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HK1099281A - Indolinone derivatives and their use in treating disease-states such as cancer - Google Patents

Indolinone derivatives and their use in treating disease-states such as cancer Download PDF

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Publication number
HK1099281A
HK1099281A HK07105373.9A HK07105373A HK1099281A HK 1099281 A HK1099281 A HK 1099281A HK 07105373 A HK07105373 A HK 07105373A HK 1099281 A HK1099281 A HK 1099281A
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HK
Hong Kong
Prior art keywords
indolin
methylene
optionally substituted
pyrrol
hydrogen
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HK07105373.9A
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Chinese (zh)
Inventor
达米安．阿奈兹
朱迪．布赖恩特
仇友玲
理查德．I.．费尔德曼
保罗．赫尔瓦廷
伊马杜尔．伊斯拉姆
莫尼卡．科恰尼
李辉松
马克．波洛科夫
余洪仪
袁沈东
Original Assignee
舍林股份公司
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Publication of HK1099281A publication Critical patent/HK1099281A/en

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Indolinone derivatives and their use in the treatment of disease states such as cancer
This application claims priority from U.S. provisional application 60/514,081 filed on 24/10/2003, which is incorporated herein by reference in its entirety.
Technical Field
The present invention relates to indolinone derivatives for use in the treatment of disease states alleviated by the inhibition of serine/threonine kinase activity designated phosphoinositide-dependent kinase 1 (PDK-1). The invention also relates to pharmaceutical compositions containing the derivatives and methods of using the compounds and compositions in the treatment of disease states such as cancer.
Background
Phosphoinositide-dependent kinase 1(PDK-1) is a serine/threonine (Ser/Thr) kinase that functions to phosphorylate and activate other Ser/Thr kinases in The AGC kinase family (see, e.g., Vanhaasebroeck, B. and D.R. Alessi, "The P13K-PDK-1 connection: more than just a road to PKB," biochem. J. (2000), Vol.346(Pt 3), pp.561-76). The best characterized substrate for PDK-1 is the intracellular Ser/Thr kinase known as AKT, which is expressed and/or activated in a variety of cancers. PDK-1 may also phosphorylate and activate serum/glucocorticoid-regulated kinase (SGK), which is structurally related to AKT. Once activated within a tumor, AKT increases tumor cell survival, resistance, growth, and angiogenesis. Three highly related isoforms of AKT are known in humans, namely AKT1, AKT2, and AKT 3. Activation of AKT is dependent on the activity of phosphatidylinositol3 kinase (PI-3 kinase), which is activated by a number of signal transduction molecules elevated in cancer cells, including growth factor receptors (e.g., Epidermal Growth Factor (EGF) receptor, ErbB2, and IGF1 receptor) and oncogenes (e.g., Ras, BCR-abl, and Src). Other potential substrates for PDK-1 include p 70S 6 kinase, p 90S 6 kinase, protein kinase C, cAMP dependent Protein Kinase (PKA), protein kinase G, and serum/glucocorticoid regulated kinase (SGK).
AKT exists predominantly in an inactive form in non-stimulated cells, and PDK-1 mediated phosphorylation of AKT converts the enzyme to a catalytically active form. This activates the loop domains such as threonine 309 of AKT2 and threonine of AKT1 by AKTPhosphorylation of amino acid 308 occurs. Phosphorylation of the homeodomain in many kinases is known to modulate the activity of their kinases. One activator of PDK-1 mediated phosphorylation of AKT is the PI-3 kinase product (3, 4, 5) PIP that binds to the Pleckstrin Homology (PH) domain of AKT3Or (3, 4) PIP2. While AKT exhibits low, basal levels of activity in normal, non-stimulated cells, AKT is often constitutively activated in tumor cells. This occurs through the upregulation of a variety of different signaling molecules or the presence of oncogene mutations commonly found in cancer cells, such as PI-3 kinase, growth factor receptors (e.g., EGFR family members), Ras, Src and BCR-ABL activation, which promote the activation of AKT. Loss of the tumor suppressor PTEN is another means of greatly increasing AKT activity in cancer cells (Besson, A. et al, "PTEN/MMAC 1/TEP1 in signal transmission and tomogenesis," Eur. J. biochem. (1999), Vol.263, No.3, pp.605-611). PTEN mutations or PTEN protein down regulation are found in a variety of tumors and cancer cell lines. PTEN is a phosphatase that removes D-3 phosphate from PI-3 kinase products such as phosphatidylinositol3, 4, 5-triphosphate and phosphatidylinositol3, 4-diphosphate (Myers, M.P. et al, "The lipid phosphorus activity of PTEN is diagnostic for The enzymes promoter function," Proc. Natl.Acad.Sci.USA (1998), Vol.95, No.23, pp.13513-13518; Stambolic, V. et al, "novel regulation of PKB/Akt-dependent Cell summary by The enzymes promoter PTEN," Cell (1998), Vol.95, pp.1, pp.29-39). Thus, loss of PTEN has the effect of increasing PI-3 kinase production and promoting constitutive activation of AKT. Cancers with greatly up-regulated levels of AKT may be particularly sensitive to the action of inhibitors of the PDK-1/AKT pathway.
Downstream substrates of PDK-l and/or AKT are associated with a number of cellular responses including proliferation, metabolism and cell survival (Testa, J.R. and A. Bellacosasa, "AKT plants a Central roll in tomogenisis," Proc. Nati.Acad. Sci. USA (2001), Vol.98, No.20, pp.10983-5; Vivanco, 1. and C.L. Sawyers, "The phosphatodynolosonitol 3-Kinase AKT pathway in human cam," nat. Rev. cam (2002), Vol.2, No.7, pp.489-501). Examples of signal transduction molecules downstream of PDK-1 or AKT involved in these pathways include BAD, p 70S 6 kinase, p21(Waf-1/Cip-1), Forkhead transcription factor, p27(kip-1), GSK-3- α/β, TSC2 (patatin), and ecNOS. The survival function of AKT is a particularly well-described Cellular activity of AKT (Datta, S.R. et al, "Cellular survival: a plane in three Akts," Genes Dev. (1999), Vol.13, No.22, pp.2905-27). AKT acts to inhibit cell death, i.e., apoptosis, caused by various agents including UV radiation, chemotherapeutic drugs, TFG- β, withdrawal of survival factors, overexpression of oncogenes such as c-myc, and detachment of cells from the extracellular matrix.
The ability to escape apoptosis is a key feature of tumor cells, which allows their uncontrolled growth and aggressive behavior. One trigger for apoptosis is disruption of normal growth regulation caused by oncogene mutations or abnormal expression of signal transduction molecules associated with cell proliferation. Thus, the apoptotic pathway provides a key means to prevent the development and progression of tumors. Cancer cells can evade apoptotic death by selective activation of signal transduction molecules that cut off apoptotic signals, such as AKT. Some oncogenes, e.g., Ras, which is activated in up to 60% of human tumors, promote both uncontrolled growth and activation of AKT. Inhibition of AKT in NIH 3T3 cells prevented transformation of these activated Ras-transfected cells. In addition, many studies have shown that combining oncogenes with expression of activated forms of AKT greatly promotes tumor formation in vivo (e.g., Holland, E.C., et al, "Combined activation of Ras and Akt in neural prognostics flexibility formation in mice," nat. Gene (2000), Vol.25, No.1, pp.55-7). Thus, PDK-1 inhibitors that block AKT activation are a means of promoting apoptosis in tumor cells, particularly but not necessarily limited to tumor cells that overexpress AKT activity.
Inhibitors of the PDK-1/AKT pathway are also expected to block the development of cancer by inhibiting tumor-stimulated angiogenesis (Dimmeler, S. and A.M.Zeiher, "Akt takes centerstage in angiogenesis signaling," Circuit. Res. (2000), Vol.86, No.1, pp.4-5; Shiojima, l. and K.Walsh, "Role of Akt signaling in vascalthomorpha and great freedom," Circuit. Res. (2002), Vol.90, No.12, pp.1243-50). AKT has been shown to regulate a variety of key responses in the angiogenic process, including endothelial cell migration, proliferation and survival in neovascularization, ecNOS regulation, endothelial cell responses to growth factors including IGF-1, agniopetin-1 and VEGF, and regulation of hypoxia inducible factor 1(HIF-1) -alpha levels.
Inhibition of the cell cycle and growth of tumor cells is another expected effect of compounds that block PDK-1 and/or AKT. Many studies have shown that inhibition of PDK-1 and/or AKT activity regulates the growth of cancer cells. These effects may occur through PDK-1 or AKT mediated regulation of a number of different important signal transduction pathways in growth regulation. For example, AKT has been shown to block the nuclear localization and/or expression of cyclin-dependent kinase inhibitors p21(Waf-1/Cip-1) and p27 (kip-1). Inhibitors that block these effects would be expected to decrease the activity of cyclin-dependent kinases, block progression through the cell cycle and slow the growth of tumor cells. AKT has been found to inhibit Myt1 and thus act as an initiator of mitosis in starfish Asterina pectinfera oocytes. In addition, PDK-1 and/or AKT regulate the expression of proteins important for cell growth by regulating mTOR, p 70S 6 kinase, and eukaryotic initiation factor 4E binding protein 1(4E-BP 1). Although the mechanism of this regulation has not been established, AKT phosphorylation has been shown to decrease expression of TSC2, thereby decreasing TSC-2 mediated inhibition of mTOR activity. This in turn promotes the activation of p 70S 6 kinase activity and the phosphorylation and inhibition of 4E-BP1 (Inoki, K. et al, "TSC 2 is phosphorylated and inhibited by Akt and expressed mTOR signaling," nat. cell. biol. (2002), Vol.12, p.12; and Potter, C.J. et al, "Akt regulated growth by direct phosphorylation Tsc2," nat. cell. biol. (2002), Vol.12, p.12). Both of these effects result in increased synthesis of mRNA encoding proteins important for cell growth. Loss of TSC2 function is associated with tuberous sclerosis, a disease that results in differentiated benign growth (hamartomas) in various organs. PDK-1 has also been shown to play a direct role in the phosphorylation and activation of p 70S 6 kinase (Alessi, D.R. et al, "3-phosphoinoside-dependent protein kinase 1(PDK-1) phosphoriylates and activities the p 70S 6 kinase in vivo and invitro," curr.biol. (1998), Vol.8, No.2, pp.69-81).
Thus, compounds that block PDK-1 mediated activation of AKT or block PDK-1 directly may be useful therapeutically active agents in a variety of disease states such as cancer.
Disclosure of Invention
The present invention relates to indolinone derivatives for use in the treatment of a mammal, particularly a human, suffering from a disease state which is alleviated by the inhibition of PDK-1 activity.
Thus, in one aspect, the present invention relates to a compound of formula (I):
wherein:
m is 0 to 4;
n is 0 to 3;
a is oxygen or sulfur;
R1is hydrogen, alkyl, -C (O) OR7or-C (O) N (R)7)2(ii) a Or
R1Is (optionally substituted with one or more groups selected from alkyl, aryl, aralkyl, halo, haloalkyl, cyano, nitro, -R8-OR7、-R8-N(R7)2、-R8-C(O)OR7、-R8-C(O)N(R7)2、-R8-N(R7)C(O)N(R7)2、-R8-N(R7)C(O)-R9-N(R7)2and-R8-N(R7)C(O)OR7Substituent(s) ofSubstituted) aryl; or
R1Is (optionally substituted with one or more groups selected from alkyl, aryl, aralkyl, halo, haloalkyl, cyano, nitro, -R8-OR7、-R8-N(R7)2、-R8-C(O)OR7、-R8-C(O)N(R7)2、-R8-N(R7)C(O)N(R7)2、-R8-N(R7)C(O)-R9-N(R7)2and-R8-N(R7)C(O)OR7Substituted with the substituent(s) of (a); or
R1Is (optionally substituted with one or more groups selected from alkyl, aryl, aralkyl, halo, haloalkyl, cyano, nitro, -R8-OR7、-R8-N(R7)2、-R8-N(R7)C(O)N(R7)2、-R8-N(R7)C(O)-R9-N(R7)2and-R8-N(R7)C(O)OR7Substituted with the substituents of (1); or
R1Is (optionally substituted with one or more groups selected from alkyl, aryl, aralkyl, halo, haloalkyl, cyano, nitro, -R8-OR7、-R8-C(O)OR7、-R8-C(O)N(R7)2、-R8-N(R7)2、-R8-N(R7)C(O)N(R7)2、-R8-N(R7)C(O)-R9-N(R7)2and-R8-N(R7)C(O)OR7Substituted with the substituents of (a) or (b);
each R2Independently selected from alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, cyano, -R8-OR7、-R8-N(R7)2、-R8-C(O)OR7、-R8-C(O)N(R7)2、-R8-S(O)tN(R7)2(wherein t is 1 or 2), -R8-N(R7)S(O)tR7(wherein t is 1 or 2), -R8-N(R7)S(O)tN(R7)2(wherein t is 1 or 2), -R8-N(R7)S(O)tN(R7)C(O)OR7(wherein t is 1 or 2), -R8-N(R7)C(O)R7、-R8-N(R7)-R8-C(O)OR7、-R8-N(R7)C(O)N(R7)2、-R8-N(R7)C(O)-R9-N(R7)2、-R8-N(R7)-R9-C(O)N(R7)2、-R8-N(R7)C(O)-R8-N(R7)-R8-C(O)OR7、-R8-N(R7)C(O)-R8-N(R7)-R8-C(O)-R8-N(R7)2、-N(R7)C(＝NR7)N(R7)2、-C(＝NR7)-N(R7)2、-R8-N＝C(R7)2(optionally substituted with one or more groups selected from alkyl, aryl, aralkyl, halo, haloalkyl, cyano, nitro, -R8-OR7、-R8-C(O)OR7、-R8-C(O)N(R7)2、-R8-N(R7)2、-R8-N(R7)C(O)-R8-N(R7)2and-R8-N(R7)C(O)OR7Substituted with the substituents) heterocyclic group and optionally substituted cyclic ureido group;
R3is hydrogen, alkyl or aralkyl;
R5is hydrogen, alkyl, aryl, aralkyl, -C (O) R11or-S (O)2R11；
Each R6Independently selected from alkyl, alkenyl, alkynyl, halogen, haloalkyl, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, -R9-OR7、-R8-C(O)OR7、-R8-C(O)N(R7)2、-R8-C(O)-R9-N(R7)2、-R8-C(O)R7、-R8-N(R7)2、-R8-N(R7)C(O)R7、-R8-N(R7)-R8-C(O)OR7、-R8-N(R7)C(O)N(R7)2、-R8-N(R7)C(O)-R9-N(R7)2、-R8-N(R7)C(O)-R10-N(R7)2、-R8-N(R7)C(O)-R8-N(R7)C(O)-R8-N(R7)2、-R8-C(O)-R9-C(O)OR7、-R8-C(O)-R9-C(O)N(R7)2、-R8-N(R7)C(O)-R8-N(R7)-R8-C(O)OR7、-R8-N(R7)C(O)-R8-N(R7)-R8-C(O)N(R7)2、-R8-N(R7)C(O)-R9-C(O)OR7、-R8-N(R7)C(O)-R9-C(O)N(R7)2、-R8-S(O)t-N(R7)2(wherein t is 1 or 2), -R8-N(R7)S(O)t-R8-N(R7)2(wherein t is 1 or 2) and-R8-N(R7)S(O)t-R7(wherein t is 1 or 2);
each R7Independently hydrogen, optionally substituted alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl;
each R8Is a bond or a straight or branched alkylene chain;
each R9Is a straight or branched alkylene chain;
R10is an amino acid residue other than a straight or branched alkylene chain; and is
Each R11Is optionally substituted alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl;
the compound of formula (I) is a single stereoisomer, a mixture of stereoisomers, a solvate or a polymorph;
the conditions were as follows:
(1) when m is 1, n is 1, A is oxygen, R1、R3And R5Each is hydrogen, and R6When it is 3-methoxy, then R2Cannot be 4-bromo, 4-iodo, 5-bromo;
(2) when m is 1, n is 0, A is oxygen, R1、R3And R5When each is hydrogen, then R2Cannot be 5-bromo, 5-iodo or 4-bromo;
(3) when R is6When it is 3-methoxy, then R2Not an optionally substituted ethenyl or ethynyl group;
(4) when m is2, n is 1, A is oxygen, R1、R3And R5Each is hydrogen, and R6When it is methoxy, then when one R is2Another R when it is 5-nitro2Cannot be 4-bromo;
(5) when m is 0, n is2, A is oxygen, R3And R5Each is hydrogen, and one R6Is 3-methyl and the other R6When it is 5-methyl, then R1Not being hydrogen, -C (O) OR7or-C (O) N (R)7)2；
(6) When m is 0, n is 0, A is oxygen, and R1And R3When each is hydrogen, then R5Cannot be hydrogen;
(7) when m is 1, n is 0, A is oxygen, and R1、R3And R5When each is hydrogen, then R2Cannot be 4-methyl, 4-bromo, 4-thiophen-2-yl or 2, 6-dimethoxypyrimidin-4-yl;
(8) when m is 1, n is 1, A is oxygen, R1、R3And R5Each is hydrogen, and R6When it is 3-methoxy, then R2Cannot be 4-indol-5-yl, 4-indol-6-yl or 4-indol-4-yl;
(9) when m is 1, n is 1, R1、R3And R5Each is hydrogen, R6Is 3-methoxy, and one R2When it is 4-indol-6-yl, then another R2Cannot be 5-nitro, 5-amino or 5- (thien-2-ylacetamino);
(10) when m is2, n is 0 or1, A is oxygen, R1、R3And R5Each is hydrogen, and R6When it is 3-methoxy, then when one R is2Another R when it is 5-amino2Cannot be a 4-amino group;
(11) when m is2, n is 0 or1, A is oxygen, R1、R3And R5Each is hydrogen, and R6When it is 3-methoxy, then when one R is2Another R when it is 4-fluoro or 4-azido2Cannot be 5-nitro;
(12) when m is 0, n is 3, A is oxygen, R1、R3And R5Each is hydrogen, and one R6Is 3-methyl and a second R6When it is 5-methyl, then the third R6Cannot be 4- (2-carboxyethyl), 4- (3-morpholin-4-ylpropyl) or 4- (3-dimethylaminopropyl);
(13) when m is 1, n is2, A is oxygen, R1、R3And R5Each is hydrogen, and one R6Is 3-methyl and the other R6Is 4- (2-carboxyethyl) or 4- [2- (3, 5-dimethoxybenzyloxycarbonyl) ethyl]When then R is2But not 5-chloro, 6-methoxy, 5-bromo, 5-iodo, 4-methyl, 5-methyl, 6-chloro, 5-methoxycarbonyl, 5-carboxy, 5-aminosulfonyl, 5-methylaminosulfonyl, 5- (2-carboxyethyl), 5-ethyl, 5-methoxy, 6-hydroxy, 6-bromo or 6-bromo;
(14) when m is 1, n is 3, A is oxygen, R1、R3And R5Each is hydrogen, and one R6Is 3-methyl and a second R6Is 5-methyl, the third R6Is 4- (2-carboxyethyl), 4- (3-dimethylaminopropyl) or 4- (3-morpholin-4-ylpropyl), then R2But not 5-chloro, 5-bromo, 5-iodo, 4-methyl, 5-methyl, 6-hydroxy, 6-methoxy, 6-morpholin-4-yl, 6-chloro, 5-methoxy, 4- (2-hydroxyethyl), 5-aminosulfonyl, 5- (1-methylethylaminosulfonyl), 5- (morpholin-4-ylsulfonyl) or 5- (dimethylaminocarbonyl);
(15) when m is 0, n is2, A is oxygen, R1、R3And R5Each is hydrogen, and one R6When it is 3-methoxy, then another R6Cannot be 5-methyl or 4- (2-carboxyethyl);
(16) when m is2, n is2, A is oxygen, R1、R3And R5Each being hydrogen, one R6Is 4- (12-carboxyethyl), and a second R6When it is 3-methyl, then two R are2' cannot be 5, 6-dimethoxy or 4-methyl-5-chloro;
(17) when m is2, n is 3, A is oxygen, R1、R3And R5Each being hydrogen, one R6Is 3-methyl and a second R6Is 5-methyl, and a third R6When it is 4- (2-carboxyethyl), then R2' cannot be 4-methyl and 5-chloro;
(18) when m is 0, n is 0, A is oxygen, R1And R5When each is hydrogen, then R5Not hydrogen, methyl, 4-chlorophenyl or 3, 5-dichlorophenyl;
(19) when m is 0, n is 1, A is oxygen, R1、R3And R5When each is hydrogen, then R2Cannot be 3-methyl or 5-ethyl;
(20) when m is 0, n is2, A is oxygen, R1、R3And R5Each being hydrogen, then together R2' cannot be 3, 4-dimethyl, 3, 5-dimethyl, 3-methyl-4- [ 2-carboxyethyl]3-methyl-4- [ 2-methoxy groupCarbonylethyl group]Or 4-methyl-3-ethoxycarbonyl;
(21) when m is 0, n is 3, A is oxygen, R1、R3And R5Each being hydrogen, then together R2' cannot be 4- [ ethoxycarbonyl]-3, 5-dimethyl, 5-methyl-3, 4-dibromo, 5-formyl-3, 4-dimethyl, 3-ethyl-4, 5-dimethyl, 5-ethoxycarbonyl-4- [ 2-ethoxycarbonylethyl]-3- [ ethoxycarbonylmethyl group]5-carboxy-3-ethyl-4-methyl, 4-methyl-3, 5-dichloro, 5-chloro-3-methoxycarbonyl-4- [ methoxycarbonylmethyl [ ]]3-acetyl-5-ethoxycarbonyl-4-methyl, 5-ethoxycarbonyl-3- (2-ethoxycarboxyethyl) -4- (ethoxycarbonylmethyl), 4-ethyl-3, 5-dimethyl, 4-prop-3-enyl-3, 5-dimethyl;
(22) when m is 1, n is 0, A is oxygen, R1、R3And R5When each is hydrogen, then R2Cannot be 5-chloro or 5-nitro;
(23) when m is 1, n is 1, A is oxygen, R1、R3And R5Each is hydrogen, R6When it is 3-methyl, then R2Cannot be 5-nitro or 5-chloro;
(24) when m is 1, n is2, A is oxygen, R1、R3And R5Each is hydrogen, and R6When' is 3, 5-dimethyl, then R2Cannot be 5-nitro or 5-chloro;
(25) when m is2, n is 0 or1, A is oxygen, R1、R3And R5Each is hydrogen, R6Is 3-methoxy, and one R2When it is 4-amino, then another R2Cannot be a 5-amino group;
(26) when m is2, n is 0 or1, A is oxygen, R1、R3And R5Each is hydrogen, R6Is 3-methoxy, and one R2When it is 5-nitro, then another R2Cannot be 4-fluoro or 4-azido;
(27) when m is 1, n is 3, A is oxygen, R1、R3And R5Each is hydrogen, and one R6Is 3-methylSecond R6Is 5-methyl and the third R6When it is 4- (3-dimethylaminopropyl) or 4- (2-carboxyethyl), then R2Cannot be 6- (pyridin-3-yl), 6- (thiophen-2-yl), 4- (2-hydroxyethyl) or 4- (2- (3- (1-methylethyl) phenoxy) ethyl;
(28) when m is 0, n is2, A is oxygen, R3And R5Each is hydrogen, and one R6Is 3-methyl and a second R6When it is 5-methyl, then R1Cannot be 4-methoxyphenyl or 3, 4-dimethoxyphenyl;
(29) when m is2, n is 1, A is oxygen, R1、R3And R5Each is hydrogen, and one R2Is 4-amino and a second R2When it is 5-amino, then R6Cannot be 3-methoxy;
(30) when m is2, n is 1, A is oxygen, R1、R3And R3Each is hydrogen, and one R2Is 4-fluoro or 4-azido, and a second R2When it is 5-nitro, then R6Cannot be 3-methoxy;
(31) when m is 0 or1, n is 3, A is oxygen, R1、R3And R5Each is hydrogen, and one R6Is 5-methyl and a second R6Is 3-methyl or 3-phenyl (optionally substituted by fluoro, chloro or cyano), the third R6is-C (O) OH or one of R7Is hydrogen or methyl and the other R7Is an alkyl group optionally substituted by hydroxy, diethylamino and/or an optionally substituted N-heterocyclic group, -C (O) N (R)7)2When then R is2Halogen not in position 5, trifluoromethoxy, -C (O) R7(wherein R is7Is morpholinyl) or-C (O) N (R)7)2(wherein each R is7Independently hydrogen, hydroxyalkyl, alkyl or phenyl); and
(32) m is 1, when n is 3, A is oxygen, R1、R3And R5Each is hydrogen, and one R6Is 3-methyl and a second R6Is 5-methyl, the third R6Is 4-bit-C(O)R7(wherein R is7Is optionally substituted N-heterocyclyl), then R6In which R cannot be in the 4-position7is-C (O) R of an optionally substituted N-heterocyclyl7，R2And not halogen or 3-pyridyl.
In another aspect, the invention relates to a compound of formula (II):
wherein:
m is 0 to 4;
a is oxygen or sulfur;
R1is hydrogen, alkyl, haloalkyl, -C (O) OR7or-C (O) N (R)7)2(ii) a Or
R1Is (optionally substituted with one or more groups selected from alkyl, aryl, aralkyl, halo, haloalkyl, cyano, nitro, -R8-OR7、-R8-N(R7)2、-R8-C(O)OR7、-R8-C(O)N(R7)2、-R8-N(R7)C(O)-R8-N(R7)2and-R8-N(R7)C(O)OR7Substituted with the substituents of (1) aryl); or
R1Is (optionally substituted with one or more groups selected from alkyl, aryl, aralkyl, halo, haloalkyl, cyano, nitro, -R8-OR7、-R8-N(R7)2、-R8-C(O)OR7、-R8-C(O)N(R7)2、-R8-N(R7)C(O)-R8-N(R7)2and-R8-N(R7)C(O)OR7Substituted with the substituent(s) of (a); or
R1Is (optionally substituted with one or more substituents selected from alkyl, aryl, aralkyl, halo, haloalkyl,Cyano, nitro, -R8-OR7、-R8-N(R7)2、-R8-C(O)OR7，、-R8-C(O)N(R7)2、-R8-N(R7)C(O)-R8-N(R7)2and-R8-N(R7)C(O)OR7Substituted with the substituents of (1); or
R1Is (optionally substituted with one or more groups selected from alkyl, aryl, aralkyl, halo, haloalkyl, cyano, nitro, -R8-OR7、-R8-N(R7)2、-R8-C(O)OR7、-R8-C(O)N(R7)2、-R8-N(R7)C(O)-R8-N(R7)2and-R8-N(R7)C(O)OR7Substituted with the substituents of (a) or (b);
each R2Independently selected from alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, cyano, -R8-OR7、-R8-N(R7)2、-R8-C(O)OR7、-R8-C(O)N(R7)2、-R8-S(O)tN(R7)2(wherein t is 1 or 2), -R8-N(R7)S(O)tR7(wherein t is 1 or 2), -R8-N(R7)S(O)tN(R7)2(wherein t is 1 or 2), -R8-N(R7)S(O)tN(R7)C(O)OR7(wherein t is 1 or 2), -R8-N(R7)C(O)R7、-R8-N(R7)-R8-C(O)OR7、-R8-N(R7)C(O)-R8-N(R7)2、-R8-N(R7)C(O)-R8-N(R7)-R8-C(O)OR7、-R8-N(R7)C(O)-R8-N(R7)-R8-C(O)-R8-N(R7)2、-N(R7)C(＝NR7)N(R7)2、-C(＝NR7)-N(R7)2、-R8-N＝C(R7)2(optionally substituted with one or more groups selected from alkyl, aryl, aralkyl, halo, haloalkyl, cyano, nitro, -R8-OR7、-R8-C(O)OR7、-R8-C(O)N(R7)2、-R8-N(R7)2、-R8-N(R7)C(O)-R8-N(R7)2and-R8-N(R7)C(O)OR7Substituted with the substituents) heterocyclic group and optionally substituted cyclic ureido group;
R3is hydrogen, alkyl or aralkyl;
R4is (optionally substituted with one or more groups selected from alkyl, aryl, aralkyl, halo, haloalkyl, cyano, nitro, -R8-OR7、-R8-N(R7)2、-R8-C(O)OR7、-R8-C(O)N(R7)2、-R8-N(R7)C(O)-R8-N(R7)2and-R8-N(R7)C(O)OR7Substituted with the substituents of (1) naphthyl; or
R4Is (optionally substituted with one or more groups selected from alkyl, aryl, aralkyl, halo, haloalkyl, cyano, nitro, -R8-OR7、-R8-OC(O)OR7、-R8-N(R7)2、-R8-C(O)OR7、-R8-C(O)N(R7)2、-R8-N(R7)C(O)-R8-N(R7)2and-R8-N(R7)C(O)OR7Substituted with the substituents of (1);
each R7Independently selected from hydrogen, alkyl, -R9-OR7Haloalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl;
each R8Is a bond or a straight or branched alkylene chain; and is
Each R9Is a straight or branched alkylene chain;
the compound of formula (II) is a single stereoisomer, a mixture of stereoisomers, or a racemic mixture of stereoisomers; or is a solvate or polymorph; or a pharmaceutically acceptable salt thereof;
the conditions were as follows:
(1) when m is2, A is oxygen, R1And R3Each being hydrogen, one R2Is 5-nitro and the other R is2When is 4-bromo, then R4Cannot be 5-methylimidazol-4-yl;
(2) when m is2, A is oxygen, R1And R3Each being hydrogen, one R2Is 5-fluoro and the other R2When it is 4-iodo or 4- (1, 3-benzodioxol-5-yl), then R4Cannot be 5-methylimidazol-4-yl;
(3) when m is 1, A is oxygen, R1And R3Each is hydrogen, and R2When it is 4- (2-hydroxyethyl), then R4Cannot be pyridin-2-yl, 6-methylpyridin-2-yl, indol-5-yl or 3-hydroxy-6-methylpyridin-2-yl;
(4) when m is 1, A is oxygen, R1And R3Each is hydrogen, and R2When it is 5-bromo or 5-ethynyl, then R4Cannot be 5-methylimidazol-4-yl;
(5) when m is 0, A is oxygen, and R1And R3When each is hydrogen, then R4Cannot be pyridin-4-yl, 4-methylthiothien-2-yl, 5-methylthiothien-2-yl, 3-methylthiothien-2-yl, furan-2-yl, thien-2-yl, 5- [3, 5-bis (trifluoromethyl) phenyl]Furan-2-yl, 5-iodofuran-2-yl, 4-ethoxycarbonyl-5-methylfuran-2-yl, 3-bromothien-2-yl, 5-chlorothien-2-yl, 4, 5-dimethylfuran-2-yl, 5-nitrothien-2-yl, 5-carboxythien-2-yl, 5-bromothien-2-yl, 4-bromothien-2-yl, 5-sulfonylfuran-2-yl, furan-2-yl, 5-methylfuran-2-yl, 5-ethylfuran-2-ylFuran-2-yl, 5-nitrofuran-2-yl, 5-bromofuran-2-yl, 5-ethylthiophen-2-yl, 5-methylimidazol-2-yl, 5-methylthiazol-2-yl, 5-methylpyrazol-3-yl, imidazol-4-yl, 4-chloropyrazol-3-yl, 2- (4-chlorobenzyl) -4-bromopyrazol-3-yl, 4-chloro-1-methylpyrazol-3-yl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl, 5-phenyl-1, 2, 4-oxadiazol-3-yl, oxadiazol-2-yl, oxadiazol-4-yl, thiadiazol-methyl, thiadiazol-3-yl, thiadiazol, 3-phenyl-1, 2, 4-oxadiazol-5-yl, 3-phenyl-1, 2, 5-oxadiazol-4-yl, 3-methylthiophen-2-yl, 5-methylimidazolyl-2-yl, bicyclo [2.2.1 ] l]Hept-5-en-2-yl, indol-3-yl; pyridin-4-yl or pyridin-2-yl;
(6) when m is 1, A is oxygen, R1And R3Each is hydrogen, and R2When it is 5-chloro or 5-nitro, then R4Cannot be indol-3-yl, thiophen-2-yl, 3-methylthiothiophen-2-yl, 5-ethylthiophen-2-yl, 5-methylthiothiophen-2-yl or imidazol-2-yl;
(7) when m is2, A is oxygen, R1And R3Each is hydrogen, and R4When it is 5-methylimidazol-4-yl, then together two R2The group cannot be 4-fluoro-5-nitro, 4-azido-5-nitro, 4-amino-5-nitro or 4, 5-diamino;
(8) when m is 1, A is oxygen, R1And R3Each is hydrogen, and R2is-S (O)2N(R7) H (wherein R7Is hydrogen, alkyl or hydroxyalkyl), then R4Not 4, 5,6, 7-tetrahydroindol-2-yl, which cannot be optionally substituted; and
(9) when m is 0, A is oxygen, R1And R3Each being hydrogen, R4And not 4-dimethylaminonaphthyl.
In another aspect, the invention relates to a method of treating a mammal, particularly a human, having a disease state that is alleviated by the inhibition of PKD-1 activity, wherein the method comprises administering to the mammal a compound of formula (I) or formula (II) as described above, including compounds described in the provisos.
In another aspect, the invention relates to a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of formula (I) or formula (II) as described above.
Detailed Description
Definition of
As used herein, the singular forms "a", "an" and "the" and the like include plural references unless the context clearly dictates otherwise. For example, "a compound" refers to one or more of the compounds, "the enzyme" includes the specific enzyme and other family members and equivalents thereof known to those skilled in the art.
Unless otherwise indicated, the following terms used in the specification and appended claims have the meanings indicated.
"alkyl" means a straight or branched chain hydrocarbon group consisting of only carbon atoms and hydrogen atoms, having no unsaturation, having 1 to 8 carbon atoms, and bonded to the rest of the molecule by a single bond, for example, methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, 1-dimethylethyl (tert-butyl), and the like. Unless otherwise specifically stated in the specification, the alkyl group may be optionally substituted by one OR more groups selected from cyano, nitro, -OR7、-N(R7)2、-C(O)R7、-C(O)OR7、-C(O)N(R7)2、-N(R7)C(O)OR7、-N(R7)C(O)R7、-S(O)pR7(wherein p is 0-2) and-S (O)pN(R7)2(wherein p is 0-2), wherein each R is7As defined in the summary above. Unless otherwise specifically stated in the specification, it is to be understood that for substituted alkyl-containing groups defined below, substitution may occur on any carbon of the alkyl group.
"alkenyl" means a straight or branched chain consisting solely of carbon and hydrogen atoms, containing at least one double bond, having from 2 to 8 carbon atoms, and being linked to the rest of the molecule by single or double bondsBranched chain hydrocarbon groups such as vinyl, prop-1-enyl, but-1-enyl, pent-1, 4-dienyl and the like. Unless otherwise specifically stated in the specification, the alkenyl group may be optionally substituted by one OR more groups selected from cyano, nitro, -OR7、-N(R7)2、-C(O)R7、-C(O)OR7、-C(O)N(R7)2、-N(R7)C(O)OR7、-N(R7)C(O)R7、-S(O)pR7(wherein p is 0-2) and-S (O)pN(R7)2(wherein p is 0-2), wherein each R is7As defined in the summary above. Unless otherwise specifically stated in the specification, it is to be understood that for groups defined below containing a substituted alkenyl group, the substitution may occur on any carbon of the alkenyl group.
"alkynyl" means a straight or branched chain hydrocarbon group consisting solely of carbon and hydrogen atoms, containing at least one triple bond, having 2 to 8 carbon atoms, and bonded to the rest of the molecule by single or double bonds, e.g., ethynyl, prop-1-ynyl, but-1-ynyl, pent-1, 4-diynyl, and the like. Unless otherwise specifically stated in the specification, the alkynyl group may be optionally substituted by one OR more groups selected from cyano, nitro, -OR7、-N(R7)2、-C(O)R7、-C(O)OR7、-C(O)N(R7)2、-N(R7)C(O)OR7、-N(R7)C(O)R7、-S(O)pR7(wherein p is 0-2) and-S (O)pN(R7)2(wherein p is 0-2), wherein each R is7As defined in the summary above. Unless otherwise specifically stated in the specification, it is to be understood that for a group defined below containing a substituted alkynyl group, the substitution may occur on any carbon of the alkynyl group.
"aryl" refers to phenyl or naphthyl. Unless otherwise specifically stated in the specification, the term "aryl" or the prefix "aryl" (such as "aryl" in "aralkyl") is intended to include aryl optionally substituted with one or more substituents selected from alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, cyano, halo, cyano, halo, alkoxy,Nitro, aryl, aralkyl, aralkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, heterocyclyl, heterocyclylalkyl, -R8-OR7、-R8-O-R9-C(O)OR7、-R8-N(R7)2、-R8-C(O)R7、-R8-C(O)OR7、-R8-C(O)N(R7)2、-R8-N(R7)C(O)OR7、-R8-N(R7)C(O)R7、-R8-S(O)pR7(wherein p is 0-2), -R8-S(O)pN(R7)2(wherein p is 0-2), -R8-N(R7)C(O)-R8-C(O)OR7and-R8-N(R7)C(O)-R8-N(R7)2Aryl substituted with the substituent of (1), wherein each R7、R8And R9As defined in the summary above.
"aralkyl" means a group of the formula-RaRbWherein R isaIs alkyl as defined above, and RbIs one or more aryl groups as defined above, such as benzyl, diphenylmethyl, and the like. The alkyl and aryl groups may be optionally substituted as defined above.
"aralkenyl" means a group of formula-RcRbWherein R iscIs alkenyl as defined above, and RbIs one or more aryl groups as defined above, such as 3-phenylprop-1-enyl and the like. The alkenyl and aryl groups may be optionally substituted as defined above.
"alkylene" or "alkylene chain" means a divalent straight or branched chain hydrocarbon group consisting of only carbon and hydrogen atoms, free of unsaturation, having 1 to 8 carbon atoms, such as methylene, ethylene, propylene, n-butylene, and the like. The alkylene chain may optionally be substituted by one OR more groups selected from halogen, cyano, nitro, aryl, cycloalkyl, heterocyclyl, cyano, nitro, -OR7、-N(R7)2、-C(O)R7、-C(O)OR7、-C(O)N(R7)2、-N(R7)C(O)OR7、-N(R7)C(O)R7、-S(O)pR7(wherein p is 0-2) and-S (O)pN(R7)2(wherein p is 0-2), wherein each R is7As defined in the summary above. The alkylene chain may be linked to the rest of the molecule via any two carbons in the chain.
"alkenylene" or "alkenylene chain" refers to a divalent straight or branched chain hydrocarbon group consisting of only carbon and hydrogen, containing at least one double bond, having 2 to 8 carbon atoms, such as vinylene, prop-1-enylene, but-1-enylene, pent-1-enylene, hex-1, 4-dienylene, and the like. The alkenylene chain may optionally be substituted with one OR more groups selected from halogen, cyano, nitro, aryl, cycloalkyl, heterocyclyl, cyano, nitro, -OR7、-N(R7)2、-C(O)R7、-C(O)OR7、-C(O)N(R7)2、-N(R7)C(O)OR7、-N(R7)C(O)R7、-S(O)pR7(wherein p is 0-2) and-S (O)pN(R7)2(wherein p is 0-2), wherein each R is7As defined in the summary above. The alkenylene chain may be linked to the rest of the molecule via any two carbons in the chain.
"amino acid residue" refers to the substitution of-C (O) -R at various "side chains" of known amino acids10-N(R7)2or-N (R)7)-R10-C(O)OR7R in the radical linking the nitrogen atom to the carboxyl atom10An alkylene linking group. For example, the amino acid residue of an α -amino acid includes the α -carbon (the carbon to which the carboxyl group and nitrogen atom are attached) and the side chain. Thus the amino acid residue of alanine is-C (CH)3) -; the amino acid residue of serine is-C (CH)2OH) -, etc. The term "amino acid" is intended to include alpha-amino acids, beta-amino acids, gamma-amino acids, and the like, as well as all optical isomers thereof.
"acetylamino" means-N (H) C (O) CH3。
"cycloalkyl" means a stable monovalent monocyclic or bicyclic hydrocarbon group consisting of only carbon and hydrogen atoms, having 3 to 10 saturated carbon atoms, and being singly bonded to the rest of the molecule, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, naphthylalkyl, and the like. Unless otherwise specifically stated in the specification, the term "cycloalkyl" is intended to include alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, cyano, nitro, aryl, aralkyl, aralkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, heterocyclyl, heterocyclylalkyl, -R, optionally substituted with one or more substituents independently selected from alkyl, alkenyl, alkynyl, halo, haloalkyl, haloalkenyl, cyano, nitro, aryl, aralkyl, aralkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, heterocyclyl, heterocyclylalkyl, -R8-OR7、-R8-O-R9-C(O)OR7、-R8-N(R7)2、-R8-C(O)R7、-R8-C(O)OR7、-R8-C(O)N(R7)2、-R8-N(R7)C(O)OR7、-R8-N(R7)C(O)R7、-R8-S(O)pR7(wherein p is 0-2), -R8-S(O)pN(R7)2(wherein p is 0-2) and-R8-N(R7)C(O)-R8-N(R7)2Cycloalkyl substituted with a substituent of (1), wherein each R is7、R8And R9As defined in the summary above.
"cycloalkylalkyl" means a compound of the formula-RaRdWherein R isaIs alkyl as defined above, and RdIs cycloalkyl as defined above. The alkyl and cycloalkyl groups may be optionally substituted as defined above.
"cycloalkylalkenyl" means a group of the formula-RfRdWherein R isfIs alkenyl as defined above, and RdIs cycloalkyl as defined above. The alkenyl and cycloalkyl groups may be optionally substituted as defined above.
"Cycloureido" refers to optionally substituted heterocyclyl groups as defined below containing an ureido group, i.e., -N (H) -C (O) -N (H) -within the ring such as imidazolidinone, hydantoin, parabanic acid, propylidene urea (tri)methylene urea), dihydrouracil, barbituric acid, alloxan, diazepan-2-one (diazapan-2-one), diazepan-2, 6-dione, diazepan-2, 5, 7-trione, and the like. The cyclic urea groups are linked to the rest of the molecule via the nitrogen atom in the urea group. Other cyclic ureido groups include those of the formula N (R)7a)RgWherein R is7aIs hydrogen or alkyl, and RgIs an optionally substituted heterocyclic radical selected from the group consisting of
I.e. a dihydrooxazine or a dihydrooxazole, respectively.
"halogen" means bromine, chlorine, fluorine or iodine.
"haloalkyl" refers to an alkyl group as defined above substituted with one or more halo groups as defined above, e.g., trifluoromethyl, difluoromethyl, trichloromethyl, 2, 2, 2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, 3-bromo-2-fluoropropyl, 1-bromomethyl-2-bromoethyl, and the like.
"haloalkenyl" refers to an alkenyl group as defined above substituted with one or more halogen groups as defined above, e.g., 2-bromovinyl, 3-bromoprop-1-enyl, and the like.
"haloalkoxy" means a compound of the formula-ORcWherein R iscIs a haloalkyl group as defined above, such as trifluoromethoxy, difluoromethoxy, trichloromethoxy, 2, 2, 2-trifluoroethoxy, 1-fluoromethyl-2-fluoroethoxy, 3-bromo-2-fluoropropoxy, 1-bromomethyl-2-bromoethoxy, and the like.
"heterocyclyl" means a stable 3-to 18-membered cyclic group consisting of carbon atoms and 1-5 heteroatoms selected from nitrogen, oxygen and sulfur. For the purposes of the present invention, a heterocyclyl group may be a monocyclic, bicyclic, tricyclic or tetracyclic system, and may include fused or bridged ring systems; and the nitrogen, carbon or sulfur atom in the heterocyclic group may be optionally oxidized; the nitrogen atom may be optionalIs quaternized; and the heterocyclic group may be aromatic or partially or fully saturated. Examples of such heterocyclic groups include, but are not limited to, aza * -yl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzothiadiazolyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranoyl, benzothiophenyl, benzotriazolyl, benzo [4, 6 ] benzofuranyl]Imidazo [1, 2-a ]]A pyridyl group; carbazolyl, cinnolinyl, dioxolanyl, dibenzofuranyl, decahydroisoquinolinyl, furanyl, furanonyl, isothiazolyl, imidazolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, indolyl, indazolyl, isoindolyl, indolinyl, dihydroisoindolyl, indolizinyl, isoxazolyl, isoxazolidinyl, morpholinyl, naphthyridinyl, oxadiazolyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxopazepine * yl, oxazolyl, oxazolidinyl, oxiranyl, piperidinyl, piperazinyl, 4-piperidonyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, pyridinyl, pyrazinyl, pyrimidinyl, and pyrazinyl, Pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, thiazolyl, thiazolidinyl, thiadiazolyl, triazolyl, tetrazolyl, tetrahydrofuryl, triazinyl, tetrahydropyranyl, thienyl, thiomorpholinyl (thiomorpholinyl), thiomorpholinyl sulfoxide and thiomorpholinyl sulfone. Unless otherwise specifically stated in the specification, the term "heterocyclyl" is intended to include alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, cyano, nitro, aryl, aralkyl, aralkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, heterocyclyl, heterocyclylalkyl, -R, optionally substituted with one or more substituents selected from alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, cyano, nitro, aryl, aralkyl, aralkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, heterocyclyl, heterocyclylalkyl, -R, and-R8-OR7、-R8-O-R9-C(O)OR7、-R8-N(R7)2、-R8-C(O)R7、-R8-C(O)OR7、-R8-C(O)N(R7)2、-R8-N(R7)C(O)OR7、-R8-N(R7)C(O)R7、-R8-S(O)pR7(wherein p is 0-2), -R8-S(O)pN(R7)2(wherein p is 0-2) and-R8-N(R7)C(O)-R8-N(R7)2Wherein each R is a hydrogen atom7、R8And R9As defined in the summary above. Preferred heterocyclyl groups are N-heterocyclyl groups, i.e. heterocyclyl groups as defined above which contain at least one nitrogen atom. Examples of such preferred N-heterocyclyl groups include pyrrolyl, pyrrolidinyl, imidazolyl, imidazolinyl, pyridyl, piperidyl, oxazolyl, oxazolidinyl, pyrazinyl, piperazinyl, morpholinyl, and pyrimidinyl.
"Heterocyclylalkyl" means a compound of the formula-RaReWherein R isaIs alkyl as defined above, and ReIs a heterocyclic group as defined above, and if the heterocyclic group is a nitrogen-containing heterocyclic group, the heterocyclic group may be attached to the alkyl group at the nitrogen atom. The heterocyclyl group may be optionally substituted as defined above. Preferred heterocyclylalkyl groups are those as defined above wherein R iseAre the preferred heterocyclylalkyl groups of the N-heterocyclyl group as defined above.
"hydroxyalkyl" means a group of the formula-RaA radical of OH, wherein RaIs an alkyl group as defined above and the hydroxyl group may be on any carbon of the alkyl group.
As used herein, "commercially available" compounds can be obtained from standard commercial sources including: acros Organics (Pittsburgh PA), Aldrich Chemical (MilwaukeeWI, including Sigma Chemical and Fluka), Apin Chemical Ltd, (Miton park UK), Avocado Research (Lancashire U.K.), BDH Inc. (Toronto, Canada), Bionet (Cornwall, U.K.), Chemicals Inc. (West Chemical PA), CreScent Chemical Co., Hauppauge NY, Eastman Organic Chemical, Eastman Kodak Company (Rochester NY), Fisher Scientific Co., Pittsburgh PA, Fisons (Lewsterissu UK), Pintitie Scientific, Syngnal, N, Junkul, Inc., mineral Co., Inc., mountain Co., and mountain Co., Inc., mountain Co., and mountain Co., Inc., mountain Co., Inc., mountain Co., Inc., mountain Co., mountain Co, Trans World Chemicals, Inc (Rockville MD) and Wako Chemicals, USA, Inc (Richmond VA).
"suitable conditions" for carrying out the synthetic steps as used herein are explicitly given herein or may be apparent by reference to publications relating to methods used in organic synthetic chemistry. The reference books and articles above describing in detail the synthesis of reactants for the preparation of the compounds of the invention also provide suitable conditions for carrying out the synthetic steps of the invention.
As used herein, "methods known to those of ordinary skill in the art" can be determined from various reference books and databases. These reference books and papers detailing the synthesis of reactants used to prepare the compounds of the present invention or which mention articles describing these preparations include, for example, "Synthetic Organic Chemistry", John Wiley & Sons, inc., New York; sandler et al, "Organic Functional Group Preparations," 2nd Ed., Academic Press, New York, 1983; h.o.house, "modern synthetic Reactions", 2nd ed., w.a.benjamin, inc.menlo Park, calif.1972; gilchrist, "Heterocyclic Chemistry", 2nd Ed., John Wiley & Sons, New York, 1992; march, "Advanced Organic Chemistry: reactions, Mechanisms and Structure ", 4th Ed., Wiley-Interscience, New York, 1992. Specific and similar reactants can be identified by known Chemical reagent indices made by Chemical AbstractService of American Chemical Society, which are available in most public and university libraries and through online databases (for more detailed information, in connection with American Chemical Society, Washington, d.c.). Non-commercially available chemicals that are known but not available in the product catalog can be prepared by custom chemical synthesis companies, many of which provide custom synthesis services (e.g., the companies listed above).
By "prodrug" is meant a compound that can be converted to the biologically active compounds of the invention under physiological conditions or by solvolysis. Thus, the term "prodrug" refers to a pharmaceutically acceptable metabolic precursor of a compound of the invention. Prodrugs may be inactive when administered to a subject in need thereof and convert in vivo to the active compounds of the invention. Prodrugs are generally rapidly converted in vivo to the parent compound of the invention, for example, by hydrolysis in blood. Prodrug compounds generally provide advantages of solubility, histocompatibility or delayed release in mammalian organisms (see Bundgard, h., Design of produgs (1985), pp.7-9, 21-24(Elsevier, Amsterdam).
A discussion of prodrugs is provided in Higuchi, T.et al, "Pro-drugs as Novel Delivery Systems," A.C.S.Symphosis Series, Vol.14 and Bioreversible Carriers in Drug Delivery, ed.Edward B.Roche, American Pharmaceutical Association and PergammonPress, 1987, both of which are incorporated herein by reference in their entirety.
The term "prodrug" is also intended to include any covalently linked carrier that releases the active compound of the invention in vivo when the prodrug is administered to a mammalian subject. Prodrugs of the compounds of the present invention may be prepared by modifying functional groups present in the compounds of the present invention in such a way that the modifications are cleaved, either by routine manipulation or in vivo, to the parent compound of the invention. Prodrugs include compounds of the present invention wherein a hydroxy, amino, or mercapto group is attached to any group that, when the prodrug of the compound of the present invention is administered to a mammalian subject, cleaves to form a free hydroxy, free amino, or free mercapto group, respectively.
By "stable compound" and "stable structure" is meant a compound that is sufficiently stable to be isolated from a reaction mixture to a useful degree of purity and formulated into an effective therapeutically active agent.
"mammal" includes humans and domestic animals such as cats, dogs, pigs, cattle, sheep, goats, horses, rabbits, and the like.
"optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not. For example, "optionally substituted aryl" means that the aryl group can be substituted or unsubstituted, and that the description includes both substituted and unsubstituted aryl groups.
"pharmaceutically acceptable carrier, diluent or excipient" includes without limitation any acceptable adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier approved by the U.S. food and drug administration for use in humans or domestic animals.
"pharmaceutically acceptable salts" include acid addition salts and base addition salts.
"pharmaceutically acceptable acid addition salts" refers to salts that retain the biological potency and properties of the free base, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and with organic acids such as acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like.
"pharmaceutically acceptable base addition salts" refers to salts that retain the biological potency and properties of the free acid, which are not biologically or otherwise undesirable. These salts are prepared by addition of an inorganic or organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Preferred inorganic salts are ammonium, sodium, potassium, calcium and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, tertiary amines, substituted amines including naturally substituted amines, cyclic amines, and basic ion exchange resins such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like. Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.
"therapeutically effective amount" refers to an amount of a compound of formula (I) or formula (II) that is sufficient to effect treatment of a disease state alleviated by inhibition of PDK-1 activity, such as cancer, as defined below, when a compound of formula (I) or formula (II) is administered to a mammal, preferably a human. The amount of a compound of formula (I) or formula (II) that constitutes a "therapeutically effective amount" depends on the compound, the condition and its severity and the age of the mammal to be treated, but can be routinely determined by one of ordinary skill in the art based on his own knowledge and the present disclosure.
As used herein, "treatment" includes treatment of a disease state, such as cancer, that is alleviated by inhibition of PDK-1 activity as disclosed herein in a mammal, preferably a human, and includes:
(i) preventing the occurrence of the disease state in a mammal, particularly when said mammal is predisposed to the disease state but has not yet been diagnosed as having it;
(ii) inhibiting the disease state, i.e., arresting its development; or
(iii) Relieving the disease state, i.e., causing regression of the condition.
The compounds of formula (I) or formula (II) or pharmaceutically acceptable salts thereof may contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers and other stereoisomeric forms which may be defined as (R) -or (S) -in terms of absolute stereochemistry, and (D) -or (L) -for amino acids. The present invention is intended to include all such possible isomers, as well as their racemic and optically pure forms. The optically active (+) and (-), (R) -and (S) -or (D) -and (L) -isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional methods such as reverse phase HPLC. Unless otherwise specified, when these formulae described herein contain olefinic double bonds or other centers of geometric asymmetry, then these formulae are intended to include both E and Z geometric isomers as well as all tautomeric forms. Furthermore, unless otherwise indicated, all names of compounds herein are intended to include all individual enantiomers, diastereomers and mixtures thereof, as well as racemic and non-racemic mixtures.
The nomenclature of the compounds of formula (I) or formula (II) used herein is a modification of the IUPAC nomenclature system, wherein the compounds herein are named derivatives of the indolinone central moiety.
For example where m is 1, n is 1, A is oxygen, R1is-CH3、R2is-N (H) C (O) NH2、R3And R5Each is hydrogen, and R6is-CH2N(H)C(O)-CH2-C (O) OH, i.e. a compound of formula:
designated herein as 5-ureido-3- [1- (4- (carboxyacetamido) methylpyrrol-2-yl) ethylene ] indolin-2-one.
Use of the Compounds of the invention
The compounds of the invention block PDK-1 activity directly or block PDK-1 mediated AKT activation, and thus the compounds of the invention are useful in the treatment of a variety of disease states associated with PDK-1 or AKT activity. In particular, the compounds of the invention are useful in the treatment of cancer by inhibiting key processes in tumor progression including cell proliferation, survival and tumor angiogenesis (Testa, j.r.and a. bellacosa, "AKT plants a central roll in tomogenisis," proc.natl.acad.sci.usa 2001), vol.98, No.20, pp.10983-5; and Vivanco, i.and c.l.sawyers, "The phosphatydilinosonitol 3-Kinase AKT pathway in human cancer," nat. rev. cancer (2002), vol.2, No.7, pp.489-501) for The treatment of cancer.
In addition, the compounds of the present invention are expected to increase the sensitivity of tumors to other chemotherapeutic agents and radiation (Page, C., et al, "Overexpression of Akt/AKT can modulated-induced therapies," Anticancer Res. (2000), Vol.20, No.1A, pp.407-16; and Brognard, J., et al, "Akt/protein kinase B interactive activity in non-small cell lung cancer and tumor diagnosis," cancer Res. (Vol.61, No.10, pp.3986-97).
In addition, the compounds of the present invention are useful as inhibitors of AKT activation for the treatment of tuberous sclerosis and as immune response modifiers (see, e.g., cantell, d., "protein B (AKT) regulation and function in Tlymphocytes," semin. immunol. (2002), vol.14, No.1, pp.19-26) for the treatment of autoimmune diseases such as rheumatoid arthritis and multiple sclerosis.
Testing of Compounds of the invention
The compounds of the invention can be tested to determine their ability to inhibit PDK-1 activity by known in vitro and in vivo assays or by the assays described herein.
For example, the compounds of the invention effectively block an assay in which PDK-1 mediates AKT activation, in which assay AKT activity is measured. Thus, the compounds of the invention block this assay by inhibiting PDK-1 enzyme activity, inhibiting AKT enzyme activity, or inhibiting PDK-1 mediated AKT activation. Furthermore, as described in detail below, the compounds of the invention block colony formation and/or growth of PC-3 prostate cancer cells and MDA-468 breast cancer cells in soft agar, an in vitro measure of potential anti-tumor activity.
Administration of the Compounds and pharmaceutical compositions of the invention
Administration of a compound of the invention or a pharmaceutically acceptable salt thereof, in pure form or in a suitable pharmaceutical composition, may be by any accepted mode of administration for the administration of active agents for similar applications. The pharmaceutical composition of the present invention can be prepared by mixing the compound of the present invention with an appropriate pharmaceutically acceptable carrier, diluent or excipient, and can be formulated into preparations in solid, semi-solid, liquid or gaseous form, such as tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants, gels, microspheres and aerosols. Typical routes of administration for these pharmaceutical compositions include, but are not limited to, oral, topical, transdermal, inhalation, parenteral, sublingual, rectal, vaginal and intranasal routes. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques. The pharmaceutical compositions of the present invention are formulated such that the active ingredients contained therein are bioavailable when the compositions are administered to a patient. The compositions to be administered to an individual or patient take the form of single dose units or multiple dose units, where for example a tablet may be a single dose unit and a container containing a compound of the invention in aerosol form may contain multiple dose units. The actual methods of preparing these dosage forms are known or will be apparent to those skilled in the art; see, for example, Remington's Pharmaceutical Sciences, 18th ed. (mack publishing Company, Easton, Pennsylvania, 1990). The compositions to be administered in any event contain a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, for the treatment of a disease or condition associated with PDK-1 activity in accordance with the teachings of the present invention.
The pharmaceutical compositions of the present invention may be in solid form or liquid form. In one aspect, the carrier is particulate and thus the composition is in the form of, for example, a tablet or powder. The carrier may be a liquid and the composition is, for example, an oral syrup, an injectable liquid or an aerosol for administration, for example by inhalation.
When intended for oral administration, the pharmaceutical composition is preferably in solid or liquid form, and semi-solid, semi-liquid, suspension and gel forms are also included within the scope of what is considered herein to be solid or liquid forms.
As a solid composition for oral administration, the pharmaceutical composition may be formulated in the form of powder, granules, compressed tablets, pills, capsules, chewing gum, films, and the like. The solid compositions typically contain one or more inert diluents or edible carriers. In addition, one or more of the following may also be present: a binder such as carboxymethyl cellulose, ethyl cellulose, microcrystalline cellulose, gum tragacanth or gelatin; excipients such as starch, lactose or dextrin; disintegrating agents such as alginic acid, sodium alginate, Primogel, corn starch, etc.; lubricants such as magnesium stearate or Sterotex; glidants such as colloidal silicon dioxide; sweetening agents such as sucrose or saccharin; flavoring agents such as peppermint, methyl salicylate, or orange flavoring; and a colorant.
When the pharmaceutical composition is in the form of a capsule, for example a gelatin capsule, it may contain, in addition to materials of the above type, a liquid carrier such as polyethylene glycol or an oil.
The pharmaceutical compositions may be in liquid form, such as elixirs, syrups, solutions, emulsions or suspensions. The liquid may be for oral administration or for delivery by injection, as two examples. When intended for oral administration, preferred compositions contain, in addition to a compound of the invention, one or more sweetening agents, preserving agents, dyes/colorants and taste enhancers. In compositions intended for administration by injection, one or more surfactants, preservatives, wetting agents, dispersing agents, suspending agents, buffers, stabilizing agents, and tonicity adjusting agents may also be included.
The liquid pharmaceutical compositions of the present invention, whether in solution, suspension or other form, may comprise one or more of the following adjuvants: sterile diluents which may be employed as solvents or suspending media such as water for injection, saline solutions preferably physiological saline, ringer's solution, isotonic sodium chloride, fixed oils such as synthetic mono-or diglycerides, polyethylene glycols, glycerol, propylene glycol or other solvents; antibacterial active agents such as benzyl alcohol or methyl paraben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for adjusting tonicity such as sodium chloride or dextrose. The parenteral formulations may be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic. Physiological saline is a preferred adjuvant. The injectable pharmaceutical composition is preferably sterile.
The liquid pharmaceutical compositions of the present invention intended for parenteral or oral administration should contain an amount of the compound of the present invention that will result in a suitable dosage. Typically, the amount is at least 0.01% of the compound of the invention in the composition. When intended for oral administration, the amount may vary from 0.1 to about 70% by weight of the composition. Preferred oral pharmaceutical compositions contain from about 4% to about 50% of a compound of the invention. Preferred pharmaceutical compositions and formulations according to the invention are prepared such that the parenteral dosage unit contains 0.01 to 1% by weight of a compound of the invention.
The pharmaceutical compositions of the invention may be for topical administration, in which case the carrier may suitably comprise a solution, emulsion, ointment or gel base. For example, the matrix may contain one or more of the following: petrolatum, lanolin, polyethylene glycols, beeswax, mineral oil, diluents such as water and ethanol, and emulsifiers and stabilizers. The thickening agent may be present in a pharmaceutical composition for topical administration. If transdermal administration is desired, the composition may comprise a transdermal patch or iontophoretic device. The concentration of the compounds of the present invention in the topical formulation may be from about 0.1 to about 10% w/v (weight per unit volume).
The pharmaceutical compositions of the invention may be administered rectally, for example, in the form of suppositories which will melt in the rectum and release the drug. The compositions for rectal administration may contain an oily base as a non-irritating excipient. These bases include, but are not limited to, lanolin, cocoa butter, and polyethylene glycols.
The pharmaceutical compositions of the present invention may contain various materials that modify the physical form of the solid or liquid dosage unit. For example, the composition may contain a material that forms an envelope around the active ingredient. The material forming the coating is generally inert and may be selected from, for example, sucrose, shellac, and other enteric coating agents. Alternatively, the active ingredient may be encapsulated in a gelatin capsule.
The pharmaceutical compositions of the invention in solid or liquid form may contain a substance (agent) which binds to the compound of the invention, thereby facilitating the delivery of the compound. Suitable agents that may have such capabilities include monoclonal or polyclonal antibodies, proteins, or liposomes.
The pharmaceutical compositions of the present invention may be comprised of dosage units that can be administered as an aerosol. The term aerosol is used to denote a variety of systems, from systems of colloidal nature to systems consisting of pressurized packaging. The drug may be delivered by a liquefied or compressed gas or by a suitable pump system that dispenses the active ingredient. Aerosols of the compounds of the invention may be delivered in single, two or three phase systems to deliver the active ingredient. The delivery of the aerosol comprises the necessary containers, actuators (activators), valves, auxiliary containers, etc., which together may form a kit of parts. One skilled in the art can determine the preferred aerosol without undue experimentation.
The pharmaceutical compositions of the present invention, whether in solid, liquid or gaseous form, may contain one or more pharmacologically active agents (pharmacological agents) known for the treatment of disease states alleviated by the inhibition of PDK-1 activity, such as cancer.
The pharmaceutical compositions of the present invention may be prepared by methods well known in the art of pharmacy. For example, pharmaceutical compositions to be administered by injection may be prepared by mixing a compound of the present invention with sterile distilled water to form a solution. Surfactants may be added to promote the formation of a homogenous solution or suspension. Surfactants are compounds that interact non-covalently with the compounds of the present invention such that dissolution or uniform suspension of the compounds in the aqueous delivery system is facilitated.
The compounds of the present invention, or pharmaceutically acceptable salts thereof, are administered in a therapeutically effective amount, which will depend on a variety of factors, including the activity of the particular compound employed; the metabolic stability and duration of action of the compound; the age, weight, general health, sex, and diet of the patient; the mode and time of administration; rate of excretion, drug combination; the severity of the particular disease or disorder; and the subject receiving treatment. Generally, a therapeutically effective daily dose is from about 0.1mg to about 20mg per kg body weight of a compound of the present invention or a pharmaceutically acceptable salt thereof per day; preferably from about 0.1mg to about 10mg per kg body weight per day; most preferably from about 0.1mg to about 7.5mg per kg of body weight per day.
Preferred embodiments of the invention
Among the compounds of formula (I) described in the summary above, a preferred group of compounds are those wherein:
m is 1 to 4;
n is 0 to 3;
a is oxygen;
R1is hydrogen or alkyl; or
R1Is (optionally substituted by one or more groups selected from-R)8-OR7、-R8-N(R7)2、-R8-C(O)N(R7)2、-R8-N(R7)C(O)N(R7)2、-R8-N(R7)C(O)-R9-N(R7)2and-R8-N(R7)C(O)OR7Substituted with the substituents of (1) aryl); or
R1Is (optionally substituted by one or more groups selected from alkyl, -R8-OR7、-R8-N(R7)2、-R8-N(R7)C(O)N(R7)2and-R8-N(R7)C(O)-R9-N(R7)2Substituted with the substituents of (1); or
R1Is (optionally substituted by one or more groups selected from alkyl and-R8-OR7Substituted with the substituents of (a) or (b);
each R2Independently selected from heterocyclyl, -R8-S(O)tN(R7)2(wherein t is 1 or 2), -R8-N(R7)2、-R8-N(R7)S(O)tN(R7)2(wherein t is 1 or 2), -R8-N(R7)S(O)tN(R7)C(O)OR7(wherein t is 1 or 2), -R8-N(R7)C(O)R7、-R8-N(R7)-R8-C(O)OR7、-R8-N(R7)C(O)N(R7)2、-R8-N(R7)C(O)-R9-N(R7)2、-R8-N(R7)-R9-C(O)N(R7)2、-R8-N(R7)C(O)-R8-N(R7)-R8-C(O)OR7、-R8-N(R7)C(O)-R8-N(R7)-R8-C(O)-R8-N(R7)2、-N(R7)C(＝NR7)N(R7)2and-R8-N＝C(R7)2；
R3Is hydrogen;
R5is hydrogen or alkyl;
each R6Independently selected from halogen, alkyl, -R8-C(O)R7、-R8-N(R7)2、-R8-C(O)OR7、-R8-C(O)N(R7)2、-R8-N(R7)-R8-C(O)OR7、-R8-N(R7)C(O)R7、-R8-C(O)-R9-C(O)OR7、-R8-N(R7)C(O)N(R7)2、-R8-N(R7)C(O)-R9-N(R7)2、-R8-N(R7)C(O)-R9-C(O)OR7、-R8-N(R7)C(O)-R8-N(R7)-R8-C(O)OR7(optionally substituted with one or more groups selected from alkyl, halo, haloalkyl, cyano, nitro, -R8-OR7、-R8-O-R9-C(O)OR7、-R8-N(R7)2、-R8-C(O)R7、-R8-C(O)OR7、-R8-C(O)N(R7)2、-R8-N(R7)C(O)OR7、-R8-N(R7)C(O)R7、-R8-S(O)pR7(wherein p is 0-2), -R8-S(O)pN(R7)2(wherein p is 0-2) and-R8-N(R7)C(O)-R8-N(R7)2Substituted with one or more substituents selected from alkyl, -R) and (optionally substituted with one or more substituents selected from alkyl, -R8-OR7、-R8-O-R9-C(O)OR7、-R8-C(O)R7、-R8-C(O)OR7、-R8-C(O)N(R7)2、-R8-N(R7)C(O)R7、-R8-N(R7)C(O)OR7、-R8-N(R7)2、-R8-N(R7)C(O)-R8-N(R7)-R8-C(O)OR7and-R8-S(O)tR7Aryl (wherein t is a substituent of 0 to 2);
each R7Independently hydrogen, optionally substituted alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl;
each R8Is a bond or a straight or branched alkylene chain; and is
Each R9Is a straight or branched alkylene chain.
In a preferred group of compounds, a preferred subgroup of compounds is that in which:
m is 1;
n is 0 or 3;
a is oxygen;
R1is hydrogen or alkyl;
R2is-R8-S(O)tN(R7)2(wherein t is 1 or 2), -R8-N(R7)C(O)R7、-R8-N(R7)-R8-C(O)OR7、-R8-N(R7)C(O)N(R7)2、-R8-N(R7)-R9-C(O)N(R7)2or-R8-N(R7)C(O)-R9-N(R7)2；
R3Is hydrogen;
R5is hydrogen or alkyl;
R6independently selected from halogen, alkyl, -R8-C(O)R7、-R8-N(R7)2、-R8-C(O)OR7、-R8-C(O)N(R7)2、-R8-N(R7)-R8-C(O)OR7、-R8-N(R7)C(O)R7、-R8-C(O)-R9-C(O)OR7、-R8-N(R7)C(O)N(R7)2、-R8-N(R7)C(O)-R9-N(R7)2、-R8-N(R7)C(O)-R9-C(O)OR7、-R8-N(R7)C(O)-R8-N(R7)-R8-C(O)OR7(optionally substituted with one or more groups selected from alkyl, halo, haloalkyl, cyano, nitro, -R8-OR7、-R8-O-R9-C(O)OR7、-R8-N(R7)2、-R8-C(O)R7、-R8-C(O)OR7、-R8-C(O)N(R7)2、-R8-N(R7)C(O)OR7、-R8-N(R7)C(O)R7、-R8-S(O)pR7(wherein p is 0-2), -R8-S(O)pN(R7)2(wherein p is 0-2) and-R8-N(R7)C(O)-R8-N(R7)2Substituted with one or more substituents selected from-R) and (optionally) a heterocyclic group8-OR7、-R8-O-R9-C(O)OR7、-R8-C(O)OR7、-R8-C(O)N(R7)2、-R8-N(R7)C(O)R7、-R8-N(R7)C(O)OR7、-R8-N(R7)2、-R8-N(R7)C(O)-R8-N(R7)-R8-C(O)OR7and-R8-S(O)tR7Aryl (wherein t is a substituent of 0 to 2);
each R7Independently hydrogen, optionally substituted alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl;
each R8Is a bond or a straight or branched alkylene chain; and is
Each R9Is a straight or branched alkylene chain.
Within this preferred subgroup of compounds, a preferred class of compounds is that in which:
m is 1;
n is 0, 1, 2 or 3;
a is oxygen;
R1is hydrogen or alkyl;
R2is-R8-S(O)tN(R7)2(wherein t is 1 or 2), -R8-N(R7)C(O)R7、-R8-N(R7)-R8-C(O)OR7、-R8-N(R7)C(O)N(R7)2、-R8-N(R7)-R9-C(O)N(R7)2or-R8-N(R7)C(O)-R9-N(R7)2；
R3Is hydrogen;
R5is hydrogen or alkyl;
each R6Independently selected from halogen, alkyl, -R8-C(O)R7、-R8-C(O)OR7、-R8-C(O)N(R7)2and-R8-C(O)-R9-C(O)OR7；
Each R7Independently hydrogen, optionally substituted alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl;
each R8Is a bond or a straight or branched alkylene chain; and is
Each R9Is a straight or branched alkylene chain.
Among preferred compounds of this class, preferred compounds are those selected from the group consisting of:
5-acetamido-3- [ (pyrrol-2-yl) methylene ] indolin-2-one;
5-ureido-3- [ (pyrrol-2-yl) methylene ] indolin-2-one;
5-trifluoroacetylamino-3- [ (pyrrol-2-yl) methylene ] indolin-2-one;
4-acetamido-3- [ (pyrrol-2-yl) methylene ] indolin-2-one;
5-ureido-3- [1- (pyrrol-2-yl) ethylene ] indolin-2-one;
5- (pyrrolidin-1-yl) acetamido-3- [ (pyrrol-2-yl) methylene ] indolin-2-one;
5- (N' -ethylureido) -3- [1- (pyrrol-2-yl) ethylene ] indolin-2-one;
5- (N' -phenylureido) -3- [1- (pyrrol-2-yl) ethylene ] indolin-2-one;
5-acetamidomethyl-3- [1- (pyrrol-2-yl) ethylene ] indolin-2-one;
5- (pyridin-3-yl) carbonylamino-3- [1- (pyrrol-2-yl) ethylene ] indolin-2-one;
5- (1, 1-dimethylethoxy) carbonylaminomethyl-3- [1- (pyrrol-2-yl) ethylene ] indolin-2-one;
5- (ureido) methyl-3- [1- (pyrrol-2-yl) ethylene ] indolin-2-one;
5- (pyridin-4-yl) carbonylamino-3- [1- (pyrrol-2-yl) ethylene ] indolin-2-one;
5-ureido-3- [1- (pyrrol-2-yl) propylene ] indolin-2-one;
5-aminoacetamido-3- [1- (pyrrol-2-yl) ethylene ] indolin-2-one;
5-ureido-3- [ (4-bromopyrrol-2-yl) methylene ] indolin-2-one;
5-ureido-3- [ (4- (piperidin-1-ylmethyl) carbonylpyrrol-2-yl) methylene ] indolin-2-one;
5-ethoxycarbonylmethylamino-3- [1- (pyrrol-2-yl) ethylene ] indolin-2-one;
5-aminocarbonylmethylamino-3- [1- (pyrrol-2-yl) ethylene ] indolin-2-one;
5- (N-ethylureido) -3- [1- (pyrrol-2-yl) ethylene ] indolin-2-one;
5-ureido-3- [ (4- ((4-methylpiperazin-1-yl) methylcarbonyl) pyrrol-2-yl) methylene ] indolin-2-one;
5-ureido-3- [ (4- (2-ethoxycarbonylethyl) carbonylpyrrol-2-yl) methylene ] indolin-2-one;
5-ureido-3- [ (4- (2-carboxyethyl) carbonylpyrrol-2-yl) methylene ] indolin-2-one;
5- (4-aminopiperidin-1-ylcarbonylamino) -3- [1- (pyrrol-2-yl) ethylene ] indolin-2-one;
5-ureido-3- [ (4- (piperazin-1-ylmethylcarbonyl) pyrrol-2-yl) methylene ] indolin-2-one;
5-ureido-3- [ (4-ethoxycarbonylpyrrol-2-yl) methylene ] indolin-2-one;
5-ureido-3- [ (4-carboxypyrrol-2-yl) methylene ] indolin-2-one;
5-ureido-3- [ (4- (2-morpholin-4-ylethyl) aminocarbonylpyrrol-2-yl) methylene ] indolin-2-one;
5-ureido-3- [ (4- (2-piperidin-1-ylethyl) aminocarbonylpyrrol-2-yl) methylene ] indolin-2-one;
5-ureido-3- [ (4- (pyridin-3-ylmethyl) aminocarbonylpyrrol-2-yl) methylene ] indolin-2-one;
5-ureido-3- [ (4- (3-piperidin-1-ylpropyl) aminocarbonylpyrrol-2-yl) methylene ] indolin-2-one;
5-ureido-3- [ (3-methyl-4-carboxypyrrol-2-yl) methylene ] indolin-2-one;
5-acetamido-3- [1- (pyrrol-2-yl) ethylene ] indolin-2-one;
4-ethoxycarbonylmethylamino-3- [ (pyrrol-2-yl) methylene ] indolin-2-one;
5-ureido-3- [ (4- (2-dimethylaminoethyl) aminocarbonylpyrrol-2-yl) methylene ] indolin-2-one;
5-ureido-3- [ (3-methyl-4- (2-piperidin-1-ylethyl) aminocarbonylpyrrol-2-yl) methylene ] indolin-2-one;
5-ureido-3- [ (4- (2- (imidazol-4-yl) ethyl) aminocarbonylpyrrol-2-yl) methylene ] indolin-2-one;
5-ureido-3- [ (4- (2- (pyridin-4-yl) ethyl) aminocarbonylpyrrol-2-yl) methylene ] indolin-2-one;
5-ureido-3- [ (4- ((3R) -3- (dimethylamino) pyrrolidin-4-yl) carbonylpyrrol-2-yl) methylene ] indolin-2-one;
5-ureido-3- [ (4- ((3S) -3- (dimethylamino) pyrrolidin-4-yl) carbonylpyrrol-2-yl) methylene ] indolin-2-one;
5-ureido-3- [ (4- (3- (pyrrolidin-1-yl) propyl) aminocarbonylpyrrol-2-yl) methylene ] indolin-2-one;
5-ureido-3- [ (4- (4- (pyrrolidin-1-yl) butyl) aminocarbonylpyrrol-2-yl) methylene ] indolin-2-one;
5-ureido-3- [ (4- (4-methylpiperazin-1-yl) carbonylpyrrol-2-yl) methylene ] indolin-2-one;
5-aminosulfonyl-3- [ (4-carboxy-3-methylpyrrol-2-yl) methylene ] indolin-2-one;
5-ureido-3- [ (4- (2-carboxyethyl) -3, 5-dimethylpyrrol-2-yl) methylene ] indolin-2-one;
5-aminosulfonyl-3- [ (3-methyl-4- (3- (piperidin-1-yl) propyl) aminocarbonylpyrrol-2-yl) methylene ] indolin-2-one;
5-ureido-3- [ (4- (2- (4-methylpiperazin-1-yl) carbonylethyl) -3, 5-dimethylpyrrol-2-yl) methylene ] indolin-2-one;
5-ureido-3- [ (4- (2-carboxyethyl) -3-methylpyrrol-2-yl) methylene ] indolin-2-one;
5-ureido-3- [ (4- (2- (pyridin-3-ylmethyl) aminocarbonylethyl) -3-methylpyrrol-2-yl) methylene ] indolin-2-one;
5-ureido-3- [ (4- (2- (pyridin-4-yl) aminocarbonylethyl) -3-methylpyrrol-2-yl) methylene ] indolin-2-one;
5-ureido-3- [ (4- (2- (2-piperidin-1-ylethyl) aminocarbonylethyl) -3-methylpyrrol-2-yl) methylene ] indolin-2-one; and
5-ureido-3- [ (4- (2- (4-methylpiperazin-1-yl) carbonylethyl) -3-methylpyrrol-2-yl) methylene ] indolin-2-one.
In the above preferred group of compounds, a preferred further subgroup of compounds is that in which:
m is 1:
n is 0 or 1;
a is oxygen;
R1is hydrogen or alkyl;
R2is-R8-N(R7)2、-R8-N(R7)C(O)R7、-R8-N(R7)-R8-C(O)OR7、-R8-N(R7)C(O)N(R7)2、-R8-N(R7)-R9-C(O)N(R7)2or-R8-N(R7)C(O)-R9-N(R7)2；
R3Is hydrogen;
R5is hydrogen or alkyl;
R6independently selected from-R8-N(R7)2、-R8-N(R7)-R8-C(O)OR7、-R8-N(R7)C(O)R7、-R8-N(R7)C(O)N(R7)2、-R8-N(R7)C(O)-R9-N(R7)2、-R8-N(R7)C(O)-R9-C(O)OR7and-R8-N(R7)C(O)-R8-N(R7)-R8-C(O)OR7；
Each R7Independently hydrogen, optionally substituted alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl;
each R8Is a bond or a straight or branched alkylene chain; and is
Each R9Is a straight or branched alkylene chain.
Within this preferred subgroup of compounds, preferred compounds are those selected from the group consisting of:
5-ureido-3- [1- (4- (1, 1-dimethylethoxycarbonylaminomethyl) pyrrol-2-yl) ethylene ] indolin-2-one;
5-ureido-3- [1- (4- (aminomethyl) pyrrol-2-yl) ethylene ] indolin-2-one;
5-ureido-3- [1- (4- (acetamidomethyl) pyrrol-2-yl) ethylene ] indolin-2-one;
5-ureido-3- [1- (4- (((1, 1-dimethylethoxycarbonylamino) methyl) carbonylaminomethyl) pyrrol-2-yl) ethylene ] indolin-2-one;
5-ureido-3- [1- (4- (aminoacetamido) methylpyrrol-2-yl) ethylene ] indolin-2-one;
5-ureido-3- [1- (4- (pyridin-4-ylcarbonylamino) methylpyrrol-2-yl) ethylene ] indolin-2-one;
5-ureido-3- [1- (4- (hydroxyacetamido) methylpyrrol-2-yl) ethylene ] indolin-2-one;
5-ureido-3- [1- (4- (1- (1, 1-dimethylethoxycarbonyl) piperidin-4-ylcarbonylamino) methylpyrrol-2-yl) ethylene ] indolin-2-one;
5-ureido-3- [1- (4- (piperidin-4-ylcarbonylamino) methylpyrrol-2-yl) ethylene ] indolin-2-one;
5-ureido-3- [1- (4- ((1, 1-dimethylethoxycarbonyl) -acetylamino) methylpyrrol-2-yl) ethylene ] indolin-2-one;
5-ureido-3- [1- (4- (1- (1, 1-dimethylethoxycarbonyl) pyrrolidin-2-ylcarbonylamino) methylpyrrol-2-yl) ethylene ] indolin-2-one;
5-ureido-3- [1- (4- ((2- (1, 1-dimethylethoxycarbonylamino) ethyl) carbonylamino) methylpyrrol-2-yl) ethylene ] indolin-2-one;
5-ureido-3- [1- (4- (carboxyacetamido) methylpyrrol-2-yl) ethylene ] indolin-2-one;
5-ureido-3- [1- (4- (pyrrolidin-2-ylcarbonylamino) methylpyrrol-2-yl) ethylene ] indolin-2-one;
5-ureido-3- [1- (4- (pyridin-3-ylcarbonylamino) methylpyrrol-2-yl) ethylene ] indolin-2-one;
5-ureido-3- [1- (4- ((2-aminoethyl) carbonylamino) methylpyrrol-2-yl) ethylene ] indolin-2-one;
5-ureido-3- [1- ((4- ((1, 2-diaminoethyl) carbonylamino) methylpyrrol-2-yl) ethylene) indolin-2-one;
5-ureido-3- [1- (4- ((1-amino-2-methoxycarbonylethyl) carbonylamino) methylpyrrol-2-yl) ethylene ] indolin-2-one;
5-ureido-3- [1- (4- ((3-amino-1-acetamidoprop-1-yl) carbonylamino) methylpyrrole-2-yl) ethylene ] indolin-2-one;
5-ureido-3- [1- (4- (piperazin-2-ylcarbonylamino) methylpyrrol-2-yl) ethylene ] indolin-2-one;
5-ureido-3- [1- (4- (1-methylpiperidin-4-ylcarbonylamino) methylpyrrol-2-yl) ethylene ] indolin-2-one;
5-ureido-3- [1- (4- (2- (piperidin-1-yl) ethylcarbonylamino) methylpyrrol-2-yl) ethylene ] indolin-2-one;
5-ureido-3- [ (4- ((morpholin-4-ylmethyl) carbonylaminomethyl) pyrrol-2-yl) methylene ] indolin-2-one;
5-ureido-3- [ (4- ((piperidin-1-yl) acetamido) methylpyrrole-2-yl) methylene ] indolin-2-one;
5-acetamido-3- [1- (4-aminomethylpyrrol-2-yl) ethylene ] indolin-2-one;
5-amino-3- [1- (4- (2-aminoethylcarbamoylmethyl) pyrrol-2-yl) ethylene ] indolin-2-one; and
5-acetylamino-3- [1- (4- (2-aminoethylcarbamoylmethyl) pyrrol-2-yl) ethylene ] indolin-2-one.
In the above preferred group of compounds, a preferred further subgroup of compounds is that in which:
m is 1;
n is 0 or 1;
a is oxygen;
R1is hydrogen or alkyl;
R2is-R8-N(R7)C(O)R7、-R8-N(R7)-R8-C(O)OR7、-R8-N(R7)C(O)N(R7)2、-R8-N(R7)-R9-C(O)N(R7)2or-R8-N(R7)C(O)-R9-N(R7)2；
R3Is hydrogen;
R5is hydrogen or alkyl;
R6independently selected from (optionally substituted by one or more groups selected from alkyl, halogen, haloalkyl, cyano, nitro, -R8-OR7、-R8-O-R9-C(O)OR7、-R8-N(R7)2、-R8-C(O)R7、-R8-C(O)OR7、-R8-C(O)N(R7)2、-R8-N(R7)C(O)OR7、-R8-N(R7)C(O)R7、-R8-S(O)pR7(wherein p is 0-2), -R8-S(O)pN(R7)2(wherein p is 0-2) and-R8-N(R7)C(O)-R8-N(R7)2Substituted with one or more substituents selected from-R) and (optionally) a heterocyclic group8-OR7、-R8-O-R9-C(O)OR7、-R8-C(O)R7、-R8-C(O)OR7、-R8-C(O)N(R7)2、-R8-N(R7)C(O)R7、-R8-N(R7)C(O)OR7、-R8-N(R7)2、-R8-N(R7)C(O)-R8-N(R7)-R8-C(O)OR7and-R8-S(O)tR7Aryl (wherein t is a substituent of 0 to 2);
each R7Independently hydrogen, optionally substituted alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl;
each R8Is a bond or a straight or branched alkylene chain; and is
Each R9Is a straight or branched alkylene chain.
Within this preferred subgroup of compounds, preferred compounds are those selected from the group consisting of:
5-ureido-3- [ (4- (3-methoxyphenyl) pyrrol-2-yl) methylene ] indolin-2-one;
5-ureido-3- [ (4- (4-methoxyphenyl) pyrrol-2-yl) methylene ] indolin-2-one;
5-ureido-3- [ (4- (3-hydroxyphenyl) pyrrol-2-yl) methylene ] indolin-2-one;
5-ureido-3- [ (4- (3-acetamidophenyl) pyrrol-2-yl) methylene ] indolin-2-one;
5-ureido-3- [ (4- (3-carboxyphenyl) pyrrol-2-yl) methylene ] indolin-2-one;
5-ureido-3- [ (4- (pyridin-3-yl) pyrrol-2-yl) methylene ] indolin-2-one;
5-ureido-3- [ (4- (3- (2-morpholin-4-ylethoxy) phenyl) pyrrol-2-yl) methylene ] indolin-2-one;
5-ureido-3- [ (4- (3-methoxycarbonylmethoxyphenyl) pyrrol-2-yl) methylene ] indolin-2-one;
5-ureido-3- [ (4- (4-methoxycarbonylphenyl) pyrrol-2-yl) methylene ] indolin-2-one;
5-ureido-3- [ (4- (3-aminocarbonylphenyl) pyrrol-2-yl) methylene ] indolin-2-one;
5-ureido-3- [ (4- (3, 4-dimethoxyphenyl) pyrrol-2-yl) methylene ] indolin-2-one;
5-ureido-3- [ (4- (4-carboxyphenyl) pyrrol-2-yl) methylene ] indolin-2-one;
5-ureido-3- [ (4- (3, 4-dihydroxyphenyl) pyrrol-2-yl) methylene ] indolin-2-one;
5-ureido-3- [ (4- (4- (1, 1-dimethylethoxycarbonylamino) methylphenyl) pyrrol-2-yl) methylene ] indolin-2-one;
5-ureido-3- [ (4- (3-aminomethylphenyl) pyrrol-2-yl) methylene ] indolin-2-one;
5-ureido-3- [ (4- (3-acetamidomethylphenyl) pyrrol-2-yl) methylene ] indolin-2-one;
5-ureido-3- [ (4- (3- (2-piperidin-1-ylethyl) aminocarbonylphenyl) pyrrol-2-yl) methylene ] indolin-2-one;
5-ureido-3- [ (4- (3- (1, 1-dimethylethoxycarbonyl) aminoacetaminomethylphenyl) pyrrol-2-yl) methylene ] indolin-2-one;
5-ureido-3- [ (4- (4-methylsulfonylphenyl) pyrrol-2-yl) methylene ] indolin-2-one;
5-ureido-3- [ (4- (4- (2-piperidin-1-ylethyl) aminocarbonylphenyl) pyrrol-2-yl) methylene ] indolin-2-one;
5-ureido-3- [ (4- (4- (2-dimethylaminoethyl) aminocarbonylphenyl) pyrrol-2-yl) methylene ] indolin-2-one;
5-ureido-3- [ (4- (4- (4-methylpiperazin-1-yl) carbonylphenyl) pyrrol-2-yl) methylene ] indolin-2-one;
5-ureido-3- [ (4- (3- (2-dimethylaminoethyl) aminocarbonylphenyl) pyrrol-2-yl) methylene ] indolin-2-one;
5-ureido-3- [ (4- (3- (4-methylpiperazin-1-yl) carbonylphenyl) pyrrol-2-yl) methylene ] indolin-2-one;
5-ureido-3- [ (4- (4- (3-hydroxypyrrolidin-1-yl) carbonylphenyl) pyrrol-2-yl) methylene ] indolin-2-one;
5-ureido-3- [ (4- (3- (3-hydroxypyrrolidin-1-yl) carbonylphenyl) pyrrol-2-yl) methylene ] indolin-2-one;
5-ureido-3- [ (4- (pyrimidin-5-yl) pyrrol-2-yl) methylene ] indolin-2-one; and
5-ureido-3- [ (4- (5-methoxypyridin-3-yl) pyrrol-2-yl) methylene ] indolin-2-one.
In the above preferred group of compounds, a preferred further subgroup of compounds is that in which:
m is 1 to 2;
n is 0;
a is oxygen;
R1is (optionally substituted by one or more groups selected from-R)8-OR7、-R8-N(R7)2、-R8-C(O)N(R7)2、-R8-N(R7)C(O)N(R7)2、-R8-N(R7)C(O)-R9-N(R7)2and-R8-N(R7)C(O)OR7Substituted with the substituents of (1) aryl); or
R1Is (optionally substituted by one or more groups selected from alkyl, -R8-OR7、-R8-N(R7)2、-R8-N(R7)C(O)N(R7)2and-R8-N(R7)C(O)-R9-N(R7)2Substituted with the substituents of (1); or
R1Is (optionally substituted by one or more groups selected from alkyl and-R8-OR7Substituted with the substituents of (a) or (b);
each R2Independently selected from-R8-N(R7)2、-R8-S(O)tN(R7)2(wherein t is 1 or 2), -R8-N(R7)C(O)N(R7)2and-R8-N(R7)C(O)-R9-N(R7)2；
R3Is hydrogen;
R5is hydrogen;
each R7Independently hydrogen, optionally substituted alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl;
each R8Is a bond or straight chain orA branched alkylene chain; and is
Each R9Is a straight or branched alkylene chain.
Within this preferred subgroup of compounds, preferred compounds are those selected from the group consisting of:
5-aminosulfonyl-3- [ (pyrrol-2-yl) (phenyl) methylene ] indolin-2-one;
5-ureido-3- [ (pyrrol-2-yl) (pyridin-4-yl) methylene ] indolin-2-one;
5-ureido-3- [ (pyrrol-2-yl) (pyridin-3-yl) methylene ] indolin-2-one;
5-ureido-3- [ (pyrrol-2-yl) (4-methoxyphenyl) methylene ] indolin-2-one;
5-ureido-3- [ (pyrrol-2-yl) (3-aminophenyl) methylene ] indolin-2-one;
5-ureido-3- [ (pyrrol-2-yl) (3- (1, 1-dimethylethoxycarbonylamino) phenyl) methylene ] indolin-2-one;
5-ureido-3- [ (pyrrol-2-yl) (2-methoxypyridin-5-yl) methylene ] indolin-2-one;
5-amino-3- [ (pyrrol-2-yl) (3- (5, 5-dimethyl-1, 3-dioxan-2-yl) propan-1-yl) methylene ] indolin-2-one; and
5-ureido-3- [ (pyrrol-2-yl) (3-aminoacetamidophenyl) methylene ] indolin-2-one.
In the above preferred group of compounds, a preferred further subgroup of compounds is that in which:
m is 1 to 4;
n is 0;
a is oxygen;
R1is hydrogen or alkyl;
each R2Independently selected from heterocyclyl, -R8-N(R7)C(O)-R8-N(R7)-R8-C(O)-R8-N(R7)2、-R8-N＝C(R7)2、-R8-N(R7)C(O)-R8-N(R7)-R8-C(O)OR7、-N(R7)C(＝NR7)N(R7)2、-R8-N(R7)S(O)tN(R7)2(wherein t is 1 or 2) and-R8-N(R7)S(O)tN(R7)C(O)OR7(wherein t is 1 or 2);
R3is hydrogen;
R5is hydrogen or alkyl;
each R7Independently hydrogen, optionally substituted alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl:
each R8Is a bond or a straight or branched alkylene chain.
Within this preferred subgroup of compounds, preferred compounds are those selected from the group consisting of:
5- (N' -aminocarbonylureido) -3- [ (pyrrol-2-yl) methylene ] indolin-2-one;
5-tetrazol-5-yl-3- [ (pyrrol-2-yl) methylene ] indolin-2-one;
4- (pyrrol-2-yl) methyleneamino-3- [ (pyrrol-2-yl) methylene ] indolin-2-one;
5- (N' - (ethoxycarbonylmethyl) ureido) -3- [1- (pyrrol-2-yl) ethylidene ] indolin-2-one;
5- ((1-pyrrol-2-yl) ethylene) aminomethyl-3- [1- (pyrrol-2-yl) ethylene ] indolin-2-one;
5- (2, 4-dioxoimidazolidin-1-yl) -3- [1- (pyrrol-2-yl) ethylene ] indolin-2-one;
5-guanidino-3- [1- (pyrrol-2-yl) ethylene ] indolin-2-one;
5-sulfamoylamino-3- [1- (pyrrol-2-yl) ethylene ] indolin-2-one; and
5- (1, 1-Dimethylethoxy) carbonylaminosulfonamido-3- [1- (pyrrol-2-yl) ethylene ] indolin-2-one.
Among the compounds of formula (I) described in the summary above, a preferred further group of compounds is the group of compounds wherein:
m is 1 to 4;
n is 0 or 1;
a is oxygen;
R1is hydrogen or alkyl;
each R2Independently selected from-R8-N(R7)2and-R8-N(R7)S(O)tR7(wherein t is 1 or 2);
R3is hydrogen;
R5is hydrogen or alkyl;
R6is-R8-N(R7)2；
Each R7Independently hydrogen, optionally substituted alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl;
each R8Is a bond or a straight or branched alkylene chain.
Within this group of compounds, preferred compounds are selected from:
6-amino-3- [ (pyrrol-2-yl) methylene ] indolin-2-one;
5-amino-3- [ (pyrrol-2-yl) methylene ] indolin-2-one;
5-methylsulfonylamino-3- [ (pyrrol-2-yl) methylene ] indolin-2-one;
5-aminomethyl-3- [ (pyrrol-2-yl) methylene ] indolin-2-one;
4-amino-3- [ (pyrrol-2-yl) methylene ] indolin-2-one;
5-amino-3- [1- (pyrrol-2-yl) ethylene ] indolin-2-one;
5-aminomethyl-3- [1- (pyrrol-2-yl) ethylene ] indolin-2-one;
5- (4, 5-dihydrooxazol-2-ylamino) -3- [1- (pyrrol-2-yl) ethylene ] indolin-2-one; and
5-amino-3- [ (4- (aminomethyl) pyrrol-2-yl) methylene ] indolin-2-one.
Among the compounds of formula (I) described in the summary above, a preferred further group of compounds is the group of compounds wherein:
m is 0 to 4;
n is 0 to 3;
a is oxygen;
R1is hydrogen, alkyl, -C (O) OR7or-C (O) N (R)7)2；
Each R2Independently selected from alkyl, halogen, haloalkyl, cyano, -R8-OR7、-R8-C(O)OR7、-R8-C(O)N(R7)2and-R8-S(O)tN(R7)2(wherein t is 1 or 2);
R3is hydrogen or alkyl;
R5is hydrogen or alkyl;
each R6Independently selected from alkyl and nitro;
each R7Independently hydrogen, optionally substituted alkyl, haloalkyl, optionally substitutedAn aryl group, an optionally substituted aralkyl group, an optionally substituted heterocyclic group or an optionally substituted heterocyclylalkyl group of (a);
each R8Is a bond or a straight or branched alkylene chain.
Within this group of compounds, preferred compounds are selected from:
6-chloro-3- [ (pyrrol-2-yl) methylene ] indolin-2-one;
5-bromo-3- [ (pyrrol-2-yl) methylene ] indolin-2-one;
6-fluoro-3- [ (pyrrol-2-yl) methylene ] indolin-2-one;
6-methyl-3- [ ((1-methyl) pyrrol-2-yl) methylene ] indolin-2-one;
6-trifluoromethyl-3- [ (1-methylpyrrol-2-yl) methylene ] indolin-2-one;
5-methoxy-3- [ (pyrrol-2-yl) methylene ] indolin-2-one;
5, 6-dimethoxy-3- [ (pyrrol-2-yl) methylene ] indolin-2-one;
4-methyl-3- [ (pyrrol-2-yl) methylene ] indolin-2-one;
7-methyl-3- [ (pyrrol-2-yl) methylene ] indolin-2-one;
5-hydroxy-3- [ (pyrrol-2-yl) methylene ] indolin-2-one;
5-methyl-3- [ (pyrrol-2-yl) methylene ] indolin-2-one;
6-carboxy-3- [ (pyrrol-2-yl) methylene ] indolin-2-one;
5-methoxy-3- [ (5-ethylpyrrol-2-yl) methylene ] indolin-2-one;
5-hydroxy-3- [ (5-ethylpyrrol-2-yl) methylene ] indolin-2-one;
5-aminosulfonyl-3- [ (pyrrol-2-yl) methylene ] indolin-2-one;
3- [ (4-nitropyrrol-2-yl) methylene ] indolin-2-one;
7-methoxy-3- [ (pyrrol-2-yl) methylene ] indolin-2-one;
7-hydroxy-3- [ (pyrrol-2-yl) methylene ] indolin-2-one;
4-methoxy-3- [ (pyrrol-2-yl) methylene ] indolin-2-one;
4-hydroxy-3- [ (pyrrol-2-yl) methylene ] indolin-2-one;
5- (2-hydroxyethyl) aminosulfonyl-3- [ (pyrrol-2-yl) methylene ] indolin-2-one;
6-methoxy-3- [ (pyrrol-2-yl) methylene ] indolin-2-one;
6-hydroxy-3- [ (pyrrol-2-yl) methylene ] indolin-2-one;
5-dimethylaminosulfonyl-3- [ (pyrrol-2-yl) methylene ] indolin-2-one;
5-methylaminosulfonyl-3- [ (pyrrol-2-yl) methylene ] indolin-2-one;
5-hydroxy-3- [1- (pyrrol-2-yl) ethylene ] indolin-2-one;
5-methoxy-3- [1- (pyrrol-2-yl) ethylene ] indolin-2-one;
5-methoxy-4-methyl-3- [ (pyrrol-2-yl) methylene ] indolin-2-one;
5-hydroxy-4-methyl-3- [ (pyrrol-2-yl) methylene ] indolin-2-one;
5, 6-dihydroxy-3- [ (pyrrol-2-yl) methylene ] indolin-2-one;
5-carboxy-3- [ (pyrrol-2-yl) methylene ] indolin-2-one;
5-aminosulfonyl-3- [ (1-pyrrol-2-yl) ethylene ] indolin-2-one;
5-hydroxy-3- [ (4-methylpyrrol-2-yl) methylene ] indolin-2-one;
5-phenylaminosulfonyl-3- [ (pyrrol-2-yl) methylene ] indolin-2-one;
5-hydroxy-3- [ (5-methylpyrrol-2-yl) methylene ] indolin-2-one;
5-hydroxy-3- [ (3-methylpyrrol-2-yl) methylene ] indolin-2-one;
5-methoxy-3- [ (4-nitropyrrol-2-yl) methylene ] indolin-2-one;
5-methoxycarbonyl-3- [ (pyrrol-2-yl) methylene ] indolin-2-one;
5-aminocarbonyl-3- [ (pyrrol-2-yl) methylene ] indolin-2-one;
5-methoxy-3- [ (3, 5-dimethylpyrrol-2-yl) methylene ] indolin-2-one;
5-methoxy-1-methyl-3- [ (pyrrol-2-yl) methylene ] indolin-2-one;
5-hydroxy-1-methyl-3- [ (pyrrol-2-yl) methylene ] indolin-2-one;
5-hydroxy-3- [ (3, 5-dimethylpyrrol-2-yl) methylene ] indolin-2-one;
4-carboxy-3- [ (pyrrol-2-yl) methylene ] indolin-2-one;
5-cyano-3- [ (pyrrol-2-yl) methylene ] indolin-2-one;
4-methoxy-5-methoxycarbonyl-7-chloro-3- [ (pyrrol-2-yl) methylene ] indolin-2-one;
5-aminosulfonyl-3- [ (pyrrol-2-yl) (ethoxycarbonyl) methylene ] indolin-2-one;
5-aminosulfonyl-3- [ (pyrrol-2-yl) (carboxy) methylene ] indolin-2-one;
5-aminosulfonyl-3- [ (pyrrol-2-yl) (aminocarbonyl) methylene ] indolin-2-one;
5-cyano-3- [1- (pyrrol-2-yl) ethylene ] indolin-2-one;
5-aminocarbonyl-3- [3- (pyrrol-2-yl) ethylene ] indolin-2-one;
5-aminosulfonyl-3- [1- (pyrrol-2-yl) propylidene ] indolin-2-one;
5-aminosulfonyl-3- [ (pyrrol-2-yl) (N, N-diethylaminocarbonyl) methylene ] indolin-2-one; and
5-aminosulfonyl-3- [ (pyrrol-2-yl) (ethylaminocarbonyl) methylene ] indolin-2-one.
Among the preferred compounds of formula (I) described above, the most preferred compounds of formula (I) are selected from:
5-ureido-3- [ (pyrrol-2-yl) methylene ] indolin-2-one;
5-ureido-3- [1- (pyrrol-2-yl) ethylene ] indolin-2-one;
5-ureido-3- [1- (pyrrol-2-yl) propylene ] indolin-2-one;
5-ureido-3- [ (pyrrol-2-yl) (3-aminophenyl) methylene ] indolin-2-one;
5-ureido-3- [1- (4- (piperidin-4-ylcarbonylamino) methylpyrrol-2-yl) ethylene ] indolin-2-one;
5-ureido-3- [ (4- (pyridin-3-yl) pyrrol-2-yl) methylene ] indolin-2-one;
5-ureido-3- [1- (4- ((2-aminoethyl) carbonylamino) methylpyrrol-2-yl) ethylene ] indolin-2-one;
5-ureido-3- [ (4- (4- (2-piperidin-1-ylethyl) aminocarbonylphenyl) pyrrol-2-yl) methylene ] indolin-2-one;
5-ureido-3- [ (4- (4- (2-dimethylaminoethyl) aminocarbonylphenyl) pyrrol-2-yl) methylene ] indolin-2-one;
5-ureido-3- [ (4- (4- (pyrrolidin-1-yl) butyl) aminocarbonylpyrrol-2-yl) methylene ] indolin-2-one;
5-ureido-3- [ (4- (3- (2-dimethylaminoethyl) aminocarbonylphenyl) pyrrol-2-yl) methylene ] indolin-2-one; and
5-acetylamino-3- [1- (4- (2-aminoethylcarbamoylmethyl) pyrrol-2-yl) ethylene ] indolin-2-one.
Among the compounds of formula (II) described in the summary above, a preferred group of compounds are those in which:
m is 0 to 4;
a is oxygen;
R1is hydrogen or alkyl;
each R2Independently selected from halogen, haloalkyl, haloalkenyl, -R8-OR7and-R8-N(R7)C(O)-R8-N(R7)2；
R3Is hydrogen or alkyl;
R4is naphthyl, pyridyl, (optionally substituted by one or more groups selected from alkyl and-R8-OC(O)R7Substituted with a substituent of (a) furyl, indolyl, (optionally substituted with one or more alkyl) imidazolyl, quinolyl or (optionally substituted with one or more substituents selected from alkyl, halogen and phenyl) pyrazolyl;
each R7Independently selected from hydrogen, alkyl, -R9-OR7Haloalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl;
each R8Is a bond or a straight or branched alkylene chain; and is
Each R9Is a straight or branched alkylene chain.
Preferred compounds of this group of compounds are compounds selected from the group consisting of:
5-ureido-3- [1- (imidazol-4-yl) ethylene ] indolin-2-one;
5-hydroxy-3- [ (imidazol-4-yl) methylene ] indolin-2-one;
5-hydroxy-3- [ (imidazol-2-yl) methylene ] indolin-2-one;
3- [ (imidazol-4-yl) methylene ] indolin-2-one;
3- [ (imidazol-2-yl) methylene ] indolin-2-one;
6-fluoro-3- [ (pyridin-2-yl) methylene ] indolin-2-one;
6-fluoro-3- [ (pyridin-4-yl) methylene ] indolin-2-one;
5-bromo-3- [ (pyridin-4-yl) methylene ] indolin-2-one;
3- [ (pyridin-3-yl) methylene ] indolin-2-one;
6-fluoro-3- [ (furan-2-yl) methylene ] indolin-2-one;
3- [ (5-methylfuran-2-yl) methylene ] indolin-2-one;
3- [ (5- (acetoxymethyl) furan-2-yl) methylene ] indolin-2-one;
3- [ (naphthalen-1-yl) methylene ] indolin-2-one;
3- [ (naphthalen-2-yl) methylene ] indolin-2-one;
6-fluoro-3- [ (indol-3-yl) methylene ] indolin-2-one;
3- [ (quinolin-4-yl) methylene ] indolin-2-one;
3- [ (5-methylimidazol-4-yl) methylene ] indolin-2-one;
3- [ (1, 3-dimethyl-5-chloropyrazol-4-yl) methylene ] indolin-2-one; and
3- [ (3-phenylpyrazol-4-yl) methylene ] indolin-2-one.
Preferred compounds of formula (I) include compounds of formula (Ia) below:
wherein:
R1is hydrogen or alkyl;
R2ais-R8-S(O)tN(R7)2(wherein t is 1 or 2), -R8-N(R7)2、-R8-N(R7)S(O)tN(R7)2(wherein t is 1 or 2), -R8-N(R7)S(O)tN(R7)C(O)OR7(wherein t is 1 or 2), -R8-N(R7)C(O)R7、-R8-N(R7)-R8-C(O)OR7、-R8-N(R7)C(O)N(R7)2、-R8-N(R7)C(O)-R9-N(R7)2、-R8-N(R7)-R9-C(O)N(R7)2、-R8-N(R7)C(O)-R8-N(R7)-R8-C(O)OR7、-R8-N(R7)C(O)-R8-N(R7)-R8-C(O)-R8-N(R7)2、-N(R7)C(＝NR7)N(R7)2or-R8-N＝C(R7)2；
R2bR selected from those described for the compounds of formula (I)2The substituents listed in the definitions;
m*is 0 to 3;
n is 0 to 3;
each R6Independently selected from halogen, alkyl, nitro, -R8-C(O)R7、-R8-N(R7)2、-R8-C(O)OR7、-R8-C(O)N(R7)2、-R8-N(R7)-R8-C(O)OR7、-R8-N(R7)C(O)R7、-R8-C(O)-R9-C(O)OR7、-R8-N(R7)C(O)N(R7)2、-R8-N(R7)C(O)-R9-N(R7)2、-R8-N(R7)C(O)-R9-C(O)OR7、-R8-N(R7)C(O)-R8-N(R7)-R8-C(O)OR7(optionally substituted with one or more groups selected from alkyl, halo, haloalkyl, cyano, nitro, -R8-OR7、-R8-O-R9-C(O)OR7、-R8-N(R7)2、-R8-C(O)R7、-R8-C(O)OR7、-R8-C(O)N(R7)2、-R8-N(R7)C(O)OR7、-R8-N(R7)C(O)R7、-R8-S(O)pR7(wherein p is 0-2), -R8-S(O)pN(R7)2(wherein p is 0-2) and-R8-N(R7)C(O)-R8-N(R7)2Substituted with one or more substituents selected from alkyl, -R) and (optionally substituted with one or more substituents selected from alkyl, -R8-OR7、-R8-O-R9-C(O)OR7、-R8-C(O)R7、-R8-C(O)OR7、-R8-C(O)N(R7)2、-R8-N(R7)C(O)R7、-R8-N(R7)C(O)OR7、-R8-N(R7)2、-R8-N(R7)C(O)-R8-N(R7)-R8-C(O)OR7and-R8-S(O)tR7Aryl (wherein t is a substituent of 0 to 2);
each R7Independently hydrogen, optionally substituted alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl;
each R8Is a bond or a straight or branched alkylene chain; and is
Each R9Is a straight or branched alkylene chain;
the compound of formula (Ia) is a single stereoisomer, a mixture of stereoisomers, a solvate or a polymorph.
Preferred compounds within the scope of formula (Ia) include those wherein:
R1is hydrogen;
R2ais-R8-N(R7)2、-R8-N(R7)S(O)tN(R7)2(wherein t is 1 or 2), -R8-N(R7)S(O)tN(R7)C(O)OR7(wherein t is 1 or 2), -R8-N(R7)C(O)R7、-R8-N(R7)-R8-C(O)OR7、-R8-N(R7)C(O)N(R7)2、-R8-N(R7)C(O)-R9-N(R7)2、-R8-N(R7)-R9-C(O)N(R7)2、-R8-N(R7)C(O)-R8-N(R7)-R8-C(O)OR7、-R8-N(R7)C(O)-R8-N(R7)-R8-C(O)-R8-N(R7)2、-N(R7)C(＝NR7)N(R7)2or-R8-N＝C(R7)2(ii) a And is
m*Is 0.
More preferred compounds within the scope of formula (Ia) include those wherein:
R1is hydrogen;
R2ais-R8-N(R7)S(O)tN(R7)2(wherein t is 1 or 2),-R8-N(R7)S(O)tN(R7)C(O)OR7(wherein t is 1 or 2), -R8-N(R7)C(O)R7、-R8-N(R7)-R8-C(O)OR7、-R8-N(R7)C(O)N(R7)2、-R8-N(R7)C(O)-R9-N(R7)2、-R8-N(R7)-R9-C(O)N(R7)2、-R8-N(R7)C(O)-R8-N(R7)-R8-C(O)OR7or-R8-N(R7)C(O)-R8-N(R7)-R8-C(O)-R8-N(R7)2(ii) a And is
m*Is 0.
Preparation of Compounds of formula (I) and formula (II)
It is understood that in the following description, combinations of substituents and/or variables of the formulas are permissible only if such combinations result in stable compounds.
It will also be appreciated by those skilled in the art that in the processes described below, the functional groups of the intermediate compounds may need to be protected with suitable protecting groups. These functional groups include hydroxyl, amino, mercapto and carboxyl groups. For hydroxy, suitable protecting groups include trialkylsilyl or diarylalkylsilyl groups (e.g., t-butyldimethylsilyl, t-butyldiphenylsilyl or trimethylsilyl), tetrahydropyranyl, benzyl, and the like. For amino, amidino and guanidino, suitable protecting groups include t-butyloxycarbonyl (dimethylethoxycarbonyl), benzyloxycarbonyl and the like. For mercapto, suitable protecting groups include-C (O) -R (where R is alkyl, aryl or aralkyl), p-methoxybenzyl, trityl and the like. For carboxylic acids, suitable protecting groups include alkyl, aryl or aralkyl esters.
Protecting groups may be introduced or removed according to standard techniques well known to those skilled in the art and as described herein.
The use of protecting groups is described in detail in Green, T.W. and P.G.M.Wutz, Protective group in Organic Synthesis (1991), 2nd Ed., Wiley-Interscience. The protecting group may also be a polymer resin such as Wang resin or 2-chlorotrityl chloride resin.
It will also be appreciated by those skilled in the art that although these protected derivatives of the compounds of the invention may not possess the same pharmacological activity as described in the summary section, they may be administered to a mammal suffering from a disease state alleviated by the inhibition of PDK-1 activity and thereafter metabolized in vivo to a pharmacologically active compound of the invention. Thus, these derivatives may be referred to as "prodrugs". All prodrugs of the compounds of the present invention are included within the scope of the present invention.
The following scheme illustrates a method for preparing a compound of formula (I) wherein a is 0. It is understood that one of ordinary skill in the art can prepare other compounds of formula (I) and compounds of formula (II) by similar methods or methods known to those of skill in the art. In general, starting components can be obtained from sources such as Aldrich, or synthesized according to sources known to those of ordinary skill in the art (see, e.g., Smith and March, March's advanced organic Chemistry: Reactions, mechanics, and Structure, 5th edition (Wiley Interscience, New York)). Furthermore, the R group is selected from the components previously shown in the specification and may be attached to the starting components, intermediate components and/or end products according to schemes known to those of ordinary skill in the art.
Unless otherwise indicated, in the following reaction schemes, each R group is as defined in the summary above.
A. Preparation of the Compound of formula (D)
The compounds of formula (D) are intermediates in the preparation of the compounds of formula (I). They are prepared as shown in the following scheme 1, POCl in scheme 13Is phosphorus oxychloride; DMF is dimethylformamide; r5aIs hydrogenOr a nitrogen protecting group such as phenylsulfonyl; r3As defined in the summary above; r7aIs alkyl or aralkyl and X is halogen:
reaction scheme 1
The compounds of formula (a) and formula (B) are commercially available or may be prepared according to methods known to those skilled in the art. In general, compounds of formula (Ca) and formula (Cb) are prepared by the methods described in Kato, M.et al, chem.pharm.Bull. (1997), Vol.45, No.11, p.1767, specifically by first treating a compound of formula (B) with a protected or unprotected pyrrole compound of formula (A) under standard Friedel-Crafts acylation conditions, for example in the presence of catalytic amounts of aluminum chloride in an aprotic solvent such as dichloromethane. The resulting reaction mixture is stirred at room temperature for about 8 to about 16 hours, preferably about 16 hours. The solvent is extracted and concentrated to give a mixture of isomers of formula (Ca) and (Cb) which is separated by standard separation techniques such as chromatography.
The isomer of formula (Ca) is then treated with standard Vismeie-Haack reaction conditions, for example in the presence of a suitable disubstituted formamide and phosphorus oxychloride in an aprotic solvent such as dichloromethane. The resulting reaction mixture is heated to between about 50 ℃ and about 60 ℃, preferably to about 55 ℃, and stirred for about 3 to 4 hours, preferably about 3.5 hours. The reaction is terminated by the addition of a strong base such as sodium hydroxide and the resulting reaction mixture is stirred at room temperature for about 8 to about 16 hours. The compound of formula (D) is isolated from the reaction mixture by standard separation techniques such as organic solvent extraction, solvent removal by concentration and chromatography.
The compound of formula (D) may be further hydrolyzed under standard hydrolysis conditions to give compounds wherein R is7aA compound which is hydrogen.
B. Preparation of the Compound of formula (H)
The compound of formula (H) isIntermediates for the preparation of compounds of formula (I). They are prepared as shown in the following scheme 2, PG in scheme 21Is tert-butoxycarbonyl (dimethylethoxycarbonyl); r1As described in the summary above; and X is halogen:
reaction scheme 2
The compounds of formula (E) and formula (F) are commercially available or can be prepared according to methods known to those skilled in the art.
In general, the compound of formula (H) is prepared by first treating the compound of formula (F) in a polar solvent such as tetrahydrofuran with a Grignard reagent of formula (E) at an initial temperature of about-30 ℃ to about 0 ℃, preferably about-30 ℃. The reaction mixture is allowed to warm gradually to room temperature over a period of about 1 hour to 2 hours, preferably about 1.5 hours. The reaction mixture is then poured into ice water and stirred for about 15 minutes to about 1 hour, preferably about 30 minutes. The compound of formula (G) is isolated from the reaction mixture by standard separation techniques such as organic solvent extraction, solvent removal by concentration and chromatography. At this point, the compound of formula (G) may be further processed under standard conditions to protect any R, if desired1A functional group.
The compound of formula (G) in an aprotic solvent such as dichloromethane is then oxidized under standard oxidation conditions to give the corresponding ketone of formula (H), which is then deprotected by standard deprotection techniques.
Alternatively, R may be used1-treatment of the compound of formula (F) with an organolithium group to give the corresponding compound of formula (G).
C. Preparation of Compounds of formula (L) and formula (La)
The formula (L) and formula (La) are intermediates for the preparation of the compounds of formula (I). They are prepared as shown in scheme 3 below, where R is1Such as the above hairPG as defined in the specification2Is a nitrogen protecting group, and R6ais-CH2NH2：
Reaction scheme 3
The compounds of formula (J) are commercially available or can be prepared according to methods known to those skilled in the art.
In general, the compounds of formula (K) are prepared according to the methods described in Loader, C.et al, Can J.chem. (1981), Vol.59, p.2673. Specifically, a solution of chlorosulfonyl isocyanate in an aprotic solvent, such as acetonitrile, is added to a solution of the compound of formula (J) in an aprotic solvent, such as acetonitrile. The resulting reaction mixture is stirred at room temperature for about 2 hours to 3 hours, preferably about 2.5 hours. The reaction mixture is then cooled to about-5 ℃ to about 5 ℃, preferably about 0 ℃, and dimethylformamide is added to the mixture. The resulting reaction mixture is heated to about 45 ℃ to 55 ℃, preferably about 50 ℃, for about 5 minutes to 20 minutes, preferably about 10 minutes, and then poured onto ice. The compound of formula (K) is isolated from the reaction mixture by standard isolation techniques, e.g. dissolving the product in an organic solvent such as ethyl acetate, filtering the resulting solvent with activated carbon, evaporating the organic solvent and recrystallizing the resulting product.
The compound of formula (K) is then reduced under standard reducing conditions, for example by catalytic hydrogenation in the presence of a nitrogen protecting group precursor such as di-tert-butyl dicarbonate in a protic solvent such as methanol, to give the compound of formula (L), which is separated from the reaction mixture by standard separation techniques such as filtration, concentration and silica gel chromatography.
The compound of formula (L) may then be deprotected to give a compound of formula (La) by standard nitrogen deprotection techniques. The compound of formula (La) may then be treated with an appropriate acylating or alkylating agent to give formula (L)a) Wherein R is6ais-R8a-N(R7)2、-R8a-N(R7)C(O)R7、-R8a-N(R7)-R8-C(O)OR7、-R8a-N(R7)C(O)-R9-C(O)OR7、-R8a-N(R7)S(O)t-R8-N(R7)2(wherein t is 1 or 2) and-R8a-N(R7)S(O)t-R7(wherein t is 1 or 2) wherein R8ais-CH2-, each R7、R8And R9As defined in the summary above.
D. Preparation of the Compound of formula (P)
The compounds of formula (P) are intermediates in the preparation of the compounds of formula (I). They are prepared as shown in the following scheme 4, scheme 4 PG3Is a nitrogen protecting group, p is 1-5, and R6Is an optionally substituted aryl or an optionally substituted heterocyclyl group:
reaction scheme 4
The compounds of formula (M) are prepared by the methods disclosed in Sonnet, p.e., j.org.chem. (1971), fol.36, p.1005 or by methods known to those skilled in the art. The compounds of formula (O) are commercially available or can be prepared according to methods known to those skilled in the art.
In general, the compounds of formula (P) are prepared by first preparing the compounds of formula (M) by the methods disclosed in Sonnet, p.e., j.org.chem. (1971), fol.36, p.1005. The compound of formula (M) is then dissolved in a polar aprotic solvent such as tetrahydrofuran and cooled to about-5 ℃ to about 5 ℃, preferably about 0 ℃. The reaction mixture is then treated with a strong base such as lithium diisopropylamide in an aprotic polar solvent such as tetrahydrofuran, and the resulting mixture is stirred at a temperature of about-5 ℃ to about 5 ℃, preferably about 0 ℃, for about 15 minutes to about 2 hours, preferably about 15 minutes. A nitrogen protecting group precursor such as tosyl chloride is then added to the reaction mixture. The resulting reaction mixture was warmed to room temperature. The compound of formula (N) is then isolated from the reaction mixture by standard separation techniques, such as dilution of the reaction mixture with an organic solvent, washing of the solution with water and brine, concentration of the solvent, and silica gel chromatography.
The compound of formula (N) is then treated under standard Suzuki coupling conditions (Miyaura, n.and Suzuki, a., chem.rev. (1995), vol.95, p.2457) to form the compound of formula (P). Specifically, the compound of formula (N) is dissolved in a protic solvent such as ethanol, and the resulting solution is heated to below reflux temperature. A molar excess of the compound of formula (O) is then added to the solution, the resulting reaction mixture is diluted with an aprotic organic solvent, such as toluene, and the resulting mixture is stirred until the reactants are completely dissolved. A palladium catalyst such as Pd (PPh) is then added in the presence of a base such as sodium bicarbonate3)4Added to the reaction mixture and the reaction mixture was stirred at reflux temperature overnight. The compound of formula (P) is then isolated from the reaction mixture by standard separation techniques such as organic solvent extraction, concentration and chromatography.
E. Preparation of the Compound of formula (T)
The compounds of formula (T) are intermediates in the preparation of the compounds of formula (I). They are prepared as shown in scheme 5 below, where R is7Is haloalkyl, and R8Is a direct bond:
reaction scheme 5
The compounds of formula (R) are commercially available or can be prepared according to methods known to those skilled in the art. The compounds of formula (Q) may be prepared according to the methods disclosed in Sonnet, p.e., j.org.chem. (1971), fol.36, p.1005 or according to methods known to the person skilled in the art.
In general, the compounds of formula (T) are prepared by first treating a compound of formula (Q) in an aprotic solvent, such as dichloroethane, with a lewis base, such as aluminum chloride. The reaction mixture is cooled to about-5 ℃ to about 5 ℃, preferably about 0 ℃, and then treated with an equimolar amount of the compound of formula (R). The reaction mixture is stirred at about-5 ℃ to about 5 ℃, preferably about 0 ℃ for about 8 hours to about 16 hours, preferably about 16 hours. The reaction was terminated by pouring the reaction mixture onto crushed ice. The resulting compound of formula (S) is then hydrolyzed under standard basic hydrolysis conditions, for example by treatment with sodium bicarbonate. The compound of formula (T) is then isolated from the reaction mixture by standard separation techniques such as organic solvent extraction and concentration.
Compounds of formula (T) may be further treated with a suitably substituted N-heterocyclyl to form compounds wherein R is7A compound of formula (T) which is a heterocyclylalkyl group which may then be used in the subsequent reaction schemes described herein to prepare the compounds of the invention. Alternatively, it may be further substituted by the formula HN (R)7)2Treating a compound of formula (T) with a suitably substituted amine to form the following wherein R9And R7A compound of formula (Ta) as defined in the summary above, which can be used in the subsequent reaction schemes described herein to prepare compounds of the invention:
F. preparation of Compounds of formula (Ia)
The compounds of formula (Ia) are compounds of formula (I) and are prepared as shown in scheme 6 below, where n, m, R are in scheme 61、R2、R3And R6As defined in the summary above:
reaction scheme 6
The compounds of formula (U) and formula (V) are commercially available or can be prepared according to methods known to those skilled in the art or disclosed herein. The unprotected amine groups in the compounds of formula (U) must be protected prior to the reaction.
In general, where R is1Is hydrogen, -C (O) OR7or-C (O) N (R)7)2The compound of formula (Ia) is prepared by treating a compound of formula (U) with a compound of formula (V) at a temperature of about 75 ℃ to 85 ℃, preferably at about 85 ℃, in the presence of an alcohol, preferably methanol or ethanol, and a catalytic amount of a base, preferably piperidine, for about 2 hours to 4 hours, preferably for about 3 hours. The compound of formula (Ia) is isolated from the reaction mixture by standard separation techniques such as chromatography.
Or, wherein R1The compounds of formula (Ia) which are alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl groups described in the summary above are prepared by heating a mixture of the compound of formula (U) and the compound of formula (V) in the presence of a catalytic amount of a base, preferably piperidine, to a temperature of from about 120 ℃ to about 140 ℃, preferably about 130 ℃, for a period of from about 8 hours to about 16 hours, preferably about 16 hours. On cooling, the compound of formula (Ia) is separated from the reaction mixture by standard separation techniques such as silica gel chromatography.
Or, wherein R1is-R8-C(O)OR7or-R8-C(O)N(R7)2By first using a compound of formula (Ia) wherein R is in a polar solvent such as ethanol1is-R8-C(O)C(O)OR7or-R8-C(O)C(O)N(R7)2Is prepared by treating a compound of formula (U) in the presence of a base such as triethylamine. The resulting reaction mixture is refluxed for about 12 hours to about 55 hours, preferably about 55 hours. And then separating R therefrom from the reaction mixture by standard separation techniques such as concentration and reverse phase HPLC1is-R8-C(O)OR7A compound of formula (Ia).
Or, wherein R1is-R8-C(O)N(R7)2By first using a compound of formula (Ia) wherein R is1is-R8-C(O)C(O)N(R7)2Is prepared by treating a compound of formula (U) with a catalytic amount of a base, preferably piperidine. The resulting reaction mixture is heated in a microwave oven at a temperature of about 150 ℃ to about 160 ℃, preferably about 160 ℃, for about 1 minute to 5 minutes, preferably about 5 minutes. The reaction mixture is then dissolved in an aprotic solvent, preferably dichloromethane, and then subjected to standard separation techniques such as acid or base washing, concentration and chromatography to isolate R therefrom1is-R8-C(O)OR7A compound of formula (Ia).
Wherein R is2The group is wherein R7-R-being alkyl, hydroxyalkyl, haloalkyl, aralkyl or heterocyclylalkyl8-OR7The compound of formula (Ia) can be converted to the corresponding compound of formula (Ia) wherein R is R under standard Lewis acid cleavage conditions, for example by treating the compound with a molar excess of boron tribromide in an aprotic solvent, such as dichloromethane7Is a compound of hydrogen.
Wherein R is2Compounds of the formula (Ia) in which the radical contains a terminal amino group can be obtained, for example, by reaction with acylating or alkylating agents, isocyanates or thioisocyanates2is-R8-N(R7)2、-R8-N(R7)S(O)tR7(wherein t is 1 or 2), -R8-N(R7)S(O)tN(R7)2(wherein t is 1 or 2), -R8-N(R7)S(O)tN(R7)C(O)OR7(wherein t is 1 or 2), -R8-N(R7)C(O)R7、-R8-N(R7)-R8-C(O)OR7、-R8-N(R7)C(O)N(R7)2、-R8-N(R7)C(O)-R9-N(R7)2、-R8-N(R7)-R9-C(O)N(R7)2、-R8-N(R7)C(O)-R8-N(R7)-R8-C(O)OR7、-R8-N(R7)C(O)-R8-N(R7)-R8-C(O)-R8-N(R7)2or-N (R)7)C(＝NR7)N(R7)2A compound of formula (Ia).
Wherein R may be treated in a similar manner to that described in U.S. Pat. No. 5,691,3642A compound of formula (Ia) which is cyano wherein R is formed2is-C (═ NR)7)-N(R7)2The compound of the present invention.
G. Preparation of Compounds of formulae (Ib), (Ic), (Id), (Ie)
The compounds of formula (Ib), (Ic), (Id) and (Ie) are compounds of formula (I) and are prepared as shown in scheme 7 below, where A is oxygen and R is in scheme 77aIs an alkyl group, and n, R1And R6As described in the summary above:
reaction scheme 7
The compounds of formula (X) and formula (W) are commercially available or can be prepared according to methods known to those skilled in the art. The compounds of formula (V) are commercially available or can be prepared according to methods known to those skilled in the art or disclosed herein.
In general, the compounds of formula (Ib), (Ic), (Id) and (Ie) are prepared by first preparing the compounds of formula (Y) and formula (Z) by the methods described in PCT published patent application WO 99/10325.
To a suspension of a compound of formula (Z) in a protic solvent, such as ethanol, is added a compound of formula (V) in the presence of a base, such as piperidine. The reaction mixture is refluxed for about 2 hours to about 3 hours, preferably about 2 hours. The compound of formula (Ib) is isolated from the reaction mixture by standard separation techniques such as precipitation, filtration and organic solvent extraction.
Then using tributyltin hydride (0.68g, 2.1mmol) and NaN under standard radical cyclization conditions3(0.39g, 2.52mmol) the compound of formula (Ib) in an organic solvent such as toluene. The reaction mixture is refluxed overnight for about 8 to about 16 hours, preferably about 16 hours. The compound of formula (Ic) is then isolated from the reaction mixture by standard separation techniques such as concentration, filtration and evaporation of the solvent.
Alternatively, the compound of formula (Z) is hydrogenated under standard catalytic hydrogenation reaction conditions to give the compound of formula (AA), which is isolated from the reaction mixture by standard separation techniques such as filtration and concentration of the solvent.
The compound of formula (AA) is then treated with a molar excess of the compound of formula (V) in the presence of a catalytic base such as piperidine. The resulting solution is mixed in a microwave reactor where it is heated to about 155 ℃ to about 165 ℃, preferably about 160 ℃, for about 5 minutes to about 10 minutes, preferably about 8 minutes. The compound of formula (Id) is isolated from the reaction mixture by redissolving the product in a polar aprotic solvent such as dimethyl sulfoxide and purified by standard techniques such as reverse phase HPLC.
Alternatively, a compound of formula (AA) in a protic solvent such as ethanol is treated with a base such as diisopropylethylamine. After about 10 to 30 minutes, preferably after about 20 minutes, the compound of formula (V) and a catalytic base such as pyrrolidine are added to the solution. The resulting reaction mixture is stirred at a temperature of about 50 ℃ to about 70 ℃, preferably about 60 ℃ for about 2 hours to about 4 hours, preferably about 3 hours. The compound of formula (Ie) is then isolated from the reaction mixture by standard separation techniques such as solvent concentration and reverse phase HPLC.
The compounds of formula (Ie) may be further reacted, for example, with acylating or alkylating agents, isocyanates or thioisocyanates to give compounds in which R2is-CH2-N(R7)2、-CH2-N(R7)S(O)tR7(wherein t is 1 or 2), -CH2-N(R7)S(O)tN(R7)2(wherein t is 1 or 2), -CH2-N(R7)S(O)tN(R7)C(O)OR7(wherein t is 1 or 2), -CH2--N(R7)C(O)R7、-CH2-N(R7)-R8-C(O)OR7、-CH2-N(R7)C(O)N(R7)2、-CH2-N(R7)C(O)-R9-N(R7)2、-CH2-N(R7)-R9-C(O)N(R7)2、-CH2-N(R7)C(O)-R8-N(R7)-R8-C(O)OR7、-CH2-N(R7)C(O)-R8-N(R7)-R8-C(O)-R8-N(R7)2or-N (R)7)C(＝NR7)N(R7)2A compound of formula (Ie).
H. Preparation of Compounds of formula (If) and formula (Ig)
Compounds of formula (If) and (Ig) are compounds of formula (I), prepared as shown in scheme 8, scheme 8 wherein n, R1And R6As described in the summary above, PG4Are isocyanate protecting groups, such as trimethylsilyl:
reaction scheme 8
The compounds of formula (BB) are commercially available or can be prepared according to methods known to those skilled in the art. The compounds of formula (V) are commercially available or can be prepared according to methods known to those skilled in the art or disclosed herein.
In general, compounds of formula (Ig) are prepared by first reducing a compound of formula (BB) to a compound of formula (CC) under standard catalytic hydrogenation conditions.
The compound of formula (CC) in an aprotic polar solvent, for example a mixture of tetrahydrofuran and dimethylformamide, is then treated with a molar excess of the protected isocyanate. The resulting reaction mixture is then stirred at room temperature for about 8 hours to about 20 hours, preferably about 18 hours. The compound of formula (DD) is isolated from the reaction mixture by standard separation techniques such as filtration, washing with an organic solvent and evaporation of the solvent.
The compound of formula (DD) in a protic solvent, preferably ethanol, is then treated with a compound of formula (V) in the presence of a catalytic amount of piperidine. The resulting reaction mixture is refluxed for about 8 hours to 20 hours, preferably about 18 hours. After cooling, the compound of formula (Ig) is isolated from the reaction mixture by standard separation techniques such as filtration and organic solvent washing.
In general, the compound of formula (If) is prepared by first treating the compound of formula (BB) with a molar excess of the compound of formula (V) in the presence of a catalytic amount of piperidine. The resulting reaction mixture is heated in a closed tube reactor to about 80 to 90 c, preferably about 85 c, for about 2 hours to about 4 hours, preferably about 3 hours. After cooling, the compound of formula (If) is isolated from the reaction mixture by standard separation techniques such as trituration, filtration and organic solvent washing.
The compound of formula (If) may then be treated with a protected isocyanate to form the corresponding compound of formula (Ig) as described above for the compound of formula (CC).
I. Preparation of Compounds of formula (Ih), (Ii), (Ij) and (Ik)
The compounds of formula (Ih), (Ii), (Ij) and (Ik) are compounds of formula (I) and are prepared as shown in scheme 9 below, wherein X is halogen, n, R in scheme 91And R6As described in the summary above, and R7Is an alkyl group
Reaction scheme 9
The compounds of formula (FF) and formula (GG) are commercially available or can be prepared according to methods known to those skilled in the art.
In general, the compounds of formula (Ih) and (Ij) are prepared by first treating the compound of formula (If) with the compound of formula (GG) in a polar aprotic solvent such as tetrahydrofuran at room temperature. The resulting reaction mixture is stirred at a temperature of about 40 to about 50 c, preferably about 45 c, for about 1 hour to about 3 hours, preferably about 2 hours. The reaction mixture is cooled to room temperature and the compound of formula (Ih) is isolated from the reaction mixture by standard separation techniques such as solvent concentration and silica gel chromatography.
The compound of formula (Ih) in a polar aprotic solvent such as dimethylformamide is then treated with a base such as triethylamine and the reaction mixture is stirred at room temperature for about 8 hours to about 20 hours, preferably about 16 hours. The compound of formula (Ij) is then isolated from the reaction mixture by standard separation techniques such as filtration and reverse phase HPLC purification.
In general, the compounds of formula (Ii) and (Ik) are prepared by first treating a compound of formula (If) with a compound of formula (FF) in a polar aprotic solvent such as tetrahydrofuran at room temperature. The resulting reaction mixture is stirred for about 8 hours to about 20 hours, preferably about 16 hours. The compound of formula (Ik) is isolated from the reaction mixture by standard separation techniques such as concentration and silica gel chromatography.
J. Preparation of the Compound of formula (IIa)
The compound of formula (IIa) is wherein R4Compounds of formula (II) which are optionally substituted imidazol-4-yl, are prepared as shown in scheme 10 below, in scheme 10m, A, R1、R2And R3As described in the summary above:
reaction scheme 10
The compounds of formula (HH) and formula (U) are commercially available or can be prepared according to methods known to those skilled in the art.
In general, compounds of formula (IIa) are prepared by first treating a compound of formula (HH) in a polar aprotic solvent such as tetrahydrofuran with the nitrogen protecting group precursor di-tert-butyl dicarbonate at room temperature in the presence of a catalytic amount of a base such as dimethylaminopyridine. The compound of formula (JJ) is then isolated from the reaction mixture by standard separation techniques such as organic extraction and concentration of the solvent.
The compound of formula (JJ) in a polar aprotic solvent such as tetrahydrofuran is then treated with a suitable grignard reagent of formula (EE) at room temperature for a period of about 8 hours to about 20 hours, preferably about 16 hours. The compound of formula (KK) is then isolated from the reaction mixture by standard separation techniques such as extraction with ethyl acetate and concentration.
The compound of formula (KK) is dissolved in an aprotic solvent such as dichloromethane and then treated with an oxidizing agent such as manganese oxide. The resulting reaction mixture is stirred at room temperature for about 8 hours to about 20 hours, preferably about 16 hours. The compound of formula (LL) is then isolated from the reaction mixture by standard separation techniques such as filtration, concentration and silica gel chromatography.
The compound of formula (LL) is then deprotected using standard nitrogen deprotection techniques to form the compound of formula (MM).
The compound of formula (MM) is then treated with a compound of formula (U) as described herein, i.e., at a temperature of about 75 ℃ to 140 ℃, preferably about 135 ℃, in the presence of a catalytic amount of piperidine to form a compound of formula (IIa), which is isolated from the reaction mixture by standard isolation techniques.
Wherein R may be further processed under standard reducing conditions2Of formula (IIa) which is nitroThe compounds form the corresponding amino-substituted compounds of formula (IIa) which can be further treated under standard conditions, for example with a molar excess of an appropriately substituted isocyanate, to form the corresponding ureido-substituted compounds of formula (IIa).
All of the compounds of the invention prepared above in free base or free acid form can be converted into their pharmaceutically acceptable salts by treatment with suitable inorganic or organic acids or bases. Salts of the compounds prepared above may be converted to their free base or free acid forms by standard techniques.
The following specific examples are provided as guidance to aid in the practice of the invention and are not intended to limit the scope of the invention.
Preparation 1
Compounds of formula (C) and formula (D)
A. AlCl was treated with (carbomethoxy) propionyl chloride (27.05g)3(24.02g) and dichloromethane (400 mL). A solution of pyrrole (10.01g) in dichloromethane (150mL) was then added dropwise. After stirring overnight, the reaction mixture was poured into ice water (500 mL). The resulting mixture was then extracted with dichloromethane (500 mL). The combined organic layers were washed with brine (500mL) and dried (MgSO)4) And concentrated to give ethyl γ -oxo-1-H-pyrrole-3-butyrate (5.14 g).
B. By POCl3(1.5mL) A solution of DMF (1.2mL) in 1, 2-dichloroethane (25mL) at 0 ℃ was treated. The resulting solution was warmed to room temperature and then treated with a solution of ethyl γ -oxo-1-H-pyrrol-3-butanoate (2.06g) in 1, 2-dichloroethane (10 mL). The reaction mixture was heated to 55 ℃. After 3.5 hours, the reaction was quenched by the addition of 1N NaOH (16mL) and then stirred at room temperature overnight. The reaction mixture was extracted with ethyl acetate (150mL) and dried (MgSO)4) Organic layer, concentrate. The resulting oil was SiO using 4: 1 hexane/ethyl acetate2(100g) Chromatography to give 5-formyl- γ -oxo-1-H-pyrrole-3-butyric acid ethyl ester (0.54 g).
Preparation 2
Compounds of formula (G) and formula (H)
A. A-30 deg.C solution of N- (dimethylethoxycarbonyl) pyrrole-2-carbaldehyde (10g, 50mmol) in THF (500mL) was added dropwise to 3- [ bis (trimethylsilyl) amino group under nitrogen]Phenylmagnesium chloride (55mL, 1M solution in THF, 55 mmol). After the addition was complete, the reaction mixture was gradually warmed and stirred at 0 ℃ for 1 hour and then at room temperature for 15 minutes. The reaction mixture was poured into ice water and stirred for 30 minutes. The reaction mixture was extracted with diethyl ether (1L). The combined organic layers were dried (MgSO)4) And (4) concentrating. SiO Using 1: 1 Hexane/Ethyl acetate2(700g) Chromatography to give [ N- (dimethylethoxycarbonyl) pyrrol-2-yl](3-aminophenyl) methanol (11.2 g).
B. A solution of [ N- (dimethylethoxycarbonyl) pyrrol-2-yl [ (3-aminophenyl) methanol (9.26g, 32.1mmol) in dichloromethane (30mL) was treated with di-tert-butyl dicarbonate (7.6g, 34.8mmol) and the mixture was refluxed for 15 hours. Concentrating the solution through SiO2(700g) Purifying by chromatography to obtain [ N- (dimethylethoxycarbonyl) pyrrol-2-yl][3-N- (Dimethylethoxycarbonyl) aminophenyl]Methanol (12.7 g).
C. With MnO2(12.5g, 0.147mol) treatment of [ N- (dimethylethoxycarbonyl) pyrrol-2-yl][3-N- (Dimethylethoxycarbonyl) aminophenyl]A solution of methanol (12.7g, 0.033mol) in dichloromethane (50 mL). After 2 days, additional dichloromethane (40mL) was added and the mixture was refluxed for 1 hour. Filtering off the solid, concentrating the filtrate to obtain [ N- (dimethylethoxycarbonyl) pyrrol-2-yl][3-N- (Dimethylethoxycarbonyl) aminophenyl]A ketone.
Preparation 3
A compound of formula (K)
A. A solution of chlorosulfonyl isocyanate in acetonitrile (25mL) was added dropwise to a 0 deg.C solution of 2-acetylpyrrole (10.9g, 100mmol) in acetonitrile (25 mL). The reaction mixture turned from yellow to black and was stirred at room temperature for 2.5 hours. The reaction mixture was cooled to 0 ℃ and DMF (10mL) was added. The resulting reaction mixture was then heated to 50 ℃ for 10 minutes and then poured onto ice to give the dark product. The product was dissolved in ethyl acetate, treated with activated carbon, and filtered. Evaporation of ethyl acetate gave a brown product. Recrystallization from ethyl acetate gave 4-cyano-2-acetylpyrrole (4.5g) as a brown solid.
B. Other compounds of formula (K) are prepared in a similar manner.
Preparation 4
A compound of formula (L)
A. To a solution of 2-acetyl-4-cyanopyrrole (3.6g, 26.86mmol) and di-tert-butyl dicarbonate (10.2g, 46.78mmol) in methanol (200mL) under nitrogen was added 10% palladium on charcoal (0.8 g). The reaction mixture was shaken under hydrogen (45psi) for 2 hours. Filtration through celite (celite), concentration to give a purple oil which was washed with hexane/ethyl acetate over SiO2Chromatography gave 2-acetyl-4- (dimethylethoxycarbonyl) aminomethylpyrrole (5.1 g).
B. Other compounds of formula (L) are prepared in a similar manner.
Preparation 5
A compound of formula (N)
4-bromopyrrole-2-carbaldehyde was prepared according to the method of Sonnet, p.e., j.org.chem. (1971), vol.36, p.1005. A solution of 4-bromopyrrole-2-carbaldehyde (2.61g) and tetrahydrofuran (100mL) was cooled to 0 ℃. LDA (7.5mL, 2N solution in THF) was added dropwise and the mixture was stirred at 0 ℃ for 1 hour. Tosyl chloride (2.88g) was then added. Warming the resulting reaction mixture toRoom temperature, overnight. The reaction mixture was diluted with ethyl acetate (100mL), washed with water (100mL) and brine (100mL), and dried (Na)2SO4) And (4) concentrating. SiO the dark solid with 4: 1 hexane/ethyl acetate2Chromatography gave N-tosyl-4-bromo-2-pyrrolcarbaldehyde (3.8 g).
Preparation 6
A compound of formula (P)
A. N-tosyl-4-bromo-2-pyrrolecarboxaldehyde (198mg, 0.603mmol) was dissolved in anhydrous ethanol (20mL) and heated below reflux. To the warm solution was added 3-methoxyphenylboronic acid (140mg, 0.921mmol), and the resulting mixture was diluted with toluene (20mL) and stirred until dissolved. Adding Pd (PPh) to the homogeneous solution3)4(683mg, 0.591mmol) then saturated NaHCO was added3(5mL), the resulting solution was stirred overnight at reflux. The reaction mixture was then diluted with ethyl acetate (50mL), washed with water (50mL) and brine (50mL), and dried (Na)2SO4) And concentrating to obtain a slurry. To this slurry was added dichloromethane (5mL) until a heterogeneous solution was obtained, which was then diluted with a solution of 20% ethyl acetate in hexane (20mL) and used 20% ethyl acetate in hexane over SiO2Purification by chromatography gave the product (130 mg). The product was then dissolved in methanol and ethyl acetate and the resulting solution was treated with 20% KOH (20 mL). After stirring overnight, the methanol was removed and the reaction mixture was extracted with ethyl acetate (2X 100 mL). The combined organic layers were washed with brine (50mL) and dried (Na)2SO4) And (4) concentrating. The residue was purified by reverse phase HPLC (acetonitrile/water) to give 4- (3-methoxyphenyl) -2-pyrrolecarboxaldehyde (70 mg).
B. Other compounds of formula (P) are prepared in a similar manner.
Preparation 7
Compounds of formula (S) and formula (T)
A. A solution of 1- (1H-pyrrol-2-ylmethylene) pyrrolidinium perchlorate (5.2g) in dichloroethane (100mL) was treated with aluminum chloride (1.93 g). The mixture was cooled to 0 ℃ and then treated with 2-bromoacetyl chloride (2.2 mL). After stirring overnight at 0 ℃, the mixture was poured onto crushed ice. Diethyl ether (60mL) and sodium bicarbonate (1.93g) were added and the mixture was stirred until the ice was completely melted. The resulting mixture was extracted with diethyl ether and concentrated to give 4- (bromoacetyl) -2-pyrrolecarboxaldehyde (1.88 g).
B. Other compounds of formula (T) are prepared in a similar manner.
Preparation 8
A compound of formula (Y)
A. A solution of 4-cyanoaniline (10g, 84mmol) in anhydrous dichloromethane (200mL) under nitrogen was cooled to-78 ℃ according to the method described in PCT published patent application WO 99/10325. To this stirred solution was added a solution of tert-butyl hypochlorite (10.9mL, 84mmol) in dry dichloromethane (20 mL). The resulting solution was stirred for 10 minutes. A solution of ethyl methylthioacetate (10.9mL, 84mmol) in dichloromethane (20mL) was added dropwise. After 1 hour, triethylamine (12mL, 86mmol) was added dropwise to the solution and the resulting reaction mixture was warmed to room temperature over 1 hour. The reaction mixture was washed with water and brine and dried (Na)2SO4) And concentrated to give an orange oil. The oil was dissolved in diethyl ether (200mL) and treated with 2N HCl (15 mL). The reaction mixture was stirred vigorously at room temperature for 18 hours. The resulting solid was collected by filtration, washed with diethyl ether and dried in vacuo to give 5-cyano-3-methylthioindol-2-one (11g) as a solid.
B. Other compounds of formula (Y) are prepared in a similar manner.
Preparation 9
A compound of formula (Z)
A. To a solution of 5-cyano-3-methylthioindol-2-one (11g, 53.92mmol) in tetrahydrofuran (200mL) at room temperature was added a saturated ammonium chloride solution (200mL) followed by active zinc (50g) according to the method described in PCT published patent application WO 99/10325. The reaction mixture was stirred at room temperature for 18 hours. The mixture was filtered through celite. The organic layer was separated and dried (Na)2SO4) And concentrating to obtain a semi-solid product. The product was SiO using hexane/ethyl acetate2Chromatography gave a brown solid which was washed with diethyl ether to give 5-cyanoindolin-2-one (6g) as an off-white solid.
B. Other compounds of formula (Z) are prepared in a similar manner.
Preparation 10
A compound of formula (AA)
A. A slurry of 5-cyanoindol-2-one (5g, 31.64mmol) and 10% palladium on charcoal (500mg) was hydrogenated at 40psi and room temperature for 24 h. Filtration through a pad of celite and concentration gave 5-aminomethylindolin-2-one (5.5g) as an orange oil.
B. Other compounds of formula (AA) are prepared in a similar manner.
Preparation 11
Compounds of formula (CC) and formula (DD)
A. A suspension of 5-nitroindolin-2-one (2.0g, 11.13mmol) and 10% palladium on charcoal (500mg) in methanol (100mL) was hydrogenated at 45psi for 2 h. The reaction mixture was filtered through celite and the resulting filter cake was washed with methanol. The filtrate was concentrated to give 5-aminoindolin-2-one as a brown solid (1.6 g).
B. To a solution of 5-aminoindolin-2-one (8.76, 58.79mmol) in tetrahydrofuran: dimethylformamide (400 mL: 60mL) was added trimethylsilyl isocyanate (10.6mL, 78.68mmol) dropwise. The reaction mixture was stirred at room temperature for 18 hours. A brown solid formed which was isolated by filtration, washed with ether and dried in vacuo to give 5-ureidoindolin-2-one (8.5 g).
C. Other compounds of formula (CC) and (DD) are prepared in a similar manner.
Preparation 12
A compound of formula (EE)
A. 5-Nitroindolenin-2-one (1.08g, 8.8mmol), 2-acetyl-4- (dimethylethoxycarbonylamino) methylpyrrole (1.5g, 6.3mmol) and piperidine (2.5mL) were placed in a closed tube reactor and stirred in a preheated oil bath at 85 ℃. After 3 hours, additional 5-nitroindolin-2-one (0.5g) was added and the reaction stirred for an additional 1 hour. The reaction mixture was cooled, triturated with ethanol and left overnight at room temperature. The solid formed was isolated by filtration and washed with ethanol to give 5-nitro-3- [ (4- (dimethylethoxycarbonylaminomethyl) pyrrol-2-yl) methylene]Indolin-2-one (0.8g) as a yellow solid;1H NMR(400MHz，DMSO)δ1.38(s，9H)，2.84(s，3H)，4.08(d，2H)，7.08(d，1H)，7.10(m，1H)，7.20(t，1H)，7.32(s，1H)，8.12(dd，1H)，8.48(d，1H)ppm。
B. other compounds of formula (EE) were prepared in a similar manner.
Preparation 12
Compounds of formulae (JJ), (KK), (LL) and (MM)
A. To a solution of imidazole-4-carbaldehyde (13.65g, 140mmol) in tetrahydrofuran (300mL) was added di-tert-butyl dicarbonate (32.6g, 150mmol) and a catalytic amount of dimethylaminopyridine at room temperature. The resulting white suspension turned into a pale yellow clear solution after 30 minutes at room temperature. The reaction was quenched with water and basified with aqueous sodium bicarbonate. The resulting reaction mixture was extracted with ethyl acetate and dried (Na)2SO4) And concentrating to obtain 27.4g 1- (dimethylethoxycarbonyl) imidazole-4-carbaldehyde as a white solid.
B. To a solution of 1- (dimethylethoxycarbonyl) imidazole-4-carbaldehyde (9.3g, 47mmol) in tetrahydrofuran (200mL) was added methyl Grignard reagent (6.6mL, 50mmol) at room temperature. The resulting reaction mixture was stirred at room temperature overnight. The reaction was quenched with water and extracted with ethyl acetate. The organic layer was dried (Na)2SO4) And concentrated to give 10g of 4- (1-hydroxyethyl) -1- (dimethylethoxycarbonyl) imidazole as an oil.
C. 4- (1-hydroxyethyl) -1- (dimethylethoxycarbonyl) imidazole (8.7g, 41mmol) was dissolved in dichloromethane (100mL) and MnO was added2(10.7g, 123 mmol). The resulting reaction mixture was stirred at room temperature overnight. The reaction mixture was filtered, concentrated, and purified by silica gel column chromatography to give 4g of 4-acetyl-1- (dimethylethoxycarbonyl) imidazole and unreacted raw materials.
D. 4-acetyl-1- (dimethylethoxycarbonyl) imidazole (1g, 4.8mmol) was dissolved in dichloromethane (50mL) and trifluoroacetic acid (2mL) was added. The resulting reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated to give 0.7g of white solid, 4-acetylimidazole as TFA salt.
E. Other compounds of formula (JJ), (KK), (LL) and (MM) are prepared in a similar manner.
Example 1
A compound of formula (IA)
A. According to Crestini, C.; saladino, R.Synth.Commun, (1994), Vol.24, NO.20, p.2835. A solution of 5-methoxyindolin-2-one (0.41g, 2.5mmol) and 2-pyrrolecarboxaldehyde (0.25g, 2.6mmol) in ethanol (5mL) was treated with piperidine (0.05g, 0.65 mmol). The reaction mixture was then heated to 85 ℃. The reaction was maintained for 3 hours. After cooling the reaction to room temperature, the reaction mixture was SiO using 3: 1 hexane/ethyl acetate2(12g) Chromatography to obtainTo 5-methoxy-3- [ (pyrrol-2-yl) methylene]Indolin-2-one; (0.48 g);1H NMR(400MHz，DMSO-d6)δ3.74(s，3H)，6.30(m，1H)，6.60-6.80(m，3H)，7.30(m，1H)，7.35(m，1H)，7.76(m，1H)，10.80(s，1H)ppm。
B. by BBr3Solution (2.0mL, 1M solution in dichloromethane, 20mmol, 5.0 equiv.) treatment of 5-methoxy-3- [ (pyrrol-2-yl) methylene]A solution of indolin-2-one (0.10g, 0.4mmol) in dichloromethane (5 mL). After stirring overnight at room temperature, the resulting reaction mixture was concentrated. The resulting oil was SiO using 1: 3 hexane/ethyl acetate2(5g) Chromatography to give 5-hydroxy-3- [ (pyrrol-2-yl) methylene]Indolin-2-one; (0.04 g);1H NMR(400MHz，DMSO-d6)δ6.30(m，1H)，6.60(m，2H)，6.78(m，1H)，6.98(m，1H)，7.32(m，1H)，7.58(m，1H)，9.00(s，1H)，10.60(s，1H)ppm。
C. alternatively, a mixture of 5-methoxyindolin-2-one (0.50g, 3.1mmol), 2-acetylpyrrole (0.28g, 2.4mmol) and piperidine (0.60g, 0.6mmol) was placed in a sealed tube and melted. The reactor was closed and the mixture was heated to 130 ℃ overnight. The reaction was then cooled to room temperature and dissolved in ethyl acetate (2 mL). Chromatography using 2: 1 Hexane/Ethyl ester (SiO)215g) to give 5-methoxy-3- [1- (pyrrol-2-yl) ethylene]Indolin-2-one; (0.24 g);1H NMR(400MHz，DMSO-d6)δ2.78(s，3H)，3.82(s，3H)，6.38(m，1H)，6.70-6.80(m，2H)，6.98(m，1H)，7.16(m，1H)，7.30(m，1H)，7.68(m，1H)ppm。
D. by BBr3Solution (1.5mL, 1M solution in dichloromethane, 1.5mmol, 3.0 equiv.) treatment of 5-methoxy-3- [1- (pyrrol-2-yl) ethylene]A solution of indolin-2-one (0.12g, 0.5mmol) in dichloromethane (5 mL). After stirring overnight at room temperature, the reaction was quenched with water (10 mL). The organic layer was separated. The aqueous layer was neutralized with saturated sodium bicarbonate solution and extracted with ethyl acetate (2X 20 mL). The combined organic layers were concentrated. Reverse phase HPLC using acetonitrile/water gave 5-hydroxy-3- [1- (pyrrol-2-yl) ylideneEthyl radical]Indolin-2-one; (0.04 g);1HNMR(400MHz，DMSO-d6)δ2.74(s，3H)，6.38(m，1H)，6.62(m，1H)，6.70(m，1H)，7.08(m，1H)，7.20(m，1H)，7.32(m，1H)，8.96(s，1H)，10.78(s，1H)ppm。
E. the following compounds were prepared in a similar manner to that described above in parts a and B or parts C and D, using appropriately substituted starting materials:
5-acetylamino-3- [1- (pyrrol-2-yl) ethylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ2.16(s，3H)，2.84(s，3H)，6.44(m，1H)，6.92(d，1H)，7.20(m，1H)，7.44(s，1H)，7.56(m，1H)，8.10(m，1H)，9.94(s，1H)，11.06(s，1H)ppm；
5- (pyridin-3-yl) carbonylamino-3- [1- (pyrrol-2-yl) ethylene]Indolin-2-one;1HNMR(400MHz，DMSO-d6)δ2.74(s，3H)，6.36(m，1H)，6.88(d，1H)，7.08(m，1H)，7.32(m，1H)，7.58(m，1H)，7.64(m，1H)，8.16(m，1H)，8.26(m，1H)，8.76(m，1H)，9.10(s，1H)，10.32(s，1H)，10.98(s，1H)ppm；
5- (pyridin-4-yl) carbonylamino-3- [1- (pyrrol-2-yl) ethylene]Indolin-2-one;1HNMR(400MHz，DMSO-d6)δ2.92(s，3H)，6.50(m，1H)，7.04(d，1H)，7.24(m，1H)，7.50(m，1H)，7.80(m，1H)，8.02(d，2H)，8.28(s，1H)，8.92(d，2H)，10.54(s，1H)，11.18(s，1H)ppm；
5-guanidino-3- [1- (pyrrol-2-yl) ethylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ2.78(s，3H)，6.40(m，1H)，6.98(d，1H)，7.06(m，1H)，7.10(m，1H)，7.24(m，3H)，7.40(m，1H)，7.58(m，1H)，9.44(s，1H)，10.96(s，1H)ppm；
5-aminosulfonylamino-3- [1- (pyrrol-2-yl) ethylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ2.74(s，3H)，6.38(m，1H)，6.82(d，1H)，6.90(s，2H)，7.04(m，1H)，7.10(m，1H)，7.36(m，1H)，7.64(m，1H)，8.92(s，1H)，10.96(s，1H)ppm；
5- (1, 1-Dimethylethoxy) carbonylaminosulfonamido-3- [1- (pyrrol-2-yl) ethylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ1.38(s，9H)，2.72(s，3H)，6.38(m，1H)，6.84(m，1H)，7.00(m，1H)，7.10(m，1H)，7.36(m，1H)，7.58(m，1H)，9.90(s，1H)，11.00(s，1H)ppm；
5- (4-Aminopiperidin-1-ylcarbonylamino) -3- [1- (pyrrol-2-yl) ethylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ1.4(m，2H)，1.9(m，2H)，2.7(s，3H)，2.9(m，2H)，3.2(m，1H)，4.1(m，2H)，6.4(s，1H)，6.8(d，1H)，7.0(m，1H)，7.3(m，2H)，7.8(s，1H)，7.9(m，2H)，8.5(s，1H)，10.9(s，1H)ppm；
6-chloro-3- [ (pyrrol-2-yl) methylene]Indolin-2-one;1H NMR(500MHz，DMSO-d6)δ6.38(m，1H)，6.84-6.91(m，2H)，7.04(dd，1H)，7.39(s，1H)，7.64(d，1H)，7.79(s，1H)，11.00(s，1H)，13.24(s，1H)ppm；
5-chloro-3- [ (pyrrol-2-yl) methylene]Indolin-2-one;1H NMR(500MHz，DMSO-d6)δ6.39(m，1H)，6.83-6.91(m，2H)，7.18(dd，1H)，7.39(s，1H)，7.75(d，1H)，7.89(s，1H)，10.98(s，1H)，13.30(s，1H)ppm；
5-bromo-3- [ (pyrrol-2-yl) methylene]Indolin-2-one;1H NMR(500MHz，DMSO-d6)δ6.38(m，1H)，6.84(m，2H)，7.29(dd，1H)，7.40(s，1H)，7.88(m，2H)，10.97(s，1H)，l3.29(s，1H)ppm；
6-fluoro-3- [ (pyrrol-2-yl) methylene]Indolin-2-one;1H NMR(500MHz，DMSO-d6)δ6.37(m，1H)，6.70(m，1H)，6.78-6.84(m，2H)，7.34(s，1H)，7.64(m，1H)，7.71(s，1H)，11.00(s，1H)，13.19(s，1H)ppm；
6-methyl-3- [ ((1-methyl) pyrrol-2-yl) methylene]Indolin-2-one;1H NMR(500MHz，DMSO-d6) δ 2.30(s, 3H), 3.78(s, 3H), 6.29(m, 1H), 6.68(s, 1H), 6.76(d, 1H), 7.14(m, 1H), 7.38(s, 1H), 7.85(d, 1H), 8.30(s, 1H), 10.38(s, 1H) ppm; and1H NMR(500MHz，DMSO-d6)δ3.88(s，3H)，6.20(m，1H)，6.64(s，1H)，6.99(m，1H)，7.12(m，1H)，7.48(s，1H)，7.58(d，1H)，8.18(d，1H)，10.32(s，1H)ppm；
6-trifluoromethyl-3- [ (1-methylpyrrol-2-yl) methylene]Indolin-2-one;1H NMR(500MHz，DMSO-d6) δ 3.82(s, 3H), 6.38(m, 1H), 7.10(s, 1H), 7.16(m, 1H), 7.24-7.32(m, 2H), 7.62(s, 1H), 8.16(d, 1H), 10.72(s, 1H) ppm; and1H NMR(500MHz，DMSO-d6)δ3.92(s，3H)，6.28(m，1H)，7.05(s，1H)，7.24-7.32(m，2H)，7.77(s，1H)，7.94(d，1H)，8.37(d，1H)，10.47(s，1H)ppm；
5- (4-methoxy) phenyl-3- [ (1-methylpyrrol-2-yl) methylene]Indolin-2-one;1HNMR(500MHz，DMSO-d6)δ3.70(m，6H)，6.34(m，1H)，6.92(d，1H)，7.02(d，2H)，7.19(dd，1H)，7.42(dd，1H)，7.48(d，2H)，7.70(s，1H)，8.18(s，1H)，8.28(m，1H)，10.51(m，1H)ppm；
5- (4- (1, 1-dimethyl) ethyl) phenyl-3- [ (1-methylpyrrol-2-yl) methylene ] indolin-2-one;
3- [ (1-Methylpyrrol-2-yl) methylene)]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ3.8(s，1H)，6.30(m，1H)，6.85(d，1H)，6.9(t，1H)，7.00(d，1H)，7.35(m，1H)，7.40(s，1H)，7.95(d，1H)，10.4(s，1H)ppm；
(z) -3- [ (1-phenylsulfonylpyrrol-2-yl) methylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ6.60(m，H)，6.80d，1H)，7.00(t，1H)，7.20(t，1H)，7.45(d，1H)，7.60(t，2H)，7.70(d，1H)，7.80(m，1H)，7.90(m，3H)，8.30(m，1H)，10.6(s，1H)ppm；
(E) -3- [ (1-phenylsulfonylpyrrol-2-yl) methylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ6.60(m，1H)，6.80(m，2H)，7.10(m，1H)，7.20(t，1H)，7.55(m，3H)，7.65(m，2H)，7.75(m，1H)，7.80(d，2H)，10.6(s，1H)ppm；
3- [ (3, 5-dimethyl-4-ethylpyrrol-2-yl) methylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ1.00(t，3H)，2.20(s，3H)，2.25(s，3H)，2.35(q，2H)，6.80(d，1H)，6.90(m，1H)，7.00(m，1H)，7.55(s，1H)，7.7(d，1H)，10.7(s，1H)ppm；
5, 6-dimethoxy-3- [ (pyrrol-2-yl) methylene]Indolin-2-one;1H NMR(400MHz，CDCl3)δ3.88(s，3H)，3.92(s，3H)，6.34(m，1H)，6.50(m，1H)，6.72(m，1H)，7.02(m，1H)，7.14(m，1H)，7.26(m，1H)，7.76(s，1H)ppm；
4-methyl-3- [ (pyrrol-2-yl) methylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ2.58(s，3H)，6.30(m，1H)，6.72(m，1H)，6.88(m，1H)，7.00(m，1H)，7.30(m，1H)，7.60(s，1H)，10.90(s，1H)ppm；
7-methyl-3- [ (pyrrol-2-yl) methylene]Indolin-2-one;1H NMR(400MHz，CDCl3)δ2.50(s，3H)，3.50(m，1H)，6.36(m，1H)，6.76(m，1H)，6.98(m，2H)，7.16(m，1H)，7.30(m，1H)，7.42(m，1H)，8.20(s，1H)ppm；
3- [ (5-ethylpyrrol-2-yl) methylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ1.10(t，3H)，2.60(q，2H)，6.00(m，1H)，6.70(m，1H)，6.80(d，1H)，6.90(m，1H)，7.00(m，1H)，7.50(d，1H)，7.60(s，1H)，10.8(s，1H)ppm；
5-methyl-3- [ (pyrrol-2-yl) methylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ2.36(s，3H)，6.36(m，1H)，6.76(m，2H)，6.98(m，1H)，7.16(m，1H)，7.28(m，2H)，7.40(s，1H)，8.00(m，1H)ppm；
6-carboxy-3- [ (pyrrol-2-yl) methylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ6.43(s，1H)，6.95(s，1H)，7.44(s，1H)，7.46(s，1H)，7.65(d，1H)，7.75(d，1H)，7.93(s，1H)，11.08(s，1H)ppm；
5-methoxy-3- [ (5-ethylpyrrol-2-yl) methylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ1.22(t，3H)，2.72(m，2H)，3.74(s，3H)，6.16(m，1H)，6.64-6.78(m，3H)，7.26(m，1H)，7.68(m，1H)，10.58(s，1H)ppm；
5-hydroxy-3- [ (5-ethylpyrrol-2-yl) methylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ1.22(t，3H)，2.70(m，2H)，6.10(m，1H)，6.52(m，1H)，6.62(m，1H)，6.70(m，1H)，6.92(m，1H)，7.48(m，1H)，10.50(s，1H)ppm；
5-aminosulfonyl-3- [ (pyrrol-2-yl) methylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ40(s，1H)，6.96(s，1H)，7.02(d，1H)，7.15(s，2H)，7.42(s，1H)，7.64(d，1H)，7.92(s，1H)，8.08(s，1H)，11.25(s，1H)ppm；
3- [ (4-Nitropyrrol-2-yl) methylene)]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ6.85(d，1H)，7.00(t，1H)，7.20(t，1H)，7.30(d，1H)，7.60(d，1H)，7.70(s，1H)，8.20(d，1H)，11.0(s，1H)ppm；
7-methoxy-3- [ (pyrrol-2-yl) methylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ3.80(s，3H)，6.36(m，1H)，6.82(m，2H)，6.92(m，1H)，7.22(m，1H)，7.34(m，1H)，7.70(m，1H)，10.90(s，1H)ppm；
7-hydroxy-3- [ (pyrrol-2-yl) methylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ6.36(m，1H)，6.62(m，1H)，6.80(m，2H)，7.08(m，1H)，7.30(m，1H)，7.62(m，1H)，9.44(m，1H)，10.90(s，1H)ppm；
4-methoxy-3- [ (pyrrol-2-yl) methylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ3.92(s，3H)，6.30(m，1H)，6.52(m，1H)，6.60(m，1H)，6.74(m，1H)，7.08(m，1H)，7.30(m，1H)，7.92(s，1H)，10.90(s，1H)ppm；
4-hydroxy-3- [ (pyrrol-2-yl) methylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ6.28(m，1H)，6.40(m，1H)，6.48(m，1H)，6.70(m，1H)，6.92(m，1H)，7.20(m，1H)，7.90(m，1H)，10.20(s，1H)，10.76(s，1H)ppm；
5- (2-hydroxyethyl) aminosulfonyl-3- [ (pyrrol-2-yl) methylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ2.78(t，2H)，3.35(t，2H)，4.62(brs，1H)，6.40(s，1H)，6.96(s，1H)，7.02(d，1H)，7.30(br s，1H)，7.42(s，1H)，7.55(d，1H)，7.92(s，1H)，8.08(s，1H)，11.25(s，1H)ppm；
6-methoxy-3- [ (pyrrol-2-yl) methylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ3.77(s，3H)，6.32(m，1H)，6.44(m，1H)，6.58(m，1H)，6.76(m，1H)，7.30(m，1H)，7.50-7.66(m，2H)，10.84(s，1H)ppm；
3- [1- (pyrrol-2-yl) ethylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ2.70(s，3H)，6.30(m，1H)，6.85(d，1H)，6.90(t，1H)，7.00(m，1H)，7.20(m，1H)，7.30(m，1H)，7.65(d，1H)，11.0(br，1H)ppm；
6-hydroxy-3- [ (pyrrol-2-yl) methylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ6.26(m，1H)，6.30(m，1H)，6.38(m，1H)，6.70(m，1H)，7.20(m，1H)，7.36(m，1H)，7.44(m，2H)，9.50(m，1H)，10.70(s，1H)ppm；
5-dimethylaminosulfonyl-3- [ (pyrrol-2-yl) methylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ2.60(s，6H)，6.40(s，1H)，6.90(s，1H)，7.02(d，1H)，7.40(s，1H)，7.50(d，1H)，8.00(s，1H)，8.08(s，1H)，11.30(s，1H)ppm；
5-methylaminosulfonyl-3- [ (pyrrol-2-yl) methylene]Indomethacin-2-one;1H NMR(400MHz，DMSO-d6)δ2.40(d，3H)，6.40(s，1H)，6.96(s，1H)，7.05(d，1H)，7.20(br s，1H)，7.42(s，1H)，7.55(d，1H)，7.92(s，1H)，8.08(s，1H)，11.25(s，1H)ppm；
5-methoxy-4-methyl-3- [ (pyrrol-2-yl) methylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ2.40(s，3H)，3.72(s，3H)，6.30(m，1H)，6.64(m，1H)，6.78(m，1H)，6.90(m，1H)，7.30(m，1H)，7.70(m，1H)，10.70(s，1H)ppm；
5-hydroxy-4-methyl-3- [ (pyrrol-2-yl) methylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ2.38(s，3H)，6.30(m，1H)，6.50(m，1H)，6.60(m，1H)，6.88(m，1H)，7.26(m，1H)，7.62(m，1H)，8.90(s，1H)，10.60(s，1H)ppm；
5, 6-dihydroxy-3- [ (pyrrol-2-yl) methylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ6.20(m，1H)，6.28(m，1H)，6.44(m，1H)，6.90(m，1H)，7.16(m，1H)，7.28(m，1H)，8.34(m，1H)，9.10(s，1H)，10.38(s，1H)ppm；
5-carboxy-3- [ (pyrrol-2-yl) methylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ6.40(s，1H)，6.85(s，1H)，6.90(d，1H)，7.40(s，1H)，7.80(d，1H)，7.92(s，1H)，8.20(s，1H)，11.25(s，1H)ppm；
5-aminosulfonyl-3- [ (1-pyrrol-2-yl) ethylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ6.40(s，1H)，7.04(d，1H)，7.21(br s，1H)，7.22(s，2H)，7.42(s，1h)，7.64(d，1H)，8.16(s，1H)，11.40(s，1H)ppm；
5-hydroxy-3- [ (4-methylpyridine)Pyrrol-2-yl) methylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ2.30(s，3H)，6.15(m，1H)，6.56(m，1H)，6.62(m，1H)，7.12(m，1H)，7.20(m，1H)，7.48(m，1H)，8.88(s，1H)，10.52(s，1H)ppm；
5-methylsulfonylamino-3- [ (pyrrol-2-yl) methylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ2.92(s，3H)，6.32(m，1H)，6.80(m，1H)，6.90(m，1H)，6.98(m，1H)，7.32(m，1H)，7.44(m，1H)，7.68(s，1H)，9.36(s，1H)，10.90(s，1H)ppm；
5-phenylaminosulfonyl-3- [ (pyrrol-2-yl) methylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ6.40(s，1H)，6.90-6.96(m，3H)，7.10(d，2H)，7.18(t，2H)，7.40(s，1H)，7.50(d，1H)，7.90(s，1H)，8.00(s，1H)，10.20(br，s，1H)，11.25(s，1H)ppm；
5-hydroxy-3- [ (5-methylpyrrol-2-yl) methylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ2.40(s，3H)，6.14(m，1H)，6.58(m，1H)，6.70(m，1H)，6.78(m，1H)，7.00(d，1H)，7.52(s，1H)，8.96(s，1H)，10.56(s，1H)ppm；
5-hydroxy-3- [ (3-methylpyrrol-2-yl) methylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ2.06(s，3H)，6.52-6.64(m，3H)，6.92(m，1H)，7.10(m，1H)，7.48(m，1H)，8.94(s，1H)，10.52(s，1H)ppm；
5-methoxy-3- [ (4-nitropyrrol-2-yl) methylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ3.74(s，3H)，6.78(m，2H)，7.30(m，2H)，7.78(s，1H)，8.22(m，1H)，10.96(s，1H)ppm；
5-methoxycarbonyl-3- [ (pyrrol-2-yl) methylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ3.90(s，3H)，6.40(s，1H)，6.90(s，1H)，7.00(d，1H)，7.40(s，1H)，7.80(d，1H)，8.00(s，1H)，8.30(s，1H)，11.25(s，1H)ppm；
5-aminocarbonyl-3- [ (pyrrol-2-yl) methylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ6.35(s，1H)，6.85(s，1H)，6.90(d，1H)，7.39(s，1H)，7.68(d，1H)，7.72(s，1H)，8.15(s，1H)，11.10(s，1H)ppm；
3- [ (3, 5-dimethylpyrrol-2-yl) methylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ2.26(s，3H)，2.30(s，3H)，5.96(s，1H)，6.84(m，1H)，6.92(s，1H)，7.06(m，1H)，7.56(s，1H)，7.70(m，1H)，10.76(s，1H)ppm；
5-methoxy-3- [ (3, 5-dimethylpyrrol-2-yl) methylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ2.24(s，3H)，2.28(s，3H)，3.74(s，3H)，5.96(m，1H)，6.64(m，1H)，6.74(s，1H)，7.38(s，1H)，7.56(s，1H)，10.56(s，1H)ppm；
5-methoxy-1-methyl-3- [ (pyrrol-2-yl) methylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ3.34(s，3H)，3.84(s，3H)，6.38(m，1H)，6.76(m，3H)，7.08(dd，1H)，7.16(s，1H)，7.26(s，1H)，7.38(s，1H)ppm；
5-hydroxy-1-methyl-3- [ (pyrrol-2-yl) methylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ3.20(s，1)，6.34(m，1H)，6.60(d，1H)，6.82(d，1H)，7.14(s，1H)，7.30(s，1H)，7.62(s，1H)，9.06(brs，1H)ppm；
5-hydroxy-3- [ (3, 5-dimethylpyrrol-2-yl) methylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ2.24(s，3H)，2.28(s，3H)，5.96(m，1H)，6.50(m，1H)，6.62(s，1H)，7.08(s，1H)，7.38(s，1H)，8.82(s，1H)，10.44(s，1H)ppm；
4-carboxy-3- [ (pyrrol-2-yl) methylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ6.40(s，1H)，6.80(s，1H)，7.20(d，1H)，7.30(t，1H)，7.42-7.48(m，2H)，8.53(s，1H)，11.05(s，1H)ppm；
5-acetamido-3- [ (pyrrol-2-yl) methylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ2.00(s，3H)，6.32(m，1H)，6.78(d，1H)，6.98(m，1H)，7.14(d，1H)，7.34(s，1H)，7.56(s，1H)，7.88(s，1H)，9.78(s，1H)，10.78(s，1H)ppm；
4-methoxy-5-methoxycarbonyl-7-chloro-3- [ (pyrrol-2-yl) methylene]Indolin-2-one;1HNMR(400MHz，DMSO-d6)δ3.84(s，3H)，3.88(s，3H)，6.42(s，1H)，7.08(m，1H)，7.48(m，1H)，7.60(s，1H)，8.08(m，1H)，11.68(s，1H)ppm；
5-trifluoroacetylamino-3- [ (pyrrol-2-yl) methylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ6.34(m，1H)，6.76(dm 2H)，7.24(d，1H)，7.90(s，1H)，10.98(s，1H)，11.14(s，1H)ppm；
4-acetamido-3- [ (pyrrol-2-yl) methylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ2.00(s，3H)，10.8(s，1H)6.30(m，1H)，6.80(m，1H)，7.00(dd，1H)，7.30(m，1H)，7.40(s，1H)，7.50(d，1H)，7.60(s，1H)，10.0(s，1H)ppm；
5- (pyrrolidin-1-yl) acetamido-3- [ (pyrrol-2-yl) methylene]Indolin-2-one;1HNMR(400MHz，DMSO-d6)δ1.70(m，4H)，2.60(m，4H)，3.20(s，2H)，6.30(m，1H)，6.80(m，1H)，7.10(m，1H)，7.30(s，1H)，7.50(m，2H)，7.60(s，1H)，9.70(s，1H)，10.8(s，1H)ppm；
5-aminocarbonyl-3- [3- (pyrrol-2-yl) ethylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ3.08(s，3H)，6.60(s，1H)，7.20(d，1H)，7.38(brs，1H)，7.45(br s，1H)，7.60(s，1H)，8.00(d，1H)，8.20(br s，1H)，8.40(s，1H)，11.10(s，1H)ppm；
4-ethoxycarbonylmethylamino-3- [ (pyrrol-2-yl) methylene]Indolin-2-one;1HNMR(400MHz，DMSO-d6)δ1.20(t，3H)，3.90(d，2H)，4.10(q，2H)，6.10(s，1H)，6.20(m，1H)，6.30(m，2H)，6.60(m，1H)，7.20(m，1H)，7.30(m，2H)，10.6(s，1H)ppm；
5-aminosulfonyl-3- [1- (pyrrol-2-yl) propylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ1.35(t，3H)，3.18(q，2H)，6.40(s，1H)，7.02(d，1H)，7.14(br s，1H)，7.22(s，2H)，7.38(s，1H)，7.64(d，1H)，7.98(s，1H)，11.40(s，1H)ppm；
5-aminosulfonyl-3- [ (pyrrol-2-yl) (phenyl) methylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ5.82(s，1H)，5.86(m，1H)，6.25(m，1H)，6.85(s，2H)，6.95(d，1H)，7.24-7.28(m，2H)，7.42(br s，1H)，7.48(d，1H)，7.50-7.52(m，3H)，11.40(s，1H)ppm；
5-Acylaminomethyl-3- [1- (pyrrol-2-yl) ethylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ2.90(s，3H)，2.78(s，3H)，4.22(d，2H)，6.38(m，1H)，6.82(d，1H)，7.18(m，2H)，7.30(m，1H)，7.60(s，1H)，8.26(t，1H)，10.96(s，1H)ppm；
5- (1, 1-Dimethylethoxy) carbonylaminomethyl-3- [1- (pyrrol-2-yl) ethylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ1.60(s，9H)，2.92(s，3H)，4.28(d，2H)，6.50(m，1H)，6.98(d，1H)，7.20(m，2H)，7.48(m，1H)，7.52(t，1H)，7.78(s，1H)，11.12(s，1H)ppm；
5-Aminoacetamido-3- [1- (pyrrol-2-yl) ethylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ2.76(s，3H)，3.78(s，2H)，6.38(m，1H)，6.90(m，1H)，7.10(m，1H)，7.38(m，2H)，8.10(m，3H)，10.32(s，1H)，11.00(s，1H)ppm；
5-ethoxycarbonylmethylamino-3- [1- (pyrrol-2-yl) ethylene]Indolin-2-one;1HNMR(400MHz，DMSO-d6)δ1.20(s，3H)，2.70(s，3H)，3.90(s，2H)，4.12(m，2H)，5.70(t，1H)，6.36(m，1H)，6.40(m，1H)，6.64(m，1H)，7.02(m，2H)，7.30(m，1H)，10.60(t，1H)ppm；
5-aminocarbonylmethylamino-3- [1- (pyrrol-2-yl) ethylene]Indolin-2-one;1HNMR(400MHz，DMSO-d6)δ2.70(s，3H)，3.60(m，2H)，5.60(t，1H)，6.36(m，2H)，6.70(m，1H)，7.00-7.15(m，3H)，7.30(m，1H)，7.36(m，1H)，10.62(s，1H)ppm；
5-aminosulfonyl-3- [ (4-carboxy-3-methylpyrrol-2-yl) methylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ1.45(m，6H)，2.56(s，3H)，2.74(m，4H)，6.98(d，1H)，7.60(d，1H)，7.73(s，1H)，7.78(s，1H)，8.24(s，1H)ppm；
5-aminosulfonyl-3- [ (3-methyl-4- (3- (piperidin-1-yl) propyl) aminocarbonylpyrrol-2-yl) methylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ1.36(m，1H)，1.64(m，3H)，1.82(m，4H)，2.84(m，2H)，2.96(s，3H)，3.04(m，2H)，3.23(m，2H)，3.41(m，2H)，7.19(d，1H)，7.40(s，2H)，7.76(d，1H)，7.85(s，1H)，8.05(s，1H)，8.27(t，1H)，8.54(s，1H)ppm
5-acetylamino-3- [1- (4-aminomethylpyrrol-2-yl) ethylene]Indolin-2-one;1HNMR(400MHz，DMSO-d6) δ 2.04(s, 3H), 2.70(s, 3H), 3.96(d, 2H), 6.86(d, 1H), 714(s, 1H), 7.44(s, 1H), 7.48(s, 1H), 8.06(s, 1H), 8.16(s, 2H), 9.90(s, 1H), 11.00(s, 1H) ppm; and
5-acetylamino-3- [1- (4- (2-aminoethylcarbamoylmethyl) pyrrol-2-yl) ethylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ2.26(s，3H)，2.72(m，2H)，2.94(s，3H)，3.26(m，2H)，4.46(d，2H)，7.08(d，1H)，7.20(s，1H)，7.46(m，1H)，7.64(dd，1H)，7.96(s，2H)，8.24(s，1H)，8.66(t，1H)，10.08(s，1H)，11.16(s，1H)ppm。
F. alternatively, a mixture of 5-aminosulfonylindolin-2-one (1.0g, 4.7mmol), 2-ethoxycarbonylpyrrole (2.5g, 14.5mmol) in ethanol (120mL) was treated with triethylamine (1.0mL, 7.2 mmol). The reaction mixture was refluxed for 24 hours. The reaction mixture was concentrated to about 20mL, treated with additional triethylamine (0.2mL, 1.44mmol), and refluxed for 55 hours. The reaction was then cooled to room temperature and concentrated. Reverse phase HPLC with acetonitrile/water to give 5-aminosulfonyl-3- [ (pyrrol-2-yl) (ethoxycarbonyl) methylene]Indolin-2-one;1HNMR(400MHz，DMSO-d6) δ 1.35(t, 3H), 4.50(q, 2H), 6.40(s, 1H), 6.65(s, 1H), 7.06(d, 1H), 7.25(s, 2H), 7.48(br s, 1H), 7.50(s, 1H), 7.68(d, 1H), 11.50(s, 1H) ppm; (45mg) and 5-aminosulfonyl-3- [ (pyrrol-2-yl) (carboxy) methylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ6.40(s，1H)，6.65(s，1H)，7.06(d，1H)，7.25(s，2H)，7.48(br s，1H)，7.68(d，1H)，7.85(s，1H)，11.50(s，1H)ppm；(48mg)。
G. the following compounds are prepared in a similar manner, but using instead of 2-ethoxycarbonylpyrrole, an appropriately substituted (aminocarbonyl) carbonylpyrrole which can be prepared according to methods known to those skilled in the art or according to the methods disclosed in Archibald, j.l. et al, j.med.chem. (1974), vol.17, pp.736-739:
5-aminosulfonyl-3- [ (pyrrol-2-yl) (aminocarbonyl) methylene]Indolin-2-one;1HNMR(400MHz，DMSO-d6) δ 6.40(s, 1H), 6.75(s, 1H), 7.00(d, 1H), 7.20(s, 2H), 7.44(br s, 1H), 7.68(d, 1H), 8.00(br s, 2H), 8.25(s, 1H), 11.20(s, 1H) ppm; and
5-aminosulfonyl-3- [ (pyrrol-2-yl) (N, N-diethylaminocarbonyl) methylene]-indolin-2-one;1H NMR(400MHz，DMSO-d6)δ0.78(t，3H)，1.30(t，3H)，3.15(m，2H)，3.36(m，1H)，3.85(m，1H)，6.40(s，1H)，6.58(s，1H)，7.02(d，1H)，7.20(br s，2H)，7.42(s，1H)，7.64(s，1H)，7.70(d，1H)，11.40(s，1H)ppm。
H. alternatively, a mixture of 5-aminosulfonylindolin-2-one (0.22g, 1.0mmol), 2- (ethylamino) carbonylpyrrole (0.33g, 2.0mmol) and piperidine (0.2mL, 2.0mmol) was irradiated in a microwave oven at 160 ℃ for 5 minutes. The reaction mixture was dissolved in dichloromethane (25 mL). The resulting mixture was washed with 0.2N HCl (25mL) and saturated sodium bicarbonate (25mL), dried (magnesium sulfate) and concentrated using hexanes/ethyl acetate over SiO2(10g) Chromatography gave 5-aminosulfonyl-3- [ (pyrrol-2-yl) (ethylaminocarbonyl) methylene]Indolin-2-one; (45mg) of a reaction mixture of,1H NMR(400MHz，DMSO-d6)δ1.16(t，3H)，3.36(q，2H)，6.40(s，1H)，6.64(s，1H)，7.02(d，1H)，7.20(br s，2H)，7.42(s，1H)，7.64(d，1H)，7.75(s，1H)，8.85(t，1H)，11.40(s，1H)ppm。
example 2
Compounds of formula (IB) and formula (IC)
A. To a suspension of 5-cyanoindolin-2-one (158mg, 1mmol) in ethanol (15mL) was added 2-acetylpyrrole (95mg, 1mmol) and piperidine (0.1 mL). The reaction mixture was refluxed for 2 hours. The gold-colored product precipitated from the reaction mixture, was filtered and washed with ethanol to give 5-cyano-3- [1- (pyrrol-2-yl) ethylene]Indolin-2-one; (160mg)1HNMR(400MHz，DMSO-d6)δ2.80(s，3H)，6.40(m，1H)，7.04(d，1H)，7.20(m，1)，7.42(m，1H)，7.60(dd，1H)，8.04(s，1H)，11.40(s，1H)ppm。
B. With tributyltin hydride (0.68g, 2.1mmol) and NaN3(0.39g, 2.52mmol) treatment of 5-cyano-3- [1- (pyrrol-2-yl) ethylene]A solution of indolin-2-one (100mg, 0.42mmol) in toluene. The resulting reaction mixture was refluxed overnight. Concentration gave a residue which was dissolved in methanol and left overnight at room temperature. An orange solid formed, filtered and dried in vacuo to give 5-tetrazol-5-yl-3- [ (pyrrol-2-yl) methylene]Indolin-2-one; (29mg) as an orange solid;1H NMR(400MHz，DMSO-d6)δ6.22(s，1H)，6.90(s，1H)，7.08(d，1H)，7.20(s，1H)，7.80(m，1H)，7.84(s，1H)，8.14(s，1H)，11.22(s，1H)ppm。
C. the following compounds of the invention are prepared in a similar manner to that described above, but using appropriately substituted starting materials:
5-cyano-3- [ (pyrrol-2-yl) methylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ6.40(m，1H)，6.88(m，1H)，7.06(d，1H)，7.48(s，1H)，7.66(dd，1H)，7.94(s，1H)，8.18(s，1H)，11.40(s，1H)ppm。
example 3
Compounds of formula (ID) and formula (IE)
A. 5-Aminomethylindolenin-2-one (160mg, 1mmol), 2-acetylpyrrole (190mg, 1.74mmol) and piperidine (0.4mL) were mixed together in a microwave reaction vessel and heated to 160 ℃ in the microwave reactor for 8 minutes. Dissolving the obtained black solid in DMSO, and purifying by reversed phase HPLC (acetonitrile/water) to obtain 5- ((1-pyrrol-2-yl) ethylene) aminomethyl-3- [1- (pyrrol-2-yl) ethylene]Indolin-2-one; (20mg) is trifluoroacetate salt;1H NMR(400MHz，DMSO)δ2.74(s，3H)，2.76(s，3H)，4.90(d，2H)，6.34(m，1H)，6.50(m，1H)，6.92(d，1H)，7.08(m，1H)，7.24(d，1H)，7.42(s，1H)，7.60(m，2H)，7.78(s，1H)，11.20(s，1H)，11.28(brs，1H)ppm。
B. alternatively, a solution of 5-aminomethyl indolin-2-one acetate (220mg, 1mmol) in ethanol (10mL) was treated with Diisopropylethylamine (DIEA) (3 mL). After 20 min, 2-Pyrrolecarboxaldehyde (95mg, 1mmol) and pyrrolidine (0.05mL) were added and the reaction mixture was stirred at 60 ℃ for 3 h. Concentrating the solvent to give an oil, purifying by reverse phase HPLC (acetonitrile/water) to give 5-aminomethyl-3- [ (pyrrol-2-yl) methylene]Indolin-2-one; as trifluoroacetate salt (70 mg);1H NMR(400MHz，DMSO-d6)δ3.98(m，2H)，6.36(m，1H)，6.84(brs，1H)，6.88(d，1H)，7.22(d，1H)，7.34(s，1H)，7.62(s，1H)，7.68(s，1H)，8.20(brs，2H)，11.00(s，1H)ppm。
C. in a similar manner to that described above in sections a and B, but using appropriately substituted starting materials, the following compounds of the invention were prepared:
5-aminomethyl-3- [1- (pyrrol-2-yl) ethylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ2.80(s，3H)，4.06(m，2H)，6.38(m，1H)，6.92(d，1H)，7.16(m，1H)，7.24(d，1H)，7.36(m，1H)，7.82(s，1H)，8.08(brs，2H)，11.08(s，1H)ppm；
4- (pyrrol-2-yl) methyleneamino-3- [ (pyrrol-2-yl) methylene]Indolin-2-one;1HNMR(400MHz，DMSO-d6)δ6.2(m，1H)，6.3(m，1H)，6.7(m，2H)，6.78(m，1H)，6.8(dd，1H)，7.0(m，1H)，7.3(m，1H)，7.58(d，1H)，7.62(s，1H)，8.3(s，1H)，10.9(s，1H)，11.7(m，2H)ppm。
example 4
A compound of formula (IF)
A. To 5-nitro-3- [ (4- (dimethylethoxycarbonylaminomethyl) -pyrrol-2-yl) methylene]To a suspension of indolin-2-one (0.8g, 2mmol) in ethyl acetate/pyridine (60mL/9mL) was added tin (II) chloride dihydrate and the reaction mixture was refluxed for 1.5 h. The reaction mixture was cooled to room temperature, filtered through celite, and the filtrate was partitioned between water and ethyl acetate. The organic layer was washed with water and filtered through celite again. The organic layer was then washed with brine and concentrated to give 5-amino-3- [ (4- (dimethylethoxycarbonylaminomethyl) pyrrol-2-yl) methylene]Indolin-2-one as a red solid (0.68 g);1h NMR (400MHz, DMSO). delta.1.38 (s, 9H), 2.62(s, 3H), 4.0(d, 2H), 4.64(s, 2H), 6.42(d, 1H), 6.58(d, 1H), 6.82(s, 1H), 7.0(s, 1H), 8.08(m, 2H), 10.52(s, 1H) ppm. Hydrolysis under standard conditions to give 5-amino-3- [ (4- (aminomethyl) pyrrol-2-yl) methylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ2.66(s，3H)，4.00(m，2H)，6.50(dd，1H)，6.64(d，1H)，7.08(s，1H)，7.26(s，1)，7.38(s，1H)，8.06(brs，1H)，10.18(s，1H)ppm。
B. preparing a compound of formula (If) below in a similar manner to that described above but using appropriately substituted starting materials:
6-amino-3- [ (pyrrol-2-yl) methylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ6.30(m，1H)，6.84(m，3H)，7.34(m，1H)，7.68(m，1H)，7.78(s，1H)，11.04(s，1H)ppm；
4-amino-3- [ (pyrrol-2-yl) methylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ5.30(s，2H)，6.15(d，1H)，6.15(dd，1H)，6.25(m，1H)，6.60(m，1H)，7.15(m，1H)，7.20(d，1H)，7.25(s，1H)，10.6(s，1H)ppm；
5-amino-3- [1- (pyrrol-2-yl) ethylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ2.68(s，3H)，4.70(s，2H)，6.30(m，1H)，6.42(m，1H)，6.60(m，1H)，6.98(m，1H)，7.04(m，1H)，7.28(m，1H)，10.60(s，1H)ppm；
5-amino-3- [ (pyrrol-2-yl) methylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ6.38(m，1H)，6.90(m，2H)，7.06(m，1H)，7.36(m，1H)，7.44(m，1H)，7.78(m，1H)，11.02(s，1H)ppm；
5-amino-3- [1- (4- (2-aminoethylcarbamoylmethyl) pyrrol-2-yl) ethylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6) δ 2.52(m, 2H), 2.72(s, 3H), 3.00(m, 2H), 4.18(d, 2H), 6.92(d, 1H), 7.00(s, 2H), 7.28(s, 1H), 7.59(s, 1H), 7.6(s, 2H), 8.42(t, 1H), 11.06(s, 1H) ppm; and
5-amino-3- [ (pyrrol-2-yl) (3- (5, 5-dimethyl-1, 3-dioxan-2-yl) propan-1-yl) methylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ0.82(s，3H)，1.22(s，3H)，1.90(m，2H)，2.03(m，2H)，3.30(m，2H)，3.70(d，2H)，4.70(t，1H)，6.58(m，1H)，7.13(d，1H)，7.22-7.28(m，2H)，7.54(m，2H)，11.38(s，1H)ppm。
example 5
A compound of formula (IG)
A. To a solution of 5-ureidoindolin-2-one (326mg, 1.71mmol) in ethanol was added 4-bromo-2-pyrrolidinecarboxaldehyde (297mg, 1.71mmol) and piperidine (0.2 mL). The reaction mixture was refluxed for 18 hours. The mixture was cooled and filtered to give a golden solid, which was washed with ethanol and diethyl ether to give 5-ureido-3- [ (4-bromopyrrol-2-yl) methylene]Indolin-2-one; (453 mg);1H NMR(400MHz，DMSO-d6)δ5.77(s，2H)；6.74-6.76(d，1H)；6.96(s，1H)，7.02-7.04(dd，1H)；7.41-7.42(m，1H)；7.52-7.53(m，1H)；7.73-7.74(d，1H)；8.34(s，1H)；10.82(bd，1H)；13.5(bs，1H)ppm。
B. or to 5-amino-3- [ (4- (aminomethyl) pyrrol-2-yl) methylene]Indolin-2-one; (178mg, 0.46mmol) in THF (30mL) was added trimethylsilyl isocyanate (0.3mL, 2.90mmol) and the reaction mixture was stirred at room temperature for 18 h. The precipitate was filtered off and washed with THF to give the brown compound 5-ureido-3- [1- (4- (1, 1-dimethylethoxycarbonylaminomethyl) pyrrol-2-yl) ethylene]Indolin-2-one; (130mg, 68%);1H NMR(400MHz，DMSO-d6)δ1.98(s，9H)，2.64(s，3H)，4.04(d，2H)，5.70(brs，2H)，6.76(d，1H)，6.92(s，1H)，7.16(m，2H)，7.78(s，1H)，8.38(s，1H)，10.80(s，1H)ppm。
C. the following compounds of formula (Ig) are prepared in a similar manner to that described in part a or B above using appropriately substituted starting materials:
5-ureido-3- [ (4- (2- (imidazol-4-yl) ethyl) aminocarbonylpyrrol-2-yl) methylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ2.85(t，2H)，3.48(m，2H)，5.78(s，2H)，6.75(d，1H)，7.04(d，1H)，7.17(s，1H)，7.44(s，1H)，7.53(s，1H)，7.70(m，2H)，8.21(t，1H)，8.36(s，1H)，8.95(s，1H)ppm；
5-ureido-3- [ (4- (2- (pyridin-4-yl) ethyl) aminocarbonylpyrrol-2-yl) methylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ3.05(t，2H)，3.48(m，2H)，5.78(s，2H)，6.74(d，1H)，7.04(d，1H)，7.15(s，1H)，7.54(s，1H)，7.70(m，2H)，7.76(d，2H)，8.19(t，1H)，8.33(s，1H)，8.72(d，2H)ppm；
5-ureido-3- [ (4- ((3R) -3- (dimethylamino) pyrrolidin-1-yl) carbonylpyrrol-2-yl) methylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ2.10(m，1H)，2.25(m，1H)，2.83(d，6H)，3.41-4.20(m，5H)，6.74(d，1H)，6.96(d，1H)，7.24(s，1H)，7.58(s，1H)，7.78(m，2H)，8.38(m，2H)，9.82(s，1H)，10.82(s，1)；
5-ureido-3- [ (4- ((3S) -3- (dimethylamino) pyrrolidin-1-yl) carbonylpyrrol-2-yl) methylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ2.10(m，1H)，2.26(m，1H)，2.83(d，6H)，3.41-4.20(m，5H)，5.78(s，2H)，6.74(d，1H)，6.95(d，1H)，7.24(s，1H)，7.58(s，1H)，7.78(s，2H)，8.38(m，2H)，9.98(s，1H)，10.82(s，1H)ppm；
5-ureido-3- [ (4- (3- (pyrrolidin-1-yl) propyl) aminocarbonylpyrrol-2-yl) methylene]Indolin-2-one:1H NMR(400MHz，DMSO-d6)δ1.83(m，4H)，1.97(m，2H)，2.87(m，2H)，3.14(m，2H)，3.25(m，2H)，3.52(m，2H)，5.78(s，2H)，6.74(d，1H)，7.04(d，1H)，7.18(s，1H)，7.55(s，1H)，7.74(m，2H)，8.24(t，1H)，8.35(s，1H)，9.47(s，1H)，10.81(s，1H)ppm；
5-ureido-3- [ (4- (4- (pyrrolidin-1-yl) butyl) aminocarbonylpyrrol-2-yl) methylene]Indolin-2-one:1H NMR(400MHz，DMSO-d6)δ1.52(m，2H)，1.63(m，2H)，1.82(m，2H)，1.97(m，2H)，2.96(m，2H)，3.14(m，2)，3.25(m，2H)，3.48(m，2H)，5.78(s，2H)，6.74(d，1H)，7.04(d，1H)，7.18(s，1H)，7.54(s，1H)，7.74(m，2H)，8.14(t，1H)，8.35(s，1H)，9.47(s，1H)，10.80(s，1H)ppm；
5-ureido-3- [ (4- (4-methylpiperazin-1-yl) carbonylpyrrol-2-yl) methylene]Indolin-2-one:1H NMR(400MHz，DMSO-d6)δ2.81(s，3H)，3.04(m，2H)，3.28(m，2H)，3.43(m，2H)，4.43(m，2)，6.74(d，1H)，6.97(d，1H)，7.11(s，1H)，7.56(s，1H)，7.65(s，1H)，7.78(s，1H)，8.40(s，1H)，9.98(s，1H)，10.81(s，1H)ppm；
5-ureido-3- [ (4- (4- (4-methylpiperazin-1-yl) carbonylphenyl) pyrrol-2-yl) methylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6) δ 2.81(s, 3H), 3.08(s, 4H), 3.40 (water-masked peak, m, 4H), 5.77(s, 1H), 6.75(d, 1H), 7.00(dd, 1H), 7.31(d, 1H), 7.45(d, 2H), 7.58(s, 1H), 7.69(d, 2H), 7.77(s, 1H), 7.88(m, 1H), 8.35(s, 1H), 9.83(bs, 1H), 10.78(s, 1H) ppm;
5-ureido-3- [ (4- (3- (2-dimethylaminoethyl) aminocarbonylphenyl) pyrrol-2-yl) methylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ2.84(sm，6H)，3.26(m 2H)，3.64(m，2H)，5.78(brs，2H)，6.76(d，1H)，7.02(dd，1H)，7.30(s，1H)，7.48(t，1H)，7.58(s，1H)，7.68(d，1H)，7.78(m，2H)，7.84(s，1H)，8.08(s，1H)，8.38(s，1)，7.26(s，1)，8.76(t，1H)，9.30(brs 1H)，10.78(s，1H)ppm；
5-ureido-3- [ (4- (3- (4-methylpiperazin-1-yl) carbonylphenyl) pyrrol-2-yl) methylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6) δ 2.83(bs, 4H); 3.10(bs, 4H); 5.78(s, 2H), 6.75-6.77(d, 1H); 6.99-7.02(dd, 1H); 7.25-7.27(d, 1H); 7.30(m, 1H); 7.45-7.49(dd, 1H); 7.58(s, 1H); 7.66(m, 1H): 7.73-7.75(d, 1H); 7.86-7.87(m, 1H); 8.36(s, 1H), 10.79(s, 1H); 13.46(s, 1H) ppm; with addition of a few drops D2O as a clarified identical sample:1H NMR(400MHz，DMSO-d6adding several drops of D2O)δ2.78(s，3H)；3.10(bs，4H)；3.31(bs，4H)；6.77-6.79(d，1H)；6.99-7.01(dd，1H)；7.22-7.23(d，1H)；7.26(s，1H)；7.43-7.47(t，1H)；7.58(s，1H)；7.62(s，1H)；7.69(d，1H)；7.71-7.73(d，1H)；7.80(s，1H)ppm；
5-ureido-3- [ (4- (2-carboxyethyl) -3, 5-dimethylpyrrol-2-yl) methylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ1.45(m，6H)，2.18(t，2H)，2.12(s，3H)，2.23(s，3H)，2.57(t，2H)，2.74(m，4H)，5.81(s，2)，6.70(d，1H)，7.08(d，1H)，7.35(s，1H)，7.68(s，1H)，8.24(s，1H)ppm；
5-ureido-3- [ (4- (2- (4-methylpiperazin-1-yl) carbonylethyl) -3, 5-dimethylpyrrol-2-yl) methylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ2.21(s，3H)，2.27(m，3H)，2.48(m，2H)，2.61(m，2H)，2.74(s，3H)，2.85(m，3H)，3.18(m，1H)，3.37(m，2H)，3.97(m，1H)，4.43(m，1H)，6.70(d，1H)，6.98(d，1H)，7.38(s，1H)，7.63(s，1H)，8.26(s，1H)，9.84(s，1H)，10.58(s，1H)ppm；
5-ureido-3- [ (4- (4- ((3R) -3-hydroxypyrrolidin-1-yl) carbonylphenyl) pyrrol-2-yl) methylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ1.70-1.90(m，2H)，3.40-3.60(m，3H)，4.25(d，1H)，4.90(br d，1H)，5.75(br s，2H)，6.75(d，1H)，7.02(d，1H)，7.29(br s，1H)，7.50(br s，2H)，7.55(s，1H)，7.60-7.68(m，2H)，7.40(s，1H)，7.86(s，1H)，8.30(s，1H)，10.80(s，1H)ppm；
5-ureido-3- [ (4- (3- ((3R) -3-hydroxypyrrolidin-1-yl) carbonylphenyl) pyrrol-2-yl) methylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ1.75-2.00(bm，2H)，3.20-3.23(d，1H)，3.49-3.61(m，2H)，4.23(bs，1H)，4.33(bs，1H)，5.78(s，2H)，6.74-6.76(d，1H)，7.03-7.05(dd，1H)，7.28-7.31(m，2H)，7.40-7.44(t，1H)，7.58(s，1H)，7.68-7.70(m，1H)，7.74(s，1H)，7.89(s，1H)，8.34(s，1H)，10.79(s，1H)，13.48(s，1H)ppm；
5-ureido-3- [ (4- (2-carboxyethyl) -3-methylpyrrol-2-yl) methylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ1.47(m，6H)，2.21(s，3H)，2.34(t，2H)，2.61(t，2H)，2.75(m，4H)，5.78(s，2H)，6.72(d，1H)，7.08(d，1H)，7.11(s，1H)，7.40(s，1H)，7.62(s，1H)，8.43(s，1H)ppm；
5-ureido-3- [ (4- (2- (pyridin-3-ylmethyl) aminocarbonylethyl) -3-methylpyrrol-2-yl) methylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ2.22(s，3H)，2.39(t，2H)，2.67(t，2H)，4.38(d，2H)，6.72(d，1H)，7.04(d，1H)，7.06(s，1H)，7.42(s，1H)，7.65(s，1H)，7.70(t，1)，7.97(d，1H)，8.26(s，1H)，8.50(t，1H)，8.65(m，2H)，10.68(s，1H)ppm；
5-ureido-3- [ (4- (2- (pyridin-4-yl) aminocarbonylethyl) -3-methylpyrrol-2-yl) methylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ2.24(s，3H)，2.75(m，4H)，6.71(d，1H)，7.03(d，1H)，7.14(s，1H)，7.42(s，1H)，7.65(s，1H)，8.02(d，2H)，8.28(s，1H)，8.50(t，1H)，8.65(d，2H)，10.65(s，1H)，11.33(s，1H)ppm；
5-ureido-3- [ (4- (2- (2-piperidin-1-ylethyl) aminocarbonylethyl) -3-methylpyrrol-2-yl) methylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ1.31(m，1H)，1.60(m，3H)，1.74(m，2H)，2.22(s，3H)，2.34(t，2H)，2.64(t，2H)，2.83(m，2H)，3.03(m，2H)，3.39(m，4H)，6.72(d，1H)，7.03(d，1H)，7.08(s，1H)，7.41(s，1H)，7.65(s，1H)，8.14(t，1H)，8.28(s，1H)，10.64(s，1H)ppm；
5-ureido-3- [ (4- (2- (4-methylpiperazin-1-yl) carbonylethyl) -3-methylpyrrol-2-yl) methylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ2.22(s，3H)，2.61(m，4H)，2.76(s，3H)，3.88(m，3H)，3.25(m，1H)，3.38(m，2H)，4.05(m，1H)，4.43(m，1H)，6.72(d，1H)，7.04(d，1H)，7.13(s，1H)，7.42(s，1H)，7.65(s，1H)，8.28(s，1H)，10.63(s，1H)ppm；
5-ureido-3- [ (4- (pyrimidin-5-yl) pyrrol-2-yl) methylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ5.78(s，2H)，6.75-6.77(d，1H)，7.05-7.07(dd，1H)，7.40(s，1H)，7.59(s，1H)，7.76(d，1H)，7.99(s，1H)，8.34(s，1H)，9.00(s，1H)，9.08(s，2H)，10.82(s，1H)，13.34(s，1H)ppm；
5-ureido-3- [ (4- (5-methoxypyridin-3-yl) pyrrol-2-yl) methylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ3.88(s，3H)，5.78(s，2H)，6.75-6.77(d，1H)，7.03-7.06(dd，1H)，7.36(s，1H)，7.55-7.58(m，2H)，7.75(s，1H)，7.93(d，1H)，8.18-8.12(d，1H)，8.34(s，1H)，8.48(d，1H)，10.78-10.79(bd，1H)ppm；
5- (ureido) methyl-3- [1- (pyrrol-2-yl) ethylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ2.78(s，3H)，4.18(d，2H)，5.50(brs，2H)，6.36(m，2H)，6.84(d，1H)，7.06(m，2H)，7.43(m，1H)，7.62(s，1H)，10.98(s，1H)ppm；
5-ureido-3- [1- (pyrrol-2-yl) propylene]Indolin-2-one;1H NMR(400MHz，DMSO)δ1.42(t，3H)，3.25(q，2H)，5.82(br s，2H)，6.50(m，1H)，6.90(d，1H)，7.19(s，1H)，7.28(d，1H)，7.43(s，1H)，7.92(s，1H)，8.54(s，1H)，10.95(s，1H)ppm；
5-ureido-3- [ (pyrrol-2-yl) (3-aminophenyl) methylene]Indolin-2-one;1H NMR(400MHz，DMSO)δ3.80(br s，3H)，5.30(s，1H)，5.65(s，1H)，5.75(m，1H)，6.20(m，1H)，6.68(d，1H)，7.05-7.15(m，3H)，7.35(br s，2H)，7.55(t，1H)，7.85(s，1H)，10.8(s，1H)ppm；
5-ureido-3- [ (pyrrol-2-yl) (3- (1, 1-dimethylethoxycarbonylamino) phenyl) methylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ1.40(s，9H)，5.36(s，1H)，5.60(br s，2H)，5.73(m，1H)，6.18(m，1H)，6.68(d，1H)，6.84(d，1H)，7.18(dd，1H)，7.32(m，2H)，7.39(t，1H)，7.52(s，1H)，7.62(d，1H)，9.50(s，1H)，10.8(s，1H)ppm；
5-ureido-3- [ (pyrrol-2-yl) (3-aminoacetanilino) methylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ3.70(m，2H)，5.48(s，1H)，5.75(m，1H)，6.20(m，1H)，6.68(d，1H)，7.02(d，1H)，7.07(dd，1H)，7.34(s，1H)，7.48-7.56(m，2H)，7.70(d，1H)，8.04(brs，3H)ppm；
5-ureido-3- [1- (pyrrol-2-yl) ethylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ2.72(s，3H)，5.70(s，2H)，6.34(m，1H)，6.76(d，1H)，7.04(m，1H)，7.20(m，1H)，7.30(m，1H)，7.76(m，1H)，8.40(s，1H)，10.82(s，1H)ppm；
5- (N' -ethylureido) -3- [1- (pyrrol-2-yl) ethylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ1.04(t，3H)，2.74(s，3H)，3.10(m，2H)，6.00(t，1H)，6.36(m，1H)，6.78(d，1H)，7.06(s，1H)，7.18(m，1H)，7.34(m，1H)，8.06(m，1H)，8.28(s，1H)，10.88(s，1H)ppm；
5- (N' -phenylureido) -3- [1- (pyrrol-2-yl) ethylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ2.76(s，3H)，6.38(m，1H)，6.84(d，1H)，6.94(m，1H)，7.08(m，1H)，7.22-7.30(m，3H)，7.34(m，1H)，7.46(m，2H)，7.90(m，1H)，8.60(s，1H)，8.64(s，1H)，10.90(s，1H)ppm；
5- (N-ethylureido) -3- [1- (pyrrol-2-yl) ethylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ1.02(t，3H)，2.76(s，3H)，3.58(m，2H)，5.44(s，2H)，6.36(m，1H)，6.90(d，1H)，7.00(m，1H)，7.10(m，1H)，7.36(m，1H)，7.48(m，1H)，11.10(s，1H)ppm；
5-ureido-3- [ (pyridine)Pyrrol-2-yl) (pyridin-4-yl) methylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ5.40(s，2H)，5.70(m，1H)，6.14(m，1H)，6.76(d，1H)，7.08(m，1H)，7.1-7.16(m，3H)，7.80(m，1H)，8.80(m，2H)，11.00(s，1H)ppm；
5-ureido-3- [ (pyrrol-2-yl) (2-methoxypyridin-5-yl) methylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ3.94(s，3H)，5.38(s，1H)，5.76(m，2H)，6.22(m，1H)，6.66(d，1H)，6.94(d，1H)，7.06(m，1H)，7.36(m，1H)，7.62(d，1H)，8.04(s，1H)，10.90(s，1H)ppm；
5-ureido-3- [ (pyrrol-2-yl) methylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ5.65(brs，2H)，6.32(m，1H)，6.72(d，1H)，6.85(b，1H)，6.92(dd，1H)，7.32(s，1H)，7.06(s，1H)，7.70(s，1H)，8.30(s，1H)，10.18(s，1H)ppm；
5- (N' -aminocarbonylureido) -3- [ (pyrrol-2-yl) methylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ6.38(m，1H)，6.78(d，1H)，6.85(b，1H)，7.18(dd，1H)，7.34(s，1H)，7.70(s，2H)，8.84(s，1H)，9.86(s，1H)，10.30(s，1H)ppm；
5-ureido-3- [ (pyrrol-2-yl) (pyridin-3-yl) methylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ5.4(s，1H)，5.6(m，3H)，6.2(m，1H)，6.7(d，1H)，7.1(dd，1H)，7.4(m，1H)，7.6(m，1H)，7.7(s，1H)，7.75(m，1H)，8.5(s，1H)，8.75(m，1H)，11(s，1H)ppm；
5-ureido-3- [ (pyrrol-2-yl) (4-methoxyphenyl) methylene]Indolin-2-one;1HNMR(400MHz，DMSO-d6)δ3.8(s，3H)，5.4(m，1H)，5.6(m，2H)，5.8(m，1H)，6.2(m，1H)，6.7(d，1H)，7.1(d，2H)，7.15(m，1H)，7.2(d，2H)，7.6(m，1H)，7.6(s，1H)，10.9(s，1H)ppm；
5-ureido-3- [1- (4- (aminomethyl) pyrrol-2-yl) ethylene]Indolin-2-ones；1H NMR(400MHz，DMSO-d6)δ2.68(s，3H)，3.98(d，2H)，5.78(brs，2H)，6.80(d，1H)，7.04(s，1H)，7.20(d，1H)，7.40(s，1H)，7.44(s，1H)，8.02(brs，2H)，8.26(s，1H)，10.88(s，1H)ppm；
5-ureido-3- [1- (4- (acetamidomethyl) pyrrol-2-yl) ethylene]Indolin-2-one;1HNMR(400MHz，DMSO-d6)δ1.80(s，3H)，2.68(s，3H)，4.18(d，2H)，5.74(brs，2H)，6.76(d，1H)，6.94(s，1H)，7.20(m，2H)，7.75(s，1H)，8.20(t，1H)，8.38(s，1H)，10.72(s，1H)ppm；
5-ureido-3- [ - (4- (((1, 1-dimethylethoxycarbonylamino) methyl) -carbonylamino-methyl) pyrrol-2-yl) ethylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ1.40(s，9H)，2.66(s，3H)，3.54(d，2H)，4.20(d，2H)，5.68(brs，2H)，6.75(d，1H)，6.94(s，1H)，7.22(m，2H)，7.80(s，1H)，8.18(t，1H)，8.38(s，10.80(s，1H)ppm；
5-ureido-3- [1- (4- (aminoacetamido) methylpyrrol-2-yl) ethylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ2.84(s，3H)，3.74(d，2H)，4.22(d，2H)，5.88(brs，2H)，6.94(d，1H)，7.16(s，1H)，7.36(d，1H)，7.42(s，1H)，8.00(s，1H)，8.20(brs，2H)，8.62(s，1H)，8.82(t，1H)，10.96(s，1H)ppm；
5-ureido-3- [1- (4- (pyridin-4-ylcarbonylamino) methylpyrrol-2-yl) ethylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ2.70(s，3H)，3.74(d，2H)，4.40(d，2H)，5.68(brs，2H)，6.76(d，1H)，7.00(s，1H)，7.20(d，1H)，7.28(s，1H)，7.78(m，3H)，8.36(s，1H)，8.22(d，2H)，9.16(t，1H)，10.82(s，1H)ppm；
5-ureido-3- [1- (4- (hydroxyacetamido) methylpyrrol-2-yl) ethylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ2.66(s，3H)，3.82(d，2H)，4.24(d，2H)，5.44(t，1H)，5.72(brs，2H)，6.76(d，1H)，6.94(s，1H)，7.20(m，2H)，7.74(s，1H)，7.78(t，1H)，8.38(s，1H)，10.80(s，1H)ppm；
5-ureido-3- [1- (4- (1- (1, 1-dimethylethoxycarbonyl) piperidin-4-ylcarbonylamino) methylpyrrol-2-yl) ethylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ1.38(s，9H)，1.20(m，2H)，1.62(d，2H)，2.28(m，1H)，2.46(m，1H)，2.64(s，3H)，2.68(m，1H)，3.88(d，2H)，4.18(d，2H)，5.68(brs，2H)，6.76(d，1H)，6.92(s，1H)，7.20(m，2H)，7.78(s，1H)，8.12(t，1H)，8.38(s，1H)，10.80(s，1H)ppm；
5-ureido-3- [1- (4- (piperidin-4-ylcarbonylamino) methylpyrrol-2-yl) ethylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ1.70(m，2H)，1.82(d，2H)，2.42(m，1H)，2.66(s，3H)，2.84(m，2H)，3.28(m，2H)，4.18(d，2H)，5.70(brs，2H)，6.76(d，1H)，6.92(s，1H)，7.24(m，2H)，7.80(s，1H)，8.24(t，1H)，8.38(s，1H)，10.32(s，1H)ppm；
5-ureido-3- [1- (4- ((1, 1-dimethylethoxycarbonyl) acetylamino) -methylpyrrol-2-yl) ethylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ1.38(s，9H)，2.64(s，3H)，3.12(s，2H)，4.18(d，2H)，5.70(brs，2H)，6.76(d，1H)，6.96(s，1H)，7.20(m，2H)，7.76(s，1H)，8.30(t，1H)，8.40(s，1H)，10.32(s，1H)ppm；
5-ureido-3- [1- (4- (1- (1, 1-dimethylethoxycarbonyl) pyrrolidin-2-ylcarbonylamino) methylpyrrol-2-yl) ethylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ1.24(s，9H)，1.80(m，3H)，2.08(m，1H)，2.66(s，3H)，3.40(m，2H)，4.18(m，3H)，5.64(brs，2H)，6.74(d，1H)，6.96(d，1H)，7.22(m，2H)，7.78(s，1H)，8.19(t，1H)，8.42(s，1H)，10.40(s，1H)ppm；
5-ureido-3- [1- (4- ((2- (1, 1-dimethylethoxycarbonylamino) ethyl) -carbonylamino) methylpyrrol-2-yl) ethylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ1.38(s，9H)，2.22(t，2H)，2.64(s，3H)，3.16(t，2H)，4.18(m，3H)，5.70(brs，2H)，6.75(d，1H)，6.92(s，1H)，7.22(m，2H)，7.74(s，1H)，8.14(t，1H)，8.34(s，1H)，10.80(s，1H)ppm；
5-ureido-3- [1- (4- (carboxyacetamido) methylpyrrol-2-yl) ethylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ2.64(s，3H)，3.18(s，2H)，4.18(d，2H)，5.68(brs，2H)，6.54(s，1H)，6.74(d，1H)，6.98(s，1H)，7.18(m，2H)，7.78(s，1H)，8.34(t，1H)，8.40(s，1H)，10.82(s，1H)ppm；
5-ureido-3- [1- (4- (pyrrolidin-2-ylcarbonylamino) methylpyrrol-2-yl) ethylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ1.84(m，3H)，2.22(m，1H)，2.64(s，3H)，3.22(m，2H)，4.06(brs，1H)，4.35(m，2H)，5.72(brs，2H)，6.78(d，1H)，6.94(d，1H)，7.16(d，1H)，7.24(s，1H)，7.82(s，1H)，8.40(s，1H)，8.56(brs，1)，8.88(t，1H)，9.24(brs，1H)，10.88(s，1H)ppm；
5-ureido-3- [1- (4- (pyridin-3-ylcarbonylamino) methylpyrrol-2-yl) ethylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ2.66(s，3H)，4.44(d，2H)，4.40(d，2H)，6.78(d，1H)，7.00(s，1H)，7.20(d，1H)，7.30(s，1H)，7.62(m，1H)，7.78(s，1H)，8.38(dd，1H)，8.40(s，1H)，8.74(q，1H)，9.22(m，2H)，10.82(s，1H)ppm；
5-ureido-3- [1- (4- ((2-aminoethyl) carbonylamino) methylpyrrol-2-yl) ethylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ2.44(s，2H)，2.54(s，3H)，3.00(q，2H)，4.20(d，2H)，5.72(brs，2H)，6.78(d，1H)，6.94(s，1H)，7.18(dd，1H)，7.22(s，1H)，7.70(brs，2H)，7.82(s，1H)，8.42(s，1H)，10.86(s，ppm；
5-ureido-3- [1- ((4- ((1, 2-diaminoethyl) carbonylamino) methylpyrrol-2-yl) ethylene) indolin-2-one;1H NMR(400MHz，DMSO-d6)δ2.50(s，3H)，3.28(m，2H)，4.20(d，2H)，4.36(dd，1H)，6.68(d，1H)，6.74(d，1H)，7.00(s，1H)，7.18(dd，1H)，7.28(s，1H)，7.82(s，1H)，8.50(brs，4H)，8.70(brs，4H)，9.00(t，1H)，10.84(s，1H)ppm；
5-ureido-3- [1- (4- ((1-amino-2-methoxycarbonylethyl) carbonylamino) -methylpyrrol-2-yl) ethylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ2.70(s，3H)，2.78(dq，2H)，3.68(s，3H)，4.20(br，1H)，4.44(dd，1H)，5.76(brs，2H)，6.78(d，1H)，6.90(s，1H)，7.28(dd，1H)，7.46(s，1H)，7.84(s，1H)，8.36(brs，2H)，8.40(s，1H)，8.78(t，1H)，10.86(s，1H)ppm；
5-ureido-3- [1- (4- ((3-amino-1-acetamidopropan-1-yl) carbonylamino) methylpyrrol-2-yl) ethylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ1.78(m，1H)，1.86(s，3H)，1.94(m，1H)，2.68(s，3H)，2.76(m，2H)，4.18(d，2H)，4.35(q，1H)，5.74(brs，2H)，6.76(d，1H)，6.88(s，1H)，7.18(dd，1H)，7.20(s，1H)，7.70(brs，2H)，7.82(s，1H)，8.20(d，1H)，8.36(t，1H)，8.42(s，1H)，10.86(s，1H)ppm；
5-ureido-3- [1- (4- (piperazin-2-ylcarbonylamino) methylpyrrol-2-yl) ethylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ2.78(s，3H)，3.08(m，4H)，3.52(m，2H)，4.02(m，1H)，4.24(dq，2H)，5.74(brs，2H)，6.78(d，1H)，6.90(s，1H)，7.18(d，1H)，7.26(s，1H)，7.84(s，1H)，8.40(s，1H)，8.92(brs，1H)，10.84(s，1H)ppm；
5-ureido-3- [1- (4- (1-methylpiperidin-4-ylcarbonylamino) methylpyrrol-2-yl) ethylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ1.76(m，2H)，1.90(d，2H)，2.36(m，1H)，2.68(s，3H)，2.74(d，3H)，2.90(m，2H)，3.40(m，2H)，4.20(d，2H)，5.72(brs，2H)，6.76(d，1H)，6.94(s，1H)，7.18(d，1H)，7.22(s，1H)，8.42(s，1H)，8.48(t，1H)，8.98(brs，1H)，10.82(s，1H)ppm；
5-ureido-3- [1- (4- (2- (piperidin-1-yl) ethylcarbonylamino) methylpyrrol-2-yl) ethylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ1.64(m，4H)，1.86(d，2H)，2.38(m，1H)，2.68(s，3H)，2.74(d，3H)，2.90(m，2H)，3.44(d，2H)，4.18(d，2H)，5.72(brs，2H)，6.74(d，1H)，6.94(s，1H)，7.20(m，2H)，7.80(s，1)，8.38(t，1H)，8.40(m，1H)，9.22(brs，1H)，10.80(s，1H)ppm；
5-ureido-3- [ (4- (piperidin-1-ylmethyl) carbonylpyrrol-2-yl) methylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ1.38(m，2H)；1.51(m，4H)；2.41(m，4H)；3.46(bs 2H)；5.77(s，2H)；6.74-6.76(d，1H)；7.05-7.07(dd，1H)；7.30(s，1H)；7.63(s，1H)；773(d，1H)；8.10-8.11(m，1H)；8.34(s，1H)；10.83(bs，1H)；13.91(bs，1H)ppm；
5-ureido-3- [ (4- ((4-methylpiperazin-1-yl) methylcarbonyl) pyrrol-2-yl) methylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ2.14(s，3H)；2.32(bs，4H)；2.49(bs，4H)；3.52(s，2H)；5.77(s，1H)；6.74-6.76(d，1H)；6.96(s，1H)，7.02-7.04(dd，1H)；7.29(d，1H)；7.63(s，1H)；7.25-7.30(d，1H)；8.08-8.09(m，1H)；8.34(s，1H)；10.84(bs，1H)；12.12(bs，2H)；14.79(bs，1H)ppm；
5-ureido-3- [ (4- (3-methoxyphenyl) pyrrol-2-yl) methylene]Indolin-2-one;1HNMR(400MHz，DMSO-d6)δ3.79(s，3H)；5.77(s，2H)；6.74-6.78(m，2H)；7.02-7.04(dd，1H)；7.15-7.20(m，2H)；7.26-7.30(m，2H)；7.57(s，1H)；7.74(d，1H)；7.82(d，1H)；8.33(s，1H)；10.76(bs，1H)；13.51(bs，1H)ppm；
5-ureido-3- [ (4- (4-methoxyphenyl) pyrrol-2-yl) methylene]Indolin-2-one;1HNMR(400MHz，DMSO-d6)δ3.76(s，3H)；5.76(s，2H)；6.74-6.76(s，1H)；6.93-6.95(ddd，2H)；7.04(dd，1H)；7.18(dd，1H)，7.52-7.55(ddd，2H)，7.56(s，1H)；7.71-7.73(m，2H)；8.32(s，1H)；10.74(bs，1H)；13.55(bs，1H)ppm；
5-ureido-3- [ (4- (3-hydroxyphenyl) pyrrol-2-yl) methylene]Indolin-2-one;1HNMR(400MHz，DMSO-d6)δ5.77(s，2H)；6.59-6.61(dd，2H)；6.74-6.76(d，1H)；6.98-7.04(m，4H)；7.13-7.18(m，2H)；7.59(s，1H)；7.73(d，1H)；8.33(s，1H)；9.36(bs，1H)；10.76(bs，1H)；13.53(bs，1H)ppm；
5-ureido-3- [ (4- (3-acetamidophenyl) pyrrol-2-yl) methylene]Indolin-2-one;1HNMR(400MHz，DMSO-d6)δ2.05(s，3H)，5.77(s，2H)；6.74-6.78(d，1H)；7.04-7.07(dd，1H)；7.18(s，1H)；7.27-7.28(m，2H)；7.41-7.44(m，1H)；7.64(s，1H)；7.71-7.72(d，2H)；7.79(s，1H)；8.33(s，1H)；9.95(s，1H)；10.76(bs，1H)；13.53(bs，1H)ppm；
5-ureido-3- [ (4- (3-carboxyphenyl) pyrrol-2-yl) methylene]Indolin-2-one;1HNMR(400MHz，DMSO-d6)δ5.92(s，2H)；6.74-6.78(d，1H)；7.09-7.12(dd，1H)；7.28(s，1H)；7.34-7.38(dd，1H)；7.41-7.44(m，1H)；7.59(s，1H)；7.66-7.68(d，1H)；7.71-7.73(d，2H)7.83(s，1H)；8.13(s，1H)；8.71(bs，1H)；10.79(bs，1H)；13.5(bs，1H)ppm；
5-ureido-3- [ (4- (pyridin-3-yl) pyrrol-2-yl) methylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ5.77(s，2H)；6.75-6.77(d，1H)；7.03-7.06(dd，1H)；7.33(s，1H)；7.34-7.40(dd，1H)；7.59(s，1H)；7.75-7.76(d，1H)；7.90-7.91(d，1H)：7.97-8.00(dt，1H)；8.33(bs，1H)；8.39-8.40(dd，1H)；8.87-8.89(d，1H)；10.77-10.79(d，1H)；13.42(bs，1H)ppm；
5-ureido-3- [ (4- (3- (2-morpholin-4-ylethoxy) phenyl) pyrrol-2-yl) methylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ3.19(bs，4H)，3.64(bs，4H)；3.99(bs，3H)；4.19(s，2H)；4.78(bs，1H)；5.82(bs，2H)；6.59-6.62(ddd，1H)；6.98-6.99(m，1H)；7.02(s，1H)；7.04-7.05(d，1H)；7.07(s，1H)；7.12-7.14(m，2H)；7.25-7.30(m，1H)；7.69(s，1H)；7.77-7.78(m，1H)；7.82(d，1H)；8.46(s，1H)；9.38(bs，1H)；13.83(bs，1H)ppm；
5-ureido-3- [ (4- (piperazin-1-ylmethyl carbonyl) pyrrol-2-yl) methylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ2.85-3.00(bs，4H)；3.35-3.45(bs，4H)；5.77(bs，2H)；6.75-6.77(d，1H)；7.01-7.04(dd，1H)；7.31(s，1H)；7.63(s，1H)；7.78(s，1H)；8.07-8.09(dd，1H)；8.40(s，1H)；8.62-8.74(bs，1H)；10.86(s，1H)；13.32(bs，1H)ppm；
5-ureido-3- [ (4- (3-methoxycarbonylmethoxyphenyl) pyrrol-2-yl) methylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ3.64(s，3H)；4.65(s，2H)；5.75(bs，2H)；6.54-6.56(dd，1H)；6.69-6.71(d，1H)；6.88-6.71(d，1H)；6.94(s，1H)；6.97-6.99(d，1H)；7.01-7.04(dd，1H)；7.08-7.12(dd，1H)；7.22(m，1H)；7.67(s，1H)；7.70(s，1H)；7.76(s，1H)；8.35(s，1H)；9.32(bs，1H)ppm；
5-ureido-3- [ (4- (4-methoxycarbonylphenyl) pyrrol-2-yl) methylene]Indolin-2-one;1HNMR(400MHz，DMSO-d6)δ3.84(s，3H)；5.78(s，2H)；6.75-6.77(d，1H)；7.04-7.06(dd，1H)；7.35(s，1H)；7.60(s，1H)；7.77-7.78(d，3H)；7.94-7.96(d，3H)；8.35(s，1H)；10.80(bs，1H)；13.41(bs，1H)ppm；
5-ureido-3- [ (4- (3-aminocarbonylphenyl) pyrrol-2-yl) methylene]Indolin-2-one;1HNMR(400MHz，DMSO-d6)δ5.77(s，2H)；6.75-6.77(d，1H)；7.05-7.07(dd，1H)；7.31(s，1H)；7.39-7.46(m，2H)；7.60(s，1H)；7.67-7.69(d，1H)；7.73-7.76(m，2H)；7.86(s，1H)；8.03(s，1H)；8.11(s，1H)；8.33(s，1H)；10.78(bs，1H)；13.49(bs，1H)ppm；
5-ureido-3- [ (4- (3, 4-dimethoxybenzene)Yl) pyrrol-2-yl) methylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ3.75(s，3H)；3.82(s，3H)；5.77(s，2H)；6.74-6.76(d，1H)；6.93-6.95(d，1H)；7.02-7.04(dd，1H)；7.12-7.14(dd，1H)；7.17-7.21(dd，1H)；7.56(s，1H)；7.73-7.75(dd，2H)；8.33(s，1H)；10.74(bs，1H)；13.55(bs，1H)ppm；
5-ureido-3- [ (4- (4-carboxyphenyl) pyrrol-2-yl) methylene]Indolin-2-one;1HNMR(400MHz，DMSO-d6)δ6.19(bs，2H)；6.71-6.73(d，1H)；7.26(s，1H)；7.43-7.45(m，2H)；7.59-7.63(m，3H)；7.83(s，1H)；7.93-7.95(d，2H)；9.74(bs，1H)；10.74(bs，1H)；13.55(bs，1H)ppm；
5-ureido-3- [ (4- (3, 4-dihydroxyphenyl) pyrrol-2-yl) methylene]Indolin-2-one;1HNMR(400MHz，DMSO-d6)δ5.77(s，2H)；6.57(s，2H)；6.69-6.75(m，2H)；6.86-6.89(dd，1H)；6.97-7.12(m，2H)；7.56-7.60(m，1H)；7.71-7.73(m，2H)；8.32-8.33(m，1H)；8.74(bs，1H)；10.69-10.73(bd，1H)；13.60(bs，1H)ppm；
5-ureido-3- [ (4- (4- (1, 1-dimethylethoxycarbonylamino) methylphenyl) pyrrol-2-yl) methylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ1.40(s，9H)；4.14-4.16(d，2H)；5.77(bs，2H)；6.74-6.76(d，1H)；7.04-7.07(m，2H)；7.22(bs，1H)；7.29-7.33(dd，1H)；7.39-7.42(dd，1H)；7.46-7.48(m，2H)；7.61(s，1H)；7.71-7.72(d，1H)；7.76-7.77(dd，1H)；8.33(s，1H)；10.76(s，1H)；13.51(s，1H)ppm；
5-ureido-3- [ (4- (3-aminomethylphenyl) pyrrol-2-yl) methylene]Indolin-2-one;1HNMR(400MHz，DMSO-d6)δ4.06(s，2H)；5.77(bs，2H)；6.75-6.77(d，1H)；7.01-7.04(dd，1H)；7.26-7.28(m，2H)；7.41-7.45(dd，1H)；7.60(s，1H)；7.62-7.64(d，1H)；7.72(s，1H)；7.76(d，1H)；7.79-7.80(dd，1H)；8.17(bs，2H)；8.36(s，1H)；10.76(s，1H)；13.46(s，1H)ppm；
5-ureido-3- [ (4- (3-acetamidomethylphenyl) pyrrol-2-yl) methylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ1.89(s，3H)；4.26-4.29(d，2H)；5.77(bs，2H)；6.74-6.76(d，1H)；7.03-7.06(dd，1H)；7.07-7.09(d，1H)，7.24(m，1H)；7.29-7.33(dd，1H)；7.49-7.50(m，2H)；7.61(s，1H)，7.73(s，1H)；7.78(m，1H)；8.33-8.37(m，2H)；10.76(s，1H)；13.51(s，1H)ppm；
5-ureido-3- [ (4- (3- (1, 1-dimethylethoxycarbonyl) aminomethylcarbonyl-aminomethyl-phenyl) pyrrol-2-yl) methylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ1.40(s，9H)；3.58-3.60(d，2H)；4.30-4.32(d，2H)；5.77(bs，2H)；6.74-6.76(d，1H)；7.01-7.08(m，3H)；7.28-7.31(m，2H)；7.47-7.50(m，2H)；7.57(s，1H)；7.73-7.74(d，1H)；7.82(bs，1H)；8.30-8.33(m，2H)；10.76(bs，1H)，13.48(bs，1H)ppm；
5-ureido-3- [ (4- (4-methylsulfonylphenyl) pyrrol-2-yl) methylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ3.20(s，3H)；5.77(bs，2H)；6.75-6.77(d，1H)；7.04-7.06(dd，1H)；7.39(s，1H)；7.61(s，1H)；7.75-7.76(d，1H)；7.85-7.90(m，4H)；7.97(m，1H)；8.35(s，1H)；10.81(bs，1H)；13.39(s，1H)ppm；
5-ureido-3- [ (4- (2-ethoxycarbonylethyl) carbonylpyrrol-2-yl) methylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ1.18(m，3H)，2.59(t，2H)，3.08(t，2H)，4.04(m，2H)，5.77(s，1H)，6.76(d，1H)，7.06(dd，1H)，7.27(s，1H)，7.64(s，1H)，7.73(s，1H)，7.99(m，1H)，8.35(s，1H)，10.85(s，1H)ppm；
5-ureido-3- [ (4- (2-carboxyethyl) carbonylpyrrol-2-yl) methylene]Indolin-2-one;1HNMR(400MHz，DMSO-d6) δ 2.5 (masked with DMSO, t, 2H), 3.02(t, 2H), 5.77(s, 1H), 6.74(d, 1H), 7.05(dd, 1H), 7.25(t, 1H), 7.62(s, 1H), 7.71(d, 1H), 7.98(m, 1H), 8.34(s, 1H), 10.84(s,1H)ppm；
5-ureido-3- [ (4- (3- (2-piperidin-1-ylethyl) aminocarbonylphenyl) pyrrol-2-yl) methylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ1.38(m，1H)，1.66(t，3H)，1.79(d，2H)，2.88(m，2H)，3.24(m，2H)，3.55(d，2H)，3.63(m，2H)，6.77(d，1H)，7.00(dd，1H)，7.23(s，1H)，7.42(t，1H)，7.59(s，1H)，7.66(d，1H)，7.72(d，1H)，7.75(d，1H)，7.77(m，1H)，8.08(t，1H)，8.74(t，1H)，9.03(s，1H)，10.75(s，1H)ppm；
5-ureido-3- [ (4-ethoxycarbonylpyrrol-2-yl) methylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ1.25(t，3H)，4.21(q，2H)，5.78(s，2H)，6.75(d，1H)，7.07(d，1H)，7.22(s，1H)，7.62(s，1H)，7.69(s，1H)，7.83(s，1H)，8.36(s，1H)，10.83(s，1H)ppm；
5-ureido-3- [ (4-carboxypyrrol-2-yl) methylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ1.51(m，6H)，2.79(m，4H)，5.93(s，2)，6.74(d，1H)，7.11(s，1H)，7.18(d，1H)，7.56(s，1H)，7.62(s，1H)，7.68(s，1H)，8.95(s，ppm；
5-ureido-3- [ (4- (2-morpholin-4-ylethyl) aminocarbonylpyrrol-2-yl) methylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ3.16(m，2H)，3.27(m，2H)，3.51-3.69(m，6H)，3.96(m，2H)，6.64(d，1H)，7.03(d，1H)，7.20(s，1H)，7.57(s，1H)，7.72(s，1H)，7.76(s，1H)，8.38(m，2H)，9.82(s，1H)ppm；
5-ureido-3- [ (4- (2-piperidin-1-ylethyl) aminocarbonylpyrrol-2-yl) methylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ1.38(m，1H)，1.63(m，3H)，1.81(m，2H)，2.92(m，2H)，3.20(m，2H)，3.56(m，4H)，6.74(d，1H)，7.03(d，1H)，7.21(s，1H)，7.57(s，1H)，7.73(s，1H)，7.77(s，1H)，8.38(m，2H)，10.81(s，1H)ppm；
5-ureido-3- [ (4- (pyridine)-3-ylmethyl) aminocarbonylpyrrol-2-yl) methylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ4.52(d，2H)，5.78(s，2H)，6.74(d，1H)，7.04(d，1H)，7.22(s，1H)，7.58(s，1H)，7.70(s，1H)，7.76(m，2H)，8.18(d，1H)，8.23(s，1H)，8.65-8.82(m，3H)，10.81(s，1H)ppm；
5-ureido-3- [ (3-methyl-4-carboxypyrrol-2-yl) methylene]Indolin-2-one;1HNMR(400MHz，DMSO-d6)δ1.51(m，6H)，2.58(s，3H)，2.78(m，4H)，5.93(s，2)，6.72(d，1)，7.19(d，1H)，7.44(s，1H)，7.60(s，1H)，7.65(s，1H)，8.73(s，1H)ppm；
5-ureido-3- [ (4- (3-piperidin-1-ylpropyl) aminocarbonylpyrrol-2-yl) methylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ1.37(m，1H)，1.61(m，3H)，1.75-1.90(m，4H)，2.85(m，2H)，3.06(m，2H)，3.26(m，2H)，3.40(m，2H)，6.74(d，1H)，7.03(d，1H)，7.18(s，1H)，7.56(s，1H)，7.73(s，1H)，7.77(s，1H)，8.24(t，1H)，8.38(s，1H)，10.81(s，1H)ppm；
5-ureido-3- [ (4- (2-dimethylaminoethyl) aminocarbonylpyrrol-2-yl) methylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ2.78(s，6H)，3.17(m，2H)，3.52(m，2H)，5.72(s，2H)，6.70(d，1H)，7.01(d，1H)，7.18(s，1H)，7.56(s，1H)，7.70(s，1H)，7.74(s，1H)，8.32(m，2H)，10.80(s，1H)ppm；
5-ureido-3- [ (3-methyl-4- (2-piperidin-1-ylethyl) aminocarbonylpyrrol-2-yl) methylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ1.38(m，1H)，1.63(m，3H)，1.81(m，2H)，2.52(s，3H)，2.92(m，2H)，3.18(m，2H)，3.55(m，4H)，6.76(d，1H)，7.07(d，1H)，7.49(s，1H)，7.72(s，1H)，7.75(s，1H)，8.18(t，1H)，8.34(s，1H)，10.80(s，1H)ppm；
5-ureido-3- [ (4-phenylpyrrol-2-yl) methylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ5.77(s，2H)；6.74-6.76(dd，1H)；7.02-7.05(dd，1H)；7.17-7.21(dd，1H)；7.26(dd，1H)；7.34-7.38(dd，2H)；7.56-7.62(m，3H)；7.74(d，1H)；7.81-7.82(dd，1H)；8.33(s，1H)；10.76(s，1H)；13.50(bs，1H)ppm；
5-ureido-3- [ (4- (4- (2-piperidin-1-ylethyl) aminocarbonylphenyl) pyrrol-2-yl) methylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ1.37(m，1H)，1.64(m，3H)，1.82(d，2H)，2.92(m，2H)，3.22(m，2H)，3.54(d，2H)，3.61(m，2H)，5.77(s，2H)，6.75(d，1H)，7.01(dd，1H)，7.33(s，1H)，7.57(s，1H)，7.72(d，2H)，7.76(d，1H)，7.86(d，2H)，7.91(m，1H)，8.35(s，1H)，8.66(t，1H)，9.00(bs，1H)，10.78(s，1H)ppm；
5-ureido-3- [ (4- ((morpholin-4-ylmethyl) carbonylaminomethyl) pyrrol-2-yl) methylene]Indomethacin-2-one;1H NMR(400MHz，DMSO-d6/TFA)δ3.10-3.20(m，2H)，3.36(m，3H)，3.70-3.80(m，2H)，3.85(m，2H)，3.90(s，2H)，4.20(d，2H)，6.72(d，1H)，6.78(s，1H)，6.96(d，1H)，7.42(s，1H)，7.50(s，1H)，7.75(s，1H)，8.85(t，1H)ppm；
5-ureido-3- [ (4- ((piperidin-1-yl) acetamido) methylpyrrol-2-yl) methylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6TFA)81.40(m, 1H), 1.70-1.90(m, 5H), 3.00(m, 2H), 3.45(d, 2H), 3.90(s, 2H), 4.15(d, 2H), 6.80(d, 1H), 6.85(s, 1H), 7.04(d, 1H), 7.30(s, 1H), 7.60(s, 1H), 8.55(br s, 1H), 8.90(t, 1H), 9.64(br s, 1H) ppm; and
5-ureido-3- [ (4- (4- (2-dimethylaminoethyl) aminocarbonylphenyl) pyrrol-2-yl) methylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ2.84(d，6H)，3.26(t，2H)，3.59(q，2H)，5.77(s，1H)，6.75(d，1H)，7.01(dd，1H)，7.33(s，1H)，7.57(s，1H)，7.72(d，2H)，7.76(m，1H)，7.86(d，2H)，7.90(m，1H)，8.35(s，1H)，8.63(t，1H)，9.27(bs，1H)，10.78(s，1H)ppm。
example 6
Compounds of formula (IH) and formula (IJ)
A. Treatment of 5-amino-3- [1- (pyrrol-2-yl) ethylene with 2-bromoethyl isocyanate (105mg, 0.63mmol) at room temperature]A solution of indolin-2-one (150mg, 0.63mmol) in dry tetrahydrofuran (15 mL). The resulting reaction mixture was stirred at 45 ℃ for 2 hours. The reaction mixture was cooled to room temperature and concentrated. SiO Using 2: 1 Hexane/Ethyl acetate2(5g) Chromatography gave 5- (N' - (2-bromoethyl) ureido) -3- [1- (pyrrol-2-yl) ethylene]Indolin-2-one and 5- (4, 5-dihydrooxazol-2-ylamino) -3- [1- (pyrrol-2-yl) ethylene]A mixture of indolin-2-ones (120 mg).
B. Treatment of 5- (N' - (2-bromoethyl) ureido) -3- [1- (pyrrol-2-yl) ethylene with triethylamine (61mg, 0.6mmol)]Indolin-2-one, 5- (4, 5-dihydrooxazol-2-ylamino) -3- [1- (pyrrol-2-yl) ethylene]A solution of indolin-2-one (120mg) and DMF (5 mL). After stirring overnight, the reaction was poured into water (25mL) to give a solid which was filtered off. Purification by reverse phase HPLC (acetonitrile/water) to give 5- (4, 5-dihydrooxazol-2-ylamino) -3- [1- (pyrrol-2-yl) ethylene]Indolin-2-one; (26 mg);1H NMR(400MHz，DMSO-d6)δ2.76(s，3H)，3.84(t，2H)，4.80(t，2H)，6.40(m，1H)，6.98(m，1H)，7.15(m，2H)，7.40(m，1H)，7.68(m，1H)，11.20(s，1H)ppm。
C. other compounds of formula (Ih) and formula (Ik) were prepared in a similar manner as described above.
Example 7
Compounds of formula (Il) and formula (IK)
A. Treatment of 5-amino-3- [1- (pyrrol-2-yl) ethylene with isocyanatoethyl acetate (195mg, 1.5mmol) at room temperature]A solution of indolin-2-one (360mg, 1.5mmol) in tetrahydrofuran (15 mL). After stirring overnight, methanol was added5mL) and the reaction was concentrated. Using 1: 2 hexane/ethyl acetate through SiO2(7.2g) chromatography gave 5- (N' - (ethoxycarbonylmethyl) ureido) -3- [1- (pyrrol-2-yl) ethylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ1.32(t，3H)，2.82(s，3H)，3.96(d，2H)，4.22(q，2H)，6.44(m，2H)，6.88(d，1H)，7.16(m，1H)，7.28(d，1H)，7.40(m，1H)，7.96(m，1H)，8.76(s，1H)，11.02(s，1H)ppm；(200mg)。
B. treatment of 5- (N' - (ethoxycarbonylmethyl) ureido) -3- [1- (pyrrol-2-yl) ethylene with NaH (16mg, 0.40mol)]A solution of indolin-2-one (95mg, 0.25mmol) in tetrahydrofuran (2.5 mL). After stirring overnight, ethyl acetate (15mL) and water (5mL) were added and the reaction mixture was neutralized with 6N HCl. Drying (NaSO)4) The organic layer was concentrated to give the crude product (90 mg). Purification by reverse phase HPLC (acetonitrile/water) to give 5- (2, 4-dioxoimidazolidin-1-yl) -3- [1- (pyrrol-2-yl) ethylene]Indolin-2-one; (8 mg);1H NMR(400MHz，DMSO-d6)δ2.72(s，3H)，4.02(s，2H)，6.36(m，1H)，6.96(d，1H)，7.04(m，2H)，7.36(d，1H)，7.60(m，1H)，8.22(s，1H)，11.14(s，1H)ppm。
B. the compounds of formula (Ii) and formula (Ik) are prepared in a similar manner as described above.
Example 8
A compound of formula (IIA)
A. 4-Acetylimidazole (0.7g, 3.1mmol) and 5-nitroindolin-2-one (0.56g, 3.1mmol) in a sealed tube were heated in the presence of piperidine at 135 ℃. After 30 minutes, the reaction mixture was cooled to room temperature and concentrated. Recrystallization from ethanol gave 0.66g of 5-nitro-3- [1- (imidazol-4-yl) ethylene ] indolin-2-one.
B. 5-Nitro-3- [1- (imidazol-4-yl) ethylene ] indolin-2-one (0.55g, 2mmol) was suspended in ethyl acetate (50mL) and tin chloride (4.6g, 20mmol) was added. The resulting reaction mixture was heated at 70 ℃ overnight. The reaction mixture was cooled to room temperature and sodium bicarbonate solution was added. Extraction with ethyl acetate gave 0.4g of 5-amino-3- [1- (imidazol-4-yl) ethylene ] indolin-2-one.
C. Reacting 5-amino-3- [ (imidazol-4 yl) methylene]Indolin-2-one (0.3g, 1.3mmol) was suspended in tetrahydrofuran (100mL) and trimethylsilyl isocyanate (0.5mL, 3.75mmol) was added. The reaction mixture was stirred at room temperature for 3 days. The reaction mixture was concentrated and dissolved in acetonitrile/water/TFA. The soluble solid was collected by filtration, dissolved in DMSO and purified by HPLC to give 80mg of 5-ureido-3- [1- (imidazol-4-yl) ethylene]Indolin-2-one; as an orange solid;1H NMR(400MHz，DMSO-d6)δ2.6(s，3H)，5.8(s，2H)，6.8(d，1H)，7.3(m，1H)，7.9(s，1H)，8.3(s，1H)，8.5(s，1H)，8.9(s，1H)，11.1(s，1H)ppm。
D. in a similar manner to that described above in sections A-C, but using appropriately substituted starting materials, the following compounds of formula (IIa) are prepared:
5-hydroxy-3- [ (imidazol 4-yl) methylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ6.70(s，2H)，7.06(s，1H)，7.72(s，1H)，8.22(s，1H)，9.10(s，1H)，11.02(s，1H)ppm；
5-hydroxy-3- [ (imidazol-2-yl) methylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ6.76(m，2H)，7.10(s，1H)，7.60(s，1H)，7.88(s，2H)，11.22(s，1H)ppm；
3- [ (imidazol-4-yl) methylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ7.30(d，1H)，7.45(t，1H)，7.70(t，1H)，8.05(d，1H)，8.20(s，1H)，8.65(s，1H)，9.50(s，1H)，11.7(s，1H)ppm；
3- [ (imidazol-2-yl) methylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ7.00(d，1H)，7.10(t，1H)，7.40(t，1H)，7.80(m，2H)，7.90(s，2H)，11.6(s，1H)ppm；
6-fluoro-3- [ (pyridin-2-yl) methylene]Indolin-2-one;1H NMR(500MHz，DMSO-d6)δ6.68(d，1H)，6.79(m，1H)，7.47(m，1H)，7.55(s，1H)，7.86(d，1H)，7.95(m，1H)，8.88(d，1H)，9.11(dd，1H)，10.78(s，1H)ppm；
6-fluoro-3- [ (pyridin-4-yl) methylene]Indolin-2-one;1H NMR(500MHz，DMSO-d6)δ6.63-6.71(m，2H)，7.38(m，1H)，7.54(s，1H)，7.62(d，2H)，8.72(d，2H)，10.84(s，1H)ppm；
3- [ (pyridin-4-yl) methylene]Indolin-2-one;1H NMR(500MHz，DMSO-d6)δ6.81-6.90(m，2H)，7.25(dd，1H)，7.38(d，1H)，7.56(s，1H)，7.63(d，2H)，8.73(d，2H)，10.66(s，1H)ppm；
5-bromo-3- [ (pyridin-4-yl) methylene]Indolin-2-one;1H NMR(500MHz，DMSO-d6)δ6.78-6.88(d，2H)，7.38(m，1H)，7.43(m，1H)，7.62(d，2H)，8.75(d，2H)，10.82(s，1H)ppm；
3- [ (pyridin-3-yl) methylene]Indolin-2-one;1H NMR(500MHz，DMSO-d6)δ6.82-6.91(m，2H)，7.26(dd，1H)，7.38(d，1H)，7.57(d，1H)，7.62(s，1H)，8.11(m，1H)，8.67(m，1H)，8.88(d，1H)，10.63(m，1H)ppm；
6-fluoro-3- [ (furan-2-yl) methylene]Indolin-2-one;1H NMR(500MHz，DMSO-d6)δ6.69(d，1H)，6.78(d，1H)，6.82(m，1H)，7.27(d，1H)，7.32(s，1H)，8.14(s，1H)，8.38(dd，1H)，10.70(m，1H)ppm；
3- [ (5-Methylfuran-2-yl) methylene]Indolin-2-one;1H NMR(500MHz，DMSO-d6)δ2.52(s，3H)，6.46(d，1H)，6.86(d，1H)，7.03(dd，1H)，7.18(d，1H)，7.20-7.27(m，2H)，8.30(m，1H)，10.47(m，1H)ppm；
3- [ (5- (acetoxymethyl) furan-2-yl) methylene]Indolin-2-one;1H NMR(500MHz，DMSO-d6)δ2.12(s，3H)，5.28(s，2H)，6.81(d，1H)，6.86(dd，1H)，7.00(dd，1H)，7.16-7.28(m，2H)，7.30(s，1H)，8.33(m，1H)，10.53(m，1H)ppm；
3- [ (5-Ethylfuran-2-yl) methylene]Indolin-2-one;1H NMR(400MHz，CDCl3)δ8.45(d，1H)，8.05(br，1H)，7.4(s，1H)，7.25(m，1H)，7.05(t，1H)，6.85(m，2H)，6.25(s，1H)，2.85(q，2H)，1.4(t，3H)ppm；
3- [ (3-methylthiophen-2-yl) methylene]Indolin-2-one;1H NMR(500MHz，DMSO-d6)δ2.41(s，3H)，6.89(d，1H)，7.00(dd，1H)，7.18(d，1H)，7.27(dd，1H)，7.74(s，1H)，7.88(d，2H)，8.15(d，1H)，10.60(m，1H)ppm；
3- [ (5-methylthiophen-2-yl) methylene]Indolin-2-one;1H NMR(500MHz，DMSO-d6)δ2.55(s，3H)，6.83(d，1H)，6.93-7.00(m，2H)，7.18(d，1H)，7.64(d，1H)，7.72(d，1H)，7.98(s，1H)，10.52(m，1H)ppm；
3- [ (4-Bromothien-2-yl) methylene]Indolin-2-one;1H NMR(500MHz，DMSO-d6)δ6.88(d，1H)，7.01(dd，1H)，7.23(dd，1H)，7.67(d，1H)，7.95(m，2H)，8.03(s，1H)，10.67(m，1H)ppm；
3- [ (naphthalen-1-yl) methylene]Indolin-2-one;1H NMR(500MHz，DMSO-d6)δ6.69(dd，1H)，6.88(m，2H)，7.17(dd，1H)，7.57-7.64(m，2H)，7.65(d，1H)，7.84(d，1H)，7.94(d，1H)，8.05(m，2H)，8.09(s，1H)，10.65(m，1H)ppm；
3- [ (naphthalen-2-yl) methylene]Indolin-2-one;1H NMR(500MHz，DMSO-d6)δ6.88(m，2H)，7.22(m，2H)，7.57-7.63(m，3H)，7.79(s，1H)，7.92-8.02(m，2H)，8.05(d，1H)，8.28(s，1H)，10.62(m，1H)ppm；
6-fluoro-3- [ (indol-3-yl) methylene]Indolin-2-one;1H NMR(500MHz，DMSO-d6)δ6.81(m，1H)，6.93(m，1H)，7.19-7.28(m，2H)，7.53(m，1H)，7.57(d，1H)，7.82(m，1H)，8.21(m，1H)，9.48(s，1H)，10.48(m，1H)，12.05(m，1H)ppm；
3- [ (quinolin-4-yl) methylene]Indomethacin-2-one;1H NMR(500MHz，DMSO-d6)δ6.65-6.72(m，2H)，6.88(d，1H)，7.21(dd，1H)，7.64(dd，1H)，7.73(m，1H)，7.84(dd，1H)，7.95(d，1H)，8.00(s，1H)，8.14(d，1H)，9.03(m，1H)，10.72(m，1H)ppm；
3- [ (5-methylimidazol-4-yl) methylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ2.50(s，3H)，6.90(d，1H)，7.00(t，1H)，7.20(t，1H)，7.80(s，1H)，7.95(d，1H)，8.00(s，1H)，11.0(s，1H)ppm；
3- [ (1, 3-dimethyl-5-chloropyrazol-4-yl) methylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6) δ 2.10(s, 3H), 3.80(s, 3H), 6.90(m, 2H), 7.00(d, 1H), 7.40(m, 2H), 10.6(s, 1H) ppm; and
3- [ (3-phenylpyrazol-4-yl) methylene]Indolin-2-one;1H NMR(400MHz，DMSO-d6)δ6.80(d，1H)，6.95(t，1H)，7.20(t，1H)，7.40(s，1H)，7.50(m，1H)，7.55(m，2H)，7.60(m，2H)，7.80(d，1H)，8.40(s，1H)，10.5(s，1H)ppm。
example 9
This example illustrates the preparation of a representative pharmaceutical composition containing a compound of the invention, or a pharmaceutically acceptable salt thereof, for oral administration:
A.
ingredient% weight/weight
Compound of the invention 20.0%
Lactose 79.5%
Magnesium stearate 0.5%
Mixing the above components, and packaging into hard gelatin capsules, each containing 100mg per capsule, which will be about a whole day in dosage.
B.
Ingredient% weight/weight
Compound of the invention 20.0%
0.9 percent of magnesium stearate
8.6 percent of starch
Lactose 69.6%
PVP (polyvinylpyrrolidone) 0.9%
Mixing the above components except magnesium stearate, and granulating with water as granulating liquid. The formulation is then dried, mixed with magnesium stearate and tableted with a suitable tableting machine.
C.
Composition (I)
Compound of the invention 0.1g
Propylene glycol 20.0g
Polyethylene glycol 40020.0 g
Polysorbate ester 801.0 g
Adding water to a sufficient amount of 100ml
The compounds of the invention were dissolved in propylene glycol, polyethylene glycol 400 and polysorbate 80. Sufficient water was then added with stirring to make the solution 100ml, the solution was filtered and bottled.
D.
Ingredient% weight/weight
Compound of the invention 20.0%
Peanut oil 78.0%
Span 60 2.0％
Melting the above materials, mixing, and encapsulating in soft elastic capsule.
E.
Ingredient% weight/weight
Compound 1.0% of the present invention
2.0 percent of methyl cellulose or carboxymethyl cellulose
0.9% saline was added to a sufficient amount of 100ml
The compounds of the invention are dissolved in a cellulose/saline solution, filtered and bottled for use.
Example 10
This example illustrates the preparation of a representative pharmaceutical formulation containing a compound of the invention, or a pharmaceutically acceptable salt thereof, for parenteral administration:
composition (I)
Compound of the invention 0.02g
Propylene glycol 20.0g
Polyethylene glycol 40020.0 g
Polysorbate ester 801.0 g
0.9% saline was added to a sufficient amount of 100ml
The compounds of the invention were dissolved in propylene glycol, polyethylene glycol 400, polysorbate 80. Sufficient 0.9% saline was then added with stirring to give 100mL of solution for intravenous injection, which was filtered through a 0.2 μm membrane filter and packaged under aseptic conditions.
Example 11
This example illustrates the preparation of a representative pharmaceutical formulation containing a compound of the invention, or a pharmaceutically acceptable salt thereof, in the form of a suppository:
ingredient% weight/weight
Compound 1.0% of the present invention
100074.5 percent of polyethylene glycol
400024.5 percent of polyethylene glycol
The ingredients were melted together, mixed on a steam bath, and poured into a mold containing a total weight of 2.5 g.
Example 12
This example illustrates the preparation of a representative pharmaceutical formulation containing a compound of the invention, or a pharmaceutically acceptable salt thereof, for insufflation:
ingredient% weight/weight
Micronized compound of the invention 1.0%
Micronized lactose 99.0%
The ingredients were ground, mixed and loaded into an insufflator equipped with a dosing pump.
Example 13
This example illustrates the preparation of a representative pharmaceutical formulation containing a compound of the invention, or a pharmaceutically acceptable salt thereof, in aerosolized form:
ingredient% weight/weight
0.005% of the compound of the present invention
89.995 percent of water
Ethanol 10.000%
The compounds of the invention are dissolved in ethanol and mixed with water. The formulation is then loaded into an atomizer equipped with a dosing pump.
Example 14
This example illustrates the preparation of a representative pharmaceutical formulation containing a compound of the invention, or a pharmaceutically acceptable salt thereof, in aerosol form:
ingredient% weight/weight
0.10% of the compound of the present invention
Propellant 11/1298.90%
Oleic acid 1.00%
The compound of the invention is dispersed in oleic acid and the propellant. The resulting mixture was then poured into an aerosol container with a metering valve.
Example 15
Cell-based assays
A. Material
Prostate cancer cells (PC-3) and breast cancer cells (MDA-468) were obtained from ATCC (Manassas, Va.). Mammalian Protein Extraction Reagent (MPER), Halt protease inhibitor cocktail, BCA protein reagent, and Supersignal Western chemistry reagent were obtained from pierce chemical Co. 10% Tris-glycine gels (1.0mm, 15-well) and nitrocellulose (0.2 micron) were obtained from Invitrogen Life Technologies (Carlsbad, Calif.). Agar was purchased from EM Science. anti-phospho-AKT (Thr308, #9275) polyclonal antibody, anti-phospho-S6-kinase (Thr389, #9205) polyclonal antibody, and anti-rabbit IgG-HRP conjugate were obtained from Cell Signaling Technologies (Beverly, MA). Nitrobluetetrazolium reagents and staurosporine were purchased from Sigma Chemical Co (st. louis, MO). LY294002 was purchased from Cayman Chemicals (Ann Arbor, MI). All other materials are reagent grade quality materials.
B. Conditions for cell growth
PC-3 cells were grown in F12K medium supplemented with 7% (v/v) fetal bovine serum (fcs) and 2mM glutamine. MDA-468 cells were grown in MEM-alpha supplemented with 10% (v/v) fcs, 2mM glutamine, 1mM sodium pyruvate, 0.1mM non-essential amino acids, 10mM Hepes and 1. mu.g/ml insulin. All cell lines were at 37 ℃ with 5% CO2Culturing in an atmosphere humidifying incubator.
C. Cell assay using western blot analysis
Treatment of cells with the compound blocks activation of AKT and/or S6-kinase, as reflected by the level of the phosphorylated active form of AKT (detected using the phospho-Thr-308-AKT antibody) or S6 kinase (detected using the phospho-Thr-389-S6-kinase antibody). For this assay, PC-3 cells were seeded in 24-well plates (Corning Costar) at 100000-120000 cells per well and cultured overnight to 90% confluence. The following day, cells were washed once with 1.5mL PBS and medium was replaced with growth medium (starvation medium) containing low serum (0.1% fcs). After overnight culture over the second night, the medium was replaced with 0.5 mL/well of starved medium. Some assays were also performed in normal growth medium (7% fcs, PC-3 or 10% fcs, MDA-468). Cells were treated with vehicle control (DMSO) or a compound of the invention at a final DMSO concentration of 1% v/v (5. mu.l per 0.5mL of medium) and cultured for that time. The culture was terminated by aspiration of the medium, the wells were washed with 1.0mL PBS, and the cells were lysed with 0.1mL of MPER reagent supplemented with protease inhibitors (Halt reagent) and phosphatase inhibitors (1mM NaF, 1mM sodium vanadate). Cell lysates were briefly centrifuged to remove insoluble debris and aliquots were taken for protein analysis (BCA) and western blot analysis. For western blot analysis, lysates were mixed with Laemmli SDS sample buffer, boiled, loaded onto a 10% Tris-glycine gel, and the amount of protein added in each lane was normalized. The electrophoresed gel was transferred to nitrocellulose paper, blocked with 5% milk in Tris-buffered saline containing 0.1% Tween 20, and incubated overnight with a primary antibody (phospho-AKT-Thr 308@ 1: 667, phospho-S6 kinase @ 1: 1000). The blot was washed three times with blocking buffer and incubated with anti-rabbit IgG-HRP @ 1: 2000 for 1 hour. The washed blots were developed using the Supersignal Western Chemimercecent detection system, the films were scanned with a Bio Rad CCD camera, and phospho-protein bands were quantitated using Bio Rad quantity-One software.
D. Soft agar potency assay
PC-3 and MDA-468 cells plated in soft agar treated with a compound of the invention showed a dose-dependent inhibition of colony growth (measured as colony size and number). The PC-3 and MDA-468 cells in compound-treated soft agar grew for approximately 2 weeks. For this assay, a layer of 0.5% agar in growth medium was laid down in a bottom layer of 2ml per well on a plate (Corning 35 mm. times.10 mm). Cells were trypsinized, dispersed into single cells with a 21-gauge needle, and plated on top of 0.3% agar/growth medium, 1.5 mL/plate, containing 4500 cells per plate. The following day, the first treatment with vehicle or compound was added in a volume of 1.0mL of 0.3% agar/growth medium containing 1% DMSO. The concentration of the compound was adjusted to reflect the total volume of agar in the plate. Cells were grown for 7 days and a second treatment (additional 1mL of 0.3% agar was added). Colonies were visualized for growth and survival every few days. Azobenzothiazole (0.5mg/mL PBS) was added on days 12-14, 0.3mL per plate, and surviving colonies were allowed to develop for 1-2 days. Plates were scanned with a Bio Rad CCD camera and colony numbers and total stained area were quantified using ImagePro software.
AKT2 and PDK-1 expression and purification
The pHisaKT2 was constructed by cloning AKT2 into pBlueBacHis2A (Invitrogen Corp.) via BamH1 and Bgl2 restriction sites, forming a fusion protein following the 38 amino acid N-terminal His tag sequence derived from this vector. The first 10 residues of the new N-terminal sequence + AKT2 are as follows: MPRGSHHHHHHGMASMTGGQQMGRDLYDDDDKDRWGSMNE VSVIKEG(AKT2 is underlined, His-6 is in bold). Similarly, pHispDK-1 was constructed by cloning PDK-1 into pBlueBacHis2A (Invitrogen Corp.) at the EcoR1 cloning site, with an N-terminal His-tag (. ICSWYHGILD)MARTTSQLYD.. (PDK-1 sequence underlined)). The new N-terminal sequence + the first 10 residues of PDK-1 are as follows: MPRGSHHHHHHGMASMTGGQQMGRDLYDDDDKDRWGSELEICSWYHGILDMARTTSQLYD... (PDK-1 is the underlined section, His-6 is in bold).
Recombinant baculovirus containing His-tagged AKT2 or His-tagged PDK-1 cDNA was prepared as follows. pHisAKT2 or pHisPDK-1 was co-transfected with Bac-N-blue (Invitrogen) virus DNA into SF-21 cells, and 3-4 days later, virus supernatants were separated and recombinant viruses were plaque-purified. cDNA clones expressing His-tagged AKT2(HisAKT-V) or His-tagged PDK-1(HisPDK-1-V) were selected and amplified as stocks for expression of recombinant proteins as described below.
To express His-tagged AKT2 and PDK-1, 10 liters of SF-21 insect cell suspension was infected with recombinant virus (i.e., HisPDK-1-V or HisAKT2-V), and cells were harvested 3-4 days after infection and cryopreserved. To purify recombinant His-tagged AKT2 and PDK-1, the cell pellet was freeze-thawed, homogenized (in Phosphate Buffered Saline (PBS) supplemented with 10% TritonX-100, 0.5M NaCl, 2g/l NaF, 2.5. mu.g/mL aprotinin, 5. mu.g/mL leupeptin, 1.25. mu.g/mL pepstatin, 0.1% beta-mercaptoethanol, and 1mM vanadate (vanidate), 10mM imidazole, adjusted to pH 7.6), and purified by two consecutive rounds of Ni2+ affinity chromatography followed by gel filtration. The enzyme was frozen in small aliquots and stored at-80 ℃ in 50mM Tris-HCl pH 7.5, 150mM NaCl pH 7.5, 0.1mM EGTA, 0.1mM EDTA, 0.2. mu.M benzamidine, 0.1% beta-mercaptoethanol, and 0.25M sucrose. Recombinant enzymes suitable for compound determination are also available from Upstate Biotechnology (PDK-1 catalog No. 14-280; AKT2 catalog No. 14-422).
Example 16
Enzyme assay
PDK-1 dependent activation of AKT2 and subsequent enzymatic Activity
The characteristics of the compounds are evaluated by an assay for determining PDK-1 dependent AKT activation by modification of published methods (e.g. Alessi, D.R. et al, "characteristics of a 3-phosphoside-dependent protein kinase bottom phosphate proteins kinase B," Current Biology (1997), Vol.7, pp.261-269).
Activity of purified human AKT2 by the enzyme in phosphatidylinositol-4, 5-bisphosphate (PIP)2) Assays that are first activated by PDK-1 in the presence are routinely determined. Once activated, AKT 2-dependent phosphorylation of the peptide substrate was measured using the Scintillation Proximity Assay (SPA).
Phospholipid vesicles were prepared as follows: phosphatidylcholine (Sigma Cat. No. P-1287) and phosphatidylserine (Sigma Cat. No. P-6641), each 2.2mg, were transferred to a borosilicate glass tube and dried under nitrogen. Mixing 1mg of PIP2(Biomol catalog No. PH-106) was suspended in 9.5mL of 10mM HEPES, pH 7.5 and transferred to the dried lipid. The tube was vortex mixed until a milky suspension was produced. The tubes were then placed in a cup-type breaking head (cup horn) sonicator (Branson Instruments) with ice water in the jacket and sonicated at medium power for 20 minutes until a clear phospholipid vesicle preparation was obtained. The vesicle suspension was frozen in aliquots at-80 ℃ until use.
The assay was performed in 96-well polypropylene V-bottom plates. Incubate at room temperature for 2 hours. The assay mixture, at a volume of 60 μ L, contained: 15mM MOPS at pH 7.2, 1mg/mL bovine serum albumin, 18mM beta glycerophosphate, 0.7mM dithiothreitol, 3mM EGTA, 10mM MgOAc, 7.5. mu.M ATP, 0.2. mu. Ci [ gamma-33P]ATP, 7.5. mu.M biotinylated peptide substrate (biotin-ARRRDGGGAQPFRPRAATF), 0.5. mu.L PIP2Phospholipid vesicles of (1), 60pg purified recombinant human PDK-1 and 172ng purified recombinant human AKT 2. The addition comes fromTest compounds in stock solutions in DMSO. After incubation at a final DMSO concentration of 2.5%, 10. mu.L of the assay mixture was transferred to a 96-well clear-bottom polystyrene plate (Wallac Isoplate) containing 0.33mg of streptavidin-coated SPA beads (Amersham Cat No. RPNQ0007) suspended in 200. mu.L of pH 7.4 phosphate buffered saline containing 50mM EDTA and 0.1% Triton X-100. After briefly shaking, the SPA beads were allowed to settle to the bottom of the plate at room temperature overnight. The amount of product formation measured with a WallacMorobeta scintillation counter is directly proportional to the incubation time and the amount of PDK-1 and inactive AKT2 added. PDK-1 is added at less than optimal levels, which allows the assay to sensitively detect inhibitors of AKT2 activation as well as direct AKT2 kinase inhibitors. The z' -factor of the assay is greater than 0.7.
Phosphorylation on the threonine phosphate residue of the peptide substrate has been shown to be dependent on activated AKT2 generated during incubation. ATP, Mg2+PDK-1, AKT2 or containing PIP2No phosphorylation was observed in the absence of vesicles. However, when purified activated human AKT1 (available from Upstate Biotechnology) was added, either PDK-1 or PIP-containing2Phosphorylation can be readily observed in the presence or absence of vesicles.
Direct assay for PDK-1 Activity
The activity of recombinant human PDK-1 was directly determined using a filter binding protocol. Incubate at room temperature for 4 hours, with a final volume of 60 μ L containing: 50mM Tris-HCl pH 7.5, 0.1mM EGTA, 0.1mM EDTA, 0.1% beta-mercaptoethanol, 1mg/mL bovine serum albumin, 10mM MgOAc, 10. mu.M ATP, 0.2. mu. Ci [ gamma-33P]ATP, 7.5. mu.M substrate peptide (H)2N-ARRRGVTTKTFCGT) and 60ng purified human PDK-1. The enzyme reaction was stopped by adding 25mM EDTA. A portion of the reaction mixture was spotted onto whatmann p81 phosphocellulose paper. The filter paper was washed three times with 0.75% phosphoric acid to remove the unreacted [ gamma-33P]ATP and washed once with acetone. After drying, the filter-bound labeled peptide was quantified using a Fuji phosphoimager.
If desired, the compounds of the invention may also be modified to determine their PDK-1 inhibitory activity by the methods disclosed in Biondi, R.M., et al, "Identification of a pocket-in PDK-1 kinase domain which is expressed with PIF and the C-tertiary residues of PKA," EMBO J. (2000) Vol.19(5), pp.979-88.
All U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications and non-patent publications referred to in this application and/or listed in the application data sheet, are incorporated herein by reference, in their entirety.
From the foregoing it will be appreciated that, although specific embodiments of the invention have been described herein for purposes of illustration, various modifications may be made without deviating from the spirit and scope of the invention. Accordingly, the invention is not limited except as by the appended claims.

Claims (30)

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof:
wherein:
m is 0 to 4;
n is 0 to 3;
a is oxygen or sulfur;
R1is hydrogen, alkyl, -C (O) OR7or-C (O) N (R)7)2(ii) a Or
R1Is (optionally substituted with one or more groups selected from alkyl, aryl, aralkyl, halo, haloalkyl, cyano, nitro, -R8-OR7、-R8-N(R7)2、-R8-C(O)OR7、-R8-C(O)N(R7)2、-R8-N(R7)C(O)N(R7)2、-R8-N(R7)C(O)-R9-N(R7)2and-R8-N(R7)C(O)OR7Substituted with the substituents of (1) aryl); or
R1Is (optionally substituted with one or more groups selected from alkyl, aryl, aralkyl, halo, haloalkyl, cyano, nitro, -R8-OR7、-R8-N(R7)2、-R8-C(O)OR7、-R8-C(O)N(R7)2、-R8-N(R7)C(O)N(R7)2、-R8-N(R7)C(O)-R9-N(R7)2and-R8-N(R7)C(O)OR7Substituted with the substituent(s) of (a); or
R1Is (optionally substituted with one or more groups selected from alkyl, aryl, aralkyl, halo, haloalkyl, cyano, nitro, -R8-OR7、-R8-N(R7)2、-R8-N(R7)C(O)N(R7)2、-R8-N(R7)C(O)-R9-N(R7)2and-R8-N(R7)C(O)OR7Substituted with the substituents of (1); or
R1Is (optionally substituted with one or more groups selected from alkyl, aryl, aralkyl, halo, haloalkyl, cyano, nitro, -R8-OR7、-R8-C(O)OR7、-R8-C(O)N(R7)2、-R8-N(R7)2、-R8-N(R7)C(O)N(R7)2、-R8-N(R7)C(O)-R9-N(R7)2and-R8-N(R7)C(O)OR7Substituted with the substituents of (a) or (b);
each R2Independently selected from alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, cyano, -R8-OR7、-R8-N(R7)2、-R8-C(O)OR7、-R8-C(O)N(R7)2、-R8-S(O)tN(R7)2(wherein t is 1 or 2), -R8-N(R7)S(O)tR7(wherein t is 1 or 2), -R8-N(R7)S(O)tN(R7)2(wherein t is 1 or 2), -R8-N(R7)S(O)tN(R7)C(O)OR7(wherein t is 1 or 2), -R8-N(R7)C(O)R7、-R8-N(R7)-R8-C(O)OR7、-R8-N(R7)C(O)N(R7)2、-R8-N(R7)C(O)-R9-N(R7)2、-R8-N(R7)-R9-C(O)N(R7)2、-R8-N(R7)C(O)-R8-N(R7)-R8-C(O)OR7、-R8-N(R7)C(O)-R8-N(R7)-R8-C(O)-R8-N(R7)2、-N(R7)C(＝NR7)N(R7)2、-C(＝NR7)-N(R7)2、-R8-N＝C(R7)2(optionally substituted with one or more groups selected from alkyl, aryl, aralkyl, halo, haloalkyl, cyano, nitro, -R8-OR7、-R8-C(O)OR7、-R8-C(O)N(R7)2、-R8-N(R7)2、-R8-N(R7)C(O)-R8-N(R7)2and-R8-N(R7)C(O)OR7Substituted with the substituents) heterocyclic group and optionally substituted cyclic ureido group;
R3is hydrogen, alkyl or aralkyl;
R5is hydrogen, alkylAryl, aralkyl, -C (O) R11or-S (O)2R11；
Each R6Independently selected from alkyl, alkenyl, alkynyl, halogen, haloalkyl, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, -R9-OR7、-R8-C(O)OR7、-R8-C(O)N(R7)2、-R8-C(O)R7、-R8-N(R7)2、-R8-N(R7)C(O)R7、-R8-C(O)-R9-N(R7)2、-R8-N(R7)-R8-C(O)OR7、-R8-N(R7)C(O)N(R7)2、-R8-N(R7)C(O)-R9-N(R7)2、-R8-N(R7)C(O)-R10-N(R7)2、-R8-N(R7)C(O)-R8-N(R7)C(O)-R8-N(R7)2、-R8-C(O)-R9-C(O)OR7、-R8-C(O)-R9-C(O)N(R7)2、-R8-N(R7)C(O)-R8-N(R7)-R8-C(O)OR7、-R8-N(R7)C(O)-R8-N(R7)-R8-C(O)N(R7)2、-R8-N(R7)C(O)-R9-C(O)OR7、-R8-N(R7)C(O)-R9-C(O)N(R7)2、-R8-S(O)t-N(R7)2(wherein t is 1 or 2), -R8-N(R7)S(O)t-R8-N(R7)2(wherein t is 1 or 2) and-R8-N(R7)S(O)t-R7(wherein t is 1 or 2);
each R7Independently hydrogen, optionally substituted alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl;
each R8Is a bond or a straight or branched alkylene chain;
each R9Is a straight or branched alkylene chain;
R10is an amino acid residue other than a straight or branched alkylene chain; and is
Each R11Is optionally substituted alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl;
the compound of formula (I) is a single stereoisomer, a mixture of stereoisomers, a solvate or a polymorph;
the conditions were as follows:
(1) when m is 1, n is 1, A is oxygen, R1、R3And R5Each is hydrogen, and R6When it is 3-methoxy, then R2Cannot be 4-bromo, 4-iodo, 5-bromo;
(2) when m is 1, n is 0, A is oxygen, R1、R3And R5When each is hydrogen, then R2Cannot be 5-bromo, 5-iodo or 4-bromo;
(3) when R is6When it is 3-methoxy, then R2Not an optionally substituted ethenyl or ethynyl group;
(4) when m is2, n is 1, A is oxygen, R1、R3And R5Each is hydrogen, and R6When it is methoxy, then when one R is2Another R when it is 5-nitro2Cannot be 4-bromo;
(5) when m is 0, n is2, A is oxygen, R3And R5Each is hydrogen, and one R6Is 3-methyl and the other R6When it is 5-methyl, then R1Not being hydrogen, -C (O) OR7or-C (O) N (R)7)2；
(6) When m is 0, n is 0, A is oxygen, and R1And R3When each is hydrogen, then R5Cannot be hydrogen;
(7) when m is 1, n is 0, A is oxygen, and R1、R3And R5When each is hydrogen, then R2Cannot be 4-methyl, 4-bromo, 4-thiophen-2-yl or 2, 6-dimethoxypyrimidin-4-yl;
(8) when m is 1, n is 1, A is oxygen, R1、R3And R5Each is hydrogen, and R6When it is 3-methoxy, then R2Cannot be 4-indol-5-yl, 4-indol-6-yl or 4-indol-4-yl;
(9) when m is 1, n is 1, R1、R3And R5Each is hydrogen, R6Is 3-methoxy, and one R2When it is 4-indol-6-yl, then another R2Cannot be 5-nitro, 5-amino or 5- (thien-2-ylacetamino);
(10) when m is2, n is 0 or1, A is oxygen, R1、R3And R5Each is hydrogen, and R6When it is 3-methoxy, then when one R is2Another R when it is 5-amino2Cannot be a 4-amino group;
(11) when m is2, n is 0 or1, A is oxygen, R1、R3And R5Each is hydrogen, and R6When it is 3-methoxy, then when one R is2Another R when it is 4-fluoro or 4-azido2Cannot be 5-nitro;
(12) when m is 0, n is 3, A is oxygen, R1、R3And R5Each is hydrogen, and one R6Is 3-methyl and a second R6When it is 5-methyl, then the third R6Cannot be 4- (2-carboxyethyl), 4- (3-morpholin-4-ylpropyl) or 4- (3-dimethylaminopropyl);
(13) when m is 1, n is2, A is oxygen, R1、R3And R5Each is hydrogen, and one R6Is 3-methyl and the other R6Is 4- (2-carboxyethyl) or 4- [2- (3, 5-dimethoxybenzyloxycarbonyl) ethyl]When then R is2But not 5-chloro, 6-methoxy, 5-bromo, 5-iodo, 4-methyl, 5-methyl, 6-chloro, 5-methoxycarbonyl, 5-carboxy, 5-aminosulfonyl, 5-methylaminosulfonyl, 5- (2-carboxyethyl), 5-ethyl, 5-methoxy, 6-hydroxy, 6-bromo or 6-bromo;
(14) when m is 1, n is 3, A is oxygen, R1、R3And R5Each is hydrogen, and one R6Is 3-methyl and a second R6Is 5-methyl, the third R6Is 4- (2-carboxyethyl), 4- (3-dimethylaminopropyl) or 4- (3-morpholin-4-ylpropyl) then R2But not 5-chloro, 5-bromo, 5-iodo, 4-methyl, 5-methyl, 6-hydroxy, 6-methoxy, 6-morpholin-4-yl, 6-chloro, 5-methoxy, 4- (2-hydroxyethyl), 5-aminosulfonyl, 5- (1-methylethylaminosulfonyl), 5- (morpholin-4-ylsulfonyl) or 5- (dimethylaminocarbonyl);
(15) when m is 0, n is2, A is oxygen, R1、R3And R5Each is hydrogen, and one R6When it is 3-methoxy, then another R6Cannot be 5-methyl or 4- (2-carboxyethyl);
(16) when m is2, n is2, A is oxygen, R1、R3And R5Each being hydrogen, one R6Is 4- (12-carboxyethyl), and a second R6When it is 3-methyl, then two R are2' cannot be 5, 6-dimethoxy or 4-methyl-5-chloro;
(17) when m is2, n is 3, A is oxygen, R1、R3And R5Each being hydrogen, one R6Is 3-methyl and a second R6Is 5-methyl, and a third R6When it is 4- (2-carboxyethyl), then R2' cannot be 4-methyl and 5-chloro;
(18) when m is 0, n is 0, A is oxygen, R1And R5When each is hydrogen, then R5Not hydrogen, methyl, 4-chlorophenyl or 3, 5-dichlorophenyl;
(19) when m is 0, n is 1, A is oxygen, R1、R3And R5When each is hydrogen, then R2Cannot be 3-methyl or 5-ethyl;
(20) when m is 0, n is2, A is oxygen, R1、R3And R5Each being hydrogen, then together R2' cannot be 3, 4-dimethyl, 3, 5-dimethyl, 3-methyl-4- [ 2-carboxyethyl]3-methyl-4- [ 2-methoxycarbonylethyl]Or 4-methyl-3-ethoxycarbonyl;
(21) when m is 0, n is 3, A is oxygen, R1、R3And R5Each being hydrogen, then together R2' cannot be 4- [ ethoxycarbonyl]-3, 5-dimethyl, 5-methyl-3, 4-dibromo, 5-formyl-3,4-dimethyl, 3-ethyl-4, 5-dimethyl, 5-ethoxycarbonyl-4- [ 2-ethoxycarbonylethyl]-3- [ ethoxycarbonylmethyl group]5-carboxy-3-ethyl-4-methyl, 4-methyl-3, 5-dichloro, 5-chloro-3-methoxycarbonyl-4- [ methoxycarbonylmethyl [ ]]3-acetyl-5-ethoxycarbonyl-4-methyl, 5-ethoxycarbonyl-3- (2-ethoxycarboxyethyl) -4- (ethoxycarbonylmethyl), 4-ethyl-3, 5-dimethyl, 4-prop-3-enyl-3, 5-dimethyl;
(22) when m is 1, n is 0, A is oxygen, R1、R3And R5When each is hydrogen, then R2Cannot be 5-chloro or 5-nitro;
(23) when m is 1, n is 1, A is oxygen, R1、R3And R5Each is hydrogen, R6When it is 3-methyl, then R2Cannot be 5-nitro or 5-chloro;
(24) when m is 1, n is2, A is oxygen, R1、R3And R5Each is hydrogen, and R6When' is 3, 5-dimethyl, then R2Cannot be 5-nitro or 5-chloro;
(25) when m is2, n is 0 or1, A is oxygen, R1、R3And R5Each is hydrogen, R6Is 3-methoxy, and one R2When it is 4-amino, then another R2Cannot be a 5-amino group;
(26) when m is2, n is 0 or1, A is oxygen, R1、R3And R5Each is hydrogen, R6Is 3-methoxy, and one R2When it is 5-nitro, then another R2Cannot be 4-fluoro or 4-azido;
(27) when m is 1, n is 3, A is oxygen, R1、R3And R5Each is hydrogen, and one R6Is 3-methyl, a second R6Is 5-methyl and the third R6When it is 4- (3-dimethylaminopropyl) or 4- (2-carboxyethyl), then R2Cannot be 6- (pyridin-3-yl), 6- (thiophen-2-yl), 4- (2-hydroxyethyl) or 4- (2- (3- (1-methylethyl) phenoxy) ethyl;
(28) when m is 0, n is2, A is oxygen, R3And R5Each is hydrogen, and one R6Is 3-methyl and a second R6When it is 5-methyl, then R1Cannot be 4-methoxyphenyl or 3, 4-dimethoxyphenyl;
(29) when m is2, n is 1, A is oxygen, R1、R3And R5Each is hydrogen, and one R2Is 4-amino and a second R2When it is 5-amino, then R6Cannot be 3-methoxy;
(30) when m is2, n is 1, A is oxygen, R1、R3And R5Each is hydrogen, and one R2Is 4-fluoro or 4-azido, and a second R2When it is 5-nitro, then R6Cannot be 3-methoxy;
(31) when m is 0 or1, n is 3, A is oxygen, R1、R3And R5Each is hydrogen, and one R6Is 5-methyl and a second R6Is 3-methyl or 3-phenyl (optionally substituted by fluoro, chloro or cyano), the third R6is-C (O) OH or one of R7Is hydrogen or methyl and the other R7Is an alkyl group optionally substituted by hydroxy, diethylamino and/or an optionally substituted N-heterocyclic group, -C (O) N (R)7)2When then R is2Halogen not in position 5, trifluoromethoxy, -C (O) R7(wherein R is7Is morpholinyl) or-C (O) N (R)7)2(wherein each R is7Independently hydrogen, hydroxyalkyl, alkyl or phenyl); and
(32) m is 1, when n is 3, A is oxygen, R1、R3And R5Each is hydrogen, and one R6Is 3-methyl and a second R6Is 5-methyl, the third R6is-C (O) R in the 4-position7(wherein R is7Is optionally substituted N-heterocyclyl), then R6In which R cannot be in the 4-position7is-C (O) R of an optionally substituted N-heterocyclyl7，R2And not halogen or 3-pyridyl.
2. The compound of claim 1, wherein:
m is 1 to 4;
n is 0 to 3;
a is oxygen;
R1is hydrogen or alkyl; or
R1Is (optionally substituted by one or more groups selected from-R)8-OR7、-R8-N(R7)2、-R8-C(O)N(R7)2、-R8-N(R7)C(O)N(R7)2、-R8-N(R7)C(O)-R9-N(R7)2and-R8-N(R7)C(O)OR7Substituted with the substituents of (1) aryl); or
R1Is (optionally substituted by one or more groups selected from alkyl, -R8-OR7、-R8-N(R7)2、-R8-N(R7)C(O)N(R7)2and-R8-N(R7)C(O)-R9-N(R7)2Substituted with the substituents of (1); or
R1Is (optionally substituted by one or more groups selected from alkyl and-R8-OR7Substituted with the substituents of (a) or (b);
each R2Independently selected from heterocyclyl, -R8-S(O)tN(R7)2(wherein t is 1 or 2), -R8-N(R7)2、-R8-N(R7)S(O)tN(R7)2(wherein t is 1 or 2), -R8-N(R7)S(O)tN(R7)C(O)OR7(wherein t is 1 or 2), -R8-N(R7)C(O)R7、-R8-N(R7)-R8-C(O)OR7、-R8-N(R7)C(O)N(R7)2、-R8-N(R7)C(O)-R9-N(R7)2、-R8-N(R7)-R9-C(O)N(R7)2、-R8-N(R7)C(O)-R8-N(R7)-R8-C(O)OR7、-R8-N(R7)C(O)-R8-N(R7)-R8-C(O)-R8-N(R7)2、-N(R7)C(＝NR7)N(R7)2and-R8-N＝C(R7)2；
R3Is hydrogen;
R5is hydrogen or alkyl;
each R6Independently selected from halogen, alkyl, nitro, -R8-C(O)R7、-R8-N(R7)2、-R8-C(O)OR7、-R8-C(O)N(R7)2、-R8-N(R7)-R8-C(O)OR7、-R8-N(R7)C(O)R7、-R8-C(O)-R9-C(O)OR7、-R8-N(R7)C(O)N(R7)2、-R8-N(R7)C(O)-R9-N(R7)2、-R8-N(R7)C(O)-R9-C(O)OR7、-R8-N(R7)C(O)-R8-N(R7)-R8-C(O)OR7(optionally substituted with one or more groups selected from alkyl, halo, haloalkyl, cyano, nitro, -R8-OR7、-R8-O-R9-C(O)OR7、-R8-N(R7)2、-R8-C(O)R7、-R8-C(O)OR7、-R8-C(O)N(R7)2、-R8-N(R7)C(O)OR7、-R8-N(R7)C(O)R7、-R8-S(O)pR7(wherein p is 0-2), -R8-S(O)pN(R7)2(wherein p is 0-2) and-R8-N(R7)C(O)-R8-N(R7)2Substituted with one or more substituents selected from alkyl, -R) and (optionally substituted with one or more substituents selected from alkyl, -R8-OR7、-R8-O-R9-C(O)OR7、-R8-C(O)R7、-R8-C(O)OR7、-R8-C(O)N(R7)2、-R8-N(R7)C(O)R7、-R8-N(R7)C(O)OR7、-R8-N(R7)2、-R8-N(R7)C(O)-R8-N(R7)-R8-C(O)OR7and-R8-S(O)tR7Aryl (wherein t is a substituent of 0 to 2);
each R7Independently hydrogen, optionally substituted alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl;
each R8Is a bond or a straight or branched alkylene chain; and is
Each R9Is a straight or branched alkylene chain.
3. The compound of claim 2, wherein:
m is 1;
n is 0 or 3;
a is oxygen;
R1is hydrogen or alkyl;
R2is-R8-S(O)tN(R7)2(wherein t is 1 or 2), -R8-N(R7)C(O)R7、-R8-N(R7)-R8-C(O)OR7、-R8-N(R7)C(O)N(R7)2、-R8-N(R7)-R9-C(O)N(R7)2or-R8-N(R7)C(O)-R9-N(R7)2；
R3Is hydrogen;
R5is hydrogen or alkyl;
R6independently selected from halogen, alkyl, nitro, -R8-C(O)R7、-R8-N(R7)2、-R8-C(O)OR7、-R8-C(O)N(R7)2、-R8-N(R7)-R8-C(O)OR7、-R8-N(R7)C(O)R7、-R8-C(O)-R9-C(O)OR7、-R8-N(R7)C(O)N(R7)2、-R8-N(R7)C(O)-R9-N(R7)2、-R8-N(R7)C(O)-R9-C(O)OR7、-R8-N(R7)C(O)-R8-N(R7)-R8-C(O)OR7(optionally substituted with one or more groups selected from alkyl, halo, haloalkyl, cyano, nitro, -R8-OR7、-R8-O-R9-C(O)OR7、-R8-N(R7)2、-R8-C(O)R7、-R8-C(O)OR7、-R8-C(O)N(R7)2、-R8-N(R7)C(O)OR7、-R8-N(R7)C(O)R7、-R8-S(O)pR7(wherein p is 0-2), -R8-S(O)pN(R7)2(wherein p is 0-2) and-R8-N(R7)C(O)-R8-N(R7)2Substituted with one or more substituents selected from-R) and (optionally) a heterocyclic group8-OR7、-R8-O-R9-C(O)OR7、-R8-C(O)OR7、-R8-C(O)N(R7)2、-R8-N(R7)C(O)R7、-R8-N(R7)C(O)OR7、-R8-N(R7)2、-R8-N(R7)C(O)-R8-N(R7)-R8-C(O)OR7and-R8-S(O)tR7Aryl (wherein t is a substituent of 0 to 2);
each R7Independently hydrogen, optionally substituted alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl;
each R8Is a bond or a straight or branched alkylene chain; and is
Each R9Is a straight or branched alkylene chain.
4. The compound of claim 3, wherein:
m is 1;
n is 0, 1, 2 or 3;
a is oxygen;
R1is hydrogenOr an alkyl group;
R2is-R8-S(O)tN(R7)2(wherein t is 1 or 2), -R8-N(R7)C(O)R7、-R8-N(R7)-R8-C(O)OR7、-R8-N(R7)C(O)N(R7)2、-R8-N(R7)-R9-C(O)N(R7)2or-R8-N(R7)C(O)-R9-N(R7)2；
R3Is hydrogen;
R5is hydrogen or alkyl;
each R6Independently selected from halogen, alkyl, nitro, -R8-C(O)R7、-R8-C(O)OR7、-R8-C(O)N(R7)2and-R8-C(O)-R9-C(O)OR7；
Each R7Independently hydrogen, optionally substituted alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl;
each R8Is a bond or a straight or branched alkylene chain; and is
Each R9Is a straight or branched alkylene chain.
5. The compound of claim 4 selected from the group consisting of:
5-acetamido-3- [ (pyrrol-2-yl) methylene ] indolin-2-one;
5-ureido-3- [ (pyrrol-2-yl) methylene ] indolin-2-one;
5-trifluoroacetylamino-3- [ (pyrrol-2-yl) methylene ] indolin-2-one;
4-acetamido-3- [ (pyrrol-2-yl) methylene ] indolin-2-one;
5-ureido-3- [1- (pyrrol-2-yl) ethylene ] indolin-2-one;
5- (pyrrolidin-1-yl) acetamido-3- [ (pyrrol-2-yl) methylene ] indolin-2-one;
5- (N' -ethylureido) -3- [1- (pyrrol-2-yl) ethylene ] indolin-2-one;
5- (N' -phenylureido) -3- [1- (pyrrol-2-yl) ethylene ] indolin-2-one;
5-acetamidomethyl-3- [1- (pyrrol-2-yl) ethylene ] indolin-2-one;
5- (pyridin-3-yl) carbonylamino-3- [1- (pyrrol-2-yl) ethylene ] indolin-2-one;
5- (1, 1-dimethylethoxy) carbonylaminomethyl-3- [1- (pyrrol-2-yl) ethylene ] indolin-2-one;
5- (ureido) methyl-3- [1- (pyrrol-2-yl) ethylene ] indolin-2-one;
5- (pyridin-4-yl) carbonylamino-3- [1- (pyrrol-2-yl) ethylene ] indolin-2-one;
5-ureido-3- [1- (pyrrol-2-yl) propylene ] indolin-2-one;
5-aminoacetamido-3- [1- (pyrrol-2-yl) ethylene ] indolin-2-one;
5-ureido-3- [ (4-bromopyrrol-2-yl) methylene ] indolin-2-one;
5-ureido-3- [ (4- (piperidin-1-ylmethyl) carbonylpyrrol-2-yl) methylene ] indolin-2-one;
5-ethoxycarbonylmethylamino-3- [1- (pyrrol-2-yl) ethylene ] indolin-2-one;
5-aminocarbonylmethylamino-3- [1- (pyrrol-2-yl) ethylene ] indolin-2-one;
5- (N-ethylureido) -3- [1- (pyrrol-2-yl) ethylene ] indolin-2-one;
5-ureido-3- [ (4- ((4-methylpiperazin-1-yl) methylcarbonyl) pyrrol-2-yl) methylene ] indolin-2-one;
5-ureido-3- [ (4- (2-ethoxycarbonylethyl) carbonylpyrrol-2-yl) methylene ] indolin-2-one;
5-ureido-3- [ (4- (2-carboxyethyl) carbonylpyrrol-2-yl) methylene ] indolin-2-one;
5- (4-aminopiperidin-1-ylcarbonylamino) -3- [1- (pyrrol-2-yl) ethylene ] indolin-2-one;
5-ureido-3- [ (4- (piperazin-1-ylmethylcarbonyl) pyrrol-2-yl) methylene ] indolin-2-one;
5-ureido-3- [ (4-ethoxycarbonylpyrrol-2-yl) methylene ] indolin-2-one;
5-ureido-3- [ (4-carboxypyrrol-2-yl) methylene ] indolin-2-one;
5-ureido-3- [ (4- (2-morpholin-4-ylethyl) aminocarbonylpyrrol-2-yl) methylene ] indolin-2-one;
5-ureido-3- [ (4- (2-piperidin-1-ylethyl) aminocarbonylpyrrol-2-yl) methylene ] indolin-2-one;
5-ureido-3- [ (4- (pyridin-3-ylmethyl) aminocarbonylpyrrol-2-yl) methylene ] indolin-2-one;
5-ureido-3- [ (4- (3-piperidin-1-ylpropyl) aminocarbonylpyrrol-2-yl) methylene ] indolin-2-one;
5-ureido-3- [ (3-methyl-4-carboxypyrrol-2-yl) methylene ] indolin-2-one;
5-acetamido-3- [1- (pyrrol-2-yl) ethylene ] indolin-2-one;
4-ethoxycarbonylmethylamino-3- [ (pyrrol-2-yl) methylene ] indolin-2-one;
5-ureido-3- [ (4- (2-dimethylaminoethyl) aminocarbonylpyrrol-2-yl) methylene ] indolin-2-one;
5-ureido-3- [ (3-methyl-4- (2-piperidin-1-ylethyl) aminocarbonylpyrrol-2-yl) methylene ] indolin-2-one;
5-ureido-3- [ (4- (2- (imidazol-4-yl) ethyl) aminocarbonylpyrrol-2-yl) methylene ] indolin-2-one;
5-ureido-3- [ (4- (2- (pyridin-4-yl) ethyl) aminocarbonylpyrrol-2-yl) methylene ] indolin-2-one;
5-ureido-3- [ (4- ((3R) -3- (dimethylamino) pyrrolidin-4-yl) carbonylpyrrol-2-yl) methylene ] indolin-2-one;
5-ureido-3- [ (4- ((3S) -3- (dimethylamino) pyrrolidin-4-yl) carbonylpyrrol-2-yl) methylene ] indolin-2-one;
5-ureido-3- [ (4- (3- (pyrrolidin-1-yl) propyl) aminocarbonylpyrrol-2-yl) methylene ] indolin-2-one;
5-ureido-3- [ (4- (4- (pyrrolidin-1-yl) butyl) aminocarbonylpyrrol-2-yl) methylene ] indolin-2-one;
5-ureido-3- [ (4- (4-methylpiperazin-1-yl) carbonylpyrrol-2-yl) methylene ] indolin-2-one;
5-aminosulfonyl-3- [ (4-carboxy-3-methylpyrrol-2-yl) methylene ] indolin-2-one;
5-ureido-3- [ (4- (2-carboxyethyl) -3, 5-dimethylpyrrol-2-yl) methylene ] indolin-2-one;
5-aminosulfonyl-3- [ (3-methyl-4- (3- (piperidin-1-yl) propyl) aminocarbonylpyrrol-2-yl) methylene ] indolin-2-one;
5-ureido-3- [ (4- (2- (4-methylpiperazin-1-yl) carbonylethyl) -3, 5-dimethylpyrrol-2-yl) methylene ] indolin-2-one;
5-ureido-3- [ (4- (2-carboxyethyl) -3-methylpyrrol-2-yl) methylene ] indolin-2-one;
5-ureido-3- [ (4- (2- (pyridin-3-ylmethyl) aminocarbonylethyl) -3-methylpyrrol-2-yl) methylene ] indolin-2-one;
5-ureido-3- [ (4- (2- (pyridin-4-yl) aminocarbonylethyl) -3-methylpyrrol-2-yl) methylene ] indolin-2-one;
5-ureido-3- [ (4- (2- (2-piperidin-1-ylethyl) aminocarbonylethyl) -3-methylpyrrol-2-yl) methylene ] indolin-2-one; and
5-ureido-3- [ (4- (2- (4-methylpiperazin-1-yl) carbonylethyl) -3-methylpyrrol-2-yl) methylene ] indolin-2-one.
6. The compound of claim 2, wherein:
m is 1;
n is 0 or 1;
a is oxygen;
R1is hydrogen or alkyl;
R2is-R8N(R7)2、-R8-N(R7)C(O)R7、-R8-N(R7)-R8-C(O)OR7、-R8-N(R7)C(O)N(R7)2、-R8-N(R7)-R9-C(O)N(R7)2or-R8-N(R7)C(O)-R9-N(R7)2；
R3Is hydrogen;
R5is hydrogen or alkyl;
R6independently selected from-R8-N(R7)2、-R8-N(R7)-R8-C(O)OR7、-R8-N(R7)C(O)R7、-R8-N(R7)C(O)N(R7)2、-R8-N(R7)C(O)-R9-N(R7)2、-R8-N(R7)C(O)-R9-C(O)OR7and-R8-N(R7)C(O)-R8-N(R7)-R8-C(O)OR7；
Each R7Independently hydrogen, optionally substituted alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl;
each R8Is a bond or a straight or branched alkylene chain; and is
Each R9Is a straight or branched alkylene chain.
7. The compound of claim 6 selected from the group consisting of:
5-ureido-3- [1- (4- (1, 1-dimethylethoxycarbonylaminomethyl) pyrrol-2-yl) ethylene ] indolin-2-one;
5-ureido-3- [1- (4- (aminomethyl) pyrrol-2-yl) ethylene ] indolin-2-one;
5-ureido-3- [1- (4- (acetamidomethyl) pyrrol-2-yl) ethylene ] indolin-2-one;
5-ureido-3- [1- (4- (((1, 1-dimethylethoxycarbonylamino) methyl) carbonylaminomethyl) pyrrol-2-yl) ethylene ] indolin-2-one;
5-ureido-3- [1- (4- (aminoacetamido) methylpyrrol-2-yl) ethylene ] indolin-2-one;
5-ureido-3- [1- (4- (pyridin-4-ylcarbonylamino) methylpyrrol-2-yl) ethylene ] indolin-2-one;
5-ureido-3- [1- (4- (hydroxyacetamido) methylpyrrol-2-yl) ethylene ] indolin-2-one;
5-ureido-3- [1- (4- (1- (1, 1-dimethylethoxycarbonyl) piperidin-4-ylcarbonylamino) methylpyrrol-2-yl) ethylene ] indolin-2-one;
5-ureido-3- [1- (4- (piperidin-4-ylcarbonylamino) methylpyrrol-2-yl) ethylene ] indolin-2-one;
5-ureido-3- [1- (4- ((1, 1-dimethylethoxycarbonyl) -acetylamino) methylpyrrol-2-yl) ethylene ] indolin-2-one;
5-ureido-3- [1- (4- (1- (1, 1-dimethylethoxycarbonyl) pyrrolidin-2-ylcarbonylamino) methylpyrrol-2-yl) ethylene ] indolin-2-one;
5-ureido-3- [1- (4- ((2- (1, 1-dimethylethoxycarbonylamino) ethyl) carbonylamino) methylpyrrol-2-yl) ethylene ] indolin-2-one;
5-ureido-3- [1- (4- (carboxyacetamido) methylpyrrol-2-yl) ethylene ] indolin-2-one;
5-ureido-3- [1- (4- (pyrrolidin-2-ylcarbonylamino) methylpyrrol-2-yl) ethylene ] indolin-2-one;
5-ureido-3- [1- (4- (pyridin-3-ylcarbonylamino) methylpyrrol-2-yl) ethylene ] indolin-2-one;
5-ureido-3- [1- (4- ((2-aminoethyl) carbonylamino) methylpyrrol-2-yl) ethylene ] indolin-2-one;
5-ureido-3- [1- ((4- ((1, 2-diaminoethyl) carbonylamino) methylpyrrol-2-yl) ethylene) indolin-2-one;
5-ureido-3- [1- (4- ((1-amino-2-methoxycarbonylethyl) carbonylamino) methylpyrrol-2-yl) ethylene ] indolin-2-one;
5-ureido-3- [1- (4- ((3-amino-1-acetamidoprop-1-yl) carbonylamino) methylpyrrole-2-yl) ethylene ] indolin-2-one;
5-ureido-3- [1- (4- (piperazin-2-ylcarbonylamino) methylpyrrol-2-yl) ethylene ] indolin-2-one;
5-ureido-3- [1- (4- (1-methylpiperidin-4-ylcarbonylamino) methylpyrrol-2-yl) ethylene ] indolin-2-one;
5-ureido-3- [1- (4- (2- (piperidin-1-yl) ethylcarbonylamino) methylpyrrol-2-yl) ethylene ] indolin-2-one;
5-ureido-3- [ (4- ((morpholin-4-ylmethyl) carbonylaminomethyl) pyrrol-2-yl) methylene ] indolin-2-one;
5-ureido-3- [ (4- ((piperidin-1-yl) acetamido) methylpyrrole-2-yl) methylene ] indolin-2-one;
5-acetamido-3- [1- (4-aminomethylpyrrol-2-yl) ethylene ] indolin-2-one;
5-amino-3- [1- (4- (2-aminoethylcarbamoylmethyl) pyrrol-2-yl) ethylene ] indolin-2-one; and
5-acetylamino-3- [1- (4- (2-aminoethylcarbamoylmethyl) pyrrol-2-yl) ethylene ] indolin-2-one.
8. The compound of claim 2, wherein:
m is 1;
n is 0 or 1;
a is oxygen;
R1is hydrogen or alkyl;
R2is-R8-N(R7)C(O)R7、-R8-N(R7)-R8-C(O)OR7、-R8-N(R7)C(O)N(R7)2、-R8-N(R7)-R9-C(O)N(R7)2or-R8-N(R7)C(O)-R9-N(R7)2；
R3Is hydrogen;
R5is hydrogen or alkyl;
R6independently selected from (optionally substituted by one or more groups selected from alkyl, halogen, haloalkyl, cyano, nitro, -R8-OR7、-R8-O-R9-C(O)OR7、-R8-N(R7)2、-R8-C(O)R7、-R8-C(O)OR7、-R8-C(O)N(R7)2、-R8-N(R7)C(O)OR7、-R8-N(R7)C(O)R7、-R8-S(O)pR7(wherein p is 0-2), -R8-S(O)pN(R7)2(wherein p is 0-2) and-R8-N(R7)C(O)-R8-N(R7)2Substituted with a substituent of (a) heterocyclic ringAnd (optionally substituted by one or more groups selected from-R)8-OR7、-R8-O-R9-C(O)OR7、-R8-C(O)R7、-R8-C(O)OR7、-R8-C(O)N(R7)2、-R8-N(R7)C(O)R7、-R8-N(R7)C(O)OR7、-R8-N(R7)2、-R8-N(R7)C(O)-R8-N(R7)-R8-C(O)OR7and-R8-S(O)tR7Aryl (wherein t is a substituent of 0 to 2);
each R7Independently hydrogen, optionally substituted alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl;
each R8Is a bond or a straight or branched alkylene chain; and is
Each R9Is a straight or branched alkylene chain.
9. The compound of claim 8 selected from the group consisting of:
5-ureido-3- [ (4- (3-methoxyphenyl) pyrrol-2-yl) methylene ] indolin-2-one;
5-ureido-3- [ (4- (4-methoxyphenyl) pyrrol-2-yl) methylene ] indolin-2-one;
5-ureido-3- [ (4- (3-hydroxyphenyl) pyrrol-2-yl) methylene ] indolin-2-one;
5-ureido-3- [ (4- (3-acetamidophenyl) pyrrol-2-yl) methylene ] indolin-2-one;
5-ureido-3- [ (4- (3-carboxyphenyl) pyrrol-2-yl) methylene ] indolin-2-one;
5-ureido-3- [ (4- (pyridin-3-yl) pyrrol-2-yl) methylene ] indolin-2-one;
5-ureido-3- [ (4- (3- (2-morpholin-4-ylethoxy) phenyl) pyrrol-2-yl) methylene ] indolin-2-one;
5-ureido-3- [ (4- (3-methoxycarbonylmethoxyphenyl) pyrrol-2-yl) methylene ] indolin-2-one;
5-ureido-3- [ (4- (4-methoxycarbonylphenyl) pyrrol-2-yl) methylene ] indolin-2-one;
5-ureido-3- [ (4- (3-aminocarbonylphenyl) pyrrol-2-yl) methylene ] indolin-2-one;
5-ureido-3- [ (4- (3, 4-dimethoxyphenyl) pyrrol-2-yl) methylene ] indolin-2-one;
5-ureido-3- [ (4- (4-carboxyphenyl) pyrrol-2-yl) methylene ] indolin-2-one;
5-ureido-3- [ (4- (3, 4-dihydroxyphenyl) pyrrol-2-yl) methylene ] indolin-2-one;
5-ureido-3- [ (4- (4- (1, 1-dimethylethoxycarbonylamino) methylphenyl) pyrrol-2-yl) methylene ] indolin-2-one;
5-ureido-3- [ (4- (3-aminomethylphenyl) pyrrol-2-yl) methylene ] indolin-2-one;
5-ureido-3- [ (4- (3-acetamidomethylphenyl) pyrrol-2-yl) methylene ] indolin-2-one;
5-ureido-3- [ (4- (3- (2-piperidin-1-ylethyl) aminocarbonylphenyl) pyrrol-2-yl) methylene ] indolin-2-one;
5-ureido-3- [ (4- (3- (1, 1-dimethylethoxycarbonyl) aminoacetaminomethylphenyl) pyrrol-2-yl) methylene ] indolin-2-one;
5-ureido-3- [ (4- (4-methylsulfonylphenyl) pyrrol-2-yl) methylene ] indolin-2-one;
5-ureido-3- [ (4- (4- (2-piperidin-1-ylethyl) aminocarbonylphenyl) pyrrol-2-yl) methylene ] indolin-2-one;
5-ureido-3- [ (4- (4- (2-dimethylaminoethyl) aminocarbonylphenyl) pyrrol-2-yl) methylene ] indolin-2-one;
5-ureido-3- [ (4- (4- (4-methylpiperazin-1-yl) carbonylphenyl) pyrrol-2-yl) methylene ] indolin-2-one;
5-ureido-3- [ (4- (3- (2-dimethylaminoethyl) aminocarbonylphenyl) pyrrol-2-yl) methylene ] indolin-2-one;
5-ureido-3- [ (4- (3- (4-methylpiperazin-1-yl) carbonylphenyl) pyrrol-2-yl) methylene ] indolin-2-one;
5-ureido-3- [ (4- (4- (3-hydroxypyrrolidin-1-yl) carbonylphenyl) pyrrol-2-yl) methylene ] indolin-2-one;
5-ureido-3- [ (4- (3- (3-hydroxypyrrolidin-1-yl) carbonylphenyl) pyrrol-2-yl) methylene ] indolin-2-one;
5-ureido-3- [ (4- (pyrimidin-5-yl) pyrrol-2-yl) methylene ] indolin-2-one; and
5-ureido-3- [ (4- (5-methoxypyridin-3-yl) pyrrol-2-yl) methylene ] indolin-2-one.
10. The compound of claim 2, wherein:
m is 1 to 2;
n is 0;
a is oxygen;
R1is (optionally substituted by one or more groups selected from-R)8-OR7、-R8-N(R7)2、-R8-C(O)N(R7)2、-R8-N(R7)C(O)N(R7)2、-R8-N(R7)C(O)-R9-N(R7)2and-R8-N(R7)C(O)OR7Substituted with a substituent of (a) aryl, or
R1Is (optionally substituted by one or more groups selected from alkyl, -R8-OR7、-R8-N(R7)2、-R8-N(R7)C(O)N(R7)2and-R8-N(R7)C(O)-R9-N(R7)2Substituted with the substituents) heterocyclic group, or
R1Is (optionally substituted by one or more groups selected from alkyl and-R8-OR7Substituted with the substituents of (a) or (b);
each R2Independently selected from-R8-N(R7)2、-R8-S(O)tN(R7)2(wherein t is 1 or 2), -R8-N(R7)C(O)N(R7)2and-R8-N(R7)C(O)-R9-N(R7)2；
R3Is hydrogen;
R5is hydrogen;
each R7Independently hydrogen, optionally substituted alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl;
each R8Is a bond or a straight or branched alkylene chain; and is
Each R9Is a straight or branched alkylene chain.
11. The compound of claim 10 selected from the group consisting of:
5-aminosulfonyl-3- [ (pyrrol-2-yl) (phenyl) methylene ] indolin-2-one;
5-ureido-3- [ (pyrrol-2-yl) (pyridin-4-yl) methylene ] indolin-2-one;
5-ureido-3- [ (pyrrol-2-yl) (pyridin-3-yl) methylene ] indolin-2-one;
5-ureido-3- [ (pyrrol-2-yl) (4-methoxyphenyl) methylene ] indolin-2-one;
5-ureido-3- [ (pyrrol-2-yl) (3-aminophenyl) methylene ] indolin-2-one;
5-ureido-3- [ (pyrrol-2-yl) (3- (1, 1-dimethylethoxycarbonylamino) phenyl) methylene ] indolin-2-one;
5-ureido-3- [ (pyrrol-2-yl) (2-methoxypyridin-5-yl) methylene ] indolin-2-one;
5-amino-3- [ (pyrrol-2-yl) (3- (5, 5-dimethyl-1, 3-dioxan-2-yl) propan-1-yl) methylene ] indolin-2-one; and
5-ureido-3- [ (pyrrol-2-yl) (3-aminoacetamidophenyl) methylene ] indolin-2-one.
12. The compound of claim 2, wherein:
m is 1 to 4;
n is 0;
a is oxygen;
R1is hydrogen or alkyl;
each R2Independently selected from heterocyclyl, -R8-N(R7)C(O)-R8-N(R7)-R8-C(O)-R8-N(R7)2、-R8-N＝C(R7)2、-R8-N(R7)C(O)-R8-N(R7)-R8-C(O)OR7、-N(R7)C(＝NR7)N(R7)2、-R8-N(R7)S(O)tN(R7)2(wherein t is 1 or 2), -R8-N(R7)S(O)tN(R7)C(O)OR7(wherein t is 1 or 2);
R3is hydrogen;
R5is hydrogen or alkyl;
each R7Independently hydrogen, optionally substituted alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl;
each R8Is a bond or a straight or branched alkylene chain.
13. The compound of claim 12 selected from the group consisting of:
5- (N' -aminocarbonylureido) -3- [ (pyrrol-2-yl) methylene ] indolin-2-one;
5-tetrazol-5-yl-3- [ (pyrrol-2-yl) methylene ] indolin-2-one;
4- (pyrrol-2-yl) methyleneamino-3- [ (pyrrol-2-yl) methylene ] indolin-2-one;
5- (N' - (ethoxycarbonylmethyl) ureido) -3- [1- (pyrrol-2-yl) ethylidene ] indolin-2-one;
5- ((1-pyrrol-2-yl) ethylene) aminomethyl-3- [1- (pyrrol-2-yl) ethylene ] indolin-2-one;
5- (2, 4-dioxoimidazolidin-1-yl) -3- [1- (pyrrol-2-yl) ethylene ] indolin-2-one;
5-guanidino-3- [1- (pyrrol-2-yl) ethylene ] indolin-2-one;
5-sulfamoylamino-3- [1- (pyrrol-2-yl) ethylene ] indolin-2-one; and
5- (1, 1-Dimethylethoxy) carbonylaminosulfonamido-3- [1- (pyrrol-2-yl) ethylene ] indolin-2-one.
14. The compound of claim 1, wherein:
m is 1 to 4;
n is 0 or 1;
a is oxygen;
R1is hydrogen or alkyl;
each R2Independently selected from-R8-N(R7)2and-R8-N(R7)S(O)tR7(wherein t is 1 or 2);
R3is hydrogen;
R5is hydrogen or alkyl;
R6is-R8-N(R7)2；
Each R7Independently hydrogen, optionally substituted alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl;
each R8Is a bond or a straight or branched alkylene chain.
15. The compound of claim 14 selected from the group consisting of:
6-amino-3- [ (pyrrol-2-yl) methylene ] indolin-2-one;
5-amino-3- [ (pyrrol-2-yl) methylene ] indolin-2-one;
5-methylsulfonylamino-3- [ (pyrrol-2-yl) methylene ] indolin-2-one;
5-aminomethyl-3- [ (pyrrol-2-yl) methylene ] indolin-2-one;
4-amino-3- [ (pyrrol-2-yl) methylene ] indolin-2-one;
5-amino-3- [1- (pyrrol-2-yl) ethylene ] indolin-2-one;
5-aminomethyl-3- [1- (pyrrol-2-yl) ethylene ] indolin-2-one;
5- (4, 5-dihydrooxazol-2-ylamino) -3- [1- (pyrrol-2-yl) ethylene ] indolin-2-one; and
5-amino-3- [ (4- (aminomethyl) pyrrol-2-yl) methylene ] indolin-2-one.
16. The compound of claim 1, wherein:
m is 0 to 4;
n is 0 to 3;
a is oxygen;
R1is hydrogen, alkyl, -C (O) OR7or-C (O) N (R)7)2；
Each R2Independently selected from alkyl, halogen, haloalkyl, cyano, -R8-OR7、-R8-C(O)OR7、-R8-C(O)N(R7)2and-R8-S(O)tN(R7)2(wherein t is 1 or 2);
R3is hydrogen or alkyl;
R5is hydrogen or alkyl;
each R6Independently selected from alkyl and nitro;
each R7Independently hydrogen, optionally substituted alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl;
each R8Is a bond or a straight or branched alkylene chain.
17. The compound of claim 16, selected from the group consisting of:
6-chloro-3- [ (pyrrol-2-yl) methylene ] indolin-2-one;
5-bromo-3- [ (pyrrol-2-yl) methylene ] indolin-2-one;
6-fluoro-3- [ (pyrrol-2-yl) methylene ] indolin-2-one;
6-methyl-3- [ ((1-methyl) pyrrol-2-yl) methylene ] indolin-2-one;
6-trifluoromethyl-3- [ (1-methylpyrrol-2-yl) methylene ] indolin-2-one;
5-methoxy-3- [ (pyrrol-2-yl) methylene ] indolin-2-one;
5, 6-dimethoxy-3- [ (pyrrol-2-yl) methylene ] indolin-2-one;
4-methyl-3- [ (pyrrol-2-yl) methylene ] indolin-2-one;
7-methyl-3- [ (pyrrol-2-yl) methylene ] indolin-2-one;
5-hydroxy-3- [ (pyrrol-2-yl) methylene ] indolin-2-one;
5-methyl-3- [ (pyrrol-2-yl) methylene ] indolin-2-one;
6-carboxy-3- [ (pyrrol-2-yl) methylene ] indolin-2-one;
5-methoxy-3- [ (5-ethylpyrrol-2-yl) methylene ] indolin-2-one;
5-hydroxy-3- [ (5-ethylpyrrol-2-yl) methylene ] indolin-2-one;
5-aminosulfonyl-3- [ (pyrrol-2-yl) methylene ] indolin-2-one;
3- [ (4-nitropyrrol-2-yl) methylene ] indolin-2-one;
7-methoxy-3- [ (pyrrol-2-yl) methylene ] indolin-2-one;
7-hydroxy-3- [ (pyrrol-2-yl) methylene ] indolin-2-one;
4-methoxy-3- [ (pyrrol-2-yl) methylene ] indolin-2-one;
4-hydroxy-3- [ (pyrrol-2-yl) methylene ] indolin-2-one;
5- (2-hydroxyethyl) aminosulfonyl-3- [ (pyrrol-2-yl) methylene ] indolin-2-one;
6-methoxy-3- [ (pyrrol-2-yl) methylene ] indolin-2-one;
6-hydroxy-3- [ (pyrrol-2-yl) methylene ] indolin-2-one;
5-dimethylaminosulfonyl-3- [ (pyrrol-2-yl) methylene ] indolin-2-one;
5-methylaminosulfonyl-3- [ (pyrrol-2-yl) methylene ] indolin-2-one;
5-hydroxy-3- [1- (pyrrol-2-yl) ethylene ] indolin-2-one;
5-methoxy-3- [1- (pyrrol-2-yl) ethylene ] indolin-2-one;
5-methoxy-4-methyl-3- [ (pyrrol-2-yl) methylene ] indolin-2-one;
5-hydroxy-4-methyl-3- [ (pyrrol-2-yl) methylene ] indolin-2-one;
5, 6-dihydroxy-3- [ (pyrrol-2-yl) methylene ] indolin-2-one;
5-carboxy-3- [ (pyrrol-2-yl) methylene ] indolin-2-one;
5-aminosulfonyl-3- [ (1-pyrrol-2-yl) ethylene ] indolin-2-one;
5-hydroxy-3- [ (4-methylpyrrol-2-yl) methylene ] indolin-2-one;
5-phenylaminosulfonyl-3- [ (pyrrol-2-yl) methylene ] indolin-2-one;
5-hydroxy-3- [ (5-methylpyrrol-2-yl) methylene ] indolin-2-one;
5-hydroxy-3- [ (3-methylpyrrol-2-yl) methylene ] indolin-2-one;
5-methoxy-3- [ (4-nitropyrrol-2-yl) methylene ] indolin-2-one;
5-methoxycarbonyl-3- [ (pyrrol-2-yl) methylene ] indolin-2-one;
5-aminocarbonyl-3- [ (pyrrol-2-yl) methylene ] indolin-2-one;
5-methoxy-3- [ (3, 5-dimethylpyrrol-2-yl) methylene ] indolin-2-one;
5-methoxy-1-methyl-3- [ (pyrrol-2-yl) methylene ] indolin-2-one;
5-hydroxy-1-methyl-3- [ (pyrrol-2-yl) methylene ] indolin-2-one;
5-hydroxy-3- [ (3, 5-dimethylpyrrol-2-yl) methylene ] indolin-2-one;
4-carboxy-3- [ (pyrrol-2-yl) methylene ] indolin-2-one;
5-cyano-3- [ (pyrrol-2-yl) methylene ] indolin-2-one;
4-methoxy-5-methoxycarbonyl-7-chloro-3- [ (pyrrol-2-yl) methylene ] indolin-2-one;
5-aminosulfonyl-3- [ (pyrrol-2-yl) (ethoxycarbonyl) methylene ] indolin-2-one;
5-aminosulfonyl-3- [ (pyrrol-2-yl) (carboxy) methylene ] indolin-2-one;
5-aminosulfonyl-3- [ (pyrrol-2-yl) (aminocarbonyl) methylene ] indolin-2-one;
5-cyano-3- [1- (pyrrol-2-yl) ethylene ] indolin-2-one;
5-aminocarbonyl-3- [3- (pyrrol-2-yl) ethylene ] indolin-2-one;
5-aminosulfonyl-3- [1- (pyrrol-2-yl) propylidene ] indolin-2-one;
5-aminosulfonyl-3- [ (pyrrol-2-yl) (N, N-diethylaminocarbonyl) methylene ] indolin-2-one; and
5-aminosulfonyl-3- [ (pyrrol-2-yl) (ethylaminocarbonyl) methylene ] indolin-2-one.
18. A compound of formula (II):
wherein:
m is 0 to 4;
a is oxygen or sulfur;
R1is hydrogen, alkyl, haloalkyl, -C (O) OR7or-C (O) N (R)7)2(ii) a Or
R1Is (optionally substituted with one or more groups selected from alkyl, aryl, aralkyl, halo, haloalkyl, cyano, nitro, -R8-OR7、-R8-N(R7)2、-R8-C(O)OR7、-R8-C(O)N(R7)2、-R8-N(R7)C(O)-R8-N(R7)2and-R8-N(R7)C(O)OR7Substituted with the substituents of (1) aryl); or
R1Is (optionally substituted with one or more groups selected from alkyl, aryl, aralkyl, halo, haloalkyl, cyano, nitro, -R8-OR7、-R8-N(R7)2、-R8-C(O)OR7、-R8-C(O)N(R7)2、-R8-N(R7)C(O)-R8-N(R7)2and-R8-N(R7)C(O)OR7Substituted with the substituent(s) of (a); or
R1Is (optionally substituted with one or more groups selected from alkyl, aryl, aralkyl, halo, haloalkyl, cyano, nitro, -R8-OR7、-R8-N(R7)2、-R8-C(O)OR7、-R8-C(O)N(R7)2、-R8-N(R7)C(O)-R8-N(R7)2and-R8-N(R7)C(O)OR7Substituted with the substituents of (1); or
R1Is (optionally substituted with one or more groups selected from alkyl, aryl, aralkyl, halo, haloalkyl, cyano, nitro, -R8-OR7、-R8-N(R7)2、-R8-C(O)OR7、-R8-C(O)N(R7)2、-R8-N(R7)C(O)-R8-N(R7)2and-R8-N(R7)C(O)OR7Substituted with the substituents of (a) or (b);
each R2Independently selected from alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, cyano, -R8-OR7、-R8-N(R7)2、-R8-C(O)OR7、-R8-C(O)N(R7)2、-R8-S(O)tN(R7)2(wherein t is 1 or 2), -R8-N(R7)S(O)tR7(wherein t is 1 or 2), -R8-N(R7)S(O)tN(R7)2(wherein t is 1 or 2), -R8-N(R7)S(O)tN(R7)C(O)OR7(wherein t is 1 or 2), -R8-N(R7)C(O)R7、-R8-N(R7)-R8-C(O)OR7、-R8-N(R7)C(O)-R8-N(R7)2、-R8-N(R7)C(O)-R8-N(R7)-R8-C(O)OR7、-R8-N(R7)C(O)-R8-N(R7)-R8-C(O)-R8-N(R7)2、-N(R7)C(＝NR7)N(R7)2、-C(＝NR7)-N(R7)2、-R8-N＝C(R7)2(optionally substituted with one or more groups selected from alkyl, aryl, aralkyl, halo, haloalkyl, cyano, nitro, -R8-OR7、-R8-C(O)OR7、-R8-C(O)N(R7)2、-R8-N(R7)2、-R8-N(R7)C(O)-R8-N(R7)2and-R8-N(R7)C(O)OR7Substituted with the substituents) heterocyclic group and optionally substituted cyclic ureido group;
R3is hydrogen, alkyl or aralkyl;
R4is (optionally substituted with one or more groups selected from alkyl, aryl, aralkyl, halo, haloalkyl, cyano, nitro, -R8-OR7、-R8-N(R7)2、-R8-C(O)OR7、-R8-C(O)N(R7)2、-R8-N(R7)C(O)-R8-N(R7)2and-R8-N(R7)C(O)OR7Substituted with the substituents of (1) naphthyl; or
R4Is (optionally substituted with one or more groups selected from alkyl, aryl, aralkyl, halo, haloalkyl, cyano, nitro, -R8-OR7、-R8-OC(O)OR7、-R8-N(R7)2、-R8-C(O)OR7、-R8-C(O)N(R7)2、-R8-N(R7)C(O)-R8-N(R7)2and-R8-N(R7)C(O)OR7Substituted with the substituents of (1);
each R7Independently selected from hydrogen, alkyl, -R9-OR7Haloalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl;
each R8Is a bond or a straight or branched alkylene chain; and is
Each R9Is a straight or branched alkylene chain;
the compound of formula (II) is a single stereoisomer, a mixture of stereoisomers, or a racemic mixture of stereoisomers; or is a solvate or polymorph; or a pharmaceutically acceptable salt thereof;
the conditions were as follows:
(1) when m is2, A is oxygen, R1And R3Each being hydrogen, one R2Is 5-nitro and the other R is2When is 4-bromo, then R4Cannot be 5-methylimidazol-4-yl;
(2) when m is2, A is oxygen, R1And R3Each being hydrogen, one R2Is 5-fluoro and the other R2When it is 4-iodo or 4- (1, 3-benzodioxol-5-yl), then R4Cannot be 5-methylimidazol-4-yl;
(3) when m is 1, A is oxygen, R1And R3Each is hydrogen, and R2When it is 4- (2-hydroxyethyl), then R4Cannot be pyridin-2-yl, 6-methylpyridin-2-yl, indol-5-yl or 3-hydroxy-6-methylpyridin-2-yl;
(4) when m is 1, A is oxygen, R1And R3Each is hydrogen, and R2When it is 5-bromo or 5-ethynyl, then R4Cannot be 5-methylimidazol-4-yl;
(5) when m is 0, A is oxygen, and R1And R3When each is hydrogen, then R4Cannot be pyridin-4-yl, 4-methylthiothien-2-yl, 5-methylthiothien-2-yl, 3-methylthiothien-2-yl, furan-2-yl, thien-2-yl, 5- [3, 5-bis (trifluoromethyl) phenyl]Furan-2-yl, 5-iodofuran-2-yl, 4-ethoxycarbonyl-5-methylfuran-2-yl, 3-bromothien-2-yl, 5-chlorothien-2-yl, 4, 5-dimethylfuran-2-yl, 5-nitrothien-2-yl, 5-carboxythien-2-yl, 5-bromothien-2-yl, 4-bromothien-2-yl, 5-sulfonylfuran-2-yl, furan-2-yl, 5-methylfuran-2-yl, 5-ethylfuran-2-yl, 5-nitrofuran-2-yl, 5-bromofuran-2-yl, 5-methylfuran-2-yl, 5-ethylthiophen-2-yl, 5-methylimidazol-2-yl, 5-methylthiazol-2-yl, 5-methylpyrazol-3-yl, imidazol-4-yl, 4-chloropyrazol-3-yl, 2- (4-chlorobenzyl) -4-bromopyrazol-3-yl, 4-chloro-1-methylpyrazol-3-yl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl, 5-phenyl-1, 2, 4-oxadiazol-3-yl, 3-phenyl-1, 2, 4-oxadiazol-5-yl, 3-phenyl-1, 2, 5-oxadiazol-4-yl, 5-methylpyrazol-3-yl, 5-thiadiazol-yl, and pharmaceutically acceptable salts thereof, 3-methylthiophen-2-yl, 5-methylimidazolyl-2-yl, bicyclo [2.2.1 ]]Hept-5-en-2-yl, indol-3-yl; pyridin-4-yl or pyridin-2-yl;
(6) when m is 1, A is oxygen, R1And R3Each is hydrogen, and R2When it is 5-chloro or 5-nitro, then R4Cannot be indol-3-yl, thiophen-2-yl, 3-methylthiothiophen-2-yl, 5-ethylthiophen-2-yl, 5-methylthiothiophen-2-yl or imidazol-2-yl;
(7) when m is2, A is oxygen, R1And R3Each is hydrogen, and R4When it is 5-methylimidazol-4-yl, then together two R2The group cannot be 4-fluoro-5-nitro, 4-azido-5-nitro, 4-amino-5-nitro or 4, 5-diamino;
(8) when m is 1, A is oxygen, R1And R3Each is hydrogen, and R2is-S (O)2N(R7) H (wherein R7Is hydrogen, alkyl or hydroxyalkyl), then R4Not 4, 5,6, 7-tetrahydroindol-2-yl, which cannot be optionally substituted; and
(9) when m is 0, A is oxygen, R1And R3Each being hydrogen, R4And not 4-dimethylaminonaphthyl.
19. The compound of claim 18, wherein:
m is 0 to 4;
a is oxygen;
R1is hydrogen or alkyl;
each R2Independently selected from halogen, haloalkyl, haloalkenyl, -R8-OR7and-R8-N(R7)C(O)-R8-N(R7)2；
R3Is hydrogen or alkyl;
R4is naphthyl, pyridyl, (optionally substituted by one or more groups selected from alkyl and-R8-OC(O)R7Substituted with a substituent of (a) furyl, indolyl, (optionally substituted with one or more alkyl) imidazolyl, quinolyl or (optionally substituted with one or more substituents selected from alkyl, halogen and phenyl) pyrazolyl;
each R7Is independently selected fromHydrogen, alkyl, -R9-OR7Haloalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl;
each R8Is a bond or a straight or branched alkylene chain; and is
Each R9Is a straight or branched alkylene chain.
20. The compound of claim 19 selected from the group consisting of:
5-ureido-3- [1- (imidazol-4-yl) ethylene ] indolin-2-one;
5-hydroxy-3- [ (imidazol-4-yl) methylene ] indolin-2-one;
5-hydroxy-3- [ (imidazol-2-yl) methylene ] indolin-2-one;
3- [ (imidazol-4-yl) methylene ] indolin-2-one;
3- [ (imidazol-2-yl) methylene ] indolin-2-one;
6-fluoro-3- [ (pyridin-2-yl) methylene ] indolin-2-one;
6-fluoro-3- [ (pyridin-4-yl) methylene ] indolin-2-one;
5-bromo-3- [ (pyridin-4-yl) methylene ] indolin-2-one;
3- [ (pyridin-3-yl) methylene ] indolin-2-one;
6-fluoro-3- [ (furan-2-yl) methylene ] indolin-2-one;
3- [ (5-methylfuran-2-yl) methylene ] indolin-2-one;
3- [ (5- (acetoxymethyl) furan-2-yl) methylene ] indolin-2-one;
3- [ (naphthalen-1-yl) methylene ] indolin-2-one;
3- [ (naphthalen-2-yl) methylene ] indolin-2-one;
6-fluoro-3- [ (indol-3-yl) methylene ] indolin-2-one;
3- [ (quinolin-4-yl) methylene ] indolin-2-one;
3- [ (5-methylimidazol-4-yl) methylene ] indolin-2-one;
3- [ (1, 3-dimethyl-5-chloropyrazol-4-yl) methylene ] indolin-2-one; and
3- [ (3-phenylpyrazol-4-yl) methylene ] indolin-2-one.
21. A method of treating a mammal having a disease state alleviated by the inhibition of PDK-1 activity, wherein the method comprises administering to the mammal a therapeutically effective amount of a compound of formula (I):
wherein:
m is 0 to 4;
n is 0 to 3;
a is oxygen or sulfur;
R1is hydrogen, alkyl, -C (O) OR7or-C (O) N (R)7)2(ii) a Or
R1Is (optionally substituted with one or more groups selected from alkyl, aryl, aralkyl, halo, haloalkyl, cyano, nitro, -R8-OR7、-R8-N(R7)2、-R8-C(O)OR7、-R8-C(O)N(R7)2、-R8-N(R7)C(O)N(R7)2、-R8-N(R7)C(O)-R9-N(R7)2and-R8-N(R7)C(O)OR7Substituted with the substituents of (1) aryl); or
R1Is (optionally substituted with one or more groups selected from alkyl, aryl, aralkyl, halo, haloalkyl, cyano, nitro, -R8-OR7、-R8-N(R7)2、-R8-C(O)OR7、-R8-C(O)N(R7)2、-R8-N(R7)C(O)N(R7)2、-R8-N(R7)C(O)-R9-N(R7)2and-R8-N(R7)C(O)OR7Substituted with the substituent(s) of (a); or
R1Is (optionally substituted with one or more groups selected from alkyl, aryl, aralkyl, halo, haloalkyl, cyano, nitro, -R8-OR7、-R8-N(R7)2、-R8-N(R7)C(O)N(R7)2、-R8-N(R7)C(O)-R9-N(R7)2and-R8-N(R7)C(O)OR7Substituted with the substituents of (1); or
R1Is (optionally substituted with one or more groups selected from alkyl, aryl, aralkyl, halo, haloalkyl, cyano, nitro, -R8-OR7、-R8-C(O)OR7、-R8-C(O)N(R7)2、-R8-N(R7)2、-R8-N(R7)C(O)N(R7)2、-R8-N(R7)C(O)-R9-N(R7)2and-R8-N(R7)C(O)OR7Substituted with the substituents of (a) or (b);
each R2Independently selected from alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, cyano, -R8-OR7、-R8-N(R7)2、-R8-C(O)OR7、-R8-C(O)N(R7)2、-R8-S(O)tN(R7)2(wherein t is 1 or 2), -R8-N(R7)S(O)tR7(wherein t is 1 or 2), -R8-N(R7)S(O)tN(R7)2(wherein t is 1 or 2), -R8-N(R7)S(O)tN(R7)C(O)OR7(wherein t is 1 or 2), -R8-N(R7)C(O)R7、-R8-N(R7)-R8-C(O)OR7、-R8-N(R7)C(O)N(R7)2、-R8-N(R7)C(O)-R9-N(R7)2、-R8-N(R7)-R9-C(O)N(R7)2、-R8-N(R7)C(O)-R8-N(R7)-R8-C(O)OR7、-R8-N(R7)C(O)-R8-N(R7)-R8-C(O)-R8-N(R7)2、-N(R7)C(＝NR7)N(R7)2、-C(＝NR7)-N(R7)2、-R8-N＝C(R7)2(optionally substituted with one or more groups selected from alkyl, aryl, aralkyl, halo, haloalkyl, cyano, nitro, -R8-OR7、-R8-C(O)OR7、-R8-C(O)N(R7)2、-R8-N(R7)2、-R8-N(R7)C(O)-R8-N(R7)2and-R8-N(R7)C(O)OR7Substituted with the substituents) heterocyclic group and optionally substituted cyclic ureido group;
R3is hydrogen, alkyl or aralkyl;
R5is hydrogen, alkyl, aryl, aralkyl, -C (O) R11or-S (O)2R11；
Each R6Independently selected from alkyl, alkenyl, alkynyl, halogen, haloalkyl, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, -R9-OR7、-R8-C(O)OR7、-R8-C(O)N(R7)2、-R8-C(O)R7、-R8-N(R7)2、-R8-N(R7)C(O)R7、-R8-C(O)-R9-N(R7)2、-R8-N(R7)-R8-C(O)OR7、-R8-N(R7)C(O)N(R7)2、-R8-N(R7)C(O)-R9-N(R7)2、-R8-N(R7)C(O)-R10-N(R7)2、-R8-N(R7)C(O)-R8-N(R7)C(O)-R8-N(R7)2、-R8-C(O)-R9-C(O)OR7、-R8-C(O)-R9-C(O)N(R7)2、-R8-N(R7)C(O)-R8-N(R7)-R8-C(O)OR7、-R8-N(R7)C(O)-R8-N(R7)-R8-C(O)N(R7)2、-R8-N(R7)C(O)-R9-C(O)OR7、-R8-N(R7)C(O)-R9-C(O)N(R7)2、-R8-S(O)t-N(R7)2(wherein t is 1 or 2), -R8-N(R7)S(O)t-R8-N(R7)2(wherein t is 1 or 2) and-R8-N(R7)S(O)t-R7(wherein t is 1 or 2);
each R7Independently hydrogen, optionally substituted alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl;
each R8Is a bond or a straight or branched alkylene chain;
each R9Is a straight or branched alkylene chain;
R10is an amino acid residue other than a straight or branched alkylene chain; and is
Each R11Is optionally substituted alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl;
the compounds of formula (I) are single stereoisomers, mixtures of stereoisomers, solvates or polymorphs.
22. The method of claim 21, wherein the mammal is a human.
23. The method of claim 22, wherein the disease state is cancer.
24. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of formula (I) or a pharmaceutically acceptable salt thereof:
wherein:
m is 0 to 4;
n is 0 to 3;
a is oxygen or sulfur;
R1is hydrogen, alkyl, -C (O) OR7or-C (O) N (R)7)2(ii) a Or
R1Is (optionally substituted with one or more groups selected from alkyl, aryl, aralkyl, halo, haloalkyl, cyano, nitro, -R8-OR7、-R8-N(R7)2、-R8-C(O)OR7、-R8-C(O)N(R7)2、-R8-N(R7)C(O)N(R7)2、-R8-N(R7)C(O)-R9-N(R7)2and-R8-N(R7)C(O)OR7Substituted with the substituents of (1) aryl); or
R1Is (optionally substituted with one or more groups selected from alkyl, aryl, aralkyl, halo, haloalkyl, cyano, nitro, -R8-OR7、-R8-N(R7)2、-R8-C(O)OR7、-R8-C(O)N(R7)2、-R8-N(R7)C(O)N(R7)2、-R8-N(R7)C(O)-R9-N(R7)2and-R8-N(R7)C(O)OR7Substituted with the substituent(s) of (a); or
R1Is (optionally substituted with one or more groups selected from alkyl, aryl, aralkyl, halo, haloalkyl, cyano, nitro, -R8-OR7、-R8-N(R7)2、-R8-N(R7)C(O)N(R7)2、-R8-N(R7)C(O)-R9-N(R7)2and-R8-N(R7)C(O)OR7Substituted with the substituents of (1); or
R1Is (optionally substituted with one or more groups selected from alkyl, aryl, aralkyl, halo, haloalkyl, cyano, nitro, -R8-OR7、-R8-C(O)OR7、-R8-C(O)N(R7)2、-R8-N(R7)2、-R8-N(R7)C(O)N(R7)2、-R8-N(R7)C(O)-R9-N(R7)2and-R8-N(R7)C(O)OR7Substituted with the substituents of (a) or (b);
each R2Independently selected from alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, cyano, -R8-OR7、-R8-N(R7)2、-R8-C(O)OR7、-R8-C(O)N(R7)2、-R8-S(O)tN(R7)2(wherein t is 1 or 2), -R8-N(R7)S(O)tR7(wherein t is 1 or 2), -R8-N(R7)S(O)tN(R7)2(wherein t is 1 or 2), -R8-N(R7)S(O)tN(R7)C(O)OR7(wherein t is 1 or 2), -R8-N(R7)C(O)R7、-R8-N(R7)-R8-C(O)OR7、-R8-N(R7)C(O)N(R7)2、-R8-N(R7)C(O)-R9-N(R7)2、-R8-N(R7)-R9-C(O)N(R7)2、-R8-N(R7)C(O)-R8-N(R7)-R8-C(O)OR7、-R8-N(R7)C(O)-R8-N(R7)-R8-C(O)-R8-N(R7)2、-N(R7)C(＝NR7)N(R7)2、-C(＝NR7)-N(R7)2、-R8-N＝C(R7)2(optionally substituted with one or more groups selected from alkyl, aryl, aralkyl, halo, haloalkyl, cyano, nitro, -R8-OR7、-R8-C(O)OR7、-R8-C(O)N(R7)2、-R8-N(R7)2、-R8-N(R7)C(O)-R8-N(R7)2and-R8-N(R7)C(O)OR7Substituted with the substituents) heterocyclic group and optionally substituted cyclic ureido group;
R3is hydrogen, alkyl or aralkyl;
R5is hydrogen, alkyl, aryl, aralkyl, -C (O) R11or-S (O)2R11；
Each R6Independently selected from alkyl, alkenyl, alkynyl, halogen, haloalkyl, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, -R9-OR7、-R8-C(O)OR7、-R8-C(O)N(R7)2、-R8-C(O)R7、-R8-N(R7)2、-R8-N(R7)C(O)R7、-R8-C(O)-R9-N(R7)2、-R8-N(R7)-R8-C(O)OR7、-R8-N(R7)C(O)N(R7)2、-R8-N(R7)C(O)-R9-N(R7)2、-R8-N(R7)C(O)-R10-N(R7)2、-R8-N(R7)C(O)-R8-N(R7)C(O)-R8-N(R7)2、-R8-C(O)-R9-C(O)OR7、-R8-C(O)-R9-C(O)N(R7)2、-R8-N(R7)C(O)-R8-N(R7)-R8-C(O)OR7、-R8-N(R7)C(O)-R8-N(R7)-R8-C(O)N(R7)2、-R8-N(R7)C(O)-R9-C(O)OR7、-R8-N(R7)C(O)-R9-C(O)N(R7)2、-R8-S(O)t-N(R7)2(wherein t is 1 or 2), -R8-N(R7)S(O)t-R8-N(R7)2(wherein t is 1 or 2) and-R8-N(R7)S(O)t-R7(wherein t is 1 or 2);
each R7Independently hydrogen, optionally substituted alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl;
each R8Is a bond or a straight or branched alkylene chain;
each R9Is a straight or branched alkylene chain;
R10is an amino acid residue other than a straight or branched alkylene chain; and is
Each R11Is optionally substituted alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl;
the compound of formula (I) is a single stereoisomer, a mixture of stereoisomers, a solvate or a polymorph;
the conditions were as follows:
(1) when m is 1, n is 1, A is oxygen, R1、R3And R5Each is hydrogen, and R6When it is 3-methoxy, then R2Cannot be 4-bromo, 4-iodo, 5-bromo;
(2) when m is 1, n is 0, A is oxygen, R1、R3And R5When each is hydrogen, then R2Cannot be 5-bromo, 5-iodo or 4-bromo;
(3) when R is6When it is 3-methoxy, then R2Not an optionally substituted ethenyl or ethynyl group;
(4) when m is2, n is 1, A is oxygen, R1、R3And R5Each is hydrogen, and R6When it is methoxy, then when one R is2Another R when it is 5-nitro2Cannot be 4-bromo;
(5) when m is 0, n is2, A is oxygen, R3And R5Each is hydrogen, and one R6Is 3-methyl and the other R6When it is 5-methyl, then R1Not being hydrogen, -C (O) OR7or-C (O) N (R)7)2；
(6) When m isIs 0, n is 0, A is oxygen, and R is1And R3When each is hydrogen, then R5Cannot be hydrogen;
(7) when m is 1, n is 0, A is oxygen, and R1、R3And R5When each is hydrogen, then R2Cannot be 4-methyl, 4-bromo, 4-thiophen-2-yl or 2, 6-dimethoxypyrimidin-4-yl;
(8) when m is 1, n is 1, A is oxygen, R1、R3And R5Each is hydrogen, and R6When it is 3-methoxy, then R2Cannot be 4-indol-5-yl, 4-indol-6-yl or 4-indol-4-yl;
(9) when m is 1, n is 1, R1、R3And R5Each is hydrogen, R6Is 3-methoxy, and one R2When it is 4-indol-6-yl, then another R2Cannot be 5-nitro, 5-amino or 5- (thien-2-ylacetamino);
(10) when m is2, n is 0 or1, A is oxygen, R1、R3And R5Each is hydrogen, and R6When it is 3-methoxy, then when one R is2Another R when it is 5-amino2Cannot be a 4-amino group;
(11) when m is2, n is 0 or1, A is oxygen, R1、R3And R5Each is hydrogen, and R6When it is 3-methoxy, then when one R is2Another R when it is 4-fluoro or 4-azido2Cannot be 5-nitro;
(12) when m is 0, n is 3, A is oxygen, R1、R3And R5Each is hydrogen, and one R6Is 3-methyl and a second R6When it is 5-methyl, then the third R6Cannot be 4- (2-carboxyethyl), 4- (3-morpholin-4-ylpropyl) or 4- (3-dimethylaminopropyl);
(13) when m is 1, n is2, A is oxygen, R1、R3And R5Each is hydrogen, and one R6Is 3-methyl and the other R6Is 4- (2-carboxyethyl) or 4- [2- (3, 5-dimethoxybenzyloxycarbonyl) ethyl]When then R is2Not being 5-chloro, 6-methoxy, 5-bromo, 5-iodo, 4-methyl, 5-methyl, 6-chloro, 5-methoxycarbonyl, 5-carboxy, 5-aminosulfonylA group, 5-methylaminosulfonyl, 5- (2-carboxyethyl), 5-ethyl, 5-methoxy, 6-hydroxy, 6-bromo, or 6-bromo;
(14) when m is 1, n is 3, A is oxygen, R1、R3And R5Each is hydrogen, and one R6Is 3-methyl and a second R6Is 5-methyl, the third R6Is 4- (2-carboxyethyl), 4- (3-dimethylaminopropyl) or 4- (3-morpholin-4-ylpropyl), then R2But not 5-chloro, 5-bromo, 5-iodo, 4-methyl, 5-methyl, 6-hydroxy, 6-methoxy, 6-morpholin-4-yl, 6-chloro, 5-methoxy, 4- (2-hydroxyethyl), 5-aminosulfonyl, 5- (1-methylethylaminosulfonyl), 5- (morpholin-4-ylsulfonyl) or 5- (dimethylaminocarbonyl);
(15) when m is 0, n is2, A is oxygen, R1、R3And R5Each is hydrogen, and one R6When it is 3-methoxy, then another R6Cannot be 5-methyl or 4- (2-carboxyethyl);
(16) when m is2, n is2, A is oxygen, R1、R3And R5Each being hydrogen, one R6Is 4- (12-carboxyethyl), and a second R6When it is 3-methyl, then two R are2' cannot be 5, 6-dimethoxy or 4-methyl-5-chloro;
(17) when m is2, n is 3, A is oxygen, R1、R3And R5Each being hydrogen, one R6Is 3-methyl and a second R6Is 5-methyl, and a third R6When it is 4- (2-carboxyethyl), then R2' cannot be 4-methyl and 5-chloro;
(18) when m is 0, n is 0, A is oxygen, R1And R5When each is hydrogen, then R5Not hydrogen, methyl, 4-chlorophenyl or 3, 5-dichlorophenyl;
(19) when m is 0, n is 1, A is oxygen, R1、R3And R5When each is hydrogen, then R2Cannot be 3-methyl or 5-ethyl;
(20) when m is 0, n is2, A is oxygen, R1、R3And R5Each being hydrogen, then together R2' cannot be 3, 4-dimethyl, 3, 5-dimethyl,3-methyl-4- [ 2-carboxyethyl group]3-methyl-4- [ 2-methoxycarbonylethyl]Or 4-methyl-3-ethoxycarbonyl;
(21) when m is 0, n is 3, A is oxygen, R1、R3And R5Each being hydrogen, then together R2' cannot be 4- [ ethoxycarbonyl]-3, 5-dimethyl, 5-methyl-3, 4-dibromo, 5-formyl-3, 4-dimethyl, 3-ethyl-4, 5-dimethyl, 5-ethoxycarbonyl-4- [ 2-ethoxycarbonylethyl]-3- [ ethoxycarbonylmethyl group]5-carboxy-3-ethyl-4-methyl, 4-methyl-3, 5-dichloro, 5-chloro-3-methoxycarbonyl-4- [ methoxycarbonylmethyl [ ]]3-acetyl-5-ethoxycarbonyl-4-methyl, 5-ethoxycarbonyl-3- (2-ethoxycarboxyethyl) -4- (ethoxycarbonylmethyl), 4-ethyl-3, 5-dimethyl, 4-prop-3-enyl-3, 5-dimethyl;
(22) when m is 1, n is 0, A is oxygen, R1、R3And R5When each is hydrogen, then R2Cannot be 5-chloro or 5-nitro;
(23) when m is 1, n is 1, A is oxygen, R1、R3And R5Each is hydrogen, R6When it is 3-methyl, then R2Cannot be 5-nitro or 5-chloro;
(24) when m is 1, n is2, A is oxygen, R1、R3And R5Each is hydrogen, and R6When' is 3, 5-dimethyl, then R2Cannot be 5-nitro or 5-chloro;
(25) when m is2, n is 0 or1, A is oxygen, R1、R3And R5Each is hydrogen, R6Is 3-methoxy, and one R2When it is 4-amino, then another R2Cannot be a 5-amino group;
(26) when m is2, n is 0 or1, A is oxygen, R1、R3And R5Each is hydrogen, R6Is 3-methoxy, and one R2When it is 5-nitro, then another R2Cannot be 4-fluoro or 4-azido;
(27) when m is 1, n is 3, A is oxygen, R1、R3And R5Each is hydrogen, and one R6Is 3-methyl, a second R6Is 5-methyl and the third R6Is 4- (3-dimethylaminopropyl) or 4- (2-carboxyethyl)) When then R is2Cannot be 6- (pyridin-3-yl), 6- (thiophen-2-yl), 4- (2-hydroxyethyl) or 4- (2- (3- (1-methylethyl) phenoxy) ethyl;
(28) when m is 0, n is2, A is oxygen, R3And R5Each is hydrogen, and one R6Is 3-methyl and a second R6When it is 5-methyl, then R1Cannot be 4-methoxyphenyl or 3, 4-dimethoxyphenyl;
(29) when m is2, n is 1, A is oxygen, R1、R3And R5Each is hydrogen, and one R2Is 4-amino and a second R2When it is 5-amino, then R6Cannot be 3-methoxy;
(30) when m is2, n is 1, A is oxygen, R1、R3And R5Each is hydrogen, and one R2Is 4-fluoro or 4-azido, and a second R2When it is 5-nitro, then R6Cannot be 3-methoxy;
(31) when m is 0 or1, n is 3, A is oxygen, R1、R3And R5Each is hydrogen, and one R6Is 5-methyl and a second R6Is 3-methyl or 3-phenyl (optionally substituted by fluoro, chloro or cyano), the third R6is-C (O) OH or one of R7Is hydrogen or methyl and the other R7Is an alkyl group optionally substituted by hydroxy, diethylamino and/or an optionally substituted N-heterocyclic group, -C (O) N (R)7)2When then R is2Halogen not in position 5, trifluoromethoxy, -C (O) R7(wherein R is7Is morpholinyl) or-C (O) N (R)7)2(wherein each R is7Independently hydrogen, hydroxyalkyl, alkyl or phenyl); and
(32) m is 1, when n is 3, A is oxygen, R1、R3And R5Each is hydrogen, and one R6Is 3-methyl and a second R6Is 5-methyl, the third R6is-C (O) R in the 4-position7(wherein R is7Is optionally substituted N-heterocyclyl), then R6In which R cannot be in the 4-position7is-C (O) R of an optionally substituted N-heterocyclyl7，R2And not halogen or 3-pyridyl.
25. A method of treating a mammal having a disease state alleviated by the inhibition of PDK-1 activity, wherein the method comprises administering to the mammal a therapeutically effective amount of a compound of formula (II):
wherein:
m is 0 to 4;
a is oxygen or sulfur;
R1is hydrogen, alkyl, haloalkyl, -C (O) OR7or-C (O) N (R)7)2(ii) a Or
R1Is (optionally substituted with one or more groups selected from alkyl, aryl, aralkyl, halo, haloalkyl, cyano, nitro, -R8-OR7、-R8-N(R7)2、-R8-C(O)OR7、-R8-C(O)N(R7)2、-R8-N(R7)C(O)-R8-N(R7)2and-R8-N(R7)C(O)OR7Substituted with the substituents of (1) aryl); or
R1Is (optionally substituted with one or more groups selected from alkyl, aryl, aralkyl, halo, haloalkyl, cyano, nitro, -R8-OR7、-R8-N(R7)2、-R8-C(O)OR7、-R8-C(O)N(R7)2、-R8-N(R7)C(O)-R8-N(R7)2and-R8-N(R7)C(O)OR7Substituted with the substituent(s) of (a); or
R1Is (optionally substituted with one or more groups selected from alkyl, aryl, aralkyl, halo, haloalkyl, cyano, nitro, -R8-OR7、-R8-N(R7)2、-R8-C(O)OR7、-R8-C(O)N(R7)2、-R8-N(R7)C(O)-R8-N(R7)2and-R8-N(R7)C(O)OR7Substituted with the substituents of (1); or
R1Is (optionally substituted with one or more groups selected from alkyl, aryl, aralkyl, halo, haloalkyl, cyano, nitro, -R8-OR7、-R8-N(R7)2、-R8-C(O)OR7、-R8-C(O)N(R7)2、-R8-N(R7)C(O)-R8-N(R7)2and-R8-N(R7)C(O)OR7Substituted with the substituents of (a) or (b);
each R2Independently selected from alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, cyano, -R8-OR7、-R8-N(R7)2、-R8-C(O)OR7、-R8-C(O)N(R7)2、-R8-S(O)tN(R7)2(wherein t is 1 or 2), -R8-N(R7)S(O)tR7(wherein t is 1 or 2), -R8-N(R7)S(O)tN(R7)2(wherein t is 1 or 2), -R8-N(R7)S(O)tN(R7)C(O)OR7(wherein t is 1 or 2), -R8-N(R7)C(O)R7、-R8-N(R7)-R8-C(O)OR7、-R8-N(R7)C(O)-R8-N(R7)2、-R8-N(R7)C(O)-R8-N(R7)-R8-C(O)OR7、-R8-N(R7)C(O)-R8-N(R7)-R8-C(O)-R8-N(R7)2、-N(R7)C(＝NR7)N(R7)2、-C(＝NR7)-N(R7)2、-R8-N＝C(R7)2(optionally substituted with one or more groups selected from alkyl, aryl, aralkyl, halo, haloalkyl, cyano, nitro, -R8-OR7、-R8-C(O)OR7、-R8-C(O)N(R7)2、-R8-N(R7)2、-R8-N(R7)C(O)-R8-N(R7)2and-R8-N(R7)C(O)OR7Substituted with the substituents) heterocyclic group and optionally substituted cyclic ureido group;
R3is hydrogen, alkyl or aralkyl;
R4is (optionally substituted with one or more groups selected from alkyl, aryl, aralkyl, halo, haloalkyl, cyano, nitro, -R8-OR7、-R8-N(R7)2、-R8-C(O)OR7、-R8-C(O)N(R7)2、-R8-N(R7)C(O)-R8-N(R7)2and-R8-N(R7)C(O)OR7Substituted with the substituents of (1) naphthyl; or
R4Is (optionally substituted with one or more groups selected from alkyl, aryl, aralkyl, halo, haloalkyl, cyano, nitro, -R8-OR7、-R8-OC(O)OR7、-R8-N(R7)2、-R8-C(O)OR7、-R8-C(O)N(R7)2、-R8-N(R7)C(O)-R8-N(R7)2and-R8-N(R7)C(O)OR7Substituted with the substituents of (1);
each R7Independently selected from hydrogen, alkyl, -R9-OR7Haloalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl;
each R8Is a bond or a straight or branched alkylene chain; and is
Each R9Is a straight or branched alkylene chain;
the compound of formula (II) is a single stereoisomer, a mixture of stereoisomers, or a racemic mixture of stereoisomers; or is a solvate or polymorph; or a pharmaceutically acceptable salt thereof.
26. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of formula (II):
wherein:
m is 0 to 4;
a is oxygen or sulfur;
R1is hydrogen, alkyl, haloalkyl, -C (O) OR7or-C (O) N (R)7)2(ii) a Or
R1Is (optionally substituted with one or more groups selected from alkyl, aryl, aralkyl, halo, haloalkyl, cyano, nitro, -R8-OR7、-R8-N(R7)2、-R8-C(O)OR7、-R8-C(O)N(R7)2、-R8-N(R7)C(O)-R8-N(R7)2and-R8-N(R7)C(O)OR7Substituted with the substituents of (1) aryl); or
R1Is (optionally substituted with one or more groups selected from alkyl, aryl, aralkyl, halo, haloalkyl, cyano, nitro, -R8-OR7、-R8-N(R7)2、-R8-C(O)OR7、-R8-C(O)N(R7)2、-R8-N(R7)C(O)-R8-N(R7)2and-R8-N(R7)C(O)OR7Substituted with the substituent(s) of (a); or
R1Is (optionally substituted with one or more groups selected from alkyl, aryl, aralkyl, halo, haloalkyl, cyano, nitro, -R8-OR7、-R8-N(R7)2、-R8-C(O)OR7、-R8-C(O)N(R7)2、-R8-N(R7)C(O)-R8-N(R7)2and-R8-N(R7)C(O)OR7Substituted with the substituents of (1); or
R1Is (optionally substituted by one or more groups selected from alkyl, arylAlkyl, halogen, haloalkyl, cyano, nitro, -R8-OR7、-R8-N(R7)2、-R8-C(O)OR7、-R8-C(O)N(R7)2、-R8-N(R7)C(O)-R8-N(R7)2and-R8-N(R7)C(O)OR7Substituted with the substituents of (a) or (b);
each R2Independently selected from alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, cyano, -R8-OR7、-R8-N(R7)2、-R8-C(O)OR7、-R8-C(O)N(R7)2、-R8-S(O)tN(R7)2(wherein t is 1 or 2), -R8-N(R7)S(O)tR7(wherein t is 1 or 2), -R8-N(R7)S(O)tN(R7)2(wherein t is 1 or 2), -R8-N(R7)S(O)tN(R7)C(O)OR7(wherein t is 1 or 2), -R8-N(R7)C(O)R7、-R8-N(R7)-R8-C(O)OR7、-R8-N(R7)C(O)-R8-N(R7)2、-R8-N(R7)C(O)-R8-N(R7)-R8-C(O)OR7、-R8-N(R7)C(O)-R8-N(R7)-R8-C(O)-R8-N(R7)2、-N(R7)C(＝NR7)N(R7)2、-C(＝NR7)-N(R7)2、-R8-N＝C(R7)2(optionally substituted with one or more groups selected from alkyl, aryl, aralkyl, halo, haloalkyl, cyano, nitro, -R8-OR7、-R8-C(O)OR7、-R8-C(O)N(R7)2、-R8-N(R7)2、-R8-N(R7)C(O)-R8-N(R7)2and-R8-N(R7)C(O)OR7Substituted with the substituents) heterocyclic group and optionally substituted cyclic ureido group;
R3is hydrogen, alkyl or aralkyl;
R4is (optionally substituted with one or more groups selected from alkyl, aryl, aralkyl, halo, haloalkyl, cyano, nitro, -R8-OR7、-R8-N(R7)2、-R8-C(O)OR7、-R8-C(O)N(R7)2、-R8-N(R7)C(O)-R8-N(R7)2and-R8-N(R7)C(O)OR7Substituted with the substituents of (1) naphthyl; or
R4Is (optionally substituted with one or more groups selected from alkyl, aryl, aralkyl, halo, haloalkyl, cyano, nitro, -R8-OR7、-R8-OC(O)OR7、-R8-N(R7)2、-R8-C(O)OR7、-R8-C(O)N(R7)2、-R8-N(R7)C(O)-R8-N(R7)2and-R8-N(R7)C(O)OR7Substituted with the substituents of (1);
each R7Independently selected from hydrogen, alkyl, -R9-OR7Haloalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl;
each R8Is a bond or a straight or branched alkylene chain; and is
Each R9Is a straight or branched alkylene chain;
the compound of formula (II) is a single stereoisomer, a mixture of stereoisomers, or a racemic mixture of stereoisomers; or is a solvate or polymorph; or a pharmaceutically acceptable salt thereof;
the conditions were as follows:
(1) when m is2, A is oxygen, R1And R3Each being hydrogen, one R2Is 5-nitro and the other R is2When is 4-bromo, then R4Cannot be 5-methylimidazol-4-yl;
(2) when m is2, A is oxygen, R1And R3Each being hydrogen, one R2Is 5-fluoro and the other R2When it is 4-iodo or 4- (1, 3-benzodioxol-5-yl), then R4Cannot be 5-methylimidazol-4-yl;
(3) when m is 1, A is oxygen, R1And R3Each is hydrogen, and R2When it is 4- (2-hydroxyethyl), then R4Cannot be pyridin-2-yl, 6-methylpyridin-2-yl, indol-5-yl or 3-hydroxy-6-methylpyridin-2-yl;
(4) when m is 1, A is oxygen, R1And R3Each is hydrogen, and R2When it is 5-bromo or 5-ethynyl, then R4Cannot be 5-methylimidazol-4-yl;
(5) when m is 0, A is oxygen, and R1And R3When each is hydrogen, then R4Cannot be pyridin-4-yl, 4-methylthiothien-2-yl, 5-methylthiothien-2-yl, 3-methylthiothien-2-yl, furan-2-yl, thien-2-yl, 5- [3, 5-bis (trifluoromethyl) phenyl]Furan-2-yl, 5-iodofuran-2-yl, 4-ethoxycarbonyl-5-methylfuran-2-yl, 3-bromothien-2-yl, 5-chlorothien-2-yl, 4, 5-dimethylfuran-2-yl, 5-nitrothien-2-yl, 5-carboxythien-2-yl, 5-bromothien-2-yl, 4-bromothien-2-yl, 5-sulfonylfuran-2-yl, furan-2-yl, 5-methylfuran-2-yl, 5-ethylfuran-2-yl, 5-nitrofuran-2-yl, 5-bromofuran-2-yl, 5-methylfuran-2-yl, 5-ethylthiophen-2-yl, 5-methylimidazol-2-yl, 5-methylthiazol-2-yl, 5-methylpyrazol-3-yl, imidazol-4-yl, 4-chloropyrazol-3-yl, 2- (4-chlorobenzyl) -4-bromopyrazol-3-yl, 4-chloro-1-methylpyrazol-3-yl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl, 5-phenyl-1, 2, 4-oxadiazol-3-yl, 3-phenyl-1, 2, 4-oxadiazol-5-yl, 3-phenyl-1, 2, 5-oxadiazol-4-yl, 5-methylpyrazol-3-yl, 5-thiadiazol-yl, and pharmaceutically acceptable salts thereof, 3-methylthiophen-2-yl, 5-methylimidazolyl-2-yl, bicyclo [2.2.1 ]]Hept-5-en-2-yl, indol-3-yl; pyridin-4-yl or pyridin-2-yl;
(6) when m is 1, A is oxygen, R1And R3Each is hydrogen, and R2When it is 5-chloro or 5-nitro, then R4Cannot be indol-3-yl, thiophen-2-yl, 3-methylthiophen-2-yl, 5-methylThien-2-yl, 5-ethylthien-2-yl, 5-methylthiothien-2-yl or imidazol-2-yl;
(7) when m is2, A is oxygen, R1And R3Each is hydrogen, and R4When it is 5-methylimidazol-4-yl, then together two R2The group cannot be 4-fluoro-5-nitro, 4-azido-5-nitro, 4-amino-5-nitro or 4, 5-diamino;
(8) when m is 1, A is oxygen, R1And R3Each is hydrogen, and R2is-S (O)2N(R7) H (wherein R7Is hydrogen, alkyl or hydroxyalkyl), then R4Not 4, 5,6, 7-tetrahydroindol-2-yl, which cannot be optionally substituted; and
(9) when m is 0, A is oxygen, R1And R3Each being hydrogen, R4And not 4-dimethylaminonaphthyl.
27. A compound of formula (Ia):
wherein:
R1is hydrogen or alkyl;
R2ais-R8-S(O)tN(R7)2(wherein t is 1 or 2), -R8-N(R7)2、-R8-N(R7)S(O)tN(R7)2(wherein t is 1 or 2), -R8-N(R7)S(O)tN(R7)C(O)OR7(wherein t is 1 or 2), -R8-N(R7)C(O)R7、-R8-N(R7)-R8-C(O)OR7、-R8-N(R7)C(O)N(R7)2、-R8-N(R7)C(O)-R9-N(R7)2、-R8-N(R7)-R9-C(O)N(R7)2、-R8-N(R7)C(O)-R8-N(R7)-R8-C(O)OR7、-R8-N(R7)C(O)-R8-N(R7)-R8-C(O)-R8-N(R7)2、-N(R7)C(＝NR7)N(R7)2or-R8-N＝C(R7)2；
Each R2bIndependently selected from alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, cyano, -R8-OR7、-R8-N(R7)2、-R8-C(O)OR7、-R8-C(O)N(R7)2、-R8-S(O)tN(R7)2(wherein t is 1 or 2), -R8-N(R7)S(O)tR7(wherein t is 1 or 2), -R8-N(R7)S(O)tN(R7)2(wherein t is 1 or 2), -R8-N(R7)S(O)tN(R7)C(O)OR7(wherein t is 1 or 2), -R8-N(R7)C(O)R7、-R8-N(R7)-R8-C(O)OR7、-R8-N(R7)C(O)N(R7)2、-R8-N(R7)C(O)-R9-N(R7)2、-R8-N(R7)-R9-C(O)N(R7)2、-R8-N(R7)C(O)-R8-N(R7)-R8-C(O)OR7、-R8-N(R7)C(O)-R8-N(R7)-R8-C(O)-R8-N(R7)2、-N(R7)C(＝NR7)N(R7)2、-C(＝NR7)-N(R7)2、-R8-N＝C(R7)2(optionally substituted with one or more groups selected from alkyl, aryl, aralkyl, halo, haloalkyl, cyano, nitro, -R8-OR7、-R8-C(O)OR7、-R8-C(O)N(R7)2、-R8-N(R7)2、-R8-N(R7)C(O)-R8-N(R7)2and-R8-N(R7)C(O)OR7Substituted with a substituent of (2) a heterocyclic groupAnd optionally substituted cyclic ureido;
m*is 0 to 3;
n is 0 to 3;
each R6Independently selected from halogen, alkyl, nitro, -R8-C(O)R7、-R8-N(R7)2、-R8-C(O)OR7、-R8-C(O)N(R7)2、-R8-N(R7)-R8-C(O)OR7、-R8-N(R7)C(O)R7、-R8-C(O)-R9-C(O)OR7、-R8-N(R7)C(O)N(R7)2、-R8-N(R7)C(O)-R9-N(R7)2、-R8-N(R7)C(O)-R9-C(O)OR7、-R8-N(R7)C(O)-R8-N(R7)-R8-C(O)OR7(optionally substituted with one or more groups selected from alkyl, halo, haloalkyl, cyano, nitro, -R8-OR7、-R8-O-R9-C(O)OR7、-R8-N(R7)2、-R8-C(O)R7、-R8-C(O)OR7、-R8-C(O)N(R7)2、-R8-N(R7)C(O)OR7、-R8-N(R7)C(O)R7、-R8-S(O)pR7(wherein p is 0-2), -R8-S(O)pN(R7)2(wherein p is 0-2) and-R8-N(R7)C(O)-R8-N(R7)2Substituted with one or more substituents selected from alkyl, -R) and (optionally substituted with one or more substituents selected from alkyl, -R8-OR7、-R8-O-R9-C(O)OR7、-R8-C(O)R7、-R8-C(O)OR7、-R8-C(O)N(R7)2、-R8-N(R7)C(O)R7、-R8-N(R7)C(O)OR7、-R8-N(R7)2、-R8-N(R7)C(O)-R8-N(R7)-R8-C(O)OR7and-R8-S(O)tR7Aryl (wherein t is a substituent of 0 to 2);
each R7Independently hydrogen, optionally substituted alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl;
each R8Is a bond or a straight or branched alkylene chain; and is
Each R9Is a straight or branched alkylene chain;
the compound of formula (Ia) is a single stereoisomer, a mixture of stereoisomers, a solvate or a polymorph.
28. The compound of claim 27, wherein:
R1is hydrogen;
R2ais-R8-N(R7)2、-R8-N(R7)S(O)tN(R7)2(wherein t is 1 or 2), -R8-N(R7)S(O)tN(R7)C(O)OR7(wherein t is 1 or 2), -R8-N(R7)C(O)R7、-R8-N(R7)-R8-C(O)OR7、-R8-N(R7)C(O)N(R7)2、-R8-N(R7)C(O)-R9-N(R7)2、-R8-N(R7)-R9-C(O)N(R7)2、-R8-N(R7)C(O)-R8-N(R7)-R8-C(O)OR7、-R8-N(R7)C(O)-R8-N(R7)-R8-C(O)-R8-N(R7)2、-N(R7)C(＝NR7)N(R7)2or-R8-N＝C(R7)2(ii) a And is
m*Is 0.
29. The compound of claim 28, wherein:
R2ais-R8-N(R7)S(O)tN(R7)2(wherein t is 1 or 2),
-R8-N(R7)S(O)tN(R7)C(O)OR7(wherein t is 1 or 2), -R8-N(R7)C(O)R7、-R8-N(R7)-R8-C(O)OR7、-R8-N(R7)C(O)N(R7)2、-R8-N(R7)C(O)-R9-N(R7)2、-R8-N(R7)-R9-C(O)N(R7)2、-R8-N(R7)C(O)-R8-N(R7)-R8-C(O)OR7or-R8-N(R7)C(O)-R8-N(R7)-R8-C(O)-R8-N(R7)2(ii) a And is
30. The compound of claim 29, wherein:
R2ais-R8-S(O)tN(R7)2(wherein t is 1 or 2), -R8-N(R7)C(O)R7、-R8-N(R7)-R8-C(O)OR7、-R8-N(R7)C(O)N(R7)2、-R8-N(R7)-R9-C(O)N(R7)2or-R8-N(R7)C(O)-R9-N(R7)2(ii) a And is
Each R6Independently selected from:
a) halogen, alkyl and nitro, and the alkyl is a substituent,
b)-R8-C(O)R7、-R8-C(O)OR7、-R8-C(O)N(R7)2、-R8-C(O)-R9-C(O)OR7、-R8-N(R7)2、-R8-N(R7)-R8-C(O)OR7、-R8-N(R7)C(O)R7、-R8-N(R7)C(O)N(R7)2、-R8-N(R7)C(O)-R9-N(R7)2、-R8-N(R7)C(O)-R9-C(O)OR7and-R8-N(R7)C(O)-R8-N(R7)-R8-C(O)OR7；
c) (optionally substituted with one or more groups selected from alkyl, halo, haloalkyl, cyano, nitro, -R8-OR7、-R8-O-R9-C(O)OR7、-R8-N(R7)2、-R8-C(O)R7、-R8-C(O)OR7、-R8-C(O)N(R7)2、-R8-N(R7)C(O)OR7、-R8-N(R7)C(O)R7、-R8-S(O)pR7(wherein p is 0-2), -R8-S(O)pN(R7)2(wherein p is 0-2) and-R8-N(R7)C(O)-R8-N(R7)2Substituted with the substituents of (a) pyridyl or pyrimidinyl; and
d) (optionally substituted by one or more groups selected from alkyl, -R8-OR7、-R8-O-R9-C(O)OR7、-R8-C(O)R7、-R8-C(O)OR7、-R8-C(O)N(R7)2、-R8-N(R7)C(O)R7、-R8-N(R7)C(O)OR7、-R8-N(R7)2、-R8-N(R7)C(O)-R8-N(R7)-R8-C(O)OR7and-R8-S(O)tR7Phenyl (wherein t is a substituent of 0 to 2).
HK07105373.9A 2003-10-24 2004-10-22 Indolinone derivatives and their use in treating disease-states such as cancer HK1099281A (en)

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