is substituted with one -OH. In some embodiments, R10 is hydrogen or (C1-10)alkyl, such as methyl, ethyl, propyl, or butyl.
[0104] Thus, for example, in some embodiments, R1 is
Figure imgf000059_0002
[0105] In certain embodiments of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-
Ai), (Z-B), (Z-Bi), (I), (I- A), (I-Ai), (I-B), or (I-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, R1 is -S(O)2NR8R9. In some embodiments, R8 and R9 are independently selected from the group consisting of hydrogen, (C3-1ojalkyl, and
(C3-10)cycloalkyl; or R8 and R9, together with the nitrogen atom to which they are attached, form a heterocycloalkyl. In some embodiments, the alkyl, cycloalkyl, or heterocycloalkyl are independently substituted with one or more -OR23, halo, oxo, or -NR19R19 substituents. In some embodiments, the alkyl, cycloalkyl, or heterocycloalkyl are independently substituted with one or more -OR23 or halo substituents. In other embodiments, R1 is -NR10S(O)2R9. In some embodiments, R10 and R9 are selected from the group consisting of hydrogen, (C1-10)alkyl, and (C3-10)cycloalkyl. In certain embodiments, R10 is hydrogen. In some embodiments, the alkyl, cycloalkyl, or heterocycloalkyl are independently substituted with one or more -OR23 or halo substituents. In other embodiments, R8 and R9 are both hydrogen. In still further embodiments, R10 is (C1-10)alkyl, such as (C1-6)alkyl, or (C1-4)alkyl, such as methyl, ethyl, or propyl.
[0106] Thus, for example, in some embodiments, R1 is:
Figure imgf000060_0001
[010η In still further embodiments of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-Ai), (Z-B), (Z-Bi), (I), (I- A), (I-B), (I-Ai), or (I-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, R1 is -C(O)OR9. In some embodiments, R9 is hydrogen, (C1-10)alkyl, or (C3-10)cycloalkyl. In some embodiments, R1 is -C(O)OH, or
-C(O)OCH3.
[0108] In still other embodiments of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-Ai), (Z-B), (Z-Bi), (I), (I- A), (I-Ai), (I-B), or (I-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, R1 is -NR8R9. In some embodiments, each R8 and R9 are independently hydrogen, (C1-10)alkyl, or (C3-10)cycloalkyl, wherein each alkyl and cycloalkyl is independently unsubstituted or substituted. In other embodiments, R8 and R9, together with the nitrogen atom to which they are attached, form a substituted or unsubstituted heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 4- to 10- member ed, 4- to 8- membered, 4- to 6-membered, or 5- or 6-membered heterocycloalkyl. In certain embodiments, the heterocycloalkyl comprises, in addition to the nitrogen atom to which R8 and R9 are attached, one or two heteroatoms independently selected from the group consisting of O, S, and N. For example, in some embodiments R8 and R9 form a 5- or 6-membered heterocycloalkyl comprising, in addition to the nitrogen to which R8 and R9 are attached, one O or one S ring atom. In some embodiments, wherein the heterocycloalkyl comprises an S ring atom, the S is in an oxidized state and forms -SO2. In certain embodiments, the heterocycloalkyl is unsubstituted. In other embodiments, the heterocycloalkyl is substituted with one or more substituents selected from the group consisting of halo, oxo, and (C1-10)alkyl, wherein each alkyl is independently unsubstituted or substituted with one or more substituents selected from the group consisting of halo, -OH, -0(C1-10)alkyl, and -0(C1-10)haloalkyl. Thus, in some embodiments, R1 is:
Figure imgf000061_0001
[0109] In still further embodiments of a compound of Formula (X), (X-A), (X-Ai), (X-B), or (X-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, R1 is -C(O)NR10NR8R9. In some embodiments, R10 is hydrogen or (C1-10)alkyl. In certain
embodiments, R10 is hydrogen. In other embodiments, R10 is (C1-10)alkyl, such as (C1-4)alkyl, for example methyl or ethyl. In some embodiments, each of R8 and R9 are independently hydrogen, (C1-10)alkyl, or (C3-10)cycloalkyl, wherein each alkyl or cycloalkyl is unsubstituted or substituted. In some embodiments, the (C1-10)alkyl is (C1-8)alkyl, or (C1-4)alkyl. In certain embodiments, the (C3-10)cycloalkyl is (C3-6)cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, the (C1-10)alkyl is methyl, ethyl, or propyl (such as isopropyl or n-propyl). In certain embodiments, each alkyl and cycloalkyl is independently unsubstituted or substituted with one or more substituents. In some embodiments, the substituents are selected from the group consisting of (C1-10)alkyl, halo, oxo, and -OR19. In some embodiments, each R19 is independently hydrogen, (C1-10)alkyl (such as (C1-8)alkyl, or (C1-4)alkyl), or (C1-10)haloalkyl (such as (C1-8jhaloalkyl, or (C1-4)haloalkyl). In other embodiments, R8 and R9 together with the nitrogen with which they are attached form a heterocycloalkyl, which may be unsubstituted or substituted. In some embodiments, the heterocycloalkyl is a S-to 8-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl comprises one to three heteroatoms, in addition to the nitrogen attached to R8 and R9, selected from the group consisting of O, N, and S. In certain embodiments, the heterocycloalkyl is substituted with one or more substituents selected from the group consisting of (C1-10)alkyl (such as (C1-8)alkyl, or (Chalky.), halo, and -OR23. In some embodiments, each (C1-10)alkyl is unsubstituted or substituted, for example with one or more halo or -OH, or a combination thereof. In some embodiments, each R23 is independently hydrogen or (C1-10)alkyl (such as (C1-6)alkyl, or (C1-4)alkyl). Thus, in certain embodiments, R1 is:
Figure imgf000062_0001
[0110] In some embodiments of any of the compounds provided herein, such as a compound of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-Ai), (Z-B), (Z-Bi), (I), (I-A), (I-B), (I- Ai), or (I-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, R3 is hydrogen, (C1-10)alkyl, or (C3-10)cycloalkyl. In certain embodiments, the (C1-10)alkyl or (C3-10)cycloalkyl is substituted with one or more halo. In some embodiments, the one or more halo is one, two, or three halo. In certain embodiments, the one or more halo is two or three halo. In some embodiments, R3 is hydrogen or cyclopropyl. In certain embodiments, R3 is hydrogen. In other embodiments, R3 is methyl. In some embodiments, R3 is halo, for example chloro or fluoro. In some embodiments, R2 is hydrogen, halo, (C1-10)alkyl, (C3-10)cycloalkyl, or - OR25. In certain embodiments, the (C1-10)alkyl or (C3-10)cycloalkyl is substituted with one or more halo. In some embodiments, the (C1-10)alkyl or (C3-10)cycloalkyl is substituted with one, two, or three halo. In some embodiments, the (C1-10)alkyl or (C3-10)cycloalkyl is substituted with two or three halo. In some embodiments, R2 is chloro, fluoro, or propyl. In some embodiments, R2 is methyl. In some embodiments, R2 is chloro or fluoro. In certain embodiments, R3 is hydrogen and R2 is chloro. In certain embodiments, both of R2 and R3 are independently halo. In certain embodiments, R2 and R3 are independently hydrogen, halo, or (C1-10)alkyl, wherein the alkyl is unsubstituted or substituted with one or more halo. In certain embodiments, R2 and R3 are independently hydrogen, halo, or unsubstituted (C1-10)alkyl. In certain embodiments, R2 and R3 are independently hydrogen, chloro, or methyl. In some embodiments, R3 is hydrogen, and R2 is halo or (C1-10)alkyl, wherein the alkyl is unsubstituted or substituted with one or more halo. In other embodiments, R3 is hydrogen, and R2 is chloro or methyl.
[0111] In certain embodiments of any of the compounds provided herein, such as a compound of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-Ai), (Z-B), (Z-Bi), (I), (I-A), (I-B),
(I-Ai), or (1-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein one or both of R2 and R3 is -OR25, the R25 is independently selected from the group consisting of (C1-10)alkyl, (C3-10)cycloalkyl, (C3-10)cycloalkyl(C1-10)alkyl, or
heterocycloalkyl; or two R25, together with the nitrogen atom to which they are attached, form a heterocycloalkyl; wherein each of the foregoing alkyl, cycloalkyl, or heterocycloalkyl moieties is independently unsubstituted or substituted with one or more halo.
[0112] In some embodiments of any of the compounds provided herein, such as a compound of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-Ai), (Z-B), (Z-Bi), (I), (I-A), (I-B), (I- Ai), or (I-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, each of X1, X2, X3, and X4 are CR4, and
Figure imgf000063_0001
[0113] In other embodiments of any of the compounds provided herein, such as a compound of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-Ai), (Z-B), (Z-Bi), (I), (I-A), (I-B), (I- Ai), or (I-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, each of X2, X3 and X4 are CR4; X1 is N; and
Figure imgf000063_0002
[0114] In certain embodiments of any of the compounds provided herein, such as a compound of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-Ai), (Z-B), (Z-Bi), (I), (I-A), (I-B), (I-Ai), or (I-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, each of X1, X3 and X4 are CR4; X2 is N; and
Figure imgf000064_0001
[0115] In some embodiments of any of the compounds provided herein, such as a compound of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-Ai), (Z-B), (Z-Bi), (I), (I-A), (I-B), (I- Ai), or (I-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, each of X1, X2, and X4 are CR4; X3 is N; and
Figure imgf000064_0002
[0116] In other embodiments of any of the compounds provided herein, such as a compound of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-Ai), (Z-B), (Z-Bi), (I), (I-A), (I-B), (I- Ai), or (I-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, each of X1, X2, and X3 are CR4; X4 is N; and
Figure imgf000064_0003
[0117] In some embodiments of any of the compounds provided herein, such as a compound of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-Ai), (Z-B), (Z-Bi), (I), (I-A), (I-B), (I- Ai), or (I-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, X1 and X4 are CR4, X2 and X3 are N; and
Figure imgf000064_0004
Figure imgf000064_0005
[0118] In some embodiments of any of the compounds provided herein, such as a compound of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-Ai), (Z-B), (Z-Bi), (I), (I-A), (I-B), (I- Ai), or (I-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, X1 and X2 are CR4, X3 and X4 are N, and
Figure imgf000065_0001
[0119] In some embodiments of any of the compounds provided herein, such as a compound of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-Ai), (Z-B), (Z-Bi), (I), (I-A), (I-B), (I- Ai), or (I-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, X2 and X3 are CR4, X1 and X4 are N, and
Figure imgf000065_0002
[0120] In some embodiments of any of the compounds provided herein, such as a compound of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-Ai), (Z-B), (Z-Bi), (I), (I-A), (I-B), (I- Ai), or (I-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, X3 and X4 are CR4, X1 and X2 are N, and
Figure imgf000065_0003
[0121] In other embodiments of any of the compounds provided herein, such as a compound of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-Ai), (Z-B), (Z-Bi), (I), (I-A), (I-B), (I- Ai), or (I-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, X1 and X3 are CR4, X2 and X4 are N, and
Figure imgf000065_0004
[0122] In some embodiments of any of the compounds provided herein, such as a compound of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-Ai), (Z-B), (Z-Bi), (I), (I-A), (I-B), (I- Ai), or (I-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, X2 and X4 are CR4, X1 and X3 are N, and
Figure imgf000066_0001
[0123] In some embodiments of any of the compounds provided herein, such as a compound of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-Ai), (Z-B), (Z-Bi), (I), (I-A), (L-B), (I- Ai), or (I-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, X3 is CR4; each of X1, X2, and X4 are N; and
Figure imgf000066_0002
[0124] In some embodiments, when at least one of X1, X2, X3 and X4 is N, each R4 is independently selected from the group consisting of hydrogen, halo, cyano, (C1-10)alkyl, and (C3-10)cycloalkyl. In certain embodiments, the (C1-10)alkyl or (C3-10)cycloalkyl are independently unsubstituted or substituted with one or more halo. In some embodiments, the (C1-10)alkyl or (C3-10)cycloalkyl are substituted with one, two, or three halo. In some embodiments, the
(C1-10)alkyl or (C3-10)cycloalkyl are substituted with two or three halo. In some embodiments, the (C1-10)alkyl is substituted with one or more halo. In certain embodiments, the (C1-10)alkyl is substituted with one, two, or three halo. In some embodiments, (C1-10)alkyl is substituted with one halo. In certain embodiments, each R4 is independently hydrogen, fluoro, chloro, cyano, methyl, ethyl, or propyl.
[0125] In some embodiments, when each of X1, X2, X3 and X4 is CR4, each R4 is
independently selected from the group consisting of hydrogen, halo, cyano, (C1-10)alkyl, -NR27R27, and (C3-10)cycloalkyl. In certain embodiments, the (C1-10)alkyl or (C3-10)cycloalkyl are independently unsubstituted or substituted with one or more halo. In certain embodiments, the (C1-10)alkyl or (C3-10)cycloalkyl are independently unsubstituted or substituted with one, two, or three halo. In some embodiments, the (C1-10)alkyl is substituted with one or more halo. In certain embodiments, the (C1-10)alkyl is substituted with one, two, or three halo. In certain embodiments, halo is fluoro or chloro. In other embodiments, each R27 is H or (C1-10)alkyl, such as (C1-8)alkyl, (C1-6)alkyl, or (C1-4)alkyl; or two R27, together with the nitrogen atom to which they are attached, form heterocycloalkyl. In certain embodiments, each R4 is independently hydrogen, fluoro, chloro, cyano, methyl, ethyl, propyl, -NH2, or -N(CH3)2.
[0126] In certain embodiments, wherein at least one of X2, X3 and X4 is N, an adjacent annular carbon is bonded to R4, and the R4 is halo, the halo is iodo or fluoro. In certain embodiments, the halo is fluoro. In some embodiments, wherein at least one of X2, X3 and X4 is N, and an adjacent annular carbon is bonded to R4, the R4 is independently hydrogen, fluoro, cyano, (C1-10)alkyl, or -OR27.
[0127] In still further embodiments, two R4 on adjacent annular carbon atoms together with the carbon atoms to which they are attached form a carbocyclyl, wherein the carbocyclyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, cyano, (C1-10)alkyl, (C3-10)cycloalkyl, (C3-ioJcycloalkyliCMoJalkyl, heterocycloalkyl, heterocycloalkyl-alkyl, -OR27, -C(O)NR27R27, -NR27C(O)R27, -NR27R27, -S(O)2NR27R27, -NR27S(O)2R27, -S(O)nsR28, and -C(O)R28. For example, two R4 on adjacent annular carbon atoms together with the carbon atoms to which they are attached may form a 5- membered or 6-membered carbocyclyl which is fused to the 6-membered ring formed by X1, X2, X3, and X4, wherein the carbocyclyl is unsubstituted or substituted. In some embodiments, the carbocyclyl is aromatic. In other embodiments, the carbocyclyl is not aromatic.
[0128] In other embodiments, two R4 on adjacent annular carbon atoms together with the carbon atoms to which they are attached form a heterocarbocyclyl, wherein the
heterocarbocyclyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, cyano, (C1-10)alkyl, (C3-10)cycloalkyl,
(C3-10)cycloalkyl(C1-10)alkyl, heterocycloalkyl connected by an annular carbon atom, heterocycloalkyl-alkyl, -OR27, -C(O)NR27R27, -S(O)2NR27R27, -S(O)n8R28, and -C(O)R28. For example, two R4 on adjacent annular carbon atoms together with the carbon atoms to which they are attached may form a 5-membered or 6-membered heterocyclyl which is fused to the 6- membered ring formed by X1, X2, X3, and X4, wherein the heterocarbocyclyl is unsubstituted or substituted. In some embodiments, the heterocyclyl is aromatic. In other embodiments, the heterocyclyl is not aromatic. In certain embodiments, the heterocyclyl is comprises 1 to 3 heteroatoms independently selected from the group consisting of O, N, and S. In certain embodiments, the heterocyclyl is a 5- or 6-membered heterocyclyl comprising 1 to 2 heteroatoms independently selected from the group consisting of O and N.
[0129] Thus, for example, in some embodiments of the compound of Formula (X), (X-A), (X- Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-Ai), (Z-B), (Z-Bi), (I), (I- A), (I-B), (I-Ai), or (I-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof:
Figure imgf000068_0001
[0130] In certain embodiments of the compound of Formula (X), (X-A), (X-Ai), (X-B), (X- Bi), (Z), (Z-A), (Z-Ai), (Z-B), (Z-Bi), (I), (I-A), (I-B), (I-Ai), or (I-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof:
Figure imgf000068_0002
. In certain embodiments, each R4 is H.
[0131] In some embodiments of the compound of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-Ai), (Z-B), (Z-Bi), (I), (I-A), (I-B), (I-Ai), or (I-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, such as any of the embodiments described above, R15 and R17 are independently hydrogen, halo, or alkyl. In some embodiments, the alkyl is independently unsubstituted or substituted with one or more halo. In some embodiments, the alkyl is independently unsubstituted or substituted with one, two, or three halo. In certain embodiments, the alkyl is independently unsubstituted or substituted with two or three halo. In certain embodiments, R15 and R17 are independently hydrogen, fluoro, chloro, methyl, ethyl, or propyl.
[0132] In some embodiments of the compound of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-Ai), (Z-B), (Z-Bi), (I), (I-A), (I-B), (I-Ai), or (I-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, such as any of the embodiments described above, R14 is (C1-10)alkyl, (C1-10)alkenyl, (C3-10)cycloalkyl, (C3-10)cycloalkenyl, heterocycloalkyl connected through an annular carbon atom, or heterocycloalkenyl connected through an annular carbon atom. In certain embodiments, R14 is (C1-10)alkyl, (C1-10)alkenyl, (C3-10)cycloalkyl, heterocycloalkyl connected through an annular carbon atom, or
heterocycloalkenyl connected through an annular carbon atom. In still further embodiments, R14 is (C1-10)alkyl, (C3-10)cycloalkyl, or heterocycloalkyl connected through an annular carbon atom. In some embodiments, R14 is (C1-u)alkyl, (C1-6)alkyl, or (C1-4)alkyl, such as hexyl, pentyl, butyl, propyl, ethyl, or methyl, which may be unsubstituted or substituted. In some embodiments, R14 is unsubstituted or substituted tert-butyl, or unsubstituted or substituted isopropyl. In some embodiments, R14 is (C1-8)alkenyl, (C1-6)alkenyl, or (C1-4)alkenyl, wherein the alkenyl comprises one or two C-C double bonds, and wherein the alkenyl may be unsubstituted or substituted. For example, in some embodiments R14 is isopropenyl. In other embodiments, R14 is a 4-, 5-, or 6- membered heterocycloalkyl comprising one to three heteroatoms independently selected from O and N, wherein the heterocycloalkyl is connected through an annular carbon atom. For example, R14 may be a (C3-5)heterocycloalkyl comprising one or two O atoms. In still further
embodiments, R14 is a 5- or 6-membered heterocycloalkenyl comprising one to three
heteroatoms independently selected from O and N, wherein the heterocycloalkenyl is connected through an annular carbon atom. In still further embodiments, R14 is (C3-10)cycloalkyl, for example (C3-e)cycloalkyl, (C3-6)cycloalkyl, or (C«)cycloalkyl. In some embodiments, R14 is cyclobutyl or cyclopropyl, unsubstituted or substituted with halo, -OR7 (such as -OH or -0(C1- i0)alkyl) or a combination thereof.
[0133] In certain embodiments, the alkyl, alkenyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl of R14 is substituted with one or more substituents as described in Formula
(X). In some embodiments, the alkyl, alkenyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl of R14 may be unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of (C1-10)alkyl, halo, -OR7, and -C(O)OR7.
Each R7 may be hydrogen or (C1-10)alkyl, such as (C1-s)alkyl, (C1-8)alkyl, or (C1-4)alkyl, for example hexyl, pentyl, butyl, propyl, ethyl, or methyl, wherein the alkyl is independently unsubstituted or substituted with one or more halo. In some embodiments, the alkyl, cycloalkyl, heterocycloalkyl, or heterocycloalkenyl is independently unsubstituted or substituted with one, two, or three halo. In certain embodiments, the alkyl, cycloalkyl, heterocycloalkyl, or heterocycloalkenyl is substituted with two or three halo. In some embodiments, the alkyl is substituted with one, two, or three alkyl. In some embodiments, R14 is (C1-10)alkyl wherein the alkyl is unsubstituted or substituted with oxo. In still other embodiments, R14 is (C1-10)alkyl substituted with -NR7R7. In some embodiments, each R7 is independently hydrogen or (C1- i0)alkyl.
[0134] In other embodiments, R14 is -OR5, wherein R5 is hydrogen, (C1-10)alkyl, or
(C3-10)cycloalkyl, wherein the alkyl or cycloalkyl is unsubstituted or substituted as described in Formula (X). In some embodiments, one or more substituents are selected from the group consisting of halo, haloalkyl, and -(OR35)n120R34. In some embodiments, R5 is (C1-10)alkyl, such as (C1-4)alkyl or (C1-2)alkyl, or (C3-10)cycloalkyl, such as (C3-6)cycloalkyl, each of which may be unsubstituted or substituted with halo or -(OR35)n120R34, or a combination thereof. In some embodiments of -(OR35)n120R34, nl2 is 0, 1, 2, or 3. In some embodiments, each R35 is independently (C1-10)alkyl or (C1-10)haloalkyl alkyl, such as (C1-4)alkyl, (C1-4)haloalkyl, (C1-3)alkyl, or (C1-3)haloalkyl. In still further embodiments, R34 is hydrogen or (C1-10)alkyl, such as (C1-4)alkyl or (C1-3)alkyl. In certain embodiments, nl2 is 0 or 1, R35 is methyl, ethyl, or propyl, and R34 is hydrogen, methyl, ethyl, or propyl.
[0135] Thus, in some embodiments of the compound of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-Ai), (Z-B), (Z-Bi), (I), (I-A), (I-B), (I-Ai), or (I-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, such as embodiments described above, R14 is:
Figure imgf000070_0001
[0136] In some embodiments, R15 is hydrogen. In other embodiments, R15 is -OR29. In some embodiments, R29 is hydrogen, (C1-10)alkyl, (C1-10)haloalkyl, (C3-10)cycloalkyl, or
(C3-10)halocycloalkyl.
[0137] Alternatively, in some embodiments of the compound of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-Ai), (Z-B), (Z-Bi), (I), (I-A), (L-B), (I-Ai), or (I-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, R14 and R15, together with the atoms to which they are attached, form a carbocyclyl or heterocyclyl. The carbocyclyl or heterocyclyl may be unsubstituted or substituted with one or two substituents independently selected from the group consisting of halo, cyano, oxo, (C1-10)alkyl,
(C3-10)cycloalkyl, (C3-10)cycloalkyl(C1-10)alkyl, -OR18, -C(O)NR,8R18, -NR18C(O)R18,
-NR,8C(O)NR,8R18, -NR18R18, -S(O)2NR18R18, -NR18S(O)2R18, -S(O)n3R21, -C(O)OR18, and -C(O)R21. In certain embodiments, R14 and R15, together with the atoms to which they are attached, form a Cs or Ce carbocyclyl. In other embodiments, R14 and R15, together with the atoms to which they are attached, form a 5- or 6-membered heterocyclyl. For example, in some embodiments, the heterocyclyl is a S- or 6-membered heterocyclyl comprising one to three heteroatoms independently selected from O and N, such as a C3-5 cycloalkyl comprising one or two O atoms. In some embodiments, the heterocyclyl is a 5- or 6-membered heterocyclyl comprising one or two N atoms, or one O atom and one N atom. In some embodiments, the carbocyclyl or heterocyclyl is unsubstituted or substituted with one or two substituents independently selected from the group consisting of (C1-10)alkyl, (C3-10)cycloalkyl, or
(C3-10)cycloalkyl(C3-10)alkyl substituents, such as (C1-8)alkyl, (C1-8)alkyl, (C1-4)alkyl, (C3- 8)cycloalkyl, (C3-6)cycloalkyl, (C3-ejcycloalkyl, (C3-8)cycloalkyl(C1-8)alkyl,
(C3-ejcycloalkyliC3-6)alkyl, and (C4-6)cycloalkyl(C1-4)alkyl. For example, in certain
embodiments, the carbocyclyl or heterocyclyl is unsubstituted or substituted with one or two substituents independently selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, cyclopropyl, cyclobutyl, cyclopropyl-methyl, and cyclobutyl-methyl. In some embodiments, the butyl is tert-butyl. In some embodiments, the carbocyclyl or heterocyclyl is substituted with one or more halo. [0138] Thus, in some embodiments of the compound of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-Ai), (Z-B), (Z-Bi), (I), (I-A), (I-B), (I-Ai), or (I-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof:
Figure imgf000072_0001
[0139] In some variations, R16 and R17 are both H. In other embodiments, R16 is (C1-10)alkyl, such as (C1-6)alkyl or (C1-4)alkyl. In some embodiments, the alkyl is unsubstituted, while in other embodiments, the alkyl is substituted. In yet other embodiments, R16 is -OR5. In some embodiments, R5 is hydrogen or (C1-10)alkyl. In certain embodiments, the alkyl is substituted with halo or -(OR35)n120R34. In some embodiments, R17 is hydrogen.
[0140] In some embodiments of the compound of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-Ai), (Z-B), (Z-Bi), (I), (I-A), (I-B), (I-Ai), or (I-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, which may include any of the embodiments described above, R16 is hydrogen, fluoro, (C1-10)alkyl, (C3-10)cycloalkyl,
(C3-10)cycloalkyl(C1-10)alkyl, heterocycloalkyl connected through an annular carbon atom, heterocycloalkyl-alkyl, -OR5, -C(O)NR5R5, -R5C(O)NR5R5, -S(O)2NR5R5, -S(O)mR6, or -C(O)R6, wherein the (C1-10)alkyl, (C3-10)cycloalkyl, (C3-10)cycloalkyl(C1-10)alkyl,
heterocycloalkyl, or heterocycloalkyl-alkyl is independently unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of (C1-10)alkyl, halo, cyano, oxo, -OR7, -C(O)OR7, -C(O)NR7R7, -NR7C(O)R7, -NR7C(O)NR7R7, -NR7R7, -S(O)2NR7R7, -NR7S(O)2R7, -S(O)ii2R13, and -C(O)R13. In some embodiments, R16 is hydrogen or fluoro. In some embodiments, R16 is hydrogen.
[0141] In certain embodiments, the compound of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-Ai), (Z-B), (Z-Bi), (I), a-A), (I-B), or (I-Bi) is:
Figure imgf000073_0001
Figure imgf000074_0001
Figure imgf000075_0001
Figure imgf000076_0001
Figure imgf000077_0002
or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or
Figure imgf000077_0001
isomer of any of the foregoing.
Figure imgf000077_0003
Figure imgf000078_0001
Figure imgf000079_0001
Figure imgf000080_0001
Figure imgf000081_0001
Figure imgf000082_0001
Figure imgf000083_0001
Figure imgf000084_0001
acceptable salt, solvate, tautomer, isotope, or isomer of any of the foregoing.
Figure imgf000084_0002
[0145] In certain embodiments, the compound of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-Ai), (Z-B), (Z-Bi), (I), a-A), (Z-B), or (Z-Bi) is:
Figure imgf000085_0001
Figure imgf000086_0001
Figure imgf000087_0001
Figure imgf000088_0002
Figure imgf000088_0001
, or a pharmaceutically acceptable salt, solvate, tautomer,
, or isomer of any of the foregoing.
[0146] In certain embodiments, the compound of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-Ai), (Z-B), (Z-Bi), (I), (I-A), (I-Ai), (Z-B), or (Z-Bi) is:
Figure imgf000088_0003
Figure imgf000089_0001
Figure imgf000090_0001
Figure imgf000091_0001
or
Figure imgf000092_0001
, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer of any of the foregoing.
[0147] In some embodiments, the compound of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-Ai), (I), (I-A), or (I-Ai) is:
Figure imgf000092_0002
Figure imgf000093_0001
or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer of any of the foregoing.
[0148] In other embodiments, the compound of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-Ai), (I), (I-A), or (I-Ai) is:
Figure imgf000093_0002
a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer of any of the foregoing.
[0149] In certain embodiments, the compound of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-Ai), (I), (I-A), or (I-Ai) is:
Figure imgf000094_0001
acceptable salt, solvate, tautomer, isotope, or isomer of any of the foregoing
[0150] In still further embodiments, the compound of Formula (X), (X-A), (X-Ai), (X-B), (X- Bi), (Z), (Z-A), (Z-Ai), (I), (I-A), or (I-Ai) is:
Figure imgf000094_0002
Figure imgf000095_0001
,
Figure imgf000095_0002
or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer of any of the foregoing
[0151] Further provided are pharmaceutical compositions comprising any of the compounds disclosed herein, such as a compound of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-B), (Z-Ai), (Z-Bi), (I), (I- A), (I-B), (I-Ai), or (I-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, and a pharmaceutically acceptable excipient
[0152] The compounds disclosed herein, such as a compound of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-Ai), (I), (I- A), or (I-Ai), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, may be prepared, for example, through the reaction routes depicted in General Schemes 1-ΠΙ.
General Reaction Scheme I
Figure imgf000096_0001
[0153] General Reaction Scheme I provides two routes to compound 1-5, which is an example of a compound of Formula (X), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof as described herein. In one route, compound 1-1 is coupled with compound 1-2 in the presence of a palladium catalyst and base to produce compound 1-3. Suitable palladium catalysts may include, for example, tetrakis(triphenylphosphine)palladium(0), and suitable bases may include, for example, aqueous sodium carbonate or potassium carbonate. In the next step, compound 1-3 is reacted with compound 1-4 in the presence of a coupling reagent and a base.
Suitable coupling reagents may include bis(di-tert-butyl(4-dimethylaminophenyl)phosphine) dichloropalladium(n) or [l,l'-bis(diphenylphosphino) ferrocene]dichloropalladium(II) or tetrakis(triphenylphosphine)palladium(0). Suitable bases may include aqueous sodium carbonate or potassium carbonate. Either of the two coupling reactions may be carried out using a solvent, for example, dioxane or dimethoxyethane. In some embodiments, the reactions are carried out between 60 °C to 120 °C, for between 8 h to 24 h. In the second route provided in General Reaction Scheme I, compound 1-4 is coupled with compound 1-1 to produce compound 1-6, which is next coupled with compound 1-2 to produce compound I-S. Similar coupling reagents and conditions may be used as were previously described for the first route.
[0154] In certain embodiments, compounds of Formula (X), (X-A), (X-Ai), (Z), (Z-A), (Z-Ai), (I), (I- A), or (I-Ai), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R1 is -C(O)NR8R9 may be prepared according to General Reaction Scheme Π.
General Reaction Scheme Π
Figure imgf000097_0001
[01SS] In General Reaction Scheme Π, compound II- 1 is combined with an amine II-2 in the presence of a coupling reagent, for example HATU ((l-[Bis(dimethylamino)methylene]-lH- l,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate)) or EDC (l-ethyl-3-(3- dimethylaminopropyl)carbodiimide). The base DIPEA (N,N-diisopropylethylamine) may also be added. In some embodiments, the reaction is carried out in a dipolar aprotic solvent, such as DMF or dioxane, and may be performed, for example, at room temperature until the reaction has gone to completion, such as for 8 h to 48 h. The compound Π-l may be prepared as described in General Reaction Scheme I above, wherein R1 is -COOH.
[0156] In certain embodiments, compounds of Formula (X), (X-A), (X-Ai), (Z), (Z-A), (Z-Ai), (I), (I- A), or (I-Ai), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R1 is -NR10C(O)R9, -NR10SO2R9, -NR,0C(O)NR8R9, or -NR10C(O)OR9 may be prepared by proceeding as shown in General Reaction Scheme ΙΠ:
Figure imgf000098_0001
[0157] Compound ΙII-4 may be prepared, for example, by reacting compound ΙΠ-1 with a carbamoyl chloride compound IU-2 in the presence of an organic base, such as diisopropylethyl amine or triethylamine. The reaction may be carried out in a solvent, such as dichloromethane, at room temperature for 4 h to 24 h. Alternatively, compound III-4 may be prepared by reacting compound ΠΙ-l with phenylchloroformate in dichloromethane in the presence of triethylamine for approximately 16 h at room temperature, and then treating resulting phenyl carbamate with an amine HNR8R9 in tetrahydrofuran at 0 °C to room temperature for 4 h to 24 h. Compound ΙΠ-6 may be prepared, for example, by reacting compound ΙΠ-1 with a chloroformate compound ΙΠ- 5, in the presence of an organic base, such as diisopropylethyl amine or triethylamine. The reaction may be carried out in a solvent, such as dichloromethane, at room temperature for 4 h to 24 h. Compound ΙΠ-8 may be prepared, for example, by reacting compound ΙΠ-1 with a sulfonyl halide compound ΙII-7 wherein X is chlorine or fluorine. This reaction may be carried out in the presence of an organic base, such as triethylamine, and in solvent such as pyridine for 4 h to 24 h at room temperature. Compound ΙΠ-1 may be prepared, for example, as described in General Reaction Scheme I above, wherein R1 is -NH2. [0158] Synthesis of the compounds of described herein may, in some embodiments, be accomplished by methods analogous to those described in the synthetic schemes above or the specific examples below.
[0159] The variables X1, X2, X3, X4, R1, R2, R3, R8, R9, R10, R14, R15, R16, and R17 in the compounds of General Reaction Schemes I-III are as described for Formula (X), Formula (Z), and Formula (I) herein. While General Reaction Schemes I-III depict the preparation of compounds of Formula (X), (X-A), (X-Ai), (Z), (Z-A), (Z-Ai), (I), (I-A), or (I-Ai), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, compounds of Formula (X-B), (X-Bi), (Z-B), (Z-Bi), (I-B), or (I-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, may also in some embodiments be prepared following analogous reaction schemes. The reactants, solvents, coupling agents, catalysts, and other compounds used to prepare compounds of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-Ai), (Z-B), (Z-Bi), (I), (I-A), (I-Ai), (I-B), or (I-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, by following General Reaction Schemes Ι-ΠΙ or by another route, may be commercially available may be prepared following organic chemical techniques.
Π. Methods of Using Compounds of Formula (X) and Pharmaceutical Compositions
Comprising Compounds of Formula (X)
[0160] Provided herein are methods of using the compounds disclosed herein, such as compounds of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-B), (Z-Ai), (Z-Bi), (I), (I-A), (I-B), (I-Ai), or (I-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or a pharmaceutical composition comprising any of the foregoing and a pharmaceutically acceptable excipient. These include methods of inhibiting a component of the SREBP pathway, such as an SREBP or SCAP; and methods of treating a disorder in a subject in need thereof. In some embodiments, the disorder is mediated by an SREBP or SCAP.
[0161] The terms "treat," "treating," or "treatment" refers to any indicia of success in the amelioration of an injury, disease, disorder, pathology, or condition, including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the injury, disease, disorder, pathology, or condition more tolerable to the subject; slowing or stopping the rate of degeneration, decline, or development; slowing the progression of injury, disease, disorder, pathology, or condition; making the final point of degeneration less debilitating; improving a subject's physical or mental well-being; or relieving or causing regression of the injury, disease, disorder, pathology, or condition. The treatment of symptoms, including the amelioration of symptoms, can be based on objective or subjective parameters, which may include the results of a physical examination, a neuropsychiatric exam, and/or a psychiatric evaluation. Certain methods and uses disclosed herein may treat cancer by, for example, decreasing the incidence of cancer, causing remission of cancer, slowing the rate of growth of cancer cells, slowing the rate of spread of cancer cells, reducing metastasis, or reducing the growth of metastatic tumors, reducing the size of one or more tumors, reducing the number of one or more tumors, or any combinations thereof.
[0162] The embodiments described herein for methods of treatment should also be considered to apply to the use of compounds of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z- B), (Z-Ai), (Z-Bi), (I), (I- A), (I-B), (I-Ai), or (I-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, for the treatment of disorders; and the use of compounds of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-B), (Z-Ai), (Z-Bi), (I), (I-A), (I-B), (I-Ai), or (I-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, for inhibiting an SREBP or inhibiting the proteolytic activation of an SREBP; and other uses of compounds of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-B), (Z-Ai), (Z-Bi), (I), (I-A), (I-B), (I-Ai), or (I-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, as described herein; and the use of compounds of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-B), (Z-Ai), (Z-Bi), (I), (I-A), (I-B), (I-Ai), or (I-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, in the manufacture of medicaments.
A. Inhibiting SREBP or SCAP
[0163] Provided herein are uses and methods of inhibiting a component of the SREBP pathway, such as an SREBP or SCAP. In some embodiments, a combination of an SREBP and SCAP is inhibited. Such methods may include contacting an SREBP with a compound of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-B), (Z-Ai), (Z-Bi), (I), (I-A), (I-B), (I- Ai), or (1-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or a pharmaceutical composition comprising any of the forgoing and a pharmaceutically acceptable excipient Such uses and methods may also include contacting SCAP with a compound of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-B), (Z-Ai), (Z-Bi), (I), (I- A), (I-B), (I-Ai), or (I-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or a pharmaceutical composition comprising any of the forgoing and a pharmaceutically acceptable excipient.
[0164] In certain embodiments, a compound of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-B), (Z-Ai), (Z-Bi), (I), (I-A), (I-B), (I-Ai), or (I-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof is administered to a subject in need thereof to inhibit a component of the SREBP pathway. In other embodiments, a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-B), (Z-Ai), (Z-Bi), (I), (I-A), (I-B), (I-Ai), or (I-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, is administered to the subject in need thereof. In certain embodiments, the amount of the compound or pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, relative to the subject's body mass, is between about 0.01 mg/kg to about 100 mg/kg. In some embodiments, about 0.7 mg to about 7 g daily, or about 7 mg to about 350 mg daily, or about 350 mg to about 1.75 g daily, or about 1.75 to about 7 g daily of the compound of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-B), (Z-Ai), (Z-Bi), (I), (I-A), (I-Ai), (I-B), or (I-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof is
administered to a subject in need thereof to inhibit a component of the SREBP pathway. In certain embodiments, the compound or pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, is administered as a pharmaceutical composition, as described herein.
[0165] The component of the SREBP pathway that is inhibited by the methods and uses described herein may be an SREBP or SCAP. In some embodiments, an SREBP is inhibited. The SREBP may be, for example, an SREBP-1 (such as SREBP-la or SREBP-1 c) or SREBP-2. In certain variations, two or three of SREBP-la, SREBP- lc, and SREBP-2 are inhibited. In some embodiments, the component is an SREBP-1. In other embodiments, the SREBP is SREBP-1 a. In certain embodiments, the component is SREBP- lc. In still other embodiments, the SREBP is SREBP-2. In other embodiments, the component of the SREBP pathway is SCAP. In some embodiments, both an SREBP and SCAP are inhibited. In certain embodiments, two or three of SREBP-la, SREBP-lc, and SREBP-2 are inhibited, and SCAP is inhibited.
[0166] Inhibition of a component of the SREBP pathway, such as an SREBP or SCAP, may include partial inhibition or full inhibition. Partial inhibition may include reducing the activity of a component of the SREBP pathway to a level that is still detectable. Full inhibition may include stopping all activity of a component of the SREBP pathway (such as stopping the activity of an SREBP or SCAP), or reducing the activity of a component of the SREBP pathway to a level below detection. Inhibition of a component of the SREBP pathway may be measured directly or indirectly, using any methods known in the art
[0167] In some embodiments, inhibition of a component of the SREBP pathway is measured directly, for example by measuring the product of a reaction catalyzed by an SREBP pathway component. Inhibition of SREBP activation (for example, by inhibiting SCAP) may in some embodiments be demonstrated by western blotting and quantitatively assessing the levels of full- length and cleaved SREBP- 1 and/or SREBP-2 proteins from a cell line (such as a hepatic cell lines) or primary cells (such as primary hepatocytes of mouse, rat or human origin).
[0168] In some embodiments, inhibition of a component of the SREBP pathway is measured indirectly, for example by measuring the level of expression of one or more genes that are regulated by SREBP. The inhibition of a component of the SREBP pathway, such as an SREBP or SCAP, may reduce the expression of one or more genes that are regulated by an SREBP, for example an SREBP-1 (such as SREBP-la or SREBP-lc) or SREBP-2. SCAP plays a role in activating SREBPs, thus inhibiting the activity of SCAP may reduce the expression of one or more genes that are regulated by an SREBP. SREBP pathway inhibition may also be determined by assessing gene transcription levels of one or more target genes of SREBP-1 and/or SREBP-2, such as one or more of ACSS2, ALDOC, CYP51A1, DHCR7, ELOVL6, FASN, FDFT1, FDPS, HMGCS1, HSD17B7, Ettl, INSIG1, LDLR, LSS, ME1, PCSK9, PMVK, RDHl 1, SC5DL, SQLE, STARD4, TM7SF2, PNPLA3, SREBFl, SREBF2, HMGCR, MVD, MVK, ACLY, MSMOl, ACACA, or ACACB. The transcription levels may be assessed, for example, by transcriptomic analysis, including but not limited to q-PCR. A reduction in one, two, three, four, five, or more of these genes may indicate inhibition of SREBP activation. This evaluation of endogenous SREBP gene expression may be assessed in cell lines (such as hepatic cell lines) or primary cells (such as primary hepatocytes of mouse, rat, or human origin). In some
embodiments, the gene transcription levels of PCSK9 or PNPLA3, or a combination thereof, are evaluated.
[0169] Therefore, provided herein are uses and methods of reducing the expression of one or more genes selected from the group consisting of ACSS2, ALDOC, CYP51A1, DHCR7, ELOVL6, FASN, FDFT1, FDPS, HMGCS1, HSD17B7, IDI1, INSIG1, LDLR, LSS, ME1, PCSK9, PMVK, RDHll, SC5DL, SQLE, STARD4, TM7SF2, PNPLA3, SREBF1, SREBF2, HMGCR, MVD, MVK, ACLY, MSMOl, ACACA, and ACACB, comprising contacting an SREBP or SCAP with a compound of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-B), (Z-Ai), (Z-Bi), (I), (I- A), (I-B), (I-Ai), or (I-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof. In some embodiments, the expression of PCSK9 is reduced. In other embodiments, the expression of PNPLA3 is reduced. In still further embodiments, both the expression of PCSK9 and PNPLA3 are reduced. In certain embodiments, one or more SREBP is contacted, for example an SREBP- 1 (such as SREBP- la or SREBP- lc) or SREBP-2, or any combinations thereof. In other embodiments, SCAP is contacted. In still further embodiments, one or more of SREBP-la, SREBP-lc, SREBP-2, and SCAP is contacted. In certain embodiments, inhibition of a component of the SREBP pathway may treat a disorder mediated by an SREBP, such as the disorders as described herein. Thus, in certain
embodiments, expression of one or more genes as described above is reduced in a subject in need thereof.
[0170] Another method of indirectly detecting SREBP pathway inhibition may include:
Serum-starving a hepatic cell line (HepG2) expressing luciferase under the control of the LSS- promoter to induce SREBP activation and increased luciferase expression. The cells may then be treated with a compound, such as a compound of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-B), (Z-Ai), (Z-Bi), (I), (I- A), (I-B), (I-Ai), or (I-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof. Following treatment, a reduction of luciferase activity reflects inhibition of SREBP activation, and non-cytotoxicity of the compound can be assessed by LDH release. B. Treating a disorder
[0171] In other aspects, provided herein are uses and methods of treating a disorder in a subject in need thereof, comprising administering to the subject in need thereof a compound of
Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-B), (Z-Ai), (Z-Bi), (I), (I-A), (I-B), (I-
Ai), or (1-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof.
In certain aspects, provided herein are uses and methods of treating a disorder in a subject in need thereof, comprising administering to the subject in need thereof a pharmaceutical composition comprising a compound of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A),
(Z-B), (Z-Ai), (Z-Bi), (I), (I-A), (I-B), (I-Ai), or (I-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, and a pharmaceutically acceptable excipient In certain embodiments, the compound is a compound of Formula (X-A), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof. In other embodiments, the compound is a compound of Formula (X-Ai), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof. In certain embodiments, the compound is a compound of
Formula (X-B), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof. In still further embodiments, the compound is a compound of Formula (X-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof. In certain embodiments, the compound is a compound of Formula (Z-A), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof. In other embodiments, the compound is a compound of Formula (Z-Ai), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof. In certain embodiments, the compound is a compound of Formula (Z-B), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof. In still further embodiments, the compound is a compound of Formula (Z-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof. In certain embodiments, the compound is a compound of Formula (I-A), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof. In other embodiments, the compound is a compound of Formula (I-Ai), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof. In certain embodiments, the compound is a compound of Formula (I-B), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof. In still further embodiments, the compound is a compound of Formula (I-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof. In some embodiments, the disorder is mediated by an SREBP. [0172] The uses and methods of treatment describe herein may use a compound of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-B), (Z-Ai), (Z-Bi), (I), (I-A), (I-B), (I-Ai), or (I-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof; or a pharmaceutical composition comprising a compound of Formula (X), (X-A), (X-Ai), (X-B), (X- Bi), (Z), (Z-A), (Z-B), (Z-Ai), (Z-Bi), (I), (I-A), (I-B), (I-Ai), or (I-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, and a pharmaceutically acceptable excipient
1. Metabolic Disorders
[0173] In some embodiments, the disorder is a metabolic disorder, such as a disorder that affects lipid metabolism, cholesterol metabolism, or insulin metabolism. In certain
embodiments, the disorder is related to lipid metabolism, cholesterol metabolism, or insulin metabolism, for example, liver disease as a result of the buildup of fat in the liver, or
cardiovascular disease.
[0174] In some embodiments, the disorder is a liver disease, such as chronic liver disease. In some embodiments, the liver disease is mediated by a component of the SREBP pathway, such as an SREBP or SCAP. In some embodiments, the liver disease is mediated by an SREBP. In certain embodiments, the liver disease is mediated by a downstream gene target of an SREBP, such as PNPLA-3. In other embodiments, the liver disease is mediated by SCAP. Thus, in some aspects, provided herein are uses and methods of treating a liver disease in a subject in need thereof, comprising administering to the subject in need thereof a compound of Formula (X), (X- A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-B), (Z-Ai), (Z-Bi), (I), (I-A), (I-Ai), (I-B), or (I-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof; or a
pharmaceutical composition comprising any of the foregoing and a pharmaceutically acceptable excipient The chronic liver disease may be, for example, primary alcoholic liver disease, nonalcoholic fatty liver disease (NAFLD), or nonalcoholic steatohepatitis (NASH). In some embodiments, the liver disease is liver fat, liver inflammation, or liver fibrosis, or a combination thereof.
[0175] In certain embodiments, the liver disease is non-alcoholic fatty liver disease (NAFLD). NAFLD is a group of conditions that are related to fat buildup in the liver. Non-alcoholic steatohepatitis (NASH) is a form of NAFLD which includes liver inflammation. In NASH, the liver inflammation may lead to liver damage and scarring, which can be irreversible, and it can also progress to cirrhosis and liver failure. NAFLD and NASH are associated with metabolic disorders such as obesity, dyslipidemia, insulin resistance, and type 2 diabetes. Other disorders associated with NAFLD and NASH include increased abdominal fat and high blood pressure. In some embodiments, NASH is mediated by a component of the SREBP pathway, such as an SREBP or SCAP.
[0176] In other aspects, provided herein are uses and methods of treating NASH in a subject in need thereof, comprising administering to the subject in need thereof a compound of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-B), (Z-Ai), (Z-Bi), (I), (I-A), (I-Ai), (I-B), or (I-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof; or a pharmaceutical composition comprising any of the foregoing and a pharmaceutically acceptable excipient Treatment of NASH may include reduction in average liver fat content, which may be evaluated, for example, by magnetic resonance imaging (MRI), magnetic resonance elastography (MRE), ultrasound, or computerized tomography (CT); reduction of the liver enzyme alanine aminotransferase (ALT); reduction of the liver enzyme aspartate aminotransferase (ALT);
reduction of liver inflammation as evaluated through histological scoring of liver biopsy;
reduction of liver fibrosis as evaluated through histological scoring of liver biopsy; reduction of liver fat content as evaluated through histological scoring of liver biopsy; or any combinations thereof. Treatment of NASH may be evaluated using the NAFLD activity score (NAS); or steatosis, activity, and fibrosis score (SAF); or other NASH diagnostic and/or scoring metrics (such as FIB4 or ELF).
[0177] Further provided herein are uses and methods of treating a disorder in a subject in need thereof, wherein the disorder is liver fibrosis associated with NASH, comprising administering to the subject in need thereof a compound of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z- A), (Z-B), (Z-Ai), (Z-Bi), (I), (I-A), (I-Ai), (I-B), or (I-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof; or a pharmaceutical composition comprising any of the foregoing and a pharmaceutically acceptable excipient In some embodiments, the liver fibrosis is mediated by SREBP. Treatment of liver fibrosis may be evaluated, for example, by magnetic resonance imaging (MRI), magnetic resonance elastography (MRE), ultrasound, or computerized tomography (CT); reduction of the liver enzyme alanine aminotransferase (ALT); reduction of the liver enzyme aspartate aminotransferase (ALT); reduction of liver inflammation and/or fibrosis as evaluated through histological scoring of liver biopsy; or any combinations thereof
[0178] Further provided herein are uses and methods of treating a disorder in a subject in need thereof, wherein the disorder is fatty liver disease, comprising administering to the subject in need thereof a compound of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-B), (Z- Ai), (Z-Bi), (I), (I- A), (I-Ai), (I-B), or (I-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof; or a pharmaceutical composition comprising any of the foregoing and a pharmaceutically acceptable excipient. In some embodiments, the fatty liver disease is mediated by SREBP. In certain embodiments, a subject may have fatty liver disease when the fat content of the subject's liver is 5% or greater. In some embodiments, a subject with fatty liver disease has NASH, or liver fibrosis associated with NASH. In certain embodiments, a subject with fatty liver disease has not been diagnosed with NASH or liver fibrosis associated with NASH. Treatment of fatty liver disease may be evaluated, for example, by magnetic resonance imaging (MRI), magnetic resonance elastography (MRE), ultrasound, or computerized tomography (CT); reduction of the liver enzyme alanine aminotransferase (ALT); reduction of the liver enzyme aspartate aminotransferase (ALT); reduction of liver inflammation as evaluated through histological scoring of liver biopsy; reduction of liver fibrosis as evaluated through histological scoring of liver biopsy; reduction of liver fat content as evaluated through histological scoring of liver biopsy; or any combinations thereof.
[0179] In some embodiments of the uses and methods of treating liver disease provided herein, such as methods of treating liver fibrosis, fatty liver disease, or NASH, the subject is
administered between about 0.01 mg/kg to about 100 mg/kg of compound of Formula (X), (X- A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-B), (Z-Ai), (Z-Bi), (I), (I-A), (I-Ai), (I-B), or (I-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, relative to the body mass of the subject In some embodiments, about 0.7 mg to about 7 g daily, or about 7 mg to about 350 mg daily, or about 350 mg to about 1.75 g daily, or about 1.75 to about 7 g daily of the compound of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-B), (Z-Ai), (Z-Bi), (I), (I-A), (I-Ai), (I-B), or (I-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof is administered to the subject in need thereof. In certain embodiments, the compound or pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, is administered as a pharmaceutical composition, as described herein.
[0180] Other metabolic disorders which may be treated with the compounds or pharmaceutical compositions described herein may include, for example, insulin resistance, hyperglycemia, diabetes mellitus, dyslipidemia, adiposopathy, obesity, and Metabolic Syndrome. In some embodiments, the metabolic disorder is mediated by a genetic factor. In other embodiments, the metabolic disorder is mediated by one or more environmental factors, such as a diet rich in fat, or a diet rich in sugar, or a combination thereof. In some embodiments, the metabolic disorder is mediated by SREBP. In some embodiments, the diabetes mellitus is type I diabetes. In certain embodiments, the diabetes mellitus is type Π diabetes.
[0181] Provided herein are uses and methods of treating diabetes in a subject in need thereof, comprising administering to the subject in need thereof a compound of Formula (X), (X-A), (X- Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-B), (Z-Ai), (Z-Bi), (I), (I-A), (I-Ai), (I-B), or (I-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof; or a
pharmaceutical composition comprising any of the foregoing and a pharmaceutically acceptable excipient. Diabetes (also known as diabetes mellitus) refers to a disease or condition that is generally characterized by metabolic defects in production and utilization of glucose which result in the failure to maintain appropriate blood sugar levels in the body. In some embodiments, the diabetes is type Π diabetes, which is characterized by insulin resistance, in which insulin loses its ability to exert its biological effects across a broad range of concentrations. In some
embodiments, the diabetes is mediated by a component of the SREBP pathway, such as an SREBP or SCAP.
[0182] Further provided herein are uses and methods of treating insulin resistance in a subject in need thereof, comprising administering to the subject in need thereof a compound of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-B), (Z-Ai), (Z-Bi), (I), (I-A), (I-Ai), (I-B), or (I-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof; or a pharmaceutical composition comprising any of the foregoing and a pharmaceutically acceptable excipient. Insulin resistance has been hypothesized to unify the clustering of hypertension, glucose intolerance, hyperinsulinemia, increased levels of triglyceride, decreased HDL cholesterol, and central and overall obesity. "Metabolic Syndrome" refers to a similar clustering of conditions, which may include abdominal obesity, hypertension, high blood sugar, high serum triglycerides (such as elevated fasting serum triglycerides), and low HDL levels, and is associated with a risk of developing cardiovascular disease and/or type Π diabetes. Further provided herein are uses and methods of treating Metabolic Syndrome in a subject in need thereof, comprising administering to the subject in need thereof a compound of Formula (X), (X- A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-B), (Z-Ai), (Z-Bi), (I), (I- A), (I-Ai), (I-B), or (I-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof; or a
pharmaceutical composition comprising any of the foregoing and a pharmaceutically acceptable excipient In some embodiments, the Metabolic Syndrome or insulin resistance is mediated by a component of the SREBP pathway, such as an SREBP or SCAP.
[0183] In some embodiments of the uses and methods of treating insulin resistance, hyperglycemia, diabetes mellitus, obesity, or Metabolic Syndrome provided herein, the subject is administered between about 0.01 mg/kg to about 100 mg/kg of compound of Formula (X), (X- A), (Χ-ΑΪ), (X-B), (X-Bi), (Z), (Z-A), (Z-B), (Z-Ai), (Z-Bi), (I), (I-A), (Ι-ΑΪ), (I-B), or (I-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, relative to the body mass of the subject In some embodiments, about 0.7 mg to about 7 g daily, or about 7 mg to about 350 mg daily, or about 350 mg to about 1.75 g daily, or about 1.75 to about 7 g daily of the compound of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-B), (Z-Ai), (Z-Bi), (I), (I-A), (I-Ai), (I-B), or (I-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof is administered to the subject in need thereof. In certain embodiments, the compound or pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, is administered as a pharmaceutical composition, as described herein.
[0184] In other embodiments, the metabolic disorder is dyslipidemia. Thus, in other aspects, provided herein are uses and methods of treating dyslipidemia in a subject in need thereof, comprising administering to the subject in need thereof a compound of Formula (X), (X-A), (X- Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-B), (Z-Ai), (Z-Bi), (I), (I-A), (I-Ai), (I-B), or (I-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof; or a
pharmaceutical composition comprising any of the foregoing and a pharmaceutically acceptable excipient Dyslipidemia refers to abnormal blood plasma levels of one or more lipids or one or more lipoproteins, or any combinations thereof. Dyslipidemia may include depressed levels or elevated levels of one or more lipids and/or one or more lipoproteins, or a combination of depressed and elevated levels (for example, elevated levels of one type of lipid and depressed levels of another type of lipid and/or lipoprotein). Dyslipidemia may include, but is not limited to, elevated low density lipoprotein cholesterol (LDL), elevated apolipoprotein B, elevated triglycerides (TGs), elevated lipoprotein(a), elevated apolipoprotein A, reduced high density lipoprotein cholesterol (HDL), or reduced apolipoprotein Al, or any combinations thereof.
Dyslipidemia, such as abnormal cholesterol or abnormal TG levels, is associated with an increased risk for vascular disease (such as heart attack or stroke), atherosclerosis, and coronary artery disease. In some embodiments of the uses and methods provided herein, the dyslipidemia is hyperlipidemia. Hyperlipidemia refers to the presence of an abnormally elevated level of lipids in the blood, and may include (1) hypercholesterolemia (an elevated cholesterol level); (2) hypertriglyceridemia, (an elevated triglyceride level); and (3) combined hyperlipidemia, (a combination of hypercholesterolemia and hypertriglyceridemia). Dyslipidemia may arise from a combination of genetic predisposition and diet, and may be associated with being overweight, diabetes, or Metabolic Syndrome. Lipid disorders may also arise as the result of certain medications (such as those used for anti-rejection regimens in people who have had organ or tissue transplants). In some embodiments, the dyslipidemia, such as hyperlipidemia, is mediated by a component of the SREBP pathway, such as an SREBP or SCAP. Thus, in some aspects, provided herein are uses and methods of reducing cholesterol levels, modulating cholesterol metabolism, modulating cholesterol catabolism, modulating the absorption of dietary cholesterol, reversing cholesterol transport, or lowering triglycerides in a subject in need thereof, comprising administering to the subject in need thereof a compound of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-B), (Z-Ai), (Z-Bi), (I), (I-A), (I-Ai), (I-B), or (I-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof; or a pharmaceutical composition comprising any of the foregoing and a pharmaceutically acceptable excipient.
[0185] In some embodiments of the uses and methods of treating dyslipidemia provided herein, such as reducing cholesterol levels, modulating cholesterol metabolism, modulating cholesterol catabolism, modulating the absorption of dietary cholesterol, reversing cholesterol transport, or lowering triglycerides in a subject in need thereof as provided herein, the subject is administered between about 0.01 mg/kg to about 100 mg/kg of compound of Formula (X), (X- A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-B), (Z-Ai), (Z-Bi), (I), (L-A), (I-Ai), (I-B), or (I-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, relative to the body mass of the subject In some embodiments, about 0.7 mg to about 7 g daily, or about 7 mg to about 350 mg daily, or about 350 mg to about 1.75 g daily, or about 1.75 to about 7 g daily of the compound of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-Ai), (Z-B), (Z-Bi), (I), (I- A), (I-Ai), (I-B), or (I-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof is administered to the subject in need thereof. In certain embodiments, the compound or pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, is administered as a pharmaceutical composition, as described herein.
[0186] In still other aspects, provided herein are uses and methods of treating adiposopathy in a subject in need thereof, comprising administering to the subject in need thereof a compound of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-Ai), (Z-B), (Z-Bi), (I), (I-A), (I-Ai), (I-B), or (I-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof; or a pharmaceutical composition comprising any of the foregoing and a
pharmaceutically acceptable excipient. In some embodiments, the adiposopathy is associated with Metabolic Syndrome. In some embodiments, the adiposopathy is mediated by a component of the SREBP pathway, such as an SREBP or SCAP.
[0187] In certain aspects, provided herein are uses and methods of treating gallstones in a subject in need thereof, comprising administering to the subject in need thereof a compound of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-Ai), (Z-B), (Z-Bi), (I), (I-A), (I-Ai), (I-B), or (I-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof; or a pharmaceutical composition comprising any of the foregoing and a
pharmaceutically acceptable excipient. Gallstones may be associated with gallbladder inflammation, pancreas inflammation, or liver inflammation. In certain embodiments, the gallstones are cholesterol gallstones, which may form when bile contains a high concentration of cholesterol and not enough bile salts. In some embodiments, the gallstones, which may include cholesterol gallstone disease, is mediated by a component of the SREBP pathway, such as an SREBP or SCAP. [0188] In other embodiments, the disorder is pancreatitis. In yet other embodiments, the disorder is endotoxic shock, systemic inflammation, or xanthoma. In still further embodiments, the disorder is atherosclerosis, coronary artery disease, angina pectoris, carotid artery disease, stroke, or cerebral arteriosclerosis. In certain embodiments, any of the foregoing disorders are mediated by a component of the SREBP pathway, such as an SREBP or SCAP.
[0189] In some embodiments of the uses and methods of treating gall stones, pancreatitis, endotoxic shock, systemic inflammation, xanthoma, atherosclerosis, coronary artery disease, angina pectoris, carotid artery disease, stroke, or cerebral arteriosclerosis provided herein, the subject is administered between about 0.01 mg kg to about 100 mg/kg of compound of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-Ai), (Z-B), (Z-Bi), (I), (I-A), (I-Ai), (I-B), or (I-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, relative to the body mass of the subject In some embodiments, about 0.7 mg to about 7 g daily, or about 7 mg to about 350 mg daily, or about 350 mg to about 1.75 g daily, or about 1.75 to about 7 g daily of the compound of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z- Ai), (Z-B), (Z-Bi), (I), (I-A), (I-Ai), (I-B), or (I-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof is administered to the subject in need thereof. In certain embodiments, the compound or pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, is administered as a pharmaceutical composition, as described herein.
[0190] In some embodiments of any of the above embodiments, the subject is overweight, obese, has insulin resistance, is pre-diabetic or has type Π diabetes. In certain embodiments of any of the preceding embodiments, the subject has NASH.
2. Hyperproliferative Disorders
[0191] In another embodiment, the disorder is a hyperproliferative disorder. Thus, in some aspects, provided herein are uses and methods of treating a hyperproliferative disorder in a subject in need thereof, comprising administering to the subject in need thereof a compound of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-Ai), (Z-B), (Z-Bi), (I), (I-A), (I-Ai), (I-B), or (I-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof; or a pharmaceutical composition comprising any of the foregoing and a
pharmaceutically acceptable excipient [0192] As described above, the metabolism of fatty acids, cholesterol, and triglycerides may play a role in hyperproliferative disorders, such as cancer. Often, during transformation of noncancerous cells to cancerous cell, cell metabolism shifts from catabolic to anabolic processes. Depending on the type of tumor, the tumor cells may synthesize up to 95% of the saturated and mono- unsaturated fatty acids. Some cancers exhibit increased synthesis of fatty acids and other lipids (such as cholesterol), and steroids (such as androgens). Elevated fatty acid synthase (FAS) expression may induce progression to S phase in cancer cells, and inhibition of FAS expression may reduce cell growth and may induce apoptosis. Thus, components of the SREBP pathway may play a role in hype^oliferative disorders.
[0193] Hyperproliferative disorders, which are disorders associated with some degree of abnormal cell proliferation, may be benign or malignant Benign hyperproliferative disorders may include pre-cancerous disorders.
[0194] In some embodiments of the uses and methods provided herein, the disorder is a benign hyperproliferative disorder. In some embodiments, the benign hyperproliferative disorder is mediated by a component of the SREBP pathway, such as an SREBP or SCAP. In other embodiments, the disorder is a malignant hyperproliferative disorder. In some embodiments, the malignant hyperproliferative disorder is mediated by a component of the SREBP pathway, such as an SREBP or SCAP.
[0195] In some embodiments, the hyperproliferative disorder is breast cancer, liver cancer, ovarian cancer, pancreatic cancer, or prostate cancer.
[0196] In some embodiments of the uses and methods of treating a hyperproliferative disorder in a subject in need thereof, as described herein, between about 0.01 mg/kg to about 100 mg/kg. In some embodiments, about 0.7 mg to about 7 g daily, or about 7 mg to about 350 mg daily, or about 350 mg to about 1.75 g daily, or about 1.75 to about 7 g daily of the compound of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-Ai), (Z-B), (Z-Bi), (I), (I-A), (I-Ai), (I-B), or (I-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, relative to the body mass of the subject, is administered to the subject in need thereof. In certain embodiments, the compound or pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, is administered as a pharmaceutical composition, as described herein. III. Dosing and Methods of Administration
[019η The dose of a compound of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z- Ai), (Z-B), (Z-Bi), (I), (I- A), (I-Ai), (I-B), or (I-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, administered to a subject in need thereof according to any of the disclosed methods may vary with the particular compound or pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof; the method of administration; the particular disorder being treated; and the characteristics of the subject (such as weight, sex, and/or age). In some embodiments, the amount of the compound or pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof is a therapeutically effective amount
[0198] The effective amount of the compound or pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, relative to the subject's body mass, may in some embodiments be between about 0.01 mg/kg to about 100 mg/kg. In some embodiments, about 0.7 mg to about 7 g daily, or about 7 mg to about 350 mg daily, or about 350 mg to about 1.75 g daily, or about 1.75 to about 7 g daily of the compound of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-Ai), (Z-B), (Z-Bi), (I), (I-A), (I-Ai), (I-B), or (I-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof is administered to a subject in need thereof. In certain embodiments, the compound or pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, is administered as a pharmaceutical composition, as described herein.
[0199] Any of the uses and methods provided herein may comprise administering to a subject in need therein a pharmaceutical composition that comprises an effective amount of a compound provided herein, such as a compound of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-Ai), (Z-B), (Z-Bi), (I), (I-A), (I-Ai), (I-B), or (I-Bi), or a corresponding amount of a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, and a
pharmaceutically acceptable excipient.
[0200] The compounds of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-Ai), (Z- B), (Z-Bi), (I), (I-A), (I-Ai), (I-B), or (I-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof as provided herein, or a pharmaceutical composition comprising any of these and a pharmaceutically acceptable excipient as provided herein, may be administered to a subject via any suitable route, including, for example, intravenous, intramuscular, subcutaneous, oral, or transdermal routes.
[0201] In certain aspects, the invention provides a method of treating a disorder in subject in need thereof by parenteral ly administering to the subject in need thereof an effective amount of a compound of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-Ai), (Z-B), (Z-Bi), (I), (I- A), (I-Ai), (I-B), or (I-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof as provided herein, or a pharmaceutical composition comprising an effective amount of any of the foregoing and a pharmaceutically acceptable excipient as provided herein. In some embodiments, the disorder is a hyperproliferative disorder. In certain embodiments, the hyperproliferative disorder is cancer. In other embodiments, the disorder is fatty liver disease. In certain embodiments, the disorder is NASH. In some embodiments, the route of administration is intravenous, intra-arterial, intramuscular, or subcutaneous. In some embodiments, the route of administration is transdermal.
[0202] In some aspects, provided herein are pharmaceutical compositions comprising a compound of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-Ai), (Z-B), (Z-Bi), (I), (I- A), (I-Ai), (I-B), or (I-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, and a pharmaceutically acceptable excipient, for the use in treating a disorder as described herein. In some embodiments, the disorder is prevented, or the onset delayed, or the development delayed. In some embodiments, the disorder is a hyperproliferative disorder. In certain embodiments, the hyperproliferative disorder is cancer. In some embodiments, the disorder is fatty liver disease. In certain embodiments, the disorder is NASH. In certain embodiments, the composition comprises a pharmaceutical formulation which is present in a one or more unit dosage forms, for example one, two, three, four, or more unit dosage forms.
IV. Kits
[0203] Also provided are articles of manufacture comprising a compound of Formula (X), (X- A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-Ai), (Z-B), (Z-Bi), (I), (I- A), (I-Ai), (I-B), or (I-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or
pharmaceutical compositions comprising same, or unit dosages comprising any of these, as described herein in suitable packaging for use in the methods described herein. Suitable packaging may include, for example, vials, vessels, ampules, bottles, jars, flexible packaging, and the like. An article of manufacture may further be sterilized and/or sealed kits.
[0204] Further provided herein are kits comprising a compound of Formula (X), (X-A), (X- Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-Ai), (Z-B), (Z-Bi), (I), (I-A), (I-Ai), (I-B), or (I-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or a
pharmaceutical composition comprising same and a pharmaceutically acceptable excipient. The kits may be used in any of the uses and methods described herein. In some embodiments, the kit further comprises instructions. The kits may be used for any one or more of the uses described herein, and, accordingly, may contain instructions for the treatment of a hyperproliferative disease (such as cancer), fatty liver disease, or NASH. The kits may comprise one or more containers. Each component (if there is more than one component) may be packaged in separate containers or some components may be combined in one container where cross-reactivity and shelf life permit.
[0205] The kits may be in unit dosage forms, bulk packages (e.g., multi-dose packages) or subunit doses. For example, kits may be provided that contain sufficient dosages of a compound of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-Ai), (Z-B), (Z-Bi), (I), (I-A), (I- Ai), (I-B), or (I-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, as disclosed herein and/or a second pharmaceutically active compound useful for a disorder detailed herein to provide effective treatment of a subject for an extended period, such as one week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 3 months, 4 months, 5 months, 7 months, 8 months, 9 months, or more. Kits may also include multiple unit doses of a compound of Formula (X), (X-A), (X-Ai), (X-B), (X-Bi), (Z), (Z-A), (Z-Ai), (Z-B), (Z-Bi), (I), (I-A), (I- Ai), (I-B), or (I-Bi), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, and instructions for use, and be packaged in quantities sufficient for storage and use in pharmacies (e.g., hospital pharmacies or compounding pharmacies).
[0206] The kits may optionally include a set of instructions, generally written instructions, although electronic storage media (e.g., magnetic diskette or optical disk) containing instructions are also acceptable, relating to the use of components) of the uses and methods as described herein. The instructions included with the kit may include information as to the components and their administration to an individual.
ENUMERATED EMBODIMENTS
[0207] Embodiment I- 1. A compound of Formula (I):
Figure imgf000117_0001
or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein:
R1 is -C(O)OR9, -C(O)NR8R9, -S(O)2NR8R9, -NR10C(O)NR8R9, -NR10C(O)R9, -NR10S(O)2R9, -OR26, -SR9, -S(O)R9, -S(O)2R9, -NR8R9, or -NR10C(O)OR9,
wherein each of R8, R9, and R10 is independently selected from the group consisting of hydrogen, (C1-10)alkyl, (C3-10)cycloalkyl, (C3-10)cycloalkyliC1-10)alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, (C6-10)aryl, (C6-10)aryl(C1-10)alkyl, heteroaryl, and heteroaryl-alkyl,
R26 is (C1-10)alkyl, (C3-10)cycloalkyl, (C3-10)cycloalkyl(C1-10)alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, (C6-10)aryl, (C6-10)aryl(C1-10)alkyl, heteroaryl, or heteroaryl-alkyl,
each (C1-10)alkyl, (C3-10)cycloalkyl, (C3-10)cycloalkyl(C1-10)alkyl, heterocycloalkyl,
heterocycloalkyl-alkyl, (C6-10)aryl, (C6-10)aryl(C1-10)alkyl, heteroaryl, and heteroaryl-alkyl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, cyano, oxo, -OR19, -C(O)NR19R19, -NR19C(O)R19, -NR19C(O)NR19R19, -NR19R19, -S(O)2NR19R19, -NR19S(O)2R19, -S(O)D4R2°, -C(O)OR19, and -C(O)R20, each R19 is independently hydrogen, (C1-10)alkyl, (C3-10)cycloalkyl,
(C3-10)cycloalkyl(C1-10)alkyl, or heterocycloalkyl; or two R19, together with the nitrogen atom to which they are attached, form a
heterocycloalkyl; wherein each of the foregoing alkyl, cycloalkyl, or heterocycloalkyl moieties is independently unsubstituted or substituted with one or more halo,
each R20 is independently (C1-10)alkyl, (C3-10)cycloalkyl,
(C3-10)cycloalkyl(C1-10)alkyl, or heterocycloalkyl, wherein each of the foregoing is independently unsubstituted or substituted with one or more halo, and
n4 is 0, l, or 2;
or R8 and R9, together with the nitrogen atom to which they are attached, form a
heterocycloalkyl, wherein the heterocycloalkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of halo, cyano, oxo, (C1-10)alkyl, (C2-i0)alkenyl, (C2-i0)alkynyl, (C3-10)cycloalkyl,
(C3-10)cycloalkyl(C1-10)alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, (C6-10)aryl, (C6-10)aryl(C1-10)alkyl, heteroaryl, heteroaryl-alkyl, -OR23, -C(O)NR23R23, -NR23C(O)R23, -NR23C(O)OR23, -NR23C(O)NR23R23, -NR23R23, -S(O)2NR23R23, -NR23S(O)2R24, -S(0>6R24, -C(O)OR23, and -C(O)R24,
wherein each R23 is independently hydrogen, (C1-10)alkyl, (C3-10)cycloalkyl,
(C3-10)cycloalkyl(C1-10)alkyl, or heterocycloalkyl; or two R23, together with the nitrogen atom to which they are attached, form a
heterocycloalkyl; wherein each of the foregoing alkyl, cycloalkyl, or heterocycloalkyl moieties is independently unsubstituted or substituted with one or more halo,
each R24 is independently (C1-10)alkyl, (C3-10)cycloalkyl,
(C3-10)cycloalkyl(C1-10)alkyl, or heterocycloalkyl, wherein each of the foregoing is independently unsubstituted or substituted with one or more halo, and n6 is O, l, or 2;
R2 and R3 are independently selected from the group consisting of hydrogen, halo, cyano,
(C1-10)alkyl, (C3-10)cycloalkyl, (C3-10)cycloalkyl(C1-10)alkyl, -OR25, -C(O)NR25R25, -NR25C(O)R25, -NR25C(O)NR25R25, -NR25R25, -S(O)2NR25R25, -NR25S(O)2R25,
-S(O)n7R30, -NR25C(O)OR25R25, -C(O)OR25, or -C(O)R30,
wherein each (C1-10)alkyl, (C3-10)cycloalkyl, and (C3-ioJcycloalkyliCMoJalkyl is
independently unsubstituted or substituted with one or more halo, each R25 is independently hydrogen (C1-10)alkyl, (C3-10)cycloalkyl,
(C3-10)cycloalkyliC1-10)alkyl, or heterocycloalkyl; or two R25, together with the nitrogen atom to which they are attached, form a heterocycloalkyl; wherein each of the foregoing alkyl, cycloalkyl, or heterocycloalkyl moieties is independently unsubstituted or substituted with one or more halo,
each R30 is independently (C1-10)alkyl, (C3-10)cycloalkyl, (C3-10)cycloalkyl(C1-10)alkyl, or heterocycloalkyl, wherein each of the foregoing is independently unsubstituted or substituted with one or more halo, and
n7 is 0, l, or 2;
X1, X2, X3 and X4 are independently CR4 or N, wherein X2, X3 and X4 may not all be N;
when at least one of X1, X2, X3 and X4 is N, each R4 is independently selected from the group consisting of hydrogen, halo, cyano, (C1-10)alkyl, (C3-10)cycloalkyl,
(C3-10)cycloalkyl(C1-10)alkyl, heterocycloalkyl connected by an annular carbon atom, heterocycloalkyl-alkyl, -OR27, -C(O)NR27R27, -S(O)2NR27R27, -S(O)neR28, -C(O)OR27, and -C(O)R28,
wherein each (C1-10)alkyl, (C3-10)cycloalkyl, (C3-10)cycloalkyl(C1-10)alkyl,
heterocycloalkyl, and heterocycloalkyl-alkyl is independently
unsubstituted or substituted with one or more halo, each R27 is independently hydrogen or (C1-10)alkyl, (C3-10)cycloalkyl,
(C3-10)cycloalkyl(C1-10)alkyl, or heterocycloalkyl; or two R27, together with the nitrogen atom to which they are attached, form a
heterocycloalkyl; wherein each of the foregoing alkyl, cycloalkyl, or heterocycloalkyl moieties is independently unsubstituted or substituted with one or more halo,
each R28 is independently (C1-10)alkyl, (C3-10)cycloalkyl,
(C3-10)cycloalkyl(C1-10)alkyl, or heterocycloalkyl, wherein each of the foregoing is independently unsubstituted or substituted with one or more halo,
n8 is 0 , 1 or 2; or
when each of X1, X2, X3 and X4 is CR4, each R4 is independently selected from the group consisting of hydrogen, halo, cyano, (C1-10)alkyl, (C3-10)cycloalkyl,
(C3-10)cycloalkyl(C1-10)alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, -OR27,
-C(O)NR27R27, -NR27C(O)R27, -NR27R27, -NR27S(O)2R27, -S(O)2NR27R27, -S(O)n8R28, -C(O)OR27, and -C(O)R28,
wherein each (C1-10)alkyl, (C3-10)cycloalkyl, (C3-10)cycloalkyl(C1-10)alkyl,
heterocycloalkyl, and heterocycloalkyl-alkyl is independently unsubstituted or substituted with one or more halo, each R27 is independently hydrogen, (C1-10)alkyl, (C3-10)cycloalkyl,
(C3-10)cycloalkyl(C1-10)alkyl, or heterocycloalkyl; or two R27, together with the nitrogen atom to which they are attached, form a
heterocycloalkyl; wherein each of the foregoing alkyl, cycloalkyl, or heterocycloalkyl moieties is independently unsubstituted or substituted with one or more halo,
each R28 is independently (C1-10)alkyl, (C3-10)cycloalkyl,
(C3-10)cycloalkyl(C1-10)alkyl, or heterocycloalkyl, wherein each of the foregoing is independently unsubstituted or substituted with one or more halo, and
n8 is O, l, or 2;
two R4 on adjacent annular carbon atoms together with the carbon atoms to which they are attached may form a carbocyclyl or heterocyclyl, wherein the carbocyclyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, cyano, (C1-10)alkyl, (C3-10)cycloalkyl, (C3-10)cycloalkyl(C1-10)alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, -OR27, -C(O)NR27R27, -NR27C(O)R27, -NR27R27, -S(O)2NR27R27, -NR27S(O)2R27, -S(O)uiR28, and -C(O)R28,
or the heterocyclyl is unsubstituted or substituted with one or more substituents
independently selected from the group consisting of halo, cyano, (C1-10)alkyl, (C3-10)cycloalkyl, (C3-10)cycloalkyl(C1-10)alkyl, heterocycloalkyl connected by an annular carbon atom, heterocycloalkyl-alkyl, -OR27, -C(O)NR27R27, -S(O)2NR27R27, -S(O)„8R28, and -C(O)R28,
each R27 is independently hydrogen, (C1-10)alkyl, (C3-10)cycloalkyl,
(C3-10)cycloalkyl(C1-10)alkyl; or two R27, together with the nitrogen atom to which they are attached, form a heterocycloalkyl; wherein each of the foregoing alkyl, cycloalkyl, or heterocycloalkyl moieties is independently unsubstituted or substituted with one or more halo,
each R28 is independently (C1-10)alkyl, (C3-10)cycloalkyl, (C3-10)cycloalkyl(C1-10)alkyl, wherein each of the foregoing is independently unsubstituted or substituted with one or more halo, and
n8 is 0, l, or 2;
R15 and R17 are independently hydrogen, halo, alkyl, or -OR29, wherein each R29 is
independently hydrogen, (C1-10)alkyl, (C3-10)cycloalkyl, or (C3-10)cycloalkyl(C1-10)alkyl, and each alkyl or cycloalkyl in R15 or R17, if present, is independently unsubstituted or substituted with one or more halo;
R14 is (C1-10)alkyl, (C1-10)alkenyl, (C3-10)cycloalkyl, (C3-10)cycloalkenyl,
(C3-10)cycloalkyl(C1-10)alkyl, heterocycloalkyl connected through an annular carbon atom, heterocycloalkenyl connected through an annular carbon atom, heterocycloalkyl- alkyl, -OR5, -C(O)NR5R5, -R5C(O)NR5R5, -S(O)2NR5R5, -S(O)„iR6, or -C(O)R6; R16 is hydrogen, fluoro, (C1-10)alkyl, (C3-10)cycloalkyl, (C3-10)cycloalkyl(C1-10)alkyl, heterocycloalkyl connected through an annular carbon atom, heterocycloalkyl-alkyl, -OR5, -C(O)NR5R5, -R^OJNR^l5, -S(O)2NR5R5, -S(O)n1R6, or -C(O)R6;
the (C1-10)alkyl, (C1-10)alkenyl, (C3-10)cycloalkyl, (C3-10)cycloalkenyl,
(C3-10)cycloalkyl(C1-10)alkyl, heterocycloalkyl, heterocycloalkenyl, or heterocycloalkyl- alkyl, of R14 or R16 is independently unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of (C1-10)alkyl, halo, cyano, oxo, -OR7, -C(O)OR7, -C(O)NR7R7, -NR7C(O)R7, -NR7C(O)NR7R7, -NR7R7, -S(O)2NR7R7, -NR7S(O)2R7, -S(O)n2R13, and -C(O)R13;
each R5 is independently hydrogen, (C1-10)alkyl, or (C3-10)cycloalkyl; or two R5, together with the nitrogen atom to which they are attached, form a heterocycloalkyl; wherein each alkyl, cycloalkyl, or heterocycloalkyl is independently unsubstituted or substituted with one or more halo;
each R6 is independently (C1-10)alkyl or (C3-10)cycloalkyl, wherein each alkyl or cycloalkyl is independently unsubstituted or substituted with one or more halo;
each nl is independently 0, 1, or 2;
each R7 is independently hydrogen, unsubstituted (C1-10)alkyl, or (C1-10)alkyl substituted with one or more halo;
each n2 is independently 0, 1, or 2,
and each R13 is independently unsubstituted (C1-10)alkyl or (C1-10)alkyl substituted with one or more halo;
or R14 and R15, together with the atoms to which they are attached, form a carbocyclyl or
heterocyclyl,
wherein the carbocyclyl or heterocyclyl is unsubstituted or substituted with one or two substituents independently selected from the group consisting of halo, cyano, oxo, (C1-10)alkyl, (C3-10)cycloalkyl, (C3-10)cycloalkyl(C1-10)alkyl, -OR18, -C(O)NR,8R18, -NR18C(O)R18, -NR18C(O)NR18R18, -NR18R18, -S(O)2NR18R18, -NR18S(O)2R18, -S(O)asR.21, -C(O)OR18, and -C(O)R21, wherein each R18 is independently hydrogen, (C1-10)alkyl, or (C3-10)cycloalkyl; or two R18, together with the nitrogen atom to which they are attached, form a heterocycloalkyl; wherein each alkyl, cycloalkyl, or heterocycloalkyl is independently unsubstituted or substituted with one or more halo each R21 is independently (C1-10)alkyl or (C3-10)cycloalkyl, wherein each alkyl or cycloalkyl is independently unsubstituted or substituted with one or more halo, and
each n3 is independently 0, 1, or 2.
[0208] Embodiment 1-2. The compound of Embodiment 1-1, wherein the compound is of Formula (I-A):
Figure imgf000123_0001
or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R1, R2, R3, R14, R15, R16, R17, X1, X2, X3, and X4 are as defined for Formula (I).
[0209] Embodiment 1-3. The compound of Embodiment 1-1, wherein the compound is of Formula (I-B):
Figure imgf000123_0002
or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R1, R2, R3, R14, R15, R16, R17, X1, X2, X3, and X4 are as defined for Formula (I).
[0210] Embodiment 1-4. The compound of any one of Embodiments I- 1 to 1-3, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R17 is hydrogen.
[0211] Embodiment 1-5. The compound of any one of Embodiments I- 1 to 1-4, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R1 is -C(O)NR8R9, -SiO^NR8R9, -NR10C(O)NR8R9, -NR10C(O)R9, -NR10C(O)OR9, or -NR10S(O)2R9
[0212] Embodiment 1-6. The compound of any one of Embodiments 1-1 to 1-5, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R1 is -NR10C(O)NR8R9.
[0213] Embodiment 1-7. The compound of any one of Embodiments I- 1 to 1-5, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R1 is -NR10C(O)OR9.
[0214] Embodiment 1-8. The compound of any one of Embodiments 1-1 to 1-5, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R1 is -NR10S(O)2R9.
[0215] Embodiment 1-9. The compound of any one of Embodiments I- 1 to 1-8, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R10 is hydrogen.
[0216] Embodiment I- 10. The compound of any one of Embodiments 1-1 to 1-5, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R1 is -QOJNR^.9, and the R8 and R9 together with the nitrogen to which they are attached form an unsubstituted or substituted heterocycloalkyl.
[0217] Embodiment 1-11. The compound of any one of Embodiments 1-1 to 1-5, or 1-10, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R1 is -0(O)ΝΚ¾9, and the R8 and R9 together with the nitrogen to which they are attached form an unsubstituted or substituted piperidinyl.
[0218] Embodiment 1-12. The compound of Embodiment I- 11, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein the piperidinyl is substituted with one to three substituents independently selected from the group consisting of -OR23, (C1-10)alkyl, and -NR23C(O)OR23.
[0219] Embodiment 1-13. The compound of any one of Embodiments 1-1 to 1-12, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R2 is halo.
[0220] Embodiment 1-14. The compound of any one of Embodiments I- 1 to I- 13 , or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein one of X1, X2, X3, and X4 are N.
[0221] Embodiment 1-15. The compound of any one of Embodiments 1-1 to 1-13, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein X1, X2, and X4 are CR4, and X3 is N.
[0222] Embodiment 1-16. The compound of any one of Embodiments I- 1 to I- 13 , or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein two of X\ X2, X3, and X4 are N.
[0223] Embodiment 1-17. The compound of any one of Embodiments 1-1 to 1-13, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein each of X1, X2, X3 and X4 is CR4.
[0224] Embodiment 1-18. The compound of any one of Embodiments I- 1 to I- 17, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein each R4 is independently selected from the group consisting of hydrogen, halo, cyano, (C1-10)alkyl, and -OR27
[0225] Embodiment I- 19. The compound of any one of Embodiments I- 1 to I- 18, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R14 is (C1-10)alkyl or heterocycloalkyl connected through an annular carbon atom, wherein the alkyl or heterocycloalkyl is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of (C1-10)alkyl, halo, -C(O)OR7, and -OR5.
[0226] Embodiment 1-20. The compound of any one of Embodiments I- 1 to I- 16, 1- 18, or I- 19, wherein at least one of X2, X3 and X4 is N, and an adjacent annular carbon is bonded to R4, wherein the R4 is independently hydrogen, fluoro, cyano, (C1-10)alkyl, or -OR27.
[0227] Embodiment 1-21. The compound of any one of Embodiments 1-1 to 1-20, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R3 is hydrogen.
[0228] Embodiment 1-22. The compound of any one of Embodiments I- 1 , 1-2, or 1-4 to 1-21 , wherein the compound is of Formula (I-Ai):
Figure imgf000126_0001
or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R1, R2, R3, R14, R15, R16, R17, X1, X2, X3, and X4 are as defined for Formula (I).
[0229] Embodiment 1-23. The compound of any one of Embodiments 1-1 or 1-3 to 1-21, wherein the compound is of Formula (I-Bi):
Figure imgf000127_0001
or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R1, R2, R3, R14, R15, R16, R17, X1, X2, X3, and X4 are as defined for Formula (I).
[0230] Embodiment 1-24. The compound of any one of Embodiments 1-1, 1-2, 1-4 to 1-7, or 1-9 to 1-22, selected from the group consisting of:
Figure imgf000127_0002
Figure imgf000128_0001
Figure imgf000129_0001
Figure imgf000130_0001
, , or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer of any of the foregoing.
[0231] Embodiment I-2S. A pharmaceutical composition, comprising the compound of any one of Embodiments 1-1 to 1-24, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, and a pharmaceutically acceptable excipient
[0232] Embodiment 1-26. A method of inhibiting a sterol regulatory element-binding protein (SREBP), comprising contacting the SREBP or contacting an SREBP cleavage activating- protein (SCAP) with a compound of any one of Embodiments 1-1 to 1-24, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or the pharmaceutical composition of Embodiment 1-25. [0233] Embodiment 1-27. A method of inhibiting the proteolytic activation of a sterol regulatory element-binding protein (SREBP), comprising contacting an SREBP cleavage activating-protein (SCAP) with a compound of any one of Embodiments 1-1 to 1-24, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or the pharmaceutical composition of Embodiment 1-25.
[0234] Embodiment 1-28. The method of Embodiment 1-26 or 1-27, wherein the SREBP is an SREBP-1.
[0235] Embodiment 1-29. The method of Embodiment 1-28, wherein the SREBP-1 is SREBP- la.
[0236] Embodiment 1-30. The method of Embodiment 1-28, wherein the SREBP-1 is SREBP- lc.
[0237] Embodiment 1-31. The method of Embodiment 1-26 or 1-27, wherein the SREBP is SREBP-2.
[0238] Embodiment 1-32. The method of any one of Embodiments 1-26 to 1-31 , wherein SREBP is inhibited in a subject in need thereof.
[0239] Embodiment 1-33. The method of any one of Embodiments 1-26 to 1-32, wherein SCAP is inhibited in a subject in need thereof.
[0240] Embodiment 1-34. The method of any one of Embodiments 1-26 to 1-33, wherein the expression of one or more genes selected from the group consisting of ACSS2, ALDOC, CYP51 Al, DHCR7, ELOVL6, FASN, FDFT1 , FDPS, HMGCS1, HSD17B7, Π3Ι1 , INSIG1, LDLR, LSS, ME1, PCSK9, PMVK, RDH11 , SC5DL, SQLE, STARD4, TM7SF2, PNPLA3, SREBFl, SREBF2, HMGCR, MVD, MVK, ACLY, MSMOl, ACACA, and ACACB is reduced after contacting the SREBP or SCAP with the compound, or pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or the pharmaceutical composition.
[0241] Embodiment 1-35. A method of treating a disorder in a subject in need thereof, comprising administering to the subject an effective amount of a compound of any one of Embodiments 1-1 to 1-24, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or the pharmaceutical composition of Embodiment 1-25.
[0242] Embodiment 1-36. A method of treating a disorder in a subject in need thereof, wherein the disorder is mediated by a sterol regulatory element-binding protein (SREBP), comprising administering to the subject an effective amount of a compound of any one of Embodiments 1-1 to 1-24, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or the pharmaceutical composition of Embodiment 1-25.
[0243] Embodiment 1-37. The method of Embodiment 1-35 or 1-36, wherein the disorder is Metabolic Syndrome, type 2 diabetes, obesity, liver disease, insulin resistance, adiposopathy, or dyslipidemia.
[0244] Embodiment 1-38. The method of Embodiment 1-37, wherein the dyslipidemia is hypertriglyceridemia or elevated cholesterol levels.
[0245] Embodiment 1-39. The method of Embodiment 1-37, wherein the liver disease is nonalcoholic steatohepatitis, liver fibrosis, or liver inflammation, or a combination thereof.
[0246] Embodiment 1-40. The method of Embodiment 1-35 or 1-36, wherein the disorder is a hyperproliferative disorder.
[0247] Embodiment 1-41. The method of Embodiment 1-40, wherein the hyperproliferative disorder is cancer.
[0248] Embodiment 1-42. The method of Embodiment 1-41 , wherein the cancer is breast cancer, liver cancer, ovarian cancer, pancreatic cancer, or prostate cancer.
[0249] Embodiment 1-43. The method of Embodiment 1-35 or 1-36, wherein the disorder is endotoxic shock, systemic inflammation, or atherosclerosis.
[0250] Embodiment 1-44. Use of a compound of any one of Embodiments 1-1 to 1-24, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, in the
manufacture of a medicament for use in treating a disorder in a subject in need thereof. [0251] Embodiment 1-45. Use of a compound of any one of Embodiments 1-1 to 1-24, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, in the
manufacture of a medicament for use in inhibiting a sterol regulatory element-binding protein (SREBP) in a subject in need thereof.
[0252] Embodiment 1-46. Use of a compound of any one of Embodiments 1-1 to 1-24, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, in the
manufacture of a medicament for use in inhibiting the proteolytic activation of a sterol regulatory element-binding protein (SREBP) in a subject in need thereof.
[0253] Embodiment 1-47. Use of a compound of any one of Embodiments 1-1 to 1-24, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, in the
manufacture of a medicament for use in treating a disorder in a subject in need thereof, wherein the disorder is mediated by a sterol regulatory element-binding protein (SREBP).
[0254] Embodiment 1-48. Use of a compound of any one of Embodiments 1-1 to 1-24, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or the pharmaceutical composition of Embodiment I-2S, for inhibiting a sterol regulatory element- binding protein (SREBP).
[0255] Embodiment 1-49. Use of a compound of any one of Embodiments 1-1 to 1-24, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or the pharmaceutical composition of Embodiment I-2S, for inhibiting an SREBP cleavage activating protein (SCAP).
[0256] Embodiment 1-50. The use of any one of Embodiments 1-45 to 1-49, wherein the SREBP is an SREBP- 1.
[0257] Embodiment 1-51. The method of Embodiment 1-50, wherein the SREBP-1 is SREBP- la.
Embodiment 1-52. The method of Embodiment 1-50, wherein the SREBP-1 is SREBP- [0259] Embodiment 1-53. The use of any one of Embodiments 1-45 to 1-49, wherein the SREBP is SREBP-2.
[0260] Embodiment 1-54. The use of any one of Embodiments 1-44 to 1-53, wherein SREBP is inhibited in a subject in need thereof.
[0261] Embodiment 1-55. The use of any one of Embodiments 1-44 to 1-54, wherein SCAP is inhibited in a subject in need thereof.
[0262] Embodiment 1-56. Use of a compound of any one of Embodiments 1-1 to 1-24, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or the
pharmaceutical composition of Embodiment 1-25, for treating a disorder in a subject in need thereof.
[0263] Embodiment 1-57. Use of a compound of any one of Embodiments 1-1 to 1-24, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or the
pharmaceutical composition of Embodiment 1-25, for treating a disorder in a subject in need thereof, wherein the disorder is mediated by a sterol regulatory element-binding protein
(SREBP).
[0264] Embodiment 1-58. The use of Embodiment 1-56 or 57, wherein the disorder is
Metabolic Syndrome, type 2 diabetes, obesity, liver disease, insulin resistance, adiposopathy, or dyslipidemia.
[0265] Embodiment 1-59. The use of Embodiment 1-58, wherein the dyslipidemia is hypertriglyceridemia or elevated cholesterol levels.
[0266] Embodiment 1-60. The use of Embodiment 1-58, wherein the liver disease is nonalcoholic steatohepatitis, liver fibrosis, or liver inflammation, or a combination thereof.
[0267] Embodiment 1-61. The use of Embodiment 1-56 or 1-57, wherein the disorder is a hyperproliferative disorder.
[0268] Embodiment 1-62. The use of Embodiment 1-61, wherein the hyperproliferative disorder is cancer. [0269] Embodiment 1-63. The use of Embodiment 1-62, wherein the cancer is breast cancer, liver cancer, ovarian cancer, pancreatic cancer, or prostate cancer.
[0270] Embodiment 1-64. The use of Embodiment 1-56 or 1-57, wherein the disorder is endotoxic shock, systemic inflammation, or atherosclerosis.
[0271] Embodiment 1-65. A method of treating non-alcoholic steatohepatitis (NASH) in a subject in need thereof, comprising administering to the subject an effective amount of a compound of any one of Embodiments 1-1 to 1-24, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or the pharmaceutical composition of Embodiment 1-25.
[0272] Embodiment 1-66. Use of a compound of any one of Embodiments 1-1 to 1-24, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or the
pharmaceutical composition of Embodiment 1-25, for treating non-alcoholic steatohepatitis (NASH) in a subject in need thereof.
[0273] Embodiment 1-67. Use of a compound of any one of Embodiments 1-1 to 1-24, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or the
pharmaceutical composition of Embodiment 1-25, in the manufacture of a medicament for use in treating non-alcoholic steatohepatitis (NASH) in a subject in need thereof.
[0274] Embodiment 1-68. A method of treating a hyperproliferative disorder in a subject in need thereof, comprising administering to the subject an effective amount of a compound of any one of Embodiments 1-1 to 1-24, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or the pharmaceutical composition of Embodiment 1-25.
[0275] Embodiment 1-69. Use of a compound of any one of Embodiments 1-1 to 1-24, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or the
pharmaceutical composition of Embodiment 1-25, for treating a hyperproliferative disorder in a subject in need thereof.
[0276] Embodiment 1-70. Use of a compound of any one of Embodiments 1-1 to 1-24, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or the pharmaceutical composition of Embodiment I-2S, in the manufacture of a medicament for treating a hyperproliferative disorder in a subject in need thereof.
[0277] Embodiment 1-71. The compound of Embodiment 1-1 , selected from the group consisting of:
Figure imgf000136_0001
Figure imgf000137_0001
Figure imgf000138_0001
Figure imgf000139_0001
and or a pharmaceutically acceptable salt, solvate, tautomer,
Figure imgf000139_0002
isotope, or isomer thereof.
[0278] Embodiment 1-72. The compound of any one of Embodiments 1-1 to 1-3, 1-22, or 1-23, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R1 is
Figure imgf000139_0003
[0279] Embodiment 1-73. The compound of any one of Embodiments 1-1 to 1-3, 1-22, or 1-23, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R1 is
Figure imgf000140_0001
[0280] Embodiment 1-74. The compound of any one of Embodiments 1-1 to 1-3, 1-22, or 1-23, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R1 is
Figure imgf000140_0002
[0281] Embodiment 1-75. The compound of any one of Embodiments 1-1 to 1-3, 1-22, or 1-23, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R1 is
Figure imgf000140_0003
[0282] Embodiment 1-76. The compound of any one of Embodiments 1-1 to 1-3, 1-22, or 1-23, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R14 is
Figure imgf000140_0004
[0283] Embodiment 1-77. A pharmaceutical composition, comprising a compound of any one of Embodiments 1-71 to 1-76, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, and a pharmaceutically acceptable excipient.
[0284] Embodiment II- 1. A compound of Formula (Z):
Figure imgf000141_0001
a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein: is -C(O)OR9, -C(O)NR8R9, -S(O)2NR8R9, -NR10C(O)NR8R9, -NR10C(O)R9, -NR10S(O)2R9, -OR26, -SR9, -S(O)R9, -S(O)2R9, -NR8R9, -NR10C(O)OR9, -C(O)R26, -NR10S(O)2NR8R9, or -C(O)NR10S(O)2R9;
wherein each of R8, R9, and R10 is independently selected from the group consisting of hydrogen, (C1-10)alkyl, (C3-10)cycloalkyl, (C3-10)cycloalkyl(C1-10)alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, (C6-10)aryl, (C6-10)aryl(C1-10)alkyl, heteroaryl, and heteroaryl-alkyl,
R26 is (C1-10)alkyl, (C3-10)cycloalkyl, (C3-10)cycloalkyl(C1-10)alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, (C6-10)aryl, (C6-10)aryl(C1-10)alkyl, heteroaryl, or heteroaryl-alkyl,
each (C1-10)alkyl, (C3-10)cycloalkyl, (C3-10)cycloalkyl(C1-10)alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, (Cfr-i0)aryl, (Cfr-i0)aryl(C1-10)alkyl, heteroaryl, and heteroaryl-alkyl of R8, R9, R10, and R26 is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, cyano, oxo, -OR19, -C(O)NR19R19, -NR19C(O)R19, -NR,9C(O)NR,9R19, -NR19R19, -S(O)2NR19R19, -NR,9S(O)2R19, -S(O)D4R2°, -C(O)OR,9, and -C(O)R20,
each R19 is independently hydrogen, (C1-10)alkyl, (C3-10)cycloalkyl,
(C3-10)cycloalkyl(C1-10)alkyl, or heterocycloalkyl; or two R19, together with the nitrogen atom to which they are attached, form a
heterocycloalkyl; wherein each of the foregoing alkyl, cycloalkyl, or heterocycloalkyl moieties is independently unsubstituted or substituted with one or more halo,
each R20 is independently (C1-10)alkyl, (C3-10)cycloalkyl,
(C3-10)cycloalkyl(C1-10)alkyl, or heterocycloalkyl, wherein each of the foregoing is independently unsubstituted or substituted with one or more halo, and
n4 is 0, l, or 2;
or R8 and R9, together with the nitrogen atom to which they are attached, form a
heterocycloalkyl, wherein the heterocycloalkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of halo, cyano, oxo, (C1-10)alkyl, (C2-i0)alkenyl, (C2-i0)alkynyl, (C3-10)cycloalkyl,
(C3-10)cycloalkyl(C1-10)alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, (C6-10)aryl, (C6-10)aryl(C1-10)alkyl, heteroaryl, heteroaryl-alkyl, -OR23, -C(O)NR23R23, -NR23C(O)R23, -NR23C(O)OR23, -NR23C(O)NR23R23, -NR23R23, -S(O)2NR23R23, -NR23S(O)2R24, -S(0>*R24, -C(O)OR23, and -C(O)R24,
wherein eachR23 is independently hydrogen, (C1-10)alkyl, (C3-10)cycloalkyl,
(C3-10)cycloalkyl(C1-10)alkyl, or heterocycloalkyl; or two R23, together with the nitrogen atom to which they are attached, form a heterocycloalkyl; wherein each of the foregoing alkyl, cycloalkyl, or heterocycloalkyl moieties is independently unsubstituted or substituted with one or more halo,
each R24 is independently (C1-10)alkyl, (C3-10)cycloalkyl,
(C3-10)cycloalkyl(C1-10)alkyl, or heterocycloalkyl, wherein each of the foregoing is independently unsubstituted or substituted with one or more halo, and
n6 is 0, 1, or 2;
R3 are independently selected from the group consisting of hydrogen, halo, cyano, (C1-10)alkyl, (C3-10)cycloalkyl, (C3-10)cycloalkyl(C1-10)alkyl, -OR25, -C(O)NR25R25, -NR25C(O)R25, -NR25C(O)NR25R25, -NR25R25, -S(O)2NR25R25, -NR25S(O)2R25,
-S(O)n7R30, -NR25C(O)OR25R25, -C(O)OR25, or -C(O)R30,
wherein each (C1-10)alkyl, (C3-10)cycloalkyl, and (C3-10)cycloalkyl(C1-10)alkyl is
independently unsubstituted or substituted with one or more halo, each R25 is independently hydrogen (C1-10)alkyl, (C3-10)cycloalkyl,
(C3-10)cycloalkyl(C1-10)alkyl, or heterocycloalkyl; or two R25, together with the nitrogen atom to which they are attached, form a heterocycloalkyl; wherein each of the foregoing alkyl, cycloalkyl, or heterocycloalkyl moieties is independently unsubstituted or substituted with one or more halo,
each R30 is independently (C1-10)alkyl, (C3-10)cycloalkyl, (C3-10)cycloalkyl(C1-10)alkyl, or heterocycloalkyl, wherein each of the foregoing is independently unsubstituted or substituted with one or more halo, and
n7 is 0, l, or 2;
X1, X2, X3 and X4 are independently CR4 or N, wherein X2, X3 and X4 may not all be N;
when at least one of X1, X2, X3 and X4 is N, each R4 is independently selected from the group consisting of hydrogen, halo, cyano, (C1-10)alkyl, (C3-10)cycloalkyl,
(C3-10)cycloalkyl(C1-10)alkyl, heterocycloalkyl connected by an annular carbon atom, heterocycloalkyl-alkyl, -OR27, -C(O)NR27R27, -S(O)2]SIR27R27, -S(O),*R28, -C(O)OR27, and -C(O)R28,
wherein each (C1-10)alkyl, (C3-10)cycloalkyl, (C3-10)cycloalkyl(C1-10)alkyl,
heterocycloalkyl, and heterocycloalkyl-alkyl is independently
unsubstituted or substituted with one or more halo, each R27 is independently hydrogen or (C1-10)alkyl, (C3-10)cycloalkyl,
(C3-10)cycloalkyl(C1-10)alkyl, or heterocycloalkyl; or two R27, together with the nitrogen atom to which they are attached, form a
heterocycloalkyl; wherein each of the foregoing alkyl, cycloalkyl, or heterocycloalkyl moieties is independently unsubstituted or substituted with one or more halo, each R28 is independently (C1-10)alkyl, (C3-10)cycloalkyl,
(C3-10)cycloalkyl(C1-10)alkyl, or heterocycloalkyl, wherein each of the foregoing is independently unsubstituted or substituted with one or more halo,
n8 is 0 , 1 or 2; or
when each of X1, X2, X3 and X4 is CR4, each R4 is independently selected from the group consisting of hydrogen, halo, cyano, (C1-10)alkyl, (C3-10)cycloalkyl,
(C3-10)cycloalkyl(C1-10)alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, -OR27,
-C(O)NR27R27, -NR27C(O)R27, -NR27R27, -NR27S(O)2R27, -S(O)2NR27R27, -S(O)ngR28, -C(O)OR27, and -C(O)R28,
wherein each (C1-10)alkyl, (C3-10)cycloalkyl, (C3-10)cycloalkyl(C1-10)alkyl,
heterocycloalkyl, and heterocycloalkyl-alkyl is independently unsubstituted or substituted with one or more halo, each R27 is independently hydrogen, (C1-10)alkyl, (C3-10)cycloalkyl,
(C3-10)cycloalkyl(C1-10)alkyl, or heterocycloalkyl; or two R27, together with the nitrogen atom to which they are attached, form a
heterocycloalkyl; wherein each of the foregoing alkyl, cycloalkyl, or heterocycloalkyl moieties is independently unsubstituted or substituted with one or more halo,
each R28 is independently (C1-10)alkyl, (C3-10)cycloalkyl,
(C3-10)cycloalkyl(C1-10)alkyl, or heterocycloalkyl, wherein each of the foregoing is independently unsubstituted or substituted with one or more halo, and
n8 is 0, 1, or 2; or
two R4 on adjacent annular carbon atoms together with the carbon atoms to which they are attached may form a carbocyclyl or heterocyclyl,
wherein the carbocyclyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, cyano, (C1-10)alkyl, (C3-10)cycloalkyl, (C3-10)cycloalkyl(C1-10)alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, -OR27, -C(O)NR27R27, -NR27C(O)R27, -NR27R27, -S(O)2NR27R27, -NR27S(O)2R27, -S(O),*R28, and -C(O)R28,
or the heterocyclyl is unsubstituted or substituted with one or more substituents
independently selected from the group consisting of halo, cyano, (C1-10)alkyl, (C3-10)cycloalkyl, (C3-10)cycloalkyl(C1-10)alkyl, heterocycloalkyl connected by an annular carbon atom, heterocycloalkyl-alkyl, -OR27, -C(O)NR27R27, -S(O)2NR27R27, -S(O)n8R28, and -C(O)R28,
each R27 is independently hydrogen, (C1-10)alkyl, (C3-10)cycloalkyl,
(C3-10)cycloalkyl(C1-10)alkyl; or two R27, together with the nitrogen atom to which they are attached, form a heterocycloalkyl; wherein each of the foregoing alkyl, cycloalkyl, or heterocycloalkyl moieties is independently unsubstituted or substituted with one or more halo,
each R28 is independently (C1-10)alkyl, (C3-10)cycloalkyl, (C3-10)cycloalkyl(C1-10)alkyl, wherein each of the foregoing is independently unsubstituted or substituted with one or more halo, and
n8 is 0, l, or 2;
R15 and R17 are independently hydrogen, halo, alkyl, or -OR29, wherein each R29 is
independently hydrogen, (C1-10)alkyl, (C3-10)cycloalkyl, or (C3-10)cycloalkyl(C1-10)alkyl, and each alkyl or cycloalkyl in R15 or R17, if present, is independently unsubstituted or substituted with one or more halo;
R14 is (C1-10)alkyl, (C1-10)alkenyl, (C3-10)cycloalkyl, (C3-10)cycloalkenyl,
(C3-10)cycloalkyl(C1-10)alkyl, heterocycloalkyl connected through an annular carbon atom, heterocycloalkenyl connected through an annular carbon atom, heterocycloalkyl- alkyl, -OR5, -C(O)NR5R5, -R5C(O)NR5R5, -S(O)2NR5R5, -S(O)n1R6, or -C(O)R6;
R16 is hydrogen, fluoro, (C1-10)alkyl, (C3-10)cycloalkyl, (C3-10)cycloalkyl(C1-10)alkyl,
heterocycloalkyl connected through an annular carbon atom, heterocycloalkyl-alkyl, -OR5, -C(O)NR5R5, -R5C(O)NR5R5, -S(O)2NR5R5, -S(O)n1R6, or -C(O)R6;
the (C1-10)alkyl, (C1-10)alkenyl, (C3-10)cycloalkyl, (C3-10)cycloalkenyl,
(C3-10)cycloalkyl(C1-10)alkyl, heterocycloalkyl, heterocycloalkenyl, or heterocycloalkyl- alkyl, of R14 or R16 is independently unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of (C1-10)alkyl, halo, cyano, oxo, -OR7, -C(O)OR7, -C(O)NR7R7, -NR7C(O)R7, -NR7C(O)NR7R7, -NR7R7, -S(O)2NR7R7, -NR7S(O)2R7, -S(O)n2R13, and -C(O)R13;
each R5 is independently hydrogen, (C1-10)alkyl, or (C3-10)cycloalkyl; or two R5, together with the nitrogen atom to which they are attached, form a heterocycloalkyl; wherein each alkyl, cycloalkyl, or heterocycloalkyl is independently unsubstituted or substituted with one or more halo;
each R6 is independently (C1-10)alkyl or (C3-10)cycloalkyl, wherein each alkyl or cycloalkyl is independently unsubstituted or substituted with one or more halo;
each nl is independently 0, 1, or 2;
each R7 is independently hydrogen, unsubstituted (C1-10)alkyl, or (C1-10)alkyl substituted with one or more halo;
each n2 is independently 0, 1, or 2,
and each R13 is independently unsubstituted (C1-10)alkyl or (C1-10)alkyl substituted with one or more halo;
or R14 and R15, together with the atoms to which they are attached, form a carbocyclyl or
heterocyclyl,
wherein the carbocyclyl or heterocyclyl is unsubstituted or substituted with one or two substituents independently selected from the group consisting of halo, cyano, oxo, (C1-10)alkyl, (C3-10)cycloalkyl, (C3-10)cycloalkyl(C1-10)alkyl, -OR18, -C(O)NR18R18, -NR18C(O)R18, -NR,8C(O)NR,8R18, -NR18R18, -S(O)2NR,8R18, -NR18S(O)2R18, -S(O)„3R21, -C(O)OR18, and -C(O)R21,
wherein each R18 is independently hydrogen, (C1-10)alkyl, or (C3-10)cycloalkyl; or two R18, together with the nitrogen atom to which they are attached, form a heterocycloalkyl; wherein each alkyl, cycloalkyl, or heterocycloalkyl is independently unsubstituted or substituted with one or more halo each R21 is independently (C1-10)alkyl or (C3-10)cycloalkyl, wherein each alkyl or cycloalkyl is independently unsubstituted or substituted with one or more halo, and
each n3 is independently 0, 1, or 2.
[0285] Embodiment II-2. The compound of Embodiment II-l , or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R1 is -C(O)OR9, -C(O)NR8R9, -S(O)2NR8R9, -NR10C(O)NR8R9, -NR10C(O)R9, -NR10S(O)2R9, -OR26, -SR9, -S(O)R9, -S(O)2R9, -NR8R9, or -NR10C(O)OR9.
[0286] Embodiment II-3. The compound of Embodiment II-l or II-2, wherein the compound is of Formula (Z-A):
Figure imgf000147_0001
or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R1, R2, R3, R14, R15, R16, R17, X1, X2, X3, and X4 are as defined for Formula (Z).
[0287] Embodiment II-4. The compound of Embodiment II-l or II-2, wherein the compound is of Formula (Z-B):
Figure imgf000147_0002
or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R1, R2, R3, R14, R15, R16, R17, X1, X2, X3, and X4 are as defined for Formula (Z).
[0288] Embodiment II-5. The compound of any one of Embodiments II-l to II-4, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R17 is hydrogen.
[0289] Embodiment II-6. The compound of any one of Embodiments II- 1 , or II-3 to II-S, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R1 is -C(O)OR9, -C(O)NR8R9, -S(O)NR8R9, -NR10S(O)2R9, -NR10C(O)OR9, -C(O)R26,
-NR10SiO^NR8R9, or -C(O)NR8S(O)2R9.
[0290] Embodiment II-7. The compound of any one of Embodiments II- 1 , or II-3 to II-6, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R1 is -C(O)NR8R9, -SiO^NR8R9, -NR10C(O)OR9, -NR10S(O)2R9, -C(O)R26, or -NR10S(O)2NR8R9.
[0291] Embodiment II-8. The compound of any one of Embodiments II-l to II-7, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R1 is -C(O)NR8R9.
[0292] Embodiment II-9. The compound of any one of Embodiments II-l to II-7, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R1 is -NR10C(O)OR9.
[0293] Embodiment II-l 0. The compound of any one of Embodiments II-l to II-7, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R1 is -NR10S(O)2R9.
[0294] Embodiment II- 11. The compound of any one of Embodiments II- 1 to II- 10, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R10 is hydrogen.
[0295] Embodiment II-12. The compound of any one of Embodiments II-l to II-l 1 , or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R8 is hydrogen. [0296] Embodiment 11-13. The compound of any one of Embodiments II- 1 to 11-12, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R9 is hydrogen, (C1-10)alkyl, or heterocycloalkyl-alkyl.
[0297] Embodiment 11-14. The compound of any one of Embodiments II- 1 to II-7, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R1 is -C(O)NR8R9, and the R8 and R9 together with the nitrogen to which they are attached form an unsubstituted or substituted heterocycloalkyl.
[0298] Embodiment II-l 5. The compound of any one of Embodiments II-l to II-7, or 11-14, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R1 is -C(O)NR8R9, and the R8 and R9 together with the nitrogen to which they are attached form an unsubstituted or substituted piperidinyl.
[0299] Embodiment II- 16. The compound of Embodiment II- 15, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein the piperidinyl is substituted with one to three substituents independently selected from the group consisting of -OR23, (C1-10)alkyl, -C(O)OR23, and -NR23C(O)OR23.
[0300] Embodiment II- 17. The compound of Embodiment II- 16, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R23 is independently hydrogen or (C1-10)alkyl.
[0301] Embodiment 11-18. The compound of any one of Embodiments II-l to 11-17, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R2 is halo or alkyl.
[0302] Embodiment II- 19. The compound of any one of Embodiment II- 1 to II- 18, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein one of X1, X2, X3, and X4 is N.
[0303] Embodiment II-20. The compound of any one of Embodiments II-l to II-18, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein X1, X2, and X4 are CR4, and X3 is N. [0304] Embodiment 11-21. The compound of any one of Embodiments II -1 to II-l 8, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein two of X', X2, X3, and X4 are N.
[0305] Embodiment 11-22. The compound of any one of Embodiments II- 1 to II- 18, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein each of X1, X2, X3 and X4 is CR4.
[0306] Embodiment 11-23. The compound of any one of Embodiments II- 1 to 11-22, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein each R4 is independently selected from the group consisting of hydrogen, halo, cyano, (C1-10)alkyl, and -OR27.
[0307] Embodiment 11-24. The compound of any one of Embodiments II-l to 11-22, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein X1 is CR4, wherein R4 is hydrogen, halo, or methyl.
[0308] Embodiment II-25. The compound of any one of Embodiments II-l to II-24, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R14 is (C1-10)alkyl or heterocycloalkyl connected through an annular carbon atom, wherein the alkyl or heterocycloalkyl is unsubstituted or substituted with one to three substituents selected from the group consisting of (C1-10)alkyl, halo, -C(O)OR7, oxo, and -OR5.
[0309] Embodiment 11-26. The compound of Embodiments II-25, or a or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R14 is (C1-10)alkyl unsubstituted or substituted with one to three substituents selected from the group consisting of (C1-10)alkyl, halo, -C(O)OR7, oxo, and -OR5.
[0310] Embodiment 11-27. The compound of any one of Embodiments II-l to 11-26, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R15, R16, and R17 are hydrogen. [0311] Embodiment 11-28. The compound of any one of Embodiments II -1 to 11-24, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R14 and R15, together with the atoms to which they are attached, form a heterocyclyl.
[0312] Embodiment 11-29. The compound of any one of Embodiments II-l to II-19, or II-25 to II-28, wherein at least one of X2, X3 and X4 is N, and an adjacent annular carbon is bonded to R4, wherein the R4 is independently hydrogen, fluoro, cyano, (C1-10)alkyl, or -OR27.
[0313] Embodiment 11-30. The compound of any one of Embodiments II -1 to 11-29, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R3 is hydrogen.
[0314] Embodiment II-31. The compound of any one of Embodiments II-l to II-29, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R3 is halo or alkyl.
[0315] Embodiment II-32. The compound of any one of Embodiments II-l to II-31 , or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R2 is halo or alkyl.
[0316] Embodiment II-33. The compound of any one of Embodiments II-l to II-31 , or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R2 is chloro.
[0317] Embodiment II-34. The compound of any one of Embodiments II-l to II-33, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein when one or more of R4, R5, R8, R9, R10, R14, R16, R19, R20, R23, R24, R25, R26, R27, R28, and R30 is heterocycloalkyl; or wherein R8 and R9, together with the nitrogen atom to which they are attached, form a heterocycloalkyl; or wherein two R18, together with the nitrogen atom to which they are attached; or wherein two R19, together with the nitrogen to which they are attached, form a heterocycloalkyl; or wherein two R25, together with the nitrogen to which they are attached, form a heterocycloalkyl; or wherein two R27, together with the nitrogen to which they are attached, form a heterocycloalkyl; each heterocycloalkyl is independently a 3- to 10-membered heterocycloalkyl. [0318] Embodiment 11-35. The compound of any one of Embodiments II -1 to 11-34, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein when one or more of R4, R8, R9, R10, R14, R16, and R26 is heterocycloalkyl-alkyl, each heterocycloalkyl- alkyl is independently (3-10 membered)heterocycloalkyl(C1-10)alkyl.
[0319] Embodiment 11-36. The compound of any one of Embodiments II -1 to 11-35, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein when one or more of R8, R9, R10, and R26 is heteroaryl, each heteroaryl is independently a 5- to 10- membered heteroaryl.
[0320] Embodiment 11-37. The compound of any one of Embodiments II -1 to 11-36, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein when one or more of R8, R9, R10, and R26 is heteroaryl-alkyl, each heteroaryl-alkyl is independently a (5-10 membered)heteroaryl(C1-10)alkyl.
[0321] Embodiment 11-38. The compound of any one of Embodiments II -1 to 11-37, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein two R4 on adjacent annular carbon atoms together with the carbon atoms to which they are attached form a carbocyclyl; or wherein R14 and R15 together with the atoms to which they are attached form a carbocyclyl; each carbocyclyl, is independently a (C3-C8)carbocyclyl.
[0322] Embodiment 11-39. The compound of any one of Embodiments II-l to II-38, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein two R4 on adjacent annular carbon atoms together with the carbon atoms to which they are attached form a heterocyclyl; or wherein R14 and R15 together with the atoms to which they are attached form a heterocyclyl; each heterocyclyl is independently a 4- to 8-membered heterocyclyl.
[0323] Embodiment 11-40. The compound of any one of Embodiments II-l to 11-39, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein when R14 or R16 is heterocycloalkenyl, each heterocycloalkenyl is independently a 3- to 8-membered heterocyloalkenyl.
[0324] Embodiment 11-41. The compound of any one of Embodiments II-l to II-3, or II-5 to 11-40, wherein the compound is of Formula (Z-Ai):
Figure imgf000153_0001
or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R1, R2, R3, R14, R15, R16, R17, X1, X2, X3, and X4 are as defined for Formula (Z).
[0325] Embodiment 11-42. The compound of any one of Embodiments II- 1 , II-2, or II-4 to II- 40, wherein the compound is of Formula (Z-Bi):
Figure imgf000153_0002
or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R1, R2, R3, R14, R15, R16, R17, X1, X2, X3, and X4 are as defined for Formula (Z).
[0326] Embodiment II-43. The compound of Embodiment II-1, selected from the group consisting of:
Figure imgf000154_0001
Figure imgf000155_0001
Figure imgf000156_0001
Figure imgf000157_0001
Figure imgf000158_0001
Figure imgf000159_0001
, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer of any of the foregoing.
[0327] Embodiment II-44. The compound of Embodiment II-l or II-2, selected from the group consisting of:
Figure imgf000159_0002
Figure imgf000160_0001
Figure imgf000161_0001
Figure imgf000162_0001
F , or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer of any of the foregoing.
[0328] Embodiment II-45. The compound of Embodiment II- 1 , selected from the group consisting of:
Figure imgf000163_0001
Figure imgf000164_0001
or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer of any of the foregoing.
[0329] Embodiment 11-46. The compound of Embodiment II- 1 , selected from the group consisting of:
Figure imgf000164_0002
isotope, or isomer of any of the foregoing. [0330] Embodiment 11-47. A pharmaceutical composition, comprising the compound of any one of Embodiments II- 1 to 11-46, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, and a pharmaceutically acceptable excipient.
[0331] Embodiment 11-48. A method of inhibiting a sterol regulatory element-binding protein (SREBP), comprising contacting the SREBP or contacting an SREBP cleavage activating- protein (SCAP) with a compound of any one of Embodiments II-l to 11-46, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or the pharmaceutical composition of Embodiment II-47.
[0332] Embodiment 11-49. A method of inhibiting the proteolytic activation of a sterol regulatory element-binding protein (SREBP), comprising contacting an SREBP cleavage activating-protein (SCAP) with a compound of any one of Embodiment II-l to 11-46, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or the
pharmaceutical composition of Embodiment II-47.
[0333] Embodiment 11-50. The method of Embodiment 11-48 or 11-49, wherein the SREBP is an SREBP-1.
[0334] Embodiment 11-51. The method of Embodiment 11-50, wherein the SREBP-1 is SREBP-la.
[0335] Embodiment II-52. The method of Embodiment II-50, wherein the SREBP-1 is SREBP-1 c.
[0336] Embodiment II-53. The method of Embodiment II-48 or II-49, wherein the SREBP is SREBP-2.
[0337] Embodiment II-54. The method of any one of Embodiments II-48 to 11-53, wherein SREBP is inhibited in a subject in need thereof.
[0338] Embodiment II-55. The method of any one of Embodiment II-48 to 11-54, wherein SCAP is inhibited in a subject in need thereof. [0339] Embodiment 11-56. The method of any one of Embodiments 11-48 to II-55, wherein the expression of one or more genes selected from the group consisting of ACSS2, ALDOC, CYP51A1, DHCR7, ELOVL6, FASN, FDFT1, FDPS, HMGCS1, HSD17B7, IDI1, INSIG1, LDLR, LSS, ME1, PCSK9, PMVK, RDH11, SC5DL, SQLE, STARD4, TM7SF2, PNPLA3, SREBF1, SREBF2, HMGCR, MVD, MVK, ACLY, MSMOl, ACACA, and ACACB is reduced after contacting the SREBP or SCAP with the compound, or pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or the pharmaceutical composition.
[0340] Embodiment 11-57. A method of treating a disorder in a subject in need thereof, comprising administering to the subject in need thereof an effective amount of a compound of any one of Embodiments II-l to II-46, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or the pharmaceutical composition of Embodiment II-47.
[0341] Embodiment 11-58. A method of treating a disorder in a subject in need thereof, wherein the disorder is mediated by a sterol regulatory element-binding protein (SREBP), comprising administering to the subject in need thereof an effective amount of a compound of any one of Embodiments II-l to II-46, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or the pharmaceutical composition of Embodiment II-47.
[0342] Embodiment 11-59. The method of Embodiment 11-57 or II-58, wherein the disorder is Metabolic Syndrome, type 2 diabetes, obesity, liver disease, insulin resistance, adiposopathy, or dyslipidemia.
[0343] Embodiment II-60. The method of Embodiment II-59, wherein the dyslipidemia is hypertriglyceridemia or elevated cholesterol levels.
[0344] Embodiment 11-61. The method of Embodiment 11-59, wherein the liver disease is nonalcoholic steatohepatitis, liver fibrosis, or liver inflammation, or a combination thereof.
[0345] Embodiment 11-62. The method of Embodiment 11-57 or II-58, wherein the disorder is a hyrjerproliferative disorder.
[0346] Embodiment 11-63. The method of Embodiment 11-62, wherein the hyperproliferative disorder is cancer. [0347] Embodiment 11-64. The method of Embodiment 11-63, wherein the cancer is breast cancer, liver cancer, ovarian cancer, pancreatic cancer, or prostate cancer.
[0348] Embodiment 11-65. The method of Embodiment 11-57 or II-58, wherein the disorder is endotoxic shock, systemic inflammation, or atherosclerosis.
[0349] Embodiment II-66. Use of a compound of any one of Embodiments II-l to II-46, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, in the
manufacture of a medicament for use in treating a disorder in a subject in need thereof.
[0350] Embodiment II-67. Use of a compound of any one of Embodiments II-l to II-46, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, in the
manufacture of a medicament for use in inhibiting a sterol regulatory element-binding protein (SREBP) in a subject in need thereof.
[0351] Embodiment II-68. Use of a compound of any one of Embodiments II-l to II-46, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, in the
manufacture of a medicament for use in inhibiting the proteolytic activation of a sterol regulatory element-binding protein (SREBP) in a subject in need thereof.
[0352] Embodiment II-69. Use of a compound of any one of Embodiments II-l to II-46, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, in the
manufacture of a medicament for use in treating a disorder in a subject in need thereof, wherein the disorder is mediated by a sterol regulatory element-binding protein (SREBP).
[0353] Embodiment II-70. Use of a compound of any one of Embodiments II-l to II-46, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or the pharmaceutical composition of Embodiment 11-47, for inhibiting a sterol regulatory element- binding protein (SREBP).
[0354] Embodiment II-71. Use of a compound of any one of Embodiments II-l to II-46, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or the pharmaceutical composition of Embodiment 11-47, for inhibiting an SREBP cleavage activating protein (SCAP). [03SS] Embodiment 11-72. The use of any one of Embodiments II-67 to II-71, wherein the SREBP is an SREBP-1.
[0356] Embodiment 11-73. The use of Embodiment II-72, wherein the SREBP-1 is SREBP-la.
[035η Embodiment II-74. The use of Embodiment II-72, wherein the SREBP-1 is SREBP-lc.
[0358] Embodiment II-75. The use of any one of Embodiments II-67 to II-71 , wherein the SREBP is SREBP-2.
[0359] Embodiment II-76. The use of any one of Embodiments II-67 to II-71, wherein SREBP is inhibited in a subject in need thereof.
[0360] Embodiment II-77. The use of any one of Embodiments II-67 to II-71, wherein SCAP is inhibited in a subject in need thereof.
[0361] Embodiment II-78. Use of a compound of any one of Embodiments II-l to II-46, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or the
pharmaceutical composition of Embodiment II-47, for treating a disorder in a subject in need thereof.
[0362] Embodiment II-79. Use of a compound of any one of Embodiments II-l to II-46, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or the
pharmaceutical composition of Embodiment II-47, for treating a disorder in a subject in need thereof, wherein the disorder is mediated by a sterol regulatory element-binding protein
(SREBP).
[0363] Embodiment II-80. The use of Embodiment II-78 or II-79, wherein the disorder is Metabolic Syndrome, type 2 diabetes, obesity, liver disease, insulin resistance, adiposopathy, or dyslipidemia.
[0364] Embodiment II-81. The use of Embodiment II-80, wherein the dyslipidemia is hypertriglyceridemia or elevated cholesterol levels. [0365] Embodiment 11-82. The use of Embodiment 11-80, wherein the liver disease is nonalcoholic steatohepatitis, liver fibrosis, or liver inflammation, or a combination thereof.
[0366] Embodiment 11-83. The use of Embodiment 11-78 or 11-79, wherein the disorder is a hyperproliferative disorder.
[0367] Embodiment II-84. The use of Embodiment II-83, wherein the hypeφroliferative disorder is cancer.
[0368] Embodiment 11-85. The use of Embodiment II-84, wherein the cancer is breast cancer, liver cancer, ovarian cancer, pancreatic cancer, or prostate cancer.
[0369] Embodiment II-86. The use of Embodiment II-78 or II-79, wherein the disorder is endotoxic shock, systemic inflammation, or atherosclerosis.
[0370] Embodiment II-87. A method of treating non-alcoholic steatohepatitis (NASH) in a subject in need thereof, comprising administering to the subject in need thereof an effective amount of a compound of any one of Embodiments II-l to II-46, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or the pharmaceutical composition of Embodiment II-47.
[0371] Embodiment II-88. Use of a compound of any one of Embodiments II-l to II-46, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or the pharmaceutical composition of Embodiment II-47, for treating non-alcoholic steatohepatitis (NASH) in a subject in need thereof.
[0372] Embodiment II-89. Use of a compound of any one of Embodiments II-l to II-46, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, in the manufacture of a medicament for use in treating non-alcoholic steatohepatitis (NASH) in a subject in need thereof.
[0373] Embodiment II-90. A method of treating a hyperproliferative disorder in a subject in need thereof, comprising administering to the subject in need thereof an effective amount of a compound of any one of Embodiments II-l to 11-46, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or the pharmaceutical composition of Embodiment
11-47.
[0374] Embodiment 11-91. Use of a compound of any one of Embodiments II-l to 11-46, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or the
pharmaceutical composition of Embodiment 11-47, for treating a hyperproliferative disorder in a subject in need thereof.
[0375] Embodiment 11-92. Use of a compound of any one of Embodiments II- 1 to 11-46, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, in the
manufacture of a medicament for use in treating a hyperproliferative disorder in a subject in need thereof.
[0376] Embodiment III- 1. A compound of Formula (X) :
Figure imgf000170_0001
or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein:
R1 is -C(O)OR9, -C(O)NR8R9, -S(O)2NR8R9, -NR10C(O)NR8R9, -NR10C(O)R9, -NR10S(O)2R9,
-OR26, -SR9, -S(O)R9, -S(O)2R9, -NR8R9, -NR10C(O)OR9, -C(O)R26, -NR10S(O)2NR8R9, - C(O)NR10S(O)2R9, or -C(O)NR10NR8R9;
wherein each of R8, R9, and R10 is independently selected from the group consisting of hydrogen, (C1-10)alkyl, (C3-10)cycloalkyl, (C3-10)cycloalkyl(C1-10)alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, (C6-10)aryl, (C6-10)aryl(C1-10)alkyl, heteroaryl, and heteroaryl-alkyl, R26 is (C1-10)alkyl, (C3-10)cycloalkyl, (C3-10)cycloalkyl(C1-10)alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, (C6-10)aryl, (C6-10)aryl(C1-10)alkyl, heteroaiyl, or heteroaryl-alkyl,
each (C1-10)alkyl, (C3-10)cycloalkyl, (C3-10)cycloalkyl(C1-10)alkyl, heterocycloalkyl,
heterocycloalkyl-alkyl, (C6-10)aryl, (C6-10)aryl(C1-10)alkyl, heteroaiyl, and heteroaryl-alkyl of R8, R9, R10, and R26 is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, (C1-10)alkyl, (C1-10)haloalkyl, cyano, oxo, -OR19,
-C(O)NR,9R19, -NR19C(O)R19, -NR,9C(O)NR,9R19, -NR19R19, -S(O)2NR,9R19, -NR,9S(O)2R,9, -S(O)n4R20, -C(O)OR19, -C(O)R20, and -(OR38)n150R19;
each R19 is independently hydrogen, (C1-10)alkyl, (C3-10)cycloalkyl,
(C3-10)cycloalkyl(C1-10)alkyl, or heterocycloalkyl; or two R19, together with the nitrogen atom to which they are attached, form a
heterocycloalkyl; wherein each of the foregoing alkyl, cycloalkyl, or heterocycloalkyl moieties is independently unsubstituted or substituted with one or more halo,
each R20 is independently (C1-10)alkyl, (C3-10)cycloalkyl,
(C3-10)cycloalkyl(C1-10)alkyl, or heterocycloalkyl, wherein each of the foregoing is independently unsubstituted or substituted with one or more halo,
each R38 is independently (C1-10)alkylene or (C1-10)haloalkylene,
each nlS is independently an integer from 1 to S, and
n4 is 0, l, or 2;
or R8 and R9, together with the nitrogen atom to which they are attached, form a
heterocycloalkyl, wherein the heterocycloalkyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, cyano, oxo, (C1-10)alkyl, (C2-10)alkenyl, (C2-10)alkynyl, (C3-10)cycloalkyl, (C3-10)cycloalkyl(C1-10)alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, (C6-10)aryl, (C6-10)aryl(C1-10)alkyl, heteroaryl, heteroaryl-alkyl, -OR23, -C(O)NR23R23, -NR23C(O)R23, -NR23C(O)OR23, -NR23C(O)NR23R23, -NR23R23, -S(O)2NR23R23, -NR23S(O)2R24, -S(O)n6R24, -C(O)OR23, -C(O)R24, and -(OR39)n160R23, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl,
heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aryl-alkyl, heteroaryl, and heteroaryl-alkyl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, oxo, alkyl, haloalkyl, -OR31, -C(O)NR31R31, -NR3,C(O)R31, -NR31C(O)OR31, -NR3,C(O)NR3,R31, -NR31S(O)2R31, and -S(O)„9R31, wherein each R31 is independently hydrogen, alkyl, or haloalkyl, and each n9 is independently 0, 1, or 2,
each R23 is independently hydrogen, (C1-10)alkyl, (C3-10)cycloalkyl,
(C3-10)cycloalkyl(C1-10)alkyl, or heterocycloalkyl; or two R23, together with the nitrogen atom to which they are attached, form a heterocycloalkyl; wherein each of the foregoing alkyl, cycloalkyl, or heterocycloalkyl moieties is independently unsubstituted or substituted with one or more halo,
each R24 is independently (C1-10)alkyl, (C3-10)cycloalkyl,
(C3-10)cycloalkyl(C1-10)alkyl, or heterocycloalkyl, wherein each of the foregoing is independently unsubstituted or substituted with one or more halo,
each R39 is independently (C1-10)alkylene or (C1-10)haloalkylene,
each nl6 is independently an integer from 1 to S, and
n6 is 0, l, or 2;
R3 are independently selected from the group consisting of hydrogen, halo, cyano, (C1-10)alkyl, (C3-10)cycloalkyl, (C3-10)cycloalkyl(C1-10)alkyl, -OR25, -C(O)NR25R25, -NR25C(O)R25, -NR25C(O)NR25R25, -NR25R25, -S(O)2NR25R25, -NR25S(O)2R25,
-S(O)n7R30, -NR25C(O)OR25R25, -C(O)OR25, and -C(O)R30,
wherein each (C1-10)alkyl, (C3-10)cycloalkyl, and (C3-10)cycloalkyl(C1-10)alkyl is
independently unsubstituted or substituted with one or more halo, each R25 is independently hydrogen (C1-10)alkyl, (C3-10)cycloalkyl,
(C3-10)cycloalkyl(C1-10)alkyl, or heterocycloalkyl; or two R25, together with the nitrogen atom to which they are attached, form a heterocycloalkyl; wherein each of the foregoing alkyl, cycloalkyl, or heterocycloalkyl moieties is independently unsubstituted or substituted with one or more halo,
each R30 is independently (C1-10)alkyl, (C3-10)cycloalkyl, (C3-10)cycloalkyl(C1-10)alkyl, or heterocycloalkyl, wherein each of the foregoing is independently unsubstituted or substituted with one or more halo, and
n7 is 0, l, or 2;
X1, X2, X3 and X4 are independently CR4 or N, wherein X2, X3 and X4 may not all be N;
when at least one of X1, X2, X3 and X4 is N, each R4 is independently selected from the group consisting of hydrogen, halo, cyano, (C1-10)alkyl, (C3-10)cycloalkyl,
(C3-10)cycloalkyl(C1-10)alkyl, heterocycloalkyl connected by an annular carbon atom, heterocycloalkyl-alkyl, -OR27, -C(O)NR27R27, -S(O)2]SIR27R27, -S(O),*R28, -C(O)OR27, and -C(O)R28,
wherein each (C1-10)alkyl, (C3-10)cycloalkyl, (C3-10)cycloalkyl(C1-10)alkyl,
heterocycloalkyl, and heterocycloalkyl-alkyl is independently
unsubstituted or substituted with one or more halo, each R27 is independently hydrogen or (C1-10)alkyl, (C3-10)cycloalkyl,
(C3-10)cycloalkyl(C1-10)alkyl, or heterocycloalkyl; or two R27, together with the nitrogen atom to which they are attached, form a
heterocycloalkyl; wherein each of the foregoing alkyl, cycloalkyl, or heterocycloalkyl moieties is independently unsubstituted or substituted with one or more halo,
each R28 is independently (C1-10)alkyl, (C3-10)cycloalkyl,
(C3-10)cycloalkyl(C1-10)alkyl, or heterocycloalkyl, wherein each of the foregoing is independently unsubstituted or substituted with one or more halo,
n8 is 0 , 1 or 2; or when each of X1, X2, X3 and X4 is CR4, each R4 is independently selected from the group consisting of hydrogen, halo, cyano, (C1-10)alkyl, (C3-10)cycloalkyl,
(C3-10)cycloalkyl(C1-10)alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, -OR27,
-C(O)NR27R27, -NR27C(O)R27, -NR27R27, -NR27S(O)2R27, -S(O)2NR27R27, -S(O),*R28, -C(O)OR27, and -C(O)R28,
wherein each (C1-10)alkyl, (C3-10)cycloalkyl, (C3-10)cycloalkyl(C1-10)alkyl,
heterocycloalkyl, and heterocycloalkyl-alkyl is independently unsubstituted or substituted with one or more halo, each R27 is independently hydrogen, (C1-10)alkyl, (C3-10)cycloalkyl,
(C3-10)cycloalkyl(C1-10)alkyl, or heterocycloalkyl; or two R27, together with the nitrogen atom to which they are attached, form a
heterocycloalkyl; wherein each of the foregoing alkyl, cycloalkyl, or heterocycloalkyl moieties is independently unsubstituted or substituted with one or more halo,
each R28 is independently (C1-10)alkyl, (C3-10)cycloalkyl,
(C3-10)cycloalkyl(C1-10)alkyl, or heterocycloalkyl, wherein each of the foregoing is independently unsubstituted or substituted with one or more halo, and
n8 is 0, 1, or 2; or
two R4 on adjacent annular carbon atoms together with the carbon atoms to which they are attached may form a carbocyclyl or heterocyclyl,
wherein the carbocyclyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, cyano, (C1-10)alkyl, (C3-10)cycloalkyl, (C3-10)cycloalkyl(C1-10)alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, -OR27, -C(O)NR27R27, -NR27C(O)R27, -NR27R27, -S(O)2NR27R27, -NR27S(O)2R27, -S(0>*R28, and -C(O)R28,
or the heterocyclyl is unsubstituted or substituted with one or more substituents
independently selected from the group consisting of halo, cyano, (C1-10)alkyl, (C3-10)cycloalkyl, (C3-10)cycloalkyl(C1-10)alkyl, heterocycloalkyl connected by an annular carbon atom, heterocycloalkyl-alkyl, -OR27, -C(O)NR27R27, -S(O)2NR27R27, -S(O)nsR28, and -C(O)R28,
each R27 is independently hydrogen, (C1-10)alkyl, (C3-10)cycloalkyl,
(C3-10)cycloalkyl(C1-10)alkyl; or two R27, together with the nitrogen atom to which they are attached, form a heterocycloalkyl; wherein each of the foregoing alkyl, cycloalkyl, or heterocycloalkyl moieties is independently unsubstituted or substituted with one or more halo,
each R28 is independently (C1-10)alkyl, (C3-10)cycloalkyl, (C3-10)cycloalkyl(C1-10)alkyl, wherein each of the foregoing is independently unsubstituted or substituted with one or more halo, and
n8 is 0, l, or 2;
R15 and R17 are independently hydrogen, halo, alkyl, or -OR29, wherein each R29 is
independently hydrogen, (C1-10)alkyl, (C3-10)cycloalkyl, or (C3-10)cycloalkyl(C1-10)alkyl, and each alkyl or cycloalkyl in R15 or R17, if present, is independently unsubstituted or substituted with one or more halo;
R14 is (C1-10)alkyl, (C1-10)alkenyl, (C3-10)cycloalkyl, (C3-10)cycloalkenyl,
(C3-10)cycloalkyl(C1-10)alkyl, heterocycloalkyl connected through an annular carbon atom, heterocycloalkenyl connected through an annular carbon atom, heterocycloalkyl- alkyl, -OR5, -0(O)ΜΙ¾5, ^50(O)ΜΙ¾5, -SCOJaNR^5, -S(O)„iR6, or -C(O)R6;
R16 is hydrogen, fluoro, (C1-10)alkyl, (C3-10)cycloalkyl, (C3-10)cycloalkyl(C1-10)alkyl,
heterocycloalkyl connected through an annular carbon atom, heterocycloalkyl-alkyl, -OR5, -C(O)NR5R5, -R^^NR^5, -S(O)2NR5R5, -S(O)n1R6, or -C(O)R6;
wherein the (C1-10)alkyl, (C1-10)alkenyl, (C3-10)cycloalkyl, (C3-10)cycloalkenyl,
(C3-10)cycloalkyl(C1-10)alkyl, heterocycloalkyl, heterocycloalkenyl, or heterocycloalkyl- alkyl of R14 or R16 is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of (C1-10)alkyl, cycloalkyl, heterocycloalkyl, halo, cyano, oxo, -OR7, -C(O)OR7, -C(O)NR7R7, -NR7C(O)R7, -NR7C(O)NR7R7, -NR7R7, -S(O)2NR7R7, -NR7S(O)2R7, -S(O)n2R13, and -C(O)R13; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently unsubstituted or substituted with one or more substituents selected from the group consisting of halo, cycloalkyl, halocycloalkyl, heterocycloalkyl, haloheterocycloalkyl, and -(OR33)n1oOR32, wherein each nlO is independently an integer from 0 to 5, each R32 is independently hydrogen, (C1-10)alkyl or (C1-10)haloalkyl, and each R33 is independently (C1-10)alkylene or (C1-10)haloalkylene;
each R5 is independently hydrogen, (C1-10)alkyl, or (C3-10)cycloalkyl; or two R5, together with the nitrogen atom to which they are attached, form a heterocycloalkyl; wherein each alkyl, cycloalkyl, or heterocycloalkyl is independently unsubstituted or substituted with one or more substituents selected from the group consisting of halo, cyano, oxo, alkyl, haloalkyl, -C(O)OR34, -C(O)NR34R34, -NR34C(O)R34, -NR34C(O)NR34R34, -NR34R34,
-S(O)2NR34R34, -NR34S(O)2R34, -S(0>,iiR34, -C(O)R34, and -(OR35)n120R34, wherein each R34 is independently hydrogen, (C1-10)alkyl, or (C1-10)haloalkyl; each nil is
independently 0, 1, or 2; each nl2 is independently an integer from 0 to 5; and each R35 is independently (C1-10)alkylene or (C1-10)haloalkylene;
each R6 is independently (C1-10)alkyl or (C3-10)cycloalkyl, wherein each alkyl or cycloalkyl is independently unsubstituted or substituted with one or more halo;
each nl is independently 0, 1, or 2;
each R7 is independently hydrogen, unsubstituted (C1-10)alkyl, or (C1-10)alkyl substituted with one or more halo;
each n2 is independently 0, 1, or 2,
and each R13 is independently unsubstituted (C1-10)alkyl or (C1-10)alkyl substituted with one or more halo;
or R14 and R15, together with the atoms to which they are attached, form a carbocyclyl or
heterocyclyl,
wherein the carbocyclyl or heterocyclyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, cyano, oxo, (C1-10)alkyl, (C3-10)cycloalkyl, (C3-10)cycloalkyl(C1-10)alkyl, -OR18, -C(O)NR18R18. -NR18C(O)R18, -NR18C(O)NR18R18, -NR18R18, -S(O)2NR18R18, -NR18S(O)2R18, -S(O)reR21, -C(O)OR18, and -C(O)R21,
wherein each (C1-10)alkyl, (C3-10)cycloalkyl, and (C3-10)cycloalkyl(C1-10)alkyl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, alkyl, haloalkyl, cyano, oxo, -C(O)OR36, -C(O)NR36R36, -NR36C(O)R36,
-NR36C(O)NR36R36, -NR36R36, -S(O)2NR36R36, -NR36S(O)2R36,
-S(O)nnR36, -C(O)R36, and -(OR37)n140R36, wherein each R36 is independently hydrogen, (C1-10)alkyl, or (C1-10)haloalkyl; each nl3 is independently 0, 1, or 2; each nl4 is independently an integer from 0 to 5; and each R37 is independently (C1-10)alkylene or (C1-10)haloalkylene; wherein each R18 is independently hydrogen, (C1-10)alkyl, or (C3-10)cycloalkyl; or two R18, together with the nitrogen atom to which they are attached, form a heterocycloalkyl; wherein each alkyl, cycloalkyl, or heterocycloalkyl is independently unsubstituted or substituted with one or more halo; each R21 is independently (C1-10)alkyl or (C3-10)cycloalkyl, wherein each alkyl or
cycloalkyl is independently unsubstituted or substituted with one or more halo; and
each n3 is independently 0, 1, or 2.
[0377] Embodiment ΠΙ-2. The compound of Embodiment III-l, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R1 is -C(O)OR9,
-C(O)NR8R9, -S(O)aNR8R9, -NR10C(O)NR8R9, -NR10C(O)R9, -NR10S(O)2R9, -OR26, -SR9, -S(O)R9, -S(O)2R9, -NR'fc9, or -NR10C(O)OR9.
[0378] Embodiment ΠΙ-3. The compound of Embodiment III-l or ΙII-2, wherein the compound is of Formula (X-A):
Figure imgf000178_0001
or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R1, R2, R3, R14, R15, R16, R17, X1, X2, X3, and X4 are as defined for Formula (X).
[0379] Embodiment III-4. The compound of Embodiment III-l or 111-2, wherein the compound is of Formula (X-B):
Figure imgf000178_0002
or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R1, R2, R3, R14, R15, R16, R17, X1, X2, X3, and X4 are as defined for Formula (X).
[0380] Embodiment ΠΙ-5. The compound of any one of Embodiments IQ-1 to ΠΙ-4, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R17 is hydrogen.
[0381] Embodiment ΠΙ-6. The compound of any one of Embodiments ΠΙ-1, or ΙII-3 to ΙII-5, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R1 is -C(O)OR9, -C(O)NR8R9, -S(O)2NR8R9, -NR10C(O)NR8R99, -NR10S(O)2R9, -NR10C(O)OR9, - C(O)R26, -NR10S(O)2NR8R9, or -C(O)NR8S(O)2R9. [0382] Embodiment 111-7. The compound of any one of Embodiments 111-1, or HI-3 to III-6, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R1 is -C(O)NR8R9, -S(O)2NR8R9, -NR10C(O)OR9, -NR10S(O)2R9, or -NR10S(O)2NR8R9.
[0383] Embodiment III-8. The compound of any one of Embodiments III-l to ΙII-7, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R1 is -C(O)NR8R9.
[0384] Embodiment 111-9. The compound of any one of Embodiments 111-1 to III-7, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R1 is -NR10C(O)OR9.
[0385] Embodiment ΙII-10. The compound of any one of Embodiment III- 1 to 7, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R1 is -NR10S(O)2R9
[0386] Embodiment ΠΙ-l 1. The compound of any one of Embodiments ΠΙ-l to III- 10, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R10 is hydrogen.
[0387] Embodiment ΓII- 12. The compound of any one of Embodiments ΓII- 1 to HI- 11 , or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R8 is hydrogen.
[0388] Embodiment ΠΙ-13. The compound of any one of Embodiments ΠΙ-l to III- 12, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R9 is hydrogen, (C1-10)alkyl, heterocycloalkyl-alkyl, or (C3-10)cycloalkyl.
[0389] Embodiment ΠΙ- 14. The compound of Embodiment ΠΙ- 13 , wherein R9 is unsubstituted methyl, ethyl, propyl, or cyclopropyl.
[0390] Embodiment KI-15. The compound of any one of Embodiments KI-1 to ΠΙ-7, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R1 is - C(O)NR8R9, and the R8 and R9 together with the nitrogen to which they are attached form an unsubstituted or substituted heterocycloalkyl. [0391] Embodiment 111-16. The compound of Embodiment 111-15, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein the heterocycloalkyl is a 4- to 8- membered heterocycloalkyl.
[0392] Embodiment III-17. The compound of any one of Embodiments III-l to ΠΙ-7, or ΙII-15, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R1 is -C(O)NR8R9, and the R8 and R9 together with the nitrogen to which they are attached form an unsubstituted or substituted piperidinyl.
[0393] Embodiment III-l 8. The compound of Embodiment III- 16 or HI- 17, or a
pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein the substituents are independently selected from the group consisting of halo, oxo, (C1-10)alkyl, -OR23, -C(O)OR23, and -NR23C(O)OR23, wherein each (C1-10)alkyl is unsubstituted or substituted with -OR31.
[0394] Embodiment III- 19. The compound of Embodiment III- 17, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein the piperidinyl is substituted with one to three substituents independently selected from the group consisting of -OR23, (C1-10)alkyl, -C(O)OR23, and -NR23C(O)OR23.
[0395] Embodiment 111-20. The compound of Embodiment III- 19, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R23 is independently hydrogen or (C1-10)alkyl.
[0396] Embodiment 111-21. The compound of any one of Embodiments III-l to IH-20, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R2 is halo or alkyl.
[0397] Embodiment 111-22. The compound of any one of Embodiments III-l to 111-21, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein one of X1, X2, X3, and X4 is N. [0398] Embodiment 111-23. The compound of any one of Embodiments III-l to 111-21, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein X1, X2, and X4 are CR4, and X3 is N.
[0399] Embodiment 111-24. The compound of any one of Embodiments III-l to IH-21, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein two of X1, X2, X3, and X4 are N.
[0400] Embodiment 111-25. The compound of any one of Embodiments III-l to 111-21, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein each of X1, X2, X3 and X4 is CR4.
[0401] Embodiment ΙII-26. The compound of any one of Embodiments ΓII-1 to ΠΙ-25, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein each R4 is independently selected from the group consisting of hydrogen, halo, cyano, (C1-10)alkyl, and -OR27.
[0402] Embodiment ΙII-27. The compound of any one of Embodiments ΓII-1 to ΠΙ-25, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein X1 is CR4, wherein R4 is hydrogen, halo, or methyl.
[0403] Embodiment ΠΙ-28. The compound of any one of Embodiments ΠΙ-l to 111-27, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R14 is (C1-10)alkyl or heterocycloalkyl connected through an annular carbon atom, wherein the alkyl or heterocycloalkyl is unsubstituted or substituted with one to three substituents selected from the group consisting of (C1-10)alkyl, halo, -C(O)OR7, oxo, and -OR5.
[0404] Embodiment 111-29. The compound of Embodiment ΠΙ-28, or a or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R14 is (C1-10)alkyl unsubstituted or substituted with one to three substituents selected from the group consisting of (C1-10)alkyl, halo, -C(O)OR7, oxo, and -OR5. [0405] Embodiment 111-30. The compound of any one of Embodiments III-l to 111-27, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R14 is unsubstituted (C3-10)cycloalkyl or (C3-10)halocycloalkyl.
[0406] Embodiment III-31. The compound of any one of Embodiments III- 1 to IH-30, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R15, R16, and R17 are hydrogen.
[0407] Embodiment 111-32. The compound of any one of Embodiments III-l to HI-27, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R14 and R15, together with the atoms to which they are attached, form a heterocyclyl.
[0408] Embodiment ΙII-33. The compound of any one of Embodiments ΓII-1 to ΠΙ-22, or ffl- 28 to 32, wherein at least one of X2, X3 and X4 is N, and an adjacent annular carbon is bonded to R4, wherein the R4 is independently hydrogen, fluoro, cyano, (C1-10)alkyl, or -OR27.
[0409] Embodiment ΓΠ-34. The compound of any one of Embodiments ΠΙ-l to 111-33, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R3 is hydrogen.
[0410] Embodiment ΙII-35. The compound of any one of Embodiments ΓII-1 to ΠΙ-33, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R3 is halo or alkyl.
[0411] Embodiment ΠΙ-36. The compound of any one of Embodiments ΠΙ-l to 111-35, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R2 is halo or alkyl.
[0412] Embodiment ΙII-37. The compound of any one of Embodiments ΓII-1 to ΠΙ-35, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R2 is chloro.
[0413] Embodiment ΠΙ-38. The compound of any one of Embodiments ΠΙ-l to 111-37, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein when one or more of R4, R5, R8, R9, R10, R14, R16, R19, R20, R23, R24, R25, R26, R27, R28, and R30 is heterocycloalkyl; or wherein R8 and R9, together with the nitrogen atom to which they are attached, form a heterocycloalkyl; or wherein two R18, together with the nitrogen atom to which they are attached; or wherein two R19, together with the nitrogen to which they are attached, form a heterocycloalkyl; or wherein two R25, together with the nitrogen to which they are attached, form a heterocycloalkyl; or wherein two R27, together with the nitrogen to which they are attached, form a heterocycloalkyl; each heterocycloalkyl is independently a 3- to 10-membered heterocycloalkyl.
[0414] Embodiment 111-39. The compound of any one of Embodiments III-l to III- 38, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein when one or more of R4, R8, R9, R10, R14, R16, and R26 is heterocycloalkyl-alkyl, each heterocycloalkyl- alkyl is independently (3-10 membered)heterocycloalkyl(C1-10)alkyl.
[0415] Embodiment III -40. The compound of any one of Embodiments III-l to IH-39, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein when one or more of R8, R9, R10, and R26 is heteroaryl, each heteroaryl is independently a 5- to 10- membered heteroaryl.
[0416] Embodiment III -41. The compound of any one of Embodiments III-l to IH-40, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein when one or more of R8, R9, R10, and R26 is heteroaryl-alkyl, each heteroaryl-alkyl is independently a (5-10 membered)heteroaryl(C1-10)alkyl.
[0417] Embodiment ΠΙ-42. The compound of any one of Embodiments ΠΙ-1 to ΙII-41, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein two R4 on adjacent annular carbon atoms together with the carbon atoms to which they are attached form a carbocyclyl; or wherein R14 and R15 together with the atoms to which they are attached form a carbocyclyl; each carbocyclyl, is independently a (C3-C8)carbocyclyl.
[0418] Embodiment ΙII-43. The compound of any one of Embodiments IQ-1 to ΠΙ-42, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein two R4 on adjacent annular carbon atoms together with the carbon atoms to which they are attached form a heterocyclyl; or wherein R14 and R15 together with the atoms to which they are attached form a heterocyclyl; each heterocyclyl is independently a 4- to 8-membered heterocyclyl.
[0419] Embodiment 111-44. The compound of any one of Embodiments III-l to 111-43, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein when R1 or R16 is heterocycloalkenyl, each heterocycloalkenyl is independently a 3- to 8-membered heterocyloalkenyl.
[0420] Embodiment 111-45. The compound of any one of Embodiments III-l to III-3, or III- 5 to 111-44, wherein the compound is of Formula (X-Ai):
Figure imgf000184_0001
or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R1, R2, R3, R14, R15, R16, R17, X1, X2, X3, and X4 are as defined for Formula (X).
[0421] Embodiment 111-46. The compound of any one of Embodiments III-l , III-2, or IH-4 to ΠΙ-44, wherein the compound is of Formula (X-Bi):
Figure imgf000184_0002
or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R1, R2, R3, R14, R15, R16, R17, X1, X2, X3, and X4 are as defined for Formula (X). [0422] Embodiment ΙII-47. The compound of Embodiment III- 1 , selected from the group consisting of:
Figure imgf000185_0001
Figure imgf000186_0001
Figure imgf000187_0001
Figure imgf000188_0001
Figure imgf000189_0001
or isomer of any of the foregoing.
Embodiment ΙII-48. The compound of Embodiment ΙII-1, selected from the group consisting of:
Figure imgf000189_0002
Figure imgf000190_0001
Figure imgf000191_0001
, or a pharmaceutically acceptable salt, solvate, tautomer, pe, or isomer of any of the foregoing.
Embodiment EH -49. The compound of Embodiment ΙII-1, selected from the group consisting of:
Figure imgf000191_0002
Figure imgf000192_0001
Figure imgf000193_0001
Figure imgf000194_0001
F , or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer of any of the foregoing.
[0423] Embodiment HI-50. The compound of Embodiment HI- 1 , selected from the group consisting of:
Figure imgf000195_0001
N , or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer of any of the foregoing.
[0424] Embodiment ΠΙ-51. A pharmaceutical composition, comprising the compound of any one of Embodiments ΠΙ-l to ΙII-50, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, and a pharmaceutically acceptable excipient
[0425] Embodiment ΠΙ-52. A method of inhibiting a sterol regulatory element-binding protein (SREBP), comprising contacting the SREBP or contacting an SREBP cleavage activating- protein (SCAP) with a compound of any one of Embodiments ΙII-l to ΠΙ-50, or a
pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or the pharmaceutical composition of Embodiment ΙII-51.
[0426] Embodiment ΙII-53. A method of inhibiting the proteolytic activation of a sterol regulatory element-binding protein (SREBP), comprising contacting an SREBP cleavage activating-protein (SCAP) with a compound of any one of Embodiments III-l to HI-50, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or the pharmaceutical composition of Embodiment 111- 51.
[042η Embodiment ΠΙ-54. The method of Embodiment III-52 or ΠΙ-53, wherein the SREBP is an SREBP-1.
[0428] Embodiment ΠΙ-55. The method of Embodiment III-54, wherein the SREBP-1 is SREBP-la.
[0429] Embodiment ΠΙ-56. The method of Embodiment ΙII-54, wherein the SREBP- 1 is SREBP-1 c.
[0430] Embodiment ΠΙ-57. The method of Embodiment ΙII-52 or ΙII-53, wherein the SREBP is SREBP-2.
[0431] Embodiment ΙII-58. The method of any one of Embodiments ΠΙ-52 to ΓΠ-57, wherein SREBP is inhibited in a subject in need thereof.
[0432] Embodiment ΠΙ-59. The method of any one of Embodiments ΠΙ-52 to ΠΙ-58, wherein SCAP is inhibited in a subject in need thereof.
[0433] Embodiment ΠΙ-60. The method of any one of Embodiments ΠΙ-52 to ΠΙ-59, wherein the expression of one or more genes selected from the group consisting of ACSS2, ALDOC, CYP51A1, DHCR7, ELOVL6, FASN, FDFT1, FDPS, HMGCS1, HSD17B7, IDI1, INSIG1, LDLR, LSS, ME1, PCSK9, PMVK, RDH11 , SC5DL, SQLE, STARD4, TM7SF2, PNPLA3, SREBFl, SREBF2, HMGCR, MVD, MVK, ACLY, MSMOl, ACACA, and ACACB is reduced after contacting the SREBP or SCAP with the compound, or pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or the pharmaceutical composition.
[0434] Embodiment ΠΙ-61. A method of treating a disorder in a subject in need thereof, comprising administering to the subject in need thereof an effective amount of a compound of any one of Embodiments III-l to ΙII-50, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or the pharmaceutical composition of Embodiment ΠΙ-51. [0435] Embodiment 111-62. A method of treating a disorder in a subject in need thereof, wherein the disorder is mediated by a sterol regulatory element-binding protein (SREBP), comprising administering to the subject in need thereof an effective amount of a compound of any one of Embodiments ΙII-1 to ΙII-50, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or the pharmaceutical composition of Embodiment ΠΙ-51.
[0436] Embodiment 111-63. The method of Embodiment HI-61 or ΠΙ-62, wherein the disorder is Metabolic Syndrome, type 2 diabetes, obesity, liver disease, insulin resistance, adiposopathy, or dyslipidemia.
[0437] Embodiment 111-64. The method of Embodiment 111-63, wherein the dyslipidemia is hypertriglyceridemia or elevated cholesterol levels.
[0438] Embodiment 111-65. The method of Embodiment 111-63, wherein the liver disease is nonalcoholic steatohepatitis, liver fibrosis, or liver inflammation, or a combination thereof.
[0439] Embodiment ΠΙ-66. The method of Embodiment ΠΙ-61 or ΙII-62, wherein the disorder is a hyperproliferative disorder.
[0440] Embodiment ΠΙ-67. The method of Embodiment ΠΙ-66, wherein the hyperproliferative disorder is cancer.
[0441] Embodiment ΠΙ-68. The method of Embodiment ΠΙ-67, wherein the cancer is breast cancer, liver cancer, ovarian cancer, pancreatic cancer, or prostate cancer.
[0442] Embodiment ΠΙ-69. The method of Embodiment ΠΙ-61 or ΙII-62, wherein the disorder is endotoxic shock, systemic inflammation, or atherosclerosis.
[0443] Embodiment ΠΙ-70. Use of a compound of any one of Embodiments ΙII-1 to ΙII-50, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, in the manufacture of a medicament for use in treating a disorder in a subject in need thereof.
[0444] Embodiment ΠΙ-71. Use of a compound of any one of Embodiments UI-1 to ΙII-50, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, in the manufacture of a medicament for use in inhibiting a sterol regulatory element-binding protein (SREBP) in a subject in need thereof.
[0445] Embodiment 111-72. Use of a compound of any one of Embodiments ΙII-1 to III- SO, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, in the manufacture of a medicament for use in inhibiting the proteolytic activation of a sterol regulatory element-binding protein (SREBP) in a subject in need thereof.
[0446] Embodiment 111-73. Use of a compound of any one of Embodiments ΙII-1 to III- SO, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, in the manufacture of a medicament for use in treating a disorder in a subject in need thereof, wherein the disorder is mediated by a sterol regulatory element-binding protein (SREBP).
[0447] Embodiment 111-74. Use of a compound of any one of Embodiments HI-1 to III- 50, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or the pharmaceutical composition of Embodiment 111-51, for inhibiting a sterol regulatory element- binding protein (SREBP).
[0448] Embodiment 111-75. Use of a compound of any one of Embodiments ΙII-1 to III- 50, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or the pharmaceutical composition of Embodiment 111-51, for inhibiting an SREBP cleavage activating protein (SCAP).
[0449] Embodiment 111-76. The use of any one of Embodiments III- 71 to IH-75, wherein the SREBP is an SREBP- 1.
[0450] Embodiment ΙII-77. The use of Embodiment ΠΙ-76, wherein the SREBP- 1 is SREBP- la.
[0451] Embodiment ΙII-78. The use of Embodiment ΠΙ-76, wherein the SREBP-1 is SREBP- lc.
[0452] Embodiment ΠΙ-79. The use of any one of Embodiments ΠΙ-71 to ΠΙ-75, wherein the SREBP is SREBP-2. [0453] Embodiment 111-80. The use of any one of Embodiments III- 71 to ΙII-75, wherein SREBP is inhibited in a subject in need thereof.
[0454] Embodiment 111-81. The use of any one of Embodiments III- 71 to IH-75, wherein SCAP is inhibited in a subject in need thereof.
[0455] Embodiment ΠΙ-82. Use of a compound of any one of Embodiments ΙII-1 to ΙII-50, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or the pharmaceutical composition of Embodiment 111-51, for treating a disorder in a subject in need thereof.
[0456] Embodiment ΠΙ-83. Use of a compound of any one of Embodiments ΙII-1 to ΙII-50, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or the pharmaceutical composition of Embodiment 111-51, for treating a disorder in a subject in need thereof, wherein the disorder is mediated by a sterol regulatory element-binding protein (SREBP).
[0457] Embodiment ΠΙ-84. The use of Embodiment ΠΙ-82 or ΙII-83, wherein the disorder is Metabolic Syndrome, type 2 diabetes, obesity, liver disease, insulin resistance, adiposopathy, or dyslipidemia.
[0458] Embodiment ΠΙ-85. The use of Embodiment III- 84, wherein the dyslipidemia is hypertriglyceridemia or elevated cholesterol levels.
[0459] Embodiment ΠΙ-86. The use of Embodiment III- 84, wherein the liver disease is nonalcoholic steatohepatitis, liver fibrosis, or liver inflammation, or a combination thereof.
[0460] Embodiment ΠΙ-87. The use of Embodiment III- 82 or ΠΙ-83, wherein the disorder is a hyperproliferative disorder.
[0461] Embodiment ΠΙ-88. The use of Embodiment III- 87, wherein the hyperproliferative disorder is cancer.
Embodiment ΙII-89. The use of Embodiment ΙII-88, wherein the cancer is breast cancer, liver cancer, ovarian cancer, pancreatic cancer, or prostate cancer. [0462] Embodiment 111-90. The use of Embodiment 111-82 or 111-83, wherein the disorder is endotoxic shock, systemic inflammation, or atherosclerosis.
[0463] Embodiment 111-91. A method of treating non-alcoholic steatohepatitis (NASH) in a subject in need thereof, comprising administering to the subject in need thereof an effective amount of a compound of any one of Embodiments 111-1 to ΠΙ-50, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or the pharmaceutical composition of Embodiment III-51.
[0464] Embodiment 111-92. Use of a compound of any one of Embodiments Hl-l to 111-50, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or the pharmaceutical composition of Embodiment UI-51, for treating non-alcoholic steatohepatitis (NASH) in a subject in need thereof.
[0465] Embodiment 111-93. Use of a compound of any one of Embodiments Hl-l to 111-50, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, in the manufacture of a medicament for use in treating non-alcoholic steatohepatitis (NASH) in a subject in need thereof.
[0466] Embodiment III-94. A method of treating a hyperproliferative disorder in a subject in need thereof, comprising administering to the subject in need thereof an effective amount of a compound of any one of Embodiments 111-1 to 111-50, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or the pharmaceutical composition of Embodiment m-51.
[0467] Embodiment 111-95. Use of a compound of any one of Embodiments HI-1 to III- 50, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or the pharmaceutical composition of Embodiment 111-51, for treating a hyperproliferative disorder in a subject in need thereof.
[0468] Embodiment 111-96. Use of a compound of any one of Embodiments ΙII-1 to III- 50, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, in the manufacture of a medicament for use in treating a hyperproliferative disorder in a subject in need thereof. EXAMPLES
[0469] The following Examples are merely illustrative and are not meant to limit any aspects of the present disclosure in any way.
Example 1: Synthesis of (4-(2'-(tert-butyI)-[2,4'-bipyridin]-4-yl)-3-chlorophenyl)(4- hydroxypiperidin-l-yl)methanone (Compound 1)
Figure imgf000201_0001
[0470] Step 1: Synthesis of 3-chloro-4-(2-chloropyridin-4-yl)benzoic acid. 4-bromo-2- chloropyridine (0.3g, 1.55 mmol), bromo-3-chloro benzoic acid (0.39 g, 1.94 mmol), cesium fluoride (0.58 g, 0.155 mmol) in water (0.9 mL) and 1,4 dioxane (6 mL) were charged into a 15 mL glass seal tube and purged with argon gas for 30 minutes. To this mixture was added Pd(amphos)2Ch (0.109 g, 0.155 mmol) and again the tube was purged with argon gas for 30 minutes. The tube was heated to 80 °C for 16h, and reaction progress was monitored by TLC and LCMS. When complete, the reaction mixture was cooled to 25-30 °C and ice-cold water was added (10 mL). The obtained solids were filtered and dried. The crude 3-chloro-4-(2- chloropyridin-4-yl)benzoic acid (0.3g) was taken for the next step without purification.
[0471] Step 2: (3^hloro-4-(2-chloropyri&n-4-yl)phenyl)(4-hydroxyp
To a stirred solution of the compound from Step 1 (0.3 g, 1.12 mmol) in DMF (6 mL) was added DIPEA(1.95 mL, 11.2 mmol) followed by the addition of HATU (1.7 g, 4.48 mmol) under nitrogen atmosphere. This mixture was stirred for 30 minutes followed by addition of 4- hydroxy piperidine (0.220 g, 2.24 mmol). The reaction was stirred at rt for 16h. The reaction progress was monitored by TLC and, when complete, the reaction mixture was cooled to 0 °C , water (30 mL) was added and the whole extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over sodium sulfate, filtered and concentrated. The crude compound was purified by siliga gel (230-400 mesh) column chromatography eluting with 0-80% ethyl acetate in pet ether to afford (3-cWoro-4-(2-cWoropyridin-^yl)phenyl)(4-hydroxypiperidin-l- yl)methanone (0.158g, 40%).
[0472] Step 3: Synthesis of (4-(2'-(tert-butyI)-[2J'-bipyridinJ-4-yI)-3^MorophenyI)(^ hydroxypiperidin-l-yl)methanone. To a stirred solution of (3-chloro-4-(2-chloropyridin-4- yl)phenyl)(4-hydroxypiperidin-l-yl)methanone (0.15 g, 0.427 mmol) in DME (3 mL) was added 2-(tert-butyl)-^(4,4,5,5-tetramemyl-l,3,2-clioxaborolan-2-yl)pyridine (0.139 g, 0.533 mmol), and K2CO3 (0.147 g, 1.06 mmol) in water (0.45 mL) at room temperature under argon atmosphere. The combination was purged with argon for 30 minutes and, and after adding palladium tetrakis (0.049g, 0.0427 mmol), again purged with argon gas for 30 minutes. The mixture was heated to 85 °C for 16 h, and the reaction progress monitored by TLC and LCMS. When the reaction was complete the reaction mixture was cooled to 0 °C, water (50 mL) added and the whole was extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude compound was purified by preparative HPLC to afford (4-(2'-(tert-butyl)-[2,4'-bipyridin]-4-yl)-3-chlorophenyl)(4- hydroxypiperidin-l-yl)methanone (42 mg, 15%). ¾ NMR (400 MHz, DMSO-de): δ 8.83 (d, J=5.6 Hz, 1H), 8.63 - 8.64 (m, lH), 8.23 (s, 1H), 8.13 (bs, 1H), 7.90 - 7.92 (dd, J= 2 Hz, J= 5.2 Hz, 1H), 7.63 - 7.65 (m, 2H), 7.59 - 7.60 (dd, J= 1.8 Hz, J= 4.8 Hz, 1H), 7.49 - 7.51 (dd, J= 1.6 Hz, J= 7.6 Hz, 1H), 4.80 (d, J=4.0Hz, 1H), 3.95 - 4.05 (m, 1H), 3.74 - 3.79 (m, 1H), 3.50 - 3.56 (m, 1H), 3.16 - 3.24 (m, 2H), 1.69 - 1.80 (m, 2H), 1.35 - 1.42 (m, 11H). LCMS: 98.64 % (m/z = 450.39 [M+H]). Example 2: Synthesis of (4-(2'-(tert-butyl)-[4,4'-bipyridin]-2-yl)-3-chlorophi hydroxypiperidin-l-yi)metfaanone (Compound 2)
Figure imgf000203_0001
[0473] (4-(2'-(tert-butyl)-[4,4,-bipyridin]-2-yl)-3-chlorophenyl)(4-hydroxypiperidi
yl)methanone was prepared in a similar fashion to the compound of Example 1, but with the reverse order of the reactions of Step 1 and Step 2. ¾ NMR (400 MHz, DMSO): 5 (ppm):
8.83(d, J=5.2Hz, 1H), 8.66(d, J=5.2Hz, 1H) 8.10(bs, 1H), 7.88 (dd, Ji= 1.6 Hz, Λ= 5.2 Hz, 1H), 7.83(s, 1H), 7.72 (d, J=8Hz, lH), 7.67 (dd, Ji= 1.6 Hz, Λ= 5.2 Hz, 1H), 7.61(d, J=l.2Hz, 1H), 7.49 (dd, Ji= 1.6 Hz, Jr= 7.6 Hz, 1H), 4.81(d, J=4Hz, 1H), 3.99-4.03 (m,lH), 3.75-3.78( m, 1H), 3.50-3.55(m, 1H), 3.25-3.32(m, 2H), 1.82-1.73 (m, 2H), 1.38 (s, l lH). LCMS 99.99% (m/z = 450.47 [M+H]). HPLC purity 99.84%.
Example 3: Synthesis of (4-(2'-(tert-butyI)-[2,4'-bipyridin]-6-yl)-3-chloroph
hydroxypiperidin-l-yl)metbanone (Compound 3)
Figure imgf000203_0002
[0474] Step 1: Synthesis of 6-bromo-2'-(tert-butyl)-2,4'-bipyridine. 2,6-dibromo-pyridine(0.3 g, 1.27 mmol), 2-tert-bu1ylpyridine-4-boronic acid pinacol ester (0.323 g, 1.14 mmol), and potassium carbonate (0.3S g, 2. S3 mmol ) in DME (6 mL) were added to a 10 mL glass seal tube and purged with nitrogen gas for 10 minutes. Palladium tetrakis (0.14 6 g, 0.12 mmol) was added and the container was again purged with nitrogen gas for 10 minutes. The container was then heated to 80 °C for 16h and the reaction monitored by TLC and LCMS. After completion, the reaction mixture was cooled to RT, S mL ice cold water was added, and the whole extracted with EtOAc (3x15 mL). The organic extracts were combined, washed with brine (3x10 mL) and dried over anhydrous sodium sulfate. The extract was then concentrated under reduced pressure and the crude product purified by column chromatography using 0-10 % EtOAc in hexane as eluent to afford 6-bromo-2'-(tert-butyl)-2,4'-bipyridine (0.210 g, 56.9%) as an off white solid.
[0475] Step 2: Synthesis of 4-(2'-(tert-butyl)-[2,4'-bipyridin]-6-yl)-3-chlorobenzoic acid. 6- bromo-2'-(tert-butyl)-2,4'-bipyridine (0.15 g, 0.52 mmol, 1 equiv), 4-carboxy-2- chlorophenylboronic acid (0.156 g, 0.78 mmol, 1.5 equiv) and potassium carbonate (0.143g, 1.035 mmol, 2 equiv) in dioxane: water (2.5:0.5 mL) were combined in a 10 mL glass seal tube and purged with nitrogen gas for 10 minutes. To the mixture was added Pd(dppf)Cl2-DCM complex (0.049 g, 0.060 mmol) and it was again purged with nitrogen gas for 10 minutes. The mixture was heated to 90 °C for 16 h, and monitored by TLC. After completion, the reaction was cooled, 5 ml water was added, and the pH of the mixture was adjusted by addition of AcOH to pH 6. The resulting mixture was extracted with EtOAc (3x20 mL). The organic extracts were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was triturated with n-hexane (3x10 mL). This residue was dissolved in diethyl ether (10 mL) and then concentrated under reduced pressure to obtain 0.3 g (crude) of 4-(2'-(tert- butyl)-[2,4'-bipyridin]-6-yl)-3-chlorobenzoic acid, which was used without further purification in the next step.
[0476] Step 3: Synthesis of (4-(2'-(ten-butyl)-[2,4'-bipyrianJ-6-yl)-3-^hlorophenyl)(4- hydroxypiperidin-l-yl)methanone. To a solution of 4-(2'-(tert-butyl)-[2,4l-bipyridin]-6-yl)-3- chlorobenzoic acid from Step 2 (0.2 g, 0.546 mmol, 1 equiv) in DMF (5 mL, 25 vol), was added DIPEA (1 mL, 5.464 equiv.) and HATU (0.83 g, 2.186 mmol, 4.0 equiv). The reaction was stirred for 30 min followed by addition of 4-hydroxy pyridine (0.11 g, 1.092 mmol, 2.0 equiv), and further stirred for 16 h. The progress of the reaction was monitored by TLC. After completion, the mixture was diluted with ethyl acetate and washed with ice-cold water (4xS niL). The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product obtained was purified by preparative HPLC to afford (4-(2- (tert-butyl)-[2,4'-bipyridin]-6-yl)-3-chloro^ (0.103 g
(27.9 % yield)) as an off white solid. The crude product was analyzed by Ή-ΝΓνΚ. (400 MHz, DMSO), δ (ppm): 8.65(d, J=5.2Hz lH), 8.16(d, J - 7.2Hz, lH), 8.11-8.07 (m, 2H), 7.89 (dd, Ji= 1.6Hz, h= 4.8Hz, 1H), 7.77 (t, J= 7.2Hz, 2H), 7.62(d, J=1.6Hz, lH), 7.50 (dd, Ji= 1.6Hz, h= 8.0Hz, 1H), 4.81(d, J - 4Hz, lH), 4.00-4.04 (m, lH), 3.78-3.75 (m, lH), 3.5-3.53 (m, lH), 3.15- 3.20 (m, 2H), 1.83-1.78 (m, 2H) 1.38(s, 11H). LCMS 99.81% (m/z 450.44 [M+H]). HPLC purity 98.46%.
Example 4: Synthesis of (4-(2'-(tert-butyl)-[3,4,-bipvridin]-5-yl)-3-chlorophenyl)(4- hydroxypiperidin-l-yI)inethanone (Compound 4)
Figure imgf000205_0001
[0477] Step 1: Synthesis of 4-(5-bromopyridin-3-yl)-3-chlorobenzoic acid. 3,5- dibromopyridine (0.5 g, 2.11 mmol, 1 equiv), 4-carboxy-2-chlorophenyl boronic acid (0.402 g, 2.00 mmol, 0.95 equiv) and sodium carbonate (0.559 g, 5.28 mmol, 2.5 equiv) in DME-H2O (3.75:1.25 mL) were combined in a 10 mL glass seal tube and purged with nitrogen gas for 10 minutes. After adding palladium tetrakis (0.122 g, 0.105 mmol, 0.05 equiv) the mixture was again purged with nitrogen gas for 10 minutes. The mixture was heated to 80 °C for 16 h and reaction monitored by TLC and LCMS. After completion, the reaction mixture was cooled to RT, 10 mL water was added and the whole was extracted with EtOAc (3x15 mL). The organic extracts were combined and washed with brine (3x10 mL) and dried over anhydrous sodium sulfate. The extract was then concentrated under reduced pressure to give crude 4-(5- bromopyridin-3-yl)-3-chlorobenzoic acid (0.350 g, crude) as a white solid.
[0478] Step 2: Synthesis of 4-(2'-(tert-butyl)-[3,4'-bipyridinJ-5-yl)-3-chlorobenzoic acid. 4-(5- bromopyridin-3-yl)-3-chlorobenzoic acid (0.150 g, 0.4799 mmol, 1 equiv), 2-tert butyl pyridine 4-boronic acid pinacol ester (0.156 g, 0.5759 mmol, 1.2 equiv) and potassium carbonate (0.133 g, 0.9598 mmol, 2 equiv) in dioxane:water (2.4:0.6 mL) were combined in a 10 mL glass seal tube and purged with nitrogen gas for 10 minutes. After adding palladium tetrakis (0.055 g, 0.0479 mmol, 0.1 equiv), the container was again purged with nitrogen gas for 10 minutes. The mixture was heated to 80 °C for 16 h and the reaction monitored by TLC. After completion, the mixture was cooled, 10 mL water added, and the mixture extracted with EtOAc (3x10 mL). The organic extracts were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 4-(2'-(tert-butyl)-[3,4'-bipyridin]-5-yl)-3-chlorobenzoic acid (0.140 g, crude).
[0479] Step 3: Synthesis of (4-(2 '-(tert-butyI)-[3,4'-bipyridinJ-5-yI)-3-chIorophenyI)(4- hydroxypiperidin-l-yl)methanone. To a solution of 4-(2'-(tert-butyl)-[3,4'-bipyridin]-5-yl)-3- chlorobenzoic acid (0.140 g, 0.3816 mmol, 1 equiv) in DMF (2.8 mL, 20 v), was added DIPEA (0.211 mL, 1.1448 mmol, 3 equiv) and HATU (0.218 g, 0.5724 mmol, 1.5 equiv). The mixture was stirred for 30 minutes, then 4-hydroxy piperidine (0.058 g, 0.5724 mmol, 1.5 equiv) was added and the mixture stirred for 16 h at RT. The progress of the reaction was monitored by TLC. After completion, the mixture was diluted with ethyl acetate and washed with cold water (4x5 mL). The organic layers were separated, combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product obtained was purified by preparative HPLC method to afford (4-(2'-(tert-butyl)-[3,4'-bipyridin]-5-yl)-3-chlorophenyl)(4- hydroxypiperidin- 1 -yl)methanone (0.103 g, 30.23 % yield) as an off white solid. *H NMR (400 MHz, DMSO de): δ (ppm): 9.07 (d, J=2 Hz, lH), 8.76 (d, J = 2 Hz, 1H), 8.63-8.62 (m, 1H), 8.35-8.34 (m, lH), 7.82 (s, 1H), 7.68-7.64 (m, 3H) 7.50-7.48 (m, 1H), 4.82 (s, lH), 4.01 (s, lH), 3.76 (s, 1H), 3.54-3.53 (m, 1H), 3.3 -3.2 (m, 2H), 1.80-1.75 (m,2H), 1.38(s, 11H); LCMS 99.86% (m/z 450.47 [M+H]). HPLC purity 99.76%. Example 5: Synthesis of (3'-(2-(fert-butyI)pyridin-4-yl)-2-chIoro-[l,r-biphenyI]-4-yl)(4- hydroxypiperidin-l-yi)metfaanone (Compound 5)
Figure imgf000207_0001
[0480] Step 1: Synthesis of (4-bromo-3^hlorophenyl)(4-hydroxypiperidin-l-yl)methanone. To a stirred solution of 3-chloro-4-bromo benzoic acid (2.0 g, 8.49 mmol) in DMF (40 mL) was added DIPEA (15.23 mL, 84.94 mmol) and HATU (12.9 g, 33.97 mmol) under a nitrogen atmosphere with stirring for 30 minutes. Next, 4-hydroxy piperidine (1.71 g, 16.98 mmol) was added, and the mixture stirred at rt for 16 h. The progress of the reaction was monitored by TLC, and when complete it was cooled to 0 °C, water (300 mL) was added, and the whole was extracted with ethyl acetate. The combined ethyl acetate layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The crude compound was purified by silica gel column chromatography, eluting with 0-80% ethyl acetate in petroleum ether to give (4-bromo- 3-chlorophenyl)(4-hydroxypiperidin-l-yl)methanone (l.lg, 41%).
[0481] Step 2: Synthesis of (3-chloro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl)(4-hydroxypiperidin-l-yl)methanone. To a stirred solution of (4-bromo-3- chlorophenyl)(4-hydroxypiperidin-l-yl)methanone (0.3 g, 0.943 mmol) in 1,4 dioxane (3 mL) in a glass seal tube was added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (0.299 g, 1.17 mmol), and KOAc (0.231 g, 2.35 mmol) at room temperature under a nitrogen atmosphere. The mixture was purged for 15 min with nitrogen, then Pd(dppf)2Ch (0.069 g, 0.094 mmol) was added and the mixture again purged for 10 min with nitrogen. The reaction vial was sealed and subjected to heating at 85 °C for 16 h. The reaction progress was monitored by TLC and, when complete, was cooled to 0 °C, water added (50 mL) and the whole extracted with ethyl acetate. The combined ethyl acetate layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give (3-chloro-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)phenyl)(4-hydroxypiperidin-l-yl)methanone as a brown oil that was used in the next step without further purification.
[0482] Step 3: Synthesis of (3'-bromo-2-chloro-[ 1, 1 '-biphenyl]-4-y\)(4-hydroxypiperidin-l- yljmethanone. To a stirred solution of (3-chloro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl)(4-hydroxypiperidin-l-yl)methanone (0.387 g, 1.05 mmol) in DMF (2.0 mL) in a microwave vial was added 1,3-dibromobenzene (0.2 g, 0.84 mmol), Na2COs (0.224 g, 2.11 mmol) in water (0.6 mL) at room temperature under a nitrogen atmosphere. The mixture was purged for 15 min with nitrogen, palladium tetrakis (0.097 g, 0.084 mmol) was added, and the mixture was again purged for 10 min with nitrogen. The reaction vial was sealed and subjected to microwave irradiation at 85 °C for 2 h. The reaction progress was monitored by TLC and when complete it was cooled to 0 °C, water (50 mL) added, and the whole was extracted with ethyl acetate. The combined ethyl acetate layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The crude compound was purified by silica gel column chromatography eluting with 5-80% ethyl acetate in petroleum ether to afford (3'-bromo-2- chloro-[l, -biphenyl]-4-yl)(4-hydroxypiperidin-l-yl)methanone as an off white solid (50 mg, 15%).
[0483] Step 4: Synthesis of(3'-(2-(tert-butyl)pyridin-4-yl)-2-chloro-fl, 1 '-biphenyl]-4-yl)(4- hydroxypiperidin-l-yl)methanone. To a stirred solution of (3'-bromo-2-chloro-[l,l'-biphenyl]-4- yl)(4-hydroxypiperidin-l-yl)methanone (0.10 g, 0.25 mmol) in DMF (2 mL) in a microwave vial was added 2-(tert-butyl)-4-(4,4,5,5-tetramemyl-l,3-dioxokn-2-yl)pyridine (0.082 g, 0.31 mmol) and K2CO3 (0.087 g, 0.634 mmol) at room temperature under a nitrogen atmosphere. The mixture was purged for 15 min with nitrogen , palladium tetrakis (0.029 g, 0.025 mmol) was added and the reaction mixture was again purged for 10 min with nitrogen. The reaction vial was then sealed and subjected to irradiation at 85 °C for 2 h. The reaction progress was monitored by TLC and, when complete, it was cooled to 0 °C, water (30 mL) was added and the whole was extracted with ethyl acetate. The combined ethyl acetate layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The crude compound was purified by preparative HPLC to afford (3,-(2-(tert-butyl)pyridin-4-yl)-2-chloro-[l,l,-biphenyl]-4-yl)(4- hydroxypiperidin- 1 -yljmethanone as an off white solid (9.5 mg, 8%). ¾ NMR (400 MHz, DMSO): δ 8.58-8.57 (m, 1H), 7.85 -7.83 (m, 2H), 7.720 (d, J= 0.8Hz, 1H) 7.636-7.545 (m, 5H) ,7.46-7.43 (m, lH) 4.80 (d, J= 4 Hz, lH), 4.01 (d, J= 6.4 Hz, 1H), 3.78 - 3.73 (m, 1H), 3.55 - 3.53 (m, lH), 3.23 - 3.20 (m, 2H), 1.792 (s, 2H), 1.374 (s, 1 lH). LCMS: 96.44 % (m/z = 449.38 [M+H]). HPLC: 96.17%.
Example 6: (4-(4-(2-(tert-butyl)pyridiii-4-yl)pyrimidin-2-yl)-3-chlorophenyl)(4- hydroxypiperidin-l-yi)metfaanone (Compound 6)
Figure imgf000209_0001
[0484] Step 1: Synthesis of 2-bromo-4-(2-(tert-butyl)pyridin-4-yl)pyrimidine. In a glass tube, 2,4-dibromopyrimidine (400 mg, 1.68 mmol) was dissolved in l,4-dioxane/H20 (9:1, 10 mL), and (2-(tert-butyl)pyridin-4-yl)boronic acid (270 mg, 1.51 mmol) and K2CO3 (695 mg, 5.04 mmol) were added under nitrogen atmosphere. The mixture was purged for 15 minutes with nitrogen, then Pd(PPh3)4 (194 mg, 0.16 mmol) was added and the reaction mixture purged for 10 minutes with nitrogen. The tube was sealed and stirred at 80 °C for 16 h. The reaction progress was monitored by TLC. After completion of the reaction, the residue was dissolved in water (10 mL) and extracted with EtOAc (3 x 20 mL). The organic extracts were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain crude material which was purified by column chromatography (Silica 100-200 mesh), eluted with 10% EA in hexanes. Removal of the solvent under reduced pressure gave 2-bromo-4-(2-(tert-buryl)pyridin- 4-yl)pyrimidine as a gummy liquid (250mg, 51%). [0485] Step 2: Synthesis of methyl 4-(4-(2-(tert-butyi)pyridin-4-yl)pyrimidin-2-yl)-3- chlorobenzoate. In a glass tube, 2-bromo^(2-(tert-butyl)pyridin-4-yl)pyrimidine (280 mg, 0.85 mmol) was dissolved in l,4-dioxane/H20 (9:1, 10 mL), and (2-chloro-4- (methoxycarbonyl)phenyl)boronic acid (138 mg, 0.77 mmol) and K2CO3 (354 mg, 2.56 mmol) were added under nitrogen atmosphere. The mixture was purged for 15 minutes with nitrogen, then Pd(PPh3)4 (99 mg, 0.08 mmol) was added and the reaction mixture purged for 10 minutes with nitrogen. The tube was sealed and stirred at 80 °C for 16 h. The reaction progress was monitored by TLC. After completion of the reaction, the residue was dissolved in water (10 mL) and extracted with EtOAc (3 x 20 mL). The organic extracts were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain crude material which was purified by column chromatography (Silica 100-200 mesh), eluted with 10% EA in hexanes. Removal of the solvent under reduced pressure gave methyl 4-(4-(2-(tert-butyl)pyridin- 4-yl)pyrimidin-2-yl)-3-chlorobenzoate as a gummy liquid (160mg, 49%). ¾ NMR (400 MHz, DMSO: δ (ppm): 9.01 (d, J= 5.2 Hz, lH), 8.75 (d, J= 4.8 Hz, 1H), 8.23 (d, J= 1.6 Hz, 1H), 8.21 (s, 1H), 8.05-8.08 (m, 1H), 7..97-7..99 (m, lH), 7.76-7.80 (m, 2H), 3.97 (s, 3H), 1.44 (s, 9H). LCMS: 94% (M+H = 382.23).
[0486] Step 3: Synthesis of 4-(4-(2-(tert-butyl)pyridin-4-yl)pyrimidin-2-yl)-3-chlorobenzoic acid. To a stirred solution of methyl 4-(4-(2-(tert-butyl)pyridin-4-yl)pyrimidin-2-yl)-3- chlorobenzoate (160 mg, 0.41 mmol) in THF/MeOH/IfcO (3:3:1, 7 mL) was added LiOH.H20 (42 mg, 1.25 mmol), and the mixture stirred at rt for 2 h. The reaction progress was monitored by TLC. After completion of reaction, THF was removed under reduced pressure. The residue was dissolved in water (10 mL) and acidified with 1JVHC1 up to pH 4, then the aqueous layer was extracted with EtOAc (3 x 15 mL). The organic extracts were combined, dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude 4-(4-(2-(tert- butyl)pyridin-4-yl)pyrimidin-2-yl)-3-chlorobenzoic acid, which was used for the next step without purification.
[0487] Step 4: Synthesis of (4-(4-(2-(tert-butyl)pyridin-4-ylJpyrimidin-2-yl)-3H;hlorophenyl)(4- hydroxypiperidin-l-yljmethanone. To a stirred solution of 4-(4-(2-(tert-butyl)pyridin-4- yl)pyrimidin-2-yl)-3-chlorobenzoic acid (110 mg, 0.29 mmol) in DMF (5 mL) was added DIPEA (154 mg, 1.19 mmol) followed by the addition of HATU (455 mg, 1.19 mmol). The mixture was stirred for 10 minutes, then 4-hydroxypiperidine (33 mg, 0.32 mmol) was added. The reaction was stirred at rt for 16 h, and reaction progress monitored by TLC. After completion of the reaction, the residue was dissolved in water (10 mL) and extracted with EtOAc (2 x 15 mL). The organic extracts were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude product which was purified by preparative HPLC. Collected fractions were concentrated under reduced pressure to afford (4-(4-(2-(tert-butyl)pyridin-4- yl)pyrimidin-2-yl)-3-chlorophenyl)(^hydroxypiperidm-l-yl)meihan (0.04g, 38%) as an off white solid. ¾ NMR (400 MHz, DMSO: δ (ppm): 9.15 (d, J= 5.2 Hz), 8.74 (d, J= 4.8 Hz, lH), 8.29 (d, J= 5.2 Hz, lH), 8.23 (s, 1H), 8.01-7.96 (m, 2H), 7.64 (d, J = 1.2 Hz, lH), 7.53-7.50 (m, lH), 4.81 (d, J= 4 Hz, lH), 3.95-4.00 (br, lH), 3.75-3.85 (br, lH), 3.51-3.53 (br, lH), 3.19-3.21 (br, 2H), 1.77-1.88 (m, 2H), 1.32-1.34 (m, llH). LCMS: (451.48[M+H]) 99.44%. HPLC:
96.33%.
Example 7: (4-(2-(2-(tert-butyl)pyridin-4-yl)pyrimidin-4-yl)-3-chlorophenyl)(4- hydroxvpiperidin-l-yl)methanone (Compound 7)
Figure imgf000211_0001
[0488] (4-(2-(2-(tert-butyl)pyridm-4-yl)pyrin^
l-yl)methanone was prepared in a similar fashion to the compound of Example 6, but with the reverse order of the reactions of Step 1 and Step 2. XH NMR (400 MHz, DMSO: δ (ppm): 9.15 (d, J= 5.2 Hz, lH), 8.75-8.74 (m, lH), 8.29-8.28 (d, J = 5.2 Hz, lH), 8.24 (br s, lH), 8.01-7.99 (m, lH), 7.97 (d, J= 7.6 Hz, lH), 7.64 (m, lH), 7.53-7.50 (m, lH), 4.82 (d, J= 4 Hz, lH), 4.00- 3.95 (br, 1H), 3.85-3.75 (br, 1H), 3.53-3.51 (br, 1H), 3.21-3.19 (br, 2H), 1.88-1.77 (m, 2H), 1.34-1.32 (m, 11H). LCMS: (451.1[M+H]) 99.44%. HPLC: 96.33%.
Example 8: (4-(6-(2-(tert-butyl)pyridin-4-yl)pyrimidin-4-yl)-3-chlorophenyl)(4- hydroxypiperidin-l-yI)methanone (Compound 8)
Figure imgf000212_0001
[0489] Step 1: Synthesis of methyl 4-(6-bromopyrimidin-4-yl)-3-chlorobenzoate. To a stirred solution of 4,6-dibromopyrimidine (300 mg, 1.261 mmol), (2-chloro-4- (methoxycarbonyl)phenyl)boronic acid (300 mg, 1.513 mmol), potassium carbonate (435 mg, 3.15 mmol) in water (1 mL) and 1,4-dioxane (3 mL) were added in a 15 mL glass sealed tube, which was purged with nitrogen gas for 30 minutes. After adding palladium tetrakis (145 mg, 0.126 mmol) it was again purged with nitrogen gas for 30 minutes and then heated to 80 °C for 16 h. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, the mixture was cooled to 25 °C-30 °C, filtered through a Celite® bed, and washed with ethyl acetate (20 mL). The combined organic layers were directly concentrated under reduced pressure to afford crude product which was purified through neutral alumina column chromatography using 0 - 50% ethyl acetate in petroleum ether as an eluent. Selected fractions were collected and concentrated under reduced pressure to afford methyl 4-(6-bromopyrimidin- 4-yl)-3-chlorobenzoate (100 mg) as an off-white solid. !H NMR (400 MHz, CDCb): δ 9.09 - 9.09 (d, J= 8.0 Hz, lH), 8.21 - 8.21 (d, J= 1.6 Hz, 1H), 8.09 - 8.07 (dd, J= 8.0, 8.0 Hz, 1H), 8.00 (d, J= 1.2 Hz, 1H), 7.78 - 7.76 (d, J = 8 Hz, 1H), 3.99 (s, 3H).
[0490] Step 2: Synthesis of methyl 4-(6-(2-(tert-butyl)pyridin-4-yl)pyrimidin-4-yl)-3- chlorobenzoate. A stirred solution of methyl 4-(6-bromopyrimidin-4-yl)-3-chlorobenzoate (100 mg, 0.305 mmol), (2-(tert-butyl)pyridin-4-yl)boronic acid (54 mg, 0.305 mmol), potassium carbonate (105 mg, 0.763 mmol ) in water (1 mL) and 1,4-dioxane (4 mL) in a 15 mL glass seal tube was purged with nitrogen gas for 30 minutes. After adding palladium tetrakis (35 mg, 0.0305 mmol), the reaction mixture was again purged with nitrogen gas for 30 minutes, sealed, and heated at 80 °C for 16 h. The reaction progress was monitored by TLC and LCMS. After completion of reaction, the mixture was cooled to 25 °C - 30 °C, filtered through a bed of Celite®, and concentrated under reduced pressure to afford crude product This was purified through neutral alumina column chromatography using 0-50% ethyl acetate in petroleum ether as an eluent to give methyl 4-(6^(2-(tm-butyl)pyridin-4-yl)pyrimidin-4-yl)-3-chlorobenzoate (70 mg, 60%) as a colorless gum.
[0491] Step 3: Synthesis of 4-(6-(2-(tert-butyl)pyridin-4-yl)pyrimidin-4-yl)-3-chlorobenzoic acid. To a stirred solution of (70 mg, 0.183 mmol) in methanol: THF:water (3:2:1, 5 mL) was added L1OH.H2O (23 mg, 0.549 mmol), and the mixture was stirred at room temperature for 2 h. The reaction progress was monitored by TLC and LCMS. After completion, the reaction mixture was concentrated under reduced pressure. The crude product was dissolved in water (10 mL) and acidified with citric acid to pH -5. The water layer was then extracted with ethyl acetate (2 x 20 mL) and the combined organic layers dried over sodium sulfate and concentrated under reduced pressure to afford 4-(6-(2-(tert-butyl)pyridin-4-yl)pyrimidm-4-yl)-3-chlorobenzoic acid (70 mg) as an off white solid.
[0492] Step 4: Synthesis of (4-(6-(2-(tert-butyl)pyridin-4-yl)pyrimidin-4-yl)-3-chlorophenyl)(4- hydroxypiperidin-l-yl)methanone. To a stirred solution of 4-(6-(2-(tert-butyl)pyridin-4- yl)pyrimidin-4-yl)-3-chlorobenzoic acid (70 mg, 0.1 0 mmol) in DMF (3 mL) and DIPEA (98 mg, 0.761 mmol) was added HATU (289 mg, 0.761 mmol), and the mixture stirred for 15 min at room temperature under nitrogen. 4-hydroxypiperidine (19 mg, 0.190 mmol) was added under nitrogen and the mixture was stirred for 16 h at room temperature. The reaction progress was monitored by TLC and LCMS. After completion, the reaction mixture was diluted with cold water (50 mL) and extracted into EtOAc (2x25 mL). The combined organic layers were washed with ice cold water (50 mL) and dried over sodium sulfate, concentrated under reduced pressure to afford crude product (100 mg) which was purified through neutral alumina column chromatography using 0-100% ethyl acetate in petroleum ether followed by 10% methanol in ethyl acetate as an eluent. Selected fractions were collected and concentrated under reduced pressure to afford (4-(6-(2-(tert-butyl)pyridin^-yl)pyrimidin-4-yl)-3-chlorophenyl)(4- hydroxypiperidin-l-yl)methanone (58 mg, 40%) as an off white solid. Ή NMR (400 MHz, DMSO): δ 9.47 - 9.47 (m, 1H), 8.74 - 8.73 (d, J = 4.8 Hz, lH), 8.57 (m, 1H), 8.21 (m, 1H), 8.01 - 8.00 (dd, J= 5.2, 5.2 Hz, lH), 7.80 - 7.78 (d, J - 8.0 Hz, lH), 7.67 - 7.67 (m, 1H), 7.55 - 7.53 (dd, J= 7.6, 7.6 Hz, 1H), 4.81 (d, lH), 4.0 (bs, 1H), 3.78 - 3.74 (m, lH), 3.53 - 3.48 (m, 1H), 3.21 - 3.20 (s, 2H), 1.80 - 1.74 (m, 2H), 1.39 (s, 11H). LCMS: 99.8 % (m/z = 451.54 [M+H]). HPLC = 98.8%.
Example 9: (4-(6-(2-(tert-butyl)pyridin-4-yl)pyrazin-2-yl)-3-chlorophenyl)(4- hydroxypiperidin-l-yi)metbanone (Compound 9)
Figure imgf000214_0001
[0493] Step 1: Synthesis of methyl 4-(6-bromopymzin-2-yl)-3-chIorobenzoate. A solution of 2,6-dibromopyrazine (500 mg, 2.1019 mmol,), (2-chloro-4-(methoxycarbonyl)phenyl)boronic acid (314 mg, 1.4713 mmol) and potassium carbonate (314 mg, 3.1528 mmol) in 1,4- dioxane/EbO (10:1, 11 mL) was purged with nitrogen gas for 15 minutes. To this mixture was added palladium tetrakis (242.76 mg, 0.21 mmol), and the combination was heated at 80 °C for 16 h. The reaction progress was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through Celite® and concentrated under reduced pressure. The residue was dissolved in water (10 mL) and extracted with EtOAc (3 x 15 mL). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain crude product which was purified by column chromatography (Silica 100-200 mesh), eluting with 25% EtOAc in petroleum ether to give methyl 4-(6-bromopyrazin-2-yl)-3- chlorobenzoate as an off-white solid (220mg, 32%). LCMS: 93.75 % (M+EN327.11). ¾ NMR (400 MHz, CDCh: δ (ppm): 8.96 (s, 1H), 8.72 (s, 1H), 8.18 (d, J= 1.6 Hz, lH), 8.06-8.06-8.04 (m, lH), 7.74 (d, J= 8 Hz, lH), 3.97 (s, 3H).
[0494] Step 2: Synthesis of 4-(6-bromopyrazin-2-yl)-3-chlorobenzoic acid. To a stirred solution of methyl 4-(6-bromopyrazin-2-yl)-3-chlorobenzoate (300 mg, 0.613 mmol) in
THF/H2O (3:1) (3.7 mL) was added L1OH.H2O (25.7 mg, 0.613 mmol), and the reaction stirred at rt for 4 h. The reaction progress was monitored by TLC. After completion of the reaction, the mixture was concentration under reduced pressure, the residue was dissolved in water (10 mL) and acidified with 1.VHC1 to pH 3, and the aqueous layer was extracted with EtOAc (3 x 20 mL). The organic extracts were combined, dried over anhydrous sodium sulfate, and
concentrated under reduced pressure to obtain crude 4-(6-bromopyrazin-2-yl)-3-chlorobenzoic acid, which was used for next step without purification (130 mg, 68%).
[0495] Step 3: Synthesis of (4-(6-bromopyrazin-2-yl)-3-chlorophenyI)(4-hydroxypiperidin-l- yljmethanone. To a stirred solution of 4-(6-bromopyrazin-2-yl)-3-chlorobenzoic acid (125 mg, 0.40 mmol) in DMF (5 mL) was added DIPEA (0.21 ml, 1.2 mmol) followed by the addition of HATU (608.9 mg, 1.6 mmol), and the mixture stirred for 10 minutes. Then was added piperidin- 4-ol (60.69 mg, 0.60 mmol). The reaction mixture was stirred at rt for 16 h and the reaction progress was monitored by TLC. After completion of the reaction, the residue was dissolved in water (10 mL) and extracted with EtOAc (3 x 15 mL). The organic extracts were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude (4-(6-bromor>yrazin-2-yl)-3-chlorophenyl)(4-hydroxypiperidin-l-yl)methanone (125mg, 73%). ¾ NMR (400 MHz, CDC13: δ (ppm): 8.94 (s, lH), 8.71 (s, lH), 7.70 (d, J= 8 Hz, 1H), 7.56 (s, 1H), 7.43-7.41 (dd, J= 1.6, 1.6 Hz, 1H), 4.14-4.09 (m, 1H), 3.71-3.68 (s, 1H), 3.46 (s, lH), 3.17 (s, lH), 3.16 (s, lH), 1.81 (s, 1H), 1.75 (s, 1H), 1.30-1.28 (m, 2H), LCMS: 95.20 % (M+H= 396.19).
[0496] Step 4: Synthesis of (4-(6-(2-(tert-butyl)pyridin-4-yl)pyrazin-2-yl)-3-chlorophenyl)(4- hydroxypiperidin-l-yl)methanone. A solution of (4-(6-bromopyrazin-2-yl)-3-chlorophenyl)(4- hydroxypiperidin-l-yl)methanone (125 mg, 0.316 mmol,), (2-(tert-butyl)pyridin-4-yl)boronic acid (82.5 mg, 0.316 mmol) and potassium carbonate (87.3 mg, 0.632 mmol ) in 1,4- dioxane/EbO (5:1, 6 mL) was purged with nitrogen gas for 15 minutes. To this mixture was added palladium tetrakis (36.55 mg, 0.031 mmol), and the mixture was heated at 80 °C for 16 h. The reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through Celite®, concentrated under reduced pressure, and the residue dissolved in water (10 mL) then extracted with EtOAc (3 x 15 mL). The organic extracts were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain crude product. The crude compound was purified by preparative HPLC. Collected fractions were concentrated under reduced pressure to afford (4-(6-(2-(tert-butyl)pyridin-4-yl)pyrazin-2-yl)-3- chlorophenyl)(4-hydroxypiperidin-l-yl)methanone (16.8 mg, 11.7%) as an off white solid. ¾ NMR (400 MHz, DMSO: δ (ppm): 9.45 (s, lH), 9.06 (s, lH), 8.70 (d, J= 5.2 Hz, lH), 8.16 (s, 1H), 7.97-7.95 (m, 1H), 7.85 (d, J= 8 Hz, lH), 7.68 (d, J= 1.6 Hz, lH), 7.56-7.53 (m, lH), 4.81 (d, J= 4 Hz, lH), 4.05-4.02 (m, lH), 3.79-3.74 (m, 1H), 3.52 (br, lH), 3.22 (br, 2H), 1.81-1.75 (br, 2H), 1.39 (s, 1 lH). LCMS: 98.89 % (M+H=451.42). HPLC: 97.30 %.
Figure imgf000216_0001
[0497] Step 1: Synthesis of methyl 4-(5-bromo-2-methoxypyridin-3-yl)-3-chlorobenzoate. 3,5- dibromo-2-methoxypyridine (300 mg, 1.124 mmol), (2-chloro-4-
(methoxycarbonyl)phenyl)boronic acid (289 mg, 1.348 mmol), sodium carbonate (297 mg, 2.801 mmol), water (1 mL) and DME (3 mL) were combined in a 15 mL glass sealed tube and purged with nitrogen gas for 30 minutes. After adding palladium tetrakis (130 mg, 0.112 mmol), the mixture was again purged with nitrogen gas for 30 minutes and then heated to 80 °C for 16 h. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, it was cooled to 25 °C - 30 °C, filtered through a bed of Celite®, and washed with ethyl acetate (20 mL). The combined organic layers were concentrated under reduced pressure to afford crude product, which was purified through neutral alumina column chromatography using 0-30% ethyl acetate in petroleum ether as an eluent Selected fractions were collected and concentrated under reduced pressure to afford methyl 4-(5-bromo-2-methoxypyridin-3-yl)-3-chlorobenzoate (200 mg) as an off-white solid. ¾ NMR (400 MHz, CDCh): δ 8.27 - 8.27 (d, J = 2.4 Hz, lH), 8.14 - 8.13 (d, J= 1.6 Hz, lH), 7.98 - 7.96 (dd, J = 8.0, 8.0 Hz, lH), 7.62 -7.61 (d, J= 2.4 H¾ lH), 7.37 - 7.35 (d, J= 8.0 Hz, lH), 3.95 (s, 3H), 3.9 (s, 3H). LCMS: 98 % (m/z = 356.16 [M+H]).
[0498] Step 2: Synthesis of methyl 4-(2 '-(tert-butyl)-6-methoxy-[3, 4'-bipyridin]-5-yl)-3- chlorobenzoate. Methyl 4-(2'-(tert-butyl)-6-methoxy-[3,4'-bipyridin]-5-yl)-3-chlorobenzoate (200 mg, 0.563 mmol), (2-(tert-butyl)pyridin-4-yl)boronic acid (147 mg, 0.563 mmol), potassium carbonate (194 mg, 1.408 mmol) in water (1 mL) and 1,4-dioxane (4 mL) were charged in 15 mL glass seal tube and purged with nitrogen gas for 30 minutes. After adding palladium tetrakis (65 mg, 0.0563 mmol), the mixture was again purged with nitrogen gas for 30 minutes, and then heated to 80 °C for 16 h. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, it was cooled 25 °C - 30 °C, filtered through a bed of Celite®, and extracted with ethyl acetate (15 mL). The combined organic layers were concentrated under reduced pressure to afford crude product, which was purified through neutral alumina column chromatography using 0-50% ethyl acetate in petroleum ether. Selected fractions were collected and concentrated under reduced pressure to afford methyl 4-(2'-(tert- butylJ-e-methoxy-tS^'-bipyridinl-S-ylJ-S-chlorobenzoate (70 mg) as a colorless gum. 'H-NMR (400 MHz, DMSO-D6): δ 8.63 - 8.61 (m, lH), 8.52 - 8.52 (d, J = 2.4 Hz, 1H), 8.18 - 8.17 (d, J = 1.6 Hz, lH), 8.02 - 7.99 (m, 1H), 7.77 - 7.76 (d, J= 2.4 Ηζ,ΙΗ), 7.50 - 7.50 (m, 1H), 7.45 - 7.43 (d, J= 8 Hz, 1H), 7.26 (m, 1H), 3.99 (s, 3H), 3.96 (s, 3H), 1.41 (s, 9H). LCMS: 80.63% (m/z = 411.1 [M+H]).
[0499] Step 3: Synthesis of 4-(2 '-(iert-butyl)-6-methoxy-[3, 4'-bipyridin]-5-yl)-3-chlorobenzoic acid. To a stirred solution of 4-(2'-(tert-butyl)-6-memoxy-[3,4'-bipyridin]-5-yl)-3-chlorobenzoic acid (240 mg, 0.585 mmol) in methanol: THF: water (3:2:1, 5 mL) was added L.OH.H2O (73 mg, 1.755 mmol), and the mixture was stirred at room temperature for 2 h. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, it was concentrated under reduced pressure, dissolved in water (10 mL) and acidified with citric acid up to pH ~5. The aqueous layer was extracted with ethyl acetate (2x20 mL), and the combined organic layers were collected and dried over sodium sulfate and concentrated under reduced pressure to afford 4-(2'- (tert-buryl)-6-methoxy-[3,4'-bipyridin]-5-yl)-3-chlorobenzoic acid (200 mg) as an off white solid.
[0500] Step 4: Synthesis of(4-(2 '-(tert-butyl)-6-methoxy-[3, 4'-bipyridin]-5-yl)-3- chIorophenyl)(4-hydroxypiperidin-l-yI)methanone. To a stirred solution of 4-(2,-(tert-butyl)-6- methoxy-[3,4'-bipyridin]-5-yl)-3-chlorobenzoic acid (200 mg, 0.505 mmol) in DMF (2 mL) and DIPEA (261 mg, 2.02 mmol) was added HATU (768 mg, 2.02 mmol), and the mixture was stirred for 15 min at room temperature under nitrogen. Then 4-hydroxypiperidine (51 mg, 0.505 mmol) was added under nitrogen. The mixture was stirred for 16 h at room temperature and the reaction progress was monitored by TLC and LCMS. After completion of reaction, it was diluted with cold water (25 mL) and extracted with ethyl acetate (2x20 mL). The combined organic layers were washed with ice cold water (50 mL) and dried over sodium sulfate, then concentrated under reduced pressure to afford crude (100 mg) product which was purified through neutral alumina column chromatography using 0-100% ethyl acetate in petroleum ether followed by 10% methanol in ethyl acetate as an eluent. Selected fractions were collected and concentrated under reduced pressure to afford (4-(2'-(tert-buryl)-6-methoxy-[3,4'-bipyridin]-5- yl)-3-chlorophenyl)(4-hydroxypiperidin-l-yl)methanone (58 mg) as an off white solid. 'H-NMR (400 MHz, DMSO): δ 8.73 -8.73 (d, J= 2.4 Hz, 1H), 8.56 - 8.55 (d, J= 5.2 Hz, 1H), 8.18 -8.17 (d, J= 2.4 Hz, 1H), 7.75 - 7.74 (m , 1H), 7.59 - 7.58 (d, J= 1.6 Hz, 1H), 7.58 - 7.57 (d, J= 1.6 Hz, 1H), 7.55 - 7.53 (d, J= 8.0 Hz, 1H), 7.44 - 7.44 (dd, J= 8.0, 8.0 Hz, 1H), 4.82 (bs, lH), 4.0 (s, 1H), 3.92 (s, 3H), 3.76 - 3.74 (m, 1H), 3.54 (s, 1H), 3.23 (m, 2H), 1.77-1.54 (m, 2H), 1.362 (s, 11H). LCMS: 99.21 % (m/z = 480.2 [M+H]). HPLC=99.71%.
Figure imgf000219_0001
[0501] Step 1: Synthesis of 4-(5-bromopyridin-3-yl)-3-chloroaniline. 3,5-dibromo- pyridine(0.300 g, 1.266 mmol), 3-cWoro-4-(4,4,5,5-teteramethyl-l,3,2-dioxaborokn-2-yl)aniline (0.291 g, 1.139 mmol) and cesium carbonate (0.824 g, 2.532 mmol) in dioxane (6 mL) were combined in a 10 mL glass seal tube and purged with nitrogen gas for 10 minutes. After adding palladium tetrakis (0.146 g, 0.126 mmol), the mixture was again purged with nitrogen gas for 10 min, then heated to 95 °C for 2.5 h. The reaction was monitored by TLC and LCMS. After completion, the reaction mixture was cooled to RT, then 10 mL water added and the mixture extracted with ethyl acetate (3x15 mL). The organic extracts were combined and were washed with brine (3x10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give crude product which was purified by silica gel column chromatography eluting with (0-15% EtOAc in hexane). The product fractions were combined and concentrated to give 4-(5-bromopyridin-3-yl)-3-chloroaniline (0.250 g, 69.63%) as off white solid. 'H-NMR (400 MHz, DMSO de): δ (ppm): ): 8.63 (1H, J=2.4, d), 8.55 (1H, J = 2.0 Hz, d), 8.03 (1H, J= 2.0 Hz, t), 7.15-7.13 (1H, J= 8.0 Hz, t), 6.73 (1H, J= 2.0 Hz, d), 6.62-6.60 (1H, m), 5.68 (2H, s), 5.68 (2H, s); LCMS: 98.62% (m/z = 285.0 [M+ H]).
[0502] Step 2: Synthesis of 4-(2'-(tert-butyl)-[3,4'-bipyridin]-5-yl)-3^hlorom 4-(5- bromopyridin-3-yl)-3-chloroaniline (0.250 g, 0.881 mmol), 2-tert butyl pyridine 4-boronic acid pinacol ester (0.276 g, 1.058 mmol) and potassium carbonate (0.244 g, 1.762 mmol) in dioxane: water (4: 1 mL) were combined in a 10 mL glass seal tube and purged with nitrogen gas for 10 minutes. After adding palladium tetrakis (0.101 g, 0.088 mmol), and again purging with nitrogen for 10 minutes, the mixture was heated to 80 °C for 16 h. The reaction was monitored by TLC. After completion, it was cooled, water (10 niL) added and the whole extracted with ethyl acetate (3x10 mL). The extracts were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude product which was purified on silica column chromatography eluting with (0-35% ethyl acetate in hexane) to give 4-(2'-(tert-butyl)-[3,4'- bipyridin]-5-yl)-3-chloroaniline (0.250 g, 83.89%) as white solid. 'H-NMR (400 MHz, DMSO d6): δ (ppm): 8.91 (1H, J=2.4, d), 8.65 (s, 1H), 8.64 (s, lH), 8.15 (1H, s), 7.78 (1H, J= 0.08, d), 7.6 (m, lH), 7.23 (lH, J= 8.0 Hz, d), 6.76 (1H, J= 2.0 Hz, d), 6.7 (s, 1H), 5.64 (2H, s), 1.37 (9H, s). LCMS: 96.96 % (m/z [M+H= 338.29]).
[0S03] Step 3: Synthesis of l-(4-(2'-(tert-butyl)-[3, 4'-bipyridin]-5-yl)-3-chlorophenyl)-3- isopropylurea. To a solution of 4-(2'-(tert-buryl)-[3,4'-bipyridin]-5-yl)-3-chloroaniline (0.100 g, 0.296 mmol) in DCM (4 mL, 20 v), was added triethylamine (0.44 g, 0.444 mmol) and 2- isocyanatopropane (0.038 g, 0.444 mmol) at 0 °C. The reaction was stirred for 16 h at RT and monitored by TLC. After completion, the reaction mass was diluted with DCM and washed with brine solution (2x5 mL). The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude product that was purified by preparative HPLC to afford l-(^(2'-(tert-butyl)-[3,4'-bipyridin]-5-yl)-3-chlorophenyl)-3-isopropylurea (0.070 g, 56.00 % yield) as an off white solid. ¾-NMR (400 MHz, DMSO de): δ (ppm):
8.98(1HJ=2.4, d), 8.69 (1H, J = 2.0 Hz, d), 8.66 (1H, s), 8.61 (1H, J= 4.8 Hz, d), 8.24-8.233 (1H, J= 2.0 , t ), 7.84 (1H, J= 2.0 Hz, d), 7.80 (1H, J= 0.8 Hz, d), 7.64-7.62 (1H, m), 7.46-7.44 (1H, J= 8.4 Hz, d), 7.35-7.32 (1H, m), 6.17-6.15 (1H, J= 7.8 Hz, d), 3.80-3.73 (lH, m), 1.37 (9H, s), 1.10 (6H, d). LCMS: 99.56% (m/z 423.40 [M+H]). HPLC: purity 99.79%.
Figure imgf000221_0001
[0504] Step 1: (4-(5-bromopyridin-3-yl)-3-chlorophenyl)(4-hydroxyp
To a stirred solution of 4-(5-bromopyridin-3-yl)-3-chlorobenzoic acid as prepared in Example 4 (0.3 g, 1.2 mmol) in DMF (5 mL) was added DIPEA (0.49 g, 3.8 mmol) followed by the addition of HATU (0.73 g, 1.9 mmol). This mixture was stirred for 10 min, then 4-hydroxypiperidine (0.143 g, 1.4 mmol) was added and the mixture stirred at rt for 16 h and monitored by TLC. After completion of the reaction, it was dissolved in water (10 mL) and extracted with ethyl acetate (2x15 mL). The extracts were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain crude (^(5-bromopyridin-3-yl)-3- chlorophenyl)(4-hydroxypiperidin-l-yl)methanone (0.2 g), which was used in step 4 without further purification.
[0505] Step 2: Synthesis of 4-bromo-2-(l,3-dioxolan-2-yl)pyridine. To a stirred solution of 4- bromopicolinaldehyde in toluene was added ethylene glycol (2.25 g, 32.5 mmol) and PTSA (0.245 g, 0.075 mmol), and the mixture was heated under reflux for 24 h. The progress of the reaction was monitored by LCMS and TLC. At completion, the reaction mixture was
concentrated and partitioned between ethyl acetate and water to give crude product which was purified by flash chromatography eluting with 20% ethyl acetate and petroleum ether to give 4- bromo-2-(l,3-dioxolan-2-yl)pyridine (2.5 g) as a pale yellow liquid. 'H-NMR (400 MHz, CDCh: δ (ppm): 8.43 (d, J=5.2 Hz, 1H), 7.72 (d, J=2 Hz, 1H), 7.47-7.45 (dd, J=2 Hz, lH), 5.83 (s, lH), 4.18-4.06 (m, 4H). [0506] Step 3: Synthesis of (2-(l,3-dioxolan-2-yl)pyridin-4-yl)boronic acid. In a glass tube was combined 4-bromo-2-(l,3-dioxolan-2-yl)pyridine (1.0 g, 4.3 mmol) in 1,4-dioxane (15 mL), 4,4,4'4'5,5,5'5,-octamethyl-2,2,-bi(l,3,2-dioxaboΓolane) (2.20 g, 8.6 mmol), and KOAc (1.2 g, 13.11 mmol) under a nitrogen atmosphere. The mixture was purged for 15 min with nitrogen, then Pd(dppf)Ch (0.354 g, 0.43 mmol) was added and the mixture purged again for 10 min with nitrogen. The mixture was sealed in the glass tube and stirred at 80 °C for 16 h, and reaction progress monitored by TLC. After completion of the reaction, the residue was dissolved in water (10 mL) and extracted with EtOAc (3x20 mL). The organic extracts were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtained crude product, which was purified by column chromatography (Florisil® 60-120 mesh), eluting with 50% ethyl acetate in hexanes. The product fractions were concentrated under reduced pressure to obtain (2- (l,3-dioxolan-2-yl)pyridin-4-yl)boronic acid as a dark brown semi solid (1 g).
[0507] Step 4: Synthesis of(4-(2'-(l, 3-dioxolan-2-yl)-[3, 4'-bipyridin]-5-yl)-3-chlorophenyl)(4- hydroxypiperidin-l-yl)methanone. (4-(5-bromopyridin-3-yl)-3-chlorophenyl)(4- hydroxypiperidin-l-yl)methanone (0.2 g, 0.5 mmol) was dissolved in 1,4-dioxane (20 mL) and (2-(l,3-dioxolan-2-yl)pyridin-4-yl)boronic acid (0.098 g, 0.5 mmol) and K2CO3 (0.211 g, 1.5 mmol) were added under a nitrogen atmosphere. The mixture was purged for 15 min with nitrogen, then Pd(PPh3)4 (0.058 g, 0.05 mmol) was added and the mixture purged again for 10 min with nitrogen. The reaction vessel was sealed and the reaction stirred at 80 °C for 16 h, with reaction progress monitored by TLC. After completion of the reaction, the residue was dissolved in water (10 mL) and extracted with ethyl acetate (3x20 mL). The organic extracts were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give crude product, which was purified by preparative HPLC. The product fractions were combined and lyophilized to give (4-(2'-(l,3-dioxolan-2-yl)-[3,4'-bipyridin]-5-yl)-3-chlorophenyl)(4- hydroxypiperidin-l-yl)methanone (62 mg) as an off-white solid.1H-NMR (400 MHz, DMSO: 6 (ppm): 9.8 (d, J = 2.0 Hz, 1H), 8.79 (d, J = 2.0 Hz, 1H), 8.68 (d J= 5.2 Hz, lH), 7.93-7.89 (m, 2H), 7.69-7.65 (m, 2H), 7.50-7.40 (m, lH), 5.82 (s, 1H) , 4.82 (s, lH), 4.19-4.1 (m, 2H), 4.04- 3.96 (m, 3H), 3.96-3.70 (m, 1H), 3.7 (m, lH), 3.50 (br 1H), 3.20 (br, 2H), 1.80-1.74 (br, 2H),1.39-1.33 (br, 2H). LCMS: (466.39 [M+H]) 98.38%. HPLC: 97.78%. Example 13: tert-butyl (l-(4-(24tert-butyl)-[3,4'-bipyridui]-5-yl)-3- chlorobenzoyl)piperidin-3-yl)carbamate (Compound 13)
Figure imgf000223_0001
[0508] To a stirred solution of 4-(2'-(tert-butyl)-[3,4'-bipyridin]-5-yl)-3-chlorobenzoic acid (100 mg,0.4098 mmol) as prepared in Example 4 in DMF (1 mL) was added tert-butyl piperidin- 3-ylcarbamate (123 mg,0.614 mmol), HATU (622.8 mg.1.639 mmol) and DIPEA (158.8 mg, 1.229 mmol), and the mixture stirred at RT for 16 h. The reaction was monitored by TLC. After completion, the reaction mixture was quenched with ice cold water and extracted with ethyl acetate. The organic layer was dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain crude compound (150 mg), which was purified by preparative HPLC. Selected fractions were concentrated under reduced pressure and lyophilized to afford tert-butyl ( 1 -(4-(2'-(tert-butyl)-[3 ,4-bipyridin] -5-y l)-3 -chlorobenzoyl)piperidin-3 -yl)carbamate (48mg) as an off white solid. 1H-NMR (400 MHz, DMSO de): δ (ppm): 9.06 (d, J - 2.0 Hz lH), 8.74 (br s, 1H), 8.62 (d, J= 5.2 Hz, lH), 8.34 (br s, 1H), 7.82 (s, 1H), 7.68-7.64 (m, 3H) 7.52- 7.40 (m, lH), 7.01 (br s, 1H), 3.92-3.70 (m, 2H), 3.43 (br s, lH), 3.15-3.10 (m, 1H), 1.80-1.76 (m,2H), 1.51-1.47 (m, 2H) 1.38-1.36 (m, 20H). LCMS: 99.46% (m/z = 549.49 [M+ H]). HPLC: 99.84%.
Example 14: (4-(2*-(tert-butyl)- [3,4'-bipyridin] -5-yl)-3-chlorophenyl)(3-hydroxypiperidin- l-yl)methanone (Compound 14)
Figure imgf000223_0002
[0509] To a stirred solution of 4-(2'-(tert-butyl)-[3,4'-bipyridin]-5-yl)-3-chlorobenzoic acid (100 mg,0.4098 mmol) in DMF (1 mL) was added HATU (622.8 mg,1.639 mmol) and DIPEA (158.8 mg, 1.229 mmol), and the mixture stirred for 10 min. Then piperidin-3-ol (62 mg, 0.614 mmol) was added, and the reaction was stirred at RT for 16 h. After completion of the reaction (as determined by TLC), the reaction mixture was quenched with ice cold water and extracted with ethyl acetate. The organic layer was dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain crude compound (ISO mg), which was purified by preparative HPLC. Compound fractions were concentrated under reduced pressure and lyophilized to afford (4-(2'-(tert-butyl)-[3,4,-bipyridin]-5-yl)-3-chlorophenyl)(3- hydroxypiperidin-l-yl)methanone. 'H-NMR (400 MHz, DMSO d6): δ (ppm): 9.07 (d, J - 2.0 Hz lH), 8.76 (d, , J - 2 Hz 1H), 8.63-8.62 (m,lH), 8.35-8.34 (m,lH), 7.83-7.82 (m, lH), 7.68-7.64 (m, 3H) 7.52-7.50 (m, lH), 5.01-4.90 (m,lH), 3.89-3.32 (m, 4H), 3.10-2.89 (m,lH), 1.81-1.43 (m,2H), 1.38-1.36 (m, 1 lH). LCMS: 98.92%. HPLC: 98.81% (m/z = 450.1[M+ H]).
Example IS: (4-(2'-(tert-butyl)-[3,4'-bipyridin]-5-yl)-3-chlorophenyl)(3-methoxypiperidiii- l-yl)methanone (Compound IS)
Figure imgf000224_0001
[0S10] To a stirred solution of 4-(2'-(tert-butyl)-[3,4'-bipyridin]-5-yl)-3-chlorobenzoic acid (100 mg,0.4098 mmol) in DMF (1 mL) was added HATU (622.8 mg,1.639 mmol) and DIPEA (158.8 mg, 1.229 mmol), and the mixture stirred for 10 min. Then 3-methoxypiperidine (71 mg, 0.614 mmol) was added, and the reaction stirred at RT for 16 h. After completion of the reaction (as determined by TLC), the reaction mixture was quenched with ice cold water and extracted with ethyl acetate. The organic layer was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude product (150 mg), which was purified by preparative HPLC. Fractions containing the product were combined and concentrated under reduced pressure and lyophilized to afford (4-(2'-(tert-buryl)-[3,4'-bipyridin]-5-yl)-3- chlorophenyl)(3-methoxypiperidin-l-yl. 1H-NMR (400 MHz, DMSO de): δ (ppm): 9.07 (d, J = 2.4 Hz lH), 8.76 (d, J = 2 Hz 1H), 8.63-8.62 (m, lH), 8.36-8.35 (m,lH), 7.83-7.82 (m, 1H), 7.68- 7.62 (m, 3H) 7.49 (m, lH), 3.95-3.75 (m, 1H), 3.34 (m,4H), 3.15 (m,3H), 1.90-1.70 (m, 3H),1.38 (s, 10H). LCMS: 99.56%. HPLC: 99.83% (m/z = 464.2 [M+ H]). Example 16: isopropyl (4-(2'-(tert-butyl)-[3,4'-bipyridin]-5-yl)-3-chlorophenyl)carbamate (Compound 16)
Figure imgf000225_0001
[0511] To a solution of 4-(2'-(tert-butyl)-[3,4'-bipyridin]-5-yl)-3-chloroaniline (0.100 g, 0.296 mmol) in DCM (4 mL, 20 v), was added triethylamine (0.44 g, 0.444 mmol) and isopropyl chloroformate (0.054 g, 0.444 mmol) at 0 °C. The reaction was then stirred for 16 h at RT. After completion (as determined by TLC), the mixture was diluted with DCM and washed with brine solution (2x5 mL). The organic layers were separated, combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure to get a crude product which was purified by preparative HPLC to afford isopropyl (4-(2'-(tert-butyl)-[3,4'-bipyridin]-5-yl)-3- chlorophenyl)carbamate (0.031 g. 24.60 % yield) as an off-white solid. !H-NMR (400 MHz, DMSO de): δ (ppm): 9.94(1H, s), 9.00 (1H, J = 2.4 Hz, d), 8.70 (1H, J= 2.0, s), 8.62-8.61 (1H, m), 8.25 (1H, t ), 7.80 (1H, J= 0.08 Hz, d), 7.64 7.42 (1H, m), 7.52 (2H, J= 1.2 d), 4.95-4.89 (1H, m), 1.37 (9H, s), 1.29-1.27 (6H, d). LCMS: 99.55% (m/z 424.1 [M+H]). HPLC purity 99.12%.
Example 17: (4-(2'-(tert-butyl)^methyl-[3^'-bipyridin]-5-yl)-3-cliloroplienyl)(4- hydroxypiperidin-l-yl)methanone (Compound 17)
Figure imgf000225_0002
[0512] Step 1: Synthesis of 5-bromo-2'-(tert-butyl)-6-methyl-3,4'-bipyridine. In a 48 mL glass seal tube was combined 3,5-dibromo-2-methylpyridine (200 mg, 0.80 mmol), (2-(tert- butyl)pyridin-4-yl)boronic acid (158 mg, 0.88 mmol), and potassium carbonate (277 mg, 2.00 mmol) in water (1 mL) and 1,4-dioxane (10 mL) which was purged with argon gas for 30 min. After adding palladium tetrakis (92 mg, 0.08 mmol), the mixture was again purged with argon gas for 30 min, then the tube was sealed and heated to 80 °C for 16h. After completion of reaction (as determined by TLC), the mixture was cooled to 25 °C - 30 °C, filtered through a Celite® bed, and extracted with ethyl acetate (20 mL). The combined organic layers were concentrated under reduced pressure to afford crude product (500 mg) which was purified with neutral alumina column chromatography using 0-30% ethyl acetate in petroleum ether as an eluent. Selected fractions were collected and concentrated under reduced pressure to afford 5- bromo-2'-(tert-butyl)-6-methyl-3,4'-bipyridine (200 mg) as an off-white solid. !H-NMR (400 MHz, CDCb): δ 8.67 - 8.64 (m, 2H), 8.03 - 8.03 (d, J= 2.0 Hz, lH), 7.47 (m, lH), 7.27 - 7.26(m, lH), 2.73 (s, 3H), 1.43 (s, 9H).
[0513] Step 2: Synthesis of (2-chloro-4-(methoxycarbonyl)phenyl)boronic. Into a 15 mL glass seal tube was combined 5-bromo-2'-(tert-butyl)-6-methyl-3,4'-bipyridine (200 mg, 0.657 mmol), (2-chloro-4-(methoxycarbonyl)phenyl)boronic acid (168 mg, 0.789 mmol), potassium carbonate (226 mg, 1.64 mmol), water (1 mL), and 1,4-dioxane (10 mL), and the mixture purged with argon gas for 30 min. After adding palladium tetrakis (75 mg, 0.065 mmol), the mixture was again purged with argon gas for 30 min, then heated to 80 °C for 16 h. After completion of the reaction (as determined by TLC), the mixture was cooled 25 °C-30 °C, filtered through a Celite® bed, and extracted with ethyl acetate. The combined organic layers were concentrated under reduced pressure to afford crude product (300 mg), which was purified with neutral alumina column chromatography using 0-50% ethyl acetate in petroleum ether as an eluent Selected fractions were collected and concentrated under reduced pressure to afford (2-chloro-4- (methoxycarbonyl)phenyl)boronic acid (150 mg) as a pale yellow gum.
[0514] Step 3: Synthesis of 4-(2'-(tert-butyl)-6-methyl-[3,4'-bipyridin]-5-yl)-3^
acid. To a stirred solution of (2-chloro-4-(methoxycarbonyl)phenyl)boronic acid (150 mg, 0.585 mmol) in methanol: THF: water (3:2:1, 5 mL) was added LiORHbO (48 mg, 1.14 mmol), and the mixture stirred at room temperature for 2h. After completion of the reaction, the mixture was concentrated under reduced pressure. The crude material was dissolved in water (10 mL) and acidified with citric acid up to pH ~5. Then the product was extracted into ethyl acetate
(2x20mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to afford product (140 mg) as an off white solid which was used in the next step without further purification.
[0515] Step 4: Synthesis of(4-(2'-(tert-butyl)-6-methyl-[3,4'-bipyridinJ-5-yl)-3- chlorophenyI)(4-hydroxypiperidin-l-yl)methanone. To a stirred solution of 4-(2'-(tert-butyl)-6- methyl-[3,4'-bipyridin]-5-yl)-3-chlorobenzoic acid (140 mg, 0.368 mmol) in DMF (3 mL) and DIPEA (0.264 mL, 1.47 mmol) was added HATU (559 mg, 1.47 mmol) and the mixture was stirred for 15 min at room temperature under argon. Then 4-hydroxypiperidine (44 mg, 0.442 mmol) was added under argon. The mixture was stirred for 16 h at room temperature. After completion of the reaction (as determined by TLC), the mixture was diluted with cold water (25 mL) and the product was extracted into ethyl acetate (2x20 mL). The combined ethyl acetate layers were washed with ice cold water (50 mL) and dried over sodium sulfate, then concentrated under reduced pressure to afford crude product which was purified by preparative HPLC to afford (^(2'-(tert-butyl)-6-memyl-[3,4'-bipyridin]-5-yl)-3-chlorophenyl)(4-hya^oxypiperidm yl)methanone (54 mg) as an off white solid. 'H-NMR (400 MHz, DMSO): δ 8.97 - 8.96 (d, J= 2.4 Hz ,1H), 8.59 - 8.58 (d, J = 5.2 Hz, 1H), 8.10 -8.09 (d, J= 2.4 Hz, 1H), 7.77 (m , lH), 7.64 - 7.60 (m, 2H), 7.54 - 7.52 (m, lH), 7.48 - 7.46 (m, lH), 4.82 - 4.81 (d, J= 3.6 Hz, 1H), 4.00 (bs, 1H), 3.79 - 3.75 (m, 1H), 3.57 - 3.55 (m, lH), 3.32 (m, 2H), 2.33 (s, 3H), 1.79 (m, 2H), 1.4 (m, 2H), 1.36 (s, 9H). LCMS: 98.59 % (m/z = 464.55 [M+H]). HPLC: 98.83%.
Example 18: (4-(2'-(tert-butyl)-2-methyl-[3,4,-bipyridin]-S-yl)-3-chlorophenyl)(4- hydroxypiperidin-l-yl)methanone (Compound 18)
Figure imgf000227_0001
[0516] This compound was prepared by a series of reactions similar to those shown in
Example 17. ^-NMR (400 MHz, DMSO-D6): δ 8.63 - 8.60 (m, 2H), 8.56 - 8.55 (d, J= 2.0 Hz, 1H), 7.63-7.61 (m, 2H), 7.54 - 7.53 (m, lH), 7.46-7.44 (dd, J= 7.6 Hz, J= 8 Hz, lH), 4.81 - 4.80 (d, J=4 Hz, 1H), 4.02 - 3.99 (s, lH), 3.78- 3.73 (m, lH), 3.50 (bs, 1H), 3.32 -3.18 (b, 2H), 2.53-2.49 (m, 3H), 1.79 - 1.73 (m, 2H), 1.36 (s, 1 lH). LCMS: 97.82 % (m/z = 464.54 [M+H]). HPLC: 99.59%.
Example 19: (4-(2'-(tert-butyl)-2-methoxy-[3,4'-bipyridin]-5-yl)-3-chlorophenyl)(4- hydroxypiperidin-l-yI)methanone (Compound 19)
Figure imgf000228_0001
[0517] This compound was prepared by a series of reactions similar to those shown in
Example 17. ^-NMR (400 MHz, DMSO): δ 8.57 - 8.56 (d, J= 5.7Hz, 5.2Hz, lH), 8.36 - 8.35 (d, J= 2.4Hz, 1H), 8.03 -8.02 (d, J= 2.4Hz,lH), 7.65 - 7.60 (m , 3H), 7.48 - 7.43 (m, 2H), 4.81 -4.80 (d, J = 3.6Hz, 1H), 4.01 (m, lH), 3.97 (s, 3H), 3.77 - 3.74 (m, 1H), 3.53 - 3.51 (m, 1H), 3.20 - 3.19 (m, 2H), 1.82 - 1.75 (m, 2H), 1.37 (m, 2H), 1.35 (s, 9H). LCMS: 99.52 % (m/z = 480.1 [M+H]). HPLC: 99.15%.
Example 20: Isopropyl (4-(2'-(l^-dioxolan-2-yI)-[3,4'-bipyridin]-5-yl)-3- chlorophenyl)carbamate (Compound 20)
Figure imgf000228_0002
[0518] Step 1: Synthesis of 4-(5-bromopyridin-3-yl)-3-chloroaniline. 3,5-dibromopyridine (1.0 g, 4.22 mmol), 3-chloro-4-(4,4,5,5-teteramethyl-l,3,2-dioxaborolan-2-yl)aniline (0.96 g, 3.78 mmol) and potassium carbonate (1.75 g, 12.66 mmol) in dioxane (25 mL) were combined in a 50 mL glass seal tube and purged with nitrogen gas for 10 min. Tetrakis palladium (0.48 g, 0.422 mmol) was added and the mixture was again purged with nitrogen gas for 10 min, then heated to 80 °C for 16 h. After completion of the reaction (as determined by TLC), the reaction mixture was cooled to RT, 10 mL water added, and the mixture extracted with ethyl acetate (3x15 mL). The organic extracts were combined, washed with brine (3x10 mL) and dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure and purified by flash column chromatography (silica gel 100-200 mesh) using 20% ethyl acetate and hexane used as an eluent. Selected fractions were collected and concentrated to give 4-(5-bromopyridin-3-yl)-3- chloroaniline (0.350 g, 97%) as an off white solid.
[0519] Step 2: Synthesis o/4-(2 '-(1, 3^oxo^-2-yl)-[3,4'-bipyridin]-5-yl)-3-chlorocm 4- (5-bromopyridin-3-yl)-3-chloroaniline (0.350 g, 1.23 mmol), (2-(l,3-dioxolan-2-yl)pyridin-4- yl)boronic acid (0.36 g, 1.85 mmol) and potassium carbonate (0.51 g, 3.78 mmol) in
dioxane:water (30 mL, 4: 1) were combined in a 50 mL glass seal tube and purged with nitrogen gas for 10 minutes. Palladium tetrakis (0.14 g, 0.123 mmol) was added and the mixture again purged with nitrogen gas for 10 minutes. The reaction mass was heated to 80 °C for 16 h. After completion of the reaction (as determined by TLC), the mixture was cooled, water (10 mL) was added, and the mixture was extracted with ethyl acetate (3x10 mL). The organic extracts were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude product, which was purified by column chromatography (silica gel 230-400) using MeOH/DCM as the mobile phase. Selected fractions containing the product were combined and concentrated to give 4-(2'-(l,3-dioxolan-2-yl)-[3,4'-bipyridin]-5-yl)-3-chloroaniline (0.200 g, 83.89%) as a yellow solid.
[0520] Step 3: Synthesis of isopropyl (4-(2 '-(1, 3-dioxolan-2-yl)-[3, 4'-bipyridin]-5-yl)-3- chlorophenytycarbamate. To a solution of 4-(2'-(l,3-dioxolan-2-yl)-[3,4'-bipyridin]-5-yl)-3- chloroaniline (0.200 g, 0.56 mmol) in DCM (10 mL, 20 v) was added triethylamine (0.17 g, 1.69 mmol) and isopropylchloroformate (0.1 g, 0.84 mmol) at 0 °C, The reaction was stirred for 16 h at RT. After completion, the reaction mass was diluted with DCM and washed with brine solution (2x5 mL). The combined organic layers were separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure to get crude product which was purified by preparative HPLC to afford isopropyl (4-(2l-(l,3-dioxolan-2-yl)-[3,4'-bipyridin]-5-yl)-3- chlorophenyljcarbamate (0.034 g, 24.60 % yield) as an off white solid. 'H-NMR (400 MHz, DMSO de): δ (ppm): 8.94 (1H, s), 8.70 (1H, J = 2.0 Hz, d), 8.66 (1H, J= 5.2 Hz, d), 8.26 (1H, J = 2 Hz, t), 7.95 (1H, 1.2 Hz, s), 7.82-7.79 (2H, m), 7.51- 7.48 (1H, m), 7.44-7.42 (d, J = 8.4 Hz, 1H), 5.86 (1H, s), 5.0-4.97 (1H, m), 4.21-4.15 (2H, m), 4.09-4.06 (2H, m) , 1.31(6H, J= 6.4 Hz, d). LCMS: 99.18% (m/z 440.1 [M+H]). HPLC: purity 97.64%.
Example 21: Synthesis of (4-(2'-(tert-butyl)-[3,4,-bipyridin]-5-yl)-3-chlorophenyl)(4- hydroxy-4-methylpiperid-n-l-yi)metfaanone (Compound 21)
Figure imgf000230_0001
[0S21] To a stirred solution of 4-(2l-(tert-butyl)-[3,4l-bipyridin]-5-yl)-3-chlorobenzoic acid (100 mg,0.4098 mmol) in DMF(1 ml) was added HATU (622.8 mg,1.639 mmol) and DIPEA (158.8 mg, 1.229 mmol). After stirring for 10 min, 4-methylpiperidin-4-ol (71 mg, 0.614 mmol) was added, and the reaction then stirred at RT for 16 h. The reaction mixture was quenched with ice cold water and extracted with EtOAc. The organic layer was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude product, which was purified by preparative HPLC. Compound fractions were combined, concentrated under reduced pressure, and lyophilized to afford (4-(2'-(tert-butyl)-[3,4l-bipyridin]-5-yl)-3-chlorophenyl)(4- hydroxy-4-methylpiperidin-l-yl)methanone as an off white solid (35 mg). 'H-NMR (400 MHz, DMSO de): δ (ppm): δ 9.07 (d, J= 2.00 Hz, lH), 8.76 (d, J= 2.40 Hz, lH), 8.63 (dd, J= 0.80,
5.20 Hz, 1H), 8.35 (t, J= 2.40 Hz, lH), 7.83 (d, J = 0.80 Hz, 1H), 7.68-7.63 (m, 3H), 7.49 (dd, J = 1.60, 7.60 Hz, lH), 4.45 (s, lH), 4.09-4.12 (m, lH), 3.34-3.37 (br, 3H), 1.60-1.40 (br, 4H), 1.38 (s, 9H), 1.19 (s, 3H). LCMS: 99.16% (m/z = 464.2 [M+ H]). HPLC 98.86%.
Example 22: Synthesis of (4-(2'-(tert-butyl)-[3,4'-bipyridin]-5-yl)-3-chIoroph hydroxy-3-methylpiperidin-l-yi)methanone (Compound 22)
[0S22] This compound was prepared by a reaction similar to that described in Example 21. *H- NMR 400 MHz, DMSO-de: δ 9.07 (d, J= 2.00 Hz, 1H), 8.77 (d, J = 2.00 Hz, lH), 8.63 (d, J = 5.20 Hz, 1H), 8.35 (t, J= 2.40 Hz, lH), 7.83 (s, 1H), 7.67-7.65 (m, 3H), 7.50-7.51 (m, lH), 4.60- 4.61 (m, lH), 4.00-4.03 (m, lH), 3.60-3.63 (m, 1H), 3.15-3.05 (m, 2H), 1.85-1.60 (m, lH), 1.60- 1.45 (m, 3H), 1.38 (s, 9H), 1.19 (s, 3H). LCMS: 99.33% (m/z = 464.52[M+ H]). HPLC: 97.15%.
Example 23: Synthesis of 2-(pyrrolidin-l-yl)ethyl(4-(2'-(tert-butyI)-[3,4'-bipyridin]-5-yl)-3- chlorophenyl)carbamate (Compound 23)
Figure imgf000231_0002
[0523] To a solution of ^(^-(tert-butyO-tS^'-bipyridinl-S-yO-S-chloroaniline (250 mg, 0.74 mmol) and Et3N (150 mg, 1.48 mmol) in DCM (5 mL) at 0 °C was added phenyl chloroformate (116 mg, 0.81 mmol). After stirring at rt for 16 h, the reaction was diluted with water 10 mL and extracted with EtOAc (3x10 mL). The organic extracts were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give crude product, which was purified by flash column chromatography (100-200 mesh) using 20% EtOAc and hexane as eluent to give phenyl (4-(2'-(tert-butyl)-[3,4'-bipyridin]-5-yl)-3-chlorophenyl)carbamate as a gummy solid (180 mg, 44%). To a solution of this compound (24 mg, 0.18 mmol) in THF (5 mL), was added NaH (10 mg, 0.18 mmol), and the mixture was stirred for 10 min. Then, 2- (pyrrolidin-l-yl)ethan-l-ol (70 mg, 0.15 mmol) was added at 0 °C and allowed to come to RT for 4 h. The reaction mass was diluted with water (10 mL) and extracted with EtOAc (3x10 mL). The extracts were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give crude product which was purified by preparative HPLC method to afford 2-(pyrrolidin-l-yl)emyl(4-(2'-(tert-butyl)-[3,4'-bipyridm]-5-yl)-3-cW
as an off white solid (25 mg, 27%). 'H-NMR 400 MHz, DMSO-ck δ 8.89 (d, J= 2.40 Hz, lH), 8.68 (d, J= 2.00 Hz, lH), 8.60 (d, J= 5.20 Hz, lH), 8.23 (t, J= 2.00 Hz, lH), 7.82 (d, J= 2.00 Hz, lH), 7.77 (d, J= 0.80 Hz, 1H), 7.57 (dd, J= 2.00, 5.20 Hz, 1H), 7.51 (dd, J= 2.00, 8.40 Hz, 1H), 7.44 (d, J= 8.40 Hz, 1H), 4.32 (t, J= 5.60 Hz, 2H), 2.85 (t, J= 5.60 Hz, 2H), 2.68 (b s, 4H), 1.83-1.86 (m, 4H), 1.44 (s, 9H). LCMS 97.00% (m/z 479.2 [M+H]). HPLC purity 97.14%.
Figure imgf000232_0001
[0524] To a solution of 4-(2'-(tert-butyl)-[3,4'-bipyridin]-5-yl)-3-chloroaniline (103.4 mg, 0.89 mmol) in DCM (20 mL), phosgene (20% in toluene) was added (0.1 ml, 0.89 mmol), and the mixture stirred for 30 min at RT. Cyclohexane-l,4-diol (103.4 mg, 0.89 mmol) was added to this mixture at 0 °C and the mixture stirred for 16 h at RT. Evaporation of the solvents under reduced pressure gave a crude product, which was purified by preparative HPLC to afford 4- hydroxycyclohexyl (4-(2l-(tert-butyl)-[3,4'-bipyridin]-5-yl)-3-chlorophenyl)carbamate as an off white solid (20 mg, 8%). 'H-NMR 400 MHz, DMSO-d6: δ 9.95 (s, lH), 9.00 (s, lH), 8.70 (s, lH), 8.62 (s, lH), 8.25 (s, lH), 7.80 (s, 2H), 7.63 (d, J = 5.20 Hz, lH), 7.53-7.53 (m, 2H), 4.73- 4.53 (m, 2H), 3.65-3.45 (m, 1H), 2.01-1.90 (m, 1H), 1.83-1.73 (m, 2H), 1.70-1.55 (m, 3H), 1.45- 1.60 (m, 2H), 1.38 (s, 9H); LCMS (98.48 %, m/z = 480.42 [M+ H]). Compound is a mixture of cis, trans isomers. HPLC: 66.14 + 33.07, LCMS: 53.18 + 45.30. Example 25: Synthesis of (3-chloro-4-(5-(6,7-dihydro-5H-cyclopenta[b]pyridin-4- yl)pyridin-3-yl)phenyi)(4-hydroxypiperidin-l-yI)metfaanone (Compound 25)
Figure imgf000233_0001
[0525] To a stirred solution of 4-bromo-6,7-dihydro-5H-cyclopenta[b]pyridine (0.4 g, 2.01 mmol) in dioxane (4.0 mL) was added bis-pinacalatodiborane (0.76 g, 3.02 mmol) and AcOK (0.59 g, 6.03 mmol) at RT under a nitrogen atmosphere. The mixture was purged for 15 minutes with nitrogen, followed by addition of Pd(dppf)2Cl2 (0.015 g, 0.201 mmol), and the reaction mixture again purged for 10 minutes with nitrogen. The reaction tube was sealed and stirred at 100 °C for 12 h. Then the reaction mixture was cooled to 25 °C, water was added (20 mL), and the product was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated to give crude 4-(4,4,5,5-tetramethyl-l,3,2- dioxaborokn-2-yl)-6,7-dihydro-5H-cyclopenta[b]pyridine which was taken for next step without purification.
[0526] To a stirred solution of this material (0.102 g, 0.41 mmol, 1.0 eq) in dioxane:water (1.5 mL), was added (4-(5-bromopyria^n-3-yl)-3-chlorophenyl)(4-hydroxypiperia^n-l-yl)methanone (0.15 g, 0.37 mmol, 1.1 eq) andK2C03 (0.154 g, 1.118 mmol, 3.0 eq), and the mixture was purged for 15 min with nitrogen. Then palladium tetrakis (0.042 g, 0.037 mmol, 0.1 eq) was added and the mixture was again purged for 10 min with nitrogen. The reaction tube was sealed and stirred at 80 °C for 16 h. Then the reaction mixture was diluted with water (10 mL) and extracted with EtOAc (3x10 mL). The organic extracts were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude product, which was purified by preparative HPLC. Fractions containing the product were combined and concentrated under reduced pressure to afford (3-chloro-4-(5-(6,7-dihydro-5H-cyclopenta[b]pyridin-4- yl)pyridin-3-yl)phenyl)(4-hydroxypiperi(im-l-yl)methanone as a white solid. 'H-NMR (400 MHz, DMSO): δ 8.85 (d, J= 6.0 Hz, 1H), 8.74 (d, J = 2.0 Hz, lH), 8.42 (d, J = 5.2Hz, 8.13 (t, J= 2.4 Hz, 1H), 7.65-7.63 (m, 2H), 7.49-7.47 (m, lH), 7.37 (d, J= 5.2 Hz 1H), 4.81 (d, J = 3.6 Hz, lH), 3.99 (s, lH), 3.78 - 3.73 (m, 1H), 3.50 (m, lH), 3.31 - 3.21 (m, 2H), 3.10 (t, J = 7.2 Hz, 4H), 2.99-(t, J = 7.6Hz, 2H), 2.11- 2.04 (m, 2H), 1.81-1.23 (m, 4H). HPLC: 99.03%, LCMS: 96.39 % (m/z = 434.46 [M+H]+).
Figure imgf000234_0001
[0527] Step 1: Methyl 3'-bromo-2-chloro-5'-fluoro-f 1, 1 '-biphenylJ-4-carboxylate. A stirred mixture of l,3-dibromo-5-fluorobenzene (400 mg, 1.575 mmol), (2-chloro-4- (methoxycarbonyl)phenyl)boronic acid (338 mg, 1.575 mmol) and potassium carbonate (544 mg, 3.937 mmol ) in water (1 mL) and 1,4-dioxane (10 mL) in 40 mL glass seal tube was purged with nitrogen gas for 30 minutes. After adding palladium tetrakis (182 mg, 0.157 mmol), the reaction mixture was again purged with nitrogen gas for 30 minutes, the tube was sealed, and the reaction heated to 80 °C for 16h. The reaction mixture was then cooled to RT and filtered through a Celite® bed and washed with ethyl acetate (20 mL). The combined organic layers were concentrated under reduced pressure to afford crude product, which was purified using neutral alumina column chromatography with 0-30% ethyl acetate in petroleum ether as an eluent. Selected fractions were collected and concentrated under reduced pressure to afford methyl S'-bromo^-chloro-S'-fluoro-tl.l'-biphenyll^carboxylate (300 mg) as an off-white solid.
[0528] Step 2: Methyl 3'-(2-(tert-butyl)pyridin-4-yl)-2<Moro-5'-flM
carboxylate. A stirred mixture of the product from Step 1 (300 mg, 0.873 mmol), (2-(tert- butyl)pyridin-4-yl)boronic acid (172 mg, 0.873 mmol), potassium carbonate (302 mg, 2.182 mmol ) in water (2 mL) and 1,4-dioxane (8 mL) in a 40 mL glass seal tube was purged with nitrogen gas for 30 minutes. After adding palladium tetrakis (101 mg, 0.0873 mmol), the reaction mixture was again purged with nitrogen gas for 30 minutes, then the tube was sealed and heated to 80 °C for 16 h. Then the reaction mixture was cooled to RT and filtered through a Celite® bed and washed with ethyl acetate (25 mL). The combined organic layers were concentrated under reduced pressure to afford crude product, which was purified through neutral alumina column chromatography using 0-50% ethyl acetate in petroleum ether as an eluent. Selected fractions were collected and concentrated under reduced pressure to afford methyl 3'-(2-(tert- butylJrjyridin^-ylJ^-chloro-S'-fluoro-tlJ'-biphenyll^-carboxylate (290 mg) as a colorless gummy material.
[0S29] Step 3: 3'-(2-(teH-butyl)pyri^n-4-yl)-2-chloro-5'-fluoro-[lJ'-bip^
acid. To a stirred mixture of the product from Step 2 (330 mg, 0.829 mmol) in
THF:methanol:water (20 mL:10 mL:5 mL) was added L1OH.H2O (105 mg, 2.488 mmol), and the mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure and dissolved in water (10 mL), then acidified with citric acid to pH ~5. The aqueous layer was extracted with ethyl acetate (2x20 mL), and the combined ethyl acetate layers were dried over sodium sulfate and concentrated under reduced pressure to afford 3'-(2- (tert-butyl)r>yridm-4-yl)-2-chloro-5'-fluoro-[l,r-biphenyl]-4-carboxylic acid (310 mg) as an off white solid.
[0530] Step 4: (3'-(2-(tert-butyl)pyri&n-4-yl)-2<:hloro-5'-fluoro-V
hydroxypiperidin-l-yl)methanone. To a stirred mixture of the product from Step 3 (310 mg, 0.807 mmol) in DMF (3 mL) and DIPEA (0.688 mL, 3.230 mmol), was added HATU (1.507 g, 3.230 mmol), and the mixture was stirred for 15min at RT under nitrogen. 4-hydroxypiperidine (100 mg, 0.807 mmol) was then added under nitrogen and the mixture was stirred for 16 h at RT. The reaction mixture was diluted with cold water (50 mL) and the product was extracted into EtOAc (2x25 mL). The combined organic layers were washed with ice cold water (50 mL), dried over sodium sulfate, and concentrated under reduced pressure to afford crude product which was purified through preparative HPLC to afford (3'-(2-(tert-butyl)pyridin-4-yl)-2-chloro-5'-fluoro- [l.l'-biphenyll-^-ylJi^hydroxypiperidin-l-ylJmethanone (26 mg) as an off white solid. 'H-NMR (400 MHz, DMSO-d6): δ 8.59 - 8.58 (m, 1H), 7.78 - 7.72 (m, 3H), 7.62 - 7.58 (m, 3H), 7.46 - 7.42 (m, 2H), 4.79 (bs, 1H), 4.02 - 3.99 (bs, lH), 3.77 - 3.75 (m, 1H), 3.62 - 3.60 (bs, 1H), 3.20 (m, 2H), 1.77 - 1.75 (bs, 2H), 1.38 (m, 2H), 1.37 (s, 9H). LCMS: 99.7 % (m/z = 467.36 [M+H]). HPLC: 98.81%.
Example 27: Synthesis of 5-(2-(tert-butyl)pyridin^yl)-2'-chloro-4'-(4-hydro-^piperidine- l-carbonyl)-[l,l'-biphenyl]-3-carbonitrae (Compound 27)
Figure imgf000236_0001
[0531] This compound was prepared using 3,5-dibromobenzonitrile in a series of reactions similar to that shown in Example 26 to give 5-(2-(tert-buryl)pyridin-4-yl)-2l-chloro-4'-(4- hydroxypiperidme-l-carbonyl)-[l,l'-biphenyl]-3-carboriitrile. XH-NMR (400 MHz, DMSO-d6: δ 8.62 (d, J= 5.20 Hz, lH), 8.42 (t, J= 1.60 Hz, lH), 8.24 (t, J= 1.60 Hz, lH), 8.06 (s, lH), 7.84 (d, J= 0.80 Hz, 1H), 7.63-7.66 (m, 3H), 7.48 (dd, J= 1.60, 8.00 Hz, lH), 4.82 (d, J= 3.60 Hz, 1H), 4.00 (br s, 1H), 3.74-3.76 (m, lH), 3.53 (br s, lH), 3.22 (br s, 2H), 1.78 (br, 2H), 1.39 (br s, 1 lH). LCMS: 99.57% (m/z = 474.1 [M+ H]); HPLC 99.67%.
Example 28: Synthesis of (3,-(2-(tert-butyl)pyridm^yl>2-chloro-5,-(dimethylamino)-[l,l'- biphenyl]-4-yl)(4-hydroxypiperidin-l-yl)memanone (Compound 28)
Figure imgf000236_0002
[0532] This compound was prepared using 3,5-dibromo-N,N-dimethylaniline in a series of reactions similar to that shown in Example 26 to give (3'-(2-(tert-butyl)pyridin-4-yl)-2-chloro-5'- (dimethy lamino)- [ 1 , 1 '-biphenyl] -4-y l)(4-hydroxypiperidin- 1 -yl)methanone. ]H-NMR: (400 MHz, DMSO): δ (ppm): 8.56-8.54 (dd, J=0.4 Hz, j=1.6 Hz, 1H), 7.64 (d, J=0.6 Hz, 1H), 7.56- 7.55 (dd, J=2.0 Hz, j=2.0 Hz, 2H), 7.51- 7.49 (dd, J=1.6 Hz, j=1.6 Hz, lH), 7.42- 7.40 (dd, J=1.6 Hz, j=1.6 Hz, 1H),7.04- 7.02 (m, 2H), 6.82- 6.81 (dd, J=1.2 Hz, j=1.2 Hz, 1H), 4.80 (d, J=4.0 Hz, lH), 3.99 (bs, lH), 3.78- 3.73 (m, 1H), 3.56 (bs, 1H), 3.24- 3.23 (bs, 2H), 3.01 (s, 6H), 1.78- 1.75 (bs, 2H), 1.40 (s, 9H). LCMS: (492.55[M+Hj) 99.30%, HPLC: 98.71%. Example 29: (4-(2'-(tert-butyl)^memyl-[3,4'-bipyridin]-5-yl)-3-chlorophi
hydroxypiperidin-l-yl)methanone (Compound 29)
Figure imgf000237_0001
[0533] This compound was prepared using 3 , 5 -dibromo-4-methylpyr idine in a similar series of reactions to that shown in Example 26 to give (4-(2'-(tert-butyl)-4-methyl-[3,4'-bipyridin]-5-yl)- 3-chlorophenyl)(4-hydroxypiperidin-l-yl)methanone. 'H-NMR (400 MHz, DMSO-d6: δ 8.63 (dd, J= 0.80, 5.20 Hz, lH), 8.50 (s, lH), 8.41 (s, lH), 7.64 (d, J= 1.20 Hz, 1H), 7.46-7.47 (m, 3H), 7.32 (dd, J= 1.60, 4.80 Hz, lH), 4.82 (s, 1H), 4.02 (br, lH), 3.76 (br, lH), 3.54-3.50 (br, 1H), 3.36-3.28 (br, 2H), 2.03 (s, 3H), 1.78 (br, 2H), 1.39 (br s, 1 lH); LCMS 98% (m/z = 464.54 [M+ H]); HPLC 99.04%.
Example 30: Synthesis of additional compounds
[0534] The compounds listed in Table 1 are prepared. Some of these compounds are prepared using the synthetic routes and procedures described above.
Table 1. Additional compounds.
Figure imgf000237_0002
236
Figure imgf000238_0001
Figure imgf000239_0001
Figure imgf000240_0001
Figure imgf000241_0001
Example 31: Reporter Screening Assay
[0S3S] This assay was used to evaluate the effect on transcriptional activity SREBP of the compounds synthesized according to Examples 1-16, 20, and 22, using an SRE-luciferase reporter construct. On day 1 , 10,000 cells were seeded in a 96 well (white) plate as per the plate map in Growth media without antibiotics. Cells were incubated at 37°C for 8 hours. After 8 hours, cells were washed with DPBS for complete removal of FBS. DPBS was completely removed and Growth media was replaced with phenol free treatment medium (90 μΐ) with different FBS concentrations. The cells were then incubated at 37°C for 24 hours with varying doses (0.01 uM to 10 uM) of compounds. Then a Luciferase assay was performed.
[0536] Reagents for performing Luciferase assay were stored at -20°C. To a tube of lyophilized assay substrate was added 1 mL Substrate Solvent and mixed well. The Substrate tube after reconstitution was covered with aluminum foil so as to keep it protected from light. The assay buffer was thawed to room temperature. To 20 mL Assay Buffer was added 200 uL of reconstituted lOOx Substrate and mixed well. The reconstituted substrate as well as the assay solution (buffer + substrate) was protected from light throughout the procedure by keeping it covered with aluminum foil.
[0537] Using a multi-channel pipette, 100 μL Assay Solution (buffer + substrate) was added directly to each sample well in Plate 1, which was incubated for 30 min (plate was covered with aluminum foil). After 30 min incubation, the plate was read for total luminescence. Each well was read for 2 seconds in a plate luminometer. (Microplate reader Envision Microplate reader from Perkin Elmer). Precaution was taken to incubate plate exactly for 30 min prior to reading on the plate reader.
[0538] Materials: SREBPvl Reporter cell line: HepG2 - #32251. Growth Medium: MEM (Coming 10-010), 10% FBS, 1% GlutaMax (Invitrogen Catalog # 35050061), μg ml Puromycin (Invitrogen Catalog # Al 113803) and 1% Penicillin-Streptomycin (Pen-Strep). Treatment Media: Phenol-free MEM (Invitrogen Catalog # 51200-038) and 1% GlutaMax (Invitrogen Catalog # 35050061). Luciferase Assay: LightSwitch Luciferase Assay Kit (Catalog # 32032). LDH assay: Pierce LDH Cytotoxicity Assay Kit (Catalog* SD249616).
[0539] The transcriptional activity results for the compounds of Examples 1-16, 20, and 22 are shown in Table 2 below.
Table 2. Results of Reporter Screening
Figure imgf000242_0001
Figure imgf000243_0001
Example 32: In vivo Activity Assay
[0540] The in vivo effect of compounds described herein, for example the compounds of Examples 1-30, or 33-52, or pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, may be assessed using the ob/ob mouse model. The ob/ob mouse is a well characterized model of obesity, fatty liver, and diabetes, which are exhibited due to a mutation in the ob gene, which encodes for leptin.
[0541] Compounds produced according to Examples 1-30 as described above, are administered by the oral route once or twice daily for 4 weeks in male ob/ob mice. Body weight and food and water intake are assessed daily, and improvements in glucose control are assessed by plasma glucose and insulin measurement Upon completion of the test period, terminal blood samples are taken and analyzed for triglyceride, cholesterol (total, HDL-C and LDL-C), blood urea nitrogen (BUN), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) levels. Liver and fat pad weights are determined and liver tissue is processed for histological determination of NASH activity scores (NAS: ballooning, inflammation, steatosis and fibrosis). Liver levels of triglycerides, cholesterol, and non-esterified fatty acids (NEFA) are also determined. Example 33: 4-(2,-(tert-butyl)-13,4'-bipyridinj-5-yl)-N-isopropyl-3- methylbenzenesulfonamide (Compound Z-814)
Figure imgf000244_0001
[0542] Step 1 - 2'-(tert-butyI)-5-(4J,5,5-tetrcmetiyI-l,3J^iomborolan-2^
To a stirred solution of S-bromo-^-ftert-butylJ-S^'-bipyridine (250.0 mg, 0.862 mmol), Bispin (328.4 mg, 1.29 mmol), and KOAc (254 mg 2.58 mmol) in dioxane (10.0 V) was added
Pd(dppf)Cl2 (63.07 mg, 0.0862 mmol) at 25 °C, and the reaction mass degassed for 15 mins, then stirred for 16 h at 80 °C. On completion of reaction (monitored by TLC), the reaction mass was concentrated under reduced pressure, the obtained residue was dissolved in ethyl acetate (50 mL), washed with water (20 mL), brine, dried over sodium sulfate, filtered and concentrated. The crude compound was purified by Florisil® column chromatography eluting with 0-30% ethyl acetate in petroleum ether to afford 2'-(tert-butyl)-5-(4,4,5,5-tetramethyl- 1,3,2- dioxaborolan-2-yl)-3,4'-bipyridine as a light brown gummy solid (430 mg).
[0543] Step 2 - 4-bromo-N-isopropyl-3-methylbenzenesulfonamide: To a stirred solution of 2- aminopropane (48.54 mg, 0.8212 mmol) in DCM (10.0 mL) was added EtoN (83.428 mg, 0.82115 mmol) at 0°C under nitrogen atmosphere. The reaction mass was stirred at 0°C for 20 min, followed by addition of 4-bromo-3-methylbenzenesulfonyl chloride (200.0 mg, 0.7425 mmol) dissolved in DCM at 0°C. The reaction mass was stirred for 16 h at 25°C. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to 25°C, water added (25 mL), and the product was extracted into dichloromethane. The organic layer was washed with brine and the organic layer dried over sodium sulfate, filtered and concentrated to give 4-bromo-N-isopropyl-3-methylbenzenesulfonamide as a light yellow solid (0.200 g) which was used in the next step without purification. [0544] Step 3 4-(2'-(teH-butyl)-[3,4'-bipyridin]-5-yl)-N-isopropyl-3- methylbenzenesulfonamide: To a stirred solution of the product from Step 2 (120.0 mg, 0.4123 mmol) in dioxane:EbO (10.0 V) was added the product of Step 1 (167.0 mg 0.4948 mmol) and K2CO3 (171.06 mg, 1.236 mmol) at room temperature under nitrogen atmosphere. The reaction mass was degassed for IS minutes with nitrogen gas followed by the addition of Pd(PPh3)4 (23.81 mg, 0.0206 mmol), and the mixture again degassed for IS minutes with nitrogen, then sealed in a glass tube and stirred at 80°C for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to 25°C, water added (25 mL), and the product extracted into ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated. The crude compound was purified with reverse phase chromatography with ammonium acetate in water and methanol as mobile phase (5% MeOH in DCM) to give 4- (2'-(tert-butyl)-[3,4'-bipyridin]-5-yl)-N-isopropyl-3-memylbenzenesulfonamide as an off white solid (75.0 mg). ¾ NMR (400 MHz, DMSO): δ 9.06 (d, J = 2.40 Hz, lH), 8.70 (d, J = 2.00 Hz, 1H), 8.62 (dd, J = 0.40, 5.20 Hz, 1H), 8.30 (t, J = 2.00 Hz, 1H), 7.82 (dd, J = 1.60, 8.00 Hz, 2H), 7.67-7.67 (m, 1H), 7.65 (t, J = 1.60 Hz, 2H), 7.58 (d, J = 8.00 Hz, lH), 3.28-3.28 (m, lH), 2.37 (s, 3H), 1.38 (s, 9H), 1.02 (d, J = 6.40 Hz, 6H). LCMS: 99.12 % (m/z = 424.21[M+1].
Example 34: l-((4-(2'-(tert-butyl)- [3,4'-bipvridin]-5-yl)-3-methylphenyl)sulfonyl)piperidin- 4-0I ( Compound Z-813)
Figure imgf000245_0001
N
[0S4S] l-((^(2'-(tert-butyl)-[3,4'-bir>yridm]-5-yl)-3-memylphenyl)sdfonyl)piperidin-4- was prepared from 2'-(tert-butyl)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,4'-bipyri(iine, 4- bromo-3-methylbenzenesulfonyl chloride and 4-hydroxypiperidine using a similar series of reactions as described in Example 33 to give a white solid. 1H NMR (400 MHz, DMSO) δ 907 (d, J = 2.40 Hz, 1H), 8.71 (d, J = 2.00 Hz, 1H), 8.62 (dd, J = 0.40, 5.20 Hz, 1H), 8.33 (t, J = 2.00 Hz, 1H), 7.83 (d, J = 0.80 Hz, 1H), 7.75 (s, 1H), 7.62-7.64 (m, 3H), 4.71 (d, J = 3.60 Hz, lH), 3.59-3.60 (m, 1H), 3.14-3.16 (m, 2H), 2.84-2.84 (m, 2H), 2.40 (s, 3H), 1.76-1.77 (m, 2H), 1.50- 1.51 (m, 2H), 1.48 (s, 9H); LCMS: 99.24 % (m/z = 466.40[M+1]).
Figure imgf000246_0001
[0546] N-((4-(2'-(tert-butyl)-[3,4'-bipyridin]-5-yl)-3-methylphenyl)sulfonyl)ace^ was prepared using a similar series of reactions as described in Example 33 to give an off white solid (75 mg). 1H NMR (400 MHz, DMSO): δ 9.07 (d, J = 2.40 Hz, 1H), 8.70 (d, J = 2.00 Hz, 1 H), 8.62 (d, J = 4.80 Hz, 1H), 8.30 (t, J = 2.00 Hz, lH), 7.85 (d, J = 16.40 Hz, 1H), 7.82 (s, 2H), 7.66 (dd, J = 2.00, 5.20 Hz, 1H), 7.59 (d, J = 8.00 Hz, 1H), 2.37 (s, 3H), 1.93 (s, 3H), 1.38 (s, 9H); LCMS: 99.12 % (m/z = 424.21 [M+l]).
Example 36: 4-(2'-(tert-butyl)-[3,4,-bipyridin]-5-yl)-N-(isopropylcarbi
methylbenzenesulfonamide (Compound Z-832)
Figure imgf000246_0002
[054η ^(^-(tert-burylJ-tS^'-bipyridinl-S-ylJ-N-iisopropylcarbamoyl)^- methylbenzenesulfonamide was prepared using a similar series of reactions as described in
245 Example 33, to produce an off white solid (14 mg). 1H NMR (400 MHz, DMSO δ 9.04 (d, J = 2.40 Hz, lH), 8.68 (d, J = 2.00 Hz, 1H), 8.61 (d, J = 5.20 Hz, 1H), 8.27 (t, J = 2.00 Hz, 1H), 7.82 (d, J = 0.40 Hz, 1H), 7.75 (t, J = 8.00 Hz, 2H), 7.66 (dd, J = 1.60, 4.80 Hz, 1H), 7.45 (d, J = 7.60 Hz, 1H), 5.97 (s, lH), 3.55-3.57 (m, lH), 2.33 (s, 3H), 1.38 (s, 9H), 0.99 (d, J = 6.80 Hz, 6H); LCMS: 99.12 % (m/z = 467.1 [M+l].
Example 37: 4-(2'-(tert-butyl)-[3,4'-bipyridin]-5-yl)-3-methylbenzenesulfonamide
(Compound Z-830)
Figure imgf000247_0001
[0548] ^(^-(tert-bulyO-IS^'-bipyridml-S-ylJ-S-methylberizenesulforiam was prepared using a similar series of reactions as described in Example 33, to produce an off white solid (34 mg). 1H NMR (400 MHz, DMSO-d6): δ 9.06 (d, J = 2.00 Hz, 1H), 8.69 (d, J = 2.00 Hz, 1H), 8.63 (d, J = 0.40 Hz, lH), 8.28 (t, J = 2.00 Hz, lH), 7.82-7.82 (m, 2H), 7.77 (dd, J = 1.60, Hz, 1H), 7.66 (dd, J = 2.00, Hz, lH), 7.56 (d, J = 8.00 Hz, lH), 7.41 (s, 2H), 2.36 (s, 3H), 1.38 (s, 9H); LCMS: 97.68 % (m/z = 381.49[M+1]).
Example 38: (3-chloiO^(2'-(4,4-difluorocydohez-l-en-l-yl)-[3,4'-bipyridin]-S- yl)phenyl)(4-hydrozypiperidin-l-yl)metfaanone (Compound Z-824)
Figure imgf000248_0001
[0549] 4-chloro-2-(4,4-diflnorocyclohex-l-en-l-yl)pyridine - A solution of 2-bromo -4- chlopyridine (0.300 g), 2-(4,4-difluorocyclohex-l-en-l-yl)^,4,5,5-tetramethyl-l,3,2- dioxaborolane (0.418 g) and cesium carbonate (1.S2 g) in dioxane (20 mL) was charged in a 20 mL glass seal tube and purged with nitrogen gas for 10 minutes. After adding Pd(dppf)Ch (0.108 g) it was again purged with nitrogen gas for 10 minutes. The reaction mass was heated to 80°C for 16 h and then cooled to RT and evaporated to dryness under reduced pressure. S ml water was added to the residue and the product was extracted into EtOAc (3x1 S mL). The extracts were combined, washed with brine (3x10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to get crude product which was purified by column chromatography to give 4-chloro-2-(4,4-difluorocyclohex-l-en-l-yl)pyridine (0.350 g, 97.76%) as a colorless liquid. ¾ NMR 400 MHz, CDCU400 MHz, DMSO-d6: δ 8.45 (d, J = 0.40 Hz, 1H), 7.35 (d, J = 52.00 Hz, 1H), 7.17 (d, J = 2.00 Hz, 1H), 6.53 (d, J = 1.20 Hz, lH), 2.80-2.65 (m, 4H), 2.23-2.10 (m, 2H); LCMS: 97.88% (m/z = 229.9 [M+ H]).
[0550] Step 1: methyl 4-(5-hromopyridin-3-yl)-3-chlorohenzoate - 3,5-dibromopyridine (6.0 g), (2-chloro-4-(methoxycarbonyl)phenyl)boronic acid (4.87 g) and potassium carbonate (10.5 g) in dioxane-ibO (60: 12 mL) were charged in 100 mL glass seal tube and purged with nitrogen gas for 10 minutes. After adding palladium tetrakis (2.98 g) it was again purged with nitrogen gas for 10 minutes. The reaction mass was heated to 80°C for 16h, cooled to RT and 50 mL water was added and extracted with EtOAc (3x25 mL). The combined extracts were washed with brine (3x10 mL) and dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure to give methyl 4-(5-bromopyridin-3-yl)-3-chlorobenzoate (4.2 g, 50.90%) as a white solid.
[0SS1] Step 2: 4-(5-bromopyridin-3-yl)-3-chlorobenzoic acid - To a solution of methyl 4-(5- bromopyridin-3-yl)-3-chlorobenzoate (4.2 g) in THF: Water (42:4.2 mL) was added LiOELEbO (1.6 g) and the reaction mass was stirred at RT for 3 h. The reaction mass was then evaporated, diluted with water, acidified with dil. HC1 to (pH 4) and the product extracted into DCM (3 x 25mL). Organic layer was washed with brine solution (2 x 15 mL) dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford 4-(5-bromopyridin-3-yl)-3- chlorobenzoic acid, 3.8 g (94.52%) as an off white solid.
[0S52] Step 3: (4-(5-bromopyridin-3-yl)-3-chlorophenyl)(4-hydroxypiperidin-l-yl)m - To a solution of 4-(5-bromopyridin-3-yl)-3-chlorobenzoic acid (3.8 g) in THF (76 mL), was added DIPEA (0.651 mL) and HATU (6.0 g). The reaction was stirred for 30 minutes, then added 4-hydroxy piperidine (1.6 g) and stirred for 16 h at RT. The reaction mass was diluted with ethyl acetate and washed with cold water (4 x 5 mL). The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude product which was purified by column chromatography to afford (4-(5-bromopyridin-3-yl)-3- chlorophenyl)(4-hydroxypiperidin-l-yl)methanone (3.8 g, 79.33 % yield) as an off white solid. ¾ NMR 400 MHz, DMSO-d6: δ 8.78 (s, lH), 8.67 (d, J = 2.00 Hz, 1H), 8.23 (d, J = 2.00 Hz, lH), 7.61 (d, J = 8.00 Hz, lH), 7.47-7.48 (m, 2H), 7.45 (d, J = 1.20 Hz, lH), 4.81 (d, J = 4.0 Hz, 1H), 4.05-3.95 (br s, 1H), 3.78-3.73 (m, lH), 3.60-3.50 (m, lH), 3.17 (d, J = 5.2 Hz, 2H), 1.76 (d, J = 26.00 Hz, 2H), 1.34-1.37 (m, 2H); LCMS: 98.86% (m/z 395.0 [M+H]).
[0553] Step 4: (3-chloro-4-(5-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl)pyridin-3- yl)phenyl)(4-hydroxypiperidin-l-yl)methanone - A solution of (4-(5-bromopyridin-3-yl)-3- chlorophenyl)(4-hydroxypiperidin-l-yl)methanone (1.0 g), bispin (1.28 g) and potassium acetate (0.62 g) in dioxane (20 mL) were charged in a 50 mL glass seal tube and purged with nitrogen gas for 10 minutes. After adding Pd(dppf)Cl2 (0.018 g, 0.025 mmol) it was again purged with nitrogen gas for 10 minutes and the reaction mass was heated to 80°C for 16 h. After completion (monitored by TLC), the reaction mixture was cooled to RT and evaporated under reduced pressure. 25 ml water was added to the residue and the product was extracted into EtOAc (3x25 mL). The combined extracts were washed with brine (3x10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give crude product which was purified by passing through a Florisil® column to (3-chloro-4-(5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)r>yridm-3-yl)phenyl)(4-hydroxypiperidin-l-yl)methanone (1.80 g, crude) as a black-brown semi-solid.
[0554] Step 5: (3-chloro-4-(2 '-(4, 4-difluorocyclohex-l-en-l-yl)-[3, 4'-bipyridin]-5- yl)phenyl)(4-hydroxypiperidin-l-yl)methanone - A solution of 4-chloro-2-(4,4-difluorocyclohex- l-en-l-yl)pyridine (0.250 g), (3-cWoro-4-(5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)pyridin-3-yl)phenyl)(^hydroxypiperidm-l-yl)methanone (0.589 g) and potassium carbonate (0.3 g, 2.18 mmol) in dioxane- water (7.5:1 mL) were charged in a 20 mL glass seal tube and purged with nitrogen gas for 10 minutes. After adding palladium tetrakis (0.126 g) it was again purged with nitrogen gas for 10 minutes and the reaction mass was heated to 80°C for 16 h. The reaction mixture was cooled to RT and evaporated under reduced pressure. 5ml of water was added to the residue and the product was extracted into EtOAc (3x15 mL). The combined extracts were washed with brine (3x10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude product which was purified by column chromatography to give (3-chloro-4-(2l-(4,4-difluorocyclohex-l-en-l-yl)-[3,4'-bipyridin]-5- yl)phenyl)(4-hydroxypiperidin-l-yl)methanone (0.190 g, 53.82%) as a white solid. ¾ NMR 400 MHz, DMSO-d6: δ 9.13 (d, J = 2.40 Hz, lH), 8.80 (d, J = 2.00 Hz, 1H), 8.78 (d, J = 2.00 Hz, 1H), 8.66 (d, J = 5.20 Hz, 1H), 8.43 (t, J = 2.40 Hz, lH), 8.03 (s, lH), 7.77 (dd, J = 1.60, 5.00 Hz, lH), 7.57-7.55 (m, 1H), 7.50 (dd, J = 1.60, 8.00 Hz, 1H), 6.77 (s, lH), 4.81 (d, J = 4.0 Hz, 1H), 4.00 (br s, lH), 3.79-3.75 (m, 1H), 3.60-3.50 (br s, 1H), 3.27 -3.10 (br s, 2H), 2.90-2.78 (m, 4H), 2.28-2.10 (m, 2H), 1.85-1.60 (m, 2H), 1.45-1.30 (br s, 2H); LCMS: 99.03% (m/z = 510.0 [M+ H]); HPLC: purity 98.33%. Example 39: (3-chloro-4-(2,-(4,4-difluorocydohezyl)-[3^,-bipyridinJ-5-yl)phi hydroxy piperidin-l-yl)methanone (Compound Z-834)
Figure imgf000251_0001
[0555] To a stirred solution of (3-chloro-4-(2'-(4,4-difluorocyclohex-l-en-l-yl)-[3,4'- birjyridin]-5-yl)phenyl)(^hydroxypiperio¾-l-yl)methanone (0.150 g) in EtOAc (6 mL), was added PtCh (0.030 g). The reaction was stirred under H2 balloon pressure at RT for 16h. After completion (LCMS), the reaction mixture was filtered through a Celite® pad and the pad was washed with methanol. The filtrate and washings were combined, concentrated under reduced pressure to give (3-cWoro-4-(2'-(4,^difluorocyclohexyl)-[3,4'-bipyridin]-5-yl)phenyl)(4- hydroxypiperidin-1 -yl)methanone (0.072 g, 48.0%) as a white solid. ¾ NMR 400 MHz, DMSO- d6: δ 9.08 (d, J = 2.00 Hz, 1H), 8.77 (d, J = 2.00 Hz, lH), 8.62 (d, J = 5.20 Hz, 1H), 8.37 (t, J = 2.40 Hz, 1H), 7.79 (s, lH), 7.71 (dd, J = 1.60, 5.20 Hz, 1H), 7.66 (dd, J = 1.60, 6.20 Hz, 1H), 7.49 (dd, J = 1.60, 7.60 Hz, 1H), 4.81 (d, J = 3.6 Hz, lH), 4.05-3.95 (br s, lH), 3.80-3.70 (m, 1H), 3.55-3.45 (m, 1H), 3.28-3.15 (m, 2H), 2.94 (t, J = 2.80 Hz, 1H), 2.20-1.70 (br m, lOH), 1.50-1.30 (m, 2H); LCMS: 99.01% (m/z = 512.5 [M+ H]), HPLC: purity 98.01%.
Example 40: Compounds Z-803, Z-811, Z-812
Figure imgf000251_0002
[0556] To a stirred solution of ^(^-(tert-butylJ-tS^'-bipyridinl-S-ylJ-S-chloroaniline (0.200 g, 0.593 mmol, 1.0 eq) in pyridine (2 mL) was added methanesulfonyl chloride (0.200 mL) at 0°C. The reaction mixture was stirred at RT for 16h. The pyridine was then evaporated under reduced pressure, and the residue purified by Prep. HPLC to give N-(4-(2,-(tert-butyl)-[3,4,-bipyridin]-5- yl)-3-chlorophenyl)methanesulfonamide. 1H NMR (400 MHz, DMSO: δ (ppm): 10.20 (s, lH), 9.02 (d, J= 2.0Hz, 1H), 8.71 (d, J= 2.0Hz, lH), 8.63- 8.61 (dd, J= 0.8Hz, J= 0.4Hz, lH), 8.27- 8.26 (t, J= 2.0Hz, 1H), 7.80 (d, J= 0.8Hz, 1H), 7.64- 7.62 (dd, J= 1.6Hz, J= 1.6Hz, 1H), 7.59- 7.54 (dd, J= 8.4Hz, J= 7.2Hz, lH), 7.42 (d, J= 2.4Hz, lH), 7.32- 7.30 (dd, J= 2.4Hz, J= 2.4Hz, lH), 3.11 (s, 3H), 1.37 (s, 9H); LCMS: 96.65% (416.1[M+H]).
[055η N-(4-(2,-(tert-butyl)-[3,4'-bipyridin]-5-yl)-3-chlorophenyl)-l,l,l- trifluoromethanesulfonamide was prepared in a similar fashion using triflic anhydride. 1H NMR (400 MHz, DMSO: δ (ppm): 10.20 (s, lH), 9.02 (d, J= 2.0Hz, lH), 8.71 (d, J= 2.0Hz, lH), 8.63-
8.61 (dd, J= 0.8Hz, J= 0.4Hz, lH), 8.27- 8.26 (t, J= 2.0Hz, lH), 7.80 (d, J= 0.8Hz, 1H), 7.64-
7.62 (dd, J= 1.6Hz, J= 1.6Hz, lH), 7.59- 7.54 (dd, J= 8.4Hz, J= 7.2Hz, lH), 7.42 (d, J= 2.4Hz, lH), 7.32- 7.30 (dd, J= 2.4Hz, J= 2.4Hz, lH), 3.11 (s, 3H), 1.37 (s, 9H); LCMS: 96.65% (416.1[M+H].
[0558] N-(4-(2'-(tert-butyl)-[3,4'-bipyridin]-5-yl)-3-chlorophenyl)-isopropylsulfamoyl urea was prepared in a similar fashion using isopropylsulfamoyl chloride. 1H NMR (400 MHz, DMSO: δ (ppm): 10.08 (s, lH), 9.00 (d, J= 2.4Hz, 1H), 8.70 (d, J= 2.0Hz, lH), 8.62- 8.61 (dd, J= 0.8Hz, J= 0.8Hz, 1H), 8.25- 8.24 (t, J= 2.0Hz, 1H), 7.80 (d, J= 0.4Hz, lH), 7.72 (d, J= 7.6Hz, lH), 7.64- 7.62 (dd, J= 1.6Hz, J= 1.6Hz, lH), 7.52 (d, J= 8.4Hz, lH), 7.38 (d, J= 2.4Hz, 1H), 7.23- 7.20 (dd, J= 2.4Hz, J= 2.4Hz, lH), 3.39- 3.36 (m, 1H), 1.37 (s, 9H), 1.05 (d, J= 6.4Hz, 6H); LCMS: 98.66% (459.63[M+H]).
Example 41: Compounds Z-804 and Z-823
Figure imgf000252_0001
[0559] Step 1: 4-(2'-(tert-butyl)-[3,4'-bipyridin]-5-yl)-3-chloroben - To a solution of 4-
(^-(tert-butyO-ta^'-bipyridinl-S-ylJ-S-chlorobenzoic acid (0.200 g, 0.546 mmol) in THF was added DIPEA (0.211 g, 1.638 mmol) and HATU (0.415 g, 1.092 mmol) and the reaction mass was stirred for 20 min. NH*C1 (0.058 g, 1.092 mmol) was added and stirred at RT for 16 h. The reaction mass was then evaporated under reduced pressure, diluted with water and extracted into DCM (3x25 mL). The organic layer was washed with saturated NaHCCh solution (2x15 mL), brine solution (2x15 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude product which was purified by column chromatography to give 4-(2- (tert-butyl)-[3,4'-bipyridin]-5-yl)-3-chlorobenzamide (0.190 g, 95.2%) as an off white solid. ¾ NMR (400 MHz, DMSO de): δ 9.07 (d, J = 2.00 Hz, lH), 8.77 (d, J = 2.00 Hz, lH), 8.63 (d, J = 0.40 Hz, lH), 8.35 (t, J = 2.40 Hz, 1H), 8.20 (s, lH), 8.12 (d, J = 2.00 Hz, 1H), 7.98 (dd, J = 1.60, 8.00 Hz, 1H), 3.47-3.73(m, 8H)7.72 (d, J = 8.00 Hz, lH), 7.66 (dd, J = 2.00, 5.00 Hz, lH), 7.62 (s, 1H), 1.38 (s, 9H); LCMS 99.87% (m/z 366.1 [M+H]).
[0560] Step 2: To a stirred solution of 4-(2'-(tert-butyl)-[3,4l-bipyridin]-5-yl)-3- chlorobenzamide (0.100 g, 0.274 mmol) in THF (3 mL) was added NaH (0.013 g, 0.548 mmol) at 0°C and the reaction mass was stirred at same temperature for lh. Then isopropylsulfonyl chloride (0.057 g, 0.411 mmol) was added and stirred for 16h at RT. The reaction was then quenched with MeOH (5mL) with ice cooling and the solvent was evaporated under reduced pressure. The residue was diluted with water and the product was extracted into DCM (3x25mL). The organic layer was washed with brine solution (2x15 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude product which was purified by prep. HPLC to give 4-(2'-(tert-butyl)-[3,4l-bipyridin]-5-yl)-3-chloro-N- (cyclopropylsulfonyl)benzamide (0.022 g 17.0%) as an off white solid. ¾ NMR (400 MHz, DMSO de): δ 12.38 (s, lH), 9.09 (d, J = 2.00 Hz, 1H), 8.78 (d, J = 2.00 Hz, 1H), 8.64 (d, J = 5.20 Hz, lH), 8.36 (t, J = 2.00 Hz, 1H), 8.21 (d, J = 1.60 Hz, 1H), 8.04 (dd, J = 2.00, 8.00 Hz, 1H), 7.79 (d, J = 8.00 Hz, lH), 7.67 (dd, J = 1.60, 5.20 Hz, 1H), 3.13-3.14 (m, 1H), 1.38 (s, 9H), 1.12- 1.13 (m, 4H); LCMS: 99.1% (m/z 470.0 [M+H]). Example 42: (4-(2*-(tert-butyl)-4-nuoro-[3,4'-bipyridinj-5-yl)-3-chIorophenyl)(4- hydroxypiperidin-l-yl)methanone (Compound Z-855)
Figure imgf000254_0001
[0561] (4-(2'-(tert-butyl)-^fluoro-[3,4'-bipyridin]^^
l-yl)methanone was prepared following the general procedures described in Example 4, to produce the product as an off white solid. ¾ NMR (400 MHz, DMSO-d6: δ 8.93 (d, J = 9.60 Hz, 1H), 8.66-8.66 (m, 2H), 7.68-7.66 (m, 3H), 7.52-7.50 (m, 2H), 4.82 (d, J = 4.00 Hz, lH), 3.99-4.01 (m, lH), 3.74-3.75 (m, lH), 3.51 (br s, 1H), 3.21-3.19 (m, 2H), 1.75-1.80 (m, 2H), 1.37 (br s, 11H); LCMS: 98% (m/z = 468.54 [M+ H]).
Example 43: (4-(2'-(tert-butyl)-4-fluoro-[3,4,-bipyridin]-5-yl)phenyl)(4-hydroxypiperidin-l- yl)methanone (Compound Z-866)
Figure imgf000254_0002
[0562] (4-(2'-(tert-buryl)-4-fluoro-[3,4,-bipyriaUn]-5-yl)phenyl)(4-hydroxypiper^
yl)methanone was prepared following the general procedures described in Example 4, to produce the product as an off white solid. ¾ NMR (400 MHz, DMSO-d6: δ 8.81-8.82 (m, 2H), 8.64-8.66 (m, 1H), 7.73-7.75 (m, 3H), 7.51-7.53 (m, 3H), 4.81 (d, J = 4.00 Hz, 1H), 4.02-4.05 (m, 1H), 3.73-3.74 (m, 1H), 3.60-3.50 (m, 1H), 3.19-3.22 (m, 2H), 1.74-1.77 (m, 2H), 1.37 (br s, 11H); LCMS: (m/z = 434.1 [M+ H]. Mp 100-104°C
Example 44: (4-(2'-(tert-butyl)-4-methoxy-[3,4'-bipyridin]-5-yl)-3-chlorophi hydroxypiperidin-l-yl)methanone (Compound Z-840)
Figure imgf000255_0001
[0563] Step 1: methyl 4-(2'-(tert-butyl)-4-fluoro-[3, 4'-bipyridin]-5-yl)-3-chlorobenzoate - 2'- (tert-butyl)-5-chloro-4-fluoro-3,4'-bipyridine (190 mg, 0.719 mmol) was dissolved in 1, 4- dioxane (9 mL) and water (1 mL) and (2-chloro-4-(methoxycarbonyl)phenyl)boronic acid (231 mg, 1.079 mmol) and CsF (327 mg, 2.15 mmol) were added under a nitrogen atmosphere. The reaction mass was purged for 15 minutes with nitrogen, Pd(amphos)Ch (50 mg, 0.071 mmol) was added and the reaction mixture was again purged for 10 minutes with nitrogen. The reaction tube was sealed and stirred at 80°C for 16 h. After completion of the reaction, the solvent was evaporated and the residue was diluted with water (10 mL) and extracted into EtOAc (3x20 mL). The combined extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain crude methyl ^(^-(tert-butylJ^fluoro-fS^'-bipyridi^-S-ylJ-S- chlorobenzoate. ¾ NMR (400 MHz, DMSO-de): δ 8.96 (d, J = 9.60 Hz, 1H), 8.64-8.64 (m, 2H), 8.14 (d, J = 1.60 Hz, 1H), 8.05-8.06 (m, 1H), 7.80 (d, J = 8.00 Hz, 1H), 7.64-7.70 (m, 1H), 7.45- 7.46 (m, lH), 3.92 (s, 3H), 1.36 (s, 9H); LCMS: (m/z = 399 [M+ H]).
[0564] Step 2: 4-(2'-(leH-butyl)-4-meihoxy-[3,4'-bipyridinJ-5-yl)-3^Morobenz acid - To a solution of methyl 4-(2'-(tert-butyl)-4-fluoro-[3,4'-bipyri(im]-5-yl)-3-cWorobenzoate (200 mg, 2.57 mmol) in THF: MeOH: H20(6 mL), was added LiOH.H20 (200 mg, 4.87 mmol) and the reaction mixture was stirred at RT for 2 h. After completion of the reaction (monitored by TLC), the solvent was evaporated and the residue was acidified with IN hydrochloric acid to pH = 4, then the product extracted into EtOAc (20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford 4-(2'-(tert-butyl)-4-methoxy- [3,4'-bir>yri(iin]-5-yl)-3-crilorobenzoic acid as white solid. ¾ NMR (400 MHz, DMSO-de): δ 13.44 (br s, 1H), 8.62-8.63 (m, 2H), 8.45 (s, 1H), 8.09 (d, J = 1.60 Hz, 1H), 7.99-8.00 (m, 1H), 7.67 (d, J = 8.00 Hz, lH), 7.62 (s, 1H), 7.42-7.44 (m, 1H), 2.50 (s, 3H), 1.37 (s, 9H); LCMS 89.5% (m/z = 395 [M- H]).
[0565] Step 3: (4-(2'-(ten-butyl)-4-methoxy-[3A'-bipyri&n]-5-y^
hydroxypiperidin-l-yl)methanone - To a solution of 4-(2'-(tert-butyl)-4-methoxy-[3,4'-bipyridin]- 5-yl)-3-chlorobenzoic acid (120 mg, 0.3125 mmol) in THF (6 mL, 20 v), was added DIPEA (160 mL, 1.242 mmol) and HATU (356 mg, 0.936 mmol). The reaction was stirred for 30 minutes, then 4-hydroxy piperidine (63 mg, 0.623 mmol) was added and the reaction mixture was stirred for 16 h at RT. After completion (monitored by TLC), the reaction mass was diluted with ethyl acetate and washed with cold water (4x5 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product obtained was purified by Prep. HPLC to afford (4-(2,-(tert-butyl)-4-methoxy-[3,4l-bipyridin]-5-yl)-3- chlorophenyl)(4-hydroxypiperidin-l-yl)methanone as off white solid (18 mg). ¾ NMR (400 MHz, DMSO-d6): δ 8.62-8.63 (m, 2H), 8.45 (s, 1H), 7.64 (d, J = 1.20 Hz, 1H), 7.58-7.64 (m, 3H), 7.47 (dd, J = 1.60, 7.60 Hz, lH), 7.43 (dd, J = 1.60, 5.20 Hz, lH), 4.81 (d, J = 4.00 Hz, lH), 4.00 (br s, 1H), 3.74-3.75 (m, lH), 3.60 (br s, lH), 3.32 (br s, 3H), 3.21-3.15 (m, 2H), 1.85-1.65 (m, 2H), 1.37 (br s, 11H); LCMS: (m/z = 480 [M+ H]). Mp 105-109°C
Example 45: (3-chloro-4-(2'-(l-hydroxy-2-methylpropan-2-yl)-[3,4'-bipyridin]-5- yl)phenyl)(4-hydroxvpiperidin-l-yl)methanone (Compound Z-856)
Figure imgf000256_0001
[0566] Step 1: ethyl 2-(4-bromopyridin-2-yl)acetate - To a stirred solution of 4-bromo-2- methylpyridine (1.2 g, 4.93 mmol, 1.0 eq) in THF (15 mL), was added diethyl carbonate (0.698 mL, 5.92 mmol, 1.2 eq) and the mixture stirred at -78°C under nitrogen atmosphere. LDA(2M) (2.96 mL, 5.92 mmol) was added dropwise over 15 min and the reaction was stirred at -78°C for 2h. The reaction was then quenched with saturated sodium chloride solution and the product extracted with EtOAc (2x50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure, to give a crude compound, which was purified by column chromatography to give ethyl 2-(4-bromopyridin-2- yl)acetate (0.500 g, 30%) as a pale yellow liquid.
[0567] Step 2: ethyl 2-(4-bromopyridin-2-yl)-2-methylpropanoate - To a stirred solution of ethyl 2-(4-bromopyridin-2-yl)acetate (0.5 g, 2.05 mmol, 1.0 eq) in D F (5 mL) at 0°C under nitrogen atmosphere was added NaH (60%) (0.246 g, 6.10 mmol, 3 eq). The reaction mass was stirred at rt for 30 mins, then cooled to 0°C followed by the addition of methyl iodide (1.486 g, 10.25 mmol, 5.0 eq) under nitrogen atmosphere and stirred at RT for 16h. The DMF was removed under reduced pressure, water (10 mL) was added and the product extracted into EtOAc (3x15 mL). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude product which was purified by column chromatography to give ethyl 2-(4-bromopyridin-2-yl)-2-methylpropanoate (0.140g, 25%) as a pale yellow liquid.
[0568] Step 3: 2-(4-bromopyridin-2-yl)-2-methylpropan-l-ol - To a stirred solution of ethyl 2- (4-bromopyridin-2-yl)-2-methylpropanoate (600 mg, 2.2 mmol, leq) in THF (10 mL) under nitrogen atmosphere, at 0°C, was added 1M BH3.THF (3.3 mL, 3.31 mmol) dropwise. The mixture was stirred at room temperature for 16h and then quenched with methanol (lOmL) and concentrated under reduced pressure to afford crude product which was diluted with water and extracted into ethyl acetate. The ethyl acetate layer was dried over sodium sulfate and
concentrated under reduced pressure to afford 2-(4-bromopyridin-2-yl)-2-methylpropan-l-ol (280 mg) as a pale yellow liquid.
[0569] Step 4: (3^hloro-4-(5-(4,4,5,5-tetramethyl-l,3,2^io borolan-2-yl)pyridin-3- yl)phenyl)(4-hydroxypiperidin-l-yl)methanone - In glass seal tube, a solution of (4-(5- bromopyridin-3-yl)-3-chlorophenyl)(4-hydroxypiperidin-l-yl)methanone (0.2g, 0.5 mmol), Bis(pin) (0.193 g, 1.0 mmol) and potassium acetate (0.147 g, 1.5 mmol ) in 1,4-dioxane (10 mL) was purged with nitrogen gas for 15 minutes. After adding PdCh (dppf) (0.036g, 0.05 mmol) it was again purged with nitrogen gas for 5 minutes and the reaction mass was stirred at 80° C for 16h. After completion of the reaction (monitored by TLC), the mixture was cooled to RT and filtered through a Celite® bed and washed with ethyl acetate (2 X SOmL). The combined organic layers were concentrated under reduced pressure to give crude product which was purified by column chromatography on Florisil® (60-120) to give (3-chloro-4-(5-(4,4,5,5-tetramethyl- 1,3,2- dioxaborolan-2-yl)pyridm-3-yl)phenyl)(^hydroxypipericUn-l-yl)methanone as a brown gummy solid.
[0570] Step 5: (3-chloro-4-(2 '-(l-hydroxy-2-methylpropan-2-yl)-[3, 4'-bipyridin]-5- yI)phenyI)(4-hydroxypiperidin-l-yl)methanone - To a stirred solution of (3-chloro-4-(5-(4,4,5,5- tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)pyridin-3 -yl)pheny l)(4-hy droxypiperidin- 1 -y l)methanone (0.19 g, 0.43 mmol) in 1,4-dioxane (8 mL) and H2O (2 mL) in a glass tube was added 2-(4- bromopyridin-2-yl)-2-methylpropan-l-ol (0.1 g, 0.43 mmol) and K2CO3 (0.178 g, 1.29 mmol). The reaction mixture was purged for 15 minutes with nitrogen and Pd(PPh3)4 (0.05 g, 0.043 mmol) was added and the mixture again purged for 10 minutes with nitrogen. The reaction mixture was stirred at 80°C for 16 h. After completion (monitored by TLC), the solvent was evaporated and water was added (50 mL) and the product extracted into EtOAc (3x45 mL). The combined extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude compound which was purified by prep- HPLC to give (3-chloro-4-(2'- (l-hya^oxy-2-methylpropan-2-yl)-[3,4'-bipyridin]-5-yl)phenyl)(4-hydroxypiperidin-l- yl)methanone (33mg) as a white solid. ¾ NMR (400 MHz, DMSO-d6): δ 9.06 (d, J = 2.40 Hz, 1H), 8.76 (d, J = 2.00 Hz, lH), 8.63 (d, J = 5.20 Hz, 1H), 8.33 (t, J = 2.40 Hz, lH), 7.79 (s, lH), 7.68-7.65 (m, 3H), 7.49 (dd, J = 1.60, J = 9.2, 1H), 4.82 (d, J = 4.00 Hz, 1H), 4.67 (t, J = 5.2 Hz, 1H), 4.04 (br s, lH), 3.79-3.74 (m, 1H), 3.63-3.61 (m, 3H), 3.25-3.15 (br s, 2H), 1.85-1.70 (m, 2H), 1.40-1.30 (br s, 8H); LCMS: 97.97 %( M+H = 466.59).
Example 46: (^(I'-itert-butylhe-itrifluoromethyl^p^'-bipyridinJ-S-yljph
hydroxy piperidin-l-yl)methanone (Compound Z-865)
Figure imgf000259_0001
[0571] (4-(2,<tert-butyl)-6-(trifluoromethyl)-[3,4'-bipyri(iin]
l-yl)methanone was prepared from 3,5-dichloro-2-(trifluorornethyl)pyridine was prepared following the general procedures described in Example 4, to produce the product as an off white solid. 1H NMR (400 MHz, DMSO-d6): δ 9.21 (d, J = 2.00 Hz, 1H), 8.66 (dd, J = 0.40, 5.20 Hz, 1H), 8.40 (d, J = 1.60 Hz, lH), 7.89 (s, 1H), 7.72 (dd, J = 1.60, 5.00 Hz, 1H), 7.54-7.49 (m, 4H), 4.81 (d, J = 3.60 Hz, lH), 4.02 (br s, 1H), 3.78-3.73 (m, 1H), 3.60-3.50 (m, lH), 3.23-3.21 (m, 2H), 1.85-1.70 (m, 2H), 1.38 (s, 11H); LCMS: 98.43% (m/z 484.65 [M+H]).
Example 47: l-(5-(2-chloro-4-(4-hydroxypiperidine-l-carbonyl)phenyl)-[3,4'-bipyridin]-2,- yl)ethan-l-one (Compound Z-797)
Figure imgf000259_0002
[0572] Step 1: l-(4-(4J,5,5-tetrcmelhyl-l,3,2^iomborolcm-2-yl)pyridm^ - To a stirred solution of 1 -(4-bromopyridin-2-y l)ethan- 1 -one (200 mg, 1 mmol) and Bispin (379 mg, 1.5 mmol) in dioxane, in a glass seal tube, was added KOAc (294 mg, 3.0 mmol) and the reaction mass was purged for 15 minutes with nitrogen. Then PdCl2(dppf) (77 mg, 0.1 mmol) was added and the reaction mixture was again purged for 10 min with nitrogen. The reaction tube was sealed and stirred at 80°C for 16 h. The reaction mass was cooled and filtered through Celite®, and the filtrate was concentrated under reduced pressure to obtain crude residue. The residue was suspended in diethyl ether (2x10 mL) and the ether layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain l-(4-(4,4,5,5- tetramemyl-l,3,2-dioxaborolan-2-yl)pyridin-2-yl)ethan-l-one (0.300 g) as a brown gummy liquid.
[0573] Step 2: l-(5-(2^hloro-4-(4-hydroxypiperidine-l-carbonyl)phenyl)-[3,4'-bip yl)ethan-l-one - To a stirred solution of the product of Step 1 (260 mg, 1.05 mmol) and (4-(5- bromopyridm-3-yl)-3-cWorophenyl)(4-hydroxypiperidin-l-yl)methanone (415 mg, 1.05 mmol) in dioxane:water (5 mL:l mL), in a glass seal tube, was added K2CO3 (435 mg, 3.15 mmol) at room temperature under nitrogen atmosphere. The reaction mass was purged for 15 minutes with nitrogen, then Pd(PPh3)4 (121 mg, 0.105 mmol) was added and the reaction mixture was again purged for 10 minutes with nitrogen. The reaction tube was sealed and stirred at 80°C for 16 h. After completion, the residue was diluted with water (10 mL) and extracted into EtOAc (3x15 mL). The combined extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain crude product which was purified by Prep. HPLC to give l-(5-(2- chloro^-(4-hydroxypiperidine-l-c^bonyl)phenyl)-[3,4'-bipyridm]-2'-yl)eth^ (80 mg,
18%) as a white solid. 1H NMR (400 MHz, DMSO: δ (ppm): 9.13 (d, J= 2.00 Hz, lH), 8.86 (dd, J= 0.40, 5.20 Hz, lH), 8.81 (d, J= 2.00 Hz, 1H), 8.43 (t, J= 2.40 Hz, lH), 8.36 (t, J= 0.40 Hz, 1H), 8.17 (dd, J= 2.00, 5.00 Hz, lH), 7.69 (d, J= 8.00 Hz, lH), 7.65 (d, J= 1.60 Hz, lH), 7.50 (dd, J= 1.60, 7.60 Hz, lH), 4.82 (d, J= 4.00 Hz, 1H), 4.01 (br s, lH), 3.74-3.79 (m, lH), 3.51-3.55 (m, 1H), 3.32 (br s, 2H), 2.70 (s, 3H), 1.76-1.81 (m, 2H), 1.36-1.38 (m, 2H); LCMS: 98.89 % (436.2[M+H]).
Example 48: (3-chloro-4-(2'-(l-hydroxyethyl)-[3,4*-bipyridin]-5-yl)phenyl)(4- hydroxypiperidin-l-yl)methanone (Compound Z-798)
Figure imgf000260_0001
[0574] To a stirred solution of 1 -(5-(2-chloro-4-(4-hydroxypiperidine- 1 -carbonyljphenyl)- [3,4'-bipyridin]-2'-yl)ethan-l-one (150 mg, 0.436 mmol) in methanol (10 mL), at 0°C was added NaBH* (26 mg, 0.68 mmol). The reaction mixture was stirred at RT for 4 h. After completion, the reaction was quenched with aqueous HC1 and extracted into EtOAc (3x15 mL). The combined extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain crude product which was purified by preparative HPLC to give (3-chloro-4- (2'-(l -hyiiroxyemylJ-IS^'-bipyridinl-S-ylJphenylJi^hydroxypiperidin-l -yl)methanone (75 mg, 50%) as a white solid. Ή NMR (400 MHz, DMSO: δ (ppm): 9.05 (d, J = 2.00 Hz, lH), 8.78 (d, J= 2.00 Hz, lH), 8.62-8.60 (m, lH), 8.31 (t, J = 2.00 Hz, lH), 7.91 (d, J= 1.60 Hz, lH), 7.73 (dd, J= 1.60, 5.20 Hz, 1H), 7.65-7.63 (m, lH), 7.49-7.47 (m, 2H), 5.40 (dd, J= 4.80, Hz, lH), 4.82-4.81 (m, lH), 4.00 (br s, lH), 3.80-3.70 (m, lH), 3.55-3.50 (m, lH), 3.22-3.21 (m, 2H), 1.80-1.75 (m, 3H), 1.44-1.42 (m, 5H); LCMS: 98.91 % (438.42[M+H]).
Example 49: (3-chloro-4-(2'-(2-hydroxypropan-2-yl)-[3,4,-bipyridin]-5-yl)phi
hydroxypiperidin-l-yi)methanone (Compound Z-796)
Figure imgf000261_0001
[0575] To a stirred solution l-(5-(2-chloro-4-(4-hydroxypiperidine-l-carbonyl)phenyl)-[3,4'- bipyridin]-2'-yl)ethan-l-one (190 mg, 0.436 mmol) in diethyl ether (10 mL), MeMgBr (3M in DEE) (0.580 mL, 1.746 mmol) was added at 0°C. The reaction mixture was stirred atRT for 16 h. After completion of reaction, the reaction mixture was quenched with ammonium chloride solution (10 mL) and extracted into EtOAc (3x15 mL). The combined extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain crude product which was purified by preparative HPLC to afford (3-chloro-4-(2'-(2-hydroxypropan-2-yl)-[3,4'- bipyridin]-5-yl)phenyl)(4-hydroxypiperidin-l-yl)methanone. 1H NMR (400 MHz, DMSO: δ (ppm): 9.04 (d, J= 2.4 Hz, lH), 8.77 (d, J= 2.4 Hz, 1H), 8.62- 8.60 (dd, J= 0.4 Hz, J= 0.8 Hz, 1H), 8.30- 8.28 (t, J= 2.0 Hz, 1H), 8.03 (d, J= 1.2 Hz, lH), 7.71- 7.65 (m, 3H), 7.50- 7.48 (dd, J= 1.6 Hz, J= 1.6 Hz, 1H), 5.29 (s, lH), 4.80 (d, J= 4.0 Hz, lH), 4.00 (bs, 1H), 3.79- 3.74 (m, 1H), 3.54- 3.50 (m, 1H), 3.31 (bs, 2H), 1.80- 1.75 (bs, 2H), 1.49- 1.35 (bs, 8H); LCMS: 97.54 % (452.1[M+H]. Example SO: (3-chloiO-4-(2,-(2-methoxypropan-2-yl)-[3,4'-bipyridin]-5-yl)ph hydroxy piperidin-l-yl)methanone (Compound Z-799)
Figure imgf000262_0001
[0576] Step 1: 4-bromo-2-(2-methoxypropan-2-yl)pyridine - To a stirred solution of 2-(4- bromopyridin-2-yl)propan-2-ol (200 mg, 0.92 mmol) in THF (5 mL), was added NaH 56% (130 mg, 2.77mmol), the mixture stirred at RT for 30 min, then Mel (667 mg, 4.62mmol) was added and the mixture stirred at RT for 12 h. After completion, the THF was removed under reduced pressure and the residue was dissolved in EtOAc and washed with water (3x15 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain crude product which was purified by column chromatography (Silica 60-120 mesh) to afford 4-bromo-2-(2-methoxypropan-2-yl)pyridine (180 mg, 84%) as a pale yellow liquid. ¾ NMR (400 MHz, CDCh: δ 8.37 (dd, J= 0.40, 5.20 Hz, lH), 7.74 (dd, J= 0.80, 1.80 Hz, 1H), 7.33 (dd, J= 2.00, 5.20 Hz, lH), 3.20 (s, 3H), 1.54 (s, 6H); LCMS: 98.70 %( M+H=232.0).
[0577] Step 2: 2-(2- ethox^ropan-2-yl)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)pyridine - To a stirred solution of 4-bromo-2-(2-methoxypropan-2-yl)pyridine (180 mg, 0.78 mmol) and Bispin (397 mg, 1.56 mmol) in dioxane in a glass tube, was added KOAc (230 mg, 2.37 mmol) and the reaction mass was purged for 15 min with nitrogen. Then PdCh(dppf) (57 mg, 0.078 mmol) was added and the reaction mixture again purged for 10 min with nitrogen. The reaction tube was sealed and stirred at 80°C for 16 h. The reaction mass was cooled, filtered through Celite®, and the filtrate concentrated under reduced pressure to obtain crude product. This was diluted with diethyl ether (2x10 mL), then the ether layer was decanted off, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 2-(2- memoxypropan-2-yl)-4-(4,4,5,5-tetramemyl-l,3,2-dioxaborol^ (0.500 g) as a brown gummy liquid.
[0578] Step 3: (3^hloro-4-(2'-(2-methoxypropan-2-yl)-[3J'-bipyr^
hydroxypiperidin-l-yl)methanone - To a stirred solution of (4-(5-bromopyridin-3-yl)-3- chlorophenyl)(4-hydroxypiperidin-l-yl)methanone (200 mg, 0.505 mmol) and the product of Step 2 above (181 mg, 0.65 mmol) in dioxane: water (5 mL: 1 mL) in a glass tube, was added K2CO3 (174 mg, 1.263 mmol) at room temperature under a nitrogen atmosphere. The reaction mass was purged for 15 minutes with nitrogen and then palladium tetrakis (58 mg, 0.050 mmol) was added and the reaction mixture was again purged for 10 minutes with nitrogen. The reaction tube was sealed and stirred at 80°C for 16 h. After completion, the residue was diluted with water (10 mL) and the product extracted into EtOAc (3x15 mL). The combined extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain crude product which was purified by Prep.HPLC to afford (3-chloro-4-(2'-(2-methoxypropan-2-yl)- [3,4'-bipyridin]-5-yl)phenyl)(4-hydroxypiperidin-l-yl)methanone (35 mg, 10 %) as a white solid. 1H NMR (400 MHz, DMSO: δ (ppm): 400 MHz, DMSO-d6: δ 9.06 (d, J= 2.00 Hz, 1H), 8.78 (d, J= 2.40 Hz, lH), 8.65 (dd, J= 0.40, 5.00 Hz, lH), 8.34 (t, J= 2.00 Hz, lH), 7.90 (d, J= 0.80 Hz, 1H), 7.75 (d, J= 1.60 Hz, 1H), 7.68 (d, J= 8.00 Hz, 1H), 7.65 (d, J= 1.20 Hz, 1H), 7.49 (dd, J= 1.60, 8.00 Hz, 1H), 4.81 (d, J^3.6 Hz, lH), 4.06- 3.96 (m, lH), 3.77- 3.74 (m, lH), 3.61-3.59 (m, lH), 3.32-3.22 (br, 2H), 3.11 (s, 3H), 1.80-1.75 (br, 2H), 1.52 (s, 6H), 1.40-1.36 (br, 2H); LCMS: 97.99% (466.2[M+H].
Example SI : (4-(7-(2-(tert-butyl)pyridin-^yl)isoquinolin-5-yl)-3-chlorophenyl)(4- hydroxypiperidin-l-yi)metfaanone (Compound Z-828) and (4-(5-(2-(tert-butyl)pyridin-4- yl)isoquinolin-7-yl)-3-chlorophenyl)(4-hydroxypiperidin-l-yl)methanone (Compound Z- 829)
Figure imgf000264_0001
[0579] Step 1: A stirred solution of 5,7-dibromoisoquinoline (500 mg, 1.724 mmol), (2-chloro- 4-(methoxycarbonyl)phenyl)boronic acid (336 mg, 1.568 mmol), potassium carbonate (201 mg, 4.356 mmol) in water (1 mL) and 1,4-dioxane (10 mL) in a 15 mL glass seal tube was purged with nitrogen gas for 30 minutes. After adding palladium tetrakis (201 mg, 0.174 mmol) it was again purged with nitrogen gas for 30 minutes and then heated to 80°C for 16 h. The reaction, mixture was cooled to 25°C - 30°C, filtered through a Celite® bed and washed with ethyl acetate (50 mL). The combined organic layers were concentrated under reduced pressure to afford crude product which was purified by column chromatography on neutral alumina to afford a mixture of regioisomers (900 mg) as an off-white solid which was used in the next reaction.
[0580] Step 2: A stirred solution of the product of Step 1 (650 mg, 1.725 mmol), (2-(tert- butyl)pyridin-4-yl)boronic acid (492 mg, 2.07 mmol) and potassium carbonate (596 mg, 4.314 mmol) in water (1 mL) and 1 ,4-dioxane (4 mL) in a 15 mL glass seal tube was purged with nitrogen gas for 30 minutes. After adding palladium tetrakis (199 mg, 0.172 mmol) it was again purged with nitrogen gas for 30 minutes and then heated to 80°C for 16 h. The mixture was cooled to 25°C-30°C, filtered through a Celite® bed and washed with ethyl acetate (15 mL). The combined organic layers were concentrated under reduced pressure to afford crude which was purified by column chromatography on neutral alumina to give product (680 mg) as a mixture of regioisomers (680 mg) as a pale yellow gum.
[0581] Step 3: The product from Step 2 was dissolved in methanol: THF: water (3:2:1) (10 mL), then LiOKHbO (199 mg, 4.744 mmol) was added and the mixture was stirred at room temperature for 2 h. After completion of the reaction, the mixture was concentrated under reduced pressure and residue dissolved in water (20 mL) and washed with ethyl acetate (2X20 mL) to remove impurities. Water layer was acidified with citric acid until pH~5 and extracted with ethyl acetate (2x25 mL). The combined ethyl acetate layers were dried over sodium sulfate and concentrated under reduced pressure to afford the product as a mixture of regioisomers (400 mg) as an off white solid.
[0582] Step 4: The product from Step 3 was dissolved in in DMF (10 mL), then DIPEA (496 mg, 3.837 mmol) and HATU (1094 mg, 2.877 mmol) was added and the mixture was stirred for 15 min at room temperature under nitrogen. Then 4-hydroxypiperidine (146 mg, 1.439 mmol) was added under nitrogen. The mixture was stirred for 16 h at room temperature. After completion of the reaction, the mixture was diluted with water (100 mL) and the product was extracted into EtOAc (2X30 mL). The combined EtOAc layers were washed with water (50 mL), dried over sodium sulfate and concentrated under reduced pressure to afford crude product which was purified by prep. HPLC to give the product (240 mg) as a mixture of regioisomers as an off white solid. This mixture of regioisomers was separated through SFC. The first eluting peak gave (4-(7-(2-(tert-butyl)pyridm^-yl)isoquino
yl)methanone (30 mg) as an off white solid as determined by appropriate NOE XH NMR experiments. ¾ NMR (400 MHz, DMSO): δ 9.53 - 9.53 (s, lH), 8.74 (m, 1H), 8.65 - 8.64 (dd, J = 4.8 Hz, J= 5.2Hz, lH), 8.53 - 8.52 (d, J= 6.0 Hz, 1H), 8.21 - 8.20 (d, J= 1.6 Hz, 1H), 7.92 (s, lH), 7.74 - 7.72 (dd, J = 5.2 Hz, J = 5.2 Hz, 1H), 7.69 - 7.69 (d, J= 1.6 Hz, 1H), 7.62 - 7.60 (d, J= 8.0 Hz, 1H), 7.54 - 7.52 (dd, J= 7.6 Hz, J= 7.6 Hz, 1H), 7.32 - 7.30 (d, J= 6.0 Hz, 1H), 4.83 - 4.82 (d, J= 4.0 Hz, lH), 4.04 (bs, 1H), 3.81 - 3.76 (m, lH), 3.64 (bs, lH), 3.25 - 3.24 (m, 2H), 1.81 (bs, 2H), 1.49 - 1.42 (bs, 2H), 1.40 (s, 9H); LCMS: 99.48 % (m/z = 500.52 [M+H]).
[0583] The second eluting peak gave (4-(5-(2-(tert-biityl)pyridin-4-yl)isoqu-nolin-7-yl)-3- chlorophenyl)(4-hydroxypiperidin-l-yl)methanone (87mg) as an off white solid as determined by appropriate NOE ¾ NMR experiments. ¾ NMR (400 MHz, DMSO): δ 9.50 (s, 1H), 8.70 - 8.69 (dd, J= 4.8 Hz, J= 5.2 Hz, 1H), 8.60 - 8.58 (d, J= 6.0 Hz, 1H), 8.37 (s, 1H), 7.93 - 7.92 (d, J= 2.0 Hz, lH), 7.74 - 7.71 (m, 2H), 7.65 - 7.65 (d, J= 1.6 Hz, 1H), 7.61 - 7.61 (s, 1H), 7.51 - 7.49 (dd, J = 7.6 Hz, J = 7.6 Hz, 1H), 7.46 - 7.44 (dd, J = 4.8 Hz, J = 4.8 Hz, lH), 4.82 - 4.81 (d, J= 4.0 Hz, lH), 4.01 (bs, lH), 3.79 - 3.74 (m, 1H), 3.54 - 3.50 (bs, 1H), 3.20 (bs, 2H), 1.80
Example 52: Effect of Compounds on Gene Expression and in vitro ADME properties
[0584] Gene Expression: The effect of selected compounds described herein on the gene expression of HepG2 cells was evaluated. HepG2 cells (P2) were seeded in 24 well plate (80,000 cells/well) for RNA extraction and in a % well plate (10,000 cells/well) for Cell Titer Glow (CTG). The media used was DMEM and contained 10% FBS. Each compound was evaluated at 500 Mm for 48 hours. Two biological replicates per experimental group were evaluated for RNA. For gene analysis, RNA was harvested with RNEasy kit and 20-100 ng used to synthesize cDN A with random primers. Quantitative PCR was performed on 1 pg to 100 ng cDNA for the following genes: ACACA, ACLY, FASN, LSS, PNPLA3. Gene expression levels were normalized with housekeeping gene, β-Actin, and relative expression levels determined using AACT method comparing treated to mock or vehicle treated cells as a baseline. "Total" gene expression refers to the average of the values of the 5 genes listed above. The results from this evaluation are presented in Table 3.
[0585] The ADME properties of kinetic solubility, half-life in human liver microsomes, and half-life in mouse liver microsomes for selected compounds were also evaluated. The results are presented in Table 3.
[0586] Kinetic Solubility Procedure: A 10 mM stock solution of a compound was prepared in DMSO, then 4 μΐ,, of the stock was added to a deep well plate containing 396 μL of pH 7.4 buffer. The sample plate was vortexed at 800 rpm for 24 h on thermomixer at room temperature. The plate was sealed well during the incubation process. The DMSO content in the sample was 1.0%. The concentration of the evaluated compound in the final incubation was 100 μΜ At the end of the incubation period, the sample plate was centrifuged at 4000 rpm for 10 min and analyzed in LC-UV against a calibration curve (CC). Values <10 μg/mL = Low; 10 to 60 μg/mL =Medium; >60 μg/πlL = High.
[0587] Half-life Human Microsomes: Compounds were evaluated for stability in human liver microsomes. A 10 mM stock solution of the compound being evaluated was prepared in DMSO and diluted with watenacetonitrile (1 : 1) to a concentration of 1 mM. A working concentration of 100 μΜ was prepared by further dilution with watenacetonitrile (1 : 1). To make the
preincubation mixture, 2.5 uL of the diluted compound was combined with 75 μΐ., of human liver microsomes at 3.33 mg/mL, and 85 μΐ^ of 100 mM potassium phosphate buffer, and this mixture was pre- incubated for 10 min at 37°C. To make the 60 minute mixture without cofactor, 32.5 uL of the preincubation mixture was combined with 17.5 μΐ. of 100 mM potassium phosphate buffer and incubated for 60 min at 37°C. To make the 0 min sample with cofactor (NADPH), 16.25 μΐ., of the preincubation mixture was combined with 200 uL of acetonitrile containing internal standard and 8.75 μΐ., of cofactor (NADPH). To make the incubation mixture, 62 \iL of cofactor (2.85 mM) was combined with the remaining incubation mixture, and incubated for 60 min at 37°C. To prepare the sample mixture to be evaluated, 25 \iL incubation mixture was combined with 200 \iL of acetonitrile containing internal standard and vortexed for 5 min at 1200 rpm, then centrifuged for 10 min at 4000 rpm. The supernatant was diluted 2 fold with water and injected on LC-MS/MS. The sample mixture was evaluated by LC-MS/MS using 10 mM ammonium acetate with 0.1 % FA as the aqueous mobile phase, and methanol as the organic mobile phase.
[0588] Half-life Mouse Microsomes: Compounds were evaluated in mouse liver microsomes following a similar procedure as described above for human liver microsomes. A similar procedure could be used to evaluate compounds in rat liver microsomes. Table 3. Entries A-F are effect of compounds on gene expression of HepG2 cells. A: ACACA; B: ACLY; C: FASN; D: LSS; E: PNPLA3; F: Total. For gene expression at the tested dose, 0- 0.309 = +++, 0.31-0.7509 = ++, >0.751 = +. Entry G is the half-life of human liver microsomes (min). Entry H is the half-life of mouse liver microsomes (min). Entry I is kinetic solubility class.
Figure imgf000268_0001
Figure imgf000269_0001
Figure imgf000270_0001
Figure imgf000271_0001
Figure imgf000272_0001
Figure imgf000273_0001
Figure imgf000274_0001
Figure imgf000275_0001
Figure imgf000276_0001
Figure imgf000277_0001
Figure imgf000278_0001
Figure imgf000279_0001
Figure imgf000280_0001
Figure imgf000281_0001
Figure imgf000282_0001
Figure imgf000283_0001
Figure imgf000284_0001
Example S3: Additional Gene Expression Testing
[0589] The effect of Compound Z-725 on expression of the genes ACACA, ACACB, ACLY, ACSS1, ACSS2, ELOVL6, FASN, HMGCR, LSS, MVK, PNPLA3, SREBP1, SREBP2, SCAP, SCD, and MVD was evaluated, following the procedure described in Example 52. The results are presented in Table 4 below.
Figure imgf000285_0001
Example 54: Western Blotting of SREBP Processing
[0590] The effect of selected compounds on SREBP processing and activation was evaluated in HepG2 cells via Western blotting. Cells were seeded at a density of 8e6 in 150mm plate in DMEM (Dulbecco's modified Eagle's medium) supplemented with 10% (V/V) heat-inactivated FBS (fetal bovine serum), penicillin G (100 units/ml) and gentamycin (0.2 mg/ml). After overnight incubation, they were washed twice in PBS, and then DMEM media with 0% FBS with 500nM of compound was added to the plate. Cells were incubated at 37°C. After 48 hours, the cells were washed and lysed to obtain cytoplasmic and nuclear extracts for Western blotting to measure SREBP expression along with topoisomerase I as loading control. The Western blot analysis of compounds Z-725, Z-826, Z-780, and Z-796 is shown in FIG. 4.
Example 55: Adipocyte differentiation and Oil Red-O Staining
[0591] The effect of compound Z-725 (Compound 1) on adipocyte differentiation in human pre-adipocyte and 3T3-L1 cells was evaluated.
[0592] Human Pre-Adipocyte differentiation: Cells were thawed and seeded at 40,625 cells/cm2 in pre-adipocyte media (ZenBio) as per manufacturer's direction. The cells were allowed to reach confluence for 48 hours, and media switched to Adipocyte Differentiation Media (ZenBio) for 7 days. The media was then switched to Adipocyte Maintenance Media (ZenBio) for additional 7 days. The compound Z-725 was added to the cells for day 1-7 during differentiation (set I), or day 7-14 during maturation (set II). Cells were then stained with oil red-0 as described below.
[0593] H 3T3-L1 cell differentiation: Cells were thawed into Pre- Adipocyte Media
(ZenBio) and grown to 80-85% confluence. Cells were seeded 50,000 cells/well into 96-wp in Pre- Adipocyte Media (ZenBio) and allowed to reach confluence for 48-72 hours. They were grown an additional 48 hours after reaching confluence, then the media was changed to
Differentiation Media (Zen Bio) and incubated for 72 hours. The media was changed to
Adipocyte Differentiation Media (ZenBio) using 150 microliters/well in 96-wp for 72 hours, then media was removed and replaced with 150 microliters of Adipocyte Maintenance Media for an additional 8-14 days, feeding cells every 2-3 days. Compound Z-725 was added to the cells for day 3-6 during differentiation (set I), or day 7-14 during maturation (set Π). Cells were then stained with oil red-0 as described below.
[0594] OilRed-O staining: After maturation, the cells were washed, then fixed in 10%
Formalin for 30-60 minutes. The formalin was removed, the cells were washed in water twice, and then the cells were incubated in 60% isopropanol for 5 minutes. The isopropanol was removed and Oil Red-0 solution added for 20 minutes with gentle rotation of plate. The stain was removed, the cells washed twice with water, and Hematoxylin added for 1 minute. The cells were washed twice with water and air dried, then images were acquired. FIG. 2 depicts images taken of the 3T3-L1 cells, and FIG. 3 depicts the images taken of human pre-adipocyte cells.
Example 56: Log D of Compounds
[0595] The Log D of selected compounds was evaluated by octanol/aqueous buffer partitioning. 500 L of organic phase (1-octanol) was added to each well of a 2 mL deep well plate, followed by 500 μL of buffer and 15 μΐ^ of test compound in DMSO (0.15 mM). The plate was vortexed for 10 seconds and incubated at room temperature for 1 hr on a plate shaker at 200 rpm. After incubation, the samples were allowed to equilibrate for 20 min and then centrifuged at 4000 rpm for 30 min for complete phase separation. The distribution of test compound in buffer and octanol phase was analyzed by HPLC-UV. Log D = Log (Area of Octanol/Area of Buffer). The results are presented in Table 5 below.
Table 5. Log D pH 7.4 Values for select compounds.
Figure imgf000287_0001
Example 57: Evaluation of in vivo pharmacokinetic properties of compounds
[0596] The in vivo pharmacokinetic properties of compounds by both intravenous and oral administration were evaluated in male Sprague Dawley rats or C57BL/6J mice.
[0597] Animals were housed in cages with clean bedding. Certified rodent diet was provided. Water was available ad libitum. Environmental controls for the animal room were set to maintain a temperature of 22°C to 25°C, humidity of 40-70% RH, and a 12-hour light /12-hour dark cycle. Normal healthy animals certified by the attending veterinarian were selected and acclimatized for minimum three days prior to initiation of study.
[0598] Surgical Procedure for Jugular Vein Cannulation of Rats: Rats were anaesthetized with a single dose of ketamine 50 mg kg i.p. + xylazine 6 mg/kg i.p. The right jugular vein was exposed, a loose ligature was placed caudally, and the cranial end of vein was ligated. A small incision was made between the ligatures into which the catheter (polyethylene SO tubing of internal diameter 0.S8 mm and outer diameter 0.96 mm) was inserted. The catheter was secured in place by tying the loose ligature around the catheterized vessel. A small incision was made in the scapular region to serve as the exit site of the catheter. The catheter was subcutaneously tunneled and exteriorized through scapular incision. A stay suture was placed in the scapular area. Patency was tested, and catheter was filled with a locking solution (heparinized saline) and sealed with a stainless steel plug. The incision was then sutured with sterile suturing material. Anti-septic solution was applied to the sutured site and animal was placed back in the home cage.
[0599] To evaluate pharmacokinetic properties of intravenous delivery, male Sprague Dawley rats were administered 2.00 mg compound /kg animal weight through the tail vein. The concentration of the compound in the plasma of the animals was evaluated at 0.083, 0.2S, 0.5, 1, 2, 4, 8, 12 and 24 hr by taking blood samples from the cannulated jugular vein. For the C5B1/6J mice, blood samples were collected through a capillary, guided in retro-orbital plexus.
[0600] To evaluate pharmacokinetic properties of oral delivery, rats (male Sprague Dawley rats) or mice (C5B1/6J) were administered 10 mg compound/kg animal weight by mouth. The concentration of compound in the plasma of the animals was evaluated at 0.2S, 0.5, 1, 2, 4, 6, 8, 12 and 24 hr by taking blood samples from the cannulated jugular vein (rats) or through a capillary, guided in retro-orbital plexus (mice).
[0601] The results of evaluation in rats are shown in Table 6 below, and the results in mice are shown in Table 7.
Table 6. Evaluation of in vivo pharmacokinetic properties in rats by intravenous delivery (IV) and by oral delivery (PO).
Figure imgf000288_0001
Dose (both IV and PO): mg/kg. CL (IV): mL/Min/Kg. AUCwast (both IV and PO): ng*hour/L. Vd = volume of distribution. CL = clearance. %F = Bioavailability of oral delivery.
Table 7. Evaluation of in vivo pharmacokinetic properties in mice by intravenous delivery (IV) and by oral delivery (PO).
Figure imgf000289_0001
volume of distribution. CL = clearance. %F = Bioavailability of oral delivery.
Example 58: Evaluation of compounds on liver gene expression in mice
[0602] The pharmacodynamic properties of selected compounds were evaluated in mice. The animals were housed in cages with clean bedding, and maintained and monitored for good health in accordance with Test Facility SOPs and at the discretion of the laboratory animal veterinarian. Certified rodent diet was provided. Food and water was available ad libitum. Environmental controls for the animal room were set to maintain a temperature of 22°C to 25°C, humidity of 40-70% RH, and a 12-hour light/12-hour dark cycle. Normal healthy animals certified by the attending veterinarian were selected and acclimatized for minimum three days prior to initiation of study. Animals were identified with body markings.
[0603] Aliquots of the compounds being evaluated were weighed and triturated with 0.5% methylcellulose (with the addition of 5% N-methyl pyrrolidone when required to remove clumping, as for Z-806) to an appropriate dose concentration. Vials were labeled with the information about study number, test item, concentration and date of preparation. A description of appearance of formulation was recorded (e.g., color, turbidity, etc.). The composition of formulation vehicle was recorded. An aliquot of each dose solution was taken before the dosing began and after dosing was finished, and stored at approximately -20°C or below for subsequent analysis. The animals were dosed orally through oral gavage needle, and time of dosing was recorded. [0604] After dosing, the mice were anesthetized using gaseous anesthesia. Blood samples were collected through a capillary, guided in retro-orbital plexus, at 6 h or at 24 h. Approximately 100 uL of blood was collected from each mouse, in pre-labeled tubes. The collected blood was stored on ice prior to centrifugation. Blood samples were then centrifuged within 1 hour of collection to separate plasma. Centrifugation was conducted at 2500 x g for 15 minutes at 4°C. The plasma was separated and transferred to pre-labeled micro-centrifuge tubes and promptly frozen at -80±10°C until bioanalysis. The results from this analysis are provided in Table 8 below.
[0605] Liver Collection at 6 h or 24 h: Immediately after blood withdrawal for
pharmacokinetic evaluation (at 6 or at 24 h), liver tissue was collected without perfusion.
Animals were euthanized using carbon dioxide gas in a CO2 chamber. The whole blood was drained by cutting the both side jugular vein and abdominal aorta. The liver was separated out. All the liver samples were divided in two parts. The first part (200 mg approx.) was snap frozen using liquid nitrogen as soon as possible. These samples were immediately transferred to -80°C for storage. The remaining part was weighed and used for bioanalysis. The results from this analysis are provided in Table 8 below.
[0606] RNA Processing and Gene Expression Analysis: Liver Tissue RNA was harvested with the RNEasy kit and 20-100 ng used to synthesize cDNA with random primers following the manufacturer's protocol. Quantitative PCR was performed on 1 pg to 100 ng cDNA for the following genes: ACACA, ACLY, FASN, LSS, PNPLA3. Gene expression levels were determined using AACT method comparing treated to vehicle treated samples as a baseline, and fold change calculated. The average value for all 5 genes above was averaged and termed to Total Fold Change The results from this evaluation are presented in Table 8.
Table 8. Effect of compounds provided herein on the liver Total Fold Change of gene expression at 6 and 24 hours after oral administration. Gene Expression at tested noted dosage. Vehicle = 0.5% Methylcellulose. Ratings: 0-0.509 = +++, 0.51-0.7509 = ++, >0.751 = +. N/A = Not Applicable
Figure imgf000290_0001
Figure imgf000291_0002
Example 57: (4-(2'-(tert-butyl)-[3,4,-bipyridin]-5-yl)-3-chlorophenyl)(6-hydroxy-3- azabicyclo[3.1.0]hexan-3-yl)methanone (X-8938)
Figure imgf000291_0001
[060η To a solution of 4-(2'-(tert-butyl)-[3,4'-bipyridin]-5-yl)-3-chlorobenzoic acid (100 mg, 0.27 mmol) in THF (10 mL) was added DIPEA (0.25 mL, 1.36 mmol) and HATU (155 mg, 0.41 mmol). The reaction mixture was stirred for 10 minutes, then 3-azabicyclo[3.1.0]hexan-6-ol (56 mg, 0.41 mmol) was added and stirred for 4 h. After completion, the reaction mass was diluted with ethyl acetate and washed with cold water (4 x 5 mL). Organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude product which was purified by prep HPLC to give (4-(2'-(tert-buryl)-[3,4l-bipyridin]-5-yl)-3- chlorophenyl)(6-hydroxy-3-azabicyclo[3.1.0]hexan-3-yl)methanone as an off white solid (30mg). !H NMR (400 MHz, DMSO-d6): δ 9.07 (d, J = 2.40 Hz, 1H), 8.75 (d, J = 2.00 Hz, lH), 8.63 (d, J = 5.20 Hz, lH), 8.34 (t, J = 2.00 Hz, lH), 7.83 (s, 1H), 7.71 (d, J = 1.20 Hz, lH), 7.66- 7.65 (m, 2H), 7.56-7.54 (m, 1H), 5.44 (d, J = 1.60 Hz, lH), 3.84 (d, J = 12.00 Hz, lH), 3.69-3.65 (m, 1H), 3.49-3.45 (m, lH), 3.42-3.32 (m, lH), 3.01 (d, J = 1.20 Hz, lH), 1.64 (d, J = 3.60 Hz, 2H), 1.38 (s, 9H); LCMS: 99.38% (m/z =448.1 [M+H]).
0608 The followin com ounds were re ared in a similar fashion:
Figure imgf000292_0001
Figure imgf000293_0001
Example 58: Isopropyl (3-chloro-4-(2,-cyclopropyl-[3,4'-bipyridin]-5-yl)phenyl)carbamate (X-8956)
Figure imgf000294_0001
[0609] Step 1: 3^hloro-4-(2'^clopropyl-[3,4'-bipyridin]-5-yl)aniline. A stirred solution of 4- bromo-2-cyclopropylpyridine (350 mg, 1.76 mmol), (5-(4-amino-2-chlorophenyl)pyridin-3- yl)boronic acid (526 mg,2.12 mmol) and potassium carbonate (730 mg, 5.30 mmol) in 1,4- dioxane (5.6 mL) and water (1.4 mL) was purged with nitrogen gas for 15 minutes. After adding palladium Pd(PPli3)4 (200 mg, 0.17 mmol), the reaction mass was again purged with nitrogen for 10 min and was heated to 80°C for 16 h. After completion of the reaction, the solvent was evaporated under reduced pressure and the crude compound was purified by column
chromatography (neutral alumina), eluted with 30% EtOAc in pet ether, collected fraction was concentrated under reduced pressure to obtain 3-chloro-4-(2'-cyclopropyl-[3,4'-bipyridin]-5- yl)aniline (0.500 g, 88%) as a gum.
[0610] Step 2: isopropyl (3^hloro-4-(2'^clopropyl-[3,4'-bipyri^n]-5-yl)phenyl)carbamate. To a stirred solution of 3-chloro-4-(2'-cyclopropyl-[3,4'-bipyridin]-5-yl)aniline (200 mg, 0.62 mmol) in pyridine, was added isopropyl carbonochloridate (85 mg, 0.70 mmol) dropwise at 0°C. The reaction mass was slowly allowed to RT and stirred for 24 h. After completion, the reaction was quenched with water (10 mL) and extracted with DCM (3x10 mL). The extracts were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by column chromatography (neutral alumina), eluted with 5% MeOH in DCM to afford isopropyl (3-chloro-4-(2'-cyclopropyl-[3,4l-bipyridin]-5- yl)phenyl)carbamate as an off white solid. ¾ NMR (400 MHz, DMSO-d6): δ 10.20 (s, 1H), 9.03 (d, J = 2.00 Hz, lH), 8.72 (d, J = 2.00 Hz, 1H), 8.50 (d, J = 5.20 Hz, lH), 8.26 (t, J = 2.00 Hz, 1H), 7.76 (d, J = 0.80 Hz, lH), 7.60-7.57 (m, 2H), 7.43 (d, J = 2.40 Hz, 1H), 7.33-7.30 (dd, J = 2.40 Hz, 8.40 Hz, 1H), 3.12 (s, 3H), 2.22-2.16 (m, lH), 0.99-0.97 (m, 4H); LCMS: 98.75 % (400.26[M+H] *). [0611] The following compounds were prepared in a similar manner.
Figure imgf000295_0001
Figure imgf000296_0002
Example 59: N-(3'-(2-(tert-butyI)pyridin-4-yl)-2-chIoro-[l,l,-biphenyl]-4- yl)methanesulfonamide (Z-883)
Figure imgf000296_0001
[0612] Step 1: 3'-(2-(tert-butyl)pyridin-4-yl)-2^hloro-[l,r-biphenyl]-4<m In a glass tube was taken 3'-bromo-2-chloro-[l,l'-biphenyl]-4-amine (0.36 g, 1.27 mmol) in 1,4-dioxane and water (10 mL). To it was added 2-(tert-butyl)^-(4,4,5,54etramethyl-l,3,2-dioxaborolan-2- yl)pyridine (0.332 g, 1.27 mmol) and K2CO3 (0.526 g, 3.81 mmol). The reaction mixture was purged for 15 minutes with nitrogen and then added Pd(pph3)* (147 mg, 0.13 mmol) and purged again for 10 minutes with nitrogen. The reaction was sealed and stirred at 80°C for 16 h. After completion of the reaction, the reaction mixture was filtered through Celite® bed and the cake was washed with ethyl acetate. Filtrate and washings were combined and concentrated. The residue was dissolved in water (20 mL) and extracted with ethyl acetate (3 x 30 mL). Organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain crude which was purified by column chromatography to give 3'-(2-(tert-butyl)pyridin-4- yl)-2-chloro-[l,r-biphenyl]-4-amine as yellow solid.
[0613] Step 2: N-(3'-(2-(tert-butyI)pyri in-4-yI)-2-chloro-[l '-biph^
yl)methanesulfonamide. To 3'-(2-(tert-butyl)pyridin-4-yl)-2-chloro-[ 1 , 1 '-biphenyl]-4-amine (124 mg, 0.369 mmol) in DCM (10 mL) was added pyridine (0.06 mL, 0.738 mmol) and
methanesulfonyl chloride (0.043 mL, 0.SS mmol) .The reaction mixture was stirred at rt for 4 h. After completion of the reaction, reaction mixture was diluted with DCM (10 mL) and washed with water (2 x 10 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain crude material which was purified by prep HPLC to afford N-(3'-(2-(tert-butyl)pyridm^-yl)-2-cWoro-[l,l'-biphenyl]^-yl)methanesulfo as a white solid. ¾ NMR (400 MHz, DMSO-d6: δ 10.12 (s, lH), 8.58-8.57 (d, J = 5.2 Hz, lH), 7.81-7.78 (m, 2H), 7.69 (s, 1H), 7.62-7.58 (t, J = 7.6 Hz, 1H), 7.54-7.49 (m, 3H), 7.38 (m, lH), 7.29-7.26 (dd, J = 8.4 Hz and 2.0 Hz, lH), 3.09 (s, 3H), 1.37 (s, 9H); LCMS: 99.02% (m/z =415. 0) [M+IT].
[0614] The following compound was synthesized in a similar manner:
Figure imgf000297_0001
Example 60: (3-chloro-4-(5-(23-dihydro-[l,4]dioxino[2^b]pyridin-8-yl)pyridin-3- yl)phenyl)(4-hydroxypiperidin-l-yl)methanone (Z-806)
Figure imgf000298_0001
/
[0615] Ste/? 7: (3^hloro-4-(5-(4,4,5,5-teirameihyl-J,3,2-^ioxaborolan-2-yI)pyridin-3- yl)phenyl)(4-hydroxypiperidin-l-y!)methanone. To a stirred solution of (4-(5-bromopyridin-3- yl)-3-chlorophenyl)(4-hydroxypiperidin-l-yl)methanone (0.100 g, 0.259 mmol, 1.0 eq) and Bispin (0.128 g, 0.S08 mmol, and 2.0 eq) in dioxane (2 mL), in a glass tube was added KOAc (0.062 g, 0.635 mmol, 2.5 eq) and the reaction mass was purged for 15minutes with nitrogen and then added PdCh (dppf) (0.020 g, 0.025 mmol, 0.1 eq) and again purged for 10 minutes with nitrogen. The reaction tube sealed and stirred at 80°C for 16 h and then filtered through Celite® and concentrated under reduced pressure to obtain a residue which was washed with diethyl ether and n-pentane. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain (3-chloro-4-(5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)r>yridm-3-yl)phenyl)(4-hydroxypiperidin-l-yl)methanone (0.150 g) as a brown gum.
[0616] Step 2: (3^hloro-4-(5-(2,3^ihydro-[l,4]doxiru)[2,3-b]pyridin-8^
y\)phenyl)(4-hydroxypiperidin-l-yl)methanone. To a stirred solution of the product from Step 1
(0.100 g, 0.277 mmol, 1.0 eq) and 8-iodo-2,3-dihydro-[l,4]dioxino[2,3-b]pyridine (0.090 g,
0.332 mmol, 1.2 eq) in a glass tube in dioxane: water (3 mL: 1 mL), was added K2CO3 (0.095 g,
0.095 mmol, 2.5 eq) at room temperature under nitrogen atmosphere. The reaction mass was purged for 15 min with nitrogen then added palladium tetrakis (0.032 g, 0.027 mmol, 0.1 eq) and again purged for 10 min with nitrogen. The reaction tube was sealed and stirred at 80°C for 16 h.
After completion, the residue was dissolved in water (8 mL) and extracted with EtOAc (3x10 mL). The extracts were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain crude product which was purified by preparative.HPLC to give (3- chloro^-(5-(2,3-dmydro-[l,4]clioxino[2,3-b]pyridin-8-yl)pyridin-3-yl)phenyl)(4- hydroxypiperidin-l-yl)methanone (0.040 g, 32%) as a white solid. ¾ NMR (400 MHz, DMSO: δ (ppm): δ 8.88 (d, J = 2.00 Hz, 1H), 8.71 (d, J = 2.00 Hz, 1H), 8.15 (t, J = 2.00 Hz, 1H), 7.85 (d, J = 4.80 Hz, 1H), 7.64-7.62 (m, 2H), 7.48 (dd, J = 1.60, 8.00 Hz, 1H), 7.19 (d, J = 5.20 Hz, 1H), 4.81 (d, J = -4.00 Hz, lH), 4.46-4.45 (m, 2H), 4.31-4.30 (m, 2H), 3.99 (bs, 1H), 3.75-3.74 (m, 1H), 3.53-3.52 (m, 1H), 3.22-3.22 (m, 2H), 1.78 (bs, 2H), 1.39 (bs, 2H); LCMS: 99.24% (452.41 [M+H]).
Example 61: Preparation of compounds from 3-chloro-4-(5-(2^-dihydro-[l,4]diozino[2^- b] pyridin-8-yl)py ridin-3-yl)aniline
Figure imgf000299_0001
Example 62: Isopropyl (3-chloro^(2*-(l-hydroxy-2-methylpropan-2-yl)-[3,4'-bipyridin]-5- yl)phenyl)carbamate (X-8908)
Figure imgf000300_0001
[0617] A stirred solution of isopropyl (4-(5-bromopyridin-3-yl)-3-chlorophenyl)carbamate (110 mg, 0.2989 mmol), 2-memyl-2-(4-(4,4,5,5-tetramemyl-l,3,2-ckoxato^^
yl)propan-l-ol (6S.0 mg, 0.3288 mmol) and potassium carbonate (124.30 mg, 0.8967 mmol) in a mixture of water (0.3 mL) and 1,4-dioxane (1.2 ml) in a 15 mL glass seal tube was purged with nitrogen gas for 15 min. After adding palladium tetrakis (34.52 mg, 0.0289 mmol) the mixture was again purged with nitrogen gas for 15 min, then the tube sealed and heated at 80°C for 16 h. After completion, the reaction mixture was cooled to rt and filtered through Celite® bed and washed with ethyl acetate (20 mL). The combined filtrate and washings were concentrated under reduced pressure to afford crude (220 mg) which was purified by preparative HPLC to give isopropyl (3-chloro-4-(2'-(l-hydroxy-2-methylpropan-2-yl)-[3,4'-bipyridin]-5- yl)phenyl)carbamate (33 mg, 26.5%) as an off white solid. ¾ NMR (400 MHz, DMSO-d6): δ 9.94 (s, lH), 8.99 (d, J = 2.00 Hz, lH), 8.70 (d, J = 2.00 Hz, 1H), 8.62 (d, J = 4.80 Hz, 1H), 8.23 (t, J = 2.00 Hz, lH), 7.80 (s, lH), 7.76 (d, J = 0.80 Hz, 1H), 7.64-7.62 (m, lH), 7.55-7.50 (m, 2H), 4.96-4.88 (m, 1H), 4.67 (t, J = 5.60 Hz, 1H), 3.61 (d, J = 5.60 Hz, 2H), 1.31 (s, 6H), 1.28 (d, J = 6.40 Hz, 6H); LCMS: 99.20 % (m/z = 440.00[M+H]).
[0618] The following compounds were prepared in a similar manner:
Figure imgf000300_0002
Example 63: Preparation of additional compounds
[0619] The following compounds were prepared following procedures described herein.
Figure imgf000301_0001
Figure imgf000302_0001
Figure imgf000303_0001
Figure imgf000304_0001
Figure imgf000305_0001
Figure imgf000306_0001
Figure imgf000307_0001

Claims

CLAIMS What is claimed is:
Claim 1. A compound of Formula (X):
Figure imgf000308_0001
or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein:
R1 is -C(0)OR9, -C(0)NR8R9, -S(0)2NR8R9, -NR10C(O)NR8R9, -NR10C(O)R9, -NR10S(O)2R9,
-OR26, -SR9, -S(0)R9, -S(0)2R9, -NR8R9, -NR10C(O)OR9, -C(0)R26, -NR10S(O)2NR8R9, - C(O)NR10S(O)^9, or -C(O)NR10NR8R9;
wherein each of R8, R9, and R10 is independently selected from the group consisting of hydrogen, (C1-10)alkyl, (C3-10)cycloalkyl, (C3-10)cycloalkyl(C1-10)alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, (C6-10)aryl, (C6-10)aryl(C1-10)alkyl, heteroaryl, and heteroaryl-alkyl,
R26 is (C1-10)alkyl, (C3-10)cycloalkyl, (C3-10)cycloalkyl(C1-10)alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, (C6-10)aryl, (C6-10)aryl(C1-10)alkyl, heteroaryl, or heteroaryl-alkyl,
each (C1-10)alkyl, (C3-10)cycloalkyl, (C3-10)cycloalkyl(C1-10)alkyl, heterocycloalkyl,
heterocycloalkyl-alkyl, (C6-10)aryl, (C6-10)aryl(C1-10)alkyl, heteroaryl, and heteroaryl-alkyl of R8, R9, R10, and R26 is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, (C1-10)alkyl, (C1-10)haloalkyl, cyano, oxo, -OR19, -C(0)NR,9R19, -NR19C(0)R19, -NR,9C(0)NR,9R19, -NR19R19, -S(0)2NR,9R19, -NR10S(O)^^ -S(O)^20, -C(0)OR19, -C(0)R20, and -(OR38>,i50R19, each R19 is independently hydrogen, (C1-10)alkyl, (C3-10)cycloalkyl,
(C3-10)cycloalkyl(C1-10)alkyl, or heterocycloalkyl; or two R19, together with the nitrogen atom to which they are attached, form a
heterocycloalkyl; wherein each of the foregoing alkyl, cycloalkyl, or heterocycloalkyl moieties is independently unsubstituted or substituted with one or more halo,
each R20 is independently (C1-10)alkyl, (C3-10)cycloalkyl,
(C3-10)cycloalkyl(C1-10)alkyl, or heterocycloalkyl, wherein each of the foregoing is independently unsubstituted or substituted with one or more halo,
each R38 is independently (C1-10)alkylene or (C1-10)haloalkylene,
each nlS is independently an integer from 1 to 5, and
n4 is 0, l, or 2;
or R8 and R9, together with the nitrogen atom to which they are attached, form a
heterocycloalkyl, wherein the heterocycloalkyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, cyano, oxo, (C1-10)alkyl, (C2-i0)alkenyl, (C2-i0)alkynyl, (C3-10)cycloalkyl, (C3-10)cycloalkyl(C1-10)alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, (C6-10)aryl, (C6-10)aryl(C1-10)alkyl, heteroaryl, heteroaryl-alkyl, -OR23, -C(0)NR23R23, -NR23C(0)R23, -NR23C(0)OR23, -NR23C(0)NR23R23, -NR23R23, -S(0)2NR23R23, -NR23S(0)2R24, -S(0>6R24, -C(0)OR23, -C(0)R24, and -(OR39)n160R23, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl,
heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aryl-alkyl, heteroaryl, and heteroaryl-alkyl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, oxo, alkyl, haloalkyl, -OR31, -C(0)NR31R31, -NR31C(0)R31, -NR31C(0)OR31, -NR31C(0)NR31R31, -NR31S(0)2R31, and -SiOVR31, wherein each R31 is independently hydrogen, alkyl, or haloalkyl, and each n9 is independently 0, 1, or 2, each R23 is independently hydrogen, (C1-10)alkyl, (C3-10)cycloalkyl,
(C3-10)cycloalkyl(C1-10)alkyl, or heterocycloalkyl; or two R23, together with the nitrogen atom to which they are attached, form a heterocycloalkyl; wherein each of the foregoing alkyl, cycloalkyl, or heterocycloalkyl moieties is independently unsubstituted or substituted with one or more halo,
each R24 is independently (C1-10)alkyl, (C3-10)cycloalkyl,
(C3-10)cycloalkyl(C1-10)alkyl, or heterocycloalkyl, wherein each of the foregoing is independently unsubstituted or substituted with one or more halo,
each R39 is independently (C1-10)alkylene or (C1-10)haloalkylene,
each nl6 is independently an integer from 1 to 5, and
n6 is 0, l, or 2;
R3 are independently selected from the group consisting of hydrogen, halo, cyano, (C1-10)alkyl, (C3-10)cycloalkyl, (C3-10)cycloalkyl(C1-10)alkyl, -OR25, -C(0)NR25R25, -NR25C(0)R25, -NR25C(0)NR25R25, -NR25R25, -S(0)2NR25R25, -NR25S(O)2R25,
-S(O)n7R3°, -NR25C(0)OR25R25, -C(0)OR25, and -C(0)R30,
wherein each (C1-10)alkyl, (C3-10)cycloalkyl, and (C3-10)cycloalkyl(C1-10)alkyl is
independently unsubstituted or substituted with one or more halo,
each R25 is independently hydrogen (C1-10)alkyl, (C3-10)cycloalkyl,
(C3-10)cycloalkyl(C1-10)alkyl, or heterocycloalkyl; or two R25, together with the nitrogen atom to which they are attached, form a heterocycloalkyl; wherein each of the foregoing alkyl, cycloalkyl, or heterocycloalkyl moieties is independently unsubstituted or substituted with one or more halo,
each R30 is independently (C1-10)alkyl, (C3-10)cycloalkyl, (C3-10)cycloalkyl(C1-10)alkyl, or heterocycloalkyl, wherein each of the foregoing is independently unsubstituted or substituted with one or more halo, and
n7 is 0, l, or 2; X1, X2, X3 and X4 are independently CR4 or N, wherein X2, X3 and X4 may not all be N;
when at least one of X1, X2, X3 and X4 is N, each R4 is independently selected from the group consisting of hydrogen, halo, cyano, (C1-10)alkyl, (C3-10)cycloalkyl,
(C3-10)cycloalkyl(C1-10)alkyl, heterocycloalkyl connected by an annular carbon atom, heterocycloalkyl-alkyl, -OR27, -C(0)NR27R27, -S(O)2NR27R27, -S(O)n8R28, -C(0)OR27, and -C(0)R28,
wherein each (C1-10)alkyl, (C3-10)cycloalkyl, (C3-10)cycloalkyl(C1-10)alkyl,
heterocycloalkyl, and heterocycloalkyl-alkyl is independently unsubstituted or substituted with one or more halo, each R27 is independently hydrogen or (C1-10)alkyl, (C3-10)cycloalkyl,
(C3-10)cycloalkyl(C1-10)alkyl, or heterocycloalkyl; or two R27, together with the nitrogen atom to which they are attached, form a
heterocycloalkyl; wherein each of the foregoing alkyl, cycloalkyl, or heterocycloalkyl moieties is independently unsubstituted or substituted with one or more halo,
each R28 is independently (C1-10)alkyl, (C3-10)cycloalkyl,
(C3-10)cycloalkyl(C1-10)alkyl, or heterocycloalkyl, wherein each of the foregoing is independently unsubstituted or substituted with one or more halo,
n8 is 0 , 1 or 2; or
when each of X1, X2, X3 and X4 is CR4, each R4 is independently selected from the group consisting of hydrogen, halo, cyano, (C1-10)alkyl, (C3-10)cycloalkyl,
(C3-10)cycloalkyl(C1-10)alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, -OR27,
-C(0)NR27R27, -NR27C(0)R27, -NR27R27, -NR27S(O)2R27, -S(0)2NR27R27, -S(0)neR28, -C(0)OR27, and -C(0)R28,
wherein each (C1-10)alkyl, (C3-10)cycloalkyl, (C3-10)cycloalkyl(C1-10)alkyl,
heterocycloalkyl, and heterocycloalkyl-alkyl is independently unsubstituted or substituted with one or more halo, each R27 is independently hydrogen, (C1-10)alkyl, (C3-10)cycloalkyl,
(C3-10)cycloalkyl(C1-10)alkyl, or heterocycloalkyl; or two R27, together with the nitrogen atom to which they are attached, form a
heterocycloalkyl; wherein each of the foregoing alkyl, cycloalkyl, or heterocycloalkyl moieties is independently unsubstituted or substituted with one or more halo,
each R28 is independently (C1-10)alkyl, (C3-10)cycloalkyl,
(C3-10)cycloalkyl(C1-10)alkyl, or heterocycloalkyl, wherein each of the foregoing is independently unsubstituted or substituted with one or more halo, and
n8 is 0, 1, or 2; or
two R4 on adjacent annular carbon atoms together with the carbon atoms to which they are attached may form a carbocyclyl or heterocyclyl,
wherein the carbocyclyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, cyano, (C1-10)alkyl, (C3-10)cycloalkyl, (C3-10)cycloalkyl(C1-10)alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, -OR27, -C(0)NR27R27, -NR27C(0)R27, -NR27R27, -S(0)2NR27R27, -NR27S(0)2R27, -S(0)„eR28, and -C(0)R28,
or the heterocyclyl is unsubstituted or substituted with one or more substituents
independently selected from the group consisting of halo, cyano, (C1-10)alkyl, (C3-10)cycloalkyl, (C3-10)cycloalkyl(C1-10)alkyl, heterocycloalkyl connected by an annular carbon atom, heterocycloalkyl-alkyl, -OR27, -C(0)NR27R27, -S(0)2NR27R27, -S(O)reR28, and -C(0)R28,
each R27 is independently hydrogen, (C1-10)alkyl, (C3-10)cycloalkyl,
(C3-10)cycloalkyl(C1-10)alkyl; or two R27, together with the nitrogen atom to which they are attached, form a heterocycloalkyl; wherein each of the foregoing alkyl, cycloalkyl, or heterocycloalkyl moieties is independently unsubstituted or substituted with one or more halo, each R28 is independently (C1-10)alkyl, (C3-10)cycloalkyl, (C3-10)cycloalkyl(C1-10)alkyl, wherein each of the foregoing is independently unsubstituted or substituted with one or more halo, and
n8 is 0, l, or 2;
R15 and R17 are independently hydrogen, halo, alkyl, or -OR29, wherein each R29 is
independently hydrogen, (C1-10)alkyl, (C3-10)cycloalkyl, or (C3-10)cycloalkyl(C1-10)alkyl, and each alkyl or cycloalkyl in R15 or R17, if present, is independently unsubstituted or substituted with one or more halo;
R14 is (C1-10)alkyl, (C1-10)alkenyl, (C3-10)cycloalkyl, (C3-10)cycloalkenyl,
(C3-10)cycloalkyl(C1-10)alkyl, heterocycloalkyl connected through an annular carbon atom, heterocycloalkenyl connected through an annular carbon atom, heterocycloalkyl- alkyl, -OR5, -C(0)NR5R5, -R5C(0)NR5R5, -S(0)2NR5R5, -S(0)n1R6, or -C(0)R6;
R16 is hydrogen, fluoro, (C1-10)alkyl, (C3-10)cycloalkyl, (C3-10)cycloalkyl(C1-10)alkyl,
heterocycloalkyl connected through an annular carbon atom, heterocycloalkyl-alkyl, -OR5, -C(0)NR5R5, -R5C(0)NR5R5, -S(0)2NR5R5, -S(0)„iR6, or -C(0)R6;
wherein the (C1-10)alkyl, (C1-10)alkenyl, (C3-10)cycloalkyl, (C3-10)cycloalkenyl,
(C3-10)cycloalkyl(C1-10)alkyl, heterocycloalkyl, heterocycloalkenyl, or heterocycloalkyl- alkyl of R14 or R16 is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of (C1-10)alkyl, cycloalkyl, heterocycloalkyl, halo, cyano, oxo, -OR7, -C(0)OR7, -C(0)NR7R7, -NR7C(0)R7, -NR7C(0)NR7R7, -NR7R7, -S(0)2NR7R7, -NR7S(O)2R7, -S(O)n2R13, and -C(0)R13;
wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently unsubstituted or substituted with one or more substituents selected from the group consisting of halo, cycloalkyl, halocycloalkyl, heterocycloalkyl, haloheterocycloalkyl, and -(OR33)n1oOR32, wherein each nlO is independently an integer from 0 to 5, each R32 is independently hydrogen, (C1-10)alkyl or (C1-10)haloalkyl, and each R33 is independently (C1-10)alkylene or (C1-10)haloalkylene;
each R5 is independently hydrogen, (C1-10)alkyl, or (C3-10)cycloalkyl; or two R5, together with the nitrogen atom to which they are attached, form a heterocycloalkyl; wherein each alkyl, cycloalkyl, or heterocycloalkyl is independently unsubstituted or substituted with one or more substituents selected from the group consisting of halo, cyano, oxo, alkyl, haloalkyl, -C(0)OR34, -C(0)NR34R34, -NR34C(0)R34, -NR34C(0)NR34R34, -NR34R34,
-S(0)2NR34R34, -NR34S(0)2R34, -S(0)n1iR34, -C(0)R34, and -(OR35)n120R34, wherein each R34 is independently hydrogen, (C1-10)alkyl, or (C1-10)haloalkyl; each nil is
independently 0, 1, or 2; each nl2 is independently an integer from 0 to 5; and each R35 is independently (C1-10)alkylene or (C1-10)haloalkylene;
each R6 is independently (C1-10)alkyl or (C3-10)cycloalkyl, wherein each alkyl or cycloalkyl is independently unsubstituted or substituted with one or more halo;
each nl is independently 0, 1, or 2;
each R7 is independently hydrogen, unsubstituted (C1-10)alkyl, or (C1-10)alkyl substituted with one or more halo;
each n2 is independently 0, 1, or 2,
and each R13 is independently unsubstituted (C1-10)alkyl or (C1-10)alkyl substituted with one or more halo;
or R14 and R15, together with the atoms to which they are attached, form a carbocyclyl or
heterocyclyl,
wherein the carbocyclyl or heterocyclyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, cyano, oxo, (C1-10)alkyl, (C3-10)cycloalkyl, (C3-10)cycloalkyl(C1-10)alkyl, -OR18, -C(0)NR,8R18, -NR18C(0)R18, -NR18C(0)NR18R18, -NR18R18, -S(0)2NR18R18, -NR,8S(0)2R18, -S(0)asR.21, -C(0)OR18, and -C(0)R21,
wherein each (C1-10)alkyl, (C3-10)cycloalkyl, and (C3-10)cycloalkyl(C1-10)alkyl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, alkyl, haloalkyl, cyano, oxo, -C(0)OR36, -C(0)NR36R36, -NR36C(0)R36,
-NR36C(0)NR36R36, -NR36R36, -S(0)2NR36R36, -NR36S(0)2R36,
-S(O)n13R36, -C(0)R36, and -(OR37)n140R36, wherein each R36 is independently hydrogen, (C1-10)alkyl, or (C1-10)haloalkyl; each nl3 is independently 0, 1, or 2; each nl4 is independently an integer from 0 to 5; and each R37 is independently (C1-10)alkylene or (C1-10)haloalkylene; wherein each R18 is independently hydrogen, (C1-10)alkyl, or (C3-10)cycloalkyl; or two R18, together with the nitrogen atom to which they are attached, form a heterocycloalkyl; wherein each alkyl, cycloalkyl, or heterocycloalkyl is independently unsubstituted or substituted with one or more halo; each R21 is independently (C1-10)alkyl or (C3-10)cycloalkyl, wherein each alkyl or
cycloalkyl is independently unsubstituted or substituted with one or more halo; and
each n3 is independently 0, 1, or 2.
Claim 2. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R1 is -C(0)OR9, -C(0)NR8R9, -S(O)2NR8R9,
-NR10C(O)NR8R9, -NR10C(O)R9, -NR10S(O)2R9, -OR26, -SR9, -S(0)R9, -S(0)2R9, -NR'fc9, or -NR10C(O)OR9.
Claim 3. The compound of claim 1 or 2, wherein the compound is of Formula (X-A):
Figure imgf000315_0001
or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R1, R2, R3, R14, R15, R16, R17, X1, X2, X3, and X4 are as defined for Formula (X).
Claim 4. The compound of claim 1 or 2, wherein the compound is of Formula (X-B):
Figure imgf000316_0001
or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R1, R2, R3, R14, R15, R16, R17, X1, X2, X3, and X4 are as defined for Formula (X).
Claim 5. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R17 is hydrogen.
Claim 6. The compound of any one of claims 1 , or 3 to 5, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R1 is -C(0)OR9, -C(0)NR8R9,
-S(0)2NR8R9, -NR10QOJNR8R9, -NR10S(O)2R9, -NR10C(O)OR9, -C(0)R26, -NR10S(O)2NR8R9, or -C(0)NR8S(O)2R9.
Claim 7. The compound of any one of claims 1 , or 3 to 6, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R1 is -C(0)NR8R9, -S(O)2NR8R9, -NR10C(O)OR9, -NR10S(O)2R9, or -NR10SiO^NR8R9.
Claim 8. The compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R1 is -C(0)NR8R9.
Claim 9. The compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R1 is -NR10C(O)OR9.
Claim 10. The compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R1 is -NR^S(O)^9.
Claim 11. The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R10 is hydrogen.
Claim 12. The compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R8 is hydrogen.
Claim 13. The compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R9 is hydrogen, (C1-10)alkyl,
(C3-10)cycloalkyl, or heterocycloalkyl-alkyl.
Claim 14. The compound of claim 13, wherein R9 is unsubstituted methyl, ethyl, propyl, or cyclopropyl.
Claim 15. The compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R1 is -C(0)NR8R9, and the R8 and R9 together with the nitrogen to which they are attached form an unsubstituted or substituted heterocycloalkyl.
Claim 16. The compound of claim 15, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein the heterocycloalkyl is a 4- to 8- membered heterocycloalkyl.
Claim 17. The compound of any one of claims 1 to 7, or 15, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R1 is -C(O)NR^9, and the R8 and R9 together with the nitrogen to which they are attached form an unsubstituted or substituted piperidinyl.
Claim 18. The compound of claim 16 or 17, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein the substituents are independently selected from the group consisting of halo, oxo, (C1-10)alkyl, -OR23, -C(0)OR23, and -NR23C(0)OR23, wherein each (C1-10)alkyl is unsubstituted or substituted with -OR31.
Claim 19. The compound of claim 17, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein the piperidinyl is substituted with one to three substituents independently selected from the group consisting of -OR23, (C1-10)alkyl, -C(0)OR23, and
-NR23C(0)OR23.
Claim 20. The compound of claim 19, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R23 is independently hydrogen or (C1-10)alkyl.
Claim 21. The compound of any one of claims 1 to 20, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R2 is halo or alkyl.
Claim 22. The compound of any one of claims 1 to 21, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein one of X1, X2, X3, and X4 is N.
Claim 23. The compound of any one of claims 1 to 21, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein X1, X2, and X4 are CR4, and X3 is N.
Claim 24. The compound of any one of claims 1 to 21, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein two of X1, X2, X3, and X4 are N.
Claim 25. The compound of any one of claims 1 to 21, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein each of X1, X2, X3 and X4 is CR4.
Claim 26. The compound of any one of claims 1 to 25, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein each R4 is independently selected from the group consisting of hydrogen, halo, cyano, (C1-10)alkyl, and -OR27.
Claim 27. The compound of any one of claims 1 to 25, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein X1 is CR4, wherein R4 is hydrogen, halo, or methyl.
Claim 28. The compound of any one of claims 1 to 27, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R14 is (C1-10)alkyl or heterocycloalkyl connected through an annular carbon atom, wherein the alkyl or heterocycloalkyl is
unsubstituted or substituted with one to three substituents selected from the group consisting of (C1-10)alkyl, halo, -C(0)OR7, oxo, and -OR5.
Claim 29. The compound of claim 28, or a or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R14 is (C1-10)alkyl unsubstituted or substituted with one to three substituents selected from the group consisting of (C1-10)alkyl, halo, -C(0)OR7, oxo, and -OR5.
Claim 30. The compound of any one of claims 1 to 27, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R14 is unsubstituted (C3-10)cycloalkyl or (C3-10)halocycloalkyl.
Claim 31. The compound of any one of claims 1 to 30, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R15, R16, and R17 are hydrogen.
Claim 32. The compound of any one of claims 1 to 27, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R14 and R15, together with the atoms to which they are attached, form a heterocyclyl.
Claim 33. The compound of any one of claims 1 to 22, or 28 to 32, wherein at least one of X2, X3 and X4 is N, and an adjacent annular carbon is bonded to R4, wherein the R4 is independently hydrogen, fluoro, cyano, (C1-10)alkyl, or -OR27.
Claim 34. The compound of any one of claims 1 to 33, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R3 is hydrogen.
Claim 35. The compound of any one of claims 1 to 33, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R3 is halo or alkyl.
Claim 36. The compound of any one of claims 1 to 35, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R2 is halo or alkyl.
Claim 37. The compound of any one of claims 1 to 35, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R2 is chloro.
Claim 38. The compound of any one of claims 1 to 37, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein when one or more of R4, R5, R8, R9, R10, R14, R16, R19, R20, R23, R24, R25, R26, R27, R28, and R30 is heterocycloalkyl; or wherein R8 and R9, together with the nitrogen atom to which they are attached, form a heterocycloalkyl; or wherein two R18, together with the nitrogen atom to which they are attached; or wherein two R19, together with the nitrogen to which they are attached, form a heterocycloalkyl; or wherein two R25, together with the nitrogen to which they are attached, form a heterocycloalkyl; or wherein two R27, together with the nitrogen to which they are attached, form a heterocycloalkyl; each heterocycloalkyl is independently a 3- to 10-membered heterocycloalkyl.
Claim 39. The compound of any one of claims 1 to 38, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein when one or more of R4, R8, R9, R10, R14, R16, and R26 is heterocycloalkyl-alkyl, each heterocycloalkyl-alkyl is independently (3-10 membered)heterocycloalkyl(C1-10)alkyl.
Claim 40. The compound of any one of claims 1 to 39, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein when one or more of R8, R9, R10, and R26 is heteroaryl, each heteroaryl is independently a 5- to 10-membered heteroaryl.
Claim 41. The compound of any one of claims 1 to 40, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein when one or more of R8, R9, R10, and R26 is heteroaryl-alkyl, each heteroaryl-alkyl is independently a (5-10 membered)heteroaryl(C1-10)alkyl.
Claim 42. The compound of any one of claims 1 to 41, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein two R4 on adjacent annular carbon atoms together with the carbon atoms to which they are attached form a carbocyclyl; or wherein R14 and R15 together with the atoms to which they are attached form a carbocyclyl; each carbocyclyl, is independently a (C3-Ce)carbocyclyl.
Claim 43. The compound of any one of claims 1 to 42, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein two R4 on adjacent annular carbon atoms together with the carbon atoms to which they are attached form a heterocyclyl; or wherein R14 and R15 together with the atoms to which they are attached form a heterocyclyl; each
heterocyclyl is independently a 4- to 8-membered heterocyclyl.
Claim 44. The compound of any one of claims 1 to 43, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein when R14 or R16 is heterocycloalkenyl, each heterocycloalkenyl is independently a 3- to 8-membered heterocyloalkenyl.
Claim 45. The compound of any one of claims 1 to 3, or 5 to 44, wherein the compound is of Formula (X-Ai):
Figure imgf000321_0001
or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R1, R2, R3, R14, R15, R16, R17, X1, X2, X3, and X4 are as defined for Formula (X).
Claim 46. The compound of any one of claims 1, 2, or 4 to 44, wherein the compound is of Formula (X-Bi):
Figure imgf000321_0002
or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R1, R2, R3, R14, R15, R16, R17, X1, X2, X3, and X4 are as defined for Formula (X).
Claim 47. The compound of claim 1, selected from the group consisting of:
Figure imgf000322_0001
Figure imgf000323_0001
Figure imgf000324_0001
Figure imgf000325_0001
Figure imgf000326_0001
isotope, or isomer of any of the foregoing.
Claim 48. The compound of claim 1, selected from the group consisting of:
Figure imgf000326_0002
Figure imgf000327_0001
Figure imgf000328_0001
N— ' N , or a pharmaceutically acceptable salt, solvate, tautomer, pe, or isomer of any of the foregoing.
Claim 49. The compound of claim 1, selected from the group consisting of:
Figure imgf000328_0002
Figure imgf000329_0001
Figure imgf000330_0001
Figure imgf000331_0001
F , or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer of any of the foregoing.
Claim 50. The compound of claim 1, selected from the group consisting of:
Figure imgf000331_0002
Figure imgf000332_0001
or isomer of any of the foregoing.
Claim SI. A pharmaceutical composition, comprising the compound of any one of claims 1 to SO, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, and a pharmaceutically acceptable excipient.
Claim 52. A method of inhibiting a sterol regulatory element-binding protein (SREBP), comprising contacting the SREBP or contacting an SREBP cleavage activating-protein (SCAP) with a compound of any one of claims 1 to SO, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or the pharmaceutical composition of claim SI.
Claim 53. A method of inhibiting the proteolytic activation of a sterol regulatory element- binding protein (SREBP), comprising contacting an SREBP cleavage activating-protein (SCAP) with a compound of any one of claims 1 to SO, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or the pharmaceutical composition of claim SI.
Claim 54. The method of claim 52 or 53, wherein the SREBP is an SREBP-1.
Claim 55. The method of claim 54, wherein the SREBP-1 is SREBP-la.
Claim 56. The method of claim 54, wherein the SREBP-1 is SREBP-1 c.
Claim 57. The method of claim 52 or 53, wherein the SREBP is SREBP-2.
Claim 58. The method of any one of claims 52 to 57, wherein SREBP is inhibited in a subject in need thereof.
Claim 59. The method of any one of claims 52 to 58, wherein SCAP is inhibited in a subject in need thereof.
Claim 60. The method of any one of claims 52 to 59, wherein the expression of one or more genes selected from the group consisting of ACSS2, ALDOC, CYP51A1, DHCR7, ELOVL6, FASN, FDFT1, FDPS, HMGCS1, HSD17B7, IDI1, INSIG1, LDLR, LSS, ME1, PCSK9, PMVK, RDH11, SC5DL, SQLE, STARD4, TM7SF2, PNPLA3, SREBF1, SREBF2, HMGCR, MVD, MVK, ACLY, MSMOl, ACACA, and ACACB is reduced after contacting the SREBP or SCAP with the compound, or pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or the pharmaceutical composition.
Claim 61. A method of treating a disorder in a subject in need thereof, comprising administering to the subject in need thereof an effective amount of a compound of any one of claims 1 to 50, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or the pharmaceutical composition of claim 51.
Claim 62. A method of treating a disorder in a subject in need thereof, wherein the disorder is mediated by a sterol regulatory element-binding protein (SREBP), comprising administering to the subject in need thereof an effective amount of a compound of any one of claims 1 to 50, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or the pharmaceutical composition of claim 51.
Claim 63. The method of claim 61 or 62, wherein the disorder is Metabolic Syndrome, type 2 diabetes, obesity, liver disease, insulin resistance, adiposopathy, or dyslipidemia.
Claim 64. The method of claim 63, wherein the dyslipidemia is hypertriglyceridemia or elevated cholesterol levels.
Claim 65. The method of claim 63, wherein the liver disease is nonalcoholic steatohepatitis, liver fibrosis, or liver inflammation, or a combination thereof.
Claim 66. The method of claim 61 or 62, wherein the disorder is a hyperproliferative disorder.
Claim 67. The method of claim 66, wherein the hyperproliferative disorder is cancer.
Claim 68. The method of claim 67, wherein the cancer is breast cancer, liver cancer, ovarian cancer, pancreatic cancer, or prostate cancer.
Claim 69. The method of claim 61 or 62, wherein the disorder is endotoxic shock, systemic inflammation, or atherosclerosis.
Claim 70. Use of a compound of any one of claims 1 to 50, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, in the manufacture of a medicament for use in treating a disorder in a subject in need thereof.
Claim 71. Use of a compound of any one of claims 1 to 50, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, in the manufacture of a medicament for use in inhibiting a sterol regulatory element-binding protein (SREBP) in a subject in need thereof.
Claim 72. Use of a compound of any one of claims 1 to 50, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, in the manufacture of a medicament for use in inhibiting the proteolytic activation of a sterol regulatory element-binding protein (SREBP) in a subject in need thereof.
Claim 73. Use of a compound of any one of claims 1 to 50, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, in the manufacture of a medicament for use in treating a disorder in a subject in need thereof, wherein the disorder is mediated by a sterol regulatory element-binding protein (SREBP).
Claim 74. Use of a compound of any one of claims 1 to 50, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or the pharmaceutical composition of claim 51, for inhibiting a sterol regulatory element-binding protein (SREBP).
Claim 75. Use of a compound of any one of claims 1 to 50, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or the pharmaceutical composition of claim 51, for inhibiting an SREBP cleavage activating protein (SCAP).
Claim 76. The use of any one of claims 71 to 75, wherein the SREBP is an SREBP- 1.
Claim 77. The use of claim 76, wherein the SREBP- 1 is SREBP- la.
Claim 78. The use of claim 76, wherein the SREBP-1 is SREBP-lc.
Claim 79. The use of any one of claims 71 to 75, wherein the SREBP is SREBP-2.
Claim 80. The use of any one of claims 71 to 75, wherein SREBP is inhibited in a subject in need thereof.
Claim 81. The use of any one of claims 71 to 75, wherein SCAP is inhibited in a subject in need thereof.
Claim 82. Use of a compound of any one of claims 1 to 50, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or the pharmaceutical composition of claim 51, for treating a disorder in a subject in need thereof.
Claim 83. Use of a compound of any one of claims 1 to 50, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or the pharmaceutical composition of claim 51, for treating a disorder in a subject in need thereof, wherein the disorder is mediated by a sterol regulatory element-binding protein (SREBP).
Claim 84. The use of claim 82 or 83, wherein the disorder is Metabolic Syndrome, type 2 diabetes, obesity, liver disease, insulin resistance, adiposopathy, or dyslipidemia.
Claim 85. The use of claim 84, wherein the dyslipidemia is hypertriglyceridemia or elevated cholesterol levels.
Claim 86. The use of claim 84, wherein the liver disease is nonalcoholic steatohepatitis, liver fibrosis, or liver inflammation, or a combination thereof.
Claim 87. The use of claim 82 or 83, wherein the disorder is a hyperproliferative disorder.
Claim 88. The use of claim 87, wherein the hyperproliferative disorder is cancer.
Claim 89. The use of claim 88, wherein the cancer is breast cancer, liver cancer, ovarian cancer, pancreatic cancer, or prostate cancer.
Claim 90. The use of claim 82 or 83, wherein the disorder is endotoxic shock, systemic inflammation, or atherosclerosis.
Claim 91. A method of treating non-alcoholic steatohepatitis (NASH) in a subject in need thereof, comprising administering to the subject in need thereof an effective amount of a compound of any one of claims 1 to SO, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or the pharmaceutical composition of claim 51.
Claim 92. Use of a compound of any one of claims 1 to SO, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or the pharmaceutical composition of claim SI, for treating non-alcoholic steatohepatitis (NASH) in a subject in need thereof.
Claim 93. Use of a compound of any one of claims 1 to 50, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, in the manufacture of a medicament for use in treating non-alcoholic steatohepatitis (NASH) in a subject in need thereof.
Claim 94. A method of treating a hyperproliferative disorder in a subject in need thereof, comprising administering to the subject in need thereof an effective amount of a compound of any one of claims 1 to 50, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or the pharmaceutical composition of claim 51.
Claim 95. Use of a compound of any one of claims 1 to 50, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or the pharmaceutical composition of claim 51, for treating a hyperproliferative disorder in a subject in need thereof.
Claim 96. Use of a compound of any one of claims 1 to 50, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, in the manufacture of a medicament for use in treating a hyperproliferative disorder in a subject in need thereof.
PCT/US2019/015458 2018-01-29 2019-01-28 Srebp inhibitors comprising a 6-membered central ring WO2019148125A1 (en)

Priority Applications (12)

Application Number Priority Date Filing Date Title
BR112020015375-3A BR112020015375A2 (en) 2018-01-29 2019-01-28 SREBP INHIBITORS UNDERSTANDING A SIX MEMBER CENTRAL RING
EA202091848A EA202091848A1 (en) 2018-10-11 2019-01-28 SREBP INHIBITORS CONTAINING 6-MEMBER CENTER RING
AU2019212959A AU2019212959A1 (en) 2018-01-29 2019-01-28 SREBP inhibitors comprising a 6-membered central ring
KR1020207024962A KR20200128531A (en) 2018-01-29 2019-01-28 SREBP inhibitors containing a six-membered central ring
CN201980023901.3A CN112243374A (en) 2018-01-29 2019-01-28 SREBP inhibitors comprising a 6-membered central ring
CA3089134A CA3089134A1 (en) 2018-01-29 2019-01-28 Srebp inhibitors comprising a 6-membered central ring
EP19743447.5A EP3746070A4 (en) 2018-01-29 2019-01-28 Srebp inhibitors comprising a 6-membered central ring
JP2020562085A JP2021512160A (en) 2018-01-29 2019-01-28 SREBP inhibitor containing 6-membered central ring
SG11202006853PA SG11202006853PA (en) 2018-01-29 2019-01-28 Srebp inhibitors comprising a 6-membered central ring
MX2020007956A MX2020007956A (en) 2018-01-29 2019-01-28 Srebp inhibitors comprising a 6-membered central ring.
IL276276A IL276276A (en) 2018-01-29 2020-07-26 Srebp inhibitors comprising a 6-membered central ring
US16/940,212 US11718628B2 (en) 2018-01-29 2020-07-27 SREBP inhibitors comprising a 6-membered central ring

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US201862623405P 2018-01-29 2018-01-29
US62/623,405 2018-01-29
US201862744397P 2018-10-11 2018-10-11
US62/744,397 2018-10-11

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US16/940,212 Continuation US11718628B2 (en) 2018-01-29 2020-07-27 SREBP inhibitors comprising a 6-membered central ring

Publications (1)

Publication Number Publication Date
WO2019148125A1 true WO2019148125A1 (en) 2019-08-01

Family

ID=67395734

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2019/015458 WO2019148125A1 (en) 2018-01-29 2019-01-28 Srebp inhibitors comprising a 6-membered central ring

Country Status (13)

Country Link
US (1) US11718628B2 (en)
EP (1) EP3746070A4 (en)
JP (1) JP2021512160A (en)
KR (1) KR20200128531A (en)
CN (1) CN112243374A (en)
AU (1) AU2019212959A1 (en)
BR (1) BR112020015375A2 (en)
CA (1) CA3089134A1 (en)
IL (1) IL276276A (en)
MX (1) MX2020007956A (en)
SG (1) SG11202006853PA (en)
TW (1) TW201940165A (en)
WO (1) WO2019148125A1 (en)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111139294A (en) * 2020-01-06 2020-05-12 中国药科大学 Application of FDPS (fully drawn protein) in preparation of drug for treating non-alcoholic steatohepatitis
WO2021097123A1 (en) * 2019-11-13 2021-05-20 Capulus Therapeutics, Llc Thiophene compounds with cyclic amides, and uses thereof
WO2022020738A1 (en) * 2020-07-24 2022-01-27 Capulus Therapeutics, Llc Srebp inhibitors comprising a thiophene central ring
US11504390B2 (en) 2019-03-20 2022-11-22 Regeneron Pharmaceuticals, Inc. Treatment of increased lipid levels with sterol regulatory element binding transcription factor 1 (SREBF1) inhibitors
US11718628B2 (en) 2018-01-29 2023-08-08 Capulus Therapeutics, Llc SREBP inhibitors comprising a 6-membered central ring

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110628737B (en) * 2019-10-14 2022-06-07 南京农业大学 Related gene for regulating cucumber dwarfing character and application thereof

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090042908A1 (en) * 2005-06-30 2009-02-12 Wyeth Amino-5-(6-membered)heteroarylimidazolone compounds and the use thereof for beta-secretase modulation
US20150249215A1 (en) * 2012-09-14 2015-09-03 Idemitsu Kosan Co., Ltd. Polymer compound, material for electronic elements, material for organic electroluminescent elements, and organic electroluminescent element

Family Cites Families (33)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6291514B1 (en) 1998-02-09 2001-09-18 3-Dimensional Pharmaceuticals, Inc. Heteroaryl amidines, methylamidines and guanidines, preparation thereof, and use thereof as protease inhibitors
CN101468965A (en) * 2003-03-24 2009-07-01 默克公司 Biaryl substituted 6-membered heterocyles as sodium channel blockers
ES2525217T3 (en) 2005-06-27 2014-12-19 Exelixis Patent Company Llc LXR modulators based on imidazole
TW200825054A (en) * 2006-10-18 2008-06-16 Wyeth Corp Quinoline compounds
GB0625659D0 (en) * 2006-12-21 2007-01-31 Cancer Rec Tech Ltd Therapeutic compounds and their use
US9233941B2 (en) 2007-02-02 2016-01-12 Baylor College Of Medicine Methods and compositions for the treatment of body weight related disorders
US20160221999A1 (en) 2007-02-02 2016-08-04 Baylor College Of Medicine Compositions and methods for the treatment of metabolic disorders
US8207196B2 (en) 2007-02-02 2012-06-26 Baylor College Of Medicine Compositions and methods for the treatment of metabolic disorders
US9212179B2 (en) 2007-02-02 2015-12-15 Baylor College Of Medicine Compositions and methods for the treatment of metabolic disorders
US8343966B2 (en) 2008-01-11 2013-01-01 Novartis Ag Organic compounds
EP2269993B1 (en) * 2008-04-23 2013-02-27 Kyowa Hakko Kirin Co., Ltd. 2-aminoquinazoline derivative
EP2405913A1 (en) 2009-03-09 2012-01-18 Bristol-Myers Squibb Company Pyridone analogs useful as melanin concentrating hormone receptor-1 antagonists
JP5970003B2 (en) 2011-03-04 2016-08-17 ローカス ファーマシューティカルズ インコーポレイテッド Aminopyrazine compounds
HUE031624T2 (en) * 2012-01-31 2017-07-28 Daiichi Sankyo Co Ltd Pyridone derivative
WO2013162061A1 (en) * 2012-04-26 2013-10-31 第一三共株式会社 Bicyclic pyrimidine compound
CN103405429A (en) * 2013-08-22 2013-11-27 中国药科大学 VEGFR-2 (Vascular Endothelial Growth Factor Receptor-2) inhibitors and use thereof
KR20160067841A (en) * 2013-08-28 2016-06-14 메디베이션 테크놀로지즈, 인크. Heterocyclic compounds and methods of use
SI3063143T1 (en) 2013-11-01 2018-09-28 Novartis Ag, Aminoheteroaryl benzamides as kinase inhibitors
PL3134396T3 (en) * 2014-04-24 2020-04-30 Novartis Ag Amino pyridine derivatives as phosphatidylinositol 3-kinase inhibitors
TWI723572B (en) * 2014-07-07 2021-04-01 日商第一三共股份有限公司 Pyridone derivatives containing tetrahydropyranylmethyl group and use thereof
WO2016073826A1 (en) 2014-11-07 2016-05-12 Fgh Biotech, Inc. Synthesis of fatostatin based polycyclic compounds
EP3237413A4 (en) * 2014-12-23 2018-09-12 FGH Biotech Compositions of fatostatin based heterocyclic compounds and uses thereof
CA2977539A1 (en) 2015-03-04 2016-09-09 Medivation Technologies, Inc. Sterol regulatory element-binding proteins (srebps) inhibitors
EP3265088A1 (en) * 2015-03-04 2018-01-10 Medivation Technologies LLC Srebp blockers for use in treating liver fibrosis, elevated cholesterol and insulin resistance
KR102498741B1 (en) * 2016-04-29 2023-02-10 에프지에이치 바이오테크 인코포레이티드 Di-substituted pyrazole compounds for the treatment of disease
TWI831738B (en) 2016-12-16 2024-02-11 美商瑞塔醫藥有限責任公司 PYRIMIDINE TRICYCLIC ENONE DERIVATIVES FOR INHIBITION OF RORγ AND OTHER USES
CA3080818A1 (en) 2017-10-30 2019-05-09 Montreal Heart Institute Methods of treating elevated plasma cholesterol
JP7446236B2 (en) * 2017-12-22 2024-03-08 ラヴェンナ ファーマシューティカルズ，インコーポレイテッド Aryl-bipyridine amine derivatives as phosphatidylinositol phosphate kinase inhibitors
AU2019212959A1 (en) 2018-01-29 2020-09-17 Capulus Therapeutics, Llc SREBP inhibitors comprising a 6-membered central ring
WO2020132700A1 (en) 2018-12-21 2020-06-25 Fgh Biotech Inc. Methods of using inhibitors of srebp in combination with niclosamide and analogs thereof
CN113631163A (en) 2019-01-28 2021-11-09 卡普勒斯疗法有限责任公司 SREBP inhibitors comprising a thiophene central ring
BR112021014466A2 (en) 2019-02-11 2021-09-21 Merck Patent Gmbh INDAZOLYL-ISOXAZOLE DERIVATIVES FOR THE TREATMENT OF DISEASES SUCH AS CANCER
KR20220128335A (en) 2019-11-13 2022-09-20 카풀루스 테라퓨틱스, 엘엘씨 SREBP Inhibitors Containing a Thiophene Central Ring

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090042908A1 (en) * 2005-06-30 2009-02-12 Wyeth Amino-5-(6-membered)heteroarylimidazolone compounds and the use thereof for beta-secretase modulation
US20150249215A1 (en) * 2012-09-14 2015-09-03 Idemitsu Kosan Co., Ltd. Polymer compound, material for electronic elements, material for organic electroluminescent elements, and organic electroluminescent element

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
DATABASE PUBCHEM [online] 12 February 2015 (2015-02-12), XP055630165, Database accession no. 226703021 *
See also references of EP3746070A4 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11718628B2 (en) 2018-01-29 2023-08-08 Capulus Therapeutics, Llc SREBP inhibitors comprising a 6-membered central ring
US11504390B2 (en) 2019-03-20 2022-11-22 Regeneron Pharmaceuticals, Inc. Treatment of increased lipid levels with sterol regulatory element binding transcription factor 1 (SREBF1) inhibitors
WO2021097123A1 (en) * 2019-11-13 2021-05-20 Capulus Therapeutics, Llc Thiophene compounds with cyclic amides, and uses thereof
CN111139294A (en) * 2020-01-06 2020-05-12 中国药科大学 Application of FDPS (fully drawn protein) in preparation of drug for treating non-alcoholic steatohepatitis
WO2022020738A1 (en) * 2020-07-24 2022-01-27 Capulus Therapeutics, Llc Srebp inhibitors comprising a thiophene central ring

Also Published As

Publication number Publication date
EP3746070A1 (en) 2020-12-09
IL276276A (en) 2020-09-30
BR112020015375A2 (en) 2020-12-08
KR20200128531A (en) 2020-11-13
AU2019212959A1 (en) 2020-09-17
US11718628B2 (en) 2023-08-08
SG11202006853PA (en) 2020-08-28
JP2021512160A (en) 2021-05-13
CN112243374A (en) 2021-01-19
US20210047340A1 (en) 2021-02-18
TW201940165A (en) 2019-10-16
EP3746070A4 (en) 2021-09-01
MX2020007956A (en) 2021-01-08
CA3089134A1 (en) 2019-08-01

Similar Documents

Publication Publication Date Title
AU2019212959A1 (en) SREBP inhibitors comprising a 6-membered central ring
US11649233B2 (en) Halo-allylamine SSAO/VAP-1 inhibitor and use thereof
ES2605388T3 (en) Trk inhibitor compound
ES2320930T3 (en) DIPIRIDIL-DIHIDROPIRAZOLONAS AND ITS USE OF DERIVATIVES OF 4- (PIRIDIN-3-IL) -2- (PIRIDIN-2-IL) -1,2-DIHIDRO-3H-PIRAZOL-3-ONA AS SPECIFIC INHIBITORS OF HIF-PROLIL- 4-HYDROXYLASES FOR THE TREATMENT OF CARDIOVASCULAR AND HEMATOLOGICAL DISEASES.
NZ586916A (en) Novel pyridinones and pyridazinones
CA2872110A1 (en) Nitrogenous heterocyclic derivatives and their application in drugs
ES2462522T3 (en) Substituted heterocyclylbenzylpyrazoles and use thereof
CA2700088A1 (en) Quinolone derivative
WO2020159889A1 (en) Srebp inhibitors comprising a thiophene central ring
KR20210027395A (en) Immunomodulatory compounds
CN111484491B (en) Substituted pyrido-cyclic compounds, process for their preparation and their use
US20210017187A1 (en) Heterocyclic compounds, preparation methods therefor, and methods of uses thereof
EP3247705A1 (en) Quinazoline and quinoline compounds and uses thereof
WO2015162456A1 (en) Amino pyridine derivatives as phosphatidylinositol 3-kinase inhibitors
WO2021097123A1 (en) Thiophene compounds with cyclic amides, and uses thereof
CN117143039A (en) Benzo five-membered nitrogen ring compound, preparation method and medical application thereof
WO2023215803A2 (en) Cytochrome bd oxidase inhibitors and uses thereof
EP4096659A1 (en) Srebp inhibitors comprising a thiophene central ring
EP4185584A1 (en) Srebp inhibitors comprising a thiophene central ring
CN110724076B (en) Para-aryldiamide compound, pharmaceutical composition containing same, preparation method and application thereof
NZ746586A (en) Pyridinyl derivatives, pharmaceutical compositions and uses thereof as aoc3 inhibitors

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: 19743447

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 3089134

Country of ref document: CA

ENP Entry into the national phase

Ref document number: 2020562085

Country of ref document: JP

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 2019743447

Country of ref document: EP

Effective date: 20200831

ENP Entry into the national phase

Ref document number: 2019212959

Country of ref document: AU

Date of ref document: 20190128

Kind code of ref document: A

REG Reference to national code

Ref country code: BR

Ref legal event code: B01A

Ref document number: 112020015375

Country of ref document: BR

ENP Entry into the national phase

Ref document number: 112020015375

Country of ref document: BR

Kind code of ref document: A2

Effective date: 20200728