WO2023192375A1 - Inhibiteurs de hsd17b13 et leurs utilisations - Google Patents

Inhibiteurs de hsd17b13 et leurs utilisations Download PDF

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WO2023192375A1
WO2023192375A1 PCT/US2023/016719 US2023016719W WO2023192375A1 WO 2023192375 A1 WO2023192375 A1 WO 2023192375A1 US 2023016719 W US2023016719 W US 2023016719W WO 2023192375 A1 WO2023192375 A1 WO 2023192375A1
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compound
solvate
pharmaceutically acceptable
acceptable salt
formula
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PCT/US2023/016719
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English (en)
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Johnny Y. Nagasawa
Andiliy G. Lai
Iriny Botrous
Andrew R. Hudson
Steven P. Govek
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Fl2022-001, Inc.
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Publication of WO2023192375A1 publication Critical patent/WO2023192375A1/fr

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    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems

Definitions

  • HSD17B13 INHIBITORS AND USES THEREOF CROSS-REFERENCE [0001]
  • This application claims benefit of U.S. Provisional Patent Application No. 63/325,048, filed on March 29, 2022 which is incorporated herein by reference in its entirety.
  • FIELD OF THE INVENTION [0002] 8IUGTMFIH LITIMQ ETI GRPSRWQHU VLEV ETI L[HTRZ[UVITRMH *0a&HIL[HTRKIQEUI *, (HSD17B13) inhibitors, methods of making such compounds, pharmaceutical compositions and medicaments comprising such compounds, and methods of using such compounds in the treatment of conditions, diseases, or disorders associated with HSD17B13 activity.
  • HSD17b13 Hydroxysteroid dehydrogenase 17f13
  • HSD17b13 Hydroxysteroid dehydrogenase 17f13
  • retinol steroids
  • bio-active lipids like leukotriene B4.
  • Loss of HSD17b13 expression and enzymatic activity is associated with decreased incidence of liver disease.
  • Inhibition of HSD17b13 enzymatic activity can be used for the treatment of liver diseases that result in hepatic inflammation, fibrosis, cirrhosis, and development of hepatocellular carcinoma.
  • X 1 , X 2 , and X 3 are each independently CR 3 or N; Y 1 is CR 4 or N; Y 2 is N(R 9 ), O, S, or C(R 4 ) 2 ; Y 3 is CR 4 or N; Y 4 is C(O), C(R 4 )2, N(R 8 ), O, or S; Y 5 is C(O), C(R 4 )2, or N(R 8 ), wherein at least one of Y 4 and Y 5 is C(O); Z 1 , Z 2 , Z 3 , and Z 4 are each independently CR 5 or N; L 1 is selected from a bond, -O-, -N(R 10a )-, -C(O)-, -S-, -S(O)-, -S(O)2-, - C(O)N(R 10a )-, -N(R 10a )C(O)-, -C(R 10 )(R 11 )
  • a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof having the structure of Formula (Ia): Formula (Ia).
  • Formula (Ia) In some embodiments is a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein L 1 is a -N(R 10a )-.
  • R 10a is hydrogen.
  • R 10a is C1-6alkyl optionally substituted with one, two, or three groups selected from halogen, - CN, hydroxy, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl.
  • R 10a is -CH3.
  • R 1 is a fused bicyclic C2-9heterocycloalkyl optionally substituted with one, two, or three R 6 , wherein the fused bicyclic C2-9heterocycloalkyl is a heterocycloalkyl ring fused with a phenyl ring.
  • R 1 is a fused bicyclic C2-9heterocycloalkyl optionally substituted with one, two, or three R 6 , wherein the fused bicyclic C2-9heterocycloalkyl is a heterocycloalkyl ring fused with a heteroaryl ring.
  • a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof wherein R 1 is a fused bicyclic C 2- 9 heterocycloalkyl optionally substituted with one, two, or three R 6 , wherein the fused bicyclic C 2-9 heterocycloalkyl is a heterocycloalkyl ring fused with a second heterocycloalkyl ring.
  • R 1 is a fused bicyclic C3- 10cycloalkyl optionally substituted with one, two, or three R 6 .
  • R 1 is a fused bicyclic C3-10cycloalkyl optionally substituted with one, two, or three R 6 , wherein the fused bicyclic C3-10cycloalkyl is a cycloalkyl ring fused with a phenyl ring.
  • each R 6 is independently selected from halogen, oxo, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1- 9 heteroaryl, -OR 10 , -N(R 10 )(R 11 ), -C(O)OR 10 , -N(R 12 )C(O)R 13 , -N(R 12 )C(O)OR 13 , - N(R 12 )S(O) 2 R 13 , -C(O)R 13 , -C(O)N(R 10 )(R 11 ), -S(O) 2 R 13 , and -S(O) 2 N(R 10 )(R 11 )-, wherein C 1-6 alkyl, C 3-6 cycloalkyl, C 2
  • each R 6 is independently selected from halogen, oxo, C1-6alkyl, C1-6haloalkyl, C6-10aryl, C1- 9heteroaryl, -OR 10 , -C(O)OR 10 , -C(O)N(R 10 )(R 11 ), and -S(O)2R 13 , wherein C1-6alkyl, C6- 10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C 1-6 alkyl, and C 1-6 haloalkyl.
  • a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof wherein R 1 is an unsubstituted fused bicyclic C 2-9 heterocycloalkyl.
  • a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof wherein R 1 is an unsubstituted fused bicyclic C3-10cycloalkyl.
  • R 1 is naphthyl optionally substituted with one, two, or three R 7 .
  • a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof Formula (II); wherein: X 1 , X 2 , and X 3 are each independently CR 3 or N; Y 1 is CR 4 or N; Y 2 is N(R 9 ), O, S, or C(R 4 ) 2 ; Y 3 is CR 4 or N; Y 4 is C(O), C(R 4 )2, N(R 8 ), O, or S; Y 5 is C(O), C(R 4 )2, or N(R 8 ), wherein at least one of Y 4 and Y 5 is C(O); Z 1 , Z 2 , Z 3 , and Z 4 are each independently CR 5 or N; L 1a is selected from a bond, -C(O)-, and -C(R 10 )(R 11 )-; R 1a is selected from: a) a monocyclic C2-5heterocycl
  • each R 6a is independently selected from halogen, -CN, oxo, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9 heterocycloalkyl, C 6-10 aryl, C 1-9 heteroaryl, -OR 10 , -SR 10 , -N(R 10 )(R 11 ), -C(O)OR 10 , - OC(O)N(R 10 )(R 11 ), -N(R 12 )C(O)N(R 10 )(R 11 ), -N(R 12 )C(O)OR 13 , -N(R 12 )S(O) 2 R 13 , - S(O)R 13 , -OC(O)R 13 , -C(O)N(R 10 )(R 11 ), -C(O)C(O)N(R 10 )
  • each R 6a is independently selected from halogen, -CN, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2- 9 heterocycloalkyl, C 6-10 aryl, C 1-9 heteroaryl, -OR 10 , -SR 10 , -N(R 10 )(R 11 ), -C(O)OR 10 , - OC(O)N(R 10 )(R 11 ), -N(R 12 )C(O)N(R 10 )(R 11 ), -N(R 12 )C(O)OR 13 , -N(R 12 )S(O)2R 13 , - S(O)R 13 , -OC(O)R 13 , -C(O)N(R 10 )(R 11 ), -C(O)C(O)N
  • a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof having the structure of Formula (IIa): Formula (IIa).
  • Formula (IIa) is a compound of Formula (II) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein L 1a is a bond.
  • a compound of Formula (II) or (IIa), or a pharmaceutically acceptable salt or solvate thereof wherein R 10a is C1-6alkyl optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3- 6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl.
  • R 10a is -CH 3 .
  • a compound of Formula (II) or (IIa), or a pharmaceutically acceptable salt or solvate thereof wherein R 1a is a monocyclic C 2- 5 heterocycloalkyl substituted with one, two, or three R 6a .
  • R 1a is a monocyclic C 2-5 heterocycloalkyl substituted with one, two, or three R 6a and wherein the monocyclic C 2-5 heterocycloalkyl is selected from piperidinyl, pyrrolidinyl, tetrahydropyranyl, and tetrahydrofuranyl.
  • each R 6a is independently selected from halogen, oxo, C1-6alkyl, C1-6haloalkyl, C6- 10aryl, C1-9heteroaryl, -OR 10 , -C(O)OR 10 , -C(O)N(R 10 )(R 11 ), and -S(O)2R 13 , wherein C1- 6alkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, C6-10aryl, -OR 10 , and C1-6haloalkyl.
  • each R 6a is independently selected from C1-6alkyl, C1- 6 haloalkyl, phenyl, and -S(O) 2 R 13 , wherein C 1-6 alkyl and phenyl are unsubstituted.
  • R 1a is a monocyclic C 3-10 cycloalkyl substituted with one, two, or three R 6b .
  • each R 6b is independently selected from halogen, C1-6alkyl, C1-6haloalkyl, C6-10aryl, C1-9heteroaryl, -OH, and - S(O)2R 13 , wherein C1-6alkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -OH, C1-6alkyl, and C1-6haloalkyl.
  • R 1a is a monocyclic C1-5heteroaryl optionally substituted with one, two, or three R 7a .
  • each R 7a is independently selected from halogen, C1-6alkyl, C1-6haloalkyl, C6-10aryl, C1-9heteroaryl, and -S(O) 2 R 13 , wherein C 1-6 alkyl, C 6-10 aryl, and C 1-9 heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C 1-6 alkyl, and C 1-6 haloalkyl.
  • R 1a is selected from ,
  • embodiments is a compound of Formula (II) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1a is a spirocyclic C5-10heterocycloalkyl optionally substituted with one, two, or three R 7a .
  • each R 7a is independently selected from C1-6alkyl, -C(O)R 13 , and -S(O)2R 13 , wherein C1-6alkyl is optionally substituted with one, two, or three groups selected from halogen, C 1-6 haloalkyl, -OR 10 , - N(R 10 )(R 11 ), and -C(O)OR 10 .
  • R 1a is selected from [0012]
  • each R 5 is H.
  • each R 3 is independently selected from H, halogen, -CN, C1- 6alkyl, C1-6haloalkyl, and -OR 10 .
  • a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient.
  • the pharmaceutical composition is formulated for administration to a mammal by intravenous administration, subcutaneous administration, oral administration, inhalation, nasal administration, dermal administration, or ophthalmic administration.
  • the pharmaceutical composition is formulated for administration to a mammal by intravenous administration, subcutaneous administration, or oral administration.
  • the pharmaceutical composition is formulated for administration to a mammal by oral administration.
  • the pharmaceutical composition is in the form of a tablet, a pill, a capsule, a liquid, a suspension, a gel, a dispersion, a solution, an emulsion, an ointment, or a lotion. In some embodiments, the pharmaceutical composition is in the form of a tablet, a pill, or a capsule. [0015] In another aspect, described herein is a method of treating or preventing a liver disease or condition in a mammal, comprising administering to the mammal a compound of Formula (I), (Ia), (II), or (IIa), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the liver disease or condition is an alcoholic liver disease or condition.
  • the liver disease or condition is a nonalcoholic liver disease or condition.
  • the liver disease or condition is liver inflammation, fatty liver (steatosis), liver fibrosis, hepatitis, cirrhosis, hepatocellular carcinoma, or combinations thereof.
  • the liver disease or condition is primary biliary cirrhosis, primary sclerosing cholangitis, cholestasis, nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), or combinations thereof.
  • NASH nonalcoholic steatohepatitis
  • NAFLD nonalcoholic fatty liver disease
  • a method of treating a disease or condition MQ E PEPPEO VLEV YRWOH FIQIJMV JTRP L[HTRZ[UVITRMH *0a&HIL[HTRKIQEUI *, ";A8*06*,# inhibition comprising administering a compound as described herein, or pharmaceutically acceptable salt or solvate thereof, to the mammal in need thereof.
  • the disease or condition in a mammal that would benefit from HSD17B13 inhibition is liver inflammation, fatty liver (steatosis), liver fibrosis, hepatitis, cirrhosis, hepatocellular carcinoma, or combinations thereof.
  • the disease or condition in a mammal that would benefit from HSD17B13 inhibition is primary biliary cirrhosis, primary sclerosing cholangitis, cholestasis, nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), or combinations thereof.
  • modulating comprises inhibiting HSD17B13 activity.
  • the mammal has a liver disease or condition selected from liver inflammation, fatty liver (steatosis), liver fibrosis, hepatitis, cirrhosis, hepatocellular carcinoma, and combinations thereof.
  • the mammal has a liver disease or condition selected from primary biliary cirrhosis, primary sclerosing cholangitis, cholestasis, nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), and combinations thereof.
  • the effective amount of the compound described herein, or a pharmaceutically acceptable salt thereof is: (a) systemically administered to the mammal; and/or (b) administered orally to the mammal; and/or (c) intravenously administered to the mammal; and/or (d) administered by inhalation; and/or (e) administered by nasal administration; or and/or (f) administered by injection to the mammal; and/or (g) administered topically to the mammal; and/or (h) administered by ophthalmic administration; and/or (i) administered rectally to the mammal; and/or (j) administered non-systemically or locally to the mammal.
  • the mammal or subject is a human.
  • compounds provided herein are administered to a human.
  • compounds provided herein are orally administered.
  • Articles of manufacture which include packaging material, a compound described herein, or a pharmaceutically acceptable salt thereof, within the packaging material, and a label that indicates that the compound or composition, or pharmaceutically acceptable salt, pharmaceutically active metabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof, is used for the treatment, prevention or amelioration of one or more symptoms of a disease or condition that would benefit from HSD17B13 inhibition, are provided.
  • HSD17b13 Hydroxysteroid dehydrogenase 17f13
  • HSD17b13 Hydroxysteroid dehydrogenase 17f13
  • rs72613567:T Relative to subjects with the common HSD17b13 allele (rs72613567:T), subjects with the TA variant have lower serum ALT and AST and lower odds of alcoholic liver disease with or without cirrhosis, nonalcoholic liver disease with or without cirrhosis, and lower odds of hepatocellular carcinoma. Liver pathology analysis reveals that the subjects with the rs72613567:TA allele have decreased odds of having liver pathology analysis classified as NASH vs normal, NASH vs simple steatosis or NASH with fibrosis vs simple steatosis.
  • Liver injury associated with the PNPLA3 rs738409 is mitigated by the presence of the rs72613567:TA allele of HSD17b13. Additionally hepatic PNPLA3 mRNA expression is decreased in subjects with the rs72613567:TA allele. The rs72613567:TA allele was found to produce a truncated protein which is unable to metabolize substrates such as estradiol, suggesting the hepatic protective effects of the rs72613567:TA allele is due to loss of enzymatic activity. [0025] Patients with NASH have shown elevated expression of hepatic of HSD17b13 mRNA relative to control subject.
  • HSD17b13 rs72613567 TA minor allele is associated with loss of HSD17b13 protein expression in the liver and protection from nonalcoholic steatohepatitis, ballooning degeneration, lobular inflammation and fibrosis.
  • HSD17b13 rs72613567 TA carriers also show increased hepatic phospholipids PC(p16:0/16:0), PE(p16:0/18:1), PC(44:5e), PC(36:2e), PE(34:0), PE(36:3) and PC(34:3) possibly due to decreased phospholipid degradation from a decreased hepatic expression of PLD4.
  • the HSD17b13 rs72613567:TA allele that has been shown to lack HSD17b13 enzymatic activity, is associated with decreased odds of developing severe fibrosis in patients with chronic HCV infection (About & Abel, NEJM, 2018, 379, 1875).
  • the major allele rs72613567:T is associated with increasing the risk of development of fibrosis, cirrhosis and HCC in HCV infected patients with the PNPLA3 rs738409:G allele (De Benedittis et al. Gastroenterol Res Pract, 2020, 2020, 4216451).
  • the loss of function minor allele HSD17b13 rs72613567:TA reduces the risk of developing cirrhosis and hepatocellular carcinoma, is associated with a lower risk of liver- related mortality in the general population and further in patients with cirrhosis (Gellbert- Kristensen et al, Hepatology, 2020, 71, 56).
  • HSD17b13 function also protects against development of HCC in subjects with alcoholic liver disease (Yang et al, Hepatology, 2019, 70, 231 and Stickel et al, Hepatology, 2020, 72, 88).
  • PNPLA3 rs738409:G is associated with increased fibrosis in patients with NAFLD.
  • the minor HSD17b13 rs72613567:TA allele has been shown to counteract the PNPLA3 rs738409:G allele and decrease the prevalence of severe inflammation, ballooning and fibrosis (Seko et al, Liver Int, 2020, 40, 1686).
  • HSD17b13 enzymatic activity due to carrying the rs72613567:TA allele may delay the onset of autoimmune hepatitis (Mederacke et al, Aliment Pharmacol Ther, 2020, 00, 1).
  • HSD17b13 rs72613567:TA allele is associated with decreased fibrosis and cirrhosis in patents with copper induced liver injury from Wilson’s disease (Ferenci et al, 2019, JHEP, 1, 2).
  • Compounds described herein, including pharmaceutically acceptable salts, prodrugs, active metabolites and pharmaceutically acceptable solvates thereof, are HSD17B13 inhibitors.
  • X 1 , X 2 , and X 3 are each independently CR 3 or N; Y 1 is CR 4 or N; Y 2 is N(R 9 ), O, S, or C(R 4 ) 2 ; Y 3 is CR 4 or N; Y 4 is C(O), C(R 4 ) 2 , N(R 8 ), O, or S; Y 5 is C(O), C(R 4 ) 2 , or N(R 8 ), wherein at least one of Y 4 and Y 5 is C(O); Z 1 , Z 2 , Z 3 , and Z 4 are each independently CR 5 or N; L 1 is selected from a bond, -O-, -N(R 10a )-, -C(O)-, -S-, -S(O)-, -S(O)2-, - C
  • a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof wherein .
  • some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein .
  • some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, .
  • some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein J is .
  • some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein J is .
  • a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof wherein J is [0036]
  • a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof wherein Y 2 is N(R 9 ) and R 9 is C1- 6alkyl.
  • a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof wherein Y 2 is C(R 4 )2.
  • a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof wherein Y 2 is C(R 4 )2 and each R 4 is independently selected from H, halogen, C1-6alkyl, and -N(R 10 )(R 11 ).
  • a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof wherein Y 2 is C(R 4 ) 2 and each R 4 is independently selected from H and C 1-6 alkyl.
  • Y 3 is N.
  • a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof wherein Y 3 is CR 4 and R 4 is H, halogen, C1-6alkyl, C1-6haloalkyl, - N(R 10 )(R 11 ), or -C(O)R 13 .
  • a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof wherein Y 3 is CR 4 and R 4 is H, halogen, or C1-6alkyl.
  • Y 1 is N.
  • a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof wherein Y 1 is CR 4 .
  • a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof wherein Y 1 is CR 4 and R 4 is H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, - N(R 10 )(R 11 ), or -C(O)R 13 .
  • a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof wherein Y 1 is CR 4 and R 4 is H, halogen, or C 1-6 alkyl.
  • X 1 , X 2 , and X 3 are each CR 3 .
  • X 1 , X 2 , and X 3 are each CR 3 and each R 3 is independently selected from H, halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, and -OR 10 .
  • a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof wherein X 1 , X 2 , and X 3 are each CR 3 and each R 3 is independently selected from H, halogen, C1-6alkyl, and C1-6haloalkyl.
  • a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof wherein X 1 , X 2 , and X 3 are each CR 3 and each R 3 is independently selected from H, halogen, and C1-6haloalkyl.
  • a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof wherein X 1 is C(F), X 2 is C(H), and X 3 is C(CF3).
  • a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof wherein X 1 is C(F), X 2 is C(F), and X 3 is C(H).
  • a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof wherein X 1 is C(F), X 2 is C(H), and X 3 is C(H).
  • a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof wherein X 1 is C(F), X 2 is C(H), and X 3 is C(F).
  • a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof wherein X 1 is C(F), X 2 is C(H), and X 3 is C(Cl).
  • a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof wherein X 1 is C(F), X 2 is C(H), and X 3 is C(CH3).
  • a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof wherein X 1 is C(Cl), X 2 is C(H), and X 3 is C(CF3).
  • a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof wherein X 1 is C(Cl), X 2 is C(H), and X 3 is C(H).
  • a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof wherein X 1 is C(H), X 2 is C(H), and X 3 is C(CF3).
  • a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof wherein X 1 is C(H), X 2 is C(H), and X 3 is C(F).
  • a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof wherein X 1 is C(H), X 2 is C(H), and X 3 is C(Cl).
  • R 2 is selected from H, halogen, C1-6alkyl, C1- 6 haloalkyl, and -OR 10 .
  • a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is H.
  • R 2 is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is halogen.
  • R 2 is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is F.
  • R 2 is Cl.
  • R 2 is C1-6alkyl.
  • a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof wherein Z 1 , Z 2 , and Z 3 are CR 5 .
  • a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof wherein Z 1 is N; and Z 2 and Z 3 are CR 5 .
  • a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof wherein Z 2 is N; and Z 1 and Z 3 are CR 5 .
  • Z 3 is N; and Z 1 and Z 2 are CR 5 .
  • a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof wherein Z 1 is CR 5 ; and Z 2 and Z 3 are N. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Z 2 is CR 5 ; and Z 1 and Z 3 are N. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Z 3 is CR 5 ; and Z 1 and Z 2 are N.
  • each R 5 is independently selected from H, halogen, -CN, C 1-6 alkyl, and -OR 10 .
  • each R 5 is H.
  • Z 1 is N; and Z 2 and Z 3 are C(H).
  • a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof wherein Z 2 is N; and Z 1 and Z 3 are C(H).
  • a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof wherein Z 3 is C(H); and Z 1 and Z 2 are N.
  • Z 4 is CR 5 .
  • Z 4 is C(H).
  • a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof wherein Z 1 , Z 2 , Z 3 , and Z 4 are C(H). In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Z 4 is N. [0042] In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein L 1 is a -N(R 10a )-. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 10a is hydrogen.
  • a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof wherein R 10a is C1-6alkyl optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1- 9heteroaryl.
  • R 10a is -CH3.
  • L 1 is a bond.
  • a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof wherein L 1 is -C(O)-. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein L 1 is -C(O)N(R 10a )-. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein L 1 is - N(R 10a )C(O)-.
  • a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof wherein R 1 is a fused bicyclic C2-9heterocycloalkyl optionally substituted with one, two, or three R 6 .
  • R 1 is a fused bicyclic C 2-9 heterocycloalkyl optionally substituted with one, two, or three R 6 , wherein the fused bicyclic C 2-9 heterocycloalkyl is a heterocycloalkyl ring fused with a phenyl ring.
  • R 1 is a fused bicyclic C2-9heterocycloalkyl optionally substituted with one, two, or three R 6 , wherein the fused bicyclic C2-9heterocycloalkyl is a heterocycloalkyl ring fused with a heteroaryl ring.
  • a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof wherein R 1 is a fused bicyclic C2-9heterocycloalkyl optionally substituted with one, two, or three R 6 , wherein the fused bicyclic C2-9heterocycloalkyl is a heterocycloalkyl ring fused with a second heterocycloalkyl ring.
  • R 1 is a fused bicyclic C 3- 10 cycloalkyl optionally substituted with one, two, or three R 6 .
  • R 1 is a fused bicyclic C 3-10 cycloalkyl optionally substituted with one, two, or three R 6 , wherein the fused bicyclic C3-10cycloalkyl is a cycloalkyl ring fused with a phenyl ring.
  • each R 6 is independently selected from halogen, oxo, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1- 9heteroaryl, -OR 10 , -N(R 10 )(R 11 ), -C(O)OR 10 , -N(R 12 )C(O)R 13 , -N(R 12 )C(O)OR 13 , - N(R 12 )S(O)2R 13 , -C(O)R 13 , -C(O)N(R 10 )(R 11 ), -S(O)2R 13 , and -S(O)2N(R 10 )(R 11 )-, wherein C1-6alkyl, C3-6cycloalkyl, C2-9hexo, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9hetero
  • each R 6 is independently selected from halogen, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 6-10 aryl, C 1-9 heteroaryl, -OR 10 , - C(O)OR 10 , -C(O)N(R 10 )(R 11 ), and -S(O) 2 R 13 , wherein C 1-6 alkyl, C 6-10 aryl, and C 1- 9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C 1-6 alkyl, and C 1-6 haloalkyl.
  • a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof wherein R 1 is an unsubstituted fused bicyclic C2- 9heterocycloalkyl.
  • R 1 is an unsubstituted fused bicyclic C 3- 10 cycloalkyl.
  • R 1 is a bicyclic C1-9heteroaryl optionally substituted with one, two, or three R 7 .
  • R 1 is naphthyl optionally substituted with one, two, or three R 7 .
  • X 1 , X 2 , and X 3 are each independently CR 3 or N; Y 1 is CR 4 or N; Y 2 is N(R 9 ), O, S, or C(R 4 )2; Z 1 , Z 2 , and Z 3 are each independently CR 5 or N; L 1 is selected from a bond, -O-, -N(R 10a )-, -C(O)-, -S-, -S(O)-, -S(O)2-, - C(O)N(R 10a )-, -N(R 10a )C(O)-, -C(R 10 )(R 11 )N(R 10a )-, and -N(R 10a )C(R 10 )(R 11 )-; R 1 is selected from: a) a fused bicyclic
  • a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof wherein Y 2 is N(R 9 ).
  • a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof wherein Y 2 is N(R 9 ) and R 9 is selected from H and C1-6alkyl.
  • a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof wherein Y 2 is N(R 9 ) and R 9 is H.
  • a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof wherein Y 2 is C(R 4 ) 2 .
  • a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof wherein Y 2 is C(R 4 ) 2 and each R 4 is independently selected from H, halogen, C 1-6 alkyl, and -N(R 10 )(R 11 ).
  • a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof wherein Y 1 is CR 4 and R 4 is H, halogen, or C1-6alkyl.
  • a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof wherein X 1 , X 2 , and X 3 are each CR 3 .
  • a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof wherein X 1 , X 2 , and X 3 are each CR 3 and each R 3 is independently selected from H, halogen, -CN, C1-6alkyl, C1-6haloalkyl, and -OR 10 .
  • a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof wherein X 1 , X 2 , and X 3 are each CR 3 and each R 3 is independently selected from H, halogen, C 1-6 alkyl, and C 1-6 haloalkyl.
  • a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof wherein X 1 , X 2 , and X 3 are each CR 3 and each R 3 is independently selected from H, halogen, and C1-6haloalkyl.
  • a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof wherein X 1 is C(F), X 2 is C(H), and X 3 is C(CF3).
  • a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof wherein X 1 is C(F), X 2 is C(F), and X 3 is C(H).
  • a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof wherein X 1 is C(F), X 2 is C(H), and X 3 is C(H).
  • a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof wherein X 1 is C(F), X 2 is C(H), and X 3 is C(F).
  • a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof wherein X 1 is C(F), X 2 is C(H), and X 3 is C(Cl).
  • a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof wherein X 1 is C(F), X 2 is C(H), and X 3 is C(CH 3 ).
  • a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof wherein X 1 is C(Cl), X 2 is C(H), and X 3 is C(CF3).
  • a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof wherein X 1 is C(H), X 2 is C(H), and X 3 is C(CF3).
  • a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof wherein X 1 is C(H), X 2 is C(H), and X 3 is C(F).
  • R 2 is H.
  • R 2 is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is halogen.
  • R 2 is F.
  • a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is Cl.
  • R 2 is C 1-6 alkyl.
  • R 2 is C1-6haloalkyl.
  • R 2 is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is -OR 10 .
  • R 2 is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is -OH.
  • Z 3 is CR 5 ; and Z 1 and Z 2 are N.
  • each R 5 is independently selected from H, halogen, -CN, C 1-6 alkyl, and -OR 10 .
  • Z 1 is N; and Z 2 and Z 3 are C(H).
  • a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof wherein Z 3 is C(H); and Z 1 and Z 2 are N.
  • a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof wherein L 1 is a -N(R 10a )-.
  • a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof wherein R 10a is C1-6alkyl optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1- 9 heteroaryl.
  • R 10a is -CH 3 .
  • L 1 is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein L 1 is -C(O)-.
  • L 1 is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein L 1 is -C(O)N(R 10a )-.
  • a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof wherein R 1 is a fused bicyclic C 2-9 heterocycloalkyl optionally substituted with one, two, or three R 6 .
  • R 1 is a fused bicyclic C2-9heterocycloalkyl optionally substituted with one, two, or three R 6 , wherein the fused bicyclic C2-9heterocycloalkyl is a heterocycloalkyl ring fused with a phenyl ring.
  • R 1 is a fused bicyclic C2-9heterocycloalkyl optionally substituted with one, two, or three R 6 , wherein the fused bicyclic C2- 9heterocycloalkyl is a heterocycloalkyl ring fused with a heteroaryl ring.
  • a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof wherein R 1 is a fused bicyclic C 2-9 heterocycloalkyl optionally substituted with one, two, or three R 6 , wherein the fused bicyclic C 2-9 heterocycloalkyl is a heterocycloalkyl ring fused with a second heterocycloalkyl ring.
  • R 1 is a fused bicyclic C3-10cycloalkyl optionally substituted with one, two, or three R 6 .
  • R 1 is a fused bicyclic C3-10cycloalkyl optionally substituted with one, two, or three R 6 , wherein the fused bicyclic C3-10cycloalkyl is a cycloalkyl ring fused with a phenyl ring.
  • each R 6 is independently selected from halogen, oxo, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1- 9 heteroaryl, -OR 10 , -N(R 10 )(R 11 ), -C(O)OR 10 , -N(R 12 )C(O)R 13 , -N(R 12 )C(O)OR 13 , - N(R 12 )S(O) 2 R 13 , -C(O)R 13 , -C(O)N(R 10 )(R 11 ), -S(O) 2 R 13 , and -S(O) 2 N(R 10 )(R 11 )-, wherein C 1-6 alkyl, C 3-6 cycloalkyl, C 2
  • each R 6 is independently selected from halogen, oxo, C1-6alkyl, C1-6haloalkyl, C6-10aryl, C1- 9heteroaryl, -OR 10 , -C(O)OR 10 , -C(O)N(R 10 )(R 11 ), and -S(O)2R 13 , wherein C1-6alkyl, C6- 10 aryl, and C 1-9 heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C 1-6 alkyl, and C 1-6 haloalkyl.
  • [0060] in some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is an unsubstituted fused bicyclic C2- 9heterocycloalkyl.
  • R 1 is an unsubstituted fused bicyclic C3- 10cycloalkyl.
  • R 1 is a bicyclic C1-9heteroaryl optionally substituted with one, two, or three R 7 .
  • R 1 is naphthyl optionally substituted with one, two, or three R 7 .
  • Formula (Ia5) is a pharmaceutically acceptable salt or solvate thereof: Formula (Ia5).
  • a compound of Formula (Ia6) or a pharmaceutically acceptable salt or solvate thereof: Formula (Ia6).
  • a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof wherein Y 3 is N.
  • a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof wherein Y 3 is CR 4 and R 4 is H, halogen, or C 1-6 alkyl.
  • Y 1 is N.
  • a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof wherein Y 1 is CR 4 and R 4 is H, halogen, C1-6alkyl, C1- 6haloalkyl, -N(R 10 )(R 11 ), or -C(O)R 13 .
  • a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof wherein Y 1 is CR 4 and R 4 is H, halogen, or C1-6alkyl.
  • X 1 , X 2 , and X 3 are each CR 3 .
  • X 1 , X 2 , and X 3 are each CR 3 and each R 3 is independently selected from H, halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, and -OR 10 .
  • a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof wherein X 1 , X 2 , and X 3 are each CR 3 and each R 3 is independently selected from H, halogen, C1-6alkyl, and C1-6haloalkyl.
  • a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof wherein X 1 , X 2 , and X 3 are each CR 3 and each R 3 is independently selected from H, halogen, and C1-6haloalkyl.
  • a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof wherein X 1 is C(F), X 2 is C(H), and X 3 is C(CF3).
  • a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof wherein X 1 is C(F), X 2 is C(F), and X 3 is C(H).
  • a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof wherein X 1 is C(F), X 2 is C(H), and X 3 is C(H).
  • a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof wherein X 1 is C(F), X 2 is C(H), and X 3 is C(F).
  • a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof wherein X 1 is C(F), X 2 is C(H), and X 3 is C(Cl).
  • a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof wherein X 1 is C(Cl), X 2 is C(H), and X 3 is C(CF3).
  • a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof wherein X 1 is C(Cl), X 2 is C(H), and X 3 is C(H).
  • a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof wherein X 1 is C(H), X 2 is C(H), and X 3 is C(CF3).
  • a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof wherein X 1 is C(H), X 2 is C(H), and X 3 is C(F).
  • a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof wherein X 1 is C(H), X 2 is C(H), and X 3 is C(Cl).
  • R 2 is selected from H, halogen, C1-6alkyl, C1- 6haloalkyl, and -OR 10 .
  • a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is H.
  • R 2 is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is halogen.
  • R 2 is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is F.
  • R 2 is Cl.
  • R 2 is C1-6alkyl.
  • R 2 is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is - OR 10 .
  • R 2 is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is -OH.
  • R 2 is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is -OCH 3 .
  • a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof wherein Z 1 is CR 5 ; and Z 2 and Z 3 are N.
  • a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof wherein Z 2 is CR 5 ; and Z 1 and Z 3 are N.
  • a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof wherein Z 3 is CR 5 ; and Z 1 and Z 2 are N.
  • each R 5 is independently selected from H, halogen, -CN, C1-6alkyl, and -OR 10 .
  • Z 1 is N; and Z 2 and Z 3 are C(H).
  • a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof wherein Z 3 is C(H); and Z 1 and Z 2 are N.
  • Z 3 is C(H); and Z 1 and Z 2 are N.
  • Z 1 and Z 2 are N.
  • L 1 is a -N(R 10a )-.
  • R 10a is hydrogen.
  • R 10a is C 1-6 alkyl optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1- 9heteroaryl.
  • R 10a is -CH 3 .
  • a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof wherein L 1 is a bond.
  • L 1 is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein L 1 is -C(O)-.
  • L 1 is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein L 1 is -C(O)N(R 10a )-.
  • a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof wherein R 1 is a fused bicyclic C2-9heterocycloalkyl optionally substituted with one, two, or three R 6 .
  • R 1 is a fused bicyclic C2-9heterocycloalkyl optionally substituted with one, two, or three R 6 , wherein the fused bicyclic C2-9heterocycloalkyl is a heterocycloalkyl ring fused with a phenyl ring.
  • R 1 is a fused bicyclic C 2-9 heterocycloalkyl optionally substituted with one, two, or three R 6 , wherein the fused bicyclic C 2- 9 heterocycloalkyl is a heterocycloalkyl ring fused with a heteroaryl ring.
  • a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof wherein R 1 is a fused bicyclic C2-9heterocycloalkyl optionally substituted with one, two, or three R 6 , wherein the fused bicyclic C2-9heterocycloalkyl is a heterocycloalkyl ring fused with a second heterocycloalkyl ring.
  • R 1 is a fused bicyclic C3-10cycloalkyl optionally substituted with one, two, or three R 6 .
  • R 1 is a fused bicyclic C3-10cycloalkyl optionally substituted with one, two, or three R 6 , wherein the fused bicyclic C3-10cycloalkyl is a cycloalkyl ring fused with a phenyl ring.
  • each R 6 is independently selected from halogen, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, C 1- 9heteroaryl, -OR 10 , -N(R 10 )(R 11 ), -C(O)OR 10 , -N(R 12 )C(O)R 13 , -N(R 12 )C(O)OR 13 , - N(R 12 )S(O) 2 R 13 , -C(O)R 13 , -C(O)N(R 10 )(R 11 ), -S(O) 2 R 13 , and -S(O) 2 N(R 10 )(R 11 )-, wherein C1-6alkyl, C3-6cycloalkyl,
  • each R 6 is independently selected from halogen, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 6-10 aryl, C 1- 9 heteroaryl, -OR 10 , -C(O)OR 10 , -C(O)N(R 10 )(R 11 ), and -S(O) 2 R 13 , wherein C 1-6 alkyl, C 6- 10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, and C1-6haloalkyl.
  • [0080] in some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is an unsubstituted fused bicyclic C2- 9heterocycloalkyl. [0081] In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is an unsubstituted fused bicyclic C3- 10cycloalkyl. [0082] In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is a bicyclic C 1-9 heteroaryl optionally substituted with one, two, or three R 7 .
  • R 1 is naphthyl optionally substituted with one, two, or three R 7 .
  • a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof wherein Y 3 is CR 4 and R 4 is H, halogen, or C 1-6 alkyl.
  • Y 1 is N.
  • a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof wherein Y 1 is CR 4 and R 4 is H, halogen, C 1-6 alkyl, C 1- 6 haloalkyl, -N(R 10 )(R 11 ), or -C(O)R 13 .
  • a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof wherein Y 1 is CR 4 and R 4 is H, halogen, or C1-6alkyl.
  • X 1 , X 2 , and X 3 are each CR 3 .
  • X 1 , X 2 , and X 3 are each CR 3 and each R 3 is independently selected from H, halogen, -CN, C1-6alkyl, C1-6haloalkyl, and -OR 10 .
  • a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof wherein X 1 , X 2 , and X 3 are each CR 3 and each R 3 is independently selected from H, halogen, C 1-6 alkyl, and C 1-6 haloalkyl.
  • a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof wherein X 1 , X 2 , and X 3 are each CR 3 and each R 3 is independently selected from H, halogen, and C 1-6 haloalkyl.
  • a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof wherein X 1 is C(F), X 2 is C(H), and X 3 is C(CF3).
  • a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof wherein X 1 is C(F), X 2 is C(F), and X 3 is C(H).
  • a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof wherein X 1 is C(F), X 2 is C(H), and X 3 is C(H).
  • a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof wherein X 1 is C(F), X 2 is C(H), and X 3 is C(F).
  • a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof wherein X 1 is C(F), X 2 is C(H), and X 3 is C(Cl).
  • a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof wherein X 1 is C(Cl), X 2 is C(H), and X 3 is C(CF 3 ).
  • a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof wherein X 1 is C(Cl), X 2 is C(H), and X 3 is C(H).
  • a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof wherein X 1 is C(H), X 2 is C(H), and X 3 is C(CF3).
  • a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof wherein X 1 is C(H), X 2 is C(H), and X 3 is C(F).
  • a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof wherein X 1 is C(H), X 2 is C(H), and X 3 is C(Cl).
  • R 2 is selected from H, halogen, C1-6alkyl, C1- 6haloalkyl, and -OR 10 .
  • a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is H.
  • R 2 is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is halogen.
  • R 2 is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is F.
  • R 2 is Cl.
  • R 2 is C 1-6 alkyl.
  • a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof wherein Z 1 is CR 5 ; and Z 2 and Z 3 are N.
  • a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof wherein Z 2 is CR 5 ; and Z 1 and Z 3 are N.
  • a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof wherein Z 3 is CR 5 ; and Z 1 and Z 2 are N.
  • each R 5 is independently selected from H, halogen, -CN, C 1-6 alkyl, and -OR 10 .
  • Z 1 is N; and Z 2 and Z 3 are C(H).
  • Z 4 is C(H).
  • a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof wherein Z 1 , Z 2 , Z 3 , and Z 4 are C(H). In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein Z 4 is N. [0090] In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein L 1 is a -N(R 10a )-. In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R 10a is hydrogen.
  • R 10a is C1-6alkyl optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C 1-6 alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1- 9heteroaryl.
  • R 10a is -CH3.
  • a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof wherein L 1 is a bond.
  • L 1 is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein L 1 is -C(O)-.
  • L 1 is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein L 1 is -C(O)N(R 10a )-.
  • a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof wherein R 1 is a fused bicyclic C2-9heterocycloalkyl optionally substituted with one, two, or three R 6 .
  • R 1 is a fused bicyclic C 2-9 heterocycloalkyl optionally substituted with one, two, or three R 6 , wherein the fused bicyclic C 2-9 heterocycloalkyl is a heterocycloalkyl ring fused with a phenyl ring.
  • R 1 is a fused bicyclic C 2-9 heterocycloalkyl optionally substituted with one, two, or three R 6 , wherein the fused bicyclic C2- 9heterocycloalkyl is a heterocycloalkyl ring fused with a heteroaryl ring.
  • a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof wherein R 1 is a fused bicyclic C2-9heterocycloalkyl optionally substituted with one, two, or three R 6 , wherein the fused bicyclic C2-9heterocycloalkyl is a heterocycloalkyl ring fused with a second heterocycloalkyl ring.
  • R 1 is a fused bicyclic C3-10cycloalkyl optionally substituted with one, two, or three R 6 .
  • R 1 is a fused bicyclic C 3-10 cycloalkyl optionally substituted with one, two, or three R 6 , wherein the fused bicyclic C 3-10 cycloalkyl is a cycloalkyl ring fused with a phenyl ring.
  • each R 6 is independently selected from halogen, oxo, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1- 9heteroaryl, -OR 10 , -N(R 10 )(R 11 ), -C(O)OR 10 , -N(R 12 )C(O)R 13 , -N(R 12 )C(O)OR 13 , - N(R 12 )S(O)2R 13 , -C(O)R 13 , -C(O)N(R 10 )(R 11 ), -S(O)2R 13 , and -S(O)2N(R 10 )(R 11 )-, wherein C 1-6 alkyl, C 3-6 cycloalkyl,
  • each R 6 is independently selected from halogen, oxo, C1-6alkyl, C1-6haloalkyl, C6-10aryl, C1- 9heteroaryl, -OR 10 , -C(O)OR 10 , -C(O)N(R 10 )(R 11 ), and -S(O)2R 13 , wherein C1-6alkyl, C6- 10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, and C1-6haloalkyl.
  • a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof wherein R 1 is an unsubstituted fused bicyclic C2- 9heterocycloalkyl.
  • R 1 is an unsubstituted fused bicyclic C 3- 10 cycloalkyl.
  • R 1 is a bicyclic C1-9heteroaryl optionally substituted with one, two, or three R 7 .
  • a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof wherein R 1 is naphthyl optionally substituted with one, two, or three R 7 .
  • R 1 is naphthyl optionally substituted with one, two, or three R 7 .
  • X 1 , X 2 , and X 3 are each independently CR 3 or N; Y 1 is CR 4 or N; Y 2 is N(R 9 ), O, S, or C(R 4 )2; Y 3 is CR 4 or N; Y 4 is C(O), C(R 4 )2, N(R 8 ), O, or S; Y 5 is C(O), C(R 4 )2, or N(R 8 ), wherein at least one of Y 4 and Y 5 is C(O); Z 1 , Z 2 , Z 3 , and Z 4 are each independently CR 5 or N; L 1a is selected from a bond, -C(O)-, and -C(R 10 )(R 11 )-; R 1a is selected from: a) a monocyclic C2-5heterocycloalkyl substituted with one, two, or three R 6a ; b) a monocyclic C 3-10 cycloalkyl substituted with one, two,
  • a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof wherein .
  • embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, .
  • some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein J is .
  • some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein J is .
  • a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof wherein Y 2 is N(R 9 ) and R 9 is H. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein Y 2 is N(R 9 ) and R 9 is C 1- 6alkyl. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein Y 2 is C(R 4 ) 2 .
  • a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof wherein Y 2 is C(R 4 ) 2 and each R 4 is independently selected from H, halogen, C 1-6 alkyl, and -N(R 10 )(R 11 ).
  • a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof wherein Y 2 is C(R 4 )2 and each R 4 is independently selected from H and C1-6alkyl.
  • Y 3 is N.
  • a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof wherein Y 3 is CR 4 .
  • a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof wherein Y 3 is CR 4 and R 4 is H, halogen, C1-6alkyl, C1- 6haloalkyl, -N(R 10 )(R 11 ), or -C(O)R 13 .
  • a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof wherein Y 3 is CR 4 and R 4 is H, halogen, or C 1-6 alkyl.
  • Y 1 is N.
  • Y 1 is CR 4 .
  • Y 1 is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein Y 1 is CR 4 and R 4 is H, halogen, C 1-6 alkyl, C 1- 6 haloalkyl, -N(R 10 )(R 11 ), or -C(O)R 13 .
  • a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof wherein Y 1 is CR 4 and R 4 is H, halogen, or C1-6alkyl.
  • a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof wherein X 1 , X 2 , and X 3 are each CR 3 .
  • a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof wherein X 1 , X 2 , and X 3 are each CR 3 and each R 3 is independently selected from H, halogen, -CN, C1-6alkyl, C1-6haloalkyl, and -OR 10 .
  • a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof wherein X 1 , X 2 , and X 3 are each CR 3 and each R 3 is independently selected from H, halogen, C 1-6 alkyl, and C 1-6 haloalkyl.
  • a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof wherein X 1 , X 2 , and X 3 are each CR 3 and each R 3 is independently selected from H, halogen, and C 1-6 haloalkyl.
  • a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof wherein X 1 is C(F), X 2 is C(H), and X 3 is C(CF3).
  • a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof wherein X 1 is C(F), X 2 is C(F), and X 3 is C(H).
  • a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof wherein X 1 is C(F), X 2 is C(H), and X 3 is C(H).
  • a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof wherein X 1 is C(F), X 2 is C(H), and X 3 is C(F).
  • a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof wherein X 1 is C(F), X 2 is C(H), and X 3 is C(Cl).
  • a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof wherein X 1 is C(F), X 2 is C(H), and X 3 is C(CH 3 ).
  • a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof wherein X 1 is C(Cl), X 2 is C(H), and X 3 is C(CF 3 ).
  • a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof wherein X 1 is C(Cl), X 2 is C(H), and X 3 is C(H).
  • a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof wherein X 1 is C(H), X 2 is C(H), and X 3 is C(CF3).
  • a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof wherein X 1 is C(H), X 2 is C(H), and X 3 is C(F).
  • R 2 is H.
  • R 2 is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is halogen.
  • R 2 is F.
  • Z 3 is CR 5 ; and Z 1 and Z 2 are N.
  • each R 5 is independently selected from H, halogen, -CN, C 1-6 alkyl, and -OR 10 .
  • Z 1 is N; and Z 2 and Z 3 are C(H).
  • Z 4 is C(H).
  • a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof wherein Z 1 , Z 2 , Z 3 , and Z 4 are C(H). In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein Z 4 is N. [00106] In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein L 1a is a bond. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein L 1a is -C(R 10 )(R 11 )-.
  • a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof wherein L 1a is -CH 2 -.
  • R 10a is C1- 6alkyl optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10 aryl, and C 1-9 heteroaryl.
  • R 10a is -CH 3 .
  • a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof wherein R 1a is a monocyclic C2-5heterocycloalkyl substituted with one, two, or three R 6a .
  • R 1a is a monocyclic C2-5heterocycloalkyl substituted with one, two, or three R 6a and wherein the monocyclic C2-5heterocycloalkyl is selected from piperidinyl, pyrrolidinyl, tetrahydropyranyl, and tetrahydrofuranyl.
  • each R 6a is independently selected from halogen, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 6-10 aryl, C 1-9 heteroaryl, -OR 10 , -C(O)OR 10 , - C(O)N(R 10 )(R 11 ), and -S(O) 2 R 13 , wherein C 1-6 alkyl, C 6-10 aryl, and C 1-9 heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C 1-6 alkyl, C 6- 10 aryl, -OR 10 , and C 1-6 haloalkyl.
  • each R 6a is independently selected from C1-6alkyl, C1-6haloalkyl, phenyl, and -S(O)2R 13 , wherein C1-6alkyl and phenyl are unsubstituted.
  • R 1a is a monocyclic C3-10cycloalkyl substituted with one, two, or three R 6b .
  • each R 6b is independently selected from halogen, C1-6alkyl, C1-6haloalkyl, C6-10aryl, C1-9heteroaryl, -OH, and - S(O)2R 13 , wherein C1-6alkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -OH, C 1-6 alkyl, and C 1-6 haloalkyl.
  • R 1a is a monocyclic C 1-5 heteroaryl optionally substituted with one, two, or three R 7a .
  • each R 7a is independently selected from halogen, C1-6alkyl, C1-6haloalkyl, C6-10aryl, C1-9heteroaryl, and -S(O)2R 13 , wherein C1- 6alkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, and C1-6haloalkyl.
  • a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof [00112] In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1a is a spirocyclic C 5-10 heterocycloalkyl optionally substituted with one, two, or three R 7a .
  • each R 7a is independently selected from C 1-6 alkyl, -C(O)R 13 , and -S(O) 2 R 13 , wherein C 1-6 alkyl is optionally substituted with one, two, or three groups selected from halogen, C 1-6 haloalkyl, -OR 10 , -N(R 10 )(R 11 ), and -C(O)OR 10 .
  • R 1a is selected from [00113]
  • X 1 , X 2 , and X 3 are each independently CR 3 or N; Y 1 is CR 4 or N; Y 2 is N(R 9 ), O, S, or C(R 4 ) 2 ; Y 3 is CR 4 or N; Y 4 is C(O), C(R 4 )2, N(R 8 ), O, or S; Y 5 is C(O), C(R 4 )2, or N(R 8 ), wherein at least one of Y 4 and Y 5 is C(O); Z 1 , Z 2 , Z 3 , and Z 4 are each independently CR 5 or N; L 1a is selected from a bond, -C(O)-, and -C(R 10 )(R 11 )-; R 1a is selected from: a) a monocyclic C2-5heterocycloalkyl substituted with one, two, or three R 6a ; b) a monocyclic C3-10cycloalkyl substituted with one, two,
  • X 1 , X 2 , and X 3 are each independently CR 3 or N; Y 1 is CR 4 or N; Y 2 is N(R 9 ), O, S, or C(R 4 )2; Z 1 , Z 2 , and Z 3 are each independently CR 5 or N; L 1a is selected from a bond, -C(O)-, and -C(R 10 )(R 11 )-; R 1a is selected from: a) a monocyclic C 2-5 heterocycloalkyl substituted with one, two, or three R 6a ; b) a monocyclic C 3-10 cycloalkyl substituted with one, two, or three R 6b ; c) a monocyclic C 1-5 heteroaryl optionally substituted with one, two, or three R 7a ; d) a spirocyclic
  • a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof wherein Y 2 is N(R 9 ).
  • a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof wherein Y 2 is N(R 9 ) and R 9 is selected from H and C1-6alkyl.
  • a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof wherein Y 2 is N(R 9 ) and R 9 is C 1- 6 alkyl.
  • a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof wherein Y 2 is C(R 4 )2.
  • a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof wherein Y 2 is C(R 4 )2 and each R 4 is independently selected from H, halogen, C1-6alkyl, and -N(R 10 )(R 11 ).
  • a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof wherein Y 2 is C(R 4 )2 and each R 4 is independently selected from H and C1-6alkyl.
  • Y 1 is N.
  • a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof wherein Y 1 is CR 4 and R 4 is H, halogen, C 1-6 alkyl, C 1- 6 haloalkyl, -N(R 10 )(R 11 ), or -C(O)R 13 .
  • a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof wherein Y 1 is CR 4 and R 4 is H, halogen, or C1-6alkyl.
  • a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof wherein X 1 , X 2 , and X 3 are each CR 3 .
  • a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof wherein X 1 , X 2 , and X 3 are each CR 3 and each R 3 is independently selected from H, halogen, -CN, C1-6alkyl, C1-6haloalkyl, and -OR 10 .
  • a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof wherein X 1 , X 2 , and X 3 are each CR 3 and each R 3 is independently selected from H, halogen, C 1-6 alkyl, and C 1-6 haloalkyl.
  • a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof wherein X 1 , X 2 , and X 3 are each CR 3 and each R 3 is independently selected from H, halogen, and C 1-6 haloalkyl.
  • a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof wherein X 1 is C(F), X 2 is C(H), and X 3 is C(CF3).
  • a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof wherein X 1 is C(F), X 2 is C(F), and X 3 is C(H).
  • a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof wherein X 1 is C(F), X 2 is C(H), and X 3 is C(F).
  • a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof wherein X 1 is C(F), X 2 is C(H), and X 3 is C(Cl).
  • a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof wherein X 1 is C(Cl), X 2 is C(H), and X 3 is C(CF3).
  • a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof wherein X 1 is C(Cl), X 2 is C(H), and X 3 is C(H).
  • a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof wherein X 1 is C(H), X 2 is C(H), and X 3 is C(F).
  • a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof wherein X 1 is C(H), X 2 is C(H), and X 3 is C(Cl).
  • R 2 is selected from H, halogen, C1-6alkyl, C1- 6haloalkyl, and -OR 10 .
  • each R 5 is independently selected from H, halogen, -CN, C 1-6 alkyl, and -OR 10 .
  • Z 1 is N; and Z 2 and Z 3 are C(H).
  • R 10a is hydrogen.
  • R 10a is C1- 6alkyl optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, and C1-9heteroaryl.
  • a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof wherein R 10a is -CH3.
  • R 1a is a monocyclic C2-5heterocycloalkyl substituted with one, two, or three R 6a .
  • R 1a is a monocyclic C 2-5 heterocycloalkyl substituted with one, two, or three R 6a and wherein the monocyclic C 2-5 heterocycloalkyl is selected from piperidinyl, pyrrolidinyl, tetrahydropyranyl, and tetrahydrofuranyl.
  • each R 6a is independently selected from halogen, oxo, C1-6alkyl, C1-6haloalkyl, C6-10aryl, C1-9heteroaryl, -OR 10 , -C(O)OR 10 , - C(O)N(R 10 )(R 11 ), and -S(O)2R 13 , wherein C1-6alkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, C6- 10aryl, -OR 10 , and C1-6haloalkyl.
  • each R 6a is independently selected from C1-6alkyl, C1-6haloalkyl, phenyl, and -S(O)2R 13 , wherein C1-6alkyl and phenyl are unsubstituted.
  • R 1a is a monocyclic C 3-10 cycloalkyl substituted with one, two, or three R 6b .
  • each R 6b is independently selected from halogen, C1-6alkyl, C1-6haloalkyl, C6-10aryl, C1-9heteroaryl, -OH, and - S(O) 2 R 13 , wherein C 1-6 alkyl, C 6-10 aryl, and C 1-9 heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -OH, C1-6alkyl, and C1-6haloalkyl.
  • R 1a is a monocyclic C 1-5 heteroaryl optionally substituted with one, two, or three R 7a .
  • each R 7a is independently selected from halogen, C1-6alkyl, C1-6haloalkyl, C6-10aryl, C1-9heteroaryl, and -S(O)2R 13 , wherein C1- 6alkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, and C1-6haloalkyl.
  • a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof [00126] In some embodiments is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1a is a spirocyclic C5-10heterocycloalkyl optionally substituted with one, two, or three R 7a .
  • each R 7a is independently selected from C 1-6 alkyl, -C(O)R 13 , and -S(O) 2 R 13 , wherein C 1-6 alkyl is optionally substituted with one, two, or three groups selected from halogen, C 1-6 haloalkyl, -OR 10 , -N(R 10 )(R 11 ), and -C(O)OR 10 .
  • R 1a is selected from [00127]
  • Formula (IIa4) is a compound of Formula (IIa5), or a pharmaceutically acceptable salt or solvate thereof: Formula (IIa5).
  • a compound of Formula (IIa6) is a pharmaceutically acceptable salt or solvate thereof: Formula (IIa6).
  • X 1 , X 2 , and X 3 are each independently CR 3 or N; Y 1 is CR 4 or N; Y 3 is CR 4 or N; Z 1 , Z 2 , and Z 3 are each independently CR 5 or N; L 1a is selected from a bond, -C(O)-, and -C(R 10 )(R 11 )-; R 1a is selected from: a) a monocyclic C2-5heterocycloalkyl substituted with one, two, or three R 6a ; b) a monocyclic C3-10cycloalkyl substituted with one, two, or three R 6b ; c) a monocyclic C1-5heteroaryl optionally substituted with one, two, or three R 7a ; d) a spirocyclic C5-10he
  • a compound of Formula (IIb), or a pharmaceutically acceptable salt or solvate thereof wherein Y 3 is CR 4 and R 4 is H, halogen, or C 1-6 alkyl.
  • Y 1 is N.
  • a compound of Formula (IIb), or a pharmaceutically acceptable salt or solvate thereof wherein Y 1 is CR 4 and R 4 is H, halogen, C1-6alkyl, C1- 6haloalkyl, -N(R 10 )(R 11 ), or -C(O)R 13 .
  • a compound of Formula (IIb), or a pharmaceutically acceptable salt or solvate thereof wherein Y 1 is CR 4 and R 4 is H, halogen, or C1-6alkyl.
  • X 1 , X 2 , and X 3 are each CR 3 .
  • X 1 , X 2 , and X 3 are each CR 3 and each R 3 is independently selected from H, halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, and -OR 10 .
  • a compound of Formula (IIb), or a pharmaceutically acceptable salt or solvate thereof wherein X 1 , X 2 , and X 3 are each CR 3 and each R 3 is independently selected from H, halogen, C 1-6 alkyl, and C 1-6 haloalkyl.
  • a compound of Formula (IIb), or a pharmaceutically acceptable salt or solvate thereof wherein X 1 , X 2 , and X 3 are each CR 3 and each R 3 is independently selected from H, halogen, and C 1-6 haloalkyl.
  • a compound of Formula (IIb), or a pharmaceutically acceptable salt or solvate thereof wherein X 1 is C(F), X 2 is C(H), and X 3 is C(CF3).
  • a compound of Formula (IIb), or a pharmaceutically acceptable salt or solvate thereof wherein X 1 is C(F), X 2 is C(F), and X 3 is C(H).
  • a compound of Formula (IIb), or a pharmaceutically acceptable salt or solvate thereof wherein X 1 is C(F), X 2 is C(H), and X 3 is C(F).
  • a compound of Formula (IIb), or a pharmaceutically acceptable salt or solvate thereof wherein X 1 is C(F), X 2 is C(H), and X 3 is C(Cl).
  • a compound of Formula (IIb), or a pharmaceutically acceptable salt or solvate thereof wherein X 1 is C(Cl), X 2 is C(H), and X 3 is C(CF3).
  • a compound of Formula (IIb), or a pharmaceutically acceptable salt or solvate thereof wherein X 1 is C(Cl), X 2 is C(H), and X 3 is C(H).
  • a compound of Formula (IIb), or a pharmaceutically acceptable salt or solvate thereof wherein X 1 is C(H), X 2 is C(H), and X 3 is C(F).
  • a compound of Formula (IIb), or a pharmaceutically acceptable salt or solvate thereof wherein X 1 is C(H), X 2 is C(H), and X 3 is C(Cl).
  • R 2 is selected from H, halogen, C1-6alkyl, C1- 6haloalkyl, and -OR 10 .
  • a compound of Formula (IIb), or a pharmaceutically acceptable salt or solvate thereof wherein Z 1 is CR 5 ; and Z 2 and Z 3 are N.
  • each R 5 is independently selected from H, halogen, -CN, C1-6alkyl, and -OR 10 .
  • Z 1 is N; and Z 2 and Z 3 are C(H).
  • R 10a is hydrogen.
  • R 10a is C1- 6alkyl optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, and C1-9heteroaryl.
  • a compound of Formula (IIb), or a pharmaceutically acceptable salt or solvate thereof wherein R 10a is -CH3.
  • R 1a is a monocyclic C 2-5 heterocycloalkyl substituted with one, two, or three R 6a .
  • R 1a is a monocyclic C 2-5 heterocycloalkyl substituted with one, two, or three R 6a and wherein the monocyclic C2-5heterocycloalkyl is selected from piperidinyl, pyrrolidinyl, tetrahydropyranyl, and tetrahydrofuranyl.
  • each R 6a is independently selected from halogen, oxo, C1-6alkyl, C1-6haloalkyl, C6-10aryl, C1-9heteroaryl, -OR 10 , -C(O)OR 10 , - C(O)N(R 10 )(R 11 ), and -S(O)2R 13 , wherein C1-6alkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, C6- 10aryl, -OR 10 , and C1-6haloalkyl.
  • each R 6a is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, phenyl, and -S(O) 2 R 13 , wherein C 1-6 alkyl and phenyl are unsubstituted.
  • R 1a is a monocyclic C 3-10 cycloalkyl substituted with one, two, or three R 6b .
  • each R 6b is independently selected from halogen, C1-6alkyl, C1-6haloalkyl, C6-10aryl, C1-9heteroaryl, -OH, and - S(O)2R 13 , wherein C1-6alkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -OH, C1-6alkyl, and C1-6haloalkyl.
  • R 1a is a monocyclic C 1-5 heteroaryl optionally substituted with one, two, or three R 7a .
  • each R 7a is independently selected from halogen, C1-6alkyl, C1-6haloalkyl, C6-10aryl, C1-9heteroaryl, and -S(O)2R 13 , wherein C1- 6alkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, and C1-6haloalkyl.
  • a compound of Formula (IIb), or a pharmaceutically acceptable salt or solvate thereof [00145] In some embodiments is a compound of Formula (IIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1a is a spirocyclic C5-10heterocycloalkyl optionally substituted with one, two, or three R 7a .
  • each R 7a is independently selected from C 1-6 alkyl, -C(O)R 13 , and -S(O) 2 R 13 , wherein C 1-6 alkyl is optionally substituted with one, two, or three groups selected from halogen, C 1-6 haloalkyl, -OR 10 , -N(R 10 )(R 11 ), and -C(O)OR 10 .
  • a compound of Formula (IIb), or a pharmaceutically acceptable salt or solvate thereof wherein R 1a is selected from [00146]
  • a compound of Formula (IIc), or a pharmaceutically acceptable salt or solvate thereof wherein Y 3 is CR 4 and R 4 is H, halogen, or C1-6alkyl.
  • Y 1 is N.
  • a compound of Formula (IIc), or a pharmaceutically acceptable salt or solvate thereof wherein Y 1 is CR 4 and R 4 is H, halogen, C1-6alkyl, C1- 6haloalkyl, -N(R 10 )(R 11 ), or -C(O)R 13 .
  • a compound of Formula (IIc), or a pharmaceutically acceptable salt or solvate thereof wherein Y 1 is CR 4 and R 4 is H, halogen, or C1-6alkyl.
  • X 1 , X 2 , and X 3 are each CR 3 .
  • X 1 , X 2 , and X 3 are each CR 3 and each R 3 is independently selected from H, halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, and -OR 10 .
  • a compound of Formula (IIc), or a pharmaceutically acceptable salt or solvate thereof wherein X 1 , X 2 , and X 3 are each CR 3 and each R 3 is independently selected from H, halogen, C1-6alkyl, and C1-6haloalkyl.
  • a compound of Formula (IIc), or a pharmaceutically acceptable salt or solvate thereof wherein X 1 , X 2 , and X 3 are each CR 3 and each R 3 is independently selected from H, halogen, and C1-6haloalkyl.
  • a compound of Formula (IIc), or a pharmaceutically acceptable salt or solvate thereof wherein X 1 is C(F), X 2 is C(H), and X 3 is C(CF3).
  • a compound of Formula (IIc), or a pharmaceutically acceptable salt or solvate thereof wherein X 1 is C(F), X 2 is C(F), and X 3 is C(H).
  • a compound of Formula (IIc), or a pharmaceutically acceptable salt or solvate thereof wherein X 1 is C(F), X 2 is C(H), and X 3 is C(F).
  • a compound of Formula (IIc), or a pharmaceutically acceptable salt or solvate thereof wherein X 1 is C(F), X 2 is C(H), and X 3 is C(Cl).
  • a compound of Formula (IIc), or a pharmaceutically acceptable salt or solvate thereof wherein X 1 is C(Cl), X 2 is C(H), and X 3 is C(CF3).
  • a compound of Formula (IIc), or a pharmaceutically acceptable salt or solvate thereof wherein X 1 is C(Cl), X 2 is C(H), and X 3 is C(H).
  • a compound of Formula (IIc), or a pharmaceutically acceptable salt or solvate thereof wherein X 1 is C(H), X 2 is C(H), and X 3 is C(F).
  • a compound of Formula (IIc), or a pharmaceutically acceptable salt or solvate thereof wherein X 1 is C(H), X 2 is C(H), and X 3 is C(Cl).
  • R 2 is selected from H, halogen, C1-6alkyl, C1- 6haloalkyl, and -OR 10 .
  • a compound of Formula (IIc), or a pharmaceutically acceptable salt or solvate thereof wherein Z 1 is CR 5 ; and Z 2 and Z 3 are N.
  • each R 5 is independently selected from H, halogen, -CN, C1-6alkyl, and -OR 10 .
  • Z 1 is N; and Z 2 and Z 3 are C(H).
  • Z 4 is C(H).
  • R 10a is C 1- 6 alkyl optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, and C1-9heteroaryl.
  • R 10a is -CH3.
  • a compound of Formula (IIc), or a pharmaceutically acceptable salt or solvate thereof wherein R 1a is a monocyclic C2-5heterocycloalkyl substituted with one, two, or three R 6a .
  • R 1a is a monocyclic C2-5heterocycloalkyl substituted with one, two, or three R 6a and wherein the monocyclic C 2-5 heterocycloalkyl is selected from piperidinyl, pyrrolidinyl, tetrahydropyranyl, and tetrahydrofuranyl.
  • each R 6a is independently selected from halogen, oxo, C1-6alkyl, C1-6haloalkyl, C6-10aryl, C1-9heteroaryl, -OR 10 , -C(O)OR 10 , - C(O)N(R 10 )(R 11 ), and -S(O)2R 13 , wherein C1-6alkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, C6- 10aryl, -OR 10 , and C1-6haloalkyl.
  • each R 6a is independently selected from C1-6alkyl, C1-6haloalkyl, phenyl, and -S(O)2R 13 , wherein C1-6alkyl and phenyl are unsubstituted.
  • R 1a is a monocyclic C3-10cycloalkyl substituted with one, two, or three R 6b .
  • each R 6b is independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 6-10 aryl, C 1-9 heteroaryl, -OH, and - S(O) 2 R 13 , wherein C 1-6 alkyl, C 6-10 aryl, and C 1-9 heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -OH, C1-6alkyl, and C1-6haloalkyl.
  • R 1a is a monocyclic C1-5heteroaryl optionally substituted with one, two, or three R 7a .
  • each R 7a is independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 6-10 aryl, C 1-9 heteroaryl, and -S(O) 2 R 13 , wherein C 1- 6alkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, and C1-6haloalkyl.
  • R 1a is selected from .
  • R 1a is a spirocyclic C 5-10 heterocycloalkyl optionally substituted with one, two, or three R 7a .
  • each R 7a is independently selected from C 1-6 alkyl, -C(O)R 13 , and -S(O) 2 R 13 , wherein C 1-6 alkyl is optionally substituted with one, two, or three groups selected from halogen, C 1-6 haloalkyl, -OR 10 , -N(R 10 )(R 11 ), and -C(O)OR 10 .
  • R 1a is selected from , , and .
  • compounds described herein are in the form of pharmaceutically acceptable salts.
  • active metabolites of these compounds having the same type of activity are included in the scope of the present disclosure.
  • the compounds described herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. The solvated forms of the compounds presented herein are also considered to be disclosed herein.
  • “Pharmaceutically acceptable,” as used herein, refers a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound, and is relatively nontoxic, i.e., the material is administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.
  • pharmaceutically acceptable salt refers to a form of a therapeutically active agent that consists of a cationic form of the therapeutically active agent in combination with a suitable anion, or in alternative embodiments, an anionic form of the therapeutically active agent in combination with a suitable cation. Handbook of Pharmaceutical Salts: Properties, Selection and Use.
  • salt-forming molecule can be in equilibrium with a neutral form, passage through biological membranes can be adjusted.
  • pharmaceutically acceptable salts are obtained by reacting a compound described herein with an acid to provide a "pharmaceutically acceptable acid addition salt.”
  • the compound described herein i.e. free base form
  • the compound described herein is basic and is reacted with an organic acid or an inorganic acid.
  • Inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and metaphosphoric acid.
  • Organic acids include, but are not limited to, 1-hydroxy-2-naphthoic acid; 2,2-dichloroacetic acid; 2-hydroxyethanesulfonic acid; 2-oxoglutaric acid; 4-acetamidobenzoic acid; 4-aminosalicylic acid; acetic acid; adipic acid; ascorbic acid (L); aspartic acid (L); benzenesulfonic acid; benzoic acid; camphoric acid (+); camphor-10-sulfonic acid (+); capric acid (decanoic acid); caproic acid (hexanoic acid); caprylic acid (octanoic acid); carbonic acid; cinnamic acid; citric acid; cyclamic acid; dodecylsulfuric acid; ethane-1,2-disulfonic acid; ethanesulfonic acid; formic acid; fumaric acid; galactaric acid; gentisic acid; glucoheptonic acid (D); glu
  • a compound described herein is prepared as a chloride salt, sulfate salt, bromide salt, mesylate salt, maleate salt, citrate salt or phosphate salt.
  • pharmaceutically acceptable salts are obtained by reacting a compound described herein with a base to provide a "pharmaceutically acceptable base addition salt.”
  • the compound described herein is acidic and is reacted with a base. In such situations, an acidic proton of the compound described herein is replaced by a metal ion, e.g., lithium, sodium, potassium, magnesium, calcium, or an aluminum ion.
  • compounds described herein coordinate with an organic base, such as, but not limited to, ethanolamine, diethanolamine, triethanolamine, tromethamine, meglumine, N-methylglucamine, dicyclohexylamine, tris(hydroxymethyl)methylamine.
  • compounds described herein form salts with amino acids such as, but not limited to, arginine, lysine, and the like.
  • Acceptable inorganic bases used to form salts with compounds that include an acidic proton include, but are not limited to, aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydroxide, lithium hydroxide, and the like.
  • the compounds provided herein are prepared as a sodium salt, calcium salt, potassium salt, magnesium salt, meglumine salt, N-methylglucamine salt or ammonium salt.
  • a reference to a pharmaceutically acceptable salt includes the solvent addition forms.
  • solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and are formed during the process of isolating or purifying the compound with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of compounds described herein are conveniently prepared or formed during the processes described herein.
  • the compounds provided herein optionally exist in unsolvated as well as solvated forms.
  • the methods and formulations described herein include the use of N-oxides (if appropriate), crystalline forms (also known as polymorphs), or pharmaceutically acceptable salts of compounds described herein, as well as active metabolites of these compounds having the same type of activity.
  • sites on the organic groups (e.g., alkyl groups, aromatic rings) of compounds described herein are susceptible to various metabolic reactions. Incorporation of appropriate substituents on the organic groups will reduce, minimize or eliminate this metabolic pathway.
  • the appropriate substituent to decrease or eliminate the susceptibility of the aromatic ring to metabolic reactions is, by way of example only, a halogen, deuterium, an alkyl group, a haloalkyl group, or a deuteroalkyl group.
  • the compounds described herein are labeled isotopically (e.g., with a radioisotope) or by another other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.
  • Compounds described herein include isotopically-labeled compounds, which are identical to those recited in the various formulae and structures presented herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that can be incorporated into the present compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine and chlorine, such as, for example, 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 35 S, 18 F, 36 Cl.
  • isotopically-labeled compounds described herein for example those into which radioactive isotopes such as 3 H and 14 C are incorporated, are useful in drug and/or substrate tissue distribution assays.
  • substitution with isotopes such as deuterium affords certain therapeutic advantages resulting from greater metabolic stability, such as, for example, increased in vivo half-life or reduced dosage requirements.
  • one or more hydrogen atoms of the compounds described herein is replaced with deuterium.
  • the compounds described herein possess one or more stereocenters and each stereocenter exists independently in either the R or S configuration.
  • the compounds presented herein include all diastereomeric, enantiomeric, atropisomers, and epimeric forms as well as the appropriate mixtures thereof.
  • the compounds and methods provided herein include all cis, trans, syn, anti,
  • E
  • Z
  • Individual stereoisomers are obtained, if desired, by methods such as, stereoselective synthesis and/or the separation of stereoisomers by chiral chromatographic columns.
  • compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds/salts, separating the diastereomers and recovering the optically pure enantiomers.
  • resolution of enantiomers is carried out using covalent diastereomeric derivatives of the compounds described herein.
  • diastereomers are separated by separation/resolution techniques based upon differences in solubility.
  • separation of stereoisomers is performed by chromatography or by the forming diastereomeric salts and separation by recrystallization, or chromatography, or any combination thereof.
  • prodrugs refers to an agent that is converted into the parent drug in vivo. Prodrugs are often useful because, in some situations, they are easier to administer than the parent drug. They are, for instance, bioavailable by oral administration whereas the parent is not.
  • the prodrug may be a substrate for a transporter. Further or alternatively, the prodrug also has improved solubility in pharmaceutical compositions over the parent drug.
  • the design of a prodrug increases the effective water solubility.
  • a prodrug is a compound described herein, which is administered as an ester (the “prodrug”) but then is metabolically hydrolyzed to provide the active entity.
  • a further example of a prodrug is a short peptide (polyaminoacid) bonded to an acid group where the peptide is metabolized to reveal the active moiety.
  • a prodrug upon in vivo administration, a prodrug is chemically converted to the biologically, pharmaceutically, or therapeutically active form of the compound.
  • a prodrug is enzymatically metabolized by one or more steps or processes to the biologically, pharmaceutically or therapeutically active form of the compound.
  • Prodrugs of the compounds described herein include, but are not limited to, esters, ethers, carbonates, thiocarbonates, N-acyl derivatives, N-acyloxyalkyl derivatives, quaternary derivatives of tertiary amines, N-Mannich bases, Schiff bases, amino acid conjugates, phosphate esters, and sulfonate esters. See for example Design of Prodrugs, Bundgaard, A. Ed., Elseview, 1985 and Method in Enzymology, Widder, K.
  • a hydroxyl group in the compounds disclosed herein is used to form a prodrug, wherein the hydroxyl group is incorporated into an acyloxyalkyl ester, alkoxycarbonyloxyalkyl ester, alkyl ester, aryl ester, phosphate ester, sugar ester, ether, and the like.
  • a hydroxyl group in the compounds disclosed herein is a prodrug wherein the hydroxyl is then metabolized in vivo to provide a carboxylic acid group.
  • a carboxyl group is used to provide an ester or amide (i.e. the prodrug), which is then metabolized in vivo to provide a carboxylic acid group.
  • compounds described herein are prepared as alkyl ester prodrugs.
  • Prodrug forms of the herein described compounds, wherein the prodrug is metabolized in vivo to produce a compound described herein as set forth herein are included within the scope of the claims.
  • some of the herein-described compounds is a prodrug for another derivative or active compound.
  • a prodrug of the compound disclosed herein permits targeted delivery of the compound to a particular region of the gastrointestinal tract. Formation of a pharmacologically active metabolite by the colonic metabolism of drugs is a commonly used “prodrug” approach for the colon-specific drug delivery systems.
  • a prodrug is formed by the formation of a covalent linkage between drug and a carrier in such a manner that upon oral administration the moiety remains intact in the stomach and small intestine.
  • This approach involves the formation of a prodrug, which is a pharmacologically inactive derivative of a parent drug molecule that requires spontaneous or enzymatic transformation in the biological environment to release the active drug.
  • Formation of prodrugs has improved delivery properties over the parent drug molecule. The problem of stability of certain drugs from the adverse environment of the upper gastrointestinal tract can be eliminated by prodrug formation, which is converted into the parent drug molecule once it reaches the colon.
  • Site specific drug delivery through site specific prodrug activation may be accomplished by the utilization of some specific property at the target site, such as altered pH or high activity of certain enzymes relative to the non-target tissues for the prodrug-drug conversion.
  • covalent linkage of the drug with a carrier forms a conjugate.
  • conjugates include, but are not limited to, azo bond conjugates, glycoside conjugates, glucuronide conjugates, cyclodextrin conjugates, dextran conjugates or amino- acid conjugates.
  • the compounds described herein are metabolized upon administration to an organism in need to produce a metabolite that is then used to produce a desired effect, including a desired therapeutic effect.
  • a “metabolite” of a compound disclosed herein is a derivative of that compound that is formed when the compound is metabolized.
  • active metabolite refers to a biologically active derivative of a compound that is formed when the compound is metabolized.
  • metabolized refers to the sum of the processes (including, but not limited to, hydrolysis reactions and reactions catalyzed by enzymes) by which a particular substance is changed by an organism. Thus, enzymes may produce specific structural alterations to a compound.
  • cytochrome P450 catalyzes a variety of oxidative and reductive reactions while uridine diphosphate glucuronyltransferases catalyze the transfer of an activated glucuronic-acid molecule to aromatic alcohols, aliphatic alcohols, carboxylic acids, amines and free sulphydryl groups.
  • Metabolites of the compounds disclosed herein are optionally identified either by administration of compounds to a host and analysis of tissue samples from the host, or by incubation of compounds with hepatic cells in vitro and analysis of the resulting compounds.
  • the compounds are rapidly metabolized in plasma.
  • the compounds are rapidly metabolized by the intestines.
  • the compounds are rapidly metabolized by the liver.
  • Synthesis of Compounds Compounds described herein are synthesized using standard synthetic techniques or using methods known in the art in combination with methods described herein. [00187] Unless otherwise indicated, conventional methods of mass spectroscopy, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques and pharmacology are employed. [00188] Compounds are prepared using standard organic chemistry techniques such as those described in, for example, March’s Advanced Organic Chemistry, 6 th Edition, John Wiley and Sons, Inc.
  • C 1 -C x includes C 1 -C 2 , C 1 -C 3 ... C 1 -C x .
  • a group designated as "C 1 -C 4 " indicates that there are one to four carbon atoms in the moiety, i.e.
  • C1-C4 alkyl indicates that there are one to four carbon atoms in the alkyl group, i.e., the alkyl group is selected from among methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl.
  • An “alkyl” group refers to an aliphatic hydrocarbon group. The alkyl group is branched or straight chain. In some embodiments, the “alkyl” group has 1 to 10 carbon atoms, i.e.
  • an alkyl is a C 1 -C 6 alkyl.
  • the alkyl is methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, or t-butyl.
  • Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tertiary butyl, pentyl, neopentyl, or hexyl.
  • An “alkylene” group refers to a divalent alkyl group. Any of the above mentioned monovalent alkyl groups may be an alkylene by abstraction of a second hydrogen atom from the alkyl.
  • an alkylene is a C1-C6alkylene. In other embodiments, an alkylene is a C1-C4alkylene. In certain embodiments, an alkylene comprises one to four carbon atoms (e.g., C 1 -C 4 alkylene). In other embodiments, an alkylene comprises one to three carbon atoms (e.g., C 1 -C 3 alkylene). In other embodiments, an alkylene comprises one to two carbon atoms (e.g., C 1 -C 2 alkylene). In other embodiments, an alkylene comprises one carbon atom (e.g., C1 alkylene).
  • an alkylene comprises two carbon atoms (e.g., C2 alkylene). In other embodiments, an alkylene comprises two to four carbon atoms (e.g., C2-C4 alkylene).
  • Typical alkylene groups include, but are not limited to, -CH2-, -CH(CH3)-, -C(CH3)2-, - CH2CH2-, -CH2CH(CH3)-, -CH2C(CH3)2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, and the like.
  • “Deuteroalkyl” refers to an alkyl group where 1 or more hydrogen atoms of an alkyl are replaced with deuterium.
  • alkenyl refers to a type of alkyl group in which at least one carbon- carbon double bond is present.
  • R is H or an alkyl.
  • an alkenyl is selected from ethenyl (i.e., vinyl), propenyl (i.e., allyl), butenyl, pentenyl, pentadienyl, and the like.
  • alkynyl refers to a type of alkyl group in which at least one carbon- carbon triple bond is present.
  • an alkenyl group has the formula -C_7- R, wherein R refers to the remaining portions of the alkynyl group.
  • R is H or an alkyl.
  • an alkynyl is selected from ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.
  • an alkynyl group MQGOWHI &7_7;% &7_77;3 &7_77;2CH3, -CH27_7;' [00198]
  • An “alkoxy” group refers to a (alkyl)O- group, where alkyl is as defined herein.
  • alkylamine refers to the –N(alkyl) x H y group, where x is 0 and y is 2, or where x is 1 and y is 1, or where x is 2 and y is 0.
  • aromatic refers to a planar ring having a delocalized t-electron system containing 4n+2 t electrons, where n is an integer.
  • aromatic includes both carbocyclic aryl (“aryl”, e.g., phenyl) and heterocyclic aryl (or “heteroaryl” or “heteroaromatic”) groups (e.g., pyridine).
  • the term includes monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of carbon or nitrogen atoms) groups.
  • the term “carbocyclic” or “carbocycle” refers to a ring or ring system where the atoms forming the backbone of the ring are all carbon atoms. The term thus distinguishes carbocyclic from “heterocyclic” rings or “heterocycles” in which the ring backbone contains at least one atom which is different from carbon. In some embodiments, at least one of the two rings of a bicyclic carbocycle is aromatic. In some embodiments, both rings of a bicyclic carbocycle are aromatic. Carbocycle includes cycloalkyl and aryl.
  • aryl refers to an aromatic ring wherein each of the atoms forming the ring is a carbon atom.
  • aryl is phenyl or a naphthyl.
  • an aryl is a phenyl.
  • an aryl is a C6-C10aryl.
  • an aryl group is a monoradical or a diradical (i.e., an arylene group).
  • cycloalkyl refers to a monocyclic or polycyclic aliphatic, non-aromatic group, wherein each of the atoms forming the ring (i.e. skeletal atoms) is a carbon atom.
  • cycloalkyls are spirocyclic, fused, or bridged compounds.
  • cycloalkyls are fully saturated.
  • cycloalkyls are partially unsaturated.
  • cycloalkyls are optionally fused with an aromatic ring, and the point of attachment is at a carbon that is not an aromatic ring carbon atom.
  • Cycloalkyl groups include groups having from 3 to 14 ring atoms.
  • cycloalkyl groups are selected from among cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, spiro[2.2]pentyl, norbornyl and bicyclo[1.1.1]pentyl.
  • a cycloalkyl is a C3-C6cycloalkyl.
  • a cycloalkyl is a monocyclic cycloalkyl.
  • Monocyclic cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • Polycyclic cycloalkyls include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like.
  • aryl is a C 1 -C 9 aryl.
  • monocyclicaryl is a C 1 -C 6 aryl.
  • monocyclic aryl is a 5-membered or 6-membered aryl.
  • bicyclic aryl is a C6-C9aryl.
  • a fused bicyclic will refer to a non-aromatic cyclic groups (also known as cycloalkyls) containing two fused rings having 6 to 14 atoms in the fused ring system.
  • the used bicyclic will refer to a non-aromatic cyclic groups (also known as cycloalkyls) containing two fused rings having 6 to 10 atoms in the fused ring system.
  • halo or, alternatively, “halogen” or “halide” means fluoro, chloro, bromo or iodo. In some embodiments, halo is fluoro, chloro, or bromo.
  • haloalkyl refers to an alkyl in which one or more hydrogen atoms are replaced by a halogen atom. In one aspect, a fluoroalkyl is a C1-C6fluoroalkyl.
  • fluoroalkyl refers to an alkyl in which one or more hydrogen atoms are replaced by a fluorine atom.
  • a fluoroalkyl is a C1-C6fluoroalkyl.
  • a fluoroalkyl is selected from trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like.
  • heteroalkyl refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g., -NH-, -N(alkyl)-, sulfur, or combinations thereof.
  • a heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl.
  • a heteroalkyl is a C 1 -C 6 heteroalkyl.
  • heteroalkylene refers to a divalent heteroalkyl group.
  • heterocycle refers to heteroaromatic rings (also known as heteroaryls) and heterocycloalkyl rings (also known as heteroalicyclic groups) containing one to four heteroatoms in the ring(s), where each heteroatom in the ring(s) is selected from O, S and N, wherein each heterocyclic group has from 3 to 14 atoms in its ring system, and with the proviso that any ring does not contain two adjacent O or S atoms.
  • heterocycles are monocyclic, bicyclic, polycyclic, spirocyclic, fused, or bridged compounds.
  • Non-aromatic heterocyclic groups include rings having 3 to 10 atoms in its ring system and aromatic heterocyclic groups include rings having 5 to 10 atoms in its ring system.
  • the heterocyclic groups include benzo-fused ring systems.
  • non-aromatic heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, oxazolidinonyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxanyl, piperazinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6- tetrahydropyridinyl, pyrrolin-2-yl, pyrrolin-3-yl, indolinyl, 2H-pyranyl, 4H- pyranyl, dioxazo
  • aromatic heterocyclic groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinox
  • a group derived from pyrrole includes both pyrrol-1-yl (N-attached) or pyrrol-3-yl (C-attached).
  • a group derived from imidazole includes imidazol-1-yl or imidazol-3-yl (both N-attached) or imidazol-2-yl, imidazol-4-yl or imidazol-5-yl (all C-attached).
  • the heterocyclic groups include benzo-fused ring systems.
  • at least one of the two rings of a bicyclic heterocycle is aromatic.
  • both rings of a bicyclic heterocycle are aromatic.
  • a heteroaryl contains 0-4 N atoms in the ring.
  • a heteroaryl contains 1-4 N atoms in the ring.
  • a heteroaryl contains 0-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring.
  • a heteroaryl contains 1-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring.
  • heteroaryl is a C 1 -C 9 heteroaryl.
  • monocyclic heteroaryl is a C 1 -C 5 heteroaryl.
  • monocyclic heteroaryl is a 5-membered or 6-membered heteroaryl.
  • bicyclic heteroaryl is a C 6 -C 9 heteroaryl.
  • a fused bicyclic will refer to a non-aromatic heterocyclic groups (also known as heterocycloalkyls) containing two fused rings having 6 to 14 atoms in the fused ring system and containing at least 1-6 heteroatoms selected from N, O, S, or P.
  • the used bicyclic will refer to a non- aromatic heterocyclic groups (also known as heterocycloalkyls) containing two fused rings having 6 to 10 atoms in the fused ring system and containing at least 1- 6 heteroatoms selected from N, O, S, or P.
  • heteroaryl or, alternatively, “heteroaromatic” refers to an aryl group that includes one or more ring heteroatoms selected from nitrogen, oxygen and sulfur.
  • heteroaryl groups include monocyclic heteroaryls and bicyclic heteroaryls.
  • Monocyclic heteroaryls include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, and furazanyl.
  • Bicyclic heteroaryls include indolizine, indole, benzofuran, benzothiophene, indazole, benzimidazole, benzotriazole, purine, quinolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthyridine, and pteridine.
  • a heteroaryl contains 0-4 N atoms in the ring.
  • a heteroaryl contains 1-4 N atoms in the ring.
  • a heteroaryl contains 0-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring.
  • a heteroaryl contains 1-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring.
  • heteroaryl is a C1-C9heteroaryl.
  • monocyclic heteroaryl is a C1- C5heteroaryl.
  • monocyclic heteroaryl is a 5-membered or 6- membered heteroaryl.
  • bicyclic heteroaryl is a C6-C9heteroaryl.
  • a group described herein when a group described herein is a bond, the referenced group is absent thereby allowing a bond to be formed between the remaining identified groups.
  • the term “moiety” refers to a specific segment or functional group of a molecule. Chemical moieties are often recognized chemical entities embedded in or appended to a molecule. [00213] The term “optionally substituted” or “substituted” means that the referenced group is optionally substituted with one or more additional group(s).
  • optional substituents are independently selected from D, halogen, -CN, - NH2, -OH, -NH(CH3), -N(CH3)2, -CH3, -CH2CH3, -CF3, -OCH3, and -OCF3.
  • substituted groups are substituted with one or two of the preceding groups.
  • substituted groups are substituted with one of the preceding groups.
  • modulate means to interact with a target either directly or indirectly so as to alter the activity of the target, including, by way of example only, to enhance the activity of the target, to inhibit the activity of the target, to limit the activity of the target, or to extend the activity of the target.
  • modulator refers to a molecule that interacts with a target either directly or indirectly. The interactions include, but are not limited to, the interactions of an agonist, partial agonist, an inverse agonist, antagonist, degrader, or combinations thereof. In some embodiments, a modulator is an agonist.
  • administer refers to the methods that may be used to enable delivery of compounds or compositions to the desired site of biological action. These methods include, but are not limited to oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular or infusion), topical and rectal administration. Those of skill in the art are familiar with administration techniques that can be employed with the compounds and methods described herein. In some embodiments, the compounds and compositions described herein are administered orally.
  • the terms “co-administration” or the like, as used herein, are meant to encompass administration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are administered by the same or different route of administration or at the same or different time.
  • the terms “effective amount” or “therapeutically effective amount,” as used herein, refer to a sufficient amount of an agent or a compound being administered, which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result includes reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system.
  • an “effective amount” for therapeutic uses is the amount of the composition comprising a compound as disclosed herein required to provide a clinically significant decrease in disease symptoms.
  • An appropriate “effective” amount in any individual case is optionally determined using techniques, such as a dose escalation study.
  • the terms “enhance” or “enhancing,” as used herein, means to increase or prolong either in potency or duration a desired effect.
  • the term “enhancing” refers to the ability to increase or prolong, either in potency or duration, the effect of other therapeutic agents on a system.
  • An “enhancing-effective amount,” as used herein, refers to an amount adequate to enhance the effect of another therapeutic agent in a desired system.
  • the terms “kit” and “article of manufacture” are used as synonyms.
  • the term “subject” or “patient” encompasses mammals. Examples of mammals include, but are not limited to, any member of the Mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like. In one aspect, the mammal is a human.
  • compositions include alleviating, abating or ameliorating at least one symptom of a disease or condition, preventing additional symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition either prophylactically and/or therapeutically.
  • Pharmaceutical compositions [00224] In some embodiments, the compounds described herein are formulated into pharmaceutical compositions. Pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable inactive ingredients that facilitate processing of the active compounds into preparations that are used pharmaceutically.
  • the compounds described herein are administered either alone or in combination with pharmaceutically acceptable carriers, excipients or diluents, in a pharmaceutical composition.
  • Administration of the compounds and compositions described herein can be affected by any method that enables delivery of the compounds to the site of action.
  • enteral routes including oral, gastric or duodenal feeding tube, rectal suppository and rectal enema
  • parenteral routes injection or infusion, including intraarterial, intracardiac, intradermal, intraduodenal, intramedullary, intramuscular, intraosseous, intraperitoneal, intrathecal, intravascular, intravenous, intravitreal, epidural and subcutaneous), inhalational, transdermal, transmucosal, sublingual, buccal and topical (including epicutaneous, dermal, enema, eye drops, ear drops, intranasal, vaginal) administration, although the most suitable route may depend upon for example the condition and disorder of the recipient.
  • compositions suitable for oral administration are presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
  • the active ingredient is presented as a bolus, electuary or paste.
  • Pharmaceutical compositions which can be used orally include tablets, push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with binders, inert diluents, or lubricating, surface active or dispersing agents.
  • Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets are coated or scored and are formulated so as to provide slow or controlled release of the active ingredient therein. All formulations for oral administration should be in dosages suitable for such administration.
  • the push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • stabilizers are added.
  • Dragee cores are provided with suitable coatings.
  • suitable coatings may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • Dyestuffs or pigments may be added to the tablets or Dragee coatings for identification or to characterize different combinations of active compound doses.
  • pharmaceutical compositions are formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion.
  • Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative.
  • the compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • the compositions may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in powder form or in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, saline or sterile pyrogen-free water, immediately prior to use.
  • compositions for parenteral administration include aqueous and non-aqueous (oily) sterile injection solutions of the active compounds which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes.
  • Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran.
  • the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
  • Pharmaceutical compositions may also be formulated as a depot preparation. Such long-acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection.
  • the compounds may be formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • compositions may take the form of tablets, lozenges, pastilles, or gels formulated in conventional manner. Such compositions may comprise the active ingredient in a flavored basis such as sucrose and acacia or tragacanth.
  • Pharmaceutical compositions may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter, polyethylene glycol, or other glycerides.
  • Pharmaceutical compositions may be administered topically, that is by non- systemic administration.
  • compositions suitable for topical administration include liquid or semi-liquid preparations suitable for penetration through the skin to the site of inflammation such as gels, liniments, lotions, creams, ointments or pastes, and drops suitable for administration to the eye, ear or nose.
  • the active ingredient may comprise, for topical administration, from 0.001% to 10% w/w, for instance from 1% to 2% by weight of the formulation.
  • compositions for administration by inhalation are conveniently delivered from an insufflator, nebulizer pressurized packs or other convenient means of delivering an aerosol spray.
  • Pressurized packs may comprise a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • pharmaceutical preparations may take the form of a dry powder composition, for example a powder mix of the compound and a suitable powder base such as lactose or starch.
  • the powder composition may be presented in unit dosage form, in for example, capsules, cartridges, gelatin or blister packs from which the powder may be administered with the aid of an inhalator or insufflator.
  • a compound disclosed herein is formulated to provide a controlled release of the compound.
  • Controlled release refers to the release of the compound described herein from a dosage form in which it is incorporated according to a desired profile over an extended period of time.
  • Controlled release profiles include, for example, sustained release, prolonged release, pulsatile release, and delayed release profiles.
  • controlled release compositions allow delivery of an agent to a subject over an extended period of time according to a predetermined profile.
  • pH-sensitive polymers The majority of enteric and colon targeted delivery systems are based on the coating of tablets or pellets, which are filled into conventional hard gelatin capsules. Most commonly used pH-dependent coating polymers are methacrylic acid copolymers, commonly known as Eudragit® S, more specifically Eudragit® L and Eudragit® S. Eudragit® L100 and S 100 are copolymers of methacrylic acid and methyl methacrylate. Additional pH-dependent coating polymers include cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP), polyvinyl acetate phthalate (PVAP) and cellulose acetate trimelliate.
  • CAP cellulose acetate phthalate
  • HPMCP hydroxypropyl methylcellulose phthalate
  • PVAP polyvinyl acetate phthalate
  • Another approach towards colon-targeted drug delivery or controlled-release systems includes embedding the drug in polymer matrices to trap it and release it in the colon. These matrices can be pH-sensitive or biodegradable. Matrix-Based Systems, such as multi-matrix (MMX)-based delayed-release tablets, ensure the drug release in the colon.
  • MMX multi-matrix
  • Additional pharmaceutical approaches to targeted delivery of therapeutics to particular regions of the gastrointestinal tract are known. Chourasia MK, Jain SK, Pharmaceutical approaches to colon targeted drug delivery systems., J Pharm Sci.2003 Jan-Apr; 6(1):33-66. Patel M, Shah T, Amin A.
  • the compounds and compositions described herein may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.
  • Methods of Dosing and Treatment Regimens [00252]
  • the compounds described herein, or a pharmaceutically acceptable salt thereof are used in the preparation of medicaments for the treatment of diseases or conditions in a mammal that would benefit from administration of an HSD17B13 inhibitor.
  • Methods for treating any of the diseases or conditions described herein in a mammal in need of such treatment involves administration of pharmaceutical compositions that include at least one compound described herein or a pharmaceutically acceptable salt, active metabolite, prodrug, or pharmaceutically acceptable solvate thereof, in therapeutically effective amounts to said mammal.
  • described herein is a method of treating or preventing a liver disease or condition in a mammal, comprising administering to the mammal a compound of Formula (I), (Ia), (Ib), (Ic), (II), (IIa), (IIb), or (IIc), or a pharmaceutically acceptable salt or solvate thereof.
  • liver disease or condition is an alcoholic liver disease or condition.
  • the liver disease or condition is a nonalcoholic liver disease or condition.
  • the liver disease or condition is liver inflammation, fatty liver (steatosis), liver fibrosis, hepatitis, cirrhosis, hepatocellular carcinoma, or combinations thereof.
  • the liver disease or condition is primary biliary cirrhosis, primary sclerosing cholangitis, cholestasis, nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), or combinations thereof.
  • the liver disease or condition is a chronic liver disease or condition.
  • described herein is a method of modulating HSD17B13 activity in a mammal, comprising administering to the mammal a compound of Formula (I), (Ia), (Ib), (Ic), (II), (IIa), (IIb), or (IIc), or a pharmaceutically acceptable salt or solvate thereof.
  • modulating comprises inhibiting HSD17B13 activity.
  • the mammal has a liver disease or condition selected from liver inflammation, fatty liver (steatosis), liver fibrosis, hepatitis, cirrhosis, hepatocellular carcinoma, and combinations thereof.
  • the mammal has a liver disease or condition selected from primary biliary cirrhosis, primary sclerosing cholangitis, cholestasis, nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), and combinations thereof.
  • NASH nonalcoholic steatohepatitis
  • NAFLD nonalcoholic fatty liver disease
  • compositions containing the compound(s) described herein are administered for prophylactic and/or therapeutic treatments.
  • the compositions are administered to a patient already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest at least one of the symptoms of the disease or condition. Amounts effective for this use depend on the severity and course of the disease or condition, previous therapy, the patient's health status, weight, and response to the drugs, and the judgment of the treating physician.
  • Therapeutically effective amounts are optionally determined by methods including, but not limited to, a dose escalation and/or dose ranging clinical trial.
  • compositions containing the compounds described herein are administered to a patient susceptible to or otherwise at risk of a particular disease, disorder, or condition. Such an amount is defined to be a "prophylactically effective amount or dose.”
  • prophylactically effective amount or dose the precise amounts also depend on the patient's state of health, weight, and the like. When used in patients, effective amounts for this use will depend on the severity and course of the disease, disorder, or condition, previous therapy, the patient's health status and response to the drugs, and the judgment of the treating physician.
  • prophylactic treatments include administering to a mammal, who previously experienced at least one symptom of the disease being treated and is currently in remission, a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt thereof, in order to prevent a return of the symptoms of the disease or condition.
  • a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt thereof, in order to prevent a return of the symptoms of the disease or condition.
  • the compounds are administered chronically, that is, for an extended period of time, including throughout the duration of the patient’s life in order to ameliorate or otherwise control or limit the symptoms of the patient’s disease or condition.
  • the dose of drug being administered is temporarily reduced or temporarily suspended for a certain length of time (i.e., a “drug holiday”).
  • the length of the drug holiday is between 2 days and 1 year, including by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, or more than 28 days.
  • the dose reduction during a drug holiday is, by way of example only, by 10%-100%, including by way of example only 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, and 100%.
  • a maintenance dose is administered if necessary. Subsequently, in specific embodiments, the dosage or the frequency of administration, or both, is reduced, as a function of the symptoms, to a level at which the improved disease, disorder, or condition is retained. In certain embodiments, however, the patient requires intermittent treatment on a long-term basis upon any recurrence of symptoms.
  • the amount of a given agent that corresponds to such an amount varies depending upon factors such as the particular compound, disease condition and its severity, the identity (e.g., weight, sex) of the subject or host in need of treatment, but nevertheless is determined according to the particular circumstances surrounding the case, including, e.g., the specific agent being administered, the route of administration, the condition being treated, and the subject or host being treated.
  • doses employed for adult human treatment are typically in the range of 0.01 mg-5000 mg per day. In one aspect, doses employed for adult human treatment are from about 1 mg to about 1000 mg per day.
  • the desired dose is conveniently presented in a single dose or in divided doses administered simultaneously or at appropriate intervals, for example as two, three, four or more sub- doses per day.
  • the daily dosages appropriate for the compound described herein, or a pharmaceutically acceptable salt thereof are from about 0.01 to about 50 mg/kg per body weight. In some embodiments, the daily dosage or the amount of active in the dosage form are lower or higher than the ranges indicated herein, based on a number of variables in regard to an individual treatment regime.
  • the daily and unit dosages are altered depending on a number of variables including, but not limited to, the activity of the compound used, the disease or condition to be treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition being treated, and the judgment of the practitioner.
  • Toxicity and therapeutic efficacy of such therapeutic regimens are determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, the determination of the LD 50 and the ED 50 .
  • the dose ratio between the toxic and therapeutic effects is the therapeutic index and it is expressed as the ratio between LD 50 and ED 50 .
  • the data obtained from cell culture assays and animal studies are used in formulating the therapeutically effective daily dosage range and/or the therapeutically effective unit dosage amount for use in mammals, including humans.
  • the daily dosage amount of the compounds described herein lies within a range of circulating concentrations that include the ED50 with minimal toxicity.
  • the daily dosage range and/or the unit dosage amount varies within this range depending upon the dosage form employed and the route of administration utilized.
  • any of the aforementioned aspects are further embodiments in which the effective amount of the compound described herein, or a pharmaceutically acceptable salt thereof, is: (a) systemically administered to the mammal; and/or (b) administered orally to the mammal; and/or (c) intravenously administered to the mammal; and/or (d) administered by injection to the mammal; and/or (e) administered topically to the mammal; and/or (f) administered non-systemically or locally to the mammal.
  • any of the aforementioned aspects are further embodiments comprising single administrations of the effective amount of the compound, including further embodiments in which (i) the compound is administered once a day; or (ii) the compound is administered to the mammal multiple times over the span of one day.
  • further embodiments comprising multiple administrations of the effective amount of the compound, including further embodiments in which (i) the compound is administered continuously or intermittently: as in a single dose; (ii) the time between multiple administrations is every 6 hours; (iii) the compound is administered to the mammal every 8 hours; (iv) the compound is administered to the mammal every 12 hours; (v) the compound is administered to the mammal every 24 hours.
  • the method comprises a drug holiday, wherein the administration of the compound is temporarily suspended or the dose of the compound being administered is temporarily reduced; at the end of the drug holiday, dosing of the compound is resumed.
  • the length of the drug holiday varies from 2 days to 1 year.
  • the compounds described herein, or a pharmaceutically acceptable salt thereof, as well as combination therapies, are administered before, during or after the occurrence of a disease or condition, and the timing of administering the composition containing a compound varies.
  • the compounds described herein are used as a prophylactic and are administered continuously to subjects with a propensity to develop conditions or diseases in order to prevent the occurrence of the disease or condition.
  • the compounds and compositions are administered to a subject during or as soon as possible after the onset of the symptoms.
  • a compound described herein is administered as soon as is practicable after the onset of a disease or condition is detected or suspected, and for a length of time necessary for the treatment of the disease.
  • the length required for treatment varies, and the treatment length is adjusted to suit the specific needs of each subject.
  • a compound described herein or a formulation containing the compound is administered for at least 2 weeks, about 1 month to about 5 years.
  • Step 2 3-Bromo-2,6-difluoro-5-(trifluoromethyl)phenol
  • Hydrogen peroxide (30 w/w in H2O, 69 mL) was slowly added to a solution of 2- (3-bromo-2,6-difluoro-5-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (23.6 g, 61 mmol) in methanol (240 mL).
  • the clear solution was stirred at rt for 5 h, quenched by the slow addition of saturated aqueous Na2S2O3 solution over ⁇ 1 h, stirred for 30 min, and then extracted twice with EtOAc.
  • Step 3 1-Bromo-2,4-difluoro-3-(methoxymethoxy)-5-(trifluoromethyl)benzene
  • Chloromethyl methyl ether (0.51 mL, 6.77 mmol) and DIEA (1.57 mL, 9.0 mmol) were added to a solution of 3-bromo-2,6-difluoro-5-(trifluoromethyl)phenol (1.25 g, 4.51 mmol) in CH2Cl2 (10 mL) at 0 b' BLI TIEGVMRQ YEU UVMTTIH EV TV RXITQMKLV% HMOWVIH with water, and then extracted with CH2Cl2.
  • Step 4 2-(2,4-Difluoro-3-(methoxymethoxy)-5-(trifluoromethyl)phenyl)-4,4,5,5- tetramethyl-1,3,2-dioxaborolane [00274]
  • Pd(dppf)Cl 2 54 mg, 0.07 mmol
  • the mixture was degassed EQH JMOOIH YMVL QMVTRKIQ , PRTI VMPIU% LIEVIH EV 1) b JRT , HE[U% GRROIH VR TV% GRQGIQVTEVIH under reduced pressure, and then purified by silica gel chromatography (0-20% EtOAc/heptanes) to give 2-(2,4-difluoro-3-(methoxymethoxy)-5-(trifluoromethyl)phenyl)- 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.36 g, 63%) as a colorless oil.
  • Step 2 2,6-Difluoro-3-(trifluoromethyl)phenol
  • Hydrogen peroxide 166 mL, 1.72 mol, 30% purity in H2O
  • a solution of (2,6-difluoro-3-(trifluoromethyl)phenyl)boronic acid 74.4 g, 329 mmol
  • Et2O ⁇ 600 mL
  • the mixture was heated to 40 °C, stirred for 4 h, and then allowed to cool to rt. The aqueous layer was separated.
  • the organic layer was cooled to 0 °C and then quenched with aqueous Na2SO3 (20% in H2O, ⁇ 500 mL) keeping the temperature ⁇ 20 °C.
  • the organic layer was separated.
  • the aqueous layer was extracted with EtOAc (2 ⁇ 300 ml).
  • Intermediate 1 was also synthesized from 2,6-difluoro-3-(trifluoromethyl)phenol (Intermediate 2, Step 2) following the procedures described for Intermediate 1 (Step 3) and Intermediate 2 (Step 4).
  • Intermediate 3 6-Chloro-3-iodo-1-methyl-1H-pyrazolo[3,4-d]pyrimidine
  • Iodomethane (7.99 mL, 128 mmol) was added to a mixture of 6-chloro-3-iodo- 1H-pyrazolo[3,4-d]pyrimidine (20.1 g, 71.3 mmol) and K2CO3 (29.6 g, 214 mmol) in DMF (200 mL) at 0 °C.
  • Step 2 6-(tert-Butoxy)-2,5-difluoronicotinaldehyde
  • DIBAL-H (1 M in toluene, 122 mL, 122 mmol) was added to a solution of 6- (tert-butoxy)-2,5-difluoronicotinonitrile (17 g, 80 mmol) in DCM (350 mL) at -78 °C. The mixture was allowed to warm to rt for 5 h, poured into sat. aq.
  • Step 3 6-(tert-Butoxy)-5-fluoro-1H-pyrazolo[3,4-b]pyridine
  • a mixture of 6-(tert-butoxy)-2,5-difluoronicotinaldehyde (10 g, 46.5 mmol), NH2NH2c;2O (98%, 42 g, 823 mmol), and NMP (120 mL) was stirred at 130 °C for 5 h, allowed to cool to rt, poured into water (700 mL), and then filtered. The filter cake was dissolved in EtOAc (800 mL).
  • Step 4 6-(tert-Butoxy)-5-fluoro-3-iodo-1H-pyrazolo[3,4-b]pyridine
  • Potassium hydroxide (13.4 g, 239 mmol) was added to a solution of 6-(tert- butoxy)-5-fluoro-1H-pyrazolo[3,4-b]pyridine (10 g, 47.8 mmol), I2 (24.3 g, 95.6 mmol), and DMF (200 mL) at 0 °C. The mixture was allowed to warm to rt overnight, poured into water (500 mL), and then extracted with EtOAc (2 ⁇ 300 mL).
  • Step 5 6-(tert-Butoxy)-5-fluoro-3-iodo-1-methyl-1H-pyrazolo[3,4-b]pyridine
  • Step 6 6-Chloro-5-fluoro-3-iodo-1-methyl-1H-pyrazolo[3,4-b]pyridine
  • Phosphorus(V) oxychloride 84.15 g, 548.8 mmol
  • DMF 160 mL
  • the mixture was stirred at 100 °C for 3.5 h, allowed to cool to rt, and concentrated.
  • Step 2 tert-Butyl 2-acetoxy-5-oxo-5,6-dihydropyridine-1(2H)-carboxylate
  • (R)-tert-butyl 2-hydroxy- 5-oxo-5,6-dihydropyridine-1(2H)-carboxylate 6.0 g, 28.1 mmol
  • K2CO3 4.28 g, 31.0 mmol
  • DMAP 344 mg, 2.81 mmol
  • toluene 250 mL
  • Step 4 tert-Butyl 5-oxo-2-phenylpiperidine-1-carboxylate
  • Step 2 N-(3-(2,4-Difluoro-3-(methoxymethoxy)-5-(trifluoromethyl)phenyl)-1-methyl- 1H-pyrazolo[3,4-d]pyrimidin-6-yl)-N,1-dimethyl-1,2,3,4-tetrahydroquinolin-3-amine [00296] N-(3-(2,4-Difluoro-3-(methoxymethoxy)-5-(trifluoromethyl)phenyl)-1-methyl- 1H-pyrazolo[3,4-d]pyrimidin-6-yl)-1-methyl-1,2,3,4-tetrahydroquinolin-3-amine (31 mg, 0.058 mmol) was weighed into an 8 mL vial.
  • N,N-Dimethylformamide (1 mL) was added. The mixture was cooled in an ice/water bath. Sodium hydride (60% in mineral oil) was added at 0 °C. The reaction was stirred for 15 min. Iodomethane (5.6 ⁇ L, 0.089 mmol) was added. The reaction was allowed to warm to rt over 1 h, diluted with 10 mL water, and then extracted with 10 mL EtOAc.
  • Step 3 2,6-Difluoro-3-(1-methyl-6-(methyl(1-methyl-1,2,3,4-tetrahydroquinolin-3- yl)amino)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-(trifluoromethyl)phenol
  • Dichloromethane (1 mL) and then TFA (200 ⁇ L) were added to N-(3-(2,4- difluoro-3-(methoxymethoxy)-5-(trifluoromethyl)phenyl)-1-methyl-1H-pyrazolo[3,4- d]pyrimidin-6-yl)-N,1-dimethyl-1,2,3,4-tetrahydroquinolin-3-amine (22 mg, 0.040 mmol).
  • Step 1 70-80 °C, 45 min-3 h or rt, 5 h-overnight.
  • Step 1 DMA instead of NMP as solvent.
  • Step 2 0 °C-rt, 20 min-18 h also 50 °C, 30 min.
  • Step 3 5:1 or 3:1 CH2Cl2/TFA, rt, 15-60 min. 1
  • Step 1 then Step 3. 2
  • Step 1 only: DIEA, NMP or DMA, 110-150 °C, 30-90 min, microwave (MOM PG was cleaved d 3 4 uring thermal coupling). Used tert-butyl 3- amino-3,4-dihydroquinoline-1(2H)-carboxylate.
  • Step 1 Isolated as a byproduct during Step 52 conditions using Intermediate 5 and benzyl 2-(aminomethyl)piperidine-1-carboxylate in Step 1.
  • Step 1 rt, 1 h then 60 °C, 15 min, microwave then 120 °C, 30 min, microwave (MOM PG was cleaved).
  • Step 1 only: 100-120 °C, 0.5-1 h, microwave (MOM PG was cleaved).
  • Step 1 KF, NMP, 120 °C, overnight), no Step 2, then Step 3 (10% Pd/C, THF, H2, rt, 1 h).
  • Step 2 3-(3-(Benzyloxy)-2,4-difluoro-5-(trifluoromethyl)phenyl)-N,1-dimethyl-N-(6- phenylpiperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine
  • a solution of tert-butyl 5-((3-(3-(benzyloxy)-2,4-difluoro-5- (trifluoromethyl)phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)(methyl)amino)-2- phenylpiperidine-1-carboxylate 140 mg, 0.197 mmol
  • HCl/EtOAc (4 M, 2 mL
  • Step 3 3-(3-(Benzyloxy)-2,4-difluoro-5-(trifluoromethyl)phenyl)-N,1-dimethyl-N-(cis- 1-(methylsulfonyl)-6-phenylpiperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine and 3-(3-(Benzyloxy)-2,4-difluoro-5-(trifluoromethyl)phenyl)-N,1-dimethyl-N-(trans- 1-(methylsulfonyl)-6-phenylpiperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine [00302] MsCl (25 ⁇ L, 0.323 mmol) was added dropwise to a solution of 3-(3- (benzyloxy)-2,4-difluoro-5-(trifluoromethyl)phenyl)-N,1-dimethyl-N-
  • Step 4 2,6-Difluoro-3-(1-methyl-6-(methyl(cis-1-(methylsulfonyl)-6-phenylpiperidin- 3-yl)amino)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-(trifluoromethyl)phenol [00303] A solution of 3-(3-(benzyloxy)-2,4-difluoro-5-(trifluoromethyl)phenyl)-N,1- dimethyl-N-(1-(methylsulfonyl)-6-phenylpiperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-6- amine (45 mg, 0.65 mmol) and TFA (2 mL) was stirred at 50 °C for 2 h, cooled to rt, poured into sat’d aq.
  • Step 1 70-120 °C, 2 h-overnight.
  • Step 1 KF instead of DIPE 1A as base.
  • Step 1 n-BuOH instead of NMP as solvent.
  • Step 4 50-70 °C.
  • Step 4 TFA/DCM (1:2).
  • No Step 2. 2 The cis/trans isomers of the OBn precursor were separated by silica gel chromatography, deprotected separately following the procedure described for Compound 3 (Step 4), purified by prep-TLC, and then separated by SFC [CHIRALPAK AD-H; 0.1%NH3H2 3 O MeOH] to give all 4 isomers.
  • Step 4 10% Pd/C, ethanol or THF, H 2 , rt, 2 h.
  • Step 2 37% formaldehyde, CH 3 OH, NaBH3CN, 0 °C-rt, 2 h.
  • Compound 6 2,6-Difluoro-3-(1-methyl-6-(methyl((1-phenylpiperidin-2-yl)methyl)amino)-1H- pyrazolo[3,4-d]pyrimidin-3-yl)-5-(trifluoromethyl)phenol
  • Step 1 tert-Butyl 2-(((3-(3-(benzyloxy)-2,4-difluoro-5-(trifluoromethyl)phenyl)-1- methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)(methyl)amino)methyl)piperidine-1- carboxylate [00307] A mixture of Intermediate 5.01 (300 mg, 0.66 mmol), tert-butyl 2- ((methylamino)methyl)piperidine-1-carboxylate (225 mg, 0.99 m
  • Step 4 2,6-Difluoro-3-(1-methyl-6-(methyl((1-phenylpiperidin-2-yl)methyl)amino)- 1H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-(trifluoromethyl)phenol [00310] A mixture of 3-(3-(benzyloxy)-2,4-difluoro-5-(trifluoromethyl)phenyl)-N,1- dimethyl-N-((1-phenylpiperidin-2-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine, THF (2 mL), and 10% Pd/C (10 mg, 0.009 mmol) was stirred under a balloon of H2 at rt for 30 min and then filtered through Celite.
  • Step 1 DIEA instead of KF as base.
  • Step 1 rt, overnight.
  • Step 2 DCM/TFA (3:1), 45 min.
  • Step 4 30-50 min.
  • Step 3 reductive amination (benzaldehyde, STAB, DCM, 2 days) with free base from Step 2 (EtOAc/ NaHCO 3 ).
  • Step 2 3-(6-(2,3-Dihydro-4H-pyrido[4,3-b][1,4]oxazin-4-yl)-1-methyl-1H- pyrazolo[4,3-c]pyridin-3-yl)-2,6-difluoro-5-(trifluoromethyl)phenol TFA salt [00314] 4-(3-(2,4-Difluoro-3-(methoxymethoxy)-5-(trifluoromethyl)phenyl)-1-methyl- 1H-pyrazolo[4,3-c]pyridin-6-yl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine was stirred in CH 2 Cl 2 (2 mL) and TFA (1 mL) at rt for 45 min, concentrated, and then purified by RP- HPLC to give 3-(6-(2,3-dihydro-4H-pyrido[4,3-b][1,4
  • Step 31 80 °C, 15 min, microwave.
  • Step 1 80 °C, 30 min, microwave then 90 °C, 90 min, microwave.
  • Step 2 3-(2,4-Difluoro-3-(methoxymethoxy)-5-(trifluoromethyl)phenyl)-1-methyl-N- (piperidin-2-ylmethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine
  • a mixture of palladium on carbon (30 mg, 0.028 mmol, 10 wt.%) and THF (3 mL) was added to a solution of benzyl 2-(((3-(2,4-difluoro-3-(methoxymethoxy)-5- (trifluoromethyl)phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6- yl)amino)methyl)piperidine-1-carboxylate (270 mg, 0.425 mmol), methanol (5 mL), and THF (5 mL).
  • Step 3 2,6-Difluoro-3-(1-methyl-6-(((1-phenylpiperidin-2-yl)methyl)amino)-1H- pyrazolo[3,4-d]pyrimidin-3-yl)-5-(trifluoromethyl)phenol
  • a mixture of 3-(2,4-difluoro-3-(methoxymethoxy)-5-(trifluoromethyl)phenyl)-1- methyl-N-(piperidin-2-ylmethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine 95 mg, 0.20 mmol
  • bromobenzene 50 mg, 0.32 mmol
  • trans-N,N'-dimethylcyclohexane-1,2-diamine 24 mg, 0.17 mmol
  • copper(I) iodide (16 mg, 0.084 mmol)
  • potassium phosphate 166 mg, 0.782 mmol
  • DMSO DMSO
  • tert-Butyl 3-amino-3,4-dihydroquinoline-1(2H)-carboxylate 800 mg, 3.22 mmol
  • NMP 3 mL
  • DIEA 0.8 mL, 2.7 mmol
  • the reaction was heated in a microwave reactor at 70 °C for 45 min, allowed to cool to rt, diluted with 20 mL water, and then extracted with 20 mL EtOAc.
  • Step 2 tert-Butyl 3-((3-iodo-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6- yl)(methyl)amino)-3,4-dihydroquinoline-1(2H)-carboxylate
  • Step 3 N-(3-Iodo-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-N-methyl-1,2,3,4- tetrahydroquinolin-3-amine
  • tert-Butyl 3-((3-iodo-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6- yl)(methyl)amino)-3,4-dihydroquinoline-1(2H)-carboxylate (448 mg, 0.861 mmol) was weighed into a 40 mL vial. Dichloromethane (3 mL) and TFA (0.6 mL) were added.
  • Step 4 N-(3-Iodo-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-N-methyl-1- (methylsulfonyl)-1,2,3,4-tetrahydroquinolin-3-amine
  • N-(3-Iodo-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-N-methyl-1,2,3,4- tetrahydroquinolin-3-amine 75 mg, 0.18 mmol was weighed into a 40 mL vial. Dichloromethane (2 mL) and TEA (70 ⁇ L, 0.50 mmol) were added.
  • Step 5 N-(3-(2,4-Difluoro-3-(methoxymethoxy)-5-(trifluoromethyl)phenyl)-1-methyl- 1H-pyrazolo[3,4-d]pyrimidin-6-yl)-N-methyl-1-(methylsulfonyl)-1,2,3,4- tetrahydroquinolin-3-amine
  • N-(3-Iodo-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-N-methyl-1- (methylsulfonyl)-1,2,3,4-tetrahydroquinolin-3-amine 63 mg, 0.13 mmol was weighed into a 2 mL microwave vial.
  • Step 6 2,6-Difluoro-3-(1-methyl-6-(methyl(1-(methylsulfonyl)-1,2,3,4- tetrahydroquinolin-3-yl)amino)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-5- (trifluoromethyl)phenol [00324] N-(3-(2,4-difluoro-3-(methoxymethoxy)-5-(trifluoromethyl)phenyl)-1-methyl- 1H-pyrazolo[3,4-d]pyrimidin-6-yl)-N-methyl-1-(methylsulfonyl)-1,2,3,4- tetrahydroquinolin-3-amine was dissolved in CH2Cl2 (1 mL).
  • Trifluoroacetic acid 200 ⁇ L was added. The reaction was stirred at rt for 30 min, concentrated, and then purified by reverse-phase HPLC (40-80% CH 3 CN in water with 0.1% TFA) to give 2,6-difluoro-3- (1-methyl-6-(methyl(1-(methylsulfonyl)-1,2,3,4-tetrahydroquinolin-3-yl)amino)-1H- pyrazolo[3,4-d]pyrimidin-3-yl)-5-(trifluoromethyl)phenol (35 mg, 49%) as a pale yellow solid.
  • Step 1 100-150 °C, microwave, 0.5-4.5 h.
  • Step 2 0.5-2 h.
  • Step 5 10- 30 min.
  • Step 6 20-60 min. 1 No Step 2.
  • 2 Synthesized from Intermediate 3 and 1-methyl-1,2,3,4- tetrahydroquinolin-3-ol following the procedures for Compound 10, Step 2 (quinolin-3-ol coupling);
  • Step 5 Intermediate 2, 2 M Na2CO3, Pd(dppf)Cl2 ⁇ CH2Cl2, dioxane, 80 °C, 2 h; and
  • Step 6 TFA, 50 °C, 2 h.
  • Step 3 was an amidation (isocyanatotrimethylsilane, TEA, 2:1 THF/DMF, 0 °C-rt, 1 h).
  • Step 3 was an acylation (methyl chloroformate, K 2 CO 3 , DMF 0-50 °C, 2 h).
  • Step 2 (S)-N-(3-(3-(Benzyloxy)-2,4-difluoro-5-(trifluoromethyl)phenyl)-1-methyl-1H- pyrazolo[3,4-d]pyrimidin-6-yl)-N,1-dimethyl-1,2,3,4-tetrahydroquinolin-3-amine
  • Pd(dppf)Cl2.CH2Cl2 (186 mg, 0.22 mmol) was added to a mixture of N-(3-iodo- 1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-N,1-dimethyl-1,2,3,4-tetrahydroquinolin-3- amine (990 mg, 2.28 mmol), Intermediate 2 (2.27 g, 5.47 mmol), Na2CO3 (2 M in H2O, 3.99 mL), and dioxane (30 mL) under N2.
  • Step 3 (S)-2,6-Difluoro-3-(1-methyl-6-(methyl(1-methyl-1,2,3,4-tetrahydroquinolin- 3-yl)amino)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-(trifluoromethyl)phenol [00332] 10% Pd/C (150 mg, 0.252 mmol) was added to a mixture of (S)-N-(3-(3- (benzyloxy)-2,4-difluoro-5-(trifluoromethyl)phenyl)-1-methyl-1H-pyrazolo[3,4- d]pyrimidin-6-yl)-N,1-dimethyl-1,2,3,4-tetrahydroquinolin-3-amine (150 mg, 0.252 mmol) and THF (5 mL).
  • Example A-1 Parenteral Pharmaceutical Composition
  • a parenteral pharmaceutical composition suitable for administration by injection 1-1000 mg of a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, is dissolved in sterile water and then mixed with 10 mL of 0.9% sterile saline.
  • a suitable buffer is optionally added as well as optional acid or base to adjust the pH.
  • Example A-2 Oral Solution
  • a sufficient amount of a compound described herein, or a pharmaceutically acceptable salt thereof is added to water (with optional solubilizer(s), optional buffer(s), and taste masking excipients) to provide a 20 mg/mL solution.
  • Example A-3 Oral Tablet [00340] A tablet is prepared by mixing 20-50% by weight of a compound described herein, or a pharmaceutically acceptable salt thereof, 20-50% by weight of microcrystalline cellulose, 1-10% by weight of low-substituted hydroxypropyl cellulose, and 1-10% by weight of magnesium stearate or other appropriate excipients.
  • Tablets are prepared by direct compression. The total weight of the compressed tablets is maintained at 100 -500 mg.
  • Example A-5 Topical Gel Composition
  • a compound described herein, or a pharmaceutically acceptable salt thereof is mixed with hydroxypropyl cellulose, propylene glycol, isopropyl myristate and purified alcohol USP.
  • the resulting gel mixture is then incorporated into containers, such as tubes, which are suitable for topical administration.
  • Example B-1 HSD17b13 NAD(P)H-Glo Biochemical Assay Materials [00344] @IGRPFMQEQV LWPEQ ;A8*06*, IQ ⁇ [PI' AWFUVTEVI3 IUVTEHMRO "AMKPE a&9UVTEHMRO E8875), 100 mM in DMSO.
  • Cofactor NAD+ Grade I free acid (Sigma 10127965001), 20 mM in H 2 O. Assay buffer final concentration: 20 mM Tris pH7.4 with 0.002% Tween-20 and 0.02% BSA. Assay performed in 384 well solid bottom plate (Corning 3570). Enzymatic activity detected by NAD(P)H-GloTM Detection System (Promega G9062). Compounds [00345] Inhibitor compounds were serially diluted in DMSO and then further diluted in assay buffer to a 10X concentration consisting of 1% DMSO.
  • HSD17b13 enzyme was diluted in 1X assay buffer to the desired enzyme concentration based on the specific activity of the enzyme lot.20 uL of diluted enzyme was added to each well along with 2.5 uL of 10X inhibitor solution. Assay plate was incubated at RT for 20 minutes, and then 2.5 uL of a 10X substrate/cofactor mix was added to each well for a final concentration of 50 uM estradiol and 1 mM NAD+. Assay plate was incubated at 37 °C for 3 hours. NAD(P)H-GloTM Detection System reagents were prepared according to manufacturer’s specifications, and 25 uL was added to each well.
  • Assay buffer final concentration 20 mM Tris pH 7.4 with 0.002% Tween-20 and 0.02% BSA. Assay performed in 384 well solid bottom plate (Corning 3570). Enzymatic activity detected by NAD(P)H-GloTM Detection System (Promega G9062). Compounds [00349] Inhibitor compounds were serially diluted in DMSO and then further diluted in assay buffer to a 10X concentration consisting of 1% DMSO. Procedure [00350] HSD17b1 enzyme was diluted in 1X assay buffer to the desired enzyme concentration based on the specific activity of the enzyme lot.20 uL of diluted enzyme was added to each well along with 2.5 uL of the 10X inhibitor solution.
  • Assay plate was incubated at RT for 20 minutes, and then 2.5 uL of a 10X substrate/cofactor mix was added to each well for a final concentration of 55 uM testosterone and 1 mM NADP. Assay plate was incubated at 37 °C for 1 hour. NAD(P)H-GloTM Detection System reagents were prepared according to manufacturer’s specifications, and 25uL was added to each well. After incubating for 1 hour at RT, luminescence was measured.
  • Example B-3 HSD17b2 NAD(P)H-Glo Biochemical Assay Materials and Setup [00351] @IGRPFMQEQV LWPEQ ;A8*06+ IQ ⁇ [PI' AWFUVTEVI3 IUVTEHMRO "AMKPE a&9UVTEHMRO E8875) 2mM in DMSO. Cofactor: NAD+ Grade I free acid (Sigma 10127965001), 20mM in H2O. Assay buffer final concentration: 20mM Tris pH7.4 with 0.002% Tween-20 and 0.02% BSA. Assay performed in 384 well solid bottom plate (Corning 3570).
  • Assay plate was incubated at RT for 20 minutes, and then 2.5 uL of 10X substrate/cofactor mix was added to each well for a final assay concentration of 1 uM estradiol and 500 uM NAD+. Assay plate was incubated at RT for 1 hour. NAD(P)H-GloTM Detection System reagents were prepared according to manufacturer’s specifications and 25 uL was added to each well. After incubating for 1 hour at RT, luminescence was measured.
  • Example B-4 In Vitro HSD17b13 Cell Based Assay Seeding [00354] HEK293 cells were plated at 4,000,000 cells per T75 flask with EMEM (ATCC Cat # 30-2003) and 10% FBS (Sigma Cat # F2442) and then incubated at 37 °C in 5% CO 2 for 18 hours. Transfection and plate [00355] After the 18 h incubation, media was replaced with 15 mL of fresh media: EMEM without Phenol Red (Quality Biological Cat # 112-212-101), 10% CSS (Sigma Cat # F6765) and GlutaMax (Gibco Cat # 35050-061).
  • pCMV6 HSD17B13 (Origene Cat # RC213132) was diluted in OptiMEM (Life Technologies, Cat # 31985-062) to 2 mL.
  • 60 uL of transfection reagent (X-tremeGENE HP Roche, Cat # 06366236001) was added, and the tube was vortexed and incubated at room temperature for 20 minutes.
  • the transfection reagent/DNA mixture was added to the cells in the T75 flask, and the cells were incubated at 37 °C in 5% CO2 for 18 hours.
  • the cells were resuspended in EMEM media with 10% CSS and plated in a 96 well plate at 80,000 cells/well, 100 uL/well. Cells were incubated at 37 °C in 5% CO 2 for 18 hours.
  • Test Compounds [00356] Compounds were serially diluted in DMSO (1000X final concentration) and then further diluted in EMEM media with 10% CSS to a 20X final concentration.10 uL of the 20X compound mix was added to each well of transfected cells, and the cells were incubated at 37 °C in 5% CO2 for 30 minutes.100 uL of EMEM media with 100 uM estradiol (Sigma cat# E8875) was added to each well, and the cells were incubated for 4 hours at 37 °C in 5% CO 2 . The cell media was collected and examined for estradiol and estrone concentrations by LCMS.
  • Example B-5 In Vitro HSD17b11 Cell Based Assay Seeding [00357] HEK293 cells were plated at 4,000,000 cells per T75 flask with EMEM (ATCC Cat # 30-2003) and 10% FBS (Sigma Cat # F2442) and then incubated at 37 °C in 5% CO2 for 18 hours. Transfection and plate [00358] After the 18 h incubation, the media was replaced with 15 mL of fresh media: EMEM without Phenol Red (Quality Biological Cat # 112-212-101), 10% CSS (Sigma Cat # F6765) and GlutaMax (Gibco Cat # 35050-061).
  • pCMV6 HSD17B11 (Origene Cat # RC205941) was diluted in OptiMEM (Life Technologies, Cat # 31985-062) to 2 mL.60 uL of transfection reagent (X-tremeGENE HP Roche, Cat # 06366236001) was added, and the tube was vortexed and incubated at room temperature for 20 minutes.
  • the transfection reagent/DNA mixture was added to the cells in the T75 flask, and the cells were incubated at 37 °C in 5% CO2 for 18 hours.
  • test Compounds [00359] Compounds were serially diluted in DMSO (1000X final concentration) and then further diluted in EMEM media with 10% CSS to a 20X final concentration.
  • Example B-6 NASH Activity Study (AMLN model)
  • AMLN diet DIO-NASH (D09100301, Research Diet, USA) (40% fat (18% trans-fat), 40% carbohydrates (20% fructose) and 2% cholesterol).
  • the animals are kept on the diet for 29 weeks.
  • liver biopsies are performed for base line histological assessment of disease progression (hepatosteatosis and fibrosis), stratified and randomized into treatment groups according to liver fibrosis stage, steatosis score, and body weight.
  • mice Three weeks after biopsy the mice are stratified into treatment groups and dosed daily by oral gavage with an HSD17B13 inhibitor for 8 weeks.
  • liver biopsies are performed to assess hepatic steatosis and fibrosis by examining tissue sections stained with H&E and Sirius Red, respectively.
  • Total collagen content in the liver is measured by colorimetric determination of hydroxyproline residues by acid hydrolysis of collagen.
  • Triglycerides and total cholesterol content in liver homogenates are measured in single determinations using autoanalyzer Cobas C-111 with commercial kit (Roche Diagnostics, Germany) according to manufacturer ⁇ s instructions.
  • Example B-7 CCl4 Fibrosis Model
  • Fibrosis is induced in C57BL/6 male mice by bi-weekly oral administration of CCl 4 .
  • CCl 4 is formulated 1:4 in oil and is oral dosed at a final concentration of 0.5ul/g mouse. After 2-4 weeks of fibrosis induction the compounds is administered daily by oral gavage for 2-8 weeks of treatment while continuing CCl 4 administration.
  • livers are formalin fixed and stained with H&E or Sirius Red stain for histopathological evaluation of inflammation and fibrosis.
  • Total collagen content is measured by colorimetric determination of hydroxyproline residues by acid hydrolysis of collagen.
  • Example B-8 Mouse PK Study [00362] The plasma pharmacokinetics of any one of the compounds disclosed herein as a test article is measured following a single bolus intravenous and oral administration to mice (CD-1, C57BL, and diet induced obesity mice).
  • An oral dosing formulation is prepared in appropriate oral dosing vehicles (vegetable oils, PEG400, Solutol, citrate buffer, or carboxymethyl cellulose) and is administered at a dose volume of 5 ⁇ 10 mL/kg at selected dose levels.
  • Plasma samples are collected by cheek pouch method at pre-determined time intervals post intravenous or oral doses into tubes containing EDTA. Plasma is isolated by centrifugation of blood at 10,000 g for 5 minutes, and aliquots are transferred into a 96- well plate and stored at -60 ⁇ C or below until analysis.
  • Calibration standards of test article are prepared by diluting DMSO stock solution with DMSO in a concentration range. Aliquots of calibration standards in DMSO are combined with plasma from na ⁇ ve mouse so that the final concentrations of calibration standards in plasma are 10-fold lower than the calibration standards in DMSO. PK plasma samples are combined with blank DMSO to match the matrix.
  • the calibration standards and PK samples are combined with ice-cold acetonitrile containing an analytical internal standard and centrifuged at 1850 g for 30 minutes at 4°C. The supernatant fractions are analyzed by LC/MS/MS and quantitated against the calibration curve. Pharmacokinetic parameters (area under the curve (AUC), Cmax, Tmax, elimination half-life (T1/2), clearance (CL), steady state volume of distribution (Vdss), and mean residence time (MRT)) are calculated via non-compartmental analysis using Microsoft Excel (version 2013).
  • Example B-9 Mouse CDA-HFD NASH Model
  • a NASH phenotype with mild fibrosis can be induced in C57BL/6 mice by feeding a choline-deficient diet with 0.1% methionine and 60% kcal fat (Research Diet A06071302) for 4-12 weeks. After 4-6 weeks of diet induction compounds can be administered daily by oral gavage for 4-8 weeks of treatment while continuing CDA-HFD feeding.
  • livers can be formalin fixed and stained with H&E and Sirius Red stain histopathological evaluation of steatosis, inflammation, and fibrosis.
  • Total collagen content can be measured by colorimetric determination of hydroxyproline residues by acid hydrolysis of collagen.
  • Collagen gene induction can be measured by qPCR analysis of Col1a1 or Col3a1.
  • Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) can be measured by a clinical chemistry analyzer.
  • ALT serum alanine aminotransferase
  • AST aspartate aminotransferase
  • EQUIVALENTS [00365] Those skilled in the art will recognize, or be able to ascertain, using no more than routine experimentation, numerous equivalents to the specific embodiments described specifically herein. Such equivalents are intended to be encompassed in the scope of the following claims. [00366] All of the above-cited references and publications are hereby incorporated by reference.

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Abstract

L'invention concerne des composés qui sont des inhibiteurs de HSD17B13, des procédés de fabrication de tels composés, des compositions pharmaceutiques et des médicaments comprenant de tels composés, ainsi que ees procédés d'utilisation de tels composés dans le traitement d'affections, de maladies ou de troubles associés à l'activité de HSD17B13.
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WO2022020730A1 (fr) * 2020-07-24 2022-01-27 Inipharm, Inc. Inhibiteurs de hsd17b13 quinazolinone et leurs utilisations
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