CN101248048A - Imidazole based LXR modulators - Google Patents

Imidazole based LXR modulators Download PDF

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CN101248048A
CN101248048A CN200680030647.2A CN200680030647A CN101248048A CN 101248048 A CN101248048 A CN 101248048A CN 200680030647 A CN200680030647 A CN 200680030647A CN 101248048 A CN101248048 A CN 101248048A
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alkyl
halogen
independently
haloalkyl
group
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CN101248048B (en
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B·B·布施
B·T·弗拉特
X-H·谷
S-P·鲁
R·马丁
R·莫汉
M·C·尼曼
E·施魏格尔
W·C·小史蒂文斯
T-L·王
Y·谢
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Exelixis Patent Co LLC
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Exelixis Inc
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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

Pyrazolyl LXR modulators
Cross Reference to Related Applications
This application claims priority from U.S. provisional patent application No. 60/694,372 filed on 27/2005 and U.S. provisional patent application No. 60/736,120 filed on 10/11/2005, both of which are incorporated herein by reference in their entirety.
Technical Field
The present 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 using these compositions to modulate the activity of liver X receptors. In particular, the invention provides pyrazole isomers and derivatives that modulate LXR activity.
Background
Nuclear receptors
Nuclear receptors are a superfamily of regulatory proteins which 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-. These proteins bind to cis-acting elements in the promoter of their target genes and regulate gene expression in response to ligands for the receptor.
Nuclear receptors can be classified according to their DNA binding properties (see, e.g., Evans, supra, and Glass (1994) endo cr. Rev.15: 391-407). For example, one class of nuclear receptors includes glucocorticoid, estrogen, androgen, luteinizing hormone, and mineralocorticoid receptors, which bind to Hormone Response Elements (HREs) in the form of homodimers and are constructed as inverted repeats (see, e.g., Glass, supra). The second class of receptors includes those activated by retinoic acid, thyroid hormone, vitamin D3, fatty acid/peroxisomal proliferators (i.e., peroxisome proliferator-activated receptors or PPAR) and ecdysone, which bind to HRE as heterodimers with the co-partner retinoid X receptor (i.e., RXR, also known as the 9-cis retinoic acid receptor; see, e.g., Levin et al (1992) Nature 355: 359-361 and Heyman et al (1992) Cell 68: 397-406).
Among nuclear receptors, RXRs are unique in that they bind to DNA in the form of homodimers and are required to bind to DNA as heterodimeric partners for many other nuclear receptors (see, e.g., Mangelsdorf et al (1995) Cell 83: 841-850). The latter receptors are referred to as the class II nuclear receptor subfamily, which includes a number of receptors identified as or associated with important regulators of gene expression.
There are three RXR Genes (see, e.g., Mangelsdorf et al (1992) Genes Dev.6: 329-344), which encode RXR α, β and γ, which are capable of heterodimerization with any class II receptor, although in vivo they appear to be preferential for different RXR subtypes by chaperone receptors (see, e.g., Chiba et al (1997) mol.cell.biol.17: 3013-3020). RXR α is the most abundant of the three RXRs in adult livers (see, e.g., Mangelsdorf et al (1992) Genes Dev.6: 329-344), suggesting that it may have a prominent role in liver function involving class II nuclear receptor modulation. See also, Wan et al (2000) mol.cell.biol.20: 4436-4444.
Orphan nuclear receptors
The nuclear receptor superfamily of regulatory proteins includes those nuclear receptors for which ligands are known and for which known ligands are absent. Nuclear receptors within the latter class are referred to as orphan nuclear receptors. The search for activators of orphan receptors has revealed previously unknown signaling pathways (see, e.g., Levin et al (1992), supra; and Heyman et al (1992), supra). For example, bile acids involved in physiological processes such as cholesterol catabolism have been reported to be ligands for farnesoid x (fxr).
Since intermediate metabolites are known to act as transcriptional regulators in bacteria and yeast, it is possible that this molecule may provide similar functions in higher organisms (see, e.g., Tomkins (1975) Science 189: 760-.
For example, one biosynthetic pathway in higher eukaryotes is the mevalonate pathway (mevalonate pathway), which leads to the synthesis of cholesterol, bile acids, porphyrins, long alcohols (dolichols), ubiquinones, carotenoids, retinoids, vitamin D, steroid hormones, and farnesylated proteins.
LXR alpha and LXR beta
LXR α is found predominantly in the liver and is found to have lower levels in kidney, intestine, spleen and adrenal tissue (see, e.g., Willy et al (1995) Gene Dev.9 (9): 1033-1045). LXR β is ubiquitous in mammals and can be found in almost all tissues examined. LXR is activated by certain naturally occurring oxidized derivatives of cholesterol (see, e.g., Lehmann et al (1997) J.biol.chem.272 (6): 3137-3140). LXR α is activated by hydroxycholesterol and promotes cholesterol metabolism (Peet et al (1998) Cell 93: 693-704). Thus, LXR appears to play a role in, for example, cholesterol metabolism (see, for example, Janowski et al (1996) Nature 383: 728-.
Nuclear receptors and diseases
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 No. WO 00/57915), osteoporosis and vitamin deficiency (see, e.g., U.S. Pat. No. 6,316,5103), hyperlipoproteinemia (see, e.g., International patent application No. WO 01/60818), hypertriglyceridemia, lipodystrophy, hyperglycemia, and diabetes (see, e.g., International patent application No. WO 01/82917), atherosclerosis and gall bladder lithiasis (see, e.g., international patent application No. WO 00/37077), skin and mucosal disorders (see, e.g., U.S. patent nos. 6,184,215 and 6,187,814, and international patent application No. WO 98/32444), acne (see, e.g., international patent application No. WO 00/49992), and tumors, parkinson's disease, and alzheimer's disease (see, e.g., international patent application No. WO 00/17334). The activity of nuclear receptors (including LXRs, FXRs and PPARs, and orphan nuclear receptors) is associated with a variety of physiological processes including, but not limited to: bile acid biosynthesis, cholesterol metabolism or catabolism, and regulation of cholesterol 7 alpha-hydroxylase gene (CYP7A1) transcription (see, e.g., Chiang et al (2000) J. biol. chem.275: 10918- Increasing transporter (ABC) binding cassette (ATP binding cassette)1) Increased expression (see, e.g., international patent application No. WO 00/78972).
Thus, there is a need for compounds, compositions and methods that modulate the activity of nuclear receptors, including LXR, FXR, PPAR, and orphan nuclear receptors. Such compounds are useful for treating, preventing, inhibiting or ameliorating one or more symptoms of a disease or disorder associated with nuclear receptor activity.
Disclosure of Invention
In one aspect, the present invention provides a compound according to formulae Ia-d below, or a pharmaceutically acceptable salt, isomer, or prodrug thereof,
they are useful as modulators of Liver X Receptor (LXR) activity, wherein R1、R2、R21、R3And G is as defined herein.
The present invention provides compounds for use in compositions and methods for modulating nuclear receptor activity. In particular, the invention provides compounds useful for modulating hepatic X receptors, LXR α and LXR β, FXR, PPAR and/or orphan nuclear receptors.
In one embodiment, the compounds provided herein are agonists of LXR. In another embodiment, the compounds provided herein are antagonists of LXR. In certain embodiments, agonists that exhibit poor potency are antagonists.
Another aspect of the invention relates to a method of treating, preventing, or ameliorating the symptoms of a disease or disorder modulated by or otherwise affected by or associated with nuclear receptor activity, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula Ia, Ib, Ic, or Id, or a pharmaceutically acceptable derivative thereof.
Another aspect of the invention relates to a method of lowering cholesterol levels in a subject in need thereof comprising administering an effective cholesterol level lowering amount of a compound of formula Ia, Ib, Ic or Id or a pharmaceutically acceptable derivative thereof.
Another aspect of the invention relates to a method of treating, preventing, inhibiting or ameliorating one or more symptoms of a disease or disorder affected by cholesterol, triglyceride or bile acid levels, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula Ia, Ib, Ic or Id or a pharmaceutically acceptable derivative thereof.
Another aspect of the invention relates to a method of modulating the activity of a nuclear receptor comprising contacting the nuclear receptor with a compound of formula Ia, Ib, Ic or Id, or a pharmaceutically acceptable derivative thereof.
Another aspect of the invention relates to a method of modulating cholesterol metabolism comprising administering an amount of a compound of formula Ia, Ib, Ic or Id, or a pharmaceutically acceptable derivative thereof, effective to modulate cholesterol levels.
Another aspect of the invention relates to a method of treating, preventing, inhibiting or ameliorating one or more symptoms of hypocholesterolemia in a subject in need thereof, the method comprising administering a therapeutically effective amount of a compound of formula Ia, Ib, Ic, or Id, or a pharmaceutically acceptable derivative thereof.
Another aspect of the invention relates to a method of increasing cholesterol efflux from a cell in a subject comprising administering a compound of formula Ia, Ib, Ic or Id, or a pharmaceutically acceptable derivative thereof, in an amount effective to increase cholesterol efflux.
Another aspect of the invention relates to increasing ATP-binding cassette (ABC) in cells of a subject1) A method of expression comprising administering an amount of a compound of formula Ia, Ib, Ic or Id, or a pharmaceutically acceptable derivative thereof, effective to increase ABC1 expression.
Another aspect of the invention relates to an in vitro method of altering the activity of a nuclear receptor comprising contacting the nuclear receptor with a compound of formula Ia, Ib, Ic or Id, or a pharmaceutically acceptable derivative thereof.
Another aspect of the invention relates to a method of lowering cholesterol levels in a subject in need thereof comprising administering an effective cholesterol level lowering amount of a compound of formula Ia, Ib, Ic or Id or a pharmaceutically acceptable derivative thereof.
Another aspect of the invention relates to a pharmaceutical composition comprising a pharmaceutically acceptable carrier, excipient and/or diluent and a compound of formula Ia, Ib, Ic or Id.
Another aspect of the invention relates to the modulation of cholesterol transport and inflammatory signaling pathways (signaling pathways) associated with the pathology of human diseases including atherosclerosis and related diseases such as myocardial infarction and ischemic stroke in a subject in need thereof comprising administering an amount of a compound of formula Ia, Ib, Ic or Id, or a pharmaceutically acceptable derivative thereof, effective to modulate cholesterol transport and inflammatory signaling pathways.
Another aspect of the present invention relates to the treatment of metabolic syndrome including a range of metabolic dysfunctions of the body including obesity, hypertension and insulin resistance and diabetes, in a subject in need thereof, including the treatment of diseases caused by metabolic and immune impairment including atherosclerosis and diabetes and autoimmune dysfunctions and autoimmune diseases, comprising administering a therapeutically effective amount of a compound of formula Ia, Ib, Ic or Id or a pharmaceutically acceptable derivative thereof.
Detailed Description
In a first embodiment, the present invention provides a compound according to one of the following structural formulae or a pharmaceutically acceptable salt, isomer or prodrug thereof:
wherein,
(A)R1is-L1-R5Wherein
L1Is a chemical bond, L5、L6、-L5-L6-L5-, or-L6-L5-L6-, wherein
Each L5Independently is- [ C (R)15)2]m-, wherein
Each R15Independently hydrogen, halogen, (C)1-C6) Alkyl, (C)3-C6) Cycloalkyl or (C)1-C6) A haloalkyl group;
each L6Independently is-C (R)11)2-、-C(R11)2C(R11)2-、-C(R11)＝C(R11)-、-C(R11)2O-、-C(R11)2NR11-、-C≡C-、-O-、-S-、-NR11-、-N(R10)CO-、-N(R10)CO2-、-CON(R10)-、-CO-、-CS-、-CO2-、-OC(＝O)-、-OC(＝O)N(R10)-、-CONR11N(R11)2-、-CONR11-、-OCONR11-、-SO2-、-N(R10)SO2-、-SO2N(R10)-、-NR10CONR10-、-NR10CSNR10-、-C(＝NR11)-、-C(＝NOR11)-、-C(＝NN(R11)2) -; aryl radical, C3-C8Cycloalkyl, ring C3-8Haloalkyl, heteroaryl, heterocyclyl, wherein said aryl, cycloalkyl, ring C3-8Haloalkyl, heteroarylOr heterocyclyl is unsubstituted or optionally substituted by one or more R14Substituted by groups;
or L1Is C2-6Alkanediyl chains wherein said alkanediyl chains are uninterrupted or optionally-C (R)11)2-、-C(R11)2C(R11)2-、-C(R11)＝C(R11)-、-C(R11)2O-、-C(R11)2NR11-、-C≡C-、-O-、-S-、-N(R10)CO-、-N(R10)CO2-、-CON(R10)-、-CO-、-CO2-、-OC(＝O)-、-OC(＝O)N(R10)-、-SO2-、-N(R10)SO2-, or-SO2N(R10) -is interrupted, and R5Is aryl, heterocyclyl, heteroaryl, C2-C6Alkenyl radical, C2-C6Alkynyl, (C)3-C8Cycloalkyl) -C1-C6Alkyl-, (C)3-C8Cycloalkenyl) -C1-C6Alkyl-, (C)3-C8Cycloalkyl) -C2-C6Alkenyl-, C3-C8Cycloalkyl, -C, -B-C, or-A-B-C, wherein
A is-O-;
b is- [ C (R)15)2]m-or C3-C8A cycloalkyl group;
c is C1-C6Alkyl radical, C1-C6Halogenated alkyl, SO2R11、SR11、SO2N(R11)2、SO2NR11COR11、C≡N、C(O)OR11、CON(R11)2Or N (R)11)2；
Wherein R is5Unsubstituted or optionally substituted by one or more R 5aThe substitution is carried out by the following steps,
wherein each R5aIndependently is C1-C6Alkyl radical, C1-C6Haloalkyl, C2-C6Alkenyl radical, C2-C6Alkynyl, (C)3-C8Cycloalkyl) -C1-C6Alkyl-, (C)3-C8Cycloalkenyl) -C1-C6Alkyl-, (C)3-C8Cycloalkyl) -C2-C6Alkenyl-, halogen, nitro, heterocyclyloxy, aryl, aryloxy, arylalkyl, aryloxyaryl, aryl C1-C6Alkoxy, -C ', -B' -C ', or-A' -B '-C',
wherein
A' is-O-;
b' is- [ C (R)15)2]m-or-C3-C8Cycloalkyl-;
c' is-H, halogen, -SO2R11、-OR11、-SR11、-N3、-COR11、-SO2N(R11)2、-SO2NR11COR11、-C≡N、-C(O)OR11、-OC(＝O)R11、-CON(R11)2、-CON(R11)OR11、-OCON(R11)2、-NR11COR11、-NR11CON(R11)2、-NR11COOR11、-N(R11)2Aryl, heteroaryl, or heterocyclyl;
wherein each R5aIs unsubstituted or optionally substituted by one or more groups which are independently C2-C6Alkenyl radical, C2-C6Alkynyl, (C)3-C8Cycloalkyl) -C1-C6Alkyl-, (C)3-C8Cycloalkenyl) -C1-C6Alkyl-, (C)3-C8Cycloalkyl) -C2-C6Alkenyl-, C0-C6Alkoxyaryl radical, C1-C6Alkyl radical, C3-C8Cycloalkyl, aryl-C1-C6Alkyl-, heteroaryl, halogen, -C [ identical to ] N, -NO2、-COR11、-COOR11、-CON(R11)2、-SO2R11、-OR11、-SR11、-SO2R11、-SO2N(R11)2、-SO2NR11COR11、-OCON(R11)2、-NR11COR11、-NR11CON(R11)2、-NR11COOR11or-N (R)11)2；
R2And R21is-L3-R7Wherein
Each L3Independently is a chemical bond-V1-CH2)n-V1-, or- (CH)2)m-V1-CH2)n-, wherein
n is 0 to 6; and is
Each V1Independently is-C (R)11)2-、-C(R11)2C(R11)2-、-C(R11)＝C(R11)-、-C(R11)2O-、-C(R11)2NR11-、-C≡C-、-O-、-S-、-NR7-、-N(R10)CO-、-N(R10)CO2-、-OCO-、-CO-、-CS-、-CONR10-、-C(＝N)(R11)-、-C(＝N-OR11)-、-C[＝N-N(R11)2]、-CO2-、-OC(＝O)-、-OC(＝O)N(R10)-、-SO2-、-N(R10)SO2-、-SO2N(R10)-、-NR10CONR10-、-NR10CSNR10-、C3-C8Cycloalkyl, or C3-C8A cyclic haloalkyl group;
or each L3Independently is C2-6Alkanediyl chains wherein said alkanediyl chains are uninterrupted or optionally-C (R)11)2-、-C(R11)2C(R11)2-、-C(R11)＝C(R11)-、-C(R11)2O-、-C(R11)2NR11-、-C≡C-、-O-、-S-、-N(R10)CO-、-N(R10)CO2-、-CON(R10)-、-CO-、-CO2-、-OC(＝O)-、-OC(＝O)N(R10)-、-SO2-、-N(R10)SO2-, or-SO 2N(R10) Interrupting; and is
Each R7Independently hydrogen, halogen, nitro, cyano, aryl, heteroaryl, heterocyclyl, -C1-C6alkyl-heterocyclyl-C1-C6Alkyl-heteroaryl, -C1-C6Alkyl-aryl, -Z, -Y-Z, or-X-Y-Z, wherein
X is-O-;
y is- [ C (R)15)2]m-、-C2-C6Alkenyl, or C3-C8A cycloalkyl group;
z is-H, -CN, halogen, -OR11、-C(＝O)R11、-C(＝O)OR11、-C(＝O)N(R11)2、-N(R11)2、-CN、-N3、-SO2R11、-S(＝O)2N(R11)2、-C(＝O)N(R11)N(R11)2、-C(＝O)N(R11)(OR11)、-OC(＝O)-R11、-OC(＝O)-N(R11)2or-N (R)11)COOR11；
Wherein R is7Unsubstituted or optionally substituted by one or more R7aIs substituted in which
R7aIs halogen, C2-C6Alkenyl, -C1-C6alkyl-heterocyclyl-C1-C6Alkyl-heteroaryl, -C1-C6Alkyl-aryl, C0-C6Alkoxy heterocyclesAryl radical, C0-C6Alkoxyheterocyclyl, haloaryl, aryloxy, arylalkoxy, aryloxyalkyl, C1-C6Alkoxyaryl, aryl C0-C6Alkyl carboxyl, C (R)11)＝C(R11)-COOR11、C0-C6Alkoxyheteroaryl group, C0-C6Alkoxyheterocyclyl, aryl, heteroaryl, heterocyclyl, C3-C8Cycloalkyl, heteroaryloxy, -Z ', -Y' -Z ', or-X' -Y '-Z', wherein
X' is-O-;
y' is- [ C (R)15)2]m-or C3-C8A cycloalkyl group;
z' is-C1-C6Alkyl, -C1-C6Haloalkyl, -OR11、-SR11、-S(＝O)2R11、-C(＝O)R11、-C(＝O)OR11、-C(＝O)N(R11)2、-N(R11)2、-N(R11)C(＝O)R11、-S(＝O)2N(R11)C(＝O)R11、-CN、-S(＝O)2N(R11)2、-C(＝O)N(R11)N(R11)2、-C(＝O)N(R11)(OR11)、-OC(＝O)-R11、-OC(＝O)-OR11、-N(R11)C(＝O)O-R11or-N (R)11)S(＝O)2R11；
Wherein each R7aUnsubstituted or optionally substituted by one or more R8The substitution is carried out by the following steps,
wherein each R8Independently halogen, nitro, cyano, heteroaryl, C1-C6Alkyl radical, C1-C6Alkoxy radical, C1-C6Haloalkyl, C1-C6Haloalkyl (OR) 11)、C0-C6Alkyl OR11、C0-C6Alkyl CON (R)11)2、C0-C6Alkyl group COR11、C0-C6Alkyl group COOR11Or C0-C6Alkyl SO2R11(ii) a And wherein if two R are present on the same carbon atom7aThey may together form a cycloalkyl or heterocyclyl group; provided that
R2And R21Is not H at the same time;
R3is-L-R6Wherein
L is a bond, -X3-(CH2)n-X3-、-(CH2)m-X3-(CH2)n-, or
-(CH2)l+w-Y3-(CH2)w-, wherein
n is 0 to 6; each w is independently 0 to 5; and is
Each X3Independently is a chemical bond, -C (R)11)2-、-C(R11)2C(R11)2-、-C(R11)＝C(R11)-、-C≡C-、-CO-、-CS-、-CONR10-、-C(＝N)(R11)-、-C(＝N-OR11)-、-C[＝N-N(R11)2]、-CO2-、-SO2-, or-SO2N(R10) -; and is
Y3is-O-, -S-, -NR7-、-N(R10)CO-、-N(R10)CO2-、-OCO-、-OC(＝O)N(R10)-、-NR10CONR10-、-N(R10)SO2-, or-NR10CSNR10-；
Or L is C2-6Alkanediyl chains wherein said alkanediyl chains are uninterrupted or optionally-C (R)11)2-、-C(R11)2C(R11)2-、-C(R11)＝C(R11)-、-C(R11)2O-、-C(R11)2NR11-、-C≡C-、-O-、-S-、-N(R10)CO-、-N(R10)CO2-、-CON(R10)-、-CO-、-CO2-、-OC(＝O)-、-OC(＝O)N(R10)-、-SO2-、-N(R10)SO2-, or-SO2N(R10) Interrupting; and is
R6Is C1-C6Alkyl radical, C1-C6Haloalkyl, aryl, C3-C8Cycloalkyl, heteroaryl, heterocyclyl, -CN, -C (═ O) R11、-C(＝O)OR11、-C(＝O)N(R11)2、-N(R11)2、-SO2R11、-S(＝O)2N(R11)2、-C(＝O)N(R11)N(R11)2or-C (═ O) N (R)11)(OR11) Wherein
Said aryl, heteroaryl, cycloalkyl, or heterocyclyl is unsubstituted or optionally substituted with one or more R6aIs substituted in which
Each R6aIndependently is-Z ", -Y" -Z ", or-X" -Y "-Z", wherein
X' is-O-;
y' is- [ C (R)15)2]m-、-C2-C6Alkenyl radical, C3-C8Cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein
Said aryl, heteroaryl, cycloalkyl, or heterocyclyl is unsubstituted or optionally substituted with at least one group, each of said at least one group is independently Z';
Z' is-H, -CN, halogen, -OR11、-C(＝O)R11、-C(＝O)OR11、-C(＝O)N(R11)2、-N(R11)2、-N3、-SO2R11、-S(＝O)2N(R11)2、-C(＝O)N(R11)N(R11)2、-N(R11)C(＝O)N(R11)2、-OC(＝O)-OR11、-C(＝O)N(R11)(OR11)、-OC(＝O)-R11、-OC(＝O)-N(R11)2or-N (R)11)COOR11；
Each R10Independently is-R11、-C(＝O)R11、-CO2R11or-SO2R11；
Each R11Independently is-hydrogen, C2-C6Alkenyl radical, C2-C6Alkynyl, (C)3-C8Cycloalkenyl) -C1-C6Alkyl-, (C)3-C8Cycloalkyl) -C2-C6Alkenyl-, -N (R)12)2、-C1-C6Alkyl, -C1-C6Haloalkyl, -C3-C8Cycloalkyl, - (C)1-C6) Alkyl radical- (C)3-C8) Cycloalkyl, aryl, - (C)1-C6) Alkyl-aryl, heteroaryl, - (C)1-C6) Alkyl-heteroaryl, heterocyclyl, or- (C)1-C6) An alkyl-heterocyclic group,
Wherein any one R11Unsubstituted or optionally substituted by one or more R12Substituted by groups;
each R12Independently of one another is hydrogen, halogen, C1-C6Haloalkyl, C1-C6Alkyl radical, C1-C6Alkoxy group, (C)0-C6Alkyl) C ═ O (OR)13)；C0-C6Alkyl OR13、C0-C6Alkyl group COR13、C0-C6Alkyl SO2R13、C0-C6Alkyl CN, C0-C6Alkyl CON (R)13)2、C0-C6Alkyl CONR13OR13、C0-C6Alkyl SO2N(R13)2、C0-C6Alkyl SR13、C0-C6Haloalkyl OR13Aryloxy, arylalkoxy, aryloxyalkyl, C0-C6Alkoxyaryl, aryl C0-C6Alkyl carboxyl, C0-C6Alkyl radical NR13SO2R13、-C0-C6Alkyl N (R)13)2Or OC0-C6Alkyl group COOR13；
Each R13Independently of each other is hydrogen, C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, (C)3-C8Cycloalkyl) -C1-C6Alkyl-, (C)3-C8Cycloalkenyl) -C1-C6Alkyl-, or (C)3-C8Cycloalkyl) -C2-C6Alkenyl-;
each R14Independently is C1-C6Alkyl radical, C1-C6Alkoxy, halogen, C1-C6Haloalkyl, C0-C6Alkyl CON (R)11)2、C0-C6Alkyl CONR11OR11、C0-C6Alkyl OR11Or C0-C6Alkyl group COOR 11；
G is a group of the formula:
Figure S2006800306472D00111
wherein
J is aryl, heteroaryl, or absent;
k is aryl, heteroaryl, or absent;
each R4Independently of one another is halogen, nitro, C2-C6Alkenyl radical, C3-C8Cycloalkyl, -C1-C6alkyl-heterocyclyl-C1-C6Alkyl-heteroaryl, -C1-C6Alkyl-aryl, -heterocyclyl-heteroaryl, CR11＝CR11COOR11Aryloxy, -S-aryl, arylalkoxy, aryloxyalkyl, C1-C6Alkoxyaryl, aryl C0-C6Alkyl carboxyl, C0-C6Alkoxyheteroaryl group, C0-C6Alkoxyheterocyclyl, aryl, heteroaryl, heterocyclyl, -M, -E-M, or-D-E-M,
wherein
D is-O-;
e is- [ C (R)15)2]m-or C3-C8A cycloalkyl group;
m is C1-C6Alkyl radical, C1-C6Haloalkyl, -COR11、-COOR11、-OC(＝O)R11、-CON(R11)2、-C≡N、-OR11、-OCON(R11)2、-OCO2-R11、-N3、-NR11COR11、-NR11SO2R11、-N(R11)2、-NR11COOR11、-SOR11、-SO2R11、-SO2NR11COR11、-SO2N(R11)2or-SR11，
Wherein each R4Unsubstituted or optionally substituted by one or more R4aThe substitution is carried out by the following steps,
wherein each R4aIndependently is halogen, aryloxy, arylalkoxy, aryloxyalkyl, -C1-C6Alkyl-aryl, C1-C6Alkoxyaryl, aryl C0-C6Alkylcarboxyl, -M'),-E ' -M ', or-D ' -E ' -M ',
d' is-O-;
e' is- [ C (R)15)2]m-or C3-C8A cycloalkyl group;
m' is-C1-C6Alkyl, -C1-C6Haloalkyl, COR11、-CON(R11)2、-N(R11)COOR11、-N(R11)2、COOR11、C≡N、OR11、-NR11COR11、NR11SO2R11、SO2R11、SO2N(R11)2Or SR11；
Each R41Independently of one another is halogen, nitro, C1-C6alkyl-heterocyclyl-C1-C6Alkyl-heteroaryl, -C 1-C6Alkyl-aryl, -M ", -E" -M ", or-D" -E "-M", wherein
D "is-O-;
e' is- [ C (R)15)2]m-or C3-C8A cycloalkyl group;
m' is-C1-C6Alkyl, -C1-C6Haloalkyl, -COR11、-COOR11、-CON(R11)2、-C≡N、-OR11、-OCON(R11)2、-OCO2-R11、-N3、-NR11COR11、-NR11SO2R11、-N(R11)2、-NR11COOR11、-SOR11、-SO2R11、-SO2NR11COR11、-SO2N(R11)2or-SR11，
Wherein each R41Unsubstituted or optionally substituted by one or more R4aSubstitution;
L2is a chemical bond, -CH ═ CHCOO-, -OC0-C6Alkyl COO-, - [ C (R)15)2]m-V2-[C(R15)2]n-, or-V2-[C(R15)2]m-V2-, wherein
n is 0 to 6; and is
Each V2Independently is-C (R)11)2-、-C(R11)2C(R11)2-、-C(R11)＝C(R11)-、-C(R11)2NR11-、-C(R11)2O-、-C≡C-、-O-、-S-、-N(R10)CO-、-N(R10)CO2-、-CON(R10)-、-CON(R11)-、-CON(R11)O-、-CO-、-CS-、-CO2-、-OR11N-、-OR11COO-、-OC(＝O)-、-OC(＝O)N(R10)-、-SO2-、-N(R10)SO2-、-SO2N(R10)-、-NR10CONR10-、C3-C8Cycloalkyl, -C (═ NR)11)-、-C(＝NOR11)-、-C(＝NN(R11)2)-、-NR10CSNR10-, -C (O) -heterocyclic group, or ring C3-8Haloalkyl wherein said heterocyclyl is unsubstituted OR optionally substituted with one OR more groups independently selected from-OR11、-COOR11and-CON (R)11)2；
Or L2Is C2-6Alkanediyl chains wherein said alkanediyl chains are uninterrupted or optionally-C (R)11)2-、-C(R11)2C(R11)2-、-C(R11)＝C(R11)-、-C(R11)2O-、-C(R11)2NR11-、-C(R11)2NR11-、-C≡C-、-O-、-S-、-N(R10)CO-、-N(R10)CO2-、-CON(R10)-、-CON(R11)-、-CON(R11)O-、-CO-、-CO2-、-OC(＝O)-、-OC(＝O)N(R10)-、-SO2-、-N(R10)SO2-、-SO2N(R10)-；
Aryl radical, C3-C8Cycloalkyl, heteroaryl, or heterocyclyl group is interrupted,
wherein said aryl, cycloalkyl, heteroaryl, or heterocyclyl is unsubstituted or optionally substituted with one or more R9Is substituted in which
Each R9Independently of one another is halogen, C1-C6Haloalkyl, C1-C6Alkyl radical, C1-C6Alkoxy radical, C0-C6Alkyl or C1-C6Alkyl group COOR11；
Each m is independently 0, 1, 2, 3, 4, 5, or 6;
q is 0, 1, 2, 3, 4 or 5; and is
q' is 0, 1, 2, 3, or 4,
(B) With the proviso that,
(i) if L is2Is not a bond or if K is not phenyl, q may be only 0;
(ii) said compound is not 2-methyl-5- (1-m-tolyl-3- (trifluoromethyl) -1H-pyrazol-5-yl) benzenesulfonamide;
(iii) if L is2Is a chemical bond, neither J nor K is present;
(iv) if K is absent, q is 1 and R4And L2Direct bonding;
(v) if L is2Is SO2Or SO2N(R10) Then R is5By at least one R5aSubstitution;
(vi) if the compound is defined by formula Ia, then
(a)R1Is not 4- (NH)2SO2) Phenyl, 4- (CH)3SO2) Phenyl, or 4- (CH)2FSO2) A phenyl group;
(b) if R is1Is 4-fluorophenyl, then G is not 4- [ (H)2NS(＝O)2-]Phenyl-; and is
(c)R2And R21Is not 4-hydroxyphenyl;
(vii) if the compound is defined by formula Ib
(a)R2And R3Is not 4- (NH)2SO2) Phenyl, 4- (CH)3SO2) Phenyl, or 4- (CH)2FSO2) A phenyl group; and is
(b)R1Is not 4-hydroxyphenyl;
(viii) if said compound is defined by formula Ic, then
(a)R2And R3Is not 4- (NH)2SO2) Phenyl, 4- (CH)3SO2) Phenyl, or 4- (CH)2FSO2) A phenyl group;
(b) j is not pyridyl; and is
(c) G is not 3-methoxyphenyl or 4-methoxyphenyl; and is
(ix) If said compound is defined by formula Id, then
(a) If L is1Is a chemical bond, then R1Is not thienyl or 5-methylthiophenyl;
(b) g is not 4- (NH) 2SO2) Phenyl, 4- (CH)3SO2) Phenyl, or 4- (CH)2FSO2) A phenyl group;
(c) if G is 4-fluorophenyl, R1Is not 4- [ (H)2NS(＝O)2-]Phenyl-;
(d) if J is Ph, L2Is a bond and q is 1, then K and R4Together is not 4-fluorophenyl, 3-fluorophenyl, 4-methoxyphenyl, or 5-chlorothiophenyl;
(e) if J is pyridyl, L2Is a bond and q is 1, then K and R4Together are not 4-fluorophenyl;
(f) if J is Ph, L2Is a bond and q is 2, then K and two R4Taken together are not 3-fluoro-4-methoxyphenyl; and is
(g)R1Is not 4-methyl-phenyl.
In one embodiment, the invention provides a compound according to formula Ia, Ib, Ic or Id, wherein
R1is-L1-R5Wherein
L1Is a chemical bond, L5、L6、-L5-L6-L5-, or-L6-L5-L6-, wherein
Each L5Independently is- [ C (R)15)2]m-, wherein
m is 0, 1, 2, 3, or 4; and is
Each R15Independently hydrogen, halogen, (C)1-C6) Alkyl, or (C)1-C6) A haloalkyl group; and is
L6is-CO-, -SO2-、-O-、-OCN(R11)-、-C3-C6Cycloalkyl, or-heterocyclyl-,
wherein said cycloalkyl, or heterocyclyl is unsubstituted or optionally substituted with one or more R14Substitution; and is
R5Is an aryl group, a heterocyclic group,Heteroaryl, -C, or-B-C, wherein
B is- [ C (R)15)2]m-or-C3-C6A cycloalkyl group; and is
C is halogen, -C1-C6Alkyl, or-C1-C6A haloalkyl group;
Wherein R is5Unsubstituted or optionally substituted by one or more R5aIs substituted in which
Each R5aIndependently halogen, nitro, heteroaryl, heterocyclyl, C2-C6Alkenyl radical, C2-C6Alkynyl, (C)3-C8Cycloalkyl) -C1-C6Alkyl-, (C)3-C8Cycloalkenyl) -C1-C6Alkyl-, (C)3-C8Cycloalkyl) -C2-C6Alkenyl-; aryl, arylalkyl, aryloxy, aryloxyaryl, aryl C1-C6Alkoxy radical, C1-C6Haloalkyl, C3-C6Cycloalkyl, SO2R11、OR11、SR11、N3、SO2R11、COR11、SO2N(R11)2、SO2NR11COR11、C≡N、C(O)OR11、CON(R11)2、CON(R11)OR11、OCON(R11)2、NR11COR11、NR11CON(R11)2、NR11COOR11Or N (R)11)2Wherein
Each R5aUnsubstituted or optionally substituted with one or more groups independently selected from: -halogen, -C1-C6Alkyl, alkoxy C0-6Alkyl SO2R11、C0-6Alkyl group COOR11、C0-6Alkoxyaryl, -C1-C6Haloalkyl, -SO2R11、-OR11、-SR11、-N3、-SO2R11、-COR11、-SO2N(R11)2、-SO2NR11COR11、-C≡N、-C(O)OR11、-CON(R11)2、-CON(R11)OR11、-OCON(R11)2、-NR11COR11、-NR11CON(R11)2、-NR11COOR11or-N (R)11)2；
R2is-L3-R7Wherein
L3Is a chemical bond; and is
R7Is halogen, aryl, heteroaryl, heterocyclyl, -Z, or-Y-Z, wherein
Y is- [ C (R)15)2]m-or-C3-C6A cycloalkyl group; and is
Z is-H, halogen, -OR11、-C(＝O)R11、-C(＝O)OR11、-C(＝O)N(R11)2、-N(R11)2、-C(＝N-OH)R11、-C(＝S)N(R11)2、-CN、-S(＝O)2N(R11)2、-C(＝O)N(R11)N(R11)2or-C (═ O) N (R)11)(OR11)；
Wherein R is7Unsubstituted or optionally substituted by one or more R7aIs substituted in which
R7aIs halogen, -Z ', -Y' -Z ', or-X' -Y '-Z', wherein
X' is-O-;
y' is- [ C (R)15)2]m-or-C3-C6A cycloalkyl group; and is
Z' is-H, halogen, -OR11、-SR11、-S(＝O)2R11、-C(＝O)R11、-C(＝O)OR11、-C(＝O)N(R11)2、-N(R11)2、-N(R11)C(＝O)R11、-CN、-S(＝O)2N(R11)2、-C(＝O)N(R11)(OR11) Or is
-N(R11)S(O＝)2R11；
R21And R3Each independently is hydrogen, halogen, C1-C6Alkyl or C1-C6A haloalkyl group; and is
G is a group of the formula,
Wherein
J is aryl or heteroaryl;
k is aryl or heteroaryl;
each R4And R41Independently of one another halogen, aryloxy, aralkoxy, aryloxyalkyl, aryl C0-C6Alkylcarboxyl, aryl, heteroaryl, heterocyclyl, heteroaryloxy, heterocyclyloxy, -M, -E-M, or-D-E-M, wherein
D is-O-;
e is- [ C (R)15)2]m-or-C3-C6A cycloalkyl group; and is
M is-C1-C6Alkyl, -C1-C6Haloalkyl, -COR11、-COOR11、-CON(R11)2、-C≡N、-OR11、-OCON(R11)2、-NR11COR11、-NR11SO2R11、-N(R11)2、-NR11COOR11、-SOR11、-SO2R11、-SO2NR11COR11、-SO2N(R11)2or-SR11，
L2Is a chemical bond;
q is 1, 2, or 3; and is
q' is 0, 1, 2, or 3;
each R10Independently is-R11、-C(＝O)R11、-CO2R11or-SO2R11(ii) a Each R11Independently is-hydrogen, -C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, (C)3-C8Cycloalkyl) -C1-C6Alkyl-, (C)3-C8Cycloalkenyl) -C1-C6Alkyl-, or (C)3-C8Cycloalkyl) -C2-C6Alkenyl-; c1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, (C)3-C8Cycloalkyl) -C1-C6Alkyl-, (C)3-C8Cycloalkenyl) -C1-C6Alkyl-, (C)3-C8Cycloalkyl) -C2-C6Alkenyl-, -C3-C8Cycloalkyl, -C1-C6Haloalkyl, -N (R)12)2Aryl, - (C)1-C6) Alkyl-aryl, heteroaryl, - (C)1-C6) Alkyl-heteroaryl, heterocyclyl, or- (C)1-C6) An alkyl-heterocyclic group, a heterocyclic group,
wherein any one R11Unsubstituted or optionally substituted by one or more R12Substituted by groups;
each R12Independently of one another is halogen, C0-C6Alkyl N (R)13)2、C1-C6Haloalkyl, C1-C6Alkyl radical, C1-C6Alkoxy group, (C)0-C6Alkyl) C ═ O (OR) 13)；
C0-C6Alkyl OR13、C0-C6Alkyl group COR13、C0-C6Alkyl SO2R13、C0-C6Alkyl CON (R)13)2、C0-C6Alkyl CONR13OR13、C0-C6Alkyl SO2N(R13)2、C0-C6Alkyl SR13、C0-C6Haloalkyl OR13Aryloxy group, aralkyloxy group, aryloxyalkyl group, C0-6Alkoxyaryl, aryl C0-6Alkyl carboxyl, C0-C6Alkyl, -NR13SO2R13or-OC0-6Alkyl group COOR13；
Each R13Independently of each other is hydrogen, C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, (C)3-C8Cycloalkyl) -C1-C6Alkyl-, (C)3-C8Cycloalkenyl) -C1-C6Alkyl-, or (C)3-C8Cycloalkyl) -C2-C6Alkenyl-; and is
Each R14Independently is C1-C6Alkyl radical, C1-C6Alkoxy, halogen, C1-C6Haloalkyl, C0-C6Alkyl CON (R)11)2、C0-C6Alkyl CONR11OR11、C0-C6Alkyl OR11Or C0-C6Alkyl group COOR11。
In one embodiment, the invention provides a compound according to formula Ia, Ib, Ic, or Id wherein:
R1is-L1-R5Wherein
L1Is a chemical bond, -C3-C8Cycloalkyl-, or L5Wherein
Each L5Independently is- [ C (R)15)2]m-, wherein
m is 0, 1, 2, or 3; and is
Each R15Independently hydrogen, halogen, (C)1-C6) Alkyl, or (C)1-C6) A haloalkyl group; and is
R5Is aryl, heterocyclyl, heteroaryl, -C, or-B-C, wherein
B is- [ C (R)15)2]m-or-C3-C6Cycloalkyl-; and is
C is-C1-C6Alkyl or-C1-C6A haloalkyl group;
wherein R is5Unsubstituted or optionally substituted by one or more R5aIs substituted in which
Each R5aIndependently halogen, nitro, heteroaryl, heterocyclyl, C 2-C6Alkenyl radical, C2-C6Alkynyl, (C)3-C8Cycloalkyl) -C1-C6Alkyl-, (C)3-C8Cycloalkenyl) -C1-C6Alkyl-, (C)3-C8Cycloalkyl) -C2-C6Alkenyl, aryl, arylalkyl, aryloxy, aryloxyaryl, aryl C1-6Alkoxy radical, C1-C6Alkyl radical, C1-C6Haloalkyl, C3-C6Cycloalkyl, SO2R11、OR11、SR11、N3、SO2R11、COR11、SO2N(R11)2、SO2NR11COR11、C≡N、C(O)OR11、CON(R11)2、CON(R11)OR11、OCON(R11)2、NR11COR11、NR11CON(R11)2、NR11COOR11Or N (R)11)2Wherein
Each R5aIs unsubstituted or optionally independently-halogen, -C1-C6Alkyl, aryloxy, C0-6Alkyl SO2R11、C0-6Alkyl group COOR11、C0-6Alkoxyaryl, -C1-C6Haloalkyl, -SO2R11、-OR11、-SR11、-N3、-SO2R11、-COR11、-SO2N(R11)2、-SO2NR11COR11、-C≡N、-C(O)OR11、-CON(R11)2、-CON(R11)OR11、-OCON(R11)2、-NR11COR11、-NR11CON(R11)2、-NR11COOR11or-N (R)11)2Substituted with one or more groups of (a);
R2is-L3-R7Wherein
L3Is a chemical bond; and is
R7is-Z or-Y-Z, wherein
Y is- [ C (R)15)2]m-or-C3-C6A cycloalkyl group; and is
Z is-H, halogen, -OR11、-C(＝O)R11、-C(＝O)OR11、-C(＝O)N(R11)2、-N(R11)2、-C(＝N-OH)R11、-C(＝S)N(R11)2、-CN、-S(＝O)2N(R11)2、-OC(＝O)-R11or-OC (═ O) -N (R)11)2；
R21Is hydrogen, halogen, C1-C6Alkyl, or C1-C6A haloalkyl group; and is
G is a radical of the formula
Figure S2006800306472D00181
Wherein
J is aryl or heteroaryl;
k is aryl or heteroaryl;
each R4And R41Independently is halogen, heteroaryl, heterocyclyl, -M, -E-M, or-D-E-M, wherein
D is-O-;
e is- [ C (R)15)2]m-or-C3-C6A cycloalkyl group; and is
M is-C1-C6Alkyl, -C1-C6Haloalkyl, -COR11、-COOR11、-CON(R11)2、-C≡N、-OR11、-SOR11、-SO2R11、-SO2N(R11)2or-SR11；
L2Is a chemical bond;
q is 1, 2, or 3, and
q' is 0, 1, 2 or 3,
each R10Independently is-R11、-C(＝O)R11、-CO2R11or-SO2R11；
Each R11Independently is-hydrogen, -C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, (C) 3-C8Cycloalkyl) -C1-C6Alkyl-, (C)3-C8Cycloalkenyl) -C1-C6Alkyl-, (C)3-C8Cycloalkyl) -C2-C6alkenyl-C3-C8Cycloalkyl, -C1-C6Haloalkyl, -N (R)12)2Aryl, - (C)1-C6) Alkyl-aryl, heteroaryl, - (C)1-C6) Alkyl-heteroaryl, heterocyclyl, or- (C)1-C6) An alkyl-heterocyclic group, a heterocyclic group,
wherein any one R11Unsubstituted or optionally substituted by one or more R12Substituted by groups;
each R12Independently halogen, OR13、N(R13)2、C1-C6Haloalkyl, C1-C6Alkyl radical, C1-C6Alkoxy group, (C)0-C6Alkyl) C ═ O (OR)13)；C0-C6Alkyl OR13、C0-C6Alkyl group COR13、C0-C6Alkyl SO2R13、C0-C6Alkyl CON (R)13)2、C0-C6Alkyl CONR13OR13、C0-C6Alkyl SO2N(R13)2、C0-C6Alkyl SR13、C0-C6Haloalkyl OR13Aryloxy group, aralkyloxy group, aryloxyalkyl group, C0-6Alkoxyaryl, aryl C0-6Alkyl carboxyl, C0-C6Alkyl, -NR13SO2R13or-OC0-6Alkyl group COOR13；
Each R13Independently of each other is hydrogen, C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, (C)3-C8Cycloalkyl) -C1-C6Alkyl-, (C)3-C8Cycloalkenyl) -C1-C6Alkyl-Or (C)3-C8Cycloalkyl) -C2-C6Alkenyl-;
each R14Independently is C1-C6Alkyl radical, C1-C6Alkoxy, halogen, C1-C6Haloalkyl, C0-C6Alkyl CON (R)11)2、C0-C6Alkyl CONR11OR11、C0-C6Alkyl OR11Or C0-C6Alkyl group COOR11。
In one embodiment, the invention provides a compound according to formula Ia or Id wherein:
R1is-L1-R5Wherein
L1Is a chemical bond, L5、L6、-L5-L6-L5-、-L6-L5-L6Wherein
Each L5Independently is- [ C (R) 15)2]m-, wherein
m is 0, 1, 2, 3, or 4; and is
Each R15Independently hydrogen, halogen, (C)1-C6) Alkyl, or (C)1-C6) A haloalkyl group; and is
L6is-CO-, -SO2-、-O-、-CON(R11)-、-C3-C6Cycloalkyl, or-heterocyclyl-,
wherein said cycloalkyl or heterocyclyl is optionally unsubstituted or substituted with one or more R14Substitution; and is
R5Is aryl, heterocyclyl, heteroaryl, -C, or-B-C, wherein
B is- [ C (R)15)2]m-or-C3-C6Cycloalkyl-;and is
C is halogen, -C1-C6Alkyl, or-C1-C6A haloalkyl group;
wherein R is5Unsubstituted or optionally substituted by one or more R5aIs substituted in which
Each R5aIndependently halogen, nitro, heteroaryl, heterocyclyl, C2-C6Alkenyl radical, C2-C6Alkynyl, (C)3-C8Cycloalkyl) -C1-C6Alkyl-, (C)3-C8Cycloalkenyl) -C1-C6Alkyl-, (C)3-C8Cycloalkyl) -C2-C6Alkenyl, aryl, arylalkyl, aryloxy, aryloxyaryl, aryl C1-6Alkoxy radical, C1-C6Alkyl radical, C1-C6Haloalkyl, C3-C6Cycloalkyl, SO2R11、OR11、SR11、N3、SO2R11、COR11、SO2N(R11)2、SO2NR11COR11、C≡N、C(O)OR11、CON(R11)2、CON(R11)OR11、OCON(R11)2、NR11COR11、NR11CON(R11)2、NR11COOR11Or N (R)11)2Wherein
Each R5aIs unsubstituted or optionally independently-halogen, -C1-C6Alkyl, aryloxy, C0-6Alkyl SO2R11、C0-6Alkyl group COOR11、C0-6Alkoxyaryl, -C1-C6Haloalkyl, -SO2R11、-OR11、-SR11、-N3、-SO2R11、-COR11、-SO2N(R11)2、-SO2NR11COR11、-C≡N、-C(O)OR11、-CON(R11)2、-CON(R11)OR11、-OCON(R11)2、-NR11COR11、-NR11CON(R11)2、-NR11COOR11or-N (R)11)2Substituted with one or more groups of (a);
R2is-L3-R7Wherein L is3Is a chemical bond; and is
R7Is halogen, aryl, heteroaryl, -Z, or-Y-Z, wherein
Y is- [ C (R)15)2]m-or-C3-C6A cycloalkyl group; and is
Z is-H, halogen, -OR11、-C(＝O)R11、-C(＝O)OR11、-C(＝O)N(R11)2、-N(R11)2、-C(＝N-OH)R11、-C(＝S)N(R11)2、-CN、-S(＝O)2N(R11)2、-OC(＝O)-R11or-OC (═ O) -N (R)11)2；
Wherein R is7Unsubstituted or optionally substituted by one or more R7aIs substituted in which
R7aIs halogen, -Z '-, -Y' -Z ', or-X' -Y '-Z' -, wherein
X' is-O-;
y' is- [ C (R)15)2]m-or C3-C6A cycloalkyl group; and is
Z' is-H, halogen, -OR11、-SR11、-S(＝O)2R11、-C(＝O)R11、-C(＝O)OR11、-C(＝O)N(R11)2、-N(R11)2、-N(R11)C(＝O)R11、-CN、-S(＝O)2N(R11)2、-C(＝O)N(R11)(OR11) or-N (R)11)S(O＝)2R11；
R21Is hydrogen, halogen, C1-C6Alkyl, or C1-C6A haloalkyl group; and is
G is a radical of the formula
Figure S2006800306472D00211
Wherein
J is aryl or heteroaryl;
k is aryl or heteroaryl;
each R4And R41Independently halogen, aryloxy, arylalkoxy, aryloxyalkyl, aryl C0-C6Alkylcarbonyl, aryl, heteroaryl, heterocyclyl, heteroaryloxy, heterocyclyloxy, -M, -E-M, or-D-E-M, wherein
D is-O-;
e is- [ C (R)15)2]m-or-C3-C6A cycloalkyl group; and is
M is-C1-C6Alkyl, -C1-C6Haloalkyl, -COR11、-COOR11、-CON(R11)2、-C≡N、-OR11、-OCON(R11)2、-NR11COR11、-NR11SO2R11、-N(R11)2、-NR11COOR11、-SOR11、-SO2R11、-SO2NR11COR11、-SO2N(R11)2or-SR11；
L2Is a chemical bond;
q is 1, 2, or 3, and
q' is 0, 1, 2 or 3,
each R10Independently is-R11、-C(＝O)R11、-CO2R11or-SO2R11；
Each R11Independently is-hydrogen, -C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, (C)3-C8Cycloalkyl) -C1-C6Alkyl-, (C)3-C8Cycloalkenyl) -C1-C6Alkyl-, (C)3-C8Cycloalkyl) -C2-C6Alkenyl-, -C3-C8Cycloalkyl, -C1-C6Haloalkyl, -N (R)12)2Aryl, - (C)1-C6) Alkyl-aryl, heteroaryl, - (C) 1-C6) Alkyl-heteroaryl, heterocyclyl, or- (C)1-C6) An alkyl-heterocyclic group, a heterocyclic group,
wherein any one R11Unsubstituted or optionally substituted by one or more R12Substituted by groups;
each R12Independently of one another is halogen, C0-C6Alkyl N (R)13)2、C1-C6Haloalkyl, C1-C6Alkyl radical, C1-C6Alkoxy group, (C)0-C6Alkyl) C ═ O (OR)13)；
C0-C6Alkyl OR13、C0-C6Alkyl group COR13、C0-C6Alkyl SO2R13、C0-C6Alkyl CON (R)13)2、C0-C6Alkyl CONR13OR13、C0-C6Alkyl SO2N(R13)2、C0-C6Alkyl SR13、C0-C6Haloalkyl OR13Aryloxy, aralkylAryloxy, aryloxyalkyl, C0-6Alkoxyaryl, aryl C0-6Alkyl carboxyl, C0-C6Alkyl, -NR13SO2R13or-OC0-6Alkyl group COOR13；
Each R13Independently of each other is hydrogen, C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, (C)3-C8Cycloalkyl) -C1-C6Alkyl-, (C)3-C8Cycloalkenyl) -C1-C6Alkyl-, or (C)3-C8Cycloalkyl) -C2-C6Alkenyl-; and is
Each R14Independently is C1-C6Alkyl radical, C1-C6Alkoxy, halogen, C1-C6Haloalkyl, C0-C6Alkyl CON (R)11)2、C0-C6Alkyl CONR11OR11、C0-C6Alkyl OR11Or C0-C6Alkyl group COOR11。
In one embodiment, the invention provides a compound according to formula Ia or Id wherein:
R1is-L1-R5Wherein:
L1is a chemical bond, -C3-C8Cycloalkyl-, or L5Wherein
Each L5Independently is- [ C (R)15)2]m-, wherein
m is 0, 1, 2, or 3; and is
Each R15Independently hydrogen, halogen, (C)1-C6) Alkyl, or (C)1-C6) A haloalkyl group; and is
R5Is aryl, heterocyclyl, heteroaryl A radical, -C, or-B-C, wherein
B is- [ C (R)15)2]m-or-C3-C6Cycloalkyl-; and is
C is-C1-C6Alkyl or-C1-C6A haloalkyl group;
wherein R is5Unsubstituted or optionally substituted by one or more R5aIs substituted in which
Each R5aIndependently halogen, nitro, heteroaryl, heterocyclyl, C2-C6Alkenyl radical, C2-C6Alkynyl, (C)3-C8Cycloalkyl) -C1-C6Alkyl-, (C)3-C8Cycloalkenyl) -C1-C6Alkyl-, (C)3-C8Cycloalkyl) -C2-C6Alkenyl, aryl, arylalkyl, aryloxy, aryloxyaryl, aryl C1-6Alkoxy radical, C1-C6Alkyl radical, C1-C6Haloalkyl, C3-C6Cycloalkyl, SO2R11、OR11、SR11、N3、SO2R11、COR11、SO2N(R11)2、SO2NR11COR11、C≡N、C(O)OR11、CON(R11)2、CON(R11)OR11、OCON(R11)2、NR11COR11、NR11CON(R11)2、NR11COOR11Or N (R)11)2Wherein
Each R5aIs unsubstituted or optionally independently-halogen, -C1-C6Alkyl, aryloxy, C0-6Alkyl SO2R11、C0-6Alkyl group COOR11、C0-6Alkoxyaryl, -C1-C6Haloalkyl, -SO2R11、-OR11、-SR11、-N3、-SO2R11、-COR11、-SO2N(R11)2、-SO2NR11COR11、-C≡N、-C(O)OR11、-CON(R11)2、-CON(R11)OR11、-OCON(R11)2、-NR11COR11、-NR11CON(R11)2、-NR11COOR11or-N (R)11)2Substituted with one or more groups of (a);
R2is-L3-R7Wherein
L3Is a chemical bond; and is
R7is-Z or-Y-Z, wherein
Y is- [ C (R)15)2]m-or-C3-C6A cycloalkyl group; and is
Z is-H, halogen, -OR11、-C(＝O)R11、-C(＝O)OR11、-C(＝O)N(R11)2、-N(R11)2、-C(＝N-OH)R11、-C(＝S)N(R11)2、-CN、-S(＝O)2N(R11)2、-OC(＝O)-R11or-OC (═ O) -N (R)11)2；
R21Is hydrogen, halogen, C1-C6Alkyl, or C1-C6A haloalkyl group; and is
G is a radical of the formula
Figure S2006800306472D00231
Wherein
J is aryl or heteroaryl;
k is aryl or heteroaryl;
each R4And R41Independently is halogen, heteroaryl, heterocyclyl, -M, -E-M, or-D-E-M, wherein
D is-O-;
e is- [ C (R) 15)2]m-or-C3-C6A cycloalkyl group; and is
M is-C1-C6Alkyl, -C1-C6Haloalkyl, -COR11、-COOR11、-CON(R11)2、-C≡N、-OR11、-SOR11、-SO2R11、-SO2N(R11)2or-SR11；
L2Is a chemical bond;
q is 1, 2, or 3, and
q' is 0, 1, 2 or 3,
each R10Independently is-R11、-C(＝O)R11、-CO2R11or-SO2R11(ii) a Each R11Independently is-hydrogen, -C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, (C)3-C8Cycloalkyl) -C1-C6Alkyl-, (C)3-C8Cycloalkenyl) -C1-C6Alkyl-, (C)3-C8Cycloalkyl) -C2-C6alkenyl-C3-C8Cycloalkyl, -C1-C6Haloalkyl, -N (R)12)2Aryl, - (C)1-C6) Alkyl-aryl, heteroaryl, - (C)1-C6) Alkyl-heteroaryl, heterocyclyl, or- (C)1-C6) An alkyl-heterocyclic group, a heterocyclic group,
wherein any one R11Unsubstituted or optionally substituted by one or more R12Substituted by groups;
each R12Independent of each otherIs halogen, OR13、N(R13)2、C1-C6Haloalkyl, C1-C6Alkyl radical, C1-C6Alkoxy group, (C)0-C6Alkyl) C ═ O (OR)13)；C0-C6Alkyl OR13、C0-C6Alkyl group COR13、C0-C6Alkyl SO2R13、C0-C6Alkyl CON (R)13)2、C0-C6Alkyl CONR13OR13、C0-C6Alkyl SO2N(R13)2、C0-C6Alkyl SR13、C0-C6Haloalkyl OR13Aryloxy group, aralkyloxy group, aryloxyalkyl group, C0-6Alkoxyaryl, aryl C0-6Alkyl carboxyl, C0-C6Alkyl, -NR13SO2R13or-OC0-6Alkyl group COOR13；
Each R13Independently of each other is hydrogen, C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, (C)3-C8Cycloalkyl) -C1-C6Alkyl-, (C)3-C8Cycloalkenyl) -C1-C6Alkyl-, or (C)3-C8Cycloalkyl) -C2-C6Alkenyl-;
each R14Independently is C1-C6Alkyl radical, C1-C6Alkoxy, halogen, C 1-C6Haloalkyl, C0-C6Alkyl CON (R)11)2、C0-C6Alkyl CONR11OR11、C0-C6Alkyl OR11Or C0-C6Alkyl group COOR11。
In another embodiment, the invention provides a compound according to formula Ia-d, wherein
R1is-L5-R5or-L6-R5Wherein
L5Is- [ C (R)15)2]m-；
L6Is C3-C8Cycloalkyl, ring C3-8Haloalkyl, or heterocyclyl, wherein said cycloalkyl, ring C3-8Haloalkyl, or heterocyclyl unsubstituted or optionally substituted with one or more R14Substituted by groups;
R5is aryl, heterocyclyl, or heteroaryl, wherein R5Unsubstituted or optionally substituted by one or more R5aIs substituted in which
Each R5aIndependently of one another is halogen, C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, (C)3-C8Cycloalkyl) -C1-C6Alkyl-, (C)3-C8Cycloalkenyl) -C1-C6Alkyl-, (C)3-C8Cycloalkyl) -C2-C6Alkenyl-, nitro-, heterocyclyloxy-, aryl-, aryloxy-, arylalkyl-, aryloxyaryl-, aryl C1-C6Alkoxy, -C ', -B' -C ', or-A' -B '-C', wherein
A' is-O-;
b' is- [ C (R)15)2]m-or-C3-C8Cycloalkyl-;
c' is-H, halogen, -SO2R11、-OR11、-SR11、-N3、-COR11、-SO2N(R11)2、-SO2NR11COR11、-C≡N、-C(O)OR11、-OC(＝O)R11、-CON(R11)2、-CON(R11)OR11、-OCON(R11)2、-NR11COR11、-NR11CON(R11)2、-NR11COOR11、-N(R11)2Aryl, heteroaryl, or heterocyclyl.
In another embodiment, the invention provides a compound according to formula Ia-d, wherein
R1is-L5-R5or-L6-R5Wherein
L5Is- [ C (R)15)2]m-；
L6Is C3-C8Cycloalkyl, ring C3-8Haloalkyl, or heterocyclyl, wherein said cycloalkyl, ring C 3-8Haloalkyl, or heterocyclyl unsubstituted or optionally substituted with one or more R14Substituted by groups;
R5is aryl, heterocyclyl, or heteroaryl, wherein R5Unsubstituted or optionally substituted by one or more R5aIs substituted in which
Each R5aIndependently of one another is halogen, C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, (C)3-C8Cycloalkyl) -C1-C6Alkyl-, (C)3-C8Cycloalkenyl) -C1-C6Alkyl-, (C)3-C8Cycloalkyl) -C2-C6Alkenyl-, nitro-, heterocyclyloxy-, aryl-, aryloxy-, arylalkyl-, aryloxyaryl-, aryl C1-C6Alkoxy, -C ', -B' -C ', or-A' -B '-C', wherein
A' is-O-;
b' is- [ C (R)15)2]m-or-C3-C8Cycloalkyl-;
c' is-H, halogen, -SO2R11、-OR11、-SR11、-N3、-COR11、-SO2N(R11)2、-SO2NR11COR11、-C≡N、-C(O)OR11、-OC(＝O)R11、-CON(R11)2、-CON(R11)OR11、-OCON(R11)2、-NR11COR11、-NR11CON(R11)2、-NR11COOR11、-N(R11)2Aryl, heteroaryl, or heterocyclyl; and is
J is aryl or heteroaryl; and is
K is aryl or heteroaryl.
In another embodiment, the invention provides a compound according to formula Ia-d, wherein
R1is-L5-R5or-L6-R5Wherein
L5Is- [ C (R)15)2]m-；
L6Is C3-C8Cycloalkyl, ring C3-8Haloalkyl, or heterocyclyl, wherein said cycloalkyl, ring C3-8Haloalkyl, or heterocyclyl unsubstituted or optionally substituted with one or more R14Substituted by groups;
R5is aryl, heterocyclyl, or heteroaryl, wherein R5Unsubstituted or optionally substituted by one or more R 5aIs substituted in which
Each R5aIndependently of one another is halogen, C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, (C)3-C8Cycloalkyl) -C1-C6Alkyl-, (C)3-C8Cycloalkenyl) -C1-C6Alkyl-, (C)3-C8Cycloalkyl) -C2-C6Alkenyl-, nitro-, heterocyclyloxy-, aryl-, aryloxy-, arylalkyl-, aryloxyaryl-, aryl C1-C6Alkoxy, -C ', -B' -C ', or-A' -B '-C', wherein
A' is-O-;
b' is- [ C (R)15)2]m-or-C3-C8Cycloalkyl-;
c' is-H, halogen, -SO2R11、-OR11、-SR11、-N3、-COR11、-SO2N(R11)2、-SO2NR11COR11、-C≡N、-C(O)OR11、-OC(＝O)R11、-CON(R11)2、-CON(R11)OR11、-OCON(R11)2、-NR11COR11、-NR11CON(R11)2、-NR11COOR11、-N(R11)2Aryl, heteroaryl, or heterocyclyl;
j is aryl or heteroaryl;
k is aryl or heteroaryl;
R2is-L3-R7Wherein
L3Is a chemical bond; and is
R7Is hydrogen, -Z, or-Y-Z, wherein
Y is- [ C (R)15)2]m-or-C2-C6An alkenyl group;
z is-H, halogen, -OR11、-C(＝O)R11、-C(＝O)OR11、-C(＝O)N(R11)2、-N(R11)2、-CN、-SO2R11or-S (═ O)2N(R11)2；
And is
R21Is hydrogen, halogen, C1-C6Alkyl, orC1-C6A haloalkyl group.
In another embodiment, the invention provides a compound according to formulae Ia and Id.
In another embodiment, the invention provides a compound according to formulae Ia and Id, where
R1is-L5-R5or-L6-R5Wherein
L5Is- [ C (R)15)2]m-；
L6Is C3-C8Cycloalkyl, ring C3-8Haloalkyl, or heterocyclyl, wherein said cycloalkyl, ring C3-8Haloalkyl, or heterocyclyl unsubstituted or optionally substituted with one or more R14Substituted by groups;
R5is aryl, heterocyclyl, or heteroaryl, wherein R 5Unsubstituted or optionally substituted by one or more R5aIs substituted in which
Each R5aIndependently of one another is halogen, C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, (C)3-C8Cycloalkyl) -C1-C6Alkyl-, (C)3-C8Cycloalkenyl) -C1-C6Alkyl-, (C)3-C8Cycloalkyl) -C2-C6Alkenyl-, nitro-, heterocyclyloxy-, aryl-, aryloxy-, arylalkyl-, aryloxyaryl-, aryl C1-C6Alkoxy, -C ', -B' -C ', or-A' -B '-C', wherein
A' is-O-;
b' is- [ C (R)15)2]m-or-C3-C8Cycloalkyl-;
c' is-H, halogen, -SO2R11、-OR11、-SR11、-N3、-COR11、-SO2N(R11)2、-SO2NR11COR11、-C≡N、-C(O)OR11、-OC(＝O)R11、-CON(R11)2、-CON(R11)OR11、-OCON(R11)2、-NR11COR11、-NR11CON(R11)2、-NR11COOR11、-N(R11)2Aryl, heteroaryl, or heterocyclyl.
In another embodiment, the invention provides a compound according to formulae Ia and Id, where
R1is-L5-R5or-L6-R5Wherein
L5Is- [ C (R)15)2]m-；
L6Is C3-C8Cycloalkyl, ring C3-8Haloalkyl, or heterocyclyl, wherein said cycloalkyl, ring C3-8Haloalkyl, or heterocyclyl unsubstituted or optionally substituted with one or more R14Substituted by groups;
R5is aryl, heterocyclyl, or heteroaryl, wherein R5Unsubstituted or optionally substituted by one or more R5aIs substituted in which
Each R5aIndependently of one another is halogen, C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, (C)3-C8Cycloalkyl) -C1-C6Alkyl-, (C)3-C8Cycloalkenyl) -C1-C6Alkyl-, (C)3-C8Cycloalkyl) -C2-C6Alkenyl-, nitro-, heterocyclyloxy-, aryl-, aryloxy-, arylalkyl-, aryloxyaryl-, aryl C 1-C6Alkoxy, -C ', -B' -C ', or-A' -B '-C', wherein
A' is-O-;
b' is- [ C (R)15)2]m-or-C3-C8Cycloalkyl-;
c' is-H, halogen, -SO2R11、-OR11、-SR11、-N3、-COR11、-SO2N(R11)2、-SO2NR11COR11、-C≡N、-C(O)OR11、-OC(＝O)R11、-CON(R11)2、-CON(R11)OR11、-OCON(R11)2、-NR11COR11、-NR11CON(R11)2、-NR11COOR11、-N(R11)2Aryl, heteroaryl, or heterocyclyl; and is
J is aryl or heteroaryl; and is
K is aryl or heteroaryl.
In another embodiment, the invention provides a compound according to formulae Ia and Id, where
R1is-L5-R5or-L6-R5Wherein
L5Is- [ C (R)15)2]m-；
L6Is C3-C8Cycloalkyl, ring C3-8Haloalkyl, or heterocyclyl, wherein said cycloalkyl, ring C3-8Haloalkyl, or heterocyclyl unsubstituted or optionally substituted with one or more R14Substituted by groups;
R5is aryl, heterocyclyl, or heteroaryl, wherein R5Unsubstituted or optionally substituted by one or more R5aIs substituted in which
Each R5aIndependently of one another is halogen, C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, (C)3-C8Cycloalkyl) -C1-C6Alkyl-, (C)3-C8Cycloalkenyl) -C1-C6Alkyl-, (C)3-C8Cycloalkyl) -C2-C6Alkenyl-, nitro-, heterocyclyloxy-, aryl-, aryloxy-, arylalkyl-, aryloxyaryl-, aryl C1-C6Alkoxy, -C ', -B' -C ', or-A' -B '-C', wherein
A' is-O-;
b' is- [ C (R)15)2]m-or-C3-C8Cycloalkyl-;
c' is-H, halogen, -SO2R11、-OR11、-SR11、-N3、-COR11、-SO2N(R11)2、-SO2NR11COR11、-C≡N、-C(O)OR11、-OC(＝O)R11、-CON(R11)2、-CON(R11)OR11、-OCON(R11)2、-NR11COR11、-NR11CON(R11)2、-NR11COOR11、-N(R11)2Aryl, heteroaryl, or heterocyclyl;
j is aryl or heteroaryl;
K is aryl or heteroaryl;
R2is-L3-R7Wherein
L3Is a chemical bond; and is
R7Is hydrogen, -Z, or-Y-Z, wherein
Y is- [ C (R)15)2]m-or-C2-C6An alkenyl group;
z is-H, halogen, -OR11、-C(＝O)R11、-C(＝O)OR11、-C(＝O)N(R11)2、-N(R11)2、-CN、-SO2R11or-S (═ O)2N(R11)2；
And is
R21Is hydrogen, halogen, C1-C6Alkyl, or C1-C6A haloalkyl group; these compounds are hereinafter referred to as compounds of formula XL.
In another embodiment, the invention provides a compound according to formula XL wherein J and K are both phenyl.
In another embodiment, the invention provides a compound according to formula XL wherein J and K are both phenyl; and is
R5Is aryl or heteroaryl, wherein R5Unsubstituted or optionally substituted by one or more R5aAnd (4) substitution.
In another embodiment, the invention provides a compound according to formula XL wherein J and K are both phenyl; and is
R5Is unsubstituted or optionally substituted by one or more R5aSubstituted phenyl, wherein each R is5aIndependently is-halogen, -C1-C6Alkyl, -C1-C6Haloalkyl, -OR11、-COR11、-C≡N、-C(O)OR11、-CON(R11)2or-N (R)11)2。
In another embodiment, the invention provides a compound according to formula XL wherein J and K are both phenyl;
R5is unsubstituted or optionally substituted by one or more R5aSubstituted phenyl, wherein each R is5aIndependently is-halogen, -C1-C6Alkyl, -C1-C6Haloalkyl, -OR 11、-COR11、-C≡N、-C(O)OR11、-CON(R11)2or-N (R)11)2(ii) a And is
Each R4Independently is halogen, aryl, heteroaryl, heterocyclyl, -M, or-E-M, wherein
E is- [ C (R)15’)2]m-, wherein
Each R15' is independently hydrogen or halogen; and is
M is-C1-C6Alkyl, -C1-C6Haloalkyl, halogen, -OR11or-SO2R11。
In another embodiment, the invention provides a compound according to formula XL wherein J and K are both phenyl; and is
R5Is unsubstituted or optionally substituted by one or more R5aSubstituted phenyl, wherein each R is5aIndependently is-halogen, -C1-C6Alkyl, -C1-C6Haloalkyl, -OR11、-COR11、-C≡N、-C(O)OR11、-CON(R11)2or-N (R)11)2。
In another embodiment, the invention provides a compound according to formula XL wherein J and K are both phenyl;
R5is unsubstituted or optionally substituted by one or more R5aSubstituted phenyl, wherein each R is5aIndependently is-halogen, -C1-C6Alkyl, -C1-C6Haloalkyl, -OR11、-COR11、-C≡N、-C(O)OR11、-CON(R11)2or-N (R)11)2(ii) a And is
Each R41Independently is halogen, -M ", or-E" -M ", wherein
E' is- [ C (R)15’)2]m-，
Wherein each R15' is independently hydrogen or halogen; and is
M' is-C1-C6Alkyl, -C1-C6Haloalkyl, or halogen.
In another embodiment, the invention provides a compound according to formula XL wherein J and K are both phenyl; and is
R5Is unsubstituted or optionally substituted by one or more R 5aSubstituted phenyl, wherein each R is5aIndependently is-halogen, -C1-C6Alkyl, -C1-C6Haloalkyl, -OR11、-COR11、-C≡N、-C(O)OR11、-CON(R11)2or-N (R)11)2。
In another embodiment, the invention provides a compound according to formula XL wherein J and K are both phenyl;
R5is unsubstituted or optionally substituted by one or more R5aSubstituted phenyl, wherein each R is5aIndependently is-halogen, -C1-C6Alkyl, -C1-C6Haloalkyl, -OR11、-COR11、-C≡N、-C(O)OR11、-CON(R11)2or-N (R)11)2(ii) a And is
R7Is hydrogen, -Z, or-Y-Z, wherein
Y is- [ C (R)15)2]m' -or-C2-C6Alkenyl radical, wherein
m' is 0, 1, or 2; and is
Z is-H, halogen, -OR11、-C(＝O)R11、-C(＝O)OR11、-C(＝O)N(R11)2、-N(R11)2、-CN、-SO2R11or-S (═ O)2N(R11)2.；
And R is21Is hydrogen.
In another embodiment, the invention provides a compound according to formula XL wherein J is heteroaryl and K is phenyl.
In another embodiment, the invention provides a compound according to formula XL wherein J is pyrrolyl, thienyl, furyl, thiazolyl, oxazolyl, or pyrazolyl, and K is phenyl.
In another embodiment, the invention provides a compound according to formula XL wherein J is pyrrolyl, thienyl, furyl, thiazolyl, oxazolyl, or pyrazolyl, and K is phenyl; and is
R5Is an aryl group or a heteroaryl group,
wherein R is5Unsubstituted or optionally substituted by one or more R 5aAnd (4) substitution.
In another embodiment, the invention provides a compound according to formula XL wherein J is pyrrolyl, thienyl, furyl, thiazolyl, oxazolyl, or pyrazolyl, and K is phenyl; and is
R5Is unsubstituted or optionally substituted by one or more R5aSubstituted phenyl, wherein each R is5aIndependently is-halogen, -C1-C6Alkyl, -C1-C6Haloalkyl, -OR11、-COR11、-C≡N、-C(O)OR11、-CON(R11)2or-N (R)11)2。
In another embodiment, the invention provides a compound according to formula XL, wherein J is pyrrolyl, thienyl, furyl, thiazolyl, oxazolyl, or pyrazolyl, and K is phenyl; and is
R5Is unsubstituted or optionally substituted by one or more R5aSubstituted phenyl, wherein each R is5aIndependently of each otherIs-halogen, -C1-C6Alkyl, -C1-C6Haloalkyl, -OR11、-COR11、-C≡N、-C(O)OR11、-CON(R11)2or-N (R)11)2(ii) a And is
Each R4Independently is halogen, aryl, heteroaryl, heterocyclyl, -M, or-E-M, wherein
E is- [ C (R)15’)2]m-, wherein
Each R15' is independently hydrogen or halogen; and is
M is-C1-C6Alkyl, -C1-C6Haloalkyl, halogen, -OR11or-SO2R11。
In another embodiment, the invention provides a compound according to formula XL wherein J is pyrrolyl, thienyl, furyl, thiazolyl, oxazolyl, or pyrazolyl, and K is phenyl; and is
R5Is unsubstituted or optionally substituted by one or more R5aSubstituted phenyl, wherein each R is5aIndependently is-halogen, -C1-C6Alkyl, -C1-C6Haloalkyl, -OR11、-COR11、-C≡N、-C(O)OR11、-CON(R11)2or-N (R)11)2(ii) a And is
Each R41Independently is halogen, -M ", or-E" -M ", wherein
E' is- [ C (R)15’)2]m-，
Wherein each R15' is independently hydrogen or halogen; and is
M' is-C1-C6Alkyl, -C1-C6Haloalkyl, or halogen.
In another embodiment, the invention provides a compound according to formula XL wherein J is pyrrolyl, thienyl, furyl, thiazolyl, oxazolyl or pyrazolyl, and K is phenyl; and is
R5Is unsubstituted or optionally substituted by one or more R5aSubstituted phenyl, wherein each R is5aIndependently is-halogen, -C1-C6Alkyl, -C1-C6Haloalkyl, -OR11、-COR11、-C≡N、-C(O)OR11、-CON(R11)2or-N (R)11)2(ii) a And is
R7Is hydrogen, -Z, or-Y-Z, wherein
Y is- [ C (R)15)2]m' -or-C2-C6Alkenyl radical, wherein
m' is 0, 1, or 2; and is
Z is-H, halogen, -OR11、-C(＝O)R11、-C(＝O)OR11、-C(＝O)N(R11)2、-N(R11)2、-CN、-SO2R11or-S (═ O)2N(R11)2；
And R is21Is hydrogen.
In an embodiment of the first aspect, the invention provides a compound according to formula Ia-d, wherein J is phenyl.
In other embodiments, the invention provides compounds according to formula Ia, Ib, Ic, or Id.
In another embodiment, the invention provides a compound according to any one of formulas Ia-Id, wherein K is phenyl or pyridinyl.
In another embodiment, the invention provides a compound according to any one of formulas Ia-Id, wherein J and K are both phenyl.
In another embodiment, the present invention provides a compound according to formula II, or a pharmaceutically acceptable salt, isomer, or prodrug thereof:
Figure S2006800306472D00341
wherein R is1、R2、R21、R4、R41、L2Q, and q' are as defined in formulas Ia-d.
In another embodiment, the present invention provides a compound according to formula III, or a pharmaceutically acceptable salt, isomer, or prodrug thereof:
Figure S2006800306472D00342
wherein R is1、R2、R21、R4、R41、L2Q, and q' are as defined in formulas Ia-d.
In another embodiment, the invention provides a compound according to formula III wherein L is2Is a chemical bond; such compounds are hereinafter referred to as compounds of formula IV.
In another embodiment, the invention provides a compound according to formula IV wherein R is5Is unsubstituted or optionally substituted by one or more R5aA substituted pyridyl group.
In another embodiment, the invention provides a compound according to formula IV wherein R is5Is unsubstituted or optionally substituted by one or more R5aA substituted pyridyl group; and each R5aIndependently is-halogen, -C1-C6Alkyl, -C1-C6Haloalkyl, -OR11、-COR11、-C≡N、-C(O)OR11、-CON(R11)2or-N (R)11)2。
In another embodiment, the invention provides a compound according to formula IV wherein R is 5Is unsubstituted or optionally substituted by one or more R5aA substituted pyridyl group; and each R41Independently hydrogen, halogen, -C1-C6Alkyl, or-C1-C6A haloalkyl group.
In another embodiment, the invention provides a compound according to formula IV wherein R is5Is unsubstituted or optionally substituted by one or more R5aA substituted pyridyl group; and R is2is-L3-R7，
Wherein
L3Is a chemical bond or-C (R)11″)2-; and is
R7Is hydrogen, halogen, -C1-C6Alkyl, -C1-C6Haloalkyl, -OR11″、-C(＝O)R11″、-C(＝O)OR11″、-C(＝O)N(R11″)2、-N(R11″)2、-CN、-SO2R11", or-S (═ O)2N(R11″)2，
Wherein each R11"is independently-H or-C1-C6An alkyl group.
In another embodiment, the invention provides a compound according to formula IV wherein R is5Is unsubstituted or optionally substituted by one or more R5aA substituted pyridyl group; and each R4Independently of one another is halogen, -C1-C6Alkyl, -C1-C6Haloalkyl, -COR11′、-COOR11′、-CON(R11′)2、-C≡N、-OR11′、-N(R11)2、-SO2R11', or-SO2N(R11′)2Wherein each R is11' independently is-hydrogen, -C1-C6Alkyl, or-C1-C6A haloalkyl group.
In another embodiment, the invention provides a compound according to formula III wherein L is1Is a chemical bond, and R5Is unsubstituted or optionally substituted by one or more R5aA substituted phenyl group.
In another embodiment, the invention provides a compound according to formula IV wherein L is1Is a chemical bond, and R 5Is unsubstituted or optionally substituted by one or more R5aSubstituted phenyl;
such compounds are hereinafter referred to as compounds of formula V.
In another embodiment, the invention provides a compound according to formula V wherein each R is hydrogen5aIndependently is halogen, -C ', or-B ' -C ', wherein
B' is- [ C (R)15’)2]m-, wherein
Each R15' is independently-H or-halogen; and is
C' is-H, -halogen, -SO2R11、-OR11、-COR11、-SO2N(R11)2、-C≡N、-C(O)OR11、-CON(R11)2or-N (R)11)2。
In another embodiment, the invention provides a compound according to formula V wherein each R is hydrogen5aIndependently is-halogen, -C1-C6Alkyl, -C1-C6Haloalkyl, -OR11、-COR11、-C≡N、-C(O)OR11、-CON(R11)2or-N (R)11)2(ii) a Such compounds are hereinafter referred to as compounds of formula Va.
In another embodiment, the inventionThe invention provides a compound according to formula V, wherein each R41Independently hydrogen, halogen, -C1-C6Alkyl, -C1-C6Haloalkyl, -COR16、-COOR16、-CON(R16)2、-C≡N、-OR16、-N(R16)2Wherein each R is16Independently of each other is hydrogen, -C1-C6Alkyl, or-C1-C6A haloalkyl group.
In another embodiment, the invention provides a compound according to formula V wherein each R is hydrogen41Independently hydrogen, halogen, -C1-C6Alkyl, or-C1-C6A haloalkyl group; this compound is hereinafter referred to as Vb compound.
In another embodiment, the invention provides a compound according to formula V wherein each R is hydrogen 4Independently of one another is halogen, nitro, C1-C6Alkyl radical, C1-C6Haloalkyl, -COR11、-COOR11、-CON(R11)2、-C≡N、-OR11、-OCON(R11)2、-OCO2-R11、-N3、-NR11COR11、-NR11SO2R11、-N(R11)2、-NR11COOR11、-SO2R11、-SO2NR11COR11、-SO2N(R11)2or-SR11。
In another embodiment, the invention provides a compound according to formula V wherein each R is hydrogen4Independently of one another is halogen, nitro, C1-C6Alkyl radical, C1-C6Haloalkyl, -COR11、-COOR11、-CON(R11)2、-C≡N、-OR11、-N(R11)2、-SO2R11or-SO2N(R11)2；
Such compounds are hereinafter referred to as compounds of formula Vc.
In another embodiment, the invention provides a compound according to formula V wherein R is2is-L3-R7Wherein
L3Is a chemical bond; and R is7Is hydrogen, halogen, nitro, cyano, -Z, or-Y-Z, wherein
Y is- [ C (R)15)2]m-；
Z is-H, halogen, -OR11、-C(＝O)R11、-C(＝O)OR11、-C(＝O)N(R11)2、-N(R11)2、-CN、-SO2R11、-S(＝O)2N(R11)2、-C(＝O)N(R11)N(R11)2、-C(＝O)N(R11)(OR11)、-OC(＝O)-R11or-OC (═ O) -N (R)11)2。
In another embodiment, the invention provides a compound according to formula V wherein R is2is-L3-R7Wherein
L3Is a chemical bond; and R is7Is hydrogen, halogen, -Z, or-Y-Z, wherein
Y is- [ C (R)15)2]m-, wherein
Z is-H, halogen, -OR11、-C(＝O)R11、-C(＝O)OR11、-C(＝O)N(R11)2、-N(R11)2、-CN、-SO2R11or-S (═ O)2N(R11)2；
Such compounds are hereinafter referred to as compounds of formula Vd.
In another embodiment, the invention provides a compound according to formula Va, wherein each R is hydrogen41Independently hydrogen, halogen, -C1-C6Alkyl, or-C1-C6A haloalkyl group; such compounds are hereinafter referred to as compounds of formula Ve.
In another embodiment, the invention provides a compound according to formula Vb wherein each R is 4Independently of one another is halogen, nitro, C1-C6Alkyl radical, C1-C6Haloalkyl, -COR11、-COOR11、-CON(R11)2、-C≡N、-OR11、-N(R11)2、-SO2R11or-SO2N(R11)2(ii) a Such compounds are hereinafter referred to as compounds of formula Vf.
In another embodiment, the invention provides a compound according to formula Vc, wherein R is a hydrogen atom2is-L3-R7Wherein
L3Is a chemical bond; and R is7Is hydrogen, halogen, -Z, or-Y-Z, wherein
Y is- [ C (R)15)2]m-, wherein
Z is-H, halogen, -OR11、-C(＝O)R11、-C(＝O)OR11、-C(＝O)N(R11)2、-N(R11)2、-CN、-SO2R11or-S (═ O)2N(R11)2；
Such compounds are hereinafter referred to as compounds of formula Vg.
In another embodiment, the invention provides a compound according to formula Vd, wherein each R is independently selected from the group consisting of5aIndependently is-halogen, -C1-C6Alkyl, -C1-C6Haloalkyl, -OR11、-COR11、-C≡N、-C(O)OR11、-CON(R11)2or-N (R)11)2(ii) a Such compounds are hereinafter referred to as compounds of formula Vh.
At another placeIn one embodiment, the invention provides a compound according to formula Ve, wherein each R is4Independently of one another is halogen, nitro, C1-C6Alkyl radical, C1-C6Haloalkyl, -COR11、-COOR11、-CON(R11)2、-C≡N、-OR11、-N(R11)2、-SO2R11or-SO2N(R11)2；
Such compounds are hereinafter referred to as compounds of formula Vi.
In another embodiment, the invention provides a compound according to formula Vf, wherein R is2is-L3-R7Wherein
L3Is a chemical bond; and R is7Is hydrogen, halogen, -Z, or-Y-Z, wherein
Y is- [ C (R)15)2]m-, wherein
Z is-H, halogen, -OR 11、-C(＝O)R11、-C(＝O)OR11、-C(＝O)N(R11)2、-N(R11)2、-CN、-SO2R11or-S (═ O)2N(R11)2。
In another embodiment, the present invention provides a compound according to formula Vg, wherein each R is independently selected from the group consisting of5aIndependently is-halogen, -C1-C6Alkyl, -C1-C6Haloalkyl, -OR11、-COR11、-C≡N、-C(O)OR11、-CON(R11)2or-N (R)11)2。
In another embodiment, the invention provides a compound according to formula Vh, wherein each R is independently selected from the group consisting of41Independently hydrogen, halogen, -C1-C6Alkyl, or-C1-C6A haloalkyl group.
In another embodiment, the invention providesCompounds according to formula Vi are provided, wherein R2is-L3-R7Wherein
L3Is a chemical bond; and R is7Is hydrogen, halogen, -Z, or-Y-Z, wherein
Y is- [ C (R)15)2]m-, wherein
Z is-H, halogen, -OR11、-C(＝O)R11、-C(＝O)OR11、-C(＝O)N(R11)2、-N(R11)2、-CN、-SO2R11or-S (═ O)2N(R11)2。
In another embodiment, the invention provides a compound according to formula V wherein R is21Is hydrogen, halogen, nitro, cyano, aryl, heteroaryl, heterocyclyl, -C1-C6alkyl-heterocyclyl-C1-C6Alkyl-heteroaryl, -C1-C6Alkyl-aryl, -Z, -Y-Z, or-X-Y-Z, wherein
X is-O-;
y is- [ C (R)15)2]m--C2-C6Alkenyl, or C3-C8A cycloalkyl group;
z is-H, -CN, halogen, -OR11、-C(＝O)R11、-C(＝O)OR11、-C(＝O)N(R11)2、-N(R11)2、-CN、-N3、-SO2R11、-S(＝O)2N(R11)2、-C(＝O)N(R11)N(R11)2、-C(＝O)N(R11)(OR11)、-OC(＝O)-R11、-OC(＝O)-N(R11)2or-N (R)11)COOR11。
In another embodiment, the invention provides a compound according to formula V wherein R is21Is hydrogen, halogen, nitro, cyano, C1-C6Alkyl, or C1-C6A haloalkyl group.
In another embodiment, the invention provides a compound according to any one of formulas Va-i, wherein R is 21Is hydrogen, halogen, nitro, cyano, C1-C6Alkyl, or C1-C6A haloalkyl group.
In another embodiment, the present invention provides a compound according to formula VI or a pharmaceutically acceptable salt, isomer, or prodrug thereof:
Figure S2006800306472D00391
wherein R is1、R2、R21、R4、R41、L2Q, and q' are as defined in formulas Ia-d.
In another embodiment, the invention provides a compound according to formula VII:
Figure S2006800306472D00401
wherein R is1、R2、R21、R4、R41、L2Q, and q' are as defined in formulas Ia-d.
In another embodiment, the invention provides a compound according to formula VII, wherein L is2Is a chemical bond or- [ C (R)15)2]m″-V2-[C(R15)2]n-, where m "is 0; n is 0 to 3; and V is2is-O-, -S-, -OC (═ O) O-, or-OC (═ O) N (R)10) -; such compounds are hereinafter referred to as compounds of formula VIII.
In another implementationIn another aspect, the invention provides a compound according to formula VIII, wherein L2Is a chemical bond; such compounds are hereinafter referred to as compounds of formula IX.
In another embodiment, the invention provides a compound according to formula IX, wherein L is1Is a chemical bond; and R is5Is unsubstituted or optionally substituted by one or more R5aSubstituted aryl or heteroaryl.
In another embodiment, the invention provides a compound according to formula X
Figure S2006800306472D00402
Wherein R is1、R2、R21、R4、R41、L2Q, and q' are as defined in formulas Ia-d.
In another embodiment, the invention provides a compound according to formula X wherein R is5Is unsubstituted or optionally substituted by one or more R5aSubstituted phenyl; such compounds are hereinafter referred to as compounds of formula XI.
In another embodiment, the invention provides a compound according to formula XI wherein each R is hydrogen5aIndependently is halogen, -C ', or-B ' -C ', wherein
B' is- [ C (R)15’)2]m-, wherein
Each R15' is independently-H or-halogen; and is
C' is-H, -halogen, -SO2R11、-OR11、-COR11、-SO2N(R11)2、-C≡N、-C(O)OR11、-CON(R11)2or-N (R)11)2。
In another embodiment, the invention provides a compound according to formula XI wherein each R is hydrogen5aIndependently is-halogen, -C1-C6Alkyl, -C1-C6Haloalkyl, -OR11、-COR11、-C≡N、-C(O)OR11、-CON(R11)2or-N (R)11)2(ii) a Such compounds are hereinafter referred to as compounds of formula XIa.
In another embodiment, the invention provides a compound according to formula XI wherein each R is hydrogen41Independently hydrogen, halogen, -C1-C6Alkyl, -C1-C6Haloalkyl, -COR16、-COOR16、-CON(R16)2、-C≡N、-OR16、-N(R16)2Wherein each R is16Independently of each other is hydrogen, -C1-C6Alkyl, or-C1-C6A haloalkyl group.
In another embodiment, the invention provides a compound according to formula XI wherein each R is hydrogen41Independently hydrogen, halogen, -C 1-C6Alkyl, or-C1-C6A haloalkyl group; such compounds are hereinafter referred to as compounds of formula XIb.
In another embodiment, the invention provides a compound according to formula XI wherein each R is hydrogen4Independently is halogen, -M, or-E-M, wherein
E is- [ C (R)15)2]m-；
M is C1-C6Alkyl radical, C1-C6Haloalkyl, -COR11、-COOR11、-CON(R11)2、-C≡N、-OR11、-OCON(R11)2、-OCO2-R11、-N3、-NR11COR11、-NR11SO2R11、-N(R11)2、-NR11COOR11、-SO2R11、-SO2NR11COR11、-SO2N(R11)2or-SR11。
In another embodiment, the invention provides a compound according to formula XI wherein each R is hydrogen4Independently is halogen, -M, or-E-M, wherein
E is- [ C (R)15’)2]m-, wherein
Each R15' is independently-H or-halogen; and is
M is-C1-C6Alkyl, -C1-C6Haloalkyl, -COR11′、-COOR11′、-CON(R11′)2、-C≡N、-OR11′、-N(R11)2、-SO2R11', or-SO2N(R11′)2Wherein
Each R11' independently is-hydrogen, -C1-C6Alkyl, or-C1-C6A halogenated alkyl group,
wherein each R11' unsubstituted OR optionally substituted by-OR13、-COOR13、-COR13、-SO2R13、-CON(R13)2、-SO2N(R13)2or-N (R)13)2Substitution;
such compounds are hereinafter referred to as compounds of formula XIc.
In another embodiment, the invention provides a compound according to formula XI wherein R is2is-L3-R7Wherein
L3Is a chemical bond, -C (R)11)2-、-O-、-S-、-NR7-、-N(R10)CO-、-CO-、-CS-、-CONR11-、-CO2-, -OC (═ O) -, or-SO2-; and is
R7Is hydrogen, halogen, heterocyclyl, -Z, or-Y-Z, wherein
Y is- [ C (R)15)2]m-；
Z is-H, halogen, -OR11、-C(＝O)R11、-C(＝O)OR11、-C(＝O)N(R11)2、-N(R11)2、-CN、-SO2R11、-S(＝O)2N(R11)2、-C(＝O)N(R11)N(R11)2、-C(＝O)N(R11)(OR11)、-OC(＝O)-R11or-OC (═ O) -N (R)11)2。
In another embodiment, the invention provides a compound according to formula XI wherein R is 2is-L3-R7Wherein
L3Is a chemical bond, -C (R)11″)2-, -CO-, or-SO2-; and is
R7Is hydrogen, halogen, heterocyclyl-C1-C6Alkyl, -C1-C6Haloalkyl, -OR11″、-C(＝O)R11″、-C(＝O)OR11″、-C(＝O)N(R11″)2、-N(R11″)2、-CN、-SO2R11", or-S (═ O)2N(R11″)2，
Wherein each R11"is independently-H or-C1-C6An alkyl group; such compounds are hereinafter referred to as compounds of formula XId.
In another embodiment, the invention provides a compound according to formula XIa, wherein each R is hydrogen41Independently hydrogen, halogen, -C1-C6Alkyl, or-C1-C6A haloalkyl group; such compounds are hereinafter referred to as compounds of formula XIe.
In another embodiment, the invention provides a compound according to formula XIb, wherein each R is4Independently is halogen, -M, or-E-M, wherein
E is- [ C (R)15’)2]m-, wherein
Each R15' is independently-H or-halogen; and is
M is-C1-C6Alkyl, -C1-C6Haloalkyl, -COR11′、-COOR11′、-CON(R11′)2、-C≡N、-OR11′、-N(R11)2、-SO2R11', or-SO2N(R11′)2Wherein
Each R11' independently is-hydrogen, -C1-C6Alkyl, -C1-C6A halogenated alkyl group,
wherein each R11' unsubstituted OR optionally substituted by-OR13、-COOR13、-COR13、-SO2R13、-CON(R13)2、-SO2N(R13)2or-N (R)13)2Substitution;
such compounds are hereinafter referred to as compounds of formula XIf.
In another embodiment, the invention provides a compound according to formula XIc, wherein R is hydrogen, oxygen, or a salt thereof2is-L3-R7Wherein L is3Is a chemical bond, -C (R)11″)2-, -CO-, or-SO 2-; and is
R7Is hydrogen, halogen, heterocyclyl-C1-C6Alkyl, -C1-C6Haloalkyl, -OR11″、-C(＝O)R11″、-C(＝O)OR11″、-C(＝O)N(R11″)2、-N(R11″)2、-CN、-SO2R11", or-S (═ O))2N(R11″)2，
Wherein each R11"is independently-H or-C1-C6An alkyl group;
such compounds are hereinafter referred to as compounds of formula XIg.
In another embodiment, the invention provides a compound according to formula XId, wherein each R is5aIndependently is-halogen, -C1-C6Alkyl, -C1-C6Haloalkyl, -OR11、-COR11、-C≡N、-C(O)OR11、-CON(R11)2or-N (R)11)2(ii) a Such compounds are hereinafter referred to as compounds of formula XIh.
In another embodiment, the invention provides a compound according to formula XIe, wherein each R is4Independently is halogen, -M, or-E-M, wherein
E is- [ C (R)15’)2]m-, wherein
Each R15' is independently-H or-halogen; and is
M is-C1-C6Alkyl, -C1-C6Haloalkyl, -COR11′、-COOR11′、-CON(R11′)2、-C≡N、-OR11′、-N(R11)2、-SO2R11', or
-SO2N(R11′)2Wherein
Each R11' independently is-hydrogen, -C1-C6Alkyl, -C1-C6A halogenated alkyl group,
wherein each R11' unsubstituted OR optionally substituted by-OR13、-COOR13、-COR13、-SO2R13、-CON(R13)2、-SO2N(R13)2or-N (R)13)2Substitution;
such compounds are hereinafter referred to as compounds of formula XIi.
In another embodiment, the invention provides a compound according to formula XIf, wherein R is2is-L3-R7Wherein L is3Is a chemical bond, -C (R)11″)2-, -CO-, or-SO2-; and is
R7Is hydrogen, halogen, heterocyclyl-C1-C6Alkyl, -C 1-C6Haloalkyl, -OR11″、-C(＝O)R11″、-C(＝O)OR11″、-C(＝O)N(R11″)2、-N(R11″)2、-CN、-SO2R11", or-S (═ O)2N(R11″)2，
Wherein each R11"is independently-H or-C1-C6An alkyl group.
In another embodiment, the invention provides a compound according to formula XIg, wherein each R is5aIndependently is-halogen, -C1-C6Alkyl, -C1-C6Haloalkyl, -OR11、-COR11、-C≡N、-C(O)OR11、-CON(R11)2or-N (R)11)2。
In another embodiment, the invention provides a compound according to formula XIh, wherein each R is41Independently hydrogen, halogen, -C1-C6Alkyl, or-C1-C6A haloalkyl group.
In another embodiment, the invention provides a compound according to formula XIi, wherein R is2is-L3-R7Wherein L3 is a bond, -C (R)11″)2-, -CO-, or-SO2-; and is
R7Is hydrogen, halogen, heterocyclyl-C1-C6Alkyl, -C1-C6Haloalkyl, -OR11″、-C(＝O)R11″、-C(＝O)OR11″、-C(＝O)N(R11″)2、-N(R11″)2、-CN、-SO2R11", or-S ═ O)2N(R11″)2，
Wherein each R11"is independently-H or-C1-C6An alkyl group.
In another embodiment, the invention provides a compound according to formula XI wherein R is21Is hydrogen, halogen, nitro, cyano, aryl, heteroaryl, heterocyclyl, -C1-C6alkyl-heterocyclyl-C1-C6Alkyl-heteroaryl, -C1-C6Alkyl-aryl, -Z, -Y-Z, or-X-Y-Z,
wherein
X is-O-;
y is- [ C (R)15)2]m-、-C2-C6Alkenyl, or C3-C8A cycloalkyl group;
z is-H, -CN, halogen, -OR11、-C(＝O)R11、-C(＝O)OR11、-C(＝O)N(R11)2、-N(R11)2、-CN、-N3、-SO2R11、-S(＝O)2N(R11)2、-C(＝O)N(R11)N(R11)2、-C(＝O)N(R11)(OR11)、-OC(＝O)-R11、-OC(＝O)-N(R11)2or-N (R)11)COOR11。
In another embodiment, the invention provides a compound according to formula XI wherein R is 21Is hydrogen, halogen, nitro, cyano, C1-C6Alkyl, or C1-C6A haloalkyl group.
In another embodiment, the invention provides a compound according to any one of formulas XIa-XIi, wherein R is21Is hydrogen, halogen, nitro, cyano, C1-C6Alkyl, or C1-C6A haloalkyl group.
In another embodiment, the invention provides a compound according to formula IX, wherein L is1Is a chemical bond; and R is5Is unsubstituted or optionally substituted by one or more R5aSubstituted pyridyl, such compounds being hereinafter referred to as compounds of formula XII.
In another embodiment, the invention provides a compound according to formula XII, wherein each R is hydrogen5aIndependently is-halogen, -C1-C6Alkyl, -C1-C6Haloalkyl, -OR11、-COR11、-C≡N、-C(O)OR11、-CON(R11)2or-N (R)11)2。
In another embodiment, the invention provides a compound according to formula XII, wherein each R is hydrogen41Independently hydrogen, halogen, -C1-C6Alkyl, or-C1-C6A haloalkyl group.
In another embodiment, the invention provides a compound according to formula XII, wherein R is2is-L3-R7Wherein L is3Is a chemical bond or-C (R)11″)2-; and is
R7Is hydrogen, halogen, -C1-C6Alkyl, -C1-C6Haloalkyl, -OR11″、-C(＝O)R11″、-C(＝O)OR11″、-C(＝O)N(R11″)2、-N(R11″)2、-CN、-SO2R11", or-S (═ O)2N(R11″)2，
Wherein each R11"independent ofis-H or-C1-C6An alkyl group.
In another embodiment, the invention provides a compound according to formula XII, wherein each R is hydrogen 4Independently of one another is halogen-C1-C6Alkyl, -C1-C6Haloalkyl, -COR11′、-COOR11′、-CON(R11′)2、-C≡N、-OR11′、-N(R11)2、-SO2R11', or-SO2N(R11′)2Wherein
Each R11' independently is-hydrogen, -C1-C6Alkyl, or-C1-C6A haloalkyl group.
In another embodiment, the invention provides a compound according to formula XII, wherein R is21Is hydrogen, halogen, nitro, cyano, C1-C6Alkyl, or C1-C6A haloalkyl group.
In another embodiment, the invention provides a compound according to formula VIII, wherein
L2is-V2-[C(R15)2]n"-, wherein
n' is 0 to 3; and V is2is-O-, -S-, -OC (═ O) O-, or-OC (═ O) N (R)10)-，
This compound is hereinafter referred to as compound of formula XIII.
In another embodiment, the invention provides a compound according to formula XIII, wherein each R is independently selected from the group consisting of5aIndependently is-halogen, -C1-C6Alkyl, -C1-C6Haloalkyl, -OR11、-COR11、-C≡N、-C(O)OR11、-CON(R11)2or-N (R)11)2。
In another embodiment, the present inventionCompounds according to formula XIII are provided, wherein each R41Independently hydrogen, halogen, -C1-C6Alkyl, or-C1-C6A haloalkyl group.
In another embodiment, the invention provides a compound according to formula XIII, wherein R is2is-L3-R7Wherein L is3Is a chemical bond or-C (R)11″)2-; and is
R7Is hydrogen, halogen, -C1-C6Alkyl, -C1-C6Haloalkyl, -OR11″、-C(＝O)R11″、-C(＝O)OR11″、-C(＝O)N(R11″)2、-N(R11″)2、-CN、-SO2R11", or-S (═ O) 2N(R11″)2，
Wherein each R11"is independently-H or-C1-C6An alkyl group.
In another embodiment, the invention provides a compound according to formula XIII, wherein each R is independently selected from the group consisting of4Independently of one another is halogen-C1-C6Alkyl, -C1-C6Haloalkyl, -COR11′、-COOR11′、-CON(R11′)2、-C≡N、-OR11′、-N(R11)2、-SO2R11', or-SO2N(R11′)2Wherein
Each R11' independently is-hydrogen, -C1-C6Alkyl, or-C1-C6A haloalkyl group.
In another embodiment, the invention provides a compound according to formula XIII, wherein R is21Is hydrogen, halogen, nitro, cyano, C1-C6Alkyl, or C1-C6A haloalkyl group.
In another embodiment, the inventionProvided are compounds according to formula Ia-d, wherein K is absent; q is 1; and L is2is-V2-[C(R15)2]n-, wherein
n is 0 to 6; and V is2is-O-, -S-, -SO2-、-CON(R10)-、-CON(R11)-、-CO-、-CO2-, -OC (═ O) -, -OC (═ O) O-, or-OC (═ O) N (R)10)-；
Such compounds are hereinafter referred to as compounds of formula XIV.
In another embodiment, the invention provides a compound according to formula XIV, wherein L is2is-CO-; and R is4Is a heterocyclic group which is unsubstituted or optionally substituted by one or more groups independently which is-M, wherein
M is-H, halogen, COR11、COOR11、C≡N、OR11、-NR11COR11、NR11SO2R11、SO2R11、SO2N(R11)2Or SR11；
Such compounds are hereinafter referred to as compounds of formula XV.
In another embodiment, the invention provides a compound according to formula XV, wherein each R is 5aIndependently is-halogen, -C1-C6Alkyl, -C1-C6Haloalkyl, -OR11、-COR11、-C≡N、-C(O)OR11、-CON(R11)2or-N (R)11)2。
In another embodiment, the invention provides a compound according to formula XV, wherein R is2is-L3-R7Wherein L is3Is a chemical bond or-C (R)11″)2-; and is
R7Is hydrogen, halogen, -C1-C6Alkyl, -C1-C6Haloalkyl, -OR11″、-C(＝O)R11″、-C(＝O)OR11″、-C(＝O)N(R11″)2、-N(R11″)2、-CN、-SO2R11", or-S (═ O)2N(R11″)2，
Wherein each R11"is independently-H or-C1-C6An alkyl group.
In another embodiment, the invention provides a compound according to formula XV, wherein each R is41Independently hydrogen, halogen, -C1-C6Alkyl, or-C1-C6A haloalkyl group.
In another embodiment, the invention provides a compound according to formula XV, wherein R is21Is hydrogen, halogen, nitro, cyano, C1-C6Alkyl, or C1-C6A haloalkyl group.
In another embodiment, the invention provides a compound according to formula XIV, wherein L is2is-O-; and R is4is-E-M, wherein
E is- [ C (R)15)2]m-; and is
M is-H, halogen, -COR11、-COOR11、-CON(R11)2、-C≡N、-OR11、-OCON(R11)2、-OCO2-R11、-N(R11)2；
Such compounds are hereinafter referred to as compounds of formula XVI.
In another embodiment, the invention provides a compound according to formula XVI, wherein each R is independently selected from the group consisting of41Independently hydrogen, halogen, -C1-C6Alkyl, or-C1-C6A haloalkyl group.
In another embodiment, the invention provides a compound according to formula XVI, wherein each R is independently selected from the group consisting of 5aIndependently is-halogen, C1-C6Alkyl radical, C1-C6Haloalkyl, -OR11、-COR11、-C≡N、-C(O)OR11、-CON(R11)2or-N (R)11)2。
In another embodiment, the invention provides a compound according to formula XVI, wherein R is2is-L3-R7Wherein L is3Is a chemical bond or-C (R)11″)2-; and is
R7Is hydrogen, halogen, -C1-C6Alkyl, -C1-C6Haloalkyl, -OR11″、-C(＝O)R11″、-C(＝O)OR11″、-C(＝O)N(R11″)2、-N(R11″)2、-CN、-SO2R11", or-S (═ O)2N(R11″)2，
Wherein each R11"is independently-H or-C1-C6An alkyl group.
In another embodiment, the invention provides a compound according to formula XVI, wherein R is21Is hydrogen, halogen, nitro, cyano, C1-C6Alkyl, or C1-C6A haloalkyl group.
In another embodiment, the invention provides a compound according to formula XIV, wherein
L2is-V2-[C(R15)2]n-, wherein
n is 0 to 6; and V is2is-CON (R)11) -or-CO2-; and is
R4Is heterocyclyl, or-E-M, wherein
E is- [ C (R)15)2]m-; and is
M is-H, halogen, -COR11、-COOR11、-CON(R11)2-C≡N、-OR11、-OCON(R11)2、-OCO2-R11、-N3、-NR11COR11、-NR11SO2R11、-N(R11)2、-NR11COOR11、-SO2R11、-SO2NR11COR11、-SO2N(R11)2or-SR11；
Such compounds are hereinafter referred to as compounds of formula XVII.
In another embodiment, the invention provides a compound according to formula XVII, wherein each R is hydrogen41Independently hydrogen, halogen, -C1-C6Alkyl, or-C1-C6A haloalkyl group.
In another embodiment, the invention provides a compound according to formula XVII, wherein each R is hydrogen5aIndependently is-halogen, -C1-C6Alkyl, -C1-C6Haloalkyl, -OR 11、-COR11、-C≡N、-C(O)OR11、-CON(R11)2or-N (R)11)2。
In another embodiment, the invention provides a compound according to formula XVII, wherein R is2is-L3-R7Wherein L is3Is a chemical bond or-C (R)11″)2-, and
R7is hydrogen, halogen, -C1-C6Alkyl, -C1-C6Haloalkyl, -OR11″、-C(＝O)R11″、-C(＝O)OR11″、-C(＝O)N(R11″)2、-N(R11″)2、-CN、-SO2R11", or-S (═ O)2N(R11″)2，
Wherein each R11Is independently-H or-C1-C6An alkyl group.
In another embodiment, the invention provides a compound according to formula XVII, wherein R is21Is hydrogen, halogen, nitro, cyano, C1-C6Alkyl, or C1-C6A haloalkyl group.
In another embodiment, the invention provides a compound according to formula Ia-d, wherein J is heteroaryl.
In another embodiment, the invention provides a compound according to formulae Ia-d, wherein J is thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, pyridyl, pyrimidinyl, or pyrazinyl.
In another embodiment, the invention provides a compound according to formula Ia-d, wherein J is thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, pyridyl, pyrimidinyl, or pyrazinyl; and K is phenyl.
In another embodiment, the invention provides a compound according to formula Ia-d, wherein J is pyridinyl.
In another embodiment, the invention provides a compound according to formula Ia-d, wherein J is pyridinyl; l is1Is a chemical bond; and R is5Is unsubstituted or optionally substituted by one or more R5aA substituted phenyl group.
In another embodiment, the invention provides a compound according to formula Ia-d, wherein J is pyridinyl; l is1Is a chemical bond; r5Is unsubstituted or optionally substituted by one or more R5aSubstituted phenyl; and K is phenyl; such compounds are hereinafter referred to as compounds of formula XVIII.
In another embodiment, the invention provides a compound according to formula XVIII, wherein each R is hydrogen41Independently hydrogen, halogen, -C1-C6Alkyl, or-C1-C6A haloalkyl group.
In another embodiment, the invention provides a compound according to formula XVIII, wherein R is2is-L3-R7Wherein L is3Is a chemical bond or-C (R)11″)2-; and is
R7Is hydrogen, halogen, -C1-C6Alkyl, -C1-C6Haloalkyl, -OR11″、-C(＝O)R11″、-C(＝O)OR11″、-C(＝O)N(R11″)2、-N(R11″)2、-CN、-SO2R11", or-S (═ O)2N(R11″)2，
Wherein each R11"is independently-H or-C1-C6An alkyl group.
In another embodiment, the invention provides a compound according to formula XVIII, wherein each R is hydrogen4Independently of one another is halogen, -C1-C6Alkyl, -C1-C6Haloalkyl, -COR11′、-COOR11′、-CON(R11′)2、-C≡N、-OR11′、-N(R11)2、-SO2R11', or-SO2N(R11′)2Wherein
Each R11' independently is-hydrogen, -C 1-C6Alkyl, or-C1-C6A haloalkyl group.
In another embodiment, the invention provides a compound according to formula XVIII, wherein each R is hydrogen5aIndependently is-halogen, -C1-C6Alkyl, -C1-C6Haloalkyl, -OR11、-COR11、-C≡N、-C(O)OR11、-CON(R11)2or-N (R)11)2。
In another embodiment, the invention provides a composition according to formulaA compound of XVIII wherein R21Is hydrogen, halogen, nitro, cyano, C1-C6Alkyl, or C1-C6A haloalkyl group.
In another embodiment, the invention provides a compound according to formula Ia-d, wherein J is thienyl, furyl, or pyrrolyl.
In another embodiment, the invention provides a compound according to formula Ia-d, wherein J is thienyl.
In another embodiment, the invention provides a compound according to formula Ia-d, wherein J is thienyl; k is phenyl; and L is2Is a chemical bond.
In another embodiment, the present invention provides a compound according to formula XIX, or a pharmaceutically acceptable salt, isomer, or prodrug thereof:
Figure S2006800306472D00511
wherein R is1、R2、R21、R4、R41、L2Q, and q' are as defined in formulas Ia-d.
In another embodiment, the invention provides a compound according to formula XIX, wherein K is absent; and L is2is-SO2-or-CO-.
In another embodiment, the invention provides a compound according to formula XIX, wherein K is absent; l is 2is-SO2-or-CO-; and R is4Is heterocyclyl OR11or-N (R)11)2，
Wherein said heterocyclyl is unsubstituted or optionally substituted by one or more-E '-M's, wherein
E' is- [ C (R)15)2]m-or C3-C8A cycloalkyl group;
m' is-H, halogen, COR11、COOR11、C≡N、OR11、-NR11COR11、NR11SO2R11、SO2R11、SO2N(R11)2Or SR11。
In another embodiment, the present invention provides a compound according to formula XX, or a pharmaceutically acceptable salt, isomer, or prodrug thereof:
Figure S2006800306472D00512
wherein R is1、R2、R21、R4、R41、L2Q, and q' are as defined in formulas Ia-d.
In another embodiment, the invention provides a compound according to formula XXI or a pharmaceutically acceptable salt, isomer, or prodrug thereof:
Figure S2006800306472D00521
wherein R is1、R2、R21、R4、R41、L2Q, and q' are as defined in formulas Ia-d.
In another embodiment, the invention provides a compound according to formula XXI wherein L is1Is a chemical bond; and R is5Is unsubstituted or optionally substituted by one or more R5aSubstituted phenyl;
such compounds are hereinafter referred to as compounds of formula XXII.
In another embodimentThe invention provides a compound according to formula XXII, wherein each R5aIndependently is halogen, nitro, heterocyclyloxy, aryloxy, -C ', -B' -C 'or-A' -B '-C',
wherein
A' is-O-;
b' is- [ C (R)15)2]m-；
C' is-H, halogen, -SO 2R11、-OR11、-SR11、-COR11、-SO2N(R11)2、-SO2NR11COR11、-C≡N、-C(O)OR11、-OC(＝O)R11、-CON(R11)2、-CON(R11)OR11、-OCON(R11)2、-NR11COR11、-NR11CON(R11)2、-NR11COOR11、-N(R11)2Aryl, heteroaryl, or heterocyclyl;
wherein each R5aIs unsubstituted or optionally independently C1-C6Alkyl radical, C3-C8Cycloalkyl, halogen, -C ≡ N, -COR11、-COOR11、-CON(R11)2、-SO2R11、-OR11、-SR11、-SO2R11、-SO2N(R11)2、-SO2NR11COR11、-OCON(R11)2、-NR11COR11、-NR11CON(R11)2、-NR11COOR11or-N (R)11)2Substituted with one or more groups.
In another embodiment, the invention provides a compound according to formula XXII, wherein each R is independently selected from the group consisting of5aIndependently is halogen, nitro, heterocyclyloxy, phenoxy, -C ', -B' -C ', or-A' -B '-C',
wherein
A' is-O-;
b' is- [ C (R)15)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)2Or a heterocyclic group;
wherein each R18Independently is-H, -C1-C6Alkyl, -C1-C6Haloalkyl, -C3-C8Cycloalkyl, aryl, heteroaryl, or heterocyclyl; and is
Wherein each R5aIs unsubstituted or optionally independently C1-C6Alkyl, halogen, -COR19、-COOR19、-CON(R19)2、-OR19Or is
-N(R19)2Is substituted with one or more groups of (a),
wherein each R19Independently is-H or-C1-C6An alkyl group;
such compounds are hereinafter referred to as compounds of formula XXIIa.
In another embodiment, the invention provides a compound according to formula XXII, wherein each R is independently selected from the group consisting of41Independently hydrogen, halogen, -C1-C6Alkyl, -C1-C6Haloalkyl, -COR16、-COOR16、-CON(R16)2、-C≡N、-OR16or-N (R)16)2Wherein each R is16Independently of each other is hydrogen, -C1-C6Alkyl, or-C1-C6A haloalkyl group.
In another embodiment, the invention provides a compound according to formula XXII, wherein each R is independently selected from the group consisting of 41Independently hydrogen, halogen, -C1-C6Alkyl, or-C1-C6A haloalkyl group; such compounds are hereinafter referred to as compounds of formula XXIIb.
In another embodiment, the invention provides a compound according to formula XXII, wherein each R is independently selected from the group consisting of4Independently of one another is halogen, nitro, CR11＝CR11COOR11-M, or-E-M, wherein
E is- [ C (R)15)2]m-or C3-C8A cycloalkyl group;
m is C1-C6Alkyl radical, C1-C6Haloalkyl, -COR11、-COOR11、-CON(R11)2、-C≡N、-OR11、-OCON(R11)2、-OCO2-R11、-NR11COR11、-NR11SO2R11、-N(R11)2、-NR11COOR11、-SO2R11、-SO2NR11COR11、-SO2N(R11)2or-SR11。
In another embodiment, the invention provides a compound according to formula XXII, wherein each R is independently selected from the group consisting of4Independently of one another is halogen, CR11′＝CR11′COOR11', -M, or-E-M, wherein
E is- [ C (R)15)2]m-or C3-C8A cycloalkyl group;
m is C1-C6Alkyl radical, C1-C6Haloalkyl, -COR11′、-COOR11′、-CON(R11′)2、-C≡N、-OR11′、-NR11′O2R11′、-N(R11′)2、-SO2R11′、-SO2NR11′COR11', or-SO2N(R11′)2，
Wherein each R11' independently is-hydrogen, -C1-C6Alkyl, or-C1-C6A halogenated alkyl group,
wherein any one R11' unsubstituted or optionally substituted by one or more R12' group substitution; each R12' independently is halogen, C1-C6Haloalkyl, C1-C6Alkyl radical, C1-C6Alkoxy, C ═ O (OR)13)、COR13、SO2R13、CON(R13)2、SO2N(R13)2or-N (R)13)2；
Such compounds are hereinafter referred to as compounds of formula XXIIc.
In another embodiment, the invention provides a compound according to formula XXII, wherein R is2is-L3-R7Wherein
L3Is a chemical bond or- (CH)2)m″-V1-(CH2)n-, wherein
m' is 0 to 3; n is 0 to 3; and V is 1is-C (R)11)2-、-O-、-S-、-NR7-、-CO-、-CO2-, -OC (═ O) -, or-SO2-; and is
R7Is hydrogen, halogen, nitro, aryl, heteroaryl, heterocyclyl-C1-C6Alkyl, -C1-C6Haloalkyl, -C2-C6Alkenyl radical, C3-C8Cycloalkyl, or- (C (R)15)2)m-Z wherein
Z is-OR11、-C(＝O)R11、-C(＝O)OR11、-C(＝O)N(R11)2、-N(R11)2、-CN、-SO2R11、-S(＝O)2N(R11)2、-C(＝O)N(R11)N(R11)2、-C(＝O)N(R11)(OR11)、-OC(＝O)-R11or-OC (═ O) -N (R)11)2，
Wherein R is7Unsubstituted or optionally substituted by one or more R7aIs substituted in which
R7aIs halogen, C1-C6Alkyl radical, C1-C6Haloalkyl, -OR20、-C(＝O)R20、-C(＝O)OR20、-C(＝O)N(R20)2、-N(R20)2、-N(R20)C(＝O)R20or-CN, wherein each R is20Independently is-H or C1-C6An alkyl group.
In another embodiment, the invention provides a compound according to formula XXII, wherein R is2is-L3-R7Wherein
L3Is a chemical bond or- (CH)2)m″-V1-(CH2)n-wherein
m' is 0 to 1; n is 0 to 2; and V is1is-CH2-, -O-, -S-, or-NR7-; and is
R7Is hydrogen, halogen, phenyl, heteroaryl, heterocyclyl-C1-C6Alkyl, -C1-C6Haloalkyl, -C2-C6Alkenyl radical, C3-C8Cycloalkyl, or- (C (R)15)2)m-Z wherein
Z is-OR11″、-C(＝O)R11″、-C(＝O)OR11″、-C(＝O)N(R11″)2、-N(R11″)2-CN, or-SO2R11″，
Wherein R is7Unsubstituted or optionally substituted by one or more R7aIs substituted in which
R7aIs halogen, C1-C6Alkyl radical, C1-C6Haloalkyl, -OR11″、-N(R11″)2、-COOR11", wherein each R11Independently is-H, -C1-C6Alkyl, -C1-C6Haloalkyl, heterocyclyl, or heteroaryl;
such compounds are hereinafter referred to as compounds of formula XXIId.
In another embodiment, the invention provides a compound according to formula XXII, wherein R is 2is-L3-R7Wherein L is3Is a chemical bond; and is
R7Is hydrogen, halogen, -C1-C3Alkyl, -C1-C3Haloalkyl, or- (C (R)15)2) -Z wherein
Z is-OR11"or-SO2R11", wherein R11"is-H or C1-C6An alkyl group.
In another embodiment, the invention provides a compound according to formula XXIIa, wherein each R is independently selected from the group consisting of41Independently hydrogen, halogen, -C1-C6Alkyl, or-C1-C6A haloalkyl group; such compounds are hereinafter referred to as compounds of formula XXIIe.
In another embodiment, the invention provides a compound according to formula XXIIb, wherein each R is independently selected from the group consisting of4Independently of one another is halogen, CR11′＝CR11′COOR11', -M, or-E-M, wherein
E is- [ C (R)15)2]m-or C3-C8A cycloalkyl group;
m is C1-C6Alkyl radical, C1-C6Haloalkyl, -COR11′、-COOR11′、-CON(R11′)2、-C≡N、-OR11′、-NR11′SO2R11′、-N(R11′)2、-SO2R11′、-SO2NR11′COR11', or-SO2N(R11′)2，
Wherein each R11' independently is-hydrogen, -C1-C6Alkyl, or-C1-C6A halogenated alkyl group,
wherein each R11' unsubstituted or optionally substituted by one or more R12' group substitution; each R12' independently is halogen, C1-C6Haloalkyl, C1-C6Alkyl radical, C1-C6Alkoxy, C ═ O (OR)13)、COR13、SO2R13、CON(R13)2or-N (R)13)2；
Such compounds are hereinafter referred to as compounds of formula XXIIf.
In another embodiment, the invention provides a compound according to formula XXIIc, wherein R is2is-L3-R7Wherein
L3Is a chemical bond or- (CH)2)m″-V1-(CH2)n-, wherein
m' is 0 to 1; n is 0 to 2; and V is 1is-CH2-, -O-, -S-, or-NR7-; and is
R7Is hydrogen, halogen, phenyl, heteroaryl, heterocyclyl-C1-C6Alkyl, -C1-C6Haloalkyl, -C2-C6Alkenyl radical, C3-C8Cycloalkyl, or- (C (R)15)2)m-Z wherein
Z is-OR11、-C(＝O)R11″、-C(＝O)OR11″、-C(＝O)N(R11″)2、-N(R11″)2-CN, or-SO2R11″，
Wherein R is7Unsubstituted or optionally substituted by one or more R7aIs substituted in which
R7aIs halogen, C1-C6Alkyl radical, C1-C6Haloalkyl, -OR11″、-N(R11″)2、-COOR11″，
Wherein R is11"is-H, -C1-C6Alkyl, -C1-C6Haloalkyl, heterocyclyl, or heteroaryl;
such compounds are hereinafter referred to as compounds of formula XXIIg.
In another embodiment, the invention provides a compound according to formula XXIId, wherein each R is independently selected from the group consisting of5aIndependently is halogen, nitro, heterocyclic oxy, phenoxy, -C ', -B' -C ', or-A' -B '-C', wherein
A' is-O-;
b' is- [ C (R)15)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)2Or a heterocyclic group;
wherein each R18Independently is-H, -C1-C6Alkyl, -C1-C6Haloalkyl, -C3-C8Cycloalkyl, aryl, heteroaryl, or heterocyclyl; and is
Wherein each R5aIs unsubstituted or optionally independently C1-C6Alkyl, halogen, -COR19、-COOR19、-CON(R19)2、-OR19or-N (R)19)2Is substituted with one or more groups of (a),
wherein R is19is-H or-C1-C6An alkyl group;
such compounds are hereinafter referred to as compounds of formula XXIIh.
In another embodiment, the invention provides a compound according to formula XXIIe, wherein each R is independently selected from the group consisting of4Independently of one another is halogen, CR11′＝CR11′COOR11-M' or-E-M, wherein
E is- [ C (R)15)2]m-or C3-C8A cycloalkyl group;
m is C1-C6Alkyl radical, C1-C6Haloalkyl, -COR11′、-COOR11′、-CON(R11′)2、-C≡N、-OR11′、-NR11′O2R11′、-N(R11′)2、-SO2R11′、-SO2NR11′COR11', or-SO2N(R11′)2，
Wherein each R11' independently is-hydrogen, -C1-C6Alkyl, or-C1-C6A halogenated alkyl group,
wherein any one R11' unsubstituted or optionally substituted by one or more R12' group substitution; each R12' independently is halogen, C1-C6Haloalkyl, C1-C6Alkyl radical, C1-C6Alkoxy radical,C＝O(OR13)、COR13、SO2R13、CON(R13)2、SO2N(R13)2or-N (R)13)2；
Such compounds are hereinafter referred to as compounds of formula XXIIi.
In another embodiment, the invention provides a compound according to formula XXIIf, wherein R is2is-L3-R7Wherein L is3Is a chemical bond or- (CH)2)m″-V1-(CH2)n-, wherein
m' is 0 to 1; n is 0 to 2; and V is1is-CH2-, -O-, -S-, or-NR7-; and is
R7Is hydrogen, halogen, phenyl, heteroaryl, heterocyclyl-C1-C6Alkyl, -C1-C6Haloalkyl, -C2-C6Alkenyl radical, C3-C8Cycloalkyl, or- (C (R)15)2)m-Z wherein
Z is-OR11″、-C(＝O)R11″、-C(＝O)OR11″、-C(＝O)N(R11″)2、-N(R11″)2-CN, or-SO2R11″，
Wherein R is7Unsubstituted or optionally substituted by one or more R7aIs substituted in which
R7aIs halogen, C1-C6Alkyl radical, C1-C6Haloalkyl, -OR11″、-N(R11″)2、-COOR11″，
Wherein R is11"is-H, -C1-C6Alkyl, -C1-C6Haloalkyl, heterocyclyl, or heteroaryl.
In another embodiment, the invention providesA compound according to formula XXIIg, wherein each R5aIndependently is halogen, nitro, heterocyclic oxy, phenoxy, -C ', -B' -C ', or-A' -B '-C', wherein
A' is-O-;
b' is- [ C (R)15)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)2Or a heterocyclic group;
wherein each R18Independently is-H, -C1-C6Alkyl, -C1-C6Haloalkyl, -C3-C8Cycloalkyl, aryl, heteroaryl, or heterocyclyl; and is
Wherein each R5aIs unsubstituted or optionally independently C1-C6Alkyl, halogen, -COR19、-COOR19、-CON(R19)2、-OR19or-N (R)19)2Wherein R is substituted by one or more groups of19is-H or-C1-C6An alkyl group.
In another embodiment, the invention provides a compound according to formula XXIIh, wherein each R is independently selected from the group consisting of41Independently hydrogen, halogen, -C1-C6Alkyl, or-C1-C6A haloalkyl group.
In another embodiment, the invention provides a compound according to formula XXIIi, wherein R is2is-L3-R7Wherein L is3Is a chemical bond or- (CH)2)m″-V1-(CH2)n-, wherein
m″Is 0 to 1; n is 0 to 2; and V is1is-CH2-, -O-, -S-, or-NR7-; and is
R7Is hydrogen, halogen, phenyl, heteroaryl, heterocyclyl-C1-C6Alkyl, -C1-C6Haloalkyl, -C2-C6Alkenyl radical, C3-C8Cycloalkyl, or- (C (R)15)2)m-Z wherein
Z is-OR11″、-C(＝O)R11″、-C(＝O)OR11″、-C(＝O)N(R11″)2、-N(R11″)2-CN, or-SO 2R11″，
Wherein R is7Unsubstituted or optionally substituted by one or more R7aIs substituted in which
R7aIs halogen, C1-C6Alkyl radical, C1-C6Haloalkyl, -OR11″、-N(R11″)2、-COOR11″，
Wherein R is11"is-H, -C1-C6Alkyl, -C1-C6Haloalkyl, heterocyclyl, or heteroaryl.
In another embodiment, the invention provides a compound according to formula XXII, wherein R is21Is hydrogen, halogen, nitro, cyano, aryl, heteroaryl, heterocyclyl, -C1-C6alkyl-heterocyclyl-C1-C6Alkyl-heteroaryl, -C1-C6Alkyl-aryl, -Z, -Y-Z, or-X-Y-Z,
wherein
X is-O-;
y is- [ C (R)15)2]m-、-C2-C6Alkenyl, or C3-C8A cycloalkyl group;
z is-H, -CNHalogen, -OR11、-C(＝O)R11、-C(＝O)OR11、-C(＝O)N(R11)2、-N(R11)2、-CN、-N3、-SO2R11、-S(＝O)2N(R11)2、-C(＝O)N(R11)N(R11)2、-C(＝O)N(R11)(OR11)、-OC(＝O)-R11、-OC(＝O)-N(R11)2or-N (R)11)COOR11。
In another embodiment, the invention provides a compound according to formula XXII, wherein R is21Is hydrogen, halogen, nitro, cyano, C1-C6Alkyl, or C1-C6A haloalkyl group.
In another embodiment, the invention provides a compound according to formulae XXIIa to XXIIi, wherein R is21Is hydrogen, halogen, nitro, cyano, C1-C6Alkyl, or C1-C6A haloalkyl group.
In another embodiment, the invention provides a compound according to formula XXI wherein
R1is-L1-R5Wherein
L1is-L5-or-L6-, wherein
Each L5is-C (R)15)2-, wherein
Each R15Independently hydrogen, halogen, (C)1-C6) Alkyl, or (C) 1-C6) A haloalkyl group; and is
L6is-CS-, -CO-, or-SO2-; and is
R5Is unsubstituted or optionally substituted by one or more R5aSubstituted aryl or heteroaryl.
In another embodimentThe invention provides a compound according to formula XXI, wherein R1is-L1-R5Wherein
L1is-L5-or-L6-, wherein
Each L5is-C (R)15)2-, wherein
Each R15Independently hydrogen, halogen, (C)1-C6) Alkyl, or (C)1-C6) A haloalkyl group;
and is
L6is-CS-, -CO-, or-SO2-; and is
R5Is unsubstituted or optionally substituted by one or more R5aSubstituted phenyl, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, pyridyl, pyrimidinyl, or pyrazinyl; such compounds are hereinafter referred to as compounds of formula XXIII.
In another embodiment, the invention provides a compound according to formula XXIII, wherein R is a hydrogen atom2is-L3-R7Wherein L is3Is a chemical bond or-C (R)11″)2-; and is
R7Is hydrogen, halogen, -C1-C6Alkyl, -C1-C6Haloalkyl, -OR11″、-C(＝O)R11″、-C(＝O)OR11″、-C(＝O)N(R11″)2、-N(R11″)2、-CN、-SO2R11", or-S (═ O)2N(R11″)2，
Wherein each R11"is independently-H or-C1-C6An alkyl group.
In another embodiment, the invention provides a compound according to formula XXIII, wherein each R is independently selected from the group consisting of5aIndependently is-halogen, -C1-C6Alkyl, -C1-C6Haloalkyl, -OR 11、-COR11、-C≡N、-C(O)OR11、-CON(R11)2or-N (R)11)2。
In another embodiment, the invention provides a compound according to formula XXIII, wherein each R is independently selected from the group consisting of41Independently hydrogen, halogen, -C1-C6Alkyl, or-C1-C6A haloalkyl group.
In another embodiment, the invention provides a compound according to formula XXIII, wherein each R is independently selected from the group consisting of4Independently of one another is halogen, -C1-C6Alkyl, -C1-C6Haloalkyl, -COR11′、-COOR11′、-CON(R11′)2、-C≡N、-OR11′、-N(R11′)2、-SO2R11', or-SO2N(R11′)2Wherein each R is11' independently is-hydrogen, -C1-C6Alkyl, or-C1-C6A haloalkyl group.
In another embodiment, the invention provides a compound according to formula XXIII, wherein R is a hydrogen atom21Is hydrogen, halogen, nitro, cyano, C1-C6Alkyl, or C1-C6A haloalkyl group.
In another embodiment, the invention provides a compound according to formula XXI wherein L is1Is a chemical bond; and R is5Is unsubstituted or optionally substituted by one or more R5aA substituted heteroaryl group.
In another embodiment, the invention provides a compound according to formula XXI wherein L is1Is a chemical bond; and R is5Is unsubstituted or optionally substituted by one or more R5aSubstituted thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, pyridyl, pyrimidinyl, or pyrazinyl.
In another embodiment, the invention provides a compound according to formula XXI wherein L is 1Is a chemical bond; and R is5Is unsubstituted or optionally substituted by one or more R5aSubstituted thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, isothiazolyl, or oxazolyl;
such compounds are hereinafter referred to as compounds of formula XXIV.
In another embodiment, the invention provides a compound according to formula XXIV, wherein each R is independently selected from the group consisting of5aIndependently is-halogen, -C1-C6Alkyl, -C1-C6Haloalkyl, -OR11、-COR11、-C≡N、-C(O)OR11、-CON(R11)2or-N (R)11)2。
In another embodiment, the invention provides a compound according to formula XXIV, wherein each R is independently selected from the group consisting of4Independently of one another is halogen, -C1-C6Alkyl, -C1-C6Haloalkyl, -COR11′、-COOR11′、-CON(R11′)2、-C≡N、-OR11′、-N(R11)2、-SO2R11', or-SO2N(R11′)2Wherein each R is11' independently is-hydrogen, -C1-C6Alkyl, or-C1-C6A haloalkyl group.
In another embodiment, the invention provides a compound according to formula XXIV wherein R is2is-L3-R7Wherein L is3Is a chemical bond or-C (R)11″)2-; and is
R7Is hydrogen, halogen, -C1-C6Alkyl, -C1-C6Haloalkyl, -OR11″、-C(＝O)R11″、-C(＝O)OR11″、-C(＝O)N(R11″)2、-N(R11″)2、-CN、-SO2R11", or-S (═ O)2N(R11″)2，
Wherein each R11"is independently-H or-C1-C6An alkyl group.
In another embodiment, the invention provides a compound according to formula XXIV, wherein each R is independently selected from the group consisting of41Independently hydrogen, halogen, -C1-C6Alkyl, or-C1-C6A haloalkyl group.
In another embodiment, the invention provides a compound according to formula XXIV wherein R is 21Is hydrogen, halogen, nitro, cyano, C1-C6Alkyl, or C1-C6A haloalkyl group.
In another embodiment, the invention provides a compound according to formula XXI wherein L is1Is a chemical bond; and R is5Is unsubstituted or optionally substituted by one or more R5aSubstituted pyridyl, pyrimidinyl, or pyrazinyl, such compounds being referred to hereinafter as compounds of formula XXV.
In another embodiment, the invention provides a compound according to formula XXV, wherein each R is independently selected from the group consisting of5aIs-halogen, -C1-C6Alkyl, -C1-C6Haloalkyl, -OR11、-COR11、-C≡N、-C(O)OR11、-CON(R11)2or-N (R)11)2。
In another embodiment, the invention provides a compound according to formula XXV, wherein each R is independently selected from the group consisting of4Independently of one another is halogen-C1-C6Alkyl, -C1-C6Haloalkyl, -COR11′、-COOR11′、-CON(R11′)2、-C≡N、-OR11′、-N(R11)2、-SO2R11', or-SO2N(R11′)2Wherein
Each R11' independently is-hydrogen, -C1-C6Alkyl, or-C1-C6A haloalkyl group.
In another embodiment, the invention provides a compound according to formula XXV, wherein R is a hydrogen atom2is-L3-R7Wherein
L3Is a chemical bond; and is
R7Is hydrogen, halogen, -C1-C6Alkyl, -C1-C6Haloalkyl, -C2-C6Alkenyl radical, C3-C8Cycloalkyl, or- (C (R)15)2)m' -Z wherein
m' is 0 to 1; and is
Z is-OR11、-C(＝O)R11、-C(＝O)OR11、-C(＝O)N(R11)2、-N(R11)2-CN, or-SO2R11，
Wherein R is11is-H or C1-C6An alkyl group.
In another embodiment, the invention provides a compound according to formula XXV, wherein each R is independently selected from the group consisting of 41Independently hydrogen, halogen, -C1-C6Alkyl, or-C1-C6A haloalkyl group.
In another embodiment, the invention provides a compound according to formula XXV, wherein R is a hydrogen atom21Is hydrogen, halogen, nitro, cyano, C1-C6Alkyl, or C1-C6A haloalkyl group.
In another embodiment, the invention provides a compound according to formula XIX, wherein K is heteroaryl; and L is2Is a chemical bond.
In another embodiment, the invention provides a compound according to formula XIX wherein K is thiaA thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, pyridyl, pyrimidinyl, or pyrazinyl group; and L is2Is a chemical bond.
In another embodiment, the invention provides a compound according to formula XIX, wherein K is pyridinyl; and L is2Is a chemical bond.
In another embodiment, the invention provides a compound according to formula XIX, wherein K is pyridinyl; l is2Is a chemical bond; l is1Is a chemical bond; and is
R5Is unsubstituted or optionally substituted by one or more R5aA substituted phenyl group.
In another embodiment, the invention provides a compound according to formula XXVI or a pharmaceutically acceptable salt, isomer, or prodrug thereof:
Figure S2006800306472D00631
wherein R is 1、R2、R21、R4、R41、L2Q, and q' are as defined for formulas Ia-d.
In another embodiment, the invention provides a compound according to formula XXVII or a pharmaceutically acceptable salt, isomer, or prodrug thereof:
wherein R is1、R2、R21、R4、R41、L2Q, and q' are as defined for formulas Ia-d.
In another embodiment, the invention provides a compound according to formula XXVIII or a pharmaceutically acceptable salt, isomer, or prodrug thereof:
Figure S2006800306472D00633
wherein R is1、R2、R21、R4、R41、L2Q, and q' are as defined for formulas Ia-d.
In another embodiment, the invention provides a compound according to formula XXVIII, wherein each R is independently selected from the group consisting of5aIs-halogen, -C1-C6Alkyl, -C1-C6Haloalkyl, -OR11、-COR11、-C≡N、-C(O)OR11、-CON(R11)2or-N (R)11)2。
In another embodiment, the invention provides a compound according to formula XXVIII, wherein each R is independently selected from the group consisting of41Independently hydrogen, halogen, -C1-C6Alkyl, or-C1-C6A haloalkyl group.
In another embodiment, the invention provides a compound according to formula XXVIII, wherein each R is independently selected from the group consisting of4Independently of one another is halogen, -C1-C6Alkyl, -C1-C6Haloalkyl, -COR11′、-COOR11′、-CON(R11′)2、-C≡N、-OR11′、-N(R11)2、-SO2R11', or-SO2N(R11′)2Wherein
Each R11' independently is-hydrogen, -C1-C6Alkyl, or-C1-C6A haloalkyl group.
In another embodiment, the invention provides a compound according to formula XXVIII, wherein R is2is-L3 -R7Wherein L is3Is a chemical bond or-C (R)11″)2-; and is
R7Is hydrogen, halogen, -C1-C6Alkyl, -C1-C6Haloalkyl, -OR11″、-C(＝O)R11″、-C(＝O)OR11″、-C(＝O)N(R11″)2、-N(R11″)2、-CN、-SO2R11", or-S (═ O)2N(R11″)2，
Wherein each R11"is independently-H or-C1-C6An alkyl group.
In another embodiment, the invention provides a compound according to formula XXVIII, wherein R is21Is hydrogen, halogen, nitro, cyano, C1-C6Alkyl, or C1-C6A haloalkyl group.
In another embodiment, the invention provides a compound according to formula Ia-d, wherein J is aryl or heteroaryl.
In another embodiment, the invention provides a compound according to formula Ia-d, wherein J is phenyl, pyridyl, thienyl, pyrrolyl, furyl, pyrimidinyl, pyrazinyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, triazolyl, triazinyl, tetrazolyl, or tetrazinyl.
In another embodiment, the invention provides a compound according to formulae Ia-d, wherein J is phenyl, pyridyl, thienyl, pyrrolyl, or furyl.
In another embodiment, the invention provides a compound according to formulae Ia-d, wherein J is phenyl, pyridyl, or thienyl.
In another embodiment, the invention provides a compound according to formula Ia-d wherein J is phenyl.
In another embodiment, the invention provides a compound according to formula Ia-d, wherein J is pyridinyl.
In another embodiment, the invention provides a compound according to formula Ia-d, wherein J is thienyl.
In another embodiment, the invention provides a compound according to formula Ia-d, wherein K is aryl or heteroaryl.
In another embodiment, the invention provides a compound according to formula Ia-d, wherein K is phenyl, pyridyl, thienyl, pyrrolyl, furyl, pyrimidinyl, pyrazinyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, triazolyl, triazinyl, tetrazolyl, or tetrazinyl.
In another embodiment, the invention provides a compound according to formula Ia-d, wherein K is phenyl, pyridyl, thienyl, pyrrolyl, or furanyl.
In another embodiment, the invention provides a compound according to formula Ia-d, wherein K is phenyl or pyridinyl.
In another embodiment, the invention provides a compound according to formula Ia-d, wherein K is pyridinyl.
In another embodiment, the invention provides a compound according to formula Ia-d wherein K is phenyl.
In another embodiment, the invention provides a compound according to formula Ia-d, wherein L2Is a chemical bond.
In another embodiment, the invention provides a compound according to formula Ia-d, wherein J is aryl or heteroaryl; and K is aryl or heteroaryl.
In another embodiment, the invention provides a compound according to formula Ia-d, wherein J is aryl or heteroaryl; k is aryl or heteroaryl; and L is2Is a chemical bond.
In another embodiment, the invention provides a compound according to formula Ia-d, wherein
J is phenyl, pyridyl, thienyl, pyrrolyl, furyl, pyrimidinyl, pyrazinyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, triazolyl, triazinyl, tetrazolyl, or tetrazinyl;
k is phenyl, pyridyl, thienyl, pyrrolyl, furyl, pyrimidinyl, pyrazinyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, triazolyl, triazinyl, tetrazolyl, or tetrazinyl; and is
L2Is a chemical bond.
In another embodiment, the invention provides a 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 is 2Is a chemical bond.
In another embodiment, the invention provides a compound according to formula Ia-d, wherein J is phenyl, pyridyl, or thienyl; k is phenyl or pyridyl; and L is2Is a chemical bond.
In another embodiment, the invention provides a compound according to formula Ia-d wherein J is phenyl; k is phenyl; and L is2Is a chemical bond.
In another embodiment, the invention provides a compound according to formula Ia-d, wherein J is pyridinyl; k is phenyl; and L is2Is a chemical bond.
In another embodiment, the invention provides a compound according to formula Ia-d, wherein J is thienyl; k is phenyl; and L is2Is a chemical bond.
In another embodiment, the invention provides a compound according to formula Ia-d wherein J is phenyl; k is pyridyl; and L is2Is a chemical bond.
In another embodiment, the invention provides a compound according to formula Ia-d, wherein J is pyridinyl; k is pyridyl; and L is2Is a chemical bond.
In another embodiment, the invention provides a compound according to formula Ia-d, wherein J is thienyl; k is pyridyl; and L is2Is a chemical bond.
In another embodiment, the invention provides a compound according to formula Ia-d, wherein R is 5Is aryl, heterocyclyl, or heteroaryl, wherein R5Unsubstituted or optionally substituted by one or more R5aAnd (4) substitution.
In another embodiment, the invention provides a compound according to formula Ia-d wherein R is5Is aryl or heteroaryl, wherein R5Unsubstituted or optionally substituted by one or more R5aAnd (4) substitution.
In another embodiment, the invention provides a compound according to formula Ia-d, wherein R is5Is phenyl, pyridyl, thienyl, pyrrolyl, furyl, pyrimidinyl, pyrazinyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, triazolyl, triazinyl, tetrazolyl, or tetrazinyl, wherein R is5Unsubstituted or optionally substituted by one or more R5aAnd (4) substitution.
In another embodiment, the invention provides a compound according to formula Ia-d, wherein L1Is a chemical bond; and R is5Is phenyl, pyridyl, thienyl, pyrrolyl, furyl, pyrimidinyl, pyrazinyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, triazolyl, triazinyl, tetrazolyl, or tetrazinyl, wherein R is5Unsubstituted or optionally substituted by one or more R5aAnd (4) substitution.
In another embodiment, the invention provides a compound according to formula Ia-d, wherein L 1Is a chemical bond; and R is5Is phenyl, pyridyl, thienyl, pyrrolyl, or furanyl, wherein R5Unsubstituted or optionally substituted by one or more R5aAnd (4) substitution.
In another embodiment, the invention provides a compound according to formula Ia-d, wherein L1Is a chemical bond; and R is5Is unsubstituted or optionally substituted by one or more R5aA substituted phenyl group.
In another embodiment, the invention provides a compound according to formula Ia-d, wherein L1Is a chemical bond; and R is5Is unsubstituted or optionally substituted by one or more R5aA substituted pyridyl group.
In another embodiment, the invention provides a compound according to formula Ia-d, wherein L1Is a chemical bond; and R is5Is unsubstituted or optionally substituted by one or more R5aSubstituted thienyl.
In another embodiment, the invention provides a compound according to formula Ia-d, wherein R is21Is hydrogen, halogen, nitro, cyano, aryl, heteroaryl, heterocyclyl, -C1-C6alkyl-heterocyclyl-C1-C6Alkyl-heteroaryl, -C1-C6Alkyl-aryl, -Z, -Y-Z, or-X-Y-Z,
wherein
X is-O-;
y is- [ C (R)15)2]m-、-C2-C6Alkenyl, or C3-C8A cycloalkyl group;
z is-H, -CN, halogen, -OR11、-C(＝O)R11、-C(＝O)OR11、-C(＝O)N(R11)2、-N(R11)2、-CN、-N3、-SO2R11、-S(＝O)2N(R11)2、-C(＝O)N(R11)N(R11)2、-C(＝O)N(R11)(OR11)、-OC(＝O)-R11、-OC(＝O)-N(R11)2or-N (R)11)COOR11。
In another embodiment, the invention provides a compound according to formula Ia-d, wherein R is 21Is hydrogen, halogen, nitro, cyano, C1-C6Alkyl, or C1-C6A haloalkyl group.
In another embodiment, the invention provides a compound according to formula XXIXa-d, wherein R is3Is hydrogen, aryl, heteroaryl, heterocyclyl, -C1-C6alkyl-heterocyclyl-C1-C6Alkyl-heteroaryl, -C1-C6Alkyl-aryl, -Z, or-Y-Z, wherein
Y is- [ C (R)15)2]m-、-C2-C6Alkenyl, or C3-C8A cycloalkyl group;
z is-H, -CN, halogen, -OR11、-C(＝O)R11、-C(＝O)OR11、-C(＝O)N(R11)2、-N(R11)2、-CN、-N3、-SO2R11、-S(＝O)2N(R11)2、-C(＝O)N(R11)N(R11)2、-C(＝O)N(R11)(OR11)、-OC(＝O)-R11、-OC(＝O)-N(R11)2or-N (R)11)COOR11。
In another embodiment, the invention provides a compound according to formula Ia-d, wherein R is3Is hydrogen, C1-C6Alkyl, or C1-C6A haloalkyl group.
In another embodiment, the invention provides a compound according to any one of formulas Ia-d, II-XXVIII, wherein R is2is-L3-R7Wherein L is3Is a chemical bond; and is
R7Is hydrogen, halogen, -Z, or-Y-Z, wherein
Y is- [ C (R)15’)2]m-or C2-C6An alkenyl group, which is a radical of an alkenyl group,
wherein each R15' is independently H, halogen, or (C)1-C6) An alkyl group; and is
Z is-H, halogen, -OR11、-C(＝O)R11、-C(＝O)OR11、-C(＝O)N(R11)2、-C(＝N-OH)R11or-C (═ S) N (R)11)2。
In another embodiment, the invention provides a compound according to any one of formulas Ia-d, II-XXVIII, wherein R is2is-L3-R7Wherein L is3Is a chemical bond; and is
R7Is hydrogen, halogen, or- [ C (R) ]15’)2]-Z wherein
Each R15' is independently H, halogen, or (C) 1-C2) An alkyl group; and is
Z is-H, halogen, -OR11″、-C(＝O)R11″、-C(＝O)OR11″、-C(＝O)N(R11″)2、-C(＝N-OH)R11", or-C (═ S) N (R)11″)2，
Wherein R is11"is-H or- (C)1-C6Alkyl groups).
In another embodiment, the invention provides a compound according to any one of formulas Ia-d, II-XXVIII, wherein R is2Is-halogen, -CF3、-CH2OH、-CH2SO2Me、-C(CH3)2OH, or-C (CH)3)2SO2Me。
In another embodiment, the invention provides a compound according to any one of formulas Ia-d, II-XXVIII, whereinR2Is-halogen, -CF3、-CH2OH, or-C (CH)3)2OH。
In another embodiment, the invention provides a compound according to any one of formulas Ia-d, II-XXVIII, wherein R is2is-CF3or-C (CH)3)2OH。
In another embodiment, the invention provides a compound according to any one of formulas Ia-d, II-XXVIII, wherein
Each R4Independently is halogen, aryl, heteroaryl, heterocyclyl, -M, or-E-M, wherein
E is- [ C (R)15’)2]m-, wherein
Each R15' is independently hydrogen or halogen; and is
M is-C1-C6Alkyl, -C1-C6Haloalkyl, halogen, -OR11or-SO2R11。
In another embodiment, the invention provides a compound according to any one of formulas Ia-d, II-XXVIII, wherein each R is4Independently of one another is halogen, -CH2-M、-C(H)(F)-M、-CF2-M, wherein
M is-C1-C6Alkyl, -C1-C6Haloalkyl, -F, -OR11', or-SO 2R11′，
Wherein R is11' is-H or-C1-C6An alkyl group.
In another embodiment, the invention provides a compound according to any one of formulas Ia-d, II-XXVIII, wherein each R is4Independently is-CH3、-CF3、-CF2H、-CH2F、-OH、-OMe、-CH2OH, or-SO2(C1-C3Alkyl groups).
In another embodiment, the invention provides a compound according to any one of formulas Ia-d, II-XXVIII, wherein each R is41Independently is halogen, -M ", or-E" -M ", wherein
E' is- [ C (R)15’)2]m-，
Wherein each R15' is independently hydrogen or halogen; and is
M' is-C1-C6Alkyl, -C1-C6Haloalkyl, or halogen.
In another embodiment, the invention provides a compound according to any one of formulas Ia-d, II-XXVIII, wherein each R is41Independently halogen, methyl, or trifluoromethyl.
In another embodiment, the invention provides a compound according to formulae Ia-d, II-IV, VI-IX, XIII, XIV-XVII, and XIX-XXI, wherein
R1is-L5-R5or-L6-R5Wherein
L5Is- [ C (R)15)2]m-；
L6Is C3-C8Cycloalkyl, ring C3-8Haloalkyl, or heterocyclyl, wherein said cycloalkyl, ring C3-8Haloalkyl, or heterocyclyl unsubstituted or optionally substituted with one or more R14Substituted by groups;
R5is aryl, heterocyclyl, or heteroaryl, wherein R5Unsubstituted or optionally substituted by one or more R 5aIs substituted in which
Each R5aIndependently of one another is halogen, C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, (C)3-C8Cycloalkyl) substituted benzeneC1-C6Alkyl-, (C)3-C8Cycloalkenyl) -C1-C6Alkyl-, (C)3-C8Cycloalkyl) -C2-C6Alkenyl-, nitro-, heterocyclyloxy-, aryl-, aryloxy-, arylalkyl-, aryloxyaryl-, aryl C1-C6Alkoxy, -C ', -B' -C ', or-A' -B '-C', wherein
A' is-O-;
b' is- [ C (R)15)2]m-or-C3-C8Cycloalkyl-;
c' is-H, halogen, -SO2R11、-OR11、-SR11、-N3、-COR11、-SO2N(R11)2、-SO2NR11COR11、-C≡N、-C(O)OR11、-OC(＝O)R11、-CON(R11)2、-CON(R11)OR11、-OCON(R11)2、-NR11COR11、-NR11CON(R11)2、-NR11COOR11、-N(R11)2Aryl, heteroaryl, or heterocyclyl.
In another embodiment, the invention provides a compound according to formula Ia-d, II-XXVIII, wherein R is21Is hydrogen, halogen, nitro, cyano, aryl, heteroaryl, heterocyclyl, -C1-C6alkyl-heterocyclyl-C1-C6Alkyl-heteroaryl, -C1-C6Alkyl-aryl, -Z, -Y-Z, or-X-Y-Z,
wherein
X is-O-;
y is- [ C (R)15)2]m-、-C2-C6Alkenyl, or C3-C8A cycloalkyl group;
z is-H, -CN, halogen, -OR11、-C(＝O)R11、-C(＝O)OR11、-C(＝O)N(R11)2、-N(R11)2、-CN、-N3、-SO2R11、-S(＝O)2N(R11)2、-C(＝O)N(R11)N(R11)2、-C(＝O)N(R11)(OR11)、-OC(＝O)-R11、-OC(＝O)-N(R11)2or-N (R)11)COOR11。
In another embodiment, the invention provides a compound according to formula Ia-d, II-XXVIII, wherein R is21Is hydrogen, halogen, nitro, cyano, C1-C6Alkyl, or C1-C6A haloalkyl group.
In another embodiment, the invention provides a compound according to formulae Ia-d, II-XXVIII, and XL, wherein R is 21Is hydrogen.
In a second aspect, the invention provides a compound according to formula XXIXa-d,
Figure S2006800306472D00711
wherein,
(A)R1is-L1-R5Wherein
L1Is a chemical bond, L5、L6、-L5-L6-L5-, or-L6-L5-L6-, wherein
Each L5Independently is- [ C (R)15)2]m-, wherein
Each m is independently 0, 1, 2, 3, 4, 5, or 6; and is
Each R15Independently hydrogen, halogen, (C)1-C6) Alkyl, or (C)1-C6) A haloalkyl group;
each L6Independently is-C (R)11)2-、-C(R11)2C(R11)2-、-C(R11)＝C(R11)-、-C(R11)2O-、-C(R11)2NR11-、-C≡C-、-O-、-S-、-NR11-、-N(R10)CO-、-N(R10)CO2-、-CON(R10)-、-CO-、-CS-、-CO2-、-OC(＝O)-、-OC(＝O)N(R10)-、-CONR11N(R11)2-、-CONR11-、-OCONR11-、-SO2-、-N(R10)SO2-、-SO2N(R10)-、-NR10CONR10-、-NR10CSNR10-、-C(＝NR11)-、-C(＝NOR11)-、-C(＝NN(R11)2) -; aryl radical, C3-C8Cycloalkyl, ring C3-8Haloalkyl, heteroaryl, or heterocyclyl, wherein said aryl, cycloalkyl, cyclohaloalkyl, heteroaryl, or heterocyclyl is unsubstituted or optionally substituted with one or more R14Substituted by groups;
or L1Is C2-6Alkanediyl chains, wherein said alkanediyl chains are uninterrupted or optionally-C (R)11)2-、-C(R11)2C(R11)2-、-C(R11)＝C(R11)-、-C(R11)2O-、-C(R11)2NR11-、-C≡C-、-O-、-S-、-N(R10)CO-、-N(R10)CO2-、-CON(R10)-、-CO-、-CO2-、-OC(＝O)-、-OC(＝O)N(R10)-、-SO2-、-N(R10)SO2-, or-SO2N(R10) -is interrupted, and
R5is aryl, heterocyclyl, heteroaryl, C2-C6Alkenyl radical, C2-C6Alkynyl, (C)3-C8Cycloalkyl) -C1-C6Alkyl-, (C)3-C8Cycloalkenyl) -C1-C6Alkyl-, (C)3-C8Cycloalkyl) -C2-C6Alkenyl-, C3-C8Cycloalkyl, -C, -B-C, or-A-B-C, wherein
A is-O-;
b is- [ C (R)15)2]m-or C3-C8A cycloalkyl group;
c is C1-C6Alkyl radical, C1-C6Halogenated alkyl, SO2R11、SR11、SO2N(R11)2、SO2NR11COR11、C≡N、C(O)OR11、CON(R11)2Or N (R)11)2；
Wherein R is5Unsubstituted or optionally substituted by one or more R5aThe substitution is carried out by the following steps,
wherein each R5aIndependently is C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, (C) 3-C8Cycloalkyl) -C1-C6Alkyl-, (C)3-C8Cycloalkenyl) -C1-C6Alkyl-, (C)3-C8Cycloalkyl) -C2-C6Alkenyl-, halogen, nitro, heterocyclyloxy, aryl, aryloxy, arylalkyl, aryloxyaryl, aryl C1-C6Alkoxy, -C ', -B' -C ', or-A' -B '-C', wherein
A' is-O-;
b' is- [ C (R)15)2]m-or-C3-C8Cycloalkyl-;
c' is-H, halogen, -SO2R11、-OR11、-SR11、-N3、-COR11、-SO2N(R11)2、-SO2NR11COR11、-C≡N、-C(O)OR11、-OC(＝O)R11、-CON(R11)2、-CON(R11)OR11、-OCON(R11)2、-NR11COR11、-NR11CON(R11)2、-NR11COOR11、-N(R11)2Aryl, heteroaryl, or heterocyclyl;
wherein each R5aIs unsubstituted or optionally independently C2-C6Alkenyl radical, C2-C6Alkynyl, (C)3-C8Cycloalkyl) -C1-C6Alkyl-, (C)3-C8Cycloalkenyl) -C1-C6Alkyl-, (C)3-C8Cycloalkyl) -C2-C6Alkenyl-, C0-C6Alkoxyaryl radical, C1-C6Alkyl radical, C3-C8Cycloalkyl, aryl C1-C6Alkyl, heteroaryl, halogen, -NO2、-C≡N、-COR11、-COOR11、-CON(R11)2、-SO2R11、-OR11、-SR11、-SO2R11、-SO2N(R11)2、-SO2NR11COR11、-OCON(R11)2、-NR11COR11、-NR11CON(R11)2、-NR11COOR11or-N (R)11)2Substituted with one or more groups of (a);
R2and R21is-L3-R7Wherein
Each L3Independently is a chemical bond-V1-(CH2)n-V1-, or- (CH)2)m-V1-(CH2)n-，
Wherein
n is 0 to 6; and is
Each V1Independently is-C (R)11)2-、-C(R11)2C(R11)2-、-C(R11)＝C(R11)-、-C(R11)2O-、-C(R11)2NR11-、-C≡C-、-O-、-S-、-NR7-、-N(R10)CO-、-N(R10)CO2-、-OCO-、-CO-、-CS-、-CONR10-、-C(＝N)(R11)-、-C(＝N-OR11)-、-C[＝N-N(R11)2]、-CO2-、-OC(＝O)-、-OC(＝O)N(R10)-、-SO2-、-N(R10)SO2-、-SO2N(R10)-、-NR10CONR10-、-NR10CSNR10-、C3-C8Cycloalkyl, or C3-C8A cyclic haloalkyl group;
or each L3Independently is C2-6Alkanediyl chains, wherein said alkanediyl chains are uninterrupted or optionally-C (R)11)2-、-C(R11)2C(R11)2-、-C(R11)＝C(R11)-、-C(R11)2O-、-C(R11)2NR11-、-C≡C-、-O-、-S-、-N(R10)CO-、-N(R10)CO2-、-CON(R10)-、-CO-、-CO2-、-OC(＝O)-、-OC(＝O)N(R10)-、-SO2-、-N(R10)SO2-, or-SO2N(R10) Interrupting; and is
Each R7Independently hydrogen, halogen, nitro, cyano, aryl, heteroaryl, heterocyclyl, -C1-C6alkyl-heterocyclyl-C1-C6Alkyl-heteroaryl, -C 1-C6Alkyl-aryl, -Z, -Y-Z, or-X-Y-Z, wherein
X is-O-;
y is- [ C (R)15)2]m--C2-C6Alkenyl, or C3-C8A cycloalkyl group;
z is-H, -CN, halogen, -OR11、-C(＝O)R11、-C(＝O)OR11、-C(＝O)N(R11)2、-N(R11)2、-CN、-N3、-SO2R11、-S(＝O)2N(R11)2、-C(＝O)N(R11)N(R11)2、-C(＝O)N(R11)(OR11)、-OC(＝O)-R11、-OC(＝O)-N(R11)2or-N (R)11)COOR11；
Wherein R is7Unsubstituted or optionally substituted by one or more R7aIs substituted in which
R7aIs halogen, C2-C6Alkenyl, -C1-C6alkyl-heterocyclyl-C1-C6Alkyl-heteroaryl, -C1-C6Alkyl-aryl, C0-C6Alkoxyheteroaryl group, C0-C6Alkoxyheterocyclyl, haloaryl, aryloxy, arylalkoxy, aryloxyalkyl, C1-C6Alkoxyaryl, aryl C0-C6Alkyl carboxyl, C (R)11)＝C(R11)-COOR11、C0-C6Alkoxyheteroaryl group, C0-C6Alkoxyheterocyclyl, aryl, heteroaryl, heterocyclyl, C3-C8Cycloalkyl, heteroaryloxy, -Z ', -Y' -Z ', or-X' -Y '-Z', wherein
X' is-O-;
y' is- [ C (R)15)2]m-or C3-C8A cycloalkyl group;
z' is-C1-C6Alkyl, -C1-C6Haloalkyl, -OR11、-SR11、-S(＝O)2R11、-C(＝O)R11、-C(＝O)OR11、-C(＝O)N(R11)2、-N(R11)2、-N(R11)C(＝O)R11、-S(＝O)2N(R11)C(＝O)R11、-CN、-S(＝O)2N(R11)2、-C(＝O)N(R11)N(R11)2、-C(＝O)N(R11)(OR11)、-OC(＝O)-R11、-OC(＝O)-OR11、-N(R11)C(＝O)O-R11or-N (R)11)S(＝O)2R11；
Wherein each R7aUnsubstituted or optionally substituted by one or more R8The substitution is carried out by the following steps,
wherein each R8Independently halogen, nitro, cyano, heteroaryl, C1-C6Alkyl radical, C1-C6Alkoxy radical, C1-C6Haloalkyl, C1-C6Haloalkyl (OR)11)、C0-C6Alkyl OR11、C0-C6Alkyl CON (R)11)2、C0-C6Alkyl group COR11、C0-C6Alkyl group COOR11Or C0-C6Alkyl SO2R11(ii) a And wherein if two R are present on the same carbon atom7aThen they together form a cycloalkyl or heterocyclyl group;
Provided that R is2And R21Is not H at the same time;
R3is-L-R6Wherein
L is a bond, -X3-(CH2)n-X3-、-(CH2)m-X3-(CH2)n-, or- (CH)2)l+w-Y3-(CH2)w-, wherein
n is 0 to 6; each w is independently 0-5; and is
Each X3Independently is chemicalBond, -C (R)11)2-、-C(R11)2C(R11)2-、-C(R11)＝C(R11)-、-C≡C-、-CO-、-CS-、-CONR10-、-C(＝N)(R11)-、-C(＝N-OR11)-、-C[＝N-N(R11)2]、-CO2-、-SO2-, or-SO2N(R10) -; and is
Y3is-O-, -S-, -NR7-、-N(R10)CO-、-N(R10)CO2-、-OCO-、-OC(＝O)N(R10)-、-NR10CONR10-、-N(R10)SO2-, or-NR10CSNR10-；
Or L is C2-6Alkanediyl chains, wherein said alkanediyl chains are uninterrupted or optionally-C (R)11)2-、-C(R11)2C(R11)2-、-C(R11)＝C(R11)-、-C(R11)2O-、-C(R11)2NR11-、-C≡C-、-O-、-S-、-N(R10)CO-、-N(R10)CO2-、-CON(R10)-、-CO-、-CO2-、-OC(＝O)-、-OC(＝O)N(R10)-、-SO2-、-N(R10)SO2-, or-SO2N(R10) Interrupting; and is
R6Is C1-C6Alkyl radical, C1-C6Haloalkyl, aryl, C3-C8Cycloalkyl, heteroaryl, heterocyclyl, -CN, -C (═ O) R11、-C(＝O)OR11、-C(＝O)N(R11)2、-N(R11)2、-SO2R11、-S(＝O)2N(R11)2、-C(＝O)N(R11)N(R11)2or-C (═ O) N (R)11)(OR11) Wherein
Said aryl, heteroaryl, cycloalkyl, or heterocyclyl is unsubstituted or optionally substituted with one or more R6aSubstitutionWherein
Each R6aindependently-Z ", -Y" -Z ", or-X" -Y "-Z", wherein
X' is-O-;
y' is- [ C (R)15)2]m-、-C2-C6Alkenyl radical, C3-C8Cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein
Said aryl, heteroaryl, cycloalkyl, or heterocyclyl is unsubstituted or optionally substituted with at least one group that is each independently Z ";
z' is-H, -CN, halogen, -OR11、-C(＝O)R11、-C(＝O)OR11、-C(＝O)N(R11)2、-N(R11)2、-N3、-SO2R11、-S(＝O)2N(R11)2、-C(＝O)N(R11)N(R11)2、-N(R11)C(＝O)N(R11)2、-OC(＝O)-OR11、-C(＝O)N(R11)(OR11)、-OC(＝O)-R11、-OC(＝O)-N(R11)2or-N (R)11)COOR11；
Each R10Independently is-R11、-C(＝O)R11、-CO2R11or-SO2R11；
Each R11Independently is-hydrogen, C2-C6Alkenyl radical, C2-C6Alkynyl, (C)3-C8Cycloalkenyl) -C1-C6Alkyl-, (C)3-C8Cycloalkyl) -C2-C6Alkenyl-, -N (R) 12)2、-C1-C6Alkyl, -C1-C6Haloalkyl, -C3-C8Cycloalkyl, - (C)1-C6) Alkyl radical- (C)3-C8) Cycloalkyl, aryl, - (C)1-C6) Alkane (I) and its preparation methodAryl, heteroaryl, - (C)1-C6) Alkyl-heteroaryl, heterocyclyl, or- (C)1-C6) An alkyl-heterocyclic group, a heterocyclic group,
wherein any one R11Unsubstituted or optionally substituted by one or more R12Substituted by groups;
each R12Independently of one another is hydrogen, halogen, C1-C6Haloalkyl, C1-C6Alkyl radical, C1-C6Alkoxy group, (C)0-C6Alkyl) C ═ O (OR)13)；C0-C6Alkyl OR13、C0-C6Alkyl group COR13、C0-C6Alkyl SO2R13、C0-C6Alkyl CN, C0-C6Alkyl CON (R)13)2、C0-C6Alkyl CONR13OR13、C0-C6Alkyl SO2N(R13)2、C0-C6Alkyl SR13、C0-C6Haloalkyl OR13Aryloxy, arylalkoxy, aryloxyalkyl, C0-C6Alkoxyaryl, aryl C0-C6Alkyl carboxyl, C0-C6Alkyl radical NR13SO2R13、-C0-C6Alkyl N (R)13)2Or OC0-C6Alkyl group COOR13；
Each R13Independently of each other is hydrogen, C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, (C)3-C8Cycloalkyl) -C1-C6Alkyl-, (C)3-C8Cycloalkenyl) -C1-C6Alkyl-, or (C)3-C8Cycloalkyl) -C2-C6Alkenyl-;
each R14Independently is C1-C6Alkyl radical, C1-C6Alkoxy, haloElement, C1-C6Haloalkyl, C0-C6Alkyl CON (R)11)2、C0-C6Alkyl CONR11OR11、C0-C6Alkyl OR11Or C0-C6Alkyl group COOR11；
G is a group of the formula,
wherein
J is aryl, heteroaryl, or absent;
hal is halogen;
each R41Independently of one another is halogen, nitro, C1-C6alkyl-heterocyclyl-C1-C6Alkyl-heteroaryl, -C 1-C6Alkyl-aryl, -M ", -E" -M ", or-D" -E "-M", wherein
D "is-O-;
e' is- [ C (R)15)2]m-or C3-C8A cycloalkyl group;
m' is-C1-C6Alkyl, -C1-C6Haloalkyl, -COR11、-COOR11、-CON(R11)2、-C≡N、-OR11、-OCON(R11)2、-OCO2-R11、-N3、-NR11COR11、-NR11SO2R11、-N(R11)2、-NR11COOR11、-SO2R11、-SO2NR11COR11、-SO2N(R11)2or-SR11Wherein each R is41Unsubstituted or optionally substituted by one or more R4aThe substitution is carried out by the following steps,
wherein each R4aIndependently is halogen, aryloxy, arylalkoxy, aryloxyalkyl, -C1-C6Alkyl-aryl, C1-C6Alkoxyaryl, aryl C0-C6Alkylcarboxyl, -M ', -E' -M ', or-D' -E '-M',
d' is-O-;
e' is- [ C (R)15)2]m-or C3-C8A cycloalkyl group;
m' is-C1-C6Alkyl, -C1-C6Haloalkyl, COR11、-CON(R11)2、-N(R11)COOR11、-N(R11)2、COOR11、C≡N、OR11、-NR11COR11、NR11SO2R11、SO2R11、SO2N(R11)2Or SR11(ii) a And is
q' is 0, 1, 2, 3, or 4, and
with the proviso that,
(i) if the compound is defined by the formula XXIXa
(a)R1Is not 4- (NH)2SO2) Phenyl, 4- (CH)3SO2) Phenyl, or 4- (CH)2FSO2) A phenyl group;
(b) if R is1Is 4-fluorophenyl, then G is not 4- [ (H)2NS(＝O)2-]Phenyl-;
(c)R2is not 4-hydroxyphenyl;
(ii) if the compound is defined by the formula XXIXb
(a)R2Is not 4- (NH)2SO2) Phenyl, 4- (CH)3SO2) Phenyl, or 4- (CH)2FSO2) A phenyl group;
(b) j is not pyridyl;
(c)R1is not 4-hydroxyphenyl;
(iii) if the compound is defined by the formula XXIXc, then
(a)R2Is not 4- (NH)2SO2) Phenyl, 4- (CH)3SO2) Phenyl, or 4- (CH)2FSO2) A phenyl group;
(b) j is not pyridyl;
(iv) If the compound is defined by the formula XXIXd
(a) If L is1Is a chemical bond, then R1Is not thienyl or 5-methylthiophenyl;
(b) if G is 4-fluorophenyl, R1Is not 4- [ (H)2NS(＝O)2-]Phenyl-;
(c)R1is not 4-Me-phenyl.
In another embodiment, the invention provides a compound according to formula XXIXa-d, wherein Hal is-Cl, -Br, or-I.
In another embodiment, the invention provides a compound according to formula XXIXa-d, I wherein R is21Is hydrogen, halogen, nitro, cyano, aryl, heteroaryl, heterocyclyl, -C1-C6alkyl-heterocyclyl-C1-C6Alkyl-heteroaryl, -C1-C6Alkyl-aryl, -Z, -Y-Z, or-X-Y-Z,
wherein
X is-O-;
y is- [ C (R)15)2]m-、-C2-C6Alkenyl, or C3-C8A cycloalkyl group; and is
Z is-H, -CN, halogen, -OR11、-C(＝O)R11、-C(＝O)OR11、-C(＝O)N(R11)2、-N(R11)2、-CN、-N3、-SO2R11、-S(＝O)2N(R11)2、-C(＝O)N(R11)N(R11)2、-C(＝O)N(R11)(OR11)、-OC(＝O)-R11、-OC(＝O)-N(R11)2or-N (R)11)COOR11。
In another embodiment, the invention provides a compound according to formula XXIXa-d, wherein R is21Is hydrogen, halogen, nitro, cyano, C1-C6Alkyl, or C1-C6A haloalkyl group.
In another embodiment, the invention provides a compound according to formula XXIXa-d, wherein R is3Is hydrogen, aryl, heteroaryl, heterocyclyl, -C1-C6alkyl-heterocyclyl-C1-C6Alkyl-heteroaryl, -C1-C6Alkyl-aryl, -Z, or-Y-Z, wherein
Y is- [ C (R) 15)2]m--C2-C6Alkenyl, or C3-C8A cycloalkyl group;
z is-H, -CN, halogen, -OR11、-C(＝O)R11、-C(＝O)OR11、-C(＝O)N(R11)2、-N(R11)2、-CN、-N3、-SO2R11、-S(＝O)2N(R11)2、-C(＝O)N(R11)N(R11)2、-C(＝O)N(R11)(OR11)、-OC(＝O)-R11、-OC(＝O)-N(R11)2or-N (R)11)COOR11。
In another embodiment, the invention provides a compound according to formula XXIXa-d, wherein R is3Is hydrogen, C1-C6Alkyl, or C1-C6A haloalkyl group.
In another embodiment, the invention provides a compound according to formula XXIXa-d, wherein J is aryl or heteroaryl.
In another embodiment, the invention provides a compound according to formula XXIXa-d, I wherein J is phenyl, pyridyl, thienyl, pyrrolyl, furyl, pyrimidinyl, pyrazinyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, triazolyl, triazinyl, tetrazolyl, or tetrazinyl.
In another embodiment, the invention provides a compound according to formula XXIXa-d, I wherein J is phenyl, pyridyl, thienyl, pyrrolyl, or furyl.
In another embodiment, the invention provides a compound according to formula XXIXa-d, wherein J is phenyl, pyridyl, or thienyl.
In another embodiment, the invention provides a compound according to formula XXIXa-d, wherein J is phenyl.
In another embodiment, the invention provides a compound according to formula XXIXa-d, wherein J is pyridinyl.
In another embodiment, the invention provides a compound according to formula XXIXa-d, wherein J is thienyl.
In another embodiment, the invention provides a compound according to formula XXIXa-d, wherein R is5Is aryl, heterocyclyl, or heteroaryl, wherein R5Unsubstituted or optionally substituted by one or more R5aAnd (4) substitution.
In another embodiment, the invention provides a compound according to formula XXIXa-d, wherein R is5Is aryl or heteroaryl, wherein R5Unsubstituted or optionally substituted by one or more R5aAnd (4) substitution.
In another embodiment, the invention provides a compound according to formula XXIXa-d,wherein R is5Is phenyl, pyridyl, thienyl, pyrrolyl, furyl, pyrimidinyl, pyrazinyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, triazolyl, triazinyl, tetrazolyl, or tetrazinyl, wherein R is5Unsubstituted or optionally substituted by one or more R5aAnd (4) substitution.
In another embodiment, the invention provides a compound according to formula XXIXa-d, wherein L1Is a chemical bond.
In another embodiment, the invention provides a compound according to formula XXIXa-d, wherein L1Is a chemical bond; and R is 5Is phenyl, pyridyl, thienyl, pyrrolyl, furyl, pyrimidinyl, pyrazinyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, triazolyl, triazinyl, tetrazolyl, or tetrazinyl, wherein R is5Unsubstituted or optionally substituted by one or more R5aAnd (4) substitution.
In another embodiment, the invention provides a compound according to formula XXIXa-d, wherein L1Is a chemical bond; and R is5Is phenyl, pyridyl, thienyl, pyrrolyl, or furanyl, wherein R5Unsubstituted or optionally substituted by one or more R5aAnd (4) substitution.
In another embodiment, the invention provides a compound according to formula XXIXa-d, wherein L1Is a chemical bond; and R is5Is unsubstituted or optionally substituted by one or more R5aA substituted phenyl group.
In another embodiment, the invention provides a compound according to formula XXIXa-d, wherein L1Is a chemical bond; and R is5Is unsubstituted or optionally substituted by one or more R5aA substituted pyridyl group.
In another embodiment, the invention provides a compound according to formula XXIXa-d, wherein L1Is a chemical bond; and R is5Is unsubstituted or optionally substituted by oneA plurality of R5aSubstituted thienyl.
In another embodiment, the invention provides a compound according to formula XXIXa-d,
wherein
R2is-L3-R7Wherein L is3Is a chemical bond; and is
R7Is hydrogen, halogen, -Z, or-Y-Z, wherein
Y is- [ C (R)15’)2]m-or C2-C6An alkenyl group, which is a radical of an alkenyl group,
wherein each R15' is independently H, halogen, or (C)1-C6) An alkyl group; and is
Z is-H, halogen, -OR11、-C(＝O)R11、-C(＝O)OR11、-C(＝O)N(R11)2、-C(＝N-OH)R11or-C (═ S) N (R)11)2。
In another embodiment, the invention provides a compound according to formula XXIXa-d,
wherein
R2is-L3-R7Wherein L is3Is a chemical bond; and is
R7Is hydrogen, halogen, or- [ C (R) ]15’)2]-Z wherein
Each R15' is independently H, halogen, or (C)1-C2) An alkyl group; and is
Z is-H, halogen, -OR11″、-C(＝O)R11″、-C(＝O)OR11″、-C(＝O)N(R11″)2、-C(＝N-OH)R11", or-C (═ S) N (R)11″)2，
Wherein R is11"is-H or- (C)1-C6Alkyl groups).
In another embodiment, the invention provides a compound according to formula XXIXa-d, wherein R is2Is-halogen, -CF3、-CH2OH、-CH2SO2Me、-C(CH3)2OH, or-C (CH)3)2SO2Me。
In another embodiment, the invention provides a compound according to formula XXIXa-d, wherein R is2Is-halogen, -CF3、-CH2OH, or-C (CH)3)2OH。
In another embodiment, the invention provides a compound according to formula XXIXa-d, wherein R is2is-CF3or-C (CH)3)2OH。
In another embodiment, the invention provides a compound according to formula XXIXa-d, wherein each R is41Independently is halogen, -M ", or-E" -M ", wherein
E' is- [ C (R)15’)2]m-，
Wherein each R15' is independently hydrogen or halogen; and is
M' is-C1-C6Alkyl, -C1-C6Haloalkyl, or halogen.
In another embodiment, the invention provides a compound according to formula XXIXa-d, wherein R is1Is L1-R5Wherein L is1Is a chemical bond; and is
R5Is phenyl or pyridyl, each unsubstituted or optionally substituted by one or two R5aIs substituted in which
Each R5aIndependently is-halogen, -CH3or-CF3；
R2is-H, -C (R)20)2OH、-CH3、-CF3Or halogen, wherein
Each R20Independently is-H, -F, -CH3or-CF3；
J is phenyl, pyridyl, or thienyl; and is
Each R41Is-halogen, -CH3、-CH2CH3、-CF3、-CF2CF3or-CH2CF3。
In another embodiment, the invention provides a compound according to formula XXIXa-d, wherein q' is 0 or 1; r1Is L1-R5Wherein L is1Is a chemical bond;
R5is unsubstituted or optionally substituted by one or two R5aSubstituted phenyl radicals in which
Each R5aIndependently is-halogen, -CH3or-CF3；
Each R2is-H, -C (R)20)2OH、-CH3、-CF3Or halogen, wherein
Each R20Independently is-H, -F, -CH3or-CF3(ii) a And is
R41Is-halogen, -CH3、-CH2CH3、-CF3、-CF2CF3or-CH2CF3。
In another embodiment, the invention provides a compound according to formula XXIXa-d, wherein each R is41Independently halogen, methyl or trifluoromethyl.
In another embodiment, the invention provides a compound according to any one of the preceding embodiments, wherein R is21Is hydrogen. In the following embodiments of the first aspect, it is to be understood that the application isThe following conditions were used:
(i) if L is2Is not a bond or q may be only 0 if K is not phenyl;
(ii) said compound is not 2-methyl-5- (1-m-tolyl-3- (trifluoromethyl) -1H-pyrazol-5-yl) benzenesulfonamide;
(iii) if L is2Is a chemical bond, neither J nor K is present;
(iv) if K is absent, q is 1 and R4And L2Direct bonding;
(v) if L is2Is SO2Or SO2N(R10) Then R is5By at least one R5aSubstitution;
(vi) if the compound is defined by formula Ia, then
(a)R1Is not 4- (NH)2SO2) Phenyl, 4- (CH)3SO2) Phenyl, or 4- (CH)2FSO2) A phenyl group;
(b) if R is1Is 4-fluorophenyl, then G is not 4- [ (H)2NS(＝O)2-]Phenyl-;
(c)R2and R21Is not 4-hydroxyphenyl;
(vii) if the compound is defined by formula Ib
(a)R2Is not 4- (NH)2SO2) Phenyl, 4- (CH)3SO2) Phenyl, or 4- (CH)2FSO2) A phenyl group; and is
(b)R1Is not 4-hydroxyphenyl;
(viii) if the compound is defined by formula Ic, then
(a)R2Is not 4- (NH)2SO2) Phenyl, 4- (CH)3SO2) Phenyl, or 4- (CH)2FSO2) Benzene and its derivativesA group;
(b) j is not pyridyl;
(c) g is not 3-or 4-methoxyphenyl; and is
(ix) If the compound is defined by formula Id, then
(a) If L is1Is a chemical bond, then R1Is not thienyl or 5-methylthiophenyl;
(b) g is not 4- (NH)2SO2) Phenyl, 4- (CH)3SO2) Phenyl, or 4- (CH)2FSO2) A phenyl group;
(c) if G is 4-fluorophenyl, R1Is not 4- [ (H)2NS(＝O)2-]Phenyl-;
(d) if J is Ph, L2Is a bond and q is 1, then K and R4Together is not 4-fluorophenyl, 3-fluorophenyl, 4-methoxyphenyl, or 5-chlorothiophenyl;
(e) if J is pyridyl, L2Is a bond and q is 1, then K and R4Together are not 4-fluorophenyl;
(f) if J is Ph, L2Is a bond and q is 2, then K and R4Together are not 3-fluoro-4-methoxyphenyl; and is
(g)R1Is not 4-methyl-phenyl.
One embodiment of the present invention relates to an isomer, a mixture of stereoisomers, a racemic mixture of stereoisomers, or a form of a tautomer of a compound represented by formula Iaa, Ibb, Icc, or Idd; or a pharmaceutically acceptable salt, prodrug, solvate, or polymorph thereof:
Figure S2006800306472D00831
wherein each R1The substituents are independently selected from R5and-L1-R5。
Another embodiment is: r1The substituent being R5(ii) a Preferred R in this embodiment5Selected from a 5-12 membered aromatic or non-aromatic ring, a 5-12 membered heterocyclyl or heteroaryl group having one or more heteroatoms N, O or S; r 5Optionally unsubstituted or substituted in substitutable positions by one or more R5aAnd (4) substituting the group. Preferably R5Is thienyl, furyl, piperidinyl, pyrrolidinyl, piperazinyl, morpholinyl, thiazolyl, indolyl, oxazolyl, isoxazolyl, pyridinyl, pyrimidinyl, imidazolyl, and phenyl.
R5aExamples of radicals include halogen, C1-6Haloalkyl, nitro, C1-6Aliphatic radical, C1-6Alkoxy radical, C0-6Alkyl OR11、NR11COR11、NR11CON(R11)2、C0-6Alkyl SO2R11、C0-6Alkyl SR11、C0-6Alkyl SO2N(R11)2-, - -, arylalkyl, aryloxyaryl, aryl C1-6Alkoxy radical, OC1-6Alkyl group COR11、OC1-6Alkyl N (R)11)2、C0-6Alkyl N (R)11)2、C0-6Alkyl group COOR11、C0-6Alkyl group COON (R)11)2、C0-6Alkyl CON (R)11)2；C0-6Alkyl C.ident. N, OC0-6Alkyl group COOR11、OC1-6Alkyl CON (R)11)2Or C1-6Alkyl OC1-6An alkyl group. R5aOptionally unsubstituted or substituted by C in a substitutable position0-6Alkyl SO2R11、C0-6Alkoxyaryl, 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 R5aIs Cl, Br, F, C1-6Alkyl radical, C1-6Haloalkyl, C1-6Alkoxy radical, OC0-6Alkyl group COOR11、OCON(R11)2、NHCOR11、CON(R11)2、NO2、OCON(R11)2And OC1-6Alkyl CON (R)11)2。R5aExamples of (B) 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、C1-6Alkyl, OCH2COOH、OCH2COOC(CH3)3、O(CH2)2N(CH2CH3)2、OC(CH3)2COOC(CH3)3And OCH and2CH2OH。
another embodiment is: r1The substituent is-L1-R5. Preferred R in this embodiment5Selected from a 5-12 membered aromatic or non-aromatic ring, a 5-12 membered heterocyclyl or heteroaryl group having one or more heteroatoms N, O or S; r 5Optionally unsubstituted or substituted in substitutable positions by one or more R5aAnd (4) substituting the group. Preferred R5Examples of (b) include phenyl, pyridyl, oxazolyl, thienyl, thiazolyl, morpholinyl, furyl, imidazolyl, piperazinyl, pyrimidinyl, isoxazolyl or piperidinyl. More preferably oxazolyl, pyridyl, phenyl, furyl, thienyl or thiazolyl. Most preferred is R5Including pyridyl or pyridyl.
L1Embodiments of (1) include a direct bond, -CS-, -C1-6Alkoxy-, -carbonyl-, -SO2-、-CON(R11)-、-CONR11OR11-、-CONR11N(R11)-、-C(＝NR11)-、-C(＝NOR11)-、-C(＝NN(R11)2) -, 5-12 membered aromatic or non-aromatic ring, 5-12 membered heteroaryl or heteroaryl (optionally unsubstituted or substituted in substitutable positions by one or more R) with one or more heteroatoms N, O or S14Substituted with groups). L is1Is- (CH)2)m-V-(CH2)n-or-V- (CH)2)n-V; m is 0 to 6; n is 0 to 6; v is independently-C (R)11)2-、-C(R11)2C(R11)2-、-C(R11)＝C(R11)-、-C(R11)2O-、-C(R11)2NR11-、-C≡C-、-O-、-S-、-NR11-、-N(R10)CO-、-N(R10)CO2-、-CON(R10)-、-CO-、-CO2-、-OC(＝O)、-OC(＝O)N(R10)-、-CONR11NR11-、-CONR11-、-OCONR11、-SO2-、-N(R10)SO2-、-SO2N(R10)-、-NR10CONR10-、-NR10CSNR10-, Ring C3-8Haloalkyl or ring C3-6An alkyl group. Preferred is L1Selected from-CS-, -CONH-, -C1-6Alkanediyl-, -CO-, -SO2-、-CH2-、-CH2O-、-CH2CH2-、-C＝O-、-CONH-、-CONHC(CH3)2-、-CONH(CH2)3OCH2-、-OCH2CH2-、-OCH2CO-、-OCH2CH2N(CH3)2-, and-CONHCH2CH2N(CH3)2-. More preferred L1Is selected from-CH2-、-CH2O-、-CH2CH2-、-C＝O-、-SO2-、-CONH-、-CONHC(CH3)2-、-CONH(CH2)3OCH2-、-CONHCH2CH2N(CH3)2-、-OCH2-and-OCH2CH2-. Preferred R5Examples of (b) are selected from phenyl, pyridyl, oxazolyl, thienyl, thiazolyl, morpholinyl, imidazolyl, piperazinyl, pyrimidinyl, isoxazolyl, and piperidinyl.
Preferred R5aExamples of (A) include halogen, haloalkyl, OCH2CON(CH3)2、OCH2COOC(CH3)3、OCH2CH2N(CH2CH3)2、OCH2COOH、OC(CH3)2COOC(CH3)2、OCON(CH3)2、OCONHCH3、OCH2CH2OH、OCONHCH2CHCH3Or NHCOCH3。R5Optionally unsubstituted or substituted in substitutable positions by one or more R5aAnd (4) substituting the group.
L1Is- (CH)2)m-V-(CH2)n-; or-V- (CH)2)n-V; m is 0 to 6; n is 0 to 6; v is independently-C (═ NR)11)-、-C(＝NOR11)-、-C(＝NN(R11)2)-；-C(R11)2-、-C(R11)2C(R11)2-、-C(R11)＝C(R11)-、C(R11)2NR11-、-C≡C-、-O-、-S-、-NR11-、-N(R10)CO-、-N(R10)CO2-、-CON(R10)-、-CO-、-CO2-、-OC(＝O)-、-OC(＝O)N(R10)-、-CONR11NR11-、-CONR11-、-SO2-、-N(R10)SO2-、-SO2N(R10) -or-NR10CONR10-、-NR10CSNR10-, Ring C3-6Haloalkyl or ring C3-6An alkyl group. Preferred is L1Examples of (A) are selected from-CONH-, -C1-6Alkyl-, -C1-6Alkoxy-, -CO-, -SO2-、-CH2-、-CH2O-、-CH2CH2-、-C＝O-、-CONH-、-CONHC(CH3)2-、-CONH(CH2)3OCH2-、-OCH2CH2-、-OCH2CO-、-OCH2CH2N(CH3)2- -and- -CONHCH2CH2N(CH3)2-. More preferred L1Is selected from-CH2-、-CH2O-、-CH2CH2-、-C＝O-、-SO2-、-CONH-、-CONHC(CH3)2-、-CONH(CH2)3OCH2-、-CONHCH2CH2N(CH3)2-, and-OCH2CH2-。
Another embodiment is: r2Independently selected from R7And L3-R7(ii) a Each R of this embodiment7Independently selected from hydrogen, C1-6Alkyl, halogen, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkyl (OR)11)、C0-6Alkyl group COOR11、C0-6Alkyl CON (R)11)2、C0-6Alkyl N (R)11)2、C1-6Alkyl OR11、C0-6Alkyl SO2N(R11)2、C0-6Alkyl C.ident.N, cyclic C3-6Alkyl C.ident. N, C0-6Alkyl CONR11N(R11)2、C0-6Alkyl CONR11OR11、C0-6Alkyl OCOR11Ring C3-6Alkyl, ring C3-6Alkyl OR11(ii) a A 5-12 membered aromatic or non-aromatic ring; or 5-12 membered heteroaryl and heterocyclyl with one or more heteroatoms N, O or S; r7Optionally unsubstituted or substituted in substitutable positions by one or more R7aSubstituted by groups;
another embodiment is: r2Is R7Each R of this embodiment7Selected from 5-12 membered aromatic or non-aromatic rings; 5-12 membered heteroaryl and heterocyclyl having one or more heteroatoms N, O or S. R 7Optionally unsubstituted or substituted in substitutable positions by one or more R7aRadical take-offGeneration;
preferred R7Is phenyl, pyridyl, thienyl, furyl, piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiazolyl, indolyl, oxazolyl, pyridyl, isoxazolyl, pyrimidinyl, naphthyl, hydrogen, CF3、C0-6Alkyl C.ident. N, CH2OH、COOCH3、COON(R11)2Or COOR11。R7Other examples of (2) include trifluoromethyl, CH2C≡N、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, Ring C3-6Alkyl, ring C3-6Alkyl OR11Ring C3-6Alkylamine, or COOCH (CH)3)2. More preferably, R7Is CF3、COOCH3COOH, or CONHCH2CH3. When R is7When it is phenyl or pyridyl, R is preferably7aSelected from halogen, C1-6Alkyl radical, C1-6Alkoxy, and C1-6A haloalkyl group. R7aAre selected from halogen, trifluoromethyl, C1-6Alkyl radical, C1-6Alkoxy, CH ═ CHCOOH, CH2COOH、OCH2COOH、OCONHCH(CH3)2、NHCOCH3、OH、OCH3、COOH、COOCH3、OCH2C(CH3)3、OCH2CH(CH3)2、OCH(CH3)2OCOCH(CH3)2、OCONHCH3、OCH2CH3And OCH (CH)3)2。
Another embodiment is: r2Is L3-R7. Each R of the present embodiment7Selected from 5-12 membered aromatic or non-aromatic rings; 5-12 membered heteroaryl and heterocyclyl having one or more heteroatoms N, O or S. R7Optionally unsubstituted or substituted in substitutable positions by one or more R7aSubstituted by groups;
preferred L in the present embodiment3Independently selected from a direct bond, -CS-, -CO-, -CONR11-、-C(＝NR11)-、-C(≡NOR11)-、-C(≡NN(R11)2)-；(CH2)m-V1-(CH2)n-, or-V1-(CH2)n-V1-; m is 0 to 6; n is 0 to 6; v 1Independently is-C (R)11)2-、-C(R11)2C(R11)2-、-C(R11)＝C(R11)-、-C(R11)2O-、-C≡C-、-O-、-S-、-NR11-、-C(R11)2NR11-、-N(R10)CO-、-N(R10)CO2、-CON(R10)-、-OCO-、-CO-、-CO2-、-OC(＝O)-、-OC(＝O)N(R10)-、-SO2-、-N(R10)SO2-、-NR10CONR10-、-NR10CSNR10-, Ring C3-6Alkyl, ring C3-6Haloalkyl or-SO2N(R10) -. More preferably L3is-CH2-、-CO-、-OCH2-、-CH2OCH2-、-CONH-、-CH2OCOH2-、-CH2NHCH2-、-CH2NC(CH3)2-、-CH2N(CH3)CH2-、-CH2COCH3-、-CH2N(CH3)2CH2-cyclohexylamine, or cyclopropylamine.
Each R7aIndependently of one another is halogen, C1-6Alkyl, aryl, heteroaryl, and heteroaryl,CR11＝CR11COOH、C1-6Alkoxy radical, C0-6Alkyl OR11、C0-6Alkyl OVCOOR11、C0-6Alkyl radical NR11COR11、C0-6Alkyl SO2NR11COR11、C0-6Alkyl SO2N(R11)2；C0-6Alkyl SR11、(C0-6Alkyl) C ═ O (OR)11)、OVOR11、C1-6Haloalkyl, OC1-6Haloalkyl, haloaryl, aryloxy, arylalkoxy, aryloxyalkyl, C1-6Alkoxyaryl, aryl C0-6Alkylcarboxyl, NR11SO2R11、OC1-6Alkyl, OC0-6Alkyl group COOR11、C0-6Alkoxyheteroaryl group, C0-6Alkoxy heterocyclic group, ring C3-6Alkyl group COOR11、C3-6A cycloalkylamine; a 5-12 membered aromatic or non-aromatic ring, or a 5-12 membered heteroaryl or heterocyclyl group having one or more heteroatoms N, O or S; r7aAre selected from halogen, trifluoromethyl, C1-6Alkyl radical, C1-6Alkoxy, CH ═ CHCOOH, CH2COOH、OCH2COOH、OCONHCH(CH3)2、NHCOCH3、OH、OCH3、COOH、COOCH3、OCH2C(CH3)3、OCH2CH(CH3)2、OCH(CH3)2OCOCH(CH3)2、OCONHCH3、OCH2CH3And OCH (CH)3)2。
Each R7aMay be unsubstituted or substituted in substitutable positions by one or more R8Substituted by groups; each R8Independently is C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Haloalkyl, C0-6Alkyl OR11、C1-6Haloalkyl OR11、C0-6Alkyl CON (R)11)2、C0-6Alkyl group COR11、C0-6Alkyl group COOR11、NR11COOR11Or C0-6Alkyl SO2R11。
R7Other examples of (2) include trifluoromethyl, CH2C≡N、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, Ring C3-6Alkyl, ring C3-6Alkyl OR11Or COOCH (CH)3)2. More preferably R7Is CF 3、COOCH3COOH, or CONHCH2CH3. When R is7When R is phenyl, pyridyl, thienyl, furyl, piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiazolyl, indolyl, oxazolyl, pyridyl, isoxazolyl, pyrimidinyl, or naphthyl, R is7aAre selected from halogen, trifluoromethyl, C1-6Alkyl radical, C1-6Alkoxy, CH ═ CHCOOH, CH2COOH、OCH2COOH、OCONHCH(CH3)2、NHCOCH3、OH、OCH3、COOH、COOCH3、OCH2C(CH3)3、OCH2CH(CH3)2、OCH(CH3)2OCOCH(CH3)2、OCONHCH3、OCH2CH3And OCH (CH)3)2. Preferably R7aSelected from halogen, C1-6Alkyl radical, C1-6Alkoxy, and C1-6A haloalkyl group.
Each R3Independently selected from R6and-L-R6(ii) a Another embodiment is: r3Is R6Wherein R is6Independently of one another is hydrogen, halogen, C1-6Alkyl radical, C1-6Haloalkyl, C1-6Haloalkyl OR11、C0-6Alkyl OR11、C0-6Alkyl CON (R)11)2、C0-6Alkyl group COR11、OCON(R11)2、CONR11OR11Nitro group, C1-6Alkyl group COOR11(ii) a A 5-12 membered aromatic or non-aromatic ring; a 5-12 membered heteroaryl or heterocyclyl having one or more heteroatoms N, O or S; preferably R6Is hydrogen or unsubstituted or optionally substituted phenyl. Each R6Optionally unsubstituted or substituted in substitutable positions by one or more R6aAnd (4) substituting the group.
Each R6aIndependently of one another is halogen, C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Haloalkyl, C1-6Haloalkyl OR11、CON(R11)2、CONR11OR11、C0-6Alkyl group COOR11；CR11＝CR11COOH、C0-6Alkyl OR11、C0-6Alkyl group COR11、C0-6Alkyl SO2R11、C0-6Alkyl OCOOR11、C0-6Alkyl radical NR11COR11、C0-6Alkyl SO2NR11COR11、C0-6Alkyl SO2N(R11)2；C0-6Alkyl SR 11、(C0-6Alkyl) C ═ O (OR)11)、OVOR11、OC1-6Haloalkyl, aryloxy, arylalkoxy, aryloxyalkyl, C1-6Alkoxyaryl, aryl C0-6Alkylcarboxyl, NR11SO2R11、OC1-6Alkyl, OC0-6Alkyl group COOR11、C0-6Alkoxyheteroaryl group, C0-6Alkoxyheterocyclyl, cycloalkyl COOR11。
Another embodiment is: r3Is L-R6L is independently selected from a direct bond, -CO-, -CONR11-、-C(＝NR11)-、-C(＝NOR11)-、-C(＝NN(R11)2)-；C2-6Alkanediyl chains wherein the alkanediyl chain is uninterrupted or optionally-C (R)11)2-、-C(R11)2C(R11)2-、-C(R11)＝C(R11)-、-C≡C-、-O-、-S-、-N(R10)CO-、-N(R10)CO2、-NR11-、-CON(R10)-、-CO-、-CO2-、-OC(＝O)-、-OC(＝O)N(R10)-、-SO2-、-N(R10)SO2-, or-SO2N(R10) -an interrupt; - (CH)2)m-V0-(CH2)n-or-V0-(CH2)n-V0-; m is 0 to 6; n is 0 to 6; v0Independently is-C (R)11)2-、-C(R11)2C(R11)2-、-C(R11)＝C(R11)-、-C(R11)2O-、-C(R11)2NR11-、-C≡C-、-O-、-S-、-OR11N-、-OR11CO-、-NR11-、-N(R10)CO-、-N(R10)CO2-、-CON(R10)-、-OCO-、-CO-、-CO2-、-OC(＝O)-、-OC(＝O)N(R10)-、-SO2-、-N(R10)SO2-、-NR10CONR10-、-NR10CSNR10-、-SO2N(R10) -, Ring C3-6Haloalkyl or ring C3-6An alkyl group; examples of L include-O-, -CH2-、-CH2O-、-CH2CH2-、-C＝O-、-SO2-、-CONH-、-CONHC(CH3)2-、-CONH(CH2)3OCH2-、-CONHCH2CH2N(CH3)2-, or-OCH2CH2-。
Each R4Independently selected from C1-6Alkyl radical, CR11＝CR11COOR11、C0-6Alkyl C.ident. N, C1-6Alkoxy radical, C0-6Alkyl OR11、C0-6Alkyl group COR11、C0-6Alkyl SO2R11、C0-6Alkyl OCOOR11、C0-6Alkyl radical NR11COR11、C0-6Alkyl SO2NR11COR11、C0-6Alkyl SO2N(R11)2、C0-6Alkyl SR11、(C0-6Alkyl) C ═ O (OR)11)、OVOR11Halogen, C1-6Haloalkyl, OC1-6Haloalkyl, aryloxy, arylalkoxy, aryloxyalkyl, C1-6Alkoxyaryl, aryl C0-6Alkylcarboxyl, NR11SO2R11、OC1-6Alkyl, OC0-6Alkyl group COOR11、C0-6Alkoxyheteroaryl group, C0-6Alkoxyheterocyclyl, cycloalkyl COOR115-12 membered aromatic or non-aromatic rings, or 5-12 membered heteroaryl or heterocyclyl with one or more heteroatoms N, O or S. Preferably R4Selected from OH, CN, C (CH) 3)2OH、SO2CH3、SO2C(CH3)3、SO2CH2CH3、SCH2CH3、SCH3、OCH3、C1-6Alkyl radical, CH2COOH、C(CH3)2COOH、NHSO2CH3F, Cl, Br, cyclobutane-COOH, OC (CH)3)2COOH、CF3、C(CH3)2COOH、CH2COOCH3、CH2CH2COOH、OCH2COOCH3And COCH3. More preferably R4Is SO2CH3、SO2CH2CH3、SCH2CH3Or SCH3。
Each R4Optionally unsubstituted or substituted in substitutable positions by one or more R4aSubstituted by groups; each R4aIndependently selected from C1-6Alkyl, (C)1-6Alkyl) C ═ O (OR)11)；C1-6Alkoxy radical, C0-6Alkyl OR11、C0-6Alkyl group COR11、C0-6Alkyl SO2R11、C0-6Alkyl SO2N(R11)2、C0-6Alkyl SR11、(C0-6Alkyl) C ═ O (OR)11) Halogen, C1-6Haloalkyl, aryloxy, arylalkoxy, aryloxyalkyl, C1-6Alkoxyaryl, aryl C0-6Alkylcarboxyl, NR11SO2R11、OC1-6Alkyl radical, C0-6Alkyl C.ident.N, or OC0-6Alkyl group COOR11。
Each R10Independently selected from R11、C(＝O)R11、CO2R11、SO2R11(ii) a Each R11Independently from hydrogen or substituted or unsubstituted C1-8An aliphatic group; c1-6A haloalkyl group;
N(R12)2(ii) a A 5-12 membered aromatic or non-aromatic ring, or a 5-12 membered heteroaryl or heterocyclyl group having one or more heteroatoms N, O or S; optionally unsubstituted or substituted in substitutable positions by one or more R12And (4) substituting the group.
Each R12Independently of one another is halogen, C1-6Haloalkyl, C1-6Alkyl radical, C1-6Alkoxy group, (C)1-6Alkyl) C ═ O (OR)13)；C1-6Alkoxyalkyl group, C0-6Alkyl group COR13、C0-6Alkyl OR13、C0-6Alkyl SO2R13、C0-6Alkyl CON (R)13)2、C0-6Alkyl CONR13OR13、C0-6Alkyl SO2N(R13)2、C0-6Alkyl SR13、(C0-6Alkyl) C ═ O (OR)13)、C0-6Haloalkyl OR13Aryloxy, arylalkoxy, aryloxyalkyl, C 0-6Alkoxyaryl, aryl C0-6Alkyl carboxyl, C0-6Alkyl radical NR13SO2R13、OC1-6Alkyl, or OC0-6Alkyl group COOR13。
Each R13Independently is hydrogen or substituted or unsubstituted C1-8An aliphatic group.
Each R14Independently is C1-6Alkyl radical, C1-6Alkoxy, halogen, C1-6Haloalkyl, C0-6Alkyl CON (R)11)2、C0-6Alkyl CONR11OR11、C0-6Alkyl OR11Or C0-6Alkyl group COOR11。
Another embodiment of the present invention is: g is independently G1, G2, or G3;
4.G1 5.G2 6.G3
each ring J or ring K may independently be absent, the same or different, and is independently selected from a 5-12 membered aromatic or non-aromatic ring or a 5-12 membered heterocyclyl or heteroaryl group having one or more heteroatoms N, O or S.
Each ring J or ring K is independently unsubstituted or substituted in a substitutable position by one or more R4And (4) substituting the group. Ring J is preferably a benzene ring or a 5-membered heteroaryl ring. Examples of ring J include phenyl, pyridyl, thienyl, furyl, morpholinyl, thiazolyl, indolyl, oxazolyl, biphenyl, naphthyl, piperidinyl, piperazinyl, or imidazolyl. Preferred ring J is thienyl or phenyl. Ring J is optionally unsubstituted or substituted in a substitutable position by one or more R4And (4) substituting the group.
Is marked as R4Suitable ring J substituents of (A) include methanesulfonyl, or C 1-6An aliphatic group, or a substituent selected from: CR11＝CR11COOR11、C1-6Alkyl radical, C1-6Alkoxy radical, C0-6Alkyl OR11、C1-6Alkyl group COR11、C0-6Alkyl SO2R11、C0-6Alkyl OCOOR11、C0-6Alkyl radical NR11COR11、C0-6Alkyl SO2NR11COR11、C0-6Alkyl SO2N(R11)2、C0-6Alkyl SR11、(C0-6Alkyl) C ═ O (OR)11)、OVOR11Halogen, C1-6Haloalkyl, OC1-6Haloalkyl, aryloxy, arylalkoxy, aryloxyalkyl, C1-6Alkoxyaryl, aryl C0-6Alkylcarboxyl, NR11SO2R11、OC1-6Alkyl, OC0-6Alkyl group COOR11、C1-6Alkoxyheteroaryl group, C0-6Alkoxyheterocyclyl group, C0-6Alkyl C [ identical to ] N, cycloalkyl COOR115-12 membered aromatic or non-aromatic rings, and 5-12 membered heteroaryl or heterocyclyl having one or more heteroatoms N, O or S. Preferred R4Examples include OH, CN, C (CH)3)2OH、SO2CH3、SO2NH2、SO2CH2CH3、SO2C(CH3)3、SCH2CH3、SCH3、OCH3、C1-6Alkyl radical, CH2COOH、C(CH3)2COOH、NHSO2CH3、F、Cl、Br、C(CH2CH3)2COOH、CH2COOCH3、C(CH3)2COOCH3、CH2CH2COOH、CH＝CHCOOH、OCH2COOCH3、COCH3、OCH3、COOC(CH3)3cyclobutane-COOH, OC (CH)3)2COOH、CH2CH3、CH3、CH(CH3)2、CH2COOCH3、OCON(CH2CH3)2、NHCOCH3Or CF3。
Examples of ring K include phenyl, pyridyl, thienyl, furyl, morpholinyl, thiazolyl, indolyl, oxazolyl, biphenyl, naphthyl, piperidinyl, piperazinyl, isoxazolyl, pyrimidinyl, or imidazolyl. Ring K is optionally unsubstituted or substituted in a substitutable position by one or more R4And (4) substituting the group. Is marked as R4Suitable ring K substituents of (A) include methanesulfonyl, or C1-6An aliphatic group, or a substituent selected from: CR11＝CR11COOR11、C1-6Alkyl radical, C1-6Alkoxy radical, C 0-6Alkyl OR11、C1-6Alkyl group COR11、C0-6Alkyl SO2R11、C0-6Alkyl OCOOR11、C0-6Alkyl radical NR11COR11、C0-6Alkyl SO2NR11COR11、C0-6Alkyl SO2N(R11)2、C0-6Alkyl SR11、(C0-6Alkyl) C ═ O (OR)11)、OVOR11、C0-6Alkyl C [ identical to ] N, halogen, C1-6Haloalkyl, OC1-6Haloalkyl, aryloxy, arylalkoxy, aryloxyalkyl, C1-6Alkoxyaryl, aryl C0-6Alkylcarboxyl, NR11SO2R11、OC1-6Alkyl, OC0-6Alkyl group COOR11、C0-6Alkoxyheteroaryl group, C0-6Alkoxyheterocyclyl, cycloalkyl COOR115-12 membered aromatic or non-aromatic rings, and 5-12 membered heteroaryl or heterocyclyl having one or more heteroatoms N, O or S. Preferably, ring K is phenyl, pyridyl, thienyl, furyl, morpholinyl, thiazolyl, indolyl, oxazolyl, biphenyl, naphthyl, piperidinyl, piperazinyl, isoxazolyl, pyrimidinyl, or imidazolyl. When ring K is phenyl or pyridyl, it is preferably replaced by methanesulfonylAnd (4) generation. Preferred R4Examples of groups include OH, CN, C (CH)3)2OH、SO2CH3、SO2NH2、SO2CH2CH3、SO2C(CH3)3、SCH2CH3、SCH3、OCH3、C1-6Alkyl radical, CH2COOH、C(CH3)2COOH、NHSO2CH3、F、Cl、Br、C(CH2CH3)2COOH、CH2COOCH3、C(CH3)2COOCH3、CH2CH2COOH、CH＝CHCOOH、OCH2COOCH3、COCH3、OCH3、COOC(CH3)3cyclobutane-COOH, OC (CH)3)2COOH、CH2CH3、CH3、CH(CH3)2、CH2COOCH3、OCON(CH2CH3)2、NHCOCH3Or CF3。
L2Is- (CH)2)m-V2-(CH2)n-or-V2-(CH2)m-V2-; m is 0 to 6; n is 0 to 6; v2Independently is-C (R)11)2-、-C(R11)2C(R11)2-、-C(R11)＝C(R11)-、-C(R11)2O-、-C(R11)2NR11-、-C≡C-、-O-、-S-、-N(R10)CO-、-N(R10)CO2-、-CON(R10)-、-CON(R11)-、-CON(R11)O-、-CO-、-CO2、-OR11N-、-OR11COO-、-OC(＝O)-、-OC(＝O)N(R10)-、-SO2-、-N(R10)SO2-、-NR10CONR10-、-SO2N(R10)-、-NR10CSNR10-, Ring C3-8Haloalkyl, or ring C3-6An alkyl group; c2-6Alkanediyl chains wherein the alkanediyl chain is uninterrupted or optionally-C (R)11)2-、-C(R11)2C(R11)2-、-C(R11)＝C(R11)-、-C(R11)2O-、-C≡C-、-O-、-S-、-N(R10)CO-、-N(R10)CO2-、-CON(R10)-、-CON(R11)-、-CON(R11)O-、-CO-、-CO2-、-OC(＝O)-、-OC(＝O)N(R10)-、-SO2-、-N(R10)SO2-, or-SO2N(R10) -an interrupt; 5-12 membered aromatic or non-aromatic ring, or 5-12 membered heteroaryl or heterocyclyl with one or more heteroatoms N, O or S, optionally unsubstituted or substituted in substitutable positions with one or more R 9And (4) substituting the group. Optionally, L2Is a direct chemical bond, -C1-6Alkyl-, -C1-6Alkoxy-, -C0-6Alkyl group COOR11-、-CH＝CHCOO-、-C0-6Alkyl CONR11-、-OC0-6Alkyl group COOR11-、-C0-6Alkyl SO2R11-、-C0-6Alkyl SO2-、-C0-6Alkyl N (R)11)-、-C0-6Alkyl O-, -OC0-6Alkyl N (R)11)-、-C0-6Alkyl radical CO-C1-6Carboxy-, -cycloalkylamine-, -C (═ NR)11)-、-C(＝NOR11)-、-C(＝NN(R11)2) -; 5-12 membered aromatic or non-aromatic ring, 5-12 membered heteroaryl or heterocyclyl with one or more heteroatoms N, O or S, optionally unsubstituted or substituted in substitutable positions with one or more R9And (4) substituting the group. Preferred is L2Selected from-CONH-, -CONHCH2-、-CH2O-、-OCH2COOCH2-、-CONHCH2-, and-C.ident.C-.
Another embodiment is: g is G1, R1Is R5And R is2Is R7. When G of formula Iaa, Ibb, Icc, or Idd is G1, a more preferred embodiment of the invention relates to compounds having one or more characteristics selected from the group consisting of:
R1is phenyl, pyridyl, thienyl, furyl, morpholinyl, thiazolyl, indolyl, oxazolyl, isoxazolyl, pyrimidinyl, or imidazolyl; r5Optionally unsubstituted or substituted in substitutable positions by one or more R5aSubstituted by groups;
R5ais halogen, trifluoromethyl, OCONHCH (CH)3)2、NHCOCH3、OH、OCH3、COOH、COOCH3、OCH2C(CH3)3、OCH2CH(CH3)2、OCH2CH2N(CH3)2、OCH(CH3)2OCOCH(CH3)2、OCONHCH3、OCH2CH3Or OCH (CH)3)2；
R2Is trifluoromethyl, 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, or COOCH (CH)3)2；
R3Is hydrogen or unsubstituted or optionally substituted phenyl;
Ring J is thienyl, thiazolyl, furyl, pyridyl, or phenyl;
ring K is unsubstituted or optionally substituted phenyl or pyridyl; and is
R4Is SO2CH3、SO2C(CH3)3、CH3、SO2NH2、SO2CH2CH3、SCH2CH3、SCH3、OCH3、CF3、OCF3、CH2CF3、C1-6Alkyl, halogen, or CH2COOH。
Another embodiment is: g is G1, R1Is R5And R is2Is R7. When G of formula Iaa, Ibb, Icc, or Idd is G1, preferred embodiments of the invention relate to compounds having one or more characteristics selected from the group consisting of:
R1is thienyl, furyl, morpholinyl, thiazolyl, indolyl, oxazolyl, pyridyl, imidazolyl, isoxazolyl, pyrimidinyl, or phenyl; r5Optionally unsubstituted or substituted in substitutable positions by one or more R5aSubstituted by groups;
R5ais halogen, trifluoromethyl, OCONH (CH)2)2CH3、OCONH(CH2CH3)2、NHCOCH3、OH、OCH3、COOH、COOCH3、OCH2C(CH3)3、OCH2CH(CH3)2、OCH(CH3)2OCOCH(CH3)2、OCONHCH3、OCH2CH3Or OCH (CH)3)2；
R2Is R selected from the group7：CH2C≡N、C(CH3)2C ≡ N, ring C3-6Alkyl C.ident.N, thienyl, furyl, morpholinyl, thiazolyl, indolyl, oxazolyl, pyridyl, imidazolyl, isoxazolyl, pyrimidinyl, or phenyl; r7Optionally unsubstituted or substituted in substitutable positions by one or more R7aSubstituted by groups;
R7aselected from halogen, trifluoromethyl, C1-6Alkyl radical, C1-6Alkoxy, CH ═ CHCOOH, CH2COOH、OCH2COOH、OCONHCH(CH3)2、NHCOCH3、OH、OCH3、COOH、COOCH3、OCH2C(CH3)3、OCH2CH(CH3)2、OCH(CH3)2OCOCH(CH3)2、OCONHCH3、OCH2CH3Or OCH (CH)3)2；
R3Is hydrogen or unsubstituted or optionally substituted phenyl;
Ring J is thienyl, thiazolyl, furyl, pyridyl, or phenyl;
ring K is optionally substituted phenyl or pyridyl; and is
R4Is CH ═ CHCOOH, SO2CH3、SO2NH2、SO2CH2CH3、SCH2CH3、SO2C(CH3)3、SCH3、OCH3、C1-6Alkyl, CF3F, Cl, or Br.
Another embodiment is: g is G1, R1Is L1-R5And R is2Is R7. When G of formula Iaa, Ibb, Icc, or Idd is G1, preferred embodiments of the invention relate to compounds having one or more characteristics selected from the group consisting of:
R1is L1-R5；R5Is phenyl, pyridyl, morpholinyl, oxazolyl, furanyl, thiazolyl, or thienyl; r5Unsubstituted or optionally substituted by R5aSubstitution;
R5ais halogen or trifluoromethyl;
L1is-CS-, CH2、CH2O、CH2CH2、C＝O、SO2、CONH、CONHC(CH3)2、CONH(CH2)3OCH2、OCH2、OCH2CO, or OCH2CH2；
R2Is trifluoromethyl, CONHCH2CH2N(CH3)2、CONHCH2CH2CH2N(CH3)2Or CONHCH2CH2CH2OCH3；
R3Is hydrogen or unsubstituted or optionally substituted by R6aSubstituted phenyl;
ring J is thienyl, pyridyl, thiazolyl, or phenyl; ring K is substituted with phenyl or pyridyl;
and is
R4Is SO2CH3、SO2NH2、SO2CH2CH3、SCH2CH3、SCH3、OCH3、C1-6Alkyl, halogen or CH2COOH。
Another embodiment is: g is G1, R1Is R5And R is2Is L3R7. When G of formula Iaa, Ibb, Icc, or Idd is G1, preferred embodiments of the invention relate to compounds having one or more characteristics selected from the group consisting of:
R1is R selected from the group5: thienyl, furyl, morpholinyl, thiazolyl, indolyl, oxazolyl, pyridyl, imidazolyl, isoxazolyl, pyrimidinyl, and phenyl;
R5Optionally unsubstituted or substituted in substitutable positions by one or more R5aSubstituted by groups;
R5ais OCH2C(CH3)3、Cl、F、Br、OCH2CH(CH3)2、OCH2CH3、CF3、COOH、OCH3、OH、NO2、OCOCH(CH3)2、NHCOCH3、OCONHCH(CH3)2、O(CH2)2、CONH2、O(CH)(CH3)2、C1-6Alkyl, OCH2COOH、OCH2COOC(CH3)3、O(CH2)2N(CH2CH3)2、OCOC(CH3)3、OC(CH2)2COOH、OCONH(CH3)2、OCONCH3、OCONHCH2CH2CH3、OC(CH3)2COOC(CH3)3Or O (CH)2)2OH；
R2Is L3-R7；R7Is phenyl, pyridyl, thienyl, furyl, morpholinyl, thiazolyl, oxazolyl, piperidinyl, imidazolyl, piperazinyl, or pyridyl;
L3is-CS-, -CO-, -C1-6Alkanediyl-, -CONH-, -CONR11-、-CONR11NR11-、-CH2OCH2-、-CH2OCH2CH2-、-OCH2-、-CH2N(CH3)2-、-CH2NHCH2-、-CONR11O-、-CH2OCOCH2-、-CH3N(CH3)(CH2)-、-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(CH2C≡N)CH2-；
R7aSelected from halogen, C1-6Alkyl radical, C1-6Alkoxy, CF3、OCH2CH2COOH、CH2COOH、COOCH3、CH2OH and OCH3；
R3Is hydrogen or unsubstituted or optionally substituted by R6aSubstituted phenyl;
ring J is thienyl, pyridyl, thiazolyl, furyl, or phenyl;
ring K is substituted phenyl or pyridyl; and is
R4Is SO2CH3、SO2CH2CH3、SCH2CH3、SCH3、SO2NH2、OCH3、C1-6Alkyl radical, CH2COOH、C(CH3)2COOH、NHSO2CH3、F、Cl、Br、CF3Or COCH3；
Another embodiment is: g is G1, R1Is L1-R5And R is2Is L3-R7. When G of formula Iaa, Ibb, Icc, or Idd is G1, preferred embodiments of the invention relate to compounds having one or more characteristics selected from the group consisting of:
R5is L1-R5；R5Selected from the group consisting of thienyl, furyl, morpholinyl, thiazolyl, indolyl, imidazolyl, piperazinyl, piperidinyl, oxazolyl, pyridinyl, isoxazolyl, pyrimidinyl, imidazolyl, and phenyl; r5Optionally unsubstituted or substituted in substitutable positions by one or more R 5aSubstituted by groups;
R5ais C1-6Alkyl radical, C1-6Alkoxy, COOH, halogen or trifluoromethyl;
L1is-CS-, -CH2-、-CH2O-、-CH2CH2-、-OCH2CH2-、-OCH2CO-、-C＝O-、-SO2-、-CONH-、-CONHC(CH3)2-、-CONH(CH2)3OCH2-, or-CONHCH2CHN(CH3)2-；
R2Is L3-R7；R7Selected from phenyl, pyridyl, thienyl, furyl, morpholinyl, thiazolyl, oxazolyl, pyridyl, isoxazolyl, pyrimidinyl, imidazolyl, CF3And COOCH3；R7Optionally unsubstituted or substituted in substitutable positions by one or more R7aSubstituted by groups;
L3is CH2、CH2OCH2、NC(CH3)2、CH2NH(CH2)2、CONH、CO、CONR11、OCH2、CH2N(CH3)2CH2、CH2OCOCH2、CH2CONHCH2、CH2CONHCH2CH2Cycloalkyl amine, CH2N(CH3)CH2Or CH2NCH(CH3)2CH2；
R7aSelected from halogen, trifluoromethyl, C1-6Alkyl radical, C1-6Alkoxy, 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、CH2N(CH2)CH2CF3And OCH (CH)3)2；
R3Is hydrogen or unsubstituted or optionally substituted by R6aSubstituted phenyl;
ring J is thienyl, thiazolyl, furyl, pyridyl, or phenyl; ring K is optionally substituted phenyl or pyridyl; and is
R4Is SO2CH3、SO2CH2CH3、SCH2CH3、SCH3、OCH3、C1-6Alkyl radical, CH2COOH、C(CH3)2COOH、NHSO2CH3F, Cl, or Br.
Another embodiment is: g is G2, and R1Is R5And R is2Is R7. When G of formula Iaa, Ibb, Icc, or Idd is G2, preferred embodiments of the invention relate to compounds having one or more characteristics selected from the group consisting of:
R1is R selected from the group5: thienyl, furyl, morpholinyl, thiazolyl, indolyl, oxazolyl, pyridyl, isoxazolyl, pyrimidinyl, imidazolyl, and phenyl;
R5Optionally unsubstituted or substituted in substitutable positions by one or more R5aSubstituted by groups;
R2is R selected from the group7: phenyl, pyridyl, thienyl, furyl, morpholinyl, thiazolyl, oxazolyl, pyridyl, isoxazolyl, pyrimidinyl, imidazolyl, CF3And COOCH3；R7Optionally unsubstituted or substituted in substitutable positions by one or more R7aSubstituted by groups;
R3is hydrogen or unsubstituted or optionally substituted phenyl;
L2selected from-CONH-, -CONHCH2-、-CH2O-、-OCH2COOCH2-、-O-、C≡C-、-OCH2CH2-, and-CONHOCH2CH(OH)CH2O-；
Ring J or K is substituted phenyl, biphenyl, pyridyl, piperidinyl, piperazinyl, morpholinyl, thienyl, or naphthyl; and is
R4Selected from SO2CH3、SO2CH2CH3、SO2CH2CH2CH3、SCH2CH3、SCH3、OCH3、C1-6Alkyl radical, CH2COOH、C(CH3)2COOH、NHSO2CH3、F、Cl、Br、C(CH3)2COOH、CH2COOCH3、C(CH3)2COOCH3、CH2CH2COOH、OCH2CON(R11)2、OCH2CH2N(CH3)2、OCH2COOH、OCH2COOCH3、CH2OH、COCH3、COOC(CH3)3cyclobutane-COOH, OC (CH)3)2COOH and CF3。
Another embodiment is: g is G2, R1Is L1-R5And R is2Is R7. When G of formula Iaa, Ibb, Icc, or Idd is G2, preferred embodiments of the invention relate to compounds having one or more characteristics selected from the group consisting of:
R1is L1-R5；R5Is substituted phenyl or pyridyl;
R5ais halogen, trifluoromethyl, C1-6Alkyl radical, C1-6Haloalkyl, nitro, C1-6Alkoxy, or OCON (C)1-6Alkyl radical)2；
L1is-CS-, -CH2-、-CH2O-、-CH2CH2-、-C＝O-、-SO2-、-CONH-、-CONHC(CH3)2-、-CONH(CH2)3OCH2-、-CONHCH2CH2N(CH3)2-, or-OCH2CH2-；
R2Is R selected from the group7: phenyl, pyridyl, thienyl, furyl, morpholinyl, thiazolyl, oxazolyl, pyridyl, CF 3Or COOCH3；
R3Is hydrogen or unsubstituted or optionally substituted by R6aSubstituted phenyl;
ring J or K is substituted phenyl, thienyl, furyl, piperazinyl, piperidinyl, or pyridyl;
L2is-CONH-, -CONHCH2-、-CH2O-、-OCH2COOCH2-、-O-、-C≡C-、-OCH2CH2-, or-CONHOCH2CH(OH)CH2O-; and is
R4Selected from halogen, C1-6Haloalkyl, C1-6Alkyl group COOR11And methylsulfonyl.
Another embodiment is: g is G2, R1Is R5And R is2Is L3R7. When G of formula Iaa, Ibb, Icc, or Idd is G2, preferred embodiments of the invention relate to compounds having one or more characteristics selected from the group consisting of:
R1is R selected from the group5: thienyl, furyl, morpholinyl, thiazolyl, indolyl, oxazolyl, pyridyl, imidazolyl, isoxazolyl, pyrimidinyl, and phenyl;
R5optionally unsubstituted or substituted in substitutable positions by one or more R5aSubstituted by groups;
R5ais halogen or trifluoromethyl;
R2is L3-R7；R7Selected from phenyl, pyridyl, thienyl, furyl, morpholinyl, thiazolyl, oxazolyl, pyridyl, phenyl, imidazolyl, isoxazole, pyrimidinyl, CF3Ring C3-6Alkyl C.ident. N, C0-6Alkyl C.ident.N, and COOCH3；R7Optionally unsubstituted or substituted in substitutable positions by one or more R7aSubstituted by groups;
L3is-CS-, CH2、CH2OCH2、NCH2(CH2)2、CH2N(CH2)2、CH2CN, CONH, CO, or CONHCH2；
R3Is hydrogen or unsubstituted or optionally substituted phenyl;
ring J or K is substituted phenyl, pyridyl, furyl, biphenyl, or naphthyl;
L2is-CS-, CONH, CONHCH2、CH2O、OCH2COOCH2、OCH2CH2Or OCH or2(ii) a And is
R4Is SO2CH3、SO2CH2CH3、SCH2CH3、CH2COOH、C(CH3)2COOH、NHSO2CH3、F、Cl、Br、SCH3、OCH3、C1-6Alkyl, COOCH2CO、OCH3、CH2COOH、CH2COOCH3、CH(CH3)2COOH、OC(CH3)2COOH、COOC(CH3)3cyclobutane-COOH, C (CH)3)2COOH、OCH2COOCH3And CF3。
Another embodiment is: g is G3, R1Is R5And R is2Is R7. When G of formula Iaa, Ibb, Icc, or Idd is G3, preferred embodiments of the invention relate to compounds having one or more characteristics selected from the group consisting of:
R1is R selected from the group5: thienyl, furyl, morpholinyl, thiazolyl, indolyl, oxazolyl, pyridyl, imidazolyl, isoxazole, pyrimidinyl, and phenyl;
R5optionally unsubstituted or substituted in substitutable positions by one or more R5aSubstituted by groups;
R2is R selected from the group7: phenyl, pyridyl, thienyl, furyl, morpholinyl, thiazolyl, oxazolyl, pyridyl, imidazolyl, isoxazole, pyrimidinyl, CF3Halogen, and COOCH3；R7Optionally unsubstituted or substituted in substitutable positions by one or more R7aSubstituted by groups;
R3is hydrogen or unsubstituted or optionally substituted phenyl;
L2selected from-CS-, -CONH-, -CONHCH 2-、-CH2O-、-OCH2COOCH2-、-COOCH2-、-CO-、-OCH2-、-OCO-、-NHCONH-、-O-、-OCH2CH2-, -OCONH-, and-SO2-；
Ring J or K is substituted phenyl, biphenyl, pyridyl, piperidyl, piperazinyl, morpholinyl, thienyl, furyl, pyrimidinyl, or naphthyl;
R4is methylsulfonyl, halogen, haloalkyl, CH2COOH、OCH2-phenyl, CH2COO-phenyl, OCH2COOH, or OCH2CHN(CH3)2(ii) a And is
R5aIs OCH2C(CH3)3、Cl、F、Br、OCH2CH(CH3)2、OCH2CH3、CF3、COOH、OCH3、OH、NO2、OCOCH(CH3)2、NHCOCH3、OCONHCH(CH3)2、O(CH2)2、CONH2、O(CH)(CH3)2、C1-6Alkyl, OCH2COOH、OCH2COOC(CH3)3、O(CH2)2N(CH2CH3)2、OCOC(CH3)3、OC(CH2)2COOH、OCONH(CH3)2、OCONCH3、OCONHCH2CH2CH3、OC(CH3)2COOC(CH3)3And O (CH)2)2OH。
Another embodiment is: g is G3, R1Is L1-R5And R is2Is R7. When G of formula Iaa, Ibb, Icc, or Idd is G3, preferred embodiments of the invention relate to compounds having one or more characteristics selected from the group consisting of:
R1is L1-R5；R5Is substituted phenyl or pyridyl;
R5ais halogen or trifluoromethyl;
L1is-CH2-、-CH2O-、-CH2CH2-、-C＝O-、-SO2-、-CS-、-CONH-、-CONHC(CH3)2-、-CONH(CH2)3OCH2-、-CONHCH2CH2N(CH3)2-, or-OCH2CH2-；
R2Is halogen, C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkyl group COOR11Or CF3；
R3Is hydrogen or unsubstituted or optionally substituted by R6aSubstituted phenyl;
ring J or K is phenyl, pyridyl, thienyl, furyl, piperidinyl, pyrrolidinyl, piperazinyl, morpholinyl, thiazolyl, indolyl, oxazolyl, isoxazolyl, pyrimidinyl, imidazolyl, or biphenyl;
L2is-CONH-, -CONHCH2-、-CH2O-、-OCH2COOCH2-、-OCH2-, or-OCH2CH2-; and is
R4Selected from halogen, C1-6Haloalkyl, C1-6Alkyl group COOR11And methylsulfonyl.
Another embodiment is: g is G3, R 1Is R5And R is2Is L3R7. When G of formula Iaa, Ibb, Icc, or Idd is G3, preferred embodiments of the invention relate to compounds having one or more characteristics selected from the group consisting of:
R1selected from the group consisting of thienyl, furyl, morpholinyl, thiazolyl, indolyl, oxazolyl, pyridyl, isoxazolyl, imidazolyl, pyrimidinyl, and phenyl; r5Optionally unsubstituted or substituted in substitutable positions by one or more R5aSubstituted by groups;
R2is L3-R7；R7Is phenyl, pyridyl, thienyl, furyl, morpholinyl, thiazolyl, oxazolyl, piperidinyl, imidazolyl, piperazinyl, pyridyl, isoxazolyl, imidazolyl, pyrimidinyl, CF3And COOCH3；R7Optionally unsubstituted or substituted in substitutable positions by one or more R7aSubstituted by groups;
L3is-CS-, -CO-, -C1-6Alkanediyl-, -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(CH2C≡N)CH2-；
R3Is hydrogen or unsubstituted or optionally substituted phenyl;
ring J or K is substituted phenyl, furyl, thienyl, pyridyl, biphenyl, or naphthyl;
L2is-CONH-, -CONHCH2-、-CH2O、-OCH2COOCH2-, or-CONHCH2-; and is
R4Is OH, CN, C (CH)3)2OH、SO2CH3、SO2CH2CH3、SCH2CH3、SCH3、SO2NH2、OCH3、C1-6Alkyl radical, CH2COOH、C(CH3)2COOH、NHSO2CH3、F、Cl、Br、CF3Or COCH3。
Another embodiment of the invention relates to a compound represented by formula Iaa-1, Iaa-2, Iaa-3, or Iaa-4 (embodiment Iaa):
Another embodiment of the invention relates to compounds represented by formula Ibb-1, Ibb-2, Ibb-3, or Ibb-4 (embodiment Ibb):
Figure S2006800306472D01021
another embodiment of the invention relates to a compound represented by formula Icc-1, Icc-2, Icc-3, or Icc-4 (embodiment Icc):
Figure S2006800306472D01022
another embodiment of the present invention relates to compounds represented by the formula Idd-1, Idd-2, Idd-3, or Idd-4 (embodiment Idd):
Figure S2006800306472D01023
in the above embodiments 1a to 1d, R1R is a group selected from5: thienyl, furyl, morpholinyl, thiazolyl, indolyl, oxazolyl, pyridyl, isoxazolyl, pyrimidinyl, imidazolyl, and phenyl; r5Optionally unsubstituted or substituted in substitutable positions by one or more R5aAnd (4) substituting the group. Preferably R5Is unsubstituted or optionally substituted by R5aSubstituted phenyl or pyridyl.
R2Is R selected from the group7: trifluoromethyl, 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 or COOCH (CH)3)2、CH2C≡N、C(CH3)2C ≡ N, ring C3-6Alkyl C ≡ N, thienyl, furyl, morpholinyl, thiazolyl, indolyl, oxazolyl, pyridyl, imidazolyl, isoxazolyl, pyrimidinyl, and phenyl; r7Optionally in substitutable positionsIs unsubstituted or substituted by one or more R7aAnd (4) substituting the group.
L1Independently selected from a direct bond, -CO-, -CONH-, -CONR11-、-C(＝NR11)-、-C(＝NOR11)-、-C(＝NN(R11)2)-；C2-6Alkanediyl chains wherein the alkanediyl chain is uninterrupted or optionally-C (R)11)2-、-C(R11)2C(R11)2-、-C(R11)＝C(R11)-、-C≡C-、-O-、-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) -an interrupt; - (CH)2)m-V0-(CH2)n-or-V0-(CH2)n-V0-; m is 0 to 6; n is 0 to 6; v0Independently is-C (R)11)2-、-C(R11)2C(R11)2-、-C(R11)＝C(R11)-、-C(R11)2O-、-C(R11)2NR11-、-C≡C-、-O-、-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-, Ring C3-8Haloalkyl or-SO2N(R10) -. More preferably L1Selected from-CONH-, -C1-6Alkyl-, -C1-6Alkoxy-, -CO-, -SO2-、-CH2-、-CH2O-、-CH2CH2-、-C＝O-、-CONH-、-CONHC(CH3)2-、-CONH(CH2)3OCH2-、-OCH2CH2-、-OCH2CH2N(CH3)2-, and-CONHCH2CH2N(CH3)2-。
L3Independently selected from a direct bond, -CO-, -CONH-, -CONR11-、-C(＝NR11)-、-C(＝NOR11)-、-C(＝NN(R11)2)-；C2-6Alkanediyl chains wherein the alkanediyl chain is uninterrupted or optionally-C (R)11)2-、-C(R11)2C(R11)2-、-C(R11)＝C(R11)-、-C≡C-、-O-、-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) -an interrupt; - (CH)2)m-V0-(CH2)n-or-V0-(CH2)n-V0-; m is 0 to 6; n is 0 to 6; v0Independently is-C (R)11)2-、-C(R11)2C(R11)2-、-C(R11)＝C(R11)-、-C(R11)2O-、-C(R11)2NR11-、-C≡C-、-O-、-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-, Ring C3-8Haloalkyl or-SO2N(R10) -. More preferably L3is-CO-, -C1-6Alkanediyl-, -CONH-, -CONR11-、-CONR11NR11-、-CH2OCH2-、-CH2OCH2CH2-、-OCH2-、-CH2N(CH3)2-、-CH2NHCH2-、-CONR11O-、-CH2OCOCH2-、-CH3N(CH3)(CH2)-、-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(CH2C≡N)CH2-。
R7aSelected from halogen, trifluoromethyl, C1-6Alkyl radical, C1-6Alkoxy, CH ═ CHCOOH, CH2COOH、OCH2COOH、OCONHCH(CH3)2、NHCOCH3、OH、OCH3、COOH、COOCH3、OCH2C(CH3)3、OCH2CH(CH3)2、OCH(CH3)2OCOCH(CH3)2、OCONHCH3、OCH2CH3Or OCH (CH)3)2。
L2Independently selected from a direct bond, -CO-, -CONH-, -CONR11-、-C(＝NR11)-、-C(＝NOR11)-、-C(＝NN(R11)2)-；C2-6Alkanediyl chains wherein the alkanediyl chain is uninterrupted or optionally-C (R)11)2-、-C(R11)2C(R11)2-、-C(R11)＝C(R11)-、-C≡C-、-O-、-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) -an interrupt; - (CH)2)m-V0-(CH2)n-or-V0-(CH2)n-V0-; m is 0 to 6; n is 0 to 6; v0Independently is-C (R)11)2-、-C(R11)2C(R11)2-、-C(R11)＝C(R11)-、-C(R11)2O-、-C(R11)2NR11-、-C≡C-、-O-、-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-, Ring C3-8Haloalkyl or-SO2N(R10) -. More specifically, L2Selected from-CONH-, -CONHCH2-、-CH2O-、-OCH2COOCH2-、-O-、C≡C-、-OCH2CH2-and-CONHOCH2CH(OH)CH2O-。
R5aIndependently selected from OCH 2C(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、C1-6Alkyl, OCH2COOH、OCH2COOC(CH3)3、O(CH2)2N(CH2CH3)2、OC(CH3)2COOC(CH3)3And OCH and2CH2and (5) OH. Preferably R5aIs halogen or trifluoromethyl.
R4Selected from OH, OH,CN、C(CH3)2OH、SO2CH3、SO2C(CH3)3、SO2NH2、SO2CH2CH3、SCH2CH3、SCH3、OCH3、C1-6Alkyl radical, CH2COOH、C(CH3)2COOH、NHSO2CH3、F、Cl、Br、C(CH3)2COOH、CH2COOCH3、C(CH3)2COOCH3、CH2CH2COOH、OCH2COOCH3、COCH3、COOC(CH3)3cyclobutane-COOH, OC (CH)3)2COOH、COOCH2CH3、OCF3And CF3。
Another embodiment of the present invention relates to compounds as described above, wherein G is selected from:
Figure S2006800306472D01051
in the above compounds, R is selected from C0-6Alkanediyl chains wherein the alkanediyl chain is uninterrupted or optionally-C (R)11)2-、-C(R11)2C(R11)2-、-C(R11)＝C(R11)-、-C(R11)2O-、-C(R11)2NR11-、-C≡C-、-O-、-S-、-N(R10)CO-、-N(R10)CO2-、-CON(R10)-、-CO-、-CO2-、-OC(＝O)-、-OC(＝O)N(R10)-、-SO2-、-N(R10)SO2-, or-SO2N(R10) -an interrupt.
Each R4Independently selected from C1-6Alkyl radical, CR11＝CR11COOR11、C1-6Alkoxy radical, C0-6Alkyl OR11、C0-6Alkyl group COR11、C0-6Alkyl SO2R11、C0-6Alkyl OCOOR11、C0-6Alkyl radical NR11COR11、C0-6Alkyl SO2NR11COR11、C0-6Alkyl SO2N(R11)2、C0-6Alkyl SR11、(C0-6Alkyl) C ═ O (OR)11)、OVOR11Halogen, C1-6Haloalkyl, C1-6Haloalkyl OR11、OC1-6Haloalkyl, aryloxy, arylalkoxy, aryloxyalkyl, C1-6Alkoxyaryl, aryl C0-6Alkylcarboxyl, NR11SO2R11、OC1-6Alkyl, OC0-6Alkyl group COOR11、C0-6Alkyl C.ident. N, C0-6Alkoxyheteroaryl group, C0-6Alkoxyheterocyclyl, cycloalkyl COOR115-12 membered aromatic or non-aromatic rings, or 5-12 membered heteroaryl or heterocyclyl with one or more heteroatoms N, O or S.
Preferred R4Selected from SO2CH3、SO2C(CH3)3、SO2CH2CH3、SCH2CH3、SCH3、OCH3、C1-6Alkyl radical, CH2COOH、C(CH3)2COOH、NHSO2CH3F, Cl, Br, cyclobutane-COOH, OC (CH)3)2COOH、CF3、C(CH3)2COOH、CH2COOCH3、CH2CH2COOH、OCH2COOCH3And COCH3. More preferably R4Is SO2CH3、SO2CH2CH3、SCH2CH3Or SCH3。
X is selected from S, NR11And O.
Each R4Optionally unsubstituted or substituted in substitutable positions by one or more R 4aSubstituted by groups; each R4aIndependently selected from hydrogen, C1-6Alkyl, (C)1-6Alkyl) C ═ O (OR)11)；C1-6Alkoxy radical, C0-6Alkyl OR11、C0-6Alkyl group COR11、C0-6Alkyl SO2R11、C0-6Alkyl SO2N(R11)2；C0-6Alkyl SR11、(C0-6Alkyl) OC ═ O (OR)11) Halogen, C1-6Haloalkyl, aryloxy, arylalkoxy, aryloxyalkyl, C1-6Alkoxyaryl, aryl C0-6Alkylcarboxyl, NR11SO2R11、OC1-6Alkyl radical, C0-6Alkyl C.ident.N, or OC0-6Alkyl group COOR11。
In a third aspect, the invention provides a pharmaceutical composition comprising a compound of any one of formulas Ia-d, II-XXVIII, and XXIXa-d, or a pharmaceutically acceptable derivative thereof, in a pharmaceutically acceptable carrier.
In another embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula XIX or a pharmaceutically acceptable derivative thereof in a pharmaceutically acceptable carrier.
In another embodiment, the present 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 present 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 present 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 packaging material and a compound of formulae Ia-d, II-XXVIII, and XXIXa-d, or a pharmaceutically acceptable derivative thereof, which compound or derivative is effective for modulating the activity of a nuclear receptor or for treating, preventing, inhibiting, or ameliorating one or more symptoms of a nuclear receptor mediated disease or disorder.
In another embodiment, the invention provides a kit comprising packaging material and a compound of formula Ia-d or a pharmaceutically acceptable derivative thereof, which compound or derivative is effective for modulating the activity of a nuclear receptor or for treating, preventing, inhibiting or ameliorating one or more symptoms of a nuclear receptor mediated disease or disorder.
In another embodiment, the invention provides a kit comprising 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 treating, preventing, inhibiting or ameliorating one or more symptoms of a nuclear receptor mediated disease or disorder, the kit further comprising a label indicating that a compound of formula Ia-d or a pharmaceutically acceptable derivative thereof is useful for modulating the activity of a nuclear receptor or for treating, preventing, inhibiting or ameliorating one or more symptoms of a nuclear receptor mediated disease or disorder or a disease or disorder associated with nuclear receptor activity.
In a sixth aspect, the invention provides a method of treating, preventing, inhibiting or ameliorating the symptoms of a disease or disorder modulated or otherwise affected by or associated with nuclear receptor activity, which method comprises administering to a subject in need thereof a therapeutically effective amount of a compound of any one of formulae Ia-d, II-XXVIII and XXIXa-d.
In a preferred embodiment of the sixth aspect, the present invention provides a method of treating, preventing, inhibiting or ameliorating the symptoms of a disease or disorder modulated or otherwise affected by or associated with nuclear receptor activity, which method comprises administering to a subject in need thereof a therapeutically effective amount of a compound according to part (a) of formulae Ia-d.
When referring herein to part (a) of formulae Ia-d in relation to a method of use of a compound of the invention (e.g. in the treatment, prevention, inhibition or alleviation of a disease or use in the manufacture of a medicament for the treatment, prevention, inhibition or alleviation of a disease) it is meant to include all compounds defined in part (a) and not to take into account the limitations of part (B) of the same formula when determining the scope of the compounds defined for their use.
In a preferred embodiment of the sixth aspect, the disease or disorder in the methods provided herein is hypercholesterolemia, hyperlipoproteinemia, hypertriglyceridemia, lipodystrophy, hyperglycemia, diabetes, dyslipidemia, atherosclerosis, cholecystolithiasis, acne vulgaris, acneiform skin disease, polyuria, parkinson's disease, cancer, alzheimer's disease, inflammation, immune dysfunction, lipid disorders, obesity, a condition characterized by epidermal barrier dysfunction, a condition of disturbed differentiation or hyperproliferation of the epidermis or mucosa, or a cardiovascular disease.
In a seventh aspect, the invention provides a method of lowering cholesterol levels in a subject in need thereof, the method comprising administering an effective cholesterol level lowering amount of a compound of any one of formulas Ia-d, II-XXVIII and XXIXa-d.
In a preferred embodiment of the seventh aspect, the invention provides a method of lowering cholesterol levels in a subject in need thereof, the method comprising administering an effective cholesterol level lowering amount of a compound according to part (a) of formulae Ia-d.
In an eighth aspect, the invention provides a method of treating, preventing, inhibiting or ameliorating one or more symptoms of a disease or disorder affected by cholesterol, triglyceride or bile acid levels, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of formulas Ia-d, II-XXVIII and XXIXa-d.
In a preferred embodiment of the eighth aspect, the present invention provides a method of treating, preventing, inhibiting or ameliorating one or more symptoms of a disease or disorder affected by cholesterol, triglyceride or bile acid levels, which method comprises administering to a subject in need thereof a therapeutically effective amount of a compound according to part (a) of formulae Ia-d.
In a ninth aspect, the invention provides a method of modulating the activity of a nuclear receptor comprising contacting the nuclear receptor with a compound of any one of formulae Ia-d, II-XXVIII, and XXIXa-d.
In a preferred embodiment of the ninth aspect, the present invention provides a method of modulating the activity of a nuclear receptor, the method comprising contacting the nuclear receptor with a compound according to moiety (a) of formulae Ia-d.
In one embodiment of the ninth aspect, the invention provides a method wherein the nuclear receptor is an orphan nuclear receptor.
In one embodiment of the ninth aspect, in the methods provided herein, the nuclear receptor is a liver X receptor.
In a preferred embodiment of the ninth aspect, in the methods provided by the invention, the nuclear receptor is a liver X receptor, wherein the liver X receptor is LXR α or LXR β.
In an eleventh aspect, the invention provides a method of modulating cholesterol metabolism comprising administering an amount of a compound of any one of formulas Ia-d, II-XXVIII and XXIXa-d effective to modulate cholesterol metabolism.
In a preferred embodiment of the eleventh aspect, the invention provides a method of modulating cholesterol metabolism comprising administering a cholesterol metabolism modulating amount of a compound according to moiety (a) of formulae 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, the method comprising administering a therapeutically effective amount of a compound of any one of formulas Ia-d, II-XXVIII, and XXIXa-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, the method comprising administering a therapeutically effective amount of a compound according to part (a) of formulae Ia-d.
In a thirteenth aspect, the invention provides a method of increasing cholesterol efflux from a cell in a subject, which method comprises administering an amount of a compound of any one of formulae Ia-d, II-XXVIII and XXIXa-d effective to increase cholesterol efflux.
In a preferred embodiment of the thirteenth aspect, the present invention provides a method of increasing cholesterol efflux from a cell in a subject, which method comprises administering a compound according to moiety (a) of formulae Ia-d in an amount effective to increase cholesterol efflux.
In a fourteenth aspect, the present invention provides a method of increasing an ATP-binding cassette (ABC) in a cell of a subject1) A method of expression comprising administering ABC which is effective to increase1Expressed amounts of a compound of any one of formulas Ia-d, II-XXVIII and XXIXa-d.
Definition of
Unless stated to the contrary, the following definitions apply to the terms used herein. For example, in the following "alkyl" is defined as containing 1 to 12 carbon atoms, but is defined as C1-6The substituents for the alkyl group are limited to alkyl moieties having 1-6 carbons. It is to be understood that all choices for any variable related to any general structure or formula herein are only correct if the choice results in a stable chemical structure as would be recognized by one skilled in the art.
When a specific embodiment is referred to by structure only, all unnamed chemical groups that make up the structure are as defined in each embodiment of the structure. For example, when referring to "in another embodiment, the invention provides a compound according to any one of formulae Ia-d, wherein K is phenyl or pyridinyl", this means that another embodiment of the invention includes each of the embodiments described in the specification having any one of formulae Ia-d, wherein K is phenyl or pyridinyl, and all other moieties are as defined in the respective embodiments.
For simplicity, chemical moieties are defined throughout and referred to primarily as monovalent chemical moieties (e.g., alkyl, aryl, etc.). However, these terms are also used to denote the corresponding multivalent moieties in the case of suitable structures that will be clear to the skilled person. For example, when an "alkyl" moiety is generally referred to as a monovalent group (e.g., CH)3-CH2-) in some cases, the divalent linking moiety can be an "alkyl" group, in which case one of skill in the art would understand that the alkyl group is a divalent group (e.g., -CH2-CH2-) which is equivalent to the term "alkylene". (also, where a divalent moiety is required and referred to as an "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 bonding valency (i.e., carbon is 4, N is 3, O is 2, and S is 2, 4, or 6, depending on the oxidation state of S). In some cases, a moiety may be defined as, for example, (A)a-B-, wherein a is 0 or 1. In this case, when a is 0, the moiety is B-, and when a is 1, the moiety is A-B-. Likewise, C0-6Alkyl OR11Simultaneously comprising-OR11And C1-C6-OR11(ii) a And when m is 0, - [ C (R) 15)2]m-is a chemical bond. There is no implicit limitation on the position of the two bonds connecting the linking group to its two supporting chemical units when the moiety is a divalent group.
For example, for a divalent cyclohexyl group, the cyclohexyl group may be attached to two different carbon atoms within the ring through two separate chemical bonds; or two bonds may be attached to the same carbon atom within the ring. In an illustrative example, if a divalent cyclopropyl group links two phenyl rings together, this definition includes 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 such compounds, and "the enzyme" includes a specific enzyme as well as other family members and equivalents thereof known to those skilled in the art. As used in the specification and the appended claims, the following terms take the meanings indicated, unless the contrary is specifically indicated.
The term "absent" as used herein means that the group is replaced by a single chemical bond. A-bond-group is understood to be reduced to a single chemical bond if the substitution of the group by a chemical bond results in two linking moieties that are both defined as chemical bonds.
The term "interrupted" as used herein refers to the insertion of the specified group at any point within the specified chain (but not at the terminus). For example, if C is defined herein3-the alkyl chain is interrupted by-O-, the following groups will be included: -CH2-O-CH2CH2-、-CH2-CH2-O-CH2、-CH(CH3)-O-CH2-, and-CH2-O-CH(CH3)-。
The terms "aliphatic" and "aliphatic group" as used herein refer to a straight, branched or cyclic C1-C12(unless otherwise specified) hydrocarbyl groups which are fully saturated or contain one or more units of non-aromatic unsaturation. For example, suitable aliphatic groups include substituted or unsubstituted straight, branched, or cyclic alkyl, alkenyl, alkynyl groups, and combinations 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 straight and branched chains containing from 1 to 12 carbon atoms.
The terms "alkenyl" and "alkynyl", when used alone or as part of a larger moiety, include straight and branched chains containing from 2 to 12 carbon atoms.
The term "alkoxy" refers to an-O-alkyl group, wherein alkyl is as defined herein.
"alkyl" means a straight and branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, which is free of unsaturation, has 1 to 12 carbon atoms, preferably 1 to 8 carbon atoms, and is attached to the rest of the molecule by a single bond, for example, methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, 1-dimethylethyl (tert-butyl), and the like. Unless otherwise stated in the specification, the above alkyl groups are optionally unsubstituted or substituted with one or more substituents selected from the group consisting of: halogen, cyano, nitro, -OR11、-N(R11)2、-COR11、-COOR11、-CON(R11)2、-N(R11)COOR10、-N(R11)COR11、-NSO2R11、-N(R11)SO2R11、-SO2OR11、-SO2R11and-SO2N(R11)2Wherein each R is10And R11As defined above in the first aspect of the invention. Unless otherwise stated in the specification, it is to be understood that for substituted alkyl-containing groups defined below, substitution may occur at any carbon atom of the alkyl group.
"alkenyl" means a straight or branched hydrocarbon chain radical consisting exclusively of carbon and hydrogen atoms, containing at least one double bond, having from 2 to 12 carbon atoms, preferably from 2 to 8 carbon atoms, andattached to the rest of the molecule by single or double bonds, such as vinyl, prop-1-enyl, but-1-enyl, pent-1, 4-dienyl and the like. Unless stated otherwise in the specification, the above alkenyl groups are optionally unsubstituted or substituted with one or more substituents selected from: halogen, cyano, nitro, -OR 11、-N(R11)2、-COR11、-COOR11、-CON(R11)2、-N(R11)COOR10、-N(R11)COR11、-NSO2R11、-N(R11)SO2R11、-SO2OR11、-SO2R11and-SO2N(R11)2Wherein each R is10And R11As defined in the first aspect of the invention. It is to be understood that for substituted alkenyl-containing groups defined below, the substitution can occur at any carbon atom of the alkenyl group.
"aryl" means an aromatic monocyclic or polycyclic ring system containing 6 to 19 carbon atoms, wherein the ring system is optionally partially or fully saturated. Aryl groups include, but are not limited to, fluorenyl, phenyl, and naphthyl. Unless otherwise indicated in the specification, the term "aryl" is meant to include aryl groups optionally unsubstituted or substituted with one or more substituents selected from: alkyl, alkenyl, halogen, haloalkyl, haloalkenyl, cyano, nitro, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, -R0-OR11、-R0-N(R11)2-、-R0-COR11、-R0-COOR11、-R0-CON(R11)2、-R0-N(R11)COOR10、-R0-N(R11)COR11、-R0-NSO2R11、-R0-N(R11)SO2R11、-R0-SO2OR11、-R0-SO2R11and-R0-SO2N(R11)2Wherein each R is0Independently selected from a substituted or unsubstituted aliphatic group, an unsubstituted heteroaromatic or heterocyclic ring, phenyl (Ph), substituted Ph, -OPh, substituted-OPh, or substituted-CH2Ph。R0Examples of the substituent on the aliphatic group or on the benzene ring of (1) include amino, alkylamino, dialkylamino, aminocarbonyl, halogen, alkyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkoxy, nitro, cyano, carboxyl, alkoxycarbonyl, alkylcarbonyl, hydroxyl, haloalkoxy or haloalkyl.
The aliphatic group or the non-aromatic heterocyclic ring may contain one or more substituents. Examples of suitable substituents on the saturated carbon atom of the aliphatic radical or of the non-aromatic heterocycle include those listed above for the unsaturated carbon atom of the aryl or heteroaryl radical, and include the following groups: o, S, NNHR0、＝NN(R0)2、＝N-、＝NNHC(O)R0、＝NNHCO2(alkyl) ═ NNHSO2(alkyl), or ═ NR0Wherein R is0Independently selected from halogen, unsubstituted or substituted aliphatic group, unsubstituted heteroaromatic or heterocyclic ring, phenyl (Ph), substituted Ph, -OPh, substituted-OPh, -CH2Ph, or substituted-CH2Ph. Examples of substituents on aliphatic groups include amino, alkylamino, dialkylamino, aminocarbonyl, halogen, alkyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkoxy, nitro, cyano, carboxyl, alkoxycarbonyl, alkylcarbonyl, hydroxyl, haloalkoxy, or haloalkyl.
Suitable substituents on the nitrogen atom of the non-aromatic heterocyclic ring include-R0、-N(R0)2、-C(O)R0、CO2R0、-C(O)C(O)R0、-SO2R、-SO2N(R0)2、-C(＝S)N(R0)2、-C(＝NH)-N(R0)2And NR0RSO2R0Wherein each R is0Independently selected from hydrogen, unsubstituted or substituted aliphatic, unsubstituted heteroaromatic or heterocyclic ring, phenyl (Ph), substituted Ph, -OPh, substituted-OPh, or substituted-CH 2Ph. Examples of the aliphatic group or the substituent on the benzene ring include amino, alkylamino, dialkylamino, aminocarbonyl, halogen, alkyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkoxy, nitro, cyano, carboxyl, alkoxycarbonyl, alkylcarbonyl, hydroxyl, haloalkoxy or haloalkyl.
The term "alkoxyaryl" as used herein refers to 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, butoxyphenyl, and dimethoxynaphthyl.
"aralkyl" or "arylalkyl" refers to a group of formula-RaRb, where Ra is an alkyl group as defined above and Rb is one or more aryl groups as defined above, such as benzyl, diphenylmethyl, and the like. The aryl group or groups and the alkyl group as described above are optionally unsubstituted or substituted.
The term "aralkoxy" or "arylalkoxy" as used herein, refers to an aralkyl group, as defined herein, appended to the parent molecule through an oxygen atom. Examples of alkoxy groups include, but are not limited to: benzyloxy, 2-phenylethoxy, 4-phenylbutoxy, 9-fluorenylmethoxy, and the like.
The term "arylcarbonyl" as used herein, means an aryl group, as defined herein, appended to the parent molecule through a carbonyl group, as defined herein. The carboxyl groups may be bound in any manner: or a carbonyl carbon bound to an aralkyl group and an oxygen bound to the parent molecule; or the carbonyl carbon is bonded to the parent molecule and the oxygen is bonded to the aralkyl group. Examples of aralkyl carboxy groups include, but are not limited to: benzylethoxy, (benzyloxy) carbonyl, (2-phenylethoxy) carbonyl, phenyl-acetoxy, and 1-oxo-5-phenyl-pentyloxy.
The term "aryloxy" as used herein, means an aryl group, as defined herein, appended to the parent molecule through an oxygen atom. Examples of "aryloxy" groups include, but are not limited to: phenoxy, 1-naphthoxy, and 2-naphthoxy.
"alkylene" and "alkylene chain" refer to a straight or branched divalent hydrocarbon chain consisting only of carbon and hydrogen, linking the rest of the molecule to a group, which does not contain unsaturation, and which has from 1 to 12 carbon atoms, preferably from 1 to 8 carbon atoms, for example, methylene, ethylene, propylene, n-butylene, and the like. The alkylene chain may be linked to the rest of the molecule and to the group by one carbon in the chain or by any two carbons in the chain. The alkylene chain is optionally unsubstituted or substituted with one or more substituents selected from the group consisting of: halogen, cyano, nitro, -OR 11、-N(R11)2、-COR11、-COOR11、-CON(R11)2、-N(R11)COOR10、-N(R11)COR11、-NSO2R11、-N(R11)SO2R11、-SO2OR11、-SO2R11and-SO2N(R11)2Wherein each R is10And R11As defined above in relation to the first aspect of the invention. The alkylene chain may be linked to the rest of the molecule by any two carbons in the chain.
"alkenylene" and "alkenylene chain" refer to a straight or branched divalent hydrocarbon chain consisting only of carbon and hydrogen connecting the remainder of the molecule to a group, containing at least one double bond, and having from 2 to 12 carbon atoms, e.g., ethenylene, propenylene, n-butenylene, and the like. The alkenylene chain is connected to the rest of the molecule by a single bond and to the group by a double or single bond. The point of attachment of the alkenylene chain to the rest of the molecule and to the group may be through one or any two carbons in the chain. Alkenylene chain optionallyUnsubstituted or substituted with one or more substituents selected from the group consisting of: halogen, cyano, nitro, -OR11、-N(R11)2、-COR11、-COOR11、-CON(R11)2、-N(R11)COOR10、-N(R11)COR11、-NSO2R11、-N(R11)SO2R11、-SO2OR11、-SO2R11and-SO2N(R11)2Wherein each R is10And R11As defined above in relation to the first aspect of the invention.
The term "heteroarylalkyl," as used herein, refers to an alkyl group attached to the parent molecule, wherein the alkyl group is substituted with one heteroaryl group, as defined herein. Examples of aryloxyalkyl groups include, but are not limited to: phenoxymethyl, naphthyloxybutyl, and phenoxyhexyl.
The term "heteroaryloxy," as used herein, refers to a heteroaryl group attached to the parent molecule, wherein the heteroaryl group is substituted with one heteroaryl group, as defined herein. Examples of aryloxyaryl groups include, but are not limited to: phenoxyphenyl, naphthoxyphenyl, and phenoxynaphthyl.
The term "carbonyl" as used herein refers to a-C (═ O) -group.
The term "carboxy" as used herein refers to a-C (═ O) O-group.
"cycloalkyl" means a stable monovalent monocyclic or bicyclic hydrocarbon group consisting solely of carbon and hydrogen atoms, which has from 3 to 10 carbon atoms (unless otherwise specified), and which is saturated or includes one or more units of unsaturation (but not aromatic), and is attached to the remainder of the molecule by a single bond, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclopent-1-enyl, cyclohexyl, cyclohex-2, 4-dienyl, decahydronaphthyl (decalinyl), and the like. Unless otherwise specifically stated in the specification, the term "cycloalkyl" is meant to includeCycloalkyl substituted or substituted with one or more substituents independently selected from the group consisting of: alkyl, alkenyl, halogen, haloalkyl, haloalkenyl, cyano, nitro, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, -OR 11、-N(R11)2、-COR11、-COOR11、-CON(R11)2、-N(R11)COOR10、-N(R11)COR11、-NSO2R11、-N(R11)SO2R11、-SO2OR11、-SO2R11and-SO2N(R11)2Wherein each R is10And R11As defined above in relation to the first aspect of the invention.
"cycloalkylalkyl" means a compound of the formula-RaRdWherein R isaIs alkyl as defined above, and RdIs cycloalkyl as defined above. As mentioned above, the above alkyl and cycloalkyl groups are optionally unsubstituted or substituted.
The term "cyclohaloalkyl" as defined herein refers to a cycloalkyl group, as defined herein, substituted with one or more halo groups, as defined herein. "Cyclohaloalkyl" groups include, but are not limited to: bromocyclohexyl, trifluorocyclopentyl, dichlorocyclohexyl, and the like.
"halo" or "halogen" refers to bromo, chloro, fluoro, or iodo.
"haloalkyl" refers to an alkyl group as defined above substituted with one or more halo groups as defined above, for example, trifluoromethyl, difluoromethyl, trichloromethyl, 2, 2, 2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, 3-bromo-2-fluoropropyl, 1-bromomethyl-2-bromoethyl, and the like.
"haloalkenyl" refers to an alkenyl group as defined above substituted with one or more halogen groups as defined above, e.g., 2-bromovinyl, 3-bromoprop-1-enyl, and the like.
The term "haloaryl" as used herein refers to an aryl group, as defined herein, substituted with one or more halo groups. Examples of halogenated aryl groups include, but are not limited to: bromophenyl, fluorophenyl, pentafluorophenyl, chloronaphthyl, chloro-iodophenyl, and the like.
"Heterocyclyl" refers to a stable 3-18 membered non-aromatic cyclic group consisting of carbon atoms and 1-5 heteroatoms selected from nitrogen, oxygen and sulfur. For purposes of this invention, a heterocyclyl group can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which can include fused or bridged ring systems; the nitrogen, carbon, or sulfur atom in the heterocyclic group may be optionally oxidized; the nitrogen atoms may optionally be quaternized; the heterocyclic group may be partially or fully saturated. Examples of such heterocyclic groups include, but are not limited to: diazacyclopentyl, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidinonyl, pyrrolidinyl, pyrazolidinyl, thiazolidinyl, tetrahydrofuranyl, trithianyl (trithianyl), tetrahydropyranyl, thiomorpholinyl, 1-oxo-thiomorpholinyl, and 1, 1-dioxo-thiomorpholinyl. Unless otherwise specified in the specification, the term "heterocyclyl" is meant to include heterocyclyl groups as defined above which are optionally unsubstituted or substituted by one or more substituents selected from: alkyl, alkenyl, halogen, haloalkyl, haloalkenyl, nitro, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, -OR 11、-N(R11)2-、-COR11、-COOR11、-CON(R11)2、-N(R11)COOR10、-N(R11)COR11、-NSO2R11、-N(R11)SO2R11、-SO2OR11、-SO2R11and-SO2N(R11)2Wherein each R is10And R11As defined above in relation to the first aspect of the invention.
"Heterocyclylalkyl" means a compound of the formula-RaReWherein R isaIs alkyl as defined above, and ReIs a heterocyclyl group as defined above which, if the heterocyclyl is a nitrogen-containing heterocyclyl, may be attached to an alkyl group at the nitrogen atom. The heterocyclyl group and alkyl are optionally unsubstituted or substituted as defined above.
The term "heterocyclyloxy," as used herein, refers to a heterocyclyl group, as defined herein, appended to the parent molecule through an oxygen atom. Examples of "heterocyclyloxy" groups include, but are not limited to: piperidinyloxy, tetrahydrofuryloxy, tetrahydrothienyloxy, tetrahydropyranyloxy, dihydropyranyl, pyrrolyloxy, oxetanyloxy (oxyethanoxy), and oxiranyloxy (oxiranyloxy).
"heteroaryl" refers to a 3-18 membered aromatic ring group consisting of carbon atoms and 1-5 heteroatoms selected from nitrogen, oxygen and sulfur. For the purposes of the present invention, heteroaryl groups may be monocyclic, bicyclic, tricyclic or tetracyclic systems, which may include fused or bridged ring systems; and the nitrogen, carbon, or sulfur atom in the heteroaryl group is optionally oxidized; the nitrogen atoms are optionally quaternized. Examples include, but are not limited to: azepine (azepinyl), acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzothiadiazolyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolanyl, benzodioxanyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothiophenyl (benzothiophenyl), benzotriazolyl, benzo [4, 6 ] benzo ]Imidazole [1, 2-a ]]Pyridyl, carbazolyl, cinnolinyl, dibenzofuranyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxo-azepinylExamples of the substituent include, but are not limited to, oxazolyl, oxiranyl, phenazinyl, phenothiazinyl, phenoxazinyl, naphthyridinyl, phthalimidyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalyl, quinolinyl, quinuclidinyl, isoquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl. Unless otherwise specifically stated in the specification, the above "heteroaryl" is meant to include heteroaryl groups as defined above which are optionally unsubstituted or substituted by one or more substituents selected from the group consisting of: alkyl, alkenyl, halogen, haloalkyl, haloalkenyl, nitro, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, -OR 11、-N(R11)2-、-COR11、-COOR11、-CON(R11)2、-N(R11)COOR10、-N(R11)COR11、-NSO2R11、-N(R11)SO2R11、-SO2OR11、-SO2R11and-SO2N(R11)2Wherein each R is10And R11As defined above in relation to the first aspect of the invention. For the purposes of the present invention, the term "N-heteroaryl" refers to a heteroaryl group as defined above which contains at least one nitrogen atom in the ring.
The term "heteroaryloxy," as used herein, refers to a heteroaryl group, as defined herein, appended to the parent molecule through an oxygen atom. Examples of "heteroaryloxy" groups include, but are not limited to: pyridyloxy, indoyloxy and quinolinyloxy.
"Heteroarylalkyl" means a compound of the formula-RaRfWherein R isaIs an alkyl group as defined above, and RfIs a heteroaryl group as defined above, which heteroaryl group, if it is a nitrogen-containing heteroaryl group, may be attached to the alkyl group at the nitrogen atom. Heteroaryl and alkyl groups are optionally unsubstituted or substituted as described aboveAnd (3) substituted.
The term "linking group" or "linker" refers to an organic moiety that links two parts of a compound. The linker is typically made of an atom such as oxygen or sulfur; for example-NH-, -CH2-CO-, -CONH-units; or a chain of atoms such as alkanediyl. The linker will generally have a molecular weight of from about 14 to 200, preferably from 14 to 96, and a length of up to about 6 atoms. Examples of linkers include saturated or unsaturated C 1-C6An alkanediyl chain which is optionally substituted or unsubstituted and wherein one or two saturated carbons of the chain are optionally substituted by-CO-, -COCO-, -CONH-, -CONHNH-, -CO-, -2-、-NHCO2-、-O-、-NHCONH-、-OCONH-、-NHNH-、-NHCO-、-S-、-SO-、-SO2-、-NH-、-SO2NH-, or-NHSO2-substituted.
The term "alkanediyl chain" refers to an optionally substituted, straight or branched carbon chain, which chain may be fully saturated or have one or more units of unsaturation. Optional substituents are as described above for the aliphatic groups. As used herein, an alkanediyl chain may include alkanediyl chains comprising from 0 to 4 fluorine substituents.
A "nuclear receptor agonist" is an agent that activates nuclear receptor activity when bound to a nuclear receptor to activate or inhibit gene function. In some cases, nuclear receptors are capable of acting through the second messenger signaling pathway, and the present invention will also be used for these effects. The degree of activation is similar to that provided by the natural hormone for the receptor, or can be stronger (optionally referred to as a "strong agonist") or weaker (optionally referred to as a "weak agonist" or "partial agonist"). One example of a nuclear receptor hormone is thyroid hormone, which is the natural hormone of the thyroid receptor, and "putative agonists" (putative agonists) are agents used to detect agonist activity.
Partial agonists or partial antagonists bind to the receptor and produce a response that is less than the response produced by full agonists at saturating ligand concentrations. A partial agonist will block the binding of a full agonist and inhibit the level of receptor activity to a level induced by the partial agonist alone. For example, partial agonists bind to the receptor and induce only a portion of the receptor changes induced by the agonist. These differences may be qualitative or quantitative. Thus, a partial agonist may induce some changes in the conformational change induced by the agonist, but not others, or it may induce only a limited degree of some changes. Some of these compounds are naturally occurring.
For example, estrogens (phytoestrogens) such as genistein (genistein) of many plants may behave as partial estrogen receptor agonists (partial estrogen receptor agonists).
A "nuclear receptor antagonist" is an agent that reduces or blocks activity mediated by the receptor's response to a receptor agonist. The activity of the antagonist may be mediated by: for example, by blocking the binding of an agonist to a receptor, or by altering the configuration of the receptor and/or the activity of the receptor. A "putative antagonist" is an agent used to detect antagonist activity.
A "nuclear receptor" is a receptor (but may also have a second messenger signaling effect) that typically binds to other transcription factors to activate or inhibit transcription of one or more genes in the nucleus. Nuclear receptors are activated by the natural cognate ligand for the receptor. Nuclear receptors are typically found in the cytoplasm or nucleus, rather than membrane bound. Nuclear receptors are members of the superfamily of regulatory proteins, such as, for example, receptors for steroids, retinoids, vitamin D, and thyroid hormones. These proteins bind to cis-acting elements in the promoter of their target genes and regulate gene expression in response to their ligands. Nuclear receptors can be classified according to their DNA binding properties. For example, glucocorticoid, estrogen, androgen, progesterone, and mineralocorticoid receptors bind to the Hormone Response Element (HRE) in a homodimeric manner, constituting inverted repeats. Another example are receptors, including those activated by retinoic acid, thyroid hormone, vitamin D3, fatty acid/peroxisome proliferators, and ecdysone, which bind to HREs in the form of heterodimers with the co-partner Retinoid X Receptor (RXR). Among the latter, the receptor is LXR.
An orphan nuclear receptor, as used herein, is a nuclear receptor for which the natural ligand is unknown.
Liver X receptors or LXRs as used herein refer to nuclear receptors involved in cholesterol biosynthesis. The term LXR as used herein refers to both LXR α and LXR β, which are two protein forms found in mammals. Liver X receptor- α or LXR α refers to the receptors described in the following references: U.S. patent nos. 5,571,696, 5,696,233, and 5,710,004, and Willy et al (1995) Gene dev.9 (9): 1033-1045. Liver X receptor- β or LXR β refers to receptors described in the following references: peet et al (1998) curr. opin. genet.dev.8 (5): 571-575; song et al (1995) an.n.y.acad.sci.761: 38-49; alberti et al (2000) Gene 243 (1-2): 93-103; and references cited therein; and U.S. patent nos. 5,571,696, 5,696,233, and 5,710,004.
"commercially available" compounds for use herein are available from standard commercial sources including Across Organics (Pittsburgh PA), Aldrich Chemical (Milwaukee WI, including Sigma Chemical and Fluka), Apin Chemicals Ltd. (Milton Park UK), Avocaado research (Lancashire U.K.), BDH Inc. (Toronto, Canada), Bionet (Cornwall, U.K.), Chemsevice Inc. (West Chemist PA), CreScent Chemical Co. (Hauppauge NY), Eastman Organic Chemical, Eastman Kodak company NY, Fisher Scientific Co. (Pittsburgh PA), Fisonss Chemical company, Leonshire K, Inc. (Rockwell Co., Inc., bark Co., Inc., and rock Chemical, Inc., and rock Chemical, Inc., rock Chemical Co., Inc., rock Chemical, rock Scientific Co., Inc., rock Co., Inc., rock Co., rock, 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 performing synthetic steps are provided explicitly herein or may be obtained by reference to publications of reference directed to methods used in synthetic organic chemistry. The reference books and papers listed above describe in detail the synthesis of reactants used in the preparation of the compounds of the invention, which will also provide suitable conditions for carrying out the synthetic steps according to the invention.
As used herein, "methods known to those of ordinary skill in the art" may be found by various reference book and database queries. Reference books and treatises detailing the synthesis of reactants for preparing the compounds of the invention, or providing references to articles describing the preparation process, include, for example, "Synthetic Organic Chemistry", John Wiley & Sons, inc., New York; sandler et al, "Organic Functional groups preparations", second edition, Academic Press, New York, 1983; house, Modem Synthetic Reactions, second edition, w.a.benjamin, inc.menlo Park, calif.1972; gilchrist, "Heterocyclic Chemistry", second edition, John Wiley & Sons, New York, 1992; march, "Advanced Organic Chemistry: reactions, Mechanisms and structures (advanced organic chemistry: Reactions, Mechanisms and structures), "fourth edition, Wiley-Interscience, New York, 1992. Specific and similar reactants may also be identified by known Chemical indexes prepared by Chemical abstracts Service of American Chemical Society, which are available in most public and university libraries and online databases (more details may be related to the American Chemical Society, Washington, D.C.; Washington, D.C.). Chemicals known in the catalog but not marketed can be prepared by specialized custom chemical synthesis laboratories, where many standard chemical suppliers (e.g., those listed above) provide custom synthesis services.
"prodrug" refers to a compound that can be converted under physiological conditions or by solvolysis into the biologically active compounds of the invention. Thus, the term "prodrug" refers to a pharmaceutically acceptable metabolic precursor of a compound of the invention. Prodrugs may be inactive when administered to a subject in need thereof, but convert in vivo to the active compounds of the invention. Prodrugs are generally rapidly converted in vivo, for example by hydrolysis in the blood, to yield the parent compound of the invention. Prodrug compounds often provide many advantages for solubility, histocompatibility, or sustained release in mammalian organisms (see Bundgard, h., Design of produgs (1985), pages 7-9, 21-24 (Elsevier, Amsterdam)). Prodrugs are discussed in Higuchi, T.et al, "Pro-drugs as Novel delivery systems," A.C.S. symposium Series, Vol.14; and "Bioreversible Carriers in Drug Design," Edward B. eds., Roche, American pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference in their entirety the term "prodrug" also refers to a compound comprising any covalently bound carrier which is capable of releasing the active compound of the invention in vivo when such a prodrug is administered to a mammalian subject, prodrugs of the invention may be prepared by modifying functional groups present in the compounds of the invention in a manner which such modifications are cleaved to the parent compound of the invention in a conventional manner of operation or in vivo due to knowledge of the pharmacodynamic processes and Drug metabolism in vivo, once the pharmaceutically active compounds of the invention are known to those skilled in the art, prodrugs of the compounds can be designed (see, for example, Nogrady (1985) Medicinal Chemistry ABiochemical Approach, Oxford university Press, New York, page 388-. Prodrugs include compounds of the present invention:
Wherein hydroxy, amino or thiol is bonded to any group that cleaves to form a free hydroxy, free amino or free thiol, respectively, when a prodrug of a compound of the invention is administered to a mammalian subject. Examples of prodrugs include, but are not limited to: formate and benzoate derivatives and analogs of alcohol and amine functional groups in the compounds of the invention.
"polymorphs" mean the different crystalline forms of a compound that are produced by at least two different arrangements of the molecules of the compound in the solid state form. Polymorphs of a particular compound differ in crystal structure, but are identical in the liquid or vapor state. Different polymorphic forms of a particular substance may differ from each other in one or more physical properties, such as solubility and separation, true density, crystal shape, compaction behavior, flow characteristics, and/or solid state stability.
By "stable compound" and "stable structure" is meant a compound that is sufficiently stable to withstand isolation to a useful degree of purity from a reaction mixture and formulation into an effective therapeutic agent.
"mammal" includes humans and domestic animals such as cats, dogs, pigs, cattle, sheep, goats, horses, rabbits, and the like.
"optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not. For example, "optionally substituted aryl" means that the aryl group can be substituted or unsubstituted, and that the description includes substituted aryl groups and unsubstituted aryl groups as defined herein.
A "pharmaceutically acceptable carrier, diluent, or excipient" includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier that has been approved by the U.S. food and drug administration for use in humans or livestock.
"pharmaceutically acceptable salts" include acid addition salts and base addition salts.
"pharmaceutically acceptable acid addition salts" refers to those salts that retain the biological efficacy and properties of the free base, 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 salts" refers to those salts that retain the biological efficacy and properties of the free acid and are not biologically or otherwise undesirable. These salts may be formed by the addition of an inorganic or organic base to the free acid. Salts derived from inorganic bases include, but are not limited to: sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts, aluminum salts, and the like. Preferred inorganic salts are ammonium, sodium, potassium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, the following: primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, 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.
By "pharmaceutically acceptable derivative" is meant a pharmaceutically acceptable salt as defined herein, and also includes esters, prodrugs, solvates and polymorphs of the compounds of the present invention.
By "therapeutically effective amount" is meant an amount of a compound of the present invention that: when administered to a mammal, preferably a human, the amount is sufficient to effectively treat a disease state associated with nuclear receptor activity as described below. The amount of a compound of the present invention that constitutes a "therapeutically effective amount" will vary depending on the compound, the condition and its severity, and the age of the mammal being treated, but can be routinely determined by one of ordinary skill in the art based on his own knowledge and the disclosure of the present invention.
By "modulating" or "modulation" is meant treating, preventing, inhibiting, increasing, or inducing a function or disorder. For example, the compounds of the present invention can regulate hyperlipidemia by lowering cholesterol in humans, thereby inhibiting hyperlipidemia.
As used herein, "treating" or "treatment" encompasses the treatment of a disease or disorder associated with nuclear receptor activity disclosed herein in a mammal (preferably a human) and includes:
i. Preventing a disease or condition associated with nuclear receptor activity from occurring in a mammal, particularly when the mammal is susceptible to the disease or condition but when the disease has not yet been diagnosed;
inhibiting, i.e., arresting the development of, a disease or disorder associated with nuclear receptor activity; or
Alleviating a disease or condition associated with nuclear receptor activity, i.e., restoring the condition.
The compounds of formula Ia, Ib, Ic or Id or pharmaceutically acceptable salts thereof may contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers and other stereoisomeric forms which may be defined as (R) -or (S) -in terms of absolute stereochemistry or, in the case of amino acidsIn other words, it is defined as (D) -or (L) -. The present invention includes all such possible isomers and racemic and optically pure forms thereof. Optionally (a)+) And (a)-) The (R) -and (S) -, or (D) -and (L) -active isomers can 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, it is contemplated that these compounds include both E and Z geometric isomers, unless otherwise specified. It will be apparent to those skilled in the art that certain compounds of the present invention may exist in tautomeric forms, and all tautomeric forms of such compounds are included within the scope of the invention. Unless otherwise indicated, the various structures described herein also include all stereochemical forms of the structures: i.e., the R and S configuration of each asymmetric center. Thus, individual stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the compounds of the present invention are intended to be included within the scope of the invention. Unless otherwise indicated, structures described herein also include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, by replacement of a hydrogen atom by deuterium or tritium, or by enrichment 13C or14Compounds having the structure of the present invention in which carbon atoms of C are replaced with carbon atoms are included in the scope of the present invention.
The chemical naming conventions and structure diagrams used herein employ and follow the chemical naming features used by the ChemDraw program (available from Cambridge corp. In particular, the Autonom program employed by Chemdraw Ultra or ISIS base (MDL Corp.) was used to obtain the compound name from the structure.
The term "atherosclerosis" refers to the process of formation of atherosclerotic plaques within the inner wall of an artery wall leading to cardiovascular atherosclerotic disease. Physicians working in the relevant medical field can understand and identify cardiovascular atherosclerotic diseases (also known as coronary heart disease or ischemic heart disease), including, but not limited to: restenosis, coronary heart disease (also known as coronary heart disease or ischemic heart disease), cerebrovascular disease (including ischemic stroke), multi-infarct dementia, and peripheral vascular disease (including intermittent claudication and erectile dysfunction).
"dyslipidemia" refers to abnormal levels of lipoproteins in plasma, including lower and/or higher levels of lipoproteins (e.g., higher levels of Low Density Lipoprotein (LDL), Very Low Density Lipoprotein (VLDL), and lower levels of High Density Lipoprotein (HDL) (less than 40 mg/dL)).
"EC" as used herein50"refers to a dose, concentration, or amount of a particular test compound that elicits a dose-dependent response at 50% of the maximum expression of a particular response that is induced, elicited, or potentiated by that particular test compound.
The term "cholesterol" refers to a steroid which is a major component of cell membranes and myelin sheaths, and cholesterol as used herein includes its general application. Cholesterol is also a precursor of steroid hormones and bile acids.
The term "triglyceride" ("TG") as used herein includes its general application. TG consists of three fatty acid molecules esterified with glycerol molecules, which function to store fatty acids that are either utilized by muscle cells to produce energy or taken up and stored in adipose tissue.
The term "hyperlipidemia" refers to the presence of abnormal higher levels of lipids in the blood. Hyperlipidemia can occur in at least three forms: (1) hypercholesterolemia, i.e., higher LDL cholesterol levels (120mg/dL or higher); (2) hypertriglyceridemia, i.e., higher triglyceride levels (150mg/dL or higher); and (3) combined hyperlipidemia, i.e., a combination of hypercholesterolemia and hypertriglyceridemia.
Exemplary primary hyperlipidemias include, but are not limited to, the following diseases:
(1) familial chylomicronemia, a rare genetic disease, causes a defect in the enzyme (LP lipase) that destroys fat molecules. LP lipase deficiency can cause the accumulation of large amounts of fat or lipoproteins in the blood;
(2) familial hypercholesterolemia, a relatively common genetic disorder, occurs because its underlying defect is a series of mutations in the LDL receptor gene, causing dysfunction of the LDL receptor and/or loss of the LDL receptor. It causes the failure of LDL receptors to effectively clear LDL, resulting in increased plasma levels of LDL and total cholesterol;
(3) familial combined hyperlipidemia, also known as compound lipoprotein-type hyperlipidemia; patients and their affected primary relatives have for many times shown a hereditary disease of high cholesterol and high triglycerides. HDL cholesterol levels are often moderately reduced;
(4) familial apolipoprotein B-100 deficiency, a relatively common autosomal congenital abnormality. This deficiency is caused by a single nucleotide mutation that results in the substitution of glutamine for arginine, which mutation results in a decrease in the affinity of LDL particles for LDL receptors. This can therefore lead to very high plasma LDL and total cholesterol levels;
(5) Familial dysbetalipoproteinemia, also known as type III hyperlipoproteinemia, is a rare genetic disorder that causes moderate to severe elevations in serum Triglyceride (TG) and cholesterol levels, with concomitant apolipoprotein E dysfunction. HDL levels are usually normal; and
(6) familial hyperlipoproteinemia, a common genetic disease, in which the concentration of plasma VLDL is elevated. It can cause mild to moderate elevation of triglyceride levels (usually not cholesterol levels) and is often accompanied by low plasma HDL levels.
Exemplary risk factors for secondary hyperlipoproteinemia include, but are not limited to, the following: (1) disease risk factors, such as type 1 diabetes, type 2 diabetes, Cushing's syndrome, hypothyroidism, and a history of certain types of renal failure;
(2) drug risk factors including contraceptive pills, hormones (such as estrogens and corticosteroids), certain diuretics, and various beta blockers; (3) dietary risk factors including dietary intake of more than 40% of total calories, intake of more than 10% of total calories, intake of more than 300mg of cholesterol per day, habitual and excessive alcohol consumption, and obesity; and (4) non-hereditary dyslipidemia.
The methods of the invention may be effectively used in combination with one or more other active Diabetes drugs depending on the desired target therapy (see, e.g., Turner, N. et al, prog.drug Res. (1998) 51: 33-94; Haffner, S.diabetes Care (1998) 21: 160-178; and DeFronzo, R. et al (eds.), Diabetes Reviews (1997) Vol.5No. 4). Numerous studies have been conducted on the benefits of oral drug combination THERAPY (see, e.g., Mahler, R., J.Clin. Endocrinol. Metab. (1999) 84: 1165-71; United kingdomProspective Diabetes Study Group: UKPDS 28, Diabetes Care (1998) 21: 87-92; dinBar, C.W. (eds.), CURRENT THERE THEREPAY INENNOLOLOGY AND METABOLISM (CURRENT THERAPY of endocrine AND METABOLISM), 6 th edition (Mosby- -Year Book, Inc., St. Louis, Mo. 1997); Chiasson, J. et al., Ann. Intern. Med. (1994): 928-935; Coniff, R. et al., Clin.r. (1997) 19: 16-26; Coniff, R. J. et al., Amiff. J. It. R. 451. Med. (1995. J. 1996) 13. J. 92. J. wo. J. 11. J. 443. J. EP.11. J. No. (Ksby., 14. P.11. 92, K., 14. A. 92, K.P.P.P.10. 443. A., USA.11, et al., 11. J. 11. J. 11. These studies indicate that the modulation of diabetes and hyperlipidemia can be further improved by adding a second drug to the treatment regimen. IC as used herein 50"refers to the amount, concentration, or dose of a particular test compound that achieves 50% inhibition of the maximal response in an assay that detects a response, such as modulation of nuclear receptor (including LXR α or LXR β) activity.
As used herein, "LXR α" (LXR alpha) refers to all mammalian forms of this receptor, including, for example, alternative splice subtypes and natural subtypes. Representative LXR α species include, but are not limited to: rat forms of this receptor (Genbank accession NM 0)31627) Mouse form (Genbank accession number BC)012646) And human form (GenBank accession No. u 22662).
As used herein, "LXR β" (LXR beta) refers to all mammalian forms of this receptor, including, for example, alternative splice subtypes and native subtypes. Representative LXR β species include, but are not limited to: rat forms (GenBank accession No. NM 031626), mouse forms (GenBank accession No. NM 009473), and human forms (GenBank accession No. u07132) of this receptor.
As used herein, "LXR" or "LXRs" refers to LXR α and LXR β.
The terms "obesity" and "obesity" refer to a Body Mass Index (BMI) greater than 27.8kg/m for males2For women, the body mass index is greater than 27.3kg/m 2(BMI-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 following uses: treating, or preventing, a disease associated with altered cholesterol transport, reverse cholesterol transport, fatty acid metabolism, cholesterol absorption, cholesterol reabsorption, cholesterol secretion, cholesterol excretion, or cholesterol metabolism, or a symptom arising from altered cholesterol transport, reverse cholesterol transport, fatty acid metabolism, cholesterol absorption, cholesterol reabsorption, cholesterol secretion, cholesterol excretion, or a complication of cholesterol metabolism.
Such diseases include, for example, hyperlipidemia, dyslipidemia, hypercholesterolemia, atherosclerosis, atherosclerotic cardiovascular disease, hyperlipoproteinemia (see, for example, international patent application publication nos. WO 00/57915 and WO 00/37077), hyperglycemia, insulin resistance, diabetes, lipodystrophy, obesity, syndrome X (U.S. patent application publication No. 20030073614, international patent application publication No. WO 01/82917), excessive lipid deposition in peripheral tissues such as skin (xanthomas) (see, for example, U.S. patent nos. 6,184,215 and 6,187,814), stroke, peripheral occlusive disease, memory loss (BrainResearch (1997), vol.752, pp.189-196), optic nerves and retinopathies (i.e., macular degeneration, retinitis pigmentosa), or repair of traumatic lesions of the peripheral nervous system (Trends in neurosciens (1994), vol.17, pp.525-530), prevention of senescence-induced degeneration (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 neurosciens (1994), Vol.17, pp.525-530), prevention of degenerative neuropathy that occurs in diseases such as diabetic neuropathy (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 disease (J.lipid Res. (1998), Vol.39, pp.1740-1743).
The present invention also provides methods of increasing reverse cholesterol transport in mammalian cells using the claimed compounds and compositions to increase expression of an ATP-binding cassette (ABCA1) (see, e.g., international patent application publication No. WO 00/78972).
Accordingly in another aspect, the invention also includes a method of removing cholesterol from a tissue deposit (e.g., an atherosclerotic plaque or xanthoma) in a patient with clinical evidence of atherosclerosis or atherosclerotic cardiovascular disease, wherein the method comprises administering to the patient a therapeutically effective amount of a compound or composition of the invention. In addition, the present invention also provides a method of preventing or reducing the primary and secondary risk of atherosclerotic cardiovascular disease including ischemic heart disease, ischemic stroke, multi-infarct dementia and intermittent claudication, comprising administering to a patient at such risk a prophylactically effective amount of a compound or composition of the present invention. The patient may have atherosclerotic cardiovascular disease at the time of administration or be at risk of developing the disease. Risk factors for developing atherosclerotic cardiovascular disease include advanced age (> 65), male gender, family history of atherosclerotic cardiovascular disease, high blood cholesterol (especially LDL or "bad" cholesterol above 100mg/dL), history of smoking and passive smoking, hypertension, diabetes, obesity and impaired mobility.
Also included herein is the use of a compound of the present invention, or a pharmaceutically acceptable derivative thereof, in combination with one or more of the following therapeutic agents, in the treatment of atherosclerosis: antihyperlipidemic drugs, plasma HDL-elevating agents, antihypercholesterolemic drugs, cholesterol biosynthesis inhibitors (e.g., HMG CoA reductase inhibitors such as lovastatin (lovastatin), simvastatin (simvastatin), pravastatin (pravastatin), fluvastatin (fluvastatin), atorvastatin (atorvastatin), and rivastatin (rivastatin)), acyl-coenzyme a: cholesterol Acyltransferase (ACAT) inhibitors, probucol (probucol), raloxifene (raloxifene), niacin, niacinamide, cholesterol absorption inhibitors, bile acid sequestrants (e.g. anion exchange resins or quaternary amines (e.g. cholestyramine or colestipol)), low density lipoprotein receptor inducers, clofibrate (clofibrate), fenofibrate (fenofibrate), bezafibrate (bezafibrate), ciprofibrate (ciprofibrate), gemfibrozil (gemfibrazilizol), vitamin B6Vitamin B12Antioxidant vitamins, beta-blockers, antidiabetic agents, angiotensin II antagonists, angiotensin converting enzyme inhibitors, platelet aggregation inhibitors, fibrinogen receptor antagonists, aspirin or fibric acid derivatives.
In one embodiment, the compounds of the present invention may be used in combination with cholesterol biosynthesis inhibitors, particularly HMG-CoA reductase inhibitors. The term HMG-CoA reductase inhibitor is intended to include all pharmaceutically acceptable salts, esters, free acid and lactone forms of compounds having HMG-CoA reductase inhibitor activity, and thus, the use of the salts, esters, free acid and lactone forms is included within the scope of the present invention. Compounds having inhibitory activity against HMG-CoA reductase can be readily identified by assay methods known in the art. For example, suitable assays are described or disclosed in U.S. Pat. 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. Pat. No. 4,444,784); pravastatin sodium (PRAVACHOL ®; see, U.S. Pat. No. 4,346,227); fluvastatin sodium (LESCOL ®; see, U.S. patent No. 5,354,772); atorvastatin calcium (LIPITOR ®; see, U.S. Pat. No. 5,273,995) and rivastatin (also known as cerivastatin; see, U.S. Pat. No. 5,177,080). The structural formulae of these compounds and other HMG-CoA reductase inhibitors which may be used in combination with the compounds of the invention are described on page 87 of M.Yalpani, "Cholesterol Loweringdrugs", Chemistry & Industry, pp.85-89 (2.5.1996). In this preferred embodiment, the HMG-CoA reductase inhibitor is selected from lovastatin and simvastatin.
The compounds of the present invention may also be used in methods of reducing hyperglycemia and insulin resistance, i.e., in methods of treating diabetes (international patent application publication No. WO 01/82917), and in methods of treating, preventing, or ameliorating a disorder associated with diabetes, hyperglycemia, or insulin resistance, or a complication arising from diabetes, hyperglycemia, or insulin resistance, including a collection of diseases, symptoms, or disorders that constitute "syndrome X" (see U.S. patent application No. 20030073614), comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound or composition of the present invention. In addition, the present invention provides a method of preventing or reducing the risk of developing hyperglycemia, insulin resistance, diabetes, or syndrome X in a patient, comprising administering to a patient at risk of such condition a prophylactically effective amount of a compound or composition of the present invention.
Diabetes (Diabetes mellitus), commonly referred to as Diabetes (Diabetes), refers to a disease process caused by a variety of causes and characterized by high levels of plasma glucose, known as hyperglycemia. See, e.g., LeRoith, D.et al, DIABETES MELLITUS (DIABETES), (Lippincott-Raven Publishers, Philadelphia, Pa.U.S. A.1996). According to the american diabetes association estimates, diabetes affects approximately 6% of the world population. Uncontrolled hyperglycemia is associated with increased and early mortality due to increased risk of macrovascular and macrovascular disease, including nephropathy, neuropathy, retinopathy, hypertension, cerebrovascular disease, and coronary heart disease. Therefore, controlling glucose homeostasis is a very important approach for the treatment of diabetes.
There are two main forms of diabetes: type 1 diabetes (formerly known as insulin-dependent diabetes mellitus or IDEM); and type 2 diabetes (formerly known as non-insulin dependent diabetes mellitus or NIDDM).
Type 2 diabetes is a disease characterized by insulin resistance with a relative, rather than absolute, insulin deficiency. Type 2 diabetes can vary from major insulin resistance with relative insulin deficiency to major insulin deficiency with partial insulin resistance. Insulin resistance is the ability to reduce insulin's ability to exert its biological effects over a wide range of concentrations. In insulin-resistant individuals, the body secretes abnormally high amounts of insulin to compensate for this deficiency. When an insufficient amount of insulin is present to compensate for insulin resistance and control glucose adequately, a state of impaired glucose tolerance develops. In a large number of individuals, insulin secretion drops further and plasma glucose levels rise, leading to the clinical state of diabetes. Type 2 diabetes is caused by an extremely deep tolerance to the effects of insulin stimulation regulation of glucose and lipid metabolism in the major insulin sensitive tissues (muscle, liver and adipose tissue). Tolerance to insulin responsiveness results in inadequate insulin activation of glucose uptake, oxidation and storage in muscle, and inadequate insulin inhibition of lipolysis in adipose tissue and glucose production and secretion in the liver. In type 2 diabetes, free fatty acid levels are often elevated in obese and some non-obese patients, and lipid oxidation is also elevated.
The premature development of atherosclerosis and the rate of rise of cardiovascular and peripheral vascular diseases are characteristic properties of patients with diabetes. Hyperlipidemia is an important trigger of these diseases. Hyperlipidemia is a disease generally characterized by an abnormal rise in serum lipids (e.g., cholesterol and triglycerides) in the bloodstream, and is an important risk factor for developing atherosclerosis and heart disease. For a review of lipid Metabolism Disorders see, for example, Wilson, j, et al, (eds.), lipid Metabolism Disorders (Disorders of lipid Metabolism), chapter 23, Endocrinology textbooks (Textbook of Endocrinology), 9 th edition, (w.b. sanders Company, philidelphia, pa.u.s.a.1998). Hyperlipidemia is generally classified into primary or secondary hyperlipidemia. Primary hyperlipidemia is often caused by genetic defects, while secondary hyperlipidemia is often caused by other factors, such as various disease states, drugs, and dietary factors. Alternatively, hyperlipidemia may result from a combination of primary and secondary factors of hyperlipidemia. Elevated cholesterol levels are associated with a variety of disease states, including coronary heart disease, angina pectoris, carotid artery disease, stroke, cerebral arteriosclerosis, and xanthoma.
Dyslipidemia, or abnormal levels of lipoproteins in plasma, is frequent in diabetes and has been shown to be a major contributor to increased incidence of coronary events and death in diabetic subjects (see, e.g., Joslin, e.ann.chim.med. (1927), vol.5, pp.1061-1079). Thus, epidemiological studies have demonstrated this correlation and have shown a several-fold increase in coronary death in diabetic subjects when compared to 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). A number of lipoprotein abnormalities in diabetic subjects have been described (Howard B., et al, Arteriosclerosis (1978), Vol.30, pp.153-162).
The compounds of the present invention may also be used effectively in combination with one or more other active diabetic agents depending on the intended target treatment (see, e.g., Turner, N. et al, prog.drug Res. (1998), Vol.51, pp.33-94; Haffner, S., Diabetes Care (1998), Vol.21, pp.160-178; and DeFronzo, R. et al (eds.), Diabetes Reviews (1997), Vol.5, No. 4). Various studies have investigated the benefits of combination therapy with oral agents (see, e.g., Mahler, R., J.Clin. Endocrinol. Metab. (1999), Vol.84, pp.1165-71; United Kingdom productive Diabetes Group: UKPDS 28, Diabetes Care (1998), Vol.21, pp.87-92; Bardin, C.W (ed.), CURRENT therapy of endocrine and metabolism (CURRENT THERAPY IN ENDOCRONO ANDMETABOLOL), 6 th edition (Mosby- -Year Book, Inc., St.Louis, Mo.1997), Chiasson, J.et al, Medn.Intern.1994, Vol.121, pp.928-928-11; Diiff, R.et al, Clin.1997, the U.19, U.1997, Medin.17, Vol.P.11, Vol.17, Vol.P.10, Vol.32, Vol.17, Vol.32, Vol.10, Vol.32, Vol.17, Vol.32, Vol.10, Vol.32, Vol.P.10, Vol.10, Vol.32, Vol.P.10, Vol.32, Vol.10, Vol.32, Vol.P.11, Vol.10, Vol.11, Vol.32, Vol.P.P.11, Vol.11, Vol.14, Vo. These studies show that the modulation of diabetes and hyperlipidemia can be further improved by the addition of a second drug in the treatment regimen.
Thus, in the treatment of diabetes, the compounds of the present invention may be combined with one or more of the following therapeutic agents: thiosemicarbazides (e.g., chlorpropamide (chlorpropamide), tolbutamide (tolbutamide), acetohexamide (acetohexamide), tolazamide (tolazamide), glyburide (glyburide), gliclazide (gliclazide), glibenclamide (glynase), glimepiride (glimepiride), and glipizide), biguanides (e.g., metformin), thiazolidinediones (e.g., ciglitazone), pioglitazone (pioglitazone), troglitazone (troglitazone), and rosiglitazone (rosiglitazone)), and related insulin activators such as selective or non-selective PPAR α, PPAR β, and PPAR γ activators; dehydroepiandrosterone (also known as DHEA or its conjugate sulfate, DHEA-SO 4); an antiglucocorticoid; a TNF α inhibitor; alpha-glucosidase inhibitors (e.g., acarbose, miglitol, and voglibose), pramlintide (a synthetic analog of the human hormone dextrin), other insulin secretagogues (e.g., repaglinide, gliquidone, and nateglinide), insulin, and the therapeutics discussed above for the treatment of atherosclerosis.
The invention further provides methods of treating obesity and complications of obesity using the compounds of the invention. Obesity is associated with 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; and Knowl, et al, am.J Clin.NutR. (1991), Vol.53, pp.1543-1551).
In addition, the compounds of the present invention may be used in combination with agents useful for the treatment of obesity or obesity-related disorders. Such agents include, but are not limited to, phenylpropanolamine (phenylpropanolamine), phentermine (phenotemine), diethylpropiophenone (diethylpropion), mazindol (mazindol), fenfluramine (fenfluramine), dexfenfluramine (dexfenfluramine), pheniramine (phentermine), beta3An adrenergic receptor agonist agent; sibutramine (sibutramine), gastrointestinal lipase inhibitors (e.g. orlistat), and leptin. Other agents useful for treating obesity or obesity-related disorders include neuropeptide Y, enterostatin (enterostatin), cholecystokinin (cholecystokinin), bombesin, dextrin, histamine H 3Receptor, dopamine D2Receptor modulators, melanocyte stimulating hormone, corticotropin releasing factor, galanin, and gamma-aminobutyric acid (GABA).
Evaluation of the use of the Compound of the present invention
Standard physiological, pharmacological, and biochemical procedures can be used to test compounds to identify compounds that have modulatory activity or biological activity at nuclear receptors including LXRs (LXR α and LXR β). Such assays include, for example, biochemical assays such as binding assays, fluorescence polarization detection, FRET-based co-activator 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 co-transfection assays, assays that employ LBD-Gal 4 chimeras and protein-protein interactions (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; beckmann instruments inc., Fullerton, CA; Precision Systems, inc., nature, MA) which allow these assays to be performed in a high throughput format. These systems typically automate the entire procedure, including pipetting of all samples and reagents, timed incubation of liquid dispensing, and final reading of the microplate in the detector appropriate for the assay. These configurable systems provide high throughput and fast start-up, as well as a high degree of adaptability and customization. The manufacturer of the system provides detailed protocols for a variety of high throughput systems. Thus, for example, screening systems for detecting modulation of gene transcription, ligand binding, and the like are described in technical reports provided by Zymark corp.
For such high throughput screening systems, detection that does not require washing or liquid separation steps is preferred, and includes biochemical detection, such as fluorescence polarization detection (see, e.g., Owicki, J., Biomol, Screen (2000October), Vol.5, No.5, pp.297), Scintillation Proximity Assay (SPA) (see, e.g., Carpenter et al, Methods mol.biol. (2002), Vol 190, pp.31-49), and Fluorescence Resonance Energy Transfer (FRET) or time-resolved FRET-based co-activator recruitment assay (Mukherjee et al, J.Steroroidchem. mol.biol. (2002 July); Vol.81, No.3, pp.217-25; (Zhou et al, mol.Endocrinol. (October., Vol.12, Vol.10, pp.1594-447) the full-length receptor binding sequence can be isolated using the LXR binding sequence containing LXR, LXR. beta. 198, as for FXR, LBD contains amino acids 244-472 of the full-length sequence.
If a fluorescently labeled ligand is available, fluorescence polarization detection provides a means of detecting binding of a compound to a target nuclear receptor by measuring the change in fluorescence polarization caused by the compound displacing a trace amount of the labeled ligand. In addition, the method can be used to monitor the association of ligand-dependent fluorescently labeled co-activator polypeptides with a nuclear receptor of interest to detect binding of ligand to the nuclear receptor of interest.
The ability of a compound to bind to a receptor, or heterodimeric complex with RXR, can also be determined in a similar manner by assessing the degree of competition of the compound with a radiolabeled ligand with known receptor affinity using the Scintillation Proximity Assay (SPA). In the method, the labeled compound (e.g.,)3H]24, 25 epoxycholesterol), which when brought into close proximity to a scintillator (which binds to nuclear receptors), such as YSI-copper-containing beads, generates an optical signal. If the radiolabeled compound is displaced from the nuclear receptor, the amount of light emitted from the scintillator-bound nuclear receptor decreases, which can be readily detected using a standard microplate liquid scintillation plate reader, such as a Wallac Microbeta reader.
Heterodimerization of LXR with RXR α 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 of these methods depend on the fact that: energy transfer from the donor molecule to the acceptor molecule occurs when the donor and acceptor are in close proximity. Typically, the purified LBD of the nuclear receptor of interest is labeled with biotin and subsequently mixed with a stoichiometric amount of europium-labeled streptavidin (Wallac Inc.) and the LBD of the purified rxra is labeled with an appropriate fluorophore, e.g., CY5 TM. Equimolar amounts of each modified LBD were mixed together and equilibrated for at least one hour before being added to the variable or constant concentration samples used to determine affinity. On flatAfter equilibration, the time resolved fluorescence signal was quantified using a fluorescence plate reader. The affinity of the compound can then be estimated from a plot of fluorescence versus concentration of the added compound.
This method can also be used to determine the interaction of ligand-dependent co-activator peptides with nuclear receptors to characterize agonist or antagonist activity of the compounds disclosed herein. Typically, assays in this case involve the use of recombinant glutathione-S-transferase (GST) -nuclear receptor Ligand Binding Domain (LBD) fusion proteins and synthetic biotinylated peptides sequenced from the receptor interaction domain of a co-activator peptide such as steroid receptor co-activator 1 (SRC-1). Typically, GST-LBD is labeled with europium chelate (donor) via europium-labeled anti-GST antibody, and the coactivator peptide is labeled with allophycocyanin via streptavidin-biotin binding.
In the presence of agonists of nuclear receptors, the polypeptide is recruited to GST-LBD, bringing europium and allophycocyanin into close proximity, and transferring energy from the europium chelate to the allophycocyanin. When the complex is excited by light at 340nm, the excitation energy absorbed by the europium chelate is transmitted to the allophycocyanin moiety, resulting in an 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 665nm indicates the intensity of the protein-protein interaction. Nuclear receptor antagonist activity can be determined by determining the ability of a compound to competitively inhibit the agonist activity of the nuclear receptor (i.e., IC) 50) To be measured.
In addition, a variety of cell-based assays can be successfully used in screening assays to identify and evaluate the specificity of the compounds of the invention. These methods include cotransfection assays, translocation assays, complementation assays, and the use of gene activation techniques to overexpress endogenous nuclear receptors.
There are three basic variations of the cotransfection detection strategy, cotransfection detection using full-length nuclear receptors, cotransfection detection using chimeric nuclear receptors containing the ligand binding domain of the target nuclear receptor fused to a heterologous DNA binding domain, and detection based on using two mammalian hybrid detection systems.
The basic cotransfection assay is based on cotransfection into cells expressing a plasmid, thereby expressing the nuclear receptor of interest in cells with a reporter plasmid that includes a reporter gene whose expression is under the control of a DNA sequence capable of interacting with the nuclear receptor (see, e.g., U.S. Pat. Nos. 5,071,773; 5,298,429 and 6,416,957). Treatment of transfected cells with an agonist of the nuclear receptor increases the transcriptional activity of the receptor, which is reflected by an increase in the expression of the reporter gene, which can be determined by a variety of standard procedures.
For those receptors that function as heterodimers with RXR, such as LXRs, co-transfection assays typically involve the use of expression plasmids for the nuclear receptor of interest and RXR. General cotransfection assays require access to full-length nuclear receptors and a response element that provides sufficient screening sensitivity and specificity for the nuclear receptor of interest.
Typically, the expression plasmid comprises: (1) a promoter, such as the SV40 early region promoter, the HSV tk promoter or the phosphoglycerate kinase (pgk) promoter, the CMV promoter, the Sr α promoter, or other suitable control elements known in the art, (2) a cloned polynucleotide sequence, such as a cDNA-encoded receptor, cofactor, or fragment thereof, linked to the promoter in a sense orientation such that transcription from the promoter can produce RNA encoding a functional protein, and (3) a polyadenylation sequence. For example, and without limitation, the expression cassettes of the invention may include 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 the research group, such as the pCMX vector originally developed from Evans lab (Willey et al. genes & Development 91033-1045(1995)) may also be used.
The transcriptional regulatory sequences within the expression cassette are selected by the practitioner based on the intended application; depending on the particular use, transcriptional regulation may employ inducible, repressible, constitutive, cell type specific, stage-specific, sex-specific, or other desired types of promoters or control sequences.
Alternatively, the expression plasmid may include an activation sequence to activate or increase expression of the endogenous chromosomal sequence. Such activating sequences include, for example, synthetic zinc finger motifs (see, e.g., U.S. Pat. Nos. 6,534,261 and 6,503,7171) or strong promoter or enhancer sequences, which together with the target sequence allow homologous or non-homologous recombination of an upstream activating sequence of the target gene.
Genes encoding the following full-length proteins described above, suitable for use in co-transfection studies and profiling compounds described herein, include human LXR α (accession number U22662), human LXR β (accession number U07132), rat FXR (accession number U18374), human FXR (accession number NM _005123), human RXR α (accession number NM _002957), human RXR β (accession number XM _042579), human RXR γ (accession number XM _053680), human PPAR α (accession number X57638), and human PPAR δ (accession number U10375). All accession numbers in this application refer to GenBank accession numbers.
The reporter plasmid can be constructed using standard molecular biology techniques by placing the cDNA encoding the reporter gene downstream of a suitable minimal promoter. For example, luciferase reporter plasmids can be constructed as follows: a cDNA encoding firefly luciferase (typically having an SV40 small t intron and a poly-A tail, (de Wet et al, (1987) mol.cell.biol.7725-735)) is placed downstream of the herpes virus thymidine kinase promoter (located at nucleotide residues-105 to +51 of the thymidine kinase nucleotide sequence, obtained, for example, from plasmid pBLCAT2(Luckow & Schutz (1987) Nucl.acid.Res.155490-5494)), which is in turn linked to a suitable Response Element (RE).
The choice of hormone responsive element depends on the type of assay to be used. Where full-length LXR α or LXR β is used, a reporter plasmid containing a known LXR RE, such as a reporter plasmid like LXREx 1-tk-luciferase, is typically used (see, U.S. Pat. No. 5,747,661, incorporated herein by reference). In the case of LXR α or LXR β -LBD-Gal4 fusions, GAL4 Upstream Activation Sequences (UAS) were used. Typically, GAL4UAS contains the sequence 5 'CGGRNNRCYNYNCNCCG-3', where Y ═ C or T, R ═ a or G, and N ═ A, C, T or G, and exists as an adaptor repeat of 4 copies.
Many methods of co-transfecting expression and reporter plasmids are known to those skilled in the art and can be used in co-transfection assays to introduce plasmids into appropriate cell types. Typically, the cell will not endogenously express a nuclear receptor that interacts with the response element used in the reporter plasmid.
A number of reporter Gene systems are known in the art and include, for example, alkaline phosphatase (see, Berger, J. et al, Gene (1988), Vol.66, pp.1-10; and Kain, S.R., methods, mol.biol. (1997), Vol.63, pp.49-60), beta-galactosidase (see, U.S. Pat. No. 5,070,012, issued to Nolan et al on 12/3 1991, and Bronstein, I. et al, J.Chemium.biolum. (1989), Vol.4, pp.99-111), chloramphenicol acetyl transferase (see, Gorman et al, mol.cell Biol. (1982), Vol.2, pp.1044-51), beta-glucuronidase, peroxidase, beta-lactamase (U.S. Pat. Nos. 5,741,657 and 5,955,604), catalytic antibodies, luciferase (U.S. Pat. No. 4634; U.56; Vol.56, pp.39509, Natural fluorescent protein (Voien., Voy.39509, Vol.3944, Vol.5944, Vol.44, and Rechen).
Use of chimeras comprising a Ligand Binding Domain (LBD) of the nuclear receptor of interest to a heterologous DNA Binding Domain (DBD) to extend the versatility of cell-based assays to defined DNA binding elements recognized by defined DNA binding domains by directing the activation of the nuclear receptor in question (see WO 95/18380). This assay extends the utility of cell-based co-transfection assays in situations where an unsatisfactory biological response or screening window of the native DNA binding domain is utilized.
Generally, the method is similar to that used for the basic cotransfection assay, except that chimeric constructs are used instead of the full-length nuclear receptors. With respect to full-length nuclear receptors, treatment of transfected cells with an agonist of nuclear receptor LBD may increase the transcriptional activity of the heterologous DNA binding domain, which is reflected by the increased expression of the reporter gene described above. Typically, for the chimeric structure, a DNA binding domain from a defined nuclear receptor, or a transcriptional regulator from yeast or bacterial origin, such as GAL4 and members of the LexA/Umut superfamily, is used.
A third cell-based assay for screening compounds of the invention is a mammalian two-hybrid assay that measures the ability of nuclear hormone receptors to interact with cofactors in the presence of ligands (see, e.g., U.S. patent nos. 5,667,973, 5,283,173, and 5,468,614). The basic approach consists in creating three plasmid structures that allow interaction between nuclear receptors and interacting proteins for coupling to a transcriptional reader in living cells. The first construct is an expression plasmid for expressing a fusion protein comprising an interacting protein, or a portion of the protein containing the interacting region, fused to a GAL4DNA binding domain. The second expression plasmid comprises DNA encoding a nuclear receptor of interest fused to a strong transcriptionally active region such as VP16, and the third construct comprises a reporter plasmid containing a reporter gene with a minimal promoter and activation sequences upstream of GAL 4.
Once all three plasmids are introduced into the cell, the GAL4DNA binding domain encoded in the first structure allows the fusion protein to bind specifically to the upstream GAL4 site of the minimal promoter. However, since the GAL4DNA binding domain usually has no strong transcriptional activity when isolated, expression of the reporter gene occurs only at low levels. In the presence of a ligand, the nuclear receptor-VP 16 fusion protein can bind to the GAL 4-interacting protein fusion protein such that the strong transcription activator VP16 is in close proximity to the GAL4 binding site and the minimal promoter region of the reporter gene. This interaction significantly enhances transcription of the reporter gene that can be identified as the various reporter genes described above. Thus, transcription of the reporter gene is driven in a ligand-dependent manner by the interaction of the interacting protein and the nuclear receptor of interest.
Any compound that is a candidate for activating LXR α or LXR β can be tested by these methods. Typically, compounds are tested at a variety of different concentrations to optimize the chance of activation of the receptor (if present) that can be detected and recognized. Typically, the assay is performed three times and varies within experimental error of less than 15%. Each experiment was typically repeated three or more times with similar results.
The activity of the reporter gene can be conveniently normalized to an internal control and the data plotted as fold activation relative to untreated cells. Positive control compounds (agonists) can be included with DMSO in the high and low controls for assay data normalization. Likewise, antagonist activity can be measured by determining the ability of a compound to competitively inhibit agonist activity.
In addition, compounds and compositions can be evaluated for the ability to increase or decrease expression of genes known to be regulated in vivo by LXR α or other nuclear receptors using Northern-blot assays (Northern-blot), RT PCR, or oligonucleotide microarray analysis to analyze RNA levels. Western blot (Western-blot) analysis can be used to determine the expression of the protein encoded by the LXR target gene. Genes known to be regulated by LXRs include ATP-binding cassette transporters ABCA1, ABCG1, ABCG5, ABCG8, sterol response element binding protein 1c (SREBP1c) gene, stearoyl CoA desaturase 1(SCD-1) and apolipoprotein apoE gene (apoE).
Established animal models exist for a number of diseases directly related to the claimed compounds, and these animal models can be used for further evaluation and characterization of the claimed compounds. These model systems include diabetic dyslipidemia using Zucker (fa/fa) rats or (db/db) mice, using apolipoprotein E deficient mice (ApoE) -/-) Spontaneous hyperlipidemia of (2), mice deficient in low-density lipoprotein receptor (LDLR)-/-) The diet ofResulting hyperlipidemia, Apo E(s) fed on a Western diet (21% fat, 0.05% cholesterol), (B) and (C)-/-) And LDLR: (-/-) Atherosclerosis in mice. In addition, LXR or FXR animal models (e.g., knockout mice) can also be used for further in vivo evaluation of the present compounds and compositions (see, e.g., Peet et al, Cell (1998), Vol.93, pp.693-704, and Sinal et al, Cell (2000), Vol.102, pp.731-744).
Administration of the Compounds of the invention
Administration of the compounds of the present invention or pharmaceutically acceptable salts thereof, in pure form or in the form of suitable pharmaceutical compositions, may be via any acceptable mode of administration of drugs that serve a similar purpose. The pharmaceutical composition of the present invention can be prepared by combining the compound of the present invention with a suitable pharmaceutically acceptable carrier, diluent or adjuvant, and can be formulated into solid, semi-solid, liquid or gaseous forms such as tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants, gels, microspheres and aerosols. The general route of administration of the pharmaceutical composition includes, 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. The pharmaceutical compositions of the present invention may be formulated so that the active ingredients contained therein are bioavailable when the compositions are administered to a patient. The composition to be administered to a subject or patient may take the form of one or more dosage units, for example, a tablet may be a single dose unit and a container of a compound of the invention in aerosol form may have a plurality of dosage units. The actual method of preparing the dosage form is known, or will be apparent, to those skilled in the art; see, for example, Remington's Pharmaceutical Sciences, 18 th edition (Mack Publishing Company, Easton, Pennsylvania, 1990). In any event, the compositions to be administered contain a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, for the treatment of a disease state associated with nuclear receptor activity in accordance with the teachings of the present invention.
The pharmaceutical compositions of the present invention may be in solid or liquid form. In one aspect, the carrier is a particle and the composition is in the form of, for example, a tablet or powder. The carrier may be a liquid and the composition is, for example, an oral syrup, an injection or an aerosol formulation effective, for example, in administration by inhalation.
When intended for oral administration, the pharmaceutical compositions are preferably in solid or liquid form, wherein semi-solid, semi-liquid, suspension and gel forms are included as solid or liquid within the forms recognized herein.
As a solid composition for oral administration, the pharmaceutical composition may be prepared in the form of powder, granules, compressed tablets, pills, capsules, gummy candies, wafers, and the like. The solid compositions typically contain one or more inert diluents or edible carriers. In addition, one or more of the following may also be present: a binder such as carboxymethyl cellulose, ethyl cellulose, microcrystalline cellulose, gum tragacanth or gelatin; excipients, such as starch, lactose or dextrin; disintegrating agents, such as alginic acid, sodium alginate, sodium carboxymethyl starch (Primogel), corn starch, and the like; lubricants, such as magnesium stearate or hydrogenated vegetable oil (Sterotex); glidants, such as colloidal silicon dioxide; sweetening agents, such as sucrose or saccharin; fragrances, such as peppermint, methyl salicylate or orange flavour; and a colorant.
When the pharmaceutical composition is in the form of a capsule, for example a gelatin capsule, it may contain, in addition to materials of the above type, a liquid carrier such as polyethylene glycol or an oil.
The pharmaceutical compositions may be in the form of, for example, elixirs, syrups, solutions, emulsions or suspensions. These liquids may be used for oral administration or for injection delivery, as two examples. When intended for oral administration, preferred compositions may contain, in addition to a compound of the present invention, one or more of sweetening agents, preserving agents, dyes/colorants and aroma-enhancing agents. In compositions intended for administration by injection, one or more of surfactants, preservatives, wetting agents, dispersing agents, suspending agents, buffers, stabilizers and isotonic agents may be included.
The liquid pharmaceutical compositions of the present invention, whether in solution, suspension or other similar 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 used as a solvent or suspending medium, polyethylene glycol, glycerol, propylene glycol or other solvents; antibacterial agents such as benzyl alcohol or methyl paraben; antioxidants, such as ascorbic acid or sodium bisulfite; chelating agents, such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates; and agents for adjusting tonicity, such as sodium chloride or dextrose. Parenteral preparations can be enclosed in ampoules, disposable syringes or double-dose vials made of glass or plastic. Physiological saline is a preferred adjuvant. Injectable pharmaceutical compositions are preferably sterile.
The liquid pharmaceutical composition of the present invention to be used for parenteral or oral administration should contain a specific amount of the compound of the present invention in order to obtain an appropriate dose. Typically, this amount is at least 0.01% of the compound of the invention in the composition. When intended for oral administration, this amount may vary between 0.1 and about 70% by weight of the composition. Preferred oral pharmaceutical compositions contain from about 4% to about 50% of a compound of the invention. Preferred pharmaceutical compositions and formulations according to the invention are formulated as parenteral dosage units containing between 0.01 and 1% by weight of a compound of the invention.
The pharmaceutical compositions of the invention may be designed for topical application, in which case the carrier may suitably comprise a solution, emulsion, ointment or gel base. The matrix, for example, may comprise one or more of the following: petrolatum, lanolin, polyethylene glycols, beeswax, mineral oil, diluents such as water and alcohol, and emulsifiers and stabilizers. Thickeners may be present in the topically applied pharmaceutical composition. If transdermal administration is desired, the composition may include a transdermal patch or an iontophoresis device. Topical formulations may contain the compounds of the present invention at a concentration of about 0.1 to about 10% w/v (weight per unit volume).
The pharmaceutical compositions of the invention may be designed for rectal administration and may be in the form of, for example, suppositories which melt in the rectum and release the drug. Compositions for rectal administration may contain an oily base as a suitable non-irritating adjuvant. Such substrates include, but are not limited to: lanolin, cocoa butter and polyethylene glycols.
The pharmaceutical compositions of the present invention may include various materials that modify the physical form of the solid or liquid dosage unit. For example, the composition may include a material that forms an encapsulating shell around the active ingredient. The material forming the encapsulating shell is generally inert and may be selected from, for example, sugar, shellac, and other enteric encapsulating agents. Alternatively, the active ingredient may be encapsulated within a gelatin capsule.
Pharmaceutical compositions of the invention in solid or liquid form may include agents that bind to the compounds of the invention and thereby facilitate delivery of the compounds. Suitable agents with such capability include monoclonal or polyclonal antibodies, proteins or liposomes.
The pharmaceutical compositions of the present invention may be comprised of dosage units capable of being administered as an aerosol. The term aerosol is used to denote a variety of systems ranging from systems of colloidal nature to systems consisting of pressurized packaging. Drug release can be achieved by liquefied or compressed gas or by a suitable pump system that dispenses the active ingredient. Aerosols of the compounds of the invention may be delivered in the form of a single, biphasic or triphasic system to release the active ingredient. The delivery of the aerosol includes the necessary containers, activators, valves, sub-containers, etc. that may be co-formed into a kit. Those skilled in the art will be able to determine the preferred aerosol without undue experimentation.
The pharmaceutical compositions of the present invention may be prepared by methods well known in the pharmaceutical art. For example, a pharmaceutical composition to be administered by injection may be prepared by combining a compound of the present invention with sterile distilled water to form a solution. Surfactants may be added to aid in the formation of a homogeneous solution or suspension. Surfactants are compounds that non-covalently interact with the compounds of the present invention to aid in the dissolution or uniform suspension of the compounds in an aqueous delivery system.
The compounds of the present invention, or pharmaceutically acceptable salts thereof, are administered in a pharmaceutically effective amount which depends on a variety of factors including: the activity of the particular compound employed; metabolic stability and length of action of the compound; the age, weight, general health, sex, and diet of the patient; the mode and time of administration; the rate of excretion; drug combination; the severity of the particular disorder and condition; and a subject receiving treatment. Generally, a pharmaceutically effective daily dose is from about 0.1mg to about 20mg of a compound of the invention, or a pharmaceutically acceptable salt thereof, per kg of body weight per day; preferably from about 0.1mg to about 10mg/kg body weight/day; most preferably from about 0.1mg to about 7.5mg/kg body weight/day.
In the use of the compounds of the present invention, or pharmaceutically acceptable derivatives thereof, may also be administered simultaneously with, before or after the administration of one or more of the above-mentioned therapeutic agents. The combination therapy comprises administering a single pharmaceutical dosage formulation comprising a compound of the invention and one or more additional active agents, and administering the compound of the invention and each active agent separately in their separate pharmaceutical dosage formulations. For example, the compound of the present invention and the HMG-CoA reductase inhibitor may be administered to the patient simultaneously in a single oral dosage composition, such as a tablet or capsule, or each agent may be administered in separate oral dosage formulations. Where separate dosage formulations are used, the compound of the invention and one or more additional active agents may be administered substantially at the same time, i.e., concurrently, or separately and staggered in time, i.e., sequentially; combination therapy is to be understood to include all such treatment regimens.
Dosage information for HMG-CoA reductase inhibitors is well known in the art, as a variety of HMG-CoA reductase inhibitors are marketed in the United states. In particular, the daily dosage of HMG-CoA reductase inhibitor may be the same or similar to the amount used for anti-hypercholesterolemia treatment, which is described in the Physicians' Desk Reference (PDR).
See, for example, PDR 50 th edition, 1996(Medical Economics Co); in particular, see page 216, the title "hypolipidemic agents (Hypolipidemics)", the subheading "HMG-CoA Reductase Inhibitors (HMG-CoA Reductase Inhibitors)", and the reference pages cited therein. Preferably, the oral dosage of the HMG-CoA reductase inhibitor is about 1-200 mg/day, more preferably about 5-160 mg/day. However, the dosage will depend on the potency of the particular HMG-CoA reductase inhibitor used and other factors as described above. HMG-CoA reductase inhibitors having sufficiently strong potency may be administered in daily doses in amounts of less than milligrams.
As an example, the daily dosage of simvastatin can be selected from 5mg, 10mg, 20mg, 40mg, 80mg, and 160 mg; as for lovastatin, selected from 10mg, 20mg, 40mg and 80 mg;
for fluvastatin sodium, selected from 20mg, 40mg and 80 mg; as for pravastatin sodium, it is selected from 10mg, 20mg and 40 mg. The daily dose of atorvastatin calcium ranges from 1mg to 160mg, more specifically, from 5mg to 80 mg. Oral administration may be given once or divided into two, three, or four doses during a day, but it is preferable that the HMG-CoA reductase inhibitor is given once daily.
Preparation of the Compounds of the invention
It will be appreciated that in the following description, combinations of substituents and/or variables of the formulae described are permissible only if such compositions result in stable compounds.
It will also be appreciated by those skilled in the art that in the following processes, the functional groups of the intermediate compounds need to be protected by suitable protecting groups. These functional groups include hydroxyl, amino, mercapto and carboxylic acid. Suitable protecting groups for hydroxy include trialkylsilyl or diarylalkylsilyl groups (e.g., t-butyldimethylsilyl, t-butyldiphenylsilyl or trimethylsilyl), tetrahydropyranyl, benzyl, and the like. Suitable protecting groups for 1, 2-dihydroxy groups include ketal-and acetal-forming groups. Suitable protecting groups for amino, amidino and guanidino include t-butyloxycarbonyl, benzyloxycarbonyl and the like. Suitable protecting groups for a mercapto group include-C (O) -R (where R is alkyl, aryl or aralkyl), p-methoxybenzyl, trityl and the like. Suitable protecting groups for carboxylic acids include alkyl, aryl or aralkyl esters.
Protecting groups are added or removed according to standard techniques well known to those skilled in the art and as described herein. The use of protecting groups is described in detail in Green, T.W. and P.G.M.Wutz, protective groups in Organic Synthesis (1991), 2 nd edition, Wiley-Interscience. The protecting group may also be a polymer resin, such as Wang resin or 2-chlorotrityl chloride resin.
It will also be appreciated by those skilled in the art that although protected derivatives of the compounds of the invention, as described above in the summary and first aspects of the invention, may not be pharmacologically active, 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 vivo to form the compounds of the invention which are pharmacologically active. The derivatives are therefore described as "prodrugs". All prodrugs of the compounds of the present invention are included within the scope of the present invention.
It is understood that one of ordinary skill in the art, in light of the following disclosure, including preparation examples and examples, and information well known to those of ordinary skill in the chemical synthesis art, can prepare compounds of the present invention that are not specifically prepared herein.
The starting materials in the synthetic examples provided herein can be obtained from commercial sources or via reference procedures or by the methods disclosed herein. All commercially available compounds were used without further purification unless otherwise indicated. Deuterated solvents, e.g. DMSO or CDCl 3(99.8% D, Cambridge Isotrope Laboratories) was used in all indicated experiments.1H NMR spectra were recorded on a Bruker Avance 400MHz NMR spectrometer. Significant peaks are summarized and generally include: number of protons, multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br s, broad singlet) and coupling constant in hertz. Chemical shifts are reported in parts per million (δ) relative to tetramethylsilane. Mass spectra were recorded on a Perkin-Elmer SCIEX HPLC/MS instrument using reverse phase conditions (acetonitrile/water, 0.05% trifluoroacetic acid) and Electrostatic (ES) ionization. The abbreviations used in the following examples have accepted meanings in the chemical literature. E.g. CH2Cl2(methylene chloride), 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-.
For illustrative purposes only, most of the structural formulae in the following reaction schemes focus on specific embodiments of the compounds of the present invention. However, it is reasonable to expect that one of ordinary skill in the art, given the teachings of this specification, will be able to utilize appropriately substituted starting materials and procedures known to those skilled in the art to prepare all of the compounds of the invention in this summary and first aspect of the invention.
In the general description following each reaction scheme, the phrase "standard isolation procedure" is intended to include one or more of the following techniques familiar to those skilled in the art of organic chemistry: organic extraction, washing of the organic solution with dilute aqueous acid or base, use of drying agents, filtration, concentration in vacuo, followed by purification by distillation, crystallization or solid-liquid chromatography. The phrase "high temperature" refers to temperatures above room temperature, and the phrase "low temperature" refers to temperatures below room temperature.
The following specific preparations (for intermediates) and examples (for the compounds, pharmaceutical compositions and methods of use of the invention) are intended as guidance in facilitating the practice of the invention and are not intended to limit the scope of the invention. Without further elaboration, it is believed that one skilled in the art can, using the preceding description and the following illustrative examples, make and use 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 those skilled in the art that various modifications and equivalent substitutions can be made without departing from the spirit and scope of the invention.
Synthesis of
Pyrazole Ia
Scheme 1
The process for preparing the compounds of the present invention is illustrated in scheme 1. The amine (001i) can be converted to hydrazine (001ii) using standard techniques that are readily apparent to those skilled in the art. Acetophenone (001iii) can be converted to a diketone (001iv) by Claisen condensation. Hydrazine (001ii) and diketones (001iv) can be condensed thermally or with the aid of catalysts such as acids to form pyrazoles (001 v). The aryl bromides such as (001v) can then be further processed by arylation reactions such as the Suzuki reaction to form the tetra-aromatic ring system (001 vi).
An alternative way of preparing the compounds of the present invention is shown in scheme 2. After addition of a substituent such as an aromatic ring, thiophenones (002iii) can be produced, and these produced ketones (002vii) can then be converted into diketones (002 viii). Diketones (002viii) and hydrazines (002ii) can be condensed thermally or with the aid of catalysts to form pyrazoles (002 vi).
Scheme 2
Example 1
3- {5- [2- (2, 5-dichloro-phenyl) -5-trifluoromethyl-2H-pyrazol-3-yl ] -thiophen-2-yl } -benzenesulfonamide
Example 1a
Preparation of 1- (5-bromo-thiophen-2-yl) -4, 4, 4-trifluoro-butane-1, 3-dione
Figure S2006800306472D01471
A2 liter three neck round bottom flask equipped with a 250mL pressure equalizing addition funnel, overhead stirrer, and thermocouple was charged with lithium hexamethyldisilazide (500mL of 1.0M THF solution, 500mmol) and THF (100 mL). A solution of 1- (5-bromo-thiophen-2-yl) -ethanone (75.5g, 368mmol) was prepared in THF (350 mL). The solution was added portionwise via cannula to the addition funnel and slowly from the addition funnel into the reaction flask at a rate such that the internal temperature was < -70 ℃ (40 minutes). The ketone flask and addition funnel were then rinsed with additional THF (25mL) to ensure complete transfer. After stirring for 15 minutes at < -70 ℃, a solution of ethyl trifluoroacetate (66mL, 553mmol) in THF (100mL) is added from an addition funnel over-45 minutes. The light brown reaction was heated to ambient temperature overnight. After stirring for-16 h, the reaction was cooled in an ice bath and carefully added 3N aqueous HCl (150mL) to proceed And (8) quenching (queue). Quenching is highly exothermic. After the addition of HCl was complete, 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). 3N HCl was added and the mixture was acidified to pH < 3. Separate the layers with Et2The aqueous acidic solution was O (3X 150 mL). The combined organic layers were washed with Na2SO4Dried, filtered and concentrated under reduced pressure to give a brown oil. The oil was taken up in benzene and concentrated under reduced pressure to remove all remaining water. The resulting oil was pumped under high vacuum and the actual product was withdrawn to give 1- (5-bromo-thiophen-2-yl) -4, 4, 4-trifluoro-butane-1, 3-dione as a pale brown solid (111.7g, 100.8% yield).1H-NMR(400MHz，CDCl3)：δ14.5(broad s，1H)，7.57(d，J＝4.0Hz，1H)，7.17(d，J＝4.0Hz，1H)，6.37(s，1H)。
Example 1b
Preparation of 5- (5-bromo-thiophen-2-yl) -1- (2, 5-dichloro-phenyl) -3-trifluoromethyl-1H-pyrazole
2.01g (9.41mmol) of 2, 5-dichlorohydrazinium hydrochloride (Aldrich), 1.79g (5.95mmol) of diketone, and 10mL of glacial acetic acid were weighed into a 250mL flask. The suspension was stirred and heated at 80-85 ℃ and 5.0mL of DMF was added to dissolve it. The resulting solution was heated at 80-85 ℃ for 1 hour, then cooled, and washed with 150mL ethyl acetate and 250mL water into a separatory funnel. Ethyl acetate was separated, washed with 200mL of 1M NaOH, 50mL of brine, and dried (Na) 2SO4) And concentrated in vacuo. The resulting yellow oil was treated with 200mL hexane to form a precipitate. The precipitate was removed by filtration and the filtrate was concentrated in vacuo to give the desired product as a pale yellow solid (2.7g), which was used for the next conversion without further purification.1H NMR(400MHz，CDCl3)：δ7.55(s，1H)，7.49(m，2H)，6.94(d，J＝4Hz，1H)，6.81(s，1H)，6.69(d，J＝4Hz，1H)。
The following compounds are prepared essentially in accordance with the previous examples:
1- (2-chlorophenyl) -5- {3- [ (phenylmethyl) oxy]Phenyl } -3- (trifluoromethyl) -1H-pyrazole; ms (es): 428.5[ M + H [ ]]+；
1- (2-chlorophenyl) -5- {4- [ (phenylmethyl) oxy]Phenyl } -3- (trifluoromethyl) -1H-pyrazole, ms (es): 429[ M + H]+。
Example 1c
Preparation of 3- {5- [2- (2, 5-dichloro-phenyl) -5-trifluoromethyl-2H-pyrazol-3-yl ] -thiophen-2-yl } -benzenesulfonamide
Figure S2006800306472D01482
439mg of bromide (993. mu. mol), 207.9mg of boric acid (1.03mmol), and 5mL of THF were weighed into a 50mL flask. The resulting solution was placed in an oil bath and heated at 80-85 ℃. When the solution is refluxed, approximately 50mg of tetrakis (triphenylphosphine) palladium (0) is added, followed by 500L of 1.0M sodium carbonate. The reaction was held at reflux for 2 hours and then washed into a separatory funnel with ethyl acetate and 1.0M sodium carbonate. Ethyl acetate was separated and dried (Na)2SO4) And concentrated in vacuo. By silica gel flash chromatography (Jones Flashmaster, 50g SiO) 2Gradient eluent: from 100% hexane to 40% ethyl acetate over 45 minutes). The appropriate fractions were combined and concentrated in vacuo to afford the product as a pale yellow solid, yield: 131mg (25%).1HNMR(400MHz，DMSO-d6)：δ8.20(s，1H)，7.98(s，1H)，7.87(m，2H)，7.82(t，J＝8Hz，2H)，7.67(d，J＝8Hz，1H)，7.64(d，J＝4Hz，1H)，7.56(s，1H)，7.49(s，2H)，7.32(d，J＝4Hz，1H)。
The following compounds are prepared essentially in accordance with the previous examples:
1- (2, 5-dichlorophenyl) -5- (5- {3- [ (1-methylethyl) sulfonyl group]Phenyl } -2-thienyl) -3- (trifluoromethyl) -1H-pyrazole, ms (es): 547[ M + H]+；
5- {5- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]-2-thienyl } -3-methyl-2- (methylthio) pyridine, ms (es): 466.2[ M + H]+；
5- {5- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]-2-thienyl } -2- (ethylsulfanyl) -3-methylpyridine; ms (es): 480.2[ M + H]+；
3-methyl-5- (5- {1- [2- (methoxy) phenyl)]-3- (trifluoromethyl) -1H-pyrazol-5-yl } -3-thienyl) -2- (methylthio) pyridine, ms (es): 462.3[ M + H]+；
4- (5- {5- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl)]-2-thienyl } pyridin-2-yl) morpholine; MS (ES)491.2, [ M + H]+；
4- (5- {5- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl)]-2-thienyl } pyridin-2-yl) piperazine-1-carboxylic acid 1, 1-dimethylethyl ester, ms (es): 590.2[ M + H]+；
(5- {5- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl) ]-2-thienyl } pyridin-3-yl) acetic acid methyl ester; ms (es): 478.1[ M + H]+；
[4- {5- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl ] amide]-2-thienyl } -3-methylphenyl) acetic acid methyl ester; ms (es): 490.0[ M + H]+；
3- {5- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]-2-thienyl } -4-fluorophenyl) acetic acid methyl ester; ms (es): 495.2[ M + H]+；
2- (5- {5- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H- [ pyrazol-5-yl)]-2-thienyl } pyridin-3-yl) -2-methylpropionic acid methyl ester; ms (es): 506.3[ M + H]+；
3- (3- {5- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-)Pyrazol-5-yl]-2-thienyl } phenyl) propanoic acid; ms (es): 477.0[ M + H]+；
3- (4- {5- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]-2-thienyl } phenyl) propanoic acid; ms (es): 477.3[ M + H]+；
4- {5- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]-2-thienyl } benzoic acid; ms (es): 449.0[ M + H]+；
3- {5- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]-2-thienyl } benzoic acid; ms (es): 449.0[ M + H]+，471.0[M+Na]+；
(2E) -3- (4- {5- [1- (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- (trifluoromethyl) -1- [3- (trifluoromethyl) pyridin-2-yl ] methyl ]-1H-pyrazol-5-yl } -2-thienyl) phenyl]Acetic acid; ms (es): 516.3[ M + H]+；
[ 3-methyl-4- (5- {3- (trifluoromethyl) -1- [3- (trifluoromethyl) pyridin-2-yl ] methyl]-1H-pyrazol-5-yl } -2-thienyl) phenyl]Methyl acetate; ms (es): 526.5[ M + H]+；
2- (ethylsulfanyl) -3-methyl-5- (5- {3- (trifluoromethyl) -1- [2- (trifluoromethyl) phenyl]-1H-pyrazol-5-yl } -2-thienyl) pyridine; ms (es): 514.2[ M + H]+；
5- {5- [1- (2, 5-dichlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]-2-thienyl } -3-methyl-2- (methylthio) pyridine; ms (es): 500.4, [ M + H ]]+；
3-methyl-2- (methylthio) -5- (5- {3- (trifluoromethyl) -1- [2- (trifluoromethyl) phenyl [)]-1H-pyrazol-5-yl } -2-thienyl) pyridine; ms (es): 500.4[ M + H]+；
5- {5- [1- (2, 5-dichlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]-3-thienyl } -3-methyl-2- (methylthio) pyridine; ms (es): 500.3[M+H]+；
1- (2-chlorophenyl) -5- {5- [3- (ethylsulfonyl) -5- (1-methylethyl) phenyl]-2-thienyl } -3- (trifluoromethyl) -1H-pyrazole; ms (es): 539.4[ M + H]+；
3- {5- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]-2-thienyl } phenyl) acetic acid; ms (es): for the35Cl，463.3([M+H]+)；
[ 4- {5- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl ] amide]-2-thienyl } phenyl) acetic acid; ms (es): for the 35Cl，463.2([M+H]+)；
2- (3- {5- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]-2-thienyl } phenyl) -2-methylpropionic acid, ═ ms (es): for the35Cl，491.1([M+H]+)；
1- (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- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]-2-thienyl } phenyl) -2-ethylbutyric acid, ms (es): 519.2[ M + H]+；
2- (4- {5- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]-2-thienyl } phenyl) -2-methylpropionic acid, ms (es): 491.4[ M + H]+；
1- (2, 5-dichlorophenyl) -5- (5- {3- [ (1-methylethyl) sulfonyl group]Phenyl } -2-thienyl) -3- (trifluoromethyl) -1H-pyrazole, ms (es): 547[ M + H]+；
2- [5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -3- (trifluoromethyl) -1H-pyrazol-1-yl]-3- (trifluoromethyl) pyridine, ms (es): 518.3[ M + H]+；
1- [ 5-chloro-2- (methoxy) phenyl]-5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -3- (trifluoromethyl) -1H-pyrazole;1H-NMR(CDCl3)：δ8.07(1H，m)，7.85(1H，m)，7.75(1H，m)，7.58(1H，t)，7.50-7.45(2H，m)，7.25(1H，d)，6.94(1H，d)，6.88(1H，d)，6.85(1H，s)，3.65(3H，s)，3.09(3H，s)。MS(ES)：513[M+H]+；
1- [ 5-chloro-2- (phenoxy) phenyl]-5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -3- (trifluoromethyl) -1H-pyrazole;1H-NMR(CDCl3)：δ8.09(1H，m)，7.88(1H，m)，7.77(1H，m)，7.66(1H，d)，7.60(1H，t)，7.39(1H，dd)，7.29(1H，d)，7.24-7.15(2H，m)，7.07(1H，t)，6.93(1H，d)，6.82(1H，d)，6.79(1H，s)，6.70-6.64(2H，m)，3.10(3H，s)。MS(ES)：575[M+H]+；
1- (2-chloro-5-fluorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -3- (trifluoromethyl) -1H-pyrazole; 1H-NMR(CDCl3)：δ8.07(1H，m)，7.86(1H，m)，7.75(1H，m)，7.63-7.49(2H，m)，7.33(1H，m)，7.31-7.23(2H，m)，6.91-6.85(2H，m)，3.08(3H，s)。MS(ES)：501[M+H]+；
1- (5-chloro-2-fluorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -3- (trifluoromethyl) -1H-pyrazole;1H-NMR(CDCl3)：δ8.09(1H，m)，7.87(1H，m)，7.77(1H，m)，7.64-7.56(2H，m)，7.50(1H，m)，7.28(1H，d)，7.17(1H，t)，6.92(1H，d)，6.88(1H，s)，3.09(3H，s)。MS(ES)：501[M+H]+；
1- [ 2-chloro-5- (methoxy) phenyl]-5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -3- (trifluoromethyl) -1H-pyrazole;1H-NMR(CDCl3)：δ8.06(1H，m)，7.85(1H，m)，7.75(1H，m)，7.58(1H，t)，7.43(1H，m)，7.25(1H，d)，7.14-7.02(2H，m)，6.89(1H，s)，6.87(1H，d)，3.85(3H，s)，3.08(3H，s)。MS(ES)：513[M+H]+；
1- [ 2-chloro-5- (trifluoromethyl) phenyl]-5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -3- (trifluoromethyl) -1H-pyrazole;1H-NMR(CDCl3)：δ8.06(1H，m)，7.90-7.83(2H，m)，7.79(1H，m)，7.76-7.67(2H，m)，7.59(1H，t)，7.25(1H，m) 6.92(1H, s), 6.84(1H, d), 3.08(3H, s); ms (es): 551 and 553[ each M + H ]]+；
4-chloro-3- [5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -3- (trifluoromethyl) -1H-pyrazol-1-yl]Phenol;1H-NMR(CDCl3)：δ8.04(1H，m)，7.84(1H，d)，7.74(1H，d)，7.57(1H，t)，7.30(1H，d)，7.24(1H，d)，6.99(1H，m)，6.93(1H，m)，6.91-6.87(2H，m)，3.09(3H，s)。MS(ES)：499[M+H]+；
4-chloro-3- [5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -3- (trifluoromethyl) -1H-pyrazol-1-yl]A benzamide;1H-NMR(DMSO-d6)：δ8.29(1H，d)，8.25-8.15(2H，m)，8.04(1H，d)，7.96-7.79(3H，m)，7.75-7.64(3H，m)，7.56(1H，m)，7.28(1H，d)，3.28(3H，s)。MS(ES)：526[M+H]+。
3- {5- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]-3-thienyl } benzenesulfonamide;1H-NMR(DMSO-d6)：δ8.07(1H，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- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]-3-thienyl } benzenesulfonamide;1H-NMR(CDCl3)：δ7.96-7.88(2H，m)，7.61-7.52(5H，m)，7.51-7.44(2H，m)，7.18(1H，d)，6.94(1H，s)，4.89(2H，s)。MS(ES)：484[M+H]+。
3- {5- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]-2-thienyl } benzenesulfonamide;1H-NMR(DMSO-d6)：δ7.89(1H，m)，7.85(1H，m)，7.81-7.69(4H，m)，7.68-7.55(3H，m)，7.51(1H，s)，7.45(2H，s)，7.28(1H，d)。MS(ES)：484[M+H]+。
4- {5- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]-2-thienyl } benzenesulfonamide;1H-NMR(DMSO-d6)：δ7.87-7.60(9H，m)，7.51(1H，s)，7.43-7.37(2H，s)，7.28(1H，d)。MS(ES)：484[M+H]+。
3- {5- [1- (2-chloro-5-hydroxyphenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]-2-thienyl } benzenesulfonamide;1H-NMR(DMSO-d6)：δ10.02(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-chloro-2- [5- {5- [3- (methylsulfonyl) phenyl ]-2-thienyl } -3- (trifluoromethyl) -1H-pyrazol-1-yl]Phenol; ms (es): 499[ M + H ]]+。
3- (5- {3- (trifluoromethyl) -1- [3- (trifluoromethyl) pyridin-2-yl]-1H-pyrazol-5-yl } -2-thienyl) benzenesulfonamide; ms (es): 519[ M + H ]+。
3- (5- {3- (trifluoromethyl) -1- [2- (trifluoromethyl) phenyl]-1H-pyrazol-5-yl } -2-thienyl) benzenesulfonamide; ms (es): 518[ M + H]+。
2- [5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -3- (trifluoromethyl) -1H-pyrazol-1-yl]A benzenesulfonamide; ms (es): 528[ M + H ]]+。
3- (5- {1- [ 5-chloro-2- (phenoxy) phenyl]-3- (trifluoromethyl) -1H-pyrazol-5-yl } -2-thienyl) benzenesulfonamide; ms (es): 576[ M + H]+。
5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1- [2- (phenoxy) phenyl]-3- (trifluoromethyl) -1H-pyrazole; ms (es): 541[ M + H]+。
2-chloro-6-methyl-3- [5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -3- (trifluoromethyl) -1H-pyrazol-1-yl]Phenol; ms (es): 513[ M + H]+。
N- (3- {5- [1- (2, 5-dichlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl)]-2-thienyl } phenyl) methanesulfonamide; ms (es): 534[ M + H ]]+。
1- (2-chlorophenyl) -5- [ 3' - (methylsulfonyl) biphenyl-3-yl]-3- (trifluoro benzene)Methyl) -1H-pyrazole, ms (es): 477.0[ M + H]+；
1- (2-chlorophenyl) -5- [ 3' - (methylsulfonyl) biphenyl-4-yl ]-3- (trifluoromethyl) -1H-pyrazole, ms (es): 477[ M + H ]]+。
2- {5- [ 3' - (methylsulfonyl) biphenyl-4-yl]-3- (trifluoromethyl) -1H-pyrazol-1-yl } -3- (trifluoromethyl) pyridine, ms (es): 512[ M + H]+。
4' - [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]Biphenyl-3-sulfonamide, ms (es): 478[ M + H]+。
1- (2-chlorophenyl) -5- { 3' - [ (1-methylethyl) sulfonyl group]Biphenyl-4-yl } -3- (trifluoromethyl) -1H-pyrazole, ms (es): 505[ M + H]+。
5- { 3' - [ (1-methylethyl) sulfonyl group]Biphenyl-4-yl } -3- (trifluoromethyl) -1- [2- (trifluoromethyl) phenyl]-1H-pyrazole, ms (es): 539[ M + H ]]+。
1- (2, 6-dichlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -3- (trifluoromethyl) -1H-pyrazole, ms (es): 517[ M + H]+。
2-methyl-2- (3- (5- (3- (trifluoromethyl) -1- (3- (trifluoromethyl) pyridin-2-yl) -1H-pyrazol-5-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-1-yl) benzoate. Ms (es): 507M + H]+。
2- (3- (5- (5- (3- (methylsulfonyl) phenyl) thiophen-2-yl) -3- (trifluoromethyl) -1H-pyrazol-1-yl) phenyl) propan-2-ol. Ms (es): 507M + H]+。
2- (5- (5- (3- (methylsulfonyl) phenyl) thiophen-2-yl) -3- (trifluoromethyl) -1H-pyrazol-1-yl) ethanol. Ms (es): 417[ M + H ] ]+。
3-chloro-2- [5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -3- (trifluoromethyl)) -1H-pyrazol-1-yl]Pyridine:1H-NMR(DMSO-d6)：δ8.73(1H，dd)，8.39(1H，dd)，8.03(1H，m)，7.90-7.83(3H，m)，7.72-7.65(2H，m)，7.55(1H，s)，7.26(1H，d)，3.27(3H，s)。MS(ES)：484[M+H]+。
1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -3- (trifluoromethyl) -1H-pyrazole; ms (es): 483[ M + H]+；
2- {5- [5- (3-methanesulfonyl-phenyl) -thiophen-2-yl]-3-trifluoromethyl-pyrazol-1-yl } -3-trifluoromethyl-pyridine; ms (es): 518[ M + H]+；
5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -3- (trifluoromethyl) -1- [2- (trifluoromethyl) phenyl]-1H-pyrazole; ms (es): 517[ M + H]+；
1- (2-methylphenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -3- (trifluoromethyl) -1H-pyrazole; ms (es): 463[ M + H]+；
1- [2- (methoxy) phenyl]-5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -3- (trifluoromethyl) -1H-pyrazole; ms (es): 479[ M + H ]]+；
1- (2-fluorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -3- (trifluoromethyl) -1H-pyrazole; ms (es): 467[ M + H ]]+；
1- (2-ethylphenyl) -5- {4- [3- (methylsulfonyl) phenyl]-2-thienyl } -3- (trifluoromethyl) -1H-pyrazole, MS (ES)477.3[ M + H ]]+。
1- (2-chlorophenyl) -5- {4- [3- (methylsulfonyl) phenyl]-2-thienyl } -3- (trifluoromethyl) -1H-pyrazole, MS (ES)483.2, 485.2[ M + H ]]+。
1- (2-chlorophenyl) -3- (trifluoromethyl) -5- {4- [3- (trifluoromethyl) phenyl ]-2-thienyl } -1H-pyrazole, MS (ES)472.3, 474.3[ M + H ]]+。
Example 2
1- (2, 5-dichloro-phenyl) -5- [5- (3-methanesulfonyl-phenyl) -thiophen-2-yl ] -3-trifluoromethyl-1H-pyrazole
Example 2a
Preparation of 1- [5- (3-methanesulfonyl-phenyl) -thiophen-2-yl ] -ethanone
Figure S2006800306472D01551
5.04g of 2-acetyl-5-bromothiophene (24.6mmol), 6.14g (30.7mmol) of boric acid, 604mg (523. mu. mol) of tetrakis (triphenylphosphine) palladium (0), 300mL of THF, and 30mL of 1.0M Na were weighed2CO3Then, the mixture was put into a 500mL flask. The resulting solution was heated at 80-85 ℃ overnight during which most of the THF was evaporated. The residue was taken up in ethyl acetate and 1.0M Na2CO3Washed into a separatory funnel. The ethyl acetate was separated and the insoluble product was filtered. The solid was washed with ethyl acetate, the filtrate was combined with the ethyl acetate extract and dried (MgSO)4) And concentrated in vacuo. The residue was then crystallized from ethyl acetate to give the product as a pale yellow powder, yield: 1.14g (16.5%). The product filtered from the extract was recovered as a colorless powder, yield: 4.30g (62.4%).1H NMR(400MHz，CDCl3)：δ8.21(s，1H)，7.92(t，J＝7Hz，2H)，7.70(d，J＝4.0Hz，1H)，7.65(t，J＝7Hz，1H)，7.44(d，J＝4Hz，1H)，3.10(s，3H)，2.59(s，3H)。
Example 2b
Preparation of 4, 4, 4-trifluoro-1- [5- (3-methanesulfonyl-phenyl) -thiophen-2-yl ] -butane-1, 3-dione
Figure S2006800306472D01552
5.42g (19.3mmol) of 1- (5- (3- (methylsulfonyl) phenyl) thiophen-2-yl) ethanone and 42mL of THF were weighed into a 250mL flask. The resulting suspension was stirred, cooled to 0-3 ℃ in an ice bath, and 23mL of lithium bis (trimethylsilyl) amide (1.0M in THF) was added. The resulting yellow thick suspension was stirred and warmed to room temperature, then ethyl trifluoroacetate (3.46mL, 29mmol) was added. After stirring at room temperature overnight, the reaction was concentrated in vacuo to remove THF. The residue was washed with ethyl acetate and 1M HCl into a separatory funnel. The ethyl acetate was separated, washed with brine and dried (MgSO)4) And concentrated in vacuo. The amorphous yellow powder obtained was pure enough for further synthetic transformation, yield: 7.2g (99%).1H NMR(400MHz，DMSO-d6)：δ8.20(d，J＝7Hz，1H)，8.08(t，J＝7Hz，1H)，7.95(d，J＝4.0Hz，1H)，7.89(d，J＝7Hz，1H)，7.78(d，J＝4Hz，1H)，7.69(t，J＝7Hz，1H)，6.22(broad s，1H)，3.26(s，3H)。
Example 2c
Preparation of 1- (2, 5-dichloro-phenyl) -5- [5- (3-methanesulfonyl-phenyl) -thiophen-2-yl ] -3-trifluoromethyl-1H-pyrazole
202.7mg (539. mu. mol) of (Z) -1, 1, 1-trifluoro-4-hydroxy-4- (5- (3- (methylsulfonyl) phenyl) thiophen-2-yl) but-3-en-2-one, 117.4mg (550. mu. mol) of 2, 5-dichlorophenylhydrazine hydrochloride, 3mL of acetic acid and 1mL of DMF are weighed into an 8mL bottle. The resulting reaction was stirred at 100 ℃ and 105 ℃ for 3 hours and then concentrated to dryness in vacuo. The residue was purified by flash chromatography on silica gel (3X 23cm, 1: 1 ethyl acetate-hexanes) and dried to give the product as a pale yellow solid, yield: 89mg (55%). 1HNMR(400MHz，CDCl3)：δ8.08(s，1H)，7.87(d，J＝9Hz，1H)，7.75(d，J＝9Hz，1H)，7.6(m，2H)，7.5(m，2H)，7.27(d，J＝4Hz，1H)，6.90(s，1H)，6.87(d，J＝4Hz，1H)，3.09(s，3H)。
The following compounds are prepared essentially in accordance with the previous examples:
1- (2, 5-dimethylphenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -3- (trifluoromethyl) -1H-pyrazole;1H-NMR(DMSO-d6)：δ8.02(1H，m)，7.90-7.79(2H，m)，7.73-7.61(2H，m)，7.47(1H，s)，7.44-7.32(3H，m)，7.23(1H，d)，3.27(3H，s)，2.36(3H，s)，1.89(3H，s)。MS(ES)：477[M+H]+。
5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1- (benzyl) -3- (trifluoromethyl) -1H-pyrazole;1H-NMR(CDCl3)：δ8.13(1H，m)，7.93-7.77(2H，m)，7.62(1H，t)，7.38-7.28(4H，m)，7.13-7.06(2H，m)，7.01(1H，d)，6.73(1H，s)，5.54(2H，s)，3.10(3H，s)。MS(ES)：463[M+H]+。
1- (2, 6-dichlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -3- (trifluoromethyl) -1H-pyrazole; ms (es): 517[ M + H]+。
Pyrazole Ib
A general synthesis of pyrazole Ib (0037) is depicted in scheme 3. First, aryl-ethylene oxide (0031) can be reacted with bromoaryl-magnesium bromide (0032) to give alcohol intermediate (0033), which can be oxidized under standard conditions to give the corresponding ketone (0034). Ethylene oxide 0031 can be readily prepared by epoxidation of styrene or by treatment of aryl-formaldehydes with trimethylsulfonium iodide under basic conditions. Intermediate 0034 can be reacted with N, N-dimethyl-formamide dimethylacetal (DMFDMA), then with hydrazine (e.g., alkyl hydrazine R)2NHNH2) Condensation gives a mixture of two pyrazole isomers 0035 and 0036. The two pyrazole isomers should be separable by typical chromatographic methods. In the next step, pyrazole 0035 can be reacted with boronic acid R 4B(OH)2Suzuki cross-coupling gave the desired product (0037).
Scheme 3
Figure S2006800306472D01571
Reactants and conditions: (a) DMFDMA, reflux; (b) r2NHNH2EtOH, reflux; (c) r4B(OH)2，K2CO3，10mol％PdCl2(dppf)，H2O, dioxane, 80 ℃.
Pyrazole Ic
A general synthesis of pyrazole Ic (00414) is shown in scheme 4. First, acetyl-bromoarene (bromoarene) (0048) (e.g., where Y is S, O, or CH)2＝CH2) Can be reacted with DMFDMA followed by hydrazine (e.g., alkylhydrazine R)2NHNH2) Condensation gave a mixture of two pyrazole isomers 00410 and 00411. Both pyrazole isomers should be resolved by typical chromatographic methods. 00410 and boronic acids R4B(OH)2Suzuki cross-coupling under standard conditions gives intermediate 00412. Pyrazole 00412 can be brominated, for example, with NBS, and then reacted with an aryl boronic acid R4B(OH)2Cross-coupling gave the desired product (00414).
Scheme 4
Figure S2006800306472D01581
Reactants and conditions: (a) DMFDMA, reflux; (b) r2NHNH2EtOH, reflux; (c) r4B(OH)2，K2CO3，10mol％PdCl2(dppf)，H2O, dioxane, 80 ℃; (d) NBS, THF; (e) r5aPhB(OH)2，K2CO3，10mol％PdCl2(dppf)，H2O, dioxane, 80 ℃.
Example 3
4- (2-chlorophenyl) -3- [5- (3-methanesulfonyl-phenyl) -thiophen-2-yl ] -1-methyl-1H-pyrazole
Example 3a
Preparation of 1- (5-bromothiophene-2-yl) -3-dimethyl amino propenone
Figure S2006800306472D01582
A stirred mixture of 2-acetyl-5-bromothiophene (1.03g, 5.0mmol) and N, N-dimethylformamide dimethyl acetal (2mL) was heated at 110 ℃. After 15h, an orange solid was recovered and dried under high vacuum to give the title compound (1.3g, quant), which was used in the next step without purification. Rf0.17 (10% EtOAc/DCM); 1H-NMR(CD2Cl2)：δ7.73(1H，d)，7.33(1H，d)，7.06(1H，d)，5.52(1H，d)，3.13(3H，s)，2.90(3H，s)。
Example 3b
Preparation of 3- (5-bromothien-2-yl) -1-methyl-1H-pyrazole
Figure S2006800306472D01591
To a stirred solution of 1- (5-bromothien-2-yl) -3-dimethylaminopropenone (0.70g, 2.7mmol) in EtOH (15mL) was added methylhydrazine (0.16mL, 3.0mmol) followed by acetic acid (0.45mL, 8.0 mmol). The resulting mixture was heated at reflux for 2 hours, cooled to ambient temperature, and then concentrated under reduced pressure. The residue was diluted with DCM (50mL) and H2Washed with brine and then dried (Na)2SO4) Concentrated and purified by chromatography (silica, DCM) to give the title compound 10a as a white solid (0.21g) and the regioisomer of pale yellow solid (regioisomer)5- (5-bromothien-2-yl)) -1-methyl-1H-pyrazole, 11a (0.35 g). 10 a: rf0.42 (DCM);1H-NMR(CD2Cl2)：δ7.36(1H，d)，7.01(2H，m)，6.41(1H，d)，3.87(3H，s)；11a：Rf0.19(DCM)；1H-NMR(CD2Cl2)：δ7.42(1H，d)，7.10(1H，d)，6.94(1H，m)，6.36(1H，d)，3.92(3H，s)。
example 3c
Preparation of 3- [5- (3-methanesulfonyl-phenyl) -thiophen-2-yl ] -1-methyl-1H-pyrazole
Figure S2006800306472D01592
3- (5-Bromothiophen-2-yl) -1-methyl-1H-pyrazole (0.20g, 0.83mmol), 3-methanesulfonyl-phenylboronic acid (0.20g, 1.0mmol), K2CO3(345mg，2.5mmol)、Cl2Pd (dppf). DCM (82mg, 10 mol%), and H2A stirred mixture of O (0.6mL) in dioxane (6mL) was sparged with argon for 5 minutes and then heated as a sealed flask at 85 ℃. After 6h, the reaction mixture was cooled to ambient temperature and filtered (Celite) TM) The filter was 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 as a white solid (0.11g, 42%).1H-NMR(CD2Cl2)：δ8.15(1H，m)，7.89(1H，m)，7.80(1H，m)，7.60(1H，m)，7.40(2H，m)，7.29(1H，d)，6.50(1H，d)，3.91(3H，s)，3.07(3H，s)。
Example 3d
Preparation of 4-bromo-3- [5- (3-methanesulfonyl-phenyl) -thiophen-2-yl ] -1-methyl-1H-pyrazole
Figure S2006800306472D01601
To 3- [5- (3-methanesulfonyl-phenyl) -thiophen-2-yl]To a stirred solution of-1-methyl-1H-pyrazole (0.10g, 0.31mmol) in DCM (3mL, anhydrous) was added N-bromosuccinimide (NBS) (56mg, 0.31 mmol). After 22h, NBS (56mg) was added again and stirring continued at ambient temperature. After 46h (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 as a white solid (98mg, 79%).1H-NMR(CD2Cl2)：δ8.17(1H，m)，7.91(1H，m)，7.82(1H，m)，7.72(1H，d)，7.61(1H，m)，7.50(1H，s)，7.44(1H，d)，3.91(3H，s)，3.08(3H，s)。
Example 3e
Preparation of 4- (2-chlorophenyl) -3- [5- (3-methanesulfonyl-phenyl) -thiophen-2-yl ] -1-methyl-1H-pyrazole
Figure S2006800306472D01602
4-bromo-3- [5- (3-methanesulfonyl-phenyl) -thiophen-2-yl]-1-methyl-1H-pyrazole (88mg, 0.22mmol), 2-chlorophenylboronic acid (41mg, 0.26mmol), K2CO3(91mg，0.66mmol)、Cl2Pd (dppf). DCM (18mg, 10 mol%), and H2A mixture of O (0.25mL) in dioxane (2.5mL) was sparged with argon for 5 minutes and then heated as a sealed flask at 80 ℃. After 4h, the reaction mixture was cooled to ambient temperature and filtered (Celite) TM) The filter was 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 (64mg, 67%). Rf0.14 (40% EtOAc/Hex);1H-NMR(CD2Cl2)：δ8.09(1H，m)，7.85-7.76(2H，m)，7.60-7.49(2H，m)，7.45(1H，s)，7.41-7.30(3H，m)，7.21(1H，d)，6.70(1H，d)，3.97(3H，s)，3.05(3H，s)；MS(ES)：429[M+H]+。
the following compounds were prepared in a similar manner from the appropriate reagents:
4- (2-chlorophenyl) -5- [5- (3-methanesulfonyl-phenyl) -thiophen-2-yl]-1-methyl-1H-pyrazole:1H-NMR(DMSO-d6)：δ8.05(1H，m)，7.93(1H，d)，7.85(1H，d)，7.75-7.63(3H，m)，7.50(1H，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-methanesulfonyl-phenyl) -thiophen-2-yl]-1- (2, 2, 2-trifluoro-ethyl) -1H-pyrazole:1H-NMR(CD2Cl2)：δ8.10(1H，m)，7.87-7.76(2H，m)，7.64-7.50(3H，m)，7.45-7.31(3H，m)，7.23(1H，d)，6.75(1H，d)，4.86-4.76(2H，m)，3.05(3H，s)；MS(ES)：497[M+H]+。
4- (2-chlorophenyl) -5- [5- (3-methanesulfonyl-phenyl) -thiophen-2-yl]-1- (2, 2, 2-trifluoro-ethyl) -1H-pyrazole:1H-NMR(CD2Cl2)：δ8.08(1H，m)，7.87-7.78(3H，m)，7.60(1H，m)，7.46-7.39(2H，m)，7.29-7.17(3H，m)，7.09(1H，d)，4.89-4.80(2H，m)，3.06(3H，s)；MS(ES)：497[M+H]+。
pyrazole Id
Scheme 5
Figure S2006800306472D01611
Reactants and conditions: (a) LiHMDS, THF; r2CO2Et-78 to 20 ℃; (b) HOAc, EtOH, refluxing; (c) k2CO3，10mol％PdCl2(dppf)，H2O, dioxane, 80 ℃.
A general synthetic method for pyrazole Id (00519) is shown in scheme 5. First, acetyl-arene (00515) may be substituted with ester R2CO2Et under claisen conditions (Cl)aisen condition) to give the corresponding 1, 3-dione (00516). The diketone 00516 may be reacted with an aryl hydrazine (00517) (e.g. where Y is S, O or CH2＝CH2) Condensation to give the corresponding 1-aryl-pyrazole (00518). The intermediate 00518 may then be reacted with boronic acid R4B(OH)2The desired product (00519) was obtained by Suzuki cross-coupling.
For example, 2' -trifluoromethyl-acetophenone 00515a (R)2＝2-CF3) Condensation with ethyl trifluoroacetate to form diketone 00516a (R)2＝CF3；R1＝2-CF3). Intermediate 00516a was reacted with 4-bromo-phenylhydrazine 00517a hydrochloride (Y ═ CH)2＝CH2) Condensation to give pyrazole 00518a (R)2＝CF3；R1＝2-CF3；Y＝CH2＝CH2) Which is cross-coupled with 3-methanesulfonyl-phenylboronic acid to give pyrazole 00519a (R)2＝CF3；R1＝2-CF3；R4＝3-MeSO2Ph；Y＝CH2＝CH2)。
Figure S2006800306472D01621
Example 4
1- (3' -methanesulfonyl-biphenyl-4-yl) -3-trifluoromethyl-5- (2-trifluoromethyl-phenyl) -1H-pyrazole
Example 4a
Preparation of 4, 4, 4-trifluoro-1- (2-trifluoromethyl-phenyl) -butane-1, 3-dione
Figure S2006800306472D01622
To a stirred solution of 2' -trifluoromethyl-acetophenone (2.25mL, 15.0mmol) in THF (20mL, anhydrous) at-78 deg.C was added 1 dropwiseA0M solution of lithium hexamethyldisilazide (LiHMDS) (15.8mL, 15.8 mmol). After 1h, the reaction mixture was cooled to-78 ℃ and ethyl trifluoroacetate (3.6mL, 30mmol) was added dropwise. After the addition was complete, the reaction mixture was warmed to ambient temperature. Slowly adding H2O (20mL), the reaction mixture was quenched and concentrated under reduced pressure. The resulting material was transferred to a separatory funnel and Et2O (60mL), washed with 1N HCl and brine, then dried (MgSO)4) And concentrated to give the title compound as an amber liquid (4.2g, 99%) which was used in the next step without purification. Rf: 0.15 (20% EtOAc/Hex).
Example 4b
Preparation of 1- (4-bromophenyl) -3-trifluoromethyl-5- (2-trifluoromethyl-phenyl) -1H-pyrazole
Figure S2006800306472D01631
To a stirred solution of 4, 4, 4-trifluoro-1- (2-trifluoromethyl-phenyl) -butane-1, 3-dione (0.40g, 1.4mmol) in EtOH (10mL) was added 4-bromophenylhydrazine hydrochloride (335mg, 1.5mmol) and acetic acid (0.4 mL). The resulting mixture was heated to reflux for 20 hours, cooled to ambient temperature and concentrated under reduced pressure. The resulting residue was diluted with DCM (80mL) and saturated NaCO3The solution was washed with brine and then dried (Na)2SO4) And purified by chromatography (silica, EtOAc/Hex, 0: 100 to 20: 80) to give the title compound as a pale yellow liquid (0.54g, 89%).1H-NMR(CD3CN)：δ7.85(d，1H)，7.63(m，2H)，7.50(d，2H)，7.37(m，1H)，7.17(d，2H)，6.92(s，1H)。
Example 4c
Preparation of 1- (3' -methanesulfonyl-biphenyl-4-yl) -3-trifluoromethyl-5- (2-trifluoromethyl-phenyl) -1H-pyrazole
Figure S2006800306472D01632
1- (4-bromophenyl) -3-trifluoromethyl-5- (2-trifluoromethyl-phenyl) -1H-pyrazole (135mg, 0.31mmol), 3-methanesulfonyl-phenylboronic acid (74mg, 0.37mmol), K2CO3(0.13g，0.93mmol)、Cl2Pd (dppf). DCM (24mg, 10 mol%), and H2A mixture of O (0.2mL) in dioxane (2mL) was sparged with argon for 5 minutes and then heated at 80 ℃ as a sealed flask. After 16h, the reaction mixture was cooled to ambient temperature and filtered (Celite) TM) The filter was 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 (121mg, 76%).1H-NMR(DMSO-d6)：δ8.15(m，1H)，8.03(d，1H)，7.91(m，2H)，7.83(d，2H)，7.71-7.76(m，3H)，7.66(m，1H)，7.40(d，2H)，7.18(s，1H)；MS(ES)：511[M+H]+。
The following compounds were prepared in a similar manner from the appropriate reagents:
4' - {3- (trifluoromethyl) -5- [2- (trifluoromethyl) phenyl]-1H-pyrazol-1-yl } biphenyl-3-sulfonamide, ms (es): 512[ M + H]+
3- (trifluoromethyl) -1- [ 3' - (trifluoromethyl) biphenyl-4-yl]-5- [2- (trifluoromethyl) phenyl]-1H-pyrazole, ms (es): 501[ M + H [ ]]+
3- (trifluoromethyl) -1- { 3' - [ (trifluoromethyl) oxy]Biphenyl-4-yl } -5- [2- (trifluoromethyl) phenyl]-1H-pyrazole, ms (es): 517[ M + H]+
1- [ 3' - (methylsulfonyl) biphenyl-3-yl]-3- (trifluoromethyl) -5- [2- (trifluoromethyl) phenyl]-1H-pyrazole, ms (es): 511[ M + H]+
5- [3- (methylsulfonyl) phenyl]-2- {3- (trifluoromethyl) -5- [2- (trifluoromethyl) phenyl]-1H-pyrazol-1-yl } -1, 3-thiazole, ms (es): 518[ M + H]+
3- (2- {3- (trifluoromethyl) -5- [2- (trifluoromethyl) phenyl]-1H-pyrazol-1-yl } -1, 3-thiazol-5-yl) benzenesulfonamide, ms (es): 519[ M + H ]]+
5- [3- (methylsulfonyl) phenyl]-2- {3- (trifluoromethyl) -5- [2- (trifluoromethyl) phenyl]-1H-pyrazol-1-yl } pyridine, ms (es): 512[ M + H ]+
The following compounds were prepared in a similar manner from the appropriate reagents and ethyl trifluoroacetate was replaced with dimethyl oxalate:
5- (2-chlorophenyl) -1- [ 3' - (methylsulfonyl) biphenyl-4-yl]-1H-pyrazole-3-carboxylic acid methyl ester, ms (es): 467[ M + H ]]+
5- (2-chlorophenyl) -1- {5- [3- (methylsulfonyl) phenyl]Pyridin-2-yl } -1H-pyrazole-3-carboxylic acid methyl ester, ms (es): 468[ M + H]+
5- (2-chlorophenyl) -1- {6- [3- (methylsulfonyl) phenyl]Pyridin-3-yl } -1H-pyrazole-3-carboxylic acid methyl ester, ms (es): 468[ M + H]+
5- {5- [3- (aminosulfonyl) phenyl]-2-thienyl } -1- (2, 5-dichlorophenyl) -1H-pyrazole-3-carboxylic acid methyl ester, ms (es): 508[ M + H ]]+。
Example 5
Preparation of 2- {5- (2-chlorophenyl) -1- [6- (3-methanesulfonyl-phenyl) -pyridin-3-yl ] -1H-pyrazol-3-yl } -propan-2-ol
Figure S2006800306472D01651
To 5- (2-chlorophenyl) -1- {6- [3- (methylsulfonyl) phenyl at 0 deg.C]To a stirred solution of pyridin-3-yl } -1H-pyrazole-3-carboxylic acid methyl ester (0.14g, 0.30mmol) in THF (3mL, anhydrous) was slowly added a 1.4M solution of methyl magnesium bromide in 3: 1 toluene/THF (0.68mL, 0.95 mmol). After the addition was complete, the flask was removed from the ice-water bath and warmed to ambient temperature.After 2h, the reaction mixture was washed with saturated NH4The Cl was quenched and extracted with EtOAc (50 mL). The combined extracts were washed with brine and dried (Na) 2SO4) Concentrated and purified by chromatography (silica, EtOAc/Hex, 35: 65 to 65: 35) to give the title compound as a white solid (50mg, 36%).1H-NMR(DCM-d2)：δ8.54(m，2H)，8.28(m，1H)，7.95(m，1H)，7.72-7.81(m，2H)，7.68(m，1H)，7.34-7.46(m，4H)，6.52(s，1H)，3.07(s，3H)，2.64(s，1H)，1.66(s，6H)；MS(ES)：468[M+H]+。
The following compounds were prepared in a similar manner from the appropriate reagents:
2- [5- (2-chlorophenyl) -1- {5- [3- (methylsulfonyl) phenyl]Pyridin-2-yl } -1H-pyrazol-3-yl radical]Propan-2-ol, ms (es): 468[ M + H]+。
2- {5- (2-chlorophenyl) -1- [ 3' - (methylsulfonyl) biphenyl-4-yl]-1H-pyrazol-3-yl } propan-2-ol, ms (es): 467[ M + H ]]+。
Example 6
Preparation of 1- {5- (2-chlorophenyl) -1- [6- (3-methanesulfonyl-phenyl) -pyridin-3-yl ] -1H-pyrazol-3-yl } -ethanone
Figure S2006800306472D01652
To a stirred solution of N, N' -dimethylethylenediamine (56. mu.L, 0.52mmol) in toluene (3mL, anhydrous) at 0 ℃ was added dropwise a 2.0M solution of trimethylaluminum in hexane (0.75mL, 1.5 mmol). After the addition was complete, the flask was removed from the ice-water bath and allowed to warm to ambient temperature. After 50 minutes, the reaction mixture was slowly added with 5- (2-chlorophenyl) -1- {6- [3- (methylsulfonyl) phenyl]A solution of pyridin-3-yl } -1H-pyrazole-3-carboxylic acid methyl ester (0.22g, 0.47mmol) in toluene (3mL, anhydrous) was heated to reflux. After 90 minutes, the reaction mixture was cooled to ambient temperature and quenched by addition of 1N HCl. The resulting mixture Extract with EtOAc (2X 50 mL). The combined extracts were washed with brine and dried (Na)2SO4) Concentrated and purified by chromatography (silica, EtOAc/Hex, 30: 70 to 60: 40) to give the title compound as a white solid (47mg, 22%).1H-NMR(DCM-d2)：δ8.65(m，1H)，8.57(m，1H)，8.30(m，1H)，7.99(m，1H)，7.79-7.87(m，2H)，7.71(m，1H)，7.36-7.47(m，4H)，7.02(s，1H)，3.09(s，3H)，2.68(s，3H)；MS(ES)：452[M+H]+。
The following compounds were prepared in a similar manner from the appropriate reagents:
1- [5- (2-chlorophenyl) -1- {5- [3- (methylsulfonyl) phenyl]Pyridin-2-yl } -1H-pyrazol-3-yl radical]Ethanone, ms (es): 452[ M + H]+
1- {5- (2-chlorophenyl) -1- [ 3' - (methylsulfonyl) biphenyl-4-yl]-1H-pyrazol-3-yl } ethanone, ms (es): 451[ M + H ]]+
Example 7
2- [1- (4-bromophenyl) -5- (2-chlorophenyl) -1H-pyrazol-3-yl ] -1, 1, 1, 3, 3-hexafluoro-propan-2-ol
Example 7a
Preparation of 2- [1- (4-bromophenyl-5- (2-chlorophenyl) -1H-pyrazol-3-yl ] -1, 1, 1, 3, 3, 3-hexafluoro-propan-2-ol
Figure S2006800306472D01661
To a stirred solution of methyl 1- (4-bromophenyl) -5- (2-chlorophenyl) -1H-pyrazole-3-carboxylate (504mg, 1.29mmol) and trifluoromethyl-trimethylsilane (CF3-TMS) (0.77mL, 5.2mmol) in toluene (8mL, anhydrous) was added dropwise a 1.0M solution of tetrabutylammonium fluoride (TBAF) in THF (0.26mL, 20 mol%, dried over 4 Å molecular sieves). After 20h, additional CF was added to the reaction mixture3TMS (0.57mL) and TBAF (0.2mL), then heated at 50 ℃. After the reaction time of 2 hours, the reaction solution is stirred, The reaction mixture was cooled to ambient temperature, diluted with DCM (50mL) and washed with H2Washed with brine and then dried (Na)2SO4) 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 as a white solid (0.10g, 16%).1H-NMR(DCM-d2)：δ7.40-7.49(m，4H)，7.31-7.36(m，2H)，7.16(d，2H)，6.71(s，1H)，5.18(s，1H)。
Example 7b
Preparation of 2- [5- (2-chlorophenyl) -1- (3' -methanesulfonyl-biphenyl-4-yl) -1H-pyrazol-3-yl ] -1, 1, 1, 3, 3-hexafluoro-propan-2-ol
Figure S2006800306472D01671
2- [1- (4-bromophenyl) -5- (2-chlorophenyl) -1H-pyrazol-3-yl]-1, 1, 1, 3, 3, 3-hexafluoro-propan-2-ol (100mg, 0.20mmol), 3-methanesulfonyl-phenylboronic acid (48mg, 0.24mmol), K2CO3(83mg，0.60mmol)、Cl2Pd (dppf). DCM (16mg, 10 mol%), and H2A mixture of O (0.2mL) in dioxane (2mL) was sparged with argon for 5 minutes and then heated at 80 ℃ as a sealed flask. After 3h, the reaction mixture was cooled to ambient temperature and filtered (Celite)TM) The filter was 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 as a white solid (94mg, 82%).1H-NMR(DCM-d2)：δ8.12(m，1H)，7.92(m，1H)，7.87(m，1H)，7.67(m，1H)，7.61(d，2H)，7.33-7.47(m，6H)，6.74(s，1H)，5.25(s，1H)，3.07(s，3H)；MS(ES)：575[M+H]+。
Pyrazole 1a methanol
The synthesis of the pyrazole methanol is outlined in scheme 6. Bromothienylketone (006A) is treated with a base followed by dimethyl oxalate to form the diketo ester (006B), which is condensed with a hydrazonium salt to form the bromothienylpyrazole product (006C). Suzuki coupling of bromothienylpyrazole with boronic acids mediated with tetrakis (triphenylphosphine) palladium gave phenylthienylpyrazole esters (006D). It undergoes Grignard reaction to yield methanol product (006E). Bromine or chlorine groups are introduced onto the pyrazole ring by reaction with NBS or NCS.
Scheme 6
Example 8
2- {1- (2-chloro-phenyl) -5- [5- (3-methanesulfonyl-phenyl) -thiophen-2-yl ] -1H-pyrazol-3-yl } -propan-2-ol
Example 8a
Preparation of 4- (5-bromo-thiophen-2-yl) -2, 4-dioxo-butyric acid methyl ester
Figure S2006800306472D01682
To a solution of 2-acetyl-5-bromothiophene (25g, 122mmol) and dimethyl oxalate (23g, 194mmol) in dry methanol (800mL) at ambient temperature was added a solution of NaOMe in MeOH (25%, 51mL, 224 mmol). The reaction mixture was stirred at 20 ℃ for 4 hours and then acidified to pH1 with 6N aqueous HCl. The yellow solid was collected by filtration and washed with H2O washes and dries under high vacuum to give 4- (5-bromo-thiophen-2-yl) -2, 4-dioxo-butyric acid methyl ester (31.3g, 88%).1H-NMR(DMSO-d6)：δ8.14(s，1H)，7.46(d，1H)，7.05(s，1H)，3.85(s，3H)。
Example 8b
Preparation of 5- (5-bromo-thiophen-2-yl) -1- (2-chloro-phenyl) -1H-pyrazole-3-carboxylic acid methyl ester
Figure S2006800306472D01691
A solution of 4- (5-bromo-thiophen-2-yl) -2, 4-dioxo-butyric acid methyl ester (15g, 50mmol) and 2-chlorophenylhydrazine hydrochloride (10.75g, 60mmol) in anhydrous MeOH (200mL) was heated under reflux for 6 h. After cooling to 20 ℃, a white solid precipitated, collected by filtration and washed with a small amount of cold MeOH and dried under high vacuum to give methyl 5- (5-bromo-thiophen-2-yl) -1- (2-chloro-phenyl) -1H-pyrazole-3-carboxylate (20g, 100%).1H-NMR(CDCl3)：δ7.48-7.55(m，3H)，7.43(m，1H)，7.11(s，1H)，6.90(d，2H)，6.65(s，1H)，3.95(s，3H)。
Example 8c
Preparation of 1- (2-chloro-phenyl) -5- [5- (3-methanesulfonyl-phenyl) -thiophen-2-yl ] -1H-pyrazole-3-carboxylic acid methyl ester
Figure S2006800306472D01692
5- (5-bromo-thiophen-2-yl) -1- (2-chloro-phenyl) -1H-pyrazole-3-carboxylic acid methyl ester (8.0g, 20mmol), 3-methanesulfonylphenylboronic acid (5.0g, 24mmol), sodium carbonate (6.0g, 56mmol) and tetrakis (triphenylphosphine) palladium (1.2g, 1.04mmol) in 1, 4-dioxane (100mL) and H2Mixture in O (5mL) at 90 ℃ in N2Stirred for 16 hours. The solid was filtered off and washed with ethyl acetate. The filtrate was concentrated in vacuo 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 the crude product. Trituration with DCM gave 1- (2-chloro-phenyl) -5- [5- (3-methanesulfonyl-phenyl) -thiophen-2-yl]-1H-pyrazole-3-carboxylic acid methyl ester (4.8 g). Combining the triturate liquors together and concentrating to give a solid which is subjected to flash chromatographyPurification on silica eluting with EtOAc-hexanes (0-60%) afforded an additional 2.8g of product. The total yield was 7.6g (80%).1H-NMR(CDCl3)：δ8.04(m，1H)，7.84(m，1H)，7.73(m，1H)，7.50-7.58(m，4H)，7.47(m，1H)，7.23(d，1H)，7.20(s，1H)，6.82(d，1H)，3.98(s，3H)，3.07(s，3H)。
Example 8d
Preparation of 2- {1- (2-chlorophenyl) -5- [5- (3-methanesulfonyl-phenyl) -thiophen-2-yl ] -1H-pyrazol-3-yl } -propan-2-ol and 1- [1- (2-chlorobenzene) -5- {5- [3- (methanesulfonyl) phenyl ] -2-thienyl } -1H-pyrazol-3-yl ] ethanone
Figure S2006800306472D01701
At-78 ℃ under N2To 1- (2-chloro-phenyl) -5- [5- (3-methanesulfonyl-phenyl) -thiophen-2-yl]To a stirred solution of-1H-pyrazole-3-carboxylic acid methyl ester (5.22g, 11.036mmol) in anhydrous THF (200mL) was added dropwise a solution of MeMgCl in THF (3.0M, 18mL, 54 mmol). The reaction solution was warmed to room temperature overnight and then saturated NH was added4Aqueous Cl was quenched at 0 ℃. The aqueous layer was separated and extracted with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate and evaporated to dryness in vacuo. The residue was purified by flash chromatography (0-60% EtOAc/hexanes) to give 2- {1- (2-chloro-phenyl) -5- [5- (3-methanesulfonyl-phenyl) -thiophen-2-yl as a white solid]-1H-pyrazol-3-yl } -propan-2-ol (2.74g, 52%) and 1- [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl ] as a white solid]-2-thienyl } -1H-pyrazol-3-yl]Ethanone (1.5g, 30%).1H-NMR(CDCl3)：δ8.04(s，1H)，7.83(m，1H)，7.71(m，1H)，7.57-7.53(m，3H)，7.50-7.43(m，2H)，7.20(d，1H)，6.73(d，1H)，6.62(s，1H)，3.07(s，3H)，2.61(s，1H)，1.68(s，6H)。MS(ES)：473[M+H]+，1H-NMR(CDCl3)：δ8.04(s，1H)，7.83(m，1H)，7.72(m，1H)，7.59-7.49(m，5H)，7.22(d，1H)，7.15(s，1H)，6.80(d，1H)，3.07(s，3H)，2.65(s，3H).MS(ES)：457[M+H]+。
The following compounds are prepared essentially in accordance with the previous examples:
3- [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Pentan-3-ol:1HNMR(CDCl3)：8.04(d，1H)，7.82(m，1H)，7.73(m，1H)，7.57-7.42(m，5H)，7.20(d，1H)，6.74(d，1H)，6.52(s，1H)，3.08(s，3H)，2.81(brs，1H)，1.89(q，4H)，0.92(t，6H)。MS(ES)501[M+H]+，483(M-OH)。
1- [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Propan-1-one:1HNMR(CDCl3)：8.04(d，1H)，7.83(m，1H)，7.73(m，1H)，7.59-7.48(m，5H)，7.22(d，1H)，7.15(s，1H)，6.80(d，1H).3.13-3.07(m，5H)，1.24(t，3H)。MS(ES)471[M+H]+。
1- [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl ]Propan-1-ol:1HNMR(CDCl3)：8.04(d，1H)，7.81(m，1H)，7.72(m，1H)，7.57-7.42(m，5H)，7.209d，1H)，6.75(d，1H)，6.63(s，1H)，4.81(t，1H)，3.07(s，3H)，2.6(brs，1H)，1.94(m，2H)，1.04(t，3H).MS(ES)473[M+H]+，455(M-OH)。
2- (5- {5- [3- (methylsulfonyl) phenyl)]-2-thienyl } -1- [2- (trifluoromethyl) phenyl]-1H-pyrazol-3-yl) propan-2-ol, ms (es): 507M + H]+
2- (5- {5- [3- (methylsulfonyl) phenyl)]-2-thienyl } -1- [3- (trifluoromethyl) pyridin-2-yl]-1H-pyrazol-3-yl) propan-2-ol, ms (es): 508[ M + H ]]+
1- (5- {5- [3- (methylsulfonyl) phenyl)]-2-thienyl } -1- [3- (trifluoromethyl) pyridin-2-yl]-1H-pyrazol-3-yl) ethanone, ms (es): 492[ M + H]+
2- [1- (3-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazole-3-Base of]Propan-2-ol, ms (es): 473[ M + H ]]+
2- [1- (4-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Propan-2-ol, ms (es): 473[ M + H ]]+
2- [1- (3-fluorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Propan-2-ol, ms (es): 457[ M + H]+
2- [1- (2-fluorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Propan-2-ol, ms (es): 457[ M + H]+
2- [1- (2-fluorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Propan-2-ol, ms (es): 457[ M + H]+
1- (5- {5- [3- (methylsulfonyl) phenyl)]-2-thienyl } -1-phenyl-1H-pyrazol-3-yl) ethanone, ms (es): 439[ M + H ]+
1- (5- {5- [3- (methylsulfonyl) phenyl)]-2-thienyl } -1-phenyl-1H-pyrazol-3-yl) ethanone, ms (es): 423[ M + H]+
2- [1- (2, 5-dichlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Propan-2-ol, ms (es): 507M + H]+
2- [1- (2-chloro-3-fluorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Propan-2-ol, ms (es): 491[ M + H]+
2- [3- (1-hydroxy-1-methylethyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-1-yl]-6- (trifluoromethyl) phenol, ms (es): 523[ M + H]+
2- (5- {5- [3- (methylsulfonyl) phenyl)]-2-thienyl } -1- [4- (trifluoromethyl) pyridin-3-yl]-1H-pyrazol-3-yl) propan-2-ol, ms (es): 508[ M + H ]]+
2- (5- {5- [3- (methylsulfonyl) phenyl)]-2-thienyl } -1- [2- (trifluoromethyl) pyridin-3-yl]-1H-pyrazol-3-yl) propan-2-ol, ms (es): 508[ M + H ]]+
2- [1- (2-chlorophenyl) -5- {5- [4- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Propan-2-ol, ms (es): 473[ M + H ]]+
2- [1- (2, 6-dichloro-3-methylphenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Propan-2-ol, ms (es): 521[ M + H]+，503(M-OH)
2- [1- (2, 6-dichlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl ]Propan-2-ol, ms (es): 507M + H]+，489(M-OH)
2- [1- (2-chlorophenyl) -5- { 1-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- [1- (2, 6-dichlorophenyl) -5- { 1-methyl-5- [3- (methylsulfonyl) phenyl]-1H-pyrrol-2-yl } -1H-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 [1, 2-c]Pyrazol-3-yl } propan-2-ol, ms (es): 479[ M + H ]]+，461(M-OH)
2- {1- (2-chlorophenyl) -6- [3- (methylsulfonyl) phenyl]-1, 4-dihydroindeno [1, 2-c]Pyrazol-3-yl } propan-2-ol, ms (es): 479[ M + H ]]+，461(M-OH)
2- [1- (2, 6-dichlorophenyl) -5- { 3-methyl-5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Propan-2-ol, ms (es): 521[ M + H]+。
2- [5- {5- [3, 4-bis (methoxy) phenyl]-2-thienyl } -1- (2-chlorophenyl) -1H-pyrazol-3-yl]Propan-2-ol; ms (es): 455[ M + H]+；
2-chloro-4- {5- [1- (2-chlorophenyl) -3- (1-hydroxy-1-methylethyl) -1H-pyrazol-5-yl]-2-thienyl } -N- (1-methylethyl) benzamide; ms (es): 514[ M + H]+；
2- [1- (2-chlorophenyl) -5- {5- [2- (methylthio) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Propan-2-ol; ms (es): 441[ M + H]+；
2- {1- (2-chlorophenyl) -5- [5- (2-fluorobiphenyl-4-yl) -2-thienyl ]-1H-pyrazol-3-yl } propan-2-ol; ms (es): 489[ M + H ]]+；
2- {1- (2-chlorophenyl) -5- [5- (3-fluorophenyl) -2-thienyl]-1H-pyrazol-3-yl } propan-2-ol; ms (es): 413[ M + H]+；
N- (3- {5- [1- (2-chlorophenyl) -3- (1-hydroxy-1-methylethyl) -1H-pyrazol-5-yl)]-2-thienyl } phenyl) acetamide; ms (es): 452[ M + H]+；
2- [1- (2-chlorophenyl) -5- (5- {4- [ (1-methylethyl) oxy ] phenyl]Phenyl } -2-thienyl) -1H-pyrazol-3-yl]Propan-2-ol; ms (es): 453[ M + H ]]+；
2- [1- (2-chlorophenyl) -5- {5- [ 2-fluoro-3- (methoxy) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Propan-2-ol; ms (es): 443[ M + H ]]+；
2- {1- (2-chlorophenyl) -5- [5- (4-chlorophenyl) -2-thienyl]-1H-pyrazol-3-yl } propan-2-ol; ms (es): 429[ M + H]+；
2- [1- (2-chlorophenyl) -5- {5- [ 5-fluoro-2- (methoxy) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Propan-2-ol; ms (es): 443[ M + H ]]+；
2- [1- (2-chlorophenyl) -5- {5- [4- (ethoxy) -3- (trifluoromethyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Propan-2-ol; ms (es): 507M + H]+；
2- {1- (2-chlorophenyl) -5- [5- (2, 3-dichlorophenyl) -2-thienyl]-1H-pyrazol-3-yl } propan-2-ol; ms (es): 463[ M + H]+；
2- [1- (2-chlorophenyl) -5- (5-pyrimidin-5-yl-2-thienyl) -1H-pyrazol-3-yl]Propan-2-ol; ms (es): 397[ M + H ] ]+；
4- {5- [1- (2-chlorophenyl) -3- (1-hydroxy-1-methylethyl) -1H-pir-ineAzol-5-yl]-2-thienyl } benzoic acid; ms (es): 439[ M + H]+；
N- (4- {5- [1- (2-chlorophenyl) -3- (1-hydroxy-1-methylethyl) -1H-pyrazol-5-yl)]-2-thienyl } phenyl) methanesulfonamide; ms (es): 488[ M + H]+；
2- {5- [1- (2-chlorophenyl) -3- (1-hydroxy-1-methylethyl) -1H-pyrazol-5-yl]-2-thienyl } -5-fluorophenol; ms (es): 429[ M + H]+；
2- [1- (2-chlorophenyl) -5- (5- { 4-fluoro-2- [ (phenylmethyl) oxy ]]Phenyl } -2-thienyl) -1H-pyrazol-3-yl]Propan-2-ol; ms (es): 519[ M + H ]]+；
3- {5- [1- (2-chlorophenyl) -3- (1-hydroxy-1-methylethyl) -1H-pyrazol-5-yl]-2-thienyl } -5-fluorobenzoic acid; ms (es): 457[ M + H]+；
2- {1- (2-chlorophenyl) -5- [5- (1-methyl-1H-indol-5-yl) -2-thienyl]-1H-pyrazol-3-yl } propan-2-ol; ms (es): 448[ M + H ]]+；
2- [1- (2-chlorophenyl) -5- (5- {2- [ (1-methylethyl) oxy ] phenyl]-5- (trifluoromethyl) phenyl } -2-thienyl) -1H-pyrazol-3-yl]Propan-2-ol; ms (es): 521[ M + H]+；
2-chloro-5- {5- [1- (2-chlorophenyl) -3- (1-hydroxy-1-methylethyl) -1H-pyrazol-5-yl]-2-thienyl } benzamide; ms (es): 472[ M + H]+；
2- {5- [5- (2-chloro-6-fluorophenyl) -2-thienyl]-1- (2-chlorophenyl) -1H-pyrazol-3-yl } propan-2-ol; ms (es): 447[ M + H ]+；
3- {5- [1- (2-chlorophenyl) -3- (1-hydroxy-1-methylethyl) -1H-pyrazol-5-yl]-2-thienyl } -N, N-dimethylbenzenesulfonamide; ms (es): 502[ M + H]+；
2-chloro-4- {5- [1- (2-chlorophenyl) -3- (1-hydroxy-1-methylethyl) -1H-pyrazol-5-yl]-2-thienyl } -N-methylbenzamide; ms (es): 486[ M + H]+；
·2-[1- (2-chlorophenyl) -5- (5- { 2-methyl-4- [ (1-methylethyl) oxy ] carbonyl]Phenyl } -2-thienyl) -1H-pyrazol-3-yl]Propan-2-ol; ms (es): 467[ M + H ]]+；
4- {5- [1- (2-chlorophenyl) -3- (1-hydroxy-1-methylethyl) -1H-pyrazol-5-yl]-2-thienyl } -N- (furan-2-ylmethyl) benzamide; ms (es): 518[ M + H]+；
2- {5- [1- (2-chlorophenyl) -3- (1-hydroxy-1-methylethyl) -1H-pyrazol-5-yl]-methyl 2-thienyl } benzoate; ms (es): 453[ M + H ]]+；
2- [5- {5- [ 3-chloro-4- (methoxy) phenyl]-2-thienyl } -1- (2-chlorophenyl) -1H-pyrazol-3-yl]Propan-2-ol; ms (es): 459[ M + H ]]+；
2- [5- (5- { 3-chloro-4- [ (1-methylethyl) oxy ] ethoxy]Phenyl } -2-thienyl) -1- (2-chlorophenyl) -1H-pyrazol-3-yl]Propan-2-ol; ms (es): 487[ M + H ]]+；
2- [1- (2-chlorophenyl) -5- {5- [4- (1, 3-thiazolidin-3-ylcarbonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Propan-2-ol; ms (es): 510[ M + H]+；
2-chloro-4- {5- [1- (2-chlorophenyl) -3- (1-hydroxy-1-methylethyl) -1H-pyrazol-5-yl ]-2-thienyl } -N-cyclopropylbenzamide; ms (es): 512[ M + H]+；
2- {5- [1- (2-chlorophenyl) -3- (1-hydroxy-1-methylethyl) -1H-pyrazol-5-yl]-2-thienyl } -4-fluorophenol; ms (es): 429[ M + H]+；
N- (2- {5- [1- (2-chlorophenyl) -3- (1-hydroxy-1-methylethyl) -1H-pyrazol-5-yl)]-2-thienyl } phenyl) methanesulfonamide; ms (es): 488[ M + H]+；
4- {5- [1- (2-chlorophenyl) -3- (1-hydroxy-1-methylethyl) -1H-pyrazol-5-yl]-2-thienyl } -2-fluorobenzoic acid; ms (es): 457[ M + H]+；
2- [1- (2-chlorophenyl) -5- {5- [4- (methylthio) -3- (trifluoromethyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Propan-2-ol; MS (ES)：509[M+H]+；
2- [1- (2-chlorophenyl) -5- {5- [ 2-methyl-5- (methoxy) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Propan-2-ol; ms (es): 439[ M + H]+；
2- [1- (2-chlorophenyl) -5- {5- [2- (methoxy) pyridin-3-yl]-2-thienyl } -1H-pyrazol-3-yl]Propan-2-ol; ms (es): 426[ M + H]+；
2- [1- (2-chlorophenyl) -5- {5- [6- (methoxy) pyridin-3-yl]-2-thienyl } -1H-pyrazol-3-yl]Propan-2-ol; ms (es): 426[ M + H]+；
2- [1- (2-chlorophenyl) -5- {5- [4- (methoxy) -3- (trifluoromethyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Propan-2-ol; ms (es): 493[ M + H ]]+；
2- [1- (2-chlorophenyl) -5- (5-pyridin-3-yl-2-thienyl) -1H-pyrazol-3-yl ]Propan-2-ol; ms (es): 396[ M + H]+；
2- {1- (2-chlorophenyl) -5- [5- (1H-indol-6-yl) -2-thienyl]-1H-pyrazol-3-yl } propan-2-ol; ms (es): 434[ M + H]+；
2- [1- (2-chlorophenyl) -5- {5- [ (1E) -3, 3-dimethylbut-1-en-1-yl]-2-thienyl } -1H-pyrazol-3-yl]Propan-2-ol; ms (es): 401[ M + H]+；
2- {5- [1- (2-chlorophenyl) -3- (1-hydroxy-1-methylethyl) -1H-pyrazol-5-yl]-2-thienyl } -1H-pyrrole-1-carboxylic acid 1, 1-dimethylethyl ester; ms (es): 484[ M + H]+；
2- [1- (2-chlorophenyl) -5- (5- {2- [ (1-methylethyl) oxy ] phenyl]Pyridin-3-yl } -2-thienyl) -1H-pyrazol-3-yl]Propan-2-ol; ms (es): 454[ M + H]+；
2- [1- (2-chlorophenyl) -5- {5- [2- (cyclopentyloxy) pyridin-3-yl]-2-thienyl } -1H-pyrazol-3-yl]Propan-2-ol; ms (es): 480[ M + H ]]+；
4- {5- [1- (2-chlorophenyl) -3- (1-hydroxy-1-methylethyl) -1H-pyrazol-5-yl]-2-thienylEthyl benzoate; ms (es): 467[ M + H ]]+；
2- {1- (2-chlorophenyl) -5- [5- (5-methylfuran-2-yl) -2-thienyl]-1H-pyrazol-3-yl } propan-2-ol; ms (es): 399[ M + H [ ]]+；
4- {5- [1- (2-chlorophenyl) -3- (1-hydroxy-1-methylethyl) -1H-pyrazol-5-yl]-2-thienyl } benzamide; ms (es): 438[ M + H]+；
N- [ (4- {5- [1- (2-chlorophenyl) -3- (1-hydroxy-1-methylethyl) -1H-pyrazol-5-yl) ]-2-thienyl } phenyl) carbonyl]Glycine methyl ester; ms (es): 510[ M + H]+；
3- {5- [1- (2-chlorophenyl) -3- (1-hydroxy-1-methylethyl) -1H-pyrazol-5-yl]-2-thienyl } benzamide; ms (es): 438[ M + H]+；
2- [1- (2-chlorophenyl) -5- {5- [3- (thiomorpholin-4-ylcarbonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Propan-2-ol; ms (es): 524[ M + H]+；
2- {5- [5- (1, 3-benzodioxol-5-yl) -2-thienyl]-1- (2-chlorophenyl) -1H-pyrazol-3-yl } propan-2-ol; ms (es): 439[ M + H]+；
2- [1- (2-chlorophenyl) -5- {5- [ 2-methyl-5- (morpholine-4-sulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Propan-2-ol; ms (es): 558[ M + H]+；
2- [5- {5- [2, 4-bis (trifluoromethyl) phenyl]-2-thienyl } -1- (2-chlorophenyl) -1H-pyrazol-3-yl]Propan-2-ol; ms (es): 531[ M + H]+；
2- [5- {5- [2, 3-bis (methoxy) phenyl]-2-thienyl } -1- (2-chlorophenyl) -1H-pyrazol-3-yl]Propan-2-ol; ms (es): 455[ M + H]+；
2- [1- (2-chlorophenyl) -5- {5- [3, 5-difluoro-2- (methoxy) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Propan-2-ol; ms (es): 461[ M + H ]]+；
2- [1- (2-chlorophenyl) -5- {5- [2- (phenoxy)Phenyl radical]-2-thienyl } -1H-pyrazol-3-yl]Propan-2-ol; ms (es): 487[ M + H ]]+；
2- [1- (2-chlorophenyl) -5- {5- [3- (trifluoromethyl) phenyl ]-2-thienyl } -1H-pyrazol-3-yl]Propan-2-ol; ms (es): 463[ M + H]+；
2- {1- (2-chlorophenyl) -5- [5- (3, 5-dichlorophenyl) -2-thienyl]-1H-pyrazol-3-yl } propan-2-ol; ms (es): 463[ M + H]+；
2- {1- (2-chlorophenyl) -5- [5- (2, 4, 5-trimethylphenyl) -2-thienyl]-1H-pyrazol-3-yl } propan-2-ol; ms (es): 437[ M + H]+；
2- [1- (2-chlorophenyl) -5- (5-naphthalen-2-yl-2-thienyl) -1H-pyrazol-3-yl]Propan-2-ol; ms (es): 445[ M + H ]]+；
2- [1- (2-chlorophenyl) -5- (5- {2- [ (1-methylethyl) oxy ] phenyl]Phenyl } -2-thienyl) -1H-pyrazol-3-yl]Propan-2-ol; ms (es): 453[ M + H ]]+；
2- [1- (2-chlorophenyl) -5- {5- [ 2-fluoro-5- (methoxy) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Propan-2-ol; ms (es): 443[ M + H ]]+；
2- {1- (2-chlorophenyl) -5- [5- (1-styryl) -2-thienyl]-1H-pyrazol-3-yl } propan-2-ol; ms (es): 421[ M + H]+；
2- [1- (2-chlorophenyl) -5- {5- [ (1E) -prop-1-en-1-yl]-2-thienyl } -1H-pyrazol-3-yl]Propan-2-ol; ms (es): 359[ M + H]+；
2- {1- (2-chlorophenyl) -5- [5- (5-fluoro-2-methylphenyl) -2-thienyl]-1H-pyrazol-3-yl } propan-2-ol; ms (es): 427[ M + H]+；
2- [1- (2-chlorophenyl) -5- {5- [2- (hydroxymethyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Propan-2-ol; ms (es): 425[ M + H]+；
2- [1- (2-chlorophenyl) -5- (5- { 5-methyl-2- [ (1-methylethyl) oxy ] phenyl ]Phenyl } -2-thienyl) -1H-pyrazol-3-yl]Propan-2-ol; ms (es):467[M+H]+；
2- [5- (2, 2' -dithiophen-5-yl) -1- (2-chlorophenyl) -1H-pyrazol-3-yl]Propan-2-ol; ms (es): 401[ M + H]+；
2- [5- (5-Biphenyl-3-yl-2-thienyl) -1- (2-chlorophenyl) -1H-pyrazol-3-yl]Propan-2-ol; ms (es): 471[ M + H]+；
2- [1- (2-chlorophenyl) -5- {5- [ 5-methyl-2- (propoxy) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Propan-2-ol; ms (es): 467[ M + H ]]+；
2- {1- (2-chlorophenyl) -5- [5- (4-propylphenyl) -2-thienyl]-1H-pyrazol-3-yl } propan-2-ol; ms (es): 437[ M + H]+；
2- [1- (2-chlorophenyl) -5- (5- {4- [ (trifluoromethyl) oxy ] chloro- ] -2]Phenyl } -2-thienyl) -1H-pyrazol-3-yl]Propan-2-ol; ms (es): 479[ M + H ]]+；
4- {5- [1- (2-chlorophenyl) -3- (1-hydroxy-1-methylethyl) -1H-pyrazol-5-yl]-2-thienyl } -N- (2-methylpropyl) benzamide; ms (es): 494[ M + H]+；
2- [1- (2-chlorophenyl) -5- {5- [3- (ethoxy) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Propan-2-ol; ms (es): 439[ M + H]+；
2- {1- (2-chlorophenyl) -5- [5- (4-ethylphenyl) -2-thienyl]-1H-pyrazol-3-yl } propan-2-ol; ms (es): 423[ M + H]+；
2- {1- (2-chlorophenyl) -5- [5- (3, 4-dichlorophenyl) -2-thienyl]-1H-pyrazol-3-yl } propan-2-ol; ms (es): 463[ M + H ]+；
2- [1- (2-chlorophenyl) -5- {5- [6- (methoxy) naphthalen-2-yl]-2-thienyl } -1H-pyrazol-3-yl]Propan-2-ol; ms (es): 475[ M + H ]]+；
2- {1- (2-chlorophenyl) -5- [5- (2-ethylphenyl) -2-thienyl]-1H-pyrazol-3-yl } propan-2-ol; ms (es): 423[ M + H]+；
2- [1- (2-chlorophenyl) -5- {5- [4- (dimethylamino) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Propan-2-ol; ms (es): 438[ M + H]+；
2- {1- (2-chlorophenyl) -5- [5- (2, 4, 5-trifluorophenyl) -2-thienyl]-1H-pyrazol-3-yl } propan-2-ol; ms (es): 449[ M + H ]]+；
2- [1- (2-chlorophenyl) -5- {5- [ 2-fluoro-5- (trifluoromethyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Propan-2-ol; ms (es): 481[ M + H]+；
2- {1- (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- [1- (2-chlorophenyl) -3- (1-hydroxy-1-methylethyl) -1H-pyrazol-5-yl)]-2-thienyl } phenyl) acetamide; ms (es): 452[ M + H]+；
2- [1- (2-chlorophenyl) -5- {5- [3- (hydroxymethyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Propan-2-ol; ms (es): 425[ M + H]+；
2- [5- {5- [ 5-chloro-2- (methoxy) phenyl]-2-thienyl } -1- (2-chlorophenyl) -1H-pyrazol-3-yl]Propan-2-ol; ms (es): 459[ M + H ]]+；
2- [1- (2-chlorophenyl) -5- {5- [2, 3, 4-tris (methoxy) phenyl ]-2-thienyl } -1H-pyrazol-3-yl]Propan-2-ol; ms (es): 485[ M + H]+；
2- [1- (2-chlorophenyl) -5- {5- [2- (trifluoromethyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Propan-2-ol; ms (es): 463[ M + H]+；
2- {1- (2-chlorophenyl) -5- [5- (1H-indol-5-yl) -2-thienyl]-1H-pyrazol-3-yl } propan-2-ol; ms (es): 434[ M + H]+；
2- [1- (2-chlorophenyl) -5- {5- [6- (ethoxy) naphthalen-2-yl]-2-thienyl } -1H-pyrazol-3-yl]Propan-2-ol; ms (es): 489[ M + H ]]+；
2- [1- (2-chlorophenyl) -5- {5- [4- (hydroxy)Methyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Propan-2-ol; ms (es): 425[ M + H]+；
2- {1- (2-chlorophenyl) -5- [5- (2, 3-difluorophenyl) -2-thienyl]-1H-pyrazol-3-yl } propan-2-ol; ms (es): 431[ M + H ]]+；
2- {1- (2-chlorophenyl) -5- [5- (2, 4-difluorophenyl) -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]-1- (2-chlorophenyl) -1H-pyrazol-3-yl } propan-2-ol; ms (es): 461[ M + H ]]+；
2- [1- (2-chlorophenyl) -5- {5- [4- (methylthio) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Propan-2-ol; ms (es): 441[ M + H]+；
2- [1- (2-chlorophenyl) -5- {5- [4- (trifluoromethyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Propan-2-ol; ms (es): 463[ M + H]+；
2- {5- [5- (6-chloro-2-fluoro-3-methylphenyl) -2-thienyl ]-1- (2-chlorophenyl) -1H-pyrazol-3-yl } propan-2-ol; ms (es): 461[ M + H ]]+；
2- {1- (2-chlorophenyl) -5- [5- (4-fluoro-3-methylphenyl) -2-thienyl]-1H-pyrazol-3-yl } propan-2-ol; ms (es): 427[ M + H]+；
2- {1- (2-chlorophenyl) -5- [5- (3, 4-difluorophenyl) -2-thienyl]-1H-pyrazol-3-yl } propan-2-ol; ms (es): 431[ M + H ]]+；
2- [1- (2-chlorophenyl) -5- {5- [4- (phenoxy) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Propan-2-ol; ms (es): 487[ M + H ]]+；
2- [1- (2-chlorophenyl) -5- {5- [ 4-chloro-2- (trifluoromethyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Propan-2-ol; ms (es): 497[ M + H]+；
2- {1- (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- (ethoxy) phenyl]-2-thienyl } -1- (2-chlorophenyl) -1H-pyrazol-3-yl]Propan-2-ol; ms (es): 473[ M + H ]]+；
2- {1- (2-chlorophenyl) -5- [5- (3-chlorophenyl) -2-thienyl]-1H-pyrazol-3-yl } propan-2-ol; ms (es): 429[ M + H]+；
2- {1- (2-chlorophenyl) -5- [5- (1H-indol-4-yl) -2-thienyl]-1H-pyrazol-3-yl } propan-2-ol; ms (es): 434[ M + H]+；
2- [1- (2-chlorophenyl) -5- {5- [ 2-chloro-4- (trifluoromethyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Propan-2-ol; ms (es): 497[ M + H]+；
N- (3- {5- [1- (2-chlorophenyl) -3- (1-hydroxy-1-methylethyl) -1H-pyrazol-5-yl) ]-2-thienyl } phenyl) methanesulfonamide; ms (es): 488[ M + H]+；
3- {5- [1- (2-chlorophenyl) -3- (1-hydroxy-1-methylethyl) -1H-pyrazol-5-yl]-2-thienyl } benzenesulfonamide; ms (es): 474[ M + H]+；
3- {5- [1- (2-chlorophenyl) -3- (1-hydroxy-1-methylethyl) -1H-pyrazol-5-yl]-2-thienyl } -N- (1-methylethyl) benzamide; ms (es): 480[ M + H ]]+；
2- [1- (2-chlorophenyl) -5- {5- [ 4-fluoro-3- (trifluoromethyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Propan-2-ol; ms (es): 481[ M + H]+；
2- [5- {5- [3, 5-bis (trifluoromethyl) phenyl]-2-thienyl } -1- (2-chlorophenyl) -1H-pyrazol-3-yl]Propan-2-ol; ms (es): 531[ M + H]+；
2- [5- (5-Biphenyl-4-yl-2-thienyl) -1- (2-chlorophenyl) -1H-pyrazol-3-yl]Propan-2-ol; ms (es): 471[ M + H]+；
2- [1- (2-chlorophenyl) -5- {5- [4- (1-methylethyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Propan-2-ol; ms (es): 437[ M + H]+；
2- [1- (2-chlorophenyl) -5- (5-ethyl-2-thienyl) -1H-pyrazol-3-yl]Propan-2-ol; ms (es): 347[ M + H]+；
2- [1- (2-chlorophenyl) -5- (5- { 3-fluoro-4- [ (phenylmethyl) oxy ]]Phenyl } -2-thienyl) -1H-pyrazol-3-yl]Propan-2-ol; ms (es): 519[ M + H ]]+；
2- [1- (2-chlorophenyl) -5- {5- [ 3-chloro-4- (trifluoromethyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl ]Propan-2-ol; ms (es): 497[ M + H]+；
2- [1- (2-chlorophenyl) -5- {5- [4- (ethylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Propan-2-ol; ms (es): 487[ M + H ]]+；
2- (5- { 3-methyl-5- [3- (methylsulfonyl) phenyl)]-2-thienyl } -1- [4- (trifluoromethyl) pyridin-3-yl]-1H-pyrazol-3-yl) propan-2-ol, ms (es): 522[ M + H]+，504(M-OH)；
2- [1- (2-chlorophenyl) -5- { 4-methyl-5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Propan-2-ol, ms (es): 487[ M + H ]]+，469(M-OH)
2- [1- (2-chlorophenyl) -5- { 3-ethyl-5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Propan-2-ol, ms (es): 501[ M + H [ ]]+，483(M-OH)
2- [1- (2-chloro-3-fluorophenyl) -5- { 3-ethyl-5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Propan-2-ol, ms (es): 519[ M + H ]]+，501(M-OH)
2- [5- { 4-bromo-5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1- (2-chlorophenyl) -1H-pyrazol-3-yl]Propan-2-ol, ms (es): 553[ M + H]+。
2- [5- { 4-bromo-3-methyl-5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1- (2-chlorophenyl) -1H-pyrazol-3-yl]Propan-2-ol, ms (es): 567[ M + H ]]+。
2- [1- (2-chlorophenyl) -5- { 3-methyl-5- [3- (methylsulfonyl) phenyl]-2-thiaThienyl } -1H-pyrazol-3-yl]Propan-2-ol, ms (es): 487[ M + H ]]+。
2- [1- (2-chlorophenyl) -5- { 3-methyl-4- [3- (methylsulfonyl) phenyl ]-2-thienyl } -1H-pyrazol-3-yl]Propan-2-ol, ms (es): 487[ M + H ]]+。
2- (1- [ 3-fluoro-2- (trifluoromethyl) phenyl)]-5- { 3-methyl-5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl) propan-2-ol, ms (es): 539[ M + H ]]+。
2- [5- { 3-bromo-5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1- (2-chlorophenyl) -1H-pyrazol-3-yl]Propan-2-ol MS (ES): 553[ M + H]+。
2- [5- { 3-chloro-5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1- (2-chlorophenyl) -1H-pyrazol-3-yl]Propan-2-ol, ms (es): 507M + H]+。
2- [1- (2-chloro-3-fluorophenyl) -5- { 3-methyl-5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Propan-2-ol, ms (es): 505[ M + H]+。
5- (5- {3- [ (1-methylethyl) sulfonyl group]Phenyl } -2-thienyl) -1- [3- (trifluoromethyl) pyridin-2-yl]-1H-pyrazole-3-carboxylic acid methyl ester, ms (es): 553.6[ M + H]+.
1- {5- (5- {3- [ (1-methylethyl) sulfonyl group]Phenyl } -2-thienyl) -1- [3- (trifluoromethyl) pyridin-2-yl]-1H-pyrazol-3-yl } ethanone, ms (es): 520[ M + H ]]+。
2- {5- (5- {3- [ (1-methylethyl) sulfonyl group]Phenyl } -2-thienyl) -1- [3- (trifluoromethyl) pyridin-2-yl]-1H-pyrazol-3-yl } propan-2-ol, ms (es): 536[ M + H]+。
2- [1- (2-chlorophenyl) -5- (5- {3- [ (1-methylethyl) sulfonyl-)]Phenyl } -2-thienyl) -1H-pyrazol-3-yl ]Propan-2-ol, ms (es): 501[ M + H [ ]]+。
2- [1- (3-Fluoropyridin-2-yl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Propan-2-ol, ms (es): 458[ M + H ]]+。
2- [1- (2-Chloropyridin-3-yl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Propan-2-ol, ms (es): 474[ M + H]+。
2- [1- (2-bromophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Propan-2-ol, ms (es): 517[ M + H]+。
2- [1- (2, 3-difluorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Propan-2-ol, ms (es): 475[ M + H ]]+。
2- (5- {5- [3- (methylsulfonyl) phenyl)]-2-thienyl } -1- {2- [ (trifluoromethyl) oxy group]Phenyl } -1H-pyrazol-3-yl) propan-2-ol, ms (es): 523[ M + H]+。
2- [1- (3-chloro-2-fluorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Propan-2-ol, ms (es): 491[ M + H]+。
2- [1- (2, 2-difluoro-1, 3-benzodioxol-4-yl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Propan-2-ol, ms (es): 519[ M + H ]]+。
2- (1- [ 2-chloro-5- (trifluoromethyl) phenyl)]-5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl) propan-2-ol, ms (es): 565[ M + Na ]]+。
2- [1- (2, 6-difluorophenyl) -5- {5- [3- (methylsulfonyl) phenyl ]-2-thienyl } -1H-pyrazol-3-yl]Propan-2-ol, ms (es): 475[ M + H ]]+。
2- [1- (3-fluoro-2-methylphenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Propan-2-ol, ms (es): 471[ M + H]+。
2- [1- (5-Fluoropyridin-3-yl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Propan-2-ol, ms (es): 458[ M + H ]]+。
2- [ 4-chloro-1- (5-fluoropyridin-3-yl) -5- {5- [3- (methylsulfonyl) benzeneBase of]-2-thienyl } -1H-pyrazol-3-yl]Propan-2-ol, ms (es): 492[ M + H]+。
2- [ 4-bromo-1- (5-fluoropyridin-3-yl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Propan-2-ol, ms (es): 538[ M + H]+。
2- (5- {5- [3- (methylsulfonyl) phenyl)]-2-thienyl } -1- [3- (trifluoromethyl) pyridin-4-yl]-1H-pyrazol-3-yl) propan-2-ol, ms (es): 508[ M + H ]]+。
2- [1- (3-Fluoropyridin-4-yl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Propan-2-ol, ms (es): 458[ M + H ]]+。
2- [1- (3, 5-dichloropyridin-4-yl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Propan-2-ol, ms (es): 508[ M + H ]]+。
2- [1- (3-Chloropyridin-4-yl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Propan-2-ol, ms (es): 474[ M + H ]+。
2- (1- [ 5-chloro-2- (phenoxy) phenyl)]-5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl) propan-2-ol; ms (es): 565[ M + H]+。
1- (1- [ 5-chloro-2- (phenoxy) phenyl)]-5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl) ethanone; ms (es): 549[ M + H]+。
3- {5- [1- (2, 5-dichlorophenyl) -3- (1-hydroxy-1-methylethyl) -1H-pyrazol-5-yl]-2-thienyl } benzenesulfonamide; ms (es): 508 and 510[ each M + H ]]+。
3- {5- [ 3-acetyl-1- (2, 5-dichlorophenyl) -1H-pyrazol-5-yl]-2-thienyl } 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-1-yl) phenyl) propan-2-ol. Ms (es): 497[ M + H]+。
2- (1- (2, 4-difluorophenyl) -5- (5- (3- (methylsulfonyl) phenyl) thiophen-2-yl) -1H-pyrazol-3-yl) propan-2-ol. Ms (es): 475[ M + H ]]+。
2- (1- (3, 5-difluorophenyl) -5- (5- (3- (methylsulfonyl) phenyl) thiophen-2-yl) -1H-pyrazol-3-yl) propan-2-ol. Ms (es): 475[ M + H ]]+。
2- (1- (3, 4-difluorophenyl) -5- (5- (3- (methylsulfonyl) phenyl) thiophen-2-yl) -1H-pyrazol-3-yl) propan-2-ol. Ms (es): 475[ M + H ]]+。
2- (1- (2, 4-dichlorophenyl) -5- (5- (3- (methylsulfonyl) phenyl) thiophen-2-yl) -1H-pyrazol-3-yl) propan-2-ol. Ms (es): 507M + H ]+。
2- (1- (2, 3-dichlorophenyl) -5- (5- (3- (methylsulfonyl) phenyl) thiophen-2-yl) -1H-pyrazol-3-yl) propan-2-ol. Ms (es): 507M + H]+。
2- (1- (2, 5-difluorophenyl) -5- (5- (3- (methylsulfonyl) phenyl) thiophen-2-yl) -1H-pyrazol-3-yl) propan-2-ol. Ms (es): 475[ M + H ]]+。
2- (1- (3, 5-dichlorophenyl) -5- (5- (3- (methylsulfonyl) phenyl) thiophen-2-yl) -1H-pyrazol-3-yl) propan-2-ol. Ms (es): 507M + H]+。
2- (1- (3, 4-dichlorophenyl) -5- (5- (3- (methylsulfonyl) phenyl) thiophen-2-yl) -1H-pyrazol-3-yl) propan-2-ol. Ms (es): 507M + H]+。
2- (1- (2-ethylphenyl) -5- (5- (3- (methylsulfonyl) phenyl) thiophen-2-yl) -1H-pyrazol-3-yl) propan-2-ol. Ms (es): 467[ M + H ]]+。
2- (5- (5- (3- (methylsulfonyl) phenyl) thiophen-2-yl) -1- (2-propylphenyl) -1H-pyrazol-3-yl) propan-2-ol. Ms (es): 481[ M + H]+。
2- (1- (5-fluoro-2-methylphenyl) -5- (5- (3- (methylsulfonyl) phenyl) thiophen-2-yl) -1H-pyrazol-3-yl) propan-2-ol. Ms (es): 471[ M + H]+。
2- (1- (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- (1- (2, 4-dichloro-6- (trifluoromethyl) phenyl) -5- (5- (3- (methylsulfonyl) phenyl) -thiophen-2-yl) -1H-pyrazol-3-yl) propan-2-ol. Ms (es): 575[ M + H ] ]+。
2- (1- (2-isopropylphenyl) -5- (5- (3- (methylsulfonyl) phenyl) thiophen-2-yl) -1H-pyrazol-3-yl) propan-2-ol. Ms (es): 481[ M + H]+。
2- (5- (5- (3- (methylsulfonyl) phenyl) thiophen-2-yl) -1- (pyridin-3-yl) -1H-pyrazol-3-yl) propan-2-ol. Ms (es): 440[ M + H ]]+。
2- (1- (2, 6-dimethylphenyl) -5- (5- (3- (methylsulfonyl) phenyl) thiophen-2-yl) -1H-pyrazol-3-yl) propan-2-ol. Ms (es): 467[ M + H ]]+。
2- (1- (2-fluoro-6- (trifluoromethyl) phenyl) -5- (5- (3- (methylsulfonyl) phenyl) thiophen-2-yl) -1H-pyrazol-3-yl) propan-2-ol. Ms (es): 525[ M + H ]]+
2- (1- (2- (difluoromethoxy) phenyl) -5- (5- (3- (methylsulfonyl) phenyl) thiophen-2-yl) -1H-pyrazol-3-yl) propan-2-ol. Ms (es): 505[ M + H]+。
2- (1- (3-fluoro-2- (trifluoromethyl) phenyl) -5- (5- (3- (methylsulfonyl) phenyl) thiophen-2-yl) -1H-pyrazol-3-yl) propan-2-ol. Ms (es): 525[ M + H ]]+。
3- (5- (1- (2-chlorophenyl) -3- (2-hydroxypropan-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) thiophen-2-yl) -1- (3-fluoro-2-methylphenyl) -1H-pyrazol-3-yl) propan-2-ol. Ms (es): 549[ M + H]+。
2- (5- (3-bromo-5- (3- (methylsulfonyl) phenyl) thiophene) -2-yl) -1- (2-chloro-3-fluorophenyl) -1H-pyrazol-3-yl) propan-2-ol. Ms (es): 569[ M + H ]]+。
2- (1- (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 + H ]]+。
2- (5- (3-chloro-5- (3- (methylsulfonyl) phenyl) thiophen-2-yl) -1- (3-fluoro-2- (trifluoromethyl) phenyl) -1H-pyrazol-3-yl) propan-2-ol. Ms (es): 559[ M + H ]]+。
2- (5- (3-bromo-5- (3- (methylsulfonyl) phenyl) thiophen-2-yl) -1- (3-fluoro-2- (trifluoromethyl) phenyl) -1H-pyrazol-3-yl) propan-2-ol. Ms (es): 603[ M + H ]]+。
2- (1- (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 + H]+。
2- (5- { 3-methyl-5- [3- (methylsulfonyl) phenyl)]-2-thienyl } -1- [2- (trifluoromethyl) pyridin-3-yl]-1H-pyrazol-3-yl) propan-2-ol. Ms (es): 522[ M + H]+。
Example 9
2- [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl ] -2-thienyl } -1H-pyrazol-3-yl ] -1, 1, 1, 3, 3, 3-hexafluoropropan-2-ol
Example 9a
Preparation of 2- [5- (5-bromothien-2-yl) -1- (2-chlorophenyl) -1H-pyrazol-3-yl ] -1, 1, 1, 3, 3, 3-hexafluoro-propan-2-ol
To 5- (5-bromothien-2-yl) -1- (2-chlorophenyl) -1H-pyrazole-3-carboxylic acid methyl ester (0.40g, 1.0mmol) and trifluoromethyl-trimethylsilane (CF) 3Stirring of-TMS) (0.59mL, 4.0mmol) in toluene (4mL, anhydrous)To the solution was added dropwise a 1.0M solution of tetrabutylammonium fluoride (TBAF) in THF (0.20mL, 20 mol%, dried over 4 Å molecular sieves). After 2h, additional CF was added to the reaction mixture3TMS (0.3mL) and TBAF (50. mu.L), then heated at 45 ℃. After 20H (total), the reaction mixture was cooled to ambient temperature, diluted with DCM (50mL) and washed with H2Washed with brine and then dried (Na)2SO4) 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). Rf0.38 (20% EtOAc/Hex); GC-MS (EI): 504, 506[ M ]+]。
Example 9b
Preparation of 2- [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl ] -2-thienyl } -1H-pyrazol-3-yl ] -1, 1, 1, 3, 3, 3-hexafluoropropan-2-ol
Figure S2006800306472D01852
2- [5- (5-bromothien-2-yl) -1- (2-chlorophenyl) -1H-pyrazol-3-yl]-1, 1, 1, 3, 3, 3-hexafluoro-propan-2-ol (84mg, 0.17mmol), 3-methanesulfonyl-phenylboronic acid (42mg, 0.21mmol), K2CO3(70mg，0.51mmol)、Cl2Pd (dppf). DCM (21mg, 15 mol%), and H2A mixture of O (0.2mL) in dioxane (2mL) was sparged with argon for 5 minutes and then heated at 80 ℃ as a sealed flask. After 3h, the reaction mixture was cooled to ambient temperature and filtered (Celite) TM) The filter was 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 as a white solid (34 mg).1H-NMR(DCM-d2)：δ8.03(m，1H)，7.83(m，1H)，7.76(m，1H)，7.55-7.62(m，4H)，7.49-7.54(m，1H)，7.29(d，1H)，6.91(d，1H)，6.86(s，1H)，5.10(s，1H)，3.05(s，3H)；MS(ES)：581[M+H]+。
The following compounds were prepared in a similar manner from the appropriate methyl ketone:
2- [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]-1, 1, 1-trifluoropropan-2-ol, ms (es): 527[ M + H]+。
The following compounds were prepared in a similar manner from a suitable formaldehyde intermediate:
1- [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]-2, 2, 2-trifluoroethanol, GC-ms (ei): 512[ M ]+]。
Example 10
2- {1- (2-chloro-phenyl) -4-fluoro-5- [5- (3-methanesulfonyl-phenyl) -thiophen-2-yl ] -1H-pyrazol-3-yl } -propan-2-ol
Example 10a
Preparation of 2-bromo-5- (2-fluoro-1, 1-dimethoxy-ethyl) -thiophene
Figure S2006800306472D01861
To a solution of 2-acetyl-5-bromothiophene (10.3g, 50mmol) in anhydrous methanol (300mL) was added selectfluor (25g, 70.57 mmol). The suspension was stirred and refluxed for 50 hours. The solvent was evaporated to give a residual solid, which was taken up in DCM. The insoluble material was filtered off, 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 eluting with EtOAc-hexanes (0-30%) to give 2-bromo-5- (2-fluoro-1, 1-dimethoxy-ethyl) -thiophene as a white solid (4.8g, 36%). 1H-NMR(CDCl3)：δ6.98(d，1H)，6.84(d，1H)，4.51(d，2H)，3.29(s，6H)。
Example 10b
Preparation of 1- (5-bromo-thiophen-2-yl) -2-fluoro-ethanone
To a stirred solution of 2-bromo-5- (2-fluoro-1, 1-dimethoxy-ethyl) -thiophene (9.4g, 35mmol) in MeCN (100mL) at 20 deg.C was added 10% aqueous HCl (50mL) and the reaction mixture was stirred at 0 deg.C for 3 hours. The solvent was removed in vacuo to give a residue, which was partitioned between DCM and water and the aqueous layer was extracted with DCM. The combined organic layers were washed with water, saturated NaHCO3The aqueous solution, and brine were washed, dried over sodium sulfate and evaporated in vacuo to give a white solid. The solid was dissolved in a minimum amount of DCM and a large amount of hexane was added. After evaporation of most of the solvent, a solid precipitated, then was collected by filtration, washed with hexane and dried under high vacuum to give 1- (5-bromo-thiophen-2-yl) -2-fluoro-ethanone (6.52g, 84%).1H-NMR(CDCl3)：δ7.64(d，1H)，7.15(d，1H)，5.26(d，2H)。
Example 10c
Preparation of 5- (5-bromo-thiophen-2-yl) -1- (2-chloro-phenyl) -4-fluoro-1H-pyrazole-3-carboxylic acid methyl ester
Figure S2006800306472D01872
To a stirred solution of 1- (5-bromo-thiophen-2-yl) -2-fluoro-ethanone (6.59g, 29.54mmol) in anhydrous THF (200mL) at-78 ℃ under nitrogen was added a THF (1.0M, 36mL, 36mmol) solution of LiHMDS, then the reaction mixture was stirred at-78 ℃ for 40 minutes, then a solution of diethyl oxalate (6mL, 44.25mmol) in anhydrous THF (50mL) was added dropwise. The mixture was warmed to 20 ℃ overnight, then quenched with 2N aqueous HCl and extracted with ether. The combined organic layers were washed with brine, dried over sodium sulfate and evaporated in vacuo to give methyl 5- (5-bromo-thiophen-2-yl) -1- (2-chloro-phenyl) -4-fluoro-1H-pyrazole-3-carboxylate (10.4g, 100%) as a dark red oil, which was used in the next reaction without further purification.
A mixture of the above oil (6.4g, 19.81mmol) and 2-chlorophenylhydrazine hydrochloride (4.0g, 22.3mmol) in dry EtOH (100mL) was refluxed for 12 hours. The solvent was then removed in vacuo to give a residue which was partitioned between EtOAc and water, the aqueous layer was separated, and extracted with EtOAc. The combined organic layers were washed with saturated NaHCO3And brine, dried over sodium sulfate and evaporated in vacuo to give the crude product. The crude product was purified by flash chromatography on silica gel eluting with EtOAc-hexanes (0-30%) to give methyl 5- (5-bromo-thiophen-2-yl) -1- (2-chloro-phenyl) -4-fluoro-1H-pyrazole-3-carboxylate (4.27g, 50%) as a dark red slurry. Ms (es): 431[ M + H ]]+。
Example 10d
Preparation of 2- {1- (2-chloro-phenyl) -4-fluoro-5- [5- (3-methanesulfonyl-phenyl) -thiophen-2-yl ] -1H-pyrazol-3-yl } -propan-2-ol
Figure S2006800306472D01881
The title compound was prepared in a similar manner to that described in examples 8c and 8d using ethyl 5- (5-bromo-thiophen-2-yl) -1- (2-chloro-phenyl) -4-fluoro-1H-pyrazole-3-carboxylate.1H-NMR(CDCl3)：δ8.03(m，1H)，7.82(m，1H)，7.72(m，1H)，7.57-7.45(m，5H)，7.27(d，1H)，6.99(d，1H)，3.07(s，3H)，2.74(s，1H)，1.72(s，6H)。
Example 11
Preparation of 2- [ 4-bromo-5- [5- (3-methanesulfonyl-phenyl) -thiophen-2-yl ] -1- (2-trifluoromethyl-phenyl) -1H-pyrazol-3-yl ] -propan-2-ol
Figure S2006800306472D01882
To 2- [5- [5- (3-methanesulfonyl-phenyl) -thiophen-2-yl ] amine at 20 deg.C]-1- (2-trifluoromethyl-phenyl) -1H-pyrazol-3-yl ]To a stirred solution of propan-2-ol (254mg, 0.5mmol) in anhydrous MeCN was added N-bromosuccinimide (94mg, 0.53mmol) and the reaction mixture was stirred at 20 ℃ overnight. Evaporation of the solvent gave a residue which was purified by fast color chromatography on silica gel eluting with EtOAC-hexane (0-60%) to give the title compound as a white solid (286mg, 98%).1H-NMR(CDCl3)：δ8.05(m，1H)，7.85-7.81(m，2H)，7.76(m，1H)，7.63-7.61(m，2H)，7.56(t，1H)，7.39(m，1H)，7.25(d，1H)，6.98(d，1H)，3.09(s，1H)，3.07(s，3H)，1.74(s，6H)。
The following compounds are prepared essentially in accordance with the previous examples:
4-bromo-1- (2, 6-dichlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -3- (trifluoromethyl) -1H-pyrazole, ms (es): 597[ M + H]+
2- [ 4-bromo-1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Propan-2-ol, ms (es): 553[ M + H]+，535(M-OH)
2- [ 4-bromo-1- (2, 6-dichlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl ] -2-thienyl } -1H-pyrazol-3-yl ] propan-2-ol, ms (es): 569(M-OH)
2- [ 4-bromo-1- (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-1- (2-ethylphenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Propan-2-ol, ms (es): 545[ M + H]+，527(M-OH)
2- (4-bromo-5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1- {2- [ (trifluoromethyl) oxy group ]Phenyl } -1H-pyrazol-3-yl) propan-2-ol, ms (es): 601[ M + H]+，584(M-OH)
2- [ 4-bromo-1- (2-bromophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thiaThienyl } -1H-pyrazol-3-yl]Propan-2-ol, ms (es): 595[ M + H]+，577(M-OH)
2- (4-bromo-5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1- [4- (trifluoromethyl) 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 } -1- [3- (trifluoromethyl) 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-thienyl } -1- [2- (trifluoromethyl) pyridin-3-yl]-1H-pyrazol-3-yl) propan-2-ol, ms (es): 586[ M + H ]]+，568(M-OH)
2- [ 4-bromo-1- (3-fluoro-2-methylphenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Propan-2-ol, ms (es): 550[ M + H ]]+，531(M-OH)
2- [ 4-bromo-1- (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)
Example 12
Preparation of 2- { 4-chloro-1- (2-fluoro-phenyl) -5- [5- (3-methanesulfonyl-phenyl) -thiophen-2-yl ] -1H-pyrazol-3-yl } -propan-2-ol
Figure S2006800306472D01891
To 2- {1- (2-fluoro-phenyl) -5- [5- (3-methanesulfonyl-phenyl) -thiophen-2-yl at 20 deg.C]To a stirred solution of-1H-pyrazol-3-yl } -propan-2-ol (115mg, 0.25mmol) in anhydrous MeCN was added N-chlorosuccinimide (35mg, 0.26mmol), and the mixture was stirred in a sealed bottle at 75 ℃ overnight. Evaporation of the solvent gave a residue which was purified by flash chromatography on silica gel eluting with EtOAC-hexane (0-60%) to give the title compound as a white solid (123mg，100％)。1H-NMR(CDCl3)：δ8.08(m，1H)，7.84(m，1H)，7.78(m，1H)，7.59-7.49(m，3H)，7.30-7.28(m，2H)，7.17(t，1H)，7.03(d，1H)，3.08(s，4H)，1.74(s，6H)。
The following compounds are prepared essentially in accordance with the previous examples: :
2- (4-chloro-5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1- [3- (trifluoromethyl) pyridin-4-yl]-1H-pyrazol-3-yl) propan-2-ol, ms (es): 542[ M + H]+。
2- [ 4-chloro-1- (3-fluoropyridin-4-yl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Propan-2-ol, ms (es): 492[ M + H]+。
2- [ 4-chloro-1- (3-chloropyridin-4-yl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Propan-2-ol, ms (es): 508[ M + H ]]+。
2- [ 4-chloro-1- (3, 5-dichloropyridin-4-yl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Propan-2-ol, ms (es): 544[ M + H]+。
2- [ 4-chloro-1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Propan-2-ol, ms (es): 507M + H]+，489(M-OH)
2- [ 4-chloro-1- (2, 6-dichlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Propan-2-ol, ms (es): 541[ M + H]+，523(M-OH)
2- (4-chloro-5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1- [2- (trifluoromethyl) phenyl]-1H-pyrazol-3-yl) propan-2-ol, ms (es): 541[ M + H]+，523(M-OH)
2- [ 4-chloro-1- (3-chloro-2-fluorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl ]Propan-2-ol, ms (es): 525[ M + H ]]+，507(M-OH)
2- [ 4-chloro-1- (2-ethylphenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thiaThienyl } -1H-pyrazol-3-yl]Propan-2-ol, ms (es): 501[ M + H [ ]]+，483(M-OH)
2- (4-chloro-5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1- {2- [ (trifluoromethyl) oxy group]Phenyl } -1H-pyrazol-3-yl) propan-2-ol, ms (es): 557[ M + H ]]+，539(M-OH)
2- [ 4-chloro-1- (2-bromophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Propan-2-ol, ms (es): 551[ M + H ]]+，533(M-OH)
2- (4-chloro-5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1- [4- (trifluoromethyl) pyridin-3-yl]-1H-pyrazol-3-yl) propan-2-ol, ms (es): 542[ M + H]+，524(M-OH)
2- (4-chloro-5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1- [2- (trifluoromethyl) pyridin-3-yl]-1H-pyrazol-3-yl) propan-2-ol, ms (es): 542[ M + H]+，524(M-OH)
2- (4-chloro-5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1- [3- (trifluoromethyl) pyridin-2-yl]-1H-pyrazol-3-yl) propan-2-ol, ms (es): 542[ M + H]+，524(M-OH)
2- [ 4-chloro-1- (3-fluoro-2-methylphenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Propan-2-ol, 505[ M + H]+，487(M-OH)
2- [ 4-chloro-1- (2-chloro-3-fluorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Propan-2-ol, ms (es): 525[ M + H ] ]+，507(M-OH)
2- [ 4-chloro-1- (2, 3-difluorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Propan-2-ol, ms (es): 509[ M + H]+，491(M-OH)
2- [ 4-chloro-1- (2, 6-dimethylphenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Propan-2-ol, ms (es): 501[ M + H [ ]]+，483(M-OH)
2- [ 4-chloro-1- (2, 6-difluorophenyl) -5- {5- [3- (methylsulfonyl) benzeneBase of]-2-thienyl } -1H-pyrazol-3-yl]Propan-2-ol, ms (es): 509[ M + H]+，491(M-OH)
2- [ 4-chloro-1- (2-chloro-6-fluorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Propan-2-ol, ms (es): 525[ M + H ]]+，507(M-OH)
2- [ 4-chloro-1- (2-chloro-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-1- (2, 4-difluorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-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-thienyl } -1- [4- (trifluoromethyl) pyridin-3-yl]-1H-pyrazol-3-yl) propan-2-ol, ms (es): 556[ M + H]+，538(M-OH)
2- [ 4-chloro-3- (1-hydroxy-1-methylethyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-1-yl]-6- (trifluoromethyl) phenol, ms (es): 557[ M + H ]]+，539(M-OH)
2- [ 4-chloro-1- (2-chlorophenyl) -5- { 1-methyl-5- [3- (methylsulfonyl) phenyl ]-1H-pyrrol-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 } -1- [4- (trifluoromethyl) pyridin-3-yl]-1H-pyrazol-3-yl) propan-2-ol, ms (es): 604[ M + H]+，524(M-79)。
Scheme 7
The ester 007C was converted to the amide as shown in scheme 7. Hydrolysis of the ester 007C afforded the acid 007TW1 which was treated with carbonyldiimidazole followed by treatment with amine to afford the amide 007TW 2.
Example 13
1- (2-chlorophenyl) -N-ethyl-5- {5- [3- (methylsulfonyl) phenyl ] -2-thienyl } -1H-pyrazole-3-carboxamide
Example 13a
Preparation of 1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl ] -2-thienyl } -1H-pyrazole-3-carboxylic acid
Figure S2006800306472D01922
To 1- (2-chloro-phenyl) -5- [5- (3-methanesulfonyl-phenyl) -thiophen-2-yl]To a solution of-1H-pyrazole-3-carboxylic acid methyl ester (5.8g, 12.3mmol) in MeOH (50mL) was added aqueous NaOH (4N, 25mL) and the mixture was refluxed for 2 hours. After cooling to 20 ℃, the solvent was removed. Water was added to dissolve the crude product, and the solution was then acidified with acetic acid. The solid was collected by filtration, washed with water and dried under high vacuum to give 1- (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 1- (2-chlorophenyl) -N-ethyl-5- {5- [3- (methylsulfonyl) phenyl ] -2-thienyl } -1H-pyrazole-3-carboxamide
To the 1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl group]To a suspension of-2-thienyl } -1H-pyrazole-3-carboxylic acid (92mg, 0.2mmol) in DCM (2mL) was added carbonyldiimidazole (39mg, 1.2 eq.) and stirring was continued at 20 ℃ for 2H. A solution of ethylamine in THF (1.8M, 0.17mL, 1.5 equiv.) is added and the mixture is stirred at 20 ℃ overnight. Evaporating the solvent to obtain a crude product, which is purified by column chromatography onPurification on silica gel eluting with MeOH-DCM (1: 19) gave 1- (2-chlorophenyl) -N-ethyl-5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazole-3-carboxamide (84 mg).1H-NMR(CDCl3)：δ8.03(m，1H)，7.83(m，1H)，7.74(m，1H)，7.62-7.45(m，5H)，7.22(m，1H)，7.19(s，1H)，6.91(m，1H)，6.82(d，1H)，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 in accordance with the previous examples:
1- { [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Carbonyl } piperidine, ms (es): 526[ M + H ]]+。
1- (2, 6-dichlorophenyl) -5- { 3-methyl-5- [3- (methylsulfonyl) phenyl]-2-thienyl } -N- (2, 2, 2-trifluoroethyl) -1H-pyrazole-3-carboxamide, ms (es): 588[ M + H]+。
1- (2, 6-dichlorophenyl) -5- { 3-methyl-5- [3- (methylsulfonyl) phenyl]-2-thienyl } -3- (pyrrolidin-1-ylcarbonyl) -1H-pyrazole, ms (es): 560[ M + H ] ]+。
1- (2-chlorophenyl) -N- [2- (diethylamino) ethyl group]-N-methyl-5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazole-3-carboxamide, MS (ES)571.3, 573.3[ M + H]+
1- (2-chlorophenyl) -N- [2- (diethylamino) ethyl group]-N-ethyl-5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazole-3-carboxamide, MS (ES)585.3, 587.3[ M + H]+
1- (2-chlorophenyl) -N- [2- (dimethylamino) ethyl]-N-methyl-5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazole-3-carboxamide, MS (ES)543.3, 545.3[ M + H]+
1- (2-chlorophenyl) -N- [3- (dimethylamino) propyl]-N-methyl-5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazole-3-carboxamide, MS (ES)557.2, 559.2[ M + H]+
N- { [1- (2-chlorophenyl) -5-{5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Carbonyl } -N-methylglycine methyl ester, MS (ES)544.2, 546.2[ M + H]+
N- { [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Carbonyl } -N-methylglycine, MS (ES)530.2, 532.2[ M + H]+
1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -N- (2-morpholin-4-ylethyl) -1H-pyrazole-3-carboxamide, MS (ES)571.3, 573.3[ M + H ]]+
1- { [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl ]-2-thienyl } -1H-pyrazol-3-yl]Carbonyl } -N, N-dimethylpiperidin-4-amine, MS (ES)569.3, 571.3[ M + H ]]+
1- { [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Carbonyl } piperidine-4-carboxylic acid, MS (ES)570.0, 572.0[ M + H]+
5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1- [2- (trifluoromethyl) phenyl]-1H-pyrazole-3-carboxylic acid, MS (ES)493.1[ M + H]+
5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -3- (pyrrolidin-1-ylcarbonyl) -1- [2- (trifluoromethyl) phenyl]-1H-pyrazole, MS (ES)546.3[ M + H]+
1- (2-chlorophenyl) -N-methyl-N- (methoxy) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazole-3-carboxamide, MS (ES)502.1, 504.1[ M + H]+
1- (2-chlorophenyl) -N- (methoxy) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazole-3-carboxamide, MS (ES)488.0, 490.0[ M + H]+
N-methyl-N- (methoxy) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1- [3- (trifluoromethyl) pyridin-2-yl]-1H-pyrazole-3-carboxamide, MS (ES)537.3[ M + H]+
5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -N- (2, 2, 2-trifluoroethyl) -1- [3- (trifluoromethyl) pyridin-2-yl]-1H-pyrazole-3-carboxamide, MS (ES)575.3[ M + H]+
1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl ]-2-thienyl } -N- (2, 2, 2-trifluoroethyl) -1H-pyrazole-3-carboxamide, ms (es)540.3, 542.3[ M + H]+
5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -N- (2, 2, 2-trifluoroethyl) -1- [2- (trifluoromethyl) phenyl]-1H-pyrazole-3-carboxamide, MS (ES)574.3[ M + H]+
3- {5- [1- (2-chlorophenyl) -3- { [ (2, 2, 2-trifluoroethyl) amino]Carbonyl } -1H-pyrazol-5-yl]-2-thienyl } benzoic acid methyl ester, MS (ES)519.3, 521.3[ M + H]+
1- (2-chlorophenyl) -5- {5- [3- (1-hydroxy-1-methylethyl) phenyl]-2-thienyl } -N- (2, 2, 2-trifluoroethyl) -1H-pyrazole-3-carboxamide, ms (es)519.3, 521.3[ M + H]+
Scheme 8
Figure S2006800306472D01951
As shown in scheme 8, 1H-pyrazol-5-ol was prepared as 008TW5, with the hydroxyl group replaced with another group. The ketoester 008TW4 was reacted with hydrazine 008TW3 to form 1H-pyrazole-5-ol 008TW5, which was converted to the corresponding triflate 008TW 7. The 008TW7 was subjected to Suzuki coupling with boronic acid to introduce the phenyl group to give the product 008TW 8.
Example 14
1- (2-chlorophenyl) -5- [3- (methylsulfonyl) phenyl ] -3- (trifluoromethyl) -1H-pyrazole
Example 14a
Preparation of 1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl trifluoromethanesulfonate
Figure S2006800306472D01952
To a mixture of 1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-ol (0.52g, 2mmol) and 2, 6-di-tert-butyl-4-methylpyridine (0.51g, 1.25 eq) in DCM (8mL) was added trifluoromethanesulfonic anhydride (374 μ L, 1.1 eq) at-78 ℃. The mixture was warmed to 20 ℃ and stirred at 20 ℃ overnight. With saturated NaHCO 3The aqueous solution was quenched, the aqueous layer separated and extracted with DCM. The combined organic layers were washed with water and Na2SO4And (5) drying. Evaporation of the solvent gave a crude product which was purified by column chromatography on silica gel eluting with EtOAc-hexane (1: 4) to give the title compound (620 mg).1H-NMR(CDCl3)：δ7.60-7.44(m，4H)，6.61(s，1H)。
Example 14b
Preparation of 1- (2-chlorophenyl) -5- [3- (methylsulfonyl) phenyl ] -3- (trifluoromethyl) -1H-pyrazole
Figure S2006800306472D01961
Preparation of 1- (2-chlorophenyl) -5- [3- (methylsulfonyl) phenyl ] boronic acid using 1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl trifluoromethanesulfonate and 3- (methylsulfonyl) phenylboronic acid in a similar manner to that described in example 1c]-3- (trifluoromethyl) -1H-pyrazole.1H-NMR(CDCl3)：δ7.90(1H，m)，7.76(1H，d)，7.57-7.47(3H，m)，7.46-7.42(3H，m)，6.92(1H，s)，2.92(3H，s)。MS(ES)：401[M+H]+。
Scheme 9
Figure S2006800306472D01962
As shown in scheme 9, the ester group on the c-phenyl ring can be converted to other functional groups such as methanol and amides, ketones and methylamines. 009TW9 was subjected to claisen condensation with ester to form diketone 009TW10, then 009TW10 was condensed with hydrazine to form pyrazole product 009TW 11. Treatment of 009TW11 with trifluoromethanesulfonic anhydride formed the trifluoride 009TW 12. 009TW12 was coupled with boronic acid Suzuki to give product 009TW13, which was treated with grignard reagent to form methanol 009TW16, while still little of the product was ketone 009TW 15. The ester 009TW13 was hydrolyzed to give the acid 009TW16 which was coupled with carbonyldiimidazole and converted to the amide 009TW 17. Reduction of 009TW17 with borane afforded amine 009TW 18.
Examples 15 and 16
2- {4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl ] -3 '- (methylsulfonyl) biphenyl-2-yl } propan-2-ol (15) and 1- {4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl ] -3' - (methylsulfonyl) biphenyl-2-yl } ethanone (16)
Example 15a
Preparation of methyl 5- (1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl) -2-hydroxybenzoate
Figure S2006800306472D01971
Methyl 5- (1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl) -2-hydroxybenzoate was prepared in a similar manner to that described in example 1b using methyl 5-acetyl-2-hydroxybenzoate. Ms (es): 397[ M + H ]]+。
Example 15b
Preparation of methyl 5- (1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl) -2- (trifluoromethanesulfonyloxy) benzoate
To a solution of methyl 5- (1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl) -2-hydroxybenzoate (1.29g, 3.25mmol) and 2, 6-lutidine (0.5mL, 1.2 equiv) in DCM (15mL) was added trifluoromethanesulfonic anhydride (0.663mL, 1.2 equiv.) at-78 deg.C, and the reaction solution was stirred for 1 hour at-78 deg.C. After quenching with water, the aqueous layer was separated and extracted with DCM. The combined organic layers were washed with saturated NaHCO3Aqueous solution and water washed over Na2SO4And (5) drying. Evaporation of the solvent gave a crude product which was purified by column chromatography on silica gel eluting with EtOAc-hexane (1: 4) to give methyl 5- (1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl) -2- (trifluoromethanesulfonyloxy) benzoate (1.64 g). Ms (es): 529[ M + H ]+。
Example 15c
Preparation of methyl 4- (1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl) -3' (methylsulfonyl) biphenyl-2-carboxylate
Figure S2006800306472D01981
Methyl 4- (1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl) -3' - (methylsulfonyl) biphenyl-2-carboxylate was prepared in a similar manner as described in example 1c using 5- (1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl) -2- (trifluoromethanesulfonyloxy) benzoate and 3- (methylsulfonyl) phenylboronic acid. Ms (es): 535[ M + H]+。
Examples 15d and 16
Preparation of 2- {4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl ] -3-' (methylsulfonyl) biphenyl-2-yl } propan-2-ol (15) and 1- {4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl ] -3- (methylsulfonyl) biphenyl-2-yl } ethanone (16)
Figure S2006800306472D01982
Preparation of 2- {4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl ] biphenyl-2-carboxylic acid methyl ester using 4- (1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl) -3' - (methylsulfonyl) biphenyl-2-carboxylic acid in a similar manner to that described in example 8d]-3' - (methylsulfonyl) biphenyl-2-yl } propan-2-ol and 1- {4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]-3' - (methylsulfonyl) biphenyl-2-yl } ethanone. 15 d:1H-NMR(CDCl3)：δ7.91(m，1H)，7.85(d，1H)，7.57-7.50(m，4H)，7.47-7.41(m，2H)，7.37(d，1H)，7.20(dd，1H)，7.01(s，1H)，6.88(s，1H)，3.07(s，3H)，2.05(s，1H)，1.25(s，6H)。MS(ES)：536[M+H]+。16：1H-NMR(CDCl3)：δ7.95(m，1H)，7.87(m，1H)，7.61(m，1H)，7.57-7.43(m，7H)，7.38(dd，1H)，7.30(d，1H)，6.92(s，1H)，3.08(s，3H)，2.13(s，3H)。MS(ES)：518[M+H]+
example 17
(4- (1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl) -3' - (methylsulfonyl) biphenyl-2-yl) (morpholino) methanone
Example 17a
Preparation of 4- (1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl) -3' - (methylsulfonyl) biphenyl-2-carboxylic acid
Figure S2006800306472D01991
4- (1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl) -3' - (methylsulfonyl) biphenyl-2-carboxylic acid methyl ester (1.37g, 2.6mmol) and NaOH (1g, 25mmol) in MeOH-H2The solution in O (2: 1, 16mL) was refluxed for 2 hours. After cooling, the solid was removed and the filtrate was acidified with formic acid. The solid was collected by filtration and washed with water, viaDrying under high vacuum gave 4- (1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl) -3' - (methylsulfonyl) biphenyl-2-carboxylic acid (1.05 g). Ms (es): 521[ M + H]+。
Example 17b
Preparation of (4- (1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl) -3' - (methylsulfonyl) biphenyl-2-yl (morpholino) methanone
Figure S2006800306472D01992
To a suspension of 4- (1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl) -3' - (methylsulfonyl) biphenyl-2-carboxylic acid (0.52g, 1mmol) in DCM (6mL) was added carbonyldiimidazole (2.43mg, 1.5mmol) and the mixture was stirred at 20 ℃ for 2H. Morpholine (0.175mL, 2mmol) was added and the mixture was stirred at 20 deg.C overnight. Evaporation of the solvent gave a crude product which was purified by column chromatography on silica gel eluting with EtOAc-hexane (1: 4 to 4: 1) to give (4- (1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl) -3' - (methylsulfonyl) biphenyl-2-yl) (morpholino) methanone (0.52 g). 1H-NMR(CDCl3)：δ7.97(m，2H)，7.77(d，1H)，7.64(m，1H)，7.58(m，1H)，7.46-7.24(m，5H)，6.89(s，1H)，3.55(m，3H)，3.33(m，2H)，3.08(s，3H)，2.87(m，2H)，2.69(m，1H)。MS(ES)：590[M+H]+。
Example 18
Preparation of 4- ((4- (1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl) -3' - (methylsulfonyl) biphenyl-2-yl) methyl) morpholine
Figure S2006800306472D02001
To BH3(1M, 4mL) in THF was added (4- (1- (2-chlorophenyl) -3- (trifluoro-phenyl)Methyl) -1H-pyrazol-5-yl) -3' - (methylsulfonyl) biphenyl-2-yl) (morpholino) methanone (460mg, 0.78mmol), the solution was stirred at 20 ℃ overnight. MeOH was added to quench the borane and the solvent was evaporated to give the crude product which was purified by column chromatography on silica gel eluting with MeOH-DCM (1: 19) to give 4- ((4- (1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl) -3' - (methylsulfonyl) biphenyl-2-yl) methyl) morpholine (0.2 g).1H-NMR(CDCl3)：δ8.25(m，1H)，7.93(m，1H)，7.72(m，1H)，7.60(m，1H)，7.55(m，1H)，7.49-7.39(m，3H)，7.33-7.26(m，2H)，7.18(m，1H)，6.85(s，1H)，3.58(m，4H)，3.16(s，3H)，3.07(s，3H)，2.14(m，4H).MS(ES)：576[M+H]+.
Scheme 10
Figure S2006800306472D02011
Aminoethylpyrazole is synthesized by alkylation of pyrazole with 1, 2-dihaloethane followed by alkylation of the amine, as shown in scheme 10. The ketone 010TW19 undergoes claisen condensation with the ester to form the diketone 010TW20, which is then addition-cyclized with hydrazine to give the pyrazole 010TW 21. 010TW21 alkylation gave chloroethylpyrazole 010TW22, which was used for the alkylation of amines to form amine 010TW 23. Final Suzuki coupling of 010TW23 with boronic acid gave 010TW 24.
Example 19
4- (2- {5- [ 3' - (methylsulfonyl) biphenyl-4-yl ] -3- (trifluoromethyl) -1H-pyrazol-1-yl } ethyl) morpholine
Example 19a
Preparation of 5- (4-bromophenyl) -3- (trifluoromethyl) -1H-pyrazole
Figure S2006800306472D02012
5- (4-bromophenyl) -3- (trifluoromethyl) -1H-pyrazole was prepared in a similar manner to that described in example 1b using 4' -bromoacetophenone. Ms (es): 291[ M + H ]]+.
Example 19b
Preparation of 5- (4-bromophenyl) -1- (2-chloroethyl) -3- (trifluoromethyl) -1H-pyrazole
Figure S2006800306472D02021
To a solution of 5- (4-bromophenyl) -3- (trifluoromethyl) -1H-pyrazole (2.05g, 7mmol) and 1-bromo-2-chloroethane (0.71mL, 1.2 equiv.) in DMF (30mL) was added NaH (0.42g, 60%, 1.5 equiv.) and the mixture was stirred at 20 ℃ overnight. The reaction was quenched with water. The solid was collected, washed with water and dried under high vacuum to give the crude product which was purified by column chromatography eluting with MeOH-DCM (6: 96) to give the product 5- (4-bromophenyl) -1- (2-chloroethyl) -3- (trifluoromethyl) -1H-pyrazole (400mg) in small amounts.1H-NMR(CDCl3)：δ7.64(d，1H)，7.31(d，1H)，6.54(s，1H)，4.41(t，2H)，3.93(t，2H).
Example 19c
Preparation of 4- (2- (5- (4-bromophenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl) ethyl) morpholine
Figure S2006800306472D02022
A solution of 5- (4-bromophenyl) -1- (2-chloroethyl) -3- (trifluoromethyl) -1H-pyrazole (200mg, 0.56mmol) and morpholine (0.245mL, 5 equiv.) in acetonitrile (2mL) was heated at 90 ℃ overnight. Evaporation of the solvent afforded 4- (2- (5- (4-bromophenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl) ethyl) morpholine. Ms (es): 404[ M + H ]+.
Example 19d
Preparation of 4- (2- (5- (3' - (methylsulfonyl) biphenyl-4-yl) -3- (trifluoromethyl) -1H-pyrazol-1-yl) ethyl) morpholine
Figure S2006800306472D02023
Preparation of 4- (2- {5- [ 3' - (methylsulfonyl) biphenyl-4-yl) using the above crude product and (3-methylsulfonyl) phenylboronic acid in a similar manner to that described in example 1c]-3- (trifluoromethyl) -1H-pyrazol-1-yl } ethyl) morpholine.1H-NMR(CDCl3)：δ8.21(m，1H)，7.95(m，2H)，7.76-7.53(m，4H)，7.46(m，1H)，6.58(s，1H)，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 compounds are prepared essentially in accordance with the previous examples:
1-methyl-4- (2- {5- [ 3' - (methylsulfonyl) biphenyl-4-yl)]-3- (trifluoromethyl) -1H-pyrazol-1-yl } ethyl) piperazine ms (es): 493[ M + H ]]+.
Scheme 11
Figure S2006800306472D02031
As shown in scheme 11, the carbonyl group can be introduced into the pyrazole system. The reaction of the diketone 011TW25 with hydrazine forms pyrazole 011TW 26. Suzuki coupling of 011TW26 with boronic acid gave 011TW27, which was then hydrolyzed to the acid 011TW 28. CDI coupling of the acid 011TW28 with an amine yielded the amine 011TW 29.
Example 20
4- { [5- {5- [3- (methylsulfonyl) phenyl ] -2-thienyl } -3- (trifluoromethyl) -1H-pyrazol-1-yl ] acetyl } morpholine
Example 20a
Preparation of methyl 2- (5- (5- (3- (methylsulfonyl) phenyl) thiophen-2-yl) -3- (trifluoromethyl) -1H-pyrazol-1-yl) acetate
Figure S2006800306472D02041
Methyl 2- (5- (5- (3- (methylsulfonyl) phenyl) thiophen-2-yl) -3- (trifluoromethyl) -1H-pyrazol-1-yl) acetate was prepared in a similar manner to that described in example 1c using methyl 2-hydrazinoacetate (in MeOH). Ms (es): 445[ M + H ] ]+。
Example 20b
Preparation of 2- (5- (5- (3- (methylsulfonyl) phenyl) thiophen-2-yl) -3- (trifluoromethyl) -1H-pyrazol-1-yl) acetic acid
Figure S2006800306472D02042
2- (5- (5- (3- (methylsulfonyl) phenyl) thiophen-2-yl) -3- (trifluoromethyl) -1H-pyrazol-1-yl) acetic acid was prepared in a similar manner as described in example 17 a.
MS(ES)：431[M+H]+。
Example 20c
Preparation of 4- { [5- {5- [3- (methylsulfonyl) phenyl ] -2-thienyl } -3- (trifluoromethyl) -1H-pyrazol-1-yl ] acetyl } morpholine
Figure S2006800306472D02043
4- { [5- {5- [3- (methylsulfonyl) phenyl ] -2-thienyl } -3- (trifluoromethyl) -1H-pyrazol-1-yl ] acetyl } morpholine was prepared in a similar manner as described in example 19.
1H-NMR(CDCl3)：δ8.15(s，1H)，7.90(m，1H)，7.86(m，1H)，7.63(m，1H)，7.42(d，1H)，7.32(d，1H)，6.73(s，1H)，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 in accordance with the previous examples:
5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1- (2-oxo-2-pyrrolidin-1-ylethyl) -3- (trifluoromethyl) -1H-pyrazole, MS (ES: 484[ M + H ]]+。
1- { [5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -3- (trifluoromethyl) -1H-pyrazol-1-yl]Acetyl } piperidine, MS (ES: 498[ M + H)]+。
5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1- (2-oxo-2-pyrrolidin-1-ylethyl) -3- (trifluoromethyl) -1H-pyrazole, ms (es): 484[ M + H]+。
Scheme 12
Figure S2006800306472D02051
The starting material (012vi) was prepared in a similar manner to scheme 1 and then further converted to the final product described in scheme 12.
Example 21
5- {5- [2- (2-chloro-phenyl) -5-trifluoromethyl-2H-pyrazol-3-yl ] -thiophen-2-yl } -2-methanesulfonyl-3-methyl-pyridine
Example 21a
Preparation of 5- {5- [2- (2-chloro-phenyl) -5-trifluoromethyl-2H-pyrazol-3-yl ] -thiophen-2-yl } -2-methanesulfonyl-3-methyl-pyridine
Figure S2006800306472D02052
5- {5- [2- (2-chloro-phenyl) -5-trifluoromethyl-2H-pyrazol-3-yl]-Thien-2-yl } -3-methyl-2-methylsulfanyl-pyridine (158mg, 0.34mmol) was dissolved in 15mL of a mixture of dichloromethane and methanol (5: 1, V/V). Then MMPP (magnesium peroxyphthalate hexahydrate, 424mg, 0.75mmol, 80% tech.) was added. The mixture was stirred at room temperature for 2 hours, then diluted with dichloromethane and filtered. The filtrate is saturated NaHCO3Washed with brine and then Na2SO4Dried and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (10 → 40% EtOAc/hexanes) to give a white solid (116mg, 69% yield).1H-NMR(400MHz，CDCl3)：δ2.73(s，3H)，3.36(s，3H)，6.89(d，J＝3.9，1H)，6.93(s，1H)，7.27(m，1H)，7.58-7.49(m，4H)，7.70-7.69(m，1H)，8.52-8.51(m，1H).MS(ES)：498.3[M+H]+.
The following compounds were prepared in a similar manner by oxidation of the appropriate sulfide:
2- (ethylsulfonyl) -3-methyl-5- (5- {3- (trifluoromethyl) -1- [2- (trifluoromethyl) phenyl-]-1H-pyrazol-5-yl } -2-thienyl) pyridine; ms (es): 546.2[ M + H]+；
3-methyl-5- (5- {1- [2- (methoxy) phenyl)]-3- (trifluoromethyl) -1H-pyrazol-5-yl } -3-thienyl) -2- (methylsulfonyl) pyridine; ms (es): 494.3[ M + H ]+；
5- {5- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]-2-thienyl } -2- (ethanesulfonyl) -3-methylpyridine; ms (es): 512.3[ M + H]+；
5- {5- [1- (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- (trifluoromethyl) -1- [2- (trifluoromethyl) phenyl]-1H-pyrazol-5-yl } -2-thienyl) pyridine; ms (es): 532.2[ M + H]+；
5- {5- [1- (2, 5-dichlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]-3-thienyl } -3-methyl-2- (methylsulfonyl) pyridine; ms (es): 532.4, 536.2[ M + H ]]+。
Scheme 13
Figure S2006800306472D02061
The starting material (013vi) was prepared in a similar manner to scheme 1 and then further converted to the final product described in scheme 13.
Example 22
Preparation of 1- (5- {5- [2- (2-chloro-phenyl) -5-trifluoromethyl-2H-pyrazol-3-yl ] -thiophen-2-yl } -pyrazol-2-yl) -piperazine
Figure S2006800306472D02071
4- (5- {5- [2- (2-chloro-phenyl) -5-trifluoromethyl-2H-pyrazol-3-yl]-thiophen-2-yl } -pyridin-2-yl) -piperazine-1-carboxylic acid tert-butyl ester (196mg, 0.33mmol) was mixed with 4mL of 50% trifluoromethyl acetic acid in dichloromethane and stirred at room temperature for 2 hours. Removing all solvent; the residue was redissolved in dichloromethane and saturated NaHCO 3The aqueous solution was neutralized to pH 7. The organic layer was washed with brine, over Na2SO4Drying and concentration in vacuo afforded a solid which was washed several times with dichloromethane to afford a yellow solid (75mg, 47% yield). 1H-NMR (400MHz, CDCl)3)：δ3.32-3.29(m，4H)，3.94-3.91(m，4H)，6.67(d，J＝8.8，1H)，6.79(d，J＝3.8，1H)，6.87(s，1H)，7.02(d，J＝3.8，1H)，7.57-7.45(m，4H)，7.63(dd，J＝8.8，J＝2.5，1H)，8.34(d，J＝2.2，1H).MS(ES)490.3，492.3，[M+H]+。
Scheme 14
The starting material (014vi) was prepared in a similar manner to scheme 1 and then further converted to the final product described in scheme 14.
Example 23
Preparation of (4- {5- [2- (2-chloro-phenyl) -5-trifluoromethyl-2H-pyrazol-3-yl ] -thiophen-2-yl } -3-methyl-phenyl) -acetic acid
Figure S2006800306472D02073
(4- {5- [2- (2-chloro-phenyl) -5-trifluoromethyl-2H-pyrazol-3-yl ] -thiophen-2-yl } -3-methyl-phenyl) -acetic acid methyl ester (122mg, 0.25mmol) was dissolved in 6mL of a mixture of THF and water (3: 1, V/V). Then lithium hydroxide monohydrate (2.3mg, 0.55mmol) was added.
After stirring at room temperature for 2 hours, the mixture was neutralized to pH7 with 1N HCl and then extracted with ethyl acetate. The combined organic layers were washed with brine, over Na2SO4Dried and concentrated in vacuo. The crude product was purified by reverse phase HPLC to give a white solid (66mg, 55% yield). 1H-NMR (400MHz, CDCl)3)：δ2.33(s，3H)，3.65(s，2H)，6.88-6.84(m，3H)，7.17-7.11(m，1H)，7.17(m，1H)，7.27(m，1H)，7.56-7.42(m，4H).MS(ES)477.2，[M+H]+。
The following compounds were prepared in a similar manner by hydrolysis of the corresponding phenylacetate ester precursor.
3- {5- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl ]-2-thienyl } -4-fluorophenyl) acetic acid; ms (es): 481.1, 484.4[ M + H ]]+；
2- (5- {5- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]-2-thienyl } pyridin-3-yl) -2-methylpropionic acid; ms (es): 492.1, 494.3[ M + H ]]+；
(5- {5- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl)]-2-thienyl } pyridin-3-yl) acetic acid; ms (es): 464.0, 466.1[ M + H ]]+；
[ 3-methyl-4- (5- {3- (trifluoromethyl) -1- [3- (trifluoromethyl) pyridin-2-yl ] methyl]-1H-pyrazol-5-yl } -2-thienyl) phenyl]Acetic acid; ms (es): 512.3[ M + H]+。
Scheme 15
Figure S2006800306472D02081
As shown in scheme 15, ketones can be converted to alcohols and oximes, which can be alkylated. Ketone 015XGU01 using NaBH4Reduction gave secondary alcohol 015XGU 02. Treatment of ketone 015XGU01 with hydroxylamine in the presence of a base gave oxime 015XGU 03. The oxime 015XGU03 was alkylated with alkyl chloride or alkyl bromide to give the O-alkylated oxime 015XGU 04.
Example 24
Preparation of 1- [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl ] -2-thienyl } -1H-pyrazol-3-yl ] ethanol
Figure S2006800306472D02091
Reacting NaBH at 0 DEG C4(600mg) 1- [1- (2-chlorophenyl) -5- {5-3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Ethanones(460mg, 1mmol) in MeOH-THF mixture (1: 3, 100mL) suspension, and the resulting mixture was stirred at room temperature (rt) for 4 h. Water was added and the solvent was removed in vacuo. The residue was partitioned between water and DCM and the aqueous layer was extracted with DCM. The combined extracts were washed with brine, over Na 2SO4Dried 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)：8.04(m，1H)，7.83-7.81(m，1H)，7.74-7.71(m，1H)，7.57-7.43(m，5H)，7.21(d，1H)，6.75(d，1H)，6.64(s，1H)，5.05(q，1H)，3.07(s，3H)，2.05(brs，1H)，1.63(d，3H).MS(ES)：459[M+H]+，441(M-OH).
Example 25
Preparation of 1- [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl ] -2-thienyl } -1H-pyrazol-3-yl ] ethanone oxime
Figure S2006800306472D02092
1- [1- (2-chlorophenyl) -5- {5-3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Ethanone (120mg, 0.263mmol), NH2OH HCl (92mg, 1.32mmol) and NaOAc (132mg, 1.6mmol) in MeOH-H2The mixture in O mixture (2: 1, 15mL) was stirred in a sealed flask at 85 ℃ for 11 hours. 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)：8.04(m，1H)，7.83-7.81(m，1H)，7.73-7.71(m，1H)，7.57-7.43(m，5H)，7.21(d，1H)，6.97(s，1H)，6.76(d，1H)，3.09(s，3H)，2.37(s，3H).MS(ES)：472[M+H]+。
The following compounds are prepared essentially in accordance with the previous examples:
1- [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazoles-3-yl]Ethanone O-methyl oxime; ms (es): 486[ M + H]+；
Example 26
Preparation of 1- [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl ] -2-thienyl } -1H-pyrazol-3-yl ] ethanone O- [2- (dimethylamino) ethyl ] oxime
Figure S2006800306472D02101
1- [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]A mixture of ethyl ketoxime (196mg, 0.415mmol), KOH (142mg, 2.3mmol), 2- (dimethylamino) ethyl chloride hydrochloride (185mg, 1.3mmol), and anhydrous DMSO (5mL) was stirred in a sealed flask at 60 ℃ for 3 hours. The reaction mixture was diluted with water and extracted with ether. The combined extracts were washed with brine, over Na 2SO4Dried 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)：.8.04(d，1H)，7.83-7.81(m，1H)，7.74-7.71(m，1H)，7.57-7.43(m，5H)，7.21(d，1H)，7.00(s，1H)，6.76(d，1H)，4.38(t，2H)，3.079s，3H)，2.78(m，2H)，2.40(brs，6H)，2.31(s，3H).
Scheme 16
Figure S2006800306472D02111
As shown in scheme 16, methanol is converted to ethers, olefins, and sulfoxides. At Ti (OPr-i)4Or 1, 4-butane magnesium dibromide, treatment of the ester 016XGU01 with EtMgBr gave cyclopropanol or cyclopentanol 016XGU 02. Alkylation of methanol with RX yields 016XGU 06. Methanol and MeSO2Reaction of Na in the presence of an acid such as TFA affords 016XGU03 and the corresponding alkene 016XGU 04. With HCl/MeOH methanol is processed to give alkenes 016XGU04 and methyl ester 016XGU 05.
Example 27
Preparation of 1- [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl ] -2-thienyl } -1H-pyrazol-3-yl ] cyclopentanol
Figure S2006800306472D02112
Magnesium turning (300mg, 12.5mmol) was introduced under nitrogen into an oven-dried flask containing anhydrous THF (150mL) and a solution of dibromobutane (0.72mL, 6.08mmol) in anhydrous THF (20mL) was added dropwise at ambient temperature at a rate such that the temperature of the reaction mixture did not exceed 40 ℃. The mixture was stirred at ambient temperature for 1 hour and the magnesium chips disappeared. Adding solid 1- (2-chloro-phenyl) -5- [5- (3-methanesulfonyl-phenyl) -thiophen-2-yl ]-1H-pyrazole-3-carboxylic acid methyl ester (2.37g, 5mmol), and the resulting dark purple solution was stirred at room temperature under nitrogen for 1 hour. Adding NH at 0 deg.C4Aqueous Cl, then extracted with EtOAc. The combined extracts were washed with brine, over Na2SO4Dried and evaporated in vacuo. The crude product was purified by flash chromatography (0-60% EtOAc/hexanes) to give the title compound as a white solid (1.4g, 56%).1HHNMR(CDCl3)：8.04(d，1H)，7.83-7.81(m，1H)，7.74-7.71(m，1H)，7.57-7.52(m，3H)，7.48-7.44(m，2H)，7.20(d，1H)，6.74(d，1H)，6.63(s，1H)，3.07(s，3H)，2.42(brs，1H)，2.20-1.83(m，8H).MS(ES)499[M+H]+，481(M-OH).
Example 28
Preparation of 1- [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl ] -2-thienyl } -1H-pyrazol-3-yl ] cyclopropanol
Figure S2006800306472D02121
A solution of EtMgBr in THF (1.0M, 11mL) was added dropwise to 1- (2-chloro-phenyl) -5- [5- (3-methanesulfonyl-phenyl) -thiophen-2-yl at room temperature under nitrogen]-1H-pyrazole-3-carboxylic acid methyl ester (950mg, 2mmol) and Ti (OiPr)4(0.7mL, 2.4mmol) in dry THF (50 mL). The resulting dark mixture was stirred at room temperature for 2 hours. Adding NH at 0 deg.C4Aqueous Cl solution and Et2And (4) extracting. The combined extracts were washed with brine, over Na2SO4Dried and evaporated in vacuo. The crude product was purified by flash chromatography (0-60% EtOAc/hexanes) followed by reverse phase HPLC to give the title compound as a white solid (85mg, 0.1%).1HNMR(CDCl3)：8.04(d，1H)，7.83-7.81(m，1H)，7.74-7.71(m，1H)，7.57-7.43(m，5H)，7.2(d，1H)，6.72(d，1H)，6.509s，1H)，3.07(s，3H)，2.92(brs，1H)，1.31(m，2H)，1.17(m，2H).MS(ES)：471[M+H]+，453(M-OH).
Example 29
Preparation of 3- [ 1-methyl-1- (methylsulfonyl) ethyl ] -5- {5- [3- (methylsulfonyl) phenyl ] -2-thienyl } -1- [ 2-trifluoromethyl) phenyl ] -1H-pyrazole and 3- (1-methylethenyl) -5- {5- [3- (methylsulfonyl) phenyl-2-thienyl } -1- [2- (trifluoromethyl) phenyl ] -1H-pyrazole)
Figure S2006800306472D02131
TFA (1mL) was added dropwise to methanol (270mg, 0.533mmol) and MeSO at 0 deg.C2Na (280mg, 2.74mmol) in CHCl3(8mL), and the resulting mixture was stirred at room temperature overnight. After dilution with water, the mixture was poured into 12% NH4Aqueous OH and extracted with DCM. The combined extracts were washed with water and brine, over Na2SO4Dried and evaporated in vacuo. The crude product was purified by flash chromatography (0-80% EtOAc/hexanes) to afford a white solidThe title compound of (152mg, 50%).1HNMR(CDCl3)：8.02(d，1H)，7.9(m，1H)，7.83(m，1H)，7.71(m，3H)，7.55(m，1H)，7.46(m，1H)，7.20(d，1H)，6.88(s，1H)，6.74(d，1H)，3.07(s，3H)，2.77(s，3H)，1.88(s，6H).MS(ES)：569[M+H]+；(40mg)。1HNMR(CDCl3)：8.03(d，1H)，7.87-7.81(m，2H)，7.73-7.66(m，3H)，7.57-7.17(m，2H)，7.17(d，1H)，6.78(s，1H)，6.65(d，1H)，5.62(s，1H)，5.18(m，1H)，3.07(s，3H)，2.19(s，3H).MS(ES)：489[M+H]+.
The following compounds are prepared essentially in accordance with the previous examples:
2- (3- [ 1-methyl-1- (methylsulfonyl) ethyl)]-5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-1-yl) -3- (trifluoromethyl) pyridine, ms (es): 570[ M + H]+
2- [3- (1-methylvinyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H- [ pyrazol-1-yl]-3- (trifluoromethyl) pyridine, ms (es): 490[ M + H [ ]]+
3- (3- [ 1-methyl-1- (methylsulfonyl) ethyl)]-5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-1-yl) -2- (trifluoromethyl) pyridine, ms (es): 570[ M + H]+
3- (1-methylvinyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1- [2- (trifluoromethyl) phenyl]-1H-pyrazole, ms (es): 490[ M + H [ ] ]+
3- (3- [ 1-methyl-1- (methylsulfonyl) ethyl)]-5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-1-yl) -2- (trifluoromethyl) pyridine, ms (es): 570[ M + H]+
Example 30
Preparation of 1- (2-chlorophenyl) -3- (1-methylvinyl) -5- {5- [3- (methylsulfonyl) phenyl ] -2-thienyl } -1H-pyrazole and 1- (2-chlorophenyl) -3- [ 1-methyl-1- (methoxy) ethyl ] -5- {5- [3- (methylsulfonyl) phenyl ] -2-thienyl } -1H-pyrazole
Figure S2006800306472D02141
A solution of HCl/MeOH (1.25M, 8mL) was added 2- {1- (2-chloro-phenyl) -5- [5- (3-methanesulfonyl-phenyl) -thiophen-2-yl]-1H-pyrazol-3-yl } -propan-2-ol (430mg, 0.864mmol) in CHCl3The reaction mixture was heated in a sealed flask at 85 ℃ for 6 hours. The solvent was removed in vacuo and the residue was purified by flash chromatography (0-50% EtOAc/hexanes) to give the title compound as a white solid (110mg, 28%).1HNMR(CDCl3)：8.05(m，1H)，7.83-7.81(m，1H)，7.74-7.72(m，1H)，7.57-7.52(m，3H)，7.49-7.41(m，2H)，7.20(d，1H)，6.79(s，1H)，6.72(d，1H)，5.64(s，1H)，5.18(m，1H)，3.07(s，3H)，2.21(s，3H).MS(ES)：455[M+H]+.(94mg，22％)：1HNMR(CDCl3)：8.04(m，1H)，7.83-7.80(m，1H)，7.74-7.71(m，1H)，7.57-7.52(m，3H)，7.50-7.41(m，2H)，7.20(d，1H)，6.74(d，1H)，6.67(s，1H)，3.23(d，3H)，3.07(s，3H)，1.63(s，6H).MS(ES)：455(M-OMe).
Example 31
Preparation of 5- {5- [3- (methylsulfonyl) phenyl ] -2-thienyl } -3- [ 1-methyl-1- (methoxy) ethyl ] -1- [2- (trifluoro-methyl) phenyl ] -1H-pyrazole and 5- {5- [3- (ethylsulfonyl) phenyl ] -2-thienyl } -3- [ 1-methyl-1- (methoxy) ethyl ] -1- [2- (trifluoromethyl) phenyl ] -1H-pyrazole
Figure S2006800306472D02151
NaH (60% in mineral oil, 40mg, 1mmol) was added to 2- (5- {5- [3- (methylsulfonyl) phenyl ] at 0 deg.C ]-2-thienyl } -1- [2- (trifluoromethyl) phenyl]-1H-pyrazol-3-yl) propan-2-ol (260mg, 0.5mmol), MeI (47L, 0.75mmol)And anhydrous DMF (8mL), and the resulting mixture was stirred at room temperature for 3 hours. Water was added at 0 ℃ to quench the reaction, followed by extraction with DCM. The combined extracts were washed with water and brine, over Na2SO4Dried and evaporated in vacuo. The crude product was first purified by flash chromatography (0-40% EtOAc/hexanes) and then by normal phase HPLC to give the title compound as two white solids. (110mg, 41%).1HNMR(CDCl3)：8.03(m，1H)，7.87-7.81(m，2H)，7.73-7.66(m，3H)，7.57-7.50(m，2H)，7.18(d，1H)，6.66(m，2H)，3.21(s，3H)，3.07(s，3H)，1.63(s，6H).MS(ES)：521[M+H]+.(71mg，26％).1HNMR(CDCl3)：7.98(m，1H)，7.87-7.85(m，1H)，7.79-7.76(m，1H)，7.72-7.66(m，3H)，7.56-7.50(m，2H)，7.18(d，1H)，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
As shown in scheme 17, esters can be converted to alcohols and amines. The ester 017XGU01 was reduced with lithium borohydride to give the primary alcohol 017XGU02 in good yield. By using NBS/PPh3Alcohol 017XGU02 was processed to convert it to the corresponding bromide 017XGU 03. Amine 017XGU04 was obtained by treating bromide 017GU03 with the corresponding amine.
Example 32
Preparation of [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl ] -2-thienyl } -1H-pyrazol-3-yl ] methanol
Figure S2006800306472D02161
Reacting LiBH at room temperature under nitrogen4(1.0M in THF, 14mL, 28mmol) 1- (2-chloro-phenyl) -5- [5- (3-methanesulfonyl-phenyl) -thiophen-2-yl was added dropwise]To a stirred solution of-1H-pyrazole-3-carboxylic acid methyl ester (4.38g, 9.26mmol) in anhydrous THF (100mL) the resulting mixture was stirred at room temperature for 3 days. Acetone (2mL) and water (2mL) were added sequentially at 0 deg.C and the solid was filtered off. The filtrate was concentrated in vacuo. The residue was taken up in EtOAc (200mL), washed with water and brine, over Na 2SO4Dried 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)：8.04(m，1H)，7.84-7.81(m，1H)，7.74-7.72(m，1H)，7.58-7.44(m，5H)，7.21(d，1H)，6.76(d，1H)，6.69(s，1H)，4.80(s，2H)，3.07(s，3H)，1.65(brs，1H).MS(ES)：445[M+H]+.
Example 33
Preparation of 4- { [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl ] -2-thienyl } -1H-pyrazol-3-yl ] methyl } morpholine
PPh at 0 deg.C3(4.36g, 16.62mmol) of [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl ] was added]-2-thienyl } -1H-pyrazol-3-yl]Methanol (6.15g, 13.85mmol) in dry DCM. After 30 min NBS (2.72g, 15.28mmol) was added portionwise at 0 ℃ and the mixture was stirred at room temperature overnight. The solvent was removed in vacuo and the crude product was purified by flash chromatography (0-50% EtOAc/hexanes) to give 3-bromomethyl-1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl as a pale yellow solid]-thien-2-yl]-1H-pyrazole (3.6g, 54%).
3-bromomethyl-1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-thien-2-yl]-1H-pyrazole (51mg, 0.1mmol), K2CO3(42mg，0.3mmol)、KI(10mg)、And a mixture of morpholine (0.3mmol) in anhydrous MeCN (5mL) was stirred under nitrogen at 90 ℃ for 6 hours. 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)：8.04(m，1H)，7.82(m，1H)，7.72(m，1H)，7.57-7.43(m，5H)，7.20(d，1H)，6.75(d，1H)，6.66(s，1H)，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 in accordance with the previous examples:
1- { [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Methyl } -4-methylpiperazine, ms (es): 527[ M + H]+
1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -3- (pyrrolidin-1-ylmethyl) -1H-pyrazole, ms (es): 498[ M + H]+
2- (4- { [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Methyl } piperazin-1-yl) pyrimidine, ms (es): 591[ M + H]+
1- [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]-N- (furan-2-ylmethyl) -N-methylmethanamine, ms (es): 538[ M + H]+
1- [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]-N- (pyridin-2-ylmethyl) methylamine, ms (es): 535[ M + H]+
4- { [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Methyl } -3-oxopiperazine-1-carboxylic acid benzyl ester, ms (es): 661[ M + H]+
1- (2-chlorophenyl) -3- (1H-imidazol-1-ylmethyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazole, ms (es): 495[ M + H [ ]]+
1- [1- (2-chlorophenyl) -5- "leaf curl5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl ]-N-methyl-N- (2-thienylmethyl) methylamine, ms (es): 554[ M + H]+
3- [ { [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Methyl } (furan-2-ylmethyl) amino]Propionitrile, MS (ES): 577[ M + H ]]+
N- { [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Methyl } -2, 2, 2-trifluoro-N- (furan-2-ylmethyl) ethylamine, ms (es): 606[ M + H]+
N- { [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Methyl } -N- (furan-2-ylmethyl) propan-2-amine, ms (es): 566[ M + H]+
N- { [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Methyl } -N- (furan-2-ylmethyl) cyclopropylamine, ms (es): 564[ M + H]+
N- { [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Methyl } -N- (furan-2-ylmethyl) -2-methylpropan-2-amine, ms (es): 580[ M + H ]]+
N- { [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Methyl } -N- (furan-2-ylmethyl) cyclohexylamine, ms (es): 606[ M + H]]+
1- [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]-N- [ (3, 5-dimethylisoxazol-4-yl) methyl ]-N-methyl methylamine, ms (es): 567[ M + H ]]+
N- { [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Methyl } -N- (pyridin-4-ylmethyl) ethylamine, ms (es): 563[ M + H]+
N- { [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Methyl } -N- (pyridin-4-ylmethyl) methylamine, ms (es): 549[ M + H]+
1- [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]-N-methyl-N- (1, 3-oxazol-2-ylmethyl) methylamine, ms (es): 539[ M + H ]]+
N- { [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Methyl } -N-methyl-2-pyridin-2-ylethylamine, ms (es): 563[ M + H]+.
N- { [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Methyl } -2-methyl-N- (1-methylethyl) propan-2-amine ms (es): 542[ M + H]+.
3- [ { [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Methyl } (ethyl) amino]Propionitrile, MS (ES): 525[ M + H ]]+，
(1S) -N- { [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Methyl } -N-methyl-1-phenylethylamine, ms (es): 562[ M + H]+.
N- { [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl ]-2-thienyl } -1H-pyrazol-3-yl]Methyl } -N-methyl-2-phenylethylamine, ms (es): 562[ M + H]+.
1- { [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Methyl } -4- (phenylmethyl) piperidine; ms (es): 602[ M + H]+；
1- { [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Methyl } piperidine-2-carboxylic acid ethyl ester; ms (es): 584[ M + H ]]+；
1- { [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Methyl } -4- (phenylmethyl) piperazine; ms (es): 603[ M + H ]]+；
N- { [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Methyl } -N- (benzyl) glycine ethyl ester; ms (es): 620[ M + H ]]+；
4- [ (4- { [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Methyl } piperazin-1-yl) acetyl]Morpholine; ms (es): 640[ M + H ]]+；
2- { [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Methyl } decahydroisoquinoline; ms (es): 566[ M + H]+；
2- [3, 4-bis (methoxy) phenyl]-N- { [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Methyl } -N-methyl ethylamine; ms (es): 622[ M + H]+；
1- { [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl ]-2-thienyl } -1H-pyrazol-3-yl]Methyl } piperidine-4-carboxylic acid ethyl ester; ms (es): 584[ M + H ]]+；
4- { [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Methyl } piperazine-1-carboxylic acid ethyl ester; ms (es): 585[ M + H [ ]]+；
N- { [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Methyl } -N-propylpropan-1-amine; ms (es): 528[ M + H ]]+；
1- { [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Methyl } -3-methylpiperidine; ms (es): 526[ M + H ]]+；
4- { [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Methyl } -2, 6-dimethylmorpholine; ms (es): 542[ M + H]+；
4- { [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Methyl } piperazine-1-carboxylic acid 1, 1-dimethylethyl ester; ms (es): 613[ M + H [ ]]+；
1- { [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Methyl } -4- (2-oxo-2-pyrrolidin-1-ylethyl) piperazine; ms (es): 624[M+H]+；
N- { [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Methyl } -2- (methoxy) -N- [2- (methoxy) ethyl]Ethylamine; ms (es): 560[ M + H ] ]+；
1- { [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Methyl } -4- (3, 4-dichlorophenyl) piperazine; ms (es): 657[ M + H ]]+；
1- { [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Methyl } -4-phenylpiperazine; ms (es): 589[ M + H]+；
3- { [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Methyl } -1, 3-thiazolidine; ms (es): 516[ M + H]+；
1- [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]-N, N-bis (pyridin-2-ylmethyl) methylamine; ms (es): 626[ M + H]+；
N- { [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Methyl } -N, N' -triethylethane-1, 2-diamine; ms (es): 571[ M + H]+；
1- { [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Methyl } -4-ethylpiperazine; ms (es): 541[ M + H]+；
1- [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]-N, N-bis (phenylmethyl) methylamine; ms (es): 624[ M + H]+]+；
1- { [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Methyl } -4-pyrrolidin-1-ylpiperidine; ms (es): 581[ M + H ]+；
1- (1, 3-benzodioxol-5-ylmethyl) -4- { [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyridineAzol-3-yl]Methyl } piperazine; ms (es): 647[ M + H ]]+；
N- { [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Methyl } -N-methylhexan-1-amine; ms (es): 542[ M + H]+；
1- { [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Methyl } -3, 5-dimethylpiperidine; ms (es): 540[ M + H ]]+；
1- { [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Methyl } -2-ethylpiperidine; ms (es): 540[ M + H ]]+；
1- { [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Methyl } -2, 5-dimethylpiperazine; ms (es): 541[ M + H]+；
1- { [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Methyl } -1, 4, 5, 6-tetrahydropyrimidine; ms (es): 511[ M + H]+；
1- { [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Methyl } azepane; ms (es): 526[ M + H ]]+；
1- { [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Methyl } -4- [5- (trifluoromethyl) pyridin-2-yl ]Piperazine; ms (es): 658[ M + H ]]+；
1- { [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Methyl } -4- [3- (trifluoromethyl) phenyl]Piperazine; ms (es): 657[ M + H ]]+；
N- { [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Methyl } -N-cyclohexylcyclohexylcyclohexylamine; ms (es): 608[ M + H]+；
1- { [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Methyl } -L-proline AAn ester; ms (es): 556[ M + H]+；
1- { [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Methyl } -1, 4-diazepane; ms (es): 527[ M + H]+；
1- (2-chlorophenyl) -3- ({2- [4- (ethoxy) phenyl)]Pyrrolidin-1-yl } methyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazole; ms (es): 618[ M + H ]]+；
1- [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]-N- [ (4-fluorophenyl) methyl group]-N-methyl methylamine; ms (es): 566[ M + H]+；
N- { [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Methyl } -N-methyl-2-morpholin-4-yl-1-phenylethylamine; ms (es): 647[ M + H ]]+；
1- { [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl ]-2-thienyl } -1H-pyrazol-3-yl]Methyl } -2-phenyl azepane; ms (es): 602[ M + H]+；
1- (2-chlorophenyl) -3- { [2- (2-methylphenyl) pyrrolidin-1-yl]Methyl } -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazole; ms (es): 588[ M + H]+；
1- (2-chlorophenyl) -3- ({2- [4- (methoxy) phenyl)]Pyrrolidin-1-yl } methyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazole; ms (es): 604[ M + H]+；
1- (2-chlorophenyl) -3- { [2- (4-methylphenyl) pyrrolidin-1-yl]Methyl } -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazole; ms (es): 588[ M + H]+；
1- (2-chlorophenyl) -3- ({2- [4- (1, 1-dimethylethyl) phenyl]Pyrrolidin-1-yl } methyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazole; ms (es): 630[ M + H]+；
1- { [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) benzeneBase of]-2-thienyl } -1H-pyrazol-3-yl]Methyl } -2-pyridin-2-yl azepane; ms (es): 603[ M + H ]]+；
1- { [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Methyl } -2- (4-methylphenyl) azepane; ms (es): 616[ M + H [ ]]+；
1- { [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Methyl } -2- (4-fluorophenyl) azepane; ms (es): 620[ M + H ] ]+；
N- { [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Methyl } -N-methyl-1-phenylethylamine; ms (es): 562[ M + H]+；
1- { [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Methyl } -2- (3, 4-dichlorophenyl) azepane; ms (es): 670[ M + H]+；
1- { [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Methyl } -2- [4- (methoxy) phenyl]Azepane; ms (es): 632[ M + H ]]+；
1- (2-chlorophenyl) -3- { [2- (3-chlorophenyl) pyrrolidin-1-yl]Methyl } -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazole; ms (es): 608[ M + H]+；
3- { [2- (4-bromophenyl) pyrrolidin-1-yl]Methyl } -1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazole; ms (es): 652[ M + H]+；
1- (2-chlorophenyl) -3- ({2- [3- (methoxy) phenyl)]Pyrrolidin-1-yl } methyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazole; ms (es): 604[ M + H]+；
1- (2-chlorophenyl) -3- ({2- [2- (methoxy) phenyl)]Pyrrolidin-1-yl } methyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazole; ms (es): 604[ M + H]+；
1- { [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl ]Methyl } -2- [3- (methoxy) phenyl]Azepane; ms (es): 632[ M + H ]]+；
1- { [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Methyl } -2- (2-thienyl) azepane; ms (es): 608[ M + H]+；
1- [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]-N-methyl-N- (3-thienylmethyl) methylamine; ms (es): 554[ M + H]+；
4- ({ [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Methyl } amino) pyrimidine-2 (1H) -thione; ms (es): 554[ M + H]+；
1- [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]-N-methyl-N- [ (3-methylisoxazol-5-yl) methyl]A methylamine; ms (es): 553[ M + H]+；
N- { [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Methyl } -N-methyl-1- (2-thienyl) ethylamine; ms (es): 568[ M + H]+；
[1- { [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl ]]-2-thienyl } -1H-pyrazol-3-yl]Methyl } piperidin-3-yl) methanol; ms (es): 542[ M + H]+；
4- { [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Methyl } -3- [4- (trifluoromethyl) phenyl]Thiomorpholine; ms (es): 674[ M + H ] ]+；
1- { [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Methyl } -2- (3-methylphenyl) azepane; ms (es): 616[ M + H [ ]]+；
1- [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]-N, N-dimethylmethylamine; ms (es): 472[M+H]+；
4- { [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Methyl } piperazine-1, 3-dicarboxylic acid 1- (1, 1-dimethylethyl) 3-methyl ester; ms (es): 671[ M + H]+；
2- (4- { [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Methyl } piperazin-1-yl) -N, N-diethylethylamine; ms (es): 612[ M + H ]]+；
1- { [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Methyl } -4- (3-phenylpropyl) piperazine; ms (es): 631[ M + H ]]+；
1- [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]-N- [ (4-ethylphenyl) methyl group]-N-methyl methylamine; ms (es): 576[ M + H]+；
1- [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]-N-methyl-N- [ (4-methyl-1H-imidazol-2-yl) methyl]A methylamine; ms (es): 552[ M + H ]]+；
[ { [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl ]-2-thienyl } -1H-pyrazol-3-yl]Methyl } (methyl) amino]Acetonitrile; ms (es): 497[ M + H]+；
1- { [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Methyl } piperidine; ms (es): 512[ M + H]+；
N- { [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Methyl } -2-methyl-N- (benzyl) propan-2-amine; ms (es): 590[ M + H ]]+；
1- [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]-N- (1H-imidazol-2-ylmethyl) -N-methyl methylamine; ms (es): 538[ M + H]+；
1- [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]-N-methyl-N- [ (5-methyl-1H-pyrazol-3-yl) methyl]A methylamine; ms (es): 552[ M + H ]]+；
1- [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]-N-methyl-N- [ (4-methylphenyl) methyl group]A methylamine; ms (es): 562[ M + H]+；
1- { [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Methyl } -2- (2-methylphenyl) azepane; ms (es): 616[ M + H [ ]]+；
1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -3- ({2- [2- (trifluoromethyl) phenyl]Pyrrolidin-1-yl } methyl) -1H-pyrazole; ms (es): 642[ M + H ]+；
1- [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]-N-methyl-N- (quinolin-8-ylmethyl) methylamine; ms (es): 599[ M + H ]]+；
4- (1- { [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Methyl } pyrrolidin-2-yl) -N, N-dimethylaniline; ms (es): 617[ M + H]+；
1- [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]-N- [ (3, 5-dimethyl-1H-pyrazol-4-yl) methyl]-N-methyl methylamine; ms (es): 566[ M + H]+；
1- (1, 3-benzothiazol-2-yl) -N- { [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Methyl } -N-methyl methylamine; ms (es): 605[ M + H]+；
N-1- { [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Methyl } -N-1, N-2-trimethyl-1-phenylethane-1, 2-diamine; ms (es): 605[ M + H]+；
1- [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]-N-methyl-N- [ (2-methyl-1,3-thiazol-4-yl) methyl]A methylamine; ms (es): 569[ M + H ]]+；
1- (1-Benzothien-2-yl) -N- { [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl ]Methyl } -N-methyl methylamine; ms (es): 604[ M + H]+；
2- (1- { [1- (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-1-yl]Methyl } -1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazole; ms (es): 652[ M + H]+；
1- [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]-N-methyl-N- (quinolin-5-ylmethyl) methylamine; ms (es): 599[ M + H ]]+；
N-butyl-N- { [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Methyl } butan-1-amine; ms (es): 556[ M + H]+；
1- { [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Methyl } -4-phenylpiperidine-4-carbonitrile; ms (es): 613[ M + H [ ]]+；
2- { [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Methyl } -6, 7-bis (methoxy) -1, 2, 3, 4-tetrahydroisoquinoline; ms (es): 620[ M + H ]]+；
4- (4-chlorophenyl) -1- { [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Methyl } -1, 2, 3, 6-tetrahydropyridine; ms (es): 620[ M + H ]]+；
1- [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl ]-2-thienyl } -1H-pyrazol-3-yl]-N-methyl-N- [ (5-phenylisoxazol-3-yl) methyl]A methylamine; ms (es): 615[ M + H ]]+；
4-bromo-1- { [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Methyl } piperidine; ms (es): 590[ M + H ]]+；
N- { [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Methyl } -N-methylglycine methyl ester; ms (es): 530[ M + H]+；
1- { [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Methyl } piperidin-3-ol; ms (es): 528[ M + H ]]+；
N- { [1- (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- { [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Methyl } -3- (4-fluorophenyl) thiomorpholine; ms (es): 624[ M + H]+；
N- { [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Methyl } -N-methylpropan-2-amine; ms (es): 500[ M + H ]]+；
N- { [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Methyl } -N, N' -trimethylpropane-1, 3-diamine; ms (es): 543[ M + H ]]+；
1- { [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl ]-2-thienyl } -1H-pyrazol-3-yl]Methyl } -4- (1-methylpropyl) piperazine; ms (es): 569[ M + H ]]+；
(2R, 6S) -1- { [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Methyl } -2, 6-dimethylpiperidine; ms (es): 540[ M + H ]]+；
N- { [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Methyl } -N- (cyclopropylmethyl) propan-1-amine; ms (es): 540[ M + H ]]+；
·1-{[1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Methyl } decahydroquinoline; ms (es): 566[ M + H]+；
N- { [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Methyl } -N-ethyl ethylamine; ms (es): 500[ M + H ]]+；
4- { [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Methyl } -1, 4-diazepan-1-carboxylic acid 1, 1-dimethylethyl ester; ms (es): 627[ M + H]+；
N- { [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Methyl } -N-methyl-2, 2-bis (methoxy) ethylamine; ms (es): 546[ M + H]+；
1- { [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Methyl } piperidin-4-ol; ms (es): 528[ M + H ]]+；
[ (2S) -1- { [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl ]-2-thienyl } -1H-pyrazol-3-yl]Methyl } pyrrolidin-2-yl]Methanol; ms (es): 528[ M + H ]]+；
1- { [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Methyl } -4-methyl-1, 4-diazepane; ms (es): 541[ M + H]+；
1- { [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Methyl } -2-methylpiperazine; ms (es): 527[ M + H]+；
N- { [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Methyl } -N-ethylcyclohexylamine; ms (es): 554[ M + H]+；
N- { [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Methyl } -N ', N' -diethyl-N-methylethyl-1, 2-diamine; ms (es): 557[ M + H ]]+；
1-butyl-4- { [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Methyl } piperazine; ms (es): 569[ M + H ]]+；
N- { [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Methyl } -N, 1-dimethylpiperidin-4-amine; ms (es): 555[ M + H ]]+；
N- { [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Methyl } -N-methylpropan-1-amine; ms (es): 500[ M + H ]]+；
N- { [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl ]-2-thienyl } -1H-pyrazol-3-yl]Methyl } -N-ethylpropan-2-amine; ms (es): 514[ M + H]+；
1- { [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Methyl } -4- [2- (methoxy) ethyl]Piperazine; ms (es): 571[ M + H]+；
N- { [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Methyl } -N- (1-methylethyl) propan-2-amine; ms (es): 528[ M + H ]]+；
1- { [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Methyl } -4-methylpiperidine; ms (es): 526[ M + H ]]+；
4- { [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Methyl } thiomorpholine; ms (es): 530[ M + H]+；
2- { [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Methyl } -1, 2, 3, 4-tetrahydroisoquinoline; ms (es): 560[ M + H ]]+；
N- { [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Methyl } -N- (benzyl) propan-2-amine; ms (es): 576[ M + H]+。
Scheme 18
Figure S2006800306472D02271
As shown in scheme 18, dimethyl carbinol can be converted to the corresponding amine. Reaction of methanol 018XGU01 with sodium azide in the presence of TFA gave azide 018XGU02 in very high yield. By using PPh 3In THF-H2Treatment in O, azide 018XGU02 was reduced to amine 018XGU 03. The amine 018XGU03 was converted to 018XGU04 by alkylation of the halide or reductive amination of formaldehyde.
Example 34
Preparation of 1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl ] -2-thienyl } -3- [ 1-methyl-1-azidoethyl ] -1H-pyrazole
(Preparation of 1-(2-chlorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}-3-[1-methyl-1-(2lambda-5-triaz-1-en-2-yn-1-yl)ethyl]-1H-pyrazole)
Figure S2006800306472D02281
Adding NaN at room temperature3(200mg, 3mmol) 2- {1- (2-chlorophenyl) -5- [5- (3-methanesulfonyl-phenyl) -thiophen-2-yl was added]-1H-pyrazol-3-yl } -propan-2-ol (474mg, 1mmol) in CHCl3(9mL) in a stirred solution. The mixture was cooled to 0 ℃. To this slurry was added TFA (0.6mL, 7.8mmol) dropwise over 5 min. The reaction was allowed to warm to room temperature overnight. Mixture in NH4Aqueous OH (1N) and CHCl3Are distributed among the devices. The organic layer was washed with water and brine, then over Na2SO4Dried 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)：8.04(m，1H)，7.84-7.81(m，1H)，7.74-7.71(m，1H)，7.57-7.42(m，5H)，7.21(d，1H)，6.75(d，1H)，6.66(s，1H)，3.07(s，3H)，1.73(s，6H).MS(ES)：498[M+H]+.
Example 35
Preparation of 2- [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl ] -2-thienyl } -1H-pyrazol-3-yl ] propan-2-amine
Figure S2006800306472D02291
PPh at room temperature3(3.3g, 12.58mmol) 3- (2-azidoprop-2-yl) -1- (2-chlorophenyl) -5- (5- (3- (methylsulfonyl) phenyl) thiophen-2-yl) -1H-pyrazole) (3.08g, 6.185mmol) in THF-H 2O mixture (6: 1, 70mL), and the resulting mixture was stirred at room temperature under nitrogen for 8 days. The solvent was removed in vacuo and the residue partitioned between water and EtOAc. The phases were separated and the aqueous phase was extracted with EtOAc. The combined extracts were washed with brine, over Na2SO4Dried and evaporated in vacuo. The crude product was purified by flash chromatography (0-60% 20% MeOH in DCM) to give the title compound as a pale yellow solid (2.43g, 89%).1HNMR(CDCl3)：8.04(m，1H)，7.83-7.80(m，1H)，7.73-7.71(m，1H)，7.56-7.41(m，5H)，7.199d，1H)，6.729d，1H)，6.63(s，1H)，3.07(s，3H)，2.43(brs，2H)，1.61(s，6H).MS(ES)455(M-NH2).
Example 36
Preparation of 1- (2-chlorophenyl) -3- (1-methyl-1-pyrrolidin-1-ylethyl) -5- {5- [3- (methylsulfonyl) phenyl ] -2-thienyl } -1H-pyrazole
Figure S2006800306472D02292
2- [1- (2-chlorophenyl) phenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Propan-2-amine (142mg, 0.3mmol), K2CO3A mixture of (83mg, 0.6mmol), 1, 4-dibromobutane (0.1mL, 0.7mmol), and anhydrous EtOH was stirred in a sealed flask at 100 deg.C for 18 hours. The solvent was removed in vacuo and the residue was purified by flash chromatography (0-40% 20% MeOH/DCM) to afford the title compound as a pale yellow solid.1HNMR(CDCl3)：8.03(m，1H)，7.86-7.83(m，1H)，7.74-7.71(m，1H)，7.61-7.47(m，5H)，7.23(d，1H)，6.93(s，1H)，6.83(d，1H)，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 compounds are prepared essentially in accordance with the previous examples:
4- {1- [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]-1-methylethyl } morpholine, ms (es): 542[ M + H ]+。
Example 37
Preparation of 2- [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl ] -2-thienyl } -1H-pyrazol-3-yl ] -N, N-dimethylpropan-2-amine
Figure S2006800306472D02301
37% HCHO (80mg, 0.986mmol) was added to 2- [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Propan-2-amine (182mg, 0.3872mmol) in formic acid (2mL) and the mixture was stirred in a sealed bottle at 95 ℃ overnight. The reaction mixture was basified with aqueous NaOH (2N) and then extracted with DCM. The combined extracts were washed with brine, over Na2SO4Dried 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)：8.03(m，1H)，7.82(m，1H)，7.71(m，1H)，7.57-7.42(m，5H)，7.20(d，1H)，6.76(m，2H)，3.07(s，3H)，2.33(brs，6H)，1.57(brs，6H).
Scheme 19
Pyrazole-methyl bromide can be converted to the corresponding pyrazole-amide as depicted in scheme 19. The bromide 019XGU01 was converted to cyanide 019XGU02 by reaction with sodium hydride. This cyanide hydrolysis gives the ester 019XGU03, which is converted to the corresponding amide by treatment with an amine in the presence of the corresponding ammonium chloride.
Example 38
Preparation of [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl ] -2-thienyl } -1H-pyrazol-3-yl ] acetonitrile
Figure S2006800306472D02311
3-bromomethyl-1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl ]-thien-2-yl]A mixture of-1H-pyrazole (720mg, 1.42mmol), NaCN (250mg, 5.1mmol), and DMSO (10mL) was stirred in a sealed flask at 100 ℃ for 5H, diluted with water, and extracted with EtOAc. The combined extracts were washed with water, brine, and Na2SO4Dried 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 (350mg, 54%).1HNMR(CDCl3)：8.03(d，1H)，7.84(m，1H)，7.72(m，1H)，7.58-7.44(m，5H)，7.22(d，1H)，6.79(d，1H)，6.73(s，1H)，3.87(s，2H)，3.09(s，3H).MS(ES)：454[M+H]+.
Example 39
Preparation of methyl [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl ] -2-thienyl } -1H-pyrazol-3-yl ] acetate
Figure S2006800306472D02312
Concentrating H at 0 deg.C2SO4(4mL) [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl ] was added dropwise]-2-thienyl } -1H-pyrazol-3-yl]Acetonitrile (148mg, 0.33mmol) in MeOH-H2O mixture (10: 1, 11mL) and the resulting mixture was stirred at 90 deg.C overnight. The mixture was diluted with cold water and then Na2CO3The solid was basified and extracted with EtOAc. The combined extracts were washed with brine, over Na2SO4Dried and evaporated in vacuo. The crude product was purified by flash chromatography (0-40% 20% MeOH in DCM) to give the title compound as a white solid (131mg, 82%).1HNMR(CDCl3)：8.04(m，1H)，7.83-7.81(m，1H)，7.73-7.71(m，1H)，7.57-7.41(m，5H)，7.20(d，1H)，6.75(d，1H)，6.699s，1H)，3.829s，2H)，3.79(s，3H)，3.08(s，3H).MS(ES)：487[M+H]+.
Example 40
Preparation of 2- [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl ] -2-thienyl } -1H-pyrazol-3-yl ] -N-ethylacetamide
[1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Methyl acetate (100mg, 0.2mmol), EtNH2A mixture of (2.0M in THF, 5mL), and ethylamine hydrochloride (200mg) was stirred in a sealed flask at 70 ℃ for 8 h. The solvent was removed in vacuo and additional EtNH was added2THF (2.0M, 5mL) and the mixture stirred at 78 ℃ for an additional 24 h. Another 3mL EtNH was added2THF, the mixture is stirred at 78 ℃ for a further 20 hours. 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)：8.04(m，1H)，7.84-7.82(m，1H)，7.74-7.71(m，1H)，7.60-7.46(m，5H)，7.21(d，1H)，6.78(d，1H)，6.61(s，1H)，6.45(brs，1H)，3.69(s，2H)，3.30(q，2H)，3.07(s，3H)，1.14(t，3H).MS(ES)：500[M+H]+.
Scheme 20
The nitrile is converted to tetrazoles, esters, and amides as depicted in scheme 20. Cyanide 020XGU01 was alkylated to yield 020XGU02, which was reduced with DIBAL-H to yield the primary amine 020XGU 03. With HCO2Et formylates primary amine 020XGU03 to yield 020XGU 04. With NaN3And NH4Cyanide 020XGU01 was treated with Cl to give tetrazole 020XGU 06. Hydrolysis of 020XGU02 gave the ester 020XGU 05.
EXAMPLE 41
Preparation of 5- { [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl ] -2-thienyl } -1H-pyrazol-3-yl ] methyl } -1H-tetrazole
Figure S2006800306472D02331
[1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl ]Acetonitrile (136mg, 0.3mmol), NaN3(59mg，0.9mmol)、NH4A mixture of Cl (49mg, 0.9mmol), and anhydrous DMF (5mL) was stirred at 120 ℃ for 24 h in a sealed flask. The mixture was poured into water and extracted with DCM. The combined extracts were washed with water and brine, over Na2SO4Dried 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)：8.04(m，1H)，7.85-7.83(m，1H)，7.74-7.71(m，1H)，7.62-7.46(m，5H)，7.22(d，1H)，6.8(d，1H)，6.66(s，1H)，4.52(s，2H)，3.08(s，3H).MS(ES)：497[M+H]+.
Example 42
Preparation of 2- [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl ] -2-thienyl } -1H-pyrazol-3-yl ] -2-methylpropanenitrile and 2- [1- (2-chlorophenyl) -5- {5- [3- (ethylsulfonyl) phenyl ] -2-thienyl } -1H-pyrazol-3-yl ] -2-methylpropanenitrile
Figure S2006800306472D02332
NaH (60%, in mineral oil, 120mg, 3mmol) was added to [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl ] at 0 deg.C under nitrogen]-2-thienyl } -1H-pyrazol-3-yl]Acetonitrile (453mg, 1mmol) and MeI (160. mu.L, 2.56mmol) in dry DMF (15mL) in a stirred solution. The reaction mixture was warmed to room temperature and stirred at room temperature for 4 hours. NH for reaction mixture4Aqueous Cl was quenched and extracted with EtOAc. The combined extracts were washed with water and brine, over Na2SO4Dried and evaporated in vacuo. The crude product was first purified by flash chromatography (0-70% EtOAc/hexanes) and again by preparative HPLC (normal phase) to afford the two title compounds as white solids. (236mg, 49%). 1HNMR(CDCl3)：8.04(m，1H)，7.84-7.82(m，1H)，7.74-7.71(m，1H)，7.58-7.43(m，5H)，7.21(d，1H)，6.77(d，1H)，6.72(s，1H)，3.07(s，3H)，1.83(s，6H).MS(ES)：482[M+H]+.(227mg，46％).1HNMR(CDCl3)：8.00(m，1H)，7.80-7.78(m，1H)，7.73-7.71(m，1H)，7.57-7.45(m，5H)，7.21(d，1H)，6.76(d，1H)，6.71(s，1H)，3.13(q，2H)，1.83(s，6H)，1.30(t，3H).MS(ES)：496[M+H]+.
Example 43
Preparation of 1- [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl ] -2-thienyl } -1H-pyrazol-3-yl ] cyclopropanecarbonitrile
Figure S2006800306472D02341
1, 2-Dibromoethane (40. mu.L, 0.46mmol) was added to [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl ] at 0 deg.C]-2-thienyl } -1H-pyrazol-3-yl]To a stirred suspension of acetonitrile (68mg, 0.15mmol), benzyltriethylammonium chloride (20mg, 0.088mmol) and 50% aqueous NaOH (2mL) was stirred the resulting mixture at room temperature overnight. After dilution with water, the mixture was extracted with ether. The combined extracts were washed with brine, over Na2SO4Dried 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)：8.04(m，1H)，7.84-7.82(m，1H)，7.74-7.71(m，1H)，7.58-7.43(m，5H)，7.21(d，1H)，6.79-6.77(m，2H)，3.079s，3H)，1.73-1.68(m，4H).MS(ES)：480[M+H]+.
The following compounds are prepared essentially in accordance with the previous examples: :
1- [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Cyclopentanecarbonitrile MS (ES): 508[ M + H ]]+
Example 44
Preparation of 2- [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl ] -2-thienyl } -1H-pyrazol-3-yl ] -2-methylpropan-1-amine
Figure S2006800306472D02351
DIBAL-H (1.0M in hexane, 1.5mL, 1.5mmol) was added dropwise to 2- [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl at-78 ℃ under nitrogen ]-2-thienyl } -1H-pyrazol-3-yl]-2-Methylpropionitrile (210mg, 0.436mmol) in a stirred solution of anhydrous DCM (10mL) and the resulting mixture stirred at-78 deg.C for 3 h. 10% Rochelle's salt solution was added dropwise at-78 ℃ to quench the reaction, and the mixture was warmed to room temperature and extracted with DCM. The combined extracts were washed with brine, over Na2SO4Dried and evaporated in vacuo. The crude product was purified by flash chromatography (0-60% 20% MeOH in DCM) to give the title compound as a white solid (160mg, 76%).1HNMR(CDCl3)：8.04(m，1H)，7.83-7.80(m，1H)，7.74-7.71(m，1H)，7.57-7.42(m，5H)，7.20(d，1H)，6.71(d，1H)，6.52(s，1H0，3.07(s，3H)，2.90(s，2H)，2.17(brs，2H)，1.39(s，6H).MS(ES)：486[M+H]+.
Example 45
Preparation of N- {2- [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl ] -2-thienyl } -1H-pyrazol-3-yl ] -2-methylpropyl } carboxamide
Figure S2006800306472D02352
2- [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]-2-methylpropan-1-amine (82mg, 0.1687mmol) and HCO2A mixture of Et (1.5mL) was stirred in a sealed flask at 75 ℃ 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)：8.21(s，1H)，8.04(m，1H)，7.84-7.80(m，1H)，7.74-7.71(m，1H)，7.57-7.42(m，5H)，7.21(d，1H)，6.73(d，1H)，6.53(s，1H)，6.50(brs，1H)，3.56(d，2H)，3.07(s，3H)，1.40(s，6H).MS(ES)：514[M+H]+.
The following compounds are prepared essentially in accordance with the previous examples:
n- {1- [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl ]-2-thienyl } -1H-pyrazol-3-yl]-1-methylethyl } carboxamide, ms (es): 500[ M + H ]]+
Example 46
Preparation of 4- { [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl ] -2-thienyl } -1H-pyrazol-3-yl ] methyl } morpholine
Figure S2006800306472D02361
NaH (60%, in mineral oil, 40mg, 1mmol) was added to a stirred mixture of bromide (102mg, 0.2mmol), 4- (2-hydroxyethyl) morpholine (40. mu.L, 0.3mmol), and anhydrous DMF (10mL) at 0 ℃ under nitrogen. The mixture was stirred at room temperature overnight and the solvent was removed in vacuo. The residue was dissolved in EtOAc, washed with water and brine, over Na2SO4Dried and evaporated in vacuo. The crude product was first purified by flash chromatography (0-15% MeOH/DCM) and again by reverse phase preparative HPLC to give the title compound as a white solid (58mg, 52%).1HNMR(CDCl3)：8.04(m，1H)，7.83-7.81(m，1H)，7.74-7.72(m，1H)，7.57-7.44(m，5H)，7.21(d，1H)，6.75(d，1H)，6.71(s，1H)，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 compounds are prepared essentially in accordance with the previous examples:
n- { [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Methyl } -2-morpholin-4-ylethylamine, ms (es): 557[ M + H ]]+
Scheme 21
As shown in scheme 21, alcohol 021XG01 can be converted to the corresponding ethers and esters containing amino groups. Alcohol 021XGU01 was converted to 021XGU02 by alkylation with an alkyl halide. The ester 021XGU03 was obtained by acylation of 021XGU01 with bromoacetyl bromide. Replacement of the bromide with an amine gave 021XGU 04.
Example 47
Preparation of [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl ] -2-thienyl } -1H-pyrazol-3-yl ] methanolin-4-yl acetate
Figure S2006800306472D02372
iPr was reacted at 0 ℃ under nitrogen2Net (0.8mL, 4.6mmol) was added [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl ]]-2-thienyl } -1H-pyrazol-3-yl]To a stirred solution of methanol (450mg, 1mmol) in anhydrous DCM (10mL) was then added bromoacetyl bromide (0.2mL, 2.3mmol) and the resulting dark mixture was stirred under nitrogen at room temperature overnight. The mixture was diluted with DCM, washed with water and Na2SO4Dried and evaporated in vacuo. The residue was purified by flash chromatography (0-80% EtOAc/hexanes) to afford the ester as a pale yellow solid (465mg, 82%). Ester (114mg, 0.2mmol), K2CO3A mixture of (90mg, 0.6mmol), morpholine (0.1mL), and anhydrous MeCN (5mL) was stirred in a sealed flask at 60 deg.C 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)：8.04(m，1H)，7.83-7.81(m，1H)，7.74-7.71(m，1H)，7.58-7.44(m，5H)，7.21(d，1H)，6.76(d，1H)，6.71(s，1H)，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 compounds are prepared essentially in accordance with the previous examples:
1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Methanol (4-methylpiperazin-1-yl) acetate, ms (es): 585[ M + H [ ] ]+
Example 48
Preparation of 2- [ ({ [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl ] -2-thienyl } -1H-pyrazol-3-yl ] methyl } oxy) methyl ] pyridine
Figure S2006800306472D02381
NaH (60% in mineral oil, 90mg, 2.25mmol) was added to [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl ] at 0 deg.C under nitrogen]-2-thienyl } -1H-pyrazol-3-yl]To a stirred mixture of methanol (222mg, 0.5mmol), 2- (bromomethyl) pyridine hydrobromide (190mg, 0.75mmol), and anhydrous DMF (5mL) was stirred at room temperature for 4 h. The reaction mixture was poured into ice water and extracted with EtOAc. The combined extracts were washed with brine, over Na2SO4Dried 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)：8.58(m，1H)，8.04(m，1H)，7.82(m，1H)，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 compounds are prepared essentially in accordance with the previous examples:
1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -3- [ ({ [5- (trifluoromethyl) furan-2-yl)]Methyl } oxy) methyl]-1H-pyrazole, which is a salt of,MS(ES)：593[M+H]+
example 50
Preparation of 1- (2-chloro-phenyl) -5- [5- (3-methanesulfonyl-phenyl) -thiophen-2-yl ] -1H-pyrazole-3-carboxylic acid
Figure S2006800306472D02391
Aqueous NaOH (2N, 80mL) was added to 1- (2-chloro-phenyl) -5- [5- (3-methanesulfonyl-phenyl) -thiophen-2-yl ]-1H-pyrazole-3-carboxylic acid methyl ester (5g, 10.57mmol) in MeOH (80mL) and the resulting mixture stirred at reflux for 10H. Volatiles were removed in vacuo and the residual solution was acidified to pH2 with aqueous HCl (6N) and extracted with EtOAc. The combined extracts were washed with water and brine, over Na2SO4Dried and evaporated in vacuo. The crude product was recrystallized from DCM/hexane to give the title compound as a white solid (4.1g, 86%).1H-NMR(DMSO-d6)：δ12.73(s，1H)，7.98(m，1H)，7.83(m，2H)，7.77(m，2H)，7.71(m，1H)，7.67(d，1H)，7.62(m，2H)，7.34(s，1H)，7.19(s，1H)，3.26(s，3H).MS(ES)：459[M+H]+.
The following compounds are prepared essentially in accordance with the previous examples:
2- [1- (2-chlorophenyl) -5- {5- [3- (ethylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]-2-methylpropionic acid, ms (es): 501[ M + H [ ]]+
Scheme 21A
The benzyl pyrazole ring was synthesized as depicted in scheme 21A. Aldehyde 022XGU01 was reacted with t-butyl carbazate to give 022XGU02 which was reduced with diborane to give benzylhydrazine 022XGU 03. Treatment of benzylhydrazine with diketonate yielded pyrazole 022XGU04 in very high yield. Suzuki coupling of 022XGU04 with boronic acid gave 022XGU05 which was converted to methanol 022XGU06 by treatment with methylmagnesium chloride.
Example 51
Preparation of 2- {1- [ (2, 3-dichlorophenyl) methyl ] -5- [ 3-methyl-3' - (methylsulfonyl) biphenyl-4-yl ] -1H-pyrazol-3-yl } propan-2-ol
Figure S2006800306472D02411
Preparation of 2- {1- [ (2, 3-dichlorophenyl) methyl ] hydrazine hydrochloride Using a suitable benzylhydrazine hydrochloride prepared according to the reported procedure (Ghali, N.I., et al, J.Org.Chem.1981, 46, 5413-one 5414) in a similar manner as described in example 8 ]-5- [ 3-methyl-3' - (methylsulfonyl) biphenyl-4-yl]-1H-pyrazol-3-yl } propan-2-ol.1HNMR(CDCl3)：8.16(m，1H)，7.93(m，1H)，7.87(m，1H)，7.66(t，1H)，7.51(m，1H)，7.41-7.34(m，2H)，7.17-7.10(m，2H)，6.57(m，1H)，6.28(s，1H)，5.25(s，2H)，3.10(s，3H)，2.68(s，1H)，2.23(s，3H)，1.66(s，6H).MS(ES)：529[M+H]+，511(M-OH)
The following compounds are prepared essentially in accordance with the previous examples:
2- {1- [ (2, 3-dichlorophenyl) methyl group]-5- [ 3' - (methylsulfonyl) biphenyl-4-yl]-1H-pyrazol-3-yl } propan-2-ol, ms (es): 515[ M + H]+，497(M-OH)
2- {5- [ 3-chloro-3' - (methylsulfonyl) biphenyl-4-yl]-1- [ (2, 3-dichlorophenyl) methyl group]-1H-pyrazol-3-yl } propan-2-ol, ms (es): 549[ M + H]+，531(M-OH)
2- {1- [ (4-chlorophenyl) methyl group]-5- [ 3-methyl-3' - (methylsulfonyl) biphenyl-4-yl]-1H-pyrazol-3-yl } propan-2-ol, ms (es): 495[ M + H [ ]]+，
5- (5- {1- [ (2, 4-difluorophenyl) methyl group]-3- (trifluoromethyl) -1H-pyrazol-5-yl } -2-thienyl) -3-methyl-2- (methylsulfonyl) pyridine; 514.2[ M + H]+
Scheme 21B
Figure S2006800306472D02421
Pyrazoles can be prepared via enamine intermediates as shown in scheme 21B. Most aryl-methyl-ketones will react with reagents such as Bredereck's reagent or N, M dimethylformamide diethylacetal to form enamines. Under mild conditions, these enamines react with arylhydrazines to regioselectively form a single pyrazole isomer.
Example 52
Preparation of 1- (2, 5-dichloro-phenyl) -5- [5- (3-methanesulfonyl-phenyl) -thiophen-2-yl ] -1H-pyrazole
1.34g of 1- [5- (3-methanesulfonyl-phenyl) -thiophen-2-yl are weighed]-ethanone, 13mL DMF, and 988L (1.2 eq) of N, N-dimethylformamide diethylacetal, added to a 100mL flask. The reaction was heated at-80 ℃ for 18 hours and then washed into a separatory funnel with ethyl acetate and water. The resulting precipitate was collected by filtration and dried under high vacuum to give the enamine product as a yellow powder, yield: 1.27g (79%).1H NMR(400MHz，DMSO-d6)：δ8.30(s，1H)，8.17(d，J＝8Hz，1H)，7.99(d，J＝8Hz，1H)，7.94(d，J＝4Hz，1H)，7.75-7.85(m，3H)，5.93(d，J＝12Hz，1H)，3.43(s，3H)，3.41(s，3H)，3.04(s，3H).
Weighing 105.7mg of enamine, 97.0mg of 2, 5-dichlorophenylhydrazine hydrochloride, 1mL DMF, and 1mL acetic acid were added to a 50mL flask. The resulting solution was heated at 95-100 ℃ for 20 hours, then washed into a separatory funnel with ethyl acetate and water. The ethyl acetate was separated, washed with brine and dried (MgSO)4) And concentrated in vacuo. The residue was purified by flash chromatography on silica gel (Jones Flashmaster, 20g SiO2Gradient from 20% ethyl acetate to 50% ethyl acetate-hexanes over 30 min). The appropriate fractions were combined and concentrated in vacuo to give the product as a colorless powder, yield: 115mg (81%).1H-NMR(400MHz，CDCl3)：δ8.07(1H，m)，7.84(1H，m)，7.78(1H，d)，7.75(1H，m)，7.60-7.53(2H，m)，7.49-7.46(2H，m)，7.24(1H，d)，6.79(1H，d)，6.67(1H，d)，3.08(3H，s).MS(ES)：451[M+H]+.
Example 53
Preparation of 4- {5- [1- (2, 5-dichlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl ] -2-thienyl } -2- (methylsulfonyl) benzoic acid
Figure S2006800306472D02431
a)EDCI、DMAP、EtOH、CH2Cl2，45℃；b)NaSMe、THF，80℃；c)MCPBA、CH2Cl2At 25 ℃; d) bis (pinacolato) diboron, pd (dppf), KOAc, DMSO, 85 ℃; e) (Ph) 3P)4Pd, v wherein R1＝2，5-Cl、Na2CO3THF-water, 80 ℃; f) LiOH, THF-MeOH-H2O, 25 ℃. 24.66g (113mmol) of acid, 26.5g (138mmol) of EDCI, 1.7g of DMAP, 425mL of dichloromethane, and 25mL of ethanol were weighed into a 1L flask. The resulting solution was heated at 40-45 ℃ for 24 hours and then concentrated in vacuo to remove the dichloromethane. The residue was washed into a separatory funnel with ethyl acetate and 1M HCl. The ethyl acetate was separated, washed with brine and dried (Na)2SO4) And concentrated in vacuo. The intermediate 4-bromo-2-fluoro-ethyl benzoate was recovered as a colorless oil, yield: 24.99g (89.8%).
The ester was treated with 12.2g of sodium thiomethoxide and 200mL of THF, and the resulting suspension was heated at 80-85 ℃ for 5 hours. The reaction was then concentrated to remove THF and washed into a separatory funnel with ethyl acetate and 1 MHCl. The ethyl acetate was separated, washed with brine and dried (Na)2SO4) And vacuum concentrated to yield the intermediate 4-bromo-2-methylsulfanyl-ethyl benzoate as a pale gray solid: 27.5g (99%).1H NMR(400MHz，CDCl3)：δ7.86(d，J＝8Hz，1H)，7.36(s，1H)，7.28(d，J＝8Hz，1H)，4.38(q，J＝7Hz，2H)，2.45(s，3H)，1.39(t，J＝7Hz，3H)。
15.0g 4-bromo-2-methylsulfanyl-benzoic acid ethyl ester (54.5mmol), 200mL dichloromethane and 28.0g MCPBA (77% max., Aldrich) were weighed and added portionwise to a 1L flask at room temperature. The resulting suspension was stirred at room temperature for 3 days, then concentrated in vacuo to remove the dichloromethane. The residue was washed into a separatory funnel with ethyl acetate and 1.0M NaOH. The ethyl acetate was separated, washed with brine and dried (Na) 2SO4) And concentrated in vacuo. Recovering the intermediate 4-bromo-2-methanesulfonyl-benzoic acid ethyl ester into colorless oil, standing for crystallization, and obtaining the yield: 16.3g (97%).1HNMR(400MHz，CDCl3)：δ8.27(s，1H)，7.82(d，J＝8Hz，1H)，7.60(d，J＝8Hz，1H)，4.44(q，J＝7Hz，2H)，3.38(s，3H)，1.41(t，J＝7Hz，3H).
Weighing 4-bromo-2-methanesulfonyl-benzoic acid ethyl ester (16.3g, 53mmol), 21g bis (pinacolyl) diboron, 19g potassium acetate, 5g [1, 1' -bis (diphenylphosphino) ferrocene]Palladium (II) dichloride dichloromethane adduct, and 150mL DMSO were added to the flask. The resulting suspension was heated at 80-85 ℃ for 20 h, then diluted with 200mL of water, 200mL of ethyl acetate and the reaction mixture was filtered through celite (celite) to remove solids. The filtrate was transferred to a separatory funnel, and the aqueous phase was separated and washed with ethyl acetate. The combined ethyl acetate washes were washed with brine and dried (Na)2SO4) And concentrated in vacuo. The residue was purified by flash chromatography on silica gel (Biotage, 65X 200 mmSiO)2Gradient eluent is 100 percentHexane to 40% ethyl acetate over 1 hour). The appropriate fractions were combined and concentrated in vacuo to give 2-methanesulfonyl-4- (4, 4, 5, 5-tetramethyl- [1, 3, 2 ] as a colorless solid]Dioxapentaborane-2-yl) -benzoic acid ethyl ester, yield: 12.65g (67%).1H-NMR(400MHz，CDCl3)：δ8.52(s，1H)，8.08(d，J＝8Hz，1H)，7.65(d，J＝8Hz，1H)，4.45(q，J＝7Hz，2H)，3.33(s，3H)，1.42(t，J＝7Hz，3H)，1.35(s，12H).
865mg (1.96mmol) of bromide v (wherein R is12, 5-Cl), 693.5mg (1.96mmol) of borate, and 20mL of THF were added to a 100mL flask. The resulting solution was heated at 80-85 deg.C, 250mg of tetrakistriphenylphosphine palladium (0) was added, followed by 2.0mL of 1.0M Na 2CO3. The reaction was held at 80-85 ℃ for 3 hours and then the reaction was concentrated to remove THF. The residue was washed into a separatory funnel with ethyl acetate and 1.0M sodium carbonate. The ethyl acetate was separated, washed with brine and dried (Na)2SO4) And concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (Jones Flashmaster, 50g SiO2Gradient eluent from 100% hexane to 40% ethyl acetate over 30 min). The appropriate fractions were combined and concentrated in vacuo to give 4- {5- [1- (2, 5-dichlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl as an intermediate as a colorless powder]-2-thienyl } -2 (methanesulfonyl) benzoic acid ethyl ester, yield: 256.4mg (22.2%); ms (es): 589 and 591[ each M + H]+.
120.2mg of the ester, 1mL of THF, and 1mL of methanol were weighed into a 50mL flask.
To this solution was added 204. mu.L of a 3.0M LiOH solution. The reaction was stirred at room temperature for 3 hours, then rinsed into a separatory funnel with ethyl acetate and 1M HCl. The ethyl acetate was separated, washed with brine and dried (Na)2SO4) And concentrated in vacuo. The crude acid was purified by reverse phase HPLC to give 4- {5- [1- (2, 5-dichlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl as a colorless powder]-2-thienyl } -2- (methylsulfonyl) benzoic acid, yield 43.0mg (38%); 1H-NMR(400MHz，DMSO-d6)：δ8.20(s，1H)，8.09(s，1H)，7.98(d，J＝8Hz，1H)，7.86(m，2H)，7.81(d，J＝8Hz，1H)，7.74(d，J＝4Hz，1H)，7.58(s，1H)，7.32(d，J＝4Hz，1H)，3.46(s，3H)；MS(ES)：561and 563[M+H]+.
The following compounds are prepared essentially in accordance with the previous examples:
3- {5- [5- (3-methanesulfonyl-phenyl) -thiophen-2-yl]-3-trifluoromethyl-pyrazol-1-yl } -thiophene-2-carboxylic acid.1H-NMR(400MHz，CDCl3)：δ8.05(1H，m)，7.88-7.81(1H，m)，7.77-7.69(2H，m)，7.57(1H，m)，7.26-7.22(2H，m)，6.89(1H，d)，6.86(1H，s)，3.08(3H，s).MS(ES)：499[M+H]+.
2- (3- {5- [1- (2, 5-dichlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl)]-2-thienyl } phenyl) -2-methylpropionic acid.1H-NMR(400MHz，CDCl3)：δ7.59(1H，d)，7.53(1H，m)，7.51-7.43(2H，m)，7.42-7.32(3H，m)，7.14(1H，d)，6.87(1H，s)，6.80(1H，d)，1.62(6H，s).MS(ES)：525[M+H]+.
3- {5- [1- (2, 5-dichlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]-2-thienyl } -5- (methylsulfonyl) benzoic acid ethyl ester; ms (es): 589 and 591[ each M + H]+.
Example 54
Preparation of 1- [ 5-chloro-2- (4-fluoro-phenoxy) -phenyl ] -5- [5- (3-methanesulfonyl-phenyl) -thiophen-2-yl ] -3-trifluoromethyl-1H-pyrazole
Figure S2006800306472D02451
a) 4-fluoro-phenylboronic acid, Cu (OAc)2、i(Pr)2EtN、CH2Cl2，25℃。
Preparation of 4-chloro-2- {5- [5- (3-methanesulfonyl-phenyl) -thiophen-2-yl ] as described in example 1]-3-trifluoromethyl-pyri-dineOxazol-1-yl } -phenol. 194mg (388. mu. mol) phenol, 159mg copper (II) acetate, 113.8mg 4-fluoroboric acid, 50mg activated 4. ANGSTROM molecular sieve, 4mL methylene chloride, and 500. mu.L diisopropylethylamine were weighed into a 50mL flask. The resulting suspension was stirred at room temperature for 21 hours, then poured into a separatory funnel with ethyl acetate and 1M NaOH. The ethyl acetate was separated, washed with brine and dried (Na)2SO4) And concentrated in vacuo. The residue was purified by flash chromatography on silica gel (Jones Flashmaster, 50g SiO 2Gradient eluent 100% hexane to 40% ethyl acetate). The appropriate fractions were combined and concentrated in vacuo to afford a colorless solid, yield: 89mg (39%).1H-NMR(400MHz，CDCl3)：δ8.09(s，1H)，7.88(d，J＝8Hz，1H)，7.76(d，J＝8Hz，1H)，7.66(d，J＝4Hz，1H)，7.61(t，J＝8Hz，1H)，7.40(d，J＝8Hz，1H)，7.30(d，J＝4Hz，1H)，6.90(m，2H)，6.79(d，J＝9Hz，2H)，6.64(m，2H)，3.10(s，3H)；MS(ES)：593[M+H]+.
Example 55
Preparation of 3- {5- [1- (2, 5-dichlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl ] -2-thienyl } benzenesulfonamide
Figure S2006800306472D02461
a) Bis (pinacolato) diboron, pd (dppf), KOAc, DMSO, 85 ℃; b) (Ph)3P)4Pd, 3-bromo-benzenesulfonamide, Na2CO3THF-water, 80 ℃.
Weigh 4.43g (10.0mmol) of bromide, 3.14g of bis (pinacolyl) diboron, 3.12g of potassium acetate, 29mL of DMSO, and 516mg of [1, 1' -bis (diphenylphosphino) ferrocene]Palladium (II) dichloride dichloromethane adduct was charged to a 100mL flask. The resulting suspension was heated at 100 ℃ for 18 hours and then washed into a separatory funnel with ethyl acetate and water. The ethyl acetate was separated, washed with water, brine and dried (MgSO)4) And concentrated in vacuo. Residue ofThe material was purified by flash chromatography on silica gel (Jones Flashmaster, two 70g columns, gradient eluent 100% hexane to 20% ethyl acetate over 40 min). The appropriate fractions were combined and concentrated in vacuo to give the product as an off-white solid mixture of boric acid and borate, yield: 1.8g (. about.35%).
Crude borate (601mg) and 312mg of 3-bromosulfonamide were weighed into a 50mL flask along with 10mL of THF. The resulting solution was heated at 80-85 deg.C, 50mg of tetrakistriphenylphosphine palladium (0) was added, followed by 1.0mL of 1.0M sodium carbonate. The reaction was held at 80-85 ℃ for three hours, then cooled and concentrated in vacuo. The residue was washed into a separatory funnel with ethyl acetate and 1.0M sodium carbonate. The ethyl acetate was separated, washed with brine and dried (MgSO) 4) And concentrated in vacuo. The product was purified by flash chromatography on silica gel (Jones Flashmaster, 70g SiO2Gradient eluent 100% hexane to 40% ethyl acetate over 30 min). The appropriate fractions were combined and concentrated in vacuo to give the product as a pale yellow powder, yield: 75mg (11%).1H-NMR(400MHz，CDCl3)：δ8.07(1H，m)，7.84(1H，m)，7.68(1H，m)，7.59(1H，m)，7.56-7.45(3H，m)，7.22(1H，d)，6.88(1H，s)，6.85(1H，d)，4.98(2H，s).MS(ES)：518[M+H]+.
Example 56
Preparation of N- [ (3- {5- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl ] -2-thienyl } phenyl) sulfonyl ] acetamide
Preparation of 3- {5- [2- (2-chloro-phenyl) -5-trifluoromethyl-2H-pyrazol-3-yl ] as described in example 1]-thiophen-2-yl } -benzenesulfonamide. 209.6mg (433. mu. mol) of sulfonamide and 866. mu.L of 1.0M lithium bis (trimethylsilyl) amide were weighed into a 250mL flask. To the solution was added 123. mu.L of acetic anhydride. The reaction was stirred at room temperature for 1 hour, then flushed with 1.0M HCl and ethyl acetateWashed into a separatory funnel. The ethyl acetate was separated, washed with brine and dried (Na)2SO4) And concentrated in vacuo. The crude product was subjected to reverse phase HPLC to give the product as a colorless powder, yield: 47.0mg (20%);1H NMR(400MHz，CDCl3)：δ8.16(s，1H)，7.91(d，J＝8Hz，1H)，7.66(d，J＝8Hz，1H)，7.4-7.6(m，5H)，7.21(d，J＝4Hz，1H)，6.89(s，1H)，6.79(d，J＝4Hz，1H)，2.04(s，3H)；MS(ES)：526[M+H]+.
the following compounds are prepared essentially according to the previous examples by replacing the appropriate anhydride:
n- [ (3- {5- [1- (2, 5-dichlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl)]-2-thienyl } phenyl) sulfonyl ]-2, 2-dimethylpropionamide; ms (es): 602 and 604[ eachM + H]+.
Example 57
Preparation of 2- [4- {5- [1- (2, 5-dichlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl ] -2-thienyl } -2- (methylsulfonyl) phenyl ] propan-2-ol and [4- {5- [1- (2, 5-dichlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl ] -2-thienyl } -2- (methylsulfonyl) phenyl ] methanol.
Figure S2006800306472D02481
a)MeMgBr、THF，0-25℃。
Preparation of 4- {5- [1- (2, 5-dichlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl ] as described in example 53]-2-thienyl } -2 (methylsulfonyl) benzoic acid ethyl ester. 209.4mg of the ester and 2.0mL of anhydrous THF were weighed and charged to a 50mL flask. The solution was cooled in an ice bath under nitrogen and 1.0mL of 1.4M MeMgBr/THF (Aldrich) was added. The reaction was removed from the cold water bath and stirred at room temperature for 1 hour, then 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 and dried (Na)2SO4) And concentrated in vacuo. The residue was purified by flash chromatography on silica gel (Biotage, 25X 150mm SiO)2Gradient eluent 100% hexane to 100% ethyl acetate over 45 minutes). The appropriate fractions were combined and concentrated in vacuo to give a cream colored semi-solid product, yield: 157.1mg (77%); 1H NMR(400MHz，CDCl3): δ 8.34(s, 1H), 7.65(d, J ═ 8Hz, 1H), 7.59(s, 1H), 7.45-7.53(m, 3H), 7.26(d, J ═ 4Hz, 1H), 6.89(s, 1H), 6.85(d, J ═ 4Hz, 1H), 4.82(br s, 1H), 3.43(s, 3H), 1.71(s, 6H); ms (es): 575 and 577[ each M + H]+.
The following compounds are prepared essentially in accordance with the previous example substituting 3-bromo-5-fluoro-benzoic acid for 4-bromo-2-fluoro-benzoic acid:
2- [3- {5- [1- (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- [1- (2, 6-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- [1- (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- [1- (2, 5-dichlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl ] -2-thienyl } -2- (methylsulfonyl) phenyl ] methanol
Figure S2006800306472D02491
a)LiBH4、THF，25℃。
102.0mg of the ester and 1.0mL of anhydrous THF were weighed into a 4mL bottle. The resulting solution was in an ice bathCooled and 200 μ L2.0M LiBH added4THF (Aldrich). The reaction was warmed to room temperature and held for 3 days. The reaction was then washed into a separatory funnel with ethyl acetate and 1M HCl. The ethyl acetate was separated, washed with brine and dried (Na) 2SO4) And concentrated in vacuo. The crude product was purified by reverse phase HPLC to give the product as a colorless solid, yield: 14.0mg (15%);1H NMR(400MHz，CDCl3): δ 8.17(s, 1H), 7.72(d, J ═ 8Hz, 1H), 7.5-7.6(m, 2H), 7.50(m, 2H), 7.26(s, 1H), 6.89(s, 1H), 6.85(d, J ═ 4Hz, 1H), 4.96(s, 2H), 3.20(s, 3H); ms (es): 547 and 549[ each M + H]+.
Example 59
Preparation of 4- (2- { [4- {5- [1- (2, 5-dichlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl ] -2-thienyl } -2- (methylsulfonyl) phenyl ] oxy } ethyl) morpholine
Figure S2006800306472D02492
a)NaHCO3、Na2SO3、H2O, 85 ℃ then Me2SO2、NaHCO3、H2O, 120 ℃; b) bis (pinacolato) diboron, pd (dppf), KOAc, DMSO, 100 ℃; c) (Ph)3P)4Pd, 5- (5-bromothiophen-2-yl) -1- (2, 5-dichlorophenyl) -3-trifluoromethyl-1H-pyrazole, Na2CO3THF-water, 80 ℃; d) BBr3、CH2Cl2、25℃；K2CO34- (2-chloroethyl) morpholine hydrochloride, DMF at 100 ℃.
41.4g of sodium sulfite, 29g of sodium bicarbonate, and 175mL of water were weighed and charged into a 1L flask. The suspension was stirred at 80-85 ℃ and sulfonyl chloride (50g) was added portionwise over 3 hours. Heating was continued for 3 hours, and then the reaction was allowed to stand at room temperature for 3 days. The intermediate sulfinate was collected by filtration, added with water, and then dried under high vacuum. Dried solid (45g) with 28.0g sodium bicarbonate 25mL of dimethyl sulfate, and 63.75mL of water were transferred to a 1L flask. The resulting suspension was heated at 120-125 ℃ for 20 hours, where it became a solution, then cooled and washed into a separatory funnel with ethyl acetate and water. The ethyl acetate was separated, washed with brine and dried (Na)2SO4) And concentrated in vacuo. The product was precipitated from dichloromethane with hexane and dried under high vacuum to give the intermediate 4-bromo-2-methanesulfonyl-1-methoxy-benzene as a colorless powder in yield: 31.1g (67%).1H NMR(400MHz，CDCl3)：δ8.08(2，1H)，7.69(d，J＝8Hz，1H)，6.96(d，J＝8Hz，1H)，4.00(s，3H)，3.21(s，3H).
15.48g (58.4mmol) of bromide, 23g of borate, 21g of potassium acetate, 5g of [1, 1' -bis (diphenylphosphino) ferrocene]Palladium (II) dichloride dichloromethane adduct and 150mL ldmso were charged to a 500mL flask. The resulting suspension was heated at-100 ℃ for 20 hours, then cooled and diluted with 200mL ethyl acetate and 200mL 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 combined ethyl acetate washes were washed with brine and dried (Na)2SO4) And concentrated in vacuo. The residue was purified by flash chromatography on silica gel (Biotage, 65X 200mm SiO)2Gradient eluent 100% hexane to 100% ethyl acetate over 1 hour). The appropriate fractions were combined and concentrated in vacuo. The partially purified product was dissolved in ethyl acetate and precipitated with hexane. Intermediate 2- (3-methanesulfonyl-4-methoxy-phenyl) -4, 4, 5, 5-tetramethyl- [1, 3, 2 ]Dioxaborolan was recovered to give a pale yellow powder, yield: 12.56g (77%).1H NMR(400MHz，CDCl3)：δ8.43(s，1H)，8.01(d，J＝8Hz，1H)，7.03(d，J＝8Hz，1H)，4.02(s，3H)，3.20(s，3H)，1.33(s，12H).
5.0g (11.3mmol) of 5- (5-bromothien-2-yl) -1- (2, 5-dichlorophenyl) -3-trifluoromethyl-1H-pyrazole, (4.43g (14.2mmol) of borate, and 100mL of THF were weighed into a 250mL flask, the resulting solution was heated at 80-85 deg.C, and 1g of tetrakistriphenylphosphine palladium (0) was added, followed by 10mL of 1.0M Na2CO3. The reaction was held at 80-85 ℃ for 3 hours and then concentrated to remove THF. The residue was washed into a separatory funnel with ethyl acetate and 1.0M sodium carbonate. The ethyl acetate was separated, washed with brine and dried (Na)2SO4) And concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (Biotage, 65X 200mm SiO)2Gradient eluent 100% hexane to 60% ethyl acetate over 1 hour). The appropriate fractions were combined and concentrated in vacuo to afford the intermediate methoxy compound as a yellow solid, yield: 2.75g (44%).
2.60g (4.75mmol) of the above methoxy compound and 75mL of methylene chloride were weighed and charged into a 250mL flask. The resulting solution was cooled to-70 ℃ and 14mL of 1.0MBBr was added3Dichloromethane. The reaction was warmed to room temperature and held at this temperature for 4 hours. The reaction was then quenched by addition of methanol and concentrated in vacuo. The residue was washed into a separatory funnel with ethyl acetate and 1M HCl. The ethyl acetate was separated, washed with brine and dried (Na) 2SO4) And concentrated in vacuo. The residue was purified by flash chromatography on silica gel (Biotage, 40X 150mm SiO)2Gradient eluent 100% hexane to 60% ethyl acetate over 1 hour). The appropriate fractions were combined and concentrated in vacuo to give 4- {5- [1- (2, 5-dichlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl as an intermediate as a colorless solid]-2-thienyl } -2- (methylsulfonyl) phenol, yield: 1.39g (54.9%); ms (es): 533 and 535[ each M + H]+。
249.2mg (467mmol) of phenol, 263mg of potassium carbonate, 368mg (1.98mmol) of 4- (2-chloroethyl) morpholine hydrochloride, and 3mL of DMF were weighed into a 50mL flask. The resulting suspension was heated at 100 ℃ and 105 ℃ for 30 minutes and then washed into a separatory funnel with ethyl acetate and 1.0M sodium carbonate. The ethyl acetate was separated, washed with brine and dried (Na)2SO4) And concentrated in vacuo. The residue was purified by flash chromatography on silica gel (Biotage, 25X 150mm SiO)2Gradient eluent of 100% dichloromethane to 89: 10: 1 dichloromethane-methanol-ammonium hydroxide over 45 minutes). The appropriate fractions were combined and concentrated in vacuo, then dissolved in dichloromethane and evaporatedThe product was precipitated by adding hexane. The precipitate was collected by filtration and dried to give the product as an off-white solid, yield: 78mg (26%). 1H NMR(400MHz，CDCl3): δ 8.11(s, 1H), 7.67(d, J ═ 8Hz, 1H), 7.59(s, 1H), 7.49(m, 2H), 7.12(d, J ═ 4Hz, 1H), 7.04(d, J ═ 8Hz, 1H), 6.86(s, 1H), 6.81(d, J ═ 4Hz, 1H), 4.26(t, J ═ 5Hz, 2H), 3.70(t, J ═ 5Hz, 4H), 3.33(s, 3H), 2.87(t, J ═ 5Hz, 2H), 2.58(t, J ═ 5Hz, 4H); ms (es): 646 and 648[ each M + H]+.
The following compounds are prepared essentially in accordance with the previous examples by replacing 4- (2-chloroethyl) morpholine hydrochloride with an alkyl halide:
5- (2- { [4- {5- [1- (2, 5-dichlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]-2-thienyl } -2- (methylsulfonyl) phenyl]Oxy } ethyl) -1H-tetrazole; ms (es): 629 and 631[ each M + H]+.
2- { [4- {5- [1- (2, 5-dichlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]-2-thienyl } -2- (methylsulfonyl) phenyl]Oxy } ethanol; ms (es): 577 and 579[ eachM + H ]]+.
Scheme 22
Figure S2006800306472D02521
Another method of making an embodiment of the present invention is shown in example 60. Directly condensing with hydrazine 4, 4, 4-trifluoro-1- [5- (3-methanesulfonyl-phenyl) -thiophen-2-yl ] -butane-1, 3-dione to form pyrazole 3- [5- (3-methanesulfonyl-phenyl) -thiophen-2-yl ] -5-trifluoromethyl-1H-pyrazole. Alkylation of pyrazoles such as 3- [5- (3-methanesulfonyl-phenyl) -thiophen-2-yl ] -5-trifluoromethyl-1H-pyrazole will yield a mixture of positional isomers, which can be isolated by one skilled in the art.
Example 60
Preparation of 1- [ (5-chloro-2-thienyl) methyl ] -3- {5- [3- (methylsulfonyl) phenyl ] -2-thienyl } -5- (trifluoromethyl) -1H-pyrazole
Figure S2006800306472D02522
Weighing 5.18g (13.8mmol)4, 4, 4-trifluoro-1- [5- (3-methanesulfonyl-phenyl) -thiophen-2-yl]Butane-1, 3-dione, 50mL of toluene, and 450. mu.L (14.3mmol) of hydrazine were charged to a 100mL flask. The resulting solution was heated at 100 ℃ for 21 hours. The reaction was then concentrated in vacuo and partially purified by flash chromatography on silica gel (Jones Flashmaster, 70g SiO)2Gradient eluent was 100% hexane to 20% ethyl acetate over 30 min. The appropriate fractions were combined, concentrated in vacuo, and precipitated from ethyl acetate with hexane to give 3- [5- (3-methanesulfonyl-phenyl) -thiophen-2-yl as an intermediate as a pale yellow semi-crystalline solid]-5-trifluoromethyl-1H-pyrazole, yield 1.24g (24%).1H NMR(400MHz，CDCl3)：δ8.15(s，1H)，7.86(d，J＝8Hz，2H)，7.62(t，J＝8Hz，1H)，7.45(d，J＝4Hz，1H)，7.39(d，J＝4Hz，1H)，6.70(s，1H)，3.12(s，3H)；MS(ES)：373[M+H]+.
96.6mg (259. mu. mol) of pyrazole, 93.5mg of potassium carbonate, 1mL of DMF, and 35.6. mu.L of 2-chloro-5-chloromethylthiophene were weighed into an 8mL bottle. The reaction was heated at 80-85 ℃ for 3 hours, then rinsed into a separatory funnel with ethyl acetate and water. Separating ethyl acetate, drying (MgSO)4) And concentrated in vacuo. HPLC analysis showed the product to be a 1: 1 mixture of isomers. Each product was purified by reverse phase HPLC to give a colorless waxy product.
1- [ (5-chloro-2-thienyl) methyl group]-3- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -5- (trifluoromethyl) -1H-pyrazole:1H NMR(400MHz，CDCl3)：δ8.19(s，1H)，7.86(m，2H)，7.60(t，J＝8Hz，1H)，7.39(d，J＝4Hz，1H)，7.34(d，J＝4Hz，1H)，6.86(m，2H)，6.78(d，J＝4Hz，1H)，5.47(s，2H)，3.11(s，3H)；MS(ES)：503[M+H]+.
1- [ (5-chloro-2-thienyl) methyl group]-5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -3- (trifluoromethyl) -1H-pyrazole:1H NMR(400MHz，CDCl3)：δ8.18(s，1H)，7.88(m，2H)，7.64(t，J＝8Hz，1H)，7.44(d，J＝4Hz，1H)，7.17(d，J＝4Hz，1H)，6.75(d，J＝4Hz，1H)，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 replacing 2-chloro-5-chloromethylthiophene with the appropriate reagents:
3- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1- (2-thienylcarbonyl) -5- (trifluoromethyl) -1H-pyrazole;1H-NMR(400MHz，CDCl3)：δ8.43(0.5H，dd，J＝1，4Hz)，8.33(0.5H，dd，J＝1，4Hz)，8.23(0.5H，t，J＝1Hz)，8.18(0.5H，t，J＝1Hz)，7.86-7.96(m，3H)，7.63(1H，q，J＝8Hz)，7.49(1H，m)，7.44(0.5H，d，J＝4Hz)，7.40(0.5H，d，J＝4Hz)，7.21-7.28(1H，m)，7.20(0.5H，s)，6.89(0.5H，s)，3.13(1.5H，s)，3.11(1.5H，s)；MS(ES)：483[M+H]+.
5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1- (2-thienylcarbonyl) -3- (trifluoromethyl) -1H-pyrazole;1H-NMR(400MHz，CDCl3)：δ8.43(0.5H，dd，J＝1，4Hz)，8.33(0.5H，dd，J＝1，4Hz)，8.23(0.5H，t，J＝1Hz)，8.18(0.5H，t，J＝1Hz)，7.86-7.96(m，3H)，7.63(1H，q，J＝8Hz)，7.49(1H，m)，7.44(0.5H，d，J＝4Hz)，7.40(0.5H，d，J＝4Hz)，7.21-7.28(1H，m)，7.20(0.5H，s)，6.89(0.5H，s)，3.13(1.5H，s)，3.11(1.5H，s)；MS(ES)：483[M+H]+.
5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1- (benzenesulfonyl) -3- (trifluoromethyl) -1H-pyrazole;1H-NMR(400MHz，CDCl3)：δ8.18(1H，m)，7.96-7.81(4H，m)，7.74-7.60(2H，m)，7.58-7.48(2H，m)，7.45(1H，d)，7.40(1H，d)，6.67(1H，s)，3.13(3H，s).MS(ES)：513[M+H]+.
3- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1- (benzenesulfonyl) -5- (trifluoromethyl) -1H-pyrazole;1H-NMR(400MHz，CDCl3)：δ8.18(1H，s)，8.14(2H，d，J＝8Hz)，7.88(2H，d，J＝8Hz)，7.60(4H，m)，7.38(2H，m)，7.00(1H，s)，3.11(3H，s)；MS(ES)：513[M+H]+.
1- [ (2, 4-difluorophenyl) methyl group]-5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -3- (trifluoromethyl) -1H-pyrazole;1H-NMR(400MHz，CDCl3)：δ8.14(1H，m)，7.89(1H，m)，7.83(1H，m)，7.63(1H，t)，7.39(1H，d)，7.06(1H，d)，6.95(1H，m)，6.89-6.79(2H，m)，6.74(1H，s)，5.54(2H，s)，3.11(3H，s).MS(ES)：499[M+H]+.
1- [ (2, 4-difluorophenyl) methyl group]-3- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -5- (trifluoromethyl) -1H-pyrazole;1H-NMR(400MHz，CDCl3)：δ8.18(1H，m)，7.91-7.81(2H，m)，7.60(1H，t)，7.39(1H，d)，7.34(1H，d)，7.10(1H，m)，6.92-6.79(3H，m)，5.48(2H，s)，3.10(3H，s).MS(ES)：499[M+H]+.
scheme 23
Figure S2006800306472D02541
Other embodiments of the invention were prepared by a combination of different routes, as shown in scheme 23. In analogy to example 60, 1- (5-bromothien-2-yl) -4, 4, 4-trifluoro-butane-1, 3-dione can be condensed directly with hydrazine to form pyrazole. As in example 60, acylation or alkylation can produce a mixture of isomers which can be separated at the bromide stage or after aryl coupling.
Example 61
Preparation of [3- (5- {1- [ (2, 4-difluorophenyl) methyl ] -3- (trifluoromethyl) -1H-pyrazol-5-yl } -2-thienyl) phenyl ] acetic acid
Figure S2006800306472D02551
5.00g (23.2mmol) of (3-bromophenyl) acetic acid, 50mL of methanol, and 50mL of 4.0M HCl/dioxane (Aldrich) were weighed into a 250mL flask. The reaction was stirred at room temperature for 3 hours and then concentrated in vacuo. The residue was washed with ethyl acetate and 10% ammonium hydroxide into a separatory funnel. Separating ethyl acetate, drying (MgSO)4) And concentrated in vacuo. Intermediate methyl (3-bromophenyl) acetate was recovered as a colorless oil, yield, 5.2g (98%).
5.18g of the ester (22.6mmol) and 7.51g of bis (pinacolyl) diboron, 6.6g of potassium carbonate, 68mL of DMSO and 1.1g of [1, 1' -bis (diphenylphosphino) ferrocene are weighed]Palladium (II) dichloride dichloromethane adduct was charged to a 250mL flask. The resulting suspension was heated at 80-85 ℃ overnight and then rinsed into a separatory funnel with water and ether. The ether was separated, washed with brine and dried (MgSO)4) And concentrated in vacuo. The residue was purified by flash chromatography on silica gel (jones flashmaster, two 70g columns, gradient eluent 100% hexane to 40% ethyl acetate over 1 hour). The appropriate fractions were combined and concentrated in vacuo to afford [3- (4, 4, 5, 5-tetramethyl- [1, 3, 2 ] as an intermediate as a pale yellow oil ]Dioxaborolan-2-yl) phenyl]Methyl acetate, yield: 3.02g (47%).1H NMR(400MHz，CDCl3)：δ7.73(m，2H)，7.3-7.4(m，2H)，3.70(s，3H)，3.65(s，2H)，1.36(s，12H)。
15.1g (50.15mmol) of 4, 4, 4-trifluoro-1- [5- (3-methanesulfonyl-phenyl) -thiophen-2-yl ] -butane-1, 3-dione, 150mL of toluene and 1.575mL (1.1 equiv.) of hydrazine were weighed into a 500mL flask. The intermediate hydrazone precipitated from the solution over 15 minutes and then the reaction was heated to 100 ℃ and 105 ℃ for 18 hours. The reaction was then concentrated to dryness in vacuo, the residue was dissolved in dichloromethane and precipitated with hexane. The semi-crystalline precipitate was collected by filtration and dried under high vacuum to give the intermediate 5- (5-bromothiophen-2-yl) -3-trifluoromethyl-1H-pyrazole as a colorless solid, yield: 9.90g (66%).
5.0g (16.8mmol) of pyrazole, 5.4g of potassium carbonate, 4.7g (22.7mmol) of 1-bromomethyl-2, 4-difluorobenzene and 50mL of DMF were weighed into a 500mL flask. The resulting suspension was stirred at 100-105 ℃ for 1 hour and then cooled to room temperature. The reaction was washed with ethyl acetate and water into a separatory funnel. The ethyl acetate was separated, washed with water, brine and dried (MgSO)4) And concentrated in vacuo. The resulting mixture of isomers was purified by flash chromatography on silica gel (5 × 30cm, 5% ethyl acetate-hexanes) to give 5- (5-bromothiophen-2-yl) -1- (2, 4-difluoro-benzyl) -3-trifluoromethyl-1H-pyrazole as a colorless oil in yield: 2.21g (31%) and 3- (5-bromo-thiophen-2-yl) -1- (2, 4-difluorobenzyl) -5-trifluoromethyl-1H-pyrazole as colorless oil, yield: 4.62g (65%).
1.124g (2.66mmol) of 5- (5-bromothien-2-yl) -1- (2, 4-difluoro-benzyl) -3-trifluoromethyl-1H-pyrazole, 1.5g of borate (5.43mmol), 100mL of THF, and 10mL of 1.0M sodium carbonate were weighed into a 250mL flask. The resulting solution was heated in an oil bath at 80-85 deg.C and 318mg of tetrakistriphenylphosphine palladium (0) was added. The reaction was heated for 18 hours and then concentrated in vacuo to remove THF. The residue was washed into a separatory funnel with ethyl acetate and 1.0M sodium carbonate. The ethyl acetate was separated, washed with brine and dried (MgSO)4) And concentrated in vacuo. The residue was purified by flash chromatography on silica gel (Jones Flashmaster, 70g SiO2Gradient eluent 100% hexane to 40% ethyl acetate over 1 hour). The appropriate fractions were combined and concentrated in vacuo to give intermediate (3- {5- [1- (2, 4-difluorobenzyl) -5-trifluoromethyl-1H-pyrazol-3-yl) as a colorless oil]-thiophen-2-yl } -phenyl) acetic acid methyl ester, yield: 445mg (34%).
The intermediate ester was dissolved in 10mL THF, 10mL methanol, and LiOH-H was added2O (150mg/2mL water) solution. The resulting solution was stirred at 60-65 ℃ for 3 hours and then concentrated in vacuo to remove methanol. For residuesDichloromethane and water were washed into the separatory funnel. The aqueous phase was separated and acidified by addition of concentrated HCl. The aqueous phase is then washed three times with dichloromethane, the washings are combined and dried (Na) 2SO4) And concentrated in vacuo. The residue was purified by reverse phase HPLC to give the acid as a colorless solid: 52mg (12%).1H NMR(400MHz，DMSO-d6)：δ7.5-7.55(m，3H)，7.40(d，J＝4Hz，1H)，7.34(t，J＝8Hz，1H)，7.23(m，2H)，7.09(s，1H)，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- {1- [ (5-chloro-2-thienyl) methyl ] methyl]-3- (trifluoromethyl) -1H-pyrazol-5-yl } -2-thienyl) phenyl]Acetic acid;1H-NMR(400MHz，CDCl3)：δ7.55-7.49(2H，m)，7.38(1H，m)，7.31(1H，d)，7.27(1H，m)，7.11(1H，d)，6.73(1H，d)，6.68(1H，d)，6.66(1H，s)，5.54(2H，s)，3.70(2H，s).MS(ES)：483[M+H]+.
example 62
Preparation of 1-methylethyl 5- {5- [3- (aminosulfonyl) phenyl ] -2-thienyl } -1- (2, 5-dichlorophenyl) -1H-pyrazole-3-carboxylate
Figure S2006800306472D02571
114mg (224mmol) of methyl 1- (2, 5-dichlorophenyl) -5- (5- (3-aminosulfonylphenyl) thiophen-2-yl) -1H-pyrazole-3-carboxylate, 156mg KF, 4mL isopropanol, and 200L concentrated HCl were weighed into a 25mL flask. The reaction was heated at 80-85 ℃ for 3 days. The reaction was then washed with ethyl acetate and water into a separatory funnel. The ethyl acetate was separated, washed with brine and dried (Na)2SO4) And concentrated in vacuo. The product was further purified by silica gel flash chromatography (Jones Flashmaster, 25g SiO2Gradient eluent of 20% acetic acidEthyl ester to 60% ethyl acetate over 30 min). The appropriate fractions were combined and concentrated in vacuo to yield the product as a colorless powder, yield: 53.3mg (44%).1H NMR(400MHz，CDCl3)：δ8.05(s，1H)，7.83(d，J＝8Hz，1H)，7.66(d，J＝8Hz，1H)，7.59(s，1H)，7.44-7.51(m，3H)，7.21(d，J＝4Hz，1H)，7.13(s，1H)，6.81(d，J＝4Hz，1H)，5.33(heptet，J＝6Hz，1H)，5.08(s，2H)，1.41(d，J＝7Hz，6H)；MS(ES)：536[M+H]+.
Example 63
Preparation of [4- {5- [1- (2, 5-dichlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl ] -2-thienyl } -2- (methylsulfonyl) phenyl ] methanol.
Figure S2006800306472D02572
a)LiBH4、THF，85℃；b)MCPBA、CH2C225 ℃ C; c) bis (pinacolato) diboron, pd (dppf), KOAc, DMSO, 100 ℃; d) (Ph)3P)4Pd, 5- (5-bromothiophen-2-yl) -1- (2, 5-dichlorophenyl) -3-difluoromethyl-1H-pyrazole, Na2CO3THF-water, 80 ℃.
4-bromo-2-methylsulfanyl-benzoic acid ethyl ester was prepared as described in example 53. 27.5g of ester (99.9mmol) and 150mL of THF were weighed and charged into a 1L flask. Then 2.0MLiBH was added4In solution in THF (50mL, 100mmol), the reaction was heated to 80-85 deg.C and held at that temperature for 23 hours. The reaction was then removed from the heat and cooled in an ice bath while quenching with acetone. The reaction was then concentrated in vacuo and washed into a separatory funnel with ethyl acetate and 1M HCl. The ethyl acetate was separated, washed with brine and dried (Na)2SO4) And concentrated in vacuo. The intermediate (4-bromo-2-methylsulfanyl-phenyl) -methanol was recovered as a colorless oil, solidified on standing, yield: 25.5g (100)+％)。1H NMR(400MHz，CDCl3)：δ7.24-7.34(m，3H)，4.69(s，2H)，2.50(s，3H).
The alcohol was then dissolved in 250mL of dichloromethane, cooled to 0-3 ℃ in an ice bath, and 44g of 3-chloroperoxybenzoic acid (77% max., Aldrich) were added in portions. The reaction was then warmed to room temperature and held at that temperature for 22 hours. The reaction was then concentrated in vacuo to remove dichloromethane, and the residue was washed into a separatory funnel with ethyl acetate and 1M NaOH. Ethyl acetate was separated, washed with 1M NaOH and dried (Na) 2SO4) And concentrated in vacuo. The residue was purified by flash chromatography on silica gel (Biotage, 65X 200mm SiO)2Gradient eluent 100% hexane to 100% ethyl acetate over 1 hour). The appropriate fractions were combined and concentrated in vacuo to give the intermediate (4-bromo-2-methanesulfonyl-phenyl) -methanol as a colorless semi-crystalline solid, yield: 17.13g (65%).1H NMR(400MHz，CDCl3)：δ8.18(s，1H)，7.77(d，J＝8Hz，1H)，7.46(d，J＝8Hz，1H)，4.92(s，2H)，3.19(s，3H)，2.94(br s，1H).
17.13g of bromide, 25g of bis (pinacolato) diboron and 5.0g of [1, 1' -bis (diphenylphosphino) ferrocene are weighed out]Palladium (II) dichloride dichloromethane adduct, 23g potassium acetate and 175mL DMSO were charged to a 1L flask. The resulting suspension was heated at 98-102 deg.C for 18 hours and then diluted with 200mL ethyl acetate and 200mL water. The resulting 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 combined ethyl acetate washes were washed with brine and dried (Na)2SO4) And concentrated in vacuo. The residue was purified by flash chromatography on silica gel (Biotage, 65X 200mm SiO)2Gradient eluent 100% hexane to 40% ethyl acetate over 1 hour). The appropriate fractions were combined and concentrated in vacuo, and the partially purified product was dissolved in dichloromethane and precipitated with hexane. Intermediate [ 2-methylsulfonyl-4- (4, 4, 5, 5-tetramethyl- [1, 3, 2 ] ]Dioxaborolan-2-yl) -phenyl]Methanol recovery as off-white powder, yield: 8.78g (43%).1H NMR(400MHz，CDCl3)：δ8.45(s，1H)，8.04(d，J＝8Hz，1H)，7.57(d，J＝8Hz，1H)，4.96(s，1H)，3.17(s，3H)，1.35(s，6H)，1.24(s，6H).
2.52g (5.7mmol) of 5- (5-bromothien-2-yl) -1- (2, 5-dichlorophenyl) -3-trifluoromethyl-1H-pyrazole, 3.6g of borate and 100mL of THF were weighed into a 250mL flask. The resulting solution was heated at 80-85 deg.C, and 200mg of tetrakistriphenylphosphine palladium (0) was added. The reaction was heated for 3 hours, then cooled and concentrated to remove THF. The residue was washed into a separatory funnel with ethyl acetate and 1.0M sodium carbonate. The ethyl acetate was separated, washed with brine and dried (Na)2SO4) And concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (Biotage, 25X 150mm SiO)2Gradient eluent 100% hexane to 100% ethyl acetate over 1 hour). The appropriate fractions were combined and concentrated in vacuo to give the product as a colorless solid, yield: 348mg (11%);1H NMR(400MHz，CDCl3): δ 8.17(s, 1H), 7.72(d, J ═ 8Hz, 1H), 7.5-7.6(m, 2H), 7.50(m, 2H), 7.26(s, 1H), 6.89(s, 1H), 6.85(d, J ═ 4Hz, 1H), 4.96(s, 2H), 3.20(s, 3H); ms (es): 547 and 549[ each M + H]+.
The following compounds are prepared essentially according to the previous examples by substituting the appropriate reagents:
[2- (methylsulfonyl) -4- (5- {3- (trifluoromethyl) -1- [3- (trifluoromethyl) pyridin-2-yl ] amide ]-1H-pyrazol-5-yl } -2-thienyl) phenyl]Methanol; ms (es): 548[ M + H]+.
Example 64
Preparation of 2- (3- (5- (1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl) thiophen-2-yl) phenoxy) -2-methylpropionic acid)
Figure S2006800306472D02591
To tert-butyl 2- (3- (5- (1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl) thiophen-2-yl) phenoxy) -2-methylpropionate (47mg,84. mu. mol) in methylene chloride (0.5mL) was added formic acid (1.0 mL). The resulting light orange solution was stirred at ambient temperature. After 5 hours at ambient temperature, LC/MS analysis of the reaction showed that 5% of the starting ester was still present. After stirring at ambient temperature for 7 hours, the reaction mixture was concentrated under reduced pressure to give the crude product. The material was purified by flash column chromatography using a secondary CH2Cl2To 10% MeOH/CH2Cl2To give 2- (3- (5- (1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl) thiophen-2-yl) phenoxy) -2-methylpropionic acid as an off-white foam (21.7mg, 51% yield). Ms (es): 509[ M + H]+.
Scheme 24
Figure S2006800306472D02601
The hydroxyl group on the C-phenyl can be converted to other groups as depicted in scheme 24. Benzyloxyphenylpyrazole 024ES01 (prepared in analogy to example 2 c) can be deprotected to give hydroxyphenyl pyrazole 024ES 02. The free hydroxyl group can be derived by the following route: copper-mediated coupling of arylboronic acids gives the diaryl ethers 024ES03, Mitsunobu reaction with alcohols gives the aryl-alkyl ethers 024ES04, reaction with heteroaryl halides gives the aryl-heteroaryl ethers 024ES05, or alkylation with alkyl halides gives the arylalkyl ethers 024ES06, which can be further derivatized or converted (see 024ES 07).
Example 65
2- (4- (1- (-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl) phenoxy) pyrimidine
Example 65a
Preparation of 3- (1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl) phenol
Figure S2006800306472D02602
To a solution of 5- (3- (benzyloxy) phenyl) -1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazole in MeOH (100mL) was added 10% palladium on carbon (1.04 g). The black suspension was shaken on a Parr hydrogenator under 40-50psi hydrogen pressure for 5 hours. At this time, the reaction was not complete as shown by HPLC analysis. The reaction suspension was treated with additional Pd/C and shaking was continued under a hydrogen pressure of 60psi for 16 hours. HPLC at this point showed no starting 5- (3- (benzyloxy) phenyl) -1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazole. The reaction mixture was filtered through a pad of celite, then washed thoroughly with MeOH. The filtrate was concentrated under reduced pressure to give 3- (1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl) phenol as a friable foam. This material is pure enough for subsequent transformation. Ms (es): 339[ M + H]+.
The following compounds are prepared essentially in accordance with the previous examples:
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]Phenol, ms (es): 339[ M + H]+.
Example 65b
Preparation of 2- (4- (1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl) phenoxy) pyrimidine
Figure S2006800306472D02611
To 4- (1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl) phenol (see hydrogenation below) (60mg, 180. mu. mol) and Cs2CO3(140mg, 400. mu. mol) to a suspension in acetonitrile (2mL) was added 2-chloropyrimidine (66mg, 580. mu. mol). The suspension was then heated to 80 ℃ in an oil bath. After stirring at 80 ℃ for 16 h, the suspension was filtered through a plug of silica gel (1g) eluting with EtOAc. The filtrate was concentrated under reduced pressure and purified by flash column chromatography eluting with a gradient from 10% to 30% EtOAc in hexanes to give 2- (4- (1- (2-chlorophenyl) 2 as a white powder) -3- (trifluoromethyl) -1H-pyrazol-5-yl) phenoxy) pyrimidine (55mg, 75% yield). Ms (es): 417[ M + H ]]+.
The following compounds are prepared essentially in accordance with the previous examples:
2- ({4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]Phenyl } oxy) pyrazine; ms (es): 417[ M + H ]]+.
Example 66
2- (3- (1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl) phenoxy) acetic acid
Example 66a
Preparation of methyl 2- (3- (1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl) phenoxy) acetate
Figure S2006800306472D02621
To 3- (1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl) phenol (229mg, 0.68mmol) and K2CO3(179mg, 1.3mmol) to a suspension in acetonitrile (3.0mL) was added methyl bromoacetate (85. mu.L, 0.90 mmol). The suspension was stirred at ambient temperature for 16 hours, at which time HPLC analysis showed a slightly longer retention time for the product to convert to. The reaction suspension was filtered through a plug of celite, then washed thoroughly with EtOAc. The filtrate was concentrated to give a pale yellow oil. This material was further purified by flash column chromatography eluting with a gradient from 0% to 28% EtOAc/hexanes to give methyl 2- (3- (1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl) phenoxy) acetate (158mg, 57% yield) as an oil. Ms (es): 411[ M + H ]+。
The following compounds are prepared essentially in accordance with the previous examples:
2- ({4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]Phenyl } oxy) ethanol, ms (es): 383[ M + H]+.
({ 4' - [1- (2-chlorophenyl) -3- (1-hydroxy-1-methylethyl) -1H-pyrazol-5-yl)]Biphenyl-3-yl } oxy) acetic acid ethyl ester, ms (es): 512[ M + Na ]]+.
2- ({ 4' - [1- (2-chlorophenyl) -3- (1-hydroxy-1-methylethyl) -1H-pyrazol-5-yl]Biphenyl-3-yl } oxy) -N, N-diethylacetamide, ms (es): 540[ M + Na ]]+.
4' - [1- (2-chlorophenyl) -3- (1-hydroxy-1-methylethyl) -1H-pyrazol-5-yl]Biphenyl-3-yl (1-methylethyl) carbamate, ms (es): 512[ M + Na ]]+.
Example 66b
Preparation of 2- (3- (2- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl) phenoxy) acetic acid
Figure S2006800306472D02631
To a solution of methyl 2- (3- (1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl) phenoxy) acetate (140mg, 0.34mmol) in MeOH (5mL) was added lithium hydroxide monohydrate (60mg, 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 CH2Cl2And H2And (4) in O. The aqueous solution was made acidic by adding 1n hcl. The layers were separated and the acidic aqueous solution was further treated with CH 2Cl2(3x) extracting. The combined organic extracts are purified over Na2SO4Dried, filtered, and concentrated under reduced pressure. The white solid is added to warm CH2Cl2And hexane, and the resulting solution was cooled in an ice bath. Filtration, washing with hexanes, and drying of the precipitated solid afforded 2- (3- (1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl) phenoxy) acetic acid as a white solid (69mg, 51% yield). Ms (es): 397[ M + H ]]+。
The following compounds are prepared essentially in accordance with the previous examples:
({4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl)]Phenyl } oxy) acetic acid, ms (es): 397[ M + H ]]+.
·
Example 67
Preparation of 4- (2- (3- (1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl) phenoxy) ethyl) morpholine
Figure S2006800306472D02632
To a solution of 3- (1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl) phenol (155mg, 0.5mmol) and triphenylphosphine (170mg, 0.65mmol) in THF (2mL) was added 2-morpholinoethanol (72. mu.L, 0.59 mmol). The solution was cooled in an ice bath and treated with diisopropyl azodicarboxylate (125. mu.L, 0.64 mmol). After a few minutes, the ice bath was removed and the reaction was stirred while warming to ambient temperature. After stirring for 16 hours, LC/MS analysis showed the 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% then 40% EtOAc in hexanes and then CH 2Cl2To 4% MeOH/CH2Cl2Gradient elution of (2). The white solid obtained was found to be contaminated with triphenylphosphine oxide. The crude product was further purified by normal phase preparative HPLC using starting from CH2Cl2To 10% isopropanol/CH2Cl2Was eluted with a gradient of (1) to give 4- (2- (3- (1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl) phenoxy) ethyl) morpholine as a thick syrup (139mg, 67% yield). Ms (es): 452[ M + H]+.
The following compounds are prepared essentially in accordance with the previous examples:
2- ({3- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]Phenyl } oxy) -N, N-dimethylethylamine. Ms (es): 410[ M + H]+。
1- [2- ({3- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]Phenyl } oxy) ethyl]Piperidine. Ms (es): 450[ M + H ]]+。
2- ({4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]Phenyl } oxy) -N, N-dimethylethylamine, ms (es): 410[ M + H]+.
4- [2- ({4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]Phenyl } oxy) ethyl]Morpholine, ms (es): 452[ M + H]+.
1- [2- ({4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]Phenyl } oxy) ethyl]Piperidine, ms (es): 450[ M + H ]]+.
Example 68
1- (2-chlorophenyl) -5- (4- { [3- (methylsulfonyl) phenyl ] oxy } phenyl) -3- (trifluoromethyl) -1H-pyrazole
Figure S2006800306472D02641
4- (1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl) phenol (169mg, 0.5mmol), 3-methanesulfonylphenylboronic acid (200mg, 1mmol), Cu (OAc)2(181mg, 1mmol) and NEt3A mixture of (35. mu.L, 2.5mmol) and molecular sieve (4A) in DCM was shaken overnight at 20 ℃. The solid was removed by filtration and the filtrate evaporated to give the crude product which was purified by column chromatography on silica gel eluting with EtOAc-hexane (1: 4 to 1: 2) to give 1- (2-chlorophenyl) -5- (4- { [3- (methylsulfonyl) phenyl]Oxy } phenyl) -3- (trifluoromethyl) -1H-pyrazole (88 mg).1H-NMR：CDCl3：7.68(m，1H)，7.55(m，2H)，7.48(m，1H，)，7.62-7.40(m，2H)，7.27(m，2H)，7.21(m，1H)，6.93(m，1H)，6.80(s，1H)，3.04(s，3H)，MS(ES)：493[M+H]+.
Scheme 25
Figure S2006800306472D02651
As shown in scheme 25, aminosulfonyl groups can be introduced onto the thiophene ring. Thiophene pyrazole 025ES01 (prepared in a similar manner to example 2 c) can be sulphonated by the action of chlorosulphonic acid to give sulphonic acid 025ES 02. Conversion to sulfonyl chloride 025ES03 followed by derivatization with an amine under basic conditions gives the sulfonamide 0025ES 04.
Example 69
1- (5- (1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl) thiophene-2-sulfonyl) -4-methylpiperazine
Example 69a
Preparation of 5- (1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl) thiophene-2-sulfonic acid
Chlorosulfonic acid (1.0mL, 15mmol) was added dropwise to 1- (2-chlorophenyl) -5- (thiophen-2-yl) -3- (trifluoromethyl) -1H-pyrazole (1.0g, 3.2mmol) in CH 2Cl2(22mL) in a cold (-78 ℃ C.) solution. After stirring at-78 ℃ for 75 minutes, the cold bath was removed and the brown solution was warmed to ambient temperature. After stirring at ambient temperature for 3 * hours, the reaction mixture was poured into ice and CH was used2Cl2And (6) diluting. The opalescent lower organic phase is separated and passed over Na2SO4And (5) drying. The organics were filtered and concentrated under reduced pressure to give a biphasic mixture which was further evacuated under high vacuum. NMR and GC/MS analysis of this material showed it to be no product. Aqueous phase from the test substance was treated with Na2SO4Saturated and extracted with EtOAc (3 ×). The organic extracts are purified over Na2SO4Drying, filtering and concentrating under reduced pressure to obtain 5- (1- (2-chlorophenyl) -3- (trifluoromethyl) -1-trifluoromethyl) syrupH-pyrazol-5-yl) thiophene-2-sulfonic acid. The crude material was used without further purification for sulfonyl chloride formation. Ms (es): 409[ M + H]+.
Example 69b
Preparation of 5- (1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl) thiophene-2-sulfonyl chloride
Figure S2006800306472D02661
5- (1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl) thiophene-2-sulfonic acid (. about.3.2 mmol, from the previous step) was combined with benzene (5.0mL) in a reaction flask. The mixture was treated with thionyl chloride (5.0mL, 69mmol) and a catalytic amount of dimethylformamide (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 give a yellow oil, a portion of which was solidified under reduced pressure. The crude material was purified by flash column chromatography eluting with a gradient of 10% to 30% EtOAc/hexanes. The product containing fractions were collected and concentrated to give 5- (1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl) thiophene-2-sulfonyl chloride as a pale yellow oil. The mostly pure material was used for the subsequent transformation without further purification.
Example 69c
Preparation of 1- (5- (1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl) thiophene-2-sulfonyl) -4-methylpiperazine
Figure S2006800306472D02662
Triethylamine (0.15mL, 1.1mmol) and a small amount of DMAP were dissolved in 1, 2-dichloroethane (2mL) in the reaction flask. The solution was treated with 1-methylpiperazine (50. mu.L, 0.45mmol) and then 5- (1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl) thiophene-2-sulfonyl chloride (145mg, 0.34mmol) in 1, 2-bisA solution in ethyl chloride (1mL) was treated. After stirring for 4 * hours at ambient temperature, the reaction mixture was stirred with CH2Cl2And water dilution to quench the reaction. Adding saturated NaHCO3Basic aqueous solution with CH2Cl2(3x) extracting. The combined organic extracts are purified over Na2SO4Drying, filtration and concentration under reduced pressure gave the crude product as a pale yellow oil. The crude product was purified by flash column chromatography using CH2Cl2To 16% acetonitrile/CH2Cl2To give 1- (5- (1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl) thiophene-2-sulfonyl) -4-methylpiperazine as a brittle white foam (90.5mg, 54% yield). Ms (es): 491[ M + H]+.
The following compounds are prepared essentially in accordance with the previous examples:
1- ({5- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]-2-thienyl } sulfonyl) piperidine ms (es): 476[ M + H ] ]+.
Scheme 26
Figure S2006800306472D02671
As shown in scheme 26, pyrazole-carboxylic acids can be converted to pyrazole-amides. Formic acid 0026ES01 (prepared in a similar manner to example 2 c) was converted to its corresponding acid chloride 026ES02 by the action of oxalyl chloride. Reaction with various amines under basic conditions produced the corresponding amide 026ES 03.
Example 70
1- { [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl ] -2-thienyl } -1H-pyrazol-3-yl ] carbonyl } piperidine-4-carboxylic acid methyl ester
Example 70a
Preparation of 1- (2-chlorophenyl) -5- (5- (3- (methylsulfonyl) phenyl) thiophen-2-yl) -1H-pyrazole-3-carbonyl chloride
Figure S2006800306472D02681
To a suspension of 1- (2-chlorophenyl) -5- (5- (3- (methylsulfonyl) phenyl) thiophen-2-yl) -1H-pyrazole-3-carboxylic acid (160mg, 0.35mmol) in PhH (1.0mL) was added a small amount of DMF. Oxalyl chloride (60 μ L, 0.69mmol) was added to the suspension. After stirring for 15 minutes at ambient temperature, gas evolution ceased and only part of the solid dissolved. After 25 minutes, dioxane (2.0mL) was added. Gas evolution resumes and most of the solids dissolve. After 30 min, additional oxalyl chloride (50 μ L, 0.57mmol) was added. After stirring for a total of 90 minutes, the reaction mixture was concentrated under reduced pressure to give 1- (2-chlorophenyl) -5- (5- (3- (methylsulfonyl) phenyl) thiophen-2-yl) -1H-pyrazole-3-carbonyl chloride as a pale brown foam. This material was used for subsequent acylation without purification.
Example 70b
Preparation of methyl 1- { [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl) -2-thienyl } -1H-pyrazol-3-yl ] carbonyl } piperine-4-carboxylate
To 1- (2-chlorophenyl) -5- (5- (3- (methylsulfonyl) phenyl) thiophen-2-yl) -1H-pyrazole-3-carbonyl chloride (0.23mmol, crude product from the previous step) in CDCl3To the solution in (1.2ml) was added N, N-diisopropylethylamine (150. mu.L, 0.86mmol) and a small amount of DMAP. The resulting mixture was treated with methyl piperidinecarboxylate (62. mu.L, 0.46 mmol). After stirring for 3 hours at ambient temperature, with H2Diluting with O and using CH2Cl2The reaction is quenched by dilution. The layers were separated and the basic aqueous layer was treated with CH2Cl2And (4) extracting. The combined organic extracts are purified over Na2SO4Drying, filtering and concentrating under reduced pressure to obtain crude productAnd (3) obtaining the product. This material was purified by flash column chromatography using from 0% to 16% MeCN/CH2Cl2Was eluted with a gradient of (1- { [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl ] methane to give a white powder]-2-thienyl } -1H-pyrazol-3-yl]Carbonyl } piperidine-4-carboxylic acid methyl ester (11mg, 8% yield). Ms (es): 584[ M + H ]]+.
The following compounds are prepared essentially in accordance with the previous examples:
1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -N-piperidin-1-yl-1H-pyrazole-3-carboxamide, ms (es): 541.3[ M + H ]+.
1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -3- (pyrrolidin-1-ylcarbonyl) -1H-pyrazole, ms (es): 512[ M + H]+.
1- { [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Carbonyl } -4-methylpiperidine, ms (es): 540[ M + H ]]+.
1- { [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Carbonyl } -4-methylpiperazine, (ES): 541[ M + H]+.
1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -N- [3- (trifluoromethyl) phenyl]-1H-pyrazole-3-carboxamide, ms (es): 602[ M + H]+.
5- [ 3-chloro-3' - (methylsulfonyl) biphenyl-4-yl]-1- (2, 6-dichlorophenyl) -N- (2, 2, 2-trifluoroethyl) -1H-pyrazole-3-carboxamide ms (es): 604[ M + H]+.
5- [ 3-chloro-3' - (methylsulfonyl) biphenyl-4-yl]-N- (2, 2, 2-trifluoroethyl) -1- [2- (trifluoromethyl) pyridin-3-yl]-1H-pyrazole-3-carboxamide ms (es): 603[ M + H ]]+.
4-chloro-5- [ 3-chloro-3' - (methylsulfonyl) biphenyl-4-yl]-N- (2, 2, 2-trifluoroethyl) -1- [2- (trifluoromethyl) pyridin-3-yl]-1H-pyrazole-3-carboxamide ms (es): 637[ M + H ]]+.
5- [ 3-chloro-3' - (methylsulfonyl) biphenyl-4-yl]-1- (2, 6-dichlorophenyl) -N- (2-hydroxy-1, 1-dimethylethyl) -1H-pyrazole-3-carboxamide ms (es): 592[ M + H ]+.
5- [ 3-chloro-3' - (methylsulfonyl) biphenyl-4-yl]-1- (2, 6-dichlorophenyl) -N- (1, 1-dimethylethyl) -1H-pyrazole-3-carboxamide ms (es): 578[ M + H ]]+.
5- [ 3-chloro-3' - (methylsulfonyl) biphenyl-4-yl]-N-cyclopropyl-1- (2, 6-dichlorophenyl) -1H-pyrazole-3-carboxamide ms (es): 560[ M + H ]]+.
5- [ 3-chloro-3' - (methylsulfonyl) biphenyl-4-yl]-N-cyclobutyl-1- (2, 6-dichlorophenyl) -1H-pyrazole-3-carboxamide ms (es): 576[ M + H]+.
5- [ 3-chloro-3' - (methylsulfonyl) biphenyl-4-yl]-N-cyclopentyl-1- (2, 6-dichlorophenyl) -1H-pyrazole-3-carboxamide ms (es): 590[ M + H ]]+.
Scheme 27
As shown in scheme 27, biphenylpyrazoles can be prepared starting from the condensation of hydrazine and diketonates and chlorinated on the pyrazole ring. Hydrazine 027ES01 can be condensed with a diketone 027ES02 to give pyrazole 027ES03 as in example 2 c. The ester function of 027ES03 can then be converted into the tertiary alcohol 027ES04 by the action of an alkylmagnesium halide in a manner analogous to example 5. The aryl bromide obtained can then be coupled with boronic acid under similar palladium catalysed coupling conditions as in example 1c to give biaryl 027ES 05. The pyrazole nucleus of 027ES05 can then be halogenated by treatment with NBS or NCS to give halo-pyrazole 027ES 06.
Example 71
2- (5- (3' - (methylsulfonyl) biphenyl-4-yl) -1- (2- (trifluoromethyl) phenyl) -1H-pyrazol-3-yl) propan-2-ol
Example 71a
Preparation of 2- (5- (4-bromophenyl) -1- (2- (trifluoromethyl) phenyl) -1H-pyrazol-3-yl) propan-2-ol
Figure S2006800306472D02702
To a stirred suspension of methyl 5- (4-bromophenyl) -1- (2- (trifluoromethyl) phenyl) -1H-pyrazole-3-carboxylate (393mg, 0.9mmol) in dry toluene (9mL) at ambient temperature was added dropwise methylmagnesium bromide (1.4mL of a 3.0M solution in ether, 4.2 mmol). After stirring for 21/4 hours at ambient temperature, saturated ammonium chloride and EtOAc were added and the reaction mixture was quenched. The aqueous layer was extracted with EtOAc (3 ×). The combined organic extracts are purified over Na2SO4Drying, filtration and concentration under reduced pressure gave 2- (5- (4-bromophenyl) -1- (2- (trifluoromethyl) phenyl) -1H-pyrazol-3-yl) propan-2-ol as a yellow-orange oil, which was used in the next step. GC/MS (EI, ═ 426[ M ]+]
Example 71b
Preparation of 2- (5- (3' - (methylsulfonyl) biphenyl-4-yl) -1- (2- (trifluoromethyl) phenyl) -1H-pyrazol-3-yl) propan-2-ol
Figure S2006800306472D02711
To a solution of 2- (5- (4-bromophenyl) -1- (2- (trifluoromethyl) phenyl) -1H-pyrazol-3-yl) propan-2-ol (115mg, 0.27mmol) and 3- (methylsulfonyl) phenylboronic acid (66mg, 0.33mmol) in 1, 2-dimethoxyethane (1.5mL) was added K 2CO3(110mg, 0.80mmol) and H2O (1.5 mL). The resulting biphasic suspension was stirred at ambient temperature and purged with nitrogen for 10 minutes. Then the reactant is treated with [1, 1' -bis (diphenylphosphino) ferrocene]Dichloroation ofPalladium (II) dichloromethane adduct (15mg, 18. mu. mol) and heated to 80 ℃ in an oil bath. The reaction was heated at 80 ℃ for three hours and then cooled to ambient temperature overnight. The cooled reaction mixture was washed with EtOAc and H2And (4) diluting with oxygen. The aqueous layer was extracted with EtOAc (3 ×). The combined organic extracts were washed with brine, over Na2SO4Dry, filter and concentrate to give the crude product as a dark oil. The crude product was purified by flash column chromatography eluting with a gradient from 10% to 100% EtOAc/hexanes to give 2- (5- (3' - (methylsulfonyl) biphenyl-4-yl) -1- (2- (trifluoromethyl) phenyl) -1H-pyrazol-3-yl) propan-2-ol as an off-white powder (122mg, 90% yield). Ms (es): 501[ M + H [ ]]+.
The following compounds are prepared essentially in accordance with the previous examples:
2- {5- [ 3' - (methylsulfonyl) biphenyl-4-yl]-1- [3- (trifluoromethyl) pyridin-2-yl]-1H-pyrazol-3-yl } propan-2-ol, ms (es): 502[ M + H]+。
2- {1- (2-chlorophenyl) -5- [ 3' - (methylsulfonyl) biphenyl-4-yl]-1H-pyrazol-3-yl } propan-2-ol, ms (es): 467[ M + H ] ]+。
4' - [1- (2-chlorophenyl) -3- (1-hydroxy-1-methylethyl) -1H-pyrazol-5-yl]-N- (1-methylethyl) biphenyl-3-carboxamide, ms (es): 474[ M + H]+。
4' - [1- (2-chlorophenyl) -3- (1-hydroxy-1-methylethyl) -1H-pyrazol-5-yl]-N- [2- (di-methylamino) ethyl]Biphenyl-3-carboxamide, ms (es): 503[ M + H]+。
2- {1- (2-chlorophenyl) -5- [ 4' - (ethylsulfonyl) biphenyl-4-yl]-1H-pyrazol-3-yl } propan-2-ol, ms (es): 481[ M + H]+。
2- {1- (2-chlorophenyl) -5- [ 3-methyl-3' - (methylsulfonyl) biphenyl-4-yl]-1H-pyrazol-3-yl } propan-2-ol ms (es): 481[ M + H]+。
2- {1- (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]-1- (2-chlorophenyl) -1H-pyrazol-3-yl } propan-2-ol ms (es): 501[ M + H [ ]]+。
1- (5- {4- [1- (2-chlorophenyl) -3- (1-hydroxy-1-methylethyl) -1H-pyrazol-5-yl ] phenyl } -2-thienyl) ethanone ms (es): 419 (M-OH).
5- {4- [1- (2-chlorophenyl) -3- (1-hydroxy-1-methylethyl) -1H-pyrazol-5-yl ] phenyl } thiophene-2-carbaldehyde, MS (ES): 405 (M-OH).
2- [1- (2-chlorophenyl) -5- {4- [2- (methoxy) pyrimidin-5-yl]Phenyl } -1H-pyrazol-3-yl]Propan-2-ol, ms (es): 421[ M + H ]+。
Example 72
2- [1- (2-chlorophenyl) -5- {4- [3- (methylsulfonyl) phenyl ] furan-2-yl } -1H-pyrazol-3-yl ] propan-2-ol
Example 72a
Preparation of 4-bromo-furan-2-carboxylic acid
Figure S2006800306472D02721
4, 5-dibromo-furan-2-carboxylic acid (57.0g, 211mmol), H2O (168mL), and HOAc (42mL) were charged to a 500mL three-necked round bottom flask equipped with an overhead mechanical stirrer and a reflux condenser. The flask was closed at three necks and the suspension was heated to reflux with a temperature controlled heating mantle keeping the temperature at 125-130 ℃. Zn powder (24.9g, 381mmol) was added portionwise over 50 minutes (previously ground in a mortar and the cake ground with a pestle). Subsequent portions are added after the previously added portions have disappeared. After the addition of the first portion of Zn, all of the 4, 5-dibromofuran-2-carboxylic acid dissolved to give a light brown solution. 25 minutes after the zinc addition was complete, a thick off-white slurry formed. HPLC analysis of the reaction slurry at this point indicated completion of the starting 4, 5-dibromofuran-2-carboxylic acidIs consumed and converted to the desired product. After 35 minutes, the heating was stopped and the slurry was cooled to ambient temperature. After cooling to ambient temperature, the reaction slurry is cooled with cold H2O (175mL) was diluted, cooled in an ice bath, and filtered. Cold H for white and gray solids 2O rinse and dry on filter paper for 3 hours. The product/Zn mixture was then evacuated under high vacuum and gently heated to give off-white flakes. A portion of the resulting solid (37.3g) was dissolved in warm acetone (1.8L, solubility about 20 g/L). The resulting solution was filtered to remove residual zinc dust and then concentrated under reduced pressure to give 4-bromo-furan-2-carboxylic acid as a white powder. This material was subjected to the formation of acid chloride without purification.1H-NMR(400MHz，DMSO-d6)：δ7.96(1H，d，J＝0.8Hz)，7.04(1H，d，J＝0.8Hz).
Example 72b
Preparation of 4-bromofuran-2-carbonyl chloride
Figure S2006800306472D02731
Crude 4-bromo-furan-2-carboxylic acid (30g, 157mmol) was placed in a 500mL round bottom flask equipped with a magnetic stir bar and a reflux condenser, the flask was alternately evacuated and charged with nitrogen several times. The solid was suspended in benzene (400mL) and washed with SOCl2(60mL, 823mmol) and the mixture heated to reflux in a heating mantle. A black tarry material formed on the wall of the reaction flask during the reaction. After refluxing for-135 minutes, a sample of the reaction was concentrated under reduced pressure and analyzed by 13C NMR. NMR was very pure, indicating the end of the reaction. [13C-NMR(400MHz，CDCl3)：δ154.9，147.6，146.3，126.0，102.5]. After refluxing for-3 hours, the reaction mixture was cooled to ambient temperature. The light brown supernatant of acid chloride was decanted from the black solid, which was rinsed with additional benzene. The benzene solutions were combined and concentrated under reduced pressure to give 4-bromofuran-2-carbonyl chloride as a pale brown oil. The crude material was used for amide formation without purification.
Example 72c
Preparation of 4-bromo-furan-2-carboxylic acid methoxy-methyl-amide
Figure S2006800306472D02741
Crude 4-bromofuran-2-carbonyl chloride (157mmol theory) was dissolved in CH in a 1L round-bottomed flask2Cl2(500 mL). The flask was immersed in an ice bath and N, O-dimethylhydroxylamine hydrochloride (19.5g, 200mmol) was added. The cold suspension was then treated with N, N-diisopropylethylamine (75mL, 430mmol) and a small amount of 4- (N, N-dimethylamino) pyridine (catalyst). After a few minutes of addition of 4- (N, N-dimethylamino) pyridine, the ice bath was removed and the light orange solution was warmed to ambient temperature. After standing at ambient temperature for-16 hours, the light brown reaction mixture was quenched with water (100mL) and CH2Cl2(500mL) dilution. The layers were separated and the organic layer was washed with 1N HCl (2X 100mL), H2O (100mL) and saturated NaHCO3(50mL) washed. Passing organic matter through Na2SO4Drying, filtration and concentration under reduced pressure gave 4-bromo-furan-2-carboxylic acid methoxy-methyl-amide as a pale brown solid (25.7g, 70% yield from crude acid). 1H NMR of this material showed it to be very pure.1H-NMR(400MHz，CDCl3)：δ7.60(1H，d，J＝0.8Hz)，7.14(1H，d，J＝0.8Hz)，3.77(3H，s)，3.35(3H，s).
Example 72d
Preparation of 1- (4-bromo-furan-2-yl) -ethanone
Figure S2006800306472D02742
A solution of 4-bromo-furan-2-carboxylic acid methoxy-methyl-amide (27.5g, 117mmol) in THF (350mL) was prepared and in an ice-salt bath (< 0 ℃ C.) Upon cooling, methylmagnesium bromide (51mL, 3.0M Et) was added slowly to the solution2O solution, 153mmol) to maintain the temperature below 0 ℃. The resulting off-white/brown suspension was stirred at-10 ℃. NH after 1 hour4TLC analysis of Cl-quenched aliquots showed no starting amide present. After 75 minutes at-10 ℃ saturated NH was added4The reaction was quenched with aqueous Cl (100 mL). In addition, H is added2O, then 3N aqueous HCl (. about.40 mL) was added to dissolve the solids. The resulting biphasic solution was concentrated on a rotary evaporator to remove most of the THF. Et for the resulting aqueous slurry2O dilution and addition of 3N HCl aqueous solution to adjust the pH to < 7. The layers were separated and the aqueous layer was washed with Et2O (3X 100 mL). The combined organic layers were washed with saturated NaHCO3Washed with aqueous solution, brine and Na2SO4Drying, filtration and concentration under reduced pressure gave 1- (4-bromo-furan-2-yl) -ethanone as a pale brown solid (20.4g, 92% yield).1H-NMR(400MHz，CDCl3)：δ7.58(1H，d，J＝0.8Hz)，7.18(1H，d，J＝0.8Hz)，2.47(3H，s).
The following compounds are prepared essentially in accordance with the previous examples:
1- (2-chlorophenyl) -5- {4- [3- (methylsulfonyl) phenyl]Furan-2-yl } -1H-pyrazole-3-carboxylic acid methyl ester, ms (es): 457[ M + H]+.
2- [1- (2-chlorophenyl) -5- {4- [3- (methylsulfonyl) phenyl]Furan-2-yl } -1H-pyrazol-3-yl radical ]Propan-2-ol, ms (es): 457[ M + H]+.
2- [1- (2-chlorophenyl) -5- {4- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Propan-2-ol, ms (es): 473[ M + H ]]+
Scheme 28
Figure S2006800306472D02751
Amides and sulfonamides can be prepared by acylation of the free amino group, as shown in scheme 28. Methanol 028ES01 (prepared in a manner analogous to example 5) can be coupled with aminophenylboronic acid under palladium-catalyzed coupling conditions analogous to example 1c to give aminobiaryl 028ES 03. The amine functionality of these compounds is then further derivatized under basic conditions to give acylated or sulfonylated derivatives 028ES 04.
Example 73
Preparation of N- (4' - (1- (2-chlorophenyl) -3- (2-hydroxypropan-2-yl) -1H-pyrazol-5-yl) biphenyl-3-yl) acetamide
Figure S2006800306472D02752
To a solution of 2- (5- (3' -aminobiphenyl-4-yl) -1- (2-chlorophenyl) -1H-pyrazol-3-yl) propan-2-ol (370mg, 0.37mmol) in acetonitrile (1.6mL) was added triethylamine (0.12mL, 0.86mmol), followed by acetyl chloride (27. mu.L, 380. mu. mol). The reaction flask was then shaken overnight at 75 ℃. 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/hexanes to give N- (4' - (1- (2-chlorophenyl) -3- (2-hydroxypropan-2-yl) -1H-pyrazol-5-yl) biphenyl-3-yl) acetamide as an oil (82mg, 49% yield). 1H NMR(400MHz CDCl3)：δ7.79(1H，s)，7.49-7.42(4H，m)，7.41-7.32(4H，m)，7.31-7.21(3H，m)，6.54(1H，s)，2.68(1H，s)，2.19(3H，s)，1.69(6H，s).MS(ES)：445[M+H]+.
The following compounds are prepared essentially in accordance with the previous examples:
n- { 4' - [1- (2-chlorophenyl) -3- (1-hydroxy-1-methylethyl) -1H-pyrazol-5-yl]Biphenyl-3-yl } methanesulfonamide ms (es): 482[ M + H ]]+.
N- { 4' - [1- (2-chlorophenyl) -3- (1-hydroxy-1-methylethyl) -1H-pyrazol-5-yl]Biphenyl-3-yl } -1, 1, 1-trifluromethyl sulfonic acidAmide ms (es): 535[ M + H]+.
Example 74
2- (5- (5- (3- (methylsulfonyl) phenyl) thiophen-2-yl) -1- (pyridin-4-yl) -1H-pyrazol-3-yl) propan-2-ol
Example 74a
Preparation of methyl 4- (5-bromothien-2-yl) -4-oxo-2- (2-pyridin-4-yl) hydrazono) butanoate
Figure S2006800306472D02761
Hydrazinopyridine 4-hydrochloride (366mg, 2.51mmol) and methyl 4- (5-bromothiophen-2-yl) -2, 4-dioxobutyrate (724mg, 2.5mmol) were suspended in MeOH (12mL) and heated to reflux to give a yellow solution. After refluxing for 24 hours, the reaction was cooled to ambient temperature and concentrated under reduced pressure to give an orange-yellow oil. LC/MS analysis showed that it was a mixture of two isomers of hydrazone with a small amount of cyclized pyrazole present. This material is subjected to dehydrative cyclization to prepare a cyclized pyrazole. Ms (es): 384[ M + H ]]+.
Example 74b
Preparation of methyl 5- (5- (3- (methylsulfonyl) phenyl) thiophen-2-yl) -1- (pyridin-4-yl) -1H-pyrazole-3-carboxylate
Figure S2006800306472D02771
Crude methyl (E-Z) -4- (5-bromothiophen-2-yl) -4-oxo-2- (2- (pyridin-4-yl) hydrazono) butanoate (2.5mmol from the previous step) was suspended in toluene (40mL), treated with p-toluenesulfonic acid monohydrate (735mg, 3.9mmol), and heated to reflux overnight via a Dean-Stark water separator. LC/MS analysis at this point showed two regioisomers of the cyclized pyrazole product. The reaction was cooled and washed with EtOAc, H2Lean of oxygenRelease, and carefully add solid Na2CO3Alkalizing. The basic aqueous solution was extracted with EtOAc (3X), and the combined organic extracts were washed with water, brine, and Na2SO4Drying, filtering and concentrating under reduced pressure to obtain orange yellow membrane. This material was purified by flash column chromatography eluting with a gradient from 0% to 100% EtOAc/hexanes to give a mixture of two pyrazole isomers. This mixture was subjected to Suzuki coupling without further purification.
Example 74c
Preparation of methyl 5- (5- (3- (methylsulfonyl) phenyl) thiophen-2-yl) -1- (pyridin-4-yl) -1H-pyrazole-3-carboxylate
Figure S2006800306472D02772
A mixture of methyl 5- (5-bromothien-2-yl) -1- (pyridin-4-yl) -1H-pyrazole-3-carboxylate (480mg, 1.3mmol) and 3- (methylsulfonyl) phenylboronic acid (390mg, 1.9mmol) with Na2CO3(1.0mL of a 2M aqueous solution, 2.0mmol) was suspended in THF (6 mL). The mixture was purged with nitrogen for-10 min with Pd (PPh) 3)4(54mg, 47. mu. mol) and heated to 65 ℃. After 4 hours at 65 ℃ the starting methyl 5- (5-bromothien-2-yl) -1- (pyridin-4-yl) -1H-pyrazole-3-carboxylate was still visible, as evidenced by LC/MS. Additional palladium catalyst was added and heating continued. After heating at 65 ℃ overnight, the reaction mixture was concentrated under reduced pressure to give a black semi-solid which was triturated with EtOAc and filtered to remove the solid. The filtrate was concentrated under reduced pressure and purified by flash column chromatography using from 0% to 50% MeCN/CH2Cl2To give a mixture of methyl 5- (5- (3- (methylsulfonyl) phenyl) thiophen-2-yl) -1- (pyridin-4-yl) -1H-pyrazole-3-carboxylate (137mg, 24% yield) and triphenylphosphine oxide. The colorless film was subjected to Grignard addition without further purification.
The following compounds are prepared essentially according to example 8:
2- (5- {5- [3- (methylsulfonyl) phenyl)]-2-thienyl } -1-pyridin-4-yl-1H-pyrazol-3-yl) propan-2-ol,1H NMR(400MHz CDCl3)：δ8.68-8.57(2H，m)，8.14(1H，m)，7.92-7.78(2H，m)，7.61(1H，t)，7.43-7.36(2H，m)，7.34(1H，d)，6.93(1H，d)，6.60(1H，s)，3.11(3H，s)，2.75(1H，s)，1.67(6H，s).MS(ES)：440[M+H]+.
2- [1- (4-methylpyridin-3-yl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Propan-2-ol, ms (es): 454[ M + H]+.
2- [1- (2, 6-Dimethylpyridin-3-yl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Propan-2-ol, ms (es): 468[ M + H ]+.
2- [1- (2-methylphenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Propan-2-ol, ms (es): 453[ M + H ]]+.
2- [1- (2, 5-dimethylphenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Propan-2-ol, ms (es): 467[ M + H ]]+.
2- [1- (2, 3-dimethylphenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Propan-2-ol, ms (es): 467[ M + H ]]+.
2- (1- [ 2-fluoro-3- (trifluoromethyl) phenyl)]-5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl) propan-2-ol, ms (es): 525[ M + H ]]+.
2- [1- (2-chloro-5-fluorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Propan-2-ol, ms (es): 491[ M + H]+.
2- [1- (2-chloro-6-methylphenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Propan-2-ol, ms (es): 487[ M + H ]]+.
2- [1- (5-chloro-2-fluorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Propan-2-ol，MS(ES)：491[M+H]+
2- [1- (2-chloro-6-fluorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Propan-2-ol, ms (es): 491[ M + H]+.
2- {1- (2, 6-dichlorophenyl) -5- [ 3-methyl-3' - (methylsulfonyl) biphenyl-4-yl]-1H-pyrazol-3-yl } propan-2-ol, ms (es): 515[ M + H ]+.
2- {1- (2, 6-dichlorophenyl) -5- [ 2-methyl-3' - (methylsulfonyl) biphenyl-4-yl]-1H-pyrazol-3-yl } propan-2-ol, ms (es): 537[ M + Na ]]+.
2- {5- [ 3-methyl-3' - (methylsulfonyl) biphenyl-4-yl]-1- [2- (trifluoromethyl) pyridin-3-yl]-1H-pyrazol-3-yl } propan-2-ol, 516[ M + H]+.
2- {5- [ 3-methyl-3' - (methylsulfonyl) biphenyl-4-yl]-1- [4- (trifluoromethyl) pyridin-3-yl]-1H-pyrazol-3-yl } propan-2-ol ms (es): 516[ M + H]+.
2- {5- [ 3' - (methylsulfonyl) biphenyl-4-yl]-1- [4- (trifluoromethyl) pyridin-3-yl]-1H-pyrazol-3-yl } propan-2-ol ms (es): 502[ M + H]+.
2- {5- [ 3-chloro-3' - (methylsulfonyl) biphenyl-4-yl]-1- [4- (trifluoromethyl) pyridin-3-yl]-1H-pyrazol-3-yl } propan-2-ol ms (es): 536[ M + H]+.
2- {1- (2, 6-dichlorophenyl) -5- [ 3' - (methylsulfonyl) biphenyl-4-yl]-1H-pyrazol-3-yl } propan-2-ol ms (es): 501[ M + H [ ]]+.
2- {5- [ 3-chloro-3' - (methylsulfonyl) biphenyl-4-yl]-1- (2, 6-dichlorophenyl) -1H-pyrazol-3-yl } propan-2-ol ms (es): 537[ M + H ]]+.
2- {5- [ 3-chloro-3' - (methylsulfonyl) biphenyl-4-yl]-1- [2- (trifluoromethyl) pyridin-3-yl]-1H-pyrazol-3-yl } propan-2-ol ms (es): 536[ M + H]+.
2- {3 '-chloro-4' - [1- (2, 6-dichlorophenyl) -3- (trifluoromethyl)) -1H-pyrazol-5-yl ]Biphenyl-3-yl } propan-2-ol MS (ES): 525[ M + H ]]+.
2- {1- (2-chlorophenyl) -5- [4- (1H-indol-6-yl) phenyl]-1H-pyrazol-3-yl } propan-2-ol, ms (es): 450[ M + Na ]]+.
2- {1- (2-chlorophenyl) -5- [4- (1H-indol-5-yl) phenyl]-1H-pyrazol-3-yl } propan-2-ol, ms (es): 428[ M + H]+.
2- {1- (2-chlorophenyl) -5- [4- (1-methyl-1H-indol-5-yl) phenyl]-1H-pyrazol-3-yl } propan-2-ol ms (es): 442[ M + H ]]+.
2- {1- (2-chlorophenyl) -5- [4- (1H-indol-4-yl) phenyl]-1H-pyrazol-3-yl } propan-2-ol, ms (es): 450[ M + Na ]]+.
2- (1- (2-chlorophenyl) -5- (3' - (trifluoromethyl) biphenyl-4-yl) -1H-pyrazol-3-yl) propan-2-ol ms (es): 457[ M + H]+.
2- (5- (2 '-chloro-4' - (trifluoromethyl) biphenyl-4-yl) -1- (2-chlorophenyl) -1H-pyrazol-3-yl) propan-2-ol ms (es): 491[ M + H]+.
2- (1- (2-chlorophenyl) -5- (4 '-fluoro-3' - (trifluoromethyl) biphenyl-4-yl) -1H-pyrazol-3-yl) propan-2-ol ms (es): 475[ M + H ]]+.
4' - (1- (2-chlorophenyl) -3- (2-hydroxypropan-2-yl) -1H-pyrazol-5-yl) biphenyl-3-sulfonamide ms (es): 468[ M + H]+.
2- (1- (2-chlorophenyl) -5- (4' - (methylsulfonyl) biphenyl-4-yl) -1H-pyrazol-3-yl) propan-2-ol (ES): 467[ M + H ]]+.
4' - (1- (2-chlorophenyl) -3- (2-hydroxypropan-2-yl) -1H-pyrazol-5-yl) biphenyl-4-sulfonamide ms (es): 468[ M + H ]+.
2- (4' - (1- (2-chlorophenyl) -3- (2-hydroxypropan-2-yl) -1H-pyrazol-5-yl) biphenyl-3-yl) propan-2-ol ms (es): 447[ M + H]+.
4' - (1- (2-chlorobenzene)3- (2-hydroxypropan-2-yl) -1H-pyrazol-5-yl) -N- (2- (di-methylamino) ethyl) biphenyl-3-sulfonamide, ms (es): 539[ M + H ]]+.
Scheme 29
Figure S2006800306472D02801
Formic acid is converted to the amide by acylation as shown in scheme 29. Formic acid 029ES01 (made in a manner analogous to example 2 c) was converted to its corresponding acid chloride 029ES02 by the action of oxalyl chloride in a manner analogous to example 70 a. The acid chloride obtained is then reacted under basic conditions analogous to example 70b with the various amines to give the corresponding amide 029ES 03.
Example 75
4- [2- (2-chloro-phenyl) -5-trifluoromethyl-2H-pyrazol-3-yl ] -N, N-dimethyl-benzamide
Example 75a
Preparation of 4- [2- (2-chloro-phenyl) -5-trifluoromethyl-2H-pyrazol-3-yl ] -benzoyl chloride
4- [2- (2-chloro-phenyl) -5-trifluoromethyl-2H-pyrazol-3-yl ] -benzoic acid was prepared in a similar manner as previously described. To a 500ml round bottom flask was added 2g of the acid, 150ml of anhydrous THF, 300. mu.L of DMF, and 1500. mu.L of oxalyl chloride. The reaction was stirred at room 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 twice more. The resulting yellow solid was then dissolved in anhydrous dichloromethane to 0.1M, which was used without further purification.
Example 75b
Preparation of 4- [2- (2-chloro-phenyl) -5-trifluoromethyl-2H-pyrazol-3-yl ] -N, N-dimethyl-benzamide
Figure S2006800306472D02811
Adding 4- [2- (2-chloro-phenyl) -5-trifluoromethyl-2H-pyrazol-3-yl to a 1-dram bottle]A 0.1M solution of benzoyl chloride (300mL, 0.3mmol) in dichloromethane, dimethylamine (27mg, 0.6mmol) and N, N-diisopropylethylamine (77.4mg, 0.6 mmol). The reaction was stirred at room temperature for 30 minutes, then placed directly on silica and purified over 10CV using a gradient of hexane to ethyl acetate 0-50%. The relevant fractions were combined and dried in vacuo to yield 108.6mg (92%) of an off-white solid; ms (es): 394[ M + H]+；1H NMR(400MHz，DMSO-d6)：δ7.84(dd，J＝7.8Hz；1.7Hz 1H)，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- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]-N- (2-morpholin-4-ylethyl) benzamide, ms (es): 479[ M + H ]]+.
N- ({4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]Phenyl } carbonyl) glycine methyl ester, ms (es): 438[ M + H]+.
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]-N- (2-oxotetrahydro-3-thienyl) benzamide, ms (es): 466[ M + H]+.
N- ({4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]Phenyl } carbonyl) - β -alanine methyl ester, ms (es): 452[ M + H ]+.
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]-N- [2- (methylsulfonyl) ethyl]Benzamide, ms (es): 472[ M + H]+.
1- ({4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]Phenyl } carbonyl) -4- [2- (methylsulfonyl) ethyl]Piperazine, ms (es): 541[ M + H]+.
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]-N- (1, 1-dioxotetrahydro-3-thienyl) benzamide, ms (es): 484[ M + H]+.
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]-N- [3- (methylsulfonyl) phenyl]Benzamide, ms (es): 520[ M + H ]]+.
4- [1- (2-chlorophenyl) -3- (1-hydroxy-1-methylethyl) -1H-pyrazol-5-yl]-N, N-dimethylbenzamide, ms (es): 384[ M + H ]]+.
1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -N-pyridin-3-yl-1H-pyrazole-3-carboxamide; ms (es): 535[ M + H]+
1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -N-pyridin-4-yl-1H-pyrazole-3-carboxamide; ms (es): 535[ M + H]+
1- (2-chlorophenyl) -N- [2- (dimethylamino) ethyl]-5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazole-3-carboxamide; ms (es): 529[ M + H]+；
1- (2-chlorophenyl) -N- [3- (methoxy) propyl]-5- {5- [3- (methylsulfonyl) phenyl ]-2-thienyl } -1H-pyrazole-3-carboxamide; ms (es): 530[ M + H]+；
4- { [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Carbonyl } morpholine; ms (es): 528[ M + H ]]+；
1- (2-chlorophenyl) -N- [6- (methoxy) pyridin-3-yl]-5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazole-3-carboxamide; ms (es): 565[ M + H]+；
1- (2-chlorophenyl) -N, N-dimethyl-5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazole-3-carboxamide; ms (es): 486[ M + H]+；
1- { [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazol-3-yl]Carbonyl } -4-cyclopentylpiperazine; ms (es): 595[ M + H]+；
1- (2-chlorophenyl) -N-methyl-N- (1-methylpiperidin-4-yl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazole-3-carboxamide; ms (es): 569[ M + H ]]+；
1- (2-chlorophenyl) -N- [3- (dimethylamino) propyl]-N-methyl-5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -1H-pyrazole-3-carboxamide; ms (es): 557[ M + H ]]+；
1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -N- (3-pyrrolidin-1-ylpropyl) -1H-pyrazole-3-carboxamide; ms (es): 569[ M + H ]]+；
1- (2-chlorophenyl) -N- [ (1-ethylpyrrolidin-3-yl) methyl]-5- {5- [3- (methylsulfonyl) phenyl ]-2-thienyl } -1H-pyrazole-3-carboxamide; ms (es): 569[ M + H ]]+；
N- (5-chloro-2-hydroxyphenyl) -4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]A benzamide; ms (es): 492[ M + H]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]-N-quinolin-6-ylbenzamide; ms (es): 493[ M + H ]]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]-N- (2, 3-dihydro-1, 4-benzodioxan-6-yl) benzamide; ms (es): 500[ M + H ]]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]-N- {4- [2, 2, 2-trifluoro-1-hydroxy-1- (trifluoromethyl) ethyl]Phenyl } benzamide; ms (es): 608[ M + H]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]-N- (3-cyanophenyl) benzamide; ms (es): 467[ M + H ]]+；
2- [ ({4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl)]Phenyl } carbonyl) amino]-5-methylbenzoic acid; ms (es): 500[ M + H ]]+；
·2-[ ({4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl)]Phenyl } carbonyl) amino]Benzoic acid; ms (es): 486[ M + H]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]-N- [2- (ethoxy) phenyl]A benzamide; ms (es): 486[ M + H]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl ]-N- (2-cyanophenyl) benzamide; ms (es): 467[ M + H ]]+；
2- [ ({4- [1- (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- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]A benzamide; ms (es): 485[ M + H]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]-N-quinolin-5-ylbenzamide; ms (es): 493[ M + H ]]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]-N- (2-piperidin-1-ylphenyl) benzamide; ms (es): 525[ M + H ]]+；
N- (5-chloro-2-morpholin-4-ylphenyl) -4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]A benzamide; ms (es): 561[ M + H ]]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]-N-isoxazol-3-ylbenzamide; ms (es): 433[ M + H ]]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]-N- [5- (1, 1-dimethylethyl) -1, 3, 4-thiadiazol-2-yl]A benzamide; ms (es): 506[ M + H]+；
2- [ ({4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl)]Phenyl } carbonyl) amino]-4-methylbenzoic acid; ms (es): 500[ M + H ]]+；
4- [1- (2-Chlorobenzene)3- (trifluoromethyl) -1H-pyrazol-5-yl radical ]-N-1H-indazol-5-ylbenzamide; ms (es): 482[ M + H ]]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]-N- {4- [ (1-methylethyl) oxy group]Phenyl } benzamide; ms (es): 500[ M + H ]]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]-N- (4-methyl-1, 3-thiazol-2-yl) benzamide; ms (es): 463[ M + H]+；
N- (2-chloro-3-hydroxy-4-methylphenyl) -4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]A benzamide; ms (es): 506[ M + H]+；
{4- [ ({4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl)]Phenyl } carbonyl) amino]Phenyl } acetic acid; ms (es): 500[ M + H ]]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]-N- (furan-2-ylmethyl) -N-methylbenzamide; ms (es): 460[ M + H ]]+；
4- ({4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]Phenyl } carbonyl) -2, 6-dimethylmorpholine; ms (es): 464[ M + H ]]+；
1- ({4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]Phenyl } carbonyl) -4- (ethanesulfonyl) piperazine; ms (es): 527[ M + H]+；
1- ({4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]Phenyl } carbonyl) -1, 4-diazepane; ms (es): 449[ M + H ]]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl ]-N-methyl-N- (pyridin-4-ylmethyl) benzamide; ms (es): 471[ M + H]+；
4- ({4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]Phenyl } carbonyl) thiomorpholine; ms (es): 452[ M + H]+；
·1-({4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]Phenyl } carbonyl) piperidin-3-ol; ms (es): 450[ M + H ]]+；
[1- ({4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl ] amide]Phenyl } carbonyl) pyrrolidin-2-yl]Methanol; ms (es): 450[ M + H ]]+；
1- ({4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]Phenyl } carbonyl) piperidin-4-ol; ms (es): 450[ M + H ]]+；
1- ({4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]Phenyl } carbonyl) -4-methyl-1, 4-diazepane; ms (es): 463[ M + H]+；
1- ({4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]Phenyl } carbonyl) -4- [2- (trifluoromethyl) phenyl]Piperazine; ms (es): 579[ M + H ]]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]-N- [2- (dimethylamino) ethyl group]-N-methylbenzamide; ms (es): 451[ M + H ]]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]-N-methyl-N- (2-thienylmethyl) benzamide; ms (es): 476[ M + H ]]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl ]-N- (4-piperidin-1-ylphenyl) benzamide; ms (es): 525[ M + H ]]+；
1- ({4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]Phenyl } carbonyl) piperidine-4-carboxylic acid; ms (es): 478[ M + H]+；
4- ({4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]Phenyl } carbonyl) morpholine; ms (es): 436[ M + H]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]-N-1, 3, 4-thiadiazol-2-ylbenzamide; ms (es): 450[ M + H ]]+；
4- [1- (2-chlorophenyl)) -3- (trifluoromethyl) -1H-pyrazol-5-yl]-N- (4-hydroxy-3-methylphenyl) benzamide; ms (es): 472[ M + H]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]-N- [4- (5-methyl-3-oxo-2, 3-dihydro-1H-pyrazol-1-yl) phenyl]A benzamide; ms (es): 538[ M + H]+；
2- [4- ({4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]Phenyl } carbonyl) piperazin-1-yl]A benzonitrile; ms (es): 536[ M + H]+；
1- ({4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]Phenyl } carbonyl) -4-pyridin-4-ylpiperazine; ms (es): 512[ M + H]+；
1- ({4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]Phenyl } carbonyl) -4- [4- (methoxy) phenyl]Piperazine; ms (es): 541[ M + H]+；
2- [4- ({4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl ]Phenyl } carbonyl) piperazin-1-yl]Phenol; ms (es): 527[ M + H]+；
4- ({4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]Phenyl } carbonyl) piperazin-2-one; ms (es): 449[ M + H ]]+；
3- ({4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]Phenyl } carbonyl) -4, 4-dimethyl-1, 3-oxazolidine; ms (es): 450[ M + H ]]+；
1- ({4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]Phenyl } carbonyl) -4- (tetrahydrofuran-2-ylmethyl) piperazine; ms (es): 519[ M + H ]]+；
1- ({4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]Phenyl } carbonyl) -4-propionyl piperazine; ms (es): 491[ M + H]+；
1- ({4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]Phenyl } carbonyl) -4-methylpiperazine; ms (es): 449[ M + H ]]+；
[1- ({4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl ] amide]Phenyl } carbonyl) pyrrolidin-3-yl]1, 1-dimethylethyl carbamate; ms (es): 535[ M + H]+；
1- ({4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]Phenyl } carbonyl) azetidine-3-carboxylic acid; ms (es): 450[ M + H ]]+；
4- [4- ({4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]Phenyl } carbonyl) piperazin-1-yl]Phenol; ms (es): 527[ M + H]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl ]-N- [2- (methoxy) ethyl]-N- (1-methylpiperidin-4-yl) benzamide; ms (es): 521[ M + H]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]-N-methyl-N- (1-methylpyrrolidin-3-yl) benzamide; ms (es): 463[ M + H]+；
1- ({4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]Phenyl } carbonyl) -1, 2, 5, 6-tetrahydropyridine-3-carboxylic acid; ms (es): 476[ M + H ]]+；
1- ({4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]Phenyl } carbonyl) -4- (1-methylpropyl) piperazine; ms (es): 491[ M + H]+；
3- [1- ({4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]Phenyl } carbonyl) piperidin-4-yl]-1H-indole; ms (es): 549[ M + H]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]-N-cyclopropyl-N- (1-methylpiperidin-4-yl) benzamide; ms (es): 503[ M + H]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]-N- [2- (dimethylamino) ethyl group]-N-ethylbenzamide; ms (es): 465[ M + H]+；
2- [4- ({4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]Phenyl radicalCarbonyl) piperazin-1-yl]Pyrazine; ms (es): 513[ M + H]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]-N- (1, 3-dioxolan-2-ylmethyl) -N-methylbenzamide; ms (es): 466[ M + H ]+；
N- (1-acetylpiperidin-4-yl) -4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]-N-cyclopropylbenzamide; ms (es): 531[ M + H]+；
1- ({4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]Phenyl } carbonyl) -4- (6-methylpyridin-2-yl) piperazine; ms (es): 526[ M + H ]]+；
1- ({4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]Phenyl } carbonyl) piperidine-2-carboxylic acid ethyl ester; ms (es): 506[ M + H]+；
1- ({4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]Phenyl } carbonyl) -4- (3-methylphenyl) piperazine; ms (es): 525[ M + H ]]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]-N-cyclopropyl-N- (1-propylpiperidin-4-yl) benzamide; ms (es): 531[ M + H]+；
1- ({4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]Phenyl } carbonyl) piperidine-4-carboxylic acid ethyl ester; ms (es): 506[ M + H]+；
1- ({4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]Phenyl } carbonyl) -4- [4- (trifluoromethyl) pyrimidin-2-yl]-1, 4-diazepane; ms (es): 595[ M + H]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]-N-methyl-N- (pyridin-3-ylmethyl) benzamide; ms (es): 471[ M + H]+；
N-butyl-4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl ]-N- (2-thienylmethyl) benzamide; ms (es): 518[ M + H]+；
1- ({4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]Phenyl } carbonyl) -4-ethylpiperazine; ms (es): 463[ M + H]+；
1- ({4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]Phenyl } carbonyl) -4- [3- (methoxy) phenyl]Piperazine; ms (es): 541[ M + H]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]-N-methyl-N- (1-methylpiperidin-4-yl) benzamide; ms (es): 477[ M + H ]]+；
N- (2-amino-2-oxyethyl) -4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]-N-methylbenzamide; ms (es): 437[ M + H]+；
1- ({4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]Phenyl } carbonyl) -4- (furan-2-ylcarbonyl) piperazine; ms (es): 529[ M + H]+；
1- ({4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]Phenyl } carbonyl) -4- (2-fluorophenyl) piperazine; ms (es): 529[ M + H]+；
1- ({4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]Phenyl } carbonyl) -4- [2- (methoxy) phenyl]Piperazine; ms (es): 541[ M + H]+；
1- ({4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]Phenyl } carbonyl) -4- [2- (2-thienyl) ethyl]Piperazine; ms (es): 545[ M + H]+；
4- [ ({4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl) ]Phenyl } carbonyl) amino]Benzoic acid; ms (es): 486[ M + H]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]-N- [3- (piperidine-1-sulfonyl) phenyl]A benzamide; ms (es): 589[ M + H]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]-N-1, 3-thiazol-2-ylbenzamide; ms (es): 449[ M + H ]]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]-N- [3- (pyrrolidine-1-sulfonyl) phenyl]A benzamide; ms (es): 575[ M + H ]]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]-N- [ 2-methyl-4- (methoxy) phenyl]A benzamide; ms (es): 486[ M + H]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]-N- {2- [ (difluoromethyl) oxy group]Phenyl } benzamide; ms (es): 508[ M + H ]]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]-N- {4- [ (difluoromethyl) oxy group]Phenyl } benzamide; ms (es): 508[ M + H ]]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]-N- (3-fluorophenyl) benzamide; ms (es): 460[ M + H ]]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]-N- [3- (morpholine-4-sulfonyl) phenyl]A benzamide; ms (es): 591[ M + H]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl ]-N- [4- (trifluoromethyl) phenyl]A benzamide; ms (es): 510[ M + H]+；
N- (3-chlorophenyl) -4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]A benzamide; ms (es): 476[ M + H ]]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]-N- [6- (methylsulfonyl) pyridin-3-yl]A benzamide; ms (es): 521[ M + H]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]-N- [2- (trifluoromethyl) phenyl]A benzamide; ms (es): 510[ M + H]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]-N- [2- (methoxy) phenyl]A benzamide; ms (es): 472[ M + H]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]-N- [ 2-fluoro-5- (trifluoromethyl) phenyl]A benzamide; ms (es): 528[ M + H ]+；
N- (2-chlorophenyl) -4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]A benzamide; ms (es): 476[ M + H ]]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]-N- [3- (methoxy) phenyl]A benzamide; ms (es): 472[ M + H]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]-N- [3- (trifluoromethyl) phenyl]A benzamide; ms (es): 510[ M + H]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]-N- {2- [ (trifluoromethyl) oxy group ]Phenyl } benzamide; ms (es): 526[ M + H ]]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]-N- [4- (pyridin-4-ylcarbonyl) phenyl]A benzamide; ms (es): 547[ M + H]+；
N- [3, 5-bis (methoxy) phenyl]-4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]A benzamide; ms (es): 502[ M + H]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]-N-pyridin-3-ylbenzamide; ms (es): 443[ M + H ]]+；
N- (2-chloro-5-hydroxyphenyl) -4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]A benzamide; ms (es): 492[ M + H]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]-N-pyridin-4-ylbenzamide; ms (es): 443[ M + H ]]+；
N-1, 3-benzodioxol-5-yl-4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]A benzamide; ms (es): 486[ M + H]+；
3- [ ({4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl)]Phenyl } carbonyl) amino]Benzoic acid; ms (es): 486[ M + H]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]-N- [ 2-methyl-6- (methoxy) phenyl]A benzamide; ms (es): 486[ M + H]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]-N- (3-methylpyridin-2-yl) benzamide; ms (es): 457[ M + H ]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]-N- {4- [ (trifluoromethyl) oxy group]Phenyl } benzamide; ms (es): 526[ M + H ]]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]-N- (3-cyclopropyl-1H-pyrazol-5-yl) benzamide; ms (es): 472[ M + H]+；
N- [3, 4-bis (methoxy) phenyl]-4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]A benzamide; ms (es): 502[ M + H]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]-N-quinolin-8-ylbenzamide; ms (es): 493[ M + H ]]+;
4-chloro-3- [ ({4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl)]Phenyl } carbonyl) amino]Benzoic acid; ms (es): 520[ M + H ]]+；
1- ({4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]Phenyl } carbonyl) azetidine-2-carboxylic acid; ms (es): 450[ M + H ]]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]-N- {3- [ (trifluoromethyl) oxy group]Phenyl } benzamide; ms (es): 526[ M + H ]]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]-N- {4- [ (trifluoromethyl) thio group]Phenyl } benzamide; ms (es): 542[ M + H]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]-N- [6- (methoxy) pyridin-3-yl]A benzamide; ms (es): 473[ M + H ] ]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]-N- (4-methylpyridin-2-yl) benzamide; ms (es): 457[ M + H]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]-N- [ 2-methyl-5- (methoxy) phenyl]A benzamide; ms (es): 486[ M + H]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]-N- (1-methyl-1H-pyrazol-5-yl) benzamide; ms (es): 446[ M + H [ ]]+；
N- [5- (acetylamino) -2-chlorophenyl ]]-4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]A benzamide; ms (es): 533[ M + H ]]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]-N- [5- (trifluoromethyl) -1, 3, 4-thiadiazol-2-yl]A benzamide; ms (es): 518[ M + H]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]-N- [ 4-chloro-2- (trifluoromethyl) phenyl]A benzamide; ms (es): 544[ M + H]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]-N- (5-methylpyridin-2-yl) benzamide; ms (es): 457[ M + H]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]-N- [2- (methoxy) -5- (trifluoromethyl) phenyl]A benzamide; ms (es): 540[ M + H ]]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]-N- (6-methylpyridin-2-yl) benzamide; ms (es): 457[ M + H ]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]-N- [4- (methoxy) biphenylRadical-3-radical]A benzamide; ms (es): 548[ M + H]+；
N- (3-chloro-4-fluorophenyl) -4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]A benzamide; ms (es): 494[ M + H]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]-N- {6- [ (trifluoromethyl) oxy group]-1, 3-benzothiazol-2-yl } benzamide; ms (es): 583[ M + H]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]-N- [ 2-fluoro-3- (trifluoromethyl) phenyl]A benzamide; ms (es): 528[ M + H ]]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]-N- [2- (1H-pyrrol-1-yl) phenyl]A benzamide; ms (es): 507M + H]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]-N- [ 2-chloro-5- (trifluoromethyl) phenyl]A benzamide; ms (es): 544[ M + H]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]-N- (1-methyl-1H-pyrazol-3-yl) benzamide; ms (es): 446[ M + H [ ]]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]-N- [5- (1, 1-dimethylethyl) -2- (methoxy) phenyl]A benzamide; ms (es): 528[ M + H ]]+；
N- [ 5-chloro-2- (methoxy) phenyl]-4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl ]A benzamide; ms (es): 506[ M + H]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]-N- (5-methyl-1, 3, 4-thiadiazol-2-yl) benzamide; ms (es): 464[ M + H ]]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]-N- (2, 6-dichlorophenyl) benzamide; ms (es): 510[ M + H]+；
4- [1- (2-chloro)Phenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]-N- (3-hydroxyphenyl) benzamide; ms (es): 458[ M + H ]]+；
2- [ ({4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl)]Phenyl } carbonyl) amino]-6- (methoxy) benzoic acid; ms (es): 516[ M + H]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]-N- (5-methylisoxazol-3-yl) benzamide; ms (es): 447[ M + H]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]-N- [ 3-fluoro-4- (methoxy) phenyl]A benzamide; ms (es): 490[ M + H [ ]]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]-N- [4- (dimethylamino) phenyl]A benzamide; ms (es): 485[ M + H]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]-N- (furan-2-ylmethyl) benzamide; ms (es): 446[ M + H [ ]]+；
4- [ ({4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl)]Phenyl } carbonyl) amino ]Piperidine-1-carboxylic acid ethyl ester; ms (es): 521[ M + H]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]-N- (tetrahydrofuran-2-ylmethyl) benzamide; ms (es): 450[ M + H ]]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]-N- (2-thienylmethyl) benzamide; ms (es): 462[ M + H ]]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]-N- [2- (dimethylamino) ethyl group]A benzamide; ms (es): 437[ M + H]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]-N- [3- (dimethylamino) -2, 2-dimethylpropyl radical]A benzamide; ms (es): 479[ M + H ]]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]-N- (2-pyrrolidin-1-ylethyl) benzamide; ms (es): 463[ M + H]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]-N- {3- [ (1-methylethyl) oxy group]Propyl } benzamide; ms (es): 466[ M + H]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]-N- { [2- (methoxy) phenyl]Methyl } benzamide; ms (es): 486[ M + H]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]-N- (3-morpholin-4-ylpropyl) benzamide; ms (es): 493[ M + H ]]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl ]-N- [2- (2-thienyl) ethyl]A benzamide; ms (es): 476[ M + H ]]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]-N- (pyridin-4-ylmethyl) benzamide; ms (es): 457[ M + H]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]-N- {2- [3- (methoxy) phenyl]Ethyl } benzamide; ms (es): 500[ M + H ]]+；
N- { [3, 4-bis (methoxy) phenyl]Methyl } -4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]A benzamide; ms (es): 516[ M + H]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]-N- {2- [4- (methoxy) phenyl]Ethyl } benzamide; ms (es): 500[ M + H ]]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]2-piperidin-1-ylethyl benzoate, ms (es): 478[ M + H]+.
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]2- (dimethylamino) ethyl benzoate, ms (es): 438[ M + H]+.
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl ] phenyl]2-piperidin-1-ylethyl benzoate, ms (es): 478[ M + H]+.
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]2-morpholin-4-ylethyl benzoate, ms (es): 480[ M + H ]]+.
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]3- (dimethylamino) propyl benzoate, ms (es): 452[ M + H ]+.
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]2- (methylsulfonyl) ethyl benzoate, ms (es): 473[ M + H ]]+.
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]2- (4-methylpiperazin-1-yl) ethyl benzoate, ms (es): 493[ M + H ]]+.
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]3- (methylsulfonyl) propyl benzoate, ms (es): 487[ M + H ]]+.
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]2- (dimethylamino) ethyl benzoate; ms (es): 438[ M + H]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]2-pyridin-2-ylethyl benzoate; ms (es): 472[ M + H]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]Benzoic acid [3, 5-dimethyl-4- (methoxy) pyridin-2-yl]Methyl ester; ms (es): 516[ M + H]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]2- (propylthio) ethyl benzoate; ms (es): 469[ M + H]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]Furan-3-ylmethyl benzoate; ms (es): 447[ M + H]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]Benzoic acid (2, 4-difluoro)Phenyl) methyl ester; ms (es): 493[ M + H ]]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl ]Furan-2-ylmethyl benzoate; ms (es): 447[ M + H]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]2- (2-methylphenyl) ethyl benzoate; ms (es): 485[ M + H]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]Benzoic acid 2- [3- (trifluoromethyl) phenyl]Ethyl ester; ms (es): 539[ M + H ]]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]3- (methylthio) propyl benzoate; ms (es): 455[ M + H]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]2-oxo-2-phenylethyl benzoate; ms (es): 485[ M + H]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]Pyridin-3-ylmethyl benzoate; ms (es): 458[ M + H ]]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]2- (phenylsulfonyl) ethyl benzoate; ms (es): 535[ M + H]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]2, 5-dichlorophenyl methyl benzoate; ms (es): 525[ M + H ]]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]Benzoic acid [4- (methylthio) phenyl group]Methyl ester; ms (es): 503[ M + H]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]Cyanomethyl benzoate; ms (es): 406[ M + H]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl ]Benzoic acid 3- [3- (trifluoromethyl) -1H-pyrazol-4-yl]Propyl ester; ms (es): 543[ M + H ]]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]2-isoxazol-4-ylethyl benzoate; ms (es): 462[ M + H ]]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]2- (2-thienyl) ethyl benzoate; ms (es): 477[ M + H ]]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl](5-methyl-1-phenyl-1H-pyrazol-4-yl) methyl benzoate; ms (es): 537[ M + H ]]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]Benzoic acid 2, 2' -dithiophen-5-ylmethyl ester; ms (es): 545[ M + H]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]3-pyridin-2-ylpropyl benzoate; ms (es): 486[ M + H]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]2- (methylthio) ethyl benzoate; ms (es): 441[ M + H]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]Pyridin-4-ylmethyl benzoate; ms (es): 458[ M + H ]]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]1, 3-benzothiazol-2-ylmethyl benzoate; ms (es): 514[ M + H]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]3-thienyl methyl benzoate; ms (es): 463[ M + H ]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]Benzoic acid 2- [ (4-methylphenyl) sulfonyl group]Ethyl ester; ms (es): 549[ M + H]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]2- (4-methyl-1, 3-thiazol-5-yl) ethyl benzoate; ms (es): 492[ M + H]+；
4- [1- (2-chlorophenyl) -3- (tris)Fluoromethyl) -1H-pyrazol-5-yl](2-phenyl-1, 3-thiazol-4-yl) methyl benzoate; ms (es): 540[ M + H ]]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]2-cyanoethyl benzoate; ms (es): 420[ M + H]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]Benzoic acid hydroxyacetic anhydride; ms (es): 425[ M + H]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]Benzoic acid [1- (phenylmethyl) -1H-imidazol-2-yl]Methyl ester; ms (es): 537[ M + H ]]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl](5-methyl-3-phenylisoxazol-4-yl) methyl benzoate; ms (es): 538[ M + H]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]Benzoic acid [4- (1H-pyrazol-1-yl) phenyl]Methyl ester; ms (es): 523[ M + H]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]Benzoic acid [2, 3-bis (methoxy) phenyl]Methyl ester; ms (es): 517[ M + H ]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]Benzoic acid (5-methyl-2-phenyl-2H-1, 2, 3-triazol-4-yl) methyl ester; ms (es): 538[ M + H]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]Benzoic acid [4- (1H-1, 2, 4-triazol-1-yl) phenyl]Methyl ester; ms (es): 524[ M + H]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]Benzoic acid [6- (phenoxy) pyridin-3-yl]Methyl ester; ms (es): 550[ M + H ]]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]Benzoic acid 2- { [4- (trifluoromethyl) pyridin-2-yl]Oxy } ethyl ester; ms (es): 556[ M + H]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]Benzoic acid 2- (3-methyl-5-oxo-4, 5-dihydro-1H-pyrazol-4-yl) ethyl ester; ms (es): 491[ M + H]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl](2-butyl-5-chloro-1H-imidazol-4-yl) methyl benzoate; ms (es): 537[ M + H ]]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl](5-pyridin-2-yl-2-thienyl) methyl benzoate; ms (es): 540[ M + H ]]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl](5-methyl-1H-imidazol-4-yl) methyl benzoate; ms (es): 461[ M + H ]]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl ]3-pyridin-3-ylpropyl benzoate; ms (es): 486[ M + H]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]Benzoic acid 2- [ (2-methylpropyl) thio group]Ethyl ester; ms (es): 483[ M + H]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]Benzoic acid [5- (2-methyl-1, 3-thiazol-4-yl) -2-thienyl]Methyl ester; ms (es): 560[ M + H ]]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]2- (2-chlorophenyl) ethyl benzoate; ms (es): 505[ M + H]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]Pyridin-2-ylmethyl benzoate; ms (es): 458[ M + H ]]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]Benzoic acid 1H-imidazol-4-ylmethyl ester; ms (es): 447[ M + H]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl](2-methylpyridin-3-yl) methyl benzoate; ms (es): 472[ M + H]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]Benzoic acid [1- (phenylsulfonyl) -1H-indol-3-yl]Methyl ester; ms (es): 636[ M + H]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]2- (1H-imidazol-1-yl) ethyl benzoate; ms (es): 461[ M + H ]]+；
4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]2- (diethylamino) ethyl benzoate; ms (es): 466[ M + H ]+；
N- ({4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]Phenyl } carbonyl) glycine, ms (es): 424[ M + H]+；
N- ({4- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]Phenyl } carbonyl) - β -alanine, ms (es): 438[ M + H]+。
Example 76
Preparation of 3- (methylsulfonyl) propyl 4- (1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl) benzoate
Figure S2006800306472D02971
To 3- (methylthio) propyl 4- (1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl) benzoate (382mg, 0.84mmol) in CH2Cl2To a solution (10mL) was added chloroperoxybenzoic acid (429mg 77% technical grade, 1.9 mmol). After stirring for 1 hour at ambient temperature, LC/MS indicated complete conversion to product. At this point, 10% aqueous sodium thiosulfate and saturated NaHCO were added3The aqueous solution quenches the reaction. CH for alkaline aqueous solution2Cl2(3x) extracting. The combined organic extracts are purified over Na2SO4Drying, filtering, and concentrating the filtrate under reduced pressure to obtain the membrane. This crude product was purified by flash column chromatography eluting with a gradient from 0% to 100% EtOAc in hexanes to give a viscous white solid3- (methylsulfonyl) propyl 4- (1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl) benzoate (345mg, 84% yield).1H NMR(400MHzCDCl3)：δ7.98-7.91(2H，m)，7.50(1H，m)，7.48-7.36(3H，m)，7.33-7.27(2H，m)，6.88(1H，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- (methylsulfonyl) phenyl ] -2-thienyl } -1- [2- (trifluoromethyl) pyridin-3-yl ] -1H-pyrazol-3-yl) propan-2-ol
Figure S2006800306472D02981
To a solution of 2- (5- (5- (3- (methylsulfonyl) phenyl) thiophen-2-yl) -1- (2- (trifluoromethyl) pyridin-3-yl) -1H-pyrazol-3-yl) propan-2-ol (10.6g, 21mmol) in MeCN (200mL) was added N-chlorosuccinimide. The resulting solution was heated to 75 ℃ in a heating mantle. Stirring at 75 deg.C for 3 hours, stopping heating, and concentrating the solution under reduced pressure to give a yellow foam. This crude product was purified by flash column chromatography eluting with a gradient from 0% to 100% EtOAc/hexanes. Fractions which were shown to be pure by TLC analysis were combined and concentrated under reduced pressure to give a white viscous foam which was shown to be contaminated with succinimide by NMR analysis. This material is charged into CH2Cl2In, use saturated Na together2CO3(2x) aqueous wash. The organic layer was washed with Na2SO4Drying, filtering and concentrating under reduced pressure to give 2- (4-chloro-5- {5- [3- (methylsulfonyl) phenyl ] as an off-white foam]-2-thienyl } -1- [2- (trifluoromethyl) pyridin-3-yl]-1H-pyrazol-3-yl) propan-2-ol (6.7g, 60% yield).1H NMR(400MHz CDCl3)：δ8.85(1H，m)，8.06(1H，t)，7.86(1H，m)，7.82-7.73(2H，m)，7.67-7.62(1H，m)，7.58(1H，t)，7.28(1H，d)，7.01(1H，d)，3.08(3H，s)，2.93(1H，s)，1.73(6H，s).MS(ES)：542[M+H]+.
The following compounds are prepared essentially in accordance with the previous examples:
2- (4-chloro-5- { 3-methyl-5- [3- (methylsulfonyl) phenyl)]-2-thienyl } -1- [2- (trifluoromethyl) pyridin-3-yl]-1H-pyrazol-3-yl) propan-2-ol, ms (es): 556[ M + H]+。
2- { 4-chloro-1- (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-chloro-5- [ 3-methyl-3' - (methylsulfonyl) biphenyl-4-yl]-1- [2- (trifluoromethyl) pyridin-3-yl]-1H-pyrazol-3-yl } propan-2-ol, ms (es): 550[ M + H ]]+.
2- { 4-chloro-5- [ 3-methyl-3' - (methylsulfonyl) biphenyl-4-yl]-1- [4- (trifluoromethyl) pyridin-3-yl]-1H-pyrazol-3-yl } propan-2-ol ms (es): 550[ M + H ]]+.
2- { 4-chloro-5- [ 3' - (methylsulfonyl) biphenyl-4-yl]-1- [4- (trifluoromethyl) pyridin-3-yl]-1H-pyrazol-3-yl } propan-2-ol ms (es): 536[ M + H]+.
2- { 4-chloro-1- (2, 6-dichlorophenyl) -5- [ 3' - (methylsulfonyl) biphenyl-4-yl]-1H-pyrazol-3-yl } propan-2-ol ms (es): 537[ M + H ]]+.
2- { 4-chloro-5- [ 3-chloro-3' - (methylsulfonyl) biphenyl-4-yl]-1- (2, 6-dichlorophenyl) -1H-pyrazol-3-yl } propan-2-ol ms (es): 571[ M + H]+.
2- { 4-chloro-5- [ 3-chloro-3' - (methylsulfonyl) biphenyl-4-yl]-1- [2- (trifluoromethyl) pyridin-3-yl]-1H-pyrazol-3-yl } propan-2-ol ms (es): 570[ M + H]+.
Example 78
Preparation of azetidin-1-yl (4- (1- (2-chlorophenyl) -3- (2-hydroxypropan-2-yl) -1H-pyrazol-5-yl) phenyl) methanone
Figure S2006800306472D02991
To a cold (-78 ℃ C.) solution of methyl 5- (4- (azetidine-1-carbonyl) phenyl) -1- (2-chlorophenyl) -1H-pyrazole-3-carboxylate (138mg, 0.35mmol) in THF (5mL) was added methylmagnesium bromide (0.3mL, 3.0M in ether, 0.9 mmol). The resulting brown solution was slowly warmed to ambient temperature overnight. The reaction was then quenched by addition of saturated aqueous ammonium chloride and EtOAc. The aqueous solution was extracted with EtOAc (3 ×), the combined organic extracts were washed with brine and dried (Na) 2SO4) Filtered and concentrated under reduced pressure to give a yellow membrane. The crude product was purified by flash column chromatography with 0% to 10% MeOH/CH2Cl2Gradient elution of (2). The main peak was collected by HPLC and the purity of the main peak was 85%. This material was further purified by reverse phase preparative HPLC using MeCN/H2O and 0.1% TFA. Carefully add solid Na to the product fraction from HPLC2CO3Making alkaline. The resulting mixture was concentrated to remove most of the MeCN. The obtained suspension in water was treated with CH2Cl2(3X) extraction, combined extracts over Na2SO4Drying overnight, filtration and concentration under reduced pressure gave azetidin-1-yl (4- (1- (2-chlorophenyl) -3- (2-hydroxypropan-2-yl) -1H-pyrazol-5-yl) phenyl) methanone as a pale brown powder (43mg, 31% yield).1HNMR(400MHz CDCl3)：δ7.54-7.48(2H，m)，7.46-7.40(2H，m)，7.39-7.31(2H，m)，7.24-7.19(2H，m)，6.54(1H，s)，4.32-4.16(4H，m)，2.63(1H，s)，2.38-2.28(2H，m)，1.68(6H，s).MS(ES)：396[M+H]+.
The following compounds are prepared essentially in accordance with the previous examples:
2- {1- (2-chlorophenyl) -5- [4- (pyrrolidin-1-ylcarbonyl) phenyl]-1H-pyrazol-3-yl } propan-2-ol, ms (es): 410[ M + H]+.
Example 79
2- [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl ] pyridin-2-yl } -1H-pyrazol-3-yl ] propan-2-ol
Example 79a
Preparation of methyl 5- (5-bromopyridin-2-yl) -1- (2-chlorophenyl) -1H-pyrazole-3-carboxylate
Figure S2006800306472D03001
A mixture of (2-chlorophenyl) hydrazine hydrochloride (1.1g, 6.1mmol) and methyl 4- (5-bromopyridin-2-yl) -2, 4-dioxobutyrate (1.7g, 6.0mmol) in MeOH (30mL) was partitioned into two microwave reaction vessels. Each reaction vessel was then heated in a microwave at 120 ℃ for 10 minutes. LC/MS analysis at this point showed the reaction was essentially complete. The solution was concentrated under reduced pressure to give a dark brown semi-solid. This material was charged to EtOAc and saturated NaHCO 3In aqueous solution. The layers were separated and the basic aqueous solution was extracted with EtOAc (3 ×). The combined organic extracts were washed with brine, over Na2SO4Dried, filtered and concentrated to give a black oil. This crude product was purified by flash column chromatography eluting with a gradient from 0% to 100% EtOAc/hexanes to give methyl 5- (5-bromopyridin-2-yl) -1- (2-chlorophenyl) -1H-pyrazole-3-carboxylate (300mg, 13% yield) as an oil.
Example 79b
Preparation of methyl 1- (2-chlorophenyl) -5- (5- (3- (methylsulfonyl) phenyl) pyridin-2-yl) -1H-pyrazole-3-carboxylate
Figure S2006800306472D03011
5- (5-Bromopyridin-2-yl) -1- (2-chlorophenyl) -1H-pyrazole-3-carboxylic acid methyl ester (200mg, 0.51mmol), 3- (methylsulfonyl) phenylboronic acid (120mg, 0.60mmol), and [1, 1' -bis (diphenylphosphino) ferrocene]Palladium (II) dichloride dichloromethane adduct (20mg, 24. mu. mol) with K2CO3(0.45mL, 3.5M aqueous solution, 1.6Mmol) were mixed in DME (2.5mL) in a microwave reaction flask. The dark mixture was heated at 120 ℃ for 5 minutes. The reaction mixture was washed with EtOAc and H2And (4) diluting with oxygen. The aqueous layer was removed and extracted with additional EtOAc. The combined organics were passed over Na2SO4Dried, treated with some decolorizing carbon, and filtered through a pad of celite. The filtrate was concentrated under reduced pressure and purified by flash column chromatography using 0% to 50% MeCN/CH 2Cl2Was eluted with a gradient of (1) - (2-chlorophenyl) -5- (5- (3- (methylsulfonyl) phenyl) pyridin-2-yl) -1H-pyrazole-3-carboxylic acid methyl ester to give a pale yellow foam. This material performs the subsequent steps. Ms (es): 468[ M + H]+.
The following compounds are prepared essentially in accordance with the previous examples:
2- [1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]Pyridin-2-yl } -1H-pyrazol-3-yl radical]The concentration of the propan-2-ol,1H NMR(400MHz CDCl3)：δ8.70(1H，m)，8.11(1H，m)，7.96(1H，m)，7.87-7.80(2H，m)，7.68(1H，t)，7.57(1H，m)，7.49-7.37(3H，m)，7.32(1H，d)，6.89(1H，s)，3.09(3H，s)，1.70(6H，s).MS(ES)：468[M+H]+.
2- [1- (2-chlorophenyl) -5- {6- [3- (methylsulfonyl) phenyl]Pyridin-3-yl } -1H-pyrazol-3-yl radicals]Propan-2-ol, ms (es): 468[ M + H]+.
2- [ 4-chloro-1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]Pyridin-2-yl } -1H-pyrazol-3-yl radical]Propan-2-ol, ms (es): 502[ M + H]+.
2- [ 4-chloro-1- (2-chlorophenyl) -5- {6- [3- (methylsulfonyl) phenyl]Pyridin-3-yl } -1H-pyrazol-3-yl radicals]Propan-2-ol, ms (es): 502[ M + H]+.
·
Example 80
Preparation of (1- (2, 6-dichlorophenyl) -5- (3-methyl-3' - (methylsulfonyl) biphenyl-4-yl) -1H-pyrazol-3-yl) (pyrrolidin-1-yl) methanone
Figure S2006800306472D03021
Methyl 1- (2, 6-dichlorophenyl) -5- (3-methyl-3' - (methylsulfonyl) biphenyl-4-yl) -1H-pyrazole-3-carboxylate (102mg, 0.20mmol) was suspended in pyrrolidine (0.6mL, 7.2mmol) and heated in a microwave at 180 ℃ for 10 min. The dark reaction mixture was concentrated under reduced pressure and azeotroped with toluene to remove most of the pyrrolidine. The crude product obtained is purified by preparative reverse phase HPLC using MeCN/H 2O eluted with 0.05% TFA. By careful addition of saturated NaHCO3The aqueous solution made the product fraction from HPLC basic. The resulting mixture was concentrated to remove most of the MeCN. The obtained suspension in water was treated with CH2Cl2(3X) extraction, combined extracts over Na2SO4Dried overnight, filtered and concentrated under reduced pressure to give (1- (2, 6-dichlorophenyl) -5- (3-methyl-3' - (methylsulfonyl) biphenyl-4-yl) -1H-pyrazol-3-yl) (pyrrolidin-1-yl) methanone as a brown solid (15mg, 14% yield).1H NMR(400MHz CDCl3)：δ8.10(1H，m)，7.91(1H，m)，7.83(1H，m)，7.62(1H，t)，7.49(1H，d)，7.42-7.34(2H，m)，7.33-7.21(2H，m)，7.13(1H，d)，7.06(1H，s)，3.99(2H，t)，3.71(2H，t)，3.08(3H，s)，2.50(3H，s)，2.03-1.86(4H，m).MS(ES)：554[M+H]+.
The following compounds are prepared essentially in accordance with the previous examples: :
5- [ 3-chloro-3' - (methylsulfonyl) biphenyl-4-yl]-1- (2, 6-dichlorophenyl) -3- (pyrrolidin-1-ylcarbonyl) -1H-pyrazole ms (es): 576[ M + H]+.
5- [ 3-chloro-3' - (methylsulfonyl) biphenyl-4-yl]-N- (2-methylpropyl) -1- [2- (trifluoromethyl) pyridin-3-yl]-1H-pyrazole-3-carboxamide ms (es): 577[ M + H ]]+.
5- [ 3-chloro-3' - (methylsulfonyl) biphenyl-4-yl]-1- (2, 6-dichlorophenyl) -N- (2-methylpropyl) -1H-pyrazole-3-carboxamide ms (es): 578[ M + H ]]+.
Example 81
(E) -3- (4- (1- (2, 6-dichlorophenyl) -3- (2-hydroxypropan-2-yl) -1H-pyrazol-5-yl) -3-methylstyryl) benzoic acid
Example 81a
Preparation of 4- (1- (2, 6-dichlorophenyl) -3- (2-hydroxypropan-2-yl) -1H-pyrazol-5-yl) -3-methylbenzaldehyde
Figure S2006800306472D03031
To 2- (5- (4-bromo-2-methylphenyl) -1- (2, 6-dichlorophenyl) -1H-pyrazol-3-yl) propan-2-ol (215mg, 0.49mmol) in THF (4ML) and Et2To a cold (-78 deg.C) solution of O (4mL) in a mixture was added lithium bis (trimethylsilyl) amide (0.5mL, 1.0M in THF, 0.5 mmol). After stirring at-78 ℃ for a few minutes, the resulting alkoxide solution was treated with n-butyllithium (1.0mL, 1.6M in hexane, 1.6 mmol). After stirring for 10 minutes at-78 ℃, LC/MS showed some starting bromide present in the reaction quenched aliquot. After 30 minutes, additional n-butyllithium (0.5mL, 1.6M in hexanes, 0.8mmol) was added. After stirring at-78 ℃ for an additional 15 minutes, the reaction mixture was treated with anhydrous N, N-dimethylformamide (0.4mL, 5.2 mmol). After a few minutes of DMF addition, the-78 ℃ bath was replaced with an ice bath and the reaction mixture was returned to room temperature overnight. The reaction was quenched by the addition of saturated NH4Cl and diluted with EtOAc. The layers were separated and the aqueous solution was extracted with EtOAc (3 ×). The combined organic extracts were washed with brine, washed with (Na)2SO4) Dried, filtered and concentrated under reduced pressure to give a yellow slurry. The crude product was purified by flash column chromatography eluting with 0% to 100% EtOAc/hexanes to give 4- (1- (2, 6-dichlorophenyl) -3- (2-hydroxypropan-2-yl) -1H-pyrazol-5-yl) -3-methylbenzaldehyde, which was carried forward without further purification. Ms (es): 389[ M + H ] ]+.
Example 81b
Preparation of (E) -methyl 3- (4- (1- (2, 6-dichlorophenyl) -3- (2-hydroxypropan-2-yl) -1H-pyrazol-5-yl) -3-methylstyryl) benzoate
To a suspension of NaH (52mg, 60% dispersion in mineral oil) in THF (7.5mL) cooled to 0 ℃ in an ice bath was added a solution of methyl 3- ((dimethoxyphosphoryl) methyl) benzoate in THF (1mL) followed by addition of THF (1mL) to rinse the phosphonate vial and washing to ensure complete transfer. The ice bath was removed and the reaction warmed to ambient temperature. After 90 minutes at ambient temperature, 4- (1- (2, 6-dichlorophenyl) -3- (2-hydroxypropan-2-yl) -1H-pyrazol-5-yl) -3-methylbenzaldehyde (0.49mmol, impure product from the previous step) was added to the reaction mixture via cannula, then the flask and cannula were washed with THF (1mL), after 1 hour 45 minutes at ambient temperature, by adding saturated NH4Aqueous Cl and EtOAc quench the reaction. The layers were separated and the aqueous layer was extracted with EtOAc (3 ×). The combined organic extracts were washed with brine, washed with (Na)2SO4) Dried, filtered and concentrated under reduced pressure to give a yellow slurry. The crude product was purified by flash column chromatography using from 0% to 40% MeCN/CH2Cl2Was eluted with a gradient of (g) to give a slightly impure product, 3- (4- (1- (2, 6-dichlorophenyl) -3- (2-hydroxypropan-2-yl) -1H-pyrazol-5-yl) -3-methylstyryl) benzoic acid (E) -methyl ester (180mg, 70% yield). This material was subjected to ester hydrolysis without further purification. Ms (es): 521[ M + H ]+.
Example 81c
(E) Preparation of (E) -3- (4- (1- (2, 6-dichlorophenyl) -3- (2-hydroxypropan-2-yl) -1H-pyrazol-5-yl) -3-methylstyryl) benzoic acid
Figure S2006800306472D03041
To a solution of methyl (E) -3- (4- (1- (2, 6-dichlorophenyl) -3- (2-hydroxypropan-2-yl) -1H-pyrazol-5-yl) -3-methylstyryl) benzoate (180mg, impurity from previous step, 0.35mmol) in THF (2.0mL) was added H2O (0.4mL), then lithium hydroxide monohydrate (25.3mg, 0.6mmol) was added. After stirring for 1 hour at ambient temperature, a biphasic mixture formed and LC/MS analysis of the reaction showed no reactant. A small amount of MeOH was added to homogenize the mixture, and then the reaction was heated to 50 ℃ in an oil bath. After stirring for 2 hours at 50 ℃, LC/MS analysis indicated the reaction was complete. The heating was stopped and after stirring overnight at ambient temperature, the reaction was quenched by the addition of 5% aqueous citric acid and EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc (3 ×). The combined organic extracts were washed with brine, washed with (Na)2SO4) Dried, filtered and concentrated under reduced pressure to give a clear membrane. This material was purified by reverse phase preparative HPLC using MeCN/H2Gradient elution of O with 0.05% TFA. The main peak from HPLC was concentrated under reduced pressure to remove most of the solvent, and the resulting acidic aqueous solution was treated with CH 2Cl2(3x) extracting. The combined organic extracts are washed with H2O wash until wash is no longer acidic (2X), over Na2SO4Dried, filtered, and concentrated under reduced pressure to give (E) -3- (4- (1- (2, 6-dichlorophenyl) -3- (2-hydroxypropan-2-yl) -1H-pyrazol-5-yl) -3-methylstyryl) benzoic acid as a white powder (45.4mg, 26% yield).1H NMR(400MHz CDCl3)：δ8.21(1H，s)，7.98(1H，d，7.69(1H，d)，7.45(1H，t)，7.39(1H，d)，7.37-7.31(2H，m)，7.23(1H，m)，7.15(1H，m)，7.12-7.07(2H，m)，7.06(1H，m)，6.46(1H，s)，2.45(3H，s)，1.71(6H，s).MS(ES)：529[M+Na]+.
Example 82
Preparation of 2- (1- (2, 6-dichlorophenyl) -5- (2-methyl-4- (2-morpholinoethylamino) phenyl) -1H-pyrazol-3-yl) propan-2-ol
Figure S2006800306472D03051
2- (5- (4-bromo-2-methylphenyl) -1- (2, 6-dichlorophenyl) -1H-pyrazol-3-yl) propan-2-ol ((160mg, 0.36mmol), 2-morpholinoethylamine (75mL, 0.57mmol), sodium tert-butoxide (54mg, 0.57mmol), biphenyl-2-yl di-tert-butylphosphine (13.1mg, 44. mu. mol), and Pd2(dba)3(19.8mg, 22. mu. mol) of the mixture was placed in a microwave reaction flask and heated at 160 ℃ for 15 minutes. After cooling, the reaction was taken up in saturated NaHCO3Aqueous and EtOAc dilution. The layers were separated and the aqueous layer was extracted with EtOAc (3 ×). The combined organic extracts were washed with brine, washed with (Na)2SO4) Dried, filtered and concentrated under reduced pressure to give a black oil. This material was purified by reverse phase preparative HPLC using MeCN/H2Gradient elution of O with 0.05% TFA. By adding saturated NaHCO3The aqueous solution basified the product peak from HPLC and concentrated under reduced pressure to remove most of the solvent. CH for alkaline aqueous solution 2Cl2(3x) extracting. The combined organic extracts are purified over Na2SO4Drying, filtration and concentration under reduced pressure gave 2- (1- (2, 6-dichlorophenyl) -5- (2-methyl-4- (2-morpholinoethylamino) phenyl) -1H-pyrazol-3-yl) propan-2-ol as a white foam (67mg, 38% yield).1H NMR(400MHz CDCl3)：δ7.34-7.29(2H，m)，7.20(1H，m)，6.84(1H，d)，6.46(1H，d)，6.32(1H，s)，6.23(1H，m)，4.32(1H，s)，3.74-3.66(4H，m)，3.15-3.07(2H，m)，2.66(1H，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 in accordance with the previous examples:
2- [1- (2, 6-dichlorophenyl) -5- { 2-methyl-4- [ (2-piperidin-1-ylethyl) amino group]Phenyl } -1H-pyrazol-3-yl]Propan-2-ol MS (ES): 487[ M + H ]]+.
2- [1- (2, 6-dichlorophenyl) -5- (2-methyl-4- { [2- (methylsulfonyl) ethyl]Amino } phenyl) -1H-pyrazol-3-yl]Propan-2-ol MS (ES): 504[ M + Na ]]+.
2- [1- (2, 6-dichlorophenyl) -5- {4- [ (1, 1-dioxo-tetrahydro-3-thienyl) amino group]-2-methylphenyl) -1H-pyrazol-3-yl]Propan-2-ol MS (ES): 516[ M + Na]+.
Scheme 30
Figure S2006800306472D03061
As scheme 30, alkoxycarbonyl biphenylpyrazoles are prepared from the condensation of hydrazines and diketones, which are further converted to methanol. The diketone 030ES01 can be condensed with hydrazine 030ES02 in a manner analogous to example 2c to give pyrazole 030ES 03. The resulting pyrazole can then be coupled with boronic acid 030ES04 under palladium catalyzed coupling conditions in a manner analogous to example 1c to give diaryl ester 030ES 05. The ester was treated with an alkyl magnesium halide in a similar manner to example 5 to give alcohol 030ES 06.
Example 82
2- {3 '-chloro-4' - [1- (2, 6-dichlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl ] biphenyl-3-yl } propan-2-ol
Example 82a
Preparation of methyl 3 '-chloro-4' - (1- (2, 6-dichlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl) biphenyl-3-carboxylate
Figure S2006800306472D03071
To a solution of 5- (4-bromo-2-chlorophenyl) -1- (2, 6-dichlorophenyl) -3- (trifluoromethyl) -1H-pyrazole (3.55g, 7.55mmol) and 3- (methoxycarbonyl) phenylboronic acid (1.77g, 9.83mmol) in 1, 2-dimethoxyethane (36mL) was added K2CO3(3.126g, 22.65mmol) andH2O (4 mL). The resulting biphasic suspension was stirred at ambient temperature and purged with nitrogen for 10 minutes. Then the reactant is treated with [1, 1' -bis (diphenylphosphino) ferrocene]Palladium (II) dichloride dichloromethane adduct (600mg, 0.734mmol) was treated and heated to 80 ℃ in an oil bath. The reaction was heated at 80 ℃ for 10 hours and then cooled to ambient temperature. The cooled reaction mixture was washed with EtOAc and H2And (4) diluting with oxygen. The aqueous layer was extracted with EtOAc (3 ×). The combined organic extracts were washed with brine, over Na2SO4Dry, filter and concentrate to give the crude product as a dark oil. The crude product was purified by flash column chromatography eluting with a gradient from 0% to 40% EtOAc/hexanes to give methyl 3 '-chloro-4' - (1- (2, 6-dichlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl) biphenyl-3-carboxylate (3.50g, 88% yield) as a solid. Ms (es): 525[ M + H ] ]+.
Example 82b
Preparation of 2- {3 '-chloro-4' - [1- (2, 6-dichlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl ] biphenyl-3-yl } propan-2-ol
Figure S2006800306472D03072
To a suspension of methyl 3 '-chloro-4' - (1- (2, 6-dichlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl) biphenyl-3-carboxylate (1.15g, 2.19mmol) in anhydrous tetrahydrofuran (10mL), stirred in an ice bath at 0 ℃, was added dropwise methylmagnesium bromide (2.04mL, 3.0M tetrahydrofuran solution, 6.12 mmol). After addition of methylmagnesium bromide, the ice bath was removed. After stirring at ambient temperature for 2 hours, saturated ammonium chloride and EtOAc were added and the reaction mixture was quenched. The aqueous layer was extracted with EtOAc (3 ×). The combined organic extracts are purified over Na2SO4Dried, filtered and concentrated under reduced pressure to give a brown oil. The crude product was purified by flash column chromatography eluting with a gradient from 0% to 100% EtOAc/hexanes to give a foamy white solid (450mg, 39% yield). Ms (es): 525[ M + H ]]+.1H-NMR(CDCl3)：δ7.73-7.67(2H，m)，7.48(1H，m)，7.44-7.28(6H，m)，7.19(1H，d)，6.98(1H，s)，1.74(1H，s)，1.62(6H，s).
The following compounds are prepared essentially in accordance with the previous examples:
2- (3- {5- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]-2-thienyl } phenyl) propan-2-ol, ms (es): 463[ M + H]+.
2- (4- {5- [1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl]-2-thienyl } phenyl) propan-2-ol, ms (es): 463[ M + H ]+.
2- [3- (5- {3- (trifluoromethyl) -1- [3- (trifluoromethyl) pyridin-2-yl]-1H-pyrazol-5-yl } -2-thienyl) phenyl]Propan-2-ol, ms (es): 498[ M + H]+.
2- [4- (5- {3- (trifluoromethyl) -1- [3- (trifluoromethyl) pyridin-2-yl]-1H-pyrazol-5-yl } -2-thienyl) phenyl]Propan-2-ol, ms (es): 498[ M + H]+.
Scheme 31
Figure S2006800306472D03081
As shown in scheme 31, 3-methoxy substituted pyrazoles (031vi) prepared as described in scheme 1 are converted to phenols 031SP1 which are treated with alkyl halides in the presence of a base to give 3-alkoxy substituted pyrazoles 031SP 2.
Example 83
Preparation of 3- (5- (5- (3- (methylsulfonyl) phenyl) thiophen-2-yl) -3- (trifluoromethyl) -1H-pyrazol-1-yl) phenol
Figure S2006800306472D03091
1- (3-methoxyphenyl) -5- (5- (3- (methylsulfonyl) phenyl) thiophen-2-yl) -3- (trifluoromethyl) -1H-pyrazole (031vi) was prepared as described in scheme 1. A solution of 1.0M boron tribromide (59.33mL, 59.33mmol) in anhydrous DCM was added slowly to a solution of 3-methoxy-substituted pyrazole (9.464g, 19.78mmol) in 20mL anhydrous DCM at-78 deg.C under nitrogen. The mixture was stirred vigorously and warmed to ambient temperature overnight. The reaction mixture was then cooled to 0 ℃ with an ice/water bath and approximately 50.0mL of MeOH was added in portions. The mixture was stirred at room temperature for 1 hour and concentrated in vacuo. The residue was dissolved in dichloromethane and neutralized to pH7 by the addition of 1N NaOH. The organic layer was washed with brine, water, separated and washed with anhydrous Na 2SO4And (5) drying. The dichloromethane was concentrated in vacuo. The resulting crude product was purified by column chromatography (30-60% EtOAc/hexanes) to give the product 3-hydroxy-substituted pyrazole (4.13g, 45% yield).1H-NMR (acetone-d 6): δ 8.83(s, 1H), 8.04(m, 1H), 7.85(m, 1H), 7.81(m, 1H), 7.61(m, 1H)7.51(m, 1H), 7.30(m, 1H), 7.06(m, 2H), 6.95(m, 1H), 6.92(m, 1H), 6.90(m 1H), 3.08(s, 3H); ms (es): 465[ M + H]+.
Example 84
Preparation of 1- (3-ethoxyphenyl) -5- (5- (3- (methylsulfonyl) phenyl) thiophen-2-yl) -3- (trifluoromethyl) -1H-pyrazole
Figure S2006800306472D03092
3- (5- (5- (3- (methylsulfonyl) phenyl) thiophen-2-yl) -3- (trifluoromethyl) -1H-pyrazol-1-yl) phenol (80mg, 0.17mmol) was dissolved in anhydrous DMF (3 mL). To this solution were added potassium carbonate (29mg, 0.20mmol) and bromoethane (38mg, 0.34mmol) in anhydrous DMF (3.0 mL). The reaction mixture was heated at 80 ℃ overnight under a nitrogen atmosphere. After the mixture was cooled, it was poured into 20.0mL of water and extracted with ethyl acetate. The combined organic layers were washed with brine and water and concentrated in vacuo. The crude product was purified by flash column chromatography (60% ethyl acetate/hexanes) to giveThe product, 3-ethoxy substituted pyrazole (65mg, 77% yield). 1H-NMR(CDCl3)：δ8.08(m，1H)，7.86(m，1H)，7.77(m，1H)，7.59(m，1H)，7.34(m，1H)，7.27(m，1H)，7.01(m，1H)，6.99(m，1H)，6.98(m，1H)，6.87(m，1H)，6.84(m，1H)，4.04(q，J＝6.8Hz，2H)，3.09(s，3H)，1.40(t，J＝6.8Hz，3H).MS(ES)：493[M+H]+.
The following compounds are prepared essentially in accordance with the previous examples:
1- (3-isopropoxyphenyl) -5- (5- (3- (methylsulfonyl) phenyl) thiophen-2-yl) -3- (trifluoromethyl) -1H-pyrazole ms (es): 507M + H]+
1- (3-isobutoxyphenyl) -5- (5- (3- (methylsulfonyl) phenyl) thiophen-2-yl) -3- (trifluoromethyl) -1H-pyrazole ms (es): 521[ M + H]+
Tert-butyl 2-methyl-2- (3- (5- (3- (methylsulfonyl) phenyl) thiophen-2-yl) -3- (trifluoromethyl) -1H-pyrazol-1-yl) phenoxy) propionate. Ms (es): 607[ M + H]+.
2- {5- [4- (3-methanesulfonyl-phenyl) -thiophen-2-yl]-3-trifluoromethyl-pyrazol-1-yl } -phenol. MS (ES)465.0[ M + H ]]+，
Diethyl- [2- (2- {5- [4- (3-methanesulfonyl-phenyl) -thiophen-2-yl]-3-trifluoromethyl-pyrazol-1-yl } -phenoxy) -ethyl]-an amine. MS (ES)564.3[ M + H]+，
[2- {5- [4- (3-methanesulfonyl-phenyl) -thiophen-2-yl ]]-3-trifluoromethyl-pyrazol-1-yl } -phenoxy) -acetic acid tert-butyl ester. MS (ES)579.4[ M + H ]]+，
1- [2- (2- {5- [4- (3-methanesulfonyl-phenyl) -thiophen-2-yl]-3-trifluoromethyl-pyrazol-1-yl } -phenoxy) -ethyl]-piperidine. MS (ES)576.3[ M + H ]]+，
4- [2- (2- {5- [4- (3-methanesulfonyl-phenyl) -thiophen-2-yl]-3-trifluoromethyl-pyrazol-1-yl } -phenoxy) -ethyl]-morpholine. MS (ES)578.4[ M + H ] ]+，
2- (2- {5- [4- (3-methanesulfonyl-phenyl) -thiophen-2-yl]-3-trifluoromethyl-pyrazol-1-yl } -phenoxymethyl) -pyridine. MS (ES)556.3[ M + H ]]+，
4- [3- (2- {5- [4- (3-methanesulfonyl-phenyl) -thiophen-2-yl]-3-trifluoromethyl-pyrazol-1-yl } -phenoxy) -propyl]-morpholine. MS (ES)592.0[ M + H]+，
1- [3- (2- {5- [4- (3-methanesulfonyl-phenyl) -thiophen-2-yl]-3-trifluoromethyl-pyrazol-1-yl } -phenoxy) -propyl]-4-methyl-piperazine. MS (ES)605.0[ M + H ]]+，
1- [2- (2, 2-dimethyl-propoxy) -phenyl]-5- [4- (3-methanesulfonyl-phenyl) -thiophen-2-yl]-3-trifluoromethyl-1H-pyrazole. MS (ES)535.3[ M + H]+，557.3[M+Na]+
2- (2- {5- [4- (3-methanesulfonyl-phenyl) -thiophen-2-yl]-3-trifluoromethyl-pyrazol-1-yl } -phenoxy) -ethanol. MS (ES)509.3[ M + H ]]+
1- [2- (3-chloro-propoxy) -phenyl]-5- [4- (3-methanesulfonyl-phenyl) -thiophen-2-yl]-3-trifluoromethyl-1H-pyrazole. MS (ES)541.3, 543.3[ M + H ]]+
1- (2-ethoxy-phenyl) -5- [4- (3-methanesulfonyl-phenyl) -thiophen-2-yl]-3-trifluoromethyl-1H-pyrazole. MS (ES)493.3[ M + H]+
1- (2-isopropoxy-phenyl) -5- [4- (3-methanesulfonyl-phenyl) -thiophen-2-yl]-3-trifluoromethyl-1H-pyrazole. MS (ES)507.3[ M + H ]]+
1- (2-isobutoxy-phenyl) -5- [4- (3-methanesulfonyl-phenyl) -thiophen-2-yl ]-3-trifluoromethyl-1H-pyrazole. MS (ES)521.4[ M + H ]]+
Scheme 32
Figure S2006800306472D03111
As shown in scheme 32, tert-butyl ester 032SP3 was treated with formic acid/DCM to give acid 032SP 4.
Example 85
Preparation of 2- (3- (5- (5- (3- (methylsulfonyl) phenyl) thiophen-2-yl) -3- (trifluoromethyl) -1H-pyrazol-1-yl) phenoxy) acetic acid
Figure S2006800306472D03112
Tert-butyl 2- (3- (5- (3- (methylsulfonyl) phenyl) thiophen-2-yl) -3- (trifluoromethyl) -1H-pyrazol-1-yl) phenoxy) acetate was prepared in the manner described in scheme 31. To a solution of tert-butyl ester (70mg, 0.12mmol) in anhydrous DCM (2.0mL) was added 2.0mL of 96% formic acid.
The reaction mixture was stirred at room temperature overnight. It was concentrated and the residue was purified by flash column chromatography on silica gel (10% MeOH/DCM) to give the product (28mg, 45% yield).1H-NMR (acetone-d 6): δ 8.01(s, 1H), 7.82(m, 1H), 7.77(m, 1H), 7.57(m, 1H), 7.45(m, 1H), 7.37(m, 1H), 7.08-7.01(br, 5H), 4.68(s, 2H), 3.05(s, 3H). ms (es): 523[ M + H]+.
The following compounds are prepared essentially in accordance with the previous examples:
[ 2- {5- [4- (3-methanesulfonyl-phenyl) -thiophen-2-yl ]]-3-trifluoromethyl-pyrazol-1-yl } -phenoxy) -acetic acid ms (es)523.3[ M + H]+
Scheme 33
Figure S2006800306472D03121
Treatment of 3-hydroxy substituted pyrazoles 033SP1 with dialkylcarbamoyl chlorides or acid chlorides in the presence of a base affords carbamates 033SP5 as shown in scheme 33.
Example 86
Preparation of dimethyl 3- (5- (5- (3- (methylsulfonyl) phenyl) thiophen-2-yl) -3- (trifluoromethyl) -1H-pyrazol-1-yl) phenylcarbamate
Figure S2006800306472D03122
To a solution of 3- (5- (5- (3- (methylsulfonyl) phenyl) thiophen-2-yl) -3- (trifluoromethyl) -1H-pyrazol-1-yl) phenol (80mg, 0.17mmol) and triethylamine (35mg, 0.34mmol) in anhydrous DCM (1.5mL) and THF (1.5mL) was added dimethylcarbamoyl chloride (28mg, 0.26 mmol). The reaction mixture was heated to reflux overnight at 85 ℃ under a nitrogen atmosphere. Cooled and concentrated in vacuo. The residue was purified by column chromatography (60% ethyl acetate/hexanes) to give the product carbamate (24mg, 26% yield).1H-NMR(CDCl3)：δ8.10(m，1H)，7.85(m，1H)，7.79(m，1H)，7.58(m，1H)，7.42(m，1H)，7.35(m，1H)，7.28(m，1H)，7.26(m，1H)，7.22(m，1H)，6.91(m，1H)，6.84(s，1H)，3.09(s，6H)，3.00(s，3H).MS(ES)：536[M+H]+.
The following compounds are prepared essentially in accordance with the previous examples:
diethyl 3- (5- (5- (3- (methylsulfonyl) phenyl) thiophen-2-yl) -3- (trifluoromethyl) -1H-pyrazol-1-yl) phenylcarbamate. Ms (es): 564[ M + H]+.
Isobutyric acid 2- {5- [4- (3-methanesulfonyl-phenyl) -thiophen-2-yl ] -3-trifluoromethyl-pyrazol-1-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-1-yl } -phenyl ester. MS (ES)549.3[ M + H]+
Dimethyl-amino radicalFormic acid 2- {5- [4- (3-methanesulfonyl-phenyl) -thiophen-2-yl ]-3-trifluoromethyl-pyrazol-1-yl } -phenyl ester. MS (ES)536.3[ M + H]+
Scheme 34
Figure S2006800306472D03131
Treatment of 3-hydroxy substituted pyrazole 034SP1 with an alkyl isocyanate in the presence of a base affords carbamate 034SP6, as shown in scheme 34.
Example 87
Preparation of methyl 3- (5- (5- (3- (methylsulfonyl) phenyl) thiophen-2-yl) -3- (trifluoromethyl) -1H-pyrazol-1-yl) phenylcarbamate
3- (5- (5- (3- (methylsulfonyl) phenyl) thiophen-2-yl) -3- (trifluoromethyl) -1H-pyrazol-1-yl) phenol (80mg, 0.17mmol) was dissolved in anhydrous DCM (1.5mL) and THF (1.5 mL). To this solution were added triethylamine (35mg, 0.34mmol) and methyl isocyanate (15mg, 0.26 mmol). The reaction mixture was stirred at room temperature under a nitrogen atmosphere overnight. The solvent was evaporated in vacuo. The residue was purified by column chromatography (60% ethyl acetate/hexane) to give the product methyl carbamate (56mg, 95% yield).1H-NMR(CDCl3)：δ8.10(m，1H)，7.86(m，1H)，7.79(m，1H)，7.59(m，1H)，7.43(m，1H)，7.32(m，1H)，7.29-7.24(br，3H)，6.91(m，1H)，6.84(m，1H)，5.02(br，1H)，3.10(s，3H)，2.89(s，3H)，2.88(s，3H).
MS(ES)：522[M+H]+
The following compounds are prepared essentially in accordance with the previous examples:
propyl 3- (5- (5- (3- (methylsulfonyl) phenyl) thiophen-2-yl) -3- (trifluoromethyl) -1H-pyrazol-1-yl) phenylcarbamate. Ms (es): 550[ M + H ]]+
Methyl-carbamic acid 2- {5- [4- (3-methanesulfonyl-phenyl) -thiophen-2-yl]-3-trifluoromethyl-pyrazol-1-yl } -phenyl ester. MS (ES)522.3[ M + H ]+
Propyl-carbamic acid 2- {5- [4- (3-methanesulfonyl-phenyl) -thiophen-2-yl]-3-trifluoromethyl-pyrazol-1-yl } -phenyl ester. MS (ES)550.3[ M + H ]]+
Isopropyl-carbamic acid 2- {5- [4- (3-methanesulfonyl-phenyl) -thiophen-2-yl]-3-trifluoromethyl-pyrazol-1-yl } -phenyl ester. MS (ES)550.3[ M + H ]]+
Scheme 35
Treatment of 3-hydroxy substituted pyrazole 035SP1 with 2-chloroacetamide in the presence of a base affords acetamide 035SP7 as shown in scheme 35.
Example 88
Preparation of N, N-dimethyl-2- (3- (5- (3- (methylsulfonyl) phenyl) thiophen-2-yl) -3- (trifluoromethyl) -1H-pyrazol-1-yl) phenoxy) acetamide.
Figure S2006800306472D03151
3- (5- (5- (3- (methylsulfonyl) phenyl) thiophen-2-yl) -3- (trifluoromethyl) -1H-pyrazol-1-yl) phenol (120mg, 0.26mmol) was dissolved in anhydrous methanol (10.0 mL). To this solution was added 25 wt% NaOMe/methanol solution (130. mu.L, 0.57mmol) and 2-chloro-N, N-dimethyl-acetamide (156mg, 1.28 mmol). Inverse directionThe mixture was heated to reflux overnight at 80 ℃ under a nitrogen atmosphere. It was cooled and concentrated in vacuo. The residue was purified by column chromatography (50% ethyl acetate/hexanes) to give the product described above (87mg, 61% yield).1H-NMR (acetone-d 6): δ 8.21(m, 1H), 8.03(m, 1H), 7.96(m, 1H), 7.76(m, 1H), 7.65(m, 1H), 7.52(m, 1H), 7.25-7.16(br, 5H), 4.94(s, 2H), 3.25(s, 3H), 3.09(s, 3H), 2.90(s, 3H), 2.88(s, 3H). ms (es): 550[ M + H ] ]+
The following compounds were prepared in a similar manner:
2- (3- (5- (5- (3- (methylsulfonyl) phenyl) thiophen-2-yl) -3- (trifluoromethyl) -1H-pyrazol-1-yl) phenoxy) -1-morpholinoethanone. Ms (es): 592[ M + H]+
N, N-diethyl-2- ({2- [5- {4- [3- (methylsulfonyl) phenyl ]]-2-thienyl } -3- (trifluoromethyl) -1H-pyrazol-1-yl]Phenyl } oxy) acetamide; ms (es): 578[ M + H ]]+；
4- [ ({2- [5- {4- [3- (methylsulfonyl) phenyl)]-2-thienyl } -3- (trifluoromethyl) -1H-pyrazol-1-yl]Phenyl } oxy) methyl]Pyridine; ms (es): 556[ M + H]+；
N- (1-methylethyl) -2- ({2- [5- {4- [3- (methylsulfonyl) phenyl)]-2-thienyl } -3- (trifluoromethyl) -1H-pyrazol-1-yl]Phenyl } oxy) acetamide; ms (es): 564[ M + H]+；
5- ({2- [5- {4- [3- (methylsulfonyl) phenyl)]-2-thienyl } -3- (trifluoromethyl) -1H-pyrazol-1-yl]Phenyl } oxy) valeronitrile; ms (es): 546[ M + H]+；
5- {4- [3- (methylsulfonyl) phenyl]-2-thienyl } -1- [2- ({ [1- (phenylmethyl) -1H-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-1-yl]Phenyl } oxy) ethyl]-1H-isoindole-1, 3(2H) -dione; ms (es): 638[ M + H ] ]+；
2- ({2- [5- {4- [3- (methylsulfonyl) phenyl]-2-thienyl } -3- (trifluoromethyl) -1H-pyrazol-1-yl]Phenyl } oxy) -N-phenylacetamide; ms (es): 598[ M + H ]]+；
6- ({2- [5- {4- [3- (methylsulfonyl) phenyl)]-2-thienyl } -3- (trifluoromethyl) -1H-pyrazol-1-yl]Phenyl } oxy) hex-2-one; ms (es): 563[ M + H]+；
1- {4- [ ({2- [5- {4- [3- (methylsulfonyl) phenyl)]-2-thienyl } -3- (trifluoromethyl) -1H-pyrazol-1-yl]Phenyl } oxy) methyl]Phenyl } -1H-1, 2, 4-triazole; ms (es): 622[ M + H]+；
5- {4- [3- (methylsulfonyl) phenyl]-2-thienyl } -1- (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- (trifluoromethyl) -1H-pyrazol-1-yl]Phenyl } oxy) acetamide; ms (es): 578[ M + H ]]+.
4- [ ({2- [5- {4- [3- (methylsulfonyl) phenyl)]-2-thienyl } -3- (trifluoromethyl) -1H-pyrazol-1-yl]Phenyl } oxy) methyl]Pyridine; ms (es): 556[ M + H]+.
N- (1-methylethyl) -2- ({2- [5- {4- [3- (methylsulfonyl) phenyl)]-2-thienyl } -3- (trifluoromethyl) -1H-pyrazol-1-yl]Phenyl } oxy) acetamide; ms (es): 564[ M + H]+.
5- ({2- [5- {4- [3- (methylsulfonyl) phenyl)]-2-thienyl } -3- (trifluoromethyl) -1H-pyrazol-1-yl ]Phenyl } oxy) valeronitrile; ms (es): 546[ M + H]+.
5- {4- [3- (methylsulfonyl) phenyl]-2-thienyl } -1- [2- ({ [1- (phenylmethyl) -1H-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-1-yl]Phenyl } oxy) ethyl]-1H-isoindoleIndole-1, 3(2H) -dione; ms (es): 638[ M + H ]]+.
2- ({2- [5- {4- [3- (methylsulfonyl) phenyl]-2-thienyl } -3- (trifluoromethyl) -1H-pyrazol-1-yl]Phenyl } oxy) -N-phenylacetamide; ms (es): 598[ M + H ]]+.
6- ({2- [5- {4- [3- (methylsulfonyl) phenyl)]-2-thienyl } -3- (trifluoromethyl) -1H-pyrazol-1-yl]Phenyl } oxy) hex-2-one; ms (es): 563[ M + H]+.
1- {4- [ ({2- [5- {4- [3- (methylsulfonyl) phenyl)]-2-thienyl } -3- (trifluoromethyl) -1H-pyrazol-1-yl]Phenyl } oxy) methyl]Phenyl } -1H-1, 2, 4-triazole; ms (es): 622[ M + H]+.
5- {4- [3- (methylsulfonyl) phenyl]-2-thienyl } -1- (2- { [ (3-nitrophenyl) methyl]Oxy } phenyl) -3- (trifluoromethyl) -1H-pyrazole; ms (es): 600[ M + H ]]+.
Scheme 36
As shown in scheme 36, treatment of 3-hydroxy substituted pyrazole 036SP1 with an alcohol in the presence of triphenylphosphine and diisopropyl azodicarboxylate affords 3-alkoxy substituted pyrazole 036SP 8.
Example 89
Preparation of N, N-dimethyl 2- (3- (5- (3- (methylsulfonyl) thiophen-2-yl) -3- (trifluoromethyl) -1H-pyrazol-1-yl) phenoxy) ethanamine.
Figure S2006800306472D03172
3- (5- (5- (3- (methylsulfonyl) phenyl) thiophen-2-yl) -3- (trifluoromethyl) -1H-pyrazol-1-yl) benzenePhenol (120mg, 0.26mmol), 2- (dimethylamino) ethanol (46mg, 0.52mmol) and triphenylphosphine (138mg, 0.52mmol) were dissolved in a solvent mixture of anhydrous THF (2.5mL) and DCM (2.5mL) and cooled at 0 ℃ under a nitrogen atmosphere. To this solution was added diisopropyl azodicarboxylate (111mg, 0.52 mmol). The reaction mixture was stirred vigorously and allowed to warm to room temperature overnight. The solvent was evaporated in vacuo and the residue was purified by HPLC to give the product (61mg, 44%).1H-NMR (acetone-d 6): δ 8.13(m, 1H), 7.93(m, 1H), 7.90(m, 1H), 7.71(m, 1H), 7.60(m, 1H), 7.47(m, 1H), 7.17-7.09(br, 5H), 4.12(t, J ═ 5.8Hz, 2H), 3.18(s, 3H), 2.65(t, J ═ 5.8Hz, 2H), 2.21(s, 6H) ms (es): 536[ M + H]+.
Example 90
Preparation of 4- (3- (5- (5- (3- (methylsulfonyl) phenyl) thiophen-2-yl) -3- (trifluoromethyl) -1H-pyrazol-1-yl) phenoxy) piperidine
Figure S2006800306472D03181
Tert-butyl 4- (3- (5- (3- (methylsulfonyl) phenyl) thiophen-2-yl) -3- (trifluoromethyl) -1H-pyrazol-1-yl) phenoxy) piperidine-1-carboxylate was prepared as described in scheme 36. Tert-butyl carbamate (83mg, 0.13mmol) was dissolved in trifluoroacetic acid (0.5mL) and anhydrous DCM (4.0 mL). Stir at room temperature under nitrogen overnight. The reaction mixture was concentrated in vacuo and the residue was taken up in DCM. Potassium carbonate was added to the DCM solution and stirred for 2 hours. The salt was filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (10% isopropanol/DCM) to give the product amine (45mg, 64%). 1H-NMR(DMSO-d6)：δ8.01(m，1H)，7.89(m，1H)，7.69(m，1H)，7.49(m，1H)，7.41(m，1H)，7.26(m，1H)，7.23(m，2H)，7.13(m，1H)，4.63(m，1H)，3.28(s，3H)，3.11(m，2H)，2.87(m，2H)，1.99(m，2H)，1.71(m，2H).MS(ES)：548[M+H]+.
The following compounds are prepared essentially in accordance with the previous examples:
4- (2- (3- (5- (3- (methylsulfonyl) phenyl) thiophen-2-yl) -3- (trifluoromethyl) -1H-pyrazol-1-yl) phenoxy) ethyl) morpholine. Ms (es): 578[ M + H ]]+
1- (2- (3- (5- (3- (methylsulfonyl) phenyl) thiophen-2-yl) -3- (trifluoromethyl) -1H-pyrazol-1-yl) phenoxy) ethyl) piperidine. Ms (es): 576[ M + H]+.
5- (5- (3- (methylsulfonyl) phenyl) thiophen-2-yl) -1- (3- (tetrahydrofuran-3-oxy) phenyl) -3- (trifluoromethyl) -1H-pyrazole. Ms (es): 535[ M + H]+.
Scheme 37
Figure S2006800306472D03191
As shown in scheme 37, hydroxy-substituted pyrazoles 037SP1 were treated with aryl boronic acids in the presence of triethylamine and copper (II) acetate to provide the product diaryl ether 037SP 9.
Example 91
Preparation of 5- (5- (3- (methylsulfonyl) phenyl) thiophen-2-yl) -1- (3-phenoxyphenyl) -3- (trifluoromethyl) -1H-pyrazole
Figure S2006800306472D03192
To a solution of 3- (5- (5- (3- (methylsulfonyl) phenyl) thiophen-2-yl) -3- (trifluoromethyl) -1H-pyrazol-1-yl) phenol (120mg, 0.26mmol) in anhydrous DCM (6.0mL) were added cu (oac)2(94mg, 0.52mmol), phenylboronic acid (63mg, 0.52mmol), and powdered 4 Å molecular sieve and triethylamine (131mg, 1.29 mmol). The reaction mixture of the different components was stirred at ambient temperature overnight. The resulting slurry was filtered through celite and evaporated in vacuo to dryness And (3) preparing. The crude product was purified by column chromatography (40% ethyl acetate/hexanes) to give the product diaryl ether (73mg, 52% yield).1H-NMR(CDCl3)：δ8.10(m，1H)，7.88(m，1H)，7.79(m，1H)，7.61(m，1H)，7.31-7.27(m，3H)，7.20(m，1H)，7.12(m，1H)，7.04(m，1H)，7.00(m，2H)，6.89(m，1H)，6.82(s，1H)，3.10(s，3H).MS (ES)：541[M+H]+.
Scheme 38
Figure S2006800306472D03201
As shown in scheme 38, 3-nitrophenyl substituted pyrazole 038SP10 was substituted with SnCl2Reduction to aniline in PdCl with 3-methanesulfonylphenylboronic acid2(dppf)、Na2CO3The coupling took place in the presence of a solvent to give product 038SP 12.
Example 92
4- (1- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl) -N- (2-morpholinoethyl) benzamide
Example 92a
Preparation of 3- (5- (5-bromothien-2-yl) -3- (trifluoromethyl) -1H-pyrazol-1-yl) aniline
Figure S2006800306472D03202
5- (5-bromothien-2-yl) -1- (3-nitrophenyl) -3- (trifluoromethyl) -1H-pyrazole (0.40g, 0.96mmol), prepared in a similar manner as described in example 1b, and stannous (II) chloride dihydrate (1.08g, 4.78mmol) were dissolved in 10.0mL of ethyl acetate. The mixture was stirred at room temperature overnight. The solvent was then evaporated in vacuo. The residue was poured into a mixture of DCM and 1N aqueous NaOH and stirred for 10 minutes. Separation of organic matterThe aqueous layer was extracted twice with DCM. The combined organic layers were washed with anhydrous Na2SO4Dried and concentrated in vacuo. The residue was purified by column chromatography (30% ethyl acetate/hexanes) to give the product aniline (327mg, 88% yield). 1H-NMR(CDCl3)：δ7.26(m，1H)，6.90(m，1H)，6.76(m，5H)，3.84(s，2H).
Example 92b
Preparation of 3- (5- (5- (3- (methylsulfonyl) phenyl) thiophen-2-yl) -3- (trifluoromethyl) -1H-pyrazol-1-yl) aniline
Figure S2006800306472D03211
To a solution of 3- (5- (5-bromothien-2-yl) -3- (trifluoromethyl) -1H-pyrazol-1-yl) aniline (1.55g, 4.0mmol) in anhydrous THF (20.0mL) was added 3- (methylsulfonyl) phenylboronic acid (0.88g, 4.4mmol), PdCl2dppf(163mg，0.20mmol)、Na2CO3(0.85, 8.0mmol), and water (2.0 mL). The reaction mixture was heated to reflux at 55 ℃ for 15 hours under a nitrogen atmosphere. It was cooled 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/hexanes) to give the product (778mg, 42%).1H-NMR (acetone-d 6): δ 7.98(m, 1H), 7.78(m, 2H), 7.55(m, 2H), 7.47(m, 1H), 7.41(m, 1H), 7.28(m, 1H), 7.11(m, 1H), 7.02(m, 1H), 6.97(m, 1H), 5.49(s, 2H), 3.05(s, 3H). ms (es): 464[ M + H ]]+.
Scheme 39
Figure S2006800306472D03212
Treatment of aniline 039P12 with an alkyl isocyanate in the presence of triethylamine affords urea 039SP13 as shown in scheme 39.
Example 93
Preparation of 1- (3- (5- (5- (3- (methylsulfonyl) phenyl) thiophen-2-yl) -3- (trifluoromethyl) -1H-pyrazol-1-yl) phenyl) urea
Figure S2006800306472D03221
To a solution of 3- (5- (5- (3- (methylsulfonyl) phenyl) -thiophen-2-yl) -3- (trifluoromethyl) -1H-pyrazol-1-yl) aniline in anhydrous DCM (1.0mL) and THF (3.0mL) were added trimethylsilyl isocyanate (112mg, 0.85mmol) and triethylamine (29mg, 0.28 mmol). The reaction mixture was stirred under nitrogen overnight. A1.0M solution of tert-butylammonium fluoride (1.42mL, 1.42mmol) in THF was added and the mixture was stirred at room temperature overnight. The solvent was evaporated in vacuo and the resulting residue was purified by HPLC to give the urea product (70mg, 49%). 1H-NMR (acetone-d 6): δ 8.56(s, 1H), 8.13(m, 1H), 7.98(m, 1H), 7.91(m, 1H), 7.69(m, 1H), 7.60(m, 1H), 7.49(m, 1H), 7.20(m, 1H), 7.17(m, 1H), 6.44(br, 2H), 3.18(s, 3H). ms (es): 507M + H]+.
Scheme 40
Figure S2006800306472D03222
As shown in scheme 40, treatment of the methanesulfonyl-substituted pyrazole 040SP14 with n-butyllithium followed by treatment with an alkyl halide affords the alkylsulfonyl-substituted pyrazole 040SP 15.
Example 94
Preparation of 1- (2, 5-dichlorophenyl) -5- (5- (3- (ethylsulfonyl) phenyl) thiophen-2-yl) -3- (trifluoromethyl) -1H-pyrazole
Figure S2006800306472D03223
1- (2, 5-dichlorophenyl) -5- (5- (3- (methylsulfonyl) phenyl) thiophen-2-yl) -3- (trifluoromethyl) -1H-pyrazole (0.5g, 0.97mmol), prepared as described in example 1c, was dissolved in anhydrous THF (8.0mL) and cooled at-78 ℃ under a nitrogen atmosphere. To this solution was added a solution of 1.6M n-BuLi (0.78mL, 1.28mmol) in hexane. The mixture was stirred at-78 ℃ for 15 min, methyl iodide (608mg, 4.28mmol) was added and stirred overnight while warming to room temperature. The reaction was carefully quenched with water and the product extracted with ethyl acetate. The organic layer was washed with brine and water, over anhydrous Na2SO4Dried and concentrated in vacuo. The residue was purified by column chromatography (50% ethyl acetate/hexane) to give the product (153mg, 30%). 1H-NMR(CDCl3)：δ8.04(m，1H)，7.83(m，1H)，7.76(m，1H)，7.60(m，1H)，7.51(m，2H)，7.26(m，1H)，6.90(s，1H)，6.87(m，1H)，3.15(q，J＝7.5Hz，2H)，1.31(t，J＝7.5Hz，3H).MS(ES)：531[M+H]+.
The following compounds are prepared essentially in accordance with the previous examples:
1- (2, 5-dichlorophenyl) -5- (5- (3- (propylsulfonyl) phenyl) thiophen-2-yl) -3- (trifluoromethyl) -1H-pyrazole.1H-NMR(CDCl3)：7.73(m，1H)，MS(ES)：545[M+H]+.
1- (2, 5-dichlorophenyl) -5- (5- {3- [ (1, 1-dimethylethyl) sulfonyl]Phenyl } -2-thienyl) -3- (trifluoromethyl) -1H-pyrazole, ms (es): 559[ M + H ]]+.
Scheme 41
As shown in scheme 41, treatment of the methanesulfonyl-substituted pyrazole 041SP14 with LHMDS followed by aldehyde treatment provided alcohol 041SP 16.
Example 95
Preparation of 1- (3- (5- (1- (2, 5-dichlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl) thiophen-2-yl) benzenesulfonyl) butan-2-ol
Figure S2006800306472D03241
To a solution of 1- (2, 5-dichlorophenyl) -5- (5- (3- (methylsulfonyl) phenyl) thiophen-2-yl) -3- (trifluoromethyl) -1H-pyrazole (0.20g, 0.39mmol) in anhydrous THF (4.0mL) cooled at-78 deg.C was slowly added a 1.6M solution of LHMDS (0.27mL, 0.43mmol) in THF under a nitrogen atmosphere. The mixture was stirred at-78 ℃ for 15 min, propionaldehyde (45mg, 0.77mmol) was added and stirred overnight while warming 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, over anhydrous Na2SO4Dried and concentrated in vacuo. The residue was purified by column chromatography (60% ethyl acetate/hexane) to give the product (156mg, 70%). 1H-NMR (acetone-d 6): δ 8.12(m, 1H), 7.98(m, 1H), 7.90(m, 1H), 7.88(m, 1H), 7.77(m, 2H), 7.68(m, 1H), 7.58(m, 1H), 7.28(s, 1H), 7.20(m, 1H), 4.02(m, 1H), 3.39(m, 2H), 1.58(m, 1H), 1.48(m, 1H), 0.9(t, J ═ 7.1Hz, 3H) ms (es): 575[ M + H ]]+.
Scheme 42
Figure S2006800306472D03242
As shown in scheme 42, pyrazole 042SP17 prepared as described in example 1b was treated with alkyl halides 042SP18 and K at 85 deg.C2CO3Processing to obtain 5- (5-bromothiophene-2-yl) -1-arylmethyl-3- (trifluoro-phenyl)Methyl) -1H-pyrazole 042SP19, the latter in PdCl2(dppf)、K2CO3Coupling with an arylboronic acid ester 042SP20 in the presence of (a) gives pyrazole 042SP 21.
Example 96
Preparation of 2- (3- (5- (1- ((5-chlorothien-2-yl) methyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl) thiophen-2-yl) phenyl) -2-methylpropionic acid
Figure S2006800306472D03251
5- (5-bromothien-2-yl) -3- (trifluoromethyl) -1H-pyrazole (3.23g, 10.88mmol), prepared in a similar manner as described in example 1b, was dissolved in anhydrous DMF (40 mL). To this solution was added 2-chloro-5- (chloromethyl) thiophene (2.0g, 11.97mmol) and K2CO3(2.25g, 16.32 mmol). The reaction mixture was heated at 85 ℃ overnight under a nitrogen atmosphere. The solvent was evaporated and the obtained residue was taken up in ethyl acetate. The reaction mixture was washed with water and brine, over anhydrous Na 2SO4And (5) drying. It was concentrated in vacuo. The residue was purified by column chromatography (10% ethyl acetate/hexanes) to give the product 5- (5-bromothiophen-2-yl) -1- ((5-chlorothien-2-yl) methyl) -3- (trifluoromethyl) -1H-pyrazole (1.39g, 30%).1H-NMR(CDCl3): 7.11(m, 1H), 6.90(m, 1H), 6.75(m, 1H), 6.67(m, 1H), 6.61(s, 1H), 5.46(s, 2H). The above product was coupled with an arylboronic acid ester in a similar manner to that described in example 1c to give the title compound (161mg, 45%).1H-NMR(CDCl3)：δ7.63(s，1H)，7.50(m，1H)，7.40(m，2H)，7.32(m，1H)，7.12(m，1H)，6.74(m，1H)，6.69(m，1H)，6.66(s，1H)，5.54(s，2H)，1.66(s，6H).MS(ES)：511[M+H]+.
The following compounds are prepared essentially in accordance with the previous examples:
2- (3- (5- (1- (2, 4-difluorobenzyl) -3- (trifluoromethyl) -1H-pyrazole-5-)Yl) thiophen-2-yl) phenyl) -2-methylpropanoic acid ms (es): 507M + H]+.
1- (5- (5- (1- (2, 4-difluorobenzyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl) thiophen-2-yl) pyridin-2-yl) piperazine ms (es): 506[ M + H]+.
2- (1- (2, 4-difluorobenzyl) -5- (5- (3- (methylsulfonyl) phenyl) thiophen-2-yl) -1H-pyrazol-3-yl) propan-2-ol ms (es): 489[ M + H ]]+.
Scheme 43
Figure S2006800306472D03261
As shown in scheme 43, treatment of aniline 043SP22 with triphosgene and triethylamine affords isocyanate 043SP23, which is reacted with an alcohol to afford carbamate 043SP 24. Carbamate 043SP24 treatment with MeMgBr yielded methanol 043SP 25.
Example 97
3- (4-methylpiperazin-1-yl) propyl 4 '- (1- (2, 6-dichlorophenyl) -3- (2-hydroxypropan-2-yl) -1H-pyrazol-5-yl) -3' -methylbiphenyl-3-ylcarbamate
Example 97a
Preparation of methyl 1- (2, 6-dichlorophenyl) -5- (3' -isocyanato-3-methylbiphenyl-4-yl) -1H-pyrazole-3-carboxylate
Methyl 5- (3' -amino-3-methylbiphenyl-4-yl) -1- (2, 6-dichlorophenyl) -1H-pyrazole-3-carboxylate (0.276g, 0.61mmol) was dissolved in anhydrous DCM (6.0mL) and cooled in a nitrogen atmosphere at 0 ℃ with an ice/water bath. To this solution were added triethylamine (74mg, 0.73mmol) and trisPhosgene (181mg, 0.61 mmol). The reaction mixture was stirred for 4 hours while warming to room temperature. Carefully quench with water and extract the reaction mixture with DCM. The organic layer was washed with water and brine, over anhydrous Na2SO4And (5) drying. The residue was concentrated in vacuo to give the crude isocyanate, which was used in the next reaction without purification.
Example 97b
Preparation of methyl 1- (2, 6-dichlorophenyl) -5- (3-methyl 3' - ((3- (4-methylpiperazin-1-yl) propoxy) carbonylaminobiphenyl-4-yl) -1H-pyrazole-3-carboxylate
Figure S2006800306472D03271
To a solution of the crude isocyanate in anhydrous DCM (6.0mL) were added triethylamine (74mg, 0.73mmol) and 3- (4-methylpiperazin-1-yl) propan-1-ol (97mg, 0.61 mmol). The reaction mixture was stirred at room temperature under a nitrogen atmosphere overnight. It was concentrated in vacuo. The crude carbamate was used in the next reaction without purification.
Example 97c
Preparation of 3- (4-methylpiperazin-1-yl) propyl 4 '- (1- (2, 6-dichlorophenyl) -3- (2-hydroxypropan-2-yl) -1H-pyrazol-5-yl) -3' -methylbiphenyl-3-ylcarbamate
Figure S2006800306472D03272
To a solution of the crude carbamate in dry THF (6.0mL) cooled at-78 deg.C under a nitrogen atmosphere was added a 3.0M MeMgBr solution (1.0mL, 3.0 mmol). It was stirred at-78 ℃ for 30 minutes and then the cold bath was removed. The mixture was stirred for 4 hours while warming to room temperature. It is prepared from water and saturated NH4And (8) quenching with Cl. The reaction mixture was extracted with ethyl acetate. Salt for organic layerWashed with water and water, and passed over anhydrous Na2SO4Drying, evaporation of the solvent in vacuo and purification of the residue by HPLC gave the product (74mg, 19% over 3 steps).1H-NMR(CDCl3)：δ7.68(br，1H)，7.45(m，1H)，7.33(m，3H)，7.23(m，3H)，7.10(m，1H)，6.64(s，1H)，6.46(s，1H)，4.22(m，1H)，2.66(s，1H)，2.46(br，11H)，2.29(s，3H)，1.87(m，2H)，1.70(s，6H)，1.61(s，3H).MS(ES)：636[M+H]+.
Scheme 44
Figure S2006800306472D03281
As shown in scheme 44, treatment of hydroxyethyl-substituted pyrazole 044P26 with trifluoromethanesulfonic anhydride and DIEA provided triflate 044SP27, which was reacted with an amine to provide aminoethyl-substituted pyrazole 044SP 28.
Example 98
Preparation of N- (2- (5- (5- (3- (methylsulfonyl) phenyl) thiophen-2-yl) -3- (trifluoromethyl) -1H-pyrazol-1-yl) ethyl) propan-2-amine
Figure S2006800306472D03282
2- (5- (5- (3- (methylsulfonyl) phenyl) thiophen-2-yl) -3- (trifluoromethyl) -1H-pyrazol-1-yl) ethanol (208mg, 0.50mmol), prepared in a similar manner as described in example 1c, was dissolved in anhydrous DCM (4.0mL) and cooled with an ice/water bath at 0 ℃ under a nitrogen atmosphere. To this solution were added DIEA (97mg, 0.75mmol) and trifluoromethanesulfonic anhydride (169mg, 0.60 mmol). The reaction mixture was stirred at 0 ℃ for 1h, and isopropylamine (148mg, 2.5mmol) was added. It was stirred overnight while warming to room temperature. The reaction mixture was concentrated in vacuo and the residue was purified by HPLC to give the product amine (148mg, 65％)。1H-NMR(CDCl3)：δ8.17(m，1H)，7.90(m，1H)，7.87(m，1H)，7.64(m，1H)，7.44(m，1H)，7.30(m，1H)，6.67(s，1H)，4.39(m，2H)，3.15(m，2H)，3.13(s，3H)，2.79(m，1H)，1.03(d，6H).MS(ES)：458[M+H]+.
The following compounds are prepared essentially in accordance with the previous examples:
n- (2- (5- (5- (3- (methylsulfonyl) phenyl) thiophen-2-yl) -3- (trifluoromethyl) -1H-pyrazol-1-yl) ethyl) cyclopentylamine. Ms (es): 484[ M + H]+.
N-benzyl-N-methyl-2- (5- (5- (3- (methylsulfonyl) phenyl) thiophen-2-yl) -3- (trifluoromethyl) -1H-pyrazol-1-yl) ethylamine. Ms (es): 520[ M + H ]]+.
N-methyl-2- (5- (5- (3- (methylsulfonyl) phenyl) thiophen-2-yl) -3- (trifluoromethyl) -1H-pyrazol-1-yl) -N- (thiophen-2-ylmethyl) ethylamine. Ms (es): 526[ M + H ]]+.
N- (furan-2-ylmethyl) -N-methyl-2- (5- (5- (3- (methylsulfonyl) phenyl) thiophen-2-yl) -3- (trifluoromethyl) -1H-pyrazol-1-yl) ethylamine. Ms (es): 510[ M + H]+
N-methyl-2- (5- (5- (3- (methylsulfonyl) phenyl) thiophen-2-yl) -3- (trifluoromethyl) -1H-pyrazol-1-yl) -N- (pyridin-4-ylmethyl) ethylamine. Ms (es): 521[ M + H]+.
1- (2- (1H-imidazol-1-yl) ethyl) -5- (5- (3- (methylsulfonyl) phenyl) thiophen-2-yl) -3- (trifluoromethyl) -1H-pyrazole. Ms (es): 467[ M + H ]]+.
1-methyl-4- (2- (5- (5- (3- (methylsulfonyl) phenyl) thiophen-2-yl) -3- (trifluoromethyl) -1H-pyrazol-1-yl) ethyl) piperazine. Ms (es): 499[ M + H ]]+.
1- (2- (5- (5- (3- (methylsulfonyl) phenyl) thiophen-2-yl) -3- (trifluoromethyl) -1H-pyrazol-1-yl) ethyl) pyrrolidin-3-ol. Ms (es): 486[ M + H ]+.
Scheme 45
Figure S2006800306472D03291
Other methods for the conversion of functional groups on the pyrazole ring are illustrated in scheme 45. Ester-substituted pyrazole compounds such as (045B1) can be converted to thioesters such as (045B2) using standard techniques using known sulfur hybridization reagents such as Lawesson's reagent. The thioester (045B2) can be converted to a difluoroether compound, as in formula (045B3), with the aid of a known gemdifluorination reagent such as DAST. Ester-substituted pyrazole compounds (045B1) can also be converted to amides, thioamides such as compound (045B4), formic acid, sulfonamides such as compound (045B5), and amines using techniques that will be apparent to those skilled in the art.
Example 99
3- (difluoro-methoxy-methyl) -5- [5- (3-methanesulfonyl-phenyl) -thiophen-2-yl ] -1- (2-trifluoromethyl-phenyl) -1H-pyrazole
Example 99a
Preparation of 5- [5- (3-methanesulfonyl-phenyl) -thiophen-2-yl ] -1- (2-trifluoromethyl-phenyl) -1H-pyrazole-3-thiocarboxylic acid O-methyl ester
Figure S2006800306472D03301
To a 50mL round bottom flask equipped with a condenser was added 5- [5- (3-methanesulfonyl-phenyl) -thiophen-2-yl]-methyl 1- (2-trifluoromethyl-phenyl) -1H-pyrazole-3-carboxylate (326mg, 644 μmol), Lawesson's reagent (520mg, 1.29mmol), and dry toluene (23 mL). The reaction solution was stirred under reflux for 1 day. The reaction solution was concentrated in vacuo and the crude material was passed through 25g of SiO 2The column was chromatographed using a gradient of 100% Hx to 50% EtOAc to give 302mg (90% yield) of the title compound. MS (ES)523.3[ M + H ]]+，545.0(M+Na)+.
Example 99b
Preparation of 3- (difluoro-methoxy-methyl) -5- [5- (3-methanesulfonyl-phenyl) -thiophen-2-yl ] -1- (2-trifluoromethyl-phenyl) -1H-pyrazole
Figure S2006800306472D03302
To N2A purged dry round bottom flask was charged with 5- [5- (3-methanesulfonyl-phenyl) -thiophen-2-yl]A solution of O-methyl (1- (2-trifluoromethyl-phenyl) -1H-pyrazole-3-thiocarbamate (280mg, 535 μmol) in anhydrous DCM (15 mL). DAST (200mL, 1.53mmol) was added to the reaction solution, and the reaction solution was stirred at room temperature for 14 hours. The reaction solution was diluted with DCM (100mL) and washed with aqueous NaCl, separated, and passed over Na2SO4Dried, filtered, and concentrated in vacuo. The crude residue is passed through 25g of SiO2The column was chromatographed using a mobile phase of 100% Hx to 50% EtOAc to give 64mg (23% yield) of the title compound.1H NMR(400MHz，CDCl3)δ8.02(s，1H)，7.80-7.89(m，2H)，7.66-7.75(m，3H)，7.50-7.58(m，2H)，7.18(d，1H)，6.83(s，1H)，6.74(d，1H)，3.47(s，3H)，3.06(s，3H)；19F NMR(400MHz，CDCl3)δ-61，-71ppm.MS(ES)529.3[M+H].
Example 100
N- [5- [5- (3-methanesulfonyl-phenyl) -thiophen-2-yl ] -1- (2-trifluoromethyl-phenyl) -1H-pyrazole-3-carbonyl ] -methanesulfonamide
Example 100a
5- [5- (3-methanesulfonyl-phenyl) -thiophen-2-yl ] -1- (2-trifluoromethyl-phenyl) -1H-pyrazole-3-carboxylic acid
Figure S2006800306472D03311
To a 100mL round bottom flask equipped with a condenser was added 5- [5- (3-methanesulfonyl-phenyl) -thiophen-2-yl ]-ethyl 1- (2-trifluoromethyl-phenyl) -1H-pyrazole-3-carboxylate (2.52g, 4.98mmol), 1N aqueous NaOH (30mL), and MeOH (25 mL). The reaction solution was stirred at 55 ℃ for 1.5 hours and then subjected to TLC analysis. The reaction solution was diluted with EtOAc (200mL), poured into a separatory funnel, and the organic phases were separated. The aqueous phase was neutralized with 1N aqueous HCl and extracted with EtOAc (70 mL. times.2). The combined organic phases are passed over Na2SO4Dried, filtered into a round bottom flask and concentrated on a rotary evaporator. The crude residue is passed through 25g of SiO2The column was chromatographed using a mobile phase of 100% Hx to 85% EtOAc to give 1.35g (55% yield) of the title compound. MS (ES)493.1[ M + H ]]+.
Example 100b
N- [5- [5- (3-methanesulfonyl-phenyl) -thiophen-2-yl ] -1- (2-trifluoromethyl-phenyl) -1H-pyrazole-3-carbonyl ] -methanesulfonamide
Figure S2006800306472D03312
Adding 5- [5- (3-methylsulfonyl-phenyl) -thiophen-2-yl to a round bottom flask]-1- (2-trifluoromethyl-phenyl) -1H-pyrazole-3-carboxylic acid (302mg, 615 μmol), oxalyl chloride (0.54mL), anhydrous DCM (10 mL)/and anhydrous DMF (100 μ L). The reaction solution was stirred at room temperature for about 1 hour and then concentrated in vacuo. The crude acid chloride intermediate obtained was used in the next reaction without further purification. To a glass vial was added acid chloride (615. mu. mol theory), methanesulfonamide (117mg, 1.23mmol), 1, 2-dichloroethane (9mL), DIEA (200. mu.L), and DMAP (10 mg). The reaction solution was stirred at 45 ℃ for 3 hours. The reaction solution was diluted with DCM (60mL) and transferred to a separatory funnel. The solution was washed with aqueous NH4Cl (50 mL. times.2) and aqueous NaCl (50 mL). The organic phase is passed through Na 2SO4Drying, filtering, and rotatingConcentrated on an evaporator and passed through 25g of SiO2Column, chromatographic purification using a mobile phase gradient of 100% Hx to 70% EtOAc afforded 182mg (52% yield) of the title compound.1H NMR(400MHz，CDCl3)δ9.07(s，1H)，8.02(s，1H)，7.91(m，1H)，7.84(d，1H)，7.74-7.80(m，2H)，7.69(d，1H)，7.55(t，1H)，7.48(m，1H)，7.23(s，1H)，7.21(d，1H)，6.77(d，1H)，3.42(s，3H)，3.07(s，3H)；19F NMR(400MHz，CDCl3)δ-60.5ppm MS(ES)570.2[M+H]+.
Example 101
Preparation of 1- (2-chloro-phenyl) -5- [5- (3-methanesulfonyl-phenyl) -thiophen-2-yl ] -1H-pyrazole-3-thiocarboxylic acid ethylamide
Figure S2006800306472D03321
To N2A purged 50mL dry round bottom flask equipped with a condenser was charged with 1- (2-chloro-phenyl) -5- [5- (3-methanesulfonyl-phenyl) -thiophen-2-yl]-1H-pyrazole-3-carboxylic acid ethylamide (100mg, 206. mu. mol), Lawesson's reagent (200mg, 494. mu. mol), and dry toluene (8 mL). The reaction solution was stirred at reflux for 14 hours. The reaction solution was cooled to room temperature, and then benzene and Et were added21: 1 mixture of O. The resulting precipitate was removed by vacuum filtration through a buchner funnel. The filtrate was concentrated on a rotary evaporator and the crude residue was passed over 12g of SiO2The column was chromatographed using a mobile phase gradient of 100% Hx to 50% EtOAc to give 39mg (38% yield) of the title compound.1H NMR(400MHz，CDCl3)δ8.68(br s，1H)，8.02(s，1H)，7.83(d，1H)，7.72(d，1H)，7.48-7.70(m，5H)，7.42(s，1H)，7.22(d，1H)，6.83(d，1H)，3.87(m，2H)，3.07(s，3H)，1.36(t，3H).MS(ES)502.3，504.3[M+H]+.
The following compounds were prepared in a manner analogous to that described above:
1- (2-chlorophenyl) -5- {5- [3- (methylsulfonyl) phenyl]-2-thienyl } -N- (2, 2, 2-trifluoroethyl) -1H-pyrazole-3-carbothioic acid amide, ms (es)556.0, 558.0[ M + H ]+
Scheme 46
Figure S2006800306472D03331
(a) 3-Pyr-boronic acid, PdCl2dppf，K2CO3；(b)R3R4NH，Pd cat
Other A-ring substitution methods using metal catalyzed carbon-carbon bond coupling methodology are illustrated in scheme 46. Pyrazole-phenyl bromide intermediates (046B6) can be reacted under Suzuki coupling conditions to prepare ortho-aryl products, such as compounds (046B 7). The aryl bromide intermediate (046B6) may also be used in Buchwald amination reactions to produce alkylamino substituted compounds, such as formula (046B 8).
Example 102
Preparation of 3- (2- {5- [5- (3-methanesulfonyl-phenyl) -thiophen-2-yl ] -3-trifluoromethyl-pyrazol-1-yl } -phenyl) -pyridine
Figure S2006800306472D03332
To a 50mL round bottom flask equipped with a condenser was added 1- (2-bromo-phenyl) -5- [5- (3-methanesulfonyl-phenyl) -thiophen-2-yl]-3-trifluoromethyl-1H-pyrazole (prepared as described in example 1 c) (110mg, 210. mu. mol), 3-pyridylboronic acid (31mg, 525. mu. mol), PdCl2dppf(25mg，10mol％)、K2CO3(58mg, 410. mu. mol), 1, 4-dioxane (8mL), and H2O (1.5 mL). The reaction solution was stirred at 75 ℃ for 20 hours. The reaction solution was diluted with EtOAc (150mL) and transferred to a separatory funnel with NH4Aqueous Cl (100mL) and aqueous NaCl (100 mL). The organic phase is passed through Na2SO4Dried, filtered, concentrated on a rotary evaporator and passed through 25g of SiO2The column was chromatographed using a mobile phase gradient of 100% Hx to 90% EtOAc to give 45mg (41% yield) of the title compound. 1H NMR(400MHz，DMSO-d6)δ8.41(m，1H)，7.99(m，2H)，7.51-7.90(m，8H)，7.24(s，1H)，7.17-7.23(m，2H)，6.87(d，1H)，3.28(s，3H)；19F NMR(400MHz，DMSO-d6)δ-61.2ppm.MS(ES)526.5[M+H]+.
Scheme 47
Figure S2006800306472D03341
(a) 4-Me-piperazine, THF, reflux; (b)30psi H210% Pd/C; (c) (i) NaNO2, HCl, (ii) sncl2.2h2o, HCl, (d) diketones, tol, HCl; (e) suzuki coupling
Other methods for synthesizing substituted arylhydrazines such as compound (047B12) are shown in scheme 47. Hydrazine can be used to prepare pyrazole compounds in analogy to the procedure described in example 1c, and the procedure in scheme 47 is an adjunct to the procedure described in scheme 46. 2-fluoro-nitrobenzene (047B9) can be reacted with an alkylamine to undergo an SNAr reaction to give a substituted aryl nitro compound (047B 10). The nitro intermediate (047B10) can be converted to the corresponding aniline (047B11) using known hydrogenation methods. The resulting aniline (047B11) can be converted to an arylhydrazine (047B12) by a diazonium salt reaction followed by a reduction reaction. When these hydrazines were applied to the pyrazole synthesis methodology described in example 1c, the final pyrazole compound containing larger and more complex aminoalkyl substituents, such as compound (047B13), could be obtained.
Example 103
1- (2- {5- [4- (3-methanesulfonyl-phenyl) -thiophen-2-yl ] -3-trifluoromethyl-pyrazol-1-yl } -phenyl) -4-methyl-piperazine
Example 103a
Preparation of 1-methyl-4- (2-nitro-phenyl) -piperazine
Figure S2006800306472D03351
To a Kontes glass tube were added 2-fluoro-nitrobenzene (3.34g, 23.7mmol), 1-methyl-piperazine (3.90mL, 35.6mmol), and anhydrous THF (10 mL). The tube was sealed and the reaction mixture was stirred at 60 ℃ for 1 day. The reaction solution was diluted with EtOAc (150mL) and NaHCO3Washing with aqueous solution over Na2SO4Drying, filtration and concentration in vacuo gave 5.07g (97% yield) of the title product. MS (ES)222.3[ M + H]+.
Example 103b
Preparation of 2- (4-methyl-piperazin-1-yl) -phenylhydrazine-HC
Figure S2006800306472D03352
To a Parr hydrogenation flask was added 1-methyl-4- (2-nitro-phenyl) -piperazine (2.72g, 12.3mmol), EtOAc (50mL), MeOH (50 mL). The flask was purged with dry nitrogen for 5 minutes, then 10% Pd on carbon (1.00g) was added. The flask was placed on a Parr hydrogenation apparatus and exposed to H at 30psi2In (1). Reaction at H2Shake for 2 hours. The flask was evacuated and the solution was filtered through a silica gel filled Buchner funnel. The filtrate was concentrated in vacuo to give 2.0g of aniline product. Crude aniline was charged to a 100mL round bottom flask along with sodium nitrite (940mg, 13.6mmol) and concentrated HCl (13 mL). The reaction was stirred at-10 ℃ for about 1 hour, then a solution of stannous (II) chloride dihydrate (10g, 45mmol) in concentrated HCl (8mL) was added. The reaction solution was stirred at-10 ℃ for 1 hour. The solution was diluted with EtOAc (200 mL) and 2N NaOH was added until it was The tin by-products are all dissolved in water. The EtOAc phase was separated and the aqueous phase was extracted with EtOAc (150X 2). The combined organic phases are passed over Na2SO4Drying, filtration and concentration in vacuo afforded 1.69g (79% yield) of the product. MS (ES)237.3[ M + H]+，259.3(M+Na)+.
Example 103c
1- (2- {5- [4- (3-methanesulfonyl-phenyl) -thiophen-2-yl ] -3-trifluoromethyl-pyrazol-1-yl } -phenyl) -4-methyl-piperazine
Figure S2006800306472D03361
The compound 1- (2- {5- [4- (3-methanesulfonyl-phenyl) -thiophen-2-yl ] is prepared in an analogous manner to that described in example 1c by using 2- (4-methyl-piperazin-1-yl) -phenylhydrazine-HCl]-3-trifluoromethyl-pyrazol-1-yl } -phenyl) -4-methyl-piperazine.1H NMR(400MHz，DMSO-d6)δ8.16(s，1H)，7.97-8.08(m，3H)，7.84(d，1H)，7.69(t，1H)，7.57(t，1H)，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(400MHz，DMSO-d6)δ-61.1ppm.MS(ES)547.3[M+H]+，569.3(M+Na)+.
The following compounds were synthesized in a similar manner to that described in example 103:
3- {5- [1- [2- (4-methylpiperazin-1-yl) phenyl]-3- (trifluoromethyl) -1H-pyrazol-5-yl]-3-thienyl } benzenesulfonamide, MS (ES)548.3[ M + H]+，570.0(M+Na)+
4- {2- [5- {4- [3- (methylsulfonyl) phenyl]-2-thienyl } -3- (trifluoromethyl) -1H-pyrazol-1-yl]Phenyl } morpholine, MS (ES)534.2[ M + H]+
4- {2- [5- (4-bromo-2-thienyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl]Phenyl } morpholine, MS (ES)458.2, 460.2[ M + H]+
5- {4- [3- (methylsulfonyl) phenyl]-2-thienyl } -1- (2-propylphenyl) -3- (trifluoromethyl) -1H-pyrazole, MS (ES)491.2[ M + H [ ] ]+
1- [2- (1-methylethyl) phenyl]-5- {4- [3- (methylsulfonyl) phenyl]-2-thienyl } -3- (trifluoromethyl) -1H-pyrazole, MS (ES)491.4[ M + H ]]+
1-methyl-4- ({2- [5- {4- [3- (methylsulfonyl) phenyl]-2-thienyl } -3- (trifluoromethyl) -1H-pyrazol-1-yl]Phenyl } methyl) piperazine, MS (ES)560.8[ M + H]+
Scheme 48
Figure S2006800306472D03371
As shown in scheme 48, biphenyl pyrazoles 048E and 048F are prepared from acetophenone 048A in a manner similar to that described in scheme 6.
Example 104
2- {5- (2-chlorophenyl) -1- [ 3-methyl-3' - (methylsulfonyl) biphenyl-4-yl ] -1H-pyrazol-3-yl } propan-2-ol
Preparation by Using 2' -Chloroacetophenone in an analogous manner to that described in example 8d
2- {5- (2-chlorophenyl) -1- [ 3-methyl-3' - (methylsulfonyl) biphenyl-4-yl]-1H-pyrazol-3-yl } propan-2-ol.1H-NMR(CDCl3)：δ8.10(s，1H)，7.91(m，1H)，7.89(m，1H)，7.83(m，1H)，7.62(m，1H)，7.46(d，1H)，7.38(d，1H)，7.34-7.16(m，4H)，6.53(s，1H)，3.09(s，3H)，2.71(s，1H)，2.23(s，3H)，1.70(s，6H).MS(ES)：481[M+H]+，463(M-OH).
The following compounds are prepared essentially in accordance with the previous examples:
preparation of methyl 5- ((2-chlorophenyl) -1- (4-bromo-2-chlorophenyl) -1H-pyrazole-3-carboxylate by Using methyl 4- (2-chlorophenyl) -2, 4-dioxo-butanoate in a similar manner to that described in example 8d MS (ES) 405[ M + H]+.
Preparation of 5- ((2-chlorophenyl) -1- [ 3-methyl-3' - (methylsulfonyl) biphenyl-4-yl by using methyl 5- ((2-chlorophenyl) -1- (4-bromo-2-chlorophenyl) -1H-pyrazole-3-carboxylate in a similar manner as described in example 8c ]-1H-pyrazole-3-carboxylic acid methyl ester. Ms (es): 481[ M + H]+.
In an analogous manner to that described in example 8d, by using 5- ((2-chlorophenyl) -1- [ 3-methyl-3' - (methylsulfonyl) biphenyl-4-yl]Preparation of methyl (E) -1H-pyrazole-3-carboxylate 2- {5- (2-chlorophenyl) -1- [ 3-methyl-3' - (methylsulfonyl) biphenyl-4-yl]-1H-pyrazol-3-yl } propan-2-ol.1H NMR(CDCl3)：δ8.10(s，1H)，791(m，1H)，7.89(M，1H)，7.83(m，1H)，7.62(m，1H)，7.46(d，1H)，7.38(d，1H)，7.34-7.16(m，4H)，6.53(s，1H)，3.09(s，3H)，2.71(s，1H)，2.23(s，3H)，1.70(s，6H).MS(ES)：481[M+H]+，463(M-OH).
2- {1- [ 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) -1- [ 3-methyl-3' - (methylsulfonyl) biphenyl-4-yl]-1H-pyrazol-3-yl } propan-2-ol, ms (es): 515[ M + H]+，497(M-OH)
2- {1- [ 3-chloro-3' - (methylsulfonyl) biphenyl-4-yl]-5- (2, 6-dichlorophenyl) -1H-pyrazol-3-yl } propan-2-ol, ms (es): 535[ M + H]+，517(M-OH)
2- {5- (2, 6-dichlorophenyl) -1- [ 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) -1- [ 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) -1- [ 3-methyl-3' - (methylsulfonyl) biphenyl-4-yl]-1H-pyrazol-3-yl } propan-2-ol, ms (es): 515[ M + H]+，497(M-OH)
2- {1- [ 3-chloro-3' - (methylsulfonyl) biphenyl-4-yl ]-5- (2, 3-dichlorophenyl) -1H-pyrazol-3-yl } propan-2-ol, ms (es): 535[ M + H]+，517(M-OH)
2- [5- (2-chlorophenyl) -1- { 3-methyl-5- [3- (methylsulfonyl) phenyl]Pyridin-2-yl } -1H-pyrazol-3-yl radical]Propan-2-ol, ms (es): 482[ M + H ]]+，464(M-OH)
2- {5- (2-chlorophenyl) -1- [3, 5-dimethyl-3' - (methylsulfonyl) biphenyl-4-yl]-1H-pyrazol-3-yl } propan-2-ol, ms (es): 495[ M + H [ ]]+，477(M-OH)
2- (5- (2-chloro-6-fluorophenyl) -1- (3' - (methylsulfonyl) biphenyl-4-yl) -1H-pyrazol-3-yl) propan-2-ol ms (es): 485[ M + H]+.
2- (5- (2, 3-difluorophenyl) -1- (3' - (methylsulfonyl) biphenyl-4-yl) -1H-pyrazol-3-yl) propan-2-ol ms (es): 469[ M + H]+.
2- (5- (2-chloro-6-fluorophenyl) -1- (3-fluoro-3' - (methylsulfonyl) biphenyl-4-yl) -1H-pyrazol-3-yl) propan-2-ol ms (es): 503[ M + H]+.
2- (5- (2, 3-difluorophenyl) -1- (3-fluoro-3' - (methylsulfonyl) biphenyl-4-yl) -1H-pyrazol-3-yl) propan-2-ol ms (es): 487[ M + H ]]+.
2- (5- (2-chloro-6-fluorophenyl) -1- (3-methyl-3' - (methylsulfonyl) biphenyl-4-yl) -1H-pyrazol-3-yl) propan-2-ol ms (es): 499[ M + H ]]+.
2- (5- (2, 3-difluorophenyl) -1- (3-methyl-3' - (methylsulfonyl) biphenylPhenyl-4-yl) -1H-pyrazol-3-yl) propan-2-ol ms (es): 483[ M + H]+.
2- (1- (3-chloro-3' - (methylsulfonyl) biphenyl-4-yl) -5- (2-chloro-6-fluorophenyl) -1H-pyrazol-3-yl) propan-2-ol ms (es): 519[ M + H ] ]+.
2- (1- (3-chloro-3' - (methylsulfonyl) biphenyl-4-yl) -5- (2, 3-difluorophenyl) -1H-pyrazol-3-yl) propan-2-ol ms (es): 503[ M + H]+.
2- (1- (3-methyl-3' - (methylsulfonyl) biphenyl-4-yl) -5- (2- (trifluoromethyl) phenyl) -1H-pyrazol-3-yl) propan-2-ol ms (es): 515[ M + H]+.
2- (1- (3-chloro-3' - (methylsulfonyl) biphenyl-4-yl) -5- (2- (trifluoromethyl) phenyl) -1H-pyrazol-3-yl) propan-2-ol ms (es): 535[ M + H]+.
2- (4-chloro-5- (2-chloro-6-fluorophenyl) -1- (2-methyl-3' - (methylsulfonyl) biphenyl-4-yl) -1H-pyrazol-3-yl) propan-2-ol ms (es): 499[ M + H ]]+.
2- (5- (2, 6-dichlorophenyl) -1- (2-methyl-3' - (methylsulfonyl) biphenyl-4-yl) -1H-pyrazol-3-yl) propan-2-ol ms (es): 515[ M + H]+.
Example 105
2- { 4-chloro-5- (2-chlorophenyl) -1- [ 3-methyl-3' - (methylsulfonyl) biphenyl-4-yl ] -1H-pyrazol-3-yl } propan-2-ol
Figure S2006800306472D03401
Preparation of 2- { 4-chloro-5- (2-chlorophenyl) -1- [ 3-methyl-3' - (methylsulfonyl) biphenyl-4-yl in a similar manner to that described in example 12]-1H-pyrazol-3-yl } propan-2-ol.1H-NMR(CDCl3)：δ8.08(m，1H)，7.91(m，1H)，7.80(m，1H)，7.62(t，1H)，7.46(d，1H)，7.43(m，1H)，7.35-7.25(m，5H)，7.13(d，1H)，3.18(s，1H)，3.08(s，3H)，2.29(s，3H)，1.76(s，3H).MS(ES)：515[M+H]+，497(M-OH)
The following compounds are prepared essentially in accordance with the previous examples:
2- { 4-chloro-5- (2-chlorophenyl) -1- [ 3' - (methylsulfonyl) biphenyl-4-yl]-1H-pyrazol-3-yl } propan-2-ol:1H-NMR(CDCl3)：δ8.10(s，1H)，7.91(m，1H)，7.81(m，1H)，7.64(m，1H)，7.53-7.33(m，8H)，3.22(s，1H)，3.08(s，3H)，1.77(s，6H).MS(ES)：501[M+H]+，483(M-OH)
2- [ 4-chloro-5- (2-chlorophenyl) -1- { 3-methyl-5- [3- (methylsulfonyl) phenyl ]Pyridin-2-yl } -1H-pyrazol-3-yl radical]Propan-2-ol, ms (es): 516[ M + H]+，498(M-OH)
2- { 4-chloro-1- [ 3-chloro-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-chloro-5- (2, 6-dichlorophenyl) -1- [ 3-methyl-3' - (methylsulfonyl) biphenyl-4-yl]-1H-pyrazol-3-yl } propan-2-ol, ms (es): 549[ M + H]+，531(M-OH)
2- { 4-chloro-5- (2, 6-dichlorophenyl) -1- [ 3-chloro-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) -1- (3-methyl-3' - (methylsulfonyl) biphenyl-4-yl) -1H-pyrazol-3-yl) propan-2-ol ms (es): 533[ M + H ]]+.
2- (4-chloro-1- (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-chloro-6-fluorophenyl) -1- (2-methyl-3' - (methylsulfonyl) biphenyl-4-yl) -1H-pyrazol-3-yl) propan-2-ol ms (es): 533[ M + H ]]+.
2- (4-chloro-5- (2, 6-dichlorophenyl) -1- (2-methyl)-3' - (methylsulfonyl) biphenyl-4-yl) -1H-pyrazol-3-yl) propan-2-ol ms (es): 549[ M + H]+.
2- (4-chloro-1- (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-chloro-1- (3-chloro-3' - (methylsulfonyl) biphenyl-4-yl) -5- (2- (trifluoromethyl) phenyl) -1H-pyrazol-3-yl) propan-2-ol ms (es): 569[ M + H ]]+.
2- (4-chloro-5- (2-chloro-6-fluorophenyl) -1- (3-fluoro-3' - (methylsulfonyl) biphenyl-4-yl) -1H-pyrazol-3-yl) propan-2-ol ms (es): 537[ M + H ]]+.
2- (4-chloro-5- (2, 3-difluorophenyl) -1- (3-fluoro-3' - (methylsulfonyl) biphenyl-4-yl) -1H-pyrazol-3-yl) propan-2-ol ms (es): 521[ M + H]+.
2- (4-chloro-1- (3-chloro-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 of the invention in tables 1 and 2 were prepared according to one of the preceding examples 1 to 105:
TABLE 1
Figure S2006800306472D03431
Figure S2006800306472D03441
Figure S2006800306472D03451
Figure S2006800306472D03461
Figure S2006800306472D03471
Figure S2006800306472D03481
Figure S2006800306472D03491
Figure S2006800306472D03501
Figure S2006800306472D03521
Figure S2006800306472D03531
Figure S2006800306472D03551
Figure S2006800306472D03561
Figure S2006800306472D03571
Figure S2006800306472D03581
Figure S2006800306472D03591
Figure S2006800306472D03601
Figure S2006800306472D03621
Figure S2006800306472D03631
Figure S2006800306472D03641
Figure S2006800306472D03661
Figure S2006800306472D03671
Figure S2006800306472D03681
Figure S2006800306472D03691
Figure S2006800306472D03701
Figure S2006800306472D03711
Figure S2006800306472D03721
Figure S2006800306472D03731
Figure S2006800306472D03741
Figure S2006800306472D03751
Figure S2006800306472D03761
Figure S2006800306472D03781
Figure S2006800306472D03791
Figure S2006800306472D03801
Figure S2006800306472D03821
Figure S2006800306472D03831
Figure S2006800306472D03841
Figure S2006800306472D03861
Figure S2006800306472D03871
Figure S2006800306472D03881
Figure S2006800306472D03891
Figure S2006800306472D03911
Figure S2006800306472D03921
Figure S2006800306472D03951
Figure S2006800306472D03961
Figure S2006800306472D03971
Figure S2006800306472D03981
Figure S2006800306472D03991
Figure S2006800306472D04001
Figure S2006800306472D04011
Figure S2006800306472D04021
Figure S2006800306472D04041
Figure S2006800306472D04051
Figure S2006800306472D04061
Figure S2006800306472D04071
Figure S2006800306472D04081
Figure S2006800306472D04091
Figure S2006800306472D04101
Figure S2006800306472D04111
Figure S2006800306472D04121
Figure S2006800306472D04131
Figure S2006800306472D04141
Figure S2006800306472D04151
Figure S2006800306472D04161
Figure S2006800306472D04171
Figure S2006800306472D04191
Figure S2006800306472D04211
Figure S2006800306472D04221
Figure S2006800306472D04231
Figure S2006800306472D04241
Figure S2006800306472D04251
Figure S2006800306472D04261
Figure S2006800306472D04271
Figure S2006800306472D04301
Figure S2006800306472D04311
Figure S2006800306472D04321
Figure S2006800306472D04341
Figure S2006800306472D04351
Figure S2006800306472D04371
Figure S2006800306472D04401
Figure S2006800306472D04411
Figure S2006800306472D04421
Figure S2006800306472D04431
Figure S2006800306472D04441
Figure S2006800306472D04451
Figure S2006800306472D04461
Figure S2006800306472D04471
Figure S2006800306472D04481
Figure S2006800306472D04491
Figure S2006800306472D04521
Figure S2006800306472D04531
Figure S2006800306472D04551
Figure S2006800306472D04561
Figure S2006800306472D04571
Figure S2006800306472D04581
Figure S2006800306472D04591
Figure S2006800306472D04601
Figure S2006800306472D04611
Figure S2006800306472D04621
Figure S2006800306472D04641
Figure S2006800306472D04651
Figure S2006800306472D04661
Figure S2006800306472D04671
Figure S2006800306472D04681
Figure S2006800306472D04691
Figure S2006800306472D04701
Figure S2006800306472D04721
Figure S2006800306472D04731
Figure S2006800306472D04741
Figure S2006800306472D04751
Figure S2006800306472D04761
Figure S2006800306472D04771
Figure S2006800306472D04781
Figure S2006800306472D04791
Figure S2006800306472D04801
Figure S2006800306472D04811
Figure S2006800306472D04831
Figure S2006800306472D04841
Figure S2006800306472D04851
Figure S2006800306472D04861
Figure S2006800306472D04871
Figure S2006800306472D04881
Figure S2006800306472D04901
Figure S2006800306472D04911
Figure S2006800306472D04931
Figure S2006800306472D04941
Figure S2006800306472D04961
Figure S2006800306472D04981
Figure S2006800306472D05001
Figure S2006800306472D05011
Figure S2006800306472D05021
Figure S2006800306472D05031
Figure S2006800306472D05041
Figure S2006800306472D05051
Figure S2006800306472D05061
Figure S2006800306472D05081
Figure S2006800306472D05091
Figure S2006800306472D05101
Figure S2006800306472D05111
Figure S2006800306472D05121
Figure S2006800306472D05131
Figure S2006800306472D05141
Figure S2006800306472D05151
Figure S2006800306472D05171
Figure S2006800306472D05181
Figure S2006800306472D05191
Figure S2006800306472D05201
Figure S2006800306472D05211
Figure S2006800306472D05221
Figure S2006800306472D05231
Figure S2006800306472D05241
Figure S2006800306472D05251
Figure S2006800306472D05261
Figure S2006800306472D05271
Figure S2006800306472D05281
Figure S2006800306472D05291
Figure S2006800306472D05301
Figure S2006800306472D05311
Figure S2006800306472D05321
Figure S2006800306472D05331
Figure S2006800306472D05341
Figure S2006800306472D05351
Figure S2006800306472D05361
Figure S2006800306472D05371
Figure S2006800306472D05381
TABLE 2
Figure S2006800306472D05391
Example 107
FRET coactivator 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 a transcriptional coactivator protein. The assay involves the use of a recombinant glutathione-S-transferase (GST) -nuclear receptor Ligand Binding Domain (LBD) fusion protein and a synthetic biotinylated peptide sequence from a coactivating peptide, such as the receptor interacting domain of steroid receptor coactivator 1 (SRC-1). Typically, GST-LBD is labeled with europium chelate (donor) via europium labeled anti-GST antibody and the coactivating peptide is labeled with allophycocyanin via streptavidin-biotin linkage.
In the presence of a nuclear receptor agonist, the peptide is recruited to GST-LBD, bringing europium and allophycocyanin into proximity to each other to enable energy transfer from the europium chelate to the allophycocyanin. After excitation of the chelate with 340nm light, the excitation energy absorbed by the europium chelate is transferred to the allophycocyanin moiety, thereby emitting at 665 nm. If the europium chelate is not brought into the vicinity of the allophycocyanin moiety, little or no energy transfer, and excitation of the europium chelate results in emission at 615 nm. The emitted optical density at 655nm therefore gives an indication of the strength of the protein-protein interaction.
The required materials are as follows:
partially purified recombinant proteins comprising glutathione-S-transferase fused in frame to the LXR-ligand binding domain (comprising amino acids 188-447 of human LXR α or amino acids 198-461 of human LXR β)
Biotinylated peptides containing the SRC-1LXXL receptor-interacting motif (B-SRC-1)
anti-GST antibody (obtained from Wallac/PE Life sciences Cat # AD0064) crosslinked with europium chelate (. alpha.GST-K)
Streptavidin-conjugated allophycocyanin (SA-APC) (obtained from Wallac/PE Life sciences CAT # AD0059A)
1 × FRET buffer: (20mM KH)2PO4/K2HPO4pH 7.3, 150mM NaCl, 2.5mM HAPS, 2mM EDTA, 1mM DTT (fresh addition)
96-well or 384-well black well plates (from LJL)
Mother liquor:
0.5M KH2PO4/K2HPO4: pH 7.3; 5M NaCl; 80mM (5%) CHAPS; 0.5M EDTA pH 8.0; 1M DTT (maintained at-20 ℃).
Preparation of screening reagent:
the following reagents were mixed and the volume adjusted to 10 μ L/well with 1x-FRET buffer to prepare the reaction mixture for the appropriate number of wells: 5 nM/well GST-hLXR α LBD, 5 nM/well GST-hLXR β LBD, 5 nM/well anti-GST antibody (Eu), 12 nM/well biotin-SRC-1 peptide, 12 nM/well APC-SA.
The method comprises the following steps:
to each well of 96-well or 384-well black plates (LJL) was added 0.5. mu.L of 1mM compound stock solution (final concentration of approximately 10. mu.M) or solvent. To each well of the multiwell plate was added 10. mu.l of the reaction mixture (prepared above). Incubate at room temperature for 1-4 hours under cover or in the dark (APC sensitive to light). Thereafter, if the reaction is not read, it can be stored at 4 ℃ for several hours without losing too much signal.
The assay plates were read using a LJL analyzer or similar device using the following conditions: groove 1: excitation light was 330nm and emission light was 615, the cell was Eu chelate. Groove 2: excitation light was 330nm, emission light was 665, and the cell was APC. For slot 1: the scintillation number of each hole is 100; integration time (1000 μ s); the interval between flashes is 1 × 10 ms; delay after scintillation is 200 mus; for slot 2: the scintillation number of each hole is 100; the accumulated time is 100 mus; the interval between flashes is 1 × 10 ms; the delay after scintillation was 65 μ s.
Example 108
Scintillation Proximity Assay (SPA)
The SPA assay measures the radioactive signal generated by the binding of 3H-24, 25-epoxycholesterol to LXR α or LXR β. The assay is based on the use of SPA beads containing a scintillator such that when bound to a receptor, the labeled ligand comes into proximity with the bead and energy from the label stimulates the scintillator to emit light. Light was measured using a standard microplate scintillation reader. The ability of a compound to bind to a receptor can be measured by assessing the extent to which the compound is able to compete with a radiolabeled ligand known to have affinity for the receptor.
Required material：
The marker:3h-24, 25-epoxy-cholesterol (Amersham)
LXR α lysate: baculovirus expressed LXR alpha/RXR heterodimers produced as crude lysates, wherein RXR has a 6-HIS tag
LXR β lysate: baculovirus expressed LXR β/RXR heterodimers produced as crude lysates, wherein RXR has a 6-HIS tag
SPA beads: yi copper His-tagged SPA bead (Amersham)
Plate: non-binding surface 96-well plates (Coming)
Protein lysate dilution buffer: (20mM Tris-HCl pH 7.9, 500mM NaCl, 5mM imidazole). 2x SPA buffer: (40mM K) 2HPO4/KH2PO4ph7.3, 100mM NaCl, 0.05% Tween 20, 20% glycerol, 4mM EDTA), 2x SPA buffer w/o EDTA: (40mM K)2HPO4/KH2PO4pH7.3, 100mM NaCl, 0.05% Tween 20, 20% glycerol)
Mother liquor
0.5M K2HPO4/KH2PO4pH 7.3; 0.5M EDTA pH 8.0; 5M NaCl; 10% Tween-20; glycerol
Preparation of protein lysates
The appropriate full-length cDNA was cloned into pBacPakhis1 vector (Clontech, Calif.) using standard procedures to make baculovirus expression plasmids for human RXR α (accession No. NM-002957), LXR α (accession No. U22662), LXR β (accession No. U07132). The cDNA was inserted into the pBAcPakhis1 vector polylinker, resulting in an in-frame fusion of the cDNA with the N-terminal multi-His tag present in pBAcPakhis 1. The correct clones were confirmed by restriction mapping and/or sequencing.
At about 1.25X 106The cell lysate was prepared by infecting healthy Sf9 insect cells at a density of 27 ℃ and culturing in a total volume of 500mL per 1L size spinner flask under standard conditions. To prepare LXR α lysates, insect cells were co-transfected with LXR α expression cassettes at an m.o.i. of 0.5-0.8 and with RXR expression cassettes at an m.o.i. of about 1.6. To prepare LXR β lysates, insect cells were co-transfected with LXR β expression cassettes at an m.o.i. of about 1.6 and with RXR expression cassettes at an m.o.i. of about 1.6. In both cases, cells were incubated at 27 ℃ for 48 hours with constant shaking and then harvested.
After incubation, cells were harvested by centrifugation and sedimentation. The cell pellet was suspended in two volumes of freshly prepared ice-cold extraction buffer (20mM Tris pH 8.0, 10mM imidazole, 400mM NaCl, 1 EDTA-free protease inhibitor tablet per 10ml of extraction buffer (Roche Catalog No. 1836170)). Cells were homogenized slowly on ice using Douncer to obtain 80-90% cell lysate. The homogenate was centrifuged for 30 minutes at 45,000rpm in a pre-cooled spinner (Ti50 or Ti70, or equivalent apparatus) at 4 ℃. Aliquots of the supernatant were frozen on dry ice and stored frozen at-80 ℃ until quantification and quality control. Aliquots of the lysates were tested in the SPA assay to ensure batch-to-batch consistency and subjected to SDS-PAGE analysis after purification using Ni-NTA resin (Qiagen), protein concentration and expression level were adjusted and then used in the screening assay.
Preparation of screening reagents
[3H]-24, 25-Epoxycholesterol (EC) solution: for a monolithic 384-well plate (or 400 wells), 21. mu.L of3H]EC (specific activity 76.5Ci/mmol, concentration 3.2mCi/mL) was added to 4.4mL of 2xSPA buffer to give a final concentration of 200 nM. For each additional 384-well plate, an additional 19.1. mu.L of 2XSPA buffer is added to an additional 4.0mL of 2 XSA buffer 3H]And (6) EC. In the hole3H]The final concentration of EC was 50 nM. LXR α lysate (prepared as above) was diluted with protein lysate dilution buffer. 1400 μ L of diluted LXR α lysate was prepared for each 384 well (or 200 well) plate and 1120 μ L of diluted LXR α lysate was prepared for each additional 384 well plate. LXR β lysate (prepared as above) was diluted with protein lysate dilution buffer. 1400 μ L of diluted LXR β lysate was prepared for each 384 well (or 200 well) plate and 1120 μ L of diluted LXR β lysate was prepared for each additional 384 well plate. SPA bead solution: for 384-well plates (or 400-well plates), 3.75mL of 2 XSPA buffer w/o EDTA, 2.25mL of H2O, and 1.5mL of Ysi His-tagged SPA beads (wells were vortexed prior to pipetting) were mixed together. For each additional 384-well plate, an additional 3.5mL of 2 XSPA buffer w/o EDTA, 2.1mL of H2O, and 1.4mL Ysi His-tagged SPA beads were mixed together.
The method comprises the following steps:
appropriate dilutions of each compound were prepared and pipetted into the appropriate wells of the multi-well plate. Mixing 9.1 uL of the alpha-amylase solution3H]EC was added to each well in columns 2-23 of the multi-well plate. Mu.l of the diluted LXR α lysate was added to each well in an odd row of the multi-well plate, columns 2-23. mu.L of the diluted LXR β lysate was added to each well of the even rows 2-23 columns of the multi-well plate. mu.L of SPA bead solution was added to each well of the 2-23 columns of the multi-well plate.
The plate was covered with a clear seal and placed in an incubator at ambient temperature for 1 hour. After incubation, the plates were analyzed using a light plate reader (MicroBeta, Wallac) using the program n ABASE3H _384 DPM. The settings for n ABASE3H _384DPM are: counting mode: a DPM; sample type: SPA; ParaLux mode: a low background; counting time: for 30 seconds.
LXR α and LXR β were analyzed in the same manner. The measured Ki represents the average of at least two dose-independent response assays. For each compound binding affinity, IC can be determined by non-linear regression analysis using one-site competition formula50To determine, wherein:
Figure S2006800306472D05441
ki was then calculated using the Cheng and Prusoff formulas, where:
Ki＝IC50/(1+[ ligand concentration]Kd of ligand)
For this assay, the typical ligand concentration was 50nM, and the Kd of the EC for this receptor was 200nM, as determined by saturation binding.
When tested in this assay, the compounds of the invention demonstrate the ability to bind to LXR α and/or LXR β.
Example 109
Cotransfection assay
To measure the ability of a compound to activate or inhibit the transcriptional activity of LXR in a cell-based assay, a co-transfection assay was used. LXRs have been shown to function as heterodimers with RXRs. For co-transfection assays, expression plasmids for LXR and RXR were introduced into mammalian cells by transient transfection along with a luciferase reporter plasmid containing one copy of the DNA sequence that binds to the LXR-RXR heterodimer (LXRE; Willy, P. et al, 1995). Treatment of transfected cells with an LXR agonist increases LXR transcriptional activity, which is measured as an increase in luciferase activity. Likewise, LXR antagonist activity can be determined by assaying the ability of a compound to competitively inhibit LXR agonist activity.
Required material
CV-1 African Green monkey kidney cell cotransfection expression plasmid, including full-length LXR alpha (pCMX-h LXR alpha, LXR beta (pCMX-hLXR beta), or RXR alpha (pCMX-RXR), reporter plasmid (LXREX 1-Tk-luciferase), and control (pCMX-galactosidase expression vector) (Willey et al, Genes & Development 91033-
Transfection reagents such as FuGENE6(Roche)
1 Xcytolysis buffer (1% Triton X100 (JT Baker X200-07), 10% glycerol (JT Baker M778-07), 5mM Ditriotreitol (Quantum BioProbe DTT 03; freshly prepared solution added before lysis)
1mM EGTA (ethylene glycol-bis (B-aminoethylether) -N, N, N ', N' -tetraacetic acid) (Sigma E-4378)
25mM zwitterionic buffer (Tricine) (ICN 807420) pH 7.8)
1 × luciferase assay buffer (pH 7.8) (0.73mM ATP, 22.3mM Tricine, 0.11mM EDTA, 33.3mM DTT)
1 Xluciferin/CoA (11mM luciferin, 3.05mM coenzyme A, 10mM HEPES)
Preparation of screening reagents
CV-1 cells were prepared 24 hours prior to the assay and seeded in T-175 flasks or 500cm2In petri dishes to achieve 70-80% confluence on the day of transfection. The number of cells to be transfected is determined by the number of plates to be screened. Each 384 well plate requires 1.92 x 10 6Cells or 5000 cells per well. DNA transfection reagents were prepared by mixing the desired plasmid DNA with the cationic transfection reagent FuGENE6(Roche) according to the instructions provided for the reagents. The optimum amount of DNA to be used is determined empirically for each cell line and the size of the container to be transfected. 10-12mL of medium was added to the DNA transfection reagent and the reaction mixture was incubated at temperature from T175cm2This mixture was added to the cells after aspirating the medium from the flask. The cells were then incubated at 37 ℃ for at least 5 hours to prepare the selected cells.
Luciferase assay reagents (per 10mL) were prepared by mixing the following reagents prior to use: 10mL of 1x luciferase assay buffer; 0.54mL 1 Xluciferin/CoA; 0.54mL of 0.2M magnesium sulfate.
Step (ii) of
Assay plates were prepared by dispensing 5 μ L of compound in each well of a 384-well plate to achieve a final concentration of 10 μ M compound and no more than 1% DMSO. Media was removed from the selected cells, the cells were trypsinized, harvested by centrifugation, counted, and seeded at a density of about 5000 cells per well in a volume of about 45 μ L in 384-well assay plates prepared above. Assay plates containing compounds and selected cells (total volume 50. mu.L) were incubated at 37 ℃ for 20 hours.
After incubation with the compound, the medium was removed from the cells and lysis buffer (30 μ L/well) was added. After 30 minutes at ambient temperature, luciferase assay buffer (30 μ L/well) was added and the assay plates were read on a luminometer (PE Biosystems Northstar reader with syringe on platform, or equivalent). The assay plates were read immediately after addition of luciferase assay buffer.
EC can be determined using LXR/LXRE cotransfection assays for inhibition of efficacy and percent activity or efficacy50/IC50The value is obtained. Efficacy is specified as the activity of the compound relative to either the high control (N- (3- ((4-fluorophenyl) - (naphthalen-2-ylsulfonyl) amino) propyl) -2, 2-dimethylpropionamide) or the low control (DMSO/vehicle). Dose response curves were obtained from the 8-point curve using concentrations varying in * LOG units. Each point represents the average of data from 4 wells of a 384 well plate.
The data from this determination are in accordance with the following equation from which EC can be determined50The value:
y ═ bottom + (top-bottom)/(1 + 10)((logEC50-X)*HillSlope))
Thus EC50/IC50Is defined as the concentration at which the agonist or antagonist responds halfway between the top (maximum) and bottom (baseline) of the major tract. EC (EC)50/IC50The values represent the evaluation values of at least 3 independent experiments. Relative efficacy of the agonist or% control was determined by comparison with the maximal response achieved by (N- (3- ((4-fluorophenyl) - (naphthalen-2-ylsulfonyl) -amino) propyl) -2, 2-dimethylpropanamide, which was determined separately in each dose response assay.
For antagonist assays, LXR agonists were added to each well of 384-well plates to elicit responses. The% inhibition of each antagonist is therefore a measure of the inhibition of agonist activity. In this example, 100% inhibition would indicate that the activity of a particular concentration of LXR agonist has decreased to a baseline level, which is defined as the activity measured in the presence of DMSO alone.
The compounds of the invention, when tested in this assay, demonstrate the ability to modulate LXR α and/or LXR β activity. Preferably, the active compounds modulate the activity, EC, of LXR50Or IC50Is about 10 μ M or less. More preferably, the EC of the preferred active compound50Or IC50About 1 μ M or less.
Example 110
In vivo studies
To evaluate the direct modulatory effect of the compounds of the invention on key target genes, animals were administered a single oral dose of test compound and tissues collected at various time points after administration. Male sex C57BL/6 mice (n-8) were dosed with vehicle or compound by oral gavage. At various time points post-dose, animals were bled retro-orbitally to collect plasma. The animals were then euthanized, tissues such as liver and intestinal mucosa were collected and rapidly frozen for further analysis. Plasma was analyzed for lipid parameters such as total cholesterol, HDL cholesterol and triglyceride levels. RNA was extracted from frozen tissues and analyzed for the modulation of key target genes by quantitative real-time PCR. To identify the specificity of LXR subtypes for target gene modulation, LXR deficient mice (LXR α -/-or LXR β -/-) and C57BL/6 wild-type controls were used in this same assay protocol.
Plasma lipid evaluation
To compare the effect of compounds on plasma cholesterol and triglycerides, the compounds were administered to the animals continuously for 1 week, with plasma lipid levels monitored daily. Male C57BL/6 mice (n =8) were gavaged daily with either vehicle or compound. Plasma samples were taken on days-1 (to group animals), 1, 3 and 7. Samples were collected three hours after each day of dosing. On study day 7, after plasma collection, animals were euthanized and tissues, such as liver and intestinal mucosa, were collected and rapidly frozen for further analysis. Plasma was analyzed for lipid parameters such as total cholesterol, HDL cholesterol and triglyceride levels. RNA was extracted from frozen tissues and analyzed for the modulation of key target genes by quantitative real-time PCR. To identify the specificity of LXR subtypes for target gene modulation, LXR deficient mice (LXR α -/-or LXR β -/-) and C were used in this same assay protocol57BL/6 wild type control.
Example 111
EC of LXR measured for Compounds of the invention50Or IC50
Compounds of the invention when tested as described in example 109 demonstrate modulation of LXRαAnd/or LXRβThe ability to be active. LXR activity is shown in the following table for various compounds of the present invention; for LXR αAnd LXRβAt least one EC50Or IC50Those compounds with values < 10 μ pM were considered active. In the following table, IC50Or EC50The data are presented below: a ═ 1 μ M, B ═ 1 to 10 μ M, and C ═ 10 μ M.
Figure S2006800306472D05471
Figure S2006800306472D05481
It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims. All publications, patents, and patent applications cited herein are incorporated by reference for all purposes.
All 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 tables, 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. The invention also includes all combinations of the various optional aspects of the invention mentioned herein. It is understood that any and all embodiments of the present invention may be combined with any other embodiment to describe other embodiments of the present invention. Moreover, any element of an embodiment may be combined with all other elements from any embodiment to describe other embodiments. Accordingly, the invention is not limited except as by the appended claims.

Claims (166)

1. A compound according to one of the following structural formulae or a pharmaceutically acceptable salt, isomer or prodrug thereof:
Figure S2006800306472C00011
wherein,
(A)R1is-L1-R5Wherein
L1Is a chemical bond, L5、L6、-L5-L6-L5-, or-L6-L5-L6-, wherein
Each L5Independently is- [ C (R)15)2]m-, wherein
Each R15Independently hydrogen, halogen, (C)1-C6) Alkyl, (C)3-C6) Cycloalkyl or (C)1-C6) A haloalkyl group;
each L6Independently is-C (R)11)2-、-C(R11)2C(R11)2-、-C(R11)＝C(R11)-、-C(R11)2O-、-C(R11)2NR11-、-C≡C-、-O-、-S-、-NR11-、-N(R10)CO-、-N(R10)CO2-、-CON(R10)-、-CO-、-CS-、-CO2-、-OC(＝O)-、-OC(＝O)N(R10）-、-CONR11N(R11)2-、-CONR11-、-OCONR11-、-SO2-、-N(R10)SO2-、-SO2N(R10)-、-NR10CONR10-、-NR10CSNR10-、-C(＝NR11)-、-C(＝NOR11)-、-C(＝NN(R11)2) -; aryl radical, C3-C8Cycloalkyl, ring C3-8Haloalkyl, heteroaryl, heterocyclyl, wherein said aryl, cycloalkyl, ring C3-8The haloalkyl, heteroaryl, or heterocyclyl is unsubstituted or optionally substituted with one or more R14Substituted by groups;
or L1Is C2-6Alkanediyl chains wherein said alkanediyl chains are uninterrupted or optionally-C (R)11)2-、-C(R11)2C(R11)2-、-C(R11)＝C(R11)-、-C(R11)2O-、-C(R11)2NR11-、-C≡C-、-O-、-S-、-N(R10)CO-、-N(R10)CO2-、-CON(R10)-、-CO-、-CO2-、-OC(＝O)-、-OC(＝O)N(R10)-、-SO2-、-N(R10)SO2-, or-SO2N(R10) -an interrupt, and R5Is aryl, heterocyclyl, heteroaryl, C2-C6Alkenyl radical, C2-C6Alkynyl, (C)3-C8Cycloalkyl) -C1-C6Alkyl-, (C)3-C8Cycloalkenyl) -C1-C6Alkyl-, (C)3-C8Cycloalkyl) -C2-C6Alkenyl-, C3-C8Cycloalkyl, -C, -B-C, or-A-B-C, wherein
A is-O-;
b is- [ C (R)15)2]m-or C3-C8A cycloalkyl group;
c is C1-C6Alkyl radical, C1-C6Halogenated alkyl, SO2R11、SR11、SO2N(R11)2、SO2NR11COR11、C≡N、C(O)OR11、CON(R11)2Or N (R)11)2(ii) a Wherein R is5Unsubstituted or optionally substituted by one or more R5aThe substitution is carried out by the following steps,
wherein each R5aIndependently is C1-C6Alkyl radical, C1-C6Haloalkyl, C 2-C6Alkenyl radical, C2-C6Alkynyl, (C)3-C8Cycloalkyl) -C1-C6Alkyl-, (C)3-C8Cycloalkenyl) -C1-C6Alkyl-, (C)3-C8Cycloalkyl) -C2-C6Alkenyl-, halogen, nitro, heterocyclyloxy, aryl, aryloxy, arylalkyl, aryloxyaryl, aryl C1-C6Alkoxy, -C ', -B' -C ', or-A' -B '-C',
wherein
A' is-O-;
b' is- [ C (R)15)2]m-or-C3-C8Cycloalkyl-;
c' is-H, halogen, -SO2R11、-OR11、-SR11、-N3、-COR11、-SO2N(R11)2、-SO2NR11COR11、-C≡N、-C(O)OR11、-OC(＝O)R11、-CON(R11)2、-CON(R11)OR11、-OCON(R11)2、-NR11COR11、-NR11CON(R11)2、-NR11COOR11、-N(R11)2Aryl, heteroaryl, or heterocyclyl;
wherein each R5aIs unsubstituted or optionally substituted by one or more groups which are independently C2-C6Alkenyl radical, C2-C6Alkynyl, (C)3-C8Cycloalkyl) -C1-C6Alkyl-, (C)3-C8Cycloalkenyl) -C1-C6Alkyl-, (C)3-C8Cycloalkyl) -C2-C6Alkenyl-, C0-C6Alkoxyaryl radical, C1-C6Alkyl radical, C3-C8Cycloalkyl, aryl-C1-C6Alkyl-, heteroaryl, halogen, -C [ identical to ] N, -NO2、-COR11、-COOR11、-CON(R11)2、-SO2R11、-OR11、-SR11、-SO2R11、-SO2N(R11)2、-SO2NR11COR11、-OCON(R11)2、-NR11COR11、-NR11CON(R11)2、-NR11COOR11or-N (R)11)2；R2And R21is-L3-R7Wherein
Each L3Independently is a chemical bond-V1-CH2)n-V1-, or- (CH)2)m-V1-CH2)n-, wherein
n is 0 to 6; and is
Each V1Independently is-C (R)11)2-、-C(R11)2C(R11)2-、-C(R11)＝C(R11)-、-C(R11)2O-、-C(R11)2NR11-、-C≡C-、-O-、-S-、-NR7-、-N(R10)CO-、-N(R10)CO2-、-OCO-、-CO-、-CS-、-CONR10-、-C(＝N)(R11)-、-C(＝N-OR11)-、-C[＝N-N(R11)2]、-CO2-、-OC(＝O)-、-OC(＝O)N(R10)-、-SO2-、-N(R10)SO2-、-SO2N(R10)-、-NR10CONR10-、-NR10CSNR10-、C3-C8Cycloalkyl, or C3-C8A cyclic haloalkyl group;
or each L3Independently is C2-6Alkanediyl chains wherein said alkanediyl chains are uninterrupted or optionally-C (R)11)2-、-C(R11)2C(R11)2-、-C(R11)＝C(R11)-、-C(R11)2O-、-C(R11)2NR11-、-C≡C-、-O-、-S-、-N(R10)CO-、-N(R10)CO2-、-CON(R10)-、-CO-、-CO2-、-OC(＝O)-、-OC(＝O)N(R10)-、-SO2-、-N(R10)SO2-, or-SO2N(R10) Interrupting; and is
Each R7Independently hydrogen, halogen, nitro, cyano, aryl, heteroaryl, heterocyclyl, -C 1-C6alkyl-heterocyclyl-C1-C6Alkyl-heteroaryl, -C1-C6Alkyl-aryl, -Z, -Y-Z, or-X-Y-Z, wherein
X is-O-;
y is- [ C (R)15)2]m-、-C2-C6Alkenyl, or C3-C8A cycloalkyl group;
z is-H, -CN, halogen, -OR11、-C(＝O)R11、-C(＝O)OR11、-C(＝O)N(R11)2、-N(R11)2、-CN、-N3、-SO2R11、-S(＝O)2N(R11)2、-C(＝O)N(R11)N(R11)2、-C(＝O)N(R11)(OR11)、-OC(＝O)-R11、-OC(＝O)-N(R11)2or-N (R)11)COOR11；
Wherein R is7Unsubstituted or optionally substituted by one or more R7aIs substituted in which
R7aIs halogen, C2-C6Alkenyl, -C1-C6alkyl-heterocyclyl-C1-C6Alkyl-heteroaryl, -C1-C6Alkyl-aryl, C0-C6Alkoxyheteroaryl group, C0-C6Alkoxyheterocyclyl, haloaryl, aryloxy, arylalkoxy, aryloxyalkyl, C1-C6Alkoxyaryl, aryl C0-C6Alkyl carboxyl, C (R)11)＝C(R11)-COOR11、C0-C6Alkoxyheteroaryl group, C0-C6Alkoxyheterocyclyl, aryl, heteroaryl, heterocyclyl, C3-C8Cycloalkyl, heteroaryloxy, -Z ', -Y' -Z ', or-X' -Y '-Z', wherein
X' is-O-;
y' is- [ C (R)15)2]m-or C3-C8A cycloalkyl group;
z' is-C1-C6Alkyl, -C1-C6Haloalkyl, -OR11、-SR11、-S(＝O)2R11、-C(＝O)R11、-C(＝O)OR11、-C(＝O)N(R11)2、-N(R11)2、-N(R11)C(＝O)R11、-S(＝O)2N(R11)C(＝O)R11、-CN、-S(＝O)2N(R11)2、-C(＝O)N(R11)N(R11)2、-C(＝O)N(R11)(OR11)、-OC(＝O)-R11、-OC(＝O)-OR11、-N(R11)C(＝O)O-R11or-N (R)11)S(＝O)2R11；
Wherein each R7aUnsubstituted or optionally substituted by one or more R8The substitution is carried out by the following steps,
wherein each R8Independently halogen, nitro, cyano, heteroaryl, C1-C6Alkyl radical, C1-C6Alkoxy radical, C1-C6Haloalkyl, C1-C6Haloalkyl (OR)11)、C0-C6Alkyl OR11、C0-C6Alkyl CON (R)11)2、C0-C6Alkyl group COR11、C0-C6Alkyl group COOR11Or C0-C6Alkyl SO2R11(ii) a And wherein if two R are present on the same carbon atom 7aThey may together form a cycloalkyl or heterocyclyl group; provided that
R2And R21Is not H at the same time;
R3is-L-R6Wherein
L is a bond, -X3-(CH2)n-X3-、-(CH2)m-X3-(CH2)n-, or- (CH)2)l+w-Y3-(CH2)w-, wherein
n is 0 to 6; each w is independently 0 to 5; and is
Each X3Independently is a chemical bond, -C (R)11)2-、-C(R11)2C(R11)2-、-C(R11)＝C(R11)-、-C≡C-、-CO-、-CS-、-CONR10-、-C(＝N)(R11)-、-C(＝N-OR11)-、-C[＝N-N(R11)2]、-CO2-、-SO2-、
or-SO2N(R10) -; and is
Y3is-O-, -S-, -NR7-、-N(R10)CO-、-N(R10)CO2-、-OCO-、-OC(＝O)N(R10)-、-NR10CONR10-、-N(R10)SO2-, or-NR10CSNR10-；
Or L is C2-6Alkanediyl chains wherein said alkanediyl chains are uninterrupted or optionally-C (R)11)2-、-C(R11)2C(R11)2-、-C(R11)＝C(R11)-、-C(R11)2O-、-C(R11)2NR11、-C≡C-、-O-、-S-、-N(R10)CO-、-N(R10)CO2-、-CON(R10)-、-CO-、-CO2-、-OC(＝O)-、-OC(＝O)N(R10)-、-SO2-、-N(R10)SO2-, or-SO2N(R10) Interrupting; and is
R6Is C1-C6Alkyl radical, C1-C6Haloalkyl, aryl, C3-C8Cycloalkyl, heteroaryl, heterocyclyl, -CN, -C (═ O) R11、-C(＝O)OR11、-C(＝O)N(R11)2、-N(R11)2、-SO2R11、-S(＝O)2N(R11)2、-C(＝O)N(R11)N(R11)2or-C (═ O) N (R)11)(OR11) Wherein
Said aryl, heteroaryl, cycloalkyl, or heterocyclyl is unsubstituted or optionally substituted with one or more R6aIs substituted in which
Each R6aIndependently is-Z ", -Y" -Z ", or-X" -Y "-Z", wherein
X' is-O-;
y' is- [ C (R)15)2]m-、-C2-C6Alkenyl radical, C3-C8Cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein
Said aryl, heteroaryl, cycloalkyl, or heterocyclyl being unsubstituted or substituted
Optionally substituted with at least one group, each of said at least one group is independently Z';
z' is-H, -CN, halogen, -OR11、-C(＝O)R11、-C(＝O)OR11、-C(＝O)N(R11)2、-N(R11)2、-N3、-SO2R11、-S(＝O)2N(R11)2、-C(＝O)N(R11)N(R11)2、-N(R11)C(＝O)N(R11)2、-OC(＝O)-OR11、-C(＝O)N(R11)(OR11)、-OC(＝O)-R11、-OC(＝O)-N(R11)2or-N (R)11)COOR11；
Each R10Independently is-R11、-C(＝O)R11、-CO2R11or-SO 2R11(ii) a Each R11Independently is-hydrogen, C2-C6Alkenyl radical, C2-C6Alkynyl, (C)3-C8Cycloalkenyl) -C1-C6Alkyl-, (C)3-C8Cycloalkyl) -C2-C6Alkenyl-, -N (R)12)2、-C1-C6Alkyl, -C1-C6Haloalkyl, -C3-C8Cycloalkyl, - (C)1-C6) Alkyl radical- (C)3-C8) Cycloalkyl, aryl, - (C)1-C6) Alkyl-aryl, heteroaryl, - (C)1-C6) Alkyl-heteroaryl, heterocyclyl, or- (C)1-C6) An alkyl-heterocyclic group,
Wherein any one R11Unsubstituted or optionally substituted by one or more R12Substituted by groups;
each R12Independently of one another is hydrogen, halogen, C1-C6Haloalkyl, C1-C6Alkyl radical, C1-C6Alkoxy group, (C)0-C6Alkyl) C ═ O (OR)13)；C0-C6Alkyl OR13、C0-C6Alkyl group COR13、C0-C6Alkyl SO2R13、C0-C6Alkyl CN, C0-C6Alkyl CON (R)13)2、C0-C6Alkyl CONR13OR13、C0-C6Alkyl SO2N(R13)2、C0-C6Alkyl SR13、C0-C6Haloalkyl OR13Aryloxy, arylalkoxy, aryloxyalkyl, C0-C6Alkoxyaryl, aryl C0-C6Alkyl carboxyl, C0-C6Alkyl radical NR13SO2R13、-C0-C6Alkyl N (R)13)2Or OC0-C6Alkyl group COOR13；
Each R13Independently of each other is hydrogen, C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, (C)3-C8Cycloalkyl) -C1-C6Alkyl-, (C)3-C8Cycloalkenyl) -C1-C6Alkyl-, or (C)3-C8Cycloalkyl) -C2-C6Alkenyl-;
each R14Independently is C1-C6Alkyl radical, C1-C6Alkoxy, halogen, C1-C6Haloalkyl, C0-C6Alkyl CON (R)11)2、C0-C6Alkyl CONR11OR11、C0-C6Alkyl OR11Or C0-C6Alkyl group COOR11；
G is a group of the formula:
Figure S2006800306472C00061
wherein
J is aryl, heteroaryl, or absent;
K is aryl, heteroaryl, or absent;
each R4Independently of one another is halogen, nitro, C2-C6Alkenyl radical, C3-C8Cycloalkyl, -C1-C6alkyl-heterocyclyl-C1-C6Alkyl-heteroaryl, -C1-C6Alkyl-aryl, -heterocyclyl-heteroaryl, CR11＝CR11COOR11Aryloxy, -S-aryl, arylalkoxy, aryloxyalkyl, C1-C6Alkoxyaryl, aryl C0-C6Alkyl carboxyl, C0-C6Alkoxyheteroaryl group, C0-C6Alkoxyheterocyclyl, aryl, heteroaryl, heterocyclyl, -M, -E-M, or-D-E-M,
wherein
D is-O-;
e is- [ C (R)15)2]m-or C3-C8A cycloalkyl group;
m is C1-C6Alkyl radical, C1-C6Haloalkyl, -COR11、-COOR11、-OC(＝O)R11、-CON(R11)2、-C≡N、-OR11、-OCON(R11)2、-OCO2-R11、-N3、-NR11COR11、-NR11SO2R11、-N(R11)2、-NR11COOR11、-SOR11、-SO2R11、-SO2NR11COR11、-SO2N(R11)2or-SR11，
Wherein each R4Unsubstituted or optionally substituted by one or more R4aThe substitution is carried out by the following steps,
wherein each R4aIndependently is halogen, aryloxy, arylalkoxy, aryloxyalkyl, -C1-C6Alkyl-aryl, C1-C6Alkoxyaryl, aryl C0-C6Alkylcarboxyl, -M ', -E' -M ', or-D' -E '-M',
d' is-O-;
e' is- [ C (R)15)2]m-or C3-C8A cycloalkyl group;
m' is-C1-C6Alkyl, -C1-C6Haloalkyl, COR11、-CON(R11)2、-N(R11)COOR11、-N(R11)2、COOR11、C≡N、OR11、-NR11COR11、NR11SO2R11、SO2R11、SO2N(R11)2Or SR11；
Each R41Independently of one another is halogen, nitro, C1-C6alkyl-heterocyclyl-C1-C6Alkyl-heteroaryl, -C1-C6Alkyl-aryl, -M ", -E" -M ", or-D" -E "-M", wherein
D "is-O-;
E' is- [ C (R)15)2]m-or C3-C8A cycloalkyl group;
m' is-C1-C6Alkyl, -C1-C6Haloalkyl, -COR11、-COOR11、-CON(R11)2、-C≡N、-OR11、-OCON(R11)2、-OCO2-R11、-N3、-NR11COR11、-NR11SO2R11、-N(R11)2、-NR11COOR11、-SOR11、-SO2R11、-SO2NR11COR11、-SO2N(R11)2or-SR11，
Wherein each R41Unsubstituted or optionally substituted by one or more R4aSubstitution;
L2is a chemical bond, -CH ═ CHCOO-, -OC0-C6Alkyl COO-, - [ C (R)15)2]m-V2-[C(R15)2]n-, or-V2-[C(R15)2]m-V2-, wherein
n is 0 to 6; and is
Each V2Independently is-C (R)11)2-、-C(R11)2C(R11)2-、-C(R11)＝C(R11)-、-C(R11)2NR11-、-C(R11)2O-、-C≡C-、-O-、-S-、-N(R10)CO-、-N(R10)CO2-、-CON(R10)-、-CON(R11)-、-CON(R11)O-、-CO-、-CS-、-CO2-、-OR11N-、-OR11COO-、-OC(＝O)-、-OC(＝O)N(R10)-、-SO2-、-N(R10)SO2-、-SO2N(R10)-、-NR10CONR10-、C3-C8Cycloalkyl, -C (═ NR)11)-、-C(＝NOR11)-、-C(＝NN(R11)2)-、-NR10CSNR10-, -C (O) -heterocyclic group, or ring C3-8Haloalkyl wherein said heterocyclyl is unsubstituted OR optionally substituted with one OR more groups independently selected from-OR11、-COOR11and-CON (R)11)2；
Or L2Is C2-6Alkanediyl chains wherein said alkanediyl chains are uninterrupted or optionally-C (R)11)2-、-C(R11)2C(R11)2-、-C(R11)＝C(R11)-、-C(R11)2O-、-C(R11)2NR11-、-C(R11)2NR11-、-C≡C-、-O-、-S-、-N(R10)CO-、-N(R10)CO2-、-CON(R10)-、-CON(R11)-、-CON(R11)O-、-CO-、-CO2-、-OC(＝O)-、-OC(＝O)N(R10)-、-SO2-、-N(R10)SO2-、-SO2N(R10)-；
Aryl radical, C3-C8Cycloalkyl, heteroaryl, or heterocyclyl group is interrupted,
wherein said aryl, cycloalkyl, heteroaryl, or heterocyclyl is unsubstituted or optionally substituted with one or more R9Is substituted in which
Each R9Independently of one another is halogen, C1-C6Haloalkyl, C1-C6Alkyl radical, C1-C6Alkoxy radical, C0-C6Alkyl or C1-C6Alkyl group COOR11；
Each m is independently 0, 1, 2, 3, 4, 5, or 6;
q is 0, 1, 2, 3, 4 or 5; and is
q' is 0, 1, 2, 3, or 4,
(B) With the proviso that,
(i) if L is2Is not a bond or if K is not phenyl, q may be only 0;
(ii) Said compound is not 2-methyl-5- (1-m-tolyl-3- (trifluoromethyl) -1H-pyrazol-5-yl) benzenesulfonamide;
(iii) if L is2Is a chemical bond, neither J nor K is present;
(iv) if K is absent, q is 1 and R4And L2Direct bonding;
(v) if L is2Is SO2Or SO2N(R10) Then R is5By at least one R5aSubstitution;
(vi) if the compound is defined by formula Ia, then
(a)R1Is not 4- (NH)2SO2) Phenyl, 4- (CH)3SO2) Phenyl, or 4- (CH)2FSO2) A phenyl group;
(b) if R is1Is 4-fluorophenyl, then G is not 4- [ (H)2NS(＝O)2-]Phenyl-; and is
(c)R2And R21Is not 4-hydroxyphenyl;
(vii) if the compound is defined by formula Ib
(a)R2And R3Is not 4- (NH)2SO2) Phenyl, 4- (CH)3SO2) Phenyl, or 4- (CH)2FSO2) A phenyl group; and is
(b)R1Is not 4-hydroxyphenyl;
(viii) if said compound is defined by formula Ic, then
(a)R2And R3Is not 4- (NH)2SO2) Phenyl, 4- (CH)3SO2) Phenyl, or 4- (CH)2FSO2) A phenyl group;
(b) j is not pyridyl; and is
(c) G is not 3-methoxyphenyl or 4-methoxyphenyl; and is
(ix) If said compound is defined by formula Id, then
(a) If L is1Is a chemical bond, then R1Is not thienyl or 5-methylthiophenyl;
(b) g is not 4- (NH)2SO2) Phenyl, 4- (CH)3SO2) Phenyl, or 4- (CH)2FSO2) A phenyl group;
(c) if G is 4-fluorophenyl, R1Is not 4- [ (H) 2NS(＝O)2-]Phenyl-;
(d) if J is Ph, L2Is a bond and q is 1, then K and R4Together is not 4-fluorophenyl, 3-fluorophenyl, 4-methoxyphenyl, or 5-chlorothiophenyl;
(e) if J is pyridyl, L2Is a bond and q is 1, then K and R4Together are not 4-fluorophenyl;
(f) if J is Ph, L2Is a bond and q is 2, then K and two R4Taken together are not 3-fluoro-4-methoxyphenyl; and is
(g)R1Is not 4-methyl-phenyl.
2. The compound of claim 1, wherein J is phenyl.
3. The compound of claim 1, wherein K is phenyl or pyridyl.
4. The compound of claim 2, wherein K is phenyl.
5. The compound of claim 4, which is a compound of the formula:
Figure S2006800306472C00101
6. the compound of claim 5, which is a compound of the formula:
Figure S2006800306472C00102
wherein R is21Is hydrogen, halogen, nitro, cyano, C1-C6Alkyl, or C1-C6A haloalkyl group.
7. The compound of claim 6, wherein L2Is a chemical bond.
8. The compound of claim 6, wherein L 1Is a chemical bond, and R5Is unsubstituted or optionally substituted by one or more R5aA substituted phenyl group.
9. The compound of claim 7, wherein L1Is a chemical bond, and R5Is unsubstituted or optionally substituted by one or more R5aA substituted phenyl group.
10. The compound of claim 9, wherein each R5aIndependently is halogen, -C ', or-B ' -C ', wherein
B' is- [ C (R)15’)2]m-, wherein
Each R15' is independently-H or-halogen; and is
C' is-H, -halogen, -SO2R11、-OR11、-COR11、-SO2N(R11)2、-C≡N、-C(O)OR11、-CON(R11)2or-N (R)11)2。
11. The compound of claim 10, wherein each R5aIndependently is-halogen, -C1-C6Alkyl, -C1-C6Haloalkyl, -OR11、-COR11、-C≡N、-C(O)OR11、-CON(R11)2or-N (R)11)2。
12. The compound of claim 9, wherein each R41Independently hydrogen, halogen, -C1-C6Alkyl or-C1-C6Haloalkyl, -COR16、-COOR16、-CON(R16)2、-C≡N、-OR16or-N (R)16)2，
Wherein each R16Independently of each other is hydrogen, -C1-C6Alkyl, or-C1-C6A haloalkyl group.
13. The compound of claim 12, wherein each R41Independently hydrogen, halogen, -C1-C6Alkyl, or-C1-C6A haloalkyl group.
14. The compound of claim 9, wherein each R4Independently of one another is halogen, nitro, C1-C6Alkyl radical, C1-C6Haloalkyl, -COR11、-COOR11、-CON(R11)2、-C≡N、-OR11、-OCON(R11)2、-OCO2-R11、-N3、-NR11COR11、-NR11SO2R11、-N(R11)2、-NR11COOR11、-SO2R11、-SO2NR11COR11、-SO2N(R11)2or-SR11。
15. The compound of claim 14, wherein each R 4Independently of one another is halogen, nitro, C1-C6Alkyl radical, C1-C6Haloalkyl, -COR11、-COOR11、-CON(R11)2、-C≡N、-OR11、-N(R11)2、-SO2R11or-SO2N(R11)2。
16. The compound of claim 9, wherein R2is-L3-R7Wherein
L3Is a chemical bond; and R is7Is hydrogen, halogen, nitro, cyano, -Z, or-Y-Z, wherein
Y is- [ C (R)15)2]m-；
Z is-H, halogen, -OR11、-C(＝O)R11、-C(＝O)OR11、-C(＝O)N(R11)2、-N(R11)2、-CN、-SO2R11、-S(＝O)2N(R11)2、-C(＝O)N(R11)N(R11)2、-C(＝O)N(R11)(OR11)、-OC(＝O)-R11or-OC (═ O) -N (R)11)2。
17. The compound of claim 16, wherein R2is-L3-R7Wherein
L3Is a chemical bond; and R is7Is hydrogen, halogen, -Z, or-Y-Z, wherein
Y is- [ C (R)15)2]m-, wherein
Z is-H, halogen, -OR11、-C(＝O)R11、-C(＝O)OR11、-C(＝O)N(R11)2、-N(R11)2、-CN、-SO2R11or-S (═ O)2N(R11)2。
18. The compound of claim 11, wherein each R41Independently hydrogen, halogen, -C1-C6Alkyl, or-C1-C6A haloalkyl group.
19. The compound of claim 13, wherein each R4Independently of one another is halogen, nitro, C1-C6Alkyl radical, C1-C6Haloalkyl, -COR11、-COOR11、-CON(R11)2、-C≡N、-OR11、-N(R11)2、-SO2R11or-SO2N(R11)2。
20. The compound of claim 15, wherein R2is-L3-R7Wherein L is3Is a chemical bond; and R is7Is hydrogen, halogen, -Z, or-Y-Z, wherein
Y is- [ C (R)15)2]m-, wherein
Z is-H, halogen, -OR11、-C(＝O)R11、-C(＝O)OR11、-C(＝O)N(R11)2、-N(R11)2、-CN、-SO2R11or-S (═ O)2N(R11)2。
21. The method of claim 17A compound in which each R is5aIndependently is-halogen, -C1-C6Alkyl, -C1-C6Haloalkyl, -OR11、-COR11、-C≡N、-C(O)OR11、-CON(R11)2or-N (R)11)2。
22. The compound of claim 18, wherein each R 4Independently of one another is halogen, nitro, C1-C6Alkyl radical, C1-C6Haloalkyl, -COR11、-COOR11、-CON(R11)2、-C≡N、-OR11、-N(R11)2、-SO2R11or-SO2N(R11)2。
23. The compound of claim 19, wherein R2is-L3-R7Wherein
L3Is a chemical bond; and R is7Is hydrogen, halogen, -Z, or-Y-Z, wherein
Y is- [ C (R)15)2]m-, wherein
Z is-H, halogen, -OR11、-C(＝O)R11、-C(＝O)OR11、-C(＝O)N(R11)2、-N(R11)2、-CN、-SO2R11or-S (═ O)2N(R11)2。
24. The compound of claim 20, wherein each R5aIndependently is-halogen, -C1-C6Alkyl, -C1-C6Haloalkyl, -OR11、-COR11、-C≡N、-C(O)OR11、-CON(R11)2or-N (R)11)2。
25. The compound of claim 21, wherein each R41Independently hydrogen, halogen, -C1-C6Alkyl, or-C1-C6A haloalkyl group.
26. The compound of claim 22, wherein R2is-L3-R7Wherein
L3Is a chemical bond; and R is7Is hydrogen, halogen, -Z, or-Y-Z, wherein
Y is- [ C (R)15)2]m-, wherein
Z is-H, halogen, -OR11、-C(＝O)R11、-C(＝O)OR11、-C(＝O)N(R11)2、-N(R11)2、-CN、-SO2R11or-S (═ O)2N(R11)2。
27. The compound of claim 4, which is a compound of the formula:
Figure S2006800306472C00131
wherein R is21Is hydrogen, halogen, nitro, cyano, C1-C6Alkyl, or C1-C6A haloalkyl group.
28. The compound of claim 25, which is a compound of the formula:
Figure S2006800306472C00132
29. The compound of claim 28, wherein
L2Is a chemical bond or- [ C (R)15)2]m″-V2-[C(R15)2]n' -, wherein
m' is 0; n' is 0 to 3; and V is2is-O-, -S-, -OC (═ O) O-, or-OC (═ O) N (R)10)-。
30. The compound of claim 29, wherein L2Is a chemical bond.
31. The compound of claim 30, wherein L1Is a chemical bond; and R is5Is unsubstituted or optionally substituted by one or more R5aSubstituted aryl or heteroaryl.
32. The compound of claim 31, which is a compound of the formula:
Figure S2006800306472C00141
33. the compound of claim 32, wherein R5Is unsubstituted or optionally substituted by one or more R5aA substituted phenyl group.
34. The compound of claim 33, wherein each R5aIndependently is halogen, -C ', or-B ' -C ', wherein
B' is- [ C (R)15’)2]m-, wherein each R15' is independently-H or-halogen; and is
C' is-H, -halogen, -SO2R11、-OR11、-COR11、-SO2N(R11)2、-C≡N、-C(O)OR11、-CON(R11)2or-N (R)11)2。
35. The compound of claim 34, wherein each R5aIndependently is-halogen, -C1-C6Alkyl, -C1-C6Haloalkyl, -OR11、-COR11、-C≡N、-C(O)OR11、-CON(R11)2or-N (R)11)2。
36. The compound of claim 33, wherein each R 41Independently hydrogen, halogen, -C1-C6Alkyl, -C1-C6Haloalkyl, -COR16、-COOR16、-CON(R16)2、-C≡N、-OR16or-N (R)16)2Wherein
Each R16Independently of each other is hydrogen, -C1-C6Alkyl, or-C1-C6A haloalkyl group.
37. The compound of claim 36, wherein each R41Independently hydrogen, halogen, -C1-C6Alkyl, or-C1-C6A haloalkyl group.
38. The compound of claim 33, wherein each R4Independently is halogen, -M, or-E-M, wherein
E is- [ C (R)15)2]m-；
M is C1-C6Alkyl radical, C1-C6Haloalkyl, -COR11、-COOR11、-CON(R11)2、-C≡N、-OR11、-OCON(R11)2、-OCO2-R11、-N3、-NR11COR11、-NR11SO2R11、-N(R11)2、-NR11COOR11、-SO2R11、-SO2NR11COR11、-SO2N(R11)2or-SR11。
39. The compound of claim 38, wherein each R4Independently is halogen, -M, or-E-M, wherein
E is- [ C (R)15’)2]m-, wherein
Each R15' is independently-H or-halogen; and is
M is-C1-C6Alkyl, -C1-C6Haloalkyl, -COR11′、-COOR11′、-CON(R11′)2、-C≡N、-OR11′、-N(R11)2、-SO2R11or-SO2N(R11′)2Wherein
Each R11' independently is-hydrogen, -C1-C6Alkyl, -C1-C6A halogenated alkyl group,
wherein each R11' unsubstituted OR optionally substituted by-OR13、-COOR13、-COR13、-SO2R13、-CON(R13)2、-SO2N(R13)2or-N (R)13)2And (4) substitution.
40. The compound of claim 33, wherein R2is-L3-R7Wherein
L3Is a chemical bond, -C (R)11)2-、-O-、-S-、-NR7-、-N(R10)CO-、-CO-、-CS-、-CONR11-、-CO2-, -OC (═ O) -, or-SO2-; and is
R7Is hydrogen, halogen, heterocyclyl, -Z, or-Y-Z, wherein
Y is- [ C (R)15)2]m-；
Z is-H, halogen, -OR11、-C(＝O)R11、-C(＝O)OR11、-C(＝O)N(R11)2、-N(R11)2、-CN、-SO2R11、-S(＝O)2N(R11)2、-C(＝O)N(R11)N(R11)2、-C(＝O)N(R11)(OR11)、-OC(＝O)-R11or-OC (═ O) -N (R)11)2。
41. A compound according to claim 40, wherein R 2is-L3-R7Wherein
L3Is a chemical bond, -C (R)11″)2-, -CO-, or-SO2-; and is
R7Is hydrogen, halogen, heterocyclyl-C1-C6Alkyl, -C1-C6Haloalkyl, -OR11″、-C(＝O)R11″、-C(＝O)OR11″、-C(＝O)N(R11″)2、-N(R11″)2、-CN、-SO2R11", or-S (═ O)2N(R11″)2，
Wherein each R11"is independently-H or-C1-C6An alkyl group.
42. The compound of claim 35, wherein each R41Independently hydrogen, halogen, -C1-C6Alkyl, or-C1-C6A haloalkyl group.
43. The compound of claim 37, wherein each R4Independently is halogen, -M, or-E-M, wherein
E is- [ C (R)15’)2]m-, wherein
Each R15' is independently-H or-halogen; and is
M is-C1-C6Alkyl, -C1-C6Haloalkyl, -COR11′、-COOR11′、-CON(R11′)2、-C≡N、-OR11′、-N(R11)2、-SO2R11', or-SO2N(R11′)2Therein, wherein
Each R11' independently is-hydrogen, -C1-C6Alkyl, or-C1-C6A halogenated alkyl group,
Wherein each R11' unsubstituted OR optionally substituted by-OR13、-COOR13、-COR13、-SO2R13、-CON(R13)2、-SO2N(R13)2or-N (R)13)2And (4) substitution.
44. A compound according to claim 39, wherein R2is-L3-R7Wherein
L3Is a chemical bond, -C (R)11″)2-, -CO-, or-SO2-; and is
R7Is hydrogen, halogen, heterocyclyl-C1-C6Alkyl, -C1-C6Haloalkyl, -OR11″、-C(＝O)R11″、-C(＝O)OR11″、-C(＝O)N(R11″)2、-N(R11″)2、-CN、-SO2R11", or-S (═ O)2N(R11″)2，
Wherein each R11"is independently-H or-C1-C6An alkyl group.
45. The compound of claim 41, wherein each R5aIndependently is-halogen, -C1-C6Alkyl, -C1-C6Haloalkyl, -OR 11、-COR11、-C≡N、-C(O)OR11、-CON(R11)2or-N (R)11)2。
46. The compound of claim 42, wherein each R4Independently is halogen, -M, or-E-M, wherein
E is- [ C (R)15’)2]m-, wherein
Each R15' is independently-H or-halogen; and is
M is-C1-C6Alkyl, -C1-C6Haloalkyl, -COR11′、-COOR11′、-CON(R11′)2、-C≡N、-OR11′、-N(R11)2、-SO2R11', or-SO2N(R11′)2，
Wherein
Each R11' independently is-hydrogen, -C1-C6Alkyl, -C1-C6A halogenated alkyl group,
wherein each R11' unsubstituted OR optionally substituted by-OR13、-COOR13、-COR13、-SO2R13、-CON(R13)2、-SO2N(R13)2or-N (R)13)2And (4) substitution.
47. A compound according to claim 43, wherein R2is-L3-R7Wherein
L3Is a chemical bond, -C (R)11″)2-, -CO-, or-SO2-; and is
R7Is hydrogen, halogen, heterocyclyl-C1-C6Alkyl, -C1-C6Haloalkyl, -OR11″、-C(＝O)R11″、-C(＝O)OR11″、-C(＝O)N(R11″)2、-N(R11″)2、-CN、-SO2R11", or-S (═ O)2N(R11″)2，
Wherein each R11"is independently-H or-C1-C6An alkyl group.
48. The compound of claim 44, wherein each R5aIndependently is-halogen, -C1-C6Alkyl, -C1-C6Haloalkyl, -OR11、-COR11、-C≡N、-C(O)OR11、-CON(R11)2or-N (R)11)2。
49. The compound of claim 45, wherein each R41Independently hydrogen, halogen, -C1-C6Alkyl, or-C1-C6A haloalkyl group.
50. A compound according to claim 46, wherein R2is-L3-R7Wherein
L3Is a chemical bond, -C (R)11″)2-, -CO-, or-SO2-; and is
R7Is hydrogen, halogen, heterocyclyl-C1-C6Alkyl, -C1-C6Haloalkyl, -OR 11″、-C(＝O)R11″、-C(＝O)OR11″、-C(＝O)N(R11″)2、-N(R11″)2、-CN、-SO2R11", or-S (═ O)2N(R11″)2，
Wherein each R11"is independently-H or-C1-C6An alkyl group.
51. The compound of claim 31, wherein R5Is unsubstituted or optionally substituted by one or more R5aA substituted pyridyl group.
52. The compound of claim 51, wherein each R5aIndependently is-halogen, -C1-C6Alkyl, -C1-C6Haloalkyl, -OR11、-COR11、-C≡N、-C(O)OR11、-CON(R11)2or-N (R)11)2。
53. The compound of claim 51, wherein each R41Independently hydrogen, halogen, -C1-C6Alkyl, or-C1-C6A haloalkyl group.
54. A compound according to claim 51, wherein R2is-L3-R7Wherein
L3Is a chemical bond or-C (R)11″)2-; and is
R7Is hydrogen, halogen, -C1-C6Alkyl, -C1-C6Haloalkyl, -OR11″、-C(＝O)R11″、-C(＝O)OR11″、-C(＝O)N(R11″)2、-N(R11″)2、-CN、-SO2R11", or-S (═ O)2N(R11″)2，
Wherein each R11"is independently-H or-C1-C6An alkyl group.
55. The compound of claim 51, wherein each R4Independently of one another is halogen, -C1-C6Alkyl, -C1-C6Haloalkyl, -COR11′、-COOR11′、-CON(R11′)2、-C≡N、-OR11′、-N(R11)2、-SO2R11', or-SO2N(R11′)2Wherein each R is11' independently is-hydrogen, -C1-C6Alkyl, or-C1-C6A haloalkyl group.
56. The compound of claim 29, wherein
L2is-V2-[C(R15)2]n"-, wherein
n "is 0 to 3; and V is2is-O-, -S-, -OC (═ O) O-, or-OC (═ O) N (R)10)-。
57. The compound of claim 56, wherein each R 5aIndependently is-halogen, -C1-C6Alkyl, -C1-C6Haloalkyl, -OR11、-COR11、-C≡N、-C(O)OR11、-CON(R11)2or-N (R)11)2。
58. The compound of claim 56, wherein each R41Independently hydrogen, halogen, -C1-C6Alkyl, or-C1-C6A haloalkyl group.
59. A compound according to claim 56, wherein R2is-L3-R7Wherein
L3Is a chemical bond or-C (R)11″)2-; and is
R7Is hydrogen, halogen, -C1-C6Alkyl, -C1-C6Haloalkyl, -OR11″、-C(＝O)R11″、-C(＝O)OR11″、-C(＝O)N(R11″)2、-N(R11″)2、-CN、-SO2R11", or-S (═ O)2N(R11″)2，
Wherein each R11"is independently-H or-C1-C6An alkyl group.
60. The compound of claim 56, wherein each R4Independently of one another is halogen, -C1-C6Alkyl, aryl, heteroaryl, and heteroaryl,-C1-C6Haloalkyl, -COR11′、-COOR11′、-CON(R11′)2、-C≡N、-OR11′、-N(R11)2、-SO2R11', or-SO2N(R11′)2Wherein
Each R11' independently is-hydrogen, -C1-C6Alkyl, or-C1-C6A haloalkyl group.
61. The compound of claim 2, wherein
K is absent; q is 1; and is
L2is-V2-[C(R15)2]n-, wherein
n is 0 to 6; and V is2is-O-, -S-, -SO2-、-CON(R10)-、-CON(R11)-、-CO-、-CO2-, -OC (═ O) -, -OC (═ O) O-, or-OC (═ O) N (R)10)-；
And R is21Is hydrogen, halogen, nitro, cyano, C1-C6Alkyl, or C1-C6A haloalkyl group.
62. The compound of claim 61, wherein
L2is-CO-; and is
R4Is a heterocyclic group which is unsubstituted or optionally substituted by one or more groups which are independently-M', wherein
M' is-H, halogen, COR11、COOR11、C≡N、OR11、-NR11COR11、NR11SO2R11、SO2R11、SO2N(R11)2Or SR11。
63. The compound of claim 62, wherein each R5aIndependently is-halogen, -C1-C6Alkyl, -C1-C6Haloalkyl, -OR11、-COR11、-C≡N、-C(O)OR11、-CON(R11)2or-N (R)11)2。
64. A compound according to claim 62, wherein R2is-L3-R7Wherein
L3Is a chemical bond or-C (R)11″)2-; and is
R7Is hydrogen, halogen, -C1-C6Alkyl, -C1-C6Haloalkyl, -OR11″、-C(＝O)R11″、-C(＝O)OR11″、-C(＝O)N(R11″)2、-N(R11″)2、-CN、-SO2R11", or-S (═ O)2N(R11″)2，
Wherein each R11"is independently-H or-C1-C6An alkyl group.
65. The compound of claim 62, wherein each R41Independently hydrogen, halogen, -C1-C6Alkyl, or-C1-C6A haloalkyl group.
66. The compound of claim 61, wherein
L2is-O-; and is
R4is-E-M, wherein
E is- [ C (R)15)2]m-；
M is-H, halogen, -COR11、-COOR11、-CON(R11)2、-C≡N、-OR11、-OCON(R11)2、-OCO2-R11、-N(R11)2。
67. The method according to claim 66The compound of (1), wherein each R41Independently hydrogen, halogen, -C1-C6Alkyl, or-C1-C6A haloalkyl group.
68. The compound of claim 66, wherein each R5aIndependently is-halogen, C1-C6Alkyl radical, C1-C6Haloalkyl, -OR11、-COR11、-C≡N、-C(O)OR11、-CON(R11)2or-N (R)11)2。
69. A compound according to claim 66, wherein R2is-L3-R7Wherein
L3Is a chemical bond or-C (R)11″)2-; and is
R7Is hydrogen, halogen, -C1-C6Alkyl, -C1-C6Haloalkyl, -OR11″、-C(＝O)R11″、-C(＝O)OR11″、-C(＝O)N(R11″)2、-N(R11″)2、-CN、-SO2R11", or-S (═ O)2N(R11″)2，
Wherein each R 11"is independently-H or-C1-C6An alkyl group.
70. The compound of claim 61, wherein
L2is-V2-[C(R15)2]n-, wherein
n is 0 to 6; and is
V2is-CON (R)11) -or-CO2-; and is
R4Is heterocyclyl, or-E-M, wherein
E is- [ C (R)15)2]m-; and is
M is-H, halogen, -COR11、-COOR11、-CON(R11)2、-C≡N、-OR11、-OCON(R11)2、-OCO2-R11、-N3、-NR11COR11、-NR11SO2R11、-N(R11)2、-NR11COOR11、-SO2R11、-SO2NR11COR11、-SO2N(R11)2or-SR11。
71. A compound according to claim 70, wherein each R41Independently hydrogen, halogen, -C1-C6Alkyl, or-C1-C6A haloalkyl group.
72. A compound according to claim 70, wherein each R5aIndependently is-halogen, -C1-C6Alkyl, -C1-C6Haloalkyl, -OR11、-COR11、-C≡N、-C(O)OR11、-CON(R11)2or-N (R)11)2。
73. A compound according to claim 70, wherein R2is-L3-R7Wherein
L3Is a chemical bond or-C (R)11″)2-; and is
R7Is hydrogen, halogen, -C1-C6Alkyl, -C1-C6Haloalkyl, -OR11″、-C(＝O)R11″、-C(＝O)OR11″、-C(＝O)N(R11″)2、-N(R11″)2、-CN、-SO2R11", or-S (═ O)2N(R11″)2，
Wherein each R11"is independently-H or-C1-C6An alkyl group.
74. The compound of claim 1, wherein J is heteroaryl; and is
R21Is hydrogen, halogen, nitro, cyano, C1-C6Alkyl, or C1-C6A haloalkyl group.
75. The compound of claim 74, wherein J is thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, pyridyl, pyrimidinyl, or pyrazinyl.
76. The compound of claim 75, wherein K is phenyl.
77. The compound of claim 75, wherein J is pyridyl.
78. The compound of claim 77, wherein L1Is a chemical bond; and R is5Is unsubstituted or optionally substituted by one or more R5aA substituted phenyl group.
79. The compound of claim 78, wherein K is phenyl.
80. A compound according to claim 79, wherein each R41Independently hydrogen, halogen, -C1-C6Alkyl, or-C1-C6A haloalkyl group.
81. A compound according to claim 79, wherein R2is-L3-R7Wherein
L3Is a chemical bond or-C (R)11″)2-; and is
R7Is hydrogen, halogen, -C1-C6Alkyl, -C1-C6Haloalkyl, -OR11″、-C(＝O)R11″、-C(＝O)OR11″、-C(＝O)N(R11″)2、-N(R11″)2、-CN、-SO2R11", or-S (═ O)2N(R11″)2，
Wherein each R11"is independently-H or-C1-C6An alkyl group.
82. A compound according to claim 79, wherein each R4Independently of one another is halogen, -C1-C6Alkyl, -C1-C6Haloalkyl, -COR11′、-COOR11′、-CON(R11′)2、-C≡N、-OR11′、-N(R11)2、-SO2R11', or-SO2N(R11′)2Wherein
Each R11' independently is-hydrogen, -C1-C6Alkyl, or-C1-C6A haloalkyl group.
83. A compound according to claim 79, wherein each R5aIndependently is-halogen, -C1-C6Alkyl, -C1-C6Haloalkyl, -OR11、-COR11、-C≡N、-C(O)OR11、-CON(R11)2or-N (R)11)2。
84. The compound of claim 75, wherein J is thienyl, furyl, or pyrrolyl.
85. The compound of claim 84, wherein J is thienyl.
86. The compound of claim 85, wherein K is phenyl and L2Is a chemical bond.
87. The compound of claim 86, which is a compound of the formula:
Figure S2006800306472C00231
88. a compound according to claim 87, which is a compound of the formula:
Figure S2006800306472C00232
89. a compound according to claim 88, which is a compound of the formula:
Figure S2006800306472C00233
90. the compound of claim 89, wherein L1Is a chemical bond; and R is5Is unsubstituted or optionally substituted by one or more R5aA substituted phenyl group.
91. The compound of claim 90, wherein each R5aIndependently is halogen, nitro, heterocyclyloxy, aryloxy, -C ', -B' -C 'or-A' -B '-C', wherein
A' is-O-;
b' is- [ C (R)15)2]m-；
C' is-H, halogen, -SO2R11、-OR11、-SR11、-COR11、-SO2N(R11)2、-SO2NR11COR11、-C≡N、-C(O)OR11、-OC(＝O)R11、-CON(R11)2、-CON(R11)OR11、-OCON(R11)2、-NR11COR11、-NR11CON(R11)2、-NR11COOR11、-N(R11)2Aryl, heteroaryl, or heterocyclyl;
wherein each R5aIs unsubstituted or optionally substituted by one or more groups which are independently C1-C6Alkyl radical, C3-C8Cycloalkyl, halogen, -C ≡ N, -COR 11、-COOR11、-CON(R11)2、-SO2R11、-OR11、-SR11、-SO2R11、-SO2N(R11)2、-SO2NR11COR11、-OCON(R11)2、-NR11COR11、-NR11CON(R11)2、-NR11COOR11or-N (R)11)2。
92. A compound according to claim 91, where each R5aIndependently is halogen, nitro, heterocyclyloxy, phenoxy, -C ', -B' -C ', or-A' -B '-C', wherein
A' is-O-;
b' is- [ C (R)15)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)2Or a heterocyclic group；
Wherein each R18Independently is-H, -C1-C6Alkyl, -C1-C6Haloalkyl, -C3-C8Cycloalkyl, aryl, heteroaryl, or heterocyclyl; and is
Wherein each R5aIs unsubstituted or optionally substituted by one or more groups which are independently C1-C6Alkyl, halogen, -COR19、-COOR19、-CON(R19)2、-OR19or-N (R)19)2，
Wherein each R19Independently is-H or-C1-C6An alkyl group.
93. The compound of claim 90, wherein each R41Independently hydrogen, halogen, -C1-C6Alkyl, -C1-C6Haloalkyl, -COR16、-COOR16、-CON(R16)2、-C≡N、-OR16or-N (R)16)2，
Wherein each R16Independently of each other is hydrogen, -C1-C6Alkyl, or-C1-C6A haloalkyl group.
94. A compound according to claim 93, where each R is41Independently hydrogen, halogen, -C1-C6Alkyl, or-C1-C6A haloalkyl group.
95. The compound of claim 90, wherein each R4Independently of one another is halogen, nitro, CR11＝CR11COOR11-M, or-E-M, wherein
E is- [ C (R)15)2]m-or C3-C8A cycloalkyl group;
m is C1-C6Alkyl radical, C 1-C6Alkyl halidesRadical, -COR11、-COOR11、-CON(R11)2、-C≡N、-OR11、-OCON(R11)2、-OCO2-R11、-NR11COR11、-NR11SO2R11、-N(R11)2、-NR11COOR11、-SO2R11、-SO2NR11COR11、-SO2N(R11)2or-SR11。
96. The compound of claim 95, wherein each R4Independently of one another is halogen, CR11′＝CR11′COOR11', -M, or-E-M, wherein
E is- [ C (R)15)2]m-or C3-C8A cycloalkyl group;
m is C1-C6Alkyl radical, C1-C6Haloalkyl, -COR11′、-COOR11′、-CON(R11′)2、-C≡N、-OR11′、-NR11′O2R11′、-N(R11′)2、-SO2R11′、-SO2NR11′COR11', or-SO2N(R11′)2，
Wherein each R11' independently is-hydrogen, -C1-C6Alkyl, or-C1-C6A halogenated alkyl group,
wherein any one R11' unsubstituted or optionally substituted by one or more R12' group substitution;
each R12' independently is halogen, C1-C6Haloalkyl, C1-C6Alkyl radical, C1-C6Alkoxy, C ═ O (OR)13)、COR13、SO2R13、CON(R13)2、SO2N(R13)2or-N (R)13)2。
97. A compound according to claim 90, wherein
R2is-L3-R7Wherein
L3Is a chemical bond or- (CH)2)m″-V1-(CH2)n-, wherein
m' is 0 to 3;
n is 0 to 3; and is
V1is-C (R)11)2-、-O-、-S-、-NR7-、-CO-、-CO2-, -OC (═ O) -, or-SO2-; and is
R7Is hydrogen, halogen, nitro, aryl, heteroaryl, heterocyclyl-C1-C6Alkyl, -C1-C6Haloalkyl, -C2-C6Alkenyl radical, C3-C8Cycloalkyl, or- (C (R)15)2)m-Z wherein
Z is-OR11、-C(＝O)R11、-C(＝O)OR11、-C(＝O)N(R11)2、-N(R11)2、-CN、-SO2R11、-S(＝O)2N(R11)2、-C(＝O)N(R11)N(R11)2、-C(＝O)N(R11)(OR11)、-OC(＝O)-R11or-OC (═ O) -N (R)11)2，
Wherein R is7Unsubstituted or optionally substituted by one or more R7aIs substituted in which
R7aIs halogen, C1-C6Alkyl radical, C1-C6Haloalkyl, -OR20、-C(＝O)R20、-C(＝O)OR20、-C(＝O)N(R20)2、-N(R20)2、-N(R20)C(＝O)R20Or a group of-CN,
wherein each R20Independently is-H or C1-C6An alkyl group.
98. A compound according to claim 97, where R 2is-L3-R7Wherein
L3Is a chemical bond or- (CH)2)m″-V1-(CH2)n-, wherein
m' is 0 to 1; n is 0 to 2; and is
V1is-CH2-, -O-, -S-, or-NR7-; and is
R7Is hydrogen, halogen, phenyl, heteroaryl, heterocyclyl-C1-C6Alkyl, -C1-C6Haloalkyl, -C2-C6Alkenyl radical, C3-C8Cycloalkyl, or- (C (R)15)2)m-Z wherein
Z is-OR11″、-C(＝O)R11″、-C(＝O)OR11″、-C(＝O)N(R11″)2、-N(R11″)2-CN, or-SO2R11″，
Wherein R is7Unsubstituted or optionally substituted by one or more R7aIs substituted in which
R7aIs halogen, C1-C6Alkyl radical, C1-C6Haloalkyl, -OR11″、-N(R11″)2、-COOR11", wherein each R11Independently is-H, -C1-C6Alkyl, -C1-C6Haloalkyl, heterocyclyl, or heteroaryl.
99. The compound of claim 98, wherein R2is-L3-R7Wherein
L3Is a chemical bond; and is
R7Is hydrogen, halogen, -C1-C3Alkyl, -C1-C3Haloalkyl, or- (C (R)15)2) -Z wherein
Z is-OR11"or-SO2R11″，
Wherein R is11"is-H or C1-C6An alkyl group.
100. The compound of claim 92, wherein each R41Independently hydrogen, halogen, -C1-C6Alkyl, or-C1-C6A haloalkyl group.
101. The compound of claim 94, wherein each R4Independently of one another is halogen, CR11′＝CR11′COOR11', -M, or-E-M, wherein
E is- [ C (R)15)2]m-or C3-C8A cycloalkyl group;
m is C1-C6Alkyl radical, C1-C6Haloalkyl, -COR11′、-COOR11′、-CON(R11′)2、-C≡N、-OR11′、-NR11′O2R11′、-N(R11′)2、-SO2R11′、-SO2NR11′COR11', or-SO2N(R11′)2，
Wherein each R11' independently is-hydrogen, -C 1-C6Alkyl, or-C1-C6A halogenated alkyl group,
wherein each R11' unsubstituted or optionally substituted by one or more R12' group substitution;
each R12' independently is halogen, C1-C6Haloalkyl, C1-C6Alkyl radical, C1-C6Alkoxy, C ═ O (OR)13)、COR13、SO2R13、CON(R13)2or-N (R)13)2。
102. The compound of claim 96, wherein R2is-L3-R7Wherein
L3Is a chemical bond or- (CH)2)m″-V1-(CH2)n-, wherein
m' is 0 to 1; n is 0 to 2; and is
V1is-CH2-, -O-, -S-, or-NR7-; and is
R7Is hydrogen, halogen, phenyl, heteroaryl, heterocyclyl-C1-C6Alkyl, -C1-C6Haloalkyl, -C2-C6Alkenyl radical, C3-C8Cycloalkyl, or- (C (R)15)2)m-Z wherein
Z is-OR11、-C(＝O)R11″、-C(＝O)OR11″、-C(＝O)N(R11″)2、-N(R11″)2-CN, or-SO2R11″，
Wherein R is7Unsubstituted or optionally substituted by one or more R7aIs substituted in which
R7aIs halogen, C1-C6Alkyl radical, C1-C6Haloalkyl, -OR11″、-N(R11″)2、-COOR11″，
Wherein R is11"is-H, -C1-C6Alkyl, -C1-C6Haloalkyl, heterocyclyl, or heteroaryl.
103. The compound of claim 98, wherein each R5aIndependently is halogen, nitro, heterocyclyloxy, phenoxy, -C ', -B' -C ', or-A' -B '-C', wherein
A' is-O-;
b' is- [ C (R)15)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)2Or a heterocyclic group;
wherein each R18Independently is-H, -C1-C6Alkyl, -C1-C6Haloalkyl, -C3-C8Cycloalkyl, aryl, heteroaryl, or heterocyclyl; and is
Wherein each R5aIs unsubstituted or optionally substituted by one or more groups which are independently C1-C6Alkyl, halogen, -COR19、-COOR19、-CON(R19)2、-OR19or-N (R)19)2，
Wherein R is19is-H or-C1-C6An alkyl group.
104. A compound according to claim 100, where each R is4Independently of one another is halogen, CR11′＝CR11′COOR11', -M, or-E-M, wherein
E is- [ C (R)15)2]m-or C3-C8A cycloalkyl group;
m is C1-C6Alkyl radical, C1-C6Haloalkyl, -COR11′、-COOR11′、-CON(R11′)2、-C≡N、-OR11′、-NR11′O2R11′、-N(R11′)2、-SO2R11′、-SO2NR11′COR11', or-SO2N(R11′)2，
Wherein each R11' independently is-hydrogen, -C1-C6Alkyl, or-C1-C6A halogenated alkyl group,
wherein any one R11' unsubstituted or optionally substituted by one or more R12' group substitution;
each R12' independently is halogen, C1-C6Haloalkyl, C1-C6Alkyl radical, C1-C6Alkoxy, C ═ O (OR)13)、COR13、SO2R13、CON(R13)2、SO2N(R13)2or-N (R)13)2。
105. A compound according to claim 101, where R2is-L3-R7Wherein
L3Is a chemical bond or- (CH)2)m″-V1-(CH2)n-, wherein
m' is 0 to 1;
n is 0 to 2; and is
V1is-CH2-, -O-, -S-, or-NR7-; and is
R7Is hydrogen, halogen, phenyl, heteroaryl, heterocyclyl-C1-C6Alkyl, -C1-C6Haloalkyl, -C2-C6Alkenyl radical, C3-C8Cycloalkyl, or- (C (R)15)2)m-Z wherein
Z is-OR11″、-C(＝O)R11″、-C(＝O)OR11″、-C(＝O)N(R11″)2、-N(R11″)2-CN, or-SO2R11″，
Wherein R is7Unsubstituted or optionally substituted by one or more R7aIs substituted in which
R7aIs halogen, C1-C6Alkyl radical, C 1-C6Haloalkyl, -OR11″、-N(R11″)2、-COOR11″，
Wherein R is11"is-H, -C1-C6Alkyl, -C1-C6Haloalkyl, heterocyclyl, or heteroaryl.
106. A compound according to claim 102, whereinEach R5aIndependently is halogen, nitro, heterocyclyloxy, phenoxy, -C ', -B' -C ', or-A' -B '-C', wherein
A' is-O-;
b' is- [ C (R)15)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)2Or a heterocyclic group;
wherein each R18Independently is-H, -C1-C6Alkyl, -C1-C6Haloalkyl, -C3-C8Cycloalkyl, aryl, heteroaryl, or heterocyclyl; and is
Wherein each R5aIs unsubstituted or optionally substituted by one or more groups which are independently C1-C6Alkyl, halogen, -COR19、-COOR19、-CON(R19)2、-OR19or-N (R)19)2，
Wherein R is19is-H or-C1-C6An alkyl group.
107. A compound according to claim 103, where each R is41Independently hydrogen, halogen, -C1-C6Alkyl, or-C1-C6A haloalkyl group.
108. A compound according to claim 104, where R2is-L3-R7Wherein
L3Is a chemical bond or- (CH)2)m″-V1-(CH2)n-, wherein
m' is 0 to 1; n is 0 to 2; and is
V1is-CH2-, -O-, -S-, or-NR7-; and is
R7Is hydrogen, halogen, phenyl, heteroaryl, heterocyclyl-C1-C6Alkyl, -C1-C6Haloalkyl, -C2-C6Alkenyl radical, C 3-C8Cycloalkyl, or- (C (R)15)2)m-Z wherein
Z is-OR11″、-C(＝O)R11″、-C(＝O)OR11″、-C(＝O)N(R11″)2、-N(R11″)2-CN, or-SO2R11″，
Wherein R is7Unsubstituted or optionally substituted by one or more R7aIs substituted in which
R7aIs halogen, C1-C6Alkyl radical, C1-C6Haloalkyl, -OR11″、-N(R11″)2、-COOR11″，
Wherein R is11"is-H, -C1-C6Alkyl, -C1-C6Haloalkyl, heterocyclyl, or heteroaryl.
109. The compound of claim 89, wherein
R1is-L1-R5Wherein
L1is-L5-or-L6-, wherein
Each L5is-C (R)15)2-, wherein
Each R15Independently hydrogen, halogen, (C)1-C6) Alkyl, or (C)1-C6) A haloalkyl group; and is
L6is-CS-, -CO-, or-SO2-; and is
R5Is unsubstituted or optionally substituted by one or more R5aSubstituted aryl or heteroaryl.
110. A compound according to claim 109, wherein
R5Is unsubstituted or optionally substituted by one or more R5aSubstituted phenyl, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, pyridyl, pyrimidinyl, or pyrazinyl.
111. A compound according to claim 110, where R2is-L3-R7Wherein
L3Is a chemical bond or-C (R)11″)2-; and is
R7Is hydrogen, halogen, -C1-C6Alkyl, -C1-C6Haloalkyl, -OR11″、-C(＝O)R11″、-C(＝O)OR11″、-C(＝O)N(R11″)2、-N(R11″)2、-CN、-SO2R11", or-S (═ O)2N(R11″)2，
Wherein each R11"is independently-H or-C1-C6An alkyl group.
112. The compound of claim 110, wherein each R 5aIndependently is-halogen, -C1-C6Alkyl, -C1-C6Haloalkyl, -OR11、-COR11、-C≡N、-C(O)OR11、-CON(R11)2or-N (R)11)2。
113. The compound of claim 110, wherein each R41Independently hydrogen, halogen, -C1-C6Alkyl, or-C1-C6A haloalkyl group.
114. The compound of claim 110, wherein each R4Independently of one another is halogen, -C1-C6Alkyl, -C1-C6Haloalkyl, -COR11′、-COOR11′、-CON(R11′)2、-C≡N、-OR11′、-N(R11′)2、-SO2R11', or-SO2N(R11′)2Wherein
Each R11' independently is-hydrogen, -C1-C6Alkyl, or-C1-C6A haloalkyl group.
115. The compound of claim 89, wherein
L1Is a chemical bond; and is
R5Is unsubstituted or optionally substituted by one or more R5aA substituted heteroaryl group.
116. A compound according to claim 115, wherein
R5Is unsubstituted or optionally substituted by one or more R5aSubstituted thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, pyridyl, pyrimidinyl, or pyrazinyl.
117. A compound according to claim 116, where R is5Is unsubstituted or optionally substituted by one or more R5aSubstituted thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, isothiazolyl, or isoxazolyl.
118. The compound of claim 117, wherein each R is 5aIndependently is-halogen, -C1-C6Alkyl, -C1-C6Haloalkyl, -OR11、-COR11、-C≡N、-C(O)OR11、-CON(R11)2or-N (R)11)2。
119. The combination of claim 117Wherein each R is4Independently of one another is halogen, -C1-C6Alkyl, -C1-C6Haloalkyl, -COR11′、-COOR11′、-CON(R11′)2、-C≡N、-OR11′、-N(R11)2、-SO2R11', or-SO2N(R11′)2Wherein
Each R11' independently is-hydrogen, -C1-C6Alkyl, or-C1-C6A haloalkyl group.
120. A compound according to claim 117, where R2is-L3-R7Wherein
L3Is a chemical bond or-C (R)11″)2-; and is
R7Is hydrogen, halogen, -C1-C6Alkyl, -C1-C6Haloalkyl, -OR11″、-C(＝O)R11″、-C(＝O)OR11″、-C(＝O)N(R11″)2、-N(R11″)2、-CN、-SO2R11", or-S (═ O)2N(R11″)2，
Wherein each R11"is independently-H or-C1-C6An alkyl group.
121. The compound of claim 117, wherein each R is41Independently hydrogen, halogen, -C1-C6Alkyl, or-C1-C6A haloalkyl group.
122. A compound according to claim 116, where R is5Is unsubstituted or optionally substituted by one or more R5aA substituted pyridyl, pyrimidinyl, or pyrazinyl group.
123. The process of claim 122A compound wherein each R5aIs-halogen, -C1-C6Alkyl, -C1-C6Haloalkyl, -OR11、-COR11、-C≡N、-C(O)OR11、-CON(R11)2or-N (R)11)2。
124. The compound of claim 122, wherein each R4Independently of one another is halogen, -C1-C6Alkyl, -C1-C6Haloalkyl, -COR11′、-COOR11′、-CON(R11′)2、-C≡N、-OR11′、-N(R11)2、-SO2R11', or-SO2N(R11′)2Wherein
Each R11' independently is-hydrogen, -C 1-C6Alkyl, or-C1-C6A haloalkyl group.
125. A compound according to claim 122, where R2is-L3-R7Wherein
L3Is a chemical bond; and is
R7Is hydrogen, halogen, -C1-C6Alkyl, -C1-C6Haloalkyl, -C2-C6Alkenyl radical, C3-C8Cycloalkyl, or- (C (R)15)2)m' -Z wherein
m' is 0 to 1; and is
Z is-OR11、-C(＝O)R11、-C(＝O)OR11、-C(＝O)N(R11)2、-N(R11)2-CN, or-SO2R11，
Wherein R is11is-H or C1-C6An alkyl group.
126. The compound of claim 122, wherein each R41Independently isHydrogen, halogen, -C1-C6Alkyl, or-C1-C6A haloalkyl group.
127. The compound of claim 85, wherein K is heteroaryl; and L is2Is a chemical bond.
128. The compound of claim 127, wherein K is thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, pyridyl, pyrimidinyl, or pyrazinyl.
129. A compound according to claim 128, where K is pyridyl.
130. A compound according to claim 129, wherein
L1Is a chemical bond; and is
R5Is unsubstituted or optionally substituted by one or more R5aA substituted phenyl group.
131. The compound of claim 85, wherein K is absent; and L is2is-SO2-or-CO-.
132. A compound according to claim 131, wherein
R4Is heterocyclyl, -OR11or-N (R)11)2、
Wherein said heterocyclyl is unsubstituted or optionally substituted by one or more-E '-M's, wherein
E' is- [ C (R)15)2]m-or C3-C8A cycloalkyl group;
m' is-H, halogen, COR11、COOR11、C≡N、OR11、-NR11COR11、NR11SO2R11、SO2R11、SO2N(R11)2Or SR11。
133. The compound of claim 1, wherein
R1is-L5-R5or-L6-R5Wherein
L5Is- [ C (R)15)2]m-；
L6Is C3-C8Cycloalkyl, ring C3-8Haloalkyl, or heterocyclyl, wherein said cycloalkyl, ring C3-8Haloalkyl, or heterocyclyl unsubstituted or optionally substituted with one or more R14Substituted by groups;
R5is aryl, heterocyclyl, or heteroaryl, wherein R5Unsubstituted or optionally substituted by one or more R5aIs substituted in which
Each R5aIndependently of one another is halogen, C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, (C)3-C8Cycloalkyl) -C1-C6Alkyl-, (C)3-C8Cycloalkenyl) -C1-C6Alkyl-, (C)3-C8Cycloalkyl) -C2-C6Alkenyl-, nitro-, heterocyclyloxy-, aryl-, aryloxy-, aralkyl-, aryloxyaryl-, aryl-C1-C6Alkoxy, -C ', -B' -C ', or-A' -B '-C', wherein
A' is-O-;
b' is- [ C (R)15)2]m-or-C3-C8Cycloalkyl-;
c' is-H, halogen, -SO2R11、-OR11、-SR11、-N3、-COR11、-SO2N(R11)2、-SO2NR11COR11、-C≡N、-C(O)OR11、-OC(＝O)R11、-CON(R11)2、-CON(R11)OR11、-OCON(R11)2、-NR11COR11、-NR11CON(R11)2、-NR11COOR11、-N(R11)2Aryl, heteroaryl, or heterocyclyl.
134. A compound according to claim 133, wherein
J is aryl or heteroaryl; and is
K is aryl or heteroaryl.
135. A compound according to claim 134, wherein
R2is-L3-R7Therein, wherein
L3Is a chemical bond; and is
R7Is hydrogen, -Z, or-Y-Z, wherein
Y is- [ C (R)15)2]m-or-C2-C6An alkenyl group;
z is-H, halogen, -OR11、-C(＝O)R11、-C(＝O)OR11、-C(＝O)N(R11)2、-N(R11)2、-CN、-SO2R11or-S (═ O)2N(R11)2And R is21Is hydrogen, halogen, C1-C6Alkyl, or C1-C6A haloalkyl group.
136. The compound of claim 1, which is of formula Ia or Id.
137. A compound according to claim 136, wherein
R1is-L5-R5or-L6-R5Wherein
L5Is- [ C (R)15)2]m-；
L6Is C3-C8Cycloalkyl, ring C3-8Haloalkyl, orHeterocyclyl, wherein said cycloalkyl, ring C3-8Haloalkyl, or heterocyclyl unsubstituted or optionally substituted with one or more R14Substituted by groups;
R5is aryl, heterocyclyl, or heteroaryl, wherein R5Unsubstituted or optionally substituted by one or more R5aIs substituted by radicals in which
Each R5aIndependently of one another is halogen, C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, (C)3-C8Cycloalkyl) -C1-C6Alkyl-, (C)3-C8Cycloalkenyl) -C1-C6Alkyl-, (C)3-C8Cycloalkyl) -C2-C6Alkenyl-, nitro-, heterocyclyloxy-, aryl-, aryloxy-, aralkyl-, aryloxyaryl-, aryl-C1-C6Alkoxy, -C ', -B' -C ', or-A' -B '-C',
wherein
A' is-O-;
b' is- [ C (R) 15)2]m-or-C3-C8Cycloalkyl-;
c' is-H, halogen, -SO2R11、-OR11、-SR11、-N3、-COR11、-SO2N(R11)2、-SO2NR11COR11、-C≡N、-C(O)OR11、-OC(＝O)R11、-CON(R11)2、-CON(R11)OR11、-OCON(R11)2、-NR11COR11、-NR11CON(R11)2、-NR11COOR11、-N(R11)2Aryl, heteroaryl, or heterocyclyl.
138. A compound according to claim 137, wherein
J is aryl or heteroaryl; and is
K is aryl or heteroaryl.
139. A compound according to claim 138, wherein
R2is-L3-R7Therein, wherein
L3Is a chemical bond; and is
R7Is hydrogen, -Z, or-Y-Z, wherein
Y is- [ C (R)15)2]m-or-C2-C6An alkenyl group;
z is-H, halogen, -OR11、-C(＝O)R11、-C(＝O)OR11、-C(＝O)N(R11)2、-N(R11)2、-CN、-SO2R11or-S (═ O)2N(R11)2And is and
R21is hydrogen, halogen, C1-C6Alkyl, or C1-C6A haloalkyl group.
140-the compound of claim 139, wherein J and K are both phenyl.
141. A compound according to claim 140, where R5Is an aryl group or a heteroaryl group,
wherein R is5Unsubstituted or optionally substituted by one or more R5aAnd (4) substitution.
142. A compound according to claim 141, where R is5Is unsubstituted or optionally substituted by one or more R5aSubstituted phenyl, wherein each R is5aIndependently is-halogen, -C1-C6Alkyl, -C1-C6Haloalkyl, -OR11、-COR11、-C≡N、-C(O)OR11、-CON(R11)2or-N (R)11)2。
143. A compound according to claim 142, wherein eachR is4Independently is halogen, aryl, heteroaryl, heterocyclyl, -M, or-E-M, wherein
E is- [ C (R)15’)2]m-, wherein
Each R15' is independently hydrogen or halogen; and is
M is-C1-C6Alkyl, -C1-C6Haloalkyl, halogen, -OR11or-SO2R11。
144. The compound of claim 142, wherein each R41Independently is halogen, -M ", or-E" -M ", wherein
E' is- [ C (R)15’)2]m-、
Wherein each R15' is independently hydrogen or halogen; and is
M' is-C1-C6Alkyl, -C1-C6Haloalkyl, or halogen.
145. A compound according to claim 142, wherein
R7Is hydrogen, -Z, or-Y-Z, wherein
Y is- [ C (R)15)2]m' -or-C2-C6Alkenyl radical, wherein
m' is 0, 1, or 2; and is
Z is-H, halogen, -OR11、-C(＝O)R11、-C(＝O)OR11、-C(＝O)N(R11)2、-N(R11)2、-CN、-SO2R11or-S (═ O)2N(R11)2；
And R is21Is hydrogen.
146. The compound of claim 139, wherein J is heteroaryl and K is phenyl.
147. The compound of claim 146, wherein J is pyrroyl, thienyl, furyl, thiazolyl, oxazolyl, or pyrazolyl.
148. The compound of claim 147, wherein R5 is aryl or heteroaryl,
wherein R is5Unsubstituted or optionally substituted by one or more R5aAnd (4) substitution.
149. A compound according to claim 148, wherein R5Is unsubstituted or optionally substituted by one or more R5aSubstituted phenyl, wherein each R is5aIndependently is-halogen, -C1-C6Alkyl, -C1-C6Haloalkyl, -OR 11、-COR11、-C≡N、-C(O)OR11、-CON(R11)2or-N (R)11)2。
150. The compound of claim 149, wherein each R is4Independently is halogen, aryl, heteroaryl, heterocyclyl, -M, or-E-M, wherein
E is- [ C (R)15’)2]m-, wherein
Each R15' is independently hydrogen or halogen; and is
M is-C1-C6Alkyl, -C1-C6Haloalkyl, halogen, -OR11or-SO2R11。
151. The compound of claim 149, wherein each R is41Independently is halogen, -M ", or-E" -M ", wherein
E' is- [ C (R)15’)2]m-、
Wherein each R15' is independently hydrogen or halogen; and is
M' is-C1-C6Alkyl, -C1-C6Haloalkyl, or halogen.
152. A compound according to claim 149, wherein
R7Is hydrogen, -Z, or-Y-Z, wherein
Y is- [ C (R)15)2]m' -or-C2-C6Alkenyl radical, wherein
m' is 0, 1, or 2; and is
Z is-H, halogen, -OR11、-C(＝O)R11、-C(＝O)OR11、-C(＝O)N(R11)2、-N(R11)2、-CN、-SO2R11or-S (═ O)2N(R11)2；
And R is21Is hydrogen.
153. The compound of claim 1, which is one of the compounds listed in table 1.
154. A compound according to one of the following formulae:
Figure S2006800306472C00381
，
wherein,
(A)R1is-L1-R5Wherein
L1Is a chemical bond, L5、L6、-L5-L6-L5-, or-L6-L5-L6-, wherein
Each L5Independently is- [ C (R)15)2]m-, wherein
Each m is independently 0, 1, 2, 3, 4, 5, or 6; and is
Each R15Independently hydrogen, halogen, (C)1-C6) Alkyl, or (C)1-C6) A haloalkyl group;
Each L6Independently is-C(R11)2-、-C(R11)2C(R11)2-、-C(R11)＝C(R11)-、-C(R11)2O-、-C(R11)2NR11-、-C≡C-、-O-、-S-、-NR11-、-N(R10)CO-、-N(R10)CO2-、-CON(R10)-、-CO-、-CS-、-CO2-、-OC(＝O)-、-OC(＝O)N(R10)-、-CONR11N(R11)2-、-CONR11-、-OCONR11-、-SO2-、-N(R10)SO2-、-SO2N(R10)-、-NR10CONR10-、-NR10CSNR10-、-C(＝NR11)-、-C(＝NOR11)-、-C(＝NN(R11)2) -; aryl radical, C3-C8Cycloalkyl, ring C3-8Haloalkyl, heteroaryl, or heterocyclyl, wherein said aryl, cycloalkyl, ring C3-8The haloalkyl, heteroaryl, or heterocyclyl is unsubstituted or optionally substituted with one or more R14Substituted by groups;
or L1Is C2-6Alkanediyl chains wherein said alkanediyl chains are uninterrupted or optionally-C (R)11)2-、-C(R11)2C(R11)2-、-C(R11)＝C(R11)-、-C(R11)2O-、-C(R11)2NR11-、-C≡C-、-O-、-S-、-N(R10)CO-、-N(R10)CO2-、-CON(R10)-、-CO-、-CO2-、-OC(＝O)-、-OC(＝O)N(R10)-、-SO2-、-N(R10)SO2-, or-SO2N(R10) -is interrupted, and R5Is aryl, heterocyclyl, heteroaryl, C2-C6Alkenyl radical, C2-C6Alkynyl, (C)3-C8Cycloalkyl) -C1-C6Alkyl-, (C)3-C8Cycloalkenyl) -C1-C6Alkyl-, (C)3-C8Cycloalkyl) -C2-C6Alkenyl-, C3-C8Cycloalkyl, -C, -B-C, or-A-B-C, wherein
A is-O-;
b is- [ C (R)15)2]m-or C3-C8A cycloalkyl group;
c is C1-C6Alkyl radical, C1-C6Halogenated alkyl, SO2R11、SR11、SO2N(R11)2、SO2NR11COR11、C≡N、C(O)OR11、CON(R11)2Or N (R)11)2；
Wherein R is5Unsubstituted or optionally substituted by one or more R5aThe substitution is carried out by the following steps,
wherein each R5aIndependently is C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, (C)3-C8Cycloalkyl) -C1-C6Alkyl-, (C)3-C8Cycloalkenyl) -C1-C6Alkyl-, (C)3-C8Cycloalkyl) -C2-C6Alkenyl-, halogen, nitro, heterocyclyloxy, aryl, aryloxy, arylalkyl, aryloxyaryl, aryl C1-C6Alkoxy, -C ', -B' -C ', or-A' -B '-C', wherein
A' is-O-;
b' is- [ C (R)15)2]m-or-C3-C8Cycloalkyl-;
c' is-H, halogen, -SO 2R11、-OR11、-SR11、-N3、-COR11、-SO2N(R11)2、-SO2NR11COR11、-C≡N、-C(O)OR11、-OC(＝O)R11、-CON(R11)2、-CON(R11)OR11、-OCON(R11)2、-NR11COR11、-NR11CON(R11)2、-NR11COOR11、-N(R11)2Aryl, heteroarylA group, or a heterocyclic group;
wherein each R5aIs unsubstituted or optionally substituted by one or more groups which are independently C2-C6Alkenyl radical, C2-C6Alkynyl, (C)3-C8Cycloalkyl) -C1-C6Alkyl-, (C)3-C8Cycloalkenyl) -C1-C6Alkyl-, (C)3-C8Cycloalkyl) -C2-C6Alkenyl-, C0-C6Alkoxyaryl radical, C1-C6Alkyl radical, C3-C8Cycloalkyl, aryl-C1-C6Alkyl-, heteroaryl, halogen, -NO2、-C≡N、-COR11、-COOR11、-CON(R11)2、-SO2R11、-OR11、-SR11、-SO2R11、-SO2N(R11)2、-SO2NR11COR11、-OCON(R11)2、-NR11COR11、-NR11CON(R11)2、-NR11COOR11or-N (R)11)2；
R2And R21Are all-L3-R7Wherein
Each L3Independently is a chemical bond, -V1-(CH2)n-V1-, or- (CH)2)m-V1-(CH2)n-，
Wherein
n is 0 to 6; and is
Each V1Independently is-C (R)11)2-、-C(R11)2C(R11)2-、-C(R11)＝C(R11)-、-C(R11)2O-、-C(R11)2NR11-、-C≡C-、-O-、-S-、-NR7-、-N(R10)CO-、-N(R10)CO2-、-OCO-、-CO-、-CS-、-CONR10-、-C(＝N)(R11)-、-C(＝N-OR11)-、-C[＝N-N(R11)2]、-CO2-、-OC(＝O)-、-OC(＝O)N(R10)-、-SO2-、-N(R10)SO2-、-SO2N(R10)-、-NR10CONR10-、-NR10CSNR10-、C3-C8Cycloalkyl, or C3-C8A cyclic haloalkyl group;
or each L3Independently is C2-6An alkanediyl chain, wherein said alkanediyl chain is optionally substituted by-C (R)11)2-、-C(R11)2C(R11)2-、-C(R11)＝C(R11)-、-C(R11)2O-、-C(R11)2NR11-、-C≡C-、-O-、-S-、-N(R10)CO-、-N(R10)CO2-、-CON(R10)-、-CO-、-CO2-、-OC(＝O)-、-OC(＝O)N(R10)-、-SO2-、-N(R10)SO2-, or-SO2N(R10) Interrupting; and is
Each R7Independently hydrogen, halogen, nitro, cyano, aryl, heteroaryl, heterocyclyl, -C1-C6alkyl-heterocyclyl-C1-C6Alkyl-heteroaryl, -C1-C6Alkyl-aryl, -Z, -Y-Z, or-X-Y-Z, wherein
X is-O-;
y is- [ C (R)15)2]m-、-C2-C6Alkenyl or C3-C8A cycloalkyl group;
z is-H, -CN, halogen, -OR11、-C(＝O)R11、-C(＝O)OR11、-C(＝O)N(R11)2、-N(R11)2、-CN、-N3、-SO2R11、-S(＝O)2N(R11)2、-C(＝O)N(R11)N(R11)2、-C(＝O)N(R11)(OR11)、-OC(＝O)-R11、-OC(＝O)-N(R11)2or-N (R)11)COOR11；
Wherein R is7Unsubstituted or optionally substituted by one or more R7aIs substituted in which
R7aIs halogen, C2-C6Alkenyl, -C1-C6alkyl-heterocyclyl-C1-C6Alkyl-heteroaryl, -C 1-C6Alkyl-aryl, C0-C6Alkoxyheteroaryl group, C0-C6Alkoxyheterocyclyl, haloaryl, aryloxy, arylalkoxy, aryloxyalkyl, C1-C6Alkoxyaryl, aryl C0-C6Alkyl carboxyl, C (R)11)＝C(R11)-COOR11、C0-C6Alkoxyheteroaryl group, C0-C6Alkoxyheterocyclyl, aryl, heteroaryl, heterocyclyl, C3-C8Cycloalkyl, heteroaryloxy, -Z ', -Y' -Z ', or-X' -Y '-Z', wherein
X' is-O-;
y' is- [ C (R)15)2]m-or C3-C8A cycloalkyl group;
z' is-C1-C6Alkyl, -C1-C6Haloalkyl, -OR11、-SR11、-S(＝O)2R11、-C(＝O)R11、-C(＝O)OR11、-C(＝O)N(R11)2、-N(R11)2、-N(R11)C(＝O)R11、-S(＝O)2N(R11)C(＝O)R11、-CN、-S(＝O)2N(R11)2、-C(＝O)N(R11)N(R11)2、-C(＝O)N(R11)(OR11)、-OC(＝O)-R11、-OC(＝O)-OR11、-N(R11)C(＝O)O-R11or-N (R)11)S(＝O)2R11；
Wherein each R7aUnsubstituted or optionally substituted by one or more R8The substitution is carried out by the following steps,
wherein each R8Independently halogen, nitro, cyano, heteroaryl, C1-C6Alkyl radical, C1-C6Alkoxy radical, C1-C6Haloalkyl, C1-C6Haloalkyl (OR)11)、C0-C6Alkyl OR11、C0-C6Alkyl CON (R)11)2、C0-C6Alkyl group COR11、C0-C6Alkyl group COOR11Or C0-C6Alkyl SO2R11(ii) a And wherein if two R are present7aOn the same carbon atom, they together form a cycloalkyl or heterocyclyl group; provided that R is2And R21Is not H at the same time;
R3is-L-R6Wherein
L is a bond, -X3-(CH2)n-X3-、-(CH2)m-X3-(CH2)n-or- (CH)2)l+w-Y3-(CH2)w-, wherein
n is 0 to 6; each w is independently 0 to 5; and is
Each X3Independently is a chemical bond, -C (R)11)2-、-C(R11)2C(R11)2-、-C(R11)＝C(R11)-、-C≡C-、-CO-、-CS-、-CONR10-、-C(＝N)(R11)-、-C(＝N-OR11)-、-C[＝N-N(R11)2]、-CO2-、-SO2-, or-SO2N(R10) -; and is
Y3is-O-, -S-, -NR7-、-N(R10)CO-、-N(R10)CO2-、-OCO-、-OC(＝O)N(R10)-、-NR10CONR10-、-N(R10)SO2-, or-NR10CSNR10-；
Or L is C2-6Alkanediyl chains wherein said alkanediyl chains are uninterrupted or optionally-C (R) 11)2-、-C(R11)2C(R11)2-、-C(R11)＝C(R11)-、-C(R11)2O-、-C(R11)2NR11-、
-C≡C-、-O-、-S-、-N(R10)CO-、-N(R10)CO2-、-CON(R10)-、-CO-、-CO2-、-OC(＝O)-、-OC(＝O)N(R10)-、-SO2-、-N(R10)SO2-, or
-SO2N(R10) Interrupting; and is
R6Is C1-C6Alkyl radical, C1-C6Haloalkyl, aryl, C3-C8Cycloalkyl, heteroaryl, heterocyclyl, -CN, -C (═ O) R11、-C(＝O)OR11、-C(＝O)N(R11)2、-N(R11)2、-SO2R11、-S(＝O)2N(R11)2、-C(＝O)N(R11)N(R11)2、-C(＝O)N(R11)(OR11)，
Wherein
Said aryl, heteroaryl, cycloalkyl, or heterocyclyl is unsubstituted or optionally substituted with one or more R6aIs substituted in which
Each R6aindependently-Z ", -Y" -Z ", or-X" -Y "-Z", wherein
X' is-O-;
y' is- [ C (R)15)2]m-、-C2-C6Alkenyl radical, C3-C8Cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein
Said aryl, heteroaryl, cycloalkyl, or heterocyclyl is unsubstituted or optionally substituted with at least one group, each of said at least one group is independently Z';
z' is-H, -CN, halogen, -OR11、-C(＝O)R11、-C(＝O)OR11、-C(＝O)N(R11)2、-N(R11)2、-N3、-SO2R11、-S(＝O)2N(R11)2、-C(＝O)N(R11)N(R11)2、-N(R11)C(＝O)N(R11)2、-OC(＝O)-OR11、-C(＝O)N(R11)(OR11)、-OC(＝O)-R11、-OC(＝O)-N(R11)2or-N (R)11)COOR11；
Each R10Independently is-R11、-C(＝O)R11、-CO2R11or-SO2R11；
Each R11Independently is-hydrogen, C2-C6Alkenyl radical, C2-C6Alkynyl, (C)3-C8Cycloalkenyl) -C1-C6Alkyl-, (C)3-C8Cycloalkyl) -C2-C6Alkenyl-, -N (R)12)2、-C1-C6Alkyl, -C1-C6Haloalkyl, -C3-C8Cycloalkyl, - (C)1-C6) Alkyl radical- (C)3-C8) Cycloalkyl, aryl, - (C)1-C6) Alkyl-aryl, heteroaryl, - (C)1-C6) Alkyl-heteroaryl, heterocyclyl, or- (C)1-C6) An alkyl-heterocyclic group, a heterocyclic group,
wherein any one R11Unsubstituted or optionally substituted by one or more R12Substituted by groups;
each R12Independently of one another is hydrogen, halogen, C 1-C6Haloalkyl, C1-C6Alkyl radical, C1-C6Alkoxy group, (C)0-C6Alkyl) C ═ O (OR)13)；C0-C6Alkyl OR13、C0-C6Alkyl group COR13、C0-C6Alkyl SO2R13、C0-C6Alkyl CN, C0-C6Alkyl CON (R)13)2、C0-C6Alkyl CONR13OR13、C0-C6Alkyl SO2N(R13)2、C0-C6Alkyl SR13、C0-C6Haloalkyl OR13Aryloxy, arylalkoxy, aryloxyalkyl, C0-C6Alkoxyaryl, aryl C0-C6Alkyl carboxyl, C0-C6Alkyl radical NR13SO2R13、-C0-C6Alkyl N (R)13)2Or OC0-C6Alkyl group COOR13；
Each R13Independently of each other is hydrogen, C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, (C)3-C8Cycloalkyl) -C1-C6Alkyl-, (C)3-C8Cycloalkenyl) -C1-C6Alkyl-, or (C)3-C8Cycloalkyl) -C2-C6Alkenyl-;
each R14Independently is C1-C6Alkyl radical, C1-C6Alkoxy, halogen, C1-C6Haloalkyl, C0-C6Alkyl CON (R)11)2、C0-C6Alkyl CONR11OR11、C0-C6Alkyl OR11Or C0-C6Alkyl group COOR11；
G is a group of the formula:
Figure S2006800306472C00431
wherein
J is aryl, heteroaryl, or absent;
hal is halogen;
each R41Independently of one another is halogen, nitro, C1-C6alkyl-heterocyclyl-C1-C6Alkyl-heteroaryl, -C1-C6Alkyl-aryl, -M ", -E" -M ", or-D" -E "-M", wherein
D "is-O-;
e' is- [ C (R)15)2]m-or C3-C8A cycloalkyl group;
m' is-C1-C6Alkyl, -C1-C6Haloalkyl, -COR11、-COOR11、-CON(R11)2、-C≡N、-OR11、-OCON(R11)2、-OCO2-R11、-N3、-NR11COR11、-NR11SO2R11、-N(R11)2、-NR11COOR11、-SO2R11、-SO2NR11COR11、-SO2N(R11)2or-SR11，
Wherein each R41Unsubstituted or optionally substituted by one or more R4aThe substitution of the group(s),
wherein each R4aIndependently is halogen, aryloxy, arylalkoxy, aryloxyalkyl, -C 1-C6Alkyl-aryl, C1-C6Alkoxyaryl, aryl C0-C6Alkylcarboxyl, -M ', -E' -M ', or-D' -E '-M',
d' is-O-;
e' is- [ C (R)15)2]m-or C3-C8A cycloalkyl group;
m' is-C1-C6Alkyl, -C1-C6Haloalkyl, COR11、-CON(R11)2、-N(R11)COOR11、-N(R11)2、COOR11、C≡N、OR11、-NR11COR11、NR11SO2R11、SO2R11、SO2N(R11)2Or SR11(ii) a And is
q' is 0, 1, 2, 3, or 4, and with the proviso that,
(i) if the compound is defined by the formula XXIXa
(a)R1Is not 4- (NH)2SO2) Phenyl, 4- (CH)3SO2) Phenyl, or 4- (CH)2FSO2) A phenyl group;
(b) if R is1Is 4-fluorophenyl, then G is not 4- [ (H)2NS(＝O)2-]Phenyl-
(c)R2Is not 4-hydroxyphenyl;
(ii) if the compound is defined by the formula XXIXb
(a)R2Is not 4- (NH)2SO2) Phenyl, 4- (CH)3SO2) Phenyl, or 4- (CH)2FSO2) A phenyl group;
(b) j is not pyridyl;
(c)R1is not 4-hydroxyphenyl;
(iii) if the compound is defined by the formula XXIXc
(a)R2Is not 4- (NH)2SO2) Phenyl, 4- (CH)3SO2) Phenyl, or 4- (CH)2FSO2) A phenyl group;
(b) j is not pyridyl;
(iv) if the compound is defined by the formula XXIXd
(a) If L is1Is a chemical bond, then R1Is not thienyl or 5-methylthiophenyl;
(b) if G is 4-fluorophenyl, R1Is not 4- [ (H)2NS(＝O)2-]Phenyl-;
(c)R1is not 4-methyl-phenyl.
155. The compound of claim 154, which is one of the species listed in table 2.
156. The compound of claim 1, wherein:
R1is-L1-R5Wherein
L1Is a chemical bond, L5、L6、-L5-L6-L5-, or-L6-L5-L6-, wherein
Each L5Independently is- [ C (R)15)2]m-, wherein
m is 0, 1, 2, 3, or 4; and is
Each R15Independently hydrogen, halogen, (C)1-C6) Alkyl, or (C)1-C6) A haloalkyl group; and is
L6is-CO-, -SO2-、-O-、-CON(R11)-、-C3-C6Cycloalkyl-, or-heterocyclyl-,
wherein said cycloalkyl, or heterocyclyl is unsubstituted or optionally substituted with one or more R14Substitution; and is
R5Is aryl, heterocyclyl, heteroaryl, -C, or-B-C, wherein
B is- [ C (R)15)2]m-or-C3-C6Cycloalkyl-; and is
C is halogen, -C1-C6Alkyl, or-C1-C6A haloalkyl group;
wherein R is5Unsubstituted or optionally substituted by one or more R5aIs substituted in which
Each R5aIndependently halogen, nitro, heteroaryl, heterocyclyl, C2-C6Alkenyl radical, C2-C6Alkynyl, (C)3-C8Cycloalkyl) -C1-C6Alkyl-, (C)3-C8Cycloalkenyl) -C1-C6Alkyl-, (C)3-C8Cycloalkyl) -C2-C6Alkenyl-; aryl, aralkyl, aryloxy, aryloxyaryl, aryl C1-6Alkoxy radical, C1-C6Alkyl radical, C1-C6Haloalkyl, C3-C6Cycloalkyl, SO2R11、OR11、SR11、N3、SO2R11、COR11、SO2N(R11)2、SO2NR11COR11、C≡N、C(O)OR11、CON(R11)2、CON(R11)OR11、OCON(R11)2、NR11COR11、NR11CON(R11)2、NR11COOR11Or N (R)11)2Wherein
Each R5aUnsubstituted or optionally substituted with one or more groups independently-halogen, -C1-C6Alkyl, aryloxy C0-6Alkyl SO2R11、C0-6Alkyl group COOR11、C0-6Alkoxyaryl, -C1-C6Haloalkyl, -SO 2R11、-OR11、-SR11、-N3、-SO2R11、-COR11、-SO2N(R11)2、-SO2NR11COR11、-C≡N、-C(O)OR11、-CON(R11)2、-CON(R11)OR11、-OCON(R11)2、-NR11COR11、-NR11CON(R11)2、-NR11COOR11or-N (R)11)2；
R2is-L3-R7Wherein
L3Is a chemical bond; and is
R7Is halogen, aryl, heteroaryl, heterocyclyl, -Z, or-Y-Z, wherein
Y is- [ C (R)15)2]m-or-C3-C6A cycloalkyl group; and is
Z is-H, halogen, -OR11、-C(＝O)R11、-C(＝O)OR11、-C(＝O)N(R11)2、-N(R11)2、-C(＝N-OH)R11、-C(＝S)N(R11)2、-CN、-S(＝O)2N(R11)2、-C(＝O)N(R11)N(R11)2or-C (═ O) N (R)11)(OR11)；
Wherein R is7Unsubstituted or optionally substituted by one or more R7aIs substituted in which
R7aIs halogen, -Z ', -Y' -Z ', or-X' -Y '-Z', wherein
X' is-O-;
y' is- [ C (R)15)2]m-or-C3-C6A cycloalkyl group; and is
Z' is-H, halogen, -OR11、-SR11、-S(＝O)2R11、-C(＝O)R11、-C(＝O)OR11、-C(＝O)N(R11)2、-N(R11)2、-N(R11)C(＝O)R11、-CN、-S(＝O)2N(R11)2、-C(＝O)N(R11)(OR11) or-N (R)11)S(O＝)2R11；
R21And R3Each independently is hydrogen, halogen, C1-C6Alkyl, or C1-C6A haloalkyl group; and G is a group of the formula:
Figure S2006800306472C00461
wherein
J is aryl or heteroaryl;
k is aryl or heteroaryl;
each R4And R41Independently is halogen, aryloxy, arylalkoxy, aryloxyalkyl,
Aryl radical C0-C6Alkylcarboxyl, aryl, heteroaryl, heterocyclyl, heteroaryloxy, heterocyclyloxy, -M, -E-M, or-D-E-M, wherein
D is-O-;
e is- [ C (R)15)2]m-or-C3-C6A cycloalkyl group; and is
M is-C1-C6Alkyl, -C1-C6Haloalkyl, -COR11、-COOR11、-CON(R11)2、-C≡N、-OR11、-OCON(R11)2、-NR11COR11、-NR11SO2R11、-N(R11)2、-NR11COOR11、-SOR11、-SO2R11、-SO2NR11COR11、-SO2N(R11)2or-SR11，L2Is a chemical bond;
q is 1, 2, or 3; and is
q' is 0, 1, 2, or 3;
each R10Independently is-R11、-C(＝O)R11、-CO2R11or-SO2R11；
Each R11Independently is-hydrogen, -C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, (C)3-C8Cycloalkyl) -C 1-C6Alkyl-, (C)3-C8Cycloalkenyl) -C1-C6Alkyl-, or (C)3-C8Cycloalkyl) -C2-C6Alkenyl-; c1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, (C)3-C8Cycloalkyl) -C1-C6Alkyl-, (C)3-C8Cycloalkenyl) -C1-C6Alkyl-, (C)3-C8Cycloalkyl) -C2-C6Alkenyl-, -C3-C8Cycloalkyl, -C1-C6Haloalkyl, -N (R)12)2Aryl, - (C)1-C6) Alkyl-aryl, heteroaryl, - (C)1-C6) Alkyl-heteroaryl, heterocyclyl, or- (C)1-C6) An alkyl-heterocyclic group, a heterocyclic group,
wherein any one R11Unsubstituted or optionally substituted by one or more R12Substituted by groups;
each R12Independently of one another is halogen, C0-C6Alkyl N (R)13)2、C1-C6Haloalkyl, C1-C6Alkyl radical, C1-C6Alkoxy group, (C)0-C6Alkyl) C ═ O (OR)13)；
C0-C6Alkyl OR13、C0-C6Alkyl group COR13、C0-C6Alkyl SO2R13、C0-C6Alkyl CON (R)13)2、C0-C6Alkyl CONR13OR13、C0-C6Alkyl SO2N(R13)2、C0-C6Alkyl SR13、C0-C6Haloalkyl OR13Aryloxy, arylalkoxy, aryloxyalkyl, C0-6Alkoxyaryl, aryl C0-6Alkyl carboxyl, C0-C6Alkyl, -NR13SO2R13or-OC0-6Alkyl group COOR13；
Each R13Independently of each other is hydrogen, C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, (C)3-C8Cycloalkyl) -C1-C6Alkyl-, (C)3-C8Cycloalkenyl) -C1-C6Alkyl-, or (C)3-C8Cycloalkyl) -C2-C6Alkenyl-; and is
Each R14Independently is C1-C6Alkyl radical, C1-C6Alkoxy, halogen, C1-C6Haloalkyl, C0-C6Alkyl CON (R)11)2、C0-C6Alkyl CONR11OR11、C0-C6Alkyl OR11Or C0-C6Alkyl group COOR11。
157. The compound of claim 1, wherein:
R1is-L1-R5Wherein
L1Is a chemical bond, -C3-C8Cycloalkyl-or L5Wherein
Each L5Independently is- [ C (R)15)2]m-, wherein
m is 0, 1, 2, or 3; and is
Each R15Independently hydrogen, halogen, (C)1-C6) Alkyl, or (C)1-C6) A haloalkyl group; and is
R5Is aryl, heterocyclyl, heteroaryl, -C, or-B-C, wherein
B is- [ C (R)15)2]m-、-C3-C6Cycloalkyl-; and is
C is-C1-C6Alkyl or-C1-C6A haloalkyl group;
wherein R is5Unsubstituted or optionally substituted by one or more R5aIs substituted in which
Each R5aIndependently halogen, nitro, heteroaryl, heterocyclyl, C2-C6Alkenyl radical, C2-C6Alkynyl, (C)3-C8Cycloalkyl) -C1-C6Alkyl-, (C)3-C8Cycloalkenyl) -C1-C6Alkyl-, (C)3-C8Cycloalkyl) -C2-C6Alkenyl-, aryl-, aralkyl-, aryloxy-, aryloxyaryl, aryl C1-6Alkoxy radical, C1-C6Alkyl radical, C1-C6Haloalkyl, C3-C6Cycloalkyl, SO2R11、OR11、SR11、N3、SO2R11、COR11、SO2N(R11)2、SO2NR11COR11、C≡N、C(O)OR11、CON(R11)2、CON(R11)OR11、OCON(R11)2、NR11COR11、NR11CON(R11)2、NR11COOR11Or N (R)11)2Wherein
Each R5aUnsubstituted or optionally substituted with one or more groups independently-halogen, -C1-C6Alkyl, aryloxy, C0-6Alkyl SO2R11、C0-6Alkyl group COOR11、C0-6Alkoxyaryl, -C1-C6HalogenatedAlkyl, -SO2R11、-OR11、-SR11、-N3、-SO2R11、-COR11、-SO2N(R11)2、-SO2NR11COR11、-C≡N、-C(O)OR11、-CON(R11)2、-CON(R11)OR11、-OCON(R11)2、-NR11COR11、-NR11CON(R11)2、-NR11COOR11or-N (R)11)2；
R2is-L3-R7Wherein
L3Is a chemical bond; and is
R7is-Z or-Y-Z, wherein
Y is- [ C (R)15)2]m-, or-C3-C6A cycloalkyl group; and is
Z is-H, halogen, -OR11、-C(＝O)R11、-C(＝O)OR11、-C(＝O)N(R11)2、-N(R11)2、-C(＝N-OH)R11、-C(＝S)N(R11)2、-CN、-S(＝O)2N(R11)2、-OC(＝O)-R11or-OC (═ O) -N (R) 11)2；
R21And R3Each independently is hydrogen, halogen, C1-C6Alkyl, or C1-C6A haloalkyl group; and G is a group of the formula:
Figure S2006800306472C00491
wherein
J is aryl or heteroaryl;
k is aryl or heteroaryl;
each R4And R41Independently is halogen, heteroaryl, heterocyclyl, -M, -E-M, or-D-E-M, wherein
D is-O-;
e is- [ C (R)15)2]m-or-C3-C6A cycloalkyl group; and is
M is-C1-C6Alkyl, -C1-C6Haloalkyl, -COR11、-COOR11、-CON(R11)2、-C≡N、-OR11、-SOR11、-SO2R11、-SO2N(R11)2or-SR11，
L2Is a chemical bond;
q is 1, 2, or 3, and
q' is 0, 1, 2 or 3,
each R10Independently is-R11、-C(＝O)R11、-CO2R11or-SO2R11；
Each R11Independently is-hydrogen, -C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, (C)3-C8Cycloalkyl) -C1-C6Alkyl-, (C)3-C8Cycloalkenyl) -C1-C6Alkyl-, (C)3-C8Cycloalkyl) -C2-C6Alkenyl-, -C3-C8Cycloalkyl, - (C)1-C6) Alkyl radical- (C)3-C8) Cycloalkyl, -C1-C6Haloalkyl, -N (R)12)2Aryl, - (C)1-C6) Alkyl-aryl, heteroaryl, - (C)1-C6) Alkyl-heteroaryl, heterocyclyl, or- (C)1-C6) An alkyl-heterocyclic group, a heterocyclic group,
wherein any one R11Unsubstituted or optionally substituted by one or more R12Substituted by groups;
each R12Independently halogen, OR13、N(R13)2、C1-C6Haloalkyl, C1-C6Alkyl radical, C1-C6Alkoxy group, (C)0-C6Alkyl) C ═ O (OR)13)；C0-C6Alkyl OR13、C0-C6Alkyl radicalCOR13、C0-C6Alkyl SO2R13、C0-C6Alkyl CON (R)13)2、C0-C6Alkyl CONR13OR13、C0-C6Alkyl SO2N(R13)2、C0-C6Alkyl SR13、C0-C6Haloalkyl OR13Aryloxy, arylalkoxy, aryloxyalkyl, C 0-6Alkoxyaryl, aryl C0-6Alkyl carboxyl, C0-C6Alkyl, -NR13SO2R13or-OC0-6Alkyl group COOR13；
Each R13Independently of each other is hydrogen, C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, (C)3-C8Cycloalkyl) -C1-C6Alkyl-, (C)3-C8Cycloalkenyl) -C1-C6Alkyl-, or (C)3-C8Cycloalkyl) -C2-C6Alkenyl-;
each R14Independently is C1-C6Alkyl radical, C1-C6Alkoxy, halogen, C1-C6Haloalkyl, C0-C6Alkyl CON (R)11)2、C0-C6Alkyl CONR11OR11、C0-C6Alkyl OR11Or C0-C6Alkyl group COOR11。
158. The compound of claim 7, wherein R5Is unsubstituted or optionally substituted by one or more R5aA substituted pyridyl group.
159. The compound of claim 158, wherein each R is5aIndependently is-halogen, -C1-C6Alkyl, -C1-C6Haloalkyl, -OR11、-COR11、-C≡N、-C(O)OR11、-CON(R11)2or-N (R)11)2。
160. The compound of claim 158, wherein each R is41Independently hydrogen, halogen, -C1-C6Alkyl, or-C1-C6A haloalkyl group.
161. A compound according to claim 158, where R is2is-L3-R7Wherein
L3Is a chemical bond or-C (R)11″)2-; and is
R7Is hydrogen, halogen, -C1-C6Alkyl, -C1-C6Haloalkyl, -OR11″、-C(＝O)R11″、-C(＝O)OR11″、-C(＝O)N(R11″)2、-N(R11″)2、-CN、-SO2R11", or-S (═ O)2N(R11″)2，
Wherein each R11"is independently-H or-C1-C6An alkyl group.
162. The compound of claim 158, wherein each R is4Independently of one another is halogen, -C1-C6Alkyl, -C1-C6Haloalkyl, -COR 11′、-COOR11′、-CON(R11′)2、-C≡N、-OR11′、-N(R11)2、-SO2R11', or-SO2N(R11′)2Wherein each R is11' independently is-hydrogen, -C1-C6Alkyl, or-C1-C6A haloalkyl group.
163. A method of treating, preventing, inhibiting or ameliorating the symptoms of a disease or disorder modulated by or otherwise affected by nuclear receptor activity or associated with a nuclear receptor, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to claim 1, part (a).
164. The method of claim 163, wherein the disease or disorder is hypercholesterolemia, hyperlipoproteinemia, hypertriglyceridemia, lipodystrophy, hyperglycemia, diabetes, dyslipidemia, atherosclerosis, cholelithiasis, acne vulgaris, acneiform skin disease, polyuria, parkinson's disease, cancer, alzheimer's disease, inflammation, immune dysfunction, lipid disorders, obesity, disorders characterized by epidermal barrier dysfunction, disorders of epidermal or mucosal differentiation or hyperproliferative disorders, or cardiovascular disease.
165. A method of modulating the activity of a nuclear receptor, comprising contacting a compound according to claim 1, part (a), with the nuclear receptor.
166. A pharmaceutical composition comprising a compound according to claim 1 or a pharmaceutically acceptable derivative thereof in a pharmaceutically acceptable carrier.
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