WO2017205684A1 - Combination therapies with farnesoid x receptor (fxr) modulators - Google Patents

Combination therapies with farnesoid x receptor (fxr) modulators Download PDF

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Publication number
WO2017205684A1
WO2017205684A1 PCT/US2017/034564 US2017034564W WO2017205684A1 WO 2017205684 A1 WO2017205684 A1 WO 2017205684A1 US 2017034564 W US2017034564 W US 2017034564W WO 2017205684 A1 WO2017205684 A1 WO 2017205684A1
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optionally substituted
heteroaryl
alkyl
aryl
alkylene
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French (fr)
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Benjamin Anthony PRATT
Raju Mohan
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Akarna Therapeutics Ltd
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Akarna Therapeutics Ltd
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Priority to RU2018145776A priority Critical patent/RU2018145776A/ru
Priority to EP17803627.3A priority patent/EP3463373A4/en
Priority to AU2017270221A priority patent/AU2017270221A1/en
Priority to JP2018562106A priority patent/JP2019517478A/ja
Priority to KR1020187037471A priority patent/KR20190040936A/ko
Priority to US16/303,741 priority patent/US20200397798A1/en
Priority to BR112018073460A priority patent/BR112018073460A2/pt
Priority to SG11201810290WA priority patent/SG11201810290WA/en
Application filed by Akarna Therapeutics Ltd filed Critical Akarna Therapeutics Ltd
Priority to CA3025007A priority patent/CA3025007A1/en
Priority to MX2018014024A priority patent/MX2018014024A/es
Priority to CN201780045766.3A priority patent/CN109843298A/zh
Publication of WO2017205684A1 publication Critical patent/WO2017205684A1/en
Priority to IL263179A priority patent/IL263179A/en
Anticipated expiration legal-status Critical
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • Metabolic disease including obesity, diabetes, hypertension, and cardiovascular disease, are diseases driven by both mulitfactorial genetics (thrifty genotypes) as well as lifestyle habits, and are now reaching epidemic proportions in developed countries. It is believed that increasingly high caloric diets combined with sedentary life styles are major contributors to the growing incidence of these diseases. Importantly hyperlipidemia is associated with many types of metabolic disease, and statistics from the American Heart Association indicate that approximately half of the adult population in the United States has plasma cholesterol levels that put individuals at risk for the development of cardiovascular disease (American Heart Association, Heart disease and stroke statistics - 2005 update; 2005: 1-59).
  • VLDL + DDL triglyceride-rich cholesterol fractions
  • nicotinic acid a second approved triglyceride lowering agent
  • VLDL VLDL
  • CHD coronary heart disease
  • stroke and peripheral vascular disease represent a truly enormous burden to the health care systems of the industrialized world.
  • CHD coronary heart disease
  • stroke and peripheral vascular disease represent a truly enormous burden to the health care systems of the industrialized world.
  • CHD coronary heart disease
  • stroke and peripheral vascular disease represent a truly enormous burden to the health care systems of the industrialized world.
  • CHD coronary heart disease
  • the present application relates to methods of treating a metabolic disorder in an individual in need thereof, comprising co-administering to the individual a therapeutically effective amount of: (a) a first agent that is an FXR modulator; and (b) at least one second agent that is an CCR2/CCR5 antagonist, ASKl inhibitor, DPP-IV inhibitor, caspase protease inhibitor, SGLT2 inhibitor, acetyl-CoA carboxylase (ACC) inhibitor, diacyl glycerol acyl transferase- 1 inhibitor, sodium -bile acid
  • cotransporter-inhibitor TLR-4 antagonist, PPAR alpha/delta agonist, or GLP-1 agonist, or a combination thereof.
  • the present application also relates to FXR modulators. Disclosed herein are FXR modulators.
  • FXR modulatators and pharmaceutical compositions that include such FXR modulatators, for use in the treatment of diseases, disorders or conditions that would benefit from FXR modulation.
  • FXR modulator described herein to a mammal in the treatment of diseases, disorders or conditions that would benefit from FXR modulation.
  • a metabolic disorder in an individual in need thereof comprising co-administering to the individual a therapeutically effective amount of: (a) a first agent that is an FXR modulator; and (b) a second agent that is a DPP-IV inhibitor.
  • methods of treating a metabolic disorder in an individual in need thereof comprising coadministering to the individual a therapeutically effective amount of: (a) a first agent that is an FXR modulator; and (b) a second agent that is an SGLT2 inhibitor.
  • a metabolic disorder in an individual in need thereof comprising co-administering to the individual a therapeutically effective amount of: (a) a first agent that is an FXR modulator; and (b) a second agent that is an ASKl inhibitor.
  • methods of treating a metabolic disorder in an individual in need thereof comprising co-administering to the individual a therapeutically effective amount of: (a) a first agent that is an FXR modulator; and (b) a second agent that is a GLP-1 agonist.
  • the FXR modulator is a com ound of Formula (I):
  • R 1 is selected from the group consisting of hydrogen, halogen, optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted -(Ci-C 2 alkylene)-(C 3 -C 8 cycloalkyl), optionally substituted C 2 -Cciheterocycloalkyl, optionally substituted -(Ci-C 2 alkylene)-(C 2 -C 9 heterocycloalkyl), optionally substituted -(Ci- C 2 alkylene)-(aryl), optionally substituted -(Ci-C 2 alkylene)-(heteroaryl), -OR 10 , -SR 10 ,
  • R 2 is selected from the group consisting of hydrogen, optionally substituted Ci-C 6 alkyl,
  • optionally substituted C 3 -C 8 cycloalkyl optionally substituted aryl, optionally substituted -(XV C 2 alkylene)-(aryl), optionally substituted heteroaryl, optionally substituted C 2 - C 9 heterocycloalkyl, and optionally substituted -(Ci-C 2 alkylene)-(heteroaryl);
  • R 3 is selected from the group consisting of hydrogen, optionally substituted Ci-C 6 alkyl,
  • R 4 and R 5 are each independently selected from the group consisting of hydrogen, halogen, optionally substituted Ci-C 6 alkyl, optionally substituted Ci-C 6 alkoxy, optionally substituted C 2 - C 6 alkenyl, and optionally substituted C 2 -C 6 alkynyl; or R 4 and R 5 together with the carbon atom to which they are attached, form an optionally substituted C 3 -C 6 cycloalkyl ring or an optionally substituted C 2 -Cvheterocycloalkyl ring;
  • R 6 is selected from the group consisting of hydrogen, halogen, optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, and -C(0)N(R 27 )R 28 ;
  • R is selected from the group consisting of hydrogen, halogen, optionally substituted Ci-C 6 alkyl, optionally substituted Ci-C 6 alkoxy, optionally substituted C2-C 6 alkenyl, and optionally substituted C 2 -C 6 alkynyl;
  • R 10 , R 13 and R 14 are each independently selected from the group consisting of hydrogen, optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted aryl, optionally substituted -(Ci-C 2 alkylene)-(aryl), optionally substituted C 2 -Cciheterocycloalkyl, optionally substituted heteroaryl, and optionally substituted -(Ci-C 2 alkylene)-(heteroaryl);
  • R u and R 12 are each independently selected from the group consisting of hydrogen, optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 - C 6 alkynyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted aryl, optionally substituted -(Ci-C 2 alkylene)-(aryl), optionally substituted C 2 -C 9 heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted -(Ci-C 2 alkylene)-(heteroaryl); or optionally R 11 and R 12 together with the nitrogen atom to which they are attached, form an optionally substituted C 2 -Cciheterocycloalkyl ring;
  • R 15 is selected from the group consisting of optionally substituted Ci-C 6 alkyl, optionally
  • R 21 and R 22 are each independently selected from the group consisting of hydrogen, optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 - C 6 alkynyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted aryl, optionally substituted -(Ci-C 2 alkylene)-(aryl), optionally substituted C 2 -C 9 heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted -(Ci-C 2 alkylene)-(heteroaryl); or optionally R 21 and R 22 together with the nitrogen atom to which they are attached, form an optionally substituted C 2 -C 9 heterocycloalkyl ring;
  • R 24 is selected from the group consisting of optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted aryl optionally substituted -(Ci-C 2 alkylene)-(aryl), optionally substituted C 2 -C 9 heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted -(Ci-C 2 alkylene)-(heteroaryl); and
  • R 25 and R 26 are each independently selected from the group consisting of hydrogen, optionally substituted Ci-C 6 alkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted aryl, optionally substituted -(Ci-C 2 alkylene)-(aryl), optionally substituted C 2 -C 9 heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted -(Ci-C 2 alkylene)-(heteroaryl); or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof
  • R 27 and R 28 are each independently selected from the group consisting of hydrogen, optionally substituted Ci-C 6 alkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted aryl, optionally substituted -(Ci-C 2 alkylene)-(aryl), optionally substituted C 2 -C 9 heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted -(Ci-C 2 alkylene)-(heteroaryl); or R 27 and R 28 together with the nitrogen atom to which they are attached, form an optionally substituted C 2 -C 9 heterocycloalkyl ring; or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof.
  • the FXR modulator is a compound of Formula (II):
  • R 1 is selected from the group consisting of hydrogen, halogen, optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted -(Ci-C 2 alkylene)-(C 3 -C 8 cycloalkyl), optionally substituted C 2 -C 9 heterocycloalkyl, optionally substituted -(Ci-C 2 alkylene)-(C 2 -C 9 heterocycloalkyl), optionally substituted -(Ci- C 2 alkylene)-(aryl), optionally substituted -(Ci-C 2 alkylene)-(heteroaryl), -OR 10 , -SR 10 ,
  • R 2 is selected from the group consisting of hydrogen, optionally substituted Ci-C 6 alkyl,
  • optionally substituted C 3 -C 8 cycloalkyl optionally substituted aryl, optionally substituted -(Ci- C 2 alkylene)-(aryl), optionally substituted heteroaryl, optionally substituted C 2 - Cgheterocycloalkyl, and optionally substituted -(Ci-C 2 alkylene)-(heteroaryl);
  • R 3 is selected from the group consisting of hydrogen, optionally substituted Ci-C 6 alkyl,
  • R 4 and R 5 are each independently selected from the group consisting of hydrogen, halogen, optionally substituted Ci-C 6 alkyl, optionally substituted Ci-C 6 alkoxy, optionally substituted C 2 - C 6 alkenyl, and optionally substituted C 2 -C 6 alkynyl; or R 4 and R 5 together with the carbon atom to which they are attached, form an optionally substituted C3-C 6 cycloalkyl ring or an optionally substituted C2-Cvheterocycloalkyl ring;
  • R 6 is selected from the group consisting of hydrogen, halogen, optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, and -C(0)N(R 27 )R 28 ;
  • R 7 is selected from the group consisting of hydrogen, halogen, optionally substituted Ci-C 6 alkyl, optionally substituted Ci-C 6 alkoxy, optionally substituted C 2 -C 6 alkenyl, and optionally substituted C 2 -C 6 alkynyl;
  • R 8 is selected from the group consisting of -CN, -C(0)OR 25 , -C(0)N(R 25 )R 26 ,
  • R 9 is selected from the group consisting of hydrogen, optionally substituted Ci-C 6 alkyl,
  • R 10 , R 13 and R 14 are each independently selected from the group consisting of hydrogen, optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted aryl, optionally substituted -(Ci-C 2 alkylene)-(aryl), optionally substituted C 2 -Cciheterocycloalkyl, optionally substituted heteroaryl, and optionally substituted -(Ci-C 2 alkylene)-(heteroaryl);
  • R u and R 12 are each independently selected from the group consisting of hydrogen, optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 - C 6 alkynyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted aryl, optionally substituted -(Ci-C 2 alkylene)-(aryl), optionally substituted C 2 -Cciheterocycloalkyl, optionally substituted heteroaryl, and optionally substituted -(Ci-C 2 alkylene)-(heteroaryl); or optionally R 11 and R 12 together with the nitrogen atom to which they are attached, form an optionally substituted C 2 -Cciheterocycloalkyl ring; R is selected from the group consisting of optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkyny
  • R , R , and R are each independently selected from the group consisting of hydrogen, optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted aryl, optionally substituted -(Ci-C 2 alkylene)-(aryl), optionally substituted C 2 -Cciheterocycloalkyl, optionally substituted heteroaryl, and optionally substituted -(Ci-C 2 alkylene)-(heteroaryl);
  • R 21 and R 22 are each independently selected from the group consisting of hydrogen, optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 - C 6 alkynyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted aryl, optionally substituted -(Ci-C 2 alkylene)-(aryl), optionally substituted C 2 -Cciheterocycloalkyl, optionally substituted heteroaryl, and optionally substituted -(Ci-C 2 alkylene)-(heteroaryl); or optionally R 21 and R 22 together with the nitrogen atom to which they are attached, form an optionally substituted C 2 -Cciheterocycloalkyl ring;
  • R 24 is selected from the group consisting of optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted aryl optionally substituted -(Ci-C 2 alkylene)-(aryl), optionally substituted C 2 -Cciheterocycloalkyl, optionally substituted heteroaryl, and optionally substituted -(Ci-C 2 alkylene)-(heteroaryl); and
  • R 25 and R 26 are each independently selected from the group consisting of hydrogen, optionally substituted Ci-C 6 alkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted aryl, optionally substituted -(Ci-C 2 alkylene)-(aryl), optionally substituted C 2 -Cciheterocycloalkyl, optionally substituted heteroaryl, and optionally substituted -(Ci-C 2 alkylene)-(heteroaryl); or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof
  • R 27 and R 28 are each independently selected from the group consisting of hydrogen, optionally substituted Ci-C 6 alkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted aryl, optionally substituted -(Ci-C 2 alkylene)-(aryl), optionally substituted C 2 -Cciheterocycloalkyl, optionally substituted heteroaryl, and optionally substituted -(Ci-C 2 alkylene)-(heteroaryl); or R 27 and R 28 together with the nitrogen atom to which they are attached, form an optionally substituted C 2 -Cciheterocycloalkyl ring; or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof.
  • R 6 and R 7 are hydrogen.
  • R 4 and R 5 are each independently optionally substituted Ci-C 6 alkyl.
  • R 4 and R 5 are methyl.
  • R 3 is -C(0)R 20 .
  • R 3 is -S(0) 2 R 2 °.
  • R 3 is -C(0)R 20 or -S(0) 2 R 20 ; and R 20 is optionally substituted aryl.
  • R 3 is -C(0)N(R 21 )R 22 .
  • R 3 is -C(0)N(R 21 )R 22 ;
  • R 21 is hydrogen and R 22 is optionally substituted aryl.
  • R 8 is -C(0)OR 25 .
  • R 8 is -C(0)OR 25 and R 25 is optionally substituted Ci-C 6 alkyl. In some embodiments of a compound of Formula (I) or (II), R 8 is -C(0)OR 25 and R 25 is methyl. In some embodiments of a compound of Formula (I) or (II), R 8 is -C(0)OR 25 and R 25 is ethyl. In some embodiments of a compound of Formula (I) or (II), R 9 is hydrogen or optionally substituted Ci-C 6 alkyl. In some embodiments of a compound of Formula (I) or (II), R 9 is hydrogen.
  • R 9 is optionally substituted Ci-C 6 alkyl. In some embodiments of a compound of Formula (I) or (II), R 9 is Ci-C 6 alkyl. In some embodiments of a compound of Formula (I) or (II), R 9 is methyl. In some embodiments of a compound of Formula (I) or (II), R 2 is hydrogen. In some embodiments of a compound of Formula (I) or (II), R 1 is hydrogen. In some embodiments of a compound of Formula (I) or (II), R 1 is Ci-C 6 alkyl, optionally substituted C 2 - C 6 alkenyl, or optionally substituted C 2 -C 6 alkynyl.
  • the FXR modulator is a com ound of Formula (III):
  • R 1 is selected from the group consisting of hydrogen, halogen, optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted -(Ci-C 2 alkylene)-(C 3 -C 8 cycloalkyl), optionally substituted C 2 -C 9 heterocycloalkyl, optionally substituted -(Ci-C 2 alkylene)-(C 2 -C 9 heterocycloalkyl), optionally substituted -(Ci- C 2 alkylene)-(aryl), optionally substituted -(Ci-C 2 alkylene)-(heteroaryl), -OR 10 , -SR 10 , -N(R U )R 12 , - N(R u )S(0) 2 R 15
  • R 4 and R 5 are each independently optionally substituted Ci-C 6 alkyl
  • R 9 is selected from the group consisting of hydrogen, optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted aryl, optionally substituted -(Ci-C 2 alkylene)-(aryl), optionally substituted C 2 -C 9 heterocycloalkyl, optionally substituted heteroaryl, and optionally sub stituted -(C i-C 2 alkyl ene)-(heteroaryl);
  • R 10 , R 13 and R 14 are each independently selected from the group consisting of hydrogen, optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted aryl, optionally substituted -(Ci-C 2 alkylene)-(aryl), optionally substituted C 2 -C 9 heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted -(Ci-C 2 alkylene)-(heteroaryl);
  • R 15 is selected from the group consisting of optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted aryl optionally substituted -(Ci-C 2 alkylene)-(aryl), optionally substituted C 2 -C 9 heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted -(Ci-C 2 alkylene)-(heteroaryl);
  • R u and R 12 are each independently selected from the group consisting of hydrogen, optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 - C 6 alkynyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted aryl, optionally substituted -(Ci-C 2 alkylene)-(aryl), optionally substituted C 2 -C 9 heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted -(Ci-C 2 alkylene)-(heteroaryl); or optionally R 11 and R 12 together with the nitrogen atom to which they are attached, form an optionally substituted C 2 -C 9 heterocycloalkyl ring;
  • R 25 is Ci-C 6 alkyl; halogen,
  • each R 31 is independently halogen, -OH, -CN, -N0 2 , -NH 2 , optionally substituted Ci-C 6 alkyl, optionally substituted Ci-C 6 alkoxy, optionally substituted Ci-C 6 alkylamine, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 2 -C 9 heterocycloalkyl, aryl, or heteroaryl; each R 32 and R 33 are each independently selected from the group consisting of hydrogen, halogen, and Ci-C 6 alkyl;
  • R 34 and R 35 are each independently selected from the group consisting of hydrogen, optionally substituted Ci-C 6 alkyl, optionally substituted C 3 -C 8 cycloalkyl, and optionally substituted C 2 - Cgheterocycloalkyl; or R 34 and R 35 together with the nitrogen atom to which they are attached, form an optionally substituted C 2 -Cciheterocycloalkyl ring or an optionally substituted heteroaryl ring;
  • n 0, 1, 2, 3, or 4;
  • r 0, 1, 2, 3, or 4;
  • t is 2, 3, or 4; or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof.
  • R 30 is F. In some embodiments of a compound of Formula (III), R 30 is F.
  • R 30 is .
  • a compound of Formula (III) R 30 is .
  • R 30 is R 32 R 33 .
  • t is 2; and each R 32
  • R and R are hydrogen. In some embodiments of a compound of Formula (III), R and R together with the nitrogen atom to which they are attached form a C 2 -Cciheterocycloalkyl ring. In some embodiments of a compound of Formula (III), R 34 and R 35 together with the nitrogen atom to which they are attached form a morpholinyl. In some embodiments of a compound of Formula (III), n is 1. In some embodiments of a compound of Formula (III), R 31 is halogen. In some embodiments of a compound of Formula (III), R 31 is F. In some embodiments of a compound of Formula (III), R 4 and R 5 are each methyl.
  • R 9 is hydrogen or optionally substituted Ci-C 6 alkyl. In some embodiments of a compound of Formula (III), R 9 is hydrogen. In some embodiments of a compound of Formula (III), R 9 is optionally substituted Ci-C 6 alkyl. In some embodiments of a compound of Formula (III), R 9 is Ci-C 6 alkyl. In some embodiments of a compound of Formula (III), R 9 is methyl.
  • the FXR modulator is a compound of Formula (Ilia), or a pharmaceutically acce table salt, stereoisomer, or solvate thereof:
  • the FXR modulator is a compound of Formula (Illb), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:
  • the FXR modulator is a com ound of Formula (IV):
  • R 1 is selected from the group consisting of hydrogen, halogen, optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted -(Ci-C 2 alkylene)-(C 3 -C 8 cycloalkyl), optionally substituted C 2 -Cciheterocycloalkyl, optionally substituted -(Ci-C 2 alkylene)-(C 2 -Cciheterocycloalkyl), optionally substituted -(Ci- C 2 alkylene)-(aryl), optionally substituted -(Ci-C 2 alkylene)-(heteroaryl), -OR 10 , -SR 10 , -N(R U )R 12 , - N(R u
  • R 4 and R 5 are each independently optionally substituted Ci-C 6 alkyl
  • R 9 is selected from the group consisting of hydrogen, optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted aryl, optionally substituted -(Ci-C 2 alkylene)-(aryl), optionally substituted C 2 -C9heterocycloalkyl, optionally substituted heteroaryl, and optionally sub stituted -(C i-C 2 alkyl ene)-(heteroaryl);
  • R 10 , R 13 and R 14 are each independently selected from the group consisting of hydrogen, optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted aryl, optionally substituted -(Ci-C 2 alkylene)-(aryl), optionally substituted C 2 -Cciheterocycloalkyl, optionally substituted heteroaryl, and optionally substituted -(Ci-C 2 alkylene)-(heteroaryl);
  • R 15 is selected from the group consisting of optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted aryl optionally substituted -(Ci-C 2 alkylene)-(aryl), optionally substituted C 2 -C 9 heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted -(Ci-C 2 alkylene)-(heteroaryl);
  • R u and R 12 are each independently selected from the group consisting of hydrogen, optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 - C 6 alkynyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted aryl, optionally substituted -(Ci-C 2 alkylene)-(aryl), optionally substituted C 2 -C 9 heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted -(Ci-C 2 alkylene)-(heteroaryl); or optionally R 11 and R 12 together with the nitrogen atom to which they are attached, form an optionally substituted C 2 -C 9 heterocycloalkyl ring;
  • R is Ci-C 6 alk l
  • each R 31 is independently halogen, -OH, -CN, -N0 2 , - H 2 , optionally substituted Ci-C 6 alkyl, optionally substituted Ci-C 6 alkoxy, optionally substituted Ci-C 6 alkylamine, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 2 -C 9 heterocycloalkyl, aryl, or heteroaryl; each R 32 and R 33 are each independently selected from the group consisting of hydrogen, halogen, and Ci-C 6 alkyl;
  • R 34 and R 35 are each independently selected from the group consisting of hydrogen, optionally substituted Ci-C 6 alkyl, optionally substituted C 3 -C 8 cycloalkyl, and optionally substituted C 2 - C 9 heterocycloalkyl; or R 34 and R 35 together with the nitrogen atom to which they are attached, form an optionally substituted C 2 -Cciheterocycloalkyl ring or an optionally substituted heteroaryl ring;
  • n 0, 1, 2, 3, or 4;
  • r 0, 1, 2, 3, or 4;
  • t is 2, 3, or 4; or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof.
  • R 30 is F. In some embodiments of a compound of Formula (IV), R 30 is F.
  • R 30 is .
  • a compound of Formula (IV) is a compound of Formula (IV)
  • R 30 is R 32 R 33 .
  • t is 2; and each R 32
  • R and R are hydrogen. In some embodiments of a compound of Formula (IV), R and R together with the nitrogen atom to which they are attached form a C 2 -Cciheterocycloalkyl ring. In some embodiments of a compound of Formula (IV), R 34 and R 35 together with the nitrogen atom to which they are attached form a morpholinyl. In some embodiments of a compound of Formula (IV), n is 1. In some embodiments of a compound of Formula (IV), R 31 is halogen. In some embodiments of a compound of Formula (IV), R 31 is F. In some embodiments of a compound of Formula (IV), R 4 and R 5 are each methyl.
  • R 9 is hydrogen or optionally substituted Ci-C 6 alkyl. In some embodiments of a compound of Formula (IV), R 9 is hydrogen. In some embodiments of a compound of Formula (IV), R 9 is optionally substituted Ci-C 6 alkyl. In some embodiments of a compound of Formula (IV), R 9 is Ci-C 6 alkyl. In some embodiments of a compound of Formula (IV), R 9 is methyl. [0019] In some embodiments of a compound of Formula (IV), the FXR modulator is a compound of Formula (IVa), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:
  • the FXR modulator is a compound of Formula (IVb), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:
  • R 1 is hydrogen. In some embodiments of a compound of Formula (III) or (IV), R 1 is Ci-C 6 alkyl, optionally substituted C 2 - C 6 alkenyl, or optionally substituted C 2 -C 6 alkynyl. In some embodiments of a compound of Formula (III) or (IV), R 25 is methyl. In some embodiments of a compound of Formula (III) or (IV), R 25 is ethyl. In some embodiments of a compound of Formula (III) or (IV), R 25 is isopropyl.
  • the FXR modulator is a compound of Formula (V):
  • R 1 is selected from the group consisting of hydrogen, halogen, optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted -(Ci-C 2 alkylene)-(C 3 -C 8 Cycloalkyl), optionally substituted C 2 -Cciheterocycloalkyl, optionally substituted -(Ci-C 2 alkylene)-(C 2 -Cciheterocycloalkyl), optionally substituted -(Ci- C 2 alkylene)-(aryl), optionally substituted -(Ci-C 2 alkylene)-(heteroaryl), -OR 10 , -SR 10 , -N(R U )R 12 , - N(R u )
  • R 4 and R 5 are each independently optionally substituted Ci-C 6 alkyl
  • R 9 is selected from the group consisting of hydrogen, optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted aryl, optionally substituted -(Ci-C 2 alkylene)-(aryl), optionally substituted C 2 -C 9 heterocycloalkyl, optionally substituted heteroaryl, and optionally sub stituted -(C i-C 2 alkyl ene)-(heteroaryl);
  • R 10 , R 13 and R 14 are each independently selected from the group consisting of hydrogen, optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted aryl, optionally substituted -(Ci-C 2 alkylene)-(aryl), optionally substituted C 2 -Cciheterocycloalkyl, optionally substituted heteroaryl, and optionally substituted -(Ci-C 2 alkylene)-(heteroaryl);
  • R 15 is selected from the group consisting of optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted aryl optionally substituted -(Ci-C 2 alkylene)-(aryl), optionally substituted C 2 -Cciheterocycloalkyl, optionally substituted heteroaryl, and optionally substituted -(Ci-C 2 alkylene)-(heteroaryl);
  • R u and R 12 are each independently selected from the group consisting of hydrogen, optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 - C 6 alkynyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted aryl, optionally substituted -(Ci-C 2 alkylene)-(aryl), optionally substituted C 2 -C 9 heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted -(Ci-C 2 alkylene)-(heteroaryl); or optionally R 11 and R 12 together with the nitrogen atom to which they are attached, form an optionally substituted C 2 -Cciheterocycloalkyl ring;
  • R 25 and R 26 are each independently selected from the group consisting of hydrogen, and
  • Ci-C 6 alkyl optionally substituted Ci-C 6 alkyl;
  • R 30 is halogen, ;
  • each R 31 is independently halogen, -OH, -CN, -N0 2 , -NH 2 , optionally substituted Ci-C 6 alkyl, optionally substituted Ci-C 6 alkoxy, optionally substituted Ci-C 6 alkylamine, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 2 -C 9 heterocycloalkyl, aryl, or heteroaryl; each R 32 and R 33 are each independently selected from the group consisting of hydrogen, halogen, and Ci-C 6 alkyl;
  • R 34 and R 35 are each independently selected from the group consisting of hydrogen, optionally substituted Ci-C 6 alkyl, optionally substituted C 3 -C 8 cycloalkyl, and optionally substituted C 2 - Cgheterocycloalkyl; or R 34 and R 35 together with the nitrogen atom to which they are attached, form an optionally substituted C 2 -Cciheterocycloalkyl ring or an optionally substituted heteroaryl ring;
  • n 0, 1, 2, 3, or 4;
  • r 0, 1, 2, 3, or 4;
  • t is 2, 3, or 4; or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof.
  • R 30 is F. In some embodiments of a compound of Formula (V), R 30 is F.
  • R 30 is .
  • a compound of Formula (V) In some embodiments of a compound of Formula (V),
  • R J0 is R 32 R 33 In some embodiments of a compound of Formula (V), t is 2; and each R 32 and R 33 are hydrogen. In some embodiments of a compound of Formula (V), R 34 and R 35 together with the nitrogen atom to which they are attached form a C 2 -Cciheterocycloalkyl ring. In some embodiments of a compound of Formula (V), R 34 and R 35 together with the nitrogen atom to which they are attached form a morpholinyl. In some embodiments of a compound of Formula (V), n is 1. In some
  • R 31 is halogen. In some embodiments of a compound of Formula (V), R 31 is F. In some embodiments of a compound of Formula (V), R 4 and R 5 are each methyl. In some embodiments of a compound of Formula (V), R 9 is hydrogen or optionally substituted Ci-C 6 alkyl. In some embodiments of a compound of Formula (V), R 9 is hydrogen. In some embodiments of a compound of Formula (V), R 9 is optionally substituted Ci-C 6 alkyl. In some embodiments of a compound of Formula (V), R 9 is Ci-C 6 alkyl. In some embodiments of a compound of Formula (V), R 9 is methyl.
  • the FXR modulator is a compound of Formula (Va), or a pharmaceutically acce table salt, stereoisomer, or solvate thereof:
  • the FXR modulator is a compound of Formula (Vb), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:
  • the FXR modulator is a compound of Formula (VI):
  • R 1 is selected from the group consisting of hydrogen, halogen, optionally substituted Ci-C 6 alkyl, optionally substituted C2-C 6 alkenyl, optionally substituted C2-C 6 alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted -(Ci-C 2 alkylene)-(C 3 -C 8 Cycloalkyl), optionally substituted C 2 -Cciheterocycloalkyl, optionally substituted -(Ci-C 2 alkylene)-(C 2 -Cciheterocycloalkyl), optionally substituted -(Ci- C 2 alkylene)-(aryl), optionally substituted -(Ci-C 2 alkylene)-(heteroaryl), -OR 10 , -SR 10 , -N(R U )R 12 , - N(R u )S(0) 2 R
  • R 4 and R 5 are each independently optionally substituted Ci-C 6 alkyl
  • R 9 is selected from the group consisting of hydrogen, optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted aryl, optionally substituted -(Ci-C 2 alkylene)-(aryl), optionally substituted C 2 -C 9 heterocycloalkyl, optionally substituted heteroaryl, and optionally sub stituted -(C i-C 2 alkyl ene)-(heteroaryl);
  • R 10 , R 13 and R 14 are each independently selected from the group consisting of hydrogen, optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted aryl, optionally substituted -(Ci-C 2 alkylene)-(aryl), optionally substituted C 2 -Cciheterocycloalkyl, optionally substituted heteroaryl, and optionally substituted -(Ci-C 2 alkylene)-(heteroaryl);
  • R 15 is selected from the group consisting of optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted aryl optionally substituted -(Ci-C 2 alkylene)-(aryl), optionally substituted C 2 -Cciheterocycloalkyl, optionally substituted heteroaryl, and optionally substituted -(Ci-C 2 alkylene)-(heteroaryl);
  • R u and R 12 are each independently selected from the group consisting of hydrogen, optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 - C 6 alkynyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted aryl, optionally substituted -(Ci-C 2 alkylene)-(aryl), optionally substituted C 2 -C 9 heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted -(Ci-C 2 alkylene)-(heteroaryl); or optionally R 11 and R 12 together with the nitrogen atom to which they are attached, form an optionally substituted C 2 -Cciheterocycloalkyl ring;
  • R 25 and R 26 are each independently selected from the group consisting of hydrogen, and
  • Ci-C 6 alkyl optionally substituted Ci-C 6 alkyl;
  • R 30 is halogen, ;
  • each R 31 is independently halogen, -OH, -CN, -N0 2 , -NH 2 , optionally substituted Ci-C 6 alkyl, optionally substituted Ci-C 6 alkoxy, optionally substituted Ci-C 6 alkylamine, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 2 -C 9 heterocycloalkyl, aryl, or heteroaryl; each R 32 and R 33 are each independently selected from the group consisting of hydrogen, halogen, and Ci-C 6 alkyl;
  • R 34 and R 35 are each independently selected from the group consisting of hydrogen, optionally substituted Ci-C 6 alkyl, optionally substituted C 3 -C 8 cycloalkyl, and optionally substituted C 2 - Cgheterocycloalkyl; or R 34 and R 35 together with the nitrogen atom to which they are attached, form an optionally substituted C 2 -Cciheterocycloalkyl ring or an optionally substituted heteroaryl ring;
  • n 0, 1, 2, 3, or 4;
  • r 0, 1, 2, 3, or 4;
  • t is 2, 3, or 4; or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof.
  • R 30 is F. In some embodiments of a compound of Formula (VI), R 30 is F.
  • R 30 is .
  • a compound of Formula (VI) In some embodiments of a compound of Formula (VI), R 30 is .
  • R 30 is R 32 R 33 .
  • t is 2; and each R 32
  • R and R are hydrogen. In some embodiments of a compound of Formula (VI), R and R together with the nitrogen atom to which they are attached form a C 2 -Cciheterocycloalkyl ring. In some embodiments of a compound of Formula (VI), R 34 and R 35 together with the nitrogen atom to which they are attached form a morpholinyl. In some embodiments of a compound of Formula (VI), n is 1. In some embodiments of a compound of Formula (VI), R 31 is halogen. In some embodiments of a compound of Formula (VI), R 31 is F. In some embodiments of a compound of Formula (VI), R 4 and R 5 are each methyl.
  • R 9 is hydrogen or optionally substituted Ci-C 6 alkyl. In some embodiments of a compound of Formula (VI), R 9 is hydrogen. In some embodiments of a compound of Formula (VI), R 9 is optionally substituted Ci-C 6 alkyl. In some embodiments of a compound of Formula (VI), R 9 is Ci-C 6 alkyl. In some embodiments of a compound of Formula (VI), R 9 is methyl.
  • the FXR modulator is a compound of Formula (Via), or a pharmaceutically acce table salt, stereoisomer, or solvate thereof:
  • the FXR modulator is a compound of Formula (VIb), or a pharmaceutically acce table salt, stereoisomer, or solvate thereof:
  • R 1 is hydrogen. In some embodiments of a compound of Formula (V) or (VI), R 1 is Ci-C 6 alkyl, optionally substituted C 2 - C 6 alkenyl, or optionally substituted C 2 -C 6 alkynyl. In some embodiments of a compound of Formula (V) or (VI), R 25 and R 26 are independently hydrogen or Ci-C 6 alkyl. In some embodiments of a compound of Formula (V) or (VI), R 25 and R 26 are hydrogen. In some embodiments of a compound of Formula (V) or (VI), R 25 and R 26 are independently Ci-C 6 alkyl.
  • the FXR modulator is a compound of Formula (VII):
  • R 1 is selected from the group consisting of hydrogen, optionally substituted Ci-C 6 alkyl,
  • R 3 is selected from the group consisting of hydrogen, optionally substituted Ci-C 6 alkyl,
  • R 4 and R 5 are each independently selected from the group consisting of hydrogen, halogen, optionally substituted Ci-C 6 alkyl, optionally substituted Ci-C 6 alkoxy, optionally substituted C 2 - C 6 alkenyl, and optionally substituted C 2 -C 6 alkynyl; or R 4 and R 5 together with the carbon atom to which they are attached, form an optionally substituted C 3 -C 6 cycloalkyl ring or an optionally substituted C 2 -Cvheterocycloalkyl ring;
  • R 6 is selected from the group consisting of hydrogen, halogen, optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, and -C(0)N(R 27 )R 28 ;
  • R 7 is selected from the group consisting of hydrogen, halogen, optionally substituted Ci-C 6 alkyl, optionally substituted Ci-C 6 alkoxy, optionally substituted C 2 -C 6 alkenyl, and optionally substituted C 2 -C 6 alkynyl;
  • R is selected from the group consisting of hydrogen, optionally substituted Ci-C 6 alkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted aryl, optionally substituted -(XV C 2 alkylene)-(aryl), optionally substituted heteroaryl, optionally substituted C 2 - C 9 heterocycloalkyl, and optionally substituted -(Ci-C 2 alkylene)-(heteroaryl);
  • R 9 and R 10 together with the carbon atoms to which they are attached, form an optionally substituted nitrogen containing 6-membered heteroaryl ring;
  • R 19 , R 20 , and R 23 are each independently selected from the group consisting of hydrogen, optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C3-C 8 cycloalkyl, optionally substituted aryl, optionally substituted -(Ci-C 2 alkylene)-(aryl), optionally substituted C 2 -Cciheterocycloalkyl, optionally substituted heteroaryl, and optionally substituted -(Ci-C 2 alkylene)-(heteroaryl);
  • R 21 and R 22 are each independently selected from the group consisting of hydrogen, optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 - C 6 alkynyl, optionally substituted C3-C 8 cycloalkyl, optionally substituted aryl, optionally substituted -(Ci-C 2 alkylene)-(aryl), optionally substituted C 2 -C 9 heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted -(Ci-C 2 alkylene)-(heteroaryl); or R 21 and R 22 together with the nitrogen atom to which they are attached, form an optionally substituted C 2 - Cgheterocycloalkyl ring;
  • R 24 is selected from the group consisting of optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted aryl optionally substituted -(Ci-C 2 alkylene)-(aryl), optionally substituted C 2 -Cciheterocycloalkyl, optionally substituted heteroaryl, and optionally substituted -(Ci-C 2 alkylene)-(heteroaryl);
  • R 25 and R 26 are each independently selected from the group consisting of hydrogen, optionally substituted Ci-C 6 alkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted aryl, optionally substituted -(Ci-C 2 alkylene)-(aryl), optionally substituted C 2 -Cciheterocycloalkyl, optionally substituted heteroaryl, and optionally substituted -(Ci-C 2 alkylene)-(heteroaryl); and
  • R 27 and R 28 are each independently selected from the group consisting of hydrogen, optionally substituted Ci-C 6 alkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted aryl, optionally substituted -(Ci-C 2 alkylene)-(aryl), optionally substituted C 2 -Cciheterocycloalkyl, optionally substituted heteroaryl, and optionally substituted -(Ci-C 2 alkylene)-(heteroaryl); or R 27 and R 28 together with the nitrogen atom to which they are attached, form an optionally substituted C 2 -Cciheterocycloalkyl ring; or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof.
  • the FXR modulator is a compound of Formula (Vila), or a pharmaceutically acce table salt, stereoisomer, or solvate thereof:
  • each R 11 is independently selected from the group consisting of halogen, -CN, amino, alkylamino, Ci-C 6 alkyl, Ci-C 6 haloalkyl, Ci-C 6 alkoxy, Ci-C 6 haloalkoxy, C3-C 8 cycloalkyl, C 2 - Cgheterocycloalkyl, aryl, heteroaryl, -C(0)OR 12 , and -C(0)N(R 13 )R 14 ;
  • each R 12 is independently selected from the group consisting of hydrogen and Ci-C 6 alkyl
  • each R 13 and R 14 are each independently selected from the group consisting of hydrogen and Ci- C 6 alkyl; or R 13 and R 14 together with the nitrogen atom to which they are attached, form an optionally substituted C 2 -Cciheterocycloalkyl ring; and
  • n 0, 1, 2, or 3.
  • the FXR modulator is a compound of Formula (Vllb), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:
  • each R 11 is independently selected from the group consisting of halogen, -CN, amino, alkylamino, Ci-C 6 alkyl, Ci-C 6 haloalkyl, Ci-C 6 alkoxy, Ci-C 6 haloalkoxy, C3-C 8 cycloalkyl, C 2 -
  • each R 12 is independently selected from the group consisting of hydrogen and Ci-C 6 alkyl; each R 13 and R 14 are each independently selected from the group consisting of hydrogen and Ci- C 6 alkyl; or R 13 and R 14 together with the nitrogen atom to which they are attached, form an optionally substituted C 2 -C 9 heterocycloalkyl ring; and
  • n 0, 1, 2, or 3.
  • the FXR modulator is a compound of Formula (VIIc), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:
  • each R 11 is independently selected from the group consisting of halogen, -CN, amino, alkylamino, Ci-C 6 alkyl, Ci-C 6 haloalkyl, Ci-C 6 alkoxy, Ci-C 6 haloalkoxy, C 3 -C 8 cycloalkyl, C 2 - Cgheterocycloalkyl, aryl, heteroaryl, -C(0)OR 12 , and -C(0)N(R 13 )R 14 ;
  • each R 12 is independently selected from the group consisting of hydrogen and Ci-C 6 alkyl
  • each R 13 and R 14 are each independently selected from the group consisting of hydrogen and Ci- C 6 alkyl; or R 13 and R 14 together with the nitrogen atom to which they are attached, form an optionally substituted C 2 -C 9 heterocycloalkyl ring; and
  • n 0, 1, 2, or 3.
  • the FXR modulator is a compound of Formula (Vlld), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:
  • each R 11 is independently selected from the group consisting of halogen, -CN, amino,
  • Ci-C 6 alkyl Ci-C 6 haloalkyl
  • Ci-C 6 alkoxy Ci-C 6 haloalkoxy
  • C 3 -C 8 cycloalkyl C 2 -
  • each R 12 is independently selected from the group consisting of hydrogen and Ci-C 6 alkyl; each R and R are each independently selected from the group consisting of hydrogen and Ci- C 6 alkyl; or R 13 and R 14 together with the nitrogen atom to which they are attached, form an optionally substituted C 2 -C 9 heterocycloalkyl ring; and
  • n 0, 1, 2, or 3.
  • the FXR modulator is a compound of Formula (Vile), or a pharmaceutically acce table salt, stereoisomer, or solvate thereof:
  • each R 11 is independently selected from the group consisting of halogen, -CN, amino, alkylamino, Ci-C 6 alkyl, Ci-C 6 haloalkyl, Ci-C 6 alkoxy, Ci-C 6 haloalkoxy, C 3 -C 8 cycloalkyl, C 2 - C 9 heterocycloalkyl, aryl, heteroaryl, -C(0)OR 12 , and -C(0)N(R 13 )R 14 ;
  • each R 12 is independently selected from the group consisting of hydrogen and Ci-C 6 alkyl
  • each R 13 and R 14 are each independently selected from the group consisting of hydrogen and Ci- C 6 alkyl; or R 13 and R 14 together with the nitrogen atom to which they are attached, form an optionally substituted C 2 -C 9 heterocycloalkyl ring; and
  • n 0, 1, or 2.
  • the FXR modulator is a compound of Formula (Vllf), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:
  • each R 11 is independently selected from the group consisting of halogen, -CN, amino,
  • Ci-C 6 alkyl Ci-C 6 haloalkyl
  • Ci-C 6 alkoxy Ci-C 6 haloalkoxy
  • C 3 -C 8 cycloalkyl C 2 -
  • each R is independently selected from the group consisting of hydrogen and Ci-C 6 alkyl;
  • each R 13 and R 14 are each independently selected from the group consisting of hydrogen and Ci-
  • n 0, 1, or 2.
  • the FXR modulator is a compound of Formula (Vllg), or a pharmaceutically acce table salt, stereoisomer, or solvate thereof:
  • each R 11 is independently selected from the group consisting of halogen, -CN, amino, alkylamino, Ci-C 6 alkyl, Ci-C 6 haloalkyl, Ci-C 6 alkoxy, Ci-C 6 haloalkoxy, C3-C 8 cycloalkyl, C 2 - C 9 heterocycloalkyl, aryl, heteroaryl, -C(0)OR 12 , and -C(0)N(R 13 )R 14 ;
  • each R 12 is independently selected from the group consisting of hydrogen and Ci-C 6 alkyl
  • each R 13 and R 14 are each independently selected from the group consisting of hydrogen and Ci- C 6 alkyl; or R 13 and R 14 together with the nitrogen atom to which they are attached, form an optionally substituted C 2 -Cciheterocycloalkyl ring; and
  • n 0, 1, or 2.
  • the FXR modulator is a compound of Formula (Vllh), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:
  • each R 11 is independently selected from the group consisting of halogen, -CN, amino, alkylamino, Ci-C 6 alkyl, Ci-C 6 haloalkyl, Ci-C 6 alkoxy, Ci-C 6 haloalkoxy, C 3 -C 8 cycloalkyl, C 2 -
  • each R 12 is independently selected from the group consisting of hydrogen and Ci-C 6 alkyl
  • each R 13 and R 14 are each independently selected from the group consisting of hydrogen and Ci-
  • n 0, 1, or 2.
  • the FXR modulator is a compound of Formula (Vlli), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:
  • each R 11 is independently selected from the group consisting of halogen, -CN, amino, alkylamino, Ci-C 6 alkyl, Ci-C 6 haloalkyl, Ci-C 6 alkoxy, Ci-C 6 haloalkoxy, C 3 -C 8 cycloalkyl, C 2 -
  • each R 12 is independently selected from the group consisting of hydrogen and Ci-C 6 alkyl
  • each R 13 and R 14 are each independently selected from the group consisting of hydrogen and Ci-
  • n 0, 1, or 2.
  • the FXR modulator is a compound of Formula (Vllj), or a pharmaceutically acce table salt, stereoisomer, or solvate thereof:
  • each R 11 is independently selected from the group consisting of halogen, -CN, amino,
  • Ci-C 6 alkyl Ci-C 6 haloalkyl, Ci-C 6 alkoxy, Ci-C 6 haloalkoxy, C 3 -C 8 cycloalkyl, C 2 - Cgheterocycloalkyl, aryl, heteroaiyl, -C(0)OR 12 , and -C(0)N(R 13 )R 14 ;
  • each R 12 is independently selected from the group consisting of hydrogen and Ci-C 6 alkyl
  • each R 13 and R 14 are each independently selected from the group consisting of hydrogen and Ci- C 6 alkyl; or R 13 and R 14 together with the nitrogen atom to which they are attached, form an optionally substituted C 2 -C 9 heterocycloalkyl ring; and
  • n 0, 1, or 2.
  • n is 0.
  • R 6 and R 7 are hydrogen.
  • R 3 is -C(0)N(R 21 )R 22 .
  • R 3 is -C(0)N(R 21 )R 22 ;
  • R 21 is hydrogen and R 22 is optionally substituted aryl.
  • R 3 is -C(0)R 20 .
  • R is -S(0) 2 R 20 .
  • R 3 is -C(0)R 20 or
  • R is -S(0) 2 R and R is optionally substituted aryl.
  • the FXR modulator is a com ound of Formula (VIII):
  • R 1 is selected from the group consisting of hydrogen, optionally substituted Ci-C 6 alkyl,
  • R 2 is selected from the group consisting of -CN, -C(0)OR 25 , -C(0)N(R 25 )R 26 , 0' N , and R 1 and R 2 together with the carbon atoms to which they are attached, form an optionally substituted C 2 -Cciheterocycloalkyl ring or an optionally substituted heteroaryl ring;
  • R 4 and R 5 are each independently selected from the group consisting of hydrogen, hal
  • R 6 is selected from the group consisting of hydrogen, halogen, optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, and -C(0)N(R 27 )R 28 ;
  • R 7 is selected from the group consisting of hydrogen, halogen, optionally substituted Ci-C 6 alkyl, optionally substituted Ci-C 6 alkoxy, optionally substituted C 2 -C 6 alkenyl, and optionally substituted C 2 -C 6 alkynyl;
  • R 8 is selected from the group consisting of hydrogen, optionally substituted Ci-C 6 alkyl,
  • optionally substituted C 3 -C 8 cycloalkyl optionally substituted aryl, optionally substituted -(Ci- C 2 alkylene)-(aryl), optionally substituted heteroaryl, optionally substituted C 2 - Cgheterocycloalkyl, and optionally substituted -(Ci-C 2 alkylene)-(heteroaryl);
  • R 25 and R 26 are each independently selected from the group consisting of hydrogen, optionally substituted Ci-C 6 alkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted aryl, optionally substituted -(Ci-C 2 alkylene)-(aryl), optionally substituted C 2 -C 9 heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted -(Ci-C 2 alkylene)-(heteroaryl); R 27 and R 28 are each independently selected from the group consisting of hydrogen, optionally substituted Ci-C 6 alkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted aryl, optionally substituted -(Ci-C 2 alkylene)-(aryl), optionally substituted C 2 -C 9 heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted -(Ci-C 2 alkylene)-(heteroaryl); or R 27 and
  • each R 31 is independently halogen, -OH, -CN, -N0 2 , -NH 2 , optionally substituted Ci-C 6 alkyl, optionally substituted Ci-C 6 alkoxy, optionally substituted Ci-C 6 alkylamine, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 2 -C 9 heterocycloalkyl, aryl, or heteroaryl; each R 32 and R 33 are each independently selected from the group consisting of hydrogen, halogen, and Ci-C 6 alkyl;
  • R 34 and R 35 are each independently selected from the group consisting of hydrogen, optionally substituted Ci-C 6 alkyl, optionally substituted C 3 -C 8 cycloalkyl, and optionally substituted C 2 - Cgheterocycloalkyl; or R 34 and R 35 together with the nitrogen atom to which they are attached, form an optionally substituted C 2 -Cciheterocycloalkyl ring or an optionally substituted heteroaryl ring;
  • p O, 1, 2, 3, or 4;
  • r is 0, 1, 2, 3, or 4;
  • t is 2, 3, or 4; or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof.
  • the FXR modulator is a compound of Formula (Villa), or a pharmaceuticall acceptable salt, stereoisomer, or solvate thereof:
  • each R 11 is independently selected from the group consisting of halogen, -CN, amino,
  • Ci-C 6 alkyl Ci-C 6 haloalkyl
  • Ci-C 6 alkoxy Ci-C 6 haloalkoxy
  • C 3 -C 8 cycloalkyl C 2 -
  • each R 12 is independently selected from the group consisting of hydrogen and Ci-C 6 alkyl
  • each R 13 and R 14 are each independently selected from the group consisting of hydrogen and Ci-
  • the FXR modulator is a compound of Formula (VHIb), or a pharmaceuticall acceptable salt, stereoisomer, or solvate thereof:
  • each R 11 is independently selected from the group consisting of halogen, -CN, amino,
  • Ci-C 6 alkyl Ci-C 6 haloalkyl
  • Ci-C 6 alkoxy Ci-C 6 haloalkoxy
  • C 3 -C 8 cycloalkyl C 2 -
  • each R 12 is independently selected from the group consisting of hydrogen and Ci-C 6 alkyl
  • each R 13 and R 14 are each independently selected from the group consisting of hydrogen and Ci-
  • n 0, 1, 2, or 3.
  • the FXR modulator is a compound of Formula (VIIIc), or a pharmaceuticall acceptable salt, stereoisomer, or solvate thereof:
  • each R 11 is independently selected from the group consisting of halogen, -CN, amino, alkylamino, Ci-C 6 alkyl, Ci-C 6 haloalkyl, Ci-C 6 alkoxy, Ci-C 6 haloalkoxy, C 3 -C 8 cycloalkyl, C 2 - C 9 heterocycloalkyl, aryl, heteroaryl, -C(0)OR 12 , -C(0)N(R 13 )R 14 ;
  • each R 12 is independently selected from the group consisting of hydrogen and Ci-C 6 alkyl; each R and R are each independently selected from the group consisting of hydrogen and Ci- C 6 alkyl; or R 13 and R 14 together with the nitrogen atom to which they are attached, form an optionally substituted C 2 -C 9 heterocycloalkyl ring; and
  • n 0, 1, 2, or 3.
  • the FXR modulator is a compound of Formula (VHId), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:
  • each R 11 is independently selected from the group consisting of halogen, -CN, amino, alkylamino, Ci-C 6 alkyl, Ci-C 6 haloalkyl, Ci-C 6 alkoxy, Ci-C 6 haloalkoxy, C3-C 8 cycloalkyl, C 2 -
  • each R 12 is independently selected from the group consisting of hydrogen and Ci-C 6 alkyl
  • each R 13 and R 14 are each independently selected from the group consisting of hydrogen and Ci-
  • n 0, 1, 2, or 3.
  • the FXR modulator is a compound of Formula (VHIe), or a pharmaceuticall acceptable salt, stereoisomer, or solvate thereof:
  • each R 11 is independently selected from the group consisting of halogen, -CN, amino, alkylamino, Ci-C 6 alkyl, Ci-C 6 haloalkyl, Ci-C 6 alkoxy, Ci-C 6 haloalkoxy, C3-C 8 cycloalkyl, C 2 -
  • each R is independently selected from the group consisting of hydrogen and Ci-C 6 alkyl;
  • each R 13 and R 14 are each independently selected from the group consisting of hydrogen and Ci-
  • n 0, 1, or 2.
  • the FXR modulator is a compound of Formula (Vlllf), or a pharmaceuticall acceptable salt, stereoisomer, or solvate thereof:
  • each R 11 is independently selected from the group consisting of halogen, -CN, amino, alkylamino, Ci-C 6 alkyl, Ci-C 6 haloalkyl, Ci-C 6 alkoxy, Ci-C 6 haloalkoxy, C3-C 8 cycloalkyl, C 2 -
  • each R 12 is independently selected from the group consisting of hydrogen and Ci-C 6 alkyl
  • each R 13 and R 14 are each independently selected from the group consisting of hydrogen and Ci-
  • n 0, 1, or 2.
  • the FXR modulator is a compound of Formula (VHIg), or a pharmaceuticall acceptable salt, stereoisomer, or solvate thereof:
  • each R 11 is independently selected from the group consisting of halogen, -CN, amino, alkylamino, Ci-C 6 alkyl, Ci-C 6 haloalkyl, Ci-C 6 alkoxy, Ci-C 6 haloalkoxy, C3-C 8 cycloalkyl, C 2 -
  • each R 12 is independently selected from the group consisting of hydrogen and Ci-C 6 alkyl
  • each R 13 and R 14 are each independently selected from the group consisting of hydrogen and Ci-
  • n 0, 1, or 2.
  • the FXR modulator is a compound of Formula (VHIh), or a pharmaceuticall acceptable salt, stereoisomer, or solvate thereof:
  • each R 11 is independently selected from the group consisting of halogen, -CN, amino, alkylamino, Ci-C 6 alkyl, Ci-C 6 haloalkyl, Ci-C 6 alkoxy, Ci-C 6 haloalkoxy, C3-C 8 cycloalkyl, C 2 -
  • each R 12 is independently selected from the group consisting of hydrogen and Ci-C 6 alkyl
  • each R 13 and R 14 are each independently selected from the group consisting of hydrogen and Ci-
  • n 0, 1, or 2.
  • the FXR modulator is a compound of Formula (Villi), or a pharmaceuticall acceptable salt, stereoisomer, or solvate thereof:
  • each R 11 is independently selected from the group consisting of halogen, -CN, amino, alkylamino, Ci-C 6 alkyl, Ci-C 6 haloalkyl, Ci-C 6 alkoxy, Ci-C 6 haloalkoxy, C 3 -C 8 cycloalkyl, C 2 -
  • each R 12 is independently selected from the group consisting of hydrogen and Ci-C 6 alkyl
  • each R 13 and R 14 are each independently selected from the group consisting of hydrogen and Ci-
  • n 0, 1, or 2.
  • the FXR modulator is a compound of Formula (Vlllj), or a pharmaceuticall acceptable salt, stereoisomer, or solvate thereof:
  • each R 11 is independently selected from the group consisting of halogen, -CN, amino,
  • Ci-C 6 alkyl Ci-C 6 haloalkyl
  • Ci-C 6 alkoxy Ci-C 6 haloalkoxy
  • C 3 -C 8 cycloalkyl C 2 -
  • each R 12 is independently selected from the group consisting of hydrogen and Ci-C 6 alkyl
  • each R 13 and R 14 are each independently selected from the group consisting of hydrogen and Ci-
  • n 0, 1, or 2.
  • n is 0.
  • R 30 is F.
  • R 30 is .
  • a compound of R34 is a compound of R34
  • R 30 is R 32 R 33 .
  • t is 2; and each R 32 and R 33 are hydrogen.
  • R 34 and R 35 together with the nitrogen atom to which they are attached form a C 2 -C 9 heterocycloalkyl ring.
  • R 34 and R 35 together with the nitrogen atom to which they are attached form a morpholinyl.
  • p is 1.
  • R 31 is halogen.
  • R 31 is F.
  • R 6 and R 7 are hydrogen.
  • R 4 and R 5 are each independently optionally substituted Ci-C 6 alkyl.
  • R 4 and R 5 are methyl.
  • R 2 is - C(0)OR 25 .
  • R 2 is -C(0)OR 25 and R 25 is optionally substituted Ci-C 6 alkyl.
  • R 2 is -C(0)OR 25 and R 25 is methyl.
  • R 2 is -C(0)OR 25 and R 25 is ethyl. In some embodiments of a compound of Formula (VIII) or (Vllla)-(VIIIj), R 2 is -C(0)OR 25 and R 25 is isopropyl. In some embodiments of a compound of Formula (VIII) or (Vllla)-(VIIIj), R 2 is -C(0)N(R 25 )R 26 . In some embodiments of a compound of Formula (VIII) or (Vllla)-(VIIIj), R 1 is hydrogen or optionally substituted Ci-C 6 alkyl.
  • R 1 is hydrogen. In some embodiments of a compound of Formula (VIII) or (Vllla)-(VIIIj), R 1 is optionally substituted Ci-C 6 alkyl. In some embodiments of a compound of Formula (VIII) or (VHIa)- (VHIj), R 1 is Ci-C 6 alkyl. In some embodiments of a compound of Formula (VIII) or (Vllla)-(VIIIj), R is methyl. In some embodiments of a compound of Formula (VIII) or (Vllla)-(VIIIj), R 8 is hydrogen.
  • the FXR modulator is a compound of Formula (XI) or a
  • R 1 is selected from the group consisting of hydrogen, optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 - C 8 cycloalkyl, optionally substituted aryl, optionally substituted -(Ci-C 2 alkylene)-(aryl), optionally substituted C 2 -C 9 heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted - (Ci-C 2 alkylene)-(heteroaryl);
  • R 1 and R 2 together with the carbon atoms to which they are attached, form an optionally substituted C 2 -Cciheterocycloalkyl ring or an optionally substituted heteroaryl ring;
  • R 3 is selected from the group consisting of hydrogen, optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 - C 8 cycloalkyl, optionally substituted aryl, optionally substituted -(Ci-C 2 alkylene)-(aryl), optionally substituted heteroaryl, optionally substituted C 2 -Cciheterocycloalkyl, optionally substituted -(Ci- C 2 alkylene)-(heteroaryl), -C(0)R 20 , -C(0)OR 20 , -S(0) 2 R 20 , -C(0)N(R 21 )R 22 , -C(0)N(R 21 )S(0) 2 R 24 , -C(0)N(R 23 )N(R 21 )R 22 , -C(0)N(R 23 )N(R 21 )S(0) 2 R 24 , -
  • R 4 and R 5 are each independently selected from the group consisting of hydrogen, halogen,
  • Ci-C 6 alkyl optionally substituted Ci-C 6 alkyl, optionally substituted Ci-C 6 alkoxy, optionally substituted C 2 - C 6 alkenyl, and optionally substituted C 2 -C 6 alkynyl; or R 4 and R 5 together with the carbon atom to which they are attached, form an optionally substituted C 3 -C 6 cycloalkyl ring or an optionally substituted C 2 -C 7 heterocycloalkyl ring;
  • R 6 is selected from the group consisting of hydrogen, halogen, optionally substituted Ci-C 6 alkyl, optionally substituted C2-C 6 alkenyl, optionally substituted C2-C 6 alkynyl, and -C(0)N(R 27 )R 28 ;
  • R 7 is selected from the group consisting of hydrogen, halogen, optionally substituted Ci-C 6 alkyl, optionally substituted Ci-C 6 alkoxy, optionally substituted C 2 -C 6 alkenyl, and optionally substituted C 2 -C 6 alkynyl;
  • R 8 is selected from the group consisting of hydrogen, optionally substituted Ci-C 6 alkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted aryl, optionally substituted -(Ci-C 2 alkylene)- (aryl), optionally substituted heteroaryl, optionally substituted C 2 -C 9 heterocycloalkyl, and optionally substituted -(Ci-C 2 alkylene)-(heteroaryl);
  • R 9 and R 10 are each independently selected from the group consisting of hydrogen, halogen, -CN, amino, alkylamino, optionally substituted Ci-C 6 alkyl, optionally substituted Ci-C 6 alkoxy, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 2 -C 9 heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
  • R , R , and R are each independently selected from the group consisting of hydrogen, optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted aryl, optionally substituted -(Ci- C 2 alkylene)-(aryl), optionally substituted C 2 -C9heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted -(Ci-C 2 alkylene)-(heteroaryl);
  • R 21 and R 22 are each independently selected from the group consisting of hydrogen, optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted aryl, optionally substituted -(XV C 2 alkylene)-(aryl), optionally substituted C 2 -C9heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted -(Ci-C 2 alkylene)-(heteroaryl); or R 21 and R 22 together with the nitrogen atom to which they are attached, form an optionally substituted C 2 -C 9 heterocycloalkyl ring;
  • R 24 is selected from the group consisting of optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted aryl optionally substituted -(Ci-C 2 alkylene)-(aryl), optionally substituted C 2 - C 9 heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted -(Ci-C 2 alkylene)- (heteroaryl);
  • R 25 and R 26 are each independently selected from the group consisting of hydrogen, optionally substituted Ci-C 6 alkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted aryl, optionally substituted -(Ci-C 2 alkylene)-(aryl), optionally substituted Ci-Cgheterocycloalkyl, optionally substituted heteroaryl, and optionally substituted -(Ci-C 2 alkylene)-(heteroaryl); and R 27 and R 28 are each independently selected from the group consisting of hydrogen, optionally substituted Ci-C 6 alkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted aryl, optionally substituted -(Ci-C 2 alkylene)-(aryl), optionally substituted Ci-Cgheterocycloalkyl, optionally substituted heteroaryl, and optionally substituted -(Ci-C 2 alkylene)-(heteroaryl); or R 27
  • the FXR modulator is a compound of Formula (XII), or a pharmaceutically acceptable salt, stereoisomer or solvate thereof:
  • R 1 is selected from the group consisting of hydrogen, optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 - C 8 cycloalkyl, optionally substituted aryl, optionally substituted -(Ci-C 2 alkylene)-(aryl), optionally substituted C 2 -Cciheterocycloalkyl, optionally substituted heteroaryl, and optionally substituted - (Ci-C 2 alkylene)-(heteroaryl);
  • R 2 is selected from the group consisting of -CN, -C(0)OR 25 , -C(0)N(R 25 )R 26 ,
  • R 1 and R 2 together with the carbon atoms to which they are attached, form an optionally substituted C 2 -C 9 heterocycloalkyl ring or an optionally substituted heteroaryl ring;
  • R 3 is selected from the group consisting of hydrogen, optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 - C 8 cycloalkyl, optionally substituted aryl, optionally substituted -(Ci-C 2 alkylene)-(aryl), optionally substituted heteroaryl, optionally substituted C 2 -Cciheterocycloalkyl, optionally substituted -(Ci- C 2 alkylene)-(heteroaryl), -C(0)R 20 , -C(0)OR 20 , -S(0) 2 R 2 °, -C(0)N(R 21 )R 22 , -C(0)N(R 21 )S(0) 2 R 24 , -C(0)N(R 23 )N(R 21 )R 22 , -C(0)N(R 23 )N(R 21 )S(0) 2 R 24 ,
  • R 4 and R 5 are each independently selected from the group consisting of hydrogen, halogen,
  • Ci-C 6 alkyl optionally substituted Ci-C 6 alkyl, optionally substituted Ci-C 6 alkoxy, optionally substituted C 2 - C 6 alkenyl, and optionally substituted C 2 -C 6 alkynyl; or R 4 and R 5 together with the carbon atom to which they are attached, form an optionally substituted C3-C 6 cycloalkyl ring or an optionally substituted C 2 -Cvheterocycloalkyl ring;
  • R 6 is selected from the group consisting of hydrogen, halogen, optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, and -C(0)N(R 27 )R 28 ;
  • R 7 is selected from the group consisting of hydrogen, halogen, optionally substituted Ci-C 6 alkyl, optionally substituted Ci-C 6 alkoxy, optionally substituted C 2 -C 6 alkenyl, and optionally substituted C 2 -C 6 alkynyl;
  • R 8 is selected from the group consisting of hydrogen, optionally substituted Ci-C 6 alkyl, optionally substituted C3-C 8 cycloalkyl, optionally substituted aryl, optionally substituted -(Ci-C 2 alkylene)- (aryl), optionally substituted heteroaryl, optionally substituted C 2 -Cciheterocycloalkyl, and optionally substituted -(Ci-C 2 alkylene)-(heteroaryl);
  • R 9 and R 10 are each independently selected from the group consisting of hydrogen, halogen, -CN, amino, alkylamino, optionally substituted Ci-C 6 alkyl, optionally substituted Ci-C 6 alkoxy, optionally substituted C3-C 8 cycloalkyl, optionally substituted C 2 -Cciheterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
  • R , R , and R are each independently selected from the group consisting of hydrogen, optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C3-C 8 cycloalkyl, optionally substituted aryl, optionally substituted -(XV C 2 alkylene)-(aryl), optionally substituted C 2 -C 9 heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted -(Ci-C 2 alkylene)-(heteroaryl);
  • R 21 and R 22 are each independently selected from the group consisting of hydrogen, optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted aryl, optionally substituted -(Ci- C 2 alkylene)-(aryl), optionally substituted C 2 -C 9 heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted -(Ci-C 2 alkylene)-(heteroaryl); or R and R together with the nitrogen atom to which they are attached, form an optionally substituted C 2 -Cciheterocycloalkyl ring;
  • R 24 is selected from the group consisting of optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted aryl optionally substituted -(Ci-C 2 alkylene)-(aryl), optionally substituted C 2 - Cgheterocycloalkyl, optionally substituted heteroaryl, and optionally substituted -(Ci-C 2 alkylene)- (heteroaryl);
  • R 25 and R 26 are each independently selected from the group consisting of hydrogen, optionally substituted Ci-C 6 alkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted aryl, optionally substituted -(Ci-C 2 alkylene)-(aryl), optionally substituted C 2 -Cciheterocycloalkyl, optionally substituted heteroaryl, and optionally substituted -(Ci-C 2 alkylene)-(heteroaryl); and R 27 and R 28 are each independently selected from the group consisting of hydrogen, optionally substituted Ci-C 6 alkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted aryl, optionally substituted -(Ci-C 2 alkylene)-(aryl), optionally substituted C 2 -Cciheterocycloalkyl, optionally substituted heteroaryl, and optionally substituted -(Ci-C 2 alkylene)-(hetero
  • R 4 and R 5 are hydrogen. In some embodiments of a compound of Formula (XI) or (XII), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, R 4 and R 5 are Ci-C 6 alkyl. In some embodiments of a compound of Formula (XI) or (XII), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, R 4 and R 5 are methyl. In some embodiments of a compound of Formula (XI) or (XII), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, R 6 and R 7 are hydrogen. In some embodiments of a compound of Formula (XI) or (XII), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, R 6 and R 7 are hydrogen. In some embodiments of a compound of Formula (XI) or (XII), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, R 6 and R 7 are hydrogen. In some embodiments
  • Formula (XI) or (XII) R° is -C(0)N(R z ')R zo and R are hydrogen.
  • R 2 is -C(0)OR 25 .
  • R 2 is -C(0)OR 25 and R 25 is optionally substituted Ci-C 6 alkyl.
  • R 2 is -C(0)OR 25 and R 25 is methyl. In some embodiments of a compound of Formula (XI) or (XII), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, R 2 is -C(0)OR 25 and R 25 is ethyl. In some embodiments of a compound of Formula (XI) or (XII), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, R 2 is -C(0)OR 25 and R 25 is isopropyl.
  • R 2 is -C(0)N(R 25 )R 26 .
  • R is hydrogen.
  • R 1 is optionally substituted Ci-C 6 alkyl.
  • R 1 is -CH 3 .
  • R 3 is -C(0)N(R 21 )R 22 .
  • R is -C(0)N(R )R
  • R is hydrogen
  • R 22 is optionally substituted aryl.
  • R 3 is -C(0)R 20 .
  • a compound of Formula (XI) or (XII) or a pharmaceutically acceptable salt,
  • R is -C(0)R and R is optionally substituted aryl.
  • R 3 is -S(0)2R 20 .
  • R 3 is -S(0)2R 20 and R 20 is optionally substituted aryl.
  • the FXR modulator is a compound of Formula (Villa), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, or a compound of Formula (XII), the FXR modulator is a compound of Formula (Xlla), or a
  • R 30 is halogen, R 32 R 33 , 0 r R 32 R 33 ;
  • each R 31 is independently halogen, -OH, -CN, -N0 2 , -NH 2 , optionally substituted Ci-C 6 alkyl, optionally substituted Ci-C 6 alkoxy, optionally substituted Ci-C 6 alkylamine, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 2 -C 9 heterocycloalkyl, aryl, or heteroaryl; each R 32 and R 33 are each independently selected from the group consisting of hydrogen, halogen, and Ci-C 6 alkyl;
  • R 34 and R 35 are each independently selected from the group consisting of hydrogen, optionally substituted Ci-C 6 alkyl, optionally substituted C 3 -C 8 cycloalkyl, and optionally substituted C 2 - C 9 heterocycloalkyl; or R 34 and R 35 together with the nitrogen atom to which they are attached, form an optionally substituted C 2 -Cciheterocycloalkyl ring;
  • p O, 1, 2, 3, or 4;
  • r is 0, 1, 2, 3, or 4;
  • t 2, 3, or 4.
  • R 30 is halogen. In some embodiments of a compound of Formula (XIa) or (Xlla), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, R 30 is F. In some some embodiments of a compound of Formula (XIa) or (Xlla), or a pharmaceutically
  • R 30 is .
  • a compound of Formula (XIa) or (Xlla) or a pharmaceutically acceptable salt, stereoisomer, or solvate
  • R 30 is R 32 R 33 .
  • t is 2.
  • p is 0.
  • p is 1.
  • R 31 is F.
  • FXR modulatators are FXR modulatators, and pharmaceutical compositions that include such FXR modulatators, for use in the treatment of diseases, disorders or conditions that would benefit from FXR modulation.
  • pharmaceutical compositions that include such FXR modulatators, for use in the treatment of diseases, disorders or conditions that would benefit from FXR modulation.
  • an FXR modulator described herein is the administration of an FXR modulator described herein to a mammal in the treatment of diseases, disorders or conditions that would benefit from FXR modulation, wherein the FXR modulator is (E)-6-(3,4-difluorobenzoyl)-N-isopropyl-4,4-dimethyl-3- (trifluoromethyl)-l,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxamide (Compound 1), (E)- isopropyl 4,4-dimethyl-6-(4-(2-morpholinoethoxy)benzoyl)-3 -(trifluorom ethyl)- 1, 4,5,6- tetrahydropyrazolo[3,4-d]azepine-8-carboxylate (Compound 2), or (E)-isopropyl 6-(3-fluoro-4-(2- mo holinoethoxy)benzoyl
  • a metabolic disorder in an individual in need thereof comprising co-administering to the individual a therapeutically effective amount of: (a) a first agent that is an FXR modulator; and (b) a second agent that is a DPP-IV inhibitor selected from sitagliptin, saxagliptin, linagliptin, alogliptin, vildagliptin, gemigliptin, anagliptin, teneligliptin, trelagliptin, dutogliptin, and omarigliptin.
  • a metabolic disorder in an individual in need thereof comprising co-administering to the individual a therapeutically effective amount of: (a) a first agent that is an FXR modulator; and (b) a second agent that is an SGLT2 inhibitor selected from canagliflozin, empagliflozin, dapagliflozin, ipragliflozin, tofogliflozin, sergliflozin etabonate, remogliflozin etabonate, and ertugliflozin.
  • a method of treating a metabolic disorder in a subject in need thereof comprising administering to the subject in need thereof an effective dose of (E)-6-(3,4- difluorobenzoyl)-N-isopropyl-4,4-dimethyl-3-(trifluoromethyl)-l,4,5,6-tetrahydropyrazolo[3,4- d]azepine-8-carboxamide (Compound 1), (E)-isopropyl 4,4-dimethyl-6-(4-(2- mo holinoethoxy)benzoyl)-3-(trifluoromethyl)-l,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8- carboxylate (Compound 2), or (E)-isopropyl 6-(3-fluoro-4-(2-morpholinoethoxy)benzoyl)-4,4- dimethyl-3-(trifluoromethyl)-l,4,5,
  • a metabolic disorder in an individual in need thereof comprising co-administering to the individual a therapeutically effective amount of: (a) a first agent that is an FXR modulator; and (b) a second agent that is an ASK1 inhibitor selected from GS-4997 (selonsertib) (5-(4-cyclopropyl-lH-imidazol-l-yl)-2-fluoro-N-(6-(4-isopropyl-4H-l,2,4- triazol-3-yl)pyridin-2-yl)-4-methylbenzamide), NQDI-1 (ethyl 2,7-dioxo-3,7-dihydro-2H- naphtho[l,2,3-de]quinoline-l-carboxylate), ML365 (2-methoxy-N-[3-[(3- methylbenzoyl)amino]phenyl]benzamide), MSC 203
  • a metabolic disorder in an individual in need thereof comprising co-administering to the individual a therapeutically effective amount of: (a) a first agent that is an FXR modulator; and (b) a second agent that is a GLP-1 agonist selected from exenatide, liraglutide, lixisenatide, albiglutide, dulaglutide, taspoglutide, and semaglutide.
  • a first agent that is an FXR modulator
  • a second agent that is a GLP-1 agonist selected from exenatide, liraglutide, lixisenatide, albiglutide, dulaglutide, taspoglutide, and semaglutide.
  • a metabolic disorder in an individual in need thereof comprising co-administering to the individual a therapeutically effective amount of: (a) a first agent that is an FXR modulator; and (b) at least one second agent that is a DPP-IV inhibitor, an SGLT2 inhibitor, an ASK1 inhibitor, a GLP-1 agonist, or a combination thereof; wherein the metabolic disorder is nonalcoholic steatohepatitis (NASH), hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, dyslipidemia, lipodystrophy, atherosclerosis, atherosclerotic disease, atherosclerotic disease events, atherosclerotic cardiovascular disease, Syndrome X, diabetes mellitus, type II diabetes, insulin insensitivity, hyperglycemia, cholestasis, obesity, diabetic nephropathy or nephrotic syndrome.
  • the metabolic disorder is nonalcoholic steatohepatitis (NASH), hyperlipidemia, hypercholesterolemia, hypertriglycerid
  • a method of treating a metabolic disorder in a subject in need thereof comprising administering to the subject in need thereof an effective dose of (E)-6-(3,4- difluorobenzoyl)-N-isopropyl-4,4-dimethyl-3-(trifluoromethyl)-l,4,5,6-tetrahydropyrazolo[3,4- d]azepine-8-carboxamide (Compound 1), (E)-isopropyl 4,4-dimethyl-6-(4-(2- mo holinoethoxy)benzoyl)-3-(trifluoromethyl)-l,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8- carboxylate (Compound 2), or (E)-isopropyl 6-(3-fluoro-4-(2-morpholinoethoxy)benzoyl)-4,4- dimethyl-3-(trifluoromethyl)-l,4,5,6-t
  • the present application relates to FXR modulatators, and pharmaceutical compositions that include such FXR modulatators, for use in the treatment of diseases, disorders or conditions that would benefit from FXR modulation.
  • FXR modulatators for use in the treatment of diseases, disorders or conditions that would benefit from FXR modulation.
  • an FXR modulator described herein is the administration of an FXR modulator described herein to a mammal in the treatment of diseases, disorders or conditions that would benefit from FXR modulation, wherein the FXR modulator is (E)-6-(3,4-difluorobenzoyl)-N-isopropyl-4,4-dimethyl-3- (trifluoromethyl)-l,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxamide (Compound 1), (E)- isopropyl 4,4-dimethyl-6-(4-(2-morpholinoethoxy)benzoyl)-3 -(trifluorom ethyl)- 1, 4,5,6- tetrahydropyrazolo[3,4-d]azepine-8-carboxylate (Compound 2), or (E)-isopropyl 6-(3-fluoro-4-(2- mo holinoethoxy)benzoyl
  • a metabolic disorder in an individual in need thereof comprising co-administering to the individual a therapeutically effective amount of: (a) a first agent that is an FXR modulator; and (b) at least one second agent that is a DPP-IV inhibitor, an SGLT2 inhibitor, an ASK1 inhibitor, a GLP-1 agonist, or a combination thereof.
  • FXR Farnesoid X receptor
  • R1H4 nuclear receptor nomenclature committee 1999
  • FXR is a member of the steroid and thyroid hormone nuclear receptor superfamily of ligand regulated transcription factors.
  • FXR is highly expressed in the liver, kidney, intestines and the adrenals and at lower levels in the vasculature (Forman et al., Cell 1995, 81(5):687-93).
  • Bile acids the end-products of cholesterol catabolism, bind directly to the ligand binding pocket of FXR and act as agonists to increase the receptor's ability to activate transcription (Makishima et al., Science 1999, 284(5418): 1362-5 1999; Mi et al., Mol Cell 2003, 11(4): 1093-100; Parks et al., Science 1999, 284(5418): 1365-8; Wang et al., Mol Cell 1999, 3(5):543-53).
  • FXR In response to bile acid binding FXR regulates a network of genes that control the synthesis, transport, and catabolism of bile acids, but also triglycerides and cholesterol (Chawla et al., Cell 2000, 103(1): 1-4; Repa and Mangelsdorf, Annu Rev Cell Dev Biol 2000, 16:459-81).
  • FXR functions as a regulator of lipid metabolism by modifying gene expression in response to quantitative changes in the metabolism and breakdown of cholesterol.
  • FXR was originally cloned and classified as an orphan member of the nuclear hormone receptor superfamily based upon DNA sequence homology. Initial studies identified farnesol as a ligand for FXR (Forman et al., Cell 1995, 81(5):687-93), however, subsequent analysis demonstrated that bile acids bind directly to the ligand binding domain of FXR and function as activators of the receptor's transcriptional activity.
  • the binding affinities of bile acids for FXR is near the concentration that these compounds reach in animals ( ⁇ ) lending support to the idea that bile acids function as endogenous ligands in vivo (Makishima et al., Science 1999, 284(5418): 1362-5 1999; Mi et al., Mol Cell 2003, 11(4): 1093-100; Parks et al., Science 1999, 284(5418): 1365-8; Wang et al., Mol Cell 1999, 3(5):543-53).
  • Activation of FXR upon bile acid binding leads to transcriptional down-regulation of cholesterol 7a-hydroxylase (CYP7A1), the rate limiting enzyme in the conversion of cholesterol to bile acids.
  • CYP7A1 cholesterol 7a-hydroxylase
  • CYP7A1 Inhibition of CYP7A1 by bile acids occurs via FXR-dependent induction of the small heterodimeric partner (SHP; also referred to as R0B2, Nuclear Receptor Nomenclature Committee 1999), a transcriptional repressor. Binding sites for FXR have been identified in the SUP promoter indicating that this gene is a direct target of FXR (Lu et al., Mol Cell 2000, 6(3):507-15; Goodwin et al., Mol Cell 2000, 6(3):517-26).
  • bile acid-dependent repression of CYP7A1 is indirect and results from a transcriptional cascade initiated by FXR.
  • NTCP sodium/taurocholate cotransporter peptide
  • BSEP bile salt export pump
  • MDR2 multidrug resistance protein 2
  • BSEP bile acids
  • MDR2 phospholipids
  • FXR agonists induce the genes encoding fibroblast growth factor 19 (Holt et al., Genes Dev 2003, 17(13): 1581-91), acylation stimulating protein (a proteolytic product of complement C3; Li et al., J Biol Chem 2005, 280(9):7427-34), apolipoprotein CII (Kast et al., Mol Endocrinol 2001, 15(10): 1720-8), and apolipoprotein AV (Prieur et al., J Biol Chem 2003,
  • SREBPlc apolipoprotein CIII (Claudel et al., Gastroenterology 2003, 125(2):544-55), an inhibitor of lipoprotein lipase, and the sterol response element binding protein lc (SREBPlc; Watanabe et al., J Clin Invest 2004, 113(10): 1408-18).
  • SREBPlc a member of basic helix-loop-helix family of transcription factors, functions as a master transcriptional regulator of the enzymes required for fatty acid synthesis
  • Dipeptidyl peptidase-IV is a serine protease, which selectively cleaves the N- terminal dipeptide from the penultimate position of Glucose-dependent Insulinotropic Polypeptide (GIP) and Glucagon-Like Peptide (GLP-1) thus making them inactive (Diabetes Obes Metab., 10, 376- 387, 2008; Diabetes Care, 30, 1979-1987, 2007).
  • GLP-1 is an incretin hormone secreted by intestinal L-Cells in response to food intake. The active GLP-1 stimulates insulin secretion, inhibits glucagon release and slows gastric emptying, which together contributes for effective glucose homeostasis in patients with type 2 diabetes.
  • DPP-IV inhibitors offer a number of potential advantages over existing diabetes therapies, including a lowered risk of hypoglycemia, weight gain and the potential for regeneration and differentiation of pancreatic beta -cells (Handbook Exp Pharmacol., 203, 53-74, 2011; Curr Med Res Opin., 23(4), 919-31, 2007).
  • DPP-IV inhibitors Because of these multiple benefits of GLP-1 mediated glucose homeostasis, orally bioavailable DPP-IV inhibitors has been developed as promising therapeutic agents for the treatment of type 2 diabetes (Am. J. Ther., 15(5), 484-91, 2008). The therapeutic potential of DPP-IV inhibitors for the treatment of type 2 diabetes have been discussed and reviewed extensively (Exp. Opin. Invest. Drugs, 12, 87-100, 2003; Exp. Opin. Ther. Patents, 13, 499-510, 2003; Exp. Opin. Investig. Drugs, 13, 1091-1102, 2004; Curr. Opin. Drug Discovery
  • SGLTs Sodium-dependent glucose cotransporters
  • Two important SGLT isoforms have been cloned and identified as SGLTl and SGLT2.
  • SGLTl is located in the gut, kidney, and heart where its expression regulates cardiac glucose transport.
  • SGLTl is a high- affinity, low-capacity transporter and therefore accounts for only a small fraction of renal glucose reabsorption.
  • SGLT2 is a low-affinity, high-capacity transporter located exclusively at the apical domain of the epithelial cells in the early proximal convoluted tubule.
  • Mitogen-activated protein kinase (MAPK) signaling cascades couple diverse extracellular and intracellular queues to appropriate cellular stress responses, including cell growth, differentiation, inflammation, and apoptosis (Kumar, S., et al. (2003) Nat. Rev. Drug Dis. 2:717-726; Pimienta, G., et al. (2007) Cell Cycle, 6: 2826-2632).
  • MAPKs exist in three groups, MAP3Ks, MAP2Ks, and MAPKs, which are sequentially activated. MAPK3s directly respond to environmental signals and
  • Apoptosis signal-regulating kinase 1 is a member of the mitogen- activated protein kinase kinase kinase ("MAP3K") family that activates the c-Jun N-terminal protein kinase (“JNK”) and p38 MAP kinase (Ichijo, H., et al. (1997) Science, 275, 90-94).
  • ASK1 is activated by a variety of stimuli including oxidative stress, reactive oxygen species (ROS), LPS, TNF-alpha , FasL, ER stress, and increased intracellular calcium concentrations (Hattori, K., et al. (2009) Cell Comm. Signal. 7: 1-10; Takeda, K., et al. (2007) Annu. Rev. Pharmacol. Toxicol. 48: 1-8.27; Nagai, H., et al. (2007) J. Biochem. Mol. Biol. 40: 1-6).
  • ROS reactive oxygen species
  • ASK1 undergoes activation via autophosphorylation at Thr838 in response to these signals and in turn phosphorylates MAP2Ks, such as MKK3/6 and MKK4/7, which then phosphorylate and activate p38 and JNK MAPKs, respectively.
  • ASK2 is a related MAP3K that shares 45% sequence homology with ASK1 (Wang, X. S., et al. (1998) Biochem. Biophys. Res. Commun. 253, 33-37. Although ASK2 tissue distribution is restricted, in some cell types ASK1 and ASK2 have been reported to interact and function together in a protein complex (Takeda, K., et al. (2007) J. Biol. Chem.
  • ASK1 is kept in an inactive state through binding to its repressor Thioredoxin (Tix) (Saitoh, M., et al. (1998) Embo J. 17:2596-2606), and through association with AKT (Zhang, L., et al. (1999) Proc. Natl. Acad. Sci. U.S.A 96:851 1-8515). Phosphorylation of ASKl protein can lead to apoptosis or other cellular responses depending on the cell type.
  • ASKl activation and signaling have been reported to play an important role in a broad range of diseases including neurodegenerative, cardiovascular, inflammatory, autoimmunity, and metabolic disorders.
  • ASKl has been implicated in mediating organ damage following ischemia and reperfusion of the heart, brain, and kidney (Watanabe et al. (2005) BBRC 333, 562-567; Zhang et al, (2003) Life Sci 74-37-43; Terada et al. (2007) BBRC 364: 1043-49).
  • Emerging evidence suggests that ASK2, either alone or in a complex with ASKl, may play important roles in human diseases as well. Therefore, therapeutic agents that function as inhibitors of ASKl and ASK2 signaling complexes have the potential to remedy or improve the lives of patients suffering from such conditions.
  • Glucagon and GLP-1 are members of structurally related peptide hormone family (secretin family). Glucagon and GLP-1 constitute a highly homologous set of peptides because these two hormones originate from a common precursor, preproglucagon, which upon tissue-specific processing leads to production of GLP-1 predominantly in the intestine and glucagon in the pancreas (Jiang, G., et al., Am. J. Physiol. Endocrinol. Metab., 2003, 284, E671-678). The receptors for these two peptides are homologous (58% identity) and belong to the class B family of G-protein coupled receptors (GPCRs).
  • GPCRs G-protein coupled receptors
  • Class-B GPCRS is also called as the secretin receptor family, which consist of 15 peptide-binding receptors in humans. GPCR receptors comprise an extracellular N-terminal domain of 100-160 residues, connected to a juxtamembrane domain (J-domain) of seven membrane-spanning co-helices with intervening loops and a C-terminal tail (Brubaker, P. L., et al., Receptors Channels, 2002, 8, 179). Class B GPCRs are activated by endogenous peptide ligands of intermediate size, typically 30-40 amino acids (Hoare, S. R. J., Drug Discovery Today, 2005, 10, 423; Gether, U., Endocrine Reviews, 2000, 21, 90).
  • Glucagon is a 29-amino acid peptide hormone processed from proglucagon in pancreatic alpha -cells by PC2. Glucagon acts via a seven transmembrane GPCRs, consisting of 485 amino acids.
  • Glucagon is released into the bloodstream when circulating glucose is low.
  • the main physiological role of glucagon is to stimulate hepatic glucose output, thereby leading to increase in glycemia (Tan, K., et al., Diabetologia, 1985, 28, 435).
  • Glucagon provides the major counter regulatory mechanism for insulin in maintaining glucose homeostasis in vivo.
  • Glucagon and its receptor represent potential targets for the treatment of diabetes.
  • Antagonising glucagon action by blocking the action of the secreted glucagon at glucagon receptor (glucagon antagonist) or by inhibiting (suppressing) the glucagon production itself represents a new avenue for intervention of diabetes and metabolic disorders (Unson, C. G., et al., Peptides, 1989, 10, 1171; Parker, J. C, Diabetes, 2000, 49, 2079;
  • the GLP-1 (7-36) amide is a product of the preproglucagon gene, which is secreted from intestinal L-cells, in response to the ingestion of food.
  • the physiological action of GLP-1 has gained considerable interest.
  • GLP-1 exerts multiple actions by stimulating insulin secretion from pancreatic beta -cells, in a glucose dependent manner (insulinotropic action).
  • GLP-1 lowers circulating plasma glucagon concentration, by inhibiting its secretion (production) from alpha -cells (Drucker D. J., Endocrinology, 2001, 142, 521-527).
  • GLP-1 also exhibits properties like stimulation of beta -cell growth, appetite suppression, delayed gastric emptying and stimulation of insulin sensitivity (Nauck, M. A., Horm. Metab. Res., 2004, 36, 852).
  • the chemokine system comprises more than 20 different chemokine receptors, which belong to the class A or rhodopsin-like family of G protein-coupled receptors (GPCRs). Almost 50 chemokine
  • Fibrosis results from a sustained inflammatory response to chronic organ injury and is characterized by the deposition of extracellular matrix proteins, including collagen types 1 and 3.
  • Hepatic fibrosis is associated with, chronic liver disease, a significant global burden that contributes to cirrhosis and hepatocellular carcinoma.
  • renal fibrosis is a common manifestation of chronic kidney disease.
  • the inflammatory response to hepatocyte injury plays a key role in hepatic
  • tibrogenesi involves recruitment of bone marrow-derived monocytes and macrophages to the site of injury, which is triggered by the activation of resident macrophages. In turn, infiltrating
  • monocytes/macrophages amplify this immune response by producing inflammatory cytokines and chemokines, which further promote recruitment of inflammatory cells and upregulate the activation of hepatic stellate cells (HSCs).
  • Fibrogenic cytokines e.g. transforming growth factor-beta [TGF-beta]
  • TGF-beta transforming growth factor-beta
  • myofibroblasts which are the primary source of scar-fanning matrix proteins, including fibrillary collagen types 1 and 3, and the contractile protein alpha-smooth muscle actin (alpha-SMA).
  • CCR2/CCR5 antagonist therapeutics include, but are not limited to, cenicriviroc (CVC), aplaviroc, vicriviroc (e.g., 5-( ⁇ 4-[(3,S)-4- ⁇ 2-methoxy-l-[4-(trifluoromethyl)phenyl]ethyl ⁇ -3-methylpiperazin-l- yl]-4-methylpiperidin-l-yl ⁇ carbonyl)-4,6-dimethylpyrimidine), maraviroc (e.g., 4,4'- difluorocyclohexylamide) and cochiiioquinone A.
  • CVC cenicriviroc
  • aplaviroc e.g., 5-( ⁇ 4-[(3,S)-4- ⁇ 2-methoxy-l-[4-(trifluoromethyl)phenyl]ethyl ⁇ -3-methylpiperazin-l- yl]-4-methylpiperidin-l-yl ⁇ carbonyl)-4,6-di
  • Caspases are the key effector molecules of the physiological death process known as apoptosis, although some are involved in activation of cytokines, rather than cell death. They are one of approximately 20 families of cysteine proteases. Caspases exist in most mammalian cells as inactive precursors (zymogens) that kill the cell once activated and can be controlled in two ways. The processing and activation of a caspase can be regulated by molecules such as FADD, APAF-1, Bel -2 family members, FLIP and IAPs. Active caspases can be controlled by a variety of inhibitors that directly interact with the protease. (Ekert, P.G.; Silke, J.; Vaux, D.L. Cell Death Differ.
  • drugs considered to be caspase protease inhibitors include, but are not limited to, emricasan, Q-VD-Oph, DEVD-CHO, zVAD-FMK, Pralnacasan (Vertex), and M867 (Merck).
  • Acetyl-CoA carboxylase is a biotin-dependent enzyme that catalyzes the irreversible
  • ACC is a large, multi-domain enzyme in
  • ACC the endoplasmic reticulum of most eukaryotes.
  • the most important function of ACC is to provide the malonyl-CoA substrate for the biosynthesis of fatty acids.
  • the human genome contains the genes for two different ACCs: ACACA and ACACB.
  • drugs include, but are not limited to, (R)-2-(l-(2-(2-methoxyphenyl)-2-((tetrahydro-2H- pyran-4-yl)oxy)ethyl)-5-methyl-6-(oxazol-2-yl)-2,4-dioxo-l,4-dihydrothieno[2,3-d]pyrimidin-3(2H)- yl)-2-methylpropanoicacid ("NDI-010976" or "GS-0976”) (Gilead), 5-(tetradecyloxy)-2-furoic acid (“TOFA”), Medica 16, and ( ⁇ - ⁇ '- ⁇ - ⁇ ⁇ ' ⁇ - ⁇ - ⁇ - methanone ("CP-640186”) (Cayman Chemical).
  • Diacylglycerol acyltransferase-1 is an enzyme involved in the formation of triyglcerides and is highly expressed in human fat metabolism sites such as intesting, liver, and adipose. Dietary trigflycerides cannot be absorbed directly in the gastrointestinal tract and are broken down into free fatty acids and monglycerol in the intestine by pancreatic lipase. Inhibition of diacylglycerol acyltransferase-1 has shown to reduce fat storage in mammals leading to reduction of body weight. Examples of drugs include, but are not limited to, pradigastat ("LCQ908"), VK5211, A 922500, amidepsine A, and amidepisne D.
  • LCQ908 pradigastat
  • VK5211 VK5211
  • a 922500 amidepsine A
  • amidepisne D amidepisne D.
  • Apical sodium-dependent bile acid transporter (ASBT or ABAT, SLC10A2) is the second member of the SLCIOA family of solute carrier proteins and has important physiological functions as a bile acid transporter from the lumen of the gastrointestinal tract to the liver via the portal vein.
  • Classes of therapeutics include dihydropyridine calcium channel blockers, and HMG-CoA reductase inhibitors (statins).
  • Examples of drugs include, but are not limited to, volixibat ("LUM-002/SHP626"), LIN 452 (Novartis), GSK2330672 (GSK), AZD-7806, S-8921, AK-105, BARI-1741, SC-435 or SC-635.
  • TLR-4 is a protein that in humans is encoded by the TLR4 gene.
  • TLR4 is a transmembrane protein, member of the toll-like receptor family, which belongs to the pattern recognition
  • PRR PRR receptor
  • LPS lipopolysaccharide
  • ligands also include several viral proteins, polysaccharide, and a variety of endogenous proteins such as low-density lipoprotein, beta-defensins, and heat shock protein.
  • Examples of drugs which are considered TLR-4 antagonists include, but are not limited to, JKB-121, amitriptyline, imipramine, naloxone, LPS-RS, cyclbenzprine, mianserin, naltrexone, propentofylline, ketotitfen, ibudilast, (+)-naltrexone, tapentradol, and eritoran.
  • PPAR alpha/delta agonists examples include, but are not limited to, GFT505, amphipathic carboxylic acids (e.g., clofibrate, gemfibrozil, ciprofibrate, bezafibrate, and fenofibrate), GW501516, aleglitzar, muraglitazar, tesaglitazar, and saroglitazar.
  • GFT505 amphipathic carboxylic acids
  • Statins also known as HMG-CoA reductase inhibitors, are a class of lipid-lowering agents.
  • Statins have been found to reduce cardiovascular disease (CVD) and mortality in those who are at high risk. Statins are effective for treating CVD in the early stages of a disease (secondary prevention) and in those at elevated risk but without CVD (primary prevention).
  • examples of drugs include, but are not limited to, atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin,
  • FXR agonists and nonalcoholic fatty liver disease (NAFLD) and Nonalcoholic staetohepatitis (NASH) are nonalcoholic fatty liver disease (NAFLD) and Nonalcoholic staetohepatitis (NASH)
  • NAFLD is a well-recognized component of the metabolic syndrome, characterized by increased serum levels of lipids and glucose, increased incidence of type II diabetes, atherosclerosis, hypertension, and breast and colon cancer. Although many NAFLD cases have benign prognosis, some develop NASH, liver fibrosis, cirrhosis, and tumor. The disruption of the Nrlh4 gene in mice showed that FXR deficiency results in fatty liver formation following feeding with a high-cholesterol diet (Sinai CJ et al. Cell. 2000; 102:731-744). In addition, FXR deficiency renders the mice more susceptible to NASH formation in a diet-induced obese mouse model (Kong B et al.
  • the primary outcome measure was improvement in NAFLD activity score by at least two points without worsening of fibrosis from baseline to the end of treatment.
  • 110 patients in the OCA arm and 109 patients in the placebo arm were included in the analysis.
  • the percentage of patients who demonstrated histological improvement in the OCA and placebo arm was 45% and 21%, respectively.
  • a decrease in the high-density lipoprotein (HDL) and an increase in the total cholesterol and low-density lipoprotein (LDL) was observed in patients in the OCA arm compared to placebo.
  • IBD inflammatory bowel disease
  • FXR has been implicated to participate in immune modulation and barrier function in the intestine.
  • FXR alleviates inflammation and preserves the integrity of the intestinal epithelial barrier in many ways by regulating the extent of the inflammatory response, maintaining the integrity and function of the intestinal barrier, and preventing bacterial translocation in the intestinal tract.
  • FXR plays an important role in the mucosal immune response, thereby exerting strong influence on immunoregulation.
  • Vavassori et al. J Immunol. 2009; 183 :6251-6261 noticed that Fxr _/" mice displayed significantly elevated pro-inflammatory cytokine mRNA expression in the colon.
  • TNBS trinitrobenzensulfonic acid
  • DSS dextrane sodium sulfate
  • FXR activation by INT-747 prevented DSS- and TNBS- induced intestinal inflammation, with improvement of colitis symptoms, inhibition of epithelial permeability, and reduced goblet cell loss.
  • FXR ligands exert anti-inflammatory activities by antagonizing other signaling pathways, in part through the interaction with other transcription factors, including activator protein-1 (AP-1), and signal transducers and activators of transcription 3 (STAT3).
  • AP-1 activator protein-1
  • STAT3 signal transducers and activators of transcription 3
  • FXR has been implicated in barrier function by regulating intestinal antibacterial growth.
  • Gut microbiota play important roles in pathogen defense, immunity, and nutrient harvest. Recent evidence suggests that there is a regulatory relationship between the development of IBD and altered gut microbiota. It has been demonstrated that BAs and gut microbiota are closely related to each other. Gut microbiota are involved in the biotransformation of BAs through deconjugation, dehydroxylation, and reconjugation of BAs. BAs have antimicrobial activities by damaging the bacterial cell membrane, thus inhibiting bacterial outgrowth.
  • intestinal FXR activation of intestinal FXR by GW4064 leads to the identification of several novel intestinal FXR target genes, including those encoding angiogenin, carbonic anhydrase 12 and inducible nitric oxide synthase, which have been reported to have antibacterial properties.
  • the cytokine IL-18 is also induced by FXR stimulation. IL-18 stimulates resistance to an array of pathogens, including intracellular and extracellular bacteria and mycobacteria, and appears to have a protective role during the early, acute phase of mucosal immune response.
  • Bile acids are increasingly implicated in the pathogenesis of functional GI disorders. New mechanisms have recently been described in the irritable bowel syndrome, chronic diarrhea and chronic idiopathic constipation. Identification of bile acid signaling through farnesoid X receptor (FXR) has led to the development of new, directly acting therapeutic agents. Despite these advances primary bile acid diarrhea (BAD) remains under-recognized partly because of the lack of a widely available diagnostic test. Functional gastrointestinal disorders (FGID) are common and constitute a significant proportion of consultations in both primary and secondary care. The most prevalent FGIDs are the irritable bowel syndrome (IBS) and functional dyspepsia, with a prevalence of around 20% each, regardless of the nationality of the population.
  • IBS irritable bowel syndrome
  • IBS irritable bowel syndrome
  • functional dyspepsia with a prevalence of around 20% each, regardless of the nationality of the population.
  • FGF-19 stimulation by obeticholic acid provides an opportunity to reverse the deficiency which is considered one of the factors leading to excessive hepatocyte BA synthesis.
  • This treatment was associated with improved stool frequency and consistency in a preliminary study of patients with BAD (Johnston FM et al. Gastroenterology. 2013; 144(Suppl. 144):S60).
  • BAD Johnston FM et al. Gastroenterology. 2013; 144(Suppl. 144):S60.
  • FXR agonists and cholestatic liver diseases primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC) and biliary atresia
  • PBC primary biliary cirrhosis
  • PSC primary sclerosing cholangitis
  • biliary atresia cholestatic liver diseases
  • PBC is a chronic, progressive, cholestatic liver disease characterized histologically by destruction of intrahepatic bile ducts and serologically by the presence of the antimitochondrial antibodies (AMAs).
  • AMA antimitochondrial antibodies
  • Epidemiological studies have reported a prevalence of PBC ranging from 19 to 365 cases per million, and an incidence of 4 to 58 cases per million persons-years. PBC may lead to hepatic fibrosis, cirrhosis, and eventually liver failure. PBC is an important indication for liver transplantation in the United States and Europe.
  • UDCA ursodeoxycholic acid
  • PSC is a progressive disease of the liver characterized by cholestasis and ongoing destruction of intra- and extra-hepatic bile ducts, leading ultimately to fibrosis, cirrhosis, and liver failure.
  • the diagnosis of PSC is made in the setting of cholestasis and chol angiographic evidence of intra- and/or extra-hepatic biliary ductal structuring.
  • Small-duct PSC is a variant of PSC which is characterized by cholestatic and histological evidence of PSC but normal cholangiography. PSC can progress to liver fibrosis, cirrhosis, and ultimately liver failure.
  • CCA cholangiocarcinoma
  • Biliary atresia is a progressive obliterative cholangiopathy that presents in infancy with jaundice due to biliary obstruction.
  • HPE hepatic portoenterostomy
  • biliary atresia progresses to end-stage liver disease in 80% of patients over a variable length of time. Approximately one-half of affected infants will require liver transplantation in the first two years of life due to complications of cirrhosis and cholestasis, including severe
  • FXR regulates lipid homeostasis and deficiency of FXR in mice increases systemic and liver lipid levels.
  • FXR deficiency has been shown to increase atherosclerotic plaque formation in male ApoE knockout mice but protect female ApoE mice from atherosclerotic plaque formation (Guo GL et al. Biochim Biophys Acta. 2006; 1761 : 1401-1409; Zhang Y et al. Arterioscler Thromb Vase Biol. 2006; 26:2316-2321; and Hanniman EA et al. J Lipid Res. 2005; 46:2595-2604).
  • the reduction of atherosclerotic plaque in the aorta area of female mice may be due to a decreased CD36 expression and foam cell formation.
  • CD36 is a long-chain fatty acid transporter and is mainly responsible for taking up oxidized LDL into macrophages. Lipid-laden macrophages become foam cells, the hall mark for atherosclerosis plaque development. This gender difference in the role of FXR in atherosclerosis development indicates again that FXR may interact with estrogen-related pathway(s) to modulate biological responses.
  • heterozygous mice demonstrated hepatosteatosis and hyperlipidemia following short-time high-fat diet (HFD) feeding.
  • HFD high-fat diet
  • the TG lowering effects of endogenous and synthetic FXR agonists have been evaluated in other rodent models as well.
  • CA prevented hepatic TG accumulation and VLDL secretion in KK-A(y) mice, a mouse model of hypertriglyceridemia (Watanabe M et al. J Clin Invest 2004; 113 : 1408-18).
  • the synthetic FXR agonist GW4064 was able to prevent liver steatosis in obese mice, such as the ob/ob and db/db models (Zhang Y et al. Proc Natl Acad Sci U S A 2006; 103 : 1006-11).
  • Diabetes is the leading cause of end-stage renal disease in developed countries.
  • diabetic nephropathy still develops and progresses.
  • Diabetic nephropathy is the most common renal complication of diabetes and the leading cause of end-stage renal disease.
  • the pathogenesis of diabetic nephropathy is complex and involves activation of multiple pathways leading to kidney damage, including the polyol pathway, advanced glycation end products, oxidative stress, proinflammatory cytokines, and profibrotic growth factors.
  • an important role for altered lipid metabolism has been recently recognized in diabetic kidney disease.
  • SREBP-1 and SREBP-2 sterol regulatory element binding proteins 1 and 2
  • transcription factors that mediate increased fatty acid and cholesterol synthesis, resulting in triglyceride and cholesterol accumulation in the kidney and are associated with inflammation, oxidative stress, fibrosis, and proteinuria.
  • SREBP-1 transgenic mice develop glomerulosclerosis and proteinuria in the absence of alterations in serum glucose or lipids, and that SREBP-lc knockout mice are protected from the renal effects of a high-fat diet (Sun L et al. J Biol Chem 2002; 277: 18919- 18927 and Jiang T et al.
  • FXR activating agonists inhibit expression of SREBP-1 and carbohydrate response element binding protein (ChREBP) in the kidney resulting in decreased fatty acid synthesis and triglyceride accumulation.
  • FXR agonists also inhibit SREBP-2 resulting in decreased cholesterol synthesis and accumulation in the kidney.
  • Gallstone disease is one of the most frequent and costly digestive diseases in western countries, as its prevalence in adults ranges from 10% to 15%. About 75% of the gallstones in the United States and westernized countries, including Italy are cholesterol gallstones. Cholesterol gallstones are associated with well-known risk factors, such as obesity, type 2 diabetes, dyslipidaemia, and hyperinsulinaemia, which are often components of the metabolic syndrome epidemic, which prevalence is greater than 35% in the adult pupulation and continues to rise in westernized countries. A complex genetic basis plays a key role in determining individual predisposition to develop cholesterol gallstones in response to environmental factors. Some "gallstone genes” might also play a potential role, including some genes governing the nuclear bile acid receptors such as farnesoid X receptor (FXR).
  • FXR farnesoid X receptor
  • GW4064 treatment prevented CGD onset in the C57L mice through FXR-mediated upregulation of Abcbl 1 and Abcb4, increasing transport of bile salts and phospholipids to the bile, reducing of the cholesterol saturation index, and providing protection from cholesterol monohydrate crystal formation.
  • mice maintenance of cholesterol and bile acid homeostasis in mice is somewhat different from that of humans.
  • the bile acid pool of mice is more hydrophilic than that of man and thus is less effective in activating FXR.
  • Control of CYP7A1 -mediated bile acid synthesis from cholesterol in mice is dominated by feed-forward activation through LXR, whereas in humans LXR is not functional in this capacity. Instead, control of bile acid synthesis in humans is dominated by feedback repression of CYP7A1 through FXR and other means.
  • bile acid synthesis from cholesterol is primarily a means to maintain bile acid homeostasis, whereas in the mouse it is a means for removal of cholesterol.
  • Amino refers to the -NH 2 radical.
  • Niro refers to the -N0 2 radical.
  • Alkyl refers to a linear or branched hydrocarbon chain radical, which is fully saturated, has from one to thirty carbon atoms, and is attached to the rest of the molecule by a single bond. Alkyls are linear or branched. Alkyls comprising any number of carbon atoms from 1 to 30 are included. An alkyl comprising up to 30 carbon atoms is referred to as a Ci-C 30 alkyl, likewise, for example, an alkyl comprising up to 12 carbon atoms is a Ci-Ci 2 alkyl. An alkyl comprising up to 6 carbons is a Ci-C 6 alkyl.
  • Alkyls (and other moieties defined herein) comprising other numbers of carbon atoms are represented similarly.
  • Alkyl groups include, but are not limited to, Ci-C 3 o alkyl, Ci- C 20 alkyl, Ci-Ci 5 alkyl, Ci-Cio alkyl, Ci-C 8 alkyl, Ci-C 6 alkyl, Ci-C 4 alkyl, C C 3 alkyl, Ci-C 2 alkyl, C 2 -C 8 alkyl, C 3 -C 8 alkyl, C 4 -C 8 alkyl, and C 5 -Ci 2 alkyl.
  • alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, 1 -methyl ethyl (isopropyl), n-butyl, i-butyl, s-butyl, n-pentyl, 1, 1 -dimethyl ethyl (t-butyl), 2-ethylpropyl, and the like.
  • Representative linear alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl and the like. Unless stated otherwise specifically in the specification, an alkyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo,
  • each R a is independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl,
  • heterocycloalkylalkyl heteroaryl or heteroarylalkyl
  • each R is independently alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.
  • alkenyl refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon double bond, and having from two to twelve carbon atoms. In certain embodiments, an alkenyl comprises two to eight carbon atoms. In certain embodiments, an alkenyl comprises two to six carbon atoms. In other embodiments, an alkenyl comprises two to four carbon atoms.
  • alkenyl is attached to the rest of the molecule by a single bond, for example, ethenyl (i.e., vinyl), prop-l-enyl (i.e., allyl), but-l-enyl, pent-l-enyl, penta-l,4-dienyl, and the like.
  • an alkenyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, trimethylsilanyl, -OR a , -SR a , -OC(0)-R a , -N(R a ) 2 , -C(0)R a , -C(0)OR a ,
  • each R a is independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, and each R is independently alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkylal
  • Alkynyl refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, having from two to twelve carbon atoms.
  • an alkynyl comprises two to eight carbon atoms.
  • an alkynyl comprises two to six carbon atoms.
  • an alkynyl has two to four carbon atoms.
  • the alkynyl is attached to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.
  • an alkynyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo,
  • each R a is independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl,
  • heterocycloalkylalkyl heteroaryl or heteroarylalkyl
  • each R is independently alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.
  • Alkylene or "alkylene chain” refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing no unsaturation and having from one to twelve carbon atoms, for example, methylene, ethylene, propylene, «-butylene, and the like.
  • the alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond.
  • the points of attachment of the alkylene chain to the rest of the molecule and to the radical group are through one carbon in the alkylene chain or through any two carbons within the chain.
  • an alkylene comprises one to eight carbon atoms (e.g., Ci-C 8 alkylene). In other embodiments, an alkylene comprises one to five carbon atoms (e.g., C 1 -C5 alkylene). In other 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., Ci alkylene).
  • an alkylene comprises five to eight carbon atoms (e.g., C 5 -C 8 alkylene). In other embodiments, an alkylene comprises two to five carbon atoms (e.g., C 2 -C 5 alkylene). In other embodiments, an alkylene comprises three to five carbon atoms (e.g., C 3 -C 5 alkylene).
  • an alkylene chain is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR a ,-SR a , -OC(0)-R a , -N(R a ) 2 , -C(0)R a , -C(0)OR a , -C(0)N(R a ) 2 , -N(R a )C(0)OR f , -OC(0)- R a R f , -N(R a )C(0)R f , -N(R a )S(0) t R f (where t is 1 or 2), -S(0) t OR a (where t is 1 or 2), -S(0) t R f (where t is 1 or 2) and -S(0) t N(R a ) 2
  • each R is independently alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, and each R is independently alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.
  • Aminoalkyl refers to a radical of the formula -R c -N(R a ) 2 or -R c -N(R a )-R c , where each R c is independently an alkylene chain as defined above, for example, methylene, ethylene, and the like; and each R a is independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.
  • Alkoxy refers to a radical of the formula -OR a where R a is an alkyl radical as defined. Unless stated otherwise specifically in the specification, an alkoxy group may be optionally substituted as described above for alkyl.
  • Aryl refers to a radical derived from a hydrocarbon ring system comprising hydrogen, 6 to 30 carbon atoms and at least one aromatic ring.
  • the aryl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the aryl is bonded through an aromatic ring atom) or bridged ring systems.
  • Aryl radicals include, but are not limited to, aryl radicals derived from the hydrocarbon ring systems of aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene.
  • an aryl group is optionally substituted by one or more of the following substituents: alkyl, alkenyl, alkynyl, halo, fluoroalkyl, cyano, nitro, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroarylalkyl, -R b -OR a , -R b -OC(0)-R a ,
  • Aryloxy refers to a radical bonded through an oxygen atom of the formula -O-aryl, where aryl is as defined above.
  • Aralkyl refers to a radical of the formula -R c -aryl where R c is an alkylene chain as defined above, for example, methylene, ethylene, and the like.
  • the alkylene chain part of the aralkyl radical is optionally substituted as described above for an alkylene chain.
  • the aryl part of the aralkyl radical is optionally substituted as described above for an aryl group.
  • alkenyl refers to a radical of the formula -R d -aryl where R d is an alkenylene chain as defined above.
  • the aryl part of the aralkenyl radical is optionally substituted as described above for an aryl group.
  • the alkenylene chain part of the aralkenyl radical is optionally substituted as defined above for an alkenylene group.
  • Aralkynyl refers to a radical of the formula -R e -aryl, where R e is an alkynylene chain as defined above.
  • the aryl part of the aralkynyl radical is optionally substituted as described above for an aryl group.
  • the alkynylene chain part of the aralkynyl radical is optionally substituted as defined above for an alkynylene chain.
  • Cycloalkyl or “carbocycle” refers to a stable, non-aromatic, monocyclic or polycyclic carbocyclic ring, which may include fused (when fused with an aryl or a heteroaryl ring, the cycloalkyl is bonded through a non-aromatic ring atom) or bridged ring systems, which is saturated or
  • cycloalkyls include, but are not limited to, cycloalkyls having from three to fifteen carbon atoms (C 3 -C 15 cycloalkyl), from three to ten carbon atoms (C 3 -C 10 cycloalkyl), from three to eight carbon atoms (C 3 -C 8 cycloalkyl), from three to six carbon atoms (C 3 -C 6 cycloalkyl), from three to five carbon atoms (C 3 -C 5 cycloalkyl), or three to four carbon atoms (C 3 -C 4 cycloalkyl).
  • Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • Polycyclic cycloalkyls include, for example, adamantyl, norbornyl, decalinyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decalin, trans-decalin, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, and bicyclo[3.3.2]decane, and 7,7-dimethyl-bicyclo[2.2.1]heptanyl.
  • the cycloalkyl is optionally substituted by one or more substituents independently selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R b -OR a , -R b -OC(0)-R a , -R b -OC(0)-OR a , -R b -OC(0)-N(R a ) 2 , -R b -N
  • Cycloalkylalkyl refers to a radical of the formula -R c -cycloalkyl where R c is an alkylene chain as defined above.
  • R c is an alkylene chain as defined above.
  • the alkylene chain and the cycloalkyl radical are optionally substituted as defined above.
  • fused refers to any ring structure described herein which is fused to an existing ring structure.
  • the fused ring is a heretocycloalkyl ring or a heteroaryl ring
  • any carbon atom on the existing ring structure which becomes part of the fused heretocycloalkyl ring or the fused heteroaryl ring may be replaced with a nitrogen atom.
  • Heteroalkyl refers to a straight or branched hydrocarbon chain alkyl radical containing no unsaturation, having from one to fifteen carbon atoms (e.g., C1-C15 alkyl) consisting of carbon and hydrogen atoms and one or two heteroatoms selected from O, N, and S, wherein the nitrogen or sulfur atoms may be optionally oxidized and the nitrogen atom may be quaternized.
  • the heteroatom(s) may be placed at any position of the heteroalkyl group including between the rest of the heteroalkyl group and the fragment to which it is attached. The heteroalkyl is attached to the rest of the molecule by a single bond.
  • a heteroalkyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR a , -SR a , -OC(0)-R a , -N(R a ) 2 , -C(0)R a , -C(0)OR a , -C(0)N(R a ) 2 , -N(R a )C(0)OR f , - OC(O)- R a R f , -N(R a )C(0)R f , -N(R a )S(0) t R f (where t is 1 or 2), -S(0) t OR a (where t is 1 or 1)
  • each R a is independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl,
  • heterocycloalkylalkyl heteroaryl or heteroarylalkyl
  • each R is independently alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.
  • Halo or halogen refers to bromo, chloro, fluoro or iodo. In some embodiments, halogen refers to chloro or fluoro.
  • Haloalkyl refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like. Unless stated otherwise specifically in the specification, a haloalkyl group may be optionally substituted.
  • Haloalkoxy similarly refers to a radical of the formula -ORa where Ra is a haloalkyl radical as defined. Unless stated otherwise specifically in the specification, a haloalkoxy group may be optionally substituted as described below.
  • Heterocycloalkyl or “heterocycle” refers to a stable 3- to 24-membered non-aromatic ring radical comprising 2 to 23 carbon atoms and from one to 8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous and sulfur.
  • the heterocycloalkyl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused (when fused with an aryl or a heteroaryl ring, the heterocycloalkyl is bonded through a non-aromatic ring atom) or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heterocycloalkyl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized; and the heterocycloalkyl radical may be partially or fully saturated.
  • heterocycloalkyls include, but are not limited to, heterocycloalkyls having from two to fifteen carbon atoms (C2-C15 heterocycloalkyl), from two to ten carbon atoms (C 2 -C 10 heterocycloalkyl), from two to eight carbon atoms (C 2 -C 8 heterocycloalkyl), from two to six carbon atoms (C 2 -C 6 heterocycloalkyl), from two to five carbon atoms (C 2 -C 5 heterocycloalkyl), or two to four carbon atoms (C 2 -C 4 heterocycloalkyl).
  • C2-C15 heterocycloalkyl having from two to fifteen carbon atoms (C2-C15 heterocycloalkyl), from two to ten carbon atoms (C 2 -C 10 heterocycloalkyl), from two to eight carbon atoms (C 2 -C 8 heterocycloalkyl), from two to six carbon atoms (C 2 -C 6 heterocycloalkyl),
  • heterocycloalkyl radicals include, but are not limited to, aziridinyl, azetidinyl, dioxolanyl, thienyl[l,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl,
  • heterocycloalkyl also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides and the oligosaccharides. Unless otherwise noted, heterocycloalkyls have from 2 to 8 carbons in the ring. It is understood that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including the heteroatoms) that make up the heterocycloalkyl (i.e. skeletal atoms of the heterocycloalkyl ring).
  • a heterocycloalkyl group is optionally substituted by one or more of the following substituents selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R b -OR a , -R b -OC(0)-R a , -R b -OC(0)-OR a , -R b -OC(0)-N(R a ) 2 , -R b -OR a ,
  • Heterocycloalkyllalkyl refers to a radical of the formula -R c -heterocycloalkyl where R c is an alkylene chain as defined above. If the heterocycloalkyl is a nitrogen-containing heterocycloalkyl, the heterocycloalkyl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heterocycloalkylslkyl radical is optionally substituted as defined above for an alkylene chain. The heterocycloalkyl part of the heterocycloalkylalkyl radical is optionally substituted as defined above for a heterocycloalkyl group.
  • Heterocycloalkylalkoxy refers to a radical bonded through an oxygen atom of the formula - 0-R c -heterocycloalkyl where R c is an alkylene chain as defined above. If the heterocycloalkyl is a nitrogen-containing heterocycloalkyl, the heterocycloalkyl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heterocycloalkylalkoxy radical is optionally substituted as defined above for an alkylene chain. The heterocycloalkyl part of the heterocycloalkylalkoxy radical is optionally substituted as defined above for a heterocycloalkyl group.
  • Heteroaryl refers to a 5- to 14-membered ring system radical comprising hydrogen atoms, one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous and sulfur, and at least one aromatic ring.
  • the heteroaryl is a 5-membered heteroaryl.
  • the heteroaryl is a 6-membered heteroaryl.
  • the heteroaryl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the heteroaryl is bonded through an aromatic ring atom) or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heteroaryl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized.
  • Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl,
  • benzothiadiazolyl benzo[b][l,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[l,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, iso
  • phenoxazinyl phthalazinyl, ptendinyl, purinyl, pyrrolyl, pyrazolyl, pyndinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl).
  • a heteroaryl group is optionally substituted by one or more of the following substituents selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted heteroaryl, optionally substituted
  • N-heteroaryl refers to a heteroaryl radical as defined above containing at least one nitrogen and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a nitrogen atom in the heteroaryl radical.
  • An N-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.
  • C-heteroaryl refers to a heteroaryl radical as defined above and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a carbon atom in the heteroaryl radical.
  • a C-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.
  • Heteroaryl oxy refers to radical bonded through an oxygen atom of the formula -O- heteroaryl, where heteroaryl is as defined above.
  • Heteroarylalkyl refers to a radical of the formula -R c -heteroaryl, where R c is an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom.
  • the alkylene chain of the heteroarylalkyl radical is optionally substituted as defined above for an alkylene chain.
  • the heteroaryl part of the heteroarylalkyl radical is optionally substituted as defined above for a heteroaryl group.
  • Heteroarylalkoxy refers to a radical bonded through an oxygen atom of the formula -O- R c -heteroaryl, where R c is an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom.
  • the alkylene chain of the heteroarylalkoxy radical is optionally substituted as defined above for an alkylene chain.
  • the heteroaryl part of the heteroarylalkoxy radical is optionally substituted as defined above for a heteroaryl group.
  • carboxylic acid bioisostere refers to a functional group or moiety that exhibits similar physical, biological and/or chemical properties as a carboxylic acid moiety.
  • Examples of carboxylic acid bioisosteres include, but are not limited to,
  • a "tautomer” refers to a molecule wherein a proton shift from one atom of a molecule to another atom of the same molecule is possible.
  • the compounds presented herein exist as tautomers.
  • a chemical equilibrium of the tautomers will exist. The exact ratio of the tautomers depends on several factors, including physical state, temperature, solvent, and pH.
  • Optional or “optionally” means that a subsequently described event or circumstance may or may not occur and that the description includes instances when the event or circumstance occurs and instances in which it does not.
  • optionally substituted aryl means that the aryl radical may or may not be substituted and that the description includes both substituted aryl radicals and aryl radicals having no substitution.
  • “Optionally substituted” and “substituted or unsubstituted” and “unsubstituted or substituted” are used interchangeably herein.
  • “Pharmaceutically acceptable salt” includes both acid and base addition salts.
  • pharmaceutically acceptable salt of any one of the compounds described herein is intended to encompass any and all pharmaceutically suitable salt forms.
  • Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
  • “Pharmaceutically acceptable acid addition salt” refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like. Also included are salts that are formed with organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and. aromatic sulfonic acids, etc.
  • acetic acid trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.
  • Exemplary salts thus include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinate suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, and the like.
  • salts of amino acids such as arginates, gluconates, and galacturonates (see, for example, Berge S.M. et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 66: 1-19 (1997)).
  • Acid addition salts of basic compounds are prepared by contacting the free base forms with a sufficient amount of the desired acid to produce the salt.
  • “Pharmaceutically acceptable base addition salt” refers to those salts that retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. In some embodiments, pharmaceutically acceptable base addition salts are formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like.
  • Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, for example, isopropyl amine, trimethylamine, diethylamine, tri ethyl amine, tripropylamine, ethanolamine, diethanolamine,
  • ethyl enedi amine ethylenedianiline, N-methylglucamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. See Berge et al., supra.
  • subject or “patient” encompasses mammals and non-mammals.
  • 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.
  • non-mammals include, but are not limited to, birds, fish and the like.
  • the mammal is a human.
  • treatment or “treating” or “ameliorating” are used interchangeably herein. These terms refers to an approach for obtaining beneficial or desired results including but not limited to therapeutic benefit and/or a prophylactic benefit.
  • therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated.
  • a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient is still afflicted with the underlying disorder.
  • the compositions are administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease has been made.
  • “Pharmaceutically acceptable salt” includes both acid and base addition salts.
  • pharmaceutically acceptable salt of any one of the compounds described herein is intended to encompass any and all pharmaceutically suitable salt forms.
  • Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
  • “Pharmaceutically acceptable acid addition salt” refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like. Also included are salts that are formed with organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and. aromatic sulfonic acids, etc.
  • acetic acid trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.
  • Exemplary salts thus include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinate suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, and the like.
  • salts of amino acids such as arginates, gluconates, and galacturonates (see, for example, Berge S.M. et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 66: 1-19 (1997)).
  • Acid addition salts of basic compounds are prepared by contacting the free base forms with a sufficient amount of the desired acid to produce the salt.
  • “Pharmaceutically acceptable base addition salt” refers to those salts that retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. In some embodiments, pharmaceutically acceptable base addition salts are formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like.
  • Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, for example, isopropyl amine, trimethylamine, diethylamine, tri ethyl amine, tripropylamine, ethanolamine, diethanolamine,
  • ethyl enedi amine ethylenedianiline, N-methylglucamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. See Berge et al., supra.
  • pharmaceutical combination means a product that results from the mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients.
  • fixed combination means that the active
  • non-fixed combination means that the active ingredients, are administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific intervening time limits, wherein such administration provides effective levels of the two compounds in the body of the patient.
  • cocktail therapy e.g. the administration of three or more active ingredients.
  • 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
  • activator is used in this specification to denote any molecular species that results in activation of the indicated receptor, regardless of whether the species itself binds to the receptor or a metabolite of the species binds to the receptor when the species is administered topically.
  • the activator can be a ligand of the receptor or it can be an activator that is metabolized to the ligand of the receptor, i.e., a metabolite that is formed in tissue and is the actual ligand.
  • antagonist refers to a small -molecule agent that binds to a nuclear hormone receptor and subsequently decreases the agonist induced transcriptional activity of the nuclear hormone receptor.
  • agonist refers to a small-molecule agent that binds to a nuclear hormone receptor and subsequently increases nuclear hormone receptor transcriptional activity in the absence of a known agonist.
  • inverse agonist refers to a small-molecule agent that binds to a nuclear hormone receptor and subsequently decreases the basal level of nuclear hormone receptor transcriptional activity that is present in the absence of a known agonist.
  • modulate means to interact with a target protein either directly or indirectly so as to alter the activity of the target protein, including, by way of example only, to inhibit the activity of the target, or to limit or reduce the activity of the target.
  • modulator refers to a compound that alters an activity of a target.
  • a modulator can cause an increase or decrease in the magnitude of a certain activity of a target compared to the magnitude of the activity in the absence of the modulator.
  • a modulator is an inhibitor, which decreases the magnitude of one or more activities of a target. In certain embodiments, an inhibitor completely prevents one or more activities of a target.
  • FXR modulatators and pharmaceutical compositions that include such FXR modulatators, for use in the treatment of diseases, disorders or conditions that would benefit from FXR modulation.
  • FXR modulator described herein to a mammal in the treatment of diseases, disorders or conditions that would benefit from FXR modulation.
  • an FXR modulator described herein is the administration of an FXR modulator described herein to a mammal in the treatment of diseases, disorders or conditions that would benefit from FXR modulation, wherein the FXR modulator is (E)-6-(3,4-difluorobenzoyl)-N-isopropyl-4,4-dimethyl-3- (trifluoromethyl)-l,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxamide (Compound 1), (E)- isopropyl 4,4-dimethyl-6-(4-(2-morpholinoethoxy)benzoyl)-3 -(trifluorom ethyl)- 1, 4,5,6- tetrahydropyrazolo[3,4-d]azepine-8-carboxylate (Compound 2), or (E)-isopropyl 6-(3-fluoro-4-(2- mo holinoethoxy)benzoyl
  • FXR modulator 1 is administered to a mammal in the treatment of diseases, disorders or conditions that would benefit from FXR modulation, wherein the FXR modulator is (E)-6-(3,4-difluorobenzoyl)-N-isopropyl-4,4-dimethyl-3- (trifluoromethyl)-l,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxamide (Compound 1), or a pharmaceutically acceptable salt thereof.
  • Compound 1 has the structure:
  • a pharmaceutically acceptable salt of Compound 1 is a hydrochloride salt. In further embodiments, the pharmaceutically acceptable salt of Compound 1 is a mono- hydrochloride salt.
  • [00175] is the administration of an FXR modulator described herein to a mammal in the treatment of diseases, disorders or conditions that would benefit from FXR modulation, wherein the FXR modulator is (E)-isopropyl 4,4-dimethyl-6-(4-(2-morpholinoethoxy)benzoyl)-3- (trifluoromethyl)-l,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxylate (Compound 2), or a pharmaceutically acceptable salt thereof.
  • Compound 2 has the structure:
  • a pharmaceutically acceptable salt of Compound 2 is a hydrochloride salt. In further embodiments, the pharmaceutically acceptable salt of Compound 2 is a mono- hydrochloride salt.
  • an FXR modulator described herein is the administration of an FXR modulator described herein to a mammal in the treatment of diseases, disorders or conditions that would benefit from FXR modulation, wherein the FXR modulator is (E)-isopropyl 6-(3-fluoro-4-(2-morpholinoethoxy)benzoyl)-4,4- dimethyl-3-(trifluoromethyl)-l,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxylate (Compound 3), or a pharmaceutically acceptable salt thereof.
  • Compound 3 has the structure:
  • a pharmaceutically acceptable salt of Compound 3 is a hydrochloride salt. In further embodiments, the pharmaceutically acceptable salt of Compound 3 is a mono- hydrochloride salt.
  • the compounds described herein exist as their pharmaceutically acceptable salts.
  • the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts.
  • the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.
  • the compounds described herein possess acidic or basic groups and therefore react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt.
  • these salts are prepared in situ during the final isolation and purification of the compounds of the invention, or by separately reacting a purified compound in its free form with a suitable acid or base, and isolating the salt thus formed.
  • the compounds described herein exist as solvates.
  • the invention provides for methods of treating diseases by administering such solvates.
  • the invention further provides for methods of treating diseases by administering such solvates as pharmaceutical
  • Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and, in some embodiments, are formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein are conveniently prepared or formed during the processes described herein. By way of example only, hydrates of the compounds described herein are conveniently prepared by recrystallization from an aqueous/organic solvent mixture, using organic solvents including, but not limited to, dioxane, tetrahydrofuran or methanol.
  • the compounds provided herein exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.
  • the compounds described herein exist in their isotopically-labeled forms.
  • the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds.
  • the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds as pharmaceutical compositions.
  • the compounds disclosed herein include isotopically-labeled compounds, which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that are incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine and chloride, such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 0, 17 0, 31 P, 32 P, 35 S, 18 F, and 36 C1, respectively.
  • Compounds described herein, and pharmaceutically acceptable salts, esters, solvate, hydrates or derivatives thereof which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention.
  • Certain isotopically-labeled compounds for example those into which radioactive isotopes such as 3 H and 14 C are incorporated, are useful in drug and/or substrate tissue distribution assays.
  • Tritiated, i. e., 3 H and carbon-14, i. e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability.
  • substitution with heavy isotopes such as deuterium, i.e., 2 H produces certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements.
  • Increased levels of deuterium incorporation produce a detectable kinetic isotope effect (KIE) that may affect the pharmacokinetic, pharmacologic and/or toxicologic parameters of Compound 1, Compound 2, or Compound 3 in comparison to Compound 1, Compound 2, or Compound 3 having naturally occurring levels of deuterium.
  • KIE detectable kinetic isotope effect
  • the isotopically labeled compound, or a pharmaceutically acceptable salt thereof is prepared by any suitable method.
  • At least one hydrogen in Compound 1 is replaced with deuterium. In some embodiments of the methods described herein, at least one hydrogen in Compound 1 is replaced with deuterium. In some embodiments of the pharmaceutical compositions described herein, at least one hydrogen in Compound 1 is replaced with deuterium.
  • At least one hydrogen in Compound 2 is replaced with deuterium. In some embodiments of the methods described herein, at least one hydrogen in Compound 2 is replaced with deuterium. In some embodiments of the pharmaceutical compositions described herein, at least one hydrogen in Compound 2 is replaced with deuterium.
  • At least one hydrogen in Compound 3 is replaced with deuterium. In some embodiments of the methods described herein, at least one hydrogen in Compound 3 is replaced with deuterium. In some embodiments of the pharmaceutical compositions described herein, at least one hydrogen in Compound 3 is replaced with deuterium.
  • the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.
  • a method of treating a metabolic disorder in an individual in need thereof comprising co-administering to the individual a therapeutically effective amount of: (a) a first agent that is an FXR modulator; and (b) at least one second agent that is a DPP-IV inhibitor, an SGLT2 inhibitor, an ASK1 inhibitor, a GLP-1 agonist, or a combination thereof; wherein the FXR modulator is a compound of Formula (I), or a pharmaceuticall acceptable salt, stereoisomer, or solvate thereof:
  • R 1 is selected from the group consisting of hydrogen, halogen, optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted -(XV C 2 alkylene)-(C 3 -C 8 cycloalkyl), optionally substituted C 2 -Cciheterocycloalkyl, optionally substituted - (Ci-C 2 alkylene)-(C 2 -C 9 heterocycloalkyl), optionally substituted -(Ci-C 2 alkylene)-(aryl), optionally substituted -(Ci-C 2 alkylene)-(heteroaryl), -OR 10 , -SR 10 , -N(R U )R 12 , - N(R u )S(0) 2
  • R 2 is selected from the group consisting of hydrogen, optionally substituted Ci-C 6 alkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted aryl, optionally substituted -(Ci-C 2 alkylene)- (aryl), optionally substituted heteroaryl, optionally substituted C 2 -Cciheterocycloalkyl, and optionally substituted -(Ci-C 2 alkylene)-(heteroaryl);
  • R 3 is selected from the group consisting of hydrogen, optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 - C 8 cycloalkyl, optionally substituted aryl, optionally substituted -(Ci-C 2 alkylene)-(aryl), optionally substituted heteroaryl, optionally substituted C 2 -C 9 heterocycloalkyl, optionally substituted -(Ci- C 2 alkylene)-(heteroaryl), -C(0)R 20 , -C(0)OR 20 , -S(0) 2 R 20 , -C(0)N(R 21 )R 22 , -C(0)N(R 21 )S(0) 2 R 24 , -C(0)N(R 23 )N(R 21 )R 22 , -C(0)N(R 23 )N(R 21 )S(0) 2 R 24 , -N(R
  • R 4 and R 5 are each independently selected from the group consisting of hydrogen, halogen, optionally substituted Ci-C 6 alkyl, optionally substituted Ci-C 6 alkoxy, optionally substituted C 2 -C 6 alkenyl, and optionally substituted C 2 -C 6 alkynyl; or R 4 and R 5 together with the carbon atom to which they are attached, form an optionally substituted C 3 -C 6 cycloalkyl ring or an optionally substituted C 2 - C 7 heterocycloalkyl ring;
  • R 6 is selected from the group consisting of hydrogen, halogen, optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, and -C(0)N(R 27 )R 28 ;
  • R is selected from the group consisting of hydrogen, halogen, optionally substituted Ci-C 6 alkyl, optionally substituted Ci-C 6 alkoxy, optionally substituted C2-C 6 alkenyl, and optionally substituted C 2 -C 6 alkynyl;
  • R 9 is selected from the group consisting of hydrogen, optionally substituted Ci-C 6 alkyl, optionally substituted C2-C 6 alkenyl, optionally substituted C2-C 6 alkynyl, optionally substituted C 3 - C 8 cycloalkyl, optionally substituted aryl, optionally substituted -(Ci-C 2 alkylene)-(aryl), optionally substituted C 2 -C 9 heterocycloalkyl, optionally substituted heteroaiyl, and optionally substituted -(Ci- C 2 alkylene)-(heteroaryl); or R 8 and R 9 together with the carbon atoms to which they are attached, form an optionally substituted C 2 -Cciheterocycloalkyl ring or an optionally substituted heteroaryl ring;
  • R 10 , R 13 and R 14 are each independently selected from the group consisting of hydrogen, optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted aryl, optionally substituted -(Ci- C 2 alkylene)-(aryl), optionally substituted C 2 -C 9 heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted -(Ci-C 2 alkylene)-(heteroaryl);
  • R 11 and R 12 are each independently selected from the group consisting of hydrogen, optionally
  • Ci-C 6 alkyl optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted aryl, optionally substituted -(Ci- C 2 alkylene)-(aryl), optionally substituted C 2 -C 9 heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted -(Ci-C 2 alkylene)-(heteroaryl); or optionally R 11 and R 12 together with the nitrogen atom to which they are attached, form an optionally substituted C 2 -C 9 heterocycloalkyl ring;
  • R 15 is selected from the group consisting of optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted aryl optionally substituted -(Ci-C 2 alkylene)-(aryl), optionally substituted C 2 - Cgheterocycloalkyl, optionally substituted heteroaryl, and optionally substituted -(Ci-C 2 alkylene)- (heteroaryl); R , R , and R are each independently selected from the group consisting of hydrogen, optionally substituted Ci-C 6 alkyl, optionally substituted C2-C 6 alkenyl, optionally substituted C2-C 6 alkynyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted aryl, optionally substituted -(Ci- C 2 alkylene)-(aryl
  • R 21 and R 22 are each independently selected from the group consisting of hydrogen, optionally
  • Ci-C 6 alkyl optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted aryl, optionally substituted -(Ci- C 2 alkylene)-(aryl), optionally substituted C 2 -C9heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted -(Ci-C 2 alkylene)-(heteroaryl); or optionally R 21 and R 22 together with the nitrogen atom to which they are attached, form an optionally substituted C 2 -C 9 heterocycloalkyl ring;
  • R 24 is selected from the group consisting of optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted aryl optionally substituted -(Ci-C 2 alkylene)-(aryl), optionally substituted C 2 - Cyheterocycloalkyl, optionally substituted heteroaryl, and optionally substituted -(Ci-C 2 alkylene)- (heteroaryl); and
  • R 25 and R 26 are each independently selected from the group consisting of hydrogen, optionally
  • Ci-C 6 alkyl optionally substituted C 3 -C 8 cycloalkyl, optionally substituted aryl, optionally substituted -(Ci-C 2 alkylene)-(aryl), optionally substituted C 2 -C 9 heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted -(Ci-C 2 alkylene)-(heteroaryl)
  • R 27 and R 28 are each independently selected from the group consisting of hydrogen, optionally
  • Ci-C 6 alkyl optionally substituted C 3 -C 8 cycloalkyl, optionally substituted aryl, optionally substituted -(Ci-C 2 alkylene)-(aryl), optionally substituted C 2 -C 9 heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted -(Ci-C 2 alkylene)-(heteroaryl); or R 27 and R 28 together with the nitrogen atom to which they are attached, form an optionally substituted C 2 - Cyheterocycloalkyl ring; or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof.
  • a method of treating a metabolic disorder in an individual in need thereof comprising co-administering to the individual a therapeutically effective amount of: (a) a first agent that is an FXR modulator; and (b) at least one second agent that is a DPP-rV inhibitor, an SGLT2 inhibitor, an ASKl inhibitor, a GLP-1 agonist, or a combination thereof; wherein the FXR modulator is a compound of Formula (II), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:
  • R 1 is selected from the group consisting of hydrogen, halogen, optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted -(XV C 2 alkylene)-(C 3 -C 8 cycloalkyl), optionally substituted C 2 -C 9 heterocycloalkyl, optionally substituted - (Ci-C 2 alkylene)-(C 2 -C 9 heterocycloalkyl), optionally substituted -(Ci-C 2 alkylene)-(aryl), optionally substituted -(Ci-C 2 alkylene)-(heteroaryl), -OR 10 , -SR 10 , -N(R U )R 12 , - N(R u )S(0) 2 R 15
  • R 2 is selected from the group consisting of hydrogen, optionally substituted Ci-C 6 alkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted aryl, optionally substituted -(Ci-C 2 alkylene)- (aryl), optionally substituted heteroaryl, optionally substituted C 2 -C 9 heterocycloalkyl, and optionally substituted -(Ci-C 2 alkylene)-(heteroaryl);
  • R 3 is selected from the group consisting of hydrogen, optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 - C 8 cycloalkyl, optionally substituted aryl, optionally substituted -(Ci-C 2 alkylene)-(aryl), optionally substituted heteroaryl, optionally substituted C 2 -C 9 heterocycloalkyl, optionally substituted -(Ci- C 2 alkylene)-(heteroaryl), -C(0)R 20 , -C(0)OR 20 , -S(0) 2 R 20 , -C(0)N(R 21 )R 22 , -C(0)N(R 21 )S(0) 2 R 24 , - C(0)N(R 23 )N(R 21 )R 22 , -C(0)N(R 23 )N(R 21 )S(0) 2 R 24 , -N(R
  • R 4 and R 5 are each independently selected from the group consisting of hydrogen, halogen, optionally substituted Ci-C 6 alkyl, optionally substituted Ci-C 6 alkoxy, optionally substituted C 2 -C 6 alkenyl, and optionally substituted C 2 -C 6 alkynyl; or R 4 and R 5 together with the carbon atom to which they are attached, form an optionally substituted C 3 -C 6 cycloalkyl ring or an optionally substituted C 2 - C 7 heterocycloalkyl ring;
  • R 6 is selected from the group consisting of hydrogen, halogen, optionally substituted Ci-C 6 alkyl, optionally substituted C2-C 6 alkenyl, optionally substituted C2-C 6 alkynyl, and -C(0)N(R )R ;
  • R 7 is selected from the group consisting of hydrogen, halogen, optionally substituted Ci-C 6 alkyl, optionally substituted Ci-C 6 alkoxy, optionally substituted C 2 -C 6 alkenyl, and optionally substituted C 2 -C 6 alkynyl;
  • R 9 is selected from the group consisting of hydrogen, optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 - C 8 cycloalkyl, optionally substituted aryl, optionally substituted -(Ci-C 2 alkylene)-(aryl), optionally substituted C 2 -C9heterocycloalkyl, optionally substituted heteroaiyl, and optionally substituted -(Ci- C 2 alkylene)-(heteroaryl); or R 8 and R 9 together with the carbon atoms to which they are attached, form an optionally substituted C 2 -C 9 heterocycloalkyl ring or an optionally substituted heteroaryl ring;
  • R 10 , R 13 and R 14 are each independently selected from the group consisting of hydrogen, optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted aryl, optionally substituted -(Ci- C 2 alkylene)-(aryl), optionally substituted C 2 -C9heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted -(Ci-C 2 alkylene)-(heteroaryl);
  • R 11 and R 12 are each independently selected from the group consisting of hydrogen, optionally
  • Ci-C 6 alkyl optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted aryl, optionally substituted -(Ci- C 2 alkylene)-(aryl), optionally substituted C 2 -C9heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted -(Ci-C 2 alkylene)-(heteroaryl); or optionally R 11 and R 12 together with the nitrogen atom to which they are attached, form an optionally substituted C 2 -C 9 heterocycloalkyl ring;
  • R 15 is selected from the group consisting of optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted aryl optionally substituted -(Ci-C 2 alkylene)-(aryl), optionally substituted C 2 - Cgheterocycloalkyl, optionally substituted heteroaryl, and optionally substituted -(Ci-C 2 alkylene)- (heteroaryl);
  • R , R , and R are each independently selected from the group consisting of hydrogen, optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted aiyl, optionally substituted -(Ci- C 2 alkylene)-(aryl), optionally substituted C 2 -C9heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted -(Ci-C 2 alkylene)-(heteroaryl);
  • R 21 and R 22 are each independently selected from the group consisting of hydrogen, optionally
  • Ci-C 6 alkyl optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C3-C 8 cycloalkyl, optionally substituted aiyl, optionally substituted -(Ci- C 2 alkylene)-(aryl), optionally substituted C 2 -C 9 heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted -(Ci-C 2 alkylene)-(heteroaryl); or optionally R 21 and R 22 together with the nitrogen atom to which they are attached, form an optionally substituted C 2 -Cciheterocycloalkyl ring;
  • R 24 is selected from the group consisting of optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted aiyl optionally substituted -(Ci-C 2 alkylene)-(aryl), optionally substituted C 2 - Cgheterocycloalkyl, optionally substituted heteroaryl, and optionally substituted -(Ci-C 2 alkylene)- (heteroaryl); and
  • R 25 and R 26 are each independently selected from the group consisting of hydrogen, optionally
  • Ci-C 6 alkyl optionally substituted C 3 -C 8 cycloalkyl, optionally substituted aiyl, optionally substituted -(Ci-C 2 alkylene)-(aryl), optionally substituted C 2 -Cciheterocycloalkyl, optionally substituted heteroaryl, and optionally substituted -(Ci-C 2 alkylene)-(heteroaryl);
  • R 27 and R 28 are each independently selected from the group consisting of hydrogen, optionally
  • Ci-C 6 alkyl optionally substituted C 3 -C 8 cycloalkyl, optionally substituted aiyl, optionally substituted -(Ci-C 2 alkylene)-(aryl), optionally substituted C 2 -Cciheterocycloalkyl, optionally substituted heteroaryl, and optionally substituted -(Ci-C 2 alkylene)-(heteroaryl); or R 27 and R 28 together with the nitrogen atom to which they are attached, form an optionally substituted C 2 - C 9 heterocycloalkyl ring; or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof.
  • the FXR modulator is a compound of Formula (I) or (II) wherein R 4 and R 5 are each independently selected from the group consisting of hydrogen, halogen, and optionally substituted Ci-C 6 alkyl.
  • the FXR modulator is a compound of Formula (I) or (II) wherein R 4 and R 5 are each independently selected from the group consisting of hydrogen and optionally substituted Ci-C 6 alkyl.
  • the FXR modulator is a compound of Formula (I) or (II) wherein R 4 and R 5 are each hydrogen.
  • the FXR modulator is a compound of Formula (I) or (II) wherein R 4 and R 5 are each independently optionally substituted Ci-C 6 alkyl. In another embodiment, the FXR modulator is a compound of Formula (I) or (II) wherein R 4 and R 5 are each methyl.
  • the FXR modulator is a compound of Formula (I) or (II) wherein R 6 and R 7 are each independently selected from the group consisting of hydrogen, halogen, and optionally substituted Ci-C 6 alkyl.
  • the FXR modulator is a compound of Formula (I) or (II) wherein R 6 and R 7 are each independently selected from the group consisting of hydrogen and optionally substituted Ci-C 6 alkyl.
  • the FXR modulator is a compound of Formula (I) or (II) wherein R 6 and R 7 are each independently optionally substituted Ci-C 6 alkyl.
  • the FXR modulator is a compound of Formula (I) or (II) wherein R 6 and R 7 are each methyl. In another embodiment, the FXR modulator is a compound of Formula (I) or (II) wherein R 6 and R 7 are each hydrogen.
  • the FXR modulator is a compound of Formula (I) or (II) wherein R 6
  • the FXR modulator is a compound of Formula (I) or (II) wherein R 6 and R 7 are hydrogen, R 4 and R 5 are independently optionally substituted
  • the FXR modulator is a compound of Formula (I) or (II) wherein R 6 and R 7 are hydrogen, R 4 and R 5 are
  • the FXR modulator is a compound of Formula (I) or (II) wherein R 6 and R 7 are hydrogen, R 4 and R 5 are methyl,
  • R is -C(0)R , and R is optionally substituted heteroaryl.
  • the FXR modulator is a compound of Formula (I) or (II) wherein R 6
  • the FXR modulator is a compound of Formula (I) or (II) wherein R 6 and R 7 are hydrogen, R 4 and R 5 are independently optionally substituted
  • the FXR modulator is a compound of Formula (I) or (II) wherein R 6 and R 7 are hydrogen, R 4 and R 5 are
  • the FXR modulator is a compound of Formula (I) or (II) wherein R 6 and R 7 are hydrogen, R 4 and R 5 are methyl,
  • the FXR modulator is a compound of Formula (I) or (II) wherein R 6 and R 7 are hydrogen, R 4 and R 5 are independently optionally substituted Ci-C 6 alkyl, R 3 is -
  • the FXR modulator is a compound of Formula (I) or (II) wherein R 6 and R 7 are hydrogen, R 4 and R 5 are independently optionally substituted Ci-C 6 alkyl, R 3 is -C(0)N(R 21 )R 22 , R 21 is hydrogen and R 22 is optionally substituted heteroaryl.
  • the FXR modulator is a compound of Formula (I) or (II) wherein R 6 and R 7 are hydrogen, R 4 and R 5 are methyl, R 3 is -C(0)N(R 21 )R 22 , R 21 is hydrogen and R 22 is optionally substituted aryl.
  • the FXR modulator is a compound of Formula (I) or (II) wherein R 6 and R 7 are hydrogen, R 4 and R 5 are methyl, R 3 is - C(0)N(R 21 )R 22 , R 21 is hydrogen and R 22 is optionally substituted heteroaryl.
  • the FXR modulator is a compound of Formula (I) or (II) wherein R is -CN.
  • the FXR modulator is a compound of Formula (I) or (II) wherein R 8 is -C(0)OR 25 .
  • R 8 is -C(0)OR 25 .
  • the FXR modulator is a compound of Formula (I) or (II) wherein R 8 is - C(0)OR 25 , and R 25 is independently selected from the group consisting of hydrogen, optionally substituted Ci-C 6 alkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted aryl, optionally substituted -(Ci-C 2 alkylene)-(aryl), optionally substituted C 2 -C 9 heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted -(Ci-C 2 alkylene)-(heteroaryl).
  • the FXR modulator is a compound of Formula (I) or (II) wherein R 8 is - C(0)OR 25 , and R 25 is independently selected from the group consisting of hydrogen, and optionally substituted Ci-C 6 alkyl.
  • the FXR modulator is a compound of Formula (I) or (II) wherein R 8 is -C(0)OR 25 , and R 25 is hydrogen.
  • the FXR modulator is a compound of Formula (I) or (II) wherein R 8 is -C(0)OR 25 , and R 25 is optionally substituted Ci-C 6 alkyl.
  • the FXR modulator is a compound of Formula (I) or (II) wherein R 8 is -C(0)OR 25 , and R 25 is unsubstituted Ci-C 6 alkyl.
  • the FXR modulator is a compound of Formula (I) or (II) wherein R 8 is - C(0)OR 25 , and R 25 is methyl.
  • the FXR modulator is a compound of Formula (I) or (II) wherein R is -C(0)OR , and R is ethyl.
  • the FXR modulator is a compound of Formula (I) or (II) wherein R 8 is -C(0)OR 25 , and R 25 is isopropyl.
  • the FXR modulator is a compound of Formula (I) or (II) wherein R 8 is -C(0)N(R 25 )R 26 . In a further embodiment of the aforementioned embodiments, the FXR modulator is a compound of Formula (I) or (II) wherein R 8 is -
  • C(0)N(R )R and R and R are each independently selected from the group consisting of hydrogen, optionally substituted Ci-C 6 alkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted aryl, optionally substituted -(Ci-C 2 alkylene)-(aryl), optionally substituted C 2 - Cgheterocycloalkyl, optionally substituted heteroaryl, and optionally substituted -(Ci-C 2 alkylene)- (heteroaryl).
  • the FXR modulator is a compound of Formula (I) or (II) wherein R 8 is -C(0)N(R 25 )R 26 , and R 25 and R 26 are each independently selected from the group consisting of hydrogen, and optionally substituted Ci-C 6 alkyl.
  • the FXR modulator is a compound of Formula (I) or (II) wherein R 8 is -C(0)N(R 25 )R 26 , and R 25 and R 26 are hydrogen.
  • the FXR modulator is a compound of Formula (I) or (II) wherein R 8 is -
  • the FXR modulator is a compound of Formula (I) or (II) wherein R 8 is -C(0)N(R 25 )R 26 , R 25 is hydrogen, and R 26 is optionally substituted Ci-C 6 alkyl.
  • the FXR modulator is a compound of Formula (I) or (II) wherein R 8 is -C(0)N(R 25 )R 26 , and R 25 and R 26 are each independently
  • the FXR modulator is a compound of Formula (I) or (II) wherein R is -C(0)N(R )R , R is hydrogen, and R are methyl.
  • the FXR modulator is a compound of Formula (I) or (II) wherein R 8 is -C(0)N(R 25 )R 26 , and R 25 and R 26 are methyl.
  • the FXR modulator is a compound of Formula (I) or (II) wherein R 8 is -C(0)N(R 25 )R 26 , and R 25 and R 26 are ethyl.
  • the FXR modulator is a In a further embodiment of the aforementioned embodiments, the FXR modulator is a compound of Formula (I) or (II) wherein R is In a further embodiment of the aforementioned embodiments, the FXR modulator is a compound of Formula (I) or (II) wherein R 8 is
  • FXR modulator is a compound of Formula (I) or (II) wherein R 8 is Q " N , and R 25 is ethyl.
  • the FXR modulator is a
  • the FXR modulator is a compound of Formula (I) or (II) wherein R 8
  • R 25 is optionally substituted Ci-C 6 alkyl.
  • the FXR modulator is a compound of Formula (I) or (II) wherein R 8 ⁇ K 0 A R 25 , and R 25 is methyl.
  • the FXR modulator is a compound of Formula (I) or (II) wherein R 8 ⁇ K 0 A R 25 , and R 25 is methyl.
  • FXR modulator is a compound of Formula (I) or (II) wherein R 8 is ⁇ K 0 A R 25 , and R 25 is ethyl.
  • the FXR modulator is a
  • the FXR modulator is a compound of Formula (I) or (II) wherein R 8
  • the FXR modulator is a compound of Formula (I) or (II) wherein R 8 ⁇ R 25 , and R 25 is methyl.
  • the FXR modulator is a compound of Formula (I) or (II) wherein R 8 ⁇ R 25 , and R 25 is methyl.
  • FXR modulator is a compound of Formula (I) or (II) wherein R 8 is N R 25 , and R 25 is ethyl.
  • the FXR modulator is a compound of Formula (I) or (II) wherein R 9 is selected from the group consisting of hydrogen and optionally substituted Ci-C 6 alkyl.
  • the FXR modulator is a compound of Formula (I) or (II) wherein R 9 is hydrogen.
  • the FXR modulator is a compound of Formula (I) or (II) wherein R 9 is optionally substituted Ci-C 6 alkyl.
  • the FXR modulator is a compound of Formula (I) or (II) wherein R 9 is unsubstituted Ci-C 6 alkyl. In a further embodiment of the aforementioned embodiments, the FXR modulator is a compound of Formula (I) or (II) wherein R 9 is methyl.
  • the FXR modulator is a compound of Formula (I) or (II) wherein R 8 and R 9 together with the carbon atoms to which they are attached, form an optionally substituted C 2 -C 9 heterocycloalkyl ring or an optionally substituted heteroaryl ring.
  • the FXR modulator is a compound of Formula (I) or (II) wherein R 8 and R 9 together with the carbon atoms to which they are attached, form an optionally substituted C 2 -Cciheterocycloalkyl ring.
  • the FXR modulator is a compound of Formula (I) or (II) wherein R 8 and R 9 together with the carbon atoms to which they are attached, form an optionally substituted heteroaryl ring.
  • the FXR modulator is a compound of Formula (I) or (II) wherein R 2 is selected from the group consisting of hydrogen, optionally substituted Ci-C 6 alkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted aryl, optionally substituted -(Ci-C 2 alkylene)-(aryl), optionally substituted heteroaryl, optionally substituted C 2 -C 9 heterocycloalkyl, and optionally substituted -(Ci-C 2 alkylene)-(heteroaryl).
  • R 2 is selected from the group consisting of hydrogen, optionally substituted Ci-C 6 alkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted aryl, optionally substituted -(Ci-C 2 alkylene)-(aryl), optionally substituted heteroaryl, optionally substituted C 2 -C 9 heterocycloalkyl, and optionally substituted -(Ci-C 2 alky
  • the FXR modulator is a compound of Formula (I) or (II) wherein R 2 is selected from the group consisting of hydrogen, and optionally substituted Ci- C 6 alkyl.
  • the FXR modulator is a compound of Formula (I) or (II) wherein R 2 is optionally substituted Ci-C 6 alkyl.
  • the FXR modulator is a compound of Formula (I) or (II) wherein R 2 is methyl.
  • the FXR modulator is a compound of Formula (I) or (II) wherein R 2 is ethyl. In a further embodiment of the aforementioned embodiments, the FXR modulator is a compound of Formula (I) or (II) wherein R 2 is hydrogen.
  • the FXR modulator is a compound of Formula (I) or (II) wherein R 1 is selected from the group consisting of hydrogen, halogen, optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C 3 - C 8 cycloalkyl, optionally substituted -(Ci-C 2 alkylene)-(C 3 -C 8 cycloalkyl), optionally substituted C 2 - C 9 heterocycloalkyl, optionally substituted -(Ci-C 2 alkylene)-(C 2 -C 9 heterocycloalkyl), optionally substituted -(Ci-C 2 alkylene)-(aryl), optionally substituted -(Ci-C 2 alkylene)-(heteroaryl),
  • the FXR modulator is a compound of Formula (I) or (II) wherein R 1 is halogen. In a further embodiment of the aforementioned embodiments, the FXR modulator is a compound of Formula (I) or (II) wherein R 1 is optionally substituted Ci-C 6 alkyl. In a further embodiment of the aforementioned embodiments, the FXR modulator is a compound of Formula (I) or (II) wherein R 1 is optionally substituted C 2 -C 6 alkenyl. In a further embodiment of the aforementioned embodiments, the FXR modulator is a compound of Formula (I) or (II) wherein R 1 is optionally substituted C 2 -C 6 alkynyl.
  • the FXR modulator is a compound of Formula (I) or (II) wherein R 1 is -OR 10 and R 10 is hydrogen. In a further embodiment of the aforementioned embodiments, the FXR modulator is a compound of Formula (I) or (II) wherein R 1 is - OR 10 and R 10 is optionally substituted Ci-C 6 alkyl. In a further embodiment of the aforementioned embodiments, the FXR modulator is a compound of Formula (I) or (II) wherein R 1 is -OR 10 and R 10 is methyl.
  • a method of treating a metabolic disorder in an individual in need thereof comprising co-administering to the individual a therapeutically effective amount of: (a) a first agent that is an FXR modulator; and (b) at least one second agent that is a DPP-rV inhibitor, an SGLT2 inhibitor, an ASK1 inhibitor, a GLP-1 agonist, or a combination thereof; wherein the FXR modulator is a compound of Formula (III), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:
  • R 1 is selected from the group consisting of hydrogen, halogen, optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted aryl, optionally substituted heteroaiyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted -(Ci- C 2 alkylene)-(C 3 -C 8 cycloalkyl), optionally substituted C 2 -Cciheterocycloalkyl, optionally substituted - (Ci-C 2 alkylene)-(C 2 -C 9 heterocycloalkyl), optionally substituted -(Ci-C 2 alkylene)-(aryl), optionally substituted -(Ci-C 2 alkylene)-(heteroaryl), -OR 10 , -SR 10 , -N(R U )R 12 , - N(R u )
  • R 4 and R 5 are each independently optionally substituted Ci-C 6 alkyl
  • R 9 is selected from the group consisting of hydrogen, optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 - C 8 cycloalkyl, optionally substituted aryl, optionally substituted -(Ci-C 2 alkylene)-(aryl), optionally substituted C 2 -C 9 heterocycloalkyl, optionally substituted heteroaiyl, and optionally substituted -(Ci- C 2 alkylene)-(heteroaryl);
  • R 10 , R 13 and R 14 are each independently selected from the group consisting of hydrogen, optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted aryl, optionally substituted -(Ci- C 2 alkylene)-(aryl), optionally substituted C 2 -C 9 heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted -(Ci-C 2 alkylene)-(heteroaryl);
  • R 15 is selected from the group consisting of optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted aryl optionally substituted -(Ci-C 2 alkylene)-(aryl), optionally substituted C 2 - C 9 heterocycloalkyl, optionally substituted heteroaiyl, and optionally substituted -(Ci-C 2 alkylene)- (heteroaryl);
  • R 11 and R 12 are each independently selected from the group consisting of hydrogen, optionally substituted Ci-C 6 alkyl, optionally substituted C2-C 6 alkenyl, optionally substituted C2-C 6 alkynyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted aryl, optionally substituted -(Ci- C 2 alkylene)-(aryl),
  • R 25 is Ci-C 6 alkyl
  • R 30 is halogen, ;
  • each R 31 is independently halogen, -OH, -CN, -N0 2 , -NH 2 , optionally substituted Ci-C 6 alkyl,
  • Ci-C 6 alkoxy optionally substituted Ci-C 6 alkylamine, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 2 -C 9 heterocycloalkyl, aryl, or heteroaryl;
  • each R 32 and R 33 are each independently selected from the group consisting of hydrogen, halogen, and Ci-C 6 alkyl;
  • R 34 and R 35 are each independently selected from the group consisting of hydrogen, optionally substituted Ci-C 6 alkyl, optionally substituted C 3 -C 8 cycloalkyl, and optionally substituted C 2 - C 9 heterocycloalkyl; or R 34 and R 35 together with the nitrogen atom to which they are attached, form an optionally substituted C 2 -Cciheterocycloalkyl ring or an optionally substituted heteroaryl ring; n is O, 1, 2, 3, or 4;
  • r 0, 1, 2, 3, or 4;
  • t 2, 3, or 4.
  • the FXR modulator is a compound of Formula (III) wherein n is 0. In another embodiment, the FXR modulator is a compound of Formula (III) wherein n is 1. In another embodiment, the FXR modulator is a compound of Formula (III) wherein n is 2. In another embodiment, the FXR modulator is a compound of Formula (III) wherein n is 3. In another embodiment, the FXR modulator is a compound of Formula (III) wherein n is 4.
  • the FXR modulator is a compound of Formula (III) wherein n is 2 and each R 31 is independently halogen, -OH, -CN, -N0 2 , -NH 2 , optionally substituted Ci-C 6 alkyl, optionally substituted Ci-C 6 alkoxy, optionally substituted Ci-C 6 alkylamine, optionally substituted C 3 -
  • C 8 cycloalkyl optionally substituted C 2 -Cciheterocycloalkyl, aryl, or heteroaryl.
  • the FXR modulator is a compound of Formula (III) wherein n is 2 and each R 31 is independently halogen, or optionally substituted Ci-C 6 alkyl. In another embodiment, the FXR modulator is a compound of Formula (III) wherein n is 2 and each R 31 is halogen. In another embodiment, the FXR modulator is a compound of Formula (III) wherein n is 2 and each R 31 is F.
  • the FXR modulator is a compound of Formula (III) wherein R 30 is F, n is 2, and each R 31 is independently halogen, -OH, -CN, -N0 2 , -NH 2 , optionally substituted Ci- C 6 alkyl, optionally substituted Ci-C 6 alkoxy, optionally substituted Ci-C 6 alkylamine, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 2 -C 9 heterocycloalkyl, aryl, or heteroaryl.
  • the FXR modulator is a compound of Formula (III) wherein R 30 is F, n is 2 and each R 31 is independently halogen, or optionally substituted Ci-C 6 alkyl. In another embodiment, the FXR modulator is a compound of Formula (III) wherein R 30 is F, n is 2 and each R 31 is halogen. In another embodiment, the FXR modulator is a compound of Formula (III) wherein R 30 is F, n is 2 and each R 31 is F.
  • the FXR modulator is a compound of Formula (III) wherein n is 1 and R 31 is halogen, -OH, -CN, -N0 2 , -NH 2 , optionally substituted Ci-C 6 alkyl, optionally substituted Ci-C 6 alkoxy, optionally substituted Ci-C 6 alkylamine, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 2 -C 9 heterocycloalkyl, aryl, or heteroaryl.
  • the FXR modulator is a compound of Formula (III) wherein n is 1 and R 31 is halogen, or optionally substituted Ci-C 6 alkyl.
  • the FXR modulator is a compound of Formula (III) wherein n is 1 and R 31 is halogen. In another embodiment, the FXR modulator is a compound of Formula (III) wherein n is 1 and R 31 is F.
  • the FXR modulator is a compound of Formula (III) wherein R 30 is F, n is 1 and R 31 is halogen, -OH, -CN, -N0 2 , -NH 2 , optionally substituted Ci-C 6 alkyl, optionally substituted Ci-C 6 alkoxy, optionally substituted Ci-C 6 alkylamine, optionally substituted C 3 - C 8 cycloalkyl, optionally substituted C 2 -C 9 heterocycloalkyl, aryl, or heteroaryl.
  • R 30 is F
  • n is 1
  • R 31 is halogen, -OH, -CN, -N0 2 , -NH 2 , optionally substituted Ci-C 6 alkyl, optionally substituted Ci-C 6 alkoxy, optionally substituted Ci-C 6 alkylamine, optionally substituted C 3 - C 8 cycloalkyl, optionally substituted C 2 -C 9 heterocycloalkyl, aryl, or hetero
  • the FXR modulator is a compound of Formula (III) wherein R 30 is F, n is 1 and R 31 is halogen, or optionally substituted Ci-C 6 alkyl. In another embodiment, the FXR modulator is a compound of Formula (III) wherein R 30 is F, n is 1 and R 31 is halogen. In another embodiment, the FXR modulator is a compound of Formula (III) wherein R 30 is F, n is 1 and R 31 is F.
  • the FXR modulator is a compound of Formula (III) wherein R 30 is . In one embodiment, the FXR modulator is a compound of Formula (III) wherein r is 0. In another embodiment, the FXR modulator is a compound of Formula (III) wherein r is 1. In another embodiment, the FXR modulator is a compound of Formula (III) wherein r is 2. In another
  • the FXR modulator is a compound of Formula (III) wherein r is 3.
  • the FXR modulator is a compound of Formula (III) wherein r is 4. In one embodiment, the FXR modulator is a compound of Formula (III) wherein each R 32 and R 33 are hydrogen. In one embodiment, the FXR modulator is a compound of Formula (III) wherein R 34 and R 35 are each independently selected from the group consisting of hydrogen, optionally substituted Ci-C 6 alkyl, optionally substituted C 3 -C 8 cycloalkyl, and optionally substituted C 2 -C 9 heterocycloalkyl.
  • the FXR modulator is a compound of Formula (III) wherein R 34 and R 35 are each independently selected from the group consisting of hydrogen, Ci-C 6 alkyl, C 3 -C 8 cycloalkyl, and C 2 - C 9 heterocycloalkyl.
  • the FXR modulator is a compound of Formula (III) wherein R 34 and R 35 together with the nitrogen atom to which they are attached form an optionally substituted C 2 -Cciheterocycloalkyl ring.
  • the FXR modulator is a compound of Formula (III) wherein R 34 and R 35 together with the nitrogen atom to which they are attached form a pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, or methylpiperazinyl.
  • the FXR modulator is a compound of Formula (III) wherein R 34 and R 35 together with the nitrogen atom to which they are attached form a morpholinyl.
  • the FXR modulator is a compound of Formula (III) wherein R 34 and R 35 together with the nitrogen atom to which they are attached form an optionally substituted heteroaryl ring.
  • the FXR modulator is a compound of Formula (III) wherein R 34 and R 35 together with the nitrogen atom to which they are attached form an imidazolyl, pyrazolyl, or pyrrol yl.
  • the FXR modulator is a compound of Formula (III) wherein R 30 is , n is 2, and each R 31 is independently halogen, -OH, -CN, -N0 2 , - H 2 , optionally substituted Ci-C 6 alkyl, optionally substituted Ci-C 6 alkoxy, optionally substituted Ci-C 6 alkylamine, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 2 -Cciheterocycloalkyl, aryl, or heteroaryl.
  • R 30 is , n is 2, and each R 31 is independently halogen, -OH, -CN, -N0 2 , - H 2 , optionally substituted Ci-C 6 alkyl, optionally substituted Ci-C 6 alkoxy, optionally substituted Ci-C 6 alkylamine, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 2 -Cciheterocycloalky
  • the FXR modulator is a compound of Formula (III) wherein R 30 is , n is 2 and each R 31 is independently halogen, or optionally substituted Ci-C 6 alkyl. In another embodiment, the FXR modulator is a compound of Formula (III) wherein R 30 is n is 2 and each R 31 is halogen. In another embodiment, the FXR modulator is a compound of Formula (III) wherein R 30 is n is 2 and each R 31 is halogen. In another embodiment, the FXR modulator is a compound of Formula (III) wherein R 30 is n is 2 and each R 31 is halogen. In another embodiment, the FXR modulator is a compound of Formula (III) wherein R 30 is n is 2 and each R 31 is halogen. In another embodiment, the FXR modulator is a compound of Formula (III) wherein R 30 is n is 2 and each R 31 is halogen. In another embodiment, the FXR modulator is a compound of Formula (III)
  • the FXR modulator is a compound of Formula (III) wherein R 30 is , n is 1 and R 31 is halogen, -OH, -CN, -N0 2 , - H 2 , optionally substituted Ci-C 6 alkyl, optionally substituted Ci-C 6 alkoxy, optionally substituted Ci-C 6 alkylamine, optionally substituted C 3 - C 8 cycloalkyl, optionally substituted C 2 -C 9 heterocycloalkyl, aryl, or heteroaryl.
  • R 30 is , n is 1 and R 31 is halogen, -OH, -CN, -N0 2 , - H 2 , optionally substituted Ci-C 6 alkyl, optionally substituted Ci-C 6 alkoxy, optionally substituted Ci-C 6 alkylamine, optionally substituted C 3 - C 8 cycloalkyl, optionally substituted C 2 -C 9 heterocycloalkyl, aryl, or heteroaryl
  • the FXR modulator is a compound of Formula (III) wherein R 30 is n is 1 and R 31 is halogen, or optionally substituted Ci-C 6 alkyl. In another embodiment, the FXR modulator
  • the FXR modulator is a compound of Formula (III) wherein R 30 is n is 1 and R 31 is F.
  • the FXR modulator is a compound of Formula (III) wherein R 30 is
  • the FXR modulator is a compound of Formula (III) wherein R is j n one embodiment, the FXR modulator is a compound of Formula (III) wherein t is 2. In another embodiment, the FXR modulator is a compound of Formula (III) wherein t is 3. In another embodiment, the FXR modulator is a compound of Formula (III) wherein t is 4. In one embodiment, the FXR modulator is a compound of Formula (III) wherein each R 32 and R 33 are hydrogen.
  • the FXR modulator is a compound of Formula (III) wherein R 34 and R 35 are each independently selected from the group consisting of hydrogen, optionally substituted Ci-C 6 alkyl, optionally substituted C 3 -C 8 cycloalkyl, and optionally substituted C 2 -C 9 heterocycloalkyl.
  • the FXR modulator is a compound of Formula (III) wherein R 34 and R 35 are each independently selected from the group consisting of hydrogen, Ci-C 6 alkyl, C 3 -C 8 cycloalkyl, and C 2 - C 9 heterocycloalkyl.
  • the FXR modulator is a compound of Formula (III) wherein R 34 and R 35 together with the nitrogen atom to which they are attached form an optionally substituted C 2 -Cciheterocycloalkyl ring.
  • the FXR modulator is a compound of Formula (III) wherein R 34 and R 35 together with the nitrogen atom to which they are attached form a pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, or methylpiperazinyl.
  • the FXR modulator is a compound of Formula (III) wherein R 34 and R 35 together with the nitrogen atom to which they are attached form a morpholinyl.
  • the FXR modulator is a compound of Formula (III) wherein R 34 and R 35 together with the nitrogen atom to which they are attached form an optionally substituted heteroaryl ring. In another embodiment, the FXR modulator is a compound of Formula (III) wherein R 34 and R 35 together with the nitrogen atom to which they are attached form an imidazolyl, pyrazolyl, or pyrrol yl.
  • the FXR modulator is a compound of Formula (III) wherein R 30 is
  • anc j eacn R 3 i is i nc j e p enc i ent iy halogen, -OH, -CN, -N0 2 , - H 2 , optionally substituted Ci-C 6 alkyl, optionally substituted Ci-C 6 alkoxy, optionally substituted Ci-C 6 alkylamine, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 2 -C 9 heterocycloalkyl, aryl, or heteroaryl.
  • the FXR modulator is a compound of Formula (III) wherein R 30 is 3 n is 2 and each R 31 is independently halogen, or optionally substituted Ci-C 6 alkyl.
  • the FXR modulator is a compound of Formula (III) wherein R 30 is
  • n 2 and each R 31 is halogen.
  • the FXR modulator is a compound of Formula
  • the FXR modulator is a compound of Formula (III) wherein R 30 is , n is 1 and R 31 is halogen, -OH, -CN, -N0 2 , - H 2 , optionally substituted Ci-C 6 alkyl, optionally substituted Ci-C 6 alkoxy, optionally substituted Ci-C 6 alkylamine, optionally substituted C 3 - Cscycloalkyl, optionally substituted C 2 -C 9 heterocycloalkyl, aryl, or heteroaryl.
  • R 30 is , n is 1 and R 31 is halogen, -OH, -CN, -N0 2 , - H 2 , optionally substituted Ci-C 6 alkyl, optionally substituted Ci-C 6 alkoxy, optionally substituted Ci-C 6 alkylamine, optionally substituted C 3 - Cscycloalkyl, optionally substituted C 2 -C 9 heterocycloalkyl, aryl, or heteroaryl.
  • the FXR modulator is a compound of Formula (III) wherein R 30 is R 32 r33 , n is 1 and R 31 is halogen, or optionally substituted Ci-C 6 alkyl. In another embodiment, the FXR modulator
  • the FXR modulator is a compound of Formula (III) wherein R 30 is R 32 r33
  • the FXR modulator is a compound of Formula (III) wherein R is
  • the FXR modulator is a compound of Formula (III) wherein R 4 and R 5 are each methyl. In a further embodiment of the aforementioned embodiments, the FXR modulator is a compound of Formula (III) wherein R 4 and R 5 are each ethyl. In a further embodiment of the aforementioned embodiments, the FXR modulator is a compound of Formula (III) wherein R 1 is hydrogen. In a further embodiment of the aforementioned embodiments, the FXR modulator is a compound of Formula (III) wherein R 1 is halogen.
  • the FXR modulator is a compound of Formula (III) wherein R 1 is optionally substituted Ci-C 6 alkyl. In a further embodiment of the aforementioned embodiments, the FXR modulator is a compound of Formula (III) wherein R 1 is methyl. In a further embodiment of the aforementioned embodiments, the FXR modulator is a compound of Formula (III) wherein R 1 is optionally substituted C 2 -C 6 alkenyl. In a further embodiment of the aforementioned embodiments, the FXR modulator is a compound of Formula (III) wherein R 1 is optionally substituted C 2 -C 6 alkynyl.
  • the FXR modulator is a compound of Formula (III) wherein R 1 is -OR 10 and R 10 is hydrogen. In a further embodiment of the aforementioned embodiments, the FXR modulator is a compound of Formula (III) wherein R 1 is -OR 1( and R 10 is optionally substituted Ci-C 6 alkyl. In a further embodiment of the aforementioned embodiments, the FXR modulator is a compound of Formula (III) wherein R 1 is -OR 10 and R 10 is methyl. In a further embodiment of the aforementioned embodiments, the FXR modulator is a compound of Formula (III) wherein R 25 is methyl.
  • the FXR modulator is a compound of Formula (III) wherein R 25 is ethyl. In a further embodiment of the aforementioned embodiments, the FXR modulator is a compound of Formula (III) wherein R 25 is isopropyl.
  • the FXR modulator is a compound of Formula (III) wherein R 9 is selected from the group consisting of hydrogen and optionally substituted Ci-C 6 alkyl.
  • R 9 is selected from the group consisting of hydrogen and optionally substituted Ci-C 6 alkyl.
  • FXR modulator is a compound of Formula (III) wherein R 9 is hydrogen. In a further embodiment of the aforementioned embodiments, the FXR modulator is a compound of Formula (III) wherein R 9 is optionally substituted Ci-C 6 alkyl. In a further embodiment of the aforementioned embodiments, the FXR modulator is a compound of Formula (III) wherein R 9 is unsubstituted Ci-C 6 alkyl. In a further embodiment of the aforementioned embodiments, the FXR modulator is a compound of Formula (III) wherein R 9 is methyl.
  • the FXR modulator is a compound having the structure of Formula (Ilia), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:
  • the FXR modulator is a compound having the structure of Formula (Illb), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:
  • the FXR modulator is a compound of Formula (Ilia) or (Illb) wherein R 1 is hydrogen. In some embodiments, the FXR modulator is a compound of Formula (Ilia) or (Illb) wherein R 1 is halogen. In some embodiments, the FXR modulator is a compound of Formula (Ilia) or (Illb) wherein R 1 is optionally substituted Ci-C 6 alkyl. In some embodiments, the FXR modulator is a compound of Formula (Ilia) or (Illb) wherein R 1 is optionally substituted C2-C 6 alkenyl.
  • the FXR modulator is a compound of Formula (Ilia) or (Illb) wherein R 1 is optionally substituted C 2 -C 6 alkynyl. In some embodiments, the FXR modulator is a compound of Formula (Ilia) or (Illb) wherein R 1 is -OR 10 and R 10 is hydrogen. In some embodiments, the FXR modulator is a compound of Formula (Ilia) or (Illb) wherein R 1 is -OR 10 and R 10 is optionally substituted Ci-C 6 alkyl.
  • the FXR modulator is a compound of Formula (Ilia) or (Illb) wherein R 1 is -OR 10 and R 10 is methyl. In a further embodiment of the aforementioned embodiments, the FXR modulator is a compound of Formula (Ilia) or (Illb) wherein R 25 is methyl. In a further embodiment of the aforementioned embodiments, the FXR modulator is a compound of Formula (Ilia) or (Illb) wherein R is ethyl. In a further embodiment of the aforementioned embodiments, the FXR modulator is a compound of Formula (Ilia) or (Illb) wherein R 25 is isopropyl.
  • a method of treating a metabolic disorder in an individual in need thereof comprising co-administering to the individual a therapeutically effective amount of: (a) a first agent that is an FXR modulator; and (b) at least one second agent that is a DPP-IV inhibitor, an SGLT2 inhibitor, an ASK1 inhibitor, a GLP-1 agonist, or a combination thereof; wherein the FXR modulator is a compound of Formula (IV), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:
  • R 1 is selected from the group consisting of hydrogen, halogen, optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted -(Ci- C 2 alkylene)-(C 3 -C 8 cycloalkyl), optionally substituted C 2 -Cciheterocycloalkyl, optionally substituted - (Ci-C 2 alkylene)-(C 2 -C 9 heterocycloalkyl), optionally substituted -(Ci-C 2 alkylene)-(aryl), optionally substituted -(Ci-C 2 alkylene)-(heteroaryl), -OR 10 , -SR 10 , -N(R U )R 12 , - N(R u )S(0)
  • R 4 and R 5 are each independently optionally substituted Ci-C 6 alkyl
  • R 9 is selected from the group consisting of hydrogen, optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 - C 8 cycloalkyl, optionally substituted aryl, optionally substituted -(Ci-C 2 alkylene)-(aryl), optionally substituted C 2 -Cciheterocycloalkyl, optionally substituted heteroaryl, and optionally substituted -(Ci- C 2 alkylene)-(heteroaryl);
  • R 10 , R 13 and R 14 are each independently selected from the group consisting of hydrogen, optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted aryl, optionally substituted -(Ci- C 2 alkylene)-(aryl), optionally substituted C 2 -Cciheterocycloalkyl, optionally substituted heteroaryl, and optionally substituted -(Ci-C 2 alkylene)-(heteroaryl);
  • R 15 is selected from the group consisting of optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted aryl optionally substituted -(Ci-C 2 alkylene)-(aryl), optionally substituted C 2 - C 9 heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted -(Ci-C 2 alkylene)- (heteroaryl);
  • R 11 and R 12 are each independently selected from the group consisting of hydrogen, optionally
  • Ci-C 6 alkyl optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted aryl, optionally substituted -(Ci- C 2 alkylene)-(aryl), optionally substituted C 2 -C 9 heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted -(Ci-C 2 alkylene)-(heteroaryl); or optionally R 11 and R 12 together with the nitrogen atom to which they are attached, form an optionally substituted C 2 -Cciheterocycloalkyl ring;
  • R 25 is Ci-C 6 alkyl
  • R 30 is halogen, ;
  • each R 31 is independently halogen, -OH, -CN, -N0 2 , -NH 2 , optionally substituted Ci-C 6 alkyl,
  • Ci-C 6 alkoxy optionally substituted Ci-C 6 alkylamine, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 2 -C 9 heterocycloalkyl, aryl, or heteroaryl;
  • each R 32 and R 33 are each independently selected from the group consisting of hydrogen, halogen, and Ci-C 6 alkyl;
  • R 34 and R 35 are each independently selected from the group consisting of hydrogen, optionally
  • Ci-C 6 alkyl optionally substituted C 3 -C 8 cycloalkyl, and optionally substituted C 2 - C 9 heterocycloalkyl; or R 34 and R 35 together with the nitrogen atom to which they are attached, form an optionally substituted C 2 -Cciheterocycloalkyl ring or an optionally substituted heteroaryl ring; n is O, 1, 2, 3, or 4;
  • r 0, 1, 2, 3, or 4;
  • t 2, 3, or 4.
  • the FXR modulator is a compound of Formula (IV) wherein n is 0. In another embodiment, the FXR modulator is a compound of Formula (IV) wherein n is 1. In another embodiment, the FXR modulator is a compound of Formula (IV) wherein n is 2. In another embodiment, the FXR modulator is a compound of Formula (IV) wherein n is 3. In another embodiment, the FXR modulator is a compound of Formula (IV) wherein n is 4.
  • the FXR modulator is a compound of Formula (IV) wherein n is 2 and each R 31 is independently halogen, -OH, -CN, -N0 2 , -NH 2 , optionally substituted Ci-C 6 alkyl, optionally substituted Ci-C 6 alkoxy, optionally substituted Ci-C 6 alkylamine, optionally substituted C 3 - C 8 cycloalkyl, optionally substituted C 2 -C 9 heterocycloalkyl, aryl, or heteroaryl.
  • n is 2 and each R 31 is independently halogen, -OH, -CN, -N0 2 , -NH 2 , optionally substituted Ci-C 6 alkyl, optionally substituted Ci-C 6 alkoxy, optionally substituted Ci-C 6 alkylamine, optionally substituted C 3 - C 8 cycloalkyl, optionally substituted C 2 -C 9 heterocycloalkyl, aryl, or heteroaryl.
  • the FXR modulator is a compound of Formula (IV) wherein n is 2 and each R 31 is independently halogen, or optionally substituted Ci-C 6 alkyl. In another embodiment, the FXR modulator is a compound of Formula (IV) wherein n is 2 and each R 31 is halogen. In another embodiment, the FXR modulator is a compound of Formula (IV) wherein n is 2 and each R 31 is F.
  • the FXR modulator is a compound of Formula (IV) wherein R 30 is F, n is 2, and each R 31 is independently halogen, -OH, -CN, -N0 2 , -NH 2 , optionally substituted Ci- C 6 alkyl, optionally substituted Ci-C 6 alkoxy, optionally substituted Ci-C 6 alkylamine, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 2 -C 9 heterocycloalkyl, aryl, or heteroaryl.
  • the FXR modulator is a compound of Formula (IV) wherein R 30 is F, n is 2 and each R 31 is independently halogen, or optionally substituted Ci-C 6 alkyl. In another embodiment, the FXR modulator is a compound of Formula (IV) wherein R 30 is F, n is 2 and each R 31 is halogen. In another embodiment, the FXR modulator is a compound of Formula (IV) wherein R 30 is F, n is 2 and each R 31 is F.
  • the FXR modulator is a compound of Formula (IV) wherein n is 1 and R 31 is halogen, -OH, -CN, -N0 2 , -NH 2 , optionally substituted Ci-C 6 alkyl, optionally substituted Ci-C 6 alkoxy, optionally substituted Ci-C 6 alkylamine, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 2 -C 9 heterocycloalkyl, aryl, or heteroaryl.
  • the FXR modulator is a compound of Formula (IV) wherein n is 1 and R 31 is halogen, or optionally substituted Ci-C 6 alkyl.
  • the FXR modulator is a compound of Formula (IV) wherein n is 1 and R 31 is halogen. In another embodiment, the FXR modulator is a compound of Formula (IV) wherein n is 1 and R 31 is F.
  • the FXR modulator is a compound of Formula (IV) wherein R 30 is F, n is 1 and R 31 is halogen, -OH, -CN, -N0 2 , -NH 2 , optionally substituted Ci-C 6 alkyl, optionally substituted Ci-C 6 alkoxy, optionally substituted Ci-C 6 alkylamine, optionally substituted C 3 - C 8 cycloalkyl, optionally substituted C 2 -C 9 heterocycloalkyl, aryl, or heteroaryl.
  • the FXR modulator is a compound of Formula (IV) wherein R 30 is F, n is 1 and R 31 is halogen, or optionally substituted Ci-C 6 alkyl. In another embodiment, the FXR modulator is a compound of Formula (IV) wherein R 30 is F, n is 1 and R 31 is halogen. In another embodiment, the FXR modulator is a compound of Formula (IV) wherein R 30 is F, n is 1 and R 31 is F.
  • the FXR modulator is a compound of Formula (IV) wherein R 30 is . In one embodiment, the FXR modulator is a compound of Formula (IV) wherein r is 0. In another embodiment, the FXR modulator is a compound of Formula (IV) wherein r is 1. In another embodiment, the FXR modulator is a compound of Formula (IV) wherein r is 2. In another
  • the FXR modulator is a compound of Formula (IV) wherein r is 3.
  • r is 3.
  • the FXR modulator is a compound of Formula (IV) wherein r is 4. In one embodiment, the FXR modulator is a compound of Formula (IV) wherein each R 32 and R 33 are hydrogen. In one embodiment, the FXR modulator is a compound of Formula (IV) wherein R 34 and R 35 are each independently selected from the group consisting of hydrogen, optionally substituted Ci-C 6 alkyl, optionally substituted C 3 -C 8 cycloalkyl, and optionally substituted C 2 -Cciheterocycloalkyl.
  • the FXR modulator is a compound of Formula (IV) wherein R 34 and R 35 are each independently selected from the group consisting of hydrogen, Ci-C 6 alkyl, C 3 -C 8 cycloalkyl, and C 2 - Cgheterocycloalkyl.
  • the FXR modulator is a compound of Formula (IV) wherein R 34 and R 35 together with the nitrogen atom to which they are attached form an optionally substituted C 2 -C 9 heterocycloalkyl ring.
  • the FXR modulator is a compound of Formula (IV) wherein R 34 and R 35 together with the nitrogen atom to which they are attached form a pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, or methylpiperazinyl.
  • the FXR modulator is a compound of Formula (IV) wherein R 34 and R 35 together with the nitrogen atom to which they are attached form a morpholinyl.
  • the FXR modulator is a compound of Formula (IV) wherein R 34 and R 35 together with the nitrogen atom to which they are attached form an optionally substituted heteroaryl ring.
  • the FXR modulator is a compound of Formula (IV) wherein R 34 and R 35 together with the nitrogen atom to which they are attached form an imidazolyl, pyrazolyl, or pyrrol yl. [00231] In another embodiment, the FXR modulator is a compound of Formula (IV) wherein R is ?
  • each R 31 is independently halogen, -OH, -CN, -N0 2 , - H 2 , optionally substituted Ci-C 6 alkyl, optionally substituted Ci-C 6 alkoxy, optionally substituted Ci-C 6 alkylamine, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 2 -C 9 heterocycloalkyl, aryl, or heteroaryl.
  • the FXR modulator is a compound of Formula (IV) wherein R 30 is
  • n i s 2 and each R 31 is independently halogen, or optionally substituted Ci-C 6 alkyl.
  • the FXR modulator is a compound of Formula (IV) wherein R 30 is
  • n 2 and each R 31 is halogen.
  • the FXR modulator is a compound of Formula
  • the FXR modulator is a compound of Formula (IV) wherein R 30 is , n is 1 and R 31 is halogen, -OH, -CN, -N0 2 , -NH 2 , optionally substituted Ci-C 6 alkyl, optionally substituted Ci-C 6 alkoxy, optionally substituted Ci-C 6 alkylamine, optionally substituted C 3 - C 8 cycloalkyl, optionally substituted C 2 -Cciheterocycloalkyl, aryl, or heteroaryl.
  • R 30 is , n is 1 and R 31 is halogen, -OH, -CN, -N0 2 , -NH 2 , optionally substituted Ci-C 6 alkyl, optionally substituted Ci-C 6 alkoxy, optionally substituted Ci-C 6 alkylamine, optionally substituted C 3 - C 8 cycloalkyl, optionally substituted C 2 -Cciheterocycloalkyl, ary
  • the FXR modulator is a compound of Formula (IV) wherein R 30 is , n is 1 and R 31 is halogen, or optionally substituted Ci-C 6 alkyl. In another embodiment, the FXR modulator
  • the FXR modulator is a compound of Formula (IV) wherein R 30 is n is 1 and R 31 is halogen.
  • the FXR modulator is a compound of Formula (IV) wherein R 30 is , n is 1 and R 31 is F.
  • the FXR modulator is a compound of Formula (IV) wherein R 30 is
  • the FXR modulator is a compound of Formula (IV) wherein R 30 is
  • the FXR modulator is a compound of Formula (IV) wherein t is 2. In another embodiment, the FXR modulator is a compound of Formula (IV) wherein t is 3. In another embodiment, the FXR modulator is a compound of Formula (IV) wherein t is 4. In one embodiment, the FXR modulator is a compound of Formula (IV) wherein each R 32 and R 33 are hydrogen. In one embodiment, the FXR modulator is a compound of Formula (IV) wherein R 34 and R 35 are each independently selected from the group consisting of hydrogen, optionally substituted Ci-C 6 alkyl, optionally substituted C 3 -C 8 cycloalkyl, and optionally substituted C 2 -C 9 heterocycloalkyl.
  • the FXR modulator is a compound of Formula (IV) wherein R 34 and R 35 are each independently selected from the group consisting of hydrogen, Ci-C 6 alkyl, C 3 -C 8 cycloalkyl, and C 2 - Cgheterocycloalkyl.
  • the FXR modulator is a compound of Formula (IV) wherein R 34 and R 35 together with the nitrogen atom to which they are attached form an optionally substituted C 2 -C 9 heterocycloalkyl ring.
  • the FXR modulator is a compound of Formula (IV) wherein R 34 and R 35 together with the nitrogen atom to which they are attached form a pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, or methylpiperazinyl.
  • the FXR modulator is a compound of Formula (IV) wherein R 34 and R 35 together with the nitrogen atom to which they are attached form a morpholinyl.
  • the FXR modulator is a compound of Formula (IV) wherein R 34 and R 35 together with the nitrogen atom to which they are attached form an optionally substituted heteroaryl ring.
  • the FXR modulator is a compound of Formula (IV) wherein R 34 and R 35 together with the nitrogen atom to which they are attached form an imidazolyl, pyrazolyl, or pyrrol yl.
  • the FXR modulator is a compound of Formula (IV) wherein R 30 is
  • anc j eacn R 3 i is i nc j e p enc i ent iy halogen, -OH, -CN, -N0 2 , - H 2 , optionally substituted Ci-C 6 alkyl, optionally substituted Ci-C 6 alkoxy, optionally substituted Ci-C 6 alkylamine, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 2 -C 9 heterocycloalkyl, aryl, or heteroaryl.
  • the FXR modulator is a compound of Formula (IV) wherein R 30 is
  • n 2 and each R 31 is independently halogen, or optionally substituted Ci-C 6 alkyl.
  • the FXR modulator is a compound of Formula (IV) wherein R 30 is
  • n 2 and each R 31 is halogen.
  • the FXR modulator is a compound of Formula
  • the FXR modulator is a compound of Formula (IV) wherein R 30 is
  • n 1 and R 31 is halogen, -OH, -CN, -N0 2 , -NH 2 , optionally substituted Ci-C 6 alkyl, optionally substituted Ci-C 6 alkoxy, optionally substituted Ci-C 6 alkylamine, optionally substituted C 3 - C 8 cycloalkyl, optionally substituted C 2 -C 9 heterocycloalkyl, aryl, or heteroaryl.
  • R 31 is halogen, -OH, -CN, -N0 2 , -NH 2 , optionally substituted Ci-C 6 alkyl, optionally substituted Ci-C 6 alkoxy, optionally substituted Ci-C 6 alkylamine, optionally substituted C 3 - C 8 cycloalkyl, optionally substituted C 2 -C 9 heterocycloalkyl, aryl, or heteroaryl.
  • the FXR modulator is a compound of Formula (IV) wherein R 30 is R 32 r33 , n is 1 and R 31 is halogen, or optionally substituted Ci-C 6 alkyl. In another embodiment, the FXR modulator
  • the FXR modulator is a compound of Formula (IV) wherein R is , n is 1 and R 31 is F.
  • the FXR modulator is a compound of Formula (IV) wherein R 30 is
  • the FXR modulator is a compound of Formula (IV) wherein R 4 and R 5 are each methyl. In a further embodiment of the aforementioned embodiments, the FXR modulator is a compound of Formula (IV) wherein R 4 and R 5 are each ethyl. In a further embodiment of the aforementioned embodiments, the FXR modulator is a compound of Formula (IV) wherein R 1 is hydrogen. In a further embodiment of the aforementioned embodiments, the FXR modulator is a compound of Formula (IV) wherein R 1 is halogen.
  • the FXR modulator is a compound of Formula (IV) wherein R 1 is optionally substituted Ci-C 6 alkyl. In a further embodiment of the aforementioned embodiments, the FXR modulator is a compound of Formula (IV) wherein R 1 is methyl. In a further embodiment of the aforementioned embodiments, the FXR modulator is a compound of Formula (IV) wherein R 1 is optionally substituted C2-C 6 alkenyl. In a further embodiment of the aforementioned embodiments, the FXR modulator is a compound of Formula (IV) wherein R 1 is optionally substituted C 2 -C 6 alkynyl.
  • the FXR modulator is a compound of Formula (IV) wherein R 1 is -OR 10 and R 10 is hydrogen. In a further embodiment of the aforementioned embodiments, the FXR modulator is a compound of Formula (IV) wherein R 1 is -OR 11 and R 10 is optionally substituted Ci-C 6 alkyl. In a further embodiment of the aforementioned embodiments, the FXR modulator is a compound of Formula (IV) wherein R 1 is -OR 10 and R 10 is methyl. In a further embodiment of the aforementioned embodiments, the FXR modulator is a compound of Formula (IV) wherein R 25 is methyl.
  • the FXR modulator is a compound of Formula (IV) wherein R 25 is ethyl. In a further embodiment of the aforementioned embodiments, the FXR modulator is a compound of Formula (IV) wherein R 25 is isopropyl.
  • the FXR modulator is a compound of Formula (IV) wherein R 9 is selected from the group consisting of hydrogen and optionally substituted Ci-C 6 alkyl.
  • R 9 is selected from the group consisting of hydrogen and optionally substituted Ci-C 6 alkyl.
  • FXR modulator is a compound of Formula (IV) wherein R 9 is hydrogen. In a further embodiment of the aforementioned embodiments, the FXR modulator is a compound of Formula (IV) wherein R 9 is optionally substituted Ci-C 6 alkyl. In a further embodiment of the aforementioned embodiments, the FXR modulator is a compound of Formula (IV) wherein R 9 is unsubstituted Ci-C 6 alkyl. In a further embodiment of the aforementioned embodiments, the FXR modulator is a compound of Formula (IV) wherein R 9 is methyl.
  • the FXR modulator is a compound having the structure of Formula (IVa), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:
  • the FXR modulator is a compound having the structure of Formula (IVb), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:
  • the FXR modulator is a compound of Formula (IVa) or (IVb) wherein R 1 is hydrogen. In some embodiments, the FXR modulator is a compound of Formula (IVa) or (IVb) wherein R 1 is halogen. In some embodiments, the FXR modulator is a compound of Formula (IVa) or (IVb) wherein R 1 is optionally substituted Ci-C 6 alkyl. In some embodiments, the FXR modulator is a compound of Formula (IVa) or (IVb) wherein R 1 is optionally substituted C2-C 6 alkenyl.
  • the FXR modulator is a compound of Formula (IVa) or (IVb) wherein R 1 is optionally substituted C 2 -C 6 alkynyl. In some embodiments, the FXR modulator is a compound of Formula (IVa) or (IVb) wherein R 1 is -OR 10 and R 10 is hydrogen. In some embodiments, the FXR modulator is a compound of Formula (IVa) or (IVb) wherein R 1 is -OR 10 and R 10 is optionally substituted Ci-C 6 alkyl. In some embodiments, the FXR modulator is a compound of Formula (IVa) or (IVb) wherein R 1 is - OR and R is methyl.
  • the FXR modulator is a compound of Formula (IVa) or (IVb) wherein R 25 is methyl. In a further embodiment of the aforementioned embodiments, the FXR modulator is a compound of Formula (IVa) or (IVb) wherein R 25 is ethyl. In a further embodiment of the aforementioned embodiments, the FXR modulator is a compound of Formula (IVa) or (IVb) wherein R 25 is isopropyl.
  • a method of treating a metabolic disorder in an individual in need thereof comprising co-administering to the individual a therapeutically effective amount of: (a) a first agent that is an FXR modulator; and (b) at least one second agent that is a DPP-rV inhibitor, an SGLT2 inhibitor, an ASKl inhibitor, a GLP-1 agonist, or a combination thereof; wherein the FXR modulator is a compound of Formula (V), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:
  • R 1 is selected from the group consisting of hydrogen, halogen, optionally substituted Ci-C 6 alkyl, optionally substituted C2-C 6 alkenyl, optionally substituted C2-C 6 alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted -(Ci- C 2 alkylene)-(C 3 -C 8 cycloalkyl), optionally substituted C 2 -C 9 heterocycloalkyl, optionally substituted - (Ci-C 2 alkylene)-(C 2 -C 9 heterocycloalkyl), optionally substituted -(Ci-C 2 alkylene)-(aryl), optionally substituted -(Ci-C 2 alkylene)-(heteroaryl), -OR 10 , -SR 10 , -N(R U )R 12 , - N(R u )S(0) 2 R 15 ; -
  • R 4 and R 5 are each independently optionally substituted Ci-C 6 alkyl
  • R 9 is selected from the group consisting of hydrogen, optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 - C 8 cycloalkyl, optionally substituted aryl, optionally substituted -(Ci-C 2 alkylene)-(aryl), optionally substituted C 2 -Cciheterocycloalkyl, optionally substituted heteroaiyl, and optionally substituted -(Ci- C 2 alkylene)-(heteroaryl);

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BR112018073460A BR112018073460A2 (pt) 2016-05-25 2017-05-25 terapias combinadas usando moduladores do receptor farnesoide x (fxr)
AU2017270221A AU2017270221A1 (en) 2016-05-25 2017-05-25 Combination therapies with farnesoid X receptor (FXR) modulators
JP2018562106A JP2019517478A (ja) 2016-05-25 2017-05-25 ファルネソイドｘレセプター（ｆｘｒ）モジュレーターとの併用療法
KR1020187037471A KR20190040936A (ko) 2016-05-25 2017-05-25 파르네소이드 x 수용체 (fxr) 조정제와의 조합 요법
US16/303,741 US20200397798A1 (en) 2016-05-25 2017-05-25 Combination therapies with farnesoid x receptor (fxr) modulators
SG11201810290WA SG11201810290WA (en) 2016-05-25 2017-05-25 Combination therapies with farnesoid x receptor (fxr) modulators
CA3025007A CA3025007A1 (en) 2016-05-25 2017-05-25 Combination therapies with farnesoid x receptor (fxr) modulators
RU2018145776A RU2018145776A (ru) 2016-05-25 2017-05-25 Комбинированные терапии модуляторами фарензоидного х-рецептора (fxr)
EP17803627.3A EP3463373A4 (en) 2016-05-25 2017-05-25 COMBINATION THERAPIES WITH FARNESOID-X RECEPTOR (FRX) MODULATORS
MX2018014024A MX2018014024A (es) 2016-05-25 2017-05-25 Terapias de combinación con moduladores del receptor x farnesoide (fxr).
CN201780045766.3A CN109843298A (zh) 2016-05-25 2017-05-25 利用法尼酯x受体(fxr)调节剂的组合疗法
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CN113874356A (zh) * 2019-04-19 2021-12-31 安道麦马克西姆有限公司 取代的吡唑类化合物的制备及其作为邻氨基苯甲酰胺前体的用途
KR102917575B1 (ko) * 2019-04-19 2026-01-23 아다마 마켓심 리미티드 치환된 피라졸의 제조 및 안트라닐아미드 전구체로서의 그의 용도
EP4061357A4 (en) * 2019-11-22 2024-01-10 Avolynt Use of sglt2 inhibitors to treat primary billiary cholangitis
US20220387467A1 (en) * 2019-11-22 2022-12-08 Avolynt Use of sglt2 inhibitors to treat primary billiary cholangitis
CN114929214A (zh) * 2019-11-22 2022-08-19 阿沃林特有限公司 Sglt2抑制剂治疗原发性胆汁性胆管炎的用途
WO2021102251A1 (en) * 2019-11-22 2021-05-27 Avolynt Use of sglt2 inhibitors to treat primary billiary cholangitis
EP4098261A4 (en) * 2020-03-11 2024-02-28 Dong-A ST Co., Ltd. PHARMACEUTICAL COMPOSITION FOR PREVENTING OR TREATING NON-ALCOHOLIC STEATOHEPATITIS
US11478533B2 (en) 2020-04-27 2022-10-25 Novo Nordisk A/S Semaglutide for use in medicine

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