WO2014100025A1 - Tgr5 agonists having an imidazole or triazole core with subtituent having a quaternary nitrogen - Google Patents

Tgr5 agonists having an imidazole or triazole core with subtituent having a quaternary nitrogen Download PDF

Info

Publication number
WO2014100025A1
WO2014100025A1 PCT/US2013/075838 US2013075838W WO2014100025A1 WO 2014100025 A1 WO2014100025 A1 WO 2014100025A1 US 2013075838 W US2013075838 W US 2013075838W WO 2014100025 A1 WO2014100025 A1 WO 2014100025A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
optionally substituted
group
halo
groups
Prior art date
Application number
PCT/US2013/075838
Other languages
French (fr)
Inventor
Brenton T. Flatt
Raju Mohan
Original Assignee
Exelixis, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Exelixis, Inc. filed Critical Exelixis, Inc.
Publication of WO2014100025A1 publication Critical patent/WO2014100025A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

  • the invention relates to agonists of the G protein-coupled receptor TGR5, compositions comprising them, methods of making the compounds and compositions and using them for the treatment of diseases TGR5 mediates or is implicated in.
  • Bile acids play essential roles in the absorption of dietary lipids and in the regulation of bile acid biosynthesis. While bile acids have long been known to be essential in dietary lipid absorption and cholesterol eatabolism, in recent years an important role for bile acids as signaling molecules has emerged. Bile acids activate mitogen-activated protein kinase pathways, are ligands for the G-protein-coupled receptor (GPCR) TGR5, and activate nuclear hormone receptors such as farnesoid X receptor a (FXR-a). Through activation of these diverse signaling pathways, bile acids can regulate their own enterohepatic circulation, but also triglyceride, cholesterol, energy, and glucose homeostasis. Thus, bile acid (BA) controlled signaling pathways are promising novel drug targets to treat common metabolic diseases, such as obesity, type ⁇ diabetes, hyperlipidemia, and atherosclerosis, Houten et at. The EMBO Journal (2006) 25, 1419-1425).
  • GPCR G-protein-coupled
  • Watanabe et aL ' Nature 2006, 439(7075) 484-489 showed that the administration of bile acids to mice increases energy expenditure in brown adipose tissue, preventing obesity and resistance to insulin.
  • This novel metabolic effect of bile acids is critically dependent on induction of the cyclic-AMP-dependent thyroid hormone activating enzyme type 2 iodothyronine deiodinase (D2) because it is lost in D2-/- mice.
  • D2 iodothyronine deiodinase
  • Treatment of brown adipocytes and human skeletal myocytes with bile acids increases D2 activity and oxygen consumption.
  • thermogenieally important tissues are specifically targeted by this mechanism because they coexpress D2 and TGR5.
  • the BA-TGR5-cAMP-D2 signaling pathway is therefore a crucial mechanism for fine-timing energy homeostasis that can be targeted to improve metabolic control,
  • Glucagon-like peptide- 1 (GLP-1) is produced by L-cells in the distal digestive tract and affects multiple metabolic parameters, including enhanced insulin secretion. glucagon suppression, and lowering of blood glucose. TGR5 expression in L-cells is linked to increased GLP-1 secretion. Katsuma, el aL, Biochem. Blophys. Res. Cornrnun. 2005, 329(1 ), 386-390) showed that bile acids promote glueagon-like peptide- 1 (GLP-1) secretion through TGR5 in a murine enteroendocrine ceil line STC- 1 . RNA interference experiments showed that reduced expression of TGR5 resulted in reduced secretion of GLP-1. Furthermore, transient transfection of STC- 1 cells with an expression plasmid containing TGR5 significantly enhanced GLP- 1 secretion.
  • WO/2008/097976 Heterocyclic Modulators of TGR5 for Treatment of Disease
  • WO/2008/091540 Substituted Bile Acids as TGR5 Modulators and Methods of Use
  • WO/2008/067219 Quinazolinone Modulators of TGR5
  • the present in vention comprises TGR5 agonists of structural formula I(Q),
  • the invention further comprises compositions comprising the compounds and/or pharmaceutically acceptable salts thereof.
  • the invention also comprises use of the compounds and compositions for treating diseases in which TGR5 is a mediator or is implicated.
  • the invention also comprises use of the compounds in and for the manufacture of medicaments, particularly for treating diseases in which TGR5 is a mediator or is implicated.
  • All of the compounds of Formulae I(Q), 11, III, IV, V, VI, and VII disclosed herein have quaternary ammonium ion moieties, and it is understood to one skilled in the art that these compounds are all in in the presence of a pharmaceutically acceptable counter ion.
  • the pharmaceutically acceptable counter ion for each of the quaternary ammonium ion moieties present in the compounds of the invention can be any pharmaceutically acceptable counter ion known to one skilled in the art.
  • These compounds with quaternary ammonium ion moieiies have more non-sytstemic effects than with the same compounds without quaternary ammonium ion moieiies.
  • Non-limiting examples of the pharmaceutically acceptable counter ions that can be used include chloride, bromide, sulfate, tosy late, phosphate, tartrate, maleate, acetate, formate, fumarate, mesylate, nitrate, oxalate, ascorbate, citrate, ammonium, arginine, diethylamine, ethylenediamine, magnesium, sodium, calcium, and potassium. It is also understood that the source of the counter ions can be from either intermolecular sources, or, when possible, intramolecular sources.
  • the present invention comprises TGR5 agonists of structural formula I(Q):
  • R 1 is R c -
  • R c is selected from phenyl, -(Cs-C6)-cycloalkyl, -CHj-phenyl, heteroaryl, and -(Ci -C 4 )alkyl optionally substituted with -OR c ' 3 , -N(R c l3 ) 2 or -S(R CI 3 ), wherein
  • the cyclic group of R 1 can be optionally substituted with I , 2, 3, 4 or 5 R uo groups, wherein the 1 , 2, 3, 4, or 5 R uo groups are independently selected from R L10A and R t l 0B , provided that R 1 cannot be substituted with more than two u l 0B groups, wherein
  • each R c t0A is independently selected from halo, cyano, and -(Ci -C 4 )alkyl optionally substituted with one, two, or three groups selected from -OH and halo;
  • each R C i0& is independently selected from -C(0)N3 ⁇ 4 (5-6 membered)heterocycloalkyl, -0-(C x -C 4 )alkyl-R c ' ⁇ -C(0)OR C12 , -OC(0)OR C!2 and -0-(Ci-C 4 )a3kyi optionally substituted with -OH or -C(0)OH;
  • R cn is cyano, nitro, -N(R C12 ) 2) -OR C12 , -SR C12 , -C(0)R C12 , -C(0)OR C12 , -C(0)N(R C12 ) 2 , -S(0)N(R C12 ) 2 , -S(0) 2 N(R C12 )3 ⁇ 4 -S(0) 2 R C!
  • each R U2 is independently selected from hydrogen, -(Ci-C 4 )alkyl, and ⁇ (C
  • each R CLl is independently selected from hydrogen, -(C[-C 4 )aikyi, and
  • R 2 is -L D -R D! ;
  • L D is -[C(R) 2 ] p -Y-[C(R) 2 ] q -;
  • p 0 or 1 :
  • q is 0 or 1 ;
  • each R is independently selected from H, -(Ci -Chalky 1, halo, -OH, and -CH 2 OH;
  • Y is a bond, -S-, -S(0) 2 -, -CH(OH)-, -0-, -O i l ) (A W )- -C(QHCt-C 4 )alkyl-, -iCi-C 4 )alkyl-S-(Ci-C 4 )alkyi-, -(Ci-C 4 )alkyl-N(R Y )-(Ci-C 4 )alliyl-, -C(H)(halo)-,
  • R D1 is selected from phenyl -(Ce-Cio)afyl, -N(H)-phenyl, -(C5-CV)cyc3oa3kyl, heterocyeloalkyl, or heteroaryi, wherein R D! can be optionally substituted with one, two, three, or four R D1 °, wherein the one, two, three, or four R Dl ° groups are independently selected from A groups and B groups, provided that R m cannot be substituted with more than two B groups;
  • each A group when they occur, is independently selected from halo, -CF 3 , -CN, --NO2, -OH, -0-(Ci-C4)alkyl optionally substituted at the alkyl group with one, two, or three substitucnts independently selected from -OH and halo, and -(Ci-C4)alkyl optionally substituted with one, two, or three substitucnts independently selected from -OH and halo; each B group, when they occur, is independently selected from -(d -C 4 )alkylN(R Di i ) 2 , -C(0)-NH 2 , -C(0 ⁇ -N(H ⁇ -OH, -C(0)-N(H)-R Dl lc ,
  • -C(0)-heterocycloalkyl optionally substituted with R D11B ; -C(0)-N(H)-(Ci -Cejalkyi optionally substituted at the alkyl group with 1 or 2 R Dl lu ; heterocyeloalkyl optionally substituted with oxo or R Di l ; heterocycloalkenyl optionally substituted with oxo or R DU ; heteroaryi optionally substituted with R D "; -0-(C ⁇ -C 4 )alkyl optionally substituted at the alkyl group with i or 2 R Dl l B ; -S(0) 2 -(4-6 membered)heterocycloalkyl optionally substituted with R° llC ; -N(H)-C(0)-(Ci-C 4 )alkyl optionally substituted at the alkyl group with 1 or 2 R D1IB ; -N(H)-C(0)-N(H)-(
  • R D1 ! C is selected from H, -OH, -CF 3 , -0-(Ci-C 4 )alkyl, -(Ci -(Co-C 3 )aikyl-(5-6 membered)heteroaryl; -(C i -C 4 )alkyl optionally substituted with one, two, or three groups independently selected from halo, -OH, -S(0) 2 OH, C(0)OH, -NH 2 , and N(H)C(-NH) H 2 ; -(Co-C 3 )alkyl-(5-6 membered)heterocycloalkyl optionally substituted with a -(5-6 membered)heteroaryl; -(Co-C?)alkyi-(5-6 membered)heterocycioalkyl substituted 1 , 2 or 3 groups selected from selected from -OH and -(Ci-C 3 )aikyl; and -(Co
  • R 5 is -[C(R 8 ) 2 ]-Q A --[C(R 8 ) 2 ] -phenyl, -[C(R3 ⁇ 4-naphthalenyl, or -[C(R 8 ) 2 ]-(5-10 membered) heteroaryl, wherein the heteroaryl is selected from (benzo[d][ 1 ,3]dioxolyl, benzo[d]isoxazolyl, quinoxalinyl.
  • each R A ' uA when they occur, is independently selected from halo, a!koxyl, hydroxy!, -CN, -OCF3, -(Ci-C 4 )alky1 and - H 2 ,
  • each R A10B when they occur, is selected from -0-(C t -C 4 )alkyl-R AU , -S(0) 2 -NH 2 , • S( O ( ' i i >. -N(H)-S(0) 2 CH 3 , -S(0) 2 N(H)-C3 ⁇ 4, -C(0)OH, -(Ci-C 4 )alkyl-OH, -C(0)NH 2 , and -(Ci-CVjaikyl substituted with one, two, or three groups seiected from -OH and halo;
  • R Al i is selected from -C(0)OH, (5-6 membered)heterocycloalkyl, halogen, cyano, nitro, -(CrC 4 )alkyl, - (R A! 2 ) 2 , -OR A12 , -SR Al2 , -N(OR A l )R A32 , -C(0)R A ' 2 , -C(0)OR A12 , -C(0)N(R AI ) 2 , -N(R Ai )S(0)R A12 , -N(R A, 2 )S(0) 2 R At2 , -S(0)N(R A12 ) 2 , -S(0) 2 N(R A12 ) 2 , -S(0) 2 R A12 , -GC(0)R A!2 , -OC(0)OR A!2 , -OC(0) (R A!2 ) 2 , - (R Ai2 )C(0)R A12 , -N(R
  • each R Al2 is independently hydrogen, ⁇ ! ( : ⁇ ( ' . ! !k i. or - «VC.. !hnk.alkyl:
  • R 5 when R 3 is not -[Cfll ⁇ -Q ⁇ is substituted with one or two Q A groups, wherein R "1 is substituted with Q A by replacing a hydrogen that is covalently bonded to carbon or nitrogen;
  • each R 8 is independently hydrogen, halogen, or methyl, or both R b taken together with the carbon to which they are both attached form either a (Cs-Ceicycloalkyl or a (3-6 memberedjheterocycloalkyl;
  • Q A is Q 1' or Q R ;
  • Q lj is -N[(Ci-C3 ⁇ 4)alkyl] wherein an alky! group of -N[(Ci-(3 ⁇ 4alkyr]j! + is optionally substituted with -(Co-C 6 )alkyl-S(0) 2 OH;
  • Q R is selected from:
  • R QA is -(C[-C 6 )a3kyl
  • R QB is -(Ci-Cf,)alkyl optionally substituted with -C(0)OH;
  • R QC is i i . -OH, -(Co--C )alkyl--CQQH or - it , ⁇ ( ' ,; salkv!.
  • each R is independently selected from H, -(Ci-Cs kyi, -OH, and -CH 2 OH;
  • R D1 is selected from phenyl -(C6-Cio)aryl, -N(H)-phenyl, -(Cs-Cejeyeloalkyi, heterocyeloalkyl, or heteroaryl, wherein R Di can be optionally substituted with 1 , 2, 3 or 4 R bllJ , wherein the 1-4 R mo groups are independently selected from A groups and B groups, provided that R m cannot be substituted wit more than two B groups;
  • each A group when they occur, is independently selected from halo, -CF 3 , -CN, -NO?., -OH; -O-iCj -Chalky! optionally substituted at the alkyl group with one, two, or three substituents independently selected from -OH and halo; and -(Ci -Chalky! optionally substituted with one, two, or three substituents independently selected from -OH and halo; each B group, when they occur, is independently selected from -(Ci-C 4 )alkylN(R D11 ) 2 , -C(0)-NH 2 , -C(0)-N(H)-OH, -C(0)-N(H)-R DUC ,
  • each R is independently selected from H, -(C3-C6)cycloalkyl, -(Ci-C 4 )lialoaIkyl; -OH, -Si O H)! I .
  • Ci0)0H, -NH 2 , -N(H)C( NH) H 2 ; ⁇ (Ci-C 4 )alkyl optionally substituted with halo, -OH or -C(0)OH; -(Cj -Csjalkyl-phenyl optionally substituted at the phenyl group with one, two, or three substituents selected from methoxy, hydroxyl and halo;
  • X C(R 4 )-
  • Y is a bond, -S- . -S(0) 2 -, - ⁇ ⁇ ⁇ ( I I. -Si O ) -. -CH(CH 3 ⁇ -8-, -eH(CH 3 )-S(0) 2 -, -CH(OH)-, -CH(CH 3 )-0-, ⁇ ( ! () ⁇ .
  • each R is independently selected from H, -CH 3 , -OH, F and -CH?OH;
  • Y is a bond, -S-, -Si O h-. -CH(CH 3 )-S(0) 2 -, -CH/CH 3 )-8-, -CH(C3 ⁇ 4)-S(0) 2 -, -CH(OH)-, -CH(CH 3 )-0-, .-C(0 , -(CH 2 )-S-, -CH .-Ni R ' K -CH(hafo)-, -CH 2 -S(0) 2 -, -S(0) 2 -N(R Y )-, -(CH 2 )-0-, or -C(0)-N(R Y )-, wherein R Y is H, -i C; • C halky! or hydroxy!(Ci-C 3 )a!kyl,
  • each R is independently selected from H, -(3 ⁇ 4, -OH, F, and -CH 2 OH;
  • R D1 is selected from phenyl, -N(H)-phenyl, -(5-6
  • R Dl is optionally substituted with 1 , 2, or 3 R Di 0 , wherein the one, two, or three R D1 ° groups are independently selected from A groups and B groups, provided that R D1 cannot be substituted with more than one B group;
  • each A group when they occur, is independently selected from halo, -CF 3 , -CN, -NO2, -OH; -0-(Ci-C4)alkyl optionally substituted with one, two, or three substituents independently selected from -OH and halo; and -(CrC 4 )alkyl optionally substituted with one, two, or three substituents independently selected from -OH and halo;
  • each R is independently selected from H, -(d-C 2 )alkyl, fluoro, -OH, and -CH 2 OH;
  • R D1 is selected from phenyl, - (H)-phenyl, cyclohexyl, cyclopentyl, piperidinyl, piperazinyl, pyrrolidinyl, morpliolinyl, 1,2,3,6-ieiraliydropyridine, beteroarylheterocycloalkyl, pyridinyl, oxazolyl, pyrazinyl, quinolinyl, 1,2,4-oxadiazolyl, 1,2,3,4-tetrahydroquinolinyl, and pyrazolyl, wherein R l can be optionally substituted 1 , 2 or 3 R Dl °, wherein the one, two, or three R D1 ° groups are independently selected from A groups and B groups, provided that R Di cannot be substituted with more than one B group;
  • each A group when they occur, is independently selected from halo, -CF 3 , -C , -NO2, -OH; -0-(Ci-C 4 )alkyl optionally substituted with one, two, or three siibstituents independently selected from -OH and halo; and -(Ci -C 4 )alkyl optionally substituted with one, two, or three siibstituents independently selected from -OH and halo;
  • the B group is selected from -0-(Ci-C 4 )alkyl-C(0)OH, -0-(Ci-C 4 )alkyl, -0-(C i -C 4 )alkyl-C(0)-(C i-C 3 )alkyl, -O-fC j -C 4 )alkylN(R D1 3 ⁇ 4,
  • 4,5-diliydro-l ,2,4-oxadiazolyl optionally substituted with oxo or -(Ci -C 4 )alkyl; -S(0) 2 -N(H)-(Ci-C4)alkyl optionally substituted at the alkyl group with one or two groups selected from -S(0) 2 OH ; OO sOH.
  • R l i and R M l b when they both exist and are each attached to nitrogen, can join to form a (5-6 membered) heterocycoaikyl optionally substituted with R ; and R m - is selected from H, -OH, -CF 3 , -0-(C !
  • X C(H)-
  • each R is independently selected from H, -(Ci-C 2 )alkyl, fiuoro, -OH, and -CH 2 OH;
  • R D1 is selected from phenyl, - (H)-phenyl, cyclohcxyl, cyclopcntyl, piperidinyl, piperazinyi, pyrrolidinyl, morpholinyl, 1,2,3,6-teirahydropyridine, heteroarylheterocycloalkyl, pyridinyl, oxazolyl, pyrazinyl, quinolinyi, 1,2,4-oxadiazolyl, 1,2,3,4-tetrahydroquinolinyl, and pyrazolyl, wherein R 01 is substituted with one, two, or three R Dl °, wherein the one, two, or three R DK ' groups are zero, one, or two A groups and zero or one B group:
  • each A group when they occur, is independently selected from halo, -CF 3 , -C , -NO 2 , -OH; -0-(Ci -Chalky 1 optionally substituted with one, two, or three substituents independently selected from -OH and halo; and -(Cj -C 4 )alkyl optionally substituted with one, two, or three substituents independently selected from -OH and halo;
  • the B group when it occurs, is selected from -0-(Ci-C 4 )alkyl optionally substituted at the alkyi group with 1 or 2 R Di l B ; -0-(Ci-C 4 )alkyl-C(0)OH; -O-i C -C a!kyi: -0-(C 1 -C 4 )alkyl-C(0)-(C i-C 3 )alky 1 ; -0-(C i -C 4 )alkylN(R Dl ; -0-(Ci-C4)a]kyl-N(H)-C(-NH)- H 2 ; -0-(Ci-C 4 )alkyl-(5-6 membered)heteroaryl; -0-(Ci-C4)alkyl-(5-6 membered)heterocycloalkyl optionally substituted with oxo or methyl; -(C 1 ⁇ C 4 )alkylN(R Dii )
  • k cyclopropane, eyclopentyl, imidazole, pyridinyl, thiazolyl, l(H)-tetrazolyl; -(C
  • R' " " 1 and R lB when they both exist and are each attached to nitrogen, can join to form a (5-6 membered) heterocycoalkyi optionally substituted with R 3 ';
  • X is -C(R 4 )-
  • Y is a bond, -S-, -S(0) 2 -, -CH(C3 ⁇ 4)-S(0) 2 -, -CH(C3 ⁇ 4)-S-, -CH(C3 ⁇ 4)-S(0) 2 -, -CH(OH)-, -CH(CH 3 )-0-, -O H ) ( ( 1 1 k -C(0 , -(CH 2 )-S-, -CH 2 -N(R Y )-, -CH(halo , -CH 2 -S(0) 2 -, -S(0) 2 -N(R Y )-, -(CH 2 )-0-, or -C(0)-N(R Y )-, wherein R Y is H, -(C C 4 )a!kyl or hydroxy i(Ci-C 4 )alkyl;
  • each R is independently selected from H, -(d -C 2 )alkyl, fluoro, -OH, and -CH 2 OH;
  • R D1 is selected from phenyl, -N(H)-phenyl, cyclohexyl, cyclopentyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, 1 ,2,3,6-ietrahydropyridinyl, heteroarylheterocycloalkyl, pyridinyl, oxazolyl, pyrazinyL quinolinyl, 1,2,4-oxadiazolyl, 1 ,2,3 ,4-tetrahydroquinolinyl, and pyrazolyl, wherein R D1 is substituted with 1, 2, or 3 R 010 , wherein the one, two, or three R bl ° groups are zero, one, or two A groups and one B group; each A group, when they occur, is independently selected from halo, -CF 5 , -CN, ⁇ NO?, -OH: ⁇ 0-(C]-C 4 )alkyl
  • the B group is selected from -0-(Ci-C 4 )alkyl-C(0)OH, -0-(Ci -C 4 )alkyl, -0-(Cj -C 4 )alkyl-C(0)-(Ci -C 3 )alkyl, -C(0)OH, -NH 2 , -(Ci -C 4 )alkyl-C(0)OH, 2,3-dihydro-lH-tetrazo.lyl, -0-(Ci-C 4 )alkylN(R D11 )2, ⁇ 0 ⁇ , ⁇ ( ., laik i- Ni H 3 ⁇ 4 ⁇ ( ⁇ ⁇ ⁇ - ⁇ -0-(Ci-C 4 )a1kyl-(5-6 membered)heteroaryl, -(d-C alkyl CR 011 )?., -C(0)-NH 2 , -C(0)-N(H)-OH, -C(0)-N
  • each R ba is independently selected from H, -(C ⁇ -Ce)cycloalkyl, -OH, -(Ci-C )haloalkyl -S(0) 2 OiL C(0)OH, - H 2 , -N(H)C(-NH) H 2 ; -(Ci-C 4 )alkyl optionally substituted with halo, -OH or -C(0)OH; and -(Ci -C 3 )alkyl-phenyl optionally substituted at the phenyl group with one, two, or three substituents selected from niethoxy, hydroxy! and halo;
  • R D1 1B is selected from H, -OH, -CF 3 , - H 2 , -C(0)OH, -0-(Ci-C 4 )alkyl, -S(0) 3 OH, -a ⁇ ⁇ ⁇ ,. -Ni ! l jU N ! I )NM.>.
  • -(CH 2 )i-4-C(0)OH cyclopropanyl, cyclopentyl, imidazolyl, pyridinyl, thiazolyl, l (H)-tetrazolyl
  • -(Ci-C 4 )alkyl optionally substituted with one, two, or three groups independently selected from halo and -OH
  • a heterocycloalkyl selected from morpholinyl, pyrrolidinyl, piperazinyl, and piperidinyl, wherein the heterocycloalkyl Is optionally substituted with 1, 2 or 3 R m i ; and phenyl optionally substituted with one, two, or three halo;
  • R lj! ' and R DUB when they both exist and are each attached to nitrogen, can join to form a (5-6 membered) heterocycoalkyi optionally substituted with R 1* ;
  • R D, !C is selected from H, -OH, -CF 3 , -0-(Ci-C 4 )alkyl, -C 0 -C 3 alkyl -imidazolyl, -Co-C 3 alkyl-pyridinyl;
  • L D is selected from -(CrC ⁇ alkyl-O-, -(Co-C 3 )alkyl- R Y -(C 0 -C 6 )alkyl-, -(C 0 -C 3 )alkyl-S-(C C rC 3 )alky ⁇ -, -(C 0 -C3)alkyl-S(0)2-(Co-C 3 )alkyl-; -C(0)N(R Y )-(Co-C 3 )alkyl-, -S(0)2-N(R Y )-(Co-C 3 )alkyl-, -C(O)-(Co-C 3 )alkyl-, -C ⁇ C-(Co-C )aikyl-, -(C 0 -C 3 )alky ⁇ -, and -(C[-C 4 )alkyl
  • L° is selected from: -(CH 2 )i -3 -0-, -(CH2)i-3-NR Y - f -(Co-C 3 )alkyl-S-(Co-C 3 )alJ yi-; -(CH 2 )i -3 -S-, -S-(CH 2 )i. 3 , -S(0) 2 -(CH 2 )i.
  • L D is selected from -(CH 2 )-0-, -(CH 2 )-NR Y -, -(CH 2 )-S-, -S-(CH 2 , -S(0) 2 -, -S(0) 2 -(CH 2 )-, -C(0)N(R Y )-(Co-C3 )aikyl-; -S(0) 2 -N(H)-(CH 2 )i.. 3 -, -( i O i-i CH . !, >-. -C ⁇ -(C 2 -C 3 )alkyi-, and -(Ci-C 4 )alkyl- optionally substituted with halo or -OH.
  • L D is selected from -iCH 2 )-0-, -(CH 2 )-NR Y -, -(CH 2 )-S-, -S-(CH 2 )-, -S(0) 2 -, -S(0) 2 -(CH 2 , -C(0)N(R Y )-(Co-C 3 )alkyl-, -S; G s>-Xi i ⁇ ' H i i i 0; . ⁇ .
  • the B group of R Di is selected from:
  • R is phenyl, -CH 2 -phenyl, -( ' C's-Cercycloalkyl, or pyridinyi, wherein R c can be optionally substituted with one, two, or three R C!0 , wherein the one, two, or three R'" i0 groups are independently selected from R cl0A and R U sJt ⁇ provided that R c cannot be substituted with more than one R.
  • R C!0B is selected from ⁇ C(0)NH 3 , (5-6 membered)heterocycloalkyl; -O-(Ci-C.0alkyl optionally substituted with -OH, -C(0)OH, or -N[-(C[-C 4 )alky3]2; and -(C x -C 4 )alkyl substituted with -N[-(Ci-C 4 )alkyl] 2.
  • R c is phenyl, -CH 2 -phenyl, -(Cs-Cei-cycloalkyl, or pyridinyl, wherein the cyclic group of R c can be optionally substituted with one, two, or three R l ° groups and, wherein the one, two, or three R C1& groups are independently selected from R L ' A and R ' B , provided that R cannot be substituted w r ith more than one R tl0B group;
  • each R 0A when they occur, is independently selected from methoxy, -CF 3 , halo, and -(Ci-C 3 )alkyl optionaily substituted with one, two, or three groups selected from halo and -OH; and
  • R cl 0b is selected from (5-6 membered)heterocycloaiky3; -(Ci ⁇ C 4 )alkyl substituted with -N[-(Ci-C 4 )alkyl] 2 ; -C(0)NH 2 ; and -0-(C C 4 )alkyl optionally substituted with -OH, -C(0)OH, or -N[-(Ci-C 4 )alkyl]2.
  • R '' is phenyl, -C3 ⁇ 4-phenyl or pyridinyl, wherein the cyclic group of R c can be optionally substituted with one, two, or three R 1"10 , wherein the one, two, or three R tJ groups are independently selected from R l0A and R ! oe , provided that R c cannot be substituted with more than one R Cl0B group;
  • each R CI0A when they occur is independently selected from -(C t -C 3 )alkyl optionally substituted with one, two, or three groups selected from -OH, methoxy, -CF3 ⁇ 4 and halo;
  • R C10B is selected from -C(0) H 2 ; (5-6 membered)heterocycloalkyl ; -(Ci-C 4 )alkyl substituted with -N[-(Ci-C )alkyl] 2 ; and -0-(C t -C 4 )alkyl optionally substitiited with -OH, • CiO iOi l . or -N[-(Ci-C )alkyl] 2 .
  • R ' ⁇ is phenyl or pyridinyl, wherein the cyclic group of R c can be optionally substituted with one, two, or three R c, °, wherein the one, two, or three R c '° groups are independently selected from R l ' l0A and R C,0B , provided that L cannot be substituted with more than one R cl0B group;
  • each R C10A when they occur, is independently selected from methoxy and halo;
  • R C10B is selected from -C(0)NH 2 ; (5-6 membered)heterocycloalkyl; -(Ci-C4)alkyl substituted with -N[-(Ci-C4)aIkyl] 2 ; and -0-(Cj -Chalky! optionally substituted with -OH, -C(0)OH, or -N[-(Ci-C,.)alkyl] 2 .
  • R c is phenyl or pyridinyl, wherein the cyclic group of R L can be optionally substituted with one or two groups seiected from methoxy, methyl and halo.
  • R ⁇ is phenyl or pyridinyl, wherein the cyclic group of R c can be optionally substituted one or two groups selected from methoxy, methyl, fluoro and chloro.
  • R is phenyl substituted with one or two groups selected from methoxy, fluoro or chloro.
  • the compound of formulae I(Q) is one of formula IT, III, IV, V, VI or VII:
  • R AI ° or R* is substituted with one Q A group; wherein this substitution with Q A occurs by replacing a hydrogen thai is covIERly bonded to carbon or nitrogen.
  • each R C1 ° is selected from fluoro, chioro and methoxy
  • R 2 is -L D -R D1 , wherein:
  • L D is selected from -(CH 2 )-0-, -(CH 2 >NH-, -(CH 2 )-S-, -S-(CH 2 )-, -S(0) 2 -, -S(0) 2 -(CH 2 )-, CiOiXili! (Cll,)i .. -S(0) 2 -N(H)-(CH 2 ) ]-3 -, lO) ( Ul.j: ⁇ : -(Ci-C 3 )alkyl- optionally substituted with halo or -OH; and -C s C-(C2-03)alkyl; and
  • D 1 is one of:
  • each A is chioro or fluoro, and B is selected from:
  • L D is selected from -S-(Ci-C 3 )alkyl-, -(CH 2 ) 2 -, and -(Ci -C3>alkyl-0-.
  • R 5 is -[C(CH 3 ) 2 ]-phenyl, -[C(CH 3 ) 2 ]-naphthalenyl, or -[C(CH 3 ) 2 ]-(5-10 membered) heteroaryl, wherein the heteroaryl is selected from benzo[d][l,3]dioxolyl, benzo[d]isoxazolyl, quinoxalmyl, quinolinyl, and 2,3,4a,8a-tetrahydrobenzo[b][l,4]dioxiny3, wherein the cyclic group of R 3 optionally substituted with one, two, or three R AL ° groups, wherein the one, two, or three R AL ° groups are independently selected from R Ai0a and R A!0B , provided that R ⁇ cannot be substituted with more than one R AI0B group;
  • each R Al0A when they occur, is independently selected from halo, -(Ci-C 3 )alkoxyl and hydroxy!;
  • R A10B is -(C] -C 4 )alkyl optionally substituted with one, two, or three groups selected from -OH and halo; -0-(Ci-C 4 )alkyl-C(0)OH; 0-(Ci-C 4 )alkyl-N[(Ci-C3)alk l] 2 ; -NH 2; , -S(0) 2 -NH 2 ; -SO2CH3; -N(H)-S0 2 CH 3 ; -S0 2 M(li)-CH 3 ; -CN; -C(0)OH; -(Ci-C 4 )alkyl-OH; -OCF 3 ; or -C ⁇ 0)N3 ⁇ 4; and
  • R 5 is -[Ci CFTsjjJ-pheny], and the phenyl group of R 5 is optionally substituted with one, two, or three R A1 ° groups, wherein the one, two, or three R A1 ° groups are independently- selected from R A10A and R A ' wB , provided that R 5 cannot be substituted with more than one R group;
  • each R" 1&A when they occur, is independently selected from halo, methoxy, and hydroxy!;
  • R A10B is ⁇ 0-(C
  • R " is substituted with one Q A group, wherein R 5 is substituted with Q A by replacing a hydrogen that is covalently bonded to carbon or nitrogen
  • R 5 is -[C(CH 3 )2]-phenyl, wherein the phenyl group is optionally substituted with one or two groups selected from halo, methoxy and hydroxy!;
  • R 5 is substituted with one Q A group, wherein R " is substituted with Q A by replacing a hydrogen that is covalently bonded to carbon or nitrogen.
  • R 5 is -[CiCHsVj-phenyl, wherein the phenyl group is optionally substituted with one or two groups selected from halo and methoxy;
  • R 5 is substituted with one Q A group, wherein R J is substituted with Q A by- replacing a hydrogen that is covalently bonded to carbon or nitrogen.
  • R 5 is:
  • C is s ubstituted with one, two, three, four, or five R l iUA groups.
  • R C is substituted with zero, one, two, three, or four R OA groups and 1 R L1JB group.
  • R° is substituted with zero, one, two, or three R UuA groups and one or two R' " ' 0b groups.
  • R DI is substituted with zero, one, two, threeA groups and one B group.
  • R D11B is -(Co ⁇ C.5)alkyl ⁇ (5-8 membered)heterocycloalkyl optionally substituted at the heierocycloaikyl group with 1 to 3 R M ⁇
  • R D11B is -CCo-C3)alkyl-(C3-C6)cycIoalkyl optionally substituted with R DU .
  • R 0Uli is and optionally substituted with one, two, or three halo.
  • the invention also comprises as another embodiment, a composition comprising a TGR5 agonist compound according to any one of the preceding embodiments together with a pharmaceutically acceptable diluent, excipient, and/or carrier.
  • a composition comprising a TGR5 agonist compound according to any one of the preceding embodiments together with a pharmaceutically acceptable diluent, excipient, and/or carrier.
  • Such compositions are substantially free of non-pharmaceutically acceptable components, i.e., contain amounts of non-pharmaceutically acceptable components lower than permitted by US regulatory requirements at the time of filing this application.
  • the composition if the compound is dissolved or suspended in water, the composition farther optionally comprises an additional pharmaceutically acceptable carrier, diluent, or excipient.
  • the invention also comprises as another embodiment a method for treating or preventing a metabolic disease in a subject in need of such treatment comprising administering to the subject an effective amount of a TGR5 agonist compound according to any one of the preceding embodiments.
  • Metabolic diseases that may be treated or prevented include, without limitation, metabolic syndrome, insulin resistance, and Type 1 and Type 2 diabetes.
  • the invention also comprises as another embodiment a method for treating obesity or type TI diabetes in a subject in need of such treatment comprising administering to the subject an effective amount of a TGR5 agonist compound or pharmaceutical composition according to any one of the preceding embodiments.
  • the invention also comprises as another embodiment a method for treating hyperiipidemia in a subject in need of such treatment comprising administering to the subject an effective amount of a TGR5 agonist compound or pharmaceutical composition according to any one of the preceding embodiments.
  • the invention also comprises as another embodiment a method for treating athersclerosis in a subject in need of such treatment comprising administering to the subject an effective amount of a TGR5 agonist compound or pharmaceutical composition according to any one of the preceding embodiments.
  • the invention also comprises as another embodiment a method for lowering blood glucose in a subject in need of such treatment comprising administering to the subject an effective amount of a TGR5 agonist compound or pharmaceutical composition according to any one of the preceding embodiments.
  • the invention also comprises as another embodiment a method for enhancing insulin secretion in a subject in need of such treatment comprising administering to the subject an effective amount of a TGR5 agonist compound or pharmaceutical composition according to any one of the preceding embodiments.
  • the invention also comprises as another embodiment a method for treating a disease associated with perturbed bile acid metabolism in a subject in need of such treatment comprising administering to the subject an effective amount of a TGR5 agonist compound or pharmaceutical composition according to any one of the preceding embodiments.
  • diseases include, but are not limited to, gall bladder stones, cholecystitis, cholangitis, choledocholitliiasis, jaundice, and obstetric cholestasis and the itch associated with it.
  • the invention also comprises as another embodiment a method for treating obesity or type TT diabetes in a subject in need of such treatment comprising co-administering to the subject, simultaneously or sequentially, an effective amount of a TGR5 agonist compound according to any one of the preceding embodiments and a second anti-diabetic drug or pharmaceutical composition comprising an effective amount of a TGR5 agonist compound according to any one of the preceding embodiments and a second anti-diabetic drug.
  • anti-diabetic drugs include:
  • Sulfonylureas e.g., tolbutamide (3 -butyl- 1 -(4-raethylphenyl)sulfonylurea), acetohexamide (4-acetyl-N-(cyclohexylcarbamoyl)benzenesu3fonamide), tolazamide (3-azepan-l-yl-l-(4-methylphenyl)siilfonyl-urea), chlorpropamide ( ⁇ - (4-chloropheiiyl)sulfonylmethaiiamide), glipizide (N-[2-[4- (cyciohexy!carbamoylsulfamoyl)phenyi]eth.yl]-5-methyl-pyrazine-2-carboxamide), giybuiide (5-chloro-N-[2-[4-(cyclohexylcarbamoylsulfamo
  • Meglitinides e.g., repaglinide (5( -)2-ethoxy-4(2((3-melhyl- 1 -(2-(i- pipeiidiny3)phenyl)-butyl)amino)-2-oxoethyi)benzoic acid), nateglinide (3-phenyl- 2-(4-propan-2-ylcyclohexyl)carbonylamino-propanoic acid), and mitiglinide ((25)- 2-benzy3-4-[(3ai?,7a,Sj-octahydro-2H-isoindol- 2-yl]-4-oxobutanoic acid))
  • Biguanidcs e.g., metformin (N,N-dimethylimidodicarbonimidic diamidc), phenformin (2-(A / -phenethylcarbamimidoyl)guanidine), and buformin (2-butyl-I - (diaudinomethyliderie)guanidine)
  • Alpha-ghicasidase inhibitors e.g., miglitol ((2i?,3R,4R,5S)-l-(2-hydroxyethyl)-2- (hydroxynietliyl)piperidisie-3,4,5-triol), acarbose ((2i?,3/?,4 ?,5S,6 ?)-5- ⁇ [(2ii,3i?,4i? ! 55,6i?)-5- ⁇ [(2i? 5 3J?,45 5 1 S' 5 6i?)-3 ! 4-dihydroxy-6-methyl-5-
  • miglitol ((2i?,3R,4R,5S)-l-(2-hydroxyethyl)-2- (hydroxynietliyl)piperidisie-3,4,5-triol)
  • acarbose ((2i?,3/?,4 ?,5S,6 ?)-5- ⁇ [(2ii,3i?,4i?
  • GLP Glucagon-like peptide
  • Amylin analogues e.g., pramlintide acetate (Symlin)
  • Dipeptidyl peptidase-4 (DPP-4) inhibitors e.g., vildagliptin, (25)-l- ⁇ 2-[(3- hydroxy- l-adamantyr)amino]acetyl ⁇ pyrrolidine-2-carbonitrile and sitagliptin ((3 ?)-3-amino-l -[9-(trifluoromet yl)-l ,4,7,8-tetrazabicyclo[4.3.0]nona-6,8-dien- 4-yl]-4-(2,4,5-trifluoroplieny3)butan- 1 - one)), and
  • Tliiazolidinediones e.g., rosiglitazone, 5-((4-(2-(raethyl-2-pyridinylamino) etlioxy)pheayl)meihyI)- 2,4-thiazoIidinedione, pioglitazone (5-((4-(2-(5-ethyI-2- pyridinyl)etlioxy)pheny ⁇ )methy1)-,(+--)- 2,4-tliiazolidinedione,) and troglitazone (5- (4-((6-hydroxy-2,5,7,8-tetramethylc roman-2-yl-met oxy)benzy )-2 ,4- thiazolidinedione)).
  • rosiglitazone 5-((4-(raethyl-2-pyridinylamino) etlioxy)pheayl)meihyI)-
  • the invention also comprises as another embodiment, a. method for inducing increased GLP-1 secretion in cell, in vitro, comprising contacting the cell with an inducing effective amount of a TGR5 agonist compound according to any one of the preceding embodiments.
  • the invention also comprises as another embodiment the use of an effective amount of a TGR5 agonist compound according to any one of the preceding embodiments for the preparation of a medicament for treating a metabolic disease in a subject in need of such treatment.
  • the invention also comprises as another embodiment, the use of an effective amount of a TGR5 agonist compound according to any one of the preceding embodiments for the preparation of a medicament for treating obesity or type II diabetes in a subject in need of such treatment.
  • the invention also comprises as another embodiment, the use of an effective amount of a TGR5 agonist compound according to any one of the preceding embodiments for the preparation of a medicament for treating hyperlipidemia in a subject in need of such treatment.
  • the invention also comprises as another embodiment, the use of an effective amount of a TGR5 agonist compound according to any one of the preceding embodiments for the preparation of a medicament for treating atherscierosis in a subject in need of such treatment.
  • the invention also comprises as another embodiment, the use of an effective amount of a TGR5 agonist compound according to any one of the preceding embodiments for the preparation of a medicament for lowering blood glucose in a subject in need of such treatment.
  • the invention also comprises as another embodiment, the use of an effective amount of a TGR5 agonist compound according to any one of the preceding embodiments for the preparation of a medicament for enhancing insulin secretion in a subject in need of such treatment.
  • the invention also comprises as another embodiment, the use of an effective amount of a TGR5 agonist compound according to any one of the preceding embodiments for the preparation of a medicament for treating a disease associated with perturbed bile acid metabolism in a subject in need of such treatment.
  • the invention also comprises as another embodiment, the use of an effective amount of a TGR5 agonist compound according to any one of the preceding embodiments and a second anti-diabetic drug for the preparation of a medicament for treating obesity or type II diabetes in a subject in need of such treatment.
  • Administration of the compounds of this disclosure, or their pharmaceutically acceptable salts, in pure form or in an appropriate pharmaceutical composition can be carried out via any of the accepted modes of administration or agents for serving similar utilities.
  • administration can be, for example, orally, nasally, parenteral!' (intravenous, intramuscular, or subcutaneous), topically, transdermallv, intravaginally, intravesically, intracistemally, or rectally, in the form of solid, semi-solid, lyophiiized powder, or liquid dosage forms, such as for example, tablets, suppositories, pills, soft elastic and hard gelatin capsules, powders, solutions, suspensions, or aerosols, or the like, preferably in unit dosage forms suitable for simple administration of precise dosages.
  • compositions will include a conventional pharmaceutical carrier, excipient, and/or diluent and a compound of this disclosure as the/an active agent, and, in addition, can include carriers and adjuvants, etc,
  • Adjuvants include preserving, wetting, suspending, sweetening, flavoring, perfuming, emulsifying, and dispensing agents. Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It can also be desirable to include isotonic agents, for example sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin.
  • a pharmaceutical composition of the compounds in this disclosure can also contain minor amounts of auxiliary substances such as wetting or emulsifying agents, pH buffering agents, antioxidants, and the like, such as, for example, citric acid, sorbitan monoiaurate, triethanolamine oleate, butylalted hydroxytoluene, etc.
  • auxiliary substances such as wetting or emulsifying agents, pH buffering agents, antioxidants, and the like, such as, for example, citric acid, sorbitan monoiaurate, triethanolamine oleate, butylalted hydroxytoluene, etc.
  • formulations depend on various factors such as the mode of drug administration (e.g., for oral administration, formulations in the form of tablets, pills or capsules are preferred) and the bioavailability of the drug substance.
  • pharmaceutical formulations have been developed especially for drugs that show poor bioavailability based upon the principle that bioavailability can be increased by increasing the surface area i.e., decreasing particle size.
  • U.S. Pat. No. 4,107,288 describes a pharmaceutical formulation having particles in the size range from 10 to 1 ,000 nm in which the active material is supported on a crosslinked matrix of macromolecules.
  • 5,145,684 describes the production of a pharmaceutical formulation in which the drug substance is pulverized to nanoparticles (average particle size of 400 nm) in the presence of a surface modifier and then dispersed in a liquid medium to give a pharmaceutical formulation that exhibits remarkably high bioavailability.
  • compositions suitable for parenteral injection can comprise physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanoi, polyols (propyieneglycol, po!yeihylenegiyeol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants.
  • One preferable route of administration is oral, using a convenient daily dosage regimen that can be adjusted according to the degree of severity of the disease-state to be treated.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is admixed with at least one inert customary excipient (or carrier) such as sodium citrate or dicalcium phosphate or
  • fillers or extenders as for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid
  • binders as for example, cellulose derivatives, starch, alignates, gelatin, polyvinylpyrrolidone, sucrose, and gum acacia
  • humectants as for example, glycerol
  • disintegrating agents as for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, croscarmellose sodium, complex silicates, and sodium carbonate
  • solution retarders as for example paraffin
  • absorption accelerators as for example,
  • Solid dosage forms as described above, can be prepared with coatings and shells, such as enteric coatings and others well known in the art. They can contain pacifying agents, and can also be of such composition that they release the active compound or compounds in a certain part of the intestinal tract in a deiayed manner. Examples of embedded compositions that can be used are polymeric substances and waxes. The active compounds can also be in microencapsulated form, if appropriate, with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. Such dosage forms are prepared, for example, by dissolving, dispersing, etc., a compound(s) of this disclosure, or a pharmaceutically acceptable salt thereof, and optional pharmaceutical adjuvants in a carrier, such as, for example, water, saline, aqueous dextrose, glycerol, ethanoi and the like; solubiiizing agents and emulsiiiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3- butylenegfycol, dimethylformamide; oils, in particular, cottonseed oil, groundnut oil, com germ oil, olive oil, castor oil and sesame oil, glycerol, tetra
  • Suspensions in addition to the active compounds, can contain suspending agents, as for example, ethoxylated isostearyl alcohols, pedyoxy ethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like.
  • suspending agents as for example, ethoxylated isostearyl alcohols, pedyoxy ethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like.
  • compositions for rectal administrations are, for example, suppositories that can be prepared by mixing the compounds of this disclosure with, for example, suitable non- irritating excipients or carriers such as cocoa butter, polyethyleneglycol or a suppository wax, which are solid at ordinary temperatures but liquid at body temperature and therefore, melt while in a suitable body cavity and release the active component therein.
  • suitable non- irritating excipients or carriers such as cocoa butter, polyethyleneglycol or a suppository wax, which are solid at ordinary temperatures but liquid at body temperature and therefore, melt while in a suitable body cavity and release the active component therein.
  • Dosage forms for topical administration of a compound of this disclosure include ointments, powders, sprays, and inhalants.
  • the active component is admixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants as can be required.
  • Ophthalmic formulations, eye ointments, powders, and solutions are also contemplated for the compounds in this disclosure.
  • Compressed gases can be used to disperse a compound of this disclosure in aerosol form.
  • Inert gases suitable for this purpose are nitrogen, carbon dioxide, etc.
  • the pharmaceutically acceptable compositions will contain about 1% to about 99% by weight of a compound(s) of this disclosure, or a pharmaceutically acceptable salt thereof, and 99% to 1% by weight of a suitable pharmaceutical excipient.
  • the composition will, be between about 5% and about 75% by weight of a compound(s) of this disclosure, or a pharmaceutically acceptable salt thereof, with the rest being suitable pharmaceutical excipients.
  • composition to be administered will, in any event, contain a therapeutically effective amount of a compound of this disclosure, or a pharmaceutically acceptable salt thereof, for treatment of a disease-state in accordance with the teachings of this disclosure.
  • the compounds of this disclosure are administered in a therapeutically effective amount which will vary depending upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of the compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular disease-states, and the host undergoing therapy.
  • the compounds of this disclosure can be administered to a patient at dosage levels in the range of about 0.1 to about 1,000 mg per day. For a normal human adult ha ving a body weight of about 70 kilograms, a, dosage in the range of about 0.0.1 to about 100 mg per kilogram of body weight per day is an example.
  • the specific dosage used can vary.
  • the dosage can depend on a number of factors including the requirements of the patient, the severity of the condition being treated, and the pharmacological activity of the compound being used.
  • the determination of optimum dosages for a particular patient is well known to one of ordinary skill in the art.
  • compositions will include a conventional pharmaceutical carrier or excipient and a compound of this disclosure as the/an active agent, and. in addition, can include other medicinal agents and pharmaceutical agents.
  • Compositions of the compounds in this disclosure can be used in combination with anticancer and/or other agents that are generally administered to a patient being treated for cancer, e.g. surgery, radiation and/or chemotherapeutic agent(s).
  • Chemotherapeutic agents that can be useful for administration in combination with compounds of Formula 1 in treating cancer include alkylating agents, platinum containing agents.
  • the compounds described herein, as well as their pharmaceutically acceptable salts or other derivatives thereof, can exist in isotopieally-labeled form, in which one or more atoms of the compounds are replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature.
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine and chloride, such as Z H (deuterium), 3 H (tritium), ! 3 C, 14 C, i5 N, l8 0, . i ?
  • Isotopically labeled compounds of the present invention as well as pharmaceutically acceptable salts, esters, prodrugs, solvates, hydrates or other derivatives thereof, generally can be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples and Preparations below, by substituting a readily available isotopically labeled reagent for a non- isoiopically labeled reagent.
  • any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom at its natural abundance.
  • a position is designated as "H” or “hydrogen”
  • the position is to be understood to have hydrogen at its natural abundance isotopic composition, with the understanding that some variation of natural isotopic abundance occurs in a synthesized compound depending upon the origin of chemical materials used in the synthesis.
  • D or “deuterium”
  • the abundance of deuterium at that position is substantially greater than the natural abundance of deuterium, which is 0.015%, and typically has at least 50% deuterium incorporation at that position.
  • the methods disclosed herein also include methods of treating diseases by- administering deuterated compounds of the invention or other isotopically-labeled compounds of the invention alone or as pharmaceutical compositions.
  • substitution of hydrogen atoms with heavier isotopes such as deuterium can afford certain therapeutic advantages resulting from greater metabolic stability (for example, increased in vivo half-life or reduced dosage requirements).
  • isotopically-labeled compounds for example those into which radioactive isotopes such as 3 H and l4 C are incorporated, are useful in drug and/or substrate tissue distribution assays such as positron emission tonography (PET). Tritiated, ( 3 H) and carbon- 14 ( i 4 C) isotopes are useful for these embodiments becau:
  • L° is a divalent moiety linking R m to the parent structure.
  • particular members defining L D may be written, for example, in the form -X-Y- or -Y-X-.
  • groups such as alkyl groups, arc part of a linker, these groups are also divalent moieties.
  • administering and variants thereof (e.g., “administering” a compound) in reference to a compound of the invention means introducing the compound or a prodrug of the compound into the system of the animal in need of treatment.
  • a compound of the invention or prodrug thereof is provided in combination with one or more other active agents (e.g., surgery, radiation, chemotherapy, and the like)
  • “administration” and its variants are each understood to include concurrent and sequential introduction of the compound or prodrug thereof and other agents.
  • Alkoxy means the group -OR wherein R is alkyl, as defined herein. Representative examples include methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, 4-methylh.exyloxy, 4-memyJ.h.eptyloxy, 4, 7-dimethyloctyloxy , and the like.
  • Alkoxycarbonyl means an alkoxy group, as defined herein, appended to a parent moiety via a. carbonyl group (i.e., a. group of the form, -C(0)OR°, wherein R° is alkyl, as defined herein).
  • alkoxycarbonyl groups include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, t-butoxycarbonyl, and n- hexylcarbonyl.
  • alkyl means a linear or branched hydrocarbon group having from 1 to 10 carbon atoms unless otherwise defined.
  • Representative examples for alkyl groups include methyl, ethyl, propyl, butyl, pentyl, hexyl, 4-methylhexyl, 4-methylheptyl, 4,7-dimethyloctyl, and the like.
  • -(CrC ⁇ alkyL which means exactly the same as (Chalky!, includes groups selected
  • Alkyl amino means an alkyl group, as defined herein, appended to a parent moiety through an -NH- group (i.e. , substituents of the form - (H)R°, where R° is an alkyl group).
  • alkylamino groups include, but are not limited to, methylamino, ethylami.no, isopropylamino, exylamino, and the like.
  • Alkylaminocarbonyl'' means an alkylamino group, as defined herein, appended to a parent moiety via a carbonyl group (i.e., a group of the form, -C(0)N(H)R°, wherein R° is alkyl, as defined herein).
  • alkylaminocarbonyl groups include, but are not limited to, methylaminocarbonyl, et ylaminocarbonyi, isopropylaminocarbonyl, t- butylaminocarbonyi, and n-hexyiaminocarbonyl,
  • Amino means a -NH 2 group.
  • Al means a monovalent, monocyclic, or polycyclic radical having 6 to 14 ring carbon atoms.
  • the monocyclic aryi radical is aromatic and whereas the polycyclic aryl radical may be partially saturated, at least one of the rings comprising a polycyclic radical is aromatic.
  • the polycyclic aryi radical includes fused, bridged, and spiro ring systems. Any 1 or 2 ring carbon atoms of any nonaromatic rings comprising a polycyclic aryl radical may be replaced by a -C(O)-, --C(S)-, or -C( ⁇ NH)- group. Unless stated otherwise, the valency may be located on any atom of any ring of the aryl group, valency rules permitting. Representative examples include phenyl, naphthyl, indanyl, and the like.
  • Carbonyl means a -C(0)- group.
  • Cvcloalkyl means a monocyclic or polycyclic hydrocarbon radical having 3 to 13 carbon ring atoms.
  • the cvcloalkyl radical may be saturated or partially unsaturated, but cannot contain an aromatic ring.
  • the cvcloalkyl radical includes fused, bridged and spiro ring systems. Examples of such radicals include cyclopropyl, cyciobutyl, cyclopenryl and cyclohexyl.
  • Dialkylamino means two alky] groups, each independently as defined herein, appended to a parent moiety through a nitrogen atom (i.e., substituents of the form -N(R 0 )?, where each R w is an alkyl group).
  • dialkylamino groups include, but are not limited to N. ' N-dimethylamino, N,N-diemylamino, N-isopropyl-M-methylamino, " N-ethyl-N- hexylamino, and the like.
  • Dia(Cx-C 4 alkyl)aminocarbonyl means a dialkylamino group, as defined herein, appended to a parent moiety via a carbonyl group (i.e., a group of the form, -C(O) " (R 0 ) 2 , wherein each R° is alkyl, as defined herein).
  • dialkylamino groups include, but are not limited to N,N-dimethylaminocarbonyl, ⁇ , ⁇ -diethylaminocarbonyl, N-isopropyl-N- methylaminocarbonyl, N-ethyl-N-hexylaminocarbonyi, and the like.
  • fused ring system and "fused ring” refer to a polycyclic ring system that contains bridged or fused rings; that is, where two rings have more than one shared atom in their ring structures.
  • fuscd-polycyclics and fused ring systems are not necessarily all aromatic ring systems.
  • fused-polycyclics share a vicinal set of atoms, for example naphthalene or 1,2,3,4-tetrahydro-naphtiialene.
  • a spiro ring system is not a fused-polycyclic by this definition, but fused polycyclic ring systems of the invention may themselves have spiro rings attached thereto via a single ring atom of the fused-polycyclic.
  • two adjacent groups on an aromatic system may be fused together to form a ring structure.
  • the fused ring structure may contain heteroatoms and may be optionally substituted with one or more groups. It should additionally be noted that saturated carbons of such fused groups (i.e., saturated ring structures) can contain two substitution groups.
  • Halo and halogen mean a fJisoro, chloro, hromo or iodo group.
  • Raloalkyl means an aikyl radical, as defined herein, substituted with one or more halo atoms.
  • halo-substituted includes irifluoromethyl, 2,2-dichloroeihyi, 2,2,2-trifiuoroethyl, perchloroethyl, 2-bromopropyl, and the like.
  • Heteroaryi means a monovalent monocyclic or polycydic radical having 5 to 14 ring atoms of which one or more of the ring atoms, for example one, two, three, or four ring atoms, are heteroatoms independently selected from -0-, -8(0) harm- (n is 0, 1, or 2), -N-, -N(R )-, and the remaining ring atoms are carbon atoms, where R* is hydrogen, aikyl, hydroxy, afkoxy, -C(0)R° or -S(0)2R°, where R° is aikyl.
  • the monocyclic heteroaryi radical is aromatic and whereas the polycyclic heteroaryi radical may be partially saturated, at least one of the rings comprising a polycydic radical is aromatic.
  • heteroaryi includes, but is not limited to, 1 ,2,4-triazolyl, 1,3,5-triazolyl, phthaliraidyl, pyridinyl, pyrrolyL imidazolyl, thienyl, furanyl, indolyl, 2,3-dihydro-lH-indolyI (including, for example, 2,3-dihydro- lH-indol-2-yl, 2,3-dihydro-lH-indol-5-yl, and the like), isoindolyl, indolinyi, isoindoiinyi, benzimidazolyl, benzodioxol-4-yl, benzoturanyl, cinnolinyl, mdolizinyl, naphthyridin-3-yl, phthalazin-3-yl, phthalazin-4-yl, pteridinyl, purinyl, quina
  • the heterocycloalkyl radical may be saturated or partially unsaturated, but cannot contain an aromatic ring.
  • the valency of the group may be located on any atom of any ring within the radical, valency rules permitting. In particular, when the point of valency is located on a nitrogen atom, R y is absent.
  • lieterocycloalkyl includes, but is not limited to, azetidinyl, pyrrolidinyl, 2-oxopyrrolidinyl, 2,5-dihydro- lH-pyrrolyl, ptperidinyl, 4-piperidonyl, morpholinyl, piperazinyl, 2-oxopiperazinyl, tetrahydropyranyl, 2-oxopipericlinyl, thiomorpholinyl, thianK ⁇ holinyl, perhydroazepinyl, pyrazolidinyl, iniidazolinyl, imidazolidinyl, dihydropyridinyl, tetrahydropyridinyl , oxazolinyl, oxazolidinyl, isoxazoiidinyl, thiazolinyl, thiazolidinyl, quinuclidinyl, isothiazolidinyl,
  • Heterocyclylalkyl means a heterocyclyl group appended to a parent moiety via an alkyl group, as defined herein.
  • heterocyclylalkyl groups include, but are not limited to, morpholin-4-ylmethyl, 2-( ⁇ 3 ⁇ 1 ⁇ -4- ⁇ 1)6 ⁇ 13 ⁇ 4 ⁇ , ⁇ 1 ⁇ -2- ⁇ 1 ⁇ 1, 2- (morpholin-2-yl)ethyl, morpholin-3-ylmet.hyl, 2-(morpholin-3-yl)ethyl, piperazin- 1 -ylmethyl, 2-(piperazin- 1 -yl)ethyl, piperidin- 1 -ylmethyl, 2-(piperidin- 1 -yl)ethyl, piperidin-2 -ylmethyl, 2-(piperidin-2-yl)ethyl, piperidin-4-ylmethyl, 2-(piperidin ⁇ 4-yl)ethyi, pyrrolidin- 1 -y
  • Hydroxyalkyl means an alkyl group, as defined herein, substituted with at least one, for example one. two, or three, hydroxy group(s), provided that if two hydroxy groups are present they are not both on the same carbon atom.
  • Representative examples include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, l-(hydroxymethyl)-2-methylbutyl, 2-hydroxybutyi, 3-hydroxybutyl, 4-hydroxybutyl,
  • substitution means the substitution may or may not occur and includes instances where said substitution occurs and instances in which it does not.
  • substituents only sterically practical and/or synthetically feasible compounds are meant to be included.
  • this substitution occurs by replacing a hydrogen that is covIERly bound to the variable with one these substituent(s). This meaning shall apply to all variables that are stated to be substituted or optionally substituted in the specification.
  • variable R L can be optionally substituted with R ' " lU , this means that this substitution, when it occurs, takes place by replacing a hydrogen that is covIERly bound to R with R C1 °.
  • variables that are described in certain instances in the specification as being optionally substituted or substituted with various substituents include, but are not limited to, R D ⁇ A groups, B groups, and R 5 ,
  • Polyethylene glycol are polymers of ethylene oxide.
  • Polyethylene glycol refers to the polymer with molecular weight less than 50,000, A polymer is made by joining molecules of ethylene oxide and water together in a repeating pattern.
  • Polyethylene glycol has the following structure: -(0 ⁇ 2 -(3 ⁇ 4- ⁇ ) ⁇ -.
  • saturated bridged ring system refers to a bicyclic or polycyclic ring system that is not aromatic. Such a system may contain isolated or conjugated unsaturation, but not aromatic or heteroaromatic rings in its core structure (but may have aromatic substitution thereon). For example, hexahydro-furo[3 ,2-6]furan, 2,3,3a,4,7,7a-hexahydro- 1 H-indene, 7-aza-bicyclo[2.2.1 ]heptane and l ,2,3,4,4a,5,8,8a-octaliydro-naphthalene are all included in the class "saturated bridged ring system.”
  • Spiro ring ' refers to a ring originating from a particular annular carbon of another ring. For example, as depicted below:
  • a ring atom of a. saturated bridged ring system (rings C and C), but noi a bridgehead atom, can be a shared atom between the saturated bridged ring system and a spiro ring (ring D) attached thereto.
  • a representative example of a spiro ring system is 2,3-dioxa-8-azaspiro[4.5]decan-8-yl.
  • Isomers means compounds having identical molecular formulae but differing in the nature or sequence of bonding of their atoms or in the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers.” Stereoisomers that are not mirror images of one another are termed “diastereomers” and stereoisomers that are nonsuperimposable mirror images are termed “enantiomers” or sometimes "optical isomers.” A carbon atom bonded to four nonidentical substituents is termed a "c iral center.” A compound with one chiral center has two enantiomeric forms of opposite chirality is termed a “racemic mixture.” A compound that has more than one chiral center has 2 n I enantiomeric pairs, where n is the number of chirai centers.
  • ком ⁇ онентs with more than one chirai center may exist as ether an individual diastereomer or as a mixture of diastereomers, termed a "diastereomeric mixture.”
  • a stereoisomer may be characterized by the absolute configuration of that chiral center. Absolute configuration refers to the arrangement in space of the substituents attached to the chiral center.
  • Enantiomers are characterized by the absolute configuration of their chirai centers and described by the R- and S-sequencing rules of Cahn, In gold and Prelog. Conventions for stereochemical nomenclature, methods for the determination of stereochemistry and the separation of stereoisomers are well known in the art (e.g.
  • N-oxide derivatives mean derivatives of compounds of the invention in which nitrogens are in an oxidized state (i.e. , N ⁇ 0), e.g. , pyridine N-oxide, and which possess the desired pharmacological activity.
  • Methodabolite refers to the break-down or end product of a compound or its salt produced by metabolism or biotransformation in the animal or human body; tor example, biotransformation to a more polar molecule such as by oxidation, reduction, or hydrolysis, or to a. conjugate (see Goodman and Oilman, "The Pharmacological Basis of Therapeutics” 8.sup.th Ed,, Pergamon Press, gilman et al. (eds), 1990 for a discussion of biotransformation).
  • the metabolite of a compound of the invention or its salt may be the biologically active form of the compound in the body.
  • a prodrug may be used such that the biologically active form, a metabolite, is released in vivo.
  • a biologically active metabolite is discovered serendipitously, that is, no prodrug design per se was undertaken.
  • An assay tor activity of a metabolite of a compound of the present invention is known to one of skill in the art in light of the present disclosure, f 0111 J "Patient” and “subject" for the purposes of the present invention includes humans and other animals, particularly mammals, and other organisms. Thus the methods are applicable to both human therapy and veterinary applications.
  • the patient is a mammal, and in another embodiment the patient is human.
  • a "pharmaceutically acceptable salt” of a compound means a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. It is understood that the pharmaceutically acceptable salts are non-toxic. Additional information on suitable pharmaceutically acceptable salts can be found in Remington 's Pharmaceutical Sciences, ⁇ T h ed., Mack Publishing Company, Easton, PA, 1985, or S. M. Berge, et ah, "Pharmaceutical Salts," J. Pharm. Set., 1977;66: 1 -19. It is also understood that the compound can have one or more pharmaceutically acceptable salts associated with it.
  • Examples of pharmaceutically acceptable acid addition salts include those formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; as well as organic acids such as acetic acid, trif!uoroacetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, oxalic acid, maleic acid, malortic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, 3-(4-hydroxybenzoyl)benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1 ,2-ethanedisulfonic acid, 2-hydroxyetbanesulfonie acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthal
  • Examples of a. pharmaceutically acceptable base addition salts include those formed when an acidic proton present in the parent compound is replaced by a metal ion, such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Preferable salts are the ammonium, potassium, sodium, calcium and magnesium salts.
  • Salts derived from pharmaceutically acceptable organic non-toxic bases include, but are not limited to, salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins.
  • organic bases examples include isopropylamine, trimethyl amine, dietbylamine, tnethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, hisiidine, caffeine, procaine, hvdrabamine, choline, betaine, eihylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, tromethamine, N-met ylglucamine, polyamine resins, and the like.
  • Exemplary organic bases are isopropy] amine, diethylamine, ethanolamine, trimetliylamme, dicyclohexylamine, choline, and caffeine.
  • Prodrug refers to compounds that are transformed (typically rapidly) in vivo to yield the parent compound of the above formulae, for example, by hydrolysis in blood.
  • Aommon examples include, but are not limited to, ester and amide forms of a compound having an active form bearing a carboxylic acid moiety.
  • Examples of pharmaceutically acceptable esters of the compounds of this invention include, but are not limited to, alkyl esters (for example with between about one and about six carbons) the alkyl group is a straight or branched chain. Acceptable esters also include cycloalkyl esters and arylalkyl esters such as, but not limited to benzyl.
  • Examples of pharmaceutically acceptable amides of the compounds of this invention include, bur are not limited to, primary amides and secondary and tertiary alkyl amides (for example with between about one and about six carbons).
  • Amides and esters of the compounds of the present invention may be prepared according to conventionai methods. A ihorough discussion of prodrugs is provided in T. Higuchi and V. Stella, "Pro-drags as Novel Delivery Systems," Vol 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drag Design, ed, Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference for ail purposes.
  • “Therapeutically effective amount” is an amount of a compound of the invention, that when administered to a patient, effectively treats the disease.
  • the amount of a compound of the invention which constitutes a “therapeutically effective amount” will vary depending upon a sundry of factors including the activity, metabolic stability, rate of excretion and duration of action of the compound, the age, weight, general health, sex, diet and species of the patient, the mode and time of administration of the compound, the concurrent administration of adjuvants or additional therapies and the severity of the disease for which the therapeutic effect is sought.
  • the therapeutically effective amount for a given circumstance can be determined without undue experimentation,
  • Treating" or "treatment” of a disease, disorder, or syndrome includes (i) preventing the disease, disorder, or syndrome from occurring in a human, i.e., causing the clinical symptoms of the disease, disorder, or syndrome not to develop in an animal that may be exposed to or predisposed to the disease, disorder, or syndrome but does not yet experience or display symptoms of the disease, disorder, or syndrome; (ii) inhibiting the disease, disorder, or syndrome, i.e., arresting its development; and (iii) relieving the disease, disorder, or syndrome, i.e., causing regression of the disease, disorder, or syndrome.
  • Enantiomers can be resolved by methods known to one of ordinary skill in the art, for example by: formation of diastereoisomeric salts or complexes which can be separated, for example, by crystallization; via formation of diastereoisomeric derivatives which can be separated, for example, by crystallization, selective reaction of one cnantiomer with an enantiomer-specific reagent, for example enzymatic oxidation or reduction, followed by separation of the modified and unmodified enantiomers; or gas-liquid or liquid chromatography in a chiral environment, for example on a chiral support, such as silica with a bound chiral ligand or in the presence of a chiral solvent.
  • enantiomer can be synthesized by asymmetric synthesis using optically active reagents, sisbstrates, catalysts or solvents or by converting on enantiomer to the other by asymmetric transformation.
  • enantiomer enriched in a particular enantiomer, the major component enantiomer can be further enriched (with concomitant loss in yield) by reciystaliization.
  • the compounds of this disclosure can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like.
  • the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds of this disclosure.
  • FAF-BSA Fatty acid-free bovine serum TFA iriflmoroaceiie acid
  • Step (by. Formation of carbinol (IV) may be achieved by treatment of aldehyde [) with methylmagnesium bromide in a suitable solvent, such as diethyl ether or THF.
  • a suitable solvent such as diethyl ether or THF.
  • Step (d)i Bromoketone (VI) may be prepared by bromination of ketone (V) under typical conditions, such as with tetrabutylammoniurn tribromidc in 1 :2 mixture of McOH- DCM.
  • Step (f): Isothiocyanate R ⁇ NCS may react with amino-ketone hydrochloride (VII) in a suitable solvent, such as DCM or toluene, and in the presence of a base, such as tnethyiamine, at elevated temperature to yield the corresponding thiourea, which may condense upon treatment with HOAc at elevated temperature to give a compound of formula
  • a suitable oxidant such as mCPBA (2.5- 3.0 eq)
  • a suitable solvent such as DCM
  • Step (i): Thione ( ⁇ ) may be converted to the corresponding sulfonyl chloride (IX) under standard conditions, such as adding NaOCl (3 eq) to thione (I A ) in a 1 : 1 mixture of DCM and IN HQ at reduced temperature, preferably below 0 °C.
  • Step (j): Compounds of formula (i c ) may be prepared by reaction of amine HN( ' R )R D3 with sulfonyl chloride (IX) in a suitable solvent, such as DCM, and in the presence of a base, such as trieihylamine.
  • a suitable solvent e.g. THF
  • Step (m): Imidazole (X) may be converted to the corresponding organolithium, as described previously, and then treated with DMF, preferably at -78 °C for 30-40 minutes, to yield aldehyde (XI).
  • Step (q): Compounds of formula (I G ) may be prepared from carbinol (XII) and a suitable nucleophile HYR m , such as a phenol or thiophenol wherein Y represents O or S, respectively, and R DI is aryl, under Mitsunobu condition— known to one skilled in the an.
  • carbinol (XII) may be converted to the corresponding chloride, for example, by treatment with thionyl chloride (2 eq) in chloroform, followed by reaction with a suitable nucleophile HYR 01 in MeCN (or acetone) and in the presence of a base (e.g. K2CO 3 ) to yield compounds of formula (I G ).
  • a suitable halogen source such as, for example, N-bromosuccinimide in DCM.
  • N-chlorosuccinimide and SelectfluorTM in a suitable solvent such as DCM or MeCN
  • thiol (XVI) may undergo de ⁇ sulfurization to afford triazole (XVII).
  • Step (w): Hydroxymethylation of triazole (XVII) may proceed under standard conditions, such as with paraformaldehyde in toluene heated at reflux, to afford the corresponding hydroxymethyltriazole, which may undergo oxidation upon treatment with a suitable oxidant, such as Mn0 2 , in THF to yield the corresponding aldehyde (XVIII).
  • a suitable oxidant such as Mn0 2
  • a base such as i 2 COj
  • ammonia may react with sulfonyl chloride (XXIX) to yield a sulfonamide (I AO ), wherein both R DU are H. Co .
  • Step (af): Imidazole (X) may be converted to the corresponding organolithiimi, as described previously, and then treated with tosyl azide in a suitable solvent (e.g. THF), preferably at -78 °C for 30 minutes, to yield azide (XXV).
  • a suitable solvent e.g. THF
  • a suitable palladium catalyst preferably Lindlar catalyst
  • a suitable solvent e.g. DCM
  • a base e.g. pyridine
  • Step (r) Under conditions previously described in step (r), imidazole (XXVII) may be brominated to give bromoimidazole (XXVIII).
  • a suitable solvent e.g. acetone
  • a base e.g. potassium carbonate
  • a suitable isocvanate and Lewis acid e.g. aluminum trichloride
  • a suitable solvent e.g. acetone
  • a base e.g. potassium carbonate
  • acid (I v ) may be treated with a suitably protected amino ester (e.g. Alanine methyl ester) and HATU in DCM to afford compounds of formula (i ).
  • a suitably protected amino ester e.g. Alanine methyl ester
  • HATU HATU
  • Step (ar) Under typical Curtius rearrangement conditions, acid (l ) may react with diphenylphosphoryl azide, a suitable alcohol (e.g. tert-butanol), an organic base (e.g. Et ) and toluene at elevated temperature, preferably 80 to 100 C C, to yield compounds of formula (I AB ).
  • a suitable alcohol e.g. tert-butanol
  • an organic base e.g. Et
  • toluene at elevated temperature, preferably 80 to 100 C C, to yield compounds of formula (I AB ).
  • a base such as Et 3 N
  • a base such as Et 3 i
  • Step (1) Reaction of imidazole (X) with butyllithium in a suitable solvent (e.g. THF) at reduced temperature, preferably at -78 °C for 30-40 minutes, may yield the corresponding organolitbium, which may react with a suitable electrophile (e.g. isocyanate or carbamoyl chloride) at the same temperature to afford a compound of formula (I D ).
  • a suitable solvent e.g. THF
  • a suitable electrophile e.g. isocyanate or carbamoyl chloride
  • phenol (XXXIII) may react with carbinol ( ⁇ ) to afford compounds of formula (i AQ ).
  • Phenol ( ⁇ ) may react under standard conditions, for example, with dimethylthiocarbamoyl chloride (1 eq) and DABCO ( 1.25 eq) in NMP at 50 °C, to yield the respective 0-aiyl-thioearbamate (XXXIV).
  • thiophenol (XXXVI) may react with carbinol (XII) to afford compounds of formula. ⁇ : I .
  • ester (I AQ or I AR ) may be hydro lyzed to yield compounds of formula (I A3 ⁇ 4 ), wherein Y is O or S, respectively.
  • acid (I AS ) may react with an amine to afford compounds of formula ( ⁇ ⁇ ), wherein Y is O or S.
  • acid ( ⁇ ' ) may be converted to compounds of formula (I j ) > wherein Y is O or S.
  • amine (I Atj ) may be converted to compounds of formula (I AV ), wherein Y is O or S.
  • a suitable electrophile for example, bromoaikyl-triaikylammonium bromide
  • acid (T BA ) may be coupled with a diamine, such as an aminoalkyltrialkylammonium bromide, to afford compounds of formula (i BB ).
  • a diamine such as an aminoalkyltrialkylammonium bromide
  • compounds of formula (i BC ), wherein R AlJ is Si O ⁇ H? may react with a suitable electrophile, for example, bromoalkyl- trialltylammonium bromide, to give compounds of formula (I BD ), TGR5/CRE-L ciferiase Assay
  • HEK 293 cells stably expressing human TGR5 (h-TGR5) or mouse TGR5 (m- TGR5) can be generated from HEK 293 CRE-Luciferase cells.
  • HEK 293 hTGR5/CRE-Luc cells are plated in DMEM in a 384 well assay plate at a density of 25k cells/45 pL per well and grown for 18-20 hours.
  • Compounds are serially diluted in DMEM containing 5% DMSO and 5 pL of compound or media alone are transferred to each well and plates were incubated for about 6 hours. Following incubation, 30 ⁇ . of lysis/luciferase buffer are added to each well. The luciferase activity is then measured on the EnVision I plate reader and the dose response data, was analyzed using Activity Base.

Landscapes

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

Abstract

TGR5 (a.k.a. GPBAR1) agonists of structural formula l(Q), (Formula I(Q)) wherein X, R1, R2, and R5 are defined in the specification, pharmaceutically acceptable salts thereof, compositions thereof, and use of the compounds and compositions for treating diseases in which TGR5 is a mediator or is implicated. The invention also comprises use of the compounds in and for the manufacture of medicaments, particularly for treating diseases in which TGR5 is a mediator or is implicated.

Description

TGR5 AGONISTS HAVING AN IMIDAZOLE OR TRIAZOLE CORE WITH SUBTITUENT HAVING A QUATERNARY NITROGEN
BACKGROUND OF THE INVENTION
Field of the invention
[0001] 'The invention relates to agonists of the G protein-coupled receptor TGR5, compositions comprising them, methods of making the compounds and compositions and using them for the treatment of diseases TGR5 mediates or is implicated in.
Summary of the Related Art
[0002] Bile acids play essential roles in the absorption of dietary lipids and in the regulation of bile acid biosynthesis. While bile acids have long been known to be essential in dietary lipid absorption and cholesterol eatabolism, in recent years an important role for bile acids as signaling molecules has emerged. Bile acids activate mitogen-activated protein kinase pathways, are ligands for the G-protein-coupled receptor (GPCR) TGR5, and activate nuclear hormone receptors such as farnesoid X receptor a (FXR-a). Through activation of these diverse signaling pathways, bile acids can regulate their own enterohepatic circulation, but also triglyceride, cholesterol, energy, and glucose homeostasis. Thus, bile acid (BA) controlled signaling pathways are promising novel drug targets to treat common metabolic diseases, such as obesity, type Π diabetes, hyperlipidemia, and atherosclerosis, Houten et at. The EMBO Journal (2006) 25, 1419-1425).
[0003] Watanabe et aL ' , Nature 2006, 439(7075) 484-489 showed that the administration of bile acids to mice increases energy expenditure in brown adipose tissue, preventing obesity and resistance to insulin. This novel metabolic effect of bile acids is critically dependent on induction of the cyclic-AMP-dependent thyroid hormone activating enzyme type 2 iodothyronine deiodinase (D2) because it is lost in D2-/- mice. Treatment of brown adipocytes and human skeletal myocytes with bile acids increases D2 activity and oxygen consumption. These effects are independent of FXR-a, and instead are mediated by increased cAMP production that stems from the binding of bile acids with TGR5. In both rodents and humans, the most thermogenieally important tissues are specifically targeted by this mechanism because they coexpress D2 and TGR5. The BA-TGR5-cAMP-D2 signaling pathway is therefore a crucial mechanism for fine-timing energy homeostasis that can be targeted to improve metabolic control,
[0004] Glucagon-like peptide- 1 (GLP-1) is produced by L-cells in the distal digestive tract and affects multiple metabolic parameters, including enhanced insulin secretion. glucagon suppression, and lowering of blood glucose. TGR5 expression in L-cells is linked to increased GLP-1 secretion. Katsuma, el aL, Biochem. Blophys. Res. Cornrnun. 2005, 329(1 ), 386-390) showed that bile acids promote glueagon-like peptide- 1 (GLP-1) secretion through TGR5 in a murine enteroendocrine ceil line STC- 1 . RNA interference experiments showed that reduced expression of TGR5 resulted in reduced secretion of GLP-1. Furthermore, transient transfection of STC- 1 cells with an expression plasmid containing TGR5 significantly enhanced GLP- 1 secretion.
[0005] TGR5 and modulators of it have been the subject of several patent applications:
WO/2008/097976 - Heterocyclic Modulators of TGR5 for Treatment of Disease WO/2008/091540 - Substituted Bile Acids as TGR5 Modulators and Methods of Use WO/2008/067219 - Quinazolinone Modulators of TGR5
WO/2008/067222 - Heterocyclic Modulators of TGR5
WO/2004/067008 - Receptor Agonists
WO/2004/043468 - Screening Method
US 2006/0199795 - Receptor Agonists
US 2008/003 1968 - Methods for increasing Cellular Energy Expenditure
SUMMARY OF THE INVENTION
[ 0006] The present in vention comprises TGR5 agonists of structural formula I(Q),
X---N
11 ^
R5 1^1 H2
R-,
H Q ) wherein X, Rl, R2, and RJ are defined hereinbelow, and pharmaceutically acceptable salts thereof. The invention further comprises compositions comprising the compounds and/or pharmaceutically acceptable salts thereof. The invention also comprises use of the compounds and compositions for treating diseases in which TGR5 is a mediator or is implicated. The invention also comprises use of the compounds in and for the manufacture of medicaments, particularly for treating diseases in which TGR5 is a mediator or is implicated.
DETAILED DESCRIPTION OF THE INVENTION
[0007] All of the compounds of Formulae I(Q), 11, III, IV, V, VI, and VII disclosed herein have quaternary ammonium ion moieties, and it is understood to one skilled in the art that these compounds are all in in the presence of a pharmaceutically acceptable counter ion. The pharmaceutically acceptable counter ion for each of the quaternary ammonium ion moieties present in the compounds of the invention can be any pharmaceutically acceptable counter ion known to one skilled in the art. These compounds with quaternary ammonium ion moieiies have more non-sytstemic effects than with the same compounds without quaternary ammonium ion moieiies. Non-limiting examples of the pharmaceutically acceptable counter ions that can be used include chloride, bromide, sulfate, tosy late, phosphate, tartrate, maleate, acetate, formate, fumarate, mesylate, nitrate, oxalate, ascorbate, citrate, ammonium, arginine, diethylamine, ethylenediamine, magnesium, sodium, calcium, and potassium. It is also understood that the source of the counter ions can be from either intermolecular sources, or, when possible, intramolecular sources.
[0008] The present invention comprises TGR5 agonists of structural formula I(Q):
X-N
R1
H Q )
or pharmaceuticaily acceptable salt thereof, wherein:
X is =N- or =C(R4)-, wherein R4 is H, -(Ci-C3)al¾yl or halo;
R1 is Rc-
Rc is selected from phenyl, -(Cs-C6)-cycloalkyl, -CHj-phenyl, heteroaryl, and -(Ci -C4)alkyl optionally substituted with -ORc'3, -N(Rc l3)2 or -S(RCI 3), wherein
the cyclic group of R1 can be optionally substituted with I , 2, 3, 4 or 5 Ruo groups, wherein the 1 , 2, 3, 4, or 5 Ruo groups are independently selected from RL10A and Rt l 0B, provided that R1 cannot be substituted with more than two u l 0B groups, wherein
each Rc t0A is independently selected from halo, cyano, and -(Ci -C4)alkyl optionally substituted with one, two, or three groups selected from -OH and halo;
each RC i0& is independently selected from -C(0)N¾ (5-6 membered)heterocycloalkyl, -0-(Cx-C4)alkyl-Rc' \ -C(0)ORC12, -OC(0)ORC!2 and -0-(Ci-C4)a3kyi optionally substituted with -OH or -C(0)OH;
Rcn is cyano, nitro, -N(RC12)2) -ORC12, -SRC12, -C(0)RC12, -C(0)ORC12, -C(0)N(RC12)2, -S(0)N(RC12)2, -S(0)2N(RC12)¾ -S(0)2RC! 2, -OC(0)RC12, -OC(0)ORC12, ■OC(0)N(RC12)2, -N(RC 12)C(0)RC12, -N(Rcl2)C(0)ORcl2, -N(RC1 )C(0)N(RC12)2, or -N(RC lz)C(=NR c ! 2)N(RC52)2 ; each RU2 is independently selected from hydrogen, -(Ci-C4)alkyl, and ■■(C| -C4)ha3oaikyi;
each RCLl is independently selected from hydrogen, -(C[-C4)aikyi, and
-(Ct-C4)ha1oa1kyl;
R2 is -LD-RD!;
LD is -[C(R)2]p-Y-[C(R)2]q-;
p is 0 or 1 :
q is 0 or 1 ;
each R is independently selected from H, -(Ci -Chalky 1, halo, -OH, and -CH2OH;
Y is a bond, -S-, -S(0)2-, -CH(OH)-, -0-, -O i l ) (A W )- -C(QHCt-C4)alkyl-, -iCi-C4)alkyl-S-(Ci-C4)alkyi-, -(Ci-C4)alkyl-N(RY)-(Ci-C4)alliyl-, -C(H)(halo)-,
-(Ci -C4)alkyl-S(0)2-, -S(0)2-N(RY)-5 -(Ci-C4)alky]-0-, or -C(0)-N(RY)-, wherein RY is FT, -(C5 -C4)a3kyL hydroxyl(C3 -C4)alkyi or -C=C-(C] -C3)alkyl-:
RD1 is selected from phenyl -(Ce-Cio)afyl, -N(H)-phenyl, -(C5-CV)cyc3oa3kyl, heterocyeloalkyl, or heteroaryi, wherein RD! can be optionally substituted with one, two, three, or four RD1°, wherein the one, two, three, or four RDl° groups are independently selected from A groups and B groups, provided that Rm cannot be substituted with more than two B groups;
each A group, when they occur, is independently selected from halo, -CF3, -CN, --NO2, -OH, -0-(Ci-C4)alkyl optionally substituted at the alkyl group with one, two, or three substitucnts independently selected from -OH and halo, and -(Ci-C4)alkyl optionally substituted with one, two, or three substitucnts independently selected from -OH and halo; each B group, when they occur, is independently selected from -(d -C4)alkylN(RDi i)2, -C(0)-NH2, -C(0}-N(H}-OH, -C(0)-N(H)-RDl lc,
-C(0)-(Ci-C4)alkyl, -C(0)OH, -C(0)0-(C1-C4)alkyl, -S(0)2-(Ci-C4)alkyl-N(RDi , -S(0)2-N(RD1 ^R01 ! c, -S(0)2-N(H)C(0)-(C C4)alky 1, -S(0)2-N(H)C(0)0-(C 1 -C4)alkyl, -S(0)2-N(H)C(0)-N(RD11)RDUB, - Si O - i C Y-C a!k v !. -C(0)-heterocycloalkyl optionally substituted with RD11B; -C(0)-N(H)-(Ci -Cejalkyi optionally substituted at the alkyl group with 1 or 2 RDl lu; heterocyeloalkyl optionally substituted with oxo or RDi l; heterocycloalkenyl optionally substituted with oxo or RDU; heteroaryi optionally substituted with RD"; -0-(C}-C4)alkyl optionally substituted at the alkyl group with i or 2 RDl l B; -S(0)2-(4-6 membered)heterocycloalkyl optionally substituted with R°llC; -N(H)-C(0)-(Ci-C4)alkyl optionally substituted at the alkyl group with 1 or 2 RD1IB; -N(H)-C(0)-N(H)-(Ci-C3)a3kyi optionally substituted at the alkyl group with RJl lh; -(Ci-C6)alkyl optionally substituted with 1 or 2 Rm ib; -C(=NH)-NH2, and -OC- (Ci-C3)alkyi optionally substituted with RD11B;
each RD1 ' is independently selected from H, -(Cs-CeJcycloalkyl, -(Ci-C4)haloalkyl; -OH, ~8(0)2OH, C(O)OH, -NH2„ -N(H)C(= H)NH2; -(Ci-C4)alky1 optionally substituted with halo, -OH or -C(0)OH; -(Ci -Csjalkyl-phenyl optionally substituted at the phenyl group with one, two, or three substituents selected from methoxy, hydroxy! and halo;
RDUB is selected from H, -OH, -CF3, -N(RD! ! )2, -C(0)OH, -0-(Ci-C4)alkyl, -Si O bOI L -C(=NH)-NH2, -N(H)C(-NH)NH2, -( i l l ) NNi S I SCi N ! hN i k
-0-(Ci-C4)alkyl-C(0)OH, -\ \ ) { l \ ) - i \ \ ) { l l )\ \ . (5-6 memberedjheteroaryl, -C(0)-(Ci-C3)alkyl; -(Ci-C4)alkyl optionally substituted with one, two, or three groups independently selected from halo and -OH; -(Ci-C4)alkyl optionally substituted with one, two, or three groups independently selected from halo, -OH, ~8(Ό)2ΟΗ, -C(0)OH, -NH2, and -N(H)C(= H)NH2; -(Co-C3)aikyl-(5-8 membered)heterocycloalkyl optionally substituted with 1, 2, or 3 RDU; -(Co-Cslalkyl-iCs-Cejcycloalkyi optionaily substituted with Ru, t; and -(C6-Cio)aryl optionally substituted with one, two, or three halo;
or RD" and RDH B, when they both exist and are each attached to nitrogen, can join together with the nitrogen to which they are attached to form a (5-6 membered) beterocycloalkyl optionally substituted with a group selected from -OH, -(Ci-C4)haloalkyl, -S(0)2OH, C(0)OH, -NH2, -NiH)C(===NH)NH2, -(C3-C6)cyeloalkyl; -(Ci-C4)alkyl optionally substituted with halo, -OH or -C(0)OH; and -(Ci-C3)alkyl-phenyl optionally substituted at the phenyl group with one, two, or three substituents selected from methoxy, hydroxy! and halo;
RD1 ! C is selected from H, -OH, -CF3, -0-(Ci-C4)alkyl, -(Ci
Figure imgf000006_0001
-(Co-C3)aikyl-(5-6 membered)heteroaryl; -(C i -C4)alkyl optionally substituted with one, two, or three groups independently selected from halo, -OH, -S(0)2OH, C(0)OH, -NH2, and N(H)C(-NH) H2; -(Co-C3)alkyl-(5-6 membered)heterocycloalkyl optionally substituted with a -(5-6 membered)heteroaryl; -(Co-C?)alkyi-(5-6 membered)heterocycioalkyl substituted 1 , 2 or 3 groups selected from selected from -OH and -(Ci-C3)aikyl; and -(Co-C3)alkyl-aryl optionally substituted at the aryl group with one, two. or three halo;
R5 is -[C(R8)2]-QA --[C(R8)2] -phenyl, -[C(R¾-naphthalenyl, or -[C(R8)2]-(5-10 membered) heteroaryl, wherein the heteroaryl is selected from (benzo[d][ 1 ,3]dioxolyl, benzo[d]isoxazolyl, quinoxalinyl. quinolinyl and 2,3,4a,8a-teixahydrobenzo[b] [ l,4]dioxinyl, wherein the cyclic group of R5 is optionally substituted with 1 -5 RA"' groups, wherein the 1-5 R' ' groups are independently selected from R' groups and R* ' groups, provided that R5 cannot be substituted with more than two RA10B groups;
each RA'uA , when they occur, is independently selected from halo, a!koxyl, hydroxy!, -CN, -OCF3, -(Ci-C4)alky1 and - H2,
each RA10B , when they occur, is selected from -0-(Ct-C4)alkyl-RAU, -S(0)2-NH2, •S( O ( 'i i >. -N(H)-S(0)2CH3, -S(0)2N(H)-C¾, -C(0)OH, -(Ci-C4)alkyl-OH, -C(0)NH2, and -(Ci-CVjaikyl substituted with one, two, or three groups seiected from -OH and halo;
RAl i is selected from -C(0)OH, (5-6 membered)heterocycloalkyl, halogen, cyano, nitro, -(CrC4)alkyl, - (RA! 2)2, -ORA12, -SRAl2, -N(ORA l )RA32, -C(0)RA'2, -C(0)ORA12, -C(0)N(RAI )2, -N(RAi )S(0)RA12, -N(RA, 2)S(0)2RAt2, -S(0)N(RA12)2, -S(0)2N(RA12)2, -S(0)2RA12, -GC(0)RA!2, -OC(0)ORA!2, -OC(0) (RA!2)2, - (RAi2)C(0)RA12, -N(RAi2)S(0)2RAi2, -N(RA12)C(0)ORAi2, -N(RA12)C(0)N(RA12)¾
-N(RA¾ )C(===NRA 1 )N(RA!2)2, and heteroar l, wherein each RAl2 is independently hydrogen, ··! ( : ·( '. ! !k i. or -«VC.. !hnk.alkyl:
wherein R5, when R3 is not -[Cfll^-Q^ is substituted with one or two QA groups, wherein R"1 is substituted with QA by replacing a hydrogen that is covalently bonded to carbon or nitrogen;
each R8 is independently hydrogen, halogen, or methyl, or both Rb taken together with the carbon to which they are both attached form either a (Cs-Ceicycloalkyl or a (3-6 memberedjheterocycloalkyl;
QA is Q1' or QR;
Qlj is -N[(Ci-C¾)alkyl] wherein an alky! group of -N[(Ci-(¾alkyr]j!+ is optionally substituted with -(Co-C6)alkyl-S(0)2OH;
QR is selected from:
Figure imgf000008_0001
RQA is -(C[-C6)a3kyl;
RQB is -(Ci-Cf,)alkyl optionally substituted with -C(0)OH; and
RQC is i i . -OH, -(Co--C )alkyl--CQQH or - it , ·( ',; salkv!.
[0010] In another embodiment of the compound of formula I(Q), or a pharmaceutically acceptable salt of any of these embodiments:
X is ( ; R" !··:
each R is independently selected from H, -(Ci-Cs kyi, -OH, and -CH2OH;
Y is -S-, -S(0)2-, -C(H)=C(H)-, -C(O)-, -(Ct-C4)alkyl-S-, -(Ci-C4)alkyI-N(R'i')-, -C(H)(halo)-, ( C i C ., )«lky! SiO . -S(0)2-N(RY)-, , C ; ;3 ikyi 0 . or -C(0)-N(RY)-, wherein RY is H, -(C1-C4)alkyl or hydroxyl(Ci-C4)aikyl;
RD1 is selected from phenyl -(C6-Cio)aryl, -N(H)-phenyl, -(Cs-Cejeyeloalkyi, heterocyeloalkyl, or heteroaryl, wherein RDi can be optionally substituted with 1 , 2, 3 or 4 RbllJ, wherein the 1-4 Rmo groups are independently selected from A groups and B groups, provided that Rm cannot be substituted wit more than two B groups;
each A group, when they occur, is independently selected from halo, -CF3, -CN, -NO?., -OH; -O-iCj -Chalky! optionally substituted at the alkyl group with one, two, or three substituents independently selected from -OH and halo; and -(Ci -Chalky! optionally substituted with one, two, or three substituents independently selected from -OH and halo; each B group, when they occur, is independently selected from -(Ci-C4)alkylN(RD11)2, -C(0)-NH2, -C(0)-N(H)-OH, -C(0)-N(H)-RDUC,
-C(0)-(Ci-C4)a11 yl, -C(0)OH, · ( (())()·(( laik l. - Si O b-i C ·(' , )aikv !..\( : K -S(0)2-N(RD1 l)RD] 5 c, -S(0)2- (H)C(0)-(Ci-C4)alkyl, -S(0)2- (H)C(0)0-(Ci-C4}alkyl, -S(0)2-N(H)C(0)-N(RDU) RD B,
Figure imgf000009_0001
-C(0)-lieierocycioalkyl optionally substituted with RDH B; -C(0)-N(H)-(Ci-C6)alkyl optionally substituted at the alkyl group with I or 2 RD, 1B; heterocycloalkyl optionally substituted with oxo or RD ; heterocycloalkenyl optionally substituted with oxo or RDU; heteroaryl optionally substituted with RDU; -0-(Ci-C4)alkyl optionally substituted at the alkyl group with 1 or 2 RollB; -S(0)2-(4-6 membered)heterocycloalkyl optionally substituted with RDi ""; -N(H)-C(0)-(Ci-C4)alkyl optionally substituted at the alkyl group with 1 or 2 R!ji ld; -N(H)-C(0)-N(H)-(Ci -C6)alkyl optionally substituted at the alkyl group with ROUB; -(Ci-C6)alkyl optionally substituted with 1 or 2 RDUB; -C(=NH)-NH2; and -C≡C-(Cj -C3)alkyl optionally substituted with RDi i B;
each R is independently selected from H, -(C3-C6)cycloalkyl, -(Ci-C4)lialoaIkyl; -OH, -Si O H)! I . Ci0)0H, -NH2, -N(H)C(=NH) H2; ~(Ci-C4)alkyl optionally substituted with halo, -OH or -C(0)OH; -(Cj -Csjalkyl-phenyl optionally substituted at the phenyl group with one, two, or three substituents selected from methoxy, hydroxyl and halo;
RDl iB is selected from H, -OH, -CF3, - (RDU)2, -C(0)OH, -0-(Ci-C4)a]kyl, -8(0)2OH, ··( '{ M l s-N l b. -N(H)C(===NH)NH2, ■( ; ! ! ) NXi l UCi ΝΠ ;N I i >.
-0-<Ci-C4)aIk}d-C(0)OH, -N(H)C(=NH)-N(H)C(=NH)NH2, (5-6 membered)heteroaryl, -C(0)-(Ci-C3)a1kyl; -(Ci~C4)alkyl optionally substituted with one, two, or three groups independently selected from halo and -OH; -(Ci-C4)alkyl optionally substituted with one, two, or three groups independently selected from halo, -OH, -S(Q)?OH, -C(0)OH, -NH2, and -N(H)C(=NH)NH2; -(Co-C3)alkyl-(5-8 membered)heterocycloalkyl optionally substituted with 1, 2 or 3 RDU; -(C0-C3)a]kyl-(C3-C6)cycioalkyl optionally substituted with Rmi; and -(C6-Cio)aryl optionally substituted with one, two, or three halo;
or R°! l and RW ! B, when they both exist and are each attached to nitrogen, can join together with the nitrogen to which they are attached to form a (5-6 membered) heterocycloalkyl optionally substituted with a group selected from -OH, -(Ci-Oijhaloalkyl, »S(0)2OH, C(0)OH, -NH2, -N(H)C(=NH)NH2, -(C3-C6)cycloalkyl, -(Ci-C4)alkyl optionally substituted with halo, -OH or -C(0)OH; and -(Ci -C3)alkyi-pkenyi optionally substituted at the phenyl group with one, two, or three substituents selected from methoxy, hydroxyl and halo; and
RDl iC is selected from H, -OH, -CF3, -0-(Cr-C4)alkyl, -(Ci-C4)alkyl-N(H)C(=NH)-NH2, -(Co-C3)alkyl-(5-6 membered)heteroaryl; -(C[-C4)alkyl optionally substituted with one, two, or three groups independently selected from halo, -OH, -S(0)2OH, C(0)OH, -NH2, and N(H)C(-NH)NH2; -(Co-C3)alkyl-(5-6 membered)heterocycloalkyl optionally substituted with a -(5-6 membered)heteroaryl; -(CQ-C3)alkyl-(5-6 membered)heterocycloalkyl substituted I, 2 or 3 groups selected from selected from -OH and -(CrC3)alkyl; and -(Co-C3)alkyl-aiyl optionally substituted at the aryl group with one. two, or three halo.
[9011] In another embodiment of the compound of formula I(Q), including ail embodiments of the compound of formual i(Q) described above, or a pharmaceutically acceptable salt of any of these embodiments:
X is =C(R4)-;
Y is a bond, -S- . -S(0)2-, -Π Ι ί ( I I. -Si O ) -. -CH(CH3}-8-, -eH(CH3)-S(0)2-, -CH(OH)-, -CH(CH3)-0-, ··( ! () }· . -(CH2)-S-, -Π i ,··\ί R ' i, -CH(halo)-, -CH2-S(0)2-, -S(0)2-N(RY)-, -(CH2)-0-( or -C(0)-N(RY , wherein RY is H, -(Ci-C3)alkyl or hydroxy !(C[ -C3)alkyl;
each R is independently selected from H, -CH3, -OH, F and -CH?OH;
Y is a bond, -S-, -Si O h-. -CH(CH3)-S(0)2-, -CH/CH3)-8-, -CH(C¾)-S(0)2-, -CH(OH)-, -CH(CH3)-0-, .-C(0 , -(CH2)-S-, -CH .-Ni R ' K -CH(hafo)-, -CH2-S(0)2-, -S(0)2-N(RY)-, -(CH2)-0-, or -C(0)-N(RY)-, wherein RY is H, -i C;•C halky! or hydroxy!(Ci-C3)a!kyl,
each R is independently selected from H, -(¾, -OH, F, and -CH2OH;
RD1 is selected from phenyl, -N(H)-phenyl,
Figure imgf000010_0001
-(5-6
membered)heterocycloalkyl, -(5-6 membered)heteroaryl-(5-6 memberedjheteroeycloalkyl, and -(5-6 memberedjheteroaryl, wherein RDl is optionally substituted with 1 , 2, or 3 RDi 0, wherein the one, two, or three RD1° groups are independently selected from A groups and B groups, provided that RD1 cannot be substituted with more than one B group;
each A group, when they occur, is independently selected from halo, -CF3, -CN, -NO2, -OH; -0-(Ci-C4)alkyl optionally substituted with one, two, or three substituents independently selected from -OH and halo; and -(CrC4)alkyl optionally substituted with one, two, or three substituents independently selected from -OH and halo;
the B group is selected from -0-(Ci-C4)alkyl-C(0)OH, -0-(Ci -C4)alkyl, -0-(Ci-C4)alkyl-C(0)-(Ci-C3)alkyl, -0-(Ci-C )alkylN(RDII)2, -(Ci-C4)alkyl-C(0)OH, -(5-6 membered)heteroaryl, -C(=NH)-NH2, -S(0)2-N(H)C(0)-(Cl-C4)alkyL
-S(0)2-N(H)C(0)0-(CrC4)alkyL -S(0)2- (HiC(0)- (H)-(Ci-C4)alky3, -S(0)2-N(H)C(Q)- (H)-(5-6 memberedjheteroeycloalkyl, -S(0)2-(Ci-C3)alkyl,
-O-iC -C : mlky!Ai ! ] }-( ·( N i l }- \ i k -0-(Ci-C4)alkyl-(5-6 membered)heteroaryl,
-(Ci -C4)alkylN(RD1% ' -C(0)-NH2, -C(0)-N(H)-OH, -C(0)-N(H)-RD11C, -C(0)-(Cj-C3)alkyl, -C(0)OH, -C(0)0-(Ci-C4)alkyl, -S(0)2-NH2; -0-(Ct-C4)alkyl-(5-6 membered)heterocycloalkyl optionally substituted with oxo or methyl; -C(0)-(5-6 membered)heterocyeloalkyl optionally substituted with -S(0)2OH, -C(0)OH, -NH2, or -C(0)-N(FT)-(Ci-Ci)a]kyl optionally substituted at the aikyl group with one or two groups selected from -S(0)2OH, -C(0)OH, -Ni k. and -N(H)C(=NH)NH2; -(5-6 membered)heterocycloalkyl optionally substituted with oxo or D11; -S(0)2-N(H)-(Ci-C4)alkyl optionally substituted at the alky! group with one or two groups selected from -S(0)2OH, C(0)OH, -NH2, and -N(H)C(=NH)NH2; -SiO)2-N(C C3)alk (C C4)alkyi optionally substituted at the (Ci-C4)alk l group with one or two groups selected from -S(0)2OH, C(0)OH, -NH2, and -N(H)C(=NH)'NH2; -S(0)2-(4-6 membered)heterocycloalkyl optionally substituted with -S(0)2OH, C(0)OH, ~NH2, or -N(H)C(=NH)NH2; -N(H)-C(0)-(Ct-C4)a1kyl optionally substituted at the alkyi group with one or two groups selected from -S(0)2OH, C(0)OH, -NH? and -N(H)C(=NH)NH2; -N(H)-C(0)- (H)-(Ci-C3)aIkyl optionally substituted at the alkyi group with -S(0)2OH, C(0)OH, -NH2, or -N(H)C(=NH)NH2; -(CrC6)alkyl optionally substituted with one or two groups selected from -S(0)2OH, C(0)OH, -NH2, and -N(H)C(=NH)NH2; and -C ( '· (Ci-C3)alkyl optionally substituted with one or two groups selected from -S(0)2OH, C(0)OH, ~NH2, and -N(H)C(=NH)NH2;
each RDl i is independently selected from H, -(CrCe.lcycloalkyl, -OH, -S(0)2OH, C(0)OH, -NH2, -N(H)C(=NH)NH2, -(C C4)haioalkyl: -(Ci-C3)alkyl-phenyl optionally substituted at the phenyl group with one, two, or three substituents selected from methoxy, hydroxyl and halo; and -(Ci-C4)alkyl optionally substituted with halo, -OH or -C(0)OH;
RD, !B is selected from H, -OH, -CF3, -N{RR l i)2, -C(0)OH, -0-(Cl-C4)alkyl, •SiO Oi l. · ( ( N! i !- N! k -Ni l i iCi NI I )Ni l >. -C(H)=1MN(H)C(=NH)NH2, (5-6 membered)heteroaryl, - (H)C(=NH)-N(H)C(=NH)NH2, -0-(Ci-C4)alkyl-C(0)OH,
-(Co-C3)alkyl-(5-8 membered)heterocycloalkyl, -C(0)-(C i -C3)alkyl; -(C|-C4)alkyl optionally substituted with one, two, or three groups independently selected from halo and -OH: -(Ci -Chalky! optionally substituted with one or two groups independently selected from halo, -OH, -Si O i. Oi i. C(0)OH, -M l :, and -N(H)C(=NH)NH2; -(Co-C )alkyl-(C3-C6)cycloalkyl optionally substituted with RDl 1; and phenyl optionally substituted with one, two, or three halo; and
RD1 3C is selected from H, -OH, -CF , -0-(Ci-C4.)alkyl; -(Ci-C4)alkyl optionally substituted with one or two groups independently selected from halo, -OH, -S(0) OH, C(0)OH, - H2, and -N(H)C(=NH) H2, -(Co-C3)alkyl-(5-6 membered)heterocycloaikyl; -C(0)-(5-6 membered)heterocycloalkyl optionally substituted with a (5-6 membered)heteroaryl; -(Co-C3.)alkyl-(5-6 membered)heterocycloalkyl substituted with one, two, or three groups selected from -OH and -(d-C3)aikyl; -(Ci-C4)alkyl-] (H)C(=NH)-NH2; -(Co-C.v)alkyl-(5-6 membered)heteroaryl; and -(Co~C )alkyl-phenyl optionally substituted at the phenyl group with one, two, or three halo.
[0012] In another embodiment of the compound of formula I(Q), including ail embodiments of the compound of formual i(Q) described above, or a pharmaceutically acceptable salt of any of these embodiments:
p is 0;
Y is a bond, -S-, -S(0)2-, -CH(CH3)-S(0)2-, -CH(CH3)-S-, -CHiCH3)-8(0)2-, -CH(OH)-, -CH(CH3)-0-, -C(H)=C(H)-, -C(0)-, -(CH2)-S-, -Cl¾-N(RY)-, -CH(halo)-, -CH2-S(0)2-, -S(0)2-N(RY)-, -(CH2)-0-, or -C(0)-N(RY)-, wherein RY is H, -(Cj-C4)aikyl or hydroxy i(C i■( ' ·, Ks ikv i:
each R is independently selected from H, -(d-C2)alkyl, fluoro, -OH, and -CH2OH;
RD1 is selected from phenyl, - (H)-phenyl, cyclohexyl, cyclopentyl, piperidinyl, piperazinyl, pyrrolidinyl, morpliolinyl, 1,2,3,6-ieiraliydropyridine, beteroarylheterocycloalkyl, pyridinyl, oxazolyl, pyrazinyl, quinolinyl, 1,2,4-oxadiazolyl, 1,2,3,4-tetrahydroquinolinyl, and pyrazolyl, wherein R l can be optionally substituted 1 , 2 or 3 RDl°, wherein the one, two, or three RD1° groups are independently selected from A groups and B groups, provided that RDi cannot be substituted with more than one B group;
each A group, when they occur, is independently selected from halo, -CF3, -C , -NO2, -OH; -0-(Ci-C4)alkyl optionally substituted with one, two, or three siibstituents independently selected from -OH and halo; and -(Ci -C4)alkyl optionally substituted with one, two, or three siibstituents independently selected from -OH and halo;
the B group is selected from -0-(Ci-C4)alkyl-C(0)OH, -0-(Ci-C4)alkyl, -0-(C i -C4)alkyl-C(0)-(C i-C3)alkyl, -O-fC j -C4)alkylN(RD1 ¾,
-0-(Cl -C4)alkyi-N(H)-C(=NH)-NH2, -0-(C C4)alkyl-(5-6 membered)heteroa.ryl, »(d -C )alkylN(RD1 % -C(0)-NH2> -C(0)-N(H)-OH, -C(0)-N(H)-RD1 ! C,
-C(0)-(Ci-C4)alkyl, -(Ci-C4)alkyl-C(0)OH, -C(0)OH, -C(0)0-(d-C4)alkyl,
-S(0)2-(d-C4)alkyl-N(RD11)2, -! S(0)2-N¾, -S(0)2-N(H)C(0)-(Ci-C4)alkyl, -S(0)2-N(H)C(0)0-(Ci-C4)alkyl, -S(0)2-N(H)C(0)-N(H)-(d-C4)alkyl, -S(0)2-N(H)C(0)-N(H)-m orphol iny 1 , -S(0)2-NiH)C(0)-N(H)-pyrrohdinyl,
-S(0)2-N(H)C(0)-N(H)-piperidinyl, -S(0)2-CH3, -C(-NH)-NH2, 2,3-dihydro-lH-tetrazoiyi; -0-(d-C4)alkyl optionally substituted at the alkyl group with I or 2 RD! lB; -0-(Ci-C4)alkyl-(5-6 memheredjheterocyeloalkyl optionally substituted with oxo or methyl; -C(0)-heterocycloa.lkyl optionally substituted with -S(0)2OH, C(0)OH or -NH2; -C(0)-N(H)-(Ci-C4)alkyl optionally substituted at the alkyl group with on or two groups selected from -S(0)2OH, C(0)OH, -NH2 and -N(H)C(=NH)NH2; heterocycloalkyl selected from IH-tetrazolyl, piperizinyl, 2,3-dihydro-l,3,4-oxadiazolyl and
4,5-diliydro-l ,2,4-oxadiazolyl optionally substituted with oxo or -(Ci -C4)alkyl; -S(0)2-N(H)-(Ci-C4)alkyl optionally substituted at the alkyl group with one or two groups selected from -S(0)2OH; OO sOH. ~ T2, and -N(H)C(=NH)NH2; -SiO)2-N(C C3)alk l-(C C4)alkyi optionally substituted at the (Ci-C4)alkyl group with one or two groups selected from -S(0)2QH, C(0)OH, -NH2, and -N(H)C(=NH)NH2; -S(0)2-(4-6 membered)heterocycloalkyl optionally substituted with -S(0)2OH, C(0)OH, -NH2, or -N(H)C(=NH)NH2; -N(H)-C(0)-(Ct-C4)a1kyl optionally substituted at the alkyl group with one or two groups selected from -S(0)2OH, C(0)OH, -N¾, and -N(H)C(=NH) H2; -N(H)-C(0)-N(H)-(Ci-C3)alkyl optionally substituted at the alkyl group with a group selected from -Si Oi .Oi l . C(0)OH, -NH2 and -N(H)C(=NH)NH2; (( ; -(',, ialkv! optionally substituted with one group selected from -S(0)2OH, C(0)OH, -NH2 and -N(H)C(=NH)NH2; and -C ( '· (Ci-C3)alkyl optionally substituted at. the alkyl group with one group selected from -S(0)2OH, C(0)OH, -NH2, and - (H)C(-NH)NH2;
each Κΰΐ 1 is independently selected from H, -(Cs-C^cycloalkyl, -(d-C4)alkyl optionally substituted with halo, -OH, or -C(0)OH, -OH, -S(0)2OH, C(0)OH, -NH?, -N(H)C(=NH)NH2; -(Ci-C3)alkyl-phenyI optionally substituted at the phenyl group with one, two, or three substitucnts selected from mct oxy, hydroxy! and alo; and -(Ci-C4)haloaIkyl;
RD, !B is selected from H, -OH, -CF,, -NH2, -C(0)OH, -0-(Ci-C4)alkyl, -8(0)2OH, •Π Ni h- NI l .. -N(H)C(=NH)NH2, -C(H)= (H)C(=NH)NH¾
-N(H)C(=NH)-N(H)C(=NH) H2, -C(0)-(Ci-C3)alkyl; -(Ci-C4)alkyl optionally substituted with one, two, or three groups independently selected from halo and -OH; -(CH2)i -4-C(0)OH, -(Cj -C4)alkyl optionally substituted with one or two groups independently selected from halo, -OH, -S(0)2OH, C(0)OH, -NH2, and -N(H)C(==NH)NH2; -0-(Ci -C4)alkyi-C(0)OH; a heterocycloalkyl selected from morphofinyf, pyrrolidinyl, piperazinyl, and piperidinyl, wherein the heterocycloalkyl can be optionally substituted with one, two, or three RDU; cyclopropanyl; cyclopentyl; imidazolyl; pyridinyl; thiazolyi; l(H)-tetrazolyl; and phenyl optionally substituted with one, two, or three halo,
or R l i and RM l b, when they both exist and are each attached to nitrogen, can join to form a (5-6 membered) heterocycoaikyl optionally substituted with R ; and Rm - is selected from H, -OH, -CF3, -0-(C!-C4)alkyl> -(Ci-C4)alkyl optionally substituted with one or two groups independently selected from halo, -OH, -S(0)2OH, C(0)OH, -NH2 and -N(H)C(=NH)NH2; a heterocycloalkyl selected from morpholinyl, pyrrolidinyl, piperidinyl and piperazinyi, wherein the heterocycloalkyl is optionally substituted with a (5-6 membered)heteroaryl; -Co-C3alkyl-(5-6 membered)heterocycloalkyl, wherein the (5-6 memberedjheterocycloalkyl group of -Co-C3alkyl-(5-6 m.embered)heterocycloalkyl is selected from morpholinyl, pyrrolidinyl, piperidinyl and piperazinyi and wherein the -Co-C3alkyl-(5-6 membered)heterocycloalkyl group is substituted with one, two, or three substituents selected from -OH and
Figure imgf000014_0001
-(Ci-C4)alkyi-N(H)C(=NH)-NH2; -Q-C3alJkyl-iraidazolyl; -Co-C3alkyl-pyridinyl; and -Co-C3alkyl-phenyl optionally substituted at the phenyl group with one, two, or three halo.
[0013] In another embodiment of the compound of formula I(Q), including all embodiments of the compound of formual 1(Q) described above, or a pharmaceutically acceptable salt of any of these embodiments:
X is =C(H)-;
P is 0;
Y is a bond, -S-, -S(0)2-, ··( '! K( I fu-Si O ) . - -CH(CH3)-S», -CH(CH3)-S(0)2-, -CH(OH)-, -CH(CH3)-0-, -C(H)=C(H)-, -C(0)-, -(CH2)-S-, -CH2-N(RY)-, -CH(halo)-, -CH2-S(0)2-S -S(0)2-N(RY)-, -(CH2)-0-, or -C(0)-N(RY)-, wherein RY is H, -(CrC4)a!kyl or hydiOxyi(Ci-C4)alkyl;
each R is independently selected from H, -(Ci-C2)alkyl, fiuoro, -OH, and -CH2OH;
RD1 is selected from phenyl, - (H)-phenyl, cyclohcxyl, cyclopcntyl, piperidinyl, piperazinyi, pyrrolidinyl, morpholinyl, 1,2,3,6-teirahydropyridine, heteroarylheterocycloalkyl, pyridinyl, oxazolyl, pyrazinyl, quinolinyi, 1,2,4-oxadiazolyl, 1,2,3,4-tetrahydroquinolinyl, and pyrazolyl, wherein R01 is substituted with one, two, or three RDl°, wherein the one, two, or three RDK' groups are zero, one, or two A groups and zero or one B group:
each A group, when they occur, is independently selected from halo, -CF3, -C , -NO2, -OH; -0-(Ci -Chalky 1 optionally substituted with one, two, or three substituents independently selected from -OH and halo; and -(Cj -C4)alkyl optionally substituted with one, two, or three substituents independently selected from -OH and halo;
the B group, when it occurs, is selected from -0-(Ci-C4)alkyl optionally substituted at the alkyi group with 1 or 2 RDi l B; -0-(Ci-C4)alkyl-C(0)OH; -O-i C -C a!kyi: -0-(C 1 -C4)alkyl-C(0)-(C i-C3)alky 1 ; -0-(C i -C4)alkylN(RDl ; -0-(Ci-C4)a]kyl-N(H)-C(-NH)- H2; -0-(Ci-C4)alkyl-(5-6 membered)heteroaryl; -0-(Ci-C4)alkyl-(5-6 membered)heterocycloalkyl optionally substituted with oxo or methyl; -(C1~C4)alkylN(RDii)2; -C(0)-NH2; -C(0>N(H)-OH; -C(0)-N(H)-RDUC;
-C(0)-(Ci-C4)alkyl; -C(0)OH; -C(0)0-(Ci-C.i)alkyl; -C(0)- eterocycloalkyl optionally substituted with -S(0)2OH, C(0)OH, or -NH2; -C(0)-N(H)-(Ci-C4)alkyl optionally substituted at the alkyl group with 1 or 2 groups selected from -S(0)2OH, ('·: () :·()! i. -NH2, and ~N(H)C(=NH) H2; -(Ct-C4)alkyl-C(0)OH; 2,3-dihydro-l H-tetrazolyl; heterocycloalkyl selected from 1 H-tetrazolyl, piperizinyl, 2,3 -dihydro- 1 ,3,4-oxadiazolyl, and 4,5-dihydro-l ,2,4-oxadiazolyl, wherein the heterocycloalkyl is optionally substituied with oxo or ~(Ci-C4)alkyl; -S(0)2-(Ci-C4)alkyI-N(Rm l)2; -S(0)2-NH2; -S(OVN(H)-(Ci-C4)alkyl optionally substituted at the alkyl group with 1 or 2 groups selected from -S(0)2OH, C(0)OH, -Ni l : and -N(H)C(=NH)NH2); -S(0)2-N(Ci-C3)alkyl-(Ci-C4)a]kyl optionally substituted at the (Ci-C4)alkyl group with one or two groups selected from -S(0)2OH, C(0)0H, -NH2, and -N(H)C(=NH)NH2; -S(0)2-(4-6 membered)heterocycloalkyl optionally substituted with -S(0)2OH, C(0)OH, - H2 or -N(H)C(=NH)NH2; -S(0)2-N(¾C(0)-(Ci -C4)alkyl; - Si O - Ni ! ! )( i () ;i)-i C -( Vjaiky !:
■•S((3)2vN(H)C(0)--N(H) Cr-C 4)alk /{; .-S(0)2-vN(H)C(0)--N(H)--moq?holinyl; -S(0)2-N(H)C(0)-N(H)-pyrrolidinyl; -S(0)2-N(H)C(0)-N(H)-piperidinyl; ~S(0)2~CH3; -N{H)-C(0)-(Cx-C4)alkyl optionally substituted at the alkyl group with one or two groups selected from -S(0)2OH, C(0)OH, -NH2, and -N(H)C(=NH)NH2; -N(H)-C(0)-N(H)-(Ci-C3)alkyl optionally substituted at the alkyl group with a group selected from -S(0)2OH, C(0)OH, -NH2, and -N(H)C(=NH)NH2; ~(C C6)alkyl optionally substituted with one group selected from -S(0)2OH, C{0)0H, -NH2 and -N(H)C(-NH)NH2; -C(=NH)-NH2; and -OC-(Ci -Chalky! optionally substituted at the alkyl group with one group selected from -S(0)2OH, C(0)OH, - N i l... and -N(H)C(=NH)NH2;
each RDl i is independently selected from H, -(CrCbleycloalkyl, -OH, -S(0)2OH, C(0)OH, -NH2, -N(H)C(=NH)NH2; -(Ci-C4)alkyl optionally substituted with halo, -OH, or -C(0)OH; -(Ci -C;i)aikyl-phenyl optionally substituted at the phenyl group with one, two, or three substituents selected from methoxy, hydroxy! and halo; and -(Ci-C4)haloalkyl;
RDUB is selected from H, -OH, -CF3, -NH2, -C(0)OH, -0-(Ci-C4)alkyl, -8(0)2OH, •Ci Ni b- Ni l... -N(H)C(=NH)NH2) -C(H)=NN(H)C(= H)NH2) -0-(Cr-C4)alky}-C(0)OH,
Figure imgf000015_0001
-C(0)-(C1-C3)aIkyl, -(( i i · ); : -C ( < ) }( ! k cyclopropane, eyclopentyl, imidazole, pyridinyl, thiazolyl, l(H)-tetrazolyl; -(C|-C4)alkyl optionally substituted with one, two, or three groups independently selected from halo and -OH; -(Ci-C/))alkyl optionally substituted with one or two groups independently selected from halo, -OH, -S(0)2OH, C(0)OH, -NH2> a d -N(H)C(-NH)NH2; a heterocycloalkyl selected from morpholinyl, pyrrolidinyl, piperazinyl, and piperidinyl, wherein the heterocycloalkyl is optionally substituted with I , 2 or 3 RlJ"; and phenyl optionally substituted with one, two, or three halo,
or R'"" 1 and R lB, when they both exist and are each attached to nitrogen, can join to form a (5-6 membered) heterocycoalkyi optionally substituted with R3'; and
RD1 !C is selected from H, -OH, -CF3, -0-(Ci-C4)alkyl; -(Ci-Oi)alkyl optionally substituted with one or two groups independently selected from halo, -OH, -S(0)20H, C(0)OH, -NH2, and -N(H)C(=NH)NH2; -(Ci-C4)alkyl-N(H)C(=NH)-NH2; -Co-C3alkyl-imidazolyl; -Co-Cjall yl-pyridmyl; a heterocycloalkyl selected from morpholinyl, pyrrolidinyl, piperidinyl, and piperazinyl, wherein the heterocycloalkyl is optionally substituted with a (5-6 membered Jheteroaryl: -Co-C3alkyl-(5-6 membered)heterocycloalkyl, wherein the (5-6 memberedjheterocycloalkyl group of -Co-C3alkyl-(5-6 membered)heterocyeloalkyl is selected from morpholinyl, pyrrolidinyl, piperidinyl and piperazinyl, and wherein the -(5-6 membered)heterocycloalkyl group is substituted with a one, two, or three groups selected from -OH and -(Ci-COalkyl; and -Co-C3alkyl-phenyl optionally substituted at the phenyl group with one, two, or three halo.
[0014] In another embodiment of the compound of formula I(Q), including all embodiments of the compound of formual i(Q) described above, or a pharmaceutically acceptable salt of any of these embodiments:
X is -C(R4)-;
p is 0;
Y is a bond, -S-, -S(0)2-, -CH(C¾)-S(0)2-, -CH(C¾)-S-, -CH(C¾)-S(0)2-, -CH(OH)-, -CH(CH3)-0-, -O H ) ( ( 1 1 k -C(0 , -(CH2)-S-, -CH2-N(RY)-, -CH(halo , -CH2-S(0)2-, -S(0)2-N(RY)-, -(CH2)-0-, or -C(0)-N(RY)-, wherein RY is H, -(C C4)a!kyl or hydroxy i(Ci-C4)alkyl;
each R is independently selected from H, -(d -C2)alkyl, fluoro, -OH, and -CH2OH;
RD1 is selected from phenyl, -N(H)-phenyl, cyclohexyl, cyclopentyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, 1 ,2,3,6-ietrahydropyridinyl, heteroarylheterocycloalkyl, pyridinyl, oxazolyl, pyrazinyL quinolinyl, 1,2,4-oxadiazolyl, 1 ,2,3 ,4-tetrahydroquinolinyl, and pyrazolyl, wherein RD1 is substituted with 1, 2, or 3 R010, wherein the one, two, or three Rbl° groups are zero, one, or two A groups and one B group; each A group, when they occur, is independently selected from halo, -CF5, -CN, ■NO?, -OH: ~0-(C]-C4)alkyl optionally substituted with one, two, or three substituents independently selected from -OH and halo; and -(Cj -C4)alkyl optionally substituted with, one, two, or three substituents independently selected from -OH and halo;
the B group is selected from -0-(Ci-C4)alkyl-C(0)OH, -0-(Ci -C4)alkyl, -0-(Cj -C4)alkyl-C(0)-(Ci -C3)alkyl, -C(0)OH, -NH2, -(Ci -C4)alkyl-C(0)OH, 2,3-dihydro-lH-tetrazo.lyl, -0-(Ci-C4)alkylN(RD11)2, ·0·· , ··( ., laik i- Ni H ¾·( ί ΝΠ ί- ΧΠ -0-(Ci-C4)a1kyl-(5-6 membered)heteroaryl, -(d-C alkyl CR011)?., -C(0)-NH2, -C(0)-N(H)-OH, -C(0)-N(H)-RD1 1C, -C(0)-(Ci-C4)alkyl, -C(0)0H, -C(0)0-(Ci-C4)alkyl, -S(0)2-(Ci-C4)alkyl-N(RD11 )2, -S(Q)2-NH2, -S(0)2-N(H)C(0)-(Ci-C4)alkyl,
-S(0)2-N(H)C(0)0-(CrC4)alkyl, -S(0)2-N(H)C(0)-N(H)-(Ci-C4)alkyl, -S(0)2-N(H)C(0)-N(H)-morpholiny], -S(0)2-N(H)C(0)-N(H)-pyrrolidinyl, -S(0)2-N(H)C(0)-N(H)-piperidinyl, -S(0)2-CH3, -C(=NH)-NH2; -0-(d -C4)alkyl optionally substituted at the alkyl group with one or two RD5 5 B; -0-(C1-C4)alkyl-(5-6 membered)heterocycloalkyl optionally substituted with oxo or methyl; -C(0)-heterocycloalkyl optionally substituted with -S(0)2OH; -C(0)-N(H)-(Ci -C4)alkyl optionally substituted at the alkyl group with one or two groups selected from -S(0)2OH; C(0)OH, -NH2 and -N(H)C(-NH) H2; heterocycloalkyl selected from lH-tetrazofyl, piperizinyl, 2 ,3 -dihydro- 1 ,3 ,4-oxadiazolyl, and 4,5-dihydro- 1 ,2,4-oxadiazolyl, wherein the heterocycloalkyl can be optionally substituted with oxo or -(CVC4)alkyi; -S(0)2-N(tf)-(Ci-C4)alkyl optionally substituted at the alkyl group with one or two groups selected from -S(0)2OH, C(0)OH, -NH2, and -N(H)C(=NH)NH2; -S(0)2-N(C1-C3)all{yl-(Ci-C4)alkyl optionally substituted at the (Ci-C4)alkyl group with one or two groups selected from -S(0)2OH, -C(0)OH, -NH2, and -N(H)C(=NH)ISlH2; -S(0)2-(4»6 menibered)heterocyeloalkyl optionally substituted with -S(0)2OH, C(0)OH, -NH2, or -N(H)C(=NH)NH2; -N(H)-C(0)-(Ct-C4)alkyl optionally substituted at the alkyl group with one or two groups selected from -S(0)2OH, C(0)OH, -N¾, and -N(H)C(=NH) H2; ~N(H)~C(O)- (H)-(Ci-C: alkyl optionally substituted at the alkyl group with a group selected from -S(0)2OH, C(0)OH, -NH2 and -N(H)C(=NH)NH2; -(d-C6)alkyl optionally substituted with one group selected from -S(0)2OH, C(0)OH, -Nil-, and -N(H)C(-NH)NH2; and -C≡C- (Ci-C3)alkyl optionally substituted at the alkyl group with one group selected from -S(0)2OH, C(0)0H, -NH.2 and -N(H)C(=NH)NH2;
each Rba is independently selected from H, -(C}-Ce)cycloalkyl, -OH, -(Ci-C )haloalkyl -S(0)2OiL C(0)OH, - H2, -N(H)C(-NH) H2; -(Ci-C4)alkyl optionally substituted with halo, -OH or -C(0)OH; and -(Ci -C3)alkyl-phenyl optionally substituted at the phenyl group with one, two, or three substituents selected from niethoxy, hydroxy! and halo;
RD1 1B is selected from H, -OH, -CF3, - H2, -C(0)OH, -0-(Ci-C4)alkyl, -S(0)3OH, -a Χί Η Π ,. -Ni ! l jU N ! I )NM.>. -C(H)=N (H)C(= H)NH2,
Figure imgf000018_0001
-C(0)-(Ci-C3)alkyl, -0-(Ci-C4)alkyl-C(0)OH,
-(CH2)i-4-C(0)OH, cyclopropanyl, cyclopentyl, imidazolyl, pyridinyl, thiazolyl, l (H)-tetrazolyl; -(Ci-C4)alkyl optionally substituted with one, two, or three groups independently selected from halo and -OH; -(Ci-C4)alkyl optionally substituted with one or two groups independently selected from halo, -OH, -S(0)2OH, C(0)OH, -NH2i and -N(H)C(=NH)NH2; a heterocycloalkyl selected from morpholinyl, pyrrolidinyl, piperazinyl, and piperidinyl, wherein the heterocycloalkyl Is optionally substituted with 1, 2 or 3 Rm i; and phenyl optionally substituted with one, two, or three halo;
or Rlj! ' and RDUB, when they both exist and are each attached to nitrogen, can join to form a (5-6 membered) heterocycoalkyi optionally substituted with R1*; and
RD, !C is selected from H, -OH, -CF3, -0-(Ci-C4)alkyl,
Figure imgf000018_0002
-C0-C3alkyl -imidazolyl, -Co-C3alkyl-pyridinyl;
-(Ci-C4)alkyl optionally substituted with one or two groups independently selected from halo, -OH, -S(0)2OH, C(0)OH, -NH2, and -N(H)C(=NH)NH2; a heterocycloalkyl selected from morpholinyl, pyrrolidinyl, piperidinyl and piperazinyl, wherein the heterocycloalkyl is optionally substituted with a (5-6 membered)heteroaryl; -Co-CSa3kyl-(5-6 mcmbercd)hctcrocycloalkyl, wherein the (5-6 mcmbcrcd)hctcrocycloalky3 group of -Co-C3alkyl-(5-6 membered)heterocycloaIkyl is selected from morpholinyl, pyrrolidinyl, piperidinyl, and piperazinyl, and wherein the -Co-C alkyi-(5-6 membered)heterocyc!oalkyi group is substituted with a group selected from one, two, or three groups selected from -OH and -(CrCyalkyl; and -Co-C3alky {-phenyl optionally substituted at the phenyl group with one, two, or three halo,
[0015] In another embodiment of the compound of formula 1(Q), or a pharmaceutically acceptable salt thereof, LD is selected from -(CrC^alkyl-O-, -(Co-C3)alkyl- RY-(C0-C6)alkyl-, -(C0-C3)alkyl-S-(CCrC3)alky}-, -(C0-C3)alkyl-S(0)2-(Co-C3)alkyl-; -C(0)N(RY)-(Co-C3)alkyl-, -S(0)2-N(RY)-(Co-C3)alkyl-, -C(O)-(Co-C3)alkyl-, -C≡C-(Co-C )aikyl-, -(C0-C3)alky{-, and -(C[-C4)alkyl- optionally substituted with halo or -OH. [9016] In another embodiment of the compoimd of formula I(Q), or a pharmaceutically acceptable salt thereof, L° is selected from: -(CH2)i-3-0-, -(CH2)i-3-NRY-f -(Co-C3)alkyl-S-(Co-C3)alJ yi-; -(CH2)i-3-S-, -S-(CH2)i.3, -S(0)2-(CH2)i.3-, -S(0)2-, -C(0)N(H)-(CH2) u3-, -S(0)2-N(H)-(CH2)i-3-, ~C(0)-(CH2V2-, -C≡C-(Co-C3)alky1-, a bond, and -(Ct-C4)alkyl- optionally substituted with ha o or -OH.
[0017] In another embodiment of the compound of formula I(Q), or a pharmaceutically acceptable salt thereof, LD is selected from -(CH2)-0-, -(CH2)-NRY-, -(CH2)-S-, -S-(CH2 , -S(0)2-, -S(0)2-(CH2)-, -C(0)N(RY)-(Co-C3 )aikyl-; -S(0)2-N(H)-(CH2)i..3-, -( i O i-i CH . !, >-. -C≡ -(C2-C3)alkyi-, and -(Ci-C4)alkyl- optionally substituted with halo or -OH.
[0018] In another embodiment of the compound of formula T.(Q), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, wherein: LD is selected from -iCH2)-0-, -(CH2)-NRY-, -(CH2)-S-, -S-(CH2)-, -S(0)2-, -S(0)2-(CH2 , -C(0)N(RY)-(Co-C3)alkyl-, -S; G s>-Xi i · ' H i i i 0; . · . · ( ; Ο Η Π : ··, -C C -{ - (. > )« = =<> !- . and -(Ci-C4)alkyl- optionally substituted with halo or -OH.
[0019] In another embodiment of the compound of formula 1(Q), or a pharmaceutically acceptable salt thereof, LD is selected from -(CH2)-0-, -(CH2)-MH-, -(CH2)-S-, -S-(CH2)-, -S(0)2-, -S(0)2-(CH2)-, -C(0)N(H)-{CH2)i.3-, -S(0)2-N(H)-(CH2)]-3-, -C(0)-(CH2)i.2-, -C=C- (C2-C3)alkyl- and -(Ci-C,i)a3kyl- optionally substituted with halo or -OH.
[0020] In another embodiment of the compound of formula I(Q), or a pharmaceutically thereof, the B group of RDi is selected from:
Figure imgf000019_0001
MT - HH-C-(CH2 3 r and I I
0 Q .
[0021] In another embodiment of the compound of formula I(Q), including all embodiments of the compound of formuai I(Q) described above, or a pharmaceutically acceptable salt of any of these embodiments:
R is phenyl, -CH2-phenyl, -('C's-Cercycloalkyl, or pyridinyi, wherein Rc can be optionally substituted with one, two, or three RC!0, wherein the one, two, or three R'"i0 groups are independently selected from Rcl0A and RU sJt\ provided that Rc cannot be substituted with more than one R.C l0B group; each RC,0A, when they occur, is independently selected from halo; -(Cj -Chalky! optionally substituted with one, two, or three groups selected from halo and -OH; methoxy; -CF3; and halo; and
RC!0B is selected from ~C(0)NH3, (5-6 membered)heterocycloalkyl; -O-(Ci-C.0alkyl optionally substituted with -OH, -C(0)OH, or -N[-(C[-C4)alky3]2; and -(Cx-C4)alkyl substituted with -N[-(Ci-C4)alkyl]2.
[0022] In another embodiment of the compound of formula I(Q), including all embodiments of the compound of formual I(Q) described above, or a pharmaceutically acceptable salt of any of these embodiments:
Rc is phenyl, -CH2-phenyl, -(Cs-Cei-cycloalkyl, or pyridinyl, wherein the cyclic group of Rc can be optionally substituted with one, two, or three R l° groups and, wherein the one, two, or three RC1& groups are independently selected from RL 'A and R 'B, provided that R cannot be substituted writh more than one Rtl0B group;
each R 0A, when they occur, is independently selected from methoxy, -CF3, halo, and -(Ci-C3)alkyl optionaily substituted with one, two, or three groups selected from halo and -OH; and
Rcl 0b is selected from (5-6 membered)heterocycloaiky3; -(Ci~C4)alkyl substituted with -N[-(Ci-C4)alkyl]2; -C(0)NH2; and -0-(C C4)alkyl optionally substituted with -OH, -C(0)OH, or -N[-(Ci-C4)alkyl]2.
[0023] In another embodiment of the compound of formula I(Q), including ail embodiments of the compound of formual 1(Q) described above, or a pharmaceutically acceptable salt of any of these embodiments:
R'' is phenyl, -C¾-phenyl or pyridinyl, wherein the cyclic group of Rc can be optionally substituted with one, two, or three R1"10, wherein the one, two, or three R tJ groups are independently selected from R l0A and R ! oe, provided that Rc cannot be substituted with more than one RCl0B group;
each RCI0A when they occur, is independently selected from -(Ct-C3)alkyl optionally substituted with one, two, or three groups selected from -OH, methoxy, -CF¾ and halo;
RC10B is selected from -C(0) H2; (5-6 membered)heterocycloalkyl ; -(Ci-C4)alkyl substituted with -N[-(Ci-C )alkyl]2; and -0-(Ct-C4)alkyl optionally substitiited with -OH, •CiO iOi l . or -N[-(Ci-C )alkyl]2.
0024J In another embodiment of the compound of formula H Q ), including all embodiments of the compound of formual I(Q) described above, or a pharmaceutically acceptable salt of any of these embodiments: R'~ is phenyl or pyridinyl, wherein the cyclic group of Rc can be optionally substituted with one, two, or three Rc,°, wherein the one, two, or three Rc'° groups are independently selected from Rl'l0A and RC,0B, provided that L cannot be substituted with more than one Rcl0B group;
each RC10A, when they occur, is independently selected from methoxy and halo;
RC10B is selected from -C(0)NH2; (5-6 membered)heterocycloalkyl; -(Ci-C4)alkyl substituted with -N[-(Ci-C4)aIkyl]2; and -0-(Cj -Chalky! optionally substituted with -OH, -C(0)OH, or -N[-(Ci-C,.)alkyl]2.
[0025] In another embodiment of the compound of formula I(Q), including all embodiments of the compound of formual T(Q) described above, or a pharmaceutically acceptable salt of any of these embodiments:
Rc is phenyl or pyridinyl, wherein the cyclic group of RL can be optionally substituted with one or two groups seiected from methoxy, methyl and halo.
[0026] In another embodiment of the compound of formula 1(Q), or a pharmaceutically acceptable salt thereof, R~ is phenyl or pyridinyl, wherein the cyclic group of Rc can be optionally substituted one or two groups selected from methoxy, methyl, fluoro and chloro.
[0027J In another embodiment of the compound of formula I(Q), or a pharmaceutically acceptable salt thereof, R is phenyl substituted with one or two groups selected from methoxy, fluoro or chloro.
[0028] In other embodiments of the compound of formula I(Q), or a pharmaceutically acceptable salt thereof, the compound of formulae I(Q) is one of formula IT, III, IV, V, VI or VII:
Figure imgf000022_0001
Figure imgf000022_0002
VI
wherein one of RAI° or R* is substituted with one QA group; wherein this substitution with QA occurs by replacing a hydrogen thai is covaiently bonded to carbon or nitrogen.
[0029J In other embodiments of the compound of Π, 111, IV, V, VI or VII, or a pharmaceutically acceptable salt thereof:
each RC1° is selected from fluoro, chioro and methoxy;
R2is -LD-RD1, wherein:
LD is selected from -(CH2)-0-, -(CH2>NH-, -(CH2)-S-, -S-(CH2)-, -S(0)2-, -S(0)2-(CH2)-, CiOiXili! (Cll,)i .. -S(0)2-N(H)-(CH2)]-3-, lO) (Ul.j: ■ : -(Ci-C3)alkyl- optionally substituted with halo or -OH; and -CsC-(C2-03)alkyl; and
D1 is one of:
Figure imgf000022_0003
wherein each A is chioro or fluoro, and B is selected from:
Figure imgf000023_0001
[0030] In another embodiment of the compound of formula I(Q), including all embodiments of the compound of formual I(Q) described above, or a pharmaceutically acceptable salt of any of these embodiments:
LD is selected from -( CM > }»<)··. -: ( '! ί > )· ΝΙ I· . -i i i l -S- . S i f ! I - 1 -S(0)2-, -S(0)2-(CH2)-, -C(0)N(H)-(CH2)i -S(0)2-N(H)-(CH2)i -C(0)-(CH2)i-2-; -( (VC' i ialky]- optionally substituted with halo or -OH; and -C=C-(C2-C3)alkyl-.
[0031] In another embodiment of the compound of formula I(Q), including all embodiments of the compound of formual i(Q) described above, or a pharmaceutically acceptable salt of any of these embodiments:
LD is selected from -S-(Ci-C3)alkyl-, -(CH2)2-, and -(Ci -C3>alkyl-0-.
[0032] In another embodiment of the compound of formula I(Q), including all embodiments of the compound of formual I(Q) described above, or a. pharmaceutically acceptable salt of any of these embodiments:
R5 is -[C(CH3)2]-phenyl, -[C(CH3)2]-naphthalenyl, or -[C(CH3)2]-(5-10 membered) heteroaryl, wherein the heteroaryl is selected from benzo[d][l,3]dioxolyl, benzo[d]isoxazolyl, quinoxalmyl, quinolinyl, and 2,3,4a,8a-tetrahydrobenzo[b][l,4]dioxiny3, wherein the cyclic group of R3 optionally substituted with one, two, or three RAL° groups, wherein the one, two, or three RAL° groups are independently selected from RAi0a and RA!0B, provided that R^ cannot be substituted with more than one RAI0B group;
each RAl0A, when they occur, is independently selected from halo, -(Ci-C3)alkoxyl and hydroxy!;
RA10B is -(C] -C4)alkyl optionally substituted with one, two, or three groups selected from -OH and halo; -0-(Ci-C4)alkyl-C(0)OH; 0-(Ci-C4)alkyl-N[(Ci-C3)alk l]2; -NH2;, -S(0)2-NH2; -SO2CH3; -N(H)-S02CH3; -S02M(li)-CH3; -CN; -C(0)OH; -(Ci-C4)alkyl-OH; -OCF3; or -C{0)N¾; and
wherein RJ is substituted with one QA group, wherein R5 is substituted with QA by replacing a hydrogen that is covalently bonded to carbon or nitrogen. [9033] In another embodiment of the compound of formula I(Q), including all embodiments of the compound of formuai I(Q) described above, or a. pharmaceutically acceptable salt of any of these embodiments:
R5 is -[Ci CFTsjjJ-pheny], and the phenyl group of R5 is optionally substituted with one, two, or three RA1° groups, wherein the one, two, or three RA1° groups are independently- selected from RA10A and RA'wB, provided that R5 cannot be substituted with more than one R group;
each R"1&A, when they occur, is independently selected from halo, methoxy, and hydroxy!;
RA10B is ~0-(C| -C4)aIkyl-C(0)Oa 0-(Ci-C4)alkyl-N[(Ci-C3)alkyl]2, -NH2, -S(0)2-NH2, -SO2CH3, -N(H)-S02CH3, -S¾N(H)-CH3( -CN, -C(0)OH, -(Ci-C4)alkyl-OH, -OCF3, -C(0)NH2, or -(Ci-C4)alkyl optionally substituted with one, two, or three groups selected from -OH and halo; and
wherein R" is substituted with one QA group, wherein R5 is substituted with QA by replacing a hydrogen that is covalently bonded to carbon or nitrogen
[0034] In another embodiment of the compound of formula I(Q), including all embodiments of the compound of formuai T(Q) described above, or a pharmaceutically acceptable salt of any of these embodiments:
R5 is -[C(CH3)2]-phenyl, wherein the phenyl group is optionally substituted with one or two groups selected from halo, methoxy and hydroxy!; and
wherein R5 is substituted with one QA group, wherein R" is substituted with QA by replacing a hydrogen that is covalently bonded to carbon or nitrogen.
[9035] In another embodiment of the compound of formula I(Q), including ail embodiments of the compound of formuai I(Q) described above, or a. pharmaceutically acceptable salt of any of these embodiments:
R5 is -[CiCHsVj-phenyl, wherein the phenyl group is optionally substituted with one or two groups selected from halo and methoxy; and
wherein R5 is substituted with one QA group, wherein RJ is substituted with QA by- replacing a hydrogen that is covalently bonded to carbon or nitrogen.
[9036] In another embodiment of the compound of formula I(Q), including ail embodiments of the compound of formuai I(Q) described above, or a. pharmaceutically acceptable salt of any of these embodiments:
R5 is:
Figure imgf000025_0001
In another embodiment of the compound of Formula I(Q), C is s ubstituted with one, two, three, four, or five Rl iUA groups.
In another embodiment of the compound of Formula I(Q), RC is substituted with zero, one, two, three, or four R OA groups and 1 RL1JB group.
[9039] In another embodiment of the compound of Formula I(Q), R° is substituted with zero, one, two, or three RUuA groups and one or two R'" '0b groups.
[0040] In another embodiment of the compound of Formula I(Q), RDI is substituted with zero, one, two, threeA groups and one B group.
[0041] In other embodiments of the compounds of formula ICQ), or in any of the above embodiments of the compounds of formula. I(Q) described herein as it may apply, or a pharmaceutically acceptable salt, of any of these compounds, RDllB is -(Ci-C4)alkyl optionally substituted with one, two, or three groups independently selected from halo, -OH, -8(0 hOH, C(0)OH,- H2, -N[(C! -€3)alkyl]3 , l,4-diazabicyclo[2.2.2]octanyl, and -N(H)C(=NH)NH2.
[0042] In other embodiments of the compounds of formula I(Q), or in any of the above embodiments of the compounds of formula I(Q) described herein as it may apply, or a pharmaceutically acceptable salt of any of these compounds, RD11B is -(Co~C.5)alkyl~(5-8 membered)heterocycloalkyl optionally substituted at the heierocycloaikyl group with 1 to 3 RM \
In other embodiments of the compounds of formula ICQ), or in any of the above embodiments of the compounds of formula I(Q) described herein as it may apply, or a pharmaceutically acceptable salt of any of these compounds, RD11B is -CCo-C3)alkyl-(C3-C6)cycIoalkyl optionally substituted with RDU.
In other embodiments of the compounds of formula ICQ), or in any of the above embodiments of the compounds of formula. I(Q) described herein as it may apply, or a pharmaceutically acceptable salt of any of these compounds, R0Uli is and optionally substituted with one, two, or three halo.
[9045] The invention also comprises as another embodiment, a composition comprising a TGR5 agonist compound according to any one of the preceding embodiments together with a pharmaceutically acceptable diluent, excipient, and/or carrier. Such compositions are substantially free of non-pharmaceutically acceptable components, i.e., contain amounts of non-pharmaceutically acceptable components lower than permitted by US regulatory requirements at the time of filing this application. In some embodiments of this aspect, if the compound is dissolved or suspended in water, the composition farther optionally comprises an additional pharmaceutically acceptable carrier, diluent, or excipient.
[0046] The invention also comprises as another embodiment a method for treating or preventing a metabolic disease in a subject in need of such treatment comprising administering to the subject an effective amount of a TGR5 agonist compound according to any one of the preceding embodiments. Metabolic diseases that may be treated or prevented include, without limitation, metabolic syndrome, insulin resistance, and Type 1 and Type 2 diabetes.
[1)047] The invention also comprises as another embodiment a method for treating obesity or type TI diabetes in a subject in need of such treatment comprising administering to the subject an effective amount of a TGR5 agonist compound or pharmaceutical composition according to any one of the preceding embodiments.
[0048] The invention also comprises as another embodiment a method for treating hyperiipidemia in a subject in need of such treatment comprising administering to the subject an effective amount of a TGR5 agonist compound or pharmaceutical composition according to any one of the preceding embodiments.
[0049] The invention also comprises as another embodiment a method for treating athersclerosis in a subject in need of such treatment comprising administering to the subject an effective amount of a TGR5 agonist compound or pharmaceutical composition according to any one of the preceding embodiments.
[9050] The invention also comprises as another embodiment a method for lowering blood glucose in a subject in need of such treatment comprising administering to the subject an effective amount of a TGR5 agonist compound or pharmaceutical composition according to any one of the preceding embodiments.
[0051] The invention also comprises as another embodiment a method for enhancing insulin secretion in a subject in need of such treatment comprising administering to the subject an effective amount of a TGR5 agonist compound or pharmaceutical composition according to any one of the preceding embodiments.
[0052] The invention also comprises as another embodiment a method for treating a disease associated with perturbed bile acid metabolism in a subject in need of such treatment comprising administering to the subject an effective amount of a TGR5 agonist compound or pharmaceutical composition according to any one of the preceding embodiments. Such diseases include, but are not limited to, gall bladder stones, cholecystitis, cholangitis, choledocholitliiasis, jaundice, and obstetric cholestasis and the itch associated with it.
0053| The invention also comprises as another embodiment a method for treating obesity or type TT diabetes in a subject in need of such treatment comprising co-administering to the subject, simultaneously or sequentially, an effective amount of a TGR5 agonist compound according to any one of the preceding embodiments and a second anti-diabetic drug or pharmaceutical composition comprising an effective amount of a TGR5 agonist compound according to any one of the preceding embodiments and a second anti-diabetic drug. Non-limiting examples of anti-diabetic drugs include:
• Sulfonylureas (e.g., tolbutamide (3 -butyl- 1 -(4-raethylphenyl)sulfonylurea), acetohexamide (4-acetyl-N-(cyclohexylcarbamoyl)benzenesu3fonamide), tolazamide (3-azepan-l-yl-l-(4-methylphenyl)siilfonyl-urea), chlorpropamide (Ν- (4-chloropheiiyl)sulfonylmethaiiamide), glipizide (N-[2-[4- (cyciohexy!carbamoylsulfamoyl)phenyi]eth.yl]-5-methyl-pyrazine-2-carboxamide), giybuiide (5-chloro-N-[2-[4-(cyclohexylcarbamoylsulfamoyl)phenyl]eihyl]-2- methoxy-benzamide), glimepiride (3 -ethyl-N,N-bis(3-ethyi -4-met yl-2-oxo-5H- pyrroi-2-yl)-4-metliyl-2-oxo-5H-pyrrole- 1 -carboxamide), gliclazide (3-(7- azabicyclo[3.3.0]oct-7-yl)-l-(4-metliyiphenyl)su3fonyl-urea), and gliquidone (3- cyclohexyl-l-[4-[2-(7-methoxy-4,4-dimethyl-l,3- dioxo~isoqmnolin-2-yl)ethyl]phenyl]sulfonyl-urea))
• Meglitinides (e.g., repaglinide (5( -)2-ethoxy-4(2((3-melhyl- 1 -(2-(i- pipeiidiny3)phenyl)-butyl)amino)-2-oxoethyi)benzoic acid), nateglinide (3-phenyl- 2-(4-propan-2-ylcyclohexyl)carbonylamino-propanoic acid), and mitiglinide ((25)- 2-benzy3-4-[(3ai?,7a,Sj-octahydro-2H-isoindol- 2-yl]-4-oxobutanoic acid))
• Biguanidcs (e.g., metformin (N,N-dimethylimidodicarbonimidic diamidc), phenformin (2-(A/-phenethylcarbamimidoyl)guanidine), and buformin (2-butyl-I - (diairiinomethyliderie)guanidine))
• Alpha-ghicasidase inhibitors (e.g., miglitol ((2i?,3R,4R,5S)-l-(2-hydroxyethyl)-2- (hydroxynietliyl)piperidisie-3,4,5-triol), acarbose ((2i?,3/?,4 ?,5S,6 ?)-5- {[(2ii,3i?,4i?!55,6i?)-5-{[(2i?53J?,45 51S'56i?)-3!4-dihydroxy-6-methyl-5-
{ [( lS,4/?,55,65)-4,5 ,6-trihydroxy-3 -(bydroxymethy 3)cyclohex-2-en- 1 - yljamino ) tetrahydro-2H-pyran-2-yl]oxy} -3 ,4-dihydroxy-6- (liydroxymethyI)tetrahydro-2H-pyran-2-yl]oxy}-6-(liydroxymethyl)tetrahydro-2H- pyran-2,3,4-trioI), and voglibose ((lS,2SJi?,4S,55)-5-(l;3-dihydroxypropan-2- ylamino)-l -(hydroxymethyl)cyclohexane-l,2,3,4-tetrol))
• Glucagon-like peptide (GLP) analogs and agonists (e.g.. exenatide and liragluttde)
* Amylin analogues (e.g., pramlintide acetate (Symlin))
* Dipeptidyl peptidase-4 (DPP-4) inhibitors (e.g., vildagliptin, (25)-l-{2-[(3- hydroxy- l-adamantyr)amino]acetyl}pyrrolidine-2-carbonitrile and sitagliptin ((3 ?)-3-amino-l -[9-(trifluoromet yl)-l ,4,7,8-tetrazabicyclo[4.3.0]nona-6,8-dien- 4-yl]-4-(2,4,5-trifluoroplieny3)butan- 1 - one)), and
• Tliiazolidinediones (e.g., rosiglitazone, 5-((4-(2-(raethyl-2-pyridinylamino) etlioxy)pheayl)meihyI)- 2,4-thiazoIidinedione, pioglitazone (5-((4-(2-(5-ethyI-2- pyridinyl)etlioxy)pheny{)methy1)-,(+--)- 2,4-tliiazolidinedione,) and troglitazone (5- (4-((6-hydroxy-2,5,7,8-tetramethylc roman-2-yl-met oxy)benzy )-2 ,4- thiazolidinedione)).
[0054] The invention also comprises as another embodiment, a. method for inducing increased GLP-1 secretion in cell, in vitro, comprising contacting the cell with an inducing effective amount of a TGR5 agonist compound according to any one of the preceding embodiments.
[0055] The invention also comprises as another embodiment the use of an effective amount of a TGR5 agonist compound according to any one of the preceding embodiments for the preparation of a medicament for treating a metabolic disease in a subject in need of such treatment.
[0056] The invention also comprises as another embodiment, the use of an effective amount of a TGR5 agonist compound according to any one of the preceding embodiments for the preparation of a medicament for treating obesity or type II diabetes in a subject in need of such treatment.
[0057] The invention also comprises as another embodiment, the use of an effective amount of a TGR5 agonist compound according to any one of the preceding embodiments for the preparation of a medicament for treating hyperlipidemia in a subject in need of such treatment.
[0058] The invention also comprises as another embodiment, the use of an effective amount of a TGR5 agonist compound according to any one of the preceding embodiments for the preparation of a medicament for treating atherscierosis in a subject in need of such treatment. [9059] The invention also comprises as another embodiment, the use of an effective amount of a TGR5 agonist compound according to any one of the preceding embodiments for the preparation of a medicament for lowering blood glucose in a subject in need of such treatment.
[0060] The invention also comprises as another embodiment, the use of an effective amount of a TGR5 agonist compound according to any one of the preceding embodiments for the preparation of a medicament for enhancing insulin secretion in a subject in need of such treatment.
[0061] The invention also comprises as another embodiment, the use of an effective amount of a TGR5 agonist compound according to any one of the preceding embodiments for the preparation of a medicament for treating a disease associated with perturbed bile acid metabolism in a subject in need of such treatment.
[0062] The invention also comprises as another embodiment, the use of an effective amount of a TGR5 agonist compound according to any one of the preceding embodiments and a second anti-diabetic drug for the preparation of a medicament for treating obesity or type II diabetes in a subject in need of such treatment.
Pharmaceutical Formulations and Dosage Forms
[0063] Administration of the compounds of this disclosure, or their pharmaceutically acceptable salts, in pure form or in an appropriate pharmaceutical composition, can be carried out via any of the accepted modes of administration or agents for serving similar utilities. Thus, administration can be, for example, orally, nasally, parenteral!)' (intravenous, intramuscular, or subcutaneous), topically, transdermallv, intravaginally, intravesically, intracistemally, or rectally, in the form of solid, semi-solid, lyophiiized powder, or liquid dosage forms, such as for example, tablets, suppositories, pills, soft elastic and hard gelatin capsules, powders, solutions, suspensions, or aerosols, or the like, preferably in unit dosage forms suitable for simple administration of precise dosages.
[0064] The compositions will include a conventional pharmaceutical carrier, excipient, and/or diluent and a compound of this disclosure as the/an active agent, and, in addition, can include carriers and adjuvants, etc,
[0065] Adjuvants include preserving, wetting, suspending, sweetening, flavoring, perfuming, emulsifying, and dispensing agents. Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It can also be desirable to include isotonic agents, for example sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin.
[0066] Tf desired, a pharmaceutical composition of the compounds in this disclosure can also contain minor amounts of auxiliary substances such as wetting or emulsifying agents, pH buffering agents, antioxidants, and the like, such as, for example, citric acid, sorbitan monoiaurate, triethanolamine oleate, butylalted hydroxytoluene, etc.
[0067] The choice of formulation depends on various factors such as the mode of drug administration (e.g., for oral administration, formulations in the form of tablets, pills or capsules are preferred) and the bioavailability of the drug substance. Recently, pharmaceutical formulations have been developed especially for drugs that show poor bioavailability based upon the principle that bioavailability can be increased by increasing the surface area i.e., decreasing particle size. For example, U.S. Pat. No. 4,107,288 describes a pharmaceutical formulation having particles in the size range from 10 to 1 ,000 nm in which the active material is supported on a crosslinked matrix of macromolecules. U.S. Pat. No. 5,145,684 describes the production of a pharmaceutical formulation in which the drug substance is pulverized to nanoparticles (average particle size of 400 nm) in the presence of a surface modifier and then dispersed in a liquid medium to give a pharmaceutical formulation that exhibits remarkably high bioavailability.
[0068] Compositions suitable for parenteral injection can comprise physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanoi, polyols (propyieneglycol, po!yeihylenegiyeol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants.
[0069] One preferable route of administration is oral, using a convenient daily dosage regimen that can be adjusted according to the degree of severity of the disease-state to be treated.
[0070] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is admixed with at least one inert customary excipient (or carrier) such as sodium citrate or dicalcium phosphate or (a) fillers or extenders, as for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders, as for example, cellulose derivatives, starch, alignates, gelatin, polyvinylpyrrolidone, sucrose, and gum acacia, (c) humectants, as for example, glycerol, (d) disintegrating agents, as for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, croscarmellose sodium, complex silicates, and sodium carbonate, (e) solution retarders, as for example paraffin, (f) absorption accelerators, as for example, quaternary ammonium compounds, (g) wetting agents, as for example, cetyl alcohol, and glycerol raonostearate, magnesium stearate and the like (h) adsorbents, as for example, kaolin and bentonite, and (i) lubricants, as for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets, and pills, the dosage forms can also comprise buffering agents.
[0071 ] Solid dosage forms, as described above, can be prepared with coatings and shells, such as enteric coatings and others well known in the art. They can contain pacifying agents, and can also be of such composition that they release the active compound or compounds in a certain part of the intestinal tract in a deiayed manner. Examples of embedded compositions that can be used are polymeric substances and waxes. The active compounds can also be in microencapsulated form, if appropriate, with one or more of the above-mentioned excipients.
[1)072] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. Such dosage forms are prepared, for example, by dissolving, dispersing, etc., a compound(s) of this disclosure, or a pharmaceutically acceptable salt thereof, and optional pharmaceutical adjuvants in a carrier, such as, for example, water, saline, aqueous dextrose, glycerol, ethanoi and the like; solubiiizing agents and emulsiiiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3- butylenegfycol, dimethylformamide; oils, in particular, cottonseed oil, groundnut oil, com germ oil, olive oil, castor oil and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethyleneglycols and fatty acid esters of sorbitan; or mixtures of these substances, and the like, to thereby form a solution or suspension.
[0073] Suspensions, in addition to the active compounds, can contain suspending agents, as for example, ethoxylated isostearyl alcohols, pedyoxy ethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like.
[0074] Compositions for rectal administrations are, for example, suppositories that can be prepared by mixing the compounds of this disclosure with, for example, suitable non- irritating excipients or carriers such as cocoa butter, polyethyleneglycol or a suppository wax, which are solid at ordinary temperatures but liquid at body temperature and therefore, melt while in a suitable body cavity and release the active component therein.
[0075] Dosage forms for topical administration of a compound of this disclosure include ointments, powders, sprays, and inhalants. The active component is admixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants as can be required. Ophthalmic formulations, eye ointments, powders, and solutions are also contemplated for the compounds in this disclosure.
[0076] Compressed gases can be used to disperse a compound of this disclosure in aerosol form. Inert gases suitable for this purpose are nitrogen, carbon dioxide, etc.
[1)077] Generally, depending on the intended mode of administration, the pharmaceutically acceptable compositions will contain about 1% to about 99% by weight of a compound(s) of this disclosure, or a pharmaceutically acceptable salt thereof, and 99% to 1% by weight of a suitable pharmaceutical excipient. In one example, the composition will, be between about 5% and about 75% by weight of a compound(s) of this disclosure, or a pharmaceutically acceptable salt thereof, with the rest being suitable pharmaceutical excipients.
[1)078] Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington's Pharmaceutical Sciences, 18th Ed., (Mack Publishing Company, Easton, Pa., 1990), The composition to be administered will, in any event, contain a therapeutically effective amount of a compound of this disclosure, or a pharmaceutically acceptable salt thereof, for treatment of a disease-state in accordance with the teachings of this disclosure.
[0079] The compounds of this disclosure, or their pharmaceutically acceptable salts, are administered in a therapeutically effective amount which will vary depending upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of the compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular disease-states, and the host undergoing therapy. The compounds of this disclosure can be administered to a patient at dosage levels in the range of about 0.1 to about 1,000 mg per day. For a normal human adult ha ving a body weight of about 70 kilograms, a, dosage in the range of about 0.0.1 to about 100 mg per kilogram of body weight per day is an example. The specific dosage used, however, can vary. For example, the dosage can depend on a number of factors including the requirements of the patient, the severity of the condition being treated, and the pharmacological activity of the compound being used. The determination of optimum dosages for a particular patient is well known to one of ordinary skill in the art.
[00801 The compositions will include a conventional pharmaceutical carrier or excipient and a compound of this disclosure as the/an active agent, and. in addition, can include other medicinal agents and pharmaceutical agents. Compositions of the compounds in this disclosure can be used in combination with anticancer and/or other agents that are generally administered to a patient being treated for cancer, e.g. surgery, radiation and/or chemotherapeutic agent(s). Chemotherapeutic agents that can be useful for administration in combination with compounds of Formula 1 in treating cancer include alkylating agents, platinum containing agents.
[0081] If formulated as a fixed dose, such combination products employ the compounds of this disclosure within the dosage range described above and the other pharmaceutically active agent(s) within its approved dosage range. Compounds of this disclosure can alternatively be used sequentially with known pharmaceutically acceptable agent(s) when a combination formulation is inappropriate.
[0082] The compounds described herein, as well as their pharmaceutically acceptable salts or other derivatives thereof, can exist in isotopieally-labeled form, in which one or more atoms of the compounds are 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 can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine and chloride, such as ZH (deuterium), 3H (tritium), ! 3C, 14C, i5N, l80, . i ?0, 3lP, "P, i5S, i8F and 36C1, respectively, Isotopically labeled compounds of the present invention, as well as pharmaceutically acceptable salts, esters, prodrugs, solvates, hydrates or other derivatives thereof, generally can be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples and Preparations below, by substituting a readily available isotopically labeled reagent for a non- isoiopically labeled reagent.
10083] In the compounds of the invention, unless otherwise stated, any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom at its natural abundance. When a position is designated as "H" or "hydrogen", the position is to be understood to have hydrogen at its natural abundance isotopic composition, with the understanding that some variation of natural isotopic abundance occurs in a synthesized compound depending upon the origin of chemical materials used in the synthesis. When a particular position is designated as "D" or "deuterium", it is to be understood that the abundance of deuterium at that position is substantially greater than the natural abundance of deuterium, which is 0.015%, and typically has at least 50% deuterium incorporation at that position.
[0084] The methods disclosed herein also include methods of treating diseases by- administering deuterated compounds of the invention or other isotopically-labeled compounds of the invention alone or as pharmaceutical compositions. In some of these situations, substitution of hydrogen atoms with heavier isotopes such as deuterium can afford certain therapeutic advantages resulting from greater metabolic stability (for example, increased in vivo half-life or reduced dosage requirements).
[0085J Moreover, certain isotopically-labeled compounds, for example those into which radioactive isotopes such as 3H and l4C are incorporated, are useful in drug and/or substrate tissue distribution assays such as positron emission tonography (PET). Tritiated, (3H) and carbon- 14 (i 4C) isotopes are useful for these embodiments becau:
Definitions
[0086J Terms used herein may be preceded and/or followed by a single dash, or a double dash, "=", to indicate the bond order of the bond between the named substituent and its parent moiety; a single dash indicates a single bond and a double dash indicates a double bond. In the absence of a single or double dash it is understood that a single bond is formed between the substituent and its parent moiety; further, substituents are intended to be read "left to right" unless a dash indicates otherwise. For example, d-Cealkoxycarbonyloxy and -OC(0)OCt -Chalky! indicate the same functionality. Also, for instance, when variable X of formual I(Q) is defined as =N- or =C(R4)-, the bonds are only to indicate attachment points and the bonds are not meant to add additional bonds to the parent structure. So, for instance, when variable X of formula I(Q) is defined as ==N-, this would mean the same thing as X being defined as N.
[0087] Certain variables used herein are indicated as divalent linking moieties, for example, L° is a divalent moiety linking Rm to the parent structure. For such divalent variables, particular members defining LD may be written, for example, in the form -X-Y- or -Y-X-. When certain groups, such as alkyl groups, arc part of a linker, these groups are also divalent moieties.
|0088] "Administration" and variants thereof (e.g., "administering" a compound) in reference to a compound of the invention means introducing the compound or a prodrug of the compound into the system of the animal in need of treatment. When a compound of the invention or prodrug thereof is provided in combination with one or more other active agents (e.g., surgery, radiation, chemotherapy, and the like), "administration" and its variants are each understood to include concurrent and sequential introduction of the compound or prodrug thereof and other agents.
[0089] "Alkoxy" means the group -OR wherein R is alkyl, as defined herein. Representative examples include methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, 4-methylh.exyloxy, 4-memyJ.h.eptyloxy, 4, 7-dimethyloctyloxy , and the like.
[009(1] "Alkoxycarbonyl" means an alkoxy group, as defined herein, appended to a parent moiety via a. carbonyl group (i.e., a. group of the form, -C(0)OR°, wherein R° is alkyl, as defined herein). Examples of alkoxycarbonyl groups include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, t-butoxycarbonyl, and n- hexylcarbonyl.
[0091] 'Alkyl" means a linear or branched hydrocarbon group having from 1 to 10 carbon atoms unless otherwise defined. Representative examples for alkyl groups include methyl, ethyl, propyl, butyl, pentyl, hexyl, 4-methylhexyl, 4-methylheptyl, 4,7-dimethyloctyl, and the like. -(CrC^alkyL which means exactly the same as (Chalky!, includes groups selected
Figure imgf000035_0001
isobutyl, and tert-butyi.
[0092] "Alkyl amino" means an alkyl group, as defined herein, appended to a parent moiety through an -NH- group (i.e. , substituents of the form - (H)R°, where R° is an alkyl group). Examples of alkylamino groups include, but are not limited to, methylamino, ethylami.no, isopropylamino, exylamino, and the like.
[1)093] "Alkylaminocarbonyl'' means an alkylamino group, as defined herein, appended to a parent moiety via a carbonyl group (i.e., a group of the form, -C(0)N(H)R°, wherein R° is alkyl, as defined herein). Examples of alkylaminocarbonyl groups include, but are not limited to, methylaminocarbonyl, et ylaminocarbonyi, isopropylaminocarbonyl, t- butylaminocarbonyi, and n-hexyiaminocarbonyl,
[9094] "Amino" means a -NH2 group.
[0095] "Aiyl" means a monovalent, monocyclic, or polycyclic radical having 6 to 14 ring carbon atoms. The monocyclic aryi radical is aromatic and whereas the polycyclic aryl radical may be partially saturated, at least one of the rings comprising a polycyclic radical is aromatic. The polycyclic aryi radical includes fused, bridged, and spiro ring systems. Any 1 or 2 ring carbon atoms of any nonaromatic rings comprising a polycyclic aryl radical may be replaced by a -C(O)-, --C(S)-, or -C(^NH)- group. Unless stated otherwise, the valency may be located on any atom of any ring of the aryl group, valency rules permitting. Representative examples include phenyl, naphthyl, indanyl, and the like.
[0092] "Carbonyl" means a -C(0)- group.
[0093] "Cvcloalkyl" means a monocyclic or polycyclic hydrocarbon radical having 3 to 13 carbon ring atoms. The cvcloalkyl radical may be saturated or partially unsaturated, but cannot contain an aromatic ring. The cvcloalkyl radical includes fused, bridged and spiro ring systems. Examples of such radicals include cyclopropyl, cyciobutyl, cyclopenryl and cyclohexyl.
[1)094] "Dialkylamino" means two alky] groups, each independently as defined herein, appended to a parent moiety through a nitrogen atom (i.e., substituents of the form -N(R0)?, where each Rw is an alkyl group). Examples of dialkylamino groups include, but are not limited to N.'N-dimethylamino, N,N-diemylamino, N-isopropyl-M-methylamino, "N-ethyl-N- hexylamino, and the like.
[0095] "Di(Cx-C4alkyl)aminocarbonyl" means a dialkylamino group, as defined herein, appended to a parent moiety via a carbonyl group (i.e., a group of the form, -C(O)" (R0)2, wherein each R° is alkyl, as defined herein). Examples of dialkylamino groups include, but are not limited to N,N-dimethylaminocarbonyl, Ν,Ν-diethylaminocarbonyl, N-isopropyl-N- methylaminocarbonyl, N-ethyl-N-hexylaminocarbonyi, and the like.
[0096] "gem-cyclopropyl" mean alkyl group that has a carbon substituted in such a way to form the following structure:
Figure imgf000036_0001
[0097] "Fused ring system" and "fused ring" refer to a polycyclic ring system that contains bridged or fused rings; that is, where two rings have more than one shared atom in their ring structures. In this application, fuscd-polycyclics and fused ring systems are not necessarily all aromatic ring systems. Typically, but not necessarily, fused-polycyclics share a vicinal set of atoms, for example naphthalene or 1,2,3,4-tetrahydro-naphtiialene. A spiro ring system is not a fused-polycyclic by this definition, but fused polycyclic ring systems of the invention may themselves have spiro rings attached thereto via a single ring atom of the fused-polycyclic. In some examples, as appreciated by one of ordinary skill in the art, two adjacent groups on an aromatic system may be fused together to form a ring structure. The fused ring structure may contain heteroatoms and may be optionally substituted with one or more groups. It should additionally be noted that saturated carbons of such fused groups (i.e., saturated ring structures) can contain two substitution groups.
0098| "Halo" and "halogen" mean a fJisoro, chloro, hromo or iodo group.
[0099] "Raloalkyl" means an aikyl radical, as defined herein, substituted with one or more halo atoms. For example, halo-substituted
Figure imgf000037_0001
includes irifluoromethyl, 2,2-dichloroeihyi, 2,2,2-trifiuoroethyl, perchloroethyl, 2-bromopropyl, and the like.
[0100] "Heteroaryi" means a monovalent monocyclic or polycydic radical having 5 to 14 ring atoms of which one or more of the ring atoms, for example one, two, three, or four ring atoms, are heteroatoms independently selected from -0-, -8(0)„- (n is 0, 1, or 2), -N-, -N(R )-, and the remaining ring atoms are carbon atoms, where R* is hydrogen, aikyl, hydroxy, afkoxy, -C(0)R° or -S(0)2R°, where R° is aikyl. The monocyclic heteroaryi radical is aromatic and whereas the polycyclic heteroaryi radical may be partially saturated, at least one of the rings comprising a polycydic radical is aromatic. The polycyclic heteoaryl radical includes fused, bridged and spiro ring systems. Any 1 or 2 ring carbon atoms of any nonaroraatic rings comprising a polycyclic heteroaryi radical may be replaced by a ~C(0)-, -C(S)-, or -C(=NH)- group. Unless stated otherwise, the valency may be located on any atom of any ring of the heteroaryi group, valency rules permitting. In particular, when the point of valency is located on the nitrogen, then Rx is absent. More specifically, the term heteroaryi includes, but is not limited to, 1 ,2,4-triazolyl, 1,3,5-triazolyl, phthaliraidyl, pyridinyl, pyrrolyL imidazolyl, thienyl, furanyl, indolyl, 2,3-dihydro-lH-indolyI (including, for example, 2,3-dihydro- lH-indol-2-yl, 2,3-dihydro-lH-indol-5-yl, and the like), isoindolyl, indolinyi, isoindoiinyi, benzimidazolyl, benzodioxol-4-yl, benzoturanyl, cinnolinyl, mdolizinyl, naphthyridin-3-yl, phthalazin-3-yl, phthalazin-4-yl, pteridinyl, purinyl, quinazolinyl, quinoxalinyl, tetrazoyl, pyrazolyl, pyrazinyl, pyrimidinyi, pyridazmyL oxazolyi, isooxazolyl, oxadiazolyl, benzoxazolyl, quinolinyl, isoquinolinyi, tetrahydroisoquinolinyl (including, for example, tetrahydroisoquinolin-4-yl, tetrahydroisoquino3in-6-yl, and the like), 2,3,3a,7a-tetrahydro- lH-isoindolyl, pyrrolo[3,2-c]pyridinyl (including, for example, pyrrolo[3 ,2-c]pyridin-2-yl, pyrrolo[3 ,2-c]pyridin-7-yl, and the like), benzopyranyl, thiazolyl, isothiazolyl, thiadiazolyf, benzothiazofyi, benzothienyl, and the N-oxide derivatives thereof.
[9101] "I-Ieterocyclyl" means a monovalent, monocyclic or polycyclic hydrocarbon radical having 3 to 13 ring atoms of which one or more of the ring atoms, for example 1, 2, 3 or 4 ring atoms, are heteroatoms independently selected from -0-, -S(0)n- (n is 0, 1 , or 2), -N= and -N(Ry)- (where Ry is hydrogen, aikyl, hydroxy, alkoxy, -C(O)R0 or -S(O)2R0, where R° is aikyl, as defined herein), and the remaining ring atoms are carbon. The heterocycloalkyl radical may be saturated or partially unsaturated, but cannot contain an aromatic ring. The heteocyeloalkyl radical includes fused, bridged and spiro ring systems. Any 1 or 2 ring carbon atoms independently may be replaced by a -C(0 , -C(S)~, or -C(=NH)- group. Unless otherwise stated, the valency of the group may be located on any atom of any ring within the radical, valency rules permitting. In particular, when the point of valency is located on a nitrogen atom, Ry is absent. More specifically the term lieterocycloalkyl includes, but is not limited to, azetidinyl, pyrrolidinyl, 2-oxopyrrolidinyl, 2,5-dihydro- lH-pyrrolyl, ptperidinyl, 4-piperidonyl, morpholinyl, piperazinyl, 2-oxopiperazinyl, tetrahydropyranyl, 2-oxopipericlinyl, thiomorpholinyl, thianK^holinyl, perhydroazepinyl, pyrazolidinyl, iniidazolinyl, imidazolidinyl, dihydropyridinyl, tetrahydropyridinyl , oxazolinyl, oxazolidinyl, isoxazoiidinyl, thiazolinyl, thiazolidinyl, quinuclidinyl, isothiazolidinyl, octahydroindolyl, octahydroLsoindolyl, decahydroisoquinolyl, tetrahydroiuryl, l ,4-dioxa-8-azaspiro[4.5]decan-8-yl and tetrahydropyranyl, and the N-oxide derivatives thereof.
[0102] "Heterocyclylalkyl" means a heterocyclyl group appended to a parent moiety via an alkyl group, as defined herein. Examples of heterocyclylalkyl groups include, but are not limited to, morpholin-4-ylmethyl, 2-(π3θφΙιο1ίη-4-ν1)6ί1¾Ί, ηιοφηο1ϊη-2-νΐπκί1ιν1, 2- (morpholin-2-yl)ethyl, morpholin-3-ylmet.hyl, 2-(morpholin-3-yl)ethyl, piperazin- 1 -ylmethyl, 2-(piperazin- 1 -yl)ethyl, piperidin- 1 -ylmethyl, 2-(piperidin- 1 -yl)ethyl, piperidin-2 -ylmethyl, 2-(piperidin-2-yl)ethyl, piperidin-4-ylmethyl, 2-(piperidin~4-yl)ethyi, pyrrolidin- 1 -ylmethyl, 2-(pyrrolidin-i~yf)ethyl, pyrrolidin-2 -ylmethyl, 2-(pyrrolidin-2-yl)ethyi.
[9103] "Hydroxyalkyl" means an alkyl group, as defined herein, substituted with at least one, for example one. two, or three, hydroxy group(s), provided that if two hydroxy groups are present they are not both on the same carbon atom. Representative examples include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, l-(hydroxymethyl)-2-methylbutyl, 2-hydroxybutyi, 3-hydroxybutyl, 4-hydroxybutyl,
2.3- dihydroxypropyl, 1 ~(hydroxymethyl)-2-hydroxy ethyl, 2,3 -dihydroxybutyl,
3.4- dihydroxybutyl, 2-(hydroxymethyi)-3-hydroxypropyi, 2-hydroxyethylene, 2,3-dihydroxypropyl, l-(hydroxymethyl)-2-hydroxyethyl, and the like.
[9104] The term "optionally substituted" means the substitution may or may not occur and includes instances where said substitution occurs and instances in which it does not. One of ordinary skill in the art would understand that with respect to any molecule described as containing one or more substituents, only sterically practical and/or synthetically feasible compounds are meant to be included. Unless otherwise specified in this specification, when a variable is said to optionally substituted or substituted with a substituent(s), this is to be understood that this substitution occurs by replacing a hydrogen that is covaiently bound to the variable with one these substituent(s). This meaning shall apply to all variables that are stated to be substituted or optionally substituted in the specification. For instance, when it is stated that variable RL can be optionally substituted with R'" lU, this means that this substitution, when it occurs, takes place by replacing a hydrogen that is covaiently bound to R with RC1°. Other non-limiting examples of variables that are described in certain instances in the specification as being optionally substituted or substituted with various substituents include, but are not limited to, RD\ A groups, B groups, and R5,
[0I05J Polyethylene glycol (PEG) are polymers of ethylene oxide. Polyethylene glycol refers to the polymer with molecular weight less than 50,000, A polymer is made by joining molecules of ethylene oxide and water together in a repeating pattern. Polyethylene glycol has the following structure: -(0Η2-(¾-Ο)η-.
[0106] "Saturated bridged ring system" refers to a bicyclic or polycyclic ring system that is not aromatic. Such a system may contain isolated or conjugated unsaturation, but not aromatic or heteroaromatic rings in its core structure (but may have aromatic substitution thereon). For example, hexahydro-furo[3 ,2-6]furan, 2,3,3a,4,7,7a-hexahydro- 1 H-indene, 7-aza-bicyclo[2.2.1 ]heptane and l ,2,3,4,4a,5,8,8a-octaliydro-naphthalene are all included in the class "saturated bridged ring system."
[0107] "Spiro ring'" refers to a ring originating from a particular annular carbon of another ring. For example, as depicted below:
Figure imgf000039_0001
a ring atom of a. saturated bridged ring system (rings C and C), but noi a bridgehead atom, can be a shared atom between the saturated bridged ring system and a spiro ring (ring D) attached thereto. A representative example of a spiro ring system is 2,3-dioxa-8-azaspiro[4.5]decan-8-yl.
[0108] "Isomers" means compounds having identical molecular formulae but differing in the nature or sequence of bonding of their atoms or in the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are termed "stereoisomers." Stereoisomers that are not mirror images of one another are termed "diastereomers" and stereoisomers that are nonsuperimposable mirror images are termed "enantiomers" or sometimes "optical isomers." A carbon atom bonded to four nonidentical substituents is termed a "c iral center." A compound with one chiral center has two enantiomeric forms of opposite chirality is termed a "racemic mixture." A compound that has more than one chiral center has 2n I enantiomeric pairs, where n is the number of chirai centers. Compounds with more than one chirai center may exist as ether an individual diastereomer or as a mixture of diastereomers, termed a "diastereomeric mixture." When one chiral center is present a stereoisomer may be characterized by the absolute configuration of that chiral center. Absolute configuration refers to the arrangement in space of the substituents attached to the chiral center. Enantiomers are characterized by the absolute configuration of their chirai centers and described by the R- and S-sequencing rules of Cahn, In gold and Prelog. Conventions for stereochemical nomenclature, methods for the determination of stereochemistry and the separation of stereoisomers are well known in the art (e.g. , see "Advanced Organic Chemistry," 3rd edition, March, Jerry, John Wiley & Sons, New York, 1985). The names and illustration used in this application to describe compounds of the invention, unless indicated otherwise, are meant to be encompassed all possible stereoisomers and any mixture, racemic or otherwise, thereof.
[0I09J The present invention also includes N-oxide derivatives of the compounds of the invention. N-oxide derivatives mean derivatives of compounds of the invention in which nitrogens are in an oxidized state (i.e. , N→0), e.g. , pyridine N-oxide, and which possess the desired pharmacological activity.
[0110] "Metabolite" refers to the break-down or end product of a compound or its salt produced by metabolism or biotransformation in the animal or human body; tor example, biotransformation to a more polar molecule such as by oxidation, reduction, or hydrolysis, or to a. conjugate (see Goodman and Oilman, "The Pharmacological Basis of Therapeutics" 8.sup.th Ed,, Pergamon Press, gilman et al. (eds), 1990 for a discussion of biotransformation). As used herein, the metabolite of a compound of the invention or its salt may be the biologically active form of the compound in the body. In one example, a prodrug may be used such that the biologically active form, a metabolite, is released in vivo. In another example, a biologically active metabolite is discovered serendipitously, that is, no prodrug design per se was undertaken. An assay tor activity of a metabolite of a compound of the present invention is known to one of skill in the art in light of the present disclosure, f 0111 J "Patient" and "subject" for the purposes of the present invention includes humans and other animals, particularly mammals, and other organisms. Thus the methods are applicable to both human therapy and veterinary applications. In another embodiment the patient is a mammal, and in another embodiment the patient is human.
[01121 A "pharmaceutically acceptable salt" of a compound means a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. It is understood that the pharmaceutically acceptable salts are non-toxic. Additional information on suitable pharmaceutically acceptable salts can be found in Remington 's Pharmaceutical Sciences, \ Th ed., Mack Publishing Company, Easton, PA, 1985, or S. M. Berge, et ah, "Pharmaceutical Salts," J. Pharm. Set., 1977;66: 1 -19. It is also understood that the compound can have one or more pharmaceutically acceptable salts associated with it.
[1)113] Examples of pharmaceutically acceptable acid addition salts include those formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; as well as organic acids such as acetic acid, trif!uoroacetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, oxalic acid, maleic acid, malortic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, 3-(4-hydroxybenzoyl)benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1 ,2-ethanedisulfonic acid, 2-hydroxyetbanesulfonie acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphors lfonic acid, glucoheptonic acid, 4,4'-methyienebis-(3-hydroxy-2-ene-l-earboxylic acid), 3-phenylpropionic acid, trimefhylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, p-toluenesulfonic acid, salicylic acid and the like.
[0114 J Examples of a. pharmaceutically acceptable base addition salts include those formed when an acidic proton present in the parent compound is replaced by a metal ion, such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Preferable salts are the ammonium, potassium, sodium, calcium and magnesium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include, but are not limited to, salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins. Examples of organic bases include isopropylamine, trimethyl amine, dietbylamine, tnethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, hisiidine, caffeine, procaine, hvdrabamine, choline, betaine, eihylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, tromethamine, N-met ylglucamine, polyamine resins, and the like. Exemplary organic bases are isopropy] amine, diethylamine, ethanolamine, trimetliylamme, dicyclohexylamine, choline, and caffeine.
[0115] "Prodrug" refers to compounds that are transformed (typically rapidly) in vivo to yield the parent compound of the above formulae, for example, by hydrolysis in blood. Aommon examples include, but are not limited to, ester and amide forms of a compound having an active form bearing a carboxylic acid moiety. Examples of pharmaceutically acceptable esters of the compounds of this invention include, but are not limited to, alkyl esters (for example with between about one and about six carbons) the alkyl group is a straight or branched chain. Acceptable esters also include cycloalkyl esters and arylalkyl esters such as, but not limited to benzyl. Examples of pharmaceutically acceptable amides of the compounds of this invention include, bur are not limited to, primary amides and secondary and tertiary alkyl amides (for example with between about one and about six carbons). Amides and esters of the compounds of the present invention may be prepared according to conventionai methods. A ihorough discussion of prodrugs is provided in T. Higuchi and V. Stella, "Pro-drags as Novel Delivery Systems," Vol 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drag Design, ed, Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference for ail purposes.
[0Π 6] "Therapeutically effective amount" is an amount of a compound of the invention, that when administered to a patient, effectively treats the disease. The amount of a compound of the invention which constitutes a "therapeutically effective amount" will vary depending upon a sundry of factors including the activity, metabolic stability, rate of excretion and duration of action of the compound, the age, weight, general health, sex, diet and species of the patient, the mode and time of administration of the compound, the concurrent administration of adjuvants or additional therapies and the severity of the disease for which the therapeutic effect is sought. The therapeutically effective amount for a given circumstance can be determined without undue experimentation,
[9117] "Treating" or "treatment" of a disease, disorder, or syndrome, as used herein, includes (i) preventing the disease, disorder, or syndrome from occurring in a human, i.e., causing the clinical symptoms of the disease, disorder, or syndrome not to develop in an animal that may be exposed to or predisposed to the disease, disorder, or syndrome but does not yet experience or display symptoms of the disease, disorder, or syndrome; (ii) inhibiting the disease, disorder, or syndrome, i.e., arresting its development; and (iii) relieving the disease, disorder, or syndrome, i.e., causing regression of the disease, disorder, or syndrome. As is known in the art, adjustments for systemic versus localized deliver}', the age, weight, general health, sex, diet and species of the patient, the mode and time of administration of the compound, the concurrent administration of adjuvants or additional therapeutically active ingredients and the severity of the disease for which the therapeutic effect is sought may be necessary, and will be ascertainable with routine experimentation. [Oi l 8] The compounds disclosed herein and their pharmaceutically acceptable salts can exist as single stereoisomers, racemates, and as mixtures of enantiomers and diasiereomers. The compounds disclosed herein can also exist as geometric isomers. All such single stereoisomers, racemates and mixtures thereof, and geometric isomers are intended to be within the scope of the compounds disclosed herein.
[0119] It is assumed that when considering generic descriptions of compounds of the disclosed herein for the purpose of constructing a compound, such construction results in the creation of a stable structure. That is, one of ordinary skill in the art would recognize that theoretically some constructs which would not normally be considered as stable compounds (that is, sterically practical and/or synthetically feasible, supra).
[1)120] Methods for the preparation and/or separation and isolation of single stereoisomers from racemic mixtures or non-racemic mixtures of stereoisomers are well known in the art. For example, optically active (R)- and (S)- isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. Enantiomers (R- and 8-isomers) can be resolved by methods known to one of ordinary skill in the art, for example by: formation of diastereoisomeric salts or complexes which can be separated, for example, by crystallization; via formation of diastereoisomeric derivatives which can be separated, for example, by crystallization, selective reaction of one cnantiomer with an enantiomer-specific reagent, for example enzymatic oxidation or reduction, followed by separation of the modified and unmodified enantiomers; or gas-liquid or liquid chromatography in a chiral environment, for example on a chiral support, such as silica with a bound chiral ligand or in the presence of a chiral solvent. It will be appreciated that where a desired enantiomer is converted into another chemical entity by one of the separation procedures described above, a further step can be required to liberate the desired enantiomeric form. Alternatively, specific enantiomer can be synthesized by asymmetric synthesis using optically active reagents, sisbstrates, catalysts or solvents or by converting on enantiomer to the other by asymmetric transformation. For a. mixture of enantiomers, enriched in a particular enantiomer, the major component enantiomer can be further enriched (with concomitant loss in yield) by reciystaliization.
[01211 Tn addition, the compounds of this disclosure can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds of this disclosure.
[0122] In addition, it is intended that the present disclosure cover compounds made either using standard organic synthetic techniques, including combinatorial chemistry or by biological methods, such as bacterial digestion, metabolism, enzymatic conversion, and the like.
[0123] The examples and scheme below depict the general synthetic procedure for the compounds disclosed herein. Synthesis of the compounds of Formulae T(Q) disclosed herein, and embodiments thereof, are not limited by these examples and schemes. One skilled in the art will know that other procedures can be used to synthesize the compounds of Formulae I(Q) disclosed herein, and that the procedures described in the examples and schemes is only one such procedure. In the descriptions below, one of ordinar skill in the art would recognize that specific reaction conditions, added reagents, solvents, and reaction temperatures can be modified for the synthesis of specific compounds that fall within the scope of this disclosure. All intermediate compounds described below, for which there is no descripton of how to synthesize such intermediates within these examples below, are commercially available compounds unless otherwise specified.
Synthesis
[0124] In all of the synthetic schemes described below (Schemes 1-27), the portion of the molecule that corresponds to R5 of the compound of formula I(Q) is substituted with one or two QA groups, wherein R~' is substituted with Q" by replacing a hydrogen that is covalently bonded to carbon or nitrogen. One skilied in the art would understand how to add QA to R' by- Schemes 28-30 described herein and by methods known to the skilled artisan.
[0125] In the following general methods, X, LD, QA, R\ R2, R4, R8, RAl°, RDI, RDi0, RDU, RDi iD, and RY are as previously defined for a compound of formula I(Q), and embodiments thereof, unless otherwise stated. The following abbreviations and acronyms are used herein. AcOH acetic acid !¾N triethylamine
or HOAc
AIB azobisisobutyronitrile GLP-1 giucagon-like peptide-! cAMP cyclic adenosine hexane
monophosphate
CD-FBS ehareoal-dextran-treated fetal MATU 0~{7- Aza benzol r jazol- l-y )- bovine seru m Ν,Ν,Ν ',Ν'- yluronium hexafluorophosphate
CMC carboxymethyl cellulose HMT hexamethylenetetramme cone. concentrated ΪΒΜΧ isob a tylm et hy I an thin e
DCM dichloroinethane KOtBu potassium tert-butoxide
DIB AH diisobutylaluminum hydride mCPB m~chloroperoxybenzoic acid
DIPEA diisopropylethylamine MeCN acetonitrile
DMEM Dulbecco's modified essential MeMgBr rn ei hy Ini agnesium b r oniide
DMF N, -dimethylformamide methanol
DMSO dimethylsulfoxide BS N-bromosuccinimide
DPBS Dulbecco's Phosphate Buffered OAc acetate
Saline
DPP-iV dipeptidyl peptidase IV PCC pyridmium chlorochromate
EDTA ethylenediaminetetraacetic acid polyethylene glycol
Et20 diethyl ether protecting group
EtOAc ethyl acetate saturated
EtOH ethanol STC-l stanniocalcm 1
FAF-BSA Fatty acid-free bovine serum TFA iriflmoroaceiie acid
FBS fetal bovine serum THF tetrahydromran
[0126] When iP represents -SCH2- and X represents =C(H>, then compounds of formula (IA) may be prepared as depicted in Scheme 1.
Figure imgf000046_0001
(Vll i) (lA)
[0127] Compounds of formula (II) are commercially available or may be prepared from known compounds using standard methodologies as exemplified in the preparations below, [0128] Step (a): An aldehyde of formula (III) may be prepared by reaction of nitrile (li) with diisobutylaluminum hydride in a suitable solvent, such as THF,
Step (by. Formation of carbinol (IV) may be achieved by treatment of aldehyde [) with methylmagnesium bromide in a suitable solvent, such as diethyl ether or THF.
Step (c): Conversion of carbinol (IV) to ketone (V) may occur under standard conditions, such as the Swera oxidation— known to one trained in the art of chemistry,
[9131] Step (d)i Bromoketone (VI) may be prepared by bromination of ketone (V) under typical conditions, such as with tetrabutylammoniurn tribromidc in 1 :2 mixture of McOH- DCM.
[0132] Step (e): Reaction of bromoketone (VI) with sodium azide in a suitable solvent, such as DMF, followed by reduction of the resulting azido-ketone under standard conditions, such as with zinc dust and hydrochloric acid in THF, may afford amino-keto e hydrochloride
(VII) .
[Θ133] Step (f): Isothiocyanate R^NCS may react with amino-ketone hydrochloride (VII) in a suitable solvent, such as DCM or toluene, and in the presence of a base, such as tnethyiamine, at elevated temperature to yield the corresponding thiourea, which may condense upon treatment with HOAc at elevated temperature to give a compound of formula
(VIII) . [9134] Step (g): Alkylation of imidazol-2-thione (VIII) with an electrophile
Figure imgf000047_0001
in a suitable solvent, such as acetone or MeCN, and in the presence of a base, such as potassium carbonate, may afford a compound of formula (ΪΛ).
[0135] Co
Figure imgf000047_0002
in (n
Scheme
Step (b): Reaction of thioether (I ) with a suitable oxidant, such as mCPBA (2.5- 3.0 eq), in a suitable solvent such as DCM may yield a compound of formula (IB).
[0137] la cj may be synthesized as shown in Scheme 3.
Figure imgf000047_0003
(VI II ) (IX)
Figure imgf000047_0004
(f)
[0138] Step (i): Thione (Γ ) may be converted to the corresponding sulfonyl chloride (IX) under standard conditions, such as adding NaOCl (3 eq) to thione (IA) in a 1 : 1 mixture of DCM and IN HQ at reduced temperature, preferably below 0 °C.
[0139] Step (j): Compounds of formula (ic) may be prepared by reaction of amine HN('R )RD3 with sulfonyl chloride (IX) in a suitable solvent, such as DCM, and in the presence of a base, such as trieihylamine.
[0140] Compounds of formula (1°) may be synthesized as depicted in Scheme 4.
Figure imgf000048_0001
0D)
Scheme 4
Step (k): Thione (VIII) may undergo desulfurization under standard conditions, such as with H202 in a mixture of HOAc-DCM, to afford imidazole (X).
[0142] Step (i): Reaction of imidazole (X) with butyllithium in a suitable solvent (e.g. THF) at redisced temperature, preferably at -78 °C for 30-40 minutes, may yield the corresponding organolithium, which may react with a suitable electrophile {e.g. isocyanate or carbamoyl chloride) at the same temperature to afford a compound of formula (1°).
formulae (I1') and (I* ) may be prepared as shown in Scheme 5.
Figure imgf000048_0002
(X! )
Figure imgf000048_0003
Scheme 5
Step (m): Imidazole (X) may be converted to the corresponding organolithium, as described previously, and then treated with DMF, preferably at -78 °C for 30-40 minutes, to yield aldehyde (XI).
[0145] Step (n): Compounds of formula (iE) may be prepared by reaction of aldehyde (XI) with a phosphorus ylide under Wittig or Horner- Emmons conditions— both known to one skilled in the an of chemistry.
[9146] Step (o): Compounds of formula (IF) may be prepared by cataly tic hydrogenolysis of aikene (IE) under standard conditions, such as in MeOH under 50-60 psi of hydrogen and over Pt02 ( 10-20 mole%). [9147] Compounds of formula (I&), wherein Y is chosen from NRY, O or S, may be prepared
Figure imgf000049_0001
[0I48J Step (p): Reduction of aldehyde (XI) using standard conditions, such as NaBH in EtOH at ambient temperature, may afford the corresponding carbinol (Xil).
[0149] Step (q): Compounds of formula (IG) may be prepared from carbinol (XII) and a suitable nucleophile HYRm, such as a phenol or thiophenol wherein Y represents O or S, respectively, and RDI is aryl, under Mitsunobu condition— known to one skilled in the an. Alternatively carbinol (XII) may be converted to the corresponding chloride, for example, by treatment with thionyl chloride (2 eq) in chloroform, followed by reaction with a suitable nucleophile HYR01 in MeCN (or acetone) and in the presence of a base (e.g. K2CO3) to yield compounds of formula (IG).
[0159] Compounds of formula (IH), wherein R4 is chosen from Br, Ci or F, may be prepared as shown in Scheme 7.
Figure imgf000049_0002
(I*)
Scheme 7
[0151] Step (r): Compounds of the formula (IH) may be prepared from imidazole (T¾) by treatment with a suitable halogen source such as, for example, N-bromosuccinimide in DCM. N-chlorosuccinimide and Selectfluor™ in a suitable solvent, such as DCM or MeCN, may be used to generate the corresponding chloro- and iluoro-substituted compounds (IH), respectively.
[0152] When LD represents -SCH2- and X is N, then compounds of formula (IJ) may be synthesized as depicted in Scheme 8.
Figure imgf000050_0001
(Xiil) (XIV) (XV/ )
Figure imgf000050_0002
Scheme 8
[0153] Compounds of formula (ΧΪΠ) are commercially available or may be prepared from known compounds using standard methodologies.
[1)154] Step (s): Ester (XIII), wherein R represents afkyl (e.g. methyl), may react with hydrazine in a suitable solvent, such as MeOH, at elevated temperature and in a sealed vessel to yield hydrazide (XIV). Alternatively acid (XIII), wherein R is H, may be converted to its hydrazide (XIV) under standard conditions— -known to one skilled in the art.
[0155] Step (t): Hydrazide (XIV) may react with isothiocyanate R'NCS in a suitable solvent, such as EtOH, at elevated temperature, preferably at reflux, to generate thiourea
(XV) .
[1)156] Step (u): Reaction of thiourea (XV) under basic conditions, such as in 5-10% aqueous " aOH at elevated temperature, preferably at reflux, may condense to yield thiol
(XVI) .
[0157] Next compounds of formula (IJ) may be prepared from thiol (XVI) under conditions previously described in step (g),
[0158] Compounds of formula (Ik) may be prepared as depicted in Scheme 9.
Figure imgf000050_0003
n
Scheme 9
[0159] Step (v): Reaction of thioether (IJ) with a suitable oxidant, such as mCPBA ( 1-1.1 equiv) in DCM, may yield compounds of formula (I ).
Compounds of formula (IL), wherein Rs is H, may be prepared as depicted in
Scheme 10.
Figure imgf000051_0001
Scheme 10
[0161] Under conditions previously described in step (k), thiol (XVI) may undergo de~ sulfurization to afford triazole (XVII).
[01 2] Step (w): Hydroxymethylation of triazole (XVII) may proceed under standard conditions, such as with paraformaldehyde in toluene heated at reflux, to afford the corresponding hydroxymethyltriazole, which may undergo oxidation upon treatment with a suitable oxidant, such as Mn02, in THF to yield the corresponding aldehyde (XVIII).
[0163J Step (x): Reaction of aldehyde (XVIII) with amine H CR^R151 under typical reductive animation conditions, such as with NaB(OAc);,H in a suitable solvent, may give compounds of formula (IL).
Figure imgf000051_0002
Scheme 11
[0164] Step (aw): Amine (lM ) may undergo diazotization under typical conditions, such as with aqueous sodium nitrite, and then may be converted to the corresponding sulfonyl chloride (XXIX) upon reaction with a mixture of copper (II) chloride, sulfur dioxide, HC1 and HO Ac.
[0165] Step (ax): Sulfonyl chloride (XXIX) may react with an amine HN(RDn )RD, ! ° in the presence of a base, such as i 2COj, to afford compounds of formula (1A ). In addition, ammonia may react with sulfonyl chloride (XXIX) to yield a sulfonamide (IAO), wherein both RDU are H. Co .
Figure imgf000052_0001
Scheme 12
[0167] Step (af): Imidazole (X) may be converted to the corresponding organolithiimi, as described previously, and then treated with tosyl azide in a suitable solvent (e.g. THF), preferably at -78 °C for 30 minutes, to yield azide (XXV).
[0168] Step (ag): Azide (XXV) may undergo catalytic hydrogenation under standard conditions, such as with a suitable palladium catalyst, preferably Lindlar catalyst, under hydrogen at ambient pressure, to give amine (XXVI).
[0169] Step (ah): Reaction of amine (XXVI) with an acid chloride in a suitable solvent (e.g. DCM) and with a base (e.g. pyridine) may afford compounds of formula (Ip).
[0170] Compounds of formula (IQ), for example, wherein R* is chosen from ar l or heteroar l, may be prepared as shown in Scheme 13.
Figure imgf000052_0002
(XXVI I) (XXVIII) (lQ)
Scheme 13
[0171] Step (r): Under conditions previously described in step (r), imidazole (XXVII) may be brominated to give bromoimidazole (XXVIII).
[1)172] Step (ai): Compounds of the formula (IQ) may be prepared from bromoimidazole (XXVIII) using standard cross-coupling conditions, such as with suitable boronic acids under Suzuki conditions known to one skilled in the art of chemistry.
[0173] Compounds of formula (IR) may be prepared as depicted in Scheme 14.
Figure imgf000053_0001
Scheme 14
[0174] Step (aj): Reaction of aldehyde (XI) and a suitable amine HN(R' )R"' under standard reductive animation conditions, such as with toluene sulfonic acid followed by sodium borohydride in EtOH at ambient temperature, may afford compounds of formula (IR).
[9175] Compounds of formula (Is) may be prepared as depicted in Scheme 15.
Figure imgf000053_0002
[0176] Step (ak): Alkylation of imidazol-2-thione (Vlli) with an electrophile R CH2Br, wherein RlJI is a benzenesulfonarnide, in a suitable solvent (e.g. acetone) and with a base (e.g. potassium carbonate) may afford compounds of formula (Is).
[0177] Compounds of formula (I1) may be prepared as depicted in Scheme 16.
Figure imgf000053_0003
Scheme 1
[0178] Step (al): Reaction of sulfonamide (Is) with a suitable isocvanate and Lewis acid (e.g. aluminum trichloride) in a solvent such as toluene, preferably at 80 °C for over 12 hours, may yield compounds of formula (1T).
[0179] Compounds of formula (lv - Iw) may be prepared as depicted in Scheme 17
Figure imgf000054_0001
Scheme 17
[9180] Step (am): Aikylation of imidazol-2-thione (VIII) with an electrophile RD1CH2Br, wherein R01 is a benzoate ester, in a suitable solvent (e.g. acetone) and with a base (e.g. potassium carbonate) may afford compounds of formula (lv).
[0181] Step (an): Hydrolysis of ester (Iu) may proceed under standard conditions, e.g. NaOH in aqueous methanol, to afford compounds of formula. (I ).
[0I82J Step (ao): Conversion of acid (iv) to compounds of formula may occur under standard peptide coupling conditions, e.g. upon addition of an amine HN(RDll)RD11D and coupling agent HATU in a suitable solvent, such as DCM or DMF.
[0183] Compounds of formula (Ix - JY) may
18
[0184] Under conditions previously described in step (ao), acid (Iv) may be treated with a suitably protected amino ester (e.g. Alanine methyl ester) and HATU in DCM to afford compounds of formula (i ).
[0185] Step (ap): Hydrolysis of ester (Ix) may proceed under standard conditions, e.g.
LiQlT in a THF-water mixture, to afford compounds of formula. (I¾).
[0186] Compounds of formula (Iz - i^) may be synthesized as shown in Scheme 19.
Figure imgf000055_0001
Schem 19
[0187] Under conditions previously described in step (ao), acid (1 ) may be treated with a suitably protected amino ester, such as one derived from Ornithine (wherein n = 2 ), and HATU in DCM to afford compounds of formula (Iz).
[0188] Step (aq): Hydrolysis of ester (Ix) and deprotection of the amine moiety may proceed under standard conditions, e.g. HC1 in dioxane (wherein R = tert-butyl and PG = BOC), to afford compounds of formula (IAA).
|0189] Compounds of formula (1AB) may be synthesized as shown in Scheme 20.
Figure imgf000055_0002
[0190] Step (ar): Under typical Curtius rearrangement conditions, acid (l ) may react with diphenylphosphoryl azide, a suitable alcohol (e.g. tert-butanol), an organic base (e.g. Et ) and toluene at elevated temperature, preferably 80 to 100 CC, to yield compounds of formula (IAB).
[0191] Compounds of formula (IAC - 1*°) may be synthesized as shown in Scheme 21.
Figure imgf000055_0003
Scheme 21 Step (as): Deprotection of carbamate (Γ ), may occur under standard conditions, such as with 1 : 1 TFA-DCM, to give compounds of formula (IAC).
0193| Step (at): Amine (iAC) may react with acid chlorides in the presence of a base, such as Et3N, to afford compounds of formula (TAD).
Figure imgf000056_0001
[0195] Step (au): Amine (iA ) may react, with sulfonyl chlorides in the presence of a base, such as Εΐ3Ν, to afford compounds of formula (IAij).
[0196] Step (au): Amine (IAC) may react with isocyanates or isothiocyanates in the presence of a base, such as Et3i , to afford compounds of formula (IAF), wherein Y is O or S, respectively.
Figure imgf000056_0002
Scheme 23
[0198] Step (k): Thione (VIII) may undergo desiilfurization under standard conditions, such as with ¾(½ in a mixture of HOAc-DCM, to afford imidazole (X).
[0199] Step (1): Reaction of imidazole (X) with butyllithium in a suitable solvent (e.g. THF) at reduced temperature, preferably at -78 °C for 30-40 minutes, may yield the corresponding organolitbium, which may react with a suitable electrophile (e.g. isocyanate or carbamoyl chloride) at the same temperature to afford a compound of formula (ID).
0200| Compounds of formula (i AQ) may be prepared as depicted in Scheme 2.4.
Figure imgf000057_0001
Scheme 24
Under conditions previously described in step (q), phenol (XXXIII) may react with carbinol (ΧΠ) to afford compounds of formula (iAQ).
)2] Compounds of formula (iAR) may be prepared as depicted in Scheme 25.
Figure imgf000057_0002
Scheme 25
Step (be): Phenol (ΧΧΧΙΠ) may react under standard conditions, for example, with dimethylthiocarbamoyl chloride (1 eq) and DABCO ( 1.25 eq) in NMP at 50 °C, to yield the respective 0-aiyl-thioearbamate (XXXIV).
[9204] Step (bd): Upon heating, such as at 240 °C for 20 min in a microwave apparatus, thiocarbarnate (XXXIV) may undergo a Newmann-Kwart rearrangement to give S-aryl- thiocarbamate (XXXV).
[0205] Step (be): Hydrolysis of thiocarbarnate (XXXV), for example, with sodium hydroxide in methanol, may afford the corresponding thiophenol (XXXVI).
[0206] Under conditions previously described in step (q), thiophenol (XXXVI) may react with carbinol (XII) to afford compounds of formula. ·: I .
Compounds of formula (iAS - 1ΑΊ) may be prepared as depicted in Scheme 26.
Figure imgf000058_0001
Scheme 26
)8] Under conditions previously described in step (an), ester (IAQ or IAR) may be hydro lyzed to yield compounds of formula (IA¾), wherein Y is O or S, respectively.
[0209] Under conditions previously described in step (ao), acid (IAS) may react with an amine to afford compounds of formula (ίΛί), wherein Y is O or S.
Compounds of formula (ΙΑϋ - IAV ) may be prepared as depicted in Scheme 27.
Figure imgf000058_0002
Under conditions previously described in steps (ar) to (as), acid (Γ ' ) may be converted to compounds of formula (I j)> wherein Y is O or S.
[9212] Under conditions previously described in steps (aw) to (ax), amine (IAtj) may be converted to compounds of formula (IAV), wherein Y is O or S.
[0213] Compounds of formula (lm - IA- ) may be prepared as depicted in Scheme 28.
Figure imgf000058_0003
Step (bf): Compounds of formula (IA¾), wherein RAlU is methoxy, may undergo demethylation under standard conditions, such as with BBr¾ in DCM, to yield the corresponding phenol (!AX).
[0215] Step (bg): Compounds of formula (iAX) may then be alkylated under standard conditions with a suitable electrophile, for example, bromoaikyl-triaikylammonium bromide, to yield compounds of formula (IA¾).
[0216] Compounds of formula (IAZ - 1BB may be prepared as depicted in Scheme 29.
Figure imgf000059_0001
Scheme 29
[0217] Under conditions previously described for step (ao), compounds of formula (iAZ) , wherein RAU' is C(0)OR, may be hydro! yzed to yield the corresponding acid (IBA).
[0218] Under conditions previously described in step (ao), acid (TBA) may be coupled with a diamine, such as an aminoalkyltrialkylammonium bromide, to afford compounds of formula (iBB).
Compounds of formula (I - IBD) may be prepared as depicted in Scheme 30.
Figure imgf000059_0002
Scheme 30
[0220] Under conditions previously described in step (bg), compounds of formula (iBC), wherein RAlJ is Si O ^ H?,, may react with a suitable electrophile, for example, bromoalkyl- trialltylammonium bromide, to give compounds of formula (IBD), TGR5/CRE-L ciferiase Assay
[0221] HEK 293 cells stably expressing human TGR5 (h-TGR5) or mouse TGR5 (m- TGR5) can be generated from HEK 293 CRE-Luciferase cells. The day before the assay, HEK 293 hTGR5/CRE-Luc cells are plated in DMEM in a 384 well assay plate at a density of 25k cells/45 pL per well and grown for 18-20 hours. Compounds are serially diluted in DMEM containing 5% DMSO and 5 pL of compound or media alone are transferred to each well and plates were incubated for about 6 hours. Following incubation, 30 μΐ. of lysis/luciferase buffer are added to each well. The luciferase activity is then measured on the EnVisionI plate reader and the dose response data, was analyzed using Activity Base.
[0222J From the foregoing it will be appreciated that, although specific embodiments of this disclosure have been described herein for purposes of illustration, various modifications may be made without deviating from the spirit and scope of the invention. Accordingly, the invention is not limited except as by the appended claims.

Claims

What is claimed is:
1. A compound of the formula:
X-
R5^ ^R2
Ri
or pharmaceutically acceptable salt thereof, wherein:
X is =N- or C'i R ; wherein R4 is H, -(Ci-C3)alkyl or halo;
IV is Rc;
Rc selected from phenyl, -(Cs-CeVcycloalkyl, -CH2-phenyl, heteroaryL and -(Ci-C4)alkyi optionally substituted with -OR013, -N(RC1J)2 or -S(RC! J), wherein the cyclic group of R1 can be optionally substitirted with 1, 2, 3, 4 or 5 R*"10 groups, wherein the 1, 2, 3, 4, or 5 Ruo groups are independently selected from RU A and RC!0B, provided that R1 cannot be substituted with more than two RCi0B groups, wherein
each R< !0a is independently selected from halo, cyano, and -(Ci-C4)alkyl optionally substituted with one, two, or three groups selected from -OH and halo;
each RC10B is independently selected from -C(0)NH2, (5-6 membered)heterocycloalkyl, -0-(Ci-C4)alkyl-Rcu, -C(0)ORC12, -OC(0)ORC12 and -O-Cd-C^alkyl optionally substituted with -OH or -C(0)OH;
RC!I is cyano, nitro, -N(RCi2)2, -ORC12, -SRC! 2, -C(0)RC! 2, -C(0)ORC! 2, -C(0)N(RCi2)2, -S(0)N(RCi2)2, -S{0)2N(RC!2)2, -S(0)2RCi2, -OC(0)RC12, -OC(0)ORCi2, -OC(0)NfRC!2)2, -N(RC12)C(0)RC12, -N(RC12)C(0)0RC12, -N(RC12)C(0)N(RC12)2, or -N(RC,2)C(=NRC12)N(RC1 )2:
each RU2 is independently selected from hydrogen, -(Ci-C4)alkyl, and -(Ci -C4)haloaikyl;
each RCL1 is independently selected from hydrogen, -(Ci-C4)alkyl, and
-(Ci-C4)haloalkyi;
R2 is— LD-RD1;
LD is -[Ci R i ' L-Y- i !> !,.-:
p is 0 or 1 :
q is 0 or 1;
each R is independently selected from H, -(Ci-C.?)alky3, halo, -OH, and -CH2OH; Y is a bond, -S-, -S(0)2-, -CH(OH)-, -0-, -O i l ) O H )-. -C(0)-(Ci-C4)alkyl-) -(Ci-C4)alkyl-S-(C C4)aUkyl-, -(C!-C4)alkyl-N(RY)-(Ci-C4)alkyI-, -C(H)(haIo)-, -(Ci-C4)alkyl-S(0)2-, -S(0)2-N(RY)-, -(Ci-C4)alkyl-0-, 0r -C(0)-N(RY , wherein RY is H, -(Ci-C4)alkyl, hydroxyl(Ci-C4)alkyl or -C=C-(Ci-C3)alkyl-;
RD! is selected from phenyl -(C6-Cio)aryi, -N(H)-phenyl, -(Cs-C^cycloalkyl, heterocycloalkyl, or heteroaryl, wherein Rbl can be optionally substituted with 1 , 2, 3 or 4 RDl°, wherein the 1-4 RD"J groups are independently selected from A groups and B groups, provided that RD1 cannot be substituted with more than two B groups;
each A group, when they occur, is independently selected from halo, -CF3, -C , -NO;., -OH, -O-(Ci-C. alkyl optionally substituted at the aikyl group with one, two, or three subs!ituen!s independently selected from -OH and halo, and -(C] -C4)alkyl optionally substituted with one, two, or three substituents independently selected from -OH and halo; each B group, when they occur, is independently selected from -(C5 ~C >alkylN(RDi i)2, -C(0)-NH2, -C(0)-N(H)-OH, -C(0)-N(H)-RD11C,
-C(0)-(Cx-C4)aikyl, -C(0)OH, -C(0)0-(Q -C4)alkyl, -S(0)2-(C, -C4)alkyl-N(RD! % -S(0)2-N(RD11)RDUC, -S(0)2-N(H)C(0)-(Ci-C4)alkyl, -S(0)2-N(H)C(0)0-(C1-C4)a]kyl, -S(0)2-N(H)C(0)-N(RDU)RDi IB, -S(0)2-(Ci-C4)alkyl; -C(0)-heterocycloalkyl optionally substituted with RDH B; -C(0)-N(H (Ci-C6)alkyl optionally substituted at the aikyl group with I or 2 RD l lB; heterocycloalkyl optionally substituted with oxo or RDH; beterocycloalkenyl optionally substituted with oxo or RDi l ; heteroaryl optionally substituted with RDU; -0-(CrC4)alkyl optionally substituted at the aikyl group with 1 or 2 RD! lB; -S(0)2-(4-6 memberedjheterocycioaikyl optionally substituted with R:J! 'C; -N(H)-C(0)-(Ci-C4)alkyl optionally substituted at the aikyl group with 1 or 2 Rbl ie; -N(H)-C(0)-N(H)-(Ci-C3)aikyl optionally substituted at the aikyl group with R0! iB; -(Ci-C5)alkyl optionally substituted with 1 or 2 RD1 ! Fs; -Ci NM i-\' I I >. and -C≡C- i C Y-C aik ! optionally substituted with RDi i B;
each R1-" 1 is independently selected from H, -(C3-Ce)cycloalkyl, -(Ci-C )haloalkyl; -OH, -S(0)2OH, C(0)OH, -NIL, -N(H)C(== H)NH2; -(C C )alkyl optionally substituted with halo, -OH or -C(0)OH; -(Ci -Csjalkyl-phenyl optionally substituted at the phenyl group with one, two, or three substituents selected from methoxy, hydroxy! and halo;
RDUB is selected from H, -OH, -CF3, - (RD1 !)2, -C(0)OH, -O-Cd-OOaJkyl, -S(0)2OH, C i Ni l ) Ni l ,. -N(H)C(-NH)NH2, ( i i ! ) W'i i i SC 'i ΝΠ ί\Η >.
-0-(Ci-C4)alkyl-C(0)OH, - (H)C(=NH)-N(H)C(=NH)NH2, (5-6 memberedjheteroaryl, -C(0)-(Ci-C3)alkyl; -(Ci-C4)alkyl optionally substituted with one, two, or three groups independently selected from halo and -OH; ~(C[-C4)alkyl optionally substituted with one, two, or three groups independently selected from halo, -OH, -S(0)2OH, -C(0)OH, -NH2, and -N(H)C =NH)NH2; -{Co-Cj)alk l-(5-8 membered)heterocycloalkyl optionally substituted with 1, 2 or 3 Rba; -(Co-C3)alkyl-(C3-C6)cycloalkyl optionally substituted with RD l i ; and -(C6-Cio)aryl optionally substituted with one, two, or three halo;
or lj1 1 and RhUb, when they both exist and are each attached to nitrogen, can join together with the nitrogen to which they are attached to form a (5-6 membered heterocycloalkyl optionally substituted with a group selected from -OH, -(Ci-C4)haloaJkyl, -S(0)2OH, C(0)OH, -NH2, -N(H)C(=NH)NH2, -(C3-C6)cycloalkyl; -(Ci-C4)alkyl optionally substituted with halo, -OH or -C(0)OH; and -(C; -C3)aikyl-phenyl optionally substituted at the phenyl group with one, two, or three substituents selected from methoxy, hydroxy! and halo;
RDnc is selected from H, -OH, -CF3, -0-(Ci-C4)alkyl, -(Ci
Figure imgf000063_0001
-(Co-C3)alkyl-(5-6 membered)heteroaryl; -(Ci-C4)alkyi optionally substituied with one, two, or three groups independently selected from halo, -OH, -S(0)2OH, C(0)OH, -NH2, and N(H)C(=NH)NH2; -(C0-C3)alkyl-(5-6 membered)heterocycloalkyl optionally substituted with a -(5-6 membered)heteroaryf; -(Co-C3)alkyl-(5-6 membered)heterocycloalkyl substituted 1 , 2 or 3 groups selected from selected from -OH and -(Ci-Csjalkyl; and -(C --C3)alkyi»aryl optsonally substituted at the aryl group with one, two, or three halo;
R5 is -[C(R8)2]-QA
R5 is -LC(R8)2]-QA -[C(R8)2]-phenyL -[C(R8)2]-naphihalenyL or -[C(R8)2]-(5-10 membered) heteroaryl, wherein the heteroaryl is selected from (benzo[d] [ 1 ,3 Jdioxolyl, bcnzo[d]isoxazo3yl, quinoxalinyl, quinolinyl and 2,3 ,4a,8a-tctrah.ydrobcnzo[b] [ 1 ,4]dioxinyl, wherein the cyclic group of R3 is optionally substituted with wherein the 1-5 RA I° groups, wherein the 1-5 R' 1 groups are independently selected from R'" J" groups and R' ' J groups, provided that R3 cannot be substituted with more than two RA! 0B groups;
each Ra1ua , when they occur, is independently selected irom halo, alkoxyi, hydroxy 1, -CM, -OCF3, t ( rC ' aikyl and -N¾,
each RA10B , when they occur, is selected from -0-(Ci
Figure imgf000063_0002
-S(0)2-NiH2, -S(0)2CH3, -N(H)-S(0)2CH3, -SiO i i i ί )-< i h. -C(0)OH, -(Ci-C4)alkyl-OH, -C(0)NH2, and -(Ci-C4)alkyl substituted with one, two, or three groups selected from -OH and halo;
RAl i is selected from -C(0)OH, (5-6 membered jheteroeycloaikyi, halogen, cyano, nitro, -(CrC4)alkyl, -M(RA! 2)2, -ORA12, -SRA!2, -N(0RA!2)RA5 2, -C(0)RA,2 s -C(0)ORA12, -C(0)N(RAi2)2, -N(RA12)S(0)RA12, -N(RA12)S(0)2RA12, -S(0)N(RA12)2, -S(0)2N(RAi2)2, -S(0)2RAi2, -0C(0)RAi2, -OC(0)ORA12, -OC(0)N(RA12)2, -N(RA12)C(0)RA12, -N(RA!2)S(0)2RA12, -N(RA12)C(0)ORA12, -N(RAi2)C{0)N(RAi )2,
■'N(RA!2)C(^MRAi 2) (RA I/')2, and heteroaryl, wherein each RAi 2 is independently hydrogen, -CCi-C4)alkyl, or -(Ci-C4)haloalkyl;
wherein R\ when R5 is not -[C(R8)?,]-QA , is substituted with one or two QA groups, wherein R5 is substituted with QA by replacing a hydrogen that is covalently bonded to carbon or nitrogen;
each R& is independently hydrogen, halogen, or methyl, or both R8 taken together with the carbon to which they are both attached form either a (C3-Ce)cycloalkyl or a (3-6 membered)heterocycloalkyl;
QA is QL or QR;
QL is -N[(Ci-C3)alkylj3 ÷ wherein an alkyl group of -N[(Ci-C3)alkyl]3+ is optionally substituted with ~(C0-C6)aUcyl-S{O)2OH;
Qk is selected from:
Figure imgf000064_0001
R(*'A is -(Ci-Cejalkyl;
RQB is -(Ci-Ce)alkyl optionally substituted with -C(0)OH; and
RQC is H, -OH, -(Co-C4)alkyl-COOH or -(Ci-C6)alkyl.
2. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
X is =C(R4)-;
each R is independently selected from H,
Figure imgf000064_0002
-OH, and -C¾OH; Y is -8-, -S(0)2-, -C(H)= (H)-, -C(0 , -(Ci-C4)alkyl-S-, -(Ci-C4)alkyl-N(R , -C(H)(halo)-, -(Ci-C4)alkyl-S(0)2-, -S(0)2-N(RY)-, -(Ci-C4)alkyl-0-, or -C(0)-N(RY)-, wherein R is H, -(Ci-C4)alkyl or hydroxyl(Ci-C4)alkyl;
RD! is selected from phenyl -(C6-Cio)aryl, -N(H)-phenyl, -(Q-Ce^ycloalkyl, heterocycloalkyl, or heteroaryl, wherein RD1 can be optionally substituted with 1, 2, 3 or 4 Rmo, wherein the 1 -4 RbllJ groups are independently selected from A groups and B groups, provided that. M cannot be substituted with more than two B groups;
each A group, when they occur, is independently selected from halo, -CF.3, -CN, -NO?, -OH; -0-(Ci-C4)aikyl optionally substituted at the aikyl group with one, two, or three substituents independently selected from -OH and halo; and -(Q -C4)alkyi optionally substituted with one, two, or three substituents independently selected from -OH and halo; each B group, when they occur, is independently selected from -(Ci -C4)alkylN(RD1 1)2, -C(0)-NH2, -C(0)-N(H)-OH, -C 0)-M(H)-RDU C, -C(0)-(C1 -C4)alkyl, -C(0)OH, -C(0)0-(Ci-C4)alkyl, -S(0)2-(C: -C4)alkyl-N(RD! % -S(0)2-N(RDi l)RD1 5 c, -S(0)2-N(H)C(0)-(Ci-C4)alkyi, -S(0)2-N(H)C(0)0-(Ci-C4)aikyl, -S(0)2-N(H)C(0)-N(RDi l) RDi iB, -S(0)2-(Cj -C4)alkyl; -C(0)-heterocycloalkyi optionally substituted with RD11 B; -C(0)-N(H)-(Ci-Ce)alkyl optionally substituted at the aikyl group with 1 or 2 RmiB; heterocyeloalkyl optionally substituted with oxo or RDU; heterocycloalkenyi optionally substituted with oxo or RDU, heteroaryl optionally substituted with RDn; -0-(Cx-C4)alkyl optionally substituted at the aikyl group with 1 or 2 RD11B; -S(Q)2-(4-6 memberedjheterocycloalkyl optionally substituted with R°l -N(H)-C(0)-(Ci-C4)alkyl optionally substituted at the aikyl group with 1 or 2 RDUB; -N(H)-C(0)- (H)-(Ci-C )alkyi optionally substituted at the aikyl group with RDI I B; -(C'rCejaikyl optionally substituted with 1 or 2 RDI ,B: -C(=NH)-NH2; and -C≡€-(Ct -Ci)alkyl optionally substituted with RDliB;
each RD! l is independently selected from H,
Figure imgf000065_0001
-(Ci-C4)haloalkyl; -OH, -S(0)2OH, C(0)OH, -NH2, -N(H)C(-NH)NH2, -(C C4)alkyl optionally substituted with halo, -OH or -CfO)OH; -(Ci -C-jjalkyl-phenyl optionally substituted at the phenyl group with one, two, or three substituents selected from methoxy, hydroxy! and halo;
RDUB is selected from H, -OH, -CF3, - (RDI !)2, -C(0)OH, -O-Cd-C^alkyl, -S(0)2OH, O Ni l ) N i l ,. -N(H)C(-NH)NH2, -C(H)- N(H)C(-NH)NH2,
-0-(Ci-C4)alkyl-C(0)OH, - < U ) { U ) - < l \ ) { (5-6 memberedjheteroaryl,
-C(0)-(Ci-C3)alkyl; -(Ci-C4)alkyl optionally substituted with one, two, or three groups independently selected from halo and -OH; ~(C[-C4)alkyl optionally substituted with one, two, or three groups independently selected from halo, -OH, -S(0)2OH, -C(0)OH, -NH2, and
Figure imgf000066_0001
-{Co-Cj)alk l-(5-8 membered)heterocycloalkyl optionally substituted with 1, 2 or 3 Rba; -(Co-C3)alkyl-(C3-C6)cycloalkyl optionally substituted with RDii ; and -(C6-Cio)aryl optionally substituted with one, two, or three halo;
or Rlj1 1 and RhUb, when they both exist and are each attached to nitrogen, can join together with the nitrogen to which they are attached to form a (5-6 membered heteroeycloalkyl optionally substituted with a group selected from -OH, -(CrC^haloalkyl, --Sf O bOU C(0)OH, -NH2, -N(H)C(=NH)NH2, -(C3-C6jeyeloalkyL -i d -C i iaikvi optionally substituted with halo, -OH or -C(0)OH; and -(Ci -C3)alkyl-phenyl optionally substituted at the phenyl group with one, two, or three substituents selected from metkoxy, hydroxy! and halo; and
RDnc is selected from H, -OH, -CF3, -0-(Ci~C4)alkyl, -(Ci
Figure imgf000066_0002
-(Co-C3>alkyl-(5-6 membered)heteroaiyl; -(Ci-C4)alkyi optionally substituted with one, two, or three groups independently selected from halo, -OH, -S(0)2OH, C(0)OH, -NH2, and N(H)C(=NH)NH2; -(Co-C3)alkyl-(5-6 membered)heterocycloalkyl optionally substituted with a -(5-6 membered)heteroaryf; -(Co-C3)alkyl-(5-6 membered)heterocycloalkyl substituted 1 , 2 or 3 groups selected from selected from -OH and -(Ci-C3)alkyl; and -(Co-Cj)a{kyi-aryl optionally substituted at the aryl group with one, two, or three halo.
3. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein:
X is -C(R4)-;
Y is a bond, -S-, -S(0)2-, -CH(CH3)-S(0)2-, -CH(C¾)-8-, -Cii(CH3)-S(0)2-, -CH(OH)-. -CH(CH3>-Q~, -C(0>, -(CH2)-S-, -( Ί i >- Ni R · ! ·. --CH(halo)- , -CH2-S(0)2-, -S(0)2-N(RY)-, -(CH2)-0-, or -C(0)-N(RY , wherein RY is H, -(Ci-C3)alkyl or hydroxy 1(C [ -C3)alkyl;
each R is independently selected from H, -C¾, -OH, F, and -CH2OH;
Y is a bond, -S-, -S(0)2-, ·( '! h CH , -Ci li C ' l i.-i i -S - . -CH(CH3)--S(0)2--, -CH(OH)-, -CH(CH3)-0-, .-C(0 , -(CH2)-S-, -CH2- (RY)-, -CH(hafo)-, -CH2-S(0)2-, -S(0)2-N(RY)-, -(CH2)-0-, or O O ) Ni \V ) . wherein RY is H, -(Ci-C3)alkyl or hydroxyI(C j -C3)alkyl,
each R. is independently selected from H, -Π ·: >. -OH, F, and -CH2OH;
R 1 is selected from phenyl, -N(H)-phenyl, -(CyC^cycloalkyl, -(5-6
membered)heterocycloalkyl, -(5-6 membered)heteroaryl-(5-6 member8d)heterocycloalkyl, and -(5-6 membered)heteroaryl, wherein R * is optionally substituted with 1 , 2, or 3 RDIIJ, wherein the one, two, or three RDl° groups are independently selected from A groups and B groups, provided that RD! cannot be substituted with more than one B group;
each A group, when they occur, is independently selected from halo, -CF3, -C , -NO2, -OH; -Q-(Ci-C4)alkyl optionally substituted with one, two, or three substituents independently selected from -OH and halo; and -(Ct-C4)alkyl optionally substituted with one, two, or three substituents independently selected from -OH and halo;
the B group is selected from -O-i C -C i Salkyl-CiO iOl l. -0-(Ci-C4)alkyl, -0-(Ci-C4)alkyl-C(0)-(Ci-C3)alkyL -0-(e, -C4)alkyIN(RDi i }2, -(CT-C4)alkyl-C(0)OH, -(5-6 membered)heteroaryl, ··( '( NH i-N i k. -Sf O .D-Xf H iC's O WC -i ' j ia!kvl,
-S(0)2-N(H)C(0)0-(CrC4)alkyl, -S(0)2-N(H)C(0)-N(H)-(Ci-C4)alkyl, -S(0)2-N(H C(0)-N(H)-(5-6 membered)heterocycloalkyl, -S(0)2-(Ci -C3)alkyl,
-0-« VtY>»lk>1-Ni i l )-Ci M i j-M k. -0-(Ci-C4 alkyl-(5-6 membered)heteroa.ryl, -(Ci-C4)alkyl (RD1 1)2, -C(0)-NH2, -C(0)-N(H)-OH, -C(0)-N(H)-RD11 C,
-C(0)-(Ci-C3)alkyl, -C(0)OH, -C(0)0-(Ci-C4)alkyl, -S(0)2- H2; -0-(Ci-C4)alkyl-(5-6 membered)heterocycloalkyl optionally substituted with oxo or methyl; -C(0)-(5-6 membered)heterocycloalkyl optionally substituted with -S(0)?OH, -C(0)OH, -NH2, or -C(0)-N(H)-(CrC4)a3kyi optionally substituted at the alkyl group with one or two groups selected from -Si Oj.Oi l. -C(0)OH, - H?, and -N(H)C(= H)NH2; -(5-6 memberediheteroeycloalkyl optionally substituted with oxo or RDi l; -S(0)2-N(H)-(Ci-C4)alkyl optionally substituted at the alkyl group with one or two groups selected from -S(0)2OH, C(0)OH, -NH2, and -N(H)C(=NH)NH2; -S(0)2-N(C1-C3)all{yl-(Ci-C4)alkyl optionally substituted at the (Ci-C4)alkyl group with one or two groups selected from -S(0)2OH, C(0)OH, -MH2, and -N(H)C(=NH)'NH2; -S(0)2-(4-6 membered)heterocycloalkyl optionally substituted with -S(0)2OH, C(0)OH, -NH2, or -N(H)C(=NH)NH2; -N(H)-C(0)-(Ci-C4)alkyl optionally substituted at the alkyl group with one or two groups selected from -S(0)2OH, C(0)OH, - Ni k and -N(H)C(=NH)NH2; •Ni l l 'i O i- Ni i l l-i t V-C aik l optionally substituted at the alkyl group with -S(0)2OH, C(0)OH, -NH2, or -N(H)C(=NH)NH2; -(Ci-C6)alkyl optionally substituted with one or two groups selected from -S(0)2OH, C(0)OH, -NH2, and -N(H)C(==NH)NH2; and -C≡C- (Ci-C3)alkyl optionally substituted with one or two groups selected from -S(0)2OH, C(0)OH, -NH2, and -N(H)C(=NH)NH2;
each RDU is independently selected from H, -(C3-C6)cycloaikyl, -OH, -S(0)2OH, C(0)OH, -NH2, -N(H)C(- H)NH2, -(Cj-C4)haloalkyl; -(Ct-C3)alkyl-phenyl optionally substituted at the phenyl group with one, two, or three substituents selected from methoxy, hydroxy 1 and halo; and -(CrC4)alkyl optionally substituted with halo, -OH or -C(0)OH;
RD1 3B is selected from H, -OH, -CF3, ~ (RDU)2, -C(0)OH, -0-(Ci~C4)alkyl, -S(0)2OH, -Ci \' H i-\H >. -Νί Π ί \l h\' M >. -C(H N(H)C(=NH)NH2, (5-6 membered)heteroaryl, -N(H)C(-NH)-N(H)C(-NH) H2, -0-(Ci-C4)alkyl-C(0)OH,
-(Co-C3)alkyl-(5-8 membered)heterocycloalkyl, -C(0)-(Ci -C3)alkyi; -(Ci-C4)alkyl optionally substituted with one, two, or three groups independently selected from halo and -OH; -(Ci-G alkyl optionally substituted with one or two groups independently selected from halo, -OH, -8(0 )2OH, C(0)OH, -NH2, and -N(H)C(=NH)NH2; -(C0-C3)alkyl-(C3-C6)cycloa3kyi optionally substituted with RDl i, and phenyl optionally substituted with one, two, or three halo; and
RD11C is selected from H, -OH, -CFj, -0-(Ci-C4)alkyl; -(C3-C4)alkyl optionally substituted with one or two groups independently selected from halo, -OH, -8(0)2,01!, C(0)OH, -NH2, and - (H)C(-NH)NH2; -(Co-C3)alkyl-(5-6 membered)heterocycloalkyl; -C(0)-(5-6 membered)heteroeycloalkyl optionally substituted with a (5-6 membered)heteroaryl; -(Co-C3.)alkyl-(5-6 membered)heterocycloalkyl substituted with one, two, or three groups selected from -OH and -(Ci-C3)alkyl; Cr-C4)alkyl-N(H)C(=NH)-ivlH2; -(Co-C3)alkyl-(5-6 membered)heteroaryl; and -(Co-C3)alkyl-phenyl optionally substituted at the phenyl group with one, two, or three halo.
4. The compound according to any one of the above claims, or a pharmaceutically acceptable salt thereof, wherein:
is 0;
Y is a bond, -S-, -S(0)2-, -CH(C¾)-S(0)2-, -CH(C¾)-S», -CH(C¾)-S(0)2-, -CH(OH)-, -CH(C¾)-0-, -C(H)=C(H)-, -C(0)-, -(CH2)-S-, -CH2-N(RY , -CH(halo)-, -CH2-S(0)2-s -S(0)2-N(RY)-, -(CH2)-0-, or -C(0)-N(RY)-, wherein RY is H, -(C C4)alkyl or hydroxy i(Ci-C4)alkyl;
each R is independently selected from H, -(Ci -C2)alkyl, iluoro, -OH, and -CH OH;
RD1 is selected from phenyl, -N(H)-phenyl, cyclohexyl, cyclopentyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, 1,2,3,6-tetrahydropyridine, heteroarylheterocycloalkyl, pyridinyl, oxazolyl, pyrazinyl, quinolinyl, 1,2,4-oxadiazolyl, 1,2,3,4-tetrahydroquinolinyl, and pyrazolyl, wherein R.D1 can be optionally substituted 1 , 2 or 3 RDl°, wherein the one, two, or three RlJi0 groups are independently selected from A groups and B groups, provided that Rm cannot be substituted with more than one B group; each A group, when they occur, is independently selected from halo, -CF5, -CN, ■NO?, -OH: ~0-(C]-C4)alkyl optionally substituted with one, two, or three substituents independently selected from -OH and halo; and -(Cj -C4)alkyl optionally substituted with, one, two, or three substituents independently selected from -OH and halo;
the B group is selected from -0-(Ci-C4)alkyl-C(0)OH, -0-(Ci -C4)alkyl, -0-(Cj -C4)alkyl-C(0)-(Ci -C3)alkyl, -0-(Ci -C4)alkylN(RD1 ¾,
-0-(C1-C4)a3kyl-N(H)-C(=NH)-NH2, -0-(Ci-C4)alkyl-(5-6 membered)heteroaryl, -(Ci-C4)alkylN(RD11)2, -C(0)~NH?, -C(0)-N(H)-OH, -C(0)-N(H)-RD11C,
-C(0)-(Ci -C4)alkyl, -(Ci-C4)alkyl-C(0)OH, -C(0)OH, -C(0)0-(Ci-C4)alkyl, -S(0)2-(Ci-C4)alkyl-N(RD1) )2, -S( 0)2-NH2, -S(0)2-N(H)C(0)-(C1-C4)alkyl, -S(0)2-N(H)C(0)0-(CrC4)alkyl, -S(0)2-N(H)C(0)-N(H)-(Ci-C4)alkyl, -S(0)2-N(H)C(0)-N(H)-morpholiny], -S(0)2-N(H)C(0)-N(H)-pyrrolidinyl, -S(0)2-N(H)C(0)-N(H)-piperidinyl, -S(0)2-CH3, -Ci NH :-NI i 2,3-dihydro-lH-tetrazoiyi; -0-(C|-C4)alk '{ optionally substituted at the alkyl group with 1 or 2 RJ, ,B; -0-(Ci-C4)alkyl-(5-6 memberedjheterocyeloalkyi optionally substituted with oxo or methyl; -C(0)-heteroeyck>alky3 optionally substituted with -S(0)2OH, C(0)OH or -NH2; -C(0)-N(H)-(Ci-C4)alkyl optionally substituted at the alkyl group with one or two groups selected from -S(0)2OH, C(0)OH, - H2 and -N(H)C(-NH)NH2; lieterocycloafkyl selected from lH-tetrazolyl, piperizinyl, 2,3-dihydro-l,3,4-oxadiazolyi and
4,5-dihydro-l ,2,4-oxadiazolyl optionally substituted with oxo or ~(Ci -C4)alkyi; -S(0)2-N(tf)-(Ci-C4)alkyl optionally substituted at the alkyl group with one or two groups selected from -S(0)2OH, C(0)OH, -NH2, and -N(H)C(=NH)NH2; -S(0)2-N(CrC3)alkvi-(CrC4)alkyi optionally substituted at the (Ci-C4)alkyl group with one or two groups selected from -S(0)2OH, C(0)OH, -NH2, and -N(H)C(=NH)NH2; -S(0)2-(4-6 menibered)heterocycloalkyl optionally substituted with -S(0)2OH, C(0)OH, -NH2, or -N(H)C(=NH)NH2; -N(H)-C(0)-(Ci-C4)alkyl optionally substituted at the alkyl group with one or two groups selected from -S(0)2OH, C(0)OH, -N¾, and -N(H)C(=NH)NH2; ~N(H)~C(O)- (H)-(Ci-C: alkyl optionally substituted at the alkyl group with a group selected from -S(0)2OH, C(0)OH, -NH2 and -N(H)C(=NH)NH2; (Ci-C6)alkyl optionally substituted with one group selected from -S(0)2OH, C(0)OH, -NH? and -N(H)C(-NH)NH2; and -OC- (Ci-C3)alkyl optionally substituted at the alkyl group with one group selected from -S(0)2OH, C(0)OH, -NH2, and -N(H)C(=NH)NH2;
each R°" is independently selected from H, -(C3-C6)cycIoalkyl, -(Ct-C4)alkyl optionally substituted with halo, -OH or -C(0)OH, -OH, -S(0)2OH, C(0)OH, -NH?, -M(H)C(= I) -I?,; -(Ci-C3)alkyl-phenyl optionally substituted at the phenyl group with one, two, or three substituents selected from methoxy, hydroxy! and halo, and -(Cj-C4)haloalkyl;
RD1 3B is selected from H, -OH, -CF3, -NH2, -C(0)OH, -0-(Ci-C4)alkyl, -S(0)2QH, -O Νί Π-ΧΗ ,. -N(H)C(= fT) H2, -C(H)= N(H)C(=NH) H¾
-N(H)C(= H N(H)C(= H)NH2, -C(0)-(Ci-C3)alkyl, -(C C4)aikyl optionally substituted with one, two, or three groups independently selected from halo and -OH; ~(CH2)j -4-C(0)OH, -(Ci-C4)alkyl optionally substituted with one or two groups independently selected from halo, -OH, -S(0)2OH, ( ! () :()! 1. -NHj, and -Ni l i ¾f ; Xl hXi h: -0-(Ci-C4)alkyl-C(0)OH; a heterocycloa!kyl selected from morphoiinyi, pyrro!idinyi, piperazinyi, and piperidinyl, wherein the heterocycloalkyl can be optionally substituted with one, two, or three RDH; cyciopropanyl; cyclopentyl; imidazolyl; pyridinyl; thiazolyl; l(H) etrazo!yl; and phenyl optionally substituted with one, two, or three halo,
or R'"" 1 and R lB, when they both exist and are each attached to nitrogen, can join to form a (5-6 membered) heterocycoalkyl optionally substituted with R3 '; and
RDl iC is selected from H, -OH, -CF3, -0-(Ci-C4)alkyl, -(Ci-C4)aikyi optionally substituted with one or two groups independently selected from halo, -OH, -S(0)2OH, C(0)OH, -NH2 and -N(H)C(=NH)NH2; a heterocycloalkyl selected from morphoiinyi, pyrrolidinyl, piperidinyl and piperazinyi, wherein the heterocycloalkyl is optionally substituted with a (5-6 memberedjheteroaryl; -Co-C3alkyl-(5-6 membered)heterocyc3oalkyl, wherein the (5-6 membered jheterocycioalkyl group of -Co-C3alkyl-(5-6 membered)heterocycloalkyl is selected from morphoiinyi, pyrrolidinyl, piperidinyl and piperazinyi and wherein the -GrC3alkyl-(5-6 mcmbcrcdjhctcrocycloalkyl group is substituted with one, two, or three substituents selected from -OH and -(Cx-C3)alkyl; -(Ci -C4)alkyl-N(H)C(=NH)-NH2; -Co-C3alkyl-imidazolyl; -Co-C3alkyl-pyridinyl; and -Co-C3alkyl-phenyl optionally substituted at the phenyl group with one, two, or three halo.
5. The compound according to any of the above claims, or a pharmaceutically acceptable salt thereof, wherein;
X is =C(H ;
p is 0;
Y is a bond, -S-, -S(0)2-, -CH(CH3)-S(0)2-, -CH(C¾)-S», -CH(CH3)-S(0)2-, -CH(OH)-, -CH(CH3)-0-, -C(H)=C(H)-, -C(0)-, -(CH2)-S-, -CH2-N(RY , -CH(halo)-, -CH2-S(0)2-, -S(0)2-N(RY)-, -(CH2)-0-, or ~C(0)-N(RY)~, wherein RY is H, -(C C4)a!kyl or hydroxy 1(C i -C4)alkyl; each R is independently selected from H, -(Ci -C2)alkyl, fiuoro, -OH, and -CH2OH;
RD1 is selected from phenyl -N(H)-phenyl, cyclohexyl, cyelopentyl, piperidinyl, piperazinyl, pyrrolidinyl, mo holinyl, 1 ,2,3,6-ietrahydropyridinyl, heteroaryl eterocycloalkyl, pyridinyl, oxazolyl, pyraziny], quinolinyl, 1 ,2,4-oxadiazolyl, 1,2,3,4-tetrahydroquinolinyl, and pyrazolyl, wherein RD1 is substituted with one, two, or three RDl°, wherein the one, two, or three RDUl groups are zero, one, or two A groups and zero or one B group;
each A group, when they occur, is independently selected from halo, -CF.3, -CN, -NO?, -OH; -0-(C j -Chalky 1 optionally substituted with one, two, or three substituents independently selected from -OH and halo; and -(C[-C4)alkyl optionally siibststuted with one, two, or three substituents independently selected from -OH and halo;
the B group, when it occurs, is selected from -O-iC-. -CYjalkyl optionally substituted at the alkyl group with 1 or 2 RDUB; -0-(Cj-C4)alkyi-C(0)OH; -0-(C,-C4)alkyl; -0-(Ci-C4)alkyl-C(0)-(Ci-C3)a]kyl; -0-(Ci-C4)alkylN(RDl l)2; -0-(Ci-C4)alkyl-N(H)-C(-NH)-NH2; -0-(Ci-C4)alkyl-(5-6 membered)heteroaryl;
-0-(Ci-C4)alkyl-(5-6 membered)heterocycloalkyl optionally substituted with oxo or methyl; -(Ci-C4) kylN(RD11)2; -C(0)-NH2; -C(0)-N(H)-OH; -C(0)-N(H)-RD11C;
-C(0)-(Ci-C4)alkyl; ~C(0)OH; -C(0)0-(Ci-C4)alkyl; -C(0)-heterocycloalkyl optionally substituted with -S(0)2OH, C(0)OH, or -NH2; -C(0)-N(H)-(Ci-C4)alkyl optionally substituted at the alkyl group with one or two groups selected from -S(0)20H, C(0)OH, »NH2, and -N(H)C(=NH)NH2; -(Ci-C4)alky1-C(0)0H; 2,3-dihydro-l H-tetrazolyl; hcicrocycloalkyi selected from 1 H-tctrazolyl , pipcrizinyi, 2,3-dihydro- l ,3,4-oxadiazolyl, and 4,5-dihydro-l ,2,4-oxadiazolyl, wherein the heterocycloalkvl is optionally substituted with oxo or -(C i -C4)alkyl; -S(0)2-(CVC4)aikyl-N(RD! !)2; -S(0)2-NH2; -S(0)2- (H)-(C | -C4)alkyi optionally substituted at the alkyl group with one or two groups selected from -S(0)2OH, C(0)OH, - H2 and -N(H)C(-NH)NH2); -S(0)2-N(CrC3)alkyl-(C1-C4)alky} optionally substituted at the (Ci -C4)alkyl group with one or two groups selected from -S(0)2OH, C(0)0H, -MH2, and -N(H)C(=NH)NH2; -S(Q)2-(4-6 memberedjheterocycloalkyi optionally substituted with -S(0)2OH, C(0)OH, - H2 or - (H)C(=NH)NH2; -S(0)2-N(H)C(0)-(Ci -C4)alkyl; -S(0)2-N(H)C(0)0-(C rC4)alkyi;
-S(0)2-N(H)C(0)- (H)-(C| -C4)alkyi; -S(0)2-N(H)C(0 )-N(H)-morpho3inyi; -S(0)2-N(H)C(0)- (H)-pysTolidinyl; -S(0)2-N(H)C(0)-N(H)-piperidinyl; -S(0)2-CH,; -N(H)-C(0)-(Ci-C4)alkyl optionally substituted at the alkyl group with one or t o groups selected from -S(0)20H, C(0)OH, -NH2> and -N(H)C(=NH)NH2; -N (H)-C(0)-N(H)-(Ci -C3)alkyl optionally substituted at the alkyl group with a group selected from -S( 0 > >OM . C(0)OH, -NH2, and -N(H)C(-NH)NH2; -(C C6)a}kyl optionally substituted with one group selected from -S(0)2OH, C(0)OH, -NH2 and -N(H)C(=NH)NH2; -C(=NH)-NH2; and -C≡C-( d -QOalkyl optionally substituted at the alkyl group with one group selected from -S(0)2OH, C(0)OH, -NH2) and -N(H)C(=NH)NH2;
each Rbl 1 is independently selected from H, -(Cs-Cejcycloalkyl, -OH, -SiO)2OH, C(0)OH, -NH2, -N(H)C(=NH)NH2; -(d-C4)alkyl optionally substituted with halo, -OH, or - C(0)OH; -(Ci-C,5)alkyl-phenyl optionally substituted at the phenyl group with one, two, or three substiiuents selected from methoxy, hydroxy! and halo; and -(d-C4)haloalkyl;
RD! 3B is selected from H, -OH, -CF3, -NH2, -C(0)OH, -0-(Ci-C4)alkyi, -S(0)2OH, -Ci ΧΙ Π-ΧΗ ,. -N(H)C(=NH)NH2, -C(H)^N(H)C(-NH)NH2, -0-(Ci-C4)alkyl-C(0)OH, -N(H)C(-NH)-N(H )C(-NH)NH2, ~C(0)-(d~d)alkyl, -(CH2)i-4-C(0)OH, eyclopropanyl, cyclopentyl, imidazolyl, pyridinyl, thiazolyl, l(H)-tetrazolyl; -(d-C4)alkyl optionally substituted with one, two, or three groups independently selected from halo and -OH; -(d-dj)alkyl optionally substituted with one or two groups independently selected from halo, -OH, -S(0)2OH, C(0)OH, -NH2, and -N(H)C(- H)NH2; a heterocycloalkyl selected from morphoiinyl, pyrrol idinyl, piperazinyl, and piperidinyl, wherein the heterocycloalkyl is optionally substituted with i, 2 or 3 Ro , and phenyl optionally substituted with one, two, or three halo,
or RD" and RD UD, when t ey both exist and are each attached to nitrogen, can join to form a (5-6 membered) heteroeycoalkyl optionally substituted with R1 ' ; and
RDUC is selected from H, -OH, -CF3, -0-(C C4)afkyl; -(Ci-C4)all yl optionally substituted with one or two groups independently selected from halo, -OH, -S(0)2OH, C(0)OH, -NH2, and -N(H)C(=NH)NH2; -i d -d iaik y i Xi Π SO N i b -N i b: -QrC3alkyl-imidazolyl; -Co-daU yl-pyridinyl; a heterocycloalkyl selected from morphoiinyl, pyrrolidinyl, piperidinyl and piperazinyl, wherein the heterocycloalkyl is optionally substituted with a (5-6 membered Jheteroaryl; -Co-C3alkyl-(5-6 membered)heterocyeloalkyl, wherein the (5-6 memberedjheterocycioalkyl group of -Co-C-?alkyl-(5-6 membered)heterocycloalkyl is selected from morphoiinyl, pyrrolidinyl, piperidinyl, and piperazinyl, and wherein the -(5-6 membered)heterocycloalkyl group is substituted with a one, two, or three groups selected from -OH and -(Ci-Cj)alkyl; and -Co-O^alkyl-phenyl optionally substituted at the phenyl group with one, two, or three halo.
6. The compound according to any one of the above claims, or a pharmaceutically acceptable salt thereof, wherein:
X is =C(R4)-;
p is 0;
Y is a bond, -8-, -8(G)2-, -CH(CH3)-S(0)2-, -CH(C¾)-S-, -CH(C¾)-S(0}2-, -CH(OH , -CH(CH3)-0-, -( 'i l n O H }- . -C(O)-, -(CH2)-S-, -CH2-N(RY , -CH(halo)-, -CH2-S(0)2-, -S(0)2-N(RY)-, -(CH2)-0-, or -C(0)- (RY)-, wherein RY is H, -(C C4)alkyl or h droxy l(Ci ~C4)alky 1 ;
each R is independently selected from H, -(Q -C2)alkyl, fiuoro, -OH, and -C¾OH;
RD1 is selected from phenyl, -N(H)-phenyl, eyclohexyl, cyelopentyl, piperidinyl, piperazinyl, pyrrolidinyl, morpbolinyl, 1 ,2,3,6-tetrahydropyridinyl, heteroarylheterocycloalkyl, pyridinyl, oxazolyl, pyrazinyl, quinolinyl, 1 ,2,4-oxadiazolyl, 1 ,2,3,4-tetrahydroquinoiinyl, and pyrazolyl, wherein RD1 is substituted with 1 , 2 or 3 RD l°, wherein the one, two, or three RD,° groups are zero, one, or two A groups and one B group; each A group, when they occur, is independently selected from halo, -CF3, -CN, -NO?, -OH; -0-(Ci -C4)alkyl optionally substituted with one, two, or three substituents independently selected from -OH and halo; and -(Ci-C4)a3kyl optionally substituted with one, two, or three substituents independently selected from -OH and halo;
the B group is selected irom -0-(Ci-C4)alkyl-C(0)OH, -0-(Ci -C4)alkyl, -Q-(C i■€4)alkyl- C(0)-(C i-C3)alky 1, -C(0)OH, -NH2, -(C i -Chalky l--C(0)OH, 2,3-dihydro-lH-tetrazolyl, -0-(Ci-C4)alkylN(RD11 )2, -0-(Ci-C4)a1kyl-N(H)-C(=NH)-NH2, -0-(C r C4)a]kyi-C5 -6 mcmbcrcd)hctcroaryl, -(C , -C4)alkylN(RD1 !)2 , -C(0)- H2, -C(0)-N(H)-OH, -C(0)-N(H)-RD! !C, -C(0)-(C C4)alkyl, -C(0)OH, -C(0)0-(d-C4)alkyl, •S( ()) ! -( ( V.C i :aik l. Ni R l ; n ! >. -S(0)2-NH2, -S(0)2- (H)C(0)-(C, -C4)alkyl,
-S(0)2-N(H)C(0)0-(Ci-C4)alkyl, -S(0)2-N(H)C(0)- (H)-(Ci-C4)alkyl, -S(0)2-N(H)C(0)-N(H)-morpholinyl, -S(0)2-N(H)C(0)-N(H)-pyrrolidinyl, -S(0)2-N(H)C(0)-N(H)-piperidinyl, -S(0)2-CH3, ··( ( M i :-NI \ . ··<)··; C ; -C4)alkyl optionally substituted at the alkyl group with one or two s h; -0-(Ci -C4)alkyl-(5-6 membered)heterocycloalkyl optionally substituted with oxo or methyl; -C(0)-heterocycloalkyl optionally substituted with -S(0)?0H; -C(0)-N(H)-(Ci -C4)alkyl optionally substituted at the alkyl group with one or two groups selected from -S(0)2OH, C(0)OH, ~'NH2 and -N(H)C(=NH)NH2; heterocycloalkyl selected from lH-tetrazolyl, piperizinyl, 2,3 -dih dro- 1 ,3 ,4-oxadiazoly I, and 4,5-dihydro- 1 ,2,4-oxadiazolyl, wherein the heterocycloalkyl can be optionally substituted with oxo or -(C] -C4)alkyl; -S(0)2-N(H)-(Ci-C_j)alkyl optionally substituted at the alkyl group with one or two groups selected from -S(0)2OH, C(0)OH, -NH2, and -N(H)C(-NH)NH2; -S(0)2-N(Ci-C3)alkyl-(Ci-C4)alkyl optionally substituted at the (Ci-C4)alkyl group with one or two groups selected from ~S(O)2OH, ~C(0)OH, -NH2, and -V H iO X U iX U .: -S(0)2-(4-6 membered)heterocycloalkyl optionally substituted with -8(Q)?OH, C(0)OH, -NH2, or -N(H)C(=NH)NH2; -N(H)-C(0)-(C C4)alkyl optionally substituted at the alkyl group with one or two groups selected from -S(0)2OH, C(0)OH, -NH2, and -N(H)C(=NH)NH2; -N(H)-C(0)-N(H)-(Ci -C.5)aikyl optionally substituted at the alkyl group with a group selected from -Si O bOi i . C(0)OH, -\M.> and -N(H)C(=NH)NH2; ·; ' i -C f. )a=k y 1 optionally substituted with one group selected from -S(G)2OH, C(0)OH, -NH2 and -N(H)C(=NH)NH2; and -OC- (Ci~C3)alkyi optionally substituted at the alkyl group with one group selected from -S(0)2OH, C(0)OH. -NH2 and -NU hO N! i iX I ! .;
each RD l ! is independently selected from H, -(C3-Ce)cycloalkyl, -OH, -(Ci-C4)haloalkyl -8(0)2OR C(0)OH, -NH2, - (H)CH H)NH2; -(Ci-C4)alkyl optionally substituted with halo, -OH or -C(0)OH; and -(Ci~C )alkyl~phenyl optionally substituted at the phenyl group with one, two, or three substituents selected from methoxy, hydroxy! and halo;
RD, 3B is selected from H, -OH, -CF3, -NH2, -C(0)OH, -0-(Ci-C4)alkyl, -S(0)2OH, -C(=NH)-NH2, -N(H)C(=NH) H2, -C(H)=NN(H)C(=NH)NH2,
-N(H)C(=NH N(H)C(=NH)'NH2, -C(0)-(Ci-C3)alkyl, -0-(Ci-C4)aikyl-C(0)OH, ■■(CH2)i ..4-C(0)OH, cyclopropanyl, cyelopentyi, imidazolyl, pyridinyl, thiazolyl, l (H)-tetrazolyl; -(CrC4)alkyl optionally substituted with one, two, or three groups independently selected from halo and -OH; -(Ci -C4)alkyi optionally substituted with one or two groups independently selected from alo, -OH, -S(Q)2OH, C(0)OH, -NH2> and -N(H)C(=NH)NH2; a heterocycloalkyi selected from morpliolinyl, pyrrolidinyl, piperazinyl, and piperidinyl, wherein the heterocycloalkyi is optionally substituted with one, two, or three RDu; and phenyl optionally substituted with one, two, or three halo;
or K°! ' and RD UB, when they both exist and are each attached to nitrogen, can join to form a (5-6 membered) heterocycoalkyl optionally substituted with R3 '; and
RDUC is selected from H, -OH, -CF3, -0-(Ci-C4)alkyl, ■{C1-C4)alkyl- (H)C(= H)-NH2, -C0-C3a3kyHmidazoryl, -Co-C3alkyl-pyridinyl;
-fCi-C4)alky{ optionally substituted with one or two groups independently selected from halo, -OH, -SiO)2OH, C(0)OH, -NH2, and -N(H)C(=NH) H2; a heterocycloalkyi selected from morpholinyl, pyrrolidinyl, piperidinyl and piperazinyl, wherein the heterocycloalkyi is optionally substituted with a (5-6 memberedjheteroaryl, -Co-C3alkyl-(5-6 membered)heterocyxloalkyl, wherein the (5-6 membered)heteroc cloalkyl group of -Co-C3alkyl-(5-6 membered)heterocycloalkyl is selected from morpholinyl, pyrrolidinyl, piperidinyl, and piperazinyl, and wherein the -Co-C3alkyl-(5-6 membered)heterocycloalkyl group is substituted with a group selected from one, two, or three groups selected from -OH and -(Ct-C3)alkyl; and -Co-C3alkyI-phenyl optionally substituted at the phenyl group with one, two, or three halo,
7. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein LD is selected from -(Ci-Cujalkyi-O-, -(Co-C3)alkyl-NR¾ -(Co-C3)alkyl-, -(Co-C3)alkyl-S-(Co-C3)al] yl-, -(Co-C3)alkyl-S(0)2-(Co-C3)alky1-; -C(0)N(RY)-(Co-C3)alky1-, -S(0)2-N(RY)-(Co-C3)alky]-, -C(0)-(Co-C3)alky1-» -OC-(Co-C3)aIkyl-, -(Co-C3)alkyk and -(C] -C4)alkyl- optionally substituted with halo or -OH.
8. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein LD is selected from: -(CH2)i-3-0-, -(CH2)3 -3-NRY-, -(Co-C3.)alkyl-S-(Co-C3)aikyl-; -(CH2)i-3-S-, - S- i i Ί ! : -S(0)2-(CH2)i.3 .-, -S(0)2-, -C(0)N(H)-<CH2)i.3 .-, -S(0)2-N(H)-(CH2)i.3-, -C(0)-(CH2)i-2-, -C≡C-(Co-C3)alkyl-, a bond, and -(Ci-C4)a!kyl- optionally substituted with halo or -OH.
9. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein LD is selected from ~(CH2)-0-, -(CH2)-NRY~, ~(CH2)-S-, ~S~(CH2)-, -S{0)2-, -S(0)2-(CH2)-, -C(0)N(RY)- Co-C3)alkyl-: -Si O j - Ni i l >-i Ci l > >i ,-. -C ίΟ Ι-Κ Ί Ι ·. !, , -. ■C=C-(C2-C3)a{kyl-, and -(C i -C4)alkyl- optionally substituted with halo or -OH.
10. The compound according to claims 1 , or a pharmaceutically acceptable salt thereof, wherein LD is selected from ~(CH2)-Q-, -(CH2)-NRY-, -(CH2)-S~, -S-(CH2)-, -S(0)2-, -S(0)2-(CH2)-, ·ί'ί() ;·Νί !·ϊν■-{ (' ·.-(' : ialkyk -S(0)2-N(H}-(CH2)i_3--, -C(0}-(CH2)U2--, -C≡C-(C2-C3)alkyl-, and -(Ci~C4)alkyl~ optionally substituted with halo or -OH.
11. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein LD is selected from -(CH2>0-, -(CH2)-NH-, -(CH2)-S-, -S-(CH2 , ~S(0)2~, -S(0)2-(CH2)-, -C(0)N(H)-(CH2)i-3-, -Si O ).>-\'i H M< 1 1 > >, ,-. -Π Ο ι- Ή . ι -CsC-(C2-C3)alkyl- and -(Ci-C4)alkyl- optionally substituted with halo or -OH.
12. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the B group of Dl is selected from: ---
Figure imgf000076_0001
13. The compound according to any one of claims 1 - 12, or a pharmaceutically acceptable salt thereof, wherein R is phenyl, -CH2-phenyl, -(Cs-CeVcycloalkyl, or pyridinyl, wherein RL can be optionally substituted with one, two, or three Rc l°, wherein the one, two, or three Rcl° groups are independently selected from RCi0A and R tjB, provided that cannot be substituted with more than one R JB group;
each RCl0A, when ihey occur, is independently selected from halo; -(Ci-Csjalkyl optionally substituted with one, two, or three groups selected from halo and -OH; niethoxy, -CFs; and halo; and
RC!0B is selected from -C(OjNH2, (5-6 membered)heterocycloalkyl; -0-(Ci-C4)alkyl optionally substituted with -OH, -C(0)OH, or -N[-(Ci-C4)alkyl]2; and -(C1-C4)alkyl substituted with -]S[-(Ci-C4)alkyl]2.
14. The compound according to any one of the above claims, or a pharmaceutically acceptable salt thereof, wherein:
Rc is phenyl, -CH2-phenyl, -(CVCeVeycloaikyi, or pyridinyl, wherein the cyclic group of Rc can be optionally substituted with one, two, or three RCl° groups and, wherein the one, two, or three R'"Kl groups are independently selected from RL 'A and RL K'B, provided that R" cannot be substituted with more than one Rtl0B group;
each RCi 0A, when they occur, is independently selected from niethoxy, -CF3, halo, and -(Ci-C alJkyi optionally substituted with one, two, or three groups selected from halo and -OH; and
R !0b is selected from (5-6 membered)heterocycloalkyl; -(Ci-C4)alkyl substituted with -Ή [-(Ci-C4)alkyl]2; -C(0)MH2; and -0-(Ci-C4.)alkyI optionally substituted with -OH, -C(0)OH, or -N[-(Ci-C4)alkyl]2.
15. The compound according to any one of the above claims, or a pharmaceutically acceptable salt thereof, wherein RL is phenyl, -CH2-phenyl or pyridinyl, wherein the cyclic group of Rc can be optionally substituted with one, two, or three RC1°, wherein the one, two, or three R l° groups are independently selected from R 0A and RUOb, provided that Rc cannot be substituted with more than one RC 10B group;
each R l0A, when they occur, is independently selected from -(CrCjjalkyl optionally substituted with one, two, or three groups selected from -OH, methoxy, -CF3 and halo;
R 10B is selected from -C(0)N¾; (5-6 membered)heteroc cloalky 1 ; -(Ci -C^!aikyl substituted with
Figure imgf000077_0001
and -0-(C [-C4)alkyi optionally substituted with -OH, •Ci O iOl l . or -\ (C : -C : )ai ky l j :.
16. The compound according to any one of the above claims, or a pharmaceutically acceptable salt thereof, wherein Rc is pheny l or pyridinyl, wherein the cyclic group of R ' can be optionally substituted with one, two, or three Ru o, wherein the one, two, or three Ru o groups are independently selected from Κ~ ιθΛ and RC1GB, provided that Rc cannot be substituted with more than one Rct0B group;
each RCU,A, when they occur, is independently selected from methoxy and halo;
RC10B is selected from -C(0)NH2; (5-6 membered)heterocyeloalkyl; -(Ci-C )alkyl substituted with
Figure imgf000077_0002
and -0-(Ci -C4)alkyl optionally substituted with -OH, -C(0)OH, or -N[-(CrC4)alkyl]2.
17. The compound according to any one of the above claims, or a pharmaceutically acceptable salt thereof, wherein Rc is phenyl or pyridinyl, wherein the cyclic group of R'' can be optionally substituted with one or two groups selected from methoxy, methyl and halo.
18. The compound according to any one of claims 1 or 2, or a pharmaceutically acceptable salt thereof, wherein Rc is phenyl or pyridinyl, wherein the cyclic group of Rc can be optionally substituted one or two groups selected from methoxy, methyl, fluoro and chloro.
19. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein RL is phenyl substituted with one or two groups selected from methoxy, fluoro or chloro.
20. The compound according to claim 1, or a pharmaceutically acceptable salt thereof,
Figure imgf000078_0001
Figure imgf000078_0002
wherein one of R 0 or R5 is substituted with one QA group; wherein this substitution with QA occurs by replacing a hydrogen that is covalentiy bonded to carbon or nitrogen.
21. The compound according to claim 20, or a pharmaceutically acceptable salt thereof, wherein
each R o is selected from fluoro, chloro and methoxy;
R2 is -LD-RD1, wherein:
LD is selected from -(CH2)-0-, -(CH2)-NH-, -(CH2)-S-, -S-(CH2)-, -S(0)2-, •ΝίΟ)>·((Ή..}··. -C(0)N(H)-(CH2)]-3-, -S(0)2-N(H)-(CH2)i-3-, -('K)Hi !I ; >·: ·(('··( = sa!kyi- optionally substituted with halo or -OH; and -C≡C-(C2-C3)alkyl; and
R is one ot:
7"?
Figure imgf000079_0001
, wherein each A is cliloro or fluoro, and B is selected from;
ff H
C— N- -0-- (CH2),„4- - (CH,^— R
Figure imgf000079_0002
22. The compound according to any one of the above claims, or a pharmaceutically acceptable salt thereof, wherein: Lu is selected from -(CH2)-0-, -(CH2)- H-, -(CH2)-S-, -S-(CH2)-, -Si ())··. -S; (); ··(( HO- . ••CiOiNiin-iCn.ii .·. -SiO)..-N(!lH('n>)i .·. -C(0)-(CH2)i.2-; -(Ct-C4)alkyl- optionally substituted with o or -OH; and -C≡€-(C2-C3)aikyk
23. The compound according to according to any one of the above claims, or a pharmaceutically acceptable salt thereof, wherein L° is selected from -S-(Ci -Chalky!-, -(CH2) -, and -(Ci-Cj)alkyl-O-.
24. The compound according to any one of the above claims, or a pharmaceutically acceptable salt thereof, wherein R5 is -[C(CH3)2]-phenyL -[C(CH3)2]-naphthaienyI, or -[C(CTH )]-(5-10 membered) heteroaryl, wherein the heteroaryl is selected from benzo[d][l,3]dioxolyl, benzo[d]isoxazoiyI, quinoxalinyl, quinolinyl and 2,3,4a,8a--tetrahydrobenzo[b][l,4]dioxirtyl, wherein the cyclic group of R5 optionally substituted with one, two, or three RAl° groups, wherein the one, two, or three RA1° groups are independently selected from Ra10A and RA10B, provided that R5 cannot be substituted with more than one RAKLB group; each RAlUA, when they occur, is independently selected from halo, -(Cj -Cj)alkoxyl and hydroxy!;
RA, 0b is -(CrC4)alkyl optionally substituted with one, two, or three groups selected from -OH and halo; -0-(Ci -C4)a1ky1-C(0)OH; 0-(Ci-C4)a1ky1-N[(Ci-C3)a1ky1]2; -NH2; -S(0)2-NH2; -S02C¾; -N(H)-S02CH3; -S02N(H)-CH3; -CN; -C(0)OH; -(Ci -C4)alkyl-OH; -OCF3; or -€(0)NH2; and
wherein R " is substituted with one QA group, wherein R5 is substituted with QA by replacing a hydrogen that is covalently bonded to carbon or nitrogen.
25. The compound according to any one of the above claims, or a pharmaceutically acceptable salt thereof, wherein R5 is -[C(CH.3)2]-phenyl, and the phenyl group of R5 is optionally substituted with one, two, or three RA1° groups, wherein the one, two, or three RA1° groups are independently selected from RAi 0A and RA l 0B, provided that = cannot be substituted with more than one RAi0B group;
each RA10A when they occur, is independently selected from halo, methoxy, and hydroxy!;
RA10B is ·() ·! ( ·•C i iaikyi- Ci O iOU.
Figure imgf000080_0001
-NH2, -S(0)2-NH2, -SO2CH3, -N(H)-S02CH3, -S02N(H)-CH3! -CN, -C(0)OH, -(Ci-C4)alkyi-OH, -OCF3, -C(0)NH2, or -(Ci-C4)alkyl optionally substituted with one, two, or three groups selected from -OH and halo; and
wherein R5 is substituted with one QA group, wherein R5 is substituted with QA by replacing a hydrogen that is covalently bonded to carbon or nitrogen.
26. The compound according to any one of the above claims, or a pharmaceutically acceptable salt thereof, wherein R5 is -iC(CH3)2j-phenyl, wherein the phenyl group is optionally substituted with one or two groups selected from halo, methoxy and hydroxy!; and wherein R'' is substituted with one QA group, wherein R5 is substituted with QA by- replacing a hydrogen that is covalently bonded to carbon or nitrogen.
27. The compound according to any one of the above claims, or a pharmaceutically acceptable salt thereof, wherein R"1 is -[C(C¾)2] -phenyl, wherein the phenyl group is optionally substituted wit one or two groups selected from halo and methoxy; and
wherein R3 is substituted with one QA group, wherein R5 is substituted with QA by replacing a hydrogen that is covalently bonded to carbon or nitrogen
28. The compound according to any one of the above claims, or a pharmaceutically
Figure imgf000081_0001
29. A composition comprising a compound according to any one of claims 1 - 28 and a pharmaceutically acceptable diluent, excipient, or carrier.
30. A method for treating obesity or type II diabetes in a subject in need of such treatment comprising administering to the subject an effective amount of a compound of any one of claims 1 - 28 or a composition of claim 29.
31. A method for treating obesity or type II diabetes in a subject in need of such treatment comprising co-administering to the subject, simultaneously or sequentially, an effective amount of a compound according to any one of claims 1 - 28 and a second anti-diabetic drug.
32. The method according to claim 31 wherein the anti-diabetic drug is a sulfonylurea, meglitinide, biguanide, alpha-glucosidase inhibitor, glucagon-like peptide (GLP) analog or agonist, amylin analogues, dipeptidyl peptidase-4 (DPP-4) inhibitor, or thiazolidinedione.
33. The method according to claim 31 wherein the anti-diabetic drug is
(2S)- 1 - {2-[(3-hydroxy- 3 -adamantyl)amino]acetyl }pyrrolidine-2-carbonitrile; or
5-((4-(2-(methyl-2-pyridinylamino) ethoxy)phenyl)methyl)-2,4-thiazolidinedione.
34. A method for inducing increased GLP- 3 secretion in cell, in vitro, comprising contacting the cell with an inducing effective amount of a compound of any one of claims I - 28 or a composition of claim 29.
35. A method for treating hyperlipidemia in a subject in need of such treatment comprising administering to the subject an effective amount of a compound of any one of claims 1 - 28 or a composition of claim 29.
36. A method for treating athersclerosis in a subject in need of such treatment comprising administering to the subject an effective amount of a compound of any one of claims 1 - 28 or a composi tion of claim 29.
37. A method for lowering blood glucose in a subject in need of such treatment comprising administering to the subject an effective amount of a compound of any one of claims 1 - 28 or a composition of claim 29.
38. A method for enhancing insulin secretion in a subject in need of such treatment comprising administering to the subject an effective amount of a compound of any one of claims 1 - 28 or a composi tion of claim 29.
39. A method for treating a disease associated with perturbed bile acid metabolism in a subject in need of such treatment comprising administering to the subject an effective amount of a compound of any one of claims 1 -■ 28 or a composition of claim 29.
PCT/US2013/075838 2012-12-17 2013-12-17 Tgr5 agonists having an imidazole or triazole core with subtituent having a quaternary nitrogen WO2014100025A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201261737931P 2012-12-17 2012-12-17
US61/737,931 2012-12-17

Publications (1)

Publication Number Publication Date
WO2014100025A1 true WO2014100025A1 (en) 2014-06-26

Family

ID=49917285

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2013/075838 WO2014100025A1 (en) 2012-12-17 2013-12-17 Tgr5 agonists having an imidazole or triazole core with subtituent having a quaternary nitrogen

Country Status (1)

Country Link
WO (1) WO2014100025A1 (en)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3210469A1 (en) 2016-02-23 2017-08-30 Bayer Cropscience AG Use of substituted thio-1,2,4-triazoles for increasing stress tolerance in plants
US10703761B2 (en) 2016-10-18 2020-07-07 City Of Hope Bile acid receptor modulators and methods of use thereof
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

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
WO2011071565A1 (en) * 2009-12-11 2011-06-16 Exelixis, Inc. Tgr5 agonists
WO2012082947A1 (en) * 2010-12-16 2012-06-21 Irm Llc Compounds and compositions as tgr5 agonists

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
WO2011071565A1 (en) * 2009-12-11 2011-06-16 Exelixis, Inc. Tgr5 agonists
WO2012082947A1 (en) * 2010-12-16 2012-06-21 Irm Llc Compounds and compositions as tgr5 agonists

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3210469A1 (en) 2016-02-23 2017-08-30 Bayer Cropscience AG Use of substituted thio-1,2,4-triazoles for increasing stress tolerance in plants
US10703761B2 (en) 2016-10-18 2020-07-07 City Of Hope Bile acid receptor modulators and methods of use thereof
US11512065B2 (en) 2019-10-07 2022-11-29 Kallyope, Inc. GPR119 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

Similar Documents

Publication Publication Date Title
ES2959622T3 (en) Substituted 4-aminoisoindoline-1,3-dione compounds and their use to treat lymphoma
EP3362443B1 (en) Compounds useful as immunomodulators
WO2014100025A1 (en) Tgr5 agonists having an imidazole or triazole core with subtituent having a quaternary nitrogen
AU2019283951A1 (en) Therapeutically active compounds and their methods of use
JP2019023189A (en) Substituted benzofuranyl and benzoxazolyl compounds and uses thereof
BR112021007115A2 (en) bifunctional compounds for dehydration of btk via the ubiquitin proteosome pathway
EP4083020A1 (en) Protein degradation agent compound preparation method and application
EA028033B1 (en) 3-pyrimidin-4-yl-oxazolidin-2-ones as inhibitors of mutant idh
WO2011071565A1 (en) Tgr5 agonists
CN111892589A (en) Glutaminase inhibitors
EP2064192A2 (en) Compounds and methods for inhibiting the interaction of bcl proteins with binding partners
WO2014033631A1 (en) N-(3-pyridyl) biarylamides as kinase inhibitors
WO2008060569A1 (en) Compounds and methods for inhibiting the interaction of bcl proteins with binding partners
TW201040168A (en) TGR5 agonists
WO2014100021A1 (en) Tgr5 agonists: imidazole and triazole compounds containing a quaternary nitrogen
US20150336960A1 (en) Aryl-substituted fused bicyclic pyridazine compounds
WO2018233620A1 (en) Use of serd with cdk4/6 inhibitor and pi3k/mtor pathway inhibitor
US12071425B2 (en) Phenoxy-pyridyl-pyrimidine compounds and methods of use
TW202130631A (en) 3-(5-methoxy-1-oxoisoindolin-2-yl)piperidine-2,6-dione derivatives and uses thereof
US20230109134A1 (en) Pyridazinone or pyridazine compound and derivative and pharmaceutical composition thereof
EP3897635A1 (en) Substituted 3-((3-aminophenyl)amino)piperidine-2,6-dione compounds, compositions thereof, and methods of treatment therewith
TW202227420A (en) Triazinedione derivatives, preparation method and medical use thereof
UA128084C2 (en) Indazole compounds as mglur4 allosteric potentiators, compositions, and methods of treating neurological dysfunction
CA2856769A1 (en) Novel 2h-indazoles as ep2 receptor antagonists
EP4186901A1 (en) Compound having kinase inhibitory activity

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: 13815925

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: 13815925

Country of ref document: EP

Kind code of ref document: A1