HK1172510A - Isoquinoline, quinoline, and quinazoline derivatives as inhibitors of hedgehog signaling - Google Patents

Description

Isoquinoline, quinoline and quinazoline derivatives as HEDGEHOG signaling inhibitors

RELATED APPLICATIONS

This patent application claims the benefit of U.S. provisional patent application No. 61/185,412 filed on 9.6.2009, which is incorporated by reference.

Technical Field

The present invention relates generally to the use of isoquinoline, quinoline, and quinazoline derivatives to treat a variety of disorders, diseases, and pathological conditions, and more particularly to the use of isoquinoline, quinoline, and quinazoline derivatives to inhibit the hedgehog signaling pathway and to the use of those compounds to treat hyperproliferative diseases and angiogenesis-mediated diseases.

Background

The Hedgehog (Hh) gene was first identified during the search for embryonic lethal mutants of Drosophila melanogaster (Drosophila melanogaster), and the Hh mutation was found to cause segment patterning of altered larvae (pattening) (Nusslein-Volhard, C.; Wieschaus, E.Nature 1980, 287, 795-. Subsequently, the gene was identified in many other invertebrates and vertebrates, including humans. There are three mammalian counterparts of the Hh gene, called Sonichehidghog (Shh), Dessert hedgehog (Dhh), and cDNA libraries (Echelard, Y.; Epstein, D.J.; et al, Cell 1993, 75, 1417-. Hh undergoes a number of processing events, including autocatalytic cleavage of the C-terminal domain with the addition of a cholesterol moiety at the cleavage site, and N-terminal palmitoylation to yield an active ligand (Lee, j.j.; Ekker, s.c.; et al, Science1994, 266, 1528-.

The receptor for the secreted Hh protein is the multichannel transmembrane protein patched (ptch). Of the two vertebrate homologues Ptch (Ptch1 and Ptch2), the role of Ptch1 is better understood. In the absence of Hh ligand, Ptch inhibits the activity of the downstream effector smoothened (smo). Binding of Hh inactivates Ptch, leading to activation of Smo (Stone, D.M.; Hynes, M.; et al, Nature 1996, 384, 129-one 134). In Drosophila (Drosophila), protein complexes comprising Fused (fu), Fused repressor (SuFu) and Costal-2(Cos2) mediate signal transduction downstream of Smo and are helped by several kinases such as protein kinase a (pka), glycogen synthase kinase 3(GSK3) and casein kinase 1(CK 1). Mammalian homologs of Fa and Cos2 have not been identified, indicating that the signal transduction mechanisms are different in mammals and Drosophila. Several mammalian specific kinases required for Shh signaling have been identified (Varjosalo, m.; Bjorklund, m.; et al, Cell 2008, 133, 537-. These proteins regulate the function of Gli (Ci in drosophila), which is currently the only recognized transcription factor acting directly downstream of Hh.

The first vertebrate Gli gene found was human Gli1, which was amplified approximately 50-fold in malignant gliomas (Kinzler, K.W.; Bigner, S.H.; et al, Science 1987, 236, 70-73). Vertebrates have three Gli proteins (Gli1, Gli2, and Gli3), all with five highly conserved tandem zinc fingers, a fairly conserved N-terminal domain, several potential PKA sites, and many additional small conserved regions at the C-terminus. Despite these similarities, the Gli subtypes differ in function. Both Gli2 and Gli3 contain activation and repressor domains. Thus, in the absence of upstream Hh signal, full-length Gli3 and Gli2 (to a lesser extent) are constitutively cleaved to produce truncated repressor forms (Dai, P.; Akimaru, H.; et al, J.biol.chem.1999, 274, 8143-. Hh signaling inhibits this cleavage, resulting in full-length Gli2 and Gli3 with activator functions. In contrast, Gli1 does not undergo proteolytic cleavage and acts as a constitutive activator. Transcription of the Gli1 gene was initiated by Hh and was also controlled by Gli 3.27. Target genes for the Hh pathway that are not Gli1 include Ptch, several Wnt and TGF superfamily proteins, cell cycle regulatory proteins such as cyclin D, and stem cell marker genes such as NANOG and SOX2.30, 31. Researchers are currently trying to comprehensively identify the Gli 1-target gene (Yoon, J.W.; Kita, Y.; et al, J.biol.chem.2002, 277, 5548-.

The Hh signal transduction pathway is critical for proper embryonic development (Ingham, P.W.; McMahon, A.P.genes Dev.2001, 15, 3059-3087). It is also necessary to suppress growth and maintain adult stem cells in the nervous system and other tissues (Machold, R.; Hayashi, S., et al, Neuron 2003, 39, 937-. The expression and role of Hh in vertebrate tissues/organs has been extensively described in recent reviews (Varjosalo, m.; taipal, j. genes de v.2008, 22, 2454-2472).

Two of the following functions of Hh in vertebrate embryonic development are critical and relatively well understood: neural tube differentiation and patterning of the anterior and posterior limbs. The predominant mechanism of Hh signaling in these functions is paracrine signaling, in which the Hh molecule acts in a gradient fashion. For example, in vertebrate limb buds, exposure to different concentrations of Shh modulates mesenchymal patterning of digits, which affects the proper growth of digits in a specific pattern (Tabin, C.J.; McMahon, A.P. science 2008, 321, 350-. During neural tube development, Shh produced by the floor leads to dorsoventral patterning, normalization of abdominal cell populations, and general cell proliferation in the brain. 40 forebrain non-split malformations involving forebrain and midface developmental disorders in which abdominal cell types are lost, which in humans are caused by mutations in the loss of Shh activity (Belloni, E.; Muenke, M.; et al, nat. Genet.1996, 14, 353-356).

Yet another important feature of Shh signaling is that Gli subtypes have unique and overlapping functions. Ex situ expression of Gil1 in the midbrain and the hindbrain of transgenic mice resulted in expression of certain abdominal cell types, while mice homozygous for mutations in the region encoding the Gli1 zinc finger domain developed normally (Hynes, M.; Stone, D.M.; et al, Neuron, 1997, 19, 15-26; Park, H.L.; Bai, C.; et al, Development 2000, 127, 1593-. However, Gli1/Gli2 double mutant mice had phenotypes with severe multiple defects, including variable loss of abdominal spinal cord and smaller lungs; thus, Gli2 plays a more important role in spinal cord and lung development than Gli 1. In contrast, Gli1/Gli3 double mutant mice did not have these phenotypes (Park, H.L.; Bai, C.; et al, DeVelopment 2000, 127, 1593-. Both Gli2 and Gli3 are involved in skeletal development, with each subtype playing a specific functional role. Gli2 mutant mice exhibited severe skeletal deformities including cleft palate, tooth defects, loss of vertebral bodies and discs, and shortened limbs and sternum (Mo, r.; Freer, a.m.; et al, DeVelopment 1997, 124, 113-. Gli3 appears to be the major mediator of Shh effects in the extremities, whereas Gli1/Gli2 double mutant mice have normal finger (toe) numbers and patterns, whereas Gli3 mutant mice show multi-finger (toe) malformations (Hui, c.c.; Joyner, a.l.nat. genet.1993, 3, 241-.

Genetic analysis of Gli mutants revealed that the need for Gli subtype development is quite divergent even in vertebrates. In zebrafish, the detour (dtr) mutation (encoding a loss-of-function allele of Gli 1) and the you-too (yot) mutation (encoding a C-terminally truncated Gli2) have a defect in somatic axis formation and expression of the Hh-target gene in brain (Karlstrom, R.O.; Tyurina, O.V.; et al, DeVelopment 2003, 130, 1549-.

In adults, the Hh pathway is essential in arresting the growth of the nervous system and other tissues and in maintaining stem cells. Zhang and Kalderon have indicated that Hh is particularly responsible for stem cells in the Drosophila ovary, and these cells cannot proliferate in the absence of Hh (Zhang, Y.; Kalderon, D.Nature 2001, 410, 599-. Other studies have shown that Hh signaling in the postnatal cerebellum not only promotes proliferation but also maintains a population of neural progenitors, which suggests that Shh signaling in the mammalian telencephalon may be involved in maintaining neural stem cell niches. The role of Hh in the proliferation of adult neural progenitor cells was confirmed by studies in which Shh was overexpressed and proliferation was inhibited with Smo antagonists (Lai, k.; Kaspar, b.k.; et al, nat. neurosci.2003, 6, 21-27).

The Hh gene has the ability to induce tissue proliferation. This function is important in embryogenesis and tissue maintenance, but inappropriate activation of this pathway can lead to tumorigenesis (Hunter, T.cell 1997, 88, 333-346). It is estimated that about 25% of all cancer deaths are tumors involved in aberrant Hh pathway activation. Tumorigenesis or tumor growth can result from abnormal upregulation of Hh ligands or deregulation of downstream component expression or function by, for example, activating Ptch loss of Smo mutations (Xie, j.; Murone, m.; et al, Nature 1998, 391, 90-92), Gil1 or Gli2 gene amplification or chromosomal translocation, SuFu loss of Gli2 protein amplification or stabilization (Bhatia, n.; thiyagara jan, s.; j. biol. chem.2006, 281, 19320-19326).

The first Hh pathway gene found to be amplified in cancer is Gli1, which is expressed at high levels in human glioblastoma and derived cell lines. Subsequently, Gli1 was found to be consistently expressed in various glial tumors, and Gli1 overexpression was shown to induce central nervous system hyperproliferation (Dahmane, N.; Sanchez, P.; et al, Development 2001, 128, 5201-. Gli1 overexpression was also observed in a range of low to high grade brain tumors in a study (Clement, v.; Sanchez, p.; current. biol.2007, 17, 165-172) that confirmed that Gil1 expression is the only reliable marker of Hh pathway activity. In addition, cell proliferation in primary cultures of many of these tumors is inhibited by Gil1 small interfering RNA. Gil1 expression was correlated with tumor grade in PDGF-induced glioma development in mice. Hh signaling components other than Gli1 also contribute to tumorigenesis of a specific subset of glioblastoma. In PDGF-induced tumors, Shh expression levels correlated with tumor grade. However, other studies found that only subtypes of glioma contained high levels of Shh.

Yet another cancer that has a defect in Hh pathway regulation is Basal Cell Carcinoma (BCC). Human Ptch was first identified due to its mutation in patients with Gorlin Syndrome (GS), a genetic disease that causes BCC shedding (Johnson, r.l.; Rothman, a.l.; et al, Science 1996, 272, 1668-. The Ptch mutations identified in BCC include deletions leading to truncated proteins and insertions or nonsense mutations accompanied by loss of heterozygosity (LOH) or other allelic mutations. These mutations inhibit Ptch's ability to suppress Smo, leading to constitutive Hh signaling. Although abnormalities in Ptch1 were detected in most BCC patients, it is now clear that the BCC subtype is also driven by Smo mutations that reduce its sensitivity to Ptch inhibition. Furthermore, overexpression of the Gli1 protein resulted in BCC-like tumors in mice, establishing the importance of Gli1 transcription in BCC tumorigenesis (Nilsson, M.; Unden, A.B.; et al, Proc. Natl. Acad. Sci. U.S. A.2000, 97, 3438-. The Gli1 transcript level can be used to distinguish BCC from certain other skin tumors (Hatta, N.; Hirano, T.; et al, J.Cutaneous Pathol.2005, 32, 131-. However, blocking Gli-based transcription did not show cessation of BCC growth.

Medulloblastoma (the most common malignant pediatric brain tumors) is associated with Ptch and Smo mutations, as well as mutations in other Hh pathway genes such as SuFu and Gli (Pomeroy, s.l.; Tamayo, p.; et al, Nature 2002, 415, 436442). Deletion and mutation-induced inactivation of the Ptch locus has been found in about 10% of sporadic medulloblastomas. The Shh pathway implicated in these tumors was further confirmed by studies in which murine medulloblastoma was treated with Smo inhibitors in mice, thereby inhibiting Cell proliferation and reducing tumor growth (Berman, D.M.; Karhadkar, S.S.; et al, Science 2002, 297, 1559-. Taylor et al identified SuFu as a tumor suppressor gene whose mutation predisposed an individual to a neural tube cell tumor. They found that a subset of children with medulloblastoma carried germline and somatic mutations of SuFu with concomitant loss of heterozygosity of the wild type allele. Several of these mutations encode truncated SuFu proteins that do not export the Gli protein from the nucleus. In addition, the tumor suppressor REN is also associated with medulloblastoma, where allelic deletions and reduced REN expression are frequently observed. It is indicated that it inhibits medulloblastoma growth by down-regulating the Hh pathway (C.; Zazzeroni, F.; Gallo, R.; et al, Proc. Natl. Acad. Sci. U.S.A.2004, 101, 10833-.

Hh has also been shown to be an early and late mediator of pancreatic cancer tumorigenesis. Shh is not detected in the normal adult pancreas, but is aberrantly expressed in 70% of pancreatic cancer samples (Thayer, S.P.; di Magliano, M.P.; et al, Nature2003, 425, 851-856). Involvement in Shh signaling has been pointed out in multiple stages of pancreatic carcinogenesis, with a variety of tumorigenic factors, including K-Ras, one of the most frequently mutated genes in pancreatic cancer (Morton, j.p.; Mongeau, m.e.; et al, proc.natl.acad.sci.u.s.a.2007, 104, 5103-. Activated Hh signaling was detected in established cell lines from primary and metastatic pancreatic cancer, while the Smo inhibitor cyclopamine induced apoptosis in subtypes of pancreatic cancer cell lines in both cultures and mice (Sheng, t.; Li, c.; et al, mol. cancer.2004, 3, 29).

Many studies have indicated that Hh signaling is implicated in prostate cancer. Sanchez and others have reported the expression of Shh-Gli pathway components in adult prostate cancer. Treatment of primary prostate tumor cultures and metastatic prostate cancer cell lines with Smo inhibitors blocked pathways and proliferation. Increased expression of Shh in prostate cancer cells upregulates Gill expression and dramatically accelerates the growth of prostate tumor xenografts (Fan, L.; Pepicelli, C.V.; et al, Endocrinology 2004, 145, 3961-. Elevated Shh activity is a distinction between metastatic prostate cancer and regional prostate cancer, and treatment of this pathway modulates the invasiveness and metastasis of these tumors (Karhadkar, s.s.; Bova, g.s.; et al, Nature 2004, 431, 707-712).

Hh signaling has also been implicated in a variety of other cancers such as lung, colorectal, bladder, endometrial, ovarian and esophageal cancers as well as rhabdomyosarcoma (Chi, S.; Huang, S.; et al, cancer Lett.2006, 244, 53-60; Watkins, D.N.; Berman, D.M.; et al, Nature2003, 422, 313-317; Qualtrough, D.; Buda, A.; et al, Mt.J.cancer 2004, 110, 831-837; McGarvey, T.W.; Maruta, Y.; Oncogene 1998, 17, 1167-1172; Feng, Y.Z.; Shiozawa, T.2006; et al, Clin. cancer Res 2007, 13, 1389-1398; Bhattacya, R.; Kton, J.J.; Clin et al, cancer Res 766 13, 1389-1398; Rhatbacya, R.R.378; J.J.J.766 J.9, J.J.9-10; Morghol. Tsu.; et al, J.J.J.J.J.766 and their therapeutic potential have been reviewed recently in Toogl et al, as Toghol.A. A. 23, et al, a signal for the therapeutic potential of cancer, a.

Aberrant activation of Hh-Gli signaling in several cancers makes it an attractive target for anticancer drug discovery. Various inhibitors of hedgehog signaling have been studied, such as cyclopamine, which is shown at G₀-G₁Natural alkaloids that stop the cell cycle and induce apoptosis in SCLC. Cyclopamine is believed to inhibit Smo by binding to its heptahelical bundle. Cyclopamine is currently used as an anti-cancer agent in preclinical and clinical studies (Kolterud, A.; Toftga ° rd, R.drug discovery Today: the. strategies 2007, 4, 229-235). Much of Smo inhibitors have been reported and can be classified as cyclopamine analogues or synthetic Smo antagonists. Several pharmaceutical companies have identified new Smo inhibitors with drug-like properties by optimizing high throughput screening results.

One such small molecule, GDC-0449, developed by Curis and Genentech, is currently in phase I/II clinical trials for progressive BCC and solid epithelial tumors (Gunzner, J.; Sutherlin, D.; et al, WO2006028958, 3/16 2006). Despite the existence of these compounds, there remains a need for effective inhibitors of the hedgehog signaling pathway.

Detailed Description

The present invention relates to compounds of formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

b is N or CH;

R₁represents hydrogen, halogen, hydroxy, amino, nitro, cyano, alkyl, alkenyl, alkoxy, alkoxycarbonyl, carbamoyl, alkylthio, sulfonyl, sulfinyl, cycloalkyl or heterocycle;

l is oxygen, NR₃，NR₃CO，NR₃SO，NR₃SO₂，SO₂NR₃，NR₃CONH，NR₃CSNH，CONR₃，CSNR₃，NR₃CHR₄，NR₃PO or NR₃PO(OH)；

Ring a is aryl, heterocycle, heteroaryl;

R₂represents hydrogen, hydroxy, halogen, amino, nitro, cyano, acyl, alkyl, alkenyl, alkynyl, alkylthio, sulfonyl, sulfinyl, alkoxy, alkoxycarbonyl, carbamoyl, acylamine,a sulfamoyl or sulfonamide;

or R₂Is aryl, heterocyclic or heteroaryl, optionally substituted with hydroxy, halogen, amino, nitro, cyano, acyl, alkyl, alkanoyl, sulfonyl, sulfinyl, alkoxy, carbamoyl, acylamine, sulfamoyl and sulfonamide;

R₃and R₄Independently selected from hydrogen or optionally substituted C_1-4An alkyl group; and m is 0 to 4.

In particular embodiments, the compounds of the present invention have the general formula Ia:

or a pharmaceutically acceptable salt thereof, wherein:

R₁represents hydrogen, halogen, hydroxy, amino, nitro, cyano, alkyl, alkenyl, alkoxy, alkoxycarbonyl, carbamoyl, alkylthio, sulfonyl, sulfinyl, cycloalkyl or heterocycle;

l is oxygen, NR₃，NR₃CO，NR₃SO，NR₃SO₂，SO₂NR₃，NR₃CONH，NR₃CSNH，CONR₃，CSNR₃，NR₃CHR₄，NR₃PO or NR₃PO(OH)；

Ring a is aryl, heterocycle, heteroaryl;

R₂represents hydrogen, hydroxy, halogen, amino, nitro, cyano, acyl, alkyl, alkenyl, alkynyl, alkylthio, sulfonyl, sulfinyl, alkoxy, alkoxycarbonyl, carbamoyl, acylamine, sulfamoyl or sulfonamide;

or R₂Is aryl, heterocycle or heteroaryl, optionally substituted with hydroxy, halogen, amino, nitroCyano, acyl, alkyl, alkanoyl, sulfonyl, sulfinyl, alkoxy, carbamoyl, acylamine, sulfamoyl and sulfonamide substitutions.

R₃And R₄Independently selected from hydrogen or optionally substituted C_1-4An alkyl group; and m is 0 to 4.

In yet another particular embodiment, the compounds of the present invention have the general formula Ib.

Or a pharmaceutically acceptable salt thereof, wherein:

R₁represents hydrogen, halogen, hydroxy, amino, nitro, cyano, alkyl, alkenyl, alkoxy, alkoxycarbonyl, carbamoyl, alkylthio, sulfonyl, sulfinyl, cycloalkyl or heterocycle;

l is oxygen, NR₃，NR₃CO，NR₃SO，NR₃SO₂，SO₂NR₃；NR₃CONH，NR₃CSNH，CONR₃，CSNR₃，NR₃CHR₄，NR₃PO or NR₃PO(OH)；

Ring a is aryl, heterocycle, heteroaryl;

R₂represents hydrogen, hydroxy, halogen, amino, nitro, cyano, acyl, alkyl, alkenyl, alkynyl, alkylthio, sulfonyl, sulfinyl, alkoxy, alkoxycarbonyl, carbamoyl, acylamine, sulfamoyl or sulfonamide;

or R₂Is aryl, heterocyclic or heteroaryl, optionally substituted with hydroxy, halogen, amino, nitro, cyano, acyl, alkyl, alkanoyl, sulfonyl, sulfinyl, alkoxy, carbamoyl, acylamine, sulfamoyl and sulfonamide.

R₃And R₄Independently selected from hydrogen or optionally substituted C_1-4An alkyl group; and m is 0 to 4.

The following definitions apply to each term used above and throughout this document.

Compounds are generally described herein using standard nomenclature. For compounds having asymmetric centers, it is understood (unless otherwise specified) to encompass all optical isomers and mixtures thereof. Furthermore, compounds having a carbon-carbon double bond may exist in the Z-and E-forms, wherein the invention includes all isomeric forms of the compounds unless otherwise specified. Where a compound exists in various tautomeric forms, the compound is not limited to any one particular tautomer, but rather is intended to encompass all tautomeric forms. Certain compounds are described herein by the general formula including variables such as X, Ar. Unless otherwise specified, each variable in the above formula is defined independently of any other variable, and each occurrence of any variable in the formula that occurs more than once is defined independently.

The term "halo" or "halogen" refers to fluorine, chlorine, bromine or iodine. The term "alkyl" as used herein alone or as part of another group refers to monovalent alkane (hydrocarbon) derived residues containing 1 to 12 carbon atoms unless otherwise defined. The alkyl group may be substituted at any possible point of attachment. An alkyl group substituted with another alkyl group is also referred to as a "branched alkyl group". Exemplary alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, dimethylpentyl, octyl, 2, 2, 4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, and the like. Exemplary substituents include, but are not limited to, one or more of the following groups: alkyl, aryl, halo (e.g. F, Cl, Br, I), haloalkyl (e.g. CCl)₃Or CF₃) Alkoxy, alkylthio, hydroxy, carboxy (-COOH), alkoxycarbonyl (-C (O) R), alkylcarbonyloxy (-OCOR), amino (-NH)₂) Carbamoyl (-NHCOOR-or-OCONHR-), urea (-NHCONHR-) or mercapto (-SH). In the present inventionIn certain preferred embodiments, the alkyl group is substituted with, for example, amino, heterocycloalkyl such as morpholine, piperazine, piperidine, azetidine, hydroxy, methoxy, or heteroaryl such as pyrrolidine.

The term "cycloalkyl" as used herein alone or as part of another group refers to hydrocarbon rings of 3 to 9, preferably 3 to 7, carbon atoms which are fully saturated and partially unsaturated. Examples include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl and the like. Furthermore, cycloalkyl groups may be substituted. Substituted cycloalkyl refers to a ring having one, two, or three substituents selected from halo, alkyl, substituted alkyl, alkenyl, alkynyl, nitro, cyano, oxo (═ O), hydroxy, alkoxy, sulfanyl, -CO₂H，-C(＝O)H，CO₂-alkyl, -C (═ O) alkyl, keto, ═ N-OH, ═ N-O-alkyl, aryl, heteroaryl, heterocycle, -NR 'R ", -C (═ O) NR' R", -CO₂NR′R″，-C(＝O)NR′R″，-NR′CO₂R″，-NR′C(＝O)R″，-SO₂NR ' R ', and-NR ' SO₂R ', wherein R ' and R ' are each independently selected from hydrogen, alkyl, substituted alkyl, and cycloalkyl, or R ' and R ' together form a heterocyclic or heteroaryl ring.

The term "alkenyl" as used herein alone or as part of another group refers to a straight, branched or cyclic hydrocarbon residue containing from 2 to 12 carbon atoms and at least one carbon-carbon double bond. Examples of such groups include vinyl, allyl, 1-propenyl, isopropenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-heptenyl, and the like. Alkenyl groups may also be substituted at any possible point of attachment. Exemplary substituents for alkenyl groups include those listed above for alkyl groups, and specifically include C₃-C₇Cycloalkyl groups such as cyclopropyl, cyclopentyl and cyclohexyl, which may be further substituted with, for example, amino, oxo, hydroxy, and the like.

The term "alkynyl" refers to straight or branched chainsAn alkynylated alkynyl group having one or more unsaturated carbon-carbon bonds, at least one of which is a triple bond. Alkynyl includes C having 2 to 8, 2 to 6 or 2 to 4 carbon atoms respectively₂-C₈Alkynyl, C₂-C₆Alkynyl and C₂-C₄Alkynyl. Exemplary alkynyl groups include ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, pentenyl, and hexenyl. Alkynyl groups may also be substituted at any possible point of attachment. Exemplary substituents for alkynyl groups include those listed above for alkyl groups, such as amino, alkylamino, and the like. The subscript number following the symbol "C" defines the number of carbon atoms that a particular group is capable of containing.

The term "alkoxy" alone or as part of another group denotes an alkyl group as described above bonded through an oxygen bridge (linkage) (-O-). Preferred alkoxy groups have 1 to 8 carbon atoms. Examples of the group include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentyloxy, isopentyloxy, n-hexyloxy, cyclohexyloxy, n-heptyloxy, n-octyloxy and 2-ethylhexyloxy.

The term "alkylthio" refers to an alkyl group as described above attached through a sulfur bridge. Preferred alkoxy and alkylthio groups are those in which the alkyl groups are connected by a heteroatom bridge. Preferred alkylthio groups have 1 to 8 carbon atoms. Examples of the group include methylthio, ethylthio, n-propylthio, n-butylthio and the like.

The term "oxo" as used herein refers to a keto (C ═ O) group. Oxo groups of substituents other than aromatic carbon atoms rendering-CH₂-conversion to-C (═ O) -.

The term "alkanoyl" refers to a group of the formula-C (O) R, wherein R is a straight or branched C₁-C₆Alkyl, cycloalkyl, aryl, or heteroaryl.

The term "alkoxycarbonyl" as used herein alone or as part of another group means an alkoxy group bonded through a carbonyl group. Alkane (I) and its preparation methodThe oxycarbonyl residue is represented by the formula-C (O) OR, wherein the R group is C, linear OR branched₁-C₆Alkyl, cycloalkyl, aryl, or heteroaryl.

The term "aryl" as used herein alone or as part of another group refers to monocyclic or bicyclic aromatic rings, such as phenyl, substituted phenyl, and the like, as well as fused groups such as naphthyl, phenanthryl, and the like. Thus, an aryl group contains at least one ring of at least 6 atoms, with up to five of said rings being present, containing up to 20 atoms, with alternating (resonant) double bonds between adjacent carbon atoms or suitable heteroatoms. Aryl groups may be optionally substituted with one or more of the following groups: including, but not limited to, halogens such as I, Br, F, or Cl; alkyl such as methyl, ethyl, propyl, alkoxy such as methoxy or ethoxy, hydroxy, carboxy, carbamoyl, alkoxycarbonyl, nitro, alkenyloxy, trifluoromethyl, amino, cycloalkyl, aryl, heteroaryl, cyano, alkyl S (O)_m(wherein m ═ 0, 1, 2), or a mercapto group.

The term "amino" as used herein alone or as part of another group refers to-NH₂The "amino" may be optionally substituted with one or two substituents, which may be the same or different, such as alkyl, aryl, arylalkyl, alkenyl, alkynyl, heteroaryl, heteroarylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, sulfanyl, carbonyl, or carboxyl. These substituents may be further optionally substituted with carboxylic acid, alkyl or aryl substituents as described herein. In certain embodiments, the amino group is substituted with a carboxy or carbonyl group to form an N-acyl or N-carbamoyl derivative.

The term "heteroatom" refers to any atom other than carbon, such as N, O or S.

The term "heteroaryl" as used herein alone or as part of another group refers to substituted and unsubstituted aromatic 5 or 6 membered monocyclic groups, 9 or 10 membered bicyclic groups, and 11 to 14 membered tricyclic groups having at least one heteroatom (O, S or N) in at least one of the rings. Each ring of the heteroaryl group containing a heteroatom can contain one or two oxygen or sulfur atoms and/or one to four nitrogen atoms, provided that the total number of heteroatoms in each ring is four or less and each ring has at least one carbon atom.

The fused rings completing the bicyclic and tricyclic groups may contain only carbon atoms and may be saturated, partially saturated, or unsaturated. The nitrogen and sulfur atoms may optionally be oxidized and the nitrogen atoms may optionally be quaternized. Bicyclic or tricyclic heteroaryl groups must include at least one fully aromatic ring, but other fused rings or rings may be aromatic or non-aromatic. The heteroaryl group may be attached at any possible nitrogen or carbon atom of any ring. The heteroaryl ring system may contain zero, one, two or three substituents selected from: halo, alkyl, substituted alkyl, alkenyl, alkynyl, aryl, nitro, cyano, hydroxy, alkoxy, sulfanyl, -CO₂H，-C(＝O)H，-CO₂-alkyl, -C (═ O) alkyl, phenyl, benzyl, phenylethyl, phenyloxy, phenylthio, cycloalkyl, substituted cycloalkyl, heterocycle, heteroaryl, -NR 'R ", -C (═ O) NR' R", -CO₂NR′R″，-C(＝O)NR′R″，-NRCO₂R″，-NR₁C(＝O)R″，-SO₂NR ' R ', and-NR ' SO₂R ', wherein R ' and R ' are each independently selected from hydrogen, alkyl, substituted alkyl, and cycloalkyl, or R ' and R ' together form a heterocyclic or heteroaryl ring.

Preferred monocyclic heteroaryls include pyrrolyl, pyrazolyl, pyrazolinyl, imidazolyl, oxazolyl, oxadiazolyl, isoxazolyl, thiazolyl, thiadiazolyl, S-isothiazolyl, furanyl, thienyl, oxadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl and the like.

Preferred bicyclic heteroaryl groups include indolyl, benzothiazolyl, benzodioxolyl, benzoxazolyl, benzothienyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuranyl, chromonyl, coumarinyl, benzopyranyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, dihydroisoindolyl, tetrahydroquinolinyl, and the like.

Preferred tricyclic heteroaryl groups include carbazolyl, benzidolyl, phenanthrolinyl, acridinyl, phenanthridinyl, xanthenyl and the like.

The term "heterocycle" or "heterocycloalkyl" as used herein alone or as part of another group refers to a cycloalkyl (non-aromatic) group in which one of the carbon atoms in the ring is replaced with a heteroatom selected from O, S or N. "heterocycle" has from 1 to 3 fused, pendant, or spiro rings, at least one of which is a heterocycle (i.e., one or more ring atoms are heteroatoms, with the remaining ring atoms being carbon). The heterocyclic ring may be optionally substituted, which means that the heterocyclic ring may be substituted at one or more substitutable ring positions with one or more groups independently selected from: alkyl (preferably lower alkyl), heterocycloalkyl, heteroaryl, alkoxy (preferably lower alkoxy), nitro, monoalkylamino (preferably lower alkylamino), dialkylamino (preferably alkylamino), cyano, halo, haloalkyl (preferably trifluoromethyl), alkanoyl, aminocarbonyl, monoalkylaminocarbonyl, dialkylaminocarbonyl, alkylamido (, preferably lower alkylamido), alkoxyalkyl (preferably lower alkoxy; lower alkyl), alkoxycarbonyl (preferably lower alkoxycarbonyl), alkylcarbonyloxy (preferably lower alkylcarbonyloxy) and aryl (preferably phenyl), said aryl being optionally substituted by halo, lower alkyl and lower alkoxy. Heterocyclic groups may generally be attached via any ring or substituent atom, provided that the result is a stable compound. The N-linked heterocyclic group is linked via a nitrogen atom of the compositional formula.

Typically, the heterocyclic ring contains 1-4 heteroatoms; in certain embodiments, each heterocycle has 1 or 2 heteroatoms per ring. Each heterocyclic ring typically contains from 3 to 8 ring members (rings having up to 7 ring members are described in certain embodiments), while heterocyclic rings that comprise fused, pendant or spiro rings typically contain from 9 to 14 ring members that include carbon atoms and contain one, two or three heteroatoms selected from nitrogen, oxygen and/or sulfur.

Examples of "heterocycle" or "heterocycloalkyl" include piperazine, piperidine, morpholine, thiomorpholine, pyrrolidine, imidazolidine, and thiazolidine (thiazolide).

The term "carbamoyl" refers herein to a compound of the formula C (O) N (R)₂Representative aminocarbonyl-containing substituents, wherein R is H, hydroxy, alkyl, carbocycle, heterocycle, carbocycle-substituted alkyl or alkoxy, or heterocycle-substituted alkyl or alkoxy, wherein alkyl, alkoxy, carbocycle, and heterocycle are as defined herein. Carbonyl (carbomoyl) groups include alkylaminocarbonyl groups (e.g. ethylaminocarbonyl, Et-NH-CO-), arylaminocarbonyl groups (e.g. phenylaminocarbonyl), aralkylaminocarbonyl groups (e.g. benzoylaminocarbonyl), heterocyclic aminocarbonyl groups (e.g. piperazinylaminocarbonyl), especially heteroarylaminocarbonyl groups (e.g. pyridylaminocarbonyl).

The term "sulfamoyl" as used herein refers to-SO₂-N(R)₂Wherein each R is independently H, alkyl, carbocycle, heterocycle, carbocycloalkyl, or heterocycloalkyl. Particular sulfamoyl groups are alkylsulfamoyl groups, such as methylsulfamoyl (-SO)₂-NHMe); arylsulfamoyl groups such as phenylsulfamoyl; aralkyl sulfamoyl groups, such as benzyl sulfamoyl groups.

The term "sulfinyl" refers herein to the group-SOR, wherein R is alkyl, carbocyclic, heterocyclic, carbocycloalkyl, or heterocycloalkyl. Particular sulfinyl groups are alkylsulfinyl (i.e. -SO-alkyl), such as methylsulfinyl; arylsulfinyl (i.e., -SO-aryl) such as phenylsulfinyl; aralkylsulfinyl, such as benzylsulfinyl.

The term "sulfonamide" refers herein to-NR-SO₂-R, wherein each R is independently H, alkyl, carbocycle, heterocycle, carbocycloalkyl or heterocycloalkyl), carbocycle or heterocycle. Particular sulfonamide groups are alkylsulfonamides (e.g., -NH-SO)₂-alkyl), such as methylsulfonamide; aryl sulfonamides (e.g. -NH-SO)₂Aryl), such as phenylsulfonamide; aralkyl sulfonamides, such as benzyl sulfonamide.

The term "sulfonyl" refers herein to-SO₂-an R group, wherein R is alkyl, carbocycle, heterocycle, carbocycloalkyl or heterocycloalkyl. Particular sulfonyl groups are alkylsulfonyl (e.g., -SO)₂-alkyl), such as methanesulfonyl; arylsulfonyl such as phenylsulfonyl; aralkylsulfonyl, for example benzylsulfonyl.

A dash ("-") that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, -CONH₂Attached through a carbon atom.

The term "substituent", as used herein, refers to a molecular moiety covalently bonded to an atom in the molecule of interest. For example, a "ring substituent" may be a moiety that: such as halogen, alkyl, haloalkyl or other groups described herein covalently bonded to a ring member atom, preferably a carbon or nitrogen atom.

The term "optionally substituted" means that the aryl or heterocyclyl group or other group may be substituted at one or more substitutable positions with one or more groups independently selected from: alkyl (preferably lower alkyl), alkoxy (preferably lower alkoxy), nitro, monoalkylamino (preferably having one to six carbons), dialkylamino (preferably having one to six carbons), cyano, halo, haloalkyl (preferably trifluoromethyl), alkanoyl, aminocarbonyl, monoalkylaminocarbonyl, dialkylaminocarbonyl, alkylamido (preferably lower alkylamido), alkoxyalkyl (preferably lower alkoxy and lower alkyl), alkoxycarbonyl (preferably lower alkoxycarbonyl), alkylcarbonyloxy (preferably lower alkylcarbonyloxy) and aryl (preferably phenyl), said aryl being optionally substituted by halo, lower alkyl and lower alkoxy. The phrase "substituted with 0 to X substituents" also means optional substitution, wherein X is the maximum number of possible substituents. Certain optionally substituted groups are substituted with 0 to 2, 3 or 4 independently selected substituents.

The term "pharmaceutically acceptable salt" of a compound as described herein is an acid or base salt, which is suitable for use withHuman or animal tissue is contacted without undue toxicity or carcinogenicity, preferably without irritation, allergic response, or other problem or complication. The salts include inorganic and organic acid salts of basic residues such as amines, and alkali metal or organic salts of acidic residues such as carboxylic acids. Specific pharmaceutical salts include, but are not limited to, the salts of the following acids: such as hydrochloric acid, phosphoric acid, hydrobromic acid, malic acid, glycolic acid, fumaric acid, sulfuric acid, sulfamic acid, sulfanilic acid, formic acid, toluenesulfonic acid, methanesulfonic acid, benzenesulfonic acid, ethanedisulfonic acid, 2-hydroxyethylsulfonic acid, nitric acid, benzoic acid, 2-acetoxybenzoic acid, citric acid, tartaric acid, lactic acid, stearic acid, salicylic acid, glutamic acid, ascorbic acid, pamoic acid, succinic acid, fumaric acid, maleic acid, propionic acid, hydroxymaleic acid, hydroiodic acid, phenylacetic acid, alkanoic acids such as acetic acid, HOOC- (CH) where n is 0-4₂)_n-COOH, etc. Similarly, pharmaceutically acceptable cations include, but are not limited to, sodium, potassium, calcium, aluminum, lithium, and ammonium. One of ordinary skill in the art will recognize other pharmaceutically acceptable salts of the compounds provided herein. In general, pharmaceutically acceptable acid or base salts can be synthesized from the parent compound containing a basic or acidic moiety by any conventional chemical method. In brief, the salts can be prepared by: reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of the two; in general, it is preferred to use nonaqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile. It will be apparent that the compounds of formula I may, but need not, be formulated as hydrates, solvates or non-covalent complexes. In addition, various crystalline forms and polymorphs are also within the scope of the present invention. Prodrugs of the compounds of formula I are also provided herein.

An "optionally substituted" group is unsubstituted or substituted at one or more possible positions with a substituent other than hydrogen. Such optional substituents include, for example, hydroxy, halogen, cyano, nitro, C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₁-C₆Alkoxy radical, C₂-C₆Alkyl ethers, C₃-C₆Alkanones, C₂-C₆Alkylthio, amino, mono-or di- (C)₁-C₆Alkyl) amino, C₁-C₆Haloalkyl, -COOH, -CONH₂Mono-or di- (C)₁-C₆Alkyl) -aminocarbonyl, -SO₂NH₂And/or mono-or di (C)₁-C₆Alkyl) sulfonamido, and carbocyclic and heterocyclic groups.

The phrase "substituted with 0 to X substituents" also refers to optional substitution, where X is the maximum number of possible substituents. Certain optionally substituted groups are substituted with 0 to 2, 3 or 4 independently selected substituents.

In a particular embodiment, a is a ring selected from the group consisting of:

examples of specific compounds of the invention are those defined below:

the invention also relates to compounds of formula (A):

or a pharmaceutically acceptable salt thereof, wherein:

k is selected from NR₃C(O)，C(O)NR₃，NR₃SO₂，SO₂NR₃And NR and₄C(O)NR₅；

A¹selected from aryl, heterocyclyl, and heteroaryl;

R₁selected from H, halo, nitro, -OR₄，C₁-C₆Alkyl radical, C₁-C₆Alkylsulfonyl, and C₁-C₆A haloalkyl group;

m＝0-4；

R₃、R₄and R₅Each independently selected from H and C₁-C₆An alkyl group;

w is selected from CH and N;

z is selected from H, halo, and C₁-C₆Alkyl radical, C₁-C₆Alkyl sulfideRadical, -NR₄R₅，-OR₄And a cyano group.

In one embodiment, the invention relates to a compound represented by formula (a):

or a pharmaceutically acceptable salt thereof, wherein:

k is selected from NR₃C(O)，C(O)NR₃，NR₃SO₂，SO₂NR₃And NR and₄C(O)NR₅；

A¹selected from phenyl and pyridyl;

R₁selected from H, halo, nitro, C₁-C₆Alkylsulfonyl, and C₁-C₆An alkyl group;

m＝0-4；

R₃、R₄and R₅Each independently selected from H and C₁-C₆An alkyl group;

w is selected from CH and N;

z is selected from H, halo, and C₁-C₆An alkyl group.

The invention also relates to compounds of formula (B):

or a pharmaceutically acceptable salt thereof, wherein:

R₃、R₄and R₅Each independently selected from H and C₁-C₆An alkyl group;

R₇selected from heterocyclic radicals, haloalkyl radicals, NR₃C(O)R₄，NR₃C(O)NR₄R₅，NR₃C(O)[C(R₃)(R₄)]_nO[C(O)]_pR₄，(CH₂)_nSO₂R₃，NR₃SO₂R₄，NR₃C(O)-Q-R₄And N (OR)₃)C(O)R₄；

n is 1 to 2;

p is 0 or 1;

q is a heterocyclic group;

u is selected from H, halo, C₁-C₆Alkyl radical, C₁-C₆Alkylthio, -NR₄R₅，-OR₄And cyano;

v is selected from CH and N;

w is selected from CH and N;

z is selected from H, halo, and C₁-C₆An alkyl group.

The invention also relates to compounds of formula (C):

or a pharmaceutically acceptable salt thereof, wherein:

R₃、R₄and R₅Each independently selected from H and C₁-C₆An alkyl group;

R₇selected from heterocyclic radicals, haloalkyl radicals, NR₃C(O)R₄，NR₃C(O)NR₄R₅，NR₃C(O)[C(R₃)(R₄)]_nO[C(O)]_pR₄，(CH₂)_nSO₂R₃，NR₃SO₂R₄，NR₃C(O)-Q-R₄And N (OR)₃)C(O)R₄；

n is 1 to 2;

p is 0 or 1;

q is a heterocyclic group;

u is selected from H, halo, C₁-C₆Alkyl radical, C₁-C₆Alkylthio, -NR₄R₅，-OR₄And cyano;

v is selected from CH and N;

z is selected from H, halo, and C₁-C₆An alkyl group.

In certain embodiments, the invention relates to compounds of formulae (i) - (xv) and pharmaceutically acceptable salts thereof as shown below:

in yet another embodiment, a method of making a compound of the invention is provided. The compounds of the invention can generally be prepared by coupling the central ring and the a ring via established amide bond formation procedures. Compound (I) and all other compounds of the present invention may contain various stereoisomers, geometric isomers, tautomers and the like. All possible isomers and mixtures thereof are included in the present invention, and the mixing ratio is not particularly limited. The quinoline compounds of formula (C) may be prepared similarly to the isoquinoline and quinazoline compounds as described below.

Isoquinoline of the general formula (4) (wherein R₁Preferably Cl) is preferably carried out as follows (scheme 1): first, commercially available (±) -2-amino-1-phenylethanol (1) is reacted with commercially available 2-chloro-5-nitrobenzoyl chloride (2) in the presence of TEA in an aprotic solvent, preferably dichloromethane, to form 2-chloro-N- (2-hydroxy-2-phenylethyl) -5-nitrobenzamide (3). The latter compound is then exposed to a dehydrating agent, preferably phosphorus pentoxide or phosphorus oxychloride, under reflux conditions and in an inert solvent, preferably toluene and xylene, to form isoquinoline (4) (Manning H.C., Goebel, T., et al, org.Lett., 2002, 4, 1075-S1078; Funabashi, K., Ratni, H., et. Al., J.Am.chem.Soc., 2001, 123, 10784-S10785).

Scheme 1

An alternative way to form isoquinoline or quinazoline 7 is the Suzuki cross-linking reaction (scheme 2). Various aryl boronic acids are reacted with compound 5 (where B is CH or N; Q is Cl, Br or I) in the presence of a palladium catalyst such as palladium (II) triphenylphosphine, dichlorobis (triphenylphosphine) palladium (0), or tetrakis (triphenylphosphine) palladium (0) to provide compounds of formula 7 (Chapoulaud, V.G. et al, Tetrahedron, 2000, 56, 5499-. The reaction can also be carried out as follows: pseudohalogens such as triflate (OTf) are used instead of halides and boron-esters are used instead of boronic acids. Compound 5(B is N and Q is Cl) was prepared by: under reflux, 4-hydroxyquinazoline was reacted with SOCl₂the/DMF reaction (Hennequin l.f. et al, j.med.chem., 1999, 42,5369-5389)。

scheme 2

Compound 7 is then reduced in the presence of a reducing agent to form intermediate 8 (scheme 3). The nitro group can be reduced in a number of ways well known to those skilled in the art of organic synthesis, including, but not limited to, catalytic hydrogenation, with SnCl₂Reduction and reduction with titanium dichloride. Preferred reducing agent herein is SnCl₂. In a particular embodiment, the reduction reaction is carried out at about 60 ℃. The reduction method can be seen in: hudlicky, m.reductions in Organic Chemistry, acsmograph 188, 1996.

Scheme 3

After reacting aldehyde (9) (wherein R' represents substituted or unsubstituted (C)₁-C₃) Alkyl) with intermediate 8, followed by reduction of the product with a reducing agent such as hydrogen, simple or complex metal hydrides, transition metals or salts thereof, but preferably with sodium cyanoborohydride, to form the N-alkyl-amino compound of formula (10) (scheme 4).

Scheme 4

Compounds 8 or 10 can be converted to 11 (wherein R is₃Is hydrogen or optionally substituted C_1-4Alkyl groups). Then, according to the method of patent WO 01/25220A1, a carboxylic acid, carboxylic anhydride or acid chloride of general formula 12 (wherein Q is chloride or O-EDC)) Compound 11 is acylated or reacted with an acid chloride, sulfonamide halide (13), isocyanate (14) or thiocyanate (15) to form an N-acyl-amino compound of formula Ia, IIa, IIIa or IVa (scheme 5). Advantageously, the reaction is carried out in an aprotic solvent in the presence of a base at ambient temperature.

The aprotic solvent for the condensation reaction may use, but is not limited to, dichloromethane, acetone, dioxane, acetonitrile, chloroform, dichloroethane, diethyl ether, THF, DMF, etc., or may be conveniently used alone or as a mixture thereof at a temperature of-60 ℃ to reflux.

Various basic reagents may be used, including, but not limited to, pyridine, triethylamine, diisopropylethylamine, methylamine, imidazole, benzimidazole, histidine, sodium hydride, and the like, preferably pyridine, or may be used alone without a solvent.

In the reaction of compound 11 with an aldehyde or ketone of formula 16 (wherein R is₄Represents hydrogen or optionally substituted C_1-4Alkyl radical, R₂And m is as defined herein) followed by reduction of the product with a reducing agent to form compound Va (scheme 5).

Solvents for the condensation reaction may be used, but are not limited to, dichloromethane, acetone, dioxane, acetonitrile, chloroform, dichloroethane, diethyl ether, THF, DMF, etc., or may be conveniently used alone or as a mixture thereof at a temperature of-60 ℃ to room temperature.

Imines can be reduced using a variety of reducing agents and reaction conditions. Sodium cyanoborohydride may be used as the reducing agent. Other reducing agents that can be used include, but are not limited to, sodium borohydride, sodium hydrosulfite, lithium aluminum hydride, red-Al, and the like. The solvent may be used at a temperature of 0 ℃ to the reflux temperature of DMF, acetonitrile, benzene, toluene, etc., which are solvents, but not limited to, alcohols such as methanol and ethanol, under neutral conditions.

Scheme 5

In scheme 6, compound 8 is reacted with nitrite in an acidic medium, in a copper (I) salt such as Cu₂Cl₂The resulting aryldiazonium salt solution is mixed with a solution of sulfur dioxide in acetic acid in the presence of a solvent to form the desired arylsulfonyl chloride (Hanson, j., Dogne j., et al, j.med.chem., 2007, 50, 3928-. Then, compound 17 is reacted with an amine of formula 18 (wherein R is₃As defined herein) to form compound Ib.

Aprotic solvents for the condensation reaction may be used, but are not limited to, dichloromethane, acetone, dioxane, acetonitrile, chloroform, dichloroethane, diethyl ether, THF, DMF, and the like, and may be conveniently used alone or as a mixture thereof at a temperature of-60 ℃ to reflux.

Various basic reagents can be used, but are not limited to, pyridine, triethylamine, di-isopropylethylamine, methylamine, imidazole, benzimidazole, histidine, sodium hydride, etc., preferably pyridine, and can be used alone without a solvent.

Scheme 6

In scheme 7, compound 19 is reduced to amine 20 using the same procedure as for the preparation of compound 8. In a particular embodiment, with SnCl₂The reduction reaction was carried out at about room temperature. Reacting the intermediate 20 with an activated acid 21 (wherein R' represents substituted or unsubstituted (C)₁-C₁₀) Alkyl, alkenyl, (C)₃-C₇) Aryl or heteroaryl) to yield the final compound Ic. In particular embodiments, the activated acid (21) is an acid halide (e.g., Q is chloride) or an activated ester (e.g., Q is O-EDC). In a particular embodiment, the reaction is carried out at about 0 ℃ to room temperature.

Scheme 7

Reacting intermediate 20 with the appropriate sulfonyl chloride R' - (SO) in the presence of a non-nucleophilic base such as TEA or diisopropylethylamine₂) Cl (21) (wherein R' represents substituted or unsubstituted (C)₁-C₁₀) Alkyl, alkenyl, (C)₃-C₇) Aryl or heteroaryl) to form the desired sulfonamide Id (scheme 8).

Scheme 8

As shown in scheme 9, formula Ie can be prepared by: with substituted aldehydes or ketones R₇COR₈(wherein R is₇Or R₈Independently or together represent hydrogen, substituted or unsubstituted (C)₁-C₁₀) Alkyl, alkenyl, aryl or heteroaryl) followed by reduction. The solvent, reducing agent and reaction conditions for the condensation reaction may be the same as those used for the preparation of compound Va.

Scheme 9

Compound 23, an isoquinazoline or quinazoline with a heteroaryl group substituted with a latent leaving group (e.g., Cl, Br, I, SO2Me, etc.) can be substituted by: with nucleophiles, e.g. amines 24, R, in the presence of inert solvents₉NHR₁₀(wherein R is₉Or R₁₀Independently or together represent substituted or unsubstitutedIs (C)₁-C₁₀) Alkyl, alkenyl; or (C)₃-C₇) Aryl or heteroaryl) or a secondary amine of the formula 25 (wherein Z, R₅And R₆As defined herein) to yield compounds If and Ig (scheme 10).

There are no particular restrictions on the nature of the solvent to be used, provided that it has no adverse effect on the reaction or on the reagents concerned and that it is capable of dissolving (at least to some extent) said reagents. Examples of suitable solvents include: aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons, in particular aromatic and aliphatic hydrocarbons, such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene and dichlorobenzene; esters such as ethyl formate, ethyl acetate, propyl acetate, butyl acetate and diethyl carbonate; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol dimethyl ether; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, isophorone and cyclohexanone; nitro compounds, which may be nitroalkanes or nitroaromatics (nitroaranes), such as nitroethane and nitrobenzene; nitriles such as acetonitrile and isobutyronitrile; amides, which may be fatty acid amides such as formamide, dimethylformamide, dimethylacetamide and hexamethylphosphoric triamide; and sulfoxides such as dimethyl sulfoxide and sulfolane.

The reaction can occur over a wide temperature range and the precise reaction temperature is not critical to the invention. In general, we have found it convenient to carry out the reaction at a temperature of from-50 ℃ to 100 ℃.

Scheme 10

Scheme 11 illustrates one of the methods for replacing the-OH group in the-COOH group of carboxylic acid 26 with a chlorine atom to prepare an acid chloride of formula 12. Various chlorine reagents and reaction conditions can be used. Sulfur oxychloride (thionyl chloride) can be used as the chlorine reagent under reflux conditions without the need for a solvent (Clayden, J., Organic chemistry. Oxford University Press.2001, 276-. Other reagents that can be used include, but are not limited to, phosphorus (V) chloride, phosphorus (III) chloride (Boyd, R; Morrison, R., Organic chemistry, 1992, 666-. Certain acids that are not HCl-resistant are capable of forming acid chlorides via the Appelye reaction (Taschner, M.J., e-EROS: Encyclopedia of Reagents for organic Synthesis, 2001).

Scheme 11

Scheme 12 illustrates that methyl ester 27 can be heated at reflux with a dilute base-like sodium hydroxide solution, potassium hydroxide solution or lithium hydroxide solution, preferably with lithium hydroxide solution, to form the acid of formula 28. Protic solvents including, but not limited to, water, dimethyl sulfoxide, dimethylformamide, dioxane and hexamethylphosphoric triamide, and tetrahydrofuran may be used. Preferably the protic solvent is a mixture of tetrahydrofuran and water. Product 28 can be further reacted with a chlorine reagent (same reaction conditions used to make 12) to form an acid chloride (where Q is chloride), and the product can also be reacted with EDCl to form an activated ester (Q is O-EDC). Compound 29 can be further reacted with amines 24 or 25 to form amide compounds Ih and Ij (scheme 12).

Scheme 12

The compounds of formula Ik, Im, Io according to the invention can be prepared by methods known in the art (e.g. Stephenson, f.m., org.synth.1963, 4, 984; Snell, j.m., Weissberger, a., et al, org.synth, 1955, 3, 788; Greenwood, f.l., et al, org.synth., 1963, 4, 108). Methylene aryl compound 30 is combined with benzoyl peroxide and N-bromosuccinimide in a 5% AcOH solution in benzene and heated to obtain benzyl bromide derivative 31. Compound 31 can be reacted with nucleophiles, such as amines 24 and 25 (where R is R) in the presence of a non-nucleophilic base such as potassium carbonate, cesium carbonate, TEA or diisopropylethylamine₅，R₆，R₉And R₁₀As defined herein), and thiol derivatives R₁₁SH 32 (wherein R₁₁Represents substituted or unsubstituted (C)₁-C₁₀) Alkyl, alkenyl, (C)₃-C₇) Aryl or heteroaryl) to yield Ik, Im and Io (scheme 13).

Scheme 13

The preparation of the compounds of formula Ip according to the invention can be carried out by: the thiol derivative (Io) is oxidized to the sulfone (Ip) in the presence of a protic solvent such as water, methanol, and ethanol (scheme 14).

The oxidizing agent used may be, but is not limited to,meta-chloroperoxybenzoic acid, peroxytrifluoroacetic acid, or hydrogen peroxide. Suitable solvents can be, but are not limited to, chloroform, dichloromethane, benzene and toluene, in admixture with alcoholic solvents, such as methanol, ethanol, isopropanolOr 1-butanol, especially ethanol. The oxidation reaction is conveniently carried out at a temperature of-60 ℃ to room temperature.

Scheme 14

The present invention provides compositions of matter that are formulations of one or more active agents and a pharmaceutically acceptable carrier. In view of this, the present invention provides compositions for administration to a mammalian subject, which may include a compound of formula I, or a pharmaceutically acceptable salt thereof.

Pharmaceutically acceptable salts of the compounds of the present invention include those derived from pharmaceutically acceptable inorganic and organic acids and bases. Examples of suitable acid salts include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, palmitate, pectate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, salicylate, succinate, sulfate, tartrate, thiocyanate, tosylate and undecanoate. Other acids, such as oxalic, while not per se pharmaceutically acceptable, may be used to prepare salts useful as intermediates in obtaining the compounds of the present invention and their pharmaceutically acceptable acid addition salts.

Salts derived from suitable bases include alkali metals (e.g., sodium and potassium), alkaline earth metals (e.g., magnesium), ammonium and N⁺(C_1-4Alkyl radical)₄And (3) salt. The present invention also contemplates the quaternization of any basic nitrogen-containing group of the compounds disclosed herein. Products which are soluble or dispersible in water or oil can be obtained by the quaternization. The compositions of the invention may be administered as follows: oral, parenteral, inhalation spray, topical, rectal, nasal, buccal, vaginal or via an implanted reservoir. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. Preferably, the composition is administered orally, intraperitoneally, or intravenously.

The pharmaceutically acceptable compositions of the present invention may be administered orally in any orally acceptable dosage form including, but not limited to, capsules, tablets, lozenges, elixirs, suspensions, syrups, wafers (wafers), chewing gums, suspensions or aqueous solutions.

Oral compositions may contain additional ingredients such as: binders such as microcrystalline cellulose, gum tragacanth or gelatin; excipients such as starch or lactose, disintegrating agents such as alginic acid, corn starch, and the like; lubricants such as magnesium stearate; glidants such as colloidal silicon dioxide; and sweetening agents such as sucrose or saccharin or flavoring agents such as peppermint, methyl salicylate, or orange flavoring agents. Where the dosage unit form is a capsule, it may additionally contain a liquid carrier such as a fatty oil. Other dosage unit forms (dosage unit form) may contain other various materials which modify the physical form of the dosage unit, for example, as coatings. Thus, the tablets or pills may be coated with sugar, shellac, or other enteric coating agents. Syrups may contain, in addition to the active ingredient, sucrose as a sweetening agent and certain preservatives, dyes and colorings and flavors.

The materials used in preparing these various compositions should be pharmaceutically or veterinarily pure and non-toxic in the amounts employed.

For the purpose of parenteral therapeutic administration, the active ingredient may be incorporated into a solution or suspension. The solution or suspension may also include the following components: sterile diluents for injection such as water, saline solution, fixed oils, polyethylene glycols, glycerin, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl paraben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for adjusting the tonicity such as sodium chloride or dextrose. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.

Pharmaceutical forms suitable for injectable use include sterile solutions, dispersions, emulsions, and sterile powders. The final form should be stable under the conditions of preparation and storage. In addition, the final pharmaceutical form should be protected against contamination and should therefore be able to inhibit the growth of microorganisms such as bacteria or fungi. A single intravenous or intraperitoneal dose may be administered. Alternatively, slow long-term infusion or multiple short-term daily infusions may be used, typically lasting 1 to 8 days. Alternate or once a few days may also be used.

Sterile injectable solutions can be prepared by: the compounds are incorporated in the required amount in one or more suitable solvents and other ingredients described above or known to those skilled in the art may be added thereto as required. Sterile injectable solutions can be prepared by: the compounds are incorporated in the required amount in an appropriate solvent with the various other ingredients required. A sterilization procedure, such as filtration, may then be performed. Generally, the dispersion is prepared by: the compounds are incorporated into a sterile vehicle which also contains a dispersion medium and the required other ingredients described above. In the case of sterile powders, preferred methods include vacuum drying or lyophilization, and the addition of any desired ingredient thereto.

Suitable pharmaceutical carriers include sterile water; saline, dextrose; water or saline solution of glucose; condensation products of castor oil with ethylene oxide in an amount of from about 30 to about 35 moles of ethylene oxide per mole of castor oil; a liquid acid; a lower alkanol; oils such as corn oil; peanut oil, sesame oil and the like, which contain an emulsifier such as a fatty acid mono-or diglyceride, or a phospholipid, e.g., lecithin, and the like; a diol; a polyalkylene glycol; aqueous media in the presence of suspending agents such as sodium carboxymethylcellulose; sodium alginate; poly (vinyl pyrrolidone); etc., alone or with a suitable partitioning agent such as lecithin; polyoxyethylene stearate, and the like. The carrier may also contain adjuvants such as preserving, stabilizing, wetting, emulsifying, and the like agents, as well as penetration enhancers. In all cases, it should be noted that the final form must be sterile and should also be able to easily pass through an injection device such as a hollow needle. The proper viscosity can be achieved and maintained by proper choice of solvent or excipient. In addition, molecular or particle coatings such as lecithin, appropriately selected particle sizes of the dispersion, or substances with surfactant properties may be used.

According to the present invention there is provided compositions containing triazine derivatives and methods for in vivo delivery of triazine derivatives in nanoparticle form, suitable for any of the aforementioned routes of administration.

U.S. Pat. nos. 5,916,596, 6,506,405, and 6,537,579 teach the preparation of nanoparticles from biocompatible polymers such as albumin. Thus, in accordance with the present invention, there is provided a method of forming nanoparticles of the present invention from an oil-in-water emulsion prepared under conditions of high shear (e.g., ultrasound, high pressure homogenization, etc.) by solvent evaporation techniques.

Alternatively, the pharmaceutically acceptable compositions of the present invention may be administered in the form of suppositories for rectal administration. They can be prepared by: the agent is mixed with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. The materials include cocoa butter, beeswax and polyethylene glycols.

The pharmaceutically acceptable compositions of the present invention may also be administered topically, particularly where the therapeutic target includes areas or organs that can be readily accessed by topical application, including ocular, skin, or lower intestinal (lower intestinal tract) diseases. Suitable topical formulations for each of these areas or organs can be readily prepared.

Topical application to the lower intestinal tract can be carried out with rectal suppository formulations (see above) or suitable enema formulations. Topical-transdermal patches may also be used.

For topical application, the pharmaceutically acceptable compositions may be formulated in a suitable ointment containing the active ingredient suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of the present invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutically acceptable compositions can be formulated as suitable lotions or creams containing the active ingredient suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

For ophthalmic use, the pharmaceutically acceptable compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or preferably, as solutions in isotonic, pH adjusted sterile saline, with or without preservatives such as benzalkonium chloride. Alternatively, for ophthalmic use, the pharmaceutically acceptable composition may be formulated as an ointment such as petrolatum.

The pharmaceutically acceptable compositions of the present invention may also be administered by nasal aerosol or inhalation. The compositions are prepared according to techniques well known in the art of pharmaceutical formulation and may be prepared as solutions in saline with benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solvating or dispersing agents.

Most preferably, the pharmaceutically acceptable compositions of the present invention are formulated for oral administration.

In accordance with the present invention, the compounds of the present invention inhibit hedgehog signaling and can be used to treat cancers associated with aberrant hedgehog signaling, cell proliferation or hyperproliferation, such as cancers including, but not limited to, tumors of the nasal cavity, paranasal sinuses, nasopharynx, oral cavity, oropharynx, larynx, hypopharynx, salivary glands, and paragangliomas. The compounds of the invention may also be useful in the treatment of cancers of the liver and biliary tree (particularly hepatocellular carcinoma), intestinal cancers, particularly colorectal cancer, ovarian cancer, small cell and non-small cell lung cancers, breast cancer, sarcomas (including fibrosarcoma, malignant fibrous histiocytoma, embryonal rhabdomyosarcoma, smooth muscle connective tissue tumor, neuro-fibrosarcoma, osteosarcoma, synovial sarcoma, liposarcoma, and alveolar soft part sarcoma), tumors of the central nervous system (particularly brain cancer), and lymphomas (including hodgkin's lymphoma, lymphoplasmacytoid lymphoma, follicular lymphoma, mucosa-associated lymphoid tissue lymphoma, mantle cell lymphoma, B-lineage large cell lymphoma, Burkitt's lymphoma, and T-cell reductoplasty type large cell lymphoma).

The compounds and methods of the present invention, when administered alone or in combination with other agents (e.g., chemotherapeutic agents or protein therapeutics described below), are also useful in the treatment of various disorders, including, but not limited to, for example: stroke, cardiovascular disease, myocardial infarction, congestive heart failure, cardiomyopathy, myocarditis, ischemic heart disease, coronary artery disease, cardiogenic shock, vascular shock, pulmonary hypertension, pulmonary edema (including cardiogenic pulmonary edema), pleural effusion, rheumatoid arthritis, diabetic retinopathy, retinitis pigmentosa, and retinopathies, including diabetic retinopathy and retinopathy of prematurity, inflammatory diseases, restenosis, asthma, acute or Adult Respiratory Distress Syndrome (ARDS), lupus, vascular leakage, protection against ischemic or reperfusion injury such as that caused during organ transplantation, induction of transplant tolerance; ischemic or reperfusion injury following angioplasty; arthritis (such as rheumatoid arthritis, psoriatic arthritis or osteoarthritis); multiple sclerosis; inflammatory bowel disease, including ulcerative colitis and crohn's disease; lupus (systemic lupus erythematosus); graft versus host disease; t-cell mediated hypersensitivity disorders including contact hypersensitivity, delayed-type hypersensitivity, and gluten irritable bowel disease (celiac disease); type I diabetes; psoriasis; contact dermatitis (including those caused by Rhus toxicodendron); georges thyroiditis; sjogren's syndrome; autoimmune hyperthyroidism, such as graves' disease; addison's disease (adrenal autoimmune disease); autoimmune glandular disease (also known as autoimmune glandular syndrome); autoimmune alopecia; pernicious anemia; white spots; autoimmune hypopituitarism; guillain-barre syndrome; other autoimmune diseases; cancers, including those in which kinases such as Src-family kinases are activated or overexpressed, such as colon cancers and thymomas, or cancers in which kinase activity promotes tumor growth or survival; glomerulonephritis, seropathy; urticaria; allergic diseases such as respiratory allergy (asthma, pollinosis, allergic rhinitis) or skin allergy; mycosis fungoides; acute inflammatory responses (such as acute or adult respiratory distress syndrome and ischemic reperfusion injury); dermatomyositis; alopecia areata; chronic actinic dermatitis; eczema; behcet's disease; palmoplantar pustulosis; pyoderma gangrene; siraiil syndrome; atopic dermatitis; systemic sclerosis; hard spot disease; peripheral limb ischemia and ischemic limb disease; skeletal diseases such as osteoporosis, osteomalacia, hyperparathyroidism, paget's disease, and renal osteodystrophy; vascular leak syndrome, including chemotherapy or immunomodulators such as IL-2 induced vascular leak syndrome; injuries or trauma to the spinal cord and brain; glaucoma, and glaucoma; retinal diseases, including macular degeneration; vitreoretinal disease; pancreatitis; vasculitis, including vasculitis, kawasaki disease, thromboangiitis obliterans, wegener's granulomatosis, and Behcet's disease; scleroderma; pre-eclampsia; thalassemia; kaposi's sarcoma; hill-forest disease; and the like.

The invention also provides methods of treating mammals suffering from the above-mentioned diseases and conditions. The amount of a compound of the invention that may be combined with a carrier material to obtain a composition in the form of a single dose will vary depending upon the host treated, the particular mode of administration. Preferably, the compositions should be formulated so that a dose of 0.01-100mg/kg body weight/day of the inhibitor can be administered to a patient receiving these compositions.

In one aspect, a compound of the invention is administered to a subject in need of such treatment in combination with a chemotherapeutic agent, an anti-inflammatory agent, an antihistamine, a chemotherapeutic agent, an immunomodulator, a therapeutic antibody or a protein kinase inhibitor, e.g., a tyrosine kinase inhibitor.

The method comprises administering one or more compounds of the invention to a mammal suffering from the disease. The method may further comprise administering a second active agent, such as a cytotoxic agent, including alkylating agents, tumor necrosis factors, intercalating agents, tubulin inhibitors, and topoisomerase inhibitors. The second active agent can be administered in the same composition or in a second composition together. Examples of suitable second active agents include, but are not limited to, cytotoxic drugs such as acivicin; aclarubicin; (ii) aristodazole hydrochloride; AcrQnine; (ii) Alexanox; aldesleukin; altretamine; an apramycin; amenthraquinone acetate; aminoglutethimide; amsacrine; anastrozole; an atramycin; an asparaginase enzyme; a triptyline; azacitidine; azatepa; (ii) azomycin; batimastat; benzotepa; bicalutamide; bisantrene hydrochloride; a salt of bisnefaride; bizelaixin; bleomycin sulphate; brequinar sodium; briprimine; busulfan; actinomycin C; caridotestosterone; a carbimide; a carbapenem; carboplatin; carmustine; a hydrochloride salt of carrubicin; kazelaixin; cediogo; chlorambucil; a sirolimus; cisplatin; cladribine; a salt of Clineratone mesylate; cyclophosphamide; cytarabine; dacarbazine; actinomycin D; daunorubicin hydrochloride; decitabine; (ii) dexomaplatin; 2, dizagutanin; 1, dizagutanin mesylate; diazaquinone; docetaxel; doxorubicin; doxorubicin hydrochloride; droloxifene; droloxifene citrate; drotaandrosterone propionate; daptomycin; edatrexae; ebhemidine hydrochloride; elsamitrucin; enloplatin; an enpu urethane; epinastine; epirubicin hydrochloride; (ii) ebuzole; esorubicin hydrochloride; estramustine; estramustine sodium phosphate; etanidazole; ethiodized oil 131; etoposide; etoposide phosphate; chlorphenethyl pyrimethanil; fadrozole hydrochloride; fazarabine; fenretinide; floxuridine; fludarabine phosphate; fluorouracil; (iii) flucitabine; a phosphorus quinolone; fostrexasin sodium; gemcitabine; gemcitabine hydrochloride; gold, Au 198; a hydroxyurea; idarubicin hydrochloride; ifosfamide; ilofovir dipivoxil; interferon alpha-2 a; interferon alpha-2 b; interferon alpha-n 1; interferon alpha-n 3; interferon beta-1 a; interferon gamma-1 b; iproplatin; irinotecan hydrochloride; lanreotide acetate; letrozole; leuprolide acetate; liazole hydrochloride; lometrexol sodium; lomustine; losoxantrone hydrochloride; (ii) maxolone; maytansine; a nitrogen mustard hydrochloride; megestrol acetate; melengestrol acetate; melphalan; (ii) a melanoril; mercaptopurine; methotrexate; methotrexate sodium; chlorpheniramine; meltupipide; mitodomide; mitocarcin (Mitocarcin); mitorubin; mitoxantrone; mitomacin; mitomycin; mitospirane culturing; mitotane; mitoxantrone hydrochloride; mycophenolic acid; nocodazole; a noramycin; ormaplatin; oshuzuren; paclitaxel; a pemetrexed; a pelithromycin; nemadectin; a salt of pellomycin sulfate; cultivating phosphoramide; pipobroman; piposulfan; piroxantrone hydrochloride; (ii) a plicamycin; pramipexole; porfimer sodium; a podomycin; deltemustine; procarbazine hydrochloride; puromycin; puromycin hydrochloride; pyrazole furan rhzomorph; (ii) lybodenosine; ludwimine; safmgol; safrog hydrochloride; semustine; octreozine; sodium phosphono-aspartate; a sparamycin; germanospiramine hydrochloride; spiromustine; spiroplatinum; streptomycin; a streptozocin; strontium chloride Sr 89; a sulfochlorophenylurea; a talithromycin; a taxane; taxoids (Taxoid); sodium tegafur; tegafur; tiloxanthraquinone hydrochloride; temoporfin; (ii) teniposide; a tiroxiron; a testosterone ester; (ii) a thiopurine; thioguanine; thiotepa; (ii) a thiazole carboxamide nucleoside; tirapazamine; topotecan hydrochloride; toremifene citrate; tritolone acetate; triciribine phosphate; trimetrexate; tritrexate glucuronate; triptorelin; tobramzole hydrochloride; uramustine; uretipi; vapreotide; verteporfin; vinblastine sulfate; vincristine sulfate; vindesine; vindesine sulfate; vinepidine sulfate; vincristate sulfate; vincristine sulfate; vinorelbine tartrate; vinblastine rosidine sulfate; vinzolidine sulfate; (ii) vorozole; zerniplatin; 1, neat setastine; and zorubicin hydrochloride.

In accordance with the present invention, compounds and compositions can be used at sub-cytotoxic levels in combination with other agents to achieve highly selective activity in the treatment of non-neoplastic disorders such as heart disease, stroke, and neurodegenerative diseases (Whitesell et al, Curr Cancer drug targets (2003), 3(5), 349-58).

Exemplary therapeutic agents that may be administered in combination with the compounds of the present invention include EGFR inhibitors, such as gefitinib, erlotinib, and cetuximab. Her2 inhibitors include canertinib, EKB-569, and GW-572016. Also included are Src inhibitors, dasatinib, and combretastatin (bicalutamide), tamoxifen, MEK-1 kinase inhibitors, MARK kinase inhibitors, PI3 inhibitors, and PDGF inhibitors such as imatinib, Hsp90 inhibitors such as 17-AAG and 17-DMAG. Also included are anti-angiogenic and anti-vascular agents that deprive cancer cells of their nutrition by interrupting blood flow to solid tumors. Castration, which also renders androgen dependent cancers non-proliferative, may also be employed. Also included are IGF1R inhibitors, inhibitors of non-receptor and receptor tyrosine kinases, and inhibitors of integrins.

The pharmaceutical compositions and methods of the invention may also contain other protein therapeutics such as cytokines, immunomodulatory drugs, and antibodies. The term "cytokine" as used herein encompasses chemokines, interleukins, lymphokines, monokines, colony stimulating factors, and receptor-associated proteins, and functional fragments thereof. As used herein, the term "functional fragment" refers to a polypeptide or peptide having a biological function or activity that is confirmed by a defined functional test. Cytokines include endothelial monocyte activating polypeptide II (EMAP-II), granulocyte-macrophage-CSF (GM-CSF), granulocyte-CSF (G-CSF), macrophage-CSF (M-CSF), IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-12, and IL-13, interferons, and the like, and are associated with specific biological, morphological, or phenotypic changes in cells or cellular mechanisms.

Other therapeutic agents for use in combination therapy include cyclosporins (e.g., cyclosporin a), CTLA4-Ig, antibodies such as ICAM-3, anti-IL-2 receptor (anti-Tac), anti-CD 45RB, anti-CD 2, anti-CD 3(OKT-3), anti-CD 4, anti-CD 80, anti-CD 86, agents that block the interaction of CD40 and gp39, such as antibodies specific for CD40 and for gpn39 (i.e., CD154), fusion proteins constructed from CD40 and gp39(CD40Ig and CD8gp39), inhibitors such as nuclear translocation inhibitors, inhibitors of NF-kappa B functions such as Deoxyspergualin (DSG), cholesterol biosynthesis inhibitors such as HM: g CoA reductase inhibitors (lovastatin and simvastatin), non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen and cyclooxygenase inhibitors such as rofecoxib, steroids such as prednisone or dexamethasone, gold compounds, antiproliferatives such as methotrexate, FK506 (tacrolimus, Prograf), mycophenolate mofetil, cytotoxic drugs such as azathioprine and cyclophosphamide, TNF-a inhibitors such as tenidap, anti-TNF antibodies or soluble TNF receptors, and rapamycin (sirolimus or rapalog) or derivatives thereof.

Where other therapeutic agents are used in combination with the compounds of the present invention, they may be used, for example, in the amounts noted in the Physician Desk Reference (PDR) or as determined by one of ordinary skill in the art.

Examples

The following examples are provided to further illustrate the invention but, of course, should not be construed as in any way limiting its scope.

All experiments were performed as follows: under anhydrous conditions (i.e., anhydrous solvents), in an argon atmosphere, with oven-dried equipment and using standard techniques for handling air-sensitive substances, unless otherwise specified. Sodium bicarbonate (NaHCO)₃) And chlorineAn aqueous solution of sodium chloride (brine) is saturated.

Analytical Thin Layer Chromatography (TLC) was performed on Merck Kiesel gel 60F 254 plates and visualized by uv light and/or anisaldehyde, potassium permanganate or phosphomolybdic acid dips.

NMR spectrum: recording at 400MHz¹H nuclear magnetic resonance spectrogram. The data are presented below: chemical shift, multiplicities (s ═ singlet, d ═ doublet, t ═ triplet, q ═ quartet, qn ═ quintet, dd ═ doublet, m ═ multiplet, bs ═ broad singlet), coupling constants (J/Hz) and integrals. Coupling constants were read and calculated directly from the spectra and were not corrected.

LC/Mass Spectrometry: electrospray (ES +) ionization was used. The protonated parent ion (M + H) or parent sodium ion (M + Na) or highest mass fragment is referenced. Unless otherwise stated, analytical gradients were from 10% ACN/water up to 100% ACN in 5 minutes.

Example 1

A solution of 2-chloro-5-nitrobenzoyl chloride (11.70g, 53.2mmol) in DCM (66.0mL) was added dropwise to a solution of triethylamine (7.40mL, 53.2mmol) in 2-amino-1-phenylethanol (7.30g, 53.2mmol) in DCM (200mL) at 0 deg.C. The reaction mixture was stirred at 0 ℃ for 1 hour. Reaction with saturated NaHCO₃The solution was quenched and the organic layer was separated. The organic layer was washed with brine, over anhydrous Na₂SO₄Dried and then concentrated under reduced pressure. The crude residue was recrystallized from hexane/EtOAc to yield the desired compound (10.76g,% yield) as a white solid.¹H NMR(400MHz，CDCl₃)：δ8.46(d，J＝2.8Hz，1H)，8.21(dd，J＝2.8，8.8Hz，1H)，7.59(d，J＝8.8Hz，1H)，7.44-7.31(m，5H)，6.65(br s，1H)，5.01(m，1H)，3.97(m，1H)，3.56(m 1H)，2.68(d，J＝2.8Hz，1H)。MS(ESI)：C₁₅H₁₃ClN₂O₄Na calculation 343, found 343(M + Na)⁺。

Example 2

2-chloro-N- (2-hydroxy-2-phenylethyl) -5-nitrobenzamide (3.40g, 10.60mmol) and POCl₃(11.86mL, 127.2mmol) and P₂O₅A mixture of (17.0g, 119.8mmol) in toluene/xylene (265.0mL, 1: 1) was refluxed for 2 days. The reaction mixture was cooled and then poured into ice-water followed by neutralization with 10% NaOH solution. The mixture was extracted with EtOAc and the combined extracts were washed with brine, over anhydrous Na₂SO₄Dried and then concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (hexane/EtOAc 95: 5 to 90: 10) followed by recrystallization from hexane/EtOAc to give the desired compound (850mg, 28%) as yellow crystals.¹H NMR(400MHz，CDCl₃)：δ8.66(d，J＝5.6Hz，1H)，8.38(d，J＝2.8Hz，1H)，8.32(dd，J＝2.8，8.8Hz，1H)，7.95(m，1H)，7.80(d，J＝5.6Hz，1H)，7.77-7.73(m，2H)，7.57(m，2H)。MS(ESI)：C₁₅H₁₀ClN₂O₂: calculation 285, actual measurement 285(M + H)⁺。

Example 3

21- (2-chloro-5-nitrophenyl) isoquinoline (785mg, 2.76mmol) and dehydrated tin (II) chloride (2.93g, 12.97mmol) were added at 70 deg.CThe mixture in ethanol (36.8mL) was heated for 1.5 hours. The reaction mixture was cooled, then poured into ice-water and subsequently saturated NaHCO₃Neutralizing the solution. The mixture was filtered through a pad of celite, washing with EtOAc. The filtrate was extracted with EtOAc and the combined extracts were washed with brine, over anhydrous Na₂SO₄Dried above and then concentrated under reduced pressure to give the desired compound (650mg, 92%) as a yellow solid.¹H NMR(400MHz，CDCl₃)：δ8.61(d，J＝5.6Hz，1H)，7.88(d，J＝8.0Hz，1H)，7.75-7.67(m，3H)，7.53(m，1H)，7.29(dd，J＝0.8，8.0Hz，1H)，6.76(m，2H)，3.76(br s，2H)。MS(ESD：C₁₅H₁₂ClN₂: calculate 255, actually measure 255(M + H)⁺。

Example 4

A solution of 2-chloro-4- (methylsulfonyl) benzoyl chloride (298mg, 1.18mmol) in DCM (3.1mL) was added dropwise to a solution of pyridine (127. mu.L, 1.57mmol) in 4-chloro-3- (isoquinolin-1-yl) aniline (100mg, 0.393mm0L) in DCM (10.0mL) at 0 ℃. The reaction mixture was allowed to warm to room temperature and stirred overnight. EtOAc was added and the mixture was washed with saturated NaHCO, respectively₃The solution and brine washes. Organic phase in anhydrous Na₂SO₄Dried and then concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (hexanes/EtOAc 1: 1 to 2: 3) to give the desired compound (86mg, 46% yield) as a white solid.¹H NMR(400MHz，DMSO-d₆)：δ10.98(s，1H)，8.61(d，J＝5.6Hz，1H)，8.12(dd，J＝0.4，1.6Hz，1H)，8.09(d，J＝8.0Hz，1H)，8.00(dd，J＝1.6，8.0Hz，1H)，7.92(m，3H)，7.83(m，2H)，7.66(m，2H)，7.58(m，1H)，3.33(s，3H)。MS(ESI)：C₂₃H₁₇Cl₂N₂O₃S: calculation 471, actual measurement 471(M + H)⁺。

Example 5

Phenyl isocyanate (29. mu.L, 0.260mmol) was added dropwise to a solution of 4-chloro-3- (isoquinolin-1-yl) aniline (60mg, 0.236mmol) in DCM (7.87mL) at room temperature. The reaction mixture was stirred overnight. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography on silica gel (hexane/EtOAc 7: 3 to 1: 1) to give the desired compound (36mg, 41% yield) as a pale yellow solid.¹H NMR(400MHz，DMSO-d₆)：δ8.94(s，1H)，8.75(s，1H)，8.60(d，J＝5.6Hz，1H)，8.08(d，J＝8.4Hz，1H)，7.93(dd，J＝0.6，5.8Hz，1H)，7.81(m，1H)，7.67(d，J＝2.0Hz，1H)，7.64(m 1H)，7.56(m，3H)，7.43(m，2H)，7.26(m，2H)，6.96(m，1H)。MS(ESI)：C₂₂H₁₇ClN₃O: calculation 374, actual measurement 374(M + H)⁺。

Example 6

Methylpyridinyl chloride HCl salt (63mg, 0.354mmol) was added to a solution of triethylamine (99. mu.L, 0.708mmol) in 4-chloro-3- (isoquinolin-1-yl) aniline (45mg, 0.177mmol) in DCM (5.90mL) at 0 ℃. The reaction mixture was allowed to warm to room temperature and stirred for 3 hours. EtOAc was added and the mixture was washed with saturated NaHCO, respectively₃The solution and brine washes. Organic phase in anhydrous Na₂SO₄Dried and then concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (hexane/EtOAc 7: 3 to1: 1) to yield the desired compound (25mg, 39% yield) as a white solid.¹H NMR(400MHz，DMSO-d₆)：δ10.94(s，1H)，8.74(m，1H)，8.62(d，J＝5.6Hz，1H)，8.16-8.04(m，5H)，7.95(dd，J＝0.8，5.6Hz，1H)，7.82(m，1H)，7.70-7.58(m，4H)。MS(ESI)：C₂₁H₁₅ClN₃O: calculate 360, actually measure 360(M + H)⁺。

Example 7

A solution of 4-chloro-3-nitrobenzene-1-sulfonyl chloride (50mg, 0.196mmol) in DCM (4.0mL) was added dropwise to a solution of 4-chloro-3- (isoquinolin-1-yl) aniline (50mg, 0.196mmol) in DCM (9.8mL) at 0 deg.C. The reaction mixture was stirred at 0 ℃ for 1 hour. Reaction with saturated NaHCO₃The solution was quenched and the mixture was extracted with EtOAc. The combined extracts were washed with brine, over anhydrous Na₂SO₄Dried and then concentrated under reduced pressure. The residue was treated with DCM to give the desired compound (69mg, 74% yield) as a pale yellow solid.¹H NMR(400MHz，DMSO-d₆)：δ11.08(s，1H)，8.64(d，J＝6.0Hz，1H)，8.44(t，J＝1.2Hz，1H)，8.17(m，2H)，8.02(d，J＝1.2Hz，2H)，7.95(m，1H)，7.69(m，1H)，7.65(d，J＝8.8Hz，1H)，7.41(m，2H)，7.27(d，J＝2.8Hz，1H)。MS(ESI)：C₂₁H₁₄Cl₂N₃O₄S: calculate 474, actually measure 474(M + H)⁺。

Example 8

4-Hydroxyquinazoline (1.20g, 8.21mmol) in SOCl with DMF (2 drops)₂The mixture in (27.4mL) was refluxed for 2 hours. Removal of SOCl under reduced pressure₂The residue was dissolved in DCM. The solutions were separately saturated NaHCO₃Washed with brine and dried over anhydrous Na₂SO₄Dried above and then concentrated under reduced pressure to give the desired compound (1.19g, 88% yield) as a white solid.¹H NMR(400MHz，CDCl₃)：δ9.06(s，1H)，8.29(m，1H)，8.09(m，1H)，7.98(m，1H)，7.75(m，1H)。MS(ESI)：C₈H₆ClN₂: calculation 165, actual measurement 165(M + H)⁺。

Example 9

4-chloroquinazoline (658mg, 4.0mmol), 3-nitrophenylboronic acid (935mg, 5.6mmol), Pd (PPh)₃)₄(231mg, 0.2mmol) and 2M K₂CO₃A mixture of the solution (4.0mL, 8.0mmol) in toluene (30.0mL) and ethanol (2.0mL) was refluxed for 6 hours. The reaction mixture was cooled and water was added. The resulting mixture was extracted with EtOAc and the combined extracts were washed with brine, over anhydrous Na₂SO₄Dried and then concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (hexane/EtOAc 10: 1 to 1: 1) to give the desired compound (771mg, 77% yield) as a pale yellow solid.¹H NMR(400MHz，CDCl₃)：δ9.43(s，1H)，8.69(m，1H)，8.45(ddd，J＝1.0，2.4，8.4Hz，1H)，8.17(m，2H)，8.05(ddd，J＝0.8，1.2，2.0Hz，1H)，7.99(m，1H)，7.80(m，1H)，7.69(m，1H)。MS(ESI)：C₁₄H₁₀N₃O₂: calculation 252, actual measurement 252(M + H)⁺。

Example 10

A mixture of 4- (3-nitrophenyl) quinazoline (700mg, 2.79mmol) and dehydrated tin (II) chloride (2.83g, 12.56mmol) in ethanol (37.2mL) was heated at 70 ℃ for 1.5 hours. The reaction mixture was cooled, then poured into ice-water and subsequently saturated NaHCO₃Neutralizing the solution. The mixture was filtered through a pad of celite, washing with EtOAc. The filtrate was extracted with EtOAc and the combined extracts were washed with brine, over anhydrous Na₂SO₄Dried above and then concentrated under reduced pressure to give the desired compound (600mg, 97%) as a yellow solid.¹H NMR(400MHz，CDCl₃)：δ9.36(s，1H)，8.19(m，1H)，8.10(d，J＝8.4Hz，1H)，7.91(m，1H)，7.60(m，1H)，7.34(t，J＝8.0Hz，1H)，7.12(m，1H)，7.09(t，J＝2.0Hz，1H)，6.88(ddd，J＝1.2，2.4，8.0Hz，1H)，3.85(s，2H)。MS(ESI)：C₁₄H₁₂N₃: calculating 222, actually measuring 222(M + H)⁺。

Example 11

Methylpyridine chloride HCl salt (60mg, 0.339mmol) was added to a solution of triethylamine (95. mu.L, 0.678mmol) in 3- (quinazolin-4-yl) aniline (50mg, 0.226mmol) in DCM (7.53mL) at 0 ℃. The reaction mixture was allowed to warm to room temperature and stirred for 30 minutes. EtOAc was added and the mixture was washed with saturated NaHCO, respectively₃The solution and brine washes. Organic phase in anhydrous Na₂SO₄Dried and then concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (hexane/EtOAc 1)1) to yield the desired compound (39mg, 53% yield) as a pale pink solid.¹H NMR(400MHz，DMSO-d₆)：δ10.94(s，1H)，9.38(s，1H)，8.76(m，1H)，8.43(t，J＝1.8Hz，1H)，8.24-8.05(m，6H)，7.79(m，1H)，7.70(ddd，J＝1.6，4.8，7.6Hz，1H)，7.63(t，J＝8.0Hz，1H)，7.57(dt，J＝1.6，7.6Hz，1H)。MS(ESI)：C₂₀H₁₅N₄O: calculation 327, actual measurement 327(M + H)⁺。

Example 12

Phenyl isocyanate (37. mu.L, 0.339mmol) was added dropwise to a solution of 3- (quinazolin-4-yl) aniline (50mg, 0.226mmol) in DCM (7.53mL) at room temperature. The reaction mixture was stirred for 4 hours. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography on silica gel (DCM/MeOH 99: 1 to 95: 5) to give the desired compound (27mg, 35% yield) as a white solid.¹H NMR(400MHz，DMSO-d₆)：δ9.36(s，1H)，8.95(s，1H)，8.74(s，1H)，8.18(d，J＝8.0Hz，1H)，8.08(m，2H)，7.99(s，1H)，7.77(m，1H)，7.64(m，1H)，7.54(t，J＝8.0Hz，1H)，7.46(d，J＝7.6Hz，2H)，7.39(d，J＝7.6Hz，1H)，7.28(t，J＝8.0Hz，2H)，6.97(t，J＝7.6Hz，1H)。MS(ESI)：C₂₁H₁₇N₄O: calculation 341, actual measurement 341(M + H)⁺。

Example 13

At room temperature, will1-chloro-2-isocyanato-3-methylbenzene (78 μ L, 0.565mmol) is added dropwise to a solution of 3- (quinazolin-4-yl) aniline (50mg, 0.226mmol) in DCM (7.53 mL). The reaction mixture was stirred for 6 hours. The precipitate was collected by filtration under reduced pressure and washed with DCM and hexane to give the desired compound (57mg, 65% yield) as a pale yellow solid.¹H NMR(400MHz，DMSO-d₆)：δ9.34(s，1H)，9.20(s，1H)，8.16(m，1H)，8.10(dd，J＝0.8，8.4Hz，1H)，8.05(m，2H)，7.98(t，J＝1.8Hz，1H)，7.76(m，1H)，7.66(m，1H)，7.52(t，J＝8.0Hz，1H)，7.36(m，2H)，7.24(m，1H)，7.19(q，J＝7.6Hz，1H)，2.27(s，3H)。MS(ESI)：C₂₂H₁₈ClN₄O: calculation 389, actual measurement 389(M + H)⁺。

Example 14

Hedgehog signal transduction inhibition assay

Hh-dependent C3H10T1/2 differentiation assay: C3H10T1/2 cells are multifunctional mesenchymal progenitor cells with the potential to differentiate into osteoblasts following stimulation by the Hh pathway. Osteoblasts produce large amounts of Alkaline Phosphatase (AP), which can be readily measured with enzymatic assays. Briefly, mouse embryonic mesodermal fibroblasts, C3H10T1/2 cells (from ATCC Cat # CCL-226), were cultured in Basal MEM medium (Gibco/Invitrogen) supplemented with 10% heat-inactivated fbs (hyclone), 50 units/ml penicillin, 50 μ g/ml streptomycin (Gibco/Invitrogen) and 2mM glutamine (Gibco/Invitrogen) at 37 ℃ in an air atmosphere containing 5% CO 2. Cells were dissociated with PBS containing 0.05% trypsin, 0.02% EDTA for passage and plating. C3H10T1/2 cells were plated in 96 wells at a density of 8x103 cells/well. Cells were grown to confluence (72 hours). At the start of the test, a medium containing 5. mu.M of 20(S) -hydroxycholesterol and 5. mu.M of 22(S) -hydroxycholesterol and/or compound was added and left for 72 hours. The medium was aspirated and the cells were washed once in PBS. Alkaline phosphatase was thus measured: mu.L of Tropix CDP-Star containing Emerald II (0.4mM Cat # MS100RY) was added to the wells and the plates were incubated at room temperature for 1 hour protected from light. Plates were read at 405nm on an Envision plate reader. Percent inhibition was plotted against compound concentration using Prism plot software as a semi-logarithmic graph, and EC50 was determined by nonlinear regression analysis of a 4-parameter logistic equation.

Claims (26)

1. A compound of formula (I)

Or a pharmaceutically acceptable salt thereof, wherein:

b is N or CH;

R₁represents hydrogen, halogen, hydroxyl, amino, nitro, cyano, alkyl, alkenyl, alkoxy, alkoxycarbonyl, carbamoyl, alkylthioA group, sulfonyl, sulfinyl, cycloalkyl or heterocycle;

l is oxygen, NR₃，NR₃CO，NR₃SO，NR₃SO₂，SO₂NR₃；NR₃CONH，NR₃CSNH，CONR₃，CSNR₃，NR₃CHR₄，NR₃PO or NR₃PO(OH)；

Ring a is aryl, heterocycle, heteroaryl;

R₂represents hydrogen, hydroxy, halogen, amino, nitro, cyano, acyl, alkyl, alkenyl, alkynyl, alkylthio, sulfonyl, sulfinyl, alkoxy, alkoxycarbonyl, carbamoyl, acylamine, sulfamoyl or sulfonamide;

or R₂Is aryl, heterocyclic or heteroaryl, optionally substituted with hydroxy, halogen, amino, nitro, cyano, acyl, alkyl, alkanoyl, sulfonyl, sulfinyl, alkoxy, carbamoyl, acylamine, sulfamoyl and sulfonamide;

R₃and R₄Independently selected from hydrogen or optionally substituted C1-4 alkyl;

m is 0 to 4.

2. A compound of formula (Ia)

Or a pharmaceutically acceptable salt thereof, wherein:

A，R₁，R₂l, and m are as defined in claim 1.

3. A compound of formula (Ib)

Or a pharmaceutically acceptable salt thereof, wherein:

A，R₁，R₂l, and m are as defined in claim 1.

4. The compound is selected from: (all structural embodiments).

5. A compound represented by the formula (A):

or a pharmaceutically acceptable salt thereof, wherein:

k is selected from NR₃C(O)，C(O)NR₃，NR₃SO₂，SO₂NR₃And NR and₄C(O)NR₅；

A¹selected from aryl, heterocyclyl, and heteroaryl;

R₁selected from H, halo, nitro, -OR₄，C₁-C₆Alkyl radical, C₁-C₆Alkylsulfonyl, and C₁-C₆A haloalkyl group;

m＝0-4；

R₃、R₄and R₅Each independently selected from H and C₁-C₆An alkyl group;

w is selected from CH and N;

z is selected from H, halo, and C₁-C₆Alkyl radical, C₁-C₆Alkylthio, -NR₄R₅，-OR₄And a cyano group.

6. The compound or pharmaceutically acceptable salt of claim 5, wherein:

k is selected from NR₃C(O)，C(O)NR₃，NR₃SO₂，SO₂NR₃And NR and₄C(O)NR₅；

A¹selected from phenyl and pyridyl;

R¹selected from H, halo, nitro, C₁-C₆Alkylsulfonyl, and C₁-C₆An alkyl group;

m＝0-4；

R₃、R₄and R₅Each independently selected from H and C₁-C₆An alkyl group;

w is selected from CH and N;

z is selected from H, halo, and C₁-C₆An alkyl group.

7. A compound represented by the formula (B):

or a pharmaceutically acceptable salt thereof, wherein:

R₃、R₄and R₅Each independently selected from H and C₁-C₆An alkyl group;

R₇selected from heterocyclic radicals, haloalkyl radicals, NR₃C(O)R₄，NR₃C(O)NR₄R₅，NR₃C(O)[C(R₃)(R₄)]_nO[C(O)]_pR₄，(CH₂)_nSO₂R₃，NR₃SO₂R₄，NR₃C(O)-Q-R₄And N (OR)₃)C(O)R₄；

n is 1 to 2;

p is 0 or 1;

q is a heterocyclic group;

u is selected from H, halo, C₁-C₆Alkyl radical, C₁-C₆Alkylthio, -NR₄R₅，-OR₄And cyano;

v is selected from CH and N;

w is selected from CH and N;

z is selected from H, halo, and C₁-C₆An alkyl group.

8. A compound represented by the formula (C):

or a pharmaceutically acceptable salt thereof, wherein:

R₃、R₄and R₅Each independently selected from H and C₁-C₆An alkyl group;

R₇selected from heterocyclic radicals, haloalkyl radicals, NR₃C(O)R₄，NR₃C(O)NR₄R₅，NR₃C(O)[C(R₃)(R₄)]_nO[C(O)]_pR₄，(CH₂)_nSO₂R₃，NR₃SO₂R₄，NR₃C(O)-Q-R₄And N (OR)₃)C(O)R₄；

n is 1 to 2;

p is 0 or 1;

q is a heterocyclic group;

u is selected from H, halo, C₁-C₆Alkyl radical, C₁-C₆Alkylthio, -NR₄R₅，-OR₄And cyano;

v is selected from CH and N;

z is selected from H, halo, and C₁-C₆An alkyl group.

9. The compound of claim 7, wherein the compound is of formula (i):

10. the compound of claim 7, wherein the compound is of formula (ii):

11. the compound of claim 7, wherein the compound is of formula (iii):

12. the compound of claim 7, wherein the compound is of formula (iv):

13. the compound of claim 7, wherein the compound is of formula (v):

14. the compound of claim 7, wherein the compound is of formula (vi):

15. the compound of claim 7, wherein the compound is of formula (vii):

16. the compound of claim 7, wherein said compound is of formula (viii):

17. the compound of claim 7, wherein said compound is of formula (ix):

18. the compound of claim 7, wherein the compound is of formula (x):

19. the compound of claim 7, wherein the compound is of formula (xi):

20. the compound of claim 7, wherein the compound is of formula (xii):

21. the compound of claim 7, wherein the compound is of formula (xiii):

22. the compound of claim 7, wherein the compound is of formula (xiv):

23. the compound of claim 8, wherein the compound is of formula (xv):

24. a process for preparing a compound according to any one of claims 1 to 23 or pharmaceutically acceptable salts, hydrates, solvates, crystal forms, salts and individual diastereomers thereof.

25. A pharmaceutical composition comprising at least one compound of any one of claims 1 to 23, or a pharmaceutically acceptable salt, hydrate, solvate, crystalline form, salt, and individual diastereomer thereof, and a pharmaceutically acceptable carrier.

26. Use of a compound of any one of claims 1 to 23 for treating an animal suffering from a tumor of one or more of the paranasal sinuses, nasopharynx, oral cavity, oropharynx, larynx, salivary glands, skin, liver, gall bladder, and biliary system, esophagus, stomach, intestine, pancreas, kidney, bladder, cervix, ovary, lung, breast, prostate, brain, connective tissue, leukemia, lymphoma, or melanoma.