WO2007002559A1 - Pyrazole based lxr modulators - Google Patents

Pyrazole based lxr modulators Download PDF

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Publication number
WO2007002559A1
WO2007002559A1 PCT/US2006/024749 US2006024749W WO2007002559A1 WO 2007002559 A1 WO2007002559 A1 WO 2007002559A1 US 2006024749 W US2006024749 W US 2006024749W WO 2007002559 A1 WO2007002559 A1 WO 2007002559A1
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WIPO (PCT)
Prior art keywords
alkyl
halogen
independently
compound according
cor
Prior art date
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PCT/US2006/024749
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French (fr)
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WO2007002559A8 (en
Inventor
Brett B. Busch
Brenton T. Flatt
Xiao-Hui Gu
Shao-Po Lu
Richard Martin
Raju Mohan
Michael Charles Nyman
Edwin Schweiger
William C. Stevens, Jr.
Tie-Lin Wang
Yinong Xie
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Exelixis, Inc.
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Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=37309323&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=WO2007002559(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Exelixis, Inc. filed Critical Exelixis, Inc.
Priority to EP06785558A priority Critical patent/EP1910307A1/en
Priority to JP2008519444A priority patent/JP5237799B2/en
Priority to CA002613517A priority patent/CA2613517A1/en
Priority to US11/993,806 priority patent/US8703805B2/en
Priority to CN200680030647.2A priority patent/CN101248048B/en
Priority to AU2006261841A priority patent/AU2006261841B8/en
Publication of WO2007002559A1 publication Critical patent/WO2007002559A1/en
Priority to NO20080391A priority patent/NO20080391L/en
Publication of WO2007002559A8 publication Critical patent/WO2007002559A8/en

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Definitions

  • This invention relates to compounds that modulate the activity of liver X receptors (LXRs).
  • the invention also provides pharmaceutical compositions comprising the compounds of the invention and methods of utilizing those compositions for modulating the activity of liver X receptor.
  • pyrazole isomers and derivatives are provided for modulating the activity of LXRs.
  • Nuclear receptors are a superfamily of regulatory proteins that are structurally and functionally related and are receptors for, e.g., steroids, retinoids, vitamin D and thyroid hormones (see, e.g., Evans (1988) Science 240:889-895). These proteins bind to cis-ac ⁇ ng elements in the promoters of their target genes and modulate gene expression in response to ligands for the receptors.
  • Nuclear receptors can be classified based on their DNA binding properties (see, e.g., Evans, supra and Glass (1994) Endocr. Rev.75:391-407).
  • one class of nuclear receptors includes the glucocorticoid, estrogen, androgen, progestin and mineralocorticoid receptors which bind as homodimers to hormone response elements (HREs) organized as inverted repeats (see, e.g., Glass, supra).
  • HREs hormone response elements
  • a second class of receptors including those activated by retinoic acid, thyroid hormone, vitamin
  • fatty acids/peroxisome proliferators (Le., peroxisome proliferator activated receptors or PPARs) and ecdysone, bind to HREs as heterodimers with a common partner, the retinoid X receptors (i.e., RXRs, also known as the 9-cis retinoic acid receptors; see, e.g., Levin et al. (1992) Nature 355:359-361 and Heyman et al. (1992) Cell 55:397-406).
  • RXRs also known as the 9-cis retinoic acid receptors
  • RXRs are unique among the nuclear receptors in that they bind DNA as a homodimer and are required as a heterodimeric partner for a number of additional nuclear receptors to bind DNA (see, e.g., Mangelsdorf et al. (1995) Cell 55:841-850).
  • the latter receptors termed the class II nuclear receptor subfamily, include many which are established or implicated as important regulators of gene expression.
  • There are three RXR genes see, e.g., Mangelsdorf et al (1992) Genes Dev. (5:329-344), coding for
  • RXR ⁇ , ⁇ , and ⁇ all of which are able to heterodimerize with any of the class II receptors, although there appear to be preferences for distinct RXR subtypes by partner receptors in vivo (see, e.g., Chiba et al. (1997) MoI Cell. Biol. 17:3013-3020).
  • RXR ⁇ is the most abundant of the three RXRs (see, e.g., Mangelsdorf et al. (1992) Genes Dev. 6:329-344), suggesting that it might have a prominent role in hepatic functions that involve regulation by class II nuclear receptors. See also, Wan et al. (2000) MoI. Cell Biol. 20:4436-4444.
  • Orphan Nuclear Receptors Included in the nuclear receptor superfamily of regulatory proteins are nuclear receptors for whom the ligand is known and those which lack known ligands. Nuclear receptors falling in the latter category are referred to as orphan nuclear receptors.
  • the search for activators for orphan receptors has led to the discovery of previously unknown signaling pathways (see, e.g., Levin et al., (1992), supra and Heyman et al., (1992), supra).
  • bile acids which are involved in physiological processes such as cholesterol catabolism, are ligands for the farnesoid X receptor (FXR).
  • LXR ⁇ is found predominantly in the liver, with lower levels found in kidney, intestine, spleen and adrenal tissue (see, e.g., Willy, et al. (1995) Gene Dev. 9(9):1033-1045)LXR ⁇ is ubiquitous in mammals and was found in nearly all tissues examined. LXRs are activated by certain naturally occurring, oxidized derivatives of cholesterol (see, e.g., Lehmann, et al. (1997) J. Biol. Chem. 272(6):3137-3140). LXR ⁇ is activated by oxycholesterol and promotes cholesterol metabolism (Peet et al. (1998) Cell 93:693-704). Thus, LXRs appear to play a role in, e.g., cholesterol metabolism (see, e.g., Janowski, et al. (1996) Nature 383:728-731). Nuclear Receptors and Disease
  • Nuclear receptor activity has been implicated in a variety of diseases and disorders, including, but not limited to, hypercholesterolemia (see, e.g., International Patent Application Publication No. WO 00/57915), osteoporosis and vitamin deficiency (see, e.g., U.S. Patent No. 6,316,5103), hyperlipoproteinemia (see, e.g., International Patent Application Publication No. WO 01/60818), hypertriglyceridemia, lipodystrophy, hyperglycemia and diabetes mellitus (see, e.g., International Patent Application Publication No. WO 01/82917), atherosclerosis and gallstones (see, e.g., International Patent Application Publication No.
  • WO 00/37077 disorders of the skin and mucous membranes (see, e.g., U.S. Patent Nos. 6,184,215 and 6,187,814, and International Patent Application Publication No. WO 98/32444), acne (see, e.g., International Patent Application Publication No. WO 00/49992), and cancer, Parkinson's disease and Alzheimer's disease (see e.g., International Patent Application Publication No. WO 00/17334).
  • the present invention provides a compound according the following formulas Ia- d,
  • liver X receptors LXR
  • R 1 , R 2 , R 21 , R 3 , and G are defined herein.
  • compositions and methods for modulating the activity of nuclear receptors are provided.
  • compounds of the invention which are useful for modulating liver X receptors, LXR ⁇ and LXR ⁇ , FXR, PPAR and/or orphan nuclear receptors are provided.
  • the compounds provided herein are agonists of LXR. In another embodiment, the compounds provided herein are antagonists of LXR. Agonists that exhibit low efficacy are, in certain embodiments, antagonists.
  • Another aspect of this invention is directed to methods of treating, preventing, or ameliorating the symptoms of a disease or disorder that is modulated or otherwise affected by nuclear receptor activity or in which nuclear receptor activity is implicated, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formulae Ia, Ib, Ic, or Id, or a pharmaceutically acceptable derivative thereof.
  • Another aspect of this invention is directed to methods of reducing cholesterol levels in a subject in need thereof, comprising administering an effective cholesterol level-reducing amount of a compound of formulae Ia, Ib, Ic or Id, or a pharmaceutically acceptable derivative thereof.
  • Another aspect of this invention is directed to methods of treating, preventing, inhibiting, or ameliorating one or more symptoms of a disease or disorder which is affected by cholesterol, triglyceride, or bile acid levels, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formulae Ia, Ib, Ic, or Id, or a pharmaceutically acceptable derivative thereof.
  • Another aspect of this invention is directed to methods of modulating nuclear receptor activity, comprising contacting the nuclear receptor with a compound of formulae Ia, Ib, Ic or Id, or a pharmaceutically acceptable derivative thereof.
  • Another aspect of this invention is directed to methods of modulating cholesterol metabolism, comprising administering an effective cholesterol metabolism-modulating amount of a compound of formulae Ia, Ib, Ic or Id, or a pharmaceutically acceptable derivative thereof.
  • Another aspect of this invention is directed to methods of treating, preventing, inhibiting or ameliorating one or more symptoms of hypocholesterolemia in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of formulae Ia, Ib, Ic or Id, or a pharmaceutically acceptable derivative thereof.
  • Another aspect of this invention is directed to methods of increasing cholesterol efflux from cells of a subject, comprising administering an effective cholesterol efflux-increasing amount of a compound of formulae Ia, Ib, Ic or Id, or a pharmaceutically acceptable derivative thereof.
  • Another aspect of this invention is directed to methods of increasing the expression of ATP- Binding Cassette (ABC 1 ) in the cells of a subject, comprising administering an effective ABC 1 expression-increasing mount of a compound of formulae Ia, Ib, Ic, or Id, or a pharmaceutically acceptable derivative thereof.
  • ABSC 1 ATP- Binding Cassette
  • Another aspect of this invention is directed to in vitro methods for altering nuclear receptor activity, comprising contacting the nuclear receptor with a compound of formulae Ia, Ib, Ic or Id, or a pharmaceutically acceptable derivative thereof.
  • Another aspect of this invention is directed to methods of reducing cholesterol levels in a subject in need thereof, comprising administering an effective cholesterol level-reducing amount of a compound of formulae Ia, Ib, Ic or Id, or a pharmaceutically acceptable derivative thereof.
  • Another aspect of this invention is directed to pharmaceutical compositions comprising a pharmaceutically acceptable carrier, excipient and/or diluent and a compound of formulae Ia, Ib, Ic or Id.
  • Another aspect of this invention is directed to regulation of cholesterol transport and inflammatory signaling pathways that are implicated in human disease pathology including atherosclerosis and associated diseases such as myocardial infarction and ischemic stroke in a subject in need thereof, comprising administering an effective cholesterol transport and inflammatory signaling pathways regulating amount of a compound of formulae Ia 5 Ib, Ic or Id, or a pharmaceutically acceptable derivative thereof.
  • Another aspect of this invention is directed to treatment of the metabolic syndrome which comprises a constellation of disorders of the body's metabolism including obesity, hypertension and insulin resistance and diabetes including treatment of diseases resulting from compromised metabolism and immunity including atherosclerosis and diabetes as well as autoimmune disorders and diseases in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of formulae Ia, Ib, Ic or Id, or a pharmaceutically acceptable derivative thereof.
  • the present invention provides a compound according to one of the following formulas,
  • R 5 is aryl, heterocyclyl, heteroaryl, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, (C 3 -C 8 cycloalkyl)- C 1 -C 6 alkyl-, (C 3 -C 8 cycloalkenyl)-Q-C 6 alkyl-, (C 3 -C 8 cycloalkyl)-C 2 -C 6 alkenyl, C 3 -C 8 cycloalkyl, -C, -B-C, -A-B-C, wherein A is -O-;
  • B is -[C(R 15 ) 2 ] m - or C 3 -C 8 cycloalkyl
  • Ci-Cealkyl Ci-Cehaloalkyl, SO 2 R 11 , SR 11 , SO 2 N(R n ) 2 , SO 2 NR 11 COR 11 , ON, C(O)OR 11 ,
  • R 5 is optionally substituted with one or more R 5a , wherein each R 5a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -
  • C 8 cycloalkyl (C 3 -C 8 cycloalkyrj-Q-Ce alkyl-, (C 3 -C 8 cycloalkenyl)-Q-C 6 alkyl-, (C 3 -C 8 cycloalkyl)-C 2 -C 6 alkenyl, halogen, nitro, heterocyclyloxy, aryl, aryloxy, arylalkyl, aryloxyaryl, aryl C 1 -C 6 alkoxy, -C, -B'-C, or -A'-B'-C wherein
  • A' is -O-;
  • B' is -[C(R 15 ) 2 ] m - or - C 3 -C 8 cycloalkyl -;
  • Y is -[C(R 15 ) 2 ] m -,-C 2 -C 6 alkenyl, or C 3 -C 8 cycloalkyl;
  • Z is -H, -CN, halogen, -OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)N(R n ) 2 , -N(R ⁇ ) 2 , -CN, -N 3 , -SO 2 R 11 , -S(O) 2 N(R n ) 2 , -C(O)N(R 1 ⁇ N(R 1 ⁇ -C(O)N(R 11 XOR 1 ⁇
  • R 7 is optionally substituted with one or more R 7a , wherein
  • R 7a is halogen, C 2 -C 6 alkenyl, -C 1 -C 6 alkyl-heterocyclyl, -C 1 -C 6 alkyl-heteroaryl, -C 1 -C 6 alkyl-aryl, C 0 -C 6 alkoxyheteroaryl, C 0 -C 6 alkoxyheterocyclyL haloaryl, aryloxy, aralkyloxy, aryloxyalkyl, Ci-C 6 alkoxyaryl, aryl C 0 -C 6 alkylcarboxy,
  • QR ⁇ QR ⁇ -COOR 11 Co-Cealkoxyheteroaryl, Co-C 6 alkoxyheterocyclyl, aryl, heteroaryl, heterocyclyl, C 3 -C 8 cycloalkyl, heteroaryloxy, -Z', -Y'-Z', or -X'-Y'-Z', wherein
  • X' is -O-;
  • Y' is -[C(R 15 )2] m - or C 3 -C 8 cycloalkyl;
  • Z' is -Q-Qalkyl, -Ci-Qjhaloalkyl, -OR 11 , -SR 11 , -S(O) 2 R 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)N(R ⁇ ) 2 , -N(R n ) 2 , -N(R n )C(O)R n ,
  • each R 7a is optionally substituted with one or more R 8 , wherein each R 8 is independently halogen, nitro, cyano, heteroaryl, Ci-C 6 alkyl, Ci-C 6 alkoxy,
  • Y 3 is -0-, -S-, -NR 7 -, -N(R 10 )CO-, -N(R 10 )CO 2 -, -OCO-, -OC(O)N(R 10 )-,
  • L is a C 2-6 alidiyl chain, wherein the alidiyl chain is optionally intem ⁇ pted by -C(R 1 !
  • R 6 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, aryl, C 3 -C 8 cycloalkyl, heteroaryl, heterocyclyl, -CN, -C(O)R 11 , -C(O)OR 11 , -C(O)N(R n ) 2 , -N(R ⁇ ) 2 , -SO 2 R 11 , -S(O) 2 N(R ⁇ ) 2 , -C(O)N(R 1 ⁇ N(R 1 ⁇ or -C(O)N(R n )(0R u ), wherein the aryl, heteroaryl, cycloalkyl, or heterocyclyl is optionally substituted with one or more R 6a , wherein each R 6a is independently -Z , -Y -Z , or -X -Y -Z , wherein X " is-O-;
  • Y " is -[C(R 15 ) 2 ] m -, -C 2 -C 6 alkenyl, C 3 -C 8 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the aryl, heteroaryl, cycloalkyl, or heterocyclyl is optionally substituted with at least one group which is each independently Z";
  • Z " is -H, -CN, halogen, -OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)N(R ⁇ ) 2 , -N(R ⁇ ) 2 , -N 3 , -SO 2 R 11 , -S(O) 2 N(R n ) 2 , -C(O)N(R 1 ⁇ N(R 11 X -N(R 1 ⁇ C(O)N(R 1 ⁇ -OC(O)-OR 11 , -C(O)N(R 11 XOR 11 ), -OC(O)-R 11 , -OC(O)-N(R 1 % or -N(R n )COOR n ; each R 10 is independently -R 11 , -C(O)R 11 , -CO 2 R 11 , or -SO 2 R 11 ; each R 11 is independently -hydrogen, C 2
  • J is aryl, heteroaryl, or absent
  • K is aryl, heteroaryl, or absent; each R 4 is independently halogen, nitro, C 2 -C 6 alkenyl, C 3 -Cg cycloalkyl, -C 1 -C 6 alkyl-heterocyclyl, -Ci-C 6 alkyl-heteroaryl, -Ci-C 6 alkyl-aryl, -heterocyclyl-aryl,
  • -heterocyclyl-heteroaryl CR 1 ⁇ CR 11 COOR 11 , aryloxy, -S-aryl, aralkyloxy, aryloxyalkyl, C 1 -C 6 alkoxyaryl, aryl C 0 -C 6 alkylcarboxy, C 0 -C 6 alkoxyheteroaryl, C 0 -C 6 alkoxyheterocyclyl, aryl, heteroaryl, heterocyclyl, -M, -E-M, or -D-E-M, wherein
  • D is -O-;
  • E is -[C(R 15 ⁇ ] 1n - or C 3 -C 8 cycloalkyl;
  • E' is -[C(R 15 ) 2 ] m - or C 3 -C 8 cycloalkyl
  • M' is -Ci-C 6 alkyl, -Q-Cehaloalkyl, COR 11 , -CON(R U ) 2 , -N(R 1 ⁇ COOR 11 , -N(R n ) 2 , COOR 11 , ON, OR 11 , -NR 11 COR 11 , NR 11 SO 2 R 11 , SO 2 R 11 , SO 2 N(R ⁇ ) 2 , orSR ⁇ ; each R 41 is independently halogen, nitro, C 1 -C 6 alkyl-heterocyclyl, -C 1 -C 6 alkyl-heteroaryl, -C 1 -C 6 alkyl-aryl, -M", -E"-M", or -D"-E"-M", wherein D" is -O-;
  • E is -[C(R I5 )2] m - or C 3 -C 8 cycloalkyl; M" is -Q-Qalkyl, -Q-Cehaloalkyl, -COR 11 , -COOR 11 , -C0N(R n ) 2 , -ON, -OR 11 ,
  • each R 41 is optionally substituted with one or more R 4a ;
  • L 2 is a C 2-6 alidiyl chain, wherein alidiyl chain is optionally interrupted by -C(R 1 ⁇ -, -C(R n ) 2 C(R n ) 2 -, -C(R 11 ⁇ C(R 11 )-, -C(R ⁇ ) 2 0-, -C(R 11 ⁇ NR 11 -, -C(R 1 ⁇ 2 NR 11 -, -OC-, -0-, -S-,
  • q may be 0 only if L 2 is not a bond or if K is not phenyl; ( ⁇ ) the compound is not 2-methyl-5-(l-m-tolyl-3-(trifluoromethyl)-1H-pyrazol-5- yl)benzenesulfonamide;
  • R 1 is not 4-(NH 2 SO 2 )phenyl, 4-(CH 3 SO 2 )phenyl, or 4-(CH 2 FSO 2 )phenyl;
  • R 2 and R 21 are not 4-hydroxyphenyl; (vii) if the compound is defined by formula Ib, then (a) R 2 and R 3 are not 4-(NH 2 SO 2 )phenyl, 4-(CH 3 SO 2 )phenyl, or 4-
  • R 2 and R 3 are not 4-(NH 2 SO 2 )phenyl, 4-(CH 3 SO 2 )phenyl, or 4- (CH 2 FSO 2 )phenyl;
  • R 1 is not 4-Me-phenyl.
  • the invention provides the compound according to formula Ia, Ib, Ic, or Id, wherein: R 1 is -i ⁇ R 5 , wherein
  • L 1 is a bond, L 5 , L 6 , -L 5 -L 6 -L 5 -, or-L 6 -L 5 -L 6 -, wherein each L 5 is independently -[C(R 5 ) 2 ] m -, wherein m is O, 1, 2, 3, or 4; and each R 15 is independently hydrogen, halogen, (Ci-C 6 )alkyl, or (Ci-C 6 )haloalkyl; and L 6 is -CO-, -SO 2 -, -O-, -CON(R 11 )-, -Cs-Qcycloalkyl-, or -heterocyclyl-, wherein the cycloalkyl, or heterocyclyl is optionally substituted with one or more R 14 ; and
  • R 5 is aryl, heterocyclyl, heteroaryl, -C, or -B-C, wherein B is -[C(R 15 ) 2 ] m - or -C 3 -C 6 CyClOaIlCyI-; and C is halogen, -Ci-C 6 alkyl, or -Q-Cshaloalkyl; wherein R 5 is optionally substituted with one or more R 5a , wherein each R 5a is independently halogen, nitro, heteroaryl, heterocyclyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, (C 3 -C 8 cycloalkyl)-Ci-C 6 alkyl-, (C 3 -C 8 cycloalkenyl)-Q-C 6 alkyl-, (C 3 -C 8 cycloalkyl)-C 2 -Ce alkenyl-; aryl, arylalkyl, ary
  • R 2 is-L 3 -R 7 , wherein
  • L 3 is a bond
  • R 7 is, halogen, aryl, heteroaryl, heterocyclyl, -Z, or -Y-Z, wherein Yis -[C(R 15 ) 2 ] m - or -C 3 -C 6 cycloalkyl;
  • Y' is -[C(R 15 ) 2 ] m - or -Cs-Qcycloalkyl
  • R 21 and R 3 are each independently hydrogen, halogen, Q-Cealkyl, or Q-C ⁇ haloalkyl; and G is a group of the formula,
  • J is aryl or heteroaryl
  • K is aryl or heteroaryl
  • each R 4 and R 41 are independently halogen, aryloxy, aralkyloxy, aryloxyalkyl, arylC 0 -C 6 alkylcarboxy, aryl, heteroaryl, heterocyclyl, heteroaryloxy, heterocyclyloxy, -M, -E-M, or - D-E-M, wherein
  • E is -[C(R 15 ) 2 ] m - or -Qs-Cecycloalkyl
  • each R 13 is independently hydrogen, C 1- C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, (C 3 -C 8 cycloalkyl)-d- C 6 alkyl-, (C 3 -Cg cycloalkenyl)-C; ⁇ -C 6 alkyl-, or (C 3 -C 8 cycloalkyl)-C 2 -C 6 alkenyl-; and each R 14 is independently C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogen, C 1 -C 6 haloalkyl, C 0 -C 6 alkylCON(R ⁇ ) 2 , C 0 -C 6 alkylCONR ⁇ OR ⁇ , C 0 -C 6 alkylOR 11 , or C 0 -C 6 alkylCOOR 11 .
  • the invention provides the compound according to formula Ia, Ib, Ic, or Id, wherein: R 1 is -L ⁇ R 5 , wherein
  • L 1 is a bond, -C 3 -C 8 cycloalkyl- or L 5 , wherein each L 5 is independently -[C(R 15 ) 2 ] m -, wherein m is O, 1, 2, or 3; and each R 15 is independently hydrogen, halogen, (CrC 6 )alkyl, or (Q-C ⁇ haloalkyl; and R 5 is aryl, heterocyclyl, heteroaryl, -C, or -B-C, wherein
  • B is-[C(R 15 ) 2 ] m -, -CrQcycloalkyl-; and C is -Q-Qalkyl or -Q-Cshaloalkyl; wherein R 5 is optionally substituted with one or more R 5a , wherein each R 5a is independently halogen, nitro, heteroaryl, heterocyclyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, (C 3 -C 8 cycloalkyO-Q-Ce alkyl-, (C 3 -C 8 cycloalkenyl)-C r C 6 alkyl-, (C 3 -C 8 cycloalkyl)-C 2 -C 6 alkenyl-, aryl, arylalkyl, aryloxy, aryloxyaryl, arylC 1-6 alkoxy, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3
  • each R 5a is optionally substituted with one or more groups which independently are -halogen, -C 1 -C 6 alkyl, aryloxy, Qy 6 alkylSO 2 R n , Q ⁇ alkylCOOR 11 , C M alkoxyaryl, -C 1 -C 6 haloalkyl, -SO 2 R 11 , -OR 11 , -SR 11 , -N 3 ,
  • L 3 is a bond
  • R 7 is -Z or -Y-Z, wherein
  • Y is -[C(R 15 ) 2 ] m -, or -Q-Cecycloalkyl
  • R 21 and R 3 are each independently hydrogen, halogen, Ci-C 6 alkyl, or Ci-C 6 haloalkyl; and G is a group of the formula,
  • J is aryl orheteroaryl
  • K is aryl or heteroaryl
  • each R 4 and R 41 are independently halogen, heteroaryl, heterocyclyl, -M, -E-M, or -D-E-M, wherein Dis-O-;
  • E is -[C(R 15 ⁇ ] 1n - or -C 3 -Qcycloalkyl
  • M is -Ci-Qalkyl, -Ci-Cghaloalkyl, -COR 11 , -COOR 11 , -CON(R ⁇ ) 2 , -CNN, -OR 11 , - SOR 11 , -SO 2 R 11 , -SO 2 N(R n ) 2 , or -SR 11 , L 2 is a bond; q is 1,2, or 3, and q' is 0, 1, 2 or 3, each R 10 is independently -R 11 , -C(K))R 11 , -CO 2 R 11 , or -SO 2 R 11 ; each R 11 is independently -hydrogen, -C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, (C 3 -C 8 cycloalkyl)-Ci- C 6 alkyl-, (C 3 -C 8 cycloalkenyl)-Ci-C 6 alky
  • the invention provides the compound according to formula Ia or Id, wherein:
  • R 1 is -L ⁇ R 5 , wherein L 1 is abond,L 5 , L 6 ,-L 5 -L 6 -L 5 -, or-L 6 -L 5 -L 6 -, wherein each L 5 is independently -[C(R I5 ) 2 ] m -, wherein mis 0, 1, 2, 3, or 4; and each R 15 is independently hydrogen, halogen, (Ci-C 6 )alkyl, or (Ci-C 6 )haloalkyl; and L 6 is -CO-, -SO 2 -, -O-, -CON(R 11 )-, -Q-Cecycloalkyl-, or-heterocyclyl-, wherein the cycloalkyl, or heterocyclyl is optionally substituted with one or more
  • R 5 is aryl, heterocyclyl, heteroaryl, -C, or -B-C, wherein B is-[C(R 15 ) 2 ] m - or -QrQjCycloalkyl-; and C is halogen, -Q-C ⁇ alkyl, or -Q-C ⁇ haloalkyl; wherein R 5 is optionally substituted with one or more R 5a , wherein each R 5a is independently halogen, nitro, heteroaryl, heterocyclyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, (C 3 -C 8 CyClOaIlCyI)-C 1 -C 6 alkyl-, (C 3 -C 8 cycloalkenyl)-C r C 6 alkyl-, (C 3 -C 8 cycloalkyl)-C 2 -C 6 alkenyl-, aryl, arylalkyl,
  • each R 5a is optionally substituted with one or more groups which independently are -halogen, -C 1 -C 6 alkyl, aryloxy CM alkylSO 2 R ⁇ , C 0 ⁇ alkylCOOR 11 , C 0 ⁇ alkoxyaryl, -C 1 -C 6 haloalkyl, -SO 2 R 11 , -OR 11 , -SR 11 , -N 3 , -SO 2 R 11 , -COR 11 , -SO 2 N(R 11 X -SO 2 NR 11 COR 11 , -ON, -C(O)OR 11 ,
  • R 2 is-L 3 -R 7 , wherein L 3 is a bond; and R 7 is, halogen, aryl, heteroaryl, heterocyclyl, -Z, or -Y-Z, wherein Y is -[C(R 15 ) 2 ] m - or -C 3 -C 6 CyClOaUCyI; and
  • R 7 is optionally substituted with one or more R 7a , wherein R 7a is halogen, -Z', -Y-Z', or-X'-Y'-Z', wherein X' isO-;
  • Y' is -[C(R 15 ⁇ ] 1n - or -C 3 -C 6 cycloalkyl; and Z' is -H, halogen, -OR 11 , -SR 11 , -S(O) 2 R 11 , -C(O)R 11 , -C(O)OR 11 ,
  • R 21 is hydrogen, halogen, Q-Qalkyl, or Q-C ⁇ haloalkyl; and G is a group of the formula,
  • J is aryl or heteroaryl
  • K is aryl or heteroaryl
  • each R 4 and R 41 are independently halogen, aryloxy, aralkyloxy, aryloxyalkyl, arylQ)-C 6 alkylcarboxy, aryl, heteroaryl, heterocyclyl, heteroaryloxy, heterocyclyloxy, -M, -E-M, or - D-E-M, wherein
  • E is -[C(R 15 ) 2 ] m - or -C 3 -C 6 cycloalkyl
  • M is -Q-Qalkyl, -Ci-Cehaloalkyl, -COR 11 , -COOR 11 , -CON(R ⁇ ) 2 , -ON, -OR 11 , -OCON(R U ) 2 , -NR 11 COR 11 , -NR 11 SO 2 R 11 , -N(R n ) 2 , -NR 11 COOR 11 , -SOR 11 , -SO 2 R 11 , -SO 2 NR 11 COR 11 , -SO 2 N(R n ) 2 , or -SR 11 ,
  • L 2 is a bond; q is 1,2, or 3; and q' is 0, 1,2, or 3; each R 10 is independently -R 11 , -C(O)R 11 , -CO 2 R 11 , or -SO 2 R 11 ; each R 11 is independently -hydrogen, -C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, (C 3 -Cg cycloalkyl)-Cr C 6 alkyl-, (C 3 -C 8 cycloalkenyl)-CrC 6 alkyl-, (C 3 -C 8 cycloalkyl)-C 2 -C 6 alkenyl-, -C 3 -C 8 cycloalkyl, -C 1 -C 6 haloalkyl, -N(R 12 ) 2 , aryl, -(CrC 6 )alkyl-aryl, heteroaryl, -(Q
  • the invention provides the compound according to formula Ia or Id, wherein:
  • R 1 is -i ⁇ -R 5 , wherein
  • L 1 is a bond, -C 3 -C 8 cycloalkyl-, or L 5 , wherein each L 5 is independently -[C(R 15 ) 2 ] m -, wherein m is O, 1, 2, or 3; and each R 15 is independently hydrogen, halogen, (Q-C ⁇ alkyl, or (CrC 6 )haloalkyl; and
  • R 5 is aryl, heterocyclyl, heteroaryl, -C, or -B-C, wherein B is-[C(R 15 ) 2 ] m - or -Qs-Cecycloalkyl-; and C is -Q-Qalkyl or -Q-Cehaloalkyl; wherein R 5 is optionally substituted with one or more R 5a , wherein each R 5a is independently halogen, nitro, heteroaryl, heterocyclyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, (C 3 -C 8 cycloalkyl)-Ci-C 6 alkyl-, (C 3 -C 8 cycloalkenyl)-C r C 6 alkyl-, (C 3 -C 8 cycloalkyl)-C 2 -C 6 alkenyl, aryl, arylalkyl, aryloxy, aryloxyaryl, arylC
  • R 7 is -Z or -Y-Z, wherein
  • Y is -[C(R 15 ) 2 ] m - or -Qs-Qcycloalkyl
  • R 21 is hydrogen, halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; and G is a group of the formula,
  • J is aryl or heteroaryl
  • K is aryl or heteroaryl
  • each R and R 41 are independently halogen, heteroaryl, heterocyclyl, -M, -E-M, or -D-E-M, wherein
  • E is -[C(R 15 ⁇ ] 1n - or -C 3 -C 6 CyClOaIlCyI; and M is -d-Cealkyl, -Q-Cehaloalkyl, -COR 11 , -COOR 11 , -C0N(R ⁇ ) 2 , -ON, -OR 11 , -
  • each R 10 is independently -R 11 , -C(O)R 11 , -CO 2 R 11 , or -SO 2 R 11 ; each R 11 is independently -hydrogen, -Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, (C 3 -C 8 cycloalkyl)-d- C 6 alkyl-, (C 3 -C 8 cycloalkenyl)-C !
  • each R 13 is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, (C 3 -C 8 cycloalkyl)-Ci- C 6 alkyl-, (C 3 -C 8 cycloalkenyl)-C r C 6 alkyl-, or (C 3 -C 8 cycloalkyl)-C 2 -C 6 alkenyl-; each R 14 is independently Cj-C 6 alkyl, Ci-C 6 alkoxy, halogen, Ci-C 6 haloalkyl, C 0 -C 6 alkylCON(R ⁇ ) 2 , C 0 -C 6 alkylCOM ⁇ OR 11 , C 0 -C 6 alkylOR 11 , or C 0 -C 6 alkylCOOR 11 .
  • the invention provides the compound according to formulas Ia-d, wherein
  • R 1 is-L 5 -R 5 or-L 6 -R 5 wherein
  • L 5 is -[C(R 15 ) 2 ] m -;
  • L 6 is C 3 -C 8 cycloalkyl, cycloC ⁇ shaloalkyl, or heterocyclyl, wherein the cycloalkyl, cycloC 3-8 haloalkyl 1, or heterocyclyl are optionally substituted with one or more radicals ofR 14 ;
  • R 5 is aryl, heterocyclyl, or heteroaryl, wherein R 5 is optionally substituted with one or more R 5a , wherein each R 5a is independently halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl,
  • A' is -O-;
  • B' is -[C(R 15 ) 2 ] m - or - C 3 -C 8 cycloalkyl -;
  • C is -H, halogen, -SO 2 R 11 , -OR 11 , -SR 11 , -N 3 , -COR 11 , -SO 2 N(R 11 ⁇ , -SO 2 NR 11 COR 11 , -CMN, -C(O)OR 11 , -OC(O)R 11 , -C0N(R n ) 2 , -C0N(R ⁇ )0R ⁇ , -0C0N(R u ) 2 , -NR 11 COR 11 , -NR 11 CON(R 11 ⁇ , -NR 11 COOR 11 , -N(R n ) 2 , aryl, heteroaryl, or heterocyclyl.
  • the invention provides the compound according to formulas Ia-d, wherein
  • R 1 is-L 5 -R 5 or-L 6 -R 5 wherein L 5 is -[C(R 15 ) 2 ] m -; L 6 is C 3 -Cg cycloalkyl, cycloC ⁇ ghaloalkyl, or heterocyclyl, wherein the cycloalkyl, cycloC 3-8 haloalkyl, or heterocyclyl are optionally substituted with one or more radicals ofR 14 ;
  • R 5 is aryl, heterocyclyl, or heteroaryl, wherein R 5 is optionally substituted with one or more R 5a , wherein each R 5a is independently halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, (C 3 -C 8 cycloalkyO-Ci-Ce alkyl-, (C 3 -C 8 cycloalkenyl)-C r C 6 alkyl-, (C 3 -C 8 cycloalkyl)-C 2 -C 6 alkenyl-, nitro, heterocyclyloxy, aryl, aryloxy, arylalkyl, aryloxyaryl, aryl C 1 -C 6 alkoxy, -C, -B'-C, or -A'-B'-C wherein A' is -O-;
  • B' is -[C(R 15 ) 2 ] m - or - C 3 -C 8 cycloalkyl -;
  • J is aryl or heteroaryl
  • K is aryl or heteroaryl
  • the invention provides the compound according to formulas Ia-d, wherein R 1 is -L 5 -R 5 or-L 6 -R 5 wherein
  • L 5 is -[C(R 15 ⁇ ] 1n -;
  • L 6 is C 3 -C 8 cycloalkyl, cycloCs-ghaloalkyl, or heterocyclyl, wherein the cycloalkyl, cycloCs-shaloalkyl, or heterocyclyl are optionally substituted with one or more radicals ofR 14 ;
  • R 5 is aryl, heterocyclyl, or heteroaryl, wherein R 5 is optionally substituted with one or more R 5a , wherein each R 5a is independently halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, (C 3 -C 8 cycloalkyiyCi-Ce alkyl-, (C 3 -C 8 cycloalkenylJ-Q-C ⁇ alkyl-, (C 3 -C 8 cycloalkyl)-C 2 -C 6 alkenyl-, nitro, heterocyclyloxy, aryl, aryl
  • A' is -O-;
  • B' is -[C(R 15 ) 2 ] m - or - C 3 -C 8 cycloalkyl -;
  • C is -H, halogen, -SO 2 R 11 , -OR 11 , -SR 11 , -N 3 , -COR 11 , -SO 2 N(R 11 ⁇ , -SO 2 NR 11 COR 11 , -ON, -C(O)OR 11 , -OC(K))R 11 , -CON(R n ) 2 , -C0N(R ⁇ )0R ⁇ , -OCON(R ⁇ ) 2 , -NR 11 COR 11 , -NR 11 CON(R 1 ⁇ -NR 11 COOR 11 , -N(R ⁇ ) 2 , aiyl, heteroaryl, orheterocyclyl; J is aryl or heteroaryl;
  • K is aryl or heteroaryl;
  • R 2 is -L 3 -R 7 , wherein
  • L 3 is a bond
  • R 7 is hydrogen, -Z, or -Y-Z, wherein Yis -[C(R 15 ) 2 ] m - or -C 2 -C 6 alkenyl;
  • Z is -H, halogen, -OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)N(R ⁇ ) 2 , -N(R ⁇ ) 2 , -CN, -SO 2 R 11 , or -S(O) 2 N(R n ) 2 ; and R 21 is hydrogen, halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • the invention provides the compound according to formulas Ia and Id. In another embodiment, the invention provides the compound according to formulas Ia and Id, wherein
  • R 1 is-L 5 -R 5 or-L 6 -R 5 wherein L 5 is -[C(R 15 ) 2 ] m -;
  • L 6 is C 3 -C 8 cycloalkyl, cycloC 3-8 haloalkyl, or heterocyclyl, wherein the cycloalkyl, cycloCj-shaloalkyll, or heterocyclyl are optionally substituted with one or more radicals ofR 14 ;
  • R 5 is aryl, heterocyclyl, or heteroaryl, wherein R 5 is optionally substituted with one or more R 5a , wherein each R 5a is independently halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, (C 3 -C 8 cycloalkyl)-C r C 6 alkyl-, (C 3 -C 8 cycloalkenyl)-C r C 6 alkyl-, (C 3 -C 8 cycloalkyl)-C 2 -C 6 alkenyl-, nitro, heterocyclyloxy, aryl, aryloxy, arylalkyl, aryloxyaryl, aryl C 1 -C 6 alkoxy, -C, -B'-C, or -A'-B'-C wherein A' is -O-;
  • B' is -[QR 15 ) 2 ] m - or - C 3 -C 8 cycloalkyl -;
  • C is -H halogen, -SO 2 R 11 , -OR 11 , -SR 11 , -N 3 , -COR 11 , -SO 2 N(R 11 ⁇ 5
  • the invention provides the compound according to formulas Ia and Id, wherein
  • R 1 is-L 5 -R 5 or-L 6 -R 5 wherein
  • L 5 is -[C(R 15 ) 2 ] m -;
  • L 6 is C 3 -C 8 cycloalkyl, cycloC ⁇ shaloalkyl, or heterocyclyl, wherein the cycloalkyl, cycloC 3-8 haloalkyl, or heterocyclyl are optionally substituted with one or more radicals ofR 14 ;
  • R 5 is aryl, heterocyclyl, or heteroaryl, wherein R 5 is optionally substituted with one or more R 5a , wherein each R 5a is independently halogen, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl,
  • A' is -O-;
  • B' is -[C(R 15 ) 2 ] m - or - C 3 -C 8 cycloalkyl -; '
  • K is aryl or heteroaryl.
  • the invention provides the compound according to formulas Ia and Id, wherein
  • R 1 is -L 5 -R 5 or-L 6 -R 5 wherein L 5 is -[C(R 15 ) 2 ] m -;
  • L 6 is C 3 -C 8 cycloalkyl, cycloC ⁇ shaloalkyl, or heterocyclyl, wherein the cycloalkyl, cycloC ⁇ shaloalkyl, or heterocyclyl are optionally substituted with one or more radicals ofR 14 ;
  • R 5 is aryl, heterocyclyl, or heteroaryl, wherein R 5 is optionally substituted with one or more R 5a , wherein each R 5a is independently halogen, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, (C 3 -C 8 cycloalkyl)-Ci-C 6 alkyl-, (C 3 -C 8 cycloalkenyl)-Ci-C 6 alkyl-, (C 3 -C 8 cycloalkyl)-C 2 -C 6 alkenyl-, nitro, heterocyclyloxy, aiyl, aiyloxy, arylalkyl, aiyloxyaiyl, aryl C 1 -C 6 alkoxy, -C, -B'-C, or -A'-B'-C wherein A'is -O-;
  • B' is -[C(R 15 ) 2 ] m - or - C 3 -C 8 cycloalkyl -;
  • C is -H, halogen, -SO 2 R 11 , -OR 11 , -SR 11 , -N 3 , -COR 11 , -SO 2 N(R 11 ⁇ ,
  • R 2 is -L 3 -R 7 , wherein
  • L 3 is a bond
  • R 7 is hydrogen, -Z, or -Y-Z, wherein Y is -[C(R 15 ) 2 ] m - or -C 2 -C 6 alkenyl; Z is -H, halogen, -OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)N(R ⁇ ) 2 , -N(R n ) 2 , -CN,
  • R 21 is hydrogen, halogen, C 1 -C 6 alkyl, or Ci-C 6 haloalkyl; such compounds are referred to hereafter and compounds of formula XL.
  • the invention provides the compound according to formula XL, wherein J and K are both phenyl.
  • the invention provides Hie compound according to formula XL, wherein J and K are both phenyl;
  • R 5 is aryl or heteroaryl, wherein R 5 is optionally substituted with one or more R 5a .
  • the invention provides the compound according to formula XL, wherein J and K are both phenyl; and
  • the invention provides the compound according to formula XL, wherein J and K are both phenyl;
  • R 5 is phenyl optionally substituted with one or more R 5a> wherein each R 5a is independently -halogen, -Q-Qalkyl, -Ci-C 6 haloalkyl, -OR 11 , -COR 11 , -ON, -C(O)OR 11 , -CON(R n ) 2 , or -N(R n ) 2 ; and each R 4 is independently halogen, aryl, heteroaryl, heterocyclyl, -M, or -E-M, wherein E is -[C(R 15' ) 2 ] m -, wherein each R 15 is independently hydrogen or halogen; and M is -Q-Qalkyl, -Q-Cehaloalkyl, halogen, -OR 11 , or -SO 2 R 11 .
  • the invention provides the compound according to formula XL, wherein J and K are both phenyl; and
  • R 5 is phenyl optionally substituted with one or more R 5aj wherein each R 5a is independently -halogen, -Q-C 6 alkyl, -Q-Qshaloalkyl, -OR 11 , -COR 11 , -CNN, -C(O)OR 11 , -C0N(R n ) 2 , or -N(R n ) 2
  • the invention provides the compound according to formula XL, wherein J and K are both phenyl;
  • R 5 is phenyl optionally substituted with one or more R 5 ⁇ wherein each R 5a is independently -halogen, -C r C 6 alkyl, -Q-Qshaloalkyl, -OR 11 , -COR 11 , -CNN, -C(O)OR 11 , -C0N(R ⁇ ) 2 , or -N(R 11 ⁇ ; and each R 41 is independently halogen, -M", or -E" -M", wherein
  • E" is -[C(R 15' ) 2 ] m -, wherein each R 15 is independently hydrogen or halogen; and M" is -Ci-C 6 alkyl, -Q-Cehaloalkyl, or halogen.
  • the invention provides the compound according to formula XL, wherein J and K are both phenyl; and
  • R 5 is phenyl optionally substituted with one or more R 5a> wherein each R 5a is independently -halogen, -Q-Cealkyl, -Ci-Cehaloalkyl, -OR 11 , -COR 11 , -ON, -C(O)OR 11 , -C0N(R ⁇ ) 2 , or -N(RV
  • the invention provides the compound according to formula XL, wherein J and K are both phenyl;
  • R 5 is phenyl optionally substituted with one or more R 5a> wherein each R 5a is independently -halogen, -Q-Qalkyl, -Q-Cehaloalkyl, -OR 11 , -COR 11 , -ON, -C(O)OR 11 , -C0N(R n ) 2 , or -N(RV and
  • R 7 is hydrogen, -Z, or -Y-Z, wherein Y is -[C(R 15 ) 2 ] m >- or -C 2 -C 6 alkenyl, wherein rri is 0, 1, or 2; and
  • the invention provides the compound according to formula XL, wherein J is heteroaryl and K is phenyl.
  • the invention provides the compound according to formula XL, wherein J is pyrroyl, thienyl, furyl, thiazoyl, oxazoyl, or pyrazoyl, and K is phenyl.
  • the invention provides the compound according to formula XL, wherein J is pyrroyl, thienyl, furyl, thiazoyl, oxazoyl, or pyrazoyl, and K is phenyl.; and R 5 is aryl or heteroaryl, wherein R 5 is optionally substituted with one or more R 5a .
  • the invention provides the compound according to formula XL, wherein J is pyrroyl, thienyl, fiiryl, thiazoyl, oxazoyl, or pyrazoyl, and K is phenyl; and
  • the invention provides the compound according to formula XL, wherein J is pyrroyl, thienyl, furyl, thiazoyl, oxazoyl, or pyrazoyl, and K is phenyl; and
  • R 5 is phenyl optionally substituted with one or more R 5a> wherein each R 5a is independently -halogen, -C r C 6 alkyl, -Q-Cehaloalkyl, -OR 11 , -COR 11 , -ON, -C(O)OR 11 , -C0N(R ⁇ ) 2 , or -N(R 11 ⁇ ; and each R 4 is independently halogen, aryl, heteroaryl, heterocyclyl, -M, or -E-M, wherein
  • E is -[C(R 15' ) 2 ] m -, wherein each R 15 is independently hydrogen or halogen; and M is -Q-Cealkyl, -Q-Cehaloalkyl, halogen, -OR 11 , or -SO 2 R 11 .
  • the invention provides the compound according to formula XL, wherein J is pyrroyl, thienyl, furyl, thiazoyl, oxazoyl, or pyrazoyl, and K is phenyl; and
  • the invention provides the compound according to formula XL, wherein J is pyrroyl, thienyl, furyl, thiazoyl, oxazoyl, or pyrazoyl, and K is phenyl.; and
  • R 7 is hydrogen, -Z, or -Y-Z, wherein
  • Y is -[C(R 15 ) 2 ] m >- or -C 2 -C 6 alkenyl, wherein m' is O, 1, or 2;
  • Z is -H, halogen, -OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)N(R 1 ⁇ , -N(R n ) 2 , -CN, -SO 2 R 11 , or -S(O) 2 N(R ⁇ ) 2.
  • R 21 is hydrogen.
  • the invention provides the compound according to formulas Ia-d, wherein J is phenyl.
  • the invention provides a compound according to formula Ia, Ib, Ic 5 or Id. In another embodiment, the invention provides the compound according to any one of formulas
  • the invention provides the compound according to any one of formulas Ia-d, wherein J and K are phenyl.
  • the invention provides the compound according to formula ⁇ ,
  • R 1 , R 2 , R 21 , R 4 , R 41 , L 2 , q, and q' are as defined in formulas Ia-d.
  • the invention provides the compound according to formula HI
  • R 1 , R 2 , R 21 , R 4 , R 41 , L 2 , q, and q' are as defined in formulas Ia-d.
  • the invention provides the compound according to formula IH wherein
  • L 2 is a bond; such compounds are referred to hereafter as compounds of formula IV.
  • the invention provides the compound according to formula IV, wherein R 5 is pyridyl optionally substituted with one or more R 5a .
  • the invention provides the compound according to formula IV, wherein R 5 is pyridyl optionally substituted with one Or more R 5a ; and each R 5a is independently -halogen, -Cj-Qalkyl, -Q-Qhaloalkyl, -OR 11 , -COR 11 , -CNN, -C(O)OR 11 , -CON(R ⁇ ) 2 , or -N(R n ) 2 .
  • the invention provides the compound according to formula IV, wherein R 5 is pyridyl optionally substituted with one or more R 5a ; and each R 41 is independently hydrogen, halogen, -Ci-C 6 alkyl, or -Ci-Cehaloalkyl. In another embodiment, the invention provides the compound according to formula IV, wherein
  • R 5 is pyridyl optionally substituted with one or more R 5a ; and R 2 is -L 3 -R 7 , wherein L 3 is a bond or -C(R n" ) 2 -; and
  • the invention provides the compound according to formula IH wherein
  • L 1 is a bond and R 5 is phenyl optionally substituted with one or more R 5a
  • the invention provides the compound according to formula IV, wherein L 1 is a bond and R 5 is phenyl optionally substituted with one or more R 5a ; such compounds are referred to hereafter as compounds of formula V.
  • the invention provides the compound according to formula V, wherein each R 5a is independently halogen -C', or -B'-C, wherein B' is -[C(R 15' ) 2 ] m -, wherein each R 15 is independently -H or -halogen; and
  • C is -H, -halogen, -SO 2 R 11 , -OR 11 , -COR 11 , -SO 2 N(R U ) 2 , -ON, -C(O)OR 11 , -C0N(R n ) 2 , or -N(R 11 ),.
  • the invention provides the compound according to formula V, wherein each R 5a is independently -halogen, -Q-C 6 alkyl, -Q-Cehaloalkyl, -OR 11 , -COR 11 , -C ⁇ N, -C(O)OR 11 , -CON(R ⁇ ) 2 , or -N(R U ) 2 ; such compounds are referred to hereafter as compounds of formula Va.
  • the invention provides the compound according to formula V, wherein each R 41 is independently hydrogen, halogen, -Q-Cealkyl, -Q-Cehaloalkyl, -COR 16 , -COOR 16 , -CON(R 16 ) 2 , -ON, -OR 16 , -N(R 16 ) 2, wherein each R 16 is independently hydrogen, -C 1 -C 6 alkyl, or -C 1 -C 6 haloalkyl.
  • the invention provides the compound according to formula V, wherein each R 41 is independently hydrogen, halogen, -CrC 6 alkyl, or -d-C ⁇ haloalkyl; such compounds are referred to hereafter as compounds of formula Vb.
  • the invention provides the compound according to formula V, wherein each R 4 is independently halogen, nitro, Q-Cealkyl, CrCehaloalkyl, -COR 11 , -COOR 11 , -C0N(R ⁇ ) 2 , -C ⁇ N, -OR 11 , -0C0N(R n ) 2 , -OCO 2 -R 11 , -N 3 , -NR 11 COR 11 , -NR 11 SO 2 R 11 , -N(R ⁇ ) 2 , -NR 11 COOR 11 , -SO 2 R 11 , -SO 2 NR 11 COR 11 , -SO 2 N(R n ) 2 , or -SR 11 .
  • the invention provides the compound according to formula V, wherein each R 4 is independently halogen, nitro, Q-Cealkyl, CrCehaloalkyl, -COR 11 , -COOR 11 , -C0N(R ⁇ ) 2 , -C ⁇ N, -OR 11 , -N(R ⁇ ) 2 , -SO 2 R 11 , or -SO 2 N(R ⁇ ) 2 ; such compounds are referred to hereafter as compounds of formula Vc.
  • the invention provides the compound according to formula V, wherein R 2 is -L 3 -R 7 , wherein L 3 is a bond; and R 7 is hydrogen, halogen, nitro, cyano, -Z, or -Y-Z, wherein
  • the invention provides the compound according to formula V, wherein R 2 is -L 3 -R 7 , wherein
  • L 3 is a bond; and R 7 is hydrogen, halogen, -Z, or -Y-Z, wherein
  • Y is -[C(R 15 ) 2 ] m -, wherein
  • Z is -H, halogen, -OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)N(R n ) 2 , -N(R U ) 2 , -CN, -SOiR ⁇ or-SCO ⁇ NCR 11 ) ⁇ such compounds are referred to hereafter as compounds of formula Vd.
  • the invention provides the compound according to formula Va, wherein each R 41 is independently hydrogen, halogen, -C 1 -Qa]]CyI, or -Q-Qhaloalkyl; such compounds are referred to hereafter as compounds of formula Ve.
  • the invention provides the compound according to formula Vb, wherein each R 4 is independently halogen, nitro, Q-Qalkyl, Q-Qhaloalkyl, -COR 11 , -COOR 11 , -C0N(R n ) 2 , -ON, -OR 11 , -N(R n ) 2 , -SO 2 R 11 , or -SO 2 N(R U ) 2 ; such compounds are referred to hereafter as compounds of formula Vf.
  • the invention provides the compound according to formula Vc, wherein R 2 is -L 3 -R 7 , wherein L 3 is a bond; and R 7 is hydrogen, halogen, -Z, or -Y-Z, wherein
  • Y is -[C(R 15 ) 2 ] m -, wherein
  • Z is -H, halogen, -OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)N(R n ) 2 , -N(R n ) 2 , -CN, -SO 2 R 11 , Or-S(O) 2 N(R 1 ⁇ 2 ; such compounds are referred to hereafter as compounds of formula Vg.
  • the invention provides the compound according to formula Vd, wherein each R 5a is independently -halogen, -C 1 -QaIlCyI 5 -Q-Qhaloalkyl, -OR 11 , -COR 11 , -C ⁇ N, -C(O)OR 11 , -CON(R n ) 2 , or -N(R n ) 2 ; such compounds are referred to hereafter as compounds of formula Vh.
  • the invention provides the compound according to formula Vf, wherein R 2 is -L 3 -R 7 , wherein
  • L 3 is a bond; and R 7 is hydrogen, halogen, -Z, or -Y-Z, wherein
  • Y is -[C(R 15 ) 2 ] m -, wherein Z is -H, halogen, -OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)N(R U ) 2 , -N(R ⁇ ) 2 , -CN,
  • the invention provides the compound according to formula Vg, wherein each R 5a is independently -halogen, -Q-Qalkyl, -Q-Qhaloalkyl, -OR 11 , -COR 11 , -CNN, -C(O)OR 11 , -CON ⁇ R n ) 2 , or -N(R n ) 2 .
  • the invention provides the compound according to formula Vh, wherein each R 41 is independently hydrogen, halogen, -C 1 -QaIkVl, or -Q-Qhaloalkyl.
  • the invention provides the compound according to formula Vi, wherein R 2 is -L 3 -R 7 , wherein
  • L 3 is a bond; and R 7 is hydrogen, halogen, -Z, or -Y-Z, wherein Y is -[C(R 15 ) 2 ] m -, wherein
  • Z is -H, halogen, -OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)N(R ⁇ ) 2 , -N(R n ) 2 , -CN, -S0 2 R ⁇ , or-S(0) 2 N(R ⁇ ) 2 .
  • the invention provides the compound according to formula V, wherein R 21 is hydrogen, halogen, nitro, cyano, aryl, heteroaryl, heterocyclyl, -C 1 -C 6 alkyl-heterocyclyl, -C 1 -C 6 alkyl-heteroaryl, -C 1 -C 6 alkyl-aryl, -Z, -Y-Z, or -X-Y-Z, wherein X is -O-;
  • Y is -[C(R 15 ) 2 ] m - -C 2 -C 6 alkenyl, or C 3 -C 8 cycloalkyl;
  • Z is -H, -CN, halogen, -OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)N(R n ) 2 , -N(R ⁇ ) 2 , -CN, -N 3 , -SO 2 R 11 , -S(O) 2 N(R U ) 2 , -C(O)N(R n )N(R n ) 2 , -C(O)N(R 11 XOR 11 ), -OC(O)-R 11 , -0C(O)-N(R u ) 2 , or -N(R n )COOR n .
  • the invention provides the compound according to formula V, wherein R 21 is hydrogen, halogen, nitro, cyano, Ci-C 6 alkyl, or Ci-Qhaloalkyl.
  • the invention provides the compound according to any of formulas Va- Vi, wherein R 21 is hydrogen, halogen, nitro, cyano, C 1 -QaIlCyI, or Q-Qhaloalkyl.
  • the invention provides the compound according to formula VI or a pharmaceutically acceptable salt, isomer, or prodrug thereof, wherein R 1 , R 2 , R 2 , R , R 41 , L 2 , q, and q' are as defined in formulas Ia-d.
  • the invention provides the compound according to formula VH
  • R 1 , R 2 , R 21 , R , R 41 , L 2 , q, and q' are as defined in formulas Ia-d.
  • the invention provides the compound according to formula VIII wherein L 2 is a bond; such compounds are referred to hereafter as compounds of formula DC.
  • the invention provides the compound according to formula IX, wherein
  • L 1 is a bond; and R 5 is aryl or heteroaryl optionally substituted with one or more R 5a .
  • the invention provides the compound according to formula X
  • R 1 , R 2 , R 21 , R 4 , R 41 , L 2 , q, and q' are as defined in formulas Ia-d.
  • the invention provides the compound according to formula X, wherein R 5 is phenyl optionally substituted with one or more R 5a ; such compounds are referred to hereafter as compounds of formula XI.
  • the invention provides the compound according to formula XI, wherein each R 5a is independently -halogen, -Q-Qalkyl, -Q-Qhaloalkyl, -OR 11 , -COR 11 , -ON, -C(O)OR 11 , -CON(R n ) 2 , or -N(R ⁇ ) 2 ; such compounds are referred to hereafter as compounds of formula XIa.
  • the invention provides the compound according to formula XI wherein each R 41 is independently hydrogen, halogen, -Q-Qalkyl, -Q-Qhaloalkyl, -COR 16 , -COOR 16 , -CON(R 16 ) 2 , -ON, -OR 16 , -N(R 16 ) ⁇ wherein each R 16 is independently hydrogen, -C 1 -C 6 alkyl, or -C 1 -C 6 haloalkyl.
  • the invention provides the compound according to formula XI wherein each R 41 is independently hydrogen, halogen, -Q-Qalkyl, or -Q-Qhaloalkyl; such compounds are referred to hereafter as compounds of formula XIb.
  • the invention provides the compound according to formula XI wherein each R 4 is independently halogen, -M, or -E-M, wherein
  • M is Q-Qalkyl, Q-Qhaloalkyl, -COR 11 , -COOR 11 , -C0N(R n ) 2 , -ON, -OR 11 , -OCON(R 11 ⁇ ,
  • the invention provides the compound according to formula XI wherein each R 4 is independently halogen, -M, or -E-M, wherein E is -[C(R 15' ) 2 ] m -, wherein each R 15 is independently -H or -halogen; and
  • M is -Q-Qalkyl, -Q-Qhaloalkyl, -COR 11' , -COOR 11 ', -C0N(R ⁇ ') 2 , -ON, -OR 11 ', -N(R n ) 2 , -SO 2 R 11 ', or -SO 2 N(R n ') 2 , wherein each R 11' is independently -hydrogen, -C 1 -C 6 alkyl, or -C 1 -C 6 haloalkyl, wherein each R 11 ' is optionally substituted with -OR 13 , -COOR 13 , -COR 13 ,
  • the invention provides the compound according to formula XI wherein R 2 is -IAR 7 , wherein
  • L 3 is a bond, -C(R n ) 2 -, -O-, -S-, -NR 7 -, -N(R 10 )CO-, -CO-, -CS-, -CONR 11 -, -CO 2 -, -OC(O)-, or -SO 2 -; and R 7 is hydrogen, halogen, heterocyclyl, -Z, or -Y-Z, wherein
  • Z is -H, halogen, -OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)N(R n ) 2 , -N(R ⁇ ) 2 , -CN, -SO 2 R 11 , -S(O) 2 N(R" ⁇ , -C(O)N(R 11 )N(R 11 ) 2 , -C(O)N(R 11 XOR 11 ), -OC(O)-R 11 , or-OC(0)-N(R ⁇ ) 2 .
  • the invention provides the compound according to formula XI, wherein
  • R 2 is -L 3 -R 7 , wherein
  • L 3 is a bond, -C(R 11 V, -CO-, or -SO 2 -;
  • R 7 is hydrogen, halogen, heterocyclyl, -CrQalkyl, -Q-C ⁇ haloalkyl, -OR 11 , -C(O)R 11" , -C(O)OR 11" , -C(O)N(R n ") 2 , -N(R n" ) 2 , -CN, -SO 2 R 11" , or -S(O) 2 N(R U" ) 2 , wherein each R 11 is independently -H or -Q-Cgalkyl; such compounds are referred to l hereafter as compounds of formula XId.
  • the invention provides the compound according to formula XIa, wherein each R 41 is independently hydrogen, halogen, -CrC ⁇ alkyl, or -Q-C ⁇ haloalkyl; such compounds are referred to hereafter as compounds of formula XIe.
  • the invention provides the compound according to formula XIb, wherein each R 4 is independently halogen, -M, or -E-M, wherein E is -[C(R 15' ) 2 ] ra -, wherein each R 15 is independently -H or -halogen; and M is -Ci-Cealkyl, -Q-Cghaloalkyl, -COR 11 ', -COOR 11' , -CON(R U' ) 2 , -ON, -OR 11' , -N(R ⁇ ) 2 ,
  • each R 11 is independently -hydrogen, -C 1 -C 6 alkyl, -C 1 -C 6 haloalkyl, wherein each R 11 ' is optionally substituted with -OR 13 , -COOR 13 , -COR 13 , -SO 2 R 13 , -CON(R 13 ) 2 , -SO 2 N(R 13 ) 2 , or -N(R 13 ) 2 ; such compounds are referred to hereafter as compounds of formula XIf.
  • the invention provides the compound according to formula XId, wherein each R 5a is independently -halogen, -C r C 6 alkyl, -Q-Cghaloalkyl, -OR 11 , -COR 11 , -ON, -C(O)OR 11 , -C0N(R n ) 2 , or -N(R n ) 2 ; such compounds are referred to hereafter as compounds of formula XIh.
  • the invention provides the compound according to formula XIe, wherein each R 4 is independently halogen, -M, or -E-M, wherein E is -[C(R 15' ) 2 ] m -, wherein each R 15 is independently -H or -halogen; and
  • M is -CrCealkyl, -Q-Cehaloalkyl, -COR 11 ', -COOR 11 ', -CON(R ⁇ ') 2 , -ON, -OR 11 ', -N(R n ) 2 , -SO 2 R 11 ', or -SO 2 N(R U ') 2 , wherein each R 1 r is independently -hydrogen, -C 1 -C 6 alkyl, -C 1 -C 6 haloalkyl, wherein each R 11' is optionally substituted with -OR 13 , -COOR 13 , -COR 13 , -SO 2 R 13 , -CON(R 13 ) 2 , -SO 2 N(R 13 ) 2 , or -N(R 13 ) 2 ; > such compounds are referred to hereafter as compounds of formula XIi.
  • the invention provides the compound according to formula XIf, wherein R 2 is -L 3 -R 7 , wherein L 3 is a bond, -C(R n" ) 2 -, -CO-, or -SO 2 -; and
  • the invention provides the compound according to formula XIh, wherein each R 41 is independently hydrogen, halogen, -CrQalkyl, or -CrCehaloalkyl.
  • the invention provides the compound according to formula XIi, wherein R 2 is -L 3 -R 7 , wherein L 3 is a bond, -C(R n ") 2 -, -CO-, or -SO 2 -; and
  • R 7 is hydrogen, halogen, heterocyclyl, -CrQalkyl, -Q-Cehaloalkyl, -OR 11" , -C(O)R 11" , -C(O)OR 11” , -C(O)N(R U ") 2 , -N(R n ") 2 , -CN, -SO 2 R 11" , or -S(O) 2 N(R 1 r ) 2 , wherein each R 11 is independently -H or -CrQalkyl.
  • the invention provides the compound according to formula XI, wherein R is hydrogen, halogen, nitro, cyano, aryl, heteroaryl, heterocyclyl, -C 1 -C 6 alkyl-heterocyclyl, -C 1 -C 6 alkyl-heteroaryl, -C 1 -C 6 alkyl-aryl, -Z, -Y-Z, or -X-Y-Z, wherein
  • Y is -[C(R 15 ) 2 ] m -, -C 2 -C 6 alkenyl, or C 3 -C 8 cycloalkyl;
  • the invention provides the compound according to formula XI, wherein R 21 is hydrogen, halogen, nitro, cyano, Q-C 6 alkyl, or CrC ⁇ haloalkyl.
  • the invention provides the compound according to any of formulas XIa-XIi, wherein R 21 is hydrogen, halogen, nitro, cyano, Q-Qalkyl, or CrC ⁇ haloalkyl.
  • the invention provides the compound according to formula K, wherein L 1 is a bond; and R 5 is pyridyl optionally substituted with one or more R 5a , such compounds are referred to hereafter as compounds of formula XII.
  • the invention provides the compound according to formula XII, wherein each R Sa is independently -halogen, -Q-Qalkyl, -Q-Cehaloalkyl, -OR 11 , -COR 11 , -ON, -C(O)OR 11 , -C0N(R n ) 2 , or -N(R ⁇ ) 2 .
  • the invention provides the compound according to formula XII, wherein each R 41 is independently hydrogen, halogen, -Q-Cealkyl, or -Q-Cehaloalkyl.
  • the invention provides the compound according to formula XlI, whereinR 2 is -L 3 -R 7 , whereinL 3 is abond or -C(R 11 ) 2 -;
  • R 7 is hydrogen, halogen, -Q-Qalkyl, -Q-Cehaloalkyl, -OR 11" , -C(O)R 11" , -C(O)OR 11” , -C(O)N(R n ") 2 , -N(R n" ) 2 , -CN, -SO 2 R 11 ", or -S(O) 2 N(R 11" ),, wherein each R 11 is independently -H or -Ci-Qalkyl.
  • the invention provides the compound according to formula XII, wherein each R 4 is independently halogen -Q-Cealkyl, -Q-Cehaloalkyl, -COR 11 ', -COOR 11 ', -CON(R n ') 2 , -ON, -OR 11 ', -N(R n ) 2 , -SO 2 R 11 ', or -SO 2 N(R n ') 2 , wherein each R 11 is independently -hydrogen, -C 1 -C 6 alkyl, or -C 1 -C 6 haloalkyl.
  • the invention provides the compound according to formula XII, wherein R 21 is hydrogen, halogen, nitro, cyano, Q-Qalkyl, or Q-Qshaloalkyl.
  • the invention provides the compound according to formula VHI, wherein L 2 is -V 2 -[C(R 15 ) 2 ] n -, wherein n" is 0-3; and V 2 is -O-, -S-, -OC(O)-, -OC(O)O-, or -OC(O)N(R 10 )-, such compounds are referred to hereafter as compounds of formula XEH.
  • the invention provides the compound according to formula XEH, wherein each R 5a is independently -halogen, -C r C 6 alkyl, -Q-Cehaloalkyl, -OR 11 , -COR 11 , -ON, -C(O)OR 11 , -CON(R n ) 2 , or -N(R U ) 2 .
  • the invention provides the compound according to formula XEH, wherein each R 41 is independently hydrogen, halogen, -Ci-C 6 alkyl, or -Ci-C ⁇ haloalkyl.
  • the invention provides the compound according to formula XEH, wherein R 2 is -L 3 -R 7 , wherein L 3 is a bond or -C(R 11 V? and
  • R 7 is hydrogen, halogen, -Q-Cealkyl, -Q-Cehaloalkyl, -OR 11" , -C(O)R 11" , -C(O)OR 11" , -C(O)N(R n ") 2 , -N(R n" ) 2 , -CN, -SO 2 R 11" , or -S(O) 2 N(R 1 r ) 2 , wherein each R 11 is independently -H or -Q-Qalkyl.
  • the invention provides the compound according to formula XEH, wherein R 21 is hydrogen, halogen, nitro, cyano, Ci-C 6 alkyl, or Ci-C ⁇ haloalkyl.
  • the invention provides the compound according to formulas Ia-d, wherein K is absent; q is 1 ; and L 2 is -V 2 -[C(R 15 ) 2 ] n -, wherein n is 0-6; and V 2 is -0-, -S-, -SO 2 -, -CON(R 10 )-, -CON(R 11 )-, -CO-, -CO 2 -, -OC(O)-, -OC(O)O-, or -OC(O)N(R 10 )-; such compounds are referred to hereafter as compounds of formula XEV.
  • the invention provides the compound according to formula XEV.
  • M is - ⁇ halogen, COR 11 , COOR 11 , ON, OR 11 , -NR 11 COR 11 , NR 11 SO 2 R 11 , SO 2 R 11 , SO 2 N(R 11 ⁇ 5 Or SR 11 ; such compounds are referred to hereafter as compounds of formula XV.
  • the invention provides the compound according to formula XV, wherein each R 5a is independently -halogen, -Q-C 6 alkyl, -Q-Qshaloalkyl, -OR 11 , -COR 11 , -ON, -C(O)OR 11 , -CON(R ⁇ ) 2 , or -N(R U ) 2 .
  • the invention provides the compound according to formula XV, wherein R 2 is -L 3 -R 7 , wherein L 3 is a bond or -C(R 1 * ) 2 -; and
  • the invention provides the compound according to formula XV, wherein each R 41 is independently hydrogen, halogen, -Q-Qalkyl, or -Q-Cehaloalkyl.
  • the invention provides the compound according to formula XV, wherein R 21 is hydrogen, halogen, nitro, cyano, Ci-C 6 alkyl, or Q-Cehaloalkyl.
  • the invention provides the compound according to formula XTV, wherein L 2 is -0-; and R 4 is -E-M, wherein E is -[C(R 15 ) 2 ] m -; and
  • M is -H, halogen, -COR 11 , -COOR 11 , -CON(R U ) 2 , -ON, -OR 11 , -0C0N(R n ) 2 , -OCO 2 -R 11 , -N(R 11 ),; such compounds are referred to hereafter as compounds of formula XVI.
  • the invention provides the compound according to formula XVI, wherein each R 41 is independently hydrogen, halogen, -Ci-C 6 alkyl, or -CrCehaloalkyl.
  • the invention provides tiie compound according to formula XVI, wherein each R 5a is independently -halogen, C r C 6 alkyl, Q-Cehaloalkyl, -OR 11 , -COR 11 , -ON, -C(O)OR 11 , -C0N(R ⁇ ) 2 , or -N(R n ) 2 .
  • the invention provides the compound according to formula XVI, wherein R 2 is -L 3 -R 7 , wherein L 3 is a bond or -C(R 1 r ) 2 -;
  • the invention provides the compound according to formula XVI, wherein R 21 is hydrogen, halogen, nitro, cyano, CrQalkyL or Q-C ⁇ haloalkyl.
  • the invention provides the compound according to formula XVH, wherein each R 5a is independently -halogen, -C r C 6 alkyl, -Q-Cehaloalkyl, -OR 11 , -COR 11 , -ON, -C(O)OR 11 , -C0N(R ⁇ ) 2 , or -N(R n ) 2 .
  • the invention provides the compound according to formula XVTI, wherein R 2 is -L 3 -R 7 , wherein L 3 is a bond or -C(R 1 r' ) 2 -; and
  • the invention provides the compound according to formula XVH, wherein R 21 is hydrogen, halogen, nitro, cyano, C 1 -QaIlCyI, or Q-Cijhaloalkyl.
  • the invention provides the compound according to formulas Ia-d, wherein J is heteroaryl.
  • the invention provides the compound according to formulas Ia-d, wherein J is thienyl, furyl, pyrrolyl, thiazoyl, oxazoyl, isothiazoyl, isoxazoyl, pyridyl, pyrimidinyl, or pyrazinyl.
  • the invention provides the compound according to formulas Ia-d, wherein J is thienyl, furyl, pyrrolyl, thiazoyl, oxazoyl, isothiazoyl, isoxazoyl, pyridyl, pyrimidinyl, or pyrazinyl; and K is phenyl.
  • the invention provides the compound according to formulas Ia-d, wherein J is pyridyl.
  • the invention provides the compound according to formulas Ia-d, wherein J is pyridyl; L 1 is a bond; and R 5 is phenyl optionally substituted with one or more R 5a .
  • the invention provides the compound according to formulas Ia-d, wherein J is pyridyl; L 1 is a bond; R 5 is phenyl optionally substituted with one or more R 5a ; and K is phenyl; such compounds are referred to hereafter as compounds of formula XVHI.
  • the invention provides the compound according to formula XVHI, wherein each R 41 is independently hydrogen, halogen, -Q-Qalkyl, or -Q-C ⁇ haloalkyl.
  • the invention provides the compound according to formula XVHI, wherein R 2 is -L 3 -R 7 , wherein L 3 is a bond or -C(R 1 v ) 2 -; and
  • the invention provides the compound according to formula XVDI, wherein R 21 is hydrogen, halogen, nitro, cyano, CrC 6 alkyl, or CrCshaloalkyl.
  • the invention provides the compound according to formulas Ia-d, wherein J is thienyl, furyl, or pyrroyl.
  • the invention provides the compound according to formulas Ia-d, wherein J is thienyl.
  • the invention provides the compound according to formulas Ia-d, wherein J is thienyl; K is phenyl; and L 2 is a bond.
  • the invention provides the compound according to formula XIX,
  • R 1 , R 2 , R 21 , R 4 , R 41 , L 2 , q, and q' are as defined in formulas Ia-d.
  • the invention provides the compound according to fonnula XTX, wherein K is absent; and L 2 is -SO 2 - or -CO-.
  • the invention provides the compound according to formula XK, wherein K is absent; L 2 is -SO 2 - or -CO-; and R 4 is heterocyclyl, OR 11 , or -N(R U ) 2 , wherein the heterocyclyl is optionally substituted with one or more -E-M', wherein E' is -[C(R 15 ) 2 ] m - or C 3 -C 8 cycloalkyl;
  • M' is -H, halogen, COR 11 , COOR 11 , ON, OR 11 , -NR 11 COR 11 , NR 11 SO 2 R 11 , SO 2 R 11 , SO 2 N(R 11 ⁇ Or SR 11 .
  • the invention provides the compound according to formula XX,
  • the invention provides the compound according to formula XXI, (wherein L 1 is a bond; and R 5 is phenyl optionally substituted with one or more R 5a ; such compounds are referred to hereafter as compounds of formula XXH.
  • the invention provides the compound according to formula XXII, wherein each R 5a is independently halogen, nitro, heterocyclyloxy, aryloxy, -C, -B'-C or -A'-B'-C wherein
  • the invention provides the compound according to formula XXII, wherein each R 5a is independently halogen, nitro, heterocyclyloxy, phenoxy, -C, -B'-C, or -A'-B'-C wherein A' is -O-; B' is -[C(R 15 ) 2 ] m -;
  • the invention provides the compound according to formula XXH, wherein each R 41 is independently hydrogen, halogen, -Q-Qalkyl, -Q-Oftaloalkyl, -COR 16 , -COOR 16 , -CON(R 16 ) 2 , -ON, -OR 16 , or -N(R 16 ) 2, wherein each R 16 is independently hydrogen, -C 1 -C 6 alkyl, or -C 1 -C 6 haloalkyl.
  • the invention provides the compound according to formula XXII, wherein each R 41 is independently hydrogen, halogen, -Ci-Qalkyl, or -CrC ⁇ haloalkyl; such compounds are referred to hereafter as compounds of formula XXIIb.
  • the invention provides the compound according to formula XXH, wherein each R 4 is independently halogen, nitro, CR 11 ⁇ R 11 COOR 11 , -M, or -E-M, wherein E is -[C(R 15 ) 2 ] m - or C 3 -C 8 cycloalkyl;
  • M is Ci-C 6 alkyl, Q-Cehaloalkyl, -COR 11 , -COOR 11 , -CON(R n ) 2 , -ON, -OR 11 , -0C0N(R. u ) 2 , -OCO 2 -R 11 , -NR 11 COR 11 , -NR 11 SO 2 R 11 , -N(R U ) 2 , -NR 11 COOR 11 , -SO 2 R 11 , -SO 2 NR 11 COR 11 , -SO 2 N(R 11 ⁇ Or-SR 11 .
  • the invention provides the compound according to formula XXDL, wherein each R 4 is independently halogen, CR 11 K]R 11 COOR 11' , -M, or -E-M, wherein E is -[C(R 15 ) 2 ] m - or C 3 -C 8 cycloalkyl; M is Ci-Cealkyl, Q-Cehaloalkyl, -COR 11' , -COOR 11' , -CON(R ⁇ ') 2 , -ON, -OR 11 ', -NR 11 O 2 R 11 ', -N(R ⁇ ') 2 , -SO 2 R 11 ', -SO 2 NR 11 COR 11 ', or -SO 2 N(R ⁇ ') 2 , wherein each R 11 ' is independently -hydrogen, -C 1 -C 6 alkyl, or -C 1 -C 6 haloalkyl, wherein any of R 11 '
  • the invention provides the compound according to formula XXII, wherein R 2 is -L 3 -R 7 , wherein L 3 is a bond or -(CE 2 ) ⁇ -(CH 2 X- wherein m" is 0-3; n is 0-3; and V 1 is -C(R U ) 2 -, -O-, -S-, -NR 7 -, -CO-, -CO 2 -, -OC(O)-, or -SO 2 -; and
  • R 7 is hydrogen, halogen, nitro, aryl, heteroaryl, heterocyclyl, -Q-Qalkyl, -Q-Cehaloalkyl, -C 2 -C 6 alkenyl, C 3 -C 8 cycloalkyl, or -(C(R 15 ) 2 ) m -Z, wherein Z is -OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)N(R ⁇ ) 2 , -N(R n ) 2 , -CN, -SO 2 R 11 ,
  • R 7 is optionally substituted with one or more R 7a , wherein
  • R 7a is halogen, C r C 6 alkyl, CrCehaloalkyl, -OR 20 , -C(O)R 20 , -C(O)OR 20 , -C(O)N(R 20 ) 2 , -N(R 20 ) 2 , -N(TR 2 ⁇ C(O)R 20 , or -CN, wherein each R 20 is independently -H or CrC 6 alkyl.
  • the invention provides the compound according to formula XXII, wherein R 2 is -L 3 -R 7 , wherein
  • L 3 is a bond or -(CU 2 ) ⁇ -V 1 -(CH 2 ) n - wherein m" is 0-1; n is 0-2; and V 1 is -CH 2 -, -0-, -S-, or -NR 7 -; and
  • R 7 is hydrogen, halogen, phenyl, heteroaryl, heterocyclyl, -Q-C 6 alkyl, -CrCehaloalkyl, -C 2 -C 6 alkenyl, C 3 -C 8 cycloalkyl, or -(C(R 15 ) 2 ) m -Z, wherein
  • Z is -OR 11" , -C(O)R 11" , -C(O)OR 11” , -C(O)N(R 1 r ') 2 , -N(R ⁇ ") 2 , -CN, or -SO 2 R 11 ", wherein R 7 is optionally substituted with one or more R 7a , wherein R 7a is halogen, Q-Qalkyl, Q-Cehaloalkyl, -OR 11 '', -N(R ⁇ " ) 2 , -COOR 11 ", wherein each R 11 " is independently -H, -Q-Qalkyl, -Q-Cehaloalkyl, heterocyclyl, or heteroaryl; such compounds are referred to hereafter as compounds of formula XXHd.
  • the invention provides the compound according to formula XXII, wherein R 2 is -L 3 -R 7 , wherein L 3 is a bond; and
  • R 7 is hydrogen, halogen, -C 1 -C 3 OIkVl, -Q-Qhaloalkyl, or -(C(R 15 ) 2 )-Z, wherein
  • Z is -OR 11 " or -SO 2 R 11" , whereinR 11" is -H or C r C 6 alkyl.
  • the invention provides the compound according to formula XXIIa, wherein each R 41 is independently hydrogen, halogen, -CrQalkyl, or -Ci-C ⁇ haloalkyl; such compounds are referred to hereafter as compounds of formula XXIIe.
  • the invention provides the compound according to formula XXHc, wherein R 2 is -L 3 -R 7 , wherein L 3 is a bond or -(C ⁇ 2 ) ⁇ rV ⁇ -(CR 2 )*- wherein m" is 0-1; n is 0-2; and V is -CH 2 -, -0-, -S-, or -NR 7 -; and
  • R 7 is hydrogen, halogen, phenyl, heteroaryl, heterocyclyl, -Q-C 6 alkyl, -CrCehaloalkyl, -C 2 -C 6 alkenyl, C 3 -C 8 cycloalkyl, or -(C(R 15 ) 2 ) m -Z, wherein
  • R 7a is halogen, C r C 6 alkyl, CrCehaloalkyl, -OR 11" , -N(R U ") 2 , -COOR 11" , wherein R 11 is -H, -CrCealkyl, -Q-Cehaloalkyl, heterocyclyl, or heteroaryl; such compounds are referred to hereafter as compounds of formula XXHg.
  • the invention provides the compound according to formula XXDf, wherein R 2 is -L 3 -R 7 , wherein L 3 is a bond or -(CB ⁇ W-V ⁇ CHaV wherein m" is 0-1 ; n is 0-2; and V 1 is -CH 2 -, -0-, -S-, or -NR 7 -; and
  • R 7 is hydrogen, halogen, phenyl, heteroaryl, heterocyclyl, -Q-Cealkyl, -Q-C ⁇ haloalkyl, -C 2 -C 6 alkenyl, C 3 -C 8 cycloalkyl, or -(C(R 15 ) 2 ) m -Z, wherein
  • Z is -OR 11 ", -C(O)R 11" , -C(O)OR 11” , -C(O)N(R 1 r ) 2 , -N(R n” ) 2 , -CN, or -SO 2 R 11" , wherein R 7 is optionally substituted with one or more R 7a , wherein
  • R 7a is halogen, C r C 6 alkyl, Q-Cghaloalkyl, -OR 11 ", -N(R n ") 2 , -COOR 11" , wherein R 11' is -H, -Ci-C 6 alkyl, -CrCehaloalkyl, heterocyclyl, or heteroaryl.
  • the invention provides the compound according to formula XXHg, wherein each R 5a is independently halogen, nitro, heterocyclyloxy, phenoxy, -C, -B'-C, or -A'-B'-C wherein A' is -O-;
  • B' is -[C(R 15 ) 2 ] m -;
  • each R 18 is independently -H, -C 1 -C 6 alkyl, -C 1 -C 6 haloalkyl, -C 3 -C 8 cycloalkyl, aryl, heteroaryl, or heterocyclyl; and wherein each R 5a is optionally substituted one or more groups which are independently C 1 -C 6 alkyl, halogen, -COR 19 , -COOR 19 , -CON(R 19 ) 2 , -OR 19 , or -N(R 19 ) 2 , wherein R 19 is -Hor-CrCealkyl.
  • the invention provides the compound according to formula XXIIh, wherein each R 41 is independently hydrogen, halogen, -Q-Qalkyl, or -Q-Cehaloalkyl.
  • the invention provides the compound according to formula XXlIi, wherein R 2 is -L 3 -R 7 , wherein L 3 is a bond or -(CH 2 V-V 1 -(CH 2 ) n - wherein m" is 0-1; n is 0-2; and V 1 is -CH 2 -, -O-, -S-, or -NR 7 -; and
  • R 7 is hydrogen, halogen, phenyl, heteroaryl, heterocyclyl, -Q-C ⁇ alkyl, -Q-Cehaloalkyl, -C 2 -C 6 alkenyl, C 3 -C 8 cycloalkyl, or -(C(R 15 ) 2 ) m -Z, wherein
  • the invention provides the compound according to formula XXII, wherein R is hydrogen, halogen, nitro, cyano, aryl, heteroaryl, heterocyclyl, -C 1 -C 6 alkyl-heterocyclyl, -C 1 -C 6 alkyl-heteroaryl, -C 1 -C 6 alkyl-aryl, -Z, -Y-Z, or -X-Y-Z, wherein X is -O-;
  • Y is -[C(R 15 ) 2 ] m -, -C 2 -C 6 alkenyl, or C 3 -C 8 cycloalkyl;
  • the invention provides the compound according to formula XXII, wherein R 21 is hydrogen, halogen, nitro, cyano, CrC ⁇ alkyl, or Q-C ⁇ haloalkyl.
  • the invention provides the compound according to any of formulas XX ⁇ a-XX ⁇ i, wherein R 21 is hydrogen, halogen, nitro, cyano, Q-C ⁇ alkyl, or Ci-Cehaloalkyl.
  • the invention provides the compound according to formula XXI, wherein
  • R 1 is -L ⁇ R 5 , wherein
  • L 1 is -L 5 - or -L 6 -, wherein each L 5 is -C(R 15 ) 2 -> wherein each R 15 is independently hydrogen, halogen, (Q-C ⁇ alkyl, or (Q-QOhaloalkyl; and L 6 is -CS-, -CO-, or -SO 2 -; and
  • R 5 is aryl or heteroaryl optionally substituted with one or more R 5a .
  • the invention provides the compound according to formula XXI, wherein R 1 is -i ⁇ R 5 , wherein
  • L 1 is -L 5 - or -L 6 -, wherein each L 5 is -C(R 15 ) 2 -, wherein each R 15 is independently hydrogen, halogen, (Q-C 6 )alkyl, or (Q-Ce ⁇ aloalkylj and
  • L 6 is -CS-, -CO-, or -SO 2 -;
  • R 5 is phenyl, thienyl, furyl, pyrrolyl, thiazoyl, oxazoyl, isothiazoyl, isoxazoyl, pyridyl, pyrimidinyl, or pyrazinyl optionally substituted with one or more R 5a ; such compounds are referred to hereafter as compounds of formula XXIII.
  • the invention provides the compound according to formula XXIII.
  • the invention provides the compound according to formula XXDI, wherein each R 5a is independently -halogen, -Q-Qalkyl, -Q-Cehaloalkyl, -OR 11 , -COR 11 , -ON, -C(O)OR 11 , -CON(R ⁇ ) 2 , or -N(R U ) 2 .
  • the invention provides the compound according to formula XXffi, wherein each R 41 is independently hydrogen, halogen, -Q-C ⁇ alkyl, or -Q-C ⁇ haloalkyl.
  • the invention provides the compound according to formula XXDI, wherein each R 4 is independently halogen -Q-Qsalkyl, -Q-Qhaloalkyl, -COR 11' , -COOR 11' , -C0N(R ⁇ ') 2 , -ON, -OR 11 ', -N(R U' ) 2 , -SO 2 R 11' , or -SO 2 N(R ⁇ ') 2 , wherein each R 11 ' is independently -hydrogen, -C 1 -C 6 alkyl, or -C 1 -C 6 haloalkyl.
  • the invention provides the compound according to formula XXIII, wherein R 21 is hydrogen, halogen, nitro, cyano, CrQalkyl, or Q-Cehaloalkyl.
  • the invention provides the compound according to formula XXI, wherein L 1 is a bond; and R 5 is heteroaryl optionally substituted with one or more R 5a .
  • the invention provides the compound according to formula XXI, wherein L 1 is a bond; and R 5 is thienyl, furyl, pyrrolyl, thiazoyl, oxazoyl, isothiazoyl, isoxazoyl, pyridyl, pyrimidinyl, or pyrazinyl optionally substituted with one or more R 5a .
  • the invention provides the compound according to formula XXI, wherein L 1 is a bond; and R 5 is thienyl, furyl, pyrrolyl, thiazoyl, oxazoyl, isothiazoyl, or isoxazoyl optionally substituted with one or more R 5a ; such compounds are referred to hereafter as compounds of formula XXTV.
  • the invention provides the compound according to formula XXIV, wherein each R 4 is independently halogen -Q-Qalkyl, -Q-Qhaloalkyl, -COR 11 ', -COOR 11' , -CON(R ⁇ ) 2 , -C ⁇ N, -OR 11 ', -N(R ⁇ ) 2 , -SO 2 R 11 ', or -SO 2 N(R ⁇ ') 2 , wherein each R 11 ' is independently -hydrogen, -C 1 -C 6 alkyl, or -C 1 -C 6 haloalkyl.
  • the invention provides the compound according to formula XXTV, wherein R 2 is -L 3 -R 7 , wherein L 3 is a bond or -C(R 11 ) 2 -; and
  • the invention provides the compound according to formula XXTV, wherein each R 41 is independently hydrogen, halogen, -C 1 -QaIlCyI, or -Q-Qhaloalkyl.
  • the invention provides the compound according to formula XXTV, wherein R 21 is hydrogen, halogen, nitro, cyano, Q-Qalkyl, or Q-Qhaloalkyl.
  • the invention provides the compound according to formula XXI, wherein L 1 is a bond; and R 5 is pyridyl, pyrimidinyl, or pyrazinyl optionally substituted with one or more R 5a such compounds are referred to hereafter as compounds of formula XXV.
  • the invention provides the compound according to formula XXV, wherein each R 5a is -halogen, -Q-Qalkyl, -Q-Qhaloalkyl, -OR 11 , -COR 11 , -CNN, -C(O)OR 11 , -CON(R ⁇ ) 2 , or-N(R ⁇ ) 2 .
  • the invention provides the compound according to formula XXV, wherein each R 4 is independently halogen -Q-Qalkyl, -Q-Qhaloalkyl, -COR 11 ', -COOR 11' , -CON(R ⁇ ' ) 2 , -CNN, -OR 11 ', -N(R ⁇ ) 2 , -SO 2 R 11' , or -SO 2 N(R ⁇ ') 2 , wherein each R 11 ' is independently -hydrogen, -C 1 -C 6 alkyl, or -Ci-C 6 haloalkyl.
  • the invention provides the compound according to formula XXV, wherein R 2 is -L 3 -R 7 , wherein L 3 is a bond; and
  • the invention provides the compound according to formula XXV, wherein each R 41 is independently hydrogen, halogen, -Q-Qalkyl, or -Q-C ⁇ haloalkyl.
  • the invention provides the compound according to formula XXV, wherein R 21 is hydrogen, halogen, nitro, cyano, CrC 6 alkyl, or Q-C ⁇ haloalkyl.
  • the invention provides the compound according to formula XTX, wherein K is heteroaryl; and L 2 is a bond.
  • the invention provides the compound according to formula XTX, wherein K is thienyl, furyl, pyrrolyl, thiazoyl, oxazoyl, isothiazoyl, isoxazoyl, pyridyl, pyrimidinyl, or pyrazinyl; and L 2 is a bond.
  • the invention provides the compound according to formula XTX, wherein K is pyridyl; and L 2 is a bond. In another embodiment, the invention provides the compound according to formula XTX, wherein K is pyridyl; L 2 is a bondjL 1 is a bond; and
  • R 5 is phenyl optionally substituted with one or more R 5a .
  • the invention provides the compound according to formula XXVI,
  • R 1 , R 2 , R 21 , R 4 , R 41 , L 2 , q, and q' are as defined in formulas Ia-d.
  • the invention provides the compound according to formula XXVH, or a pharmaceutically acceptable salt, isomer, or prodrug thereof, wherein R 1 , R 2 , R 21 , R 4 , R 41 , L 2 , q, and q' are as defined in formulas Ia-d.
  • the invention provides the compound according to formula XXVIII,
  • the invention provides the compound according to formula XXVm, wherein each R 5a is -halogen, -CrQalkyl, -Q-C ⁇ haloalkyl, -OR 11 , -COR 11 , -ON, -C(O)OR 11 , -CON(R n ) 2 , or-N(R u ) 2 .
  • the invention provides the compound according to formula XXVHI, wherein each R 41 is independently hydrogen, halogen, -Q-Cealkyl, or -Ci-C ⁇ haloalkyl.
  • the invention provides the compound according to formula XXVHI, wherein R 2 is -L 3 -R 7 , wherein L 3 is a bond or -C(R 11 Vs and
  • the invention provides the compound according to formula XXVIH, wherein R 21 is hydrogen, halogen, nitro, cyano, Q-C 6 alkyl, or CrQhaloalkyl.
  • the invention provides the compound according to formula Ia-d, wherein J is aryl or heteroaryl.
  • the invention provides the compound according to formula Ia-d, wherein J is phenyl, pyridyl, thienyl, pyrrolyl, furanyl, pyrimidinyl, pyrazinyl, imidazoyl, pyrazoyl, oxazoyl, thiazoyl, isoxazoyl, isothiazoyl, triazoyl, triazinyl, tetrazoyl, or tetrazinyl.
  • the invention provides the compound according to formula Ia-d, wherein J is phenyl, pyridyl, thienyl, pyrrolyl, or furanyl.
  • the invention provides the compound according to formula Ia-d, wherein J is phenyl, pyridyl, or thienyl. In another embodiment, the invention provides the compound according to formula Ia-d, wherein J is phenyl.
  • the invention provides the compound according to formula Ia-d, wherein J is pyridyl.
  • the invention provides the compound according to formula Ia-d, wherein J is thienyl.
  • the invention provides the compound according to formula Ia-d, wherein K is aryl or heteroaryl.
  • the invention provides the compound according to formula Ia-d, wherein K is phenyl, pyridyl, thienyl, pyrrolyl, furanyl, pyrimidinyl, pyrazinyl, imidazoyl, pyrazoyl, oxazoyl, thiazoyl, isoxazoyl, isothiazoyl, Mazoyl, triazinyl, tetrazoyl, or tetrazinyl.
  • the invention provides the compound according to formula Ia-d, wherein K is phenyl, pyridyl, thienyl, pyrrolyl, or furanyl.
  • the invention provides the compound according to formula Ia-d, wherein K is phenyl or pyridyl. In another embodiment, the invention provides the compound according to formula Ia-d, wherein K is pyridyl.
  • the invention provides the compound according to formula Ia-d, wherein K is phenyl.
  • the invention provides the compound according to formula Ia-d, wherein L 2 is a bond.
  • the invention provides the compound according to formula Ia-d, wherein J is aryl or heteroaryl; and K is aryl or heteroaryl.
  • the invention provides the compound according to formula Ia-d, wherein J is aryl or heteroaryl; K is aryl or heteroaryl; and L 2 is a bond. In another embodiment, the invention provides the compound according to formula Ia-d, wherein
  • J is phenyl, pyridyl, thienyl, pyrrolyl, furanyl, pyrimidinyl, pyrazinyl, imidazoyl, pyrazoyl, oxazoyl, thiazoyl, isoxazoyl, isothiazoyl, triazoyl, triazinyl, tetrazoyl, or tetrazinyl;
  • K is phenyl, pyridyl, thienyl, pyrrolyl, furanyl, pyrimidinyl, pyrazinyl, imidazoyl, pyrazoyl, oxazoyl, thiazoyl, isoxazoyl, isothiazoyl, triazoyl, triazinyl, tetrazoyl, or tetrazinyl; and L 2 is a bond.
  • the invention provides the compound according to formula Ia-d, wherein J is phenyl, pyridyl, thienyl, pyrrolyl, or furanyl; K is phenyl, pyridyl, thienyl, pyrrolyl, or furanyl; and L 2 is a bond.
  • the invention provides the compound according to formula Ia-d, wherein J is phenyl, pyridyl, or thienyl; K is phenyl or pyridyl; and L 2 is a bond. In another embodiment, the invention provides the compound according to formula Ia-d, wherein J is phenyl; K is phenyl; and L 2 is a bond.
  • the invention provides the compound according to formula Ia-d, wherein J is pyridyl; K is phenyl; and L 2 is a bond.
  • the invention provides the compound according to formula Ia-d, wherein J is thienyl; K is phenyl; and L 2 is a bond.
  • the invention provides the compound according to formula Ia-d, wherein J is phenyl; K is pyridyl; and L 2 is a bond.
  • the invention provides the compound according to formula Ia-d, wherein J is pyridyl; K is pyridyl; and L 2 is a bond. In another embodiment, the invention provides the compound according to formula Ia-d, wherein J is thienyl; K is pyridyl; and L is a bond.
  • the invention provides the compound according to formula Ia-d, wherein R 5 is aryl, heterocyclyl, or heteroaryl, wherein R 5 is optionally substituted with one or more R Sa .
  • the invention provides the compound according to formula Ia-d, wherein R 5 is aryl or heteroaryl, wherein R 5 is optionally substituted with one or more R 5a .
  • the invention provides the compound according to formula Ia-d, wherein R 5 is phenyl, pyridyl, thienyl, pyrrolyl, furanyl, pyrimidinyl, pyrazinyl, imidazoyl, pyrazoyl, oxazoyl, thiazoyl, isoxazoyl, isothiazoyl, triazoyl, triazinyl, tetrazoyl, or tetrazinyl wherein R 5 is optionally substituted with one or more R 5a .
  • the invention provides the compound according to formula Ia-d, wherein L 1 is a bond; and R 5 is phenyl, pyridyl, thienyl, pyrrolyl, furanyl, pyrimidinyl, pyrazinyl, imidazoyl, pyrazoyl, oxazoyl, thiazoyl, isoxazoyl, isothiazoyl, triazoyl, triazinyl, tetrazoyl, or tetrazinyl, wherein R 5 is optionally substituted with one or more R 5a .
  • the invention provides the compound according to formula Ia-d, wherein L 1 is a bond; and R 5 is phenyl, pyridyl, thienyl, pyrrolyl, or furanyl, wherein R 5 is optionally substituted with one or more R 5a .
  • the invention provides the compound according to formula Ia-d, wherein L 1 is a bond; and R 5 is phenyl optionally substituted with one or more R 5a .
  • the invention provides the compound according to formula Ia-d, wherein L 1 is a bond; and R 5 is pyridyl optionally substituted with one or more R 5a .
  • the invention provides the compound according to formula Ia-d, wherein L 1 is a bond; and R 5 is thienyl optionally substituted with one or more R 5a .
  • the invention provides the compound according to formula Ia-d wherein R 21 is hydrogen, halogen, nitro, cyano, aryl, heteroaryl, heterocyclyl, -C 1 -C 6 alkyl-heterocyclyl, -C 1 -C 6 alkyl-heteroaryl, -C 1 -C 6 alkyl-aryl, -Z, -Y-Z, or -X-Y-Z, wherein Xis -O-;
  • Y is -[C(R 15 ) 2 ] m -, -C 2 -C 6 alkenyl, or C 3 -C 8 cycloalkyl;
  • Z is -H, -CN, halogen, -OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)N(R 11 ⁇ , -N(R U ) 2 , -CN, -N 3 , -SO 2 R 11 , -S(O) 2 N(R U ) 2 , -C(O)N(R 1 ⁇ N(R 1 ⁇ -C(O)N(R 11 XOR 11 ),
  • the invention provides the compound according to formula Ia-d wherein R 21 is hydrogen, halogen, nitro, cyano, C 1 -QaIlCyI, or CrQhaloalkyl.
  • the invention provides the compound according to formula XXKa-d wherein R 3 is hydrogen, aryl, heteroaryl, heterocyclyl, -C 1 -C 6 alkyl-heterocyclyl, -C 1 -C 6 alkyl-heteroaryl, -C 1 -C 6 alkyl-aryl, -Z, or -Y-Z wherein
  • Y is -[C(R 15 ) 2 ] m -, -C 2 -C 6 alkenyl, or C 3 -C 8 cycloalkyl;
  • Z is -H, -CN, halogen, -OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)N(R U ) 2 , -N(R U ) 2 , -CN, -N 3 , -SO 2 R 11 , -S(O) 2 N(R n ) 2 , -C(O)N(R ⁇ )N(R ⁇ ) 2 , -C(O)N(R u )(0R ⁇ ), -OC(O)-R 11 , -0C(O)-N(R ⁇ ) 2 , or -N(R ⁇ )COOR n .
  • the invention provides the compound according to formula Ia-d wherein R 3 is hydrogen, CrC 6 alkyl, or CrCehaloalkyl.
  • the invention provides the compound according to any of the formulas Ia-d, ⁇ -XXVm, wherein R 2 is -halogen, -CF 3 , -CH 2 OH, -CH 2 SO 2 Me, -C(CH 3 ) 2 OH, or -C(CH 3 ) 2 SO 2 Me.
  • the invention provides the compound according to any of the formulas Ia-d, ⁇ -XXVm, wherein R 2 is -halogen, -CF 3 , -CH 2 OH, or -C(CH 3 ) 2 OH.
  • the invention provides the compound according to any of the formulas Ia-d, ⁇ -XXVm, wherein R 2 is -CF 3 or -C(CHs) 2 OH. hi another embodiment, the invention provides the compound according to any of the formulas
  • each R 4 is independently halogen, aryl, heteroaryl, heterocyclyl, -M, or -E-M, wherein E is -[C(R 15' ) 2 ] m -, wherein each R 15 is independently hydrogen or halogen; and M is -Q-C 6 alkyl, -Q-Cehaloalkyl, halogen, -OR 11 , or -SO 2 R 11 .
  • the invention provides the compound according to any of the formulas Ia-d, II-XXVIII, wherein each R 4 is independently halogen, -CH 2 - M, -C(H)(F)- M, -CF 2 -M, wherein
  • M is -CrCealkyl, -Q-Cehaloalkyl, -F, -OR 11 ', or -SO 2 R 11' whereinR 11 ' is -H or -Q-Qalkyl.
  • the invention provides the compound according to any of the formulas Ia-d, H-XXVHI, wherein each R 4 is independently -CH 3 , -CF 3 , -CF 2 H, -CH 2 F, -OH, -OMe, -CH 2 OH, or -SO 2 (C 1 -C 3 alkyl).
  • the invention provides the compound according to any of the formulas Ia-d, ⁇ -XXVi ⁇ , whereineach R 41 is independently halogen, -M", or-E"-M", wherein E" is -[QR 15' ) 2 ] m -, wherein each R 15 is independently hydrogen or halogen; and M" is -CrQalkyl, -Q-Cehaloalkyl, or halogen.
  • the invention provides the compound according to formulas Ia-d, ⁇ -XXVTH, wherein each R 41 is independently halogen, methyl or trifluoromethyl.
  • the invention provides the compound according to formulas Ia-d, II-IV, VI-DC, Xm, XrV-XV ⁇ , and XK-XXI wherein R 1 is -L 5 -R s or-L 6 -R 5 wherein
  • L 5 is -[C(R 15 ) 2 ] m -;
  • L 6 is C 3 -Cg cycloalkyl, cycloQ-shaloalkyl, or heterocyclyl, wherein the cycloalkyl, cycloCs-ghaloalkyl 1, or heterocyclyl are optionally substituted with one or more radicals ofR 14 ;
  • R 5 is aryl, heterocyclyl, or heteroaryl, wherein R 5 is optionally substituted with one or more R 5a , wherein each R 5a is independently halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, (C 3 -C 8 CyClOaIlCyI)-C 1 -C 6 alkyl-, (C 3 -C 8 cycloalkenyl)-C r C 6 alkyl-, (C 3 -C 8 cycloalkyl)-C 2 -C 6 alkenyl-, nitro, heterocyclyloxy, ary
  • A' is -O-
  • B' is -[C(R 15 ) 2 ] m - or - C 3 -C 8 cycloalkyl -;
  • C is -H, halogen, -SO 2 R 11 , -OR 11 , -SR 11 , -N 3 , -COR 11 , -SO 2 N(R 11 ⁇ ,
  • the invention provides the compound according to formulas Ia-d, ⁇ -XXVi ⁇ , wherein R 21 is hydrogen, halogen, nitro, cyano, aryl, heteroaryl, heterocyclyl, -C 1 -C 6 alkyl-heterocyclyl, -C 1 -C 6 alkyl-heteroaryl, -Ci-C 6 alkyl-aryl, -Z, -Y-Z, or -X-Y-Z, wherein Xis -O-;
  • Y is -[C(R 15 ) 2 ] m -, -C 2 -C 6 alkenyl, or C 3 -C 8 cycloalkyl;
  • the invention provides the compound according to formulas Ia-d, ⁇ -XXVi ⁇ , wherein R 21 is hydrogen, halogen, nitro, cyano, CrQalkyl, or Q-Cehaloalkyl.
  • the invention provides Hie compound according to for ⁇ iulas Ia-d, ⁇ -XXVi ⁇ , and XL wherein R 21 is hydrogen.
  • the invention provides intermediate compounds according to one of the formulas XXKa-d,
  • R 1 is -i ⁇ R 5 , wherein
  • L 1 is a C 2-6 alidiyl chain wherein the alidiyl chain is optionally interrupted by -C(R 1 ⁇ 2 -, -CrtOTtV, -C(R 11 H ⁇ (R 11 )-, -C(R ⁇ ) 2 0-, -C(R 1 ⁇ 2 NR 11 -, -OC-, -0-, -S-,
  • R 5 is aryl, heterocyclyl, heteroaryl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, (C 3 -C 8 cycloalkyl)-CrC 6 alkyl-, (C 3 -C 8 cycloalkenyl)-Ci-C 6 alkyl-, (C 3 -C 8 cycloalkyl)-C 2 -C 6 alkenyl-, C 3 -C 8 cycloalkyl, -C, -B-C, or -A-B-C, wherein A is -O-;
  • B is -[C(R 15 ) 2 ] m - or C 3 -C 8 cycloalkyl
  • B' is -[C(R 15 ) 2 ] m - or - C 3 -C 8 cycloalkyl -;
  • C is -H, halogen, -SO 2 R 11 , -OR 11 , -SR 11 , -N 3 , -COR 11 , -SO 2 N(R ⁇ ) 2 , -SO 2 NR 11 COR 11 , -ON, -C(O)OR 11 , -OC(O)R 11 , -C0N(R n ) 2 , -CON(R 11 PR 11 , -0C0N(R n ) 2 , -NR 11 COR 11 , -NR 11 C0N(R 11 ) 2 , -NR 11 COOR 11 , -N(R n ) 2 , aryl, heteroaryl, or heterocyclyl; wherein each R 5a is optionally substituted one or more groups which are independently
  • R 2 and R 21 are -L 3 -R 7 , wherein each L 3 is independently a bond -V-(CH 2 VV 1 -, or -(CH ⁇ -V ⁇ CBt ⁇ n - wherein n is 0-6; and each V 1 is independently -C(R ⁇ ) 2 -, -C(R 11 ⁇ C(R 1 V, -C(R 11 H ⁇ (R 11 )-, -C(R ⁇ ) 2 0-,
  • Y is -[C(R 15 ) 2 ] m - -C 2 -C 6 alkenyl, or C 3 -C 8 cycloalkyl;
  • R 7 is optionally substituted with one or more R 7a , wherein
  • Y' is -[CCR 15 ) 2 ] m - or C 3 -C 8 cycloalkyl
  • each R 7a is optionally substituted with one or more R 8 , wherein each R is independently halogen, nitro, cyano, heteroaryl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, Ci-C 6 haloalkyl, C 1 -C 6 haloalkyl(OR ⁇ ), C 0 -C 6 alkylOR 11 , QrC 6 a]kylCON(R u ) 2 , C 0 -C 6 alkylCOR 11 , C 0 -C 6 alkylCOOR 11 , or C 0 -C 6 alkylSO 2 R u ; and wherein if two R 7a are present on the same carbon, then they may be taken together to form a cycloalkyl or heterocyclyl group; provided that R 2 and R 21 are not simultaneously -H; R 3 is -L-R 6 , wherein
  • Y is -[C(R 15 ) 2 ] m -, -C 2 -C 6 alkenyl, C 3 -C 8 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the aryl, heteroaryl, cycloalkyl, or heterocyclyl is optionally substituted with at least one group which is each independently Z";
  • each R 10 is independently -R 11 , -C(O)R 11 , -CO 2 R 11 , or -SO 2 R 11 ; each R 11 is independently -hydrogen, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, (C 3 -C 8 cycloalkenyl)-Ci-C 6 alkyl-, (Cz-C z cycloalkyl)-C 2 -C 6 alkenyl-, -N(R 12 ) 2 , -C 1 -C 6 alkyl, -Ci-C 6 haloalkyl, -C 3 -C 8 cycloalkyl, -(C 1 - C 6 )alkyl-(C 3 -C 8 )cycloalkyl, aryl, -(Ci-C 6 )alkyl-aryl, heteroaryl, -(Ci-C 6 )
  • G is a group of the formula
  • J is aryl, heteroaryl, or absent;
  • E" is -[C(R 15 ) 2 ] m - or C 3 -C 8 cycloalkyl;
  • M" is -Ci-C 6 alkyl, -Ci-Cehaloalkyl, -COR 11 , -COOR 11 , -CON(R U ) 2 , -ON, -OR 11 ,
  • each R 41 is optionally substituted with one or more R 43 , wherein each R ⁇ is independently halogen, aryloxy, aralkyloxy, aryloxyalkyl, -Ci-C 6 alkyl-aryl, Ci-C 6 alkoxyaryl, aryl C 0 -C 6 alkylcarboxy, -M', -E'-M', or -D'-E'-M'
  • D' is -O-
  • F is -[C(R 15 ) 2 ] m - or C 3 -C 8 cycloalkyl
  • M' is -Q-Qalkyl, -d-C ⁇ haloalkyl, COR 11 , -C0N(R n ) 2 , -N(R ⁇ )C00R n , -N(R n ) 2 , COOR 11 , ON, OR 11 , -NR 11 COR 11 , NR 11 SO 2 R 11 , SO 2 R 11 , SOsNlT ⁇ or SR ⁇ and q' is 0, 1, 2, 3, or 4, and provided that,
  • R 2 is not 4-hydroxyphenyl
  • R 2 is not 4-(NH 2 SO 2 )phenyl, 4-(CH 3 SO 2 )phenyl, or 4-(CH 2 FSO 2 )phenyl
  • R 1 isnot4-hydroxyphenyl
  • R 2 is not 4-(NH 2 SO 2 )phenyl, 4-(CH 3 SO 2 )phenyl, or 4-(CH 2 FSO 2 )phenyl
  • R 1 is not 4-Me-phenyl
  • the invention provides the compound according to formula XXEXa-d, wherein Hal is -Cl, -Br, or -I.
  • the invention provides the compound according to fonnula XXEXa-d wherein R 21 is hydrogen, halogen, nitro, cyano, aryl, heteroaryl, heterocyclyl, -Ci-C 6 alkyl-heterocyclyl, -C 1 -C 6 alkyl-heteroaryl, -C 1 -C 6 alkyl-aryl, -Z, -Y-Z, or -X-Y-Z, wherein X is -O-;
  • Y is -[C(R 15 ) 2 ] ra -, -C 2 -C 6 alkenyl, or C 3 -C 8 cycloalkyl;and
  • the invention provides the compound according to formula XXtXa-d wherein R 21 is hydrogen, halogen, nitro, cyano, Q-Qalkyl, or Ci-C ⁇ haloalkyl.
  • the invention provides the compound according to formula XXEXa-d wherein R 3 is hydrogen, aryl, heteroaryl, heterocyclyl, -Ci-C 6 alkyl-heterocyclyl, -C 1 -C 6 alkyl-heteroaryl, -C 1 -C 6 alkyl-aryl, -Z, or -Y-Z wherein
  • Y is -[C(R 15 ) 2 ] m - -C 2 -C 6 alkenyl, or C 3 -C 8 cycloalkyl;
  • Z is -H, -CN, halogen, -OR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)N(R ⁇ ) 2 , -N(R ⁇ ) 2 , -CN, -N 3 , -SO 2 R 11 , -S(O) 2 N(R ⁇ ) 2 , -C(O)N(R ⁇ )N(R ⁇ ) 2 , -C(O)N(R 11 XOR 11 ), -OC(O)-R 11 , -0C(O)-N(R ⁇ ) 2 , or -N(R ⁇ )COOR n ;
  • the invention provides the compound according to fonnula XXEXa-d wherein R 3 is hydrogen, Ci-C 6 alkyl, or Q-Cehaloalkyl.
  • the invention provides the compound according to formula XXEXa-d, wherein J is aryl or heteroaryl.
  • the invention provides the compound according to formula XXEXa-d, wherein J is phenyl, pyridyl, thienyl, pyrrolyl, furanyl, pyrimidinyl, pyrazinyl, imidazoyl, pyrazoyl, oxazoyl, thiazoyl, isoxazoyl, isothiazoyl, triazoyl, triazinyl, tet ⁇ zoyl, or tetrazinyl.
  • the invention provides the compound according to formula XXEXa-d, wherein J is phenyl, pyridyl, thienyl, pyrrolyl, or furanyl.
  • the invention provides the compound according to formula XXIXa-d, wherein J is phenyl, pyridyl, or thienyl.
  • the invention provides the compound according to formula XXIXa-d, wherein J is phenyl. In another embodiment, the invention provides the compound according to formula XXEXa-d, wherein J is pyridyl.
  • the invention provides the compound according to formula XXEXa-d, wherein J is thienyl.
  • the invention provides the compound according to formula XXEXa-d, wherein R 5 is aryl, heterocyclyl, or heteroaryl, wherein R 5 is optionally substituted with one or more R 5 a.
  • the invention provides tiie compound according to formula XXIXa-d, wherein R 5 is aryl or heteroaryl, wherein R 5 is optionally substituted with one or more R 5a .
  • the invention provides the compound according to formula XXEXa-d, wherein R 5 is phenyl, pyridyl, thienyl, pyrrolyl, furanyl, pyrimidinyl, pyrazinyl, imidazoyl, pyrazoyl, oxazoyl, thiazoyl, isoxazoyl, isothiazoyl, triazoyl, triazinyl, tetrazoyl, or tetrazinyl wherein R 5 is optionally substituted with one or more R 5a .
  • the invention provides the compound according to formula XXEXa-d, wherein L 1 is a bond. In another embodiment, the invention provides the compound according to formula XXEXa-d, wherein L 1 is a bond; and R 5 is phenyl, pyridyl, thienyl, pyrrolyl, furanyl, pyrimidinyl, pyrazinyl, imidazoyl, pyrazoyl, oxazoyl, thiazoyl, isoxazoyl, isothiazoyl, triazoyl, triazinyl, tetrazoyl, or tetrazinyl, wherein R 5 is optionally substituted with one or more R 5a .
  • the invention provides the compound according to formula XXEXa-d, wherein L 1 is a bond; and R 5 is phenyl, pyridyl, thienyl, pyrrolyl, or furanyl, wherein R 5 is optionally substituted with one or more R 5a .
  • the invention provides the compound according to formula XXEXa-d, wherein L 1 is a bond; and R 5 is phenyl optionally substituted with one or more R 5a .
  • the invention provides the compound according to formula XXIXa-d, wherein L 1 is a bond; and R 5 is pyridyl optionally substituted with one or more R 5a .
  • the invention provides the compound according to formula XXDCa-d, wherein L 1 is a bond; and R 5 is thienyl optionally substituted with one or more R 5a .
  • the invention provides the compound according to formulas XXIXa-d, wherein R 2 is -L 3 -R 7 , wherein L 3 is a bond; and
  • R 7 is hydrogen, halogen, -Z, or -Y-Z, wherein
  • Y is -[C(R 15' ) 2 ] m - or C 2 -C 6 alkenyl, wherein each R 15' is independently H, halogen, or (Ci-C 6 )alkyl;
  • the invention provides the compound according to formulas XXIXa-d, wherein R 2 is -L 3 -R 7 , wherein L 3 is a bond;
  • R 7 is hydrogen, halogen, or -[C(R 15 ) 2 ]-Z, wherein each R 15' is independently H, halogen, or (Q-Q ⁇ alkyl;
  • the invention provides the compound according to formulas XXIXa-d, wherein R 2 is -halogen, -CF 3 , -CH 2 OH, -CH 2 SO 2 Me, -C(CH 3 ) 2 OH, or -C(CH 3 ) 2 SO 2 Me.
  • the invention provides the compound according to formulas XXIXa-d, wherein R 2 is -halogen, -CF 3 , -CH 2 OH, or -C(CH 3 ) 2 OH.
  • the invention provides the compound according to formulas XXBCa-d, whereinR 2 is -CF 3 or -C(CH 3 ) 2 OH.
  • the invention provides the compound according to formulas XXDCa-d, wherein each R 41 is independently halogen, -M", or -E" -M", wherein
  • E" is -[C(R 15' ) 2 ] m -, wherein each R 15 is independently hydrogen or halogen;
  • M" is -CrC 6 alkyl, -Q-C ⁇ haloalkyl, or halogen.
  • the invention provides the compound according to formula XXIXa-d, wherein R 1 is L x -R 5 , wherein L 1 is a bond;
  • R 5 is phenyl or pyridyl, each optionally substituted with one or two R 5a , wherein eachR 5a is independently -halogen, -CH 3 , or -CF 3 ;
  • R 2 is -H, -C(R 2 ⁇ ) 2 OH, -CH 3 , -CF 3 , or halogen, wherein each R 20 is independently -H, -F, -CH 3 , or -CF 3 ;
  • J is phenyl, pyridyl, or thienyl; and each R 41 is -halogen, -CH 3 , -CH 2 CH 3 , -CF 3 , -CF 2 CF 3 , or -CH 2 CF 3 .
  • the invention provides the compound according to formula XXTXa-d, wherein q' is 0 or 1; R 1 is L ⁇ R 5 , wherein L 1 is a bond;
  • R 5 is phenyl optionally substituted with one or two R 5a , wherein each R 5a is independently -halogen, -CH 3 , or -CF 3 ; each R 2 is -H, -C(R 20 ) 2 OH 5 -CH 3 , -CF 3 , or halogen, wherein each R 20 is independently -H, -F, -CH 3 , or -CF 3 ; and R 41 is -halogen, -CH 3 , -CH 2 CH 3 , -CF 3 , -CF 2 CF 3 , or -CH 2 CF 3 .
  • the invention provides the compound according to formulas XXTXa-d, wherein each R 41 is independently halogen, methyl or trifluoromethyl.
  • the invention provides the compound according any of the previous embodiments wherein R 21 is hydrogen.
  • R 21 is hydrogen
  • (i) q may be 0 only if L 2 is not a bond or if K is not phenyl;
  • the compound is not 2-methyl-5-(l-m-tolyl-3-(trifluorometiiyl)-1H- ⁇ yrazol-5- yl)benzenesulfonamide;
  • R 2 is not 4-(NH 2 SO 2 )phenyl, 4-(CH 3 SO 2 )phenyl, or 4-(CH 2 FSO 2 )phenyl; b) R 1 isnot4-hydroxyphenyl;
  • R 2 is not 4-(NH 2 SO 2 )phenyl, 4-(CH 3 SO 2 )phenyl, or 4-(CH 2 FSO 2 )phenyl;
  • J is not pyridyl;
  • G is not 3- or 4-methoxyphenyl
  • R 1 is not 4-Me-phenyl.
  • One embodiment of the invention relates to compounds represented by formulae Iaa, Ibb, Ice or Idd:
  • each R 1 substitutent is independently selected from the group consisting of R 5 and -L 1 -R 5 .
  • R 1 substitutent is R 5 ;
  • Preferred R 5 for this embodiment is selected from the group consisting of 5-12 membered aromatic or non-aromatic ring, 5-12 membered heterocyclyl or heteroaryl having one or more heteroatoms N, O or S; R 5 is optionally substituted at a substitutable position with one or more radicals of R 5a .
  • R 5 is preferably thienyl, furanyl, piperidinyl, pyrrolidinyl, piperazinyl, morpholinyl, thiazolyl, indolyl, oxazolyl, isoxazolyl, pyridinyl, pyrimidinyl, imidazolyl and phenyl.
  • R 5a groups include halogen, Cw haloalkyl, nitro, d* aliphatic group, C 1-6 alkoxy,
  • R 5a is optionally substituted at substitutable position with C 0 * alkylSO 2 R ⁇ , C 0 * alkoxyaryl, 5-12 membered aromatic or non-aromatic ring, or 5-12 membered heterocyclyl or heteroaryl having one or more heteroatoms N, O or S.
  • R 5a is Cl, Br, F, C 1-6 alkyl, C M haloalkyl, C 1-6 alkoxy, OC 0 ⁇ alkylCOOR 11 , OCON(R n ) 2 , NHCOR 11 , C0N(R n ) 2 , NO 2 , OCON(R ⁇ ) 2 , and OC 1-6 alkylCON(R u ) 2 .
  • R 5a examples include OCH 2 C(CH 3 ) 3 , Cl, F, Br, OCH 2 CH(CH 3 ) 2 , OCH 2 CH 3 , CF 3 , COOH, OCH 3 , OH, NO 2 , OCOCH(CH 3 ) 2 , OCOC(CH 3 ) 3 , NHCOCH 3 , OCON(CH 3 ) 2 , OCONHCH 3 , OCON (CH 2 ) 2 CH 3 , OCONHCH(CH 3 ) 2 , O(CH 2 ) 2 , CONH 2 , O(CH)(CH 3 ) 2 , C w alkyl, OCH 2 COOH, OCH 2 COOC(CH 3 ) 3 , OCCH ⁇ NCCH ⁇ H ⁇ , OC(CH 3 ) 2 COOC(CH 3 ) 3 , and OCH 2 CH 2 OH.
  • R 1 substituted is -L 1 -R 5 .
  • Preferred R 5 for this embodiment is selected from the group consisting of 5-12 membered aromatic or non-aromatic ring, 5-12 membered heterocyclyl or heteroaryl having one or more heteroatoms N, O or S; R 5 is optionally substituted at a substitutable position with one or more radicals of R 5a .
  • Examples of preferred R 5 include phenyl, pyridinyl, oxazolyl, thienyl, thiazolyl, morpholinyl, furanyl, imidazolyl, piperazinyl, pyrimidinyl, isoxazolyl or piperidinyl.
  • L 1 includes a direct bond, -CS-, -Q-salkoxy-, -carbonyl-, -SO 2 -, -CON(R 11 )-,
  • R 5 examples of preferred R 5 are selected from the group consisting of phenyl, pyridinyl, oxazolyl, thienyl, thiazolyl, morpholinyl, imidazolyl, piperazinyl, pyrimidinyl, isoxazolyl and piperidinyl.
  • R 5a examples include halogen, haloalkyl, OCH 2 CON(CH 3 ) 2 , OCH 2 COOC(CH 3 ) 3 , OCH 2 CH 2 N(CH 2 CH 3 ) 2 , OCH 2 COOH, OC(CH 3 ) 2 COOC(CH 3 ) 2 , OCON(CH 3 ) 2 , OCONHCH 3 , OCH 2 CH 2 OH, OCONHCH 2 CHCH 3 , OrNHCOCH 3 .
  • R 5 is optionally substituted at a substitutable position with one or more radicals of R 5a .
  • R 2 is independently selected from the group consisting of R 7 and L 3 -R 7 ; each R 7 for this embodiment is independently selected from hydrogen, C 1-6 alkyl, halogen, Ci -6 haloalkyl, C w alkoxy, C 1-6 haloalkylCOR 11 ), C 0 ⁇ alkylCOOR 11 , C 0 ⁇ alkylCONCR n ) 2 , C 0 ⁇ alkylNCR n ) 2 , C 1-6 alkylOR 11 , C 0 ⁇ alkylSO ⁇ CR 11 ) ⁇ C 0 ⁇ alkylC ⁇ N, cycloC ⁇ alkylON, Co 6 alkylCONR ⁇ NCR u ) 2 , Qy 6 811QrICQNR 11 OR 11 , C 0-6 alkylOCOR 11 , CyCIoC 3-6 alkyl, cycloC ⁇ alkylOR 11 ; 5-12 membered aromatic or non-aromatic ring
  • R 7 is optionally substituted at a substitutable position with one or more radicals of R 7a ;
  • Preferred R 7 is phenyl, pyridinyl, thienyl, furanyl, piperidinyl, pyrrolidinyl, piperazinyl, morpholinyl, thiazolyl, indolyl, oxazolyl, pyridinyl, isoxazolyl, pyrimidinyl, naphthyl, hydrogen, CF 3 , C 0-6 alkylCsN, CH 2 OH, COOCH 3 , C00N(R ⁇ ) 2 or COOR 11 .
  • R 7 is CF 3 , COOCH 3 , COOH, or CONHCH 2 CH 3 .
  • R 7 is phenyl or pyridinyl
  • preferred R 7a is selected from the group consisting of halogen, Q-5 alkyl, Q_5 alkoxy, and C 1-6 haloalkyl.
  • R 2 is L 3 -R 7 .
  • Each R 7 for this embodiment is selected from the group consisting of 5-12 membered aromatic or non-aromatic ring; 5-12 membered heteroaryl and heterocyclyl having one or more heteroatoms N, O or S.
  • R 7 is optionally substituted at a substitutable position with one or more radicals of R 7a ;
  • L 3 is -CH 2 -, -CO-, -OCH 2 -, -CH 2 OCH 2 -, -CONH-, -CH 2 OCOH 2 -, -CH 2 NHCH 2 -, -CH 2 NC(CH 3 ) T , -CH 2 N(CH 3 )CH 2 -, -CH 2 COCH 3 -, -CH 2 N(CH 3 ) 2 CH 2 -, cyclohexamine or cyclopropanamine.
  • Each R 7a may be substituted at a substitutable position with one or more radicals of R 8 ; each R 8 is independently C 1-6 alkyl, Ci -6 alkoxy, Ci -6 haloalkyl, Q -6 alkylOR 11 , Ci -6 haloalkylOR 11 , C M alkylCON(R ⁇ ) 2 , C M alkylCOR 11 , C 0 ⁇ alkylCOOR 11 , NR 11 COOR 11 , or C 0-6 alkylSO 2 R n .
  • R 7 is CF 3 , COOCH 3 , COOH, or CONHCH 2 CH 3 .
  • R 7 is phenyl, pyridinyl, thienyl, furanyl, piperidinyl, pyrrolidinyl, piperazinyl, morpholinyl, thiazolyl, indolyl, oxazolyl, pyridinyl, isoxazolyl, pyrimidinyl, naphthyl.
  • Preferred R 7a is selected from the group consisting of halogen, C 1-6 alkyl, C 1 ⁇ alkoxy, and C 1-6 haloalkyl.
  • R 3 is independently selected from the group consisting of R 6 and -L-R 6 ; Another embodiment is that R 3 is R 6 where R 6 is independently hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkylOR 11 , Co 6 alkylOR 11 , Co 6 alkylCON(R n ) 2 , C 0-6 alkylCOR 11 , 0C0N(R n ) 2 , CONR 11 OR 11 , nitro, C 1-6 alkylCOOR 11 ; 5-12 membered aromatic or non-aromatic ring; 5-12 membered heteroaryl or heterocyclyl having one or more heteroatoms N, O or S; Preferred R 6 is hydrogen or optionally substituted phenyl.
  • Each R 6 is optionally substituted at a substitutable position with one or more radicals ofR & .
  • Each R 6a is independently halogen, C 1-6 alkyl, Ci -6 alkoxy, Q -6 haloalkyl, Ci -6 haloalkylOR 11 ,
  • R 4 is selected from the group consisting of OH, CN, C(CH 3 ) 2 OH, SO 2 CH 3 , SO 2 C(CH 3 ) 3 , SO 2 CH 2 CH 3 , SCH 2 CH 3 , SCH 3 , OCH 3 , Ci -6 alkyl, CH 2 COOH, C(CH 3 ) 2 COOH, NHSO 2 CH 3 , F, Cl, Br, cyclobutane-COOH, OC(CHs) 2 COOH, CF 3 , C(CH 3 ) 2 COOH, CH 2 COOCH 3 , CH 2 CH 2 COOH, OCH 2 COOCH 3 , and COCH 3 . More preferably, R 4 is SO 2 CH 3 , SO 2 CH 2 CH 3 , SCH 2 CH 3 , or SCH 3 . Each R 4 is optionally substituted at a substitutable position with one or more radicals of R 4a ;
  • Each R 13 is independently hydrogen or
  • Each R 14 is independently C 1-6 alkyl, C 1 ⁇ alkoxy, halogen, C 1-6 haloalkyl, Co 6 alkylCON ⁇ 11 ⁇ , C 0-6 alkylCONR n OR ⁇ , Co 6 alkylOR 11 , or C 06 alkylCOOR 11 .
  • G is independently Gl, G2 or G3;
  • Each Ring J or Ring K may be independently absent, same or different and is independently selected from a 5-12 rnembered aromatic or non-aromatic ring, or 5-12 membered heterocyclyl or heteroaryl having one or more hetero atoms, N, S or O.
  • Ring J or Ring K independently is optionally substituted at a substitutable position with one or more radicals of R 4 .
  • Ring J is preferably a phenyl ring or a 5-membered heteroaryl ring.
  • Ring J examples include phenyl, pyridinyl, thienyl, furanyl, mo ⁇ holinyl, thiazolyl, indolyl, oxazolyl, biphenyl, naphthyl, piperidinyl, piperazinyl, or imidazolyl.
  • a preferred Ring J is thienyl or phenyl.
  • J is optionally substituted at a substitutable position with one or more radicals of R 4 .
  • Ring K examples include phenyl, pyridinyl, thienyl, furanyl, morpholinyl, thiazolyl, indolyl, oxazolyl, biphenyl, naphthyl, piperidinyl, piperazinyl, isoxazolyl, pyrimidinyl, or imidazolyl. Ring K is optionally substituted at a substitutable position with one or more radicals of R 4 .
  • Suitable Ring K substituents designated as R 4 include, mefhylsulfonyl, or C 1-6 aliphatic or substituents selected from the group consisting of CR 11 ⁇ CR 11 COOR 11 , C 1-6 alkyl, C 1-6 alkoxy, C 0 ⁇ alkylOR 11 , C w alkylCOR 11 , C 0 ⁇ alkylSO 2 R u , C 0-6 alkylOCOOR 11 , C 0 * alky]NR n COR u , C 0 ⁇ alkyl SO 2 NR 11 COR 11 , C M alkyl SO 2 N(R U ) 2 , C 0-6 alkylSR 11 , (CM alkyl)CO(0R ⁇ ), OVOR 11 , C 0 ⁇ alkylC ⁇ N, halogen, C 1-6 haloalkyl, OC 1-6 haloalkyl, aryloxy, aralkyloxy, aryl
  • Ring K is phenyl, pyridinyl, thienyl, furanyl, morpholinyl, thiazolyl, indolyl, oxazolyl, biphenyl, naphthyl, piperidinyl, piperazinyl, isoxazolyl, pyrimidinyl, or imidazolyl.
  • Ring K is a phenyl or pyridinyl, it is preferably substituted by methylsulfonyl.
  • L 2 is -(CH 2 )m-V 2 -(CH 2 ) n - or -V 2 -(CH 2 ) m -V 2 -; m is 0-6; n is 0-6; V 2 is independently -C(R 1 V, -C(R 11 ⁇ C(R 1 V, -C(R 1 VC(R 11 )-, -C(R ⁇ ) 2 0-, -C(R n ) 2 NR ⁇ -, -OC-, -0-, -S-, -N(R 10 )CO-, -N(R 10 )C ⁇ 2-, -CON(R 10 )-, -CON(R 11 )-, -C0N(R n )0-, -CO-, -CO 2 , -OR 11 N-, -OR 11 COO-, -OC(O)-, -OC(O)N(R 10 )-, -SO 2
  • a preferred L 2 is selected from the group consisting of -CONH-, -CONHCH 2 -, -CH 2 O-, -OCH 2 COOCH 2 -, -CONHCH 2 -, and -OC-.
  • G is Gl
  • R 1 is R 5
  • R 2 is R 7 .
  • Idd is Gl
  • a more preferred embodiment of this invention relates to a compound having one or more features selected from the group consisting of:
  • R 1 is phenyl, pyridinyl, thienyl, furanyl, morpholinyl, thiazolyl, indolyl, oxazolyl, isoxazolyl, pyrimidinyl, or imidazolyl;
  • R 5 is optionally substituted at a substitutable position with one or more radicals of R 5a ;
  • R 5a is halogen, trifluoromethyl, OCONHCH(CH S ) 2 , NHCOCH 3 , OH, OCH 3 , COOH, COOCH 3 , OCH 2 C(CHs) 3 , OCH 2 CH(CHs) 2 , OCH 2 CH 2 N(CHs) 2 , OCH(CH 3 ) 2 OCOCH(CH 3 ) 2 , OCONHCH 3 , OCH 2 CH 3 , or OCH(CH 3 ) 2 ;
  • R 2 is trifluoromethyl, COOCH 3 , CH 2 OH, CONHCH 2 CH 3 , CONHOCH 2 CH(OH) CH 2 OH, CONHCH 2 CH 2 N(CH 3 ) 2 , CONHCH 2 CH 2 OCH 3 , CONHCH 2 CH 2 OCH 3 , CH 2 COOCH 3 , CON(CHs) 2 , COOCH(CHs) 2 , CONHCH 2 CH 2 CH 2 OCH 3 , OCOCH(CH 3
  • Ring J is thienyl, thiazolyl, furanyl, pyridinyl or phenyl;
  • Ring K is optionally substituted phenyl or pyridinyl
  • R 4 is SO 2 CH 3 , SO 2 C(CHs) 3 , CH 3 , SO 2 NH 2 , SO 2 CH 2 CH 3 , SCH 2 CH 3 , SCH 3 , OCH 3 , CF 3 , OCF 3 ,
  • G is Gl
  • R 1 is R 5
  • R 2 is R 7 .
  • Idd is Gl
  • a more preferred embodiment of this invention relates to a compound having one or more features selected from the group consisting of:
  • R 1 is thienyl, furanyl, morpholinyl, thiazolyl, indolyl, oxazolyl, pyridinyl, imidazolyl, isoxazolyl, pyrimidinyl or phenyl;
  • R 5 is optionally substituted at a substitutable position with one or more radicals of R 5a ;
  • R 5a is halogen, trifluoromethyl, OCONH(CH 2 ) 2 CH 3 , OCONH(CH 2 CH 3 ) 2 , NHCOCHs, OH, OCH 3 , COOH, COOCH 3 , OCH 2 C(CH 3 ) 3 , OCH 2 CH(CH 3 ) 2 , OCH ⁇ H ⁇ OCOCH ⁇ Hs ⁇ , OCONHCH 3 , OCH 2 CH 3 , or OCH(CHs) 2 ;
  • R 3 is hydrogen or optionally substituted phenyl
  • Ring J is thienyl, thiazolyl, furanyl, pyridinyl, or phenyl
  • Ring K is optionally substituted phenyl or pyridinyl
  • G is Gl
  • R 1 is L 1 -R 5
  • R 2 is R 7
  • G of formulae Iaa, Ibb, Ice, or Idd is Gl
  • a more preferred embodiment of this invention relates to a compound having one or more features selected from the group consisting of: 006/024749
  • R 1 is L 1 -R 5 '
  • R 5 is phenyl, pyridinyl, morpholinyl, oxazolyl, furanyl, thiazolyl or thienyl;
  • R 5 is optionally substituted with R 5a ;
  • R 5a is halogen or trifluoromethyl;
  • R 2 is trifluoromethyl, CONHCH 2 CH 2 N(CH 3 ) 2 , CONHCH 2 CH 2 CH 2 N(CHS) 2 , or
  • R 3 is hydrogen or phenyl optionally substituted with R 6a ;
  • Ring J is thienyl, pyridinyl, thiazolyl or phenyl; Ring K is substituted phenyl or pyridinyl; and R 4 is SO 2 CH 3 , SO 2 NH 2 , SO 2 CH 2 CH 3 , SCH 2 CH 3 , SCH 3 , OCH 3 , C w alkyl, halogen or CH 2 COOH.
  • G is Gl
  • R 1 is R 5
  • R 2 is L 3 R 7
  • G of formulae Iaa, Ibb, Ice, or Idd is Gl
  • a more preferred embodiment of this invention relates to a compound having one or more features selected from the group consisting of:
  • R 1 is R 5 selected from the group consisting of thienyl, furanyl, morpholinyl, thiazolyl, indolyl, oxazolyl, pyridinyl, imidazolyl, isoxazolyl, pyrimidinyl and phenyl; R 5 is optionally substituted at a substitutable position with one or more radicals of R 5a ;
  • R 5a is OCH 2 C(CHs) 3 , Cl, F, Br, OCH 2 CH(CHs) 2 , OCH 2 CH 3 , CF 3 , COOH, OCH 3 , OH, NO 2 ,
  • OCOCH(CH 3 ) 2 NHCOCH 3 , OCONHCH(CH 3 ) 2 , 0(CH 2 ) 2 , CONH 2 , 0(CH)(CH 3 ) 2 , C w alkyl,
  • R 2 is L 3 -R 7 ;
  • R 7 is phenyl, pyridinyl, thienyl, furanyl, morpholinyl, thiazolyl, oxazolyl, piperidinyl, imidazolyl, piperazinyl, or pyridinyl;
  • L 3 is -CS-, -CO-, -Cu 6 alidiyl-, -CONH-, -CONR 11 -, -CONR 11 NR 11 -, -CH 2 OCH 2 -,
  • R 7a is selected from the group consisting of halogen, C 1-6 alkyl, Cu alkoxy, CF 3 , OCH 2 CH 2 COOH,
  • R 3 is hydrogen or phenyl optionally substituted with R 6a ;
  • Ring J is thienyl, pyridinyl, thiazolyl, furanyl or phenyl; Ring K is substituted phenyl or pyridinyl; and R 4 is SO 2 CH 3 , SO 2 CH 2 CH 3 , SCH 2 CH 3 , SCH 3 , SO 2 NH 2 , OCH 3 , C 1-6 alkyl, CH 2 COOH, C(CHs) 2 COOH, NHSO 2 CH 3 , F, Cl, Br, CF 3 or COCH 3 ;
  • G is Gl
  • R 1 is L 1 -R 5
  • R 2 is L 3 -R 7
  • G of formulae Iaa, Ibb, Ice, or Idd is Gl
  • a more preferred embodiment of this invention relates to a compound having one or more features selected from the group consisting of:
  • R 5 is L 1 -R 5 ;
  • R 5 is selected from the group consisting of thienyl, furanyl, morpholinyl, thiazolyl, indolyl, imidazolyl, piperazinyl, piperidinyl, oxazolyl, pyridinyl, isoxazolyl, pyrimidinyl, imidazolyl and phenyl;
  • R 5 is optionally substituted at a substitutable position with one or more radicals of R 5a ;
  • R 5a is Cw alkyl, C 1 - S alkoxy, COOH 5 halogen or trifluoromethyl;
  • L 1 is -CS-, -CH 2 -, -CH 2 O-, -CH 2 CH 2 -, -OCH 2 CH 2 -, -OCH 2 CO-, -CO-, -SO 2 -, -CONH-,
  • R 2 is L 3 -R 7 ;
  • R 7 is selected from the group consisting of phenyl, pyridinyl, thienyl, furanyl, morpholinyl, thiazolyl, oxazolyl, pyridinyl, isoxazolyl, pyrimidinyl, imidazolyl, CF 3 , and COOCH 3 ;
  • R 7 is optionally substituted at a substitutable position with one or more radicals of
  • L 3 is CH 2 , CH 2 OCH 2 , NC(CHs) 2 , CH 2 NH(CH 2 ) 2 , CONH, CO, CONR 11 , OCH 2 , CH 2 N(CH 3 ) 2 CH 2 , CH 2 OCOCH 2 , CH 2 CONHCH 2 , CH 2 CONHCH 2 CH 2 , cycloalkylamine, CH 2 N(CH 3 )CH 2 , or CH 2 NCH(CHs) 2 CH 2 ;
  • R 7a is selected from the group consisting of halogen, trifluoromethyl, C ⁇ alkyl, Q ⁇ alkoxy,
  • R 3 is hydrogen or phenyl optionally substituted with R & ;
  • Ring J is thienyl, thiazolyl, furanyl, pyridinyl, or phenyl;
  • Ring K is optionally substituted phenyl or pyridinyl;
  • R 4 is SO 2 CH 3 , SO 2 CH 2 CH 3 , SCH 2 CH 3 , SCH 3 , OCH 3 , C M alkyl, CH 2 COOH, C(CH 3 ) 2 COOH, NHSO 2 CH 3 , F, Cl, or Br.
  • G is G2 and R 1 is R 5 and R 2 is R 7 .
  • R 1 is R 5 and R 2 is R 7 .
  • G of formulae Iaa, Ibb, Ice, or Idd is G2
  • a more preferred embodiment of this invention relates to a compound having one or more features selected from the group consisting of:
  • R 1 is R 5 selected from the group consisting of thienyl, furanyl, morpholinyl, thiazolyl, indolyl, oxazolyl, pyridinyl, isoxazolyl, pyrimidinyl, imidazolyl and phenyl; R 5 is optionally substituted at a substitutable position with one or more radicals of R 5a ; R 2 is R 7 selected from the group consisting of phenyl, pyridinyl, thienyl, furanyl, morpholinyl, thiazolyl, oxazolyl, pyridinyl, isoxazolyl, pyrimidinyl, imidazolyl, CF 3 , and COOCH 3 ; R 7 is optionally substituted at a substitutable position with one or more radicals of R 7a ; R 3 is hydrogen or optionally substituted phenyl; L 2 is selected from the group consisting of -CONH-, -CON
  • Ring J or K is substituted phenyl, biphenyl, pyridinyl, piperidinyl, piperazinyl, morpholinyl, thienyl, ornaphthyl; and
  • R 4 is selected from the group consisting of SO 2 CH 3 , SO 2 CH 2 CH 3 , SO 2 CH 2 CH 2 CH 3 , SCH 2 CH 3 , SCH 3 , OCH 3 , C 1 - S alkyl, CH 2 COOH, C(CH 3 ) 2 COOH, NHSO 2 CH 3 , F, Cl, Br, C(CH 3 ) 2 COOH,
  • G is G2
  • R 1 is L 1 -R 5 and R 2 is R 7 .
  • G of formulae Iaa, Ibb, Ice, or Idd is G2
  • a more preferred embodiment of this invention relates to a compound having one or more features selected from the group consisting of: R 1 is L 1 -R 5 ; R 5 is substituted phenyl or pyridinyl;
  • R 5a is halogen, trifluoromethyl, C 1-6 alkyl, C 1-6 haloalkyl, nitro, Cw alkoxy, or OCON(C 1 ⁇ alkyl) 2 ;
  • R 2 is R 7 is selected from the group consisting of phenyl, pyridinyl, Ihienyl, furanyl, morpholinyl, thiazolyl, oxazolyl, pyridinyl, CF 3 , or COOCH 3 ;
  • R 3 is hydrogen or phenyl optionally substituted with R 6a ;
  • Ring J or K is substituted phenyl, thienyl, furanyl, piperazinyl, piperidinyl or pyridinyl;
  • L 2 is -CONH-, -CONHCH 2 -, -CH 2 O-, -OCH 2 COOCH 2 -, -0-, -C ⁇ C-, -OCH 2 CH 2 -, or
  • R 4 is selected from the group consisting of halogen, C 1-6 haloalkyl, C 1-6 alkylCOOR 11 , and methyl sulfonyl.
  • G is G2
  • R 1 is R 5 and R 2 is L 3 R 7 .
  • a more preferred embodiment of this invention relates to a compound having one or more features selected from the group consisting of:
  • R 1 is R 5 selected from the group consisting of thienyl, furanyl, morpholinyl, thiazolyl, indolyl, oxazolyl, pyridinyl, imidazolyl, isoxazolyl, pyrimidinyl and phenyl;
  • R 5 is optionally substituted at a substitutable position with one or more radicals of R 5a ;
  • R 5a is halogen or trifluoromethyl;
  • R 2 is L 3 -R 7 ;
  • R 7 is selected from the group consisting of phenyl, pyridinyl, thienyl, furanyl, morpholinyl, thiazolyl, oxazolyl, pyri
  • L 3 is -CS-, CH 2 , CH 2 OCH 2 , NCH 2 (CH 2 ) 2 , CH 2 N(CH 2 ) 2 , CH 2 CN, CONH, CO, or CONHCH 2 ;
  • R 3 is hydrogen or optionally substituted phenyl;
  • Ring J or K is substituted phenyl, pyridinyl, furanyl, biphenyl or naphthyl;
  • L 2 is -CS-, CONH, CONHCH 2 , CH 2 O, OCH 2 COOCH 2 , OCH 2 CH 2 , or or OCH 2 ;
  • R 4 is SO 2 CH 3 , SO 2 CH 2 CH 3 , SCH 2 CH 3 , CH 2 COOH, C(CH 3 ) 2 COOH, NHSO 2 CH 3 , F, Cl, Br, SCH 3 , OCH 3 , C 1-6 alkyl, COOCH 2 CO, OCH 3 , CH 2 COOH, CH 2 COOCH 3 , CH(CH 3 ) 2 COOH,
  • G is G3, R 1 is R 5 and R 2 is R 7 .
  • R 1 is R 5 and R 2 is R 7 .
  • G of formulae Iaa, Ibb, Ice, or Idd is G3, a more preferred embodiment of this invention relates to a compound having one or more features selected from the group consisting of:
  • R 1 is R 5 selected from the group consisting of thienyl, furanyl, morpholinyl, thiazolyl, indolyl, oxazolyl, pyridinyl, imidazolyl, isoxazole, pyrimidinyl and phenyl; R 5 is optionally substituted at a substitutable position with one or more radicals of R 5a ;
  • R 2 is R 7 selected from the group consisting of phenyl, pyridinyl, thienyl, furanyl, morpholinyl, thiazolyl, oxazolyl, pyridinyl, imidazolyl, isoxazole, pyrimidinyl, CF 3 , halogen, and COOCH 3 ;
  • R 7 is optionally substituted at a substitutable position with one or more radicals of R 7a ;
  • R 3 is hydrogen or optionally substituted phenyl;
  • L 2 is selected from the group consisting of -CS-, -CONH-, -CONHCH 2 -, -CH 2 O-, -OCH 2 COOCH 2 -, -COOCH 2 -, -CO-, -OCH 2 -, -OCO-, -NHCONH-, -0-, -OCH 2 CH 2 -, -OCONH-, and -SO 2 -;
  • Ring J or K is substituted phenyl, biphenyl, pyridinyl, piperidinyl, piperazinyl, morpholinyl, thienyl, furanyl, pyrimidinyl or naphthyl;
  • R 4 is methylsulfonyl, halogen, haloalkyl, CH 2 COOH, OCH 2 -phenyl, CH 2 COO-phenyl,
  • R 5a is OCH 2 C(CHa) 3 , Cl, F, Br, OCH 2 CH(CH 3 ) 2 , OCH 2 CH 3 , CF 3 , COOH, OCH 3 , OH, NO 2 ,
  • OCOCHCCH ⁇ NHCOCH 3 , OCONHCH(CH 3 ) 2 , 0(CH 2 ) 2 , CONH 2 , 0(CH)(CH 3 ) 2 , C w alkyl, OCH 2 COOH, OCH 2 COOC(CH 3 ) 3 , O(CH 2 ) 2 N(CH 2 CH 3 ) 2 , OCOC(CH 3 ) 3 , OC(CH 2 ) 2 COOH,
  • G is G3, R 1 is L 1 -R 5 and R 2 is R 7 .
  • R 1 is L 1 -R 5
  • R 5 is substituted phenyl or pyridinyl
  • R 5a is halogen or trifluoromethyl
  • L 1 is -CH 2 -, -CH 2 O-, -CH 2 CH 2 -, -O0-, -SO 2 -, -CS-, -CONH-, -CONHC(CH 3 ) 2 -,
  • R 2 is halogen, C w alkyl, C w alkoxy, C M alkylCOOR 11 , or CF 3 ;
  • R 3 is hydrogen or phenyl optionally substituted with R 6a ;
  • Ring J or K is phenyl, pyridinyl, thienyl, furanyl, piperidinyl, pyrrolidinyl, piperazinyl, mo ⁇ holinyl, thiazolyl, indolyl, oxazolyl, isoxazolyl, pyrimidinyl, imidazolyl, or biphenyl;
  • L 2 is -CONH-, -CONHCH 2 -, -CH 2 O-, -OCH 2 COOCH 2 -, -OCH 2 -, or -OCH 2 CH 2 -;
  • R 4 is selected from the group consisting of halogen, C 1-6 haloalkyl, C 1-6 alkylCOOR 11 , and methyl sulfonyl.
  • G is G3, R 1 is R 5 and R 2 is L 3 R 7 .
  • R 1 is selected from the group consisting of thienyl, furanyl, morpholinyl, thiazolyl, indolyl, oxazolyl, pyridinyl, isoxazolyl, imidazolyl, pyrimidinyl and phenyl;
  • R 5 is optionally substituted at a substitutable position with one or more radicals of R 5a ;
  • R 2 is L 3 -R 7 ;
  • R 7 is phenyl, pyridinyl, thienyl, furanyl, mo ⁇ holinyl, thiazolyl, oxazolyl, piperidinyl, imidazolyl, piperazinyl, pyridinyl, isoxazolyl, imidazolyl, pyrimidinyl, CF 3 , and COOCH 3 ;
  • R 7 is optionally substituted at a substitutable position with one or more radicals of R 7a ;
  • L 3 is -CS-, -CO-, -C 1-6 alidiyl-, -CONH-, -CONR 11 -, -CONR 11 NR 11 -, -CH 2 OCH 2 -, -CH 2 OCH 2 CH 2 -, -OCH 2 -, -CH 2 N(CH 3 ) 2 -, -CH 2 NHCH 2 -, -CONR 11 O-, -CH 2 OCOCH 2 -, -CH 3 N(CH 3 )(CH 2 )-, -CS-, -CH 2 N(cyclopropane)CH 2 -, -CH 2 NC(CH 3 ) 2 CH 2 -, -CH 2 N(cyclohexane)CH 2 -, -CH 2 NCH(CH 3 ) 2 CH 2 -, -CH 2 N(CF 3 )(CH 2 ) 2 -,
  • R 3 is hydrogen or optionally substituted phenyl
  • Ring J or K is substituted phenyl, furanyl, thienyl, pyridinyl, biphenyl or naphthyl;
  • L 2 is -CONH-, -CONHCH 2 -, -CH 2 O, -OCH 2 COOCH 2 -, or -CONHCH 2 -;
  • R 4 is OH, CN, C(CH 3 ) 2 OH, SO 2 CH 3 , SO 2 CH 2 CH 3 , SCH 2 CH 3 , SCH 3 , SO 2 NH 2 , OCH 3 , C 1-6 alkyl,
  • Another embodiment of this invention relates to compounds represented by formulae Iaa-1, Iaa-2, Iaa-3 or Iaa-4 (Embodiment Iaa):
  • Another embodiment of this invention relates to compounds represented by formulae Ibb-1, Ibb-2, Ibb-3, or Ibb-4 (Embodiment Ibb):
  • Another embodiment of this invention relates to compounds represented by formulae Icc-1, Icc- 2, Icc-3, or Icc-4 (Embodiment Ice):
  • Another embodiment of this invention relates to compounds represented by formulae Idd-1, Idd-2, Idd-3, or Idd-4 (Embodiment Idd):
  • R 1 is R 5 selected from the group consisting of thienyl, furanyl, morpholinyl, thiazolyl, indolyl, oxazolyl, pyridinyl, isoxazolyl, pyrimidinyl, imidazolyl, and phenyl; R 5 is optionally substituted at a substitutable position with one or more radicals of R 5a .
  • R 5 is phenyl or pyridinyl optionally substituted with R 5a .
  • R 2 is R 7 selected from the group consisting of trifluoromethyl, COOCH 3 , CH 2 OH, COMICH 2 CH 3 , CONHOCH 2 CH(OH) CH 2 OH, CONHCH 2 CH 2 N(CH 3 ) 2 , CONHCH 2 CH 2 OCH 3 , CONHCH 2 CH 2 OCH 3 , CH 2 COOCH 3 , CON(CH S ) 2 , COOCH(CH 3 V CONHCH 2 CH 2 CH 2 OCH 3 , OCOCH(CH 3 ) 2 , OCH 2 CON(CH 3 ) 2 , CH 2 CONHCH 2 (CH 3 ), C(OHb) 2 OH, COOH, nitro or COOCH(CH 3 ) 2 , CH 2 ON, QCH 3 ) 2 ON, cycloQ ⁇ alkylON, thienyl, furanyl, morpholinyl, thiazolyl, indolyl, oxazolyl, pyridinyl, imidazolyl,
  • L 1 is selected from the group consisting of -CONH-, -C 1-6 alkyl-, -C 1 ⁇ alkoxy-, -CO-, -SO 2 -, -CH 2 -, -CH 2 O-, -CH 2 CH 2 -, -CO-, -CONH-, -CONHC(CHs) 2 -, -CONH(CH 2 ) 3 OCH 2 -, -OCH 2 CH 2 -, -OCH 2 CH 2 N(CH 3 V, and -CONHCH 2 CH 2 N(CH 3 ) 2 -.
  • L 3 is -CO-, -C 1-6 alidiyl-, -CONH-, -CONR 11 -, -CONR 11 NR 11 -, -CH 2 OCH 2 -, -CH 2 OCH 2 CH 2 -, -OCH 2 -, -CH 2 N(CH 3 V, -CH 2 NHCH 2 -, -CONR 11 O-, -CH 2 OCOCH 2 -, -CH 3 N(CH 3 )(CH 2 )-, -CH 2 N(cyclopropane)CH 2 -, -CH 2 NC(CHs) 2 CH 2 -, -CH 2 N(cyclohexane)CH 2 -, -CH 2 NCH(CHs) 2 CH 2 -, -CH 2 N(CF 3 )(CH 2 V, -CH 2 N(CH 3 )(CH 2 )CH 2 OCOCH 2 CH 2 -,
  • L 2 is selected from the group consisting of -CONH-, -CONHCH 2 -, -CH 2 O-, -OCH 2 COOCH 2 -, -0-, OC-, -OCH 2 CH 2 - and -CONHOCH 2 CH(OH)CH 2 O-.
  • R 5a is independently selected from the group consisting of OCH 2 C(CH 3 ) 3 , Cl, F, Br,
  • R 5a is halogen or trifluoromethyl.
  • R 4 is selected from the group consisting of OH, CN, C(CH 3 ) 2 OH, SO 2 CH 3 ,
  • R is selected from the group consisting of C 0 ⁇ alidiyl chain wherein the alidiyl chain is optionally interrupted by -C(R 1 V, -C(R 11 ⁇ C(R 1 ⁇ -, -QTt ⁇ QR 11 )-, -C(R ⁇ ) 2 O-, -C(R 11 ⁇ NR 11 -, -OC-, -0-, -S-, -N(R 10 )CO-, -N(R 10 )CO 2 -, -CON(R 10 )-, -CO-, -CO 2 -, -OC(O)-, -OQK ) )N(R 10 )-, -SO 2 -, -N(R 10 )SO 2 -, or -SO 2 N(R 10 )-.
  • Each R 4 is independently selected from, C 1-6 alkyl, CR 11 ⁇ CR 11 COOR 11 , C 1-5 alkoxy, C 0 ⁇ alkylOR 11 , C 0 ⁇ alkylCOR 11 , C 0 ⁇ alkylSO 2 R n , C 0 ⁇ alkylOCOOR 11 , C 0 ⁇ 3UCyINR 11 COR 11 , Co 6 alkylSO 2 NR n COR n , C 0 ⁇ alkyl SO 2 N(R ⁇ ) 2 , C 0 ⁇ alkylSR 11 , (C 0-6 alkyl)O0(0R n ), OVOR 11 , halogen, C 1-6 haloalkyl, Ci-shaloalkylOR 11 , OQ- ⁇ haloalkyl, aryloxy, aralkyloxy, aryloxyalkyl, C 1 ⁇ alkoxyaryl, arylCo ⁇ alkylcarboxy
  • R 4 is selected from the group consisting of SO 2 CH 3 , SO 2 C(CH 3 ) 3 , SO 2 CH 2 CH 3 , SCH 2 CH 3 , SCH 3 , OCH 3 , C 1-6 alkyl, CH 2 COOH, C(CH 3 ) 2 COOH, NHSO 2 CH 3 , F, Cl, Br, cyclobutane-COOH, OC ⁇ H ⁇ COOH, CF 3, C(CH 3 ) 2 COOH, CH 2 COOCH 3 , CH 2 CH 2 COOH, OCH 2 COOCH 3 , and COCH 3 . More preferably, R 4 is SO 2 CH 3 , SO 2 CH 2 CH 3 , SCH 2 CH 3 , or SCH 3 .
  • X is selected from the group consisting of S, NR 11 and O.
  • Each R 4 is optionally substituted at a substitutable position with one or more radicals of R 42 ;
  • Each R 421 is independently selected from hydrogen, C 1-6 alkyl, (Ci -6 alkyfyCXXOR 11 ); C 1-6 alkoxy, C ⁇ 6 alkylOR 11 , C 0-6 alkylCOR 11 , C 06 alkylSO 2 R ⁇ , C 0 ⁇ RU ⁇ lSO 2 N(R 1 !
  • the invention provides a pharmaceutical composition comprising a compound of any of formulas Ia-d, II-XXVIII, and XXEXa-d, or a pharmaceutically acceptable derivative thereof, in a pharmaceutically acceptable carrier.
  • the invention provides a pharmaceutical composition comprising a compound of formula XTX, or a pharmaceutically acceptable derivative thereof, in a pharmaceutically acceptable carrier.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula XXII, or a pharmaceutically acceptable derivative thereof, in a pharmaceutically acceptable carrier.
  • the invention provides a pharmaceutical composition comprising a compound of formula XXV, or a pharmaceutically acceptable derivative thereof, in a pharmaceutically acceptable carrier
  • the invention provides a pharmaceutical composition comprising a compound of formula XXIIi, or a pharmaceutically acceptable derivative thereof, in a pharmaceutically acceptable carrier.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula Ia-d, or a pharmaceutically acceptable derivative thereof, in a pharmaceutically acceptable carrier.
  • the invention provides a kit, comprising a packaging material and a compound of any of formula Ia-d, ⁇ -XXVUI, and XXIXa-d, or a pharmaceutically acceptable derivative thereof, which is effective for modulating the activity of a nuclear receptor or for treatment, prevention, inhibition, or amelioration of one or more symptoms of nuclear receptor mediated diseases or disorders.
  • the invention provides a kit, comprising a packaging material, and a compound of formula Ia-d, or a pharmaceutically acceptable derivative thereof, which is effective for modulating the activity of a nuclear receptor or for treatment, prevention, inhibition, or amelioration of one or more symptoms of nuclear receptor mediated diseases or disorders.
  • the invention provides a kit, comprising a packaging material, a compound of formula Ia-d, or a pharmaceutically acceptable derivative thereof, which is effective for modulating the activity of a nuclear receptor or for treatment, prevention, inhibition, or amelioration of one or more symptoms of nuclear receptor mediated diseases or disorders, further comprising a label that indicates that the compound of formula Ia-d, or pharmaceutically acceptable derivative thereof, is used for modulating the activity of a nuclear receptor or for treatment, prevention or amelioration of one or more symptoms of nuclear receptor mediated diseases or disorders, or diseases or disorders in which nuclear receptor activity is implicated.
  • the invention provides a method of treating, preventing, inhibiting, or ameliorating the symptoms of a disease or disorder that is modulated or otherwise affected by nuclear receptor activity or in which nuclear receptor activity is implicated, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any of formula Ia-d, B-
  • the invention provides a method of treating, preventing, inhibiting, or ameliorating the symptoms of a disease or disorder that is modulated or otherwise affected by nuclear receptor activity or in which nuclear receptor activity is implicated, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to part (A) of formulas Ia-d.
  • part (A) of formulas Ia-d is referenced herein with respect to methods of using compounds of the invention, such as for treatment, prevention, inhibition, or amelioration of disease, or for use in preparation of a medicament for the treatment, prevention, or amelioration of disease, it is meant that all compounds defined by part (A) are included and the provisos of part (B) of the same formulas are not to be considered when determining the scope of the compounds defined for the uses therein.
  • the invention provides the method wherein the disease or disorder is hypercholesterolemia, hyperlipoproteinemia, hypertriglyceridemia, lipodystrophy, hyperglycemia, diabetes mellitus, dyslipidemia, atherosclerosis, gallstone disease, acne vulgaris, acneiform skin conditions, diabetes, Parkinson's disease, cancer, Alzheimer's disease, inflammation, immunological disorders, lipid disorders, obesity, conditions characterized by a perturbed epidermal barrier function, conditions of disturbed differentiation or excess proliferation of the epidermis or mucous membrane, or cardiovascular disorders.
  • the disease or disorder is hypercholesterolemia, hyperlipoproteinemia, hypertriglyceridemia, lipodystrophy, hyperglycemia, diabetes mellitus, dyslipidemia, atherosclerosis, gallstone disease, acne vulgaris, acneiform skin conditions, diabetes, Parkinson's disease, cancer, Alzheimer's disease, inflammation, immunological disorders, lipid disorders, obesity, conditions characterized by a perturbed epidermal barrier function, conditions of disturbed differentiation or excess proliferation of
  • the invention provides a method of reducing cholesterol levels in a subject in need thereof, comprising administering an effective cholesterol level-reducing amount of a compound of any of formula Ia-d, H-XXVIII, and XXEXa-d,
  • the invention provides a method of reducing cholesterol levels in a subject in need thereof, comprising administering an effective cholesterol level-reducing amount of a compound according to part (A) of formulas Ia-d.
  • the invention provides a method of treating, preventing, or ameliorating one or more symptoms of a disease or disorder which is affected by cholesterol, triglyceride, or bile acid levels, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any of formula Ia-d, ⁇ -XXVUI, and XXIXa-d.
  • the invention provides a method of treating, preventing, or ameliorating one or more symptoms of a disease or disorder which is affected by cholesterol, triglyceride, or bile acid levels, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to part (A) of formulas Ia-d.
  • the invention provides a method of modulating nuclear receptor activity, comprising contacting the nuclear receptor with a compound of any of formula Ia-d, H-XXVHI, and XXEXa-d.
  • the invention provides a method of modulating nuclear receptor activity, comprising contacting the nuclear receptor with a compound according to part (A) of formulas Ia-d.
  • the invention provides the method wherein the nuclear receptor is an orphan nuclear receptor.
  • the invention provides the method wherein the nuclear receptor is a liver X receptor. In a preferred embodiment of the ninth aspect, the invention provides the method wherein the nuclear receptor is a liver X receptor, wherein the liver X receptor is LXR ⁇ or LXR ⁇ .
  • the invention provides a method of modulating cholesterol metabolism, comprising administering an effective cholesterol metabolism-modulating amount of a compound of any of formula Ia-d, H-XXVlII, and XXKa-d.
  • the invention provides a method of modulating cholesterol metabolism, comprising administering an effective cholesterol metabolism-modulating amount of a compound according to part (A) of formulas Ia-d.
  • the invention provides a method of treating, preventing, inhibiting, or ameliorating one or more symptoms of hypocholesterolemia in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of any of formula Ia-d, H-XXVIII, and XXrXa-d.
  • the invention provides a method of treating, preventing, inhibiting, or ameliorating one or more symptoms of hypocholesterolemia in a subject in need thereof, comprising administering a therapeutically effective amount of a compound according to part (A) of formulas Ia-d.
  • the invention provides a method of increasing cholesterol efflux from cells of a subject, comprising administering an effective cholesterol efflux-increasing amount of a compound of any of formula Ia-d, H-XXVDI, and XXEXa-d.
  • the invention provides a method of increasing cholesterol efflux from cells of a subject, comprising administering an effective cholesterol efflux-increasing amount of a compound according to part (A) of formulas Ia-d.
  • the invention provides a method of increasing the expression of ATP-Binding Cassette (ABC 1 ) in the cells of a subject, comprising administering an effective ABC 1 expression-increasing amount of a compound of any of formula Ia-d, H-XXVHI, and XXDCa-d. Definitions
  • alkyl is defined hereinbelow as containing from 1 to 12 carbon atoms, but a substituent defined as C ⁇ alkyl is limited to an alkyl moiety of from 1 to 6 carbons. All selections of any variables in connection with any of the general structures or formulas herein are understood to be proper only when said selection yields a stable chemical structure as recognized by one skilled in the art.
  • a bivalent linking moiety can be "alkyl,” in which case those skilled in the art will understand the alkyl to be a divalent radical (e.g., -CH 2 -CH 2 -), which is equivalent to the term “alkylene.”
  • alkyl a divalent radical
  • aryl a divalent moiety that is required and is stated as being “aryl”
  • All atoms are understood to have their normal number of valences for bond formation (i.e., 4 for carbon, 3 for N, 2 for O 5 and 2, 4, or 6 for S, depending on the oxidation state of the S).
  • a moiety may be defined, for example, as (A) a -B-, wherein a is 0 or 1. In such instances, when a is 0, the moiety is B-, and when a is 1 the moiety is A-B-.
  • C 0-6 alkylOR 11 includes both — OR 11 and C 1 -C 6 -OR 11 , and -[C(R 15 ) 2 ] m - is a bond when m is 0.
  • a moiety is a divalent radical, there is no implied limitation on the location of the two bonds connecting the linking radical to its two supporting chemical units.
  • the cyclohexyl can be connected either through two separate chemical bonds to two distinct carbons atoms within the ring; or the two bonds can be connected to the same carbon atom in the ring.
  • this definition encompasses both 1 ,2-diphenylcyclopropyl and 1 , 1 -diphenylcyclopropyl units.
  • interrupted by means the group specified is inserted at any point within the specified chain, but not at the termini.
  • a C 3 -alkyl chain, as defined herein, is interrupted by -O-, then the following groups would be encompassed: -CH 2 -O-CH 2 CH 2 -, -CH 2 -CH 2 - 0-CH 2 , -CH(CHs)-O-CH 2 -, and -CH 2 -O-CH(CH 3 )-.
  • alphatic and aliphatic group as used herein means straight-chain, branched or cyclic C 1 -C 12 (unless stated otherwise) hydrocarbon radicals which are completely saturated or which contain one or more units of unsaturation but which are not aromatic.
  • suitable aliphatic groups include substituted or unsubstituted linear, branched or cyclic alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.
  • alkyl used alone or as part of a larger moiety include both straight and branched chains containing one to twelve carbon atoms.
  • alkenyl and alkynyl used alone or as part of a larger moiety include both straight and branched chains containing two to twelve carbon atoms.
  • alkoxy refers to an -O-alkyl radical, where alkyl is defined herein.
  • Alkyl refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to twelve carbon atoms, preferably one to eight, and which is attached to the rest of the molecule by a single bond, e.g., methyl, ethyl, 77-propyl, 1-methylethyl (iso-propyl), n-butyl, r ⁇ -pentyl, 1,1-dimethylethyl (t-buryl), and the like.
  • the alkyl radical is optionally substituted by one or more substituents selected from the group consisting of halo, cyano, nitro, -OR 11 , -N(R 1 x )z, -COR 11 , -COOR 11 , -CON(R U ) 2 , -N(R 1 ⁇ COOR 10 , -N(R n )C0R n , -NSO 2 R 11 , -N(R ⁇ )SO 2 R 11 , -SO 2 OR 11 , -SO 2 R 11 , and -SO 2 N(R n ) 2 where each R 10 and R 11 are as defined above in the first aspect of the invention.
  • alkyl refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing at least one double bond, having from two to eight carbon atoms, and which is attached to the rest of the molecule by a single bond or a double bond, e.g., ethenyl, prop-1- enyl, but-1-enyl, pent-1-enyl, penta-l,4-dienyl, and the like.
  • the alkenyl radical is optionally substituted by one or more substituents selected from the group consisting of halo, cyano, nitro, -OR 11 , -N(R ⁇ ) 2 , -COR 11 , -COOR 11 , -CON(R n ) 2 , -N(R ⁇ )COOR 10 , -N(R 11 XX ) R 11 , -NSO 2 R 11 , -N(R ⁇ )SO 2 R n , -SO 2 OR 11 , -SO 2 R 11 , and -SO 2 N(R n ) 2 where each R and R are as defined above in the first aspect of the invention.
  • substituents selected from the group consisting of halo, cyano, nitro, -OR 11 , -N(R ⁇ ) 2 , -COR 11 , -COOR 11 , -CON(R n ) 2 , -N(R ⁇
  • Aryl refers to aromatic monocyclic or multicyclic ring system containing from 6 to 19 carbon atoms, where the ring system is optionally partially or fully saturated.
  • Aryl groups include, but are not limited to groups such as fluorenyl, phenyl and naphthyl.
  • aryl is meant to include aryl radicals optionally substituted by one or more substituents selected from the group consisting of alkyl, alkenyl, halogen, haloalkyl, haloalkenyl, cyano, nitro, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, -R°-0R ⁇ , -R°-N(R ⁇ ) 2 -, -R°-C0R ⁇ , -R°-C00R ⁇ , -R ⁇ CON(R 1 ⁇ - R°-N(R ⁇ )COOR 10 , -R ⁇ NCR ⁇ COR 11 , -R°-NS0 2 R n , -R ⁇ N(R 1 ⁇ SO 2 R 11 , -R°-SO 2 OR
  • substitutents on the aliphatic group or phenyl ring of R 0 include amino, alkylamino, dialkylamino, aminocarbonyl, halogen, alkyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkoxy, nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, hydroxy, haloalkoxy or haloalkyl.
  • An aliphatic group or non-aromatic heterocyclic ring may contain one or more substituents.
  • substitutents on the aliphatic group include amino, alkylamino, dialkylamino, aminocarbonyl, halogen, alkyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkoxy, nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, hydroxy, haloalkoxy or haloalkyl.
  • Suitable substituents on the nitrogen of a non-aromatic heterocyclic ring include -R 0 , -N(R°) 2 , -
  • each R 0 is independently selected from hydrogen, unsubstituted or substituted aliphatic group, an unsubstituted heteroaryl or heterocyclic ring, phenyl (Ph), substituted Ph, -OPh, substituted -OPh, or substituted -CH 2 Ph.
  • substitutents on the aliphatic group or the phenyl ring include amino, alkylamino, dialkylamino, aminocarbonyl, halogen, alkyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkoxy, nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, hydroxy, haloalkoxy or haloalkyl.
  • alkoxyaryl as used herein means an aryl group, as defined herein, substituted with one or more alkoxy groups, as defined herein.
  • alkoxyaryl groups include, but are not limited to, methoxyphenyl, butyloxyphenyl, and dimethoxynaphthyl.
  • Alkyl or arylalkyl refers to a radical of the formula -RaRb where Ra is an alkyl radical as defined above and Rb is one or more aryl radicals as defined above, e.g., benzyl, diphenylmethyl and the like. The aryl radicals) and the alkyl radical is optionally substituted as described above.
  • aralkyloxy or “arylalkoxy” as used herein, means an aralkyl group, as defined herein, appended to the parent molecule through a oxygen atom. Examples of aralkyloxy include, but are not limited to, benzyloxy, 2-phenylethoxy, 4-phenylbutoxy, 9-fluorenylmethoxy, and the like.
  • arylalkylcarboxy means an arylakyl group, as defined herein, appended to the parent molecule through a carboxy group, as defined herein.
  • the carboxy group can be bonded in either sense; either with the carbonyl carbon bonded to the arylalkyl group and the oxygen bonded to the parent molecule; or the carbonyl bonded to the parent molecule and the oxygen bonded to the arylalkyl group.
  • arylalkylcarboxy groups include, but are not limited to, benzylacetoxy, (benzyloxy)carbonyl, (2-phenylethoxy)carbonyl, phenyl-acetyloxy, and l-oxo-5-phenyl-pentyloxy.
  • aryloxy as used herein, means an aryl group, as defined herein, appended to a parent molecule through an oxygen atom.
  • aryloxy examples include, but are not limited to phenoxy, 1-naphthyloxy, and2-naphthyloxy.
  • Alkylene and “alkylene chain” refer to a straight or branched divalent hydrocarbon chain, linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing no unsaturation and having from one to twelve carbon atoms, preferably having from one to eight carbons, e.g., methylene, ethylene, propylene, r ⁇ -butylene, and the like.
  • the alkylene chain may be attached to the rest of the molecule and to the radical group through one carbon within the chain or through any two carbons within the chain.
  • the alkylene chain is optionally substituted by one or more substituents selected from the group consisting of halo, cyano, nitro, -OR 11 , -N(R n ) 2 , -COR 11 , -COOR 11 ,
  • each R 10 and R 11 are as defined above in the first aspect of the invention.
  • the alkylene chain may be attached to the rest of the molecule through any two carbons within the chain.
  • alkenylene and alkenylene chain refer to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one double bond and having from two to twelve carbon atoms, e.g., ethenylene, propenylene, n-butenylene, and the like.
  • the alkenylene chain is attached to the rest of the molecule through a single bond and to the radical group through a double bond or a single bond.
  • the points of attachment of the alkenylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain.
  • the alkenylene chain is optionally substituted by one or more substituents selected from the group consisting of halo, cyano, nitro, -OR 11 , -N(R n ) 2 , -COR 11 , -COOR 11 , -C0N(R n ) 2 , -N(R n )COOR 10 , -N(R ⁇ )C0R u , -NSO 2 R 11 , -N(R 1 ⁇ SO 2 R 11 , -SO 2 OR 11 , -SO 2 R 11 , and -SO 2 N(R 1 J ) 2 where each R 10 and R 11 are as defined above in the first aspect of the invention.
  • aryloxyalkyl as used herein, means an alkyl group appended to the parent molecule, wherein the alkyl group is substituted with one aryloxy group, as defined herein.
  • aryloxyalkyl groups include, but are not limited to phenoxymethyl, naphthyloxybutyl, and phenoxyhexyl.
  • aryloxyaryl as used herein, means an aryl group appended to the parent molecule, wherein the aryl group is substituted with one aryloxy group, as defined herein.
  • aryloxyaryl groups include, but are not limited to phenoxyphenyl, naphthyloxyphenyl, and phenoxynaphthyl.
  • Cycloalkyl refers to a stable monovalent monocyclic or bicyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, having from three to ten carbon atoms (unless stated otherwise), and which is saturated or includes one more unsaturated units (but is not aromatic) and is attached to the rest of the molecule by a single bond, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cylcopent-1-enyl, cyclohexyl, cyclohex-2,4-dienyl, decalinyl and the like.
  • cycloalkyl is meant to include cycloalkyl radicals which are optionally substituted by one or more substituents independently selected from the group consisting of alkyl, alkenyl, halo, haloalkyl, haloalkenyl, cyano, nitro, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, -OR 11 , -N(R U ) 2 , -COR 11 , -COOR 11 , -C0N(R n ) 2 , -N(R U )COOR 10 , -N(R ⁇ )C0R n , -NSO 2 R 11 , -N(R 1 ⁇ SO 2 R 11 , -SO 2 OR 11 , -SO 2 R 11 , and -SO 2
  • Cycloalkylalkyl refers to a radical of the formula -R 9 R d where R a is an alkyl radical as defined above and R d is a cycloalkyl radical as defined above.
  • the alkyl radical and the cycloalkyl radical may be optionally substituted as defined above.
  • cyclohaloalkyl as used herein means a cycloalkyl group, as defined herein which is substituted by one or more halo groups, as defined herein.
  • cyclohaloalkyl groups include, but are not limited to, bromocyclohexyl, trifluorocyclopentyl, dichlorocyclohexyl and the like.
  • ' ⁇ alo or ' ⁇ alogen refers to bromo, chloro, fluoro or iodo.
  • ' ⁇ aloalkyl refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1- fluoromethyl-2-fluoroethyl, 3-bromo-2-fluoropropyl, l-bromomethyl-2-bromoethyl, and the like.
  • alkenyl radical as defined above, that is substituted by one or more halo radicals, as defined above, e.g., 2-bromoethenyl, 3-bromoprop-l-enyl, and the like.
  • haloaryl as used herein, means an aryl group, as defined herein, substituted with one or more halo groups.
  • haloaryl groups include, but are not limited to, bromophenyl, fluorophenyl, pentafluorophenyl, chloronaphthyl, chloro-iodophenyl, and the like.
  • ' ⁇ eterocyclyl refers to a stable 3- to 18-membered non-aromatic ring radical which consists of carbon atoms and from one to five heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur.
  • the heterocyclyl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heterocyclyl radical is optionally oxidized; the nitrogen atom is optionally quaternized; and the heterocyclyl radical may be partially or fully saturated.
  • heterocyclyl radicals include, but are not limited to, dioxolanyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, thiazolidinyl, tetraliydrofuranyl, trithianyl, tetrahydropyranyl, thiomo ⁇ holinyl, thiamorpholinyl, 1-oxo-thiomo ⁇ holinyl, and 1,1-diox
  • heterocyclyl is meant to include heterocyclyl radicals as defined above which are optionally substituted by one or more substituents selected from the group consisting of alkyl, alkenyl, halo, haloalkyl, haloalkenyl, nitro, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, -OR 11 , -N(R ⁇ ) 2 -, -COR 11 , -COOR 11 , -CON(R ⁇ ) 2 , -N(R 1 ⁇ COOR 10 , -N(R n )C0R u , -NSO 2 R 11 , -N(R 1 ⁇ SO 2 R 11 , -SO 2 OR 11 , -SO 2 R 11 , and -SO 2 N(R
  • ' ⁇ eterocyclylalkyl refers to a radical of the formula -RaRe where Ra is an alkyl radical as defined above and Re is a heterocyclyl radical as defined above, and if the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl may be attached to the alkyl radical at the nitrogen atom.
  • the heterocyclyl radical and the alkyl radical is optionally substituted as defined above.
  • heterocyclyloxy means a heterocyclyl group, as defined herein, appended to a parent molecule through an oxygen atom.
  • heterocyclyloxy groups include, but are not limited to piperidinyloxy, tetrahydroforanyloxy, telrahydrotheinyloxy tetrahydropyranyloxy, dihydropyranyloxy, pyrrolidinyloxy, oxetanyloxy, and oxiranyloxy.
  • ' ⁇ eteroaryl refers to a 3- to 18-membered aromatic ring radical which consists of carbon atoms and from one to five heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur.
  • the heteroaryl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heteroaryl radical is optionally oxidized; the nitrogen atom is optionally quaternized.
  • Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzthiazolyl, benzindolyl, benzothiadiazolyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[l,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, indolizinyl, isoxazolyl,
  • heteroaryl is meant to include heteroaryl radicals as defined above which are optionally substituted by one or more substituents selected from the group consisting of alkyl, alkenyl, halo, haloalkyl, haloalkenyl, nitro, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, -OR 11 , -N(R n ) 2 -, -COR 11 , -COOR 11 , -CON(R ⁇ ) 2 , -N(R U )COOR 10 , -N(R u )COR n , -NSO 2 R 11 , -N(R u )SO 2 R n , -SO 2 OR 11 , -SO 2 R 11 , and -S ⁇ 2 N(R
  • N-heteroaryl refers to heteroaryl radicals as defined above containing at least one nitrogen atom in ring.
  • heteroaryloxy as used herein, means a heteroaryl group, as defined herein, appended to a parent molecule through an oxygen atom. Examples of “heteroaryloxy” groups include, but are not limited to pyridyloxy, indolyloxy, and quinolyloxy.
  • ' ⁇ eteroarylalkyl refers to a radical of the formula -R 3 R f where R 3 is an alkyl radical as defined above and R f is a heteroaryl radical as defined above, and if the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl may be attached to the alkyl radical at the nitrogen atom.
  • the heteroaryl radical and the alkyl radical are optionally substituted as defined above.
  • linker group means an organic moiety that connects two parts of a compound.
  • Linkers are typically comprised of an atom such as oxygen or sulfur, a unit such as -NH-, - CH 2 -, -CO-, -CONH-, or a chain of atoms, such as an alidiyl chain.
  • the molecular mass of a linker is typically in the range of about 14 to 200, preferably in the range of 14 to 96 with a length of up to about six atoms.
  • linkers include a saturated or unsaturated C 1 -C 6 alidiyl chain which is optionally substituted, and wherein one or two saturated carbons of the chain are optionally replaced by -CO-, - COCO-, -CONH-, -CONHNH-, -CO 2 -, -NHCO 2 -, -O-, -NHCONH-, -OCONH-, -NHNH-, -NHCO-, - S-, -SO-, -SO 2 -, -NH-, -SO 2 NH-, or -NHSO 2 -.
  • alidiyl chain refers to an optionally substituted, straight or branched carbon chain that may be fully saturated or have one or more units of unsaturation.
  • the optional substituents are as described above for an aliphatic group.
  • Alidiyl chain used herein may include alidiyl chains containing 0-4 fluorine substituents.
  • An "agonist for a nuclear receptor” is an agent that, when bound to the nuclear receptor, activates nuclear receptor activity to activate or repress gene function. In some cases, nuclear receptors can act through second messenger signaling pathways, and the invention would apply to these actions as well.
  • the activation can be similar in degree to that provided by a natural hormone for the receptor, or can be stronger (optionally referred to as a "strong agonisf), or can be weaker (optionally referred to as a "weak agonisf or "partial agonisf').
  • An example of a hormone for a nuclear receptor is thyroid hormone, which is a natural hormone for the thyroid receptor.
  • a "putative agonisf is an agent to be tested for agonist activity.
  • Partial agonists or partial antagonists bind to receptors and yield a response less than that of a full agonist at saturating ligand concentrations.
  • a partial agonist will block binding of a full agonist and suppress receptor activity to the level induced by the partial agonist alone.
  • partial agonists bind to receptors and induce only part of the changes in the receptors that are induced by agonists. The differences can be qualitative or quantitative.
  • a partial agonist can induce some of the conformation changes induced by agonists, but not others, or it may only induce certain changes to a limited extent Some of these compounds are naturally produced. For example, many plant estrogens (phytoestrogens), such as genistein, can behave as partial estrogen receptor agonists.
  • an "antagonist for a nuclear receptor” is an agent that reduces or blocks activity mediated by the receptor in response to an agonist of the receptor.
  • the activity of the antagonist can be mediated, e.g., by blocking binding of the agonist to the receptor, or by altering receptor configuration and/or activity of the receptor.
  • a “putative antagonisf is an agent to be tested for antagonist activity.
  • a “nuclear receptor” is a receptor that activates or represses transcription of one or more genes in the nucleus (but can also have second messenger signaling actions), typically in conjunction with other transcription factors. The nuclear receptor is activated by the natural cognate ligand for the receptor. Nuclear receptors are ordinarily found in the cytoplasm or nucleus, rather than being membrane-bound.
  • Nuclear receptor is a member of a superfamily of regulatory proteins that are receptors for, e.g., steroids, retinoids, vitamin D and thyroid hormones. These proteins bind to cis-acting elements in the promoters of their target genes and modulate gene expression in response to a ligand therefor. Nuclear receptors may be classified based on their DNA binding properties. For example, the glucocorticoid, estrogen, androgen, progestin and mineralocorticoid receptors bind as homodimers to hormone response elements (BDREs) organized as inverted repeats.
  • BDREs hormone response elements
  • receptors including those activated by retinoic acid, thyroid hormone, vitamin D 3 , fatty acids/peroxisome proliferators and ecdysone, that bind to HREs as heterodimers with a common partner, the retinoid X receptor (RXR).
  • RXR retinoid X receptor
  • LXR LXR.
  • an orphan nuclear receptor is a nuclear receptor for which the natural ligand is unknown.
  • liver X receptor or LXR refers to a nuclear receptor implicated in cholesterol biosynthesis.
  • LXR refers to both LXR ⁇ and LXR ⁇ , two forms of the protein found in mammals.
  • Liver X receptor- ⁇ . or LXR ⁇ refers to the receptor described in U.S. Pat. Nos. 5,571,696, 5,696,233 and 5,710,004, and WUIy et al. (1995) Gene Dev. 9(9):1033-1045.
  • Liver X receptor- ⁇ or LXR ⁇ refers to the receptor described in Peet et al. (1998) Curr. Opin. Genet. Dev. 8(5):571-575; Song et al. (1995) Ann. N.Y.
  • compounds which are "commercially available” may be obtained from standard commercial sources including Acros Organics (Pittsburgh PA), Aldrich Chemical (Milwaukee WI, including Sigma Chemical and Fluka), Apin Chemicals Ltd. (Milton Park UK), Avocado Research (Lancashire U.K.), BDH Inc. (Toronto, Canada), Bionet (Cornwall, UJC), Chemservice Inc. (West Chester PA), Crescent Chemical Co. (Hauppauge NY), Eastman Organic Chemicals, Eastman Kodak Company (Rochester NY), Fisher Scientific Co. (Pittsburgh PA), Fisons Chemicals (Leicestershire UK), Frontier Scientific (Logan UT), ICN Biomedicals, Inc.
  • suitable conditions for carrying out a synthetic step are explicitly provided herein or may be discerned by reference to publications directed to methods used in synthetic organic chemistry.
  • Prodrugs is meant to indicate a compound that may be converted under physiological conditions or by solvolysis to a biologically active compound of the invention.
  • prodrug refers to a metabolic precursor of a compound of the invention that is pharmaceutically acceptable.
  • a prodrug may be inactive when administered to a subject in need thereof, but is converted in vivo to an active compound of the invention.
  • Prodrugs are typically rapidly transformed in vivo to yield the parent compound of the invention, for example, by hydrolysis in blood.
  • the prodrug compound often offers advantages of solubility, tissue compatibility or delayed release in a mammalian organism (see, Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam).
  • prodrugs are also meant to include any covalently bonded carriers which release the active compound of the invention in vivo when such prodrug is administered to a mammalian subject
  • Prodrugs of a compound of the invention may be prepared by modifying functional groups present in the compound of the invention in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound of the invention.
  • prodrugs include compounds of the invention wherein a hydroxy, amino or mercapto group is bonded to any group that, when the prodrug of the compound of the invention is administered to a mammalian subject, cleaves to form a free hydroxy, free amino or free mercapto group, respectively.
  • prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of the invention and the like.
  • 'Tolymorph refers to the different crystal forms of a compound, resulting from the possibility of at least two different arrangements of the molecules of the compound in the solid state. Polymorphs of a given compound will be different in crystal structure but identical in liquid or vapor states. Different polymorphic forms of a given substance may differ from each other with respect to one or more physical properties, such as solubility and dissociation, true density, crystal shape, compaction behavior, flow properties, and/or solid state stability.
  • Solid compound and “stable structure” are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent
  • “Mammal” includes humans and domestic animals, such as cats, dogs, swine, cattle, sheep, goats, horses, rabbits, and the like.
  • Optional or “optionally” means that the subsequently described event of circumstances may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not.
  • optionally substituted aryl means that the aryl radical may or may not be substituted and that the description includes both substituted aryl radicals as defined herein and aryl radicals having no substitution.
  • “Pharmaceutically acceptable carrier, diluent or excipienf includes without limitation any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersing agent suspending agent stabilizer, isotonic agent solvent or emulsifier which has been approved by the United States Food and Drug Administration as being acceptable for use in humans or domestic animals.
  • “Pharmaceutically acceptable salt 3 ' includes both acid and base addition salts.
  • “Pharmaceutically acceptable acid addition salt 3 ' refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.
  • “Pharmaceutically acceptable base addition salt 5 ' refers to those salts which retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Preferred inorganic salts are the ammonium, sodium, potassium, calcium, and magnesium salts.
  • Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, dietibylamine, triethylarnine, tripropylamine, ethanolamine,
  • Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine.
  • “Pharmaceutically acceptable derivative” refers to pharmaceutically acceptable salts as defined herein and also includes esters, prodrugs, solvates and polymorphs of the compounds of the invention.
  • “Therapeutically effective amount” refers to that amount of a compound of the invention which, when administered to a mammal, preferably a human, is sufficient to effect treatment, as defined below, for a disease-state associated with nuclear receptor activity.
  • the amount of a compound of the invention which constitutes a "therapeutically effective amounf will vary depending on the compound, the condition and its severity, and the age of the mammal to be treated, but can be determined routinely by one of ordinary skill in the art having regard to his own knowledge and to this disclosure.
  • “Modulating” or “modulate” refers to the treating, prevention, suppression, enhancement or induction of a function or condition.
  • the compounds of the present invention can modulate hyperlipidemia by lowering cholesterol in a human, thereby suppressing hyperlipidemia.
  • Treating covers the treatment of a disease or condition associated with the nuclear receptor activity as disclosed herein, in a mammal, preferably a human, and includes: i. Preventing a disease or condition associated with the nuclear receptor activity from occurring in a mammal, in particular, when such mammal is predisposed to the disease or condition but has not yet been diagnosed as having it; ⁇ . inhibiting a disease or condition associated with the nuclear receptor activity, Ie., arresting its development; or iii. relieving a disease or condition associated with the nuclear receptor activity, Ie., causing regression of the condition.
  • the compounds of formulae Ia, Ib, Ic or Id or their pharmaceutically acceptable salts may contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)- or, as (D)- or (L)- for amino acids.
  • the present invention is meant to include all such possible isomers, as well as, their racemic and optically pure forms.
  • Optically active (*) and (-), (R)- and (S)-, or (D)- and (L)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as reverse phase HPLC.
  • structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms.
  • compounds having the present structure except for the replacement of a hydrogen atom by a deuterium or tritium, or the replacement of a carbon atom by a 13 C- or 14 C-enriched carbon are within the scope of this invention.
  • Atherosclerosis refers to process whereby atherosclerotic plaques form within the inner lining of the artery wall leading to atherosclerotic cardiovascular diseases.
  • Atherosclerotic cardiovascular diseases can be recognized and understood by physicians practicing in the relevant fields of medicine, and include without limitation, restenosis, coronary heart disease (also known as coronary artery heart disease or ischemic heart disease), cerebrovascular disease including ischemic stroke, multi- infarct dementia, and peripheral vessel disease, including intermittent claudication, and erectile dysfunction.
  • ECs 0 refers to a dosage, concentration or amount of a particular test compound that elicits a dose-dependent response at 50% of maximal expression of a particular response that is induced, provoked or potentiated by the particular test compound.
  • cholesterol refers to a steroid alcohol that is an essential component of cell membranes and myelin sheaths and, as used herein, incorporates its common usage. Cholesterol also serves as a precursor for steroid hormones and bile acids.
  • TGs triglyceride ⁇
  • TGs consist of three fatty acid molecules esterified to a glycerol molecule and serve to store fatty acids which are used by muscle cells for energy production or are taken up and stored in adipose tissue.
  • hyperlipidemia refers to the presence of an abnormally elevated level of lipids in the blood. Hyperlipidemia can appear in at least three forms: (1) hypercholesterolemia, Le., an elevated
  • LDL cholesterol level 120 mg/dL and above
  • hypertriglyceridemia Le., an elevated triglyceride level
  • hypertriglyceridemia Le., a combination of hypercholesterolemia and hypertriglyceridemia.
  • Exemplary Primary Hyperlipidemia include, but are not limited to, the following: (1) Familial Hyperchylomicronemia, a rare genetic disorder which causes a deficiency in an enzyme, LP lipase, that breaks down fat molecules.
  • the LP lipase deficiency can cause the accumulation of large quantities of fat or lipoproteins in the blood;
  • Familial Hypercholesterolemia a relatively common genetic disorder caused where the underlying defect is a series of mutations in the LDL receptor gene that result in malfunctioning LDL receptors and/or absence of the LDL receptors. This brings about ineffective clearance of
  • Familial Combined Hyperlipidemia also known as multiple lipoprotein-type hyperlipidemia; an inherited disorder where patients and their affected first-degree relatives can at various times manifest high cholesterol and high triglycerides. Levels of HDL cholesterol are often moderately decreased;
  • Familial Defective Apolipoprotein B-IOO is a relatively common autosomal dominant genetic abnormality. The defect is caused by a single nucleotide mutation that produces a substitution of glutamine for arginine which can cause reduced affinity of LDL particles for the LDL receptor. Consequently, this can cause high plasma LDL and total cholesterol levels; Familial Dysbetalipoproteinemia, also referred to as Type III Hyperlipoproteinemia, is an uncommon inherited disorder resulting in moderate to severe elevations of serum triglyceride (TG) and cholesterol levels with abnormal apolipoprotein E function. HDL levels are usually normal; and Familial Hypertriglyceridemia, is a common inherited disorder in which the concentration of plasma VLDL is elevated. This can cause mild to moderately elevated triglyceride levels (and usually not cholesterol levels) and can often be associated with low plasma HDL levels.
  • Familial Dysbetalipoproteinemia also referred to as Type III Hyperlipoproteinemia
  • TG serum
  • Risk factors in exemplary Secondary Hyperlipidemia include, but are not limited to, the following: (1) disease risk factors, such as a history of type 1 diabetes, type 2 diabetes, Cushing's syndrome, hypothyroidism and certain types of renal failure; (2) drug risk factors, which include, birth control pills; hormones, such as estrogen, and corticosteroids; certain diuretics; and various beta. blockers; (3) dietary risk factors include dietary fat intake per total calories greater than 40%; saturated fat intake per total calories greater than 10%; cholesterol intake greater than 300 mg per day; habitual and excessive alcohol use; and obesity; and (4) non-genetic dyslipidemias.
  • the methods of the present invention can be used effectively in combination with one or more additional active diabetes agents depending on the desired target therapy (see, e.g., Turner, N.
  • IC 50 refers to an amount, concentration or dosage of a particular test compound that achieves a 50% inhibition of a maximal response, such as modulation of nuclear receptor, including the LXR ⁇ or LXR ⁇ activity, in an assay that measures such response.
  • LXR ⁇ refers to all mammalian forms of such receptor including, for example, alternative splice isoforms and naturally occurring isoforms.
  • Representative LXR ⁇ species include, without limitation the rat (Genbank Accession NM_031627), mouse (Genbank Accession BC 0 12646), and human (GenBank Accession No. U22662) forms of the receptor.
  • ⁇ f LXR ⁇ refers to all mammalian forms of such receptor including, for example, alternative splice isoforms and naturally occurring isoforms.
  • LXR ⁇ species include, without limitation the rat (GenBank Accession TMM_031626), mouse (Genbank Accession NM_009473), and human (GenBank Accession No. U07132) forms of the receptor.
  • LXR or “LXRs” refers to both LXR ⁇ and LXR ⁇ .
  • BMI Body Mass Index
  • the compounds of the invention exhibit valuable pharmacological properties in mammals, and are particularly useful as selective LXR agonists, antagonists, inverse agonists, partial agonists and antagonists, for the treatment, or prevention of diseases associated with, or symptoms arising from the complications of, altered cholesterol transport, cholesterol reverse transport, fatty acid metabolism, cholesterol absorption, cholesterol re-absorption, cholesterol secretion, cholesterol excretion, or cholesterol metabolism.
  • diseases include, for example, hyperlipidemia, dyslipidemia, hypercholesterolemia, atherosclerosis, atherosclerotic cardiovascular diseases, hyperlipoproteinemia, (see, e.g., Patent Application Publication Nos.
  • WO 00/57915 and WO 00/37077 hyperglycemia, insulin resistance, diabetes, lipodystrophy, obesity, syndrome X (US Patent Application No. 20030073614, International Patent Application Publication No. WO 01/82917), excess lipid deposition in peripheral tissues such as skin (xanthomas) (see, e.g., U.S. Patent Nos. 6,184,215 and 6,187,814), stroke, peripheral occlusive disease, memory loss (Brain Research (1997), Vol. 752, pp.
  • WO 01/82917 multiple sclerosis (Annals of Clinical Biochem. (1996), Vol.33, No.2, pp. 148-150), and autoimmune diseases (J Lipid Res. (1998), Vol.39, pp. 1740-1743). Also provided, are methods of increasing the expression of ATP-Binding Cassette (ABCAl),
  • the invention also includes methods to remove cholesterol from tissue deposits such as atherosclerotic plaques or xanthomas in a patient with atherosclerosis or atherosclerotic cardiovascular disease manifest by clinical signs of such disease, wherein the methods comprise administering to the patient a therapeutically effective amount of a compound or composition of the present invention.
  • the instant invention also provides a method for preventing or reducing the risk of a first or subsequent occurrence of an atherosclerotic cardiovascular disease event including ischemic heart disease, ischemic stroke, multi-infarct dementia, and intermittent claudication comprising the administration of a prophylactically effective amount of a compound or composition of the present invention to a patient at risk for such an event.
  • the patient may already have atherosclerotic cardiovascular disease at the time of administration, or may be at risk for developing it.
  • Risk factors for developing atherosclerotic cardiovascular disease events include increasing age (65 and over), male gender, a family history of atherosclerotic cardiovascular disease events, high blood cholesterol (especially LDL or "bad” cholesterol over 100 mg/dL), cigarette smoking and exposure to tobacco smoke, high blood pressure, diabetes, obesity and physical inactivity.
  • a compound of the invention in combination with one or more of the following therapeutic agents in treating atherosclerosis: antihyperlipidemic agents, plasma HDL-raising agents, antihypercholesterolemic agents, cholesterol biosynthesis inhibitors (for example, BDVIG CoA reductase inhibitors, such as lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, and rivastatin), acyl- coenzyme A:cholesterol acytransferase (ACAT) inhibitors, probucol, raloxifene, nicotinic acid, niacinamide, cholesterol absorption inhibitors, HMG-CoA reductase inhibitor-cholesterol absorption inhibitor combinations (e.g., Vytorin), bile acid sequestrants (such as anion exchange resins, or quaternary amines (e.g., cholestyramine
  • compounds of the invention are used in combination with a cholesterol biosynthesis inhibitor, particularly an HMG-CoA reductase inhibitor.
  • HMG-CoA reductase inhibitor is intended to include all pharmaceutically acceptable salt, ester, free acid and lactone forms of compounds which have HMG-CoA reductase inhibitory activity and, therefore, the use of such salts, esters, free acids and lactone forms is included within the scope of this invention.
  • Compounds which have inhibitory activity for HMG-CoA reductase can be readily identified using assays well-known in the art For instance, suitable assays are described or disclosed in U.S. Patent No. 4,231,938 and WO 84/02131.
  • HMG-CoA reductase inhibitors include, but are not limited to, lovastatin (MEVACOR®; see, U.S. Patent No. 4,231,938); simvastatin (ZOCOR®; see, U.S. Patent No. 4,444,784); pravastatin sodium (PRAVACHOL®; see, U.S. Patent No. 4,346,227); fluvastatin sodium (LESCOL®; see, U.S. Patent No. 5,354,772); atorvastatin calcium (LIPITOR®; see, U.S. Patent No.
  • HMG-CoA reductase inhibitor is selected from lovastatin and simvastatin.
  • the compounds of the present invention can also be used in methods for decreasing hyperglycemia and insulin resistance, i.e., in methods for treating diabetes (International Patent Application Publication No.
  • WO 01/82917 in methods of treatment, prevention, or amelioration of disorders related to, or arising as complications of diabetes, hyperglycemia or insulin resistance including the cluster of disease states, conditions or disorders that make up "Syndrome X" (See US Patent Application 20030073614) comprising the administration of a therapeutically effective amount of a compound or composition of the present invention to a patient in need of such treatment
  • the instant invention also provides a method for preventing or reducing the risk of developing hyperglycemia, insulin resistance, diabetes or syndrome X in a patient, comprising the administration of a prophylactically effective amount of a compound or composition of the present invention to a patient at risk for developing such a condition.
  • Diabetes mellitus commonly called diabetes, refers to a disease process derived from multiple causative factors and characterized by elevated levels of plasma glucose, referred to as hyperglycemia. See, e.g., LeRoith, D. et al, (eds.), DIABETES MELLITUS (Lippincott-Raven Publishers, Philadelphia, Pa. U.SA. 1996). According to the American Diabetes Association, diabetes mellitus is estimated to affect approximately 6% of the world population. Uncontrolled hyperglycemia is associated with increased risk and premature mortality due to an increased risk for macr ⁇ vascular and macrovascular diseases, including nephropathy, neuropathy, retinopathy, hypertension, cerebrovascular disease and coronary heart disease.
  • type 1 diabetes (formerly referred to as insulin- dependent diabetes or IDEM); and type 2 diabetes (formerly referred to as noninsulin dependent diabetes or NIDDM).
  • IDEM insulin-dependent diabetes
  • NIDDM noninsulin dependent diabetes
  • Type 2 diabetes is a disease characterized by insulin resistance accompanied by relative, rather than absolute, insulin deficiency. Type 2 diabetes can range from predominant insulin resistance with relative insulin deficiency to predominant insulin deficiency with some insulin resistance. Insulin resistance is the diminished ability of insulin to exert its biological action across a broad range of concentrations. In insulin resistant individuals, the body secretes abnormally high amounts of insulin to compensate for this defect. When inadequate amounts of insulin are present to compensate for insulin resistance and adequate control of glucose, a state of impaired glucose tolerance develops. In a significant number of individuals, insulin secretion declines further and the plasma glucose level rises, resulting in the clinical state of diabetes.
  • Type 2 diabetes can be due to a profound resistance to insulin stimulating regulatory effects on glucose and lipid metabolism in the main insulin-sensitive tissues: muscle, liver and adipose tissue. This resistance to insulin responsiveness results in insufficient insulin activation of glucose uptake, oxidation and storage in muscle and inadequate insulin repression of lipolysis in adipose tissue and of glucose production and secretion in liver.
  • free fatty acid levels are often elevated in obese and some non-obese patients and lipid oxidation is increased.
  • Hyperlipidemia is an important precipitating factor for these diseases.
  • Hyperlipidemia is a condition generally characterized by an abnormal increase in serum lipids, e.g., cholesterol and triglyceride, in the bloodstream and is an important risk factor in developing atherosclerosis and heart disease.
  • serum lipids e.g., cholesterol and triglyceride
  • hyperlipidemia is usually classified as primary or secondary hyperlipidemia.
  • Primary hyperlipidemia is generally caused by genetic defects, while secondary hyperlipidemia is generally caused by other factors, such as various disease states, drugs, and dietary factors. Alternatively, hyperlipidemia can result from both a combination of primary and secondary causes of hyperlipidemia. Elevated cholesterol levels are associated with a number of disease states, including coronary artery disease, angina pectoris, carotid artery disease, strokes, cerebral arteriosclerosis, and xanthoma.
  • the compounds of the invention may be used in combination with one or more of the following therapeutic agents in treating diabetes: sulfonylureas (such as chlo ⁇ ropamide, tolbutamide, acetohexamide, tolazamide, glyburide, gliclazide, glynase, glimepiride, and glipizide), biguanides (such as metformin), thiazolidinediones (such as ciglitazone, pioglitazone, and rosiglitazone), and related insulin sensitizers, such as selective and non-selective activators of PPAR ⁇ , PPAR ⁇ / ⁇ and PPAR ⁇ ; dehydroepiandrosterone (also referred to as DHEA or its conjugated sulphate ester, DHEA- SO4); antiglucocorticoids; TNF ⁇ inhibitors; ⁇ -glucosidase inhibitors (such as acarbose, mime,
  • Obesity is linked to a variety of medical conditions including diabetes and hyperlipidemia. Obesity is also a known risk factor for the development of type 2 diabetes (See, e.g., Barrett-Conner, E., Epidemol. Rev. (1989), Vol. 11, pp. 172-181; andKnowler, et al., Am. J Clin. Nutr. (1991), Vol. 53, pp. 1543-1551).
  • the compounds of the invention can be used in combination with agents used in treated obesity or obesity-related disorders.
  • agents include, but are not limited to, phenylpropanolamine, phentermine, diethylpropion, mazindol, fenfluramine, dexfenfluramine, phentiramine, ⁇ 3 adrenoceptor agonist agents; sibutramine, gastrointestinal lipase inhibitors (such as orlistat), and leptins.
  • agents used in treating obesity or obesity-related disorders include neuropeptide Y, enterostatin, cholecytokinin, bombesin, amylin, histamine H 3 receptors, dopamine D 2 receptor modulators, melanocyte stimulating hormone, corticotrophin releasing factor, galanin and gamma amino butyric acid (GABA).
  • GABA gamma amino butyric acid
  • Such assays include, for example, biochemical assays such as binding assays, fluorescence polarization assays, FRET based coactivator recruitment assays (see, generally, Glickman et al., J. Biomolecular Screening (2002), Vol. 7, No. 1, pp. 3-10, as well as cell based assays including the co-transfection assay, the use of LBD-GaI 4 chimeras and protein-protein interaction assays, (see, Lehmann. et al., J. Biol Chem. (1997), Vol. 272, No. 6, pp. 3137-3140.
  • High throughput screening systems are commercially available (see, e.g., Zymark Corp., Hopkinton, MA; Air Technical Industries, Mentor, OH; Beckman Instruments Inc., Fullerton, CA; Precision Systems, Inc., Natick, MA) that enable these assays to be run in a high throughput mode. These systems typically automate entire procedures, including all sample and reagent pipetting, liquid dispensing timed incubations, and final readings of the microplate in detector(s) appropriate for the assay. These configurable systems provide high throughput and rapid start up as well as a high degree of flexibility and customization. The manufacturers of such systems provide detailed protocols for various high throughput systems. Thus, for example, Zymark Corp. provides technical bulletins describing screening systems for detecting the modulation of gene transcription, ligand binding, and the like.
  • Assays that do not require washing or liquid separation steps are preferred for such high throughput screening systems and include biochemical assays such as fluorescence polarization assays (see, for example, Owicki, I, Biomol. Screen (2000 October), Vol. 5, No. 5, pp. 297), scintillation proximity assays (SPA) (see, for example, Carpenter et al., Methods MoI. Biol. (2002), VoI 190, pp. 31- 49) and fluorescence resonance energy transfer energy transfer (FRET) or time resolved FRET based coactivator recruitment assays (Mukherjee et al., J. Steroid Biochem. MoI. Biol. (2002 July); Vol. 81, No. 3, pp.
  • biochemical assays such as fluorescence polarization assays (see, for example, Owicki, I, Biomol. Screen (2000 October), Vol. 5, No. 5, pp. 297), scintillation proximity assays (SPA) (see, for example,
  • LBD isolated ligand binding domain
  • fluorescence polarization assays provide a way of detecting binding of compounds to the nuclear receptor of interest by measuring changes in fluorescence polarization that occur as a result of the displacement of a trace amount of the label ligand by the compound. Additionally this approach can also be used to monitor the ligand dependent association of a fluorescently labeled coactivator peptide to the nuclear receptor of interest to detect ligand binding to the nuclear receptor of interest.
  • the ability of a compound to bind to a receptor, or heterodimer complex with RXR can also be measured in a homogeneous assay format by assessing the degree to which the compound can compete off a radiolabelled ligand with known affinity for the receptor using a scintillation proximity assay (SPA).
  • SPA scintillation proximity assay
  • the radiolabelled compound is displaced from the nuclear receptor the amount of light emitted from the nuclear receptor bound scintillant decreases, and this can be readily detected using standard microplate liquid scintillation plate readers such as, for example, a Wallac MicroBeta reader.
  • the heterodimerization of LXR with RXR ⁇ can also be measured by fluorescence resonance energy transfer (FRET), or time resolved FRET, to monitor the ability of the compounds provided herein to bind to LXR or other nuclear receptors. Both approaches rely upon the fact that energy transfer from a donor molecule to an acceptor molecule only occurs when donor and acceptor are in close proximity.
  • FRET fluorescence resonance energy transfer
  • the purified LBD of the nuclear receptor of interest is labeled with biotin then mixed with stoichiometric amounts of europium labeled streptavidin (Wallac Inc.), and the purified LBD of RXR ⁇ is labeled with a suitable fluorophore such as CY5TM.
  • Equirnolar amounts of each modified LBD are mixed together and allowed to equilibrate for at least 1 hour prior to addition to either variable or constant concentrations of the sample for which the affinity is to be determined. After equilibration, the time-resolved fluorescent signal is quantitated using a fluorescent plate reader. The affinity of the compound can then be estimated from a plot of fluorescence versus concentration of compound added.
  • the assay in this case involves the use a recombinant Glutathiones-transferase (GST)-nuclear receptor ligand binding domain (LBD) fusion protein and a synthetic biotinylated peptide sequenced derived from the receptor interacting domain of a co-activator peptide such as the steroid receptor coactivator 1 (SRC-I).
  • GST Glutathiones-transferase
  • LBD nuclear receptor ligand binding domain
  • SRC-I steroid receptor coactivator 1
  • GST-LBD is labeled with a europium chelate (donor) via a europium-tagged anti-GST antibody, and the coactivator peptide is labeled with allophycocyanin via a streptavidin-biotin linkage.
  • the peptide In the presence of an agonist for the nuclear receptor, the peptide is recruited to the GST-LBD bringing europium and allophycocyanin into close proximity to enable energy transfer from the europium chelate to the allophycocyanin.
  • excitation energy absorbed by the europium chelate Upon excitation of the complex with light at 340 nm excitation energy absorbed by the europium chelate is transmitted to the allophycocyanin moiety resulting in emission at 665 nm. If the europium chelate is not brought in to close proximity to the allophycocyanin moiety there is little or no energy transfer and excitation of the europium chelate results in emission at 615 nm. Thus the intensity of light emitted at 665 nm gives an indication of the strength of the protein-protein interaction.
  • the activity of a nuclear receptor antagonist can be measured by determining the ability of a compound to competitively inhibit (Le., IC 50 ) the activity of an agonist for the nuclear
  • cell based assay methodologies may be successfully used in screening assays to identify and profile the specificity of compounds of the present invention. These approaches include the co-transfection assay, translocation assays, complementation assays and the use of gene activation technologies to over express endogenous nuclear receptors.
  • co-transfection assays using full- length nuclear receptor co-transfection assays using chimeric nuclear receptors comprising the ligand binding domain of the nuclear receptor of interest fused to a heterologous DNA binding domain, and assays based around the use of the mammalian two hybrid assay system.
  • the basic co-transfection assay is based on the co-transfection into the cell of an expression plasmid to express the nuclear receptor of interest in the cell with a reporter plasmid comprising a reporter gene whose expression is under the control of DNA sequence that is capable of interacting with that nuclear receptor (see, for example, US Patents Nos. 5,071,773; 5,298,429 and 6,416,957).
  • Treatment of the transfected cells with an agonist for the nuclear receptor increases the transcriptional activity of that receptor which is reflected by an increase in expression of the reporter gene which may be measured by a variety of standard procedures.
  • the co- transfection assay typically includes the use of expression plasmids for both the nuclear receptor of interest and RXR.
  • Typical co-transfection assays require access to the full length nuclear receptor and suitable response elements that provide sufficient screening sensitivity and specificity to the nuclear receptor of interest.
  • the expression plasmid comprises: (1) a promoter, such as an SV40 early region promoter, HSV tk promoter or phosphoglycerate kinase (pgk) promoter, CMV promoter, Sr ⁇ promoter or other suitable control elements known in the art, (2) a cloned polynucleotide sequence, such as a cDNA encoding a receptor, co-factor, or fragment thereof, ligated to the promoter in sense orientation so that transcription from the promoter will produce a RNA that encodes a functional protein, and (3) a polyadenylation sequence.
  • a promoter such as an SV40 early region promoter, HSV tk promoter or phosphoglycerate kinase (pgk) promoter, CMV promoter, Sr ⁇ promoter or other suitable control elements known in the art
  • a cloned polynucleotide sequence such as a cDNA encoding a receptor, co-factor, or fragment thereof
  • an expression cassette of the invention may comprise the cDNA expression cloning vectors, or other preferred expression vectors known and commercially available from vendors such as Invitrogen, (CA), Stratagene, (CA) or Clontech, (CA).
  • expression vectors developed by academic groups such as the pCMX vectors originally developed in the Evans lab (Willey et al. Genes & Development 9 1033-1045 (1995)) may also be used.
  • the transcriptional regulatory sequences in an expression cassette are selected by the practitioner based on the intended application; depending upon the specific use, transcription regulation can employ inducible, repressible, constitutive, cell-type specific, developmental stage-specific, sex- specific, or other desired type of promoter or control sequence.
  • the expression plasmid may comprise an activation sequence to activate or increase the expression of an endogenous chromosomal sequence.
  • activation sequences include for example, a synthetic zinc finger motif (for example, see US Patents 6,534,261 and 6,503,7171) or a strong promoter or enhancer sequence together with a targeting sequence to enable homologous or nonhomologous recombination of the activating sequence upstream of the gene of interest.
  • Genes encoding the following full-length previously described proteins which are suitable for use in the co-transfection studies and profiling the compounds described herein, include human LXR ⁇ (accession U22662), human LXR ⁇ (accession U07132), rat FXR (accession Ul 8374), human FXR (accession NM_005123), human RXR ⁇ (accession NM_002957), human RXR ⁇ (accession XM_042579), human RXR ⁇ (accession XM_053680), human PPAR ⁇ (accession X57638) and human PPAR ⁇ (accession Ul 0375). All accession numbers in this application refer to GenBank accession numbers.
  • Reporter plasmids may be constructed using standard molecular biological techniques by placing cDNA encoding for the reporter gene downstream from a suitable minimal promoter.
  • luciferase reporter plasmids may be constructed by placing cDNA encoding firefly luciferase (typically with SV40 small t intron and poly-A tail, (de Wet et al., (1987) MoI. Cell. Biol.
  • hormone response element is dependent upon the type of assay to be used.
  • a reporter plasmid comprising a known LXR RE would typically be used, such as for example in a reporter plasmid such as LXRExI -tk-luciferase, (see U.S. patent No. 5,747,661, which is hereby incorporated by reference).
  • GAL4 Upstream Activating Sequences UAS
  • Numerous methods of co-transfecting the expression and reporter plasmids are known to those of skill in the art and may be used for the co-transfection assay to introduce die plasmids into a suitable cell type. Typically such a cell will not endogenously express nuclear receptors that interact with the response elements used in the reporter plasmid.
  • reporter gene systems include, for example, alkaline phosphatase (see, Berger, I, et al., Gene (1988), Vol. 66, pp. 1-10; and Kain, S.R, Methods. MoI. Biol. (1997), Vol. 63, pp. 49-60), ⁇ -galactosidase (See, U.S. Patent No. 5,070,012, issued Dec, 3, 1991 to Nolan et al., and Bronstein, L, et al., J. Chemilum. Biolum. (1989), Vol.4, pp. 99-111), chloramphenicol acetyltransferase (See, Gorman et al., MoI.
  • chimeras comprising the ligand binding domain (LBD) of the nuclear receptor of interest to a heterologous DNA binding domain (DBD) expands the versatility of cell based assays by directing activation of the nuclear receptor in question to defined DNA binding elements recognized by defined DNA binding domain (see WO95/18380). This assay expands the utility of cell based co- transfection assays in cases where the biological response or screening window using the native DNA binding domain is not satisfactory.
  • the methodology is similar to that used with the basic co-transfection assay, except that a chimeric construct is used in place of the full length nuclear receptor.
  • a chimeric construct is used in place of the full length nuclear receptor.
  • treatment of the transfected cells with an agonist for the nuclear receptor LBD increases the transcriptional activity of the heterologous DNA binding domain which is reflected by an increase in expression of the reporter gene as described above.
  • the DNA binding domains from defined nuclear receptors, or from yeast or bacterially derived transcriptional regulators such as members of the GAL 4 and Lex A / Umud super families are used.
  • a third cell based assay of utility for screening compounds of the present invention is a mammalian two-hybrid assay that measures the ability of the nuclear hormone receptor to interact with a cofactor in the presence of a ligand (see, for example, US Patent Nos. US 5,667,973, 5,283,173 and 5,468,614).
  • the basic approach is to create three plasmid constructs that enable the interaction of the nuclear receptor with the interacting protein to be coupled to a transcriptional readout within a living cell.
  • the first construct is an expression plasmid for expressing a fusion protein comprising the interacting protein, or a portion of that protein containing the interacting domain, fused to a GAL4 DNA binding domain.
  • the second expression plasmid comprises DNA encoding the nuclear receptor of interest fused to a strong transcription activation domain such as VP16, and the third construct comprises the reporter plasmid comprising a reporter gene with a minimal promoter and GAL4 upstream activating sequences.
  • the GAL4 DNA binding domain encoded in the first construct allows for specific binding of the fusion protein to GAL4 sites upstream of a minimal promoter.
  • the GAL4 DNA binding domain typically has no strong transcriptional activation properties in isolation, expression of the reporter gene occurs only at a low level.
  • the nuclear receptor-VP16 fusion protein can bind to the GAL4-interacting protein fusion protein bringing the strong transcriptional activator VP16 in close proximity to the GAL4 binding sites and minimal promoter region of the reporter gene. This interaction significantly enhances the transcription of the reporter gene which can be measured for various reporter genes as described above. Transcription of the reporter gene is thus driven by the interaction of the interacting protein and nuclear receptor of interest in a ligand dependent fashion.
  • Any compound which is a candidate for activation of LXR ⁇ or LXR ⁇ may be tested by these methods.
  • compounds are tested at several different concentrations to optimize the chances that activation of the receptor will be detected and recognized if present
  • assays are performed in triplicate and vary within experimental error by less than 15%. each experiment is typically repeated three or more times with similar results.
  • Activity of the reporter gene can be conveniently normalized to the internal control and the data plotted as fold activation relative to untreated cells.
  • a positive control compound (agonist) may be included along with DMSO as high and low controls for normalization of the assay data.
  • antagonist activity can be measured by determining the ability of a compound to competitively inhibit the activity of an agonist
  • the compounds and compositions can be evaluated for their ability to increase or decrease the expression of genes known to be modulated by LXR ⁇ or LXR ⁇ and other nuclear receptors in vivo, using Northern-blot, RT PCR or oligonucleotide microarray analysis to analyze RNA levels.
  • Western-blot analysis can be used to measure expression of proteins encoded by LXR target genes.
  • Genes that are known to be regulated by the LXRs include the ATP binding cassette transporters ABCAl, ABCGl, ABCG5, ABCG8, the sterol response element binding protein Ic (SREBPIc) gene, stearoyl CoA desaturase 1 (SCD-I) and the apolipoproteinapoE gene (ApoE).
  • SREBPIc sterol response element binding protein Ic
  • SCD-I stearoyl CoA desaturase 1
  • ApoE apolipoproteinapoE
  • mice Established animal models exist for a number of diseases of direct relevance to the claimed compounds and these can be used to further profile and characterize the claimed compounds.
  • These model systems include diabetic dislipidemia using Zucker (fa/fa) rats or (db/db) mice, spontaneous hyperlipidemia using apolipoprotein E deficient mice (ApoE 7" ), diet-induced hyperlipidemia, using low density lipoprotein receptor deficient mice (LDLR 7 ) and atherosclerosis using both the Apo E( 7 O and LDLRCO mice fed a western diet. (21% fat, 0.05% cholesterol).
  • LXR or FXR animal models e.g., knockout mice
  • LXR or FXR animal models can be used to further evaluate the present compounds and compositions in vh'o (see, for example, Peet, et al., Cell (1998), Vol. 93, pp. 693-704, and Yale, et al., Cell (2000), Vol. 102, pp. 731-744).
  • compositions of the invention can be prepared by combining a compound of the invention with an appropriate pharmaceutically acceptable carrier, diluent or excipient, (and may be formulated into preparations in solid, semi-solid, liquid or gaseous forms, such as tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants, gels, microspheres, and aerosols.
  • compositions of the invention are formulated so as to allow the active ingredients contained therein to be bioavailable upon administration of the composition to a patient.
  • Compositions that will be administered to a subject or patient take the form of one or more dosage units, where for example, a tablet may be a single dosage unit, and a container of a compound of the invention in aerosol form may hold a plurality of dosage units.
  • compositions to be administered will, in any event, contain a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, for treatment of a disease-state associated with the activity of anuclear receptor in accordance with the teachings of this invention.
  • a pharmaceutical composition of the invention may be in the form of a solid or liquid.
  • the carrier(s) are particulate, so that the compositions are, for example, in tablet or powder form.
  • the carriers) may be liquid, with the compositions being, for example, an oral syrup, injectable liquid or an aerosol, which is useful in, e.g., inhalatory administration.
  • the pharmaceutical composition When intended for oral administration, the pharmaceutical composition is preferably in either solid or liquid form, where semi-solid, semi-liquid, suspension and gel forms are included within the forms considered herein as either solid or liquid.
  • the pharmaceutical composition may be formulated into a powder, granule, compressed tablet, pill, capsule, chewing gum, wafer or the like form.
  • a solid composition will typically contain one or more inert diluents or edible carriers.
  • binders such as carboxymethylcellulose, ethyl cellulose, microcrystalline cellulose, gum tragacanth or gelatin; excipients such as starch, lactose or dextrins, disintegrating agents such as alginic acid, sodium alginate, Primogel, com starch and the like; lubricants such as magnesium stearate or Sterotex; glidants such as colloidal silicon dioxide; sweetening agents such as sucrose or saccharin; a flavoring agent such as peppermint, methyl salicylate or orange flavoring; and a coloring agent
  • excipients such as starch, lactose or dextrins, disintegrating agents such as alginic acid, sodium alginate, Primogel, com starch and the like
  • lubricants such as magnesium stearate or Sterotex
  • glidants such as colloidal silicon dioxide
  • sweetening agents such as sucrose or saccharin
  • a flavoring agent such as peppermint, methyl
  • the pharmaceutical composition when in the form of a capsule, e.g., a gelatin capsule, it may contain, in addition to materials of the above type, a liquid carrier such as polyethylene glycol or oil.
  • a liquid carrier such as polyethylene glycol or oil.
  • the pharmaceutical composition may be in the form of a liquid, e.g., an elixir, syrup, solution, emulsion or suspension.
  • the liquid may be for oral administration or for delivery by injection, as two examples.
  • preferred composition contain, in addition to the present compounds, one or more of a sweetening agent, preservatives, dye/colorant and flavor enhancer.
  • composition intended to be administered by injection one or more of a surfactant, preservative, wetting agent, dispersing agent, suspending agent, buffer, stabilizer and isotonic agent may be included.
  • the liquid pharmaceutical compositions of the invention may include one or more of the following adjuvants: sterile diluents such as water for injection, saline solution, preferably physiological saline, Ringer's solution, isotonic sodium chloride, fixed oils such as synthetic mono or diglycerides which may serve as the solvent or suspending medium, polyethylene glycols, glycerin, propylene glycol or other solvents; antibacterial agents such as benzyl alcohol or methyl paraben; antioxidants such as ascprbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose.
  • the parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.
  • Physiological saline is a preferred adjuvants.
  • a liquid pharmaceutical composition of the invention intended for either parenteral or oral administration should contain an amount of a compound of the invention such that a suitable dosage will be obtained. Typically, this amount is at least 0.01% of a compound of the invention in the composition. When intended for oral administration, this amount may be varied to be between 0.1 and about 70% of the weight of the composition.
  • Preferred oral pharmaceutical compositions contain between about 4% and about 50% of the compound of the invention.
  • Preferred pharmaceutical compositions and preparations according to the present invention are prepared so that a parenteral dosage unit contains between 0.01 to 1% by weight of the compound of the invention.
  • the pharmaceutical composition of the invention may be intended for topical administration, in which case the carrier may suitably comprise a solution, emulsion, ointment or gel base.
  • the base for example, may comprise one or more of the following: petrolatum, lanolin, polyethylene glycols, bee wax, mineral oil, diluents such as water and alcohol, and emulsifiers and stabilizers.
  • Thickening agents may be present in a pharmaceutical composition for topical administration. If intended for transdennal administration, the composition may include a transdermal patch or iontophoresis device.
  • Topical formulations may contain a concentration of the compound of the invention from about 0.1 to about 10% w/v (weight per unit volume).
  • the pharmaceutical composition of the invention may be intended for rectal administration, in the form, e.g., of a suppository, which will melt in the rectum and release the drug.
  • the composition for rectal administration may contain an oleaginous base as a suitable nonirritating excipient.
  • bases include, without limitation, lanolin, cocoa butter and polyethylene glycol.
  • the pharmaceutical composition of the invention may include various materials, which modify the physical form of a solid or liquid dosage unit.
  • the composition may include materials that form a coating shell around the active ingredients.
  • the materials that form the coating shell are typically inert, and may be selected from, for example, sugar, shellac, and other enteric coating agents.
  • the active ingredients may be encased in a gelatin capsule.
  • the pharmaceutical composition of the invention in solid or liquid form may include an agent that binds to the compound of the invention and thereby assists in the delivery of the compound. Suitable agents that may act in this capacity include a monoclonal or polyclonal antibody, a protein or a liposome.
  • the pharmaceutical composition of the invention may consist of dosage units that can be administered as an aerosol.
  • aerosol is used to denote a variety of systems ranging from those of colloidal nature to systems consisting of pressurized packages. Delivery may be by a liquefied or compressed gas or by a suitable pump system that dispenses the active ingredients. Aerosols of compounds of the invention may be delivered in single phase, bi-phasic, or tri-phasic systems in order to deliver the active ingredient(s). Delivery of the aerosol includes the necessary container, activators, valves, subcontainers, and the like, which together may form a kit One skilled in the art, without undue experimentation may determine preferred aerosols.
  • compositions of the invention may be prepared by methodology well known in the pharmaceutical art.
  • a pharmaceutical composition intended to be administered by injection can be prepared by combining a compound of the invention with sterile, distilled water so as to form a solution.
  • a surfactant may be added to facilitate the formation of a homogeneous solution or suspension.
  • Surfactants are compounds that non-covalently interact with the compound of the invention so as to facilitate dissolution or homogeneous suspension of the compound in the aqueous delivery system.
  • the compounds of the invention 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, and diet of the patient; the mode and time of administration; the rate of excretion; the drug combination; the severity of the particular disorder or condition; and the subject undergoing therapy.
  • a therapeutically effective daily dose is from about 0.1 mg to about 20 mg/kg of body weight per day of a compound of the invention, or a pharmaceutically acceptable salt thereof; preferably, from about 0.1 mg to about 10 mg/kg of body weight per day; and most preferably, from about 0.1 mg to about 7.5 mg/kg of body weight per day.
  • Compounds of the invention, or pharmaceutically acceptable derivatives thereof may also be administered simultaneously with, prior to, or after administration of one or more of therapeutic agents described above in the Utility of the Compounds of the Invention.
  • Such combination therapy includes administration of a single pharmaceutical dosage formulation which contains a compound of the invention and one or more additional active agents, as well as administration of the compound of the invention and each active agent in its own separate pharmaceutical dosage formulation.
  • a compound of the invention and an HMG-CoA reductase inhibitor can be administered to the patient together in a single oral dosage composition such as a tablet or capsule, or each agent administered in separate oral dosage formulations.
  • a single oral dosage composition such as a tablet or capsule
  • the compounds of the invention and one or more additional active agents can be administered at essentially the same time, Le., concurrently, or at separately staggered times, i.e., sequentially; combination therapy is understood to include all these regimens.
  • HMG-CoA reductase inhibitors Dosage information for HMG-CoA reductase inhibitors is well known in the art, since several HMG-CoA reductase inhibitors are marketed in the U.S.
  • the daily dosage amounts of the HMG-CoA reductase inhibitor may be the same or similar to those amounts which are employed for anti-hypercholesterolemic treatment and which are described in the Physicians' Desk Reference (PDR).
  • PDR Physicians' Desk Reference
  • the oral dosage amount of HMG-CoA reductase inhibitor is from about 1 to 200 mg/day and, more preferably, from about 5 to 160 mg/day.
  • dosage amounts will vary depending on the potency of the specific HMG-CoA reductase inhibitor used as well as other factors as noted above.
  • An HMG-CoA reductase inhibitor which has sufficiently greater potency may be given in sub-milligram daily dosages.
  • the daily dosage amount for simvastatin may be selected from 5 mg, 10 mg, 20 mg, 40 mg, 80 mg and 160 mg for lovastatin, 10 mg, 20 mg, 40 mg and 80 mg; for fluvastatin sodium, 20 mg, 40 mg and 80 mg; and for pravastatin sodium, 10 mg, 20 mg, and 40 mg.
  • the daily dosage amount for atorvastatin calcium may be in the range of from 1 mg to 160 mg and, more particularly, from 5 mg to 80 mg.
  • Oral administration may be in a single or divided doses of two, three, or four times daily, although a single daily dose of the HMG-CoA reductase inhibitor is preferred.
  • Suitable protecting groups include hydroxy, amino, mercapto and carboxylic acid.
  • Suitable protecting groups for hydroxy include trialkylsilyl or diarylalkylsilyl (e.g., t-butyldimethylsilyl, t-buryldiphenylsilyl or trimethylsilyl), tetrahydropyranyl, benzyl, and the like.
  • Suitable protecting groups for 1,2-dihydroxys include ketal- and acetal-forming groups.
  • Suitable protecting groups for amino, amidino and guanidino include t-butoxycarbonyl, benzyloxycarbonyl, and the like.
  • Suitable protecting groups for mercapto include -C(O)-R (where R is alkyl, aryl or aralkyl), /nmethoxybenzyl, trityl and the like.
  • Suitable protecting groups for carboxylic acid include alkyl, aryl or aralkyl esters.
  • Protecting groups may be added or removed in accordance with standard techniques, which are well-known to those skilled in the art and as described herein. The use of protecting groups is described in detail in Green, TVW. and P.G.M. Wutz, Protective Groups in Organic Synthesis (1991), 2nd Ed., Wiley-Interscience.
  • the protecting group may also be a polymer resin such as a Wang resin or a 2-chlorotriryl chloride resin.
  • the phrase "standard isolation procedures” is meant to include one or more of the following techniques familiar to one schooled in the art of organic chemistry: organic extraction, washing of organic solutions with dilute aqueous acid or base, use of drying agents, filtration, concentration in vacuo, followed by purification using distillation, crystallization, or solid-liquid phase chromatography.
  • elevated temperature refers to a temperature above ambient temperature
  • reduced temperature refers to a temperature below ambient temperature.
  • Amines (OOli) can be converted to hydrazines (OOlii) using standard techniques that are readily apparent to one skilled in the arts.
  • Acetophenones (OOli ⁇ ) can be converted to diketones (OOlrv) via a Claisen condensation.
  • Hydrazines (OOlii) and diketones (OOliv) can be condensed to form pyrazoles (OOlv) thermally or with the aid of catalysts such as acid.
  • Aryl bromides such as (00Iv) can then be elaborated further by an arylation reaction such as a Suzuki reaction to form a tetra-aryl ring system (OOlvi).
  • the resulting brown biphasic mixture was combined with the aqueous layer and diluted with Et 2 O ( ⁇ 700 mL). The mixture was acidified by the addition of 3N HCl to pH ⁇ 3. The layers were separated and the acidic aqueous was extracted with Et 2 O (3 x 150 mL). The combined organic layers were dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure to afford a brown oil. This oil was taken up in benzene and concentrated under reduced pressure to remove any residual water present.
  • reaction was purified by silica gel flash chromatography (Jones Flashmaster, 50 g SiO 2 , gradient elution from 100% hexanes to 40% ethyl acetate over 45 minutes). Appropriate fractions were combined and concentrated in vacuo affording the product as a faintly yellow solid, yield: 131 mg (25 %).

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Abstract

Compounds of the invention, such as compounds of Formulae Ia, Ib, Ic, or Id and pharmaceutically acceptable salts, isomers, and prodrugs thereof, which are useful as modulators of the activity of liver X receptors, where R1, R2, R21, R3, and G are defined herein. Pharmaceutical compositions containing the compounds and methods of using the compounds are also disclosed.

Description

PYRAZOLE BASED LXR MODULATORS
Cross-reference to related applications
This application claims priority to United States Provisional Application Number 60/694,372, filed June 27, 2005, and United States Provisional Application Number 60/736,120, filed November 10, 2005, both of which are hereby incorporated by reference in their entirety. Field of the invention
This invention relates to compounds that modulate the activity of liver X receptors (LXRs). The invention also provides pharmaceutical compositions comprising the compounds of the invention and methods of utilizing those compositions for modulating the activity of liver X receptor. In particular, pyrazole isomers and derivatives are provided for modulating the activity of LXRs.
BACKGROUND OF THE INVENTION Nuclear Receptors
Nuclear receptors are a superfamily of regulatory proteins that are structurally and functionally related and are receptors for, e.g., steroids, retinoids, vitamin D and thyroid hormones (see, e.g., Evans (1988) Science 240:889-895). These proteins bind to cis-acύng elements in the promoters of their target genes and modulate gene expression in response to ligands for the receptors.
Nuclear receptors can be classified based on their DNA binding properties (see, e.g., Evans, supra and Glass (1994) Endocr. Rev.75:391-407). For example, one class of nuclear receptors includes the glucocorticoid, estrogen, androgen, progestin and mineralocorticoid receptors which bind as homodimers to hormone response elements (HREs) organized as inverted repeats (see, e.g., Glass, supra). A second class of receptors, including those activated by retinoic acid, thyroid hormone, vitamin
D3, fatty acids/peroxisome proliferators (Le., peroxisome proliferator activated receptors or PPARs) and ecdysone, bind to HREs as heterodimers with a common partner, the retinoid X receptors (i.e., RXRs, also known as the 9-cis retinoic acid receptors; see, e.g., Levin et al. (1992) Nature 355:359-361 and Heyman et al. (1992) Cell 55:397-406).
RXRs are unique among the nuclear receptors in that they bind DNA as a homodimer and are required as a heterodimeric partner for a number of additional nuclear receptors to bind DNA (see, e.g., Mangelsdorf et al. (1995) Cell 55:841-850). The latter receptors, termed the class II nuclear receptor subfamily, include many which are established or implicated as important regulators of gene expression. There are three RXR genes (see, e.g., Mangelsdorf et al (1992) Genes Dev. (5:329-344), coding for
RXRα, β, and γ, all of which are able to heterodimerize with any of the class II receptors, although there appear to be preferences for distinct RXR subtypes by partner receptors in vivo (see, e.g., Chiba et al. (1997) MoI Cell. Biol. 17:3013-3020). In the adult liver, RXRα is the most abundant of the three RXRs (see, e.g., Mangelsdorf et al. (1992) Genes Dev. 6:329-344), suggesting that it might have a prominent role in hepatic functions that involve regulation by class II nuclear receptors. See also, Wan et al. (2000) MoI. Cell Biol. 20:4436-4444. Orphan Nuclear Receptors Included in the nuclear receptor superfamily of regulatory proteins are nuclear receptors for whom the ligand is known and those which lack known ligands. Nuclear receptors falling in the latter category are referred to as orphan nuclear receptors. The search for activators for orphan receptors has led to the discovery of previously unknown signaling pathways (see, e.g., Levin et al., (1992), supra and Heyman et al., (1992), supra). For example, it has been reported that bile acids, which are involved in physiological processes such as cholesterol catabolism, are ligands for the farnesoid X receptor (FXR).
Because it is known that products of intermediary metabolism act as transcriptional regulators in bacteria and yeast, such molecules may serve similar functions in higher organisms (see, e.g., Tomkins (1975) Science 189:760-763 and O'Malley (1989) Endocrinology 725:1119-1120). For example, one biosynthetic pathway in higher eukaryotes is the mevalonate pathway, which leads to the synthesis of cholesterol, bile acids, poφhyrin, dolichol, ubiquinone, carotenoids, retinoids, vitamin D, steroid hormones and farnesylated proteins. LXRq and LXRB
LXRα is found predominantly in the liver, with lower levels found in kidney, intestine, spleen and adrenal tissue (see, e.g., Willy, et al. (1995) Gene Dev. 9(9):1033-1045)LXRβ is ubiquitous in mammals and was found in nearly all tissues examined. LXRs are activated by certain naturally occurring, oxidized derivatives of cholesterol (see, e.g., Lehmann, et al. (1997) J. Biol. Chem. 272(6):3137-3140). LXRα is activated by oxycholesterol and promotes cholesterol metabolism (Peet et al. (1998) Cell 93:693-704). Thus, LXRs appear to play a role in, e.g., cholesterol metabolism (see, e.g., Janowski, et al. (1996) Nature 383:728-731). Nuclear Receptors and Disease
Nuclear receptor activity has been implicated in a variety of diseases and disorders, including, but not limited to, hypercholesterolemia (see, e.g., International Patent Application Publication No. WO 00/57915), osteoporosis and vitamin deficiency (see, e.g., U.S. Patent No. 6,316,5103), hyperlipoproteinemia (see, e.g., International Patent Application Publication No. WO 01/60818), hypertriglyceridemia, lipodystrophy, hyperglycemia and diabetes mellitus (see, e.g., International Patent Application Publication No. WO 01/82917), atherosclerosis and gallstones (see, e.g., International Patent Application Publication No. WO 00/37077), disorders of the skin and mucous membranes (see, e.g., U.S. Patent Nos. 6,184,215 and 6,187,814, and International Patent Application Publication No. WO 98/32444), acne (see, e.g., International Patent Application Publication No. WO 00/49992), and cancer, Parkinson's disease and Alzheimer's disease (see e.g., International Patent Application Publication No. WO 00/17334). Activity of nuclear receptors, including LXRs, FXRs and PPARs, and orphan nuclear receptors, has been implicated in physiological processes including, but not limited to, bile acid biosynthesis, cholesterol metabolism or catabolism, and modulation of cholesterol 7α- hydroxylase gene (CYP7A1) transcription (see, e.g., Chiang et al. (2000) J. Biol. Chem. 275:10918- 10924), HDL metabolism (see, e.g., Urizar et al. (2000) J. Biol. Chem. 275:39313-39317 and International Patent Application Publication No. WO 01/03705), and increased cholesterol efflux and increased expression of ATP binding cassette transporter protein (ABC1) (see, e.g., International Patent Application Publication No. WO 00/78972).
Thus, there is a need for compounds, compositions and methods of modulating the activity of nuclear receptors, including LXRs, FXRs, PPARs and orphan nuclear receptors. Such compounds are useful in the treatment, prevention, inhibition or amelioration of one or more symptoms of diseases or disorders in which nuclear receptor activity is implicated. SUMMARY OF THE INVENTION
In one aspect, the present invention provides a compound according the following formulas Ia- d,
Figure imgf000004_0001
or a pharmaceutically acceptable salt, isomer, or prodrug thereof, which are useful as modulators of the activity of liver X receptors (LXR), where R1, R2, R21, R3, and G are defined herein.
Compounds for use in compositions and methods for modulating the activity of nuclear receptors are provided. In particular, compounds of the invention which are useful for modulating liver X receptors, LXRα and LXRβ, FXR, PPAR and/or orphan nuclear receptors are provided.
In one embodiment, the compounds provided herein are agonists of LXR. In another embodiment, the compounds provided herein are antagonists of LXR. Agonists that exhibit low efficacy are, in certain embodiments, antagonists.
Another aspect of this invention is directed to methods of treating, preventing, or ameliorating the symptoms of a disease or disorder that is modulated or otherwise affected by nuclear receptor activity or in which nuclear receptor activity is implicated, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formulae Ia, Ib, Ic, or Id, or a pharmaceutically acceptable derivative thereof.
Another aspect of this invention is directed to methods of reducing cholesterol levels in a subject in need thereof, comprising administering an effective cholesterol level-reducing amount of a compound of formulae Ia, Ib, Ic or Id, or a pharmaceutically acceptable derivative thereof.
Another aspect of this invention is directed to methods of treating, preventing, inhibiting, or ameliorating one or more symptoms of a disease or disorder which is affected by cholesterol, triglyceride, or bile acid levels, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formulae Ia, Ib, Ic, or Id, or a pharmaceutically acceptable derivative thereof.
Another aspect of this invention is directed to methods of modulating nuclear receptor activity, comprising contacting the nuclear receptor with a compound of formulae Ia, Ib, Ic or Id, or a pharmaceutically acceptable derivative thereof.
Another aspect of this invention is directed to methods of modulating cholesterol metabolism, comprising administering an effective cholesterol metabolism-modulating amount of a compound of formulae Ia, Ib, Ic or Id, or a pharmaceutically acceptable derivative thereof.
Another aspect of this invention is directed to methods of treating, preventing, inhibiting or ameliorating one or more symptoms of hypocholesterolemia in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of formulae Ia, Ib, Ic or Id, or a pharmaceutically acceptable derivative thereof.
Another aspect of this invention is directed to methods of increasing cholesterol efflux from cells of a subject, comprising administering an effective cholesterol efflux-increasing amount of a compound of formulae Ia, Ib, Ic or Id, or a pharmaceutically acceptable derivative thereof.
Another aspect of this invention is directed to methods of increasing the expression of ATP- Binding Cassette (ABC1) in the cells of a subject, comprising administering an effective ABC1 expression-increasing mount of a compound of formulae Ia, Ib, Ic, or Id, or a pharmaceutically acceptable derivative thereof.
Another aspect of this invention is directed to in vitro methods for altering nuclear receptor activity, comprising contacting the nuclear receptor with a compound of formulae Ia, Ib, Ic or Id, or a pharmaceutically acceptable derivative thereof.
Another aspect of this invention is directed to methods of reducing cholesterol levels in a subject in need thereof, comprising administering an effective cholesterol level-reducing amount of a compound of formulae Ia, Ib, Ic or Id, or a pharmaceutically acceptable derivative thereof. Another aspect of this invention is directed to pharmaceutical compositions comprising a pharmaceutically acceptable carrier, excipient and/or diluent and a compound of formulae Ia, Ib, Ic or Id.
Another aspect of this invention is directed to regulation of cholesterol transport and inflammatory signaling pathways that are implicated in human disease pathology including atherosclerosis and associated diseases such as myocardial infarction and ischemic stroke in a subject in need thereof, comprising administering an effective cholesterol transport and inflammatory signaling pathways regulating amount of a compound of formulae Ia5 Ib, Ic or Id, or a pharmaceutically acceptable derivative thereof. Another aspect of this invention is directed to treatment of the metabolic syndrome which comprises a constellation of disorders of the body's metabolism including obesity, hypertension and insulin resistance and diabetes including treatment of diseases resulting from compromised metabolism and immunity including atherosclerosis and diabetes as well as autoimmune disorders and diseases in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of formulae Ia, Ib, Ic or Id, or a pharmaceutically acceptable derivative thereof.
DETAILED DESCRIPTION OF THE INVENTION
In a first embodiment, the present invention provides a compound according to one of the following formulas,
Figure imgf000006_0001
or a pharmaceutically acceptable salt, isomer, or prodrug thereof, wherein, (A) R1 is -iλR5, wherein
L1 is a bond, L5, L6, -L5-L6-L5-, or -L6-L5-L6-, wherein each L5 is independently -[C(R15)2]m-, wherein each R15 is independently hydrogen, halogen, (Ci-Ce)alkyl, (C3-C6)cycloalkyl, or (Q-Q-Jhaloalkyl; each L6 is independently -C(Rn)2-, -C(R11^C(R1 V, -C(R11^=C(R11)-, -C(RU)2O-, -C(Rπ)2NRn-, -OC-, -0-, -S-, -NR11-, -N(R10)CO-, -N(R10)CO2-, -CON(R10)-, -CO-, -CS-, -CO2-, -OC(O)-, -OC(=O)N(R10)-, -CONR11N(R1V, -CONR11-, -OCONR11-, -SO2-, -N(R10)SO2-, -SO2N(R10)-, -NR10CONR10-, -NR10CSNR10-, -C(=NRn)-, -C(^NOR11)-, -C(=NN(Rπ)2)-, aryl, C3-C8 cycloalkyl, cycloC^haloalkyl, heteroaryl, heterocyclyl, wherein the aryl, cycloalkyl, cycloC^ghaloalkyl, heteroatyl, or heterocyclyl are optionally substituted with one or more radicals of R14; or L1 is a C2-6 alidiyl chain, wherein the alidiyl chain is optionally interrupted by -C(Rπ)2-,
-C(R11^C(R1V, -C(R11^(R11)-, -C(Rn)2O-, -C(R11^NR11-, -OC-, -0-, -S-, -N(R10)CO, -N(R10)CO2-, -CON(R10)-, -CO-, -CO2-, -0C(=0)-, -OC(=O)N(R10)-, -SO2-,
-N(R10)SO2-; or -SO2N(R10)-, and
R5 is aryl, heterocyclyl, heteroaryl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, (C3-C8 cycloalkyl)- C1-C6 alkyl-, (C3-C8 cycloalkenyl)-Q-C6 alkyl-, (C3-C8 cycloalkyl)-C2-C6 alkenyl, C3-C8 cycloalkyl, -C, -B-C, -A-B-C, wherein A is -O-;
B is -[C(R15)2]m- or C3-C8 cycloalkyl;
C is Ci-Cealkyl, Ci-Cehaloalkyl, SO2R11, SR11, SO2N(Rn)2, SO2NR11COR11, ON, C(O)OR11,
CON(R1V oTN(R1V wherein R5 is optionally substituted with one or more R5a, wherein each R5a is independently C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-
C8 cycloalkyl, (C3-C8 cycloalkyrj-Q-Ce alkyl-, (C3-C8 cycloalkenyl)-Q-C6 alkyl-, (C3-C8 cycloalkyl)-C2-C6 alkenyl, halogen, nitro, heterocyclyloxy, aryl, aryloxy, arylalkyl, aryloxyaryl, aryl C1-C6 alkoxy, -C, -B'-C, or -A'-B'-C wherein
A' is -O-; B' is -[C(R15)2]m- or - C3-C8 cycloalkyl -;
C is -H, halogen, -SO2R11, -OR11, -SR11, -N3, -COR11, -SO2N(R1V -SO2NR11COR11, -C=N, -C(O)OR11, -OC(O)R11, -CON(R1V -CON(R1 ^OR11, -OCON(R1V -NR11COR11, -NR11CON(R1V -NR11COOR11, -N(R1 V aryl, heteroaryl, or heterocyclyl; wherein each R5a is optionally substituted one or more groups which are independently C2-C6 alkenyl, C2-C6 alkynyl, (C3-C8 cycloalkyl)-CrC6 alkyl-, (C3-C8 cycloalkenyl)-
C1-C6 alkyl-, (C3-C8 cycloalkyl)-C2-C6 alkenyl-, C0-C6 alkoxyaryl, C1-C6 alkyl, C3-C8 cycloalkyl, aryl, aryl-Q-Q alkyl-, heteroaryl, halogen, -NO2, -ON, -COR11,
-COOR11, -CON(RU)2> -SO2R11, -OR11, -SR11, -SO2R11, -SO2N(R1V
-SO2NR11COR11, -OCON(R1V -NR11COR11, -NR11CON(R1 V -NR11COOR11, or -N(R1V
R2 and R21 are -L3-R7, wherein each L3 is independently a bond -V-(CH2VV1-, or -(CEbVV^CEbV wherein n is 0-6; and each V1 is independently -C(Rπ)2-, -C(R1 ^2C(R1 \-, -C(R11^(R11)-, -C(Rn)2O-, -C(Rn)2NRπ-, -OC-, -0-, -S-, -NR7-, -N(R10)CO-, -N(R10)CO2-, -OCO-, -CO-, -CS-, -CONR10-, -C(=N)(Rπ)-, -C(=N-0Rπ)-, -C[=N-N(Rπ)2], -CO2-, -OC(O)-, -OC(O)N(R10)-, -SO2-, -N(R10)SO2-, -SO2N(R10)-, -NR10CONR10-, -NR10CSNR10-, C3-Cg cycloalkyl, or C3-C8 cyclohaloalkyl; or each L3 is independently a O2-5 alidiyl chain, wherein the alidiyl chain is optionally interrupted by -C(Rn)2-, -C(R11^C(R1 V, -C(R11^(R11)-, -C(Rπ)2O-, -C(R11^NR11-, -C=C-, -0-, -S-, -N(R10)CO-, -N(R10)CO2-, -CON(R10)-, -CO-, -CO2-, -OC(O)-, -OC(O)N(R10)-, -SO2-, -N(R10)SO2-, or -SO2N(R10); and each R7 is independently hydrogen, halogen, nitro, cyano, aryl, heteroaryl, heterocyclyl, -C1-C6 alkyl-heterocyclyl, -Ci-C6 alkyl-heteroaryl, -C1-C6 alkyl-aryl, -Z, -Y-Z, or -X-Y-Z, wherein XiS -O-;
Y is -[C(R15)2]m-,-C2-C6 alkenyl, or C3-C8 cycloalkyl;
Z is -H, -CN, halogen, -OR11, -C(O)R11, -C(O)OR11, -C(O)N(Rn)2, -N(Rπ)2, -CN, -N3, -SO2R11, -S(O)2N(Rn)2, -C(O)N(R1^N(R1 \ -C(O)N(R11XOR1 \
-OC(O)-R11, -0C(O>N(Rn)2, or -N(R1 ^COOR11; wherein R7 is optionally substituted with one or more R7a, wherein
R7a is halogen, C2-C6 alkenyl, -C1-C6 alkyl-heterocyclyl, -C1-C6 alkyl-heteroaryl, -C1-C6 alkyl-aryl, C0-C6 alkoxyheteroaryl, C0-C6alkoxyheterocyclyL haloaryl, aryloxy, aralkyloxy, aryloxyalkyl, Ci-C6alkoxyaryl, aryl C0-C6 alkylcarboxy,
QR^QR^-COOR11, Co-Cealkoxyheteroaryl, Co-C6alkoxyheterocyclyl, aryl, heteroaryl, heterocyclyl, C3-C8 cycloalkyl, heteroaryloxy, -Z', -Y'-Z', or -X'-Y'-Z', wherein
X' is -O-; Y' is -[C(R15)2]m- or C3-C8 cycloalkyl;
Z' is -Q-Qalkyl, -Ci-Qjhaloalkyl, -OR11, -SR11, -S(O)2R11, -C(O)R11, -C(O)OR11, -C(O)N(Rπ)2, -N(Rn)2, -N(Rn)C(O)Rn,
-S(O)2N(Rn)C(O)Rn, -CN, -S(O)2N(RU)2, -C(O)N(R1 ^N(R1 \ -C(O)N(Rπ)(0Rn), -OC(O)-R11, -OC(O)-OR11, -N(Rn)C(O)0-Rπ, or -N(R1^S(O)2R11; wherein each R7a is optionally substituted with one or more R8, wherein each R8 is independently halogen, nitro, cyano, heteroaryl, Ci-C6 alkyl, Ci-C6 alkoxy,
Ci-C6 haloalkyl, Ci-C6 haloalkyl(ORπ), C0-C6 alkylOR11, C0-C6 alkylCON(Rπ)2, C0-C6 alkylCOR11, C0-C6 alkylCOOR11, or C0-C6 alkylSO2Rπ; and wherein if two R7a are present on the same carbon, then they may be taken together to form a cycloalkyl or heterocyclyl group; provided that R2 and R21 are not simultaneously -H; R3 is -L-R6, wherein L is a bond, -X3-(CH2)n-X3-, -(CH2)m-X3-(CH2)n- or -(CH2)1+W-Y3-(CH2V wherein n is 0-6; each w is independently 0-5; and each X3 is independently a bond, -C(Rn)2-, -C(R1^2C(R1 \-, -C(R")=^11)-, -OC-, -CO-, -CS-, -CONR10-, -C(=N)(RU)-, -Q=N-OR11)-, -C[=N-N(Rn)2], -CO2-, -SO2-, or
-SO2N(R10)-; and Y3 is -0-, -S-, -NR7-, -N(R10)CO-, -N(R10)CO2-, -OCO-, -OC(O)N(R10)-,
-NR10CONR10-, -N(R10)SO2-, or -NR10CSNR10-; or L is a C2-6 alidiyl chain, wherein the alidiyl chain is optionally intemαpted by -C(R1 !)2-, -COF^QRV, -C(R11^(R11)-, -C(RΠ)2O-, -C(RΠ)2NRU-, -OC-, -0-, -Ss -N(R10)CO-, -N(R10)CO2-, -CON(R10)-, -CO-, -CO2-, -0C(=0)-, -OC(O)N(R10)-, -SO2-, -N(R10)SO2-, or -SO2N(R10); and
R6 is C1-C6 alkyl, C1-C6 haloalkyl, aryl, C3-C8 cycloalkyl, heteroaryl, heterocyclyl, -CN, -C(O)R11, -C(O)OR11, -C(O)N(Rn)2, -N(Rπ)2, -SO2R11, -S(O)2N(Rπ)2, -C(O)N(R1 ^N(R1 \ or -C(O)N(Rn)(0Ru), wherein the aryl, heteroaryl, cycloalkyl, or heterocyclyl is optionally substituted with one or more R6a, wherein each R6a is independently -Z , -Y -Z , or -X -Y -Z , wherein X" is-O-;
Y" is -[C(R15)2]m-, -C2-C6 alkenyl, C3-C8 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the aryl, heteroaryl, cycloalkyl, or heterocyclyl is optionally substituted with at least one group which is each independently Z";
Z" is -H, -CN, halogen, -OR11, -C(O)R11, -C(O)OR11, -C(O)N(Rπ)2, -N(Rπ)2, -N3, -SO2R11, -S(O)2N(Rn)2, -C(O)N(R1^N(R11X -N(R1 ^C(O)N(R1 \ -OC(O)-OR11, -C(O)N(R11XOR11), -OC(O)-R11, -OC(O)-N(R1 % or -N(Rn)COORn; each R10 is independently -R11, -C(O)R11, -CO2R11, or -SO2R11; each R11 is independently -hydrogen, C2-C6 alkenyl, C2-C6 alkynyl, (C3-C8 cycloalkenyty-Q-Ce alkyl-,
(C3-C8 cycloalkyl)-C2-C6 alkenyl-, -N(R12^, -C1-C6 alkyl, -C1-C6 haloalkyl, -C3-C8 cycloalkyl, -(C1- C6)alkyl-(C3-Cs)cycloalkyl, aryl, -(Ci-C6)alkyl-aryl, heteroatyl, -(Ci-C6)alkyl-heteroaryl, heterocyclyl, or -(Ci-C6)alkyl-heterocyclcyl, wherein any of R11 is optionally substituted with one or more radicals of R12; each R12 is independently hydrogen, halogen, Ci-Qjhaloalkyl, C1-C6 alkyl, C1-C6 alkoxy, (C0-C6 alkyl)O0(0R13); C0-C6 alkylOR13, C0-C6 alkylCOR13, C0-C6 alkylSO2R13, C0-C6 alkylCN, C0-C6 alkylCON(R13)2, C0-C6 alkylCONR13OR13, C0-C6 alkylSO2N(R13)2, C0-C6 alkylSR13, C0-C6 haloalkylOR13, aryloxy, aralkyloxy, aryloxyalkyl, Co-C6alkoxyaryl, aryl C0-C6 alkylcarboxy, C0-C6 alky]NR13SO2 R13, -C0-C6 alkylN(R13)2, or OC0-C6 alkylCOOR13; each R13 is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, (C3-C8 cycloalkyl)-CrC6 alkyl-, (C3-C8 cycloalkenyl)-CrC6 alkyl-, or (C3-C8 cycloalkyl)-C2-C6 alkenyl-; each R14 is independently C1-C6 alkyl, C1-C6 alkoxy, halogen, Ci-C6 haloalkyl, C0-C6 alkylCON(Rπ)2, C0-C6 alkylCONRnORπ, C0-C6 alkylOR11, or C0-C6 alkylCOOR11; G is a group of the formula,
Figure imgf000010_0001
wherein
J is aryl, heteroaryl, or absent;
K is aryl, heteroaryl, or absent; each R4 is independently halogen, nitro, C2-C6 alkenyl, C3-Cg cycloalkyl, -C1-C6 alkyl-heterocyclyl, -Ci-C6 alkyl-heteroaryl, -Ci-C6 alkyl-aryl, -heterocyclyl-aryl,
-heterocyclyl-heteroaryl, CR1^CR11COOR11, aryloxy, -S-aryl, aralkyloxy, aryloxyalkyl, C1-C6 alkoxyaryl, aryl C0-C6 alkylcarboxy, C0-C6 alkoxyheteroaryl, C0-C6 alkoxyheterocyclyl, aryl, heteroaryl, heterocyclyl, -M, -E-M, or -D-E-M, wherein
D is -O-; E is -[C(R15^]1n- or C3-C8 cycloalkyl;
M is CrC6alkyl, Q-Cehaloalkyl, -COR11, -COOR11, -0C(=0)Rn, -CON(Rπ)2, -ON, -OR11, -0C0N(Rύ)2, -OCO2-R11, -N3, -NR11COR11, -NR11SO2R11, -N(Rπ)2, -NR11COOR11, -SO2R11, -SO2NR11COR11, -SOR11, -SO2N(RU)2, or -SR11, wherein each R4 is optionally substituted with one or more R4*, wherein each R^ is independently halogen, aryloxy, aralkyloxy, aryloxyalkyl, Ci-C6 alkoxyaryl, aryl -Ci-Q alkyl-aryl, C0-C6 alkylcarboxy, -M', -E'-M', or -D'-E'-M' D' is -O-;
E' is -[C(R15)2]m- or C3-C8 cycloalkyl;
M' is -Ci-C6alkyl, -Q-Cehaloalkyl, COR11, -CON(RU)2, -N(R1 ^COOR11, -N(Rn)2, COOR11, ON, OR11, -NR11COR11, NR11SO2R11, SO2R11, SO2N(Rπ)2, orSRπ; each R41 is independently halogen, nitro, C1-C6 alkyl-heterocyclyl, -C1-C6 alkyl-heteroaryl, -C1-C6 alkyl-aryl, -M", -E"-M", or -D"-E"-M", wherein D" is -O-;
E" is -[C(RI5)2]m- or C3-C8 cycloalkyl; M" is -Q-Qalkyl, -Q-Cehaloalkyl, -COR11, -COOR11, -C0N(Rn)2, -ON, -OR11,
-0C0N(Rπ)2, -OCO2-R11, -N3, -NR11COR11, -NR11SO2R11, -N(Rn)2, -NR11COOR11, - SOR11, -SO2R11, -SO2NR11COR11, -SO2N(Rπ)2, or -SR11, wherein each R41 is optionally substituted with one or more R4a;
L2 is a bond, -CH=CHCOO-, -OCo-CealkylCOO-, -[C(R15)2]m-V2-[C(R15)2]n-, or -V2-[C(R15)2]m-V2-, wherein n is 0-6; and each V2 is independently -C(R1V, -C(R11^C(R1 V, -C(Rπ)=C(Rπ)-, -C(R11^NR11-, -C(Rπ)20-, -OC-, -0-, -S-, -N(R10)CO-, -N(R10)CO2-, -CON(R10)-, -CON(R11)-, -CON(R11P-, -CO-, -CS-, -CO2-, -OR11N-, -OR11COO-, -0C(=0)-, -OC(O)N(R10)-, -SO2-, -N(Rlft)SO2-, -SO2N(R10)-, -NR10CONR10-, C3-C8 cycloalkyl, -C(=NRn)-, -C(=N0Rπ)-,
-C(=NN(Rπ)2)-, -NR10CSNR10-, -C(O)-heterocyclyl, or cycloC3-8haloalkyl, wherein the heterocyclyl is optionally substituted with one or more groups independently selected from - OR11, -COOR11, and -C0N(Rπ)2; or L2 is a C2-6 alidiyl chain, wherein alidiyl chain is optionally interrupted by -C(R1 \-, -C(Rn)2C(Rn)2-, -C(R11^C(R11)-, -C(Rπ)20-, -C(R11^NR11-, -C(R1^2NR11-, -OC-, -0-, -S-,
-N(R10)CO-, -N(R10)CO2-, -CON(R10)-, -CON(R11)-, -CON(Rπ)O-, -CO-, -CO2-, -OC(O)-, -OC(O)N(R10)-, -SO2-, -N(R10)SO2-, -SO2N(R10)-; aryl, C3-C8 cycloalkyl, heteroaryl, or heterocyclyl wherein the aryl, cycloalkyl, heteroaryl, or heterocyclyl is optionally substituted with one or more R9, wherein each R9 is independently halogen, C1-C6 haloalkyl, C1-C6 alkyl, C1-C6 alkyloxy, C0-C6 alkyl or C1-C6 alkylCOOR11; each m is independently 0, 1, 2, 3, 4, 5 or 6; qis O, 1, 2, 3, 4 or 5; q' is 0, 1, 2, 3, or 4, and (B) provided that,
(i) q may be 0 only if L2 is not a bond or if K is not phenyl; (ϋ) the compound is not 2-methyl-5-(l-m-tolyl-3-(trifluoromethyl)-1H-pyrazol-5- yl)benzenesulfonamide;
(iii) if L2 is a bond, then both J and K are not absent; (iv) if K is absent, then q is 1 and R4 is bonded directly to L2; (v) if L2 is SO2 or SO2N(R10), then R5 is substituted with at least one R5a; (vi) if the compound is defined by formula Ia, men
(a) R1 is not 4-(NH2SO2)phenyl, 4-(CH3SO2)phenyl, or 4-(CH2FSO2)phenyl;
(b) if R1 is 4-fluorophenyl, then G is not 4-[(H2NS(=O)2-]phenyl-; and
(c) R2 and R21 are not 4-hydroxyphenyl; (vii) if the compound is defined by formula Ib, then (a) R2 and R3 are not 4-(NH2SO2)phenyl, 4-(CH3SO2)phenyl, or 4-
(CH2FSO2)phenyl; and (b) R1 is not 4-hydroxyphenyl; (viii) if the compound is defined by formula Ic, then
(a) R2 and R3 are not 4-(NH2SO2)phenyl, 4-(CH3SO2)phenyl, or 4- (CH2FSO2)phenyl;
(b) J is not pyridyl; and
(c) G is not 3- or 4-methoxyphenyl; and (ix) if the compound is defined by formula Id, then
(a) if L1 is a bond, then R1 is not thienyl or 5-methylthienyl; (b) G is not 4-(NH2SO2)phenyl, 4-(CH3SO2)phenyl, or 4-(CH2FSO2)phenyl;
(c) if G is 4-fluorophenyl, then R1 is not 4-[(H2NS(=O)2-]phenyl-;
(d) if J = Ph, L2 is a bond, and q is 1, then K and R4 together are not 4- fluorophenyl, 3-fluorophenyl, 4-methoxyphenyl, or 5-chlorothienyl;
(e) if J = pyridyl, L2 is a bond, and q is 1, then K and R4 together are not 4- fluorophenyl;
(f) if J= Ph, L2 is a bond, and q is 2, then K and both R4 together are not 3-fluoro- 4-methoxyphenyl; and
(g) R1 is not 4-Me-phenyl. In one embodiment, the invention provides the compound according to formula Ia, Ib, Ic, or Id, wherein: R1 is -iλR5, wherein
L1 is a bond, L5, L6, -L5-L6-L5-, or-L6-L5-L6-, wherein each L5 is independently -[C(R 5)2]m-, wherein m is O, 1, 2, 3, or 4; and each R15 is independently hydrogen, halogen, (Ci-C6)alkyl, or (Ci-C6)haloalkyl; and L6 is -CO-, -SO2-, -O-, -CON(R11)-, -Cs-Qcycloalkyl-, or -heterocyclyl-, wherein the cycloalkyl, or heterocyclyl is optionally substituted with one or more R14; and
R5 is aryl, heterocyclyl, heteroaryl, -C, or -B-C, wherein B is -[C(R15)2]m- or -C3-C6CyClOaIlCyI-; and C is halogen, -Ci-C6alkyl, or -Q-Cshaloalkyl; wherein R5 is optionally substituted with one or more R5a, wherein each R5a is independently halogen, nitro, heteroaryl, heterocyclyl, C2-C6 alkenyl, C2-C6 alkynyl, (C3-C8 cycloalkyl)-Ci-C6 alkyl-, (C3-C8 cycloalkenyl)-Q-C6 alkyl-, (C3-C8 cycloalkyl)-C2-Ce alkenyl-; aryl, arylalkyl, aryloxy, aryloxyaryl, arylC1-6 alkoxy, C1-C6 alkyl, Ci-C6 haloalkyl, C3-C6cycloalkyl, SO2R11, OR11, SR11, N3, SO2R11, COR11, SO2N(Rπ)2, SO2NR11COR11, C=N, C(O)OR11, CON(RU)2, C0N(Rπ)0Rn 0C0N(Rπ)2j NR11COR11, NR11CON(R11^ NR11COOR11, or N(R11K wherein each R5a is optionally substituted with one or more groups which independently are -halogen, -Ci-C6 alkyl, aryloxy Co-ό alkylSOiR11, CQ^ alkylCOOR11, C0^ alkoxyaryl, -Ci-C6 haloalkyl, -SO2R11, -OR11, -SR11, -N3, -SO2R11, -COR11, "SO2N(Rπ)2, -SO2NR11COR11, -C=N, -C(O)OR11, -C0N(Rπ)2, .CON(R11PR11, -0C0N(Rπ)2, -NR11COR11, -NR11CON(R11^,
-NR11COOR11, or -N(Rπ)2; R2 is-L3-R7, wherein
L3 is a bond; and
R7 is, halogen, aryl, heteroaryl, heterocyclyl, -Z, or -Y-Z, wherein Yis -[C(R15)2]m- or -C3-C6cycloalkyl; and
Z is -H, halogen, -OR11, -C(=O)Rπ, -C(=O)ORπ, -C(O)N(Rπ)2, -N(Rπ)2, -C(=N-0H)Rπ, -C(=S)N(RU)2, -CN, -S(O)2N(R1 \, -C(O)N(R1 ^N(R11K or -C(=0)N(Rn)(0Rπ); wherein R7 is optionally substituted with one or more R7a, wherein R7a is halogen -Z', -Y'-Z', or-X'-Y'-Z', wherein X' is-O-;
Y' is -[C(R15)2]m- or -Cs-Qcycloalkyl; and
Z' is -H, halogen, -OR11, -SR11, -S(O)2R11, -C(=O)Rπ, -C(=0)0Rπ, -C(=0)N(Rn)2, -N(Rπ)2, -N(RH)C(=O)Rπ, -CN, -SC=O)2N(R1 \ - -C(=0)N(Rn)(0Rπ), or -N(Rn)S(O=)2Rπ;
R21 and R3 are each independently hydrogen, halogen, Q-Cealkyl, or Q-Cδhaloalkyl; and G is a group of the formula,
Figure imgf000014_0001
, wherein
J is aryl or heteroaryl; K is aryl or heteroaryl; each R4 and R41 are independently halogen, aryloxy, aralkyloxy, aryloxyalkyl, arylC0-C6 alkylcarboxy, aryl, heteroaryl, heterocyclyl, heteroaryloxy, heterocyclyloxy, -M, -E-M, or - D-E-M, wherein
D is-O-;
E is -[C(R15)2]m- or -Qs-Cecycloalkyl; and
M is -CrC6alkyl, -Q-Cehaloalkyl, -COR11, -COOR11, -C0N(Rn)2, -C=N, -OR11, -0C0N(Rπ)2, -NR11COR11, -NR11SO2R11, -N(Rπ)2, -NR11COOR11, -SOR11, -SO2R11, -SO2NR11COR11, -SO2N(Rπ)2, or -SR11,
L is a bond; q is 1, 2, or 3; and q' is 0, 1, 2, or 3; each R10 is independently -R11, -Q=O)R11, -CO2R11, or -SO2R11; each R11 is independently -hydrogen, -C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, (C3-C8 cycloalkyl)-Cr C6 alkyl-, (C3-C8 cycloalkeny^-d-Q alkyl-, or (C3-C8 cycloalkyl)-C2-C6 alkenyl-; C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, (C3-C8 CyClOaIlCyI)-C1-C6 alkyl-, (C3-C8 cycloalkenyl)-CrC6 alkyl-, (C3-C8 cycloalkyl)-C2-C6 alkenyl-, -C3-C8 cycloalkyl, -C1-C6 haloalkyl, -N(R12^, aryl, -(CrC6)alkyl-aryl, heteroaryl, -(Ci-C6)alkyl-heteroaryl, heterocyclyl, or -(Ci-C6)alkyl-heterocyclyl, wherein any of R11 is optionally substituted with one or more radicals of R12; each R12 is independently halogen, C0-C6alkylN(R13)2, Q-Qhaloalkyl, C1-C6 alkyl, C1-C6 alkoxy, (C0-C6 alkyl)O0(0R13); C0-C6 alkylOR13, C0-C6 alkylCOR13, C0-C6 alkylSO2R13, C0-C6 alkylCON(R13)2, C0-C6 alkylCONR13OR13, C0-C6 alkylSO2N(R13)2, C0-C6 alkylSR13, C0-C6 haloalkylOR13, aryloxy, amlkyloxy, aryloxyalkyl, Cαealkoxyaryl, arylCM alkylcarboxy, C0-C6 alkyl, -NR13SO2 R13, or
-OQw alkylCOOR13; each R13 is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, (C3-C8 cycloalkyl)-d- C6 alkyl-, (C3-Cg cycloalkenyl)-C;ι-C6 alkyl-, or (C3-C8 cycloalkyl)-C2-C6 alkenyl-; and each R14 is independently C1-C6 alkyl, C1-C6 alkoxy, halogen, C1-C6 haloalkyl, C0-C6 alkylCON(Rπ)2, C0-C6 alkylCONRπORπ, C0-C6 alkylOR11, or C0-C6 alkylCOOR11.
In one embodiment, the invention provides the compound according to formula Ia, Ib, Ic, or Id, wherein: R1 is -L^R5, wherein
L1 is a bond, -C3-C8 cycloalkyl- or L5, wherein each L5 is independently -[C(R15)2]m-, wherein m is O, 1, 2, or 3; and each R15 is independently hydrogen, halogen, (CrC6)alkyl, or (Q-C^haloalkyl; and R5 is aryl, heterocyclyl, heteroaryl, -C, or -B-C, wherein
B is-[C(R15)2]m-, -CrQcycloalkyl-; and C is -Q-Qalkyl or -Q-Cshaloalkyl; wherein R5 is optionally substituted with one or more R5a, wherein each R5a is independently halogen, nitro, heteroaryl, heterocyclyl, C2-C6 alkenyl, C2-C6 alkynyl, (C3-C8 cycloalkyO-Q-Ce alkyl-, (C3-C8 cycloalkenyl)-CrC6 alkyl-, (C3-C8 cycloalkyl)-C2-C6 alkenyl-, aryl, arylalkyl, aryloxy, aryloxyaryl, arylC1-6 alkoxy, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6cycloalkyl, SO2R11, OR11, SR11, N3, SO2R11, COR11,
SO2N(Rπ)2, SO2NR11COR11, ON, C(O)OR11, CON(RU)2, CON(Rπ)ORπ OCON(R11)2,NR11COR11 JNRπCON(R11)2,NRπCOOR11,orN(R11)2, wherein each R5a is optionally substituted with one or more groups which independently are -halogen, -C1-C6 alkyl, aryloxy, Qy6 alkylSO2Rn, Q^ alkylCOOR11, CM alkoxyaryl, -C1-C6 haloalkyl, -SO2R11, -OR11, -SR11, -N3,
-SO2R11, -COR11, -SO2N(Rπ)2, -SO2NR11COR11, -ON, -C(O)OR11, -CON(Rπ)2, .CON(R11PR11, -OCON(R11X -NR11COR11, -NR11CON(R11^, -NR11COOR11, or -N(Rn)2; R2 is -L3-R7, wherein
L3 is a bond; and
R7 is -Z or -Y-Z, wherein
Y is -[C(R15)2]m-, or -Q-Cecycloalkyl; and
Z is -H, halogen, -OR11, -C(K))R11, -C(K))OR11, -C(K))N(R1 \ -N(RU)2, -C(=N-OH)RU, -C(=S)N(Rn)2, -CN, -S(KJ)2N(R1 \ -OC(=O)-Rπ, or -OC(=O)-N(R11)2;
R21 and R3 are each independently hydrogen, halogen, Ci-C6 alkyl, or Ci-C6 haloalkyl; and G is a group of the formula,
Figure imgf000016_0001
, wherein
J is aryl orheteroaryl; K is aryl or heteroaryl; each R4 and R41 are independently halogen, heteroaryl, heterocyclyl, -M, -E-M, or -D-E-M, wherein Dis-O-;
E is -[C(R15^]1n- or -C3-Qcycloalkyl; and
M is -Ci-Qalkyl, -Ci-Cghaloalkyl, -COR11, -COOR11, -CON(Rπ)2, -CNN, -OR11, - SOR11, -SO2R11, -SO2N(Rn)2, or -SR11, L2 is a bond; q is 1,2, or 3, and q' is 0, 1, 2 or 3, each R10 is independently -R11, -C(K))R11, -CO2R11, or -SO2R11; each R11 is independently -hydrogen, -C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, (C3-C8 cycloalkyl)-Ci- C6 alkyl-, (C3-C8 cycloalkenyl)-Ci-C6 alkyl-, (C3-C8 cycloalkyl)-C2-C6 alkenyl-, -C3-C8 cycloalkyl, -(Ci-C6)alkyl-(C3-C8)cycloalkyl, -Ci-C6 haloalkyl, -N(R12)2, aryl, -(CrC6)alkyl-aryl, heteroaryl, -(d-C6)alkyl-heteroaryl, heterocyclyl, or -(Ci-C6)alkyl-heterocyclyl, wherein any of R11 is optionally substituted with one or more radicals of R12; each R12 is independently halogen, OR13, N(R13)2, Ci-Cehaloalkyl, C1-C6 alkyl, Ci-C6 alkoxy, (C0-C6 alkyl)CK)(OR13); C0-C6 alkylOR13, C0-C6 alkylCOR13, C0-C6 alkylSO2R13, C0-C6 alkylCON(R13)2, C0-C6 alkylCOKIR13OR13, C0-C6 alkylSO2N(R13)2, C0-C6 alkylSR13, C0-C6 haloalkylOR13, aryloxy, aralkyloxy, aryloxyalkyl, Co^alkoxyaryl, arylCo-6 alkylcarboxy, C0-C6 alkyl, -ISIR13SO2 R13, or -OQ^ alkylCOOR13; each R13 is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, (C3-C8 cycloalkyl)-Cr C6 alkyl-, (C3-C8 cycloalkenyl)-CrC6 alkyl-, or (C3-C8 cycloalkyl)-C2-C6 alkenyl-; each R14 is independently C1-C6 alkyl, C1-C6 alkoxy, halogen, C1-C6 haloalkyl, C0-C6 alkylCON(Rπ)2, C0-C6 alkylCONRnORπ, C0-C6 alkylOR11, or C0-C6 alkylCOOR11.
In one embodiment, the invention provides the compound according to formula Ia or Id, wherein:
R1 is -L^R5, wherein L1 is abond,L5, L6,-L5-L6-L5-, or-L6-L5-L6-, wherein each L5 is independently -[C(RI5)2]m-, wherein mis 0, 1, 2, 3, or 4; and each R15 is independently hydrogen, halogen, (Ci-C6)alkyl, or (Ci-C6)haloalkyl; and L6 is -CO-, -SO2-, -O-, -CON(R11)-, -Q-Cecycloalkyl-, or-heterocyclyl-, wherein the cycloalkyl, or heterocyclyl is optionally substituted with one or more
R14; and
R5 is aryl, heterocyclyl, heteroaryl, -C, or -B-C, wherein B is-[C(R15)2]m- or -QrQjCycloalkyl-; and C is halogen, -Q-Cόalkyl, or -Q-Cόhaloalkyl; wherein R5 is optionally substituted with one or more R5a, wherein each R5a is independently halogen, nitro, heteroaryl, heterocyclyl, C2-C6 alkenyl, C2-C6 alkynyl, (C3-C8 CyClOaIlCyI)-C1-C6 alkyl-, (C3-C8 cycloalkenyl)-CrC6 alkyl-, (C3-C8 cycloalkyl)-C2-C6 alkenyl-, aryl, arylalkyl, aryloxy, aryloxyaryl, arylC1-6 alkoxy, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6cycloalkyl, SO2R11, OR11, SR11, N3, SO2R11, COR11, SO2N(Rπ)2, SO2NR11COR11, ON, C(O)OR11, CON(Rn)2, C0N(Rn)0Rπ
OCON(R11X NR11COR11, NR11C0N(R11)2, NR11COOR11, or N(R11X wherein each R5a is optionally substituted with one or more groups which independently are -halogen, -C1-C6 alkyl, aryloxy CM alkylSO2Rπ, C0^ alkylCOOR11, C0^ alkoxyaryl, -C1-C6 haloalkyl, -SO2R11, -OR11, -SR11, -N3, -SO2R11, -COR11, -SO2N(R11X -SO2NR11COR11, -ON, -C(O)OR11,
-C0N(Rπ)2, .CON(R11PR11, -OCON(R11X -NR11COR11, -NR11CON(R.11)!, -NR11COOR11, or -N(Rπ)2; R2 is-L3-R7, wherein L3 is a bond; and R7 is, halogen, aryl, heteroaryl, heterocyclyl, -Z, or -Y-Z, wherein Y is -[C(R15)2]m- or -C3-C6CyClOaUCyI; and
Z is -H, halogen, -OR11, -C(O)R11, -C(O)OR11, -C(O)N(R1 \ -N(Rn)2, -C(=N-OH)Rn, -C(=S)N(Rπ)2, -CN, -S(O)2N(R1 !)2, -C(O)N(R1 ^N(R1 \ or -C(O)N(Rn)(0Rn); wherein R7 is optionally substituted with one or more R7a, wherein R7a is halogen, -Z', -Y-Z', or-X'-Y'-Z', wherein X' isO-;
Y' is -[C(R15^]1n- or -C3-C6cycloalkyl; and Z' is -H, halogen, -OR11, -SR11, -S(O)2R11, -C(O)R11, -C(O)OR11,
-C(O)N(Rn)2, -N(Rπ)2, -N(Rn)C(O)Rπ, -CN, -S(O)2N(R11),, -C(O)N(Rπ)(0Rπ), or -N(R1 ^SCCN)2R11; R21 is hydrogen, halogen, Q-Qalkyl, or Q-Cόhaloalkyl; and G is a group of the formula,
Figure imgf000018_0001
, wherein
J is aryl or heteroaryl; K is aryl or heteroaryl; each R4 and R41 are independently halogen, aryloxy, aralkyloxy, aryloxyalkyl, arylQ)-C6 alkylcarboxy, aryl, heteroaryl, heterocyclyl, heteroaryloxy, heterocyclyloxy, -M, -E-M, or - D-E-M, wherein
D isO-;
E is -[C(R15)2]m- or -C3-C6cycloalkyl; and
M is -Q-Qalkyl, -Ci-Cehaloalkyl, -COR11, -COOR11, -CON(Rπ)2, -ON, -OR11, -OCON(RU)2, -NR11COR11, -NR11SO2R11, -N(Rn)2, -NR11COOR11, -SOR11, -SO2R11, -SO2NR11COR11, -SO2N(Rn)2, or -SR11,
L2 is a bond; q is 1,2, or 3; and q' is 0, 1,2, or 3; each R10 is independently -R11, -C(O)R11, -CO2R11, or -SO2R11; each R11 is independently -hydrogen, -C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, (C3-Cg cycloalkyl)-Cr C6 alkyl-, (C3-C8 cycloalkenyl)-CrC6 alkyl-, (C3-C8 cycloalkyl)-C2-C6 alkenyl-, -C3-C8 cycloalkyl, -C1-C6 haloalkyl, -N(R12)2, aryl, -(CrC6)alkyl-aryl, heteroaryl, -(Q-C^alkyl-heteroaryl, heterocyclyl, or -(C1-C6)alkyl-heterocyclyl, wherein any of R11 is optionally substituted with one or more radicals of R12; each R12 is independently halogen, C0-C6alkylN(R13)2> Q-Cehaloalkyl, C1-C6 alkyl, C1-C6 alkoxy, (C0-C6 alkyl)C=O(OR13); C0-C6 alkylOR13, C0-C6 alkylCOR13, C0-C6 alkylSO2R13, C0-C6 alkylCON(R13)2, C0-C6 alkylCONR13OR13, C0-C6 alkylSO2N(R13)2, C0-C6 alkylSR13, C0-C6 haloalkylOR13, aryloxy, aralkyloxy, aryloxyalkyl, Co^alkoxyaryl, arylCo^ alkylcarboxy, C0-C6 alkyl, -NR13SO2 R13, or -OCαe alkylCOOR13; each R13 is independently hydrogen C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, (C3-C8 cycloalkyl)-CrC6 alkyl-, (C3-C8 cycloalkenyl)-Ci-C6 alkyl-, or (C3-C8 cycloalkyl)-C2-C6 alkenyl-; and each R14 is independently C1-C6 alkyl, C1-C6 alkoxy, halogen, C1-C6 haloalkyl, C0-C6 alkylCON(Rn)2, C0-C6 alkylCONRnORn, C0-C6 alkylOR11, or C0-C6 alkylCOOR11.
In one embodiment, the invention provides the compound according to formula Ia or Id, wherein:
R1 is -iλ-R5, wherein
L1 is a bond, -C3-C8 cycloalkyl-, or L5, wherein each L5 is independently -[C(R15)2]m-, wherein m is O, 1, 2, or 3; and each R15 is independently hydrogen, halogen, (Q-C^alkyl, or (CrC6)haloalkyl; and
R5 is aryl, heterocyclyl, heteroaryl, -C, or -B-C, wherein B is-[C(R15)2]m- or -Qs-Cecycloalkyl-; and C is -Q-Qalkyl or -Q-Cehaloalkyl; wherein R5 is optionally substituted with one or more R5a, wherein each R5a is independently halogen, nitro, heteroaryl, heterocyclyl, C2-C6 alkenyl, C2-C6 alkynyl, (C3-C8 cycloalkyl)-Ci-C6 alkyl-, (C3-C8 cycloalkenyl)-CrC6 alkyl-, (C3-C8 cycloalkyl)-C2-C6 alkenyl, aryl, arylalkyl, aryloxy, aryloxyaryl, arylC1-6 alkoxy, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6cycloalkyl, SO2R11, OR11, SR11, N3, SO2R11, COR11, SO2N(Rπ)2, SO2NR11COR11, ON, C(O)OR11, C0N(Rπ)2, C0N(Rπ)0Rπ 0C0N(Rn)2, NR11COR11, NRnCON(Rn)2, NR11COOR11, or N(R11^, wherein each RSa is optionally substituted with one or more groups which independently are -halogen, -C1-C6 alkyl, aryloxy, C0-6 alkylSO2Rn, C0-6 alkylCOOR11, C0* alkoxyaryl, -C1-C6 haloalkyl, -SO2R11, -OR11, -SR11, -N3, -SO2R11, -COR11, "SO2N(Rn)2, -SO2NR11COR11, -ON, -C(O)OR11, -CON(RU)2, .CON(R11PR11, -0C0N(Rπ)2, -NR11COR11, -NR11CON(R11^, -NR11COOR11,or-N(Ru)2; R2 is -L3-R7, wherein L3 is a bond; and
R7 is -Z or -Y-Z, wherein
Y is -[C(R15)2]m- or -Qs-Qcycloalkyl; and
Z is -H, halogen, -OR11, -C(O)R11, -C(=0)0Rπ, -C(O)N(R1 \ -N(Rπ)2, -C(=N-0H)Rn, -C(=S)N(Rπ)2, -CN, -S(O)2N(Rπ)2, -OC(O)-R11, or -OC(O)-N(R11^;
R21 is hydrogen, halogen, C1-C6 alkyl, or C1-C6 haloalkyl; and G is a group of the formula,
Figure imgf000020_0001
5 wherein
J is aryl or heteroaryl; K is aryl or heteroaryl; each R and R41 are independently halogen, heteroaryl, heterocyclyl, -M, -E-M, or -D-E-M, wherein
D is-O-;
E is -[C(R15^]1n- or -C3-C6CyClOaIlCyI; and M is -d-Cealkyl, -Q-Cehaloalkyl, -COR11, -COOR11, -C0N(Rπ)2, -ON, -OR11, -
SOR11, -SO2R11, -SO2N(Rn)2, or -SR11; L2 is a bond; q is 1, 2, or 3, and q' is 0, 1, 2 or 3, each R10 is independently -R11, -C(O)R11, -CO2R11, or -SO2R11; each R11 is independently -hydrogen, -Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, (C3-C8 cycloalkyl)-d- C6 alkyl-, (C3-C8 cycloalkenyl)-C!-C6 alkyl-, (C3-C8 cycloalkyl)-C2-C6 alkenyl-C3-C8 cycloalkyl, -Ci-C6 haloalkyl, -N(R12)2, aryl, -(Ci-C6)alkyl-aryl, heteroaryl, -(CrC6)alkyl-heteroaryl, heterocyclyl, or -(CrC6)alkyl-heterocyclyl, wherein any of R11 is optionally substituted with one or more radicals of R12; each R12 is independently halogen, OR13, N(R13X Q-Cehaloalkyl, C1-C6 alkyl, C1-C6 alkoxy, (C0-C6 alkyl)O0(0R13); C0-C6 alkylOR13, C0-C6 alkylCOR13, C0-C6 alkylSO2R13, C0-C6 alkylCON(R13)2, C0-C6 alkylCONR13OR13, C0-C6 alkylSO2N(R13)2, C0-C6 alkylSR13, C0-C6 haloalkylOR13, aryloxy, aralkyloxy, aryloxyalkyl, Co-ealkoxyaryl, arylCM alkylcarboxy, C0-C6 alkyl, -NR13SO2 R13, or
-OC0-6 alkylCOOR13; each R13 is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, (C3-C8 cycloalkyl)-Ci- C6 alkyl-, (C3-C8 cycloalkenyl)-CrC6 alkyl-, or (C3-C8 cycloalkyl)-C2-C6 alkenyl-; each R14 is independently Cj-C6 alkyl, Ci-C6 alkoxy, halogen, Ci-C6 haloalkyl, C0-C6 alkylCON(Rπ)2, C0-C6 alkylCOM^OR11, C0-C6 alkylOR11, or C0-C6 alkylCOOR11.
In another embodiment, the invention provides the compound according to formulas Ia-d, wherein
R1 is-L5-R5 or-L6-R5 wherein
L5 is -[C(R15)2]m-; L6 is C3-C8 cycloalkyl, cycloC^shaloalkyl, or heterocyclyl, wherein the cycloalkyl, cycloC3-8haloalkyl 1, or heterocyclyl are optionally substituted with one or more radicals ofR14;
R5 is aryl, heterocyclyl, or heteroaryl, wherein R5 is optionally substituted with one or more R5a, wherein each R5a is independently halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl,
(C3-C8 cycloalkyl)-Ci-C6 alkyl-, (C3-C8 cycloalkeny^-Q-Ce alkyl-, (C3-C8 cycloalkyl)-C2-C6 alkenyl-, nitro, heterocyclyloxy, aryl, aryloxy, arylalkyl, aryloxyaryl, aryl C1-C6 alkoxy, -C, -B -C5 or -A'-B'-C wherein
A' is -O-; B' is -[C(R15)2]m- or - C3-C8 cycloalkyl -;
C is -H, halogen, -SO2R11, -OR11, -SR11, -N3, -COR11, -SO2N(R11^, -SO2NR11COR11, -CMN, -C(O)OR11, -OC(O)R11, -C0N(Rn)2, -C0N(Rπ)0Rπ, -0C0N(Ru)2, -NR11COR11, -NR11CON(R11^, -NR11COOR11, -N(Rn)2, aryl, heteroaryl, or heterocyclyl. In another embodiment, the invention provides the compound according to formulas Ia-d, wherein
R1 is-L5-R5 or-L6-R5 wherein L5 is -[C(R15)2]m-; L6 is C3-Cg cycloalkyl, cycloC^ghaloalkyl, or heterocyclyl, wherein the cycloalkyl, cycloC3-8haloalkyl, or heterocyclyl are optionally substituted with one or more radicals ofR14;
R5 is aryl, heterocyclyl, or heteroaryl, wherein R5 is optionally substituted with one or more R5a, wherein each R5a is independently halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, (C3-C8 cycloalkyO-Ci-Ce alkyl-, (C3-C8 cycloalkenyl)-CrC6 alkyl-, (C3-C8 cycloalkyl)-C2-C6 alkenyl-, nitro, heterocyclyloxy, aryl, aryloxy, arylalkyl, aryloxyaryl, aryl C1-C6 alkoxy, -C, -B'-C, or -A'-B'-C wherein A' is -O-;
B' is -[C(R15)2]m- or - C3-C8 cycloalkyl -;
C is -H, halogen, -SO2R11, -OR11, -SR11, -N3, -COR11, -SO2N(R11^, -SO2NR11COR11, -ON, -C(O)OR11, -OC(=O)Rπ, -CON(RU)2, -C0N(Rπ)0Rn, -OCON(Rn)2, -NR11COR11, -NR11CON(R11K -NR11COOR11, -N(Rπ)2, aryl, heteroaryl, or heterocyclyl; and
J is aryl or heteroaryl; and K is aryl or heteroaryl.
In another embodiment, the invention provides the compound according to formulas Ia-d, wherein R1 is -L5-R5 or-L6-R5 wherein
L5 is -[C(R15^]1n-;
L6 is C3-C8 cycloalkyl, cycloCs-ghaloalkyl, or heterocyclyl, wherein the cycloalkyl, cycloCs-shaloalkyl, or heterocyclyl are optionally substituted with one or more radicals ofR14; R5 is aryl, heterocyclyl, or heteroaryl, wherein R5 is optionally substituted with one or more R5a, wherein each R5a is independently halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, (C3-C8 cycloalkyiyCi-Ce alkyl-, (C3-C8 cycloalkenylJ-Q-Cδ alkyl-, (C3-C8 cycloalkyl)-C2-C6 alkenyl-, nitro, heterocyclyloxy, aryl, aryloxy, arylalkyl, aryloxyaryl, aryl C1-C6 alkoxy, -C, -B'-C, or -A'-B'-C wherein
A' is -O-; B' is -[C(R15)2]m- or - C3-C8 cycloalkyl -; C is -H, halogen, -SO2R11, -OR11, -SR11, -N3, -COR11, -SO2N(R11^, -SO2NR11COR11, -ON, -C(O)OR11, -OC(K))R11, -CON(Rn)2, -C0N(Rπ)0Rπ, -OCON(Rπ)2, -NR11COR11, -NR11CON(R1 \ -NR11COOR11, -N(Rπ)2, aiyl, heteroaryl, orheterocyclyl; J is aryl or heteroaryl;
K is aryl or heteroaryl; R2 is -L3-R7, wherein
L3 is a bond; and
R7 is hydrogen, -Z, or -Y-Z, wherein Yis -[C(R15)2]m- or -C2-C6 alkenyl;
Z is -H, halogen, -OR11, -C(O)R11, -C(O)OR11, -C(O)N(Rπ)2, -N(Rπ)2, -CN, -SO2R11, or -S(O)2N(Rn)2; and R21 is hydrogen, halogen, C1-C6 alkyl, or C1-C6 haloalkyl.
In another embodiment, the invention provides the compound according to formulas Ia and Id. In another embodiment, the invention provides the compound according to formulas Ia and Id, wherein
R1 is-L5-R5 or-L6-R5 wherein L5 is -[C(R15)2]m-;
L6 is C3-C8 cycloalkyl, cycloC3-8haloalkyl, or heterocyclyl, wherein the cycloalkyl, cycloCj-shaloalkyll, or heterocyclyl are optionally substituted with one or more radicals ofR14;
R5 is aryl, heterocyclyl, or heteroaryl, wherein R5 is optionally substituted with one or more R5a, wherein each R5a is independently halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, (C3-C8 cycloalkyl)-CrC6 alkyl-, (C3-C8 cycloalkenyl)-CrC6 alkyl-, (C3-C8 cycloalkyl)-C2-C6 alkenyl-, nitro, heterocyclyloxy, aryl, aryloxy, arylalkyl, aryloxyaryl, aryl C1-C6 alkoxy, -C, -B'-C, or -A'-B'-C wherein A' is -O-;
B' is -[QR15)2]m- or - C3-C8 cycloalkyl -; C is -H halogen, -SO2R11, -OR11, -SR11, -N3, -COR11, -SO2N(R11^5
-SO2NR11COR11, -C≡N, -C(O)OR11, -OC(O)R11, -C0N(Rπ)2, -C0N(Rπ)0Rπ, -0C0N(Rπ)2, -NR11COR11, -NR11CON(R1 % -NR11COOR11, -N(Rn)2, aryl, heteroaryl, orheterocyclyl. In another embodiment, the invention provides the compound according to formulas Ia and Id, wherein
R1 is-L5-R5 or-L6-R5 wherein
L5 is -[C(R15)2]m-; L6 is C3-C8 cycloalkyl, cycloC^shaloalkyl, or heterocyclyl, wherein the cycloalkyl, cycloC3-8haloalkyl, or heterocyclyl are optionally substituted with one or more radicals ofR14;
R5 is aryl, heterocyclyl, or heteroaryl, wherein R5 is optionally substituted with one or more R5a, wherein each R5a is independently halogen, Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl,
(C3-C8 cycloalkyl)-Ci-C6 alkyl-, (C3-C8 cycloalkenyl)-Ci-C6 alkyl-, (C3-C8 cycloalkyl)-C2-C6 alkenyl-, nitro, heterocyclyloxy, aryl, aryloxy, arylalkyl, aryloxyaryl, aryl C1-C6 alkoxy, -C, -B'-C, or -A'-B'-C wherein
A' is -O-; B' is -[C(R15)2]m- or - C3-C8 cycloalkyl -; '
C is -H, halogen, -SO2R11, -OR11, -SR11, -N3, -COR11, -SO2N(R11^, -SO2NR11COR11, -C≡N, -C(O)OR11, -OQ=O)R11, -C0N(Rn)2, -C0N(Rn)0Rπ, -OCON(Rπ)2, -NR11COR11, -NR11CON(R1 \ -NR11COOR11, -N(Rπ)2, aryl, heteroaryl, or heterocyclyl; and J is aryl or heteroaryl; and
K is aryl or heteroaryl.
In another embodiment, the invention provides the compound according to formulas Ia and Id, wherein
R1 is -L5-R5 or-L6-R5 wherein L5 is -[C(R15)2]m-;
L6 is C3-C8 cycloalkyl, cycloC^shaloalkyl, or heterocyclyl, wherein the cycloalkyl, cycloC^shaloalkyl, or heterocyclyl are optionally substituted with one or more radicals ofR14;
R5 is aryl, heterocyclyl, or heteroaryl, wherein R5 is optionally substituted with one or more R5a, wherein each R5a is independently halogen, Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, (C3-C8 cycloalkyl)-Ci-C6 alkyl-, (C3-C8 cycloalkenyl)-Ci-C6 alkyl-, (C3-C8 cycloalkyl)-C2-C6 alkenyl-, nitro, heterocyclyloxy, aiyl, aiyloxy, arylalkyl, aiyloxyaiyl, aryl C1-C6 alkoxy, -C, -B'-C, or -A'-B'-C wherein A'is -O-;
B' is -[C(R15)2]m- or - C3-C8 cycloalkyl -; C is -H, halogen, -SO2R11, -OR11, -SR11, -N3, -COR11, -SO2N(R11^,
-SO2NR11COR11, -C=N, -C(O)OR11, -OC(O)R11, -C0N(Rπ)2, -C0N(Rπ)0Rπ, -0C0N(Rπ)2, -NR11COR11, -NRπC0N(Rπ)2, -NR11COOR11, -N(Rπ)2, aryl, heteroaryl, or heterocyclyl; J is aryl or heteroaryl; K is aryl or heteroaryl;
R2 is -L3-R7, wherein
L3 is a bond; and
R7 is hydrogen, -Z, or -Y-Z, wherein Y is -[C(R15)2]m- or -C2-C6 alkenyl; Z is -H, halogen, -OR11, -C(O)R11, -C(O)OR11, -C(O)N(Rπ)2, -N(Rn)2, -CN,
-SO2R11, or-S(0)2N(R11)2; and
R21 is hydrogen, halogen, C1-C6 alkyl, or Ci-C6 haloalkyl; such compounds are referred to hereafter and compounds of formula XL.
In another embodiment, the invention provides the compound according to formula XL, wherein J and K are both phenyl.
In another embodiment, the invention provides Hie compound according to formula XL, wherein J and K are both phenyl; and
R5 is aryl or heteroaryl, wherein R5 is optionally substituted with one or more R5a. In another embodiment, the invention provides the compound according to formula XL, wherein J and K are both phenyl; and
R5 is phenyl optionally substituted with one or more R5^ wherein each R5a is independently -halogen, -Q-Qalkyl, -Ci-Cehaloalkyl, -OR11, -COR11, -C=N, -C(O)OR11, -CON(Rn)2, or -N(RU)2
In another embodiment, the invention provides the compound according to formula XL, wherein J and K are both phenyl;
R5 is phenyl optionally substituted with one or more R5a> wherein each R5a is independently -halogen, -Q-Qalkyl, -Ci-C6haloalkyl, -OR11, -COR11, -ON, -C(O)OR11, -CON(Rn)2, or -N(Rn)2; and each R4 is independently halogen, aryl, heteroaryl, heterocyclyl, -M, or -E-M, wherein E is -[C(R15')2]m-, wherein each R15 is independently hydrogen or halogen; and M is -Q-Qalkyl, -Q-Cehaloalkyl, halogen, -OR11, or -SO2R11. In another embodiment, the invention provides the compound according to formula XL, wherein J and K are both phenyl; and
R5 is phenyl optionally substituted with one or more R5aj wherein each R5a is independently -halogen, -Q-C6alkyl, -Q-Qshaloalkyl, -OR11, -COR11, -CNN, -C(O)OR11, -C0N(Rn)2, or -N(Rn)2 In another embodiment, the invention provides the compound according to formula XL, wherein J and K are both phenyl;
R5 is phenyl optionally substituted with one or more R5^ wherein each R5a is independently -halogen, -CrC6alkyl, -Q-Qshaloalkyl, -OR11, -COR11, -CNN, -C(O)OR11, -C0N(Rπ)2, or -N(R11^; and each R41 is independently halogen, -M", or -E" -M", wherein
E" is -[C(R15')2]m-, wherein each R15 is independently hydrogen or halogen; and M" is -Ci-C6alkyl, -Q-Cehaloalkyl, or halogen.
In another embodiment, the invention provides the compound according to formula XL, wherein J and K are both phenyl; and
R5 is phenyl optionally substituted with one or more R5a> wherein each R5a is independently -halogen, -Q-Cealkyl, -Ci-Cehaloalkyl, -OR11, -COR11, -ON, -C(O)OR11, -C0N(Rπ)2, or -N(RV
In another embodiment, the invention provides the compound according to formula XL, wherein J and K are both phenyl;
R5 is phenyl optionally substituted with one or more R5a> wherein each R5a is independently -halogen, -Q-Qalkyl, -Q-Cehaloalkyl, -OR11, -COR11, -ON, -C(O)OR11, -C0N(Rn)2, or -N(RV and
R7 is hydrogen, -Z, or -Y-Z, wherein Y is -[C(R15)2]m>- or -C2-C6 alkenyl, wherein rri is 0, 1, or 2; and
Z is -H, halogen, -OR11, -C(O)R11, -C(=0)0Rn, -C(O)N(R1 \ -N(R11K -CN, -SO2R11, or -S(=O)2N(Rπ)2.; and R21 is hydrogen.
In another embodiment, the invention provides the compound according to formula XL, wherein J is heteroaryl and K is phenyl.
In another embodiment, the invention provides the compound according to formula XL, wherein J is pyrroyl, thienyl, furyl, thiazoyl, oxazoyl, or pyrazoyl, and K is phenyl.
In another embodiment, the invention provides the compound according to formula XL, wherein J is pyrroyl, thienyl, furyl, thiazoyl, oxazoyl, or pyrazoyl, and K is phenyl.; and R5 is aryl or heteroaryl, wherein R5 is optionally substituted with one or more R5a. In another embodiment, the invention provides the compound according to formula XL, wherein J is pyrroyl, thienyl, fiiryl, thiazoyl, oxazoyl, or pyrazoyl, and K is phenyl; and
R5 is phenyl optionally substituted with one or more R5a= wherein each R5a is independently -halogen, -d-C6alkyl, -Ci-Cehaloalkyl, -OR11, -COR11, -CNN, -C(O)OR11, -C0N(Rπ)2, or -N(R11),. In another embodiment, the invention provides the compound according to formula XL, wherein J is pyrroyl, thienyl, furyl, thiazoyl, oxazoyl, or pyrazoyl, and K is phenyl; and
R5 is phenyl optionally substituted with one or more R5a> wherein each R5a is independently -halogen, -CrC6alkyl, -Q-Cehaloalkyl, -OR11, -COR11, -ON, -C(O)OR11, -C0N(Rπ)2, or -N(R11^; and each R4 is independently halogen, aryl, heteroaryl, heterocyclyl, -M, or -E-M, wherein
E is -[C(R15')2]m-, wherein each R15 is independently hydrogen or halogen; and M is -Q-Cealkyl, -Q-Cehaloalkyl, halogen, -OR11, or -SO2R11.
In another embodiment, the invention provides the compound according to formula XL, wherein J is pyrroyl, thienyl, furyl, thiazoyl, oxazoyl, or pyrazoyl, and K is phenyl; and
R5 is phenyl optionally substituted with one or more R5a= wherein each R5a is independently -halogen, -Q-C6alkyl, -Q-Cehaloalkyl, -OR11, -COR11, -ON, -C(O)OR11, -C0N(Rπ)2, or -N(R11^; and eachR41 is independently halogen, -M", or -E" -M", wherein E" is -[C(R15)2]m-, wherein each R15 is independently hydrogen or halogen; and M" is -Q-Cealkyl, -Ci-Cehaloalkyl, or halogen. In another embodiment, the invention provides the compound according to formula XL, wherein J is pyrroyl, thienyl, furyl, thiazoyl, oxazoyl, or pyrazoyl, and K is phenyl.; and
R5 is phenyl optionally substituted with one or more R5a= wherein each R5a is independently -halogen, -Ci-C6alkyl, -Q-Cghaloalkyl, -OR11, -COR11, -ON, -C(O)OR11, -CON(Rn)2, or -N(R11^aIId
R7 is hydrogen, -Z, or -Y-Z, wherein
Y is -[C(R15)2]m>- or -C2-C6 alkenyl, wherein m' is O, 1, or 2; and
Z is -H, halogen, -OR11, -C(O)R11, -C(O)OR11, -C(O)N(R1 \, -N(Rn)2, -CN, -SO2R11, or -S(O)2N(Rπ)2.; and R21 is hydrogen.
In an embodiment of the first aspect, the invention provides the compound according to formulas Ia-d, wherein J is phenyl.
In other embodiments, the invention provides a compound according to formula Ia, Ib, Ic5 or Id. In another embodiment, the invention provides the compound according to any one of formulas
Ia-d, wherein K is phenyl or pyridyl.
In another embodiment, the invention provides the compound according to any one of formulas Ia-d, wherein J and K are phenyl.
In another embodiment, the invention provides the compound according to formula π,
Figure imgf000028_0001
or a pharmaceutically acceptable salt, isomer, or prodrug thereof, wherein R1, R2, R21, R4, R41, L2, q, and q' are as defined in formulas Ia-d.
In another embodiment, the invention provides the compound according to formula HI
Figure imgf000029_0001
or a pharmaceutically acceptable salt, isomer, or prodrug thereof, wherein R1, R2, R21, R4, R41, L2, q, and q' are as defined in formulas Ia-d. In another embodiment, the invention provides the compound according to formula IH wherein
L2 is a bond; such compounds are referred to hereafter as compounds of formula IV.
In another embodiment, the invention provides the compound according to formula IV, wherein R5 is pyridyl optionally substituted with one or more R5a.
In another embodiment, the invention provides the compound according to formula IV, wherein R5 is pyridyl optionally substituted with one Or more R5a; and each R5a is independently -halogen, -Cj-Qalkyl, -Q-Qhaloalkyl, -OR11, -COR11, -CNN, -C(O)OR11, -CON(Rπ)2, or -N(Rn)2.
In another embodiment, the invention provides the compound according to formula IV, wherein R5 is pyridyl optionally substituted with one or more R5a; and each R41 is independently hydrogen, halogen, -Ci-C6alkyl, or -Ci-Cehaloalkyl. In another embodiment, the invention provides the compound according to formula IV, wherein
R5 is pyridyl optionally substituted with one or more R5a; and R2 is -L3-R7, wherein L3 is a bond or -C(Rn")2-; and
R7 is hydrogen, halogen, -Ci-C6alkyl, -Ci-Cehaloalkyl, -OR11", -Q=O)R11", -C(O)OR11", -C(O)N(Rπ")2, -N(Rn")2, -CN, -SO2R11", or -S(O)2N(R1 \ wherein each R11 is independently -H or -Q-Qalkyl.
In another embodiment, the invention provides the compound according to formula IV, wherein R5 is pyridyl optionally substituted with one or more R5a; and each R4 is independently halogen -Q-Qalkyl, -CrOftaloalyl, -COR11', -COOR11', -CON(R.π')2, -C=N, -OR11', -N(Rπ)2, -SO2R11', or -SO2N(RU')2, wherein each R11' is independently -hydrogen, -C1-C6 alkyl, or -Ci-C6 haloalkyl. In another embodiment, the invention provides the compound according to formula IH wherein
L1 is a bond and R5 is phenyl optionally substituted with one or more R5a In another embodiment, the invention provides the compound according to formula IV, wherein L1 is a bond and R5 is phenyl optionally substituted with one or more R5a; such compounds are referred to hereafter as compounds of formula V.
In another embodiment, the invention provides the compound according to formula V, wherein each R5a is independently halogen -C', or -B'-C, wherein B' is -[C(R15')2]m-, wherein each R15 is independently -H or -halogen; and
C is -H, -halogen, -SO2R11, -OR11, -COR11, -SO2N(RU)2, -ON, -C(O)OR11, -C0N(Rn)2, or -N(R11),. In another embodiment, the invention provides the compound according to formula V, wherein each R5a is independently -halogen, -Q-C6alkyl, -Q-Cehaloalkyl, -OR11, -COR11, -C≡N, -C(O)OR11, -CON(Rπ)2, or -N(RU)2; such compounds are referred to hereafter as compounds of formula Va.
In another embodiment, the invention provides the compound according to formula V, wherein each R41 is independently hydrogen, halogen, -Q-Cealkyl, -Q-Cehaloalkyl, -COR16, -COOR16, -CON(R16)2, -ON, -OR16, -N(R16)2, wherein each R16 is independently hydrogen, -C1-C6 alkyl, or -C1-C6 haloalkyl.
In another embodiment, the invention provides the compound according to formula V, wherein each R41 is independently hydrogen, halogen, -CrC6alkyl, or -d-Cόhaloalkyl; such compounds are referred to hereafter as compounds of formula Vb. In another embodiment, the invention provides the compound according to formula V, wherein each R4 is independently halogen, nitro, Q-Cealkyl, CrCehaloalkyl, -COR11, -COOR11, -C0N(Rπ)2, -C≡N, -OR11, -0C0N(Rn)2, -OCO2-R11, -N3, -NR11COR11, -NR11SO2R11, -N(Rπ)2, -NR11COOR11, -SO2R11, -SO2NR11COR11, -SO2N(Rn)2, or -SR11.
In another embodiment, the invention provides the compound according to formula V, wherein each R4 is independently halogen, nitro, Q-Cealkyl, CrCehaloalkyl, -COR11, -COOR11, -C0N(Rπ)2, -C≡N, -OR11, -N(Rπ)2, -SO2R11, or -SO2N(Rπ)2; such compounds are referred to hereafter as compounds of formula Vc.
In another embodiment, the invention provides the compound according to formula V, wherein R2 is -L3-R7, wherein L3 is a bond; and R7 is hydrogen, halogen, nitro, cyano, -Z, or -Y-Z, wherein
Yis -[C(R15)2]m-; Z is -H, halogen, -OR11, -C(=O)Rn, -C(O)OR11, -CC=O)N(R1 \ -N(RU)2, -CN, -SO2R11, -SHWR11)^ -C(=0)N(R11)N(R11)2, -CC=O)N(R11XOR11), -OC(O)-R11, or -OC(0)-N(Rπ)2.
In another embodiment, the invention provides the compound according to formula V, wherein R2 is -L3-R7, wherein
L3 is a bond; and R7 is hydrogen, halogen, -Z, or -Y-Z, wherein
Y is -[C(R15)2]m-, wherein
Z is -H, halogen, -OR11, -C(O)R11, -C(O)OR11, -C(O)N(Rn)2, -N(RU)2, -CN, -SOiR^ or-SCO^NCR11)^ such compounds are referred to hereafter as compounds of formula Vd.
In another embodiment, the invention provides the compound according to formula Va, wherein each R41 is independently hydrogen, halogen, -C1-Qa]]CyI, or -Q-Qhaloalkyl; such compounds are referred to hereafter as compounds of formula Ve.
In another embodiment, the invention provides the compound according to formula Vb, wherein each R4 is independently halogen, nitro, Q-Qalkyl, Q-Qhaloalkyl, -COR11, -COOR11, -C0N(Rn)2, -ON, -OR11, -N(Rn)2, -SO2R11, or -SO2N(RU)2; such compounds are referred to hereafter as compounds of formula Vf.
In another embodiment, the invention provides the compound according to formula Vc, wherein R2 is -L3-R7, wherein L3 is a bond; and R7 is hydrogen, halogen, -Z, or -Y-Z, wherein
Y is -[C(R15)2]m-, wherein
Z is -H, halogen, -OR11, -C(O)R11, -C(O)OR11, -C(O)N(Rn)2, -N(Rn)2, -CN, -SO2R11, Or-S(O)2N(R1^2; such compounds are referred to hereafter as compounds of formula Vg. In another embodiment, the invention provides the compound according to formula Vd, wherein each R5a is independently -halogen, -C1-QaIlCyI5 -Q-Qhaloalkyl, -OR11, -COR11, -C≡N, -C(O)OR11, -CON(Rn)2, or -N(Rn)2; such compounds are referred to hereafter as compounds of formula Vh.
In another embodiment, the invention provides the compound according to formula Ve, wherein each R4 is independently halogen, nitro, Q-Qalkyl, Q-Qhaloalkyl, -COR11, -COOR11, -CON(Rn)2, -C=N, -OR11, -N(Rπ)2, -SO2R11, or -SO2NCRU)2; such compounds are referred to hereafter as compounds of formula Vi. In another embodiment, the invention provides the compound according to formula Vf, wherein R2 is -L3-R7, wherein
L3 is a bond; and R7 is hydrogen, halogen, -Z, or -Y-Z, wherein
Y is -[C(R15)2]m-, wherein Z is -H, halogen, -OR11, -C(O)R11, -C(O)OR11, -C(O)N(RU)2, -N(Rπ)2, -CN,
-SO2R1V-S(O)2NOR.1^.
In another embodiment, the invention provides the compound according to formula Vg, wherein each R5a is independently -halogen, -Q-Qalkyl, -Q-Qhaloalkyl, -OR11, -COR11, -CNN, -C(O)OR11, -CON<Rn)2, or -N(Rn)2. In another embodiment, the invention provides the compound according to formula Vh, wherein each R41 is independently hydrogen, halogen, -C1-QaIkVl, or -Q-Qhaloalkyl.
In another embodiment, the invention provides the compound according to formula Vi, wherein R2 is -L3-R7, wherein
L3 is a bond; and R7 is hydrogen, halogen, -Z, or -Y-Z, wherein Y is -[C(R15)2]m-, wherein
Z is -H, halogen, -OR11, -C(O)R11, -C(O)OR11, -C(O)N(Rπ)2, -N(Rn)2, -CN, -S02Rπ, or-S(0)2N(Rπ)2.
In another embodiment, the invention provides the compound according to formula V, wherein R21 is hydrogen, halogen, nitro, cyano, aryl, heteroaryl, heterocyclyl, -C1-C6 alkyl-heterocyclyl, -C1-C6 alkyl-heteroaryl, -C1-C6 alkyl-aryl, -Z, -Y-Z, or -X-Y-Z, wherein X is -O-;
Y is -[C(R15)2]m- -C2-C6 alkenyl, or C3-C8 cycloalkyl;
Z is -H, -CN, halogen, -OR11, -C(O)R11, -C(O)OR11, -C(O)N(Rn)2, -N(Rπ)2, -CN, -N3, -SO2R11, -S(O)2N(RU)2, -C(O)N(Rn)N(Rn)2, -C(O)N(R11XOR11), -OC(O)-R11, -0C(O)-N(Ru)2, or -N(Rn)COORn.
In another embodiment, the invention provides the compound according to formula V, wherein R21 is hydrogen, halogen, nitro, cyano, Ci-C6alkyl, or Ci-Qhaloalkyl.
In another embodiment, the invention provides the compound according to any of formulas Va- Vi, wherein R21 is hydrogen, halogen, nitro, cyano, C1-QaIlCyI, or Q-Qhaloalkyl. In another embodiment, the invention provides the compound according to formula VI
Figure imgf000033_0001
or a pharmaceutically acceptable salt, isomer, or prodrug thereof, wherein R1, R2, R2 , R , R41, L2, q, and q' are as defined in formulas Ia-d.
In another embodiment, the invention provides the compound according to formula VH
Figure imgf000033_0002
wherein R1, R2, R21, R , R41, L2, q, and q' are as defined in formulas Ia-d.
In another embodiment, the invention provides the compound according to formula VII, wherein L2 is a bond or -[C(R15)2]m»-V2-[C(R15)2]n-, wherein m" is 0; n is 0-3; and V2 is -O-, -S-, -OC(=O)-, -OC(=O)O-, or -OC(=O)N(R10)-; such compounds are referred to hereafter as compounds of formula VHI. hi another embodiment, the invention provides the compound according to formula VIII wherein L2 is a bond; such compounds are referred to hereafter as compounds of formula DC. hi another embodiment, the invention provides the compound according to formula IX, wherein
L1 is a bond; and R5 is aryl or heteroaryl optionally substituted with one or more R5a.
Li another embodiment, the invention provides the compound according to formula X
Figure imgf000033_0003
wherein R1, R2, R21, R4, R41, L2, q, and q' are as defined in formulas Ia-d. hi another embodiment, the invention provides the compound according to formula X, wherein R5 is phenyl optionally substituted with one or more R5a; such compounds are referred to hereafter as compounds of formula XI. In another embodiment, the invention provides the compound according to formula XI wherein each R5a is independently halogen, -C, or -B'-C, wherein B' is -[C(R15')2]m-, wherein each R15 is independently -H or -halogen; and C is -H, -halogen, -SO2R11, -OR11, -COR11, -SO2N(RU)2, -C=N, -C(O)OR11, -CON(Rn)2, or
-N(Rn)2.
In another embodiment, the invention provides the compound according to formula XI, wherein each R5a is independently -halogen, -Q-Qalkyl, -Q-Qhaloalkyl, -OR11, -COR11, -ON, -C(O)OR11, -CON(Rn)2, or -N(Rπ)2; such compounds are referred to hereafter as compounds of formula XIa. In another embodiment, the invention provides the compound according to formula XI wherein each R41 is independently hydrogen, halogen, -Q-Qalkyl, -Q-Qhaloalkyl, -COR16, -COOR16, -CON(R16)2, -ON, -OR16, -N(R16)^ wherein each R16 is independently hydrogen, -C1-C6 alkyl, or -C1-C6 haloalkyl.
In another embodiment, the invention provides the compound according to formula XI wherein each R41 is independently hydrogen, halogen, -Q-Qalkyl, or -Q-Qhaloalkyl; such compounds are referred to hereafter as compounds of formula XIb.
In another embodiment, the invention provides the compound according to formula XI wherein each R4 is independently halogen, -M, or -E-M, wherein
Eis -[C(R15)2]m-; M is Q-Qalkyl, Q-Qhaloalkyl, -COR11, -COOR11, -C0N(Rn)2, -ON, -OR11, -OCON(R11^,
-OCO2-R11, -N3, -NR11COR11, -NR11SO2R11, -N(Rn)2, -NR11COOR11, -SO2R11, -SO2NR11COR11, -SO2N(Rn)2, or -SR11.
In another embodiment, the invention provides the compound according to formula XI wherein each R4 is independently halogen, -M, or -E-M, wherein E is -[C(R15')2]m-, wherein each R15 is independently -H or -halogen; and
M is -Q-Qalkyl, -Q-Qhaloalkyl, -COR11', -COOR11', -C0N(Rπ')2, -ON, -OR11', -N(Rn)2, -SO2R11', or -SO2N(Rn')2, wherein each R11' is independently -hydrogen, -C1-C6 alkyl, or -C1-C6 haloalkyl, wherein each R11' is optionally substituted with -OR13, -COOR13, -COR13,
-SO2R13, -CON(R13)2, -SO2N(R13)2, or -N(R13)2; such compounds are referred to hereafter as compounds of formula X3c. In another embodiment, the invention provides the compound according to formula XI wherein R2 is -IAR7, wherein
L3 is a bond, -C(Rn)2-, -O-, -S-, -NR7-, -N(R10)CO-, -CO-, -CS-, -CONR11-, -CO2-, -OC(O)-, or -SO2-; and R7 is hydrogen, halogen, heterocyclyl, -Z, or -Y-Z, wherein
Yis -[C(Rls)2]m-;
Z is -H, halogen, -OR11, -C(O)R11, -C(O)OR11, -C(O)N(Rn)2, -N(Rπ)2, -CN, -SO2R11, -S(O)2N(R"^, -C(O)N(R11)N(R11)2, -C(O)N(R11XOR11), -OC(O)-R11, or-OC(0)-N(Rπ)2. In another embodiment, the invention provides the compound according to formula XI, wherein
R2 is -L3-R7, wherein
L3 is a bond, -C(R11V, -CO-, or -SO2-; and
R7 is hydrogen, halogen, heterocyclyl, -CrQalkyl, -Q-Cδhaloalkyl, -OR11 , -C(O)R11", -C(O)OR11", -C(O)N(Rn")2, -N(Rn")2, -CN, -SO2R11", or -S(O)2N(RU")2, wherein each R11 is independently -H or -Q-Cgalkyl; such compounds are referred to l hereafter as compounds of formula XId.
In another embodiment, the invention provides the compound according to formula XIa, wherein each R41 is independently hydrogen, halogen, -CrCδalkyl, or -Q-Cόhaloalkyl; such compounds are referred to hereafter as compounds of formula XIe.
In another embodiment, the invention provides the compound according to formula XIb, wherein each R4 is independently halogen, -M, or -E-M, wherein E is -[C(R15')2]ra-, wherein each R15 is independently -H or -halogen; and M is -Ci-Cealkyl, -Q-Cghaloalkyl, -COR11', -COOR11', -CON(RU')2, -ON, -OR11', -N(Rπ)2,
-SO2R11', or -SO2N(Rir)2, wherein each R11 is independently -hydrogen, -C1-C6 alkyl, -C1-C6 haloalkyl, wherein each R11' is optionally substituted with -OR13, -COOR13, -COR13, -SO2R13, -CON(R13)2, -SO2N(R13)2, or -N(R13)2; such compounds are referred to hereafter as compounds of formula XIf.
In another embodiment, the invention provides the compound according to formula XIc, wherein R2 is -L3-R7, wherein L3 is a bond, -C(Rπ")2-, -CO-, or -SO2-; and R7 is hydrogen, halogen, heterocyclyl, -CrQalkyl, -Q-CehaloalkyL, -OR11", -C(O)R11", -C(=0)0Ru", -C(O)N(RU")2, -N(Rn")2, -CN, -SO2R11", or -SC=O)2N(R1 r)2, wherein each R11 is independently -H or -CrQalkyl; such compounds are referred to hereafter as compounds of formula XIg. In another embodiment, the invention provides the compound according to formula XId, wherein each R5a is independently -halogen, -CrC6alkyl, -Q-Cghaloalkyl, -OR11, -COR11, -ON, -C(O)OR11, -C0N(Rn)2, or -N(Rn)2; such compounds are referred to hereafter as compounds of formula XIh.
In another embodiment, the invention provides the compound according to formula XIe, wherein each R4 is independently halogen, -M, or -E-M, wherein E is -[C(R15')2]m-, wherein each R15 is independently -H or -halogen; and
M is -CrCealkyl, -Q-Cehaloalkyl, -COR11', -COOR11', -CON(Rπ')2, -ON, -OR11', -N(Rn)2, -SO2R11', or -SO2N(RU')2, wherein each R1 r is independently -hydrogen, -C1-C6 alkyl, -C1-C6 haloalkyl, wherein each R11' is optionally substituted with -OR13, -COOR13, -COR13, -SO2R13, -CON(R13)2, -SO2N(R13)2, or -N(R13)2; > such compounds are referred to hereafter as compounds of formula XIi.
In another embodiment, the invention provides the compound according to formula XIf, wherein R2 is -L3-R7, wherein L3 is a bond, -C(Rn")2-, -CO-, or -SO2-; and
R7 is hydrogen, halogen, heterocyclyl, -Q-Cealkyl, -CrCehaloalkyl, -OR11", -C(=O)Rn", -C(O)OR11", -C(=O)N(Rn")2, -N(RU")2, -CN, -SO2R11", or -S(O)2N(R11")^ wherein each R11 is independently -H or -CrC6alkyl.
In another embodiment, the invention provides the compound according to formula XIg, wherein each R5a is independently -halogen, -CrC6alkyl, -CrCehaloalkyl, -OR11, -COR11, -C=N, -C(O)OR11, -CON(Rn)2, or -N(Rπ)2.
In another embodiment, the invention provides the compound according to formula XIh, wherein each R41 is independently hydrogen, halogen, -CrQalkyl, or -CrCehaloalkyl.
In another embodiment, the invention provides the compound according to formula XIi, wherein R2 is -L3-R7, wherein L3 is a bond, -C(Rn")2-, -CO-, or -SO2-; and
R7 is hydrogen, halogen, heterocyclyl, -CrQalkyl, -Q-Cehaloalkyl, -OR11", -C(O)R11", -C(O)OR11", -C(O)N(RU")2, -N(Rn")2, -CN, -SO2R11", or -S(O)2N(R1 r)2, wherein each R11 is independently -H or -CrQalkyl. In another embodiment, the invention provides the compound according to formula XI, wherein R is hydrogen, halogen, nitro, cyano, aryl, heteroaryl, heterocyclyl, -C1-C6 alkyl-heterocyclyl, -C1-C6 alkyl-heteroaryl, -C1-C6 alkyl-aryl, -Z, -Y-Z, or -X-Y-Z, wherein
Xis -O-; Y is -[C(R15)2]m-, -C2-C6 alkenyl, or C3-C8 cycloalkyl;
Z is -H, -CN, halogen, -OR11, -C(O)R11, -C(=O)ORU, -C(O)N(Rπ)2, -N(Rπ)2, -CN, -N3, -SO2R11, -S(=O)2N(Rπ)2, -C(O)N(Rπ)N(Rπ)2, -C(O)N(R11XOR11), -OC(O)-R11, -0C(=0)-N(Rπ)2, or -N(Rn)C00Rπ.
In another embodiment, the invention provides the compound according to formula XI, wherein R21 is hydrogen, halogen, nitro, cyano, Q-C6alkyl, or CrCόhaloalkyl.
In another embodiment, the invention provides the compound according to any of formulas XIa-XIi, wherein R21 is hydrogen, halogen, nitro, cyano, Q-Qalkyl, or CrCδhaloalkyl.
Li another embodiment, the invention provides the compound according to formula K, wherein L1 is a bond; and R5 is pyridyl optionally substituted with one or more R5a, such compounds are referred to hereafter as compounds of formula XII.
In another embodiment, the invention provides the compound according to formula XII, wherein each RSa is independently -halogen, -Q-Qalkyl, -Q-Cehaloalkyl, -OR11, -COR11, -ON, -C(O)OR11, -C0N(Rn)2, or -N(Rπ)2.
In another embodiment, the invention provides the compound according to formula XII, wherein each R41 is independently hydrogen, halogen, -Q-Cealkyl, or -Q-Cehaloalkyl.
In another embodiment, the invention provides the compound according to formula XlI, whereinR2is -L3-R7, whereinL3 is abond or -C(R11 )2-; and
R7 is hydrogen, halogen, -Q-Qalkyl, -Q-Cehaloalkyl, -OR11", -C(O)R11", -C(O)OR11", -C(O)N(Rn")2, -N(Rn")2, -CN, -SO2R11", or -S(O)2N(R11"),, wherein each R11 is independently -H or -Ci-Qalkyl.
In another embodiment, the invention provides the compound according to formula XII, wherein each R4 is independently halogen -Q-Cealkyl, -Q-Cehaloalkyl, -COR11', -COOR11', -CON(Rn')2, -ON, -OR11', -N(Rn)2, -SO2R11', or -SO2N(Rn')2, wherein each R11 is independently -hydrogen, -C1-C6 alkyl, or -C1-C6 haloalkyl. In another embodiment, the invention provides the compound according to formula XII, wherein R21 is hydrogen, halogen, nitro, cyano, Q-Qalkyl, or Q-Qshaloalkyl.
In another embodiment, the invention provides the compound according to formula VHI, wherein L2 is -V2-[C(R15)2]n-, wherein n" is 0-3; and V2 is -O-, -S-, -OC(O)-, -OC(O)O-, or -OC(O)N(R10)-, such compounds are referred to hereafter as compounds of formula XEH.
In another embodiment, the invention provides the compound according to formula XEH, wherein each R5a is independently -halogen, -CrC6alkyl, -Q-Cehaloalkyl, -OR11, -COR11, -ON, -C(O)OR11, -CON(Rn)2, or -N(RU)2.
In another embodiment, the invention provides the compound according to formula XEH, wherein each R41 is independently hydrogen, halogen, -Ci-C6alkyl, or -Ci-Cδhaloalkyl.
En another embodiment, the invention provides the compound according to formula XEH, wherein R2 is -L3-R7, wherein L3 is a bond or -C(R11V? and
R7 is hydrogen, halogen, -Q-Cealkyl, -Q-Cehaloalkyl, -OR11", -C(O)R11", -C(O)OR11", -C(O)N(Rn")2, -N(Rn")2, -CN, -SO2R11", or -S(O)2N(R1 r)2, wherein each R11 is independently -H or -Q-Qalkyl.
In another embodiment, the invention provides the compound according to formula XEn, wherein each R4 is independently halogen -Q-Qalkyl, -CrQftaloalkyl, -COR11', -COOR11', -CON(Rπ')2, -C=N, -OR11', -N(Rn)2, -SO2R11', or -SO2N(RU')2, wherein each R11 is independently -hydrogen, -C1-C6 alkyl, or -C1-C6 haloalkyl.
En another embodiment, the invention provides the compound according to formula XEH, wherein R21 is hydrogen, halogen, nitro, cyano, Ci-C6alkyl, or Ci-Cδhaloalkyl. In another embodiment, the invention provides the compound according to formulas Ia-d, wherein K is absent; q is 1 ; and L2 is -V2-[C(R15)2]n-, wherein n is 0-6; and V2 is -0-, -S-, -SO2-, -CON(R10)-, -CON(R11)-, -CO-, -CO2-, -OC(O)-, -OC(O)O-, or -OC(O)N(R10)-; such compounds are referred to hereafter as compounds of formula XEV. In another embodiment, the invention provides the compound according to formula
XIV, wherein L2 is -CO-; and R4 is heterocyclyl optionally substituted with one or more groups which independently are -M wherein
M is -ϋ halogen, COR11, COOR11, ON, OR11, -NR11COR11, NR11SO2R11, SO2R11, SO2N(R11^5 Or SR11; such compounds are referred to hereafter as compounds of formula XV.
In another embodiment, the invention provides the compound according to formula XV, wherein each R5a is independently -halogen, -Q-C6alkyl, -Q-Qshaloalkyl, -OR11, -COR11, -ON, -C(O)OR11, -CON(Rπ)2, or -N(RU)2. In another embodiment, the invention provides the compound according to formula XV, wherein R2 is -L3-R7, wherein L3 is a bond or -C(R1 * )2-; and
R7 is hydrogen, halogen, -Q-Qalkyl, -CrCehaloalkyl, -OR11", -CO=O)R11", -C(=O)ORU", -C(O)N(Rn")2, -N(Rn")2, -CN, -SO2R11", or -S(O)2N(R11")^ wherein each R1 r is independently -H or -CrC6alkyl.
In another embodiment, the invention provides the compound according to formula XV, wherein each R41 is independently hydrogen, halogen, -Q-Qalkyl, or -Q-Cehaloalkyl.
In another embodiment, the invention provides the compound according to formula XV, wherein R21 is hydrogen, halogen, nitro, cyano, Ci-C6alkyl, or Q-Cehaloalkyl. In another embodiment, the invention provides the compound according to formula XTV, wherein L2 is -0-; and R4 is -E-M, wherein E is -[C(R15)2]m-; and
M is -H, halogen, -COR11, -COOR11, -CON(RU)2, -ON, -OR11, -0C0N(Rn)2, -OCO2-R11, -N(R11),; such compounds are referred to hereafter as compounds of formula XVI.
In another embodiment, the invention provides the compound according to formula XVI, wherein each R41 is independently hydrogen, halogen, -Ci-C6alkyl, or -CrCehaloalkyl.
In another embodiment, the invention provides tiie compound according to formula XVI, wherein each R5a is independently -halogen, CrC6alkyl, Q-Cehaloalkyl, -OR11, -COR11, -ON, -C(O)OR11, -C0N(Rπ)2, or -N(Rn)2.
In another embodiment, the invention provides the compound according to formula XVI, wherein R2 is -L3-R7, wherein L3 is a bond or -C(R1 r )2-; and
R7 is hydrogen, halogen, -C1-QaIkVl, -Ci-Cehaloalkyl, -OR11", -C(O)R11", -C(=0)0Ru", -C(=0)N(Rπ")2, -N(Rn")2, -CN, -SO2R11", or -S(O)2N(R11 "% ■ wherein each R1 l" is independently -H or -Q-Qalkyl.
In another embodiment, the invention provides the compound according to formula XVI, wherein R21 is hydrogen, halogen, nitro, cyano, CrQalkyL or Q-Cδhaloalkyl.
In another embodiment, the invention provides the compound according to formula XTV, wherein L2 is -V2-[C(R15)2]n-, wherein n is 0-6; and V2 is -CON(R11)- or -CO2-; and R4 is heterocyclyl, or -E-M, wherein E is -[C(R15)2]m-; and M is -H, halogen, -COR11, -COOR11, -CON(Rn)2, -C=N, -OR11, -OCON(R11^, -OCO2-R11, -N3, -NR11COR11, -NR11SO2R11, -N(Rπ)2, -NR11COOR11, -SO2R11, -SO2NR11COR11, -SO2N(Rπ)2, or -SR11; such compounds are referred to hereafter as compounds of formula XVlI. In another embodiment, the invention provides the compound according to formula XVH, wherein each R41 is independently hydrogen, halogen, -Q-Qalkyl, or -Q-Cδhaloalkyl.
In another embodiment, the invention provides the compound according to formula XVH, wherein each R5a is independently -halogen, -CrC6alkyl, -Q-Cehaloalkyl, -OR11, -COR11, -ON, -C(O)OR11, -C0N(Rπ)2, or -N(Rn)2. In another embodiment, the invention provides the compound according to formula XVTI, wherein R2 is -L3-R7, wherein L3 is a bond or -C(R1 r')2-; and
R7 is hydrogen, halogen, -Q-Qalkyl, -Q-Cehaloalkyl, -OR11", -C(=O)Rπ", -C(O)OR11", -C(=0)N(Rπ")2, -N(Rπ")2, -CN, -SO2R11", or -S(O)2N(R11"^, wherein each R11 is independently -H or -Q-Cδalkyl.; In another embodiment, the invention provides the compound according to formula XVH, wherein R21 is hydrogen, halogen, nitro, cyano, C1-QaIlCyI, or Q-Cijhaloalkyl.
In another embodiment, the invention provides the compound according to formulas Ia-d, wherein J is heteroaryl.
In another embodiment, the invention provides the compound according to formulas Ia-d, wherein J is thienyl, furyl, pyrrolyl, thiazoyl, oxazoyl, isothiazoyl, isoxazoyl, pyridyl, pyrimidinyl, or pyrazinyl.
In another embodiment, the invention provides the compound according to formulas Ia-d, wherein J is thienyl, furyl, pyrrolyl, thiazoyl, oxazoyl, isothiazoyl, isoxazoyl, pyridyl, pyrimidinyl, or pyrazinyl; and K is phenyl. In another embodiment, the invention provides the compound according to formulas Ia-d, wherein J is pyridyl.
In another embodiment, the invention provides the compound according to formulas Ia-d, wherein J is pyridyl; L1 is a bond; and R5 is phenyl optionally substituted with one or more R5a.
In another embodiment, the invention provides the compound according to formulas Ia-d, wherein J is pyridyl; L1 is a bond; R5 is phenyl optionally substituted with one or more R5a; and K is phenyl; such compounds are referred to hereafter as compounds of formula XVHI.
In another embodiment, the invention provides the compound according to formula XVHI, wherein each R41 is independently hydrogen, halogen, -Q-Qalkyl, or -Q-Cδhaloalkyl. In another embodiment, the invention provides the compound according to formula XVHI, wherein R2 is -L3-R7, wherein L3 is a bond or -C(R1 v )2-; and
R7 is hydrogen, halogen, -d-C6alkyl, -Q-Cehaloalkyl, -OR11", -C(=O)Rn", -C(O)OR11", -C(=0)N(Rn")2, -N(Rπ")2, -CN, -SO2R11", or -S(=O)2N(Rπ")2, wherein each R11 is independently -H or -Q-Cδalkyl.
In another embodiment, the invention provides the compound according to formula XVHI, wherein each R4 is independently halogen -Q-Qalkyl, -Q-Qhaloalkyl, -COR11', -COOR11', -CON(RU')2, -G=N, -OR11', -N(Rn)2, -SO2R11', or -SO2N(Rn')2, wherein each R11 is independently -hydrogen, -C1-C6 alkyl, or -C1-C6 haloalkyl. In another embodiment, the invention provides the compound according to formula XVHI, wherein each R5a is independently -halogen, -Ci-C6alkyl, -Q-Qshaloalkyl, -OR11, -COR11, -C=N, -C(O)OR11, -CON(RU)2, or -N(Rn)2.
In another embodiment, the invention provides the compound according to formula XVDI, wherein R21 is hydrogen, halogen, nitro, cyano, CrC6alkyl, or CrCshaloalkyl. In another embodiment, the invention provides the compound according to formulas Ia-d, wherein J is thienyl, furyl, or pyrroyl.
In another embodiment, the invention provides the compound according to formulas Ia-d, wherein J is thienyl.
In another embodiment, the invention provides the compound according to formulas Ia-d, wherein J is thienyl; K is phenyl; and L2 is a bond.
In another embodiment, the invention provides the compound according to formula XIX,
Figure imgf000041_0001
or a pharmaceutically acceptable salt, isomer, or prodrug thereof, wherein R1, R2, R21, R4, R41, L2, q, and q' are as defined in formulas Ia-d.
In another embodiment, the invention provides the compound according to fonnula XTX, wherein K is absent; and L2 is -SO2- or -CO-.
In another embodiment, the invention provides the compound according to formula XK, wherein K is absent; L2 is -SO2- or -CO-; and R4 is heterocyclyl, OR11, or -N(RU)2, wherein the heterocyclyl is optionally substituted with one or more -E-M', wherein E' is -[C(R15)2]m- or C3-C8 cycloalkyl;
M' is -H, halogen, COR11, COOR11, ON, OR11, -NR11COR11, NR11 SO2R11, SO2R11, SO2N(R11^ Or SR11. In another embodiment, the invention provides the compound according to formula XX,
Figure imgf000042_0001
or a pharmaceutically acceptable salt, isomer, or prodrug thereof, wherein R1, R2, R21, R4, R41, L2, q, and q' are as defined in formulas Ia-d. Ih another embodiment, the invention provides the compound according to formula XXI,
Figure imgf000042_0002
or a pharmaceutically acceptable salt, isomer, or prodrug thereof, wherein R , R , R , R , R , L , q, and q' are as defined in formulas Ia-d. In another embodiment, the invention provides the compound according to formula XXI,( wherein L1 is a bond; and R5 is phenyl optionally substituted with one or more R5a; such compounds are referred to hereafter as compounds of formula XXH.
In another embodiment, the invention provides the compound according to formula XXII, wherein each R5a is independently halogen, nitro, heterocyclyloxy, aryloxy, -C, -B'-C or -A'-B'-C wherein
A' is -O-; B' is -[C(R15)2]mS
C is -H, halogen, -SO2R11, -OR11, -SR11, -COR11, -SO2N(Rn)2, -SO2NR11COR11, -ON, -C(O)OR11, -OQK))R11, -C0N(Rπ)2, -CON(Rπ)ORπ, -0C0N(Rπ)2, -NR11COR11, -NRnC0N(Rn)2, -NR11COOR11, -N(Rn)2, aryl, heteroaryl, or heterocyclyl; wherein each R a is optionally substituted one or more groups which are independently C1-C6 alkyl, C3-C8 cycloalkyl, halogen, -C=N, -COR11, -COOR11, -C0N(Rπ)2> -SO2R11, -OR11, -SR11, -SO2R11, -SO2N(Rπ)2, -SO2NR11COR11, -0C0N(Rπ)2, -NR11COR11, -NRuC0N(Rπ)2, -NR11COOR11, or -N(R.n)2. In another embodiment, the invention provides the compound according to formula XXII, wherein each R5a is independently halogen, nitro, heterocyclyloxy, phenoxy, -C, -B'-C, or -A'-B'-C wherein A' is -O-; B' is -[C(R15)2]m-;
C is -H, halogen, -OR18, -COR18, -ON, -C(O)OR18, -0C(=0)R18, -CON(R18)2, -0C0N(R18;h, -NR18COR18, -NR18CON(R18)2, -NR18COOR18, -N(R18)2, or heterocyclyl; wherein each R18 is independently -H, -C1-C6 alkyl, -C1-C6 haloalkyl, -C3-Cg cycloalkyl, aryl, heteroaryl, or heterocyclyl; and wherein each R5a is optionally substituted one or more groups which are independently C1-C6 alkyl, halogen, -COR19, -COOR19, -CON(R19)2, -OR19, or -N(R19)2, wherein each R19 is independently -H or -Q-Cόalkyl; such compounds are referred to hereafter as compounds of formula XXIIa.
In another embodiment, the invention provides the compound according to formula XXH, wherein each R41 is independently hydrogen, halogen, -Q-Qalkyl, -Q-Oftaloalkyl, -COR16, -COOR16, -CON(R16)2, -ON, -OR16, or -N(R16)2, wherein each R16 is independently hydrogen, -C1-C6 alkyl, or -C1-C6 haloalkyl.
In another embodiment, the invention provides the compound according to formula XXII, wherein each R41 is independently hydrogen, halogen, -Ci-Qalkyl, or -CrCδhaloalkyl; such compounds are referred to hereafter as compounds of formula XXIIb.
In another embodiment, the invention provides the compound according to formula XXH, wherein each R4 is independently halogen, nitro, CR11^R11COOR11, -M, or -E-M, wherein E is -[C(R15)2]m- or C3-C8 cycloalkyl;
M is Ci-C6alkyl, Q-Cehaloalkyl, -COR11, -COOR11, -CON(Rn)2, -ON, -OR11, -0C0N(R.u)2, -OCO2-R11, -NR11COR11, -NR11SO2R11, -N(RU)2, -NR11COOR11, -SO2R11, -SO2NR11COR11, -SO2N(R11^ Or-SR11. In another embodiment, the invention provides the compound according to formula XXDL, wherein each R4 is independently halogen, CR11K]R11COOR11', -M, or -E-M, wherein E is -[C(R15)2]m- or C3-C8 cycloalkyl; M is Ci-Cealkyl, Q-Cehaloalkyl, -COR11', -COOR11', -CON(Rπ')2, -ON, -OR11', -NR11O2R11', -N(Rπ')2, -SO2R11', -SO2NR11COR11', or -SO2N(Rπ')2, wherein each R11' is independently -hydrogen, -C1-C6 alkyl, or -C1-C6 haloalkyl, wherein any of R11' is optionally substituted with one or more radicals of R12'; each R12 is independently halogen, CrCehaloalkyl, C1-C6 alkyl, C1-C6 alkoxy,
C=O(OR13), COR13, SO2R13, CON(R13)2, SO2N(R13)2, or -N(R13)2; such compounds are referred to hereafter as compounds of formula XXIIc.
In another embodiment, the invention provides the compound according to formula XXII, wherein R2 is -L3-R7, wherein L3 is a bond or -(CE2)^-(CH2X- wherein m" is 0-3; n is 0-3; and V1 is -C(RU)2-, -O-, -S-, -NR7-, -CO-, -CO2-, -OC(O)-, or -SO2-; and
R7 is hydrogen, halogen, nitro, aryl, heteroaryl, heterocyclyl, -Q-Qalkyl, -Q-Cehaloalkyl, -C2-C6 alkenyl, C3-C8 cycloalkyl, or -(C(R15)2)m-Z, wherein Z is -OR11, -C(O)R11, -C(O)OR11, -C(O)N(Rπ)2, -N(Rn)2, -CN, -SO2R11,
-S(O)2N(Rπ)2, -C(O)N(R11)N(R11)2, -C(O)N(R1^(OR1 \ -OC(O)-R11, or -OC(O)-N(R11),, wherein R7 is optionally substituted with one or more R7a, wherein
R7a is halogen, CrC6alkyl, CrCehaloalkyl, -OR20, -C(O)R20, -C(O)OR20, -C(O)N(R20)2, -N(R20)2, -N(TR2^C(O)R20, or -CN, wherein each R20 is independently -H or CrC6alkyl.
In another embodiment, the invention provides the compound according to formula XXII, wherein R2 is -L3-R7, wherein
L3 is a bond or -(CU2)^-V1 -(CH2)n- wherein m" is 0-1; n is 0-2; and V1 is -CH2-, -0-, -S-, or -NR7-; and
R7 is hydrogen, halogen, phenyl, heteroaryl, heterocyclyl, -Q-C6alkyl, -CrCehaloalkyl, -C2-C6 alkenyl, C3-C8 cycloalkyl, or -(C(R15)2)m-Z, wherein
Z is -OR11", -C(O)R11", -C(O)OR11", -C(O)N(R1 r')2, -N(Rπ")2, -CN, or -SO2R11", wherein R7 is optionally substituted with one or more R7a, wherein R7a is halogen, Q-Qalkyl, Q-Cehaloalkyl, -OR11'', -N(Rπ")2, -COOR11", wherein each R11" is independently -H, -Q-Qalkyl, -Q-Cehaloalkyl, heterocyclyl, or heteroaryl; such compounds are referred to hereafter as compounds of formula XXHd. In another embodiment, the invention provides the compound according to formula XXII, wherein R2 is -L3-R7, wherein L3 is a bond; and
R7 is hydrogen, halogen, -C1-C3OIkVl, -Q-Qhaloalkyl, or -(C(R15)2)-Z, wherein
Z is -OR11" or -SO2R11", whereinR11" is -H or CrC6alkyl. In another embodiment, the invention provides the compound according to formula XXIIa, wherein each R41 is independently hydrogen, halogen, -CrQalkyl, or -Ci-Cδhaloalkyl; such compounds are referred to hereafter as compounds of formula XXIIe.
In another embodiment, the invention provides the compound according to formula XXUb, wherein each R4 is independently halogen, CRu'=CRu'COORπ', -M, or -E-M, wherein E is -[C(R15)2]m- or C3-C8 cycloalkyl;
M is CrCealkyl, d-Cehaloalkyl, -COR11', -COOR11', -CON(Rπ')25 -C≡N, -OR11', -NR11' SO2R11', -N(Rn')2, -SO2R11', -SO2NR11COR11', or -SO2N(Rn')2, wherein each R11 is independently -hydrogen, -C1-C6 alkyl, or -C1-C6 haloalkyl, wherein each R11 is optionally substituted with one or more radicals of R12 ; each R12' is independently halogen, C1-C6 haloalkyl, C1-C6 alkyl, C1-C6 alkoxy, C=O(OR13), COR13, SO2R13, CON(R13)2, or -N(R13)2; such compounds are referred to hereafter as compounds of formula XXHf.
In another embodiment, the invention provides the compound according to formula XXHc, wherein R2 is -L3-R7, wherein L3 is a bond or -(CΑ2)πrVι -(CR2)*- wherein m" is 0-1; n is 0-2; and V is -CH2-, -0-, -S-, or -NR7-; and
R7 is hydrogen, halogen, phenyl, heteroaryl, heterocyclyl, -Q-C6alkyl, -CrCehaloalkyl, -C2-C6 alkenyl, C3-C8 cycloalkyl, or -(C(R15)2)m-Z, wherein
Z is -OR11, -C(=0)Rn", -C(=O)ORn", -CC=O)N(R1 r')2, -N(Rn")2, -CN, or -SO2R11", wherein R7 is optionally substituted with one or more R7a, wherein
R7a is halogen, CrC6alkyl, CrCehaloalkyl, -OR11", -N(RU")2, -COOR11", wherein R11 is -H, -CrCealkyl, -Q-Cehaloalkyl, heterocyclyl, or heteroaryl; such compounds are referred to hereafter as compounds of formula XXHg.
In another embodiment, the invention provides the compound according to formula XXIId, wherein each R5a is independently halogen, nitro, heterocyclyloxy, phenoxy, -C, -B'-C, or -A'-B'-C wherein A' is -O-; B' is -[C(R15)2]m-; C is -H, halogen, -OR18, -COR18, -C=N, -C(O)OR18, -OC(O)R18, -CON(R18)2, -OCON^18^, -NR18COR18, -NR18CON(R18)2, -NR18COOR18, -N(R18)2, or heterocyclyl; wherein each R18 is independently -H, -C1-C6 alkyl, -C1-C6 haloalkyl, -C3-C8 cycloalkyl, aryl, heteroaryl, or heterocyclyl; and wherein each R5a is optionally substituted one or more groups which are independently
C1-C6 alkyl, halogen, -COR19, -COOR19, -CON(R19)2, -OR19, or -N(R19)2, wherein R19 is -H or -Q-Qalkyl; such compounds are referred to hereafter as compounds of formula XXHi.
In another embodiment, the invention provides the compound according to formula XXIIe, wherein eachR4 is independently halogen, CR^=CR11COOR11, -M or -E-M, wherein E is -[C(R15)2]m- or C3-C8 cycloalkyl;
M is Q-Qalkyl, CrCehaloalkyl, -COR11', -COOR11', -C0N(Rn')2, -C=N, -OR11', -NR11O2R11', -N(Rπ')2, -SO2R11', -SO2NR11COR11', or -SO2N(Rir)2, wherein each R11' is independently -hydrogen, -C1-C6 alkyl, or -C1-C6 haloalkyl, wherein any of R1 ! is optionally substituted with one or more radicals of R12 ; each R12 is independently halogen, Q-Cόhaloalkyl, C1-C6 alkyl, C1-C6 alkoxy, C=O(OR13), COR13, SO2R13, CON(R13)2, SO2N(R13)2, or -N(R13)2; such compounds are referred to hereafter as compounds of formula XXHi.
In another embodiment, the invention provides the compound according to formula XXDf, wherein R2 is -L3-R7, wherein L3 is a bond or -(CB^W-V^CHaV wherein m" is 0-1 ; n is 0-2; and V1 is -CH2-, -0-, -S-, or -NR7-; and
R7 is hydrogen, halogen, phenyl, heteroaryl, heterocyclyl, -Q-Cealkyl, -Q-Cδhaloalkyl, -C2-C6 alkenyl, C3-C8 cycloalkyl, or -(C(R15)2)m-Z, wherein
Z is -OR11", -C(O)R11", -C(O)OR11", -C(O)N(R1 r)2, -N(Rn")2, -CN, or -SO2R11", wherein R7 is optionally substituted with one or more R7a, wherein
R7a is halogen, CrC6alkyl, Q-Cghaloalkyl, -OR11", -N(Rn")2, -COOR11", wherein R11' is -H, -Ci-C6alkyl, -CrCehaloalkyl, heterocyclyl, or heteroaryl. In another embodiment, the invention provides the compound according to formula XXHg, wherein each R5a is independently halogen, nitro, heterocyclyloxy, phenoxy, -C, -B'-C, or -A'-B'-C wherein A' is -O-;
B' is -[C(R15)2]m-;
C is -H, halogen, -OR18, -COR18, -C=N, -C(O)OR18, -OC(O)R18, -CON(R18)2, -OCON(R18)2,
-NR18COR18, -NR18CON(R18)2, -NR18COOR18, -N(R18)2, or heterocyclyl; wherein each R18 is independently -H, -C1-C6 alkyl, -C1-C6 haloalkyl, -C3-C8 cycloalkyl, aryl, heteroaryl, or heterocyclyl; and wherein each R5a is optionally substituted one or more groups which are independently C1-C6 alkyl, halogen, -COR19, -COOR19, -CON(R19)2, -OR19, or -N(R19)2, wherein R19 is -Hor-CrCealkyl.
In another embodiment, the invention provides the compound according to formula XXIIh, wherein each R41 is independently hydrogen, halogen, -Q-Qalkyl, or -Q-Cehaloalkyl.
In another embodiment, the invention provides the compound according to formula XXlIi, wherein R2 is -L3-R7, wherein L3 is a bond or -(CH2V-V1 -(CH2)n- wherein m" is 0-1; n is 0-2; and V1 is -CH2-, -O-, -S-, or -NR7-; and
R7 is hydrogen, halogen, phenyl, heteroaryl, heterocyclyl, -Q-Cόalkyl, -Q-Cehaloalkyl, -C2-C6 alkenyl, C3-C8 cycloalkyl, or -(C(R15)2)m-Z, wherein
Z is -OR11", -C(O)R11", -C(=O)ORn", -C(K))N(R1 \ -N(Rπ")2, -CN, or -SO2R11", wherein R7 is optionally substituted with one or more R7a, wherein R7a is halogen, Q-Qalkyl, Q-Cehaloalkyl, -OR11", -N(Rπ")2, -COOR11", wherein R11 is -H, -Q-Cealkyl, -Q-Cδhaloalkyl, heterocyclyl, or heteroaryl. In another embodiment, the invention provides the compound according to formula XXII, wherein R is hydrogen, halogen, nitro, cyano, aryl, heteroaryl, heterocyclyl, -C1-C6 alkyl-heterocyclyl, -C1-C6 alkyl-heteroaryl, -C1-C6 alkyl-aryl, -Z, -Y-Z, or -X-Y-Z, wherein X is -O-;
Y is -[C(R15)2]m-, -C2-C6 alkenyl, or C3-C8 cycloalkyl;
Z is -H, -CN, halogen, -OR11, -QK))R11, -C(O)OR11, -C(O)N(Rn)2, -N(RU)2, -CN, -N3, -SO2R11, -S(O)2N(Rn)2, -C(=O)N(Rn)N(Ru)2, -C(O)N(R11XOR11), -OC(O)-R11, -0C(O)-N(Ru)2, or -N(R1 ^COOR1 *; In another embodiment, the invention provides the compound according to formula XXII, wherein R21 is hydrogen, halogen, nitro, cyano, CrCβalkyl, or Q-Cόhaloalkyl.
In another embodiment, the invention provides the compound according to any of formulas XXπa-XXπi, wherein R21 is hydrogen, halogen, nitro, cyano, Q-Cόalkyl, or Ci-Cehaloalkyl.
In another embodiment, the invention provides the compound according to formula XXI, wherein
R1 is -L^R5, wherein
L1 is -L5- or -L6-, wherein each L5 is -C(R15)2-> wherein each R15 is independently hydrogen, halogen, (Q-C^alkyl, or (Q-QOhaloalkyl; and L6 is -CS-, -CO-, or -SO2-; and
R5 is aryl or heteroaryl optionally substituted with one or more R5a. In another embodiment, the invention provides the compound according to formula XXI, wherein R1 is -iΛR5, wherein
L1 is -L5- or -L6-, wherein each L5 is -C(R15)2-, wherein each R15 is independently hydrogen, halogen, (Q-C6)alkyl, or (Q-Ce^aloalkylj and
L6 is -CS-, -CO-, or -SO2-; and
R5 is phenyl, thienyl, furyl, pyrrolyl, thiazoyl, oxazoyl, isothiazoyl, isoxazoyl, pyridyl, pyrimidinyl, or pyrazinyl optionally substituted with one or more R5a; such compounds are referred to hereafter as compounds of formula XXIII. In another embodiment, the invention provides the compound according to formula
XXIII, wherein R2 is -L3-R7, wherein L3 is a bond or -C(Rπ")2-; and
R7 is hydrogen, halogen, -CrC6alkyl, -Q-Cshaloalkyl, -OR11", -C(=O)Rπ", -C(O)OR11", -C(=O)N(RU")2, -N(RU")2, -CN, -SO2R11", or -SeO)2N(R1 r')2, wherein each R11" is independently -H or -Q-C6alkyl. In another embodiment, the invention provides the compound according to formula XXDI, wherein each R5a is independently -halogen, -Q-Qalkyl, -Q-Cehaloalkyl, -OR11, -COR11, -ON, -C(O)OR11, -CON(Rπ)2, or -N(RU)2.
In another embodiment, the invention provides the compound according to formula XXffi, wherein each R41 is independently hydrogen, halogen, -Q-Cδalkyl, or -Q-Cόhaloalkyl. In another embodiment, the invention provides the compound according to formula XXDI, wherein each R4 is independently halogen -Q-Qsalkyl, -Q-Qhaloalkyl, -COR11', -COOR11', -C0N(Rπ')2, -ON, -OR11', -N(RU')2, -SO2R11', or -SO2N(Rπ')2, wherein each R11' is independently -hydrogen, -C1-C6 alkyl, or -C1-C6 haloalkyl.
In another embodiment, the invention provides the compound according to formula XXIII, wherein R21 is hydrogen, halogen, nitro, cyano, CrQalkyl, or Q-Cehaloalkyl.
In another embodiment, the invention provides the compound according to formula XXI, wherein L1 is a bond; and R5 is heteroaryl optionally substituted with one or more R5a. In another embodiment, the invention provides the compound according to formula XXI, wherein L1 is a bond; and R5 is thienyl, furyl, pyrrolyl, thiazoyl, oxazoyl, isothiazoyl, isoxazoyl, pyridyl, pyrimidinyl, or pyrazinyl optionally substituted with one or more R5a.
In another embodiment, the invention provides the compound according to formula XXI, wherein L1 is a bond; and R5 is thienyl, furyl, pyrrolyl, thiazoyl, oxazoyl, isothiazoyl, or isoxazoyl optionally substituted with one or more R5a; such compounds are referred to hereafter as compounds of formula XXTV.
In another embodiment, the invention provides the compound according to formula XXIV, wherein each R5a is independently -halogen, -Ci-C6alkyl, -Ci-Qhaloalkyl, -OR11, -COR11, -C=N, -C(O)OR11, -CON(Rπ)2, or -N(Rπ)2.
In another embodiment, the invention provides the compound according to formula XXIV, wherein each R4 is independently halogen -Q-Qalkyl, -Q-Qhaloalkyl, -COR11', -COOR11', -CON(Rπ)2, -C≡N, -OR11', -N(Rπ)2, -SO2R11', or -SO2N(Rπ')2, wherein each R11' is independently -hydrogen, -C1-C6 alkyl, or -C1-C6 haloalkyl. In another embodiment, the invention provides the compound according to formula XXTV, wherein R2 is -L3-R7, wherein L3 is a bond or -C(R11 )2-; and
R7 is hydrogen, halogen, -Q-Qalkyl, -Q-Qhaloalkyl, -OR11", -C(=O)Rπ", -C(O)OR11", -C(=0)N(Rπ")2, -N(Rn")2, -CN, -SO2R11'', Or-S(O)2N(R11"^, wherein each R11 is independently -H or -Q-Qalkyl. In another embodiment, the invention provides the compound according to formula XXTV, wherein each R41 is independently hydrogen, halogen, -C1-QaIlCyI, or -Q-Qhaloalkyl.
In another embodiment, the invention provides the compound according to formula XXTV, wherein R21 is hydrogen, halogen, nitro, cyano, Q-Qalkyl, or Q-Qhaloalkyl.
In another embodiment, the invention provides the compound according to formula XXI, wherein L1 is a bond; and R5 is pyridyl, pyrimidinyl, or pyrazinyl optionally substituted with one or more R5a such compounds are referred to hereafter as compounds of formula XXV.
In another embodiment, the invention provides the compound according to formula XXV, wherein each R5a is -halogen, -Q-Qalkyl, -Q-Qhaloalkyl, -OR11, -COR11, -CNN, -C(O)OR11, -CON(Rπ)2, or-N(Rπ)2. In another embodiment, the invention provides the compound according to formula XXV, wherein each R4 is independently halogen -Q-Qalkyl, -Q-Qhaloalkyl, -COR11', -COOR11', -CON(Rπ')2, -CNN, -OR11', -N(Rπ)2, -SO2R11', or -SO2N(Rπ')2, wherein each R11' is independently -hydrogen, -C1-C6 alkyl, or -Ci-C6 haloalkyl. In another embodiment, the invention provides the compound according to formula XXV, wherein R2 is -L3-R7, wherein L3 is a bond; and
R7 is hydrogen, halogen, -Q-Qalkyl, -Q-Cδhaloalkyl, -C2-C6 alkenyl, C3-C8 cycloalkyl, or -(C(R15KW-Z, wherein m' is 0-1; and Z is -OR11, -C(=O)Rn, -C(O)OR11, -C(O)N(R11^, -N(Rπ)2, -CN, or -SO2R11, wherein R11 is -H or Ci-Cealkyl.
In another embodiment, the invention provides the compound according to formula XXV, wherein each R41 is independently hydrogen, halogen, -Q-Qalkyl, or -Q-Cόhaloalkyl.
In another embodiment, the invention provides the compound according to formula XXV, wherein R21 is hydrogen, halogen, nitro, cyano, CrC6alkyl, or Q-Cόhaloalkyl.
In another embodiment, the invention provides the compound according to formula XTX, wherein K is heteroaryl; and L2 is a bond. In another embodiment, the invention provides the compound according to formula XTX, wherein K is thienyl, furyl, pyrrolyl, thiazoyl, oxazoyl, isothiazoyl, isoxazoyl, pyridyl, pyrimidinyl, or pyrazinyl; and L2 is a bond.
In another embodiment, the invention provides the compound according to formula XTX, wherein K is pyridyl; and L2 is a bond. In another embodiment, the invention provides the compound according to formula XTX, wherein K is pyridyl; L2 is a bondjL1 is a bond; and
R5 is phenyl optionally substituted with one or more R5a.
In another embodiment, the invention provides the compound according to formula XXVI,
Figure imgf000050_0001
or a pharmaceutically acceptable salt, isomer, or prodrug thereof, wherein R1, R2, R21, R4, R41, L2, q, and q' are as defined in formulas Ia-d.
In another embodiment, the invention provides the compound according to formula XXVH,
Figure imgf000051_0001
or a pharmaceutically acceptable salt, isomer, or prodrug thereof, wherein R1, R2, R21, R4, R41, L2, q, and q' are as defined in formulas Ia-d. In another embodiment, the invention provides the compound according to formula XXVIII,
Figure imgf000051_0002
or a pharmaceutically acceptable salt, isomer, or prodrug thereof, wherein R1, R2, R21, R4, R41, L2, q, and q' are as defined in formulas Ia-d. In another embodiment, the invention provides the compound according to formula XXVm, wherein each R5a is -halogen, -CrQalkyl, -Q-Cόhaloalkyl, -OR11, -COR11, -ON, -C(O)OR11, -CON(Rn)2, or-N(Ru)2.
In another embodiment, the invention provides the compound according to formula XXVHI, wherein each R41 is independently hydrogen, halogen, -Q-Cealkyl, or -Ci-Cόhaloalkyl. In another embodiment, the invention provides the compound according to formula XXVHI, wherein each R4 is independently halogen -CrC6alkyl, -Q-Cehaloalkyl, -COR11', -COOR11', -CON(Rn')2, -C=N, -OR11', -N(Rn)2, -SO2R11', or -SO2N(Rn')2, wherein each R11' is independently -hydrogen, -C1-C6 alkyl, or -C1-C6 haloalkyl.
In another embodiment, the invention provides the compound according to formula XXVHI, wherein R2 is -L3-R7, wherein L3 is a bond or -C(R11Vs and
R7 is hydrogen, halogen, -Ci-C6alkyl, -Q-Cehaloalkyl, -OR11", -C(O)R11", -C(=0)0Rn", -C(=0)N(Rn")2, -N(RU")2, -CN, -SO2R11", or -S(=O)2N(Rπ")2, wherein each R11" is independently -H or -Q-Qalkyl.
In another embodiment, the invention provides the compound according to formula XXVIH, wherein R21 is hydrogen, halogen, nitro, cyano, Q-C6alkyl, or CrQhaloalkyl. In another embodiment, the invention provides the compound according to formula Ia-d, wherein J is aryl or heteroaryl.
In another embodiment, the invention provides the compound according to formula Ia-d, wherein J is phenyl, pyridyl, thienyl, pyrrolyl, furanyl, pyrimidinyl, pyrazinyl, imidazoyl, pyrazoyl, oxazoyl, thiazoyl, isoxazoyl, isothiazoyl, triazoyl, triazinyl, tetrazoyl, or tetrazinyl.
In another embodiment, the invention provides the compound according to formula Ia-d, wherein J is phenyl, pyridyl, thienyl, pyrrolyl, or furanyl.
In another embodiment, the invention provides the compound according to formula Ia-d, wherein J is phenyl, pyridyl, or thienyl. In another embodiment, the invention provides the compound according to formula Ia-d, wherein J is phenyl.
In another embodiment, the invention provides the compound according to formula Ia-d, wherein J is pyridyl.
In another embodiment, the invention provides the compound according to formula Ia-d, wherein J is thienyl.
In another embodiment, the invention provides the compound according to formula Ia-d, wherein K is aryl or heteroaryl.
In another embodiment, the invention provides the compound according to formula Ia-d, wherein K is phenyl, pyridyl, thienyl, pyrrolyl, furanyl, pyrimidinyl, pyrazinyl, imidazoyl, pyrazoyl, oxazoyl, thiazoyl, isoxazoyl, isothiazoyl, Mazoyl, triazinyl, tetrazoyl, or tetrazinyl.
In another embodiment, the invention provides the compound according to formula Ia-d, wherein K is phenyl, pyridyl, thienyl, pyrrolyl, or furanyl.
In another embodiment, the invention provides the compound according to formula Ia-d, wherein K is phenyl or pyridyl. In another embodiment, the invention provides the compound according to formula Ia-d, wherein K is pyridyl.
In another embodiment, the invention provides the compound according to formula Ia-d, wherein K is phenyl.
In another embodiment, the invention provides the compound according to formula Ia-d, wherein L2 is a bond.
In another embodiment, the invention provides the compound according to formula Ia-d, wherein J is aryl or heteroaryl; and K is aryl or heteroaryl.
In another embodiment, the invention provides the compound according to formula Ia-d, wherein J is aryl or heteroaryl; K is aryl or heteroaryl; and L2 is a bond. In another embodiment, the invention provides the compound according to formula Ia-d, wherein
J is phenyl, pyridyl, thienyl, pyrrolyl, furanyl, pyrimidinyl, pyrazinyl, imidazoyl, pyrazoyl, oxazoyl, thiazoyl, isoxazoyl, isothiazoyl, triazoyl, triazinyl, tetrazoyl, or tetrazinyl;
K is phenyl, pyridyl, thienyl, pyrrolyl, furanyl, pyrimidinyl, pyrazinyl, imidazoyl, pyrazoyl, oxazoyl, thiazoyl, isoxazoyl, isothiazoyl, triazoyl, triazinyl, tetrazoyl, or tetrazinyl; and L2 is a bond. In another embodiment, the invention provides the compound according to formula Ia-d, wherein J is phenyl, pyridyl, thienyl, pyrrolyl, or furanyl; K is phenyl, pyridyl, thienyl, pyrrolyl, or furanyl; and L2 is a bond.
In another embodiment, the invention provides the compound according to formula Ia-d, wherein J is phenyl, pyridyl, or thienyl; K is phenyl or pyridyl; and L2 is a bond. In another embodiment, the invention provides the compound according to formula Ia-d, wherein J is phenyl; K is phenyl; and L2 is a bond.
In another embodiment, the invention provides the compound according to formula Ia-d, wherein J is pyridyl; K is phenyl; and L2 is a bond.
In another embodiment, the invention provides the compound according to formula Ia-d, wherein J is thienyl; K is phenyl; and L2 is a bond.
In another embodiment, the invention provides the compound according to formula Ia-d, wherein J is phenyl; K is pyridyl; and L2 is a bond.
In another embodiment, the invention provides the compound according to formula Ia-d, wherein J is pyridyl; K is pyridyl; and L2 is a bond. In another embodiment, the invention provides the compound according to formula Ia-d, wherein J is thienyl; K is pyridyl; and L is a bond.
In another embodiment, the invention provides the compound according to formula Ia-d, wherein R5 is aryl, heterocyclyl, or heteroaryl, wherein R5 is optionally substituted with one or more RSa. In another embodiment, the invention provides the compound according to formula Ia-d, wherein R5 is aryl or heteroaryl, wherein R5 is optionally substituted with one or more R5a.
In another embodiment, the invention provides the compound according to formula Ia-d, wherein R5 is phenyl, pyridyl, thienyl, pyrrolyl, furanyl, pyrimidinyl, pyrazinyl, imidazoyl, pyrazoyl, oxazoyl, thiazoyl, isoxazoyl, isothiazoyl, triazoyl, triazinyl, tetrazoyl, or tetrazinyl wherein R5 is optionally substituted with one or more R5a. In another embodiment, the invention provides the compound according to formula Ia-d, wherein L1 is a bond; and R5 is phenyl, pyridyl, thienyl, pyrrolyl, furanyl, pyrimidinyl, pyrazinyl, imidazoyl, pyrazoyl, oxazoyl, thiazoyl, isoxazoyl, isothiazoyl, triazoyl, triazinyl, tetrazoyl, or tetrazinyl, wherein R5 is optionally substituted with one or more R5a. In another embodiment, the invention provides the compound according to formula Ia-d, wherein L1 is a bond; and R5 is phenyl, pyridyl, thienyl, pyrrolyl, or furanyl, wherein R5 is optionally substituted with one or more R5a.
In another embodiment, the invention provides the compound according to formula Ia-d, wherein L1 is a bond; and R5 is phenyl optionally substituted with one or more R5a. In another embodiment, the invention provides the compound according to formula Ia-d, wherein L1 is a bond; and R5 is pyridyl optionally substituted with one or more R5a.
In another embodiment, the invention provides the compound according to formula Ia-d, wherein L1 is a bond; and R5 is thienyl optionally substituted with one or more R5a.
In another embodiment, the invention provides the compound according to formula Ia-d wherein R21 is hydrogen, halogen, nitro, cyano, aryl, heteroaryl, heterocyclyl, -C1-C6 alkyl-heterocyclyl, -C1-C6 alkyl-heteroaryl, -C1-C6 alkyl-aryl, -Z, -Y-Z, or -X-Y-Z, wherein Xis -O-;
Y is -[C(R15)2]m-, -C2-C6 alkenyl, or C3-C8 cycloalkyl;
Z is -H, -CN, halogen, -OR11, -C(O)R11, -C(O)OR11, -C(O)N(R11^, -N(RU)2, -CN, -N3, -SO2R11, -S(O)2N(RU)2, -C(O)N(R1 ^N(R1 \ -C(O)N(R11XOR11),
-OC(O)-R11, -0C(O)-N(Ru)2, or -N(Rn)COORu.
In another embodiment, the invention provides the compound according to formula Ia-d wherein R21 is hydrogen, halogen, nitro, cyano, C1-QaIlCyI, or CrQhaloalkyl.
In another embodiment, the invention provides the compound according to formula XXKa-d wherein R3 is hydrogen, aryl, heteroaryl, heterocyclyl, -C1-C6 alkyl-heterocyclyl, -C1-C6 alkyl-heteroaryl, -C1-C6 alkyl-aryl, -Z, or -Y-Z wherein
Y is -[C(R15)2]m-, -C2-C6 alkenyl, or C3-C8 cycloalkyl;
Z is -H, -CN, halogen, -OR11, -C(O)R11, -C(O)OR11, -C(O)N(RU)2, -N(RU)2, -CN, -N3, -SO2R11, -S(O)2N(Rn)2, -C(O)N(Rπ)N(Rπ)2, -C(O)N(Ru)(0Rπ), -OC(O)-R11, -0C(O)-N(Rπ)2, or -N(Rπ)COORn.
In another embodiment, the invention provides the compound according to formula Ia-d wherein R3 is hydrogen, CrC6alkyl, or CrCehaloalkyl.
In another embodiment, the invention provides the compound according to any of the formulas Ia-d, π-XXViπ, wherein R2 is -L3-R7, wherein L3 is a bond; and R7 is hydrogen, halogen, -Z, or -Y-Z, wherein Y is -[C(R15')2]m- or C2-C6alkenyl, wherein each R15' is independently H, halogen, or (Q-QOalkyl; and Z is -H, halogen, -OR11, -C(O)R11, -QK))OR11, -C(O)N(R11^, -Q=N-OH)R11, or -C(=S)N(Rπ)2. hi another embodiment, the invention provides the compound according to any of the formulas Ia-d, π-XXVm, wherein R2 is -L3-R7, wherein L3 is a bond; and R7 is hydrogen, halogen, or -[C(R15 )2]-Z, wherein each R15 is independently H, halogen, or (Q-C^alkyl; and Z is -H, halogen, -OR11", -C(O)R11", -C(O)OR11", -C(O)N(Rπ")2, -Q=N-OH)R1 \ or
-C(=S)N(Rπ")2, wherein R11" is -H or -(C1-C6 alkyl).
In another embodiment, the invention provides the compound according to any of the formulas Ia-d, π-XXVm, wherein R2 is -halogen, -CF3, -CH2OH, -CH2SO2Me, -C(CH3)2OH, or -C(CH3)2SO2Me. hi another embodiment, the invention provides the compound according to any of the formulas Ia-d, π-XXVm, wherein R2 is -halogen, -CF3, -CH2OH, or -C(CH3)2OH. hi another embodiment, the invention provides the compound according to any of the formulas Ia-d, π-XXVm, wherein R2 is -CF3 or -C(CHs)2OH. hi another embodiment, the invention provides the compound according to any of the formulas
Ia-d, π-XXVm, wherein each R4 is independently halogen, aryl, heteroaryl, heterocyclyl, -M, or -E-M, wherein E is -[C(R15')2]m-, wherein each R15 is independently hydrogen or halogen; and M is -Q-C6alkyl, -Q-Cehaloalkyl, halogen, -OR11, or -SO2R11.
In another embodiment, the invention provides the compound according to any of the formulas Ia-d, II-XXVIII, wherein each R4 is independently halogen, -CH2- M, -C(H)(F)- M, -CF2-M, wherein
M is -CrCealkyl, -Q-Cehaloalkyl, -F, -OR11', or -SO2R11' whereinR11' is -H or -Q-Qalkyl. hi another embodiment, the invention provides the compound according to any of the formulas Ia-d, H-XXVHI, wherein each R4 is independently -CH3, -CF3, -CF2H, -CH2F, -OH, -OMe, -CH2OH, or -SO2(C1-C3alkyl). In one embodiment, the invention provides the compound according to any of the formulas Ia-d, π-XXViπ, whereineach R41 is independently halogen, -M", or-E"-M", wherein E" is -[QR15')2]m-, wherein each R15 is independently hydrogen or halogen; and M" is -CrQalkyl, -Q-Cehaloalkyl, or halogen.
In another embodiment, the invention provides the compound according to formulas Ia-d, π-XXVTH, wherein each R41 is independently halogen, methyl or trifluoromethyl.
In another embodiment, the invention provides the compound according to formulas Ia-d, II-IV, VI-DC, Xm, XrV-XVΗ, and XK-XXI wherein R1 is -L5-Rs or-L6-R5 wherein
L5 is -[C(R15)2]m-;
L6 is C3-Cg cycloalkyl, cycloQ-shaloalkyl, or heterocyclyl, wherein the cycloalkyl, cycloCs-ghaloalkyl 1, or heterocyclyl are optionally substituted with one or more radicals ofR14; R5 is aryl, heterocyclyl, or heteroaryl, wherein R5 is optionally substituted with one or more R5a, wherein each R5a is independently halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, (C3-C8 CyClOaIlCyI)-C1-C6 alkyl-, (C3-C8 cycloalkenyl)-CrC6 alkyl-, (C3-C8 cycloalkyl)-C2-C6 alkenyl-, nitro, heterocyclyloxy, aryl, aryloxy, arylalkyl, aryloxyaryl, aryl Q-Q alkoxy, -C, -B'-C, or -A'-B'-C wherein
A' is -O-;
B' is -[C(R15)2]m- or - C3-C8 cycloalkyl -;
C is -H, halogen, -SO2R11, -OR11, -SR11, -N3, -COR11, -SO2N(R11^,
-SO2NR11COR11, -ON, -C(O)OR11, -OC(O)R11, -CON(RU)2, -CON(R11PR11, -0C0N(Rn)2, -NR11COR11, -NR11CON(R1 %,
-NR11COOR11, -N(Rπ)2, aryl, heteroaryl, or heterocyclyl.
In another embodiment, the invention provides the compound according to formulas Ia-d, π-XXViπ, wherein R21 is hydrogen, halogen, nitro, cyano, aryl, heteroaryl, heterocyclyl, -C1-C6 alkyl-heterocyclyl, -C1-C6 alkyl-heteroaryl, -Ci-C6 alkyl-aryl, -Z, -Y-Z, or -X-Y-Z, wherein Xis -O-;
Y is -[C(R15)2]m-, -C2-C6 alkenyl, or C3-C8 cycloalkyl; Z is -H, -CN, halogen, -OR11, -C(=O)RU, -C(=O)ORn, -C(O)N(R11^, -N(Rπ)2, -CN, -N3, -SO2R11, -S(=O)2N(Rn)2, -CKONfR11^11^ -C(O)N(R11XOR11), -0C(=0)-Rπ, -0C(=0)-N(Rπ)2, or -N(R11XX)OR11.
In another embodiment, the invention provides the compound according to formulas Ia-d, π-XXViπ, wherein R21 is hydrogen, halogen, nitro, cyano, CrQalkyl, or Q-Cehaloalkyl.
In another embodiment, the invention provides Hie compound according to forøiulas Ia-d, π-XXViπ, and XL wherein R21 is hydrogen.
In a second aspect, the invention provides intermediate compounds according to one of the formulas XXKa-d,
Figure imgf000057_0001
wherein,
(A) R1 is -iλR5, wherein
L1 is a bond, L5, L6, -L5-L6-L5-, or -L6-L5-L6-, wherein each L5 is independently -[C(R15)2]m-, wherein each m is independently 0, 1, 2, 3, 4, 5 or 6; and each R15 is independently hydrogen, halogen, (CrC6)alkyl, or (Q-C^haloalkyl; each L6 is independently -C(RU)2-, -C(R11^C(R1 V, -C(R11^=C(R11)-, -C(Rπ)20-, -C(Rn)2NRn-, -OC-, -0-, -S-, -NR11-, -N(Riσ)C0-, -N(R10)CO2-, -CON(R10)-, -CO-, -CS-, -CO2-, -0C(=0)-, -OC(=O)N(R10)-, -CONR11N(R1 V, -CONR11-, -OCONR11-, -SO2-, -N(R1G)SO2-, -SO2N(R10)-, -NR10CONR10-, -NR10CSNR10-, -C(=NRπ)-,
-C(=N0Rπ)-, -C(=NN(Rn)2)-; aryl, C3-C8 cycloalkyl, cycloC^shaloalkyl, heteroaryl, or heterocyclyl, wherein the aryl, cycloalkyl, cyclohaloalkyl heteroaryl, or heterocyclyl are optionally substituted with one or more radicals of R14; or L1 is a C2-6 alidiyl chain wherein the alidiyl chain is optionally interrupted by -C(R1 ^2-, -CrtOTtV, -C(R11H^(R11)-, -C(Rπ)20-, -C(R1 ^2NR11-, -OC-, -0-, -S-,
-N(R10)CO-, -N(R10)CO2-, -CON(R10)-, -CO-, -CO2-, -OC(O)-, -OC(=O)N(R10)-, -SO2-, -N(R10)SO2-, or -SO2N(R10)-, and
R5 is aryl, heterocyclyl, heteroaryl, C2-C6 alkenyl, C2-C6 alkynyl, (C3-C8 cycloalkyl)-CrC6 alkyl-, (C3-C8 cycloalkenyl)-Ci-C6 alkyl-, (C3-C8 cycloalkyl)-C2-C6 alkenyl-, C3-C8 cycloalkyl, -C, -B-C, or -A-B-C, wherein A is -O-;
B is -[C(R15)2]m- or C3-C8 cycloalkyl;
C is CrQalkyl, Q-Cehaloalkyl, SO2R11, SR11, SO2N(R11^5 SO2NR11COR11, C=N, C(O)OR11, CON(Rn)2, orN(Rn)2; wherein R5 is optionally substituted with one or more R a, wherein each R5a is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, (C3-C8 cycloalky^-Q- i
C6 alkyl-, (C3-C8 cycloalkeny^-Ci-Q alkyl-, (C3-C8 cycloalkyl)-C2-C6 alkenyl-, halogen, nitro, heterocyclyloxy, aryl, aryloxy, arylalkyl, aryloxyaryl, aryl C1-C6 alkoxy, -C, -B'-C, or -A'-B'-C wherein A' is -O-;
B' is -[C(R15)2]m- or - C3-C8 cycloalkyl -;
C is -H, halogen, -SO2R11, -OR11, -SR11, -N3, -COR11, -SO2N(Rπ)2, -SO2NR11COR11, -ON, -C(O)OR11, -OC(O)R11, -C0N(Rn)2, -CON(R11PR11, -0C0N(Rn)2, -NR11COR11, -NR11C0N(R11)2, -NR11COOR11, -N(Rn)2, aryl, heteroaryl, or heterocyclyl; wherein each R5a is optionally substituted one or more groups which are independently
C2-C6 alkenyl, C2-C6 alkynyl, (C3-C8 cycloalkyl)-CrC6 alkyl-, (C3-C8 cycloalkenyl)- CrC6 alkyl-, (C3-C8 cycloalkyl)-C2-C6 alkenyl-, C0-C6 alkoxyaryl, C1-C6 alkyl, C3-C8 cycloalkyl, aryl, 3TyI-C1-C6 alkyl-, heteroaryl, halogen, -NO2, -C=N, -COR11, -COOR11, -C0N(Rπ)2, -SO2R11, -OR11, -SR11, -SO2R11, -SO2N(Rπ)2, -SO2NR11COR11, -0C0N(Rπ)2, -NR11COR11, -NR11CON(R1^2, -NR11COOR11, or
-N(Rπ)2; R2 and R21 are -L3-R7, wherein each L3 is independently a bond -V-(CH2VV1-, or -(CH^-V^CBtøn- wherein n is 0-6; and each V1 is independently -C(Rπ)2-, -C(R11^C(R1 V, -C(R11H^(R11)-, -C(Rπ)20-,
-C(Rn)2NRn-, -C=C-, -0-, -S-, -NR7-, -N(R10)CO-, -N(R10)CO2-, -OCO-, -CO-, -CS-, -CONR10-, -C(=N)(Rn)-, -Q=N-OR11)-, -C[=N-N(Rn)2], -CO2-, -0C(=0)-, -OC(=O)N(R10)-, -SO2-, -N(R10)SO2-, -SO2N(R10)-, -NR10CONR10-, -NR10CSNR10-, C3-C8 cycloalkyl, or C3-C8 cyclohaloalkyl; or each L3 is independently a C2-S alidiyl chain, wherein the alidiyl chain is optionally interrupted by -C(Rn)2-, -C(R11^C(R1 V, -C(R11^(R11)-, -C(Rπ)2O-, -C(R11^NR11-, -C=C-, -0-, -S-, -N(R10)CO-, -N(R10)CO2-, -CON(R10)-, -CO-, -CO2-, -0C(=0)-, -OC(=O)N(R10)-, -SO2-, -N(R10)SO2-, or -SO2N(R10); and each R7 is independently hydrogen, halogen, nitro, cyano, aryl, heteroaryl, heterocyclyl, -C1-C6 alkyl-heterocyclyl, -C1-C6 alkyl-heteroaryl, -C1-C6 alkyl-aryl, -Z, -Y-Z, or -X-Y-Z, wherein Xis -O-;
Y is -[C(R15)2]m- -C2-C6 alkenyl, or C3-C8 cycloalkyl; Z is -H, -CN5 halogen, -OR11, -C(O)R11, -C(O)OR11, -C(=O)N(RU)2, -N(Rn)2, -CN,
-N3, -SO2R11, -S(O)2N(Rn)2, -C(O)N(Rπ)N(Rn)2, -C(O)N(R11XOR11), -OC(=O)-Rπ, -0C(=0)-N(Rπ)2, or -N(Rn)C00Rn; wherein R7 is optionally substituted with one or more R7a, wherein
R7a is halogen, C2-C6 alkenyl, -Ci-Ce alkyl-heterocyclyl, -C1-C6 alkyl-heteroaryl, -Ci-Cδ alkyl-aryl, C0-C6 alkoxyheteroaryl, Co-C6alkoxyheterocyclyl, haloaryl, aryloxy, aralkyloxy, aryloxyalkyl, CrCβalkoxyaryl, aryl Co-C6 alkylcarboxy, C(Rπ)=CCR11)-COOR11, Co-Cealkoxyheteroaryl, Co-C6alkoxyheterocyclyl, aryl, heteroaryl, heterocyclyl, C3-C8 cycloalkyl, heteroaryloxy, -Z', -Y' -Z', or -X' -Y' -Z', wherein X' is -O-;
Y' is -[CCR15)2]m- or C3-C8 cycloalkyl;
Z' is -CrCealkyl, -CrCehaloalkyl, -OR11, -SR11, -S(O)2R11, -CC=O)R11,
-CC=O)OR11, -CC=O)N(Rπ)2, -N(Rn)2, -N(R1^C(O)R11,
-S(=O)2NCR11)CC=O)R11, -CN, -S(O)2N(Rπ)2, -CC=O)NCR11JN(R")* -CC=O)NCR11XOR11), -OC(O)-R11, -OC(O)-OR11, -N(R1^C(O)O-R11, or
-N(Rπ)S(O)2Rn; wherein each R7a is optionally substituted with one or more R8, wherein each R is independently halogen, nitro, cyano, heteroaryl, C1-C6 alkyl, C1-C6 alkoxy, Ci-C6 haloalkyl, C1-C6 haloalkyl(ORπ), C0-C6 alkylOR11, QrC6 a]kylCON(Ru)2, C0-C6 alkylCOR11, C0-C6 alkylCOOR11, or C0-C6 alkylSO2Ru; and wherein if two R7a are present on the same carbon, then they may be taken together to form a cycloalkyl or heterocyclyl group; provided that R2 and R21 are not simultaneously -H; R3 is -L-R6, wherein
L is a bond, -X3-(CH2)n-X3-, -(CH2)m-X3-(CH2)π- or -(CH2 WY3-(CH2V wherein n is 0-6; each w is independently 0-5; and each X3 is independently a bond, -C(Rπ)2-, -C(R11^C(R1 V, -C(R11^C(R11)-, -C≡C-, -CO-, -CS-, -CONR10-, -Q=N)(R11)-, -C(=N-ORπ)-, -C[=N-N(RU)2], -CO2-, -SO2-, or -SO2N(R10)-; and Y3 is -O-, -S-, -NR7-, -N(R1O)CO-, -N(R10)CO2-, -000-,-OCC=O)N(R10)-, -NR10CONR10-, -N(R10)SO2-, or -NR10CSNR10-; or L is a C2-6 alidiyl chain, wherein the alidiyl chain is optionally interrupted by -C(R1 !)2-,
-QR^QR11)^ -^11J=C(R11)-, -C(Rn)2O-, -C(Rπ)2NRu-, -OC-, -0-, -S-, -N(R10)CO-, -N(R10)CO2-, -CON(R10)-, -CO-, -CO2-, -OC(O)-, -OC(O)N(R10)-, -SO2-, -N(R10)SO2-, or
-SO2N(R10); and
R6 is C1-C6 alkyl, Ci-C6 haloalkyl, aryl, C3-C8 cycloalkyl, heteroaryl, heterocyclyl, -CN, -Q=O)R1 \ -C(=0)0Ru, -C(O)N(Rn)2, -N(Rπ)2, -SO2R11, -S(=O)2N(Rπ)2, -C(O)N(R1 ^N(R11K or -C(O)N(Rπ)(0Rπ)5 wherein the aryl, heteroaryl, cycloalkyl, or heterocyclyl is optionally substituted with one or more R6a, wherein each R6a is independently -Z ,-Y -Z , or -X -Y -Z , wherein X" is-O-;
Y is -[C(R15)2]m-, -C2-C6 alkenyl, C3-C8 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the aryl, heteroaryl, cycloalkyl, or heterocyclyl is optionally substituted with at least one group which is each independently Z";
Z" is -H, -CN, halogen, -OR11, -C(O)R11, -C(O)OR11, -C(=O)N(RU)2, -N(Rn)2, -N3,
-SO2R11, -S(=O)2N(Rn)2, -C(=0)N(R11)N(R11)2, - N(R11XX=O)N(R1 \ -OC(O)-OR11, -C(O)N(R11XOR11), -OQ=O)-R11, -OQ=O)-N(R11)2, or
-N(Ru)C00Rπ; each R10 is independently -R11, -C(O)R11, -CO2R11, or -SO2R11; each R11 is independently -hydrogen, C2-C6 alkenyl, C2-C6 alkynyl, (C3-C8 cycloalkenyl)-Ci-C6 alkyl-, (Cz-Cz cycloalkyl)-C2-C6 alkenyl-, -N(R12)2, -C1-C6 alkyl, -Ci-C6 haloalkyl, -C3-C8 cycloalkyl, -(C1- C6)alkyl-(C3-C8)cycloalkyl, aryl, -(Ci-C6)alkyl-aryl, heteroaryl, -(Ci-C6)alkyl-heteroaryl, heterocyclyl, or -(Ci-C6)alkyl-heterocyclcyl, wherein any of R11 is optionally substituted with one or more radicals of R12; each R12 is independently hydrogen, halogen, Ci-Cshaloalkyl, Ci-C6 alkyl, Ci-C6 alkoxy, (C0-C6 alkyl)CO(0R13); C0-C6 alkylOR13, C0-C6 alkylCOR13, C0-C6 alkylSO2R13, C0-C6 alkylCN, C0-C6 alkylCON(R13)2, C0-C6 alkylCONR13OR13, C0-C6 alkylSO2N(R13)2, C0-C6 alkylSR13, QrC6 haloalkylOR13, aryloxy, aralkyloxy, aryloxyalkyl, Co-C6alkoxyaryl, aryl C0-C6 alkylcarboxy, C0-C6 alkylNR13SO2 R13, -C0-C6 alkylN(R13)2, or OC0-C6 alkylCOOR13; each R13 is independently hydrogen,Cl-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, (C3-C8 cycloalkyl)-Ci-C6 alkyl-, (C3-C8 cycloalkenyl)-Ci-C6 alkyl-, or (C3-C8 cycloalkyl)-C2-C6 alkenyl-; each R14 is independently C1-C6 alkyl, C1-C6 alkoxy, halogen, C1-C6 haloalkyl, C0-C6 alkylCON(Rπ)2, C0-C6 alkylCOM^OR11, C0-C6 alkylOR11, or C0-C6 alkylCOOR11;
G is a group of the formula,
Figure imgf000061_0001
wherein J is aryl, heteroaryl, or absent; Hal is halogen; each R41 is independently halogen, nitro, Ci-C6 alkyl-heterocyclyl, -Ci-C6 alkyl-heteroaryl, -Ci-C6 alkyl-aryl, -M", -E"-M", or -D"-E"-M", wherein D" is -O-;
E" is -[C(R15)2]m- or C3-C8 cycloalkyl; M" is -Ci-C6alkyl, -Ci-Cehaloalkyl, -COR11, -COOR11, -CON(RU)2, -ON, -OR11,
-OCON(Rn)2, -OCO2-R11, -N3, -NR11COR11, -NR11SO2R11, -N(R11^, -NR11COOR11, -SO2R11, -SO2NR11COR11, -SO2N(Rπ)2, or -SR11, wherein each R41 is optionally substituted with one or more R43, wherein each R^ is independently halogen, aryloxy, aralkyloxy, aryloxyalkyl, -Ci-C6 alkyl-aryl, Ci-C6 alkoxyaryl, aryl C0-C6 alkylcarboxy, -M', -E'-M', or -D'-E'-M'
D' is -O-;
F is -[C(R15)2]m- or C3-C8 cycloalkyl;
M' is -Q-Qalkyl, -d-Cβhaloalkyl, COR11, -C0N(Rn)2, -N(Rπ)C00Rn, -N(Rn)2, COOR11, ON, OR11, -NR11COR11, NR11SO2R11, SO2R11, SOsNlT^ or SR^ and q' is 0, 1, 2, 3, or 4, and provided that,
(i) if the compound is defined by formula XXDCa, then
(a) R1 is not 4-(NH2SO2)phenyl, 4-(CH3SO2)phenyl, or 4-(CH2F SO2)phenyl; (b) if R1 is 4-fluorophenyl, then G is not 4-[(H2NS(=O)2-]phenyl-
(c) R2 is not 4-hydroxyphenyl; (ii) if the compound is defined by formula XXTXb, then
(a) R2 is not 4-(NH2SO2)phenyl, 4-(CH3SO2)phenyl, or 4-(CH2FSO2)phenyl
(b) Jisnotpyridyl;
(c) R1 isnot4-hydroxyphenyl; (iii) ifthe compound is defined by formula XXEXc, then
(a) R2 is not 4-(NH2SO2)phenyl, 4-(CH3SO2)phenyl, or 4-(CH2FSO2)phenyl
(b) Jisnotpyridyl;
(iv) ifthe compound is defined by formula XXEXd, then
(a) if L1 is a bond, then R1 is not thienyl or 5-methyltbienyl; (b) if G is 4-fluorophenyl, then R1 is not 4-[(H2NS(O)2-]phenyl-
(c) R1 is not 4-Me-phenyl
In another embodiment, the invention provides the compound according to formula XXEXa-d, wherein Hal is -Cl, -Br, or -I.
In another embodiment, the invention provides the compound according to fonnula XXEXa-d wherein R21 is hydrogen, halogen, nitro, cyano, aryl, heteroaryl, heterocyclyl, -Ci-C6 alkyl-heterocyclyl, -C1-C6 alkyl-heteroaryl, -C1-C6 alkyl-aryl, -Z, -Y-Z, or -X-Y-Z, wherein X is -O-;
Y is -[C(R15)2]ra-, -C2-C6 alkenyl, or C3-C8 cycloalkyl;and
Z is -H, -CN, halogen, -OR11, -C(=O)Rπ, -C(O)OR11, -CC=O)N(R1 \ -N(Rπ)2, -CN, -N3, -SO2R11, -S(=O)2N(Rπ)2, -C(K))N(R1 ^N(R1 \ -C(O)N(R11XOR11X
-OC(O)-R11, -0C(O)-N(Rπ)2, or -N(Rπ)COORn;
In another embodiment, the invention provides the compound according to formula XXtXa-d wherein R21 is hydrogen, halogen, nitro, cyano, Q-Qalkyl, or Ci-Cδhaloalkyl.
In another embodiment, the invention provides the compound according to formula XXEXa-d wherein R3 is hydrogen, aryl, heteroaryl, heterocyclyl, -Ci-C6 alkyl-heterocyclyl, -C1-C6 alkyl-heteroaryl, -C1-C6 alkyl-aryl, -Z, or -Y-Z wherein
Y is -[C(R15)2]m- -C2-C6 alkenyl, or C3-C8 cycloalkyl;
Z is -H, -CN, halogen, -OR11, -C(O)R11, -C(O)OR11, -C(O)N(Rπ)2, -N(Rπ)2, -CN, -N3, -SO2R11, -S(O)2N(Rπ)2, -C(O)N(Rπ)N(Rπ)2, -C(O)N(R11XOR11), -OC(O)-R11, -0C(O)-N(Rπ)2, or -N(Rπ)COORn;
In another embodiment, the invention provides the compound according to fonnula XXEXa-d wherein R3 is hydrogen, Ci-C6alkyl, or Q-Cehaloalkyl.
In another embodiment, the invention provides the compound according to formula XXEXa-d, wherein J is aryl or heteroaryl. In another embodiment, the invention provides the compound according to formula XXEXa-d, wherein J is phenyl, pyridyl, thienyl, pyrrolyl, furanyl, pyrimidinyl, pyrazinyl, imidazoyl, pyrazoyl, oxazoyl, thiazoyl, isoxazoyl, isothiazoyl, triazoyl, triazinyl, tetøzoyl, or tetrazinyl.
In another embodiment, the invention provides the compound according to formula XXEXa-d, wherein J is phenyl, pyridyl, thienyl, pyrrolyl, or furanyl.
In another embodiment, the invention provides the compound according to formula XXIXa-d, wherein J is phenyl, pyridyl, or thienyl.
In another embodiment, the invention provides the compound according to formula XXIXa-d, wherein J is phenyl. In another embodiment, the invention provides the compound according to formula XXEXa-d, wherein J is pyridyl.
In another embodiment, the invention provides the compound according to formula XXEXa-d, wherein J is thienyl.
In another embodiment, the invention provides the compound according to formula XXEXa-d, wherein R5 is aryl, heterocyclyl, or heteroaryl, wherein R5 is optionally substituted with one or more R5a.
In another embodiment, the invention provides tiie compound according to formula XXIXa-d, wherein R5 is aryl or heteroaryl, wherein R5 is optionally substituted with one or more R5a.
In another embodiment, the invention provides the compound according to formula XXEXa-d, wherein R5 is phenyl, pyridyl, thienyl, pyrrolyl, furanyl, pyrimidinyl, pyrazinyl, imidazoyl, pyrazoyl, oxazoyl, thiazoyl, isoxazoyl, isothiazoyl, triazoyl, triazinyl, tetrazoyl, or tetrazinyl wherein R5 is optionally substituted with one or more R5a.
In another embodiment, the invention provides the compound according to formula XXEXa-d, wherein L1 is a bond. In another embodiment, the invention provides the compound according to formula XXEXa-d, wherein L1 is a bond; and R5 is phenyl, pyridyl, thienyl, pyrrolyl, furanyl, pyrimidinyl, pyrazinyl, imidazoyl, pyrazoyl, oxazoyl, thiazoyl, isoxazoyl, isothiazoyl, triazoyl, triazinyl, tetrazoyl, or tetrazinyl, wherein R5 is optionally substituted with one or more R5a.
In another embodiment, the invention provides the compound according to formula XXEXa-d, wherein L1 is a bond; and R5 is phenyl, pyridyl, thienyl, pyrrolyl, or furanyl, wherein R5 is optionally substituted with one or more R5a.
In another embodiment, the invention provides the compound according to formula XXEXa-d, wherein L1 is a bond; and R5 is phenyl optionally substituted with one or more R5a. In another embodiment, the invention provides the compound according to formula XXIXa-d, wherein L1 is a bond; and R5 is pyridyl optionally substituted with one or more R5a.
In another embodiment, the invention provides the compound according to formula XXDCa-d, wherein L1 is a bond; and R5 is thienyl optionally substituted with one or more R5a. In another embodiment, the invention provides the compound according to formulas XXIXa-d, wherein R2 is -L3-R7, wherein L3 is a bond; and
R7 is hydrogen, halogen, -Z, or -Y-Z, wherein
Y is -[C(R15')2]m- or C2-C6alkenyl, wherein each R15' is independently H, halogen, or (Ci-C6)alkyl; and
Z is -H, halogen, -OR11, -C(=O)RU, -QH))OR11, -CC=O)N(R11^, -C(=N-0H)Rn, or -C(=S)N(Rπ)2.
In another embodiment, the invention provides the compound according to formulas XXIXa-d, wherein R2 is -L3-R7, wherein L3 is a bond; and
R7 is hydrogen, halogen, or -[C(R15 )2]-Z, wherein each R15' is independently H, halogen, or (Q-Q^alkyl; and
Z is -H, halogen, -OR11", -C(O)R11", -C(=0)0Rn", -C(O)N(R1 % -C(^=N-OH)R11", or -C(=S)N(Rn")2, wherein R11" is -H or -(C1-C6 alkyϊ).
In another embodiment, the invention provides the compound according to formulas XXIXa-d, wherein R2is -halogen, -CF3, -CH2OH, -CH2SO2Me, -C(CH3)2OH, or -C(CH3)2SO2Me.
In another embodiment, the invention provides the compound according to formulas XXIXa-d, wherein R2 is -halogen, -CF3, -CH2OH, or -C(CH3)2OH. In another embodiment, the invention provides the compound according to formulas XXBCa-d, whereinR2is -CF3 or -C(CH3)2OH.
In one embodiment, the invention provides the compound according to formulas XXDCa-d, wherein each R41 is independently halogen, -M", or -E" -M", wherein
E" is -[C(R15')2]m-, wherein each R15 is independently hydrogen or halogen; and
M" is -CrC6alkyl, -Q-Cδhaloalkyl, or halogen.
In another embodiment, the invention provides the compound according to formula XXIXa-d, wherein R1 is Lx-R5, wherein L1 is a bond; and
R5 is phenyl or pyridyl, each optionally substituted with one or two R5a, wherein eachR5a is independently -halogen, -CH3, or -CF3; R2is -H, -C(R2α)2OH, -CH3, -CF3, or halogen, wherein each R20 is independently -H, -F, -CH3, or -CF3; J is phenyl, pyridyl, or thienyl; and each R41 is -halogen, -CH3, -CH2CH3, -CF3, -CF2CF3, or -CH2CF3.
In another embodiment, the invention provides the compound according to formula XXTXa-d, wherein q' is 0 or 1; R1 is LΛR5, wherein L1 is a bond;
R5 is phenyl optionally substituted with one or two R5a, wherein each R5a is independently -halogen, -CH3, or -CF3; each R2 is -H, -C(R20)2OH5 -CH3, -CF3, or halogen, wherein each R20 is independently -H, -F, -CH3, or -CF3; and R41 is -halogen, -CH3, -CH2CH3, -CF3, -CF2CF3, or -CH2CF3.
In another embodiment, the invention provides the compound according to formulas XXTXa-d, wherein each R41 is independently halogen, methyl or trifluoromethyl.
In another embodiment, the invention provides the compound according any of the previous embodiments wherein R21 is hydrogen. In the following embodiments of the first aspect, it is understood that the following provisos apply:
(i) q may be 0 only if L2 is not a bond or if K is not phenyl;
(ii) the compound is not 2-methyl-5-(l-m-tolyl-3-(trifluorometiiyl)-1H-ρyrazol-5- yl)benzenesulfonamide;
(iii) if L2 is a bond, then both J and K are not absent,
(iv) if K is absent, then q is 1 and R4 is bonded directly to L2;
(v) if L2 is SO2 or SO2N(R10), then R5 is substituted with at least one R5a;
(vi) if the compound is defined by formula Ia, then a) R1 is not 4-(NH2SO2)phenyl, 4-(CH3SO2)phenyl, or 4-(CH2FSO2)phenyl; b) if R1 is 4-fluoroρhenyl, then G is not 4-[(H2NS(=O)2-]phenyl-; c) R2is not4-hydroxyphenyl;
(vii) if the compound is defined by formula Ib, then a) R2 is not 4-(NH2SO2)phenyl, 4-(CH3SO2)phenyl, or 4-(CH2FSO2)phenyl; b) R1 isnot4-hydroxyphenyl;
(viii) if the compound is defined by formula Ic, then a) R2 is not 4-(NH2SO2)phenyl, 4-(CH3SO2)phenyl, or 4-(CH2FSO2)phenyl; b) J is not pyridyl; c) G is not 3- or 4-methoxyphenyl
(ix) if the compound is defined by formula Id, then a) if L1 is a bond, then R1 is not thienyl or 5-methylthienyl; b) G is not 4-(NH2SO2)phenyl, 4-(CH3SO2)phenyl, or 4-(CH2FSO2)phenyl; c) if G is 4-fluorophenyl, then R1 is not 4-[(H2NS(=O)2-]phenyl-; d) if J = Ph, L2 is a bond, and q is 1, then K and R4 together are not 4- fluorophenyl, 3-fluorophenyl, 4-methoxyphenyl, or 5-chlorothienyl; e) if J = pyridyl, L2 is a bond, and q is 1, then K and R4 together are not 4- fluorophenyl; f) if J = Ph, L2 is a bond, and q is 2, then K and both R4 together are not 3-fluoro-
4-methoxyphenyl; g) R1 is not 4-Me-phenyl.
One embodiment of the invention relates to compounds represented by formulae Iaa, Ibb, Ice or Idd:
Figure imgf000066_0001
as an isomer, a mixture of stereoisomers, a racemic mixture thereof of stereoisomers, or as a tautomer; or as a pharmaceutically acceptable salt, prodrug, solvate or polymorph thereof, wherein each R1 substitutent is independently selected from the group consisting of R5 and -L1-R5.
Another embodiment is that R1 substitutent is R5; Preferred R5 for this embodiment is selected from the group consisting of 5-12 membered aromatic or non-aromatic ring, 5-12 membered heterocyclyl or heteroaryl having one or more heteroatoms N, O or S; R5 is optionally substituted at a substitutable position with one or more radicals of R5a. R5 is preferably thienyl, furanyl, piperidinyl, pyrrolidinyl, piperazinyl, morpholinyl, thiazolyl, indolyl, oxazolyl, isoxazolyl, pyridinyl, pyrimidinyl, imidazolyl and phenyl. Examples of R5a groups include halogen, Cw haloalkyl, nitro, d* aliphatic group, C1-6 alkoxy,
Qw alkylOR11, NR11COR11, NR11CON(R1 \ C0* alkylSO2Ru, C0* alkylSR11, C0-6 alkylSO2N(Rπ)2-5 -, arylalkyl, aryloxyaryl, arylC1-6 alkoxy, OQ* alkylCOR11, OC1-6 alkyM(Rπ)2, C0-6 alkylN(Rn)2, C0* alkylCOOR11, C0* alkylCOON(Rn)2, C0-6 alkylCON(Rπ)2; C0* alkylC≡N, OC0* alkylCOOR11, OCi* alkylCON(Rπ)2, or C1* alkylOQ* alkyl. R5a is optionally substituted at substitutable position with C0* alkylSO2Rπ, C0* alkoxyaryl, 5-12 membered aromatic or non-aromatic ring, or 5-12 membered heterocyclyl or heteroaryl having one or more heteroatoms N, O or S. Preferably, R5a is Cl, Br, F, C1-6 alkyl, CM haloalkyl, C1-6 alkoxy, OC0^ alkylCOOR11, OCON(Rn)2, NHCOR11, C0N(Rn)2, NO2, OCON(Rπ)2, and OC1-6 alkylCON(Ru)2. Examples of R5a include OCH2C(CH3)3, Cl, F, Br, OCH2CH(CH3)2, OCH2CH3, CF3, COOH, OCH3, OH, NO2, OCOCH(CH3)2, OCOC(CH3)3, NHCOCH3, OCON(CH3)2, OCONHCH3, OCON (CH2)2CH3, OCONHCH(CH3)2, O(CH2)2, CONH2, O(CH)(CH3)2, Cw alkyl, OCH2COOH, OCH2COOC(CH3)3, OCCH^NCCH^H^, OC(CH3)2COOC(CH3)3, and OCH2CH2OH.
Another embodiment is that R1 substituted is -L1-R5. Preferred R5 for this embodiment is selected from the group consisting of 5-12 membered aromatic or non-aromatic ring, 5-12 membered heterocyclyl or heteroaryl having one or more heteroatoms N, O or S; R5 is optionally substituted at a substitutable position with one or more radicals of R5a. Examples of preferred R5 include phenyl, pyridinyl, oxazolyl, thienyl, thiazolyl, morpholinyl, furanyl, imidazolyl, piperazinyl, pyrimidinyl, isoxazolyl or piperidinyl. More preferably, oxazolyl, pyridinyl, phenyl, furanyl, thienyl or thiazolyl. Most preferred R5 includes pyridinyl or pyridinyl. Embodiments for L1 include a direct bond, -CS-, -Q-salkoxy-, -carbonyl-, -SO2-, -CON(R11)-,
-CONR11OR11-, -CONR11N(R11)-, -Q=NR11)-, -Q=NOR11)-, -Q=NN(R1 !)2)-, 5-12 membered aromatic or non-aromatic ring, 5-12 membered heteroaryl or heterocyclyl having one or more heteroatoms N, O, or S which is optionally substituted at a substitutable position with one or more radicals of R14. Another embodiment for L1 is -(CH2)m-V-(CH2)n- or -V-(CH2)n-V; m is 0-6; n is 0-6; V is independently -C(Rn)2-, -C(R11^C(R1V, -C(R11KXR11)-, -€(Rn)20-, -C(R11^NR1 \ -OC-, -0-, -S-, -NR11-, -N(R10)CO-, -N(R10)CO2 -, -CON(R10)-, -CO-, -CO2-, -0C(=0), -OQ=O)N(R10)-, -CONR11NR11-, -CONR11-, -OCONR11, -SO2-, -N(R10)SO2-, -SO2N(R10)-, -NR10CONR10-, -NR10CSNR10-, cycloC^shaloalkyl or CVcIoC3-6 alkyl. A preferred L1 is selected from the group consisting of -CS-, -CONH-, -Ci-6 alidiyl-, -CO-, -SO2-, -CH2-, -CH2O-, -CH2CH2-, -C=O-, -CONH-, -C0NHC(CH3)r, -CONH(CH2)3OCH2-, -OCH2CH2-, -OCH2CO-, -OCH2CH2N(CH3)2-, and -CONHCH2CH2N(CHS)2-. More preferred L1 is selected from the group consisting of -CH2-, -CH2O-, -CH2CH2-, -C=O-, -SO2-, -CONH-, -CONHC(CH3)2-, -CONH(CH2)3OCH2-, -CONHCH2CH2N(CH3)2-, -OCH2- and -OCH2CH2-. Examples of preferred R5 are selected from the group consisting of phenyl, pyridinyl, oxazolyl, thienyl, thiazolyl, morpholinyl, imidazolyl, piperazinyl, pyrimidinyl, isoxazolyl and piperidinyl.
Examples of preferred R5a include halogen, haloalkyl, OCH2CON(CH3)2, OCH2COOC(CH3)3, OCH2CH2N(CH2CH3)2, OCH2COOH, OC(CH3)2COOC(CH3)2, OCON(CH3)2, OCONHCH3, OCH2CH2OH, OCONHCH2CHCH3, OrNHCOCH3. R5 is optionally substituted at a substitutable position with one or more radicals of R5a.
L1 is -(CH2)m-V-(CH2)n-;or -V-(CH2)n-V; m is 0-6; n is 0-6; V is independently -CC=NR11)-, -CC=NOR11)-, -C(=NN(R11)2)-;-C(R11)2-, -C(TL11^C(TR1 V, -C(R11HXR11)-, C(Rn)2N R11-, -OC-, -0-, -S-, -NR11-, -N(R10)CO-S -NCR10)CO2-, -CON(R10)-, -CO-, -CO2-, -0C(=0)-, -OQ=O)N(R10)-, -CONR11NR11-, -CONR11-, -SO2-, -NCR10)SO2-, -SO2NCR10)- or -NR10CONR10-, -NR10CSNR.10-, CyCIoC3-6 haloalkyl or CyCIoC3-6 alkyl. Examples of preferred L1 are selected from the group consisting of -CONH-, -C1-6 alkyl-, -C1-6 alkoxy-, -CO-, -SO2-, -CH2-, -CH2O-, -CH2CH2-, -C=O-, -CONH-, -CONHC(CHs)2-, -CONH(CH2)3OCH2-, -OCH2CH2-, -OCH2CO-, -OCH2CH2NCCH3)2- and -CONHCH2CH2N(CH3)2-. More preferred L1 is selected from the group consisting Of -CH2-, -CH2O-, -CH2CH2-, -C=O-, -SO2-, -CONH-, -CONHC(CH3)2-, -CONH(CH2)3OCH2-, -CONHCH2CH2N(CH3V, and -OCH2CH2-.
Another embodiment is that R2 is independently selected from the group consisting of R7 and L3-R7; each R7 for this embodiment is independently selected from hydrogen, C1-6 alkyl, halogen, Ci-6 haloalkyl, Cw alkoxy, C1-6 haloalkylCOR11), C0^ alkylCOOR11, C0^ alkylCONCRn)2, C0^ alkylNCRn)2, C1-6 alkylOR11, C0^ alkylSO^CR11)^ C0^ alkylC≡N, cycloC^ alkylON, Co6 alkylCONRπNCRu)2, Qy6 811QrICQNR11OR11, C0-6 alkylOCOR11, CyCIoC3-6 alkyl, cycloC^ alkylOR11; 5-12 membered aromatic or non-aromatic ring; or 5-12 membered heteroaryl and heterocyclyl having one or more heteroatoms N, O or S; R7 is optionally substituted at a substitutable position with one or more radicals ofR7a; Another embodiment is that R2 is R7, each R7 for this embodiment is selected from the group
1 consisting of 5-12 membered aromatic or non-aromatic ring; 5-12 membered heteroaryl and heterocyclyl having one or more heteroatoms N, O or S. R7 is optionally substituted at a substitutable position with one or more radicals of R7a;
Preferred R7 is phenyl, pyridinyl, thienyl, furanyl, piperidinyl, pyrrolidinyl, piperazinyl, morpholinyl, thiazolyl, indolyl, oxazolyl, pyridinyl, isoxazolyl, pyrimidinyl, naphthyl, hydrogen, CF3, C0-6 alkylCsN, CH2OH, COOCH3, C00N(Rπ)2 or COOR11. Other examples of R7 include trifluoromeihyl, CH2C=N, C(CHs)2C=N, COOCH3, CH2OH, CONHCH2CH3, C0NH0CH2CH(0H) CH2OH, CONHCH2CH2N(CH3)2, CONHCH2CH2OCH3, CONHCH2CH2OCH3, CH2COOCH3, CON(CH3)2, COOCH(CH3)2, CONHCH2CH2CH2OCHS, OCOCH(CHS)2, OCH2CON(CHS)2, CH2CONHCH2(CH3), C(CH3)2OH, COOH, nitro, cycloC3-6 alkyl, cycloC^ alkylOR11, cycloC3-6 alkylamine, or COOCH(CHs)2. More preferably, R7 is CF3, COOCH3, COOH, or CONHCH2CH3. When R7 is phenyl or pyridinyl, preferred R7a is selected from the group consisting of halogen, Q-5 alkyl, Q_5 alkoxy, and C1-6 haloalkyl. Examples of R7a is selected from the group consisting of halogen, trifluoromethyl, C1-6alkyl, C^alkoxy, CH=CHCOOH, CH2COOH, OCH2COOH, OCONHCH(CH3)2, NHCOCH3, OH, OCH3, COOH, COOCH3, OCH2C(CH3)3, OCH2CH(CH3)2, OCH(CH3)2OCOCH(CH3)2, OCONHCH3, OCH2CH3, and OCH(CH3)2.
Another embodiment is that R2 is L3-R7. Each R7 for this embodiment is selected from the group consisting of 5-12 membered aromatic or non-aromatic ring; 5-12 membered heteroaryl and heterocyclyl having one or more heteroatoms N, O or S. R7 is optionally substituted at a substitutable position with one or more radicals of R7a;
A preferred L3 for this embodiment is independently selected from a direct bond, -CS-, -CO-, -CONR11-, -C(=NRπ)-, -C(=N0Rn)-, -C(≡NN(Rπ)2)-; CCH2)m-Vi-(CH2)n-, or -Vi-CCH2VV1-; m is 0-6; n is 0-6; Vi is independently -C(RU)2-, -CCR11^C(R1V, -CCR11^=C(R11)-, -C(Rπ)2O-, -CsC-, -0-, -S-, -NR11-, -C(Rπ)2NRn-, -NCR10)CO-, -NCR10)CO2, -CON(R10)-, -OCO-, -CO-, -CO2-, -0C(=0>, -OC(O)NCR10)-, -SO2-, -NCR10)SO2-, -NR10CONR10-, -NR10CSNR10-, cycloC3-6 alkyl, CVcIoC3-6 haloalkyl or -SO2NCR10)-. More preferably, L3 is -CH2-, -CO-, -OCH2-, -CH2OCH2-, -CONH-, -CH2OCOH2-, -CH2NHCH2-, -CH2NC(CH3)T, -CH2N(CH3)CH2-, -CH2COCH3-, -CH2N(CH3)2CH2-, cyclohexamine or cyclopropanamine.
Each R7a is independently a halogen, Ci-6 alkyl, CRn=CRπC00H, CM alkoxy, C0^ alkylOR11, C0-6 alkyl OVCOOR11, C0^ alkylNRnCORu, C0^ alkyl SO2NR11COR11, Co6 alkylSO2N(Rπ)2; C0^ alkylSR11, (C0-6 alkyl)C=O(ORn), OVOR11, Cw haloalkyl, OCW haloalkyl, haloaryl, aryloxy, aralkyloxy, aryloxyalkyl, Q-6 alkoxyaryl, arylCo-6 alkylcarboxy, NR11SO2 R11, OC1-6 alkyl, OC0-6 alkylCOOR11, C0-6 alkoxyheteroaryl, C^alkoxyheterocyclyl, cycloC3-6alkylCOORn, C3^cycloalkylamine; 5-12 membered aromatic or non-aromatic ring, or 5-12 membered heteroaryl or heterocyclyl having one or more heteroatoms N, O or S; Examples of R7a is selected from the group consisting of halogen, trifluoromethyl, Ci^alkyl, Ci^alkoxy, CH=CHCOOH, CH2COOH, OCH2COOH, OCONHCH(CH3)2, NHCOCH3, OH, OCH3, COOH, COOCH3, OCH2C(CH3)3, OCH2CH(CH3)2, OCH(CH3)2OCOCH(CH3)2, OCONHCH3, OCH2CH3, and OCH(CH3)2.
Each R7a may be substituted at a substitutable position with one or more radicals of R8; each R8 is independently C1-6 alkyl, Ci-6 alkoxy, Ci-6 haloalkyl, Q-6 alkylOR11, Ci-6 haloalkylOR11, CM alkylCON(Rπ)2, CM alkylCOR11, C0^ alkylCOOR11, NR11COOR11, or C0-6 alkylSO2Rn.
Other examples of R7 include trifluoromethyl, CH2ON, C(CH3)2C=N, COOCH3, CH2OH, CONHCH2CH3, CONHOCH2CH(OH)CH2OH, CONHCH2CH2N(CH3)2, CONHCH2CH2OCH3, CONHCH2CH2OCH3, CH2COOCH3, CON(CH3)2, COOCH(CH3)2, CONHCH2CH2CH2OCH3, OCOCH(CH3)2, OCH2CON(CH3)2, CH2CONHCH2(CH3), C(CH3)2OH, COOH, nitro, cycloC^ alkyl, cycloCw alkylOR11 or COOCH(CH3)2. More preferably, R7 is CF3, COOCH3, COOH, or CONHCH2CH3. When R7 is phenyl, pyridinyl, thienyl, furanyl, piperidinyl, pyrrolidinyl, piperazinyl, morpholinyl, thiazolyl, indolyl, oxazolyl, pyridinyl, isoxazolyl, pyrimidinyl, naphthyl. Examples of R7a is selected from the group consisting of halogen, trifluoromethyl, C1-6alkyl, C1-6alkoxy, CH=CHCOOH, CH2COOH, OCH2COOH, OCONHCH(CH3)2, NHCOCH3, OH, OCH3, COOH, COOCH3, OCH2C(CHs)3, OCH2CH(CH3)2, OCH(CH3)2OCOCH(CH3)2, OCONHCH3, OCH2CH3, and OCH(CH3)2. Preferred R7a is selected from the group consisting of halogen, C1-6 alkyl, C1^ alkoxy, and C1-6 haloalkyl.
Each R3 is independently selected from the group consisting of R6 and -L-R6; Another embodiment is that R3 is R6 where R6 is independently hydrogen, halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 haloalkylOR11, Co6 alkylOR11, Co6 alkylCON(Rn)2, C0-6 alkylCOR11, 0C0N(Rn)2, CONR11OR11, nitro, C1-6 alkylCOOR11; 5-12 membered aromatic or non-aromatic ring; 5-12 membered heteroaryl or heterocyclyl having one or more heteroatoms N, O or S; Preferred R6 is hydrogen or optionally substituted phenyl. Each R6 is optionally substituted at a substitutable position with one or more radicals ofR&. Each R6a is independently halogen, C1-6 alkyl, Ci-6 alkoxy, Q-6 haloalkyl, Ci-6 haloalkylOR11,
C0N(Rn)2, CONR11OR11, Co6 alkylCOOR11; CR11^CR11COOH, C0-6 alkylOR11, Co6 alkylCOR11, Qw alkylSO2Rn,
Co6 alkylOCOOR11, C0-6 alkyM^COR11, Co6 alkyl SO2NR11COR11' Co6 alkyl SO2N(R.n)2; Co6 alkylSR11, (Co6 alkyl)C=O(ORn), OVOR11, OCi-6 haloalkyl, aryloxy, aralkyloxy, aryloxyalkyl, Ci-6 alkoxyaryl, arylCoδ alkylcarboxy, NR11SO2 R11, OQ-6 alkyl, OCo6 alkylCOOR11, Co6 alkoxyheteroaryl, Coδalkoxyheterocyclyl, cycloalky ICOOR11.
Another embodiment is that R3 is L-R6, L is independently selected from direct bond, -CO-, -CONR11-, -Q=NR11)-, -C(=N0Rπ)-, -Q=NN(R11K)-; C2* alidiyl chain, wherein the alidiyl chain is optionally interrupted by -C(Rπ)2-, -C(R1 ^2C(R1 V, -C(Rπ)=C(Rn)-, -OC-, -0-, -S-, -N(R10)CO-, -N(R10)CO2, -NR11-, -CON(R10)-, -CO-, -CO2-, -0C(=0>, -OQ=O)N(R10)-, -SO2-, -N(R10)SO2-, or -SO2N(R10)-; -(CH2)m-V0-(CH2)n- or -V0-(CH2)n-V0-; m is 0-6; n is 0-6; V0 is independently -C(Rπ)2-, -QTt^QUV, -C(R11KI(R11)-, -C(Rπ)20-, -C(R11^NR11-, -C≡C-, -0-, -S-, -OR11N-, -OR11CO-, -NR11-, -N(R10)CO-, -N(R10)CO2-, -CON(R10)-, -OCO-, -CO-, -CO2-, -0C(=0>, -OC(=O)N(R10)-, -SO2-, -N(R10)SO2-, -NR10CONR10-, -NR10CSNR10-, -SO2N(R10)-, cycloC^ haloalkyl or cycloC^ alkyl; Examples of L include -0-, -CH2-, -CH2O-, -CH2CH2-, -C=O-, -SO2-, -CONH-, -CONHC(CH3)Z-, -CONH(CH2)3OCH2-5 -CONHCH2CH2N(CH3)2-, or -OCH2CH2-.
Each R4 is independently selected from, C1-6 alkyl, CR11^CR11COOR11, CO6 alkylON, CM alkoxy, Co6 alkylOR11, Co5 alkylCOR11, Co6 alkylSO2Rπ, C0^ alkylOCOOR11, Co6 311Cy]NR11COR11, Co6 alkylSO2NRnCORn, Co6 alkyl SO2N(RU)2, C0-6 alkylSR11, (Co6 alkyl)C=O(ORπ), OVOR11, halogen, d-ehaloalkyl, OCi-6 haloalkyl, aryloxy, aralkyloxy, atyloxyalkyl, Q-5 alkoxyaryl, arylCoδ alkylcarboxy, NR11SO2R11, OQ-6 alkyl, OC05 alkylCOOR11, C0-6 alkoxyheteroaryl, Co-salkoxyheterocyclyl, cycloalkyl COOR11, 5-12 membered aromatic ring or non-aromatic ring, or 5-12 membered heteroaryl or heterocyclyl having one or more heteroatoms N, O or S. Preferred R4 is selected from the group consisting of OH, CN, C(CH3)2OH, SO2CH3, SO2C(CH3)3, SO2CH2CH3, SCH2CH3, SCH3, OCH3, Ci-6 alkyl, CH2COOH, C(CH3)2COOH, NHSO2CH3, F, Cl, Br, cyclobutane-COOH, OC(CHs)2COOH, CF3, C(CH3)2COOH, CH2COOCH3, CH2CH2COOH, OCH2COOCH3, and COCH3. More preferably, R4 is SO2CH3, SO2CH2CH3, SCH2CH3, or SCH3. Each R4 is optionally substituted at a substitutable position with one or more radicals of R4a;
Each R43 is independently selected from, C1-6 alkyl, (Ci-6 alkyl)C=O(ORπ); C1^ alkoxy, Coδ alkylOR11, Co6 alkylCOR11, C0-6 alkylSO2Rπ, C0-6 alkylSO2N(Rπ)2, Co6 alkylSR11, (Co6 alkyl)C=O(ORπ), halogen, Ci-δhaloalkyl, aryloxy, aralkyloxy, aryloxyalkyl, Ci^ alkoxyaryl, arylCos alkylcarboxy, NR11SO2R11, OCH; alkyl, C0-6 alkylON, or OCo6 alkylCOOR11. Each R10 is independently selected from R11, C(=O)Rπ, CO2R11, SO2R11; each R11 is independently selected from hydrogen or substituted or unsubstituted C1-8 aliphatic group; Q-όhaloalkyl; N(R12)2; 5-12 membered aromatic or non-aromatic ring, or 5-12 membered heteroaryl or heterocyclyl having one or more heteroatoms, N, S or O; which is optionally substituted at a substitutable position with one or more radicals of R12. Each R12 is independently halogen, Ci-shaloalkyl, C1-S alkyl, C1-6 alkoxy, (C1-6 alkyl)C=O(OR13); C1-6 alkoxyalkyl, Cos alkylCOR13, Co6 alkylOR13, Co6 alkylSO2R13, Co6 alkylCON(R13)2, Co6 alkylCONR13OR13, Co6 alkylSO2N(R13)2, Q* alkylSR13, (Co6 alkyl)C=O(OR13), Co6 haloalkylOR13, aryloxy, aralkyloxy, aryloxyalkyl, Co6 alkoxyaryl, 8TyIC0-6 alkylcarboxy, Co6 alkylNR13Sθ2R13, 0CM alkyl, or OCo5 alkylCOOR13. Each R13 is independently hydrogen or substituted or unsubstituted Cμ8 aliphatic group.
Each R14 is independently C1-6 alkyl, C1^ alkoxy, halogen, C1-6 haloalkyl, Co6 alkylCON^11^, C0-6 alkylCONRnORπ, Co6 alkylOR11, or C06 alkylCOOR11.
Another embodiment of the invention is that G is independently Gl, G2 or G3;
Figure imgf000071_0001
Each Ring J or Ring K may be independently absent, same or different and is independently selected from a 5-12 rnembered aromatic or non-aromatic ring, or 5-12 membered heterocyclyl or heteroaryl having one or more hetero atoms, N, S or O.
Each Ring J or Ring K independently is optionally substituted at a substitutable position with one or more radicals of R4. Ring J is preferably a phenyl ring or a 5-membered heteroaryl ring.
Examples of Ring J include phenyl, pyridinyl, thienyl, furanyl, moφholinyl, thiazolyl, indolyl, oxazolyl, biphenyl, naphthyl, piperidinyl, piperazinyl, or imidazolyl. A preferred Ring J is thienyl or phenyl. Ring
J is optionally substituted at a substitutable position with one or more radicals of R4.
Suitable Ring J substituents designated as R4 include, methylsulfonyl, or Q-6 aliphatic or substituents selected from the group consisting of CR11^CR11COOR11, Cw alkyl, Q-β alkoxy, C0^ alkylOR11, C1-6 alkylCOR11, C0^ alkylSO2Rn, Qw alkylOCOOR11, C0^ 8DQrDSIR11COR11, C0* alkylSO2NRπCORπ, C0^ alkyl SO2N(Rπ)2, CM alkylSR11, (CM alkyl)C=O(ORu), OVOR11, halogen, Ci-ghaloalkyl, OC1-6 haloalkyl, aryloxy, aralkyloxy, aryloxyalkyl, C1-6 alkoxyaryl, arylCo^ alkylcarboxy, Ml11SO2R11, OC1-6 alkyl, OQH5 alkylCOOR11, C1-6 alkoxyheteroaryl, Q^alkoxyheterocyclyl, C0-6 alkylC≡N, cycloalkylCOOR11, 5-12 membered aromatic ring or non-aromatic ring, and 5-12 membered heteroaryl or heterocyclyl having one or more heteroatoms N, O or S. Examples of preferred R4 include OH, CN, C(CHs)2OH, SO2CH3, SO2NH2, SO2CH2CH3, SO2C(CH3) 3, SCH2CH3, SCH3, OCH3, Cw alkyl, CH2COOH, C(CHs)2COOH, NHSO2CH3, F, Cl, Br, C(CH2CH3)2COOH, CH2COOCH3, C(CH3)2COOCH3, CH2CH2COOH, CH=CHCOOH, OCH2COOCH3, COCH3, OCH3, COOC(CH3)3, cyclobutane-COOH, OC(CH3)2COOH, CH2CH3, CH3, CH(CHs)2, CH2COOCH3, OCON(CH2CH3)2, NHCOCH3, or CF3.
Examples of Ring K include phenyl, pyridinyl, thienyl, furanyl, morpholinyl, thiazolyl, indolyl, oxazolyl, biphenyl, naphthyl, piperidinyl, piperazinyl, isoxazolyl, pyrimidinyl, or imidazolyl. Ring K is optionally substituted at a substitutable position with one or more radicals of R4. Suitable Ring K substituents designated as R4 include, mefhylsulfonyl, or C1-6 aliphatic or substituents selected from the group consisting of CR11^CR11COOR11, C1-6 alkyl, C1-6 alkoxy, C0^ alkylOR11, Cw alkylCOR11, C0^ alkylSO2Ru, C0-6 alkylOCOOR11, C0* alky]NRnCORu, C0^ alkyl SO2NR11COR11, CM alkyl SO2N(RU)2, C0-6 alkylSR11, (CM alkyl)CO(0Rπ), OVOR11, C0^ alkylC≡N, halogen, C1-6haloalkyl, OC1-6 haloalkyl, aryloxy, aralkyloxy, aryloxyalkyl, C1-6 alkoxyaryl, arylCα-6 alkylcarboxy, NR11SO2R11, OC1-6 alkyl, 0CM alkylCOOR11, CM alkoxyheteroaryl, Q^alkoxyheterocyclyl, cycloalkyl COOR11, 5-12 membered aromatic ring or non-aromatic ring, and 5-12 membered heteroaryl or heterocyclyl having one or more heteroatoms N, O or S. Preferably, Ring K is phenyl, pyridinyl, thienyl, furanyl, morpholinyl, thiazolyl, indolyl, oxazolyl, biphenyl, naphthyl, piperidinyl, piperazinyl, isoxazolyl, pyrimidinyl, or imidazolyl. When Ring K is a phenyl or pyridinyl, it is preferably substituted by methylsulfonyl. Examples of preferred R4 groups include include OH, CN, C(CH3)2OH, SO2CH3, SO2NH2, SO2CH2CH3, SO2C(CH3) 3, SCH2CH3, SCH3, OCH3, Ci-6 alkyl, CH2COOH, C(CH3)2COOH, NHSO2CH3, F, Cl, Br, C(CH2CHs)2COOH, CH2COOCH3, C(CH3)2COOCH3, CH2CH2COOH, CH=CHCOOH5 OCH2COOCH3, COCH3, OCH3, COOC(CH3)3, cyclobutane-COOH, OC(CH3)2COOH, CH2CH3, CH3, CH(CHj)2, CH2COOCH3, OCON(CH2CHs)2, NHCOCH3, orCF3.
L2 is -(CH2)m-V2-(CH2)n- or -V2-(CH2)m-V2-; m is 0-6; n is 0-6; V2 is independently -C(R1V, -C(R11^C(R1V, -C(R1VC(R11)-, -C(Rπ)20-, -C(Rn)2NRπ-, -OC-, -0-, -S-, -N(R10)CO-, -N(R10)Cθ2-, -CON(R10)-, -CON(R11)-, -C0N(Rn)0-, -CO-, -CO2, -OR11N-, -OR11COO-, -OC(O)-, -OC(O)N(R10)-, -SO2-, -N(R10)SO2-, -NR10CONR10-, -SO2N(R10)-, -NR10CSNR10-, cycloC3-8haloalkyl or CyCbC3-6 alkyl; C2-6 alidiyl chain wherein alidiyl chain is optionally interrupted by -C(R1V, -C(Rπ)2C(Rπ)2-, -C(R1VC(R11)-, -C(R11^O-, -C=C-, -0-, -S-, -N(R10)CO-, -N(R10)CO2-, -CON(R10)-, -CON(R11)-, -C0N(Rn)0-, -CO-, -CO2-, -OC(O)-, -OC(O)N(R10)-, -SO2-, -N(R!0)SO2-, or -SO2N(R10)-; 5-12 membered aromatic or non-aromatic ring, or 5-12 membered heteroaryl or heterocyclyl having one or more heteroatoms, N, S or O which is optionally substituted at a substitutable position with one or more radicals of R9. Alternatively, L2 is a direct bond, -Ci-6 alkyl-, -Cu alkoxy-, -CM alkylCOOR11-, -CHOHCOO-, -C^alkylCONR11-, -OCWilkylCOOR11-, -Co^alkylSOzR11-, -C^alkylSOs-, -C^alkyNOl11)-, -Co^alkylO-, -OC0^ alkylN(Rn)-, -O6 alkylCO-, -Cu carboxyl-, -cycloalkylamine-, -C(=NRn)-, -C(=NORn)-, -C(=NN(Rπ)2)-; 5-12 membered aromatic or non-aromatic ring, 5-12 membered heteroaryl or heterocyclyl having one or more heteroatoms, N, S or O which is optionally substituted at a substitutable position with one or more radicals of R9. A preferred L2 is selected from the group consisting of -CONH-, -CONHCH2-, -CH2O-, -OCH2COOCH2-, -CONHCH2-, and -OC-. Another embodiment is that G is Gl, R1 is R5 and R2 is R7. When G of formulae Iaa, Ibb, Ice, or
Idd is Gl, a more preferred embodiment of this invention relates to a compound having one or more features selected from the group consisting of:
R1 is phenyl, pyridinyl, thienyl, furanyl, morpholinyl, thiazolyl, indolyl, oxazolyl, isoxazolyl, pyrimidinyl, or imidazolyl; R5 is optionally substituted at a substitutable position with one or more radicals of R5a;
R5a is halogen, trifluoromethyl, OCONHCH(CHS)2, NHCOCH3, OH, OCH3, COOH, COOCH3, OCH2C(CHs)3, OCH2CH(CHs)2, OCH2CH2N(CHs)2, OCH(CH3)2OCOCH(CH3)2, OCONHCH3, OCH2CH3, or OCH(CH3)2; R2 is trifluoromethyl, COOCH3, CH2OH, CONHCH2CH3, CONHOCH2CH(OH) CH2OH, CONHCH2CH2N(CH3)2, CONHCH2CH2OCH3, CONHCH2CH2OCH3, CH2COOCH3, CON(CHs)2, COOCH(CHs)2, CONHCH2CH2CH2OCH3, OCOCH(CH3)Z, OCH2CON(CHS)2, CH2CONHCH2(CH3), C(CH3)2OH, COOH, nitro or COOCH(CHs)2; R3 is hydrogen or optionally substituted phenyl;
Ring J is thienyl, thiazolyl, furanyl, pyridinyl or phenyl;
Ring K is optionally substituted phenyl or pyridinyl; and
R4 is SO2CH3, SO2C(CHs)3, CH3, SO2NH2, SO2CH2CH3, SCH2CH3, SCH3, OCH3, CF3, OCF3,
CH2CF3, C1-6 alkyl, halogen or CH2COOH. Another embodiment is that G is Gl , R1 is R5 and R2 is R7. When G of formulae Iaa, Ibb, Ice, or
Idd is Gl, a more preferred embodiment of this invention relates to a compound having one or more features selected from the group consisting of:
R1 is thienyl, furanyl, morpholinyl, thiazolyl, indolyl, oxazolyl, pyridinyl, imidazolyl, isoxazolyl, pyrimidinyl or phenyl; R5 is optionally substituted at a substitutable position with one or more radicals of R5a;
R5a is halogen, trifluoromethyl, OCONH(CH2)2CH3, OCONH(CH2CH3)2, NHCOCHs, OH, OCH3, COOH, COOCH3, OCH2C(CH3)3, OCH2CH(CH3)2, OCH^H^OCOCH^Hs^, OCONHCH3, OCH2CH3, or OCH(CHs)2;
R2 is R7 selected from CH2C≡N, C(CH3)2C=N, cycloG^ alkylC≡N, thienyl, furanyl, morpholinyl, thiazolyl, indolyl, oxazolyl, pyridinyl, imidazolyl, isoxazolyl, pyrimidinyl or phenyl; R7 is optionally substituted at a substitutable position with one or more radicals of R7a; R7a is selected from the group consisting of halogen, trifluoromethyl, C1-6alkyl, Ci-ealkoxy, CH=CHCOOH, CH2COOH, OCH2COOH, OCONHCH(CH3)2, NHCOCH3, OH, OCH3, COOH, COOCH3, OCH2C(CH3)S, OCH2CH(CH3)2, OCH(CHS)2OCOCH(CHS)2, OCONHCH3, OCH2CH3, or OCH(CH3)2;
R3 is hydrogen or optionally substituted phenyl; Ring J is thienyl, thiazolyl, furanyl, pyridinyl, or phenyl; Ring K is optionally substituted phenyl or pyridinyl; and
R4 is CH=CHCOOH, SO2CH3, SO2NH2, SO2CH2CH3, SCH2CH3, SO2C(CHs)3, SCH3, OCH3, Q-6 alkyl, CF3, F, Cl, or Br.
Another embodiment is that G is Gl, R1 is L1-R5 and R2 is R7. When G of formulae Iaa, Ibb, Ice, or Idd is Gl, a more preferred embodiment of this invention relates to a compound having one or more features selected from the group consisting of: 006/024749
R1 is L1-R5' R5 is phenyl, pyridinyl, morpholinyl, oxazolyl, furanyl, thiazolyl or thienyl; R5 is optionally substituted with R5a; R5a is halogen or trifluoromethyl;
L1 is -CS-, CH2, CH2O, CH2CH2, C=O, SO2, CONH, CONHC(CH3)2, CONH(CH2)3OCH2, OCH2, OCH2CO, or OCH2CH2;
R2 is trifluoromethyl, CONHCH2CH2N(CH3)2, CONHCH2CH2CH2N(CHS)2, or
CONHCH2CH2CH2 OCH3.
R3 is hydrogen or phenyl optionally substituted with R6a;
Ring J is thienyl, pyridinyl, thiazolyl or phenyl; Ring K is substituted phenyl or pyridinyl; and R4 is SO2CH3, SO2NH2, SO2CH2CH3, SCH2CH3, SCH3, OCH3, C w alkyl, halogen or CH2COOH.
Another embodiment is that G is Gl, R1 is R5 and R2 is L3R7. When G of formulae Iaa, Ibb, Ice, or Idd is Gl, a more preferred embodiment of this invention relates to a compound having one or more features selected from the group consisting of:
R1 is R5 selected from the group consisting of thienyl, furanyl, morpholinyl, thiazolyl, indolyl, oxazolyl, pyridinyl, imidazolyl, isoxazolyl, pyrimidinyl and phenyl; R5 is optionally substituted at a substitutable position with one or more radicals of R5a;
R5a is OCH2C(CHs)3, Cl, F, Br, OCH2CH(CHs)2, OCH2CH3, CF3, COOH, OCH3, OH, NO2,
OCOCH(CH3)2, NHCOCH3, OCONHCH(CH3)2, 0(CH2)2, CONH2, 0(CH)(CH3)2, Cw alkyl,
OCH2COOH, OCH2COOC(CH3)3, O(CH2)2N(CH2CH3)2, OCOC(CH3)3, OC(CH2)2COOH, OCONH(CH3)2, OCONCH3, OCONHCH2CH2CH3, OC(CH3;hCOOC(CH3)3, or O(CH2)2OH;
R2 is L3-R7; R7is phenyl, pyridinyl, thienyl, furanyl, morpholinyl, thiazolyl, oxazolyl, piperidinyl, imidazolyl, piperazinyl, or pyridinyl;
L3 is -CS-, -CO-, -Cu6 alidiyl-, -CONH-, -CONR11-, -CONR11NR11-, -CH2OCH2-,
-CH2OCH2CH2-, -OCH2-, -CH2N(CH3V, -CH2NHCH2-, -CONR11O-, -CH2OCOCH2-, -CH3N(CH3)(CH2)-, -CH2N(cyclopropane)CH2-, -CH2NC(CHs)2CH2-,
-CH2N(cyclohexane)CH2-, -CH2NCH(CH3)2CH2-, -CH2N(CF3)(CH2V,
-CH2N(CH3)(CH2)CH2OCOCH2CH2-, -CONHCH2CH2N(CH3V or -CH2N(CH2ON)CH2-;
R7a is selected from the group consisting of halogen, C1-6alkyl, Cu alkoxy, CF3, OCH2CH2COOH,
CH2COOH, COOCH3, CH2OH and OCH3; R3 is hydrogen or phenyl optionally substituted with R6a;
Ring J is thienyl, pyridinyl, thiazolyl, furanyl or phenyl; Ring K is substituted phenyl or pyridinyl; and R4 is SO2CH3, SO2CH2CH3, SCH2CH3, SCH3, SO2NH2, OCH3, C1-6 alkyl, CH2COOH, C(CHs)2COOH, NHSO2CH3, F, Cl, Br, CF3 or COCH3;
Another embodiment is that G is Gl, R1 is L1-R5 and R2 is L3-R7. When G of formulae Iaa, Ibb, Ice, or Idd is Gl, a more preferred embodiment of this invention relates to a compound having one or more features selected from the group consisting of:
R5 is L1-R5; R5 is selected from the group consisting of thienyl, furanyl, morpholinyl, thiazolyl, indolyl, imidazolyl, piperazinyl, piperidinyl, oxazolyl, pyridinyl, isoxazolyl, pyrimidinyl, imidazolyl and phenyl; R5 is optionally substituted at a substitutable position with one or more radicals of R5a; R5a is Cw alkyl, C1-S alkoxy, COOH5 halogen or trifluoromethyl;
L1 is -CS-, -CH2-, -CH2O-, -CH2CH2-, -OCH2CH2-, -OCH2CO-, -CO-, -SO2-, -CONH-,
-CONHC(CH3)2-, -CONH(CH2)3OCH2-, or -CONHCH2CHN(CHS)2-;
R2 is L3-R7; R7 is selected from the group consisting of phenyl, pyridinyl, thienyl, furanyl, morpholinyl, thiazolyl, oxazolyl, pyridinyl, isoxazolyl, pyrimidinyl, imidazolyl, CF3, and COOCH3; R7 is optionally substituted at a substitutable position with one or more radicals of
R7a;
L3 is CH2, CH2OCH2, NC(CHs)2, CH2NH(CH2)2, CONH, CO, CONR11, OCH2, CH2N(CH3)2CH2, CH2OCOCH2, CH2CONHCH2, CH2CONHCH2CH2, cycloalkylamine, CH2N(CH3)CH2, or CH2NCH(CHs)2CH2; R7a is selected from the group consisting of halogen, trifluoromethyl, C^alkyl, Q^alkoxy,
CH=CHCOOH, CH2COOH, OCH2COOH, OCONHCH(CH3)2, NHCOCH3, OH, OCH3, COOH, COOCH3, OCH2C(CHs)3, OCH2CH(CHs)2, OCH^H^OCOCH^H^, OCONHCH3, OCH2CH3, CH2N(CH2)CH2CF3, and OCH(CHs)2; R3 is hydrogen or phenyl optionally substituted with R&; Ring J is thienyl, thiazolyl, furanyl, pyridinyl, or phenyl; Ring K is optionally substituted phenyl or pyridinyl; and
R4 is SO2CH3, SO2CH2CH3, SCH2CH3, SCH3, OCH3, CM alkyl, CH2COOH, C(CH3)2COOH, NHSO2CH3, F, Cl, or Br.
Another embodiment is that G is G2 and R1 is R5 and R2 is R7. When G of formulae Iaa, Ibb, Ice, or Idd is G2, a more preferred embodiment of this invention relates to a compound having one or more features selected from the group consisting of:
R1 is R5 selected from the group consisting of thienyl, furanyl, morpholinyl, thiazolyl, indolyl, oxazolyl, pyridinyl, isoxazolyl, pyrimidinyl, imidazolyl and phenyl; R5 is optionally substituted at a substitutable position with one or more radicals of R5a; R2 is R7 selected from the group consisting of phenyl, pyridinyl, thienyl, furanyl, morpholinyl, thiazolyl, oxazolyl, pyridinyl, isoxazolyl, pyrimidinyl, imidazolyl, CF3, and COOCH3; R7 is optionally substituted at a substitutable position with one or more radicals of R7a; R3 is hydrogen or optionally substituted phenyl; L2 is selected from the group consisting of -CONH-, -CONHCH2-, -CH2O-, -OCH2COOCH2-, -0-,
OC-, -OCH2CH2-, and -CONHOCH2CH(OH)CH2O-; Ring J or K is substituted phenyl, biphenyl, pyridinyl, piperidinyl, piperazinyl, morpholinyl, thienyl, ornaphthyl; and
R4 is selected from the group consisting of SO2CH3, SO2CH2CH3, SO2CH2 CH2CH3, SCH2CH3, SCH3, OCH3, C1-S alkyl, CH2COOH, C(CH3)2COOH, NHSO2CH3, F, Cl, Br, C(CH3)2COOH,
CH2COOCH3, C(CH3)2COOCH3, CH2CH2COOH, OCH2CON(R1 \ OCH2CH2N(CH3;h,
OCH2COOH, OCH2COOCH3, CH2OH, COCH3, COOC(CH3)3, cyclobutane-COOH,
OC(CHs)2COOH and CF3.
Another embodiment is that G is G2, R1 is L1-R5 and R2 is R7. When G of formulae Iaa, Ibb, Ice, or Idd is G2, a more preferred embodiment of this invention relates to a compound having one or more features selected from the group consisting of: R1 is L1-R5; R5 is substituted phenyl or pyridinyl;
R5a is halogen, trifluoromethyl, C1-6 alkyl, C1-6 haloalkyl, nitro, Cw alkoxy, or OCON(C1^ alkyl)2; L1 is -CS-, -CH2-, -CH2O-, -CH2CH2-, -C=O-, -SO2-, -CONH-, -CONHC(CHs)2-, -CONH(CH2)3OCH2-, -CONHCH2CH2N(CH3)2 -, or -OCH2CH2-;
R2 is R7 is selected from the group consisting of phenyl, pyridinyl, Ihienyl, furanyl, morpholinyl, thiazolyl, oxazolyl, pyridinyl, CF3, or COOCH3; R3 is hydrogen or phenyl optionally substituted with R6a;
Ring J or K is substituted phenyl, thienyl, furanyl, piperazinyl, piperidinyl or pyridinyl; L2 is -CONH-, -CONHCH2-, -CH2O-, -OCH2COOCH2-, -0-, -C≡C-, -OCH2CH2-, or
-CONHOCH2CH(OH)CH2O-; and
R4 is selected from the group consisting of halogen, C1-6 haloalkyl, C1-6 alkylCOOR11, and methyl sulfonyl.
Another embodiment is that G is G2, R1 is R5 and R2 is L3R7. When G of formulae Iaa, Ibb, Ice, or Idd is G2, a more preferred embodiment of this invention relates to a compound having one or more features selected from the group consisting of: R1 is R5 selected from the group consisting of thienyl, furanyl, morpholinyl, thiazolyl, indolyl, oxazolyl, pyridinyl, imidazolyl, isoxazolyl, pyrimidinyl and phenyl; R5 is optionally substituted at a substitutable position with one or more radicals of R5a; R5a is halogen or trifluoromethyl; R2 is L3-R7;R7 is selected from the group consisting of phenyl, pyridinyl, thienyl, furanyl, morpholinyl, thiazolyl, oxazolyl, pyridinyl, phenyl, imidazolyl, isoxazole, pyrimidinyl, CF3, cycloC^ alkylC≡N, C0^ alkylC≡N, and COOCH3; R7 is optionally substituted at a substitutable position with one or more radicals of R7a;
L3 is -CS-, CH2, CH2OCH2, NCH2 (CH2)2, CH2N(CH2)2, CH2CN, CONH, CO, or CONHCH2; R3 is hydrogen or optionally substituted phenyl;
Ring J or K is substituted phenyl, pyridinyl, furanyl, biphenyl or naphthyl; L2 is -CS-, CONH, CONHCH2, CH2O, OCH2COOCH2, OCH2CH2, or or OCH2; and
R4 is SO2CH3, SO2CH2CH3, SCH2CH3, CH2COOH, C(CH3)2COOH, NHSO2CH3, F, Cl, Br, SCH3, OCH3, C1-6 alkyl, COOCH2CO, OCH3, CH2COOH, CH2COOCH3, CH(CH3)2COOH,
OC(CH3)2COOH, COOC(CH3)3, cyclobutane-COOH, C(CHs)2COOH, OCH2COOCH3, and CF3.
Another embodiment is that G is G3, R1 is R5 and R2 is R7. When G of formulae Iaa, Ibb, Ice, or Idd is G3, a more preferred embodiment of this invention relates to a compound having one or more features selected from the group consisting of:
R1 is R5 selected from the group consisting of thienyl, furanyl, morpholinyl, thiazolyl, indolyl, oxazolyl, pyridinyl, imidazolyl, isoxazole, pyrimidinyl and phenyl; R5 is optionally substituted at a substitutable position with one or more radicals of R5a;
R2 is R7 selected from the group consisting of phenyl, pyridinyl, thienyl, furanyl, morpholinyl, thiazolyl, oxazolyl, pyridinyl, imidazolyl, isoxazole, pyrimidinyl, CF3, halogen, and COOCH3;
R7 is optionally substituted at a substitutable position with one or more radicals of R7a; R3 is hydrogen or optionally substituted phenyl;
L2 is selected from the group consisting of -CS-, -CONH-, -CONHCH2-, -CH2O-, -OCH2COOCH2-, -COOCH2-, -CO-, -OCH2-, -OCO-, -NHCONH-, -0-, -OCH2CH2-, -OCONH-, and -SO2-;
Ring J or K is substituted phenyl, biphenyl, pyridinyl, piperidinyl, piperazinyl, morpholinyl, thienyl, furanyl, pyrimidinyl or naphthyl; R4 is methylsulfonyl, halogen, haloalkyl, CH2COOH, OCH2-phenyl, CH2COO-phenyl,
OCH2COOH, or OCH2CHN(CH3)2; and
R5a is OCH2C(CHa)3, Cl, F, Br, OCH2CH(CH3)2, OCH2CH3, CF3, COOH, OCH3, OH, NO2,
OCOCHCCH^, NHCOCH3, OCONHCH(CH3)2, 0(CH2)2, CONH2, 0(CH)(CH3)2, Cw alkyl, OCH2COOH, OCH2COOC(CH3)3, O(CH2)2N(CH2CH3)2, OCOC(CH3)3, OC(CH2)2COOH,
OCONH(CH3)2, OCONCH3, OCONHCH2CH2CH3, OC(CH3)2COOC(CH3)3, and
O(CH2)2OH.
Another embodiment is that G is G3, R1 is L1-R5 and R2 is R7. When G of formulae Iaa, Ibb, Ice, or Idd is G3, a more preferred embodiment of this invention relates to a compound having one or more features selected from the group consisting of: R1 is L1-R5; R5 is substituted phenyl or pyridinyl; R5a is halogen or trifluoromethyl; L1 is -CH2-, -CH2O-, -CH2CH2-, -O0-, -SO2-, -CS-, -CONH-, -CONHC(CH3)2-,
-CONH(CH2)3OCH2-, -CONHCH2CH2N(CH3)2 -, or -OCH2CH2-; R2 is halogen, Cw alkyl, Cw alkoxy, CM alkylCOOR11, or CF3;
R3 is hydrogen or phenyl optionally substituted with R6a; Ring J or K is phenyl, pyridinyl, thienyl, furanyl, piperidinyl, pyrrolidinyl, piperazinyl, moφholinyl, thiazolyl, indolyl, oxazolyl, isoxazolyl, pyrimidinyl, imidazolyl, or biphenyl; L2 is -CONH-, -CONHCH2-, -CH2O-, -OCH2COOCH2-, -OCH2 -, or -OCH2CH2-; and R4 is selected from the group consisting of halogen, C1-6 haloalkyl, C1-6 alkylCOOR11, and methyl sulfonyl.
Another embodiment is that G is G3, R1 is R5 and R2 is L3R7. When G of formulae Iaa, Ibb, Ice, or Idd is G3, a more preferred embodiment of this invention relates to a compound having one or more features selected from the group consisting of: R1 is selected from the group consisting of thienyl, furanyl, morpholinyl, thiazolyl, indolyl, oxazolyl, pyridinyl, isoxazolyl, imidazolyl, pyrimidinyl and phenyl; R5 is optionally substituted at a substitutable position with one or more radicals of R5a;
R2 is L3-R7; R7is phenyl, pyridinyl, thienyl, furanyl, moφholinyl, thiazolyl, oxazolyl, piperidinyl, imidazolyl, piperazinyl, pyridinyl, isoxazolyl, imidazolyl, pyrimidinyl, CF3, and COOCH3; R7 is optionally substituted at a substitutable position with one or more radicals of R7a;
L3 is -CS-, -CO-, -C1-6 alidiyl-, -CONH-, -CONR11-, -CONR11NR11-, -CH2OCH2-, -CH2OCH2CH2-, -OCH2-, -CH2N(CH3)2-, -CH2NHCH2-, -CONR11O-, -CH2OCOCH2-, -CH3N(CH3)(CH2)-, -CS-, -CH2N(cyclopropane)CH2-, -CH2NC(CH3)2CH2-, -CH2N(cyclohexane)CH2-, -CH2NCH(CH3)2CH2-, -CH2N(CF3)(CH2)2-,
-CH2N(CH3)(CH2)CH2OCOCH2CH2-, -CONHCH2CH2N(CH3)2-, or -CH2N(CH2ON)CH2-; R3 is hydrogen or optionally substituted phenyl;
Ring J or K is substituted phenyl, furanyl, thienyl, pyridinyl, biphenyl or naphthyl; L2 is -CONH-, -CONHCH2-, -CH2O, -OCH2COOCH2-, or -CONHCH2-; and R4 is OH, CN, C(CH3)2OH, SO2CH3, SO2CH2CH3, SCH2CH3, SCH3, SO2NH2, OCH3, C1-6 alkyl,
CH2COOH, C(CH3)2COOH, NHSO2CH3, F, Cl, Br, CF3 or COCH3.
Another embodiment of this invention relates to compounds represented by formulae Iaa-1, Iaa-2, Iaa-3 or Iaa-4 (Embodiment Iaa):
Figure imgf000080_0001
Another embodiment of this invention relates to compounds represented by formulae Ibb-1, Ibb-2, Ibb-3, or Ibb-4 (Embodiment Ibb):
Figure imgf000080_0002
Another embodiment of this invention relates to compounds represented by formulae Icc-1, Icc- 2, Icc-3, or Icc-4 (Embodiment Ice):
Figure imgf000080_0003
Another embodiment of this invention relates to compounds represented by formulae Idd-1, Idd-2, Idd-3, or Idd-4 (Embodiment Idd):
Figure imgf000080_0004
Of the above embodiments la-Id, R1 is R5 selected from the group consisting of thienyl, furanyl, morpholinyl, thiazolyl, indolyl, oxazolyl, pyridinyl, isoxazolyl, pyrimidinyl, imidazolyl, and phenyl; R5 is optionally substituted at a substitutable position with one or more radicals of R5a. Preferably, R5 is phenyl or pyridinyl optionally substituted with R5a.
R2 is R7 selected from the group consisting of trifluoromethyl, COOCH3, CH2OH, COMICH2CH3, CONHOCH2CH(OH) CH2OH, CONHCH2CH2N(CH3)2, CONHCH2CH2OCH3, CONHCH2CH2OCH3, CH2COOCH3, CON(CHS)2, COOCH(CH3V CONHCH2CH2CH2OCH3, OCOCH(CH3)2, OCH2CON(CH3)2, CH2CONHCH2(CH3), C(OHb)2OH, COOH, nitro or COOCH(CH3)2, CH2ON, QCH3)2ON, cycloQ^ alkylON, thienyl, furanyl, morpholinyl, thiazolyl, indolyl, oxazolyl, pyridinyl, imidazolyl, isoxazolyl, pyrimidinyl and phenyl; R7 is optionally substituted at a substitutable position with one or more radicals of R7a. L1 is independently selected from direct bond, -CO-, -CONH-, -CONR11-, -Q=NR11)-,
-C(=N0Rπ)-, -Q=NN(R1 !)2)-; C2-6 alidiyl chain, wherein the alidiyl chain is optionally interrupted by -C(R1V, -C(Rn)2C(Rπ)2-, -C(R11KXR11)-, -OC-, -0-, -S-, -N(R10)CO-, -N(R10)CO2, -NR11-, -OR11-, -CON(R10)-, -CO-, -CO2-, -OC(O)-, -OQ=O)N(R10)-, -SO2-, -N(R10)SO2-, or -SO2N(R10)-; -(CH2)m-V0-(CH2)n- or -V0-(CH2VV0-; m is 0-6; n is 0-6; V0 is independently -QRπ)2-, -C(R11^C(R11V, -C(R11K(R11)-, -C(Rπ)2O-, -C(R11^NR11-, -OC-, -0-, -S-, -NR11-, -CR11NR11-, -N(R10)CO-, -N(R10)CO2-, -CON(R10)-, -OCO-, -COR11-, -COOR11-, -CO-, -CO2, -OC(O), -OC(O)N(R10)-, -SO2-, -N(R10)SO2-, -NR10COR10-, -NR10CSNR10-, cycloCs.ghaloalkyl or -SO2N(R10)-. More specifically, L1 is selected from the group consisting of -CONH-, -C1-6 alkyl-, -C1^ alkoxy-, -CO-, -SO2-, -CH2-, -CH2O-, -CH2CH2-, -CO-, -CONH-, -CONHC(CHs)2-, -CONH(CH2)3OCH2-, -OCH2CH2-, -OCH2CH2N(CH3V, and -CONHCH2CH2N(CH3)2-.
L3 is independently selected from direct bond, -CO-, -CONH-, -CONR11-, -Q=NR11)-, -Q=NOR1 l)-, -C(=NN(R11)2)-; C2-6 alidiyl chain, wherein the alidiyl chain is optionally interrupted by -C(R1V,
Figure imgf000081_0001
-C(R11K(R1V, "C≡C-, -0-, -S-, -N(R10)CO-, -N(R10)CO2, -NR11-, -OR11-, -CON(R10)-, -CO-, -CO2-, -OC(O)-, -OC(O)N(R10)-, -SO2-, -N(R10)SO2-, or -SO2N(R10)-; -(CH2)m-V0-(CH2)n- or -Vo-(CH2VV0-; m is 0-6; n is 0-6; V0 is independently -C(R1V, -C(R11^C(R11V, -C(R11K(R-11)-, -C(RU)2O-, -C(Ru)2NRπ-, -OC-, -0-, -S-, -NR11-, -CR11NR11-, -N(R10)CO-, -N(R10)CO2-, -CON(R10)-, -OCO-, -COR11-, -COOR11-, -CO-, -CO2, -OC(O), -OC(O)N(R10)-, -SO2-, -N(R10)SO2-, -NR10COR10-, -NR10CSNR10-, cycloC^haloalkyl or -SO2N(R10)-. More specifically, L3 is -CO-, -C1-6 alidiyl-, -CONH-, -CONR11-, -CONR11NR11-, -CH2OCH2-, -CH2OCH2CH2-, -OCH2-, -CH2N(CH3V, -CH2NHCH2-, -CONR11O-, -CH2OCOCH2-, -CH3N(CH3)(CH2)-, -CH2N(cyclopropane)CH2-, -CH2NC(CHs)2CH2-, -CH2N(cyclohexane)CH2-, -CH2NCH(CHs)2CH2-, -CH2N(CF3)(CH2V, -CH2N(CH3)(CH2)CH2OCOCH2CH2-,
-CONHCH2CH2N(CH3V, or -CH2N(CH2ON)CH2-. R7a is selected from the group consisting of halogen, trifluoromethyl, C1-6alkyl, C1-6alkoxy, CH=CHCOOH, CH2COOH, OCH2COOH, OCONHCH(CHS)2, NHCOCH3, OH3 OCH3, COOH, COOCH3, OCH2C(CH3)3, OCH2CH(CH3)2, OCH(CH3)2θCOCH(CH3)2, OCONHCH3, OCH2CH3, or OCH(CH3)2. L2 is independently selected from direct bond, -CO-, -CONH-, -CONR11-, -C(=NRπ)-,
-C(=N0Rπ)-, -C(=NN(Rπ)2)-; C2-6 alidiyl chain, wherein the alidiyl chain is optionally interrupted by -C(R1V,
Figure imgf000082_0001
-C(R1VC(R11)-, -OC-, -0-, -S-, -N(R10)CO-, -N(R10)CO2, -NR11-, -OR11-, -CON(R10)-, -CO-, -CO2-, -OCX=O)-, -OC(=O)N(R10)-, -SO2-, -N(R10)SO2-, or -SO2N(R10)-; -(CH2)m-Vo-(CH2)n- or -Vo-(CH2)n-Vo-; m is 0-6; n is 0-6; V0 is independently -C(Rn)2-, -C(R11^C(R11V, -C(R.11)=^11)-. -C(Rn)2O-5 -C(R11^NR11-, -OC-, -0-, -S-, -NR11-, -CR11NR11-, -N(R10)CO-, -N(R10)CO2-, -CON(R10)-, -OCO-, -COR11-, -COOR11-, -CO-, -CO2, -OC(K)), -OC(O)N(R10)-, -SO2-, -N(R10)SO2-, -NR10COR10-, -NR10CSNR10-, cycloC^haloalkyl or -SO2N(R10)-. More specifically, L2 is selected from the group consisting of -CONH-, -CONHCH2-, -CH2O-, -OCH2COOCH2-, -0-, OC-, -OCH2CH2- and -CONHOCH2CH(OH)CH2O-. R5a is independently selected from the group consisting of OCH2C(CH3)3, Cl, F, Br,
OCH2CH(CH3)2, OCH2CH3, CF3, COOH, OCH3, OH, NO2, OCOCH(CH3)2, OCOC(CH3)3, NHCOCH3, OCON(CH3)2, OCONHCH3, OCON(CH2)2CH3, OCONHCH(CH3)2, O(CH2)2, CONH2, O(CH)(CH3)2, Cw alkyl, OCH2COOH, OCH2COOC(CH3)3, 0(CHi)2^(CB2CIh)2, OC(CHs)2COOC(CH3)3, and OCH2CH2OH. Preferred R5a is halogen or trifluoromethyl. R4 is selected from the group consisting of OH, CN, C(CH3)2OH, SO2CH3, SO2C(CH3)3,
SO2NH2, SO2CH2CH3, SCH2CH3, SCH3, OCH3, C1-6 alkyl, CH2COOH, C(CHs)2COOH, NHSO2CH3, F, Cl, Br, C(CHs)2COOH, CH2COOCH3, C(CH3)2COOCH3, CH2CH2COOH, OCH2COOCHs, COCH3, COOC(CH3)s, cyclobutane-COOH, OC(CH3)2COOH, COOCH2CH3, OCF3, and CF3.
Another embodiment of this invention relates to compounds as described above wherein G is selected from the group consisting of:
Figure imgf000082_0002
Of the above compounds, R is selected from the group consisting of C0^ alidiyl chain wherein the alidiyl chain is optionally interrupted by -C(R1V, -C(R11^C(R1 \-, -QTt^QR11)-, -C(Rπ)2O-, -C(R11^NR11-, -OC-, -0-, -S-, -N(R10)CO-, -N(R10)CO2-, -CON(R10)-, -CO-, -CO2-, -OC(O)-, -OQK))N(R10)-, -SO2-, -N(R10)SO2-, or -SO2N(R10)-. Each R4 is independently selected from, C1-6 alkyl, CR11^CR11COOR11, C1-5 alkoxy, C0^ alkylOR11, C0^ alkylCOR11, C0^ alkylSO2Rn, C0^ alkylOCOOR11, C0^ 3UCyINR11COR11, Co6 alkylSO2NRnCORn, C0^ alkyl SO2N(Rπ)2, C0^ alkylSR11, (C0-6 alkyl)O0(0Rn), OVOR11, halogen, C1-6haloalkyl, Ci-shaloalkylOR11, OQ-όhaloalkyl, aryloxy, aralkyloxy, aryloxyalkyl, C1^ alkoxyaryl, arylCo^ alkylcarboxy, NR11SO2R11, OC1-6 alkyl, OC0^ alkylCOOR11, C0-6 alkylON, Co6 alkoxyheteroaryl, Coόalkoxyheterocyclyl, cycloalkylCOOR11, a 5-12 membered aromatic ring or non-aromatic ring, or 5-12 membered heteroaryl or heterocyclyl having one or more heteroatoms N, O or S. Preferred R4 is selected from the group consisting of SO2CH3, SO2C(CH3)3, SO2CH2CH3, SCH2CH3, SCH3, OCH3, C1-6 alkyl, CH2COOH, C(CH3)2COOH, NHSO2CH3, F, Cl, Br, cyclobutane-COOH, OC^H^COOH, CF3, C(CH3)2COOH, CH2COOCH3, CH2CH2COOH, OCH2COOCH3, and COCH3. More preferably, R4 is SO2CH3, SO2CH2CH3, SCH2CH3, or SCH3.
X is selected from the group consisting of S, NR11 and O.
Each R4 is optionally substituted at a substitutable position with one or more radicals of R42;
Each R421 is independently selected from hydrogen, C1-6 alkyl, (Ci-6 alkyfyCXXOR11); C1-6 alkoxy, C^6 alkylOR11, C0-6 alkylCOR11, C06 alkylSO2Rπ, C0^ RU^lSO2N(R1 !)2; C^6 alkylSR11, (Qw alkyl)OC=O(ORπ), halogen, C1-6 haloalkyl, aryloxy, aralkyloxy, aryloxyalkyl, C1-6 alkoxyaryl, arylCo-δ alkylcarboxy, NR11SO2R11, OC1-6 alkyl, Co6 alkylC≡N, or OCa* alkylCOOR11. '
In a third aspect, the invention provides a pharmaceutical composition comprising a compound of any of formulas Ia-d, II-XXVIII, and XXEXa-d, or a pharmaceutically acceptable derivative thereof, in a pharmaceutically acceptable carrier. In another embodiment, the invention provides a pharmaceutical composition comprising a compound of formula XTX, or a pharmaceutically acceptable derivative thereof, in a pharmaceutically acceptable carrier.
In another embodiment, the invention provides a pharmaceutical composition comprising a compound of formula XXII, or a pharmaceutically acceptable derivative thereof, in a pharmaceutically acceptable carrier.
In another embodiment, the invention provides a pharmaceutical composition comprising a compound of formula XXV, or a pharmaceutically acceptable derivative thereof, in a pharmaceutically acceptable carrier In another embodiment, the invention provides a pharmaceutical composition comprising a compound of formula XXIIi, or a pharmaceutically acceptable derivative thereof, in a pharmaceutically acceptable carrier.
In another embodiment, the invention provides a pharmaceutical composition comprising a compound of formula Ia-d, or a pharmaceutically acceptable derivative thereof, in a pharmaceutically acceptable carrier.
In a fourth aspect, the invention provides a kit, comprising a packaging material and a compound of any of formula Ia-d, π-XXVUI, and XXIXa-d, or a pharmaceutically acceptable derivative thereof, which is effective for modulating the activity of a nuclear receptor or for treatment, prevention, inhibition, or amelioration of one or more symptoms of nuclear receptor mediated diseases or disorders.
In another embodiment, the invention provides a kit, comprising a packaging material, and a compound of formula Ia-d, or a pharmaceutically acceptable derivative thereof, which is effective for modulating the activity of a nuclear receptor or for treatment, prevention, inhibition, or amelioration of one or more symptoms of nuclear receptor mediated diseases or disorders.
Ih another embodiment, the invention provides a kit, comprising a packaging material, a compound of formula Ia-d, or a pharmaceutically acceptable derivative thereof, which is effective for modulating the activity of a nuclear receptor or for treatment, prevention, inhibition, or amelioration of one or more symptoms of nuclear receptor mediated diseases or disorders, further comprising a label that indicates that the compound of formula Ia-d, or pharmaceutically acceptable derivative thereof, is used for modulating the activity of a nuclear receptor or for treatment, prevention or amelioration of one or more symptoms of nuclear receptor mediated diseases or disorders, or diseases or disorders in which nuclear receptor activity is implicated.
In a sixth aspect, the invention provides a method of treating, preventing, inhibiting, or ameliorating the symptoms of a disease or disorder that is modulated or otherwise affected by nuclear receptor activity or in which nuclear receptor activity is implicated, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any of formula Ia-d, B-
XXVm, andXXIXa-d,
In a preferred embodiment of the sixth aspect, the invention provides a method of treating, preventing, inhibiting, or ameliorating the symptoms of a disease or disorder that is modulated or otherwise affected by nuclear receptor activity or in which nuclear receptor activity is implicated, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to part (A) of formulas Ia-d. When part (A) of formulas Ia-d is referenced herein with respect to methods of using compounds of the invention, such as for treatment, prevention, inhibition, or amelioration of disease, or for use in preparation of a medicament for the treatment, prevention, or amelioration of disease, it is meant that all compounds defined by part (A) are included and the provisos of part (B) of the same formulas are not to be considered when determining the scope of the compounds defined for the uses therein.
In a preferred embodiment of the sixth aspect, the invention provides the method wherein the disease or disorder is hypercholesterolemia, hyperlipoproteinemia, hypertriglyceridemia, lipodystrophy, hyperglycemia, diabetes mellitus, dyslipidemia, atherosclerosis, gallstone disease, acne vulgaris, acneiform skin conditions, diabetes, Parkinson's disease, cancer, Alzheimer's disease, inflammation, immunological disorders, lipid disorders, obesity, conditions characterized by a perturbed epidermal barrier function, conditions of disturbed differentiation or excess proliferation of the epidermis or mucous membrane, or cardiovascular disorders.
In a seventh aspect, the invention provides a method of reducing cholesterol levels in a subject in need thereof, comprising administering an effective cholesterol level-reducing amount of a compound of any of formula Ia-d, H-XXVIII, and XXEXa-d,
In a preferred embodiment of the seventh aspect, the invention provides a method of reducing cholesterol levels in a subject in need thereof, comprising administering an effective cholesterol level-reducing amount of a compound according to part (A) of formulas Ia-d. In an eighth aspect, the invention provides a method of treating, preventing, or ameliorating one or more symptoms of a disease or disorder which is affected by cholesterol, triglyceride, or bile acid levels, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any of formula Ia-d, π-XXVUI, and XXIXa-d.
In a preferred embodiment of the eighth aspect, the invention provides a method of treating, preventing, or ameliorating one or more symptoms of a disease or disorder which is affected by cholesterol, triglyceride, or bile acid levels, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to part (A) of formulas Ia-d.
In a ninth aspect, the invention provides a method of modulating nuclear receptor activity, comprising contacting the nuclear receptor with a compound of any of formula Ia-d, H-XXVHI, and XXEXa-d.
In a preferred embodiment of the ninth aspect, the invention provides a method of modulating nuclear receptor activity, comprising contacting the nuclear receptor with a compound according to part (A) of formulas Ia-d. In an embodiment of the ninth aspect, the invention provides the method wherein the nuclear receptor is an orphan nuclear receptor.
In an embodiment of the ninth aspect, the invention provides the method wherein the nuclear receptor is a liver X receptor. In a preferred embodiment of the ninth aspect, the invention provides the method wherein the nuclear receptor is a liver X receptor, wherein the liver X receptor is LXRα or LXRβ.
In an eleventh aspect, the invention provides a method of modulating cholesterol metabolism, comprising administering an effective cholesterol metabolism-modulating amount of a compound of any of formula Ia-d, H-XXVlII, and XXKa-d. In a preferred embodiment of the eleventh aspect, the invention provides a method of modulating cholesterol metabolism, comprising administering an effective cholesterol metabolism-modulating amount of a compound according to part (A) of formulas Ia-d.
In a twelfth aspect, the invention provides a method of treating, preventing, inhibiting, or ameliorating one or more symptoms of hypocholesterolemia in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of any of formula Ia-d, H-XXVIII, and XXrXa-d.
In a preferred embodiment of the twelfth aspect, the invention provides a method of treating, preventing, inhibiting, or ameliorating one or more symptoms of hypocholesterolemia in a subject in need thereof, comprising administering a therapeutically effective amount of a compound according to part (A) of formulas Ia-d.
In a thirteenth aspect, the invention provides a method of increasing cholesterol efflux from cells of a subject, comprising administering an effective cholesterol efflux-increasing amount of a compound of any of formula Ia-d, H-XXVDI, and XXEXa-d.
In a preferred embodiment of the thirteenth aspect, the invention provides a method of increasing cholesterol efflux from cells of a subject, comprising administering an effective cholesterol efflux-increasing amount of a compound according to part (A) of formulas Ia-d.
In a fourteenth aspect, the invention provides a method of increasing the expression of ATP-Binding Cassette (ABC1) in the cells of a subject, comprising administering an effective ABC1 expression-increasing amount of a compound of any of formula Ia-d, H-XXVHI, and XXDCa-d. Definitions
The following definitions apply to the terms used herein, unless expressly stated to the contrary. So, for example, "alkyl" is defined hereinbelow as containing from 1 to 12 carbon atoms, but a substituent defined as C^alkyl is limited to an alkyl moiety of from 1 to 6 carbons. All selections of any variables in connection with any of the general structures or formulas herein are understood to be proper only when said selection yields a stable chemical structure as recognized by one skilled in the art.
When particular embodiments are referred to by structure only, all otherwise unnamed chemical groups making up that structure are as defined in each embodiment of that structure. So, for example, when it is stated, "fri another embodiment, the invention provides the compound according to any one of formulas Ia-d, wherein K is phenyl or pyridyl," it is meant that another embodiment of the invention comprises each embodiment of any one of formulas Ia-d described in the specification in which K is phenyl or pyridyl and all other moieties are as defined in the respective embodiment.
For simplicity, chemical moieties are defined and referred to throughout primarily as univalent chemical moieties (e.g., alkyl, aryl, etc.). Nevertheless, such terms are also used to convey corresponding multivalent moieties under the appropriate structural circumstances clear to those skilled in the art. For example, while an "alkyl" moiety generally refers to a monovalent radical (e.g. CH3-CH2- ), in certain circumstances a bivalent linking moiety can be "alkyl," in which case those skilled in the art will understand the alkyl to be a divalent radical (e.g., -CH2-CH2-), which is equivalent to the term "alkylene." (Similarly, in circumstances in which a divalent moiety is required and is stated as being "aryl," those skilled in the art will understand that the term "aryl" refers to the corresponding divalent moiety, arylene.) All atoms are understood to have their normal number of valences for bond formation (i.e., 4 for carbon, 3 for N, 2 for O5 and 2, 4, or 6 for S, depending on the oxidation state of the S). On occasion a moiety may be defined, for example, as (A)a-B-, wherein a is 0 or 1. In such instances, when a is 0, the moiety is B-, and when a is 1 the moiety is A-B-. Similarly, C0-6 alkylOR11 includes both — OR11 and C1-C6-OR11, and -[C(R15)2]m- is a bond when m is 0. In the instances when a moiety is a divalent radical, there is no implied limitation on the location of the two bonds connecting the linking radical to its two supporting chemical units. For example, for a divalent cyclohexyl radical, the cyclohexyl can be connected either through two separate chemical bonds to two distinct carbons atoms within the ring; or the two bonds can be connected to the same carbon atom in the ring. In an illustrative example, if a divalent cyclopropyl radical connects connect two phenyl rings together, this definition encompasses both 1 ,2-diphenylcyclopropyl and 1 , 1 -diphenylcyclopropyl units.
As used herein the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. For example, "a compound" refers to one or more of such compounds, while "the enzyme" includes a particular enzyme as well as other family members and equivalents thereof as known to those skilled in the art. As used in the specification and appended claims, unless specified to the contrary, the following terms have the meaning indicated. The term "absent" as used herein means the group is replaced by a single bond. If replacing the group with a bond results in two connected moieties both defined as bonds, then -bond-bond- groups are understood to reduce to a single bond.
The term "interrupted by" as used herein means the group specified is inserted at any point within the specified chain, but not at the termini. For example, if a C3-alkyl chain, as defined herein, is interrupted by -O-, then the following groups would be encompassed: -CH2-O-CH2 CH2-, -CH2-CH2- 0-CH2, -CH(CHs)-O-CH2-, and -CH2-O-CH(CH3)-.
The terms "alphatic" and "aliphatic group" as used herein means straight-chain, branched or cyclic C1-C12 (unless stated otherwise) hydrocarbon radicals which are completely saturated or which contain one or more units of unsaturation but which are not aromatic. For example, suitable aliphatic groups include substituted or unsubstituted linear, branched or cyclic alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.
The terms "alkyl", "alkoxy", "hydroxyalkyl", "alkoxyalkyl", and "alkoxycarbonyl", used alone or as part of a larger moiety include both straight and branched chains containing one to twelve carbon atoms.
The terms "alkenyl" and "alkynyl" used alone or as part of a larger moiety include both straight and branched chains containing two to twelve carbon atoms.
The term "alkoxy" refers to an -O-alkyl radical, where alkyl is defined herein.
"Alkyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to twelve carbon atoms, preferably one to eight, and which is attached to the rest of the molecule by a single bond, e.g., methyl, ethyl, 77-propyl, 1-methylethyl (iso-propyl), n-butyl, rø-pentyl, 1,1-dimethylethyl (t-buryl), and the like. Unless stated otherwise specifically in the specification, the alkyl radical is optionally substituted by one or more substituents selected from the group consisting of halo, cyano, nitro, -OR11, -N(R1 x)z, -COR11, -COOR11, -CON(RU)2, -N(R1 ^COOR10, -N(Rn)C0Rn, -NSO2 R11, -N(Rπ)SO2 R11, -SO2OR11, -SO2R11, and -SO2N(Rn)2 where each R10 and R11 are as defined above in the first aspect of the invention. Unless stated otherwise specifically in the specification, it is understood that for radicals, as defined below, that contain a substituted alkyl group that the substitution can occur on any carbon of the alkyl group. "Alkenyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing at least one double bond, having from two to eight carbon atoms, and which is attached to the rest of the molecule by a single bond or a double bond, e.g., ethenyl, prop-1- enyl, but-1-enyl, pent-1-enyl, penta-l,4-dienyl, and the like. Unless stated otherwise specifically in the specification, the alkenyl radical is optionally substituted by one or more substituents selected from the group consisting of halo, cyano, nitro, -OR11, -N(Rπ)2, -COR11, -COOR11, -CON(Rn)2, -N(Rπ)COOR10, -N(R11XX)R11, -NSO2R11, -N(Rπ)SO2Rn, -SO2OR11, -SO2R11, and -SO2N(Rn)2 where each R and R are as defined above in the first aspect of the invention. Unless stated otherwise specifically in the specification, it is understood that for radicals, as defined below, that contain a substituted alkenyl group that the substitution can occur on any carbon of the alkenyl group.
"Aryl" refers to aromatic monocyclic or multicyclic ring system containing from 6 to 19 carbon atoms, where the ring system is optionally partially or fully saturated. Aryl groups include, but are not limited to groups such as fluorenyl, phenyl and naphthyl. Unless stated otherwise specifically in the specification, the term "aryl" is meant to include aryl radicals optionally substituted by one or more substituents selected from the group consisting of alkyl, alkenyl, halogen, haloalkyl, haloalkenyl, cyano, nitro, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, -R°-0Rπ, -R°-N(Rπ)2-, -R°-C0Rπ, -R°-C00Rπ, -R^CON(R1 \ - R°-N(Rπ)COOR10, -R^NCR^COR11, -R°-NS02Rn, -R^N(R1 ^SO2R11, -R°-SO2ORn, -R0-SO2Rn, and -R^SO2N(R1 % where each R0 is independently selected from a substituted or an unsubstituted aliphatic group, an unsubstituted heteroaryl or heterocyclic ring, phenyl (Ph), substituted Ph, -OPh, substituted -OPh, or substituted -CH2Ph. Examples of substitutents on the aliphatic group or phenyl ring of R0 include amino, alkylamino, dialkylamino, aminocarbonyl, halogen, alkyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkoxy, nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, hydroxy, haloalkoxy or haloalkyl. An aliphatic group or non-aromatic heterocyclic ring may contain one or more substituents.
Examples of suitable substituents on the saturated carbon of an aliphatic group or of non-aromatic heterocyclic ring include those listed above for unsaturated carbon of an aryl or heteroaryl group and including the Mowing:=O, =S, =NNHR°, =NN(R°)2, -N-, =NNHC(0)R°, =NNHC02 (alkyl), =NNHSO2(alkyl), or =NR°, where R0 is independently selected from hydrogen, unsubstituted or substituted aliphatic group, an unsubstituted heteroaryl or heterocyclic ring, phenyl (Ph), substituted Ph, -OPh, substituted -OPh, -CH2Ph or substituted -CH2Ph. Examples of substitutents on the aliphatic group include amino, alkylamino, dialkylamino, aminocarbonyl, halogen, alkyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkoxy, nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, hydroxy, haloalkoxy or haloalkyl. Suitable substituents on the nitrogen of a non-aromatic heterocyclic ring include -R0, -N(R°)2, -
C(O)R0, CO2R0, -C(O)C(O)R°,-SO2R, -SO^Λ, -Q=S)N(R^ -C(=NH)-N(R°)2, and NR0RSO2R0 wherein each R0 is independently selected from hydrogen, unsubstituted or substituted aliphatic group, an unsubstituted heteroaryl or heterocyclic ring, phenyl (Ph), substituted Ph, -OPh, substituted -OPh, or substituted -CH2Ph. Examples of substitutents on the aliphatic group or the phenyl ring include amino, alkylamino, dialkylamino, aminocarbonyl, halogen, alkyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkoxy, nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, hydroxy, haloalkoxy or haloalkyl.
The term "alkoxyaryl" as used herein means an aryl group, as defined herein, substituted with one or more alkoxy groups, as defined herein. Examples of alkoxyaryl groups include, but are not limited to, methoxyphenyl, butyloxyphenyl, and dimethoxynaphthyl.
"Aralkyl" or "arylalkyl" refers to a radical of the formula -RaRb where Ra is an alkyl radical as defined above and Rb is one or more aryl radicals as defined above, e.g., benzyl, diphenylmethyl and the like. The aryl radicals) and the alkyl radical is optionally substituted as described above. The term "aralkyloxy" or "arylalkoxy" as used herein, means an aralkyl group, as defined herein, appended to the parent molecule through a oxygen atom. Examples of aralkyloxy include, but are not limited to, benzyloxy, 2-phenylethoxy, 4-phenylbutoxy, 9-fluorenylmethoxy, and the like.
The term "arylalkylcarboxy" as used herein, means an arylakyl group, as defined herein, appended to the parent molecule through a carboxy group, as defined herein. The carboxy group can be bonded in either sense; either with the carbonyl carbon bonded to the arylalkyl group and the oxygen bonded to the parent molecule; or the carbonyl bonded to the parent molecule and the oxygen bonded to the arylalkyl group. Examples of arylalkylcarboxy groups include, but are not limited to, benzylacetoxy, (benzyloxy)carbonyl, (2-phenylethoxy)carbonyl, phenyl-acetyloxy, and l-oxo-5-phenyl-pentyloxy.
The term "aryloxy" as used herein, means an aryl group, as defined herein, appended to a parent molecule through an oxygen atom. Examples of "aryloxy" groups include, but are not limited to phenoxy, 1-naphthyloxy, and2-naphthyloxy.
"Alkylene" and "alkylene chain" refer to a straight or branched divalent hydrocarbon chain, linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing no unsaturation and having from one to twelve carbon atoms, preferably having from one to eight carbons, e.g., methylene, ethylene, propylene, rø-butylene, and the like. The alkylene chain may be attached to the rest of the molecule and to the radical group through one carbon within the chain or through any two carbons within the chain. The alkylene chain is optionally substituted by one or more substituents selected from the group consisting of halo, cyano, nitro, -OR11, -N(Rn)2, -COR11, -COOR11,
-CON(RU)2, -N(Rπ)COOR10, -N(Ru)C0Rn, -NSO2R11, -N(R1^SO2R11, -SO2OR11, -SO2R11, and -SO^CR11^ where each R10 and R11 are as defined above in the first aspect of the invention. The alkylene chain may be attached to the rest of the molecule through any two carbons within the chain.
"Alkenylene" and "alkenylene chain" refer to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one double bond and having from two to twelve carbon atoms, e.g., ethenylene, propenylene, n-butenylene, and the like. The alkenylene chain is attached to the rest of the molecule through a single bond and to the radical group through a double bond or a single bond. The points of attachment of the alkenylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain. The alkenylene chain is optionally substituted by one or more substituents selected from the group consisting of halo, cyano, nitro, -OR11, -N(Rn)2, -COR11, -COOR11, -C0N(Rn)2, -N(Rn)COOR10, -N(Rπ)C0Ru, -NSO2R11, -N(R1 ^SO2R11, -SO2OR11, -SO2R11, and -SO2N(R1 J)2 where each R10 and R11 are as defined above in the first aspect of the invention.
The term "aryloxyalkyl" as used herein, means an alkyl group appended to the parent molecule, wherein the alkyl group is substituted with one aryloxy group, as defined herein. Examples of aryloxyalkyl groups include, but are not limited to phenoxymethyl, naphthyloxybutyl, and phenoxyhexyl.
The term "aryloxyaryl" as used herein, means an aryl group appended to the parent molecule, wherein the aryl group is substituted with one aryloxy group, as defined herein. Examples of aryloxyaryl groups include, but are not limited to phenoxyphenyl, naphthyloxyphenyl, and phenoxynaphthyl.
The term "carbonyl" as used herein, means a -C(=0)- group.
The term "carboxy" as used herein, means a-C(=0)0- group.
"Cycloalkyl" refers to a stable monovalent monocyclic or bicyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, having from three to ten carbon atoms (unless stated otherwise), and which is saturated or includes one more unsaturated units (but is not aromatic) and is attached to the rest of the molecule by a single bond, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cylcopent-1-enyl, cyclohexyl, cyclohex-2,4-dienyl, decalinyl and the like. Unless otherwise stated specifically in the specification, the term "cycloalkyl" is meant to include cycloalkyl radicals which are optionally substituted by one or more substituents independently selected from the group consisting of alkyl, alkenyl, halo, haloalkyl, haloalkenyl, cyano, nitro, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, -OR11, -N(RU)2, -COR11, -COOR11, -C0N(Rn)2, -N(RU)COOR10, -N(Rπ)C0Rn, -NSO2R11, -N(R1 ^SO2R11, -SO2OR11, -SO2R11, and -SO2N(Rπ)2 where each R10 and Rπare as defined above in the first aspect of the invention.
"Cycloalkylalkyl" refers to a radical of the formula -R9Rd where Ra is an alkyl radical as defined above and Rd is a cycloalkyl radical as defined above. The alkyl radical and the cycloalkyl radical may be optionally substituted as defined above.
The term "cyclohaloalkyl" as used herein means a cycloalkyl group, as defined herein which is substituted by one or more halo groups, as defined herein. Examples of "cyclohaloalkyl" groups include, but are not limited to, bromocyclohexyl, trifluorocyclopentyl, dichlorocyclohexyl and the like. 'Ηalo" or 'Ηalogen" refers to bromo, chloro, fluoro or iodo.
'Ηaloalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1- fluoromethyl-2-fluoroethyl, 3-bromo-2-fluoropropyl, l-bromomethyl-2-bromoethyl, and the like. 'Ηaloalkenyl" refers to an alkenyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., 2-bromoethenyl, 3-bromoprop-l-enyl, and the like.
The term "haloaryl" as used herein, means an aryl group, as defined herein, substituted with one or more halo groups. Examples of haloaryl groups include, but are not limited to, bromophenyl, fluorophenyl, pentafluorophenyl, chloronaphthyl, chloro-iodophenyl, and the like. 'Ηeterocyclyl" refers to a stable 3- to 18-membered non-aromatic ring radical which consists of carbon atoms and from one to five heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. For purposes of this invention, the heterocyclyl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heterocyclyl radical is optionally oxidized; the nitrogen atom is optionally quaternized; and the heterocyclyl radical may be partially or fully saturated. Examples of such heterocyclyl radicals include, but are not limited to, dioxolanyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, thiazolidinyl, tetraliydrofuranyl, trithianyl, tetrahydropyranyl, thiomoφholinyl, thiamorpholinyl, 1-oxo-thiomoφholinyl, and 1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in the specification, the term "heterocyclyl" is meant to include heterocyclyl radicals as defined above which are optionally substituted by one or more substituents selected from the group consisting of alkyl, alkenyl, halo, haloalkyl, haloalkenyl, nitro, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, -OR11, -N(Rπ)2-, -COR11, -COOR11, -CON(Rπ)2, -N(R1 ^COOR10, -N(Rn)C0Ru, -NSO2R11, -N(R1 ^SO2R11, -SO2OR11, -SO2R11, and -SO2N(Rπ)2 where each R10 and R11 are as defined above in the first aspect of the invention.
'Ηeterocyclylalkyl" refers to a radical of the formula -RaRe where Ra is an alkyl radical as defined above and Re is a heterocyclyl radical as defined above, and if the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl may be attached to the alkyl radical at the nitrogen atom. The heterocyclyl radical and the alkyl radical is optionally substituted as defined above.
The term "heterocyclyloxy" as used herein, means a heterocyclyl group, as defined herein, appended to a parent molecule through an oxygen atom. Examples of "heterocyclyloxy" groups include, but are not limited to piperidinyloxy, tetrahydroforanyloxy, telrahydrotheinyloxy tetrahydropyranyloxy, dihydropyranyloxy, pyrrolidinyloxy, oxetanyloxy, and oxiranyloxy.
'Ηeteroaryl" refers to a 3- to 18-membered aromatic ring radical which consists of carbon atoms and from one to five heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. For purposes of this invention, the heteroaryl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heteroaryl radical is optionally oxidized; the nitrogen atom is optionally quaternized. Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzthiazolyl, benzindolyl, benzothiadiazolyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[l,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pMialimidyl pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl. Unless stated otherwise specifically in the specification, the term "heteroaryl" is meant to include heteroaryl radicals as defined above which are optionally substituted by one or more substituents selected from the group consisting of alkyl, alkenyl, halo, haloalkyl, haloalkenyl, nitro, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, -OR11, -N(Rn)2-, -COR11, -COOR11, -CON(Rπ)2, -N(RU)COOR10, -N(Ru)CORn, -NSO2R11, -N(Ru)SO2Rn, -SO2OR11, -SO2R11, and -Sθ2N(Rπ)2 where each R10 and R1We as defined above in the first aspect of the invention. For purposes of this invention, the tern "N-heteroaryl" refers to heteroaryl radicals as defined above containing at least one nitrogen atom in ring. The term "heteroaryloxy" as used herein, means a heteroaryl group, as defined herein, appended to a parent molecule through an oxygen atom. Examples of "heteroaryloxy" groups include, but are not limited to pyridyloxy, indolyloxy, and quinolyloxy.
'Ηeteroarylalkyl" refers to a radical of the formula -R3Rf where R3 is an alkyl radical as defined above and Rf is a heteroaryl radical as defined above, and if the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl may be attached to the alkyl radical at the nitrogen atom. The heteroaryl radical and the alkyl radical are optionally substituted as defined above.
The term "linker group" or "linker" means an organic moiety that connects two parts of a compound. Linkers are typically comprised of an atom such as oxygen or sulfur, a unit such as -NH-, - CH2-, -CO-, -CONH-, or a chain of atoms, such as an alidiyl chain. The molecular mass of a linker is typically in the range of about 14 to 200, preferably in the range of 14 to 96 with a length of up to about six atoms. Examples of linkers include a saturated or unsaturated C1-C6 alidiyl chain which is optionally substituted, and wherein one or two saturated carbons of the chain are optionally replaced by -CO-, - COCO-, -CONH-, -CONHNH-, -CO2-, -NHCO2-, -O-, -NHCONH-, -OCONH-, -NHNH-, -NHCO-, - S-, -SO-, -SO2-, -NH-, -SO2NH-, or -NHSO2-.
The term "alidiyl chain" refers to an optionally substituted, straight or branched carbon chain that may be fully saturated or have one or more units of unsaturation. The optional substituents are as described above for an aliphatic group. Alidiyl chain used herein may include alidiyl chains containing 0-4 fluorine substituents. An "agonist for a nuclear receptor" is an agent that, when bound to the nuclear receptor, activates nuclear receptor activity to activate or repress gene function. In some cases, nuclear receptors can act through second messenger signaling pathways, and the invention would apply to these actions as well. The activation can be similar in degree to that provided by a natural hormone for the receptor, or can be stronger (optionally referred to as a "strong agonisf), or can be weaker (optionally referred to as a "weak agonisf or "partial agonisf'). An example of a hormone for a nuclear receptor is thyroid hormone, which is a natural hormone for the thyroid receptor. A "putative agonisf is an agent to be tested for agonist activity.
Partial agonists or partial antagonists bind to receptors and yield a response less than that of a full agonist at saturating ligand concentrations. A partial agonist will block binding of a full agonist and suppress receptor activity to the level induced by the partial agonist alone. For example, partial agonists bind to receptors and induce only part of the changes in the receptors that are induced by agonists. The differences can be qualitative or quantitative. Thus, a partial agonist can induce some of the conformation changes induced by agonists, but not others, or it may only induce certain changes to a limited extent Some of these compounds are naturally produced. For example, many plant estrogens (phytoestrogens), such as genistein, can behave as partial estrogen receptor agonists.
An "antagonist for a nuclear receptor" is an agent that reduces or blocks activity mediated by the receptor in response to an agonist of the receptor. The activity of the antagonist can be mediated, e.g., by blocking binding of the agonist to the receptor, or by altering receptor configuration and/or activity of the receptor. A "putative antagonisf is an agent to be tested for antagonist activity. A "nuclear receptor" is a receptor that activates or represses transcription of one or more genes in the nucleus (but can also have second messenger signaling actions), typically in conjunction with other transcription factors. The nuclear receptor is activated by the natural cognate ligand for the receptor. Nuclear receptors are ordinarily found in the cytoplasm or nucleus, rather than being membrane-bound. Nuclear receptor is a member of a superfamily of regulatory proteins that are receptors for, e.g., steroids, retinoids, vitamin D and thyroid hormones. These proteins bind to cis-acting elements in the promoters of their target genes and modulate gene expression in response to a ligand therefor. Nuclear receptors may be classified based on their DNA binding properties. For example, the glucocorticoid, estrogen, androgen, progestin and mineralocorticoid receptors bind as homodimers to hormone response elements (BDREs) organized as inverted repeats. Another example are receptors, including those activated by retinoic acid, thyroid hormone, vitamin D3, fatty acids/peroxisome proliferators and ecdysone, that bind to HREs as heterodimers with a common partner, the retinoid X receptor (RXR). Among the latter receptors is LXR.
As used herein, an orphan nuclear receptor is a nuclear receptor for which the natural ligand is unknown.
As used herein, liver X receptor or LXR refers to a nuclear receptor implicated in cholesterol biosynthesis. As used herein, the term LXR refers to both LXRα and LXRβ, two forms of the protein found in mammals. Liver X receptor-α. or LXRα refers to the receptor described in U.S. Pat. Nos. 5,571,696, 5,696,233 and 5,710,004, and WUIy et al. (1995) Gene Dev. 9(9):1033-1045. Liver X receptor-β or LXRβ refers to the receptor described in Peet et al. (1998) Curr. Opin. Genet. Dev. 8(5):571-575; Song et al. (1995) Ann. N.Y. Acad. ScL 761:38-49; Alberti et al. (2000) Gene 243(1- 2):93-103; and references cited therein; and in U.S. Pat. Nos.5,571,696, 5,696,233 and 5,710,004.
As used herein, compounds which are "commercially available" may be obtained from standard commercial sources including Acros Organics (Pittsburgh PA), Aldrich Chemical (Milwaukee WI, including Sigma Chemical and Fluka), Apin Chemicals Ltd. (Milton Park UK), Avocado Research (Lancashire U.K.), BDH Inc. (Toronto, Canada), Bionet (Cornwall, UJC), Chemservice Inc. (West Chester PA), Crescent Chemical Co. (Hauppauge NY), Eastman Organic Chemicals, Eastman Kodak Company (Rochester NY), Fisher Scientific Co. (Pittsburgh PA), Fisons Chemicals (Leicestershire UK), Frontier Scientific (Logan UT), ICN Biomedicals, Inc. (Costa Mesa CA), Key Organics (Cornwall U.K.), Lancaster Synthesis (Windham NH), Maybridge Chemical Co. Ltd. (Cornwall U.K.), Parish Chemical Co. (Orem UT), Pfaltz & Bauer, Inc. (Waterbury CN), Polyorganix (Houston TX), Pierce Chemical Co. (Rockford IL), Riedel de Haen AG (Hannover, Germany), Spectrum Quality Product, Inc. (New Brunswick, NJ), TCI America (Portland OR), Trans World Chemicals, Inc. (Rockville MD), and Wako Chemicals USA, Inc. (Richmond VA). As used herein, "suitable conditions" for carrying out a synthetic step are explicitly provided herein or may be discerned by reference to publications directed to methods used in synthetic organic chemistry. The reference books and treatise set forth above that detail the synthesis of reactants useful in the preparation of compounds of the present invention, will also provide suitable conditions for carrying out a synthetic step according to the present invention.
As used herein, "methods known to one of ordinary skill in the art" may be identified though various reference books and databases. Suitable reference books and treatise that detail the synthesis of reactants useful in the preparation of compounds of the present invention, or provide references to articles that describe the preparation, include for example, "Synthetic Organic Chemistry", John Wiley & Sons, Inc., New York; S. R. Sandler et at, "Organic Functional Group Preparations," 2nd Ed., Academic Press, New York, 1983; H. O. House, 'Modern Synthetic Reactions", 2nd Ed., W. A. Benjamin, Inc. Menlo Park, Calif. 1972; T. L. Gilchrist, heterocyclic Chemistry", 2nd Ed., John Wiley & Sons, New York, 1992; J. March, "Advanced Organic Chemistry: Reactions, Mechanisms and Structure", 4th Ed., Wiley-Interscience, New York, 1992. Specific and analogous reactants may also be identified through the indices of known chemicals prepared by the Chemical Abstract Service of the American Chemical Society, which are available in most public and university libraries, as well as through on-line databases (the American Chemical Society, Washington, D.C. may be contacted for more details). Chemicals that are known but not commercially available in catalogs may be prepared by custom chemical synthesis houses, where many of the standard chemical supply houses (e.g., those listed above) provide custom synthesis services.
"Prodrugs" is meant to indicate a compound that may be converted under physiological conditions or by solvolysis to a biologically active compound of the invention. Thus, fee term "prodrug" refers to a metabolic precursor of a compound of the invention that is pharmaceutically acceptable. A prodrug may be inactive when administered to a subject in need thereof, but is converted in vivo to an active compound of the invention. Prodrugs are typically rapidly transformed in vivo to yield the parent compound of the invention, for example, by hydrolysis in blood. The prodrug compound often offers advantages of solubility, tissue compatibility or delayed release in a mammalian organism (see, Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam). A discussion of prodrugs is provided in Higuchi, T., et at, "Pro-drugs as Novel Delivery Systems," A.C.S. Symposium Series, Vol. 14, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated in full by reference herein. The term "prodrug" is also meant to include any covalently bonded carriers which release the active compound of the invention in vivo when such prodrug is administered to a mammalian subject Prodrugs of a compound of the invention may be prepared by modifying functional groups present in the compound of the invention in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound of the invention. By virtue of knowledge of pharmacodynamic processes and drug metabolism in vivo, those of skill in this art, once a pharmaceutically active compound is known, can design prodrugs of the compound (see, e.g., Nogrady (1985) Medicinal Chemistry A Biochemical Approach, Oxford University Press, New York, pages 388-392). Prodrugs include compounds of the invention wherein a hydroxy, amino or mercapto group is bonded to any group that, when the prodrug of the compound of the invention is administered to a mammalian subject, cleaves to form a free hydroxy, free amino or free mercapto group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of the invention and the like.
'Tolymorph" refers to the different crystal forms of a compound, resulting from the possibility of at least two different arrangements of the molecules of the compound in the solid state. Polymorphs of a given compound will be different in crystal structure but identical in liquid or vapor states. Different polymorphic forms of a given substance may differ from each other with respect to one or more physical properties, such as solubility and dissociation, true density, crystal shape, compaction behavior, flow properties, and/or solid state stability.
"Stable compound" and "stable structure" are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent
"Mammal" includes humans and domestic animals, such as cats, dogs, swine, cattle, sheep, goats, horses, rabbits, and the like.
"Optional" or "optionally" means that the subsequently described event of circumstances may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. For example, "optionally substituted aryl" means that the aryl radical may or may not be substituted and that the description includes both substituted aryl radicals as defined herein and aryl radicals having no substitution.
"Pharmaceutically acceptable carrier, diluent or excipienf includes without limitation any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersing agent suspending agent stabilizer, isotonic agent solvent or emulsifier which has been approved by the United States Food and Drug Administration as being acceptable for use in humans or domestic animals.
"Pharmaceutically acceptable salt3' includes both acid and base addition salts. "Pharmaceutically acceptable acid addition salt3 ' refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.
"Pharmaceutically acceptable base addition salt5' refers to those salts which retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Preferred inorganic salts are the ammonium, sodium, potassium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, dietibylamine, triethylarnine, tripropylamine, ethanolamine,
2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine.
"Pharmaceutically acceptable derivative" refers to pharmaceutically acceptable salts as defined herein and also includes esters, prodrugs, solvates and polymorphs of the compounds of the invention.
"Therapeutically effective amount" refers to that amount of a compound of the invention which, when administered to a mammal, preferably a human, is sufficient to effect treatment, as defined below, for a disease-state associated with nuclear receptor activity. The amount of a compound of the invention which constitutes a "therapeutically effective amounf will vary depending on the compound, the condition and its severity, and the age of the mammal to be treated, but can be determined routinely by one of ordinary skill in the art having regard to his own knowledge and to this disclosure. "Modulating" or "modulate" refers to the treating, prevention, suppression, enhancement or induction of a function or condition. For example, the compounds of the present invention can modulate hyperlipidemia by lowering cholesterol in a human, thereby suppressing hyperlipidemia.
"Treating" or "treatment" as used herein covers the treatment of a disease or condition associated with the nuclear receptor activity as disclosed herein, in a mammal, preferably a human, and includes: i. Preventing a disease or condition associated with the nuclear receptor activity from occurring in a mammal, in particular, when such mammal is predisposed to the disease or condition but has not yet been diagnosed as having it; ϋ. inhibiting a disease or condition associated with the nuclear receptor activity, Ie., arresting its development; or iii. relieving a disease or condition associated with the nuclear receptor activity, Ie., causing regression of the condition. The compounds of formulae Ia, Ib, Ic or Id or their pharmaceutically acceptable salts may contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)- or, as (D)- or (L)- for amino acids. The present invention is meant to include all such possible isomers, as well as, their racemic and optically pure forms. Optically active (*) and (-), (R)- and (S)-, or (D)- and (L)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as reverse phase HPLC. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. It will be apparent to one skilled in the art that certain compounds of this invention may exist in tautomeric forms, all such tautomeric forms of the compounds being within the scope of the invention. Unless otherwise stated, structures depicted herein are also meant to include all stereochemical forms of the structure; Le., the R and S configurations for each asymmetric center. Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structure except for the replacement of a hydrogen atom by a deuterium or tritium, or the replacement of a carbon atom by a 13C- or 14C-enriched carbon are within the scope of this invention.
The chemical naming protocol and structure diagrams used herein employ and rely on the chemical naming features as utilized by the ChemDraw program (available from Cambridgesoft Corp., Cambridge, MA). In particular, the compound names were derived from the structures using the Autonom program as utilized by Chemdraw Ultra or ISIS base (MDL Corp.).
The term "atherosclerosis" refers to process whereby atherosclerotic plaques form within the inner lining of the artery wall leading to atherosclerotic cardiovascular diseases. Atherosclerotic cardiovascular diseases can be recognized and understood by physicians practicing in the relevant fields of medicine, and include without limitation, restenosis, coronary heart disease (also known as coronary artery heart disease or ischemic heart disease), cerebrovascular disease including ischemic stroke, multi- infarct dementia, and peripheral vessel disease, including intermittent claudication, and erectile dysfunction. The term "dyslipidemia" refers to abnormal levels of lipoproteins in blood plasma including both depressed and/or elevated levels of lipoproteins (e.g., elevated levels of Low Density Lipoprotein, (LDL), Very Low Density Lipoprotein (VLDL) and depressed levels of High Density Lipoprotein (HDL) (less than 40 mg/dL)). As used herein, "ECs0" refers to a dosage, concentration or amount of a particular test compound that elicits a dose-dependent response at 50% of maximal expression of a particular response that is induced, provoked or potentiated by the particular test compound.
The term "cholesterol" refers to a steroid alcohol that is an essential component of cell membranes and myelin sheaths and, as used herein, incorporates its common usage. Cholesterol also serves as a precursor for steroid hormones and bile acids.
The term "triglyceride^)" ("TGs"), as used herein, incorporates its common usage. TGs consist of three fatty acid molecules esterified to a glycerol molecule and serve to store fatty acids which are used by muscle cells for energy production or are taken up and stored in adipose tissue.
The term "hyperlipidemia" refers to the presence of an abnormally elevated level of lipids in the blood. Hyperlipidemia can appear in at least three forms: (1) hypercholesterolemia, Le., an elevated
LDL cholesterol level (120 mg/dL and above); (2) hypertriglyceridemia, Le., an elevated triglyceride level; (150 mg/dL and above) and (3) combined hyperlipidemia, Le., a combination of hypercholesterolemia and hypertriglyceridemia.
Exemplary Primary Hyperlipidemia include, but are not limited to, the following: (1) Familial Hyperchylomicronemia, a rare genetic disorder which causes a deficiency in an enzyme, LP lipase, that breaks down fat molecules. The LP lipase deficiency can cause the accumulation of large quantities of fat or lipoproteins in the blood;
(2) Familial Hypercholesterolemia, a relatively common genetic disorder caused where the underlying defect is a series of mutations in the LDL receptor gene that result in malfunctioning LDL receptors and/or absence of the LDL receptors. This brings about ineffective clearance of
LDL by the LDL receptors resulting in elevated LDL and total cholesterol levels in the plasma;
(3) Familial Combined Hyperlipidemia, also known as multiple lipoprotein-type hyperlipidemia; an inherited disorder where patients and their affected first-degree relatives can at various times manifest high cholesterol and high triglycerides. Levels of HDL cholesterol are often moderately decreased;
(4) Familial Defective Apolipoprotein B-IOO is a relatively common autosomal dominant genetic abnormality. The defect is caused by a single nucleotide mutation that produces a substitution of glutamine for arginine which can cause reduced affinity of LDL particles for the LDL receptor. Consequently, this can cause high plasma LDL and total cholesterol levels; Familial Dysbetalipoproteinemia, also referred to as Type III Hyperlipoproteinemia, is an uncommon inherited disorder resulting in moderate to severe elevations of serum triglyceride (TG) and cholesterol levels with abnormal apolipoprotein E function. HDL levels are usually normal; and Familial Hypertriglyceridemia, is a common inherited disorder in which the concentration of plasma VLDL is elevated. This can cause mild to moderately elevated triglyceride levels (and usually not cholesterol levels) and can often be associated with low plasma HDL levels.
Risk factors in exemplary Secondary Hyperlipidemia include, but are not limited to, the following: (1) disease risk factors, such as a history of type 1 diabetes, type 2 diabetes, Cushing's syndrome, hypothyroidism and certain types of renal failure; (2) drug risk factors, which include, birth control pills; hormones, such as estrogen, and corticosteroids; certain diuretics; and various beta. blockers; (3) dietary risk factors include dietary fat intake per total calories greater than 40%; saturated fat intake per total calories greater than 10%; cholesterol intake greater than 300 mg per day; habitual and excessive alcohol use; and obesity; and (4) non-genetic dyslipidemias. The methods of the present invention can be used effectively in combination with one or more additional active diabetes agents depending on the desired target therapy (see, e.g., Turner, N. et al. Prog. Drug Res. (1998) 51:33-94; Haffher, S. Diabetes Care (1998) 21: 160178; and DeFronzo, R. et al. (eds.), Diabetes Reviews (1997) Vol. 5 No. 4). A number of studies have investigated the benefits of combination therapies with oral agents (see, e.g., Mahler, R., J. Clin. Endocrinol. Metab. (1999)84:1165- 71; United Kingdom Prospective Diabetes Study Group: UKPDS 28, Diabetes Care (1998)21 :87-92; Bardin, C.W.(ed.), CURRENT THERAPY IN ENDOCRINOLOGY AND METABOLISM, 6th Edition (Mosby-Year Book, Inc., St. Louis, Mo. 1997); Chiasson, J. et al., Ann. Intern. Med. (1994) 121: 928-935; Coniff, R. et al., Clin.Ther. (1997) 19: 16-26; Coniff, R. et al., Am. J. Med. (1995) 98: 443-451; and Iwamoto, Y. et al, Diabet Med. (1996)13: 365-370; Kwiterovich, P. Am. J. Cardiol (1998) 82(12A):3U-17U). These studies indicate that diabetes and hyperlipidemia modulation can be further improved by the addition of a second agent to therapeutic regimenAs used herein, "IC50" refers to an amount, concentration or dosage of a particular test compound that achieves a 50% inhibition of a maximal response, such as modulation of nuclear receptor, including the LXRα or LXRβ activity, in an assay that measures such response. As used herein, "LXRα" (LXR alpha) refers to all mammalian forms of such receptor including, for example, alternative splice isoforms and naturally occurring isoforms. Representative LXRα species include, without limitation the rat (Genbank Accession NM_031627), mouse (Genbank Accession BC012646), and human (GenBank Accession No. U22662) forms of the receptor. As used herein, ςfLXRβ" (LXR beta) refers to all mammalian forms of such receptor including, for example, alternative splice isoforms and naturally occurring isoforms. Representative LXRβ species include, without limitation the rat (GenBank Accession TMM_031626), mouse (Genbank Accession NM_009473), and human (GenBank Accession No. U07132) forms of the receptor. As used herein "LXR" or "LXRs" refers to both LXRα and LXRβ.
The terms "obese" and "obesity" refers to a Body Mass Index (BMI) greater than 27.8 kg/m2 for men and 27.3 kg/m2 for women (BMI equals weight (kg)/(height)2(m2).
Use of the Compounds of the Invention
The compounds of the invention exhibit valuable pharmacological properties in mammals, and are particularly useful as selective LXR agonists, antagonists, inverse agonists, partial agonists and antagonists, for the treatment, or prevention of diseases associated with, or symptoms arising from the complications of, altered cholesterol transport, cholesterol reverse transport, fatty acid metabolism, cholesterol absorption, cholesterol re-absorption, cholesterol secretion, cholesterol excretion, or cholesterol metabolism. These diseases include, for example, hyperlipidemia, dyslipidemia, hypercholesterolemia, atherosclerosis, atherosclerotic cardiovascular diseases, hyperlipoproteinemia, (see, e.g., Patent Application Publication Nos. WO 00/57915 and WO 00/37077), hyperglycemia, insulin resistance, diabetes, lipodystrophy, obesity, syndrome X (US Patent Application No. 20030073614, International Patent Application Publication No. WO 01/82917), excess lipid deposition in peripheral tissues such as skin (xanthomas) (see, e.g., U.S. Patent Nos. 6,184,215 and 6,187,814), stroke, peripheral occlusive disease, memory loss (Brain Research (1997), Vol. 752, pp. 189-196), optic nerve and retinal pathologies (Le., macular degeneration, retintis pigmentosa), repair of traumatic damage to the central or peripheral nervous system (Trends in Neurosciences (1994), Vol. 17, pp. 525-530), prevention of the degenerative process due to aging (American Journal of Pathology (1997), Vol. 151, pp. 1371-1377), Parkinson's disease or Alzheimer's disease (see, e.g., International Patent Application Publication No. WO 00/17334; Trends in Neurosciences (1994), Vol. 17, pp. 525-530), prevention of degenerative neuropathies occurring in diseases such as diabetic neuropathies (see, e.g., International Patent Application Publication No. WO 01/82917), multiple sclerosis (Annals of Clinical Biochem. (1996), Vol.33, No.2, pp. 148-150), and autoimmune diseases (J Lipid Res. (1998), Vol.39, pp. 1740-1743). Also provided, are methods of increasing the expression of ATP-Binding Cassette (ABCAl),
(see, e.g., International Patent Application Publication No. WO 00/78972) thereby increasing reverse cholesterol transport in mammalian cells using the claimed compounds and compositions. Accordingly in another aspect, the invention also includes methods to remove cholesterol from tissue deposits such as atherosclerotic plaques or xanthomas in a patient with atherosclerosis or atherosclerotic cardiovascular disease manifest by clinical signs of such disease, wherein the methods comprise administering to the patient a therapeutically effective amount of a compound or composition of the present invention. Additionally, the instant invention also provides a method for preventing or reducing the risk of a first or subsequent occurrence of an atherosclerotic cardiovascular disease event including ischemic heart disease, ischemic stroke, multi-infarct dementia, and intermittent claudication comprising the administration of a prophylactically effective amount of a compound or composition of the present invention to a patient at risk for such an event. The patient may already have atherosclerotic cardiovascular disease at the time of administration, or may be at risk for developing it. Risk factors for developing atherosclerotic cardiovascular disease events include increasing age (65 and over), male gender, a family history of atherosclerotic cardiovascular disease events, high blood cholesterol (especially LDL or "bad" cholesterol over 100 mg/dL), cigarette smoking and exposure to tobacco smoke, high blood pressure, diabetes, obesity and physical inactivity. Also contemplated herein is the use of a compound of the invention, or a pharmaceutically acceptable derivative thereof, in combination with one or more of the following therapeutic agents in treating atherosclerosis: antihyperlipidemic agents, plasma HDL-raising agents, antihypercholesterolemic agents, cholesterol biosynthesis inhibitors (for example, BDVIG CoA reductase inhibitors, such as lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, and rivastatin), acyl- coenzyme A:cholesterol acytransferase (ACAT) inhibitors, probucol, raloxifene, nicotinic acid, niacinamide, cholesterol absorption inhibitors, HMG-CoA reductase inhibitor-cholesterol absorption inhibitor combinations (e.g., Vytorin), bile acid sequestrants (such as anion exchange resins, or quaternary amines (e.g., cholestyramine or colestipol), low density lipoprotein receptor inducers, clofibrate, fenofibrate, benzofibrate, cipofibrate, gemfibrizol, vitamin B6, vitamin Bi2, anti-oxidant vitamins, β-blockers, anti-diabetes agents, angiotensin II antagonists, angiotensin converting enzyme inhibitors, platelet aggregation inhibitors, fibrinogen receptor antagonists, aspirin or fibric acid derivatives.
In one embodiment compounds of the invention are used in combination with a cholesterol biosynthesis inhibitor, particularly an HMG-CoA reductase inhibitor. The term HMG-CoA reductase inhibitor is intended to include all pharmaceutically acceptable salt, ester, free acid and lactone forms of compounds which have HMG-CoA reductase inhibitory activity and, therefore, the use of such salts, esters, free acids and lactone forms is included within the scope of this invention. Compounds which have inhibitory activity for HMG-CoA reductase can be readily identified using assays well-known in the art For instance, suitable assays are described or disclosed in U.S. Patent No. 4,231,938 and WO 84/02131. Examples of suitable HMG-CoA reductase inhibitors include, but are not limited to, lovastatin (MEVACOR®; see, U.S. Patent No. 4,231,938); simvastatin (ZOCOR®; see, U.S. Patent No. 4,444,784); pravastatin sodium (PRAVACHOL®; see, U.S. Patent No. 4,346,227); fluvastatin sodium (LESCOL®; see, U.S. Patent No. 5,354,772); atorvastatin calcium (LIPITOR®; see, U.S. Patent No. 5,273,995) and rosuvastatin (CRESTOR®).The structural formulas of these and additional HMG-CoA reductase inhibitors that can be used in combination with the compounds of the invention are described at page 87 of M. Yalpani, "Cholesterol Lowering Drugs," Chemistry & Industry, pp. 85- 89 (5 February 1996). Ih presently preferred embodiments, the HMG-CoA reductase inhibitor is selected from lovastatin and simvastatin. The compounds of the present invention can also be used in methods for decreasing hyperglycemia and insulin resistance, i.e., in methods for treating diabetes (International Patent Application Publication No. WO 01/82917), and in methods of treatment, prevention, or amelioration of disorders related to, or arising as complications of diabetes, hyperglycemia or insulin resistance including the cluster of disease states, conditions or disorders that make up "Syndrome X" (See US Patent Application 20030073614) comprising the administration of a therapeutically effective amount of a compound or composition of the present invention to a patient in need of such treatment Additionally, the instant invention also provides a method for preventing or reducing the risk of developing hyperglycemia, insulin resistance, diabetes or syndrome X in a patient, comprising the administration of a prophylactically effective amount of a compound or composition of the present invention to a patient at risk for developing such a condition.
Diabetes mellitus, commonly called diabetes, refers to a disease process derived from multiple causative factors and characterized by elevated levels of plasma glucose, referred to as hyperglycemia. See, e.g., LeRoith, D. et al, (eds.), DIABETES MELLITUS (Lippincott-Raven Publishers, Philadelphia, Pa. U.SA. 1996). According to the American Diabetes Association, diabetes mellitus is estimated to affect approximately 6% of the world population. Uncontrolled hyperglycemia is associated with increased risk and premature mortality due to an increased risk for macrσvascular and macrovascular diseases, including nephropathy, neuropathy, retinopathy, hypertension, cerebrovascular disease and coronary heart disease. Therefore, control of glucose homeostasis is a critically important approach for the treatment of diabetes. There are two major forms of diabetes: type 1 diabetes (formerly referred to as insulin- dependent diabetes or IDEM); and type 2 diabetes (formerly referred to as noninsulin dependent diabetes or NIDDM).
Type 2 diabetes is a disease characterized by insulin resistance accompanied by relative, rather than absolute, insulin deficiency. Type 2 diabetes can range from predominant insulin resistance with relative insulin deficiency to predominant insulin deficiency with some insulin resistance. Insulin resistance is the diminished ability of insulin to exert its biological action across a broad range of concentrations. In insulin resistant individuals, the body secretes abnormally high amounts of insulin to compensate for this defect. When inadequate amounts of insulin are present to compensate for insulin resistance and adequate control of glucose, a state of impaired glucose tolerance develops. In a significant number of individuals, insulin secretion declines further and the plasma glucose level rises, resulting in the clinical state of diabetes. Type 2 diabetes can be due to a profound resistance to insulin stimulating regulatory effects on glucose and lipid metabolism in the main insulin-sensitive tissues: muscle, liver and adipose tissue. This resistance to insulin responsiveness results in insufficient insulin activation of glucose uptake, oxidation and storage in muscle and inadequate insulin repression of lipolysis in adipose tissue and of glucose production and secretion in liver. In Type 2 diabetes, free fatty acid levels are often elevated in obese and some non-obese patients and lipid oxidation is increased.
Premature development of atherosclerosis and increased rate of cardiovascular and peripheral vascular diseases are characteristic features of patients with diabetes. Hyperlipidemia is an important precipitating factor for these diseases. Hyperlipidemia is a condition generally characterized by an abnormal increase in serum lipids, e.g., cholesterol and triglyceride, in the bloodstream and is an important risk factor in developing atherosclerosis and heart disease. For a review of disorders of lipid metabolism, see, e.g., Wilson, J. et al, (ed.), Disorders of Lipid Metabolism, Chapter 23, Textbook of Endocrinology, 9th Edition, (W. B. Sanders Company, Philadelphia, Pa. U.S A. 1998). Hyperlipidemia is usually classified as primary or secondary hyperlipidemia. Primary hyperlipidemia is generally caused by genetic defects, while secondary hyperlipidemia is generally caused by other factors, such as various disease states, drugs, and dietary factors. Alternatively, hyperlipidemia can result from both a combination of primary and secondary causes of hyperlipidemia. Elevated cholesterol levels are associated with a number of disease states, including coronary artery disease, angina pectoris, carotid artery disease, strokes, cerebral arteriosclerosis, and xanthoma.
Dyslipidemia, or abnormal levels of lipoproteins in blood plasma, is a frequent occurrence among diabetics, and has been shown to be one of the main contributors to the increased incidence of coronary events and deaths among diabetic subjects (see, e.g., Joslin, E. Ann. Chim. Med. (1927), Vol. 5, pp. 1061-1079). Epidemiological studies since then have confirmed the association and have shown a several-fold increase in coronary deaths among diabetic subjects when compared with non-diabetic subjects (see, e.g., Garcia, M. J. et al., Diabetes (1974), Vol.23, pp. 105-11 (1974); and Laakso, M. and Lehto, S., Diabetes Reviews (1997), Vol.5, No.4, pp.294-315). Several lipoprotein abnormalities have been described among diabetic subjects (Howard B., et al., Arteriosclerosis (1978), Vol. 30, pp. 153- 162). The compounds of the invention can also be used effectively in combination with one or more additional active diabetes agents depending on the desired target therapy (see, e.g., Turner, N. et al., Prog. Drug Res. (1998), Vol. 51, pp.33-94; Haffiier, S., Diabetes Care (1998), Vol.21, pp. 160-178; and DeFronzo, R. et al. (eds.), Diabetes Reviews (1997), Vol. 5, No. 4). A number of studies have investigated the benefits of combination therapies with oral agents (see, e.g., Mahler, R., J. Clin. Endocrinol. Metab. (1999), Vol. 84, pp. 1165-71; United Kingdom Prospective Diabetes Study Group: UKPDS 28, Diabetes Care (1998), Vol. 21, pp. 87-92; Bardin, C. W.(ed.), CURRENT THERAPY IN ENDOCRINOLOGY AND METABOLISM, 6th Edition (Mosby-Year Book, Inc., St. Louis, Mo. 1997); Chiasson, J. et al., Ann. Intern. Med. (1994), Vol. 121, pp. 928-935; Coniff, R. et al., Clin. Ther. (1997), Vol.19, pp. 16-26; Coniff, R. et al., Am. J. Med. (1995), Vol. 98, pp. 443-451; Iwamoto, Y. et al., Diabet. Med. (1996), Vol. 13, pp. 365-370; Kwiterovich, P., Am. J. Cardiol (1998), Vol. 82 (12A), pp. 3U- 17U). These studies indicate that diabetes and hyperlipidemia modulation can be further improved by the addition of a second agent to therapeutic regimen.
Accordingly, the compounds of the invention may be used in combination with one or more of the following therapeutic agents in treating diabetes: sulfonylureas (such as chloφropamide, tolbutamide, acetohexamide, tolazamide, glyburide, gliclazide, glynase, glimepiride, and glipizide), biguanides (such as metformin), thiazolidinediones (such as ciglitazone, pioglitazone, and rosiglitazone), and related insulin sensitizers, such as selective and non-selective activators of PPARα, PPARβ/δ and PPARγ; dehydroepiandrosterone (also referred to as DHEA or its conjugated sulphate ester, DHEA- SO4); antiglucocorticoids; TNFαinhibitors; α-glucosidase inhibitors (such as acarbose, miglitol, and voglibose), pramlintide (a synthetic analog of the human hormone amylin), other insulin secretogogues (such as repaglinide, gliquidone, and nateglinide), insulin, as well as therapeutic agents discussed above for treating atherosclerosis.
Further provided by this invention are methods of using the compounds of the invention to treat obesity, as well as the complications of obesity. Obesity is linked to a variety of medical conditions including diabetes and hyperlipidemia. Obesity is also a known risk factor for the development of type 2 diabetes (See, e.g., Barrett-Conner, E., Epidemol. Rev. (1989), Vol. 11, pp. 172-181; andKnowler, et al., Am. J Clin. Nutr. (1991), Vol. 53, pp. 1543-1551).
In addition, the compounds of the invention can be used in combination with agents used in treated obesity or obesity-related disorders. Such agents, include, but are not limited to, phenylpropanolamine, phentermine, diethylpropion, mazindol, fenfluramine, dexfenfluramine, phentiramine, β3 adrenoceptor agonist agents; sibutramine, gastrointestinal lipase inhibitors (such as orlistat), and leptins. Other agents used in treating obesity or obesity-related disorders include neuropeptide Y, enterostatin, cholecytokinin, bombesin, amylin, histamine H3 receptors, dopamine D2 receptor modulators, melanocyte stimulating hormone, corticotrophin releasing factor, galanin and gamma amino butyric acid (GABA). Evaluation of the Use of the Compounds of the Invention Standard physiological, pharmacological and biochemical procedures are available for testing the compounds to identify those that possess biological activities that modulate the activity or nuclear receptors, including the LXRs (LXRα and LXRβ). Such assays include, for example, biochemical assays such as binding assays, fluorescence polarization assays, FRET based coactivator recruitment assays (see, generally, Glickman et al., J. Biomolecular Screening (2002), Vol. 7, No. 1, pp. 3-10, as well as cell based assays including the co-transfection assay, the use of LBD-GaI 4 chimeras and protein-protein interaction assays, (see, Lehmann. et al., J. Biol Chem. (1997), Vol. 272, No. 6, pp. 3137-3140.
High throughput screening systems are commercially available (see, e.g., Zymark Corp., Hopkinton, MA; Air Technical Industries, Mentor, OH; Beckman Instruments Inc., Fullerton, CA; Precision Systems, Inc., Natick, MA) that enable these assays to be run in a high throughput mode. These systems typically automate entire procedures, including all sample and reagent pipetting, liquid dispensing timed incubations, and final readings of the microplate in detector(s) appropriate for the assay. These configurable systems provide high throughput and rapid start up as well as a high degree of flexibility and customization. The manufacturers of such systems provide detailed protocols for various high throughput systems. Thus, for example, Zymark Corp. provides technical bulletins describing screening systems for detecting the modulation of gene transcription, ligand binding, and the like.
Assays that do not require washing or liquid separation steps are preferred for such high throughput screening systems and include biochemical assays such as fluorescence polarization assays (see, for example, Owicki, I, Biomol. Screen (2000 October), Vol. 5, No. 5, pp. 297), scintillation proximity assays (SPA) (see, for example, Carpenter et al., Methods MoI. Biol. (2002), VoI 190, pp. 31- 49) and fluorescence resonance energy transfer energy transfer (FRET) or time resolved FRET based coactivator recruitment assays (Mukherjee et al., J. Steroid Biochem. MoI. Biol. (2002 July); Vol. 81, No. 3, pp. 217-25; (Zhou et al., MoI. Endocrinol. (1998 October), Vol. 12, No. 10, pp. 1594-604). Generally such assays can be preformed using either the full length receptor, or isolated ligand binding domain (LBD). In the case of LXRα, the LBD comprises amino acids 188-447, for LXRβ the LDB comprises amino acids 198-461, and for FXR, the LBD comprises amino acids 244 to 472 of the full length sequence. If a fluorescently labeled ligand is available, fluorescence polarization assays provide a way of detecting binding of compounds to the nuclear receptor of interest by measuring changes in fluorescence polarization that occur as a result of the displacement of a trace amount of the label ligand by the compound. Additionally this approach can also be used to monitor the ligand dependent association of a fluorescently labeled coactivator peptide to the nuclear receptor of interest to detect ligand binding to the nuclear receptor of interest.
The ability of a compound to bind to a receptor, or heterodimer complex with RXR, can also be measured in a homogeneous assay format by assessing the degree to which the compound can compete off a radiolabelled ligand with known affinity for the receptor using a scintillation proximity assay (SPA). In this approach, the radioactivity emitted by a radiolabelled compound (for example, [3ETJ 24,25 Epoxycholesterol) generates an optical signal when it is brought into close proximity to a scintillant such as a YSI-copper containing bead, to which the nuclear receptor is bound. If the radiolabelled compound is displaced from the nuclear receptor the amount of light emitted from the nuclear receptor bound scintillant decreases, and this can be readily detected using standard microplate liquid scintillation plate readers such as, for example, a Wallac MicroBeta reader.
The heterodimerization of LXR with RXRα can also be measured by fluorescence resonance energy transfer (FRET), or time resolved FRET, to monitor the ability of the compounds provided herein to bind to LXR or other nuclear receptors. Both approaches rely upon the fact that energy transfer from a donor molecule to an acceptor molecule only occurs when donor and acceptor are in close proximity. Typically the purified LBD of the nuclear receptor of interest is labeled with biotin then mixed with stoichiometric amounts of europium labeled streptavidin (Wallac Inc.), and the purified LBD of RXRα is labeled with a suitable fluorophore such as CY5™. Equirnolar amounts of each modified LBD are mixed together and allowed to equilibrate for at least 1 hour prior to addition to either variable or constant concentrations of the sample for which the affinity is to be determined. After equilibration, the time-resolved fluorescent signal is quantitated using a fluorescent plate reader. The affinity of the compound can then be estimated from a plot of fluorescence versus concentration of compound added.
This approach can also be exploited to measure the ligand dependent interaction of a coactivator peptide with a nuclear receptor in order to characterize the agonist or antagonist activity of the compounds disclosed herein. Typically the assay in this case involves the use a recombinant Glutathiones-transferase (GST)-nuclear receptor ligand binding domain (LBD) fusion protein and a synthetic biotinylated peptide sequenced derived from the receptor interacting domain of a co-activator peptide such as the steroid receptor coactivator 1 (SRC-I). Typically GST-LBD is labeled with a europium chelate (donor) via a europium-tagged anti-GST antibody, and the coactivator peptide is labeled with allophycocyanin via a streptavidin-biotin linkage.
In the presence of an agonist for the nuclear receptor, the peptide is recruited to the GST-LBD bringing europium and allophycocyanin into close proximity to enable energy transfer from the europium chelate to the allophycocyanin. Upon excitation of the complex with light at 340 nm excitation energy absorbed by the europium chelate is transmitted to the allophycocyanin moiety resulting in emission at 665 nm. If the europium chelate is not brought in to close proximity to the allophycocyanin moiety there is little or no energy transfer and excitation of the europium chelate results in emission at 615 nm. Thus the intensity of light emitted at 665 nm gives an indication of the strength of the protein-protein interaction. The activity of a nuclear receptor antagonist can be measured by determining the ability of a compound to competitively inhibit (Le., IC50) the activity of an agonist for the nuclear receptor
In addition, a variety of cell based assay methodologies may be successfully used in screening assays to identify and profile the specificity of compounds of the present invention. These approaches include the co-transfection assay, translocation assays, complementation assays and the use of gene activation technologies to over express endogenous nuclear receptors.
Three basic variants of the co-transfection assay strategy exist, co-transfection assays using full- length nuclear receptor, co transfection assays using chimeric nuclear receptors comprising the ligand binding domain of the nuclear receptor of interest fused to a heterologous DNA binding domain, and assays based around the use of the mammalian two hybrid assay system.
The basic co-transfection assay is based on the co-transfection into the cell of an expression plasmid to express the nuclear receptor of interest in the cell with a reporter plasmid comprising a reporter gene whose expression is under the control of DNA sequence that is capable of interacting with that nuclear receptor (see, for example, US Patents Nos. 5,071,773; 5,298,429 and 6,416,957). Treatment of the transfected cells with an agonist for the nuclear receptor increases the transcriptional activity of that receptor which is reflected by an increase in expression of the reporter gene which may be measured by a variety of standard procedures.
For those receptors that function as heterodimers with RXR, such as the LXRs, the co- transfection assay typically includes the use of expression plasmids for both the nuclear receptor of interest and RXR. Typical co-transfection assays require access to the full length nuclear receptor and suitable response elements that provide sufficient screening sensitivity and specificity to the nuclear receptor of interest. Typically, the expression plasmid comprises: (1) a promoter, such as an SV40 early region promoter, HSV tk promoter or phosphoglycerate kinase (pgk) promoter, CMV promoter, Srα promoter or other suitable control elements known in the art, (2) a cloned polynucleotide sequence, such as a cDNA encoding a receptor, co-factor, or fragment thereof, ligated to the promoter in sense orientation so that transcription from the promoter will produce a RNA that encodes a functional protein, and (3) a polyadenylation sequence. For example and not limitation, an expression cassette of the invention may comprise the cDNA expression cloning vectors, or other preferred expression vectors known and commercially available from vendors such as Invitrogen, (CA), Stratagene, (CA) or Clontech, (CA). Alternatively expression vectors developed by academic groups such as the pCMX vectors originally developed in the Evans lab (Willey et al. Genes & Development 9 1033-1045 (1995)) may also be used. The transcriptional regulatory sequences in an expression cassette are selected by the practitioner based on the intended application; depending upon the specific use, transcription regulation can employ inducible, repressible, constitutive, cell-type specific, developmental stage-specific, sex- specific, or other desired type of promoter or control sequence. Alternatively, the expression plasmid may comprise an activation sequence to activate or increase the expression of an endogenous chromosomal sequence. Such activation sequences include for example, a synthetic zinc finger motif (for example, see US Patents 6,534,261 and 6,503,7171) or a strong promoter or enhancer sequence together with a targeting sequence to enable homologous or nonhomologous recombination of the activating sequence upstream of the gene of interest. Genes encoding the following full-length previously described proteins, which are suitable for use in the co-transfection studies and profiling the compounds described herein, include human LXRα (accession U22662), human LXRβ (accession U07132), rat FXR (accession Ul 8374), human FXR (accession NM_005123), human RXRα (accession NM_002957), human RXRβ (accession XM_042579), human RXRγ (accession XM_053680), human PPARα (accession X57638) and human PPARδ (accession Ul 0375). All accession numbers in this application refer to GenBank accession numbers.
Reporter plasmids may be constructed using standard molecular biological techniques by placing cDNA encoding for the reporter gene downstream from a suitable minimal promoter. For example luciferase reporter plasmids may be constructed by placing cDNA encoding firefly luciferase (typically with SV40 small t intron and poly-A tail, (de Wet et al., (1987) MoI. Cell. Biol. 7 725-735) down stream from the herpes virus thymidine kinase promoter (located at nucleotides residues-105 to +51 of the thymidine kinase nucleotide sequence, obtained for example, from the plasmid pBLCAT2 (Luckow & Schutz (1987) Nucl. Acid. Res.15 5490-5494)) which is linked in turn to the appropriate response element (TRE).
The choice of hormone response element is dependent upon the type of assay to be used. In the case of the use of the full-length LXRα or LXRβ a reporter plasmid comprising a known LXR RE would typically be used, such as for example in a reporter plasmid such as LXRExI -tk-luciferase, (see U.S. patent No. 5,747,661, which is hereby incorporated by reference). In the case of a LXRα or LXRβ-LBD-Gal4 fusion, GAL4 Upstream Activating Sequences (UAS) would be used. Typically the GAL4 UAS would comprise the sequence 5'CGGRNNRCYNYNCNCCG-S', where Y = C or T, R =A or G, and N = A, C, T or G, and would be present as a tandem repeat of 4 copies. Numerous methods of co-transfecting the expression and reporter plasmids are known to those of skill in the art and may be used for the co-transfection assay to introduce die plasmids into a suitable cell type. Typically such a cell will not endogenously express nuclear receptors that interact with the response elements used in the reporter plasmid.
Numerous reporter gene systems are known in the art and include, for example, alkaline phosphatase (see, Berger, I, et al., Gene (1988), Vol. 66, pp. 1-10; and Kain, S.R, Methods. MoI. Biol. (1997), Vol. 63, pp. 49-60), β-galactosidase (See, U.S. Patent No. 5,070,012, issued Dec, 3, 1991 to Nolan et al., and Bronstein, L, et al., J. Chemilum. Biolum. (1989), Vol.4, pp. 99-111), chloramphenicol acetyltransferase (See, Gorman et al., MoI. Cell Biol. (1982), Vol. 2, pp. 1044-51), β-glucuronidase, peroxidase, β-lactamase (U.S. Patent Nos. 5,741,657 and 5,955,604), catalytic antibodies, luciferases (US. Patents 5,221,623; 5,683,888; 5,674,713; 5,650,289; and 5,843,746) and naturally fluorescent proteins (Tsien, RY., Annu. Rev. Biochem. (1998), Vol.67, pp.509-44).
The use of chimeras comprising the ligand binding domain (LBD) of the nuclear receptor of interest to a heterologous DNA binding domain (DBD) expands the versatility of cell based assays by directing activation of the nuclear receptor in question to defined DNA binding elements recognized by defined DNA binding domain (see WO95/18380). This assay expands the utility of cell based co- transfection assays in cases where the biological response or screening window using the native DNA binding domain is not satisfactory.
In general the methodology is similar to that used with the basic co-transfection assay, except that a chimeric construct is used in place of the full length nuclear receptor. As with the full length nuclear receptor, treatment of the transfected cells with an agonist for the nuclear receptor LBD increases the transcriptional activity of the heterologous DNA binding domain which is reflected by an increase in expression of the reporter gene as described above. Typically for such chimeric constructs, the DNA binding domains from defined nuclear receptors, or from yeast or bacterially derived transcriptional regulators such as members of the GAL 4 and Lex A / Umud super families are used.
A third cell based assay of utility for screening compounds of the present invention is a mammalian two-hybrid assay that measures the ability of the nuclear hormone receptor to interact with a cofactor in the presence of a ligand (see, for example, US Patent Nos. US 5,667,973, 5,283,173 and 5,468,614). The basic approach is to create three plasmid constructs that enable the interaction of the nuclear receptor with the interacting protein to be coupled to a transcriptional readout within a living cell. The first construct is an expression plasmid for expressing a fusion protein comprising the interacting protein, or a portion of that protein containing the interacting domain, fused to a GAL4 DNA binding domain. The second expression plasmid comprises DNA encoding the nuclear receptor of interest fused to a strong transcription activation domain such as VP16, and the third construct comprises the reporter plasmid comprising a reporter gene with a minimal promoter and GAL4 upstream activating sequences.
Once all three plasmids are introduced into a cell, the GAL4 DNA binding domain encoded in the first construct allows for specific binding of the fusion protein to GAL4 sites upstream of a minimal promoter. However because the GAL4 DNA binding domain typically has no strong transcriptional activation properties in isolation, expression of the reporter gene occurs only at a low level. In the presence of a ligand, the nuclear receptor-VP16 fusion protein can bind to the GAL4-interacting protein fusion protein bringing the strong transcriptional activator VP16 in close proximity to the GAL4 binding sites and minimal promoter region of the reporter gene. This interaction significantly enhances the transcription of the reporter gene which can be measured for various reporter genes as described above. Transcription of the reporter gene is thus driven by the interaction of the interacting protein and nuclear receptor of interest in a ligand dependent fashion.
Any compound which is a candidate for activation of LXRα or LXRβ may be tested by these methods. Generally, compounds are tested at several different concentrations to optimize the chances that activation of the receptor will be detected and recognized if present Typically assays are performed in triplicate and vary within experimental error by less than 15%. each experiment is typically repeated three or more times with similar results.
Activity of the reporter gene can be conveniently normalized to the internal control and the data plotted as fold activation relative to untreated cells. A positive control compound (agonist) may be included along with DMSO as high and low controls for normalization of the assay data. Similarly, antagonist activity can be measured by determining the ability of a compound to competitively inhibit the activity of an agonist Additionally the compounds and compositions can be evaluated for their ability to increase or decrease the expression of genes known to be modulated by LXRα or LXRβ and other nuclear receptors in vivo, using Northern-blot, RT PCR or oligonucleotide microarray analysis to analyze RNA levels. Western-blot analysis can be used to measure expression of proteins encoded by LXR target genes. Genes that are known to be regulated by the LXRs include the ATP binding cassette transporters ABCAl, ABCGl, ABCG5, ABCG8, the sterol response element binding protein Ic (SREBPIc) gene, stearoyl CoA desaturase 1 (SCD-I) and the apolipoproteinapoE gene (ApoE).
Established animal models exist for a number of diseases of direct relevance to the claimed compounds and these can be used to further profile and characterize the claimed compounds. These model systems include diabetic dislipidemia using Zucker (fa/fa) rats or (db/db) mice, spontaneous hyperlipidemia using apolipoprotein E deficient mice (ApoE7"), diet-induced hyperlipidemia, using low density lipoprotein receptor deficient mice (LDLR7) and atherosclerosis using both the Apo E(7O and LDLRCO mice fed a western diet. (21% fat, 0.05% cholesterol). Additionally LXR or FXR animal models (e.g., knockout mice) can be used to further evaluate the present compounds and compositions in vh'o (see, for example, Peet, et al., Cell (1998), Vol. 93, pp. 693-704, and Sinai, et al., Cell (2000), Vol. 102, pp. 731-744).
Administration of the Compounds of the Invention
Administration of the compounds of the invention, 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 of agents for serving similar utilities. The pharmaceutical compositions of the invention can be prepared by combining a compound of the invention with an appropriate pharmaceutically acceptable carrier, diluent or excipient, (and may be formulated into preparations in solid, semi-solid, liquid or gaseous forms, such as tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants, gels, microspheres, and aerosols. Typical routes of administering such pharmaceutical compositions include, without limitation, oral, topical, transdermal, inhalation, parenteral, sublingual, rectal, vaginal, and intranasal. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques. Pharmaceutical compositions of the invention are formulated so as to allow the active ingredients contained therein to be bioavailable upon administration of the composition to a patient. Compositions that will be administered to a subject or patient take the form of one or more dosage units, where for example, a tablet may be a single dosage unit, and a container of a compound of the invention in aerosol form may hold a plurality of dosage units. 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, Pennsylvania, 1990). The composition to be administered will, in any event, contain a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, for treatment of a disease-state associated with the activity of anuclear receptor in accordance with the teachings of this invention. A pharmaceutical composition of the invention may be in the form of a solid or liquid. In one aspect, the carrier(s) are particulate, so that the compositions are, for example, in tablet or powder form. The carriers) may be liquid, with the compositions being, for example, an oral syrup, injectable liquid or an aerosol, which is useful in, e.g., inhalatory administration.
When intended for oral administration, the pharmaceutical composition is preferably in either solid or liquid form, where semi-solid, semi-liquid, suspension and gel forms are included within the forms considered herein as either solid or liquid.
As a solid composition for oral administration, the pharmaceutical composition may be formulated into a powder, granule, compressed tablet, pill, capsule, chewing gum, wafer or the like form. Such a solid composition will typically contain one or more inert diluents or edible carriers. In addition, one or more of the following may be present: binders such as carboxymethylcellulose, ethyl cellulose, microcrystalline cellulose, gum tragacanth or gelatin; excipients such as starch, lactose or dextrins, disintegrating agents such as alginic acid, sodium alginate, Primogel, com starch and the like; lubricants such as magnesium stearate or Sterotex; glidants such as colloidal silicon dioxide; sweetening agents such as sucrose or saccharin; a flavoring agent such as peppermint, methyl salicylate or orange flavoring; and a coloring agent
When the pharmaceutical composition is in the form of a capsule, e.g., a gelatin capsule, it may contain, in addition to materials of the above type, a liquid carrier such as polyethylene glycol or oil.
The pharmaceutical composition may be in the form of a liquid, e.g., an elixir, syrup, solution, emulsion or suspension. The liquid may be for oral administration or for delivery by injection, as two examples. When intended for oral administration, preferred composition contain, in addition to the present compounds, one or more of a sweetening agent, preservatives, dye/colorant and flavor enhancer.
In a composition intended to be administered by injection, one or more of a surfactant, preservative, wetting agent, dispersing agent, suspending agent, buffer, stabilizer and isotonic agent may be included.
The liquid pharmaceutical compositions of the invention, whether they be solutions, suspensions or other like form, may include one or more of the following adjuvants: sterile diluents such as water for injection, saline solution, preferably physiological saline, Ringer's solution, isotonic sodium chloride, fixed oils such as synthetic mono or diglycerides which may serve as the solvent or suspending medium, polyethylene glycols, glycerin, propylene glycol or other solvents; antibacterial agents such as benzyl alcohol or methyl paraben; antioxidants such as ascprbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic. Physiological saline is a preferred adjuvant An injectable pharmaceutical composition is preferably sterile.
A liquid pharmaceutical composition of the invention intended for either parenteral or oral administration should contain an amount of a compound of the invention such that a suitable dosage will be obtained. Typically, this amount is at least 0.01% of a compound of the invention in the composition. When intended for oral administration, this amount may be varied to be between 0.1 and about 70% of the weight of the composition. Preferred oral pharmaceutical compositions contain between about 4% and about 50% of the compound of the invention. Preferred pharmaceutical compositions and preparations according to the present invention are prepared so that a parenteral dosage unit contains between 0.01 to 1% by weight of the compound of the invention.
The pharmaceutical composition of the invention may be intended for topical administration, in which case the carrier may suitably comprise a solution, emulsion, ointment or gel base. The base, for example, may comprise one or more of the following: petrolatum, lanolin, polyethylene glycols, bee wax, mineral oil, diluents such as water and alcohol, and emulsifiers and stabilizers. Thickening agents may be present in a pharmaceutical composition for topical administration. If intended for transdennal administration, the composition may include a transdermal patch or iontophoresis device. Topical formulations may contain a concentration of the compound of the invention from about 0.1 to about 10% w/v (weight per unit volume).
The pharmaceutical composition of the invention may be intended for rectal administration, in the form, e.g., of a suppository, which will melt in the rectum and release the drug. The composition for rectal administration may contain an oleaginous base as a suitable nonirritating excipient. Such bases include, without limitation, lanolin, cocoa butter and polyethylene glycol.
The pharmaceutical composition of the invention may include various materials, which modify the physical form of a solid or liquid dosage unit. For example, the composition may include materials that form a coating shell around the active ingredients. The materials that form the coating shell are typically inert, and may be selected from, for example, sugar, shellac, and other enteric coating agents. Alternatively, the active ingredients may be encased in a gelatin capsule.
The pharmaceutical composition of the invention in solid or liquid form may include an agent that binds to the compound of the invention and thereby assists in the delivery of the compound. Suitable agents that may act in this capacity include a monoclonal or polyclonal antibody, a protein or a liposome. The pharmaceutical composition of the invention may consist of dosage units that can be administered as an aerosol. The term aerosol is used to denote a variety of systems ranging from those of colloidal nature to systems consisting of pressurized packages. Delivery may be by a liquefied or compressed gas or by a suitable pump system that dispenses the active ingredients. Aerosols of compounds of the invention may be delivered in single phase, bi-phasic, or tri-phasic systems in order to deliver the active ingredient(s). Delivery of the aerosol includes the necessary container, activators, valves, subcontainers, and the like, which together may form a kit One skilled in the art, without undue experimentation may determine preferred aerosols.
The pharmaceutical compositions of the invention may be prepared by methodology well known in the pharmaceutical art. For example, a pharmaceutical composition intended to be administered by injection can be prepared by combining a compound of the invention with sterile, distilled water so as to form a solution. A surfactant may be added to facilitate the formation of a homogeneous solution or suspension. Surfactants are compounds that non-covalently interact with the compound of the invention so as to facilitate dissolution or homogeneous suspension of the compound in the aqueous delivery system.
The compounds of the invention, 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, and diet of the patient; the mode and time of administration; the rate of excretion; the drug combination; the severity of the particular disorder or condition; and the subject undergoing therapy. Generally, a therapeutically effective daily dose is from about 0.1 mg to about 20 mg/kg of body weight per day of a compound of the invention, or a pharmaceutically acceptable salt thereof; preferably, from about 0.1 mg to about 10 mg/kg of body weight per day; and most preferably, from about 0.1 mg to about 7.5 mg/kg of body weight per day. Compounds of the invention, or pharmaceutically acceptable derivatives thereof, may also be administered simultaneously with, prior to, or after administration of one or more of therapeutic agents described above in the Utility of the Compounds of the Invention. Such combination therapy includes administration of a single pharmaceutical dosage formulation which contains a compound of the invention and one or more additional active agents, as well as administration of the compound of the invention and each active agent in its own separate pharmaceutical dosage formulation. For example, a compound of the invention and an HMG-CoA reductase inhibitor can be administered to the patient together in a single oral dosage composition such as a tablet or capsule, or each agent administered in separate oral dosage formulations. Where separate dosage formulations are used, the compounds of the invention and one or more additional active agents can be administered at essentially the same time, Le., concurrently, or at separately staggered times, i.e., sequentially; combination therapy is understood to include all these regimens.
Dosage information for HMG-CoA reductase inhibitors is well known in the art, since several HMG-CoA reductase inhibitors are marketed in the U.S. In particular, the daily dosage amounts of the HMG-CoA reductase inhibitor may be the same or similar to those amounts which are employed for anti-hypercholesterolemic treatment and which are described in the Physicians' Desk Reference (PDR). For example, see the 50th Ed. of the PDR, 1996 (Medical Economics Co); in particular, see at page 216 the heading 'Hypolipidemics," sub-heading 'ΗMG-CoA Reductase Inhibitors," and the reference pages cited therein. Preferably, the oral dosage amount of HMG-CoA reductase inhibitor is from about 1 to 200 mg/day and, more preferably, from about 5 to 160 mg/day. However, dosage amounts will vary depending on the potency of the specific HMG-CoA reductase inhibitor used as well as other factors as noted above. An HMG-CoA reductase inhibitor which has sufficiently greater potency may be given in sub-milligram daily dosages.
As examples, the daily dosage amount for simvastatin may be selected from 5 mg, 10 mg, 20 mg, 40 mg, 80 mg and 160 mg for lovastatin, 10 mg, 20 mg, 40 mg and 80 mg; for fluvastatin sodium, 20 mg, 40 mg and 80 mg; and for pravastatin sodium, 10 mg, 20 mg, and 40 mg. The daily dosage amount for atorvastatin calcium may be in the range of from 1 mg to 160 mg and, more particularly, from 5 mg to 80 mg. Oral administration may be in a single or divided doses of two, three, or four times daily, although a single daily dose of the HMG-CoA reductase inhibitor is preferred.
Preparation of the Compounds of the Invention
It is understood that in the following description, combinations of substituents and/or variables of the depicted formulae are permissible only if such contributions result in stable compounds.
It will also be appreciated by those skilled in the art that in the processes described below the functional groups of intermediate compounds may need to be protected by suitable protecting groups. Such functional groups include hydroxy, amino, mercapto and carboxylic acid. Suitable protecting groups for hydroxy include trialkylsilyl or diarylalkylsilyl (e.g., t-butyldimethylsilyl, t-buryldiphenylsilyl or trimethylsilyl), tetrahydropyranyl, benzyl, and the like. Suitable protecting groups for 1,2-dihydroxys include ketal- and acetal-forming groups. Suitable protecting groups for amino, amidino and guanidino include t-butoxycarbonyl, benzyloxycarbonyl, and the like. Suitable protecting groups for mercapto include -C(O)-R (where R is alkyl, aryl or aralkyl), /nmethoxybenzyl, trityl and the like. Suitable protecting groups for carboxylic acid include alkyl, aryl or aralkyl esters.
Protecting groups may be added or removed in accordance with standard techniques, which are well-known to those skilled in the art and as described herein. The use of protecting groups is described in detail in Green, TVW. and P.G.M. Wutz, Protective Groups in Organic Synthesis (1991), 2nd Ed., Wiley-Interscience. The protecting group may also be a polymer resin such as a Wang resin or a 2-chlorotriryl chloride resin.
It will also be appreciated by those skilled in the art, although such protected derivatives of compounds of the invention, as described above in the Summary of the Invention and first aspect of the invention, may not possess pharmacological activity as such, they may be administered to a mammal having a disease associated with defects in cholesterol transport, glucose metabolism, fatty acid metabolism and cholesterol metabolism, and thereafter metabolized in the body to form compounds of the invention which are pharmacologically active. Such derivatives may therefore be described as "prodrugs". All prodrugs of compounds of the invention are included within the scope of the invention. It is understood that one of ordinary skill in the art would be able to make the compounds of the invention not specifically prepared herein in light of the following disclosure, including the Preparations and Examples, and information known to those of ordinary skill in the chemical synthesis field.
Starting materials in the synthesis examples provided herein are either available from commercial sources or via literature procedures or by methods disclosed herein. All commercially available compounds were used without further purification unless otherwise indicated. Deuterated solvents such as DMSO or CDCl3 (99.8% D, Cambridge Isotope Laboratories) were used in all experiments as indicated. 1H NMR spectra were recorded on a Bruker Avance 400 MHz NMR spectrometer. Significant peaks are tabulated and typically include: number of protons, multiplicity (s, singlet; d, double; t, triplet; q, quartet; m, multiplet; br s, broad singlet) and coupling constants) in Hertz. Chemical shifts are reported as parts per million (δ) relative to tetramethylsilane. Mass spectra were recorded on a Perkin-Elrner SCIEX HPLC/MS instrument using reverse-phase conditions (acetonitrile/water, 0.05% trifluoroacetic acid) and electrospray (ES) ionization. Abbreviations used in the examples below have their accepted meanings in the chemical literature. For example, CH2Cl2 (dichloromethane), C6H6 (benzene), TFA (trifluoroacetic acid), EtOAc (Ethyl Acetate), Et2O (diethyl ether), DMAP (4-dimethylaminopyridine), DMF (N,N-dimethylformamide) and THF (tetrahydrofuran). Flash chromatography was performed using Merck Silica Gel 60 (230-400 mesh).
For purposes of illustration only, most of the formulae in the following Reaction Schemes are directed to specific embodiments of the compounds of invention. However, one of ordinary skill in the art, in view of the teachings of this specification would reasonably be expected to be able to prepare all the compounds of the invention in the Summary of the Invention and first aspect of the invention utilizing the appropriately-substituted starting materials and methods known to one skilled in the art.
In the general descriptions immediately following each Reaction Scheme, the phrase "standard isolation procedures" is meant to include one or more of the following techniques familiar to one schooled in the art of organic chemistry: organic extraction, washing of organic solutions with dilute aqueous acid or base, use of drying agents, filtration, concentration in vacuo, followed by purification using distillation, crystallization, or solid-liquid phase chromatography. The phrase "elevated temperature" refers to a temperature above ambient temperature and the phrase "reduced temperature" refers to a temperature below ambient temperature.
The following specific Preparations (for intermediates) and Examples (for compounds, pharmaceutical compositions and methods of use of the invention) are provided as a guide to assist in the practice of the invention, and are not intended as a limitation on the scope of the invention. Without further description, it is believed that one of ordinary skill in the art can, using the preceding description and the following illustrative examples, make and utilize the compounds of the present invention and practice the claimed methods. It should be understood that the foregoing discussion and examples merely present a detailed description of certain preferred embodiments. It will be apparent to one of ordinary skill in the art that various modifications and equivalents can be made without departing from the spirit and scope of the invention. SYNTEBESIS
Pyrazole Ia
Scheme 1
Figure imgf000119_0001
The method for preparing compounds of the invention is illustrated in Scheme 1. Amines (OOli) can be converted to hydrazines (OOlii) using standard techniques that are readily apparent to one skilled in the arts. Acetophenones (OOliϋ) can be converted to diketones (OOlrv) via a Claisen condensation. Hydrazines (OOlii) and diketones (OOliv) can be condensed to form pyrazoles (OOlv) thermally or with the aid of catalysts such as acid. Aryl bromides such as (00Iv) can then be elaborated further by an arylation reaction such as a Suzuki reaction to form a tetra-aryl ring system (OOlvi).
An alternative means of preparing compounds of the present invention is shown in Scheme 2. Thiophene ketones (002iϋ) can be elaborated upon by addition of substituents such as aryl rings and these (002vϋ) elaborated ketones can then be converted to diketones (002vϋi). Diketones (002viϋ) and hydrazines (002ii) can condense to form pyrazoles (002vi) either thermally or with the aid of catalyst Scheme 2
Figure imgf000120_0001
Example 1
3-{5-[2~(2,5-Dichhroψhe}ψl)-5-Mfluorometlψl-2H-p)^"cιzol-3-yl]4hiophen-2-yl}-bemene
Example Ia
Preparation of 'l-(5-Bromo-thiopPien-2-yl)-4,4,4-trifluoro-butane-l,3-dione
Figure imgf000120_0002
In a 2-L, three-necked round bottom flask fitted with a 250 mL pressure equalizing addition funnel, an overhead stirrer, and a thermocouple was placed lithium hexamethyldisilazide (500 mL of a 1.0 M solution in THF, 500 mmol) and THF (100 mL). A solution of l-(5-bromo-thiophen-2-yl)- ethanone (75.5 g, 368 mmol) was prepared in THF (350 mL). This solution was added via cannula to the addition funnel in portions and added slowly from the addition funnel to the reaction flask at a rate such that the internal temperature was < -70 °C (~ 40 minutes). The ketone flask and addition funnel were then rinsed with additional THF (25 mL) to insure complete transfer. After stirring for 15 minutes at < -70 0C, ethyl trifluoroacetate (66 mL, 553 mmol) was added from the addition funnel as a solution in THF (100 mL) over ~ 45 minutes. The pale brown reaction was allowed to warm to ambient temperature overnight After stirring for ~ 16 hours the reaction was cooled in an ice bath and carefully quenched by the addition of 3N aqueous HCl (150 mL). The quench was highly exothermic. After the completion of the HCl addition the basic aqueous layer was separated and the organic layer was concentrated under reduced pressure to remove most of the THF. The resulting brown biphasic mixture was combined with the aqueous layer and diluted with Et2O (~700 mL). The mixture was acidified by the addition of 3N HCl to pH < 3. The layers were separated and the acidic aqueous was extracted with Et2O (3 x 150 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to afford a brown oil. This oil was taken up in benzene and concentrated under reduced pressure to remove any residual water present. The resulting oil was pumped down under high vacuum and seeded with authentic product to afford l-(5-bromo-thiophen-2-yl)-4,4,4-trifluoro-butane- l,3-dione (111.7 g, 100.8 % yield) as apale brown solid. 1H-NMR (400 MHz, CDCl3): δ 14.5 (broad s, IH), 7.57 (d, J= 4.0 Hz, IH), 7.17 (d, J= 4.0 Hz, IH), 6.37 (s, IH).
Example Ib Preparation of5-(5-Bromo4hiophen-2-yl)-l-(2,5-dichloroψhenyl)-3-ttiflιιoromethyl-lH-pyi'azole
Figure imgf000121_0001
Into a 250 mL flask was weighted 2.01 g (9.41 mmol) of 2,5-dichlorophenylhydrazine hydrochloride (Aldrich), 1.79 g (5.95 mmol) of diketone, and 10 mL of glacial acetic acid. The suspension was stirred and heated at 80-850C and 5.0 mL of DMF was added to effect dissolution. The resulting solution was heated at 80-85 0C for 1 h then was cooled and washed into a separatory funnel with 150 mL of ethyl acetate and 250 mL of water. The ethyl acetate was separated, washed with 200 mL of 1 M NaOH, 50 mL of brine, then was dried (Na2SO4), and was concentrated in vacuo. The resulting yellow oil was treated with 200 mL of hexanes and a precipitate formed. The precipitate was removed by filtration and the filtrate was concentrated in vacuo affording the desired product as a faintly yellow solid (2.7g) which was used in the next transformation without further purification. 1H NMR (400 MHz, CDCl3): δ 7.55 (s, IH), 7.49 (m, 2H), 6.94 (d, J= 4 Hz, IH)56.81 (s, IH), 6.69 (d, J= 4 Hz, IH). The following compounds are prepared essentially according to the previous examples:
• l-(2-chlorophenyl)-5-{3-[(phenylmethyl)oxy]phenyl}-3-(trifluoromethyl)-1H-pyrazole; MS(ES): = 428.5PVR-H]+,
• l-(2-cMorophenyl)-5-{4-[(phenylmethyl)oxy]phenyl}-3-(trifluoromethyl)-1H-pyrazole, MS(ES): 429 [M+H]+.
Example Ic
Preparation of 3-{5-[2-(2,5Φichlowψheψl)-5-tιifluowmethyl-2H-pyrazol-3-ylJ-thiophen-2-yl}- benzenesulfonamide
Figure imgf000122_0001
Into a 50 mL flask was weighed 439 nig of bromide (993 μmol), 207.9 nig of boronic acid (1.03 mmol), and 5 mL of THF. The resulting solution was placed in an oil bath and was heated at 80- 85 0C. As the solution approached reflux c.a. 50 mg of tetrakis(triphenylphosphine)palladium (0) was added followed by 500 L of 1.0 M sodium carbonate. The reaction was maintained at reflux for 2 Ii then was washed into a separatory funnel with ethyl acetate and 1.0 M sodium carbonate. The ethyl acetate was separated, dried (Na2SO4), and was concentrated in vacuo. The reaction was purified by silica gel flash chromatography (Jones Flashmaster, 50 g SiO2, gradient elution from 100% hexanes to 40% ethyl acetate over 45 minutes). Appropriate fractions were combined and concentrated in vacuo affording the product as a faintly yellow solid, yield: 131 mg (25 %). 1HNMR (400 MHz, DMSO-J6): δ 8.20 (s, IH), 7.98 (s, IH), 7.87 (m, 2H), 7.82 (t, J= 8 Hz, 2H), 7.67 (d, J= 8 Hz, IH), 7.64 (d, J= 4 Hz, IH), 7.56 (s, IH), 7.49 (s, 2H), 7.32 (d, J= 4 Hz, IH). The following compounds are prepared essentially according to the previous examples:
• l-(2,5-dichlorophenyl)-5-(5-{3-[(l-methyle%l)suh°onyl]phenyl}-2-iWenyl)-3-(trifluoromethyl)- lH-pyrazole, MS (ES): 547 [M+H]+;
• 5-{5-[l-(2-cMorophenyl)-3-(1rifluoromethyl)-1H-pyrazol-5-yl]-2-thienyl}-3-methyl-2- (methylthio)pyridine, MS (ES): 466.2 [M+H]+;
• 5-{5-[l-(2-chlorophenyl)-3-(trmuoromethyl)-1H-pyrazol-5-yl]-2-trύenyl}-2-(ethylthio)-3- methylpyridine; MS (ES): 480.2 [M+H]+; • 3-methyl-5-(5-{l-[2-(methyloxy)phenyl]-3<tiifluoromethyl)-1H-pyrazol-5-yl}-3-thienyl)-2- (methylthio)pyridine, MS (ES): 462.3 [M+H]+;
• 4-(5-{5-[l-(2-chlorophenyl)-3-(trMuoromethyl)4H-pyrazol-5-yl]-2-1hienyl}pyridin-2- yl)morpholine; MS (ES): 491.2,[M+H]+;
• l,l-dimethyle%14-(5-{5-[l-(2-chlorophenyl)-3-(trifluorometliyl)-1H-pyrazol-5-yl]-2- thienyl}pyridin-2-yl)piperazine-l-carboxylate, MS (ES): 590.2 [M+H]+;
• methyl (5-{5-[l-(2-cUorophenyl)-3-(1rifluorome1hyl)-1H-pyrazol-5-yl]-2-tWenyl}pyridin-3- yl)acetate; MS (ES): 478.1 [M+H]+;
• methyl(4-{5-[l-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-2-thienyl}-3- methylphenyl)acetate; MS (ES): 490.0 |M+H]+; • methyl (3-{5-[l-(2-chlorophenyl)-3-(1rifluoromethyl)-1H-pyrazol-5-yl]-2-thienyl}-4- fluorophenyl)acetate; MS (ES): 495.2 [M+H]+;
• methyl 2-(5-{5-[l-(2-chlorophenyl)-3-(trffluo methylpropanoate; MS (ES): 506.3 [M+H]+; • 3-(3-{5-[l-(2-cUorophenyl)-3-(trifluorome1hyl)-1H-pyrazol-5-yl]-2-iMenyl}phenyl)propanok acid; MS (ES): 477.0 [M+H]+;
• 3-(4-{5-[l-(2-ctøorophenyl)-3-(trifluorom MS (ES): 477.3 [M+H]+;
• 4-{5-[l-(2-clilorophenyl)-3-(trMuoromethyl)-1H-pyrazol-5-yl]-2-thienyl}benzoic acid; MS (ES): 449.0 [M+H]+;
• 3-{5-[l-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-2-thienyl}benzoic acid; MS (ES): 449.0 |M+H]+,471.0 [MHNa]+;
• (2E)-3-(4-{5-[l-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-2-thienyl}phenyl)prop-2- enoic acid; MS (ES): 474.9 [M+H]+,497.3 [M+Na]+; • [4-fluoro-3-(5-{3-(lrffluoromethyl)-l-[3-(trifluoiOmethyl)pyridin-2-yl]-1H-pyraz thienyl)phenyl]acetic acid; MS (ES): 516.3 [M+H]+;
• methyl [3-me1hyl-4-(5-{3-(trifluoromethyl)-l-[3- thienyl)phenyl]acetate; MS (ES): 526.5 [M+H]+;
• 2-(e%liMo)-3-methyl-5-(5-{3-(tiffluoro^ thienyl)pyridine; MS (ES): 514.2 [M+H]+;
• 5-{5-[l-(2,5-dichlorophenyl)-3-(trifluoromethyl)-1H-pyi^ol-5-yl]-2-thienyl}-3-methyl-2- (methylthio)pyridine; MS (ES): 500.4,[M+H]+;
• 3-methyl-2-(methyltMo)-5-(5-{3-(trMuoromethyl)-l-[2-(trifluoromethyl)phenyl]-1H-py^ 2-thienyl)pyridine; MS (ES): 500.4 [M+H]+; • 5-{5-[l-(2,5-dichlorophenyl)-3-(trifluorometiiyl)-1H-pyrazol-5-yl]-3-thienyl}-3-methyl-2- (methylthio)pyridine; MS (ES): 500.3 [M+H]+;
• l-(2-cMorophenyl)-5-{5-[3-(e%lsulfonyl)-5-(l-me1hylelhyl)phenyl]-2-thienyl}-3- (trifluoromethyl)-1H-pyrazole, MS(ES): 539.4 [M+H]+;
• (S-IS-fl^-cUoropheny^-S^trMuoromeihy^-1H-pyrazol-S-yy^-ihienylJpheny^acetic acid, MS (ES): 463.3([M+H]+ for 35Cl);
• (4-{5-[l-(2-cUorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-2-thienyl}phenyl)acetic acid, MS (ES): 463.2 ([M+H]+ for 35Cl); • 2-(3-{5-[l-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-2-thienyl}phenyl)-2- methylpropanoic acid, = MS (ES): 491.1(|M+H]+ &r 35Cl);
• l-(3-{5^1-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-2- thienyl}phenyl)cyclobutanecarboxylic acid MS (ES): 503.3[M+H]+. ; • 2-(3-{5-[l-(2-chlorophenyl)-3-(trifluoromethyl)4H-pyrazol-5-yl]-2-thienyl}phenyl)-2- ethylbutanoic acid, MS (ES): 519.2IMfH]+;
• 2-(4-{541-(2-cMorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-2-thienyl}phenyl)-2- methylpropanoic acid, MS (ES): 491.4[M+H]+. ;
• l-(2,5-dichlorophenyl)-5-(5-{3-[(l-methyle%l)sιilfonyl]phenyl}-2-thienyl)-3-(trffluorom lH-pyrazole, MS (ES): 547 [M+H]+;
• 2-[5-{5-[3-(methylsulfonyl)phenyl]-2-iMenyl}-3-(1rffluoromethyl)-1H-pyrazol-l-yl]-3- (trifluoromethyl)pyridineMS (ES): 518.3 [M+H]+.
• l-[5-cMoro-2-(methyloxy)phenyl]-5-{5-[3-(m lH-pyrazole; 1H-NMR (CDCl3): δ 8.07 (IH, m), 7.85 (IH, m), 7.75 (IH, m), 7.58 (IH, t), 7.50-7.45 (2H, m), 7.25 (IH, d), 6.94 (IH, d), 6.88 (IH, d), 6.85 (IH, s), 3.65 (3H, s), 3.09 (3H, s). MS (ES):
513 IMfH]+.
• l-[5-cUoro-2-φhenyloxy)phenyl]-5-{5-[3-(methylsulfonyl)phenyl]-2-tWenyl}-3-(trffl lH-pyrazole; 1H-NMR(CDCl3): δ 8.09 (IH, m), 7.88 (IH, m), 7.77 (IH, m), 7.66 (IH, d), 7.60 (IH, t), 7.39 (IH, dd), 7.29 (IH, d), 7.24-7.15 (2H, m), 7.07 (IH, t), 6.93 (IH, d), 6.82 (IH, d), 6.79 (IH, s), 6.70-6.64 (2H, m), 3.10 (3H, s). MS (ES): 575 [M+H]+.
• l-(2-cMoro-5-fluorophenyl)-5-{5-[3-(met^ pyrazole; 1H-NMR (CDCl3): δ 8.07 (IH, m), 7.86 (IH, m), 7.75 (IH, m), 7.63-7.49 (2H, m), 7.33 (IH, m), 7.31-7.23 (2H, m), 6.91-6.85 (2H, m), 3.08 (3H, s). MS (ES): 501 |M+H]+
• l^S-cUoro^-fluoropheny^-S-IS-P^methylsulfony^phenylJ^-Menyll-S^trifluoromethy^-1H- pyrazole; 1H-NMR (CDCl3): δ 8.09 (IH, m), 7.87 (IH, m), 7.77 (IH, m), 7.64-7.56 (2H, m), 7.50
(IH, m), 7.28 (IH, d), 7.17 (IH, t), 6.92 (IH, d), 6.88 (IH, s), 3.09 (3H, s). MS (ES): 501 [M+H]+
• l-[2-cMoro-5-(metiiyloxy)phenyl]-5-{5-[3-(methylsulfonyl)phenyl]-2-iMenyl}-3-(trffl lH-pyrazole; 1H-NMR(CDCl3): δ 8.06 (IH, m), 7.85 (IH, m), 7.75 (IH, m), 7.58 (IH, t), 7.43 (IH, m), 7.25 (IH, d), 7.14-7.02 (2H, m), 6.89 (IH, s), 6.87 (IH, d), 3.85 (3H, s), 3.08 (3H, s). MS (ES): 513 [M+H]+
• l-[2-cMoro-5-(trifluoromethyl)phenyl]-5-{5-[3-(me1hylsulfonyl)phenyl]-2-thienyl}-3- (trifluoromethyl)-1H-pyrazole; 1H-NMR (CDCl3): δ 8.06 (IH, m), 7.90-7.83 (2H, m), 7.79 (IH, m), 7.76-7.67 (2H, m), 7.59 (IH, t), 7.25 (IH, m), 6.92 (IH, s), 6.84 (IH, d), 3.08 (3H, s); MS (ES): 551 and 553 [each M+H]+.
• 4-chloro-3-[5-{5-[3-(methylsulfonyl)phenyl^ yl]phenol; 1H-NMR (CDCl3): δ 8.04 (IH, m), 7.84 (IH, d), 7.74 (IH, d), 7.57 (IH, t), 7.30 (IH, d), 7.24 (IH, d), 6.99 (IH, m), 6.93 (IH, m), 6.91-6.87 (2H, m), 3.09 (3H, s). MS (ES): 499 [M+H]+.
• 4-cMoro-3-[5-{5-[3-(methylsulfonyl)phe^^ yl]benzamide; 1H-NMR(DMSO-J6): δ 8.29 (IH, d), 8.25-8.15 (2H, m), 8.04 (IH, d), 7.96-7.79 (3H, m), 7.75-7.64 (3H, m), 7.56 (IH, m), 7.28 (IH, d), 3.28 (3H, s). MS (ES): 526 [M+H]+.
• 3-{5-[l-(2-cUorophenyl)-3-(ttifluoromethyl)-1H-pyrazol-5-yl]-3-thienyl}benzenesulfonamide; 1H- NMR (DMSO-J15): δ 8.07 (IH, m), 8.01-7.96 (2H, m), 7.90-7.70 (5H, m), 7.67-7.57 (3H, m), 7.39
(2H, s). MS (ES): 484 [M+H]+.
• 4-{5-[l-(2-chlorophenyl)-3-(trifluoro
NMR(CDCl3): δ 7.96-7.88 (2H, ra), 7.61-7.52 (5H, m), 7.51-7.44 (2H, m), 7.18 (IH, d), 6.94 (IH, s), 4.89 (2H, s). MS (ES): 484 [M+H]+. • 3-{5-[l-(2-cUorophenyl)-3-(1rMuoromethyl)-1H-pyrazol-5-yl]-2-thienyl}benzenesulfonamide; 1H- NMR PMSO-J6): δ 7.89 (IH, m), 7.85 (IH, m), 7.81-7.69 (4H, m), 7.68-7.55 (3H, m), 7.51 (IH, s), 7.45 (2H, s), 7.28 (IH, d). MS (ES): 484 [M+H]+.
• 4-{5-[l-(2-chlorophenyl)-3-(1rffiuorome1hyl^
NMR(DMSO-J6): δ 7.87-7.60 (9H, m), 7.51 (IH, s), 7.43-7.37 (2H, s), 7.28 (IH, d). MS (ES): 484 [MH-H]+.
• 3-{5-[l-(2-cMoro-5-hydroxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-2- thienyljbenzenesulfonamide; 1H-NMR (DMSO- J5): δ 10.02(1H, s), 7.94(1H, s), 7.78(2H, m), 7.58-7.65(1H, m), 7.54(1H, d), 7.47(2H, s), 7.36(1H, t), 7.21-7.25(1H, m), 7.13-7.09(2H, m), 6.96(1H, m), MS (ES): 500 [M+H]+. • 4-cUoro-2-[5-{5-[3-(methylsulfonyl)pte^^ yl]phenol; MS (ES): 499 [MH-H]+.
• 3-(5-{3-(1rifluorome1hyl)-l-[3-(trifluoromeihyl)pyridin-2-yl]-1H-pyrazol-5-yl}-2- thienyl)benzenesulfonamide;MS (ES): 519 [MH-H+.
• 3-(5-{3-(trifluoromethyl)-l-[2-(trifluoromethyl)phenyl]-1H-pyrazol-5-yl}-2- thienyl)benzenesulfonamide; MS (ES): 518 [M+H]+.
• 2-[5-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}-3-(1rifluoromethyl)-1H-pyrazol-l- yl]benzenesulfonamide; MS (ES): 528 [M+H]+. • 3-(5-{l-[5-chloro-2-φhenyloxy)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl}-2- thienyl)benzenesulfonamide; MS (ES): 576 [M+H]+.
• 5-{5-[3-(Me%lsulfonyl)phenyl]-2^ pyrazole; MS (ES): 541 [M+H]+. • 2-chloro -6-methyl-3-[5-{5-[3-(methylsulfony^ l-yl]phenol;MS (ES): 513 [M+H]+.
• N-(3-{5-[l-(2,5-dichlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-2- thienyl}phenyl)methanesulfonamide; MS (ES): 534 [M+H]+.
• l-(2-chlorophenyl)-5-[3'-(methylsulfonyl)biphenyl-3-yl]-3-(trifluoromethyl>lH-pyr-^ 477.0 [M+H]+;
• l-(2-chlorophenyl)-5-[3'-(methylsulfonyl)biphenyl-4-yl]-3-(trifluoromethyl)-1H-pyrazoH 477 [M+H]+.
• 2-{5-[3'-(methylsulfonyl)biphenyl4-yl]-3<trifluoromethyl)-1H-pyrazol-l-yl}-3- (trifluoromethyl)pyridine, MS(ES): 512 [M+H]+. • 4'-[l-(2-chlorophenyl>3-(tiifluoromethyl)-1H-pyrazol-5-yl]biphenyl-3-sulfonamide, MS(ES): 478 [M+H]+
• l-(2-chlorophenyl)-5-{3'-[(l-methylefty^ MS(ES): 505 [M+H]+.
• 5-{3'-[(l -methylethyl)sulfonyl]biphenyl-4-yl}-3-(trifluoromethyl)- 1 -[2-(trifluoromethyl)phenyl]- lH-pyrazole, MS(ES): 539 |M+H]+.
• l-(2,6-dichlorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-tMenyl}-3-(trifluoromethyl pyrazole, MS(ES): 517 [M+H]+
• 2-methyl-2-(3-(5-(3-(1trifluoromethy)l4-(3-(trifluoromethyl)pyridm-2-yl)-1H-pyraz yl)thiophen-2-yl)phenyl)propanoic acid. MS (ES): 526 [M+H]+. • methyl 3-(5-(5-(3-(methylsulfonyl)phenyl)thiophen-2-yl)-3-(trifluoromethyl)-1H-pyrazol-l- yl)benzoate. MS (ES): 507 [M+H]+.
• 2-(3-(5-(5-(3-(methylsulfonyl)phenyty^ yl)phenyl)propan-2-ol. MS (ES): 507 |M+H]+.
• 2-(5-(5-(3-(methylsulfonyl)phenyl)thiophen-2-yl)-3-(tiffluorome1hyl)-1H-pyi^ MS (ES): 417 |M+H]+.
• S-cMoro^-p-IS-P^meihylsulfonyOphenyy^-iMenyll-S^trifluorome&y^-1H-pyra^^ yl]pyridine: 1H-NMRpMSO-^): δ 8.73 (IH, dd), 8.39 (IH, dd), 8.03 (IH, m), 7.90-7.83 (3H, m), 7.72-7.65 (2H, m), 7.55 (IH, s), 7.26 (IH, d), 3.27 (3H, s). MS (ES): 484 [M+H]+ • l-(2-ddorophenyl)-5-{5-[3-(me1hylsu^ MS (ES): 483 [MH-HT;
• 2-{5-[5-(3-Me1hanesulfonyl-phenyl)-iMophen-2-yl]-3-trifluoiOmethyl-pyrazol-l-yl}-3- trifluoromethyl-pyridine; MS (ES): 518 |M+H]+; • 5-{5-[3-(methylsulfonyl)phenyl]-2-thien^ pyrazole; MS (ES): 517 |M+H]+;
• l-(2-methylphenyl)-5-{5-[3-(me1hylsulfonyl)pte MS (ES): 463 [M+H]+;
• l-[2-(methyloxy)phenyl]-5-{5-[3-(methylsulfonyl)phenyl]-2-iWenyl}-3-(1rifluoromethyl)-1H- pyrazole; MS (ES): 479 [M+H]+;
• l-(2-fluorophenyl)-5-{5-[3-(methylsulfony^ MS (ES): 467 |M+HJ+;
• l<2-e%lphenyl)-5-{4-[3-(methylsulfonyl)pheny^ (ES) 477.3 IM+Hf • l-(2-chlorophenyl)-5-{4-[3<methylsulfonyl)phenyl]-2-thienyl}-3-(trifl pyrazole,MS (ES) 483.2, 485.2 [M+H]+ l-(2-cMorophenyl)-3-(trifluoromethyl)^ MS (ES) 472.3, 474.3 [M+HJ+.
Example 2 l-(2,5-Dichloroφhejψl)-5-[5-(3-methammlfonylψheψl)4hiophen-2-yl]-3-Mfluorome pyrazole
Example 2a Preparation of l-[5-(3-Methanesulfonylψlienyl)-thiophen-2-yl]-etharione
Figure imgf000127_0001
Into a 500 mL flask was weighed 5.04 g of 2-acetyl-5-bromothiophene (24.6 mmol), 6.14 g
(30.7 mmol) of boronic acid, 604 mg (523 μmol) of tetrakis(triphenylphosphine)palladium (0), 300 mL of TKDF, and 30 mL of 1.0 M Na2CO3. The resulting solution was heated at 80-85 0C overnight during which time much of the THF evaporated. The residue was washed into a separatory funnel with ethyl acetate and 1.0 M Na2CO3. The ethyl acetate was separated and filtered of the insoluble product. The solids were washed with ethyl acetate and the filtrate was combined with the ethyl acetate extracts, was dried (MgSO4), and concentrated in vacuo. The residue was then crystallized from ethyl acetate affording the product as a faintly yellow powder, yield: 1.14 g (16.5%). The product filtered from the extraction was recovered as a colorless powder, yield: 4.30 g (62.4%). 1H NMR (400 MHz, CDCl3): δ 8.21 (s, IH), 7.92 (t, J= 7 Hz, 2H), 7.70 (d, J= 4.0 Hz, IH), 7.65 (t, J= 7 Hz, IH), 7.44 (d, J= 4 Hz, IH), 3.10 (s, 3H), 2.59 (s, 3H).
Example 2b Preparation of '4 ',4 [4-Trifluoro-I-[5-(3-methamsu^onyl-phenyl)-thiophen-2-ylJ'butaιτe-l,3-dione
Figure imgf000128_0001
Into a 250 mL flask was weighed 5.42 g (19.3 mmol) of l-(5-(3- (me&ylsulfonyl)phenyl)thiophen-2-yl)ethanone and 42 mL of THF. The resulting suspension was stirred and cooled to 0-3 0C in an ice bath and 23 mL of a lithium bis(trime1hylsilyl)amide solution (1.0 M in THF) was added. The resulting thick yellow suspension was stirred and allowed to warm to room temperature then ethyl trifluoroacetate (3.46 mL, 29 mmol) was added. After stirring at room temperature overnight the reaction was concentrated in vacuo to remove THF. The residue was washed into a separatory funnel with ethyl acetate and 1 M HCl. The ethyl acetate was separated, washed with brine, dried (MgSO4), and concentrated in vacuo. The resulting amorphous yellow powder was pure enough for further synthetic transformations, yield: 7.2 g (99%). 1H MVlR (400 MHz, DMSO-4): δ 8.20 (d, J= 7 Hz, IH), 8.08 (t, J= 7 Hz, 1 H), 7.95 (d, J= 4.0 Hz, IH), 7.89 (d, J= 7 Hz, IH), 7.78 (d, J = 4 Hz, IH), 7.69 (t, J= 7 Hz, IH), 6.22 (broad s, IH), 3.26 (s, 3H).
Example 2c Preparation of l-(2,5-Dichloroψheiψl)-5-[5-(3-methanesulfonyl-phenyl)-thiophen-2-yl]-3- trfli uoromethyl-lH-pyrazole
Figure imgf000128_0002
Into an 8 mL vial was weighed 202.7 mg (539 μmol) of (Z)-l,l,l-trifluoro-4-hydroxy-4-(5-(3- (methylsulfony^phenyl^ophen^-y^but-S-en^-one, 117.4 mg (550 μmol) of 2,5- dichloropheήylhydrazine hydrochloride, 3 mL of acetic acid, and 1 mL of DMF. The resulting reaction was stirred at 100-105 0C for 3 h then was concentrated to dryness in vacuo. The residue was purified by silica gel flash chromatography (3 x 23 cm, 1:1 ethyl acetate-hexanes) and was dried affording the product as a faintly yellow solid, yield: 89 mg (55%). 1H NMR (400 MHz, CDCl3): δ 8.08 (s, IH), 7.87 (d, J= 9 Hz, IH), 7.75 (d, J= 9 Hz, IH), 7.6 (m, 2H), 7.5 (m, 2H), 7.27 (d, J= 4 Hz, IH), 6.90 (s,
IH), 6.87 (d, J= 4 Hz, IH), 3.09 (s, 3H).
The following compounds are prepared essentially according to the previous examples:
• l-(2,5-dimethylphenyl)-5-{5-[3-(methylsu^ pyrazole; 1H-NMR (DMSO-4): δ 8.02 (IH, m), 7.90-7.79 (2H, m), 7.73-7.61 (2H, m), 7.47 (IH, s),
7.44-7.32 (3H5 m), 7.23 (IH, d), 3.27 (3H, s), 2.36 (3H, s), 1.89 (3H, s). MS (ES): 477 |M+H]+.
• 5-{5-[3-(methylsulfonyl)phenyl]-2-ttøen^
NMR (CDCl3): δ 8.13 (IH, m), 7.93-7.77 (2H, m), 7.62 (IH, t), 7.38-7.28 (4H, m), 7.13-7.06 (2H, m), 7.01 (IH, d), 6.73 (IH, s), 5.54 (2H, s), 3.10 (3H, s). MS (ES): 463 |M+H]+. • l-(2,6-dichlorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-iWenyl}-3-(trifluoromethyl)-1H- pyrazole, MS(ES): 517 |M+H]+.
Pyrazolelb
A general synthesis of pyrazole Ib (0037) is depicted in Scheme 3. First, an aryl-oxirane (0031) can be reacted with a bromoaryl-magnesium bromide (0032) to yield an alcohol intermediate (0033), which can be oxidized under standard conditions to give the corresponding ketone (0034). Oxiranes 0031 can be prepared readily from epoxidation of styrenes or treatment of aryl-carboxaldehydes with trimethylsulfonium iodide under basic conditions. Intermediate 0034 can be condensed with N,N- dimethyl-formamide dimethyl acetal (DMFDMA) and then a hydrazine, for example, an alkylhydrazine, R2NHNH2, to provide a mixture of two pyrazole isomers, 0035 and 0036. Resolution of the two pyrazole isomers should be possible via typical chromomatography methods. Next, pyrazole 0035 can undergo Suzuki cross-coupling with a boronic acid, R4B(OH)2, to afford the desired product (0037).
Scheme 3
Figure imgf000130_0001
Reactions and conditions: (a) DMFDMA, reflux; φ) R2NHNH2, EtOH, reflux; (c) R4B(OH)2, K2CO3, 10mol% PdCl2(dppf), H2O5 dioxane, 800C. Pyrazole Ic
A general synthesis of pyrazole Ic (00414) is shown in Scheme 4. First, an acetyl-bromoarene (0048), for example, where Y is S, O or CH2=CH2, can be condensed with DMFDMA followed by hydrazine, for example an alkylhydrazine, R2NHNH2, to afford a mixture of two pyrazole isomers, 00410 and 00411. Resolution of the two pyrazole isomers should be possible via typical chromomatography methods. Suzuki cross-coupling of 00410 with a boronic acid, R4B(OH)2, under standard conditions can provide intermediate 00412. Pyrazole 00412 can be brominated, such as with NBS, and then cross-coupled with an arylboronic acid, R4B(OH)2, to yield the desired product (00414).
Scheme 4
Figure imgf000130_0002
Reactions and conditions: (a) DMFDMA5 reflux; (b) R2NHNH2, EtOH5 reflux; (c) R4B(OH)2, K2CO3, 10mol% PdCl2(dppf), H2O5 dioxane, 80°C; (d) NBS5 THF; (e) R52PhB(OH)2, K2CO3, 10mol% PdCl2(dppf)5 H2O5 dioxane, 800C.
Example 3 4-(2-chloropheψl)-3-[5-(3-methamsulfoψlφhefψl)-tMophen-2-ylj-l-metJψM
Example 3a PreparaUonofl-(5-bromothiophen-2-yl)-3-dimethylanιmopvpenone
Figure imgf000131_0001
A stirred mixture of 2-acetyl-5-bromothiophene (1.03 g, 5.0 mmol) and N,N-dimethyl- formamide dimethyl acetal (2 mL) was heated at HO0C. After 15 h orange solids were recovered and dried under high vacuum to yield the title compound (1.3 g, quant), which was used in the next step without purification. R/O.17 (10% EtOAc/DCM); 1H-NMR (CD2Cl2): δ 7.73 (IH, d), 7.33 (IH5 d), 7.06
(IH, d), 5.52 (IH5 d), 3.13 (3H5 s), 2.90 (3H, s).
Example 3b Preparation of3~(5-bromothiophen-2-yl)-l-methyl-lH-pyrazoh
Figure imgf000131_0002
To a stirred solution of l-(5-bromotrdophen-2-yl)-3-dimethylaminopropenone (0.70 g, 2.7 mmol) in EtOH (15 mL) was added methylhydrazine (0.16 mL5 3.0 mmol) and then acetic acid (0.45 mL, 8.0 mmol). The resulting mixture was heated at reflux for 2 h, allowed to cool to ambient temperature and then concentrated under reduced pressure. The residue was diluted with DCM (50 mL), washed with H2O and brine, then dried (Na2SO4), concentrated and purified by chromatography (silica,
DCM) to yield the title compound 10a (0.21 g) as a white solid and regioisomer, 5-(5-bromothiophen-2- yl)-l-methyl-1H-pyrazole, 11a (0.35 g) as a pale yellow solid.10a: R/O.42 (DCM); 1H-NMR (CD2Cl2): δ 7.36 (IH, d), 7.01 (2H, m), 6.41 (IH3 d), 3.87 (3H5 s); 11a: R/0.19 (DCM); 1H-NMR (CD2Cl2): δ 7.42 (IH, d), 7.10 (IH, d), 6.94 (IH, m)56.36 (IH5 d), 3.92 (3H, s).
Example 3c Preparation of 3~[5-(3-methcmesulfoψlψheψl)-thiophen-2-ylJ-l-met}ψl-lH-pyrazole
Figure imgf000132_0001
A stirred mixture of 3-(5-bromothiophen-2-yl)-l-methyl-1H-pyrazole (0.20 g, 0.83 mmol), 3- methanesulfonyl-phenylboronic acid (0.20 g, 1.0 mmol), K2CO3 (345 mg, 2.5 mmol), Cl2Pd(dppf)'DCM (82 mg, 10 mol%) and H2O (0.6 mL) in dioxane (6 mL) was sparged with Argon for 5 min and then heated at 85°C as a sealed flask. After 6 h the reaction mixture was allowed to cool to ambient temperature, filtered (Celite™) and the filter agent rinsed with EtOAc. The combined filtrates were concentrated under reduced pressure and purified by chromatography (silica, EtOAc/DCM, 2:98 to 5:95) to give the title compound (0.11 g, 42%) as a white solid.1H-NMR (CD2Cl2): δ 8.15 (IH, m), 7.89 (IH, m), 7.80 (IH, m), 7.60 (IH, m), 7.40 (2H, m), 7.29 (IH, d), 6.50 (IH, d), 3.91 (3H, s), 3.07 (3H, s).
Example 3d Prepω"ation of4-bromo~3-[5-(3-methcmesιdfoψlψheψl)~thiop}ien-2-ylJ-l-met}ψl-lH-pfyf-azole
Figure imgf000132_0002
To a stirred solution of S-fS^-methanesuHbnyl-phenylJ-thiophen^-ylJ-l-methyl-1H-pyrazole (0.10 g, 0.31 mmol) in DCM (3 mL, anhyd) was added N-bromosuccinimide (NBS) (56 mg, 0.31 mmol). After 22 h additional NBS (56 mg) was added and stirring was continued at ambient temperature. After 46 h (total) the reaction mixture was concentrated under reduced pressure and purified by chromatography (silica, EtOAc/Hex, 20:80 to 40:60) to give the title compound (98 mg, 79%) as a white solid. 1H-NMR (CD2Cl2): δ 8.17 (IH, m), 7.91 (IH, m), 7.82 (IH, m), 7.72 (IH, d), 7.61 (IH, m), 7.50 (IH, s), 7.44 (IH, d), 3.91 (3H, s), 3.08 (3H, s).
Example 3e
Preparation of 4-(2-c}?lθfOpheψl)-3-[5-(3-methamsulfoψlψheψl)-thiophen-2-ylJ-l-me pyrazole
Figure imgf000132_0003
A mixture of 4-bromo-3-[5-(3-me1hanesuIfonyl-phenyl)-thiophen-2-yl]-l-methyl-1H-pyrazole (88 mg, 0.22 mmol), 2-cbJorophenylboronic acid (41 mg, 0.26 mmol), K2CO3 (91 mg, 0.66 mmol), Cl2Pd(dρpf)-DCM (18 mg, 10 mol%) and H2O (0.25 mL) in dioxane (2.5 mL) was sparged with Argon for 5 min and then heated at 80°C as a sealed flask. After 4 h the reaction mixture was allowed to cool to ambient temperature, filtered (Celite™) and the filter agent rinsed with EtOAc. The combined filtrates were concentrated under reduced pressure and purified by chromatography (silica, EtOAc/Hex, 30:70 to 40:60) to give the title compound (64 mg, 67%). R/0.14 (40% EtOAc/Hex); 1H-NMR (CD2Cl2): δ 8.09 (IH, m), 7.85-7.76 (2H, m), 7.60-7.49 (2H, m), 7.45 (IH, s), 7.41-7.30 (3H, m), 7.21 (IH, d), 6.70 (IH, d), 3.97 (3H, s), 3.05 (3H, s); MS (ES): 429 [M+Hf . The following compounds were prepared from appropriate reagents in a similar manner:
• 4-(2-chlorophenyl)-5-[5-(3-methanesulfonyl-phenyl)-tMophen-2-yl]-l-me1hyl-1H-pyrazole: 1H- NMR (DMS(M): δ 8.05 (IH, m), 7.93 (IH, d), 7.85 (IH, d), 7.75-7.63 (3H, m), 7.50 (IH, m), 7.38-7.26 (4H, m), 3.97 (3H, s), 3.27 (3H, s); MS (ES): 429 [M+H]+.
• 4-(2-chlorophenyl)-3-[5-(3-methanesiUfonyl-phenyl)-Mophen-2-yl]-l-(2,2,2-trifluoro-ethyl)-1H- pyrazole: 1H-NMR(CD2Cl2): δ 8.10 (IH, m), 7.87-7.76 (2H, m), 7.64-7.50 (3H, m), 7.45-7.31 (3H, m), 7.23 (IH, d), 6.75 (IH, d), 4.86-4.76 (2H, m), 3.05 (3H, s); MS (ES): 497 [M+H]+.
• 4-(2-Cωorophenyl)-5-[5-(3-me1hanesulfonyl-phenyl)-thiophen-2-yl]-l-(2,2,2-1rffluoro-e%l)-1H- pyrazole: 1H-NMR (CD2Cl2): δ 8.08 (IH, m), 7.87-7.78 (3H, m), 7.60 (IH, m), 7.46-7.39 (2H, m), 7.29-7.17 (3H, m), 7.09 (IH, d), 4.89-4.80 (2H5 m), 3.06 (3H, s); MS (ES): 497 [M+H]+.
Pyrazoleld
Scheme 5
Figure imgf000133_0001
Reaction and conditions: (a) LiHMDS, THF; R2CO2Et, -78 to 20°C; (b) HOAc, EtOH, reflux; (c) K2CO3, 10mol%PdCl2(dppf), H2O, dioxane, 800C.
A general synthesis of pyrazole Id (00519) is shown in Scheme 5. First, an acetyl-arene (00515) can be Ireated with an ester, R2CO2Et, under Claisen conditions to yield the corresponding 1,3- diketone (00516). Diketone 00516 can be condensed with an arylliydrazine (00517), for example, where Y is S, O or CH2=CH2, to afford the corresponding 1-aryl-pyrazole (00518). Intermediate 00518 then can undergo Suzuki cross-coupling with a boronic acid, R4B(OH)2, to give the desired product (00519). For example, 2'-trifluoromethyl-acetophenone 00515a (R2 = 2-CF3) was condensed with ethyl trifluoroacetate to yield diketone 00516a (R2 = CF3; R1 = 2-CF3). Intermediate 00516a was condensed with 4-bromo-phenylhydrazine hydrochloride 00517a (Y=CH2=1CH2) to provide pyrazole 00518a (R2=CF3; R1=2-CF3; Y=CH2=CH2), which underwent cross-coupling with 3-methanesulfonyl- phenylboronic acid to afford pyrazole 00519a (R2 = CF3; R1 = 2-CF3; R4 = 3-MeSO2Ph; Y =
Figure imgf000134_0001
Example 4 l-(3'-methωιesulfoiψl-biphertyl-4-yl)-3-triflmromethyl-5-(2-Mfluoromettø Example 4a
Preparation of 4,4,4-tιifluoro-l-(2-ϋifluoromethyl-pherryl)-bιιtane-l,3-dione
Figure imgf000134_0002
To a stirred solution of 2'-trifluoromethyl-acetophenone (2.25 mL, 15.0 mmol) in THF (20 mL, anhyd) at -78°C added dropwise a 1.0M solution of lithium hexamethyldisilazide (LiHMDS) (15.8 mL, 15.8 mmol). After 1 h the reaction mixture was cooled to -78°C and charged dropwise with ethyl trifluoroacetate (3.6 mL, 30 mmol). After addition was complete, the reaction mixture was allowed to warm to ambient temperature. The reaction mixture was quenched by slow addition of H2O (20 mL) and concentrated under reduced pressure. The resulting material was transferred to a separatory funnel, diluted with Et2O (60 mL), washed with IN HCl and brine, then dried (MgSO4) and concentrated to yield the title compound (4.2 g, 99%) as an amber liquid, which was used in the next step without purification. R/: 0.15 (20% EtOAc/Hex).
Example 4b Prepω-ationofl-(4-bromopheψl)-3-ϋiflιιoromethyl-5-(2-Mfluorometlψlψheψl)-lH-pyf'azole
Figure imgf000134_0003
To a stirred solution of 4,4,4-trifluoro-l-(2-trifluoromethyl-phenyl)-butane-l,3-dione (0.40 g,
1.4 mmol) in EtOH (10 mL) was added 4-bromophenylhydrazine hydrochloride (335 mg, 1.5 mmol) and acetic acid (0.4 mL). The resulting mixture was heated at reflux for 20 h, allowed to cool to ambient temperature and concentrated under reduced pressure. The resulting residue was diluted with DCM (80 mL), washed with satd NaCO3 and brine, then dried (Na2SO4), concentrated and purified by chromatography (silica, EtOAc/Hex, 0:100 to 20:80) to give the title compound (0.54 g, 89%) as a pale yellow liquid. 1H-NMR (CD3CN): δ 7.85 (d, IH), 7.63 (m, 2H), 7.50 (d, 2H), 7.37 (m, IH), 7.17 (d, 2H), 6.92 (s, IH).
Example 4c
Preparation of l-(3'-methariesιdfθ}ψl-bipheψl-4-yl)-3-tιifluorometJψl-5-(2-triflιιoromet}ψlφheψl)-lH- pyrazole
Figure imgf000135_0001
A mixture of l-(4-bromophenyl)-3-tiifluoromethyl-5-(2-trifluoromethyl-phenyl)-1H-pyrazole
(135 mg, 0.31 mmol), 3-methanesulfonyl-phenylboronic acid (74 mg, 0.37 mmol), K2CO3 (0.13 g, 0.93 mmol), Cl2Pd(dppf)-DCM (24 mg, 10 mol%) and H2O (0.2 mL) in dioxane (2 mL) was sparged with Argon for 5 min and then heated at 8O0C as a sealed flask. After 16 h the reaction mixture was allowed to cool to ambient temperature, filtered (Celite™) and the filter agent rinsed with EtOAc. The combined filtrates were concentrated under reduced pressure and purified by chromatography (silica, EtOAc/Hex, 0:100 to 40:60) to give the title compound (121 mg, 76%). 1H-NMR PMSO-^): δ 8.15 (m, IH), 8.03 (d, IH), 7.91 (m, 2H), 7.83 (d, 2H), 7.71-7.76 (m, 3H), 7.66 (m, IH), 7.40 (d, 2H), 7.18 (s, IH); MS(ES): 511 [M+H]+ The following compounds were prepared from appropriate reagents in a similar manner:
• 4'-{3-(1iffluoromethyl)-5-[2-(tiiflu^
MS(ES): 512 [M+H]+
• 3-(trffluoromethyl)-l-[3'-(trffiuorome%^^ pyrazole, MS(ES): 501 [M+H]+ • 3-(trifluoromethyl)-l-{3'-[(1rMuoromethyl)oxy]biphenyl4-yl}-5-[2-(trifluoromethyl)phenyl]-1H- pyrazole, MS(ES): 517 [M+H]+
• l-[3'-(methylsutfonyl)biphenyl-3-yl]-3-(1rifluoromethyl)-5-[2-(1rifluoromethyl)phenyl]-1H- pyrazole, MS(ES): 511 [M+H]+
• 5-[3-(methylsulfonyl)phenyl]-2-{3-(Mfluoromethyl)-5-[2-(trMuoromethyl)phenyl]-1H-pyrazol-l- yl}-l,3-1hiazole, MS(ES): 518 [M+H]+ • 3-(2-{3-(trifluoromethyl)-5-[2-(trifluoro^ benzenesulfonamide, MS(ES): 519 [M+H]+
• 5-[3-(methylsulfonyl)phenyl]-2-{3-(triflu^ yl}pyridme, MS(ES): 512 [M+H]+ • The following compounds were prepared in a similar manner from appropriate reagents and by replacing ethyl trifluoroacetate with dimethyl oxalate:
• me1hyl 5-(2-cUorophenyl)-l-[3'-(methylsιilfonyl)biphenyl-4-yl]-1H-pyrazole-3-carboxylate, MS(ES): 467 [M+H]+
• methyl 5-(2-cUorophenyl)-l-{5-[3-(meUiylsuheonyl)phenyl]pyridin-2-yl}-1H-pyrazole-3- carboxylate, MS(ES): 468 [M+H]+
• methyl 5-(2-cMorophenyl)-l-{6-[3-(methylsulfonyl)phenyl]pyridin-3-yl}-1H-pyrazole-3- carboxylate, MS(ES): 468 [M+H]+
• methyl 5-{5-[3-(aminosulfonyl)phenyl]-2-thienyl}-l-(2,5-dichlorophenyl)-1H-pyrazole-3- carboxylate; MS (ES): 508 [M+H]+;
Example 5
Prepω"ationof2-{5-(2-chlorophenyl)-l-[6-(3-methanesulforψlψhenyl)-pyrMin-3^ propan-2-ol
Figure imgf000136_0001
To a stirred solution of methyl 5-(2-chlorophenyl)-l-{6-[3-(metiiylsulfonyl)phenyl]pyridin-3- yl}-1H-pyrazole-3-carboxylate (0.14 g, 030 mmol) in THF (3 mL, anhyd) at OC was added slowly a 1.4M solution of methylmagnesium bromide in 3:1 toluene/THF (0.68 mL, 0.95 mmol). After addition was complete the flask was removed from an ice-water bath and allowed to warm to ambient temperature. After 2 h the reaction mixture was quenched with satd NH4Cl and extracted with EtOAc (50 mL). The combined extracts were washed with brine, dried (Na2SO4), concentrated and purified by chromatography (silica, EtOAc/Hex, 35:65 to 65:35) to yield the title compound (50 mg, 36%) as a white solid. 1H-NMR (DCM-J2): δ 8.54 (m, 2H), 8.28 (m, IH), 7.95 (m, IH), 7.72-7.81 (m, 2H), 7.68 (m, IH), 7.34-7.46 (m, 4H), 6.52 (s, IH), 3.07 (s, 3H), 2.64 (s, IH), 1.66 (s, 6H); MS(ES): 468 |M+H]+ The following compounds were prepared from appropriate reagents in a similar manner: • 2-[5-(2-cMorophenyl)-l-{5-[3<methylsulfonyl)phenyl]pyridm-2-yl}-1H-pyrazol-3-yl]propan-2-ol, MS(ES): 468 [M+H]+ • 2-{5-(2-cMorophenyl)-l-[3'-(methylsulfonyl)biphenyl-4-yl]-1H-pyrazol-3-yl}propan-2-ol, MS(ES): 467 [M+H]+
Example 6 Prepω-ationofl-{5-(2-chloropherψl)-l-[6-(3-rnethamsulfo}ψlψherιyl)-py}idfa ethanone
Figure imgf000137_0001
To a stirred solution of N,N'-dimethylethylenediamine (56 μL, 0.52 mmol) in toluene (3 mL, anhyd) at 0°C was added dropwise a 2.0M solution of trimethylaluminum in hexanes (0.75 mL, 1.5 mmol). After addition was complete the flask was removed from the ice-water bath and allowed to warm to ambient temperature. After 50 min the reaction mixture was charged slowly with a solution of methyl 5-(2-cUorophenyl)-l-{6-[3-(methylsu]fonyl)phenyl]pyridin-3-yl}-1H-pyrazole-3-carboxylate (0.22 g, 0.47 mmol) in toluene (3 mL, anhyd) and then heated at reflux. After 90 min the reaction mixture was allowed to cool to ambient temperature and quenched by addition of IN HCl. The resulting mixture was extracted with EtOAc (2 x 50 mL). The combined extracts were washed with brine, dried (Na2SO4), concentrated and purified by chromatography (silica, EtOAc/Hex, 30:70 to 60:40) to yield the title compound (47 mg, 22%) as a white solid.1H-NMR (DCM-d2): δ 8.65 (m, IH), 8.57 (m, IH), 8.30 (m,lH), 7.99 (m, IH), 7.79-7.87 (m, 2H), 7.71 (m, IH), 7.36-7.47 (m, 4H), 7.02 (s, IH), 3.09 (s, 3H), 2.68 (s, 3H); MS(ES): 452 [M+H]+.
The following compounds were prepared from appropriate reagents in a similar manner: • l-[5-(2-cMorophenyl)-l-{5-[3-(methylsufø^
MS(ES): 452 [M+H]+
• l-{5-(2-cMorophenyl)-l-[3'-(methylsulfonyl)biphenyl-4-yl]4H-pyrazol-3-yl}ethanone, MS(ES): 451 [M+H]+
Example 7 2-[l-(4-bromophenyl)-5-(2-chloropheψl)-lH-pyrazol-3-yl]-l, 1, 1, 3, 3, 3-hexqfluoro-propan-2-ol
Example 7a
Prepω-alionof2-[l-(4-bromopheψl)-5-(2-chloropheψl)-lH-pyι-azol-3-yl]-lJJ,3,3 propan-2-ol
Figure imgf000137_0002
To a stirred solution of l-(4-bromophenyl)-5-(2-chlorophenyl)-1H-pyrazole-3-carboxylic acid methyl ester (504 mg, 1.29 mmol) and trifluoromethyl-trimethylsilane (CF3-TMS) (0.77 mL, 5.2 mmol) in toluene (8 mL, anhyd) was added dropwise a 1.0M solution of tetrabutylammonium fluoride (TBAF) in THF (0.26 mL, 20 mol%, dried over 4A molecular sieves). After 20 h the reaction mixture was charged with additional CF3-TMS (0.57 mL) and TBAF (0.2 mL), then heated at 50°C. After 2 h the reaction mixture was allowed to cool to ambient temperature, diluted with DCM (50 mL), washed with
H2O and brine, then dried (Na2SO4) and concentrated under reduced pressure. The resulting residue was purified by chromatography (silica, EtOAc/Hex, 0:100 to 20:80) to give the title compound (0.10 g,
16%) as a white solid.1H-NMR (DCM-^2): δ 7.40-7.49 (m, 4H), 7.31-7.36 (m, 2H), 7.16 (d, 2H), 6.71 (s, IH), 5.18 (s, IH).
Example 7b
Preparation of '2-[5-(2-chlorop]ierψl)-l-(3'-methmjesulfoψl-bipheψl-4-yl)-lH-pyrazol-3-ylJ-
1, 1, 1, 3, 3, 3-hexqflwro-propan-2-ol
Figure imgf000138_0001
A mixture of 2-[l-(4-bromophenyl)-5-(2-chlorophenyl)-1H-pyrazol-3-yl]-l, 1,1,3,3,3- hexafluoro-propan-2-ol (100 mg, 0.20 mmol), 3-methanesutfonyl-phenylboronic acid (48 mg, 0.24 mmol), K2CO3 (83 mg, 0.60 mmol), Cl2Pd(dppf)-DCM (16 mg, 10 mol%) and H2O (0.2 mL) in dioxane (2 mL) was sparged with Argon for 5 min and then heated at 80°C as a sealed flask. After 3 h the reaction mixture was allowed to cool to ambient temperature, filtered (Celite™) and the filter agent rinsed with EtOAc. The combined filtrates were concentrated under reduced pressure and purified by chromatography (silica, EtOAc/Hex, 0:100 to 50:50) to give the title compound (94 mg, 82%) as a white solid. 1H-NMR (DCM-c?2): δ 8.12 (m, IH), 7.92 (m, IH), 7.87 (m, IH), 7.67 (m, IH), 7.61 (d, 2H), 7.33-7.47 (m, 6H), 6.74 (s, IH), 5.25 (s, IH), 3.07 (s, 3H); MS(ES): 575 [M+H]+
Pyrazole Ia Carbinols The synthesis of pyrazole carbinols are depicted in Scheme 6. Bromothienyl ketone (006A) was treated with a base and then dimethyl oxalate to form a diketo ester (006B), which condensed with a hydrazine salt to form bromothienylpyrazole product (006C). Suzuki coupling of the bromothienylpyrazole with a boronic acid mediated with palladium tetrakis(triphenylphosphine) affords a phenylthienylpyrazole ester (006D). It was submitted to Grignard reaction to afford a carbinol product (006E). Bromo or chloro groups were introduced onto the pyrazole ring via reactions with NBS or NCS.
Scheme 6
Figure imgf000139_0001
Example 8
2-{l-(2-chloroφheψl)-5-[5-(3-methmesulforψlψheψl)-thiopheri-2~yl]-lH-^
Example 8a Preparation of4-(5-bromo-thiophen-2-yl)-2,4-dioxo-butyric acid methyl ester
Figure imgf000139_0002
■ To a solution of 2-acetyl-5-bromothiophene (25 g, 122 mmol) and dimethyl oxalate (23 g, 194 mmol) in dry methanol (800 mL) was added a solution of NaOMe in MeOH (25%, 51 mL, 224 mmol) at ambient temperature. The reaction mixture was stirred at 2O0C for 4 h and then acidified to pH 1 with 6 N aqueous HCl. The yellow solid was collected by filtration, washed with H2O, and dried under high vacuum to afford 4-(5-bromo-thiophen-2-yl)-2,4-dioxo-butyric acid methyl ester (31.3g, 88%). H- NMR pMSO-de): δ 8.14 (s, IH), 7.46 (d, IH)57.05 (s, IH), 3.85 (s, 3H).
Example 8b
Preparation of 5-(5-bιvmo4hiophen-2-yl)-l-(2-chloro-phenyl)-lH-pyrazole-3~cω~boxylic acid methyl ester
Figure imgf000140_0001
A solution of 4-(5-bromo-thiophen-2-yl)-2,4-dioxo-butyric acid methyl ester (15 g, 50 mmol) and 2- chlorophenylhydrazine hydrochloride (10.75 g, 60 mmol) in dry MeOH (200 mL) was heated to reflux for 6 h. After cooling to 2O0C, a white solid precipitated and was collected by filtration, washed with a small volume of cold MeOH and dried under high vacuum to afford 5-(5-bromo-thiophen-2-yl)-l-(2- chloro-phenyl)-1H-pyrazole-3-carboxylic acid methyl ester (20 g, 100%). 1H-NMR (CDCl3): δ 7.48- 7.55 (m, 3H), 7.43 (m, IH), 7.11 (s, IH), 6.90 (d, 2H), 6.65 (s, IH), 3.95 (s, 3H).
Example 8c
Preparation of l-(2-chloroψheψl)-5-[5-(3-methanesulfoψlψheψl)-thiophen-2-ylJ-lH-pyi"azole-3~ carboxylic acid methyl ester
Figure imgf000140_0002
A mixture of 5-(5-bromo-iMophen-2-yl)-l-(2<Woro-phenyl)-1H-pyia2ole-3-caώoxylic acid methyl ester (8.0 g, 20 mmol), 3-methylsulfonylphenylboronic acid (5.0 g, 24 mmol), sodium carbonate (6.0 g, 56 mmol) and palladium tetrakis(triphenylphosphine) (1.2 g, 1.04 mmol) in 1.4-dioxane (100 mL) and H2O (5 mL) was stirred at 9O0C under N2 for 16 h. Solid was filtered off and washed with ethyl acetate. The filtrate was concentrated under vacuum to give a residue, which was partitioned between ethyl acetate and water. The aqueous layer was separated and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and evaporated to give a crude. It was triturated by DCM to afford l-(2-chloro-phenyl)"-5-[5-(3-methanesulfonyl-phenyl)-ώiophen-2-yl]-1H- pyrazole-3-carboxylic acid methyl ester (4.8 g). The mother liquors from trituration were combined and concentrated to give a solid, which was purified by flash chromatography on silica gel eluted with EtOAc-hexane (0-60%) to afford another 2.8 g of product. The total yield was 7.6 g (80%). 1H-NMR (CDCl3): δ 8.04 (m, IH), 7.84 (m, IH), 7.73 (m, IH), 7.50-7.58 (m, 4H), 7.47 (m, IH), 7.23 (d, IH), 7.20 (s, IH), 6.82 (d, IH), 3.98 (s, 3H), 3.07 (s, 3H). Example 8d
Preparation of 2-{l-(2-chlorophe}τyl)-5-l5-(3-methamsulfonyl-phenyl)4H yl}-propan-2-ol and l-[l-(2-chlorophenyl)-5-{5-[3-(methykulfonyl)phenyl]-24hienyl}-lH-pyrazol-3- yljethanone
Figure imgf000141_0001
To a stirred solution of l-(2-chloro-phenyl)-5-[5-(3-methanesulfonyl-phenyl)-tlτiophen-2-yl]- lH-pyrazole-3-carboxylic acid methyl ester (5.22 g, 11.036 mmol) in dry THF (200 mL) was added dropwise a solution of MeMgCl in THF (3.0 M, 18 mL, 54 mmol) at -78 0C under N2. The reaction solution was allowed to warm to rt overnight and then quenched with saturated aqueous NH4Cl at O0C. The aqueous layer was separated and extracted with EtOAc. The combined organic layers were washed with brine, dried with sodium sulfate and evaporated in vacuo. The residue was purified by flash chromatography (0-60% EtOAc/hexanes) to afford 2-{l-(2-chloro-phenyl)-5-[5-(3-methanesulfonyl- phenyl)-thiophen-2-yl]-1H-pyrazoI-3-yl}-propan-2-ol as a white solid (2.74 g, 52%) and l-[l-(2- cMoropheny^-S-IS-p^melhylsuuOny^pheny^^-thienylJ-1H-pyrazol-S-ylJefhanone as a white solid (1.5g, 30%). 1H-NMR (CDCl3): δ 8.04 (s, IH), 7.83 (m, IH), 7.71 (m, IH), 7.57-7.53 (m, 3H), 7.50- 7.43 (m, 2H), 7.20 (d, IH), 6.73 (d, IH), 6.62 (s, IH), 3.07 (s, 3H), 2.61 (s, IH), 1.68 (s, 6H). MS(ES): 473 [M+H]+, 1H-NMR(CDCl3): δ 8.04 (s, IH), 7.83 (m, IH), 7.72 (m, IH), 7.59-7.49 (m, 5H), 7.22 (d, IH), 7.15 (s, IH), 6.80 (d, IH)93.07 (s, 3H), 2.65 (s, 3H). MS(ES): 457 [M+H]+. The following compounds are prepared essentially according to the previous examples:
• 3-[l-(2-chlorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-tUenyl}-1H-pyrazol-3-ylJpentan-3-ol: 1HNMR(CDCl3): δ 8.04 (d, IH), 7.82 (m, IH), 7.73 (m, IH), 7.57-7.42 (m, 5H), 7.20 (d, IH), 6.74 (d, IH), 6.52 (s, IH), 3.08 (s, 3H), 2.81 (brs, IH), 1.89 (q, 4H), 0.92 (t, 6H). MS(ES) 501 [M+H]+, 483 (M-OH). • l-[l-(2-cMorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-tMenyl}-1H-pyrazol-3-yl]propan-l-one: 1HNMR(CDCl3): δ 8.04 (d, IH), 7.83 (m, IH), 7.73 (m, IH), 7.59-7.48 (m, 5H), 7.22 (d, IH), 7. 15 (s, IH), 6.80 (d, IH).3.13-3.07 (m, 5H), 1.24 (t, 3H). MS(ES) 471 [M+H]+.
• l-[l-(2-cMorophenyI)-5-{5-p-(methylsuIfonyl)phenyl]-2-thienyl}-1H-pyrazol-3-yl]propan-l-ol: 1HNMR(CDCl3): δ 8.04 (d, IH), 7.81 (m, IH), 7.72 (m, IH), 7.57-7.42 (m, 5H)57.209d, IH), 6.75 (d, IH), 6.63 (s, IH), 4.81 (t, IH), 3.07 (s, 3H), 2.6(brs, IH), 1.94 (m, 2H), 1.04 (t, 3H). MS(ES) 473
[M+Hf, 455 (M-OH).
• 2-(5-{5-[3-(methylsuhponyl)phenyl]-2-thienyl}-l-[2-(trMuoromethyl)phenyl]-1H-ρyrazol-3- yl)propan-2-ol, MS(ES): 507 |M+H]+ • 2-(5-{5-[3-(methylsulfonyl)phenyl]^ yl)propan-2-ol, MS(ES): 508 [M+H]+
• l-(5-{5-[3-(methylsulfonyl)phenyl]-2^ yl)ethanone, MS(ES): 492 [MH-H]+ • 2-[l-(3-cUorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}-1H-pyrazol-3-yl]propan-2-ol, MS(ES): 473 [M+H]+
• 2-[l-(4-chlorophenyl)-5-{5-[3-(me1hylsι^onyl)phenyl]-2-iMenyl}-1H-pyrazol-3-yl]ρropan-2-ol, MS(ES): 473 [M+H]+
• 2-[l-(3-fluorophenyl)-5-{5-[3-(metiiylsulfonyl)phenyl]-2-thienyl}-1H-pyrazol-3-yl]propan-2-ol, MS(ES): 457 [M+H]+
• 2-[l-(2-fluorophenyl)-5-{5-[3-(methylsu^^ MS(ES): 457 [M+H]+
• 2-[l-(2-fluorophenyl)-5-{5-[3-(me1hylsu^ MS(ES): 457 [M+H]+ • l-(5-{5-[3-(me1hylsulfonyl)phenyl]-2-1hienyl}-l-phenyl-1H-pyrazol-3-yl)ethanone, MS(ES): 439 [M+H]+
• l-(5-{5-[3-(methylsulfonyl)ρhenyl]-2-thienyl}-l-phenyl-1H-ρyrazol-3-yl)ethanone MS(ES): 423 [M+H]+
• 2-[l-(2,5-dichlorophenyl)-5-{5-[3-(methyl ol, MS(ES): 507 [M+H]+
• 2-[l-(2-chloro-3-fluorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}-1H-pyrazol-3- yl]propan-2-ol, MS(ES): 491 (MH-H]+
• 2-[3-(l-hyckoxy-l-methyle%l)-5-{5-[3-(methylsulfonyl)phenyl]-2-tMenyl}-1H-pyrazol-l-yl]-6- (trifluoromethyl)phenol, MS(ES): 523 [M+H]+ • 2-(5-{5-[3-(methylsulfonyl)phenyl]-2-^ yl)propan-2-ol, MS(ES): 508 [M+H]+
• 2-(5-{5-[3-(methylsulfonyl)phenyl]-2-^ yl)propan-2-ol5 MS(ES): 508 [M+H]+
• 2-[l-(2-cMorophenyl)-5-{5-[4-(methylsulfonyl)phenyl]-2-1hienyl}-1H-pyrazol-3-yl]propan-2-ol, MS(ES): 473 [MH-H]+
• 2-[l-(2,6-dichloro-3-methylphenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}-1H-pyrazol-3- yl]propan-2-ol, MS(ES): 521 PVH-H]+, 503 (M-OH) • 2-[l-(2,6-dichlorophenyl)-5-{5-[3-(me1hylsulfonyl)phenyl]-2-ihienyl}-1H-pyrazDl-3-yl]propan-2- ol, MS(ES): 507 [M+H]+, 489 (M-OH)
• 2-[l-(2-cUorophenyl)-5-{l-methyl-5-[3-(methylsulfonyl)phenyl]-1H-pyrrol-2-yl}-1H-pyrazol-3 yl]propan-2-ol, MS(ES): 470 [M+H]+, 452 (M-OH) • 2-[l-(2,6-dichlorophenyl)-5-{l-methyl-5-[3-(methylsiifonyl)phenyl]-1H-pyrrol-2-yl}4H-pyrazol- 3-yl]propan-2-ol, MS(ES): 504 [M+H]+, 486 (M-OH)
• 2-{ 1 -(2-chlorophenyl)-7-[3-(methylsulfonyl)phenyl]- 1 ,4-dihydroindeno[l ,2-c]pyrazol-3-yl}propan- 2-ol, MS(ES): 479 [M+H]+, 461 (M-OH)
• 2-{l-(2-chlorophenyl)-6-[3-(methylsulfonyl)phenyl]-l,4-dihydroindeno[l,2-c]pyrazol-3-yl}propan- 2-ol, MS(ES): 479 [MfH]+, 461 (M-OH)
• 2-[l-(2,6-dichlorophenyl)-5-{3-methyl-5-[3-^ yl]propan-2-ol, MS(ES): 521 [M+H]+.
• 2-[5-{5-[3,4-bis(meihyloxy)phenyl]-2-tliienyl}-l-(2-chlorophenyl)-1H-pyrazol-3-yl]propan-2-ol; MS (ES): 455 [M+H]+; • 2-chloro4-{5-[l-(2-cMorophenyl)-3-(l-hydro}^-l-methyle%l)-1H-pyrazol-5-yl]-2-ihienyl}-N-(l- methylethyl)benzamide; MS (ES): 514 [M+H]+;
• 2-[l-(2-chlorophenyl)-5-{5-[2-(methyliMo)phenyl]-2-1hienyl}-1H-pyrazol-3-yl]propan-2-ol; MS (ES): 441 |M+H]+;
• 2-{ l-(2-chlorophenyl)-5-[5-(2-fluorobiphenyl-4-yl)-2-thienyl]-1H-pyrazol-3-yl}propan-2-ol; MS (ES): 489 [M+H]+;
• 2-{l-(2-chlorophenyl)-5-[5-(3-fluorophenyl)-2-thienyl]-1H-pyrazol-3-yl}propan-2-ol; MS (ES): 413 [M+H]+;
• N-(3-{5-[l-(2-chlorophenyl)-3-(l-hydroxy-l-methylethyl)-1H-pyrazol-5-yl]-2- thienyl}phenyl)acetamide; MS (ES): 452 [M+H]+; • 2-[l-(2-cUorophenyl)-5-(5-{4-[(l-methyle%l)oxy]phenyl}-2-ihienyl)-1H-pyrazol-3-yl]propan-2- ol; MS (ES): 453 [M+H]+;
• 2-[l-(2-chlorophenyl)-5-{5-[2-fluoro-3-(me1liyloxy)phenyl]-2-thienyl}-1H-pyrazol-3-yl]propan-2- ol; MS (ES): 443 [M+H]+;
• 2-{l-(2-chlorophenyl)-5-[5-(4-chlorophenyl)-2-thienyl]-1H-pyrazol-3-yl}propan-2-ol; MS (ES): 429 [M+H]+;
• 2-[l-(2-cMorophenyl)-5-{5-[5-fluoro-2-(methyloxy)phenyl]-2-Menyl}-1H-pyrazol-3-yl]propan-2- ol; MS (ES): 443 [M+H]+; • 2-[l-(2-cUorophenyl)-5-{5-[4-(e%loxy)-3-(tiifluoromeUiyl)phenyl]-2-tMenyl}-1H-pyrazol-3- yl]propan-2-ol; MS (ES): 507 IMfH]+;
• 2-{l-(2-cMorophenyl)-5-[5-(2,3-dichlorophenyl)-2-thienyl]-1H-pyrazol-3-yl}propan-2-ol; MS (ES): 463 [M+H]+; • 2-[l-(2-chlorophenyl)-5-(5-pyrinti^ MS (ES):
397 [MH-H]+;
• 4-{5-[l-(2-cMorophenyl)-3-(14iydroxy-l-methy^ MS (ES): 439 [MH-H]+;
• N-(4-{5-[l-(2-chlorophenyl)-3-(l-hydroxy-l-methylethyl)-1H-pyrazol-5-yl]-2- thienyl}phenyl)methanesulfonamide; MS (ES): 488 [M+H]+;
• 2-{5-[l-(2<;morophenyl)-3-(l-hydroxy-l-methyle%l)-1H-pyrazol-5-yl]-2-thienyl}-5- fluorophenol; MS (ES): 429 [M+H]+;
• 2-[l-(2-clτlorophenyl)-5-(5-{4-fluoro-2-[(phenylmethyl)oxy]phenyl}-2-thienyl)-1H-pyrazol-3- yl]propan-2-ol; MS (ES): 519 [M+H]+; • 3-{5-[l-(2-cUorophenyl)-3-(l-hydroxy-l-methylethyl)-1H-pyrazol-5-yl]-2-thienyl}-5- fluorobenzoic acid; MS (ES): 457 |M+HJ+;
• 2-{ l-(2-chlorophenyl)-5-[5-(l-methyl-1H-indol-5-yl)-2-thienyl]-1H-pyrazol-3-yl}propan-2-ol; MS (ES): 448 [MH-H]+;
• 2-[l-(2-cUorophenyl)-5-(5-{2-[(l-methyle%l)oxy]-5<trifluoromethyl)phenyl}-2-thienyl)-1H- pyrazol-3-yl]propan-2-ol; MS (ES): 521 [M+H]+;
• 2-cMoro-5-{5-[l-(2-chlorophenyl)-3-(l-hydroxy-l-methyletliyl)-1H-pyrazol-5-yl]-2- thienyl}benzamide; MS (ES): 472 [M+H]+;
• 2-{5-[5-(2-cUoro-6-fluorophenyl)-2-thienyl]-l-(2-chlorophenyl)-1H-pyrazol-3-yl}propan-2-ol; MS (ES): 447 [MH-H]+; • 3-{5-[l-(2-cMorophenyl)-3-(l-hydroxy-l-methyle1hyl)-1H-pyrazol-5-yl]-2-tlτienyl}-N,N- dimethylbenzenesulfonamide; MS (ES): 502 [M+H]+;
• 2-chloro4-{5-[l-(2-chlorophenyl)-3-(l-hydroxy-l-methyle%l)-1H-pyrazol-5-yl]-2-thienyl}-N- meihylbenzamide; MS (ES): 486 [MfHJ+;
• 2-[l-(2-cMorophenyl)-5-(5-{2-methyl-4-[(l-methyle%l)oxy]phenyl}-2-thienyl)-1H-pyrazol-3- yl]propan-2-ol; MS (ES): 467 1M+H]+;
• 4-{5-[l-(2-chlorophenyl)-3<l-hydroxy-^ ylmethyl)benzamide; MS (ES): 518 [MH-Hl+; • methyl 2-{5-[l-(2-chlorophenyl)-3-(l-hydroxy-l-methylethyl)-1H-pyrazol-5-yl]-2- thienyl}benzoate; MS (ES): 453 [M+H]+;
• 2-[5-{5-[3-cMoro4-(methyloxy)phenyl]-2-^ ol; MS (ES): 459 [M+H]+; • 2-[5-(5-{3-cMoro-4-[(l-methyle%l)oxy]phenyl}-2-thienyl)-l-(2-cMorophenyl)-1H-pyrazol-3- yl]propan-2-ol; MS (ES): 487 [M+H]+;
• 2-[l-(2-cUotOphenyl)-5-{5-[4-(l,3-thiazolidin-3-ylcarbonyl)phenyl]-2-thienyl}-1H-pyrazol-3- yl]propan-2-ol; MS (ES): 510 [M+H]+;
• 2-chloro-4-{5-[l-(2-dilorophenyl)-3-(l-hydroxy-l-methyle%l)-1H-pyrazol-5-yl]-2-thienyl}-N- cyclopropylbenzamide; MS (ES): 512 [M+H]+;
• 2-{5-[l-(2-chlorophenyl)-3-(l-hydroxy-l-methylethyl)-1H-pyrazol-5-yl]-2-thienyl}-4- fluorophenol; MS (ES): 429 [M+H]+;
• N-(2-{5-[l-(2-chlorophenyl)-3-(l-hydroxy-l-methylethyl)-1H-pyrazol-5-yl]-2- thienyl}phenyl)methanesulfonamide; MS (ES): 488 [M+H]+; • 4-{5-[l-(2-chlorophenyl)-3-(l-hydroxy-l-methyle%l)-1H-pyrazol-5-yl]-2-thienyl}-2- fluorobenzoic acid; MS (ES): 457 [M+H]+;
• 2-[l-(2-cMorophenyl)-5-{5-[4-(methylthio)-3-^^ yl]propan-2-ol; MS (ES): 509 [M+H]+;
• 2-[l-(2-chlorophenyl)-5-{5-[2-meihyl-5-(methyloxy)phenyl]-2-thienyl}-1H-pyrazol-3-yl]propan-2- ol; MS (ES): 439 [M+H]+;
• 2-[l-(2-cMorophenyl)-5-{5-[2-(methyloxy)pyridm-3-yl]-2-thienyl}-1H-pyrazol-3-yl]propan-2-ol; MS (ES): 426 [MH-H]+;
• 2-[l-(2-chlorophenyl)-5-{5-[6-(me1hyloj^)pyridin-3-yl]-2-thienyl}-1H-pyrazol-3-yl]propan-2-ol; MS (ES): 426 [Mf-H]+; • 2-[l-(2-cMorophenyl)-5-{5-[4-(methyloxy)-3-(trifluoromethyl)phenyl]-2-1hienyl}-1H-pyrazol-3- yl]propan-2-ol; MS (ES): 493 [M+H]+;
• 2-[l-(2-cMorophenyl)-5-(5-pyridM-3-yl-2-tbienyl)-1H-ρyrazol-3-yl]propan-2-ol; MS (ES): 396 [M+H]+;
• 2-{l-(2-cMorophenyl)-5-[5-(lH-indol-6-yl)-2-thienyl]-1H-pyrazol-3-yl}propan-2-ol; MS (ES): 434 [M+H]+;
• 2-[l-(2-cMorophenyl)-5-{5-[(lE)-3,3-dimethylbut-l-en-l-yl]-2-tMenyl}-1H-pyrazol-3-yl]propan-2- ol; MS (ES): 401 [M+H]+; • l,l-dimeUiyle%12-{5-[l-(2-cMorophenyl)-3-(l-hydroxy-l-methylethyl)-1H-pyrazol-5-yl]-2- thienyl}-1H-pyrrole-l-carboxylate; MS (ES): 484 [M+H]+;
• 2-[l-(2-chlorophenyl)-5-(5-{2-[(l-methyle%l)oxy]pyridm-3-yl}-2-iMenyl)-1H-pyra2Dl-3- yl]propan-2-ol; MS (ES): 454 [M+H]+; • 2-[l-(2-cMorophenyl)-5-{5-[2-(cyclopentyloxy)pyridin-3-yl]-2-iMenyl}-1H-pyrazol-3-yl]propan-2- ol; MS (ES): 480 [M+H]+;
• ethyl 4-{5-[l-(2-chlorophenyl)-3-(l-hydroxy-l-methyle1hyl)-1H-pyrazol-5-yl]-2-thienyl}benzoate; MS (ES): 467 [M+H]+;
• 2-{l-(2-cMorophenyl)-5-[5-(5-methylfiu:an-2-yl)-2-thienyl]-1H-pyrazol-3-yl}propan-2-ol; MS (ES): 399 [M+H]+;
• 4-{5-[l-(2-cMorophenyl)-3-(l-hydroxy-l-methyle1hyl)-1H-pyrazol-5-yl]-2-1hienyl}benzaniide; MS (ES): 438 |M+H]+;
• methylN-[(4-{5-[l-(2-chlorophenyl)-3-(l-hydroxy-l-methyleihyl)-1H-pyrazol-5-yl]-2- thienyl}phenyl)carbonyl]glycinate; MS (ES): 510 [M+H]+; • 3-{5-[l-(2-chlorophenyl)-3-(l-hydroxy-l-methylethyl)-1H-pyrazol-5-yl]-2-thienyl}benzamide; MS (ES): 438 [M+H]+;
• 2-[l-(2-chlorophenyl)-5-{5-[3-(tMomoφholm-4-ylcarbonyl)phenyl]-2-tWenyl}-1H-pyrazol-3- yl]propan-2-ol; MS (ES): 524 [M+H]+;
• 2-{5-[5-(l,3-benzodioxol-5-yl)-2-tlτienyl]-l-(2-chlorophenyl)-1H-pyrazol-3-yl}propan-2-ol; MS (ES): 439 [MH-H]+;
• 2-[l-(2-cMorophenyl)-5-{5-[2-me1hyl-5-(moφholin4-ylsulfonyl)phenyl]-2-thienyl}-1H-pyrazol-3- yl]propan-2-ol; MS (ES): 558 [M+H]+;
• 2-[5-{5-[2,4-bis(trifluoromethyl)phenyl]-2-iMenyl}-l-(2-chlorophenyl)-1H-pyrazol-3-y^ ol; MS (ES): 531 [M-I-H]+; • 2-[5-{5-[2,3-bis(methylo^)phenyl]-2-iMenyl}-l-(2-chlorophenyl)-1H-pyrazol-3-yl]propan-2-ol; MS (ES): 455 [M+H]+;
• 2-[l-(2-cUorophenyl)-5-{5-[3,5-dffluoro-2-(methyloxy)phenyl]-2-1hienyl}-1H-pyrazol-3- yl]propan-2-ol; MS (ES): 461 [M+H]+;
• 2-[l-(2-chlorophenyl)-5-{5-[2-(phenyloxy)phenyl]-2-thienyl}-1H-pyra2ol-3-yl]propan-2-ol; MS (ES): 487 [M+H]+;
• 2-[l-(2-cMorophenyl)-5-{5-[3-(trifluorome^^ MS (ES): 463 |M+H]+; • 2-{ l^-cUoiOphenyO-S-tS-CS^-dichlorophenyl^-tMeny^-1H-pyrazol-S-yljpropan-l-ol; MS (ES): 463 |MfH]+;
• 2-{l-(2-cMorophenyl)-5-[5-(2,4,5-trimethylphenyl)-2-iMenyl]-1H-pyrazol-3-yl}propan-2-ol; MS (ES): 437 [M+HJ+; • 2-[l-(2-clJorophenyl)-5-(5-naphthalen-2-yl-2-thienyl)-1H-pyrazol-3-yl]propan-2-ol; MS (ES): 445 [M+H]+;
• 2-[l-(2-cMorophenyl)-5-(5-{2-[(l-methyle%l)oxy]phenyl}-2-thienyl)-1H-pyrazol-3-yl]propan-2- ol; MS (ES): 453 [M+H]+;
• 2-[l-(2-cUorophenyl)-5-{5-[2-fluoro-5-(methyloxy)phenyl]-2-thienyl}-1H-pyrazol-3-yl]propan-2- ol; MS (ES): 443 [M+H]+;
• 2-{l-(2-cUorophenyl)-5-[5-(l-phenylethenyl)-2-thienyl]-1H-pyrazol-3-yl}propan-2-ol; MS (ES): 421 [MfHJ+;
• 2-[l-(2-chlorophenyl)-5-{5-[(lE)-prop-l-en-l-yl]-2-thienyl}-1H-pyrazol-3-yl]propan-2-ol; MS (ES): 359 [MH-H]+; • 2-{ l-(2-chlorophenyl)-5-[5-(5-fluoro-2-methylphenyl)-2-1hienyl]-1H-pyrazol-3-yl}propan-2-ol; MS (ES): 427 [M+H]+;
• 2-[l-(2-cMorophenyl)-5-{5-[2-(Thydroxym MS (ES): 425 [M-I-Hl+;
• 2-[l-(2-cUorophenyl)-5-(5-{5-methyl-2-[(l-methyle%l)oxy]phenyl}-2-1hienyl)-1H-pyrazol-3- yl]propan-2-ol; MS (ES): 467 [M+HJ+;
• 2-[5-(2,2'-bithien-5-yl)-l-(2-chlorophenyl)-1H-pyrazol-3-yl]propan-2-ol; MS (ES): 401 [M+H]+;
• 2-[5-(5-biphenyl-3-yl-2-thienyl)-l-(2-chlorophenyl)-1H-pyrazol-3-yl]propan-2-ol; MS (ES): 471 [M+H]+;
• 2-[l-(2-chlorophenyl)-5-{5-[5-methyl-2-(propyloxy)phenyl]-2-thienyl}-1H-pyrazol-3-yl]propan-2- ol; MS (ES): 467 [M+HJ+;
• 2-{l-(2-chlorophenyl)-5-[5-(4-propylphenyl)-2-thienyl]-1H-pyrazol-3-yl}propan-2-ol; MS (ES): 437 IMfHJ+;
• 2-[l-(2-cMorophenyl)-5-(5-{4-[(trifluoromethyl)oxy]phenyl}-2-tlύenyl)-1H-pyrazol-3-yl]propan-2- ol; MS (ES): 479 [M+HJ+; • 4-{5-[l-(2-chlorophenyl)-3-(l-hydroxy-l-methyle%l)-1H-pyrazol-5-yl]-2-thienyl}-N-(2- methylpropyl)benzamide; MS (ES): 494 [MH-H]+;
• 2-[l-(2-chlorophenyl)-5-{5-[3-(ethyloxy)phenyl]-2-thienyl}-1H-pyrazol-3-yl]propan-2-ol; MS (ES): 439 jM+HJ+; • 2-{l-(2-chlorophenyl)-5-[5-(4-ethylphenyl)-2-thienyl]-1H-pyrazol-3-yl}propan-2-ol; MS (ES): 423 [MH-H]+;
• 2-{ l^-chlorophenyO-S-tS-CS^-dchlorophenyl^-thienyy-1H-pyrazol-S-ylJpropan^-ol; MS (ES): 463 [M+H]+; • 2-[l-(2-cMorophenyl)-5-{5-[6-(methyloxy)naphthalen-2-yl]-2-ilτienyl}-1H-pyrazol-3-yl]propan-2- ol; MS (ES): 475 [M+H]+;
• 2-{l-(2-cMorophenyl)-5-[5-(2-e%lphenyl)-2-tMenyl]-1H-pyrazol-3-yl}propan-2-ol; MS (ES): 423 [M+H]+;
• 2-[l-(2-cMorophenyl)-5-{5-[4-(dme^ MS (ES): 438 |M+H]+;
• 2-{ l-(2-clτlorophenyl)-5-[5-(2,4,5-trifluorophenyl)-2-thienyl]-1H-pyrazol-3-yl}propan-2-ol; MS (ES): 449 |M+HJ+;
• 2-[l-(2-cUorophenyl)-5-{5-[2-fluoro-5-(lrifluoromethyl)phenyl]-2-iMenyl}-1H-pyrazol-3- yl]propan-2-ol; MS (ES): 481 [M+H]+; • 2-{l-(2-chlorophenyl)-5-[5-(2,3,4-trifluorophenyl)-2-thienyl]-1H-pyrazol-3-yl}propan-2-ol; MS (ES): 449 |M+H]+;
• N-(4-{5-[l-(2-chlorophenyl)-3-(l-hydroxy-l-me1hylethyl)-1H-pyrazol-5-yl]-2- 1iiienyl}phenyl)acetamide; MS (ES): 452 [MfH]+;
• 2-[l-(2-chlorophenyl)-5-{5-[3-(tydroxymefliyl)phenyl]-2-thienyl}-1H-pyrazol-3-yl]propan-2-ol; MS (ES): 425 [M+HJ+;
• 2-[5-{5-[5-cMoro-2-(methyloxy)phenyl]-2-ihienyl}-l-(2-chlorophenyl)-1H-pyrazol-3-yl]propan-2- ol; MS (ES): 459 |M+Hl+;
• 2-[l<2-chlorophenyl)-5-{5-[2,3,4-tris(methyloxy)phenyl]-2-thienyl}-1H-pyrazDl-3-yl]propan-2-ol; MS (ES): 485 (M+HJ+; • 2-[l-(2-cMorophenyl)-5-{5-[2-(trffluoro MS (ES): 463 [M+H]+;
• 2-{l-(2-chlorophenyl)-5-[5-(lH-indol-5-yl)-2-thienyl]-1H-pyrazol-3-yl}propan-2-ol; MS (ES): 434 [M+HJ+;
• 2-[l-(2-cMorophenyl)-5-{5-[6-(e%loxy)naphthalen-2-yl]-2-iMenyl}-1H-pyrazol-3-yl]propm>2-o MS (ES): 489 (M+HJ+;
• 2-[l-(2-cMorophenyl)-5-{5-[4-(hycfroxyme1hyl)phenyl]-2-thienyl}-1H-pyrazol-3-yl]propan-2-ol; MS (ES): 425 [M+HJ+; • 2-{l-(2-cMorophenyl)-5-[5-(2,3-difluorophenyl)-2-thienyl]-1H-pyrazol-3-yl}propan-2-ol; MS • (ES): 431 IMfEQ+;
• 2-{l-(2-cUorophenyl)-5-[5-(2,4-difluoiOphenyl)-2-thienyl]-1H-pyrazol-3-yl}propan-2-ol; MS (ES): 431 [M+H]+; • 2-{5-[5-(2-chloro-6-fluoro-3-methylphenyl)-2-thienyl]-l-(2-chlorophenyl)-1H-pyrazol-3- yl}propan-2-ol; MS (ES): 461 [M+H]+;
• 2-[l-(2-cωorophenyl)-5-{5-[4-(methylthio)phenyl]-2-tlτienyl}-1H-pyrazol-3-yl]propan-2-ol; MS (ES): 441 |M+H]+;
• 2-[l-(2-chlorophenyl)-5-{5-[4-(trifluoromeihyl)phenyl]-2-thienyl}-1H-pyrazol-3-yl]propan-2-ol; MS (ES): 463 |M+H]+;
• 2-{5-[5-(6-cMoro-2-fluoro-3-methylphenyl)-2-thienyl]-l-(2-chlorophenyl)-1H-pyrazol-3- yl}propan-2-ol; MS (ES): 461 [M+H]+;
• 2-{l-(2-cUorophenyl)-5-[5-(4-fluoro-3-me1hylphenyl)-2-thienyl]-1H-pyrazol-3-yl}piOpan-2-ol; MS (ES): 427 [M+H]+; • 2-{l-(2-chlorophenyl)-5-[5-(3,4-difluorophenyl)-2-thienyl]-1H-pyrazol-3-yl}propan-2-ol; MS (ES): 431 [M+H]+;
• 2-[l-(2-chlorophenyl)-5-{5-[4-(phenyloxy)phenyl]-2-thienyl}-1H-pyrazol-3-yl]propan-2-ol; MS (ES): 487 [M+H]+;
• 2-[l-(2-cUorophenyl)-5-{5-[4-chloro-2-(trifluoromethyl)phenyl]-2-tWenyl}-1H-pyrazol-3- yl]propan-2-ol; MS (ES): 497 [M+H]+;
• 2-{ l-(2-chlorophenyl)-5-[5-(2,5-dichlorophenyl)-2-thienyl]-1H-pyrazol-3-yl}propan-2-ol; MS (ES): 463 [M+H]+;
• 2-[5-{5-[2-chloro-4-(ethyloxy)phenyl]-2-iMenyl}-l-(2-chlorophenyl)-1H-pyrazol-3-yl]propan-2-ol; MS (ES): 473 [M+H]+; • 2-{l-(2-chlorophenyl)-5-[5-(3-cMorophenyl)-2-thienyl]-1H-pyrazol-3-yl}propan-2-ol; MS (ES): 429 [M+H]+;
• 2-{l-(2-chlorophenyl)-5-[5-(lH-indol-4-yl)-2-thienyl]-1H-pyrazol-3-yl}propan-2-ol; MS (ES): 434 [M+H]+;
• 2-[l-(2-cMorophenyl)-5-{5-[2-chloro4-(trifluorome1hyl)phenyl]-2-tliienyl}-1H-pyrazol-3- yl]propan-2-ol; MS (ES): 497 [M+H]+;
• N-(3-{5-[l-(2-chlorophenyl)-3-(l-hydroxy-l-methylethyl)-1H-pyrazol-5-yl]-2- tlτienyl}phenyl)methanesulfonamide; MS (ES): 488 [M+H]+; • 3-{5-[l-(2-chlorophenyl)-3-(l-hydroxy-l-methylethyl)-1H-pyrazol-5-yl]-2- thienyl}benzenesulfonamide; MS (ES): 474 [M+H]+;
• 3-{5-[l-(2-cUorophenyl)-3-(l-hydroxy-l-methyle%l)4H-pyrazol-5-yl]-2-thienyl}-N-(l- methylethyl)benzamide; MS (ES): 480 |MfHJ+; • 2-[l-(2-chlorophenyl)-5-{5-[4-fluoro-3-(1rifluoromethyl)phenyl]-2-tMenyl}-1H-pyrazol-3- yl]propan-2-ol; MS (ES): 481 [MH-HJ+;
• 2-[5-{5-[3,5-bis(trifluoromethyl)phenyl]-2-tMenyl}-l-(2-chlorophenyl)-1H-pyrazol-3-yl]propan-2- ol; MS (ES): 531 [MH-H]+;
• 2-[5-(5-biphenyl4-yl-2-thienyl)-l-(2-chlorophenyl)-1H-pyrazol-3-yl]propan-2-ol; MS (ES): 471 [M+HJ+;
• 2-[l-(2-chlorophenyl)-5-{5-[4<l-methyle%l)phenyl]-2-thienyl}-1H-pyrazol-3-yl]propan-2-ol; MS (ES): 437 |M+H]+;
• 2-[l-(2-chlorophenyl)-5-(5-ethyl-2-thienyl)-1H-pyrazol-3-yl]propan-2-ol; MS (ES): 347 [MfHJ+;
• 2-[l-(2-chlorophenyl)-5-(5-{3-fluoro^[(phenylmethyl)oxy]phenyl}-2-thienyl)-1H-pyrazol-3- yl]propan-2-ol; MS (ES): 519 [M+H]+;
• 2-[l-(2-cWorophenyl)-5-{5-[3-chloro4-(trifluoromethyl)phenyl]-2-Menyl}-1H-pyrazol-3- yl]propan-2-ol; MS (ES): 497 [M+HJ+;
• 2-[l-(2-chlorophenyl)-5-{5-[4-(e%lsulfonyl)phenyl]-2-Menyl}-1H-pyrazol-3-yl]propan-2-ol; MS (ES): 487 [MfHJ+; • 2-(5-{3-methyl-5-[3-(methylsulfonyl)phenyl]-2-thienyl}-l-[4-(trifluoromethyl) pyridin-3-yl]-1H- pyrazol-3-yl)propan-2-ol, MS(ES): 522 [M+HJ+ 504 (M-OH)
• 2-[l-(2-cMorophenyl)-5-{4-methyl-5-[3-(methylsulfonyl)phenyl]-2-thienyl}-1H-pyrazol-3- yl]propan-2-ol, MS(ES): 487 [M-HHJ+, 469 (M-OH)
• 2-[l-(2-cMorophenyl)-5-{3-ethyl-5-[3-(me^ 2-ol, MS(ES): 501 [MH-HJ+, 483 (M-OH)
• 2-[l-(2-chloro-3-fluorophenyl)-5-{3-e%l-5-[3-(methylsulfonyl)phenyl]-2-thienyl}-1H-pyrazol-3- yl]propan-2-ol, MS(ES): 519 [MH-HJ+ 501 (M-OH)
• 2-[5-{4-bromo-5-[3-(metiiylsulfonyl)phenyl]-2-tMenyl}-l-(2-cUorophenyl)4H-pyrazol-3- yl]propan-2-ol, MS(ES): 553 [MfH]+ • 2-[5-{4-bromo-3-methyl-5-[3-(methylsulfonyl)phenylJ-2-thienyl}-l-(2-chlorophenyl)-1H-pyrazol- 3-ylJpropan-2-ol, MS(ES): 567 [MH-HJ+.
• 2-[l-(2-chlorophenyl)-5-{3-methyl-5-[3-(methylsulfonyl)phenyl]-2-thienyl}-1H-pyrazol-3- yl]propan-2-ol, MS(ES): 487 [M+HJ+. • 2-[l-(2-chlorophenyl)-5-{3-methyl4-[3-(methylsulfonyl)phenyl]-2-1hienyl}-1H-pyrazol-3- yl]propan-2-ol, MS(ES): 487 [M+H]+.
• 2-(l-[3-fluoro-2-(trifluoromethyl)ph^ lH-pyrazol-3-yl)propan-2-ol, MS(ES): 539 [M+H]+. • 2-[5-{3-bromo-5-[3-(methykulfonyl)phenyl]-2-tMenyl}-l-(2-cMorophenyl)-1H-pyrazol-3- yl]propan-2-ol MS(ES): 553 |M+H]+.
• 2-[5-{3-cMoro-5-[3-(methylsulfonyl)phenyl]-2-1hienyl}-l-(2-clτlorophenyl)-1H-pyrazol-3- yl]propan-2-ol, MS(ES): 507 [M+H]+.
• 2-[l-(2-chloro-3-fluorophenyl)-5-{3-methyl-5-[3-(methylsulfonyl)phenyl]-2-tWenyl}-1H-pyrazo^ 3-yl]propan-2-ol, MS(ES): 505 [M+H]+
• methyl 5-(5-{3-[(l-methyle%l)sulfonyl]ph^ pyrazole-3-carboxylate, MS(ES): 5536 [M+H]+
• l-{5-(5-{3-[(l-methyle%l)sdfonyl]phenyl}-2-Menyl)-l-[3-(trifluoromethyl)pyridin-2-yl]-1H- pyrazol-3-yl}ethanone, MS(ES): 520 [MH-H]+. • 2-{5-(5-{3-[(l-methyle%l)sulfonyl]phenyl}-2-Menyl)-l-[3-(1rifluoromethyl)pyridin-2-yl]-1H- pyrazol-3-yl}propan-2-ol, MS(ES): 536 [M+H]+.
• 2-[l-(2-cMorophenyl)-5-(5-{3-[(l-methyle%l)sulfonyl]phenyl}-2-ftienyl)-1H-pyrazol-3- yl]propan-2-ol, MS(ES): 501 |M+H]+.
• 2-[l-(3-fluoropyridfo-2-yl)-5-{5-[3-(me&ylsu^^ ol, MS(ES): 458 |M+H]+.
• 2-[l-(2-cMoropyridin-3-yl)-5-{5-[3-(me1hylsulfonyl)phenyl]-2-thienyl}-1H-pyrazDl-3-y^ ol, MS(ES): 474 [M+H]+.
• 2-[l-(2-bromophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}-1H-pyra2Dl-3-yl]propan-2-ol, MS(ES): 517 |M+H]+. • 2-[l-(23-dffluorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-1hienyl}-1H-pyrazol-3-yl]propan-2- ol, MS(ES): 475 [M+H]+.
• 2-(5-{5-[3-(methylsulfonyl)phenyl]-2^ yl)propan-2-ol, MS(ES): 523 [MH-H]+.
• 2-[l-(3-chloro-2-fluorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}-1H-pyrazol-3- yl]propan-2-ol, MS(ES): 491 [M+H]+.
• 2-[l-(2,2-dffluoro-l,3-beiizDdioxol-4-yl)-5-{5-[3<methylsulfonyl)phenyl]-2-tWenyl}-1H-pyrazol- 3-yl]propan-2-ol, MS(ES): 519 [M+H]+. • 2-(l-[2-chloro-5-(trifluoromethyl)phenyl]-5-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}-1H-pyr^ 3-yl)propan-2-ol, MS(ES): 565 [MH-Na]+.
• 2-[l-(2,6-difluorophenyl)-5-{5-[3-(methylsι#onyl)phenyl]-2-thienyl}-1H-pyrazol-3-yl]propan-2- ol, MS(ES): 475 [M+H]+. • 2-[l-(3-fluoro-2-methylphenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}-1H-pyrazol-3- yl]propan-2-ol, MS(ES): 471 [M+H]+
• 2-[l-(5-fluoropyridin-3-yl)-5-{5-[3-(methylsιdfonyl)phenyl]-2-thienyl}-1H-pyrazol-3-yl]propan-2- ol, MS(ES): 458 [M+H]+.
• 2-[4-cUoro-l-(5-fluoropyridin-3-yl)-5-{5-[3-(me1hylsulfonyl)phenyl]-2-thienyl}-1H-pyrazol-3- yl]propan-2-ol, MS(ES): 492 [M+H]+.
• 2-[4-bromo-l-(5-fluoropyridin-3-yl)-5-{5-[3-(methylsιιlfonyl)phenyl]-2-tMenyl}-1H-pyrazol-3- yl]propan-2-ol, MS(ES): 538 [M+H]+.
• 2-(5-{5-[3-(methylsulfonyl)phenyl]-2-tMenyl^^ yl)propan-2-ol, MS(ES): 508 [M+H]+ • 2-[l-(3-fluoropyridin-4-yl)-5-{5-[3-(methylsι^^ ol, MS(ES): 458 [M+H]+.
• 2-[l-(3,5-dicUoropyridin-4-yl)-5-{5-[3-(me1hylsulfonyl)phenyl]-2-iMenyl}-1H-pyrazDl-3- yl]propan-2-ol, MS(ES): 508 [M+H]+.
• 2-[l-(3-cUoropyridin-4-yl)-5-{5-[3-(methylsιαlfonyl)phenyl]-2-thienyl}-1H-pyrazol-3-yl]p^ ol, MS(ES): 474 [M+H]+.
• 2-(l-[5-cUoro-2-(phenyloxy)phenyl]-5-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}-1H-pyrazol-3- yl)propan-2-ol; MS (ES): 565 |M+H]+.
• l^l-fS-chloro^-φhenylo^phenylJ-S-IS-P^methylsulfony^phenyy^-tMenylJ-1H-pyrazol-S- yl)ethanone; MS (ES): 549 |M+H]+. • 3-{5-[l-(2,5-dichlorophenyl)-3-(l-hydroxy-l-methylethyl)-1H-pyrazol-5-yl]-2- thienyl}benzenesulfonamide; MS (ES): 508 and 510 [each MfEQ+.
• 3-{5-[3-ace1yl-l-(2,5-dichlorophenyl)-1H-pyrazol-5-yl]-2-iMenyl}benzenesulfonamide; MS (ES): 492 and 494 [each M+H]+.
• 2-(3-(3-(2-hydroxypropan-2-yl)-5-(5-(3-(methylsulfonyl)phenyl)thiophen-2-yl)-1H-pyrazol-l- yl)phenyl)propan-2-ol. MS (ES): 497 [MH-H]+.
• 2-(l-(2,4-difluorophenyl)-5-(5-(3-(methylsulfonyl)phenyl)thiophen-2-yl)4H-pyi^ol-3-yl)propa^^ 2-ol. MS (ES): 475 [MH-H]+. • 2-(l -(3,5-difluorophenyl)-5-(5-(3-(meihylsulfonyl)phenyl)thiophen-2-yl)- lH-pyrazol-3-yl)propan- 2-ol. MS (ES): 475 |M+H]+.
• 2-(l-(3,4-dffluorophenyl)-5-(5-(3-(me1hylsulfonyl)phenyl)iMophen-2-yl)-1H-pyrazol-3-yl)propan- 2-ol. MS (ES): 475 [M+H]+ • 2-(l-(2,4-dicMorophenyl)-5-(5-(3-(methylsu^ 2-ol. MS (ES): 507 [M+H]+.
• 2-(l-(2,3-dicUorophenyl)-5-(5-(3-(methylsulfonyl)phenyl)tMophen-2-yl)-1H-pyrazol-3-yl^ 2-ol. MS (ES): 507 [M+H]+.
• 2-(.l-(2,5-cIifluorophenyl)-5-(5-(3-(methylsu^ 2-ol. MS (ES): 475 [M-HH]+.
• 2-(l-(3,5-dicMorophenyl)-5-(5-(3-(met^ 2-ol. MS (ES): 507 [M+H]+.
• 2-(l-(3,4-dicUorophenyl)-5-(5-(3-(methylsulfonyl)phenyl)iWophen-2-yl)-1H-pyrazol-3-yl)pro^ 2-ol. MS (ES): 507 [MB-H]+. • 2-(l-(2-e%lphenyl)-5-(5-(3-(methylsul^ MS (ES): 467 [M+H]+.
• 2-(5-(5-(3-(methylsulfonyl)phenyl)tMophen-2-yl)-l-(2-propylphenyl)-1H-pyrazol-3-yl)propan-2-ol. MS (ES): 481 [M+H]+.
• 2-(l-(5-fluoro-2-methylphenyl)-5-(5-(3-(methylsulfonyl)phenyl)tMophen-2-yl)-1H-pyrazol-3- yl)propan-2-ol. MS (ES): 471 [M+H]+.
• 2-(l<3-chloro-2-methylphenyl)-5-(5-(3-(methylsulfonyl)phenyl)thiophen-2-yl)-1H-pyrazol-3- yl)propan-2-ol. MS (ES): 487 [M+H]+.
• 2-(l-(2,4-dicUoro-6-(trifluoromethyl)phenyl)-5-(5-(3-(methylsulfonyl)phenyl)-thiophen-2-yl)- pyrazol-3-yl)propan-2-ol. MS (ES): 575 [M+H]+. • 2-(l-(2-isopropylphenyl)-5-(5-(3-(methylsulfonyl)phenyl)thiophen-2-yl)-1H-pyrazol-3-yl)propaii- 2-ol. MS (ES): 481 |M+H]+.
• 2-(5-(5-(3-(me1hylsιdfonyl)phenyl)iWophen-2-yl)-l-φyridin-3-yl)-1H-pyrazol-3-yl)propan^ MS (ES): 440[M+H]+
• 2-(l-(2,6-dimethylphenyl)-5-(5-(3-(me1hylsulfonyl)phenyl)tMophen-2-yl)-1H-pyrazol-3-yl^ 2-ol. MS (ES): 467(M+H]+.
• 2<l-(2-fluoro-6-(1rMuoromethyl)phenyl)-5-(5-(3-(methylsulfonyl)phenyl)1hiophen-2-yl)-1H- pyrazol-3-yl)propan-2-ol. MS (ES): 525[M+H]+ • 2-(l -(2-(difluoromethoxy)phenyl)-5-(5-(3-(methylsulfonyl)phenyl)thiophen-2-yl)- lH-ρyrazol-3- yl)propan-2-ol. MS (ES): 505|M+H]+.
• 2-(l-(3-fluoro-2-(trifluoromethyl)phenyl)^^ pyrazol-3-yl)propan-2-ol. MS (ES): 525[M+H]+. • 3-(5-(l-(2-chlorophenyl)-3-(2-hydiO}ς^ropan-2-yl)-1H-pyrazol-5-yl)thiophen-2-yl)-N-(2- (dimethylamino)ethyl)benzenesulfonamide. MS (ES): 545[M+H]+.
• 2-(5-(3-bromo-5-(3-(methylsulfonyl)phenyl)tWophen-2-yl)-l<3-fluoro-2-methylphenyl)-1H- pyrazol-3-yl)propan-2-ol. MS (ES): 549[M+H|+.
• 2-(5-(3-bromo-5-(3-(meUiylsulfonyl)phenyl)ihiophen-2-yl)-l-(2-chloro-3-fluorophenyl)-1H- pyrazol-3-yl)propan-2-ol. MS (ES): 569[M+BQ+.
• 2-(l-(2-chloro-3-fluorophenyl)-5-(3-chloro-5-(3-(methylsulfonyl)phenyl)thiophen-2-yl)-1H- pyrazol-3-yl)propan-2-ol. MS (ES): 525|M+BQ+.
• 2-(5-(3-chloro-5-(3-(methylsulfonyl)phenyl)thiophen-2-yl)- 1 -(3-fluoro-2-(trifluoromethyl)phenyl)- lH-pyrazol-3-yl)propan-2-ol.MS (ES): 559[M+H]+. • 2-(5-(3-bromo-5-(3-(methylsulfonyl)phenyty^ lH-pyrazol-3-yl)propan-2-ol.MS (ES): 603[M+H]+.
• 2-(l-(3-fluoro-2-methylphenyl)-5-(3-methyl-5<3-(methylsulfonyl)phenyl)thiophen-2-yl)-1H- pyrazol-3-yl)propan-2-ol. MS (ES): 485[M+H1+.
• 2-(5-{3-methyl-5-[3-(methylsulfonyl^^ pyrazol-3-yl)propan-2-ol, MS(ES): 522 [M+H|+.
Example 9
2~[l-(2-chlorophertyty-5-{5-[3-(nwthyl$ulfortyl)phenyl]-2^ hexqfluoropropan-2-ol
Example 9a Preparation of2-[5-(5-bromothiophen-2-yl)-l-(2-chlorophe}ψl)-lH-pyrazol-3-yl]-l, 1, 1,3,3,3- hexqfluoro-propan-2-ol
Figure imgf000154_0001
To a stirred solution of 5-(5-bromothiophen-2-yl)-l-(2-chlorophenyl)-1H-pyrazole-3-carboxylic acid methyl ester (0.40 g, 1.0 mmol) and trifluoromethyl-trimethylsilane (CF3-TMS) (0.59 mL, 4.0 mmol) in toluene (4 mL, anhyd) was added dropwise a 1.0M solution of tetrabutylammonium fluoride (TBAF) in THF (0.20 mL, 20 mol%, dried over 4A molecular sieves). After 2 h the reaction mixture was charged with additional CF3-TMS (0.3 mL) and TBAF (50 μL), then heated at 450C. After 20 h (total) the reaction mixture was allowed to cool to ambient temperature, diluted with DCM (50 mL), washed with H2O and brine, then dried (Na2SO4) and concentrated under reduced pressure. The resulting residue was purified by chromatography (silica, EtOAc/Hex, 0:100 to 30:70) to give the title compound (86 mg). R/0.38 (20% EtOAc/Hex); GC-MS(El): 504, 506 |M*]-
Example 9b
Preparation of 2-[l-(2-chloropheryl)-5-{5-[3-(methylsulfonyl)pher^
1, 1, l,3,3,3-hexqfluoropropan-2-ol
Figure imgf000155_0001
A mixture of 2-[5-(5-bromothiophen-2-yl)-l-(2-chlorophenyl)-1H-pyrazol-3-yl]-l, 1,1,3,3,3- hexafluoro-propan-2-ol (84 mg, 0.17 mmol), 3-methanesulfonyl-phenylboronic acid (42 mg, 0.21 mmol), K2CO3 (70 mg, 0.51 mmol), Cl2Pd(dppf)-DCM (21 mg, 15 mol%) and H2O (0.2 mL) in dioxane (2 mL) was sparged with Argon for 5 min and then heated at 8O0C as a sealed flask. After 3 h the reaction mixture was allowed to cool to ambient temperature, filtered (Celite™) and the filter agent rinsed with EtOAc. The combined filtrates were concentrated under reduced pressure and purified by chromatography (silica, EtOAc/Hex, 0:100 to 50:50) to give the title compound (34 mg) as a white solid. 1H-NMR (DCM-J2): δ 8.03 (m, IH), 7.83 (m, IH), 7.76 (m, IH), 7.55-7.62 (m, 4H), 7.49-7.54 (m, IH), 7.29 (d, IH), 6.91 (d, IH), 6.86 (s, IH), 5.10 (s, IH), 3.05 (s, 3H); MS(ES): 581 [M+H]+. The following compound was prepared from the appropriate methyl ketone intermediate in a similar manner:
• 2-[l-(2-chlorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}-1H-pyrazol-3-yl]-l,l,l- trifluoropropan-2-ol,MS(ES): 527 [M+H]+
The following compound was prepared from the appropriate carboxaldehyde intermediate in a similar manner:
• l-[l-(2-cMorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}-1H-pyrazol-3-yl]-2,2,2- trifluoroethanol, GC-MS(EI): 512 [M1].
Example 10 2-{l-(2-Chloroψhenyl)-4φMro-5-[5-(3-nιethmesulfoψlφhenyl)4hiophen-2-yl]-^ propan-2-ol
Example 10a Preparation of2-bromo-5-(2-fluoro-l, l-dimethoxy-etlτyl)-thiophene
Figure imgf000156_0001
To a solution of 2-acetyl-5-bromothiophene (10.3 g, 50 mmol) in dry methanol (300 mL) was added selectfluor (25 g, 70.57 mmol). The suspension was stirred at reflux for 50 h. Evaporation of solvent gave a residual solid, which was taken up in DCM. The insoluble material was filtered off and the filtrate was washed with water, dried over sodium sulfate and evaporated in vacuo. The crude product was purified by flash chromatography on silica gel eluted with EtOAc-hexane (0-30%) to afford 2- bromo-5-(2-fluoro-l,l-dimethoxy-ethyl)-thiophene as a white solid (4.8 g, 36%). 1H-NMR (CDCl3): δ 6.98 (d, IH), 6.84 (d, IH), 4.51 (d, 2H), 3.29 (s, 6H).
Example 10b Preparation of l-(5-bromo-thiopken-2~yl)~2-fluoro-ethanone
Figure imgf000156_0002
To a stirred solution of 2-bromo-5-(2-fluoro-l,l-dimethoxy-ethyl)-thiophene (9.4 g, 35 mmol) in MeCN (100 mL) was added 10% aq. HCl (50 mL) at 2O0C and the reaction mixture was stirred at 0C for 3 h. Solvent was removed in vacuo to afford a residue, which was partitioned between DCM and water, the aqueous layer was extracted with DCM. The combined organic layers were washed with water, sat aq. NaHCO3 and brine, dried over sodium sulfate and evaporated in vacuo to give a white solid. It was dissolved in minimum volume of DCM, and a large volume of hexane was added. After evaporation of most of the solvent, solid precipitated and was then collected with filtration, washed with hexane and dried under high vacuum to afford l-(5-bromo-thiophen-2-yl)-2-fluoro-ethanone (6.52 g, 84%). 1H- NMR (CDCl3): δ 7.64 (d, IH), 7.15 (d, IH), 5.26 (d, 2H). Example 10c
Preparation of5-(5-bromo4hiophen-2-yl)-l-(2-chloroφheψl)-4-flιιoro-lH-pyrazole-3-carbo^lic acid methyl ester
Figure imgf000157_0001
To a stirred solution of l-(5-bromo-thiophen-2-yl)-2-fluoro-ethanone (6.59 g, 29.54 mmol) in dry THF (200 mL) was added a solution of LiHMDS in THF (1.0 M, 36 mL, 36 mmol) under nitrogen at -780C and the reaction mixture was stirred at -78 0C for 40 min, then a solution of diethyl oxalate (6 mL, 44.25 mmol) in dry THF (50 mL) was added dropwise. The mixture was allowed to warm to 2O0C overnight, then quenched with 2 N aq. HCl and extracted with ether. The combined organic layers were washed with brine, dried over sodium sulfate and evaporated in vacuo to afford 5-(5-bromo-thiophen-2- yl)-l-(2-chloro-phenyl)-4-fluoro-1H-pyrazole-3-carboxylic acid methyl ester as a dark-red oil (10.4 g, 100%), which was used in the next reaction without further purification. A mixture of the above oil (6.4 g, 19.81 mmol) and 2-chlorophenylhydrazine hydrochloride (4.0 g, 22.3 mmol) in dry EtOH (100 mL) was refluxed for 12 h. Solvent was then removed in vacuo to give a residue, which was partitioned between EtOAc and water and aqueous layer was separated and extracted with EtOAc. The combined organic layers were washed with sat. NaHCO3 and brine, dried over sodium sulfate and evaporated in vacuo to give a crude. The crude product was purified by flash chromatography on silica gel eluted with EtOAc-hexane (0-30%) to afford 5-(5-bromo-thiophen-2-yl)- l-(2-chloro-phenyl)-4-fluoro-1H-pyrazole-3-carboxylic acid methyl ester as a dark-red syrup (4.27g, 50%). MS(ES): 431 [M+H]+.
Example 1Od Prepafation of 2-{l-(2-Chhroψhenyl)-4φAoro-5-[5-(3-methωτesulfonylψhenyl)4hioplτen-2-yl]-lH^ pyrazol-3-yl}-propan-2-ol
Figure imgf000157_0002
The title compound was prepared in a manner similar to that described in Examples 8c and 8d by using 5-(5-bromo-thiophen-2-yl)-l-(2-chloro-phenyl)-4-fluoro-1H-pyrazole-3-carboxylic acid ethyl ester. 1H-NMR (CDCl3): δ 8.03 (m, IH), 7.82 (m, IH), 7.72 (m, IH), 7.57-7.45 (m, 5H), 7.27 (d, IH), 6.99 (d, IH), 3.07 (s, 3H), 2.74 (s, IH), 1.72 (s, 6H).
Example 11
Preparation of ~2-[4-Bromo-5-[5-(3-methcaiesulfoψlφheψl)4hioplτen-2-yl]-l-(2-Mflιωromethyl- phenyl)-lH-py}"azol-3-yl]-p"opan-2-ol
Figure imgf000158_0001
To a stirred solution of 2-[5-[5-(3-methanesulfonyl-phenyl)-thiophen-2-yl]-l-(2- trifluorome1hyl-phenyl)-1H-pyrazol-3-yl]-propan-2-ol (254mg, 0.5mmol) in dry MeCN was added N- bromosuccinimide (94 mg, 0.53 mmol) at 20 0C and the reaction mixture was stirred at 20 0C overnight. Evaporation of solvent gave a residue, which was purified by flash chromatography on silica gel eluted with EtOAC-hexane (0-60%) to afford the title compound as a white solid (286 mg, 98%). 1H-NMR (CDCl3): δ 8.05 (m, IH), 7.85-7.81 (m, 2H)5 7.76 (m, IH), 7.63-7.61 (m, 2H), 7.56 (t, IH), 7.39 (m, IH), 7.25 (d, IH), 6.98 (d, IH), 3.09 (s, IH), 3.07 (s, 3H), 1.74 (s, 6H). The following compounds are prepared essentially according to the previous examples: • 4-bromo-l-(2,6-dicUorophenyl)-5-{5-[3-(me1hylsuh0onyl)phenyl]-2-1rdenyl}-3-(tiifluoromethyl)- lH-pyrazole, MS(ES): 597 [MH-H]+
• 2-[4-bromo-l-(2-cMorophenyl)-5-{5-[3-(memylsulfonyl)phenyl]-2-thienyl}-1H-pyrazol-3- yl]propan-2-ol, MS(ES): 553 [M+H]+, 535 (M-OH)
• 2-[4-bromo-l-(2,6-dichlorophenyl)-5-{5-[3-(memylsuh°onyl)phenyl]-2-thienyl}-1H-pyrazol-3- yl]propan-2-ol, MS(ES): 569 (M-OH)
• 2-[4-bromo-l-(3-chloro-2-fluorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}-1H-pyrazol-3- yl]propan-2-ol, MS(ES): 551 (M-OH)
• 2-[4-bromo-l-(2-e%lphenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-iMenyl}-1H-pyrazol-3- yl]propan-2-ol, MS(ES): 545 [M+H]+, 527 (M-OH) • 2-(4-bromo-5-{5-[3-(methylsuhconyl)phenyl]-2-iMenyl}-l-{2-[(tιifluoromethyl)oxy]phenyl}-1H- pyrazol-3-yl)propan-2-ol, MS(ES): 601 [M+H]+, 584 (M-OH)
• 2-[4-bromo-l-(2-bromophenyl)-5-{5-[3-(me1hylsuhOnyl)phenyl]-2-thienyl}-1H-pyrazol-3- yl]propan-2-ol, MS(ES): 595 [M+H]+, 577 (M-OH)
• 2-(4-bromo-5-{5-[3-(me1hylsurfonyl)phenyl]-2-thienyl}-l-[4-(trMuoromethyl)pyridin-3-yl]-1H- pyrazol-3-yl)propan-2-ol, MS(ES): 586 [M+H]+, 568 (M-OH)
• 2-(4-Bromo-5-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}-l-[3-(1rifluoromethyl)pyridin-2-yl]-1H- pyrazol-3-yl)propan-2-ol, MS(ES): 586 [M+H]+, 568 (M-OH)
• 2-(4-Bromo-5-{5-[3-(methylsulfonyl)phenyl]-2-tMenyl}-l-[2-(trifluoromethyl)pyridin-3-yl]-1H- pyrazol-3-yl)propan-2-ol, MS(ES): 586 [MfHj+, 568 (M-OH) • 2-[4-Bromo-l-(3-fluoro-2-methylph^ 3-yl]propan-2-ol, MS(ES): 550 [M+H]+, 531 (M-OH)
• 2-[4-Bromo-l-(2-chloro-3-fluorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}-1H-pyrazol- 3-yl]propan-2-ol, MS(ES): 569 [M+H]+, 551 (M-OH)
Exanψlel2
Preparation ofi-{4-Chloro-l-(2-flmroψheryl)-5-[5-(3-methmesulfoψlψheiψl)-thiophen^ pyrazol-3-yl}-propan-2-ol
Figure imgf000159_0001
To a stirred solution of 2-{l-(2-Fluoro-phenyl)-5-[5-(3-methanesulfonyl-phenyl)-thiophen-2- yl]-1H-pyrazol-3-yl}-propan-2-ol (115 mg, 0.25 mmol) in dry MeCN was added N-chlorosuccinimide
(35 mg, 0.26 mmol) at 2O0C and the reaction mixture was stirred in a sealed vial at 750C overnight.
Evaporation of solvent gave a residue, which was purified by flash chromatography on silica gel eluting with EtOAC-hexane (0-60%) to afford the title compound as a white solid (123 mg, 100%). 1H-NMR
(CDCl3): δ 8.08 (m, IH), 7.84 (m, IH), 7.78 (m, IH), 7.59-7.49 (m, 3H), 7.30-7.28 (m, 2H), 7.17 (t, IH), 7.03 (d, IH), 3.08 (s, 4H), 1.74 (s, 6H).
The following compounds are prepared essentially according to the previous examples:
• 2-(4-cUoro-5-{5-[3-(methylsuhconyl)phenyl]-2-Menyl}-l-[3-(trifluoromethyl)pyridin-4-yl]-1H- pyrazol-3-yl)propan-2-ol, MS(ES): 542 [M+H]+.
• 2-[4-cMoro-l-(3-fluoropyridin-4-yl)-5-{5-[3-(methylsuhconyl)phenyl]-2-thienyl}-1H-pyrazol-3- yl]propan-2-ol, MS(ES): 492 [MR-H]+.
• 2-[4-cMoro-l-(3-cMoropyridin4-yl)-5-{5-[3-(methylsuheonyl)phenyl]-2-tMenyl}-1H-pyrazol-3- yl]propan-2-ol, MS(ES): 508 [M+H]+.
• 2-[4-cUoro-l-(3,5-dichloropyridm-4-yl)-5-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}-1H-pyrazol-3- yl]propan-2-ol, MS(ES): 544 |M+H]+ • 2-[4-CMoro-l-(2-chlorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}-1H-pyrazol-3- yl]propan-2-ol, MS(ES): 507 [MfH]+ 489 (M-OH)
• 2-[4-chloro-l-(2,6-dichlorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-tMenyl}-1H-pyrazol-3- yl]propan-2-ol, MS(ES): 541[M+H]+, 523 (M-OH)
• 2-(4-chloro-5-{5-[3-(methylsuhconyl)phenyl]-2-iMenyl}-l-[2-(1rifluoromethyl)phenyl]-1H-pyrazol- 3-yl)propan-2-ol, MS(ES): 541 [M-HH]+ 523 (M-OH) • 2-[4-chloro-l-(3-cMoro-2-fluorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}-1H-pyrazol-3- yl]propan-2-ol, MS(ES): 525 [M+H]+ 507 (M-OBT)
• 2-[4-cMoro-l-(2-eftylphenyl)-5-{5-[3-(me^ 2-ol, MS(ES): 501 [M+H]+, 483 (M-OH) • 2-(4-cMoro-5-{5-[3-(methylsulfonyl)phenyl]-2-Menyl}-l-{2-[(trmuoromethyl)oxy]phenyl}-1H- pyrazol-3-yl)propan-2-ol, MS(ES): 557 [M+H]+, 539 (M-OH)
• 2-[4-CMoro-l-(2-bromophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-1hienyl}-1H-pyrazol-3- yl]propan-2-ol, MS(ES): 551 [M+H]+, 533 (M-OH)
• 2-(4-CMoro-5-{5-[3-(methylsulfonyl)pte^^ pyrazol-3-yl)propan-2-ol, MS(ES): 542 [M+H]+, 524 (M-OH)
• 2-(4-CMoro-5-{5-[3-(methylsulfonyl)phenyl]-2-tiτienyl}-l-[2-(trifluoromethyl)pyridm^ pyrazol-3-yl)propan-2-ol, MS(ES): 542 (MH-H]+, 524 (M-OH)
• 2-(4-CMoro-5-{5-[3-(methylsulfonyl^ pyrazol-3-yl)propan-2-ol, MS(ES): 542 [M+H]+, 524 (M-OH) • 2-[4-chloro -l-(3-fluoro-2-methylphenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-iMenyl}-1H-pyrazol- 3-yl]propan-2-ol, 505 [M+H]+, 487 (M-OH)
• 2-[4-chloro -l-(2-cMoro-3-fluorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-iMenyl}-1H-pyrazol- 3-yl]propan-2-ol, MS(ES): 525 |M+H]+ 507 (M-OH)
• 2-[4-CMoro-l-(2,3-difluorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}-1H-pyrazol-3- yl]propan-2-ol, MS(ES): 509 [MH-H]+, 491 (M-OH)
• 2-[4-CMoro-l-(2,6-dimethylphenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-Menyl}-m-pyrazol-3- yl]propan-2-ol, MS(ES): 501 [M+H]+, 483 (M-OH)
• 2-[4-CMoro-l-(2,6-difluorophenyl)-5-{5-[3-(methylsιdfonyl)phenyl]-2-thienyl}-1H-pyrazol-3- yl]propan-2-ol, MS(ES): 509 [M+H]+, 491 (M-OH) • 2-[4-chloro -l-(2-cMoro-6-fluorophenyl)-5-{5-[3-(melhylsulfonyl)phenyl]-2-tMenyl}-1H-pyrazol- 3-yl]propan-2-ol, MS(ES): 525 [M+H]+ 507 (M-OH)
• 2-[4-CMoro-l-(2-cMoro-6-dimethylphenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}-1H- pyrazol-3-yl]propan-2-ol, MS(ES): 521 [M+H]+ 503 (M-OH)
• 2-[4-chloro -l-(2,4-dmuorophenyl)-5-{5-[3<methylsulfonyl)phenyl]-2-thienyl}-m-pyrazol-3- yl]propan-2-ol, MS(ES): 509 [M+H]+, 491 (M-OH)
• 2-(4-chloro-5-{3-methyl-5-[3-(methylsulfonyl)phenyl]-2-tMenyl}-l-[4-(trifluoromeihyl) pyridin-3- yl]-1H-pyrazol-3-yl)propan-2-ol, MS(ES): 556 [IVH-H]+, 538 (M-OH) • 2-[4-cMoro-3-(l-hydro^-l-methylethyl)-5-{5-[3-(meihylsιM)nyl)phenyl]-2-iMenyl}-1H-pyrazol- l-yl]-6-(trifluoromethyl)phenol, MS(ES): 557 [M+H]+, 539 (M-OH)
• 2-[4-chloro-l-(2-chlorophenyl)-5-{l-methyl-5-[3-(methylsulfonyl)phenyl]-1H-pyrtOl-2-yl}-1H- pyrazol-3-yl]propan-2-ol, MS(ES): 504 [M+H]+, 486 (M-OH)
2-(4-chloro-5-{3-methyl-5-[3-(methylsulfonyl)phenyl]-2-thienyl}-l-[4-(ttifluoromethyl) pyridin-3-yl]- lH-pyrazol-3-yl)propan-2-ol, MS(ES): 604 [M+H]+, 524 (M-79).
Scheme 7
Figure imgf000161_0001
As depicted in Scheme 7 ester 007C was transformed into amides. Ester 007C was hydrolyzed to give acid 007TW1, which treated with carbonyldiirnidazole and then an amine to afford amide 007TW2.
Example 13 l-(2-chhropherψl)-N^thyl-5-{5-[3-(methylsulfo}ψl)pherψl]-2-thierψl}-^ carboxamide Example 13a
Prepω"ationofl-(2-chlorophe}ψl)-5-{5-[3-(metTψlsulfoiψl)pher^l]-2-thienyl}-lH- carboxylic acid
Figure imgf000161_0002
To a solution of l-(2-chloro-phenyl)-5-[5-(3-methanesulfonyl-phenyl)-thiophen-2-yl]-1H- pyrazole-3-carboxylic acid methyl ester (5.8 g, 12.3 mmol) in MeOH (50 mL) was added aqueous NaOH (4 N, 25 mL) and the mixture was refluxed for 2 h. After cooling to 200C, solvent was removed. Water was added to dissolve the crude and then the solutiuon was acidified with acetic acid. Solid was collected by filtration and washed with water and dried under high vacuum to give l-(2-chlorophenyl)- 5-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}-1H-pyrazole-3-carboxylic acid (5.1 g). MS(ES): 459 |M+H]+. Example 13b
Preparation of l-(2-chloropheψl)-N-ethyl~5-{5~[3φtetlψlmlfoψl)phenyl]-24hieriyl}-^ carboxamide
Figure imgf000162_0001
To a suspension of l-(2-chloroρhenyl)-5-{5-[3-(methylsulfonyl)ρhenyl]-2-1nienyl}-1H- pyrazole-3-carboxylic acid (92 mg, 0.2 mmol) in DCM (2 mL) was added carbonyldiimidazole (39 mg, 1.2 equiv) and stirring was continued for 2 h at 20 0C. A solution of ethylamine in THF (1.8 M, 0.17 mL, 1.5 equiv) was added and the mixture was stirred overnight at 200C. Evaporation of solvent gave a crude, which was purified by column chromatography on silica gel eluting with MeOH-DCM (1 : 19) to afford l-(2-cMorophenyl)-N-e%l-5-{5-[3-(methylsuhOnyl)phenyl]-2-thienyl}-1H-pyrazole-3- carboxamide (84 mg). 1H-MlR (CDC13): δ 8.03 (m, IH), 7.83 (m, IH), 7.74 (m, IH), 7.62 - 7.45 (m, 5H), 7.22 (m, IH), 7.19 (s, IH), 6.91 (m, IH), 6.82(d, IH), 3.55 - 3.43 (m, 2H), 3.07 (3s, H), 1.25 (s, 3H). MS(ES): 486 [M+H]+. The following compounds are prepared essentially according to the previous examples: • l-ltl^-cWorophenyO-S-IS-p-^ethylsulfonyOphenylj^-thienylJ-1H-pyrazol-S- yl]carbonyl}piperidine, MS(ES): 526 βVI+H]+.
• l-(2,6-diclilorophenyl)-5-{3-methyl-5-[3-(methylsulfonyl)phenyl]-2-tlτienyl}-N-(2,2,2- trifluoroethyl)-1H-pyrazole-3-carboxamide, MS(ES): 588 [M+H]+.
• l-(2,6-dichlorophenyl)-5-{3-me1hyl-5-[3-(methyIsulfonyl)phenyl]-2-thienyl}-3-φyrroUdin-l- ylcarbonyiyiH-pyrazole, MS(ES): 560 [M+H]+.
• l-(2-cMorophenyl)-N-[2-(die%larr^^ thienyl}-1H-pyrazoIe-3-carboxamide, MS (ES) 571.3, 573.3 βVI+H]+
• l-(2-cUorophenyl)-N-[2-(die%larr^ lH-pyrazole-3-carboxamide, MS (ES) 585.3, 587.3 [M+H]+ • l-(2-cMorophenyl)-N-[2-(dimethylamino)e%l]-N-methyl-5-{5-[3-(methylsulfonyl)ρhenyl]-2- thienyl}-1H-pyrazole-3-carboxamide, MS (ES) 543.3, 545.3 [M+H]+
• l-(2-clτlorophenyl)-N-[3-(dimethylanτmo)propyI]-N-me11iyl-5-{5-[3-(methyIsuheonyl)phenyl]-2- thienyl}-1H-pyrazole-3-carboxamide, MS (ES) 557.2, 559.2 [M+H]+
• methylN-{[l-(2-cMorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}-1H-pyrazol-3- yl]carbonyl}-N-methylglycinate, MS (ES) 544.2, 546.2 |M+H]+ • N-{[l-(2-chlorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-iMenyl}4H-pyrazol-3-yl]carbonyl}-N- methylglycine, MS (ES) 530.2, 532.2 [M+H]+
• l-(2-chlorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}-N-(2-moφholin-4-yle%l)-lH- pyrazole-3-carboxamide, MS (ES) 571.3, 573.3 [M+H]+ • l-lfl^-cUoropheny^-S-IS-P^meihylsulfony^phenyy^-iMenylJ-lH-pyrazol-S-ylJcarbonyl}- N,N-dime1hylpiperidin-4-amine, MS (ES) 569.3, 571.3 [M+H]+
• l-ltl^-chloropheny^-S-IS-P^me&ylsulfony^phenyy^-tlTienyll-lH-pyrazol-S- yl]carbonyl}piperidine-4-carboxylic acid, MS(ES) 570.0, 572.0 [M+H]+
• 5-{5-[3-(me&ylsulfonyl)phenyl]-2-te carboxylic acid, MS (ES) 493.1 [MfB]+
• 5-{5-[3^methylsulfony^phenyy^-ihienyll-S-φyrrolidin-l-ylcarbony^-l-P- (trifluoromethyl)phenyl]-lH-pyra2Dle, MS (ES) 546.3 [M+H]+
• l-(2-chlorophenyl)-N-methyl-N-(meUiyloxy)-5-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}-lH- pyrazole-3-carboxamide, MS (ES) 502.1, 504.1 [M+H]+ • l^-cUoropheny^-N^me^loxy^S-fS-P-^e&ylsulfony^phenylJ^-thieny^-lH-pyrazole-S- carboxamide, MS (ES) 488.0, 490.0 |M+H]+
• N-metiiyl-N-(methyloxy)-5-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}-l-[3- (trifluoromethyl)pyridin-2-yl]-lH-pyrazole-3-carboxamide, MS (ES) 537.3 [M+H]+
• 5-{57[3-(methylsulfonyl)phenyl]-2-^ 2-yl]-lH-pyrazole-3-carboxamide, MS (ES) 575.3 [M+H]+
• l-(2-chlorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-tMenyl}-N-(2,2,2-trifluoroe%l)-lH- pyrazole-3-carboxamide, MS (ES) 540.3, 542.3 [MfH]+
• 5-{5-[3-(me%kulfonyl)phenyl]-2-to^ lH-pyrazole-3-carboxamideMS (ES) 574.3 |M+H]+ • methyl 3-{5-[l-(2-chlorophenyl)-3-{[(2,2,2-trifluoroe%l)amino]carbonyl}-lH-pyrazol-5-yl]-2- thienyl}benzoate, MS (ES) 519.3, 521.3 [MH-H]+
• l-(2-cUorophenyl)-5-{5-[3-(l-hydroxy-l-m^ lH-pyrazole-3-carboxamide, MS (ES) 519.3, 521.3 [M+H]+
Scheme 8 Ar-NHNH2
Figure imgf000164_0001
Figure imgf000164_0002
As depicted in Scheme 8, lH-pyrazol-5-ol 008TW5 was prepared and the hydroxy group was substituted with other groups. Ketoester 008TW4 reacted with hydrazine 008TW3 to form lH-Pyrazol- 5-ol 008TW5, which was converted to the corresponding triflate 008TW7.008TW7 was submitted to Suzuki coupling reaction with a boronic acid to introduce a phenyl group to afford product 008TW8.
Example 14 l-(2-chbropheψl)-5-[3-(met}ψlsulfoiiyl)pJieψl]-3-(trfli mmmetJτyl)-lH^
Example 14a Preparation of 'l-(2-chlorophe}^l)-3-(Mfluorometlψl)-lH-pyi'azol-5-ylMfli{orontetlΗmesdfonate
Figure imgf000164_0003
To a mixture of l-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-ol (0. 52 g, 2 mmol) and 2,6-di-te7^-butyl-4-methylpyridine (0. 51 g, 1.25 equiv) in DCM (8 mL) was added triflic anhydride (374 μL, 1.1 equiv) at- 780C. The mixture was warmed to 200C and stirred overnight at 200C. It was quenched with sat aqueous NaHCO3 and the aqueous layer was separated and extracted with DCM. The combined organic layers were washed water and dried over Na2SO4. Evaporation of solvent gave a crude, which was purified by column chromatography on silica gel eluting with EtOAc-hexane (1 :4) to give Hie title compound (620 mg). 1H-NMR (CDCl3): δ 7.60-7.44 (m, 4H), 6.61 (s, IH).
Example 14b Preparctionofl-(2-chloropheiψl)-5-[3-(metItylsulfoψl)pheψl]-3-(trifluoromet^
Figure imgf000164_0004
l-(2-cUorophenyl)-5-[3-(methylsuhconyl)phenyl]-3-(tifluoromethyl)-1H-pyrazole was prepared in a manner similar to that described in Examples Ic by using l-(2-chlorophenyl)-3- (trifluoromethyl)-1H-pyrazol-5-yltrifluoromethanesulfonate and 3-(methylsulfonyl)phenylboronic acid. 1H-NMR(CDCl3): δ 7.90 (IH, m), 7.76 (IH, d), 7.57-7.47 (3H, m), 7.46-7.42 (3H, m), 6.92 (IH, s), 2.92 (3H, s). MS (ES): 401 [M+H]+. Scheme 9
Figure imgf000165_0001
Figure imgf000165_0002
Figure imgf000165_0003
Figure imgf000165_0004
As depicted in Scheme 9, ester group on c-phenyl ring can be transformed into other functional groups such as carbinols and amides, ketones and methylamines. Claisen condensation of 009TW9 with an ester to form diketone 009TW10 was followed by condensation of 009TW10 with a hydrazine to form pyrazole product 009TW11. Treatment of 009TW11 with triflic anhydride to form triflate 009TW12. Suzuki coupling of 009TW12 with a boronic acid afforded product 009TW13, which was treated with Grignard reagent to form carbinol 009TW16, together with ketone 009TW15 as a minor product Ester 009TW13 was hydrolyzed to give acid 009TW16, which was transformed into amide 009TW17 via cabonyldiimidazole coupling. Reduction of 009TW17 with borane afforded amine 009TW18. Example 15 and 16
2-{4-[l-(2-chlorophenyl)-3-(1rifluoromethyl)-lH-pyrazol-5-yl]-3'^ yljpropan-2-ol (15) and l-{4-[l-(2-chloropheψl)-3-(ϋifluorometlτyl)-lH-pyrazol-5-yl]-3'- (methylsulfonyl)biphenyl-2-yl}ethanorιe (16) Example 15a
Preparation of methyl 5-(l-(2-chloropher^l)-3-(trifluoroinet^l)-lH-pyrazol-5-yl)-2-hyάvxyberizoate
Figure imgf000166_0001
Methyl 5-(l-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2-hydroxybenzoate was prepared in a manner similar to that described in Examples Ib by using methyl 5-acetyl-2- hydroxybenzoate. MS (ES): 397 [M+H]+.
Example 15b
Preparation of methyl 5-(l-(2-chhrophenyl)-3-(trifluorometlτyl)-lH-pyrazol-5-yl)-2- (Mfluoromethyl$ulfonyloxy)benzoate
Figure imgf000166_0002
To a solution of methyl 5-(l-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2- hydroxybenzoate (1.29 g, 3.25 mmol) and 2,6-lutidine (0.5 mL, 1.2 equiv) in DCM (15 mL) was added triflic anhydride (0.663 mL, 1.2 equiv) at -780C and the reaction solution was stirred for 1 h at -78 0C. After quenching with water, aqueous layer was separated and extracted with DCM. The combined organic layers were washed with saturated aqueous NaHCO3 and water and dried over Na2SO4. Evaporation of solvent gave a crude, which was purified by column chromatography on silica gel eluting with EtOAc-hexane (1:4) to afford methyl 5-(l-(2-chlorophenyl)-3-(trifluoromethyl)-1H- pyrazol-5-yl)-2-(trifluoromethylsuhOnyloxy)benzoate (1.64 g). MS (ES): 529 [M+H]+.
Example 15c
Preparation ofmetliyl 4-(l-(2-chloropheψl)-3-(trifluoromethyl)-lH-pyrazol-5-yl)-3 '- (met}ψlsulfonyl)biphe}ψl-2-carboxylate
Figure imgf000167_0001
Me%14-(l-(2^ωorophenyl)-3-(trffluoromethyl)-1H-pyrazDl-5-yl)-3'-
(methylsulfonyl)biphenyl-2-carboxylate was prepared in a manner similar to that described in Examples Ic by using 5-(l-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2- (trifluoromethylsulfonyloxy)benzoate and 3-(methylsulfonyl)phenylboronic acid. MS (ES): 535 [M+H1+.
Example 15d and 16
Preparation of '2-{4-[l-(2~chforopJieψl)-3-(triflwromethyl)-lH-pyt'cιzol-5-yl]-3'-
(methylsulfonyl)biphenyl-2-yl}propan-2-ol (15) and l-{4-[l-(2-chlorophenyl)-3-(trifluoromethyl)-lH- py}"ozol-5-yl]-3'-(methylsulfonyl)biphenyl-2-yl}ethanone (16)
Figure imgf000167_0002
2-{4-[l-(2-cMorophenyl)-3-(trMuoromethyl)-1H-pyrazol-5-yl]-3'-(methylsulfonyl)biphenyl-2- yl}propan-2-ol and l-{4-[l-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-3'-
(methylsulfonyl)biphenyl-2-yl}ethanone were prepared in a manner similar to that described in Examples 8d by using methyl 4-(l-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)-3'- (methylsulfonyl)biphenyl-2-carboxylate. 15d: 1H-NMR (CDCl3): δ 7.91 (m, IH), 7.85 (d, IH), 7.57- 7.50 (m, 4H), 7.47-7.41 (m, 2H), 7.37 (d, IH), 7.20 (dd, IH), 7.01 (s, IH), 6.88 (s, IH), 3.07 (s, 3H), 2.05 (s, IH)5 1.25 (s, 6H). MS(ES): 536 [M+H]+. 16: 1H-NMR (CDCl3): δ 7.95 (m, IH), 7.87 (m, IH), 7.61 (m, IH), 7.57-7.43 (m, 7H), 7.38 (dd, IH), 7.30 (d, IH), 6.92 (s, IH), 3.08 (s, 3H), 2.13 (s, 3H). MS(ES): 518 [M+H]+
Example 17
(4-(l-(2-chlorophenyl)-3-(Mfluoromethyl)AH-pyrazol-5-yl)-3'-(meϋ yl) (morpholinojmethanone
Example 17a
Prepcιrationof4-(l-(2-Moropheψl)-3-(trifluoromethyl)-lH-pyr-azol-5-y^^
2-carhoxylic acid
Figure imgf000168_0001
A solution of methyl 4-(l-(2-cMorophenyl)-3-(trifluoromethyl)-1H-ρyrazol-5-yl)-3'- (methylsulfonyl)biphenyl-2-carboxylate (1.37 g, 2.6 mmol) and NaOH (1 g, 25 mmol) in MeOH-H2O (2:1, 16 mL) was refluxed for 2 h. After cooling, solid was removed and the filtrate was acidified with formic acid. Solid was collected by filtration and washed with water and dried under high vacuum to afford 4-(l-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)-3'-(methylsulfonyl)biphenyl-2- carboxylic acid (1.05 g). MS(ES): 521 [M+HJ+.
Example 17b
Preparation of (4-(l-(2-chloropherψl)-3-(ttifluoromethyl)-lH-pyrazol-5-yl)-3 '- (methylsulfonyl)bipheηyl-2-yl)(moψholino)methanone
Figure imgf000168_0002
To a suspension of 4-(l-(2-cMorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)-3'- (methylsulfonyl)biphenyl-2-carboxylic acid (0.52 g, 1 mmol) in DCM (6 mL) was added carbonyldimidazole (2.43 mg, 1.5 mmol) and the mixture was stirred for 2 h at 20 0C. Morpholine (0.175 mL, 2 mmol) was added and the mixture was stirred overnight at 20 0C. Evaporation of solvent gave a crude, which was purified by column chromatography on silica gel eluting with EtOAc-hexane (1:4 to 4:1) to afford (4-(l-(2-cMorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)-3'- (methylsulfonyl)biphenyl-2-yl)(morpholino)methanone (0.52 g). 1H-NMR (CDCl3): δ 7.97 (m, 2H), 7.77 (d, IH), 7.64 (m, IH), 7.58 (m, IH), 7.46-7.24 (m, 5H), 6.89 (s, IH), 3.55 (m, 3H), 3.33 (m, 2H), 3.08 (s, 3H), 2.87 (m,2H), 2.69 (m, IH). MS(ES): 590 [M+H]+.
Example 18
PrepωAation of4-((4-(l-(2-chloropheψl)-3-(Mfluoromethyl)-lH-pyι-azol-5-yI)-3'- (methylsulfoψl)biphenyl-2-yl)methyl)moψholine
Figure imgf000169_0001
To a solution of BH3 (1 M, 4 mL) in THF was added (4-(l-(2-chlorophenyl)-3- (trifluoromethyl)-1H-pyrazol-5-yl)-3'-^ (460 mg, 0.78 mmol) and the solution was stirred overnight at 20 0C. MeOH was added to quench borane and solvent was evaporated to afford a crude, which was purified by column chromatography on silica gel eluting with MeOH-DCM (1:19) to afford 4-((4-(l-(2-chlorophenyl)-3-(trifluoromethyl)-1H- pyrazol-5-yl)-3'-(methylsulfonyl)biphenyl-2-yl)methyl)moφholine (0.2 g). 1H-NMR (CDCl3): δ 8.25 (m, IH), 7.93 (m, IH), 7.72 (m, IH), 7.60 (m, IH), 7.55 (m, IH), 7.49-7.39 (m, 3H), 7.33-7.26 (m, 2H), 7.18 (m, IH), 6.85 (s, IH), 3.58 (m, 4H), 3.16 (s, 3H), 3.07 (s, 3H), 2.14 (m, 4H). MS(ES): 576 [M+H]+.
Scheme 10
Figure imgf000169_0002
As depicted in Scheme 10, aminoethylpyrazoles were synthesized via alkylation of pyrazole with 1,2-dihaloethane followed by subsequent alkylation of amines. Claisen condensation of ketone 010TW19 with an ester to form diketone 010TW20 was followed by addition-cyclization with hydrazine to give pyrazole 010TW21. Alkylation of 010TW21 afforded chloroethylpyrazole 010TW22, which was used for alkylation of amines to form amines 010TW23. Final Suzuki coupling of 010TW23 with a boronic acid afforded 010TW24.
Example 19 4-(2-{5-[3'-(methyhulfo}ψl)bipherιyl-4-yl]-3-(1rifluoronieϋψl)-lH^
Example 19a Preparation of 5-(4-bromopheτiyl)-3-(trifluorometliyl)-lH-pyrcιzole
Figure imgf000170_0001
5-(4-bromophenyl)-3-(trifluoromethyl)-1H-pyrazole was prepared in a manner similar to that described in Examples Ib by using 4'-bromoacetophenone. MS (ES): 291 [MH-H]+. Example 19b
Preparation of '5-(4~bromopheψl)-l~(2-chloroethyl)-3φiflmrometfyl)-lH-pyrazoh
Figure imgf000170_0002
To a solution of 5-(4-bromophenyl)-3-(trifluoromethyl)-1H-pyrazole (2.05 g, 7 mmol) and 1- bromo-2-chloroethane (0.71 mL, 1.2 equiv) in DMF (30 mL) was added NaH (0.42g, 60%, 1.5 equiv) and the mixture was stirred overnight at 200C. The reaction was quenched by water. Solid was collected and washed by water and dried under high vacuum to give a crude, which was purified by column cliromatography eluting with MeOH-DCM (6:96) to give 5-(4-bromophenyl)-l-(2-chloroethyl)-3- (trifluoromethyl)-1H-pyrazole (400 mg) as a minor product. 1H-NMR (CDCl3): δ 7.64 (d, IH), 7.31 (d, IH), 6.54 (s, IH), 4.41 (t, 2H), 3.93 (t, 2H). Example 19c
Prepcvαtionoj ' 4-(2-(5-(4-bronκ)plτenyl)-3-(Mflιιoromethyl)-lH-py}"αzol~l-yl)ethyl)morpholi}τe
Figure imgf000170_0003
A solution of 5-(4-bromophenyl)-l-(2-cUoroethyl)-3-(trifluoromethyl)-1H-pyrazole (200 mg, 0.56 mmol) and morpholine (0.245 mL, 5 equiv) in acetonitrile (2 mL) was stirred overnight at 90 0C. Evaporation of solvent gave of 4-(2-(5-(4-bromophenyl)-3-(trifluoromethyl)-1H-pyrazol-l- yl)ethyl)morpholine. MS (ES): 404 [M+H]+.
Example 19d
Preparation of 4-(2-(5-(3'-(metlψlsulfoψl)biphenyl-4-yl)-3-(ϋiflmrom yl)ethyl)morpholine
Figure imgf000171_0001
4-(2-{5-[3Kmethylsulfonyl)biphenyl-4-yl]-3-(trifluoromethyl)-1H-pyrazol-l- yl}ethyl)morpholine was prepared in a manner similar to that described in Examples Ic by using the above crude product and (3-methylsulfonyl)phenylboronic acid. 1H-NMR (CDCI3): δ 8.21 (m, IH), 7.95 (m, 2H), 7.76-7.53 (m, 4H), 7.46 (m, IH), 6.58 (s, IH), 4.30 (t, 2H), 3.59 (m, 4H), 3.13 (t, 3H), 2.84 (t, 2H), 2.36 (m, 4H). MS (ES): 480 [M+H]+.
The following compound is prepared essentially according to the previous examples: • l-methyl-4-(2-{5-[3'-(melhylsulfonyl)biphenyl-4-yl]-3-(trifluoromethyl)-1H-pyrazol-l- yl}ethyl)piperazine MS(ES): 493 [M+H]+.
Scheme 11
Figure imgf000171_0002
As depicted in Scheme 11, a carbonyl group can be introduced into the pyrazole system. Diketone 011TW25 reacted with a hydrazine to form pyrazole 011TW26. Suzuki coupling of 011TW26 with a boronic acid afforded 011TW27, whose ester group was then hydrolyzed to give acid 011TW28. CDI coupling of acid 011TW28 with amines afforded amides 011TW29
Example 20 4-{[5-{5-[3-(methylstdfoψl)pheψlJ-2-thieψl}-3-(ttifluoromethyl)-lH-^
Example 20a
Preparation of Methyl 2-(5-(5-(3φiethylsulfoψl)pheψl)thiophen-2-yl)-3-(Mfluoromethyl)-lH- pyrazol-l-yl)acetate
Figure imgf000172_0001
Methyl 2-(5-(5<3-(methylsulfonyl)phenyl)tM^^ yl)acetate was prepared in a manner similar to that described in Examples Ic by using methyl 2- hydrazinoacetate (in MeOH). MS(ES): 445 [MH-H]+. Example 20b
Preparation of 2-(5-(5-(3-(metJψkulforιyl)phe}τyl)thiophen-2-yl)-3-(Mfluoromethyl)-lH^ yl)acetic acid
Figure imgf000172_0002
2-(5-(5-(3-(methylsulfonyl)phenyl)th^ acid was prepared in a manner similar to that described in Example 17a MS(ES): 431 [M+H]+.
Example 20c
Preparation of 4-{[5-{5-[3-(methylsulfoiτyl)pheiτyl]-24hienyl}-3~(1riflwrom yl]acetyl}morpholine
Figure imgf000172_0003
4-{[5-{5-[3-(methylsutfonyl)phenyl]-2-t^ was prepared in a manner similar to that described in Examples 19.
1H-NMR(CDCl3): δ 8.15 (s, IH), 7.90 (m, IH), 7.86 (m, IH), 7.63 (m, IH), 7.42 (d, IH), 7.32 (d, IH), 6.73 (s, IH), 5.12 (s, 2H), 3.76-3.72 (m, 4H), 3.66 (t, 2H), 3.57 (t, 2H), 3.11 (s, 3H). MS (ES): 500 [M+H]+.
The following compounds are prepared essentially according to the previous examples:
• 5-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}-l-(2-oxo-2-pyrrolidin-l-ylethyl)-3- (trifluoromethyl)-1H-pyrazole, MS(ES: 484 [M+H]+.
• l-{[5-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}-3-(trifluoromethyl)-1H-ρyrazol-l- yl]acetyl}piperidine, MS(ES: 498 [M+H]+. 5-{5-[3<methylsulfonyl)phenyl]-2-thienyl}-l-(2-oxo-2-pyrrolidin-l-ylethyl)-3- (trifluoromethyl)-1H-pyrazole, MS(ES): 484 [M+H]+ .
Scheme 12
Figure imgf000173_0001
The starting materials (012vi) were prepared in similar manner of Scheme 1 , followed by further transformations to make final products as described in Scheme 12.
Example 21
5'{5-[2-(2-Chloroφhenyl)-5-Mflιιoroinethyl-2H-pyi"azol'3-yl]4hiophen-2-yl}-2-m methyl-pyiϊdine Example 21a
Pjvpω~ationof5~{5-[2-(2-Chlomφheψl)-5-titømrometIψ!-2H-jψrazol-3-yfa methanesulfonyl-3-methyl-pyιϊdine
Figure imgf000173_0002
5-{5-[2-(2-CMoro-phenyl)-5-trMuoromethyl-2H-pyrazol-3-yl]-thiophen-2-yl}-3-methyl-2- methylsulfanyl-pyridine (158 mg, 0.34 mmol) was dissolved in 15 mL mixture of dichloromethane and methanol (5 : 1, VfV). MMPP (magnesium monoperoxyphthalate hexahydrate, 424 mg, 0.75 mmol, 80% tech.) was added then. The mixture was stirred at room temperature for 2 hrs, then diluted with dichloromethane, and filtered. The filtrate was washed with saturated NaHCO3 and brine, dried over Na2SO4, and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (10 → 40% EtOAc/Hexane) to give a white solid (116 mg, 69% yield). 1H-NMR (400MHz, CDCl3): δ 2.73 (s, 3H), 3.36 (s, 3H), 6.89(d, J= 3.9, IH), 6.93 (s, IH), 7.27 (m, IH), 7.58 - 7.49 (m, 4H), 7.70-7.69 (m, IH), 8.52- 8.51(m, IH). MS (ES): 498.3 [MfH]+. The following compounds were made in similar manner by oxidation of appropriate sulfides: • 2-(e%lsulfonyl)-3-methyl-5-(5-{3-(1rifluoromethyl)-l-[2-(1rffluoromethyl)phenyl]-1H-pyrazol-5- yl}-2-thienyl)pyridine; MS (ES): 546.2 [M+H]+; • 3-memyl-5-(5-{l-[2-(methyloxy)phenyl]-3-(tri^^ (methylsulfonyl)pyridine; MS (ES): 494.3 [M+H]+;
• 5-{5-[l-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-2-iMenyl}-2-(e%lsulfonyl)-3- methylpyridine; MS (ES): 512.3 [M+H]+; • 5-{5-[l-(2,5-dichlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-2-thienyl}-3-methyl-2- (methylsulfonyl)pyridine; MS (ES): 532.4546.1[M+H]+;
• 3-methyl-2-(methylsulfonyl)-5-(5-{3-(trita yl}-2-thienyl)pyridine; MS (ES): 532.2[M+H]+;
• 5-{5-[l-(2,5-dchlorophenyl)-3-(ttMuoromethyl)-1H-pyrazol-5-yl]-3-tiiienyl}-3-methyl-2- (methylsulfonyl)pyridine; MS (ES): 532.4,536.2 [MfH]+;
Scheme 13
Figure imgf000174_0001
The starting materials (013vi) were prepared in similar manner of Scheme 1 followed by further transformations to make final products as described in Scheme 13. Example 22
Preparation of l-(5-{5-[2-(2-Chlowψheψl)-5-Mfluoromethyl-2H-pyrazol-3-ylJ-thiophen-2-yl}- pyridin-2-yl)-piperazine
Figure imgf000174_0002
4-(5-{5-[2-(2-CWorcHphenyl)-5-trifluoromethyl-2H-pyrazol-3-yl]-thiophen-2-yl}-pyridin-2-yl)- piperazine-1-carboxylic acid føf-butyl ester (196 mg, 0.33 mmol) was mixed with 4 mL 50% trifluoromethylacetic acid in dichloromethane, and stirred at room temperature for 2 hrs. All solvent was removed; the residue was redissolved in dichloromethane and neutralized to pΗ 7 by saturated
NaHCO3. The organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo to give a solid that was washed several times with dichloromethane to give yellow solid (75 mg, 47% yield). IH-NMR (400MHz, CDCl3): δ 3.32 - 3.29 (m, 4H), 3.94 - 3.91 (m, 4H), 6.67 (d, J= 8.8, IH),
6.79 (d, J= 3.8, IH), 6.87 (s, IH), 7.02 (d, J= 3.8, IH), 7.57 - 7.45 (m, 4H), 7.63 (dd, J= 8.8, J= 2.5,
IH), 8.34 (d, J= 2.2, IH). MS (ES) 490.3, 492.3, [M+H]+. Scheme 14
Figure imgf000175_0001
014vi
The starting materials (014vi) were prepared in similar manner of Scheme 1 by further transformations to make final products as described in Scheme 14
Exanφle23
Preparation of ^-{S-P-Q-Chloroψhenyty-S-Mfluorometlψl-lH-pyrazol-S-ylJ^hiophen-l-yfy-S-methyl- phenyl)-acetic acid
Figure imgf000175_0002
(4-{5-[2-(2-CMoro-phenyl)-5-trifluoromethyl-2H-pyrazol-3-yl]-thiophen-2-yl}-3-methyl- phenyl)-acetic acid methyl ester (122 mg, 0.25 mmol) was dissolved in 6 mL mixture of TΗF and water (3 : 1, WV). Lithium hydroxide monohydrate (2.3 mg, 0.55 mmol) was then added. After stirring at room temperature for 2 hrs, the mixture was neutralized to pΗ 7 by IN HCl, and then extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo. The crude product was purified by reverse ΗPLC to give a white solid (66 mg, 55% yield). 1Η-NMR (400MΗz, CDCl3): δ 2.33 (s, 3H), 3.65 (s, 2H), 6.88 - 6.84 (m, 3H), 7.17 - 7.11 (m, IH), 7.17 (m, IH), 7.27 (m, IH), 7.56 - 7.42 (m, 4H). MS (ES) 477.2, [M+H]+. The following compounds were made in similar manner by hydrolysis of corresponding phenylacetate ester precursors.
• (3-{5-[l-(2-cMorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-2-thienyl}-4-fluorophenyl)acetic acid; MS (ES): 481.1,484.4 [M+H]+;
• 2-(5-{5-[l-(2-cMorophenyl)-3-(1rifluoromethyl)-1H-pyrazol-5-yl]-2-thienyl}pyridin-3-yl)-2- methylpropanoic acid; MS (ES): 492.1,494.3 βVI+H]+;
• (5-{5-[l-(2-cMorophenyl)-3-(trmuoromethyl)-1H-pyrazol-5-yl]-2-tiiienyl}pyridin-3-yl)acetic acid; MS (ES): 464.0,466.1 [M+H]+; • [3-methyl4-(5-{3-(trifluoromethyl)4-[3-(1rifluoromethyl)pyridin-2-yl]-1H-pyrazol-5-yl}-2- thienyl)phenyl]acetic acid; MS (ES): 512.3 |M+H]+;
Scheme 15
Figure imgf000176_0001
As depicted in Scheme 15, a ketone can be transformed into alcohols and oximes, which can be alkylated. Ketone 015XGU01 was reduced with NaBH4 to a secondary alcohol 015XGU02. Oxime 015XGU03 was obtained by treatment of ketone 015XGU01 with hydroxylamine in the presence of a base. Oxime 015XGU03 was alkylated with alkyl chloride or alkyl bromide to give the O-alkylated oxime 015XGU04.
Example 24
Preparation of l-[l-(2^Moroplwnyl)-5-{5-[3-(methylsulfonyl)phenyl]-24hierψl}-lH- yljethanol
Figure imgf000176_0002
NaBH4 (600mg) was added at 0 °C to a suspension of l-[l-(2-chlorophenyl)-5-{5-3- (methylsurfonyl)phenyl]-2-thienyl}-1H-pyrazol-3-yl]ethanone (460mg, lmmol) in a mixture of MeOH- THF (1 :3, 10OmL), and the resulting mixture was stirred at rt for 4h. Water was added, and the solvent was removed in vacuo. The residue was partitioned between water and DCM, the aqueous was extracted with DCM. The combined extracts were washed with brine, dried over Na2SO4, and evaporated in vacuo. The crude product was purified by flash chromatography (0-80% EtOAc/hexanes) to give the title compound as a white solid (423mg, 92%). 1HNMR (CDCl3): δ 8.04 (m, IH), 7.83-7.81 (m, IH), 7.74-7.71 (m, IH), 7.57-7.43 (m, 5H), 7.21 (d, IH), 6.75 (d, IH), 6.64 (s, IH), 5.05 (q, IH)5 3.07 (s, 3H), 2.05 (brs, IH), 1.63 (d, 3H). MS(ES): 459 [M+H]+, 441 (M-OH). Example 25
Prepω"ctionofl-[l-(2-cUoropheψl)-5-{5-[3-(methyl$ulfonyl)pheψl]-2~thiejψl}-^ yljethanone oxime
Figure imgf000177_0001
A mixture of l-[l-(2-cMorophenyl)-5-{5-3-(methylsulfonyl)phenyl]-2-thienyl}-1H-pyrazol-3- yl]ethanone (120mg, 0.263mmol), NH2OHHCl (92mg, 1.32mmol), and NaOAc (132mg, 1.6mmol) in a mixture OfMeOH-H2O (2:1, 15mL) was stirred at 850C in a sealed vial for Hh. The solvent was removed in vacuo, and the residue was purified by flash chromatography (0-60% EtOAc/hexanes) to give the title compound as a white solid (115mg, 93%). 1HNMR (CDCl3): δ 8.04 (m, IH)57.83-7.81 (m, IH), 7.73-7.71 (m, IH), 7.57-7.43 (m, 5H), 7.21 (d, IH), 6.97 (s, IH), 6.76 (d, IH), 3.09 (s, 3H), 2.37 (s, 3H). MS(ES): 472 PVI+H]+.
The following compound is prepared essentially according to the previous examples: • l-[l-(2-cMorophenyl)-5-{5-[3-(methylsu[fonyI)phenylJ-2-thienyl}-1H-pyrazol-3-yl]ethaiione
O-methyloxime MS(ES): 486 [M+H]+ Example 26
Prepω"aUonofl-[l~(2~chloropherψl)-5-{5-[3-(methylmlfonyl)phenyl]-24hieψl}-lH- yljethanone O-[2-(dimethylamnio)ethyl]oxime
Figure imgf000177_0002
A mixture of l-fl^-cUorophenyl^-jS-P^meihylsulfony^phenylJ^-ihienyll-1H-pyrazol-S- yl]ethanone oxime (196mg, 0.415mmol), KOH (142mg, 2.3mmol), 2-(dimethylamino)ethyl chloride hydrochloride (185mg, IJmrnol), and anhydrous DMSO (5mL) was stirred at 600C in a sealed vial for
3h. The reaction mixture was diluted with water, extracted with ether. The combined extracts were washed with brine, dried over Na2SO4, and evaporated in vacuo. The residue was purified by flash chromatography (0-30% MeOH/DCM) to give the title compound as a white solid. (50mg, 22%). 1HNMR (CDCl3): δ8.04(d, IH), 7.83-7.81 (m, IH), 7.74-7.71 (m, IH), 7.57-7.43 (m, 5H), 7.21 (d, IH),
7.00 (s, IH), 6.76 (d, IH), 4.38 (% 2H), 3.079s, 3H), 2.78 (m, 2H), 2.40 (brs, 6H), 2.31 (s, 3H).
Scheme 16
Figure imgf000178_0001
As depicted in Scheme 16, A carbinol can be transformed into ethers, alkenes and sulfoxide. Ester 016XGU01 was treated with EiMgBr in the presence of Ti(OPr-i)4 . or 1,4-butane dimagnesiumbromide to give the cyclopropanol or cyclopentanol 016XGU02. The carbinol was alkylated with RX to give 016XGU06. The carbinol reacted with MeSO2Na in the presence of acid such as TFA to give 016XGU03 and the corresponding olefin 016XGU04. The olefin 016XGU04 and methyl ether 016XGU05 were obtained by treatment of the carbinol with HCI/MeOH.
Example 27
Prepω'athn ofl-[l-(2-chloropheryl)-5-{5-[3-(methylsulforψl)pherψl]-24fo yljcyclopentanol
Figure imgf000178_0002
Magnesium turnings (30Qmg, 12.5mmol) was introduced into a oven-dried flask under N2, covered with anhydrous THF (15OmL), and a solution of dibromobutane (0.72mL, 6.08mrnol) in anhydrous THF (2OmL) was added dropwise at ambient temperature at such a rate that the temperature of the reaction mixture did not rise above 400C. The mixture was stirred at ambient temperature for Ih, and the magnesium turnings disappeared. l-(2-chloro-phenyl)-5-[5-(3-methanesulfonyl-phenyl)- thiophen-2-yl]-1H-pyrazole-3-carboxylic acid methyl ester (2.37g, 5mmol) was added as a solid, and the resulting dark-purple solution was stirred at room temperature under N2 for Ih, At O0C aqueous NH4Cl solution was added, and then extracted with EtOAc, The combined extracts were washed with brine, dried over Na2SO4. and evaporated in vacuo. The crude product was purified by flash chromatography (0-60%EtOAc/hexanes) to afford the title compound as a white solid (1.4g, 56%). 1HNMR(CDCl3): 58.04(d, IH), 7.83-7.81(m, IH), 7.74-7.71 (m, IH), 7.57-7.52 (m, 3H), 7.48-7.44 (m, 2H), 7.20 (d, IH), 6.74 (d, IH), 6.63 (s, IH), 3.07 (s, 3H), 2.42 (brs, IH), 2.20-1.83 (m, 8H). MS(ES) 499 [M+H]+, 481 (M-OH).
Example 28 Preparation ofl-[l-(2-chlorophenyl)-5-{5-[3-(metJ^hulfonyl)phenyl]-24hienyl}-lH-pyi"azo cyclopropanol
Figure imgf000179_0001
A solution of EtMgBr in THF (1.0M, 1 ImL) was added dropwise at rt to a stirred solution of 1-
(2-chloro-phenyl)-5-[5-(3-me1hanesuhconyl-phenyl)-thiophen-2-yl]-1H-pyrazole-3-carboxylic acid methyl ester (950mg, 2mmol) and Ti(OiPr)4 (OJmL, 2.4mmol) in anhydrous THF (5OmL) under N2.
The resulting dark mixture was stirred at rt for 2h. At O0C aqueous NH4Cl solution was added, extracted with Et2O. The combined extracts were washed with brine, dried over Na2SO4, and evaporated in vacuo. The crude product was purified first by flash chromatography (0-60% EtOAc/hexanes) and then by reverse HPLC to give the title compounds as a white solid (85mg, 0.1%). 1HNMR (CDCl3): δ 8.04 (d, IH), 7.83-7.81 (m, IH), 7.74-7.71 (m, IH), 7.57-7.43 (m, 5H), 7.2 (d, IH), 6.72 (d, IH), 6.50 9s,
IH), 3.07 (s, 3H), 2.92 (brs, IH), 1.31 (m, 2H), 1.17 (m, 2H). MS(ES): 471[M+H]+, 453 (M-OH).
Example 29 Preparation of 3-[l-methyM-(mettylsulfonyl)ethyl]-5-{5-[3-(m^
(triflυoromethyl)pheψl]-lH-pyrazole, cmd 3-(l-methylethenyiy^ thienyl}-l-[2-(trifluoromethyl)pJ'ienyl]-lH-pyrazole),
Figure imgf000180_0001
TFA (ImL) was added dropwise at O C to a stirred mixture of the carbinol (270mg, 0.533mmol) and MeSO2Na (280mg, 2.74mmol) in CHCl3 (8mL), the resulting mixture was stirred at rt overnight After dilution with water, the mixture was poured into 12% aqueous ISlH4OH solution, and extracted with DCM. The combined extracts were washed with water and brine, dried over Na2SO4, and evaporated in vacuo. The crude product was purified by flash chromatography (0-80% EtOAc/hexanes) to give the title compounds as white solid. (152mg, 50%). 1HMMQR. (CDCl3): δ 8.02 (d, IH), 7.9 (m, IH), 7.83 (m, IH), 7.71 (m, 3H), 7.55 (m, IH), 7.46 (m, IH), 7.20 (d, IH), 6.88 (s, IH), 6.74 (d, IH), 3.07 (s, 3H), 2.77 (s, 3H), 1.88 (s, 6H). MS(ES): 569 [M+H]+; (40mg). 1HNMR (CDCl3): δ 8.03 (d, IH), 7.87-7.81 (m, 2H), 7.73-7.66 (m, 3H), 7.57-7.17 (m, 2H), 7.17 (d, IH), 6.78 (s, IH), 6.65 (d, IH), 5.62 (s,lH), 5.18 (m, IH), 3.07 (s, 3H), 2.19 (s, 3H). MS(ES): 489 (M+H]+. The following compounds are prepared essentially according to the previous examples:
• 2-(3-[l-methyl-l-(methylsulfonyl)ethyl]-5-{5-[3<methylsulfonyl)phenyl]-2-thienyl}-1H- pyrazoH-yl)-3-(trifluoromethyl)pyridine, MS(ES): 570[M+H]+ • 2-[3-(l-methyle1henyl)-5-{5-[3-(methylsu]fonyl)phenyl]-2-tMenyl}-1H-ρyrazol-l-yl]-3- (trifluoromethyl)pyridine, MS(ES): 490 [M+HΓ
• 3-(3-[l-methyl-l-(methylsulfonyl)e%l]-5-{5-[3<methylsurfonyl)phenyl]-2-thienyl}-1H- pyrazol-l-yl)-2-(trifluoromethyl)pyridine MS(ES): 570|M+H]+
• 3-(l-methylethenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-tMenyl}-l-[2-(trifluoromethyl)phenyl]- lH-pyrazole, MS(ES): 490 [M+H]+
• 3-(3-[l-methyl-l-(methylsulfonyl)e%l]-5-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}-1H- pyrazol-l-yl)-2-(trifluoromethyl)pyridine, MS(ES): 570|M+H]+
Example 30
Prepa~ationofl-(2-chloropheψl)-3-(l-methyktheψl)^ pyrazole and l-(2-chloropherιyl)-3-[l-methyl-l-(methyloxy)ethyl]-5-{5-[3-(methylm^ thienyl}~lH-pyrazole
Figure imgf000181_0001
A solution of HClMeOH (1.25M, SmL) was added to stirred solution of 2-{l-(2-chloro- phenyl)-5-[5-(3-meώanesulfonyl-phenyl)-1hiophen-2-yl]-1H-pyrazol-3-yl}-propan-2-ol (430mg,
0.864mmol) in CHCl3, and the reaction mixture was stirred at 850C in a sealed vial for 6h. The solvent was removed in vacuo, and the residue was purified by flash chromatography (0-50% EtOAc/hexanes) to give the title compounds as white solid. (110mg, 28%): 1HNMR (CDCl3): δ 8.05 (m, IH), 7.83-7.81 (m, IH), 7.74-7.72 (m, IH), 7.57-7.52 (m, 3H), 7.49-7.41 (m, 2H), 7.20 (d, IH), 6.79 (s, IH), 6.72 (d, IH)5 5.64 (s, IH), 5.18 (m, IH), 3.07 (s, 3H), 2.21 (s, 3H). MS(ES): 455 [M+H]+. (94mg, 22%): 1HNMR(CDCl3): δ 8.04 (m, IH), 7.83-7.80 (m, IH), 7.74-7.71 (m, IH), 7.57-7.52 (m, 3H), 7.50-7.41 (m, 2H), 7.20 (d, IH)5 6.74 (d, IH)5 6.67 (s, IH), 3.23 (d, 3H), 3.07 (s5 3H), 1.63 (s, 6H). MS(ES): 455 (M-OMe).
Example 31
Prepω-ation of5-{5-[3-(inethylmlfoψl)pheψl]-24hieψl}-3-[l'metIψl-l-(metlψlo^ (triflnoro-methyl)phenyl]-lH-pyrazole and5-{5-[3--(etnylsuifonyl)phenyl]-2-thienyl}-3--[l~methyl-l- (methyhxy)ethyl]-l-[2-(tιifluoromethyl)pheττyl]ΛH-pyrazole
Figure imgf000181_0002
NaH (60% in mineral oil, 40mg, lmmol) was added at O0C to a stirred mixture of 2-(5-{5-[3- (memylsuhconyl)phenyl]-2-tWenyl}-l-[2-(trifluoromethyl)phenyl]-1H-p5TOzol-3-yl)propan-2-ol (260mg, 0.5mmol), MeI (47μL, 0.75mmol) and anhydrous DMF (8mL), and the resulting mixture was stirred at rt for 3h. At O0C water was added to quench the reaction, then extracted with DCM. The combined extracts were washed with water and brine, dried over Na2SO4, and evaporated in vacuo. The crude product was purified first by flash chromatography (0-40% EtOAc/hexanes), then by normal phase HPLC to give the two title compounds as white solid. (1 lOmg, 41%). 1HNMR (CDCl3): δ 8.03 (m, IH), 7.87-7.81 (m, 2H), 7.73-7.66 (m, 3H), 7.57-7.50 (m, 2H), 7.18 (d, IH), 6.66 (m, 2H), 3.21 (s, 3H), 3.07 (s, 3H), 1.63 (s, 6H). MS(ES): 521 |M+HJ+. (71mg, 26%). 1HNMR (CDCl3): δ 7.98 (m, IH), 7.87-7.85 (m, IH), 7.79-7.76 (m, IH), 7.72-7.66 (m, 3H), 7.56-7.50 (m, 2H), 7.18 (d, IH), 6.66 (m, 2H), 3.21 (s, 3H), 3.13 (q, 2H), 1.63 (s, 6H), 1.29 (t, 3H) . MS(ES): 535 |M+H]+.
Scheme 17
Figure imgf000182_0001
As depicted in Scheme 17, An ester can be transformed into alcohols and amines. Ester 017XGU01 was reduced with lithium borohydride to give primary alcohol 017XGU02 in good yields. Alcohol 017XGU02 was converted to the corresponding bromide 017XGU03 by treatment with NBSZPPh3. Amine 017XGU04 was obtained by treatment of bromide 017GU03 with the corresponding an amine.
Exanψle32
Preparation of [l-(2-chbropheψl)-5-{5-[3-(methylsulfonyl)phenylj !-2-thienyl}-lH-pyrazol-3- yljmethanol
Figure imgf000182_0002
LiBH4 (LOM in THF, 14mL, 28mmol) was added dropwise at rt to a stirred solution of l-(2- chloro-phenyl)-5-[5-(3-methanesulfonyl-phenyl)-thiophen-2-yl]-1H-pyrazole-3-carboxylic acid methyl ester (4.38g, 9.26mmol) in anhydrous THF (10OmL) under N2, and the resulting mixture was stirred at rt for 3d. Acetone (2mL) and water (2mL) was added successively at O0C and the solid was filtered off. The filtrate was concentrated in vacuo. The residue was taken up in EtOAc (20OmL), washed with water and brine, dried over Na2SO4 and evaporated in vacuo. The crude product was purified by flash chromatography (0-90% EtOAc/hexanes) to give the title compound as a white solid (3.1g, 75%). 1HNMR (CDCl3): δ 8.04 (m, IH), 7.84-7.81 (m, IH), 7.74-7.72 (m, IH), 7.58-7.44 (m, 5H), 7.21 (d, IH), 6.76 (d, IH), 6.69 (s, IH), 4.80 (s, 2H), 3.07 (s, 3H), 1.65 (brs, IH). MS(ES): 445 [M+Hj+. Example 33
PrepccrcMonof4-{ll-(2-chlorophenyl)-5-{5-l3-(methylmlfo^ yljmethyljmorpholine
Figure imgf000183_0001
PPh3 (4.36g, 16.62mmol) was added at O0C to a stirred solution of [l-(2-chlorophenyl)-5-{5-[3-
(me1hylsulfonyl)phenyl]-2-thienyl}-1H-pyrazol-3-yl]methanol (6.15g, 13.85mmol) in dry DCM. After 30min, NBS (2.72g, 15.28mmol) was added portionwise at O0C, and the mixture was stirred at rt overnight The solvent was removed in vacuo, and the crude product was purified by flash chromatography (0-50%EtOAc/hexanes) to afford 3-bromomethyl-l-(2-chlorophenyl)-5-{5-[3- (metiiylsuMony^phenyll-thiphen^-yl]- lH-pyrazole as a pale-yellow solid (3.6g, 54%).
A mixture of 3-bromomethyl-l-(2-chlorophenyl)-5-{5-[3-(methylsuhOnyl)phenyl]-thiphen-2- yl]-1H-pyrazole (51mg, O.lmmol), K2CO3 (42mg, 0.3mmol), KI (lOmg), and morpholine (0.3mmol) in anhydrous MeCN (5mL) was stirred at 900C for 6h under N2. The solid was filtered off, and the filtrate was concentrated in vacuo. The crude product was purified by flash chromatography (0-80% EtOAc/hexanes) to give the title compound as a pale-yellow solid (50mg, 96%). 1HNMR (CDCl3): δ 8.04 (m, IH), 7.82 (m, IH), 7.72 (m, IH), 7.57-7.43(m, 5H), 7.20 (d, IH), 6.75 (d, IH), 6.66 (s, IH), 3.77 (m, 4H), 3.66 (s, 2H), 3.07 (s, 3H), 2.60 (m, 4H). MS(ES): 514 [M+H]+. The following compounds are prepared essentially according to the previous examples:
• l-{[l-(2-chlorophenyl)-5-{5-[3-(methylsuhconyl)phenyl]-2-tMenyl}-1H-pyrazol-3-yl]methyl}- 4-methylpiperazine, MS(ES): 527 [M+Hf
• l-(2-chlorophenyl)-5-{5-[3-(methylsuhOnyl)phenyl]-2-thienyl}-3-(pyiroUdin-l-y]methyl)-1H- pyrazole, MS(ES): 498 [M+H]+
• 2-(4-{[l-(2-chlorophenyl)-5-{5-[3-(methylsuhcbnyl)phenyl]-2-thienyl}-1H-pyrazol-3- yl]methyl}piperazk-l-yl)pyrimidine, MS(ES): 591 [M+H]+ • l-[l-(2-cMorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-iMenyl}-1H-pyrazol-3-yl]-N-(&ran-
2-ylmethyl)-N-metliylmethanamine, MS(ES): 538 [M+H]+
• l-[l-(2-cMorophenyl)-5-{5-[3-(methylsuhconyl)phenyl]-2-thienyl}-1H-pyrazol-3-yl]-N- (pyridin-2-ylmethyl)methanamine, MS(ES): 535 [M+H]+
• Phenylmethyl4-{[l-(2-chlorophenyl)-5-{5-[3-(methylsuhOnyl)phenyl]-2-thienyl}-1H-pyrazol- 3-yl]methyl}-3-oxopiperazine-l-carboxylate, MS(ES): 661 [M+H]+ • l-(2-cMorophenyl)-3-(lH-Mdazol4-ylmethyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}- lH-pyrazole, MS(ES): 495 !MfBTJ+
• l-[l-(2-cUorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-iMenyl}-1H-pyrazol-3-yl]-N-methyl- N-(2-thienylmethyl)meHianamine, MS(ES): 554 [M+H]+ • 3-[{[l-(2-cMorophenyl)-5-{5-[3-(methylsιΛfonyl)phenyl]-2-thienyl}-1H-ρyrazol-3- yl]methyl}(furan-2-ylmethyl)amino]propanemtrile, MS(ES): 577 PVB-H]+
• N-{[l-(2-cMorophenyl)-5-{5-[3-(methylsιM)nyl)phenyl]-2-thienyl}-1H-ρyra∞l-3-yl]m^ 2,2,2-1rifluoro-N-(&ran-2-ylmethyl)ethanamine, MS(ES): 606|M+H]+
• N-{[l-(2-chlorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}-1H-pyra2»l-3-yl]me1hyl}- N-(&ran-2-ylmethyl)propan-2-amine, MS(ES): 566 [M+H]+
• N-{[l-(2-cMorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}-1H-pyrazDl-3-yl]methyl}- N-(furan-2-ylmethyl)cyclopropanamine, MS(ES): 564 |M+H]+
• N-{[l-(2-cMorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}-1H-pyrazOl-3-yl]me1hyl}- N-(furan-2-ylmethyl)-2-methylpropan-2-amine, MS(ES): 580 [M+H]+ • N-{[l-(2-chlorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}-1H-pyrazol-3-yl]methyl}- N-(furan-2-ylmethyl)cyclohexanamine, MS(ES): 606 PVI+H]+
• l-[l-(2-cMorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}-1H-ρyrazol-3-yl]-N-[(3,5- dime%Hsoxazol-4-yl)methyl]-N-methylmethanamine, MS(ES): 567 [M+H]+
• N-{[l-(2-cHorophenyl)-5-{5-[3-(methyls^ N-(pyridin-4-ylmethyl)ethanamine, MS(ES): 563[M+H]+
• N-{[l-(2-chlorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-iMenyl}4H-pyrazol-3-yl]methyl}- N-(pyridin-4-ylmetliyl)methanamine, MS(ES): 549 |M+H]+
• l-[l-(2-chlorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-iMenyl}-1H-pyrazol-3-yl]-N-methyl- N-(l,3-oxa2Dl-2-ylmethyl)methanamine, MS(ES): 539 |M+H]+ • N-{[l-(2-cMoiOphenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}-1H-pyrazDl-3-yl]methyl}- N-methyl-2-pyridin-2-ylethanamine, MS(ES): 563 [M+BQ+.
• N-{[l-(2-cMorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-tWenyl}-1H-pyrazol-3-yl]me% 2-methyl-N-(l-methyletliyl)propan-2-amine MS(ES): 542 [M+H]+.
• 3-[{[l-(2-cMoroρhenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}-1H-pyrazol-3- yl]methyl}(ethyl)amino]propanenitrile, MS(ES): 525 [M+H]+,
• (lS)-N-{[l-(2-chlorophenyl)-5-{5-[3-(meihylsulfonyl)phenyl]-2-thienyl}-1H-pyrazol-3- yl]methyl}-N-methyl-l-phenylethanamine, MS(ES): 562 [MfET]+. • N-{[l-(2-chlorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}-1H-pyrazDl-3-yl]methyl}- N-methyl-2-phenylethanamine, MS(ES): 562 [M+H]+
• l-{[l-(2-chlorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-iMenyl}-1H-pyrazol-3-yl]methyl}- 4-(phenylmethyl)piperidine; MS (ES): 602 [M+H]+; • ethyl l-{[l-(2-cUorophenyl)-5-{5-[3-(methylsitfonyl)phenyl]-2-iMenyl}-1H-pyrazol-3- yl]methyl}piperidine-2-carboxylate; MS (ES): 584 [M+H]+;
• l-{[l-(2-cMorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}-1H-pyrazol-3-yl]methyl}- 4-(phenylmethyl)piperazine; MS (ES): 603 [M+H]+;
• e%lN-{[l-(2-cMorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}-1H-pyrazol-3- yl]methyl}-N-(phenylmethyl)glycinate; MS (ES): 620 [M+H]+;
• 4-[(4-{[l-(2-clτlorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-fliienyl}-1H-pyrazol-3- yl]methyl}piperazin-l-yl)acetyl]moφholine; MS (ES): 640 [M+H]+;
• 2-{[l-(2-chlorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-iMenyl}-1H-pyrazol-3- yl]methyl}decahydroisoquinoline; MS (ES): 566 |M+H]+; • 2-[3,4-bis(methyloxy)phenyl]-N-{[l-(2-chlorophenyl)-5-{5-[3-(metiiylsulfonyl)phenyl]-2- thienyl}-1H-pyrazol-3-yl]methyl}-N-methylethanamine; MS (ES): 622 [M+H]+;
• e%l l-{[l-(2-chlorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}-1H-pyrazol-3- yl]methyl}piperidine-4-carboxylate; MS (ES): 584 [M+H]+;
• e%14-{[l-(2-chlorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}-1H-pyrazol-3- yl]methyl}piperazine-l-carboxylate; MS (ES): 585 \M+H\+;
• N-{[l-(2-cMorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}-1H-pyrazol-3-yl]m N-propylpropan-1-amine; MS (ES): 528 [M+H]+;
• l-{[l-(2-chlorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}-1H-pyrazol-3-yl]methyl}- 3-methylpiperidine; MS (ES): 526 |M+E[|+; • 4-{[l-(2-chlorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}-1H-pyrazol-3-yl]methyl^
2,6-dimetliylmorpholine; MS (ES): 542 [M+H]+;
• l,l-dimethyle%l4-{[l-(2-cMorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-1hienyl}-1H- pyrazol-3-yl]methyl}pipera2dne-l-carboxylate; MS (ES): 613 [M+H]+;
• l-{[l-(2-chlorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-ihienyl}-1H-pyrazol-3-yl]me1hyl} 4-(2-oxo-2-pyrroUdin-l-ylethyl)piperazine; MS (ES): 624 [M+H]+;
• N-{[l-(2-cUorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-tWenyl}-1H-pyrazol-3-yl]methyl}- 2-(methyloxy)-N-[2-(methyloxy)ethyl]ethanamine; MS (ES): 560 |M+H]+; • l-{[l-(2-cWorophenyl)-5-{5-[3-(methylεαilfonyl)phenyl]-2-1hienyl}-1H-pyrazol-3-yl]methyl}- 4-(3,4-dichlorophenyl)piperazine; MS (ES): 657 |M+H]+;
• l-{[l-(2-cUorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-iMenyl}-1H-pyrazDl-3-yl]methyl}- 4-phenylpiperazine; MS (ES): 589 [M+H]+; • 3-{[l<2-cUorophenyl)-5-{5-[3-(methylsi^onyl)phenyl]-2-thienyl}-1H-pyrazol-3-yl]methyl}- 1,3-thiazolidine; MS (ES): 516 [M+H]+;
• l-[l-(2-chlorophenyl)-5-{5-[3-(me%bulfonyl)phenyl]-2-iMenyl}-1H-pyrazol-3-yl]-N,N- bisφyridin-2-ylmethyl)methanamine; MS (ES): 626 [M+H]+;
• N-{[l-(2-chlorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-tMenyl}-1H-pyrazol-3-yl]me1iiyl}- N^N-triethyletiiane-l^-diamine; MS (ES): 571 [M+H]+;
• l-{[l-(2-cMorophenyl)-5-{5-[3-(metiiylsulfonyl)phenyl]-2-iMenyl}-1H-pyrazol-3-yl]me1hyl}- 4-e%lpiperazine; MS (ES): 541 [M+H]+;
• l-[l-(2-cMorophenyl)-5-{5-[3-(methylsιM)nyl)phenyl]-2-thienyl}-m-pyrazDl-3-yl]-N,N- bis(phenylmethyl)methanamine; MS (ES): 624 [M+H]+; • l-{[l-(2-chlorophenyl)-5-{5-[3-(methylsιJfonyl)phenyl]-2-Uτienyl}-1H-pyrazol-3-yl]methyl}-
4-pyrrolidin-l-ylpiperidine; MS (ES): 581 [M+H]+;
• l-(l,3-benzodioxol-5-ylmethyl)-4-{[l-(2-chlorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2- thienyl}-1H-pyrazDl-3-yl]methyl}piperazine; MS (ES): 647 [M+H]+;
• N-{[l-(2-chlorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-tWenyl}-1H-pyrazol-3-yl]methyl}- N-methylhexan-1-amine; MS (ES): 542 [M+H]+;
• l-{[l-(2-chlorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-iMenyl}-1H-pyrazol-3-yl]methyl}- 3,5-dimethylpiperidine; MS (ES): 540 [M+H]+;
• l-{[l-(2-chlorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-1hienyl}-1H-pyrazol-3-yl]methyl}- 2-ethylpiperidine; MS (ES): 540 [M+H]+; • l-{[l-(2-chlorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-iMenyl}-1H-pyrazDl-3-yl]methyl}-
2,5-dimetiiylpiperazine; MS (ES): 541 [M+H]+;
• l-{[l-(2-cMorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}-1H-pyrazol-3-yl]methyl}- 1,4,5,6-tetrahydropyrimidine; MS (ES): 511 |M+H]+;
• l-{[l-(2-chloiOphenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}-1H-ρyrazol-3- yl]methyl}azepane; MS (ES): 526 [M+H]+;
• l-{[l-(2-cMorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}-1H-pyrazol-3-yl]methyl}- 4-[5-(trifluoromethyl)pyridin-2-yl]piperazine; MS (ES): 658 [M+H]+; • l-{[l-(2-cMorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}-1H-pyrazol-3-yl]methyl}- 4-[3-(trifluoromethyl)phenyl]piperazine; MS (ES): 657 [MfHJ+;
• N-{[l-(2-cUorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}-1H-pyrazol-3-yl]methyl}- N-cyclohexylcyclohexanamine; MS (ES): 608 [MfH]+; • methyl l-{[l-(2-cMorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-tiτienyl}-1H-pyra2X)l-3- yl]methyl}-L-prolinate; MS (ES): 556 |M+HJ+;
• l-{[l-(2-cMorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}-1H-pyrazol-3-yl]methyl}- 1,4-diazepane; MS (ES): 527 [M+H]+;
• l-(2-cUorophenyl)-3-({2-[4-(ethyloxy)phenyl]pyrrolidin-l-yl}methyl)-5-{5-[3- (methylsulfonyl)phenyl]-2-thienyl}-1H-pyrazole; MS (ES): 618 [MfH]+;
• l-tl^-cMorophenyO-S-fS-P-^e^lsulfony^phenyη^-tMenyll-1H-pyrazol-S-ylJ-N-P- fluorophenyl)methyl]-N-methylmethanamine; MS (ES): 566 PVB-HJ+;
• N-{[l-(2-cMorophmyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}-1H-pyrazol-3-yl]metliyl}- N-methyl-2-morpholin-4-yl-l-phenylethanamine; MS (ES): 647 [M+HJ+; • l-{[l-(2-chlorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-iMenyl}-1H-pyrazol-3-yl]methyl}-
2-phenylazepane; MS (ES): 602 [MfHJ+;
• l-(2-clilorophenyl)-3-{[2-(2-methylphenyl)pyirolidin-l-yl]methyl}-5-{5-[3- (methylsulfonyl)phenyl]-2-tMenyl}-1H-pyrazole; MS (ES): 588 [MfH]+;
• l-(2-chlorophenyl)-3-({2-[4-(methyloxy)phenyl]pyrrolidin-l-yl}methyl)-5-{5-[3- (methylsulfonyl)phenyl]-2-thienyl}-1H-pyrazole; MS (ES): 604 [MfHj+;
• l-(2-chloiOphenyl)-3-{[2-(4-methylphenyl)pyrrolidin-l-yl]methyl}-5-{5-[3- (methylsulfonyl)phenyl]-2-thienyl}-1H-pyrazole; MS (ES): 588 [MfHj+;
• l-(2-chlorophenyl)-3-({2-[4-(l,l-dimethyle%l)phenyl]pyrrolidin-l-yl}methyl)-5-{5-[3- (methylsulfonyl)phenyl]-2-tiτienyl}-1H-pyrazole; MS (ES): 630 |M+H|+; • l-{[l-(2-chlorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-tMenyl}-1H-pyrazol-3-yl]methyl}-
2-pyridin-2-ylazepane; MS (ES): 603 [MfHJ+;
• l-{[l-(2-chlorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-1hienyl}-1H-pyrazol-3-yl]methyl}- 2-(4-methylphenyl)azepane; MS (ES): 616 [MfHJ+;
• l-{[l-(2-chlorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-1hienyl}-1H-pyrazol-3-ylJmethyl}- 2-(4-fluorophenyl)azepane; MS (ES): 620 [MfHJ+;
• N-{[l-(2-cUorophenyl)-5-{5-[3-(methylsiffi)nyl)phenyl]-2-tMenyl}-1H-pyra2ol-3-yl]methyl}- TSf-methyl-1-phenylethanamine; MS (ES): 562 [MHHJ+; • l-{[l-(2-cWorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-iWenyl}-1H-pyrazol-3-yl]me% 2-(3,4-dichlorophenyl)azepane; MS (ES): 670 [M+H]+;
• l-{[l-(2-chlorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}-1H-pyrazDl-3-yl]me%0 2-[4-(methyloxy)phenyl]azepane; MS (ES): 632 [M+H]+; • l-(2-chlorophenyl)-3-{[2-(3-chlorophenyl)pyrrolidin-l-yl]methyl}-5-{5-[3-
(methylsulfonyl)phenyl]-2-thienyl}-1H-ρyrazole; MS (ES): 608 [M+H]+;
• 3-{[2-(4-bromophenyl)pyrrolidin-l-yl]me1hyl}-l-(2-chlorophenyl)-5-{5-[3- (methylsulfonyl)phenyl]-2-thienyl}-1H-pyrazole; MS (ES): 652 [M+H]+;
• l-(2-chlorophenyl)-3-({2-[3-(methyloxy)phenyl]pyrrolidin-l-yl}methyl)-5-{5-[3- (methylsulfonyl)phenyl]-2-tMenyl}-1H-pyrazole; MS (ES): 604 [M+H]+;
• l-(2-chlorophenyl)-3-({2-[2-(methylo>ς/)phenyl]pyrrolidin-l-yl}methyl)-5-{5-[3- (methylsulfonyl)phenyl]-2-thienyl}-1H-pyrazole; MS (ES): 604 [M+HJ+;
• l-{[l-(2-chlorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-tMenyl}-1H-pyrazol-3-yl]methyl}- 2-[3-(methyloxy)phenyl]azepane; MS (ES): 632 [M+H]+; • l-{[l-(2-cMorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}-1H-pyrazol-3-yl]methyl}-
2-(2-thienyl)azepane; MS (ES): 608 [M+H]+;
• l-[l-(2-cMorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}-1H-pyrazol-3-yl]-N-methyl- N-(3-thienylmethyl)methanamine; MS (ES): 554 [M+H]+;
• 4-({[l-(2-chlorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}-1H-pyrazol-3- yl]methyl}amino)pyrimidine-2(lH)-thione; MS (ES): 554 [MfH]+;
• l-[l-(2-cWorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-tMenyl}-1H-pyi^ol-3-yl]-N-methyl- N-[(3-methylisoxazol-5-yl)methyl]methanamine; MS (ES): 553 [M+H]+;
• N-{[l-(2-cMorophenyl)-5-{5-[3-(methylsιilfonyl)phenyl]-2-iMenyl}-1H-pyrazol-3-yl]methyl}- N-methyl-l-(2-thienyl)ethanamine; MS (ES): 568 [M+H]+; • (l-{[l-(2-cMorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}-1H-pyra2Dl-3- yl]methyl}piperidin-3-yl)methanol; MS (ES): 542 [M+H]+;
• 4-{[l-(2-cUorOphenyl)-5-{5-[3-(methylsu]fonyl)phenyl]-2-iMenyl}-1H-pyrazol-3-yl]methyl}- 3-[4-(trifluoromethyl)phenyl]tliiomoφholine; MS (ES): 674 [MfH+;
• l-{[l-(2-cWoiOphenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-iMenyl}-1H-pyrazol-3-yl]me1hyl}^ 2-(3~methylphenyl)azepane; MS (ES): 616 |M+H]+;
• l-[l-(2-cMorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-1hienyl}-1H-ρyrazol-3-yl]-N,N- dimethylmethanamine; MS (ES): 472 [M+H]+; • l-(U-dimethylethyl) 3-methyl 4-{[l-(2-chloroρhenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2- thienyl}-1H-pyrazol-3-yl]methyl}piperazine-l,3-dicarboxylate; MS (ES): 671 [M+H]+;
• 2-(4-{[l-(2-cMorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}-1H-pyrazol-3- yl]methyl}piperazin-l-yl)-N,N-die%lethanamine; MS (ES): 612 [M+H]+; • l-{[l-(2-chlorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-Menyl}-1H-pyra2Dl-3-yl]methyl}-
4-(3-phenylpiOpyl)piperazine; MS (ES): 631 [M+H]+;
• l-[l-(2-cMorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-tiiienyl}-1H-pyrazol-3-yl]-N-[(4- ethylphenyl)methyl]-N-methylmethanamine; MS (ES): 576 [M+H]+;
• l-[l-(2-cldorophenyl)-5-{5-[3-(me1hylsulfonyl)phenyl]-2-thienyl}-1H-pyrazol-3-yl]-N-meth^ N-[(4-methyl-1H-imidazol-2-yl)me1hyl]methanamine; MS (ES): 552 [M+H]+;
• [{[l-(2-cUorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}-1H-pyrazol-3- yl]methyl}(methyl)amino]acetonitrile; MS (ES): 497 [M+H]+;
• l-ltl^-chloropheny^-S-IS-P-^ethylsulfony^phenyy^-thienyO-1H-pyrazol-S- yl]methyl}piperidine; MS (ES): 512 [M+H]+; • N-{[l-(2-cUorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}-1H-pyrazol-3-yl]methyl}- 2-methyl-N-(phenylmethyl)propan-2-amine; MS (ES): 590 [M+H]+;
• l-[l-(2-cMorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}-1H-pyrazol-3-yl]-N-(lH- imidazol-2-ylmethyl)-N-methylmethanamine; MS (ES): 538 [M+H]+;
• l-[l-(2-cUorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}-1H-pyrazol-3-yl]-N-methyl- N-[(5-methyl-1H-pyrazol-3-yl)methyl]methanamine; MS (ES): 552 [MfH]+;
• l-[l-(2-chlorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-tMenyl}-1H-pyrazol-3-yl]-N-methyl- N-[(4-methylphenyl)methyl]methanamine; MS (ES): 562 |M+H]+;
• l-{[l-(2-cωorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}-1H-pyrazol-3-yl]methyl}- 2-(2-methylphenyl)azepane; MS (ES): 616 [M+H]+; • l-(2-chlorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}-3-({2-[2-
(trifluoromethyl)phenyl]pyrroKdin-l-yl}methyl)-1H-pyrazole; MS (ES): 642 [M+H]+;
• l-[l-(2-cUorophenyl)-5-{5-[3-(me1hylsulfonyl)phenyl]-2-iMenyl}-1H-pyrazol-3-yl]-N-methyl- N-(quinolin-8-ylmeihyl)methanamine; MS (ES): 599 [M+H]+;
• 4-(l-{[l-(2-cMorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}-1H-pyrazol-3- yl]methyl}ρyrrolidin-2-yl)-N,N-dimetIiylaniline; MS (ES): 617 [M+H]+;
• l-[l-(2-cMorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}-1H-pyrazol-3-yl]-N-[(3,5- dimethyl-1H-pyrazol-4-yl)methyl]-N-methylmeflianamine; MS (ES): 566 [M+H]+; • l-(l,3-berizotMazol-2-yl)-N-{[l-(2-cMorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}- lH-pyrazol-3-yl]methyl}-N-methylme1hanainine; MS (ES): 605 [M+H]+;
• N~1~ {[l^-chlorophenyO-S-IS-p-Cme&ylsulfonyOphenylj^-thienyO-1H-pyrazol-S- yl]methyl}-N~l~,N~2~,N~2~- trimethyl-l-phenyle1hane-l,2-diamine; MS (ES): 605 [M+H]+; • l-[l-(2-chlorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-iMenyl}-1H-pyrazol-3-yl]-N-me%
N-[(2-methyl-l,3-1hiazol-4-yl)methyl]methanainine; MS (ES): 569 [M+HJ+;
• l^l-benzothien^-y^-N-ltl^-cMoropheny^-S-IS-P-^e^lsulfony^phenyll^-thienyO-1H- pyrazol-3-yl]methyl}-N-methylmeihanamine; MS (ES): 604 [M+H]+;
• 2-(l-{[l-(2-chlorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}-1H-pyrazol-3- yl]methyl}pyrrolidin-2-yl)-1H-indole; MS (ES): 613 [M+H]+;
• 3-{[2-(2-bromophenyl)pyrrolidin-l-yl]methyl}-l-(2-chlorophenyl)-5-{5-[3- (methylsulfonyl)phenyl]-2-ihienyl}-1H-pyrazole; MS (ES): 652 [MfHJ+;
• l-[l-(2-chlorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}-1H-pyrazol-3-yl]-N-methyl- N-(quinolin-5-ylmethyl)methanamine; MS (ES): 599 [M+H]+; • N-butyl-N-{[l-(2-cMorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}4H-pyrazol-3- yl]methyl}butan-l-amine; MS (ES): 556 [M+H]+;
• l-{[l-(2-chlorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-tbienyl}-1H-pyrazol-3-yl]methyl}- 4-phenylpiperidine4-carbonitrile; MS (ES): 613 [M+H]+;
• 2-{[l-(2-chlorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}-1H-pyrazol-3-yl]methyl}- 657-bis(methyloxy)-l,2,3,4-tetrahydroisoquinoline; MS (ES): 620 [M+H]+;
• 4-(4-chlorophenyl)-l-{[l-(2-chlorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}-1H- pyrazol-3-yl]methyl}-l,2,3,6-tetrahydropyridine; MS (ES): 620 |M+H]+;
• l-fl^-chloropheny^-S-IS-p^methylsulfony^phenyy^-thienylj-1H-pyrazol-S-yy-N-meihyl^ N-[(5-phenylisoxazol-3-yl)methyl]methanamine; MS (ES): 615 [M+H]+; • 4-bromo-l-{[l-(2-cMorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-iMenyl}-1H-pyrazol-3- yl]methyl}piperidine; MS (ES): 590 [M+H]+;
• methylN-{[l-(2-chlorophenyl)-545-[3-(methylsulfonyl)phenyl]-2-tMenyl}-1H-pyrazol-3- yl]methyl}-N-methylglycinate; MS (ES): 530 [M+Hj+;
• l-{[l-(2-cMorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}-1H-pyrazol-3- yl]me1hyl}piperidin-3-ol; MS (ES): 528 [M+H]+;
• N-{[l-(2-chlorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}-1H-pyrazol-3-yl]methyl}- N-methyl-2-phenylpropan-2-amine; MS (ES): 576 [M+H]+; • 4-{[l-(2-cMorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-ftdenyl}-1H-pyrazol-3-yl]methyl}- 3-(4-fluorophenyl)thiomorpholine; MS (ES): 624 [M+H]+;
• N-{[l-(2-chlorophenyl)-5-{5-[3-(methylsiilfonyl)phenyl]-2-thienyl}-1H-pyra-Ol-3-yl]methyl}- N-methylpropan-2-amine; MS (ES): 500 [M+H]+; • N-{[l-(2-chlorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-tWenyl}-1H-pyrazol-3-yl]methyl} N,lSr,lSr-trimethylpropane-l,3-diamine; MS (ES): 543 [M+H]+;
• l-{[l-(2-cMorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-iMenyl}-1H-pyrazol-3-yl]methyl}- 4-(l-methylpropyl)piperazine; MS (ES): 569 [M+H]+;
• (2R,6S)-l-{[l-(2-cMorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}-m-pyrazol-3- yl]methyl}-2,6-dimeihylpipeπdine; MS (ES): 540 |M+H]+;
• N-{[l-(2-cUorophenyl)-5-{5-[3-(me1hylsulfonyl)phenyl]-2-thienyl}-1H-pyrazol-3-yl]methyl}- N-(cyclopropylmethyl)propan-l-amine; MS (ES): 540 [M+H]+;
• l-{[l-(2-cWorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}-1H-pyrazDl-3- yl]methyl}decahydroquinoline; MS (ES): 566 [M+H]+; • N-{[l-(2-cMorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-iMenyl}-1H-pyrazol-3-yl]me1hyl^ N-ethylethanamine; MS (ES): 500 |M+H]+;
• 1,1-dimethylethyl 4-{[l-(2-cMorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}-1H- pyrazol-3-yl]methyl}-l,4-diazepane-l-carboxylate; MS (ES): 627 |M+H]+;
• N-{[l-(2-cMorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}-1H-pyrazol-3-yl]methyl}- N-methyl-2,2-bis(methyloxy)e1hanamine; MS (ES): 546 (M+H]+;
• l-Ifl^-cWorophenyO-S-IS-P^me^lsulfony^phenyy^-lWenylJ-1H-pyrazol-S- yl]methyl}piperidin-4-ol; MS (ES): 528 [M+H]+;
• [(2S)-l-{[l-(2-chlorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-tWenyl}-1H-pyrazol-3- yl]methyl}pyrrolidin-2-yl]meihanol; MS (ES): 528 [M+H]+; • l-{[l-(2-cMorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}-1H-pyrazol-3-yl]methyl}-
4-methyl-l,4-diazepane; MS (ES): 541 [M+H]+;
• l-{[l-(2-cMorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-iMenyl}-1H-pyrazol-3-yl]me1hyl}- 2-methylpiperazine; MS (ES): 527 [M+H]+;
• N-{[l-(2-chlorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-tiύenyl}-1H-pyra2»l-3-yl]methyl}- N-ethylcyclohexanamine; MS (ES): 554 \M+Η\+;
, • N-{[l-(2-cUorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}-1H-pyrazol-3-yl]methyl}- N^-diefhyl-N-methyleihane-l^-diainine; MS (ES): 557 [M+H]+; l-butyl-4-{[l-(2-chlorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-iMenyl}-1H-pyrazol-3- yl]methyl}piperazine; MS (ES): 569 JMfET]+;
N-{[l-(2-cMorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-iWenyl}-1H-pyrazol-3-yl]methyl}- N,l-dimethylpiperidin-4-amine; MS (ES): 555 [M+Hf;
N-{[l-(2-cUorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}-1H-pyrazol-3-yl]methyl}- N-methylpropan-1-amine; MS (ES): 500 |M+H]+;
N-{[l-(2-clτlorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}-1H-pyrazol-3-yl]me% N-ethylpropan-2-amine; MS (ES): 514 [M+H]+; l-{[l-(2-chlorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-t!iienyl}-1H-pyrazDl-3-yl]methyl}- 4-[2-(methyloxy)ethyl]piperazine; MS (ES): 571 |M+H|+;
N-{[l-(2-cMorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-tMenyl}-1H-pyrazol-3-yl]methyl}- N-(l-methylethyl)propan-2-amine; MS (ES): 528 [M+H]+; l-{[l-(2-cUorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}-1H-pyrazol-3-yl]methyl}- 4-methylpiperidine; MS (ES): 526 [M+H]+;
4-{[l-(2-cWorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}-1H-pyrazol-3- yl]me1hyl}thiomoφholine; MS (ES): 530 [M+H]+;
2-{[l<2-cMorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}-1H-pyrazol-3-yl]metiiyl}- 1,2,3,4-tetrahydroisoquinoline; MS (ES): 560 [M+HT;
N-{[l-(2-cMorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}-1H-pyrazol-3-yl]me1hyl}- N-(phenylmethyl)propan-2-amine; MS (ES): 576 [M+H]+;
Scheme 18
Figure imgf000192_0001
Figure imgf000192_0002
As depicted in Scheme 18, Dimethylcarbinol can be transformed into the corresponding amines. Carbinol 018XGU01 reacted with sodium azide in the presence of TFA to give azide 018XGU02 in good yield. Azide 018XGU02 was reduce to the amine 018XGU03 by treatment with PPh3 in THF-H2O. Amine 018XGU03 was converted to 018XGU04 by alkylation with a halide or reductive-amination of aldehydrides.
Example 34
Prepω-ationofl-(2-chloropJκnyl)-5-{5~[3-(methyhulfo}τyl)pheiψl]-24hie (2lambda~5~triaz-l-en-2-yn-l-yl)ethylJ-lH-pyrazole
Figure imgf000193_0001
NaN3 (200mg, 3mmol) was added to a stirred solution of 2-{l-(2-chlorophenyl)-5-[5-(3- memanesulfonyl-phenyl)-thiophen-2-yl]-1H-pyrazol-3-yl}-propan-2-ol (474mg, lmmol) in CHCl3
(9mL) at rt And the mixture was cooled to O0C. To this slurry was added dropwise TFA (0.6mL,
7.8mmol) over 5min. The reaction was allowed to warm to rt overnight The mixture was partitioned between aqueous NH4OH (IN) and CHCl3. The organic layer was washed with water and brine, then dried OVCrNa2SO4, and evaporated in vacuo. The residue was purified by flash chromatography (0-40% EtOAc/hexanes).to give the title compound as a white solid (380mg, 76%). 1HNMR (CDCl3): δ 8.04
(m, IH), 7.84-7.81 (m, IH), 7.74-7.71 (m, IH), 7.57-7.42 (m, 5H), 7.21 (d, IH), 6.75 (d, IH), 6.66 (s,
IH), 3.07 (s, 3H), 1.73 (s, 6H). MS(ES): 498 [M+H]+.
Example 35
Prepω'ationof2-[l-(2-chlorophenyl)-5-{5-[3-(mettyhulfoψl)pheψl]-24M ylJpropan-2-amήie
Figure imgf000193_0002
PPh3 (3.3g, 12.58mmol) was added at rt to a solution of the 3-(2-azidopropan-2-yl)-l-(2- cUorophenyl)-5-(5-(3-(me1hylsulfonyl)phenyl)thiophen-2-yl)-1H-pyrazole) (3.08g, 6.185mmoi) in a mixture of THF-H2O (6:1, 7OmL), and the resulting mixture was stirred at rt under N2 for 8d. The solvent was removed in vacuo, and the residue was partitioned between water and EtOAc. The two phases were separated, and the aqueous phase was extracted with EtOAc. The combined extracts were washed with brine, dried over Na2SO4, and evaporated in vacuo. The crude product was purified by flash chromatography (0-60% 20%MeOH/DCM) to give the title compound as a light-yellow solid (2.43g, 89%). 1HNMR (CDCl3): δ 8.04 (m, IH), 7.83-7.80 (m, IH), 7.73-7.71 (m, IH), 7.56-7.41 (m, 5H), 7.19 9d, IH), 6.72 9d, IH), 6.63 (s, IH), 3.07 (s, 3H), 2.43 (brs, 2H), 1.61 (s, 6H). MS(ES) 455 (M-NH2).
Example 36
Preparation ofl-(2-chlorophenyl)-3-(l-metlψl-l-pytΥolidin-l-ylet}ψl)-5-{5-[3-(methylsu^^ 2-thienyl}-lH-pyi'azole
Figure imgf000194_0001
A mixture of the 2-[l-(2-chlorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-ihienyl}-1H- pyrazol-3-yl]propan-2-amine (142mg, 0.3mmol), K2CO3 (83mg, 0.6mmol), 1,4-dibromobutane (O.lmL, 0.7mmol) and anhydrous EtOH was stirred at 10O0C in a sealed vial for 18h. The solvent was removed in vacuo, and the residue was purified by flash chromatography (0-40% 20% MeOH/DCM) to give the title compound as a pale-yellow solid. 1HNMR (CDCl3): δ 8.03 (m, IH), 7.86-7.83 (m, IH), 7.74-7.71 (m, IH), 7.61-7.47 (m, 5H), 7.23 (d, IH), 6.93 (s, IH), 6.83 (d, IH), 3.68 (m, 2H), 3.08 (s, 3H), 2.17 (m, 2H), 2.04 (s, 6H), 1.83 (m, 2H). MS(ES): 526 [M+H]+. The following compound is prepared essentially according to the previous examples: 4-{l-[l<2-cHorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}-1H-pyrazol-3-yl]-l- methylethyl}morpholine, MS(ES): 542 |M+H]+
Example 37
Prepω-ation of 2-[l-(2-chlorophenyl)-5-{5-[3-(methylmlfonyl)pheny^ N,N-dimethylpropan-2-amine
Figure imgf000194_0002
37% HCHO (80mg, 0.986mmol) was added to a solution of 2-[l-(2-chlorophenyl)-5-{5-[3-
(methylsulfonyl)phenyl]-2-tMenyl}-1H-pyra2»l-3-yl]propan-2-arnine (182mg, 0.3872mmol) in formic acid (2mL), and the mixture was stirred at 95 C in a sealed vial overnight. The reaction mixture was basifled with aqueous NaOH (2N)5 and then extracted with DCM. The combined extracts were washed with brine, dried over Na2SO4, and evaporated in vacuo. The residue was purified by flash chromatography (0-70% 20%MeOH/DCM) to give the title compound as a pale-yellow solid (62mg, 32%). 1HNMR (CDCl3): δ 8.03 (m, IH), 7.82 (m, IH), 7.71 (m, IH), 7.57-7.42 (m, 5H), 7.20 (d, IH), 6.76 (m, 2H), 3.07 (s, 3H), 2.33 (brs, 6H), 1.57 (brs, 6H). Scheme 19
Figure imgf000195_0001
Figure imgf000195_0002
As depicted in Scheme 19, pyrazole-methyl bromide can be converted to the corresponding pyrazole-arnides. Bromide 019XGU01 was converted to the cyanide 019XGU02 by reacting with sodium cyanide. The cyanide was hydrolyzed to afford ester 019XGU03, which was converted to the corresponding amides by treatment with the amine in the presence of the corresponding ammonium chloride.
Example 38
Prepω'ationof[l-(2-chloropheιψl)-5-{5~[3-(imtlψlmlforiyl)phe^ yljacetonitrile
Figure imgf000195_0003
A mixture of the 3-bromomethyl-l-(2-chlorophenyl)-5-{5-[3-(methylsulfonyl)ρhenyl]-thiphen- 2-yl]-1H-pyrazole (720mg, 1.42mmol), NaCN (250mg, 5.1mmol), and DMSO (1OmL) was stirred in a sealed vial at 10O0C for 5h, diluted with water, and extracted with EtOAc. The combined extracts were washed with water, brine, dried over Na^SO4, and evaporated in vacuo. The crude product was purified by flash chromatography (0-80% EtOAc/hexanes) to give the title compound as a white solid (35Orøg, 54%). 2HNMR (CDCl3): δ 8.03 (d, IH), 7.84 (m, IH), 7.72 (m, IH)5 7.58-7.44 (m, 5H), 7.22 (d, IH), 6.79 (d, IH), 6.73 (s, IH), 3.87 (s, 2H), 3.09 (s, 3H). MS(ES): 454 (M+H]+.
Example 39
PreparcMon ofMetJi^l[l-(2-chhropheψl)-5-{5-[3-(methylsulfoψ acetate
Figure imgf000195_0004
Concentrated H2SO4 (4mL) was added dropwise at O0C to a stirred solution of the [l-(2- cUorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}-1H-pyrazol-3-yl]acetonitrile (148mg,
0.33mmol) in a mixture Of MeOH-H2O (10:1, HmL), and the resulting mixture was stirred at 900C overnight The mixture was diluted with cold water, then basifled with Na2CO3 solid, extracted with EtOAc. The combined extracts were washed with brine, dried over Na2SO4, and evaporated in vacuo.
The crude product was purified by flash chromatography (0-40% 20%MeOH/DCM) to afford the title compound as a white solid (131mg, 82%). 1HNMR (CDCl3): δ 8.04 (m, IH), 7.83-7.81 (m, IH), 7.73-
7.71 (m, IH), 7.57-7.41 (m, 5H), 7.20 (d, IH), 6.75 (d, IH), 6.69 9s, IH), 3.82 9s, 2H), 3.79 (s, 3H),
3.08 (s, 3H). MS(ES): 487 |M+HJ+. Example 40 frepω"ation of2-[l-(2-chlorophenyl)-5-{5-[3-(metliylsulforyl)pherψ^ ethylacetamide
Figure imgf000196_0001
A mixture of the methyl [l-(2-chlorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}-1H- pyrazol-3-yl] acetate (lOOmg, 0.2mmol), EtNH2 (2.0M in THF, 5mL) and ethylamine hydrochloride
(200mg) was stirred at 700C in a sealed vial for 8h. The solvent was removed in vacuo, another
EtNH2/THF (2.0M, 5mL) was added, the mixture was stirred at 780C for another 24h. Another 3mL of
EtNH2ATHF was added, and the mixture was stirred at 780C for another 2Oh. The solvent was removed in vacuo, and the crude product was purified by flash chromatography (0-30% 20%MeOH/DCM) to give the title compound as a white solid (85mg, 83%). 1HNMR (CDCl3): δ 8.04 (m, IH), 7.84-7.82 (m,
IH), 7.74-7.71 (m, lH),7.60-7.46 (m, 5H), 7.21 (d, IH), 6.78 (d, IH), 6.61 (s, IH), 6.45 (brs, IH), 3.69
(s, 2H), 3.30 (q, 2H), 3.07 (s, 3H), 1.14 (t, 3H). MS(ES): 500 [M+H]+.
Scheme 20
Figure imgf000197_0001
As depicted in Scheme 20, nilriles can be transformed into tetrazoles, esters and amides. The cyanide 020XGU01 was alkylated to give 020XGU02, which was reduced with DD3AL-H to give the primary 020XGU03. 020XGU04 was obtained by formylation of the primary amine 020XGU03 with HCO2Et Treatment of the cyanide 020XGU01 with NaN3 and NH4Cl gave the tetrazole 020XGU06. 020XGU02 was hydrolyzed to give the ester 020XGU05.
Example 41
Prepω-ationof5~{[l~(2~chlompJieiψl)-5-{5-[3~(inethyl$ulfoψl)pheryl]-2~t^^ yl]methyl}~lH-tetrθ2θle
Figure imgf000197_0002
A mixture of [l-(2-chlorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-fcienyl}-1H-pyrazol-3- yljacetonitrile (136mg, 0.3mmol), NaN3 (59mg, 0.9mmol), NH4Cl (49mg, 0.9mmol), and anhydrous DMF (5mL) was stirred in a sealed vial at 1200C for 24h. The mixture was poured into water, and extracted with DCM. The combined extracts were washed with water and brine, dried over Na^SO4, and evaporated in vacuo. The crude product was purified by flash chromatography (0-80% 20% MeOH/DCM) to give the title compound as a white solid (116mg, 78%). 1HNMR (CDCl3): δ 8.04 (m, IH), 7.85-7.83 (m, IH)5 7.74-7.71 (m, IH)5 7.62-7.46 (m, 5H), 7.22 (d, IH), 6.8 (d, IH), 6.66 (s, IH), 4.52 (s, 2H), 3.08 (s, 3H). MS(ES): 497 [M+H]+. Example 42
Preparation of '2-[l-(2-chlorophenyl)-5-{5-[3-(methylmlfo}τyl)phe}^ methyl propamnitrile and 2-[l-(2-chlorophenyl)-5-{5-[3-(ety
3-yl]-2-meβψlpropanenitrile
Figure imgf000198_0001
NaH (60% in mineral oil, 120mg, 3mmol) was added at O0C to a stirred solution of the [l-(2- cMorophenyl)-5-{5-[3-(methylsulfonyl)ph lmmol) and MeI (160μL, 2.56mmol) in anhydrous DMF (15mL) under N2. The reaction mixture was allowed to warm to rt and stirred at rt for 4h. The reaction mixture was quenched with aqueous NH4Cl solution, and extracted with EtOAc. The combined extracts were washed with water and brine, dried over Na2SO4, and evaporated in vacuo. The crude product was purified first by flash chromatography (0-70% EtOAc/hexanes), again by preparative HPLC (normal phase) to give the two title compounds as white solid. (236mg, 49%). 1HNMR (CDCl3): δ 8.04 (m, IH), 7.84-7.82 (m, IH), 7.74-7.71 (no, IH), 7.58-7.43 (m, 5H), 7.21 (d, IH), 6.77 (d, IH), 6.72 (s, IH), 3.07 (s, 3H), 1.83 (s, 6H). MS(ES): 482 [M+H]+. (227mg, 46%). 1HNMR (CDCl3): δ 8.00 (m, IH), 7.80-7.78 (m, IH), 7.73-7.71 (m, IH), 7.57-7.45 (m, 5H), 7.21 (d, IH), 6.76 (d, IH), 6.71 (s, IH), 3.13 (q, 2H), 1.83 (s, 6H), 1.30 (t, 3H). MS(ES): 496 [M+H]+.
Example 43 Preparation of 'l-[l-(2-chlorophenyl)-5-{5-[3-(methylmlfonyl)phenyl]-24hiefψl}-lH-pyi'azol-3- yljcyclopropanecarbonitrile
Figure imgf000198_0002
1,2-dibromoethane (40 μL 0.46 mmol) was added to a stirred suspension of the [l-(2- clTloropheny^-S-IS-P^methylsulfony^phenyy^-tWenylj-1H-pyrazDl-S-yljacetonitrile (68mg, 0.15mmol), benzyltriethylammonium chloride (20mg, 0.088mmol), and 50% aqueous NaOH (2mL) at O0C, the resulting mixture was stirred at rt overnight After diluted with water, the mixture was extracted with ether. The combined extracts were washed with brine, dried over Na2SO4, and evaporated in vacuo. The crude product was purified by flash chromatography (0-70% EtOAc/hexanes) to give the title compound as a white solid (59mg, 82%). 1HNMR (CDCl3): δ 8.04 (m, IH), 7.84-7.82 (m, IH), 7.74-7.71 (m, lH),7.58-7.43 (m, 5H), 7.21 (d, IH), 6.79-6.77 (m, 2H), 3.07 9s, 3H), 1.73-1.68 (m, 4H). MS(ES): 480 [M+H]+.
The following compounds are prepared essentially according to the previous examples: • l-[l<2-chlorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}-1H-pyrazol-3- yl]cyclopeantanecarbonitrile MS(ES): 508 [M+H]+
Example 44
Prepω-ation of2-[l-(2-chlorophenyl)-5-{5-[3-(metlψlsulfonyl)phenyl]-2-thieψ^ methylpropan-1-amine
Figure imgf000199_0001
DIBAL-H (1.0M in hexanes, 1.5mL, 1.5mmol) was added dropwise at -780C to a stirred solution of 2-[l-(2-chlorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}-1H-pyrazol-3-yl]-2-methyl propanenitrile (210mg, 0.436mmol) in dry DCM (1OmL) under N2, the resulting mixture was stirred at - 780C for 3h. At -780C 10% aqueous Rochelle's salt solution was added dropwise to quench the reaction, the mixture was allowed to warm to rt, and extracted with DCM. The combined extracts were washed with brine, dried over Na2SO4, and evaporated in vacuo. The crude product was purified by flash chromatography (0-60% 20% MeOH/DCM) to give the title compound as a white solid (160mg, 76%). 1HNMR(CDCl3): δ 8.04 (m, IH), 7.83-7.80 (m, IH), 7.74-7.71 (m, IH), 151-1 Al (m, 5H), 7.20 (d, IH), 6.71 (d, IH), 6.52 (s, IHO, 3.07 (s, 3H), 2.90 (s, 2H), 2.17 (brs, 2H), 1.39 (s, 6H). MS(ES): 486 [M+H]+. Example 45
Prepω-ation ofN-{2-[l-(2-chlorophenyl)-5-{5-[3-(methylsulfoψl)pheψlJ-2-thierψl}-lH-
2-methylpropyl}formamide
A mixture of 2-[l-(2-chlorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}-1H-pyrazol-3- yl]-2-methylpropan-l-amine (82mg, 0.1687mmol) and HCO2Et (1.5mL) was stirred at 750C in a sealed vial overnight The solvent was removed in vacuo, and the residue was purified by flash chromatography (0-40% 20%MeOH/DCM) to give the title compound as a white solid (72mg, 83%).
1HNMR (CDCl3): δ 8.21 (s, IH), 8.04 (m, IH), 7.84-7.80 (m, IH), 7.74-7.71 (m, IH), 7.57-7.42 (m, 5H), 7.21 (d, IH), 6.73 (d, IH), 6.53 (s, IH), 6.50 (brs, IH), 3.56 (d, 2H), 3.07 (s, 3H), 1.40 (s, 6H). MS(ES): 514 [M+H]+.
The following compounds are prepared essentially according to the previous examples: • N-{l-[l-(2-chlorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}-1H-pyrazol-3-yl]-l- methylethyl}formamide, MS(ES): 500 [M+H]+
Example 46 PrepωΛation of4-{[l-(2-chlorophenyl)-5-{5-[3-(methylmlfonyl)p yl]methyl}morpholine
Figure imgf000200_0001
NaH (60% in mineral oil, 40mg, lmmol) was added to a stirred mixture of the bromide
(102mg, 0.2mmol), 4-(2-hydroxyethyl)morpholine (40μL, 0.3mmol) and anhydrous DMF (1OmL) at O0C under N2. The mixture was stirred at rt overnight, and the solvent was removed in vacuo. The residue was dissolved in EtOAc, washed with water and brine, dried over Na2SO4, and evaporated in vacuo. The crude product was purified first by flash chromatography (0-15% MeOH/DCM), again by reverse phase preparative HPLC to give the title compound as a white solid (58mg, 52%). 1HNMR (CDCl3): δ 8.04 (m, IH), 7.83-7.81 (m, IH), 7.74-7.72 (m, IH), 7.57-7.44 (m, 5H), 7.21 (d, IH), 6.75 (d, IH), 6.71 (s, IH), 4.66 (s, 2H), 3.75-3.70 (m, 6H), 3.08 (s, 3H), 2.66 (m, 2H), 2.52 (m, 4H). MS(ES): 558 [M+H]+. The following compound is prepared essentially according to the previous examples: • N-{[l-(2-chlorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}-1H-pyrazol-3-yl]methyl}- 2-morpholin-4-ylethanamine, MS(ES): 557 [M+Hf
Scheme 21
Figure imgf000201_0001
As depicted in Scheme 21, alcohol 021XG01 can be transformed into the corresponding ethers and esters containing amino groups. Alcohol 021XGU01 was converted to 021XGU02 by alkylation with alkyl halides. Ester 021XGU03 was obtained by acylation of 021XGU01 with bromoacetyl bromide. Replacement of the bromide with amines afforded 021XGU04.
Example 47
Prepω~ationof[l-(2-chhropherψl)-5-{5-[3-(methylsulfoιψl)phenyl]-24hie morpJτolin-4-ylacetate
Figure imgf000201_0002
JPr2NEt (0.8mL, 4.6mmol) was added at O0C to a stirred solution of [l-(2-chlorophenyl)-5-{5-
[3-(methylsulfonyl)phenyl]-2-thienyl}-1H-pyrazol-3-yl]methanol (450mg, lmmol) in dry DCM (1OmL) under N2 followed by bromoacetyl bromide (0.2mL, 2.3mmol), the resulting dark mixture was stirred at rt overnight under N2. The mixture was diluted with DCM, washed with water, dried over Na2SO4, and evaporated in vacuo. The residue was purified by flash chromatography (0-80% EtOAc/hexanes) to give the ester as a pale-yellow solid (465mg, 82%). A mixture of the ester (114mg, 0.2mmol), K2CO3 (90mg, O.βmmol), morpholine (O.lmL), and anhydrous MeCN (5mL) was stirred in a sealed vial at 600C overnight The solvent was removed in vacuo, and the residue was purified by flash chromatography (0-100% EtOAc/hexanes) to give the title compound as a white solid (82mg, 72%). 1HNMR (CDCl3): δ 8.04 (m, IH), 7.83-7.81 (m, 1H),7.74-7.71 (m, IH), 7.58-7.44 (m, 5H), 7.21 (d, IH), 6.76 (d, IH), 6.71 (s, IH), 5.27 (s, 2H), 3.77 (t, 4H), 3.32 (d, 2H), 3.08 (s, 3H), 2.63 (t, 4H). MS(ES): 572 [M+H]+.
The following compound is prepared essentially according to the previous examples: • l-(2-chlorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-iMenyl}-1H-pyrazol-3-yl]methyl (4- methylpiperazin-l-yl)acetate, MS(ES): 585 βVl+H]+
Example 48
Preparation of '2-[({[l-(2-chloropherψl)-5-{5-[3-(metlψlmlfonyl)phωτyl]-24hienyl}-lH-^ yl]metJτyl}oxy)methyl]pyridine
Figure imgf000202_0001
NaH (60% in mineral oil, 90mg, 2.25mmol) was added at O0C to a stirred mixture of [l-(2- chlorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}-1H-pyrazol-3-yl]methanol (222mg,
0.5mmol), 2-(bromomethyl)pyridine hydrobromide (190mg, 0.75mmol), and anhydrous DMF (5mL) under N2, the resulting mixture was stirred at rt for 4h. The reaction mixture was poured into ice-water, and extracted with EtOAc. The combined extracts were washed with brine, dried over Na2SO4, and evaporated in vacuo. The crude product was purified by flash chromatography (0-100% EtOAc/hexanes) to give the title compound as a colorless semi-solid (179mg, 67%).1HNMR (CDCl3): δ 8.58 (m, IH), 8.04 (m, IH), 7.82 (m, IH), 7.74-7.71 (m, 2H), 7.57-7.44 (m, 6H), 7.20 (m, 2H), 6.76 (m, 2H), 4.78 (m, 4H), 3.08 (s, 3H). MS(ES): 536 [M+H]+.
The following compound is prepared essentially according to the previous examples: • l^-chlorophenyO-S-IS-P-^emylsulfony^phenyy^-thienyO-S-KJP-^uoromethyl) furan-
2-yl]methyl}oxy)methyl]-1H-pyrazole, MS(ES): 593 [M+H]+
Example 50
Preparation of l-(2-chloroφheψl)-5-[5-(3-metham$ιdfoψlφheψl)4hiophen-2-yl]-lH^ carboxylic acid
Figure imgf000202_0002
Aqueous NaOH solution (2N, 8OmL) was added to a suspension of l-(2-chloro-phenyl)-5-[5- (3-methanesulfonyl-phenyl)-thiophen-2-yl]-1H-pyrazole-3-carboxylic acid methyl ester (5g, 10.57mmol) in MeOH (8OmL), and the resulting mixture was stirred at reflux for 1Oh. The volatiles was removed in vacuo, the residual solution was acidified with aqueous HCl (6N) to pH 2, extracted with EtOAc. The combined extracts were washed with water and brine, dried over Na2SO4, and evaporated in vacuo. The crude product was recrystallized from DCM/hexane to give the title compound as a white solid (4.1g, 860Zo)-1H-NMR (DMSO-de): δ 12.73 (s, IH), 7.98 (m, IH), 7.83 (m, 2H), 7.77 (m, 2H), 7.71 (m, IH), 7.67 (d, IH), 7.62 (m, 2H), 7.34 (s, IH), 7.19 (s, IH), 3.26 (s, 3H). MS(ES): 459 [M+H]+.
The following compounds are prepared essentially according to the previous examples: • 2-[l-(2-cMorophenyl)-5-{5-[3-(ethylsιilfonyl)phenyl]-2-tiτienyl}-1H-pyrazol-3-yl]-2- methylpropanoic acid, MS(ES): 501 P+H]+
Scheme 21A
Figure imgf000203_0001
As depicted in Scheme 2 IA, a-ring benzyl pyrazoles was synthesized. Aldehyde 022XGU01 reacted with tert-butyl carbazate to give 022XGU02, which was reduced with diborane to give benzylhydrazine 022XGU03. Treatment of the benzylhydrazine with a diketone ester gave pyrazole
022XGU04 in high yield. Suzuki coupling of 022XGU04 with a boronic acid afforded 022XGU05, which was converted to the carbinol 022XGU06 by treatment with methylmagnesium chloride.
Example 51 Prepω"ationof2-{l-[(2,3-dichloropherψl)metlψl]-5-[3-methyl-3'-(tnethylsulfo^ pyrazol-3-yl}propan-2-ol
Figure imgf000204_0001
Figure imgf000204_0002
2-{l-[(2,3-dichlorophenyl)methyl]-5-[3-methyl-3'-(methylsulfonyl)biphenyl-4-yl]-1H-pyrazol- 3-yl}propan-2-ol was prepared in a manner similar to that as described in Example 8 using the appropriate benzylhydrazine hydrochloride prepared by the reported procedure (Ghali, NJ. et al J. Org. Chem. 1981,46, 5413-5414.) 1HNMR(CDCl3): δ 8.16 (m, IH), 7.93 (m, IH), 7.87 (m, IH), 7.66 (t, IH), 7.51 (m, IH), 7.41-7.34 (m, 2H), 7.17-7.10 (m, 2H), 6.57 (m, IH), 6.28 (s, IH), 5.25 (s, 2H), 3.10 (s, 3H), 2.68 (s, IH), 2.23 (s, 3H), 1.66 (s, 6H). MS(ES): 529 [M+H]+, 511 (M-OH) The following compounds are prepared essentially according to the previous examples:
• 2-{l-[(2,3-dichlorophenyl)methyl]-5-[3Hmethylsulfonyl)biphenyl-4-yl]-1H-pyrazol-3- yl}propan-2-ol, MS(ES): 515 [M+H]+, 497 (M-OH)
• 2-{5-[3-cUoro-3'-(mefeylsulfonyl)biphenyl4-yl]-l-[(2,3-dicUorophenyl)mefliyl]-1H-pyrazol- 3-yl}propan-2-ol, MS(ES): 549 [M+H]+, 531 (M-OH) • 2-{ l-[(4-cUorophenyl)memyl]-5-[3-methyl-3'-(methylsuhconyl)biphenyl-4-yl]-1H-pyrazol-3- yl}propan-2-ol, MS(ES): 495 [M+H]+,
• 5-(5-{l-[(2,4-difluorophenyl)methyl]-3-(1rffluoromethyl)-1H-pyrazol-5-yl}-2-thienyl)-3- methyl-2-(methylsulfonyl)pyridine; 514.2 [M+H]+
Scheme 21B
Figure imgf000205_0001
As depicted in Scheme 21B, pyrazoles can be prepared via an enamine intermediate. Most aryl- methyl-ketones will react with a reagent such as Bredereck's reagent or ΛζN-dimethylformamide diethyl acetal to form an eneamine. Under mild conditions, such eneamines react with arylhydrazines to regioselectively afford a single pyrazole isomer.
Example 52 Preparationofl-(2,5-Dichloro-phenyl)-5-[5-β-methmnmlfonyl-phenyl)4h^
Figure imgf000205_0002
Into a 100 mL flask was weighed 1.34 g of l-[5-(3- Methanesulfonyl-phenyl)-thiophen-2-yl]- ethanone, 13 mL of DMF, and 988 μL (1.2 eq) of ΛζN-dimethylformamide diethyl acetal. The reaction was heated at ~800C for 18 h then was washed into a separatory funnel with ethyl acetate and water. The resulting precipitate was collected by filtration and was dried under high vacuum affording the eneamine product as a yellow powder, yield: 127 g (79%). 1H^MR (400MHz5DMSO-^ a 8.30(s, IH), 8.17(d, J= 8 Hz, IH), 7.99(d, J= 8 Hz, lH), 7.94(d,J=4Hz, lH), 7.75-7.85(m, 3H), 5.93(d,J= 12 Hz, IH), 3.43(s, 3H), 3.41(s, 3H), 3.04(s, 3H).
Into a 50 mL flask was weighed 105.7 mg of eneamine, 97.0 mg of 2,5- dichlorophenylhydrazine hydrochloride, 1 mL of DMF and 1 mL of acetic acid. The resulting solution was heated at 95-1000C for 20 h then was washed into a separatory funnel with ethyl acetate and water. The ethyl acetate was separated, washed with brine, was dried (MgSO4), and concentrated in vacuo. The residue was purified by silica gel flash chromatography (Jones Flashmaster, 20 g SiO2, gradient from 20% ethyl acetate to 50% ethyl acetate-hexanes over 30 minutes). Appropriate fractions were combined and concentrated in vacuo affording the product as a colorless powder, yield: 115 mg (81%). 1H-NMR (400MHz, CDCl3): δ 8.07 (IH, m), 7.84 (IH, m), 7.78 (IH, d), 7.75 (IH, m), 7.60-7.53 (2H, m), 7.49-7.46 (2H, m), 7.24 (IH, d), 6.79 (IH, d), 6.67 (IH, d), 3.08 (3H, s). MS (ES): 451 |M+H]+. Example 53
Preparation of '4-{5-[l-(2,5-dichloropheψl)-3-(trifluoromethyl)-lH-pyrazol-5-ylJ-2-thienyl}-2-
(methylsulfo}iyl)benzoic acid
Figure imgf000206_0001
a) EDCI, DMAP, EtOH, CH2Cl2, 450C; b) NaSMe, THF, 800C; c) MCPBA, CH2Cl2, 250C; d)
Bis(pinacolato)diboron, Pd(dppf), KOAc, DMSO, 850C; e) (Ph3P)4Pd, v where R1 = 2,5-Cl, Na2CO3, THF-water, 800C; f) LiOH, THF-MeOH-H20, 250C.
Into a 1 L flask was weighed 24.66 g (113 mmol) of acid, 26.5 g (138 mmol) of EDCI, 1.7 g of DMAP, 425 mL of dichloromethane, and 25 mL of ethanol. The resulting solution was heated at 40-45 0C for 24 h then was concentrated in vacuo to remove dichloromethane. The residue was washed into a separatory funnel with ethyl acetate and 1 M HCl. The ethyl acetate was separated, washed with brine, was dried (Na2SO4) and was concentrated in vacuo. The intermediate 4-Bromo-2-fluoro-benzoic acid ethyl ester was recovered as a colorless oil, yield: 24.99 g (89.8%).
The ester was treated with 12.2 g of sodium thiomethoxide and 200 mL of THF and the resulting suspension was heated at 80-850C for 5 h. The reaction was then concentrated to remove THF and was washed into a separatory funnel with ethyl acetate and 1 M HCl. The ethyl acetate was separated, washed with brine, was dried (Na2SO4), and concentrated in vacuo affording the intermediate 4-Bromo-2-methylsulfanyl-benzoic acid ethyl ester as a light gray solid, yield: 27.5 g (99%). 1H NMR (400MHz, CDCl3): δ 7.86(d, J= 8 Hz, IH), 7.36(s, IH), 7.28(d, J= 8 Hz, IH), 4.38(q, J= 7 Hz, 2H), 2.45(s, 3H), 1.39(t, J= 7 Hz, 3H).
Into a 1 L flask was weighed 15.0 g of 4-Bromo-2-methylsulfanyl-benzoic acid ethyl ester (54.5 mmol), 200 mL of dichloromethane, and 28.0 g of MCPBA (77% max., Aldrich) was added portionwise at room temperature. The resulting suspension was stirred at room temperature for three days then was concentrated in vacuo to remove dichloromethane. The residue was washed into a separatory funnel with ethyl acetate and 1.0 M NaOH. The ethyl acetate was separated, washed with brine, was dried (Na2SO4), and concentrated in vacuo. The intermediate 4-Bromo-2-meUianesulfbnyl- benzoic acid ethyl ester was recovered as a colorless oil which crystallized on standing, yield: 16.3 g (97%). 1H NMR (400MHz, CDCl3): δ 8.27(s, IH), 7.82(d, J= 8 Hz, IH), 7.60(d, J= 8 Hz, IH), 4.44(q, J= 7 Hz, 2H), 3.38(s, 3H), 1.41(t, J= 7 Hz, 3H). The 4-Bromo-2-methanesulfonyl-benzoic acid ethyl ester (16.3 g, 53 mmol) was weighed into a flask with 21 g of bis(pinacolato)diboron, 19 g of potassium acetate, 5 g of dichloro[l,l'- bis(diphenylphosphino)ferrocene]palladium (D) dicloromethane adduct, and 150 niL of DMSO. The resulting suspension was heated at 80-850C for 20 h then was diluted with 200 mL of water, 200 mL of ethyl acetate, and the reaction mixture was filtered through celite to remove solids. The filtrate was transferred to a separatory funnel and the aqueous phase was separated and washed with ethyl acetate. The ethyl acetate washings were combined, washed with brine, were dried (Na2SO4) and concentrated in vacuo. The residue was purified by silica gel flash chromatography (Biotage, 65 x 200 mm SiO2, gradient elution from 100% hexanes to 40% ethyl acetate over 1 h). Appropriate fractions were combined and concentrated in vacuo affording the 2-Methanesulfonyl-4-(4,4,5,5-tetramethyl-
[l,3,2]dioxaborolan-2-yl)-benzoic acid ethyl ester as a colorless solid, yield: 12.65 g (67%). 1H-NMR (400MHz, CDCl3): δ 8.52(s, IH), 8.08(d, J= 8 Hz, IH), 7.65(d, J== 8 Hz, IH), 4.45(q, J= 7 Hz, 2H), 333(s, 3H), 1.42(t,J= 7 Hz, 3H), 1.35(s, 12H).
Into a 100 mL flask was weighed 865 mg (1.96 mmol) of bromide v (where R1 = 2,5-Cl), 693.5 mg (1.96 mmol) of boronate, and 20 mL of THF. The resulting solution was heated at 80-850C and ~ 250 mg of tetrakistriphenylphosphine palladium (0) was added followed by 2.0 mL of 1.0 M Na2CO3. The reaction was maintained at 80-85 0C for 3 h then was concentrated to remove THF. The residue was washed into a separatory funnel with ethyl acetate and 1.0 M sodium carbonate. The ethyl acetate was separated, washed with brine, was dried (Na2SO4), and concentrated in vacuo. Crude product was purified by silica gel flash chromatography (Jones Flashmaster, 50 g SiO2, gradient elution from 100% hexanes to 40% ethyl acetate over 30 minutes). Appropriate fractions were combined and concentrated in vacuo affording the intermediate ethyl 4-{5-[l-(2,5-dichlorophenyl)-3-(trifluoromethyl)-1H-pyrazol- 5-yl]-2-thienyl}-2(methylsulfonyl)benzoate as a colorless powder, yield: 256.4 mg (22.2%); MS (ES): 589 and 591 [each M+H]+. Into a 50 mL flask was weighed 120.2 mg of ester, 1 mL of THF, and 1 mL of methanol. To the solution was added 204 μL of a 3.0 M LiOH solution. The reaction was stirred at room temperature for 3 h then was washed into a separatory funnel with ethyl acetate and 1 M HCl. The ethyl acetate was separated, washed with brine, was dried (Na2SO4), and concentrated in vacuo. The crude acid was purified by reverse-phase HPLC to afford 4-{5-[l-(2,5-dichlorophenyl)-3-(trifluoromethyl)-1H-pyrazol- 5-yl]-2-tMenyl}-2-(methylsulfonyl)benzoic acid as a colorless powder, yield 43.0 mg (38%); 1H-NMR (400MHz, DMSCMy): δ 8.20(s, IH), 8.09(s, IH), 7.98(4 J= 8 Hz, IH), 7.86(m, 2H), 7.81(d, J= 8 Hz, IH), 7.74(d, J= 4 Hz, IH), 7.58(s, IH)57.32(4 J= 4 Hz, IH), 3.46(s, 3H); MS (ES): 561 and 563 IM+H]+. The following compounds are prepared essentially according to the previous examples:
• 3-{5-[5-(3-Me1hanesulfonyl-phenyl)-tMophen-2-yl]-3-trifluoromethyl-pyrazol-l-yl}-thiophene- 2-carboxylic acid. 1H-NMR (400MHz, CDCl3): δ 8.05 (IH, m), 7.88-7.81 (IH, m), 7.77-7.69 (2H, m), 7.57 (IH, m), 7.26-7.22 (2H, m), 6.89 (IH, d), 6.86 (IH, s), 3.08 (3H, s). MS (ES): 499 IM+Hf.
• 2-(3-{5-[l-(2,5-dichlorophenyl)-3-(trMuorometiiyl)-1H-pyrazol-5-yl]-2-thienyl}phenyl)-2- methylpropanoic acid. 1H-NMR (400MHz, CDCl3): δ 7.59 (IH, d), 7.53 (IH, m), 7.51-7.43 (2H, m), 7.42-7.32 (3H, m), 7.14 (IH5 d), 6.87 (IH, s), 6.80 (IH, d), 1.62 (6H, s). MS (ES): 525 [M+H]+. • Ethyl 3-{5-[l-(2,5-dichlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-2-thienyl}-5-
(methylsulfonyl)benzoate; MS (ES): 589 and 591 [eachM+H]+.
Example 54
Prepω"ationofl-[5-Chloro-2-(4φmroή3hemxy)-phe}τyl]-5-[5-(3w yl]-3-trifiuorometlτyl-lH-pyrazole
Figure imgf000208_0001
a) 4-F-phenylboronic acid, Cu(OAc)2, '(Pr)2EtN, CH2Cl2, 250C.
4-CUoro-2-{5-[5-(3-me1hanesulfonyl-phenyl)-iMophen-2-yl]-3-trifluoromethyl-pyrazol-l-yl}- phenol was prepared as described in Example 1. Into a 50 mL flask was weighed 194 mg (388 μmol) of phenol, 159 mg of copper (D) acetate, 113.8 mg of 4-fluoroboronic acid, -50 mg of activated 4 angstrom molecular sieves, 4 mL of dichloromethane, and 500 μL of diisopropylethylamine. The resulting suspension was stirred at room temperature for 21 h then was poured into a separatory funnel with ethyl acetate and 1 M NaOH. The ethyl acetate was separated, washed with brine, was dried (Na2SO4), and concentrated in vacuo. The residue was purified by silica gel flash chromatography (Jones Flashmaster, 50 g SiO2, gradient elution from 100% hexanes to 40% ethyl acetate). Appropriate fractions were combined and concentrated in vacuo affording the product as a colorless solid, yield: 89 mg (39%) . 1H-NMR (400MHz, CDCl3): δ 8.09(s, IH), 7.88(d, J= 8 Hz, IH), 7.76(d, J= 8 Hz, IH), 7.66(d, J= 4 Hz, IH), 7.61(t, J= 8 Hz, IH), 7.40(d, J= 8 Hz, IH), 7.30(d, J= 4 Hz, IH), 6.90(m, 2H), 6.79(d, J= 9 Hz, 2H), 6.64(m, 2H), 3.10(s, 3H); MS (ES): 593 [M+H]+.
Example 55 Preparation of3-{5-[l-(2,5-dichlorophe}τyl)-3-(Mfluoroniethyl)-lH-pyrazol-5-yl]-2- thienyl}benzenesulfonamide.
Figure imgf000209_0001
a) Bis(pinacolato)diboron, Pd(dppf), KOAc, DMSO, 85 ºC; b) (Ph3P)4Pd, 3-Br-
Benzenesulfonamide, Na2CO3, THF-water, 80 ºC.
Into a 100 mL flask was weighed 4.43 g (10.0 mmol) of bromide, 3.14 g of bis(pinacolato)diboron, 3.12 g of potassium acetate, 29 mL of DMSO and 516 mg of dichloro[l,l'- bis(diphenylphosphino)ferrocene]palladium (H) dicloromethane adduct The resulting suspension was heated at 100 ºC for 18 h then was washed into a separatory funnel with ethyl acetate and water. The ethyl acetate was separated, washed with water, brine, was dried (MgSO4), and concentrated in vacuo.
The residue was purified by silica gel flash chromatography (Jones Flashmaster, two 70 g columns, gradient elution from 100% hexanes to 20% ethyl acetate over 40 minutes). Appropriate fractions were combined and concentrated in vacuo to afford the product as an off-white solid mixture of boronic acid and boronate, yield: 1.8 g (-35%).
The crude boronate (601 mg) was weighed into a 50 mL flask with 312 mg of 3- bromosulfonamide and 10 mL of TBDF. The resulting solution was heated at 80-85 ºC and ~50 mg of tetrakistriphenylphosphine palladium (0) was added followed by 1.0 mL of 1.0 M sodium carbonate.
The reaction was maintained at 80-85 ºC for three hours then was cooled and concentrated in vacuo.
The residue was washed into a separatory funnel with ethyl acetate and 1.0 M sodium carbonate. The ethyl acetate was separated, washed with brine, was dried (MgSO4), and concentrated in vacuo. The product was purified by silica gel flash chromatography (Jones Flashmaster, 70 g SiO2, gradient elution from 100% hexanes to 40% ethyl acetate over 30 minutes). Appropriate fractions were combined and concentrated in vacuo affording the product as a faintly yellow powder, yield: 75 mg (11%). 1H-NMR
(400MHz, CDCl3): δ 8.07 (IH, m), 7.84 (IH, m), 7.68 (IH, m), 7.59 (IH, m), 7.56-7.45 (3H, m), 7.22
(lH,d), 6.88 (IH, s), 6.85 (IH, d), 4.98 (2H, s). MS (ES): 518 [M+H]+.
Example 56 Prepω"ation ofN~[(3-{5-[l-(2-chloropheψl)-3-(1riflwromethyl)-^ ihienyl}phenyl)sulfonyl]acetamide
Figure imgf000209_0002
S-IS-P-Cl-CMoro-phenyO-S-trffluoromeliiyl-lH-pyrazol-S-yy-thiophen-l-yl}- benzenesulfonamide was prepared as described in Example 1. Into a 250 mL flask was weighed 209.6 mg (433 μmol) of the sulfonamide and 866 μL of 1.0 M lithium bis(trimethylsilyl)amide. To the solution was added 123 μL of acetic anhydride. The reaction was stirred at room temperature for 1 h then was washed into a separatory funnel with 1.0 M HCl and ethyl acetate. The ethyl acetate was separated, washed with brine, was dried (Na2SO4), and was concentrated in vacuo. The crude product was purified by reverse-phase HPLC affording the product as a colorless powder, yield: 47.0 mg (20%); 1HNMR (400MHz, CDCl3): δ 8.16(s, IH), 7.91(d, J= 8 Hz, IH), 7.66(d, J= 8 Hz, IH), 7.4- 7.6(m, 5H), 7.21(d, J= 4 Hz, IH), 6.89(s, IH), 6.79(d, J= 4 Hz, IH), 2.04(s, 3H); MS (ES): 526 (M+H]+.
The following compounds are prepared essentially according to the previous examples by substituting the appropriate anhydride:
• N-[(3-{5-[l-(2,5-dichlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-2- thienyljpheny^sulfonylj^-dimethylpropanamide; MS (ES): 602 and 604 [each MfH]+. Example 57
Preparation of 2-[4-{5-[l-(2,5-dichlomphenyl)-3~(triflwromethyl)-lH-pyr (methylsύfoiiyl)pheiiyl]propω%-2-ol and [4-{5-[l-(2,5-dicM
5-yl]-2-thtenyl}-2-(nwthylsύfonyl)phenyl]methanol.
Figure imgf000210_0001
a) MeMgBr, THF, 0-25 ºC.
Ethyl 4-{5-[l-(2,5-dichlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-2-thienyl}- 2(methylsulfonyl)benzoate was prepared as described in Example 53. Into a 50 mL flask was weighed 209.4 mg of ester and 2.0 mL of anhydrous THF. The solution was cooled under nitrogen in an ice bath and 1.0 mL of 1.4 M MeMgBr in THF (Aldrich) was added. The reaction was removed from cooling and was stirred at room temperature for 1 h then was quenched by addition of saturated ammonium chloride. The reaction was washed into a separatory funnel with ethyl acetate and saturated ammonium chloride. The ethyl acetate was separated, washed with brine, was dried (Na2SO4), and concentrated in vacuo. The residue was purified by silica gel flash chromatography (Biotage, 25 x 150 mm SiO2, gradient elution from 100% hexanes to 100% ethyl acetate over 45 minutes). Appropriate fractions were combined and concentrated in vacuo affording the product as a cream colored semi-solid, yield: 157.1 mg (77%); 1HNMR (400MHz, CDCl3): δ 8.34(s, IH), 7.65(d, J= 8 Hz, IH), 7.59(s, IH), 7.45- 7.53(m, 3H), 7.26(d, J= 4 Hz, IH), 6.89(s, IH), 6.85(d, J= 4 Hz5 IH), 4.82(br s, IH), 3.43(s, 3H), 1.71(s, 6H);MS (ES): 575 and 577 [eachM+H]+.
The following compounds are prepared essentially according to the previous examples by substituting 3-Bromo-5-fluoro-benzoic acid for 4-Bromo-2-fluoro-benzoic acid: • 2-[3-{5-[l-(2,5-dichlorophenyl)-3^trifluoromethyl)-1H-pyrazol-5-yl]-2-thienyl}-5-
(methylsulfonyl)phenyl]propan-2-ol; MS (ES): 575 and 577 [each M+H]+.
• 2-[3-{5-[l-(2,6-dichlorophenyl)-3-(trMuoromethyl)-1H-pyrazol-5-yl]-2-thienyl}-5- (methylsulfonyl)phenyl]ρropan-2-ol; MS (ES): 575 and 577 [each M+H]+.
• 2-[3-{5-[l-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-2-thienyl}-5- (methylsulfonyl)phenyl]propan-2-ol; MS (ES): 541 [M+H]+.
Example 58
Preparation of [4-{5-[l-(2,5-dichloropheψl)-3-(triflmronwtJφl)-lH-p)razo
(methylsulfonyl)phenyl]methanol.
Figure imgf000211_0001
a) LiBH4, THF, 25 ºC.
Into a 4 mL vial was weighed 102.0 mg of ester and 1.0 mL of anhydrous THF. The resulting solution was cooled in an ice bath and 200 uL of 2.0 M LiBH4 in THF (Aldrich) was added. The reaction was allowed to warm to room temperature where it remained for 3 days. The reaction was then washed into a separatory funnel with ethyl acetate and 1 M HCl. The ethyl acetate was separated, washed with brine, was dried (Na2SO4), and concentrated in vacuo. The crude material was purified by reverse-phase HPLC to afford the product as a colorless solid, yield: 14.0 mg (15%); 1HNMR (400MHz, CDCl3): δ 8.17(s, IH), 7.72(d,J= 8 Hz, IH)57.5-7.6(m, 2H), 7.50(m, 2H), 7.26(s, IH), 6.89(s, IH), 6.85(d, J= 4 Hz, IH), 4.96(s, 2H), 3.20(s, 3H); MS (ES): 547 and 549 [eachM+H]+.
Example 59 Preparation of 4~(2-{[4-{5-[l-(2,5-dichlorophenyl)-3-(Mfluoromethyl)-lH^
(methylsulfonyl)phenyl]oxy}ethyl)morpholine.
Figure imgf000212_0001
a) NaHCO3, Na2SO3, H20, 85 ºC, then Me2SO2, NaHCO3, H20, 120 ºC; b) Bis(pinacolato)diboron, Pd(c(ppf), KOAc, DMSO, 100 ºC. c) (Ph3P)4Pd, 5-(5-Bromothiophen-2-yl)-l-(255-dichloroρhenyl)-3- trifluoromethyl-1H-pyrazole, Na2CO3, THF-water, 80 ºC; d) BBr3, CH2Cl2, 25 ºC; K2CO3, 4-(2- Chloroethyl)moφholine hydrochloride, DMF, 100 ºC.
Into a IL flask was weighed 41.4 g of sodium sulfite, 29 g of sodium bicarbonate, and 175 rriL of water. The suspension was stirred at 80-85 ºC and sulfonyl chloride (50 g) was added portionwise over 3 h. Heating was continued for 3 h then the reaction was allowed to stand at room temperature for 3 days. The intermediate sulfinate was collected by filtration with added water then was dried under high vacuum. The dry solids (45 g) were returned to a 1 L flask along with 28.0 g of sodium bicarbonate, 25 mL of dimethylsulfate, and 63.75 mL of water. The resulting suspension was heated at 120-125 ºC, where it became a solution, for 20 h then was cooled and washed into a separatory funnel with ethyl acetate and water. The ethyl acetate was separated, washed with brine, was dried (Na2SO4), and concentrated in vacuo. The product was precipitated from dichloromethane with hexanes and was dried under high vacuum to afford the intermediate 4-Bromo-2-methanesulfonyl-l-methoxy-benzene as a colorless powder, yield: 31.1 g (67%). 1H NMR (400MHz, CDCl3): δ 8.08(2, lH), 7.69(d,J= 8Hz, IH), 6.96(d, J= 8 Hz3 IH), 4.00(s, 3H), 3.21(ss 3H).
Into a 500 mL flask was weighed 15.48 g (58.4 mmol) of bromide, 23 g of boronate, 21 g of potassium acetate, 5 g of dichloro[l,r-bis(diphenylphosphino)ferrocene]palladium(ir) dicloromethane adduct, and 150 mL of DMSO. The resulting suspension was heated at ~100 ºC for 20 h then was cooled and diluted with 200 mL of ethyl acetate and 200 mL of water. The suspension was filtered through celite to remove solids and the filtrate was transferred to a separatory funnel. The aqueous phase was separated and washed with ethyl acetate. The ethyl acetate washings were combined, washed with brine, were dried (Na2SO4) and concentrated in vacuo. The residue was purified by silica gel flash chromatography (Biotage, 65 x 200 mm SiO2, gradient elution from 100% hexanes to 100% ethyl acetate over 1 h). Appropriate fractions were combined and concentrated in vacuo. The partially purified product was dissolved in ethyl acetate and was precipitated with hexanes. The intermediate 2- (3-Methanesulfonyl-4-methoxy-phenyl)-4,4,5,5-tetramethyl-[l,3,2]dioxaborolane was recovered as a faintly yellow powder, yield: 12.56 g (77%). 1HNMR ^OOMHZ, CDCl3): δ 8.43(s, lH), 8.01(d,J= 8 Hz, IH), 7.03(d, J= 8 Hz, IH), 4.02(s, 3H), 3.20(s, 3H), 1.33(s, 12H).
Into a 250 mL flask was weighed 5.0 g (11.3 mmol) of 5-(5-Bromothiophen-2-yl)-l-(2,5- dichlorophenyl)-3-trifluoromethyl-1H-pyrazole, (4.43 g (14.2 mmol) of boronate, and 100 mL of THF. The resulting solution was heated at 80-85 ºC and ~ 1 g of tetrakistriphenylphosphine palladium (0) was added followed by 10 mL of 1.0 M Na2CO3. The reaction was maintained at 80-85 ºC for 3 h then was concentrated to remove THF. The residue was washed into a separatory funnel with ethyl acetate and 1.0 M sodium carbonate. The ethyl acetate was separated, washed with brine, was dried (Na2SO4), and concentrated in vacuo. Crude product was purified by silica gel flash chromatography (Biotage, 65 x 200 mm SiO2, gradient elution from 100% hexanes to 60% ethyl acetate over 1 h). Appropriate fractions were combined and concentrated in vacuo affording the intermediate methoxy compound as a yellow solid, yield: 2.75 g (44%).
The methoxy compound described, 2.60 g, (4.75 mmol)was weighed into a 250 mL flask along with 75 mL of dichloromethane. The resulting solution was cooled to —70 ºC and 14 mL of 1.0 M BBr3 in dichloromethane was added. The reaction was allowed to warm to room temperature where it remained for 4 h. The reaction was then quenched by addition of methanol and was concentrated in vacuo. The residue was washed into a separatory funnel with ethyl acetate and 1 M HCl. The ethyl acetate was separated, washed with brine, was dried (Na2SO4), and concentrated in vacuo. The residue was purified by silica gel flash chromatography (Biotage, 40 x 150 mm SiO2, gradient elution from 100% hexanes to 60% ethyl acetate over 1 h). Appropriate fractions were combined and concentrated in vacuo affording the intermediate 4-{5-[l-(2,5-dicUorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]- 2-thienyl}-2-(methylsulfonyl)phenol as a colorless solid, yield: 1.39 g (54.9%); MS (ES): 533 and 535 [each MH-H]+. Into a 50 mL flask was weighed 249.2 mg (467 mmol) of phenol, 263 mg of potassium carbonate, 368 mg (1.98 mmol) of 4-(2-Chloroethyl)moφholine hydrochloride, and 3 mL of DMF. The resulting suspension was heated at 100-105 ºC for 30 minutes then was washed into a separatory funnel with ethyl acetate and 1.0 M sodium carbonate. The ethyl acetate was separated, washed with brine, was dried (Na2SO4), and concentrated in vacuo. The residue was purified by silica gel flash chromatography (Biotage, 25 x 150 mm SiO2, gradient elution from 100% dichloromethane to 89:10:1 dichloromethane-methanol-ammonium hydroxide over 45 minutes). Appropriate fractions were combined and concentrated in vacuo then were dissolved in dichloromethane and product was precipitated by addition of hexanes. The precipitate was collected by filtration and was dried affording the product as an off-white solid, yield: 78mg(26%). 1H NMR (400MOHz, CDCl3): δ 8.1 l(s, IH), 7.67(d, J= 8 Hz, IH), 7.59(s, IH), 7.49(m, 2H), 7.12(d, J= 4 Hz, IH), 7.04(d, J= 8 Hz, IH), 6.86(s, IH), 6.81(d, J= 4 Hz, IH), 4.26(t, J= 5 Hz, 2H), 3.70(t, J= 5 Hz, 4H), 3.33(s, 3H), 2.87(t, J= 5 Hz, 2H), 2.58(t, J= 5 Hz, 4H); MS (ES): 646 and 648 [each M+H]+. The following compounds are prepared essentially according to the previous examples by substituting an alkyl halide for 4-(2-Chloroethyl)morpholine hydrochloride:
• 5-(2-{[4-{5-[l-(2,5-dichlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-2-thienyl}-2- (methylsulfonyl)phenyl]oxy}ethyl)-1H-tetrazole; MS (ES): 629 and 631 [eachM+H]+.
• 2-{[4-{5-[l-(2,5-dichlorophenyl)-3-(trMuoromethyl)-1H-pyrazol-5-yl]-2-thienyl}-2- (methylsulfonyl)phenyl]oxy}ethanol; MS (ES): 577 and 579 [each M+H]+.
Scheme 22
Figure imgf000214_0001
Another method used for preparing examples of the invention is shown as Example 60. 4,4,4- Trifluoro- 1 -[5-(3-methanesulfonyl-phenyl)-thiophen-2-yl]-butane- 1 ,3-dione was condensed directly with hydrazine to form pyrazole 3-[5-(3-Methanesuhconyl-phenyl)-thiophen-2-yl]-5-trifluoromethyl-1H- pyrazole. Alkylation of a pyrazole such as 3-[5-(3-Methanesuhconyl-phenyl)-thiophen-2-yl]-5- trifluoromethyl-1H-pyrazole could result in a mixture of positional isomers which could be separated by one skilled in the art Example 60
Figure imgf000214_0002
Preparation of 'l-[(5-chloro-24hieψl)met}ψlJ-3-{5-[3-(met}ψlsulfonyl)pheψlJ-2-thie}τyl}-5-
(trifluoromethyiyiH-pyra∑ole.
Into a 100 mL flask was weighed 5.18 g (13.8 mmol) of 4,4,4-Trifluoro-l-[5-(3- methanesulfonyl-phenyl)-thiophen-2-yl]-butane-l ,3-dione, 50 mL of toluene, and 450 μL (14.3 mmol)of hydrazine. The resulting solution was heated at 100 ºC for 21 h. The reaction was then concentrated in vacuo and was partially purified by silica gel flash chromatography (Jones Flashmaster,
70 g SiO2, gradient elution from 100% hexanes to 20% ethyl acetate over 30 minutes. Appropriate fractions were combined, concentrated in vacuo, and were precipitated from ethyl acetate with hexanes to afford the intermediate 3-[5-(3-Methanesulfonyl-phenyl)-thiophen-2-yl]-5-trifluoromethyl-1H- pyrazole as a faintly yellow, semi-crystalline solid, yield: 1.24 g (24%). 1H NMR (400MHz, CDCl3): δ
8.15(S, IH), 7.86(d, J= 8 Hz, 2H), 7.62(t, J= 8 Hz, IH), 7.45(d, J= 4 Hz, IH), 7.39(d, J= 4 Hz, IH),
6.70(s, IH), 3.12(s, 3H); MS (ES): 373 [M+H]+.
Into an 8 mL vial was weighed 96.6 mg (259 μmol) of pyrazole, 93.5 mg of potassium carbonate, 1 mL of DMF, and 35.6 μL of 2-Chloro-5-chloromethylthiophene. The reaction was heated at 80-85 ºC for 3 h then was washed into a separatory funnel with ethyl acetate and water. The ethyl acetate was separated, was dried (MgSO4), and concentrated in vacuo. HPLC analysis showed the product to be a 1 : 1 mixture of isomers. Each was purified by reverse-phase HPLC purification to afford the products as colorless waxes. l-[(5-chloro-2-tMenyl)methyl]-3-{5-[3-(me%^ lH-pyrazole: 1HNMR (400MHz, CDCl3): δ 8.19(s, IH), 7.86(m, 2H), 7.60(t,J= 8 Hz, IH), 7.39(d,J
= 4 Hz, IH), 7.34(d, J= 4 Hz, IH), 6.86(m, 2H), 6.78(d, J= 4 Hz, IH), 5.47(s, 2H), 3.1 l(s, 3H); MS
(ES): 503 [M+H]+. l-[(5-chloro-2-thienyl)methyl]-5-{5^ lH-pyrazole: 1HNMR (400MHz, CDCl3): δ 8.18(s, IH), 7.88(m, 2H), 7.64(t,J= 8 Hz, IH), 7.44(d,J = 4 Hz, IH), 7.17(d, J= 4 Hz, IH), 6.75(d, J= 4 Hz, IH), 6.71(m, 2H), 5.56(s, 2H), 3.13(s, 3H); MS
(ES): 503 [M+H]+.
The following compounds are prepared essentially according to the previous examples by substituting an appropriate reagent for 2-Chloro-5-chloromethylthiophene.
• 3-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}-l-(2-tMenylcarbonyl)-5-(trifluoromethyl)-1H- pyrazole; 1H-NMR (400MHz, CDCl3): δ 8.43(0.5 H, dd, J= 1,4 Hz), 8.33(0.5 H, dd, J= 1,4
Hz), 8.23(0.5 H, t, J= 1 Hz), 8.18(0.5 H, t, J= 1 Hz), 7.86-7.96(m, 3H), 7.63(1H, q, J= 8 Hz), 7.49(1H, m), 7.44(0.5 H, d, J= 4 Hz), 7.40(0.5 H, d, J= 4 Hz), 7.21-7.28(1H, m), 7.20(0.5 H, s), 6.89(0.5H, s), 3.13(1.5 H, s), 3.11(1.5H, s); MS (ES): 483 [M+H]+.
• 5-{5-[3-(methylsuheonyl)phenyl]-2-thienyl}-l-(2-thienylcarbonyl)-3-(trifluoromethyl)-1H- pyrazole; 1H-NMR (400MHz, CDCl3): δ 8.43(0.5 H, dd, J= 1,4 Hz), 8.33(0.5 H, dd, J= 1,4
Hz), 8.23(0.5 H, t, J= 1 Hz), 8.18(0.5 H, t, J= 1 Hz), 7.86-7.96(m, 3H), 7.63(1H, q, J= 8 Hz), 7.49(1H, m), 7.44(0.5 H, d, J= 4 Hz), 7.40(0.5 H, d, J= 4 Hz), 7.21-7.28(1H, m), 7.20(0.5 H, s), 6.89(0.5H, s), 3.13(1.5 H, s), 3.11(1.5H, s); MS (ES): 483 [M+H]+. 5-{5-[3-(methylsulfonyl)phenyl]-2-tft pyrazole; 1H-NMR (400MHz, CDCl3): δ 8.18 (IH, m), 7.96-7.81 (4H, m), 7.74-7.60 (2H, m), 7.58-7.48 (2H, m), 7.45 (IH, d), 7.40 (IH, d), 6.67 (IH, s), 3.13 (3H, s). MS (ES): 513 |M+H]+.
3-{5-[3-(me&ylsulfonyl)phenyl]-2-ttø^ pyrazole; 1H-NMR (400MHz, CDCl3): δ 8.18(1H, s), 8.14(2H, d, J= 8 Hz), 7.88(2H, d, J= 8 Hz), 7.60(4H, m), 7.38(2H, m), 7.00(1H, s), 3.11(3H, s); MS (ES): 513 [M+Hj+. l-[(2,4-dMuorophenyl)methyl]-5-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}-3- (trifluoromethyl)-1H-pyrazole; 1H-NMR (400MHz, CDCl3): δ 8.14 (IH, m), 7.89 (IH, m), 7.83 (IH, m), 7.63 (IH, t), 7.39 (IH, d), 7.06 (IH, d), 6.95 (IH, m), 6.89-6.79 (2H, m), 6.74 (IH, s), 5.54 (2H, s), 3.11 (3H, s). MS (ES): 499 |M+H]+. l-[(2,4-dMuorophenyl)methyl]-3-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}-5- (trifluoromethyl)-1H-pyrazole; 1H-NMR (400MHz, CDCl3): δ 8.18 (IH, m), 7.91-7.81 (2H, m), 7.60 (IH51), 7.39 (IH, d), 7.34 (IH, d), 7.10 (IH, m), 6.92-6.79 (3H, m), 5.48 (2H, s), 3.10 (3H, s). MS (ES): 499 [M+H]+.
Scheme 23
Figure imgf000216_0001
Other examples of the invention were prepared by a different route of assembly as shown in Scheme 23. Similar to Example 60, l-(5-Bromothiophen-2-yl)-4,4,4-trifluoro-butane-l,3-dione can be condensed with hydrazine directly to form a pyrazole. As in Example 60, acylation or alkylation can produce a mixture of isomers which could be separated at the stage of the bromide or such a mixture could be separated after aryl coupling.
Example 61
Figure imgf000217_0001
Prepω-ation of[3-(5-{l-[(2,4-diβuowpheψl)metfψlJ-3-(trιβtιorometIψl)-lH-^-azol-5-yl}-2- thienyl)phenyl] acetic acid
Into a 250 mL flask was weighed 5.00 g (23.2 mmol) of (3-Bromophenyl)acetic acid, 50 mL of methanol, and 50 mL of 4.0 M HCl in dioxane (Aldrich). The reaction was stirred at room temperature for 3 h then was concentrated in vacuo. The residue was washed into a separatory funnel with ethyl acetate and 10% ammonium hydroxide. The ethyl acetate was separated, was dried (MgSO4), and was concentrated in vacuo. The intermediate (3-Bromophenyl)acetic acid methyl ester was recovered as a colorless oil, yield, 5.2 g (98%). Into a 250 mL flask was weighed 5.18 g of ester (22.6 mmol) along with 7.51 g of bis(pinacolato)diboron, 6.6 g of potassium carbonate, 68 mL of DMSO, and 1.1 g of dichloro[l,l'- bis(diphenylphosplτino)ferrocene]palladium (D) dicloromethane adduct. The resulting suspension was heated at 80-85 ºC overnight then was washed into a separatory funnel with water and ether. The ether was separated, washed with brine, was dried (MgSO4), and was concentrated in vacuo. The residue was purified by silica gel flash chromatography (Jones Flashmaster, two 70 g columns, gradient elution from 100% hexanes to 40% ethyl acetate over 1 h). Appropriate fractions were combined and concentrated in vacuo to afford the intermediate [3-(4,4,5,5-Tetrametbyl-[l,3,2]dioxaborolan-2- yl)phenyl]acetic acid methyl ester as a faintly yellow oil, yield: 3.02 g (47%). 1H NlVlR (400MHz, CDCl3): δ 7.73(m, 2H), 7.3-7.4(m, 2H), 3.70(s, 3H), 3.65(s, 2H), 1.36(s, 12H). Into a 500 mL flask was weighed 15.1 g (50.15 mmol) of 4,4,4-Trifluoro-l-[5-(3- methanesulfonyl-phenyl)-thiophen-2-yl]-butane-l,3-dione, 150 mL of toluene, and 1.575 mL (1.1 eq) of hydrazine. The intermediate hydrazone precipitated from solution over 15 minutes then the reaction was heated to 100- 105 ºC where it remained for 18 h. The reaction was then concentrated to dryness in vacuo and the residue was dissolved in dichloromethane and precipitated with hexanes,. The semicrystalline precipitate was collected by filtration and was dried under high vacuum to afford the intermediate 5-(5-Bromothiophen-2-yl)-3-trifluoromethyl-1H-pyrazole as a colorless solid, yield: 9.90 g(66%).
Into a 500 mL flask was weighed 5.0 g (16.8 mmol) of pyrazole, 5.4 g of potassium carbonate, 4.7 g (22.7 mmol) of l-Bromomethyl-2,4-difluorobenzene, and 50 mL of DMF. The resulting suspension was stirred at 100- 105 ºC for 1 h then was allowed to cool to room temperature. The reaction was washed into a separatory funnel with ethyl acetate and water. The ethyl acetate was separated, washed with water, brine, was dried (MgSO4), and concentrated in vacuo. The resulting mixture of isomers was purified by silica gel flash chromatography (5 x 30 cm, 5% ethyl acetate- hexanes) to afford the 5-(5-BromoiMophen-2-yl)-l-(2,4-dffluoro-ben2yl)-3-trifluoromethyl-1H-pyrazole as a colorless oil, yield: 2.21 g (31%) and 3-(5-Bromo-thiophen-2-yl)-l-(2,4-difluorobenzyl)-5- trifluoromethyl-1H-pyrazole as a colorless oil, yield: 4.62 g (65%).
Into a 250 mL flask was weighed 1.124 g (2.66 mmol) of 5-(5-Bromothiophen-2-yl)-l-(2,4- difluoro-ben^l)-3-trifiuoromethyl-1H-ρyrazole, 1.5 g of boronate (5.43 mmol), 100 mL of THF, and 10 mL of 1.0 M sodium carbonate. The resulting solution was heated at 80-85 ºC in an oil bath and 318 mg of tetrakistriphenylphosphine palladium (0) was added. The reaction was heated for 18 h then was concentrated in vacuo to remove THF. The residue was washed into a separatory funnel with ethyl acetate and 1.0 M sodium carbonate. The ethyl acetate was separated, washed with brined, was dried (MgSO4), and concentrated in vacuo. The residue was purified by silica gel flash chromatography (Jones Flashmaster, 70 g SiO2, gradient elution from 100% hexanes to 40% ethyl acetate over 1 h). Appropriate fractions were combined and concentrated in vacuo to afford the intermediate (3-{5-[l- (2,4-Dffluorobenzyl)-5-1rifluoromethyl-1H-pyrazol-3-yl]-thiophen-2-yl}-phenyl)acetic acid methyl ester as a colorless oil, yield: 445 mg (34%).
The intermediate ester was dissolved in 10 mL of THF, 10 mL of methanol, and a solution of LiOH-H2O (150 mg in 2 mL of water) was added. The resulting solution was stirred at 60-65 ºC for 3 h then was concentrated in vacuo to remove methanol. The residue was washed into a separatory funnel with dichloromethane and water. The aqueous phase was separated and was acidified by addition of concentrated HCl. The aqueous phase was then washed with dichloromethane three times and the washings were combined, dried (Na2SO4), and concentrated in vacuo. The residue was purified by reverse-phase HPLC to afford the acid as a colorless solid, yield: 52 mg (12%). 1HNMR (400MHz, DMSO-ck): δ 7.5-7.55(m, 3H), 7.40(d, J= 4 Hz, IH), 7.34(1, J= 8 Hz, IH), 7.23(m, 2H), 7.09(s, IH), 7.0-7.08(m, 2H), 5.59(s, 2H), 3.59(s, 2H); MS (ES): 479 |M+H]+.
The following compounds are prepared essentially according to the previous examples by substituting the appropriate reagents:
• [3-(5-{l-[(5-chloro-2-thienyl)methyl]-3-(trinuoromethyl)-1H-pyrazol-5-yl}-2- thienyl)phenyl]acetic acid; 1H-NMR (400MHz, CDCl3): δ 7.55-7.49 (2H, m), 7.38 (IH, m), 7.31 (IH, d), 7.27 (IH, m), 7.11 (IH, d), 6.73 (IH, d), 6.68 (IH, d), 6.66 (IH, s), 5.54 (2H, s), 3.70
(2H, s). MS (ES): 483 |M+H]+.
Example 62
211 Preparation ofl~methyletJψl5-{5-[3-(ωnimsdfofψl)plienyl]-24hieψl}4-(2,5-dichlorop pyrazole-3-cω-boxylate
Figure imgf000219_0001
Into a 25 mL flask was weighed 114 mg (224 mmol) of methyl l-(2,5-dichlorophenyl)-5-(5-(3- sulfamoylphenyl)thiophen-2-yl)-1H-pyrazole-3-carboxylate, 156 mg of KF, 4 mL of isopropyl alcohol, and 200 μL of concentrated HCl. The reaction was heated at 80-85 ºC for 3 days. The reaction was then washed into a separatory funnel with ethyl acetate and water. The ethyl acetate was separated, washed with brine, was dried (Na2SO4), and concentrated in vacuo. Product was further purified by silica gel flash chromatography (Jones Flashmaster, 25 g SiO2, gradient elution from 20% ethyl acetate to 60% ethyl acetate over 30 minutes). Appropriate fractions were combined and concentrated in vacuo to afford the product as a colorless powder, yield: 53.3 mg (44%). 1HNMR (400MHz, CDCl3): δ 8.05(s, IH), 7.83(d, J= 8 Hz, IH), 7.66(d, J= 8 Hz, IH), 7.59(s, IH), 7.44-7.51(m, 3H), 7.21(d, J= 4 Hz, IH), 7.13(S, IH), 6.81(d, J= 4 Hz, IH), 5.33(heptet, J= 6 Hz, IH), 5.08(s, 2H), 1.41(d, J= 7 Hz, 6 H); MS (ES): 536 [M+H]+.
Example 63
Prepω-ationof[4-{5-[l-(2,5-dichhropheψl)-3-(Mflmromethyl)AH-p^
(methybulfonyl)phenyl]methcmol.
Figure imgf000219_0002
a) LiBH4, THF, 85 ºC; b) MCPBA, CH2C2, 25 ºC; c) Bis(pinacolato)diboron, Pd(dppf), KOAc5 DMSO,
100 ºC. C) (Ph3P)4Pd, 5-(5-Bromothiophen-2-yl)-l-(2,5-dichlorophenyl)-3-trifluorome1hyl-1H- pyrazole, Na2CO3, THF-water, 80 ºC.
4-Bromo-2-methylsulfanyl-benzoic acid ethyl ester was prepared as described in Example 53.
Into a 1 L flask was weighed 27.5 g of ester (99.9 mmol) and 150 mL of THF. A solution of 2.0 M LiBH4 in THF (50 mL, 100 mmol) was then added and the reaction was heated to 80-85 ºC where it remained for 23h. The reaction was then removed from heat and was cooled in an ice bath as it was quenched by addition of acetone. The reaction was then concentrated in vacuo and was washed into a separatory funnel with ethyl acetate and 1 M HCl. The ethyl acetate was separated, washed with brine, was dried (Na2SO4), and concentrated in vacuo. The intermediate (4-Bromo-2-methylsulfanyl-phenyl)- methanol was recovered as a colorless oil that solidified on standing, yield: 25.5 g (100+%). 1H NMR (400MHz, CDCl3): δ 7.24-7.34(m, 3H), 4.69(s, 2H), 2.50(s, 3H).
The alcohol was then dissolved in 250 mL of dichloromethane, was cooled to 0-3 ºC in an ice bath, and 44 g of 3-chloroperbenzoic acid (77% max., Aldrich) was added portionwise. The reaction was then allowed to warm to room temperature where it remained for 22 h. The reaction was then concentrated in vacuo to remove dichloromethane and the residue was washed into a separatory funnel with ethyl acetate and 1 M NaOH. The ethyl acetate was separated, washed with 1 M NaOH, was dried (Na2SO4), and concentrated in vacuo. The residue was purified by silica gel flash chromatography (Biotage, 65 x 200 mm SiO2, gradient elution from 100% hexanes to 100% ethyl acetate over 1 h). Appropriate fractions were combined and concentrated in vacuo to afford the intermediate (4-Bromo-2- methanesulfonyl-phenyl)-methanol as a colorless, semi-crystalline solid, yield: 17.13 g (65%). 1H NMR (400MHz, CDCl3): δ 8.18(s, IH), 7.77(d, J= 8 Hz, IH), 7.46(d, J= 8 Hz, IH), 4.92(s, 2H), 3.19(s, 3H), 2.94(br s, lH).
Into a 1 L flask was weighed 17.13 g of bromide, 25 g of bis(pinacolato)diboron, 5.0 g of dichloro[l,r-bis(diphenylphosphino)ferrocene]palladium (H) dicloromethane adduct, 23 g of potassium acetate, and 175 mL of DMSO. The resulting suspension was heated at 98-102 ºC for 18 h then was diluted with 200 mL of ethyl acetate and 200 mL of water. The resulting suspension was filtered through celite to femove solids and the filtrate was transferred to a separatory funnel. The aqueous phase was separated and washed with ethyl acetate. The ethyl acetate washings were combined, washed with brine, were dried (Na2SO4) and concentrated in vacuo. The residue was purified by silica gel flash chromatography (Biotage, 65 x 200 mm SiO2, gradient elution from 100% hexanes to 40% ethyl acetate over 1 h). Appropriate fractions were combined and concentrated in vacuo. The partially purified product was dissolved in dichloromethane and was precipitated with hexanes. The intermediate [2-Methanesulfonyl-4-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-phenyl]-methanol was recovered as an off-white powder, yield: 8.78 g (43%). 1H NMR (400MHz, CDCl3): δ 8.45(s, IH), 8.04(d, J= 8 Hz, IH), 7.57(d,J= 8 Hz, IH), 4.96(s, IH), 3.17(s, 3H)3 1.35(s, 6H), 1.24(s, 6H). Into a 250 mL flask was weighed 2.52 g (5.7 mmol) of 5-(5-Bromothiophen-2-yI)-l-(2,5- dichlorophenyl)-3-trifluoromethyl-1H-pyrazole, 3.6 g of boronate, and 100 mL of THF. The resulting solution was heated at 80-85 ºC and -200 mg of tetrakistriphenylphosphine palladium (0) was added. The reaction was heated for 3 h then was cooled and concentrated to remove THF. The residue was washed into a separatory funnel with ethyl acetate and 1.0 M sodium carbonate. The ethyl acetate was separated, washed with brine, was dried (Na2SO4), and concentrated in vacuo. The crude product was purified by silica gel flash chromatography (Biotage, 25 x 150 mm SiO2, gradient elution from 100% hexanes to 100% ethyl acetate over 1 h). Appropriate fractions were combined and concentrated in vacuo to afford the product as a colorless solid, yield: 348 mg (11%); 1H NMR (400MHz, CDCl3): δ 8.17(s, IH), 7.72(d, J= 8 Hz, IH), 7.5-7.6(m, 2H), 7.50(m, 2H), 7.26(s, IH), 6.89(s, IH), 6.85(d, J= 4 Hz, IH), 4.96(s, 2H), 3.20(s, 3H); MS (ES): 547 and 549 [eachM+H]+.
The following compound is prepared essentially according to the previous examples by substituting the appropriate reagents: , • [2-(methylsulfonyl)-4-(5-{3-(trifluorom
5-yl}-2-thienyl)phenyl]methanol; MS (ES): 548 |M+H]+.
Example 64
Preparation of '2-(3-(5-(l-β-chlorophenyl)-3-(Mfluorornethyl)-lH-pyrazol-5-yl)thiophen-2- yl)phenoxy)-2-methylpropanoicacid)
Figure imgf000221_0001
To a solution of tert-butyl 2-(3-(5-(l-(2-cMorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5- yl)thiophen-2-yl)phenoxy)-2-metliylpropanoate (47 mg, 84 μmol) in dichloromethane (0.5 mL) was added formic acid (1.0 mL). The resulting pale orange solution was allowed to stir at ambient temperature. After 5 hours at ambient temperature, LC/MS analysis of the reaction showed -5% of the starting ester remaining. After 7 hours stirring at ambient temperature the reaction mixture was concentrated under reduced pressure to afford crude product. This material was purified by flash column chromatography eluting with a gradient from CH2Cl2 to 10 % MeOHZCH2Cl2 to afford 2-(3-(5-(l-(2- cMorophenyl)-3-(tiifluorome1hyl)-1H-pyrazol-5-yl)thiophen-2-yl)phenoxy)-2-methylpropanoic acid (21.7 mg, 51% yield) as an off white foam. MS(ES): 509 βVI+H]+. Scheme 24
Figure imgf000222_0001
As depicted in Scheme 24, hydroxyl group on C-phenyl can be transformed into other groups. Benzyloxyphenyl pyrazoles 024ES01 (prepared in a manner similar to Example 2c) can be deprotected to afford hydroxyphenyl pyrazoles 024ES02. The free hydroxyl group can be derivatized via: copper- mediated arylboronic acid coupling to afford diaryl ethers 024ES03, Mitsunobu reaction with alcohols to afford aryl-alkyl ethers 024ES04, reaction with heteroaryl halides to afford aryl-heteroaryl ethers 024ES05, or alkylated with alkyl halides to afford aryl alkyl ethers 024ES06, which may be further derivatized or transformed (See 024ES07).
Example 65 2-(4-(l-(2-chloropherιyl)-3-(trifluoroirτethyl)-lH-pyrazol-5-yl)pherιo^
Example 65a Preparation of 3-(l-(2-chlorophenyl)-3-(trifluoromethyl)-lH-pyrazol-5-yl)phenol
Figure imgf000222_0002
To a solution of 5-(3-(lDenzyloxy)phenyl)-l-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazole in MeOH (10OmL) was added 10% palladium on carbon (1.04g). The black suspension was shaken on the Parr hydrogenator at 40-50psi hydrogen pressure for 5 hours. At this time the reaction was incomplete as evidenced by HPLC analysis. The reaction suspension was treated with additional Pd/C and shaken under 60psi hydrogen pressure for an additional 16 hours. At this time HPLC showed no remaining starting 5-(3-(benzyloxy)phenyl)-l-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazole. The reaction mixture was filtered through a pad of Celite that was then washed thoroughly with MeOH. The filtrate was concentrated under reduced pressure to afford 3-(l-(2-chlorophenyl)-3-(trifluoromethyl)-1H- pyrazol-5-yl)phenol as a brittle foam. This material was pure enough for use in subsequent transformations. MS(ES): 339 |M+H]+.
The following compound is prepared essentially according to the previous examples: 4-[l-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenol, MS(ES): 339 |M+H]+.
Example 65b Prepω"ation of2-(4-(l-(2-chloroplτerψl)-3-(triflιιoromethyl)-lH-pyrazol-5-yl)phem^
Figure imgf000223_0001
To a suspension of 4-(l-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)phenol (ref hydrogenation below) (60 mg, 180 μmol) and Cs2CO3 (140 mg, 400 μmol) in acetonitrile (2 mL) was added 2-chloropyrimidine (66 mg, 580 μmol). The suspension was then heated to 80°C in an oil bath. After stirring for 16 hours at 80 ºC the suspension was filtered through a plug of silica gel (1 g), which was eluted with EtOAc. The filtrate was concentrated under reduced pressure and purified by flash column chromatography eluting with a gradient from 10% to 30% EtOAc/hexane to afford 2-(4-(l-(2- cMorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)phenoxy)pyrimidine (55 mg, 75% yield) as a white powder. MS(ES): 417|M+H]+.
The following compound is prepared essentially according to the previous examples: 2-({4-[l-(2-chlorophenyl)-3-(trifluoromethyl)4H-pyrazol-5-yl]phenyl}oxy)pyrazine MS(ES): 417 [M+H]+.
Example 66 l-fS-fl^-chbropheψlJ-S-ftrifliωwmetfψlJ-lH-pyf'a∑ol-S-ylJpheno^jaceticadd
Example 66a Preparation of methyl 2-(3-(l-(2-chlorophenyl)~3-(trifluoromethyl)-^
Figure imgf000223_0002
To a suspension of 3-(l-(2-cUorophenyl)-3-(trifluorometliyl)-1H-pyrazol-5-yl)phenol (229 mg, 0.68 mmol) and K2CO3 (179 mg, 1.3 mmol) in acetonitrile (3.0 mL) was added methyl bromoacetate (85 uL, 0.90 mmol). The suspension was stirred at ambient temperature for 16 hours at which time HPLC analysis showed conversion to a product with a slightly longer retention time. The reaction suspension was filtered through a plug of Celite that was then washed thoroughly with EtOAc. The filtrate was concentrated to afford a pale yellow oil. This material was further purified by flash column chromatography eluting with a gradient from 0% to 28% EtOAc/hexane to afford methyl 2-(3-(l-(2- cMorophenyl)-3-(1rifluoromethyl)-1H-pyrazol-5-yl)phenoxy)acetate (158 mg, 57% yield) as an oil. MS(ES): 411[M+H]+. The following compounds are prepared essentially according to the previous examples:
• 2-({4-[l-(2-cMorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl}oxy)ethanol,MS(ES): 383 [M+H]+.
• ethyl ({4'-[l-(2-chlorophenyl)-3-(l-hydroxy-l-methylethyl)-1H-pyrazol-5-yl]biphenyl-3- yl}oxy)acetate, MS(ES): 512 [MfNa]+.
• 2-({4l-[l-(2-chlorophenyl)-3-(l-hydroxy-l-methylethyl)-1H-pyrazol-5-yl]biphenyl-3-yl}oxy)- N,N-diethylacetamide, MS(ES): 540 [MfNa]+. • 4l-[l-(2-chlorophenyl)-3-(l-hydroxy-l-methyle%l)-1H-pyrazol-5-yl]biphenyl-3-yl (1- methylethyl)carbamate, MS(ES): 512 [MH-Na]+.
Example 66b Preparationof2-(3-(l-(2-chloropherιyl)-3-(Mflιu)romethyl)-lH-pyi"azol-5-yl)phenoxy)aceticacM
Figure imgf000224_0001
To a solution of methyl 2-(3-(l-(2-cUorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5- yl)phenoxy)acetate (140 mg, 0.34 mmol) in MeOH (5 mL), was added lithium hydroxide monohydrate (60 mg, 1.42 mmol). The resulting mixture was stirred at ambient temperature for 18 hours. The reaction mixture was then concentrated under reduced pressure and the residue was taken up in CH2Cl2 and H2O. The aqueous was made acidic by the addition of 1 N HCl. The layers were separated and the acidic aqueous was further extracted with CH2Cl2 (3x). The combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. This white solid was taken up in warm CH2Cl2 and hexane and the resulting solution was cooled in an ice bath. Filtration, washing with hexane and drying of the precipitated solids afforded 2-(3-(l-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol- 5-yl)phenoxy)acetic acid (69 mg, 51% yield) as a white solid. MS(ES): 397[MH-H]+. The following compound is prepared essentially according to the previous examples: • ({^[l^-cWorophenyiyS^irifluoromeihy^-1H-pyrazol-S-ylJpheny^o^acetic acid, MS(ES): 397 |M+H]+.
Example 67
Prepω-ationof4-(2-(3-(l-(2-chloropheψl)-3~(Mflιιoromethyl)-lHψyf-azol-5^ ethyl)morpholine
Figure imgf000225_0001
To a solution of 3-(l-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)phenol (155 mg, 0.5 mmol) and triphenylphosphine (170 mg, 0.65 mmol) in THF (2 mL) was added 2- morpholinoethanol (72 μL, 0.59 mmol). The solution was cooled in an ice bath and treated with diisopropylazodicarboxylate (125 μL, 0.64 mmol). After a few minutes the ice bath was removed and the reaction was allowed to stir while warming to ambient temperature. After stirring for 16 hours LC/MS analysis showed desired product and triphenylphosphine oxide as the major peaks. The reaction solution was concentrated under reduced pressure and the resulting yellow oil was purified by flash column chromatography eluting with 30% followed by 40% EtOAc/hexane, and then a gradient of CH2Cl2 to 4% MeOHZCH2Cl2. The white solid that was obtained was found to be contaminated with triphenylphosphine oxide. This crude product was further purified by normal phase preparative HPLC eluting with a gradient from CH2Cl2 to 10% isopropanol/CH2Cl2 to afford 4-(2-(3-(l-(2-chlorophenyl)- 3-(trifluoromethyl)-1H-pyrazol-5-yl)phenoxy)ethyl)moφholine (139 mg, 67% yield) as a thick syrup. MS(ES): 452|M+H]+. The following compounds are prepared essentially according to the previous examples:
• 2-({3-[l-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]ρhenyl}oxy)-N,N- dimethylethanamine. MS(ES): 410[M+H]+.
• l-[2-({3-[l-(2-cMorophenyl)-3-(trifluoro^ MS(ES): 450[M+H]+. • 2-({4-[l-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl}oxy)-N,N- dimethylethanamine, MS(ES): 410 [M+H]+
• 4-[2-({4-[l-(2-chiorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5- yl]phenyl}oxy)ethyl]morpholine, MS(ES): 452 (MfETJ+ l-[2-({4-[l-(2-cUorophenyl)-3-(1xifluoromethyl)-1H-pyrazol-5-yl]phenyl}oxy)eihyl]piperi MS(ES): 450 [M+H]+.
Example 68 l-(2-chlorophenyl)-5-(4-{[3-(methylsιφnyl)p^
Figure imgf000226_0001
A mixture of 4-(l-(2-cUorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)phenol (169 mg, 0.5 mmol), 3-methylsulfonylphenylboronic acid (200 mg, 1 mmol), Cu(OAc)2 (181 mg, 1 mmol), and NEt3 (35 μL, 2.5 mmol) and molecule sieves (4A) in DCM was shaken overnight at 20 ºC. Solid was removed by filtration and filtrate was evaporated to give a crude, which was purified by column chromatography on silica gel eluting with EtOAc-hexane (1 :4 to 1 :2) to afford l-(2-chlorophenyl)- 5-(4-{[3-(methylsulfonyl)phenyl]oxy}phenyl)-3-(trifluorometiiyl)-1H-pyrazole (88 mg). 1H-NMDR: CDCB: 7.68 (m, IH), 7.55 (m, 2H), 7.48 (m, IH5), 7.62 - 7.40 (m, 2H), 7.27 (m, 2H), 7.21 (m, IH), 6.93 (m, IH), 6.80 (s, IH), 3.04(s, 3H), MS(ES): 493 [M+H]+.
Scheme 25
Figure imgf000226_0002
As depicted in Scheme 25, aminosulfonyl groups can be introduced to the thiophene ring. Thiophene pyrazoles 025ES01 (Prepared in a manner similar to Example 2c) can be sulfonated by the action of chlorosulfbnic acid to afford sulfonic acids 025ES02. Conversion to the sulfonyl chlorides 025ES03 followed by derivatization with amines under basic conditions affords sulfonamides 0025ES04.
Example 69 l-(5-(l-(2-chhropJwnyl)-3-(Mflwromethyl)-lH~pyrazol-5-yl)thiophen-2-y^ methylpiperazine Example 69a
Prepω-ationof5-(l-(2-chloropheψl)-3-(tinflwroτmthyl)-lH-p)v-azol-5-yl)thiopfa
Figure imgf000227_0001
Chlorosulfonic acid (LOmL, 15 mmol) was added dropwise to a cold (-78ºC) solution of l-(2- cUorophenyl)-5-(thiophen-2-yl)-3-(trifluoromethyl)-1H-pyrazole (LOg, 3.2 mmol) in CH2Cl2 (22mL) After 75 minutes stirring at -78°C the cooling bath was removed and the brown solution was allowed to warm to ambient temperature. After 3 1A hours stirring at ambient temperature, the reaction mixture was poured onto ice and diluted with CH2Cl2. The milky lower organic phase was separated and dried over Na2SO4. Filtration and concentration under reduced pressure of the organics gave a biphasic mixture that was further pumped down under high vacuum. NMR and GGMS analysis of this material showed it not to be the product. The aqueous phase from the workup was saturated with Na2SO4 and extracted with EtOAc (3x). These organic extract were dried over Na2SO4, filtered and concentrated under reduced pressure to afford 5-(l-(2-cMorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)thiophene-2- sulfonic acid as a yellow syrup. This crude material was carried on to the sulfonyl chloride fonnation without purification. MS(ES): 409|M+H]+.
Example 69b Preparation of 5-(l-(2-chlorophωiyl)-3-(tiiflwromethyl)-lH-pyrcEθl~5^
Figure imgf000228_0001
5-(l-(2-CMorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)thiophene-2-sulfonic acid (-3.2 mmol from previous step) was combined with benzene (5.0 mL) in a reaction vial. This mixture was treated with thionyl chloride (5.OmL, 69 mmol) and a catalytic amount of dmethylformamide (0.1 mL). The reaction was then heated to reflux in an oil bath. After refluxing for 1 hour the reaction mixture was concentrated under reduced pressure to afford a yellow oil that partially solidified under reduced pressure. This crude material was purified by flash column chromatography eluting with a gradient from 10% to 30% EtOAc/hexane. Product-containing fractions were collected and concentrated to afford 5- (l-(2-cUorophenyl)-3-(trMuoromethyl)-1H-pyrazol-5-yl)thiophene-2-surfonyl chloride as a pale yellow oil. The mostly pure material was carried on to subsequent transformations without further purification.
Example 69c
Preparation of l-(5-(l-(2-chlorophenyl)-3-(trifluoromethyl)-lH-pyψazol-5-yl)tM methylpiperazirie
Figure imgf000228_0002
Triethylamine (0.15mL, 1.1 mmol) and a small amount of DMAP were dissolved in 1 ,2- dichloroethane (2 mL) in a reaction vial. This solution was treated with 1 -methyl piperazine (50 μL, 0.45 mmol) followed by 5-(l-(2-cMorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)thiophene-2- sulfonyl chloride (145 mg, 0.34 mmol) as a solution in 1,2-dichloroethane (1 mL). After stirring 4 V2 hours at ambient temperature the reaction was quenched by dilution with CH2Cl2 and water. Saturated NaHCO3 was added and the basic aqueous was extracted with CH2Cl2 (3x). The combined organic extracts were dried over Na2SO4, filtered and concentrated under reduced pressure to afford crude product as a pale yellow oil. This crude product was purified by flash column chromatography eluting ■ with a gradient from CH2Cl2 to 16% acetonitrile/CH2Cl2 to afford l-(5-(l-(2-chlorophenyl)-3-
(1rifluoromethyl)-1H-pyrazol-5-yl)tMophen-2-ylsulfonyl)4-methylpipera2me (90.5 mg, 54% yield) as a brittle white foam. MS(ES): 491 [M+H]+.
The following compound is prepared essentially according to the previous examples: • l-({5-[l-(2-cMorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-2-thienyl}sulfonyl)piperidine
MS(ES): 476[M+H]+. Scheme 26
Figure imgf000229_0001
As depicted in Scheme 26, pyrazole-carboxylic acid can be transformed into pyrazole-amides. Carboxylic acid 0026ES01 (prepared in a manner similar to Example 2c) can be converted to its corresponding acid chloride 026ES02 by the action of oxalyl chloride. Reaction with various amines under basic conditions leads to the corresponding amides 026ES03.
Example 70
Methyl l-{[l-(2-chloropheψl)-5-{5-[3-(methylsulforyl)pheriyl]-24M yl]carbonyl}piperidine-4-carboxylate
Example 70a
Preparation of l-(2-chloropJκfψl)-5-(5-(3-(nntlτylsιdfonyl)pheψl)thiophen-2-yl)-lH^ caώonyl chloride
Figure imgf000229_0002
To a suspension of l-(2-chlorophenyl)-5-(5-(3-(methylsulfonyl)phenyl)thiophen-2-yl)-1H- pyrazole-3-carboxylic acid (160 mg, 0.35 mmol) in PhH (1.0 mL) was added a small amount of DMF. Oxalyl chloride (60 μL, 0.69 mmol) was added to the suspension. After stirring for 15 minutes at ambient temperature, gas evolution had ceased and only part of the solids had dissolved. After 25 minutes dioxane (2.0 mL) was added. There was renewed gas evolution and most of the solids dissolved. After 30 minutes additional oxalyl chloride (50 μL, 0.57 mmol) was added. There was vigorous gas evolution and after a total of 90 minutes stirring the reaction mixture was concentrated under reduced pressure to afford 1 -(2-chlorophenyl)-5-(5-(3-(methylsurfonyl)phenyl)thiophen-2-yl)- IH- pyrazole-3-carbonyl chloride as a pale brown foam. This material was carried on to the subsequent acylation without purification.
Example 70b
Preparation of "methyl l-{[l-(2-chbropheψl)-5-{5-[3φrethylsulfoψl)pheψlJ-2-thie}ψl}-lH-pyi"azol-3- yl]carboψl}piperidine-4-carboxylate
Figure imgf000230_0001
To a solution of l-(2-chlorophenyl)-5-(5-(3-(methylsulfonyl)phenyl)thiophen-2-yl)-1H- pyrazole-3-carbonyl chloride (0.23 mmol crude from previous step) in CDCl3 (1.2 ml) was added N5N- diisopropylethylamine (150 μL, 0.86 mmol) and a small amount of DMAP. The resulting mixture was treated with methyl isonipecotate (62 μL, 0.46 mmol). After stirring for 3 hours at ambient temperature the reaction was quenched by dilution with H2O, and dilution with CH2Cl2. The layers were separated and the basic aqueous layer was extracted with CH2Cl2. The combined organic extracts were dried over Na2SO4, filtered and concentrated under reduced pressure to afford crude product This material was purified by flash column chromatography eluting with a gradient from 0% to 16% MeCN in CH2Cl2 to afford methyl l-{[l-(2-chlorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}-1H-pyrazol-3- yl]carbonyl}piperidine-4-carboxylate (11 mg, 8% yield) as a white powder. MS(ES): 584 [M+H]+. The following compounds are prepared essentially according to the previous examples:
• l^-chloropheny^-S-fS-P-^nemylsutfony^phenylJ^-thienylj-N-piperidin-l-yl-1H-pyrazole- 3-carboxamide, MS(ES): 541.3[MH-H]+ • l-(2-cUorophenyl)-5-{5-[3-(memylsulfonyl)phenyl]-2-tMenyl}-3-(pyrrolidin-l-ylcarbonyl)- lH-pyrazole, MS(ES): 512 [M+H]+.
• l-ltl^-chlorophenyO-S-IS-P-^ethylsulfonyOphenylJ^-thienyll-1H-pyrazol-S- yl]carbonyl}-4-metliylpiperidine, MS(ES): 540 [M+H]+.
• l-ftl^-chloropheny^-S-IS-P-^e^lsulfony^phenyy^-thienyO-1H-pyrazol-S- yl]carbonyl}-4-methylpiperazine, (ES): 541 [M+H]+.
• l-(2-cUorophenyl)-5-{5-[3-(memylsulfonyl)phenyl]-2-thienyl}-N-[3-(trifiuoromethyl)phenyl]- lH-pyrazole-3-carboxamide, MS(ES): 602 [M+H]+.
• 5-[3-cUoro-3'-(methylsulfonyl)biphenyl4-yl]4-(2,6-dichlorophenyl)-N-(2,2,2-trifluoroethyl)- lH-pyrazole-3-carboxamide MS(ES): 604 [M+H]+. • 5-[3-chloro-3'-(methylsulfonyl)biphenyl-4-yl]-N-(2,2,2-trifluoroethyl)-l-[2- (trifluoromethyl)pyridin-3-yl]-1H-pyrazole-3-carboxanτide MS(ES): 603 [M+H]+.
• 4-chloro-5-[3-chloro-3Kme%lsulfony (trffluoromethyl)pyridin-3-yl]-1H-pyrazole-3-caAoxamide MS(ES): 637 [M+H]+. • 5-[3-chloro-3Hmethylsulfonyl)biphenyl-4-yl]-l-(2,6-dichlorophenyl)-N-(2-hydroxy-l,l- dimethylethyl)-1H-pyra2Dle-3-carboxamide MS(ES): 592 [MfH]+.
• 5-[3-chloro-3'-(methylsulfonyl)biphenyl-4-yl]-l-(2,6-dichlorophenyl)-N-(l,l-dimethyle%l)- lH-pyrazole-3-carboxarnide MS(ES): 578 [M+H]+.
• 5-[3-cUoro-3'-(methylsulfonyl)biphenyl-4-yl]-N-cyclopropyl-l-(2,6-dichlorophenyl)-1H- pyrazole-3-carboxamide MS(ES): 560 [M+H]+.
• 5-[3-cUoro-3'-(methylsu]fonyl)biphenyl-4-yl]-N-cyclobutyl-l-(2,6-dichlorophenyl)-1H- pyrazole-3-carboxamide MS(ES): 576 [M+H]+.
• S-P-chloro-S'-^ethylsulfony^biphenyM-yy-N-cyclopentyl- 1 -(2,6-dichlorophenyl)- IH- pyrazole-3-carboxamide MS(ES): 590 [MH-H]+. Scheme 27
Figure imgf000231_0001
As depicted in Scheme 27, biphenylpyrazoles can be prepared starting from the condensation of a hydrazine with a diketo ester and can be chlorinated on the pyrazole ring. Hydrazines 027ES01 can be condensed with diketones 027ES02 as in Example 2c to afford pyrazoles 027ES03. The ester functionality of 027ES03 can then be converted to a tertiary alcohol 027ES04 by the action of alkylmagnesium halides in a manner similar to Example 5. The resulting aryl bromide can then be coupled to a boronic acid under palladium catalyzed coupling conditions similar to those in Example Ic to afford biaryls 027ES05. The pyrazole nucleus of 027ES05 can then be halogenated by treatment with JNBS or NCS to afford the halo-pyrazoles 027ES06. Example 71
2-(5-(3'-(Methylmlfonyl)biphenyl-4^
Example 71a
Preparation of 2-(5-(4-bromopl%myl)A-(2φψwromethyl)pte
Figure imgf000232_0001
To a suspension of methyl 5-(4-bromophenyl)-l-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3- carboxylate (393 mg, 0.9 mmol) in dry toluene (9 mL) stirred at ambient temperature was added methylmagnesium bromide (1.4 mL of a 3.0M solution in ether, 4.2 mmol) dropwise. After 2 1A hours stirring at ambient temperature the reaction mixture was quenched by the addition of saturated ammonium chloride and EtOAc. The aqueous layer was extracted with EtOAc (3x). The combined organic extract were dried over Na2SO4, filtered and concentrated under reduced pressure to afford 2-(5- (4-bromophenyl)-l-(2-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)propan-2-ol as an orange-yellow oil, which was carried on to the subsequent step. GGMS (EI, = 426 [M+]
Example 71b Preparation of 2-(5-(3'-(methylsιdfo}iyl)biphenyl-4-yl)-l-(2-(trifluoromethy^ yl)propan-2-ol
Figure imgf000232_0002
To a solution of 2-(5-(4-bromophenyl)-l-(2-(ttffluoromethyl)phenyl)-1H-pyrazol-3-yl)propan-2-ol (115 mg, 0.27 mmol) and 3-(methylsulfonyl)phenylboronic acid (66 mg, 0.33 mmol) in 1,2-dimethoxyethane (1.5 mL) was added K2CO3 (110 mg, 0.80 mmol) and H2O (1.5 mL). The resulting biphasic suspension was stirred at ambient temperature and sparged with nitrogen for 10 minutes. The reaction was then treated with dichloro[l , 1 '-bis(diphenylphosphino)ferrocene]palladium (H) dichloromethane adduct (15 mg, 18μmol) and heated to 80°C in an oil bath. The reaction was heated at 8OºC for three hours and then allowed to cool to ambient temperature overnight The cooled reaction mixture was diluted with EtOAc and H2O. The aqueous layer was extracted with EtOAc (3x). The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated to afford crude product as a dark oil. The crude product was purified by flash-column chromatography eluting with a gradient from 10% to 100% EtOAc/hexane to afford 2-(5-(3'-(methylsdfonyl)biphenyl-4-yl)4-(2-(trifluoromethyl)phenyl)- lH-pyrazol-3-yl)propan-2-ol (122 mg, 90% yield) as an off-white powder. MS(ES): 501 [MfH]+ The following compounds are prepared essentially according to the previous examples:
• 2-{5-[3'-(meUiylsulfonyl)biphenyl4-yl]-l-[3-(1riQuoromethyl)pyridin-2-yl]-1H-pyrazol-3- yl}propan-2-ol, MS(ES): 502 [M+H]+.
• 2-{l-(2-cUorophenyl)-5-[3'-(methylsulfonyl)biphenyl-4-yl]-1H-pyrazol-3-yl}propaii-2-ol, MS(ES): 467 [M+H]+.
• 4'-[l-(2-chlorophenyl)-3-(l-hydroxy-l-methyletliyl)-1H-pyrazol-5-yl]-N-(l- methylethyl)biphenyl-3-carboxamide, MS(ES): 474 |M+H]+. • 4t-[l-(2-chlorophenyl)-3-(l-hydroxy-l-methylethyl)-1H-pyrazol-5-yl]-N-[2- (dimethylamino)ethyl]biphenyl-3-carboxamide, MS(ES): 503 [M+H]+.
• 2-{l-(2-chlorophenyl)-5-[4'-(ethylsuhOnyl)biphenyl-4-yl]-1H-pyrazol-3-yl}propan-2-ol, MS(ES): 481 [M+H]+.
• 2-{l-(2-chlorophenyl)-5-[3-methyl-3'-(metliylsulfonyl)biphenyl-4-yl]-1H-pyrazol-3-yl}propan- 2-ol MS(ES): 481 [M+H]+
• 2-{l-(2-chlorophenyl)-5-[3-fluoro-3'-(methylsulfonyl)biphenyl-4-yl]-1H-pyrazol-3-yl}propan- 2-ol MS(ES): 485[M+H]+.
• 2-{5-[3-chloro-3'-(methylsulfonyl)biphenyl-4-yl]-l-(2-chlorophenyl)-1H-pyrazol-3-yl}propan- 2-ol MS(ES): 501 |M+H]+ • l-(5-{4-[l-(2-chlorophenyl)-3-(l-hydroxy-l-methyletliyl)-1H-pyrazol-5-yl]phenyl}-2- thienyl)ethanone MS(ES): 419 (M-OH)
• 5-{4-[l-(2-chlorophenyl)-3-(l-hydroxy-l-methylethyl)-1H-pyrazol-5-yl]phenyl}thiophene-2- carbaldehyde, MS(ES): 405 (M-OH)
• 2-[l-(2-chlorophenyl)-5-{4-[2-(me1hyloxy)pyrirmdin-5-yl]phenyl}-1H-pyrazol-3-yl]propan-2- ol, MS(ES): 421 [M+H]+
Example 72 2-[l-(2-chlorophenyl)-5-{4-[3-(methylmlfonyl)pherψl]f^
Example 72a Preparation of4-bromo-finw7-2-carboxylic acid
Figure imgf000233_0001
A 500 mL three-necked round-bottom flask fitted with an overhead mechanical stirrer and reflux condenser was charged with 4,5-dibromo-furan-2-carboxylic acid (57.0 g, 211 mtnol), H2O (168 mL), and HOAc (42 mL). The third neck of the flask was stoppered and the suspension was heated to reflux with a temperature controlled heating mantle held at 125-130 ºC. Zn dust (24.9 g, 381 mmol) (previously ground in a mortar and pestle to break up lumps) was added portionwise over 50 minutes. Subsequent portions are added after most of the previously added portion has disappeared. After the first portions of the Zn were added, all of the 4,5-dibromofuran-2-carboxylic acid dissolves to give a pale brown solution. Twenty-five minutes after the conclusion of the zinc addition a thick grey-white slurry had formed. HPLC analysis of the reaction slurry at this time indicated complete consumption of the starting 4,5-dibromofuran-2-carboxylic acid and conversion to the desired product After 35 minutes, heating was discontinued, and the slurry was allowed to cool to ambient temperature. After cooling to ambient temperature the reaction slurry was diluted with cold H2O (175 mL), cooled in an ice bath, and then filtered. The white and grey solids were rinsed with cold H2O, and dried on the filter for 3 hours. The product/Zn mixture was then pumped down under high vacuum with gentle heating to afford white-grey flakes. A portion of the resulting solids (37.3 g) was dissolved in warm acetone (1.8L, solubility about 20g/L). The resulting solution was filtered to remove residual zinc dust, and then concentrated under reduced pressure to afford 4-bromo-furan-2-carboxylic acid as a white powder. This material was carried on to the acid chloride formation without purification. 1H-NMR (400MHz, DMSO-de): δ 7.96 (IH, d, J = 0.8 Hz), 7.04 (IH, d, J = 0.8 Hz). Example 72b
Preparation of4-bromofitrωι-2-carbonyl chloride
Figure imgf000234_0001
The crude 4-bromo-furan-2-carboxylic acid (30 g, 157 mmol) was placed in a 500 mL round bottom flask equipped with a magnetic stirring bar and a reflux condenser, and the flask was alternately evacuated and filled with nitrogen several times. The solids were suspended in benzene (400 mL), treated with SOCl2 (60 mL, 823 mmol) and the mixture was heated to reflux in a heating mantle. Dark tarry materials form on the walls of the reaction flask during the course of the reaction. After ~135 minutes at reflux a sample of the reaction was concentrated under reduced pressure and analyzed by 13C NMR. The NMR was quite clean and showed the reaction to be complete. [13C-NMR (400MHz, CDCl3): δ 154.9, 147.6, 146.3, 126.0, 102.5] After ~3 hours at reflux the reaction mixture was allowed to cool to ambient temperature. The pale brown supernatant solution of the acid chloride was decanted from the dark solids, and the solids were rinsed with additional benzene. The benzene solutions were combined and concentrated under reduced pressure to afford 4-bromoruran-2-carbonyl chloride as a pale brown oil. This crude material was carried on to the amide formation without purification.
Example 72c Preparation of4-bromo-fia'an-2-carboxylic acidmethoxy-methyl-amide
Figure imgf000235_0001
The crude 4-bromofuran-2-carbonyl chloride (157 mmol theoretical) was dissolved in CH2Cl2 (500 mL) in a 1 L round bottomed flask. The flask was immersed in an ice bath and N,O-dimethyl- hydroxylamine hydrochloride (19.5 g, 200 mmol) was added. The cold suspension was then treated withNjN-diisopropylethylamine (75 mL, 430 mmol), and a small amount of 4-(N5N- dimethylamino)pyridine (catalytic). Several minutes after the addition of the 4-(N,N- dimethylamino)pyridine the ice bath was removed and the pale orange solution was allowed to warm to ambient temperature. After standing at ambient temperature for ~ 16 hours the pale brown reaction mixture was quenched with water (100 mL) and diluted with CH2Cl2 (500 mL). The layers were separated and the organic layer was washed with IN HCl (2 x 100 mL), H2O (100 mL), and saturated NaHCO3 (50 mL). The organics were dried over Na2SO4, filtered, and concentrated under reduced pressure to afford 4-bromo-furan-2-carboxylic acid methoxy-methyl-amide (25.7 g, 70% yield from crude acid) as a pale brown solid. IH NMR of the material showed it to be very clean. 1H-NMR (400MHz, CDCl3): δ 7.60 (IH, d, J= 0.8 Hz), 7.14 (IH, d, J= 0.8 Hz), 3.77 (3H, s), 3.35 (3H, s).
Example 72d Preparation ofl-(4-bromo-furan-2-yl)-ethanone
Figure imgf000235_0002
A solution of 4-bromo-furan-2-carboxylic acid methoxy-methyl-amide (27.5 g, 117 mmol) in THF (350 mL) was prepared and cooled in an ice-salt bath (< 0°C) to this solution was added methylmagnesium bromide (51 mL of a 3.0 M solution in Et20, 153 mmol) slowly so as to maintain the temperature below 0 °C. The resulting off-white / brown suspension was stirred at ~ -10 ºC. TLC analysis of aiiNHjCl-quenched aliquot after 1 hour showed no starting amide present. After 75 minutes at- 10 °C the reaction was quenched by the addition of saturated aqueous NH4Cl (100 mL). Additional H2O was added followed by 3N aqueous HCl (~4Q mL) to dissolve the solids. The resulting biphasic solution was concentrated on the rotary evaporator to remove most of the THF. The resulting aqueous slurry was diluted with Et2O, and 3N aqueous HCl was added to bring the pH < 7. The layers were separated and the aqueous layer was extracted with Et2O (3 x 100 mL). The combined organic layers were washed with saturated aqueous NaHCO3, brine, dried over Na2SO4, filtered and concentrated under reduced pressure to afford l-(4-bromo-furan-2-yl)-ethanone (20.4 g, 92% yield) as a pale brown solid. 1H-NMR (400MHz, CDCl3): δ 7.58 (IH, d, J= 0.8 Hz), 7.18 (IH, d, J= 0.8 Hz), 2.47 (3H, s). The following compounds are prepared essentially according to the previous examples:
• methyl l-(2-cUorophenyl)-5-{4-[3-(me1hylsu]fonyl)phenyl]furan-2-yl}-1H-pyrazole-3- carboxylate, MS(ES): 457[M+H]+.
• 2-[l-(2-cMorophenyl)-5-{4-[3-(methylsulfonyl)phenyl]furan-2-yl}-1H-pyrazol-3-yl]propan-2- ol, MS(ES): 457 [M+H]+.
• 2-[l-(2-chlorophenyl)-5-{4-[3-(methylsulfonyl)phenyl]-2-thienyl}-1H-pyrazol-3-yl]propan-2- ol, MS(ES): 473 [M+H]+
Scheme 28
C(O)Aryl
Figure imgf000236_0001
As depicted in Scheme 28, amides and sulfonamides can be prepared via acylation of a free amino groups. Carbinols 028ES01 (prepared in a manner similar to Example 5) can be coupled under palladium-catalyzed coupling conditions similar to Example Ic with aminophenyl boronic acids to afford amino biaryls 028ES03. The amine functionality of these can then be further derivatized under basic conditions to afford acylated or sulfonylated derivatives 028ES04. Example 73
Preparation of N-(4'-(l-(2-chlorophenyl)-3-(2Jιydroxypropm-2-yl)-lH-pyrazol-5-yl)bi^^ yl)acetamide
Figure imgf000236_0002
To a solution of 2-(5-(3'-ammobiphenyl-4-yl)-l-(2-cMorophenyl)-1H-pyrazol-3-yl)propan-2-ol (370 mg, 0.37 mmol) in acetonitrile (1.6 mL) was added triethylamine (0.12 mL, 0.86 mmol) followed by acetyl chloride (27 μL, 380 μmol). The reaction vial was then shaken at 75ºC overnight. After cooling the reaction solution was concentrated under reduced pressure and the crude product was purified by flash column chromatography eluting with a gradient from 0% to 100% EtOAc/hexane to afford N-(4'- (l-(2-cUorophenyl)-3-(2-hydroxypropan-2-yl)-1H-pytazol-5-yl)biphenyl-3-yl)acetamide (82 mg, 49% yield) as an oil. 1HNMR (400 MHz CDCl3): δ 7.79 (IH, s), 7.49-7.42 (4H, m), 7.41-7.32 (4H, m), 7.31- 7.21 (3H, m), 6.54 (IH, s), 2.68 (IH, s), 2.19 (3H, s), 1.69 (6H, s).MS(ES): 445[M+H]+. The Mowing compounds are prepared essentially according to the previous examples: • N-{4'-[l-(2-chlorophenyl)-3-(l-hydroxy-l-methylethyl)-1H-pyrazol-5-yl]biphenyl-3- yl}methanesulfonamide MS(ES): 482[M+H]+. • N-{4'-[l-(2-chlorophenyl)-3-(l-hydroxy-l-methyletliyl)-1H-pyrazol-5-yl]biphenyl-3-yl}-l,l,l- trifluoromethanesulfonamide MS(ES): 535 [M+H]+.
Example 74 2-(5-(5-(3-(methylsulfonyl)phenyl)thiophen-2-yl)-l-(pyiidin-4-yl)-lH-py^
Example 74a Preparation of methyl 4-(5-bromothiophen-2-yl)-4-oxo-2-(2-(pyιidm-4-yl)hydrazono)bιιtanoate
Figure imgf000237_0001
4-Hydrazinopyridine hydrochloride (366 mg, 2.51 mmol) and methyl 4-(5-bromothiophen-2- yl)-2,4-dioxobutanoate (724 mg, 2.5 mmol) were suspended in MeOH (12 mL) and heated to reflux to afford a yellow solution. After refluxing for 24 hours the reaction was allowed to cool to ambient temperature and was concentrated under reduced pressure to afford an orange oil. LC/MS analysis showed it to be a mixture of two isomers of the hydrazone with a small amount of cyclized pyrazole present. This material was carried on the dehydrative cyclization to prepare the cyclized pyrazole. MS(ES): 384[M+H]+.
Example 74b Preparation of methyl 5-(5-(3-(methylsulfoψl)pJmψl)thiophen-2-yl)-l-(pyridin-4-yl)-lH- carboxylate
Figure imgf000238_0001
The crude (E-Z)-methyl 4-(5-bromothiophen-2-yl)4-oxo-2-(2-(pyridin-4-yl)hydrazono)- butanoate (2.5 mmol from previous step) was suspended in toluene (40 mL), treated with p- toluenesulfonic acid monohydrate (735 mg, 3.9 mmol) and heated to reflux under a Dean-Stark water separator overnight. LC/MS analysis at this time showed two regioisomers of the cyclized pyrazole product The reaction was cooled and diluted with EtOAc, H2O, and basified by careful addition of solid
Na2CO3. The basic aqueous was extracted with EtOAc (3x), and the combined organic extracts were washed with water, brine, dried over Na2SO4, filtered and concentrated under reduced pressure to afford an orange film. This material was purified by flash column chromatography eluting with a gradient from 0% to 100% EtOAc/hexane to afford a mixture of two isomeric pyrazoles. This mixture was carried on to the Suzuki coupling with no further purification.
Example 74c
Preparation of methyl 5-(5-(S-(methylmlfo}iyl)phenyl)thiophen-2-yl)-l-(py^ carboxylate
Figure imgf000238_0002
A mixture of methyl 5-(5-bromothiophen-2-yl)-l-(pyridin-4-yl)-1H-pyrazole-3-carboxylate (480 mg, 1.3 mmol) and 3-(methylsulfonyl)phenylboronic acid (390 mg, 1.9 mmol) was suspended in THF (6 mL) with Na2CO3 (1.0 mL of a 2M aqueous solution, 2.0 mmol). The mixture was sparged with nitrogen for ~ 10 minutes, treated with Pd(PPh3)4 (54 mg, 47 μmol), and heated to 65°C. After 4 hours at 65°C there was still starting methyl 5-(5-bromothiophen-2-yl)-l-(pyridin4-yl)-1H-pyrazole-3- carboxylate visible as evidenced by LC/MS. Additional palladium catalyst was added and heating was continued. After heating at 65°C overnight the reaction mixture was concentrated under reduced pressure to afford a dark semi-solid that was triturated with EtOAc and filtered to remove the solids. The filtrate was concentrated under reduced pressure and purified by flash column chromatography eluting with a gradient from 0% to 50%MeCN/CH2Cl2 to afford methyl 5-(5-(3-(methylsulfonyl)phenyl)- thiophen-2-yl)-l-(pyridin-4-yl)-1H-pyrazole-3-carboxylate (137 mg, 24% yield) as a mixture with triphenylphosphine oxide. This colorless film will be carried on to the Grignard addition without further purification. The following compounds are prepared essentially according to Example 8:
• 2-(5-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}-l-pyridin-4-yl-1H-pyrazol-3-yl)propan-2-ol, 1H NMR (400 MHz CDCl3): δ 8.68-8.57 (2H, m), 8.14 (IH, m), 7.92-7.78 (2H, m), 7.61 (IH, t), 7.43-7.36 (ZH, m), 7.34 (IH, d), 6.93 (IH, d), 6.60 (IH, s), 3.11 (3H, s), 2.75 (IH, s), 1.67 (6H, s). MS(ES): 440 [M+H]+.
• 2-[l-(4-methylpyridin-3-yl)-5-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}-1H-pyrazol-3- yl]propan-2-ol, MS(ES): 454 [M+H]+.
• 2-[l-(2,6-dime&ylpyridin-3-yl)-5-{5-[3-(me1hylsulfonyl)phenyl]-2-tMenyl}-1H-pyrazol-3- yl]propan-2-ol, MS(ES): 468[M+H]+. • 2-[l-(2-methylphenyl)-5-{5-[3-(methylsulfony^ ol, MS(ES): 453 [M+H]+.
• 2-[l-(2,5-dimethylphenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}-1H-pyrazol-3- yl]propan-2-ol, MS(ES): 467 [M+H]+
• 2-[l-(2,3-dimethylphenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}-1H-pyrazol-3- yl]propan-2-ol, MS(ES): 467[M+H]+.
• 2-(l-[2-fluoro-3-(trifluoromethyl)phenyl]-5-{5-[3-(methylsulfonyl)phenyl]-2-tMenyl}-lH^ pyrazol-3-yl)propan-2-ol, MS(ES): 525 [M+H]+
• 2-[l-(2-cMoro-5-fluorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-iMenyl}-1H-pyrazol-3- yl]propan-2-ol, MS(ES): 491 [M+H]+. • 2-[l-(2-chloro-6-methylphenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}-1H-pyrazol-3- yl]propan-2-ol, MS(ES): 487 [M+H]+.
• 2-[l-(5-chloro-2-fluorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}-1H-pyrazol-3- yl]propan-2-ol, MS(ES): 491 [M+H]+
• 2-[l-(2-cMoro-6-fluorophenyl)-5-{5-[3-(me1hylsulfonyl)phenyl]-2-tMenyl}-1H-pyrazol-3- yl]propan-2-ol, MS(ES): 491 [M+H]+.
• 2-{l-(2,6-dichlorophenyl)-5-[3-methyl-3!-(methylsulfonyl)biphenyl4-yl]-1H-pyrazol-3- yl}propan-2-ol, MS(ES): 515 [M+H]+.
• 2-{l-(2,6-dichlorophenyl)-5-[2-methyl-3'-(methylsulfonyl)biphenyl4-yl]4H-pyrazol-3- yl}propan-2-ol, MS(ES): 537 [M+Na]+. • 2-{5-[3-methyl-3Hmethylsulfonyl)biphenyl4-yl]-l-[2-(trMuoromethyl)pyridh-3-yl]-1H- pyrazol-3-yl}propan-2-ol, 516 [MH-H]+.
• 2-{5-[3-methyl-3Hmethylsulfonyl)biphenyl4-yl]-l-[4-(trifluoromethyl)pyridin-3-yl]-1H- pyrazol-3-yl}propan-2-ol MS(ES): 516 [MH-H]+. • 2-{5-[3'-(methylsulfonyl)biphenyl-4-yl]-l-[4-(ttffluoromethyl)pyridin-3-yl]-1H-pyrazol-3- yl}propan-2-ol MS(ES): 502 [M+H]+.
• 2-{5-[3-cMoro-3'-(methylsulfonyl)b^^^ pyrazol-3-yl}propan-2-ol MS(ES): 536 [M+H]+. • 2-{ l-(2,6-dicUorophenyl)-5-[3'-(methylsulfonyl)biphenyl4-yl]-1H-pyrazol-3-yl}propaii-2-ol
MS(ES): 501 [M+H]+.
• 2-{5-[3-cMoro-3'-(methylsulfonyl)biphenyl4-yl]-l-(2,6-dichlorophenyl)-1H-pyrazol-3- yl}propan-2-ol MS(ES): 537 [M+H]+.
• 2-{5-[3-cliloro-3Kmethylsιdfonyl)biphenyl-4-yl]-l-[2-(tώauoromethyl)pyridm^ pyrazol-3-yl}propan-2-ol MS(ES): 536 [M+H]+.
• 2-{3'-cUoro-4'-[l-(2,6-dicMorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]biphenyl-3- yl}propan-2-ol MS(ES): 525 [M+H]+.
2-{ l-(2-chlorophenyl)-5-[4-(lH-indol-6-yl)phenyl]-1H-pyrazDl-3-yl}propan-2-ol, MS(ES): 450 IMfNa]+. • 2-{ l-(2-chlorophenyl)-5-[4-(lH-indol-5-yl)phenyl]-1H-pyraz»l-3-yl}propan-2-ol, MS(ES): 428 [M+H]+.
• 2-{l-(2-chlorophenyl)-5-[4-(l -methyl- lH-indol-5-yl)phenyl]-1H-pyrazol-3-yl}propan-2-ol MS(ES): 442 [M+H]+.
• 2-{ l-(2-chlorophenyl)-5-[4-(lH-indol-4-yl)phenyl]-1H-pyrazol-3-yl}propan-2-ol, MS(ES):450 [M+Na]+.
• 2-(l-(2-cWorophenyl)-5-(3'-(tiifluorometiiyl)biphenyl-4-yl)-1H-pyrazol-3-yl)propan-2-ol. MS (ES): 457[M+H]+.
• 2-(5-(2'-chloro44trifluoromethyl)biphenyM-yl)-l-(2-chlorophenyl)-1H-pyrazol-3-yl)propan- 2-ol. MS (ES): 491[M+H]+. • 2-(l-(2-chlorophenyl)-5-(4'-fluoro-3'-(trifluoromeUiyl)biphenyM-yl)-1H-pyrazol-3-yl)propan-
2-ol. MS (ES): 475[M+H]+
• 4'-(l-(2-cMorophenyl)-3-(2-hydroxypropan-2-yl)-1H-pyr^ol-5-yl)biphenyl-3-sulfonamide. MS (ES): 468[M-HH]+.
• 2-(l-(2-chlorophenyl)-5-(4'-(methylsulfonyl)biphenyl4-yl)-1H-pyrazol-3-yl)propan-2-^^ 467[M+H]+.
• 4^1-(2-clτlorophenyl)-3-(2-hydro}^ropan-2-yl)-1H-pyrazol-5-yl)biphenyl-4-sulfonamide. MS (ES): 468[M+H]+ 2-(4'-(l-(2-cMoroplienyl)-3-(2-hydroxypropan-2-yl)-1H-pyrazol-5-yl)biphenyl-3-yl)propan-2- 1 ol. MS (ES): 447[M+H]+.
4-(l-(2-chlorophenyl)-3-(2-hydroxypropan-2-yl)-1H-pyrazol-5-yl)-N-(2- (dimethylamino)ethyl)biphenyl-3-sulfonainide. MS (ES): 539[M+H]+.
Scheme 29
Figure imgf000241_0001
As depicted in Scheme 29, carboxylic acids can be transformed into amides via acylation. Carboxylic acids 029ES01 (Made in a manner similar to Example 2c) can be converted to their corresponding acid chlorides, 029ES02, by the action of oxalyl chloride in a manner similar to Example 70a. The resulting acid chloride can then be reacted with various amines under basic conditions similar to Example 70b to afford the corresponding amides 029ES03.
Example 75 4-[2-(2-Chbroψheιψl)-5-Mfluowmethyl-2H-pyrazol-3-ylJ-N,N-dimetlψl-berEamide
Example 75a
Prepctration of 4-[2-(2^hloroφheψl)-5-Mfluoromethyl-2H-pyrazol-3-yl]-bemoyl chloride 4-[2-(2-Chloro-phenyl)-5-trifluoromethyl-2H-pyrazol-3-yl]-benzoic acid was prepared in a similar manner as described previously. To a 500ml round bottom flask was added 2g of the acid, ~150ml of dry THF, 300μL of DMF and 1500μL of oxalyl chloride. The reaction was stirred atroom temperature for 30 minutes. The solvent was removed under reduced pressure and the resulting yellow solid was dissolved in dichloromethane and dried under reduced pressure two more times. The resulting yellow solid was then dissolved to 0.1M in dry dichloromethane and used without further purification.
Example 75b Prepω"ation of4-[2-(2-Chloro-phenyl)-54rifluorometl^
Figure imgf000241_0002
In a 1 dram vial was added 4-[2-(2-CMoro-phenyl)-5-trifluoromethyl-2H-pyrazol-3-yl]-benzoyl chloride (300 mL, 0.3 mmol) as a 0.1M solution in Dichloromethane, Dimethyl-amine (27 mg, 0.6 mmol) andN,N-Diisopropylethylamine (77.4mg, O.βmmol). The reaction was stirred at room temperature for 30min and then placed directly on silica and purified using a gradient of Hexane to Ethyl Acetate 0-50% over 10 CV. The relevant fractions were combined and dried in vacuo to give 108.6mg (92%) of an off white solid; MS (ES): 394 [M+H]+; 1HNMR (400 MHz, OMSOd6): δ 7.84 (dd, J= 7.8Hz; 1.7 Hz IH), 7.73-7.58 (m, 3H), 7.45-7.35 (m, 5H), 3.00 (s, 3H), 2.89 (s, 3H). The following compounds were synthesized in a similar manner:
• 4-[l-(2-cUorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-N-(2-moφholin-4- ylethyl)benzamide, MS(ES): 479 [M+H]+.
• methyl N-({4-[l-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5- yl]phenyl}carbonyl)glycinate, MS(ES): 438 [M+H]+. • 4-[l-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-N-(2-oxotetrahydro-3- thienyl)benzamide, MS(ES): 466 [TVB-H]+.
• methyl N-({4-[l -(2-chlorophenyl)-3-(trifluoromethyl)- lH-pyrazol-5-yl]phenyl}carbonyl)-beta- alaninate, MS(ES): 452 [M+H]+.
• 4-[l-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-N-[2- (methylsulfonyl)ethyl]benzamide, MS(ES): 472 [M+H]+.
• l-({4-[l-(2-cMorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl}carbonyl)-4-[2- (methylsulfonyl)ethyl]piperazine, MS(ES): 541 [M+H]+.
• 4-[l-(2-cMorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-N-(l,l-dioxidotetrahydro-3- thienyl)benzamide, MS(ES): 484 [M+H]+. • 4-[l-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-N-[3-
(methylsulfonyl)phenyl]benzamide, MS(ES): 520 |M+H]+.
• 4-[l-(2-cUorophenyl)-3-(l-hydroxy-l-methylethyl)-1H-pyrazol-5-yl]-N,N- dimethylbenzamide, MS(ES): 384 [M+H]+.
• l-(2-cMorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-trύenyl}-N-pyridm-3-yl-1H-pyrazole-3- carboxamide; MS (ES): 535 [M+H]+
• l-(2-cMorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}-N-pyridk-4-yl-1H-pyrazole-3- carboxamide; MS (ES): 535 [M+H]+
• l-(2-cMorophenyl)-N-[2-(dimethylarnm^ lH-pyrazole-3-carboxamide; MS (ES): 529 [M+H]+; • l-(2-cMorophenyl)-N-[3-(methyloxy)propyl]-5-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}-1H- pyrazole-3-carboxamide; MS (ES): 530 |M+H]+;
• 4-{[l-(2-chlorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}-1H-pyrazol-3- yl]carbonyl}moφholine; MS (ES): 528 [M+H]+; • l-(2-cMorophenyl)-N-[6-(methyloxy)pyri^ lH-pyrazole-3-carboxamide; MS (ES): 565 [M+H]+;
• l-(2-cMorophenyl)-N,N-dimethyl-5-{5-[3-^ carboxamide; MS (ES): 486 IMfH]+; • l-{[l-(2-chlorophenyl)-5-{5-[3<me1hylsu]fonyl)phenyl]-2-iWenyl}-1H-pyrazol-3- yl]carbonyl}-4-cyclopentylpiperazine; MS (ES): 595 [M+H]+;
• 1 -(2-chlorophenyl)-N-methyl-N-(l -me1hylpiperidin-4-yl)-5-{5-[3-(methylsulfonyl)phenyl]-2- thienyl}-1H-pyrazole-3-carboxamide; MS (ES): 569 [M+H]+;
• l-(2-chlorophenyl)-N-[3-(dimethylamino)propyl]-N-methyl-5-{5-[3-(me1hylsulfon^ 2-thienyl}-1H-pyrazole-3-carboxamide; MS (ES): 557 [M+H]+;
• l-(2-cUorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-1hienyl}-N-(3-pyrrolidin-l-ylpropyl)- lH-pyrazole-3-carboxamide; MS (ES): 569 [M+H]+;
• l-(2-cMorophenyl)-N-[(l-ethylpy^^ thienyl}-1H-pyiazole-3-carboxamide; MS (ES): 569 [M+H]+; • N-(5-cUoro-2-hydroxyphenyl)-4-[l-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5- yl]benzamide; MS (ES): 492 [M+H]+;
• 4-[l-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-N-qιώiolin-6-ylbenza^ MS (ES): 493 [M+H]+;
• 4-[l-(2-chlorophenyl)-3-(tiMuorome1hyl)-1H-pyrazol-5-yl]-N-(2,3-dihydro-l,4-ben^^ yl)benzamide; MS (ES): 500 [M+H]+;
• 4-[l-(2-cUorophenyl)-3-(1rffluoromethyl)-1H-pyrazol-5-yl]-N-{4-[2,2,2-1rifluoro-l-hy^ (trifluoromethyl)e1hyl]phenyl}benzamide; MS (ES): 608 [M+H]+;
• 4-[l -(2-chlorophenyl)-3-(trifluoromethyl)- lH-pyrazol-5-yl]-N-(3-cyanophenyl)benzamide; MS (ES): 467 [M+H]+; • 2-[({4-[l-(2-chlorophenyl)-3-(trifluorome1hyl)-1H-pyrazol-5-yl]ρhenyl}carboiiyl)amino]-5- methylbenzoic acid; MS (ES): 500 [M+H]+; '
• 2-[({4-[l-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5- yl]phenyl}carbonyl)amino]benzoic acid; MS (ES): 486 [M+H]+;
• 4-[l-(2-cMorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-N-[2-(ethyloxy)phenyl]benza^ MS (ES): 486 [M+H]+;
• 4-[l-(2-cWorophenyl)-3-(1rifluoromethyl)-1H-pyrazol-5-yl]-N-(2-cyanophenyl)benzan^ MS (ES): 467 [M+H]+; • 2-[({4-[l-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5- yl]phenyl}carbonyl)amino]pyridine-3-carboxylic acid; MS (ES): 487 [M+H]+;
• N-[4-(aminocarbonyl)phenyl]-4-[l-(2-cUorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5- yl]benzamide; MS (ES): 485 [M+H]+; • 4-[l-(2-cMorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-N-quinolin-5-ylbeiX-^mide; MS
(ES): 493 [M+H]+;
• 4-[l-(2-cUorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-N-(2-piperidin-l- ylphenyl)benzamide; MS (ES): 525 IMfH]+;
• N-(5-chloro-2-moφholin-4-ylphenyl)-4-[l-(2-chlorophenyl)-3-(trifluorometiiyl)-1H-pyrazol-5- yl]benzamide; MS (ES): 561 |M+H]+;
• 4-[l-(2-cUorophenyl)-3-(ttMuoromethyl)-1H-pyrazol-5-yl]-N-isoxazol-3-ylbenzamide; MS (ES): 433 [M+H]+;
• 4-[l-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-N-[5-(l,l-dimethylethyl)-ls3,4- thiadiazol-2-yl]benzamide; MS (ES): 506 [M+H]+; • 2-[({4-[l-(2-cUorophenyl)-3-(tffluoromethyl)-1H-pyrazol-5-yl]phenyl}carbonyl)amino]-4- methylbenzoic acid; MS (ES): 500 JMfH]+;
• 4-[l-(2-chloropheiiyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-N-1H-indazol-5-ylbenzam MS (ES): 482 [MH-H]+;
• 4-[l-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-N-{4-[(l- methιyle1hyl)oxy]phenyl}benzamide; MS (ES): 500 [M+H]+;
• 4-[l-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazDl-5-yl]-N-(4-me1hyl-l,3-thiazol-2- yl)benzamide; MS (ES): 463 [M+H]+;
• N-(2-cUoro-3-hydroxy-4-methylphenyl)-4-[l-(2-cMorophenyl)-3-(1rifluorometiiyl)-1H- pyrazol-5-yl]benzamide; MS (ES): 506 [M+H]+; • {4-[({4-[l-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5- yl]phenyl}carbonyl)amino]phenyl}acetic acid; MS (ES): 500 [M+H]+;
• 4-[l-(2-chlorophenyl)-3-(trifluorome^ methylbenzamide; MS (ES): 460 [M+H]+;
• 4-({4-[l-(2-cMorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl}carbonyl)-2,6- dimethylmorpholine; MS (ES): 464 [M+H]+;
• l-({4-[l-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl}carbonyl)4- (ethylsulfonyl)piperazine; MS (ES): 527 [M+H]+; • l-({4-[l-(2-cUorophenyl)-3-(1rifluoromethyl)-1H-pyrazol-5-yl]phenyl}carbonyl)-l,4- diazepane; MS (ES): 449 [M+H]+;
• 4-[l-(2-cUorophenyl)-3-(tffluoromethyl)-1H-pyrazol-5-yl]-N-methyl-N-(pyridin-4- ylmethyl)benzamide; MS (ES): 471 [M+H]+; • 4-({4-[l-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5- yl]phenyl}carbonyl)thiomoφholine; MS (ES): 452 [M+H]+;
• l-({4-[l-(2-cUorophenyl)-3-(trMuorome1hyl)-1H-pyrazol-5-yl]phenyl}carbonyl)piperidiii-3-ol; MS (ES): 450 [M+H]+;
• [l-({4-[l-(2-chlorophenyl)-3-(1rifluoromethyl)-1H-pyrazol-5-yl]phenyl}carbonyl)pyrrolidin-2- yl]methanol; MS (ES): 450 [M+H]+;
• l-({4-[l-(2-cMorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl}carbonyl)piperidm MS (ES): 450 [M+H]+;
• 1 -({4-[l -(2-chlorophenyl)-3-(trifluoromethyl)- lH-pyrazol-5-yl]phenyl}carbonyl)-4-methyl- 1 ,4- diazepane; MS (ES): 463 [M+H]+; • l-({4-[l-(2-cMorophenyl)-3-(trifluoromethyl)4H-pyrazol-5-yl]plienyl}carbonyl)-4-[2-
(trifluoromethyl)phenyl]piperazine; MS (ES): 579 [M+H]+;
• 4-[l-(2-cUorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-N-[2-(dime1hylamino)ethyl]-N- methylbenzamide; MS (ES): 451 [M+H]+;
• 4-[l-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-N-me1iiyl-N-(2- thienylmethyl)benzamide; MS (ES): 476 |M+H]+;
• 4-[l-(2-cUorophenyl)-3-(1rffluoromethyl)-1H-pyrazol-5-yl]-N-(4-piperidin-l- ylphenyl)benzamide; MS (ES): 525 [M+H]+;
• l-({4-[l-(2-cUorophenyl)-3-(trifIuoromethyl)-1H-pyrazol-5-yl]phenyl}carbonyl)piperidine-4- carboxylic acid; MS (ES): 478 |M+H]+; • 4-({4-[l-(2-cUorophenyl)-3-(trifluoromeih.yl)-1H-pyrazol-5-yl]phenyl}carbonyl)moφholine;
MS (ES): 436 IMfH]+;
• 4-[l-(2-cUorophenyl)-3-(1rifluorome1hyl)-1H-pyrazol-5-yl]-N-l,3,4-thiadiazol-2-ylbenzan^ MS (ES): 450 [M+H]+;
• 4-[l-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-N-(4-hydroxy-3- methylphenyl)benzamide; MS (ES): 472 |M+H]+;
• 4-[l-(2-chlorophenyl)-3-(tffluoromethyl)-1H-pyrazol-5-yl]-N-[4-(5-methyl-3-oxo-2,3-dihydro- lH-pyrazDl-l-yl)phenyl]benzamide; MS (ES): 538 [M+H]+; • 2-[4-({4-[l-(2-cMorophenyl)-3-(tiffluorOmethyl)-1H-pyrazol-5-yl]phenyl}carbonyl)piperazin- l-yl]benzonitrile; MS (ES): 536 [M+H]+;
• l-({4-[l-(2-cMorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl}carbonyl)-4-pyridin-Φ ylpiperazine; MS (ES): 512 [M+H]+; • 1 -({4-[l -(2-chlorophenyl)-3-(trifluoromethyl)- lH-pyrazol-5-yl]phenyl}carbonyl)-4-[4-
(methyloxy)phenyl]piperazine; MS (ES): 541 [M+H]+;
• 2-[4-({4-[l-(2-cMorophenyl)-3-(1rifluorOmethyl)-1H-pyrazol-5-yl]phenyl}carbonyl)pipei^in- l-yl]phenol; MS (ES): 527 [MfH]+;
• 4-({4-[l-(2-cUorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl}carbonyl)piperazin-2- one; MS (ES): 449 [M+H]+;
• 3-({4-[l-(2-cMorophenyl)-3-(trifluorome&^ 1,3-oxazolidine; MS (ES): 450 [M+H]+;
• l-({4-[l-(2-cMorophenyl)-3-(trifluorometlαyl)-1H-pyrazol-5-yl]phenyl}carbonyl)4- (tjetrahydrofuran-2-ylmethyl)piperazine; MS (ES): 519 [M+H]+; • l-({4-[l-(2-cMorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl}carbonyl)4- propanoylpiperazine; MS (ES): 491 [M+H]+;
• l-({4-[l-(2-chlorophenyl)-3-(1rifluoromethyl)-1H-pyrazol-5-yl]phenyl}carbonyl)-4- methylpiperazine; MS (ES): 449 [M+H]+;
• l,l-dimethyle%l [l-({4-[l-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5- yl]phenyl}carbonyl)pyrrolidin-3-yl]carbamate; MS (ES): 535 [M+H]+;
• l-({4-[l-(2-chlorophenyl)-3-(lrifluoromethyl)-1H-pyrazol-5-yl]phenyl}carbonyl)azetidine-3- carboxylic acid; MS (ES): 450 |M+Hj+;
• 4-[4-({4-[l-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl}carbonyl)piperazin- l-yl]phenol; MS (ES): 527 [M+H]+; • 4-[l-(2-cMorophenyl)-3-(1rffluoromethyl)-1H-pyrazol-5-yl]-N-[2-(methyloxy)etliyl]-N-(l- methylpiperidin-4-yl)benzamide; MS (ES): 521 [M+Hj+;
• 4-[l-(2-cUorophenyl)-3-(trifluorome1hyl)-1H-pyrazol-5-yl]-N-meUiyl-N-(l-methylpyiτoli 3-yl)benzamide; MS (ES): 463 [M+HJ+;
• l-({4-[l-(2-cUorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl}carbonyl)-l,2,5,6- tetrahydropyridine-3-carboxylic acid; MS (ES): 476 [M+H]+;
• l-({4-[l-(2-cUorophenyl)-3-(tiifluorome1hyl)-1H-pyrazol-5-yl]phenyl}carbonyl)-4-(l- methylpropyl)piperazine; MS (ES): 491 [M+HJ+; • 3-[l-({4-[l-(2-cMorophenyl)-3-(ttffluorome 4-yl]-1H-indole; MS (ES): 549 [MfHJ+;
• 4-[l-(2-cUorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-N-cyclopropyl-N-(l- methylpiperidin-4-yl)benzamide; MS (ES): 503 [M-HH]+; • 4-[l-(2-cMorophenyl)-3-(tiifluorOmethyl)-1H-pyrazol-5-yl]-N-[2-(dimethylamino)ethyl]-N- ethylbenzamide; MS (ES): 465 [MfHJ+;
• 2-[4-({4-[l-(2-cMorophenyl)-3-(trMuoromethyl)-1H-pyrazol-5-yl]phenyl}carbonyl)piperazin- l-yljpyrazine; MS (ES): 513 [MfH]+;
• 4-[l<2-chlorophenyl)-3-(trifluoromethyl)4H-pyrazol-5-yl]-N-(l,3-dioxolan-2-ylmethyl)-N- methylbenzamide; MS (ES): 466 [MfH]+;
• N-(l-acetylpiperidk-4-yl)-4-[l-(2-cUorophenyl)-3-(1rifluoromethyl)-1H-pyrazol-5-yl]-N- cyclopropylbenzamide; MS (ES): 531 IMfH]+;
• l-({4-[l-(2-cMorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl}carbonyl)-4-(6- methylpyridin-2-yl)piperazine; MS (ES): 526 [M+H]+; • ethyl l-({4-[l-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5- yl]phenyl}carbonyl)piperidine-2-carboxylate; MS (ES): 506 [M+H]+;
• l-({4-[l-(2-cUorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl}carbonyl)-4-(3- methylphenyl)piperazine; MS (ES): 525 IMfHJ+;
• 4-[l-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-N-cyclopropyl-N-(l- propylpiperidin-4-yl)benzamide; MS (ES): 531 [MfHJ+;
• ethyl l-({4-[l-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5- yl]phenyl}carbonyl)piperidine4-carboxylate; MS (ES): 506 [M+H]+;
• l-({4-[l-(2-chlorophenyl)-3-(tiiQuoromethyl)-1H-pyrazol-5-yl]phenyl}carbonyl)-4-[4- (trmuoromethyl)pyrimidin-2-yl]-l,4-diazepane; MS (ES): 595 [M+H]+; • 4-[l-(2-cMorophenyl)-3-(trifluoromethyl)4H-pyrazol-5-yl]-N-methyl-N-(pyridin-3- ylmethyl)benzamide; MS (ES): 471 [M-fHJ+;
• N-butyl-4-[l-(2-chlorophenyl)-3-(tiifluoromethyl)-1H-pyrazol-5-yl]-N-(2- tbienylmethyl)benzamide; MS (ES): 518 [MfHJ+;
• l-({4-[l-(2-cUorophenyl)-3-(trifluorometliyl)-1H-pyrazol-5-yl]phenyl}carbonyl)4- ethylpiperazine; MS (ES): 463 [M-fH]+;
• l-({4-[l-(2-cMorophenyl)-3-(trifluoromethyl)-1H-pyrazDl-5-yl]phenyl}carbonyl)-4-[3- (methyloxy)phenyljpiperazine; MS (ES): 541 IMfHJ+; • 4-[l-(2-cUorophenyl)-3-(1rifluoromethyl)-1H-pyrazol-5-yl]-N-methyl-N-(l-methylpiperi^ yl)benzamide; MS (ES): 477 [M+H]+;
• N-(2-amino-2-oxoethyl)4-[l-(2-cUorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-N- meihylbenzamide; MS (ES): 437 [M+H]+; • l-({4-[l-(2-cUorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl}carbonyl)4-(furan-2- ylcarbonyl)piperazine; MS (ES): 529 [M+H]+;
• l-({4-[l-(2-cUorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl}carbonyl)-4-(2- fluorophenyl)piperazine; MS (ES): 529 [M+H]+;
• l-({4-[l-(2-cWorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl}carbonyl)4-[2- (methyloxy)phenyl]piperazine; MS (ES): 541 |M+H]+;
• l-({4-[l-(2-cMorophenyl)-3-(1rifluoromethyl)4H-pyrazol-5-yl]phenyl}carbonyl)-4-[2-(2- thienyl)ethyl]piperazine; MS (ES): 545 [M+H]+;
• 4-[({4-[l-(2-chlorophenyl)-3-(trifluorometiiyl)-1H-pyrazol-5-
, yl]phenyl}carbonyl)amino]benzoic acid; MS (ES): 486 [MfH]+; • 4-[l-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-N-[3-(piperidin-l- ylsulfonyl)phenyl]benzamide; MS (ES): 589 [M+H]+;
• 4-[l-(2-cUorophenyl)-3-(trifluorome1hyl)-1H-pyrazol-5-yl]-N-l,3-tbJazol-2-ylbenzamide; MS (ES): 449 [M+H]+;
• 4-[l-(2-cMorophenyl)-3-(trMuoromethyl)-1H-pyrazol-5-yl]-N-[3-(pyrrolidin-l- ylsulfonyl)phenyl]benzamide; MS (ES): 575 [M+H]+;
• 4-[l-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-N-[2-methyl-4- (methyloxy)phenyl]benzamide; MS (ES): 486 [MfHQ+;
• 4-[l-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-N-{2- [(dffluoromethyl)oxy]phenyl}benzamide; MS (ES): 508 [M+H]+; • 4-[l-(2-clτlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-N-{4-
[(difluoromethyl)oxy]phenyl}benzamide; MS (ES): 508 [M+H]+;
• 4-[l-(2-chlorophenyl)-3-(ttifluoromethyl)-1H-pyrazol-5-yl]-N-(3-fluorophenyl)benzamide; MS (ES): 460 [M+H]+;
• 4-[l-(2-cMorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-N-[3-(morpholin-4- ylsulfonyl)phenyl]benzamide; MS (ES): 591 [M+H]+;
• 4-[l-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-N-[4- (trifluoromethyl)phenyl]benzamide; MS (ES): 510 [M+H]+; • N-(3-cWoiOphenyl)4-[l-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]tenzamide; MS (ES): 476 [M+H]+;
• 4-[l-(2-cMorophenyl)-3-(1riflTO^ yljbenzamide; MS (ES): 521 [M+H]+; • 4-[l-(2-cMorOphenyl)-3-(trifluoromeihyl)-1H-pyrazol-5-yl]-N-[2- (trifluoromethyl)phenyl]benzamide; MS (ES): 510 [M+H]+;
• 4-[l-(2-cUorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-N-[2- (methyloxy)phenyl]benzamide; MS (ES): 472 [M+H]+;
• 4-[l-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-N-[2-fluoro-5- (trifluorometliyl)phenyl]benzamide; MS (ES): 528 [M+H]+;
• N-(2-cMorophenyl)4-[l-(2-cUorophenyl)-3-(tiifluoromethyl)-1H-pyrazol-5-yl]benzamide; MS (ES): 476 [M+H]+;
• 4-[l-(2-cMorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-N-[3- (methyloxy)phenyl]benzamide; MS (ES): 472 [M+H]+; • 4-[l-(2-cMorophenyl)-3-(trifluoroniethyl)-1H-pyrazol-5-yl]-N-[3-
(trifluoromethyl)phenyl]benzamide; MS (ES): 510 [M+H]+;
• 4-[l-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-N-{2- [(trifluoromethyl)oxy]phenyl}benzamide; MS (ES): 526 [M+H]+;
• 4-[l-(2-cMorophenyl)-3-(triiluorome1hyl)-1H-pyrazol-5-yl]-N-[4-(pyridin-4- ylcarbonyl)phenyl]benzamide; MS (ES): 547 |M+H]+;
• N-[3,5-bis(methylo^)phenyl]-4-[l-(2-chlorophenyl)-3-(ttffluoromethyl)-1H-pyrazol-5- yl]benzamide; MS (ES): 502 [M+H]+;
• 4-[l-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-N-pyridin-3-ylbenzatnide; MS (ES): 443 [M+H]+; • N-(2-cUoro-5-hydroxyphenyl)-4-[l-(2-cMorophenyl)-3-(ttffluorome1hyl)-1H-pyrazol-5- yljbenzamide; MS (ES): 492 [M+H]+;
• 4-[l-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-N-pyridin-4-ylben2mnide; MS (ES): 443 [M+H]+;
• N-l,3-benzodioxol-5-yl4-[l-(2-cMorophenyl)-3-(trifluoromethyl)-1H-pyrazDl-5-yl]benzamide; MS (ES): 486 |M+H]+;
• 3-[({4-[l-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5- yl]phenyl}carbonyl)amino]benzoic acid; MS (ES): 486 [M+H]+; • 4-[l-(2-cMorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-N-[2-methyl-6- (methyloxy)phenyl]benzamide; MS (ES): 486 [M+H]+;
• 4-[l-(2-cUorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-N-(3-methylpyridin-2- yl)benzamide; MS (ES): 457 [MfH]+; • 4-[l-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-N-{4- [(trifluoromethyl)oxy]phenyl}benzamide; MS (ES): 526 [M+H]+;
• 4-[l-(2-cMorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-N-(3-cyclopropyl-1H-pyrazol-5- yl)benzamide; MS (ES): 472 [MfH]+;
• N-[3,4-bis(melhyloxy)phenyl]-4-[l-(2-cMorophenyl)-3-(tiMuorome1hyl)-1H-pyrazol-5- yl]benzamide; MS (ES): 502 |M+H]+;
• 4-[l-(2-cMorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-N-quinolm-8-ylbenzaπiide; MS (ES): 493 [M+H]+;
• 4-cUoro-3-[({4-[l-(2-cMorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5- yl]phenyl}carbonyl)amino]benzoic acid; MS (ES): 520 [M+H]+; • l-({4-[l-(2-cMorophenyl)-3-(tiifluoromethyl)-1H-pyrazol-5-yl]phenyl}carbonyl)azBtidine-2- carboxylic acid; MS (ES): 450 [M+H]+;
• 4-[l-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-N-{3- [(trifluoromethyl)oxy]phenyl}benzamide; MS (ES): 526 [M+H]+;
• 4-[l-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-N-{4- [(trifluorome1hyl)thio]phenyl}benzamide; MS (ES): 542 [M+H]+;
• 4-[l-(2-cMorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-N-[6-(me1hyloxy)pyridin-3- yl]benzamide; MS (ES): 473 [M+H]+;
• 4-[l-(2-cUorophenyl)-3-(tffluoromethyl)-1H-pyrazol-5-yl]-N-(4-methylpyridin-2- yl)benzamide; MS (ES): 457 [M+H]+; • 4-[l-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-N-[2-methyl-5- (metbyloxy)phenyl]benzamide; MS (ES): 486 [M+H]+;
• 4-[l-(2-cUorophenyl)-3-(tiifluoromethyl)-1H-pyrazol-5-yl]-N-(l-methyl-1H-pyrazol-5- yl)benzamide; MS (ES): 446 [M+H]+;
• N-[5-(acetylamino)-2-cMorophenyl]-4-[l -(2-chlorophenyl)-3-(trifluoromethyl)- lH-pyrazol-5- yl]benzamide; MS (ES): 533 [M+H]+;
• 4-[l-(2-cUorophenyl)-3-(tiffluorome% thiadiazol-2-yl]benzamide; MS (ES): 518 [M+H]+; • 4-[l-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-N-[4-cliloro-2- (trifluoromethyl)phenyl]benzamide; MS (ES): 544 [M+H]+;
• 4-[l-(2-cUorophenyl)-3-(tiifluoromethyl)-1H-pyrazol-5-yl]-N-(5-methylpyridin-2- yl)benzamide; MS (ES): 457 [M+HJ+; • 4-[l-(2-cUorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-N-[2-(methyloxy)-5-
(trifluoromethyl)ρhenyl]benzamide; MS (ES): 540 [MfHJ+;
• 4-[l-(2-cUorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-N-(6-methylpyridin-2- yl)benzamide; MS (ES): 457 [MfHJ+;
• 4-[l-(2-cUorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-N-[4-(metiiyloxy)biphenyl-3- yl]benzamide; MS (ES): 548 |MfHJ+;
• N-(3-cMoro4-fluorophenyl)-4-[l-(2-cUorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5- yl]benzamide; MS (ES): 494 [MfHJ+;
• 4-[l-(2-cUorophenyl)-3-(tiifluoromethyl)-1H-pyrazol-5-yl]-N-{6-[(trifluoromethyl)oxy]-l,3^ benzothiazol-2-yl}benzamide; MS (ES): 583 [MfHJ+; • 4-[l-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-N-[2-fluoro-3-
(trifluoromethyl)phenyl]benzamide; MS (ES): 528 [M+H]+;
• 4-[l-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-N-[2-(lH-pyrrol-l- yl)phenyl]benzamide; MS (ES): 507 \M+Η\+;
• 4-[l-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-N-[2-chloro-5- (trifluorometliyl)phenyl]benzamide; MS (ES): 544 [M+H]+;
• 4-[l-(2-cUorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-N-(l-methyl-1H-pyrazol-3- yl)benzamide; MS (ES): 446 |M+H]+;
• 4-[l-(2-cWorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-N-[5-(l,l-dime1hylethyl)-2- (methyloxy)phenyl]benzamide; MS (ES): 528 [M+H]+; • N-[5-cMoro-2-(methyloxy)phenyl]4-[l-(2-cMorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5- yl]benzamide; MS (ES): 506 [M+H]+;
• 4-[l-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-N-(5-methyl-l,3,4-thiadiazol-2- yl)benzamide; MS (ES): 464 [M+H]+;
• 4-[l-(2-cUorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-N-(2,6-dcMorophenyl)ben2amide; MS (ES): 510 [M+H]+;
• 4-[l-(2-cUorophenyl)-3-(trifluoromethy^ MS (ES): 458 |M+H|+; 2-[({4-[l-(2-cMorophenyl)-3-(trifluoro (methyloxy)benzoic acid; MS (ES): 516 [M+H]+;
4-[l-(2-cMorophenyl)-3-(1rifluoromethyl)-1H-pyra2Dl-5-yl]-N-(5-metiiylisoxazol-3- yl)benzamide; MS (ES): 447 [M+H]+;
4-[l -(2-chlorophenyl)-3-(trifluoromethyl)- lH-pyrazol-5-yl]-N-[3-fluoro-4- (methyloxy)phenyl]benzarnide; MS (ES): 490 [M+H]+;
4-[l-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-N-[4- (dimethylamino)phenyl]benzamide; MS (ES): 485 [M+H]+;
• 4-[l-(2-cMorophenyl)-3-(trifluoromethy^^ MS (ES): 446 [M+H]+;
• ethyl 4-[({4-[l-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5- yl]phenyl}carbonyl)arnino]piperidine-l-carboxylate; MS (ES): 521 [MH-Bf]+;
• 4-[l-(2-cMorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-N-(te1rahydrofuran-2- ylmethyl)benzamide; MS (ES): 450 [M+H]+; • 4-[l-(2-cMorophenyl)-3-(tiMuorome1hyl)-1H-pyrazol-5-yl]-N-(2-thienylmethyl)benzanii
MS (ES): 462 [MfHQ+;
• 4-[l-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-N-[2- (dimethylamino)e%l]benzamide; MS (ES): 437 [M+H|+;
• 4-[l-(2-cMorophenyl)-3-(trifluoro dimethylpropyl]benzamide; MS (ES): 479 [M+H]+;
• 4-[l-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazDl-5-yl]-N-(2-pyrrolidin-l- ylethyl)benzamide; MS (ES): 463 [M+H]+; .
• 4-[l-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-N-{3-[(l- metliylethyl)oxy]propyl}benzamide; MS (ES): 466 [M+H]+; • 4-[l-(2-cMorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-N-{[2-
(methyloxy)phenyl]methyl}benzamide; MS (ES): 486 [M+H]+;
• 4-[l-(2-cMorophenyl)-3-(ttffluoromethyl)-1H-pyrazol-5-yl]-N-(3-moφholin-4- ylpropyl)benzamide; MS (ES): 493 (M+H]+;
• 4-[l-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-N-[2-(2-tMenyl)e%l]benza^ MS (ES): 476 [M+H]+;
• 4-[l-(2-chlorophenyl)-3-(1rifluorome^ MS (ES): 457 [M+H]+; • 4-[l-(2-chlorophenyl)-3-(trifluorometliyl)-1H-pyrazol-5-yl]-N-{2-[3- (meftyloxy)phenyl]e%l}benzamide; MS (ES): 500 [M+H]+;
• N-{[3,4-bis(methyloxy)phenyl]methyl}4-[l-(2-cMorophenyl)-3-(tiifluoromethyl)-1H-pyrazol- 5-yl]benzamide; MS (ES): 516 [M+H]+; • 4-[l-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-N-{2-[4- (methyloxy)phenyl]ethyl}benzamide; MS (ES): 500 [M+H]+;
• 2-piperidin-l-ylethyl 4-[l-(2-cUorophenyl)-3-(ttffluoromethyl)-1H-pyrazol-5-yl]benzoate, MS(ES): 478 [M+H]+.
• 2-(dimethylamino)ethyl 4-[l-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]benzoa1je, MS(ES): 438 [M+H]+.
• 2-piperidin-l-ylethyl 4-[l-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]benzoate, MS(ES): 478 [M+H]+.
• 2-morpholin-4-ylethyl 4-[l-(2-cUorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]beiizoate, MS(ES): 480 [M+H]+. • 3-(dimethylamino)propyl 4-[l-(2-cMorophenyl)-3-(tiifluoromethyl)-1H-pyrazol-5-yl]benzoate,
MS(ES): 452 [M+H]+.
• 2-(methylsulfonyl)ethyl 4-[l-(2-cUorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]benzoate, MS(ES): 473 [M+H]+.
• 2-(4-methylpiperazin-l-yl)ethyl 4-[l-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5- yl]benzoate, MS(ES): 493 [M+H]+.
• 3-(methylsulfonyl)propyl 4-[l-(2-chlorophenyl)-3-(trifluorometiiyl)-1H-pyrazol-5-yl]benzoate, MS(ES): 487 [M+H]+
• 2-(dimethylammo)ethyl 4-[l-(2-cUorophenyl)-3-(trMuorome1hyl)-1H-pyrazol-5-yl] MS (ES): 438 [M+H]+; • 2-pyridin-2-ylethyl 4-[l-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]benzoate; MS (ES): 472 [M+H]+;
• [3,5-dme&yl4-(methyloxy)pyridm-2-yl]m^ pyrazol-5-yl]benzoate; MS (ES): 516 [M+H]+;
• 2-(propylthio)ethyl 4-[l-(2-cUorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]benzoate; MS (ES): 469 [MH-H]+;
• furan-3-ylmethyl 4-[l-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]benzoate; MS (ES): 447 |M+H]+; • (2,4-difluorophenyl)methyl 4-[l -(2-chlorophenyl)-3-(trifluoromethyl)- lH-pyrazol-5- yl]benzoate; MS (ES): 493 [M+H]+;
• furan-2-ylmethyl 4-[l-(2-cMorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]benzoate; MS (ES): 447 [M+H]+; • 2-(2-methylphenyl)eihyl 4-[l-(2-cUorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]benzoate;
MS (ES): 485 |M+H]+;
• 2-[3-(ϋMuoromethyl)phenyl]ethyl4-[l-(2-cUorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5 yl]benzoate; MS (ES): 539 [M+H]+;
• 3-(methyltMo)propyl 4-[l-(2-cMorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]benzoate; MS (ES): 455 [M+H]+;
• 2-oxo-2-phenylethyl 4-[l-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]benzoate; MS (ES): 485 |M+H]+;
• pyridin-3-ylmethyl 4-[l-(2-chlorophenyl)-3-(trifluorome1hyl)-1H-pyrazol-5-yl]benzoate; MS (ES): 458 [M+H]+; • 2-(phenylsulfonyl)ethyl 4-[l-(2-cblorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]benzoate;
MS (ES): 535 [M+H]+;
• (2,5-dicMorophenyl)methyl4-[l-(2-chlorophenyl)-3-(1rifluoromethyl)-1H-pyrazol-5- yl]benzoate; MS (ES): 525 [M+H]+;
• [4-(methylthio)phenyl]metliyl 4-[l -(2-chlorophenyl)-3-(trifluoromethyl)- lH-pyrazol-5- yl]benzoate; MS (ES): 503 [M+H]+;
• cyanomethyl4-[l-(2-cMorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]benzoate; MS (ES): 406 |M+H]+;
• 3-[3-(tiifluoromethyl)-1H-pyrazQM^^ pyrazol-5-yl]benzoate; MS (ES): 543 [M+H]+; • 2-isoxazol-4-ylethyl4-[l-(2-cUorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]benzoate; MS
(ES): 462 [MH-HI+;
• 2-(2-thienyl)ethyl 4-[l-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]benzoate; MS (ES): 477 [MH-HI+;
• (5-methyl-l-phenyl-1H-pyrazol-4-yl)methyl4-[l-(2-chlorophenyl)-3-(trifluoromethyl)-1H- pyrazol-5-yl]benzoate; MS (ES): 537 [M+H]+;
• 2,2'-biMen-5-ylmethyl4-[l-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]benzoate; MS (ES): 545 [MH-Hl+ • 3-pyridin-2-ylpropyl 4-[l-(2-cMorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]benzoate; MS (ES): 486 [MfHJ+;
• 2-(methylthio)ethyl 4-[l-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]benzoate; MS (ES): 441 [M+H]+; • pyridin-4-ylmethyl 4-[l-(2-cUorophenyl)-3-(trifluoromeihyl)-1H-pyrazol-5-yl]benzoate; MS (ES): 458 [MfHJ+;
• l,3-benzothiazol-2-ylmethyl4-[l-(2-cMo yl]benzoate; MS (ES): 514 [MH-H]+;
• 3-thienylmetbyl 4-[l-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]benzoate; MS (ES): 463 [Mf-H]+;
• 2-[(4-methylphenyl)sulfonyl]e%14-[l-(2-chlorophenyl)-3-(1rifluoromethyl)-1H-pyrazol-5- yl]benzoate; MS (ES): 549 [M+HJ+; • 2-(4-methyl-l,3-thiazol-5-yl)ethyl 4-[l-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5- yl]benzoate; MS (ES): 492 |M+H]+; • (2-phenyl-l,3-thiazol-4-yl)methyl 4-[l-(2-cUorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5- yl]benzoate; MS (ES): 540 [M+HJ+;
• 2-cyanoethyl 4-[l-(2-chlorophenyl)-3-(trifluorometliyl)-1H-pyrazol-5-yl]benzoate; MS (ES): 420 [M+H]+;
• 4-[l-(2-chlorophenyl)-3-(trifluorometiiyl)-1H-pyrazol-5-yl]benzoic hydroxyacetic anhydride; MS (ES): 425 [M+H]+;
• [l-(phenylmethyl)4H-imidazol-2-yl]methyl4-[l-(2-chlorophenyl)-3-(trifluoromethyl)-1H- pyrazol-5-yl]benzoate; MS (ES): 537 [MfHJ+;
• (5-me1hyl-3-phenylisoxazol-4-yl)methy^ 5-yl]benzoate; MS (ES): 538 [MfHJ+; • [4-(lH-pyrazol-l-yl)phenyl]methyl 4-[l-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5- yl]benzoate; MS (ES): 523 |M+HJ+;
• [2,3-bis(methyloxy)phenyl]methyl4-[l-(2-cMorophenyl)-3-(tiifluoromethyl)-1H-pyrazol^^ yl]benzoate; MS (ES): 517 |M+H]+;
• (5-methyl-2-phenyl-2H-l,2,3-1riazol-4-yl)methyl4-[l-(2-chlorophenyl)-3-(1rifluoromethyl)- lH-pyrazol-5-yl]benzoate; MS (ES): 538 [M-fHJ+;
• [4-(lH-l,2,4-triazol-l-yl)phenyl]me%H 5-yl]benzoate; MS (ES): 524 [MfH]+; • [6-(phenyloxy)pyridin-3-yl]me1hyl 4-[l-(2-c^^ yl]benzoate; MS (ES): 550 [M+H]+;
• 2-{[4-(trifluoromethyl)pyridin-2^^ pyrazol-5-yl]benzoate; MS (ES): 556 [MH-H]+; • 2-(3-methyl-5-oxo4,5-dihydro-1H-pyrazol-4-yl)ethyl 4-[l-(2-chlorophenyl)-3-
(trifluoromethyl)-1H-pyrazol-5-yl]benzoate; MS (ES): 491 [M-I-H]+;
• (2-butyl-5-chloro-1H-imi<teol-4-yl)m pyrazol-5-yl]benzoate; MS (ES): 537 [MH-HJ+;
• (5-pyridm-2-yl-2-tMenyl)methyl 4-[l-(2-chlorophenyl)-3-(tiffluoromeihyl)-1H-pyrazol-5- yljbenzoate; MS (ES): 540 [M+HJ+;
• (5-methyl-1H-irrudazol-4-yl)mefcyM yljbenzoate; MS (ES): 461 [M+HJ+;
• 3-pyridin-3-ylpropyl 4-[l-(2-cMorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]benzoate; MS (ES): 486 [M+H]+; • 2-[(2-methylpropyl)thio]ethyl 4-[l-(2-chlorophenyl)-3-(trifluorOmethyl)-1H-pyrazol-5- yl]benzoate; MS (ES): 483 [M+HJ+;
• [5-(2-methyl-l,3-tlύazol4-yl)-2-thienyl]methyl4-[l-(2-chlorophenyl)-3-(trifluoromethyl)-l^ pyrazol-5-yl]benzoate; MS (ES): 560 [MfHJ+;
• 2-(2-cMorophenyl)ethyl 4-[l-(2-cMorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]benzoate; MS (ES): 505 [M+Hj+;
• pyridin-2-ylmethyl 4-[l-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]benzoate; MS (ES): 458 [M+HJ+;
• lH-imidazDl-4-ylme1hyl 4-[l-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]benzoate MS (ES): 447 [M+H|+; • (2-methylpyridin-3-yl)methyl 4-[l-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5- yl]benzoate; MS (ES): 472 |M+HJ+;
• [l-(phenylsulfonyl)-1H-indol-3-yl]methyl4-[l-(2-cMorophenyl)-3-(trifluoromethyl)-1H- pyrazol-5-yl]benzoate; MS (ES): 636 [M-I-H]+;
• 2-(lH-iinidazol-l-yl)e1hyl4-[l-(2-chloro MS (ES): 461 |M+Hj+;
• 2-(diethylamino)e&yl 4-[l-(2-cMorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]ben^^ MS (ES): 466 [M+Hj+; • ^({^[l^-cMoropheny^-S^trifluorome^^-1H-pyrazol-S-yyphenylJcarbony^glycine, MS(ES): 424 [M+H]+.
• N-({4-[l-(2-cUorophenyl)-3-(tiifluoromethyl)-1H-pyiazol-5-yl]phenyl}carbonyl)-beta-alanine, MS(ES): 438 [M+H]+. Example 76
Preparation of 'S-fmethylsulfoψlJpropyl^l^-chlojvpheψlJ-SφifluoromethylJ-lH-pyrazol-S- yl)benzoate
Figure imgf000257_0001
To a solution of 3-(methylthio)propyl 4-(l-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5- yl)benzoate (382 mg, 0.84 mmol) in CH2Cl2 (10 mL) was added 3-chloroperoxybenzoic acid (429 mg of 77% technical grade, 1.9 mmol). After stirring at ambient temperature for 1 hour LC/MS indicated complete conversion to product. At this time the reaction was quenched by the addition of 10% aqueous sodium thiosulfate solution and saturated aqueous NaHCO3. The basic aqueous was extracted with CH2Cl2 (3x). The combined organic extracts were dried over Na2SO4, filtered and the filtrate concentrated under reduced pressure to afford a thin film. This crude product was purified by flash column chromatography eluting with a gradient from 0% to 100% EtOAc/hexane to afford 3- (methylsulfonyl)propyl 4-(l-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)benzoate (345 mg, 84% yield) as a sticky white solid. 1H NMR (400 MHz CDCl3): δ 7.98-7.91 (2H, m), 7.50 (IH, m), 7.48-7.36 (3H, m), 7.33-7.27 (2H, m), 6.88 (IH, s), 4.77 (2H, t), 3.45 (2H, t), 3.00 (3H, s). MS(ES):
487[M+H]+.
Example 77
Preparation of 2-(4-chloro-5-{5-[3-(methylsulfoψl)pheryl]-24hienyl^ yl]-lH-pyrazol-3-yl)propan-2-ol
Figure imgf000257_0002
To a solution of 2-(5-(5-(3-(methylsulfonyl)phenyl)tMophen-2-yl)-l-(2-(trifluoromethyl)- pyridin-3-yl)-1H-pyrazol-3-yl)propan-2-ol (10.6g, 21 mmol) in MeCN (200 mL) was added N- chlorosuccinimide. The resulting solution was heated to 75°C in a heating mantle. After stirring for 3 hours at 75°C heating was discontinued and the solution was concentrated under reduced pressure to afford a yellow foam. This crude product was purified by flash column chromatography eluting with a gradient from 0% to 100% EtOAc/hexane. Fractions that were pure by TLC analysis were combined and concentrated under reduced pressure to afford a white sticky foam that was contaminated with succinimide as evidenced by MVER. analysis. This material was taken up in CH2Cl2 and washed with saturated aqueous Na2CO3 (2x). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to afford 2-(4-chloro-5-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}-l-[2- (trifluoromethyl)pyridin-3-yl]-1H-pyrazol-3-yl)propan-2-ol (6.7 g, 60% yield) as an off-white foam. 1H NMR (400 MHz CDCl3): δ 8.85 (IH, m), 8.06 (IH, t), 7.86 (IH, m), 7.82-7.73 (2H, m), 7.67-7.62 (IH, m), 7.58 (IH, t), 7.28 (IH, d), 7.01 (IH, d), 3.08 (3H, s), 2.93 (IH, s), 1.73 (6H, s). MS(ES): 542|M+H]+.
The following compounds are prepared essentially according to the previous examples:
• 2-(4-chloro-5-{3-methyl-5-[3-(methylsulfonyl)phenyl]-2-thienyl}-l-[2- (trifluoromethyl)pyridin-3-yl]-1H-pyrazol-3-yl)propan-2-ol, MS(ES): 556 βVt+H]+.
• 2-{4-cMoro-l-(2,6-dichlorophenyl)-5-[3-methyl-3'-(methylsulfonyl)biphenyl-4-yl]-1H-pyrazol- 3-yl}propan-2-ol, MS(ES): 549 |M+H]+.
• 2-{4-cMoro-5-[3-methyl-3Mmethylsu]fony^ lH-pyrazol-3-yl}propan-2-ol, MS(ES): 550 [M+H]+.
• 2-{4-cMoro-5-[3-metiiyl-3'-(methylsuffonyl)biphenyl-4-yl]-l-[4-(trifluoromethyl)pyridin-3-yl]- lH-pyrazol-3-yl}propan-2-ol MS(ES): 550 [M+H]+. • 2-{4-cliloro-5-[3Hmethylsuhconyl)biphenyl-4-yl]-l-[4-(trifluorometiiyl)pyridin-3-yl]-1H- pyrazol-3-yl}propan-2-ol MS(ES): 536 [M+H]+.
• 2-{4-chloro-l-(2,6-dichlorophenyl)-5-[3'-(methylsuhconyl)biphenyl-4-yl]-1H-pyrazol-3- yl}propan-2-ol MS(ES): 537 [M+H]+.
• 2-{4-cMoro-5-[3-cMoro-3'-(methylsuhconyl)biphenyl-4-yl]-l-(2,6-dichlorophenyl)-1H-pyrazol- 3-yl}propan-2-ol MS(ES): 571 |M+H]+.
• 2-{4-chloro-5-[3-cUoro-3'-(methylsulfonyl)biphenyl-4-yl]-l-[2-(trifluorome1hyl)pyridin-3-yl]- lH-pyrazol-3-yl}propan-2-ol MS(ES): 570 [M+Iff.
Example 78
Prepω-ationofmetidin-l-yl(4-(l-(2-chloropherryl)-3-(24τyfa^ phenyl)methanone
Figure imgf000259_0001
To a cooled (-78°C) solution of methyl 5-(4-(azetidine-l-carbonyl)phenyl)-l-(2-chlorophenyl)-1H- pyrazole-3-carboxylate (138 mg, 0.35 mmol) in THF (5 mL) was added methymagnesium bromide (0.3 mL of a 3.0M solution in ether, 0.9 mmol). The resulting brown solution was allowed to slowly warm to ambient temperature overnight. The reaction was then quenched by the addition of saturated aqueous ammonium chloride solution and EtOAc. The aqueous was extracted with EtOAc (3x) and the combined organic extracts were washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure to afford a yellow film. This crude product was purified by flash column chromatography eluting with a gradient of 0% to 10% MeOH in CH2Cl2. The main peak was collected and was -85% pure by HPLC. This material was further purified by reverse phase preparative HPLC eluting with MeCNZH2O with 0.1% TFA. The product fractions from the HPLC were made basic by the careful addition of solid Na2CO3. The resulting mixture was concentrated to remove most of the MeCN. The resulting aqueous suspension was extracted with CH2Cl2 (3x), and the combined extracts were dried over Na2SO4 overnight, filtered and concentrated under reduced pressure to afford azetidin-l-yl(4- (l-(2-chlorophenyl)-3-(2-hydroxypropan-2-yl)-1H-pyrazol-5-yl)phenyl)methanone (43 mg, 31% yield) as apale brown powder. 1HNMR (400 MHz CDCl3): δ 7.54-7.48 (2H, m), 7.46-7.40 (2H, m), 7.39- 7.31 (2H, m), 7.24-7.19 (2H, m), 6.54 (IH5 s), 4.32-4.16 (4H, m), 2.63 (IH, s), 2.38-2.28 (2H, m), 1.68 (6H, s). MS(ES): 396 |M+H]+.
The following compounds are prepared essentially according to the previous examples: • 2-{ l-(2-chlorophenyl)-5-[4-(pyrrolidin-l-ylcarbonyl)phenyl]-1H-pyrazol-3-yl}piOpan-2-ol,
MS(ES): 410 |M+H]+.
Example 79 2-[l-(2-chlorophenyl)-5-{5-[3-(metlτylsulfonyl)p]τe^
Example 79a Preparation ofmeάryl 5-(5-bromop)ridm-2-yl)-l-(2-chlorophe}ψl)-lH-pyrazole-3-carboxylate
Figure imgf000259_0002
A mixture of (2-chlorophenyl)hydrazine hydrochloride (l.lg, 6.1 mmol) and methyl 4-(5- bromopyridin-2-yl)-2,4-dioxobutanoate (1.7g, 6.0 mmol) in MeOH (30 mL) was divided into two microwave reaction vessels. Each reaction vessel was then heated in the microwave at 120°C for ten minutes. LC/MS analysis at this time showed the reaction to be essentially complete. The solutions were concentrated under reduced pressure to afford a dark brown semi-solid. This material was taken up in
EtOAc and saturated aqueous NaHCO3. The layers were separated and the basic aqueous was extracted with EtOAc (3X). Combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated to afford a dark oil. This crude product was purified by flash column chromatography eluting with a gradient from 0% to 100% EtOAc in hexane to afford methyl 5-(5-bromopyridin-2-yl)-l- (2-chlorophenyl)-1H-pyrazole-3-carboxylate (300 mg, 13% yield) as an oil.
Example 79b
Preparation of methyl l-(2-chlowphenyl)-5-(5-(3-(methylsulfonyl)phe}ψl)pyιidin-2-yl)-lH- carboxylate
Figure imgf000260_0001
Methyl S^S-bromopyridin^-y^-l^-chloropheny^-1H-pyrazole-S-carboxylate (200mg, 0.51 mmol), 3-(methylsulfonyl)phenylboronic acid (120 mg, 0.60 mmol) and dichloro[l,l'-bis(diphenyl- phosphino)ferrocene]palladium (H) dichloromethane adduct (20 mg, 24 μmol), and K2CO3 (0.45 mL of a 3.5M aqueous solution, 1.6 mmol) were combined in DME (2.5 mL) in a microwave reaction vessel. The dark mixture was heated at 120°C for 5 minutes. The reaction mixture was diluted with EtOAc and H2O. The aqueous layer was removed and extracted with additional EtOAc. The combined organics were dried over Na2SO4, treated with some decolorizing carbon and filtered through a pad of Celite. Concentration of the filtrates under reduced pressure and purification by flash column chromatography eluting with 0% to 50% MeCN/CH2Cl2 afforded methyl l-(2-chlorophenyl)-5-(5-(3- (methylsulfonyl)phenyl)pyridin-2-yl)-1H-pyrazole-3-carboxylate as a pale yellow foam. This material was carried on to the subsequent step. MS(ES): 468 [M+H]+.
The following compounds are prepared essentially according to the previous examples: • 2-[l-(2-chlorophenyl)-5-{5-[3-(me1hylsulfonyl)phenyl]pyridin-2-yl}-1H-pyrazol-3-yl]propan-
2-ol, 1HNMR (400 MHz CDCl3): δ 8.70 (IH, m), 8.11 (IH, m), 7.96 (IH, m), 7.87-7.80 (2H, m), 7.68 (IH, t), 7.57 (IH, m), 7.49-7.37 (3H, m), 7.32 (IH, d), 6.89 (IH, s), 3.09 (3H, s), 1.70 (6H, s). MS(ES): 468 [M+H]+. • 2-[l-(2-cUorophenyl)-5-{6-[3-(methylsulfonyl)phenyl]pyridm-3-yl}-1H-pyrazol-3-yl]propan- 2-ol, MS(ES): 468 [MB-H]+.
• 2-[4-cUoro-l-(2-chlorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]pyridin-2-yl}-1H-pyrazol-3- yl]propan-2-ol, MS(ES): 502 [M+H]+.
• 2-[4-chloro-l-(2-cMorophenyl)-5-{6-[3-(methylsulfonyl)phenyl]pyridin-3-yl}-1H-pyrazol-3- yl]propan-2-ol, MS(ES): 502 [M+H]+.
Example 80
Preparation of (l-(2,6-dicMoropheψl)-5-(3-methyl-3'-(met1iylsulfoψl)biphejψl-4-yl)-^ yl)(pyri"olidin-l-yl)methanom
Figure imgf000261_0001
Methyl 1 -(2,6-dicUorophenyl)-5-(3-methyl-3'-(methylsulfonyl)biphenyl-4-yl)- lH-pyrazole-3- carboxylate (102 mg, 0.20 mmol) was suspended in pyrrolidine (0.6 mL, 7.2 mmol) and heated in the microwave at 180ºC for 10 minutes. The dark reaction mixture was concentrated under reduced pressure and azeotroped with toluene to remove most of the pyrrolidine. The resulting crude product was purified by preparative reverse phase HPLC eluting with MeCNZH2O with 0.05% TFA. The product fractions from the HPLC were made basic by the careful addition of saturated aqueous NaHCO3. The resulting mixture was concentrated to remove most of the MeCN. The resulting aqueous suspension was extracted with CH2Cl2 (3x), and the combined extracts were dried over Na2SO4 overnight, filtered and concentrated under reduced pressure to afford (l-(2,6-dichlorophenyl)-5-(3- methyl-S'-^ethylsutfony^biphenyM-y^-1H-pyrazol-S-y^φyrrolidin-l-y^methanone (15 mg, 14% yield) as a brown solid. 1HNMR (400 MHz CDCl3): 58.10 (IH, m), 7.91 (IH, m), 7.83 (IH, m), 7.62 (IH, t), 7.49 (IH, d), 7.42-7.34 (2H, m), 7.33-7.21 (2H, m), 7.13 (IH, d), 7.06 (IH, s), 3.99 (2H, t), 3.71 (2H, t), 3.08 (3H5 s), 2.50 (3H, s), 2.03-1.86 (4H, m). MS(ES): 554 [M+H]+. The following compounds are prepared essentially according to the previous examples: • 5-[3-cUoro-3'-(methylsuh°onyl)biphenyl4-yl]-l-(2,6-dichlorophenyl)-3-(pvrrolidii>l- ylcarbbnyl)-1H-pyrazole MS(ES): 576 [M+H]+.
• 5-[3-chloro-3'-(methylsuhOnyl)biphenyl-4-yl]-N-(2-methylpropyl)-l-[2- (trifluoromethyl)pyridin-3-yl]-1H-ρyrazole-3-carboxamide MS(ES): 577 jM+H]+.
• 5-[3-chloro-3l-(methylsulfonyl)biphenyl4-yl]-l-(2,6-dichlorophenyl)-N-(2-methylpropyl)-1H- pyrazole-3-carboxamide MS(ES): 578 [M+H]+. Example 81
(E)-3-(4-(l-(2£-dicUoropheψl)-3-(2-hyώ-oxypropωϊ-2-yl)4H^ acid
Example 81a
Prepai-ationof4-(l-(2,6-dichloropheψl)-3-(2-lψdroxypropan-2-yl)4H-pyrazol-5^ methylbenzaldehyde
Figure imgf000262_0001
To a cold (-78ºC) solution of 2-(5-(4-bromo-2-methylphenyl)-l-(2,6-dichlorophenyl)-1H- pyrazol-3-yl)propan-2-ol (215 mg, 0.49 mmol) in a mixture of THF (4 ML) and Et2O (4 mL) was added lithium bis(trimethylsilyl)amide (0.5 mL of a 1.0M solution in THF, 0.5 mmol). After several minutes stirring at-78°C the resulting alkoxide solution was treated with n-butyllithium (LO mL of a 1.6M solution in hexane, 1.6 mmol). After 10 minutes stirring at -78°C, LOMS showed some starting bromide present in a quenched aliquot of the reaction. After 30 minutes additional n-butyllithium was added (0.5 mL of a 1.6M solution in hexane, 0.8 mmol). After an additional 15 minutes stirring at- 78ºC the reaction mixture was treated with dry N,N-dimethylformamide (0.4 mL, 5.2 mmol). Several minutes after the addition of the DMF, the — 78°C bath was replaced with an ice bath and the reaction
I mixture was allowed to come to ambient temperature overnight. The reaction was quenched by the addition of saturated NH4C1 and diluted with EtOAc. The layers were separated and the aqueous was extracted with EtOAc (3x). Combined organic extracts were washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure to afford a yellow syrup. The crude product was purified by flash column chromatography eluting with 0% to 100% EtOAc/hexane to afford 4-(l-(2,6- dichlorophenyl)-3-(2-hydroxypropan-2-yl)-1H-pyrazol-5-yl)-3-methylbenzaldehyde which was carried on to the next step without further purification. MS(ES): 389 [M+H]+.
Example 81b Preparation of(E)-meihyl 3-(4-(l-(2, 6-dichloropherψl)-3-(2-hydrox}propan-2-yl)-lH-py}'azol-5-yl)-3- methylstyiyl)benzoate
Figure imgf000262_0002
To a suspension of NaH (52 mg of a 60% dispersion in mineral oil) in TEDF (7.5 mL) cooled to
OºC in an ice bath was added methyl 3-((dimethoxyphosphoryl)methyl)benzoate as a solution in THF (1 mL) followed by a THF (1 mL) rinse of the phosphonate vial and syringe to insure complete transfer.
The ice bath was removed and the reaction was allowed to warm to ambient temperature. After 90 minutes at ambient temperature, 4-(l-(2,6-dichlorophenyl)-3-(2-hydroxypropan-2-yl)-1H-pyrazol-5-yl)-
3-methylbenzaldehyde (0.49 mmol impure from previous step) was added via cannula to the reaction mixture followed by a THF (1 mL) rinse of the flask and cannula, after 1 hour-45 minutes at ambient temperature the reaction was quenched by addition of saturated aqueous ISIH4Cl and EtOAc. The layers were separated and the aqueous was extracted with EtOAc (3x). Combined organic extracts were washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure to afford a yellow syrup. The crude product was purified by flash column chromatography eluting with a gradient from
0% to 40% MeCN/CH2Cl2 to afford (E)-methyl 3-(4-(l-(2,6-dichlorophenyl)-3-(2-hydroxypropan-2- yl)-1H-pyrazol-5-yl)-3-methylstyryl)benzoate (180 mg, 70% yield) of slightly impure product This material was carried on to the ester hydrolysis without further purification. MS(ES): 521 [M+H]+. Example 81c
Preparation of '(E)-3-(4-(l-(2,6-dichloropherψl)-3-(2-hydvxypropan-2-yl)-lH-pyt"a∑ol-5-yl)-3- methylstytγtybejizoic acid
Figure imgf000263_0001
To a solution of (E)-methyl 3-(4-(l-(2,6-dichlorophenyl)-3-(2-hydroxypropan-2-yl)-1H- pyrazol-5-yl)-3-methylstyryl)benzoate (180 mg of impure material from previous step, 0.35 mmol) in THF (2.0 mL) was added H2O (0.4 mL) followed by lithium hydroxide monohydrate (25.3 mg, 0.6 mmol). After stirring for 1 hour at ambient temperature a biphasic mixture had formed, and LC/MS analysis of the reaction showed no reaction, a small amount of MeOH was added to homogenize the mixture, and the reaction was then heated to 50 °C in an oil bath. After 2 hours stirring at 50ºC, LC/MS analysis showed the reaction to be complete. Heating was discontinued, and after stirring at ambient temperature overnight, the reaction was quenched by the addition of 5% aqueous citric acid, and EtOAc. The layers were separated and the aqueous was extracted with EtOAc (3x). Combined organic extracts were washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure to afford a clear film. This material was purified by reverse phase preparative HPLC eluting with a gradient of MeCNZH2O with 0.05% TFA. The major peak from the HPLC was concentrated under reduced pressure to remove most of the solvents, and the resulting acidic aqueous was extracted with CH2Cl2 (3x). The combined organic extracts were washed with H2O until the washings were no longer acidic (2x), dried over Na2SO4, filtered, and concentrated under reduced pressure to afford (E)-3-(4-(l -(2,6- dicUorophenyl)-3-(2-hydroxypropan-2-yl)-1H-pyrazol-5-yl)-3-methylstyryl)benzoic acid (45.4 mg, 26% yield) as a white powder. 1HNMR (400 MHz CDCl3): δ 8.21 (IH, s), 7.98 (IH, d, 7.69 (IH, d), 7.45 (IH, t), 7.39 (IH, d), 7.37-7.31 (2H, m), 7.23 (IH5 m), 7.15 (IH, m), 7.12-7.07 (2H, m), 7.06 (IH, m), 6.46 (IH, s), 2.45 (3H5 s), 1.71 (6H, s). MS(ES): 529 [M+Naf.
Example 82
Preparation of 2-(l-(2,6-dichloropheriyl)-5-(2-metlτyl-4-(2-moipholimetlψlmιim)pfo
3-yl)propan-2-ol
Figure imgf000264_0001
A mixture of 2-(5-(4-bromo-2-methylphenyl)-l-(2,6-dichlorophenyl)-1H-pyrazol-3-yl)propan- 2-ol ((160 mg, 0.36 mmol), 2-moφholinoethanamine (75 mL, 0.57 mmol), sodium tert-butoxide (54 mg, 0.57 mmol), biphenyl-2-yldi-tert-butylphosphine (13.1 mg, 44 μmol), and Pd2(dba)3 (19.8 mg, 22 μmol) was placed in a microwave reaction vial and heated at 160ºC for 15 minutes. After cooling, the reaction was diluted with saturated aqueous NaHCO3, and EtOAc. The layers were separated and the aqueous was extracted with EtOAc (3x). Combined organic extracts were washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure to afford a dark oil. This material was purified by reverse phase preparative HPLC eluting with a gradient of MeCNZH2O with 0.05% TFA. The product peak from the HPLC was basified by addition of saturated aqueous NaHCO3, and concentrated under reduced pressure to remove most of the solvents. The basic aqueous was extracted with CH2Cl2 (3x). The combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure to afford 2-(l-(2,6-dicUorophenyl)-5-(2-inethyl-4-(2-moφholmoethylarnino)- phenyl)-1H-pyrazol-3-yl)propan-2-ol (67 mg, 38% yield) as a white foam. 1HNMR (400 MHz CDCl3): δ 7.34-7.29 (2H, m), 7.20 (IH, m), 6.84 (IH, d), 6.46 (IH, d), 6.32 (IH, s), 6.23 (IH, m), 4.32 (IH, s), 3.74-3.66 (4H, m), 3.15-3.07 (2H, m), 2.66 (IH, s), 2.63-2.55 (2H, t), 2.48-2.40 (4H, m), 2.33 (3H, s), 1.67 (6H, s). MS(ES): 489 |M+H]+. The following compounds are prepared essentially according to the previous examples: 2-[l-(2,6-dicMorophenyl)-5-{2-methyl4-[(2-piperidin-l-yle%l)amino]phenyl}-1H-pyrazol-3- yl]propan-2-ol MS(ES): 487 [M+H]+.
2-[l-(2,6-dicMorOphenyl)-5-(2-methyl-4-{[2-(methylsulfonyl)e&yl]aniino}phenyl)-1H- pyrazol-3-yl]propan-2-ol MS(ES): 504 DMR-Na]+.
2-[l-(2,6-dichlorophenyl)-5-{4-[(l,l-doxidotetrahydro-3-tMenyl)amino]-2-methylphenyl}-1H- pyrazol-3-yl]propan-2-ol MS(ES): 516 [M+Naf.
Scheme 30
Figure imgf000265_0001
As depicted in Scheme 30, alkoxycarbonylbiphenylpyrazoles were prepared from the condensation of a hydrazine with a diketone and were further transformed into carbinols. Diketone 030ES01 can be condensed with hydrazine 030ES02 in a manner similar to Example 2c to afford pyrazole 030ES03. The resulting pyrazole can then be coupled with boronic acid 030ES04 under palladium-catalyzed coupling conditions in a manner similar to Example Ic to afford biaryl ester 030ES05. Treatment of the ester with an alkylmagnesium halide in a manner similar to Example 5 affords alcohol 030ES06.
Example 82 2-{3'-chloro-4'-[l-(2,6-dichlorophenyl)-3-(Mflιιoromethyl)-lH-pyi'azol-5-yl]^^
Example 82a
Preparation ofmetlψl 3 '-chloro-4'-(l-(2, 6-dichloropherψl)-3-(trifluoromethyl)-lH-pyrazol-5- yl)biphenyl-3-carboxylate
Figure imgf000265_0002
To a solution of 5-(4-bromo-2-cUorophenyl)-l-(2,6-dichlorophenyl)-3-(trifluoromethyl)-1H- pyrazole (3.55g, 7.55 mmol) and 3-(methoxycarbonyl)phenylboronic acid (1.77 g, 9.83 mmol) in 1,2- dimethoxyethane (36mL) was added K2CO3 (3.126 g, 22.65 mmol) and H2O (4 mL). The resulting biphasic suspension was stirred at ambient temperature and sparged with nitrogen for 10 minutes. The reaction was then treated with dichloro[l,r-bis(diphenylphosphino)ferrocene]palladium (TT) dichloromethane adduct (600 mg, 0.734mmol) and heated to 80°C in an oil bath. The reaction was heated at 80°C for 10 hours and then allowed to cool to ambient temperature. The cooled reaction mixture was diluted with EtOAc and H2O. The aqueous layer was extracted with EtOAc (3x). The combined organic extracts were washed with brine, dried OVCrNa2SO4, filtered and concentrated to afford crude product as a dark oil. The crude product was purified by flash-column chromatography eluting with a gradient from 0% to 40% EtOAc/hexane to afford methyl 3'-chloro-4'-(l-(2,6- dicUorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)biphenyl-3-carboxylate (3.50 g, 88% yield) solid. MS(ES): 525 [M+H]+.
Example 82b
Preparation of '2-{3'-chloro-4'-[l-(2,6-dichloropheψl)'3-φifluoromet}ψl)-lH-jψ'azol-5-ylJbipheψl-3- yl}propat%-2-ol
Figure imgf000266_0001
To a suspension of methyl 3'-chloro-4'-(l-(2,6-dichlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-
5-yl)biphenyl-3-carboxylate(1.15 g, 2.19 mmol) in dry tetrahydrofuran (10 mL) stirred at OºC in icebath was added methylmagnesium bromide (2.04 mL of a 3.0M solution in tetrahydrofuran, 6.12 mmol) dropwise. After adding the,methylmagnesium bromide, the icebath was removed. After 2 hours stirring at ambient temperature the reaction mixture was quenched by the addition of saturated ammonium chloride and EtOAc. The aqueous layer was extracted with EtOAc (3x). The combined organic extract were dried over Na2SO4, filtered and concentrated under reduced pressure to afford brown oil. The crude product was purified by flash-column chromatography eluting with a gradient from 0% to 100% EtOAc/hexane to afford (450 mg, 39% yield) foamed white solid. MS(ES): 525 [M+H]+. 1H- NMR(CDCl3): δ 7.73-7.67 (2H, m), 7.48 (IH, m), 7.44-7.28 (6H, m), 7.19 (IH, d), 6.98 (IH, s), 1.74 (lH, s), 1.62 (6H, s).
The following compounds are prepared essentially according to the previous examples: • 2-(3-{5-[l-(2-cUorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-2-thienyl}phenyl)propan-2- ol, MS(ES): 463 [M+H]+. 2-(4-{5-[l-(2-cMorophenyl)-3-(trMuoromethyl)-1H-pyrazol-5-yl]-2-tMenyl}phenyl)propan-2- ol, MS(ES): 463 [M+H]+.
2-[3-(5-{3-(trifluoromethyl)-1^3-(1rmuoromethyl)pyridin-2-yl]4H-pyrazol-5-yl}-2- thienyl)phenyl]propan-2-ol, MS(ES): 498 [M+H]+.
2-[4-(5-{3-(trifluoromethyl)-1^3-(trifluorome%^^ thienyl)phenyl]propan-2-ol, MS(ES): 498 [M+H]+.
Scheme 31
Figure imgf000267_0001
Figure imgf000267_0002
As depicted in Scheme 31, 3-methoxy substituted pyrazole (031vi) prepared as described in
Scheme 1 was transformed into phenol 031SP1, which was treated with alkyl halide in the presence of a base to afford 3-alkoxy substituted pyrazole 031SP2.
Example 83
Figure imgf000267_0003
Preparation of3-(5-(5-(3-(imthylsώfonyl)phenyl)thioplmι-2-yiy^ yl)phenol. l-(3-methoxyphenyl)-5-(5-(3-(methylsulfonyl)phenyl)Mophen-2-yl)-3-(trifluoromethyl)-1H- pyrazole (03 lvi) was prepared as described in Schemel . A solution of 1.0 M boron tribromide (59.33 mL, 59.33 mmol) in anhydrous DCM was slowly added to a solution of the 3-methoxy substituted pyrazole (9.464 g, 19.78 mmol) in 20 mL of anhydrous DCM at -78 ºC under nitrogen. The mixture was vigorously stirred and allowed to warm to ambient temperature overnight The reaction mixture was then cooled to 0 ºC with an ice/water bath and about 50.0 mL of MeOH was added in portion. The mixture was stirred at room temperature for 1 h and concentrated in vacuo. The residue was dissolved in dichloromethane and neutralized to pH 7 by adding 1 N NaOH. The organic layer was washed with brine, water, separated and dried with anhydrous Na2SO4. The dichloromethane was concentrated in vacuo. The resulting crude product was purified by column chromatography (30-60 % EtOAc/hexane), providing the product 3-hydroxy substituted pyrazole (4.13 g, 45% yield). 1H-NMR (Acetone-d6): δ 8.83 (s, IH), 8.04 (m, 1 H), 7.85 (m, IH), 7.81 (m, 1 H), 7.61 (m, 1 H) 7.51 (m, 1 H), 7.30 (m, 1 H), 7.06 (m, 2 H), 6.95 (m, 1 H), 6.92 (m, 1 H), 6.90 (m 1 H), 3.08 (s, 3 H); MS (ES): 465 [M+H]+. Example 84
Preparation of l-(3-ethoxypheψl)-5-(5-(3-(methylsulfoψl)pheψl)thiophen-2-yl)-3-fø
IH-pyrazole
Figure imgf000268_0001
3-(5-(5-(3-(me1hylsulfonyl)phenyl)tMophen-2-yl)-3-(trifluoromethyl)-1H-pyrazol-l-yl)phenol (8 0.17 mmol) was dissolved in anhydrous DMF (3 mL). To this solution was added potassium carbonate (29 mg, 0.20 mmol) and ethyl bromide (38 mg, 0.34 mmol) in anhydrous DMF (3.0 mL). The reaction mixture was heated at 80 ºC under nitrogen atmosphere for overnight. After the mixture was cooled off, it was poured into 20.0 mL of water and extract with ethyl acetate. The combined organic layer was washed with brine and water and concentrated in vacuo. The crude product was purified by flash column chromatography (60% ethyl acetate in hexane), providing the product 3-ethoxy substituted pyrazole (65 mg, 77% yield). 1H-NMR(CDCl3): δ 8.08 (m, IH), 7.86 (m, 1 H), 7.77 (m, IH), 7.59 (m, 1 H), 7.34 (m, 1 H), 7.27 (m, 1 H), 7.01 (m, 1 H), 6.99 (m, 1 H)56.98 (m, 1 H), 6.87 (m, 1 H), 6.84 (m, 1 H), 4.04 (q, J - 6.8 Hz, 2 H), 3.09 (s, 3 H), 1.40 (t, J = 6.8 Hz, 3 H). MS (ES): 493 [M+H]+. The following compounds are prepared essentially according to the previous examples: • l-(3-isopropoxyphenyl)-5-(5-(3-(me&ylsulfon^ pyrazole. MS (ES): 507 [M+H]+
• l-(3-isobutoxyphenyl)-5-(5-(3-(memylsulfonyl)phenyl)iMophen-2-yl)-3-(1rifluoromethyl)-1H- pyrazole. MS (ES): 521 |M+H]+
• tert-Butyl2-methyl-2-(3-(5-(5-(3-(methylsulfonyl)phenyl)thiophen-2-yl)-3-(trifluoromethyl)- lH-pyrazol-l-yl)phenoxy)propanoate. MS (ES): 607 [M+H]+. • 2-{5-[4-(3-Me1hanesιrifonyl-phenyl)-iM^^ MS (ES) 465.0 [M+H]+,
• Diethyl-[2-(2-{5-[4-(3-methanesulfonyl-phe^ yl}-phenoxy)-e%l]-amine. MS (ES) 564.3 [M+H]+, • (2-{5-[4-(3-Methanesulfonyl-phenyl)-thiophen-2-yl]-3-trifluoromethyl-pyrazol-l-yl}- phenoxy)-acetic acid tert-butyl ester. MS (ES) 579.4 [M+H]+,
• l-[2-(2-{5-[4-(3-Methanesιι]fonyl-phenyl)-thiophen-2-yl]-3-1rifluoromethyl-pyrazol-l-yl}- phenoxy)-ethyl]-piperidine. MS (ES) 576.3 [M+H]+,
• 4-[2-(2-{5-[4-(3-Methanesulfonyl-phenyl)-tiτiophen-2-yl]-3-trifluoromethyl-pyrazol-l-yl}- phenoxy)-ethyl]-moφholine. MS (ES) 578.4 [M+H]+,
• 2-(2-{5-[4-(3-Me1hanesu]fonyl-phenyl)-thiophen-2-yl]-3-t]ffluoromethyl-pyrazol-l-yl}- phenoxymethyl)-pyridine. MS (ES) 556.3 [M+H]+,
• 4-[3-(2-{5-[4-(3-Methanesιilfonyl-phenyl)-iMoplien-2-yl]-3-trifluoromethyl-pyrazol-l-yl}- phenoxy)-propyl]-moφholine. MS (ES) 592.0 |M+H]+ • l-[3-(2-{5-[4-(3-Methanesulfonyl-phenyl)-thiophen-2-yl]-3-trifluoromethyl-pyrazol-l-yl}- phenoxy)-propyl]-4-methyl-piperazine. MS (ES) 605.0 [M+H]+,
• l-[2-(2,2-Dime1hyl-propoxy)-phenyl]-5-[4-(3-me1hanesulfonyl-phenyl)-thiophen-2-yl]-3- trifluoromethyl-1H-pyrazole. MS (ES) 535.3 [M+H]+, 557.3 [MfNa]+
• 2-(2-{5-[4-(3-Methanesulfonyl-phmyl)-thiophen-2-yl]-3-tiifluorome1hyl-pyrazol-l-yl}- phenoxy)-ethanol. MS (ES) 509.3 [M+H]+
• l-[2-(3-CMoro-propoxy)-phenyl]-5-[4-(3-meihanesulfonyl-phenyl)-1hiophen-2-yl]-3- trifluoromethyl-1H-pyrazole. MS (ES) 541.3, 543.3 [M+H]+
• l-(2-Ethoxy-phenyl)-5-[4-(3-methanesulfonyl-phenyl)-ihiophen-2-yl]-3-tiMuoromethyl-1H- pyrazole. , MS (ES) 493.3 [M+H]+ • l-(2-Isopropo^-phenyl)-5-[4-(3-methanesulfonyl-phenyl)-Mophen-2-yl]-3-tiifluoromeihyl- lH-pyrazole. , MS (ES) 507.3 [MH-H]+
• l-(2-Isobutoxy-phenyl)-5-[4-(3-me&anesulfo^ pyrazole. , MS (ES) 521.4 [M+H]+
Scheme 32
Figure imgf000270_0001
As depicted in Scheme 32, t-butyl ester 032SP3 was treated with formic acid in DCM to afford acid O32SP4.
Example 85
Figure imgf000270_0002
Preparation of 2-(3-(5-(5-(3-(methylsulfonyl)pheττyl)thiophen-2-yl)-3-(trifl yl)phenoxy)acetic acid. tert-Butyl 2-(3-(5-(5-(3-(methylsulfonyl)pte^ l-yl)phenoxy)acetate was prepared in a manner described in Scheme 31. To a solution of the t-butyl ester (70 mg, 0.12 mmol) in anhydrous DCM (2.0 mL) was added 2.0 mL of 96% formic acid. The reaction mixture was stirred at room temperature for overnight. It was concentrated and the residue was purified by flash silica gel column chromatography (10% MeOH/ DCM), providing the product (28 mg, 45% yield). 1H-NMR (Acetone-d6): δ 8.01 (s, IH), 7.82 (m, 1 H), 7.77 (m, 1 H), 7.57 (m, 1 H), 7.45 (m, 1 H), 7.37 (m, 1 H), 7.08-7.01 (br, 5 H), 4.68 (s, 2 H), 3.05 (s, 3 H). MS (ES): 523 |M+H]+. The following compounds are prepared essentially according to the previous examples:
• (2-{5-[4-(3-Methanesuhconyl-phenyl)-iMophen-2-yl]-3-trifluoromethyl-pyrazol-l-yl}- phenoxy)-acetic acid. MS (ES) 523.3 [M+H]+
Scheme 33
Figure imgf000270_0003
As depicted in Scheme 33, 3-hydroxy substituted pyrazole 033SP1 was treated with dialkyl carbamic chloride or acyl chloride in the presence of base to afford carbamate or ester, 033SP5.
Example 86 Prepm-ationof3-(5-(5-(3-(mzthylmlfonyl)phenyl)M yl)phenyl dimethylcarbamate
Figure imgf000271_0001
To a solution of 3-(5-(5-(3-(me1hylsuh0onyl)phenyl)iMophen-2-yl)-3-(trifluorometliyl)-1H- pyrazol-l-yl)phenol (80 mg, 0.17 mmol) andtriethylamine (35 mg, 0.34 mmol) in anhydrous DCM (1.5 mL) and THF (1.5 mL) was added dimethyl carbamic chloride (28 mg, 0.26 mmol). The reaction mixture was heated to reflux at 85 ºC under nitrogen atmosphere for overnight. It was cooled off and concentrated in vacuo. The residue was purified by column chromatography (60% ethyl acetate in hexane) to yield product carbamate (24 mg, 26% yield). 1H-NMR (CDCl3): 58.10 (m, 1 H), 7.85 (m, 1 H), 7.79 (m, 1 H), 7.58 (m, 1 H), 7.42 (m, 1 H), 7.35 (m, 1 H), 7.28 (m, 1 H), 7.26 (m, 1 H), 7.22 (m, 1 H), 6.91 (m, 1 H), 6.84 (s, 1 H), 3.09 (s, 6 H), 3.00 (s, 3 H). MS (ES): 536 [M+H]+. The following compounds are prepared essentially according to the previous examples:
• 3-(5-(5-(3-(methylsuhconyl)phenyl)iMophen-2-yl)-3-(1rifluorome1hyl)-1H-pyrazol-l-yl)phenyl diethylcarbamate. MS (ES): 564 [M+H]+.
• Isobutyric acid 2-{5-[4-(3-methanesulfonyl-phenyl)-thiophen-2-yl]-3-trifluoromethyl-pyrazol- l-yl}-phenyl ester. , MS (ES) 535.3 [M+H]
• 2,2-Dimethyl-propionic acid 2-{5-[4-(3-methanesulfonyl-phenyl)-thiophen-2-yl]-3- trifluoromethyl-pyrazol-l-yl}-phenyl ester. MS (ES) 549.3 [M+H]+
• Dimethyl-carbamic acid 2-{5-[4-(3-me1hanesuhconyl-phenyl)-thiophen-2-yl]-3-trifluoromethyl- pyrazol-l-yl}-phenyl ester. MS (ES) 536.3 |M+H]+
Scheme 34
Figure imgf000271_0002
As depicted in Scheme 34, 3-hydroxy substituted pyrazole 034SP1 was treated with alkyl isocyanate in the presence of base to afford carbamate 034SP6.
Example 87
Prepω"ationof3-(5-(5-(3-(methylsulfonyl)phenyl)th\ophen-2^ yl)phenyl methylcarbamate.
Figure imgf000272_0001
3-(5-(5-(3-(memylsιdfonyl)phenyl)tMophe^
(80 mg, 0.17 mmol) was dissolved in anhydrous DCM (1.5 mL) and TEiF (1.5 mL). To this solution was added triethylamine (35 mg, 0.34 mmol) and methyl isocyanate (15 mg, 0.26 mmol). The reaction mixture was stirred at room temperature under nitrogen atmosphere for overnight. The solvent was evaporated in vacuo. The residue was purified by column chromatography (60% ethyl acetate in hexane) to yield the product methylcarbamate (56 mg, 95% yield). 1H-NIVlR(CDCl3): 68.10 (m, 1 H), 7.86 (m, 1 H), 7.79 (m, 1 H), 7.59 (m, 1 H), 7.43 (m, 1 H), 7.32 (m, 1 H), 7.29-7.24 (br, 3 H), 6.91 (m, 1 H), 6.84 (m, 1 H), 5.02 (br, 1 H), 3.10 (s, 3 H), 2.89 (s, 3 H), 2.88 (s, 3 H). MS (ES): 522 [M+H]+
The following compounds are prepared essentially according to the previous examples:
• 3-(5-(5-(3-(methylsuhconyl)phenyl)thiophen-2-yl)-3-(trifluoromethyl)- lH-pyrazol- 1 -yl)phenyl propylcarbamate. MS (ES): 550 [M+H]+
• Methyl-carbamic acid 2-{5-[4-(3-methanesulfonyl-phenyl)-thiophen-2-ylJ-3-trifluoromethyl- pyrazol-l-yl}-phenyl ester. MS (ES) 522.3 [M+H]+
• Propyl-carbamic acid 2-{5-[4-(3-methanesuhconyl-phenyl)-thiophen-2-yl]-3-trifluoromethyl- pyrazol-l-yl}-phenyl ester. MS (ES) 550.3 [M+H]+
• Isopropyl-carbamic acid 2-{5-[4-(3-methanesulfonyl-phenyl)-tlτiophen-2-yl]-3-trifluoromethyl- pyrazol-l-yl}-phenyl ester. MS (ES) 550.3 βVl+H]+ Scheme 35
Figure imgf000273_0001
As depicted in Scheme 35, 3-hydroxy substituted pyrazole 035SP1 was treated with 2- chloroacetamide in the presence of base to afford acetamide 035SP7.
Exanφle88 Preparation of N,N-dimethyl-2-(3-(5-(5-(3-(methylsulfonyl)phenyl)thiopfa lH-pyrazol-l-yl)phenoxy)acetωnide .
Figure imgf000273_0002
3-(5-(5-(3-(methylsuh°onyl)phenyl)iMophen-2-yl)-3-(1rffluoromethyl)-1H-pyrazol-l-yl)^^^ (120 mg, 0.26 mmol) was dissolved in anhydrous methanol (10.0 mL). To this solution was added a 25 wt% solution of NaOMe in methanol (130 μL, 0.57 mmol) and 2-chloro-N,N-dimethyl- acetamide (156 mg, 1.28 mmol). The reaction mixture was heated to reflux at 80 ºC under nitrogen atmosphere for overnight It was cooled off and concentrated in vacuo. The residue was purified by column chromatography (50% ethyl acetate in hexane) to yield the product (87 mg, 61% yield). 1H-NMR (Acetone-d6): 58.21 (m, 1 H), 8.03 (m, 1 H), 7.96 (m, 1 H), 7.76 (m, 1 H), 7.65(m, 1 H), 7.52 (m, 1 H), 7.25-7.16 (br, 5 H), 4.94 (s, 2 H), 3.25 (s, 3 H), 3.09 (s, 3 H), 2.90 (s, 3 H), 2.88 (s, 3 H). MS (ES): 550
IMfHJ+
The following compounds were prepared in a similar manner:
• 2-(3-(5-(5-(3-(methylsulfonyl)phenyl)thiophen-2-yl)-3-(trifluoromethyl)-1H-pyrazol-l- yl)phenoxy)-l-morρholinoethanone. MS (ES): 592 [MfH]+ • N,N-die%l-2-({2-[5-{4-[3-(methylsulfonyl)phenyl]-2-tMenyl}-3-(trifluoromethyl)-1H- pyrazol-l-yl]ρhenyl}oxy)acetamide; MS (ES): 578 |M+H]+;
• 4-[({2-[5-{4-[3-(methylsulfonyl)phenyl]-2-thienyl}-3-(trifluoromethyl)-1H-ρyrazol-l- yl]phenyl}oxy)methyl]pyridine; MS (ES): 556 [M+H]+;
• N-(l-methyle%l)-2-({2-[5-{4-[3-(methylsulfonyl)phenyl]-2-thienyl}-3-(trifluoromethyl)-1H- pyrazol-l-yl]phenyl}oxy)acetamide; MS (ES): 564 [M+H]+; • 5-({2-[5-{4-[3-(methylsulfonyl)phenyl]-2-tliienyl}-3-(1rffluoromethyl)-1H-pyrazol-l- yl]phenyl}oxy)pentanenitrile; MS (ES): 546 [M+H]+;
• 5-{4-[3-(methylsulfonyl)phenyl]-2-^^ yl]methyl}oxy)phenyl]-3-(trifluoiOmethyl)-1H-pyrazole; MS (ES): 635 [M+H]+; • 2-[2-({2-[5-{4-[3-(methylsulfonyl)phenyl]-2-thienyl}-3-(trifluoromethyl)-1H-pyrazol-l- yl]phenyl}oxy)ethyl]-1H-isomdole-l,3(2H)-dione; MS (ES): 638 [M+H]+;
• 2-({2-[5-{4-[3-(methylsulfonyl)phenyl]-2-thienyl}-3-(ttifluoromethyl)-1H-pyrazol-^ yl]phenyl}osy)-N-phenylacetamide; MS (ES): 598 [M+H]+;
• 6-({2-[5-{4-[3-(methylsι^onyl)phenyl]-2-iMenyl}-3-(trifluoromethyl)-1H-pyrazol-l- yl]phenyl}oxy)hexan-2-one; MS (ES): 563 [M+H]+;
• l-{4-[({2-[5-{4-[3-(methylsulfonyl)phenyl]-2-thienyl}-3-(trifluoromethyl)4H-pyrazol-l- yl]phenyl}oxy)methyl]phenyl}-1H-l,2,4-triazole; MS (ES): 622 [M+H]+;
• 5-{4-[3-(methylsι^onyl)phenyl]-2-1hienyl}-l-(2-{[(3-nitrophenyl)methyl]oxy}phenyl)-3- (trifluoromethyl)-1H-pyrazole; MS (ES): 600 [M+H]+; • N,N-diethyl-2-({2-[5-{4-[3-(methylsulfonyl)phenyl]-2-thienyl}-3-(trifluorometiiyl)-1H- pyrazDl-l-yl]phenyl}oxy)acetamide; MS (ES): 578 [M+H]+.
• 4-[({2-[5-{4-[3-(methylsιilfonyl)phenyl]-2-iMenyl}-3<trifluoroniethyl)-1H-pyrazol-l- yl]phenyl}oxy)methyl]pyridine; MS (ES): 556 [M+H]+.
• N-(l-methyle%l)-2-({2-[5-{4-[3-(methylsulfonyl)phenyl]-2-thienyl}-3-(trifluoromelhyl)- pyrazol-l-yl]phenyl}oxy)acetamide; MS (ES): 564 [M+H]+.
• 5-({2-[5-{4-[3-(methylsιαlfonyl)phenyl]-2-thieιiyl}-3-(trifluoromethyl)-1H-pyrazol-l- yl]phenyl}oxy)pentanenitrile; MS (ES): 546 [M+H]+.
• 5-{4-[3-(methylsulfonyl)phenyl]-2-thienyl}-l-[2-({[l-(phenylmethyl)4H-imidazol-2- yl]methyl}oxy)phenyl]-3-(trifluoromethyl)-1H-pyrazole; MS (ES): 635 [M+H]+. • 2-[2-({2-[5-{4-[3-(methylsulfonyl)phenyl]-2-thienyl}-3-(trifluoromethyl)-1H-pyrazol-l- yl]phenyl}oxy)ethyl]-1H-isoindole-l,3(2H)-dione; MS (ES): 638 |M+H]+.
• 2-({2-[5-{4-[3-(methylsulfonyl)phenyl]-2-tiύenyl}-3-(ttffluoromethyl)-1H-pyrazol-l- yl]phenyl}oxy)-N-phenylacetamide; MS (ES): 598 [M+H]+.
• 6-({2-[5-{4-[3-(methylsulfonyl)phenyl]-2-iWenyl}-3-(trMuoromethyl)-1H-pyrazol-l- yl]phenyl}oxy)hexan-2-one; MS (ES): 563 [M+H]+.
• l-{4-[({2-[5-{4-[3-(methylsulfonyl)phenyl]-2-thienyl}-3-(1rffluoromefhyl)-1H-pyrazol-l- yl]phenyl}oxy)me1hyl]phenyl}-1H-l,2,4-1riazole; MS (ES): 622 [M+H]+. 5-{4-[3-(methylsulfonyl)phenyl]-2-1hienyl}-l-(2-{[(3-nitrophenyl)methyl]oxy}phenyl)-3- (trifluoromethyl)-1H-pyrazole; MS (ES): 600 [MH-H]+.
Scheme 36
Figure imgf000275_0001
As depicted in Scheme 36, 3-hydroxy substituted pyrazole 036SP1 was treated with an alcohol in the presence of triphenyl phosphine and dϋsopropyl azodicarboxylate to afford 3-alokoxy substituted pyrazole 036SP8.
Example 89
Preparation oj rN, N-dimethyl-2-(3-(5-(5-(3-(methylmlfonyl)phenyl)thio^ lH-pyrazol-l-yl)phenoxy)ethanamine.
Figure imgf000275_0002
3-(5-(5-(3-(meΛylsulfonyl)phenyl)1tø^
(120 mg, 0.26 mmol), 2-(dimethylamino)ethanol (46 mg, 0.52 mmol) andtriphenylphosphine (138 mg, 0.52 mmol) were dissolved in a mixture solvent of anhydrous THF (2.5 rriL) and DCM (2.5 mL) and cooled off at 0 ºC under nitrogen atmosphere. To this solution was added diisopropyl azodicarboxylate (111 mg, 0.52 mmol). The reaction mixture was stirred vigorously and warmed up to room temperature overnight The solvent was evaporated in vacuo and the residue was purified by HPLC, providing the product (61 mg, 44%). 1H-NMR (Acetone-d6): 58.13 (m, 1 H), 7.93 (m, 1 H), 7.90 (m, 1 H), 7.71 (m, 1 H), 7.60 (m, 1 H), 7.47 (m, 1 H), 7.17-7.09 (br, 5 H), 4.12 (t, J= 5.8 Hz, 2 H), 3.18 (s, 3 H), 2.65 (t, J= 5.8 Hz, 2 H), 2.21 (s, 6 H). MS (ES): 536 [M+H]+.
Example 90
Prepω-ationof4-(3-(5-(5-(3-(methylsulfonyl)phenyl)thiophen-2-yl)-3-(M yl)phenoxy)piperidine
Figure imgf000276_0001
tert-Butyl 4-(3-(5-(5-(3-(meώylsulfonyl)ph^ l-yl)phenoxy)piperidine-l-carboxylate was prepared as described in Scheme 36. The t-butyl carbamate (83 mg, 0.13 mmol) was dissolved in trifluoroacetic acid (0.5 mL) and anhydrous DCM (4.0 mL). It was stirred at room temperature under nitrogen atmosphere for overnight The reaction mixture was concentrated in vacuo and the residue was taken into DCM. Potassium carbonate was added into the DCM solution and it was stirred for 2 hours. The salt was filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (10% isopropyl alcohol in DCM), providing the product amine (45 mg, 64%). %). 1H-NMR (DMSO-d6): 58.01 (m, 1 H), 7.89 (m, 1 H), 7.69 (m, 1 H), 7.49 (m, 1 H), 7.41 (m, 1 H), 7.26 (m, 1 H), 7.23 (m, 2 H), 7.13 (m, 1 H), 4.63 (m, 1 H), 3.28 (s, 3 H), 3.11 (m, 2 H), 2.87 (m, 2 H), 1.99 (m, 2 H), 1.71 (m, 2 H). MS (ES): 548 [M+H]+. The following compounds are prepared essentially according to the previous examples:
• 4-(2-(3-(5-(5-(3-(methylsurfonyl)phenyl)thiophen-2-yl)-3-(1rMuoromethyl)-1H-pyrazol-l- yl)phenoxy)ethyl)moφholine. MS (ES): 578 [M+H]+
• 1 -(2-(3-(5-(5-(3-(methylsuhconyl)phenyl)thiophen-2-yl)-3-(trifluoromethyl)- lH-pyrazol- 1 - yl)phenoxy)ethyl)piperidine. MS (ES): 576 [M+H]+.
• 5-(5-(3-(methylsurfonyl)phenyl)tUophen-2-yl)-l-(3-(tetrahydrofϋran-3-yloxy)phenyl)-3- (trifluoromethyl)-1H-pyrazole. MS (ES): 535 [M+H]+.
Scheme 37
Figure imgf000276_0002
As depicted in Scheme 37, the hydroxyl substituted pyrazole 037SP1 was treated with arylboronic acid in the presence of triethylamine and copper (D) acetate to afford the product diaryl ether 037SP9.
Example 91 Prepω-ation of5-(5-(3-(methylmlfonyl)pheiτyl)thiophen-2-yl)-l-(3-phe}wy^ lH-pyrazok.
Figure imgf000277_0001
To a solution of 3-(5-(5-(3-(methylsulfonyl)phenyl)tMophen-2-yl)-3-(trifluoromethyl)-1H- pyrazol-l-yl)phenol (120 mg, 0.26 mmol) in anhydrous DCM (6.0 mL) was added Cu(OAc)2 (94 mg, 0.52 mmol), phenylboronic acid (63 mg, 0.52 mmol) and powdered 4 A molecular sieves and triethylamine (131 mg, 1.29 mmol). The heterogenerous reaction mixture was stirred at ambient temperature for overnight The resulting slurry was filtered through celite and the solvent was evaporated in vacuo. The crude product was purified by column chromatography (40% ethyl acetate in hexane), providing product diary ether (73 mg, 520ZOyJeId)-1H-ISlMR(CDCl3): 58.10 (m, 1 H), 7.88 (m, 1 H), 7.79 (m, 1 H), 7.61 (m, 1 H), 7.31-7.27 (m, 3 H), 7.20 (m, 1 H), 7.12 (m, 1 H), 7.04 (m, 1 H), 7.00 (m, 2 H), 6.89 (m, 1 H), 6.82 (s, 1 H), 3.10 (s, 3 H). MS (ES): 541 [M+H]+.
Scheme 38
Figure imgf000277_0002
As depicted in Scheme 38, the 3-nitrophenyl substituted pyrazole 038SP10 was reduced with SnCl2 to aniline, which coupled with 3-methylsulfonylphenyl boronic acid in the presence of PdCl2dppf, Na2CO3 to afford the product 038SP12.
Example 92 4-(l-(2-chhrophenyl)-3-(trifluoromethyl)-lH-pyrazol-5-yl)-N-(2-morpto
Example 92a Preparation oj 3-(5-(5-bromothiophen-2-yl)-3-(trifluoroιnethyl)-lH-pyrazol-l-yl)ωriline
Figure imgf000278_0001
To a solution of 5-(5-bromoiMophen-2-yl)-l-(3-nitrophenyl)-3-(1rifluoromethyl)-1H-pyrazole (0.40 g, 0.96 mmol), prepared in a manner similar to that described in Example Ib, and stannous (H) chloride dihydrate (1.08 g, 4.78 mmol) was dissolved in 10.0 mL of ethyl acetate . The mixture was stirred at room temperature for overnight. The solvent was then evapotated in vacuo. The residue was taken in a mixture of DCM and 1 N aqueous NaOH and stirred for 10 minutes. The organic layer was separated and the aqueous layer was extracted with DCM twice. The combined organic layer was dried with anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (30% ethyl acetate in hexane) providing the product aniline (327 mg, 88% yield). 1H- NMR (CDCl3): δ7.26 (m, 1 H), 6.90 (m, 1 H), 6.76 (m, 5H), 3.84 (s, 2 H).
Example 92b
Preparation oj '3-(5-(5-(3-(methylmlfonyl)phenyl)thiophen-2-yl)-3-(Mflwromethy>l)-^ yl)aniline
Figure imgf000278_0002
To a solution of the 3-(5-(5-bromoiMopheh-2-yl)-3-(trifluoromethyl)-1H-pyrazol-l-yl)aniline (1.55 g, 4.0 mmol) in anhydrous THF (20.0 mL) was added 3-(methylsulfonyl)phenylboronic acid (0.88 g, 4.4 mmol), PdCl2dppf (163 mg, 0.20 mmol), Na2CO3 (0.85, 8.0 mmol) and water (2.0 mL). The reaction mixture was heated to reflux at 55 ºC under nitrogen atmosphere for 15 hours. It was cooled off and passed through a pad of celite. The solvent was evaporated in vacuo and the resulting residue was purified by column chromatography (50% ethyl acetate in hexane), providing the product (778 mg, 42%). 1H-NMR (Acetone-d6): 57.98 (m, 1 H), 7.78 (m, 2 H), 7.55 (m, 2 H), 7.47 (m, 1 H), 7.41 (m, 1 H), 7.28 (m, 1 H), 7.11 (m, 1 H), 7.02 (m, 1 H), 6.97 (m, 1 H), 5.49 (s, 2 H), 3.05 (s, 3 H). MS (ES): 464 [M+H]+.
Scheme 39
Figure imgf000279_0001
As depicted in Scheme 39, the aniline 039P12 was treated with alkyl isocyanate in the presence of triethylamine to afford urea 039SP13.
Example 93
Preparation of l-(3-(5-(5-(3-(methylsulfoiiyl)phenyl)thiophen-2-yl)-3- φifluoromethyty-lH-pyrazol-l- yl)phenyl)wea .
Figure imgf000279_0002
To a solution of the 3-(5-(5-(3-(methylsuh°onyl)phenyl)-thiophen-2-yl)-3-(trifluoromethyl)-1H- pyrazol- 1 -yl)aniline in anhydrous DCM (1.0 mL) and THF (3.0 mL) was added trimethylsilyl isocyanate (112 mg, 0.85 mmol) and triethyl amine (29 mg, 0.28 mmol). The reaction mixture was stirred under nitrogen atmosphere for overnight A 1.0 M solution of tetra-butylammonium fluoride (1.42 mL, 1.42 mmol) in THF was added and the mixture was stirred at room temperature for overnight The solvent was evaporated in vacuo and the resulting residue was purified by HPLC, providing the ureaproduct(70 mg, 49%). 1H-NMR (Acetone-d6): 58.56 (s, 1 H), 8.13 (m, 1 H), 7.98 (m, 1 H), 7.91 (m, 1 H), 7.69 (m, 1 H), 7.60 (m, 1 H), 7.49 (m, 1 H), 7.20 (m, 1 H), 7.17 (m, 1 H), 6.44 (br, 2 H), 3.18 (s, 3 H). MS (ES): 507 [M+H]+.
Scheme 40
Figure imgf000279_0003
As depicted in Scheme 40, the methylsuhonyl substituted pyrazole 040SP14 was treated with n-butyl lithium and then alkyl halide to afford the alkyl sulfbnyl substituted pyrazole 040SP15. Example 94
Prepω'ationofl-(2,5-dichlorophe}τyl)-5-(5-(3-(ethylsύfoπyl)p^^ lH-pyrάzole .
Figure imgf000280_0001
1 ^jS-dichloropheny^-S-CS^S-^ethylsulfony^phenyQfhiophen^-y^-S^trifluoromethyl)- IH- pyrazole (0.5 g, 0.97 mniol), prepared as described in Example Ic, was dissolved in anhydrous TEIF (8.0 mL) and cooled at -78 ºC under nitrogen atmosphere. To this solution a 1.6 M solution n-BuLi (0.78 mL, 1.28 mmol) in hexane was added . The mixture was stirred at -78 ºC for 15 min. and iodomethane (608 mg, 4.28 mmol) was added and it was stirred for overnight while it warmed up to room temperature. The reaction was quenched carefully with water and the product was extracted with ethyl acetate. The organic layer was washed with brine and water and dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (50% ethyl acetate in hexane), providing the product (153 mg, 30%). 1H-NMR (CDCl3): 68.04 (m, 1 H), 7.83 (m, 1 H), 7.76 (m, 1 H), 7.60 (m, 1 H), 7.51 (m, 2 H), 7.26 (m, 1 H), 6.90 (s, 1 H), 6.87 (m, 1 H), 3.15 (q, J= 7.5 Hz, 2 H), 1.31 (t, J = 7.5 Hz, 3 H). MS (ES): 531 |M+H]+.
The following compounds are prepared essentially according to the previous examples:
• l-(2,5-dichlorophenyl)-5-(5-(3-(propylsuhOnyl)phenyl)tMophen-2-yl)-3-(1rifluoromethyl) -1H- pyrazole. 1H-NMR(CDCl3): 57.73 (m, 1 H), MS (ES): 545 [M+H]+.
• l-(2,5-dichlorophenyl)-5-(5-{3-[(l,l-dimethylethyl)sulfonyl]phenyl}-2-thienyl)-3- (trifluoromethyl)-1H-pyrazole, MS(ES): 559 [M+H]+.
Scheme 41
Figure imgf000280_0002
As depicted in Scheme 41, the methylsulfonyl substituted pyrazole 041SP14 was treated with LHMDS and then an aldehyde to afford the alcohol 041SP16. Example 95
Prepω-ationoflφ-(5-(l-(2,5-dichloropheψl)-3-(Mfluorometlψl)-lH-pyιmo^ yl)phenylsulfonyl)butan-2-ol.
Figure imgf000281_0001
To a solution of l-(2,5-dichlorophenyl)-5-(5-(3-(methylsulfonyl)phenyl)thiophen-2-yl)-3- (trifluoromethyl)-1H-pyrazole (0.20 g, 0.39 mmol) in anhydrous THF (4.0 mL) cooled at -78 ºC under nitrogen atmosphere was added slowly a 1.6 M solution LHMDS (0.27 mL, 0.43 mmol) in THF. The mixture was stirred at -78 ºC for 15 min. and propionaldehyde (45 mg, 0.77 mmol) was added and it was stirred for overnight while it warmed up to room temperature. The reaction was quenched with water and the product was extracted with ethyl acetate. The organic layer was washed with brine and water and dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (60% ethyl acetate in hexane), providing the product (156 mg, 70%). 1H-NMR (Acetone-d6): 58.12 (m, 1 H), 7.98 (m, 1 H), 7.90 (m, 1 H), 7.88 (m, 1 H), 7.77 (m, 2 H), 7.68 (m, 1 H), 7.58 (m, 1 H), 7.28 (s, 1 H), 7.20 (m, 1 H), 4.02 (m, 1 H), 3.39 (m, 2 H), 1.58 (m, 1 H), 1.48 (m, 1 H), 0.9 (t, J= 7.1 Hz, 3 H). MS (ES): 575 [M+H]+.
Scheme 42
Figure imgf000281_0002
As depicted in Scheme 42, pyrazole 042SP17 prepared as described in Example Ib was treated with alkyl halide 042SP18 and K2CO3 at 85 ºC to afford 5-(5-bromothiophen-2-yl)-l-arylmethyl-3- (trifluoromethyl)-1H-pyrazole 042SP19, which was coupled with an aryl boronic eater 042SP20 in the presence of PdCl2(dppf), K2CO3, resulting in the pyrazole 042SP21. Example 96
Prepω'ation of2-(3-(5-(l-((5-chlorothiophen-2-yl)methyl)-3-(Mfluomfnethy^ yl)thiophen-2-yl)phenyl)-2-metJψlpropanoic acid
Figure imgf000282_0001
5-(5-bromothiophen-2-yl)-3-(trifluorome1hyl)-1H-pyra2;ole (3.23 g, 10.88 mmol), prepared in a manner similar to that described in Example Ib, was dissolved in anhydrous DMF (40 mL). To this solution was added2-chloro-5-(chloromethyl)thiophene (2.0 g, 11.97 mmol) and K2CO3 (2.25 g, 16.32 mmol). The reaction mixture was heated at 85 ºC under nitrogen atmosphere for overnight. The solvent was evaporated and the resulting residue was taken into ethyl acetate. The reaction mixture was washed with water and brine and dried over anhydrous Na2SO4. It was concentrated in vacuo. The residue was purified by column chromatography (10% ethyl acetate in hexane), providing the product 5-(5- bromotMophen-2-yl)-l-((5-chloroiMophen-2-yl)methyl)-3-(1iffluoromethyl)-1H-pyrazole (1.39 g, 30%). 1H-NMR(CDCl3): 57.11 (m, 1 H), 6.90 (m, 1 H), 6.75 (m, 1 H), 6.67 (m, 1 H), 6.61 (s, 1 H), 5.46 (s, 2 H). The above product was coupled with an aryl boronic ester in a manner similar to that described in Example Ic, providingthe title compound (161 mg, 45%). 1H-NMR(CDCl3): 67.63 (s, 1 H), 7.50 (m, 1 H), 7.40 (m, 2 H), 7.32 (m, 1 H), 7.12 (m, 1 H), 6.74 (m, 1 H), 6.69 (m, 1 H), 6.66 (s, 1 H), 5.54 (s, 2 H), 1.66 (s, 6 H). MS (ES): 511 |M+H]+. The following compounds are prepared essentially according to the previous examples:
• 2-(3-(5-(l-(2,4-άΗuorobenzyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)thiophen-2-yl)phenyl)-2- methylpropanoic acid. MS (ES): 507 |pVI+H]+.
• l-(5-(5-(l-(2,4-dffluorobenzyl)-3-(trifluoro yl)piperazine. MS (ES): 506 |M+H]+.
• 2-(l-(2,4-dMuorobenzyl)-5-(5-(3-(methylsulfonyl)phenyl)lMophen-2-yl)-1H-pyrazol-3- yl)propan-2-ol. MS (ES): 489 |M+H]+. Scheme 43
Figure imgf000283_0001
As depicted in Scheme 43, the aniline 043SP22 was treated with triphosgene and triethylarnine to afford isocyanate 043SP23, which was reacted with alcohol, providing the carbamate 043SP24. The cabarmate 043SP24 was treated with MeMgBr to produce the carbinol 043SP25. Example 97
3-(4-methylpiperazin-l-yl)propyl4'-(l-(2,6-dichhwphenyl)-3-(2-hyaOxypropan^ yl)-3 '-methylbipJienylS-ylcarbamate
Example 97a
Preparation of methyl l-(2, 6-dichlorophenyl)-5-(3 '-isocyanato-3-methylbiphe}τyl-4-yl)-lH- pyrazole-3-carboxylate
Figure imgf000283_0002
methyl S-CS'-arriino-S-meihylbiphenyM-y^-l^ό-dichloropheny^-1H-pyrazole-S-carboxylate (0.276 g, 0.61 mmol) was dissolved in anhydrous DCM (6.0 mL) and cooled off under nitrogen atmosphere at 0 ºC with an ice /water bath. To this solution was added triethyl amine (74 mg, 0.73 mmol) and triphosgene (181 mg, 0.61 mmol). The reaction mixture was stored for 4 hours while it warmed up to room temperature. It was quenched carefully with water and the reaction mixture was extracted with DCM. The organic layer was washed with water and brine and dried over anhydrous Na2SO4. The residue was concentrated in vacuo, providing the crude product isocyanate, which was used for the next reaction without purification.
Example 97b Preparation of methyl l-(2, 6-dichloropheψl)-5-(3-methyl-3 '-((3-(4-meihylpiperazin-l- yl)pvpoxy)carbonylamino)biphe}τyl-4-yl)-lH-pyι-azole-3-cω-boxylate
Figure imgf000284_0001
To a solution of the crude isocyanate in anhydrous DCM (6.0 mL) was added trietbyl amine (74 mg, 0.73 mmol) and 3-(4-methylpiperazin-l-yl)propan-l-ol (97 mg, 0.61 mmol). The reaction mixture was stirred under nitrogen atmosphere at room temperature for overnight. It was concentrated in vacuo. The crude product carbamate was used for the next reaction without purification.
Example 97c
Preparation of3-(4-meihylpiperazin-l-yl)propyl 4'-(1-Q16-dichlorophenyl)-3-(2-lτydroxypropan-2-yl)- lH-pyrazol-5-yl)-3 '-methylbiphenyl-3-ylcarbamate
Figure imgf000284_0002
To a solution of the crude carbamate in anhydrous TBDF (6.0 mL) cooled off under nitrogen atmosphere at -78 ºC was added a 3.0 M solution of MeMgBr (1.0 mL, 3.0 mmol). It was stirred at -78 ºC for 30 minutes and the cold bath was then removed. The mixture was stirred for 4 hours while it warmed up to room temperature. It was quenched with water and aq. NH4Cl. The reaction mixture was extracted with ethyl acetate. The organic layer was washed with brine and water and dried over anhydrous Na2SO4. The solvent was evaporated in vacuo and the residue was purified by HPLC, providing the product (74 mg, 19% over 3 steps). 1H-NMR (CDCl3): 57.68 (tar, 1 H), 7.45 (m, 1 H), 7.33 (m, 3 H), 7.23 (m, 3 H), 7.10 (m, 1 H), 6.64 (s, 1 H), 6.46 (s, 1 H), 4.22 (m, 1 H), 2.66 (s, 1 H), 2.46 (tar, 11 H), 2.29 (s, 3 H), 1.87 (m, 2H), 1.70 (s, 6H), 1.61 (s, 3 H). MS (ES): 636 |M+H]+.
Scheme 44
Figure imgf000285_0001
As depicted in Scheme 44, the hydroxyetliyl substituted pyrazole 044P26 was treated with triflic anhydride and DIEA to afford the trifilate 044SP27, which was reacted with amine, resulting in the aminoethylsubstituted pyrazole 044SP28.
Example 98
Preparation ofN-(2-(5-(5-(3-(methylmlfonyl)phenyl)thiophen-2-yl)-3-(Mfluorometlψl)-lH^ yl)ethyl)propan-2-amine
Figure imgf000285_0002
2-(5-(5-(3-(methylsulfonyl)phenyl)thiophen-2-yl)-3-(trifluoromethyl)- lH-pyrazol- 1 -yl)ethanol (208 mg, 0.50 mmol), prepared in a manner similar to that describes Example Ic, was dissolved in anhydrous DCM (4.0 mL) and cooled off at 0 ºC under nitrogen atmosphere with an ice/water bath. To this solution was added DIEA (97 mg, 0.75 mmol) and triflic anhydride (169 mg, 0.60 mmol). The reaction mixture was stirred at 0 ºC for an hour and isopropyl amine (148 mg, 2.5 mmol) was added. It was stirred for overnight while it warmed up to room temperature. The reaction mixture was concentrated in vacuo and the residue was purified by HPLC, providing the product amine (148 mg, 65%). %). 1H-NMR (CDCl3): 58.17 (m, 1 H), 7.90 (m, 1 H), 7.87 (m, 1 H), 7.64 (m, 1 H), 7.44 (m, 1 H), 7.30 (m, 1 H), 6.67 (s, 1 H), 4.39 (m, 2 H), 3.15 (m, 2 H), 3.13 (s, 3 H), 2.79 (m, 1 H), 1.03 (d, 6 H). MS (ES): 458 |M+H]+. The following compounds are prepared essentially according to the previous examples:
• N-(2-(5-(5-(3-(metiiylsulfonyl)phenyl)tMophen-2-yl)-3-(tMuoromethyl)-1H-pyrazol-l- yl)e%l)cyclopentanarnine. MS (ES): 484 [M+H]+.
• N-benzyl-N-methyl-2-(5-(5-(3-(methylsulfon^ pyrazol-l-yl)ethanamine. MS (ES): 520 [M+H]+.
• N-methyl-2-(5-(5-(3-(methylsιtfonyl)phe^ yl)-N-(thiophen-2-ylmethyl)ethanamine. MS (ES): 526 [M+H]+.
• N-(furan-2-ylmethyl)-N-methyl-2-(5-(5-(3-(methylsulfonyl)phenyl)thiophen-2-yl)-3- (trifluoromethyl)-1H-pyrazol-l-yl)ethanamine. MS (ES): 510 \M+H\+
• N-methyl-2-(5-(5-(3-(methylsulfonyl)phenyl)tMophen-2-yl)-3-(1rifluoromethyl)-1H-pyra∞ yl)-N-(pyridin-4-ylinethyl)ethanamine. MS (ES): 521 [M+Hf.
• l-(2-(lH-imidazol-l-yl)ethyl)-5-(5-(3-(methylsulfonyl)phenyl)thiophen-2-yl)-3- (trifluoromethyl)-1H-pyrazole. MS (ES): 467 [M+H]+.
• l-methyl-4-(2-(5-(5-(3-(me1hylsulfonyl)phenyl)thiophen-2-yl)-3-(trifluoromethyl)-1H-pyrazol- l-yl)ethyl)piperazine. MS (ES): 499 [M+H)+.
• l<2-(5-(5-(3-(methylsulfonyl)phenyl)tMophen-2-yl)-3-(1rifluoromethyl)-1H-pyrazol-l- yl)ethyl)pyrroUdin-3-ol. MS (ES): 486 |M+H]+.
Scheme 45
Figure imgf000286_0001
Additional methods for function group conversion on the pyrazole ring are illustrated in Scheme 45. Ester substituted pyrazole compound, such as formula (045B1) can be converted to thioesters, such as compound (045B2) using standard techniques that use known reagents of thiation such as Lawesson's reagent. Thioester (045B2) can be converted to difluoroethers compounds, such as formula (045B3), with the aid of known reagents of gem difluorination such as DAST. Ester substituted pyrazole compound (045B1) can also be converted to amides, thioamides, such as compound (045B4), carboxylic acids, sulfonamides such as compound (045B5), and amines using techniques that are readily apparent to one skilled in the arts.
Example 99
3-(Diflmro-methoxy-ιitethyl)-5-[5-(3-methmesulfonylφhenyl)4hiophm-2-yl^ phenyl)-lH-pyrazole
Example 99a
Prepω*atiorιof5-[5-(3-MetIimesulfi)7iylψJmψl)-thiophen-2-yl]-l-(2-trffl pyrazole-3-carbothioic acid O-metJψl ester
Figure imgf000287_0001
To a 50 mL round bottom flask attached with condenser was added 5-[5-(3-Methanesuh°onyl- phenyl)-thiophen-2-yl]-l-(2-trifluoromethyl-phenyl)-1H-pyrazole-3-carboxylic acid methyl ester (326 mg, 644 μmol), Lawesson's reagent (520 mg, 1.29 mmol) and anhydrous toluene (23 mL). The reaction solution was stirred at reflux for 1 day. The reaction solution was concentrated in vacuo, and the crude material was chromatographed through a 25 g SiO2 column using a gradient of 100 % Hx to 50 % EtOAc to afford 302 mg (90 % yield) of the title compound. MS (ES) 523.3 [M+H]+, 545.0 (MH-Na)+.
Example 99b
Preparationof3~φifluoro-methoxy-methyl)-5-[5-(3-methamsulfonylφ^^ tιifluoromethyl-phenyl)-lH-pyra∑ole
Figure imgf000287_0002
To a dry, N2 purged round bottom flask was added 5-[5-(3-Methanesulfonyl-phenyl)-thiophen- 2-yl]-l-(2-trifluoromethyl-phenyl)-1H-pyrazole-3-carbothioic acid O-methyl ester (280 mg, 535 μmol) in a solution of anhydrous DCM (15 mL). To the reaction solution was added DAST (200 mL, 1.53 mmol), and the reaction solution was stirred at room temperature for 14 hrs. The reaction solution was diluted with DCM (100 mL) and washed with aq. NaCl, partitioned, dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was chromatographed through a 25 g SiO2 column using a mobile phase of 100 Hx to 50 % EtOAc to afford 64 mg (23 % yield) of the title compound. 1H NMR (400 MHz, CDCl3) δ 8.02 (s, IH), 7.80-7.89 (m, 2H), 7.66-7.75 (m, 3H), 7.50-7.58 (m, 2H), 7.18 (d, IH), 6.83 (s, IH), 6.74 (d, IH), 3.47 (s, 3H), 3.06 (s, 3H); 19F NMR (400 MHz, CDCl3) δ - 61, -71 ppm. MS (ES) 529.3 [M+H].
Example 100
N-[5-[5-(3-MetJιmesulforiylφhenyl)4hiophen-2-yl]-l-(2-trifluorometlψ^ carbonylj-methanesulfonamide
Example 100a
5-[5-(3-Methamsύfonyl-pheryl)4hiophen-2-yl]-l-β^ acid
Figure imgf000288_0001
To a 100 mL round bottom flask attached with condenser was added 5-[5-(3-Methanesuhcbnyl- phenyQ-thiophen-l-yy-l^-trifluoromethyl-phenyQ-1H-pyrazole-S-carboxylic acid ethyl ester (2.52g, 4.98 mmol), IN aq NaOH (30 mL), and MeOH (25 mL). The reaction solution was stirred at 55 ºC for 1.5 hr prior to TLC analysis. The reaction solution was diluted with EtOAc (200 mL), poured into a separatory funnel and the organic phase was partitioned. The aqueous phase was neutralized by the addition of aq 1 N HCl and extracted with EtOAc (70 mL x 2). The combined organic phase was dried over Na2SO4, filtered into a round bottom flask and concentrated on the Rotavapor. The crude residue was chromatographed thru a 25 g SiO2 column using a mobile phase gradient of 100% Hx to 85 % EtOAc to afford 1.35 g (55 % yield) title compound. MS (ES) 493.1 [M+H]+.
Example 100b N-[5-[5-(3-Methamsidfoττylφheryl)4hioplτen-2-yl]-l-(2-Mfluoromethyl^ carbonylj-methanesulfonamide
Figure imgf000288_0002
To round bottom flask was added 5-[5-(3-Methanesulfonyl-phenyl)-thiophen-2-yl]-l-(2- trifluoromethyl-phenyl)-1H-pyrazole-3-carboxylic acid (302 mg, 615 μmol), oxalyl chloride (0.54 mL), anhydrous DCM (10 mL), and anhydrous DMF (100 μL). The reaction solution was stirred at room temperature for approximately 1 hr prior to concentration in vacuo. The resulting crude acid chloride intermediate was used in the next reaction without further purification. To a glass vial was added acid chloride (615 μmol theoretical), methanesulfonamide (117 mg, 1.23 mmol), 1, 2-dichloroethane (9 mL), DIEA (200 μL), and DMAP (10 mg). The reaction solution was stirred at 45 ºC for 3 hrs. The reaction solution was diluted with DCM (60 mL) and transferred to a separatory funnel. The solution was washed with aq NH4Cl (50 mL x 2) and with aq NaCl (50 mL). The organic phase was dried over Na2SO4, filtered, concentrated on the Rotavapor and chromatographed through a 25 g SiO2 column using a mobile phase gradient of 100 % Hx to 70 % EtOAc to afford 182 mg (52 % yield) of the title compound. 1H NMR (400 MHz, CDCl3) δ 9.07 (s, IH), 8.02 (s, IH), 7.91 (m, IH), 7.84 (d, IH), 7.74- 7.80 (m, 2H), 7.69 (d, IH), 7.55 (t, IH), 7.48 (m, IH), 7.23 (s, IH), 7.21 (d, IH), 6.77 (d, IH), 3.42 (s, 3H), 3.07 (s, 3H); 19F NMR (400 MHz, CDCl3) δ -60.5 ppm MS (ES) 570.2 [M+H]+.
Example 101
Preparation of l-(2-Chloro-phenyl)-5-[5-β-rnethcmesulfony^ carbothioic acid etliylamide
Figure imgf000289_0001
To a dry, N2 purged 50 mL round bottom flask attached with condenser was added l-(2- CUoro-pheny^-S-^^S-methanesulfonyl-pheny^-thiophen^-yy-1H-pyrazole-S-carboxylic acid ethylamide (100 mg, 206 μmol), Lawesson's reagent (200 mg, 494 μmol), and anhydrous toluene (8 mL). The reaction solution was allowed to stir at reflux for 14 hrs. The reaction solution was allowed to cool to room temperature prior to addition of a 1:1 mixture of benzene and Et2O. The resulting precipitate was removed by vacuum filtration through a Buchner funnel. The filtrate was concentrated on the Rotavapor and the crude residue was chromatographed through a 12 g SiO2 column using a mobile phase gradient of 100 % Hx to 50 % EtOAc to afford 39 mg (38 % yield) of the title compound. 1H NMR (400 MHz, CDCl3) δ 8.68 (br s, IH), 8.02 (s, IH), 7.83 (d, IH), 7.72 (d, IH), 7.48-7.70 (m, 5H), 7.42 (s, IH), 7.22 (d, IH), 6.83 (d, IH), 3.87 (m, 2H), 3.07 (s, 3H), 1.36 (t, 3H). MS (ES) 502.3, 504.3 [MH-H]+.
The following compound was prepared in a similar manner to that described above: • l-(2-chlorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-tWenyl}-N-(2,2>trifluoroethyl)-1H- pyrazole-3-carbothioamide, MS (ES) 556.0, 558.0 [M+H]+
Scheme 46
Figure imgf000290_0001
(a) 3-Pyr-boronic acid, PdCI2dppf, K2CO3; (b) R3R4NH, Pd cat
Additional methods for A-ring substitution which use metal catalyzed carbon-carbon bond coupling methodology are illustrated in Scheme 46. The pyrazole-phenyl bromide intermediate (046B6) can be reacted under Suzuki coupling conditions to prepare the ortho-asyl products, such as compound (046B7). The aryl bromide intermediate (046B6) can also be used in Buchwald amination reaction to prepare alkylamino substituted compounds, such as formula (046B8).
Example 102
Preparation of 3-(2-{5-[5-(3-Methcmesulfonylψhenyl)4hiophen-2-yl]-3-Mfluorome phenyl)-pyridine
Figure imgf000290_0002
To a 50 mL round bottom flask attached with condenser was added l-(2-Bromo-phenyl)-5-[5- (3-memanesuhOnyl-phenyl)-thiophen-2-yl]-3-trifluoromethyl-1H-pyrazole (prepared following the described in Example Ic) (110 mg, 210 μmol), 3-pyridylboronic acid (31 mg, 525 μmol), PdCl2dppf (25 mg, 10 mol %), K2CO3 (58 mg, 410 μmol), 1,4-dioxane (8 mL) and H2O (1.5 mL). The reaction solution was allowed to stir at 75 ºC for 20 hrs. The reaction solution was diluted with EtOAc (150 mL) and transferred to a separatory funnel and washed with aq NH4Cl (100 mL) and aq NaCl (100 mL). The organic phase was dried over Na2SO4, filtered, concentrated on the Rotavapor and chromatographed through a 25 g SiO2 column using a mobile phase gradient of 100 % Hx to 90 % EtOAc to afford 45 mg (41 % yield) of the title compound. 1H NMR (400 MHz, DMSCMy) δ 8.41 (m, IH), 7.99 (m, 2H), 7.51-7.90 (m, 8H)5 7.24 (s, IH), 7.17-7.23 (m, 2H), 6.87 (d, IH), 3.28 (s, 3H); 19F NMR (400 MHz, DMSO-J6) δ -61.2 ppm. MS (ES) 526.5 [M+H]+.
Scheme 47
Figure imgf000291_0001
Additional methods for synthesizing substituted arylhydrazines, such as compound (047B12) are shown in Scheme 47. The hydrazines can be used to prepare pyrazole compounds, similar to those described in Example Ic, and the method in Scheme 47 is a complementary method to that described in Scheme 46. 2-Fluoro-nitrobenzene (047B9) can be reacted with alkylamines to undergo a SNAT reaction to yield substituted arylnitro compounds (047B10). The nitro intermediate (047B10) can be converted to the corresponding aniline (047B11) using known hydrogenation methods. The resulting aniline (047B11) can be converted to the arylhydrazine (047B12) by reaction through the diazonium salt followed by reduction. When these hydrazines are applied to the pyrazole synthesis methodology described in Example 1 c, final pyrazole compounds containing larger and more complex aminoalkyl substituents, such as compound (047B13) are available.
Example 103 l-(2-{5-[4-(3-MetJιamsulfoiψlφherιyl)4hfop}ιen-2-yl]-3-Mfluoromethyl- methyl-piperazine Example 103a
Preparation of l-Methyl-4-(2-niti"o-phenyl)-piperiήne
Figure imgf000291_0002
To a Kontes glass tube was added 2-fluoro-nitrobenzene (3.34 g, 23.7 mmol), 1-methyl- piperizine (3.90 mL, 35.6 mmol), and anhydrous THF (10 mL). The tube was sealed and the reaction mixture was allowed to stir at 60 ºC for 1 day. The reaction solution was diluted with EtOAc (150 mL), washed with aq NaHCO3, dried over Na2SO4, filtered, and concentrated in vacuo to afford 5.07 g (97 % yield) of the title product MS (ES) 222.3 [M+H]+.
Example 103b Preparation of 2-(4-Methyl-piperazin-l-yl)-phenylhydrazine-HCl
Figure imgf000292_0001
To a Parr Hydrogenation flask was added l-Methyl-4-(2-nitro-phenyl)-piperizine (2.72 g, 12.3 mmol), EtOAc (50 mL), MeOH (50 niL). The flask was purged with dry N2 for 5 min prior to addition of 10 % Pd/carbon (1.00 g). The flask was placed onto the Parr hydrogenation apparatus and exposed to H2 at 30 psi. The reaction was allowed to shake under H2 pressure for 2 hrs. The flask was vented and the solution was filtered through a silica gel padded Buchner funnel. The filtrate was concentrated in vacuo to afford 2.Og aniline product. The crude aniline was added to a 100 mL round bottom flask along with sodium nitrite (940 mg, 13.6 mmol), and cone. HCl (13 mL). The reaction was stirred at -10 ºC for approximately 1 hr prior to addition of tin(D) chloride-dihydrate (10 g, 45 mmol) in a solution of cone. HCl (8 mL). The reaction solution was stirred at -10 ºC for 1 hr. The solution was diluted with EtOAc (200 mL) and 2N aq NaOH was added until all tin byproduct was water soluble. The EtOAc phase was partitioned and the aq phase was extracted with EtOAc (150 x 2). The combined organic phase was dried over Na2SO4, filtered, and concentrated in vacuo to afford 1.69 g (79 % yield) of product MS (ES) 237.3 [M+H]+, 259.3 (M+Na)+. Example 103c l-(2-{5-[4-(3-Methamsdfonyl-pheriyl)4hiophen-2-yl]-3-fr^ methyl-piperazine
Figure imgf000292_0002
The compound 1 -(2-{5-[4-(3-Methanesulfonyl-phenyl)-thiophen-2-yl]-3-trifluoromethyl- pyrazol-l-yl}-phenyl)-4-methyl-piperazine was prepared in a manner similar to that described in Example Ic by using 2-(4-Me%l-piperazin-l-yl)-phenylhydrazine-HCl. 1H NMR (400 MHz, DMSO- d6) δ 8.16 (s, IH), 7.97-8.08 (m, 3H), 7.84 (d, IH), 7.69 (t, IH), 7.57 (t, IH), 7.44-7.57 (m, 2H), 7.17- 7.28 (m, 2H), 3.28 (s, 3H), 2.67 (br s, 2H), 2.03 (s, 3H), 1.86-2.14 (m, 6H); 19F NMR (400 MHz, TMS0-d6) δ -61.1 ppm. MS (ES) 547.3 |M+H]+, 569.3 (MfNa)+. The following compounds were synthesized in a manner similar to that described in Example 103 :
• 3-{5-[l-[2-(4-me1hylpiperazm-l-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]-3- thienyl}benzenesulfonamide, MS (ES) 548.3 [M+H]+, 570.0 (MH-Na)+
• 4-{2-[5-{4-[3-(me1hylsulfonyl)phenyl]-2-iMenyl}-3-(trifluoromethyl)-1H-pyrazol-l- yl]phenyl}morpholine, MS (ES) 534.2 [MH-H]+ 4-{2-[5-(4-bromo-2-tMenyl)-3-(t^ 458.2, 460.2 [MH-H]+
5-{4-[3-(me1hylsulfonyl)phenyl]-2-iMenyl}-l-(2-propylphenyl)-3-(tiifluoromethyl)-1H- pyrazole, MS (ES) 491.2 [M+H]+ l-[2-(l-methyle%l)phenyl]-5-{4-[3-(methylsulfonyl)phenyl]-2-tMenyl}-3-(tiffluorome% lH-pyrazole, MS (ES) 491.4 [MHhH]+ l-methyl4-({2-[5-{4-[3-(methylsulfony^ yl]phenyl}methyl)piperazine,MS (ES) 560.8 [MH-H]+
Scheme 48
Figure imgf000293_0001
As depicted in Scheme 48, biphenyl pyrazole 048E and 048F were prepared from acetophenone 048A in a manner similar to that described in Scheme 6.
Example 104
2-{5-(2-chforopheψl)-l-[3-met}ψl-3'-(methylsulforιyl)bipheψl-4-yl]-lfr^
Figure imgf000293_0002
2-{5-(2-chlorophenyl)-l-[3-methyl-3?-(methylsulfonyl)biphenyl-4-yl]-1H-pyrazol-3-yl}propan-
2-ol was prepared in a manner similar to that as described in Example 8d by using T- chloroacetophenone. 1H-NMR (CDCl3): δ 8.10 (s, IH), 7.91 (m, IH), 7.89 (m, IH), 7.83 (m, IH), 7.62 (m, IH), 7.46 (d, IH), 7.38 (d, IH), 7.34-7.16 (m, 4H), 6.53 (s, IH), 3.09 (s, 3H), 2.71 (s, IH), 2.23 (s,
3H), 1.70 (s, 6H). MS(ES): 481 [M+H]+, 463 (M-OH).
The following compounds are prepared essentially according to the previous examples:
• 5-((2-chlorophenyl)-l-(4-bromo-2-chlorophenyl)-1H-pyrazole-3-carboxylic acid methyl ester was prepared in a manner similar to that as described in Example 8b by using 4-(2- chlorophenyl)-2,4-dioxo-butyric acid methyl ester . MS(ES): 405 [M+H]+.
• S-^-chlorophenyO-l-P-methyl-S'-^e^lsulfony^biphenyM-yy-1H-pyrazole-S-carboxylic acid methyl ester was prepared in a manner similar to that as described in Example 8c. by using 5-((2-chlorophenyl)-l-(4-bromo-2-chlorophenyl)-1H-pyrazole-3-carboxylic acid methyl ester . MS(ES): 481 [M+H]+.
• 2-{5-(2-cMorophenyl)-l-[3-me1hyl-3'-(methylsulfonyl)biphenyl-4-yl]-1H-pyrazol-3-yl}propan- 2-ol was prepared in a manner similar to that as described in Example 8d by using 5-((2- chlorophenyl)- 1 -[3-methyl-3 '-(methylsulfonyl)biphenyl-4-yl]- lH-pyrazole-3-carboxylic acid methyl ester. 1H-NMR (CDCl3): δ 8.10 (s, IH), 7.91 (m, IH), 7.89 (M, IH), 7.83 (m, IH), 7.62 (m, IH), 7.46 (d, IH), 7.38 (d, IH), 7.34-7.16 (m, 4H), 6.53 (s, IH), 3.09 (s, 3H), 2.71 (s, IH),
2.23 (s, 3H)5 1.70 (s, 6H). MS(ES): 481 [M+H]+, 463 (M-OH).
• 2-{l-[3-chloro-3'-(methylsulfonyl)biphenyl-4-yl]-5-(2-chlorophenyl)-1H-pyrazol-3-yl}propan- 2-ol, MS(ES): 501 [M+H]+, 483 (M-OH)
• 2-{5-(2,6-dichlorophenyl)-l-[3-me1hyl-3'-(methylsulfonyl)biphenyl-4-yl]-1H-pyrazol-3- yl}propan-2-ol, MS(ES): 515 [M+H]+ 497 (M-OH)
• 2-{l-[3-chloro-3'-(methylsulfonyl)biphenyl-4-yl]-5-(2,6-dichlorophenyl)-1H-pyrazol-3- yl}propan-2-ol, MS(ES): 535 |M+EQ+ 517 (M-OH)
• 2-{5-(2,6-dichlorophenyl)-l-[3'-(methylsulfonyl)biphenyl-4-yl]-1H-pyrazol-3-yl}propan-2-ol, MS(ES): 501 |M+H]+ 483 (M-OH) • 2-{5-(2,3-dichlorophenyl)-l-[3'-(methylsulfonyl)biphenyl-4-yl]-1H-pyrazol-3-yl}propan-2-ol,
MS(ES): 501 |M+H]+, 483 (M-OH)
• 2-{5-(2,3-dichlorophenyl)-l-[3-methyl-3'-(me1hylsulfonyl)biphenyl-4-yl]-1H-pyrazol-3- yl}propan-2-ol, MS(ES): 515 [M+H]+, 497 (M-OH)
• 2-{l-[3-cMoro-3'-(me1hylsulfonyl)biphenyl-4-yl]-5-(2,3-dichlorophenyl)-1H-pyrazol-3- yl}propan-2-ol, MS(ES): 535 [MH-H]+, 517 (M-OH)
• 2-[5-(2-chlorophenyl)-l-{3-methyl-5-[3-(methylsulfonyl)phenyl]pyridin-2-yl}-1H-pyrazol-3- yl]propan-2-ol, MS(ES): 482 [M+H]+, 464 (M-OH) • 2-{5-(2-cMorophenyl)-l-[3,5-dime1hyl-3'-(methylsulfonyl)biphenyl-4-yl]-1H-pyrazol-3- yl}propan-2-ol, MS(ES): 495 [M+H]+, 477 (M-OH)
• 2-(5-(2-cUoro-6-fluorophenyl)-l-(3'-(methylsulfonyl)biphenyl-4-yl)-1H-pyrazol-3-yl)propan- 2-ol. MS (ES): 485 |M+H]+. • 2-(5-(2,3-dffluorophenyl)-l-(3'-(methylsulfonyl)biphenyl-4-yl)-1H-pyrazol-3-yl)propan-2-ol. MS (ES): 469 [M+H]+.
• 2-(5-(2-chloro-6-fluorophenyl)-l-(3-fluoro-3'-(metliylsulfonyl)biphenyl-4-yl)-1H-pyrazol-3- yl)propan-2-ol. MS (ES): 503 [M+H]+.
• 2-(5-(2,3-dffluorophenyl)4-(3-fluoro-3'-(methylsulfonyl)biphenyl-4-yl)-1H-pyrazol-3- yl)propan-2-ol. MS (ES): 487 [M+Hf .
• 2-(5-(2-cMoro-6-fluorophenyl)-l-(3-methyl-3'-(methylsulfonyl)biphenyl-4-yl)-1H-pyrazol-3- yl)propan-2-ol. MS (ES): 499 |M+H]+.
• 2-(5-(2,3-dffluorophenyl)-l-(3-methyl-3'-(methylsulfonyl)biphenyl-4-yl)-1H-pyrazol-3- yl)propan-2-ol. MS (ES): 483[M+H]+. * 2-(l-(3-chloro-3'-(methylsulfonyl)biphenyl-4-yl)-5-(2-cUoro-6-fluorophenyl)-1H-pyrazol-3- yl)propan-2-ol. MS (ES): 519|M+H]+
• 2-(l-(3-cUoro-3'-(me1hylsulfonyl)biphenyl-4-yl)-5-(2,3-difluorophenyl)-1H-pyrazol-3- yl)propan-2-ol. MS (ES): 503[M+H]+.
• 2-(l-(3-methyl-3'-(methylsulfonyl)biphenyl4-yl)-5-(2-(trifluoromethyl)phenyl)-1H-py^ yl)propan-2-ol. MS (ES): 515[M+H]+.
• 2-(l-(3-cMoro-3'-(me1hylsuffonyl)biph^^ yl)propan-2-ol. MS (ES): 535[M+H]+.
• 2-(4-chloro-5-(2-chloro-6-fluorophenyl)-l-(2-methyl-3'-(methylsulfonyl)biphenyl4-yl)-1H- pyrazol-3-yl)propan-2-ol. MS (ES): 499[M+H]+. • 2-(5-(2,6-dichlorophenyl)-l-(2-methyl-3'-(methylsulfonyl)biphenyl-4-yl)-1H-pyrazol-3- yl)propan-2-ol. MS (ES): 515 |M+H]+.
2-{4-chloro-5-(2-chloropheψl)-l-[3-metfyl-3'-(metJφlsulfoψl)bipheψl-4-yl]-^
2-ol
Figure imgf000295_0001
2-{4-cUoro-5-(2-cWorophenyl)-l-[3-me%^ yl}propan-2-ol was prepared in a manner similar to that as described in Example 12. 1H-NMR (CDCl3): δ 8.08 (m, IH), 7.91 (m, IH), 7.80 (m, IH), 7.62 (t, IH), 7.46 (d, IH), 7.43 (m, IH), 7.35-7.25 (m, 5H), 7.13 (d, IH), 3.18 (s, IH), 3.08 (s, 3H)52.29 (s, 3H)5 1.76 (s, 3H). MS(ES): 515 [M+HJ+, 497 (M-OH)
The following compounds are prepared essentially according to the previous examples:
• 2-{4-cUoro-5-(2-cUorophenyl)-l-[3Hπiethylsulfonyl)biphenyl-4-yl]-1H-pyrazol-3-yl}propan- 2-ol: 1H-NMR(CDCl3): δ 8.10 (s, IH), 7.91 (m, IH), 7.81 (m, IH), 7.64 (m, IH), 7.53-7.33 (m, 8H), 3.22 (s, IH), 3.08 (s, 3H), 1.77 (s, 6H). MS(ES): 501 [MH-H]+, 483 (M-OH) • 2-[4-cMoro-5-(2-cMorophenyl)-l-{3-methyl-5-[3-(methylsulfonyl)phenyl]pyridin-2-yl}-1H- pyrazol-3-yl]propan-2-ol, MS(ES): 516 [M+H]+, 498(M-OH)
• 2-{4-cUoro-l-[3-cMoro-3'-(methylsulfonyl)biphenyl-4-yl]-5-(2-chlorophenyl)-1H-pyrazol-3- yl}propan-2-ol, MS(ES): 534 [M+H]+, 517 (M-OH)
• 2-{4-cUoro-5-(2,6-dichlorophenyl)-l-[3-methyl-3'-(methylsulfonyl)biphenyl-4-yl]-1H-pyrazol- 3-yl}propan-2-ol, MS(ES): 549 [M+H]+, 531 (M-OH)
• 2-{4-cMoro-5-(2,6-dicUorophenyl)-l-[3-cUoro-3'-(methylsulfonyl)biphenyl-4-yl]-1H-pyrazol- 3-yl}propan-2-ol, MS(ES): 569[M+H]+, 551(M-OH)
• 2-(4-chloro-5-(2-chloro-6-fluorophenyl)-l-(3-methyl-3'-(methylsulfonyl)biphenyl-4-yl)-1H- pyrazol-3-yl)propan-2-ol. MS (ES): 533|M+H]+ • 2-(4-chloro-l-(3-chloro-3'-(methylsulfonyl)biphenyl-4-yl)-5-(2-chloro-6-fluorophenyl)-1H- pyrazol-3-yl)propan-2-ol. MS (ES): 553[M+H]+.
• 2-(4-chloro-5-(2-cMoro-6-fluorophenyl)4-(2-methyl-3'-(methylsulfonyl)biphenyl-4-yl)-1H- pyrazol-3-yl)propan-2-ol. MS (ES): 533[M+H]+.
• 2-(4-cMoro-5-(2,6-dicUorophenyl)-l-(2-methyl-3'-(me1hylsulfonyl)biphenyl-4-yl)-1H-pyrazol- 3-yl)propan-2-ol. MS (ES): 549[MfH]+.
• 2-(4-chloro-l-(3-methyl-3'-(methylsulfonyl)biphenyl-4-yl)-5-(2-(trifluoromethyl)-phenyl)-1H- pyrazol-3-yl)propan-2-ol. MS (ES): 549[M+H]+.
• 2-(4-cMoro-l-(3-cMoro-3'-(methylsulfonyl)biphenyl4-yl)-5-(2-(1xifluoromethyl)phenyl)-1H- pyrazol-3-yl)propan-2-ol. MS (ES): 569[M+H]+. • 2-(4-chloro-5-(2-chloro-6-fluorophenyl)-l-(3-fluoro-3'-(methylsulfonyl)biphenyl-4-yl)-1H- pyrazol-3-yl)propan-2-ol. MS (ES): 537 [M+H]+.
• 2-(4-cMoro-5-(2,3-difluorophenyl)-l-(3-fluoro-3'-(methylsulfonyl)biphenyl-4-yl)-1H-pyrazol- 3-yl)propan-2-ol. MS (ES): 521 [M+H]+. • 2-(4-cUoro-l-(3-cMoro-3'-(methylsulfonyl)biphenyl-4-yl)-5-(2,3-difluorophenyl)-1H-pyrazol-
3-yl)propan-2-ol. MS (ES): 537 [M+H]+.
Example 106
The following compounds the invention, in Tables 1 and 2, were prepared according to one of the previous Examples 1-105:
Table 1
Figure imgf000298_0001
Figure imgf000299_0001
Figure imgf000300_0001
Figure imgf000301_0001
Figure imgf000302_0001
Figure imgf000303_0001
Figure imgf000304_0001
Figure imgf000305_0001
Figure imgf000306_0001
Figure imgf000307_0001
Figure imgf000308_0001
Figure imgf000309_0001
Figure imgf000310_0001
Figure imgf000311_0001
Figure imgf000312_0001
Figure imgf000313_0001
Figure imgf000314_0001
Figure imgf000315_0001
Figure imgf000316_0001
Figure imgf000317_0001
Figure imgf000318_0001
Figure imgf000319_0001
Figure imgf000320_0001
Figure imgf000321_0001
Figure imgf000322_0001
Figure imgf000323_0001
Figure imgf000324_0001
Figure imgf000325_0001
Figure imgf000326_0001
Figure imgf000327_0001
Figure imgf000328_0001
Figure imgf000329_0001
Figure imgf000330_0001
Figure imgf000331_0001
Figure imgf000332_0001
Figure imgf000333_0001
Figure imgf000334_0001
Figure imgf000335_0001
Figure imgf000336_0001
Figure imgf000337_0001
Figure imgf000338_0001
Figure imgf000339_0001
Figure imgf000340_0001
Figure imgf000341_0001
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Figure imgf000344_0001
Figure imgf000345_0001
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Figure imgf000348_0001
Figure imgf000349_0001
Figure imgf000350_0001
Figure imgf000351_0001
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Figure imgf000354_0001
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Figure imgf000365_0001
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Figure imgf000378_0001
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Figure imgf000380_0001
Figure imgf000381_0001
Figure imgf000382_0001
Figure imgf000383_0001
Figure imgf000384_0001
Figure imgf000385_0001
Figure imgf000386_0001
Figure imgf000387_0001
Figure imgf000388_0001
Figure imgf000389_0001
Figure imgf000390_0001
Figure imgf000391_0001
Figure imgf000392_0001
Figure imgf000393_0001
Figure imgf000394_0001
Figure imgf000395_0001
Figure imgf000396_0001
Figure imgf000397_0001
Figure imgf000398_0001
Figure imgf000399_0001
Figure imgf000400_0001
Figure imgf000401_0001
Figure imgf000402_0001
Figure imgf000403_0001
Figure imgf000404_0001
Figure imgf000405_0001
Figure imgf000406_0001
Figure imgf000407_0001
Figure imgf000408_0001
Figure imgf000409_0001
Figure imgf000410_0001
Figure imgf000411_0001
Figure imgf000412_0001
Figure imgf000413_0001
Figure imgf000414_0001
Figure imgf000415_0001
Figure imgf000416_0001
Figure imgf000417_0001
Figure imgf000418_0001
Figure imgf000419_0001
Figure imgf000420_0001
Figure imgf000421_0001
Figure imgf000422_0001
Figure imgf000423_0001
Figure imgf000424_0001
Figure imgf000425_0001
Figure imgf000426_0001
Figure imgf000427_0001
Figure imgf000428_0001
Figure imgf000429_0001
Figure imgf000430_0001
Figure imgf000431_0001
Figure imgf000432_0001
Figure imgf000433_0001
Figure imgf000434_0001
Figure imgf000435_0001
Figure imgf000436_0001
Figure imgf000437_0001
Figure imgf000438_0001
Figure imgf000439_0001
Figure imgf000440_0001
Figure imgf000441_0001
Figure imgf000442_0001
Figure imgf000443_0001
Figure imgf000444_0001
2006/024749
Figure imgf000445_0001
Figure imgf000446_0001
Figure imgf000447_0001
Figure imgf000448_0001
Figure imgf000449_0001
Figure imgf000450_0001
Figure imgf000451_0001
Figure imgf000452_0001
Figure imgf000453_0001
Figure imgf000454_0001
Figure imgf000455_0001
Figure imgf000456_0001
Figure imgf000457_0001
Figure imgf000458_0001
Figure imgf000459_0001
Figure imgf000460_0001
Figure imgf000461_0001
Figure imgf000462_0001
Figure imgf000463_0001
Figure imgf000464_0001
Figure imgf000465_0001
Figure imgf000466_0001
006/024749
Figure imgf000467_0001
Figure imgf000468_0001
Figure imgf000469_0001
Figure imgf000470_0001
Figure imgf000471_0001
Figure imgf000472_0001
Figure imgf000473_0001
Figure imgf000474_0001
Figure imgf000475_0001
Figure imgf000476_0001
Figure imgf000477_0001
Figure imgf000478_0001
Figure imgf000479_0001
Figure imgf000480_0001
Figure imgf000481_0001
Table 2
Figure imgf000482_0001
Example 107
FRET Coacttvator assay
The FRET coactivator assay measures the ability of LXR ligands to promote protein-protein interactions between the ligand binding domain (LBD) of LXR and transcriptional coactivator proteins. The assay involves the use a recombinant Glutathiones-transferase (GST)-nuclear receptor ligand binding domain (LBD) fusion protein and a synthetic biotinylated peptide sequence derived from the receptor interacting domain of a co-activator peptide such as the steroid receptor coactivator 1 (SRC-I).
Typically GST-LBD is labeled with a europium chelate (donor) via a europium-tagged anti-GST antibody, and the coactivator peptide is labeled with allophycocyanin via a streptavidin-biotin linkage.
In the presence of an agonist for the nuclear receptor, the peptide is recruited to the GST-LBD bringing europium and allophycocyanin into close proximity to enable energy transfer from the europium chelate to the allophycocyanin. Upon excitation of the complex with light at 340 nm excitation energy absorbed by the europium chelate is transmitted to the allophycocyanin moiety resulting in emission at 665 nm. If the europium chelate is not brought into close proximity to the allophycocyanin moiety there is little or no energy transfer and excitation of the europium chelate results in emission at 615 nm. Thus the intensity of light emitted at 665 nm gives an indication of the strength of the protein-protein interaction.
Required Materials: Partially purified recombinant protein comprising glirtaftiione-S-transferase fused in frame to the LXR- ligand binding domain (comprising amino acids 188-447 of human LXRα, or amino acids 198-461 of human LXRβ)
Biotinylated peptide containing a SRC-I LXXLL receptor interaction motif (B-SRC-I).
Anti-GST antibody conjugated to a Europium chelate (αGST-K) (From Wallac/PE Life Sciences Cat# AD0064).
Streptavidin linked allophycocyanin (SA-APC) (From Wallac/PE Life Sciences CAT# AD0059A).
Ix FRET Buffer: (20 mM KH2PO4ZK2HPO4 pH 7.3, 150 mM NaCl, 2.5 mM CHAPS, 2 mM EDTA, 1 mM DTT (add fresh)).
96 well or 384 well black multiwell plates (from LJL) Stock Solutions:
0.5 MKH2PO4ZK2HPO4: pH 7.3; 5 MNaCl; 80 mM (5%) CHAPS; 0.5 MEDTApH 8.0; 1 M
DTT(keep at-20°C)
Preparation of Screening Reagents:
Prepare reaction mixture for the appropriate number of wells by combining the following reagents 5 nM/well GST-hLXRαLBD, 5 nM/well GST-hLXRβLBD, 5 nM/well Anti-GST antibody
(Eu), 12 nM/well biotin-SRC-1 peptide, 12 nM/well APC-SA adjust the volume to 10 μL/well with Ix-
FRET buffer. Procedure:
Add 0.5 μL of a 1 mM stock compound (for approx. 10 μM final concentration) or solvent to each well in a 96 well or 384 well black plate (LJL). Add 10 μl reaction mixture (prepared above) to each well of the multiwell plate. Incubate covered or in the dark (die APC is light sensitive) at ambient temperature for 1-4 hours. After this time if reactions are not read they can be stored at 4°C for several more hours without too much loss of signal.
Read the plate using an LJL Analyst, or similar instrument, using the following conditions: Channel 1: Excitation is 330 nm and emission is 615. This is for Eu chelate; Channel 2: Excitation is 330 nm and emission is 665. This is for APC; For channel 1: Flashes per well = 100; Integration time = 1000 us; interval between flashes = 1x10 ms; Delay after flash = 200 us; For channel 2: Flashes per well = 100; Integration time = 100 μs; interval between flashes = 1x10 ms; Delay after flashes = 65 μs.
Example 108
Scintillation proximity assay (SPA) The SPA assay measures the radioactive signal generated by the binding of 3H-24,25- epoxycholesterol to LXRα or LXRβ. The basis of the assay is the use of SPA beads containing a scintillant, such that when binding to the receptor brings the labeled ligand into proximity with the bead, the energy from the label stimulates the scintillant to emit light. The light is measured using a standard microplate scintillation reader. The ability of a ligand to bind to a receptor can be measured by assessing the degree to which tiie compound can compete off a radiolabeled ligand with known affinity for the receptor.
Required Materials:
Label: 3H-24,25-epoxy-cholesterol (Amersham)
LXRα lysate: Baculovirus expressed LXRα/RXR heterodimer with RXR having a 6-HIS tag produced as acrude lysate LXRβ lysate: Baculovirus expressed LXRβ/RXR heterodimer with RXR having a 6-FflS tag produced as a crude lysate
SPA beads: Ysi copper His-tag SPA beads (Amersham) Plates: Non-binding surface 96-well plate (Corning) Protein lysate dilution buffer: (20 mM Tris-HCl pH 7.9, 500 mM NaCl, 5 mM Imidazole). 2x SPA Buffer: (40 mM K2HPO4ZKH2PO4 pH7.3, 100 mM NaCl, 0.05% Tween 20, 20% Glycerol, 4 mM EDTA) 2x SPA Buffer w/o EDTA: (40 mM K2HPO4ZICH2PO4 pH7.3, 10OmM NaCL 0.05% Tween 20, 20% Glycerol) Stock Solutions
0.5 M K2HPO4ZKH2PO4 pH 7.3; 0.5 M EDTA pH 8.0; 5 MNaCl; 10% Tween-20; Glycerol
Preparation of protein lysates
Baculovirus expression plasmids for human RXRα .(accession No NM_002957),_ LXRα (accession No U22662), LXRβ (accession No U07132) were made by cloning the appropriate full- length cDNAs into the pBacPakhisl vector (Clontech, CA) following standard procedures. Insertion of the cDNAs into the pBAcPakhisl vector polylinker created an in frame fusion to the cDNA to an N- terminal poly-His tag present in pBacPakhisl. Correct cloning was confirmed by restriction mapping, and /or sequencing. Cell lysates were prepared by infecting healthy, Sf9 insect cells at a density of approximately
1.25xlO6 /ml at 27ºC, in a total volume of 500 mL per IL sized spinner flasks, cultured under standard conditions. To prepare LXRα lysate, insect cells were co-transfected with the LXRα expression cassette at an M.O.I of 0.5 to 0.8 and with the RXR expression cassette at a M.O.I. of approximately 1.6. To prepare LXRβ lysate, insect cells were co-transfected with the LXRβ expression cassette at an M.O.I of approximately 1.6 and with the RXR expression cassette at a M.O.I. of approximately 1.6. In both cases cells were incubated for 48 hours at 27°C with constant shaking prior to harvesting.
After incubation, cells were harvested by centrifugation and pelleted. Cell pellets were resuspended in two volumes of ice-cold freshly prepared extraction buffer (2OmM Tris pH 8.0, 1OmM Imidazole, 40OmM NaCl, containing one EDTA free protease inhibitor tablet (Roche Catalog No: 1836170) per 10 ml of extraction buffer). Cells were homogenized slowly on ice using a Douncer to achieve 80-90% cell lysis. The homogenate was centrifuged in a pre-chilled rotor (Ti50 or Ti70, or equivalent) at 45,000 rpm for 30 minutes at 4°C. Aliquots of the supernatant were frozen on dry ice and stored frozen at -8OºC until quantification and quality control. Aliquots of the lysates were tested in the SPA assay to ensure lot to lot consistency, and via SDS-PAGE analysis after purification using Ni-NTA Resin (Qiagen) and adjusted for protein concentration and expression level prior to use in screening assays. Preparation of Screening Reagents
[3H] 24,25 Epoxycholesterol (EC) solution: For a single 384-well plate (or 400 wells), 21 μL of [3H] EC (specific activity 76.5 Ci/mmol, concentration 3.2 mCi/mL) was added to 4.4 mL of 2x SPA buffer to provide for a final concentration of 200 nM. For each additional 384-well plate, an additional 19.1 μL of [3H] EC was added to 4.0 mL of additional 2x SPA buffer. The final concentration of [3H] EC in the well was 50 nM. LXRα lysate (prepared as above) was diluted with protein lysate dilution buffer. 1400 μL of diluted LXRα lysate was prepared per 384-well plate, (or 200 wells) and 1120 μL of diluted LXRα lysate was prepared for each additional 384-well plate. LXRβ lysate (prepared as above) was diluted with protein lysate dilution buffer. 1400 μL of diluted LXRβ lysate was prepared per 384- well plate, (or 200 wells) and 1120 μL of diluted LXRβ lysate was prepared for each additional 384- well plate. SPA bead solution: For a 384-well plate (or 400 wells), 3.75 mL of 2x SPA buffer w/o EDTA, 2.25 mL OfH2O, and 1.5 mL of Ysi His-tag SPA beads (vortex well before taking) were mixed together. For each additional 384-well plate, an additional 3.5 mL of 2x SPA buffer w/o EDTA, 2.1 mL OfH2O5 and 1.4 mL of Ysi His-tag SPA beads were mixed together.
Procedure:
Appropriate dilutions of each compound were prepared and pipetted into the appropriate wells of a multiwell plate. 9.1 μL of [3H] EC was added to each well of column 2-23 of the multiwell plate. 5 μl of diluted LXRα lysate was added to each well of column 2-23 on odd rows of the multiwell plate. 5 μL of diluted LXRβ lysate was added to each well of column 2-23 on even rows of the multiwell plate.
17.5 μL of SPA bead solution was added to each well of column 2-23 of the multiwell plate.
The plates were covered with clear sealer and placed in an incubator at ambient temperature for 1 hour. After incubation plates were analyzed using a luminescent plate reader (MicroBeta, Wallac) using the program n ABASE 3H_384DPM. The setting for n ABASE 3H_384DPM was: Counting Mode: DPM; Sample Type: SPA; ParaLuxMode: low background; Count time: 30 sec.
Assays for LXRα and LXRβ were performed in the identical manner. The determined Ki represents the average of at least two independent dose response experiments. The binding affinity for each compound may be determined by non-linear regression analysis using the one site competition formula to determine the IC50 where:
Y = Bottom + (Top -Bottom)
Q+jQX-IqgfCStK
The Ki is than calculated using the Cheng and Prusoff equation where: Ki = IC5o/(l + [Concentration of Ligand]/Kd of Ligand)
For this assay, typically the Concentration of Ligand = 50 nM and the Kd of EC for the receptor is 200 nM as determined by saturation binding.
The compounds of the invention demonstrated the ability to bind to LXRα and/or LXRβ when tested in this assay. Example 109
Co-Transβction Assay
To measure the ability of compounds to activate or inhibit the transcriptional activity of LXR in a cell based assay, the co-transfection assay was used. It has been shown that LXR functions as a heterodimer with RXR. For the co-transfection assay, expression plasmids for LXR and RXR are introduced via transient transfection into mammalian cells along with a luciferase reporter plasmid that contains one copy of a DNA sequence that is bound by LXR-RXR heterodimers (LXRE; Willy, P. etal.
1995). Treatment of transfected cells with an LXR agonist increases the transcriptional activity of LXR, which is measured by an increase in luciferase activity. Similarly, LXR antagonist activity can be measured by determining the ability of a compound to competitively inhibit the activity of a LXR agonist
Required Materials
CV-I African Green Monkey Kidney Cells Co-transfection expression plasmids, comprising full- length LXRα (pCMX-h LXRa1 LXRβ (pCMX-hLXRβ), or RXRa (pCMX-RXR), reporter plasmid
(LXRExI -Tk-Luciferase), and control (pCMX-Galactosidase expression vector) (Willey et al. Genes &
Development^ 1033-1045 (1995)).
Transfection reagent such as FuGENE6 (Roche).
Ix Cell lysis buffer (1 % Triton X 100 (JT Baker X200-07), 10% Glycerol (JT Baker M778-07), 5 mM Ditriotreitol (Quantum Bioprobe DTT03 ; add fresh before lysing),
1 mM EGTA (Ethylene Glycol-bis (B-Amino ethyl ether)-N,N,N',N'-Tetracetic Acid) (Sigma E-4378),
25 mM Tricine (ICN 807420) pH 7.8)
Ix Luciferase assay buffer (pH at 7.8) (0.73 mM ATP, 22.3 mM Tricine, 0.11 mM EDTA, 33.3 mM
DTT) Ix Luciferrin/CoA (11 mM Luciferin, 3.05 mM Coenzyme A, 10 mM HEPES)
Preparation of Screening Reagents
CV-I cells were prepared 24 hours prior to the experiment by plating them into T-175 flasks or
500 cm2 dishes in order to achieve 70-80% confluency on the day of the transfection. The number of cells to be transfected was determined by the number of plates to be screened, each 384 well plate requires 1.92x106 cells or 5000 cells per well. DNA Transfection Reagent was prepared by mixing the required plasmid DNAs with a cationic lipid transfection reagent FuGENEό (Roche) by following the instructions provided with the reagents. Optimal DNA amounts were determined empirically per cell line and size of vessel to be transfected. 10-12 mL of media was added to the DNA Transfection
Reagent and this mixture was added to the cells after aspirating media from the Tl 75 cm2 flask. Cells were then incubated at least 5 hours at 37°C to prepare screening cells.
Luciferase assay reagent was prepared by combining before use (per 10 mL): 10 mL Ix
Luciferase assay buffer; 0.54 mL of Ix Luciferrin/CoA; 0.54 mL of 0.2 M Magnesium sulfate Procedure
Assay plates were prepared by dispensing 5 μL of compound per well of a 384 well plate to achieve final compound concentration of 10 μM and no more than 1% DMSO. Media was removed from the screening cells, the cells trypsinized, harvested cells by centrifugation, counted, and plated at a density of approximately 5000 cells per well in the 384 well assay plate prepared above in a volume of about 45 μL. Assay plates containing both compounds and screening cells (50 μL in total volume) were incubated for 20 hours at 37°C.
After incubation with compounds, media was removed from the cells and lysis buffer (30 μL/well) added. After 30 minutes at ambient temperature, luciferase assay buffer (30 μL/well) was added and the assay plates read on a luminometer (PE Biosystems Northstar reader with on-board injectors, or equivalent). Plates were read immediately after addition of luciferase assay buffer.
The LXR/LXRE co-transfection assay can be used to establish the EC5o/IC5o values for potency and percent activity or inhibition for efficacy. Efficacy defines the activity of a compound relative to a high control ((ΛL(3-((4-fluorophenyl)-(naphthalene-2-suh°onyl)arnino)propyl)-2^- dimethylpropionamide)) or a low control (DMSO/vehicle). The dose response curves are generated from an 8 point curve with concentrations differing by 1A LOG units, each point represents the average of 4 wells of data from a 384 well plate.
The data from this assay is fitted to the following equation, from the EQo value may be solved:
Y^Bottom÷Crop-Bottom)^^^®0^^™810^ The EC50/ΪC50 is therefore defined as the concentration at which an agonist or antagonist elicits a response that is halfway between the Top (maximum) and Bottom (baseline) values. The EC50/IC50 values represented are the averages of at least 3 independent experiments. The determination of the relative efficacy or % control for an agonist is by comparison to the maximum response achieved by ((JV'-(3-((4-fluorophenyl)-(naphUialene-2-suhconyl)-ammo)propyl)-2,2-dimethylpropionamide) that is measured individually in each dose response experiment
For the antagonist assay, a LXR agonist can be added to each well of a 384 well plate to elicit a response. The % inhibition for each antagonist is therefore a measurement of the inhibition of the activity of the agonist. In this example, 100% inhibition would indicate that the activity of a specific concentration of LXR agonist has been reduced to baseline levels, defined as the activity of the assay in the presence of DMSO only.
Compounds of the invention, when tested in this assay, demonstrated the ability to modulate the activity of LXRα and/or LXRβ. Preferably, the active compounds modulate the activity of LXR with a EC50 or IC50 of about lOμM or less. More preferably, the EC50 or IC50 of the preferred active compounds is about 1 μM or less.
Example HO In vivo Studies In order to evaluate direct regulation of key target genes by the compounds of the invention, animals are administered a single oral dose of the test compound and tissues collected at various time points after dose. Male Cs7BL/6 mice (μ-B) are dosed by oral gavage with vehicle or compound. At various time points after the dose, animals are bled via the retro orbital sinus for plasma collection. Animals are then euthanized and tissues, such as liver and intestinal mucosa are collected and snap frozen for further analysis. Plasma is analyzed for a lipid parameters, such as total cholesterol, HDL cholesterol and triglyceride levels. RNA is extracted for frozen tissues and can be analyzed by quantitative real time PCR for regulation of key target genes. To identify specificity of target gene regulation by LXR subtypes, LXR deficient mice (LXRα-/- or LXRpV-) and C57BL/6 wild-type controls are used in this same protocol. Plasma Lipid Evaluation:
To compare the effects of compounds on plasma cholesterol and triglycerides, animals are dosed with compound for one week and plasma lipid levels are monitored throughout the study. Male
C57BL/6 mice (n=8) are dosed daily by oral gavage with vehicle or compound. Plasma samples are taken on day —1 (in order to group animals), day 1, 3, and 7. Samples are collected three hours after the daily dose. On day 7 of the study, following plasma collection, animals are euthanized and tissues, such as liver and intestinal mucosa are collected and snap frozen for further analysis. Plasma is analyzed for lipid parameters, such as total cholesterol, HDL cholesterol and triglyceride levels. RNA is extracted for frozen tissues and can be analyzed by quantitative real time PCR for regulation of key target genes. To identify specificity of target gene regulation by LXR subtypes, LXR deficient mice (LXRα-/- or LXRβ- /-) and Cs7BL/6 wild-type controls are used in this same protocol.
Example 111
Measured EC50 orICso for LXR for compoυnds of the invention
Compounds of the invention, when tested as described in Example 109, demonstrated the ability to modulate the activity OfLXR0 and/or LXRp. LXR activities for various compounds of the invention are presented in the following table; those compounds with EC50 or IC5O values < 10 μM for at least one of LXRα and LXRp are considered to be active. In the following Table, IC50 or EC50 data is represented as follows: A = < 1 μM, B = I - IO μm, and C= > 10 μM.
Figure imgf000489_0001
Figure imgf000490_0001
Figure imgf000491_0001
It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be incorporated within the spirit and purview of this application and scope of the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated herein by reference for all purposes.
All of the U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications and non-patent publications referred to in this specification and/or listed in the Sheet, are incorporated herein by reference, in their entirety.
From the foregoing it will be appreciated that, although specific embodiments of the invention have been described herein for purposes of illustration, various modifications may be made without deviating from the spirit and scope of the invention. This invention also encompasses all combinations of alternative aspects of the invention noted herein. It is understood that any and all embodiments of the present invention may be taken in conjunction with any other embodiment to describe additional embodiments of the present invention. Furthermore, any elements of an embodiment may be combined with any and all other elements from any of the embodiments to describe additional embodiments.
Accordingly, the invention is not limited except as by the appended claims.

Claims

We claim:
1. A compound according to one of the following formulas,
Figure imgf000493_0001
or a pharmaceutically acceptable salt, isomer, or prodrug thereof, wherein, (A) R1 is -IΛR5, wherein
L1 is a bond, L5, L6, -L5-L6-L5-, or -L6-L5-L6-, wherein each L5 is independently -[C(R15)2]m-5 wherein each R15 is independently hydrogen, halogen, (CrC^alkyl, (C3-C6)cycloalkyl, or (Ci-C6)haloalkyl; each L6 is independently -C(R1V, -C(R11^C(R1V -C(R1VQR11)-, -C(R11^O-,
-C(Rn)2NRπ-, -OC-, -0-, -S-, -NR11-, -N(R10)CO-, -N(R10)CO2-, -CON(R10)-, -CO-, -CS-, -CO2-, -OC(O)-, -OC(O)N(R10)-, -CONR11N(R1V, -CONR11-, -OCONR11-, -SO2-, -N(R10)SO2-, -SO2N(R10)-, -NR10CONR10-, -NR10CSNR10-, -Q=NR11)-, -C(=N0Rπ)-, -C(=NN(Rπ)2)-; aryl, C3-C8 cycloalkyl, cycloC^shaloalkyl, heteroaryl, heterocyclyl, wherein the aryl, cycloalkyl, cycloC3-8haloalkyl heteroaryl, or heterocyclyl are optionally substituted with one or more radicals of R14; or L1 is a C2_g alidiyl chain wherein the alidiyl chain is optionally interrupted by -C(R1 V, -C(Rπ)2C(Rπ)2-, -C(R11^=C(R11)-, -C(R11^O-, -C(R11^NR11-, -C≡C-, -0-, -S-, -N(R10)CO-, -N(R10)CO2-, -CON(R10)-, -CO-, -CO2-, -OC(O)-, -OC(O)N(R10)-, -SO2-, -N(R10)SO2-, or -SO2N(R10)-, and
R5 is aryl, heterocyclyl, heteroaryl, C2-C6 alkenyl, C2-C6 alkynyl, (C3-C8 cycloalkyO-CrQ alkyl-, (C3-C8 cycloalkeny^-d-Ce alkyl-, (C3-C8 cycloalkyl)-C2-C6 alkenyl-, C3-C8 cycloalkyl, -C, -B-C, or -A-B-C, wherein
Ais -O-; B is -[C(R15)2]m- or C3-C8 cycloalkyl;
C is Q-Qalkyl, Q-Cehaloalkyl, SO2R11, SR11, SO2N(R1V SO2NR11COR11, ON, C(O)OR11, CON(R1V OrN(R1V wherein R5 is optionally substituted with one or more R5a, wherein each R5a is independently C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, (C3- C8 cycloalky^-d-Ce alkyl-, (C3-C8 cycloalkenyl)-Ci-C6 alkyl-, (C3-C8 cycloalkyl)-C2-C6 alkenyl-, halogen, nitro, heterocyclyloxy, aryl, aryloxy, arylalkyl, aryloxyaryl, aryl C1-C6 alkoxy, -C, -B'-C, or -A'-B'-C wherein A' is -O-;
B' is -[C(R15)2]m- or - C3-C8 cycloalkyl-; C is -H, halogen, -SO2R11, -OR11, -SR11, -N3, -COR11, -SO2N(Rπ)2, -SO2NR11COR11, -G≡N,
-C(O)OR11, -0C(=0)Rn, -CON(Rn)2, -C0N(Rπ)0Rn, -0C0N(Rn)2, -NR11COR11, -NRπC0N(Rπ)2, -NR11COOR11, -N(Rπ)2, aryl, heteroaryl, or heterocyclyl; wherein each R5a is optionally substituted one or more groups which are independently C2-C6 alkenyl, C2-C6 alkynyl, (C3-C8 cycloalkyl)-Q-C6 alkyl-, (C3-C8 cycloalkenyl)- C1-C6 alkyl-, (C3-C8 cycloalkyl)-C2-C5 alkenyl-, C0-C6 alkoxyaryl, Ci-C6 alkyl, C3-C8 cycloalkyl, aryl, aryl-Ci-C6 alkyl-, heteroaryl, halogen, -ON, -NO2, -COR11, -COOR11, -C0N(Ru)2, -SO2R11, -OR11, -SR11, -SO2R11, -SO2N(R1V -SO2NR11COR11, -0C0N(Rπ)2, -NR11COR11, -NR11CON(R1V -NR11COOR11, or -N(R11),; R2 and R21 are -L3-R7, wherein each L3 is independently a bond -^-(CH^n-V1-, or -(CH^-V^CEbV wherein n is 0-6; and each V1 is independently -C(R1V, -C(R11^C(R1 V, -C(R11^=C(R11)-, -C(RU)2O-, -C(RU)2NRU-, -CsC-, -0-, -S-, -NR7-, -N(R10)CO-, -N(R10)CO2-, -OCO-, -CO-, -CS-, -CONR10-, -C(=N)(Rπ)-, -C(=N-0Rπ)-, -Ct=N-N(R11^], -CO2-, -OC(O)-,
-OC(O)N(R10)-, -SO2-, -N(R10)SO2-, -SO2N(R10)-, -NR10CONR10-, -NR10CSNR10-, C3-C8 cycloalkyl, or C3-C8 cyclohaloalkyl; or each L3 is independently a C2-6 alidiyl chain, wherein the alidiyl chain is optionally interrupted by -C(Rπ)2-, -C(R11^C(R1V -C(Rπ)O(Rπ)-, -C(Rπ)2O-, -C(R11^NR11-, -C≡C-, -0-, -S-, -N(R10)CO-, -N(R10)CO2-, -CON(R10)-, -CO-, -CO2-, -0C(=0>, -OC(O)N(R10)-,
-SO2-, -N(R10)SO2-, or -SO2N(R10); and each R7 is independently hydrogen, halogen, nitro, cyano, aryl, heteroaryl, heterocyclyl, -Ci-C6 alkyl-heterocyclyl, -Cj-C6 alkyl-heteroaryl, -Ci-C6 alkyl-aryl, -Z, -Y-Z, or -X-Y-Z, wherein
X is -O-; Y is -[C(R15)2]m-, -C2-C6 alkenyl, or C3-C8 cycloalkyl;
Z is -H, -CN, halogen, -OR11, -CH))R11, -C(O)OR11, -Q=O)N(R1 \ -N(RU)2, -CN, -N3, -SO2R11, -S(=O)2N(Rπ)2, -C(=0)N(Rn)N(Rn)2, -C(O)N(R11XOR11), -OC(O)-R11, -OC(O)-N(R1V or -N(Rn)C00Rπ; wherein R7 is optionally substituted with one or more R7a, wherein
R7a is halogen, C2-C6 alkenyl, -Ci-Ce alkyl-heterocyclyl, -Ci-Ce alkyl-heteroaryl, -Ci-C6 alkyl-aryl, C0-C6 alkoxyheteroaryl, Co-C6alkoxyheterocyclyl, haloaryl, aryloxy, aralkyloxy, aryloxyalkyl, Ci-C6alkoxyaryl, aryl Co-C6 alkylcarboxy, C^^QR^-COOR11, Co-Cealkoxyheteroaryl, Q-Qalkoxyheterocyclyl, aryl, heteroaryl, heterocyclyl, C3-C8 cycloalkyl, heteroaryloxy, -Z', -Y'-Z', or -X'-Y'-Z', wherein
X' is -O-;
Y' is -[C(R15)2]m- or C3-C8 cycloalkyl; Z' is -Ci-Cealkyl, -CrCghaloalkyl, -OR11, -SR11, -S(O)2R11, -C(O)R11,
-C(O)OR11, -C(O)N(Rπ)2, -N(Rπ)2, -N(Rπ)C(O)Rπ,
-S(O)2N(R1^C(O)R11, -CN, -S(O)2N(RU)2, -C(O)N(R1 ^N(R11^, -C(O)N(R11XOR11), -OC(O)-R11, -OC(O)-OR11, -N(R1 ^C(O)O-R11, or -N(Rπ)S(O)2Rπ; wherein each R7a is optionally substituted with one or more R8, wherein each R8 is independently halogen, nitro, cyano, heteroaryl, Ci-C6 alkyl, Ci-C6 alkoxy, Ci-C6 haloalkyl, C1-C6 haloalkyl(ORu), C0-C6 alkylOR11, C0-C6 alkylCON(Rn)2, C0-C6 alkylCOR11, C0-C6 alkylCOOR11, or C0-C6 alkylSO2Rπ; and wherein if two R7a are present on the same carbon, then they may be taken together to form a cycloalkyl or heterocyclyl group; provided that R2 and R21 are not simultaneously -H;
R3 is -L-R6, wherein
L is a bond, -X3-(CH2)n-X3-, -(CH2)m-X3-(CH2)n- or -(CH2)i+w-Y3-(CH2)w- wherein n is 0-6; each w is independently 0-5; and each X3 is independently a bond, -C(Rn)2-, -C(Rn)2C(Rn)2-, -C(R11^C(R11)-, -OC-, -CO-, -CS-, -CONR10-, -C(=N)(Rπ)-, -C(^N-OR11)-, -Q=N-N(R11)2], -CO2-, -SO2-, or
-SO2N(R10)-; and
Y3 is -0-, -S-, -NR7-, -N(R10)CO-, -N(R10)CO2-, -OCO-, -OC(O)N(R10)-, -NR10CONR10-, -N(R10)SO2-, or -NR10CSNR10-; or L is a C2-6 alidiyl chain, wherein the alidiyl chain is optionally interrupted by -C(R1 ^2-, -C(Rn)2C(Rπ)2-, -C(R11H^(R11)-, -C(Rπ)2O-, -C(R11^NR11-, -OC-, -0-, -S-, -N(R10)CO-,
-N(R10)CO2-, -CON(R10)-, -CO-, -CO2-, -OC(O)-, -OC(O)N(R10)-, -SO2-, -N(R10)SO2-, or -SO2N(R10); and R6 is C1-C6 alkyl, C1-C6 haloalkyl, aryl, C3-C8 cycloalkyl, heteroaryl, heterocyclyl, -CN, -C(=0)Rπ, -C(=O)ORn, -C(=0)N(Rn)2, -N(Rπ)2, -SO2R11, -SC=O)2N(R1 \ -CC=O)NCR1 ^N(R1 \ or -C(=O)NCRn)(ORn), wherein the aryl, heteroaryl, cycloalkyl, or heterocyclyl is optionally substituted with one or more R6a, wherein eachR6a is independently -Z ,-Y -Z , or-X -Y -Z , wherein X" is-O-;
Y is -[C(R15)2]m-, -C2-C6 alkenyl, C3-C8 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the aryl, heteroaryl, cycloalkyl, or heterocyclyl is optionally substituted with at least one group which is each independently Z";
Z" is -H, -CN, halogen, -OR11, -C(=O)Rπ, -C(=O)ORU, -C(=O)N(RU)2, -N(R11K -N3, -SO2R11, -SC=O)2N(R11K -C(=O)N(Rπ)N(RnK -N(R11^=O)N(R11K
-OCC=O)-OR11, -CC=O)N(R11XOR11), -0C(=0)-Rπ, -0C(=0)-N(Ru)2, or -N(Rπ)C00Ru; eachR10 is independently -R11, -C(=O)Rπ, -CO2R11, or -SO2R11; each R11 is independently -hydrogen, C2-C6 alkenyl, C2-C6 alkynyl, (C3-C8 cycloalkenyl)-Ci-C6 alkyl-, (C3-C8 cycloalkyl)-C2-C6 alkenyl-, -N(R12K -C1-C6 alkyl, -Ci-C6 haloalkyl, -C3-C8 cycloalkyl, -(C1- C6)alkyl-(C3-Cg)cycloalkyl, aryl, -(Q-C^alkyl-aryl, heteroaryl, -(Ci-C6)alkyl-heteroaryl, heterocyclyl, or-(CrC6)alkyl-heterocyclcyl, wherein any of R11 is optionally substituted with one or more radicals of R12; each R12 is independently hydrogen, halogen, Q-Qhaloalkyl, C1-C6 alkyl, Ci-C6 alkoxy, (C0-C6 alkyl)CO(0R13); C0-C6 alkylOR13, Q,-C6 alkylCOR13, C0-C6 alkylSO2R13, C0-C6 alkylCN, C0-C6 alkylCON(R13)2, C0-C6 alkylCONR13OR13, C0-C6 alkylSC^N^K C0-C6 alkylSR13, C0-C6 haloalkylOR13, aryloxy, aralkyloxy, aryloxyalkyl, Co-C6alkoxyaryl, aryl C0-C6 alkylcarboxy, C0-C6 alkylNR13SO2 R13, -C0-C6 alkyIN(R13K or OC0-C6 alkylCOOR13; each R13 is independently hydrogen, Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, (C3-C8 cycloalkyty-Q- C6 alkyl-, (C3-C8 cycloalkenyFj-Q-Ce alkyl-, or (C3-C8 cycloalkyl)-C2-C6 alkenyl-; each R14 is independently C1-C6 alkyl, C1-C6 alkoxy, halogen, C1-C6 haloalkyl, C0-C6 alkylCONfTR.11^, C0-C6 alkylCONRπORu, C0-C6 alkylOR11, or C0-C6 alkylCOOR11; G is a group of the formula,
Figure imgf000497_0001
wherein
J is aryl, heteroaryl, or absent; K is aryl, heteroaryl, or absent; each R4 is independently halogen, nitro, C2-C6 alkenyl, C3-C8 cycloalkyl, -C1-C6 alkyl-heterocyclyl, -C1-C6 alkyl-heteroaryl, -C]-C6 alkyl-aryl, -heterocyclyl-aryl,
-heterocyclyl-heteroaryl, CR11^CR11COOR11, aryloxy, -S-aryl, aralkyloxy, aryloxyalkyl, C1-C6 alkoxyaryl, aryl CQ-C6 alkylcarboxy, C0-C6 alkoxyheteroaryl, Co-C6 alkoxyheterocyclyl, aryl, heteroaryl, heterocyclyl, -M, -E-M, or -D-E-M, wherein
D is -O-; E is -[C(R15)2]m- or C3-C8 cycloalkyl;
M is Ci-C6alkyl, Q-Cehaloalkyl, -COR11, -COOR11, -OC(O)R11, -CON(R11^5 -Cs=N, -OR11, -0C0N(Rπ)2, -OCO2-R11, -N3, -NR11COR11, -NR11SO2R11, -N(Rn)2, -NR11COOR11, -SOR11, -SO2R11, -SO2NR11COR11, -SO2N(R11);;, or -SR11, wherein each R4 is optionally substituted with one or more R48, wherein each R4*1 is independently halogen, aryloxy, aralkyloxy, aryloxyalkyl, -C1-C6 alkyl-aryl, C1-C6 alkoxyaryl, aryl C0-C6 alkylcarboxy, -M', -E'-M', or -D'-E'-M' D' is -O-;
F is -[C(R15)2]m- or C3-C8 cycloalkyl;
M' is -d-Cealkyl, -d-Cghaloalkyl, COR11, -C0N(Rπ)2, -N(R1 ^COOR11, -N(Rπ)2, COOR11, G≡N, OR11, -NR11COR11, NR11SO2R11, SO2R11,
SO2N(Rπ)2, orSRπ; each R41 is independently halogen, nitro, Cj-C6 alkyl-heterocyclyl, -C1-C6 alkyl-heteroaryl, -C1-C6 alkyl-aryl, -M", -E"-M", or -D"-E"-M", wherein
D" is -O-; E" is -[C(R15)2]m- or C3-C8 cycloalkyl;
M" is -Ci-Qalkyl, -Q-Qhaloalkyl, -COR11, -COOR11, -C0N(Rπ)2, -ON, -OR11, -0C0N(Rπ)2, -OCO2-R11, -N3, -NR11COR11, -NR11SO2R11, -N(Rn)2, -NR11COOR11, -SOR11, -SO2R11, -SO2NR11COR11, -SO2N(Rn)2, or -SR11, wherein each R41 is optionally substituted with one or more R^; L2 is a bond, -CH=CHCOO-, -OQrCealkylCOO-, -[C(R15)2]m-V2-[C(R15)2]n-, or
-V2-[C(R15)2]m-V2-, wherein n is 0-6; and each V2 is independently -C(Rπ)2-, -C(R1 ^2C(R1 V, -C(Rπ)=C(Rπ)-, -C(Rπ)2NRπ-, -C(Rπ)2O-, -C≡C-, -O-, -S-, -N(R10)CO, -N(R10)COr, -CON(R1V, -CON(R11)-, -CON(R11P-, -CO-, -CS-, -CO2-, -OR11N-, -OR11COO-, -OC(O)-, -OC(O)N(R10)-, -SO2-, -N(R10)SO2-, -SO2N(R10)-, -NR10CONR10-, C3-C8 cycloalkyl, -C(=NRU)-, -C(=NORU>,
-C(=NN(Rn)2)-, -NR10CSNR10-, -C(O)-heterocyclyl, or cycloQ-ghaloalkyl, wherein the heterocyclyl is optionally substituted with one or more groups independently selected from - OR11, -COOR11, and -C0N(Rn)2; or L2 is a C2-6 alidiyl chain, wherein alidiyl chain is optionally interrupted by -C(R1 ^2-, -C(RU)2C(RU)2-, -C(R11^(R11)-, -C(RU)2O-, -C(R11^NR11-, -C(R11^NR11-, -C≡C-, -0-, -S-,
-N(R10)CO-, -N(R10)CO2-, -CON(R10)-, -CON(R11)-, -C0N(Rn)0-, -CO-, -CO2-, -OC(O)-, -OC(O)N(R10)-, -SO2-, -N(R10)SO2-, -SO2N(R10)-; aryl, C3-C8 cycloalkyl, heteroaryl, or heterocyclyl wherein the aryl, cycloalkyl, heteroaryl, or heterocyclyl is optionally substituted with ' one or more R9, wherein each R9 is independently halogen, Ci-C6 haloalkyl, C1-C6 alkyl, Ci-C6 alkyloxy, C0-C6 alkyl or Ci-C6 alkylCOOR11; each m is independently 0, 1, 2, 3, 4, 5 or 6; q is O, 1, 2, 3, 4 or 5; and q' is O, 1, 2, 3, or 4, (B) provided that,
(i) q may be O only if L2 is not a bond or if K is not phenyl;
(ϋ) the compound is not 2-methyl-5-(l-m-tolyl-3-(trifluoromethyl)-1H-pyrazol-5- yl)benzenesulfonamide; (iii) if L2 is a bond, then both J and K are not absent;
(iv) if K is absent, then q is 1 and R4 is bonded directly to L2;
(v) if L2 is SO2 or SO2N(R10), then R5 is substituted with at least one R5a;
(vi) if the compound is defined by formula Ia, then
(a) R1 is not 4-(NH2SO2)phenyl, 4-(CH3SO2)phenyl, or 4-(CH2FSO2)phenyl;
(b) if R1 is 4-fluorophenyl, then G is not 4-[(H2NS(O)2- ]phenyl-; and
(c) R2 and R21 are not 4-hydroxyphenyl; (vii) if the compound is defined by formula Ib, then
(a) R2 and R3 are not 4-(NH2SO2)phenyl, 4- (CH3SO2)phenyl, or 4-(CH2FSO2)phenyl; and
(b) R1 is not 4-hydroxyphenyl; (viii) if the compound is defined by formula Ic, then
(a) R2 and R3 are not 4-(NH2SO2)phenyl, 4- (CH3SO2)phenyl, or 4-(CH2FSO2)phenyl;
(b) J is not pyridyl; and
(c) G is not 3- or 4-methoxyphenyl; and (ix) if the compound is defined by formula Id, then
(a) if L1 is a bond, then R1 is not thienyl or 5- methylthienyl;
(b) G is not 4-(NH2SO2)ρhenyl, 4-(CH3SO2)phenyl, or 4- (CH2FSO2)phenyl; (c) if G is 4-fluorophenyl, then R1 is not 4-[(H2NS(O)2-
]phenyl-;
(d) if J = Ph, L2 is a bond, and q is 1, then K and R4 together are not 4-fluorophenyl, 3-fluorophenyl, 4- methoxyphenyl, or 5-chlorothienyl; (e) if J = pyridyl, L2 is a bond, and q is 1, then K and R4 together are not 4-fluorophenyl;
(f) if J = Ph, L2 is a bond, and q is 2, then K and both R4 together are not 3-fluoro-4-methoxyphenyl; and
(g) R1 isnot4-Me-phenyl. 2. The compound according to claim 1 , wherein J is phenyl.
3. The compound according to claim 1, wherein K is phenyl or pyridyl.
4. The compound according to claim 2 wherein K is phenyl.
5. The compound according to claim 4, of the formula,
Figure imgf000500_0001
or a pharmaceutically acceptable salt, isomer, or prodrug thereof. 6. The compound according to claim 5, of the formula,
Figure imgf000500_0002
or a pharmaceutically acceptable salt, isomer, or prodrug thereof, wherein R21 is hydrogen, halogen, nitro, cyano, Q-C6alkyl, or Q-Qhaloalkyl.
7. The compound according to claim 6, wherein L2 is a bond.
8. The compound according to claim 6, wherein L1 is a bond and R5 is phenyl optionally substituted with one or more R5a. 9. The compound according to claim 7, wherein L1 is a bond and R5 is phenyl optionally substituted with one or more R5a.
10. The compound according to claim 9, wherein each R5a is independently halogen, -C, or -B'-C, wherein
B' is -[C(R15 )2]m-, wherein each R15 is independently -H or -halogen; and
C is -H, -halogen, -SO2R11, -OR11, -COR11, -SO2N(Rπ)2, -ON, -C(O)OR11, -CON(Rn)2, or -N(RU)2.
11. The compound according to claim 10, wherein each R5a is independently -halogen, -Q-Qalkyl, -Ci-Cghaloalkyl, -OR11, -COR11, -C=N, -C(O)OR11, -C0N(Rπ)2, or-N(Rπ)2. 12. The compound according to claim 9, wherein each R41 is independently hydrogen, halogen, -Ci-C6alkyl, or-d-Cβhaloalkyl, -COR16, -COOR16, -CON(R16)2, -C=N, -OR16, or-N(R16)2, wherein each R16 is independently hydrogen, -C1-C6 alkyl, or -C1-C6 haloalkyl.
13. The compound according to claim 12, wherein each R41 is independently hydrogen, halogen, -CrC6alkyl, or -Q-Cehaloalkyl.
14. The compound according to claim 9, wherein each R4 is independently halogen, nitro, Ci-C6alkyl, Q-Cehaloalkyl, -COR11, -COOR11, -C0N(Rn)2, -C=N, -OR11, -OCON(Rπ)2, -OCO2-R11, -N3, -NR11COR11, -NR11SO2R11, -N(Rπ)2, -NR11COOR11, -SO2R11, -SO2NR11COR11, -SO2N(Rπ)2, or -SR11.
15. The compound according to claim 14, wherein each R4 is independently halogen, nitro, Q-Cgalkyl, Q-Cβhaloalkyl, -COR11, -COOR11, -C0N(Rn)2, -C=N, -OR11, -N(Rπ)2, -SO2R11, or -SO2N(Rn)2. 16. The compound according to claim 9, wherein R is -L -R , wherein
L3 is a bond; and R7 is hydrogen, halogen, nitro, cyano, -Z, or -Y-Z, wherein Yis -[C(R15)2]m-;
Z is -H, halogen, -OR11, -C(O)R11, -C(=0)0Rπ, -C(O)N(Rπ)2, -N(R1V -CN, -SO2R11, -S(O)2N(R1V -CKWl^N^V -C(O)N(R11XOR11), -OC(O)-R11, or -OC(O)-N(R1V
17. The compound according to claim 16, wherein R2 is -L3-R7, wherein L3 is a bond; and R7 is hydrogen, halogen, -Z, or -Y-Z, wherein
Y is -[C(R15)2]m-, wherein
Z is -H, halogen, -OR11, -C(O)R11, -C(O)OR11, -C(O)N(Rπ)2, -N(Rπ)2, -CN, -SO2R11, or -S(O)2N(Rπ)2.
18. The compound according to claim 11, wherein each R41 is independently hydrogen, halogen, -CrC6alkyl, or -Q-Cehaloalkyl.
19. The compound according to claim 13, wherein each R4 is independently halogen, nitro, Ci-Cealkyl, d-Cehaloalkyl, -COR11, -COOR11, -CON(Rn)2, -C=N, -OR11, -N(Rπ)2, -SO2R11, or -SO2N(Rπ)2.
20. The compound according to claim 15, wherein R is -L -R , wherein L3 is a bond; and R7 is hydrogen, halogen, -Z, or -Y-Z, wherein
Y is -[C(R15)2]m-, wherein
Z is -H, halogen, -OR11, -C(O)R11, -C(O)OR11, -C(O)N(Rπ)2, -N(Rπ)2, -CN, -SO2R11, or -S(O)2N(Rn)2.
21. The compound according to claim 17, wherein each R5a is independently -halogen, -Q-C6alkyl, -Q-Cehaloalkyl, -OR11, -COR11, -C=N, -C(O)OR11, -CON(RU)2, or -N(RU)2.
22. The compound according to claim 18, wherein each R4 is independently halogen, nitro, CrC6alkyl, Q-Cehaloalkyl, -COR11, -COOR11, -C0N(Rπ)2, -C=N, -OR11, -N(Rπ)2, -SO2R11, or -SO2N(Rπ)2.
23. The compound according to claim 19, wherein R2 is -L3-R7, wherein L3 is a bond; and R7 is hydrogen, halogen, -Z, or -Y-Z, wherein
Y is -[C(R15)2]m-, wherein
Z is -H, halogen, -OR11, -Q=O)R11, -C(O)OR11, -C(=O)N(RU)2, -N(Rπ)2, -CN,
-SO2Rn, or-S(=O)2N(Rn)2.
24. The compound according to claim 20, wherein each R5a is independently -halogen, -CrC6alkyl, -CrCδhaloalkyl, -OR11, -COR11, -ON, -C(O)OR11, -C0N(Rn)2, or -N(Rπ)2.
25. The compound according to claim 21, wherein each R41 is independently hydrogen, halogen, -Q-Cealkyl, or -Q-Cehaloalkyl.
26. The compound according to claim 22, wherein R2 is -L3-R7, wherein L3 is a bond; and R7 is hydrogen, halogen, -Z, or -Y-Z, wherein Y is -[C(R15)2]m-, wherein
Z is -H, halogen, -OR11, -C(O)R11, -C(=O)ORU, -C(=O)N(RU)2, -N(Rn)2, -CN, -SO2Rn, or-S(=O)2N(Rπ)2.
27. The compound according to claim 4, of the formula,
Figure imgf000502_0001
or a pharmaceutically acceptable salt, isomer, or prodrug thereof, wherein R21 is hydrogen, halogen, nitro, cyano, Ci-C6alkyl, or CrQhaloalkyl. 28. The compound according to claim 25, of the formula,
Figure imgf000502_0002
or a pharmaceutically acceptable salt, isomer, or prodrug thereof. 29. The compound according to claim 28, wherein
L2 is a bond or -[C(R15)2]m»-V2-[C(R15)2]rf-, wherein m" is 0; n' is 0-3; and V2 is -O-, -S-, -OC(=O>, -OC(O)O-, or -OC(=O)N(R10)-
30. The compound according to claim 29, wherein L2 is a bond.
31. The compound according to claim 30, wherein L1 is a bond; and R5 is aryl or heteroaryl optionally substituted with one or more R5a. 32. The compound according to claim 31, of the formula
Figure imgf000503_0001
or a pharmaceutically acceptable salt, isomer, or prodrug thereof.
33. The compound according to claim 32, wherein R5 is phenyl optionally substituted with one or moreR5a. 34. The compound according to claim 33, wherein each R5a is independently halogen, -C, or -B'-C, wherein
B' is -[C(R15 )2]m-, wherein each R15 is independently -H or -halogen; and C is -H, -halogen, -SO2R11, -OR11, -COR11, -SO2N(Rn)2, -C=N, -C(O)OR11, -CON(RU)2, or -N(Rπ)2. 35. The compound according to claim 34, wherein each R5a is independently -halogen, -Q-C6alkyl, -Ci-Cehaloalkyl, -OR11, -COR11, -ON, -C(O)OR11, -C0N(Rπ)2, or -N(Rπ)2.
36. The compound according to claim 33, wherein each R41 is independently hydrogen, halogen, -Q-C6alkyl, -Q-Qhaloalkyl, -COR16, -COOR16, -CON(R16)2, -CMN, -OR16, or -N(R16)2, herein each R16 is independently hydrogen, -Ci-C6 alkyl, or -C1-C6 haloalkyl. 37. The compound according to claim 36, wherein each R41 is independently hydrogen, halogen, -d-Cealkyl, or -CrCehaloalkyl.
38. The compound according to claim 33, wherein each R4 is independently halogen, -M, or -E-M, wherein
E is -[C(R15)2]m-; M is q-Qalkyl, d-Cghaloalkyl, -COR11, -COOR11, -C0N(Rπ)2, -C≡N, -OR11, -0C0N(Ru)2,
-OCO2-R11, -N3, -NR11COR11, -NR11SO2R11, -N(Rπ)2, -NR11COOR11, -SO2R11, -SO2NR11COR11, -SO2N(Rπ)2, or -SR11.
39. The compound according to claim 38, wherein each R4 is independently halogen, -M, or -E-M, wherein E is -[C(R15 )2]m-, wherein each R15' is independently -H or -halogen; and M is -Q-Cealkyl, -Q-Qhaloalkyl, -COR11', -COOR11', -CON(Rn')2, -ON, -OR11', -N(Rn)2, -SO2R11', or -SO2N(Rπ')2, wherein each R11' is independently -hydrogen, -C1-C6 alkyl, -C1-C6 haloalkyl, wherein each R11' is optionally substituted with -OR13, -COOR13, -COR13, -SO2R13, -CON(R13)2, -SO2N(R13)2, or -N(R13)2.
40. The compound according to claim 33, wherein R2 is -L3-R7, wherein
L3 is a bond, -C(Rπ)2-, -O-, -S-, -NR7-, -N(R10)CO-, -CO-, -CS-, -CONR11-, -CO2-, -OC(=O)-, or -SO2-; and
R7 is hydrogen, halogen, heterocyclyl, -Z, or -Y-Z, wherein Yis-[C(R15)2]m-;
Z is -H, halogen, -OR11, -C(O)R11, -C(H))OR11, -C(O)N(R1 \ -N(Rπ)2, -CN, -SO2R11, -S(O)2N(Rπ)2, -C(O)N(R11)N(R11)2, -C(O)N(Ru)(0Ru), -OC(O)-R11, or-OC(0)-N(Rn)2.
41. The compound according to claim 40, wherein R2 is -L3-R7, wherein L3 is a bond, -C(RU")2-, -CO-, or -SO2-; and
R7 is hydrogen, halogen, heterocyclyl, -Ci-C6alkyl, -Ci-Cehaloalkyl, -OR11 , -C(O)R11", -C(O)OR11", -C(O)N(RU")2, -N(RU")2, -CN, -SO2R11", or -S(O)2N(R11"),, wherein each R11' is independently -H or -Ci-C6alkyl. 42. The compound according to claim 35, wherein each R41 is independently hydrogen, halogen, -Q-Qalkyl, or -CrCghaloalkyl.
43. The compound according to claim 37, wherein each R4 is independently halogen, -M, or -E-M, wherein
E is -[C(R15 )2]m-, wherein each R15 is independently -H or -halogen; and
M is -Q-Cόalkyl, -Q-Cehaloalkyl, -COR11', -COOR11', -CON(Rn')2, -CNN, -OR11', -N(Rπ)2, -SO2R11', or -SO2N(Rπ)2, wherein each R l is independently -hydrogen, -C1-C6 alkyl, or -Cj-Cδ haloalkyl, wherein each R11' is optionally substituted with -OR13, -COOR13, -COR13, -SO2R13, -CON(R13)2, -SO2N(R1V, or -N(R13)2.
44. The compound according to claim 39, wherein R2 is -L3-R7, wherein
L3 is a bond, -C(RU")2-, -CO-, or -SO2-; and R7 is hydrogen, halogen, heterocyclyl, -Ci-Qalkyl, -Q-Qhaloalkyl, -OR11 , -C(=O)Rπ", -C(O)OR11 ', -C(O)N(Rπ")2, -N(Rπ")2, -CN, -SO2R11", or -S(O)2N(R11"^, wherein each R11 is independently -H or -Q-Qalkyl. 45. The compound according to claim 41, wherein each R5a is independently -halogen, -Q-Qalkyl, -Q-Qhaloalkyl, -OR11, -COR11, -C=N, -C(O)OR11, -C0N(Rπ)2, or -N(Rπ)2.
46. The compound according to claim 42, wherein each R4 is independently halogen, -M, or -E-M, wherein
E is -[C(R15')2]m-, wherein each R15 is independently -H or -halogen; and
M is -Q-Qalkyl, -Q-Qhaloalkyl, -COR11', -COOR11', -C0N(Rπ)2, -C≡N, -OR11', -N(Rπ)2, -SO2R11', or -SO2N(R11^2, wherein each R11' is independently -hydrogen, -C1-C6 alkyl, -Q-Q haloalkyl, wherein each R11' is optionally substituted with -OR13, -COOR13, -COR13, -SO2R13, -CON(R13)2, -SO2N(R13)2, or -N(R13)2.
47. The compound according to claim 43, wherein R2 is -L3-R7, wherein
L3 is a bond, -C(RU")2-, -CO-, or -SO2-; and
R7 is hydrogen, halogen, heterocyclyl, -Q-Qalkyl, -Q-Qhaloalkyl, -OR11 , -C(O)R11", -C(=0)0Rπ", -C(O)N(Rn")2, -N(Rn")2, -CN, -SO2R11", or -S(O)2N(R11"),, wherein each R11' is independently -H or -Q-Qalkyl.
48. The compound according to claim 44, wherein each R5a is independently -halogen, -Q-C6alkyl, -Q-Qhaloalkyl, -OR11, -COR11, -ON, -C(O)OR11, -CON(RU)2, or -N(RU)2.
49. The compound according to claim 45, wherein each R41 is independently hydrogen, halogen, -Q-Qalkyl, or -Q-Qhaloalkyl.
50. The compound according to claim 46, wherein R2 is -L3-R7, wherein
L3 is a bond, -C(R11V, -CO-, or -SO2-; and
R7 is hydrogen, halogen, heterocyclyl, -Q-Qalkyl, -Q-Qhaloalkyl, -OR11 , -C(=O)Rπ", -C(=0)0Rπ", -C(O)N(Rn")2, -N(Rπ")2, -CN, -SO2R11", or -S(O)2N(R11"),, wherein each R11 is independently -H or -Q-Qalkyl.
51. The compound according to claim 31 , wherein R5 is pyridyl optionally substituted with one or moreR5a.
52. The compound according to claim 51, wherein each R5a is independently -halogen, -Ci-Qalkyl, -Ci-Qhaloalkyl, -OR11, -COR11, -ON, -C(O)OR11, -C0N(Rπ)2, or -N(Rπ)2.
53. The compound according to claim 51, wherein each R41 is independently hydrogen, halogen, -Ci-C6alkyl, or -d-Qhaloalkyl. 54. The compound according to claim 51 , wherein R2 is -L3-R7, wherein L3 is a bond or -C(RU")2-; and
R7 is hydrogen, halogen, -CrC6alkyl, -Q-Cehaloalkyl, -OR11", -C(O)R11", -C(O)OR11', -C(=O)N(RU")2, -N(RU")2, -CN, -SO2R11", or -SC=O)2N(R1 \ wherein each R11 is independently -H or -Q-Qalkyl. 55. The compound according to claim 51, wherein each R4 is independently halogen -C1-QaIlCyI, -Q-Cehaloalkyl, -COR11', -COOR11', -C0N(Rπ')2, -ON, -OR11', -N(Rπ)2, -SO2R11', or -SO2N(Rπ')2, wherein each R11 is independently -hydrogen, -C1-C6 alkyl, or -C1-C6 haloalkyl.
56. The compound according to claim 29, wherein L2 is -V2-[C(R15)2]n»-, wherein n" is 0-3; and V2 is -O-, -S-, -OC(O)-, -OC(O)O-, or -OC(O)N(R10)-.
57. The compound according to claim 56, wherein each R5a is independently -halogen, -Q-Qalkyl, -Q-Qhaloalkyl, -OR11, -COR11, -ON, -C(O)OR11, -CON(RU)2, or -N(Rπ)2.
58. The compound according to claim 56, wherein each R41 is independently hydrogen, halogen, -CrC6alkyl, or -d-Cehaloalkyl. 59. The compound according to claim 56, wherein R2 is -L3-R7, wherein L3 is a bond or -C(R11V; and
R7 is hydrogen, halogen, -Q-C6alkyl, -Q-Cehaloalkyl, -OR11", -C(O)R1 *", -C(O)OR11", -C(O)N(Rπ")2, -N(Rπ")2, -CN, -SO2R11", or -S(O)2N(Rn")2, wherein each R11 is independently -H or -Ci-Cδalkyl. 60. The compound according to claim 56, wherein each R4 is independently halogen -d-C6alkyl, -Ci-Cehaloalkyl, -COR11', -COOR11', -CON(Rn')2, -ON, -OR11', -N(Rπ)2, -SO2R11', or -SO2N(Rπ)2, wherein each R11 is independently -hydrogen, -C1-C6 alkyl, or -C]-C6 haloalkyl. 61. The compound according to claim 2, wherein K is absent; q is 1 ; and
L2 is -V2-[C(R15)2]n-, wherein n is 0-6; and V2 is -0-, -S-, -SO2-, -CON(R10)-, -CON(R11)-, -CO-, -CO2-, -OC(O)-, -OC(O)O-, or -OC(O)N(R10)-; and R21 is hydrogen, halogen, nitro, cyano, Q-Cealkyl, or Ci-Cehaloalkyl.
62. The compound according to claim 61, wherein L2 is -CO-; and
R4 is heterocyclyl optionally substituted with one or more groups which independently are -M', wherein
M' is -H, halogen, COR11, COOR11, C=N, OR11, -NR11COR11, NR11SO2R11, SO2R11, SO2N(Rπ)2, orSRn.
63. The compound according to claim 62, wherein each R5a is independently -halogen, -CrCgalkyl, -d-Cehaloalkyl, -OR11, -COR11, -ON, -C(O)OR11, -CON(Rπ)2, or -N(Rn)2. 64. The compound according to claim 62, wherein R2 is -L3-R7, wherein L3 is a bond or -C(RU")2-; and
R7 is hydrogen, halogen, -Q-Qsalkyl, -CrCehaloalkyl, -OR11", -Q=O)R11", -C(O)OR11", -C(O)N(R11"),, -N(Rπ")2, -CN, -SO2R11", or -SC=O)2N(R11"),, wherein each R11 is independently -H or -Ci-C6alkyl. 65. The compound according to claim 62, wherein each R41 is independently hydrogen, halogen, -Ci-Qalkyl, or -d-Cβhaloalkyl.
66. The compound according to claim 61, wherein L2 is -0-; and
R4 is -E-M, wherein E is-[C(R15)2]m-;
M is -H, halogen, -COR11, -COOR11, -CON(RU)2, -C=N, -OR11, -0C0N(Rn)2, -OCO2-R11, -N(Rπ)2.
67. The compound according to claim 66, wherein each R41 is independently hydrogen, halogen, -CrQalkyl, or -CrOftaloalkyl. 68. The compound according to claim 66, wherein each R5a is independently -halogen, CrCβalkyl, Q-Cόhaloalkyl, -OR11, -COR11, -ON, -C(O)OR11, -CON(RU)2, or -N(Rπ)2.
69. The compound according to claim 66, wherein R2 is -L3-R7, wherein L3 is a bond or -C(Rn")2-; and
R7 is hydrogen, halogen, -Q-C6alkyl, -Q-Cehaloalkyl, -OR11", -C(O)R11", -C(O)OR11", -C(O)N(Rπ")2, -N(Rπ")2, -CN, -SO2R11", or -S(O)2N(R11");;, wherein each R11 is independently -H or -Q-Qalkyl.
70. The compound according to claim 61 , wherein L2 is -V2-[C(R15)2]n-, wherein n is 0-6; and
V2 is -CON(R11)- or -CO2-; and R4 is heterocyclyl, or -E-M, wherein
E is -[C(R15)2]m-; and M is -H, halogen, -COR11, -COOR11, -CON(R11^, -ON, -OR11, -0C0N(Ru)2,
-OCO2-R11, -N3, -NR11COR11, -NR11SO2R11, -N(Rn)2, -NR11COOR11, -SO2R11, -SO2NR11COR11, -SO2N(Rπ)2, or -SR11.
71. The compound according to claim 70, wherein each R41 is independently hydrogen, halogen, -d-Cgalkyl, or-Q-Qshaloalkyl. 72. The compound according to claim 70, wherein each R5a is independently -halogen, -Q-Cgalkyl, -Q-Qshaloalkyl, -OR11, -COR11, -ON, -C(O)OR11, -C0N(Rπ)2, or -N(Rπ)2.
73. The compound according to claim 70, wherein R2 is -L3-R7, wherein L3 is a bond or -C(R1 r')2-; and
R7 is hydrogen, halogen, -d-Cealkyl, -Q-Cehaloalkyl, -OR11", -C(=O)RU", -C(O)OR11", -C(O)N(R11"^, -N(Rn")2, -CN, -SO2R11", or -S(O)2N(R11")^ wherein each R11 is independently -H or -Q-Qalkyl.
74. The compound according to claim 1 , wherein J is heteroaryl; and
R21 is hydrogen, halogen, nitro, cyano, CrCβalkyl, or Q-Cehaloalkyl.
75. The compound according to claim 74, wherein J is thienyl, furyl, pyrrolyl, thiazoyl, oxazoyl, isothiazoyl, isoxazoyl, pyridyl, pyrimidinyl, or pyrazinyl.
76. The compound according to claim 75, wherein K is phenyl.
77. The compound according to claim 75, wherein J is pyridyl.
78. The compound according to claim 77, wherein L1 is a bond; and R5 is phenyl optionally substituted with one or more R5a. 19 The compound according to claim 78, wherein K is phenyl.
80. The compound according to claim 79, wherein each R41 is independently hydrogen, halogen, -Q-Qalkyl, or -d-Qhaloalkyl.
81. The compound according to claim 79, wherein R2 is -L3-R7, wherein
L3 is a bond or -C(Rπ")2-; and R7 is hydrogen, halogen, -CrC6alkyl, -d-Cehaloalkyl, -OR11", -C(O)R11",
-C(O)OR11", -C(O)N(R11"),, -N(Rπ")2, -CN, -SO2R11", or -S(O)2N(Rπ")2, wherein each R11 is independently -H or -Ci-Cβalkyl.
82. The compound according to claim 19, wherein each R4 is independently halogen -CrC6alkyl, -Q-Qhaloalkyl, -COR11', -COOR11', -C0N(Rπ')2, -ON, -OR11', -N(Rπ)2, -SO2R11', or -SO2N(Rn')2, wherein each R11 is independently -hydrogen, -C1-C6 alkyl, or -C1-C6 haloalkyl. 83. The compound according to claim 79, wherein each R5a is independently -halogen, -Q-C6alkyl, -d-Cehaloalkyl, -OR11, -COR11, -ON, -C(O)OR11, -CON(Rπ)2, or -N(Rπ)2. 84 The compound according to claim 75, wherein J is thienyl, furyl, or pyrroyl.
85. The compound according to claim 84, wherein J is thienyl.
86. The compound according to claim 85, wherein K is phenyl and L2 is a bond. 87. The compound according to claim 86, of the formula
Figure imgf000509_0001
or a pharmaceutically acceptable salt, isomer, or prodrug thereof. 88. The compound according to claim 87, of the formula,
Figure imgf000509_0002
or a pharmaceutically acceptable salt, isomer, or prodrug thereof. 89. The compound according to claim 88, of the formula,
Figure imgf000509_0003
or a pharmaceutically acceptable salt, isomer, or prodrug thereof.
90. The compound according to claim 89, wherein L1 is a bond; and R5 is phenyl optionally substituted with one or more R5a.
91. The compound according to claim 90, wherein each R5a is independently halogen, nitro, heterocyclyloxy, aryloxy, -C, -B'-C or -A'-B'-C wherein A' is -O-;
B' is -[C(R15)2]m-;
C is -H, halogen, -SO2R11, -OR11, -SR11, -COR11, -SO2N(Rn)2, -SO2NR11COR11, -ON5 -C(O)OR11, -OC(=O)Rπ, -CON(R11^5 -CON(R1 ^OR11, -0C0N(Rπ)2, -NR11COR11, -NRπC0N(Rπ)2, -NR11COOR11, -N(RU)2, aryl, heteroaryl, orheterocyclyl; wherein each R5a is optionally substituted one or more groups which are independently C1-C6 alkyl, C3-C8 cycloalkyl, halogen, -C=N, -COR11, -COOR11, -CON(R11)^ -SO2R11, -OR11, -SR11, -SO2R11, -SO2N(Rπ)2, -SO2NR11COR11, -OCON(R.11^, -NR11COR11, -NR11CON(R11^, -NR11COOR11, or -N(Rπ)2. 92. The compound according to claim 91, wherein each R5a is independently halogen, nitro, heterocyclyloxy, phenoxy, -C, -B'-C, or -A'-B'-C wherein A' is -O-; B' is -[C(R15)2]m-;
C is -H, halogen, -OR18, -COR18, -C=N, -C(O)OR18, -0C(=O)R18, -CON(R18)2, -OCON(R18)2, -NR18COR18, -NR18CON(R18)2, -NR18COOR18, -N(R18)2, or heterocyclyl; wherein each R18 is independently -H, -C1-C6 alkyl, -C1-C6 haloalkyl, -C3-C8 cycloalkyl, aryl, heteroaryl, orheterocyclyl; and wherein each R5a is optionally substituted one or more groups which are independently C1-C6 alkyl, halogen, -COR19, -COOR19, -CON(R19)2, -OR19, or -N(R19)2, wherein each R19 is independently -H or -Q-Qalkyl.
93. The compound according to claim 90, wherein each R41 is independently hydrogen, halogen, -d-Cealkyl, -Q-Qshaloalkyl, -COR16, -COOR16, -CON(R16)2, -C=N, -OR16, or -N(R16)2j wherein each R16 is independently hydrogen, -C1-C6 alkyl, or -C1-C6 haloalkyl.
94. The compound according to claim 93, wherein each R41 is independently hydrogen, halogen, -Q-Qalkyl, or -Q-Cehaloalkyl.
95. The compound according to claim 90, wherein each R is independently halogen, nitro, CR11^R11COOR11, -M, or -E-M, wherein
E is -[C(R15)2]m- or C3-C8 cycloalkyl;
M is CrQalkyl, Q-Cehaloalkyl, -COR11, -COOR11, -C0N(Rn)2, -ON, -OR11, -0C0N(Ru)2, -OCO2-R11, -NR11COR11, -NR11SO2R11, -N(Rn)2, -NR11COOR11, -SO2R11, -SO2NR11COR11,
-SO2N(R11^ Or-SR11.
96. The compound according to claim 95, wherein each R4 is independently halogen, CR^=CR11 COOR11', -M, or -E-M, wherein E is -[C(R15)2]m- or C3-C8 cycloalkyl;
M is Q-Qalkyl, Cj-Cehaloalkyl, -COR11', -COOR11', -C0N(Rπ')2, -G=N, -OR11', -NR11O2R11',
-N(Rπ')2, -SO2R11', -SO2NR11COR11', or -SO2N(R11'^, wherein each R1 ! is independently -hydrogen, -Ci-C6 alkyl, or -C1-C6 haloalkyl, wherein any of R11 is optionally substituted with one or more radicals of R12 ; each R12 is independently halogen, Q-Cshaloalkyl, Ci-C6 alkyl, Ci-C6 alkoxy, C=O(OR13), COR13, SO2R13, CON(R13)2, SO2N(R13)2, or -N(R13)2.
97. The compound according to claim 90, wherein R2is -L3-R7, wherein L3 is abond or -(CH^-V^CEbV wherein m" is 0-3; n is 0-3; and
V1 is -C(Rπ)2-, -O-, -S-, -NR7-, -CO-, -CO2-, -OC(=O)-, or -SO2-; and R7 is hydrogen, halogen, nitro, aryl, heteroaryl, heterocyclyl, -Ci-C6alkyl, -Ci-Cδhaloalkyl, -C2-C6 alkenyl, C3-C8 cycloalkyl, or -(C(R15)2)m-Z, wherein
Z is -OR11, -C(O)R11, -C(=0)0Rπ, -C(O)N(R1 \ -N(Rn)2, -CN, -SO2R11, ■®=OW<&\ -C(=0)N(R11)N(R11)2, -C(O)N(R11XOR11), ^OC(O)-R11, or -OC(O)-N(R11),, wherein R7 is optionally substituted with one or more R7a, wherein R7a is halogen, Q-Qalkyl, Ci-Qhaloalkyl,
-OR20, -C(O)R20, -C(O)OR20, -C(O)N(R20)2, -N(R20)2, -N(R2(>)C(O)R20, or -CN, wherein each R20 is independently -H or Ci-C6alkyl.
98. The compound according to claim 97, wherein R2 is -L3-R7, wherein L3 is a bond or -(CBby-V^CH^- wherein m" is 0-1; n is 0-2; and
V1 is -CH2-, -0-, -S-, or -NR7-; and
R7 is hydrogen, halogen, phenyl, heteroaryl, heterocyclyl, -Ci-C6alkyl, -d-Cόhaloalkyl, -C2-C6 alkenyl, C3-C8 cycloalkyl, or -(C(R15)2)m-Z, wherein Z is -OR11", -C(O)R11", -C(O)OR11", -C(O)N(R11\ -N(RU")2, -CN, or -SO2R11", wherein R7 is optionally substituted with one or more R7a, wherein
R7a is halogen, Q-C6alkyl, Q-Qhaloalkyl, -OR11'', -N(Rπ")2, -COOR11", wherein each R11" is independently -H, -Ci-Qalkyl, -Q-Cδhaloalkyl, heterocyclyl, or heteroaryl.
99. he compound according to claim 98, wherein R is -L -R , wherein L3 is a bond; and
R7 is hydrogen, halogen, -Ci-C3alkyl, -Q-C^aloalkyl, or -(C(R15)2)-Z, wherein
Z iS -OR11Or-SO2R11", wherein R11" is -H or CrQalkyl.
100. The compound according to claim 92, wherein each R41 is independently hydrogen, halogen, -Ci-Qalkyl, or -Q-Cehaloalkyl.
101. The compound according to claim 94, wherein each R4 is independently halogen, CRn'=CRn COOR11', -M, or -E-M, wherein E is -[C(R15)2jm- or C3-C8 cycloalkyl;
M is Q-Qalkyl, Q-Cehaloalkyl, -COR11', -COOR11', -CON(Rπ')2, -ON, -OR11', -NR11O2R11', -N(Rπ')2, -SO2R11', -SO2NR11COR11', or -SO2N(Rπ')2, lχ wherein each R11 is independently -hydrogen, -C1-C6 alkyl, or -C1-C6 haloalkyl, wherein each R11 is optionally substituted with one or more radicals of R12 ; each R12 is independently halogen, C1-C6 haloalkyl, C1-C6 alkyl, C1-C6 alkoxy, C=O(OR13), COR13, SO2R13, CON(R13)2, or -N(R13)2.
102. The compound according to claim 96, wherein R2 is -L3-R7, wherein
L3 is a bond or -(CH^rf-V^CEbV wherein m" is 0-1; n is 0-2; and
V1 is -CH2-, -O-, -S-, or -NR7-; and
R7 is hydrogen, halogen, phenyl, heteroaryl, heterocyclyl, -Q-Cδalkyl, -CrCehaloalkyl, -C2-C6 alkenyl, C3-C8 cycloalkyl, or -(C(R15)2)m-Z, wherein
Z is -OR11, -C(=O)Rπ", -Q=O)OR11 ', -C(O)N(R1 r)2, -N(RU")2, -CN, or -SO2R11", wherein R7 is optionally substituted with one or more R7a, wherein
R7a is halogen, d-Qalkyl, CrQhaloalkyl, -OR11", -N(Rπ")2, -COOR11", wherein R11 is -H, -Ci-C6alkyl, -Q-Cehaloalkyl, heterocyclyl, or heteroaryl.
103. The compound according to claim 98, wherein each R5a is independently halogen, nitro, heterocyclyloxy, phenoxy, -C, -B'-C, or -A'-B'-C wherein A' is -O-;
B' is -[C(R15)2]m-;
C is -H, halogen, -OR18, -COR18, -C=N, -C(O)OR18, -OC(=O)R18, -CON(R18)2, -OCON(R18)2,
-NR18COR18, -NR18CON(R18)2, -NR18COOR18, -N(R18)2, or heterocyclyl; wherein each R18 is independently -H, -C1-C6 alkyl, -C1-C6 haloalkyl, -C3-C8 cycloalkyl, aryl, heteroaryl, or heterocyclyl; and wherein each R5a is optionally substituted one or more groups which are independently C1-C6 alkyl, halogen, -COR19, -COOR19, -CON(R19)2, -OR19, or -N(R19)2, whereinR19 is -Hor-Q-C6alkyl.
104. The compound according to claim 100, wherein each R4 is independently halogen, CR^=CR11COOR11', -M, or -E-M, wherein E is -[C(R15)2]m- or C3-C8 cycloalkyl;
M is d-Cealkyl, Q-Cehaloalkyl, -COR11', -COOR11', -CON(RU')2, -CE=N, -OR11', -NR11O2R11', -N(Rπ')2, -SO2R11', -SO2NR11COR11', or -SO2N(R11')2, wherein each R11 is independently -hydrogen, -C1-C6 alkyl, or -C1-C6 haloalkyl, wherein any of R11' is optionally substituted with one or more radicals of R12 ; each R12 is independently halogen, CrCδhaloalkyl, C1-C6 alkyl, C1-C6 alkoxy, C=O(OR13), COR13, SO2R13, CON(R13)2, SO2N(R13)2, or-N(R13)2. 105. The compound according to claim 101, wherein R2 is -L3-R7, wherein L3 is a bond or -(CH^m-V^CH^n- wherein m" is 0-1; n is 0-2; and
V1 is -CH2-, -O-, -S-, or -NR7-; and R7 is hydrogen, halogen, phenyl, heteroaryl, heterocyclyl, -Q-Qalkyl, -CrCghaloalkyl, -C2-C6 alkenyl, C3-C8 cycloalkyl, or -(C(R15)2)m-Z, wherein
Z is -OR11", -Q=O)R11", -C(=O)ORπ", -CC=O)N(R1 r')2, -N(Rπ")2, -CN, or -SO2R11", wherein R7 is optionally substituted with one or more R7a, wherein R7a is halogen, Q-Cealkyl, CrQjhaloalkyl, -OR11", -N(Rπ")2, -COOR11", wherein R11 is -H, -Q-Cealkyl, -Q-Cehaloalkyl, heterocyclyl, or heteroaryl.
106. The compound according to claim 102, wherein each R5a is independently halogen, nitro, heterocyclyloxy, phenoxy, -C, -B'-C, or -A'-B'-C wherein A' is -O-; B' is -[C(R15)2]m-; C is -H, halogen, -OR18, -COR18, -C=N, -C(O)OR18, -OC(=O)R18, -CON(R18)2, -OCON(R18)2,
-NR18COR18, -NR18CON(R18)2, -NR18COOR18, -N(R18)2, or heterocyclyl; wherein each R18 is independently -H, -C1-C6 alkyl, -C1-C6 haloalkyl, -C3-C8 cycloalkyl, aryl, heteroaryl, or heterocyclyl; and wherein each R5a is optionally substituted one or more groups which are independently C1-C6 alkyl, halogen, -COR19, -COOR19, -CON(R19)2, -OR19, or -N(R19)2, wherein R19 is -H or -d-Qalkyl.
107. The compound according to claim 103, wherein each R41 is independently hydrogen, halogen, -d-Qalkyl, or -Q-Qhaloalkyl.
108. The compound according to claim 104, wherein R2 is -L3-R7, wherein L3 is a bond or -(CH^m-V^CHaV wherein m" is 0-1; n is 0-2; and V1 is -CH2-, -O-, -S-, or -NR7-; and R7 is hydrogen, halogen, phenyl, heteroaryl, heterocyclyl, -Q-C6alkyl, -Q-Cehaloalkyl, -C2-C6 alkenyl, C3-C8 cycloalkyl, or -(C(R15)2)m-Z, wherein
Z is -OR11", -C(O)R11", -C(O)OR11", -C(=0)N(Rn")2, -N(Rn")2, -CN, or -SO2R11", wherein R7 is optionally substituted with one or more R7a, wherein
R7a is halogen, Ci-C6alkyl, Q-Cehaloalkyl, -OR11", -N(Rn")2, -COOR11", wherein R11 is -H, -Q-Cβalkyl, -Ci-Cόhaloalkyl, heterocyclyl, or heteroaryl.
109. The compound according to claim 89, wherein R1 is -iλR5, wherein
L1 is -L5- or -L6-, wherein each L5 is -C(R15)2-, wherein each R15 is independently hydrogen, halogen, (CrC6)alkyl, or
(CrC6)haloalkyl; and L6 is -CS-, -CO-, or -SO2-; and R5 is aryl or heteroaryl optionally substituted with one or more R5a.
110. The compound according to claim 109, wherein R5 is phenyl, thienyl, furyl, pyrrolyl, thiazoyl, oxazoyl, isothiazoyl, isoxazoyl, pyridyl, pyrimidinyl, or pyrazinyl optionally substituted with one or more R5a.
111. The compound according to claim 110, wherein R2 is -L3-R7, wherein
L3 is a bond or -C(R11V; and
R7 is hydrogen, halogen, -Q-C6alkyl, -Q-Cehaloalkyl, -OR11", -C(O)R11", -C(O)OR11", -C(O)N(Rπ")2, -N(RU")2, -CN, -SO2R11", or -S(O)2N(R1 r)2, wherein each R11 is independently -H or -Ci-C6alkyl.
112. The compound according to claim 110, wherein each R5a is independently -halogen, -Q-Qalkyl, -Q-Cehaloalkyl, -OR11, -COR11, -CNN, -C(O)OR11, -C0N(Rπ)2, or -N(Rπ)2.
113. The compound according to claim 110, wherein each R41 is independently hydrogen, halogen, -d-Cealkyl, or -Ci-Qhaloalkyl.
114. The compound according to claim 110, wherein each R4 is independently halogen -Ci-C6alkyl, -Q-Cshaloalkyl, -COR11', -COOR11', -C0N(Rπ)2, -CMN, -OR11', -N(Rn')2, -SO2R11', or -SO2N(Rn')2, wherein each R11 is independently -hydrogen, -Ci-C6 alkyl, or -Ci-C6 haloalkyl.
115. The compound according to claim 89, wherein L1 is a bond; and
R5 is heteroaryl optionally substituted with one or more R5a. 116. The compound according to claim 115, wherein
R5 is thienyl, furyl, pyrrolyl, thiazoyl, oxazoyl, isothiazoyl, isoxazoyl, pyridyl, pyrimidinyl, or pyrazinyl optionally substituted with one or more R5a.
117. The compound according to claim 116, wherein R5 is thienyl, furyl, pyrrolyl, thiazoyl, oxazoyl, isothiazoyl, or isoxazoyl optionally substituted with one or more R5a. 118. The compound according to claim 117, wherein each R5a is independently -halogen, -Ci-C6alkyl, -Ci-Qhaloalkyl, -OR11, -COR11, -ON, -C(O)OR11, -CON(Rπ)2, or-N(Ru)2.
119. The compound according to claim 117 wherein each R4 is independently halogen -Ci-C6alkyl, -Ci-Cehaloalkyl, -COR11', -COOR11', -C0N(Rn')2, -ON, -OR11', -N(Rπ)2, -SO2R11', or -SO2N(Rπ')2, wherein each R11 is independently -hydrogen, -Cj-C6 alkyl, or -Ci-C6 haloalkyl.
120. The compound according to claim 117, wherein R2 is -L3-R7, wherein
L3 is a bond or -C(Rn")2-; and
R7 is hydrogen, halogen, -Ci-C6alkyl, -d-Cehaloalkyl, -OR11", -C(=O)RU", -C(O)OR11", -C(=0)N(Rn")2, -N(Rπ")2, -CN, -SO2R11'', or -S(O)2N(R1 r')2, wherein each R11 is independently -H or -Ci-Cδalkyl.
121. The compound according to claim 117, wherein each R41 is independently hydrogen, halogen, -Ci-C6alkyl, or -Ci-Cehaloalkyl.
122. The compound according to claim 116, wherein R5 is pyridyl, pyrimidinyl, or pyrazinyl optionally substituted with one or more R5a. 123. The compound according to claim 122, wherein each R5a is -halogen, -Q-C6alkyl, -Ci-Qhaloalkyl, -OR11, -COR11, -ON, -C(O)OR11, -CON(Rn)2, or-N(Rn)2.
124. The compound according to claim 122, wherein each R4 is independently halogen -d-C6alkyl, -d-Cehaloalkyl, -COR11', -COOR11', -CON(Rn')2, -C=N, -OR11', -N(Rπ)2, -SO2R11', or -SO2N(Rπ')2, wherein each R11 is independently -hydrogen, -C1-C6 alkyl, or -C1-C6 haloalkyl. 125. The compound according to claim 122, wherein R2 is -L3-R7, wherein L3 is a bond; and
R7 is hydrogen, halogen, -Q-Qalkyl, -Q-Cβhaloalkyl, -C2-C6 alkenyl, C3-C8 cycloalkyl, or -(C(R15)2)m-Z, wherein m' is 0-1; and Z is -OR11, -C(=O)Rn, -C(O)OR11, -C(K))N(R1 \, -N(Rπ)2, -CN, or -SO2R11, wherein R11 is -H or Q-Qalkyl.
126. The compound according to claim 122, wherein each R41 is independently hydrogen, halogen, -Q-Qalkyl, or -Ci-Cehaloalkyl.
127. The compound according to claim 85, wherein K is heteroaryl; and L2 is a bond. 128. The compound according to claim 127, wherein K is thienyl, furyl, pyrrolyl, thiazoyl, oxazoyl, isothiazoyl, isoxazoyl, pyridyl, pyrimidinyl, or pyrazinyl.
129. The compound according to claim 128, wherein K is pyridyl.
130. The compound according to claim 129, wherein L1 is a bond; and R5 is phenyl optionally substituted with one or more R5a.
131. The compound according to claim 85, wherein K is absent; and L2 is -SO2- or -CO-.
132. The compound according to claim 131, wherein R4 is heterocyclyl, -OR11, or -N(Rn)2, wherein the heterocyclyl is optionally substituted with one or more -F-M', wherein E' is -[C(R15)2]m- or C3-C8 cycloalkyl;
M' is -H, halogen, COR11, COOR11, ON, OR11, -NR11COR11, NR11 SO2R11, SO2R11, SO2N(R11^, or SR11.
133. The compound according to claim 1, wherein
R1 is -L5-R5 or-L6-R5 wherein L5 is -[C(R15)2]m-;
L6 is C3-C8 cycloalkyl, cycloC^shaloalkyl, or heterocyclyl, wherein the cycloalkyl, cycloC3-8haloa]kyl 1, or heterocyclyl are optionally substituted with one or more radicals ofR14; R5 is aryl, heterocyclyl, or heteroaryl, wherein R5 is optionally substituted with one or more R5a, wherein each R5a is independently halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, (C3-C8 cycloalkyl)-CrC6 alkyl-, (C3-C8 cycloalkenyl)-Q-C6 alkyl-, (C3-C8 cycloalkyl)-C2-C6 alkenyl-, nitro, heterocyclyloxy, aryl, aryloxy, arylalkyl, aryloxyaryl, aryl C1-C6 alkoxy, -C, -B'-C, or -A'-B'-C wherein A' is -O-;
B' is -[C(R15)2]m- or - C3-C8 cycloalkyl-;
C is -H, halogen, -SO2R11, -OR11, -SR11, -N3, -COR11, -SO2N(R11^, -SO2NR11COR11, -ON, -C(O)OR11, -OC(O)R11, -CON(RU)2,
-C0N(Rn)0Rn, -0C0N(Rn)2, -NR11COR11, -NR11C0N(R11)2, -NR11COOR11, -N(Rπ)2, aryl, heteroaryl, or heterocyclyl.
134. The compound according to claim 133, wherein
J is aryl or heteroaryl; and K is aryl or heteroaryl.
135. The compound according to claim 134, wherein
R2 is -L3-R7, wherein
L3 is a bond; and
R7 is hydrogen, -Z, or -Y-Z, wherein Y is -[C(R15)2]m- or -C2-C6 alkenyl;
Z is -H, halogen, -OR11, -C(K))R11, -C(O)OR11, -C(O)N(Rπ)2, -N(Rπ)2, -CN,
-SO2R11, or -S(O)2N(Rπ)2 and R21 is hydrogen, halogen, C1-C6 alkyl, or Ci-C6 haloalkyl. .
136. The compound according to claim 1, of formulas Ia or Id. 137. The compound according to claim 136, wherein
R1 is -L5-R5 or -L6-R5 wherein
L5 is -[C(R15)2]m-;
L6 is C3-C8 cycloalkyl, cycloC^shaloalkyl, or heterocyclyl, wherein the cycloalkyl, cycloC^shaloalkyl, or heterocyclyl are optionally substituted with one or more radicals of R14; R5 is aryl, heterocyclyl, or heteroaryl, wherein R5 is optionally substituted with one or more R5a, wherein each R5a is independently halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, (C3-C8 cycloalkyl)-CrC6 alkyl-, (C3-C8 cycloalkenyl)-Q-C6 alkyl-, (C3-C8 cycloalkyl)-C2-C6 alkenyl-, nitro, heterocyclyloxy, aryl, aryloxy, arylalkyl, aryloxyaryl, aryl C1-C6 alkoxy,
-C, -B'-C, or -A'-B'-C wherein A' is -O-;
B' is -[C(R15)2]m- or - C3-C8 cycloalkyl-; C is -H, halogen, -SO2R11, -OR11, -SR11, -N3, -COR11, -SO2N(Rπ)2,
-SO2NR11COR11, -C=N, -C(O)OR11, -OC(=O)Rπ, -CON(Rn)2, -CON(R11PR11, -0C0N(Rπ)2, -NR11COR11, -NR11CON(R11^, -NR11COOR11, -N(Rπ)2, aryl, heteroaryl, or heterocyclyl.
138. The compound according to claim 137 wherein J is aryl or heteroaryl; and
K is aryl or heteroaryl.
139. The compound according to claim 138, wherein
R2 is -L3-R7, wherein
L3 is a bond; and R7 is hydrogen, -Z, or -Y-Z, wherein
Y is -[C(R15)2]m- or -C2-C6 alkenyl;
Z is -H, halogen, -OR11, -C(O)R11, -C(=0)0Rn, -C(=O)N(Rπ)2, -N(Rn)2, -CN, -SO2R11, or -S(O)2N(Rn)2 and R21 is hydrogen, halogen, C1-C6 alkyl, or C1-C6 haloalkyl. 140. The compound according to claim 139, wherein J and K are both phenyl.
141. The compound according to claim 140, wherein R5 is aryl or heteroaryl, wherein R5 is optionally substituted with one or more R5a.
142. The compound according to claim 141, wherein R5 is phenyl optionally substituted with one or more R5a- wherein each R5a is independently -halogen, -Q-Qalkyl, -d-Cehaloalkyl, -OR11, -COR11, -C=N, -C(O)OR11, -C0N(Rπ)2, or -N(Rπ)2
143. The compound according to claim 142, wherein each R4 is independently halogen, aryl, heteroaryl, heterocyclyl, -M, or -E-M, wherein
E is -[C(R15')2]m-, wherein each R15' is independently hydrogen or halogen; and M is -d-Cealkyl, -Ci-Cehaloalkyl, halogen, -OR11, or -SO2R11.
144. The compound according to claim 142, wherein each R41 is independently halogen, -M", or - E"-M", wherein
E" is -[C(R15)2]m-, wherein each R15 is independently hydrogen or halogen; and M" is -Q-Qalkyl, -Q-Cehaloalkyl, or halogen. 145. The compound according to claim 142, wherein
R7 is hydrogen, -Z, or -Y-Z, wherein Y is -[C(R15)2]m>- or -C2-C6 alkenyl, wherein m' is 0, 1, or 2; and
Z is -H, halogen, -OR11, -C(O)R11, -C(K))OR11, -C(O)N(R11^, -N(Rn)2, -CN, -SO2R11, or -S(O)2N(R11),.; and R21 is hydrogen. 146. The compound according to claim 139, wherein J is heteroaryl and K is phenyl.
147. The compound according to claim 146, wherein J is pyrroyl, thienyl, furyl, thiazoyl, oxazoyl, or pyrazoyl.
148. The compound according to claim 147, wherein R5 is aryl or heteroaryl, wherein R5 is optionally substituted with one or more R5a. 149. The compound according to claim 148, wherein R5 is phenyl optionally substituted with one or more R5a- wherein each R5a is independently -halogen, -Q-C6alkyl, -Q-Cehaloalkyl, -OR11, -COR11, -CsN, -C(O)OR11, -C0N(Rn)2, or -N(RU)2.
150. The compound according to claim 149, wherein each R4 is independently halogen, aryl, heteroaryl, heterocyclyl, -M, or -E-M, wherein E is -[C(R15')2]m-, wherein each R15 is independently hydrogen or halogen; and M is -Ci-Cealkyl, -Q-Cehaloalkyl, halogen, -OR11, or -SO2R11.
151. The compound according to claim 149, wherein each R41 is independently halogen, -M", or - E"-M", wherein E" is -[C(R15')2]m-, wherein each R15 is independently hydrogen or halogen; and M" is -Q-Cealkyl, -Q-Cehaloalkyl, or halogen.
152. The compound according to claim 149, wherein
R7 is hydrogen, -Z, or -Y-Z, wherein Y is -[C(R15)2]m>- or -C2-C6 alkenyl, wherein m' is 0, 1, or 2; and
Z is -H, halogen, -OR11, -C(O)R11, -C(O)OR11, -C(O)N(Rπ)2, -N(Rn)2, -CN, -SO2R11, or -S(O)2N(Rπ)2.; and R21 is hydrogen.
153. The compound according to claim 1 which is one of the compounds listed in Table 1.
154. A compound according to one of the formulas,
Figure imgf000520_0001
wherein,
(A) R1 is -iΛ-R5, wherein
L1 is a bond, L5, L6, -L5-L6-L5-, or -L6-L5-L6-, wherein each L5 is independently -[C(R15)2]m-, wherein each m is independently 0, 1, 2, 3, 4, 5 or 6; and each R15 is independently hydrogen, halogen, (CrC6)alkyl, or (Q-Cβ^aloalkyl; each L6 is independently -C(R1V -C(R11^C(R11V, -C(R11^=C(R11)-, -C(R11^O-, -C(Rn)2NRn-, -C≡C-, -O-, -S-, -NR11-, -N(R10)CO-, -N(R!0)CO2-, -CON(R10)-, -CO-, -CS-, -CO2-, -OC(=O>-, -OC(K))N(R10)-, -CONR11N(R1V, -CONR11-, -OCONR11-, -SO2-, -N(R10)SO2-, -SO2N(R10)-, -NR10CONR10-, -NR10CSNR10-, -C(=NRU)-, -CC=NOR11)-, -C(=NN(RU)2)-; aryl, C3-C8 cycloalkyl, cycloQ-ghaloalkyl, heteroaryl, or heterocyclyl, wherein the aryl, cycloalkyl, cycloCs-shaloalkyl, heteroaryl, or heterocyclyl are optionally substituted with one or more radicals of R14; or L1 is a C2-6 alidiyl alidiyl chain wherein the alidiyl chain is optionally interrupted by
-C(Rn)2-, -C(Ru)2C(Rπ)2-, -C(R1VC(R11)-, -C(RU)2O-, -C(Rn)2NRu-, -OC-, -0-, -S-, -N(R10)CO-, -N(R10)CO2-, -CON(R10)-, -CO-, -CO2-, -0C(=0)-, -OC(O)N(R10)-, -SO2-,
-N(R10)SO2-, or -SO2N(R10)-, and
R5 is aryl, heterocyclyl, heteroaryl, C2-C6 alkenyl, C2-C6 alkynyl, (C3-Cg cycloalkyty-Q-Ce alkyl-, (C3-C8 cycloalkenyl)-CrC6 alkyl-, (C3-C8 cycloalkyl)-C2-C6 alkenyl-, C3-C8 cycloalkyl, -C, -B-C, or -A-B-C, wherein Ais -O-;
B is -[C(R15)2]m- or C3-C8 cycloalkyl;
C is Q-Qalkyl, Ci-Qshaloalkyl, SO2R11, SR11, SO2N(R1V SO2NR11COR11, C=N, C(O)OR11, CON(R11K OrN(R1V wherein R5 is optionally substituted with one or more R5a, wherein each R5a is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, (C3-C8 cycloalkyty-Q- C6 alkyl-, (C3-C8 cycloalkenyl)-CrC6 alkyl-, (C3-C8 cycloalkyl)-C2-C6 alkenyl-, halogen, nitro, heterocyclyloxy, aryl, aryloxy, arylalkyl, aiyloxyaryl, aryl C1-C6 alkoxy, -C, -B'-C, or -A'-B'-C wherein A' is -O-;
B' is -[C(R15)2]m- or - C3-C8 cycloalkyl-;
C is -H, halogen, -SO2R11, -OR11, -SR11, -N3, -COR11, -SO2N(Rπ)2, -SO2NR11COR11, -C=N, -C(O)OR11, -OC(O)R11, -C0N(Rπ)2, -C0N(Rπ)0Rn, -0C0N(Rπ)2; -NR11COR11, -NR11C0N(R11)2, -NR11COOR11, -N(Rπ)2, aryl, heteroaryl, or heterocyclyl; wherein each R5a is optionally substituted one or more groups which are independently
C2-C6 alkenyl, C2-C6 alkynyl, (C3-C8 cycloalkyl)-Ci-C6 alkyl-, (C3-C8 cycloalkenyl)- C1-C6 alkyl-, (C3-C8 cycloalkyl)-C2-C6 alkenyl-, C0-C6 alkoxyaryl, C1-C6 alkyl, C3-C8 cycloalkyl, aryl, aryl-CrC6 alkyl-, heteroaryl, halogen, -NO2, -ON, -COR11, -COOR11, -C0N(Rπ)2, -SO2R11, -OR11, -SR11, -SO2R11, -SO2N(R11^, -SO2NR11COR11, -0C0N(Rπ)2, -NR11COR11, -NR11CON(R1^2, -NR11COOR11, or
-N(Rπ)2; R2 and R21 are -L3-R7, wherein each L3 is independently a bond -^-(CH^n-V1-, or -(CH^-V1-^^- wherein n is 0-6; and each V1 is independently -C(Rπ)2-, -C(R11^C(R1 %-, -C(R11^=C(R11)-, -C(Rπ)2O-,
-C(Rn)2NRn-, -C=C-, -0-, -S-, -NR7-, -N(R10)CO-, -N(R10)CO2-, -OCO-, -CO-, -CS-, -CONR10-, -C(=N)(Rn)-, -C(=N-0Rn>, -Q=N-N(R11^], -CO2-, -0C(=0)-, -0C(=0)N(R1(})-, -SO2-, -N(R10)SO2-, -SO2N(R10)-, -NR10CONR10-, -NR10CSNR10-, C3-C8 cycloalkyl, or C3-C8 cyclohaloalkyl; or each L3 is independently a C2-6 alidiyl chain, wherein the alidiyl chain is optionally interrupted by -C(Rn)2-, -C(R11^C(R1 V, -C(R11^=C(R11)-, -C(Rπ)2O-, -C(Rπ)2NRπ-, -OC-, -0-, -S-, -N(R10)CO-, -N(R10)CO2-, -CON(R10)-, -CO-, -CO2-, -0C(=0)-, -OC(O)N(R10)-, -SO2-, -N(R10)SO2-, or -SO2N(R10); and each R7 is independently hydrogen, halogen, nitro, cyano, aryl, heteroaryl, heterocyclyl, -C1-C6 alkyl-heterocyclyl, -C1-C6 alkyl-heteroaryl, -C1-C6 alkyl-aryl, -Z, -Y-Z, or -X-Y-Z, wherein
Xis -0-; Y is -[C(R15)2]m-, -C2-C6 alkenyl or C3-C8 cycloalkyl; Z is -H, -CN5 halogen, -OR11, -C(=O)Rπ, -C(O)OR11, -C(O)N(Rπ)2, -N(Rπ)2, -CN, -N3, -SO2R11, -S(=O)2N(RU)2, -C(O)N(Rπ)N(Rπ)2, -C(O)N(R11XOR11^ -OC(O)-R11, -0C(O)-N(Rn)2, or-N(Ru)COORπ; wherein R7 is optionally substituted with one or more R7a, wherein R7a is halogen, C2-C6 alkenyl, -C1-C6 alkyl-heterocyclyl, -C1-C6 alkyl-heteroaryl, -C1-C6 alkyl-aryl, C0-C6 alkoxyheteroaryl, Co-C6a]koxyheterocyclyl, haloaryl, aryloxy, aralkyloxy, aryloxyalkyl, Ci-Cδalkoxyaryl, aryl C0-C6 alkylcarboxy, C(R11^C(R1VCOOR11, Co-Cealkoxyheteroaryl, Q-Qalkoxyheterocyclyl, aryl, heteroaryl, heterocyclyl, C3-C8 cycloalkyl, heteroaryloxy, -Z', -Y'-Z', or -X'-Y'-Z', wherein
X' is -O-;
Y' is -[C(R15)2]m- or C3-C8 cycloalkyl;
Z' is -Ci-C6alkyl, -Ci-Cehaloalkyl, -OR11, -SR11, -S(O)2R11, -C(O)R11, -C(O)OR11, -C(O)N(Rn)2, -N(Rπ)2, -N(R1 ^C(O)R1 \ -SC=O)BN(R11XX=O)R11, -CN, -S(O)2N(Rπ)2, -C(O)N(R1^N(R11^,
-C(O)N(R1^(OR11X -OC(O)-R11, -OC(O)-OR11, -N(Rπ)C(O)0-Rn, or -N(R1^S(O)2R11; wherein each R7a is optionally substituted with one or more R8, wherein each R8 is independently halogen, nitro, cyano, heteroaryl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkyl(ORn), C0-C6 alkylOR11, C0-C6 alkylCON(Rπ)2, C0-C6 alkylCOR11, C0-C6 alkylCOOR11, or C0-C6 alkylSO2Rn; and wherein if two R7a are present on the same carbon, then they may be taken together to form a cycloalkyl or heterocyclyl group; provided that R2 and R21 are not simultaneously -H; R3 is -L-R6, wherein L is a bond, -X3-(CH2)n-X3-, -(CH2)m-X3-(CH2)n- or -(CH2)1+W-Y3-(CH2V wherein n is 0-6; each w is independently 0-5; and each X3 is independently a bond, -C(R1V, -C(R1^2C(R1 V, -C(R11^C(R11)-, -OC-, -CO-, -CS-, -CONR10-, -Q=N)(R11)-, -CO=N-OR11)-, -Cf=N-N(R11)2], -CO2-, -SO2-, or -SO2N(R10)-; and Y3 is -0-, -S-, -NR7-, -N(R10)CO-, -N(R10)CO2-, -OCO-,-OC(=O)N(R10)-,
-NR10CONR10-, -N(R10)SO2-, or -NR10CSNR10-; or L is a C2-6 alidiyl chain, wherein the alidiyl chain is optionally interrupted by -C(R1 ^2-, -C(Rπ)2C(Rn)2-, -C(R11^(R11)-, -C(Rπ)2O-, -CCR^NR11-, -OC-, -0-, -S-, -N(R10)CO-, -N(R10)CO2-5 -CON(R10)-, -CO-, -CO2-, -OC(=O)-, -OC(=O)N(R10)-, -SO2-, -N(R10)SO2-, or -SO2N(R10); and
R6 is C1-C6 alkyl, C1-C6 haloalkyl, aryl, C3-C8 cycloalkyl, heteroaryl, heterocyclyl, -CN, -C(O)R11, -C(O)OR11, -C(=0)N(Rn)2, -N(RU)2, -SO2R11, -S(O)2N(R1 % -C(O)N(R1 ^N(R11^ -C(O)N(Ru)(0Rn), wherein the aryl, heteroaryl, cycloalkyl, or heterocyclyl is optionally substituted with one or more R6a, wherein each R6a is independently -Z ,-Y -Z , or-X -Y -Z , wherein
X" is-O-; Y" is -[C(R15^]1n-, -C2-C6 alkenyl, C3-C8 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the aryl, heteroaryl, cycloalkyl, or heterocyclyl is optionally substituted with at least one group which is each independently Z' ' ;
Z" is -H, -CN, halogen, -OR11, -C(O)R11, -C(O)OR11, -C(O)N(RU)2, -N(R11^, -N3, -SO2R11, -S(O)2N(Rπ)2, -C(O)N(Rn)N(Rn)2j - N(Rπ)C(O)N(Rπ)2,
-OC(O)-OR11, -C(O)N(R11XOR11), -OC(O)-R11, -OC(O)-N(R1 \ or -N(Rn)COORn; each R10 is independently -R11, -C(O)R11, -CO2R11, or -SO2R11; each R11 is independently -hydrogen, C2-C6 alkenyl, C2-C6 alkynyl, (C3-C8 cycloalkenyl)-Ci-C6 alkyl-, (C3-C8 cycloalkyl)-C2-C6 alkenyl-, -N(R12^, -Ci-C6 alkyl, -C1-C6 haloalkyl, -C3-C8 cycloalkyl, -(C1- C6)alkyl-(C3-C8)cycloalkyl, aryl, -(Ci-C6)alkyl-aryl, heteroaryl, -(Ci-C6)alkyl-heteroaryl, heterocyclyl, or -(CrC6)alkyl-heterocyclcyl, wherein any of R11 is optionally substituted with one or more radicals of R12; each R12 is independently hydrogen, halogen, Ci-Cehaloalkyl, C1-C6 alkyl, Ci-C6 alkoxy, (C0-C6 alkyl)CO(0R13); C0-C6 alkylOR13, C0-C6 alkylCOR13, C0-C6 alkylSO2R13, C0-C6 alkylCN, C0-C6 alkylCON(R13)2, C0-C6 alkylCONR13OR13, C0-C6 alkylSO2N(R13)2, C0-C6 alkylSR13, C0-C6 haloalkylOR13, aryloxy, aralkyloxy, aryloxyalkyl, Co-C6alkoxyaryl, aryl C0-C6 alkylcarboxy, C0-C6 alkylNR13SO2 R13, -C0-C6 alkylN(R13)2, or OC0-C6 alkylCOOR13; each R13 is independently hydrogen, Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, (C3-C8 cycloalkyl)-CrC6 alkyl-, (C3-C8 cycloalkenyl)-Ci-C6 alkyl-, or (C3-C8 cycloalkyl)-C2-C6 alkenyl-; each R14 is independently Ci-C6 alkyl, CrC6 alkoxy, halogen, CrC6 haloalkyl, C0-C6 alkylCONQR.11^, C0-C6 alkylCOM^OR11, C0-C6 alkylOR11, or C0-C6 alkylCOOR11; G is a group of the formula,
Figure imgf000524_0001
wherein J is aryl, heteroaryl, or absent; Hal is halogen; each R41 is independently halogen, nitro, C1-C6 alkyl-heterocyclyl, -C1-C6 alkyl-heteroaryl,
-C1-C6 alkyl-aryl, -M", -E"-M", or -D"-E"-M", wherein D" is -O-;
E" is -[C(R15)2]m- or C3-C8 cycloalkyl;
M" is -Ci-C6alkyl, -Q-Cehaloalkyl, -COR11, -COOR11, -C0N(Rn)2, -ON, -OR11, -OCON(RU)2, -OCO2-R11, -N3, -NR11COR11, -NR11SO2R11, -N(RU)2, -NR11COOR11,
-SO2R11, -SO2NR11COR11, -SO2N(Rπ)2, or -SR11, wherein each R41 is optionally substituted with one or more R4*1, wherein each R43 is independently halogen, aryloxy, aralkyloxy, aryloxyalkyl, -C1-C6 alkyl-aryl, C1-C6 alkoxyaryl, aryl C0-C6 alkylcarboxy, -M', -E'-M', or -D'-E'-M' D' is -O-;
E' is -[C(R15)2]m- or C3-C8 cycloalkyl;
M' is -Q-Cealkyl, -Ci-Qfraloalkyl, COR11, -C0N(Rπ)2, -N(R1 ^COOR11, -N(RU)2, COOR11, C=N, OR11, -NR11COR11, NR11SO2R11, SO2R11, SO2N(R11^ Or SR11J aUd q' is 0, 1, 2, 3, or 4, and provided that,
(i) if the compound is defined by formula XXDCa, then
(a) R1 is not 4-(NH2SO2)phenyl, 4-(CH3SO2)phenyl, or
4-(CH2F SO2)phenyl; (b) if R1 is 4-fluorophenyl, then G is not
4-[(H2NS(=O)2-]phenyl- (c) R2 is not 4-hydroxyphenyl; (ii) if the compound is defined by formula XXKb, then
(a) R2 is not 4-(NH2SO2)phenyl, 4-(CH3SO2)phenyl, or 4-(CH2FSO2)phenyl
(b) J isnotpyridyl; (c) R1 is not 4-hydroxyphenyl; (ϋi) if the compound is defined by formula XXEXc, then
(a) R2 is not 4-(NH2SO2)phenyl, 4-(CH3SO2)phenyl, or
4-(CH2FSO2)phenyl (b) Jisnotpyridyl;
(iv) if the compound is defined by formula XXEXd, then
(a) if L1 is a bond, then R1 is not thienyl or 5-methylthienyl;
(b) if G is 4-fluorophenyl, then R1 is not 4-[(H2NS(=O)2-]phenyl-
(c) R1 is not 4-Me-phenyl
155. A compound according to claim 154 which is one ofthe species listed in Table 2.
156. A compound according to claim 1 , wherein: R1 is -L^R5, wherein
L1 is a bond, L5, L6, -L5-L6-L5-, or-L6-L5-L6-, wherein each L5 is independently -{C(R15)2]m-, wherein mis O, 1, 2, 3, or 4; and each R15 is independently hydrogen, halogen, (CrC6)alkyl, or (CrC6)haloalkyl; and L6 is -CO-, -SO2-, -O-, -CON(R11)-, -Cs-Qcycloalkyl-, or -heterocyclyl-, wherein the cycloalkyl, or heterocyclyl is optionally substituted with one or more R14; and R5 is aryl, heterocyclyl, heteroaryl, -C, or -B-C, wherein
B is -[C(R15)2]m- or -Qj-Cecycloalkyl-; and C is halogen, -CrQalkyl, or -Q-Cehaloalkyl; wherein R5 is optionally substituted with one or more R5a, wherein each R5a is independently halogen, nitro, heteroaryl, heterocyclyl, C2-C6 alkenyL, C2-C6 alkynyl, (C3-C8 qycloalkyl>CrC6 alkyl-, (C3-C8 cycloalkenyl>CrC6 alkyl-, (C3-C8 cycloalkyl)- C2-C6 alkenyl-; aryl, arylalkyl, aryloxy, aryloxyaryl, arylC1-6 alkoxy, Ci-C6 alkyl, C1-C6 haloalkyl, C3-C6cycloalkyl, SO2R11, OR11, SR11, N3, SO2R11, COR11, SO2N(Rn)2,
SO2NR11COR11, ON, C(O)OR11, CON(RU)2, C0N(Rπ)0Rn OCON(R11)^ NR11COR11,NR11CON(R11)2,NR11COOR11,orN(R11)2, wherein each R5a is optionally substituted with one or more groups which independently are -halogen, -C1-C6 alkyl, aryloxy C0-6 alkylSO2Rπ, C0-O alkylCOOR11, C0^ alkoxyaiyl, -C1-C6 haloalkyl, -SO2R11, -OR11, -SR11, -N3, -SO2R11, -COR11, -SO2N(Rπ)2, -SO2NR11COR11, -G=N, -C(O)OR11, -CON(Rπ)2, .C0N(Ru)0Rn, -OCON(R")^ -NR11COR11, -NR11CON(R1 \ -NR11COOR11, or -N(Rπ)2; R2 is-L3-R7, wherein
L3 is a bond; and
R7 is, halogen, aryl, heteroaryl, heterocyclyl, -Z, or -Y-Z, wherein Yis -[C(R15)2]m- or -Qs-Qcycloalkyl; and
Z is -H, halogen, -OR11, -Q=O)R11, -C(=O)ORn, -QO)N(Rπ)2, -N(Rπ)2, -C(=N-0H)Rπ, -C(=S)N(R11)2, -CN, -S(O)2N(R1 \, -C(O)N(R1 ^N(R11K or
-QK))N(R11XOR11); wherein R7 is optionally substituted with one or more R7a, wherein R7a is halogen -Z', -Y'-Z', or-X'-Y'-Z', wherein
X' is-O-; Y' is -[C(R15)2]m- or -Gj-Qcycloalkyl; and
Z' is -H, halogen, -OR11, -SR11, -S(O)2R11, -C(O)R11, -C(O)OR11, -C(O)N(Rπ)2, -N(Rn)2, -N(Rπ)C(O)Rπ, -CN, -S(O)2N(R11^, - -C(O)N(R11XOR11), or -N^^O^R11;
R21 and R3 are each independently hydrogen, halogen, C1-QaIlCyI, or Q-Cδhaloalkyl; and G is a group of the formula,
Figure imgf000526_0001
, wherein J is aryl or heteroaryl; K is aryl or heteroaryl; each R4 and R41 are independently halogen, aryloxy, aralkyloxy, aryloxyalkyl, arylCQ-C6 alkylcarboxy, aryl, heteroaryl, heterocyclyl, heteroaryloxy, heterocyclyloxy, -M, -E-M, or -
D-E-M, wherein D isO-;
E is -[C(R15)2]m- or -Q-Qcycloalkyl; and
M is -Q-Qalkyl, -Ci-Cehaloalkyl, -COR11, -COOR11, -CON(Rπ)2, -ON, -OR11, -OCON(Rπ)2, -NR11COR11, -NR11SO2R11, -N(Rπ)2, -NR11COOR11, -SOR11, -SO2R11,
-SO2NR11COR11, -SO2N(Rπ)2, or -SR11, L2 is a bond; q is 1, 2, or 3; and q' is 0, 1, 2, or 3; each R10 is independently -R11, -C(=O)Rπ, -CO2R11, or -SO2R11; each R11 is independently -hydrogen, -C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, (C3-C8 cycloalkyl>CrC6 alkyl-, (C3-C8 cycloalkenylKVCδ alkyl-, or (C3-C8 cycloalkyl>C2-C6 alkenyl-; C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, (C3-C8 cycloalkyl)-CrC6 alkyl-, (C3-C8 cycloalkenyl>CrC6 alkyl-, (C3-C8 cycloalkyl>C2-C6 alkenyl-, -C3-C8 cycloalkyl, -C1-C6 haloalkyl, -N(R12)2, aryl, -(Q-QOalkyl-aryl, heteroaryl, -(CrC^alkyl-heteroaryl, heterocyclyl, or -(C]-C6)alkyl-heterocycryl, wherein any of R11 is optionally substituted with one or more radicals of R12; each R12 is independently halogen, Q-C6alkylN(R13)2, Ci-Qshaloalkyl, C1-C6 alkyl, C1-C6 alkoxy, (C0-C6 alkyl)C=O(OR13); C0-C6 alkylOR13, C0-C6 alkylCOR13, C0-C6 alkylSO2R13, C0-C6 alkylCON(R13)2, C0-C6 alkylCONR13OR13, C0-C6 alkylSO2N(R13)2, C0-C6 alkylSR13, C0-C6 haloalkylOR13, aryloxy, aralkyloxy, aryloxyalkyl, Q^alkoxyaryl, arylCαe alkylcarboxy, C0-C6 alkyl, -NR13SO2 R13, or
-OCα^ alkylCOOR13; each R13 is independently hydrogen, Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, (C3-C8 cycloalkyl>CrC6 alkyl-, (C3-C8 cycloalkenyl)-CrC6 alkyl-, or (C3-C8 cycloalkyl)-C2-C6 alkenyl-; and each R14 is independently C1-C6 alkyl, C1-C6 alkoxy, halogen, C1-C6 haloalkyl, C0-C6 alkylCON(Rπ)2, C0-C6 alkylCONRnORu, C0-C6 alkylOR11, or C0-C6 alkylCOOR11. 157. A compound according to claim 1 , wherein: R1 is -L^R5, wherein
L1 is a bond, -C3-C8 cycloalkyl- or L5, wherein each L5 is independently -[C(R15)2]m-, wherein m is 0, 1, 2, or 3; and each R15 is independently hydrogen, halogen, (Q-C^alkyl, or (Q-C^haloalkyl; and R5 is aryl, heterocyclyl, heteroaryl, -C, or -B-C, wherein B is-[C(R15)2]m-, -Q-Qcycloalkyl-; and C is -CrQalkyl or -Q-Cδhaloalkyl; wherein R5 is optionally substituted with one or more R5a, wherein each R5a is independently halogen, nitro, heteroaryl, heterocyclyl, C2-C6 alkenyl, C2-C6 alkynyl, (C3-C8 cycloalkyl>CrC6 alkyl-, (C3-C8 cycloalkenyl>CrC6 alkyl-, (C3-C8 cycloalkyl> C2-C6 alkenyl-, aryl, arylalkyl, aryloxy, aryloxyaryl, arylC1-6 alkoxy, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6cycloalkyl, SO2R11, OR11, SR11, N3, SO2R11, COR11, SO2N(R11^5 SO2NR11COR11, ON, C(O)OR11, C0N(Rπ)2, C0N(Rπ)0Rπ 0C0N(Rπ)2, NR11COR11, NR11CON(R11);,, NR11COOR1V N(Rn)2, wherein each R5a is optionally substituted with one or more groups which independently are -halogen, -C1-C6 alkyl, aryloxy, Qμ$ alkylSO2Rn, Co-6 alkylCOOR11, C0^ alkoxyaryl, -C1-C6 haloalkyl, -SO2R11, -OR11, -SR11, -N3,
-SO2R11, -COR11, -SO2N(Rπ)2, -SO2NR11COR11, -ON, -C(O)OR11, -CON(RU)2, .C0N(Rn)0Rπ, -OCONfR11^ -NR11COR11, -NRπCON(Rπ)2, -NR11COOR1V -N(Rπ)2; R2 is -L3-R7, wherein L3 is a bond; and
R7 is — Z or -Y-Z, wherein
Y is -[C(R15)2]m-, or -C3-C6cycloalkyl; and
Z is -H, halogen, -OR11, -C(O)R11, -C(O)OR11, -C(O)N(R11^, -N(Rn)2, -C(=N-0H)Rπ, -C(=S)N(Rn)2, -CN, -S(O)2N(R1 \ -OC(O)-R11, or -OC(O)-N(R11^;
R21 and R3 are each independently hydrogen, halogen, C1-C6 alkyl, or C1-C6 haloalkyl; and G is a group of the formula,
Figure imgf000528_0001
j Wherein
J is aryl or heteroaryl; K is aryl or heteroaryl; each R4 and R41 are independently halogen, heteroaryl, heterocyclyl, -M, -E-M, or -D-E-M, wherein
D is-O-;
E is -[C(R15)2]m- or -QrQcycloalkyl; and M is -Q-Qalkyl, -Q-Cehaloalkyl, -COR11, -COOR11, -CON(RU)2, -G=N, -OR11, -
SOR11, -SO2R11, -SO2N(RU)2, or -SR11, L2 is a bond; q is 1, 2, or 3, and q' is 0, 1, 2 or 3, each R10 is independently -R11, -C(O)R11, -CO2R11, or -SO2R11; each R11 is independently -hydrogen, -C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, (C3-C8 cycloalkyl>CrC6 alkyl-, (C3-C8 cycloa]kenyl)-CrC6 alkyl-, (C3-C8 cycloalkyl)-C2-C6 alkenyl-, -C3-C8 cycloalkyl,
-(Ci-C6)alkyl-(C3-C8)cycloalkyl, -C1-C6 haloalkyl, -N(R12)2, aiyl, -(Q-Qalkyl-aryl, heteroaryl,
-(C1-C6)alkyl-heteroaryl, heterocyclyl, or -(CrC6)alkyl-heterocyclyl, wherein any of R11 is optionally substituted with one or more radicals of R12; each R12 is independently halogen, OR13, N(R13)2, Q-Cehaloalkyl, C1-C6 alkyl, C1-C6 alkoxy, (C0-C6 alkyl)C=O(OR13); C0-C6 alkylOR13, C0-C6 alkylCOR13, C0-C6 alkylSO2R13, C0-C6 alkylCON(R13)2, C0-C6 alkylCONR13OR13, C0-C6 alkylSO2N(R13)2, C0-C6 alkylSR13, C0-C6 haloalkylOR13, aryloxy, aralkyloxy, aryloxyalkyl, CWlkoxyaryl, arylCo^ alkylcarboxy, C0-C6 alkyl, -NR13SO2 R13, or
-OC^ alkylCOOR13; each R13 is independently hydrogen Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, (C3-C8 cycloalkyl)-Ci-C6 alkyl-,
(C3-C8 cycloalkenyl)-CrC6 alkyl-, or (C3-C8 cycloalkyl)-C2-C6 alkenyl-; each R14 is independently C1-C6 alkyl, C1-C6 alkoxy, halogen, C1-C6 haloalkyl, C0-C6 alky ICON(R11^, C0-C6 alkylCONRnORπ, C0-C6 alkylOR11, or C0-C6 alkylCOOR11.
158. The compound according to claim 7, wherein R5 is pyridyl optionally substituted with one or moreR5a.
159. The compound according to claim 158, wherein each R5a is independently -halogen, -Q-C6alkyl, -Q-Cehaloalkyl, -OR11, -COR11, -ON, -C(O)OR11, -C0N(Rπ)2, or -N(Rn)2. 160. The compound according to claim 158, wherein each R41 is independently hydrogen, halogen, -d-Cealkyl, or-Q-Cehaloalkyl.
161. The compound according to claim 158, wherein R2 is -L3-R7, wherein
L3 is a bond or -C(Rπ")2-; and
R7 is hydrogen, halogen, -Q-Qalkyl, -Q-Cehaloalkyl, -OR11", -C(=O)Rπ", -C(=O)ORπ", -C(=O)N(Rn")2, -N(Rn")2, -CN, -SO2R11", or -S^O)2N(R1 r)2, wherein each R11 is independently -H or -Q-Qalkyl.
162. The compound according to claim 158, wherein each R4 is independently halogen -CrC6alkyl, -Q-Qhaloalkyl, -COR11', -COOR11', -C0N(Rπ')2, -G=N, -OR11', -N(Rπ)2, -SO2R11', or -SO2N(R11'^, wherein each R11 is independently -hydrogen, -C1-C6 alkyl, or -C1-C6 haloalkyl. 163. A method of treating, preventing, inhibiting, or ameliorating the symptoms of a disease or disorder that is modulated or otherwise affected by nuclear receptor activity or in which nuclear receptor activity is implicated, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to part (A) of claim 1.
164. The method of claim 163 wherein the disease or disorder is hypercholesterolemia, hyperlipoproteinemia, hypertriglyceridemia, lipodystrophy, hyperglycemia, diabetes mellitus, dyslipidemia, atherosclerosis, gallstone disease, acne vulgaris, acneiform skin conditions, diabetes, Parkinson's disease, cancer, Alzheimer's disease, inflammation, immunological disorders, lipid disorders, obesity, conditions characterized by a perturbed epidermal barrier function, conditions of disturbed differentiation or excess proliferation of the epidermis or mucous membrane, or cardiovascular disorders.
165. A method of modulating nuclear receptor activity, comprising contacting the nuclear receptor with a compound according to part (A) of claim 1.
166. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable derivative thereof in a pharmaceutically acceptable carrier.
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