MX2007002342A - Cyclopamine analogues and methods of use thereof - Google Patents

Abstract

The present invention provides compositions and methods for modulating smoothened­dependent pathway activation. The present invention provides analogs of cyclopamine that can be used to counteract the phenotypic effects of unwanted activation of a hedgehog pathway, such as resulting from hedgehog gain-of-function, Ptc loss-of-function or smoothened gain-of­function mutations. The compounds of the present invention are particularly useful in treating cancers.

Description

CYCLOPAMINE ANALOGS AND METHODS OF USING THEMSELVES DESCRIPTION OF THE INVENTION The hedgehog signaling pathway is essential for numerous processes during embryonic development. Members of the hedgehog family of secreted proteins control cell proliferation, differentiation and tissue base. The via was first deciphered in the fruit fly Drosophila, although it has already been shown to be highly conserved in invertebrates and vertebrates, including humans. The total activity of the hedgehog signaling pathway declines after embryogenesis in most cells, but the pathway remains active in certain types of adult cells. Recently, it has been shown that uncontrolled activation of the hedgehog pathway results in certain types of cancer as detailed below. The hedgehog polypeptide is a secreted protein that functions as a signaling ligand in the hedgehog's pathway. Exemplary hedgehog genes and proteins are described in PCT publications WO 95/18856 and WO 96/17924. Three different forms of the hedgehog protein are found in humans; sonic hedgehog (Shh), desert hedgehog (Dhh) and Indian hedgehog (Ihh). The sonic hedgehog is the most predominant member of the hedgehog in mammals and is also the best characterized ligand in the hedgehog family. Before the secretion, the Shh undergoes an unfolding intramolecular and lipid modification reaction. The peptide modified by lipids is responsible for all signaling activities. Two transmembrane proteins are involved in signal transduction in the hedgehog pathway; the superimposed receiver of twelve transmembranes (Ptc) and the flattened protein of seven transmembranes (Smo). The findings in the technique suggest that the hedgehog acts by binding to Ptc, thereby releasing a Ptc inhibitory effect in Smo. Since Ptc and Smo are transmembrane proteins, a suggested scenario is that they are physically associated to form a receptor complex, through indirect mechanisms of action they are also plausible. The de-repression of Smo from the inhibition of Ptc most probably implies a conformational change in Smo. Ptc, however, is not essential for the activity of the Smo, since the Smo becomes constitutively activated in the complete absence of the superimposed protein (Alcedo et al., Supra; Quirk et al. (1997) Cold Spring Harbor Symp. Quant. Biol. 62: 217-226). Once Smo is de-repressed, it is rapidly and highly phosphorylated and causes transduction of a signal that activates transcription through the transcription factors (homologs of Dropophila's Ci protein) (Alexandre et al., 1996). Genes Dev. 10: 2003-13)). The transcription factor Glil over-regulates many genes involved in growth and development (Alexandre et al., supra). Hedgehog signaling is essential in many stages of development, especially in the formation of left-right symmetry. The loss or reduction of hedgehog signaling leads to multiple developmental deficiencies and malformations, one of the most notable being cyclopia (Vellón et al. (1996) Nature Genetics 14: 353-6). Recently, it has been reported that the activation of hedgehog pathway mutations occurs in sporadic basal cell carcinoma (Xie et al (1998) Nature 391: 90-2) and primitive neuroectodermal tumors of the central nervous system (Reifenberger et al. (1998) Cancer Res 58: 1798-803). Uncontrolled activation of the hedgehog pathway has also been shown in numerous types of cancer such as Gl tract cancers including pancreatic, esophageal, gastric cancer (Berman et al. (2003) Nature 425: 846-51, Thayer et al. (2003) Nature 425: 851-56) lung cancer (Watkins et al. (2003) Nature 422: 313-317, prostate cancer (Karhadkar et al. (2004) Nature 431: 707-12, Sheng et al. (2004) Molecular Cancer 3: 29-42, Fan et al. (2004) Endocrinology 145: 3961-70), breast cancer (Kubo et al. (2004) Cancer Research 64: 6071-74, Lewis et al. (2004) Journal of Mammary Gland Biology and Neoplasia 2: 165-181) and hepatocellular cancer (Sicklick et al. (2005) ASCO conference, Mohini et al. (2005) AACR conference).

The inhibition of small molecules of hedgehog pathway activity has been shown to result in cell death in a number of different types of cancer that have uncontrolled hedgehog path activation (See for example, Berman et al., 2003, Nature 425: 846-51). Antagonists of the hedgehog pathway are currently being explored in a large number of clinical conditions wherein a therapeutic effect can be obtained for a condition or disorder by inhibiting one or more aspects of the activity of the Hedgehog pathway. Although the main focus has been on cancer, researchers have found that the inhibition of small molecules of the hedgehog pathway has been shown to improve the symptoms of psoriasis (Tas, et al 2004 Dermatology 209: 126-131, patent application North American published 20040072913 (incorporated herein by reference)). Psoriasis is a chronic, very common skin disorder usually characterized by skin lesions that usually contain erythematous papules and plaques with a silver-colored crust, although there are variations in the skin and other parts of the body. It is currently believed that psoriasis is an autoimmune disease, but its etiology is still poorly understood. A hedgehog pathway inhibitor that has attracted considerable interest is the cyclopamine of the natural product. Cyclopamine was first isolated from the lily Veratrujn californicum in 1966 after it was found that offspring of sheep grazing was born with severe deformities at birth. In an effort to identify the agent (s) responsible for causing these deformities at birth, the FDA investigated possible sources of tetragenes and identified the jervine family of steroidal alkaloids, including the compound's cyclopamine, such as the tetragenes responsible for birth deformities. Much later, it was found that the cyclopamine mechanism of action was through the inhibition of hedgehog activity (Cooper et al (1998) Science 280: 1603-7, Chen et al., (2002) Genes and Development 16: 2743-8). Cyclopamine and related compounds have been shown to have anti-cancer activities through action in the hedgehog pathway. Despite the initial promise, none of the members of this family of compounds, or analogs thereof, have been successfully developed as an anticancer agent. The present invention meets this need and has other related advantages. The present invention provides analogs of steroidal alkaloids of the cyclopamine family that are useful for inhibiting cell proliferation and / or promoting apoptosis in a cell, such as in the treatment of proliferative disorders such as cancers. The The hedgehog pathway antagonists of the present invention can be used to inhibit the proliferation (or other biological consequences) of cells or tissues, such as in a patient, characterized as having a Ptc loss of function phenotype, a gain-of-function phenotype. of Smo or a gain phenotype of the Hedgehog. In certain uses, the present methods are used to counteract the phenotypic effects of unwanted activation of a Hedgehog pathway, such as resulting from a gain of hedgehog function, loss of Ptc function, or Smooth Function Gain mutations. . For example, the present methods may involve contacting a cell (in vi tro or in vivo) with a hedgehog pathway antagonist of the present invention (defined below) in an amount sufficient to antagonize activation of the Smo-dependent pathway. Such antagonism will stop or delay unwanted cell proliferation and can lead to cell death. In certain embodiments, the methods and compounds of the present invention can be used to regulate cell proliferation and / or cell death in vi tro and / or in vivo such as in the treatment of malignant disorders of the head, neck, nasal cavity, sinuses, nasopharynx, oral cavity, lower pharynx, larynx, hypopharynx, salivary glands, paragangliomas, pancreas, stomach, skin, esophagus, liver and biliary tree, bones, intestine, colon, rectum, ovaries, prostate, lung, breast, lymphatic system, blood, central nervous system of the spinal cord or brain. In certain embodiments, the methods and compounds of the present invention can be used to treat the symptoms of psoriasis in a subject. The compounds of the present invention can be used to treat psoriasis as a single agent or in combination with one or more anti-psoriasis agents. In particular embodiments, the compounds of the present invention are administered topically to a subject in need thereof. The compounds of the present invention can be further formulated as a pharmaceutical preparation comprising a pharmaceutically acceptable excipient, for administration to a patient as a means to treat cancer. The hedgehog pathway antagonists of the present invention and / or preparations comprising them can be administered to a patient to treat conditions involving unwanted cell proliferation, eg, cancer and / or tumors of the head, neck, nasal cavity, paranasal sinuses. , nasopharynx, oral cavity, lower pharynx, larynx, hypopharynx, salivary glands, paragangliomas pancreas, stomach, skin, esophagus, liver and biliary tree, bones, intestine, colon, rectum, ovaries, prostate, lung, breast, lymphatic system, blood, central nervous system of the spinal cord or brain. In certain embodiments, such compounds or preparations are administered systemically, for example, parenterally and / or locally, for example, topically. Definitions Definitions of terms used herein mean that they incorporate the current recognized present definitions for each term in the chemical and pharmaceutical fields. When appropriate, an exemplification is provided. The definitions apply to the terms as used throughout this specification, unless otherwise limited in specific examples, either individually or as part of a larger group. The term "heteroatom" is recognized in the art and refers to an atom of any element other than carbon or hydrogen. Exemplary heteroatoms include boron, nitrogen, oxygen, phosphorus, sulfur and selenium. The term "alkyl" is recognized in the art, and includes saturated aliphatic groups, including straight chain alkyl groups, branched chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl groups, and alkyl groups substituted with cycloalkyl. In certain embodiments, a straight chain or branched chain alkyl has about 30 or less carbon atoms in its main structure (e.g., C? -C30 for straight chain, C3-C3o for branched chain) and alternatively, about 20 or less. Likewise, the cycloalkyls have from about 3 to about 10 carbon atoms in their structure in the ring, and alternatively about 5, 6 or 7 carbons in the structure in the ring. The alkyl groups, unless otherwise specified, may be optionally substituted with suitable substituents. The number of substituents is normally limited by the number of valencies available in the alkyl group; in this way an alkyl group can be replaced by the replacement of one or more of the hydrogen atoms that are present in the unsubstituted group. Suitable substituents for alkyl groups include halo, = 0, = N-CN, = N-0R ', = NR', OR ', NR'2, SR', S02R ', S02NR'2, NR'S02R', NR 'C0NR'2, NR' COOR ', NR'COR', CN, COOR ', CONR' 2, OOCR ', COR' and N02, wherein each R 'is independently H, C? -C6 alkyl, heteroalkyl C2-C ?, Ci-Cd acyl, C2-C6 heteroacyl, Cß-C ar ar aryl, C?-C? Hetero heteroaryl, C ar-C? Ar arylalkyl or C6-C? Hetero heteroarylalkyl, each of which is optionally substituted with one or more groups selected from halo, C? -C4 alkyl, C? -C4 heteroalkyl, Ci-C? acyl, Ci-C? heteroacyl, hydroxy, amino and = 0; and where two R 'in the same substituent or in adjacent atoms can be linked to a 3-7 membered ring optionally containing up to three heteroatoms selected from N, O and S; Unless the carbon number is otherwise specified, "lower alkyl" refers to an alkyl group, as defined above, but has from one to about ten carbons, alternatively from one to about six carbon atoms in its structure of principal. Likewise, "lower alkenyl" and "lower alkynyl" have similar chain lengths. The term "aralkyl" is also recognized and refers to an alkyl group substituted with an aryl group (eg, an aromatic or heteroaromatic group). The terms "alkenyl" and "alkynyl" are recognized in the art and refer to aliphatic unsaturated groups analogous in length and of possible substitution to the alkyls described above, but containing at least one double or triple bond respectively and may contain a mixture both double and triple links. The alkenyl and alkynyl groups are also optionally substituted unless otherwise specified, by the same substituents described above for alkyl groups. "Heteroaryl", "heteroalkenyl" and "heteroalkynyl" and the like are defined similarly to the corresponding hydrocarbyl groups (alkyl, alkenyl and alkynyl), but the terms "hetero" refer to groups containing 1-3 heteroatoms of 0, S or N or combinations thereof within the main residue; thus, at least one carbon atom of a corresponding alkyl, alkenyl or alkynyl group is replaced by one of the specified heteroatoms to form a heteroalkyl, heteroalkenyl or heteroalkynyl group. The typical and preferred sizes for heteroforms of alkyl, alkenyl and alkynyl groups are generally the same as for the corresponding hydrocarbyl groups and the substituents which may occur in the heteroforms are the same as those described above for the hydrocarbyl groups. For reasons of chemical stability, it is also understood that, unless otherwise specified, such groups do not include more than two contiguous heteroatoms except where an oxo group occurs in N or S as in a sulfonyl group. The term "aryl" is recognized in the art and refers to simple ring aromatic groups of 5, 6 and 7 members which may include from zero to four heteroatoms, for example, benzene, naphthalene, anthracene, pyrene, pyrrole, furan , thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine, and the like. Those aryl groups having heteroatoms in the structure in the ring can also be referred to as "arylheterocycles" or "heteroaromatics". He The aromatic ring can be substituted at one or more positions on the ring with such substituents as described above, for example, halogen, azide, alkyl, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxy, amino, nitro, sulfhydryl , imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic portions, -CF3, -CN or the like. The term "aryl" also includes systems in the polycyclic ring having two or more cyclic rings in which two or more carbons are common to two adjacent rings (the rings are "fused rings") wherein at least one of the rings is aromatic, for example, the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and / or heterocyclyls. The terms ortho, meta and para are recognized in the art and refer to 1,2-, 1,3- and 1,4-disubstituted benzenes, respectively. For example, the names 1,2-dimethylbenzene and ortho-dimethylbenzene are synonymous. The terms "heterocyclyl", "heteroaryl" or "heterocyclic group" are recognized in the art and refer to structures in the ring of 3 to about 10 members, alternatively rings of 3 to about 7 members whose structures in the ring include one to four heteroatoms. Heterocycles can also be police.

Heterocyclyl groups include, for example, thiophene, thianthrene, furan, pyran, isobenzofuran, chromene, xanthene, fenoxanteno, pyrrole, imidazole, pyrazole, isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, pyrimidine, phenanthroline, phenazine, phenarsazine, phenothiazine, furazan, phenoxazine, pyrrolidine, oxolane, thiolane, oxazole, piperidine, piperazine, morpholine, lactones, lactams such as azetidinones and pyrrolidinones, sultans, sultones and the like. The heterocyclic ring may be substituted at one or more positions with such substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic portion, -CF3, -CN or the like. The terms "polycyclyl" or "polycyclic group" are art-recognized and refer to two or more rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and / or heterocyclyls) in which two or more carbons are common to two adjacent rings, by For example, the rings are "fused rings". The rings that join through non-adjacent atoms are called "bridged" rings. Each of the rings of the polycycle can be substituted with such substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl , carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic portion, -CF3, -CN or the like. The term "carbocycle" is recognized in the art and refers to an aromatic or non-aromatic ring in which each ring atom is carbon. The term "nitro" is recognized in the art and refers to -N02; the term "halogen" is recognized in the art and refers to -F, -Cl, -Br or -I; the term "sulfhydryl" is recognized in the art and refers to -SH; the term "hydroxyl" means -OH; and the term "sulfonyl" is recognized in the art and refers to -S02 ~. "Halide" specifies the corresponding anion of the halogens, and "pseudohalides" has the definition established in 560 of "Advanced Inorganic Chemistry" by Cotton and Wilkinson. The terms "amine", "amino" and "ammonium" are recognized in the art and refer to both amines without substitute as substitutes, for example, a portion that can be represented by the general formulas: wherein R50, R51 and R52 each independently represents a hydrogen, an alkyl, an alkenyl, - (CH2) m-R61 or R50 and R51, taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the structure in the ring; R61 represents an aryl, a cycloalkyl, a cycloalkenyl, a heterocycle or a polycycle; and m is zero or an integer in the range of 1 to 8. In other embodiments, R50 and R51 (and optionally R52) each independently represents a hydrogen, an alkyl, an alkenyl or - (CH2) m-R61. Thus, the term "alkylamine" includes an amine group, as defined above, having a substituted or unsubstituted alkyl attached thereto, that is, at least one of R50 and R51 is an alkyl group. The term "acylamino" is recognized in the art and refers to a portion that can be represented by the general formula: wherein R50 is as defined above, and R54 represents a hydrogen, an alkyl, an alkenyl or - (CH2) m-R61, wherein m and R61 are as defined above. The term "amido" is recognized in the art as a carbonyl substituted with amino and includes a portion that can be represented by the general formula: wherein R50 and R51 are as defined above. Certain embodiments of the amide in the present invention will not include imides which may be unstable. The term "alkylthio" refers to an alkyl group, as defined above, having a sulfur radical attached thereto. In certain embodiments, the "alkylthio" moiety is represented by one of -S-alkyl, -S-alkenyl, -S-alkenyl, and -S (CH2) ra-R61, wherein m is R61 as defined above. Representative alkylthio groups include methylthio, ethylthio and the like.

The term "carboxyl" is recognized in the art and includes such portions as may be represented by the general formulas: wherein X50 is a bond or represents an oxygen or a sulfur and R55 and R56 represent a hydrogen, an alkyl, an alkenyl, - (CH2) m-R61 or a pharmaceutically acceptable salt, R56 represents a hydrogen, an alkyl, an alkenyl or - (CH2) m-R61, where m and R61 are as defined above. Where X50 is an oxygen and R55 or R56 is not hydrogen, the formula represents an "ester". Where X50 is an oxygen, and R55 is as defined above, the portion is referred to herein as a carboxyl group, and particularly when R55 is a hydrogen, the formula represents a "carboxylic acid". Where X50 is an oxygen, and R56 is hydrogen, the formula represents a "formate". In general, where the oxygen atom of the above formula is replaced by sulfur, the formula represents a "thiolcarbonyl" group. Where X50 is a sulfur and R55 or R56 is not hydrogen, the formula represents a "thiolyester". Where X50 is a sulfur and R55 is hydrogen, the formula represents a "thiolcarboxylic acid". Where X50 is a sulfur and R56 is hydrogen, the formula represents a "thiolformiate". On the other hand, where X50 is a bond, and R55 is not hydrogen, the above formula represents a "ketone" group. Where X50 is a bond, and R55 is hydrogen, the above formula represents an "aldehyde" group. The term "carbamoyl" refers to -0 (C = 0) NRR ', where R and R' are independently H, groups aliphatics, aryl groups or heteroaryl groups. The term "oxo" refers to an oxygen carbonyl (= 0). The terms "alkoxy" or "alkoxy" are recognized in the art and refer to an alkyl group, as defined above, having an oxygen radical attached thereto. Representative alkoxy groups include methoxy, ethoxy, propyloxy, tert-butoxy and the like. An "ether" is two hydrocarbons covalently bonded by an oxygen. Accordingly, the substituent of an alkyl illustrating that an alkyl ether is or appears to an alkoxy, such as may be represented by one of -O-alkyl, -O-alkenyl, -0-alkynyl, -0- (CH2) m -R61, where my R61 are as described above. The term "sulfonate" is recognized in the art and refers to a portion that can be represented by the general formula: wherein R57 is a pair of electron, hydrogen, alkyl, cycloalkyl or aryl. The term "sulfate" is recognized in the art and includes a portion that can be represented by the general formula: in which R57 is as defined above. The term "sulfonamido" is recognized in the art and includes a portion that can be represented by the general formula: wherein R50 and R56 are as defined above. The term "sulfamoyl" is recognized in the art and refers to a portion that can be represented by the General Formula : wherein R50 and R51 are as defined above. The term "sulfonyl" is recognized in the art and refers to a portion that can be represented by the general formula: wherein R58 is one of the following: hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl. The term "sulfoxide" is recognized in the art and refers to a portion that can be represented by the general formula: wherein R58 is as defined above. The term "phosphoryl" is recognized in the art and can generally be represented by the formula: Q50 OR59 wherein Q50 represents S or O, and R59 represents hydrogen, a lower alkyl or an aryl. When it is used to replace, for example, an alkyl, the phosphorylaryl group of the phosphorylalkyl can be represented by the general formulas: wherein Q50 and R59, each independently are defined above, and Q51 represents O, S or N. When Q50 is S, the phosphoryl portion is a "phosphorothioate". The term "phosphoramidite" is recognized in the art and can be represented in the general formulas: wherein Q51, R50, R51 and R59 are as defined above.

The term "phosphonamidite" is recognized in the art and can be represented in the general formulas: wherein Q51, R50, R51 and R59 are as defined above, and R60 represents a lower alkyl or an aryl. Analogous substitutions can be made to alkenyl and alkynyl groups, which produce for example, aminoalkenyls, aminoalkynyls, amidoalkenyls, amidoalkynyls, iminoalkenyls, iminoalkynyls, thioalkenyls, thioalkynyls, alkenyls or alkynyls substituted by carbonyl. The definition of each expression, for example, alkyl, m, n and the like, when it occurs more than once in any structure, is intended to be independent of its definition elsewhere in the same structure. The term "selenoalkyl" is recognized in the art and refers to an alkyl group having a substituted seleno group attached thereto. Exemplary "selenoethers" which can be substituted on the alkyl are selected from one of -Se-alkyl, -Se-alkenyl, -Se- alkynyl and -Se- (CH2) m-R61, m and R61 are defined above. The terms triflyl, tosyl, mesyl, nonaflyl are recognized in the art and refer to trifluoromethanesulfonyl, p-toluenesulfonyl, methanesulfonyl and nonafluorobutansulfonyl groups, respectively. The terms triflate, tosylate, mesylate and nonaflate are recognized in the art and refer to trifluoromethanesulfonate ester, p-toluenesulfonate ester, methanesulfonate ester and functional groups of the nonafluorobutanesulfonate ester and molecules containing such groups, respectively. The abbreviations Me, Et, Ph, Tf, Nf, Ts and Ms represent methyl, ethyl, phenyl, trifluoromethanesulfonyl, nonafluorobutansulfonyl, p-toluenesulfonyl and methanesulfonyl, respectively. A more complete list of abbreviations used by organic chemists of ordinary skill in the art appears in the first issue of each volume of the Journal of Organic Chemistry; This list is normally presented in a table entitled Standard List of Abbreviations. Certain compounds contained in the compositions of the present invention can exist in particular geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, R and S enantiomers, diastereomers, isomers (D), isomers (L), racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention. Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All isomers, as well as mixtures thereof, are intended to be included in this invention. If, for example, a particular enantiomer of the compound of the present invention is desired, it can be prepared by asymmetric synthesis, or by derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is unfolded to provide the desired enantiomers pure Alternatively, wherein the molecule contains a basic functional group, such as amino, or an acidic functional group, such as carboxyl, the diastereomeric salts are formed with an appropriate optically active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic media well known in the art, and the subsequent recovery of the pure enantiomers. Similarly, a particular enantiomer in a racemic mixture can be separated from its enantiomer by chiral chromatographic methods known in the art. It will be understood that "substitution" or "substituted with" includes the implicit condition that such substitution is in accordance with the permitted valency of the substituted atom and the substituent, and that the substitution results in a compound stable, for example, which does not spontaneously undergo the transformation such as by re-arrangement, cyclization, elimination or other reaction. The term "substituted" is also contemplated to include all acceptable substituents of the organic compounds. In a broad aspect, acceptable substituents include acyclic and cylindrical, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. Exemplary substituents include, for example, those described herein above. The acceptable substituents may be one or more and the same or different for the appropriate organic compounds. For purposes of this invention, heteroatoms such as nitrogen may have hydrogen substituents and / or any acceptable substituents of organic compounds described herein, which satisfy the valences of heteroatoms. This invention is not intended to be limited in any way by the acceptable substituents of the organic compounds. The phrase "protection group" as used herein means temporary substituents which protect a potentially reactive functional group from unwanted chemical transformations. Examples of such protecting groups include esters of carboxylic acids, silyl ethers of alcohols, and acetals and ketals of aldehydes and ketones, respectively. The chemistry field of the protection group has been revised (Greene, T.W., Wuts, P.G.M, Protective Groups in Organic Syn Thesis, 2nd edition, Wiley: New York, 1991). Protected forms of the inventive compounds are included within the scope of this invention. For purposes of this invention, the chemical elements are identical according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 67th edition, 1986-87, inner cover. The phrase "aberrant modification or mutation" of a gene refers to such genetic lesions as for example deletions, substitution or addition of nucleotides to a gene, as well as total chromosomal re-arrangements of the gene and / or abnormal methylation of the gene. Likewise, the bad expression of a gene refers to aberrant levels of transcription of the gene relative to those levels in a normal cell under similar conditions, as well as splicing of the non-natural type of mRNA transcribed from the gene. The "basal cell carcinomas" exist in a variety of clinical and histological forms such as nodular-ulcerative syndrome, superficial, pigmented, morphea-like, fibroepithelioma and nevus. Basal cell carcinomas are the most common cutaneous neoplasms found in humans. Most new cases of skin cancers not related to melanoma fall within this category. The term "carcinoma" refers to a new malignant growth composed of epithelial cells that tend to infiltrate surrounding tissues and give rise to metastasis. Exemplary carcinomas include: "basal cell carcinoma," which is an epithelial tumor of the skin that, although rarely metastasizing, has potential for local invasion and destruction; "squamous cell carcinoma", which refers to carcinomas that originate from the squamous epithelium and that have cuboid cells; "carsinosarcoma", which includes malignant tumors composed of carcinomatous and sarcomatous tissues; "adenocystic carcinoma", carcinoma marked by cylinders or bands of hyaline or mucin stroma separated or surrounded by nests or cords of small epithelial cells, which occur in the mammary and salivary glands, and the mucous glands of the respiratory tract; "squamous cell carcinoma", which refers to cancer cells which tend to differentiate in the same way as those of the epidermis; that is, they tend to form spiny cells and experience cornification; "Nasopharyngeal carcinoma," which refers to a malignant tumor that originates from the epithelial lining of the space behind the nose; and "renal cell carcinoma", which belongs to the renal parenchymal carcinoma composed of tubular cells in variable dispositions.

Other carcinomatous epithelial growths are "papillomas", which refer to benign tumors derived from the epithelium and which have a papillomavirus as a causative agent; and "epidermoidomas", which refer to brain or meningeal tumor formed by inclusion ofectodermal elements at the time of closure of the neural cavity. The term "ED50" means the dose of a drug which produces 50% of its response or maximum effect. An "effective amount" of a subject compound, with respect to the present methods of treatment, refers to an amount of the antagonist in a preparation which, when applied as part of a desired dosage regimen, results in, for example, a change in the rate of cell proliferation and / or the survival rate of a cell according to clinically acceptable standards for the disorder being treated. The terms "of epithelium", "epithelial" and "epithelium" refer to the cellular cover of the internal and external surfaces of the body (cutaneous, mucous and serous), including glands and other structures derived therefrom, for example, epithelial cells of the cornea, esophagus, epidermal and hair follicle. Other exemplary epithelial tissue includes: olfactory epithelium, which is the pseudo-stratified epithelial lining from the olfactory region of the nasal cavity, and which contains the receptors for the sense of taste; glandular epithelium, which refers to the epithelium composed of secretory cells; Squamous epithelium, which refers to the epithelium composed of cells similar to flattened plaques. The term epithelium may also refer to transitional epithelium, similar to that which is typically found by coating hollow organs that undergo greater mechanical change due to contraction and distention, for example, tissue which represents a transition between the epithelium scaly stratified and columnar. The "growth state" of a cell refers to the rate of proliferation of the cell and / or the state of differentiation of the cell. An "altered growth state" is a growth state characterized by an abnormal rate of proliferation, for example, a cell exhibiting an increased or decreased rate of proliferation relative to a normal cell. The term "hedgehog pathway antagonist" refers to an agent that inhibits the function of the hedgehog pathway, for example, it represents transcription of target genes (Glil and Ptc genes), which in normal cells are induced by the contact of the cell with the hedgehog. In addition, to alter a smoothed dependent pathway, in certain modalities of the antagonists via the hedgehog of the Current invention can be used to overcome a loss of Ptc function, smoothed function gain and / or hedgehog gain of function. The terms "loss of function" and "gain of function" when appropriate, refer to an aberrant modification or mutation of for example, a Ptc gene, a hedgehog gene, or a smoothed gene, or a decrease or increase in the level of expression of such a gene, which results in a phenotype, for example, which resembles contacting a cell with a hedgehog protein, such as an aberrant activation of a hedgehog pathway or appears to have loss of Smo function. The mutation may include a loss of the ability of the Ptc or Smo gene product (s) to regulate the activity level of Gli / Ci proteins, eg, Glil, Gli2 and Gli3. As used herein, "immortalized cells" refers to cells which have been altered through chemical and / or recombinant means so that the cells have the ability to develop through an indefinite number of divisions in culture. The term "LD50" means the dose of a drug which is lethal in 50% of test objects. A "patient" or "subject" that is treated by the present method can mean any human or non-human animal. The phrase "pharmaceutically acceptable" is used in the present to refer to those compounds, materials, compositions and / or dosage forms which are within the scope of the medical judgment of sound, suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response , or another problem or complication, in proportion to a reasonable benefit / risk ratio. The phrase "pharmaceutically acceptable carrier" as used herein, means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, manufacturing aid (e.g., lubricant, talc magnesium, stearate of calcium or zinc, or stearic acid), or solvent encapsulating material, involved in transmitting or transporting the subject compound from an organ, or portion of the body, or other organ, or portion of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and is not harmful to the patient. Some examples of materials which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose acetate and cellulose; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and waxes for suppositories; (9) oils, such as peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline solution; (18) Ringer's solution, (19) ethyl alcohol; (20) pH buffer solutions; (21) polyesters, polycarbonates and / or polyanhydrides; and (22) other non-toxic compatible substances employed in pharmaceutical formulations. The term "prodrug" is intended to encompass compounds, which under physiological conditions, are converted to the therapeutically active agents of the present invention. A common method for making a prodrug is to include selected portions which are hydrolyzed under physiological conditions that reveal the desired molecule. In other embodiments, the prodrug is converted by an enzymatic activity (or other physiological activity) of the host animal. As used herein, "proliferate" and "proliferation" refers to cells that experience mitosis Throughout this application, the term "proliferative skin disorder" refers to any disease / disorder of the skin marked by unwanted or aberrant proliferation of skin tissue. These conditions are usually characterized by epidermal cell proliferation or incomplete cell differentiation and include, for example, X-linked ichthyosis, psoriasis, atopic dermatitis, allergic contact dermatitis, epidermolytic hyperkeratosis and seborrheic dermatitis. For example, epidermodisplasia is a form of defective development of the epidermis. Another example is "epidermolysis", which refers to a relaxed state of the epidermis with formation of blisters and papules either spontaneously or, at the site of trauma. The term "Therapeutic Index" refers to the therapeutic Index of a drug defined as LD50 / ED50. The term "transformed cells" refers to cells which they have spontaneously converted to a state of unrestricted growth, that is, they have acquired the ability to grow through an indefinite number of divisions in culture. Transformed cells can be characterized by such terms as neoplastic, anaplastic and / or hyperplastic, with respect to their loss of growth control.

The term "subject" as used herein, refers to an animal, usually a mammal or a human being, that has been the subject of treatment, observation and / or experiment. When the term is used in conjunction with the administration of a compound or drug, then the subject has been the subject of treatment, observation and / or administration of the compound or drug. The phrase "therapeutically effective amount" as used herein, means the amount of a compound, material or composition comprising a compound of the present invention which is effective to produce some desired therapeutic effect in at least one sub-population of cells in an animal in a reasonable benefit / risk ratio applicable to any medicinal treatment. The phrases "parenteral administration" and "parenterally administered" as used herein, means modes of administration other than enteric and topical administration, usually by injection, and include limitation, injection and intravenous, intramuscular, intra-arterial, intrathecal, intracapsular, intraorbital, intracardiac infusion, intradermal, intraperitoneal, trans-tracheal, subcutaneous, subcuticular, intra-articular, sub-capsular, sub-araquinoid, intra-spinal and intra-sternal. The phrases "systemic administration", "Systemically administered", "Peripheral administration" and "Peripherally administered" as used herein means the administration of a compound, drug or other material other than directly to the site of hedgehog-mediated disorder, so that it enters the patient's system and, in this way, is subject to metabolism and other similar processes, for example, subcutaneous administration. The term "sugar" as used herein, refers to a natural or unnatural monosaccharide, disaccharide or oligosaccharide, comprising one or more pyranose or furanose rings. The sugar can be covalently linked to the steroidal alkaloid of the present invention via an ether connection or through an alkyl linkage. In certain embodiments, the saccharide moiety can be covalently linked to a steroidal alkaloid of the present invention at an anomeric center of a saccharide ring. The term "di-radical" as used herein, refers to any of a series of divalent groups, from alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl groups, and and heteroaryl and heteroaralkyl. For example 18 ^ is a di-radical alkyl; it is also a di-radical I rent; \ = / is an aralkyl di-radical; Y is a di-radical (alkyl) heteroaralkyl. Typical examples include alkylene alkylene of the general structure (CH2) X wherein X is 1-6, and the corresponding alkenylene and alkynylene linkers have 2-6 carbon atoms and one or more double or triple bonds; cycloalkylene groups having 3-8 members in the ring; and aralkyl groups where an open valence is in the Compounds of the Invention The present invention provides cyclopamine analogues as well as isolated and purified forms thereof, including synthetic and semi-synthetic analogs, as well as pharmaceutical compositions containing such analogues. In one embodiment, the present invention provides compounds represented by a compound of Formula 1: (1) a pharmaceutically acceptable salt thereof; wherein each R1 and R8 is independently H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl, halide, sulfhydryl, alkylthio, arylthio, aralkylthio, hydroxyl, alkoxy, aryloxy, acyloxy, amino, alkylamino, arylamino, acylamino, aralkylamino, nitro, acylthio, carboxamide, sulfonamide, carboxyl, nitrile, sulfate, -OP (L) (OR20) 2, -XC (L) -R21 or -XC (L) -X-R21; wherein R1 can also be a sugar; X is O or NR where R is H, alkyl, alkenyl, alkenyl, aryl, cycloalkyl or aralkyl; L is O or S; R2 and R9 are independently H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, alkoxy, aryloxy, acyloxy, halide, sulfhydryl, alkylthio, arylthio, aralkylthio, hydroxyl, amino, alkylamino, arylamino, acylamino, aralkylamino, heteroaryl or heteroaralkyl; each R5 and R11 is independently H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, alkoxy, aryloxy, acyloxy, halide, hydroxyl, amino, alkylamino, arylamino, acylamino, aralkylamino, alkylselene, aralkylselene, arylselene, alkylthio, aralkylthio, arylthio, heteroaryl or heteroaralkyl; each R3, R4, R6, R7, R13 and R14 is independently H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, alkoxy, aryloxy, acyloxy, halide, hydroxyl, amino, alkylamino, arylamino, acylamino, aralkylamino, heteroaryl or heteroaralkyl; or R1 and R2 and / or R8 and R9 taken together, together with the carbon to which they are bound form - (C = 0) -, - (C = S) -, - (C = N (OR20)) -, - (C = N (R20)) -, - (C = N (N (R20) (R20))), or form an optionally substituted 3-8 membered ring; or R4 and R5 taken together and / or R5 and R6 taken together and / or R10 and R11 taken together form a double bond or form a group represented by wherein Z is NR21, O, or C (R23) (R23); R12 is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, hydroxyl, aralkyl, heteroaryl, heteroaralkyl, haloalkyl, alkoxy, -C (0) R21, -C02R21, -S02R21, -C (0) N (R21) (R21), - [C (R21) 2] q-R21, - [(W) -N (R21) C (0)] qR21, - [(W) -C (0) qR21, - [(W) -C (0) 0} qR21, - [(W) -OC (0)] qR21, - [(W) -S02] qR21, - [(W) -N (R21) S02] qR21, - [(W) -C (0) N (R21)] qR21, - [(W) -0] qR21, - [(W) -N (R21)] qR21, or - [(W) -S] qR21; where W is a di-radical and q is 1, 2, 3, 4, 5 or 6; R15, R16 and R17 are independently H, alkoxy, aryloxy, acyloxy, halide, hydroxyl, amino, alkylamino, arylamino, acylamino, aralkylamino; or R15 and R16 taken together, together with the carbon to which they are bonded, form -C (0) - or -C (S) -; R18 and R19 are independently H, alkyl, aralkyl, halide, amido or ester; R 20 is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl or heteroaralkyl; or any two cases of R20 in the same substituent may be taken together to form an optionally substituted 4-8 membered ring; R21 is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl or - [C (R20) 2] P-R25 wherein p is 0-6; or any two cases of R21 in the same substituent may be taken together to form an optionally substituted 4-8 membered ring; R23 is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl, halide, alkoxy, aryloxy, acyloxy, silyloxy, nitrile, -C (0) R21, -C02R21, -SO-2R21, and -C (O) N (R21) 2; R25 is hydroxyl, acylamino, -N (R20) COR20, N (R20) C (O) OR20, -N (R20) SO2 (R20), -COR20N (R20) 2, -OC (O) R20N (R20), -S02N (R20) (R20), -N (R20) ) (R20), -COOR20, -C (O) N (OH) (R21), OS (0) 2OR20, -S (0) 2OR2 °, -OP (L) (OR20) (OR20), -NP ( O) (OR20) (OR20) or -P (O) (OR20) (OR20). In certain embodiments, the compounds of the present invention are represented by 1 and the appended definitions, wherein R 13, R 14, R 15, R 16 and R 17 are hydrogen. In certain embodiments, the compounds of the present invention are represented by 1 and the appended definitions, wherein R 1 is hydroxyl, sugar, -OP (L) (OR20) 2, -X- C (L) -R21 or -XC ( L) -X-R21; or R1 and R2 taken together, together with the carbon to which they bind, form -C (O) -. In certain embodiments, the compounds of the present invention are represented by 1 and the appended definitions, wherein R 4 and R 5 taken together form a double bond. In certain embodiments, the compounds of the present invention are represented by 1 and the appended definitions, wherein R 1 and R 2 taken together, together with the carbon to which they are linked, form -C (O) -. In certain embodiments, the compounds of the present invention are represented by 1 and the appended definitions, wherein R 1 is hydroxyl and R 2 is H. In certain embodiments, the compounds of the present invention are represented by 1 and the definitions annexes, wherein R 1 is hydroxyl, R 2 is H; and R5 and R6 taken together form a double bond; or R5 and R6 taken together form a group represented by Ib; where: Z is C (R23) (R23). In certain embodiments, the compounds of the present invention are represented by 1 and the appended definitions, wherein R 10 and R 11 taken together form a double bond; or R10 and R11 taken together form a group represented by Ib; wherein: Z is C (R23) (R23) In certain embodiments, the compounds of the present invention are represented by 1 and the appended definitions, wherein R5 and R6 taken together form a double bond and R10 and R11 taken together form a double bond. In certain embodiments, the compounds of the present invention are represented by 1 and the appended definitions, wherein R 1 and R 2 taken together, together with the carbon to which they are linked, they form -C (0) -; R4 and R5 taken together form a double bond; and R10 and R11 taken together form a double bond; or R10 and R11 taken together form a group represented by Ib; where: Z is C (R23) (R23). In certain embodiments, the compounds of the present invention are represented by 1 and the appended definitions, wherein R 1 is hydroxyl and R 2 is H; R10 and R11 taken together form a double bond; or R10 and R11 taken together form a group represented by Ib; Z is C (R23) (R23). In certain embodiments, the compounds of the present invention are represented by 1 and the appended definitions, wherein R 8 and R 9 are hydrogen; or R8 and R9 taken together, together with the carbon to which they are bonded, is -C (O) -. In certain embodiments, the compounds of the present invention are represented by 1 and the appended definitions, wherein R 12 is H, alkyl, cycloalkyl, aralkyl, heteroaryl, heteroaralkyl, haloalkyl, hydroxyl, alkoxy, - [(W) -N (R21) C (0)] qR21, - [(W) -N (R21) S02] qR21, - [(W) -C (0 ) N (R21)] qR21, - [(W) -Oq] R21, - [(W) -C (0)] qR21, or - [(W) -C (0) 0] qR21. In certain embodiments, the compounds of the present invention are represented by 1 and the appended definitions, wherein R 13, R 14, R 15, R 16 and R 17 are hydrogen; and R12 is H, alkyl, cycloalkyl, aralkyl, heteroaryl, heteroaralkyl, haloalkyl, hydroxyl, alkoxy, - [(W) -N (R21) C (0)] qR21, - [(W) -N (R21) S02] qR21, - [(W) -C (O) N (R21)] qR21, - [(W) -Oq] R21, - [(W) -C (0)] qR21, or - [(W) -C (0) 0] qR21. In certain embodiments, the compounds of the present invention are represented by 1 and the appended definitions, wherein R 4 and R 5 taken together form a double bond; R1 and R2 taken together, together with the carbon to which they bind, form -C (O) -; and R12 is H, alkyl, cycloalkyl, aralkyl, heteroaryl, heteroaralkyl, haloalkyl, hydroxyl, alkoxy, - [(W) -N (R21) C (O)] qR21, - [(W) -N (R21) S02] qR21, - [(W) -C (0) N (R21)] qR21, - [(W) -Oq] R21, - [(W) -C (0)] qR21, or - [(W) -C (0) 0] qR21. In certain embodiments, the compounds of the present invention are represented by 1 and the appended definitions, wherein R 1 is hydroxyl and R 2 is H; and R12 is H, alkyl, cycloalkyl, aralkyl, heteroaryl, heteroaralkyl, haloalkyl, hydroxyl, alkoxy, - [(W) - N (R1) C (0)] qR21, - [(W) -N (R21) S02] qR21, - [(W) -C (O) N (R21)] qR21, - [(W) -Oq] R21, - [(W) -C (0)] qR21, or - [(W) -C (0) 0] qR21. In certain embodiments, the compounds of the present invention are represented by a compound of the formula: wherein: R12 is H, alkyl, aryl, cycloalkyl, heterocycloalkyl, hydroxyl, aralkyl, heteroaryl, heteroaralkyl, haloalkyl, alkoxy, C (0) R21, -C02R21, -S02R21, -C (0) N (R21) (R21) ), - [C (R21) 2] P-R21, - [(W) -N (R21) C (O)] qR21, - [(W) -C (0) qR > 2¿1 - [(W) -C (0) 0} qR 2¿1 - [(W) -OC (0)] qR > 2¿1 - [(W) - S02] qR -, 2¿11, - [(W) -N (R> 2¿11 <) S02] qRi2¿11, T r.2 ] qR11, - [(W) -0] qR21, - [(W) -N (R21)] qR21, or - [(W) -S] qR21; q is 1, 2, 3, 4, 5 or 6; R20 is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, or heteroaralkyl; or any two cases of R20 may be taken together to form an optionally substituted 4-8 membered ring; R21 is H, alkyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl or - [C (R20) 2] P-R25, or any two cases of R21 can be taken together to form an optionally substituted 4-8 membered ring; R25 is hydroxyl, acylamino, -N (R20) COR20, -N (R20) C (O) OR20, -N (R20) SO2 (R20), -COR20N (R20) 2, -OC (0) R20N (R20), -S02N (R20) (R20), -N (R20) (R20), -COOR20, -C (0) N (OH) (R21), -OS (0) 2OR19, -S (0) 2OR20, -0P (L) (OR20) (OR20), -NP (0) (OR20) (OR20) or -P (0) (OR20) (OR20). The present invention specifically provides compounds represented by the group consisting of: In certain embodiments, the compounds of the present invention are represented by any of the aforementioned compounds and the appended definitions, wherein the compound is represented by the formula: In one embodiment, the present invention provides compounds represented by a compound of Formula 2: (2) or a pharmaceutically acceptable salt thereof; wherein each R1 and R8 is independently H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl, halide, sulfhydryl, alkylthio, arylthio, aralkylthio, hydroxyl, alkoxy, aryloxy, acyloxy, amino, alkylamino, arylamino, acylamino, aralkylamino, nitro, acylthio, carboxamide, sulfonamide, carboxyl, nitrile, sulfate, -OP (L) (OR20) 2, -XC (L) -R21 or -XC (L) -X-R21; wherein R1 can also be a sugar; X is O or NR where R is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl or aralkyl, L is O or S R2 and R9 is independently H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, alkoxy , aryloxy, acyloxy, halide, sulfhydryl, alkylthio, arylthio, aralkylthio, hydroxyl, amino, alkylamino, arylamino, acylamino, aralkylamino, heteroaryl or heteroaralkyl; each R5 and R11 is independently H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, alkoxy, aryloxy, acyloxy, halide, hydroxyl, amino, alkylamino, arylamino, acylamino, aralkylamino, alkylselene, aralkylselene, arylselene, alkylthio, aralkylthio, arylthio, heteroaryl or heteroaralkyl; each R3, R4, R6, R7, R13 and R14 is independently H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, alkoxy, aryloxy, acyloxy, halide, hydroxyl, amino, alkylamino, arylamino, acylamino, aralkylamino, heteroaryl or heteroaralkyl; wherein R1 and R2 and / or R8 and R9 taken together, together with the carbon to which they are bonded, form -C (= 0) -, - (C = N (OR20)) -, -C (= N (R20 )) -, -C (= N (N (R20) (R20))), or form a ring of 3-8 members optionally substituted; or R4 and R5 taken together and / or R5 and R6 taken together and / or R10 and R11 taken together form a double bond or form a group represented by Ib wherein Z is NR21, 0, or C (R23) (R23); R12 is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, hydroxyl, aralkyl, heteroaryl, heteroaralkyl, haloalkyl, alkoxy, -C (0) R21, -C02R21, -S02R21, -C (0) N (R21) (R21), - [C (R21) 2] q-R21, - [(W) -N (R21) C (0)] qR21, - [(W) -C (0) qR21, - [(W) -C (0) 0] qR21, - [(W) -0C (0)] qR21, "[(W) -S02] qR21, - [(W) -N (R21) S02] qR21, - [(W ) -C (0) N (R21)] qR21, - [(W) -0] qR21, - [(W) -N (R21)] qR21, or - [(W) -S] qR21; where W is a di-radical and q is 1, 2, 3, 4, 5 or R15, R16 and R17 are independently H, alkoxy, aryloxy, acyloxy, halide, hydroxyl, amino, alkylamino, arylamino, acylamino, aralkylamino; or R15 and R16 taken together, together with the carbon to which they are bound, form -C (0) - or -C (S) -; R18 and R19 are independently H, alkyl, aralkyl, halide, amido or ester; R 20 is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl or heteroaralkyl; or any two cases of R20 in the same substituent can be taken together to form a ring of 4-8 members optionally substituted; R21 is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl or - [C (R20) 2] P-R25 wherein p is 0-6; or any two cases of R21 in the same substituent may be taken together to form an optionally substituted 4-8 membered ring; R23 is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl, halide, alkoxy, aryloxy, acyloxy, silyloxy, nitrile, -C (0) R21, -C02R21, -S02R21, and -C (O) N (R21) 2; Y R25 is hydroxyl, acylamino, -N (R20) COR20, -N (R20) C (O) OR20, -N (R20) SO2 (R20), -COR20N (R20) 2, -OC (O) R20N (R20) , -S02N (R20) (R20), -N (R20) (R20), -COOR20, -C (O) N (OH) (R21), -OS (0) 2OR2 °, -S (0) 2OR20, - OP (L) (OR20) (OR20), -NP (O) (OR20) (OR20) or -P (O) (OR20) (OR20). with the proviso that there is at least one group represented by the formula Ib in the compound of the formula 2. In certain embodiments, the compounds of the present invention are represented by 1 and the appended definitions, wherein in the present R 13, R 14 , R15, R16 and R17 are hydrogen. In certain embodiments, the compounds of the present invention are represented by 1 and the appended definitions, wherein R 1 is hydroxyl, sugar, -OP (L) (OR20) 2, -X- C (L) -R21 or -XC ( L) -X-R21; or R1 and R2 taken together, together with the carbon to which they bind, form -C (O) -. In certain embodiments, the compounds of the present invention are represented by 1 and the appended definitions, wherein R 4 and R 5 taken together form a double bond. In certain embodiments, the compounds of the present invention are represented by 1 and the appended definitions, wherein R 1 and R 2 taken together, together with the carbon to which they are linked, form -C (O) -. In certain embodiments, the compounds of the present invention are represented by 1 and the definitions annexes, wherein R1 is hydroxyl and R2 is H. In certain embodiments, the compounds of the present invention are represented by 1 and the appended definitions, wherein R1 is hydroxyl, R2 is H; and R5 and R6 taken together form a double bond; or R5 and R6 taken together form a group represented by Ib; where: Z is C (R23) (R23). In certain embodiments, the compounds of the present invention are represented by 1 and the appended definitions, wherein R 10 and R 11 taken together form a double bond; or R10 and R11 taken together form a group represented by Ib; where: Z is C (R23) (R23). In certain embodiments, the compounds of the present invention are represented by 1 and the appended definitions, wherein R 5 and R 6 taken together form a double bond and R 10 and R 11 taken together form a double bond.

In certain embodiments, the compounds of the present invention are represented by 1 and the appended definitions, wherein R 1 and R 2 taken together, together with the carbon to which they are linked, form -C (0) -; R4 and R5 taken together form a double bond; and R10 and R11 taken together form a double bond; or R10 and R11 taken together form a group represented by Ib; where: Z is C (R23) (R23). In certain embodiments, the compounds of the present invention are represented by 1 and the appended definitions, wherein R 1 is hydroxyl and R 2 is H; R10 and R11 taken together form a double bond; or R10 and R11 taken together form a group represented by Ib; where: Z is C (R23) (R23). In certain embodiments, the compounds of the present invention are represented by 1 and the appended definitions, wherein R 8 and R 9 are hydrogen; or R8 and R9 taken together, together with the carbon to which they are bonded, is -C (O) -.

In certain embodiments, the compounds of the present invention are represented by 1 and the appended definitions, wherein R 12 is H, alkyl, cycloalkyl, aralkyl, heteroaryl, heteroaralkyl, haloalkyl, hydroxyl, alkoxy, - [(W) -N (R21 ) C (0)] qR21, - [(W) -N (R21) S02] qR21, - [(W) -C (0) N (R21)] qR21, - [(W) -Oq] R21, - [(W) -C (0)] qR21, or - [(W) -C (0) 0] qR21. In certain embodiments, the compounds of the present invention are represented by 1 and the appended definitions, wherein R 13, R 14, R 15, R 16 and R 17 are hydrogen; and R12 is H, alkyl, cycloalkyl, aralkyl, heteroaryl, heteroaralkyl, haloalkyl, hydroxyl, alkoxy, - [(W) -N (R21) C (0)] qR21, - [(W) -N (R21) S02] qR21, - [(W) -C (O) N (R21)] qR21, - [(W) -Oq] R21, - [(W) -C (0)] qR21, or - [(W) -C (0) 0] qR21. In certain embodiments, the compounds of the present invention are represented by 1 and the appended definitions, wherein R 4 and R 5 taken together form a double bond; R1 and R2 taken together, together with the carbon to which they bind, form -C (O) -; and R12 is H, alkyl, cycloalkyl, aralkyl, heteroaryl, heteroaralkyl, haloalkyl, hydroxyl, alkoxy, - [(W) -N (R21) C (O)] qR21, - [(W) -N (R21) S02] qR21, - [(W) -C (0) N (R21)] qR21, - [(W) -Oq] R21, - [(W) -C (O)] qR21, or - [(W) -C (0) 0] qR21. In certain embodiments, the compounds of the present invention are represented by 1 and the definitions annexes, wherein R1 is hydroxyl and R2 is H; and R12 is H, alkyl, cycloalkyl, aralkyl, heteroaryl, heteroaralkyl, haloalkyl, hydroxyl, alkoxy, - [(W) -N (R21) C (0)] qR21, - [(W) -N (R21) S02] qR21, - [(W) -C (O) N (R21)] qR21, - [(W) -Oq] R21, - [(W) -C (0)] qR21, or - [(W) -C (0) 0] qR21. In certain embodiments, the compounds of the present invention are represented by a compound of the formula: wherein: R12 is H, alkyl, aryl, cycloalkyl, heterocycloalkyl, hydroxyl, aralkyl, heteroaryl, heteroaralkyl, haloalkyl, alkoxy, C (0) R21, -C02R21, S02R21, -C (0) N (R21) (R21) , - [C (R21) 2] q-R21, - [(W) -N (R21) C (0)] qR21, - [(W) -C (0) qR21, - [(W) -C ( 0) 0} qR21, - [(W) -OC (0)] qR21, - [(W) -S02] qR21, - [(W) -N (R21) S02] qR21, - [(W) -C (0) N (R21)] qR21, - [(W) -0] qR21, - [(W) -N (R21)] qR21, or - [(W) -S] qR21; q is 1, 2, 3, 4, 5 or 6; R20 is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, or heteroaralkyl; or any two cases of R20 may be taken together to form an optionally substituted 4-8 membered ring; R21 is H, alkyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl or - [C (R20) 2] P-R25, or any two cases of R21 can be taken together to form an optionally substituted 4-8 membered ring; R25 is hydroxyl, acylamino, -N (R20) COR20, N (R20) C (O) OR20, -N (R20) SO2 (R20), -COR20N (R20) 2, -OC (0) R20N (R20), -S02N (R20) (R20), -N (R20) (R20), -COOR20, -C (O) N (OH) (R21), OS (0) 2OR20, -S (0) 2OR2 °, -0P (L) (OR20) (OR20), -NP (O) (OR20) (OR20) or -P (0) (OR20) (OR20). The present invention specifically provides compounds represented by the group consisting of: In certain embodiments, the compounds of the present invention are represented by any of the aforementioned compounds and the appended definitions, where the compound is represented by the formula: In certain embodiments, the present invention relates to a pharmaceutical composition comprising any one or more of the aforementioned compounds; and a pharmaceutically acceptable excipient. Synthesis of Steroidal Alkaloid Compounds The cyclopropyl steroidal alkaloid derivatives of the present invention can be prepared directly from an isolated steroidal alkaloid as a natural (or synthesized) product or N-protected forms of these compounds. Suitable nitrogen protection groups include, but are not limited to Fmoc, Alloc, Boc, Troc, trifluoroacetate, Tosyl, Cbz, ethyl cyanide, and Bn. A variety of cylcopropane agents can be used to cyclopropane the steroidal alkaloid, 1,1-haloalkylmetal complexes, including reactive species referred to as carbenoids, are commonly used for cyclopropanate olefins. These reagents are usually made using a diiodoalkane or diazoalkane and a metal or organometallic species, such as Et2Zn, iBu3Al, samarium, copper, rhodium or palladium. In certain embodiments, Et2Zn and diiodomethane are used to affect cyclopropanation. Other known methods of cyclopropanation such as those using sulfur delusions to react with an olefin conjugated to a carbonyl to add a CH2 or CH-alkyl or CH-aryl group, and metal-catalyzed decomposition of diazoalkyl and a-diazocarbonyl compounds, such as diazomethane and ethyl diazoacetate, may also be used; these methods readily provide cyclopropanes having alkyl, aryl, alkoxycarbonyl (-COOR), or acyl substituents. For example, the addition of ethyl diazopropionate (Et02C-C (N2) -Me) to an olefinic compound in an organic solvent containing a metal catalyst such as copper or palladium results in the formation of a cyclopropane containing a group represented by the formula Ib in which Z represents C (R23) 2, in which one of R23 is Me and the other R23 is COOEt. By carefully selecting the cyclopropanation agent, site selectivity can be achieved in the cyclopropanation of steroidal alkaloids with more than one olefin. For example, if diiodomethane and Et2Zn are used for cyclopropanane jervine under certain conditions only the electron richest olefin will be reacted. The diastereoselectivity of cyclopropanation can be controlled in a number of ways. For example, decreasing the temperature of the cyclopropanation reaction can lead to higher diastereoselectivities. Alternatively, a chiral cyclopropanation agent can be used which can be distinguished between each face Diastereo of the steroidal alkaloid. Facial selectivity in cyclopropanation can also be achieved by using directed substrate reactions (ie, cyclopropanation of aryl alcohols using Et2Zn / CH2I2 reagents). The cyclopropanation reactions can be conducted in an aprotic solvent, preferably one in which the reaction ingredients are substantially soluble. Suitable solvents include ethers, such as diethyl ether, 1,2-dimethoxyethane, diglyme, t-butylmethyl ester, tetrahydrofuran and the like; halogenated solvents, such as chloroform, dichloromethane, dichloroethane and the like; aliphatic or aromatic hydrocarbon solvents; such as benzene, xylene, toluene, hexane, pentane and the like; esters and ketones, such as ethyl acetate, acetone and 2-butanone; polar aprotic solvents, such as acetonitrile, dimethisulfoxide, dimethylformamide and the like; or combinations of two or more solvents. In a preferred embodiment, dichloromethane is the solvent used for cyclopropanation when a dialkylzinc and diiodomethane is used. After synthesis of the cyclopropanated steroidal alkaloid nucleus, the compound can be derived using a variety of functionalization reactions known in the art. Representative examples include coupling reactions of palladium to alkenyl halides or arylhalides, oxidations, reductions, reactions with nucleophiles, reactions with electrophiles, pericyclic reactions, installation of protection groups, removal of protection groups and the like. In the presence of Lewis or Bronsted acids the cyclopropyl cyclopamine analogs of the present invention undergo in this sense an unobserved re-arrangement and ring expansion to produce novel cyclopamine analogs in which the D ring has expanded by a carbon . The cyclopropylamino ring can be substituted or unsubstituted. In cases where the cyclopropyl ring is substituted, the methylene-linked groups of the cyclopropane will be installed on the D-ring after the re-arrangement and expansion of the ring. Suitable acids include, but are not limited to Znl2, BF3, methanesulfonic acid, diaryloxyphosphoric acids and HCl. In a preferred embodiment of the invention, the Lewis acid used is BF3. These homologous analogs can be further functionalized using a variety of functionalization reactions known in the art. Representative examples include coupling reactions for alkylhalides or arylhalides, oxidations, reductions, reactions with nucleophiles, reactions with electrophiles, pericyclic reactions, installation of protection groups, removal of protection groups and the like. Methods of the Invention The present invention further provides methods for treating, improving one or more symptoms of, and reducing the severity of hyperproliferative disorders, i.e., cancer, as well as other disorders or conditions mediated by hedgehog. Hedgehog pathway antagonists are currently being explored in a large number of clinical conditions wherein a therapeutic effect can be obtained by a condition or disorder inhibiting one or more aspects of the activity of Urchin's pathway. Although the main focus has been on cancer, researchers have found that the inhibition of the small molecule of the hedgehog pathway improves the symptoms of psoriasis (Tas, et al., 2004 Dermatology 209: 126-131, published North American patent application). 20040072913 (incorporated herein by reference)). Psoriasis is a chronic skin disorder, very common, usually characterized by skin lesions that usually contain papules and erythematous plaques with a silver-colored crust, although there are variations in both the skin and other parts of the body. It is currently thought that psoriasis is an autoimmune disease, but its etiology is still poorly understood. In one study, the topical application of cyclopamine to psoriasis lesions leads to total or partial return of the lesion with a decrease in inflammatory cells (Tas et al., Supra).

The hedgehog pathway antagonists of the present invention can be used to treat or prevent psoriasis when administered as a single agent or when administered in combination with one or more anti-psoriasis agents including, but not limited to, corticosteroids, tar, calcipotriene , tazarotene, calcineurin inhibitors, ultraviolet irradiation, methotrexate, retinoids, cyclosporine, immunomodulatory drugs, etanercept, alefacept, efelizumab and infliximab. Many tumors and proliferative conditions have shown that they depend on the route of the hedgehog. The growth of such cells and survival can be affected by treatment with the compounds of the present invention. For example, inhibition of small molecules of the hedgehog pathway has been shown to inhibit the growth of basal cell carcinoma (Williams, et al., 2003 PNAS 100: 4616-21), medulloblastoma (Berman et al., 2002 Science 297: 1559-61), pancreatic cancer (Berman et al., 2003 Nature 425: 846-51), gastrointestinal cancers (Berman et al., 2003 Nature 425: 846-51, published PCT application WO 05/013800), esophageal cancer (Berman et al., 2003 Nature 425: 846-51), lung cancer (Watkins et al., 2003, Nature 422: 313-7), and prostate cancer (Karhadkar et al., 2004, Nature 431: 707 -12). In addition, it has been shown that many types of cancers have uncontrolled activation of the hedgehog pathway, for example, breast cancer (Kubo et al., 2004, Cancer Research 64: 6071-4), heptacellular cancer (Patil et al., 2004, 96th Annual AACR conference, extract # 2942 Sicklick et al., 2005. ASCO annual meeting, extract # 9610), hematological malignancies (Watkins and Matsui, unpublished results), basal cell carcinoma (Bale &Yu, 2001. Human Molec, Genet 10: 757-762 Xie et al., 1998 Nature 391: 90-92), medulloblastoma (Pietsch et al., 1997. Cancer Res. 57: 2085-88), and gastric cancer (Ma et al., 2005 Carcinogenesis May 19, 2005 (Epub )). Cancers or neoplastic diseases and related disorders that can be treated by the administration of compounds and compositions of the present invention, include, but are not limited to, Adrenal Cortical Cancer, Anal Cancer, Aplastic Anemia, Bile Duct Cancer, Bladder Cancer, Cancer of Bones, Brain / CNS Tumors, Breast Cancer, Cervical Cancer, Non-Hodgkin's Lymphoma, Colon Cancer, Rectum Cancer, Endometrial Cancer, Esophagus Cancer, Ewing's Tumor Family, Eye Cancer, Vesicle Cancer Biliary, Gastrointestinal Carcinoid Tumors, Gastrointestinal Stromal Tumors, Gestational Trophoblastic Disease, Hodgkin's Disease, Kaposi's Sarcoma, Kidney Cancer, Laryngeal and Hypopharyngeal Cancer, Acute Lymphocytic Leukemia, Acute Myeloid Leukemia, Leukemia in Children, Chronic Lymphocytic Leukemia, Chronic Myeloid Leukemia, Liver Cancer, Lung Cancer, Carcinoid Lung Tumor, Non-Hodgkin's Lymphoma, Breast Cancer in Men, Malignant Mesothelioma, Multiple Myeloma, Syndrome Myelodysplastic, Nasal Cavity and Paranasal Cancer, Nasopharyngeal Cancer, Neuroblastoma, Oral Cavity Cancer, Lower Jaw Cancer, Osteosarcoma, Ovarian Cancer, Pancreatic Cancer, Penile Cancer, Puititary Tumor, Prostate Cancer, Retinoblastoma, Rhabdomyosarcoma, Cancer of Salivary Gland, Sarcoma, Melanoma Skin Cancer, Skin Cancer without Melanoma, Stomach Cancer, Testicular Cancer, Thymus Cancer, Thyroid Cancer, Uterine Sarcoma, Vaginal Cancer, Vulvar Cancer, Waldenstrom Macroglobulinemia and Wilm's Tumor. The methods and compositions of the present invention can be used in the treatment of human cancers, for example, basal cell carcinomas and other tumors of epithelial tissues such as the skin. In addition, the compounds of the present invention can be used as part of a treatment of basal cell carcinoma, pancreatic cancer, prostate cancer, sarcoma, lymphomas, leukemia, gastrointestinal cancer, multiple myeloma, small cell lung cancer, glioma, cancer of breast, hepatocellular or medulloblastoma by administering a quantity therapeutically effective of at least one of the compounds of the present invention as a single agent or in combination with another anti-cancer agent. The methods and compositions of the present invention can be used in the treatment of neoplastic or hyperplastic transformations such as can occur in the central nervous system. For example, the compounds of the present invention can be used to cause such transformed cells to become either post-mitotic or apoptotic. The present method can therefore be used as part of a treatment for example, for malignant gliomas, meningiomas, medulloblastomas, neuroectodermal tumors and ependymomas. In one embodiment, the present method can be used as part of a treatment regimen for malignant medulloblastoma and other malignant neuroectodermal tumors of the primary CNS. In certain embodiments, the present invention relates to a method of treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of one or more of the aforementioned compounds. In certain embodiments, the present invention relates to a method for treating cancer, which comprises administering to a subject in need thereof a Therapeutically effective of a compound of any one or more of the aforementioned compounds, wherein the cancer is located in the head, neck, nasal cavity, paranasal sinuses, nasopharynx, oral cavity, lower jaw, larynx, hypopharynx, salivary glands, paragangliomas, pancreas, stomach, skin, esophagus, liver and biliary tree, bones, intestine, colon, rectum, ovaries, prostate, lung, breast, lymphatic system, blood, central nervous system of the spinal cord or brain. In certain embodiments, the present invention relates to a method of treating cancer, which comprises administering to a subject in need thereof a therapeutically effective amount of a compound of one or more of the aforementioned compounds, wherein the cancer is a cell carcinoma. basal, pancreatic cancer, prostate cancer, sarcoma, lymphomas, leukemia, gastric cancer, esophageal cancer, biliary cancer, colon cancer, multiple myeloma, small cell lung cancer, glioma, breast cancer, hepatocellular or medulloblastoma. In certain embodiments, the present invention relates to the aforementioned method wherein the compound is used in combination with radiation therapy or another anti-cancer chemotherapeutic agent. In certain embodiments, the present invention relates to any aforementioned method wherein the compound is administered locally to a tumor or systemically to a patient. In certain embodiments, the present invention relates to any aforementioned method wherein the mode of administration of the compound is inhalation, oral, intravenous, sublingual, ocular, transdermal, rectal, vaginal, topical, intramuscular, intra-arterial, intrathecal, subcutaneous. , buccal or nasal. In certain embodiments, the present invention relates to any aforementioned method wherein the mode of administration is oral, intravenous or topical. In certain embodiments, the present invention relates to a method for antagonizing the hedgehog pathway in a cell, comprising contacting a smoothed cell expression with an effective amount of any one or more of the aforementioned compounds. In certain embodiments, the present invention relates to a method for antagonizing the hedgehog pathway in a cell, comprising contacting a smoothed cell expression with an effective amount of any one or more of the aforementioned compounds, wherein the expression The smoothed cell is contacted with the compound in vi tro. In certain embodiments, the present invention relates to a method for antagonizing the pathway of the hedgehog in a cell, comprising contacting a smoothed cell expression with an effective amount of any one or more of the aforementioned compounds, wherein the softened cell expression is contacted with the compound in vivo. In certain embodiments, the present invention relates to a method for antagonizing the hedgehog pathway in a cell, comprising contacting a smoothed cell expression with an effective amount of any one or more of the aforementioned compounds, wherein Expression Smo cellular is inside the body of a patient. In certain embodiments, the present invention relates to a method of treating or preventing psoriasis in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of any one or more of the aforementioned compounds. In certain embodiments, the present invention relates to the aforementioned method for treating or preventing psoriasis wherein the mode of administration of the compound is topical. In certain embodiments, one or more compounds of the present invention are used to treat or prevent psoriasis in combination with one or more anti-psoriasis agents including, but not limited to inhibitors of corticosteroids, tar, calcipotriene, tazarotene, calcineurin, ultraviolet irradiation, methotrexate, retinoids, cyclosporine, immunomodulatory drugs, etanercept, alefacept, efalizumab and infliximab. Cancer Treatment in Combination with Chemotherapy or Radiation Therapy In certain embodiments, one or more compounds of the present invention are used to treat or prevent cancer or neoplastic disease in combination with one or more anti-cancer chemotherapeutic agents, including, but not limited to, gemcitabine. , methotrexate, taxol, mercaptopurine, thioguanine, hydroxyurea, citarbina, cyclophosphamide, ifosfamide, nitrosoureas, cisplatin, carboplatin, mitomycin, dacarabazine, procarbizine, etoposides, prednisolone, dexamethasone, citarbina, camptechin, bleomycin, doxorubicin, idarubicin, daunorubicin, dactinomycin, plicamycin , mitoxantrone, asparaginase, vinblastine, vincristine, vinorelbine, paclitaxel and docetaxel. In a preferred embodiment, one or more compounds of the present invention is used to treat or prevent cancer or neoplastic disease in combination with a chemotherapeutic or other anti-cancer agent including, but not limited to radiation (e.g., -radikation), nitrogen mustards (eg, cyclophosphamide, Ifosfamide, Trofosfamide, Chlorambucil, Estramustine and Melphalan), Nitrosoureas (eg carmustine (BCNU) and Lomustine (CCNU)), Alkylsulfonates (e.g., busulfan and Treosulfan), Triazenes (e.g., Dacarbazine and Temozolomide), compounds containing Platinum (e.g., Cisplatin, Carboplatin, and oxaliplatin), Vinca alkaloids (e.g., vincristine, Vinblastine, Vindesine and Vinorelbine), Taxoids (for example, paclitaxel and Docetaxol), Epipodophyllins (eg, etoposide, Teniposide, Topotecan, 9-Aminocanfothecin, Camptoirinotecan, Crisnatol, Mitomycin C and Mitomycin C), Anti-metabolites, DHFR inhibitors (e.g., methotrexate and trimetrexate), IMP dehydrogenase inhibitors (e.g., icophenolic acid, thiazofurine, ribavirin and EICAR), inhibitors of ribonucleotide reductase (e.g., hydroxyurea and deferoxamine), analogs of uracil (e.g., cytarabine C), cytosine arabinoside, and Fludarabine), Purine analogs (eg, mercaptopurine and Thioguanine), Anti-estrogens (eg, Tamoxifen, Raloxifene and Megestrol), ago LHRH monitors (eg, goscrclin and Leuprolide acetate), Anti-androgens (eg, Futamide and Bicalutamide), Vitamin D3 analogs (eg, EB 1089, CB 1093, and KH 1060), photodynamic therapies (e.g. , Vertoporphine (BPD-MA), Phthalocyanine, Pc4 photosensitizer and Demetoxy-hypocrelin A (2Ba-2-DMHA)), Cytokines (for example, Interferon a, Interferon? and tumor necrosis factor), Isoprenylation inhibitors (for example, Lovastatin), dopaminergic neurotoxins (e.g., l-methyl-4-phenylpyridinium ion), cell cycle inhibitors (e.g., staurosporine), Actinomycins (e.g., Actinomycin D and Dactinomycin), Bleomycins (e.g., bleomycin A2, Bleomycin B2 and Peplomycin), Anthracyclines (eg daunorubicin, Doxorubicin (adriamycin), Idarubicin, Epirubicin, Pirarubicin, Zorubicin and Mitoxantrone), MDR inhibitors (eg verapamil), Ca2 + APTase inhibitors (eg, tapsigargin), Antibodies (eg , Avastin, Erbitux, Rituxan and Bexxar), corticosteroids (for example, prednilone, predisone, etc.), Imatinib, Thalidomide, Lenalidomide, Bortezomib, Gemcitabine, Erlotinib, Gefitinib, Sorafenib and Sutinib. The chemotherapeutic agent and / or radiation therapy can be administered according to therapeutic protocols well known in the art. It will be apparent to those skilled in the art that the administration of the chemotherapeutic agent and / or radiation therapy may be varied depending on the disease being treated and the known effects of the chemotherapeutic agent and / or radiation therapy in that disease. Also, according to the knowledge of the experienced practitioner, the therapeutic protocols (e.g., dose amounts and schedules of administration) may be varied in view of the observed effects of the therapeutic agents administered (ie. say, antineoplastic agent or radiation) in the patient, and in view of the observed responses of the disease to the therapeutic agents administered, and adverse effects observed. Also, in general, the compounds of the present invention and the chemotherapeutic agent do not have to be administered in the same pharmaceutical composition, and may, due to different physical and chemical characteristics, have to be administered by different routes. For example, the compounds of the present invention can be administered intravenously to generate and maintain good blood levels, although the chemotherapeutic agent can be administered orally. The determination of the mode of administration and the prudence of administration, when possible, in the same pharmaceutical composition, is adequate within the knowledge of the experienced physician. The initial administration can be done according to established protocols known in the art, and then, based on the effects observed, the dosage, modes of administration and administration schedules can be modified by the experienced physician. The particular choice of the chemotherapeutic agent or radiation will depend on the diagnosis of the doctors and their judgment of the patient's condition and the appropriate treatment protocol.

A compound of the present invention, and the chemotherapeutic agent and / or radiation can be administered at the same time (eg, simultaneously, essentially simultaneously or within the same treatment protocol) or sequentially, depending on the nature of the proliferative disease, the condition of the patient, and the current choice of the chemotherapeutic agent and / or radiation that is administered together (i.e., within a simple treatment protocol) with a compound of the present invention. If a compound of the present invention and the chemotherapeutic agent and / or radiation are not administered simultaneously or essentially simultaneously, then the optimal order of administration of the compound of the present invention, and the chemotherapeutic agent and / or radiation, may be different for different tumors. Thus, in certain situations the compound of the present invention may be administered first followed by the administration of the chemotherapeutic agent and / or radiation; and in other situations the chemotherapeutic agent and / or radiation may be administered first followed by the administration of a compound of the present invention. This alternative administration can be repeated during a simple treatment protocol. The determination of the order of administration, and the number of administration repetitions of each therapeutic agent during a treatment protocol is suitable within the knowledge of the experienced physician after evaluation of the disease being treated and the condition of the patient. For example, the chemotherapeutic agent and / or radiation may be administered first, especially if it is a cytotoxic agent, and then continued treatment with the administration of a compound of the present invention followed, when determined to be advantageous, by the administration of the chemotherapeutic agent and / or radiation, etc., until the treatment protocol is completed. Thus, according to experience and knowledge, the practitioner may modify each protocol for the administration of a component (therapeutic agent, i.e., the compound of the present invention, chemotherapeutic agent or radiation) of the treatment according to the needs of the individual patient, as the treatment proceeds. Pharmaceutical Compositions In another embodiment, the present invention provides pharmaceutically acceptable compositions which comprise a therapeutically effective amount of one or more of the compounds described above (Formula 1 and 2), formulated together with one or more pharmaceutically acceptable carriers (additives) and / or diluents. The Pharmaceutical compositions of the present invention can be formulated especially for administration in solid or liquid form, including those adapted for the following: (1) oral administration, for example, concoctions (aqueous or non-aqueous solutions or suspensions), tablets for example, those intended for oral, sublingual and systemic absorption, boluses, powders, granules, pastes for application to the tongue; (2) parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection such as, for example, a sterile solution or suspension or sustained release formulation; (3) topical application, for example, as a cream, ointment or a controlled release patch or spray applied to the skin; (4) intravaginally or intra-rectally, for example, as a uterine device, cream or foam; (5) sublingual; (6) ocular; (7) transdermal; (8) pulmonary; or (9) nasally. As stated above, certain embodiments of the present compounds may contain a basic functional group, such as amino or alkylamino, and are thus capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable acids. The term "pharmaceutically acceptable salts" in this regard refers to non-toxic, inorganic and organic acid addition salts of the compounds of the present invention. These salts can be prepared in if you in the vehicle or the dose form manufacturing processes, or by reacting a purified compound of the invention in its free bae form with a suitable organic or inorganic acid, and isolating the salt thus formed during the subsequent purification. Representative salts include salts of hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate and laurylsulfonate, and the like. (See for example, Berge et al (1977) "Pharmaceutical Salts"; J. Pharm. Sci. 66: 1-19). The pharmaceutically acceptable salts of the compounds of the present invention include the conventional non-toxic salts or quaternary ammonium salts of the compounds, for example, from non-toxic organic or inorganic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric, and the like; and salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, palmitic, maleic, hydroximic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic , fumaric, toluenesulfonic, methanesulfonic, ethanedisulfonic, oxalic, isothionic and the like.

In other cases, the compounds of the present invention may contain one or more acidic functional groups and are thus capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable bases. The term "pharmaceutically acceptable salts" in these cases refers to the relatively non-toxic inorganic and organic base addition salts of compounds of the present invention. These salts can likewise be prepared in itself in the administration vehicle or the dosage form manufacturing process or by separately reacting the purified compound in its free acid form with a suitable base, such as hydroxide, carbonate or bicarbonate. of a pharmaceutically acceptable metal cation, with ammonia or with a pharmaceutically acceptable primary, secondary or tertiary organic amine. Representative alkali or alkaline earth salts include lithium, sodium, potassium, calcium, magnesium and aluminum salts and the like. Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like (See, for example, Berge et al., Supra) Wetting agents, emulsifiers and lubricants, such as lauryl sulfate. sodium and magnesium stearate, as well as coloring agents, release agents, coating agents, sweeteners, flavors and perfume agents, preservatives and antioxidants can also be present in the compositions. Examples of pharmaceutically acceptable antioxidants include: (1) water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbylpalmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol and the like; and (3) metal chelating agents, such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid and the like. Methods for preparing these formulations or compositions include the step of entering into association a compound of the present invention with the carrier and, optionally, one or more essential ingredients. In general, the formulations are prepared by uniformly and intimately linking a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, forming the product. Pharmaceutical compositions of the present invention suitable for parenteral administration comprise one or more compounds of the invention in combination with one or more sterile pharmaceutically acceptable isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders which can be reconstituted into sterile injectable solutions or dispersions. before use, which may contain sugars, alcohols, antioxidants, buffers, bacteriostats, solutes which supply the isotonic formulation with the blood of the intended recipient or suspending or thickening agents. Examples of suitable aqueous and non-aqueous carriers which can be employed in the pharmaceutical compositions of the invention include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin by the maintenance of the required particle size in the case of dispersions and by the use of surfactants. These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms in the compounds of the present invention can be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenolsorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugar, sodium chloride and the like in the compositions. In addition, prolonged absorption of the injectable pharmaceutical form can be effected by the inclusion of agents which retard absorption such as aluminum monostearate and gelatin. In some cases, in order to prolong the effect of a drug, it is desirable to delay the absorption of the drug from subcutaneous or intramuscular injection. This can be achieved by the use of a liquid suspension of crystalline or amorphous material having poor aqueous solubility. The rate of absorption of the drug then depends on its rate of dissolution which, in turn, may depend on the crystal size and crystal form. Alternatively, the delayed absorption of a parenterally administered drug form is achieved by dissolving or suspending the drug in an oily vehicle. Injectable depot forms are made by forming microencapsulated matrices of the compounds of the present invention in biodegradable polymers such as polylactide-polyglycolide. Depending on the relationship of drug to the polymer, and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly (orthoesters) and poly (anhydrides). Depot injectable formulations are also prepared by trapping the drug in liposomes or microemulsions which are compatible with body tissue. Formulations of the invention suitable for oral administration may be in the form of capsules, beads, pills, tablets, lozenges (using flavored bases, usually sucrose and acacia or tragacanth), powders, granules or as a solution or suspension in a liquid. aqueous or non-aqueous, or as an emulsion liquid oil in water or water in oil, or as an elixir or syrup, or as pills (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and / or as rinses mouths and the like, each containing a predetermined amount of a compound of the present invention as an active ingredient. A compound of the present invention can also be administered as a bolus, remedy or paste. When the compounds of the present invention are administered as pharmaceuticals, to humans and animals, these can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99% (more preferably 10 to 10%). at 30%) of the active ingredient in combination with a pharmaceutically acceptable carrier. These compounds can be administered to humans and other animals for therapy by any suitable route of administration, including orally, nasally, or for example, by spraying, rectal, intravaginal, parenteral, intracisternal and topically, as mediantes powders, ointments or drops, including buccal and sublingually. Regardless of the route of administration selected, the compounds of the present invention, which may be used in a suitable hydrated form and / or the pharmaceutical compositions of the present invention, are formulated into pharmaceutically acceptable dosage forms by conventional methods known to those skilled in the art. of experience in the technique. The current dose levels of the active ingredients in the pharmaceutical compositions of the present invention can be varied such that an amount of the active ingredient is obtained which is effective to achieve the desired therapeutic response for a particular patient, composition and mode of administration, without being toxic to the patient. The level of dose selected will depend on a variety of factors including the activity of the compound particular of the present invention employed, or the ester, salt or amide thereof, the administration route of administration time, the rate of excretion or metabolism of the particular compound that is employed, the rate and degree of absorption, the duration of the treatment , other drugs, compounds and / or materials used in combination with the particular compound employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and similar factors well known in the medical arts. A physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the required pharmaceutical composition. For example, the physician or veterinarian could initiate the dose of the compounds of the invention used in the pharmaceutical composition at levels below that required in order to achieve the desired therapeutic effect and gradually increase the dose until the desired effect is achieved. In general, an adequate daily dose of a compound of the invention will be that amount of the compound which is the lowest effective dose to produce a therapeutic effect. Such an effective dose will generally depend on the factors described above. In general, oral, intravenous, intracerebroventricular and subcutaneous doses of the compounds of the present invention for a patient, when used for the indicated analgesic effects, will vary from about 0.0001 to about 100 mg per kilogram of body weight per day. If desired, the effective daily dose of the active compound will be administered as two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally in unit dosage forms. The preferred dosage is one administration per day. Although it is possible for a compound of the present invention to be administered alone, it is preferable to administer the compound as a pharmaceutical formulation (composition). The subject receiving this treatment is any animal in need, including primates, in particular human beings, and other mammals such as horses, cattle, pigs and sheep; and poultry and pets in general. The compound of the invention can be administered as such or in mixtures with pharmaceutically acceptable carriers and can also be administered together with antimicrobial agents such as penicillins, cephalosporins, aminoglycosides and glycopeptides. Conjunctive therapy thus includes sequential, simultaneous and separate administration of the active compound so that the therapeutic effects of the first administered do not disappear completely when it is administered subsequently. Exemplification The invention now generally described will be more readily understood for reference to the following examples, which are included merely for purposes of illustration of certain aspects and embodiments of the present invention, and are not intended to limit the invention. Example 1 Preparation of a Cyclopamine Derivative Part A To a solution of cyclopamine 2 (250 mg, 0.6 mmol, 1 eq) in DCM (10 mL) at room temperature was added Fmoc-OSu (205 mg, 0.6 mmol, 1 eq) and the resulting mixture was stirred at room temperature for the night. The solution resulting from the unpurified Fmoc-cyclopamine was then cooled to 0 ° C and treated with 15% diethyl zinc in toluene (0.5 mL, 0.6 mmol, 1 eq) and stirred for 30 minutes (Flask A). Diiodomethane (0.4 mL, 0.6 mmol, 10 eq) was treated in DCM (20 mL) at 0 ° C with 15% diethyl zinc in toluene (3 mL, 3 mmoles, 5 eq) and the resulting solution was stirred for 5 minutes (flask B). The contents of flask B were transferred to flask A through a cannula and the resulting suspension was stirred for 5 hours at room temperature. The reaction was quenched with HCl (1M), stirred for 10 minutes (until all the white solid was redissolved) and extracted with DCM (5x). The organic extracts were dried (MgSO 4), filtered over Celite and concentrated in vacuo. The residue was purified by flash chromatography (1: 1 Hex / AcOEt). The target 11,12-monocyclopropane was obtained as a 9: 1 mixture of diastereoisomers, together with 20% bis-cyclopropanated disatereomeric products (80% total recovery). This mixture was separated using preparative SFC chromatography.

Part B Fmoc-monocyclopropyl cyclopamine 3 (100 mg, 0.15 mmol, 1 eq) in DCM (2 mL) was treated at room temperature with diethylamine (0.5 mL, 4.8 mmol, 32 eq) overnight, the resulting solution was concentrated in vacuo and The residue was taken up in silica gel and purified by flash chromatography (2: 1 → 1: 1 Hex / AcOEt, then 95: 5 → 20:80 DCM / MeOH). The desired product was obtained as a white solid (95% yield). MS (ESI (+)) m / e 426.31 (M + H) +. Example 2 Preparation of a Cyclopamine Derivative: Part A To a solution of hydrocinnamic acid 5 (3.01 g, 20 mmol, 3 eq) in anhydrous chloroform (30 mL) at 75 ° C was added thionyl chloride (1.75 mL, 24.1 mmol, 1.2 eq) in drops over a period of 3 hours. minutes The mixture was refluxed for 3.5 hours. The solvent was removed by distillation to give the acid chloride without purification as a light yellow viscous liquid. The unpurified product was used without further purification. Part B To a biphasic mixture of 7 (3.16 g, 24.1 mmol, 1.2 eq) in DCM (30 mL) and an aqueous solution of NaOH (2.0 M, mL, 3 eq) at 25 ° C was added a solution of the acid chloride 6 (3.38 g, 20 mmol, 1 eq) in DCM (10 L) and the resulting mixture was stirred at 25 ° C for 3 hours. The mixture was then neutralized with aqueous HCl (2 M, 30 mL). The organic layer was then separated and the aqueous layer was extracted with DCM (3 x 50 mL). The combined organic layers were washed with HCl (2.0 M, 25 mL), water (3 x 50 mL), saturated brine. (50 mL), dried over magnesium sulfate and the solvent was evaporated under reduced pressure. The crude product was taken to silica gel chromatography using 5% of MeOH: DCM as an eluent and the column was then eluted with 10% MeOH: DCM to produce 1141 g of compound 8. Part C To a mixture of acid 8 (264 mg, 1 mmol, 1 eq), EDCI (231 mg, 1.2 mmol, 1.2 eq) and triethylamine (168 μl, 1.2 mmol, 1.2 eq) in DCM (2 mL) at 0 ° C allylamine (90.3 μL, 1.2 mmol, 1.2 eq) was added and the resulting mixture was stirred at 0 ° C for 1 hour and allowed to warm to 25 ° C over a period of 2 hours. The reaction mixture was added to water (50 mL), extracted with DCM (4 x 25 mL), the combined organic layers were washed with 1 M HCl (2 x 25 mL), water (3 x 25 mL), Saturated brine (25 mL), dried over magnesium sulfate and the solvent was removed by evaporation under reduced pressure to yield 287.5 mg of the desired product. This material was used without further purification. Part D To a solution of allylamide 9 (70 mg, 0.23 mmol, 1 eq) in acetone (1 mL) and water (0.3 mL) was added to a solution of osmium tetroxide (0.35 mL, 0.035 mmol, 0.15 eq, 2.5 p / p in t-butanol). The reaction mixture was immediately cooled on ice immediately after the addition of the Os04 solution and the resulting dark brown solution was stirred at 0 ° C for 15 minutes. Sodium periodate (110 mg, 0.51 mmol, 2.2 eq) was added in 5 portions to the above mixture and stirring was continued for 1 hour at 0 ° C and allowed to warm to 25 ° C over a period of 2 hours. The reaction mixture was diluted with DCM (3 mL), filtered through a short plug of magnesium sulfate and the filter cake was washed with DCM (4 x 3 mL). The filtrate was concentrated and the residue (67.9 mg) was filtered through a short plug of silica gel RP using 5% MeOH: DCM to yield 38.9 mg of the desired product. Part E 1 10 4 To a suspension of 1 (10 mg, 0.023 mmol, 1 eq) in acetonitrile (2 mL) was added a solution of aldehyde 10 (17 mg, 0.056 mmol, 2.4 eq) in acetonitrile (0.3 mL) followed by sodium triacetoxy borohydride (6.5 mg, 0.031 mmol, 1.3 eq) and the reaction mixture was stirred at 25 ° C for 16 hours. The solvent was then evaporated under reduced pressure and the residue was taken to gel chromatography of silica (7 cm x 10 mm) using 3% methanol: DCM to yield 24.6 mg of the unpurified material. This material was re-subjected to column chromatography on silica gel using 2% MeOH: DCM and 18.2 mg of an impure product was recovered which was further purified by TLC preparation using 3% MeOH: DCM as the solvent of development (2 cycles) to produce 6.3 mg of the desired product. MS (ESI (+)) m / e 714.4 (M + H) +. Example 3 Preparation of a Cyclopamine Derivative: 11 Part A 2 12 Cyclopamine 2 (20 mg, 0.049 mmol, 1 eq) was suspended in dry toluene (0.6 mL) and cyclohexanone (150 μL, 1.47 mmol, 30 eq) was added followed by aluminum isopropoxide (79 mg, 0.392 mmol, 8 eq). The resulting mixture was heated refluxed for 2 hours, cooled to room temperature, diluted with AcOEt and quenched with Rochelle's saline. The biphasic mixture was stirred overnight, the layers were separated, the aqueous was extracted with AcOEt and the combined organic extracts were dried (MgSO4) filtered, and concentrated in vacuo. The residue was purified by flash chromatography (DCM, DCM / MeOH 98: 2 and 95: 5). The objective was obtained as a white crystalline solid (70% yield). Part B Diiodomethane (40 μl, 0.5 mmol, 25 eq) was treated in DCM (0.52 mL) at 0 ° C with 15% diethyl zinc in toluene (0.2 mL, 0.2 mmol, 10 eq) and the resulting solution was stirred for 5 minutes. Compound 12 (10 mg, 0.02 mmol, 1 eq) in DCM (0.35 mL) was added and the resulting mixture was stirred at room temperature (ice bath removed) for 3 hours, quenched with 2 N NaOH and stirred for 10 minutes, the layers were separated and the aqueous was extracted with DCM (2 x). The organic extracts were dried (MgSO 4), filtered and concentrated in vacuo. The residue was purified by flash chromatography (DCM / MeOH 92: 8). The cyclopropanated material was obtained as a white solid. MS (ESI (+)) m / e 424.5 (M + H) +. Example 4 Preparation of a Cyclopamine Derivative 13 Part A To a solution of cyclopamine 2 (250 mg, 0.6 mmol, 1 eq) in DCM (10 mL) at room temperature was added Fmoc-OSu (205 mg, 0.6 mmol, 1 eq), the resulting mixture was stirred at room temperature for overnight and concentrated in vacuo. The unpurified Fmoc-cyclopamine was obtained as a whitish foam.

Part B 3 14 An unpurified Fmoc-cyclopamine 3 solution (15 mg, 0.024 mmol, 1 eq) in DCM (0.5 mL) was cooled to -78 ° C and treated with sodium hydrogen carbonate (4 mg, 0.047 mmol, 1.96 eq) followed by mCPBA (4 mg, 0.024 mmol, 1 eq). The reaction mixture was stirred at -78 ° C for 1 hour, diluted with H20 and extracted with DCM (3 x). The organic extracts were washed with 10% NaHCO3, and brine, dried (MgSO4), filtered and concentrated in vacuo. Unpurified material was purified by preparative TLC (Hex / AcoEt 1: 2) to produce the epoxide as a white foam (70% yield). Part C A solution of compound 14 (11 mg, 0.017 mmol, 1 eq) in DCM (0.5 mL) was treated at room temperature with Et2NH (0.5 mL, 4.8 mmol, 282 eq), the resulting solution was stirred at room temperature overnight and concentrated in vacuo. The residue was purified by preparative TLC (DCM / MeOH 9: 1). Compound 13 was obtained as a white solid (90% yield). MS (ESI (+)) m / e 428.5 (M + H) +. Example 5 Preparation of a Cyclopamine Derivative: Part A 16 Compound 2 (1.30 g, 3.2 mmol, 1 eq) was kneaded and loaded into the reaction vessel. Potassium carbonate (0.91 g, 6.6 mmol, 2.1 eq) was kneaded and loaded into the reaction vessel followed by dichloroethane (6.0 mL, 76 mmol, 23.8 eq) and anhydrous DMSO (5 mL). The reaction was heated at 70 ° C for 36 hours under a nitrogen atmosphere. The reaction was cooled to room temperature, diluted with DCM (15 mL) and washed twice with water (2 x 15 mL). The organic layer was dried over sodium sulfate, filtered (DCM rinsing when necessary) and concentrated to dryness to yield a pale yellow solid. Flash chromatography (DCM / EtOAc) produced the target material as a white crystalline solid. Part B Compound 16 (0.111 g, 0.233 mmol, 1 eq) was transferred to the reaction flask, placed under a nitrogen atmosphere, and dissolved in anhydrous DCM (2 mL). Chloroodiomethane (0.238 mL, 3.27 mmol, 14 eq) was added. The solution was cooled to -15 ° C. Diethylzinc (1M in heptane, 1.63 mL, 1.63 mmol, 6.5 equivalents) was added in drops for 30 minutes carefully controlling the exotermin. The reaction was maintained between -10 ° C and -14 ° C for several hours, until the TLC indicated that the starting material had been consumed. The reaction was then quenched by the careful addition of THF (6 mL) and then aqueous citrate buffer (pH 4. 5, 10 mL). The layers were allowed to warm to room temperature. Saturated sodium sulfate (10 mL). The layers were mixed well, transferred to a separatory funnel with excess DCM and the organic layer was collected. The organic layer was washed with aqueous sodium hydroxide (1N, 10 mL), and saturated sodium sulfate (10 L), dried over sodium sulfate before concentration to dryness. The unpurified material was purified by flash chromatography to produce the desired product in 55% yield. Example 6 Preparation of a Cyclopamine Derivative: 17 To a solution of compound 11 (5 mg, 0.01 mmol, 1 eq) and compound 10 (10 mg, 0.04 mmol, 3 eq) in anhyd DCM (5 mL) was added solid sodium triacetoxy borohydride (8 mg, 0.04 mmol). , 3 eq) and the resulting suspension it was stirred at 25 ° C for 2 hours. The reaction mixture was quenched with sodium bicarbonate, extracted with DCM (4 x 10 mL), the organic layer was collected and washed with saturated brine (1 x 20 mL), dried over magnesium sulfate and concentrated under pressure. reduced. The crude product was purified by PTLC (DCM / MeOH 95: 5) to yield 8 mg of the desired product. Example 7 Preparation of a Cyclopamine Derivative: Part A Cyclopamine 2 (20 mg, 0.049 mmol) was suspended in dry toluene (0.6 mL) and cyclohexanone (150 μL, 1.47 mmol, 30 eq) was added followed by aluminum isopropoxide (79 mg, 0.392 mmol, 8 eq). The resulting mixture was heated to reflux for 2 hours, cooled to room temperature, diluted with ethyl acetate and quenched with solution Saline of Rochelle. The biphasic mixture was stirred overnight, the layers were separated, the aqueous was extracted with ethyl acetate and the combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash chromatography (DCM, DCM / methanol 98: 2 and 95: 5). Target 12 was obtained as a white crystalline solid (70% yield). Part B Diiodomethane (40 μl, 0.5 mmol, 2.5 eq) was treated at 0 ° C in DCM (0.52 mL) with 15% diethyl zinc in toluene (0.2 mL, 0.2 mmol, 1 eq) and the resulting solution was stirred for 5 minutes ( where a white precipitate was observed). Enone 12 (10 mg, 0.02 mmol, 1 eq) in DCM (0.35 mL) was added and the resulting mixture was stirred at room temperature (ice bath removed) for 3 hours, quenched with NaOH (2 N) and The mixture was stirred for 10 minutes, the layers were separated and the aqueous one was extracted with DCM (twice). The organic extracts were dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (DCM / methanol 92: 8). The material Cyclopropanated was obtained as a white solid. Part C To a solution of cyclopropylenone 11 (10 mg, 24 μmol, 1 eq) in DCM (0.5 mL) at 0 ° C under argon was added BF3.Et20 (30 μL, 0.24 mmol, 10 eq) and the resulting solution was stirred at 0 ° C for 1.5 hours, diluted with DCM and quenched with saturated sodium bicarbonate. The organic phase was washed with saturated sodium bicarbonate and the combined aqueous layers were extracted with DMC. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by preparative TLC (DCM / methanol: 9: 1). Objective 18 was obtained as a white solid (90% yield). MS (ESI (+)) m / e 424.62 (M + H) \ Example 8 Preparation of a Cyclopamine Derivative: 19 Part A To a solution of cyclopamine 2 (250 mg, 0.6 mmol, 1 eq) in DCM (10 mL) at room temperature was added Fmoc-OSu (205 mg, 0.6 mmol, 1 eq) and the resulting mixture was stirred at room temperature for the night. The resulting solution of the unpurified Fmoc-cyclopamine was then cooled to 0 ° C and treated with 15% diethyl zinc in toluene (0.5 ml, 0.6 mmol, 1 eq) and stirred for 30 minutes) Flask A, yellowish solution) . Diiodomethane (0.4 ml, 6 mmol, 10 eq) was treated in DCM (20 mL) at 0 ° C with 15% diethyl zinc in toluene (3 mL, 3 mmol, 5 eq) and the resulting solution was stirred for 5 minutes (flask B, white precipitate). The contents of flask B were transferred to flask A by cannula and the resulting suspension was stirred for 5 hours at room temperature. The reaction was quenched with 1N hydrochloric acid, stirred for 10 minutes (until all the white solid was re-dissolved) and extracted with DCM (5x). The organic extracts were dried over MgSO4, filtered over Celite and concentrated in empty. The residue was purified by flash chromatography (hexanes / ethyl acetate 1: 1). Objective 11,12-monocyclopropane 5 was obtained as a 9: 1 mixture of diastereoisomers, together with 20% bis-cyclopropanated diatereomeric products (80% total recovery). This mixture was separated using preparative SFC chromatography. Part B Fmoc-cyclopropylcyclopamine 3 (14 mg, 22 μmol, 1 eq) was dissolved in DCM (0.5 mL), cooled to 0 ° C and treated with BF3.Et20 (27 μL, 0.22 mmol, 10 equivalents) for 1 hour, it was quenched with saturated sodium bicarbonate, the layers were separated and the aqueous was extracted with DCM. The combined extracts were dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by preparative thin layer chromatography (hexane / ethyl acetate 2: 1). The expanded Fmoc-cyclopamine, objective, was obtained as a clear oil. A solution of the unpurified expanded Fmoc-cyclopamine (20 mg, 31 μmol, 1 eq) in DCM (0.5 mL) was treated with Et2NH (0.5 mL, 4.8 mmol, 154 eq) overnight, concentrated in vacuo and the residue was purified by flash chromatography (DCM, DCM / methanol 98: 2 and 95: 5). The desired compound was obtained as an oil, which crystallized to rest. MS (ESI (+)) m / e 426.29 (M + H) +. Example 9 Preparation of a Cyclopamine Derivative: twenty Part A Compound 6 (23 mg, 54 μmol, 1 eq) was dissolved in DCM (1 mL) and methyl iodide (0.17 mL, 0.54 mmol, 10 eq) was added. The reaction was allowed to stir at room temperature under a nitrogen atmosphere overnight. The next morning TLC / LC-MS indicated that there was still some SM. A spatula of Na2C03 was added and the mixture was stirred for another hour. Unpurified material was loaded onto Biotage Si + M and eluted with DCM / EtOAc / MeOH (82.5 / 10 / 7.5). The amorphous material obtained: 16 mg. MS (ESI (+)) m / e 440.32 (M + H) +. Example 10 Preparation of a Cyclopamine Derivative: twenty-one Part A THF (20 mL) hydroxynamoyl chloride 22 (1.13 g, 6.7 mmol, 1 eq) and allylamine (0.77 mL, 10 mmol, 15 eq) were solubilized and the reaction was stirred at room temperature for 24 hours. A white precipitate formed. The reaction mixture was filtered. The filtrate was dried over MgSO4, filtered and concentrated under vacuum. The colorless oil that was converted to a waxy solid (1.1 g) was isolated. To a solution of allylamide (0.81 mg, 0.27 mmol, 1 eq) in a mixture of acetone: water (9 ml, 3: 1) at 0 ° C was added a solution of Os04 80.55 ml, 2.5 p / p in t -BuOH) and The resulting brownish mixture was stirred for 10 minutes. The solid sodium periodate (0.13 g, 0.59 mmol, 2.2 eq) was added in three portions and the mixture was stirred at 0 ° C and allowed to warm to 25 ° C over a period of 2 hours. The clear whitish cream mixture was diluted with DCM (25 mL), dried with magnesium sulfate, the solids were filtered through a pad of celite, the filtrate was concentrated under reduced pressure. The unpurified material slowly develops a yellow black color. Unpurified material was loaded onto Biotage 25 + S and purified by eluting with hexane / EtOAc (1: 1 to 1: 2) to obtain a colorless oil, which solidified once dry (250 mg). Part B To a solution of 18 (108 mg, 0.25 mmol, 1 eq) and aldehyde 21 (100 mg, 0.52 mmol, 2.1 eq) in DCM (5 mL) was added sodium triacetoxyborohydride (100 mg, 0.47 mmol, 1.9 eq) in one portion and the slurry was stirred at room temperature for 7 hours. The reaction was quenched by adding MeOH and filtered through celite. Evaporation to dryness yielded 230 mg of the oil. The material was purified by chromatography (Si02, column 3 x 4 cm) eluting with hexane / EtOAc (4: 6 to 2: 8) to yield 38 mg of the desired product. MS (ESI (+)) m / e 599.74 (M + H) +. Example 11 Preparation of a Cyclopamine Derivative: Part A 2-Phenylethanesulfonyl chloride 25 81.13 g was solubilized, 5.5 mmoles, 1 eq) and allylamine (0.56 ml, 7.3 mmoles, 1.3 eq) in THF (20 ml) and allowed to react overnight at room temperature for 24 hours. A white precipitate formed. The reaction mixture was filtered. The filtrate was dried over MgSO4, filtered and concentrated under vacuum. The slightly yellow oil was isolated (1.1 g). The unpurified material was used directly in the next step. To a solution of allyl sulfonamide (0.15 g, 0.66 mmoles, 1. eq) in acetone: water (4 ml, 3: 1) at 0 ° C was added a solution of Os04 (0.13 ml, 2.5 p / p in t- BuOH) and the mixture The resulting brownish was stirred for 10 minutes. The solid sodium periodate (0.31 g, 1.46 mmol, 2.2 eq) was added in three portions and the mixture was stirred at 0 ° C and allowed to warm to 25 ° C over a period of 2 hours. The creamy, light whitish mixture was diluted with DDM (25 mL), dried with magnesium sulfate, the solids filtered through a pad of celite, the filtrate was concentrated under reduced pressure. Unpurified material was purified on Sio2 (2 cm x 12 cm column) eluting with hexane / EtOAc (7: 3) to give the desired material (16 mg). Part B To a solution of 18 (15 mg, 35.4 μmol, 1 eq) and aldehyde 26 (167 mg, 70 μmol, 2 eq) in DCM (3 mL) was added sodium triacetoxyborohydride (20 mg, 94 μmol, 2.6 eq) in one portion at room temperature. After 24 hours, the reaction was quenched by adding a few drops of MeOH and filtering on celite. Unpurified material was purified by 1 mm preparative TLC (First elution: Toluene / Acetone (9: 1), second elution, Toluene / Acetone (4: 1)) to yield 4 mg of a colorless oil. MS (ES (+)) m / e 635.43 (M + H) +.

Example 12 Preparation of a Cyclopamine Derivative: Part A 16 Compound 2 (1.30 g, 3.2 mmol, 1 eq) was kneaded and loaded into the reaction vessel. The potassium carbonate (0.91 g, 6.6 mmol, 2.1 eq) was kneaded and charged into the reaction vessel followed by dichloroethane (6.0 mL, 76 mmol, 23.8 eq) and anhydrous DMSO (5 mL). The reaction was heated at 70 ° C for 36 hours under a nitrogen atmosphere. The reaction was cooled to room temperature, diluted with DCM (15 mL) and washed twice with water (2 x 15 mL). The organic layer was dried over sodium sulfate, filtered (DCM rinsing when necessary), and concentrated to dryness to yield a pale yellow solid. Instant chromatography (DCM / EtOAc) produced the target material as a white crystalline solid.

Part B Compound 16 (0.111 g, 0.233 mmol, 1 eq) was transferred to the reaction flask, placed under a nitrogen atmosphere, and dissolved in anhydrous DCM (2 mL). Chloroodiomethane (0.238 ml, 3.27 mmol, 14 eq) was added. The solution was cooled to -15 ° C. Diethylzinc (1M in heptane, 1.63 ml, 1.63 mmol, 6.5 equivalents) was added in drops for 30 minutes carefully controlling the exotherm. The reaction was maintained between -10 ° C and -14 ° C for several hours, until TLC indicated that the starting material had been consumed. The reaction was quenched by the careful addition of THF (6 mL) and then the aqueous citrate buffer (pH 4.5, 10 mL). The layers were allowed to warm to room temperature, saturated sodium sulfate (10 mL). The layers were mixed well, transferred to a separatory funnel with excess DCM and the organic layer was collected. The organic layer was washed with aqueous sodium hydroxide (1M, 10 mL), and saturated sodium sulfate (10 mL), dried over sodium sulfate before concentration to dryness. The unpurified material was purified by flash chromatography to produce the desired product in 55% yield. Part C Compound 15 81.25 g, 2.56 mmol, 1 eq) was dissolved in DCM (22 mL) under a nitrogen atmosphere and the solution was cooled to 0.9 ° C internal temperature. BF3_OEt2 (1.6 ml, 12.8 mmol, 5 eq) was added portionwise over several hours while monitoring the reaction by LCMS. The reaction was allowed to slowly warm to 10 ° C until it was complete. The reaction was quenched with MeOH (5 mL) at 0 ° C, diluted with KOH (2 M, 30 mL) and stirred at room temperature for 2 hours. The layers were separated and the organic layer was washed with water, dried over Na 2 SO, filtered and concentrated to dryness. Chromatography with DCM / EtOAc gave the desired product. Example 13 Preparation of a Cyclopamine Derivative Part A Compound 27 (29 mg, 60 μmol, 1 equivalent) was placed into a 5 ml round bottom flask. Butanone (2 mL) and Al (OIPC) 3 (12.3 mg, 60 μmol, 1 equivalent). The contents of the round bottom were heated to reflux under argon for 7 hours. The reaction mixture was then stirred at room temperature for 10 hours. The reaction mixture was then quenched with a solution (2 mL) formed by mixing citric acid (500 g), NaOH (15.7 g) and water (500 mL). The resulting mixture was stirred rapidly until the emulsion dissipated. The mixture was then extracted with EtOAc (3 x 10 mL). The organic layers were collected, dried over Na 2 SO, and concentrated. Unpurified material was purified by column chromatography. MS (ESI (+)) m / e 486.26 (M + H) +.

Example 14 Preparation of a Cyclopamine Derivative: 29 Part A Compound 28 (25 mg, 0.051 mmol, 1 eq) was dissolved in anhydrous 2-methoxyethanol (1 mL, 12.7 mmol, 234 eq). Potassium carbonate (7.1 mg, 0.051 mmol, 1 eq) was added and the reaction was heated to 120 ° C. The reaction was monitored by TLC. When the TLC indicated that the reaction had stopped, the reaction was cooled to room temperature. The reaction was then diluted with ethyl acetate and washed with water. The organic layer was dried over sodium sulfate and concentrated to dryness. Chromatography with DCM / EtOAc gave the desired product. MS (ESI (+)) m / e 526.66 (M + H) +.

Example 15 Preparation of a Cyclopamine Derivative: Part A To a solution of hydrocinnamic acid 5 (3.01 g, 20 mmol, 1 eq) in 30 ml of anhydrous chloroform at 75 ° C was added thionyl chloride (1.75 ml, 24.1 mmol, 1.2 eq) in drops over a period of 3 minutes . The mixture was refluxed for 3.5 hours. The solvent was distilled to give the unpurified acid chloride as a light yellow viscous liquid. The unpurified product was used without further purification. Part B To a biphasic mixture of 7 (3.16 g, 24.1 mmol, 1.2 eq) in DCM (30 mL) and an aqueous solution of NaOH (2.0 M, ml, 3 eq) at 25 ° C was added a solution of the acid chloride 6 (3.38 g, 20 mmol, 1 eq) in DCM (10 mL) and the resulting mixture was stirred at 25 ° C for 3 hours. The mixture was then neutralized with aqueous HCl (2M, 30 mL). The organic layer was then separated and the aqueous layer was extracted with DCM (3 x 50 mL). The combined organic layers were washed with HCl (2.0 M, 25 mL), water (3 x 50 1), saturated brine (50 mL), dried over magnesium sulfate and the solvent was evaporated under reduced pressure. The crude product was chromatographed on silica gel using 5% MeOH: DCM as eluent and the column was then eluted with 10% MeOH: DCM to produce 1141 g of compound 8. Part C To a mixture of acid 8 (264 mg, 1 mmol, 1 eq), ECI (231 mg, 1.2 mmol, 1.2 eq) and triethylamine (168 μl, 1.2 mmol, 1.2 eq) in DCM (2 mL) at 0 ° C allylamine (90.3 μL, 1.2 mmol, 1.2 eq) was added, and the resulting mixture was stirred at 0 ° C for 1 hour and allowed to warm to 25 ° C over a period of 2 hours. The reaction mixture was added to water (50 mL), extracted with DCM (4 x 25 mL), the combined organic layers were washed with 1 M HCl (2 x 25 mL), water (3 x 25 mL), saturated brine (25 mL), dried over magnesium sulfate and the solvent was evaporated under reduced pressure to yield 287.5 mg of the desired product. This material was used without further purification. Part D To a solution of allylamide 9 (70 mg, 0.23 mmol, 1 eq) in 1 acetone (mL) and water (0.3 mL) was added a solution of osmium tetroxide (0.35 ml, 0.035 mmol, 2.5 p / p in t -butanol) and the reaction mixture was immediately cooled in an ice bath after the Os04 solution was added. The resulting dark brown solution was stirred at 0 ° C for 15 minutes. Sodium periodate (110 mg, 0.51 mmol, 2.2 eq) was added in 5 portions to the above mixture and stirring was continued for 1 hour at 0 ° C and allowed to warm to 25 ° C over a period of 2 hours. The reaction mixture was diluted with DCM (3 mL) filtered through a short plug of magnesium sulfate and the filter cake was washed with DCM (several times). The filtrate was concentrated and the residue (67.9 mg) was filtered through a short plug of silica gel RP using 5% MeOH: DCM as eluent to yield 38.9 mg of the desired product.

Part E To a solution of 19 (0.0242 g, 0.0569 mmol, 1 eq) and aldehyde 10 (0.0346 g, 0.114 mmol) in 3.0 ml of DCM at 23 ° C was added sodium triacetoxy borohydride (24.1 mg, 0.114 mmol, 2 eq). ) in one portion and the resulting mixture was stirred for 16 hours. After completing the conversion of the starting material into the desired product as is evident from LCMS and TLC, the mixture was taken up in 2.5 ml of methanol and purified by preparative reverse phase HPLC (Acetonitrile-20 mM sodium carbonate buffer, basic method). The fractions were concentrated, and incorporated in a minimum volume of acetonitrile, the solution was frozen and lyophilized to give 0.007 g (0.0098 mmol, 17%) as a white solid. MS (ESI (+)) m / e 714.6 (M + H) +. Example 16 Preparation of a Cyclopamine Derivative: Part A To a solution of 18 (35 mg, 0.08 mmol, 1 eq) and aldehyde 32 (34 mg, 0.17 mmol, 2.0 eq) in THF (2.0 mL) was added sodium triacetoxyborohydride (35 mg, 0.17 mmol, 2.0 equivalents) in a portion. The solution was allowed to stir at 23 ° C for 12 hours. The mixture was then concentrated and purified by silica gel chromatography using a 1: 1 gradient of hexanes: ethyl acetate followed by 1: 2, 1: 4 and simple ethyl acetate. He was eluting some material so that the column was then rinsed with 9: 1 methyl acetate: methanol. The desired product was co-eluted with some aldehyde so that the material was then purified by preparative HPLC, (basic method 50_100) The desired fractions were frozen and lyophilized to yield an oily residue (12 mg, 0.02 mmol, 24% performance). MS (ESI (+)) m / e 614.44 (M + H) + Example 17 Preparation of a Cyclopamine Derivative: 33 Part A 18 34 33 To a solution of 18 (8.0 mg, 0.02 mmol, 1 eq) and aldehyde 34 (6.0 mg, 0.04 mmol, 2.0 eq) in CH2C12 (1.0 mL) was added sodium triacetoxyborohydride (8.0 mg, 0.17 mmol, 2.0 eq) in a portion. The solution was allowed to stir at 23 ° C for 12 hours. The mixture was then concentrated and purified by silica gel chromatography using a 1: 1 gradient of hexanes: ethyl acetate followed by 1: 2 and 1: 4 to isolate the desired product eluting with some aldehyde. The material was then purified by preparative HPLC. The desired fractions were frozen and lyophilized to yield a white powder (4.9 mg, 0.009 mmol, 45% yield). MS (ESI (+)) m / e 570.41 (M + H) +.

Example 18 Preparation of a Cyclopamine Derivative: Part A To a solution of 18 (6.0 mg, 0.01 mmol, 1 eq) and benzaldehyde 36 (3.0 mg, 0.02 mmol, 2.0 eq) in CH2C12 (0.5 mL) was added sodium traicexyborohydride (6.0 mg, 0.02 mmol, 2.0 eq) in a portion. The solution was allowed to stir at 23 ° C for 12 hours. The mixture was then concentrated and purified by silica gel chromatography using a 4: 1 gradient of hexanes: ethyl acetate followed by 1: 1 to isolate the desired product co-eluting with some aldehyde. The material was purified by preparative HPLC. The desired fractions were frozen and lyophilized to yield white powder (0.6 mg, 0.001 mmol, 8% yield).

Example 19 Preparation of a Cyclopamine Derivative: 37 Part A 18 38 37 To a solution of 18 (6.0 mg, 0.01 mmol, 1 eq) and 4-phenoxybenzaldehyde 38 (6.0 mg, 0.02 mmol, 2.0 eq) in CH2C12 (0.5 mL) was added sodium triacetoxyborohydride (6.0 mg, 0.02 mmol, 2.0 eq). ) in one portion. The solution was allowed to stir at 23 ° C for 12 hours. The mixture was then concentrated and purified by silica gel chromatography using a gradient of 4: 1 hexanes: ethyl acetate followed by 1: 1 to isolate the desired product co-eluting with some aldehyde. The material was purified by preparative HPLC. The desired fractions were frozen and lyophilized to produce the white powder (1.8 mg 0.003 mmol, 21% yield). MS (ESI (+)) m / e 606.4 (M + H) +.

Example 20 Preparation of a Cyclopamine Derivative: 39 Part A 18 40 39 To a mixture of 18 (40 mg, 0.09 mmol, 1 eq) and sodium bicarbonate (15 mg, 0.18 mmol, 2.0 eq) in CH2C12 (0.5 mL) bromoethanol 40 (33 μL, 0.47 mmol, 5.0 eq) was added. The solution was heated to reflux for 4 hours. The mixture was then concentrated and purified by silica gel chromatography using a gradient of DCM for 38: 1: 1 dichloromethane: ethyl acetate, then 36: 3: 1, then 17: 2: 1 to isolate the desired product as one oil (12 mg, 0.026 mmol, 27% yield). MS (ESI (+)) m / e 468.24 (M + H) +.

Example 21 Preparation of a Cyclopamine Derivative 41 Part A 18 42 41 To a solution of 18 (100 mg, 0.24 mmol, 1 eq) and aldehyde 42 (42 mg, 0.35 mmole, 1.5 eq) in CH2C12 (2.5 mL) was added sodium triacetoxyborohydride (100 mg, 0.47 mmol, 2.0 eq) in one portion. The solution was allowed to stir at 23 ° C for 12 hours and showed only 50% conversion by LCMS. To the mixture was added an additional equivalent of aldehyde 36 (26 mg, 0.24 mmol, 1.0 eq) and sodium triacetoxyborohydride (48 mg, 0.24 mmol, 1.0 eq) and allowed to stir for 2 hours. The mixture was then concentrated and purified by silica gel chromatography using a 1: 1 gradient of hexanes: ethyl acetate followed by 1: 2 and 1: 4 to isolate the desired product co-eluting with some aldehyde. He The material was then purified by preparative HPLC. The desired fractions were frozen and lyophilized to yield the white powder (53 mg, 0.10 mmol, 43% yield), MS (ESI (+)), m / e 526.66 (M + H) +. Example 22 Preparation of a Cyclopamine Derivative: 43 Part A 18 4 43 To a solution of 18 (15 mg, 0.04 mmol, 1 eq) and aldehyde 44 (6.0 mg, 0.04 mmol, 1.0 eq) in CH2C12 (0.6 mL) was added sodium triacetoxyborohydride (15 mg, 0.07 mmol, 2.0 eq) in one portion. The solution was allowed to stir at 23 ° C for 12 hours and showed only 50% conversion by LCMS. To the mixture was added an additional equivalent of aldehyde 44 (6.0 mg, 0.04 mmol, 1.0 eq) and sodium triacetoxyborohydride (7.5 mg, 0.04 mmol, 1.0 eq) and allowed to stir for 12 hours. The mixture was concentrated then and purified by silica gel chromatography using a gradient of 1: 1 hexanes: ethyl acetate followed by 1: 2, and 1: 4 to isolate the desired product as an oil (12 mg, 0.19 mmol, 54% performance). Ms (ESI (+)) m / e 635.43 (M + H) +. Example 23 Preparation of a Cyclopamine Derivative Four. Five Part AA a mixture of 18 (12 mg, 0.03 mmol, 1 eq) and potassium carbonate (40 mg, 0.28 mmol, 10 eq) in DMF (0.5 mL) was added 2- (dimethylamino) ethylchloride 46 hydrochloride (20 mg , 0.14 mmole, 50 eq). The solution was stirred for 2 hours at 23 ° C and no reaction took place. The solution was then heated to 65 ° C for 12 hours, quenched with water (2 mL) and then extracted with diethyl ether (2 x 10 mL). The combined organic solutions were washed with brine and dried with MgSO4. The mixture was concentrated and then purified by preparative HPLC. The desired fractions were frozen and lyophilized to yield white powder (17, 1.8 mg, 0.004 mmol, 13% yield). MS (ESI (+)) m / e 495.71 (M + H) +. Example 24 Preparation of a Cyclopamine Derivative: 47 Part A To a solution of 18 (100 mg, 0.24 mmol, 1 eq) and chloroacetamide 48 (250 mg, 1.2 mmol, 5.0 eq) in CH2C12 (1.0 mL) was added triethylamine (160 μL, 1.2 mmol, 5.0 eq). The solution was heated to reflux and stirred for 72 hours. The mixture was then concentrated and purified by silica gel chromatography using a 4: 2 gradient of hexanes: ethyl acetate followed by 2: 1, 1: 1 and 1: 2 to isolate the desired product as a two part mixture. . The same column conditions were repeated and the desired product was isolated as an oil (17 mg, 0.14 mmol, 12% yield). Example 25 Preparation of a Cyclopamine Derivative: 18 49 Compound 18 (103 mg, 0.25 mmol, 1 equivalent) was dissolved in DMC (3.0 mL) and cooled to -78 ° C. To this solution was added znCPBA (77% by weight, 54 mg, 0.24 mmol, 1.0 equivalent) and then the solution was allowed to warm to 22 ° C for 12 hours. The reaction has become 50% conversion (LCMS). The solution was quenched with sodium bicarbonate and extracted with DCM. The combined organics were dried with magnesium sulfate, filtered and concentrated. The material was then purified with silica gel chromatography using a gradient of DCM: EtOAc: MeOH of 95: 2.5: 2.5, then 92.5: 5.0: 2.5, then 85: 10: 5 to isolate the desired product, co-eluting with a small amount of something else. The combined fractions were concentrated and purified by preparative HPLC to yield 3.4 mg of the desired product. MS (ESI (+)) m / e 440.63 (M + H) +. Example 26 Inhibition of the hedgehog pathway in cell culture using cyclopamine analogs The killing effects of specific hedgehog pathway cancer cells can be determined using the following assay. C3H10T1 / 2 cells differentiate into osteoblasts when contacted with the sonic hedgehog peptide (Shh-N). In the differentiation; these osteoblates produce high levels of alkaline phosphatase (AP) which can be measured in an enzymatic assay (Nakamura et al., 1997 BBRC 237: 465). Compounds that block differentiation of C3H10T1 / 2 within osteoblasts (an event dependent on Shh) can therefore be identified by a reduction in AP production (van der Horst et al., 2003 Bone 33: 899).

The test details are described later. The results approximate (EC50 for inhibition) of the differentiation assay are shown below in Table 1. Cell Culture Assay Protocol Mouse embryonic mesodermal fibroblast cells C3H10T1 / 2 (obtained from ATCC) were grown in Basal Media MEM (Gibco / Invitrogen) supplemented with 10% heat-inactivated FBS (Hyclone), 50 units / ml penicillin and 50 μg / ml streptomycin (Gibo / Invitrogen) at 37C with 5% C02 in air atmosphere Alkaline Phosphatase Assay C3H10T1 / 2 cells were plated in 96 wells with a density of 8x103 cells / well. Cells were grown to confluence (72 hours). After the treatment of sonic hedgehog compound (250 ng / mL), (R &D Systems), the cells were used in 110 μl of lysis buffer (50 mM Tris pH 7.4, 0.1% TritonXlOO), the plates produced sound and the lysates were rolled through 0.2 μm plates of PVDF (Corning). 40 μl of lysates were evaluated for AP activity in alkaline buffer solution (Sigma) containing 1 mg / ml of p-Nitrophenyl Phosphate. After incubation for 30 minutes at 37C, the plates were read on an Envision plate reader at 405 nm. The total protein was quantified with BCA protein assay kit from Pierce according to the manufacturer's instructions. AP activity was normalized against total protein. Note that "A" indicates that the IC50 is less than 200 nM, "B" indicates that the IC50 is 200-500 nM, "C" indicates that the IC50 is > 500 nM.

Table 1 - EC5o Approximate for Compound Inhibition ECd0 of Differentiation Test IC 4 A II C 17 A 18 A 19 B 20 C 21 A 24 B 27 C 28 C 29 A 30 A 31 A 33 A 35 A 37 C 39 C 41 A 43 B 45 B 47 B EXAMPLE 27 Preparative Supercritical Fluid Chromatographic Purification Method (SFC) A preparative supercritical fluid chromatography method for the purification of compounds of the present invention is described. Hardware Used: SFC: PrepSFC Berger System Ultra-violet detector: K-2501 Knauer molding Column: Berger 5 micron silicon, 200 mm by 250 mm SFC conditions: Mobile phases: C02 - 95%; methanol - 5% Flow rate: 50.00 ml / minute Column temperature: 35C Isocratic for 40 minutes in 5% methanol in supercritical C02 Volume per injection: 1000 uL Sample concentrations are normally activated at 5.0 mg / ml Sample Preparation : The samples are dissolved in 20% of DCM / 80% methanol The products are eluted between 25 and 40 minutes Ultra-Violet Detector Parameters Wavelength = 210 nm; and Resolution = 1.0 nm Example 28 Liquid Chromatography Mass Spectrometry Method (LCMS) A liquid chromatography mass spectrometric method for the compounds of the present invention is described.

[A] Input Phase Method Report Waters Alliance Mobile Phase 2795 LC Solvents A% 0.0 B% 10.0 Acetonitrile C% 90.0 Water 20 mM NH4HC03 D% 0.0 Water 0. ÍA Flow ramp 1.00 Flow (ml / min) 1,500 Delay time (mins) 4.00 Minimum pressure (Bar) 0 Maximum pressure (Bar) 300 Degasser in operation Cycle volume 100.0 μl Waters Alliance Column 2795 LC Column Position Column 3 Balance Time (mins) 0.00 Column Temperature (° C) 35 Column Temperature Limit (° C) 5 Waters Alliance Rapid Equilibrium 2795 LC System Path out of place System Flow (ml / min) 0.00 System time (mins) 0.00 Rebalance time (mins) 0.00 Pre-column volume (μl) 0.00 Waters Alliance 2795 1/0 Switch 1 No change Switch 2 No change Switch 3 No change Switch 4 No change Analog output set Flow rate Gradient Schedule Waters Alliance 2795 LC The gradient schedule contains 5 inputs which are: Time to%; B%; C%; D%; Flow; Curve Waters Alliance External Event Schedule 2795 LC No entries in the Pump External Event Schedule. Waters Alliance Injection Parameters 2795 Sequential Injection Type Full Mode Partial Loop Pre-sample Air Limit 4.0 Post-Sample Air Limit 4.0 Pre-charge Time (mins) 0.00 Waters Alliance Autosampler Parameters 2795 Sample Temperature (° C) 20 Sample Temperature Limit (° C) 20 Immersion Depth (mn) 0 Immersion Speed Normal Search Well Bottom Fake Check Plate Height Waters Alliance Wash Parameters 2795 Injection Frequency Injection Rinse time (s) 3 Wash time (s) 10 Wash cycles 2 Secondary Wash Volume (μl) 600.0 Wash sequence PDA Water996 Start of Wavelength (nm) 220.00 End of Wavelength ( nm) 400.00 Resolution (nm) 1.2 Sampling rate (spectrum / s) 1000 Filter response 1 Exposure time (ms) Automatic Interpolate 656 Yes Acquisition stop time (mins) 4.00 Save to disk: Yes Channel 1 Analogue PDA Waters996 Output Mode Off Channel 2 Analogue PDA Waters996 Output Mode Off End of Report (B) Experiment Report Name Preset Experiment Creation Time Friday, June 4, 2004 10:25:33 Instrument Identifier Version Number 1.0 Duration (min) 4.0 Calibration file name C: /MassLynx/Infitiny_2002.PROVACQUDB/NAICS_040409.cal Delay Valve of Solvent Delay Allowed 0 Number of Functions 1 Function 1: Ms Scan, Time 0.00 at 3.50, Mass 200.00 a 1000. 00 ES + Scan Type MS Ion Mode ES + Centroid Data Format Parameter File C: /Masslynx/Infinity_2002.PRO/ACQU DB / default.ipr Start Mass 200.0 Final Mass 1000.0 Sweep Time (sec) 1.0 Inter-Survey Time (sec ) 0.2 Start Time (min) 0.00 End Time (min) 3.5 [C] ZQ Tone Parameters Source (ES +) Parameters Verification Reading Capillarity (kV) 3.20 3.27 Cone (V) 35.00 37.24 Extractor (V) 3.00 2.81 Lenses RF (V) 0.00 0.00 Source temperature (° C) 130 129 Desolvation temperature (° C) 350 350 Cone gas flow (L / Hr) 20 33 Desolvation gas flow (L / Hr) 450 466 Analyzer Parameters Verification Verification Resolution LM 115.0 Resolution HM 115.0 Energy 1 for Ion 0.5 Multiplier (V) 550 -547 Pressure Gauges Pirani Pressure (mbar) < le-4 mBars MUX Configuration Standard Probe Incorporation by Reference All North American patents and published US patent applications cited herein are hereby incorporated by reference. Equivalents Those skilled in the art will recognize, or be able to verify using no more than routine experimentation, many equivalents to the specific embodiments of the invention, described herein. Such equivalents are intended to be encompassed by the following claims.

Claims (52)

1. CLAIMS computes this from the Formula or a pharmaceutically acceptable salt thereof; characterized in that each R1 and R8 is independently H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl, halide, sulfhydryl, alkylthio, arylthio, aralkylthio, hydroxyl, alkoxy, aryloxy, acyloxy, amino, alkylamino, arylamino, acylamino, aralkylamino, nitro, acylthio, carboxamide, sulfonamide, sulfate, -0P (L) (OR20) 2, -X- C (L) -R21 or -XC (L) -X-R21; wherein R1 can also be a sugar; each X is independently 0 or NR where R is H, alkyl, alkenyl, alkenyl, aryl, cycloalkyl or aralkyl; L is 0 or S; R2 and R9 are independently H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, nitrile, aralkyl, alkoxy, aryloxy, acyloxy, carboxyl, halide, sulfhydryl, alkylthio, arylthio, aralkylthio, hydroxyl, amino, alkylamino, arylamino, acylamino, aralkylamino, heteroaryl or heteroaralkyl; each R5 and R11 is independently H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, alkoxy, aryloxy, acyloxy, halide, hydroxyl, amino, alkylamino, arylamino, acylamino, aralkylamino, alkylselene, aralkylselene, arylselene, alkylthio, aralkylthio, arylthio, heteroaryl or heteroaralkyl; each R3, R4, R6, R7, R13 and R14 is independently H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, alkoxy, aryloxy, acyloxy, halide, hydroxyl, amino, alkylamino, arylamino, acylamino, aralkylamino, heteroaryl or heteroaralkyl; or R1 and R2 and / or R8 and R9 taken together, together with the carbon to which they are bound form - (C = 0) -, - (C = S) -, - (C = N (OR20)) -, - (C = N (R20)) -, - (C = N (N (R20) (R20))), or form an optionally substituted 3-8 membered ring containing up to two heteroatoms selected from N, O and S; or R4 and R5 taken together and / or R5 and R6 taken together and / or R10 and R11 taken together form a double bond or form a group represented by Ib wherein Z is NR21, 0, or C (R23) (R23); R12 is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, hydroxyl, aralkyl, heteroaryl, heteroaralkyl, haloalkyl, alkoxy, -C (0) R21, -C02R21, -S02R21, -C (0) N (R21) (R21), - [C (R21) 2] q-R21, - [(W) -N (R21) C (0)] qR21, - [(W) -C (0)] qR21, - [(W ) -C (0) 0] qR21, - [(W) -0C (0)] qR21, - [(W) -S02] qR21, - [(W) -N (R21) S02] qR21, - [( W) -C (0) N (R21)] qR21, - [(W) -0] qR21, - [(W) -N (R21)] qR21, or - [(W) -S] qR21; wherein each W is independently a di-radical and q is 1, 2, 3, 4, 5 or 6; R15, R16 and R17 are independently H, alkoxy, aryloxy, acyloxy, halide, hydroxyl, amino, alkylamino, arylamino, acylamino, aralkylamino; or R15 and R16 taken together, together with the carbon to which they are bonded, form -C (0) - or -C (S) -; R18 and R19 are independently H, alkyl, aralkyl, halide, amido or ester; each R20 is independently H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl or heteroaralkyl; or any two cases of R20 in the same substituent may be taken together to form an optionally substituted 4-8 membered ring; each R21 is independently H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl or - [C (R20) 2] P-R25 wherein p is 0-6; or any two cases of R21 in the same substituent can be taken together to form an optionally substituted 4-8 membered ring which contains 0-3 heteroatoms selected from N, O, S and P; each R23 is independently H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl, halide, alkoxy, aryloxy, acyloxy, silyloxy, nitrile, C (0) R21, -C02R21, -SO-2R21, and -C (O) N (R21) 2; each R25 is independently H, hydroxyl, acylamino, -N (R20) COR20, -N (R20) C (O) OR20, -N (R20) S02 (R20), COR20N (R20) 2, -OC (O) R20N (R20) (R20), -S02N (R20) (R20), -N (R20) (R20), -COOR20, -C (0) N (OH) (R21), -OS (0) 2OR20, -S (0) 2OR20, OP (L) (OR20) (OR20), -NP (O) (OR20) (OR20), or -P (O) (OR20) (OR20).
2. 2. The compound according to claim 1, characterized in that R13, R14, R15, R16 and R17 are hydrogen.
3. 3. The compound according to claim 1, characterized in that R1 is hydroxyl, sugar, -OP (L) (OR20) 2, -X-C (L) -R21 or -X-C (L) -X-R21; or R1 and R2 taken together, together with the carbon to which they bind, form -C (O) -.
4. 4. The compound according to claim 1, characterized in that R4 and R5 taken together they form a double bond.
5. 5. The compound according to claim 4, characterized in that R1 and R2 taken together, together with the carbon to which they are bonded, form -C (0) -.
6. 6. The compound according to claim 1, characterized in that R1 is hydroxyl and R2 is H.
7. The compound according to claim 6, characterized in that R5 and R6 taken together form a double bond; or R5 and R6 taken together form a group represented by Ib; where: Z is C (R23) (R23).
8. 8. The compound according to claim 1, characterized in that R10 and R11 taken together form a double bond; or R10 and R11 taken together form a group represented by Ib; where: Z is C (R23) (R23).
9. 9. The compound according to claim 1, characterized in that R5 and R6 taken together form a double bond and R10 and R11 taken together form a double bond.
10. 10. The compound according to claim 5, characterized in that R10 and R11 taken together form a double bond; or R10 and R11 taken together form a group represented by Ib; where: Z is C (R23) (R23).
11. 11. The compound according to claim 6, characterized in that R10 and R11 taken together form a double bond; or R10 and R11 taken together form a group represented by Ib; where: Z is C (R23) (R23).
12. 12. The compound according to claim 1, characterized in that R8 and R9 are hydrogen; or R8 and R9 taken together, together with the carbon to which link, is -C (0) -.
13. The compound according to claim 1, characterized in that R12 is H, alkyl, cycloalkyl, aralkyl, heteroaryl, heteroaralkyl, haloalkyl, hydroxyl, alkoxy, - [(W) -N (R21) C (0)] qR21, - [(W) -N (R1) S02] qR21, - [(W) -C (0) N (R21)] qR21, - [(W) -0] qR21, - [(W) -C (0 )] qR21 or - [(W) -C (0) 0] qR21.
14. The compound according to claim 2, characterized in that R12 is H, alkyl, cycloalkyl, aralkyl, heteroaryl, heteroaralkyl, haloalkyl, hydroxyl, alkoxy, - [(W) -N (R21) C (0)] qR21, - [(W) -N (R21) S02] qR21, - [(W) -C (0) N (R21)] qR21, - [(W) -0] qR21, - [(W) -C (0 )] qR21 or - [(W) -C (0) 0] qR21.
15. 15. The compound according to claim 5, characterized in that R12 is H, alkyl, cycloalkyl, aralkyl, heteroaryl, heteroaralkyl, haloalkyl, hydroxyl, alkoxy, - [(W) -N (R21) C (0)] qR21, - [(W) -N (R21) S02] qR21, - [(W) -C (0) N (R21)] qR21, - [(W) -0] qR21, - [(W) -C (0 )] qR21 or - [(W) -C (0) 0] qR21.
16. 16. The compound according to claim 6, characterized in that R12 is H, alkyl, cycloalkyl, aralkyl, heteroaryl, heteroaralkyl, haloalkyl, hydroxyl, alkoxy, - [(W) -N (R21) C (0)] qR21, - [(W) -N (R21) S02] qR21, - [(W) -C (0) N (R21)] qR21, - [(W) -0] qR21, - [(W) -C (0 )] qR -.2¿11 or - [(W) -C (0) 0] qR 21
17. 17. A compound of the formula: characterized in that: R12 is H, alkyl, aryl, cycloalkyl, heterocycloalkyl, hydroxyl, aralkyl, heteroaryl, heteroaralkyl, haloalkyl, alkoxy, -C (0) R21, -C02R21, -S02R21, -C (0) N (R21) (R21), - [C (R21) 2] P-R21, - [(W) -N (R21) C (O)] qR21, - [(W) -C (0) qR21, - [(W) -C (0) 0] qR21, - [(W) -OC (0)] qR21, - [(W) - S02] qR21, - [(W) -N (R21) S02] qR21, - [(W) -C (0) N (R21)] qR21, - [(W) -0] qR21, - [(W) -N (R21) ] qR21, or - [(W) -S], R21; q is 1, 2, 3, 4, 5 or 6; each R20 is independently H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, or heteroaralkyl; or any two cases of R20 in the same substituent may be taken together to form an optionally substituted ring of 4-8 members containing 0-3 heteroatoms selected from O, N, S and P; each R21 is independently H, alkyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl or - [C (R20) 2] P-R25, wherein p is 0-6; or any two cases of R21 in the same substituent may be taken together to form an optionally substituted 4-8 membered ring containing 0-3 heteroatoms selected from O, N, S and P; each R25 is independently H, hydroxyl, acylamino, -N (R20) COR20, -N (R20) C (O) OR20, -N (R20) S02 (R20), -COR20N (R20) 2, -OC (O) R20N (R20), -S02N (R20) (R20), -N (R20) (R20), -COOR20, -C (0) N (OH) (R21), -OS (0) 2OR20, -S (0) 2OR20, -OP (L) (OR20) (OR20), -NP (O) (OR20) (OR20) or -P (O) (OR20) (OR20).
18. 18. A compound selected from the group consisting of: 25 25
19. 19. The compound according to claim 1, characterized in that it has the formula:
20. 20. A compound of Formula 2: or a pharmaceutically acceptable salt thereof; characterized in that each R1 and R8 is independently H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl, halide, sulfhydryl, alkylthio, arylthio, aralkylthio, hydroxyl, alkoxy, aryloxy, acyloxy, amino, alkylamino, arylamino, acylamino, aralkylamino, nitro, acylthio, carboxamide, sulfonamide, sulfate, -OP (L) (OR20) 2, -XC (L) -R21 or -XC (L) -X-R21; wherein R1 can also be a sugar; each X is independently 0 or NR where R is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl or aralkyl; L is 0 or S; R2 and R9 are independently H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, nitrile, aralkyl, alkoxy, aryloxy, acyloxy, carboxyl, halide, sulfhydryl, alkylthio, arylthio, aralkylthio, hydroxyl, amino, alkylamino, arylamino, acylamino , aralkylamino, heteroaryl or heteroaralkyl; each R5 and R11 is independently H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, alkoxy, aryloxy, acyloxy, halide, hydroxyl, amino, alkylamino, arylamino, acylamino, aralkylamino, alkylselene, aralkylselene, arylselene, alkylthio, aralkylthio, arylthio, heteroaryl or heteroaralkyl; each R3, R4, R6, R7, R13 and R14 is independently H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, alkoxy, aryloxy, acyloxy, halide, hydroxyl, amino, alkylamino, arylamino, acylamino, aralkylamino, heteroaryl or heteroaralkyl; or R1 and R2 taken together and / or R8 and R9 taken together, together with the carbon to which they are bonded form - (C = 0) -, - (C = S) -, - (C = N (OR20)) - , - (C = N (R20)) -, - (C = N (N (R20) (R20))), or form an optionally substituted 3-8 membered ring containing up to two heteroatoms selected from N, 0 and S; or R4 and R5 taken together and / or R5 and R6 taken together and / or R10 and R11 taken together form a double bond or form a group represented by Ib wherein Z is NR21, O, or C (R23) (R23); R12 is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, hydroxyl, aralkyl, heteroaryl, heteroaralkyl, haloalkyl, alkoxy, -C (0) R21, -C02R21, -S02R21, -C (0) N (R21) (R21), - [C (R21) 2] q-R21, - [(W) -N (R21) C (0)] qR21, - [(W) -C (0)] qR21, - [(W ) -C (0) 0] qR21, - [(W) -0C (0)] qR21, - [(W) -S02] qR21, - [(W) -N (R21) S02] qR21, - [( W) -C (0) N (R1)] qR21, - [(W) -0] qR21, - [(W) -N (R21)] qR21, or - [(W) -S] qR21; wherein each W is independently a di-radical and q is 1, 2, 3, 4, 5 or 6; R15, R16 and R17 are independently H, alkoxy, aryloxy, acyloxy, halide, hydroxyl, amino, alkylamino, arylamino, acylamino, aralkylamino; or R15 and R16 taken together, together with the carbon to which they are bonded, form -C (0) - or -C (S) -; R18 and R19 are independently H, alkyl, aralkyl, halide, amido or ester; each R20 is independently H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl or heteroaralkyl; or any two cases of R20 in the same substituent may be taken together to form an optionally substituted 4-8 membered ring; each R21 is independently H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl or - [C (R20) 2] P-R25 wherein p is 0-6; or any two cases of R in the same substituent may be taken together to form an optionally substituted 4-8 membered ring which contains 0-3 heteroatoms selected from N, O, S and Picada R23 is independently H, alkyl, alkenyl, alkynyl , aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl, halide, alkoxy, aryloxy, acyloxy, silyloxy, nitrile, -C (0) R21, -C02R21, -S02R21, and -C (O) N (R21) 2; each R25 is independently hydroxyl, acylamino, -N (R20) COR20, -N (R20) C (O) OR20, -N (R20) S02 (R20), -COR0N (R20) 2, -OC (O) R20N (R20) (R20), -S02N (R20) (R20), -N (R20) (R20), -COOR20, -C (0) N (OH) (R21), -OS (0) 2OR20, -S (0) 2OR20, -OP (L) (OR20) (OR20), -NP (O) (OR20) (OR20) or -P (O) (OR20) (OR20). with the proviso that there is at least one group represented by the formula Ib in the compound of the formula

    2.
21. 21. The compound according to claim 20, characterized in that R13, R14, R15, R16 and R17 are hydrogen.
22. 22. The compound according to claim 20, characterized in that R1 is hydroxyl, sugar, -OP (L) (OR20) 2, -X-C (L) -R21, or -X-C (L) -X-R21; or R1 and R2 taken together, together with the carbon to which they are bonded, form -C (O)
23. 23. The compound according to claim 20, characterized in that R4 and R5 taken together form a double bond.
24. 24. The compound according to claim 23, characterized in that R1 and R2 taken together, together with the carbon to which they are bonded, form -C (O) -.
25. 25. The compound according to claim 20, characterized in that R1 is hydroxyl and R2 is H.
26. 26. The compound according to claim 25, characterized in that R5 and R6 taken together form a double bond; or R5 and R6 taken together form a group represented by Ib; wherein: Z is C (R23) (R23)
27. 27. The compound according to claim 20, characterized in that R10 and R11 taken together form a double bond; or R10 and R11 taken together form a group represented by Ib; \? < lb) where: Z is C (R23) (R23).
28. 28. The compound according to claim 20, characterized in that R5 and R6 taken together and R10 and R11 taken together form a group represented by Ib; where Z is C (R23) (R23).
29. 29. The compound according to claim 24, characterized in that R10 and R11 taken together form a double bond; or R10 and R11 taken together form a group represented by Ib; where: Z is C (R23) (R23).
30. 30. The compound according to claim 25, characterized in that R10 and R11 taken together form a double bond; or R10 and R11 taken together form a group represented by Ib; where: Z is C (R23) (R23).
31. 31. The compound according to claim 20, characterized in that R8 and R9 are hydrogen; or R8 and R9 taken together, together with the carbon to which they are bonded, is -C (O) -.
32. 32. The compound according to claim 20, characterized in that R12 is H, alkyl, cycloalkyl, aralkyl, heteroaryl, heteroaralkyl, haloalkyl, - [(W) -N (R21) C (O)] qR21, - [(W) -N (R21) S02] qR21, - [(W) -C (0 ) N (R21)] qR21, - [(W) -0] qR21, - [(W) -C (0)] qR21 or - [(W) -C (0) O] qR21.
33. 33. The compound according to claim 21, characterized in that R12 is H, alkyl, cycloalkyl, aralkyl, heteroaryl, heteroaralkyl, haloalkyl, hydroxyl, alkoxy, - [(W) -N (R21) C (O)] qR21, - [(W) -N (R21) S02] qR21, - [(W) -C (0) N (R1)] qR21, - [(W) -0] qR21, - [(W) -C (0 )] qR21 or - [(W) -C (0) 0] qR21.
34. 34. The compound according to claim 24, characterized in that R12 is H, alkyl, cycloalkyl, aralkyl, heteroaryl, heteroaralkyl, haloalkyl, hydroxyl, alkoxy, - [(W) -N (R21) C (0)] qR21, - [(W) -N (R21) S02] qR21, - [(W) -C (0) N (R21)] qR21, - [(W) -0] qR21, - [(W) -C (0 )] qR21 or - [(W) -C (0) 0] qR21.
35. 35. The compound according to claim 25, characterized in that R12 is H, alkyl, cycloalkyl, aralkyl, heteroaryl, heteroaralkyl, haloalkyl, hydroxyl, alkoxy, - [(W) -N (R21) C (0)] qR21, - [(W) -N (R21) S02] qR21, - [(W) -C (0) N (R21)] qR21, - [(W) -0] qR21, - [(W) -C (0 )] qR21 or - [(W) -C (0) 0] qR21.
36. 36. A compound of the formula: characterized in that: R12 is H, alkyl, aryl, cycloalkyl, heterocycloalkyl, hydroxyl, aralkyl, heteroaryl, heteroaralkyl, haloalkyl, alkoxy, -C (0) R21, -C02R21, -S02R21, -C (0) N (R21) ( R21), - [C (R21) 2] P-R21, - [(W) -N (R21) C (O)] qR21, - [(W) -C (0) qR21, - [(W) - C (0) 0 } qR21, - [(W) -OC (0)] qR21, - [(W) -S02] qR21, - [(W) -N (R21) S02] qR21, - [(W) -C (0) N (R21)] qR21, - [(W) -0] qR21, - [(W) -N (R21)] qR21, or - [(W) -S] qR21; q is 1, 2, 3, 4, 5 or 6; each R20 is independently H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, or heteroaralkyl; or any two cases of R20 in the same substituent may be taken together to form an optionally substituted ring of 4-8 members containing 0-3 heteroatoms selected from O, N, S and P; each R21 is independently H, alkyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl or - [C (R20) 2] P-R25, where p is 0-6; or any two cases of R21 in the same substituent may be taken together to form an optionally substituted 4-8 membered ring containing 0-3 heteroatoms selected from O, N, S and P; each R25 is independently H, hydroxyl, acylamino, -N (R20) COR20, -N (R20) C (O) OR20, -N (R20) S02 (R20), -COR20N (R20) 2, -OC (O) R20N (R20) (R20), -S02N (R20) (R20), -N (R20) (R20), -COOR20, -C (0) N (OH) (R21), -OS (0) 2OR19, - S (0) 2OR20, -OP (O) (OR20) (OR20), -NP (O) (OR20) (OR20) or -P (O) (OR20) (OR20).
37. 37. A compound selected from the group consisting of:
38. 38. The compound according to claim 20, characterized in that it has the formula:
39. 39. A pharmaceutical composition, characterized in that it comprises any of claims 1-38; and a pharmaceutically acceptable excipient.
40. 40. A method for treating cancer in a subject, characterized in that it comprises administering to a subject in need thereof a therapeutically effective amount of one or more of the compound of any one of claims 1 to 38.
41. 41. The method according to claim 40, characterized because the cancer is located in the head, neck, nasal cavity, paranasal sinuses, nasopharynx, oral cavity, lower jaw, larynx, hypopharynx, salivary glands, paragangliomas, pancreas, stomach, skin, esophagus, liver and biliary tree, bones, intestine, colon, rectum, ovaries, prostate, lung, breast, lymphatic system, blood, central nervous system of spinal cord or brain.
42. 42. The method of compliance with the claim 40, characterized in that the cancer is basal cell carcinoma, pancreatic cancer, prostate cancer, sarcoma, lymphomas, leukemia, gastric cancer, esophageal cancer, biliary cancer, colon cancer, multiple myeloma, small cell lung cancer, glioma , breast cancer, hepatocellular or medulloblastoma.
43. 43. The method according to claim 40, characterized in that the compound is used in combination with radiation therapy or another anti-cancer chemotherapeutic agent.
44. 44. The method according to claim 40, characterized in that the compound is administered locally to a tumor or systemically.
45. 45. The method according to claim 40, characterized in that the mode of administration to the compound is inhalation, oral, intravenous, sublingual, ocular, transdermal, rectal, vaginal, topical, intramuscular, intra-arterial, intrathecal, subcutaneous, buccal or nasal.
46. 46. The method according to claim 40, characterized in that the mode of administration is oral, intravenous or topical.
47. 47. A method for antagonizing the hedgehog pathway in a cell, characterized in that it comprises contacting a smoothed cell expression with an effective amount of any one or more of the compound according to any of claims 1 to 38.
48. 48. The method of according to claim 47, characterized in that the contact is in vi tro.
49. 49. The method according to claim 47, characterized in that the contact is in vivo.
50. 50. The method according to claim 47, characterized in that the smoothed cell expression is within the body of an organism.
51. 51. A method for treating psoriasis in a subject, characterized in that it comprises administering to a subject with need thereof, a therapeutically effective amount of any one or more of the compound according to any one of claims 1 to 38.
52. 52. The method according to claim 51, characterized in that the mode of administration of the compound is topical.