[go: up one dir, main page]

WO2012082947A1 - Compounds and compositions as tgr5 agonists - Google Patents

Compounds and compositions as tgr5 agonists Download PDF

Info

Publication number
WO2012082947A1
WO2012082947A1 PCT/US2011/064983 US2011064983W WO2012082947A1 WO 2012082947 A1 WO2012082947 A1 WO 2012082947A1 US 2011064983 W US2011064983 W US 2011064983W WO 2012082947 A1 WO2012082947 A1 WO 2012082947A1
Authority
WO
WIPO (PCT)
Prior art keywords
pyrazol
phenylpyrrolidin
carbonyl
methyl
fluorophenyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2011/064983
Other languages
French (fr)
Inventor
Wenqi Gao
Thomas Lau
Shifeng Pan
Dean Paul Phillips
Xia Wang
Yang Yang
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
IRM LLC
Original Assignee
IRM LLC
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by IRM LLC filed Critical IRM LLC
Publication of WO2012082947A1 publication Critical patent/WO2012082947A1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the invention relates to compounds, compositions and methods for modulating
  • Bile acids are released from the gallbladder after each meal and subsequently facilitate the digestion of nutrients. A multitude of endocrine, neural, and metabolic signaling pathways are activated upon food intake to coordinate the effective use of the available energy. Bile acids are known to be involved in lipid absorption and cholesterol homeostasis. However, bile acids are also regarded as signaling hormones endowed with paracrine and endocrine functions related to the homeostasis of cholesterol levels, control of lipid and carbohydrate metabolism, and regulation of the immune system. TGR5 (also known as GPBARl or M-BAR) has been identified as the endogenously specific metabo tropic receptor of bile acids.
  • such compounds and the pharmaceutically acceptable salts, pharmaceutically acceptable solvates (e.g. hydrates), the N-oxide derivatives, prodrug derivatives, protected derivatives, enantiomers, racemic mixtures, individual stereoisomers and mixture of stereoisomers thereof, have a structure according to Formula (I):
  • R 1 and R 2 are each independently selected from Ci-Cealkyl, and C2-C 6 alkene, and taken together with the N atom to which they are attached form a 4 to 6 membered heterocycloalkyl ring containing a N heteroatom, a 9 to 14 membered fused bicyclic heterocycloalkyl ring containing a N heteroatom, or a 9 to 14 membered fused bicyclic heteroaryl containing an N heteroatom, wherein such heterocycloalkyl and fused bicyclic heteroaryl are each optionally substituted with 1 to 5 substituents independently selected from halogen, deuterium, C - C 6 alkyl, Ci-Cehaloalkyl, -CN, R 9 , -OR 9 , phenyl, phenoxy, Cioaryl and Ci 4 aryl, wherein such phenyl, phenoxy, Cioaryl and Ci 4 aryl are each optionally substituted with 1 to 5 substituents independently selected from halogen
  • Ci-Cealkylene ,arylene and heteroarylene of L2 are optionally substituted with 1 to 3 substituents independently selected from deuterium, R 9 and -C(0)OR 9 ;
  • Ci-C 6 alkylene optionally substituted with 1 to 3 substituents independently selected deuterium, R 9 and -C(0)OR 9 , or Ci-Cealkenylene optionally substituted with 1 to 3 substituents independently selected from deuterium, R 9 and -C(0)OR 9 ;
  • U is selected from a -NR 9 -, -NR 9 C(0)0-, -NR 9 (CH 2 ) q -, -C(0)NR 9 -, -S(0) 2 -, -0-, C Cealkylene, phenylene, Cioarylene, Ci 4 arylene, a 5, 6, 9, 10 or 14 membered heteroarylene containing 1 to 2 heteroatoms independently selected from N, O and S, wherein the Ci-Cealkylene, arylene and heteroarylene of L 4 are optionally substituted with 1 to 3 substituents independently selected from deuterium, R 9 and -C(0)OR 9 ;
  • R 3 is selected from Ci-Cealkyl, Ci-Cehaloalkyl, C 3 -C 8 cycloalkyl, -L 3 R 6 , phenyl, Cioaryl, C] 4 aryl, a 5, 6, 9, 10 or 14 membered heteroaryl containing 1 to 3 N heteroatoms and optionally one heteroatom selected from O and S, and a 4 to 7 membered heterocycloalkyl ring containing 1 to 2 heteroatoms independently selected from N, O and S, wherein the Ci-Cealkyl, aryl, heterocycloalkyl, C 3 - Cscycloalkyl and heteroaryl groups of R 3 are each optionally substituted with 1 to 3 substituents independently selected from halogen, R 9 , R 6 , -OR 9 , -N(R 9 ) 2 , - C(0)N(R 9 ) 2 , -C(0)NR 9 OH, -C(0)OR 9 , -C(0)OL 3 R 6
  • R 4 is selected from H, Ci-Cealkyl, phenyl, Cioaryl, Ci 4 aryl, C 3 -Cscycloalkyl, 5-6 membered heteroaryl containing one or more N heteroatoms, wherein the Cr C 6 alkyl, aryl, heteroaryl and C 3 -Cscycloalkyl groups of R 4 are each optionally substituted with 1 to 3 substituents independently selected from halogen, -CN, R 9 , and -OR 9 ;
  • R 5 is H, Ci-C 6 alkyl or C C 6 haloalkyl.
  • R 6 is C 3 -C 8 cycloalkyl, phenyl, Cioaryl, Ci 4 aryl, a 5, 6, 9, 10 or 14 membered
  • heteroaryl containing 1 to 2 heteroatoms independently selected from N, O and S, a 4 to 7 membered heterocycloalkyl ring containing 1 to 2 heteroatoms independently selected from N, O and S, and a 9 to 14 membered fused bicyclic heterocycloalkyl ring containing containing 1 to 2 heteroatoms independently selected from N, O and S, each of which is optionally substituted with 1 to 5 substituents independently selected from halogen, deuterium, R 9 , -OR 9 , -CN and - C(0)OR 9 ;
  • R 9 is H, Ci-C 6 alkyl optionally substituted with 1 to 4 -OH groups or Ci-Cehaloalkyl;
  • R 11 is H or Ci-C 6 alkyl;
  • R 12 is Ci-C 4 alkyl, -CH 2 C(0)OH or -(CHR 13 )C(0)OH;
  • R 13 is H or Ci-C 4 alkyl
  • each m is independently 1 , 2 or 3 ;
  • each n is independently 1, 2 or 3, and
  • each q is independently 1, 2, 3, 4, 5, or 6.
  • such the compounds of Formula (I) are compounds having the structure of Formula (II):
  • R 10 and R 20 are each independently selected from H, -OR 9 , deuterium or halogen;
  • R 30 is selected from phenyl, phenoxy, Cioaryl and Ci 4 aryl, each of which is optionally substituted with 1 to 5 substituents independently selected from halogen, deuterium and -OR 9 ;
  • R 40 is selected from H, deuterium, Ci-Cealkyl and Ci-Cehaloalkyl;
  • each R 50 is independently selected from H or deuterium
  • L 2 is selected from -C(0)-, -C(0)0-, -(CH 2 ) q C(0)0-, -S(0) 2 - C C 6 alkylene, phenylene, Cioarylene, C ⁇ arylene, a 5, 6, 9, 10 or 14 membered heteroarylene containing 1 to 2 heteroatoms independently selected from N, O and S, or a bond, wherein the Ci-Cealkylene ,arylene and heteroarylene of L 2 are optionally substituted with 1 to 3 substituents independently selected from deuterium, R 9 and -C(0)OR 9 ;
  • L 3 is C]-C 6 alkylene optionally substituted with 1 to 3 substituents independently
  • U is selected from a -NR 9 -, -NR 9 C(0)0-, -NR 9 (CH 2 ) q -, -C(0)NR 9 -, -S(0) 2 -, -0-, C C 6 alkylene, phenylene, Cioarylene, C ⁇ arylene, a 5, 6, 9, 10 or 14 membered heteroarylene containing 1 to 2 heteroatoms independently selected from N, O and S, wherein the Ci-Cealkylene, arylene and heteroarylene of L 4 are optionally substituted with 1 to 3 substituents independently selected from deuterium, R 9 and -C(0)OR 9 ;
  • R 3 is selected from Ci-Cealkyl, Ci-Cehaloalkyl, C3-Cscycloalkyl, -L 3 R 6 , phenyl, Cioaryl, Ci 4 aryl, a 5, 6, 9, 10 or 14 membered heteroaryl containing 1 to 3 N heteroatoms and optionally one heteroatom selected from O and S, and a 4 to 7 membered heterocycloalkyl ring containing 1 to 2 heteroatoms independently selected from N, O and S, wherein the Ci-Cealkyl, aryl, heterocycloalkyl, C3- Cscycloalkyl and heteroaryl groups of R 3 are each optionally substituted with 1 to 3 substituents independently selected from halogen, R 9 , R 6 , -OR 9 , -N(R 9 ) 2 , - C(0)N(R 9 ) 2 , -C(0)NR 9 OH, -C(0)OR 9 , -C(0)OL 3 R 6 , -
  • heteroatoms and optionally one heteroatom selected from O and S;
  • R 4 is selected from H, Ci-Cealkyl, phenyl, Cioaryl, Ci 4 aryl, C 3 -Cscycloalkyl, 5-6 membered heteroaryl containing one or more N heteroatoms, wherein the Cr C 6 alkyl, aryl, heteroaryl and C 3 -Cscycloalkyl groups of R 4 are each optionally substituted with 1 to 3 substituents independently selected from halogen, -CN, R 9 , and -OR 9 ;
  • R 5 is H, Ci-C 6 alkyl or C C 6 haloalkyl.
  • R 6 is C 3 -C 8 cycloalkyl, phenyl, Cioaryl, Ci 4 aryl, a 5, 6, 9, 10 or 14 membered
  • heteroaryl containing 1 to 2 heteroatoms independently selected from N, O and S, a 4 to 7 membered heterocycloalkyl ring containing 1 to 2 heteroatoms independently selected from N, O and S, and a 9 to 14 membered fused bicyclic heterocycloalkyl ring containing containing 1 to 2 heteroatoms independently selected from N, O and S, each of which is optionally substituted with 1 to 5 substituents independently selected from halogen, deuterium, R 9 , -OR 9 , -CN and - C(0)OR 9 ;
  • R 9 is H, Ci-C 6 alkyl optionally substituted with 1 to 4 -OH groups or Ci-Cehaloalkyl;
  • R 11 is H or Ci-C 6 alkyl;
  • R 12 is Ci-C 4 alkyl, -CH 2 C(0)OH or -(CHR 13 )C(0)OH;
  • R 13 is H or C C 4 alkyl
  • each m is independently 1, 2 or 3;
  • each n is independently 1, 2 or 3, and
  • each q is independently 1, 2, 3, 4, 5, or 6.
  • compounds of Formula (I) are compounds having the structure of Formula (III), Formula (IV) or Formula (V):
  • R 1 and R 2 are each independently selected from Ci-Cealkyl and C 2 - C 6 alkene, and taken together with the N atom to which they are attached form a 1,2,3,4- tetrahydroisoquinoline or an azetidine, each of which is optionally substituted with 1 to 3 substituents independently selected from halogen, deuterium, -CN, R 9 , -OR 9 , phenyl and phenoxy, wherein such phenyl and phenoxy are each optionally substituted with 1 to 5 substituents independently selected from halogen, deuterium and -OR 9 .
  • compounds of Formula (I) or Formula (II) are compou
  • R 10 and R 20 are each independently selected from H, deuterium or F.
  • R 40 is selected from H, deuterium, -CH 3 - CF 3 and -CF 2 CH 3 .
  • R 30 is selected from phenyl, phenoxy, Cioaryl and Ci 4 aryl, each of which is optionally substituted with 1 to 5 substituents independently selected from F, deuterium and methoxy.
  • R 4 is selected from H, methyl, ethyl, propyl, butyl, phenyl, pyridinyl, pyrimidinyl, and cyclohexyl, each of which is optionally substituted with 1 to 3 substituents independently selected from -F, -Br, - CI, -CN, R 9 , and -OR 9 .
  • R 3 is selected from -CH 3 , -CH(CH 3 ) 2 , -C(CH 3 ) 3 , -CH 2 C(CH 3 ) 3 , - CH 2 CH 2 C(CH 3 ) 3 , -CF 3 , cyclopropyl, cyclohexyl, phenyl, tetrahydro-2H-pyranyl, oxazolyl, oxadiazolyl, pyrazolyl, isoxazolyl, 1H- benzo[d][l,2,3]triazolyl, piperidinyl, pyridinyl, pyrimidinyl, benzthiazolyl and tetrazolyl, each of which is each optionally substituted with 1 to 3 substituents independently selected from -F, -Br, -CI, R 9 , -OR 9 , -N(R 9 ) 2
  • R 9 is H, methyl, ethyl, -CH(CH 3 ) 2 , -C(CH 3 ) 3 , -CF 3 , propyl substituted with 1 to 2 -OH groups.
  • R 5 is H or methyl.
  • R 12 is methyl, ethyl or n-propyl.
  • R 13 is H or methyl
  • compositions comprising a therapeutically effective amount of a compound of any of the aforementioned compounds of Formulas (I)-(VIII), and a pharmaceutically acceptable excipient.
  • kits for treating a TGR5 mediated disease or disorder wherein the medicament comprises a therapeutically effective amount of any of the aforementioned compounds of Formulas (I)-(VIII).
  • the TGR5 mediated disease or disorder is selected from diabetes, an inflammatory disorders and an autoimmune disease.
  • the TGR5 mediated disease or disorder is type II diabetes or psoriasis.
  • Another aspect provided herein is the use of a compound of Formulas (I)-(VIII) in the manufacture of a medicament for treating a TGR5 mediated disease or disorder, wherein the disease or disorder is selected from diabetes, an inflammatory disorders and an autoimmune disease.
  • the TGR5 mediated disease or disorder is type II diabetes or psoriasis.
  • TGR5 mediated disease or disorder comprising administering to a subject in need thereof, a therapeutically effective amount of any of the aforementioned compounds of Formulas (I)-(VIII).
  • the TGR5 mediated disease or disorder is selected from diabetes, an inflammatory disorders and an autoimmune disease.
  • the TGR5 mediated disease or disorder is type II diabetes or psoriasis.
  • the compound is an agonist of TGR5.
  • Another aspect provided herein is a compound for use in a method of medical treatment, wherein the method of medical treatment is for treating a TGR5 mediated disease or disorder, wherein the disease is selected from diabetes, an inflammatory disorders and an autoimmune disease, and wherein the compound is any of the aforementioned compounds of Formulas (I)-(VIII), or pharmaceutically acceptable salt thereof.
  • the TGR5 mediated disease or disorder is type II diabetes or psoriasis.
  • alkene or "alkenyl”, as used herein, refers to a partially unsaturated branched or straight chain hydrocarbon having at least one carbon-carbon double bond. Atoms oriented about the double bond are in either the cis (Z) or trans (E) conformation.
  • C 2 -C 4 alkenyl refers to an alkenyl group containing at least 2, and at most 4, 5, 6, 7 or 8 carbon atoms, respectively.
  • alkenyl groups include ethenyl, propenyl, allyl (2-propenyl), butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl and the like. In certain embodiments an alkene or alkenyl group is optionally substituted.
  • alkenylene refers to a saturated branched or straight chain divalent hydrocarbon radical derived from an alkenyl group. In certain embodiments an alkenylene group is optionally substituted.
  • C 2 -C3 alkenylene refers to an alkenylene group containing at least 2, and at most 3, 4, 5, 6, 7 or 8 carbon atoms respectively.
  • Non-limiting examples of alkenylene groups as used herein include, ethenlene, n-propenylene, isopropenylene, n-butenylene, isobutenylene, sec- butenylene, t-butenylene, n-pentenylene, isopentenylene, hexenylene and the like.
  • alkyl refers to a saturated branched or straight chain hydrocarbon. An alkyl group can be optionally substituted.
  • Q- C 3 alkyl refers to an alkyl group containing at least 1, and at most 3, 4, 5, 6, 7 or 8 carbon atoms, respectively.
  • Non- limiting examples of alkyl groups as used herein include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, hexyl, heptyl, octyl, nonyl, decyl and the like.
  • an alkyl group is optionally substituted.
  • alkylene refers to a saturated branched or straight chain divalent hydrocarbon radical derived from an alkyl group. In certain embodiments the alkylene group is optionally substituted.
  • Ci-C 3 alkylene, “Cr C 4 alkylene”, “C C 5 alkylene”, “C C 6 alkylene”, “C C 7 alkylene” and “C C 8 alkylene” refer to an alkylene group containing at least 1, and at most 3, 4, 5, 6, 7 or 8 carbon atoms respectively.
  • Non-limiting examples of alkylene groups as used herein include, methylene, ethylene, n-propylene, isopropylene, n-butylene, isobutylene, sec-butylene, t-butylene, n- pentylene, isopentylene, hexylene and the like.
  • alkyne or “alkynyl”, as used herein, refers to a partially unsaturated branched or straight chain hydrocarbon radical having at least one carbon-carbon triple bond.
  • C 2 -C 4 alkynyl refers to an alkynyl group containing at least 2, and at most 4, 5, 6, 7 or 8 carbon atoms, respectively.
  • alkynyl groups include ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl and the like.
  • the alkyne or alkynyl group is optionally substituted.
  • alkynylene refers to a saturated branched or straight chain divalent hydrocarbon radical derived from an alkynyl group. In certain embodiments the alkynylene group is optionally substituted.
  • C 2 -C 3 alkynylene refers to an alkynylene group containing at least 2, and at most 3, 4, 5, 6, 7 or 8 carbon atoms respectively.
  • alkenylene groups include, ethynlene, propynylene, butynylene, pentynylene, hexynylene and the like.
  • alkoxy refers to the group -OR a , where R a is an alkyl group as defined herein. In certain embodiments the alkoxy group is optionally substituted.
  • C C 3 alkoxy refers to an alkoxy group wherein the alkyl moiety contains at least 1, and at most 3, 4, 5, 6, 7 or 8, carbon atoms.
  • Non-limiting examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butyloxy, t- butyloxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, nonyloxy, decyloxy and the like.
  • Cioaryl refers to naphthenyl or azulenyl, each of which is optionally substituted.
  • C] 4 aryl refers to anthracenyl or phenanthrenyl, each of which is optionally substituted.
  • arylene means a divalent radical derived from a phenyl, Cioaryl or a Ci 4 aryl group. In certain embodiments the arylene group is optionally substituted.
  • cyano refers to a -CN group.
  • cycloalkyl refers to a saturated, monocyclic, fused bicyclic, fused tricyclic or bridged polycyclic ring assembly.
  • C 3 - C 5 cycloalkyl refers to a saturated, monocyclic, fused bicyclic, fused tricyclic or bridged polycyclic ring assembly.
  • C 3 -C 5 cycloalkyl refers to a saturated, monocyclic, fused bicyclic, fused tricyclic or bridged polycyclic ring assembly.
  • C 3 - C 5 cycloalkyl refers to a saturated, monocyclic, fused bicyclic or bridged polycyclic ring assembly contain at least 3, and at most 5, 6, 7, 8, 9 or 10, carbon atoms.
  • cycloalkyl group is optionally substituted.
  • cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl,
  • cycloalkylene as used means a divalent radical derived from a cycloalkyl group. In certain embodiments the cycloalkylene group is optionally substituted.
  • halogen refers to fluorine (F), chlorine (CI), bromine (Br), or iodine (I).
  • halo refers to the halogen radicals: fluoro (-F), chloro (-C1), bromo (-Br), and iodo (-1).
  • haloalkyl or “halo-substituted alkyl,” as used herein, refers to an alkyl group as defined herein, substituted with one or more halogen groups, wherein the halogen groups are the same or different. In certain embodiments the haloalkyl group is optionally substituted.
  • Non- limiting examples of such branched or straight chained haloalkyl groups include methyl, ethyl, propyl, isopropyl, isobutyl and n-butyl substituted with one or more halogen groups, wherein the halogen groups are the same or different, including, but not limited to, trifluoromethyl, pentafluoroethyl, and the like.
  • haloalkenyl or “halo-substituted alkenyl,” as used herein, refers to an alkenyl group as defined herein, substituted with one or more halogen groups, wherein the halogen groups are the same or different. In certain embodiments the haloalkenyl group is optionally substituted.
  • Non-limiting examples of such branched or straight chained haloalkenyl groups include ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl and the like substituted with one or more halogen groups, wherein the halogen groups are the same or different.
  • haloalkynyl or “halo-substituted alkynyl,” as used herein, refers to an alkynyl group as defined above, substituted with one or more halogen groups, wherein the halogen groups are the same or different. In certain embodiments the haloalkynyl group is optionally substituted.
  • Non-limiting examples of such branched or straight chained haloalkynyl groups include ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl, and the like substituted with one or more halogen groups, wherein the halogen groups are the same or different.
  • haloalkoxy or "halo-substituted-alkoxy,” as used herein, refers to an alkoxy group as defined herein, substituted with one or more halogen groups, wherein the halogen groups are the same or different. In certain embodiments the haloalkoxy group is optionally substituted.
  • Non-limiting examples of such branched or straight chained haloalkynyl groups include methoxy, ethoxy, n-propoxy, isopropoxy, n- butyloxy, t-butyloxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, nonyloxy, decyloxy and the like, substituted with one or more halogen groups, wherein the halogen groups are the same or different.
  • heteroalkyl refers to an alkyl group as defined herein wherein one or more carbon atoms are independently replaced by one or more of oxygen, sulfur, nitrogen, or combinations thereof.
  • heteroaryl refers to monocyclic, fused bicyclic, and fused tricyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic, at least one ring in the system contains one or more heteroatoms selected from nitrogen, oxygen and sulfur, and wherein each ring in the system contains 3 to 7 ring members.
  • a heteroaryl group may contain one or more substituents. In certain embodiments the heteroaryl group is optionally substituted.
  • heteroaryl groups include benzofuranyl, benzofurazanyl, benzoxazolyl, benzopyranyl, benzthiazolyl, benzothienyl, benzazepinyl, benzimidazolyl, benzothiopyranyl, benzo[l,3]dioxole, benzo[b]furyl, benzo[b]thienyl, cinnolinyl, furazanyl, furyl, furopyridinyl, imidazolyl, indolyl, indolizinyl, indolin-2-one, indazolyl, isoindolyl, isoquinolinyl, isoxazolyl, isothiazolyl, 1,8-naphthyridinyl, oxazolyl, oxaindolyl, oxadiazolyl, pyrazolyl, pyrrolyl, phthal
  • heteroarylene as used means a divalent radical derived from a heteroaryl group. In certain embodiments the heteroarylene group is optionally substituted.
  • the heterocycloalkyl group is optionally substituted.
  • heterocycloalkyl groups include azetidinyl, morpholino, pyrrolidinyl, pyrrolidinyl-2-one, piperazinyl, piperidinyl, piperidinyl-2-one, piperidinyl-3-one, piperidinyl-4-one, l,4-dioxa-8-aza-spiro[4.5]dec-8-yl, 2H-pyrrolyl, 2- pyrrolinyl, 3-pyrrolinyl, 1,3-dioxolanyl, 2-imidazolinyl, imidazolidinyl, 2-pyrazolinyl, pyrazolidinyl, 1,4-dioxanyl, 1 ,4-dithianyl, thiomorpholinyl, azepanyl, hexahydro-1,4- diazepinyl, tetrahydrofuranyl, dihydrofuranyl
  • heterocycloalkylene means a divalent radical derived from a heterocycloalkyl group. In certain embodiments the heterocycloalkylene group is optionally substituted.
  • heteroatom refers to one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon.
  • hydroxyl refers to the group -OH.
  • hydroxyalkyl or hydroxyl-substituted-alkyl
  • hydroxyalkyl refers to an alkyl group as defined herein substituted with one or more hydroxyl group.
  • Non-limiting examples of branched or straight chained "C1-C6 hydroxyalkyl groups as used herein include methyl, ethyl, propyl, isopropyl, isobutyl and n-butyl groups substituted with one or more hydroxyl groups.
  • heterocycloalkyl hydroxyl, alkoxy, mercaptyl, cyano, halo, carbonyl, thiocarbonyl, isocyanato, thiocyanato, isothiocyanato, nitro, perhaloalkyl, perfluoroalkyl, and amino, including mono- and di-substituted amino groups, and the protected derivatives thereof.
  • solvate refers to a complex of variable stoichiometry formed by a solute (by way of example, a compound of Formula (I), or a salt thereof, as described herein) and a solvent.
  • a solvent are water, acetone, methanol, ethanol and acetic acid.
  • administering means providing a compound of Formula (I), a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate, or prodrug thereof to a subject in need of treatment.
  • agent or “test agent,” as used herein, includes any substance, molecule, element, compound, entity, or a combination thereof. It includes, but is not limited to a protein, a polypeptide, a small organic molecule, a polysaccharide, a polynucleotide, and the like. It can be a natural product, a synthetic compound, or a chemical compound, or a combination of two or more substances. Unless otherwise specified, the terms “agent”, “substance”, and “compound” can be used interchangeably.
  • cardiovascular disease refers to diseases affecting the heart or blood vessels or both, including but not limited to: arrhythmia; atherosclerosis and its sequelae; angina; myocardial ischemia; myocardial infarction; cardiac or vascular aneurysm; vasculitis, stroke; peripheral obstructive arteriopathy of a limb, an organ, or a tissue; reperfusion injury following ischemia of the brain, heart or other organ or tissue; endotoxic, surgical, or traumatic shock; hypertension, valvular heart disease, heart failure, abnormal blood pressure; shock; vasoconstriction (including that associated with migraines); vascular abnormality, inflammation, insufficiency limited to a single organ or tissue.
  • carrier refers to chemical compounds or agents that facilitate the incorporation of a compound described herein into cells or tissues.
  • co-administration or “combined administration” or the like as used herein are meant to encompass administration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration or at the same time.
  • contacting has its normal meaning and refers to combining two or more molecules (by way of example only, a small molecule organic compound and a polypeptide) or combining molecules and cells (by way of example only, a compound and a cell).
  • Contacting can occur in-vitro, by way of example only, combining two or more agents or combining a compound and a cell or a cell lysate in a test tube or other container.
  • Contacting can also occur in a cell or in-situ, by way of example only, contacting two polypeptides in a cell by coexpression in the cell of recombinant polynucleotides encoding the two polypeptides, or in a cell lysate. Contacting can occur in-vivo.
  • dilute a compound described herein prior to delivery refers to chemical compounds that are used to dilute a compound described herein prior to delivery. Diluents can also be used to stabilize compounds described herein.
  • an “effective amount” or “therapeutically effective amount,” as used herein, refer to a sufficient amount of a compound described herein being administered which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result can be reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system.
  • an “effective amount” for therapeutic uses is the amount of the composition comprising a compound as disclosed herein required to provide a clinically significant decrease in disease symptoms.
  • An appropriate "effective" amount in any individual case may be determined using techniques, such as a dose escalation study.
  • the terms “enhance” or “enhancing,” as used herein, means to increase or prolong either in potency or duration a desired effect.
  • the term “enhancing” refers to the ability to increase or prolong, either in potency or duration, the effect of other therapeutic agents on a system.
  • An “enhancing- effective amount,” as used herein, refers to an amount adequate to enhance the effect of another therapeutic agent in a desired system.
  • iatrogenic means a condition, disorder, or disease created or worsened by medical or surgical therapy.
  • inflammatory disorders refers to those diseases or conditions that are characterized by one or more of the signs of pain (dolor, from the generation of noxious substances and the stimulation of nerves), heat (calor, from
  • vasodilatation redness (rubor, from vasodilatation and increased blood flow), swelling (tumor, from excessive inflow or restricted outflow of fluid), and loss of function (functio laesa, which may be partial or complete, temporary or permanent).
  • Inflammation takes many forms and includes, but is not limited to, inflammation that is one or more of the following: acute, adhesive, atrophic, catarrhal, chronic, cirrhotic, diffuse, disseminated, exudative, fibrinous, fibrosing, focal, granulomatous, hyperplastic, hypertrophic, interstitial, metastatic, necrotic, obliterative, parenchymatous, plastic, productive, proliferous, pseudomembranous, purulent, sclerosing, seroplastic, serous, simple, specific, subacute, suppurative, toxic, traumatic, and/or ulcerative.
  • Inflammatory disorders further include, without being limited to those affecting the blood vessels (polyarteritis, temporarl arteritis); joints (arthritis:
  • compositions in which it is contained.
  • pharmaceutically acceptable refers a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compounds described herein. Such materials are administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.
  • pharmaceutically acceptable salt refers to a formulation of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compounds described herein.
  • prevent refers to a complete inhibition of development of primary or secondary tumors or any secondary effects of disease.
  • the terms “combination” or “pharmaceutical combination,” as used herein mean 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.
  • the term “fixed combination” means that the active ingredients, by way of example, a compound of Formula (I) and an additional therapeutic agent, are both administered to a patient simultaneously in the form of a single entity or dosage.
  • the term “non-fixed combination” means that the active ingredients, by way of example, a compound of Formula (I) and an additional therapeutic agent, are both administered to a patient as separate entities either
  • composition refers to a mixture of at least one compound of Formula (I) described herein with other chemical components, such as carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and/or excipients.
  • prodrug refers to an agent that is converted into the parent drug in vivo.
  • a non-limiting example of a prodrug of the compounds described herein is a compound described herein administered as an ester which is then metabolically hydrolyzed to a carboxylic acid, the active entity, once inside the cell.
  • a further example of a prodrug is a short peptide bonded to an acid group where the peptide is metabolized to reveal the active moiety.
  • subject includes mammals, especially humans. It also encompasses other non-human animals such as cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys.
  • terapéuticaally effective amount refers to any amount of a compound which, as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder.
  • the term also includes within its scope amounts effective to enhance normal physiological function.
  • treat refers to methods of alleviating, abating or ameliorating a disease or condition symptoms, preventing additional symptoms, ameliorating or preventing or delaying the underlying metabolic causes of symptoms, inhibiting the disease or condition, arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition either prophylactically (prevent or delay the onset of the disease, or to prevent the manifestation of clinical or subclinical symptoms thereof) and/or therapeutically.
  • TGR5 mediated diseases or disorders include, but are not limited to, gallstones, cholestasis, diabetes, an inflammatory disorders and an autoimmune disease, such as, by way of example only, type II diabetes or psoriasis.
  • autoimmune diseases and/or disorders and autoimmune -mediated diseases and/or disorders include, but are not limited to, destructive arthritis, rheumatoid arthritis, systemic lupus erythematosus, Sjogren's syndrome, multiple sclerosis, dermatomyositis, progressive systemic sclerosis, diseases affecting the nose including allergic rhinitis, and inflammatory disease in which autoimmune reactions are implicated or having an
  • autoimmune component or aetiology including autoimmune haematological disorders (e.g. haemolytic anaemia, aplastic anaemia, pure red cell anaemia and idiopathic
  • thrombocytopenia primary binary cirrhosis (PBC)
  • PBC primary binary cirrhosis
  • lupus systemic lupus erythematosus, polychondritis, sclerodoma, Wegener granulamatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Steven-Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel disease (e.g.
  • ulcerative colitis and Crohn's disease endocrine opthalmopathy
  • Grave's disease sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary billiary cirrhosis, uveitis (anterior and posterior), keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitial lung fibrosis, psoriatic arthritis and glomerulonephritis (with and without nephrotic syndrome, e.g. including idiopathic nephrotic syndrome or minimal change nephropathy).
  • Such inflammatory diseases and/or disorders include, but are not limited to, uveitis, atherosclerosis, atherogenesis, glomerulonephritis, Kawasaki disease, inflammatory responses, polymyositis, arthritis, neurological inflammation, chronic arthritis inflammation and osteoarthritis.
  • R 1 and R 2 are each independently selected from Ci-Cealkyl, and C2-C 6 alkene, and taken together with the N atom to which they are attached form a 4 to 6 membered heterocycloalkyl ring containing a N heteroatom, a 9 to 14 membered fused bicyclic heterocycloalkyl ring containing a N heteroatom, or a 9 to 14 membered fused bicyclic heteroaryl containing an N heteroatom, wherein such heterocycloalkyl and fused bicyclic heteroaryl are each optionally substituted with 1 to 5 substituents independently selected from halogen, deuterium, C - C 6 alkyl, Ci-Cehaloalkyl, -CN, R 9 , -OR 9 , phenyl, phenoxy, Cioaryl and Ci 4 aryl, wherein such phenyl, phenoxy, Cioaryl and Ci 4 aryl are each optionally substituted with 1 to 5 substituents independently selected from
  • Ci-Cealkylene ,arylene and heteroarylene of L2 are optionally substituted with 1 to 3 substituents independently selected from deuterium, R 9 and -C(0)OR 9 ;
  • Ci-C 6 alkylene optionally substituted with 1 to 3 substituents independently selected deuterium, R 9 and -C(0)OR 9 , or Ci-Cealkenylene optionally substituted with 1 to 3 substituents independently selected from deuterium, R 9 and -C(0)OR 9 ;
  • U is selected from a -NR 9 -, -NR 9 C(0)0-, -NR 9 (CH 2 ) q -, -C(0)NR 9 -, -S(0) 2 -, -0-, C Cealkylene, phenylene, Cioarylene, Ci 4 arylene, a 5, 6, 9, 10 or 14 membered heteroarylene containing 1 to 2 heteroatoms independently selected from N, O and S, wherein the Ci-Cealkylene, arylene and heteroarylene of L 4 are optionally substituted with 1 to 3 substituents independently selected from deuterium, R 9 and -C(0)OR 9 ;
  • R 3 is selected from Ci-Cealkyl, Ci-Cehaloalkyl, C 3 -C 8 cycloalkyl, -L 3 R 6 , phenyl, Cioaryl, C] 4 aryl, a 5, 6, 9, 10 or 14 membered heteroaryl containing 1 to 3 N heteroatoms and optionally one heteroatom selected from O and S, and a 4 to 7 membered heterocycloalkyl ring containing 1 to 2 heteroatoms independently selected from N, O and S, wherein the Ci-Cealkyl, aryl, heterocycloalkyl, C 3 - Cscycloalkyl and heteroaryl groups of R 3 are each optionally substituted with 1 to 3 substituents independently selected from halogen, R 9 , R 6 , -OR 9 , -N(R 9 ) 2 , - C(0)N(R 9 ) 2 , -C(0)NR 9 OH, -C(0)OR 9 , -C(0)OL 3 R 6
  • R 4 is selected from H, Ci-Cealkyl, phenyl, Cioaryl, Ci 4 aryl, C 3 -Cscycloalkyl, 5-6 membered heteroaryl containing one or more N heteroatoms, wherein the Cr C 6 alkyl, aryl, heteroaryl and C 3 -Cscycloalkyl groups of R 4 are each optionally substituted with 1 to 3 substituents independently selected from halogen, -CN, R 9 , and -OR 9 ;
  • R 5 is H, Ci-C 6 alkyl or C C 6 haloalkyl.
  • R 6 is C 3 -C 8 cycloalkyl, phenyl, Cioaryl, Ci 4 aryl, a 5, 6, 9, 10 or 14 membered
  • heteroaryl containing 1 to 2 heteroatoms independently selected from N, O and S, a 4 to 7 membered heterocycloalkyl ring containing 1 to 2 heteroatoms independently selected from N, O and S, and a 9 to 14 membered fused bicyclic heterocycloalkyl ring containing containing 1 to 2 heteroatoms independently selected from N, O and S, each of which is optionally substituted with 1 to 5 substituents independently selected from halogen, deuterium, R 9 , -OR 9 , -CN and - C(0)OR 9 ;
  • R 9 is H, Ci-C 6 alkyl optionally substituted with 1 to 4 -OH groups or Ci-Cehaloalkyl;
  • R 11 is H or Ci-C 6 alkyl;
  • R 12 is Ci-C 4 alkyl, -CH 2 C(0)OH or -(CHR 13 )C(0)OH;
  • R 13 is H or Ci-C 4 alkyl
  • each m is independently 1 , 2 or 3 ;
  • each n is independently 1, 2 or 3, and
  • each q is independently 1, 2, 3, 4, 5, or 6.
  • such the compounds of Formula (I) are compounds having the structure of Formula (II):
  • R 10 and R 20 are each independently selected from H, -OR 9 , deuterium or halogen;
  • R 30 is selected from phenyl, phenoxy, Cioaryl and Ci 4 aryl, each of which is optionally substituted with 1 to 5 substituents independently selected from halogen, deuterium and -OR 9 ;
  • R 40 is selected from H, deuterium, Ci-Cealkyl and Ci-Cehaloalkyl;
  • each R 50 is independently selected from H or deuterium
  • L 2 is selected from -C(0)-, -C(0)0-, -(CH 2 ) q C(0)0-, -S(0) 2 - C C 6 alkylene, phenylene, Cioarylene, C ⁇ arylene, a 5, 6, 9, 10 or 14 membered heteroarylene containing 1 to 2 heteroatoms independently selected from N, O and S, or a bond, wherein the Ci-Cealkylene ,arylene and heteroarylene of L 2 are optionally substituted with 1 to 3 substituents independently selected from deuterium, R 9 and -C(0)OR 9 ;
  • L 3 is C]-C 6 alkylene optionally substituted with 1 to 3 substituents independently
  • U is selected from a -NR 9 -, -NR 9 C(0)0-, -NR 9 (CH 2 ) q -, -C(0)NR 9 -, -S(0) 2 -, -0-, C C 6 alkylene, phenylene, Cioarylene, C ⁇ arylene, a 5, 6, 9, 10 or 14 membered heteroarylene containing 1 to 2 heteroatoms independently selected from N, O and S, wherein the Ci-Cealkylene, arylene and heteroarylene of L 4 are optionally substituted with 1 to 3 substituents independently selected from deuterium, R 9 and -C(0)OR 9 ;
  • R 3 is selected from Ci-Cealkyl, Ci-Cehaloalkyl, C3-Cscycloalkyl, -L 3 R 6 , phenyl, Cioaryl, Ci 4 aryl, a 5, 6, 9, 10 or 14 membered heteroaryl containing 1 to 3 N heteroatoms and optionally one heteroatom selected from O and S, and a 4 to 7 membered heterocycloalkyl ring containing 1 to 2 heteroatoms independently selected from N, O and S, wherein the Ci-Cealkyl, aryl, heterocycloalkyl, C3- Cscycloalkyl and heteroaryl groups of R 3 are each optionally substituted with 1 to 3 substituents independently selected from halogen, R 9 , R 6 , -OR 9 , -N(R 9 ) 2 , - C(0)N(R 9 ) 2 , -C(0)NR 9 OH, -C(0)OR 9 , -C(0)OL 3 R 6 , -
  • heteroatoms and optionally one heteroatom selected from O and S;
  • R 4 is selected from H, Ci-Cealkyl, phenyl, Cioaryl, Ci 4 aryl, C 3 -Cscycloalkyl, 5-6 membered heteroaryl containing one or more N heteroatoms, wherein the Cr C 6 alkyl, aryl, heteroaryl and C 3 -Cscycloalkyl groups of R 4 are each optionally substituted with 1 to 3 substituents independently selected from halogen, -CN, R 9 , and -OR 9 ;
  • R 5 is H, Ci-C 6 alkyl or C C 6 haloalkyl.
  • R 6 is C 3 -C 8 cycloalkyl, phenyl, Cioaryl, Ci 4 aryl, a 5, 6, 9, 10 or 14 membered
  • heteroaryl containing 1 to 2 heteroatoms independently selected from N, O and S, a 4 to 7 membered heterocycloalkyl ring containing 1 to 2 heteroatoms independently selected from N, O and S, and a 9 to 14 membered fused bicyclic heterocycloalkyl ring containing containing 1 to 2 heteroatoms independently selected from N, O and S, each of which is optionally substituted with 1 to 5 substituents independently selected from halogen, deuterium, R 9 , -OR 9 , -CN and - C(0)OR 9 ;
  • R 9 is H, Ci-C 6 alkyl optionally substituted with 1 to 4 -OH groups or Ci-Cehaloalkyl;
  • R 11 is H or Ci-C 6 alkyl;
  • R 12 is Ci-C 4 alkyl, -CH 2 C(0)OH or -(CHR 13 )C(0)OH;
  • R 13 is H or C C 4 alkyl
  • each m is independently 1, 2 or 3;
  • each n is independently 1, 2 or 3, and
  • each q is independently 1, 2, 3, 4, 5, or 6.
  • compounds of Formula (I) are compounds having the structure of Formula (III), Formula (IV) or Formula (V):
  • compounds of Formula (I) or Formula (II) are compounds having the structure of Formula (VI), Formula (VII) or Formula (VIII):
  • the compounds of Formulas (I)-(VIII), pharmaceutically acceptable salts, solvates, N-oxides, prodrugs and isomers thereof, and pharmaceutical compositions provided herein also includes all suitable isotopic variations of such compounds, and pharmaceutically acceptable salts, solvates, N-oxides, prodrugs and isomers thereof, and pharmaceutical compositions.
  • An isotopic variation of a compound of the invention or a pharmaceutically acceptable salt thereof is defined as one in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature.
  • isotopes that may be incorporated into the compounds of the invention and pharmaceutically acceptable salts thereof include but are not limited to isotopes of hydrogen, carbon, nitrogen and oxygen such as 2 H, 3 H, n C, 13 C, 14 C, 15 N, 17 0,
  • isotopic variations of the compounds of the invention and pharmaceutically acceptable salts thereof are useful in drug and/or substrate tissue distribution studies.
  • 3 H and 14 C isotopes may be used for their ease of preparation and detectability.
  • substitution with isotopes such as 2 H may afford certain therapeutic advantages resulting from greater metabolic stability, such as increased in-vivo half-life or reduced dosage requirements.
  • Isotopic variations of the compounds, and pharmaceutically acceptable salts, solvates, N-oxides, prodrugs and isomers thereof, and pharmaceutical compositions provided herein are prepared by conventional procedures using appropriate isotopic variations of suitable reagents.
  • the compounds of Formula (I)-(VIII) described herein are prepared as a pharmaceutically acceptable acid addition salt by reacting the free base form of the compound of Formula (I)-(VIII) with a pharmaceutically acceptable organic acid or inorganic acid.
  • a pharmaceutically acceptable base addition salt of compounds of Formula (I)-(VIII) described herein is prepared by reacting the free acid form of the compound of Formula (I)-(VIII) with a pharmaceutically acceptable organic base or inorganic base.
  • the salt forms of the compounds of Formula (I)-(VIII) described herein are prepared using salts of the starting materials or intermediates.
  • the compounds of Formula (I)-(VIII) described herein are in the form of other salts including, but not limited to, oxalates and trifluoroacetates.
  • hemisalts of acids and bases are formed, for example, hemisulphate and hemicalcium salts.
  • Such pharmaceutically acceptable acid addition salts of compounds of Formula (I)-(VIII) include, but are not limited to, a hydrobromide, hydrochloride, hydroiodide, sulfate, bisulphate, nitrate, phosphate, succinate, maleate, formate, acetate, adipate, besylatye, bicarbonate/carbonate, propionate, fumarate, citrate, tartrate, lactate, benzoate, salicylate, glutamate, aspartate, p-toluenesulfonate, benzenesulfonate, methanesulfonate, ethanesulfonate, naphthalenesulfonate (e.g.
  • 2-naphthalenesulfonate hexanoate salt, bisulphate/sulphate, borate, camsylate, cyclamate, edisylate, esylate, gluceptate, gluconate, glucuronate, pyruvate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, orotate, oxalate, oxaloacetate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate, saccharate, stearate, tannate, tosylate, trifluoroacetate and xinofoate salts.
  • organic acid or inorganic acids used to form certain pharmaceutically acceptable acid addition salts of compounds of Formula (I)-(VIII) include, but are not limited to, hydrobromic, hydrochloric, sulfuric, nitric, phosphoric, succinic, maleic, formic, acetic, propionic, fumaric, citric, tartaric, lactic, benzoic, salicylic, glutamic, aspartic, p- toluenesulfonic, benzenesulfonic, methanesulfonic, ethanesulfonic, naphthalenesulfonic such as 2-naphthalenesulfonic, or hexanoic acid.
  • Such pharmaceutically acceptable base addition salt of a compound of Formula (I)-(VIII) include, but are not limited to, aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts.
  • the free acid or free base forms of the compounds of Formula (I)-(VIII) described herein are prepared from the corresponding base addition salt or acid addition salt from, respectively.
  • a compound Formula (I)-(VIII) in an acid addition salt form is converted to the corresponding free base by treating with a suitable base (by way of example only, an ammonium hydroxide solution, a sodium hydroxide, and the like).
  • a compound of Formula (I)-(VIII) in a base addition salt form is converted to the corresponding free acid by treating with a suitable acid (by way of example only, hydrochloric acid).
  • the compounds of Formula (I)-(VIII) described herein in unoxidized form are prepared from N-oxides of compounds Formula (I)-(VIII) by treating with a reducing agent (by way of example only, sulfur, sulfur dioxide, triphenyl phosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, tribromide, or the like) in a suitable inert organic solvent (by way of example only, acetonitrile, ethanol, aqueous dioxane, or the like) at 0 to 80°C.
  • a reducing agent by way of example only, sulfur, sulfur dioxide, triphenyl phosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, tribromide, or the like
  • a suitable inert organic solvent by way of example only, acetonitrile, ethanol, aqueous dioxane, or the like
  • prodrug derivatives of compounds Formula (I)-(VIII) described herein are prepared using methods known to those of ordinary skill in the art (e.g., for further details see Saulnier et al., (1994), Bioorganic and Medicinal Chemistry Letters, Vol. 4, p. 1985).
  • appropriate prodrugs are prepared by reacting a non- derivatized compound of Formula (I)-(VIII) with a suitable carbamylating agent (by way of example only, 1,1-acyloxyalkylcarbanochloridate, para-nitrophenyl carbonate, or the like).
  • the compounds of Formula (I)-(VIII) described herein are prepared as protected derivatives using methods known to those of ordinary skill in the art. A detailed description of the techniques applicable to the creation of protecting groups and their removal can be found in T. W. Greene, "Protecting Groups in Organic Chemistry,” 3 rd edition, John Wiley and Sons, Inc., 1999.
  • the compounds of Formula (I)-(VIII) described herein are prepared or formed, as solvates (e.g., hydrates).
  • hydrates of compounds of Formula (I)-(VIII) are prepared by recrystallization from an aqueous/organic solvent mixture, using organic solvents such as dioxin, tetrahydrofuran or methanol.
  • the compounds of Formula (I)-(VIII) described herein are prepared as their individual stereoisomers.
  • the compounds of Formula (I)-(VIII) described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers and recovering the optically pure enantiomers.
  • resolution of enantiomers is carried out using covalent diastereomeric derivatives of the compounds of Formula (I)-(VIII), or by using dissociable complexes (e.g., crystalline diastereomeric salts).
  • Diastereomers have distinct physical properties (e.g., melting points, boiling points, solubility, reactivity, etc.) and are readily separated by taking advantage of these dissimilarities.
  • the diastereomers are separated by chromatography, or by separation/resolution techniques based upon differences in solubility.
  • the optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that would not result in racemization.
  • a more detailed description of the techniques applicable to the resolution of stereoisomers of compounds from their racemic mixture can be found in Jean Jacques, Andre Collet, Samuel H. Wilen, "Enantiomers, Racemates and Resolutions," John Wiley And Sons, Inc., 1981.
  • Non-limiting examples of synthetic schemes used to make compounds of Formula (I)-(VIII) described herein are illustrated in reaction schemes (I)-(IX), wherein m, n, q, L 1 , 2, L 3 , L 4 , R 1 , R 2 R 3 , R 4 R 5 , R 6 , R 9 , R 10 , R 20 , R 30 , R 40 and R 50 are as defined herein.
  • Reaction scheme (II) illustrates the synthesis of certain embodiments of compounds of Formula (I).
  • Reaction scheme (III) illustrates the synthesis of certain embodiments of compounds of Formula (I).
  • Reaction scheme (IV) illustrates the synthesis of certain embodiments of compounds of Formula (I).
  • Reaction scheme (V) illustrates the synthesis of certain embodiments of compounds of Formula (I).
  • BAs Bile acids
  • Bile acids are known to be involved in lipid absorption and cholesterol homeostasis. However, bile acids are also regarded as signaling hormones endowed with paracrine and endocrine functions related to the homeostasis of cholesterol levels, control of lipid and carbohydrate metabolism, and regulation of the immune system.
  • TGR5 also known as GPBAR1 or M-BAR
  • GPBAR1 or M-BAR has been identified as the endogenously specific metabotropic receptor of bile acids, and the activation of the membrane TGR5 receptor is thought to be the pathway to non-genomic functions of bile acids.
  • TGR5 is a member of the Rhodopsin-like subfamily of G-protein-coupled receptors (GPCR's) that mediates some of the endocrine functions of its bile acid ligands. TGR5 is highly expressed in the adipose tissue and in macrophages. In addition, TGR5 expression levels are high in the gall bladder, the gastrointestinal tract and in immune cells such as dendritic cells and monocytes, and show enrichment in organs like the spleen and lung, intestine (Werner et al. 2004; Kawatama et al. 2003) and in certain areas of the central nervous system.
  • GPCR's G-protein-coupled receptors
  • TGR5 agonists inhibit production of the pro-inflammatory cytokine TNFa and the Thl-driving cytokine IL-12 (but not IL-10) in human DC and monocytes, and in LPS- stimulated whole blood and PBMC.
  • TLCA inhibits IFNy (but not IL-4) production in activated DC/T cell co-cultures and in LPS stimulated human whole blood (Werner et al 2004).
  • IFNy but not IL-4
  • IL-6 IL-6
  • TGR5 ligand TLCA which is produced by intestinal Clostridia, is found in higher levels in children that do not have autoimmune disease (J. Allergy Clin Immunol 2001, 107:29-39).
  • oral bile acid (dehydrocholic acid) treatment was efficacious in more than 80% of psoriasis patients in one study (Pathophysiology 2003, 10:57), and bile acids have been used by traditional Chinese medicine in chronic
  • agonists of TGR5 are expected to be useful in the treatment of autoimmune diseases characterized by Thl pathology helping to redirect the response towards a Th2 phenotype.
  • autoimmune diseases include, but are not limited to, psoriasis.
  • Psoriasis is an autoimmune disease with a prevalence of between 1.5 and 4% in the population, occurring most commonly in Caucasians. Many patients also develop psoriatic arthritis which impacts quality of life even more. With few safe and cost effective treatments available, psoriasis remains an unmet medical need.
  • TGR5 is associated with the intracellular accumulation of cyclic adenosine monophosphate (cAMP), which is widely expressed in diverse cell types.
  • cAMP cyclic adenosine monophosphate
  • the activation of TGR5 in macrophages decreases proinflammatory cytokine production
  • the stimulation of TGR5 by bile acids in adipocytes and myocytes enhances energy expenditure.
  • This control of energy metabolism by TGR5 involves the c-AMP-dependent induction of type 2 iodothyronine deiodinase (D2) enzyme.
  • D2 type 2 iodothyronine deiodinase
  • the up-regulation of D2 depends on the activation the membrane bound TGR5 by bile acids, which then mobilizes cAMP.
  • T 4 prohormone thyroxine
  • T 3 active hormone activity and increased energy expenditure.
  • GLP-1 glucose-dependent gut incretin glucose-like peptide 1
  • TGR5 expression levels are high in the small and large intestine. Mice lacking the TGR5 receptor showed increased weight and body fat when on a high fat diet (WO2006070718).
  • TGR5 agonists cause an increase in the secretion of GLP-1 both in-vitro and in-vivo (EP1591120), and lead to prevention of hyperglycemia and improved glucose tolerance in the GK rat model (WO2007127505).
  • the beneficial action of TGR5 agonists on TNFa levels may also be beneficial in Type II diabetes, where elevated levels contribute to insulin resistance and other pathologies.
  • TGR5 appears to be important in the regulation of nitric oxide production via c-AMP-dependent activation of endothelial nitric oxide synthase (eNOS). This may scavange bile acid induced reactive oxygen species and protect the liver against lipid peroxidation and bile acid-induced injury.
  • eNOS endothelial nitric oxide synthase
  • the number of people in the world with diabetes is estimated to increase 46% between 2000 and 2010 and to double by the year 2025 to approximately 300 million people. The majority of these increases will be type II (non- insulin dependent) diabetes resulting largely from physical inactivity, poor diet, stress and obesity.
  • Type II insulin-resistant diabetes mellitus afflicts an estimated 6% of adults in Western countries.
  • the heterogeneity of the disorder is highlighted by the lack of long-term efficacy of existing therapies in a significant proportion of patients.
  • the high economic and social cost of diabetes emphasizes the need for effective strategies for the prevention and treatment of the disease. Inducing GLP-1 secretion and glucose-stimulated insulin secretion can normalize glucose levels without causing hypoglycemia. Therefore, because TGR5 agonists increase glucose dependent GLP-1 secretion, they are useful in the treatment of Type II Diabetes.
  • TGR5 agonists have the potential for additive/synergistic effects with DPP-4 inhibitors for Type II insulin-resistant diabetes mellitus treatment.
  • the ability of TGR5 agonists to decrease TNFa has a positive impact on the inflammatory component of Type II Diabetes.
  • TGR5 with its ability to enhance incretin levels, is involved in metabolic diseases and energy homeostasis, plus TGR5, with its ability to decrease pro-inflammatory cytokines, is involved in autoimmune diseases and inflammatory disorders. This suggests a role for TGR5 agonists in the treatment of Type II Diabetes, inflammatory disorders and Th-l mediated autoimmune diseases.
  • TGR5 agonists in the treatment of Type II Diabetes, inflammatory disorders and Th-l mediated autoimmune diseases.
  • methods utilizing such compounds and composition to enhance TGR5 activity to treat diseases and/or disorders associated with TGR5 activity include, but are not limited to, diabetes, inflammatory disorders and autoimmune diseases.
  • the compounds, compositions and methods provided herein are used to treat gallstones, cholestasis, Type II Diabetes, psoriasis and Th-1 mediated autoimmune diseases.
  • This methods provided herein are either prophylactic or therapeutic treatment of TGR5-related disorders and/or TGR5-related diseases. Such methods involve administering to a subject in need of treatment a compound of Formula (I)-(VIII), or a pharmaceutical composition that contains a therapeutically effective amount of one or more compounds of Formula (I)-(VIII), wherein such compounds are an agonists of TGR5.
  • prophylactic or therapeutic treatment methods are used to treat diabetes, gallstones, cholestasis, inflammatory disorders and autoimmune diseases, including but not limited to, Type II Diabetes, psoriasis and Th-1 mediated autoimmune diseases.
  • Animal subjects include both domestic animals and livestock, raised either as pets or for commercial purposes. Examples include, but are not limited to, dogs, cats, cattle, horses, sheep, hogs, and goats.
  • such compounds have minimal systemic exposure and are primarily gastrointestinally exposed.
  • the present invention further provides a method for preventing or treating any of the diseases or disorders described herein in a subject in need of such treatment, which method comprises administering to a subject a therapeutically effective amount (See, "Administration and Pharmaceutical Compositions", infra) of a compound of Formula (I)-(VIII) or a pharmaceutically acceptable salt, solvate, N-oxide, prodrug or isomers thereof.
  • a pharmaceutical compositions containing therapeutically effective amount of a compound of Formula (I)-(VIII) or a pharmaceutically acceptable salt, solvate, N-oxide, prodrug, enantiomer or isomers thereof.
  • the required dosage will vary depending on the mode of administration, the particular condition to be treated and the effect desired.
  • compositions which comprise at least one compound of Formulas (I)-(VIII) described herein, pharmaceutically acceptable salts and/or solvates thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.
  • such compounds and compositions are administered singly or in combination with one or more additional therapeutic agents.
  • the method of administration of such compounds and compositions include, but are not limited to, oral administration, rectal administration, parenteral, intravenous administration, intravitreal administration, intramuscular administration, inhalation, intranasal administration, topical administration, ophthalmic administration or otic administration.
  • such compounds of Formula (I)-(VIII) are agonists of TGR5, formulated in an amount sufficient to inhibit production of the pro-inflammatory cytokine TNFa and the Thl-driving cytokine IL-12 both in-vitro and in-vivo.
  • such compounds of Formula (I)-(VIII) are agonists of TGR5, formulated in an amount sufficient to increases thyroid hormone activity and increased energy expenditure both in-vitro and in-vivo.
  • such compounds of Formula (I)-(VIII) are agonists of TGR5, formulated in an amount sufficient to increase the secretion of GLP-1 both in-vitro and in-vivo.
  • the therapeutically effective amount will vary depending on, among others, the disease indicated, the severity of the disease, the age and relative health of the subject, the potency of the compound administered, the mode of administration and the treatment desired.
  • the daily dosage of a compound of Formula (I)-(VIII) satisfactory results are indicated to be obtained systemically at daily dosages of from about 0.03 to 2.5mg/kg per body weight.
  • the daily dosage of a compound of Formula (I)-(VIII), administered by inhalation is in the range from 0.05 micrograms per kilogram body weight ⁇ g/kg) to 100 micrograms per kilogram body weight ⁇ g/kg).
  • the daily dosage of a compound of Formula (I)-(VIII), administered orally is in the range from 0.01 micrograms per kilogram body weight ⁇ g/kg) to 100 milligrams per kilogram body weight (mg/kg).
  • An indicated daily dosage in the larger mammal e.g.
  • unit dosage forms for oral administration comprise from about 1 to 50 mg of a compound of Formula (I)-(VIII).
  • compositions which comprise at least one compound of Formulas (I)-(VIII) described herein, or pharmaceutically acceptable salts and/or solvates thereof.
  • processes include admixing a compound of the Formula (I)-(VIII) described herein, and pharmaceutically acceptable salts and solvates thereof, with one or more pharmaceutically acceptable carriers, diluents or excipients.
  • the pharmaceutical compositions comprising a compound of Formula (I)-(VIII) in free form or in a
  • compositions are manufactured by mixing, granulating and/or coating methods.
  • such compositions are optionally contain excipients, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers.
  • excipients such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers.
  • such compositions are sterilized.
  • the pharmaceutical compositions containing at least one compound of Formula (I)-(VIII) are administered orally as discrete dosage forms, wherein such dosage forms include, but are not limited to, capsules, gelatin capsules, caplets, tablets, chewable tablets, powders, granules, syrups, flavored syrups, solutions or suspensions in aqueous or non-aqueous liquids, edible foams or whips, and oil-in-water liquid emulsions or water-in-oil liquid emulsions.
  • the capsules, gelatin capsules, caplets, tablets, chewable tablets, powders or granules, used for the oral administration of at least one compound of Formula (I)-(VIII) are prepared by admixing at least one compound of Formula (I)-(VIII) (active ingredient) together with at least one excipient using conventional pharmaceutical compounding techniques.
  • excipients used in oral dosage forms described herein include, but are not limited to, binders, fillers, disintegrants, lubricants, absorbents, colorants, flavors, preservatives and sweeteners.
  • Non-limiting examples of such binders include, but are not limited to, corn starch, potato starch, starch paste, pre-gelatinized starch, or other starches, sugars, gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, tragacanth, guar gum, cellulose and its derivatives (by way of example only, ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethylcellulose, methyl cellulose, hydroxypropyl methylcellulose and microcrystalline cellulose), magnesium aluminum silicate, polyvinyl pyrrolidone and combinations thereof.
  • natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, tragacanth, guar gum, cellulose and its derivatives (by way of example only, ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethylcellulose, methyl cellulose, hydroxyprop
  • Non-limiting examples of such fillers include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof.
  • the binder or filler in pharmaceutical compositions provided herein are present in from about 50 to about 99 weight percent of the pharmaceutical composition or dosage form.
  • Non-limiting examples of such disintegrants include, but are not limited to, agar- agar, alginic acid, sodium alginate, calcium carbonate, sodium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, pre-gelatinized starch, other starches, clays, other algins, other celluloses, gums, and combinations thereof.
  • the amount of disintegrant used in the pharmaceutical compositions provided herein is from about 0.5 to about 15 weight percent of disintegrant, while in other embodiments the amount is from about 1 to about 5 weight percent of disintegrant.
  • Non-limiting examples of such lubricants include, but are not limited to, sodium stearate, calcium stearate, magnesium stearate, stearic acid, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, sodium lauryl sulfate, talc, hydrogenated vegetable oil (by way of example only, peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, sodium oleate, ethyl oleate, ethyl laureate, agar, silica, a syloid silica gel (AEROSIL 200, manufactured by W.R.
  • AEROSIL 200 AEROSIL 200, manufactured by W.R.
  • the amount of lubricants used in the pharmaceutical compositions provided herein is in an amount of less than about 1 weight percent of the pharmaceutical compositions or dosage forms.
  • diluents include, but are not limited to, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycine or combinations thereof.
  • tablets and capsules are prepared by uniformly admixing at least one compound of Formula (I)-(VIII) (active ingredients) with liquid carriers, finely divided solid carriers, or both, and then shaping the product into the desired presentation if necessary.
  • tablets are prepared by compression. In other embodiments, tablets are prepared by molding.
  • At least one compound of Formula (I)-(VIII) is orally administered as a controlled release dosage form.
  • dosage forms are used to provide slow or controlled-release of one or more compounds of Formula (I)-(VIII). Controlled release is obtained using, for example, hydroxypropylmethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or a combination thereof.
  • controlled- release dosage forms are used to extend activity of the compound of Formula (I)-(VIII), reduce dosage frequency, and increase patient compliance.
  • Administration of compounds of Formula (I)-(VIII) as oral fluids such as solution, syrups and elixirs are prepared in unit dosage forms such that a given quantity of solution, syrups or elixirs contains a predetermined amount of a compound of Formula (I)-(VIII).
  • Syrups are prepared by dissolving the compound in a suitably flavored aqueous solution, while elixirs are prepared through the use of a non-toxic alcoholic vehicle.
  • Suspensions are formulated by dispersing the compound in a non-toxic vehicle.
  • Non-limiting examples of excipients used in as oral fluids for oral administration include, but are not limited to, solubilizers, emulsifiers, flavoring agents, preservatives, and coloring agents.
  • solubilizers and emulsifiers include, but are not limited to, water, glycols, oils, alcohols, ethoxylated isostearyl alcohols and polyoxy ethylene sorbitol ethers.
  • Non-limiting examples of preservatives include, but are not limited to, sodium benzoate.
  • Non-limiting examples of flavoring agents include, but are not limited to, peppermint oil or natural sweeteners or saccharin or other artificial sweeteners.
  • compositions containing at least one compound of Formula (I)-(VIII) are administered parenterally by various routes including, but not limited to, subcutaneous, intravenous (including bolus injection), intramuscular, and intraarterial.
  • parenteral dosage forms are administered in the form of sterile or sterilizable injectable solutions, suspensions, dry and/or lyophylized products ready to be dissolved or suspended in a pharmaceutically acceptable vehicle for injection (reconstitutable powders) and emulsions.
  • Vehicles used in such dosage forms include, but are not limited to, Water for Injection USP; aqueous vehicles such as, but not limited to, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection; water-miscible vehicles such as, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.
  • aqueous vehicles such as, but not limited to, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection
  • water-miscible vehicles such as, but not limited to, ethyl
  • compositions containing at least one compound of Formula (I)-(VIII) are administered transdemally.
  • transdermal dosage forms include "reservoir type” or “matrix type” patches, which are applied to the skin and worn for a specific period of time to permit the penetration of a desired amount of a compound of Formula (I)-(VIII).
  • transdermal devices are in the form of a bandage comprising a backing member, a reservoir containing the compound optionally with carriers, optionally a rate controlling barrier to deliver the compound to the skin of the host at a controlled and predetermined rate over a prolonged period of time, and means to secure the device to the skin.
  • matrix transdermal formulations are used.
  • Formulations for transdermal delivery of a compound of Formula (I)-(VIII) include an effective amount of a compound of Formula (I)-(VIII), a carrier and an optional diluent.
  • a carrier includes, but is not limited to, absorbable pharmacologically acceptable solvents to assist passage through the skin of the host, such as water, acetone, ethanol, ethylene glycol, propylene glycol, butane- 1, 3 -diol, isopropyl myristate, isopropyl palmitate, mineral oil, and combinations thereof.
  • such transdermal delivery systems include penetration enhancers to assist in delivering one or more compounds of Formula (I)-(VIII) to the tissue.
  • penetration enhancers include, but are not limited to, acetone; various alcohols such as ethanol, oleyl, and tetrahydrofuryl; alkyl sulfoxides such as dimethyl sulfoxide; dimethyl acetamide; dimethyl formamide; polyethylene glycol; pyrrolidones such as
  • polyvinylpyrrolidone polyvinylpyrrolidone
  • Kollidon grades Polyvidone
  • urea urea
  • various water- soluble or insoluble sugar esters such as Tween 80 (polysorbate 80) and Span 60 (sorbitan monostearate).
  • the pH of such a transdermal pharmaceutical composition or dosage form, or of the tissue to which the pharmaceutical composition or dosage form is applied is adjusted to improve delivery of one or more compounds of Formula (I)-(VIII).
  • the polarity of a solvent carrier, its ionic strength, or tonicity are adjusted to improve delivery.
  • compounds such as stearates are added to advantageously alter the hydrophilicity or lipophilicity of one or more compounds of Formula (I)-(VIII) so as to improve delivery.
  • such stearates serve as a lipid vehicle for the formulation, as an emulsifying agent or surfactant, and as a delivery- enhancing or penetration-enhancing agent.
  • different salts, hydrates or solvates of the compounds of Formula (I)-(VIII) are used to further adjust the properties of the resulting composition.
  • At least one compound of Formula (I)-(VIII) is administered by topical application of pharmaceutical composition containing at least one compound of Formula (I)-(VIII) in the form of lotions, gels, ointments solutions, emulsions, suspensions or creams.
  • suitable formulations for topical application to the skin are aqueous solutions, ointments, creams or gels, while formulations for ophthalmic administration are aqueous solutions.
  • Such formulations optionally contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives.
  • Such topical formulations include at least one carrier, and optionally at least one diluent.
  • Such carriers and diluents include, but are not limited to, water, acetone, ethanol, ethylene glycol, propylene glycol, butane- 1, 3 -diol, isopropyl myristate, isopropyl palmitate, mineral oil, and combinations thereof.
  • such topical formulations include penetration enhancers to assist in delivering one or more compounds of Formula (I)-(VIII) to the tissue.
  • penetration enhancers include, but are not limited to, acetone; various alcohols such as ethanol, oleyl, and tetrahydrofuryl; alkyl sulfoxides such as dimethyl sulfoxide; dimethyl acetamide; dimethyl formamide; polyethylene glycol; pyrrolidones such as
  • compositions containing at least one compound of Formula (I)-(VIII) are administered by inhalation.
  • Dosage forms for inhaled administration are formulated as aerosols or dry powders.
  • Aerosol formulations for inhalation administration comprise a solution or fine suspension of at least one compound of Formula (I)-(VIII) in a pharmaceutically acceptable aqueous or non-aqueous solvent.
  • compositions optionally comprise a powder base such as lactose, glucose, trehalose, mannitol or starch, and optionally a performance modifier such as L- leucine or another amino acid, and/or metals salts of stearic acid such as magnesium or calcium stearate.
  • a powder base such as lactose, glucose, trehalose, mannitol or starch
  • a performance modifier such as L- leucine or another amino acid, and/or metals salts of stearic acid such as magnesium or calcium stearate.
  • compounds of Formula (I)-(VIII) are be administered directly to the lung by inhalation using a Metered Dose Inhaler (“MDI”), which utilizes canisters that contain a suitable low boiling propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas, or a Dry Powder Inhaler (DPI) device which uses a burst of gas to create a cloud of dry powder inside a container, which is then be inhaled by the patient.
  • MDI Metered Dose Inhaler
  • DPI Dry Powder Inhaler
  • capsules and cartridges of gelatin for use in an inhaler or insufflator are formulated containing a powder mixture of a compound of Formula (I)-(VIII) and a powder base such as lactose or starch.
  • compounds of Formula (I)-(VIII) are delivered to the lung using a liquid spray device, wherein such devices use extremely small nozzle holes to aerosolize liquid drug formulations that can then be directly inhaled into the lung.
  • compounds of Formula (I)-(VIII) are delivered to the lung using a nebulizer device, wherein a nebulizers creates an aerosols of liquid drug formulations by using ultrasonic energy to form fine particles that can be readily inhaled.
  • compounds of Formula (I)-(VIII) are delivered to the lung using an electrohydrodynamic (“EHD”) aerosol device wherein such EHD aerosol devices use electrical energy to aerosolize liquid drug solutions or suspensions.
  • EHD electrohydrodynamic
  • the pharmaceutical composition containing at least one compound of Formula (I)-(VIII), or pharmaceutically acceptable salts and solvates thereof, described herein also contain one or more absorption enhancers.
  • absorption enhancers include, but are not limited to, sodium glycocholate, sodium caprate, N-lauryl-P-D-maltopyranoside, EDTA, and mixed micelles.
  • pharmaceutical compositions containing at least one compound of Formula (I)-(VIII) are administered nasally.
  • the dosage forms for nasal administration are formulated as aerosols, solutions, drops, gels or dry powders.
  • compositions containing at least one compound of Formula (I)-(VIII) are administered rectally in the form of suppositories, enemas, ointment, creams rectal foams or rectal gels.
  • suppositories are prepared from fatty emulsions or suspensions, cocoa butter or other glycerides.
  • compositions containing at least one compound of Formula (I)-(VIII) are administered opthamically as eye drops.
  • Such formulations are aqueous solutions that optionally contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives.
  • compositions containing at least one compound of Formula (I)-(VIII) are administered otically as ear drops.
  • Such formulations are aqueous solutions that optionally contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives.
  • compositions containing at least one compound of Formula (I)-(VIII) are formulated as a depot preparation. Such long acting formulations are administered by implantation (for example subcutaneously or
  • such formulations include polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • a compound of Formulas (I)-(VIII) provided herein, or a pharmaceutically acceptable salt, N-oxide, isomer or solvate thereof, or a pharmaceutical composition containing at least one compound of Formula (I)-(VIII) provided herein is administered alone (without an additional therapeutic agent) for the treatment of one or more of the TGR5 -related diseases and/or disorders described herein.
  • a compound of Formulas (I)-(VIII) provided herein, or a pharmaceutically acceptable salt, N-oxide, isomer or solvate thereof, or a pharmaceutical composition containing at least one compound of Formulas (I)-(VIII) provided herein is administered in combination with one or more additional therapeutic agents, for the treatment of one or more of the TGR5 -related diseases and/or disorders described herein.
  • a compound of Formulas (I)-(VIII) provided herein, or a pharmaceutically acceptable salt, N-oxide, isomer or solvate thereof, or a pharmaceutical composition containing at least one compound of Formula (I)-(VIII) provided herein is formulated in combination with one or more additional therapeutic agents and administered for the treatment of one or more of the TGR5 -related diseases and/or disorders described herein.
  • a compound of Formulas (I)-(VIII) provided herein, or a pharmaceutically acceptable salt, N-oxide, isomer or solvate thereof, or a pharmaceutical composition containing at least one compound of Formula (I)-(VIII) provided herein is administered sequentially with one or more additional therapeutic agents, for the treatment of one or more of the TGR5-related diseases and/or disorders described herein.
  • the combination treatments provided herein include administration of a compound of Formulas (I)-(VIII) provided herein, or a pharmaceutically acceptable salt, N-oxide, isomer or solvate thereof, or a pharmaceutical composition containing at least one compound of Formula (I)-(VIII) provided herein, prior to
  • the combination treatments provided herein include administration of a compound of Formulas (I)-(VIII) provided herein, or a pharmaceutically acceptable salt, N-oxide, isomer or solvate thereof, or a pharmaceutical composition containing at least one compound of Formula (I)-(VIII) provided herein, subsequent to administration of one or more additional therapeutic agents, for the treatment of one or more of the TGR5 -related diseases and/or disorders described herein.
  • the combination treatments provided herein include administration of a compound of Formulas (I)-(VIII) provided herein, or a pharmaceutically acceptable salt, N-oxide, isomer or solvate thereof, or a pharmaceutical composition containing at least one compound of Formula (I)-(VIII) provided herein, concurrently with one or more additional therapeutic agents, for the treatment of one or more of the TGR5- related diseases and/or disorders described herein.
  • the combination treatments provided herein include administration of a compound of Formulas (I)-(VIII) provided herein, or a pharmaceutically acceptable salt, N-oxide, isomer or solvate thereof, or a pharmaceutical composition containing at least one compound of Formula (I)-(VIII) provided herein, formulated with one or more additional therapeutic agents, for the treatment of one or more of the TGR5 -related diseases and/or disorders described herein.
  • the compounds of Formula (I)-(VIII) provided herein, or a pharmaceutically acceptable salts, N- oxides, isomers or solvates thereof, and the additional therapeutics agent(s) act additively.
  • the compounds of Formula (I)-(VIII) provided herein, or a pharmaceutically acceptable salts, N-oxides, isomers or solvates thereof, and the additional therapeutics agent(s) act synergistically.
  • the additional therapeutic agents used in combination with at least one compound of Formula (I)-(VIII) described herein, or a pharmaceutically acceptable salt, N-oxide, isomer or solvate thereof include, but are not limited to immunomodulatory, antiinflammatory substances and other anti-diabetes therapeutic agents.
  • the other anti-diabetes therapeutic agents used in combination with at least one compound of Formula (I)-(VIII) described herein or a pharmaceutically acceptable salt, N- oxide, isomer or solvate thereof include, but are not limited, sulfonylureas (by way of example, chloropropamide, acetohexamide, glimepiride, glipizide, glyburide, tolazamide, tolbutamide), meglitinides (by way of example, repaglinide, nateglinide) biguanides (by way of example, metformin), thiazolidinediones (by way of example, rosiglitazone,
  • alpha-glucosidase inhibitors by way of example, acarbose, miglitol.
  • the anti-inflammatory agents used in combination with at least one compound of Formula (I)-(VIII) described herein or a pharmaceutically acceptable salt, N-oxide, isomer or solvate thereof include, but are not limited to, non-steroidal anti-inflammatory drugs such as salicylic acid, acetylsalicylic acid, methyl salicylate, diflunisal, salsalate, olsalazine, sulfasalazine, acetaminophen, indomethacin, sulindac, etodolac, mefenamic acid, meclofenamate sodium, tolmetin, ketorolac, dichlofenac, ibuprofen, naproxen, naproxen sodium, fenoprofen, ketoprofen, flurbinprofen, oxaprozin, piroxicam, meloxicam, ampiroxicam, droxicam, pivoxicam, tenoxicam, na
  • leukotriene antagonists including, but not limited to, zileuton, aurothioglucose, gold sodium thiomalate and auranofin, steroids including, but not limited to, alclometasone diproprionate, amcinonide, beclomethasone dipropionate, betametasone, betamethasone benzoate, betamethasone diproprionate, betamethasone sodium phosphate, betamethasone valerate, clobetasol proprionate, clocortolone pivalate, hydrocortisone, hydrocortisone derivatives, desonide, desoximatasone, dexamethasone, flunisolide, flucoxinolide, flurandrenolide, halcinocide, medrysone, methylprednisolone, methprednisolone acetate, methylprednisolone sodium succ
  • the immunomodulatory agents used in combination with at least one compound of Formula (I)-(VIII) described herein, or a pharmaceutically acceptable salt or solvate thereof include, but are not limited to, azathioprine, tacrolimus, cyclosporin methothrexate, leflunomide, corticosteroids, cyclophosphamide, cyclosporine A, cyclosporin G, mycophenolate mofetil, ascomycin, rapamycin (sirolimus), FK-506, mizoribine, deoxyspergualin, brequinar, mycophenolic acid, malononitriloamindes (such as, by way of example only, leflunamide), T cell receptor modulators, and cytokine receptor modulators, peptide mimetics, and antibodies (such as, by way of example only, human, humanized, chimeric, monoclonal, polyclonal, Fvs, ScFvs, Fab or F(ab)
  • T cell receptor modulators include, but are not limited to, anti-T cell receptor antibodies (such as, by way of example only, anti-CD4 antibodies (such as, by way of example only, cM-T412 (Boehringer), IDEC-CE9.1TM (IDEC and SKB), mAB 4162W94, Orthoclone and OKTcdr4a (Janssen-Cilag)), anti-CD3 antibodies (such as, by way of example only, Nuvion (Product Design Labs), OKT3 (Johnson & Johnson), or Rituxan (IDEC)), anti-CD5 antibodies (such as, by way of example only, an anti-CD5 ricin-linked immunoconjugate), anti-CD7 antibodies (such as, by way of example only, CHH-380 (Novartis)), anti-CD8 antibodies, anti-CD40 ligand monoclonal antibodies (such as, by way of example only, IDEC- 131 (IDEC)), anti-CD52 antibodies (such as, by way of example only,
  • cytokine receptor modulators include, but are not limited to, soluble cytokine receptors (such as, by way of example only, the extracellular domain of a TNF-oc receptor or a fragment thereof, the extracellular domain of an IL- ⁇ receptor or a fragment thereof, and the extracellular domain of an IL-6 receptor or a fragment thereof), cytokines or fragments thereof (such as, by way of example only, interleukin (IL)-2, IL-3, IL-4, IL-5, IL- 6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-15, TNF-.alpha., interferon (IFN)-cc, IFN- ⁇ , IFN- ⁇ , and GM-CSF), anti-cytokine receptor antibodies (such as, by way of example only, anti- IFN receptor antibodies, anti-IL-2 receptor antibodies (such as, by way of example only, Zenapax (Protein Design Labs)), anti-IL-4 receptor antibodies,
  • the cytokines or modulator of cytokine function used in combination with at least one compound of Formula (I)-(VIII) described herein, or a pharmaceutically acceptable salt or solvate thereof include, but are not limited to, interleukin-2 (IL-2), interleukin-3 (IL-3), interleukin-4 (IL-4), interleukin-5 (IL-5), interleukin-6 (IL-6), interleukin-7 (IL-7), interleukin-9 (IL-9), interleukin- 10 (IL-10), interleukin- 12 (IL-12), interleukin 15 (IL-15), interleukin 18 (IL-18), platelet derived growth factor (PDGF), erythropoietin (Epo), epidermal growth factor (EGF), fibroblast growth factor (FGF), granulocyte macrophage stimulating factor (GM-CSF), granulocyte colony stimulating factor (G-CSF), macrophage colony stimulating factor (M-CSF), prolactin, alpha-
  • a compound of Formula (I)-(VIII) described herein, or a pharmaceutically acceptable salt, N-oxide, isomer or solvate thereof, or a pharmaceutical composition containing such compounds of Formula (I)-(VIII), is administered to a patient who has not previously undergone or is not currently undergoing treatment with another therapeutic agent.
  • kits that include one or more containers containing a compound of Formula (I)-(VIII) useful for the treatment or prevention of a TGR5 -related disease or disorder.
  • a compound of Formula (I)-(VIII) useful for the treatment or prevention of a TGR5 -related disease or disorder.
  • pharmaceutical packs or kits include one or more containers containing a compound of Formula (I)-(VIII) useful for the treatment or prevention of a TGR5-related disease or disorder and one or more containers containing an additional therapeutic agent.
  • such pharmaceutical packs or kits optionally include instructions for its administration of a compound of Formula (I)-(VIII).
  • the compound of Formula (I)-(VIII) is in free form or in pharmaceutically acceptable salt or N- oxide form.
  • reaction was concentrated to dryness and purified by silica gel chromatography (40 g, 5-50 % ethyl acetate/hexanes) to give tert-butyl 4-(l-(4-fluorophenyl)-4-(methoxycarbonyl)-lH-pyrazol-5- yl)piperidine-l-carboxylate (7) as an oil.
  • reaction solution was diluted with 0.5 mL water, filtered through 0.45 ⁇ Whatman filter and then purified by reversed phase HPLC (C-18, 100 mlVrnin, 10-90%, water (0.05 % TFA)/ACN) to yield tert-butyl 4-(l-(4- fluorophenyl)-4-(3-phenylpyrrolidine- 1-carbonyl)- lH-pyrazol-5-yl)piperidine- 1-carboxylate (Ex. No. 1) as a white solid.
  • cAMP HTRF assays Compounds were assessed for their ability to activate human TGR5 in cAMP HTRF assays (Cisbio). Briefly, Jurkat cells stably expressing either human TGR5 were seeded into 384-well plates (Greiner) in AIM V media supplemented with IB MX (ImM) followed by transfer of agonist compounds in DMSO by Pintool (GNF Systems). After a 30- 60 minute incubation at 37 °C, cAMP HiRange HTRF reagents were added (Cisbio) and incubated for 1 hour followed by reading the emission at both 620nM and 665nM on the Envision (Perkin Elmer). Data is expressed as the emission ratio 665/620 and normalized to the DMSO alone control. Percent efficacy is calculated relative to a known TGR5 full agonist.
  • Formula (II) have EC 50 values from 1 nM to 5 ⁇ . In other examples, compounds of Formula (I) and Formula (II) have EC 50 values from 1 nM to 4 ⁇ . In other examples, compounds of Formula (I) and Formula (II) have EC 50 values from 1 nM to 3 ⁇ . In other examples, compounds of Formula (I) and Formula (II) have EC 50 values from 1 nM to 2 ⁇ . In other examples, compounds of Formula (I) and Formula (II) have EC5 0 values from 1 nM to 1 ⁇ . In other examples, compounds of Formula (I) and Formula (II) have EC5 0 values from 1 nM to 500nM.
  • compounds of Formula (I) and Formula (II) have EC5 0 values from 1 nM to 400nM. In other examples, compounds of Formula (I) and Formula (II) have EC5 0 values from 1 nM to 300nM. In other examples, compounds of Formula (I) and Formula (II) have EC5 0 values from 1 nM to 200nM. In other examples, compounds of Formula (I) and Formula (II) have EC5 0 values from 1 nM to ⁇ . In other examples, compounds of Formula (I) and Formula (II) have EC5 0 values from 1 nM to 80nM.
  • compounds of Formula (I) and Formula (II) have EC5 0 values from 1 nM to 60nM. In other examples, compounds of Formula (I) and Formula (II) have EC5 0 values from 1 nM to 40nM. In other examples, compounds of Formula (I) and Formula (II) have EC 5 0 values from 1 nM to 20nM. In other examples, compounds of Formula (I) and Formula (II) have EC5 0 values from 1 nM to ⁇ . In other examples, compounds of Formula (I) and Formula (II) have EC5 0 values from 1 nM to 5nM.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Diabetes (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Endocrinology (AREA)
  • Engineering & Computer Science (AREA)
  • Obesity (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Emergency Medicine (AREA)
  • Hematology (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention provides compounds of formula (I), pharmaceutical compositions comprising such compounds and methods of using such compounds to treat or prevent diseases or disorders associated with TGR5.

Description

COMPOUNDS AND COMPOSITIONS AS TGR5 AGONISTS
FIELD OF THE INVENTION
[0001] The invention relates to compounds, compositions and methods for modulating
TGR5.
BACKGROUND OF THE INVENTION
[0002] Bile acids (BAs) are released from the gallbladder after each meal and subsequently facilitate the digestion of nutrients. A multitude of endocrine, neural, and metabolic signaling pathways are activated upon food intake to coordinate the effective use of the available energy. Bile acids are known to be involved in lipid absorption and cholesterol homeostasis. However, bile acids are also regarded as signaling hormones endowed with paracrine and endocrine functions related to the homeostasis of cholesterol levels, control of lipid and carbohydrate metabolism, and regulation of the immune system. TGR5 (also known as GPBARl or M-BAR) has been identified as the endogenously specific metabo tropic receptor of bile acids.
SUMMARY OF THE INVENTION
[0003] Provided herein are compounds and pharmaceutical compositions thereof, which are useful agonists of TGR5.
[0004] In one aspect provided herein such compounds, and the pharmaceutically acceptable salts, pharmaceutically acceptable solvates (e.g. hydrates), the N-oxide derivatives, prodrug derivatives, protected derivatives, enantiomers, racemic mixtures, individual stereoisomers and mixture of stereoisomers thereof, have a structure according to Formula (I):
Figure imgf000003_0001
(I) wherein,
R1 and R2 are each independently selected from Ci-Cealkyl, and C2-C6alkene, and taken together with the N atom to which they are attached form a 4 to 6 membered heterocycloalkyl ring containing a N heteroatom, a 9 to 14 membered fused bicyclic heterocycloalkyl ring containing a N heteroatom, or a 9 to 14 membered fused bicyclic heteroaryl containing an N heteroatom, wherein such heterocycloalkyl and fused bicyclic heteroaryl are each optionally substituted with 1 to 5 substituents independently selected from halogen, deuterium, C - C6alkyl, Ci-Cehaloalkyl, -CN, R9, -OR9, phenyl, phenoxy, Cioaryl and Ci4aryl, wherein such phenyl, phenoxy, Cioaryl and Ci4aryl are each optionally substituted with 1 to 5 substituents independently selected from halogen, deuterium and - 9;
Figure imgf000004_0001
2 is selected from -C(O)-, -C(0)0-, -(CH2)qC(0)0-, -S(0)2- C C6alkylene, phenylene, Cioarylene, C^arylene, a 5, 6, 9, 10 or 14 membered heteroarylene containing 1 to 2 heteroatoms independently selected from N, O and S, or a bond, wherein the Ci-Cealkylene ,arylene and heteroarylene of L2 are optionally substituted with 1 to 3 substituents independently selected from deuterium, R9 and -C(0)OR9;
is Ci-C6alkylene optionally substituted with 1 to 3 substituents independently selected deuterium, R9 and -C(0)OR9, or Ci-Cealkenylene optionally substituted with 1 to 3 substituents independently selected from deuterium, R9 and -C(0)OR9; U is selected from a -NR9-, -NR9C(0)0-, -NR9(CH2)q -, -C(0)NR9-, -S(0)2-, -0-, C Cealkylene, phenylene, Cioarylene, Ci4arylene, a 5, 6, 9, 10 or 14 membered heteroarylene containing 1 to 2 heteroatoms independently selected from N, O and S, wherein the Ci-Cealkylene, arylene and heteroarylene of L4 are optionally substituted with 1 to 3 substituents independently selected from deuterium, R9 and -C(0)OR9;
R3 is selected from Ci-Cealkyl, Ci-Cehaloalkyl, C3-C8cycloalkyl, -L3R6 , phenyl, Cioaryl, C]4aryl, a 5, 6, 9, 10 or 14 membered heteroaryl containing 1 to 3 N heteroatoms and optionally one heteroatom selected from O and S, and a 4 to 7 membered heterocycloalkyl ring containing 1 to 2 heteroatoms independently selected from N, O and S, wherein the Ci-Cealkyl, aryl, heterocycloalkyl, C3- Cscycloalkyl and heteroaryl groups of R3 are each optionally substituted with 1 to 3 substituents independently selected from halogen, R9, R6, -OR9, -N(R9)2, - C(0)N(R9)2, -C(0)NR9OH, -C(0)OR9, -C(0)OL3R6, - L3C(0)OR9, -C(0)R9, - CN, -S(0)2R9, -S(0)2N(R9)2, -S(0)2NR9C(0)R9, - S(0)2L3C(0)OR9, - OS(0)2N(R9)2, -S(0)2NR9OH, -OL3C(0)OR9, -C(0)NR9L3C(0)OR9, -L3R6
Figure imgf000005_0001
and a 5 membered heteroaryl containing 1 to 4 N heteroatoms and optionally one heteroatom selected from O and S;
R4 is selected from H, Ci-Cealkyl, phenyl, Cioaryl, Ci4aryl, C3-Cscycloalkyl, 5-6 membered heteroaryl containing one or more N heteroatoms, wherein the Cr C6alkyl, aryl, heteroaryl and C3 -Cscycloalkyl groups of R4 are each optionally substituted with 1 to 3 substituents independently selected from halogen, -CN, R9, and -OR9;
R5 is H, Ci-C6alkyl or C C6haloalkyl.
R6 is C3-C8cycloalkyl, phenyl, Cioaryl, Ci4aryl, a 5, 6, 9, 10 or 14 membered
heteroaryl containing 1 to 2 heteroatoms independently selected from N, O and S, a 4 to 7 membered heterocycloalkyl ring containing 1 to 2 heteroatoms independently selected from N, O and S, and a 9 to 14 membered fused bicyclic heterocycloalkyl ring containing containing 1 to 2 heteroatoms independently selected from N, O and S, each of which is optionally substituted with 1 to 5 substituents independently selected from halogen, deuterium, R9, -OR9, -CN and - C(0)OR9;
R9 is H, Ci-C6alkyl optionally substituted with 1 to 4 -OH groups or Ci-Cehaloalkyl; R11 is H or Ci-C6alkyl;
R12 is Ci-C4alkyl, -CH2C(0)OH or -(CHR13)C(0)OH;
R13 is H or Ci-C4alkyl;
each m is independently 1 , 2 or 3 ;
each n is independently 1, 2 or 3, and
each q is independently 1, 2, 3, 4, 5, or 6.
[0005] In certain embodiments, such the compounds of Formula (I) are compounds having the structure of Formula (II):
Figure imgf000006_0001
(Π)
wherein,
R10 and R20 are each independently selected from H, -OR9, deuterium or halogen;
R 30 is selected from phenyl, phenoxy, Cioaryl and Ci4aryl, each of which is optionally substituted with 1 to 5 substituents independently selected from halogen, deuterium and -OR9;
R40 is selected from H, deuterium, Ci-Cealkyl and Ci-Cehaloalkyl;
each R50 is independently selected from H or deuterium;
Figure imgf000007_0001
L2 is selected from -C(0)-, -C(0)0-, -(CH2)qC(0)0-, -S(0)2- C C6alkylene, phenylene, Cioarylene, C^arylene, a 5, 6, 9, 10 or 14 membered heteroarylene containing 1 to 2 heteroatoms independently selected from N, O and S, or a bond, wherein the Ci-Cealkylene ,arylene and heteroarylene of L2 are optionally substituted with 1 to 3 substituents independently selected from deuterium, R9 and -C(0)OR9;
L3 is C]-C6alkylene optionally substituted with 1 to 3 substituents independently
selected deuterium, R9 and -C(0)OR9, or Ci-Cealkenylene optionally substituted with 1 to 3 substituents independently selected from deuterium, R9 and -C(0)OR9;
U is selected from a -NR9-, -NR9C(0)0-, -NR9(CH2)q -, -C(0)NR9-, -S(0)2-, -0-, C C6alkylene, phenylene, Cioarylene, C^arylene, a 5, 6, 9, 10 or 14 membered heteroarylene containing 1 to 2 heteroatoms independently selected from N, O and S, wherein the Ci-Cealkylene, arylene and heteroarylene of L4 are optionally substituted with 1 to 3 substituents independently selected from deuterium, R9 and -C(0)OR9;
R3 is selected from Ci-Cealkyl, Ci-Cehaloalkyl, C3-Cscycloalkyl, -L3R6 , phenyl, Cioaryl, Ci4aryl, a 5, 6, 9, 10 or 14 membered heteroaryl containing 1 to 3 N heteroatoms and optionally one heteroatom selected from O and S, and a 4 to 7 membered heterocycloalkyl ring containing 1 to 2 heteroatoms independently selected from N, O and S, wherein the Ci-Cealkyl, aryl, heterocycloalkyl, C3- Cscycloalkyl and heteroaryl groups of R3 are each optionally substituted with 1 to 3 substituents independently selected from halogen, R9, R6, -OR9, -N(R9)2, - C(0)N(R9)2, -C(0)NR9OH, -C(0)OR9, -C(0)OL3R6, - L3C(0)OR9, -C(0)R9, CN, -S(0)2R9, -S(0)2N(R9)2, -S(0)2NR9C(0)R9, - S(0)2L3C(0)OR9, - 9)2, -S(0)2NR9OH, -OL3C(0)OR9, -C(0)NR9L3C(0)OR9, -L3R6
Figure imgf000008_0001
heteroatoms and optionally one heteroatom selected from O and S;
R4 is selected from H, Ci-Cealkyl, phenyl, Cioaryl, Ci4aryl, C3-Cscycloalkyl, 5-6 membered heteroaryl containing one or more N heteroatoms, wherein the Cr C6alkyl, aryl, heteroaryl and C3-Cscycloalkyl groups of R4 are each optionally substituted with 1 to 3 substituents independently selected from halogen, -CN, R9, and -OR9;
R5 is H, Ci-C6alkyl or C C6haloalkyl.
R6 is C3-C8cycloalkyl, phenyl, Cioaryl, Ci4aryl, a 5, 6, 9, 10 or 14 membered
heteroaryl containing 1 to 2 heteroatoms independently selected from N, O and S, a 4 to 7 membered heterocycloalkyl ring containing 1 to 2 heteroatoms independently selected from N, O and S, and a 9 to 14 membered fused bicyclic heterocycloalkyl ring containing containing 1 to 2 heteroatoms independently selected from N, O and S, each of which is optionally substituted with 1 to 5 substituents independently selected from halogen, deuterium, R9, -OR9, -CN and - C(0)OR9;
R9 is H, Ci-C6alkyl optionally substituted with 1 to 4 -OH groups or Ci-Cehaloalkyl; R11 is H or Ci-C6alkyl;
R12 is Ci-C4alkyl, -CH2C(0)OH or -(CHR13)C(0)OH;
R13 is H or C C4alkyl;
each m is independently 1, 2 or 3;
each n is independently 1, 2 or 3, and
each q is independently 1, 2, 3, 4, 5, or 6.
[0006] In certain embodiments, compounds of Formula (I) are compounds having the structure of Formula (III), Formula (IV) or Formula (V):
Figure imgf000009_0001
(HI) (IV) (V).
[0007] In certain embodiments of compounds of Formula (I), Formula (III), Formula (IV) or Formula (V), R1 and R2 are each independently selected from Ci-Cealkyl and C2- C6alkene, and taken together with the N atom to which they are attached form a 1,2,3,4- tetrahydroisoquinoline or an azetidine, each of which is optionally substituted with 1 to 3 substituents independently selected from halogen, deuterium, -CN, R9, -OR9, phenyl and phenoxy, wherein such phenyl and phenoxy are each optionally substituted with 1 to 5 substituents independently selected from halogen, deuterium and -OR9.
[0008] In certain embodiments, compounds of Formula (I) or Formula (II) are compou
Figure imgf000009_0002
[0009] In certain embodiments of the compounds of Formula (I), Formula (II) and Formula (VI), Formula (VII) or Formula (VIII), R10 and R20 are each independently selected from H, deuterium or F.
[00010] In certain embodiments of the compounds of Formula (I), Formula (II) and Formula (VI), Formula (VII) or Formula (VIII), R40 is selected from H, deuterium, -CH3 - CF3 and -CF2CH3.
[00011] In certain embodiments of the compounds of Formula (I), Formula (II) and
Formula (VI), Formula (VII) or Formula (VIII), R 30 is selected from phenyl, phenoxy, Cioaryl and Ci4aryl, each of which is optionally substituted with 1 to 5 substituents independently selected from F, deuterium and methoxy.
[00012] In certain embodiments of the compounds of Formulas (I)-(VIII), R4 is selected from H, methyl, ethyl, propyl, butyl, phenyl, pyridinyl, pyrimidinyl, and cyclohexyl, each of which is optionally substituted with 1 to 3 substituents independently selected from -F, -Br, - CI, -CN, R9, and -OR9.
[00013] In certain embodiments of the compounds of Formulas (I)-(VIII), R3 is selected from -CH3, -CH(CH3) 2, -C(CH3)3, -CH2C(CH3)3, - CH2CH2C(CH3)3, -CF3, cyclopropyl, cyclohexyl, phenyl, tetrahydro-2H-pyranyl, oxazolyl, oxadiazolyl, pyrazolyl, isoxazolyl, 1H- benzo[d][l,2,3]triazolyl, piperidinyl, pyridinyl, pyrimidinyl, benzthiazolyl and tetrazolyl, each of which is each optionally substituted with 1 to 3 substituents independently selected from -F, -Br, -CI, R9, -OR9, -N(R9)2, -C(0)N(R9)2, -C(0)NR9OH, -C(0)OR9, -C(0)OL3R6, - L3C(0)OR9, -C(0)R9, -CN, -S(0)2R9, -S(0)2N(R9)2, -S(0)2NR9C(0)R9, - S(0)2L3C(0)OR9,-OS(0)2N(R9)2, -S(0)2NR9OH, -OL3C(0)OR9, -C(0)NR9L3C(0)OR9,
Figure imgf000010_0001
tetrazolyl, pyrazolyl and -L3R6.
[00014] In certain embodiments of the compounds of Formulas (I)-(VIII), R9 is H, methyl, ethyl, -CH(CH3) 2, -C(CH3)3, -CF3, propyl substituted with 1 to 2 -OH groups.
[00015] In certain embodiments of the compounds of Formulas (I)-(VIII), R5 is H or methyl.
[00016] In certain embodiments of the compounds of Formulas (I)-(VIII), R12 is methyl, ethyl or n-propyl.
[00017] In certain embodiments of the compounds of Formulas (I)-(VIII), R13 is H or methyl.
[00018] In certain embodiments of the compounds of Formula (I), Formula (II) or Formula (III), are selected from: tert-butyl 4-[l-(4-fluorophenyl)-4-[(3-phenylpyrrolidin-l- yl)carbonyl]-lH-pyrazol-5-yl]piperidine-l-carboxylate, tert-butyl 4-[l-(4-bromophenyl)-4- [(3-phenylpyrrolidin-l-yl)carbonyl]-lH-pyrazol-5-yl]piperidine-l-carboxylate, tert-butyl 4- [ 1 -(4-fluorophenyl)-4- { [(3R)-3 -phenylpyrrolidin- 1 -yl]carbonyl } - 1 H-pyrazol-5 -yl]piperidine- 1-carboxylate, tert-butyl 4-[l-(4-chlorophenyl)-4-{ [3-(4-fluorophenyl)pyrrolidin-l- yl]carbonyl}-lH-pyrazol-5-yl]piperidine-l-carboxylate, tert-butyl 4-[l-(4-chlorophenyl)-4- { [(3R)-3-(4-fluorophenyl)pyrrolidin-l-yl]carbonyl}-lH-pyrazol-5-yl]piperidine-l- carboxylate, tert-butyl 4-[l-(2,4-difluorophenyl)-4-{[(3R)-3-phenylpyrrolidin-l- yl]carbonyl}-lH-pyrazol-5-yl]piperidine-l-carboxylate, tert-butyl 4-[l-(4-chloro-2- fluorophenyl)-4- { [(3R)-3-phenylpyrrolidin- l-yl]carbonyl } - 1 H-pyrazol-5 -yl]piperidine- 1 - carboxylate, tert-butyl 4-[l-(4-fluorophenyl)-4-{ [3-(4-fluorophenyl)pyrrolidin-l- yl]carbonyl}-lH-pyrazol-5-yl]piperidine-l-carboxylate, tert-butyl 4-[l-(4-methoxyphenyl)-4- {[(3R)-3-phenylpyrrolidin-l-yl]carbonyl}-lH-pyrazol-5-yl]piperidine-l-carboxylate, tert- butyl 4- [ 1 -(4-cy anophenyl)-4- { [(3R)-3 -phenylpyrrolidin- 1 -yljcarbonyl } - 1 H-pyrazol-5 - yljpiperidine- 1 -carboxylate, tert-butyl 4-(4- { [(3R)-3-phenylpyrrolidin- l-yl]carbonyl } - 1- (pyrimidin-2-yl)-lH-pyrazol-5-yl)piperidine-l -carboxylate, tert-butyl 4-[l-(2-chloro-4- fluorophenyl)-4- { [(3R)-3-phenylpyrrolidin- l-yl]carbonyl } - 1 H-pyrazol-5 -yljpiperidine- 1 - carboxylate, tert-butyl 4-[l-(4-fluorophenyl)-4-{ [3-(2-fluorophenyl)pyrrolidin-l- yl]carbonyl}-lH-pyrazol-5-yl]piperidine-l-carboxylate, tert-butyl 4-[l-(4-methylphenyl)-4- {[(3R)-3-phenylpyrrolidin-l-yl]carbonyl}-lH-pyrazol-5-yl]piperidine-l-carboxylate, tert- butyl 4- [ 1 -(4-chlorophenyl)-4- [(3-methyl-3 -phenylpyrrolidin- 1 -yl)carbonyl] - 1 H-pyrazol-5 - yljpiperidine- 1 -carboxylate, tert-butyl 4-(l-phenyl-4-{ [(3R)-3-phenylpyrrolidin-l- yl]carbonyl}-lH-pyrazol-5-yl)piperidine-l-carboxylate, tert-butyl (3S)-3-[l-(4- chlorophenyl)-4-{[(3R)-3-phenylpyrrolidin-l-yl]carbonyl}-lH-pyrazol-5-yl]pyrrolidine-l- carboxylate, tert-butyl (3R)-3-[l-(4-chlorophenyl)-4-{[(3R)-3-phenylpyrrolidin-l- yl]carbonyl}-lH-pyrazol-5-yl]piperidine-l-carboxylate, tert-butyl (3R)-3-[l-(4- chlorophenyl)-4-{[(3R)-3-phenylpyrrolidin-l-yl]carbonyl}-lH-pyrazol-5-yl]pyrrolidine-l- carboxylate, tert-butyl 3-[ 1 -(4-chlorophenyl)-4- { [(3R)-3-phenylpyrrolidin- 1 -yljcarbonyl } - lH-pyrazol-5-yl]pyrrolidine-l -carboxylate, tert-butyl 3-[l-(4-fluorophenyl)-4-{ [(3R)-3- phenylpyrrolidin- 1 -yljcarbonyl } - 1 H-pyrazol-5 -yl] azetidine- 1 -carboxylate, tert-butyl 3- [ 1 -(4- fluorophenyl)-4-[(3-phenylpyrrolidin-l-yl)carbonyl]-lH-pyrazol-5-yl]piperidine-l- carboxylate, 1-methylcyclopropyl 4-[l-(4-chlorophenyl)-4-{ [(3R)-3-phenylpyrrolidin-l- yljcarbonyl } - lH-pyrazol-5 -yljpiperidine- 1 -carboxylate, 1 - { 4- [ 1 -(4-chlorophenyl)-4- [(3 - phenylpyrrolidin- 1 -yl)carbonyl] - 1 H-pyrazol-5 -yljpiperidin- 1 -yl } -3 ,3 -dimethylbutan- 1 -one, propan-2-yl 4-[l-(4-chlorophenyl)-4-[(3-phenylpyrrolidin-l-yl)carbonyl]-lH-pyrazol-5- yljpiperidine- 1 -carboxylate, benzyl 4- [ 1 -(4-chlorophenyl)-4- [(3 -phenylpyrrolidin- 1 - yl)carbonyl]-lH-pyrazol-5-yl]piperidine-l-carboxylate, propan-2-yl 4-[l-(4-chlorophenyl)-4- {[(3R)-3-phenylpyrrolidin-l-yl]carbonyl}-lH-pyrazol-5-yl]piperidine-l-carboxylate, tert- butyl 4- [ 1 -(4-chlorophenyl)-4- { [(3R)-3 -phenylpyrrolidin- 1 -yljcarbonyl } - 1 H-pyrazol-5 -yl] - 1, 2,3, 6-tetrahydropyridine-l -carboxylate, benzyl 4-({4-[l-(4-fluorophenyl)-4-{[(3R)-3- phenylpyrrolidin- 1 -yljcarbonyl } - 1 H-pyrazol-5 -yljpiperidin- 1 -yl } methyl)piperidine- 1 - carboxylate, l-benzoyl-4-[l-(4-chlorophenyl)-4-[(3-phenylpyrrolidin-l-yl)carbonyl]-lH- pyrazol-5-yl]piperidine, 4-[l-(4-chlorophenyl)-4-[(3-phenylpyrrolidin-l-yl)carbonyl]-lH- pyrazol-5 -yl] - 1 -cyclohexanecarbonylpiperidine, 1 - { 4- [ 1 -(4-chlorophenyl)-4- { [(3R)-3 - phenylpyrrolidin- 1 -yl]carbonyl } - 1 H-pyrazol-5 -yl]piperidin- 1 -yl } -3 ,3-dimethylbutan- 1 -one, l-benzoyl-4-[l-(4-chlorophenyl)-4-{ [(3R)-3-phenylpyrrolidin-l-yl]carbonyl}-lH-pyrazol-5- yl]piperidine, 4-[l-(4-chlorophenyl)-4-{[(3R)-3-phenylpyrrolidin-l-yl]carbonyl}-lH- pyrazol-5-yl]-l-cyclohexanecarbonylpiperidine, 4-[l-(4-chlorophenyl)-4-{ [(3R)-3- phenylpyrrolidin- 1 -yl]carbonyl } - 1 H-pyrazol-5 -yl] - 1 - [(2-fluorophenyl)carbonyl]piperidine, 4-[l-(4-chlorophenyl)-4-{[(3R)-3-phenylpyrrolidin-l-yl]carbonyl}-lH-pyrazol-5-yl]-l-[(3- fluorophenyl)carbonyl]piperidine, 4-[l-(4-chlorophenyl)-4-{ [(3R)-3-phenylpyrrolidin-l- yl]carbonyl}-lH-pyrazol-5-yl]-l-[(4-fluorophenyl)carbonyl]piperidine, 4-[l-(4- chlorophenyl)-4-{[(3R)-3-phenylpyrrolidin-l-yl]carbonyl}-lH-pyrazol-5-yl]-l-[(4- chlorophenyl)carbonyl]piperidine, 4-[ 1 -(4-chlorophenyl)-4- { [(3R)-3-phenylpyrrolidin- 1 - yl]carbonyl}-lH-pyrazol-5-yl]-l-[(oxan-4-yl)carbonyl]piperidine, 4-[l-(4-chlorophenyl)-4- { [(3R)-3 -phenylpyrrolidin- 1 -yl]carbonyl } - 1 H-pyrazol-5 -yl] - 1 - [(2,5-dimethyl- 1 ,3 -oxazol-4- yl)carbonyl]piperidine, 4- [ 1 -(4-chlorophenyl)-4- { [(3R)-3 -phenylpyrrolidin- 1 -yl]carbonyl } - lH-pyrazol-5-yl]-l-[(3-methoxyphenyl)carbonyl]piperidine, 4-[l-(4-chlorophenyl)-4-{ [(3R)-
3 - phenylpyrrolidin- l-yl]carbonyl} - lH-pyrazol-5-yl]- 1-[(4- methoxyphenyl)carbonyl]piperidine, 4-[l-(4-chlorophenyl)-4-{[(3R)-3-phenylpyrrolidin-l- yl]carbonyl } - lH-pyrazol-5 -yl] - 1 - [(5 -methyl- 1 ,3 ,4-oxadiazol-2-yl)carbonyl]piperidine, 4- [ 1 - (4-chlorophenyl)-4-{ [(3R)-3-phenylpyrrolidin-l-yl]carbonyl}-lH-pyrazol-5-yl]-l-{ [l- methyl-5-(trifluoromethyl)-lH-pyrazol-3-yl]carbonyl}piperidine, 4-[l-(4-chlorophenyl)-4- { [(3R)-3 -phenylpyrrolidin- 1 -yl]carbonyl } - 1 H-pyrazol-5 -yl] - 1 - [( 1 ,5-dimethyl- 1 H-pyrazol-3 - yl)carbonyl]piperidine, 5-({4-[l-(4-chlorophenyl)-4-{ [(3R)-3-phenylpyrrolidin-l- yl]carbonyl } - lH-pyrazol-5 -yl]piperidin- 1 -yl } carbonyl)-2-methylpyridine, (2R)-2-amino- 1 - {4-[l-(4-fluorophenyl)-4-{ [(3R)-3-phenylpyrrolidin-l-yl]carbonyl}-lH-pyrazol-5- yl]piperidin- 1 -yl } -4,4-dimethylpentan- 1 -one, 4-(methoxycarbonyl)phenyl 4- [ l-(4- fluorophenyl)-4- { [(3R)-3-phenylpyrrolidin- l-yl]carbonyl } - 1 H-pyrazol-5 -yl]piperidine- 1 - carboxylate, 4-fluorophenyl 4-[l-(4-fluorophenyl)-4-{[(3R)-3-phenylpyrrolidin-l- yl]carbonyl}-lH-pyrazol-5-yl]piperidine-l-carboxylate, phenyl 4-[l-(4-fluorophenyl)-4- {[(3R)-3-phenylpyrrolidin-l-yl]carbonyl}-lH-pyrazol-5-yl]piperidine-l-carboxylate, methyl
4- [l-(4-fluorophenyl)-4-{[(3R)-3-phenylpyrrolidin-l-yl]carbonyl}-lH-pyrazol-5- yl]piperidine-l-carboxylate, l-(3,5-dimethyl-l,2-oxazole-4-sulfonyl)-4-[l-(4-fluorophenyl)- 4-{[(3R)-3-phenylpyrrolidin-l-yl]carbonyl}-lH-pyrazol-5-yl]piperidine, 4-[l-(4- chlorophenyl)-4- [(3 -phenylpyrrolidin- 1 -yl)carbonyl] - 1 H-pyrazol-5 -yl] - 1 - methanesulfonylpiperidine, l-(benzenesulfonyl)-4-[l-(4-chlorophenyl)-4-{ [(3R)-3- phenylpyrrolidin- 1 -yljcarbonyl } - 1 H-pyrazol-5 -yljpiperidine, tert-butyl 4- [ 1 -(4- chlorophenyl)-4-{[(3R)-3-phenylpyrrolidin-l-yl]carbonyl}-lH-pyrazol-5-yl]piperidine-l- carboxylate, l-benzyl-4-[l-(4-chlorophenyl)-4-[(3-phenylpyrrolidin-l-yl)carbonyl]-lH- pyrazol-5-yl]piperidine, 4-((4-(4-(3,3-difluoro-4-phenylpyrrolidine-l-carbonyl)-l-(4- fluorophenyl)- 1 H-pyrazol-5 -yl)piperidin- 1 -yl)methyl)benzenesulfonamide, 4- [ 1 -(4- chlorophenyl)-4-{[(3R)-3-phenylpyrrolidin-l-yl]carbonyl}-lH-pyrazol-5-yl]-l-[(4- fluorophenyl)methyl]piperidine, 4-[l-(4-chlorophenyl)-4-{ [(3R)-3-phenylpyrrolidin-l- yljcarbonyl } - lH-pyrazol-5 -yl] - 1 - [(2-fluorophenyl)methyl]piperidine, 4-( { 4- [ 1 -(4- chlorophenyl)-4-{[(3R)-3-phenylpyrrolidin-l-yl]carbonyl}-lH-pyrazol-5-yl]piperidin-l- yl } methyl)benzoic acid, 4- [ 1 -(4-chlorophenyl)-4- [(3 -phenylpyrrolidin- 1 -yl)carbonyl] - 1H- pyrazol-5-yl]-l-cyclohexylpiperidine, 4-({4-[l-(4-chlorophenyl)-4-{ [(3R)-3- phenylpyrrolidin- 1 -yl]carbonyl } - 1 H-pyrazol-5 -yl]piperidin- 1 -yl } methyl)benzonitrile, 4- [ 1 - (4-chlorophenyl)-4-{ [(3R)-3-phenylpyrrolidin-l-yl]carbonyl}-lH-pyrazol-5-yl]-l-(oxan-4- ylmethyl)piperidine, 3-({4-[l-(4-chlorophenyl)-4-{[(3R)-3-phenylpyrrolidin-l-yl]carbonyl}- lH-pyrazol-5-yl]piperidin-l-yl}methyl)benzoic acid, l-benzyl-4-[l-(4-fluorophenyl)-4- { [(3R)-3 -phenylpyrrolidin- 1 -yl]carbonyl } - 1 H-pyrazol-5 -yl]piperidine, 4- { [4-( 1 -cyclohexyl-
4- {[(3R)-3-phenylpyrrolidin-l-yl]carbonyl}-lH-pyrazol-5-yl)piperidin-l- yl] methyl }benzonitrile, l-benzyl-4-[l-(4-chlorophenyl)-4-{[(3R)-3-phenylpyrrolidin-l- yl]carbonyl}-lH-pyrazol-5-yl]piperidine, 4-({4-[l-(4-chlorophenyl)-4-[(l, 2,3,4- tetrahydroisoquinolin-2-yl)carbonyl]-lH-pyrazol-5-yl]piperidin-l-yl}methyl)benzonitrile, 4- ({4-[l-(4-chloro-2-fluorophenyl)-4-{ [(3R)-3-phenylpyrrolidin-l-yl]carbonyl}-lH-pyrazol-5- yl]piperidin- 1 -yl } methyl)benzonitrile, 4-({ 4- [ l-(2,4-difluorophenyl)-4- { [(3R)-3- phenylpyrrolidin- 1 -yl]carbonyl } - 1 H-pyrazol-5 -yl]piperidin- 1 -yl } methyl)benzonitrile, methyl
2- {4-[l-(2,4-difluorophenyl)-4-{[(3R)-3-phenylpyrrolidin-l-yl]carbonyl}-lH-pyrazol-5- yl]piperidin- 1 -yl } -2-phenylacetate, 4-( { 4- [ 1 -(4-fluorophenyl)-4- { [3 -(4- fluorophenyl)pyrrolidin- 1 -yl]carbonyl } - lH-pyrazol-5 -yl]piperidin- 1 -yl } methyl)benzonitrile,
5- ({4-[l-(4-fluorophenyl)-4-{[(3R)-3-phenylpyrrolidin-l-yl]carbonyl}-lH-pyrazol-5- yl]piperidin- 1 -yl } methyl)- 1 -methyl- 1H- 1 ,2,3-benzotriazole, 4-[ 1 -(4-fluorophenyl)-4- { [(3R)-
3 - phenylpyrrolidin- l-yl]carbonyl} - lH-pyrazol-5-yl]- 1-[(4- methanesulfonylphenyl)methyl]piperidine, 4-({4-[l-(4-fluorophenyl)-4-{ [(3R)-3-(4- fluorophenyl)pyrrolidin- 1 -yljcarbonyl } - lH-pyrazol-5 -yljpiperidin- 1 -yl } methyl)benzonitrile,
4- ({4-[l-(4-fluorophenyl)-4-{[(3S)-3-(4-fluorophenyl)pyrrolidin-l-yl]carbonyl}-lH-pyrazol-
5- yl]piperidin- 1 -yl } methyl)benzonitrile, 1 - [(4-methanesulfonylphenyl)methyl] -4- [ 1 -(4- methoxyphenyl)-4-{[(3R)-3-phenylpyrrolidin-l-yl]carbonyl}-lH-pyrazol-5-yl]piperidine, 4- (5 - { 1 - [(4-methanesulfonylphenyl)methyl]piperidin-4-yl } -4- { [(3R)-3 -phenylpyrrolidin- 1 - yl]carbonyl}-lH-pyrazol-l-yl)benzonitrile, 2-(5-{ l-[(4- methanesulfonylphenyl)methyl]piperidin-4-yl}-4-{[(3R)-3-phenylpyrrolidin-l-yl]carbonyl}- lH-pyrazol-l-yl)pyrimidine, 5-chloro-2-(5-{ l-[(4-methanesulfonylphenyl)methyl]piperidin-
4- yl } -4- { [(3R)-3 -phenylpyrrolidin- 1 -yljcarbonyl } - 1 H-pyrazol- 1 -yl)pyridine, 1 - [(4- methanesulfonylphenyl)methyl]-4-(4- { [(3R)-3-phenylpyrrolidin- 1 -yljcarbonyl } - lH-pyrazol-
5- yl)piperidine, 4-(4-{[(3S,4S)-3-fluoro-4-phenylpyrrolidin-l-yl]carbonyl}-l-(4- fluorophenyl)-lH-pyrazol-5-yl)-l-[(4-methanesulfonylphenyl)methyl]piperidine, 4-(4- {[(4R)-2,2-dihydrogenio-4-(2,3,4,5,6-pentahydrogeniophenyl)pyrrolidin-l-yl]carbonyl}-l- (4-fluorophenyl)- lH-pyrazol-5-yl)- 1 - [(4-methanesulfonylphenyl)methyl]piperidine, 4-[ 1 -(4- fluorophenyl)-4-{ [(3R)-3-(2, 3,4,5, 6-pentahydrogeniophenyl)pyrrolidin-l-yl]carbonyl}-lH- pyrazol-5 -yl] - 1 - [(4-methanesulfonylphenyl)methyl]piperidine, 4-( { 4- [ 1 -(4-fluorophenyl)-4- { [(3R)-3-(3-fluorophenyl)pyrrolidin- l-yl]carbonyl} - lH-pyrazol-5-yl]piperidin- 1- yl}methyl)benzonitrile, 4-[l-(4-fluorophenyl)-4-{ [(3S)-3-phenyl-3- (trifluoromethyl)pyrrolidin- 1 -yljcarbonyl } - 1 H-pyrazol-5 -yl] - 1 - [(4- methanesulfonylphenyl)methyl]piperidine, 4- [ 1 -(4-fluorophenyl)-4- { [3 -phenyl-3 - (trifluoromethyl)pyrrolidin- 1 -yl]carbonyl } - 1 H-pyrazol-5 -yl] - 1 - [(4- methanesulfonylphenyl)methyl]piperidine, 4-[l-(4-fluorophenyl)-4-{[(3R)-3-phenyl-3- (trifluoromethyl)pyrrolidin- 1 -yl]carbonyl } - 1 H-pyrazol-5 -yl] - 1 - [(4- methanesulfonylphenyl)methyl]piperidine, 4-({4-[l-(4-fluorophenyl)-4-{ [(3R)-3-(2- methoxyphenyl)pyrrolidin- 1 -yl]carbonyl } - 1 H-pyrazol-5 -yl]piperidin- 1 - yl } methyl)benzonitrile, 4- [ 1 - (4-fluorophenyl)-4- [(3 -phenoxypyrrolidin- 1 -yl)carbonyl] - 1 H- pyrazol-5 -yl] - 1 - [(4-methanesulfonylphenyl)methyl]piperidine, 4- { [4-( 1 -phenyl-4- { [(3R)-3- phenylpyrrolidin- 1 -yl]carbonyl } - 1 H-pyrazol-5 -yl)piperidin- 1 -yl]methyl } benzonitrile, 4- [ 1 - (4-chlorophenyl)-4-{ [(3R)-3-phenylpyrrolidin-l-yl]carbonyl}-lH-pyrazol-5-yl]-l-(l- phenylethyl)piperidine, 4-[l-(4-chlorophenyl)-4-{ [(3R)-3-phenylpyrrolidin-l-yl]carbonyl}- lH-pyrazol-5-yl]-l-[(3,4-difluorophenyl)methyl]piperidine, 4-[l-(4-chlorophenyl)-4-{[(3R)- 3 -phenylpyrrolidin- l-yl]carbonyl} - lH-pyrazol-5-yl]- 1- { [4- (trifluoromethyl)phenyl] methyl }piperidine, 4-({ 4-[ 1 -(4-fluorophenyl)-4- { [(3R)-3-(4- methoxyphenyl)pyrrolidin- 1 -yljcarbonyl } - 1 H-pyrazol-5 -yljpiperidin- 1 - yl } methyl)benzonitrile, 4- [ l-(4-fluorophenyl)-4- { [(3R)-3-phenylpyrrolidin- l-yl]carbonyl } - lH-pyrazol-5-yl]-l-(2,2,2-trifluoroethyl)piperidine, 2-[4-({4-[l-(4-fluorophenyl)-4-{ [(3R)-3- phenylpyrrolidin- 1 -yljcarbonyl } - 1 H-pyrazol-5 -yljpiperidin- 1 -yl } methyl)phenoxy] acetic acid, (3S,4R)-l-{ [l-(4-fluorophenyl)-5-{ l-[(4-methanesulfonylphenyl)methyl]piperidin-4- yl } - lH-pyrazol-4-yl]carbonyl } -4-phenylpyrrolidin-3-ol, 2-chloro-5-( {4-[ 1 -(4-fluorophenyl)-
4- {[(3R)-3-phenylpyrrolidin-l-yl]carbonyl}-lH-pyrazol-5-yl]piperidin-l- yl } methyl)pyridine, 4-({ 4- [ l-(4-fluorophenyl)-4- { [(3R)-3-phenylpyrrolidin- l-yl]carbonyl } - lH-pyrazol-5-yl]piperidin-l-yl}methyl)benzonitrile, 5-({4-[l-(4-fluorophenyl)-4-{ [(3R)-3- phenylpyrrolidin- 1 -yljcarbonyl } - 1 H-pyrazol-5 -yljpiperidin- 1 -yl } methyl)pyridine-2- carbonitrile, 5-fluoro-2-(5-{ l-[(4-methanesulfonylphenyl)methyl]piperidin-4-yl}-4-{ [(3R)-3- phenylpyrrolidin- 1 -yljcarbonyl } - 1 H-pyrazol- 1 -yl)pyridine, 3 -( { 4- [ 1 -(4-fluorophenyl)-4- { [(3R)-3 -phenylpyrrolidin- 1 -yljcarbonyl } - 1 H-pyrazol-5 -yljpiperidin- 1 -yl } methyl)pyridine, 3-fluoro-4-({4-[l-(4-fluorophenyl)-4-{ [(3R)-3-phenylpyrrolidin-l-yl]carbonyl}-lH-pyrazol-
5- yl]piperidin- 1 -yl } methyl)benzonitrile, 4- [ l-(4-fluorophenyl)-3-methyl-4- { [(3R)-3- phenylpyrrolidin- 1 -yljcarbonyl } - 1 H-pyrazol-5 -yl] - 1 - [(4- methanesulfonylphenyl)methyl]piperidine, 3 -bromo-4-( { 4- [ 1 -(4-fluorophenyl)-4- { [(3R)-3 - phenylpyrrolidin- 1 -yljcarbonyl } - 1 H-pyrazol-5 -yljpiperidin- 1 -yl } methyl)benzonitrile, 5 -( { 4- [ 1 -(4-fluorophenyl)-4- { [(3R)-3 -phenylpyrrolidin- 1 -yljcarbonyl } - 1 H-pyrazol-5 -yljpiperidin- l-yl}methyl)-2-methanesulfonylpyridine, 4-({4-[l-(4-fluorophenyl)-4-{ [(3R)-3- phenylpyrrolidin- 1 -yljcarbonyl } - 1 H-pyrazol-5 -yljpiperidin- 1 -yl } methyl)benzene- 1 - sulfonamide, 4-[l-(4-fluorophenyl)-4-{ [(3R)-3-phenylpyrrolidin-l-yl]carbonyl}-lH-pyrazol- 5-yl]-l-[(4-fluorophenyl)methyl]piperidine, 2-fluoro-4-({4-[l-(4-fluorophenyl)-4-{ [(3R)-3- phenylpyrrolidin- 1 -yljcarbonyl } - 1 H-pyrazol-5 -yljpiperidin- 1 -yl } methyl)benzonitrile, 4-( { 4- [ 1 -(4-fluorophenyl)-4- { [(3R)-3 -phenylpyrrolidin- 1 -yljcarbonyl } - 1 H-pyrazol-5 -yljpiperidin- 1 -yl } methyl)pyridine, [4-( { 4- [ 1 -(4-fluorophenyl)-4- { [(3R)-3 -phenylpyrrolidin- 1 - yljcarbonyl } - lH-pyrazol-5 -yljpiperidin- 1 -yl } methyl)phenyl] sulf amate, 4-( { 4- [ 1 -(4- fluorophenyl)-4-{ [(3R)-3-phenylpyrrolidin-l-yl]carbonyl}-lH-pyrazol-5-yl]piperidin-l- yl}methyl)-N-methylbenzene-l-sulfonamide, 4-(l-{4-[l-(4-fluorophenyl)-4-{[(3R)-3- phenylpyrrolidin- 1 -yljcarbonyl } - 1 H-pyrazol-5 -yljpiperidin- 1 -yl } ethyl)benzonitrile, [5-( { 4- [ 1 -(4-fluorophenyl)-4- { [(3R)-3 -phenylpyrrolidin- 1 -yljcarbonyl } - 1 H-pyrazol-5 -yljpiperidin- 1 -yl } methyl)pyridin-2-yl]methanol, 1 - [(3 ,4-difluorophenyl)methyl] -4- [ 1 -(4-fluorophenyl)-4- { [(3R)-3 -phenylpyrrolidin- 1 -yljcarbonyl } - 1 H-pyrazol-5 -yljpiperidine, methyl 5 -( { 4- [ 1 -(4- fluorophenyl)-4-{ [(3R)-3-phenylpyrrolidin-l-yl]carbonyl}-lH-pyrazol-5-yl]piperidin-l- yl}methyl)pyridine-2-carboxylate, l-[(2,4-difluorophenyl)methyl]-4-[l-(4-fluorophenyl)-4- { [(3R)-3 -phenylpyrrolidin- 1 -yljcarbonyl } - 1 H-pyrazol-5 -yljpiperidine, 4-( { 4- [ 1 -(4- fluorophenyl)-4-{ [(3R)-3-phenylpyrrolidin-l-yl]carbonyl}-lH-pyrazol-5-yl]piperidin-l- yl}methyl)-N-hydroxybenzene-l-sulfonamide, 2-fluoro-4-({4-[l-(4-fluorophenyl)-4-{ [(3R)- 3 -phenylpyrrolidin- 1 -yljcarbonyl } - lH-pyrazol-5 -yljpiperidin- 1 -yl } methyl)benzamide, 1 - [(2- chloro-4-fluorophenyl)methyl]-4-[l-(4-fluorophenyl)-4-{[(3R)-3-phenylpyrrolidin-l- yl]carbonyl}-lH-pyrazol-5-yl]piperidine, S-[4-({4-[l-(4-fluorophenyl)-4-{[(3R)-3- phenylpyrrolidin- 1 -yljcarbonyl } - 1 H-pyrazol-5 -yljpiperidin- 1 -yl } methyl)phenyl] -2- hydroxypropane- 1 -sulfonamido, 4-({ 4- [ 1 -(4-fluorophenyl)-4- { [(3R)-3-phenylpyrrolidin- 1 - yljcarbonyl } - lH-pyrazol-5 -yljpiperidin- 1 -yl } methyl)benzamide, 1 - [(4-fluoro-2- methoxyphenyl)methyl]-4-[l-(4-fluorophenyl)-4-{ [(3R)-3-phenylpyrrolidin-l-yl]carbonyl}- lH-pyrazol-5-yl]piperidine, 2-fluoro-5-({4-[l-(4-fluorophenyl)-4-{[(3R)-3-phenylpyrrolidin- 1 -yljcarbonyl } - 1 H-pyrazol-5 -yljpiperidin- 1 -yl } methyl)benzonitrile, 4- [ 1 -(4-fluorophenyl)-4- { [(3R)-3 -phenylpyrrolidin- 1 -yljcarbonyl } - 1 H-pyrazol-5 -yl] - 1 - [(3- fluorophenyl)methyl]piperidine, l-[(4-fluoro-3-methoxyphenyl)methyl]-4-[l-(4- fluorophenyl)-4-{ [(3R)-3-phenylpyrrolidin-l-yl]carbonyl}-lH-pyrazol-5-yl]piperidine, (E)- N-{ l-[4-({4-[l-(4-fluorophenyl)-4-{ [(3R)-3-phenylpyrrolidin-l-yl]carbonyl}-lH-pyrazol-5- yljpiperidin- 1 -yl } methyl)phenyl]ethylidene }hydroxylamine, 4-[ 1 -(4-fluorophenyl)-4- { [(3R)- 3-phenylpyrrolidin-l-yl]carbonyl}-lH-pyrazol-5-yl]-l-[(2,3,4- trifluorophenyl)methyl]piperidine, 2-chloro-4-({4-[l-(4-fluorophenyl)-4-{ [(3R)-3- phenylpyrrolidin- l-yl]carbonyl } - 1 H-pyrazol-5 -yljpiperidin- 1 -yl } methyl)pyridine, (5E)-5- {[4-({4-[l-(4-fluorophenyl)-4-{ [(3R)-3-phenylpyrrolidin-l-yl]carbonyl}-lH-pyrazol-5- yljpiperidin- 1 -yl } methyl)phenyl]methylidene } - 1 ,3 -thiazolidine-2,4-dione, 2-( { 4- [ 1 -(4- fluorophenyl)-4-{ [(3R)-3-phenylpyrrolidin-l-yl]carbonyl}-lH-pyrazol-5-yl]piperidin-l- yl}methyl)pyridine, tert-butyl 2-{4-[l-(4-fluorophenyl)-4-{ [(3R)-3-phenylpyrrolidin-l- yl]carbonyl}-lH-pyrazol-5-yl]piperidin-l-yl} acetate, l-{[3-fluoro-4-(2H-l,2,3,4-tetrazol-5- yl)phenyl]methyl}-4-[l-(4-fluorophenyl)-4-{ [(3R)-3-phenylpyrrolidin-l-yl]carbonyl}-lH- pyrazol-5-yl]piperidine, N-(2,3-dihydroxypropyl)-4-({4-[l-(4-fluorophenyl)-4-{ [(3R)-3- phenylpyrrolidin- 1 -yljcarbonyl } - 1 H-pyrazol-5 -yljpiperidin- 1 -yl } methyl)benzamide, 2- chloro-4-({4-[l-(4-fluorophenyl)-4-{ [(3R)-3-phenylpyrrolidin-l-yl]carbonyl}-lH-pyrazol-5- yljpiperidin- 1 -yl } methyl)pyrimidine, 1 -[4-( {4-[ 1 -(4-fluorophenyl)-4- { [(3R)-3- phenylpyrrolidin- 1 -yljcarbonyl } - 1 H-pyrazol-5 -yl]piperidin- 1 -yl } methyl)phenyl]ethan- 1 -one, 2- { [ 1 -(4-fluorophenyl)-5 - { 1 - [(4-methanesulfonylphenyl)methyl]piperidin-4-yl } - 1 H-pyrazol- 4-yl]carbonyl}-l,2,3,4-tetrahydroisoquinoline, 4-[l-(4-fluorophenyl)-4-{[(3R)-3- phenylpyrrolidin- 1 -yljcarbonyl } - 1 H-pyrazol-5 -yl] - 1 - [(4-methanesulfonylphenyl)methyl] - 1,2,3,6-tetrahydropyridine, 4-[l-(4-fluorophenyl)-4-{ [(3R)-3-phenylpyrrolidin-l- yl]carbonyl}-lH-pyrazol-5-yl]-l-[(4-methylphenyl)methyl]piperidine, tert-butyl 3-{ [4-({4- [ 1 -(4-fluorophenyl)-4- { [(3R)-3 -phenylpyrrolidin- 1 -yl]carbonyl } - 1 H-pyrazol-5 -yl]piperidin- 1-yl } methyl)phenyl]formamido }propanoate, 4-[ 1 -(4-fluorophenyl)-4- { [(3R)-3- phenylpyrrolidin- 1 -yl]carbonyl } - 1 H-pyrazol-5 -yl] - 1 - [2-(4- methanesulfonylphenyl)ethyl]piperidine, 4- [ 1 -(4-fluorophenyl)-4- [(3 -phenylazetidin- 1 - yl)carbonyl] - lH-pyrazol-5 -yl] - 1 - [(4-methanesulfonylphenyl)methyl]piperidine, 5 -( { 4- [ 1 -(4- fluorophenyl)-4-{ [(3R)-3-phenylpyrrolidin-l-yl]carbonyl}-lH-pyrazol-5-yl]piperidin-l- yl}methyl)pyridine-2-carboxylic acid, 3-{[4-({4-[l-(4-fluorophenyl)-4-{[(3R)-3- phenylpyrrolidin- 1 -yl]carbonyl } - 1 H-pyrazol-5 -yl]piperidin- 1 - yl } methyl)phenyl]formamido }propanoic acid, 1 - [(3-chloro-4-fluorophenyl)methyl] -4- [ 1 -(4- fluorophenyl)-4-{ [(3R)-3-phenylpyrrolidin-l-yl]carbonyl}-lH-pyrazol-5-yl]piperidine, 4-[l- (4-fluorophenyl)-3-methyl-4-{ [(3R)-3-phenylpyrrolidin-l-yl]carbonyl}-lH-pyrazol-5-yl]-l- [(4-methanesulfonylphenyl)methyl]- 1,2,3,6-tetrahydropyridine, 4-[l-(4-fluorophenyl)-4- {[(3R)-3-phenylpyrrolidin-l-yl]carbonyl}-lH-pyrazol-5-yl]-l-{ [4-(2H-l,2,3,4-tetrazol-5- yl)phenyl]methyl}piperidine, l-(4-fluorophenyl)-5-{ l-[(4- methanesulfonylphenyl)methyl] azetidin-3 -yl } -4- [(3 -methyl-3-phenylpyrrolidin- 1 - yl)carbonyl]- lH-pyrazole, 5-( { 4- [ l-(4-fluorophenyl)-4- [(3-methyl-3-phenylpyrrolidin- 1 - yl)carbonyl]-lH-pyrazol-5-yl]piperidin-l-yl}methyl)pyridine-2-carboxylic acid, 2-fluoro-5- ({4-[l-(4-fluorophenyl)-4-{[(3R)-3-phenylpyrrolidin-l-yl]carbonyl}-lH-pyrazol-5- yl]piperidin- 1 -yl } methyl)benzamide, N- { [4-( { 4- [ l-(4-fluorophenyl)-4- { [(3R)-3- phenylpyrrolidin- 1 -yl]carbonyl } - 1 H-pyrazol-5 -yl]piperidin- 1 - yl } methyl)benzene] sulfonyl } acetamide, 1 - [2-(2-benzyl-2H- 1,2,3 ,4-tetrazol-5-yl)ethyl] -4- [ 1 - (4-fluorophenyl)-4-{ [(3R)-3-phenylpyrrolidin-l-yl]carbonyl}-lH-pyrazol-5-yl]piperidine, 4- ({4-[l-(4-fluorophenyl)-4-{[(3R)-3-phenylpyrrolidin-l-yl]carbonyl}-lH-pyrazol-5-yl]- 1,2,3, 6-tetrahydropyridin-l-yl}methyl)pyridine, 4-[l-(4-fluorophenyl)-4-{[(3R)-3- phenylpyrrolidin- 1 -yl]carbonyl } - 1 H-pyrazol-5 -yl] - 1 - [(3 -methylphenyl)methyl]piperidine, 4- ({4-[l-(4-fluorophenyl)-4-{[(3R)-3-phenylpyrrolidin-l-yl]carbonyl}-lH-pyrazol-5- yl]piperidin- 1 -yl } methyl)-N-hydroxybenzamide, 4- [ l-(4-fluorophenyl)-4- { [(3R)-3- phenylpyrrolidin- 1 -yljcarbonyl } - 1 H-pyrazol-5 -yl] - 1 - [2-(4-fluorophenyl)ethyl]piperidine, 2- ({4-[l-(4-fluorophenyl)-4-{[(3R)-3-phenylpyrrolidin-l-yl]carbonyl}-lH-pyrazol-5- yl]piperidin- 1 -yl } methyl)- 1 ,3-benzothiazole, 1 -(cyclopropylmethyl)-4-[ 1 -(4-fluorophenyl)-4- { [(3R)-3 -phenylpyrrolidin- 1 -yl]carbonyl } - 1 H-pyrazol-5 -yl]piperidine, 4- [ 1 -(4- fluorophenyl)-4-{ [(3R)-3-phenylpyrrolidin-l-yl]carbonyl}-lH-pyrazol-5-yl]-l-(2- methanesulfonylethyl)piperidine, l-(4-fluorophenyl)-5-{ l-[2-(4- methanesulfonylphenyl)ethyl]azetidin-3-yl}-4-[(3-methyl-3-phenylpyrrolidin-l-yl)carbonyl]- lH-pyrazole, 4-(2-{4-[l-(4-fluorophenyl)-4-{[(3R)-3-phenylpyrrolidin-l-yl]carbonyl}-lH- pyrazol-5 -yl]piperidin- 1 -yl } ethyl)benzoic acid, 4-( { 4- [ 1 -(4-chlorophenyl)-4- { [(3R)-3- methyl-3 -phenylpyrrolidin- l-yl]carbonyl } - lH-pyrazol-5-yl]piperidin- 1 - yl } methyl)benzonitrile, 4-({ 4- [ 1- (4-fluorophenyl) -4- [(3 -methyl- 3 -phenylpyrrolidin- 1 - yl)carbonyl]-lH-pyrazol-5-yl]piperidin-l-yl}methyl)benzonitrile, 3-({4-[l-(4-fluorophenyl)- 4-{[(3R)-3-phenylpyrrolidin-l-yl]carbonyl}-lH-pyrazol-5-yl]piperidin-l- yl } methyl)benzonitrile, 4-({ 4- [ l-(4-fluorophenyl)-4- { [(3R)-3-methyl-3-phenylpyrrolidin- 1- yl]carbonyl } - lH-pyrazol-5-yl]piperidin- 1 -yl } methyl)benzonitrile, 4-( {4-[ 1 -(4-fluorophenyl)- 4- { [(3 S)-3-methyl-3 -phenylpyrrolidin- 1 -yl]carbonyl } - 1 H-pyrazol-5 -yl]piperidin- 1 - yl } methyl)benzonitrile, 4- [ l-(4-fluorophenyl)-4- { [(3R)-3-phenylpyrrolidin- l-yl]carbonyl } - lH-pyrazol-5-yl]-l-(3,3,3-trifluoropropyl)piperidine, tert-butyl 3-{4-[l-(4-fluorophenyl)-4- { [(3R)-3 -phenylpyrrolidin- 1 -yl]carbonyl } - 1 H-pyrazol-5 -yl]piperidin- 1 -yl } pyrrolidine- 1 - carboxylate, l-(l-benzylpyrrolidin-3-yl)-4-[l-(4-fluorophenyl)-4-{ [(3R)-3-phenylpyrrolidin- 1 -yl]carbonyl } - 1 H-pyrazol-5 -yl]piperidine, 1 - [( 1 ,3 -dimethyl- 1 H-pyrazol-5 -yl)methyl] -4- [ 1 - (4-fluorophenyl)-4-{ [(3R)-3-phenylpyrrolidin-l-yl]carbonyl}-lH-pyrazol-5-yl]piperidine, 1- [(3,5-dimethyl-l,2-oxazol-4-yl)methyl]-4-[l-(4-fluorophenyl)-4-{ [(3R)-3-phenylpyrrolidin- l-yl]carbonyl}-lH-pyrazol-5-yl]piperidine, 4-({4-[l-(4-chlorophenyl)-4-{[(3S)-3-(2- fluorophenyl)pyrrolidin- 1 -yl]carbonyl } - lH-pyrazol-5 -yl]piperidin- 1 -yl } methyl)benzonitrile, 4-({4-[l-(4-chlorophenyl)-4-{ [(3R)-3-(2-fluorophenyl)pyrrolidin-l-yl]carbonyl}-lH- pyrazol-5 -yl]piperidin- 1 -yl } methyl)benzonitrile, 4-( { 4- [ 1 -(2,4-difluorophenyl)-4- { [(3R)-3 - phenylpyrrolidin- 1 -yl]carbonyl } - 1 H-pyrazol-5 -yl]piperidin- 1 -yl } methyl)benzoic acid, 4- [ 1 - (2,4-difluorophenyl)-4- { [(3R)-3 -phenylpyrrolidin- 1 -yl]carbonyl } - 1 H-pyrazol-5 -yl] - 1 - { [4- (lH-l,2,3,4-tetrazol-5-yl)phenyl]methyl}piperidine, 4-[l-(4-chloro-2-fluorophenyl)-4- {[(3R)-3-phenylpyrrolidin-l-yl]carbonyl}-lH-pyrazol-5-yl]-l-{ [4-(lH-l,2,3,4-tetrazol-5- yl)phenyl]methyl}piperidine, 4-[l-(4-fluorophenyl)-4-[(3-methyl-3-phenylpyrrolidin-l- yl)carbonyl]-lH-pyrazol-5-yl]-l-{ [4-(lH-l,2,3,4-tetrazol-5-yl)phenyl]methyl}piperidine, 2- [4-({4-[l-(4-fluorophenyl)-4-{ [(3R)-3-phenylpyrrolidin-l-yl]carbonyl}-lH-pyrazol-5- yl]piperidin-l-yl}methyl)phenyl]propanoic acid, 2-[4-({4-[l-(4-fluorophenyl)-4-{ [(3R)-3- phenylpyrrolidin- 1 -yljcarbonyl } - 1 H-pyrazol-5 -yl]piperidin- 1 -yl } methyl)phenyl] acetic acid, 4-( { 4- [ 1 -(4-fluorophenyl)-4- { [(3R)-3 -phenylpyrrolidin- 1 -yljcarbonyl } - 1 H-pyrazol-5 - yljpiperidin- 1 -yl } methyl)benzoic acid, 1 -[(1 ,5-dimethyl- lH-pyrazol-3-yl)methyl]-4- [ 1 -(4- fluorophenyl)-4-{ [(3R)-3-phenylpyrrolidin-l-yl]carbonyl}-lH-pyrazol-5-yl]piperidine, 4- ({ 4- [ 1 -(4-fluorophenyl)-4- [(3-methyl-3-phenylpyrrolidin- 1 -yl)carbonyl]- lH-pyrazol-5- yljpiperidin- 1 -yl } methyl)benzoic acid, 4- [ 1 -(4-fluorophenyl)-4- [(3 -methyl-3 - phenylpyrrolidin- 1 -yl)carbonyl] - 1 H-pyrazol-5 -yl] - 1 - [(4- methanesulfonylphenyl)methyl]piperidine, 5-({4-[l-(4-fluorophenyl)-4-{ [(3R)-3- phenylpyrrolidin- 1 -yljcarbonyl } - 1 H-pyrazol-5 -yljpiperidin- 1 -yl } methyl)- 1 ,2-oxazole-3 - carboxylic acid, 5-({4-[l-(4-fluorophenyl)-4-{ [(3R)-3-phenylpyrrolidin-l-yl]carbonyl}-lH- pyrazol-5-yl]piperidin-l-yl}methyl)-l-methyl-lH-pyrazole-3-carboxylic acid, 2-{ [4-({4-[l- (4-fluorophenyl)-4-{ [(3R)-3-phenylpyrrolidin-l-yl]carbonyl}-lH-pyrazol-5-yl]piperidin-l- yl}methyl)benzene]sulfonyl} acetic acid, (2E)-3-[4-({4-[l-(4-fluorophenyl)-4-{ [(3R)-3- phenylpyrrolidin- 1 -yljcarbonyl } - 1 H-pyrazol-5 -yljpiperidin- 1 -yl } methyl)phenyl]prop-2- enoic acid, 4- [ 1 -(4-fluorophenyl)-4- { [3-(2-fluorophenyl)pyrrolidin- 1 -yljcarbonyl } - 1H- pyrazol-5 -yl] - 1 - [(4-methanesulfonylphenyl)methyl]piperidine, 1 - { [4- (ethanesulfonyl)phenyl]methyl}-4-[l-(4-fluorophenyl)-4-{[(3R)-3-phenylpyrrolidin-l- yl]carbonyl}-lH-pyrazol-5-yl]piperidine, 4-[l-(4-fluorophenyl)-4-[(2,2,5,5-tetrahydrogenio- 3-methyl-3 -phenylpyrrolidin- 1 -yl)carbonyl] - 1 H-pyrazol-5 -yl] - 1 - [(4- methanesulfonylphenyl)methyl]piperidine, 4-[l-(4-fluorophenyl)-4-{[(3R)-3- phenylpyrrolidin- l-yl]carbonyl}- 1 H-pyrazol-5 -yl] - 1- { [4-(propane-2- sulfonyl)phenyl] methyl }piperidine, 4- { 4- [(3 ,3 -difluoro-4-phenylpyrrolidin- 1 -yl)carbonyl] - 1 - (4-fluorophenyl)-lH-pyrazol-5-yl}-l-[(4-methanesulfonylphenyl)methyl]piperidine, 4-(4- { [(4R)-3 ,3-difluoro-4-phenylpyrrolidin- 1 -yl]carbonyl } - 1 -(4-fluorophenyl)- lH-pyrazol-5-yl)- l-[(4-methanesulfonylphenyl)methyl]piperidine, 4-(4-{ [(4S)-3,3-difluoro-4- phenylpyrrolidin- l-yl]carbonyl } - 1 -(4-fluorophenyl)- lH-pyrazol-5-yl)- 1 -[(4- methanesulfonylphenyl)methyl]piperidine, tert-butyl N-{4-[l-(4-fluorophenyl)-4-{[(3R)-3- phenylpyrrolidin- 1 -yl]carbonyl } - 1 H-pyrazol-5 -yl]cyclohexyl } carbamate, N- { 4- [ 1 -(4- fluorophenyl)-4-{ [(3R)-3-phenylpyrrolidin-l-yl]carbonyl}-lH-pyrazol-5-yl]cyclohexyl}-4- methanesulfonylaniline, 5 -fluoro-2-(5 - { 1 - [(4-methanesulfonylphenyl)methyl]piperidin-4- yl}-4-{ [(3R)-3-phenylpyrrolidin-l-yl]carbonyl}-lH-pyrazol-l-yl)pyrimidine, 5-fluoro-2-(5- { l-[(4-methanesulfonylphenyl)methyl]piperidin-4-yl} -4-{ [(3S)-3-phenyl-3- (trifluoromethyl)pyrrolidin- 1 -yljcarbonyl } - 1 H-pyrazol- 1 -yl)pyrimidine, 2- { 4- [(3 ,3 -difluoro- 4-phenylpyrrolidin-l-yl)carbonyl]-5-{ l-[(4-methanesulfonylphenyl)methyl]piperidin-4-yl}- lH-pyrazol-l-yl}-5-fluoropyrimidine, 2-(4-{ [(4R)-3,3-difluoro-4-phenylpyrrolidin-l- yljcarbonyl } -5- { 1- [(4-methanesulfonylphenyl)methyl]piperidin-4-yl } - lH-pyrazol- 1 -yl)-5- fluoropyrimidine, 2-(4-{ [(4S)-3,3-difluoro-4-phenylpyrrolidin-l-yl]carbonyl}-5-{ l-[(4- methanesulfonylphenyl)methyl]piperidin-4-yl}-lH-pyrazol-l-yl)-5-fluoropyrimidine, 5- fluoro-2-(4-{ [(3R)-3-phenylpyrrolidin-l-yl]carbonyl}-5-[l-(pyrimidin-5-ylmethyl)piperidin- 4-yl]-lH-pyrazol-l-yl)pyrimidine, 4-({4-[l-(5-fluoropyrimidin-2-yl)-4-{[(3R)-3- phenylpyrrolidin- 1 -yljcarbonyl } - 1 H-pyrazol-5 -yljpiperidin- 1 -yl } methyl)benzene- 1 - sulfonamide, 5-chloro-2-(5-{ l-[(4-methanesulfonylphenyl)methyl]piperidin-4-yl}-4-{[(3R)-
3- phenylpyrrolidin- l-yl]carbonyl } - lH-pyrazol- 1 -yl)pyrimidine, 4-( { 4- [ l-(5- bromopyrimidin-2-yl)-4-{[(3R)-3-phenylpyrrolidin-l-yl]carbonyl}-lH-pyrazol-5- yljpiperidin- 1 -yl } methyl)benzene- 1 -sulfonamide, 4-( { 4- [ 1 -(5-fluoropyrimidin-2-yl)-4- { [(3R)-3 -phenylpyrrolidin- 1 -yljcarbonyl } - 1 H-pyrazol-5 -yljpiperidin- 1 - yl}methyl)benzonitrile, 3-fluoro-4-({4-[l-(5-fluoropyrimidin-2-yl)-4-{ [(3R)-3- phenylpyrrolidin- 1 -yljcarbonyl } - 1 H-pyrazol-5 -yljpiperidin- 1 -yl } methyl)benzonitrile, 2-(5 - { l-[(6-chloropyridin-3-yl)methyl]piperidin-4-yl}-4-{ [(3R)-3-phenylpyrrolidin-l- yl]carbonyl}-lH-pyrazol-l-yl)-5-fluoropyrimidine, 5-fluoro-2-(4-{[(3R)-3-phenylpyrrolidin- l-yl]carbonyl}-5-(l-{ [6-(lH-pyrazol-l-yl)pyridin-3-yl]methyl}piperidin-4-yl)-lH-pyrazol-l- yl)pyrimidine, 5-({4-[l-(5-fluoropyrimidin-2-yl)-4-{[(3R)-3-phenylpyrrolidin-l- yljcarbonyl } - lH-pyrazol-5 -yljpiperidin- 1 -yl } methyl)pyridin-2-amine, 5 -( { 4- [ 1 -(5 - fluoropyrimidin-2-yl)-4-{[(3R)-3-phenylpyrrolidin-l-yl]carbonyl}-lH-pyrazol-5- yl]piperidin-l-yl}methyl)pyrimidin-2-amine, 5-fluoro-2-(4-{[(3R)-3-phenylpyrrolidin-l- yljcarbonyl } -5- [ 1 -(pyridin-4-ylmethyl)piperidin-4-yl] - 1 H-pyrazol- 1 -yl)pyrimidine, 4- [(4- { 4- [(3,3-difluoro-4-phenylpyrrolidin-l-yl)carbonyl]-l-(5-fluoropyrimidin-2-yl)-lH-pyrazol-5- yl } piperidin- 1 -yl)methyl]benzonitrile, 2-(5 - { 1 - [(6-chloropyridin-3 -yl)methyl]piperidin-4- yl } -4- [(3 ,3 -difluoro-4-phenylpyrrolidin- 1 -yl)carbonyl] - lH-pyrazol- 1 -yl)-5 -fluoropyrimidine,
4- [(4- { 4- [(3 ,3 -difluoro-4-phenylpyrrolidin- 1 -yl)carbonyl] - 1 -(5 -fluoropyrimidin-2-yl)- 1 H- pyrazol-5 -yl }piperidin- 1 -yl)methyl]benzene- 1 -sulfonamide, 2- { 4- [(3 ,3 -difluoro-4- phenylpyrrolidin- 1 -yl)carbonyl] -5 - [ 1 -(pyridin-4-ylmethyl)piperidin-4-yl] - 1 H-pyrazol- 1 -yl } -
5- fluoropyrimidine, 4-{[4-(4-{ [(4R)-3,3-difluoro-4-phenylpyrrolidin-l-yl]carbonyl}-l-(4- fluorophenyl)-lH-pyrazol-5-yl)piperidin-l-yl]methyl}benzene-l-sulfonamide, 4-{ [4-(4- {[(4S)-3,3-difluoro-4-phenylpyrrolidin-l-yl]carbonyl}-l-(4-fluorophenyl)-lH-pyrazol-5- yl)piperidin- 1 -yljmethyl } benzene- 1 -sulfonamide, 4- { 4- [(3 ,3 -difluoro-4-phenylpyrrolidin- 1 - yl)carbonyl] - 1 -(4-fluorophenyl)-3-methyl- 1 H-pyrazol-5 -yl } - 1 - [(4- methanesulfonylphenyl)methyl]piperidine, 2- { 4- [(3 ,3 -difluoro-4-phenylpyrrolidin- 1 - yl)carbonyl]-5-(l-{ [6-(trifluoromethyl)pyridin-3-yl]methyl}piperidin-4-yl)-lH-pyrazol-l- yl } -5 -fluoropyrimidine, 2- { 4- [(3 ,3-difluoro-4-phenylpyrrolidin- 1 -yl)carbonyl] -5- { 1 - [(6- methoxypyridin-3-yl)methyl]piperidin-4-yl}-lH-pyrazol-l-yl}-5-fluoropyrimidine, 2-(4- {[(4R)-3,3-difluoro-4-phenylpyrrolidin-l-yl]carbonyl}-5-(l-{[6-(trifluoromethyl)pyridin-3- yl]methyl}piperidin-4-yl)-lH-pyrazol-l-yl)-5-fluoropyrimidine, 2-(4-{[(4R)-3,3-difluoro-4- phenylpyrrolidin- 1 -yljcarbonyl } -5 - { 1 - [(6-methoxypyridin-3 -yl)methyl]piperidin-4-yl } - 1H- pyrazol- 1 -yl)-5-fluoropyrimidine, 2-(4- { [(4R)-3 ,3-difluoro-4-phenylpyrrolidin- 1 - yl]carbonyl}-5-(l-{[4-(trifluoromethane)sulfonylphenyl]methyl}piperidin-4-yl)-lH-pyrazol- l-yl)-5-fluoropyrimidine, 2-(4-{ [(4S)-3,3-difluoro-4-phenylpyrrolidin-l-yl]carbonyl}-5-(l- {[4-(trifluoromethane)sulfonylphenyl]methyl}piperidin-4-yl)-lH-pyrazol-l-yl)-5- fluoropyrimidine, 4-( { 4- [ 1 -(4-fluorophenyl)-4- { [3 -(4-fluorophenyl)pyrrolidin- 1 - yljcarbonyl } - lH-pyrazol-5 -yljpiperidin- 1 -yl } methyl)benzene- 1 -sulfonamide, 4- [ 1 -(4- fluorophenyl)-4- { [3-(4-fluorophenyl)pyrrolidin- 1 -yljcarbonyl } - 1 H-pyrazol-5 -yl] - 1 - [(4- methanesulfonylphenyl)methyl]piperidine, 4-({4-[l-(4-fluorophenyl)-4-{ [(3R)-3-(4- fluorophenyl)pyrrolidin- 1 -yljcarbonyl } - lH-pyrazol-5 -yljpiperidin- 1 -yl } methyl)benzene- 1 - sulfonamide, 4-({4-[l-(4-fluorophenyl)-4-{ [(3S)-3-(4-fluorophenyl)pyrrolidin-l- yljcarbonyl } - lH-pyrazol-5 -yljpiperidin- 1 -yl } methyl)benzene- 1 -sulfonamide, 4- [ 1 -(4- fluorophenyl)-4-{ [(3R)-3-(4-fluorophenyl)pyrrolidin-l-yl]carbonyl}-lH-pyrazol-5-yl]-l-[(4- methanesulfonylphenyl)methyl]piperidine, 4-[l-(4-fluorophenyl)-4-{[(3S)-3-(4- fluorophenyl)pyrrolidin- 1 -yljcarbonyl } - lH-pyrazol-5 -yl] - 1 - [(4- methanesulfonylphenyl)methyl]piperidine, 4-{ [4-(4-{ [3,3-difluoro-4-(4- fluorophenyl)pyrrolidin-l-yl]carbonyl}-l-(4-fluorophenyl)-lH-pyrazol-5-yl)piperidin-l- yl] methyl } benzene- 1 -sulfonamide, 4-(4- { [3,3-difluoro-4-(4-fluorophenyl)pyrrolidin- 1 - yl]carbonyl } - l-(4-fluorophenyl)- lH-pyrazol-5-yl)- 1 - [(4- methanesulfonylphenyl)methyl]piperidine, methyl 2-(4-{4-[(3,3-difluoro-4-phenylpyrrolidin- l-yl)carbonyl]-l-(4-fluorophenyl)-lH-pyrazol-5-yl}piperidin-l-yl)-2-(4- methanesulfonylphenyl)acetate, 4-{ [4-(4-{ [(4R)-3,3-difluoro-4-(4-fluorophenyl)pyrrolidin-l- yl]carbonyl}-l-(4-fluorophenyl)-lH-pyrazol-5-yl)piperidin-l-yl]methyl}benzene-l- sulfonamide, 4-{ [4-(4-{[(4S)-3,3-difluoro-4-(4-fluorophenyl)pyrrolidin-l-yl]carbonyl}-l-(4- fluorophenyl)-lH-pyrazol-5-yl)piperidin-l-yl]methyl}benzene-l-sulfonamide, 4-(4-{ [(4R)- 3,3-difluoro-4-(4-fluorophenyl)pyrrolidin-l-yl]carbonyl}-l-(4-fluorophenyl)-lH-pyrazol-5- yl)-l-[(4-methanesulfonylphenyl)methyl]piperidine, 4-(4-{[(4S)-3,3-difluoro-4-(4- fluorophenyl)pyrrolidin-l-yl]carbonyl}-l-(4-fluorophenyl)-lH-pyrazol-5-yl)-l-[(4- methanesulfonylphenyl)methyl]piperidine, 4-{ [4-(4-{ [3-(4-fluorophenyl)pyrrolidin-l- yl]carbonyl}-l-(5-fluoropyrimidin-2-yl)-lH-pyrazol-5-yl)piperidin-l-yl]methyl}benzene-l- sulfonamide, 4-{ [4-(4-{[3,3-difluoro-4-(4-fluorophenyl)pyrrolidin-l-yl]carbonyl}-l-(5- fluoropyrimidin-2-yl)-lH-pyrazol-5-yl)piperidin-l-yl]methyl}benzene-l-sulfonamide, 2-(4- { [3 ,3-difluoro-4-(4-fluorophenyl)pyrrolidin- 1 -yljcarbonyl } -5 - { 1 - [(4- methanesulfonylphenyl)methyl]piperidin-4-yl } - 1 H-pyrazol- 1 -yl)-5 -fluoropyrimidine, 4- { 4- [(3,3-difluoro-4-phenylpyrrolidin-l-yl)carbonyl]-l-(4-fluorophenyl)-lH-pyrazol-5-yl}-l-[(3- fluoro-4-methanesulfonylphenyl)methyl]piperidine, 5-fluoro-2-(4-{ [3-(4- fluorophenyl)pyrrolidin-l-yl]carbonyl}-5-{ l-[(4-methanesulfonylphenyl)methyl]piperidin-4- yl } - 1 H-pyrazol- 1 -yl)pyrimidine, 4- { [4-(4- { [(3R)-3 -(4-fluorophenyl)pyrrolidin- 1 - yl]carbonyl}-l-(5-fluoropyrimidin-2-yl)-lH-pyrazol-5-yl)piperidin-l-yl]methyl}benzene-l- sulfonamide, 4- { [4-(4- { [(3 S)-3 -(4-fluorophenyl)pyrrolidin- 1 -yljcarbonyl } - 1 -(5- fluoropyrimidin-2-yl) - 1 H-pyrazol-5 -yl)piperidin- 1 -yl] methyl } benzene- 1 - sulfonamide , 5 - fluoro-2-(4-{ [(3R)-3-(4-fluorophenyl)pyrrolidin-l-yl]carbonyl}-5-{ l-[(4- methanesulfonylphenyl)methyl]piperidin-4-yl } - 1 H-pyrazol- 1 -yl)pyrimidine, 5 -fluoro-2-(4- { [(3S)-3 -(4-fluorophenyl)pyrrolidin- 1 -yljcarbonyl } -5 - { 1 - [(4- methanesulfonylphenyl)methyl]piperidin-4-yl}-lH-pyrazol-l-yl)pyrimidine, 4-{ [4-(4- { [(4R)-3 ,3 -difluoro-4-(4-fluorophenyl)pyrrolidin- 1 -yljcarbonyl } - 1 -(5 -fluoropyrimidin-2-yl)- lH-pyrazol-5-yl)piperidin-l-yl]methyl}benzene-l-sulfonamide, 2-(4-{[(4R)-3,3-difluoro-4- (4-fluorophenyl)pyrrolidin- 1 -yljcarbonyl } -5 - { 1 - [(4- methanesulfonylphenyl)methyl]piperidin-4-yl}-lH-pyrazol-l-yl)-5-fluoropyrimidine, 2-(4- { [3 ,3-difluoro-4-(4-fluorophenyl)pyrrolidin- 1 -yljcarbonyl } -5 - { 1 - [(4- methanesulfonylphenyl)methyl]piperidin-4-yl } - 1 H-pyrazol- 1 -yl)-5 -fluoropyridine, 4- { 4- [(3 ,3-difluoro-4-phenylpyrrolidin- 1 -yl)carbonyl] - 1 -(4-fluorophenyl)- 1 H-pyrazol-5 -yl } - 1 - { [4- methanesulfonyl-2-(trifluoromethyl)phenyl]methyl } piperidine, 5 - [(4- { 4- [(3 ,3 -difluoro-4- phenylpyrrolidin- 1 -yl)carbonyl] - 1 -(4-fluorophenyl)- 1 H-pyrazol-5 -yl } piperidin- 1 -yl)methyl] - 2-methanesulfonylbenzonitrile, 2-(4-{[(4R)-3,3-difluoro-4-(4-fluorophenyl)pyrrolidin-l- yljcarbonyl } -5- { 1- [(4-methanesulfonylphenyl)methyl]piperidin-4-yl } - lH-pyrazol- 1 -yl)-5- fluoropyridine, 4- { 4- [(3 ,3 -difluoro-4-phenylpyrrolidin- 1 -yl)carbonyl] - 1 -(4-fluorophenyl)- lH-pyrazol-5-yl } - 1 - [(2-fluoro-4-methanesulfonylphenyl)methyl]piperidine, 4- { 4- [(3 ,3 - difluoro-4-phenylpyrrolidin- 1 -yl)carbonyl]- 1 -(4-fluorophenyl)- lH-pyrazol-5-yl } - 1 - [(4- methanesulfonylphenyl)-l,l-(dideuterium) methyljpiperidine, 4-{[4-(4-{[(4R)-3,3-difluoro- 4-phenylpyrrolidin- l-yl]carbonyl} - l-(2,4-difluorophenyl)- lH-pyrazol-5-yl)piperidin- 1- yl] methyl } benzene- 1 -sulfonamide, 4-(4- { [3,3-difluoro-4-(4-fluorophenyl)pyrrolidin- 1 - yljcarbonyl } - l-(4-fluorophenyl)- lH-pyrazol-5-yl)- 1 - [(4-methanesulfonylphenyl)- 1 , 1 - (dideuterium) methyljpiperidine, l-[(4-methanesulfonylphenyl)methyl]-4-(l-methyl-4- {[(3R)-3-phenylpyrrolidin-l-yl]carbonyl}-lH-pyrazol-5-yl)piperidine, 4-(4-{[3,3-difluoro-4- (4-fluorophenyl)pyrrolidin- 1 -yljcarbonyl } - 1 -propyl- lH-pyrazol-5-yl)- 1 -[(4- methanesulfonylphenyl)methyl]piperidine, 1 - [(4-methanesulfonylphenyl)methyl] -4-(4- { [(3R)-3-phenylpyrrolidin- 1 -yljcarbonyl } - 1 -propyl- lH-pyrazol-5-yl)piperidine, 4-(l -butyl- 4-{[(3R)-3-phenylpyrrolidin-l-yl]carbonyl}-lH-pyrazol-5-yl)-l-[(4- methanesulfonylphenyl)methyl]piperidine, 4- { 4- [(3 ,3 -difluoro-4-phenylpyrrolidin- 1 - yl)carbonyl] - 1 -propyl- 1 H-pyrazol-5-yl } - 1 - [(4-methanesulfonylphenyl)methyl]piperidine, 4- [(4-{4-[(3,3-difluoro-4-phenylpyrrolidin-l-yl)carbonyl]-l-propyl-lH-pyrazol-5-yl}piperidin- 1 -yl)methyl]benzene- 1 -sulfonamide, 4- [(4- { 4- [(3 ,3-difluoro-4-phenylpyrrolidin- 1 - yl)carbonyl] - 1 -propyl- 1 H-pyrazol-5-yl } piperidin- 1 -yl)methyl]benzene- 1 -sulfonamide, 4- { 1 - butyl-4- [(3 ,3-difluoro-4-phenylpyrrolidin- 1 -yl)carbonyl] - lH-pyrazol-5 -yl } - 1 - [(4- methanesulfonylphenyl)methyl]piperidine, 4-(4-{[(4R)-3,3-difluoro-4-phenylpyrrolidin-l- yl]carbonyl}-l-ethyl-lH-pyrazol-5-yl)-l-[(4-methanesulfonylphenyl)methyl]piperidine, 4- {[4-(4-{ [(4R)-3,3-difluoro-4-phenylpyrrolidin-l-yl]carbonyl}-l-ethyl-lH-pyrazol-5- yl)piperidin- 1 -yljmethyl } benzene- 1 -sulfonamide, 4- [(4- { 1 -butyl-4- [(3 ,3 -difluoro-4- phenylpyrrolidin- 1 -yl)carbonyl] - 1 H-pyrazol-5 -yl } piperidin- 1 -yl)methyl]benzene- 1 - sulfonamide, 4-{ [4-(4-{[(4R)-3,3-difluoro-4-phenylpyrrolidin-l-yl]carbonyl}-l-propyl-lH- pyrazol-5-yl)piperidin-l-yl]methyl}benzene-l-sulfonamide, 4-{[4-(4-{[(4S)-3,3-difluoro-4- phenylpyrrolidin- l-yl]carbonyl } - 1 -propyl- lH-pyrazol-5-yl)piperidin- l-yl]methyl }benzene- 1-sulfonamide, 4-(l-ethyl-4-{ [(3R)-3-phenylpyrrolidin-l-yl]carbonyl}-lH-pyrazol-5-yl)-l- [(4-methanesulfonylphenyl)methyl]piperidine, 4-{[l-(4-fluorophenyl)-4-{ [(3R)-3- phenylpyrrolidin- 1 -yljcarbonyl } - 1 H-pyrazol-5 -yljmethyl } - 1 -(4- methanesulfonylphenyl)piperidine, 4- { 4- [(3 ,3-difluoro-4-phenylpyrrolidin- 1 -yl)carbonyl]- 1- (4-fluorophenyl)- lH-pyrazol-5-yl } - 1 - [ l-(4-methanesulfonylphenyl)ethyl]piperidine, 3- [ l-(4- chlorophenyl)-4-{[(3R)-3-phenylpyrrolidin-l-yl]carbonyl}-lH-pyrazol-5-yl]-l-(4- methanesulfonylphenyl)piperidine, N-[l-(4-fluorophenyl)-4-{[(3R)-3-phenylpyrrolidin-l- yl]carbonyl}-lH-pyrazol-5-yl]-l-(4-methanesulfonylphenyl)piperidin-4-amine, 3-[l-(4- chlorophenyl)-4-{ [(3R)-3-phenylpyrrolidin-l-yl]carbonyl}-lH-pyrazol-5-yl]-l-[(4- methanesulfonylphenyl)methyl]piperidine, 4- [ 1 -(4- { 4- [(3 ,3-difluoro-4-phenylpyrrolidin- 1 - yl)carbonyl]- l-(4-fluorophenyl)- lH-pyrazol-5-yl }piperidin- l-yl)-2,2,2- trifluoroethyl]benzonitrile, 4- [ 1 -(4-fluorophenyl)-4- { [(3R)-3 -phenylpyrrolidin- 1 - yljcarbonyl } - lH-pyrazol-5 -yl] -N- [(4-methanesulfonylphenyl)methyl]cyclohexan- 1 -amine, 4- [ 1 -(4-fluorophenyl)-4- { [(3R)-3 -phenylpyrrolidin- 1 -yljcarbonyl } - 1 H-pyrazol-5 -yl] - 1 - [(4- methanesulfonylphenyl)methyl]-l-methylpiperidin-l-ium, 4-[l-(4-fluorophenyl)-4-{ [(3R)-3- phenylpyrrolidin- 1 -yljcarbonyl } - 1 H-pyrazol-5 -yl] - 1 - [(4-methanesulfonylphenyl)methyl] - 1 - methylpiperidin-l-ium, and l-ethyl-4-[l-(4-fluorophenyl)-4-{ [(3R)-3-phenylpyrrolidin-l- yl]carbonyl } - lH-pyrazol-5 -yl] - 1 - [(4-methanesulfonylphenyl)methyl]piperidin- 1 -ium.
[00019] Another aspect provided herein are pharmaceutical compositions comprising a therapeutically effective amount of a compound of any of the aforementioned compounds of Formulas (I)-(VIII), and a pharmaceutically acceptable excipient.
[00020] Another aspect provided herein are medicaments for treating a TGR5 mediated disease or disorder, wherein the medicament comprises a therapeutically effective amount of any of the aforementioned compounds of Formulas (I)-(VIII). In certain embodiments of such medicaments, the TGR5 mediated disease or disorder is selected from diabetes, an inflammatory disorders and an autoimmune disease. In certain embodiments of such medicaments, the TGR5 mediated disease or disorder is type II diabetes or psoriasis.
[00021] Another aspect provided herein is the use of a compound of Formulas (I)-(VIII) in the manufacture of a medicament for treating a TGR5 mediated disease or disorder, wherein the disease or disorder is selected from diabetes, an inflammatory disorders and an autoimmune disease. In certain embodiments of such uses the TGR5 mediated disease or disorder is type II diabetes or psoriasis.
[00022] Another aspect provided herein is methods for treating a TGR5 mediated disease or disorder comprising administering to a subject in need thereof, a therapeutically effective amount of any of the aforementioned compounds of Formulas (I)-(VIII). In certain embodiments of such methods, the TGR5 mediated disease or disorder is selected from diabetes, an inflammatory disorders and an autoimmune disease. In certain embodiments of such methods, the TGR5 mediated disease or disorder is type II diabetes or psoriasis. In certain embodiments of such methods, the compound is an agonist of TGR5.
[00023] Another aspect provided herein is a compound for use in a method of medical treatment, wherein the method of medical treatment is for treating a TGR5 mediated disease or disorder, wherein the disease is selected from diabetes, an inflammatory disorders and an autoimmune disease, and wherein the compound is any of the aforementioned compounds of Formulas (I)-(VIII), or pharmaceutically acceptable salt thereof. In certain embodiments of this aspect, the TGR5 mediated disease or disorder is type II diabetes or psoriasis.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
[00024] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which this invention pertains. The following references provide one of skill with a general definition of many of the terms used in this invention: Oxford Dictionary of Biochemistry and Molecular Biology, Smith et al. (eds.), Oxford University Press (revised ed., 2000); Dictionary of Microbiology and Molecular Biology, Singleton et al. (Eds.), John Wiley & Sons (3rd ed., 2002); and A Dictionary of Biology (Oxford Paperback Reference), Martin and Hine (Eds.), Oxford University Press (4th ed., 2000). In addition, the following definitions are provided to assist the reader in the practice of the invention.
[00025] The term "alkene" or "alkenyl", as used herein, refers to a partially unsaturated branched or straight chain hydrocarbon having at least one carbon-carbon double bond. Atoms oriented about the double bond are in either the cis (Z) or trans (E) conformation. As used herein, the terms "C2-C4alkenyl", "C2-C5alkenyl", "C2-C6alkenyl", "C2-C7alkenyl", and "C2-C8alkenyl" refer to an alkenyl group containing at least 2, and at most 4, 5, 6, 7 or 8 carbon atoms, respectively. Non-limiting examples of alkenyl groups, as used herein, include ethenyl, propenyl, allyl (2-propenyl), butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl and the like. In certain embodiments an alkene or alkenyl group is optionally substituted.
[00026] The term "alkenylene," as used herein, refers to a saturated branched or straight chain divalent hydrocarbon radical derived from an alkenyl group. In certain embodiments an alkenylene group is optionally substituted. As used herein, the terms "C2-C3 alkenylene", "C2- C4alkenylene", "C2-C5alkenylene", "C2-C6alkenylene", "C2-C7alkenylene" and "C2- Csalkenylene" refer to an alkenylene group containing at least 2, and at most 3, 4, 5, 6, 7 or 8 carbon atoms respectively. Non-limiting examples of alkenylene groups as used herein include, ethenlene, n-propenylene, isopropenylene, n-butenylene, isobutenylene, sec- butenylene, t-butenylene, n-pentenylene, isopentenylene, hexenylene and the like.
[00027] The term "alkyl," as used herein, refers to a saturated branched or straight chain hydrocarbon. An alkyl group can be optionally substituted. As used herein, the terms "Q- C3alkyl", "Ci-C4alkyl", "Ci-C5alkyl", "Ci-C6alkyl", "Ci-C7alkyl" and "Ci-C8alkyl" refer to an alkyl group containing at least 1, and at most 3, 4, 5, 6, 7 or 8 carbon atoms, respectively. Non- limiting examples of alkyl groups as used herein include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, hexyl, heptyl, octyl, nonyl, decyl and the like. In certain embodiments an alkyl group is optionally substituted.
[00028] The term "alkylene," as used herein, refers to a saturated branched or straight chain divalent hydrocarbon radical derived from an alkyl group. In certain embodiments the alkylene group is optionally substituted. As used herein, the terms "Ci-C3alkylene", "Cr C4alkylene", "C C5alkylene", "C C6alkylene", "C C7alkylene" and "C C8alkylene" refer to an alkylene group containing at least 1, and at most 3, 4, 5, 6, 7 or 8 carbon atoms respectively. Non-limiting examples of alkylene groups as used herein include, methylene, ethylene, n-propylene, isopropylene, n-butylene, isobutylene, sec-butylene, t-butylene, n- pentylene, isopentylene, hexylene and the like.
[00029] The term "alkyne" or "alkynyl", as used herein, refers to a partially unsaturated branched or straight chain hydrocarbon radical having at least one carbon-carbon triple bond. As used herein, the terms "C2-C4alkynyl", "C2-C5alkynyl", "C2-C6alkynyl", "C2-C7alkynyl", and "C2-C8alkynyl" refer to an alkynyl group containing at least 2, and at most 4, 5, 6, 7 or 8 carbon atoms, respectively. Non-limiting examples of alkynyl groups, as used herein, include ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl and the like. In certain embodiments the alkyne or alkynyl group is optionally substituted.
[00030] The term "alkynylene," as used herein, refers to a saturated branched or straight chain divalent hydrocarbon radical derived from an alkynyl group. In certain embodiments the alkynylene group is optionally substituted. As used herein, the terms "C2-C3alkynylene", "C2-C4alkynylene", "C2-C5alkynylene", "C2-C6alkynylene", "C2-C7alkynylene" and "C2- Csalkynylene" refer to an alkynylene group containing at least 2, and at most 3, 4, 5, 6, 7 or 8 carbon atoms respectively. Non-limiting examples of alkenylene groups as used herein include, ethynlene, propynylene, butynylene, pentynylene, hexynylene and the like.
[00031] The term "alkoxy," as used herein, refers to the group -ORa, where Ra is an alkyl group as defined herein. In certain embodiments the alkoxy group is optionally substituted. As used herein, the terms "C C3alkoxy", "C C4alkoxy", "C C5alkoxy", "C C6alkoxy", "Ci-C7alkoxy" and "Ci-Csalkoxy" refer to an alkoxy group wherein the alkyl moiety contains at least 1, and at most 3, 4, 5, 6, 7 or 8, carbon atoms. Non-limiting examples of alkoxy groups, as used herein, include methoxy, ethoxy, n-propoxy, isopropoxy, n-butyloxy, t- butyloxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, nonyloxy, decyloxy and the like.
[00032] The term "Cioaryl," as used herein, refers to naphthenyl or azulenyl, each of which is optionally substituted.
[00033] The term "C]4aryl," as used herein, refers to anthracenyl or phenanthrenyl, each of which is optionally substituted.
[00034] The term "arylene," as used means a divalent radical derived from a phenyl, Cioaryl or a Ci4aryl group. In certain embodiments the arylene group is optionally substituted.
[00035] The term "cyano," as used herein, refers to a -CN group.
[00036] The term "cycloalkyl," as used herein, refers to a saturated, monocyclic, fused bicyclic, fused tricyclic or bridged polycyclic ring assembly. As used herein, the terms "C3- C5cycloalkyl", "C3-C6cycloalkyl", "C3-C7cycloalkyl", "C3-C8cycloalkyl, "C3-C9cycloalkyl and "C3-Ciocycloalkyl refer to a cycloalkyl group wherein the saturated, monocyclic, fused bicyclic or bridged polycyclic ring assembly contain at least 3, and at most 5, 6, 7, 8, 9 or 10, carbon atoms. In certain embodiments the cycloalkyl group is optionally substituted. Non- limiting examples of cycloalkyl groups, as used herein, include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl,
decahydronaphthalenyl and the like.
[00037] The term "cycloalkylene," as used means a divalent radical derived from a cycloalkyl group. In certain embodiments the cycloalkylene group is optionally substituted.
[00038] The term "halogen," as used herein, refers to fluorine (F), chlorine (CI), bromine (Br), or iodine (I).
[00039] The term "halo," as used herein, refers to the halogen radicals: fluoro (-F), chloro (-C1), bromo (-Br), and iodo (-1).
[00040] The terms "haloalkyl" or "halo-substituted alkyl," as used herein, refers to an alkyl group as defined herein, substituted with one or more halogen groups, wherein the halogen groups are the same or different. In certain embodiments the haloalkyl group is optionally substituted. Non- limiting examples of such branched or straight chained haloalkyl groups, as used herein, include methyl, ethyl, propyl, isopropyl, isobutyl and n-butyl substituted with one or more halogen groups, wherein the halogen groups are the same or different, including, but not limited to, trifluoromethyl, pentafluoroethyl, and the like.
[00041] The terms "haloalkenyl" or "halo-substituted alkenyl," as used herein, refers to an alkenyl group as defined herein, substituted with one or more halogen groups, wherein the halogen groups are the same or different. In certain embodiments the haloalkenyl group is optionally substituted. Non-limiting examples of such branched or straight chained haloalkenyl groups, as used herein, include ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl and the like substituted with one or more halogen groups, wherein the halogen groups are the same or different.
[00042] The terms "haloalkynyl" or "halo-substituted alkynyl," as used herein, refers to an alkynyl group as defined above, substituted with one or more halogen groups, wherein the halogen groups are the same or different. In certain embodiments the haloalkynyl group is optionally substituted. Non-limiting examples of such branched or straight chained haloalkynyl groups, as used herein, include ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl, and the like substituted with one or more halogen groups, wherein the halogen groups are the same or different.
[00043] The term "haloalkoxy" or "halo-substituted-alkoxy," as used herein, refers to an alkoxy group as defined herein, substituted with one or more halogen groups, wherein the halogen groups are the same or different. In certain embodiments the haloalkoxy group is optionally substituted. Non-limiting examples of such branched or straight chained haloalkynyl groups, as used herein, include methoxy, ethoxy, n-propoxy, isopropoxy, n- butyloxy, t-butyloxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, nonyloxy, decyloxy and the like, substituted with one or more halogen groups, wherein the halogen groups are the same or different.
[00044] The term "heteroalkyl," as used herein, refers to an alkyl group as defined herein wherein one or more carbon atoms are independently replaced by one or more of oxygen, sulfur, nitrogen, or combinations thereof.
[00045] The term "heteroaryl," as used herein, refers to monocyclic, fused bicyclic, and fused tricyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic, at least one ring in the system contains one or more heteroatoms selected from nitrogen, oxygen and sulfur, and wherein each ring in the system contains 3 to 7 ring members. A heteroaryl group may contain one or more substituents. In certain embodiments the heteroaryl group is optionally substituted. Non- limiting examples of heteroaryl groups, as used herein, include benzofuranyl, benzofurazanyl, benzoxazolyl, benzopyranyl, benzthiazolyl, benzothienyl, benzazepinyl, benzimidazolyl, benzothiopyranyl, benzo[l,3]dioxole, benzo[b]furyl, benzo[b]thienyl, cinnolinyl, furazanyl, furyl, furopyridinyl, imidazolyl, indolyl, indolizinyl, indolin-2-one, indazolyl, isoindolyl, isoquinolinyl, isoxazolyl, isothiazolyl, 1,8-naphthyridinyl, oxazolyl, oxaindolyl, oxadiazolyl, pyrazolyl, pyrrolyl, phthalazinyl, pteridinyl, purinyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, quinoxalinyl, quinolinyl, quinazolinyl, 4H-quinolizinyl, thiazolyl, thiadiazolyl, thienyl, triazinyl,triazolyl and tetrazolyl.
[00046] The term "heteroarylene," as used means a divalent radical derived from a heteroaryl group. In certain embodiments the heteroarylene group is optionally substituted.
[00047] The term "heterocycloalkyl," as used herein, refers to a cycloalkyl, as defined herein, wherein one or more of the ring carbons are replaced by a moiety selected from -0-, - N=, -NR-, -C(O)-, -S-, -S(O) - or -S(0)2-, wherein R is hydrogen, C C4alkyl or a nitrogen protecting group, with the proviso that the ring of said group does not contain two adjacent O or S atoms. In certain embodiments the heterocycloalkyl group is optionally substituted. Non-limiting examples of heterocycloalkyl groups, as used herein, include azetidinyl, morpholino, pyrrolidinyl, pyrrolidinyl-2-one, piperazinyl, piperidinyl, piperidinyl-2-one, piperidinyl-3-one, piperidinyl-4-one, l,4-dioxa-8-aza-spiro[4.5]dec-8-yl, 2H-pyrrolyl, 2- pyrrolinyl, 3-pyrrolinyl, 1,3-dioxolanyl, 2-imidazolinyl, imidazolidinyl, 2-pyrazolinyl, pyrazolidinyl, 1,4-dioxanyl, 1 ,4-dithianyl, thiomorpholinyl, azepanyl, hexahydro-1,4- diazepinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, thioxanyl, azetidinyl, oxetanyl, thietanyl, oxepanyl, thiepanyl, 1,2,3,6-tetrahydropyridinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl, and 3-azabicyclo[4.1.0]heptanyl.
[00048] The term "heterocycloalkylene," as used means a divalent radical derived from a heterocycloalkyl group. In certain embodiments the heterocycloalkylene group is optionally substituted.
[00049] The term "heteroatom," as used herein, refers to one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon.
[00050] The term "hydroxyl," as used herein, refers to the group -OH.
[00051] The term "hydroxyalkyl" or hydroxyl-substituted-alkyl," as used herein, refers to an alkyl group as defined herein substituted with one or more hydroxyl group. Non-limiting examples of branched or straight chained "C1-C6 hydroxyalkyl groups as used herein include methyl, ethyl, propyl, isopropyl, isobutyl and n-butyl groups substituted with one or more hydroxyl groups.
[00052] The term "optionally substituted," as used herein, means that the referenced group may or may not be substituted with one or more additional group(s) individually and independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl,
heterocycloalkyl, hydroxyl, alkoxy, mercaptyl, cyano, halo, carbonyl, thiocarbonyl, isocyanato, thiocyanato, isothiocyanato, nitro, perhaloalkyl, perfluoroalkyl, and amino, including mono- and di-substituted amino groups, and the protected derivatives thereof. Non- limiting examples of optional substituents include, halo, -CN, =0, -OR, -C(0)R, -C(0)OR, - OC(0)R, -OC(0)OR, -C(0)NHR, -C(0)NR2, -OC(0)NHR, -OC(0)NR2, -SR-, -S(0)R, - S(0)2R, -NHR, -N(R)2, -NHC(0)R, -NRC(0)R, -NHC(0)OR, -NRC(0)OR, S(0)2NHR, - S(0)2N(R)2, -NHS(0)2, -NRS(0)2, -NHS(0)2R, -NRS(0)2R, C C8alkyl, C C8alkoxy, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, halo-substituted Ci-Csalkyl, halo-substituted Cr Csalkoxy, where each R is independently selected from H, halo, Ci-Csalkyl, Ci-Csalkoxy, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, halo-substituted Ci-Csalkyl, and halo- substituted Ci-Csalkoxy. The placement and number of such substituent groups is done in accordance with the well-understood valence limitations of each group, for example =0 is a suitable substituent for an alkyl group but not for an aryl group.
[00053] The term "solvate," as used herein, refers to a complex of variable stoichiometry formed by a solute (by way of example, a compound of Formula (I), or a salt thereof, as described herein) and a solvent. Non-limiting examples of a solvent are water, acetone, methanol, ethanol and acetic acid.
[00054] The term "acceptable" with respect to a formulation, composition or ingredient, as used herein, means having no persistent detrimental effect on the general health of the subject being treated.
[00055] The term "administration" or "administering" of the subject compound means providing a compound of Formula (I), a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate, or prodrug thereof to a subject in need of treatment.
[00056] The term "agent" or "test agent," as used herein, includes any substance, molecule, element, compound, entity, or a combination thereof. It includes, but is not limited to a protein, a polypeptide, a small organic molecule, a polysaccharide, a polynucleotide, and the like. It can be a natural product, a synthetic compound, or a chemical compound, or a combination of two or more substances. Unless otherwise specified, the terms "agent", "substance", and "compound" can be used interchangeably.
[00057] The term "cardiovascular disease," as used herein refers to diseases affecting the heart or blood vessels or both, including but not limited to: arrhythmia; atherosclerosis and its sequelae; angina; myocardial ischemia; myocardial infarction; cardiac or vascular aneurysm; vasculitis, stroke; peripheral obstructive arteriopathy of a limb, an organ, or a tissue; reperfusion injury following ischemia of the brain, heart or other organ or tissue; endotoxic, surgical, or traumatic shock; hypertension, valvular heart disease, heart failure, abnormal blood pressure; shock; vasoconstriction (including that associated with migraines); vascular abnormality, inflammation, insufficiency limited to a single organ or tissue.
[00058] The term "carrier," as used herein, refers to chemical compounds or agents that facilitate the incorporation of a compound described herein into cells or tissues.
[00059] The terms "co-administration" or "combined administration" or the like as used herein are meant to encompass administration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration or at the same time.
[00060] The term "contacting," as used herein, has its normal meaning and refers to combining two or more molecules (by way of example only, a small molecule organic compound and a polypeptide) or combining molecules and cells (by way of example only, a compound and a cell). Contacting can occur in-vitro, by way of example only, combining two or more agents or combining a compound and a cell or a cell lysate in a test tube or other container. Contacting can also occur in a cell or in-situ, by way of example only, contacting two polypeptides in a cell by coexpression in the cell of recombinant polynucleotides encoding the two polypeptides, or in a cell lysate. Contacting can occur in-vivo.
[00061] The term "diluent," as used herein, refers to chemical compounds that are used to dilute a compound described herein prior to delivery. Diluents can also be used to stabilize compounds described herein.
[00062] The terms "effective amount" or "therapeutically effective amount," as used herein, refer to a sufficient amount of a compound described herein being administered which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result can be reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an "effective amount" for therapeutic uses is the amount of the composition comprising a compound as disclosed herein required to provide a clinically significant decrease in disease symptoms. An appropriate "effective" amount in any individual case may be determined using techniques, such as a dose escalation study.
[00063] The terms "enhance" or "enhancing," as used herein, means to increase or prolong either in potency or duration a desired effect. Thus, in regard to enhancing the effect of therapeutic agents, the term "enhancing" refers to the ability to increase or prolong, either in potency or duration, the effect of other therapeutic agents on a system. An "enhancing- effective amount," as used herein, refers to an amount adequate to enhance the effect of another therapeutic agent in a desired system.
[00064] The term "iatrogenic," as used herein, means a condition, disorder, or disease created or worsened by medical or surgical therapy.
[00065] The term "inflammatory disorders", as used herein, refers to those diseases or conditions that are characterized by one or more of the signs of pain (dolor, from the generation of noxious substances and the stimulation of nerves), heat (calor, from
vasodilatation), redness (rubor, from vasodilatation and increased blood flow), swelling (tumor, from excessive inflow or restricted outflow of fluid), and loss of function (functio laesa, which may be partial or complete, temporary or permanent). Inflammation takes many forms and includes, but is not limited to, inflammation that is one or more of the following: acute, adhesive, atrophic, catarrhal, chronic, cirrhotic, diffuse, disseminated, exudative, fibrinous, fibrosing, focal, granulomatous, hyperplastic, hypertrophic, interstitial, metastatic, necrotic, obliterative, parenchymatous, plastic, productive, proliferous, pseudomembranous, purulent, sclerosing, seroplastic, serous, simple, specific, subacute, suppurative, toxic, traumatic, and/or ulcerative. Inflammatory disorders further include, without being limited to those affecting the blood vessels (polyarteritis, temporarl arteritis); joints (arthritis:
crystalline, osteo-, psoriatic, reactive, rheumatoid, Reiter's); gastrointestinal tract (Disease,); skin (dermatitis); or multiple organs and tissues (systemic lupus erythematosus).
[00066] The term "pharmaceutically acceptable," as used herein, refers a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compounds described herein. Such materials are administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.
[00067] The term "pharmaceutically acceptable salt," as used herein, refers to a formulation of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compounds described herein.
[00068] The term "prevent" or "prevention," as used herein, refers to a complete inhibition of development of primary or secondary tumors or any secondary effects of disease.
[00069] The terms "combination" or "pharmaceutical combination," as used herein mean 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. The term "fixed combination" means that the active ingredients, by way of example, a compound of Formula (I) and an additional therapeutic agent, are both administered to a patient simultaneously in the form of a single entity or dosage. The term "non-fixed combination" means that the active ingredients, by way of example, a compound of Formula (I) and an additional therapeutic agent, are both administered to a patient as separate entities either
simultaneously, concurrently or sequentially with no specific time limits, wherein such administration provides therapeutically effective levels of the 2 compounds in the body of the patient. The latter also applies to cocktail therapy, e.g. the administration of 3 or more active ingredients.
[00070] The terms "composition" or "pharmaceutical composition," as used herein, refers to a mixture of at least one compound of Formula (I) described herein with other chemical components, such as carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and/or excipients.
[00071] The term "prodrug," as used herein, refers to an agent that is converted into the parent drug in vivo. A non-limiting example of a prodrug of the compounds described herein is a compound described herein administered as an ester which is then metabolically hydrolyzed to a carboxylic acid, the active entity, once inside the cell. A further example of a prodrug is a short peptide bonded to an acid group where the peptide is metabolized to reveal the active moiety.
[00072] The term "subject" includes mammals, especially humans. It also encompasses other non-human animals such as cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys.
[00073] The term "therapeutically effective amount," as used herein, refers to any amount of a compound which, as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder. The term also includes within its scope amounts effective to enhance normal physiological function.
[00074] The terms "treat," "treating" or "treatment," as used herein, refers to methods of alleviating, abating or ameliorating a disease or condition symptoms, preventing additional symptoms, ameliorating or preventing or delaying the underlying metabolic causes of symptoms, inhibiting the disease or condition, arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition either prophylactically (prevent or delay the onset of the disease, or to prevent the manifestation of clinical or subclinical symptoms thereof) and/or therapeutically.
[00075] The compound names provided herein were obtained using ChemDraw Ultra 10.0 (CambridgeSoft®) or JChem version 5.3.1 (ChemAxon).
[00076] Other objects, features and advantages of the methods, compositions and combinations described herein will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating specific embodiments, are given by way of illustration only.
Description of Preferred Embodiments
[00077] Provided herein are compounds of Formula (I), pharmaceutically acceptable salts, solvates, N-oxides, prodrugs and isomers thereof that are agonists of TGR5.
[00078] Further provided herein are compounds, pharmaceutically acceptable salts, solvates, N-oxides, prodrugs, enantiomers and isomers thereof, and pharmaceutical compositions containing such pharmaceutically acceptable salts, solvates, N-oxides, prodrugs, enantiomers and isomers thereof, for the treatment and/or prevention of TGR5 mediated diseases and/or disorders.
[00079] Also provided herein are compounds, pharmaceutically acceptable salts, solvates, N-oxides, prodrugs, enantiomers and isomers thereof, and pharmaceutical compositions containing such pharmaceutically acceptable salts, solvates, N-oxides, prodrugs, enantiomers and isomers thereof, in combination with one or more additional therapeutic agents for the treatment and/or prevention of TGR5 mediated diseases and/or disorders.
[00080] Such TGR5 mediated diseases or disorders include, but are not limited to, gallstones, cholestasis, diabetes, an inflammatory disorders and an autoimmune disease, such as, by way of example only, type II diabetes or psoriasis. [00081] Such autoimmune diseases and/or disorders and autoimmune -mediated diseases and/or disorders include, but are not limited to, destructive arthritis, rheumatoid arthritis, systemic lupus erythematosus, Sjogren's syndrome, multiple sclerosis, dermatomyositis, progressive systemic sclerosis, diseases affecting the nose including allergic rhinitis, and inflammatory disease in which autoimmune reactions are implicated or having an
autoimmune component or aetiology, including autoimmune haematological disorders (e.g. haemolytic anaemia, aplastic anaemia, pure red cell anaemia and idiopathic
thrombocytopenia), primary binary cirrhosis (PBC), lupus, systemic lupus erythematosus, polychondritis, sclerodoma, Wegener granulamatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Steven-Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel disease (e.g. ulcerative colitis and Crohn's disease), endocrine opthalmopathy, Grave's disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary billiary cirrhosis, uveitis (anterior and posterior), keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitial lung fibrosis, psoriatic arthritis and glomerulonephritis (with and without nephrotic syndrome, e.g. including idiopathic nephrotic syndrome or minimal change nephropathy).
[00082] Such inflammatory diseases and/or disorders include, but are not limited to, uveitis, atherosclerosis, atherogenesis, glomerulonephritis, Kawasaki disease, inflammatory responses, polymyositis, arthritis, neurological inflammation, chronic arthritis inflammation and osteoarthritis.
Compounds and compositions
[00083] The aforementioned compounds and pharmaceutically acceptable salts, solvates, N-oxides, prodrugs, enantiomers and isomers thereof, that are agonists of TGR5 are compounds having structures acco Formula (II):
Figure imgf000035_0001
(I)
wherein, R1 and R2 are each independently selected from Ci-Cealkyl, and C2-C6alkene, and taken together with the N atom to which they are attached form a 4 to 6 membered heterocycloalkyl ring containing a N heteroatom, a 9 to 14 membered fused bicyclic heterocycloalkyl ring containing a N heteroatom, or a 9 to 14 membered fused bicyclic heteroaryl containing an N heteroatom, wherein such heterocycloalkyl and fused bicyclic heteroaryl are each optionally substituted with 1 to 5 substituents independently selected from halogen, deuterium, C - C6alkyl, Ci-Cehaloalkyl, -CN, R9, -OR9, phenyl, phenoxy, Cioaryl and Ci4aryl, wherein such phenyl, phenoxy, Cioaryl and Ci4aryl are each optionally substituted with 1 to 5 substituents independently selected from halogen, deuterium and - 9;
Figure imgf000036_0001
2 is selected from -C(O)-, -C(0)0-, -(CH2)qC(0)0-, -S(0)2- C C6alkylene, phenylene, Cioarylene, C^arylene, a 5, 6, 9, 10 or 14 membered heteroarylene containing 1 to 2 heteroatoms independently selected from N, O and S, or a bond, wherein the Ci-Cealkylene ,arylene and heteroarylene of L2 are optionally substituted with 1 to 3 substituents independently selected from deuterium, R9 and -C(0)OR9;
is Ci-C6alkylene optionally substituted with 1 to 3 substituents independently selected deuterium, R9 and -C(0)OR9, or Ci-Cealkenylene optionally substituted with 1 to 3 substituents independently selected from deuterium, R9 and -C(0)OR9; U is selected from a -NR9-, -NR9C(0)0-, -NR9(CH2)q -, -C(0)NR9-, -S(0)2-, -0-, C Cealkylene, phenylene, Cioarylene, Ci4arylene, a 5, 6, 9, 10 or 14 membered heteroarylene containing 1 to 2 heteroatoms independently selected from N, O and S, wherein the Ci-Cealkylene, arylene and heteroarylene of L4 are optionally substituted with 1 to 3 substituents independently selected from deuterium, R9 and -C(0)OR9;
R3 is selected from Ci-Cealkyl, Ci-Cehaloalkyl, C3-C8cycloalkyl, -L3R6 , phenyl, Cioaryl, C]4aryl, a 5, 6, 9, 10 or 14 membered heteroaryl containing 1 to 3 N heteroatoms and optionally one heteroatom selected from O and S, and a 4 to 7 membered heterocycloalkyl ring containing 1 to 2 heteroatoms independently selected from N, O and S, wherein the Ci-Cealkyl, aryl, heterocycloalkyl, C3- Cscycloalkyl and heteroaryl groups of R3 are each optionally substituted with 1 to 3 substituents independently selected from halogen, R9, R6, -OR9, -N(R9)2, - C(0)N(R9)2, -C(0)NR9OH, -C(0)OR9, -C(0)OL3R6, - L3C(0)OR9, -C(0)R9, - CN, -S(0)2R9, -S(0)2N(R9)2, -S(0)2NR9C(0)R9, - S(0)2L3C(0)OR9, - OS(0)2N(R9)2, -S(0)2NR9OH, -OL3C(0)OR9, -C(0)NR9L3C(0)OR9, -L3R6
Figure imgf000037_0001
and a 5 membered heteroaryl containing 1 to 4 N heteroatoms and optionally one heteroatom selected from O and S;
R4 is selected from H, Ci-Cealkyl, phenyl, Cioaryl, Ci4aryl, C3-Cscycloalkyl, 5-6 membered heteroaryl containing one or more N heteroatoms, wherein the Cr C6alkyl, aryl, heteroaryl and C3 -Cscycloalkyl groups of R4 are each optionally substituted with 1 to 3 substituents independently selected from halogen, -CN, R9, and -OR9;
R5 is H, Ci-C6alkyl or C C6haloalkyl.
R6 is C3-C8cycloalkyl, phenyl, Cioaryl, Ci4aryl, a 5, 6, 9, 10 or 14 membered
heteroaryl containing 1 to 2 heteroatoms independently selected from N, O and S, a 4 to 7 membered heterocycloalkyl ring containing 1 to 2 heteroatoms independently selected from N, O and S, and a 9 to 14 membered fused bicyclic heterocycloalkyl ring containing containing 1 to 2 heteroatoms independently selected from N, O and S, each of which is optionally substituted with 1 to 5 substituents independently selected from halogen, deuterium, R9, -OR9, -CN and - C(0)OR9;
R9 is H, Ci-C6alkyl optionally substituted with 1 to 4 -OH groups or Ci-Cehaloalkyl; R11 is H or Ci-C6alkyl;
R12 is Ci-C4alkyl, -CH2C(0)OH or -(CHR13)C(0)OH;
R13 is H or Ci-C4alkyl;
each m is independently 1 , 2 or 3 ;
each n is independently 1, 2 or 3, and
each q is independently 1, 2, 3, 4, 5, or 6.
[00084] In certain embodiments, such the compounds of Formula (I) are compounds having the structure of Formula (II):
Figure imgf000038_0001
(Π)
wherein,
R10 and R20 are each independently selected from H, -OR9, deuterium or halogen;
R 30 is selected from phenyl, phenoxy, Cioaryl and Ci4aryl, each of which is optionally substituted with 1 to 5 substituents independently selected from halogen, deuterium and -OR9;
R40 is selected from H, deuterium, Ci-Cealkyl and Ci-Cehaloalkyl;
each R50 is independently selected from H or deuterium;
Figure imgf000039_0001
L2 is selected from -C(0)-, -C(0)0-, -(CH2)qC(0)0-, -S(0)2- C C6alkylene, phenylene, Cioarylene, C^arylene, a 5, 6, 9, 10 or 14 membered heteroarylene containing 1 to 2 heteroatoms independently selected from N, O and S, or a bond, wherein the Ci-Cealkylene ,arylene and heteroarylene of L2 are optionally substituted with 1 to 3 substituents independently selected from deuterium, R9 and -C(0)OR9;
L3 is C]-C6alkylene optionally substituted with 1 to 3 substituents independently
selected deuterium, R9 and -C(0)OR9, or Ci-Cealkenylene optionally substituted with 1 to 3 substituents independently selected from deuterium, R9 and -C(0)OR9;
U is selected from a -NR9-, -NR9C(0)0-, -NR9(CH2)q -, -C(0)NR9-, -S(0)2-, -0-, C C6alkylene, phenylene, Cioarylene, C^arylene, a 5, 6, 9, 10 or 14 membered heteroarylene containing 1 to 2 heteroatoms independently selected from N, O and S, wherein the Ci-Cealkylene, arylene and heteroarylene of L4 are optionally substituted with 1 to 3 substituents independently selected from deuterium, R9 and -C(0)OR9;
R3 is selected from Ci-Cealkyl, Ci-Cehaloalkyl, C3-Cscycloalkyl, -L3R6 , phenyl, Cioaryl, Ci4aryl, a 5, 6, 9, 10 or 14 membered heteroaryl containing 1 to 3 N heteroatoms and optionally one heteroatom selected from O and S, and a 4 to 7 membered heterocycloalkyl ring containing 1 to 2 heteroatoms independently selected from N, O and S, wherein the Ci-Cealkyl, aryl, heterocycloalkyl, C3- Cscycloalkyl and heteroaryl groups of R3 are each optionally substituted with 1 to 3 substituents independently selected from halogen, R9, R6, -OR9, -N(R9)2, - C(0)N(R9)2, -C(0)NR9OH, -C(0)OR9, -C(0)OL3R6, - L3C(0)OR9, -C(0)R9, CN, -S(0)2R9, -S(0)2N(R9)2, -S(0)2NR9C(0)R9, - S(0)2L3C(0)OR9, - 9)2, -S(0)2NR9OH, -OL3C(0)OR9, -C(0)NR9L3C(0)OR9, -L3R6
Figure imgf000040_0001
heteroatoms and optionally one heteroatom selected from O and S;
R4 is selected from H, Ci-Cealkyl, phenyl, Cioaryl, Ci4aryl, C3-Cscycloalkyl, 5-6 membered heteroaryl containing one or more N heteroatoms, wherein the Cr C6alkyl, aryl, heteroaryl and C3-Cscycloalkyl groups of R4 are each optionally substituted with 1 to 3 substituents independently selected from halogen, -CN, R9, and -OR9;
R5 is H, Ci-C6alkyl or C C6haloalkyl.
R6 is C3-C8cycloalkyl, phenyl, Cioaryl, Ci4aryl, a 5, 6, 9, 10 or 14 membered
heteroaryl containing 1 to 2 heteroatoms independently selected from N, O and S, a 4 to 7 membered heterocycloalkyl ring containing 1 to 2 heteroatoms independently selected from N, O and S, and a 9 to 14 membered fused bicyclic heterocycloalkyl ring containing containing 1 to 2 heteroatoms independently selected from N, O and S, each of which is optionally substituted with 1 to 5 substituents independently selected from halogen, deuterium, R9, -OR9, -CN and - C(0)OR9;
R9 is H, Ci-C6alkyl optionally substituted with 1 to 4 -OH groups or Ci-Cehaloalkyl; R11 is H or Ci-C6alkyl;
R12 is Ci-C4alkyl, -CH2C(0)OH or -(CHR13)C(0)OH;
R13 is H or C C4alkyl;
each m is independently 1, 2 or 3;
each n is independently 1, 2 or 3, and
each q is independently 1, 2, 3, 4, 5, or 6.
[00085] In certain embodiments, compounds of Formula (I) are compounds having the structure of Formula (III), Formula (IV) or Formula (V):
Figure imgf000041_0001
(III) (IV) (V).
[00086] In certain embodiments, compounds of Formula (I) or Formula (II) are compounds having the structure of Formula (VI), Formula (VII) or Formula (VIII):
Figure imgf000041_0002
(VI) (VII) (VIII).
[00087] Non- limiting examples of such compounds of Formulas (I)-(VIII) are presented in the examples and tables provided herein.
[00088] The compounds of Formulas (I)-(VIII), pharmaceutically acceptable salts, solvates, N-oxides, prodrugs and isomers thereof, and pharmaceutical compositions provided herein also includes all suitable isotopic variations of such compounds, and pharmaceutically acceptable salts, solvates, N-oxides, prodrugs and isomers thereof, and pharmaceutical compositions. An isotopic variation of a compound of the invention or a pharmaceutically acceptable salt thereof is defined as one in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature. Examples of isotopes that may be incorporated into the compounds of the invention and pharmaceutically acceptable salts thereof include but are not limited to isotopes of hydrogen, carbon, nitrogen and oxygen such as 2H, 3H, nC, 13C, 14C, 15N, 170,
18 O, 35 S, 18 F, 36 CI and 123 I. Certain isotopic variations of the compounds of the invention and pharmaceutically acceptable salts thereof, for example, those in which a radioactive isotope such as 3H or 14C is incorporated, are useful in drug and/or substrate tissue distribution studies. In particular examples, 3H and 14C isotopes may be used for their ease of preparation and detectability. In other examples, substitution with isotopes such as 2H may afford certain therapeutic advantages resulting from greater metabolic stability, such as increased in-vivo half-life or reduced dosage requirements. Isotopic variations of the compounds, and pharmaceutically acceptable salts, solvates, N-oxides, prodrugs and isomers thereof, and pharmaceutical compositions provided herein are prepared by conventional procedures using appropriate isotopic variations of suitable reagents.
Processes for Making Compounds of Formula (I) and Formula (II)
[00089] General procedures for preparing compounds of Formula (I) and Formula (II) are described in the Examples, infra. In the reactions described, reactive functional groups, for example hydroxyl, amino, imino, thio or carboxy groups, where these are desired in the final product, may be protected to avoid their unwanted participation in the reactions.
Conventional protecting groups may be used in accordance with standard practice (see e.g., T.W. Greene and P. G. M. Wuts in "Protective Groups in Organic Chemistry," John Wiley and Sons, 1991).
[00090] In certain embodiments, the compounds of Formula (I)-(VIII) described herein are prepared as a pharmaceutically acceptable acid addition salt by reacting the free base form of the compound of Formula (I)-(VIII) with a pharmaceutically acceptable organic acid or inorganic acid. In other embodiments, a pharmaceutically acceptable base addition salt of compounds of Formula (I)-(VIII) described herein is prepared by reacting the free acid form of the compound of Formula (I)-(VIII) with a pharmaceutically acceptable organic base or inorganic base. Alternatively, the salt forms of the compounds of Formula (I)-(VIII) described herein are prepared using salts of the starting materials or intermediates. In certain embodiments, the compounds of Formula (I)-(VIII) described herein are in the form of other salts including, but not limited to, oxalates and trifluoroacetates. In certain embodiments, hemisalts of acids and bases are formed, for example, hemisulphate and hemicalcium salts.
[00091] Such pharmaceutically acceptable acid addition salts of compounds of Formula (I)-(VIII) include, but are not limited to, a hydrobromide, hydrochloride, hydroiodide, sulfate, bisulphate, nitrate, phosphate, succinate, maleate, formate, acetate, adipate, besylatye, bicarbonate/carbonate, propionate, fumarate, citrate, tartrate, lactate, benzoate, salicylate, glutamate, aspartate, p-toluenesulfonate, benzenesulfonate, methanesulfonate, ethanesulfonate, naphthalenesulfonate (e.g. 2-naphthalenesulfonate), hexanoate salt, bisulphate/sulphate, borate, camsylate, cyclamate, edisylate, esylate, gluceptate, gluconate, glucuronate, pyruvate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, orotate, oxalate, oxaloacetate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate, saccharate, stearate, tannate, tosylate, trifluoroacetate and xinofoate salts.
[00092] The organic acid or inorganic acids used to form certain pharmaceutically acceptable acid addition salts of compounds of Formula (I)-(VIII) include, but are not limited to, hydrobromic, hydrochloric, sulfuric, nitric, phosphoric, succinic, maleic, formic, acetic, propionic, fumaric, citric, tartaric, lactic, benzoic, salicylic, glutamic, aspartic, p- toluenesulfonic, benzenesulfonic, methanesulfonic, ethanesulfonic, naphthalenesulfonic such as 2-naphthalenesulfonic, or hexanoic acid.
[00093] Such pharmaceutically acceptable base addition salt of a compound of Formula (I)-(VIII) include, but are not limited to, aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts.
[00094] In certain embodiments, the free acid or free base forms of the compounds of Formula (I)-(VIII) described herein are prepared from the corresponding base addition salt or acid addition salt from, respectively. For example a compound Formula (I)-(VIII) in an acid addition salt form is converted to the corresponding free base by treating with a suitable base (by way of example only, an ammonium hydroxide solution, a sodium hydroxide, and the like). For example, a compound of Formula (I)-(VIII) in a base addition salt form is converted to the corresponding free acid by treating with a suitable acid (by way of example only, hydrochloric acid).
[00095] In certain embodiments, the compounds of Formula (I)-(VIII) described herein in unoxidized form are prepared from N-oxides of compounds Formula (I)-(VIII) by treating with a reducing agent (by way of example only, sulfur, sulfur dioxide, triphenyl phosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, tribromide, or the like) in a suitable inert organic solvent (by way of example only, acetonitrile, ethanol, aqueous dioxane, or the like) at 0 to 80°C.
[00096] In certain embodiments, prodrug derivatives of compounds Formula (I)-(VIII) described herein are prepared using methods known to those of ordinary skill in the art (e.g., for further details see Saulnier et al., (1994), Bioorganic and Medicinal Chemistry Letters, Vol. 4, p. 1985). For example, appropriate prodrugs are prepared by reacting a non- derivatized compound of Formula (I)-(VIII) with a suitable carbamylating agent (by way of example only, 1,1-acyloxyalkylcarbanochloridate, para-nitrophenyl carbonate, or the like).
[00097] In certain embodiments, the compounds of Formula (I)-(VIII) described herein are prepared as protected derivatives using methods known to those of ordinary skill in the art. A detailed description of the techniques applicable to the creation of protecting groups and their removal can be found in T. W. Greene, "Protecting Groups in Organic Chemistry," 3rd edition, John Wiley and Sons, Inc., 1999.
[00098] In certain embodiments, the compounds of Formula (I)-(VIII) described herein are prepared or formed, as solvates (e.g., hydrates). In certain embodiments, hydrates of compounds of Formula (I)-(VIII) are prepared by recrystallization from an aqueous/organic solvent mixture, using organic solvents such as dioxin, tetrahydrofuran or methanol.
[00099] In certain embodiments, the compounds of Formula (I)-(VIII) described herein are prepared as their individual stereoisomers. In other embodiments, the compounds of Formula (I)-(VIII) described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers and recovering the optically pure enantiomers. In certain embodiments, resolution of enantiomers is carried out using covalent diastereomeric derivatives of the compounds of Formula (I)-(VIII), or by using dissociable complexes (e.g., crystalline diastereomeric salts). Diastereomers have distinct physical properties (e.g., melting points, boiling points, solubility, reactivity, etc.) and are readily separated by taking advantage of these dissimilarities. In certain embodiments, the diastereomers are separated by chromatography, or by separation/resolution techniques based upon differences in solubility. The optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that would not result in racemization. A more detailed description of the techniques applicable to the resolution of stereoisomers of compounds from their racemic mixture can be found in Jean Jacques, Andre Collet, Samuel H. Wilen, "Enantiomers, Racemates and Resolutions," John Wiley And Sons, Inc., 1981.
[000100] Compounds of Formula (I)-(VIII) are made by processes described herein and as illustrated in the Examples. In certain embodiments, compounds of Formula (I) -(VIII) are made by:
(a) optionally converting a compound of the invention into a pharmaceutically acceptable salt;
(b) optionally converting a salt form of a compound of the invention to a non-salt form; (c) optionally converting an unoxidized form of a compound of the invention into a pharmaceutically acceptable N-oxide;
(d) optionally converting an N-oxide form of a compound of the invention to its unoxidized form;
(e) optionally resolving an individual isomer of a compound of the invention from a mixture of isomers;
(f) optionally converting a non-derivatized compound of the invention into a
pharmaceutically acceptable prodrug derivative; and
(g) optionally converting a prodrug derivative of a compound of the invention to its non- derivatized form.
[000101] Non-limiting examples of synthetic schemes used to make compounds of Formula (I)-(VIII) described herein are illustrated in reaction schemes (I)-(IX), wherein m, n, q, L1, 2, L3, L4, R1, R2 R3, R4 R5, R6, R9, R10, R20, R30, R40 and R50 are as defined herein.
Figure imgf000045_0001
[000103] Reaction scheme (II) illustrates the synthesis of certain embodiments of compounds of Formula (I).
Reaction Scheme (II)
Figure imgf000046_0001
[000104] Reaction scheme (III) illustrates the synthesis of certain embodiments of compounds of Formula (I).
Reaction Scheme III)
Figure imgf000046_0002
[000105] Reaction scheme (IV) illustrates the synthesis of certain embodiments of compounds of Formula (I).
Reaction Scheme (IV)
Figure imgf000046_0003
[000106] Reaction scheme (V) illustrates the synthesis of certain embodiments of compounds of Formula (I).
Reaction Scheme (V)
Figure imgf000047_0001
[000107] Insofar as the production of the starting materials is not particularly described, the compounds are known or can be prepared analogously to methods known in the art or as disclosed in the Examples hereinafter.
[000108] Detailed examples of the synthesis of compounds of Formula (I) can be found in the Examples, infra.
Pharmacology and Utility
[000109] A multitude of endocrine, neural, and metabolic signaling pathways are activated upon food intake to coordinate the effective use of the available energy. Bile acids (BAs) are released from the gallbladder after each meal and subsequently facilitate the digestion of nutrients. Since concentrations of BAs increase postprandially in the serum, they are also signals of food availability that bridge nutrition with metabolism.
[000110] Bile acids are known to be involved in lipid absorption and cholesterol homeostasis. However, bile acids are also regarded as signaling hormones endowed with paracrine and endocrine functions related to the homeostasis of cholesterol levels, control of lipid and carbohydrate metabolism, and regulation of the immune system. TGR5 (also known as GPBAR1 or M-BAR) has been identified as the endogenously specific metabotropic receptor of bile acids, and the activation of the membrane TGR5 receptor is thought to be the pathway to non-genomic functions of bile acids.
[000111] TGR5 is a member of the Rhodopsin-like subfamily of G-protein-coupled receptors (GPCR's) that mediates some of the endocrine functions of its bile acid ligands. TGR5 is highly expressed in the adipose tissue and in macrophages. In addition, TGR5 expression levels are high in the gall bladder, the gastrointestinal tract and in immune cells such as dendritic cells and monocytes, and show enrichment in organs like the spleen and lung, intestine (Werner et al. 2004; Kawatama et al. 2003) and in certain areas of the central nervous system. Both primary and secondary bile acids, such as lithocholic acid (LCA) and taurolithocholic acid (TLCA), have been shown to be the natural ligands of this receptor (Maruyama et al. 2002) and to inhibit LPS-induced TNFa and IL-12 production in monocytes/macrophages (Kawamata et al. 2003). [000112] TGR5 agonists inhibit production of the pro-inflammatory cytokine TNFa and the Thl-driving cytokine IL-12 (but not IL-10) in human DC and monocytes, and in LPS- stimulated whole blood and PBMC. In addition, TLCA inhibits IFNy (but not IL-4) production in activated DC/T cell co-cultures and in LPS stimulated human whole blood (Werner et al 2004). These inflammatory cytokines have been shown to play key roles in the pathogenesis of autoimmune diseases, such as psoriasis. A recent report described TGR5 expression in Kupffer cells in the liver and activation of this receptor leads to down regulation of expression of TNFa, IL-la, IL-Ι β, and IL-6 in LPS stimulated cell model (Keitel et al 2008).
[000113] The natural TGR5 ligand TLCA, which is produced by intestinal Clostridia, is found in higher levels in children that do not have autoimmune disease (J. Allergy Clin Immunol 2001, 107:29-39). In addition, oral bile acid (dehydrocholic acid) treatment was efficacious in more than 80% of psoriasis patients in one study (Pathophysiology 2003, 10:57), and bile acids have been used by traditional Chinese medicine in chronic
inflammatory diseases (Biochem. Pharmacol. 2002, 63:533). Together, this gives further support for pursuing low molecular weight agonists of TGR5 for autoimmune diseases.
[000114] Thus, agonists of TGR5 are expected to be useful in the treatment of autoimmune diseases characterized by Thl pathology helping to redirect the response towards a Th2 phenotype. Such autoimmune diseases include, but are not limited to, psoriasis. Psoriasis is an autoimmune disease with a prevalence of between 1.5 and 4% in the population, occurring most commonly in Caucasians. Many patients also develop psoriatic arthritis which impacts quality of life even more. With few safe and cost effective treatments available, psoriasis remains an unmet medical need.
[000115] TGR5 is associated with the intracellular accumulation of cyclic adenosine monophosphate (cAMP), which is widely expressed in diverse cell types. Although the activation of TGR5 in macrophages decreases proinflammatory cytokine production, the stimulation of TGR5 by bile acids in adipocytes and myocytes enhances energy expenditure. This control of energy metabolism by TGR5 involves the c-AMP-dependent induction of type 2 iodothyronine deiodinase (D2) enzyme. The up-regulation of D2 depends on the activation the membrane bound TGR5 by bile acids, which then mobilizes cAMP. D2 then locally converts the prohormone thyroxine (T4) to the active hormone 3, 5, 3 '-triiodothyronine (T3), which gives rise to increases thyroid hormone activity and increased energy expenditure. [000116] Bile acid stimulation of TGR5 has been shown to regulate multiple metabolic processes including glucose-dependent gut incretin glucose-like peptide 1 (GLP-1) secretion and mitochondrial energy homeostasis. TGR5 expression levels are high in the small and large intestine. Mice lacking the TGR5 receptor showed increased weight and body fat when on a high fat diet (WO2006070718). Specific receptor agonists cause an increase in the secretion of GLP-1 both in-vitro and in-vivo (EP1591120), and lead to prevention of hyperglycemia and improved glucose tolerance in the GK rat model (WO2007127505). The beneficial action of TGR5 agonists on TNFa levels may also be beneficial in Type II diabetes, where elevated levels contribute to insulin resistance and other pathologies.
[000117] In addition, TGR5 appears to be important in the regulation of nitric oxide production via c-AMP-dependent activation of endothelial nitric oxide synthase (eNOS). This may scavange bile acid induced reactive oxygen species and protect the liver against lipid peroxidation and bile acid-induced injury.
[000118] The number of people in the world with diabetes is estimated to increase 46% between 2000 and 2010 and to double by the year 2025 to approximately 300 million people. The majority of these increases will be type II (non- insulin dependent) diabetes resulting largely from physical inactivity, poor diet, stress and obesity. Type II insulin-resistant diabetes mellitus afflicts an estimated 6% of adults in Western nations. The heterogeneity of the disorder is highlighted by the lack of long-term efficacy of existing therapies in a significant proportion of patients. The high economic and social cost of diabetes emphasizes the need for effective strategies for the prevention and treatment of the disease. Inducing GLP-1 secretion and glucose-stimulated insulin secretion can normalize glucose levels without causing hypoglycemia. Therefore, because TGR5 agonists increase glucose dependent GLP-1 secretion, they are useful in the treatment of Type II Diabetes.
Furthermore, TGR5 agonists have the potential for additive/synergistic effects with DPP-4 inhibitors for Type II insulin-resistant diabetes mellitus treatment. In addition, the ability of TGR5 agonists to decrease TNFa has a positive impact on the inflammatory component of Type II Diabetes.
[000119] TGR5, with its ability to enhance incretin levels, is involved in metabolic diseases and energy homeostasis, plus TGR5, with its ability to decrease pro-inflammatory cytokines, is involved in autoimmune diseases and inflammatory disorders. This suggests a role for TGR5 agonists in the treatment of Type II Diabetes, inflammatory disorders and Th-l mediated autoimmune diseases. [000120] Thus, provided herein are compounds and compositions which are agonists of TGR5. Also provided herein are methods utilizing such compounds and composition to enhance TGR5 activity to treat diseases and/or disorders associated with TGR5 activity. Such diseases and/or disorders include, but are not limited to, diabetes, inflammatory disorders and autoimmune diseases. By way of example only, the compounds, compositions and methods provided herein are used to treat gallstones, cholestasis, Type II Diabetes, psoriasis and Th-1 mediated autoimmune diseases.
[000121] This methods provided herein are either prophylactic or therapeutic treatment of TGR5-related disorders and/or TGR5-related diseases. Such methods involve administering to a subject in need of treatment a compound of Formula (I)-(VIII), or a pharmaceutical composition that contains a therapeutically effective amount of one or more compounds of Formula (I)-(VIII), wherein such compounds are an agonists of TGR5. In certain embodiments, such prophylactic or therapeutic treatment methods are used to treat diabetes, gallstones, cholestasis, inflammatory disorders and autoimmune diseases, including but not limited to, Type II Diabetes, psoriasis and Th-1 mediated autoimmune diseases.
[000122] The methods of treatment provide herein are effective for both human and animal subjects. Animal subjects include both domestic animals and livestock, raised either as pets or for commercial purposes. Examples include, but are not limited to, dogs, cats, cattle, horses, sheep, hogs, and goats.
[000123] In certain embodiments of compounds of Formula (I), Formula (II), Formula (IV) and Formula (VII), such compounds have minimal systemic exposure and are primarily gastrointestinally exposed.
[000124] In accordance with the foregoing, the present invention further provides a method for preventing or treating any of the diseases or disorders described herein in a subject in need of such treatment, which method comprises administering to a subject a therapeutically effective amount (See, "Administration and Pharmaceutical Compositions", infra) of a compound of Formula (I)-(VIII) or a pharmaceutically acceptable salt, solvate, N-oxide, prodrug or isomers thereof.
[000125] Also provided herein are methods for preventing or treating any of the diseases or disorders described herein in a subject in need of such treatment, which method comprises administering to a subject a pharmaceutical compositions containing therapeutically effective amount of a compound of Formula (I)-(VIII) or a pharmaceutically acceptable salt, solvate, N-oxide, prodrug, enantiomer or isomers thereof. For any of the above uses, the required dosage will vary depending on the mode of administration, the particular condition to be treated and the effect desired.
Administration and Pharmaceutical Compositions
[000126] For the therapeutic uses of compounds of Formula (I)-(VIII), or pharmaceutically acceptable salts, solvates, N-oxides, prodrugs and isomers thereof, described herein, such compounds are administered in therapeutically effective amounts either alone or as part of a pharmaceutical composition. Accordingly, provided herein are pharmaceutical
compositions, which comprise at least one compound of Formulas (I)-(VIII) described herein, pharmaceutically acceptable salts and/or solvates thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients. In addition, such compounds and compositions are administered singly or in combination with one or more additional therapeutic agents. The method of administration of such compounds and compositions include, but are not limited to, oral administration, rectal administration, parenteral, intravenous administration, intravitreal administration, intramuscular administration, inhalation, intranasal administration, topical administration, ophthalmic administration or otic administration.
[000127] In certain embodiments, such compounds of Formula (I)-(VIII) are agonists of TGR5, formulated in an amount sufficient to inhibit production of the pro-inflammatory cytokine TNFa and the Thl-driving cytokine IL-12 both in-vitro and in-vivo. In other embodiments, such compounds of Formula (I)-(VIII) are agonists of TGR5, formulated in an amount sufficient to increases thyroid hormone activity and increased energy expenditure both in-vitro and in-vivo. In other embodiments, such compounds of Formula (I)-(VIII) are agonists of TGR5, formulated in an amount sufficient to increase the secretion of GLP-1 both in-vitro and in-vivo.
[000128] The therapeutically effective amount will vary depending on, among others, the disease indicated, the severity of the disease, the age and relative health of the subject, the potency of the compound administered, the mode of administration and the treatment desired. In certain embodiments, the daily dosage of a compound of Formula (I)-(VIII), satisfactory results are indicated to be obtained systemically at daily dosages of from about 0.03 to 2.5mg/kg per body weight. In certain embodiments, the daily dosage of a compound of Formula (I)-(VIII), administered by inhalation, is in the range from 0.05 micrograms per kilogram body weight ^g/kg) to 100 micrograms per kilogram body weight ^g/kg). In other embodiments, the daily dosage of a compound of Formula (I)-(VIII), administered orally, is in the range from 0.01 micrograms per kilogram body weight ^g/kg) to 100 milligrams per kilogram body weight (mg/kg). An indicated daily dosage in the larger mammal, e.g.
humans, is in the range from about 0.5mg to about lOOmg of a compound of Formula (I)- (VIII), conveniently administered, e.g. in divided doses up to four times a day or in controlled release form. In certain embodiment, unit dosage forms for oral administration comprise from about 1 to 50 mg of a compound of Formula (I)-(VIII).
[000129] Other aspects provided herein are processes for the preparation of pharmaceutical composition which comprise at least one compound of Formulas (I)-(VIII) described herein, or pharmaceutically acceptable salts and/or solvates thereof. In certain embodiments, such processes include admixing a compound of the Formula (I)-(VIII) described herein, and pharmaceutically acceptable salts and solvates thereof, with one or more pharmaceutically acceptable carriers, diluents or excipients. In certain embodiments, the pharmaceutical compositions comprising a compound of Formula (I)-(VIII) in free form or in a
pharmaceutically acceptable salt or solvate form, in association with at least one
pharmaceutically acceptable carrier, diluent or excipient are manufactured by mixing, granulating and/or coating methods. In other embodiments, such compositions are optionally contain excipients, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers. In other embodiments, such compositions are sterilized.
Oral Dosage Forms
[000130] In certain embodiments, the pharmaceutical compositions containing at least one compound of Formula (I)-(VIII) are administered orally as discrete dosage forms, wherein such dosage forms include, but are not limited to, capsules, gelatin capsules, caplets, tablets, chewable tablets, powders, granules, syrups, flavored syrups, solutions or suspensions in aqueous or non-aqueous liquids, edible foams or whips, and oil-in-water liquid emulsions or water-in-oil liquid emulsions.
[000131] The capsules, gelatin capsules, caplets, tablets, chewable tablets, powders or granules, used for the oral administration of at least one compound of Formula (I)-(VIII) are prepared by admixing at least one compound of Formula (I)-(VIII) (active ingredient) together with at least one excipient using conventional pharmaceutical compounding techniques. Non- limiting examples of excipients used in oral dosage forms described herein include, but are not limited to, binders, fillers, disintegrants, lubricants, absorbents, colorants, flavors, preservatives and sweeteners. [000132] Non-limiting examples of such binders include, but are not limited to, corn starch, potato starch, starch paste, pre-gelatinized starch, or other starches, sugars, gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, tragacanth, guar gum, cellulose and its derivatives (by way of example only, ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethylcellulose, methyl cellulose, hydroxypropyl methylcellulose and microcrystalline cellulose), magnesium aluminum silicate, polyvinyl pyrrolidone and combinations thereof.
[000133] Non-limiting examples of such fillers include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof. In certain embodiments, the binder or filler in pharmaceutical compositions provided herein are present in from about 50 to about 99 weight percent of the pharmaceutical composition or dosage form.
[000134] Non-limiting examples of such disintegrants include, but are not limited to, agar- agar, alginic acid, sodium alginate, calcium carbonate, sodium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, pre-gelatinized starch, other starches, clays, other algins, other celluloses, gums, and combinations thereof. In certain embodiments, the amount of disintegrant used in the pharmaceutical compositions provided herein is from about 0.5 to about 15 weight percent of disintegrant, while in other embodiments the amount is from about 1 to about 5 weight percent of disintegrant.
[000135] Non-limiting examples of such lubricants include, but are not limited to, sodium stearate, calcium stearate, magnesium stearate, stearic acid, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, sodium lauryl sulfate, talc, hydrogenated vegetable oil (by way of example only, peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, sodium oleate, ethyl oleate, ethyl laureate, agar, silica, a syloid silica gel (AEROSIL 200, manufactured by W.R. Grace Co. of Baltimore, Md.), a coagulated aerosol of synthetic silica (marketed by Degussa Co. of Piano, Tex.), CAB-O-SIL (a pyrogenic silicon dioxide product sold by Cabot Co. of Boston, Mass.) and combinations thereof. In certain embodiments, the amount of lubricants used in the pharmaceutical compositions provided herein is in an amount of less than about 1 weight percent of the pharmaceutical compositions or dosage forms. [000136] Non-limiting examples of such diluents include, but are not limited to, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycine or combinations thereof.
[000137] In certain embodiments, tablets and capsules are prepared by uniformly admixing at least one compound of Formula (I)-(VIII) (active ingredients) with liquid carriers, finely divided solid carriers, or both, and then shaping the product into the desired presentation if necessary. In certain embodiments, tablets are prepared by compression. In other embodiments, tablets are prepared by molding.
[000138] In certain embodiments, at least one compound of Formula (I)-(VIII) is orally administered as a controlled release dosage form. Such dosage forms are used to provide slow or controlled-release of one or more compounds of Formula (I)-(VIII). Controlled release is obtained using, for example, hydroxypropylmethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or a combination thereof. In certain embodiments, controlled- release dosage forms are used to extend activity of the compound of Formula (I)-(VIII), reduce dosage frequency, and increase patient compliance.
[000139] Administration of compounds of Formula (I)-(VIII) as oral fluids such as solution, syrups and elixirs are prepared in unit dosage forms such that a given quantity of solution, syrups or elixirs contains a predetermined amount of a compound of Formula (I)-(VIII). Syrups are prepared by dissolving the compound in a suitably flavored aqueous solution, while elixirs are prepared through the use of a non-toxic alcoholic vehicle. Suspensions are formulated by dispersing the compound in a non-toxic vehicle. Non-limiting examples of excipients used in as oral fluids for oral administration include, but are not limited to, solubilizers, emulsifiers, flavoring agents, preservatives, and coloring agents. Non-limiting examples of solubilizers and emulsifiers include, but are not limited to, water, glycols, oils, alcohols, ethoxylated isostearyl alcohols and polyoxy ethylene sorbitol ethers. Non-limiting examples of preservatives include, but are not limited to, sodium benzoate. Non-limiting examples of flavoring agents include, but are not limited to, peppermint oil or natural sweeteners or saccharin or other artificial sweeteners.
Parenteral Dosage Forms
[000140] In certain embodiments pharmaceutical compositions containing at least one compound of Formula (I)-(VIII) are administered parenterally by various routes including, but not limited to, subcutaneous, intravenous (including bolus injection), intramuscular, and intraarterial. [000141] Such parenteral dosage forms are administered in the form of sterile or sterilizable injectable solutions, suspensions, dry and/or lyophylized products ready to be dissolved or suspended in a pharmaceutically acceptable vehicle for injection (reconstitutable powders) and emulsions. Vehicles used in such dosage forms include, but are not limited to, Water for Injection USP; aqueous vehicles such as, but not limited to, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection; water-miscible vehicles such as, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.
Transdermal Dosage Forms
[000142] In certain embodiments pharmaceutical compositions containing at least one compound of Formula (I)-(VIII) are administered transdemally. Such transdermal dosage forms include "reservoir type" or "matrix type" patches, which are applied to the skin and worn for a specific period of time to permit the penetration of a desired amount of a compound of Formula (I)-(VIII). By way of example only, such transdermal devices are in the form of a bandage comprising a backing member, a reservoir containing the compound optionally with carriers, optionally a rate controlling barrier to deliver the compound to the skin of the host at a controlled and predetermined rate over a prolonged period of time, and means to secure the device to the skin. In other embodiments, matrix transdermal formulations are used.
[000143] Formulations for transdermal delivery of a compound of Formula (I)-(VIII) include an effective amount of a compound of Formula (I)-(VIII), a carrier and an optional diluent. A carrier includes, but is not limited to, absorbable pharmacologically acceptable solvents to assist passage through the skin of the host, such as water, acetone, ethanol, ethylene glycol, propylene glycol, butane- 1, 3 -diol, isopropyl myristate, isopropyl palmitate, mineral oil, and combinations thereof.
[000144] In certain embodiments, such transdermal delivery systems include penetration enhancers to assist in delivering one or more compounds of Formula (I)-(VIII) to the tissue. Such penetration enhancers include, but are not limited to, acetone; various alcohols such as ethanol, oleyl, and tetrahydrofuryl; alkyl sulfoxides such as dimethyl sulfoxide; dimethyl acetamide; dimethyl formamide; polyethylene glycol; pyrrolidones such as
polyvinylpyrrolidone; Kollidon grades (Povidone, Polyvidone); urea; and various water- soluble or insoluble sugar esters such as Tween 80 (polysorbate 80) and Span 60 (sorbitan monostearate).
[000145] In other embodiments, the pH of such a transdermal pharmaceutical composition or dosage form, or of the tissue to which the pharmaceutical composition or dosage form is applied, is adjusted to improve delivery of one or more compounds of Formula (I)-(VIII). In other embodiments, the polarity of a solvent carrier, its ionic strength, or tonicity are adjusted to improve delivery. In other embodiments, compounds such as stearates are added to advantageously alter the hydrophilicity or lipophilicity of one or more compounds of Formula (I)-(VIII) so as to improve delivery. In certain embodiments, such stearates serve as a lipid vehicle for the formulation, as an emulsifying agent or surfactant, and as a delivery- enhancing or penetration-enhancing agent. In other embodiments, different salts, hydrates or solvates of the compounds of Formula (I)-(VIII) are used to further adjust the properties of the resulting composition.
Topical Dosage Forms
[000146] In certain embodiments at least one compound of Formula (I)-(VIII) is administered by topical application of pharmaceutical composition containing at least one compound of Formula (I)-(VIII) in the form of lotions, gels, ointments solutions, emulsions, suspensions or creams. Suitable formulations for topical application to the skin are aqueous solutions, ointments, creams or gels, while formulations for ophthalmic administration are aqueous solutions. Such formulations optionally contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives.
[000147] Such topical formulations include at least one carrier, and optionally at least one diluent. Such carriers and diluents include, but are not limited to, water, acetone, ethanol, ethylene glycol, propylene glycol, butane- 1, 3 -diol, isopropyl myristate, isopropyl palmitate, mineral oil, and combinations thereof.
[000148] In certain embodiments, such topical formulations include penetration enhancers to assist in delivering one or more compounds of Formula (I)-(VIII) to the tissue. Such penetration enhancers include, but are not limited to, acetone; various alcohols such as ethanol, oleyl, and tetrahydrofuryl; alkyl sulfoxides such as dimethyl sulfoxide; dimethyl acetamide; dimethyl formamide; polyethylene glycol; pyrrolidones such as
polyvinylpyrrolidone; Kollidon grades (Povidone, Polyvidone); urea; and various water- soluble or insoluble sugar esters such as Tween 80 (polysorbate 80) and Span 60 (sorbitan monostearate). [000149] In certain embodiments pharmaceutical compositions containing at least one compound of Formula (I)-(VIII) are administered by inhalation. Dosage forms for inhaled administration are formulated as aerosols or dry powders. Aerosol formulations for inhalation administration comprise a solution or fine suspension of at least one compound of Formula (I)-(VIII) in a pharmaceutically acceptable aqueous or non-aqueous solvent. In addition, such pharmaceutical compositions optionally comprise a powder base such as lactose, glucose, trehalose, mannitol or starch, and optionally a performance modifier such as L- leucine or another amino acid, and/or metals salts of stearic acid such as magnesium or calcium stearate.
[000150] In certain embodiments, compounds of Formula (I)-(VIII) are be administered directly to the lung by inhalation using a Metered Dose Inhaler ("MDI"), which utilizes canisters that contain a suitable low boiling propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas, or a Dry Powder Inhaler (DPI) device which uses a burst of gas to create a cloud of dry powder inside a container, which is then be inhaled by the patient. In certain embodiments, capsules and cartridges of gelatin for use in an inhaler or insufflator are formulated containing a powder mixture of a compound of Formula (I)-(VIII) and a powder base such as lactose or starch. In certain embodiments, compounds of Formula (I)-(VIII) are delivered to the lung using a liquid spray device, wherein such devices use extremely small nozzle holes to aerosolize liquid drug formulations that can then be directly inhaled into the lung. In other embodiments, compounds of Formula (I)-(VIII) are delivered to the lung using a nebulizer device, wherein a nebulizers creates an aerosols of liquid drug formulations by using ultrasonic energy to form fine particles that can be readily inhaled. In other embodiments, compounds of Formula (I)-(VIII) are delivered to the lung using an electrohydrodynamic ("EHD") aerosol device wherein such EHD aerosol devices use electrical energy to aerosolize liquid drug solutions or suspensions.
[000151] In certain embodiments, the pharmaceutical composition containing at least one compound of Formula (I)-(VIII), or pharmaceutically acceptable salts and solvates thereof, described herein, also contain one or more absorption enhancers. In certain embodiments, such absorption enhancers include, but are not limited to, sodium glycocholate, sodium caprate, N-lauryl-P-D-maltopyranoside, EDTA, and mixed micelles. [000152] In certain embodiments pharmaceutical compositions containing at least one compound of Formula (I)-(VIII) are administered nasally. The dosage forms for nasal administration are formulated as aerosols, solutions, drops, gels or dry powders.
[000153] In certain embodiments pharmaceutical compositions containing at least one compound of Formula (I)-(VIII) are administered rectally in the form of suppositories, enemas, ointment, creams rectal foams or rectal gels. In certain embodiments such suppositories are prepared from fatty emulsions or suspensions, cocoa butter or other glycerides.
[000154] In certain embodiments pharmaceutical compositions containing at least one compound of Formula (I)-(VIII) are administered opthamically as eye drops. Such formulations are aqueous solutions that optionally contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives.
[000155] In certain embodiments pharmaceutical compositions containing at least one compound of Formula (I)-(VIII) are administered otically as ear drops. Such formulations are aqueous solutions that optionally contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives.
[000156] In certain embodiments pharmaceutical compositions containing at least one compound of Formula (I)-(VIII) are formulated as a depot preparation. Such long acting formulations are administered by implantation (for example subcutaneously or
intramuscularly) or by intramuscular injection. In certain embodiments, such formulations include polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
Combination Treatment
[000157] In certain embodiments, a compound of Formulas (I)-(VIII) provided herein, or a pharmaceutically acceptable salt, N-oxide, isomer or solvate thereof, or a pharmaceutical composition containing at least one compound of Formula (I)-(VIII) provided herein, is administered alone (without an additional therapeutic agent) for the treatment of one or more of the TGR5 -related diseases and/or disorders described herein.
[000158] In other embodiments, a compound of Formulas (I)-(VIII) provided herein, or a pharmaceutically acceptable salt, N-oxide, isomer or solvate thereof, or a pharmaceutical composition containing at least one compound of Formulas (I)-(VIII) provided herein, is administered in combination with one or more additional therapeutic agents, for the treatment of one or more of the TGR5 -related diseases and/or disorders described herein.
[000159] In other embodiments, a compound of Formulas (I)-(VIII) provided herein, or a pharmaceutically acceptable salt, N-oxide, isomer or solvate thereof, or a pharmaceutical composition containing at least one compound of Formula (I)-(VIII) provided herein, is formulated in combination with one or more additional therapeutic agents and administered for the treatment of one or more of the TGR5 -related diseases and/or disorders described herein.
[000160] In other embodiments, a compound of Formulas (I)-(VIII) provided herein, or a pharmaceutically acceptable salt, N-oxide, isomer or solvate thereof, or a pharmaceutical composition containing at least one compound of Formula (I)-(VIII) provided herein, is administered sequentially with one or more additional therapeutic agents, for the treatment of one or more of the TGR5-related diseases and/or disorders described herein.
[000161] In other embodiments, the combination treatments provided herein include administration of a compound of Formulas (I)-(VIII) provided herein, or a pharmaceutically acceptable salt, N-oxide, isomer or solvate thereof, or a pharmaceutical composition containing at least one compound of Formula (I)-(VIII) provided herein, prior to
administration of one or more additional therapeutic agents, for the treatment of one or more of the TGR5 -related diseases and/or disorders described herein.
[000162] In other embodiments, the combination treatments provided herein include administration of a compound of Formulas (I)-(VIII) provided herein, or a pharmaceutically acceptable salt, N-oxide, isomer or solvate thereof, or a pharmaceutical composition containing at least one compound of Formula (I)-(VIII) provided herein, subsequent to administration of one or more additional therapeutic agents, for the treatment of one or more of the TGR5 -related diseases and/or disorders described herein.
[000163] In certain embodiments, the combination treatments provided herein include administration of a compound of Formulas (I)-(VIII) provided herein, or a pharmaceutically acceptable salt, N-oxide, isomer or solvate thereof, or a pharmaceutical composition containing at least one compound of Formula (I)-(VIII) provided herein, concurrently with one or more additional therapeutic agents, for the treatment of one or more of the TGR5- related diseases and/or disorders described herein.
[000164] In certain embodiments, the combination treatments provided herein include administration of a compound of Formulas (I)-(VIII) provided herein, or a pharmaceutically acceptable salt, N-oxide, isomer or solvate thereof, or a pharmaceutical composition containing at least one compound of Formula (I)-(VIII) provided herein, formulated with one or more additional therapeutic agents, for the treatment of one or more of the TGR5 -related diseases and/or disorders described herein.
[000165] In certain embodiments of the combination therapies described herein, the compounds of Formula (I)-(VIII) provided herein, or a pharmaceutically acceptable salts, N- oxides, isomers or solvates thereof, and the additional therapeutics agent(s) act additively. In other embodiments of the combination therapies described herein, the compounds of Formula (I)-(VIII) provided herein, or a pharmaceutically acceptable salts, N-oxides, isomers or solvates thereof, and the additional therapeutics agent(s) act synergistically.
[000166] The additional therapeutic agents used in combination with at least one compound of Formula (I)-(VIII) described herein, or a pharmaceutically acceptable salt, N-oxide, isomer or solvate thereof, include, but are not limited to immunomodulatory, antiinflammatory substances and other anti-diabetes therapeutic agents.
[000167] The other anti-diabetes therapeutic agents used in combination with at least one compound of Formula (I)-(VIII) described herein or a pharmaceutically acceptable salt, N- oxide, isomer or solvate thereof include, but are not limited, sulfonylureas (by way of example, chloropropamide, acetohexamide, glimepiride, glipizide, glyburide, tolazamide, tolbutamide), meglitinides (by way of example, repaglinide, nateglinide) biguanides (by way of example, metformin), thiazolidinediones (by way of example, rosiglitazone,
pioglitazone),and alpha-glucosidase inhibitors (by way of example, acarbose, miglitol).
[000168] The anti-inflammatory agents used in combination with at least one compound of Formula (I)-(VIII) described herein or a pharmaceutically acceptable salt, N-oxide, isomer or solvate thereof include, but are not limited to, non-steroidal anti-inflammatory drugs such as salicylic acid, acetylsalicylic acid, methyl salicylate, diflunisal, salsalate, olsalazine, sulfasalazine, acetaminophen, indomethacin, sulindac, etodolac, mefenamic acid, meclofenamate sodium, tolmetin, ketorolac, dichlofenac, ibuprofen, naproxen, naproxen sodium, fenoprofen, ketoprofen, flurbinprofen, oxaprozin, piroxicam, meloxicam, ampiroxicam, droxicam, pivoxicam, tenoxicam, nabumetome, phenylbutazone,
oxyphenbutazone, antipyrine, aminopyrine, apazone and nimesulide, leukotriene antagonists including, but not limited to, zileuton, aurothioglucose, gold sodium thiomalate and auranofin, steroids including, but not limited to, alclometasone diproprionate, amcinonide, beclomethasone dipropionate, betametasone, betamethasone benzoate, betamethasone diproprionate, betamethasone sodium phosphate, betamethasone valerate, clobetasol proprionate, clocortolone pivalate, hydrocortisone, hydrocortisone derivatives, desonide, desoximatasone, dexamethasone, flunisolide, flucoxinolide, flurandrenolide, halcinocide, medrysone, methylprednisolone, methprednisolone acetate, methylprednisolone sodium succinate, mometasone furoate, paramethasone acetate, prednisolone, prednisolone acetate, prednisolone sodium phosphate, prednisolone tebuatate, prednisone, triamcinolone, triamcinolone acetonide, triamcinolone diacetate, and triamcinolone hexacetonide and other anti-inflammatory agents including, but not limited to, methotrexate, colchicine, allopurinol, probenecid, thalidomide or a derivative thereof, 5 -aminosalicylic acid, retinoid, dithranol or calcipotriol, sulfinpyrazone and benzbromarone.
[000169] The immunomodulatory agents used in combination with at least one compound of Formula (I)-(VIII) described herein, or a pharmaceutically acceptable salt or solvate thereof, include, but are not limited to, azathioprine, tacrolimus, cyclosporin methothrexate, leflunomide, corticosteroids, cyclophosphamide, cyclosporine A, cyclosporin G, mycophenolate mofetil, ascomycin, rapamycin (sirolimus), FK-506, mizoribine, deoxyspergualin, brequinar, mycophenolic acid, malononitriloamindes (such as, by way of example only, leflunamide), T cell receptor modulators, and cytokine receptor modulators, peptide mimetics, and antibodies (such as, by way of example only, human, humanized, chimeric, monoclonal, polyclonal, Fvs, ScFvs, Fab or F(ab)2 fragments or epitope binding fragments), nucleic acid molecules (such as, by way of example only, antisense nucleic acid molecules and triple helices), small molecules, organic compounds, and inorganic compounds. Examples of T cell receptor modulators include, but are not limited to, anti-T cell receptor antibodies (such as, by way of example only, anti-CD4 antibodies (such as, by way of example only, cM-T412 (Boehringer), IDEC-CE9.1™ (IDEC and SKB), mAB 4162W94, Orthoclone and OKTcdr4a (Janssen-Cilag)), anti-CD3 antibodies (such as, by way of example only, Nuvion (Product Design Labs), OKT3 (Johnson & Johnson), or Rituxan (IDEC)), anti-CD5 antibodies (such as, by way of example only, an anti-CD5 ricin-linked immunoconjugate), anti-CD7 antibodies (such as, by way of example only, CHH-380 (Novartis)), anti-CD8 antibodies, anti-CD40 ligand monoclonal antibodies (such as, by way of example only, IDEC- 131 (IDEC)), anti-CD52 antibodies (such as, by way of example only, CAMPATH 1H (Ilex)), anti-CD2 antibodies, anti-CDl la antibodies (such as, by way of example only, Xanelim (Genentech)), anti-B7 antibodies (such as, by way of example only, IDEC- 114 (IDEC)), CTLA4-immunoglobulin, and other toll receptor-like (TLR) modulators. Examples of cytokine receptor modulators include, but are not limited to, soluble cytokine receptors (such as, by way of example only, the extracellular domain of a TNF-oc receptor or a fragment thereof, the extracellular domain of an IL-Ιβ receptor or a fragment thereof, and the extracellular domain of an IL-6 receptor or a fragment thereof), cytokines or fragments thereof (such as, by way of example only, interleukin (IL)-2, IL-3, IL-4, IL-5, IL- 6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-15, TNF-.alpha., interferon (IFN)-cc, IFN-β, IFN- γ, and GM-CSF), anti-cytokine receptor antibodies (such as, by way of example only, anti- IFN receptor antibodies, anti-IL-2 receptor antibodies (such as, by way of example only, Zenapax (Protein Design Labs)), anti-IL-4 receptor antibodies, anti-IL-6 receptor antibodies, anti-IL-10 receptor antibodies, and anti-IL-12 receptor antibodies), anti-cytokine antibodies (such as, by way of example only, anti-IFN antibodies, anti-TNF-oc antibodies, anti-IL-Ιβ antibodies, anti-IL-6 antibodies, anti-IL-8 antibodies (such as, by way of example only, ABX-IL-8 (Abgenix)), and anti-IL-12 antibodies).
[000170] The cytokines or modulator of cytokine function used in combination with at least one compound of Formula (I)-(VIII) described herein, or a pharmaceutically acceptable salt or solvate thereof, include, but are not limited to, interleukin-2 (IL-2), interleukin-3 (IL-3), interleukin-4 (IL-4), interleukin-5 (IL-5), interleukin-6 (IL-6), interleukin-7 (IL-7), interleukin-9 (IL-9), interleukin- 10 (IL-10), interleukin- 12 (IL-12), interleukin 15 (IL-15), interleukin 18 (IL-18), platelet derived growth factor (PDGF), erythropoietin (Epo), epidermal growth factor (EGF), fibroblast growth factor (FGF), granulocyte macrophage stimulating factor (GM-CSF), granulocyte colony stimulating factor (G-CSF), macrophage colony stimulating factor (M-CSF), prolactin, alpha-, beta-, and gamma-interferon, interferon β-la, interferon β-lb, interferon oc-1, interferon oc-2a (roferon), interferon a- 2b, pegylated interferons (by way of example only, peginterferon oc-2a and peginterferon oc-2b), intron, Peg-Intron, Pegasys, consensus interferon (infergen), albumin-interferon a and albuferon.
[000171] In other embodiments, a compound of Formula (I)-(VIII) described herein, or a pharmaceutically acceptable salt, N-oxide, isomer or solvate thereof, or a pharmaceutical composition containing such compounds of Formula (I)-(VIII), is administered to a patient who has not previously undergone or is not currently undergoing treatment with another therapeutic agent.
[000172] Where the compounds of Formula (I)-(VIII) are administered in conjunction with other therapies, dosages of the co-administered compounds will of course vary depending on the type of co-drug employed, on the specific drug employed, on the condition being treated and so forth.
Kits
[000173] Also provided herein are pharmaceutical packs or kits that include one or more containers containing a compound of Formula (I)-(VIII) useful for the treatment or prevention of a TGR5 -related disease or disorder. In other embodiments, such
pharmaceutical packs or kits include one or more containers containing a compound of Formula (I)-(VIII) useful for the treatment or prevention of a TGR5-related disease or disorder and one or more containers containing an additional therapeutic agent. In certain embodiments, such pharmaceutical packs or kits optionally include instructions for its administration of a compound of Formula (I)-(VIII). In certain embodiments of such kits, the compound of Formula (I)-(VIII) is in free form or in pharmaceutically acceptable salt or N- oxide form.
[000174] One of skill in the art will appreciate that the above transformations are only representative of methods for preparation of the compounds of the present invention, and that other well known methods can similarly be used.
Examples
[000175] The compounds provided herein are further exemplified, but not limited, by the following example that illustrates the preparation of compounds of Formula (I) and Formula (II).
Example 1
Preparation of tert-butyl 4-(l-(4-fluorophenyl)-4-(3-phenylpyrrolidine-l-carbonyl)-lH- pyrazol-5-yl)piperidine-l-carboxylate (Ex. No. 1)
[000176] The preparation of (tert-butyl 4-(l-(4-fluorophenyl)-4-(3-phenylpyrrolidine-l- carbonyl)-lH-pyrazol-5-yl)piperidine-l-carboxylate is illustrated in scheme 1.
Scheme 1:
Figure imgf000064_0001
Figure imgf000064_0002
Ex. No. 1
[000177] To a solution of the l-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (1) (6.9 g, 30 mmol) in dichlormethane (DCM) (75 mL) was added Meldrum's acid (2) (4.76 g, 33 mmol, 1.1 eq) followed by 4-dimethylaminopyridine (DMAP) (5.13g, 45 mmol , 1.5 eq). The solution was cooled to 0 °C, then l-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI) (8.63 g, 42 mmol, 1.4 eq) was added in small portions over approximately 5 minutes. The reaction was stirred for 17 hours and allowed to warm to room temperature. The reaction was quenched with water (50 mL), and the layers were allowed to separate. The organic layer was washed with 0.1 M HC1 3 times. The combined organics were dried over sodium sulfate, filtered, and concentrated to give tert-butyl 4-(2,2-dimethyl- 4,6-dioxo-l,3-dioxane-5-carbonyl)piperidine-l-carboxylate (3) as a syrup which solidified on standing.
[000178] Tert-butyl 4-(2,2-dimethyl-4,6-dioxo- 1 ,3-dioxane-5-carbonyl)piperidine- 1- carboxylate (3) was heated to 50 °C in methanol until the reaction was complete (2-4 hours) by LC-MS. The methanol was evaporated to dryness and the crude product was purified by silica gel chromatography (80 g of silica) using a gradient of 10-100 % ethyl acetate/hexanes to give tert-butyl 4-(3-methoxy-3-oxopropanoyl)piperidine-l-carboxylate (4). [000179] Tert-butyl 4-(3-methoxy-3-oxopropanoyl)piperidine-l-carboxylate (4) (7.55 g, 26.5 mmol) was dissolved in DCM (50 mL) and treated with dimethylformamide dimethylacetal (DMFDMA) (17 mL, 127 mmol, 4.8 eq) at reflux for 4 hours (complete by LC-MS). The solvent was evaporated to give (Z)-tert-butyl 4-(3-(dimethylamino)-2- (methoxycarbonyl)acryloyl)piperidine-l-carboxylate (5) as a crude product that was carried forward without any further purification.
[000180] (Z)-tert-butyl 4-(3-(dimethylamino)-2-(methoxycarbonyl)acryloyl)piperidine-l- carboxylate (5) (2 g, 5.9 mmol) was treated with 4-fluorophenylhydrazine hydrochloride (6) (1.15 g, 7.1 mmol, 1.2 eq) in ethanol (2 mL) at 80 °C overnight. The reaction was concentrated to dryness and purified by silica gel chromatography (40 g, 5-50 % ethyl acetate/hexanes) to give tert-butyl 4-(l-(4-fluorophenyl)-4-(methoxycarbonyl)-lH-pyrazol-5- yl)piperidine-l-carboxylate (7) as an oil.
[000181] Tert-butyl 4-(l-(4-fluorophenyl)-4-(methoxycarbonyl)-lH-pyrazol-5- yl)piperidine-l-carboxylate (7) was dissolved in dioxane (20 mL) and treated with 3 M LiOH (2.6 mL) at 80 °C until complete by LC-MS (4-6 hours). The reaction was cooled to room temperature, quenched with 10% citric acid solution (3-5 mL), diluted with water (~3 mL) and extracted with ethyl acetate. The extracts were combined and dried over magnesium sulfate, filtered, and concentrated to dryness to give 5-(l-(tert-butoxycarbonyl)piperidin-4- yl)-l-(4-fluorophenyl)-lH-pyrazole-4-carboxylic acid (8) which was used in the next step without further purification.
[000182] 5-(l-(tert-butoxycarbonyl)piperidin-4-yl)-l-(4-fluorophenyl)-lH-pyrazole-4- carboxylic acid (8) (50 mg, 0.13 mmol) was dissolved in acetonitrile (1 mL) and treated with diisopropylethylamine (48 μL·, 0.28 mmol, 2 eq.) and HATU (53 mg, 0.14 mmol, 1.1 eq.). After 5 minutes, 3-phenylpyrroldine hydrochloride (26 mg, 0.14 mmol) was added. After 60 minutes, the reaction was complete by HPLC. The reaction solution was diluted with 0.5 mL water, filtered through 0.45 μΜ Whatman filter and then purified by reversed phase HPLC (C-18, 100 mlVrnin, 10-90%, water (0.05 % TFA)/ACN) to yield tert-butyl 4-(l-(4- fluorophenyl)-4-(3-phenylpyrrolidine- 1-carbonyl)- lH-pyrazol-5-yl)piperidine- 1-carboxylate (Ex. No. 1) as a white solid. ]H NMR (CDC13) δ 7.64 (1H), 7.36-7.32 (5H), 7.24-7.18 (4H), 4.15-3.92 (3H), 3.75-3.42 (3H), 2.96-2.82 (1H), 2.58-2.35 (3H), 2.18-1.92 (3H), 1.69-1.60 (3H), 1.44 (9H); HPLC-MS calculated for C30H35FN4O3 (M+H+) 519.3, found 519.3; RT 2.6 min. (3.5 min) (C18, 10-90%, water (0.05 % TFA)/ACN). [000183] By repeating the procedures described in Example 1, using appropriate starting materials, the following compounds of Formula (I) or Formula (II), as identified in Table 1, were obtained.
Table 1
Figure imgf000066_0001
Figure imgf000068_0001
Figure imgf000069_0001
Example 23
Preparation of (S)-l-methylcyclopropyl 4-(l-(4-chlorophenyl)-4-(3-phenylpyrrolidine-l- carbonyl)-lH-pyrazol-5-yl)piperidine-l-carboxylate (Ex. No. 23)
[000184] The preparation of (S)-l-methylcyclopropyl 4-(l-(4-chlorophenyl)-4-(3- phenylpyrrolidine-l-carbonyl)-lH-pyrazol-5-yl)piperidine-l-carboxylate (Ex. No. 23) is illustrated in scheme 2.
Scheme 2:
Figure imgf000069_0002
Ex. No. 23
[000185] 1-methylcyclopropyl 4-nitrophenyl carbonate (196 mg, 0.83 mmol, 1.04 eq) was added to a solution of (S)-(l-(4-chlorophenyl)-5-(piperidin-4-yl)-lH-pyrazol-4-yl)(3- phenylpyrrolidin-l-yl)methanone (deprotected compound 5) (350 mg, 0.8 mmol, 1. eq) and NEt3 (167 μί, 1.2 mmol, 1.5 eq) in DCE (6 mL). After stirring overnight at 55 °C, the reaction was concentrated and purified by silica gel chromatography using a gradient of 0-5 % methanol/DCM to give (S)-l-methylcyclopropyl 4-(l-(4-chlorophenyl)-4-(3- phenylpyrrolidine-l-carbonyl)-lH-pyrazol-5-yl)piperidine-l-carboxylate (Ex. No. 23) as a colorless foam. ]H NMR (CD3OD) δ 7.83 (d, J = 12.6 Hz, IH), 7.59 (t, J = 8.6 Hz, 2H), 7.46 (d, / = 8.5 Hz, 2H), 7.36-7.21 (m, 5H), 4.12 (br. s, IH), 4.05-3.84 (m, 2H), 3.73-3.44 (m, 4H), 2.96-2.86 (m, IH), 2.66 (br. s, 2H), 2.45-2.34 (m, IH), 2.24-1.86 (m, 3H), 1.73-1.64 (m, 2H), 1.52-1.50 (m, 3H), 0.86-0.84 (m, 2H), 0.63-0.62 (m, 2H). HPLC-MS calculated for C30H33CIN4O3 (M+H+) 534.06, found 534.23.
Example 24
Preparation of l-(4-(l-(4-fluorophenyl)-4-(3-phenylpyrrolidine-l-carbonyl)-lH-pyrazol-5- yl)piperidin-l-yl)-3,3-dimethylbutan-l-one (Ex. No. 24)
[000186] The preparation of l-(4-(l-(4-fluorophenyl)-4-(3-phenylpyrrolidine-l-carbonyl)- lH-pyrazol-5-yl)piperidin-l-yl)-3,3-dimethylbutan-l-one (Ex. No. 24) is illustrated in scheme 3.
Figure imgf000070_0001
Ex. No. 24
[000187] 3,3-dimethylbutanoyl chloride (20 μΕ, 0.14 mmol, 1.4 eq) was added to a solution of (l-(4-fluorophenyl)-5-(piperidin-4-yl)-lH-pyrazol-4-yl)(3-phenylpyrrolidin-l- yl)methanone (deprotected compound 6) (43 mg, 0.1 mmol, 1 eq) and DIEA (35 μΕ, 0.2 mmol, 2 eq) in DCM (1 mL). The reaction was stirred at room temperature for 2 hours, loaded directly onto a silica gel column, and purified using a gradient of 0-5 %
methanol/DCM to give l-(4-(l-(4-fluorophenyl)-4-(3-phenylpyrrolidine-l-carbonyl)-lH- pyrazol-5-yl)piperidin-l-yl)-3,3-dimethylbutan-l-one (Ex. No. 24) as a colorless solid. ]H NMR (CDCI3) δ 7.71-7.65 (IH), 7.50-7.46 (2H), 7.38-7.28 (6H), 7.25-7.21 (IH), 4.79-4.76 (IH), 3.99-3.87 (2H), 3.77-3.61 (2H), 3.57-3.40 (2H), 3.10-3.00 (IH), 2.97-2.88 (IH), 2.42- 2.34 (2H), 2.24 (2H), 1.91-1.66 (4H), 1.03-1.02 (9H). HPLC-MS calculated for C31H37CIN4O2 (M+H+) 534.10, found, 534.20; RT 2.7 min. (3.5 min) (C18, 10-90%, water (0.05 % TFA)/ACN).
[000188] By repeating the procedures described in example 23 and 24, using appropriate starting materials, the following compounds of Formula (I) or Formula (II), as identified in Table 2, were obtained.
Table 2
Figure imgf000071_0001
Figure imgf000072_0001
Figure imgf000073_0001
Figure imgf000074_0001
Figure imgf000075_0001
Figure imgf000076_0001
Example 56
Preparation of (R)-(5-(l-benzylpiperidin-4-yl)-l-(4-chlorophenyl)-lH-pyrazol-4-yl)(3- phenylpyrrolidin-l-yl)methanone (Ex. No. 56)
[000189] The preparation of (R)-(5-(l-benzylpiperidin-4-yl)-l-(4-chlorophenyl)-lH- pyrazol-4-yl)(3-phenylpyrrolidin-l-yl)methanone (Ex. No. 55) is illustrated in scheme 4.
Scheme 4:
Figure imgf000077_0001
Ex. No. 55 Ex. No. 56
[000190] To a solution of (R)-tert-butyl 4-(l-(4-chlorophenyl)-4-(3-phenylpyrrolidine-l- carbonyl)-lH-pyrazol-5-yl)piperidine-l-carboxylate (Ex. No. 55) (100 mg, 0.19 mmol) in DCM (1 mL) was added 0.5 mL of TFA and the solution was stirred for 1 hour at room temperature. Upon completion of the reaction, the solvent was concentrated en vacuo and then the residue was dissolved in DCM and washed with saturated bicarbonate solution. The organic layer was dried over sodium sulfate, filtered, and concentrated to dryness and used in the subsequent step without any further purification.
[000191] To a solution of the product from the above step in acetonitrile (2 mL) was added benzaldehyde (25 mg, 0.24 mmol, 1.25 eq), sodium triacetoxyborohydride (80 mg, 0.38 mmol, 2 eq) and catalytic acetic acid (~1 drop). The mixture was heated to 50 °C for 1 hour. The mixture was then diluted with 0.5 mL water, filtered through a 0.45 μΜ Whatman filter and purified by reversed phase HPLC (C-18, 100 mL/min, 10-90%, water (0.05 %
TFA)/ACN) to yield (R)-(5-(l-benzylpiperidin-4-yl)-l-(4-chlorophenyl)-lH-pyrazol-4-yl)(3- phenylpyrrolidin-l-yl)methanone (Ex. No. 56) as a white solid. ]H NMR (CDC13) δ 7.64 (1H), 7.48 (2H), 7.34-7.20 (12H), 4.17-3.89 (2H), 3.80-3.30 (6H), 2.90 (2H), 2.73 (1H), 2.44-2.04 (5H), 1.86 (2H); HPLC-MS calculated for C32H33CIN4O (M+H+) 525.2, found 525.0; RT 2.8 min. (4.5 min) (C18, 10-90%, water (0.05 % TFA)/ACN).
Example 57
Preparation of 4-((4-(4-(3,3-difluoro-4-phenylpyrrolidine-l-carbonyl)-l-(4-fluorophenyl)- lH-pyrazol-5-yl)piperidin-l-yl)methyl)benzenesulfonamide (Ex. No. 57)
[000192] The preparation of 4-((4-(4-(3,3-difluoro-4-phenylpyrrolidine-l-carbonyl)-l-(4- fluorophenyl)-lH-pyrazol-5-yl)piperidin-l-yl)methyl)benzenesulfonamide (Ex. No. 57) is illustrated in scheme 5.
Scheme 5
Figure imgf000078_0001
Figure imgf000078_0002
[000193] To a a solution of l-bromo-4-(2,2-difluorovinyl)benzene (1.14 g, 5.2 mmol) in acetonitrile (10 mL) was added N-benzyl-l-methoxy-N-((trimethylsilyl)methyl)methanamine (2.0 mL, 7.8 mmol) and lithium fluoride (263 mg, 10.1 mmol). The reaction vessel was purged with argon, sealed, and sonicated at room temperature for 17 hours. The crude reaction mixture was filtered to remove the inorganic salts and concentrated to dryness then purified by silica gel chromatography (0-40 % ethyl acetate/hexanes) to give l-benzyl-4-(4- bromophenyl)-3,3-difluoropyrrolidine as a colorless, semi-viscous liquid.
[000194] To a solution of l-benzyl-4-(4-bromophenyl)-3,3-difluoropyrrolidine (5.5 g, 16 mmol) in acetic acid (80 mL) was added 10 % palladium on carbon (1.7 g, 1.6 mmol, Degussa type wet). The vessel was sealed and fitted with a hydrogen- filled balloon and stirred vigourously overnight. Upon completion, the catalyst was removed by filtration on pad of celite and concentrated to dryness to give the product (3,3-difluoro-4- phenylpyrrolidine acetate) as a white to off-white solid. [000195] To a 40 mL microwave reaction vessel was added 3,3-difluoro-4- phenylpyrrolidine acetate (1.0 g, 4.1 mmol), and tert-butyl 4-(2,2-dimethyl-4,6-dioxo-l,3- dioxane-5-carbonyl)piperidine-l-carboxylate (1.8 g, 4.9 mmol), dioxane (15 mL) and diisopropylethylamine (1.8 mL, 10.3 mmol). The vessel was sealed and heated to 120 °C for 20 minutes. Upon completion, the reaction was diluted with 10 % citric acid and extracted with ethyl acetate. The combined organics were washed with brine, dried over magnesium sulfate, filtered concentrated en vacuo and purified by silica gel chromatography (50-100% Ethyl acetate/Hexanes) to give tert-butyl 4-(3-(3,3-difluoro-4-phenylpyrrolidin-l-yl)-3- oxopropanoyl)piperidine-l-carboxylate as syrup.
[000196] Tert-butyl 4-(3-(3,3-difluoro-4-phenylpyrrolidin-l-yl)-3- oxopropanoyl)piperidine-l-carboxylate (7.55 g, 17.3 mmol) was dissolved in DCM (50 mL) and treated with dimethylformamide dimethylacetal (DMFDMA) (11 mL, 83 mmol, 4.8 eq) at reflux for 4 hours (complete by LC-MS). The solvent was evaporated to give ((Z)-tert- butyl 4-(2-(3,3-difluoro-4-phenylpyrrolidine-l-carbonyl)-3-
(dimethylamino)acryloyl)piperidine-l-carboxylate) as a crude product that was carried forward without any further purification.
[000197] To a solution of (Z) -tert-butyl 4-(2-(3,3-difluoro-4-phenylpyrrolidine-l-carbonyl)-
3- (dimethylamino)acryloyl)piperidine-l-carboxylate (250 mg, 0.5 mmol) in n-butanol (3 mL) was added 4-fluorophenylhydrazine hydrochloride (248 mg, 1.5 mmol) and
diisopropylethylamine (0.7 mL, 5 mmol). The mixture was heated to 90 °C for 2 hours and was then filtered on celite, washed with ethyl acetate and concentrated to dryness. Tert-butyl
4- (4-(3,3-difluoro-4-phenylpyrrolidine-l-carbonyl)-l-(4-fluorophenyl)-lH-pyrazol-5- yl)piperidine-l-carboxylate was obtained as an oil upon purification by silica gel
chromatography (20-100 % ethyl acetate/hexanes).
[000198] To a solution of tert-butyl 4-(4-(3,3-difluoro-4-phenylpyrrolidine-l-carbonyl)-l-(4- fluorophenyl)-lH-pyrazol-5-yl)piperidine-l-carboxylate (100 mg, 0.18 mmol) in DCM (1 mL) was added 0.5 mL of TFA and the solution was stirred for 1 hour at room temperature. Upon completion of the reaction, the solvent was concentrated en vacuo and then the residue was dissolved in DCM and washed with saturated bicarbonate solution. The organic layer was dried over sodium sulfate, filtered, and concentrated to dryness and used in the subsequent step without any further purification.
[000199] To a solution of the product from the above step in acetonitrile (2 mL) was added 4- (bromomethyl)benzenesulfonamide (56.3 mg, 0.24 mmol, 1.25 eq) and K2C03. The mixture was heated to 50 °C for 1 hour. The mixture was then diluted with 0.5 mL water, filtered through a 0.45 μΜ Whatman filter and purified by reversed phase HPLC (C-18, 100 mL/min, 10-90%, water (0.05 % TFA)/ACN) to yield (4-((4-(4-(3,3-difluoro-4-phenylpyrrolidine-l-carbonyl)-l-(4- fluorophenyl)-lH-pyrazol-5-yl)piperidin-l-yl)methyl)benzenesulfonamide) (Ex. No. 57). The material was then resolved by chiral HPLC (stationary phase: 20X250 mm ChiralPaklA, mobile phase: 70/25/5 Hexane/chloroform/ethanol, flow rate: 18 mL/min) to yield Examples 218 and 219, respectively.
[000200] By repeating the procedures described in example 56 and 57, using appropriate starting materials, compounds of Formula (I) or Formula (II), as identified in Table 3, were obtained.
Example 280
Preparation of (R)-4-(l-(4-fluorophenyl)-4-(3-phenylpyrrolidine-l-carbonyl)-lH-pyrazol-5- yl)-l-methyl-l-(4-(methylsulfonyl)benzyl)piperidin-l-ium (Ex. No. 280)
Example 280
Figure imgf000080_0001
[000201] A solution of (R)-(l-(4-fluorophenyl)-5-(l-(4-(methylsulfonyl)benzyl)piperidin- 4-yl)-lH-pyrazol-4-yl)(3-phenylpyrrolidin-l-yl)methanone (100 mg, 0.17 mmol) in acetonitrile (2 mL) was treated with excess bromomethane (0.5 mL) and heated to 80 °C until complete conversion was observed by HPLC-MS. The solvent and excess reagents were removed by evaporation to give the quaternary ammonium salt, (R)-4-(l-(4-fluorophenyl)-4- (3 -phenylpyrrolidine- 1 -carbonyl) - 1 H-pyrazol- 5 -yl) - 1 -methyl- 1 - (4-
(methylsulfonyl)benzyl)piperidin-l-ium. HPLC-MS calculated for C34H38FN403S+ (M+) 601.3, found 601.3; RT 2.09 min. (4.5 min) (C18, 10-100%, water (0.05 % TFA)/ACN.
[000202] By repeating the procedures described in example 280, using appropriate starting materials, compounds of Formula (I) or Formula (II), as identified in Table 3, were obtained.
Table 3
Physical Data
Example
Structure 1H NMR 400 MHz (CDC13 or acetone-d6) No.
and/or MS (m/z)
Figure imgf000081_0001
Figure imgf000082_0001
Physical Data
Example
Structure 1H NMR 400 MHz (CDC13 or acetone-d6) No.
and/or MS (m/z)
HPLC-MS calculated for C33H34FN70 (M+H+) 564.3, found 564.4; RT 2.5 min.
73
(4.5 min) (C18, 10-90%, water (0.05 %
TFA)/ACN
HPLC-MS calculated for C33H35FN403S (M+H+) 587.2, found 587.4; RT 2.5 min.
74
(4.5 min) (C18, 10-90%, water (0.05 %
TFA)/ACN
HPLC-MS calculated for C33H31F2N50 (M+H+) 552.2, found 552.3; RT 2.5 min.
75
(4.5 min) (C18, 10-90%, water (0.05 %
TFA)/ACN
HPLC-MS calculated for C33H31F2N50 (M+H+) 552.2, found 552.3; RT 2.5 min.
76
(4.5 min) (C18, 10-90%, water (0.05 %
TFA)/ACN
HPLC-MS calculated for C34H38N404S (M+H+) 599.3, found 599.2; RT 2.3 min.
77
(4.5 min) (C18, 10-90%, water (0.05 %
TFA)/ACN
HPLC-MS calculated for C34H35N503S (M+H+) 594.2, found 594.3; RT 2.4 min.
78
(4.5 min) (C18, 10-90%, water (0.05 %
TFA)/ACN
HPLC-MS calculated for C31H34N603S (M+H+) 571.2, found 571.3; RT 2.8 min.
79
(4.5 min) (C18, 10-90%, water (0.05 %
TFA)/ACN
Figure imgf000084_0001
Figure imgf000085_0001
Figure imgf000086_0001
Figure imgf000087_0001
Physical Data
Example
Structure 1H NMR 400 MHz (CDC13 or acetone-d6) No.
and/or MS (m/z)
HPLC-MS calculated for C34H37FN403S (M+H+) 601.3, found 601.3; RT 0.9 min.
105
(3.5 min) (C18, 10-90%, water (0.05 %
TFA)/ACN
HPLC-MS calculated for C33H31BrFN50 (M+H+) 612.2, found 612.2; RT 2.3 min.
106
(4.5 min) (C18, 10-90%, water (0.05 %
TFA)/ACN
HPLC-MS calculated for C32H34FN503S (M+H+) 588.2, found 588.2; RT 1.3 min.
107
(3.5 min) (C18, 10-90%, water (0.05 %
TFA)/ACN
HPLC-MS calculated for C32H34FN503S (M+Na+) 610.4, found 610.4; RT 1.5 min.
108
(3.5 min) (C18, 10-90%, water (0.05 %
TFA)/ACN
HPLC-MS calculated for C32H32F2N40 (M+H+) 527.3, found 527.2; RT 1.5 min.
109
(3.5 min) (C18, 10-90%, water (0.05 %
TFA)/ACN
HPLC-MS calculated for C33H31F2N50 (M+H+) 552.3, found 552.3; RT 2.2 min.
110
(4.5 min) (C18, 10-90%, water (0.05 %
TFA)/ACN
HPLC-MS calculated for C31H32FN50 (M+H+) 510.3, found 510.2; RT 1.2 min.
111
(3.5 min) (C18, 10-90%, water (0.05 %
TFA)/ACN Physical Data
Example
Structure 1H NMR 400 MHz (CDC13 or acetone-d6) No.
and/or MS (m/z)
HPLC-MS calculated for C32H34FN504S (M+H+) 604.2, found 604.2; RT 0.9 min.
112
(3.5 min) (C18, 10-90%, water (0.05 %
TFA)/ACN
HPLC-MS calculated for C33H36FN503S (M+H+) 602.2, found 602.0; RT 1.3 min.
113
(4.5 min) (C18, 10-90%, water (0.05 %
TFA)/ACN
HPLC-MS calculated for C34H34FN50 (M+H+) 548.3, found 548.3; RT 1.5 min.
114
(3.5 min) (C18, 10-90%, water (0.05 %
TFA)/ACN
HPLC-MS calculated for C32H34FN502 (M+H+) 540.3, found 540.3; RT 1.2 min.
115
(3.5 min) (C18, 10-90%, water (0.05 %
TFA)/ACN
HPLC-MS calculated for C32H31F3N40 (M+H+) 545.2, found 545.3; RT 2.0 min.
116
(3.5 min) (C18, 10-90%, water (0.05 %
TFA)/ACN
HPLC-MS calculated for C33H34FN503 (M+H+) 568.3, found 568.3; RT 1.7 min.
117
(3.5 min) (C18, 10-90%, water (0.05 %
TFA)/ACN
118 FJCCO ;N '" HPLC-MS calculated for C32H31F3N40
(M+H+) 545.2, found 545.2; RT 1.5min. (3.5 min) (C18, 10-90%, water (0.05 %
TFA)/ACN
HPLC-MS calculated for C32H34FN504S (M+H+) 604.3, found 604.3; RT 0.9min. (3.5
119
min) (C18, 10-90%, water (0.05 %
TFA)/ACN
Figure imgf000090_0001
Physical Data
Example
Structure 1H NMR 400 MHz (CDC13 or acetone-d6) No.
and/or MS (m/z)
HPLC-MS calculated for C34H36FN502 (M+H+) 566.3, found 566.3; RT 1.4 min.
128
(3.5 min) (C18, 10-90%, water (0.05 %
TFA)/ACN
HPLC-MS calculated for C32H30F4N4O (M+H+) 563.2, found 563.3; RT 2.0 min.
129
(3.5 min) (C18, 10-90%, water (0.05 %
TFA)/ACN
F
HPLC-MS calculated for C31H31C1FN50 (M+H+) 544.2, found 544.0; RT 1.3 min.
130
xx.¾ -ro (3.5 min) (C18, 10-90%, water (0.05 %
TFA)/ACN
HPLC-MS calculated for C36H34FN503S (M+H+) 636.2, found 636.3; RT 2.3 min.
131 ■<-ro,¾ cro (4.5 min) (C18, 10-90%, water (0.05 %
TFA)/ACN
HPLC-MS calculated for C31H32FN50 (M+H+) 510.3, found 510.3; RT 1.3 min.
132
(3.5 min) (C18, 10-90%, water (0.05 %
TFA)/ACN
HPLC-MS calculated for C31H37FN403 (M+H+) 533.3, found 533.3; RT 1.6 min.
133
(3.5 min) (C18, 10-90%, water (0.05 %
TFA)/ACN
HPLC-MS calculated for C33H32F2N60 -N' N-N.H (M+H+) 595.3, found 595.3; RT 1.8 min.
134
(3.5 min) (C18, 10-90%, water (0.05 %
TFA)/ACN
HPLC-MS calculated for C36H40FN5O4 (M+H+) 626.3, found 626.1; RT 1.1 min.
135
(3.5 min) (C18, 10-90%, water (0.05 %
TFA)/ACN Physical Data
Example
Structure 1H NMR 400 MHz (CDC13 or acetone-d6) No.
and/or MS (m/z)
HPLC-MS calculated for C30H30C1FN6O (M+H+) 545.2, found 545.0; RT 1.3 min.
136
(3.5 min) (C18, 10-90%, water (0.05 %
TFA)/ACN
HPLC-MS calculated for C34H35FN402 (M+H+) 551.3, found 551.3; RT 2.1 min.
137
(3.5 min) (C18, 10-90%, water (0.05 %
TFA)/ACN
HPLC-MS calculated for C32H33FN403S (M+H+) 573.2, found 573.4; RT 1.4 min.
138
(3.5 min) (C18, 10-90%, water (0.05 %
TFA)/ACN
HPLC-MS calculated for C33H33FN403S (M+H+) 585.2, found 585.1; RT 1.2 min.
139
(3.5 min) (C18, 10-90%, water (0.05 %
TFA)/ACN
HPLC-MS calculated for C33H35FN40 (M+H+) 523.3, found 523.4; RT 2.1 min.
140
(3.5 min) (C18, 10-90%, water (0.05 %
TFA)/ACN
HPLC-MS calculated for C40H46FN5O4 (M+H+) 680.4, found 680.3; RT 1.6 min.
141
(3.5 min) (C18, 10-90%, water (0.05 %
TFA)/ACN
HPLC-MS calculated for C34H37FN403S (M+H+) 601.3, found 601.3; RT 1.0 min.
142
(3.5 min) (C18, 10-90%, water (0.05 %
TFA)/ACN Physical Data
Example
Structure 1H NMR 400 MHz (CDC13 or acetone-d6) No.
and/or MS (m/z)
HPLC-MS calculated for C32H33FN403S (M+H+) 573.2, found 573.3; RT 1.6 min.
143
(3.5 min) (C18, 10-90%, water (0.05 %
TFA)/ACN
HPLC-MS calculated for C32H32FN503 (M+H+) 554.2, found 554.2; RT 1.3 min.
144
(3.5 min) (C18, 10-90%, water (0.05 %
TFA)/ACN n.n f HPLC-MS calculated for C36H38FN504
(M+H+) 624.3, found 624.1; RT 1.2 min.
145
(3.5 min) (C18, 10-90%, water (0.05 %
TFA)/ACN
HPLC-MS calculated for C32H31C1F2N40 (M+H+) 561.2, found 561.3; RT 2.1 min.
146
(3.5 min) (C18, 10-90%, water (0.05 %
TFA)/ACN
HPLC-MS calculated for C34H35FN403S (M+H+) 599.2, found 599.2; RT 1.3 min.
147
(3.5 min) (C18, 10-90%, water (0.05 %
TFA)/ACN
HPLC-MS calculated for C33H33FN80 (M+H+) 577.3, found 577.2; RT 1.4 min.
148
(3.5 min) (C18, 10-90%, water (0.05 %
TFA)/ACN
Figure imgf000094_0001
Physical Data
Example
Structure 1H NMR 400 MHz (CDC13 or acetone-d6) No.
and/or MS (m/z)
HPLC-MS calculated for C33H35FN40 (M+H+) 523.3, found 523.4; RT 2.1 min.
155
(3.5 min) (C18, 10-90%, water (0.05 %
TFA)/ACN
HPLC-MS calculated for C33H34FN503 (M+H+) 568.3, found 568.3; RT 0.9 min.
156
(3.5 min) (C18, 10-90%, water (0.05 %
TFA)/ACN
HPLC-MS calculated for C33H34F2N40 (M+H+) 541.3, found 541.3; RT 2.0 min.
157
(3.5 min) (C18, 10-90%, water (0.05 %
TFA)/ACN
HPLC-MS calculated for C33H32FN50S (M+H+) 566.2, found 566.3; RT 2.3 min.
158
(3.5 min) (C18, 10-90%, water (0.05 %
TFA)/ACN
HPLC-MS calculated for C29H33FN40 (M+H+) 473.3, found 473.3; RT 2.2 min.
159
(4.5 min) (C18, 10-90%, water (0.05 %
TFA)/ACN
HPLC-MS calculated for C28H33FN403S (M+H+) 525.2, found 525.2; RT 1.9 min.
160
(3.5 min) (C18, 10-90%, water (0.05 %
TFA)/ACN
Figure imgf000096_0001
Figure imgf000097_0001
Figure imgf000098_0001
Physical Data
Example
Structure 1H NMR 400 MHz (CDC13 or acetone-d6) No.
and/or MS (m/z)
HPLC-MS calculated for C33H32F2N80 (M+H+) 595.66, found 595.30; RT 2.1 min.
176
(3.5 min) (C18, 10-90%, water (0.05 %
TFA)/ACN).
F
On HPLC-MS calculated for C33H32C1FN80
(M+H+) 612.11, found 612.25; RT 2.7 min.
177
(4.5 min) (C18, 10-90%, water (0.05 %
TFA)/ACN).
CI
HPLC-MS calculated for C34H35FN80 (M+H+) 591.69, found 591.40; RT 2.4 min.
178
(4.5 min) (C18, 10-90%, water (0.05 %
TFA)/ACN).
F
HPLC-MS calculated for C35H37FN403 (M+H+) 581.69, found 581.30; RT 2.5 min.
179
(4.5 min) (C18, 10-90%, water (0.05 %
TFA)/ACN).
F
HPLC-MS calculated for C34H35FN403 (M+H+) 567.67, found 567.30; RT 2.3 min.
180
(4.5 min) (C18, 10-90%, water (0.05 %
TFA)/ACN).
F
Figure imgf000100_0001
Figure imgf000101_0001
Figure imgf000102_0001
Figure imgf000103_0001
Figure imgf000104_0001
Figure imgf000105_0001
Figure imgf000106_0001
Figure imgf000107_0001
Figure imgf000108_0001
Figure imgf000109_0001
Figure imgf000110_0001
Figure imgf000111_0001
Figure imgf000112_0001
Figure imgf000113_0001
Figure imgf000114_0001
Figure imgf000115_0001
Physical Data
Example
Structure 1H NMR 400 MHz (CDC13 or acetone-d6) No.
and/or MS (m/z)
HPLC-MS calculated for C36H42FN403S+ (M+) 629.3, found 629.3; RT 2.29 min. (4.5
281
min) (C18, 10-100%, water (0.05 %
TFA)/ACN
HPLC-MS calculated for C35H40FN4O3S+ (M+) 615.3, found 615.3; RT 2.12 min. (4.5
282
min) (C18, 10-100%, water (0.05 %
TFA)/ACN
Assays
[000203] Compounds were assessed for their ability to activate human TGR5 in cAMP HTRF assays (Cisbio). Briefly, Jurkat cells stably expressing either human TGR5 were seeded into 384-well plates (Greiner) in AIM V media supplemented with IB MX (ImM) followed by transfer of agonist compounds in DMSO by Pintool (GNF Systems). After a 30- 60 minute incubation at 37 °C, cAMP HiRange HTRF reagents were added (Cisbio) and incubated for 1 hour followed by reading the emission at both 620nM and 665nM on the Envision (Perkin Elmer). Data is expressed as the emission ratio 665/620 and normalized to the DMSO alone control. Percent efficacy is calculated relative to a known TGR5 full agonist.
Certain Assay Results
[000204] Various compounds of Formula (I) and (II) in free form or in pharmaceutically acceptable salt form, exhibit pharmacological properties, for example, as indicated by the in vitro tests described in this application. The EC50 value in those experiments is given as that concentration of the test compound in question that provoke a response halfway between the baseline and maximum responses. In certain examples compounds of Formula (I) and
Formula (II) have EC50 values from 1 nM to 5 μΜ. In other examples, compounds of Formula (I) and Formula (II) have EC50 values from 1 nM to 4 μΜ. In other examples, compounds of Formula (I) and Formula (II) have EC50 values from 1 nM to 3 μΜ. In other examples, compounds of Formula (I) and Formula (II) have EC50 values from 1 nM to 2 μΜ. In other examples, compounds of Formula (I) and Formula (II) have EC50 values from 1 nM to 1 μΜ. In other examples, compounds of Formula (I) and Formula (II) have EC50 values from 1 nM to 500nM. In other examples, compounds of Formula (I) and Formula (II) have EC50 values from 1 nM to 400nM. In other examples, compounds of Formula (I) and Formula (II) have EC50 values from 1 nM to 300nM. In other examples, compounds of Formula (I) and Formula (II) have EC50 values from 1 nM to 200nM. In other examples, compounds of Formula (I) and Formula (II) have EC50 values from 1 nM to ΙΟΟηΜ. In other examples, compounds of Formula (I) and Formula (II) have EC50 values from 1 nM to 80nM. In other examples, compounds of Formula (I) and Formula (II) have EC50 values from 1 nM to 60nM. In other examples, compounds of Formula (I) and Formula (II) have EC50 values from 1 nM to 40nM. In other examples, compounds of Formula (I) and Formula (II) have EC 50 values from 1 nM to 20nM. In other examples, compounds of Formula (I) and Formula (II) have EC50 values from 1 nM to ΙΟηΜ. In other examples, compounds of Formula (I) and Formula (II) have EC50 values from 1 nM to 5nM.
[000205] By way of example only, the EC50 for TGR5 activation by certain compounds of Formula (I) and Formula (II) are listed in Table 4 below. The identifying number for each is the Ex. No. given for the compound in the Example above.
Table 4
Figure imgf000117_0001
22 1.359 163 0.047
23 0.166 164 0.028
24 1.71 165 0.151
25 0.192 166 0.006
26 0.975 167 0.013
27 0.293 168 0.171
28 0.438 169 0.042
29 0.085 170 0.868
30 0.413 171 0.041
31 0.315 172 0.188
32 1.328 173 0.009
33 0.518 174 0.647
34 0.315 175 1.279
35 0.354 176 0.599
36 0.983 177 0.215
37 0.677 178 0.346
38 0.810 179 0.683
39 2.144 180 0.119
40 4.342 181 0.965
41 0.677 182 1.914
42 0.37 183 0.858
43 1.960 184 0.010
44 1.311 185 1.362
45 0.861 186 3.390
46 0.260 187 0.025
47 1.499 188 0.213
48 0.087 189 0.008
49 0.164 190 0.01
50 0.165 191 0.014
51 1.600 192 0.036
52 0.128 193 0.015
53 1.313 194 0.017
54 0.357 195 0.34
55 0.113 196 0.865
56 0.084 197 0.141
57 198 0.04
58 0.033 199 0.383
59 0.045 200 0.08
60 1.502 201 0.039
61 0.39 202 0.657
62 0.013 203 0.605
63 0.481 204 0.108
64 2.28 205 0.129
65 0.011 206 0.493
66 2.968 207 0.034
67 0.445 208 0.034
68 0.316 209 0.024
69 0.023 210 0.267
70 0.013 211 1.006
71 0.085 212 0.891
72 0.083 213 0.261 73 0.198 214 0.132
74 0.003 215 0.114
75 0.041 216 0.165
76 0.296 217 0.734
77 0.191 218 0.009
78 0.031 219 0.252
79 0.266 220 0.039
80 0.091 221 0.153
81 1.358 222 0.567
82 0.005 223 0.17
83 0.01 224 0.246
84 0.01 225 0.225
85 0.030 226 0.77
86 0.075 227 0.014
87 0.361 228 0.011
88 0.443 229 0.009
89 0.460 230 0.093
90 0.533 231 0.007
91 0.013 232 0.055
92 0.081 233 0.04
93 0.023 234 0.026
94 0.063 235 0.329
95 1.390 236 0.02
96 0.188 237 0.534
97 2.358 238 0.011
98 1.589 239 0.437
99 0.004 240 0.244
100 0.007 241 0.477
101 0.009 242 0.199
102 0.01 243 0.02
103 0.012 244 0.113
104 0.011 245 0.131
105 0.013 246 0.934
106 0.011 247 0.091
107 0.013 248 0.514
108 0.014 249 0.152
109 0.014 250 0.092
110 0.017 251 0.125
111 0.018 252 0.319
112 0.018 253 0.298
113 0.023 254 0.051
114 0.023 255 0.01
115 0.033 256 0.014
116 0.033 257 0.174
117 0.036 258 0.011
118 0.036 259 0.465
119 0.042 260 0.083
120 0.044 261 0.041
121 0.046 262 0.03
122 0.057 263 0.071
123 0.069 264 0.289 124 0.069 265 0.127
125 0.069 266 0.11
126 0.078 267 0.307
127 0.069 268 0.304
128 0.098 269 0.092
129 0.101 270 0.091
130 0.111 271 4.35
131 0.121 272 0.064
132 0.140 273 0.017
133 0.153 274 0.025
134 0.159 275 0.134
135 0.165 276 0.174
136 0.167 277 0.231
137 0.177 278 0.149
138 0.184 279 1.883
139 0.186 280 0.138
140 0.208 281 0.135
141 0.261 282 0.035
[000206] It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference for all purposes.

Claims

WE CLAIM:
1. A compound having the structure of Formula (I):
Figure imgf000121_0001
(I)
wherein,
R1 and R2 are each independently selected from Ci-Cealkyl, and C2-C6alkene, and taken together with the N atom to which they are attached form a 4 to 6 membered heterocycloalkyl ring containing a N heteroatom, a 9 to 14 membered fused bicyclic heterocycloalkyl ring containing a N heteroatom, or a 9 to 14 membered fused bicyclic heteroaryl containing an N heteroatom, wherein such heterocycloalkyl and fused bicyclic heteroaryl are each optionally substituted with 1 to 5 substituents independently selected from halogen, deuterium, Ci-Cealkyl, Ci-Cehaloalkyl, -CN, R9, -OR9, phenyl, phenoxy, Cioaryl and Ci4aryl, wherein such phenyl, phenoxy, Cioaryl and Ci4aryl are each optionally substituted with 1 to 5 substituents independently selected from halogen, deuterium and -OR9;
Figure imgf000121_0002
L2 is selected from -C(O)-, -C(0)0-, -(CH2)qC(0)0-, -S(0)2- C C6alkylene, phenylene, Cioarylene, Ci4arylene, a 5, 6, 9, 10 or 14 membered heteroarylene containing 1 to 2 heteroatoms independently selected from N, O and S, or a bond, wherein the Ci-Cealkylene ,arylene and heteroarylene of L2 are optionally substituted with 1 to 3 substituents independently selected from deuterium, R9 and -C(0)OR9;
L3 is C]-C6alkylene optionally substituted with 1 to 3 substituents independently selected deuterium, R9 and -C(0)OR9, or Ci-Cealkenylene optionally substituted with 1 to 3 substituents independently selected from deuterium, R9 and -C(0)OR9;
L4 is selected from a -NR9-, -NR9C(0)0-, -NR9(CH2)q -, -C(0)NR9-, -S(0)2-, -0-, Ci-C6alkylene, phenylene, Cioarylene, Ci4arylene, a 5, 6, 9, 10 or 14 membered heteroarylene containing 1 to 2 heteroatoms independently selected from N, O and S, wherein the Ci-Cealkylene, arylene and heteroarylene of L4 are optionally substituted with 1 to 3 substituents independently selected from deuterium, R9 and -C(0)OR9;
R3 is selected from Ci-Cealkyl, Ci-Cehaloalkyl, C3-Cscycloalkyl, -L3R6 , phenyl, Cioaryl, Ci4aryl, a 5, 6, 9, 10 or 14 membered heteroaryl containing 1 to 3 N heteroatoms and optionally one heteroatom selected from O and S, and a 4 to 7 membered heterocycloalkyl ring containing 1 to 2 heteroatoms
independently selected from N, O and S, wherein the Ci-Cealkyl, aryl, heterocycloalkyl, C3-Cscycloalkyl and heteroaryl groups of R3 are each optionally substituted with 1 to 3 substituents independently selected from halogen, R9, R6, -OR9, -N(R9)2, -C(0)N(R9)2, -C(0)NR9OH, -C(0)OR9, - C(0)OL3R6, - L3C(0)OR9, -C(0)R9, -CN, -S(0)2R9, -S(0)2N(R9)2, - S(0)2NR9C(0)R9, - S(0)2L3C(0)OR9, -OS(0)2N(R9)2, -S(0)2NR9OH, -
OL3C(0)OR9, -C(0)NR9L3C(0)OR9, -L3R6
Figure imgf000122_0001
5 membered heteroaryl containing 1 to 4 N heteroatoms and optionally heteroatom selected from O and S; R4is selected from H, Ci-Cealkyl, phenyl, Cioaryl, Ci4aryl, C3-Cscycloalkyl, 5-6 membered heteroaryl containing one or more N heteroatoms, wherein the Q- C6alkyl, aryl, heteroaryl and C3-Cscycloalkyl groups of R4 are each optionally substituted with 1 to 3 substituents independently selected from halogen, -CN, R9, and -OR9;
R5 is H, C C6alkyl or C C6haloalkyl.
R6is C3-Cscycloalkyl, phenyl, Cioaryl, C]4aryl, a 5, 6, 9, 10 or 14 membered
heteroaryl containing 1 to 2 heteroatoms independently selected from N, O and S, a 4 to 7 membered heterocycloalkyl ring containing 1 to 2 heteroatoms independently selected from N, O and S, and a 9 to 14 membered fused bicyclic heterocycloalkyl ring containing containing 1 to 2 heteroatoms independently selected from N, O and S, each of which is optionally substituted with 1 to 5 substituents independently selected from halogen, deuterium, R9, -OR9, -CN and -C(0)OR9;
R9 is H, Ci-C6alkyl optionally substituted with 1 to 4 -OH groups or Cr
Cehaloalkyl;
R11 is H or C C6alkyl;
R12 is Ci-C4alkyl, -CH2C(0)OH or -(CHR13)C(0)OH;
R13 is H or Ci-C4alkyl;
each m is independently 1, 2 or 3;
each n is independently 1, 2 or 3, and
each q is independently 1, 2, 3, 4, 5, or 6,
and pharmaceutically acceptable salts and enantiomers thereof.
2. The compound of claim 1, wherein the compound of Formula (I) is a compound
having the structure of Formula (II):
Figure imgf000123_0001
(Π)
wherein,
R10 and R20 are each independently selected from H, -OR9, deuterium or halogen;
30
R is selected from phenyl, phenoxy, Cioaryl and Ci4aryl, each of which is
optionally substituted with 1 to 5 substituents independently selected from halogen, deuterium and -OR9;
R40 is selected from H, deuterium, Ci-Cealkyl and Ci-Cehaloalkyl, and each R50 is independently selected from H or deuterium.
3. The compound of claim 1, wherein the compound of Formula (I) is a compound
Figure imgf000124_0001
(HI) (IV) (V).
The compound of claim 1 or claim 3, wherein,
R1 and R2 are each independently selected from Ci-Cealkyl, and C2-C6alkene, and taken together with the N atom to which they are attached form a 1,2,3,4- tetrahydroisoquinoline or an azetidine, each of which is optionally substituted with 1 to 3 substituents independently selected from halogen, deuterium,-CN, R9, -OR9, phenyl and phenoxy, wherein such phenyl and phenoxy are each optionally substituted with 1 to 5 substituents independently selected from halogen, deuterium and -OR9.
The compound of claim 1 or claim 2, wherein the compound of Formula (I) or
Formula (II) is a compound having the structure of Formula (VI), Formula (VII) or
Formula (VIII):
Figure imgf000125_0001
6. The compound of claim 2 or claim 5, wherein R and R are each independently selected from H, deuterium or F.
7. The compound of any one of claims 2 or claim 5-6, wherein R40 is selected from H, deuterium, -CH3 -CF3 and -CF2CH3.
8. The compound of any one of claims 2 or claim 5-7, wherein R30 is selected from
phenyl, phenoxy, Cioaryl and Ci4aryl, each of which is optionally substituted with 1 to 5 substituents independently selected from F, deuterium and methoxy.
9. The compound of any one of claims 1 to 8, wherein,
R4is selected from H, methyl, ethyl, propyl, butyl, phenyl, pyridinyl, pyrimidinyl, and cyclohexyl, each of which is optionally substituted with 1 to 3 substituents independently selected from -F, -Br, -CI, -CN, R9, and -OR9.
10. The compound of any one of claims 1 to 9, wherein,
R3 is selected from -CH3, -CH(CH3) 2, -C(CH3)3, -CH2C(CH3)3,
- CH2CH2C(CH3)3, -CF3, cyclopropyl, cyclohexyl, phenyl, tetrahydro-2H- pyranyl, oxazolyl, oxadiazolyl, pyrazolyl, isoxazolyl,
lH-benzo[d][l,2,3]triazolyl, piperidinyl, pyridinyl, pyrimidinyl, benzthiazolyl and tetrazolyl, each of which is each optionally substituted with 1 to 3 substituents independently selected from -F, -Br, -CI, R9, -OR9, -N(R9)2, - C(0)N(R9)2, -C(0)NR9OH, -C(0)OR9, -C(0)OL3R6, - L3C(0)OR9, -C(0)R9, -CN, -S(0)2R9, -S(0)2N(R9)2, -S(0)2NR9C(0)R9, - S(0)2L3C(0)OR9,- OS(0)2N(R9)2, -S(0)2NR9OH, -OL3C(0)OR9, -C(0)NR9L3C(0)OR9,
Figure imgf000125_0002
, tetrazolyl, pyrazolyl and -L3R6.
11. The compound of any one of claims 1 to 10, wherein,
R9 is H, methyl, ethyl, -CH(CH3) 2, -C(CH3)3, -CF3, propyl substituted with 1 to 2 -OH groups.
12. The compound of any one of claims 1 to 11, wherein R5 is H or methyl.
13. The compound of any one of claims 1 to 12, wherein R12is methyl, ethyl or n-propyl.
14. The compound of any one of claims 1 to 12, wherein R13 is H or methyl.
15. The compound of claim 1 or claim 2, selected from
tert-butyl 4-[l-(4-fluorophenyl)-4-[(3-phenylpyrrolidin-l-yl)carbonyl]-lH-pyrazol- 5 -yljpiperidine- 1 -carboxylate;
tert-butyl 4-[l-(4-bromophenyl)-4-[(3-phenylpyrrolidin-l-yl)carbonyl]-lH-pyrazol- 5 -yljpiperidine- 1 -carboxylate;
tert-butyl 4- [ l-(4-fluorophenyl)-4- { [(3R)-3-phenylpyrrolidin- 1 -yljcarbonyl } - 1H- pyrazol-5-yl]piperidine-l-carboxylate;
tert-butyl 4- [ l-(4-chlorophenyl)-4- { [3-(4-fluorophenyl)pyrrolidin- 1 -yljcarbonyl } - lH-pyrazol-5-yl]piperidine-l-carboxylate;
tert-butyl 4-[l-(4-chlorophenyl)-4-{ [(3R)-3-(4-fluorophenyl)pyrrolidin-l- yl]carbonyl}-lH-pyrazol-5-yl]piperidine-l-carboxylate;
tert-butyl 4- [ l-(2,4-difluorophenyl)-4- { [(3R)-3-phenylpyrrolidin- 1 -yljcarbonyl } - 1H- pyrazol-5-yl]piperidine-l-carboxylate;
tert-butyl 4-[l-(4-chloro-2-fluorophenyl)-4-{ [(3R)-3-phenylpyrrolidin-l- yl]carbonyl}-lH-pyrazol-5-yl]piperidine-l-carboxylate;
tert-butyl 4- [ l-(4-fluorophenyl)-4- { [3-(4-fluorophenyl)pyrrolidin- l-yl]carbonyl } - lH-pyrazol-5-yl]piperidine-l-carboxylate;
tert-butyl 4-[l-(4-methoxyphenyl)-4-{ [(3R)-3-phenylpyrrolidin-l-yl]carbonyl}-lH- pyrazol-5-yl]piperidine-l-carboxylate;
tert-butyl 4- [ l-(4-cyanophenyl)-4- { [(3R)-3-phenylpyrrolidin- 1 -yljcarbonyl } - 1H- pyrazol-5-yl]piperidine-l-carboxylate;
tert-butyl 4-(4-{[(3R)-3-phenylpyrrolidin-l-yl]carbonyl}-l-(pyrimidin-2-yl)-lH- pyrazol-5-yl)piperidine-l-carboxylate;
tert-butyl 4-[l-(2-chloro-4-fluorophenyl)-4-{ [(3R)-3-phenylpyrrolidin-l- yl]carbonyl}-lH-pyrazol-5-yl]piperidine-l-carboxylate;
tert-butyl 4- [ l-(4-fluorophenyl)-4- { [3-(2-fluorophenyl)pyrrolidin- l-yl]carbonyl } - lH-pyrazol-5-yl]piperidine-l-carboxylate; tert-butyl 4-[l-(4-methylphenyl)-4-{[(3R)-3-phenylpyrrolidin-l-yl]carbonyl}-lH- pyrazol-5-yl]piperidine-l-carboxylate;
tert-butyl 4-[l-(4-chlorophenyl)-4-[(3-methyl-3-phenylpyrrolidin-l-yl)carbonyl]-lH- pyrazol-5-yl]piperidine-l-carboxylate;
tert-butyl 4-(l-phenyl-4-{ [(3R)-3-phenylpyrrolidin-l-yl]carbonyl}-lH-pyrazol-5- yl)piperidine- 1-carboxylate;
tert-butyl (3S)-3-[l-(4-chlorophenyl)-4-{ [(3R)-3-phenylpyrrolidin-l-yl]carbonyl}- lH-pyrazol-5-yl]pyrrolidine- 1-carboxylate;
tert-butyl (3R)-3-[l-(4-chlorophenyl)-4-{[(3R)-3-phenylpyrrolidin-l-yl]carbonyl}- lH-pyrazol-5-yl]piperidine- 1-carboxylate;
tert-butyl (3R)-3-[l-(4-chlorophenyl)-4-{[(3R)-3-phenylpyrrolidin-l-yl]carbonyl}- lH-pyrazol-5-yl]pyrrolidine- 1-carboxylate;
tert-butyl 3-[l-(4-chlorophenyl)-4-{ [(3R)-3-phenylpyrrolidin-l-yl]carbonyl}-lH- pyrazol-5-yl]pyrrolidine- 1-carboxylate;
tert-butyl 3- [ l-(4-fluorophenyl)-4- { [(3R)-3-phenylpyrrolidin- 1 -yljcarbonyl } - 1H- pyrazol-5 -yl] azetidine- 1 -carboxylate;
tert-butyl 3-[l-(4-fluorophenyl)-4-[(3-phenylpyrrolidin-l-yl)carbonyl]-lH-pyrazol- 5-yl]piperidine- 1 -carboxylate;
1-methylcyclopropyl 4-[l-(4-chlorophenyl)-4-{ [(3R)-3-phenylpyrrolidin-l- yl]carbonyl}-lH-pyrazol-5-yl]piperidine- 1-carboxylate;
1 - { 4- [ 1 -(4-chlorophenyl)-4- [(3 -phenylpyrrolidin- 1 -yl)carbonyl] - lH-pyrazol-5 - yljpiperidin- 1 -yl } -3,3-dimethylbutan- 1-one;
propan-2-yl 4-[l-(4-chlorophenyl)-4-[(3-phenylpyrrolidin-l-yl)carbonyl]-lH- pyrazol-5-yl]piperidine-l-carboxylate;
benzyl 4- [ 1 -(4-chlorophenyl)-4- [(3 -phenylpyrrolidin- 1 -yl)carbonyl]- lH-pyrazol-5- yljpiperidine- 1 -carboxylate;
propan-2-yl 4-[l-(4-chlorophenyl)-4-{ [(3R)-3-phenylpyrrolidin-l-yl]carbonyl}-lH- pyrazol-5-yl]piperidine-l-carboxylate;
tert-butyl 4- [ l-(4-chlorophenyl)-4- { [(3R)-3-phenylpyrrolidin- 1 -yljcarbonyl } - 1H- pyrazol-5-yl]- 1,2,3, 6-tetrahydropyridine- 1-carboxylate;
benzyl 4-({4-[l-(4-fluorophenyl)-4-{ [(3R)-3-phenylpyrrolidin-l-yl]carbonyl}-lH- pyrazol-5 -yljpiperidin- 1 -yl } methyl)piperidine- 1-carboxylate; 1 -benzoyl-4- [ 1 -(4-chlorophenyl)-4- [(3-phenylpyrrolidin- 1 -yl)carbonyl] - 1 H-pyrazol- 5-yl]piperidine;
4- [ 1 -(4-chlorophenyl)-4- [(3 -phenylpyrrolidin- 1 -yl)carbonyl] - 1 H-pyrazol-5-yl] - 1 - cyclohexanec arbonylpiperidine ;
l-{4-[l-(4-chlorophenyl)-4-{[(3R)-3-phenylpyrrolidin-l-yl]carbonyl}-lH-pyrazol-5- yljpiperidin- 1 -yl } -3,3-dimethylbutan- 1-one;
l-benzoyl-4-[l-(4-chlorophenyl)-4-{ [(3R)-3-phenylpyrrolidin-l-yl]carbonyl}-lH- pyrazol-5 -yljpiperidine ;
- [ 1 -(4-chlorophenyl)-4- { [(3R)-3-phenylpyrrolidin- 1 -yljcarbonyl } - lH-pyrazol-5- 1] - 1 -cyclohexanecarbonylpiperidine ;
- [ 1 -(4-chlorophenyl)-4- { [(3R)-3-phenylpyrrolidin- 1 -yljcarbonyl } - lH-pyrazol-5- l]-l-[(2-fluorophenyl)carbonyl]piperidine;
- [ 1 -(4-chlorophenyl)-4- { [(3R)-3-phenylpyrrolidin- 1 -yljcarbonyl } - lH-pyrazol-5- 1] - 1 - [(3 -fluorophenyl)c arbony ljpiperidine ;
- [ 1 -(4-chlorophenyl)-4- { [(3R)-3-phenylpyrrolidin- 1 -yljcarbonyl } - lH-pyrazol-5- l]-l-[(4-fluorophenyl)carbonyl]piperidine;
- [ 1 -(4-chlorophenyl)-4- { [(3R)-3-phenylpyrrolidin- 1 -yljcarbonyl } - lH-pyrazol-5- l]-l-[(4-chlorophenyl)carbonyl]piperidine;
- [ 1 -(4-chlorophenyl)-4- { [(3R)-3-phenylpyrrolidin- 1 -yljcarbonyl } - lH-pyrazol-5- l]-l-[(oxan-4-yl)carbonyl]piperidine;
- [ 1 -(4-chlorophenyl)-4- { [(3R)-3-phenylpyrrolidin- 1 -yljcarbonyl } - lH-pyrazol-5- l]-l-[(2,5-dimethyl-l,3-oxazol-4-yl)carbonyl]piperidine;
- [ 1 -(4-chlorophenyl)-4- { [(3R)-3-phenylpyrrolidin- 1 -yljcarbonyl } - lH-pyrazol-5- 1] - 1 - [(3 -methoxyphenyl)carbonyl]piperidine;
- [ 1 -(4-chlorophenyl)-4- { [(3R)-3-phenylpyrrolidin- 1 -yljcarbonyl } - lH-pyrazol-5- l]-l-[(4-methoxyphenyl)carbonyl]piperidine;
- [ 1 -(4-chlorophenyl)-4- { [(3R)-3-phenylpyrrolidin- 1 -yljcarbonyl } - lH-pyrazol-5- 1] - 1 - [(5 -methyl- 1 ,3 ,4-oxadiazol-2-yl)carbonyl]piperidine;
- [ 1 -(4-chlorophenyl)-4- { [(3R)-3-phenylpyrrolidin- 1 -yljcarbonyl } - lH-pyrazol-5- 1] - 1 - { [ 1 -methyl- 5 - (trifluoromethyl)- 1 H-pyrazol- 3 -yl] carbonyl } piperidine ;
- [ 1 -(4-chlorophenyl)-4- { [(3R)-3-phenylpyrrolidin- 1 -yljcarbonyl } - lH-pyrazol-5- l]-l-[(l,5-dimethyl-lH-pyrazol-3-yl)carbonyl]piperidine; 5-({4-[l-(4-chlorophenyl)-4-{ [(3R)-3-phenylpyrrolidin-l-yl]carbonyl}-lH-pyrazol- 5-yl]piperidin-l-yl}carbonyl)-2-methylpyridine;
(2R)-2-amino-l-{4-[l-(4-fluorophenyl)-4-{ [(3R)-3-phenylpyrrolidin-l-yl]carbonyl}- lH-pyrazol-5-yl]piperidin-l-yl}-4,4-dimethylpentan-l-one;
4-(methoxycarbonyl)phenyl 4- [ l-(4-fluorophenyl)-4- { [(3R)-3-phenylpyrrolidin- 1 - yl]carbonyl}-lH-pyrazol-5-yl]piperidine-l-carboxylate;
4-fluorophenyl 4-[l-(4-fluorophenyl)-4-{[(3R)-3-phenylpyrrolidin-l-yl]carbonyl}- lH-pyrazol-5-yl]piperidine-l-carboxylate;
phenyl 4-[l-(4-fluorophenyl)-4-{[(3R)-3-phenylpyrrolidin-l-yl]carbonyl}-lH- pyrazol-5-yl]piperidine-l-carboxylate;
methyl 4-[l-(4-fluorophenyl)-4-{ [(3R)-3-phenylpyrrolidin-l-yl]carbonyl}-lH- pyrazol-5-yl]piperidine-l-carboxylate;
l-(3,5-dimethyl-l,2-oxazole-4-sulfonyl)-4-[l-(4-fluorophenyl)-4-{ [(3R)-3- phenylpyrrolidin-l-yl]carbonyl}-lH-pyrazol-5-yl]piperidine;
4- [ 1 -(4-chlorophenyl)-4- [(3 -phenylpyrrolidin- 1 -yl)carbonyl] - 1 H-pyrazol-5-yl] - 1 - methanesulf onylpiperidine ;
l-(benzenesulfonyl)-4-[l-(4-chlorophenyl)-4-{ [(3R)-3-phenylpyrrolidin-l- yl]carbonyl}-lH-pyrazol-5-yl]piperidine;
tert-butyl 4- [ l-(4-chlorophenyl)-4- { [(3R)-3-phenylpyrrolidin- 1 -yljcarbonyl } - 1H- pyrazol-5-yl]piperidine-l-carboxylate;
1 -benzyl-4- [ 1 -(4-chlorophenyl)-4- [(3 -phenylpyrrolidin- 1 -yl)carbonyl] - 1 H-pyrazol-
5- yl]piperidine;
4-((4-(4-(3 ,3 -difluoro-4-phenylpyrrolidine- 1 -carbonyl)- 1 -(4-fluorophenyl) - 1 H- pyrazol-5-yl)piperidin-l-yl)methyl)benzenesulfonamide;
4- [ 1 -(4-chlorophenyl)-4- { [(3R)-3-phenylpyrrolidin- 1 -yljcarbonyl } - lH-pyrazol-5- yl] - 1 - [(4-fluorophenyl)methyl]piperidine;
4- [ 1 -(4-chlorophenyl)-4- { [(3R)-3-phenylpyrrolidin- 1 -yljcarbonyl } - lH-pyrazol-5- yl] - 1 - [(2-fluorophenyl)methyl]piperidine;
4- ({4-[l-(4-chlorophenyl)-4-{ [(3R)-3-phenylpyrrolidin-l-yl]carbonyl}-lH-pyrazol-
5- yl]piperidin- 1 -yl } methyl)benzoic acid;
4- [ 1 -(4-chlorophenyl)-4- [(3 -phenylpyrrolidin- 1 -yl)carbonyl] - 1 H-pyrazol-5-yl] - 1 - cyclohexylpiperidine ; 4- ({4-[l-(4-chlorophenyl)-4-{ [(3R)-3-phenylpyrrolidin-l-yl]carbonyl}-lH-pyrazol-
5- yl]piperidin- 1 -yl }methyl)benzonitrile;
4- [ 1 -(4-chlorophenyl)-4- { [(3R)-3-phenylpyrrolidin- 1 -yljcarbonyl } - lH-pyrazol-5- yl] - 1 -(oxan-4-ylmethyl)piperidine ;
3- ({4-[l-(4-chlorophenyl)-4-{ [(3R)-3-phenylpyrrolidin-l-yl]carbonyl}-lH-pyrazol-
5- yl]piperidin- 1 -yl } methyl)benzoic acid;
l-benzyl-4-[l-(4-fluorophenyl)-4-{[(3R)-3-phenylpyrrolidin-l-yl]carbonyl}-lH- pyrazol-5 -yljpiperidine ;
4- { [4-(l-cyclohexyl-4-{[(3R)-3-phenylpyrrolidin-l-yl]carbonyl}-lH-pyrazol-5- yl)piperidin- 1 -yl] methyl } benzonitrile ;
l-benzyl-4-[l-(4-chlorophenyl)-4-{[(3R)-3-phenylpyrrolidin-l-yl]carbonyl}-lH- pyrazol-5 -yljpiperidine ;
4-({4-[l-(4-chlorophenyl)-4-[(l,2,3,4-tetrahydroisoquinolin-2-yl)carbonyl]-lH- pyrazol-5 -yljpiperidin- 1 -yl } methyl)benzonitrile;
4-( { 4- [ 1 -(4-chloro-2-fluorophenyl)-4- { [(3R)-3 -phenylpyrrolidin- 1 -yljcarbonyl } - 1 H- pyrazol-5 -yljpiperidin- 1 -yl } methyl)benzonitrile;
4-({4-[l-(2,4-difluorophenyl)-4-{ [(3R)-3-phenylpyrrolidin-l-yl]carbonyl}-lH- pyrazol-5 -yljpiperidin- 1 -yl } methyl)benzonitrile;
methyl 2- {4-[ 1 -(2,4-difluorophenyl)-4- { [(3R)-3-phenylpyrrolidin- 1 -yljcarbonyl } - lH-pyrazol-5-yl]piperidin-l-yl}-2-phenylacetate;
4- ({4-[l-(4-fluorophenyl)-4-{ [3-(4-fluorophenyl)pyrrolidin-l-yl]carbonyl}-lH- pyrazol-5 -yljpiperidin- 1 -yl } methyl)benzonitrile;
5- ({4-[l-(4-fluorophenyl)-4-{ [(3R)-3-phenylpyrrolidin-l-yl]carbonyl}-lH-pyrazol- 5-yl]piperidin- 1 -yl } methyl)- 1 -methyl- 1 H- 1 ,2,3 -benzotriazole ;
4- [ 1 -(4-fluorophenyl)-4- { [(3R)-3 -phenylpyrrolidin- 1 -yljcarbonyl } - 1 H-pyrazol-5 -yl] - l-[(4-methanesulfonylphenyl)methyl]piperidine;
4-({4-[l-(4-fluorophenyl)-4-{ [(3R)-3-(4-fluorophenyl)pyrrolidin-l-yl]carbonyl}-lH- pyrazol-5 -yl]piperidin- 1 -yl } methyl)benzonitrile;
4-( { 4- [ 1 -(4-fluorophenyl)-4- { [(3 S)-3 -(4-fluorophenyl)pyrrolidin- 1 -yl]carbonyl } - 1 H- pyrazol-5 -yl]piperidin- 1 -yl } methyl)benzonitrile;
l-[(4-methanesulfonylphenyl)methyl]-4-[l-(4-methoxyphenyl)-4-{ [(3R)-3- phenylpyrrolidin-l-yl]carbonyl}-lH-pyrazol-5-yl]piperidine; 4- (5-{ l-[(4-methanesulfonylphenyl)methyl]piperidin-4-yl}-4-{ [(3R)-3- phenylpyrrolidin- 1 -yljcarbonyl } - 1 H-pyrazol- 1 -yl)benzonitrile;
2-(5-{ l-[(4-methanesulfonylphenyl)methyl]piperidin-4-yl}-4-{ [(3R)-3- phenylpyrrolidin- 1 -yljcarbonyl } - 1 H-pyrazol- 1 -yl)pyrimidine;
5- chloro-2-(5-{ l-[(4-methanesulfonylphenyl)methyl]piperidin-4-yl}-4-{ [(3R)-3- phenylpyrrolidin- 1 -yljcarbonyl } - 1 H-pyrazol- 1 -yl)pyridine;
l-[(4-methanesulfonylphenyl)methyl]-4-(4-{ [(3R)-3-phenylpyrrolidin-l- yl]carbonyl}-lH-pyrazol-5-yl)piperidine;
4-(4-{[(3S,4S)-3-fluoro-4-phenylpyrrolidin-l-yl]carbonyl}-l-(4-fluorophenyl)-lH- pyrazol-5-yl)-l-[(4-methanesulfonylphenyl)methyl]piperidine;
4-(4-{[(4R)-2,2-dihydrogenio-4-(2, 3,4,5, 6-pentahydrogeniophenyl)pyrrolidin-l- yljcarbonyl } - 1 -(4-fluorophenyl)- lH-pyrazol-5 -yl)- 1 - [(4- methanesulfonylphenyl)methyl]piperidine;
4-[l-(4-fluorophenyl)-4-{[(3R)-3-(2,3,4,5,6-pentahydrogeniophenyl)pyrrolidin-l- yljcarbonyl } - 1 H-pyrazol-5 -yl] - 1 - [(4-methanesulfonylphenyl)methyl]piperidine; 4-( {4-[ 1 -(4-fluorophenyl)-4- { [(3R)-3-(3-fluorophenyl)pyrrolidin- 1 -yl]carbonyl } - 1H- pyrazol-5 -yl]piperidin- 1 -yl } methyl)benzonitrile;
4-[l-(4-fluorophenyl)-4-{[(3S)-3-phenyl-3-(trifluoromethyl)pyrrolidin-l- yl]carbonyl } - 1 H-pyrazol-5 -yl] - 1 - [(4-methanesulfonylphenyl)methyl]piperidine; 4- [ 1 -(4-fluorophenyl)-4- { [3-phenyl-3-(trifluoromethyl)pyrrolidin- 1 -yl]carbonyl } - lH-pyrazol-5-yl]-l-[(4-methanesulfonylphenyl)methyl]piperidine;
4-[l-(4-fluorophenyl)-4-{[(3R)-3-phenyl-3-(trifluoromethyl)pyrrolidin-l- yl]carbonyl } - 1 H-pyrazol-5 -yl] - 1 - [(4-methanesulfonylphenyl)methyl]piperidine; 4-( { 4- [ 1 -(4-fluorophenyl)-4- { [(3R)-3 -(2-methoxyphenyl)pyrrolidin- 1 -yl]carbonyl } - 1 H-pyrazol- 5 -yl]piperidin- 1 -yl } methyl)benzonitrile ;
4- [ 1 -(4-fluorophenyl)-4- [(3-phenoxypyrrolidin- 1 -yl)carbonyl] - 1 H-pyrazol- 5 -yl] - 1 - [(4-methanesulfonylphenyl)methyl]piperidine;
4- { [4-(l-phenyl-4- { [(3R)-3-phenylpyrrolidin- l-yl]carbonyl} - lH-pyrazol-5- yl)piperidin- 1 -yl] methyl } benzonitrile ;
4- [ 1 -(4-chlorophenyl)-4- { [(3R)-3-phenylpyrrolidin- 1 -yl]carbonyl } - lH-pyrazol-5- yl] - 1 - ( 1 -phenylethyl)piperidine ;
4- [ 1 -(4-chlorophenyl)-4- { [(3R)-3-phenylpyrrolidin- 1 -yl]carbonyl } - lH-pyrazol-5- yl] - 1 - [(3 ,4-difluorophenyl)methyl]piperidine; 4- [ 1 -(4-chlorophenyl)-4- { [(3R)-3-phenylpyrrolidin- 1 -yljcarbonyl } - lH-pyrazol-5- yl]-l-{ [4-(trifluoromethyl)phenyl]methyl }piperidine;
4-( { 4- [ 1 -(4-fluorophenyl)-4- { [(3R)-3 -(4-methoxyphenyl)pyrrolidin- 1 -yljcarbonyl } - 1 H-pyrazol- 5 -yljpiperidin- 1 -yl } methyl)benzonitrile ;
4- [ 1 -(4-fluorophenyl)-4- { [(3R)-3 -phenylpyrrolidin- 1 -yljcarbonyl } - 1 H-pyrazol-5 -yl] -
1- (2,2,2-trifluoroethyl)piperidine;
2- [4-({4-[l-(4-fluorophenyl)-4-{ [(3R)-3-phenylpyrrolidin-l-yl]carbonyl}-lH- pyrazol-5 -yljpiperidin- 1 -yl } methyl)phenoxy] acetic acid;
(3 S ,4R)- 1 - { [ 1 -(4-fluorophenyl)-5 - { 1 - [(4-methanesulfonylphenyl)methyl]piperidin- 4-yl } - lH-pyrazol-4-yl]carbonyl } -4-phenylpyrrolidin-3-ol;
2- chloro-5-({4-[l-(4-fluorophenyl)-4-{[(3R)-3-phenylpyrrolidin-l-yl]carbonyl}-lH- pyrazol-5 -yljpiperidin- 1 -yl } methyl)pyridine ;
4- ( { 4- [ 1 -(4-fluorophenyl)-4- { [(3R)-3 -phenylpyrrolidin- 1 -yljcarbonyl } - 1 H-pyrazol-
5- yl]piperidin- 1 -yl }methyl)benzonitrile;
5-({4-[l-(4-fluorophenyl)-4-{ [(3R)-3-phenylpyrrolidin-l-yl]carbonyl}-lH-pyrazol- 5-yl]piperidin-l-yl}methyl)pyridine-2-carbonitrile;
5-fluoro-2-(5-{ l-[(4-methanesulfonylphenyl)methyl]piperidin-4-yl}-4-{ [(3R)-3- phenylpyrrolidin- 1 -yljcarbonyl } - 1 H-pyrazol- 1 -yl)pyridine;
3- ({4-[l-(4-fluorophenyl)-4-{ [(3R)-3-phenylpyrrolidin-l-yl]carbonyl}-lH-pyrazol- 5-yl]piperidin- 1 -yl }methyl)pyridine;
3- fluoro-4-({4-[l-(4-fluorophenyl)-4-{ [(3R)-3-phenylpyrrolidin-l-yl]carbonyl}-lH- pyrazol-5 -yljpiperidin- 1 -yl } methyl)benzonitrile;
4- [l-(4-fluorophenyl)-3-methyl-4-{ [(3R)-3-phenylpyrrolidin-l-yl]carbonyl}-lH- pyrazol-5 -yl] - 1 - [(4-methanesulfonylphenyl)methyl]piperidine;
3- bromo-4-( { 4- [ 1 -(4-fluorophenyl)-4- { [(3R)-3 -phenylpyrrolidin- 1 -yl]carbonyl } - 1 H- pyrazol-5 -yl]piperidin- 1 -yl } methyl)benzonitrile;
5- ({4-[l-(4-fluorophenyl)-4-{ [(3R)-3-phenylpyrrolidin-l-yl]carbonyl}-lH-pyrazol- 5-yl]piperidin-l-yl}methyl)-2-methanesulfonylpyridine;
4- ( { 4- [ 1 -(4-fluorophenyl)-4- { [(3R)-3 -phenylpyrrolidin- 1 -yl]carbonyl } - 1 H-pyrazol-
5- yl]piperidin- 1 -yl }methyl)benzene- 1 -sulfonamide;
4- [ 1 -(4-fluorophenyl)-4- { [(3R)-3 -phenylpyrrolidin- 1 -yl]carbonyl } - 1 H-pyrazol-5 -yl] - l-[(4-fluorophenyl)methyl]piperidine; 2-fluoro-4-({4-[l-(4-fluorophenyl)-4-{ [(3R)-3-phenylpyrrolidin-l-yl]carbonyl}-lH- pyrazol-5 -yljpiperidin- 1 -yl } methyl)benzonitrile;
4- ( { 4- [ 1 -(4-fluorophenyl)-4- { [(3R)-3 -phenylpyrrolidin- 1 -yljcarbonyl } - 1 H-pyrazol-
5- yl]piperidin- 1 -yl }methyl)pyridine;
[4-({4-[l-(4-fluorophenyl)-4-{ [(3R)-3-phenylpyrrolidin-l-yl]carbonyl}-lH-pyrazol- 5-yl]piperidin-l-yl}methyl)phenyl] sulfamate;
4- ( { 4- [ 1 -(4-fluorophenyl)-4- { [(3R)-3 -phenylpyrrolidin- 1 -yljcarbonyl } - 1 H-pyrazol-
5- yl]piperidin- 1 -yl } methyl)-N-methylbenzene- 1 -sulfonamide ;
4- (l-{4-[l-(4-fluorophenyl)-4-{ [(3R)-3-phenylpyrrolidin-l-yl]carbonyl}-lH- pyrazol-5 -yljpiperidin- 1 -yl } ethyl)benzonitrile;
[5-({4-[l-(4-fluorophenyl)-4-{ [(3R)-3-phenylpyrrolidin-l-yl]carbonyl}-lH-pyrazol-
5- yl]piperidin-l-yl}methyl)pyridin-2-yl]methanol;
1 - [(3 ,4-difluorophenyl)methyl] -4- [ 1 -(4-fluorophenyl)-4- { [(3R)-3-phenylpyrrolidin- 1 -yljcarbonyl } - 1 H-pyrazol-5 -yljpiperidine;
methyl 5-({4-[l-(4-fluorophenyl)-4-{ [(3R)-3-phenylpyrrolidin-l-yl]carbonyl}-lH- pyrazol-5 -yljpiperidin- 1 -yl } methyl)pyridine-2-carboxylate ;
1 - [(2,4-difluorophenyl)methyl] -4- [ 1 -(4-fluorophenyl)-4- { [(3R)-3-phenylpyrrolidin- 1 -yljcarbonyl } - 1 H-pyrazol-5 -yljpiperidine;
4- ( { 4- [ 1 -(4-fluorophenyl)-4- { [(3R)-3 -phenylpyrrolidin- 1 -yljcarbonyl } - 1 H-pyrazol-
5- yl]piperidin- 1 -yl }methyl)-N-hydroxybenzene- 1 -sulfonamide;
2-fluoro-4-({4-[l-(4-fluorophenyl)-4-{ [(3R)-3-phenylpyrrolidin-l-yl]carbonyl}-lH- pyrazol-5 -yljpiperidin- 1 -yl } methyl)benzamide;
l-[(2-chloro-4-fluorophenyl)methyl]-4-[l-(4-fluorophenyl)-4-{ [(3R)-3- phenylpyrrolidin-l-yl]carbonyl}-lH-pyrazol-5-yl]piperidine;
S-[4-({4-[l-(4-fluorophenyl)-4-{ [(3R)-3-phenylpyrrolidin-l-yl]carbonyl}-lH- pyrazol-5 -yljpiperidin- 1 -yl } methyl)phenyl] -2-hydroxypropane- 1 -sulfonamido;
4- ( { 4- [ 1 -(4-fluorophenyl)-4- { [(3R)-3 -phenylpyrrolidin- 1 -yljcarbonyl } - 1 H-pyrazol-
5- yl]piperidin- 1 -yl }methyl)benzamide;
1- [(4-fluoro-2-methoxyphenyl)methyl]-4-[l-(4-fluorophenyl)-4-{ [(3R)-3- phenylpyrrolidin-l-yl]carbonyl}-lH-pyrazol-5-yl]piperidine;
2- fluoro-5-({4-[l-(4-fluorophenyl)-4-{ [(3R)-3-phenylpyrrolidin-l-yl]carbonyl}-lH- pyrazol-5 -yljpiperidin- 1 -yl } methyl)benzonitrile; 4- [ 1 -(4-fluorophenyl)-4- { [(3R)-3 -phenylpyrrolidin- 1 -yljcarbonyl } - 1 H-pyrazol-5 -yl] - l-[(3-fluorophenyl)methyl]piperidine;
l-[(4-fluoro-3-methoxyphenyl)methyl]-4-[l-(4-fluorophenyl)-4-{ [(3R)-3- phenylpyrrolidin-l-yl]carbonyl}-lH-pyrazol-5-yl]piperidine;
(E)-N-{ l-[4-({4-[l-(4-fluorophenyl)-4-{ [(3R)-3-phenylpyrrolidin-l-yl]carbonyl}- 1 H-pyrazol- 5 -yljpiperidin- 1 -yl } methyl)phenyl] ethylidene } hydroxylamine ;
4- [ 1 -(4-fluorophenyl)-4- { [(3R)-3 -phenylpyrrolidin- 1 -yljcarbonyl } - 1 H-pyrazol-5 -yl] -
1- [(2,3,4-trifluorophenyl)methyl]piperidine;
2- chloro-4-({4-[l-(4-fluorophenyl)-4-{[(3R)-3-phenylpyrrolidin-l-yl]carbonyl}-lH- pyrazol-5 -yl]piperidin- 1 -yl } methyl)pyridine ;
(5E)-5-{[4-({4-[l-(4-fluorophenyl)-4-{[(3R)-3-phenylpyrrolidin-l-yl]carbonyl}-lH- pyrazol-5 -yl]piperidin- 1 -yl } methyl)phenyl]methylidene } - 1 ,3 -thiazolidine-2,4-dione ; 2-( { 4- [ 1 -(4-fluorophenyl)-4- { [(3R)-3 -phenylpyrrolidin- 1 -yl]carbonyl } - 1 H-pyrazol-
5- yl]piperidin- 1 -yl }methyl)pyridine;
tert-butyl 2- { 4- [ l-(4-fluorophenyl)-4- { [(3R)-3-phenylpyrrolidin- 1 -yl]carbonyl } - 1H- pyrazol-5 -yl]piperidin- 1 -yl } acetate;
1- { [3-fluoro-4-(2H-l,2,3,4-tetrazol-5-yl)phenyl]methyl}-4-[l-(4-fluorophenyl)-4- { [(3R)-3-phenylpyrrolidin-l-yl]carbonyl}-lH-pyrazol-5-yl]piperidine;
N-(2,3-dihydroxypropyl)-4-({4-[l-(4-fluorophenyl)-4-{[(3R)-3-phenylpyrrolidin-l- yl]carbonyl } - 1 H-pyrazol-5 -yl]piperidin- 1 -yl } methyl) benzamide;
2- chloro-4-({4-[l-(4-fluorophenyl)-4-{[(3R)-3-phenylpyrrolidin-l-yl]carbonyl}-lH- pyrazol-5 -yl]piperidin- 1 -yl } methyl)pyrimidine ;
1- [4-({4-[l-(4-fluorophenyl)-4-{ [(3R)-3-phenylpyrrolidin-l-yl]carbonyl}-lH- pyrazol-5 -yl]piperidin- 1 -yl } methyl)phenyl]ethan- 1 -one ;
2- { [ 1 -(4-fluorophenyl)-5 - { 1 - [(4-methanesulfonylphenyl)methyl]piperidin-4-yl } - 1 H- pyrazol-4-yl]carbonyl } - 1 ,2,3 ,4-tetrahydroisoquinoline;
4- [ 1 -(4-fluorophenyl)-4- { [(3R)-3 -phenylpyrrolidin- 1 -yl]carbonyl } - 1 H-pyrazol-5 -yl] - l-[(4-methanesulfonylphenyl)methyl]- 1,2,3, 6-tetrahydropyridine;
4- [ 1 -(4-fluorophenyl)-4- { [(3R)-3 -phenylpyrrolidin- 1 -yl]carbonyl } - 1 H-pyrazol-5 -yl] - l-[(4-methylphenyl)methyl]piperidine;
tert-butyl 3- { [4-({ 4- [ l-(4-fluorophenyl)-4- { [(3R)-3-phenylpyrrolidin- 1 - yl]carbonyl } - 1 H-pyrazol-5 -yl]piperidin- 1 -yl } methyl)phenyl]formamido } propanoate; 4- [ 1 -(4-fluorophenyl)-4- { [(3R)-3 -phenylpyrrolidin- 1 -yljcarbonyl } - 1 H-pyrazol-5 -yl] - l-[2-(4-methanesulfonylphenyl)ethyl]piperidine;
4- [ 1 -(4-fluorophenyl)-4- [(3-phenylazetidin- 1 -yl)carbonyl] - 1 H-pyrazol-5-yl] - 1 - [(4- methanesulfonylphenyl)methyl]piperidine;
5- ({4-[l-(4-fluorophenyl)-4-{ [(3R)-3-phenylpyrrolidin-l-yl]carbonyl}-lH-pyrazol- 5-yl]piperidin-l-yl}methyl)pyridine-2-carboxylic acid;
3- { [4-({4-[l-(4-fluorophenyl)-4-{ [(3R)-3-phenylpyrrolidin-l-yl]carbonyl}-lH- pyrazol-5 -yljpiperidin- 1 -yl } methyl)phenyl]formamido } propanoic acid;
l-[(3-chloro-4-fluorophenyl)methyl]-4-[l-(4-fluorophenyl)-4-{ [(3R)-3- phenylpyrrolidin-l-yl]carbonyl}-lH-pyrazol-5-yl]piperidine;
4- [l-(4-fluorophenyl)-3-methyl-4-{ [(3R)-3-phenylpyrrolidin-l-yl]carbonyl}-lH- pyrazol-5 -yl] - 1 - [(4-methanesulfonylphenyl)methyl] - 1 ,2,3 ,6-tetrahydropyridine ;
4- [ 1 -(4-fluorophenyl)-4- { [(3R)-3 -phenylpyrrolidin- 1 -yl]carbonyl } - 1 H-pyrazol-5 -yl] - l-{ [4-(2H-l,2,3,4-tetrazol-5-yl)phenyl]methyl}piperidine;
1- (4-fluorophenyl)-5-{ l-[(4-methanesulfonylphenyl)methyl]azetidin-3-yl}-4-[(3- methyl-3 -phenylpyrrolidin- l-yl)carbonyl]- lH-pyrazole;
5- ({4-[l-(4-fluorophenyl)-4-[(3-methyl-3-phenylpyrrolidin-l-yl)carbonyl]-lH- pyrazol-5 -yl]piperidin- 1 -yl } methyl)pyridine-2-carboxylic acid;
2- fluoro-5-({4-[l-(4-fluorophenyl)-4-{ [(3R)-3-phenylpyrrolidin-l-yl]carbonyl}-lH- pyrazol-5 -yl]piperidin- 1 -yl } methyl)benzamide;
N-{ [4-({4-[l-(4-fluorophenyl)-4-{[(3R)-3-phenylpyrrolidin-l-yl]carbonyl}-lH- pyrazol-5 -yl]piperidin- 1 -yl } methyl)benzene] sulfonyl } acetamide;
l-[2-(2-benzyl-2H-l,2,3,4-tetrazol-5-yl)ethyl]-4-[l-(4-fluorophenyl)-4-{[(3R)-3- phenylpyrrolidin-l-yl]carbonyl}-lH-pyrazol-5-yl]piperidine;
4- ( { 4- [ 1 -(4-fluorophenyl)-4- { [(3R)-3 -phenylpyrrolidin- 1 -yl]carbonyl } - 1 H-pyrazol-
5- yl]- 1,2,3, 6-tetrahydropyridin-l-yl}methyl)pyridine;
4- [ 1 -(4-fluorophenyl)-4- { [(3R)-3 -phenylpyrrolidin- 1 -yl]carbonyl } - 1 H-pyrazol-5 -yl] - l-[(3-methylphenyl)methyl]piperidine;
4- ( { 4- [ 1 -(4-fluorophenyl)-4- { [(3R)-3 -phenylpyrrolidin- 1 -yl]carbonyl } - 1 H-pyrazol-
5- yl]piperidin-l-yl}methyl)-N-hydroxybenzamide;
4- [ 1 -(4-fluorophenyl)-4- { [(3R)-3 -phenylpyrrolidin- 1 -yl]carbonyl } - 1 H-pyrazol-5 -yl] - l-[2-(4-fluorophenyl)ethyl]piperidine; 2- ( { 4- [ 1 -(4-fluorophenyl)-4- { [(3R)-3 -phenylpyrrolidin- 1 -yljcarbonyl } - 1 H-pyrazol- 5-yl]piperidin- 1 -yl }methyl)- 1 ,3-benzothiazole;
l-(cyclopropylmethyl)-4- [ 1 -(4-fluorophenyl)-4- { [(3R)-3-phenylpyrrolidin- 1 - yl]carbonyl}-lH-pyrazol-5-yl]piperidine;
4- [ 1 -(4-fluorophenyl)-4- { [(3R)-3 -phenylpyrrolidin- 1 -yljcarbonyl } - 1 H-pyrazol-5 -yl] - 1 - (2-methanesulf onylethyl)piperidine ;
l-(4-fluorophenyl)-5-{ l-[2-(4-methanesulfonylphenyl)ethyl]azetidin-3-yl}-4-[(3- methyl-3 -phenylpyrrolidin- l-yl)carbonyl]- lH-pyrazole;
4-(2-{4-[l-(4-fluorophenyl)-4-{ [(3R)-3-phenylpyrrolidin-l-yl]carbonyl}-lH- pyrazol-5 -yljpiperidin- 1 -yl } ethyl)benzoic acid;
4-({4-[l-(4-chlorophenyl)-4-{ [(3R)-3-methyl-3-phenylpyrrolidin-l-yl]carbonyl}- 1 H-pyrazol- 5 -yljpiperidin- 1 -yl } methyl)benzonitrile ;
4- ({4-[l-(4-fluorophenyl)-4-[(3-methyl-3-phenylpyrrolidin-l-yl)carbonyl]-lH- pyrazol-5 -yljpiperidin- 1 -yl } methyl)benzonitrile;
3- ({4-[l-(4-fluorophenyl)-4-{ [(3R)-3-phenylpyrrolidin-l-yl]carbonyl}-lH-pyrazol-
5- yl]piperidin- 1 -yl }methyl)benzonitrile;
4- ({4-[l-(4-fluorophenyl)-4-{ [(3R)-3-methyl-3-phenylpyrrolidin-l-yl]carbonyl}-lH- pyrazol-5 -yljpiperidin- 1 -yl } methyl)benzonitrile;
4-({4-[l-(4-fluorophenyl)-4-{ [(3S)-3-methyl-3-phenylpyrrolidin-l-yl]carbonyl}-lH- pyrazol-5 -yljpiperidin- 1 -yl } methyl)benzonitrile;
4- [ 1 -(4-fluorophenyl)-4- { [(3R)-3 -phenylpyrrolidin- 1 -yljcarbonyl } - 1 H-pyrazol-5 -yl] - 1 - (3 , 3 , 3 -trifluoropropyl)piperidine ;
tert-butyl 3- { 4- [ l-(4-fluorophenyl)-4- { [(3R)-3-phenylpyrrolidin- 1 -yl]carbonyl } - 1H- pyrazol-5-yl]piperidin-l-yl}pyrrolidine-l-carboxylate;
l-(l-benzylpyrrolidin-3-yl)-4-[l-(4-fluorophenyl)-4-{[(3R)-3-phenylpyrrolidin-l- yl]carbonyl}-lH-pyrazol-5-yl]piperidine;
l-[(l,3-dimethyl-lH-pyrazol-5-yl)methyl]-4-[l-(4-fluorophenyl)-4-{ [(3R)-3- phenylpyrrolidin-l-yl]carbonyl}-lH-pyrazol-5-yl]piperidine;
l-[(3,5-dimethyl-l,2-oxazol-4-yl)methyl]-4-[l-(4-fluorophenyl)-4-{ [(3R)-3- phenylpyrrolidin-l-yl]carbonyl}-lH-pyrazol-5-yl]piperidine;
4-( {4-[ 1 -(4-chlorophenyl)-4- { [(3S)-3-(2-fluorophenyl)pyrrolidin- 1 -yl]carbonyl } - 1H- pyrazol-5 -yl]piperidin- 1 -yl } methyl)benzonitrile; 4-({4-[l-(4-chlorophenyl)-4-{ [(3R)-3-(2-fluorophenyl)pyrrolidin-l-yl]carbonyl}- 1 H-pyrazol- 5 -yljpiperidin- 1 -yl } methyl)benzonitrile ;
4-({4-[l-(2,4-difluorophenyl)-4-{ [(3R)-3-phenylpyrrolidin-l-yl]carbonyl}-lH- pyrazol-5 -yljpiperidin- 1 -yl } methyl)benzoic acid;
4- [ 1 -(2,4-difluorophenyl)-4- { [(3R)-3-phenylpyrrolidin- 1 -yljcarbonyl } - lH-pyrazol-
5- yl]-l-{[4-(lH-l,2,3,4-tetrazol-5-yl)phenyl]methyl}piperidine;
4-[l-(4-chloro-2-fluorophenyl)-4-{ [(3R)-3-phenylpyrrolidin-l-yl]carbonyl}-lH- pyrazol-5-yl]-l-{[4-(lH-l,2,3,4-tetrazol-5-yl)phenyl]methyl}piperidine;
4- [ 1 -(4-fluorophenyl)-4- [(3-methyl-3 -phenylpyrrolidin- 1 -yl)carbonyl] - 1 H-pyrazol-
5- yl]-l-{[4-(lH-l,2,3,4-tetrazol-5-yl)phenyl]methyl}piperidine;
2-[4-({4-[l-(4-fluorophenyl)-4-{ [(3R)-3-phenylpyrrolidin-l-yl]carbonyl}-lH- pyrazol-5 -yljpiperidin- 1 -yl } methyl)phenyl]propanoic acid;
2-[4-({4-[l-(4-fluorophenyl)-4-{ [(3R)-3-phenylpyrrolidin-l-yl]carbonyl}-lH- pyrazol-5 -yljpiperidin- 1 -yl } methyl)phenyl] acetic acid;
4- ( { 4- [ 1 -(4-fluorophenyl)-4- { [(3R)-3 -phenylpyrrolidin- 1 -yljcarbonyl } - 1 H-pyrazol-
5- yl]piperidin- 1 -yl } methyl)benzoic acid;
1- [(l,5-dimethyl-lH-pyrazol-3-yl)methyl]-4-[l-(4-fluorophenyl)-4-{ [(3R)-3- phenylpyrrolidin-l-yl]carbonyl}-lH-pyrazol-5-yl]piperidine;
4-({4-[l-(4-fluorophenyl)-4-[(3-methyl-3-phenylpyrrolidin-l-yl)carbonyl]-lH- pyrazol-5 -yljpiperidin- 1 -yl } methyl)benzoic acid;
4- [ 1 -(4-fluorophenyl)-4- [(3-methyl-3 -phenylpyrrolidin- 1 -yl)carbonyl] - 1 H-pyrazol-
5- yl] - 1 - [(4-methanesulfonylphenyl)methyl]piperidine ;
5-({4-[l-(4-fluorophenyl)-4-{ [(3R)-3-phenylpyrrolidin-l-yl]carbonyl}-lH-pyrazol- 5-yl]piperidin-l-yl}methyl)-l,2-oxazole-3-carboxylic acid;
5-({4-[l-(4-fluorophenyl)-4-{ [(3R)-3-phenylpyrrolidin-l-yl]carbonyl}-lH-pyrazol- 5-yl]piperidin-l-yl}methyl)-l-methyl-lH-pyrazole-3-carboxylic acid;
2- { [4-({4-[l-(4-fluorophenyl)-4-{ [(3R)-3-phenylpyrrolidin-l-yl]carbonyl}-lH- pyrazol-5 -yljpiperidin- 1 -yl } methyl)benzene] sulfonyl } acetic acid;
(2E)-3-[4-({4-[l-(4-fluorophenyl)-4-{ [(3R)-3-phenylpyrrolidin-l-yl]carbonyl}-lH- pyrazol-5 -yljpiperidin- 1 -yl } methyl)phenyl]prop-2-enoic acid;
4- [ 1 -(4-fluorophenyl)-4- { [3-(2-fluorophenyl)pyrrolidin- 1 -yljcarbonyl } - lH-pyrazol-
5- yl] - 1 - [(4-methanesulfonylphenyl)methyl]piperidine ; 1- { [4-(ethanesulfonyl)phenyl]methyl}-4-[l-(4-fluorophenyl)-4-{ [(3R)-3- phenylpyrrolidin-l-yl]carbonyl}-lH-pyrazol-5-yl]piperidine;
4-[l-(4-fluorophenyl)-4-[(2,2,5,5-tetrahydrogenio-3-methyl-3-phenylpyrrolidin-l- yl)carbonyl]-lH-pyrazol-5-yl]-l-[(4-methanesulfonylphenyl)methyl]piperidine;
4- [ 1 -(4-fluorophenyl)-4- { [(3R)-3 -phenylpyrrolidin- 1 -yljcarbonyl } - 1 H-pyrazol-5 -yl] - 1 - { [4- (propane-2- sulf onyl)phenyl] methyl } piperidine ;
4- { 4- [(3 ,3-difluoro-4-phenylpyrrolidin- 1 -yl)carbonyl]- 1 -(4-fluorophenyl)- 1H- pyrazol-5 -yl } - 1 - [(4-methanesulf onylphenyl)methyl]piperidine;
4-(4- { [(4R)-3,3-difluoro-4-phenylpyrrolidin- 1 -yljcarbonyl } - 1 -(4-fluorophenyl)- 1H- pyrazol-5-yl)-l-[(4-methanesulfonylphenyl)methyl]piperidine;
4- (4-{[(4S)-3,3-difluoro-4-phenylpyrrolidin-l-yl]carbonyl}-l-(4-fluorophenyl)-lH- pyrazol-5-yl)-l-[(4-methanesulfonylphenyl)methyl]piperidine;
tert-butyl N- { 4- [ l-(4-fluorophenyl)-4- { [(3R)-3-phenylpyrrolidin- 1 -yljcarbonyl } - 1H- pyrazol-5 -yl] cyclohexy 1 } c arbamate ;
N- { 4- [ 1 -(4-fluorophenyl)-4- { [(3R)-3 -phenylpyrrolidin- 1 -yljcarbonyl } - lH-pyrazol-
5- yl]cyclohexyl}-4-methanesulfonylaniline;
5-fluoro-2-(5-{ l-[(4-methanesulfonylphenyl)methyl]piperidin-4-yl}-4-{ [(3R)-3- phenylpyrrolidin- 1 -yljcarbonyl } - 1 H-pyrazol- 1 -yl)pyrimidine;
5-fluoro-2-(5-{ l-[(4-methanesulfonylphenyl)methyl]piperidin-4-yl}-4-{ [(3S)-3- phenyl-3-(trifluoromethyl)pyrrolidin- l-yl]carbonyl } - IH-pyrazol- 1 -yl)pyrimidine;
2- { 4- [(3 ,3-difluoro-4-phenylpyrrolidin- 1 -yl)carbonyl] -5 - { 1 - [(4- methanesulfonylphenyl)methyl]piperidin-4-yl } - 1 H-pyrazol- 1 -yl } -5- fluoropyrimidine ;
2-(4-{[(4R)-3,3-difluoro-4-phenylpyrrolidin-l-yl]carbonyl}-5-{ l-[(4- methanesulfonylphenyl)methyl]piperidin-4-yl}-lH-pyrazol-l-yl)-5- fluoropyrimidine ;
2-(4-{[(4S)-3,3-difluoro-4-phenylpyrrolidin-l-yl]carbonyl}-5-{ l-[(4- methanesulfonylphenyl)methyl]piperidin-4-yl}-lH-pyrazol-l-yl)-5- fluoropyrimidine ;
5-fluoro-2-(4-{[(3R)-3-phenylpyrrolidin-l-yl]carbonyl}-5-[l-(pyrimidin-5- ylmethyl)piperidin-4-yl]- IH-pyrazol- l-yl)pyrimidine;
4-({4-[l-(5-fluoropyrimidin-2-yl)-4-{[(3R)-3-phenylpyrrolidin-l-yl]carbonyl}-lH- pyrazol-5-yl]piperidin-l-yl}methyl)benzene-l-sulfonamide; 5-chloro-2-(5-{ l-[(4-methanesulfonylphenyl)methyl]piperidin-4-yl}-4-{ [(3R)-3- phenylpyrrolidin- 1 -yljcarbonyl } - 1 H-pyrazol- 1 -yl)pyrimidine;
4-({4-[l-(5-bromopyrimidin-2-yl)-4-{[(3R)-3-phenylpyrrolidin-l-yl]carbonyl}-lH- pyrazol-5-yl]piperidin-l-yl}methyl)benzene-l-sulfonamide;
4- ({4-[l-(5-fluoropyrimidin-2-yl)-4-{[(3R)-3-phenylpyrrolidin-l-yl]carbonyl}-lH- pyrazol-5 -yljpiperidin- 1 -yl } methyl)benzonitrile;
3- fluoro-4-({4-[l-(5-fluoropyrimidin-2-yl)-4-{[(3R)-3-phenylpyrrolidin-l- yljcarbonyl } - 1 H-pyrazol-5 -yl]piperidin- 1 -yl } methyl) benzonitrile ;
2-(5-{ l-[(6-chloropyridin-3-yl)methyl]piperidin-4-yl}-4-{ [(3R)-3-phenylpyrrolidin- 1 -yljcarbonyl } - 1 H-pyrazol- 1 -yl)-5 -fluoropyrimidine;
5- fluoro-2-(4-{[(3R)-3-phenylpyrrolidin-l-yl]carbonyl}-5-(l-{[6-(lH-pyrazol-l- yl)pyridin-3 -yljmethyl } piperidin-4-yl)- 1 H-pyrazol- 1 -yl)pyrimidine;
5-({4-[l-(5-fluoropyrimidin-2-yl)-4-{[(3R)-3-phenylpyrrolidin-l-yl]carbonyl}-lH- pyrazol-5 -yljpiperidin- 1 -yl } methyl)pyridin-2-amine;
5-({4-[l-(5-fluoropyrimidin-2-yl)-4-{[(3R)-3-phenylpyrrolidin-l-yl]carbonyl}-lH- pyrazol-5-yl]piperidin- 1 -yl } methyl)pyrimidin-2-amine;
5-fluoro-2-(4-{[(3R)-3-phenylpyrrolidin-l-yl]carbonyl}-5-[l-(pyridin-4- ylmethyl)piperidin-4-yl]- lH-pyrazol- l-yl)pyrimidine;
4- [(4- { 4- [(3 ,3 -difluoro-4-phenylpyrrolidin- 1 -yl)carbonyl] - 1 -(5 -fluoropyrimidin-2- yl)-l H-pyrazol-5 -yl } piperidin- 1 -yl)methyl]benzonitrile;
2-(5-{ l-[(6-chloropyridin-3-yl)methyl]piperidin-4-yl}-4-[(3,3-difluoro-4- phenylpyrrolidin-l-yl)carbonyl]-lH-pyrazol-l-yl)-5-fluoropyrimidine;
4- [(4- { 4- [(3 ,3 -difluoro-4-phenylpyrrolidin- 1 -yl)carbonyl] - 1 -(5 -fluoropyrimidin-2- yl)-l H-pyrazol-5 -yl } piperidin- 1 -yl)methyl]benzene- 1 -sulfonamide;
2- { 4- [(3 ,3-difluoro-4-phenylpyrrolidin- 1 -yl)carbonyl] -5 - [ 1 -(pyridin-4- ylmethyl)piperidin-4-yl]- lH-pyrazol- 1-yl) -5-fluoropyrimidine;
4- { [4-(4- { [(4R)-3,3-difluoro-4-phenylpyrrolidin- 1 -yljcarbonyl } - 1 -(4-fluorophenyl)-
1 H-pyrazol- 5 -yl)piperidin- 1-yl] methyl } benzene- 1 - sulfonamide ;
4-{ [4-(4-{ [(4S)-3,3-difluoro-4-phenylpyrrolidin-l-yl]carbonyl}-l-(4-fluorophenyl)-
1 H-pyrazol- 5 -yl)piperidin- 1-yl] methyl } benzene- 1 - sulfonamide ;
4- { 4- [(3 ,3-difluoro-4-phenylpyrrolidin- 1 -yl)carbonyl]- 1 -(4-fluorophenyl)-3-methyl- lH-pyrazol-5-yl } - 1- [(4-methanesulfonylphenyl)methyl]piperidine; 2- { 4- [(3 ,3-difluoro-4-phenylpyrrolidin- 1 -yl)carbonyl] -5 -( 1 - { [6- (trifluoromethyl)pyridin-3-yl]methyl }piperidin-4-yl)- IH-pyrazol- 1 -yl } -5- fluoropyrimidine ;
2- { 4- [(3 ,3-difluoro-4-phenylpyrrolidin- 1 -yl)carbonyl] -5 - { 1 - [(6-methoxypyridin-3- yl)methyl]piperidin-4-yl } - IH-pyrazol- 1 -yl } -5-fluoropyrimidine;
2-(4-{[(4R)-3,3-difluoro-4-phenylpyrrolidin-l-yl]carbonyl}-5-(l-{[6- (trifluoromethyl)pyridin-3-yl]methyl}piperidin-4-yl)-lH-pyrazol-l-yl)-5- fluoropyrimidine ;
2-(4-{[(4R)-3,3-difluoro-4-phenylpyrrolidin-l-yl]carbonyl}-5-{ l-[(6- methoxypyridin-3-yl)methyl]piperidin-4-yl}-lH-pyrazol-l-yl)-5-fluoropyrimidine; 2-(4-{[(4R)-3,3-difluoro-4-phenylpyrrolidin-l-yl]carbonyl}-5-(l-{[4- (trifluoromethane)sulfonylphenyl]methyl}piperidin-4-yl)-lH-pyrazol-l-yl)-5- fluoropyrimidine ;
2-(4-{[(4S)-3,3-difluoro-4-phenylpyrrolidin-l-yl]carbonyl}-5-(l-{[4- (trifluoromethane)sulfonylphenyl]methyl}piperidin-4-yl)-lH-pyrazol-l-yl)-5- fluoropyrimidine ;
4-({4-[l-(4-fluorophenyl)-4-{ [3-(4-fluorophenyl)pyrrolidin-l-yl]carbonyl}-lH- pyrazol-5-yl]piperidin-l-yl}methyl)benzene-l-sulfonamide;
4- [ 1 -(4-fluorophenyl)-4- { [3-(4-fluorophenyl)pyrrolidin- 1 -yljcarbonyl } - lH-pyrazol-
5- yl] - 1 - [(4-methanesulfonylphenyl)methyl]piperidine ;
4-({4-[l-(4-fluorophenyl)-4-{ [(3R)-3-(4-fluorophenyl)pyrrolidin-l-yl]carbonyl}-lH- pyrazol-5-yl]piperidin-l-yl}methyl)benzene-l-sulfonamide;
4-( { 4- [ 1 -(4-fluorophenyl)-4- { [(3 S)-3 -(4-fluorophenyl)pyrcolidin- 1 -yljcarbonyl } - 1 H- pyrazol-5-yl]piperidin-l-yl}methyl)benzene-l-sulfonamide;
4- [ 1 -(4-fluorophenyl)-4- { [(3R)-3-(4-fluorophenyl)pyrrolidin- l-yl]carbonyl } - 1H- pyrazol-5 -yl] - 1 - [(4-methanesulfonylphenyl)methyl]piperidine;
4- [ 1 -(4-fluorophenyl)-4- { [(3S)-3 -(4-fluorophenyl)pyrrolidin- 1 -yljcarbonyl } - 1 H- pyrazol-5 -yl] - 1 - [(4-methanesulfonylphenyl)methyl]piperidine;
4-{ [4-(4-{ [3,3-difluoro-4-(4-fluorophenyl)pyrrolidin-l-yl]carbonyl}-l-(4- fluorophenyl) - 1 H-pyrazol- 5 -yl)piperidin- 1 -yl] methyl } benzene- 1 - sulfonamide ;
4-(4- { [3 ,3-difluoro-4-(4-fluorophenyl)pyrrolidin- 1 -yl]carbonyl } - 1 -(4-fluorophenyl)- lH-pyrazol-5-yl)-l-[(4-methanesulfonylphenyl)methyl]piperidine; methyl 2-(4- { 4- [(3 ,3-difluoro-4-phenylpyrrolidin- 1 -yl)carbonyl]- 1 -(4-fluorophenyl)- lH-pyrazol-5-yl}piperidin-l-yl)-2-(4-methanesulfonylphenyl)acetate;
4-{ [4-(4-{ [(4R)-3,3-difluoro-4-(4-fluorophenyl)pyrrolidin-l-yl]carbonyl}-l-(4- fluorophenyl) - 1 H-pyrazol- 5 -yl)piperidin- 1 -yl] methyl } benzene- 1 - sulfonamide ;
4-{ [4-(4-{ [(4S)-3,3-difluoro-4-(4-fluorophenyl)pyrrolidin-l-yl]carbonyl}-l-(4- fluorophenyl) - 1 H-pyrazol- 5 -yl)piperidin- 1 -yl] methyl } benzene- 1 - sulfonamide ;
4-(4-{[(4R)-3,3-difluoro-4-(4-fluorophenyl)pyrrolidin-l-yl]carbonyl}-l-(4- fluorophenyl)-lH-pyrazol-5-yl)-l-[(4-methanesulfonylphenyl)methyl]piperidine;
4-(4-{[(4S)-3,3-difluoro-4-(4-fluorophenyl)pyrrolidin-l-yl]carbonyl}-l-(4- fluorophenyl)-lH-pyrazol-5-yl)-l-[(4-methanesulfonylphenyl)methyl]piperidine;
4-{ [4-(4-{ [3-(4-fluorophenyl)pyrrolidin-l-yl]carbonyl}-l-(5-fluoropyrimidin-2-yl)-
1 H-pyrazol- 5 -yl)piperidin- 1 -yl] methyl } benzene- 1 - sulfonamide ;
4-{ [4-(4-{ [3,3-difluoro-4-(4-fluorophenyl)pyrrolidin-l-yl]carbonyl}-l-(5- fluoropyrimidin-2-yl)- 1 H-pyrazol-5 -yl)piperidin- 1 -yl]methyl } benzene- 1 - sulfonamide;
2-(4-{[3,3-difluoro-4-(4-fluorophenyl)pyrrolidin-l-yl]carbonyl}-5-{ l-[(4- methanesulfonylphenyl)methyl]piperidin-4-yl}-lH-pyrazol-l-yl)-5- fluoropyrimidine ;
4- { 4- [(3 ,3-difluoro-4-phenylpyrrolidin- 1 -yl)carbonyl]- 1 -(4-fluorophenyl)- 1H- pyrazol-5-yl}-l-[(3-fluoro-4-methanesulfonylphenyl)methyl]piperidine;
5- fluoro-2-(4- { [3-(4-fluorophenyl)pyrrolidin- l-yl]carbonyl} -5- { l-[(4- methanesulfonylphenyl)methyl]piperidin-4-yl } - 1 H-pyrazol- 1 -yl)pyrimidine ;
4- { [4-(4- { [(3R)-3-(4-fluorophenyl)pyrrolidin- 1 -yl]carbonyl } - l-(5-fluoropyrimidin- 2-yl)- lH-pyrazol-5-yl)piperidin- l-yl]methyl}benzene- 1- sulfonamide;
4- { [4-(4-{ [(3S)-3-(4-fluorophenyl)pyrrolidin- l-yl]carbonyl }- l-(5-fluoropyrimidin- 2-yl)- lH-pyrazol-5-yl)piperidin- l-yl]methyl}benzene- 1- sulfonamide;
5- fluoro-2-(4-{[(3R)-3-(4-fluorophenyl)pyrrolidin-l-yl]carbonyl}-5-{ l-[(4- methanesulfonylphenyl)methyl]piperidin-4-yl } - 1 H-pyrazol- 1 -yl)pyrimidine ;
5-fluoro-2-(4-{[(3S)-3-(4-fluorophenyl)pyrrolidin-l-yl]carbonyl}-5-{ l-[(4- methanesulfonylphenyl)methyl]piperidin-4-yl } - 1 H-pyrazol- 1 -yl)pyrimidine ;
4-{ [4-(4-{ [(4R)-3,3-difluoro-4-(4-fluorophenyl)pyrrolidin-l-yl]carbonyl}-l-(5- fluoropyrimidin-2-yl)- 1 H-pyrazol-5 -yl)piperidin- 1 -yl]methyl } benzene- 1 - sulfonamide; 2-(4-{[(4R)-3,3-difluoro-4-(4-fluorophenyl)pyrrolidin-l-yl]carbonyl}-5-{ l-[(4- methanesulfonylphenyl)methyl]piperidin-4-yl}-lH-pyrazol-l-yl)-5- fluoropyrimidine ;
2-(4-{[3,3-difluoro-4-(4-fluorophenyl)pyrrolidin-l-yl]carbonyl}-5-{ l-[(4- methanesulfonylphenyl)methyl]piperidin-4-yl}-lH-pyrazol-l-yl)-5-fluoropyridine;
4- { 4- [(3 ,3-difluoro-4-phenylpyrrolidin- 1 -yl)carbonyl]- 1 -(4-fluorophenyl)- 1H- pyrazol-5 -yl } - 1 - { [4-methanesulfonyl-2-(trifluoromethyl)phenyl]methyl } piperidine;
5- [(4- { 4- [(3 ,3 -difluoro-4-phenylpyrrolidin- 1 -yl)carbonyl] - 1 -(4-fluorophenyl)- 1 H- pyrazol-5 -yl } piperidin- 1 -yl)methyl] -2-methanesulfonylbenzonitrile;
2-(4-{[(4R)-3,3-difluoro-4-(4-fluorophenyl)pyrrolidin-l-yl]carbonyl}-5-{ l-[(4- methanesulfonylphenyl)methyl]piperidin-4-yl}-lH-pyrazol-l-yl)-5-fluoropyridine; 4- { 4- [(3 ,3-difluoro-4-phenylpyrrolidin- 1 -yl)carbonyl]- 1 -(4-fluorophenyl)- 1H- pyrazol-5-yl}-l-[(2-fluoro-4-methanesulfonylphenyl)methyl]piperidine;
4- { 4- [(3 ,3-difluoro-4-phenylpyrrolidin- 1 -yl)carbonyl]- 1 -(4-fluorophenyl)- 1H- pyrazol-5 -yl } - 1 - [(4-methanesulf onylphenyl)- 1 , 1 -(dideuterium) methyljpiperidine; 4-{ [4-(4-{ [(4R)-3,3-difluoro-4-phenylpyrrolidin-l-yl]carbonyl}-l-(2,4- difluorophenyl) - 1 H-pyrazol- 5 -y l)piperidin- 1 -yl] methyl } benzene- 1 - sulfonamide ; 4-(4- { [3 ,3-difluoro-4-(4-fluorophenyl)pyrrolidin- 1 -yl]carbonyl } - 1 -(4-fluorophenyl)- 1 H-pyrazol- 5 -yl) - 1 - [(4-methanesulf onylphenyl) -1,1- (dideuterium)
methyl]piperidine;
1 - [(4-methanesulfonylphenyl)methyl] -4-( 1 -methyl-4- { [(3R)-3-phenylpyrrolidin- 1 - yl]carbonyl}-lH-pyrazol-5-yl)piperidine;
4-(4- { [3 ,3-difluoro-4-(4-fluorophenyl)pyrrolidin- 1 -yl]carbonyl } - 1 -propyl- 1 H- pyrazol-5-yl)-l-[(4-methanesulfonylphenyl)methyl]piperidine;
l-[(4-methanesulfonylphenyl)methyl]-4-(4-{ [(3R)-3-phenylpyrrolidin-l- yl] carbonyl } - 1 -propyl- 1 H-pyrazol- 5 -yl)piperidine ;
4-(l-butyl-4-{ [(3R)-3-phenylpyrrolidin-l-yl]carbonyl}-lH-pyrazol-5-yl)-l-[(4- methanesulfonylphenyl)methyl]piperidine;
4- { 4- [(3 ,3-difluoro-4-phenylpyrrolidin- 1 -yl)carbonyl]- 1 -propyl- lH-pyrazol-5-yl } - 1 - [(4-methanesulfonylphenyl)methyl]piperidine;
4- [(4- { 4- [(3 ,3 -difluoro-4-phenylpyrrolidin- 1 -yl)carbonyl] - 1 -propyl- 1 H-pyrazol-5- yl } piperidin- 1 -yl)methyl]benzene- 1 - sulfonamide ; 4- [(4- { 4- [(3 ,3 -difluoro-4-phenylpyrrolidin- 1 -yl)carbonyl] - 1 -propyl- 1 H-pyrazol-5- yl } piperidin- 1 -yl)methyl]benzene- 1 - sulfonamide ;
4- { 1 -butyl-4- [(3 ,3 -difluoro-4-phenylpyrrolidin- 1 -yl)carbonyl] - 1 H-pyrazol-5 -yl } - 1 - [(4-methanesulfonylphenyl)methyl]piperidine;
4-(4-{[(4R)-3,3-difluoro-4-phenylpyrrolidin-l-yl]carbonyl}-l-ethyl-lH-pyrazol-5- yl)-l- [(4-methanesulfonylphenyl)methyl]piperidine ;
4- { [4-(4- { [(4R)-3,3-difluoro-4-phenylpyrrolidin- 1 -yfjcarbonyl } - 1 -ethyl- lH-pyrazol-
5- yl)piperidin-l-yl]methyl}benzene-l-sulfonamide;
4-[(4-{ l-butyl-4-[(3,3-difluoro-4-phenylpyrrolidin-l-yl)carbonyl]-lH-pyrazol-5- yl } piperidin- 1 -yl)methyl]benzene- 1 - sulfonamide ;
4- { [4-(4- { [(4R)-3,3-difluoro-4-phenylpyrrolidin- 1 -yfjcarbonyl } - 1 -propyl- 1H- pyrazol-5 -yl)piperidin- 1 -yl] methyl } benzene- 1 - sulfonamide ;
4-{ [4-(4-{ [(4S)-3,3-difluoro-4-phenylpyrrolidin-l-yl]carbonyl}-l-propyl-lH- pyrazol-5 -yl)piperidin- 1 -yl] methyl } benzene- 1 - sulfonamide ;
4-(l-ethyl-4-{ [(3R)-3-phenylpyrrolidin-l-yl]carbonyl}-lH-pyrazol-5-yl)-l-[(4- methanesulfonylphenyl)methyl]piperidine;
4-{ [l-(4-fluorophenyl)-4-{ [(3R)-3-phenylpyrrolidin-l-yl]carbonyl}-lH-pyrazol-5- yl]methyl } - 1 -(4-methanesulfonylphenyl)piperidine;
4- { 4- [(3 ,3-difluoro-4-phenylpyrrolidin- 1 -yl)carbonyl]- 1 -(4-fluorophenyl)- 1H- pyrazol-5 -yl } - 1 - [ 1 -(4-methanesulfonylphenyl)ethyl]piperidine;
3-[l-(4-chlorophenyl)-4-{ [(3R)-3-phenylpyrrolidin-l-yl]carbonyl}-lH-pyrazol-5- yl] - 1 - (4-methanesulf onylphenyl)piperidine ;
N-[l-(4-fluorophenyl)-4-{ [(3R)-3-phenylpyrrolidin-l-yl]carbonyl}-lH-pyrazol-5- yl]-l-(4-methanesulfonylphenyl)piperidin-4-amine;
3- [l-(4-chlorophenyl)-4-{ [(3R)-3-phenylpyrrolidin-l-yl]carbonyl}-lH-pyrazol-5- yl] - 1 - [(4-methanesulfonylphenyl)methyl]piperidine ;
4- [l-(4-{4-[(3,3-difluoro-4-phenylpyrrolidin-l-yl)carbonyl]-l-(4-fluorophenyl)-lH- pyrazol-5-yl}piperidin-l-yl)-2,2,2-trifluoroethyl]benzonitrile; 4-[l-(4-fluorophenyl)- 4-{ [(3R)-3-phenylpyrrolidin-l-yl]carbonyl}-lH-pyrazol-5-yl]-N-[(4- methanesulfonylphenyl)methyl]cyclohexan-l-amine;
4- [ 1 -(4-fluorophenyl)-4- { [(3R)-3 -phenylpyrrolidin- 1 -yl]carbonyl } - 1 H-pyrazol-5 -yl] - 1 - [(4-methanesulfonylphenyl)methyl] - 1 -methylpiperidin- 1 -ium; 4- [ 1 -(4-fluorophenyl)-4- { [(3R)-3 -phenylpyrrolidin- 1 -yljcarbonyl } - 1 H-pyrazol-5 -yl] - 1 - [(4-methanesulfonylphenyl)methyl] - 1 -methylpiperidin- 1 -ium, and
l-ethyl-4-[l-(4-fluorophenyl)-4-{[(3R)-3-phenylpyrrolidin-l-yl]carbonyl}-lH- pyrazol-5 -yl] - 1 - [(4-methanesulfonylphenyl)methyl]piperidin- 1 -ium.
16. A pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of claims 1-15 and a pharmaceutically acceptable excipient.
17. A medicament for treating a TGR5 mediated disease or disorder, wherein the
medicament comprises a therapeutically effective amount of a compound of any one of claims 1-15.
18. The medicament of claim 17, wherein the TGR5 mediated disease or disorder is selected from diabetes, an inflammatory disorders and an autoimmune disease.
19. The medicament of claim 18, wherein the TGR5 mediated disease or disorder is type II diabetes or psoriasis.
20. The use of a compound of any one of claims 1-15 in the manufacture of a
medicament for treating a TGR5 mediated disease or disorder, wherein the disease or disorder is selected from diabetes, an inflammatory disorders and an autoimmune disease.
21. The use of claim 20, wherein the TGR5 mediated disease or disorder is type II
diabetes or psoriasis.
22. A method for treating a TGR5 mediated disease or disorder comprising administering to a subject in need thereof, a therapeutically effective amount of a compound of any one of claims 1-15.
23. The method of claim 22, wherein the TGR5 mediated disease or disorder is selected from diabetes, an inflammatory disorders and an autoimmune disease.
24. The method of claim 23, wherein the TGR5 mediated disease or disorder is type II diabetes or psoriasis.
25. A compound for use in a method of medical treatment, wherein the method of
medical treatment is for treating a TGR5 mediated disease or disorder selected from diabetes, an inflammatory disorders and an autoimmune disease, and wherein the compound is a compound of any one of claims 1-15, or pharmaceutically acceptable salt thereof.
26. The compound of claim 25, wherein the TGR5 mediated disease or disorder is type II diabetes or psoriasis.
PCT/US2011/064983 2010-12-16 2011-12-14 Compounds and compositions as tgr5 agonists Ceased WO2012082947A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US42386410P 2010-12-16 2010-12-16
US61/423,864 2010-12-16

Publications (1)

Publication Number Publication Date
WO2012082947A1 true WO2012082947A1 (en) 2012-06-21

Family

ID=45509651

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2011/064983 Ceased WO2012082947A1 (en) 2010-12-16 2011-12-14 Compounds and compositions as tgr5 agonists

Country Status (1)

Country Link
WO (1) WO2012082947A1 (en)

Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014047707A1 (en) * 2012-09-28 2014-04-03 Cristália Produtos Químicos Farmacêuticos Ltda Heteroaromatic compounds, method for preparing the compounds, pharmaceutical compositions, uses and method for treating acute and chronic pain
WO2014100025A1 (en) * 2012-12-17 2014-06-26 Exelixis, Inc. Tgr5 agonists having an imidazole or triazole core with subtituent having a quaternary nitrogen
WO2014100021A1 (en) * 2012-12-17 2014-06-26 Exelixis, Inc. Tgr5 agonists: imidazole and triazole compounds containing a quaternary nitrogen
WO2014192868A1 (en) * 2013-05-30 2014-12-04 大日本住友製薬株式会社 Cyclic aminomethyl pyrimidine derivative
WO2015067549A1 (en) * 2013-11-05 2015-05-14 Bayer Pharma Aktiengesellschaft (aza)pyridopyrazolopyrimidinones and indazolopyrimidinones as inhibitors of fibrinolysis
WO2015090496A1 (en) 2013-12-17 2015-06-25 Merck Patent Gmbh N1-(3,3,3-trifluoro-2-hydroxo-2-methylpropionyl)-piperidine derivatives as inhibitors of pyruvate dehydrogenase kinase
WO2015175855A1 (en) * 2014-05-16 2015-11-19 Emory University Chemokine cxcr4 and ccr5 receptor modulators and used related thereto
WO2017167676A1 (en) 2016-03-29 2017-10-05 Merck Patent Gmbh N1-(3,3,3-trifluoro-2-hydroxy-2-methylpropionyl)-piperidine derivatives as inhibitors of pyruvate dehydrogenase kinase
WO2017186653A1 (en) 2016-04-28 2017-11-02 Merck Patent Gmbh Piperidinyl derivatives
CN108409561A (en) * 2017-05-11 2018-08-17 上海本素医药科技有限公司 A kind of preparation method of 5-aminoketoglutarate hydrochloride and intermediate
US10668167B2 (en) 2016-06-02 2020-06-02 Abbvie Inc. Glucocorticoid receptor agonist and immunoconjugates thereof
US10772970B2 (en) 2017-12-01 2020-09-15 Abbvie Inc. Glucocorticoid receptor agonist and immunoconjugates thereof
WO2021174048A1 (en) 2020-02-28 2021-09-02 Kallyope, Inc. Gpr40 agonists
US11279702B2 (en) 2020-05-19 2022-03-22 Kallyope, Inc. AMPK activators
US11407768B2 (en) 2020-06-26 2022-08-09 Kallyope, Inc. AMPK activators
US11512065B2 (en) 2019-10-07 2022-11-29 Kallyope, Inc. GPR119 agonists
US11919879B2 (en) 2021-06-16 2024-03-05 Celgene Corporation Carboxylic acid containing azetidinyl compounds for the treatment of neurodegenerative diseases

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1591120A1 (en) 2003-01-28 2005-11-02 Takeda Chemical Industries, Ltd. Receptor agonists
WO2006070718A1 (en) 2004-12-27 2006-07-06 Banyu Pharmaceutical Co., Ltd. Drugs for diseases accompanying changes in total bile acid pool or lipid metabolism disorders and method of screening these drugs
WO2007127505A2 (en) 2006-01-20 2007-11-08 Smithkline Beecham Corporation Use of sulfonamide derivatives in the treatment of disorders of the metabolism and the nervous system
WO2010093845A1 (en) * 2009-02-12 2010-08-19 Exelixis, Inc. Triazole and imidazole derivatives for use as tgr5 agonists in the treatment of diabetes and obesity

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1591120A1 (en) 2003-01-28 2005-11-02 Takeda Chemical Industries, Ltd. Receptor agonists
WO2006070718A1 (en) 2004-12-27 2006-07-06 Banyu Pharmaceutical Co., Ltd. Drugs for diseases accompanying changes in total bile acid pool or lipid metabolism disorders and method of screening these drugs
WO2007127505A2 (en) 2006-01-20 2007-11-08 Smithkline Beecham Corporation Use of sulfonamide derivatives in the treatment of disorders of the metabolism and the nervous system
WO2010093845A1 (en) * 2009-02-12 2010-08-19 Exelixis, Inc. Triazole and imidazole derivatives for use as tgr5 agonists in the treatment of diabetes and obesity

Non-Patent Citations (13)

* Cited by examiner, † Cited by third party
Title
"A Dictionary of Biology (Oxford Paperback Reference", 2000, OXFORD UNIVERSITY PRESS
"Dictionary of Microbiology and Molecular Biology", 2002, JOHN WILEY & SONS
"Oxford Dictionary of Biochemistry and Molecular Biology", 2000, OXFORD UNIVERSITY PRESS
DATABASE REGISTRY [Online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; 14 May 2008 (2008-05-14), XP002671298, retrieved from STN Database accession no. 1020714-10-6 *
DATABASE REGISTRY [Online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; 19 July 2006 (2006-07-19), XP002671302, retrieved from STN Database accession no. 894687-28-6 *
DATABASE REGISTRY [Online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; 20 July 2006 (2006-07-20), XP002671301, retrieved from STN Database accession no. 894886-79-4 *
DATABASE REGISTRY [Online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; 22 May 2008 (2008-05-22), XP002671297, retrieved from STN Database accession no. 1021960-12-2 *
DATABASE REGISTRY [Online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; 8 May 2008 (2008-05-08), XP002671300, retrieved from STN Database accession no. 1020060-91-6 *
DATABASE REGISTRY [Online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; 9 May 2008 (2008-05-09), XP002671299, retrieved from STN Database accession no. 1020185-12-9 *
JEAN JACQUES; ANDRE COLLET; SAMUEL H. WILEN: "Enantiomers, Racemates and Resolutions", 1981, JOHN WILEY AND SONS, INC.
SAULNIER ET AL., BIOORGANIC AND MEDICINAL CHEMISTRY LETTERS, vol. 4, 1994, pages 1985
T. W. GREENE: "Protecting Groups in Organic Chemistry", 1999, JOHN WILEY AND SONS, INC.
T.W. GREENE; P. G. M. WUTS: "Protective Groups in Organic Chemistry", 1991, JOHN WILEY AND SONS

Cited By (31)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014047707A1 (en) * 2012-09-28 2014-04-03 Cristália Produtos Químicos Farmacêuticos Ltda Heteroaromatic compounds, method for preparing the compounds, pharmaceutical compositions, uses and method for treating acute and chronic pain
WO2014100025A1 (en) * 2012-12-17 2014-06-26 Exelixis, Inc. Tgr5 agonists having an imidazole or triazole core with subtituent having a quaternary nitrogen
WO2014100021A1 (en) * 2012-12-17 2014-06-26 Exelixis, Inc. Tgr5 agonists: imidazole and triazole compounds containing a quaternary nitrogen
JPWO2014192868A1 (en) * 2013-05-30 2017-02-23 大日本住友製薬株式会社 Cyclic aminomethylpyrimidine derivatives
WO2014192868A1 (en) * 2013-05-30 2014-12-04 大日本住友製薬株式会社 Cyclic aminomethyl pyrimidine derivative
US9732065B2 (en) 2013-05-30 2017-08-15 Sumitomo Dainippon Pharma Co., Ltd. Cyclic aminomethyl pyrimidine derivative
EA029373B1 (en) * 2013-11-05 2018-03-30 Байер Фарма Акциенгезельшафт (aza)pyridopyrazolopyrimidinones and indazolopyrimidinones as inhibitors of fibrinolysis
AU2014345771B2 (en) * 2013-11-05 2018-09-13 Bayer Pharma Aktiengesellschaft (aza)pyridopyrazolopyrimidinones and indazolopyrimidinones as inhibitors of fibrinolysis
JP2016535052A (en) * 2013-11-05 2016-11-10 バイエル ファーマ アクチエンゲゼルシャフト (Aza) pyridopyrazolopyrimidinones and indazolopyrimidinones as inhibitors of fibrinolysis
CN105683194A (en) * 2013-11-05 2016-06-15 拜耳制药股份公司 (aza)pyridopyrazolopyrimidinones and indazolopyrimidinones as inhibitors of fibrinolysis
US9598417B2 (en) 2013-11-05 2017-03-21 Bayer Pharma Aktiengesellschaft (Aza)pyridopyrazolopyrimidinones and indazolopyrimidinones and their use
TWI657089B (en) * 2013-11-05 2019-04-21 德商拜耳製藥股份有限公司 (aza)pyridopyrazolopyrimidinones and indazolopyrimidinones and their use
US10098883B2 (en) 2013-11-05 2018-10-16 Bayer Pharma Aktiengesellschaft (Aza)pyridopyrazolopyrimidinones and indazolopyrimidinones and their use
US10668071B2 (en) 2013-11-05 2020-06-02 Bayer Pharma Aktiengesellschaft (Aza)pyridopyrazolopyrimidinones and indazolopyrimidinones and their use
WO2015067549A1 (en) * 2013-11-05 2015-05-14 Bayer Pharma Aktiengesellschaft (aza)pyridopyrazolopyrimidinones and indazolopyrimidinones as inhibitors of fibrinolysis
WO2015090496A1 (en) 2013-12-17 2015-06-25 Merck Patent Gmbh N1-(3,3,3-trifluoro-2-hydroxo-2-methylpropionyl)-piperidine derivatives as inhibitors of pyruvate dehydrogenase kinase
WO2015175855A1 (en) * 2014-05-16 2015-11-19 Emory University Chemokine cxcr4 and ccr5 receptor modulators and used related thereto
US11026936B2 (en) 2016-03-29 2021-06-08 Merck Patent Gmbh Piperidinyl-propanone derivatives
WO2017167676A1 (en) 2016-03-29 2017-10-05 Merck Patent Gmbh N1-(3,3,3-trifluoro-2-hydroxy-2-methylpropionyl)-piperidine derivatives as inhibitors of pyruvate dehydrogenase kinase
WO2017186653A1 (en) 2016-04-28 2017-11-02 Merck Patent Gmbh Piperidinyl derivatives
US10668167B2 (en) 2016-06-02 2020-06-02 Abbvie Inc. Glucocorticoid receptor agonist and immunoconjugates thereof
CN108409561A (en) * 2017-05-11 2018-08-17 上海本素医药科技有限公司 A kind of preparation method of 5-aminoketoglutarate hydrochloride and intermediate
CN108409561B (en) * 2017-05-11 2022-03-29 厦门本素药业有限公司 Preparation method of 5-aminolevulinic acid hydrochloride and intermediate
US10772970B2 (en) 2017-12-01 2020-09-15 Abbvie Inc. Glucocorticoid receptor agonist and immunoconjugates thereof
US11512065B2 (en) 2019-10-07 2022-11-29 Kallyope, Inc. GPR119 agonists
WO2021174048A1 (en) 2020-02-28 2021-09-02 Kallyope, Inc. Gpr40 agonists
US12264171B2 (en) 2020-02-28 2025-04-01 Kallyope, Inc. GPR40 agonists
US11279702B2 (en) 2020-05-19 2022-03-22 Kallyope, Inc. AMPK activators
US11851429B2 (en) 2020-05-19 2023-12-26 Kallyope, Inc. AMPK activators
US11407768B2 (en) 2020-06-26 2022-08-09 Kallyope, Inc. AMPK activators
US11919879B2 (en) 2021-06-16 2024-03-05 Celgene Corporation Carboxylic acid containing azetidinyl compounds for the treatment of neurodegenerative diseases

Similar Documents

Publication Publication Date Title
WO2012082947A1 (en) Compounds and compositions as tgr5 agonists
JP6495886B2 (en) Heteroaromatic compounds as BTK inhibitors
CN102574789B (en) Pyrrolidone carboxamide derivatives as modulators of chemokine-R (CHEMR23)
JP7657792B2 (en) Melanocortin subtype-2 receptor (MC2R) antagonists and uses thereof - Patents.com
KR101421852B1 (en) Imidazole derivatives as casein kinase inhibitors
CN112218863B (en) O-glycoprotein-2-acetylamino-2-deoxy-3-D-pyranosidase inhibitor
WO2010127152A2 (en) Compounds and compositions as microsomal prostaglandin e synthase-1 inhibitors
ZA200407665B (en) New compounds.
AU2004227854B2 (en) Di-aryl substituted pyrrole modulators of metabotropic glutamate receptor-5
KR20090052884A (en) Pyrimidone Compounds as UBS-3 Inhibitors
CN102317278B (en) 4-azetidinyl-1-heteroaryl-hexalin the antagonist of CCR2
CN1639153A (en) Indolylmaleimide derivatives
AU1571001A (en) Tyrosine kinase inhibitors
NZ551017A (en) Substituted 2-quinolyl-oxazoles useful as PDE4 inhibitors
EP1458383A2 (en) Heteroaryl substituted pyrazole modulators of metabotropic glutamate receptor-5
JP2007538035A (en) Pyridazinone derivatives, processes for their preparation and their use as medicaments
JP2009543782A (en) Novel heterocyclic substituted piperazine compounds having CXCR3 antagonist activity
KR20150091080A (en) Pyridine-2-amides useful as cb2 agonists
CN102015687A (en) Muscarinic receptor agonists, compositions, methods of treatment thereof, and processes for preparation thereof 177
CN1537112A (en) New pyrimidine compounds
US9067930B2 (en) 2-oxo-piperidinyl derivatives
EP2274302A2 (en) Compounds and compositions as itpkb inhibitors
CA2975157A1 (en) Sulfonamide-substituted indole modulators of rorc2 and methods of use thereof
JP2020510007A (en) Polycyclic amines as opioid receptor modulators
TW202039479A (en) Chemical compounds

Legal Events

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

Ref document number: 11811219

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 11811219

Country of ref document: EP

Kind code of ref document: A1