[go: up one dir, main page]

HK1061235A - Triazolopyridines as anti-inflammatory agents - Google Patents

Triazolopyridines as anti-inflammatory agents Download PDF

Info

Publication number
HK1061235A
HK1061235A HK04104273.6A HK04104273A HK1061235A HK 1061235 A HK1061235 A HK 1061235A HK 04104273 A HK04104273 A HK 04104273A HK 1061235 A HK1061235 A HK 1061235A
Authority
HK
Hong Kong
Prior art keywords
alkyl
phenyl
heteroaryl
cycloalkyl
heterocyclyl
Prior art date
Application number
HK04104273.6A
Other languages
Chinese (zh)
Inventor
马克．A．多姆布罗斯基
艾伦．J．杜普兰蒂尔
埃伦．R．莱尔德
迈克尔．A．利塔维克
金．F．麦克卢尔
Original Assignee
辉瑞产品公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 辉瑞产品公司 filed Critical 辉瑞产品公司
Publication of HK1061235A publication Critical patent/HK1061235A/en

Links

Description

Triazolopyridines as anti-inflammatory agents
The present invention relates to novel triazolopyridines, intermediates for their preparation, pharmaceutical compositions containing them and their medical use. The compounds of the present invention are potent inhibitors of MAP kinase, preferably p38 kinase. They are useful in the treatment of inflammation, osteoarthritis, rheumatoid arthritis, cancer, reperfusion or ischemia in stroke or heart attack, autoimmune diseases and other disorders.
Intracellular signal transduction is the means by which cells respond to extracellular stimuli. Irrespective of the nature of cell surface receptors (e.g. protein tyrosine kinases or seven transmembrane G-protein coupled), protein kinases and phosphatases and phospholipases are essential mechanisms by which signals are further transmitted within the cell (Marshall, j.c. cell, 80, 179-278 (1995)). Protein kinases can be divided into five classes, the two main classes being tyrosine kinases and serine/threonine kinases, depending on whether the enzyme phosphorylates its substrate on a particular tyrosine or serine/threonine residue (Hunter, T.methods in enzymology (protein Kinase Classification) p.3, Hunter, T.; Sefton, B.M.; eds. vol.200, Academic Press; San Diego, 1991).
With respect to most biological responses, multiple intracellular kinases are involved, and a single kinase may be involved in more than one signaling pathway. These kinases are often cytolytic and can be readily localized to the nucleus or ribosome where they can affect transcriptional and translational activities, respectively. The involvement of kinases in transcriptional control is currently better understood than their role in translation, as described in studies on growth factor-induced signal transduction with the involvement of MAP/ERK kinases (Marshall, C.J.Cell, 80, 179 (1995); Herskowitz, I.Cell, 80, 187 (1995); Hunter, T.Cell, 80, 225 (1995); Seger, R. and Krebs, E.G.FASJ.735 (1995)).
Although many signaling pathways are part of the homeostasis of normal cells, a number of cytokines (e.g., IL-1 and TNF) and certain other inflammatory mediators (e.g., COX-2 and iNOS) are produced only in response to stress signals such as bacterial Lipopolysaccharide (LPS). Early evidence suggesting that protein kinases are involved in signal transduction pathways leading to LPS-induced cytokine biosynthesis, came from the study of Weinstein (Weinstein et al, j. immunol.151, 3829(1993)), but did not identify the specific protein kinases involved. In a similar view, Han (Han et al, Science 265, 808(1994)) identified murine p38 as a kinase, a tyrosine phosphorylated in response to LPS. Additional evidence for the involvement of p38 kinase in the LPS-stimulated signal transduction pathway that triggers proinflammatory cytokine biosynthesis is provided by Lee (Lee et al, Nature, 372, 739(1994)), who discovered p38 kinase (CSBP1 and 2) to be a molecular target for a new class of anti-inflammatory agents. Thus, compounds that inhibit p38 will inhibit IL-1 and TNF synthesis in human monocytes. Such results have been reported (Lee et al, int.J.Immunopharmac., 10(7), 835 (1988)) and Lee et al, Annals N.Y.Acad.Sci., 696, 149 (1993)).
FIG. 1 shows a schematic view of a
MAP kinase family: general characteristics
It is now recognised that CSBP/p38 is one of several kinases involved in the stress response signal transduction pathway parallel to and largely independent of a similar mitogen-activated protein kinase (MAP) cascade (figure 1). Stress signals include LPS, pro-inflammatory cytokines, oxidants, UV light and osmotic pressure, which activate kinases upstream of CSBP/p38, which in turn phosphorylate CSBP/p38 on threonine 180 and tyrosine 182, resulting in CSBP/p38 activation. MAPKAP kinase-2 and MAPKAP kinase-3 have been identified as downstream substrates of CSBP/p38, which in turn phosphorylate the heat shock protein Hsp 27. MAPKAP-2 is known to be essential for LPS-induced TNF α biosynthesis (Kotlyarov et al, Nature Cell biol., 1, 94(1999), see also Cohen, P.trends Cell biol., 353-361 (1997)).
In addition to inhibiting IL-1 and TNF, CSBP/p38 kinase inhibitors also reduce the synthesis of a variety of pro-inflammatory proteins, including IL-6, IL-8, GM-CSF, and COX-2. Inhibitors of CSBP/p38 kinase have also been shown to inhibit TNF-induced expression of VCAM-1 on endothelial cells, TNF-induced phosphorylation and activation of cytolytic PLA2, and IL-1 stimulated synthesis of collagenase and stromelysin. These and additional data demonstrate that CSBP/p38 is involved not only in cytokine synthesis, but also in cytokine signaling (Cohen, P. trends Cell biol., 353-361(1997) review of CSBP/p38 kinase).
Interleukin (IL-1) and Tumor Necrosis Factor (TNF) are biological substances produced by various cells, such as monocytes or macrophages. IL-1 has been shown to mediate a variety of biological activities that are thought to be important for immunomodulation and other physiological conditions such as inflammation (see, e.g., Dinarello et al, Rev. infection. disease, 6, 51 (1984)). The myriad of known IL-1 biological activities include activation of T helper cells, induction of fever, stimulation of prostaglandin or collagenase production, neutrophil chemotaxis, induction of acute phase proteins, and inhibition of plasma iron levels.
There are many disease states in which excessive or deregulated IL-production is involved in exacerbating and/or causing the disease. These include rheumatoid arthritis, osteoarthritis, endotoxemia and/or toxic shock syndrome, other acute or chronic inflammatory conditions such as endotoxin-induced inflammatory reactions or inflammatory bowel disease, tuberculosis, atherosclerosis, muscle degeneration, cachexia, psoriatic arthritis, leiter's syndrome, rheumatoid arthritis, gout, traumatic arthritis, rubella arthritis and acute synovitis. Recent evidence has also linked IL-1 activity to diabetes and pancreatic beta cell disease (Dinarello, J. clinical Immunology, 5(5), 287-297 (1985)).
Excessive or unregulated TNF production has been implicated in mediating or exacerbating a number of diseases including rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other joint inflammations; sepsis, septic shock, endotoxic shock, gram-negative sepsis, toxic shock syndrome, adult respiratory distress syndrome, cerebral malaria, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcoidosis, bone resorption disease, reperfusion injury, graft-versus-host reaction, allograft rejection, fever and myalgia resulting from infection, such as influenza, cachexia secondary to infection or malignancy, cachexia secondary to Acquired Immune Deficiency Syndrome (AIDS), AIDS, ARC (AIDS-related complex), keloid formation, scar tissue formation, Crohn's disease, ulcerative colitis, or heartburn.
Interleukin-8 (IL-8) is a chemokine produced by several cell types, including monocytes, fibroblasts, endothelial cells and keratinocytes. Production from endothelial cells is induced by IL-1, TNF or Lipopolysaccharide (LPS). IL-8 stimulates a number of functions in vitro. It has been shown to have chemoattractant properties for neutrophils, T lymphocytes and basophils. In addition, it induces histamine release by basophils in normal and atopic individuals, as well as lysosomal enzyme release and burst respiration by neutrophils. IL-8 has also been shown to increase the surface expression of Mac-1(CD11b/CD18) on neutrophils without the need for protein re-synthesis. This may contribute to adhesion of neutrophils to vascular endothelial cells. Many diseases are characterized by massive neutrophil infiltration. Disorders associated with increased IL-8 production, which is responsible for chemotaxis of neutrophils towards inflammatory sites, would benefit from compounds that inhibit IL-8 production.
IL-1 and TNF affect a wide range of cells and tissues and these and other leukocyte derived cytokines are important determinant inflammatory mediators of a wide range of disease states and conditions. Inhibition of these cytokines is beneficial in controlling, reducing and alleviating many of these disease states.
In addition to IL-1, TNF, and IL-8, as described above, inhibition of signal transduction via CSBP/p38 is also a very effective mechanism for regulating the excessive destructive activation of the immune system, as would be expected from the synthesis and/or action of several other pro-inflammatory proteins (e.g., IL-6, GM-CSF, COX-2, collagenase, and stromelysin). This expectation is supported by the potential, diverse anti-inflammatory activities described for CSBP/p38 kinase inhibitors (Badger et al, J.Pharm. exp. Thera., 279 (3): 1453-1461 (1996); Griswold et al, Pharmacol. Comm., 7, 323-229 (1996)).
There remains a need in the art for compounds that are cytokine inhibitory anti-inflammatory drugs, i.e., compounds that are capable of inhibiting CSBP/p38/RK kinase, for treatment.
CSBP/p38/RK kinase inhibitors are well known to those skilled in the art. International patent publication WO 00/40243, published on 7/13/2000, relates to pyridine-substituted pyridine compounds, which are said to be p38 inhibitors. International patent publication WO00/63204, published 10/26/2000, relates to substituted azole compounds, which are known to be p38 inhibitors. International patent publication WO 00/31065, published 6/2/2000, relates to certain heterocyclic compounds which are known to be p38 inhibitors. International patent publication WO 00/06563, published 2.10.2000, relates to substituted imidazole compounds which are referred to as p38 inhibitors. International patent publication WO 00/41698, published on 7/20/2000, relates to certain omega-carboxyaryl substituted diphenyl urea compounds, which are said to be p38 inhibitors. U.S. patent 5,716,955 relates to certain substituted imidazole compounds, which are said to be p38 inhibitors. U.S. patent 5,716,972 relates to certain pyridyl substituted imidazole compounds, which are said to be p38 inhibitors. U.S. patent 5,756,499 relates to certain substituted imidazole compounds, which are said to be p38 inhibitors.
Summary of The Invention
The invention relates to compounds of formula I
Wherein Het is an optionally substituted 5-membered heteroaryl group containing one to two heteroatoms selected from nitrogen, sulfur and oxygen, wherein at least one of said heteroatoms must be nitrogen;
R2selected from the group consisting of hydrogen, (C)1-C6) Alkyl or other suitable substituent;
R3selected from the group consisting of hydrogen, (C)1-C6) Alkyl or other suitable substituent;
s is an integer from zero to five;
and pharmaceutically acceptable salts and prodrugs thereof.
The invention also relates to pharmaceutically acceptable acid addition salts of the compounds of formula I. The acids used to prepare the pharmaceutically acceptable acid addition salts of the base compounds of the invention described above are those which form non-toxic acid addition salts, i.e., salts containing pharmaceutically acceptable anions such as chloride, bromide, iodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, acid citrate, tartrate, bitartrate, succinate, maleate, fumarate, gluconate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate (i.e., 1' -methylene-bis- (2-hydroxy-3-naphthoate)).
The invention also relates to base addition salts of formula I. Chemical bases which can be used as reagents to prepare pharmaceutically acceptable base salts of acidic compounds of formula I are those which form non-toxic base salts with such compounds. Such non-toxic base salts include, but are not limited to, those derived from such pharmacologically acceptable cations, such as alkali metal cations (e.g., potassium and sodium) and alkaline earth metal cations (e.g., calcium and magnesium), ammonium or water-soluble amine addition salts, such as N-methylglucamine (meglumine), and lower alkanolammonium, and base salts of other pharmaceutically acceptable organic amines.
The compounds of the present invention include all stereoisomers (e.g., cis and trans isomers) and all optical isomers (e.g., R and S enantiomers) of the compounds of formula I, as well as racemic, diastereomeric and other mixtures of such isomers.
The compounds and prodrugs of the invention may exist in several tautomeric forms, including the enol and imine forms, the keto and enamine forms, and geometric isomers and mixtures thereof. All such tautomeric forms are included within the scope of the invention. The tautomers are present in solution as a mixture of tautomers. In solid form, usually one tautomer predominates. Even if one tautomer is described, the present invention includes all tautomers of these compounds.
The invention also includes atropisomers of the invention. Atropisomers refer to compounds of formula I that can be separated into rotation-constrained isomers.
The compounds of the present invention may contain ethylenic double bonds. When such linkages are present, the compounds of the present invention exist in both cis and trans configurations and mixtures thereof.
"suitable substituents" are intended to mean chemically and pharmaceutically acceptable functional groups, i.e., moieties that do not negate the inhibitory activity of the compounds of this invention. Such suitable substituents may be selected by those skilled in the art as is conventional. Illustrative examples of suitable substituents include, but are not limited to, halo, perfluoroalkyl, perfluoroalkoxy, alkyl, alkenyl, alkynyl, hydroxy, oxo, mercapto, alkylthio, alkoxy, aryl or heteroaryl, aryloxy or heteroaryloxy, aralkyl or heteroarylalkyl, aralkoxy or heteroarylalkoxy, HO- (C ═ O) -groups, amino, alkyl-and dialkyl-amino, carbamoyl, alkylcarbonyl, alkoxycarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, acylcarbonyl, acyloxycarbonyl, alkylsulfonyl, arylsulfonyl, and the like.
More particularly, the invention also relates to compounds of the formula
Wherein Het is an optionally substituted 5-membered heteroaryl with (R)3)s-phenyl groups together are selected from the group consisting of:
each R1Independently selected from hydrogen, (C)1-C6) Alkyl, phenyl, (C)1-C10) Heteroaryl, (C)1-C10) Heterocyclyl and (C)3-C10) A cycloalkyl group; wherein each of the above R1(C1-C6) Alkyl, phenyl, (C)1-C10) Heteroaryl, (C)1-C10) Heterocyclyl and (C)3-C10) The cycloalkyl substituents may be optionally substituted with one to four moieties, the substituents being independently selected from the group consisting of: halo, (C)1-C6) Alkyl, (C)2-C6) Alkenyl, (C)2-C6) Alkynyl, perhalogenated (C)1-C6) Alkyl, phenyl, (C)1-C10) Heteroaryl, (C)1-C10) Heterocyclic group, (C)3-C10) Cycloalkyl, hydroxy, (C)1-C6) Alkoxy, perhalogenated (C)1-C6) Alkoxy, phenoxy, (C)1-C10) heteroaryl-O-, (C)1-C10) heterocyclyl-O-, (C)3-C10) cycloalkyl-O-, (C)1-C6) alkyl-S-, (C)1-C6) alkyl-SO2-、(C1-C6) alkyl-NH-SO2-、-NO2Amino group, (C)1-C6) Alkylamino [ (C)1-C6) Alkyl radical]2Amino group, (C)1-C6) alkyl-SO2-NH-、(C1-C6) Alkyl- (C ═ O) -NH-, (C)1-C6) Alkyl- (C ═ O) - [ ((C)1-C6) Alkyl) -N]-, phenyl- (C ═ O) -NH-, phenyl- (C ═ O) - [ ((C)1-C6) Alkyl) -N]-、-CN、(C1-C6) Alkyl- (C ═ O) -, phenyl- (C ═ O) -, and1-C10) Heteroaryl- (C ═ O) -, (C)1-C10) Heterocyclyl- (C ═ O) -, (C)3-C10) Cycloalkyl- (C ═ O) -, HO- (C ═ O) -, and1-C6) alkyl-O- (C ═ O) -, H2N(C＝O)-、(C1-C6) alkyl-NH- (C ═ O) -, [ (C)1-C6) Alkyl radical]2-N- (C ═ O) -, phenyl-NH- (C ═ O) -, phenyl- [ ((C)1-C6) Alkyl) -N]-(C＝O)-、(C1-C10) heteroaryl-NH- (C ═ O) -, (C)1-C10) heterocyclyl-NH- (C ═ O) -, (C)3-C10) cycloalkyl-NH- (C ═ O) -, (C)1-C6) Alkyl- (C ═ O) -O-and phenyl- (C ═ O) -O-; wherein two R are1(C1-C6) Alkyl groups may be taken together with the nitrogen atom to which they are attached to form a five to six membered heterocyclyl or heteroaryl ring;
R2selected from hydrogen, -CN, (C)1-C6) Alkyl, (C)2-C6) Alkenyl, (C)2-C6) Alkynyl, (C)3-C10) Cycloalkyl, phenyl, (C)1-C10) Heteroaryl, (C)1-C10) Heterocyclyl and (R)1)2-N-; wherein each of the above (C)1-C6) Alkyl, (C)3-C10) Cycloalkyl, phenyl, (C)1-C10) Heteroaryl and (C)1-C10) The heterocyclyl substituents may optionally be independently substituted with one to four moieties, the substituents being independently selected from the group consisting of: halo, (C)1-C6) Alkyl, (C)2-C6) Alkenyl, (C)2-C6) Alkynyl, perhalogenated (C)1-C6) Alkyl, phenyl, (C)3-C10) Cycloalkyl group, (C)1-C10) Heteroaryl, (C)1-C10) Heterocyclyl, formyl, -CN, (C)1-C6) Alkyl- (C ═ O) -, phenyl- (C ═ O) -, HO- (C ═ O) -, and1-C6) alkyl-O- (C ═ O) -, (C)1-C6) alkyl-NH- (C ═ O) -, [ (C)1-C6) Alkyl radical]2-N- (C ═ O) -, phenyl-NH- (C ═ O) -, phenyl- [ ((C)1-C6) Alkyl) -N]-(C＝O)-、-NO2Amino group, (C)1-C6) Alkylamino [ (C)1-C6) Alkyl radical]2-amino, (C)1-C6) Alkyl- (C ═ O) -NH-, (C)1-C6) Alkyl- (C ═ O) - [ ((C)1-C6) Alkyl) -N]-, phenyl- (C ═ O) -NH-, phenyl- (C ═ O) - [ ((C)1-C6) Alkyl) -N]-、H2N-(C＝O)-NH-、(C1-C6) alkyl-HN- (C ═ O) -NH-, [ (C)1-C6) Alkyl radical]2N-(C＝O)-NH-、(C1-C6) alkyl-HN- (C ═ O) - [ ((C)1-C6) Alkyl) -N]-、[(C1-C6) Alkyl radical]2N-(C＝O)-[((C1-C6) Alkyl) -N]-, phenyl-HN- (C ═ O) -NH-, (phenyl)2N- (C ═ O) -NH-, phenyl-HN- (C ═ O) - [ ((C)1-C6) Alkyl) -N]-, (phenyl)2N-(C＝O)-[((C1-C6) Alkyl) -N]-、(C1-C6) alkyl-O- (C ═ O) -NH-, (C)1-C6) alkyl-O-(C＝O)-[((C1-C6) Alkyl) -N]-, phenyl-O- (C ═ O) -NH-, phenyl-O- (C ═ O) - [ ((C)1-C6) Alkyl) -N]-、(C1-C6) alkyl-SO2-NH-, phenyl-SO2-NH-、(C1-C6) alkyl-SO2-, phenyl-SO2-, hydroxy, (C)1-C6) Alkoxy, perhalogenated (C)1-C6) Alkoxy, phenoxy, (C)1-C6) Alkyl- (C ═ O) -O-, phenyl- (C ═ O) -O-, H2N-(C＝O)-O-、(C1-C6) alkyl-HN- (C ═ O) -O-, [ (C)1-C6) Alkyl radical]2N- (C ═ O) -O-, phenyl-HN- (C ═ O) -O-, (phenyl)2N- (C ═ O) -O-; wherein when said R is2When the phenyl group contains two adjacent substituents, such substituents may optionally form, together with the carbon atom to which they are attached, a five to six membered carbocyclic or heterocyclic ring; wherein each of said phenyl-containing moieties may alternatively be optionally substituted with one or two groups independently selected from (C)1-C6) Alkyl, halo, (C)1-C6) Alkoxy, perhalogenated (C)1-C6) Alkyl and perhalogenated (C)1-C6) Alkoxy groups;
each R3Independently selected from the group consisting of: halo, (C)1-C6) Alkyl, (C)2-C6) Alkenyl, (C)2-C6) Alkynyl, perhalogenated (C)1-C6) Alkyl, phenyl, (C)1-C10) Heteroaryl, (C)1-C10) Heterocyclic group, (C)3-C10) Cycloalkyl, hydroxy, (C)1-C6) Alkoxy, perhalogenated (C)1-C6) Alkoxy, phenoxy, (C)1-C10) heteroaryl-O-, (C)1-C10) heterocyclyl-O-, (C)3-C10) cycloalkyl-O-, (C)1-C6) alkyl-S-, (C)1-C6) alkyl-SO2-、(C1-C6) alkyl-NH-SO2-、-NO2Amino group, (C)1-C6) Alkylamino [ (C)1-C6) Alkyl radical]2Amino group, (C)1-C6) alkyl-SO2-NH-、(C1-C6) Alkyl- (C ═ O) -NH-, (C)1-C6) Alkyl- (C ═ O) - [ ((C)1-C6) Alkyl) -N]-, phenyl- (C ═ O) -NH-, phenyl- (C ═ O) - [ ((C)1-C6) Alkyl) -N]-、-CN、(C1-C6) Alkyl- (C ═ O) -, phenyl- (C ═ O) -, and1-C10) Heteroaryl- (C ═ O) -, (C)1-C10) Heterocyclyl- (C ═ O) -, (C)3-C10) Cycloalkyl- (C ═ O) -, HO- (C ═ O) -, and1-C6) alkyl-O- (C ═ O) -, H2N(C＝O)-、(C1-C6) alkyl-NH- (C ═ O) -, [ (C)1-C6) Alkyl radical]2-N- (C ═ O) -, phenyl-NH- (C ═ O) -, phenyl- [ ((C)1-C6) Alkyl) -N]-(C＝O)-、(C1-C10) heteroaryl-NH- (C ═ O) -, (C)1-C10) heterocyclyl-NH- (C ═ O) -, (C)3-C10) cycloalkyl-NH- (C ═ O) -and (C)1-C6) Alkyl- (C ═ O) -O-; wherein two adjacent R3The substituents may form, together with the carbon atom to which they are attached, a five to six membered carbocyclic or heterocyclic ring;
s is an integer from zero to five;
R4and R6Each independently selected from hydrogen, halo or R9-B-(CH2)n-a group of compositions;
n is an integer from zero to six;
each B is independently a bond, - (CHR)10)-、-O-、-S-、-(SO2)-、-(C＝O)-、-O-(C＝O)-、-(C＝O)-O-、-(C＝O)-NR10-、-(R10-N)-、-(R10-N)-SO2-、-(R10-N)-(C＝O)-、-SO2-(NR10)-、-(R10-N)-(C＝O)-(NR11)-、-(O)-(C＝O)-(NR10) -or- (R)10-N)-(C＝O)-O-；
R5And R7Each independently selected from the group consisting of: hydrogen, R14-(CR15H)p-, phenyl, (C)1-C10) Heteroaryl, (C)1-C10) Heterocyclic group, (C)3-C10) Cycloalkyl group, (C)1-C6) Alkyl- (SO)2) -, phenyl- (SO)2)-、H2N-(SO2)-、(C1-C6) alkyl-NH- (SO)2)-、[(C1-C6) Alkyl radical]2N-(SO2) -, phenyl-NH- (SO)2) -, (phenyl)2N-(SO2)-、R16-(C1-C6) Alkyl- (C ═ O) -, phenyl- (C ═ O) -, and1-C10) Heteroaryl- (C ═ O) -, (C)1-C10) Heterocyclyl- (C ═ O) -, (C)3-C10) Cycloalkyl- (C ═ O) -, (C)1-C6) alkyl-O- (C ═ O) -, (C)1-C10) heterocyclyl-O- (C ═ O) -, (C)3-C10) cycloalkyl-O- (C ═ O) -, H2N-(C＝O)-、(C1-C6) alkyl-NH- (C ═ O) -, phenyl-NH- (C ═ O) -, (C)1-C10) heteroaryl-NH- (C ═ O) -, (C)1-C10) heterocyclyl-NH- (C ═ O) -, (C)3-C10) cycloalkyl-NH- (C ═ O) -, [ (C)1-C6) Alkyl radical]2N- (C ═ O) -, (phenyl)2N- (C ═ O) -, phenyl- [ ((C)1-C6) Alkyl) -N]-(C＝O)-、(C1-C10) Heteroaryl- [ ((C)1-C6) Alkyl) -N]-(C＝O)-、(C1-C10) Heterocyclyl- [ ((C)1-C6) Alkyl) -N]- (C ═ O) -, and (C)3-C10) Cycloalkyl- [ ((C)1-C6) Alkyl) -N]- (C ═ O) -; wherein each of the above-mentioned phenyl, heterocyclyl, heteroaryl or cycloalkyl radicals R5And R7The substituents may optionally be independently substituted with one to four moieties, the substituents being independently selected from the group consisting of: halo, R16-(C1-C6) Alkyl, (C)2-C6) Alkenyl, (C)2-C6) Alkynyl, perhalogenated (C)1-C6) Alkyl, (C)3-C10) Cycloalkyl, phenyl, benzyl, (C)1-C10) Heterocyclic group, (C)1-C10) Heteroaryl, (C)1-C6) alkyl-SO2-, formyl, -CN, (C)1-C6) Alkyl- (C ═ O) -, (C)3-C10) Cycloalkyl- (C ═ O) -, phenyl- (C ═ O) -, and1-C10) Heterocyclyl- (C ═ O) -, (C)1-C10) Heteroaryl- (C ═ O) -, HO- (C ═ O) -, and1-C6) alkyl-O- (C ═ O) -, (C)3-C10) cycloalkyl-O- (C ═ O) -, (C)1-C10) heterocyclyl-O- (C ═ O) -, (C)1-C6) alkyl-NH- (C ═ O) -, (C)3-C10) cycloalkyl-NH- (C ═ O) -, phenyl-NH- (C ═ O) -, (C)1-C10) heterocyclyl-NH- (C ═ O) -, (C)1-C10) heteroaryl-NH- (C ═ O) -, [ (C)1-C6) Alkyl radical]2-N- (C ═ O) -, phenyl- [ ((C)1-C6) Alkyl) -N]- (C ═ O) -, hydroxy, (C)1-C6) Alkoxy, perhalogenated (C)1-C6) Alkoxy group, (C)3-C10) cycloalkyl-O-, phenoxy, (C)1-C10) heterocyclyl-O-, (C)1-C10) heteroaryl-O-, (C)1-C6) Alkyl- (C ═ O) -O-, (C)3-C10) Cycloalkyl- (C ═ O) -O-, phenyl- (C ═ O) -O-, (C ═ O-, (C)1-C10) Heterocyclyl- (C ═ O) -O-, (C)1-C10) Heteroaryl- (C ═ O) -O-, -NO2Amino group, (C)1-C6) Alkylamino [ (C)1-C6) Alkyl radical]2-amino, carboxamido, (C)1-C6) Alkyl- (C ═ O) -NH-, (C)3-C10) Cycloalkyl- (C ═ O) -NH-, phenyl- (C ═ O) -NH-, (C ═ O-), (C1-C10) Heterocyclyl- (C ═ O) -NH-, (C)1-C10) Heteroaryl- (C ═ O) -NH-, (C)1-C6) Alkyl- (C ═ O) - [ ((C)1-C6) Alkyl) -N]-, phenyl- (C ═ O) - [ ((C)1-C6) Alkyl) -N]-、(C1-C6) alkyl-SO2-NH-、(C3-C10) cycloalkyl-SO2-NH-, phenyl-SO2-NH-、(C1-C10) heterocyclyl-SO2-NH-and (C)1-C10) heteroaryl-SO2-NH-; wherein each of said phenyl and heteroaryl moieties may be optionally substituted with one or two groups independently selected from halo, (C)1-C6) Alkyl, (C)1-C6) Alkoxy, perfluoro (C)1-C6) Alkyl and perfluoro (C)1-C6) An alkoxy group;
p is an integer from one to six;
R9selected from hydrogen, -CF3、-CN、R13-(R12CH)m-, phenyl, (C)1-C10) Heterocyclic group, (C)1-C10) Heteroaryl and (C)3-C10) Cycloalkyl groups; wherein each of the above R9Phenyl, (C)1-C10) Heteroaryl, (C)1-C10) Heterocyclyl and (C)3-C10) The cycloalkyl substituents may be optionally substituted with one to four moieties, the substituents being independently selected from the group consisting of: halo, (C)1-C6) Alkyl, (C)2-C6) Alkenyl, (C)2-C6) Alkynyl, perhalogenated (C)1-C6) Alkyl, phenyl, (C)1-C10) Heteroaryl, (C)1-C10) Heterocyclic group, (C)3-C10) Cycloalkyl, hydroxy, (C)1-C6) Alkoxy, perhalogenated (C)1-C6) Alkoxy, phenoxy, (C)1-C10) heteroaryl-O-, (C)1-C10) heterocyclyl-O-, (C)3-C10) cycloalkyl-O-, (C)1-C6) alkyl-S-, (C)1-C6) alkyl-SO2-、(C1-C6) alkyl-NH-SO2-、-NO2Amino group, (C)1-C6) Alkylamino [ (C)1-C6) Alkyl radical]2Amino group, (C)1-C6) alkyl-SO2-NH-、(C1-C6) Alkyl- (C ═ O) -NH-, (C)1-C6) Alkyl- (C ═ O) - [ ((C)1-C6) Alkyl) -N]-, phenyl- (C ═ O) -NH-, phenyl- (C ═ O) - [ ((C)1-C6) Alkyl) -N]-、-CN、(C1-C6) Alkyl- (C ═ O) -, phenyl- (C ═ O) -, and1-C10) Heteroaryl- (C ═ O) -, (C)1-C10) Heterocyclyl- (C ═ O) -, (C)3-C10) Cycloalkyl- (C ═ O) -, HO- (C ═ O) -, and1-C6) alkyl-O- (C ═ O) -, H2N(C＝O)-、(C1-C6) alkyl-NH- (C ═ O) -, [ (C)1-C6) Alkyl radical]2-N- (C ═ O) -, phenyl-NH- (C ═ O) -, phenyl- [ ((C)1-C6) Alkyl) -N]-(C＝O)-、(C1-C10) heteroaryl-NH- (C ═ O) -, (C)1-C10) heterocyclyl-NH- (C ═ O) -, (C)3-C10) cycloalkyl-NH- (C ═ O) -, (C)1-C6) Alkyl- (C ═ O) -O-and phenyl- (C ═ O) -O-; wherein said phenyl group, (C)1-C10) Heteroaryl, (C)1-C10) Heterocyclyl and (C)3-C10) Two adjacent R of cycloalkyl9The substituents may, together with the carbon or heteroatom to which they are attached, form a five or six membered carbocyclic or heterocyclic ring;
m is an integer from one to six;
R10is hydrogen, (C)1-C6) alkyl-SO2-or (C)1-C6) An alkyl group;
R11is hydrogen or (C)1-C6) An alkyl group;
each R12Independently selected from hydrogen, amino, (C)1-C6) Alkoxy and (C)1-C6) Alkyl groups;
R13selected from the group consisting of: hydrogen, (C)1-C6) Alkyl, (C)2-C6) Alkenyl, (C)2-C6) Alkynyl, phenyl, (C)1-C10) Heteroaryl, (C)1-C10) Heterocyclic group, (C)3-C10) Cycloalkyl, hydroxy, (C)1-C6) Alkoxy, perhalogenated (C)1-C6) Alkoxy, phenoxy, (C)1-C10) heteroaryl-O-, (C)1-C10) heterocyclyl-O-, (C)3-C10) cycloalkyl-O-, (C)1-C6) alkyl-S-, (C)1-C6) alkyl-SO2-、(C1-C6) alkyl-NH-SO2-、-NO2Amino group, (C)1-C6) Alkylamino [ (C)1-C6) Alkyl radical]2Amino group, (C)1-C6) alkyl-SO2-NH-, phenyl-SO2-NH-、(C1-C6) alkyl-SO2-[((C1-C6) Alkyl) -N]-, phenyl-SO2-[((C1-C6) Alkyl) -N]-、(C1-C6) Alkyl- (C ═ O) -NH-, (C)1-C6) Alkyl- (C ═ O) - [ ((C)1-C6) Alkyl) -N]-, phenyl- (C ═ O) -NH-, phenyl- (C ═ O) - [ ((C)1-C6) Alkyl) -N]-、-CN、(C1-C6) Alkyl- (C ═ O) -, phenyl- (C ═ O) -, and1-C10) Heteroaryl- (C ═ O) -, (C)1-C10) Heterocyclyl- (C ═ O) -, (C)3-C10) Cycloalkyl- (C ═ O) -, HO- (C ═ O) -, and1-C6) alkyl-O- (C ═ O) -, H2N(C＝O)-、(C1-C6) alkyl-NH- (C ═ O) -, [ (C)1-C6) Alkyl radical]2-N- (C ═ O) -, phenyl-NH- (C ═ O) -, phenyl- [ ((C)1-C6) Alkyl) -N]-(C＝O)-、(C1-C10) heteroaryl-NH- (C ═ O) -, (C)1-C10) heterocyclyl-NH- (C ═ O) -, (C)3-C10) cycloalkyl-NH- (C ═ O) -, (C)1-C6) Alkyl- (C ═ O) -O-and phenyl- (C ═ O) -O-;
R14selected from the group consisting of: hydrogen, halo, (C)1-C6) Alkyl, (C)2-C6) An alkenyl group,(C2-C6) Alkynyl, perhalogenated (C)1-C6) Alkyl, (C)3-C10) Cycloalkyl, phenyl, (C)1-C10) Heterocyclic group, (C)1-C10) Heteroaryl, phenyl- (S ═ O) -, (C)1-C6) alkyl-SO2-, phenyl-SO2-、H2N-SO2-、(C1-C6) alkyl-NH-SO2-, phenyl-NH-SO2-、[(C1-C6) Alkyl radical]2N-SO2-, (phenyl)2N-SO2-, formyl, -CN, (C)1-C6) Alkyl- (C ═ O) -, phenyl- (C ═ O) -, and1-C10) Heteroaryl- (C ═ O) -, (C)1-C10) Heterocyclyl- (C ═ O) -, (C)3-C10) Cycloalkyl- (C ═ O) -, HO- (C ═ O) -, R16-(C1-C6) alkyl-O- (C ═ O) -, (C)3-C10) cycloalkyl-O- (C ═ O) -, (C)1-C10) heterocyclyl-O- (C ═ O) -, H2N-(C＝O)-、R16-(C1-C6) alkyl-NH- (C ═ O) -, (C)3-C10) cycloalkyl-NH- (C ═ O) -, phenyl-NH- (C ═ O) -, (C)1-C10) heterocyclyl-NH- (C ═ O) -, (C)1-C10) heteroaryl-NH- (C ═ O) -, [ (C)1-C6) Alkyl radical]2-N- (C ═ O) -, phenyl- [ ((C)1-C6) Alkyl) -N]-(C＝O)-、(C1-C10) Heteroaryl- [ ((C)1-C6) Alkyl) -N]-(C＝O)-、(C1-C10) Heterocyclyl- [ ((C)1-C6) Alkyl) -N]-(C＝O)-、(C3-C10) Cycloalkyl- [ ((C)1-C6) Alkyl) -N]- (C ═ O) -, hydroxy, R16-(C1-C6) Alkoxy, perhalogenated (C)1-C6) Alkoxy group, (C)3-C10) cycloalkyl-O-, phenoxy, (C)1-C10) heterocyclyl-O-, (C)1-C10) heteroaryl-O-, R16-(C1-C6) Alkyl- (C ═ O) -O-, (C)3-C10) Cycloalkyl- (C ═ O) -O-, phenyl- (C ═ O) -O-, (C ═ O-, (C)1-C10) Heterocyclyl- (C ═ O) -O-, (C)1-C10) Heteroaryl- (C ═ O) -O-, -NO2Amino, R16-(C1-C6) Alkylamino [ (C)1-C6) Alkyl radical]2-amino, carboxamido, R16-(C1-C6) Alkyl- (C ═ O) -NH-, (C)3-C10) Cycloalkyl- (C ═ O) -NH-, phenyl- (C ═ O) -NH-, (C ═ O-), (C1-C10) Heterocyclyl- (C ═ O) -NH-, (C)1-C10) Heteroaryl- (C ═ O) -NH-, R16-(C1-C6) Alkyl- (C ═ O) - [ ((C)1-C6) Alkyl) -N]-, phenyl- (C ═ O) - [ ((C)1-C6) Alkyl) -N]-、R16-(C1-C6) alkyl-SO2-NH-、(C3-C10) cycloalkyl-SO2-NH-, phenyl-SO2-NH-、(C1-C10) heterocyclyl-SO2-NH-and (C)1-C10) heteroaryl-SO2-NH-; wherein each of the above-mentioned phenyl, heterocyclyl, heteroaryl or cycloalkyl radicals R14The substituents may optionally be independently substituted with one to four moieties, the substituents being independently selected from the group consisting of: halo, R16-(C1-C6) Alkyl, (C)2-C6) Alkenyl, (C)2-C6) Alkynyl, perhalogenated (C)1-C6) Alkyl, (C)3-C10) Cycloalkyl, phenyl, benzyl, (C)1-C10) Heterocyclic group, (C)1-C10) Heteroaryl, (C)1-C6) alkyl-SO2-, formyl, -CN, R16-(C1-C6) Alkyl- (C ═ O) -, (C)3-C10) Cycloalkyl- (C ═ O) -, phenyl- (C ═ O) -, and1-C10) Heterocyclyl- (C ═ O) -, (C)1-C10) Heteroaryl- (C ═ O) -, HO- (C ═ O) -, and1-C6) alkyl-O- (C ═ O) -, (C)3-C10) cycloalkyl-O- (C ═ O) -, (C)1-C10) heterocyclyl-O- (C ═ O) -, (C)1-C10) heteroaryl-O- (C ═ O) -, H2N-(C＝O)-、R16-(C1-C6) alkyl-NH- (C ═ O) -, (C)3-C10) cycloalkyl-NH- (C ═ O) -, phenyl-NH- (C ═ O) -, (C)1-C10) heterocyclyl-NH- (C ═ O) -, (C)1-C10) heteroaryl-NH- (C ═ O) -, [ (C)1-C6) Alkyl radical]2-N- (C ═ O) -, phenyl- [ ((C)1-C6) Alkyl) -N]- (C ═ O) -, hydroxy, R16-(C1-C6) Alkoxy, perhalogenated (C)1-C6) Alkoxy group, (C)3-C10) cycloalkyl-O-, phenoxy, (C)1-C10) heterocyclyl-O-, (C)1-C10) heteroaryl-O-, R16-(C1-C6) Alkyl- (C ═ O) -O-, (C)3-C10) Cycloalkyl- (C ═ O) -O-, phenyl- (C ═ O) -O-, (C ═ O-, (C)1-C10) Heterocyclyl- (C ═ O) -O-, (C)1-C10) Heteroaryl- (C ═ O) -O-, -NO2Amino, R16-(C1-C6) Alkylamino [ (C)1-C6) Alkyl radical]2-amino, carboxamido, R16-(C1-C6) Alkyl- (C ═ O) -NH-, (C)3-C10) Cycloalkyl- (C ═ O) -NH-, phenyl- (C ═ O) -NH-, (C ═ O-), (C1-C10) Heterocyclyl- (C ═ O) -NH-, (C)1-C10) Heteroaryl- (C ═ O) -NH-, R16-(C1-C6) Alkyl- (C ═ O) - [ ((C)1-C6) Alkyl) -N]-, phenyl- (C ═ O) - [ ((C)1-C6) Alkyl) -N]-、R16-(C1-C6) alkyl-SO2-NH-、(C3-C10) cycloalkyl-SO2-NH-, phenyl-SO2-NH-、(C1-C10) heterocyclyl-SO2-NH-and (C)1-C10) heteroaryl-SO2-NH-; wherein each of said phenyl and heteroaryl moieties may be optionally substituted with one or two groups independently selected from the group consisting of halo, (C)1-C6) Alkyl, (C)1-C6) Alkoxy, perfluoro (C)1-C6) Alkyl and perfluoro (C)1-C6) Alkoxy groups;
each R15Independently selected from hydrogen, halo, (C)1-C6) Alkyl, (C)2-C6) Alkenyl, perhalogenated (C)1-C6) Alkyl, HO- (C ═ O) -, (C)1-C6) alkyl-O- (C ═ O) -, H2N-(C＝O)-、(C1-C6) alkyl-NH- (C ═ O) -, [ (C)1-C6) Alkyl radical]2-N- (C ═ O) -, hydroxy, (C)1-C6) Alkoxy group, (C)1-C6) Alkyl- (C ═ O) -O-, amino, (C ═ O)1-C6) Alkylamino [ (C)1-C6) Alkyl radical]2-amino, carboxamido and (C)1-C6) Alkyl- (C ═ O) -NH-;
each R16Independently selected from hydrogen, halo, (C)1-C6) Alkyl, (C)2-C6) Alkenyl, (C)2-C6) Alkynyl, perhalogenated (C)1-C6) Alkyl, (C)1-C10) Heterocyclic group, HO- (C ═ O) -, and (C)1-C6) alkyl-O- (C ═ O) -, H2N-(C＝O)-、(C1-C6) alkyl-NH- (C ═ O) -, [ (C)1-C6) Alkyl radical]2-N- (C ═ O) -, hydroxy, (C)1-C6) Alkoxy, perhalogenated (C)1-C6) Alkoxy group, (C)1-C6) Alkyl- (C ═ O) -O-, -NO2Amino group, (C)1-C6) Alkylamino [ (C)1-C6) Alkyl radical]2-amino, carboxamido and (C)1-C6) Alkyl- (C ═ O) -NH-; wherein said (C)1-C10) The heterocyclic group may be optionally substituted with one to three substituents independently selected from the group consisting of halo, (C)1-C6) Alkyl, (C)1-C6) Alkoxy, benzyl, amino, (C)1-C6) Alkylamino and [ (C)1-C6) Alkyl radical]2-amino groups;
or R4And R6Or R4And R7Or R5And R6May form, together with the atoms to which they are attached, an optionally substituted five-to ten-membered saturated, unsaturated or aromatic ring, optionally containing two to three substituents independently selected from NH, N, O, S, SO or SO2A heteroatom of (a); wherein said ring may be optionally substituted with one to three substituents independently selected from the group consisting of: oxo, halo, (C)1-C6) Alkyl, phenyl, (C)1-C10) Heteroaryl, (C)1-C10) Heterocyclic group, (C)3-C10) Cycloalkyl, hydroxy, (C)1-C6) Alkoxy, phenoxy, (C)1-C10) heteroaryl-O-, (C)1-C10) heterocyclyl-O-, (C)3-C10) cycloalkyl-O-, (C)1-C6) alkyl-S-, (C)1-C6) alkyl-SO2-, phenyl-S-, phenyl- (S ═ O) -, phenyl-SO2-、(C1-C6) alkyl-NH-SO2-、[(C1-C6) Alkyl radical]2N-SO2-, phenyl-NH-SO2-, (phenyl)2N-SO2-, phenyl- [ N (C)1-C6) Alkyl radical]-SO2-, formyl, (C)1-C6) Alkyl- (C ═ O) -, phenyl- (C ═ O) -, and1-C10) Heteroaryl- (C ═ O) -, (C)1-C10) Heterocyclyl- (C ═ O) -, (C)3-C10) Cycloalkyl- (C ═ O) -, HO- (C ═ O) -, and1-C6) alkyl-O- (C ═ O) -, (C)1-C10) heterocyclyl-O- (C ═ O) -, (C)3-C10) cycloalkyl-O- (C ═ O) -, H2N-(C＝O)-、(C1-C6) alkyl-NH- (C ═ O) -, [ (C)1-C6) Alkyl radical]2-N- (C ═ O) -, phenyl-NH- (C ═ O) -, phenyl- [ ((C)1-C6) Alkyl) -N]-(C＝O)-、(C1-C10) heteroaryl-NH- (C ═ O) -, (C)1-C10) Heteroaryl- [ ((C)1-C6) Alkyl) -N]-(C＝O)-、(C1-C10) heterocyclyl-NH- (C ═ O) -, (C)1-C10) Heterocyclyl- [ ((C)1-C6) Alkyl) -N]-(C＝O)-、(C3-C10) cycloalkyl-NH- (C ═ O) -, (C)3-C10) Cycloalkyl- [ ((C)1-C6) Alkyl) -N]- (C ═ O) -, amino, (C) and (d) and (1-C6) Alkylamino [ (C)1-C6) Alkyl radical]2-amino, (C)1-C6) alkyl-SO2-NH-, phenyl-SO2-NH-、(C1-C6) alkyl-SO2-[((C1-C6) Alkyl) -N]-, phenyl-SO2-[((C1-C6) Alkyl) -N]-, carboxamido, (C)1-C6) Alkyl- (C ═ O) -NH-, (C)1-C6) Alkyl- (C ═ O) - [ ((C)1-C6) Alkyl) -N]-, phenyl- (C ═ O) -NH-, phenyl- (C ═ O) - [ ((C)1-C6) Alkyl) -N]-、(C1-C10) Heteroaryl- (C ═ O) -NH-, (C)1-C10) Heteroaryl- (C ═ O) - [ ((C)1-C6) Alkyl) -N]-、(C1-C10) Heterocyclyl- (C ═ O) -NH-, (C)1-C10) Heterocyclyl- (C ═ O) - [ ((C)1-C6) Alkyl) -N]-、(C3-C10) Cycloalkyl- (C ═ O) -NH-, (C)3-C10) Cycloalkyl- (C ═ O) - [ ((C)1-C6) Alkyl) -N]-、H2N-(C＝O)-NH-、(C1-C6) alkyl-HN- (C ═ O) -NH-, (C)1-C6) alkyl-HN- (C ═ O) - [ ((C)1-C6) Alkyl) -N]-、[(C1-C6) Alkyl radical]2-N-(C＝O)-NH-、[(C1-C6) Alkyl radical]2-N-(C＝O)-[((C1-C6) Alkyl) -N]-, phenyl-HN- (C ═ O) -NH-, phenyl-HN- (C ═ O) - [ ((C)1-C6) Alkyl) -N]-, (phenyl)2-N- (C ═ O) -NH-, (phenyl)2-N-(C＝O)-[((C1-C6) Alkyl) -N]-、(C1-C10) heteroaryl-HN- (C ═ O) -NH-, (C)1-C10) heteroaryl-HN- (C ═ O) - [ ((C)1-C6) Alkyl) -N]-、[(C1-C10) Heteroaryl radical]2-N-(C＝O)-[((C1-C6) Alkyl) -N]-、[(C1-C10) Heteroaryl radical]2-N-(C＝O)-NH-、(C1-C10) heterocyclyl-HN- (C ═ O) -NH-, (C)1-C10) heterocyclyl-HN- (C ═ O) - [ ((C)1-C6) Alkyl) -N]-、[(C1-C10) Heterocyclic radical]2-N-(C＝O)-[((C1-C6) Alkyl) -N]-、[(C1-C10) Heterocyclic radical]2-N-(C＝O)-NH-、(C3-C10) cycloalkyl-HN- (C ═ O) -NH-, (C)3-C10) cycloalkyl-HN- (C ═ O) - [ ((C)1-C6) Alkyl) -N]-、[(C3-C10) Cycloalkyl radicals]2-N-(C＝O)-[((C1-C6) Alkyl) -N]-、[(C3-C10) Cycloalkyl radicals]2-N-(C＝O)-NH-、(C1-C6) Alkyl- (C ═ O) -O-, phenyl- (C ═ O) -O-, (C ═ O-, (C)1-C10) Heteroaryl- (C ═ O) -O-, (C)1-C10) Heterocyclyl- (C ═ O) -O-, (C)3-C10) Cycloalkyl- (C ═ O) -O-, (C)1-C6) alkyl-NH- (C ═ O) -O-, phenyl-NH- (C ═ O) -O-, (C1-C10) heteroaryl-NH- (C ═ O) -O-, (C)1-C10) heterocyclyl-NH- (C ═ O) -O-and (C)3-C10) cycloalkyl-NH- (C ═ O) -O-;
or a pharmaceutically acceptable salt thereof.
The term "alkyl" as used herein, as well as the alkyl portion of other groups referred to herein (e.g., alkoxy), can be straight or branched chain (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl), which can also be cyclic (e.g., cyclopropyl or cyclobutyl); optionally substituted with 1 to 3 suitable substituents as defined above, e.g. fluoro, chloro, trifluoromethyl, (C)1-C6) Alkoxy group, (C)6-C10) Aryloxy, trifluoromethoxy, difluoromethoxy or (C)1-C6) An alkyl group. The expression "each of said alkyl groups" as used herein relates to any of the aforementioned alkyl moieties within an alkoxy, alkenyl or alkylamino group or the like. Preferred alkyl groups include (C)1-C4) Alkyl, most preferablyAnd is selected to be methyl.
The term "cycloalkyl" as used herein relates to a mono-or bicyclic carbocyclic ring (e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclopentenyl, cyclohexenyl, bicyclo [2.2.1 ] ring]Heptyl, bicyclo [3.2.1]Octyl and bicyclo [5.2.0]Nonyl, etc.); optionally containing 1-2 double bonds, and optionally substituted with 1 to 3 suitable substituents as defined above, e.g. fluoro, chloro, trifluoromethyl, (C)1-C6) Alkoxy group, (C)6-C10) Aryloxy, trifluoromethoxy, difluoromethoxy or (C)1-C6) An alkyl group. The expression "each of said cycloalkyl groups" as used herein relates to any of the aforementioned alkyl moieties within a group such as alkoxy, alkenyl or alkylamino. Preferred cycloalkyl groups include cyclobutyl, cyclopentyl and cyclohexyl.
The term "halogen" as used herein includes fluorine, chlorine, bromine or iodine or fluoride, chloride, bromide or iodide.
The term "haloalkyl" as used herein refers to an alkyl group as described above substituted with one or more halogens, including but not limited to chloromethyl, dichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2, 2, 2-trichloroethyl, and the like; optionally substituted with 1 to 3 suitable substituents as defined above, e.g. fluoro, chloro, trifluoromethyl, (C)1-C6) Alkoxy group, (C)6-C10) Aryloxy, trifluoromethoxy, difluoromethoxy or (C)1-C6) An alkyl group.
The term "alkenyl" as used herein denotes straight or branched chain unsaturated groups of 2 to 6 carbon atoms, including but not limited to ethenyl, 1-propenyl, 2-propenyl (allyl), isopropenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, and the like; optionally substituted with 1 to 3 suitable substituents as defined above, e.g. fluoro, chloro, trifluoromethyl, (C)1-C6) Alkoxy group, (C)6-C10) Aryloxy, trifluoromethoxy, difluoromethoxyOr (C)1-C6) An alkyl group.
The term "(C) as used herein2-C6) Alkynyl "is used to denote a straight or branched hydrocarbon chain having a triple bond, including but not limited to ethynyl, propynyl, butynyl, and the like; optionally substituted with 1 to 3 suitable substituents as defined above, e.g. fluoro, chloro, trifluoromethyl, (C)1-C6) Alkoxy group, (C)6-C10) Aryloxy, trifluoromethoxy, difluoromethoxy or (C)1-C6) An alkyl group.
The term "carbonyl" or "(C ═ O)" (as used in the expressions alkylcarbonyl, alkyl- (C ═ O) -or alkoxycarbonyl) as used herein, refers to the attachment of the > C ═ O moiety to a second moiety such as alkyl or amino (i.e., amido). Alkoxycarbonylamino (i.e., alkoxy (C ═ O) -NH-) refers to alkylcarbamate groups. Carbonyl is also defined herein equivalently as (C ═ O). Alkylcarbonylamino refers to groups such as acetamide.
The term "phenyl- [ ((C) as used herein1-C6) Alkyl) -N]- (C ═ O) - "means a disubstituted amide group of formula
The term "aryl" as used herein denotes an aromatic group such as phenyl, naphthyl, tetrahydronaphthyl, indanyl and the like; optionally substituted with 1 to 3 suitable substituents as defined above, e.g. fluoro, chloro, trifluoromethyl, (C)1-C6) Alkoxy group, (C)6-C10) Aryloxy, trifluoromethoxy, difluoromethoxy or (C)1-C6) An alkyl group.
The term "heteroaryl" as used herein refers to an aromatic heterocyclic group, typically having one heteroatom selected from O, S and N in the ring. In addition to the heteroatoms, the aromatic groups may optionally have up to four N atoms in the ring. For example, heteroaryl groupsIncluding pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, thienyl, furyl, imidazolyl, pyrrolyl, oxazolyl (e.g., 1, 3-oxazolyl, 1, 2-oxazolyl), thiazolyl (e.g., 1, 2-thiazolyl, 1, 3-thiazolyl), pyrazolyl, tetrazolyl, triazolyl (e.g., 1, 2, 3-triazolyl, 1, 2, 4-triazolyl), oxadiazolyl (e.g., 1, 2, 3-oxadiazolyl), thiadiazolyl (e.g., 1, 3, 4-thiadiazolyl), quinolinyl, isoquinolinyl, benzothienyl, benzofuranyl, indolyl, and the like; optionally substituted with 1 to 3 suitable substituents as defined above, e.g. fluoro, chloro, trifluoromethyl, (C)1-C6) Alkoxy group, (C)6-C10) Aryloxy, trifluoromethoxy, difluoromethoxy or (C)1-C6) An alkyl group. Particularly preferred heteroaryl groups include oxazolyl, imidazolyl, pyridyl, thienyl, furyl, thiazolyl and pyrazolyl (these heteroaryl groups are R)4、R5、R6And R7Most preferred is heteroaryl).
The term "heterocyclyl" as used herein, refers to a cyclic group containing from 1 to 9 carbon atoms and from 1 to 4 heteroatoms selected from N, O, S or NR'. Examples of such rings include azetidinyl, tetrahydrofuryl, imidazolidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, thiomorpholinyl, tetrahydrothiazinyl, tetrahydrothiadiazinyl, morpholinyl, oxetanyl, tetrahydrodiazinyl, oxazinyl, oxathiazinyl, indolinyl, isoindolyl, quinuclidinyl, chromanyl, isochromanyl, benzoxazinyl, and the like. Examples of such monocyclic saturated or partially saturated ring systems are tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, imidazolidin-1-yl, imidazolidin-2-yl, imidazolidin-4-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperazin-1-yl, piperazin-2-yl, piperazin-3-yl, 1, 3-oxazolidin-3-yl, thiomorpholinyl, 1, 2-tetrahydrothiazin-2-yl, 1, 3-tetrahydrothiazin-3-yl, tetrahydrothiadiazinyl, morpholinyl, 1, 2-tetrahydrodiazin-2-yl, 1, 3-tetrahydrodiazin-1-yl, 1, 4-oxazin-2-yl,1, 2, 5-oxathiazin-4-yl, and the like; optionally substituted with 1 to 3 suitable substituents as defined above, e.g. fluoro, chloro, trifluoromethyl, (C)1-C6) Alkoxy group, (C)6-C10) Aryloxy, trifluoromethoxy, difluoromethoxy or (C)1-C6) An alkyl group. Preferred heterocyclyl groups include tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl.
An embodiment of the invention are compounds of formula I wherein R2Is (C)1-C6) Alkyl, phenyl, (C)3-C10) Cycloalkyl group, (C)1-C10) Heteroaryl or (C)1-C10) A heterocyclic group.
Another embodiment of the present invention are the compounds of formula I wherein R is2Is (C)1-C6) Alkyl, optionally substituted with one to four groups independently selected from halo, hydroxy, (C)1-C6) Alkyl, (C)2-C6) Alkenyl, (C)2-C6) Alkynyl, (C)1-C6) Alkoxy, perhalogenated (C)1-C6) Alkyl, perhalogenated (C)1-C6) Alkoxy, -CN, -NO2Amino group, (C)1-C6) Alkylamino [ (C)1-C6) Alkyl radical]2-amino, HO- (C ═ O) -, (C)1-C6) Alkyl- (C ═ O) -, (C)1-C6) alkyl-O- (C ═ O) -, (C)1-C6) alkyl-CO2-、(C1-C6) Alkyl- (C ═ O) -NH-, (C)1-C6) alkyl-NH- (C ═ O) -, (C)1-C6) Alkyl- (C ═ O) - [ ((C)1-C6) Alkyl) -N]-、(C1-C6) Alkyl- [ ((C)1-C6) Alkyl) -N]-(C＝O)-、(C1-C6) alkyl-SO2-NH-、(C1-C6) alkyl-SO2-, optionally substituted phenyl- (C ═ O) -O-, optionally substituted phenoxy, optionally substituted phenyl-NH- (C ═ O) -, optionally substituted phenyl- (C ═ OSubstituted phenyl- [ ((C)1-C6) Alkyl) -N]- (C ═ O) -, optionally substituted phenyl- (C ═ O) -NH-, optionally substituted phenyl- (C ═ O) - [ ((C ═ O) - ]1-C6) Alkyl) -N]-。
A preferred embodiment of the present invention are compounds of formula I wherein R is2Is (C)1-C4) An alkyl group.
Another embodiment of the present invention are the compounds of formula I wherein R is2Is optionally substituted (C)3-C6) A cycloalkyl group; wherein the substituents are independently selected from the group consisting of: halo, (C)1-C6) Alkyl, (C)2-C6) Alkenyl, (C)2-C6) Alkynyl, perhalogenated (C)1-C6) Alkyl, phenyl, (C)3-C10) Cycloalkyl group, (C)1-C10) Heteroaryl, (C)1-C10) Heterocyclyl, formyl, -CN, (C)1-C6) Alkyl- (C ═ O) -, phenyl- (C ═ O) -, HO- (C ═ O) -, and1-C6) alkyl-O- (C ═ O) -, (C)1-C6) alkyl-NH- (C ═ O) -, [ (C)1-C6) Alkyl radical]2-N- (C ═ O) -, phenyl-NH- (C ═ O) -, phenyl- [ ((C)1-C6) Alkyl) -N]-(C＝O)-、-NO2Amino group, (C)1-C6) Alkylamino [ (C)1-C6) Alkyl radical]2-amino, (C)1-C6) Alkyl- (C ═ O) -NH-, (C)1-C6) Alkyl- (C ═ O) - [ ((C)1-C6) Alkyl) -N]-, phenyl- (C ═ O) -NH-, phenyl- (C ═ O) - [ ((C)1-C6) Alkyl) -N]-、H2N-(C＝O)-NH-、(C1-C6) alkyl-HN- (C ═ O) -NH-, [ (C)1-C6) Alkyl radical]2N-(C＝O)-NH-、(C1-C6) alkyl-HN- (C ═ O) - [ ((C)1-C6) Alkyl) -N]-、[(C1-C6) Alkyl radical]2N-(C＝O)-[((C1-C6) Alkyl) -N]-, phenyl-HN- (C ═ O) -NH-, (phenyl)2N- (C ═ O) -NH-, phenyl-HN- (C ═ O) - [ ((C)1-C6) Alkyl) -N]-, (phenyl)2N-(C＝O)-[((C1-C6) Alkyl) -N]-、(C1-C6) alkyl-O- (C ═ O) -NH-, (C)1-C6) alkyl-O- (C ═ O) - [ ((C)1-C6) Alkyl) -N]-, phenyl-O- (C ═ O) -NH-, phenyl-O- (C ═ O) - [ ((C)1-C6) Alkyl) -N]-、(C1-C6) alkyl-SO2-NH-, phenyl-SO2-NH-、(C1-C6) alkyl-SO2-, phenyl-SO2-, hydroxy, (C)1-C6) Alkoxy, perhalogenated (C)1-C6) Alkoxy, phenoxy, (C)1-C6) Alkyl- (C ═ O) -O-, phenyl- (C ═ O) -O-, H2N-(C＝O)-O-、(C1-C6) alkyl-HN- (C ═ O) -O-, [ (C)1-C6) Alkyl radical]2N- (C ═ O) -O-, phenyl-HN- (C ═ O) -O-, (phenyl)2N- (C ═ O) -O-; wherein each of said phenyl-containing moieties may be optionally substituted with one or two groups independently selected from (C)1-C6) Alkyl, halo, (C)1-C6) Alkoxy, perhalogenated (C)1-C6) Alkyl and perhalogenated (C)1-C6) Alkoxy groups; more preferably, the substituents are independently selected from the group consisting of: halo, (C)1-C6) Alkyl, (C)2-C6) Alkenyl, perhalogenated (C)1-C6) Alkyl, -CN, (C)1-C6) Alkyl- (C ═ O) -, HO- (C ═ O) -, and1-C6) alkyl-O- (C ═ O) -, (C)1-C6) alkyl-NH- (C ═ O) -, [ (C)1-C6) Alkyl radical]2-N- (C ═ O) -, amino, (C) and (d) and (1-C6) Alkylamino [ (C)1-C6) Alkyl radical]2-amino, (C)1-C6) Alkyl- (C ═ O) -NH-, (C)1-C6) Alkyl- (C ═ O) - [ ((C)1-C6) Alkyl) -N]-、H2N-(C＝O)-NH-、(C1-C6) alkyl-HN- (C ═ O) -NH-, [ (C)1-C6) Alkyl radical]2N-(C＝O)-NH-、(C1-C6) alkyl-HN- (C ═ O) - [ ((C)1-C6) Alkyl) -N]-、[(C1-C6) Alkyl radical]2N-(C＝O)-[((C1-C6) Alkyl) -N]-, hydroxy, (C)1-C6) Alkoxy, perhalogenated (C)1-C6) Alkoxy group, (C)1-C6) Alkyl- (C ═ O) -O-, H2N-(C＝O)-O-、(C1-C6) alkyl-HN- (C ═ O) -O-and [ (C)1-C6) Alkyl radical]2N-(C＝O)-O-。
Another embodiment of the present invention are the compounds of formula I wherein R is2Is optionally substituted (C)1-C10) A heterocyclic group; wherein the substituents are independently selected from the group consisting of: halo, (C)1-C6) Alkyl, (C)2-C6) Alkenyl, (C)2-C6) Alkynyl, perhalogenated (C)1-C6) Alkyl, phenyl, (C)3-C10) Cycloalkyl group, (C)1-C10) Heteroaryl, (C)1-C10) Heterocyclyl, formyl, -CN, (C)1-C6) Alkyl- (C ═ O) -, phenyl- (C ═ O) -, HO- (C ═ O) -, and1-C6) alkyl-O- (C ═ O) -, (C)1-C6) alkyl-NH- (C ═ O) -, [ (C)1-C6) Alkyl radical]2-N- (C ═ O) -, phenyl-NH- (C ═ O) -, phenyl- [ ((C)1-C6) Alkyl) -N]-(C＝O)-、-NO2Amino group, (C)1-C6) Alkylamino [ (C)1-C6) Alkyl radical]2-amino, (C)1-C6) Alkyl- (C ═ O) -NH-, (C)1-C6) Alkyl- (C ═ O) - [ ((C)1-C6) Alkyl) -N]-, phenyl- (C ═ O) -NH-, phenyl- (C ═ O) - [ ((C)1-C6) Alkyl) -N]-、H2N-(C＝O)-NH-、(C1-C6) alkyl-HN- (C ═ O) -NH-, [ (C)1-C6) Alkyl radical]2N-(C＝O)-NH-、(C1-C6) alkyl-HN- (C ═ O) - [ ((C)1-C6) Alkyl) -N]-、[(C1-C6) Alkyl radical]2N-(C＝O)-[((C1-C6) Alkyl) -N]-, phenyl-HN- (C ═ O) -NH-, (phenyl)2N- (C ═ O) -NH-, phenyl-HN- (C ═ O) - [ ((C)1-C6) Alkyl) -N]-, (phenyl)2N-(C＝O)-[((C1-C6) Alkyl) -N]-、(C1-C6) alkyl-O- (C ═ O) -NH-, (C)1-C6) alkyl-O- (C ═ O) - [ ((C)1-C6) Alkyl) -N]-, phenyl-O- (C ═ O) -NH-, phenyl-O- (C ═ O) - [ ((C)1-C6) Alkyl) -N]-、(C1-C6) alkyl-SO2-NH-, phenyl-SO2-NH-、(C1-C6) alkyl-SO2-, phenyl-SO2-, hydroxy, (C)1-C6) Alkoxy, perhalogenated (C)1-C6) Alkoxy, phenoxy, (C)1-C6) Alkyl- (C ═ O) -O-, phenyl- (C ═ O) -O-, H2N-(C＝O)-O-、(C1-C6) alkyl-HN- (C ═ O) -O-, [ (C)1-C6) Alkyl radical]2N- (C ═ O) -O-, phenyl-HN- (C ═ O) -O-, (phenyl)2N- (C ═ O) -O-; wherein each of said phenyl-containing moieties may be optionally substituted with one or two groups independently selected from (C)1-C6) Alkyl, halo, (C)1-C6) Alkoxy, perhalogenated (C)1-C6) Alkyl and perhalogenated (C)1-C6) Alkoxy groups; more preferably, the substituents are independently selected from the group consisting of: halo, (C)1-C6) Alkyl, (C)2-C6) Alkenyl, perhalogenated (C)1-C6) Alkyl, -CN, (C)1-C6) Alkyl- (C ═ O) -, HO- (C ═ O) -, and1-C6) alkyl-O- (C ═ O) -, (C)1-C6) alkyl-NH- (C ═ O) -, [ (C)1-C6) Alkyl radical]2-N- (C ═ O) -, amino, (C) and (d) and (1-C6) Alkylamino [ (C)1-C6) Alkyl radical]2-amino, (C)1-C6) Alkyl- (C ═ O) -NH-, (C)1-C6) Alkyl- (C ═ O) - [ ((C)1-C6) Alkyl) -N]-、H2N-(C＝O)-NH-、(C1-C6) alkyl-HN- (C ═ O) -NH-, [ (C)1-C6) Alkyl radical]2N-(C＝O)-NH-、(C1-C6) alkyl-HN- (C ═ O) - [ ((C)1-C6) Alkyl) -N]-、[(C1-C6) Alkyl radical]2N-(C＝O)-[((C1-C6) Alkyl) -N]-, hydroxy, (C)1-C6) Alkoxy, perhalogenated (C)1-C6) Alkoxy group, (C)1-C6) Alkyl- (C ═ O) -O-, H2N-(C＝O)-O-、(C1-C6) alkyl-HN- (C ═ O) -O-and [ (C)1-C6) Alkyl radical]2N-(C＝O)-O-。
Another embodiment of the present invention are the compounds of formula I wherein R is2Is optionally substituted (C)1-C10) A heteroaryl group; wherein the substituents are independently selected from the group consisting of: halo, (C)1-C6) Alkyl, (C)2-C6) Alkenyl, (C)2-C6) Alkynyl, perhalogenated (C)1-C6) Alkyl, phenyl, (C)3-C10) Cycloalkyl group, (C)1-C10) Heteroaryl, (C)1-C10) Heterocyclyl, formyl, -CN, (C)1-C6) Alkyl- (C ═ O) -, phenyl- (C ═ O) -, HO- (C ═ O) -, and1-C6) alkyl-O- (C ═ O) -, (C)1-C6) alkyl-NH- (C ═ O) -, [ (C)1-C6) Alkyl radical]2-N- (C ═ O) -, phenyl-NH- (C ═ O) -, phenyl- [ ((C)1-C6) Alkyl) -N]-(C＝O)-、-NO2Amino group, (C)1-C6) Alkylamino [ (C)1-C6) Alkyl radical]2-amino, (C)1-C6) Alkyl- (C ═ O) -NH-, (C)1-C6) Alkyl- (C ═ O) - [ ((C)1-C6) Alkyl) -N]-, phenyl- (C ═ O) -NH-, phenyl- (C ═ O) - [ ((C)1-C6) Alkyl) -N]-、H2N-(C＝O)-NH-、(C1-C6) alkyl-HN- (C ═ O) -NH-, [ (C)1-C6) Alkyl radical]2N-(C＝O)-NH-、(C1-C6) alkyl-HN- (C ═ O)-[((C1-C6) Alkyl) -N]-、[(C1-C6) Alkyl radical]2N-(C＝O)-[((C1-C6) Alkyl) -N]-, phenyl-HN- (C ═ O) -NH-, (phenyl)2N- (C ═ O) -NH-, phenyl-HN- (C ═ O) - [ ((C)1-C6) Alkyl) -N]-, (phenyl)2N-(C＝O)-[((C1-C6) Alkyl) -N]-、(C1-C6) alkyl-O- (C ═ O) -NH-, (C)1-C6) alkyl-O- (C ═ O) - [ ((C)1-C6) Alkyl) -N]-, phenyl-O- (C ═ O) -NH-, phenyl-O- (C ═ O) - [ ((C)1-C6) Alkyl) -N]-、(C1-C6) alkyl-SO2-NH-, phenyl-SO2-NH-、(C1-C6) alkyl-SO2-, phenyl-SO2-, hydroxy, (C)1-C6) Alkoxy, perhalogenated (C)1-C6) Alkoxy, phenoxy, (C)1-C6) Alkyl- (C ═ O) -O-, phenyl- (C ═ O) -O-, H2N-(C＝O)-O-、(C1-C6) alkyl-HN- (C ═ O) -O-, [ (C)1-C6) Alkyl radical]2N- (C ═ O) -O-, phenyl-HN- (C ═ O) -O-, (phenyl)2N- (C ═ O) -O-; wherein each of said phenyl-containing moieties may be optionally substituted with one or two groups independently selected from (C)1-C6) Alkyl, halo, (C)1-C6) Alkoxy, perhalogenated (C)1-C6) Alkyl and perhalogenated (C)1-C6) Alkoxy groups; more preferably, the substituents are independently selected from the group consisting of: halo, (C)1-C6) Alkyl, (C)2-C6) Alkenyl, perhalogenated (C)1-C6) Alkyl, -CN, (C)1-C6) Alkyl- (C ═ O) -, HO- (C ═ O) -, and1-C6) alkyl-O- (C ═ O) -, (C)1-C6) alkyl-NH- (C ═ O) -, [ (C)1-C6) Alkyl radical]2-N- (C ═ O) -, amino, (C) and (d) and (1-C6) Alkylamino [ (C)1-C6) Alkyl radical]2-amino, (C)1-C6) Alkyl- (C ═ O) -NH-, (C)1-C6) Alkyl- (C ═ O) - [ ((C)1-C6) Alkyl) -N]-、H2N-(C＝O)-NH-、(C1-C6) alkyl-HN- (C ═ O) -NH-, [ (C)1-C6) Alkyl radical]2N-(C＝O)-NH-、(C1-C6) alkyl-HN- (C ═ O) - [ ((C)1-C6) Alkyl) -N]-、[(C1-C6) Alkyl radical]2N-(C＝O)-[((C1-C6) Alkyl) -N]-, hydroxy, (C)1-C6) Alkoxy, perhalogenated (C)1-C6) Alkoxy group, (C)1-C6) Alkyl- (C ═ O) -O-, H2N-(C＝O)-O-、(C1-C6) alkyl-HN- (C ═ O) -O-and [ (C)1-C6) Alkyl radical]2N-(C＝O)-O-。
Another preferred embodiment of the present invention are compounds of the formula I, in which R is2Is optionally substituted phenyl; wherein the substituents are independently selected from the group consisting of: halo, (C)1-C6) Alkyl, (C)2-C6) Alkenyl, (C)2-C6) Alkynyl, perhalogenated (C)1-C6) Alkyl, phenyl, (C)3-C10) Cycloalkyl group, (C)1-C10) Heteroaryl, (C)1-C10) Heterocyclyl, formyl, -CN, (C)1-C6) Alkyl- (C ═ O) -, phenyl- (C ═ O) -, HO- (C ═ O) -, and1-C6) alkyl-O- (C ═ O) -, (C)1-C6) alkyl-NH- (C ═ O) -, [ (C)1-C6) Alkyl radical]2-N- (C ═ O) -, phenyl-NH- (C ═ O) -, phenyl- [ ((C)1-C6) Alkyl) -N]-(C＝O)-、-NO2Amino group, (C)1-C6) Alkylamino [ (C)1-C6) Alkyl radical]2-amino, (C)1-C6) Alkyl- (C ═ O) -NH-, (C)1-C6) Alkyl- (C ═ O) - [ ((C)1-C6) Alkyl) -N]-, phenyl- (C ═ O) -NH-, phenyl- (C ═ O) - [ ((C)1-C6) Alkyl) -N]-、H2N-(C＝O)-NH-、(C1-C6) alkyl-HN- (C ═ O) -NH-, [ (C)1-C6) Alkyl radical]2N-(C＝O)-NH-、(C1-C6) alkyl-HN- (C ═ O) - [ ((C)1-C6) Alkyl) -N]-、[(C1-C6) Alkyl radical]2N-(C＝O)-[((C1-C6) Alkyl) -N]-, phenyl-HN- (C ═ O) -NH-, (phenyl)2N- (C ═ O) -NH-, phenyl-HN- (C ═ O) - [ ((C)1-C6) Alkyl) -N]-, (phenyl)2N-(C＝O)-[((C1-C6) Alkyl) -N]-、(C1-C6) alkyl-O- (C ═ O) -NH-, (C)1-C6) alkyl-O- (C ═ O) - [ ((C)1-C6) Alkyl) -N]-, phenyl-O- (C ═ O) -NH-, phenyl-O- (C ═ O) - [ ((C)1-C6) Alkyl) -N]-、(C1-C6) alkyl-SO2-NH-, phenyl-SO2-NH-、(C1-C6) alkyl-SO2-, phenyl-SO2-, hydroxy, (C)1-C6) Alkoxy, perhalogenated (C)1-C6) Alkoxy, phenoxy, (C)1-C6) Alkyl- (C ═ O) -O-, phenyl- (C ═ O) -O-, H2N-(C＝O)-O-、(C1-C6) alkyl-HN- (C ═ O) -O-, [ (C)1-C6) Alkyl radical]2N- (C ═ O) -O-, phenyl-HN- (C ═ O) -O-, (phenyl)2N- (C ═ O) -O-; wherein each of said phenyl-containing moieties may be optionally substituted with one or two groups independently selected from (C)1-C6) Alkyl, halo, (C)1-C6) Alkoxy, perhalogenated (C)1-C6) Alkyl and perhalogenated (C)1-C6) Alkoxy groups; more preferably, the substituents are independently selected from the group consisting of: halo, (C)1-C6) Alkyl, (C)2-C6) Alkenyl, perhalogenated (C)1-C6) Alkyl, -CN, (C)1-C6) Alkyl- (C ═ O) -, HO- (C ═ O) -, and1-C6) alkyl-O- (C ═ O) -, (C)1-C6) alkyl-NH- (C ═ O) -, [ (C)1-C6) Alkyl radical]2-N- (C ═ O) -, amino, (C) and (d) and (1-C6) Alkylamino [ (C)1-C6) Alkyl radical]2-amino, (C)1-C6) Alkyl- (C ═ O) -NH-, (C)1-C6) Alkyl- (C ═ O) - [ ((C)1-C6) Alkyl) -N]-、H2N-(C＝O)-NH-、(C1-C6) alkyl-HN- (C ═ O) -NH-, [ (C)1-C6) Alkyl radical]2N-(C＝O)-NH-、(C1-C6) alkyl-HN- (C ═ O) - [ ((C)1-C6) Alkyl) -N]-、[(C1-C6) Alkyl radical]2N-(C＝O)-[((C1-C6) Alkyl) -N]-, hydroxy, (C)1-C6) Alkoxy, perhalogenated (C)1-C6) Alkoxy group, (C)1-C6) Alkyl- (C ═ O) -O-, H2N-(C＝O)-O-、(C1-C6) alkyl-HN- (C ═ O) -O-and [ (C)1-C6) Alkyl radical]2N-(C＝O)-O-。
A more preferred embodiment of the present invention are compounds of formula I wherein R is2Is (R)1)2-N-, wherein each R1Independently selected from hydrogen, (C)1-C6) Alkyl, phenyl, (C)1-C10) Heteroaryl, (C)1-C10) Heterocyclyl and (C)3-C10) A cycloalkyl group; wherein each of the above R1(C1-C6) Alkyl, phenyl, (C)1-C10) Heteroaryl, (C)1-C10) Heterocyclyl and (C)3-C10) The cycloalkyl substituents may be optionally substituted with one to four moieties, the substituents being independently selected from the group consisting of: halo, (C)1-C6) Alkyl, (C)2-C6) Alkenyl, (C)2-C6) Alkynyl, perhalogenated (C)1-C6) Alkyl, phenyl, (C)1-C10) Heteroaryl, (C)1-C10) Heterocyclic group, (C)3-C10) Cycloalkyl, hydroxy, (C)1-C6) Alkoxy, perhalogenated (C)1-C6) Alkoxy, phenoxy, (C)1-C10) heteroaryl-O-, (C)1-C10) heterocyclyl-O-, (C)3-C10) Ring (C)alkyl-O-, (C)1-C6) alkyl-S-, (C)1-C6) alkyl-SO2-、(C1-C6) alkyl-NH-SO2-、-NO2Amino group, (C)1-C6) Alkylamino [ (C)1-C6) Alkyl radical]2Amino group, (C)1-C6) alkyl-SO2-NH-、(C1-C6) Alkyl- (C ═ O) -NH-, (C)1-C6) Alkyl- (C ═ O) - [ ((C)1-C6) Alkyl) -N]-, phenyl- (C ═ O) -NH-, phenyl- (C ═ O) - [ ((C)1-C6) Alkyl) -N]-、-CN、(C1-C6) Alkyl- (C ═ O) -, phenyl- (C ═ O) -, and1-C10) Heteroaryl- (C ═ O) -, (C)1-C10) Heterocyclyl- (C ═ O) -, (C)3-C10) Cycloalkyl- (C ═ O) -, HO- (C ═ O) -, and1-C6) alkyl-O- (C ═ O) -, H2N(C＝O)-、(C1-C6) alkyl-NH- (C ═ O) -, [ (C)1-C6) Alkyl radical]2-N- (C ═ O) -, phenyl-NH- (C ═ O) -, phenyl- [ ((C)1-C6) Alkyl) -N]-(C＝O)-、(C1-C10) heteroaryl-NH- (C ═ O) -, (C)1-C10) heterocyclyl-NH- (C ═ O) -, (C)3-C10) cycloalkyl-NH- (C ═ O) -, (C)1-C6) Alkyl- (C ═ O) -O-and phenyl- (C ═ O) -O-; wherein two R are1(C1-C6) The alkyl group may form a five to six membered heterocyclic or heteroaryl ring together with the nitrogen atom.
Another embodiment of the present invention are the compounds of formula I wherein R is2Is (R)1)2-N-, wherein each R1Independently selected from hydrogen, (C)1-C4) Alkyl, phenyl and (C)1-C10) A heterocyclic group; wherein said (C)1-C4) Alkyl, phenyl and (C)1-C10) The heterocyclyl group may be optionally substituted with one to four moieties, the substituents being independently selected from the group consisting of: halo, (C)1-C6) Alkyl, (C)2-C6) Alkenyl, (C)2-C6) Alkynyl, perhalogenated (C)1-C6) Alkyl, hydroxy, (C)1-C6) Alkoxy, perhalogenated (C)1-C6) Alkoxy, amino, (C)1-C6) Alkylamino [ (C)1-C6) Alkyl radical]2Amino group, (C)1-C6) alkyl-SO2-NH-、(C1-C6) Alkyl- (C ═ O) -NH-, -CN, (C)1-C6) Alkyl- (C ═ O) -, HO- (C ═ O) -, and1-C6) alkyl-O- (C ═ O) -, H2N(C＝O)-、(C1-C6) alkyl-NH- (C ═ O) -, [ (C)1-C6) Alkyl radical]2-N- (C ═ O) -and (C)1-C6) Alkyl- (C ═ O) -O-; more preferably, it is optionally substituted with 1-3 substituents independently selected from halo, methyl, hydroxy and amino.
Another embodiment of the present invention, referred to as phenyl-pyrrolyl-triazolopyridines, are those groups of the compound of formula I wherein the compound has the formula:
other embodiments of the present invention include each of the above R2Embodiments are directed to those compounds of formula (Ia).
Preferred embodiments of the present invention referred to as phenyl-imidazolyl-triazolopyridines are those groups of the compound of formula I wherein the compound has the formula:
other embodiments of the present invention include each of the above R2Embodiments are directed to those compounds of formula (Ib).
Another embodiment of the present invention, referred to as phenyl-pyrazolyl-triazolopyridines, are those groups of compounds of formula I wherein the compounds have the formula:
other embodiments of the present invention include each of the above R2Embodiments are directed to those compounds of formula (Ic).
Another embodiment of the present invention, referred to as phenyl-oxazolyl-triazolopyridines, is a compound of formula I wherein the compound has the formula:
other embodiments of the present invention include each of the above R2Embodiments are directed to those compounds of formula (Id).
Another embodiment of the present invention, referred to as phenyl-isoxazolyl-triazolopyridines, are those groups of compounds of formula I wherein the compounds have the formula:
other embodiments of the present invention include each of the above R2Embodiments are also directed to those compounds of formula (Ie).
Another embodiment of the present invention, referred to as phenyl-pyrazolyl-triazolopyridines, is a compound of formula I wherein the compound has the formula:
other embodiments of the present invention include each of the above R2Embodiments are also directed to those compounds of formula (If).
Another embodiment of the present invention, referred to as phenyl-thiazolyl-triazolopyridines, are those groups of the compound of formula I wherein the compound has the formula:
other embodiments of the present invention include each of the above R2Embodiments are directed to those compounds of formula (Ig).
Another embodiment of the present invention, referred to as phenyl-isothiazolyl-triazolopyridines, are those groups of the compound of formula I wherein the compound has the formula:
other embodiments of the present invention include each of the above R2Embodiments are also directed to those compounds of formula (Ih).
Another embodiment of the invention are compounds of formula I (and I (a), I (c), I (e), I (f), and I (h)) wherein R is4Is hydrogen. Other embodiments of the invention include compounds of formula I (and I (a), I (c), I (e), I (f), and I (h)) wherein R4Is hydrogen and is substituted with R as defined above2The embodiments of (1) are combined.
Another embodiment of the invention are compounds of formula I (and I (a), I (c), I (e), I (f), and I (h)) wherein R is4Is R9-B-(CH2)nN is zero. Other embodiments of the invention include compounds of formula I (and I (a), I (c), I (e), I (f), and I (h)) wherein R4Is R9-B-(CH2)nN is zero and is identical with R mentioned above2The embodiments of (1) are combined.
Another embodiment of the invention are compounds of formula I (and I (a), I (c), I (e), I (f), and I (h)) wherein R is4Is R9-B-(CH2)nN is an integer from one to six, more preferably one to five, more preferably one to three. Other embodiments of the invention include compounds of formula I (and I (a), I (c), I (e), I (f), and I (h)) wherein R4Is R9-B-(CH2)nN is an integer of from one to six, more preferably one to five, more preferably one to three, and with the above-mentioned R2The embodiments of (1) are combined.
Another embodiment of the invention are compounds of formula I (and I (a), I (c), I (e), I (f), and I (h)) wherein R is4Is R9-B-(CH2)n-, n is zero, B is a bond, R9Is R13-(R12CH)m-. Other embodiments of the invention include compounds of formula I (and I (a), I (c), I (e), I (f), and I (h)) wherein R4Is R9-B-(CH2)nN is zero, R9Is R13-(R12CH) and with the above-mentioned R2The embodiments of (1) are combined. A more preferred embodiment of the invention are the compounds of formula I (and I (c), I (e) and I (f) wherein R4Is R9-B-(CH2)nN is zero, R9Is R13-(R12CH)m-, m is one to six, R12And R13Each is hydrogen.
Another embodiment of the invention are compounds of formula I (and I (a), I (c), I (e), I (f), and I (h)) wherein R is4Is R9-B-(CH2)n-; n is zero; b is- (C ═ O) -NR10-、-(R10-N)-、-SO2-(NR10)-、-(R10-N)-(C＝O)-(NR11) -or- (R)10-N)-(C＝O)-O-；R9Selected from the group consisting of hydrogen and R13-(R12CH)m-a group of compositions; more preferably, wherein R9Is R13-(R12CH)m-; m is 1 to 6; r10Is hydrogen or methyl; each R12Independently selected from the group consisting of hydrogen or methyl; r13Selected from the group consisting of: hydrogen, (C)1-C6) Alkyl, (C)2-C6) Alkenyl, (C)2-C6) Alkynyl, phenyl, (C)1-C10) Heteroaryl, (C)1-C10) Heterocyclic group, (C)3-C10) Cycloalkyl, hydroxy, (C)1-C6) Alkoxy, perhalogenated (C)1-C6) Alkoxy, phenoxy, (C)1-C10) heteroaryl-O-, (C)1-C10) heterocyclyl-O-, (C)3-C10) cycloalkyl-O-, (C)1-C6) alkyl-S-, (C)1-C6) alkyl-SO2-、(C1-C6) alkyl-NH-SO2-、-NO2Amino group, (C)1-C6) Alkylamino [ (C)1-C6) Alkyl radical]2Amino group, (C)1-C6) alkyl-SO2-NH-, phenyl-SO2-NH-、(C1-C6) alkyl-SO2-[((C1-C6) Alkyl) -N]-, phenyl-SO2-[((C1-C6) Alkyl) -N]-、(C1-C6) Alkyl- (C ═ O) -NH-, (C)1-C6) Alkyl- (C ═ O) - [ ((C)1-C6) Alkyl) -N]-, phenyl- (C ═ O) -NH-, phenyl- (C ═ O) - [ ((C)1-C6) Alkyl) -N]-、-CN、(C1-C6) Alkyl- (C ═ O) -, phenyl- (C ═ O) -, and1-C10) Heteroaryl- (C ═ O) -, (C)1-C10) Heterocyclyl- (C ═ O) -, (C)3-C10) Cycloalkyl- (C ═ O) -, HO- (C ═ O) -, and1-C6) alkyl-O- (C ═ O) -, H2N(C＝O)-、(C1-C6) alkyl-NH- (C ═ O) -, [ (C)1-C6) Alkyl radical]2-N- (C ═ O) -, phenyl-NH- (C ═ O) -, phenyl- [ ((C)1-C6) Alkyl) -N]-(C＝O)-、(C1-C10) heteroaryl-NH- (C ═ O) -, (C)1-C10) heterocyclyl-NH- (C ═ O) -, (C)3-C10) cycloalkyl-NH- (C ═ O) -, (C)1-C6) Alkyl- (C ═ O) -O-and phenyl- (C ═ O) -O-. Other embodiments of the invention include compounds of formula I (and I (a), I (c), I (e), I (f), and I (h)In which R is4Is R9-B-(CH2)n-; n is zero; b is- (C ═ O) -NR10-、-(R10-N)-、-SO2-(NR10)-、-(R10-N)-(C＝O)-(NR11) -or- (R)10-N)-(C＝O)-O-；R9Is hydrogen or R13-(R12CH)m- (more preferably, wherein R9Is R13-(R12CH)m-) according to the formula (I); m is 1 to 6; r10Is hydrogen or methyl; each R12Independently selected from the group consisting of hydrogen or methyl; r13Is as described above and is related to R above2The embodiments of (1) are combined.
Another embodiment of the invention are compounds of formula I (and I (a), I (c), I (e), I (f), and I (h)) wherein R is4Is R9-B-(CH2)n-; n is zero; b is- (R)10-N)-；R9Is hydrogen or R13-(R12CH)m-; m is 1 to 6; r10Is hydrogen or methyl; r12Is hydrogen or methyl; r13Selected from the group consisting of hydrogen, (C)1-C6) Alkyl, hydroxy, (C)1-C6) Alkoxy, amino, (C)1-C6) Alkylamino [ (C)1-C6) Alkyl radical]2Amino group, (C)2-C6) Alkenyl, (C)2-C6) Alkynyl, phenyl, (C)1-C10) Heteroaryl, (C)1-C10) Heterocyclyl and (C)3-C10) Cycloalkyl groups. Other embodiments of the invention include compounds of formula I (and I (a), I (c), I (e), I (f), and I (h)) wherein R4Is R9-B-(CH2)n-; n is zero; b is- (R)10-N)-；R9Is hydrogen or R13-(R12CH)m-; m is 1 to 6; r10Is hydrogen or methyl; r12Is hydrogen or methyl; r13Selected from the group consisting of hydrogen, (C)1-C6) Alkyl, hydroxy, (C)1-C6) Alkoxy, amino, (C)1-C6) Alkylamino [ (C)1-C6) Alkyl radical]2Amino group,(C2-C6) Alkenyl, (C)2-C6) Alkynyl, phenyl, (C)1-C10) Heteroaryl, (C)1-C10) Heterocyclyl and (C)3-C10) Cycloalkyl and with the above R2The embodiments of (1) are combined. A more preferred embodiment of the invention are compounds of formula I (and I (c), I (e) and I (f)) wherein R is4Is R9-B-(CH2)n-; n is zero; b is- (R)10-N)-；R9Is R13-(R12CH)m-; m is 1 to 6; r10、R12And R13Each is hydrogen.
Another embodiment of the invention are compounds of formula I (and I (a), I (c), I (e), I (f), and I (h)) wherein R is4Is R9-B-(CH2)n-; n is zero; b is a bond; r9Selected from the group consisting of optionally substituted phenyl, (C)1-C10) Heterocyclic group, (C)1-C10) Heteroaryl and (C)3-C10) Cycloalkyl groups; wherein each of the above R9Phenyl, (C)1-C10) Heterocyclic group, (C)1-C10) Heteroaryl and (C)3-C10) The cycloalkyl substituents may be optionally substituted with one to four moieties, the substituents being independently selected from the group consisting of: halo, (C)1-C6) Alkyl, (C)2-C6) Alkenyl, (C)2-C6) Alkynyl, perhalogenated (C)1-C6) Alkyl, phenyl, (C)1-C10) Heteroaryl, (C)1-C10) Heterocyclic group, (C)3-C10) Cycloalkyl, hydroxy, (C)1-C6) Alkoxy, perhalogenated (C)1-C6) Alkoxy, phenoxy, (C)1-C10) heteroaryl-O-, (C)1-C10) heterocyclyl-O-, (C)3-C10) cycloalkyl-O-, (C)1-C6) alkyl-S-, (C)1-C6) alkyl-SO2-、(C1-C6) alkyl-NH-SO2-、-NO2Amino group, (C)1-C6) Alkylamino [ (C)1-C6) Alkyl radical]2Amino group, (C)1-C6) alkyl-SO2-NH-、(C1-C6) Alkyl- (C ═ O) -NH-, (C)1-C6) Alkyl- (C ═ O) - [ ((C)1-C6) Alkyl) -N]-, phenyl- (C ═ O) -NH-, phenyl- (C ═ O) - [ ((C)1-C6) Alkyl) -N]-、-CN、(C1-C6) Alkyl- (C ═ O) -, phenyl- (C ═ O) -, and1-C10) Heteroaryl- (C ═ O) -, (C)1-C10) Heterocyclyl- (C ═ O) -, (C)3-C10) Cycloalkyl- (C ═ O) -, HO- (C ═ O) -, and1-C6) alkyl-O- (C ═ O) -, H2N(C＝O)-、(C1-C6) alkyl-NH- (C ═ O) -, [ (C)1-C6) Alkyl radical]2-N- (C ═ O) -, phenyl-NH- (C ═ O) -, phenyl- [ ((C)1-C6) Alkyl) -N]-(C＝O)-、(C1-C10) heteroaryl-NH- (C ═ O) -, (C)1-C10) heterocyclyl-NH- (C ═ O) -, (C)3-C10) cycloalkyl-NH- (C ═ O) -, (C)1-C6) Alkyl- (C ═ O) -O-and phenyl- (C ═ O) -O-. Other embodiments of the invention include compounds of formula I (and I (a), I (c), I (e), I (f), and I (h)) wherein R4Is R9-B-(CH2)n-; n is zero; b is a bond; r9Is as described above and is related to R above2The embodiments of (1) are combined.
Another embodiment of the invention are compounds of formula I (and I (a), I (c), I (e), I (f), and I (h)) wherein R is4Is R9-B-(CH2)n-; n is zero; b is- (C ═ O) -NR10-、-(R10-N)-、-SO2-(NR10)-、-(R10-N)-(C＝O)-(NR11) -or- (R)10-N)-(C＝O)-O-；R9Selected from the group consisting of optionally substituted phenyl, (C)1-C10) Heterocyclic group, (C)1-C10) Heteroaryl and (C)3-C10) Cycloalkyl groups; wherein each of the above R9Phenyl, (C)1-C10) Heterocyclic group, (C)1-C10) Heteroaryl and (C)3-C10) The cycloalkyl substituents may be optionally substituted with one to four moieties, the substituents being independently selected from the group consisting of: halo, (C)1-C6) Alkyl, (C)2-C6) Alkenyl, (C)2-C6) Alkynyl, perhalogenated (C)1-C6) Alkyl, phenyl, (C)1-C10) Heteroaryl, (C)1-C10) Heterocyclic group, (C)3-C10) Cycloalkyl, hydroxy, (C)1-C6) Alkoxy, perhalogenated (C)1-C6) Alkoxy, phenoxy, (C)1-C10) heteroaryl-O-, (C)1-C10) heterocyclyl-O-, (C)3-C10) cycloalkyl-O-, (C)1-C6) alkyl-S-, (C)1-C6) alkyl-SO2-、(C1-C6) alkyl-NH-SO2-、-NO2Amino group, (C)1-C6) Alkylamino [ (C)1-C6) Alkyl radical]2Amino group, (C)1-C6) alkyl-SO2-NH-、(C1-C6) Alkyl- (C ═ O) -NH-, (C)1-C6) Alkyl- (C ═ O) - [ ((C)1-C6) Alkyl) -N]-, phenyl- (C ═ O) -NH-, phenyl- (C ═ O) - [ ((C)1-C6) Alkyl) -N]-、-CN、(C1-C6) Alkyl- (C ═ O) -, phenyl- (C ═ O) -, and1-C10) Heteroaryl- (C ═ O) -, (C)1-C10) Heterocyclyl- (C ═ O) -, (C)3-C10) Cycloalkyl- (C ═ O) -, HO- (C ═ O) -, and1-C6) alkyl-O- (C ═ O) -, H2N(C＝O)-、(C1-C6) alkyl-NH- (C ═ O) -, [ (C)1-C6) Alkyl radical]2-N- (C ═ O) -, phenyl-NH- (C ═ O) -, phenyl- [ ((C)1-C6) Alkyl) -N]-(C＝O)-、(C1-C10) heteroaryl-NH- (C ═ O) -, (C)1-C10) heterocyclyl-NH- (C ═ O) -, (C)3-C10) cycloalkyl-NH- (C ═ O) -, (C)1-C6) Alkyl- (C ═ O) -O-and phenyl- (C ═ O) -O-. Other embodiments of the invention include compounds of formula I (and I (a), I (c), I (e), I (f), and I (h)) wherein R4Is R9-B-(CH2)n-; n is zero; b is- (C ═ O) -NR10-、-(R10-N)-、-SO2-(NR10)-、-(R10-N)-(C＝O)-(NR11) -or- (R)10-N)-(C＝O)-O-；R9Is as described above and is related to R above2The embodiments of (1) are combined.
Another embodiment of the invention are compounds of formula I (and I (a), I (c), I (e), I (f), and I (h)) wherein R is4Is R9-B-(CH2)n-; n is an integer from one to six, more preferably one to five, more preferably one to three; b is a bond; r9Selected from the group consisting of optionally substituted phenyl, (C)1-C10) Heterocyclic group, (C)1-C10) Heteroaryl and (C)3-C10) Cycloalkyl groups; wherein each of the above R9Phenyl, (C)1-C10) Heterocyclic group, (C)1-C10) Heteroaryl and (C)3-C10) The cycloalkyl substituents may be optionally substituted with one to four moieties, the substituents being independently selected from the group consisting of: halo, (C)1-C6) Alkyl, (C)2-C6) Alkenyl, (C)2-C6) Alkynyl, perhalogenated (C)1-C6) Alkyl, phenyl, (C)1-C10) Heteroaryl, (C)1-C10) Heterocyclic group, (C)3-C10) Cycloalkyl, hydroxy, (C)1-C6) Alkoxy, perhalogenated (C)1-C6) Alkoxy, phenoxy, (C)1-C10) heteroaryl-O-, (C)1-C10) heterocyclyl-O-, (C)3-C10) cycloalkyl-O-, (C)1-C6) alkyl-S-, (C)1-C6) alkyl-SO2-、(C1-C6) alkyl-NH-SO2-、-NO2Amino group, (C)1-C6) Alkylamino [ (C)1-C6) Alkyl radical]2Amino group, (C)1-C6) alkyl-SO2-NH-、(C1-C6) Alkyl- (C ═ O) -NH-, (C)1-C6) Alkyl- (C ═ O) - [ ((C)1-C6) Alkyl) -N]-, phenyl- (C ═ O) -NH-, phenyl- (C ═ O) - [ ((C)1-C6) Alkyl) -N]-、-CN、(C1-C6) Alkyl- (C ═ O) -, phenyl- (C ═ O) -, and1-C10) Heteroaryl- (C ═ O) -, (C)1-C10) Heterocyclyl- (C ═ O) -, (C)3-C10) Cycloalkyl- (C ═ O) -, HO- (C ═ O) -, and1-C6) alkyl-O- (C ═ O) -, H2N(C＝O)-、(C1-C6) alkyl-NH- (C ═ O) -, [ (C)1-C6) Alkyl radical]2-N- (C ═ O) -, phenyl-NH- (C ═ O) -, phenyl- [ ((C)1-C6) Alkyl) -N]-(C＝O)-、(C1-C10) heteroaryl-NH- (C ═ O) -, (C)1-C10) heterocyclyl-NH- (C ═ O) -, (C)3-C10) cycloalkyl-NH- (C ═ O) -, (C)1-C6) Alkyl- (C ═ O) -O-and phenyl- (C ═ O) -O-. Other embodiments of the invention include compounds of formula I (and I (a), I (c), I (e), I (f), and I (h)) wherein R4Is R9-B-(CH2)n-; n is an integer from one to six, more preferably one to five, more preferably one to three; b is a bond; r9Is as described above and is related to R above2Is/are as follows
The embodiments are combined.
Another embodiment of the invention are compounds of formula I (and I (a), I (c), I (e), I (f), and I (h)) wherein R is4Is R9-B-(CH2)n-; n is an integer from one to six, more preferably one to five, more preferably one to three; b is- (C ═ O) -NR10-、-(R10-N)-、-SO2-(NR10)-、-(R10-N)-(C＝O)-(NR11) -or- (R)10-N)-(C＝O)-O-；R9Selected from the group consisting of optionally substituted phenyl, (C)1-C10) Heterocyclic group, (C)1-C10) Heteroaryl and (C)3-C10) Cycloalkyl groupGroup (b); wherein each of the above R9Phenyl, (C)1-C10) Heterocyclic group, (C)1-C10) Heteroaryl and (C)3-C10) The cycloalkyl substituents may be optionally substituted with one to four moieties, the substituents being independently selected from the group consisting of: halo, (C)1-C6) Alkyl, (C)2-C6) Alkenyl, (C)2-C6) Alkynyl, perhalogenated (C)1-C6) Alkyl, phenyl, (C)1-C10) Heteroaryl, (C)1-C10) Heterocyclic group, (C)3-C10) Cycloalkyl, hydroxy, (C)1-C6) Alkoxy, perhalogenated (C)1-C6) Alkoxy, phenoxy, (C)1-C10) heteroaryl-O-, (C)1-C10) heterocyclyl-O-, (C)3-C10) cycloalkyl-O-, (C)1-C6) alkyl-S-, (C)1-C6) alkyl-SO2-、(C1-C6) alkyl-NH-SO2-、-NO2Amino group, (C)1-C6) Alkylamino [ (C)1-C6) Alkyl radical]2Amino group, (C)1-C6) alkyl-SO2-NH-、(C1-C6) Alkyl- (C ═ O) -NH-, (C)1-C6) Alkyl- (C ═ O) - [ ((C)1-C6) Alkyl) -N]-, phenyl- (C ═ O) -NH-, phenyl- (C ═ O) - [ ((C)1-C6) Alkyl) -N]-、-CN、(C1-C6) Alkyl- (C ═ O) -, phenyl- (C ═ O) -, and1-C10) Heteroaryl- (C ═ O) -, (C)1-C10) Heterocyclyl- (C ═ O) -, (C)3-C10) Cycloalkyl- (C ═ O) -, HO- (C ═ O) -, and1-C6) alkyl-O- (C ═ O) -, H2N(C＝O)-、(C1-C6) alkyl-NH- (C ═ O) -, [ (C)1-C6) Alkyl radical]2-N- (C ═ O) -, phenyl-NH- (C ═ O) -, phenyl- [ ((C)1-C6) Alkyl) -N]-(C＝O)-、(C1-C10) heteroaryl-NH- (C ═ O) -, (C)1-C10) heterocyclyl-NH- (C ═ O) -, (C)3-C10) Cycloalkyl radicals-NH-(C＝O)-、(C1-C6) Alkyl- (C ═ O) -O-and phenyl- (C ═ O) -O-. Other embodiments of the invention include compounds of formula I (and I (a), I (c), I (e), I (f), and I (h)) wherein R4Is R9-B-(CH2)n-; n is an integer from one to six, more preferably one to five, more preferably one to three; b is- (C ═ O) -NR10-、-(R10-N)-、-SO2-(NR10)-、-(R10-N)-(C＝O)-(NR11) -or- (R)10-N)-(C＝O)-O-；R9Is as described above and is related to R above2The embodiments of (1) are combined.
Another embodiment of the invention are compounds of formula I (and I (a), I (c), I (e), I (f), and I (h)) wherein R is4Is R9-B-(CH2)n-; n is an integer from one to six, more preferably one to five, more preferably one to three; b is a bond; r9Is R13-(R12CH)m-; m is 1 to 6; r10Is hydrogen or methyl; each R12Independently selected from the group consisting of hydrogen or methyl; r13Selected from the group consisting of: hydrogen, (C)1-C6) Alkyl, (C)2-C6) Alkenyl, (C)2-C6) Alkynyl, phenyl, (C)1-C10) Heteroaryl, (C)1-C10) Heterocyclic group, (C)3-C10) Cycloalkyl, hydroxy, (C)1-C6) Alkoxy, perhalogenated (C)1-C6) Alkoxy, phenoxy, (C)1-C10) heteroaryl-O-, (C)1-C10) heterocyclyl-O-, (C)3-C10) cycloalkyl-O-, (C)1-C6) alkyl-S-, (C)1-C6) alkyl-SO2-、(C1-C6) alkyl-NH-SO2-、-NO2Amino group, (C)1-C6) Alkylamino [ (C)1-C6) Alkyl radical]2Amino group, (C)1-C6) alkyl-SO2-NH-, phenyl-SO2-NH-、(C1-C6) alkyl-SO2-[((C1-C6) Alkyl) -N]-, phenyl-SO2-[((C1-C6) Alkyl) -N]-、(C1-C6) Alkyl- (C ═ O) -NH-, (C)1-C6) Alkyl- (C ═ O) - [ ((C)1-C6) Alkyl) -N]-, phenyl- (C ═ O) -NH-, phenyl- (C ═ O) - [ ((C)1-C6) Alkyl) -N]-、-CN、(C1-C6) Alkyl- (C ═ O) -, phenyl- (C ═ O) -, and1-C10) Heteroaryl- (C ═ O) -, (C)1-C10) Heterocyclyl- (C ═ O) -, (C)3-C10) Cycloalkyl- (C ═ O) -, HO- (C ═ O) -, and1-C6) alkyl-O- (C ═ O) -, H2N(C＝O)-、(C1-C6) alkyl-NH- (C ═ O) -, [ (C)1-C6) Alkyl radical]2-N- (C ═ O) -, phenyl-NH- (C ═ O) -, phenyl- [ ((C)1-C6) Alkyl) -N]-(C＝O)-、(C1-C10) heteroaryl-NH- (C ═ O) -, (C)1-C10) heterocyclyl-NH- (C ═ O) -, (C)3-C10) cycloalkyl-NH- (C ═ O) -, (C)1-C6) Alkyl- (C ═ O) -O-and phenyl- (C ═ O) -O-. Other embodiments of the invention include compounds of formula I (and I (a), I (c), I (e), I (f), and I (h)) wherein R4Is R9-B-(CH2)n-; n is an integer from one to six, more preferably one to five, more preferably one to three; b is a bond; r9Is R13-(R12CH)m-; m is 1 to 6; r10Is hydrogen or methyl; each R12Independently selected from the group consisting of hydrogen or methyl; r13Is as described above and is related to R above2The embodiments of (1) are combined.
Another embodiment of the invention are compounds of formula I (and I (a), I (c), I (e), I (f), and I (h)) wherein R is4Is R9-B-(CH2)n-; n is an integer from one to six, more preferably one to five, more preferably one to three; b is- (C ═ O) -NR10-、-(R10-N)-、-SO2-(NR10)-、-(R10-N)-(C＝O)-(NR11) -or- (R)10-N)-(C＝O)-O-；R9Is R13-(R12CH)m-; m is 1 to 6; r10Is hydrogen or methyl; each R12Independently selected from the group consisting of hydrogen or methyl; r13Selected from the group consisting of: hydrogen, (C)1-C6) Alkyl, (C)2-C6) Alkenyl, (C)2-C6) Alkynyl, phenyl, (C)1-C10) Heteroaryl, (C)1-C10) Heterocyclic group, (C)3-C10) Cycloalkyl, hydroxy, (C)1-C6) Alkoxy, perhalogenated (C)1-C6) Alkoxy, phenoxy, (C)1-C10) heteroaryl-O-, (C)1-C10) heterocyclyl-O-, (C)3-C10) cycloalkyl-O-, (C)1-C6) alkyl-S-, (C)1-C6) alkyl-SO2-、(C1-C6) alkyl-NH-SO2-、-NO2Amino group, (C)1-C6) Alkylamino [ (C)1-C6) Alkyl radical]2Amino group, (C)1-C6) alkyl-SO2-NH-, phenyl-SO2-NH-、(C1-C6) alkyl-SO2-[((C1-C6) Alkyl) -N]-, phenyl-SO2-[((C1-C6) Alkyl) -N]-、(C1-C6) Alkyl- (C ═ O) -NH-, (C)1-C6) Alkyl- (C ═ O) - [ ((C)1-C6) Alkyl) -N]-, phenyl- (C ═ O) -NH-, phenyl- (C ═ O) - [ ((C)1-C6) Alkyl) -N]-、-CN、(C1-C6) Alkyl- (C ═ O) -, phenyl- (C ═ O) -, and1-C10) Heteroaryl- (C ═ O) -, (C)1-C10) Heterocyclyl- (C ═ O) -, (C)3-C10) Cycloalkyl- (C ═ O) -, HO- (C ═ O) -, and1-C6) alkyl-O- (C ═ O) -, H2N(C＝O)-、(C1-C6) alkyl-NH- (C ═ O) -, [ (C)1-C6) Alkyl radical]2-N- (C ═ O) -, phenyl-NH- (C ═ O) -, phenyl- [ ((C)1-C6) Alkyl) -N]-(C＝O)-、(C1-C10) heteroaryl-NH- (C ═ O) -, (C)1-C10) heterocyclyl-NH- (C ═ O) -, (C)3-C10) cycloalkyl-NH- (C ═ O) -, (C)1-C6) Alkyl- (C ═ O) -O-and phenyl- (C ═ O) -O-. Other embodiments of the invention include compounds of formula I (and I (a), I (c), I (e), I (f), and I (h)) wherein R4Is R9-B-(CH2)n-; n is an integer from one to six, more preferably one to five, more preferably one to three; b is- (C ═ O) -NR10-、-(R10-N)-、-SO2-(NR10)-、-(R10-N)-(C＝O)-(NR11) -or- (R)10-N)-(C＝O)-O-；R9Is R13-(R12CH)m-; m is 1 to 6; r10Is hydrogen or methyl; each R12Independently selected from the group consisting of hydrogen or methyl; r13Is as described above and is related to R above2The embodiments of (1) are combined.
Another embodiment of the invention are compounds of formula I (and I (c) and I (f) wherein R7Is selected from the group consisting of R16-(C1-C6) Alkyl- (C ═ O) -, phenyl- (C ═ O) -, and1-C10) Heteroaryl- (C ═ O) -, (C)1-C10) Heterocyclyl- (C ═ O) -, (C)3-C10) Cycloalkyl- (C ═ O) -, (C)1-C6) alkyl-O- (C ═ O) -, H2N-(C＝O)-、(C1-C6) alkyl-NH- (C ═ O) -, phenyl-NH- (C ═ O) -, (C)1-C10) heteroaryl-NH- (C ═ O) -, (C)1-C10) heterocyclyl-NH- (C ═ O) -and (C)3-C10) cycloalkyl-NH- (C ═ O) -; wherein each of the above-mentioned phenyl, heterocyclyl, heteroaryl or cycloalkyl radicals R7The substituents may optionally be independently substituted with one to four moieties, the substituents being independently selected from the group consisting of: halo, R16-(C1-C6) Alkyl, (C)2-C6) Alkenyl, (C)2-C6) Alkynyl, perhalogenated (C)1-C6) Alkyl, (C)3-C10) Cycloalkyl, phenyl, benzyl, (C)1-C10) Heterocyclic group, (C)1-C10) Heteroaryl, (C)1-C6) alkyl-SO2-, formyl, -CN, (C)1-C6) Alkyl- (C ═ O) -, (C)3-C10) Cycloalkyl- (C ═ O) -, phenyl- (C ═ O) -, and1-C10) Heterocyclyl- (C ═ O) -, (C)1-C10) Heteroaryl- (C ═ O) -, HO- (C ═ O) -, and1-C6) alkyl-O- (C ═ O) -, (C)3-C10) cycloalkyl-O- (C ═ O) -, (C)1-C10) heterocyclyl-O- (C ═ O) -, (C)1-C6) alkyl-NH- (C ═ O) -, (C)3-C10) cycloalkyl-NH- (C ═ O) -, phenyl-NH- (C ═ O) -, (C)1-C10) heterocyclyl-NH- (C ═ O) -, (C)1-C10) heteroaryl-NH- (C ═ O) -, [ (C)1-C6) Alkyl radical]2-N- (C ═ O) -, phenyl- [ ((C)1-C6) Alkyl) -N]- (C ═ O) -, hydroxy, (C)1-C6) Alkoxy, perhalogenated (C)1-C6) Alkoxy group, (C)3-C10) cycloalkyl-O-, phenoxy, (C)1-C10) heterocyclyl-O-, (C)1-C10) heteroaryl-O-, (C)1-C6) Alkyl- (C ═ O) -O-, (C)3-C10) Cycloalkyl- (C ═ O) -O-, phenyl- (C ═ O) -O-, (C ═ O-, (C)1-C10) Heterocyclyl- (C ═ O) -O-, (C)1-C10) Heteroaryl- (C ═ O) -O-, -NO2Amino group, (C)1-C6) Alkylamino [ (C)1-C6) Alkyl radical]2-amino, carboxamido, (C)1-C6) Alkyl- (C ═ O) -NH-, (C)3-C10) Cycloalkyl- (C ═ O) -NH-, phenyl- (C ═ O) -NH-, (C ═ O-), (C1-C10) Heterocyclyl- (C ═ O) -NH-, (C)1-C10) Heteroaryl- (C ═ O) -NH-, (C)1-C6) Alkyl- (C ═ O) - [ ((C)1-C6) Alkyl) -N]-, phenyl- (C ═ O) - [ ((C)1-C6) Alkyl) -N]-、(C1-C6) alkyl-SO2-NH-、(C3-C10) cycloalkyl-SO2-NH-, phenyl-SO2-NH-、(C1-C10) heterocyclyl-SO2-NH-and (C)1-C10) heteroaryl-SO2-NH-; wherein each of said phenyl and heteroaryl moieties may be optionally substituted with one or two groups independently selected from the group consisting of halo, (C)1-C6) Alkyl, (C)1-C6) Alkoxy, amino, (C)1-C6) Alkylamino and [ (C)1-C6) Alkyl radical]2-amino groups. A more preferred embodiment of the invention are the compounds of formula I (c) wherein R7Is hydrogen. Other embodiments of the invention include compounds of formula I (and I (c) and I (f) wherein R7Is as defined above and each of the aforementioned I (c) and I (f) R4Embodiments and each of the above R2The embodiments are combined.
Another embodiment of the invention are compounds of formula I (and I (c) and I (f) wherein R7Selected from the group consisting of hydrogen and optionally substituted phenyl, (C)1-C10) Heteroaryl, (C)1-C10) Heterocyclyl and (C)3-C10) Cycloalkyl groups. Other embodiments of the invention include compounds of formula I (and I (c) and I (f) wherein R7Is as defined above and each of the aforementioned I (c) and I (f) R4Embodiments and each of the above R2The embodiments are combined.
Another preferred embodiment of the present invention are compounds of formula I (and I (c) and I (f) wherein R7Is R14-(CR15H)p-; p is one to six, preferably one to four; r14Selected from the group consisting of: hydrogen, halo, (C)1-C6) Alkyl, (C)2-C6) Alkenyl, (C)2-C6) Alkynyl, perhalogenated (C)1-C6) Alkyl, (C)3-C10) Cycloalkyl, phenyl, (C)1-C10) Heterocyclic group, (C)1-C10) Heteroaryl, formyl, -CN, (C)1-C6) Alkyl- (C ═ O) -, phenyl- (C ═ O) -, and1-C10) Heteroaryl- (C ═ O) -, (C)1-C10) Heterocyclyl- (C ═ O) -, (C)3-C10) Cycloalkyl- (C ═ O) -, HO- (C ═ O) -, R16-(C1-C6) alkyl-O- (C ═ O) -, (C)3-C10) cycloalkyl-O- (C ═ O) -, (C)1-C10) heterocyclyl-O- (C ═ O) -, (C)1-C10) heteroaryl-O- (C ═ O) -, H2N-(C＝O)-、R16-(C1-C6) alkyl-NH- (C ═ O) -, (C)3-C10) cycloalkyl-NH- (C ═ O) -, phenyl-NH- (C ═ O) -, (C)1-C10) heterocyclyl-NH- (C ═ O) -, (C)1-C10) heteroaryl-NH- (C ═ O) -, [ (C)1-C6) Alkyl radical]2-N- (C ═ O) -, phenyl- [ ((C)1-C6) Alkyl) -N]-(C＝O)-、(C1-C10) Heteroaryl- [ ((C)1-C6) Alkyl) -N]-(C＝O)-、(C1-C10) Heterocyclyl- [ ((C)1-C6) Alkyl) -N]-(C＝O)-、(C3-C10) Cycloalkyl- [ ((C)1-C6) Alkyl) -N]- (C ═ O) -, hydroxy, R16-(C1-C6) Alkoxy, perhalogenated (C)1-C6) Alkoxy group, (C)3-C10) cycloalkyl-O-, phenoxy, (C)1-C10) heterocyclyl-O-, (C)1-C10) heteroaryl-O-, R16-(C1-C6) Alkyl- (C ═ O) -O-, (C)3-C10) Cycloalkyl- (C ═ O) -O-, phenyl- (C ═ O) -O-, (C ═ O-, (C)1-C10) Heterocyclyl- (C ═ O) -O-, (C)1-C10) Heteroaryl- (C ═ O) -O-, amino, R16-(C1-C6) Alkylamino [ (C)1-C6) Alkyl radical]2-amino, carboxamido, R16-(C1-C6) Alkyl- (C ═ O) -NH-, (C)3-C10) Cycloalkyl- (C ═ O) -NH-, phenyl- (C ═ O) -NH-, (C ═ O-), (C1-C10) Heterocyclyl- (C ═ O) -NH-, (C)1-C10) Heteroaryl- (C ═ O) -NH-, R16-(C1-C6) Alkyl- (C ═ O) - [ ((C)1-C6) Alkyl) -N]-, phenyl- (C ═ O) - [ ((C)1-C6) Alkyl) -N]-、R16-(C1-C6) alkyl-SO2-NH-、(C3-C10) cycloalkyl-SO2-NH-, phenyl-SO2-NH-、(C1-C10) heterocyclyl-SO2-NH-and (C)1-C10) heteroaryl-SO2-NH-; wherein each of the above-mentioned phenyl, heterocyclyl, heteroaryl or cycloalkyl radicals R14The substituents may optionally be independently substituted with one to four moieties, the substituents being independently selected from the group consisting of: halo, R16-(C1-C6) Alkyl, (C)2-C6) Alkenyl, (C)2-C6) Alkynyl, perhalogenated (C)1-C6) Alkyl, (C)3-C10) Cycloalkyl, phenyl, benzyl, (C)1-C10) Heterocyclic group, (C)1-C10) Heteroaryl, (C)1-C6) alkyl-SO2-, formyl, -CN, R16-(C1-C6) Alkyl- (C ═ O) -, (C)3-C10) Cycloalkyl- (C ═ O) -, phenyl- (C ═ O) -, and1-C10) Heterocyclyl- (C ═ O) -, (C)1-C10) Heteroaryl- (C ═ O) -, HO- (C ═ O) -, and1-C6) alkyl-O- (C ═ O) -, (C)3-C10) cycloalkyl-O- (C ═ O) -, (C)1-C10) heterocyclyl-O- (C ═ O) -, (C)1-C10) heteroaryl-O- (C ═ O) -, H2N-(C＝O)-、R16-(C1-C6) alkyl-NH- (C ═ O) -, (C)3-C10) cycloalkyl-NH- (C ═ O) -, phenyl-NH- (C ═ O) -, (C)1-C10) heterocyclyl-NH- (C ═ O) -, (C)1-C10) heteroaryl-NH- (C ═ O) -, [ (C)1-C6) Alkyl radical]2-N- (C ═ O) -, phenyl- [ ((C)1-C6) Alkyl) -N]- (C ═ O) -, hydroxy, R16-(C1-C6) Alkoxy, perhalogenated (C)1-C6) Alkoxy group, (C)3-C10) cycloalkyl-O-, phenoxy, (C)1-C10) heterocyclyl-O-, (C)1-C10) heteroaryl-O-, R16-(C1-C6) Alkyl- (C ═ O) -O-, (C)3-C10) Cycloalkyl- (C ═ O) -O-, phenyl- (C ═ O) -O-, (C ═ O-, (C)1-C10) Heterocyclyl- (C ═ O) -O-, (C)1-C10) Heteroaryl- (C ═ O) -O-, -NO2Amino, R16-(C1-C6) Alkylamino [ (C)1-C6) Alkyl radical]2-amino, carboxamido, R16-(C1-C6) Alkyl- (C ═ O) -NH-, (C)3-C10) Cycloalkyl- (C ═ O) -NH-, phenyl- (C ═ O) -NH-, (C ═ O-), (C1-C10) Heterocyclyl- (C ═ O) -NH-, (C)1-C10) Heteroaryl- (C ═ O) -NH-, R16-(C1-C6) Alkyl- (C ═ O) - [ ((C)1-C6) Alkyl) -N]-, phenyl- (C ═ O) - [ ((C)1-C6) Alkyl) -N]-、R16-(C1-C6) alkyl-SO2-NH-、(C3-C10) cycloalkyl-SO2-NH-, phenyl-SO2-NH-、(C1-C10) heterocyclyl-SO2-NH-and (C)1-C10) heteroaryl-SO2-NH-; wherein each of said phenyl and heteroaryl moieties may be optionally substituted with one or two groups independently selected from the group consisting of halo, (C)1-C6) Alkyl, (C)1-C6) Alkoxy, amino, (C)1-C6) Alkylamino or [ (C)1-C6) Alkyl radical]2-amino groups;
each R15Independently selected from hydrogen, halo, (C)1-C6) Alkyl, (C)2-C6) Alkenyl, perhalogenated (C)1-C6) Alkyl, HO- (C ═ O) -, (C)1-C6) alkyl-O- (C ═ O) -, H2N-(C＝O)-、(C1-C6) alkyl-NH- (C ═ O) -, [ (C)1-C6) Alkyl radical]2-N- (C ═ O) -, hydroxy, (C)1-C6) Alkoxy, perhalogenated (C)1-C6) Alkoxy, amino, (C)1-C6) Alkylamino [ (C)1-C6) Alkyl radical]2-amino, carboxamido and (C)1-C6) Alkyl- (C ═ O) -NH-groupsGroup (b);
each R16Independently selected from hydrogen, halo, (C)1-C6) Alkyl, (C)2-C6) Alkenyl, (C)2-C6) Alkynyl, perhalogenated (C)1-C6) Alkyl, (C)1-C10) Heterocyclic group, HO- (C ═ O) -, and (C)1-C6) alkyl-O- (C ═ O) -, H2N-(C＝O)-、(C1-C6) alkyl-NH- (C ═ O) -, [ (C)1-C6) Alkyl radical]2-N- (C ═ O) -, hydroxy, (C)1-C6) Alkoxy, perhalogenated (C)1-C6) Alkoxy group, (C)1-C6) Alkyl- (C ═ O) -O-, -NO2Amino group, (C)1-C6) Alkylamino [ (C)1-C6) Alkyl radical]2-amino, carboxamido and (C)1-C6) Alkyl- (C ═ O) -NH-.
Other embodiments of the invention include compounds of formula I (and I (c) and I (f) wherein R7Is as defined above and each of the aforementioned I (c) and I (f) R4Embodiments and each of the above R2The embodiments are combined.
Another preferred embodiment of the present invention are compounds of formula I (and I (c) and I (f) wherein R7Is R14-(CR15H)p-; p is one to six, preferably one to four; r14Selected from the group consisting of: hydrogen, halo, (C)1-C6) Alkyl, (C)2-C6) Alkenyl, (C)3-C10) Cycloalkyl, phenyl, (C)1-C10) Heterocyclic group, (C)1-C10) Heteroaryl, HO- (C ═ O) -, R16-(C1-C6) alkyl-O- (C ═ O) -, H2N-(C＝O)-、R16-(C1-C6) alkyl-NH- (C ═ O) -, phenyl-NH- (C ═ O) -, (C)1-C10) heterocyclyl-NH- (C ═ O) -, [ (C)1-C6) Alkyl radical]2-N- (C ═ O) -, phenyl- [ ((C)1-C6) Alkyl) -N]-(C＝O) -, hydroxy, R16-(C1-C6) Alkoxy, phenoxy, amino, R16-(C1-C6) Alkylamino [ (C)1-C6) Alkyl radical]2-amino, R16-(C1-C6) Alkyl- (C ═ O) -NH-; wherein each of the above-mentioned phenyl, heterocyclyl, heteroaryl or cycloalkyl radicals R14The substituents may optionally be independently substituted with one to four moieties, the substituents being independently selected from the group consisting of: halo, R16-(C1-C6) Alkyl, (C)2-C6) Alkenyl, (C)2-C6) Alkynyl, perhalogenated (C)1-C6) Alkyl, (C)1-C6) alkyl-SO2-, formyl, -CN, R16-(C1-C6) Alkyl- (C ═ O) -, HO- (C ═ O) -, and1-C6) alkyl-O- (C ═ O) -, H2N-(C＝O)-、R16-(C1-C6) alkyl-NH- (C ═ O) -, [ (C)1-C6) Alkyl radical]2-N- (C ═ O) -, hydroxy, R16-(C1-C6) Alkoxy, perhalogenated (C)1-C6) Alkoxy radical, R16-(C1-C6) Alkyl- (C ═ O) -O-, amino, R16-(C1-C6) Alkylamino [ (C)1-C6) Alkyl radical]2-amino, carboxamido, R16-(C1-C6) Alkyl- (C ═ O) -NH-, R16-(C1-C6) Alkyl- (C ═ O) - [ ((C)1-C6) Alkyl) -N]-and R16-(C1-C6) alkyl-SO2-NH-；
Each R15Independently selected from hydrogen, halo, (C)1-C6) Alkyl, (C)2-C6) Alkenyl, perhalogenated (C)1-C6) Alkyl, HO- (C ═ O) -, (C)1-C6) alkyl-O- (C ═ O) -, H2N-(C＝O)-、(C1-C6) alkyl-NH- (C ═ O) -, [ (C)1-C6) Alkyl radical]2-N- (C ═ O) -, hydroxy, (C)1-C6) Alkoxy radicalBasic, perhalogenated (C)1-C6) Alkoxy, amino, (C)1-C6) Alkylamino [ (C)1-C6) Alkyl radical]2-amino, carboxamido and (C)1-C6) Alkyl- (C ═ O) -NH-; wherein no more than two of said R15The group may not be hydrogen;
each R16Independently selected from hydrogen, halo, (C)1-C6) Alkyl, (C)2-C6) Alkenyl, (C)2-C6) Alkynyl, perhalogenated (C)1-C6) Alkyl, (C)1-C10) Heterocyclic group, HO- (C ═ O) -, and (C)1-C6) alkyl-O- (C ═ O) -, H2N-(C＝O)-、(C1-C6) alkyl-NH- (C ═ O) -, [ (C)1-C6) Alkyl radical]2-N- (C ═ O) -, hydroxy, (C)1-C6) Alkoxy, perhalogenated (C)1-C6) Alkoxy group, (C)1-C6) Alkyl- (C ═ O) -O-, -NO2Amino group, (C)1-C6) Alkylamino [ (C)1-C6) Alkyl radical]2-amino, carboxamido and (C)1-C6) Alkyl- (C ═ O) -NH-. Other embodiments of the invention include compounds of formula I (and I (c) and I (f)) wherein R7Is as defined above and each of the aforementioned I (c) and I (f) R4Embodiments and each of the above R2The embodiments are combined.
A more preferred embodiment of the present invention are compounds of formula I (c) wherein R is7Is R14-(CR15H)p-; p is one to four; r14Selected from the group consisting of hydrogen, (C)2-C4) Alkenyl, HO- (C ═ O) -, (C)1-C3) alkyl-O- (C ═ O) -, H2N-(C＝O)-、(C1-C3) alkyl-NH- (C ═ O) -, [ (C)1-C3) Alkyl radical]2-N- (C ═ O) -, hydroxy, (C)1-C3) Alkoxy, amino, (C)1-C4) Alkylamino [ (C)1-C4) Alkyl radical]2-amino and(C1-C3) Alkyl- (C ═ O) -NH-; each R15Independently selected from hydrogen, (C)1-C2) Alkyl, hydroxyl and amino. More preferred compounds of formula I (c) are those wherein R is4And R7The mixed molecular weight of the substituents is less than 200 AMU. More preferably, R4And R7The mixed molecular weight of the substituents is less than 100 AMU.
Another embodiment of the present invention are compounds of formula I (and I (b)) wherein R is5Is hydrogen. Other embodiments of the invention include compounds of formula I (and I (b)) wherein R is5Is hydrogen and is associated with each of the above-mentioned R2The embodiments are combined.
Another embodiment of the present invention are compounds of formula I (and I (b)) wherein R is5Is (C)1-C10) Heterocyclyl or (C)1-C10) A heteroaryl group; wherein each of the above heterocyclyl and heteroaryl substituents may be optionally independently substituted with one to four moieties, the substituents being independently selected from the group consisting of halo, (C)1-C6) Alkyl, (C)1-C6) Alkoxy, HO- (C ═ O) -, (C)1-C6) alkyl-O- (C ═ O) -, H2N-(C＝O)-、(C1-C6) alkyl-NH- (C ═ O) -and [ (C)1-C6) Alkyl radical]2-N- (C ═ O) -. Other embodiments of the invention include compounds of formula I (and I (b)) wherein R is5Is said optionally substituted (C)1-C10) Heterocyclyl or (C)1-C10) Heteroaryl, and with each of the above R2The embodiments are combined. More preferred heterocyclyl compounds are pyrrolidinyl, piperidinyl and azetidinyl.
Another preferred embodiment of the present invention are compounds of formula I (and I (b)) wherein R is5Is R14-(CR15H)p-; p is 1 to 6; r14Selected from the group consisting of: hydrogen, (C)1-C6) Alkyl, (C)2-C6) Alkenyl, perhaloGeneration (C)1-C6) Alkyl, (C)3-C10) Cycloalkyl, phenyl, (C)1-C10) Heterocyclic group, (C)1-C10) Heteroaryl, phenyl- (S ═ O) -, (C)1-C6) alkyl-SO2-, phenyl-SO2-、H2N-SO2-、(C1-C6) alkyl-NH-SO2-, phenyl-NH-SO2-、[(C1-C6) Alkyl radical]2N-SO2-、(C1-C6) Alkyl- (C ═ O) -, phenyl- (C ═ O) -, and1-C10) Heteroaryl- (C ═ O) -, (C)1-C10) Heterocyclyl- (C ═ O) -, (C)3-C10) Cycloalkyl- (C ═ O) -, HO- (C ═ O) -, R16-(C1-C6) alkyl-O- (C ═ O) -, (C)3-C10) cycloalkyl-O- (C ═ O) -, (C)1-C10) heterocyclyl-O- (C ═ O) -, (C)1-C10) heteroaryl-O- (C ═ O) -, H2N-(C＝O)-、(C1-C6) alkyl-NH- (C ═ O) -, (C)3-C10) cycloalkyl-NH- (C ═ O) -, phenyl-NH- (C ═ O) -, (C)1-C10) heterocyclyl-NH- (C ═ O) -, (C)1-C10) heteroaryl-NH- (C ═ O) -, [ (C)1-C6) Alkyl radical]2-N- (C ═ O) -, phenyl- [ ((C)1-C6) Alkyl) -N]-(C＝O)-、(C1-C10) Heteroaryl- [ ((C)1-C6) Alkyl) -N]-(C＝O)-、(C1-C10) Heterocyclyl- [ ((C)1-C6) Alkyl) -N]-(C＝O)-、(C3-C10) Cycloalkyl- [ ((C)1-C6) Alkyl) -N]- (C ═ O) -, hydroxy, R16-(C1-C6) Alkoxy, perhalogenated (C)1-C6) Alkoxy group, (C)3-C10) cycloalkyl-O-, phenoxy, (C)1-C10) heterocyclyl-O-, (C)1-C10) heteroaryl-O-, R16-(C1-C6) Alkyl- (C ═ O) -O-, (C)3-C10) Cycloalkyl- (C ═ O) -O-, phenyl- (C ═ O) -O-, (C ═ O-, (C)1-C10) Heterocyclyl- (C ═ O) -O-, (C)1-C10) Heteroaryl- (C ═ O) -O-, -NO2Amino, R16-(C1-C6) Alkylamino [ (C)1-C6) Alkyl radical]2-amino, carboxamido, R16-(C1-C6) Alkyl- (C ═ O) -NH-, (C)3-C10) Cycloalkyl- (C ═ O) -NH-, phenyl- (C ═ O) -NH-, R16-(C1-C6) alkyl-SO2-NH-、(C3-C10) cycloalkyl-SO2-NH-, phenyl-SO2-NH-、(C1-C10) heterocyclyl-SO2-NH-and (C)1-C10) heteroaryl-SO2-NH-; wherein each of the above-mentioned phenyl, heterocyclyl, heteroaryl or cycloalkyl radicals R14The substituents may optionally be independently substituted with one to four moieties, the substituents being independently selected from the group consisting of: halo, R16-(C1-C6) Alkyl, (C)2-C6) Alkenyl, (C)2-C6) Alkynyl, perhalogenated (C)1-C6) Alkyl, (C)3-C10) Cycloalkyl, phenyl, benzyl, (C)1-C10) Heterocyclic group, (C)1-C10) Heteroaryl, (C)1-C6) alkyl-SO2-, formyl, -CN, R16-(C1-C6) Alkyl- (C ═ O) -, (C)3-C10) Cycloalkyl- (C ═ O) -, phenyl- (C ═ O) -, and1-C10) Heterocyclyl- (C ═ O) -, (C)1-C10) Heteroaryl- (C ═ O) -, HO- (C ═ O) -, and1-C6) alkyl-O- (C ═ O) -, (C)3-C10) cycloalkyl-O- (C ═ O) -, (C)1-C10) heterocyclyl-O- (C ═ O) -, (C)1-C10) heteroaryl-O- (C ═ O) -, H2N-(C＝O)-、R16-(C1-C6) alkyl-NH- (C ═ O) -, (C)3-C10) cycloalkyl-NH- (C ═ O) -, phenyl-NH- (C ═ O) -, (C)1-C10) heterocyclyl-NH- (C ═ O) -, (C)1-C10) heteroaryl-NH- (C ═ O) -, [ (C)1-C6) Alkyl radical]2-N- (C ═ O) -, phenyl- [ ((C)1-C6) Alkyl radical)-N]- (C ═ O) -, hydroxy, R16-(C1-C6) Alkoxy, perhalogenated (C)1-C6) Alkoxy group, (C)3-C10) cycloalkyl-O-, phenoxy, (C)1-C10) heterocyclyl-O-, (C)1-C10) heteroaryl-O-, R16-(C1-C6) Alkyl- (C ═ O) -O-, (C)3-C10) Cycloalkyl- (C ═ O) -O-, phenyl- (C ═ O) -O-, (C ═ O-, (C)1-C10) Heterocyclyl- (C ═ O) -O-, (C)1-C10) Heteroaryl- (C ═ O) -O-, -NO2Amino, R16-(C1-C6) Alkylamino [ (C)1-C6) Alkyl radical]2-amino, carboxamido, R16-(C1-C6) Alkyl- (C ═ O) -NH-, (C)3-C10) Cycloalkyl- (C ═ O) -NH-, phenyl- (C ═ O) -NH-, (C ═ O-), (C1-C10) Heterocyclyl- (C ═ O) -NH-, (C)1-C10) Heteroaryl- (C ═ O) -NH-, R16-(C1-C6) Alkyl- (C ═ O) - [ ((C)1-C6) Alkyl) -N]-, phenyl- (C ═ O) - [ ((C)1-C6) Alkyl) -N]-、R16-(C1-C6) alkyl-SO2-NH-、(C3-C10) cycloalkyl-SO2-NH-, phenyl-SO2-NH-、(C1-C10) heterocyclyl-SO2-NH-and (C)1-C10) heteroaryl-SO2-NH-; wherein each of said phenyl and heteroaryl moieties may be optionally substituted with one or two groups independently selected from the group consisting of halo, (C)1-C6) Alkyl, (C)1-C6) Alkoxy, amino, (C)1-C6) Alkylamino or [ (C)1-C6) Alkyl radical]2-amino groups. Other embodiments of the invention include compounds of formula I (and I (b)) wherein R is5Is said R14-(CR15H)p-; p is 1 to 6; r14Is as defined above and each of the above R2The embodiments are combined.
Another preferred embodiment of the invention isSuch compounds of formula I (and I (b)), wherein R5Is R14-(CHR15)p-; p is 1 to 6; r14Selected from the group consisting of: hydrogen, (C)1-C6) Alkyl, (C)2-C6) Alkenyl, (C)3-C10) Cycloalkyl, phenyl, (C)1-C10) Heterocyclic group, (C)1-C10) Heteroaryl, HO- (C ═ O) -, R16-(C1-C6) alkyl-O- (C ═ O) -, H2N-(C＝O)-、R16-(C1-C6) alkyl-NH- (C ═ O) -, phenyl-NH- (C ═ O) -, (C)1-C10) heterocyclyl-NH- (C ═ O) -, [ (C)1-C6) Alkyl radical]2-N- (C ═ O) -, phenyl- [ ((C)1-C6) Alkyl) -N]- (C ═ O) -, hydroxy, R16-(C1-C6) Alkoxy, phenoxy, amino, R16-(C1-C6) Alkylamino [ (C)1-C6) Alkyl radical]2-amino, R16-(C1-C6) Alkyl- (C ═ O) -NH-; wherein each of the above-mentioned phenyl, heterocyclyl, heteroaryl or cycloalkyl radicals R14The substituents may optionally be independently substituted with one to four moieties, the substituents being independently selected from the group consisting of: halo, R16-(C1-C6) Alkyl, (C)2-C6) Alkenyl, (C)2-C6) Alkynyl, perhalogenated (C)1-C6) Alkyl, (C)1-C6) alkyl-SO2-, formyl, -CN, R16-(C1-C6) Alkyl- (C ═ O) -, HO- (C ═ O) -, and1-C6) alkyl-O- (C ═ O) -, H2N-(C＝O)-、R16-(C1-C6) alkyl-NH- (C ═ O) -, [ (C)1-C6) Alkyl radical]2-N- (C ═ O) -, hydroxy, R16-(C1-C6) Alkoxy, perhalogenated (C)1-C6) Alkoxy radical, R16-(C1-C6) Alkyl- (C ═ O) -O-, amino, R16-(C1-C6) Alkylamino [ (C)1-C6) Alkyl radical]2-amino, carboxamido, R16-(C1-C6) Alkyl- (C ═ O) -NH-, R16-(C1-C6) Alkyl- (C ═ O) - [ ((C)1-C6) Alkyl) -N]-and R16-(C1-C6) alkyl-SO2-NH-；
Each R15Independently selected from hydrogen, halo, (C)1-C6) Alkyl, (C)2-C6) Alkenyl, perhalogenated (C)1-C6) Alkyl, HO- (C ═ O) -, (C)1-C6) alkyl-O- (C ═ O) -, H2N-(C＝O)-、(C1-C6) alkyl-NH- (C ═ O) -, [ (C)1-C6) Alkyl radical]2-N- (C ═ O) -, hydroxy, (C)1-C6) Alkoxy, perhalogenated (C)1-C6) Alkoxy, amino, (C)1-C6) Alkylamino [ (C)1-C6) Alkyl radical]2-amino, carboxamido and (C)1-C6) Alkyl- (C ═ O) -NH-; wherein no more than two of said R15The group may not be hydrogen;
each R16Independently selected from hydrogen, halo, (C)1-C6) Alkyl, (C)2-C6) Alkenyl, (C)2-C6) Alkynyl, perhalogenated (C)1-C6) Alkyl, (C)1-C10) Heterocyclic group, HO- (C ═ O) -, and (C)1-C6) alkyl-O- (C ═ O) -, H2N-(C＝O)-、(C1-C6) alkyl-NH- (C ═ O) -, [ (C)1-C6) Alkyl radical]2-N- (C ═ O) -, hydroxy, (C)1-C6) Alkoxy, perhalogenated (C)1-C6) Alkoxy group, (C)1-C6) Alkyl- (C ═ O) -O-, -NO2Amino group, (C)1-C6) Alkylamino [ (C)1-C6) Alkyl radical]2-amino, carboxamido and (C)1-C6) Alkyl- (C ═ O) -NH-.
Other embodiments of the present invention include compounds of formula I (and I (b))In which R is5Is said R14-(CHR15)p-; p is 1 to 6; r14、R15And R16Is as defined above and each of the above R2The embodiments are combined.
A more preferred embodiment of the present invention are compounds of formula I (and I (b)) wherein R is5Is R14-(CHR15)p-; p is 1 to 6; r14Selected from the group consisting of hydrogen, (C)2-C4) Alkenyl, (C)1-C10) Heterocyclic group, HO- (C ═ O) -, and (C)1-C3) alkyl-O- (C ═ O) -, H2N-(C＝O)-、(C1-C3) alkyl-NH- (C ═ O) -, hydroxy, (C)1-C3) Alkoxy, amino, (C)1-C3) Alkylamino and [ (C)1-C2) Alkyl radical]2-amino groups; each R15Independently selected from hydrogen, (C)1-C6) Alkyl, hydroxy, (C)1-C3) Alkoxy, perhalogenated (C)1) Alkoxy, amino, (C)1-C2) Alkylamino [ (C)1-C2) Alkyl radical]2-amino, carboxamido and (C)1-C6) Alkyl- (C ═ O) -NH-; wherein no more than two of said R15The group may not be hydrogen.
Another embodiment of the invention are compounds of formula I (and I (a), I (b), I (d), I (g)) wherein R6Is hydrogen. Other embodiments of the invention include compounds of formula I (and I (a), I (b), I (d), I (g)) wherein R6Is hydrogen and is substituted with each of the above I (a) R4Embodiment (I), (b) R5Embodiments or each of the foregoing R2The embodiments are combined.
Another embodiment of the invention are compounds of formula I (and I (a), I (b), I (d), I (g)) wherein R6Is R9-B-(CH2)nN is zero. Other embodiments of the invention include compounds of formula I (and I (a), I (b), I (d), I (g)) wherein R6Is R9-B-(CH2)nN is zero and is in contact with each of the above I (a) R4Embodiment (I), (b) R5Embodiments or each of the foregoing R2The embodiments are combined.
Another embodiment of the invention are compounds of formula I (and I (a), I (b), I (d), I (g)) wherein R6Is R9-B-(CH2)nN is an integer from one to six, more preferably one to five, more preferably one to three. Other embodiments of the invention include compounds of formula I (and I (a), I (b), I (d), I (g)) wherein R6Is R9-B-(CH2)nN is an integer from one to five and with each of the above I (a) R4Embodiment (I), (b) R5Embodiments or each of the foregoing R2The embodiments are combined.
Another embodiment of the invention are compounds of formula I (and I (a), I (b), I (d), I (g)) wherein R6Is R9-B-(CH2)n-; n is zero; b is a bond; r9Selected from hydrogen, -CF3、-CN、(C1-C10) Heteroaryl, (C)1-C10) Heterocyclyl or (C)3-C10) Cycloalkyl groups; wherein each of the above (C)1-C10) Heteroaryl, (C)1-C10) Heterocyclyl and (C)3-C10) The cycloalkyl group may be optionally substituted with one to three moieties, the substituents being independently selected from the group consisting of: halo, (C)1-C6) Alkyl, (C)2-C6) Alkenyl, (C)2-C6) Alkynyl, perhalogenated (C)1-C6) Alkyl, hydroxy, (C)1-C6) Alkoxy, perhalogenated (C)1-C6) Alkoxy group, (C)1-C6) alkyl-S-, (C1-C6) alkyl-SO2-、(C1-C6) alkyl-NH-SO2-、-NO2Amino group, (C)1-C6) Alkylamino [ (C)1-C6) Alkyl radical]2Amino group, (C)1-C6) Alkyl radical-SO2-NH-、(C1-C6) Alkyl- (C ═ O) -NH-, (C)1-C6) Alkyl- (C ═ O) - [ ((C)1-C6) Alkyl) -N]-、-CN、(C1-C6) Alkyl- (C ═ O) -, HO- (C ═ O) -, and1-C6) alkyl-O- (C ═ O) -, H2N(C＝O)-、(C1-C6) alkyl-NH- (C ═ O) -, [ (C)1-C6) Alkyl radical]2-N- (C ═ O) -and (C)1-C6) Alkyl- (C ═ O) -O-. Other embodiments of the invention include compounds of formula I (and I (a), I (b), I (d), I (g)) wherein R6Is R9-B-(CH2)n-; n is zero; b is a bond; r9Is as defined above and each of the above I (a) R4Embodiment (I), (b) R5Embodiments or each of the foregoing R2The embodiments are combined.
Another embodiment of the invention are compounds of formula I (and I (a), I (b), I (d), I (g)) wherein R6Is R9-B-(CH2)n-; n is zero; b is- (C ═ O) -NR10-、-(R10-N)-、-(R10-N)-SO2-、-(R10-N)-(C＝O)-、＞C＝O、-O-(C＝O)-、-SO2-(NR10)-、-(R10-N)-(C＝O)-(NR11) -; and R9Selected from the group consisting of hydrogen, (C)3-C10) Cycloalkyl or phenyl; wherein the above-mentioned phenyl and (C)3-C10) The cycloalkyl group may be optionally substituted with one to three moieties, the substituents being independently selected from the group consisting of: halo, (C)1-C6) Alkyl, (C)2-C6) Alkenyl, (C)2-C6) Alkynyl, perhalogenated (C)1-C6) Alkyl, hydroxy, (C)1-C6) Alkoxy, perhalogenated (C)1-C6) Alkoxy group, (C)1-C6) alkyl-S-, (C)1-C6) alkyl-SO2-、(C1-C6) alkyl-NH-SO2-、-NO2Amino group, (C)1-C6) Alkylamino [ (C)1-C6) Alkyl radical]2Amino group, (C)1-C6) alkyl-SO2-NH-、(C1-C6) Alkyl- (C ═ O) -NH-, (C)1-C6) Alkyl- (C ═ O) - [ ((C)1-C6) Alkyl) -N]-、-CN、(C1-C6) Alkyl- (C ═ O) -, HO- (C ═ O) -, and1-C6) alkyl-O- (C ═ O) -, H2N(C＝O)-、(C1-C6) alkyl-NH- (C ═ O) -, [ (C)1-C6) Alkyl radical]2-N- (C ═ O) -and (C)1-C6) Alkyl- (C ═ O) -O-. Other embodiments of the invention include compounds of formula I (and I (a), I (b), I (d), I (g)) wherein R6Is R9-B-(CH2)n-; n is zero; b is- (C ═ O) -NR10-、-(R10-N)-、-(R10-N)-SO2-、-(R10-N)-(C＝O)-、＞C＝O、-O-(C＝O)-、-SO2-(NR10)-、-(R10-N)-(C＝O)-(NR11)-；R9Is as defined above and each of the above I (a) R4Embodiment (I), (b) R5Embodiments or each of the foregoing R2The embodiments are combined.
Another preferred embodiment of the invention are compounds of the formula I (and I (a), I (b), I (d), I (g)) in which R is6Is R9-B-(CH2)n-; n is zero; b is- (C ═ O) -NR10-、-(R10-N)-、＞C＝O、-O-(C＝O)-、-(R10-N) - (C ═ O) -or- (R)10-N)-(C＝O)-(NR11)-；R9Is R13-(R12CH)m-; m is 1 to 6; r10Is hydrogen or methyl; r12Is hydrogen or methyl; r13Selected from the group consisting of: hydrogen, (C)1-C6) Alkyl, (C)1-C6) Alkoxy, phenyl, (C)1-C10) Heteroaryl, (C)1-C10) Heterocyclic group, (C)3-C10) Cycloalkyl, amino, (C)1-C6) Alkylamino [ (C)1-C6) Alkyl radical]2Amino group, (C)1-C6) alkyl-SO2-NH-, phenyl-SO2-NH-、(C1-C6) alkyl-SO2-[((C1-C6) Alkyl) -N]-, phenyl-SO2-[((C1-C6) Alkyl) -N]-, hydroxy, (C)1-C6) Alkoxy, perhalogenated (C)1-C6) Alkoxy, phenoxy, (C)1-C10) heteroaryl-O-, (C)1-C10) heterocyclyl-O-, (C)3-C10) cycloalkyl-O-, (C)1-C6) alkyl-S-, (C)1-C6) alkyl-SO2-、(C1-C6) alkyl-NH-SO2-、-NO2Amino group, (C)1-C6) Alkylamino [ (C)1-C6) Alkyl radical]2Amino group, (C)1-C6) alkyl-SO2-NH-、(C1-C6) Alkyl- (C ═ O) -NH-, (C)1-C6) Alkyl- (C ═ O) - [ ((C)1-C6) Alkyl) -N]-, phenyl- (C ═ O) -NH-, phenyl- (C ═ O) - [ ((C)1-C6) Alkyl) -N]-、-CN、(C1-C6) Alkyl- (C ═ O) -, phenyl- (C ═ O) -, and1-C10) Heteroaryl- (C ═ O) -, (C)1-C10) Heterocyclyl- (C ═ O) -, (C)3-C10) Cycloalkyl- (C ═ O) -, (C)1-C10) heteroaryl-NH- (C ═ O) -, (C)1-C10) heterocyclyl-NH- (C ═ O) -, (C)3-C10) cycloalkyl-NH- (C ═ O) -, HO- (C ═ O) -, and1-C6) alkyl-O- (C ═ O) -, H2N(C＝O)-、(C1-C6) alkyl-NH- (C ═ O) -, [ (C)1-C6) Alkyl radical]2-N- (C ═ O) -, phenyl-NH- (C ═ O) -, phenyl- [ ((C)1-C6) Alkyl) -N]-(C＝O)-、(C1-C6) Alkyl- (C ═ O) -O-and phenyl- (C ═ O) -O-. Other embodiments of the invention include compounds of formula I (and I (a), I (b), I (d), I (g)) wherein R6Is R9-B-(CH2)n-; n is zero; b is- (C ═ O) -NR10-、-(R10-N)-、＞C＝O、-O-(C＝O)-、-(R10-N)-(C＝O)-Or- (R)10-N)-(C＝O)-(NR11)-；R9Is R13-(R12CH)m-; m is 1 to 6; r10Is hydrogen or methyl; r12Is hydrogen or methyl; r13Is as defined above and each of the above I (a) R4Embodiment (I), (b) R5Embodiments or each of the foregoing R2The embodiments are combined.
Another preferred embodiment of the invention are compounds of the formula I (and I (a), I (b), I (d), I (g)) in which R is6Is R9-B-(CH2)n-; n is zero; b is- (R)10-N)-；R9Is hydrogen or R13-(R12CH)m-; m is 1 to 6; r10Is hydrogen or methyl; r12Is hydrogen or methyl; r13Selected from the group consisting of hydrogen, (C)1-C6) Alkyl, hydroxy, (C)1-C6) Alkoxy, amino, (C)1-C6) Alkylamino [ (C)1-C6) Alkyl radical]2Amino group, (C)2-C6) Alkenyl, (C)2-C6) Alkynyl, phenyl, (C)1-C10) Heteroaryl, (C)1-C10) Heterocyclyl and (C)3-C10) Cycloalkyl groups. Other embodiments of the invention include compounds of formula I (and I (a), I (b), I (d), I (g)) wherein R6Is R9-B-(CH2)n-; n is zero; b is- (R)10-N)-；R9Is hydrogen or R13-(R12CH)m-; m is 1 to 6; r10Is hydrogen or methyl; r12Is hydrogen or methyl; r13Is as defined above and each of the above I (a) R4Embodiment (I), (b) R5Embodiment of or each the above (R)3)sThe embodiments are combined.
Another embodiment of the invention are compounds of formula I (and I (a), I (b), I (d), I (g)) wherein R6Is R9-B-(CH2)n-; n is one to six, preferably one to four; b is- (C ═ O) -NR10-、-(R10-N)-、-(R10-N) - (C ═ O) -or- (R)10-N)-(C＝O)-(NR11)-；R9Is R13-(R12CH)m-; m is 1 to 6; r10Is hydrogen or methyl; r12Is hydrogen or methyl; r13Selected from the group consisting of: hydrogen, (C)1-C6) Alkyl, (C)1-C6) Alkoxy, phenyl, (C)1-C10) Heteroaryl, (C)1-C10) Heterocyclic group, (C)3-C10) Cycloalkyl, amino, (C)1-C6) Alkylamino [ (C)1-C6) Alkyl radical]2Amino group, (C)1-C6) alkyl-SO2-NH-, phenyl-SO2-NH-、(C1-C6) alkyl-SO2-[((C1-C6) Alkyl) -N]-, phenyl-SO2-[((C1-C6) Alkyl) -N]-, hydroxy, (C)1-C6) Alkoxy, perhalogenated (C)1-C6) Alkoxy, phenoxy, (C)1-C10) heteroaryl-O-, (C)1-C10) heterocyclyl-O-, (C)3-C10) cycloalkyl-O-, (C)1-C6) alkyl-S-, (C)1-C6) alkyl-SO2-、(C1-C6) alkyl-NH-SO2-、-NO2Amino group, (C)1-C6) Alkylamino [ (C)1-C6) Alkyl radical]2Amino group, (C)1-C6) alkyl-SO2-NH-、(C1-C6) Alkyl- (C ═ O) -NH-, (C)1-C6) Alkyl- (C ═ O) - [ ((C)1-C6) Alkyl) -N]-, phenyl- (C ═ O) -NH-, phenyl- (C ═ O) - [ ((C)1-C6) Alkyl) -N]-、-CN、(C1-C6) Alkyl- (C ═ O) -, phenyl- (C ═ O) -, and1-C10) Heteroaryl- (C ═ O) -, (C)1-C10) Heterocyclyl- (C ═ O) -, (C)3-C10) Cycloalkyl- (C ═ O) -, (C)1-C10) heteroaryl-NH- (C ═ O) -, (C)1-C10) heterocyclyl-NH- (C ═ O) -, (C)3-C10) cycloalkyl-NH- (C ═ O) -, HO- (C ═ O) -, andO)-、(C1-C6) alkyl-O- (C ═ O) -, H2N(C＝O)-、(C1-C6) alkyl-NH- (C ═ O) -, [ (C)1-C6) Alkyl radical]2-N- (C ═ O) -, phenyl-NH- (C ═ O) -, phenyl- [ ((C)1-C6) Alkyl) -N]-(C＝O)-、(C1-C6) Alkyl- (C ═ O) -O-and phenyl- (C ═ O) -O-. Other embodiments of the invention include compounds of formula I (and I (a), I (b), I (d), I (g)) wherein R6Is R9-B-(CH2)n-; n is one to four; b is- (C ═ O) -NR10-、-(R10-N)-、-(R10-N) - (C ═ O) -or- (R)10-N)-(C＝O)-(NR11)-；R9Is R13-(R12CH)m-; m is 1 to 6; r10Is hydrogen or methyl; r12Is hydrogen or methyl; r13Is as defined above and each of the above I (a) R4Embodiment (I), (b) R5Embodiment of or each the above (R)2)sThe embodiments are combined.
Another embodiment of the invention are compounds of formula I (and I (a), I (b), I (d), I (g)) wherein R6Is R9-B-(CH2)n-; n is an integer from one to six, more preferably one to five, more preferably one to three; b is a bond; r9Selected from the group consisting of optionally substituted phenyl, (C)1-C10) Heterocyclic group, (C)1-C10) Heteroaryl and (C)3-C10) Cycloalkyl groups; wherein each of the above R9Phenyl, (C)1-C10) Heterocyclic group, (C)1-C10) Heteroaryl and (C)3-C10) The cycloalkyl substituents may be optionally substituted with one to four moieties, the substituents being independently selected from the group consisting of: halo, (C)1-C6) Alkyl, (C)2-C6) Alkenyl, (C)2-C6) Alkynyl, perhalogenated (C)1-C6) Alkyl, phenyl, (C)1-C10) Heteroaryl, (C)1-C10) Heterocyclic group, (C)3-C10) Cycloalkyl, hydroxyBase, (C)1-C6) Alkoxy, perhalogenated (C)1-C6) Alkoxy, phenoxy, (C)1-C10) heteroaryl-O-, (C)1-C10) heterocyclyl-O-, (C)3-C10) cycloalkyl-O-, (C)1-C6) alkyl-S-, (C)1-C6) alkyl-SO2-、(C1-C6) alkyl-NH-SO2-、-NO2Amino group, (C)1-C6) Alkylamino [ (C)1-C6) Alkyl radical]2Amino group, (C)1-C6) alkyl-SO2-NH-、(C1-C6) Alkyl- (C ═ O) -NH-, (C)1-C6) Alkyl- (C ═ O) - [ ((C)1-C6) Alkyl) -N]-, phenyl- (C ═ O) -NH-, phenyl- (C ═ O) - [ ((C)1-C6) Alkyl) -N]-、-CN、(C1-C6) Alkyl- (C ═ O) -, phenyl- (C ═ O) -, and1-C10) Heteroaryl- (C ═ O) -, (C)1-C10) Heterocyclyl- (C ═ O) -, (C)3-C10) Cycloalkyl- (C ═ O) -, HO- (C ═ O) -, and1-C6) alkyl-O- (C ═ O) -, H2N(C＝O)-、(C1-C6) alkyl-NH- (C ═ O) -, [ (C)1-C6) Alkyl radical]2-N- (C ═ O) -, phenyl-NH- (C ═ O) -, phenyl- [ ((C)1-C6) Alkyl) -N]-(C＝O)-、(C1-C10) heteroaryl-NH- (C ═ O) -, (C)1-C10) heterocyclyl-NH- (C ═ O) -, (C)3-C10) cycloalkyl-NH- (C ═ O) -, (C)1-C6) Alkyl- (C ═ O) -O-and phenyl- (C ═ O) -O-. Other embodiments of the invention include compounds of formula I (and I (a), I (b), I (d), I (g)) wherein R6Is R9-B-(CH2)n-; n is an integer from one to six, more preferably one to five, more preferably one to three; b is a bond; r9Is as described above and is compatible with each of the above I (a) R4Embodiment (I), (b) R5Embodiments or each of the foregoing R2The embodiments are combined.
Another embodiment of the present invention is as suchCompounds of formula (I) (and I (a), I (b), I (d), I (g)) wherein R6Is R9-B-(CH2)n-; n is an integer from one to six, more preferably one to five, more preferably one to three; b is- (C ═ O) -NR10-、-(R10-N)-、-SO2-(NR10)-、-(R10-N)-(C＝O)-(NR11) -or- (R)10-N)-(C＝O)-O-；R9Selected from the group consisting of optionally substituted phenyl, (C)1-C10) Heterocyclic group, (C)1-C10) Heteroaryl and (C)3-C10) Cycloalkyl groups; wherein each of the above R9Phenyl, (C)1-C10) Heterocyclic group, (C)1-C10) Heteroaryl and (C)3-C10) The cycloalkyl substituents may be optionally substituted with one to four moieties, the substituents being independently selected from the group consisting of: halo, (C)1-C6) Alkyl, (C)2-C6) Alkenyl, (C)2-C6) Alkynyl, perhalogenated (C)1-C6) Alkyl, phenyl, (C)1-C10) Heteroaryl, (C)1-C10) Heterocyclic group, (C)3-C10) Cycloalkyl, hydroxy, (C)1-C6) Alkoxy, perhalogenated (C)1-C6) Alkoxy, phenoxy, (C)1-C10) heteroaryl-O-, (C)1-C10) heterocyclyl-O-, (C)3-C10) cycloalkyl-O-, (C)1-C6) alkyl-S-, (C)1-C6) alkyl-SO2-、(C1-C6) alkyl-NH-SO2-、-NO2Amino group, (C)1-C6) Alkylamino [ (C)1-C6) Alkyl radical]2Amino group, (C)1-C6) alkyl-SO2-NH-、(C1-C6) Alkyl- (C ═ O) -NH-, (C)1-C6) Alkyl- (C ═ O) - [ ((C)1-C6) Alkyl) -N]-, phenyl- (C ═ O) -NH-, phenyl- (C ═ O) - [ ((C)1-C6) Alkyl) -N]-、-CN、(C1-C6) Alkyl- (C ═ O) -, phenyl- (C ═ O) -, and1-C10) Heteroaryl- (C ═O)-、(C1-C10) Heterocyclyl- (C ═ O) -, (C)3-C10) Cycloalkyl- (C ═ O) -, HO- (C ═ O) -, and1-C6) alkyl-O- (C ═ O) -, H2N(C＝O)-、(C1-C6) alkyl-NH- (C ═ O) -, [ (C)1-C6) Alkyl radical]2-N- (C ═ O) -, phenyl-NH- (C ═ O) -, phenyl- [ ((C)1-C6) Alkyl) -N]-(C＝O)-、(C1-C10) heteroaryl-NH- (C ═ O) -, (C)1-C10) heterocyclyl-NH- (C ═ O) -, (C)3-C10) cycloalkyl-NH- (C ═ O) -, (C)1-C6) Alkyl- (C ═ O) -O-and phenyl- (C ═ O) -O-. Other embodiments of the invention include compounds of formula I (and I (a), I (b), I (d), I (g)) wherein R6Is R9-B-(CH2)n-; n is an integer from one to six, more preferably one to five, more preferably one to three; b is- (C ═ O) -R10-N-、-(R10-N)-、-SO2-(R10)-N-、-(R10-N)-(C＝O)-(NR11) -or- (R)10-N)-(C＝O)-O-；R9Is as described above and is compatible with each of the above I (a) R4Embodiment (I), (b) R5Embodiments or each of the foregoing R2
The embodiments are combined.
Another embodiment of the invention are compounds of formula I (and I (a), I (b), I (d), I (g)) wherein R6Is R9-B-(CH2)n-; n is an integer from one to six, more preferably one to five, more preferably one to three; b is a bond; r9Is R13-(R12CH)m-; m is 1 to 6; r10Is hydrogen or methyl; each R12Independently selected from the group consisting of hydrogen or methyl; r13Selected from the group consisting of: hydrogen, (C)1-C6) Alkyl, (C)2-C6) Alkenyl, (C)2-C6) Alkynyl, phenyl, (C)1-C10) Heteroaryl, (C)1-C10) Heterocyclic group, (C)3-C10) Cycloalkyl, hydroxy, (C)1-C6) Alkoxy, perhalogenated (C)1-C6) Alkoxy, phenoxy, (C)1-C10) heteroaryl-O-, (C)1-C10) heterocyclyl-O-, (C)3-C10) cycloalkyl-O-, (C)1-C6) alkyl-S-, (C)1-C6) alkyl-SO2-、(C1-C6) alkyl-NH-SO2-、-NO2Amino group, (C)1-C6) Alkylamino [ (C)1-C6) Alkyl radical]2Amino group, (C)1-C6) alkyl-SO2-NH-, phenyl-SO2-NH-、(C1-C6) alkyl-SO2-[((C1-C6) Alkyl) -N]-, phenyl-SO2-[((C1-C6) Alkyl) -N]-、(C1-C6) Alkyl- (C ═ O) -NH-, (C)1-C6) Alkyl- (C ═ O) - [ ((C)1-C6) Alkyl) -N]-, phenyl- (C ═ O) -NH-, phenyl- (C ═ O) - [ ((C)1-C6) Alkyl) -N]-、-CN、(C1-C6) Alkyl- (C ═ O) -, phenyl- (C ═ O) -, and1-C10) Heteroaryl- (C ═ O) -, (C)1-C10) Heterocyclyl- (C ═ O) -, (C)3-C10) Cycloalkyl- (C ═ O) -, HO- (C ═ O) -, and1-C6) alkyl-O- (C ═ O) -, H2N(C＝O)-、(C1-C6) alkyl-NH- (C ═ O) -, [ (C)1-C6) Alkyl radical]2-N- (C ═ O) -, phenyl-NH- (C ═ O) -, phenyl- [ ((C)1-C6) Alkyl) -N]-(C＝O)-、(C1-C10) heteroaryl-NH- (C ═ O) -, (C)1-C10) heterocyclyl-NH- (C ═ O) -, (C)3-C10) cycloalkyl-NH- (C ═ O) -, (C)1-C6) Alkyl- (C ═ O) -O-and phenyl- (C ═ O) -O-. Other embodiments of the invention include compounds of formula I (and I (a), I (b), I (d), I (g)) wherein R6Is R9-B-(CH2)n-; n is an integer from one to six, more preferably one to five, more preferably one to three; b is- (C ═ O) -R10-N-、-(R10-N)-、-SO2-(R10)-N-、-(R10-N)-(C＝O)-(NR11) -or- (R)10-N)-(C＝O)-O-；R9Is R13-(R12CH)m-; m is 1 to 6; r10Is hydrogen or methyl; each R12Independently selected from the group consisting of hydrogen or methyl; r13Is as described above and is compatible with each of the above I (a) R4Embodiment (I), (b) R5Embodiments or each of the foregoing R2The embodiments are combined.
Another embodiment of the invention are the compounds of formula I, wherein s is an integer from zero to four, and each R is3Independently selected from the group consisting of: halo, (C)1-C6) Alkyl, (C)2-C6) Alkenyl, (C)2-C6) Alkynyl, perhalogenated (C)1-C6) Alkyl, phenyl, (C)1-C10) Heteroaryl, (C)1-C10) Heterocyclic group, (C)3-C10) Cycloalkyl, hydroxy, (C)1-C6) Alkoxy, perhalogenated (C)1-C6) Alkoxy, phenoxy, (C)1-C10) heteroaryl-O-, (C)1-C10) heterocyclyl-O-, (C)3-C10) cycloalkyl-O-, (C)1-C6) alkyl-S-, (C)1-C6) alkyl-SO2-、(C1-C6) alkyl-NH-SO2-、-NO2Amino group, (C)1-C6) Alkylamino [ (C)1-C6) Alkyl radical]2Amino group, (C)1-C6) alkyl-SO2-NH-、(C1-C6) Alkyl- (C ═ O) -NH-, (C)1-C6) Alkyl- (C ═ O) - [ ((C)1-C6) Alkyl) -N]-, phenyl- (C ═ O) -NH-, phenyl- (C ═ O) - [ ((C)1-C6) Alkyl) -N]-、-CN、(C1-C6) Alkyl- (C ═ O) -, phenyl- (C ═ O) -, and1-C10) Heteroaryl- (C ═ O) -, (C)1-C10) Heterocyclyl- (C ═ O) -, (C)3-C10) Cycloalkyl- (C ═ O) -, HO- (C ═ O) -, and1-C6) alkyl-O- (C ═ O) -, H2N(C＝O)-、(C1-C6) alkyl-NH- (C ═ O) -, [ (C)1-C6) Alkyl radical]2-N- (C ═ O) -, phenyl-NH- (C ═ O) -, phenyl- [ ((C)1-C6) Alkyl) -N]-(C＝O)-、(C1-C10) heteroaryl-NH- (C ═ O) -, (C)1-C10) heterocyclyl-NH- (C ═ O) -, (C)3-C10) cycloalkyl-NH- (C ═ O) -and (C)1-C6) Alkyl- (C ═ O) -O-. Other embodiments of the invention include compounds of formula I (and I (a), I (b), I (c), I (d), I (e), I (f), and I (g)) wherein R is3Is as defined above and each of the above R6Embodiment mode R7Embodiment mode R4Embodiment mode R5Embodiments or each of the foregoing R2The embodiments are combined.
Another embodiment of the invention are the compounds of formula I, wherein s is an integer from zero to four, and each R is3Independently selected from the group consisting of halo, -CN, (C)1-C6) Alkyl, (C)2-C6) Alkenyl, (C)2-C6) Alkynyl and perhalogenated (C)1-C6) Alkyl groups. Other embodiments of the invention include compounds of formula I (and I (a), I (b), I (c), I (d), I (e), I (f), and I (g)) wherein R is3Is as defined above and each of the above R6Embodiment mode R7Embodiment mode R4Embodiment mode R5Embodiments or each of the foregoing R2The embodiments are combined.
Another embodiment of the invention are the compounds of formula I, wherein s is an integer from zero to four, one or two R3Independently selected from the group consisting of halo, (C)1-C6) Alkyl, perhalogenated (C)1-C6) Alkyl, hydroxy, (C)1-C6) Alkoxy, perhalogenated (C)1-C6) Alkoxy group, (C)1-C6) Alkylamino [ (C)1-C6) Alkyl radical]2-amino, -CN and H2N (C ═ O) -. Other embodiments of the invention include those of formula I (and I (a), I (and I (b)), (I)b) I (c), I (d), I (e), I (f) and I (g) compounds, wherein R3Is as defined above and each of the above R6Embodiment mode R7Embodiment mode R4Embodiment mode R5Embodiments or each of the foregoing R2The embodiments are combined.
Another embodiment of the invention are the compounds of formula I, wherein s is an integer from zero to four, and one R is3Selected from phenyl, (C)1-C10) Heteroaryl, (C)1-C10) Heterocyclyl and (C)3-C10) Cycloalkyl groups. Other embodiments of the invention include compounds of formula I (and I (a), I (b), I (c), I (d), I (e), I (f), and I (g)) wherein R is3Is as defined above and each of the above R6Embodiment mode R7Embodiment mode R4Embodiment mode R5Embodiments or each of the foregoing R2The embodiments are combined.
Another embodiment of the invention are the compounds of formula I, wherein s is an integer from zero to four, and one R is3Selected from the group consisting of hydroxyl, (C)1-C6) Alkoxy, perhalogenated (C)1-C6) Alkoxy, phenoxy, (C)1-C10) heteroaryl-O-, (C)1-C10) heterocyclyl-O-, (C)3-C10) cycloalkyl-O-, (C)1-C6)-S-、(C1-C6) alkyl-SO2-and (C)1-C6)-NH-SO2-the group of compositions. Other embodiments of the invention include compounds of formula I (and I (a), I (b), I (c), I (d), I (e), I (f), and I (g)) wherein R is3Is as defined above and each of the above R6Embodiment mode R7Embodiment mode R4Embodiment mode R5Embodiments or each of the foregoing R2The embodiments are combined.
Another embodiment of the invention are the compounds of formula I, wherein s is an integer from zero to four, and one R is3Selected from amino, (C)1-C6) Alkyl, [ (C)1-C6) Alkyl radical]2-amino, (C)1-C6) alkyl-SO2-NH-、(C1-C6) Alkyl- (C ═ O) -NH-, (C)1-C6) Alkyl- (C ═ O) - [ ((C)1-C6) Alkyl) -N]-, phenyl- (C ═ O) -NH-and phenyl- (C ═ O) - [ ((C)1-C6) Alkyl) -N]-the group of compositions. Other embodiments of the invention include compounds of formula I (and I (a), I (b), I (c), I (d), I (e), I (f), and I (g)) wherein R is3Is as defined above and each of the above R6Embodiment mode R7Embodiment mode R4Embodiment mode R5Embodiments or each of the foregoing R2The embodiments are combined.
Another embodiment of the invention are the compounds of formula I, wherein s is an integer from zero to four, and one R is3Is selected from (C)1-C6) Alkyl- (C ═ O) -, phenyl- (C ═ O) -, and1-C10) Heteroaryl- (C ═ O) -, (C)1-C10) Heterocyclyl- (C ═ O) -, (C)3-C10) Cycloalkyl- (C ═ O) -, (C)1-C10) heteroaryl-NH- (C ═ O) -, (C)1-C10) heterocyclyl-NH- (C ═ O) -, (C)3-C10) cycloalkyl-NH- (C ═ O) -, HO- (C ═ O) -, and1-C6) alkyl-O- (C ═ O) -, H2N(C＝O)-、(C1-C6) alkyl-NH- (C ═ O) -, [ (C)1-C6) Alkyl radical]2-N- (C ═ O) -, phenyl-NH- (C ═ O) -, phenyl- [ ((C)1-C6) Alkyl) -N]- (C ═ O) -, and (C)1-C6) Alkyl- (C ═ O) -O-. Other embodiments of the invention include compounds of formula I (and I (a), I (b), I (c), I (d), I (e), I (f), and I (g)) wherein R is3Is as defined above and each of the above R6Embodiment mode R7Embodiment mode R4Embodiment mode R5Embodiments or each of the foregoing R2The embodiments are combined.
Another embodiment of the present invention is such a formula IA compound wherein s is an integer from zero to three, each R3Independently selected from the group consisting of halo, (C)1-C6) Alkyl, perhalogenated (C)1-C6) Alkyl, hydroxy, (C)1-C6) Alkoxy, perhalogenated (C)1-C6) Alkoxy, -NO2Amino group, (C)1-C6) Alkylamino [ (C)1-C6) Alkyl radical]2-amino, -CN and H2N (C ═ O) -. Other embodiments of the invention include compounds of formula I (and I (a), I (b), I (c), I (d), I (e), I (f), and I (g)) wherein R is3Is as defined above and each of the above R6Embodiment mode R7Embodiment mode R4Embodiment mode R5Embodiments or each of the foregoing R2The embodiments are combined.
Another embodiment of the invention are the compounds of formula I, wherein s is an integer from zero to two, each R3Independently selected from the group consisting of halo, (C)1-C6) Alkyl, perhalogenated (C)1-C6) Alkyl, (C)1-C6) Alkoxy, perhalogenated (C)1-C6) Alkoxy and-CN. Other embodiments of the invention include compounds of formula I (and I (a), I (b), I (c), I (d), I (e), I (f), and I (g)) wherein R is3Is as defined above and each of the above R6Embodiment mode R7Embodiment mode R4Embodiment mode R5Embodiments or each of the foregoing R2The embodiments are combined.
Another embodiment of the invention are the compounds of formula I, wherein s is an integer from zero to three, and each R is3Independently selected from the group consisting of fluorine, chlorine and methyl. Other embodiments of the invention include compounds of formula I (and I (a), I (b), I (c), I (d), I (e), I (f), and I (g)) wherein R is3Is as defined above and each of the above R6Embodiment mode R7Embodiment mode R4Embodiment mode R5Embodiments or each of the foregoing R2Implementation methodThe formula (II) is combined.
Examples of particularly preferred compounds of formula I are as follows:
3-isopropyl-6- (4-phenyl-oxazol-5-yl) - [1, 2, 4] triazolo [4, 3-a ] pyridine;
3-ethyl-6- (4-m-tolyl-oxazol-5-yl) - [1, 2, 4] triazolo [4, 3-a ] pyridine;
3-cyclopropyl-6- [4- (4-fluoro-phenyl) -oxazol-5-yl ] - [1, 2, 4] triazolo [4, 3-a ] pyridine;
3-cyclobutyl-6- [4- (4-fluoro-phenyl) -oxazol-5-yl ] - [1, 2, 4] triazolo [4, 3-a ] pyridine;
3-cyclobutyl-6- (4-phenyl-oxazol-5-yl) - [1, 2, 4] triazolo [4, 3-a ] pyridine;
3-cyclopropyl-6- (4-phenyl-oxazol-5-yl) - [1, 2, 4] triazolo [4, 3-a ] pyridine;
3-ethyl-6- (4-phenyl-oxazol-5-yl) - [1, 2, 4] triazolo [4, 3-a ] pyridine;
3-ethyl-6- [4- (4-fluoro-phenyl) -oxazol-5-yl ] - [1, 2, 4] triazolo [4, 3-a ] pyridine;
6- [4- (4-fluoro-phenyl) -oxazol-5-yl ] -3-isopropyl- [1, 2, 4] triazolo [4, 3-a ] pyridine;
3-cyclobutyl-6- (4-m-tolyl-oxazol-5-yl) - [1, 2, 4] triazolo [4, 3-a ] pyridine;
3-isopropyl-6- (4-m-tolyl-oxazol-5-yl) - [1, 2, 4] triazolo [4, 3-a ] pyridine;
6- [4- (4-fluoro-3-methyl-phenyl) -oxazol-5-yl ] -3-isopropyl- [1, 2, 4] triazolo [4, 3-a ] pyridine;
3-cyclopropyl-6- [4- (4-fluoro-3-methyl-phenyl) -oxazol-5-yl ] - [1, 2, 4] triazolo [4, 3-pyridine;
6- [4- (4-fluoro-phenyl) -oxazol-5-yl ] -3-phenyl- [1, 2, 4] triazolo [4, 3-a ] pyridine;
3-isopropyl-6- (2-methyl-4-phenyl-oxazol-5-yl) - [1, 2, 4] triazolo [4, 3-a ] pyridine; and
6- [4- (4-fluoro-phenyl) -2-methyl-oxazol-5-yl ] -3-isopropyl- [1, 2, 4] triazolo [4, 3-a ] pyridine.
Other specific triazolopyridine compounds of formula I include the following:
6- [3- (4-fluoro-phenyl) -5-methyl-isoxazol-4-yl ] -3-isopropyl- [1, 2, 4] triazolo [4, 3-a ] pyridine;
3-difluoromethyl-6- (4-phenyl-oxazol-5-yl) - [1, 2, 4] triazolo [4, 3-a ] pyridine;
3-isoxazol-5-yl-6- (4-phenyl-oxazol-5-yl) - [1, 2, 4] triazolo [4, 3-a ] pyridine;
6- (4-phenyl-oxazol-5-yl) -3- (2, 2, 2-trifluoro-ethyl) - [1, 2, 4] triazolo [4, 3-a ] pyridine;
6- [3- (4-fluoro-phenyl) -5-methyl-isoxazol-4-yl ] -3-phenyl- [1, 2, 4] triazolo [4, 3-a ] pyridine;
6- [4- (2, 4-difluoro-phenyl) -oxazol-5-yl ] -3-isopropyl- [1, 2, 4] triazolo [4, 3-a ] pyridine;
6- [4- (4-fluoro-phenyl) -thiazol-5-yl ] -3-isopropyl- [1, 2, 4] triazolo [4, 3-a ] pyridine;
6- [4- (2, 4-difluoro-phenyl) -thiazol-5-yl ] -3-isopropyl- [1, 2, 4] triazolo [4, 3-a ] pyridine;
6- [3- (2, 4-difluoro-phenyl) -5-methyl-isoxazol-4-yl ] -3-isopropyl- [1, 2, 4] triazolo [4, 3-a ] pyridine;
6- [3- (2, 4-difluoro-phenyl) -5-methyl-isoxazol-4-yl ] -3-phenyl- [1, 2, 4] triazolo [4, 3-a ] pyridine;
[3- (4-fluoro-phenyl) -4- (3-isopropyl- [1, 2, 4] triazolo [4, 3-a ] pyridin-6-yl) -isoxazol-5-yl ] -methanol;
[4- (4-fluoro-phenyl) -5- (3-isopropyl- [1, 2, 4] triazolo [4, 3-a ] pyridin-6-yl) oxazol-2-yl ] methanol;
[4- (2, 4-difluoro-phenyl) -5- (3-isopropyl- [1, 2, 4] triazolo [4, 3-a ] pyridin-6-yl) -oxazol-2-yl ] -methanol;
6- [4- (3-chloro-4-fluoro-phenyl) -oxazol-5-yl ] -3-isopropyl- [1, 2, 4] triazolo [4, 3-a ] pyridine;
6- [5- (2, 4-difluoro-phenyl) -3H-imidazol-4-yl ] -3-isopropyl- [1, 2, 4] triazolo [4, 3-a ] pyridine;
6- [5- (4-fluoro-phenyl) -3H-imidazol-4-yl ] -3-isopropyl- [1, 2, 4] triazolo [4, 3-a ] pyridine;
6- [5- (4-fluoro-phenyl) -3-methyl-3H-imidazol-4-yl ] -3-isopropyl- [1, 2, 4] triazolo [4, 3-a ] pyridine;
6- [5- (4-fluoro-phenyl) -3-pyrrolidin-3-yl-3H-imidazol-4-yl ] -3-isopropyl [1, 2, 4] triazolo [4, 3-a ] pyridine;
6- [4- (4-fluoro-phenyl) -2-methyl-oxazol-5-yl ] -3-phenyl- [1, 2, 4] triazolo [4, 3-a ] pyridine;
6- [5- (4-fluoro-3-methyl-phenyl) -3H-imidazol-4-yl ] -3-phenyl- [1, 2, 4] triazolo [4, 3-a ] pyridine;
6- [4- (4-fluoro-3-methyl-phenyl) -oxazol-5-yl ] -3-phenyl- [1, 2, 4] triazolo [4, 3-a ] pyridine;
6- [3- (2, 4-difluoro-phenyl) -5-methyl-1H-pyrazol-4-yl ] -3-isopropyl- [1, 2, 4] triazolo [4, 3-a ] pyridine;
6- [3- (4-fluoro-phenyl) -5-methyl-1H-pyrazol-4-yl ] -3-phenyl- [1, 2, 4] triazolo [4, 3-a ] pyridine;
6- [3- (4-fluoro-phenyl) -5-methyl-1H-pyrazol-4-yl ] -3-isopropyl- [1, 2, 4] triazolo [4, 3-a ] pyridine;
6- [4- (3, 4-difluoro-phenyl) -oxazol-5-yl ] -3-isopropyl- [1, 2, 4] triazolo [4, 3-a ] pyridine;
6- [5- (3, 4-difluoro-phenyl) -3H-imidazol-4-yl ] -3-isopropyl- [1, 2, 4] triazolo [4, 3-a ] pyridine;
6- [5- (3, 4-difluoro-phenyl) -3-methyl-3H-imidazol-4-yl ] -3-isopropyl- [1, 2, 4] triazolo [4, 3-a ] pyridine;
6- [5- (2, 4-difluoro-phenyl) -2-methyl-3H-imidazol-4-yl ] -3-isopropyl- [1, 2, 4] triazolo [4, 3-a ] pyridine;
6- [ 3-azetidin-3-yl-5- (4-fluoro-phenyl) -3H-imidazol-4-yl ] -3-isopropyl- [1, 2, 4] triazolo [4, 3-a ] pyridine;
6- [4- (2, 4-difluoro-phenyl) -2-methyl-thiazol-5-yl ] -3-isopropyl- [1, 2, 4] triazolo [4, 3-a ] pyridine;
6- [4- (4-chloro-phenyl) -oxazol-5-yl ] -3-isopropyl- [1, 2, 4] triazolo [4, 3-a ] pyridine;
6- [4- (3-chloro-phenyl) -oxazol-5-yl ] -3-isopropyl- [1, 2, 4] triazolo [4, 3-a ] pyridine;
6- [5- (4-chloro-phenyl) -3H-imidazol-4-yl ] -3-isopropyl- [1, 2, 4] triazolo [4, 3-a ] pyridine;
6- [4- (3-fluoro-phenyl) -oxazol-5-yl ] -3-isopropyl- [1, 2, 4] triazolo [4, 3-a ] pyridine;
6- [5- (4-fluoro-phenyl) -2-piperidin-4-yl-3H-imidazol-4-yl ] -3-phenyl- [1, 2, 4] triazolo [4, 3-a ] pyridine;
2- [4- (4-fluoro-phenyl) -5- (3-phenyl- [1, 2, 4] triazolo [4, 3-a ] pyridin-6-yl) -1H-imidazol-2-yl ] -ethanesulfonamide;
4- (4-fluoro-phenyl) -5- (3-isopropyl- [1, 2, 4] triazolo [4, 3-a ] pyridin-6-yl) -1H-imidazole-2-carboxamide;
4- (4-fluoro-phenyl) -5- (3-phenyl- [1, 2, 4] triazolo [4, 3-a ] pyridin-6-yl) -1H-imidazole-2-carboxylic acid;
6- [5- (4-fluoro-phenyl) -1H-imidazol-4-yl ] -3-phenyl- [1, 2, 4] triazolo [4, 3-a ] pyridine;
3-isopropyl-6- (5-m-tolyl-1H-imidazol-4-yl) - [1, 2, 4] triazolo [4, 3-a ] pyridine;
3-phenyl-6- (5-m-tolyl-1H-imidazol-4-yl) - [1, 2, 4] triazolo [4, 3-a ] pyridine;
6- [5- (4-fluoro-phenyl) -3-pyrrolidin-3-yl-3H-imidazol-4-yl ] -3-phenyl- [1, 2, 4] triazolo [4, 3-a ] pyridine;
6- [5- (4-fluoro-phenyl) -2-methyl-1H-imidazol-4-yl ] -3-phenyl- [1, 2, 4] triazolo [4, 3-a ] pyridine;
3-isopropyl-6- (3-pyrrolidin-3-yl-5-m-tolyl-3H-imidazol-4-yl) - [1, 2, 4] triazolo [4, 3-a ] pyridine;
3-isopropyl-6- (2-methyl-5-m-tolyl-1H-imidazol-4-yl) - [1, 2, 4] triazolo [4, 3-a ] pyridine;
6- [5- (4-fluoro-phenyl) -2-piperazin-2-yl-1H-imidazol-4-yl ] -3-isopropyl- [1, 2, 4] triazolo [4, 3-a ] pyridine;
n- [4- (4-fluoro-phenyl) -5- (3-isopropyl- [1, 2, 4] triazolo [4, 3-a ] pyridin-6-yl) -1H-imidazol-2-yl ] -acetamide;
n- [4- (4-fluoro-phenyl) -5- (3-phenyl- [1, 2, 4] triazolo [4, 3-a ] pyridin-6-yl) -1H-imidazol-2-yl ] -acetamide;
3-isopropyl-6- (2-piperazin-2-yl-5-m-tolyl-1H-imidazol-4-yl) - [1, 2, 4] triazolo [4, 3-a ] pyridine;
n- [5- (3-isopropyl- [1, 2, 4] triazolo [4, 3-a ] pyridin-6-yl) -4-m-tolyl-1H-imidazol-2-yl ] -acetamide;
n- [5- (3-phenyl- [1, 2, 4] triazolo [4, 3-a ] pyridin-6-yl) -4-m-tolyl-1H-imidazol-2-yl ] -acetamide;
6- [5- (4-fluoro-phenyl) -2-piperidin-4-yl-1H-imidazol-4-yl ] -3-isopropyl [1, 2, 4] triazolo [4, 3-a ] pyridine;
3-isopropyl-6- (2-piperidin-4-yl-5-m-tolyl-3H-imidazol-4-yl) - [1, 2, 4] triazolo [4, 3-a ] pyridine;
6- [3- (4-fluoro-phenyl) -isothiazol-4-yl ] -3-isopropyl- [1, 2, 4] triazolo [4, 3-a ] pyridine;
3- (4-fluoro-phenyl) -4- (3-isopropyl- [1, 2, 4] triazolo [4, 3-a ] pyridin-6-yl) -isothiazole-5-carboxamide;
6- [3- (4-fluoro-phenyl) -isothiazol-4-yl ] -3-phenyl- [1, 2, 4] triazolo [4, 3-a ] pyridine;
6- [3- (4-fluoro-phenyl) -5-methyl-isothiazol-4-yl ] -3-isopropyl- [1, 2, 4] triazolo [4, 3-a ] pyridine;
3- (2-chloro-phenyl) -6- [3- (4-fluoro-phenyl) -1H-pyrazol-4-yl ] - [1, 2, 4] triazolo [4, 3-a ] pyridine;
4- [3- (2-chloro-phenyl) - [1, 2, 4] triazolo [4, 3-a ] pyridin-6-yl ] -5- (4-fluoro-phenyl) -2H-pyrazol-3-ylamine;
3- (2-chloro-phenyl) -6- (3-m-tolyl-1H-pyrazol-4-yl) - [1, 2, 4] triazolo [4, 3-a ] pyridine;
4- [3- (2-chloro-phenyl) - [1, 2, 4] triazolo [4, 3-a ] pyridin-6-yl ] -5-m-tolyl-2H-pyrazol-3-ylamine;
ethyl {6- [3- (4-fluoro-phenyl) -1H-pyrazol-4-yl ] - [1, 2, 4] triazolo [4, 3-a ] pyridin-3-yl } -acetate;
{6- [ 5-amino-3- (4-fluoro-phenyl) -1H-pyrazol-4-yl ] - [1, 2, 4] triazolo [4, 3-a ] pyridin-3-yl } -acetic acid ethyl ester;
n-ethyl-2- {6- [3- (4-fluoro-phenyl) -1H-pyrazol-4-yl ] - [1, 2, 4] triazolo [4, 3-a ] pyridin-3-yl } -acetamide;
2- {6- [ 5-amino-3- (4-fluoro-phenyl) -1H-pyrazol-4-yl ] - [1, 2, 4] triazolo [4, 3-a ] pyridin-3-yl } -N-ethyl-acetamide;
6- [3- (3-chloro-phenyl) -1H-pyrazol-4-yl ] -3-phenyl- [1, 2, 4] triazolo [4, 3-a ] pyridine;
5- (3-chloro-phenyl) -4- (3-phenyl- [1, 2, 4] triazolo [4, 3-a ] pyridin-6-yl) -2H-pyrazol-3-ylamine;
6- [3- (3-chloro-phenyl) -1H-pyrazol-4-yl ] -3-isopropyl- [1, 2, 4] triazolo [4, 3-a ] pyridine;
5- (3-chloro-phenyl) -4- (3-isopropyl- [1, 2, 4] triazolo [4, 3-a ] pyridin-6-yl) -2H-pyrazol-3-ylamine;
6- [3- (4-fluoro-phenyl) -1H-pyrazol-4-yl ] -3-isopropyl- [1, 2, 4] triazolo [4, 3-a ] pyridine;
5- (4-fluoro-phenyl) -4- (3-isopropyl- [1, 2, 4] triazolo [4, 3-a ] pyridin-6-yl) -2H-pyrazol-3-ylamine;
n- [5- (4-fluoro-phenyl) -4- (3-isopropyl- [1, 2, 4] triazolo [4, 3-a ] pyridin-6-yl) -2H-pyrazol-3-yl ] -N ', N' -dimethyl-ethane-1, 2-diamine;
2- [3- (4-fluoro-phenyl) -4- (3-isopropyl- [1, 2, 4] triazolo [4, 3-a ] pyridin-6-yl) -pyrazol-1-yl ] -N, N-dimethyl-acetamide;
6- [3- (4-chloro-phenyl) -1H-pyrazol-4-yl ] -3-isopropyl- [1, 2, 4] triazolo [4, 3-a ] pyridine;
6- [3- (4-fluoro-phenyl) -1H-pyrazol-4-yl ] -3-phenyl- [1, 2, 4] triazolo [4, 3-a ] pyridine;
5- (4-fluoro-phenyl) -4- (3-phenyl- [1, 2, 4] triazolo [4, 3-a ] pyridin-6-yl) -2H-pyrazol-3-ylamine;
6- [3- (2, 4-difluoro-phenyl) -1H-pyrazol-4-yl ] -3-phenyl- [1, 2, 4] triazolo [4, 3-a ] pyridine;
5- (2, 4-difluoro-phenyl) -4- (3-phenyl- [1, 2, 4] triazolo [4, 3-a ] pyridin-6-yl) -2H-pyrazol-3-ylamine;
2- [3- (4-fluoro-phenyl) -4- (3-phenyl- [1, 2, 4] triazolo [4, 3-a ] pyridin-6-yl) -pyrazol-1-yl ] -N, N-dimethyl-acetamide;
6- [3- (2, 4-difluoro-phenyl) -5-methyl-1H-pyrazol-4-yl ] -3-phenyl- [1, 2, 4] triazolo [4, 3-a ] pyridine;
2- [3- (2, 4-difluoro-phenyl) -4- (3-phenyl- [1, 2, 4] triazolo [4, 3-a ] pyridin-6-yl) -pyrazol-1-yl ] -N, N-dimethyl-acetamide;
6- [4- (3-fluoro-phenyl) -oxazol-5-yl ] -3-phenyl- [1, 2, 4] triazolo [4, 3-a ] pyridine;
ethyl [6- (4-m-tolyl-oxazol-5-yl) - [1, 2, 4] triazolo [4, 3-a ] pyridin-3-yl ] -acetate;
3- (2-chloro-phenyl) -6- (4-m-tolyl-oxazol-5-yl) - [1, 2, 4] triazolo [4, 3-a ] pyridine; and
3-phenyl-6- (4-m-tolyl-oxazol-5-yl) - [1, 2, 4] triazolo [4, 3-a ] pyridine.
The invention also includes isotopically-labeled compounds, which are identical to those recited in formula I, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as2H、3H、13C、14C、15N、18O、17O、31P、32P、35S、18F and36and (4) Cl. Compounds of the present invention, prodrugs thereof, and pharmaceutically acceptable salts of said compounds or of said prodrugs which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention. Certain isotopically-labelled compounds of the invention, e.g. incorporating a radioactive isotope (e.g. incorporating3H and14C) can be used in drug and/or substrate tissue distribution assays. Tritium, tritium,Namely, it is3H and carbon-14, i.e.14The C isotopes are particularly preferred because of their ease of preparation and detection. Further, by heavier isotopes, e.g. deuterium, i.e.2H, may be preferred in some cases because of the higher metabolic stability that may provide therapeutic benefits, such as increased in vivo half-life or reduced dosage requirements. Isotopically-labelled compounds of formula I of the present invention and prodrugs thereof can generally be prepared by substituting a readily available isotopically-labelled reagent for a non-isotopically-labelled reagent in the course of performing the procedures disclosed in the schemes and/or in the examples and preparations below.
A compound of formula I, or a pharmaceutically acceptable salt thereof, may be used in the manufacture of a medicament for the prophylactic or therapeutic treatment of any disease state in a human or other mammal that is exacerbated or caused by excessive or deregulated cytokine production by such mammalian cells, such as, but not limited to, monocytes and/or macrophages.
The compounds of formula (I) are capable of inhibiting proinflammatory cytokines such as IL-1, IL-6, IL-8 and TNF and are therefore useful in therapy. IL-1, IL-6, IL-8 and TNF affect a wide range of cells and tissues and these cytokines, as well as other leukocyte derived cytokines, are important determinant inflammatory mediators of a wide range of disease states and conditions. Inhibition of these pro-inflammatory cytokines is beneficial in controlling, reducing and alleviating many of these disease states.
Accordingly, the present invention provides a method of treating a cytokine mediated disease comprising administering an effective cytokine interfering amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
Certain compounds of formula (I) are capable of inhibiting induced proinflammatory proteins, such as COX-2, which has many other names, such as prostaglandin endoperoxide synthase-2 (PGHS-2), and are therefore useful in therapy. The pro-inflammatory lipid mediators of these Cyclooxygenase (COX) pathways are produced by an inducible COX-2 enzyme. Thus, the COX-2 regulation responsible for these arachidonic acid derived products, such as prostaglandins, affects a wide range of cells and tissues. The expression of COX-1 is not affected by the compound of formula (I). This selective inhibition of COX-2 is recognized as reducing or diminishing the propensity for ulceration associated with COX-1 inhibition, thereby inhibiting prostaglandins, which are essential for cytoprotective effects. Thus, inhibition of these proinflammatory mediators is beneficial in controlling, reducing and alleviating many of these disease states. These inflammatory mediators, specifically prostaglandins, have been most prominently involved in pain, for example in the sensitization of pain receptors, or in edema. Thus, pain management in this regard includes the treatment of neuromuscular pain, headache, cancer pain, and arthritic pain. The compounds of formula (I) or pharmaceutically acceptable salts thereof are useful in therapy in humans or other mammals by inhibiting the synthesis of COX-2 enzyme.
Accordingly, the present invention provides a method of inhibiting COX-2 synthesis comprising administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. The invention also provides methods of treating humans or other mammals by inhibiting the synthesis of COX-2 enzyme.
Specifically, the compounds of formula (I) or pharmaceutically acceptable salts thereof may be used to treat any disease state in humans or other mammals that is exacerbated or caused by excessive or deregulated IL-1, IL-8 or TNF production by such mammalian cells, such as, but not limited to, monocytes and/or macrophages.
Thus, in another aspect, the present invention relates to a method of inhibiting IL-1 production in a mammal in need thereof, comprising administering to said mammal an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
There are many disease states in which excessive or deregulated IL-production is involved in exacerbating and/or causing the disease. These include rheumatoid arthritis, osteoarthritis, meningitis, ischemic and hemorrhagic stroke, neurotrauma/occlusive head injury, stroke, endotoxemia and/or toxic shock syndrome, other acute or chronic inflammatory disease states such as inflammatory reactions or inflammatory bowel disease induced by endotoxin, tuberculosis, atherosclerosis, muscle degeneration, multiple sclerosis, cachexia, bone resorption, psoriatic arthritis, reiter's syndrome, rheumatoid arthritis, gout, traumatic arthritis, rubella arthritis and acute synovitis. Recent evidence has also linked IL-1 activity to diabetes, pancreatic beta cell disease, and Alzheimer's disease.
Treatment of p38 mediated disease states with p38 inhibitors may include, but is not limited to, neurodegenerative diseases such as alzheimer's disease, parkinson's disease, and multiple sclerosis, among others. In a further aspect, the present invention relates to a method of inhibiting TNF production in a mammal in need thereof, which comprises administering to said mammal an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
Excessive or unregulated TNF production has been implicated in mediating or exacerbating a number of diseases including rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other joint conditions; sepsis, septic shock, endotoxic shock, gram-negative sepsis, toxic shock syndrome, adult respiratory distress syndrome, stroke, cerebral malaria, chronic obstructive pulmonary disease, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcoidosis, bone resorption diseases such as osteoporosis, cardiac, brain and kidney reperfusion injury, graft-to-host reaction, allograft rejection, fever and myalgia resulting from infection, such as influenza (including HIV-induced types), cerebral malaria, meningitis, ischemic and hemorrhagic stroke, cachexia secondary to infection or malignancy, cachexia secondary to Acquired Immune Deficiency Syndrome (AIDS), AIDS, ARC (AIDS-related complex), keloid formation, scar tissue formation, inflammatory bowel disease, crohn's disease, ulcerative colitis, and heartburn.
The compounds of formula (I) are also useful in the treatment of viral infections where such viruses are susceptible to upregulation of TNF, or will cause TNF production in vivo. The viruses targeted for treatment herein are those that produce TNF as a result of infection, or those that are susceptible to inhibition by TNF-inhibiting compounds of formula (I), e.g., reducing replication, either directly or indirectly. Such viruses include, but are not limited to, HIV-1, HIV-2 and HIV-3, Cytomegalovirus (CMV), influenza, adenovirus, and viruses of the herpes class, such as, but not limited to, herpes zoster and herpes simplex. Thus, in a further aspect, the present invention relates to a method of treating a mammal having Human Immunodeficiency Virus (HIV), comprising administering to such mammal an effective TNF inhibiting amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
The compounds of formula (I) may also be used in veterinary therapy of mammals other than humans in need of inhibition of TNF production. TNF-mediated animal diseases include those disease states described above, but are specifically viral infections. Examples of such viral infections include, but are not limited to, lentivirus infections, such as equine infectious anemia virus, caprine arthritis virus, ovine myelinating virus, dyspnea virus, or retroviral infections, such as, but not limited to, Feline Immunodeficiency Virus (FIV), bovine immunodeficiency virus, or canine immunodeficiency virus or other retroviral infections.
The compounds of formula (I) may also be used topically for the treatment of local disease states mediated or exacerbated by excessive cytokine production, such as IL-1 or TNF, respectively, such as joint inflammation, eczema, contact dermatitis, psoriasis and other inflammatory skin conditions, such as sunburn; inflammatory ocular disorders including conjunctivitis; burning, pain, and other inflammation-related conditions. Periodontal disease is also caused by local and systemic production of cytokines. Thus, the use of a compound of formula (I) is a further aspect of the invention for the control of inflammation associated with cytokine production in such oral diseases, such as gingivitis and periodontitis.
The compounds of formula (I) have also been shown to inhibit the production of IL-8 (interleukin-8, NAP). Thus, in a further aspect, the present invention relates to a method of inhibiting IL-8 production in a mammal in need thereof, which comprises administering to said mammal an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
There are many disease states in which excessive or deregulated IL-8 production is involved in exacerbating and/or causing the disease. These diseases are characterized by a massive neutrophil infiltration, such as psoriasis, inflammatory bowel disease, asthma, cardiac and renal reperfusion injury, adult respiratory distress syndrome, thrombosis, and glomerulonephritis. All of these diseases are associated with increased production of IL-8, IL-8 being responsible for chemotaxis of neutrophils to inflammatory sites. In contrast to other inflammatory cytokines (IL-1, TNF, and IL-6), IL-8 has unique properties that promote chemotaxis and activation of neutrophils. Therefore, inhibition of IL-8 production will directly reduce neutrophil infiltration.
The compounds of formula (I) are administered in an amount sufficient to inhibit the production of cytokines, particularly IL-1, IL-6, IL-8 or TNF, so as to down-regulate to normal levels, or in some cases to below normal levels, in order to ameliorate or prevent a disease state. In the context of the present invention, abnormal IL-1, IL-6, IL-8 or TNF levels constitute: (i) free (cell-unbound) IL-1, IL-6, IL-8, or TNF levels greater than or equal to 1 picogram per ml; (ii) IL-1, IL-6, IL-8 or TNF optionally associated with a cell; or (iii) IL-1, IL-6, IL-8 or TNF is present in cells or tissues producing IL-1, IL-6, IL-8 or TNF, respectively, above basal levels.
The discovery that compounds of formula (I) are inhibitors of cytokines, particularly IL-1, IL-6, IL-8 and TNF, is based on the effect of compounds of formula (I) on IL-1, IL-8 and TNF production in vitro assays, such as those described herein or well known to those skilled in the art.
The term "inhibiting IL-1(IL-6, IL-8 or TNF) production" as used herein refers to:
a) reducing in vivo excessive cytokine (IL-1, IL-6, IL-8 or TNF) levels in humans to normal or subnormal levels by inhibiting the in vivo release of cytokines from all cells, including but not limited to monocytes or macrophages;
b) down-regulating, at the genomic level, excessive in vivo levels of a cytokine (IL-1, IL-6, IL-8 or TNF) in humans to normal or below normal levels;
c) down-regulated to normal or below normal levels by inhibiting direct synthesis of cytokines (IL-1, IL-6, IL-8 or TNF) as a post-translational event; or
d) Downregulating, at the translational level, excessive cytokine (IL-1, IL-6, IL-8 or TNF) levels in humans to normal or subnormal levels.
As used herein, the term "TNF-mediated disease or condition" refers to any and all conditions in which TNF plays a role either through its own production or by causing the release of another monokine, such as but not limited to IL-1, IL-6 or IL-8. For example, a disease state in which IL-1 is the major component and its production or action is exacerbated or secreted in response to TNF would therefore be considered a disease state mediated by TNF.
The term "cytokine" as used herein refers to any secreted polypeptide that affects the function of cells and is a molecule that modulates interactions between cells in the immune, inflammatory or hematopoietic response. Cytokines include, but are not limited to, monokines and lymphokines, regardless of which cell produces them. For example, monokines are considered to be produced and secreted by monocytes, such as macrophages and/or monocytes. However, many other cells also produce monokines, such as neutrophils, fibroblasts, basophils, neutrophils, endothelial cells, brain astrocytes, bone marrow stromal cells, epidermal keratinocytes and B lymphocytes. Lymphokines are generally thought to be produced by lymphocytes. Examples of cytokines include, but are not limited to, interleukin-1 (IL-1), interleukin-6 (IL-6), interleukin-8 (IL-8), tumor necrosis factor-alpha (TNF-alpha), and tumor necrosis factor-beta (TNF-beta).
The term "cytokine interfering" or "cytokine inhibitory amount" as used herein refers to an effective amount of a compound of formula (I) which, when administered to a patient, results in a reduction in the in vivo level of the cytokine to normal or below normal levels, for the treatment of a disease state exacerbated or caused by excessive or deregulated cytokine production.
As used herein, a cytokine in the phrase "inhibiting a cytokine for use in treating an HIV-infected person" is a cytokine that is involved in (a) initiating and/or maintaining T cell activation and/or T cell-mediated HIV gene expression and/or replication of activated T cells, and/or (b) any cytokine-mediated disease-related problems, such as cachexia or muscle degeneration.
Since TNF-beta (also known as lymphotoxin) has close structural homology to TNF-alpha (also known as cachectin) and both induce similar biological responses and bind to the same cellular receptor, both TNF-alpha and TNF-beta are inhibited by the compounds of the present invention and are therefore collectively referred to herein as "TNF" unless specifically described to the contrary.
A relatively new member of the MAP kinase family, known as CSBP, p38 or RK, has been identified by several laboratories (Lee et al, Nature, Vol.300, n (72), 739-. The activation of this protein kinase via bisphosphorylation has been observed in different cell systems, both with stimulation with a broad spectrum of stimuli, such as physicochemical stress responses, and with treatment with lipopolysaccharides or pro-inflammatory cytokines, such as interleukin-1 and tumor necrosis factor. The compounds of formula (I) of the present invention are cytokine biosynthesis inhibitors and have been determined to be potent selective inhibitors of CSBP/p38/RK kinase activity. These inhibitors help to determine the signaling pathways involved in the inflammatory response. Rather, the crucial signal transduction pathway can be assigned to the role of lipopolysaccharide in cytokine production by macrophages. In addition to those diseases already mentioned herein, treatment of stroke, neurotrauma/CNS head injury, cardiac, brain and kidney reperfusion injury, thrombosis, glomerulonephritis, diabetes and pancreatic beta cell disease, multiple sclerosis, muscle degeneration, eczema, psoriasis, sunburn and conjunctivitis are also included.
The anti-inflammatory activity of cytokine inhibitors was subsequently tested in a number of animal models. Model systems were chosen that were relatively insensitive to cyclooxygenase inhibitors in order to reveal the unique activity of cytokine inhibitors. These inhibitors exhibit significant activity in many of these in vivo studies. Most prominent is its effectiveness in a collagen-induced arthritis model and its inhibitory effect on TNF production in an endotoxic shock model. In the latter study, a decrease in plasma TNF levels was associated with survival and protection from survival from endotoxic shock-related death. Also of importance is the effectiveness of the compounds in inhibiting bone resorption in the rat embryonic long bone organ culture system. Griswold et al, (1988) Arthritis Rheum.31: 1406-1412; badger et al, (1989) circ. shock 27, 51-61; votta et al, (1994) in vitro. bone 15, 533-538; lee et al, (1993). B Ann.N.Y.Acad.Sci.696, 149-170.
It is also well established that both IL-6 and IL-8 are produced during rhinovirus (HRV) infection and are attributable to the common cold and increased asthma associated with HRV infection (Turner et al, (1998), Clin. Infec. Dis., Vol.26, p.840; Teren et al, (1997), am. J. Respir. Crit. Care Med., Vol.155, p.1362; Gruberg et al, (1997), am. J. Respir. Crit. Care Med., Vol.156, p.609; Zhu et al, J. Clin. invest. 1996, Vol.97, p 421). Infection of lung epithelial cells with HRV has also been shown to result in the production of IL-6 and IL-8 in vitro (Subauste et al, J.Clin.invest. (1995), Vol.96, p.549). Epithelial cells represent the major site of HRV infection. Thus, another aspect of the invention is a therapeutic method for reducing inflammation associated with rhinovirus infection, which is not necessarily a direct consequence of the virus itself.
Another aspect of the present invention relates to the novel use of these p 38/cytokine inhibitors for the treatment of chronic inflammatory or proliferative or angiogenic diseases resulting from excessive or inappropriate angiogenesis.
Chronic diseases with inappropriate angiogenesis factors are various ocular neovascularization such as diabetic retinopathy and macular degeneration. Other chronic diseases with excessive or increased vascular tissue proliferation are tumor growth and metastasis, atherosclerosis and certain joint inflammations. Thus, cytokine inhibitors would be useful in blocking the angiogenic factors of these disease states.
The term "excessive or increased proliferation of inappropriate formation of blood vessels" as used herein includes, but is not limited to, diseases characterized by hemangiomas and ocular diseases.
The term "inappropriate angiogenesis" as used herein includes, but is not limited to, diseases characterized by vesicle proliferation, with tissue proliferation, such as occurs in cancer, metastases, arthritis and atherosclerosis.
The invention also includes a method of treating or preventing a disorder treated or prevented by inhibiting ERK/MAP in a mammal, preferably a human, comprising administering to said mammal an effective amount of a compound of formula I.
Accordingly, the present invention provides a method of treating a p38 kinase mediated disease in a mammal, preferably a human, in need thereof which comprises administering to said mammal an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
Preferred p 38-mediated diseases to be treated include, but are not limited to, psoriatic arthritis, Laert's syndrome, rheumatoid arthritis, gout, traumatic arthritis, rubella arthritis and acute synovitis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other joint inflammations, sepsis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, Alzheimer's disease, stroke, ischemic and hemorrhagic stroke, neurotrauma/occlusive head injury, asthma, adult respiratory distress syndrome, chronic obstructive pulmonary disease, cerebral malaria, meningitis, chronic pulmonary inflammatory disease, silicosis, pulmonary myositis, bone resorption diseases, osteoporosis, restenosis, cardiac reperfusion injury, cerebral and renal reperfusion injury, chronic renal failure, thrombosis, glomerulonephritis, Diabetes, diabetic retinopathy, macular degeneration, graft-versus-host reactions, allograft rejection, inflammatory bowel disease, Crohn's disease, ulcerative colitis, neurodegenerative diseases, multiple sclerosis, muscle degeneration, diabetic retinopathy, macular degeneration, tumor growth and metastasis, angiogenic diseases, rhinovirus infections, oral diseases (such as gingivitis and periodontitis), eczema, contact dermatitis, psoriasis, sunburn and conjunctivitis.
The term "treating" as used herein refers to reversing, alleviating, inhibiting the progression of, or preventing the disorder or condition to which the term applies, or one or more symptoms of such disorder or condition. The term "treatment" as used herein refers to the action of treatment as just defined.
The invention also includes pharmaceutical compositions for treating a condition selected from the group consisting of: arthritis, psoriatic arthritis, reiter's syndrome, gout, traumatic arthritis, rubella arthritis and acute synovitis, rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other joint inflammations, sepsis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, alzheimer's disease, stroke, neurotrauma, asthma, adult respiratory distress syndrome, cerebral malaria, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcoidosis, bone resorption diseases, osteoporosis, restenosis, cardiac and renal reperfusion injury, thrombosis, glomerulonephritis, diabetes, graft-versus-host reaction, allograft rejection, inflammatory bowel disease, crohn's disease, ulcerative colitis, multiple sclerosis, muscle degeneration, eczema, contact dermatitis, rheumatoid arthritis, osteoarthritis, rheumatoid arthritis, chronic pulmonary inflammation, chronic pulmonary inflammatory disease, chronic pulmonary inflammatory bowel disease, pulmonary sarcoidosis, bone resorption diseases, osteoporosis, restenosis, cardiac and renal reperfusion injury, thrombosis, glomerulonephritis, diabetes, graft-versus-host reaction, inflammatory bowel disease, crohn's disease, ulcerative colitis, multiple sclerosis, muscle degeneration, eczema, contact dermatitis, Psoriasis, sunburn or conjunctivitis shock (conjectionvisshock), which composition comprises a therapeutically effective amount of a compound of formula I and a pharmaceutically acceptable carrier.
The invention also includes a pharmaceutical composition for treating a condition in a mammal, including a human, which is treated by inhibition of ERK/MAP kinase, which comprises a therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier.
The invention also includes a pharmaceutical composition for treating a condition in a mammal, including a human, which is treated by inhibition of p38 kinase, which composition comprises a therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier.
The invention also includes pharmaceutical compositions comprising prodrugs of compounds of formula I. Compounds of formula I having a free amino, amido, hydroxy or carboxy group can be converted into prodrugs. Prodrugs include compounds wherein an amino acid residue or a polypeptide chain of two or more (e.g., two, three or four) amino acid residues is covalently bonded via a peptide bond to a free amino, hydroxyl or carboxyl group of the compound of formula I. Amino acid residues include the 20 naturally occurring amino acids, generally indicated by three letter symbols, and also include 4-hydroxyproline, hydroxylysine, streptavidin (demosine), isostreptavidin, 3-methylhistidine, norvaline, β -alanine, γ -aminobutyric acid, citrulline, homocysteine, homoserine, ornithine and methionine sulfone. Prodrugs also include compounds wherein carbonates, carbamates, amides and alkyl esters are covalently bonded to the above substituents of formula I through the carbonyl carbon prodrug side chain.
The invention also includes sustained release compositions.
One of ordinary skill in the art will appreciate that the compounds of the present invention may be used to treat diseases in different combinations. One of ordinary skill in the art will also appreciate that in treating a particular disease with a compound of the present invention, the disease can be treated in combination with a variety of existing therapeutic agents.
With respect to the treatment of rheumatoid arthritis, the compounds of the present invention may be combined with such agents as TNF- α inhibitors, such as anti-TNF monoclonal antibodies (e.g., Remicade, CDP-870 and D)2E7) And TNF receptor immunoglobulin molecules (e.g., Enbrel ), COX-2 inhibitors (e.g., celecoxib, rofecoxib, valdecoxib, and etoricoxib), small doses of methotrexate, leflunomide, hydroxychloroquine, d-penicillamine, auranofin, or gold for parenteral or oral administration.
The compounds of the present invention may also be used in combination with existing therapeutic agents for the treatment of osteoarthritis. Suitable drugs for combined use include standard non-steroidal anti-inflammatory agents (hereinafter NSAIDs) such as piroxicam, diclofenac, propionic acids such as naproxen, flubiprofen, fenoprofen, ketoprofen and ibuprofen, fenamates such as mefenamic acid, indomethacin, sulindac, azapropazone, pyrazolones such as phenylbutazone, salicylates such as aspirin, COX-2 inhibitors such as celecoxib, valdecoxib, rofecoxib and etoricoxib, analgesics and intra-articular therapies such as corticosteroids, and hyaluronic acids such as hyalgan and synvisc.
The compounds of the invention may also be used in combination with anticancer agents, such as endostatin and angiostatin, or cytotoxic agents, such as doxorubicin, daunorubicin, cisplatin, etoposide, paclitaxel, taxotere, and alkaloids, such as vincristine, farnesyl transferase inhibitors, VegF inhibitors, and antimetabolite agents, such as methotrexate.
The compounds of the invention may also be used in combination with antiviral agents, such as Viracept, AZT, acyclovir and famciclovir, and antibacterial compounds, such as Valant.
The compounds of the present invention may also be used in combination with cardiovascular agents, such as calcium channel blockers, lipid lowering agents, such as statins, fibrates, beta-blockers, ACE inhibitors, angiotensin-2 receptor antagonists and platelet aggregation inhibitors.
The compounds of the present invention may also be used in combination with CNS agents such as antidepressants (e.g., sertraline), antiparkinsonian agents (e.g., benzethynylamine, L-dopa, Requip, Mirapex, MAOB inhibitors such as selegiline and rasagiline, comP inhibitors such as Tasmar, A-2 inhibitors, dopamine reuptake inhibitors, NMDA antagonists, nicotinic agonists, dopamine agonists and neuronal nitric oxide synthase inhibitors) and anti-Alzheimer's disease agents (e.g., donepezil, tacrine, COX-2 inhibitors, propentofylline or metrazine esters).
The compounds of the invention may also be used in combination with an osteoporosis agent, such as raloxifene, droloxifene, lasofoxifene or fosomax, and an immunosuppressant, such as FK-506 and rapamycin.
Detailed description of the invention
The compounds of formula I may be prepared according to the following reaction schemes and discussions. Unless indicated to the contrary, m, n, p, s, B, R in the reaction schemes and the discussion that follows1To R16And Het and structural formula I are as defined above.
Scheme 1
Scheme 2
Scheme 3
Scheme 4
Scheme 5
Scheme 6
Scheme 7
Scheme 8
Scheme 1 involves the preparation of compounds of formula I from compounds of formula III in two steps. Referring to scheme 1, compounds of formula III-wherein L is a suitable leaving group, e.g., fluoro, bromo, chloro or methylsulfonyl (MeSO)2) Preferably bromine or chlorine, is thus converted to the corresponding compound of formula II, reacted with hydrazine to form the hydrazinopyridine, and then reacted with an acylating agent. The reaction of the compound of the formula III with hydrazine is carried out in a polar solvent, such as pyridine, ethanol or tert-butanol, or in pure hydrazine, preferably in pure hydrazine. The reaction with hydrazine is carried out at a temperature of about 40 ℃ to about 80 ℃, preferably about 70 ℃ for about 10 minutes to about 60 minutes, preferably about 15 minutes. The acylation of the resulting hydrazinopyridine to provide the compound of formula II is carried out using an acid chloride in the presence of a base, such as triethylamine, in a solvent, such as dichloromethane, tetrahydrofuran, N-dimethylformamide, preferably dichloromethane, for a period of time between about 10 minutes and about 120 minutes, preferably about 30 minutes, at a temperature of about 0 ℃ to about 22 ℃, preferably about 0 ℃. Alternatively, hydrazinopyridines are acylated with carboxylic acids to give compounds of formula II using amide coupling agents in a manner well known to those skilled in the art.
The compounds of formula II can be converted into compounds of formula I: using a suitable dehydrating agent, or under conditions promoting cyclodehydration. Suitable dehydrating agents for the conversion of compounds of formula II to compounds of formula I include phosphorus oxychloride and dichlorotriphenylphosphorane, preferably phosphorus oxychloride. The reaction using phosphorus oxychloride is carried out in neat phosphorus oxychloride at a temperature of between about 60 ℃ and about 110 ℃ for a time of between about 2 hours and about 16 hours. The reaction using dichlorotriphenylphosphorane is carried out in the presence of a base, such as triethylamine, in a polar solvent, such as acetonitrile, at a temperature of about 60 ℃ to reflux for a period of from about 1 hour to about 8 hours.
The compound of formula III may be prepared according to the method of scheme 2.
Scheme 2 relates to the preparation of compounds of formula III, which are intermediates useful in the preparation of compounds of formula I in scheme 1. Referring to scheme 2, compounds of formula III-wherein (R)3)sphenyl-Het of formula (c) or (f) can be prepared from compounds of formula VII by reaction with an aminating agent. Suitable aminating agents include those of formula H in polar solvents2N-NH-R7A hydrazine. Suitable solvents include alcohols such as ethanol, propanol, butanol or mixtures of alcohols with acetic acid, preferably ethanol or ethanol/acetic acid. The above reaction is carried out at a temperature of about 10 ℃ to about 100 ℃, preferably about 22 ℃ to 65 ℃, for about 1 hour to about 24 hours, preferably about 3 hours.
Or, a compound of formula III-wherein (R)3)s-phenyl-Het is of formula (e) -may be prepared from a compound of formula VII by reaction with hydroxylamine hydrochloride and a base. Suitable bases include pyridine or trialkylamines, with pyridine being preferred. Suitable solvents include N, N-dimethylformamide, tetrahydrofuran or pyridine, preferably pyridine. The above reaction is carried out at a temperature of about 0 ℃ to about 100 ℃, preferably about 60 ℃ for about 1 hour to about 48 hours, preferably about 20 hours.
The compound of formula VII is prepared from a compound of formula IV by reacting an acetal, such as dimethylformamide-dimethylacetal, at a temperature of from about 60 c to about 90 c, preferably about 80 c, for a period of from about 1 hour to about 6 hours, preferably about 3 hours.
Or, a compound of formula III-wherein (R)3)s-phenyl-Het is of sub-formula (c) or (f) -may be prepared from a compound of formula VIII: by a process analogous to the conversion of the compound of formula VII to the compound of formula III, with an aminating agent, e.g. H2N-NH-R7。
Or, a compound of formula III-wherein (R)3)s-phenyl-Het is of formula (e) -may be prepared from compounds of formula VIII: following a procedure analogous to the conversion of the compound of formula VII to the compound of formula III, reaction with hydroxylamine hydrochloride is carried out.
The compound of formula VIII is prepared from the compound of formula IV by reaction with an isothiocyanate. Suitable isothiocyanates include those of formula R4-N ═ C ═ S compounds. The reaction with the isothiocyanate is facilitated by the addition of a base, such as sodium hydride, lithium diisopropylamide, or other suitable strong base. Suitable solvents for the above reaction include pyridine, N-dimethylformamide or tetrahydrofuran, preferably pyridine. The above reaction is carried out at a temperature of about 0 ℃ to about 30 ℃ for about 0.5 hours to about 4 hours. Following the deprotonation reaction with the base described above, the appropriate isothiocyanate is added and carried out at a temperature of about 0 ℃ to about 30 ℃ for about 10 minutes to about 20 hours, preferably about 22 ℃ for about 0.5 hours to about 24 hours.
Or, a compound of formula III-wherein (R)3)s-phenyl-Het is of formula (d) -may be prepared from compounds of formula VI with R in the presence of cuprous acetate and a source of ammonia in a polar solvent6- (C ═ O) -H aldehyde reaction. Suitable ammonia sources include ammonium trifluoroacetate, ammonia and ammonium acetate, with ammonium acetate being preferred. The above reaction may be carried out neat or in the presence of a solvent, such as an alcohol (methanol, ethanol or butanol) and acetic acid. The above reaction may be carried out at a temperature of about 20 ℃ to about 80 ℃ for about 15 minutes to about 4 hours, preferably under pure conditions, at about 60 ℃ for about 2 hours.
The compound of formula VI is prepared from the compound of formula V by reacting sodium methoxide, or sodium ethoxide, or sodium tert-butoxide, preferably sodium methoxide, in an alcoholic solvent such as methanol, ethanol, isopropanol, preferably methanol, at a temperature of 0 ℃ to 30 ℃, preferably 22 ℃, for a period of from 15 minutes to about 3 hours, preferably 30 minutes. The above reaction is followed by an aqueous acidic operation.
The compound of the formula V isBy reacting a compound of formula IV with Br in a polar solvent2Prepared by reaction. Suitable solvents include acetic acid, chloroform or dichloromethane, preferably acetic acid. The above reaction is carried out at a temperature of about 0 ℃ to about 30 ℃, preferably about 22 ℃ (room temperature) for about 10 minutes to about 4 hours, preferably about 30 minutes.
Or, a compound of formula III-wherein (R)3)s-phenyl-Het is of formula (a) -may be prepared from a compound of formula IX by reaction with a source of ammonia and cuprous acetate in a polar solvent. Suitable ammonia sources include ammonium trifluoroacetate, ammonia and ammonium acetate, with ammonium acetate being preferred. The above reaction may be carried out neat or in the presence of a solvent, such as an alcohol (methanol, ethanol or butanol) and acetic acid. The above reaction may be carried out at a temperature of about 20 ℃ to about 80 ℃ for about 15 minutes to about 4 hours, preferably under pure conditions, at about 60 ℃ for about 2 hours.
The compound of formula IX is prepared by reacting a compound of formula IV with a reagent of the formula,
wherein L is a leaving group such as chloro, bromo, iodo or methanesulfonyl. Suitable bases include NaH and n-butyllithium. Suitable solvents include THF and DMF. The above reaction may be carried out at a temperature of about-30 ℃ to the reflux temperature of the solvent for about 5 minutes to about 24 hours.
Alternatively, the compound of formula iii (e) may be prepared from formula IV according to the methods described in US5,859,257 or US5,633,272.
The compounds of formulae IV and VI are prepared according to the method of scheme 6. Additional synthetic routes involving compounds of formula IV are described in the literature: davies, i.w.; marcoux, j. -f.; culey, e.g.; journet, m.; cai, d.w.; palucki, m.; wu, j.; larsen, r.d.; rossen, k.; pye, p.j.; dimichole, l.; dormer, p.; reider, p.j.; J.Orq.chem., Vol.65, pp.8415-8420 (2000). The compounds of formula X are prepared by methods well known to those skilled in the art.
Alternatively, the compounds of formulae III (g) and (h) may be prepared from the compounds of formula IV as described in the literature (Gauthier, J.Y.; Leblanc, Y.; Black, C.; Chan, C. -C.; Cromlish, W.A.; Gordon, R.; Kennedey, B.P.; Lau, C.K.; Leger, S.; Wang, Z.; Ethier, D.; Guay, J.; Mancini, J.; Riendeu, D.; Tagari, P.; Vickers, P.; Wong, E.; Xu, L.; Prasit, P.Bioorg.Med.Chem.Lett.1996, 6, 87-92).
Scheme 3 relates to compounds of formula III-wherein (R)3)s-phenyl-Het is a preparation of formula (b) or (d), which are intermediates in scheme 1, useful for preparing compounds of formula I. Referring to scheme 3, compounds of formula III-wherein (R)3)sphenyl-Het is of formula (b) may be prepared by reaction of a compound of formula XI with a compound of formula in the presence of a polar solvent,
suitable solvents include N, N-dimethylformamide, chloroform, dimethyl sulfoxide, tetrahydrofuran and ethanol, preferably N, N-dimethylformamide. The above reaction is carried out at a temperature of about 15 c to about 80 c, preferably 60 c, for about 4 hours to about 4 days, preferably 4 hours.
Or, a compound of formula III-wherein (R)3)s-phenyl-Het is of formula (d) -can be prepared by conversion of a compound of formula XI with a compound of formula R in the presence of a catalyst and a source of ammonia in a manner analogous to that of the conversion of a compound of formula VI in scheme 2 to a compound of formula III6- (C ═ O) -H aldehyde.
A compound of formula XI wherein (R)3)s-phenyl-Het is of formula (d) -is prepared by reacting a compound of formula XII in an alcoholic solvent such as methanol, ethanol, isopropanol, preferably methanol, with sodium methoxide, or sodium ethoxide, or sodium tert-butoxide, preferably sodium methoxide, at 0 deg.CTo 30 c, preferably 22 c, for a period of from 15 minutes to about 3 hours, preferably 30 minutes. The above reaction is followed by an aqueous acidic operation.
The compounds of the formula XII are prepared by reacting a compound of the formula XIV with Br in a polar or nonpolar solvent2Prepared by reaction. Suitable solvents include acetic acid, dichloromethane, chloroform, preferably acetic acid. The above reaction is carried out at a temperature of about 0 ℃ to about 30 ℃, preferably about 22 ℃ (room temperature) for about 10 minutes to 4 hours, preferably 30 minutes.
The compound of formula XIV is prepared by reacting a compound of formula XV (wherein P2And P3Independently is (C)1-C6) Alkyl) with a compound of formula (R) in a solvent3)s-phenyl- (CH)2) M Grignard reagent (where M is an activating group, such as magnesium bromide or chloride). Suitable solvents include tetrahydrofuran, diethyl ether, dioxane, dimethylether, preferably tetrahydrofuran. The above reaction is carried out at a temperature of about 0 ℃ to about 30 ℃, preferably about 22 ℃ for about 6 hours to about 48 hours, preferably about 6 hours.
Compounds of formula XV can be prepared by methods well known to those of ordinary skill in the art, see Gomtsyan, a., orq.lett., 2, 11-13 (2000). Formula (R)3)s-phenyl- (CH)2) the-M reagent is commercially available or can be prepared by one skilled in the art.
Scheme 4 relates to the preparation of compounds of formula III, wherein (R)3)s-phenyl-Het is of sub-formula (b) or (d), R6Is hydrogen and L is a suitable leaving group, as described, for example, in scheme 1. Referring to scheme 4, compounds of formula III-wherein (R)3)sphenyl-Het is of formula (d) -may be prepared by reacting a compound of formula XVI in the presence of a base with an isocyanide of formula,
suitable bases include potassium carbonate, triethylamine and piperazine, preferably potassium carbonate. Suitable solvents include polar solvents such as tetrahydrofuran or N, N-dimethylformamide, preferably N, N-dimethylformamide. The above reaction may be carried out at a temperature between about 22 ℃ and about 70 ℃, preferably about 22 ℃ for about 2 hours to about 4 hours, and then at a temperature of about 70 ℃ for about 6 hours to about 10 hours.
A compound of formula III-wherein (R)3)sphenyl-Het of the formula (b) -may be prepared in a similar manner by first reacting a compound of the formula XVI with a suitable compound of the formula NH under dehydrating conditions2R5Amine reaction to prepare the intermediate formula XVIII imine. Such conditions include in a solvent such as tetrahydrofuran or dichloromethane, a compound of the formula XVI and an amine NH2R5Treated with a dehydrating agent such as anhydrous magnesium sulfate or molecular sieves. Alternatively, the imine of the formula XVIII can be prepared as described in the literature and subsequently reacted in an aqueous medium (Sisko, J.; Kassik, A.J.; Mellinger, M.; Filan, J.J.; Allen, A.; Olsen, M.A.; J.Org.chem.2000, 65, 1516-. The reaction of the imine of formula XVI with a suitable isocyanide of formula XVII is carried out at about 22 ℃ for about 1 day to about 21 days, preferably about 1 day.
Compounds of formula XVI are known in the literature (see Corey, E.J.; Loh, T-P.; AchyuthaRao, S.; Daley, D.C.; Sarstor, S.J. Org.Chem., 1993, 58, 5600-.
Scheme 5 relates to an alternative preparation of compounds of formula III, which are intermediates in scheme 1, useful for preparing compounds of formula I. Referring to scheme 5, compounds of formula III can be prepared from compounds of formula XIX by the methods of scheme 2, supra.
The compound of formula XIX can be prepared from a compound of formula XX with a compound of formula (R) in the presence of a base and a solvent3)s-phenyl-CO2P1Preparation of esters, in which P1Is methyl or ethyl. Suitable bases include sodium hydride, lithium diisopropylamide or sodium alcoholate, preferably sodium ethylate. Suitable solvents include alcohols, such as methanol, ethanol, propanol, butanol, or tetrahydroFuran, preferably ethanol. The above reaction is carried out at a temperature of about 23 ℃ to about 65 ℃, preferably about 50 ℃ for about 2 hours to about 24 hours, preferably about 20 hours.
The compounds of formula XX may be prepared by methods well known to those skilled in the art.
Scheme 6 relates to the preparation of compounds of formula IV and VI, which are intermediates in scheme 2, useful for preparing compounds of formula I.
Compounds of formula IV may be prepared by reacting a compound of formula XXI, wherein OL is acetoxy, bromo or chloro, with a reducing agent. Suitable reducing agents for reducing compounds of formula XXI wherein OL is acetoxy include titanium-coated graphite, nickel chloride and sodium borohydride. Suitable reducing agents for reducing compounds of formula XXI, wherein OL is bromine or chlorine, include zinc dust, sodium naphthalenide and samarium iodide.
Compounds of formula XXI, wherein OL is a leaving group, e.g., acetoxy, may be prepared by reacting a compound of formula VI, e.g., pyridine, with an acylating agent (e.g., acetyl chloride or acetic anhydride) in the presence of a base, e.g., pyridine, at a temperature of from about 10 ℃ to about 65 ℃, preferably about 50 ℃, for a period of from about 1 hour to about 4 hours, preferably about 2 hours. Compounds of formula XXI, wherein OL is a leaving group, such as chloro or bromo, may be prepared from compounds of formula VI: in acetic acid, with a halogenating agent, such as oxalyl chloride, thionyl chloride, phosphorus pentachloride, phosphorus oxychloride, and bromine, at a temperature of from about 10 ℃ to about 65 ℃, preferably about 50 ℃, for a time of from about 1 hour to about 4 hours, preferably about 2 hours.
Compounds of formula VI can be prepared from compounds of formula XXII: with the formula (R) being appropriately substituted3)sphenyl-M Grignard reactions, where M is an activating group, such as magnesium bromide or chloride (see, for example, Jackson, W.R.; Jacobs, H.A.; Jayatilake, G.S.; Matthews, B.R.; Watson, K.G.Aust. J.chem.1990, 43, 2045-. Formula (R)3)sthe-phenyl-M reagent is commercially available or can be prepared by one skilled in the art.
The preparation of the compound of the formula XVI and the conversion into trimethylsilyl cyanohydrin of the formula XXII can be carried out by methods known to the person skilled in the art, for example Pirrung, m.; shuey, s.w.; chem.1994, 59, 3890-.
Scheme 7 relates to the preparation of compounds of formula IV, which are intermediates in the preparation of compounds of formula III in scheme 2. Referring to scheme 7, compounds of formula IV are prepared from compounds of formula XXIII: in a solvent with a compound of formula (R)3)sphenyl-M Grignard reaction, where M is an activating group, such as magnesium bromide or magnesium chloride. Suitable solvents include tetrahydrofuran, dioxane, dimethylether or diethylether, preferably tetrahydrofuran. The above reaction is carried out at a temperature of about-78 deg.c to 0 deg.c for about 10 minutes to about 24 hours, preferably about 2 hours. Formula (R)3)sthe-phenyl-M reagent is commercially available or can be prepared by one skilled in the art.
The compound of formula XXIII is thus prepared from a compound of formula XXIV, with a hydroxylamine of formula
Wherein P is2And P3Independently is (C)1-C6) The alkyl group, preferably the methyl group,
and an activator. Suitable activators include carbonyldiimidazole or oxalyl chloride, preferably carbonyldiimidazole. Suitable solvents include dichloromethane or dichloroethane.
The compound of formula XXIV is prepared from a compound of formula XXVI: by acid hydrolysis, for example with sulfuric acid/water (preferably 1: 1), at a temperature of about 100 ℃ to about 120 ℃, preferably about 110 ℃, for a period of from about 1 hour to about 6 hours, preferably about 4 hours. Alternatively, the compound of formula XXII is prepared by base hydrolysis: for example, with lithium hydroxide in water at a temperature of from about 23 c to about 100 c, preferably about 80 c, for a period of from about 4 to 10 hours.
Scheme 8 relates to the preparation of compounds of formula I wherein (R)3)s-phenyl-Het is (b) or (d), R6Are hydrogen, which are intermediates in scheme 1, useful in the preparation of compounds of formula I. Referring to scheme 8, compounds of formula I-wherein (R)3)s-phenyl-Het is (b) or (d), R6Is hydrogen-can be prepared from an aldehyde of formula XXVII, as described in scheme 4 above for the conversion of a compound of formula XVI to a compound of formula III. The compounds of formula XXVII are prepared from compounds of formula XXVIII by formylation. Suitable conditions for formylation include metal halogen displacement with magnesium isopropyl chloride in a solvent such as tetrahydrofuran at a temperature of about 0 c for about 30 minutes, followed by addition of N, N-dimethylformamide at a temperature of about 0 c and then reaction at a temperature of about 50 c for about 2.5 hours.
Compounds of formula XXVIII are prepared as described in the literature (Moran, d.b.; Morton, g.o.; Alright, J.d., J.heterocyclic. chem., Vol.23, pp.1071-1077(1986)) or from compounds of formula XXIX, wherein L' is bromo or fluoro, as described in scheme 1 for the conversion of compounds of formula III to compounds of formula I. The compounds of formula XXIX are commercially available.
The basic compounds of formula I are capable of forming a variety of different salts with various inorganic and organic acids. Although such salts must be pharmaceutically acceptable for administration to animals, it is often the case in practice that a pharmaceutically unacceptable salt of a compound of formula I is first isolated from the reaction mixture and then converted to the free base compound by simple treatment with a basic reagent and subsequently the free base is converted to a pharmaceutically acceptable acid addition salt. The acid addition salts of the base compounds of this invention are readily prepared by treating the base compound with a substantially equivalent amount of the selected inorganic or organic acid in an aqueous solvent medium or a suitable organic solvent, such as methanol or ethanol. After careful evaporation of the solvent, the desired solid salt was obtained.
The acids used to prepare the pharmaceutically acceptable acid addition salts of the base compounds of the present invention are those which form non-toxic acid addition salts, i.e., salts containing pharmaceutically acceptable anions, such as the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate or bisulfate, phosphate or acid phosphate, acetate, lactate, citrate or acid citrate, tartrate or bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, and pamoate salts (i.e., 1' -methylene-bis- (2-hydroxy-3-naphthoate)).
Compounds of formula I which are also acidic-e.g. wherein R1-R16Including COOH or tetrazole moieties, are capable of forming salts with a variety of pharmacologically acceptable cations. Examples of such salts include alkali or alkaline earth metal salts, specifically sodium and potassium salts. These salts are prepared by conventional techniques. The chemical bases used as reagents to prepare the pharmaceutically acceptable base salts of the present invention are those that form non-toxic base salts with the acidic compounds of formula I as described herein. These non-toxic base salts include those derived from pharmacologically acceptable cations such as sodium, potassium, calcium, and magnesium. These salts are readily prepared by treating the corresponding acidic compound with an aqueous solution containing the desired pharmacologically acceptable cation and then evaporating the resulting solution to dryness, preferably under reduced pressure. Alternatively, they may be prepared by mixing together a lower alkanol solution of the acidic compound and the desired alkali metal alkoxide and then evaporating the resulting solution to dryness in the same manner as before. In both cases, it is preferred to employ stoichiometric amounts of reagents in order to ensure complete reaction and maximum product yield.
The activity of the compounds of the present invention against the various disorders described above can be determined according to one or more of the following assays. IC of all tested compounds of the invention in TNF α and MAPKAP in vitro assays50ED in vivo TNF alpha assay of less than 10. mu.M50Less than 50 mg/kg.
The compounds of the invention also have varying activity (i.e., selectivity) for one or more p38 kinases (i.e., α, β, γ, and δ). Certain compounds are more selective for p38 alpha than for p38 beta, gamma and delta, othersThe selectivity of the compound on p38 beta is better than p38 alpha, gamma and delta, and the selectivity of other compounds on p38 alpha and beta is better than p38 gamma and delta. Selectivity was measured in standard assays as IC of inhibition in each assay50And (4) the ratio.
TNF-alpha production inhibition by human LPS-treated monocytes
Monocytes were isolated from heparinized blood (1.5 ml of 1000 units/ml heparin for injection per 50ml of sample, Elkins-Sinn, Inc.) using an Accuspin System-Histopaque-1077 tube (Sigma A-7054). 35ml of whole blood was added to each tube and the tubes were centrifuged at 2100rpm for 20 minutes at room temperature in a Beckman GS-6KR centrifuge with a stopper. The monocytes collected at the interface were removed, diluted with Macrophage serum-free medium (Gibco-BRL) (medium) to a final volume of 50ml, centrifuged for 10 minutes, and collected. The supernatant was discarded and the pellet of cells was washed 2 times with 50ml of medium. The suspended cell samples were counted prior to the second wash. Based on the counting results, the washed cells were diluted with a medium containing 1% FBS to a final concentration of 2.7 × 106Cells/ml, 75. mu.l of cell suspension was added to each well of a 96-well plate.
Compound preparation
Compound testing is routinely performed at final concentrations from 2 μ M to.016 μ M, but can be tested at other concentrations, depending on activity. The test drug was diluted with DMSO to a final concentration of 2 mM. Using this stock solution, the compound was first diluted 1: 25 (5. mu.l of 2mM stock solution + 120. mu.l of medium containing 400ng/ml LPS and 1% FBS) and 40. mu.l of this dilution was diluted with 360. mu.l of medium containing LPS. Mu.l of this solution was transferred to 80. mu.l of medium containing LPS and 0.4% DMSO and serially diluted (1/5) resulting in solutions containing 8. mu.M, 1.6. mu.M, 0.32. mu.M and 0.064. mu.M test drug.
Assay method
Suspension to monocytesAdd 25. mu.l of diluted compound to the solution and bring the cells to 37 ℃ and 5% CO2The cells were incubated for 4 hours.
The 96 well plates were then centrifuged at 2000rpm for 10 minutes at 4 ℃ in a Beckman GS-6KR centrifuge to remove cells and cell debris. Remove 90 μ l of each supernatant, transfer to a 96-well round bottom plate, and centrifuge the plate a second time to ensure removal of all cell debris. Remove 80. mu.l of supernatant and transfer to a new round bottom plate.
Supernatants were analyzed for TNF-. alpha.content using R & D ELISA. To an ELISA well containing 25. mu.l of assay diluent RD1F and 75. mu.l of assay diluent RD5, 25. mu.l of each sample was added. The assay was performed following kit instructions, but using 100. mu.l of conjugate and substrate solution.
Explanation of the invention
The amount of TNF-alpha immunoreactivity in the sample is calculated as follows:
control% ((X-B)/(TOT-B). times.100)
Wherein X is OD of the well of the test compound450
B-OD of blank well of reagent on ELISA450
In total ═ OD of cells treated with 0.1% DMSO only450
MAPKAP kinase-2 assay
Monocyte preparation
Monocytes were collected from heparinized human blood as described above. The washed cells were seeded in 6-well clumping plates at a density of 1X 107Cells/well (in 2ml medium). Plates were incubated at 37 ℃ 5% CO2After incubation for 2 hours in the environment and adhesion of monocytes, the culture medium supernatant containing non-adhered cells was removed by aspiration and 2ml of fresh medium was added to each well. Plates were incubated at 37 ℃ 5% CO2Incubate overnight in the environment.
Cell activation
The medium was removed by suction. The attached cells were washed twice with fresh medium, and then 2ml of DMEM medium containing 10% heat-inactivated FBS was added to each well. Stock solutions of 30mM test compounds in DMSO were prepared and diluted to 1250, 250, 50, 10, 2, and 0.4 μ M in DMEM containing 1% DMSO and 10% FBS. Addition of 20. mu.l of these test drug dilutions to a single well of monocyte cultures resulted in final test drug concentrations of 12.5, 2.5, 0.5, 0.1, 0.02 and 0.004. mu.M. After preincubation for 10 minutes, 20. mu.l of 10. mu.g/ml LPS solution was added to each well and the plates were incubated at 37 ℃ for 30 minutes. The medium was then removed by aspiration, the attached monocytes were washed twice with phosphate buffered saline, and then 1ml of phosphate buffered saline containing 1% Triton X-100 (lysis buffer, also containing 1 Complete) was added to each wellTMDiscs (Boehringer #1697498) per 10ml buffer). The plate was incubated on ice for 10 minutes, and then the lysate was harvested and transferred to centrifuge tubes. After all samples were harvested, they were clarified by centrifugation (45,000rpm, 20min) and the supernatant recovered.
MAPKAP kinase-2 immunoprecipitation
To microcentrifuge tubes containing 1ml of a PBS suspension of 5% protein G-agarose (Sigma # P3296), each tube containing one of the above lysates, was added 5. mu.l of anti-MAPKAP kinase-2 antiserum (Upstate Biotechnology # 06-534). These mixtures were incubated at 4 ℃ for 1 hour (with shaking) and then centrifuged to recover the beads containing bound IgG, washed twice with 1ml50mM Tris pH7.5, 1mM EDTA, 1mM EGTA, 0.5mM orthovanadate, 0.1% 2-mercaptoethanol, 1% Triton X-100, 5mM sodium pyrophosphate, 10mM sodium glycerophosphate, 0.1mM phenylmethanesulfonyl chloride, 1. mu.g/ml leupeptin, 1. mu.g/ml pepstatin, and 50mM sodium fluoride (buffer A) by repeated centrifugation. Individual monocyte extracts (prepared as above) were then transferred to tubes each containing an IgG-coated G protein-agarose pellet and the mixtures incubated at 4 ℃ for 2 hours (with shaking). The beads were then harvested by centrifugation and the resulting bead pellet washed once with 0.5ml buffer A containing 0.5M NaCl, once with 0.5ml buffer A, and once with 0.1ml buffer consisting of 20mM MOPS pH7.2, 25mM sodium glycerophosphate, 5mM EGTA, 1mM orthovanadate and 1mM dithiothreitol (buffer B).
Evaluation of MAPKAP kinase-2 Activity
A stock solution of the kinase reaction mixture was prepared as follows: 2.2. mu.l 10mCi/ml gamma 32P]ATP, 88. mu.l of 1.3. mu.g/ml MAPKAP kinase-2 substrate peptide solution (Upstate Biotechnology #12-240), 11. mu.l of 10mM ATP, 8.8. mu.l of 1M MgCl2770. mu.l of buffer B. To each immunocomplex-G protein-pellet, 40. mu.l of the kinase reaction mixture was added, and the tube was incubated at 30 ℃ for 30 minutes. The tubes were then clarified by centrifugation and 25. mu.l each of the supernatants were spotted onto P81 filter paper discs (Whatman # 3698-023). After all the fluid was immersed in the filter paper, each plate was placed in a single well of a 6-well clustered plate, and the filter paper was washed with 2ml of 0.75% phosphoric acid (3 times for 15min) followed by acetone (10 min). The filter paper was then air dried and transferred to a liquid scintillation vial containing 5ml of scintillation fluid. Radioactivity was measured in a liquid scintillation counter. The amount of radioactivity bound to the filter paper at each test drug concentration was expressed as a percentage relative to the value observed for cells stimulated with LPS in the absence of test drug.
In vivo inhibition of TNF alpha
Rats were weighed and given vehicle (0.5% methylcellulose, Sigma) or drug. One hour later, animals were injected i.p. with LPS (50. mu.g/rat, Sigma L-4130). After 90 minutes, by CO2Animals were sacrificed by asphyxiation and exsanguination by cardiac puncture. Blood was collected in a Vaccutainer tube and spun at 3000rpm for 20 minutes. Using ELISA (R)&D Systems) serum TNF α levels were determined.
The invention also encompasses pharmaceutical compositions containing prodrugs of compounds of formula I and methods of treatment or prevention comprising administering prodrugs of compounds of formula I. Compounds of formula I having a free amino, amido, hydroxy or carboxy group can be converted into prodrugs. Prodrugs include compounds wherein an amino acid residue or a polypeptide chain of two or more (e.g., two, three or four) amino acid residues is covalently bonded via a peptide bond to a free amino, hydroxyl or carboxyl group of the compound of formula I. Amino acid residues include the 20 naturally occurring amino acids, generally indicated by three letter symbols, and also include 4-hydroxyproline, hydroxylysine, streptavidin, isostreptavidin, 3-methylhistidine, norvaline, β -alanine, γ -aminobutyric acid, citrulline, homocysteine, homoserine, ornithine and methionine sulfone. Prodrugs also include compounds wherein carbonates, carbamates, amides and alkyl esters are covalently bonded to the above substituents of formula I through the carbonyl carbon prodrug side chain.
The compositions of the present invention may be formulated in conventional manner using one or more pharmaceutically acceptable carriers. Thus, the active compounds of the present invention may be formulated for oral, buccal, intranasal, parenteral (e.g., intravenous, intramuscular, or subcutaneous) or rectal administration or in a dosage form suitable for administration by inhalation or insufflation.
For oral administration, the pharmaceutical compositions may, for example, take the form of tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients, for example binders (for example pregelatinized corn starch, polyvinylpyrrolidone or hydroxypropylmethylcellulose), fillers (for example lactose, microcrystalline cellulose or calcium phosphate), lubricants (for example magnesium stearate, talc or silicon dioxide), disintegrants (for example potato starch or sodium starch glycolate) or wetting agents (for example sodium lauryl sulfate). The tablets may be coated according to methods well known in the art. Oral liquid preparations may, for example, take the form of solutions, syrups or suspensions, or they may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (for example sorbitol syrup, methyl cellulose or hydrogenated edible fats), emulsifying agents (for example lecithin or acacia), non-aqueous vehicles (for example almond oil, oily esters or ethanol) and preservatives (for example methyl or propyl p-hydroxybenzoate or sorbic acid).
For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner.
The compounds of formula I may also be formulated in sustained release dosage forms according to methods well known to those of ordinary skill in the art. Examples of such formulations can be found in U.S. patents 3,538,214, 4,060,598, 4,173,626, 3,119,742 and 3,492,397, which are incorporated herein by reference in their entirety.
The active compounds of the present invention may be formulated for parenteral administration by injection, including by conventional catheterization techniques or infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be a powder which is reconstituted with a suitable carrier, for example sterile pyrogen-free water, before use.
The active compounds of the present invention may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.
For intranasal administration or administration by inhalation, the active compounds of the invention are suitably delivered in the form of a solution or suspension from a pump spray container which is squeezed or aspirated by the patient, or as an aerosol from a pressurised container or nebuliser, with the use of a suitable propellant, e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, a valve providing metered release may determine the dosage unit. The pressurized container or nebulizer may contain a solution or suspension of the active compound. Capsules and cartridges (made, for example, from gelatin) for use in an inhaler or insufflator may be formulated containing a powder mix of a compound of the invention and a suitable powder base such as lactose or starch.
The doses of active compounds according to the invention suggested for oral, parenteral or buccal administration to normal adults for the treatment of the above-mentioned disorders (e.g. inflammation) are 0.1 to 200mg of active ingredient per unit dose, which may be administered, for example, in 1 to 4 divided doses per day.
Aerosols for the treatment of the above-mentioned conditions in normal adults (e.g. adult respiratory distress syndrome) are preferably arranged to contain from 20 μ g to 1000 μ g of a compound of the invention per metered dose or "puff" of aerosol. The total daily aerosol dose will be in the range 100 μ g to 10 mg. The administration may be several times per day, for example 2,3, 4 or 8 times, each time for example 1, 2 or 3 doses.
Aerosol combination formulations for use in the treatment of the above conditions in an average adult human are preferably arranged so that each metered dose or "puff of aerosol contains from about 0.01mg to about 100mg of the active compound of the invention, preferably from about 1mg to about 10mg of the compound. The administration may be several times per day, for example 2,3, 4 or 8 times, each time for example 1, 2 or 3 doses.
The aerosol formulation for treating the above conditions in an average adult human is preferably arranged to contain from about 0.01mg to about 2000mg of ERK kinase inhibitor per metered dose or "puff" of aerosol, preferably from about 1mg to about 200mg of p38 kinase inhibitor. The administration may be several times per day, for example 2,3, 4 or 8 times, each time for example 1, 2 or 3 doses.
The following examples illustrate the preparation of the compounds of the present invention. The melting point is uncorrected. NMR data are reported in parts per million (δ) and are referenced to the deuterium lock signal from the sample solvent (deuterated chloroform unless indicated to the contrary). Mass spectral data were obtained using a Micromass ZMD APCI mass spectrometer equipped with Gilson gradient high performance liquid chromatography. The following solvents and gradients were used in the analysis. Solvent A: 98% water/2% acetonitrile/0.01% formic acid, solvent B: acetonitrile containing 0.005% formic acid. Typically, the gradient starts at 95% solvent a and ends at 100% solvent B over about 4 minutes. Mass spectra of the major eluting components were then obtained in either cationic or anionic mode, scanning molecular weights ranging from 165 to 1100 amu. The specific rotation was measured at room temperature using the sodium D line (589 nm). Commercial reagents were used without further purification. THF represents tetrahydrofuran. DMF means N, N-dimethylformamide. Chromatography refers to column chromatography, performed using 32-63mm silica gel, under nitrogen pressure (flash chromatography). Room or ambient temperature means 20-25 ℃. For convenience and to increase the yield, all non-aqueous reactions were carried out under nitrogen atmosphere. Concentration under reduced pressure means the use of a rotary evaporator.
One of ordinary skill in the art will appreciate that in some instances, protecting groups may be required during preparation. After the target molecule is prepared, the protecting group can be removed by methods well known to those of ordinary skill in the art, for example, as described in Greene and Wuts, Protective Groups in organic Synthesis, (2nd Ed., John Wiley & Sons, 1991).
Example 1
3-isopropyl-6- (4-phenyl-oxazol-5-yl) - [1, 2, 4] triazolo [4, 3-a ] pyridine
A) 6-chloro-N-methoxy-N-methyl-nicotinamide
To a solution of 6-chloronicotinic carboxylic acid (40g, 284mmol) in dichloromethane (500ml) was added 5ml of N, N-Dimethylformamide (DMF). A solution of 2M oxalyl chloride in dichloromethane (167ml, 330mmol) was added dropwise at ambient temperature. The reaction mixture was heated to 40 ℃ for 2 hours and then stirred at room temperature for 18 hours. The acid chloride solution was concentrated in vacuo and placed under vacuum for 1 hour. To a solution of N, O-dimethylhydroxylamine hydrochloride (32g, 330mmol) in dichloromethane (400ml) was added triethylamine (70 ml); the mixture was then cooled to 0 ℃. A solution of the previously formed acid chloride in methylene chloride (100ml) was added dropwise, maintaining the temperature at 0 ℃. After addition, the ice bath was removed and the reaction mixture was allowed to warm to room temperature and stirred for 20 hours. The reaction mixture was then partitioned with saturated sodium hydrogen phosphate, the organic layer was extracted, washed with water, brine, dried over sodium sulfate, and filtered. The solution was concentrated in vacuo to give the title compound (48.9g, 96%).
B) 6-chloro-pyridine-3-carbaldehyde
Corey，E.J.；Loh，T-P.；AchyuthaRao，S.；Daley，D.C.；Sarshar，S.J.Org.Chem.1993，58，5600-5602.
A solution of 6-chloro-N-methoxy-N-methyl-nicotinamide (5g, 25mmol) in tetrahydrofuran (50ml) was cooled in an ice bath under nitrogen in a flame-dried flask. A1.5M solution of diisobutylaluminum hydride in toluene (24.9ml, 37mmol) was added at a rate to maintain the internal temperature of the reaction below 20 ℃. The reaction was then stirred at room temperature for 3 hours. The completed reaction was cooled in an ice bath and carefully quenched with 1N hydrochloric acid. Stirring was continued for 15 minutes without an ice bath. The reaction mixture was extracted with ethyl acetate; the extract was washed with brine, dried over magnesium sulfate, filtered, and the filtrate was concentrated in vacuo to give a yellow solid (3.3 g). The solid was dissolved in ether and filtered through celite to remove some insoluble material. The filtrate was diluted with hexane and petroleum ether to allow the specified compound to crystallize overnight. The precipitate was collected and dried (850mg, 24%). The melting point is 77-78 ℃. The second crop was collected and dried (375mg, 11%).
C) 2-chloro-5- (4-phenyl-oxazol-5-yl) -pyridine
A solution of 6-chloro-pyridine-3-carbaldehyde (1.98g, 14.0mmol), phenylmethanesulfonylmethylisonitrile (Joseph Sisko, Mark Mellinger, Peter W.Sheldrake, and Neil H.Baine, Organic Synthesis, Vol.77, 198-containing 205(1999)) (3.8g, 14.0mmol) and potassium carbonate (2.13g, 15.4mmol) in DMF (20ml) was stirred at ambient temperature for 4 hours and then heated at 70 ℃ for 18 hours. The reaction was cooled to room temperature, quenched with water, and the mixture extracted with ethyl acetate (3 ×). The organic layers were combined, washed with water, brine, dried over sodium sulfate, filtered and the filtrate was concentrated in vacuo to a dark oil. The residue was purified by flash chromatography (eluting with hexane/ethyl acetate 4: 1) to give the title compound as a yellow solid, 2.55g (71%).
D)5- (4-phenyl-oxazol-5-yl) -pyridin-2-yl-hydrazine
A suspension of 2-chloro-5- (4-phenyl-oxazol-5-yl) -pyridine (2.55g, 9.9mmol) in hydrazine (8ml) was heated at 70 ℃ until a solution formed (approximately 20 min). The hydrazine product was removed from the heat and concentrated in vacuo to afford the named compound as a dark solid (2.5g, 100%).
E) Isobutyric acid N' - [5- (4-phenyl-oxazol-5-yl) -pyridin-2-yl ] -hydrazide
Isobutyryl chloride (1.04ml, 9.9mmol) was added dropwise to a solution of 5- (4-phenyl-oxazol-5-yl) -pyridin-2-yl-hydrazine (2.5g, 9.9mmol) and N, N-diisopropylethylamine (8.6ml, 50mmol) in dichloromethane (8ml) at 0 ℃; the mixture was stirred at 0 ℃ for 2 hours. The reaction was quenched with water and extracted with dichloromethane (3 ×). The organic layers were combined, washed with water, brine, dried over sodium sulfate, filtered, and the filtrate was concentrated in vacuo to a dark viscous solid. The residue was purified by flash chromatography (eluting with ethyl acetate/hexane 3: 1) to give the title compound as a yellow solid.
F) 3-isopropyl-6- (4-phenyl-oxazol-5-yl) - [1, 2, 4] triazolo [4, 3-a ] pyridine
Isobutyric acid N' - [5- (4-phenyl-oxazol-5-yl) -pyridin-2-yl ] -hydrazide (730mg, 2.26mmol) was dissolved in phosphorus oxychloride (10ml) and heated at 75 ℃ for 18 hours. The reaction was cooled in an ice bath, added to a beaker containing water (50ml), and the mixture was made alkaline by the dropwise addition of 3N sodium hydroxide. The basic mixture was extracted with ethyl acetate (3 ×); the organic layers were combined, washed with brine, dried over sodium sulfate, filtered and the filtrate was concentrated in vacuo to a yellow oil. The residue was recrystallized from ethyl acetate/methanol (95/5) to give the title compound as yellow crystals (294mg, 43%). The filtrate was purified by flash chromatography (eluting with ethyl acetate/methanol 97: 3) to afford more of the title compound (220mg, 32%).
Example 2
3-ethyl-6- (4-m-tolyl-oxazol-5-yl) - [1, 2, 4] triazolo [4, 3-a ] pyridine
The compound is prepared in analogy to example 1, starting in step C from 3-methylphenyl-tosylmethylisonitrile (Joseph Sisko, Mark Mellinger, Peter W.Sheldrake, and Neil H.Baine, Organic Synthesis, Vol.77, 198-. LCMS (M/z) 305M + 1.
Example 3
3-cyclopropyl-6- [4- (4-fluoro-phenyl) -oxazol-5-yl ] - [1, 2, 4] triazolo [4, 3-a ] pyridine
The compound is prepared in analogy to example 1, starting in step C from 4-fluorophenyl-tosylmethylisonitrile (Joseph Sisko, Mark Mellinger, Peter W.Sheldrake, and N Neil H.Baine, Tetrahedron Letters, Vol.37, No.45, 8113-. LCMS (M/z) 321M + 1.
Example 4
3-cyclobutyl-6- [4- (4-fluoro-phenyl) -oxazol-5-yl ] - [1, 2, 4] triazolo [4, 3-a ] pyridine
The compound is prepared in analogy to example 1, starting from 4-fluorophenyl-tosylmethylisonitrile in step C and from cyclobutanecarbonyl chloride in step E. LCMS (M/z) 335M + 1.
Example 5
3-difluoromethyl-6- (4-phenyl-oxazol-5-yl) - [1, 2, 4] triazolo [4, 3-a ] pyridine
The compound is prepared in a similar manner to example 1, starting from the acid chloride of difluoroacetic acid (prepared using 1 drop of DMF in oxalyl chloride in dichloromethane) in step E and using triethylamine in dichlorotriphenylphosphorane in acetonitrile in step F. LCMS (M/z)313M + 1.
Example 6
3-isoxazol-5-yl-6- (4-phenyl-oxazol-5-yl) - [1, 2, 4] triazolo [4, 3-a ] pyridine
The compound is prepared in analogy to example 1, starting in step E from the acid chloride of isoxazole-5-carboxylic acid (prepared using a solution of oxalyl chloride in dichloromethane containing 1 drop DMF). LCMS (M/z) 330M + 1.
Example 7
6- (4-phenyl-oxazol-5-yl) -3- (2, 2, 2-trifluoro-ethyl) - [1, 2, 4] triazolo [4, 3-a ] pyridine
The compound is prepared in analogy to example 1, starting from the acid chloride of 3, 3, 3-trifluoropropionic acid (prepared using 1 drop of DMF in oxalyl chloride in dichloromethane) in step E and using dichlorotriphenylphosphorane in acetonitrile in step F. LCMS (M/z) 345M + 1.
Example 8
3-cyclobutyl-6- (4-phenyl-oxazol-5-yl) - [1, 2, 4] triazolo [4, 3-a ] pyridine
The compound is prepared in a similar manner to example 1, starting from cyclobutanecarbonyl chloride in step E. LCMS (M/z) 317M + 1.
Example 9
3-cyclopropyl-6- (4-phenyl-oxazol-5-yl) - [1, 2, 4] triazolo [4, 3-a ] pyridine
This compound is prepared in a similar manner to example 1, starting from cyclopropanecarbonyl chloride in step E. LCMS (M/z) 303M + 1.
Example 10
3-ethyl-6- (4-phenyl-oxazol-5-yl) - [1, 2, 4] triazolo [4, 3-a ] pyridine
The compound is prepared in a similar manner to example 1, starting from propionyl chloride in step E. LCMS (M/z) 291M + 1.
Example 11
3-ethyl-6- [4- (4-fluoro-phenyl) -oxazol-5-yl ] - [1, 2, 4] triazolo [4, 3-a ] pyridine
The compound is prepared in analogy to example 1, starting from 4-fluorophenyl-tosylmethylisonitrile in step C and from propionyl chloride in step E. LCMS (M/z) 309M + 1.
Example 12
6- [4- (4-fluoro-phenyl) -oxazol-5-yl ] -3-isopropyl- [1, 2, 4] triazolo [4, 3-a ] pyridine
The compound is prepared in analogy to example 1, starting from 4-fluorophenyl-tosylmethylisonitrile in step C. LCMS (M/z) 323M + 1.
Example 13
3-cyclobutyl-6- (4-m-tolyl-oxazol-5-yl) - [1, 2, 4] triazolo [4, 3-a ] pyridine
The compound is prepared in a similar manner to example 1, starting from 3-methylphenyl-tosylmethylisonitrile in step C and cyclobutanecarbonyl chloride in step E. LCMS (M/z) 331M + 1.
Example 14
3-isopropyl-6- (4-m-tolyl-oxazol-5-yl) - [1, 2, 4] triazolo [4, 3-a ] pyridine
The compound is prepared in a similar manner to example 1, starting from 3-methylphenyl-tosylmethylisonitrile in step C. LCMS (M/z) 319M + 1.
Example 15
6- [4- (4-fluoro-3-methyl-phenyl) -oxazol-5-yl ] -3-isopropyl- [1, 2, 4] triazolo [4, 3-a ] pyridine
The compound is prepared in analogy to example 1, starting from 4-fluoro-3-methylphenyl-tosylmethylisonitrile (prepared from 4-fluoro-3-methylbenzaldehyde, which is prepared from 4-fluoro-3-methylphenylmagnesium bromide and DMF) in step C. LCMS (M/z) 337M + 1.
Example 16
3-cyclopropyl-6- [4- (4-fluoro-3-methyl-phenyl) -oxazol-5-yl ] - [1, 2, 4] triazolo [4, 3-a ] pyridine
This compound is prepared in analogy to example 1, starting from 4-fluoro-3-methylphenyl-tosylmethylisonitrile in step C and from cyclopropanecarbonyl chloride in step E. LCMS (M/z) 335M + 1.
Example 17
6- [4- (4-fluoro-phenyl) -oxazol-5-yl ] -3-phenyl- [1, 2, 4] triazolo [4, 3-a ] pyridine
The compound is prepared in analogy to example 1, starting from 4-fluorophenyl-tosylmethylisonitrile in step C and from benzoyl chloride in step E. LCMS (M/z)357M + 1.
Example 18
3-isopropyl-6- (2-methyl-4-phenyl-oxazol-5-yl) - [1, 2, 4] triazolo [4, 3-a ] pyridine
A) 2-chloro-5- (2-methyl-4-phenyl-oxazol-5-yl) -pyridine
To a stirred, cold (0 ℃) solution of 6-chloro-pyridine-3-carbaldehyde and 5mg of zinc iodide in 3ml of dichloromethane was added 0.40ml of trimethylsilyl cyanide via syringe under nitrogen. The ice bath was removed and the yellow solution/suspension was stirred at 22 ℃ for 1.5 h. The mixture was diluted with dilute aqueous sodium bicarbonate and extracted with dichloromethane (2 ×). The extract was washed with water, dried (magnesium sulfate), filtered, and the filtrate was concentrated to a yellow oil. The oil was extracted with 1ml of anhydrous diethyl ether (Et)2O) and added slowly via syringe to a stirred 1.1ml of phenylmagnesium bromide (3M Et at 0 deg.C2O solution) with 1ml Et2And O in a mixture. Add 2ml more Et2After O, the resulting paste was heated under reflux. After 1.75 hours, the mixture was cooled to 22 ℃ with 6ml of 2N hydrochloric acid, 2ml of Et2O and 2ml ethyl acetate. The mixture was stirred for 1 hour, then extracted with ethyl acetate (3 ×). The ethyl acetate extract was washed with water, brineDry (magnesium sulfate), filter, and concentrate the filtrate to a yellow oil. This material was purified by flash chromatography (eluting with 35: 65 ethyl acetate/hexanes) to give benzoin 2- (6-chloro-pyridin-3-yl) -2-hydroxy-1-phenyl-ethanone. The material was then concentrated twice from 1ml pyridine and 0.75ml acetic anhydride. The resulting acetate was heated at reflux in 15ml acetic acid and 1.6g ammonium acetate. The mixture was cooled to 22 ℃, concentrated to a yellow oil, diluted with aqueous sodium bicarbonate and extracted with ethyl acetate (2 ×). The combined extracts were washed with brine, dried (magnesium sulfate), filtered, and the filtrate was concentrated to an orange oil and purified by flash chromatography (eluting with 1: 3 ethyl acetate/hexanes) to give 273mg of 2-chloro-5- (2-methyl-4-phenyl-oxazol-5-yl) pyridine as a light yellow solid.
B)5- (2-methyl-4-phenyl-oxazol-5-yl) -pyridin-2-yl-hydrazine
A mixture of 120mg 2-chloro-5- (2-methyl-4-phenyl-oxazol-5-yl) -pyridine in 1ml hydrazine (98%) was heated at 70 ℃ for 45 minutes, then 0.5ml dichloromethane was added to better mix the hydrazine and chloropyridine. When the dichloromethane had been evaporated, 0.5ml ethanol was added and the mixture was heated for 11 hours. The layers were separated. The ethanol layer was diluted with ethyl acetate, washed with aqueous sodium carbonate (2 ×), dried (magnesium sulfate), filtered and the filtrate evaporated to give 110mg of crude 5- (2-methyl-4-phenyl-oxazol-5-yl) -pyridin-2-yl-hydrazine as an orange solid. This material was used in the next step without purification.
C) Isobutyric acid N' - [5- (2-methyl-4-phenyl-oxazol-5-yl) -pyridin-2-yl ] -hydrazide
To a stirred, cold (0 ℃) solution of 5- (2-methyl-4-phenyl-oxazol-5-yl) -pyridin-2-yl-hydrazine in 0.5ml dichloromethane, 0.3ml DMF and 0.325ml N, N-diisopropylethylamine was added 0.02ml isobutyryl chloride. After 5 minutes, another 0.005ml of isobutyryl chloride was added and after one minute the reaction was quenched with water. The mixture was extracted with dichloromethane (3x), washed with water (2x), brine (1x), dried (sodium sulfate), filtered, and the filtrate was concentrated to a dark orange oil. This oil was purified by flash chromatography (eluting with 5: 1 ethyl acetate/hexanes) to give 23mg of isobutyric acid N' - [5- (2-methyl-4-phenyl-oxazol-5-yl) -pyridin-2-yl ] -hydrazide as an orange solid.
D) 3-isopropyl-6- (2-methyl-4-phenyl-oxazol-5-yl) - [1, 2, 4] triazolo [4, 3-a ] pyridine
A mixture of 23mg of isobutyric acid N' - [5- (2-methyl-4-phenyl-oxazol-5-yl) -pyridin-2-yl ] -hydrazide in 0.68ml of phosphorus oxychloride was heated at 60 ℃ for 16 hours. The mixture was cooled to 22 ℃ and carefully added to 25ml of water. The aqueous mixture was made basic with 3N sodium hydroxide and extracted with ethyl acetate (3 ×). The combined extracts were washed with brine, dried (sodium sulfate), filtered, and the filtrate was concentrated to a dark yellow oil. This oil was purified by flash chromatography (eluting with 97: 3 ethyl acetate/methanol) to give 14mg of 3-isopropyl-6- (2-methyl-4-phenyl-oxazol-5-yl) - [1, 2, 4] triazolo [4, 3-a ] pyridine as a pale yellow solid.
LCMS(m/z)319 M+1。
1H NMR(400Mz)CDCl3δ8.18(s，1H)，7.85(d，1H，J＝9.8Hz)，7.60-7.62(m，2H)，7.42-7.49(m，4H)，3.32-3.34(m，1H)，2.63(s，3H)，1.51(d，6H，J＝6.7Hz)。
Example 19
6- [4- (4-fluoro-phenyl) -2-methyl-oxazol-5-yl ] -3-isopropyl- [1, 2, 4] triazolo [4, 3-a ] -pyridine
The compound is prepared in analogy to example 18, starting from 4-fluorophenylmagnesium bromide in step A. LCMS (M/z) 337M + 1.
The compounds of examples 20-33 may be prepared according to the methods of examples 1-19.
Example 33
6- [5- (4-fluoro-phenyl) -3H-imidazol-4-yl ] -3-isopropyl- [1, 2, 4] triazolo [4, 3-a ] pyridine
A) 3-isopropyl- [1, 2, 4] triazolo [4, 3-a ] pyridine-6-carbaldehyde
A mixture of 22.1g of 5-bromo-2-fluoropyridine with 10ml of 55% aqueous hydrazine in 165ml of pyridine was heated at reflux for 7 hours. The mixture was cooled to 22 ℃ and concentrated to near dryness. The resulting pale yellow solid was suspended in aqueous sodium hydroxide and toluene, stirred and the solid collected by vacuum filtration to give 22g of 5-bromo-pyridin-2-yl-hydrazine as a yellowish solid.
To a stirred, cold (0 ℃) solution of 5.5g 5-bromo-pyridin-2-yl-hydrazine in 40ml dichloromethane, 30ml N, N-dimethylformamide and 26ml N, N-diisopropylethylamine 3.1ml isobutyryl chloride was added dropwise. The mixture was stirred at 0 ℃ for 1 hour, and a precipitate formed. The mixture was diluted with water and the solid collected by filtration to give 5.9g of isobutyric acid N' - (5-bromo-pyridin-2-yl) -hydrazide as a slightly yellowish solid.
A mixture of 3g of N' - (5-bromo-pyridin-2-yl) -hydrazide isobutyrate in 25ml of phosphorus oxychloride was heated at 80 ℃ for 18 hours. The mixture was cooled with an ice bath and slowly added to a beaker containing dilute sodium hydroxide. The mixture was extracted with ethyl acetate (3 ×); the extracts were washed with brine, dried (sodium sulfate), filtered and the filtrate concentrated to give 3.4g of a dark oil. This oil was purified by flash chromatography (eluting with 6: 1 ethyl acetate/hexane) to give 2.0g of 6-bromo-3-isopropyl- [1, 2, 4] triazolo [4, 3-a ] pyridine as a dark oil.
To a stirred, cold (0 ℃ C.) dark brown solution of 0.48g of 6-bromo-3-isopropyl- [1, 2, 4] triazolo [4, 3-a ] pyridine in 5ml of tetrahydrofuran was slowly added 1.3ml of a 2M solution of isopropylmagnesium chloride in tetrahydrofuran. After 30 minutes, N-dimethylformamide was added; the ice bath was removed and the mixture was heated to 50 ℃ for 150 minutes. The mixture was cooled to 22 ℃, diluted with 1M hydrochloric acid and stirred for 10 minutes. The mixture was made basic with saturated aqueous sodium carbonate and extracted with ethyl acetate (3 ×). The combined extracts were washed with brine (2 ×), dried (sodium sulfate), filtered, and the filtrate was concentrated to give a pale yellow solid, which was crystallized (ethyl acetate, hexane, and methanol) to give 0.19g of 3-isopropyl- [1, 2, 4] triazolo [4, 3-a ] pyridine-6-carbaldehyde as a yellowish solid.
B)6- [5- (4-fluoro-phenyl) -3H-imidazol-4-yl ] -3-isopropyl- [1, 2, 4] triazolo [4, 3-a ] pyridine
0.2g of 3-isopropyl- [1, 2, 4] triazolo [4, 3-a ] pyridine-6-carbaldehyde in 50ml of tetrahydrofuran is stirred with 0.1g of concentrated ammonium hydroxide solution at 22 ℃ for 18 hours. To the resulting intermediate imine were added 0.09g of piperazine and 0.3g of 4-fluorophenyl-tosylmethyl isonitrile. The resulting mixture was stirred at 22 ℃ for 24 hours, then the mixture was diluted with water and extracted with dichloromethane. The extract was washed with water, brine, dried (sodium sulfate), filtered and the filtrate was concentrated. The residue was purified by flash chromatography (85: 15 ethyl acetate/methanol) to give 6- [5- (4-fluoro-phenyl) -3H-imidazol-4-yl ] -3-isopropyl- [1, 2, 4] triazolo [4, 3-a ] pyridine which crystallized upon standing as a white solid. LCMSM/z 322(M + 1). For related work, see Sisko, j.; kasick, a.j.; mellinger, m.; finan, j.j.; allen, a.; olsen, m.a.j.org.chem.2000, 65, 1516-.

Claims (15)

1. A compound of the formula
Wherein Het is an optionally substituted 5-membered heteroaryl with (R)3)s-phenyl groups together are selected from the group consisting of:
each R1Independently selected from hydrogen, (C)1-C6) Alkyl, phenyl, (C)1-C10) Heteroaryl, (C)1-C10) Heterocyclyl and (C)3-C10) A cycloalkyl group; wherein each of the above R1(C1-C6) Alkyl, phenyl, (C)1-C10) Heteroaryl, (C)1-C10) Heterocyclyl and (C)3-C10) The cycloalkyl substituents may be optionally substituted with one to four moieties, the substituents being independently selected from the group consisting of: halo, (C)1-C6) Alkyl, (C)2-C6) Alkenyl, (C)2-C6) Alkynyl, perhalogenated (C)1-C6) Alkyl, phenyl, (C)1-C10) Heteroaryl, (C)1-C10) Heterocyclic group, (C)3-C10) Cycloalkyl, hydroxy, (C)1-C6) Alkoxy, perhalogenated (C)1-C6) Alkoxy, phenoxy, (C)1-C10) heteroaryl-O-, (C)1-C10) heterocyclyl-O-, (C)3-C10) cycloalkyl-O-, (C)1-C6) alkyl-S-, (C)1-C6) alkyl-SO2-、(C1-C6) alkyl-NH-SO2-、-NO2Amino group, (C)1-C6) Alkylamino [ (C)1-C6) Alkyl radical]2Amino group, (C)1-C6) alkyl-SO2-NH-、(C1-C6) Alkyl- (C ═ O) -NH-, (C)1-C6) Alkyl- (C ═ O) - [ ((C)1-C6) Alkyl) -N]-, phenyl- (C ═ O) -NH-, phenyl- (C ═ O) - [ ((C)1-C6) Alkyl) -N]-、-CN、(C1-C6) Alkyl- (C ═ O) -, phenyl- (C ═ O) -, and1-C10) Heteroaryl- (C ═ O) -, (C)1-C10) Heterocyclyl- (C ═ O) -, (C)3-C10) Cycloalkyl- (C ═ O) -, HO- (C ═ O) -, and1-C6) alkyl-O- (C ═ O) -, H2N(C＝O)-、(C1-C6) alkyl-NH- (C ═ O) -, [ (C)1-C6) Alkyl radical]2-N-(C＝O)-, phenyl-NH- (C ═ O) -, phenyl- [ ((C)1-C6) Alkyl) -N]-(C＝O)-、(C1-C10) heteroaryl-NH- (C ═ O) -, (C)1-C10) heterocyclyl-NH- (C ═ O) -, (C)3-C10) cycloalkyl-NH- (C ═ O) -, (C)1-C6) Alkyl- (C ═ O) -O-and phenyl- (C ═ O) -O-; wherein two R are1(C1-C6) Alkyl groups may be taken together with the nitrogen atom to which they are attached to form a five to six membered heterocyclyl or heteroaryl ring;
R2selected from hydrogen, -CN, (C)1-C6) Alkyl, (C)2-C6) Alkenyl, (C)2-C6) Alkynyl, (C)3-C10) Cycloalkyl, phenyl, (C)1-C10) Heteroaryl, (C)1-C10) Heterocyclyl and (R)1)2-N-; wherein each of the above (C)1-C6) Alkyl, (C)3-C10) Cycloalkyl, phenyl, (C)1-C10) Heteroaryl and (C)1-C10) The heterocyclyl substituents may optionally be independently substituted with one to four moieties, the substituents being independently selected from the group consisting of: halo, (C)1-C6) Alkyl, (C)2-C6) Alkenyl, (C)2-C6) Alkynyl, perhalogenated (C)1-C6) Alkyl, phenyl, (C)3-C10) Cycloalkyl group, (C)1-C10) Heteroaryl, (C)1-C10) Heterocyclyl, formyl, -CN, (C)1-C6) Alkyl- (C ═ O) -, phenyl- (C ═ O) -, HO- (C ═ O) -, and1-C6) alkyl-O- (C ═ O) -, (C)1-C6) alkyl-NH- (C ═ O) -, [ (C)1-C6) Alkyl radical]2-N- (C ═ O) -, phenyl-NH- (C ═ O) -, phenyl- [ ((C)1-C6) Alkyl) -N]-(C＝O)-、-NO2Amino group, (C)1-C6) Alkylamino [ (C)1-C6) Alkyl radical]2-amino, (C)1-C6) Alkyl- (C ═ O) -NH-, (C)1-C6) Alkyl- (C ═ O) - [ ((C)1-C6) Alkyl) -N]-, phenyl- (C ═O) -NH-, phenyl- (C ═ O) - [ ((C)1-C6) Alkyl) -N]-、H2N-(C＝O)-NH-、(C1-C6) alkyl-HN- (C ═ O) -NH-, [ (C)1-C6) Alkyl radical]2N-(C＝O)-NH-、(C1-C6) alkyl-HN- (C ═ O) - [ ((C)1-C6) Alkyl) -N]-、[(C1-C6) Alkyl radical]2N-(C＝O)-[((C1-C6) Alkyl) -N]-, phenyl-HN- (C ═ O) -NH-, (phenyl)2N- (C ═ O) -NH-, phenyl-HN- (C ═ O) - [ ((C)1-C6) Alkyl) -N]-, (phenyl)2N-(C＝O)-[((C1-C6) Alkyl) -N]-、(C1-C6) alkyl-O- (C ═ O) -NH-, (C)1-C6) alkyl-O- (C ═ O) - [ ((C)1-C6) Alkyl) -N]-, phenyl-O- (C ═ O) -NH-, phenyl-O- (C ═ O) - [ ((C)1-C6) Alkyl) -N]-、(C1-C6) alkyl-SO2-NH-, phenyl-SO2-NH-、(C1-C6) alkyl-SO2-, phenyl-SO2-, hydroxy, (C)1-C6) Alkoxy, perhalogenated (C)1-C6) Alkoxy, phenoxy, (C)1-C6) Alkyl- (C ═ O) -O-, phenyl- (C ═ O) -O-, H2N-(C＝O)-O-、(C1-C6) alkyl-HN- (C ═ O) -O-, [ (C)1-C6) Alkyl radical]2N- (C ═ O) -O-, phenyl-HN- (C ═ O) -O-, (phenyl)2N- (C ═ O) -O-; wherein when said R is2When the phenyl group contains two adjacent substituents, such substituents may optionally form, together with the carbon atom to which they are attached, a five to six membered carbocyclic or heterocyclic ring; wherein each of said phenyl-containing moieties may alternatively be optionally substituted with one or two groups independently selected from (C)1-C6) Alkyl, halo, (C)1-C6) Alkoxy, perhalogenated (C)1-C6) Alkyl and perhalogenated (C)1-C6) Alkoxy groups;
each R3Independently selected from the group consisting of: halo, (C)1-C6) Alkyl, (C)2-C6) Alkenyl, (C)2-C6) Alkynyl, perhalogenated (C)1-C6) Alkyl, phenyl, (C)1-C10) Heteroaryl, (C)1-C10) Heterocyclic group, (C)3-C10) Cycloalkyl, hydroxy, (C)1-C6) Alkoxy, perhalogenated (C)1-C6) Alkoxy, phenoxy, (C)1-C10) heteroaryl-O-, (C)1-C10) heterocyclyl-O-, (C)3-C10) cycloalkyl-O-, (C)1-C6) alkyl-S-, (C)1-C6) alkyl-SO2-、(C1-C6) alkyl-NH-SO2-、-NO2Amino group, (C)1-C6) Alkylamino [ (C)1-C6) Alkyl radical]2Amino group, (C)1-C6) alkyl-SO2-NH-、(C1-C6) Alkyl- (C ═ O) -NH-, (C)1-C6) Alkyl- (C ═ O) - [ ((C)1-C6) Alkyl) -N]-, phenyl- (C ═ O) -NH-, phenyl- (C ═ O) - [ ((C)1-C6) Alkyl) -N]-、-CN、(C1-C6) Alkyl- (C ═ O) -, phenyl- (C ═ O) -, and1-C10) Heteroaryl- (C ═ O) -, (C)1-C10) Heterocyclyl- (C ═ O) -, (C)3-C10) Cycloalkyl- (C ═ O) -, HO- (C ═ O) -, and1-C6) alkyl-O- (C ═ O) -, H2N(C＝O)-、(C1-C6) alkyl-NH- (C ═ O) -, [ (C)1-C6) Alkyl radical]2-N- (C ═ O) -, phenyl-NH- (C ═ O) -, phenyl- [ ((C)1-C6) Alkyl) -N]-(C＝O)-、(C1-C10) heteroaryl-NH- (C ═ O) -, (C)1-C10) heterocyclyl-NH- (C ═ O) -, (C)3-C10) cycloalkyl-NH- (C ═ O) -and (C)1-C6) Alkyl- (C ═ O) -O-; wherein two adjacent R3The substituents may form, together with the carbon atom to which they are attached, a five to six membered carbocyclic or heterocyclic ring;
s is an integer from zero to five;
R4and R6Each independently selected from hydrogen, halo or R9-B-(CH2)n-a group of compositions;
n is an integer from zero to six;
each B is independently a bond, - (CHR)10)-、-O-、-S-、-(SO2)-、-(C＝O)-、-O-(C＝O)-、-(C＝O)-O-、-(C＝O)-NR10-、-(R10-N)-、-(R10-N)-SO2-、-(R10-N)-(C＝O)-、-SO2-(NR10)-、-(R10-N)-(C＝O)-(NR11)-、-(O)-(C＝O)-(NR10) -or- (R)10-N)-(C＝O)-O-；
R5And R7Each independently selected from the group consisting of: hydrogen, R14-(CR15H)p-, phenyl, (C)1-C10) Heteroaryl, (C)1-C10) Heterocyclic group, (C)3-C10) Cycloalkyl group, (C)1-C6) Alkyl- (SO)2) -, phenyl- (SO)2)-、H2N-(SO2)-、(C1-C6) alkyl-NH- (SO)2)-、[(C1-C6) Alkyl radical]2N-(SO2) -, phenyl-NH- (SO)2) -, (phenyl)2N-(SO2)-、R16-(C1-C6) Alkyl- (C ═ O) -, phenyl- (C ═ O) -, and1-C10) Heteroaryl- (C ═ O) -, (C)1-C10) Heterocyclyl- (C ═ O) -, (C)3-C10) Cycloalkyl- (C ═ O) -, (C)1-C6) alkyl-O- (C ═ O) -, (C)1-C10) heterocyclyl-O- (C ═ O) -, (C)3-C10) cycloalkyl-O- (C ═ O) -, H2N-(C＝O)-、(C1-C6) alkyl-NH- (C ═ O) -, phenyl-NH- (C ═ O) -, (C)1-C10) heteroaryl-NH- (C ═ O) -, (C)1-C10) heterocyclyl-NH- (C ═ O) -, (C)3-C10) cycloalkyl-NH- (C ═ O) -, [ (C)1-C6) Alkyl radical]2N- (C ═ O) -, (phenyl)2N- (C ═ O) -, phenyl- [ ((C)1-C6) Alkyl) -N]-(C＝O)-、(C1-C10) Heteroaryl- [ ((C)1-C6) Alkyl) -N]-(C＝O)-、(C1-C10) Heterocyclyl- [ ((C)1-C6) Alkyl) -N]- (C ═ O) -, and (C)3-C10) Cycloalkyl- [ ((C)1-C6) Alkyl) -N]- (C ═ O) -; wherein each of the above-mentioned phenyl, heterocyclyl, heteroaryl or cycloalkyl radicals R5And R7The substituents may optionally be independently substituted with one to four moieties, the substituents being independently selected from the group consisting of: halo, R16-(C1-C6) Alkyl, (C)2-C6) Alkenyl, (C)2-C6) Alkynyl, perhalogenated (C)1-C6) Alkyl, (C)3-C10) Cycloalkyl, phenyl, benzyl, (C)1-C10) Heterocyclic group, (C)1-C10) Heteroaryl, (C)1-C6) alkyl-SO2-, formyl, -CN, (C)1-C6) Alkyl- (C ═ O) -, (C)3-C10) Cycloalkyl- (C ═ O) -, phenyl- (C ═ O) -, and1-C10) Heterocyclyl- (C ═ O) -, (C)1-C10) Heteroaryl- (C ═ O) -, HO- (C ═ O) -, and1-C6) alkyl-O- (C ═ O) -, (C)3-C10) cycloalkyl-O- (C ═ O) -, (C)1-C10) heterocyclyl-O- (C ═ O) -, (C)1-C6) alkyl-NH- (C ═ O) -, (C)3-C10) cycloalkyl-NH- (C ═ O) -, phenyl-NH- (C ═ O) -, (C)1-C10) heterocyclyl-NH- (C ═ O) -, (C)1-C10) heteroaryl-NH- (C ═ O) -, [ (C)1-C6) Alkyl radical]2-N- (C ═ O) -, phenyl- [ ((C)1-C6) Alkyl) -N]- (C ═ O) -, hydroxy, (C)1-C6) Alkoxy, perhalogenated (C)1-C6) Alkoxy group, (C)3-C10) cycloalkyl-O-, phenoxy, (C)1-C10) heterocyclyl-O-, (C)1-C10) heteroaryl-O-, (C)1-C6) Alkyl- (C ═ O) -O-, (C)3-C10) Cycloalkyl- (C ═ O) -O-, phenyl- (C ═ O) -O-, (C ═ O-, (C)1-C10) Heterocyclyl- (C ═ O) -O-, (C)1-C10) Heteroaryl- (C ═ O) -O-, -NO2An amino group,(C1-C6) Alkylamino [ (C)1-C6) Alkyl radical]2-amino, carboxamido, (C)1-C6) Alkyl- (C ═ O) -NH-, (C)3-C10) Cycloalkyl- (C ═ O) -NH-, phenyl- (C ═ O) -NH-, (C ═ O-), (C1-C10) Heterocyclyl- (C ═ O) -NH-, (C)1-C10) Heteroaryl- (C ═ O) -NH-, (C)1-C6) Alkyl- (C ═ O) - [ ((C)1-C6) Alkyl) -N]-, phenyl- (C ═ O) - [ ((C)1-C6) Alkyl) -N]-、(C1-C6) alkyl-SO2-NH-、(C3-C10) cycloalkyl-SO2-NH-, phenyl-SO2-NH-、(C1-C10) heterocyclyl-SO2-NH-and (C)1-C10) heteroaryl-SO2-NH-; wherein each of said phenyl and heteroaryl moieties may be optionally substituted with one or two groups independently selected from halo, (C)1-C6) Alkyl, (C)1-C6) Alkoxy, perfluoro (C)1-C6) Alkyl and perfluoro (C)1-C6) An alkoxy group;
p is an integer from one to six;
R9selected from hydrogen, -CF3、-CN、R13-(R12CH)m-, phenyl, (C)1-C10) Heterocyclic group, (C)1-C10) Heteroaryl and (C)3-C10) Cycloalkyl groups; wherein each of the above R9Phenyl, (C)1-C10) Heteroaryl, (C)1-C10) Heterocyclyl and (C)3-C10) The cycloalkyl substituents may be optionally substituted with one to four moieties, the substituents being independently selected from the group consisting of: halo, (C)1-C6) Alkyl, (C)2-C6) Alkenyl, (C)2-C6) Alkynyl, perhalogenated (C)1-C6) Alkyl, phenyl, (C)1-C10) Heteroaryl, (C)1-C10) Heterocyclic group, (C)3-C10) Cycloalkyl, hydroxy, (C)1-C6) Alkoxy, perhalogenated (C)1-C6) Alkoxy, phenoxy, (C)1-C10) heteroaryl-O-, (C)1-C10) heterocyclyl-O-, (C)3-C10) cycloalkyl-O-, (C)1-C6) alkyl-S-, (C)1-C6) alkyl-SO2-、(C1-C6) alkyl-NH-SO2-、-NO2Amino group, (C)1-C6) Alkylamino [ (C)1-C6) Alkyl radical]2Amino group, (C)1-C6) alkyl-SO2-NH-、(C1-C6) Alkyl- (C ═ O) -NH-, (C)1-C6) Alkyl- (C ═ O) - [ ((C)1-C6) Alkyl) -N]-, phenyl- (C ═ O) -NH-, phenyl- (C ═ O) - [ ((C)1-C6) Alkyl) -N]-、-CN、(C1-C6) Alkyl- (C ═ O) -, phenyl- (C ═ O) -, and1-C10) Heteroaryl- (C ═ O) -, (C)1-C10) Heterocyclyl- (C ═ O) -, (C)3-C10) Cycloalkyl- (C ═ O) -, HO- (C ═ O) -, and1-C6) alkyl-O- (C ═ O) -, H2N(C＝O)-、(C1-C6) alkyl-NH- (C ═ O) -, [ (C)1-C6) Alkyl radical]2-N- (C ═ O) -, phenyl-NH- (C ═ O) -, phenyl- [ ((C)1-C6) Alkyl) -N]-(C＝O)-、(C1-C10) heteroaryl-NH- (C ═ O) -, (C)1-C10) heterocyclyl-NH- (C ═ O) -, (C)3-C10) cycloalkyl-NH- (C ═ O) -, (C)1-C6) Alkyl- (C ═ O) -O-and phenyl- (C ═ O) -O-; wherein said phenyl group, (C)1-C10) Heteroaryl, (C)1-C10) Heterocyclyl and (C)3-C10) Two adjacent R of cycloalkyl9The substituents may, together with the carbon or heteroatom to which they are attached, form a five or six membered carbocyclic or heterocyclic ring;
m is an integer from one to six;
R10is hydrogen, (C)1-C6) alkyl-SO2-or (C)1-C6) An alkyl group;
R11is hydrogen or (C)1-C6) An alkyl group;
each R12Independently selected from hydrogen, amino, (C)1-C6) Alkoxy and (C)1-C6) Alkyl groups;
R13selected from the group consisting of: hydrogen, (C)1-C6) Alkyl, (C)2-C6) Alkenyl, (C)2-C6) Alkynyl, phenyl, (C)1-C10) Heteroaryl, (C)1-C10) Heterocyclic group, (C)3-C10) Cycloalkyl, hydroxy, (C)1-C6) Alkoxy, perhalogenated (C)1-C6) Alkoxy, phenoxy, (C)1-C10) heteroaryl-O-, (C)1-C10) heterocyclyl-O-, (C)3-C10) cycloalkyl-O-, (C)1-C6) alkyl-S-, (C)1-C6) alkyl-SO2-、(C1-C6) alkyl-NH-SO2-、-NO2Amino group, (C)1-C6) Alkylamino [ (C)1-C6) Alkyl radical]2Amino group, (C)1-C6) alkyl-SO2-NH-, phenyl-SO2-NH-、(C1-C6) alkyl-SO2-[((C1-C6) Alkyl) -N]-, phenyl-SO2-[((C1-C6) Alkyl) -N]-、(C1-C6) Alkyl- (C ═ O) -NH-, (C)1-C6) Alkyl- (C ═ O) - [ ((C)1-C6) Alkyl) -N]-, phenyl- (C ═ O) -NH-, phenyl- (C ═ O) - [ ((C)1-C6) Alkyl) -N]-、-CN、(C1-C6) Alkyl- (C ═ O) -, phenyl- (C ═ O) -, and1-C10) Heteroaryl- (C ═ O) -, (C)1-C10) Heterocyclyl- (C ═ O) -, (C)3-C10) Cycloalkyl- (C ═ O) -, HO- (C ═ O) -, and1-C6) alkyl-O- (C ═ O) -, H2N(C＝O)-、(C1-C6) alkyl-NH- (C ═ O) -, [ (C)1-C6) Alkyl radical]2-N- (C ═ O) -, phenyl-NH- (C ═ O) -, phenyl- [ ((C)1-C6) Alkyl) -N]-(C＝O)-、(C1-C10) Hetero compoundaryl-NH- (C ═ O) -, (C)1-C10) heterocyclyl-NH- (C ═ O) -, (C)3-C10) cycloalkyl-NH- (C ═ O) -, (C)1-C6) Alkyl- (C ═ O) -O-and phenyl- (C ═ O) -O-;
R14selected from the group consisting of: hydrogen, halo, (C)1-C6) Alkyl, (C)2-C6) Alkenyl, (C)2-C6) Alkynyl, perhalogenated (C)1-C6) Alkyl, (C)3-C10) Cycloalkyl, phenyl, (C)1-C10) Heterocyclic group, (C)1-C10) Heteroaryl, phenyl- (S ═ O) -, (C)1-C6) alkyl-SO2-, phenyl-SO2-、H2N-SO2-、(C1-C6) alkyl-NH-SO2-, phenyl-NH-SO2-、[(C1-C6) Alkyl radical]2N-SO2-, (phenyl)2N-SO2-, formyl, -CN, (C)1-C6) Alkyl- (C ═ O) -, phenyl- (C ═ O) -, and1-C10) Heteroaryl- (C ═ O) -, (C)1-C10) Heterocyclyl- (C ═ O) -, (C)3-C10) Cycloalkyl- (C ═ O) -, HO- (C ═ O) -, R16-(C1-C6) alkyl-O- (C ═ O) -, (C)3-C10) cycloalkyl-O- (C ═ O) -, (C)1-C10) heterocyclyl-O- (C ═ O) -, H2N-(C＝O)-、R16-(C1-C6) alkyl-NH- (C ═ O) -, (C)3-C10) cycloalkyl-NH- (C ═ O) -, phenyl-NH- (C ═ O) -, (C)1-C10) heterocyclyl-NH- (C ═ O) -, (C)1-C10) heteroaryl-NH- (C ═ O) -, [ (C)1-C6) Alkyl radical]2-N- (C ═ O) -, phenyl- [ ((C)1-C6) Alkyl) -N]-(C＝O)-、(C1-C10) Heteroaryl- [ ((C)1-C6) Alkyl) -N]-(C＝O)-、(C1-C10) Heterocyclyl- [ ((C)1-C6) Alkyl) -N]-(C＝O)-、(C3-C10) Cycloalkyl- [ ((C)1-C6) Alkyl) -N]- (C ═ O) -, hydroxy, R16-(C1-C6) Alkoxy, perhalogenated (C)1-C6) Alkoxy group, (C)3-C10) cycloalkyl-O-, phenoxy, (C)1-C10) heterocyclyl-O-, (C)1-C10) heteroaryl-O-, R16-(C1-C6) Alkyl- (C ═ O) -O-, (C)3-C10) Cycloalkyl- (C ═ O) -O-, phenyl- (C ═ O) -O-, (C ═ O-, (C)1-C10) Heterocyclyl- (C ═ O) -O-, (C)1-C10) Heteroaryl- (C ═ O) -O-, -NO2Amino, R16-(C1-C6) Alkylamino [ (C)1-C6) Alkyl radical]2-amino, carboxamido, R16-(C1-C6) Alkyl- (C ═ O) -NH-, (C)3-C10) Cycloalkyl- (C ═ O) -NH-, phenyl- (C ═ O) -NH-, (C ═ O-), (C1-C10) Heterocyclyl- (C ═ O) -NH-, (C)1-C10) Heteroaryl- (C ═ O) -NH-, R16-(C1-C6) Alkyl- (C ═ O) - [ ((C)1-C6) Alkyl) -N]-, phenyl- (C ═ O) - [ ((C)1-C6) Alkyl) -N]-、R16-(C1-C6) alkyl-SO2-NH-、(C3-C10) cycloalkyl-SO2-NH-, phenyl-SO2-NH-、(C1-C10) heterocyclyl-SO2-NH-and (C)1-C10) heteroaryl-SO2-NH-; wherein each of the above-mentioned phenyl, heterocyclyl, heteroaryl or cycloalkyl radicals R14The substituents may optionally be independently substituted with one to four moieties, the substituents being independently selected from the group consisting of: halo, R16-(C1-C6) Alkyl, (C)2-C6) Alkenyl, (C)2-C6) Alkynyl, perhalogenated (C)1-C6) Alkyl, (C)3-C10) Cycloalkyl, phenyl, benzyl, (C)1-C10) Heterocyclic group, (C)1-C10) Heteroaryl, (C)1-C6) alkyl-SO2-, formyl, -CN, R16-(C1-C6) Alkyl- (C ═ O) -, (C)3-C10) Cycloalkyl- (C ═ O) -, phenyl- (C ═ O)-、(C1-C10) Heterocyclyl- (C ═ O) -, (C)1-C10) Heteroaryl- (C ═ O) -, HO- (C ═ O) -, and1-C6) alkyl-O- (C ═ O) -, (C)3-C10) cycloalkyl-O- (C ═ O) -, (C)1-C10) heterocyclyl-O- (C ═ O) -, (C)1-C10) heteroaryl-O- (C ═ O) -, H2N-(C＝O)-、R16-(C1-C6) alkyl-NH- (C ═ O) -, (C)3-C10) cycloalkyl-NH- (C ═ O) -, phenyl-NH- (C ═ O) -, (C)1-C10) heterocyclyl-NH- (C ═ O) -, (C)1-C10) heteroaryl-NH- (C ═ O) -, [ (C)1-C6) Alkyl radical]2-N- (C ═ O) -, phenyl- [ ((C)1-C6) Alkyl) -N]- (C ═ O) -, hydroxy, R16-(C1-C6) Alkoxy, perhalogenated (C)1-C6) Alkoxy group, (C)3-C10) cycloalkyl-O-, phenoxy, (C)1-C10) heterocyclyl-O-, (C)1-C10) heteroaryl-O-, R16-(C1-C6) Alkyl- (C ═ O) -O-, (C)3-C10) Cycloalkyl- (C ═ O) -O-, phenyl- (C ═ O) -O-, (C ═ O-, (C)1-C10) Heterocyclyl- (C ═ O) -O-, (C)1-C10) Heteroaryl- (C ═ O) -O-, -NO2Amino, R16-(C1-C6) Alkylamino [ (C)1-C6) Alkyl radical]2-amino, carboxamido, R16-(C1-C6) Alkyl- (C ═ O) -NH-, (C)3-C10) Cycloalkyl- (C ═ O) -NH-, phenyl- (C ═ O) -NH-, (C ═ O-), (C1-C10) Heterocyclyl- (C ═ O) -NH-, (C)1-C10) Heteroaryl- (C ═ O) -NH-, R16-(C1-C6) Alkyl- (C ═ O) - [ ((C)1-C6) Alkyl) -N]-, phenyl- (C ═ O) - [ ((C)1-C6) Alkyl) -N]-、R16-(C1-C6) alkyl-SO2-NH-、(C3-C10) cycloalkyl-SO2-NH-, phenyl-SO2-NH-、(C1-C10) heterocyclyl-SO2-NH-and (C)1-C10) heteroaryl-SO2-NH-; wherein each of said phenyl and heteroaryl moieties may be optionally substituted with one or two groups independently selected from the group consisting of halo, (C)1-C6) Alkyl, (C)1-C6) Alkoxy, perfluoro (C)1-C6) Alkyl and perfluoro (C)1-C6) Alkoxy groups;
each R15Independently selected from hydrogen, halo, (C)1-C6) Alkyl, (C)2-C6) Alkenyl, perhalogenated (C)1-C6) Alkyl, HO- (C ═ O) -, (C)1-C6) alkyl-O- (C ═ O) -, H2N-(C＝O)-、(C1-C6) alkyl-NH- (C ═ O) -, [ (C)1-C6) Alkyl radical]2-N- (C ═ O) -, hydroxy, (C)1-C6) Alkoxy group, (C)1-C6) Alkyl- (C ═ O) -O-, amino, (C ═ O)1-C6) Alkylamino [ (C)1-C6) Alkyl radical]2-amino, carboxamido and (C)1-C6) Alkyl- (C ═ O) -NH-;
each R16Independently selected from hydrogen, halo, (C)1-C6) Alkyl, (C)2-C6) Alkenyl, (C)2-C6) Alkynyl, perhalogenated (C)1-C6) Alkyl, (C)1-C10) Heterocyclic group, HO- (C ═ O) -, and (C)1-C6) alkyl-O- (C ═ O) -, H2N-(C＝O)-、(C1-C6) alkyl-NH- (C ═ O) -, [ (C)1-C6) Alkyl radical]2-N- (C ═ O) -, hydroxy, (C)1-C6) Alkoxy, perhalogenated (C)1-C6) Alkoxy group, (C)1-C6) Alkyl- (C ═ O) -O-, -NO2Amino group, (C)1-C6) Alkylamino [ (C)1-C6) Alkyl radical]2-amino, carboxamido and (C)1-C6) Alkyl- (C ═ O) -NH-; wherein said (C)1-C10) The heterocyclic group may be optionally substituted with one to three substituents independently selected from the group consisting of halo, (C)1-C6) Alkyl, (C)1-C6) Alkoxy, benzyl, amino, (C)1-C6) Alkylamino and [ (C)1-C6) Alkyl radical]2-amino groups;
or R4And R6Or R4And R7Or R5And R6May form, together with the atoms to which they are attached, an optionally substituted five-to ten-membered saturated, unsaturated or aromatic ring, optionally containing two to three substituents independently selected from NH, N, O, S, SO or SO2A heteroatom of (a); wherein said ring may be optionally substituted with one to three substituents independently selected from the group consisting of: oxo, halo, (C)1-C6) Alkyl, phenyl, (C)1-C10) Heteroaryl, (C)1-C10) Heterocyclic group, (C)3-C10) Cycloalkyl, hydroxy, (C)1-C6) Alkoxy, phenoxy, (C)1-C10) heteroaryl-O-, (C)1-C10) heterocyclyl-O-, (C)3-C10) cycloalkyl-O-, (C)1-C6) alkyl-S-, (C)1-C6) alkyl-SO2-, phenyl-S-, phenyl- (S ═ O) -, phenyl-SO2-、(C1-C6) alkyl-NH-SO2-、[(C1-C6) Alkyl radical]2N-SO2-, phenyl-NH-SO2-, (phenyl)2N-SO2-, phenyl- [ N (C)1-C6) Alkyl radical]-SO2-, formyl, (C)1-C6) Alkyl- (C ═ O) -, phenyl- (C ═ O) -, and1-C10) Heteroaryl- (C ═ O) -, (C)1-C10) Heterocyclyl- (C ═ O) -, (C)3-C10) Cycloalkyl- (C ═ O) -, HO- (C ═ O) -, and1-C6) alkyl-O- (C ═ O) -, (C)1-C10) heterocyclyl-O- (C ═ O) -, (C)3-C10) cycloalkyl-O- (C ═ O) -, H2N-(C＝O)-、(C1-C6) alkyl-NH- (C ═ O) -, [ (C)1-C6) Alkyl radical]2-N- (C ═ O) -, phenyl-NH- (C ═ O) -, phenyl- [ ((C)1-C6) Alkyl radical)-N]-(C＝O)-、(C1-C10) heteroaryl-NH- (C ═ O) -, (C)1-C10) Heteroaryl- [ ((C)1-C6) Alkyl) -N]-(C＝O)-、(C1-C10) heterocyclyl-NH- (C ═ O) -, (C)1-C10) Heterocyclyl- [ ((C)1-C6) Alkyl) -N]-(C＝O)-、(C3-C10) cycloalkyl-NH- (C ═ O) -, (C)3-C10) Cycloalkyl- [ ((C)1-C6) Alkyl) -N]- (C ═ O) -, amino, (C) and (d) and (1-C6) Alkylamino [ (C)1-C6) Alkyl radical]2-amino, (C)1-C6) alkyl-SO2-NH-, phenyl-SO2-NH-、(C1-C6) alkyl-SO2-[((C1-C6) Alkyl) -N]-, phenyl-SO2-[((C1-C6) Alkyl) -N]-, carboxamido, (C)1-C6) Alkyl- (C ═ O) -NH-, (C)1-C6) Alkyl- (C ═ O) - [ ((C)1-C6) Alkyl) -N]-, phenyl- (C ═ O) -NH-, phenyl- (C ═ O) - [ ((C)1-C6) Alkyl) -N]-、(C1-C10) Heteroaryl- (C ═ O) -NH-, (C)1-C10) Heteroaryl- (C ═ O) - [ ((C)1-C6) Alkyl) -N]-、(C1-C10) Heterocyclyl- (C ═ O) -NH-, (C)1-C10) Heterocyclyl- (C ═ O) - [ ((C)1-C6) Alkyl) -N]-、(C3-C10) Cycloalkyl- (C ═ O) -NH-, (C)3-C10) Cycloalkyl- (C ═ O) - [ ((C)1-C6) Alkyl) -N]-、H2N-(C＝O)-NH-、(C1-C6) alkyl-HN- (C ═ O) -NH-, (C)1-C6) alkyl-HN- (C ═ O) - [ ((C)1-C6) Alkyl) -N]-、[(C1-C6) Alkyl radical]2-N-(C＝O)-NH-、[(C1-C6) Alkyl radical]2-N-(C＝O)-[((C1-C6) Alkyl) -N]-, phenyl-HN- (C ═ O) -NH-, phenyl-HN- (C ═ O) - [ ((C)1-C6) Alkyl) -N]-, (phenyl)2-N- (C ═ O) -NH-, (phenyl)2-N-(C＝O)-[((C1-C6) Alkyl) -N]-、(C1-C10) heteroaryl-HN- (C ═ O) -NH-, (C)1-C10) heteroaryl-HN- (C ═ O) - [ ((C)1-C6) Alkyl) -N]-、[(C1-C10) Heteroaryl radical]2-N-(C＝O)-[((C1-C6) Alkyl) -N]-、[(C1-C10) Heteroaryl radical]2-N-(C＝O)-NH-、(C1-C10) heterocyclyl-HN- (C ═ O) -NH-, (C)1-C10) heterocyclyl-HN- (C ═ O) - [ ((C)1-C6) Alkyl) -N]-、[(C1-C10) Heterocyclic radical]2-N-(C＝O)-[((C1-C6) Alkyl) -N]-、[(C1-C10) Heterocyclic radical]2-N-(C＝O)-NH-、(C3-C10) cycloalkyl-HN- (C ═ O) -NH-, (C)3-C10) cycloalkyl-HN- (C ═ O) - [ ((C)1-C6) Alkyl) -N]-、[(C3-C10) Cycloalkyl radicals]2-N-(C＝O)-[((C1-C6) Alkyl) -N]-、[(C3-C10) Cycloalkyl radicals]2-N-(C＝O)-NH-、(C1-C6) Alkyl- (C ═ O) -O-, phenyl- (C ═ O) -O-, (C ═ O-, (C)1-C10) Heteroaryl- (C ═ O) -O-, (C)1-C10) Heterocyclyl- (C ═ O) -O-, (C)3-C10) Cycloalkyl- (C ═ O) -O-, (C)1-C6) alkyl-NH- (C ═ O) -O-, phenyl-NH- (C ═ O) -O-, (C1-C10) heteroaryl-NH- (C ═ O) -O-, (C)1-C10) heterocyclyl-NH- (C ═ O) -O-and (C)3-C10) cycloalkyl-NH- (C ═ O) -O-;
or a pharmaceutically acceptable salt thereof.
2. A compound according to claim 1, wherein R2Is optionally substituted (C)1-C6) Alkyl, phenyl, (C)3-C10) Cycloalkyl group, (C)1-C10) Heteroaryl or (C)1-C10) A heterocyclic group.
3. A compound according to claim 1, wherein R2Is (C)1-C6) Alkyl, optionally substituted with one to four groups independently selected from halo, hydroxy, (C)1-C6) Alkyl, (C)2-C6) Alkenyl, (C)2-C6) Alkynyl, (C)1-C6) Alkoxy, perhalogenated (C)1-C6) Alkyl, perhalogenated (C)1-C6) Alkoxy, -CN, -NO2Amino group, (C)1-C6) Alkylamino [ (C)1-C6) Alkyl radical]2-amino, HO- (C ═ O) -, (C)1-C6) Alkyl- (C ═ O) -, (C)1-C6) alkyl-O- (C ═ O) -, (C)1-C6) alkyl-CO2-、(C1-C6) Alkyl- (C ═ O) -NH-, (C)1-C6) alkyl-NH- (C ═ O) -, (C)1-C6) Alkyl- (C ═ O) - [ ((C)1-C6) Alkyl) -N]-、(C1-C6) Alkyl- [ ((C)1-C6) Alkyl) -N]-(C＝O)-、(C1-C6) alkyl-SO2-NH-、(C1-C6) alkyl-SO2-, optionally substituted phenyl- (C ═ O) -O-, optionally substituted phenoxy, optionally substituted phenyl-NH- (C ═ O) -, optionally substituted phenyl- [ ((C ═ O) -, optionally substituted phenyl [ ((C ═ O) - ]1-C6) Alkyl) -N]- (C ═ O) -, optionally substituted phenyl- (C ═ O) -NH-, optionally substituted phenyl- (C ═ O) - [ ((C ═ O) - ]1-C6) Alkyl) -N]-。
4. The compound according to claim 1, wherein the compound has the formula:
5. the compound according to claim 1, wherein the compound has the formula:
6. the compound according to claim 1, wherein the compound has the formula:
7. the compound according to claim 1, wherein the compound has the formula:
8. the compound according to claim 1, wherein the compound has the formula:
9. a compound according to claim 1, wherein R4Is hydrogen.
10. A compound according to claim 1, wherein R7Selected from the group consisting of hydrogen and optionally substituted phenyl, (C)1-C10) Heteroaryl, (C)1-C10) Heterocyclyl and (C)3-C10) Cycloalkyl groups.
11. A compound according to claim 1, wherein R6Is hydrogen.
12. A compound according to claim 1, wherein s is an integer from zero to two, each R3Independently selected from the group consisting of halo, (C)1-C6) Alkyl, perhalogenated (C)1-C6) Alkyl, (C)1-C6) Alkoxy, perhalogenated (C)1-C6) Alkoxy and-CN groupsAnd (3) forming a group.
13. The compound according to claim 1, wherein the compound is selected from the group consisting of:
3-isopropyl-6- (4-phenyl-oxazol-5-yl) - [1, 2, 4] triazolo [4, 3-a ] pyridine;
3-ethyl-6- (4-m-tolyl-oxazol-5-yl) - [1, 2, 4] triazolo [4, 3-a ] pyridine;
3-cyclopropyl-6- [4- (4-fluoro-phenyl) -oxazol-5-yl ] - [1, 2, 4] triazolo [4, 3-a ] pyridine;
3-cyclobutyl-6- [4- (4-fluoro-phenyl) -oxazol-5-yl ] - [1, 2, 4] triazolo [4, 3-a ] pyridine;
3-cyclobutyl-6- (4-phenyl-oxazol-5-yl) - [1, 2, 4] triazolo [4, 3-a ] pyridine;
3-cyclopropyl-6- (4-phenyl-oxazol-5-yl) - [1, 2, 4] triazolo [4, 3-a ] pyridine;
3-ethyl-6- (4-phenyl-oxazol-5-yl) - [1, 2, 4] triazolo [4, 3-a ] pyridine;
3-ethyl-6- [4- (4-fluoro-phenyl) -oxazol-5-yl ] - [1, 2, 4] triazolo [4, 3-a ] pyridine;
6- [4- (4-fluoro-phenyl) -oxazol-5-yl ] -3-isopropyl- [1, 2, 4] triazolo [4, 3-a ] pyridine;
3-cyclobutyl-6- (4-m-tolyl-oxazol-5-yl) - [1, 2, 4] triazolo [4, 3-a ] pyridine;
3-isopropyl-6- (4-m-tolyl-oxazol-5-yl) - [1, 2, 4] triazolo [4, 3-a ] pyridine;
6- [4- (4-fluoro-3-methyl-phenyl) -oxazol-5-yl ] -3-isopropyl- [1, 2, 4] triazolo [4, 3-a ] pyridine;
3-cyclopropyl-6- [4- (4-fluoro-3-methyl-phenyl) -oxazol-5-yl ] - [1, 2, 4] triazolo [4, 3-pyridine;
6- [4- (4-fluoro-phenyl) -oxazol-5-yl ] -3-phenyl- [1, 2, 4] triazolo [4, 3-a ] pyridine;
3-isopropyl-6- (2-methyl-4-phenyl-oxazol-5-yl) - [1, 2, 4] triazolo [4, 3-a ] pyridine; and
6- [4- (4-fluoro-phenyl) -2-methyl-oxazol-5-yl ] -3-isopropyl- [1, 2, 4] triazolo [4, 3-a ] pyridine.
14. A method of treating an ERK/MAP kinase mediated disease in a mammal in need thereof, which comprises administering to said mammal an effective amount of a compound according to any preceding claim.
15. A pharmaceutical composition for the treatment of a condition in a mammal, including a human, to be treated by inhibition of ERK/MAP kinase comprising a therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier.
HK04104273.6A 2001-03-09 2002-02-08 Triazolopyridines as anti-inflammatory agents HK1061235A (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
US60/274,840 2001-03-09

Publications (1)

Publication Number Publication Date
HK1061235A true HK1061235A (en) 2004-09-10

Family

ID=

Similar Documents

Publication Publication Date Title
CN1496366A (en) Triazolopyridines as anti-inflammatory agents
US6664395B2 (en) Benzotriazoles anti-inflammatory compounds
CN1211381C (en) Substituted imidazoles useful in treatment of inflammatory diseases
CN1681805A (en) Novel imidazole compounds as transforming growth factor (TGF) inhibitors
CN1681810A (en) Novel oxazole and thiazole compounds as transforming growth factor (TGF) inhibitors
CN1083473A (en) Novel imidazole compound and its pharmaceutical composition
CN1703405A (en) Aminobenzamide derivatives as glycogen synthase kinase 3 beta inhibitors
CN1294133C (en) Imidazo-pyrimidine derivatives as ligands for GABA receptors
CN1582285A (en) Heteroaryl amines as glycogen synthase kinase 3beta inhibitors (GSK3 inhibitors)
CN1218801A (en) Trisubstituted imidazole compounds, preparation method and application thereof, and pharmaceutical composition containing them
CN1795184A (en) Di-aryl substituted pyrazole modulators of metabotropic glutamate receptor-5
CN1860118A (en) Compounds and compositions as protein kinase inhibitors
CN1422273A (en) 1,5-disubstituted-3,4-dihydro-1H-pyrimido [4,5-D] pyrimidi-2-one compounds and their use in treating CSBP/P38 kinase mediated diseases
CN1284945A (en) Substituted pyriding and pyridazine compounds and their pharmaceutical use
CN1681502A (en) Novel triazole compounds as transforming growth factors (TGF) inhibitors
CN1681501A (en) Pyrazole derivatives as transforming growth factor (TGF) inhibitors
CN1518550A (en) Imidazo[1,2-A]pyridine derivatives for preventing and treating herpes virus infection
CN1681809A (en) Novel isothiazole and isoxazole compounds as transforming growth factor (TGF) inhibitors
CN1202171A (en) Pyrido[2,3-d]pyrimidine derivatives and pharmaceutical compositions thereof
CN1794990A (en) Diaryl-substituted pyrrole modulators of metabotropic glutamate receptor-5
CN1768055A (en) Tetracyclic imidazole derivatives as modulators of metabotropic glutamate receptor-5
CN1646131A (en) Novel compounds
CN1701069A (en) 3,4-disubstituted pyrroles and their for use in treating inflammatory diseases
CN1856493A (en) Aminopyridine derivatives as inducible NO-synthase inhibitors
CN1246858A (en) Substituted pyrimidine compounds and their use