Indian Patents. 268493:CYCLOPAMINE ANALOGS

Title of Invention	CYCLOPAMINE ANALOGS
Abstract	The invention provides novel derivatives of cyclopamine having the following formula.

Full Text	CYCLOPAMINE ANALOGS RELATED APPLICATIONS [0001] This application claims priority to USSN 60/878,018, filed December 28, 2006, and USSN 60/941,596, filed June 1, 2007, both of which are hereby incorporated by reference in their entirety. BACKGROUND OF THE INVENTION [0002] The present invention generally relates to cyclopamine analogs and pharmaceutical compositions thereof, and methods for preparing such analogs and compositions. These compounds and compositions are useful for the treatment of disorders mediated by the hedgehog pathway, such as cancer. [0003] Inhibition of the hedgehog pathway in certain cancers has been shown to result in inhibition of tumor growth. For example, anti-hedgehog antibodies have been shown to antagonize the function of the hedgehog pathway and inhibit the growth of tumors. Small molecule inhibition of hedgehog pathway activity has also been shown to result in cell death in a number of cancer types. [0004] Research in this area has focused primarily on the elucidation of hedgehog pathway biology and the discovery of new hedgehog pathway inhibitors. Although inhibitors of the hedgehog pathway have been identified, there still exists the need to identify more potent inhibitors of the hedgehog pathway. [0005] PCT publication WO 2006/026430 published 9 March 2006 and assigned to the same assignee as the present application, discloses a wide variety of cyclopamine analogs, focusing on those with unsaturation in the A or B ring. In the present application, the surprisingly potent analogs contain completely saturated A and B rings. SUMMARY OF THE INVENTION [0006] The present invention relates to analogs of steroidal alkaloids, such as cyclopamine, pharmaceutical compositions containing these compounds, and methods for preparing these compounds. In one embodiment, the present invention relates to a compound represented by the following structure: or a pharmaceutically acceptable salt thereof; wherein R1 is H, alkyl, -OR, amino, sulfonamide, sulfamido, -OC(O)R5, - N(R5)C(O)R5, or a sugar; R2 is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, nitrile, or heterocycloalkyl; or R1 and R2 taken together form =O, =S, =N(OR), =N(R), =N(NR2), =C(R)2; R3 is H, alkyl, alkenyl, or alkynyl; R4 is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl, haloalkyl, -OR5, -C(O)R5, -CO2R5, -SO2R5, -C(O)N(R5)(R5), -[C(R)2]q-R5, -[(W)-N(R)C(O)]qR5, -[(W)-C(O)]qR5, -[(W)-C(O)O]qR5, -[(W)-OC(O)]qR5, -[(W)-SO2]qR5, -[(W)-N(R5)SO2]qR5, -[(W)-C(O)N(R5)]qR5, -[(W)-O]qR5, -[(W)-N(R)]qR5, -W-NRYXor -[(W)-S]qR5; wherein each W is independently a diradical; each q is independently 1, 2, 3,4, 5, or 6; X" is a halide; each R5 is independently H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl or -[C(R)2]P-R6; wherein p is 0-6; or any two occurrences of R5 can be taken together to form a 4-8 membered optionally substituted ring which contains 0-3 heteroatoms selected from N, O, S, and P; each R6 is independently hydroxyl, -N(R)COR, -N(R)C(O)OR, -N(R)SO2(R), -C(O)N(R)2, -OC(O)N(R)(R), -SO2N(R)(R), -N(R)(R), -COOR, -C(O)N(OH)(R), -OS(O)2OR, -S(O)2OR, -OP(O)(OR)(OR), -NP(O)(OR)(OR), or -P(O)(OR)(OR); and each R is independently H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl or aralkyl; provided mat when R2, R3, and R4 are H; R1 is not hydroxyl or a sugar; further provided that when R4 is hydroxyl, then R1 is not a sugar or hydroxyl, and R1 and R2 are not C=O. [0007] In certain embodiments, R1 is H, hydroxyl, alkoxyl, aryloxy, or amino. In other embodiments, R1 and R2 taken together along with the carbon to which they are bonded, form =O, =N(OR), or =S. In other embodiments, R3 is H and/or R4 is H, alkyl, hydroxyl, aralkyl, -[C(R)2]q-R5, -[(W)-N(R)C(O)]qR5, -[(W)-N(R)SO2]qR5, -[(W)-C(O)N(R)]qR5, -[(W)-O]qR5, -[(W)-C(O)]qR5, or -[(W)-C(O)O]qR5. In other embodiments, R1 is H or -OR, R2 is H or alkyl, and R4 is H. In others, R2 is H or alkyl, R3 is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, or aralkyl; and/or R4 is H, alkyl, aralkyl, -[(W)-N(R)C(O)]qR5, -[(W)-N(R)SO2]qR5, -[(W)-C(O)N(R)]qR5, -[(W)-O]qR5, -[(W)-C(O)]qR5, or -[(W)-C(O)O]qR5. In other embodiments, R1 is sulfonamido. [0008] In another embodiment, the present invention relates to a compound selected from the group consisting of: or a pharmaceutically acceptable salt thereof. [0009] In certain embodiments, the compounds mentioned above are isolated. [0010] In another embodiment, the present invention relates to an isolated compound selected from the group consisting of: or a pharmaceutically acceptable salt thereof. [0011] In another embodiment, the present invention relates to a compound represented by the following structure: or a pharmaceutically acceptable salt thereof; wherein R1 is H, alkyl, -OR, amino, sulfonamide sulfamido, -OC(O)R5, - N(R5)C(O)R5, or a sugar; R2 is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, nitrile, or heterocycloalkyl; or R1 and R2 taken together form =O, =S, =N(OR), =N(R), =N(NR2), =C(R)2; R3is H, alkyl, alkenyl, or alkynyl; R4 is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl, haloalkyl, -OR5, -C(O)R5, -CO2R5, -SO2R5, -C(O)N(R5)(R5), -[C(R)2]q-R5, -[(W)-N(R)C(O)]qR5, -[(W)-C(O)]qR5, -[(W)-C(O)O]qR5, -[(W)-OC(O)]qR5, -[(W)-SO2]qR5, -[(W)-N(R5)SO2]qR5, -[(W)-C(O)N(R5)]qR5, -[(W)-O]qR5, -[(W)-N(R)]qR5, -W-NR53+X , or -[(W)-S]qR5; wherein each W is, independently, a diradical; each q is, independently, 1,2, 3,4, 5, or 6; X" is a halide; each R5 is, independendy, H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl or -[C(R)2]P-R6; wherein p is O-6; or any two occurrences of R5 can be taken together to form a 4-8 membered optionally substituted ring which contains O-3 heteroatoms selected from N, O, S, and P; each R6 is, independendy, hydroxyl, -N(R)COR, -N(R)C(O)OR, -N(R)SO2(R), -C(O)N(R)2, -OC(O)N(R)(R), -SO^RXR), -N(R)(R), -COOR, -C(O)N(OH)(R), -OS(O)2OR, -S(O)2OR, -OP(O)(OR)(OR), -NP(O)(OR)(OR), or-P(O)(OR)(OR); each R is, independently, H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl or aralkyl; each of R7 and R7 is H; or R7 and R7 taken togetiier form =O; R8 and R9 are H; or R and R taken together form a bond; and provided that when R3, R4, R8, R9 are H and R7 and R7 taken together form =O; R1 can not be hydroxyl and R2 can not be H; provided that when R3, R4, R8, R9 are H and, R7 and R7' taken together form =O; R1 can not be acetate and R2 can not be H; provided that when R3, R4, R8, R9 are H and, R7 and R7' are H; R1 and R2 taken together can not be =O; and provided that when R3, R4, R8, R9 are H and, R7 and R7' are H; R1 and R2 can not be H. [0012] In some embodiments, the compound is epimerically pure and/or isolated. In other embodiments, R4 is alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl, haloalkyl, -OR5, -[C(R)2]q-R5, -[(W)-N(R)C(O)]qR5, -[(W)-C(O)]qR5, -[(W)-C(O)O]qR5, -[(W)-OC(O)]qR5, -[(W)-SO2]qR5, -[(W)-N(R5)SO2]qR5, -[(W)-C(O)N(R5)]qR5, -[(W)-O]qR5, -[(W)-N(R)]qR5, or -[(W)-S]qR5. Each of R7 and RT can be H. In addition, R1 and R2 taken together form =O. [0013] In another embodiment, the present invention relates to a compound selected from the group consisting of: or a pharmaceutically acceptable salt thereof. [0014] In certain embodiments, the above compounds are epimerically pure and/or isolated. [0015] In another embodiment, the present invention relates to an epimerically pure compound selected from the group consisting of: or a pharmaceutically acceptable salt thereof. [0016] Another aspect of the present invention relates to a pharmaceutical composition including any of the aforementioned compounds, and a pharmaceutically acceptable excipient. [0017] In one embodiment, the present invention relates to a process for preparing cyclopropyl derivatives of cyclopamine and related analogs having the formula 136: wherein Y is CR7R8; R1 is H, alkyl, amino, hydroxyl, carboxyl, carbamoyl, alkoxy, hydroxyl, sugar or a protected hydroxyl group; R2 is H, alkyl, alkenyl, alkynyl, nitrile, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, or heteroaralkyl; or R1 and R2 taken together form =O, =S, =N(OR9), =N(R9), =C(R9)2,or=N(N(R9)2); each of R3, R4, and R5 is, independently, H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, or heteroaralkyl; or R3 and R4 or R4 and R5 taken together form a bond; R6 is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl, haloalkyl, -OR9, -C(O)R9, -CO2R9, -SO2R9, -C(O)N(R9)(R9), -[C(R9)2]qR9, -[(W)-N(R9)C(O)]qR9, -[(W)-C(O)]qR9, -[(W)-C(O)O]qR9, -[(W)-OC(O)]qR9, -[(W)-SO2]qR9, -[(W)-N(R9)SQ2]qR9, -[(W)-C(O)N(R9)]qR9, -[(W)-O]qR9, -[(W)-N(R9)]qR9, -[(W)-S]qR9, or a nitrogen protecting group; wherein each W is independently a diradical; each q is independently 1, 2, 3, 4, 5, or 6; each of R7 and R8 is, independently, H, alkyl, alkenyl, aryl, nitrile, amido, halide, or ester; and each R9 is, independendy, H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl,aralkyl, heteroaryl, or heteroaralkyl. [0018] The process includes the steps of contacting a compound of formula 136a with a haloalkylzinc phosphate cyclopropanating agent to yield a compound of formula 136. wherein R1, R2, R3, R4, R5, R6 are as defined in compound 136. [0019] In another embodiment, the present invention provides methods for preparing a compound of formula 137: wherein Y is CR7R8; R1 is H, alkyl, amino, hydroxyl, carboxyl, carbamoyl, alkoxy, hydroxyl, sugar or a protected hydroxyl group; R2 is H, alkyl, alkenyl, alkynyl, nitrile, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, or heteroaralkyl; or R1 and R2 taken together form =O, =S, =N(OR9), =N(R9), =C(R9)2,or=N(N(R9)2); each of R3, R4, and R5 is, independently, H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, or heteroaralkyl; or R3 and R4 or R4 and R5 taken together form a bond; R6 is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl, haloalkyl, -OR9, -C(O)R9, -CO2R9, -SO2R9, -C(O)N(R9)(R9), -[C(R9)2]qR9, -[(W)-N(R9)C(O)]qR9, -[(W)C(O)]qR9, -[(W)-C(O)O]qR9, -[(W)-OC(O)]qR9, -[(W)-SO2]qR9, -[(W)-N(R9)SO2]qR9, -[(W)-C(O)N(R9)]qR9, -[(W)-O]qR9, -[(W)-N(R9)]qR9, -[(W)-S]qR9, or a nitrogen protecting group; wherein each W is, independently, a diradical; each q is independently 1, 2, 3, 4, 5, or 6; each of R7 and R8 is, independently, H, alkyl, alkenyl, aryl, nitrile, amido, halide, or ester; and each R9 is independently H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl,aralkyl, heteroaryl, or heteroaralkyl. The process includes the steps of: first contacting a compound of formula 137a with a haloalkylzinc phosphate cyclopropanating agent; wherein R1, R2, R3, R4, R5, R6 are as defined in compound 137; to form a compound with formula 137b wherein R1, R2, R3, R4, R5, R6 and Y are as defined in compound 137; and then contacting the compound of formula 137b with an acid to give a compound of formula 137. [OO2O] In certain embodiments, R7 and R8 can both be H; in other embodiments R1 can be a protected hydroxyl; and/or R6 is a nitrogen protecting group. [OO21] In certain embodiments, the haloalkylzinc phosphate cyclopropanating agent is formed by combining a phosphoric acid of formula 141a, a dialkylzinc, and a dihaloalkylane of formula 141b: wherein each of X and X' is, independently, chloride, bromide, or iodide; each of R7 and R8 is, independently, H, alkyl, halide, amido, nitro, or ester; each of R10 and R11 is, independently, alkyl, alkenyl, aralkyl, aryl, heteroaryl, heteroaralkyl; or R10 and R11 taken together have the formula 141c, 141d, or 141e; wherein m is, independently for each occurrence, 0,1, 2, 3, or 4; n is, independently for each occurrence, 0,1, or 2; and each of R12, R13, R14, R15, R16, R17 and R18 is, independently, alkyl, aryl, aralkyl, or halide. [0022] In another embodiment, the present invention relates to a process for preparing a compound of formula 142: [0023] The process includes the steps of contacting a compound of formula 142a with a cyclopropanating agent to form a compound formula 142b; and combining the compound of formula 142b with an acid to give the compound of formula 142; wherein Y is CR7R8; R1 is a protected hydroxyl group; R2 is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, or heteroaralkyl; each of R3, R4, and R5 is, independently, H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, or heteroaralkyl; or R3 and R4 or R4 and R5 taken together form a bond; R6 is a nitrogen protecting group; each of R7 and R8 is, independently, H, alkyl, alkenyl, aryl, nitrile, amido, halide, or ester; and each R9 is, independendy, H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, or heteroaralkyl. In certain embodiments, R7 and R8 can both be H; in other embodiments the protected hydroxyl group can be an ester or a carbonate; the nitrogen protecting can be a carbamate or an amide; R7 and R8 can both be H and the nitrogen protecting can be a carbamate or an amide; R2 and R3 can be H and R4 and R5 taken together can form a bond; and/or the cyclopropanating agent is generated from a dihaloalkane and a metal species (e.g., dialkyl zinc or a zinc copper couple). [0024] In certain embodiments the cyclopropanating agent is generated from a dihaloalkane species and a dialkyl zinc species, and a phosphoric acid species or a salt thereof. The phosphoric acid species can have a structure of formula 151: or a salt thereof; wherein each of R10 and R11 is independently alkyl, alkenyl, aralkyl, aryl, heteroaryl, heteroaralkyl; or R10 and R11 taken together have the formula 151a, 151b, or 151c; wherein m independently for each occurrence is 0, 1, 2, 3, or 4; n independently for each occurrence is 0,1, or 2; each of R12, R13, R14, R15, R16, R17 and R18 is, independently, alkyl, aryl, aralkyl, or halide. [0025] In certain embodiments the acid is a Bronsted acid (e.g., acetic acid, trifluoromethanesulfonic acid, phosphoric acid, methanesulfonic acid or HC1). In other embodiments the acid is a Lewis acid (e.g., BF3, zinc chloride, zinc methanesulfonate, or a zinc salt). [0026] The present invention also relates to a process for preparing a compound of formula 156: [0027] The process includes the steps of: contacting a compound of formula 156a with a cyclopropanating agent to form a compound formula 156b; and combining the compound of formula 156b with an acid to give the compound of formula 156; where R1 is an oxygen protecting group selected from the group consisting of formate, acetate, chloroacetate, dichloroacetate, trichloroacetate, pivaloate, benzoate, alkyl carbonate, alkenyl carbonate, aryl carbonates, aralkyl carbonate, 2,2,2-trichloroethyl carbonate, alkoxymethyl ether, aralkoxymethyl ether, alkylthiomethl edier, aralkylthio ether, arylthio ether, trialkylsilyl edier, alkylarylsilyl ether, benzyl ether, arylmethyl ether, allyl ether; and R is a nitrogen protecting group selected from the group consisting of formyl, chloroacetyl, trichloroacetyl, trifluoroacetyl, phenyl acetyl, benzoyls, alkyl carbamates, aralkyl carbamates, aryl carbamates, allyl, aralkyl, triarylmethyl, alkoxymethyl, aralkoxymethyl, N-2-cyanoethyl, diarylphosphinamides, dialkylphosphinamidates, diarylphosphinamidates, and trialkylsilyl. [0028] In certain embodiments the cyclopropanating agent is formed by combining a phosphoric acid of formula 58a, a dialkylzinc, and a dihaloalkylane of formula 158b: wherein each of X and X' is, independently, chloride, bromide, or iodide; each of R and R8 is, independently, H, alkyl, halide, amido, or ester; each of R10 and R11 is, independently, alkyl, alkenyl, aralkyl, aryl, heteroaryl, heteroaralkyl; or R10 and R11 taken together have the formula 158c, 158d, or 158e; wherein m independently for each occurrence is 0, 1, 2, 3, or 4; n independently for each occurrence is 0,1, or 2; each of R12, R13, R14, R15, R16, R17 and R18 is, independently, alkyl, aryl, aralkyl, or halide. [0029] The oxygen protecting group can be, in some embodiments, selected from alkyl carbonates, aralkyl carbonates (e.g., benzylcarbonate), benzoates, pivaloate, or formate. The nitrogen protecting group can be selected from benzoyl, trichloroacetyl, trifluoroacetyl, formyl, alkyl carbamates, aralkyl carbamates (e.g., benzylcarbamate), aryl carbamates, diarylphosphinamides, dialkylphosphinamidates, or diarylphosphinamidates. DETAILED DESCRIPTION OF THE INVENTION Definitions [0030] The definitions of terms used herein are meant to incorporate the present state-of-the-art definitions recognized for each term in the chemical and pharmaceutical fields. Where appropriate, exemplification is provided. The definitions apply to the terms as they are used throughout this specification, unless otherwise limited in specific instances, either individually or as part of a larger group. [0031] As used herein, the definition of each expression, e.g., alkyl, m, n, etc., when it occurs more than once in any structure, is intended to be independent of its definition elsewhere in the same structure. [0032] The term "acylamino" refers to a moiety that may be represented by the general formula: wherein R50 and R54 independently represent a hydrogen, an alkyl, an alkenyl or -(CH2)m-R61, where 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. [0033] The terms "alkenyl" and "alkynyl" refer to unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond respectively. [0034] The terms "alkoxyl" or "alkoxy" refers to an alkyl group, as defined above, having an oxygen radical attached thereto. Representative alkoxyl groups include methoxy, ethoxy, propyloxy, tert-butoxy and the like. [0035] The term "alkyl" refers to the radical of saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups. In certain embodiments, a straight chain or branched chain alkyl has 30 or fewer carbon atoms in its backbone (e.g., C1-C30 for straight chain, C3-C30 for branched chain), 2O or fewer. Likewise, certain cycloalkyls have from 3-10 carbon atoms in their ring structure, and others have 5, 6 or 7 carbons in the ring structure. [0036] The term "alkylthio" refers to an alkyl group, as defined above, having a sulfur radical attached mereto. In certain embodiments, the "alkylthio" moiety is represented by one of -S-alkyl, -S-alkenyl, -S-alkynyl, and -S-(CH2)m-R61, wherein m and R61 are defined above. Representative alkylthio groups include methyltbio, ethyl thio, and the like. [0037] The term "amido" is art recognized as an amino-substituted carbonyl and includes a moiety that may be represented by the general formula: wherein R50 and R51 each independently represent a hydrogen, an alkyl, an alkenyl, -(CH2)m-R61, 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, or R50 and R51, taken together with me N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure. Certain embodiments of the amide in the present invention will not include imides which may be unstable. [0038] The terms "amine" and "amino" are art-recognized and refer to both unsubstituted and substituted amines, e.g., a moiety mat may be represented by the general formulas: wherein R50 and R51 (and optionally R52) each independently represent a hydrogen, an alkyl, an alkenyl, or -(CH2)m-R61, where R61 is defined as above. Thus, the term "alkylamine" includes an amine group, as defined above, having a substituted or unsubstituted alkyl attached thereto, i.e., at least one of R50 and R51 is an alkyl group. [0039] The term "aralkyl", as used herein, refers to an alkyl group substituted with an aryl group (e.g., an aromatic or heteroaromatic group). [0040] The term "aryl" as used herein includes 5-, 6- and 7-membered single-ring aromatic groups that may include from zero to four heteroatoms, for example, benzene, anthracene, naphthalene, pyrene, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine, and the like. Those aryl groups having heteroatoms in the ring structure may also be referred to as "aryl heterocycles" or "heteroaromatics." The aromatic ring may be substituted at one or more ring positions with such substituents as described above, for example, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moieties, -CF3, -CN, or the like. The term "aryl" also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings (the rings are "fused rings") wherein at least one of the rings is aromatic, e.g., the other cyclic rings may be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or heterocyclyls. [0041] The term "Bronsted acid" refers to any substance that can act as a hydrogen ion (proton) donor. [0042] The term "carboxyl" is defined to include esters, thiocarboxyl, aldehydes, ketones and the like and thus includes such moieties as may be represented by the general formulas: wherein X50 is a bond or represents an oxygen or a sulfur, and each of R55 and R56 represents independently a hydrogen, an alkyl, an alkenyl, -(CH2)m-R61, where m and R61 are defined above. [0043] The term "diradical" refers to any of a series of divalent groups from alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, and heteroaralkyl (alkyl)heteroaralkyl diradical. Typical examples include alkylenes of general structure (CH2)X where X is 1-6, and corresponding alkenylene and alkynylene linkers having 2-6 carbon atoms and one or more double or triple bonds; cycloalkylene groups having 3-8 ring members; and aralkyl groups wherein one open valence is on the aryl ring and one is on the alkyl portion such as and its isomers. [0044] The term "haloalkyl", as used herein, refers to an alkyl group where anywhere from 1 to all hydgrogens have been replaced with a halide. A "perhaloalkyl" is where all of the hydrogens have been replaced with a halide. [0045] The term "heteroatom" as used herein means an atom of any element other man carbon or hydrogen. Examples of heteroatoms include boron, nitrogen, oxygen, phosphorus, sulfur and selenium. [0046] The terms "heterocyclyl" or "heterocyclic group" refer to 3- to 10- membered ring structures, in some instances from 3- to 7-membered rings, whose ring structures include one to four heteroatoms. Heterocycles can also be polycycles. Heterocyclyl groups include, for example, thiophene, thianthrene, furan, pyran, isobenzofuran, chromene, xanthene, phenoxathiin, 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, sultams, 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 moiety, -CF3, -CN, or the like. [0047] The term "isolated" in connection with a compound of the present invention means the compound is not in a cell or organism and the compound is separated from some or all of the components that typically accompany it in nature. [0048] The term "Lewis acid" refers to any substance that can act as an electron pair acceptor. [0049] Unless the number of carbons is otherwise specified, "lower alkyl" as used herein means an alkyl group, as defined above, but having from one to ten carbons, in some embodiments from one to six carbon atoms in its backbone structure. Likewise, "lower alkenyl" and "lower alkynyl" have similar chain lengths. Certain alkyl groups are lower alkyls. In some embodiments, a substituent designated herein as alkyl is a lower alkyl. [0050] As used herein, the term "nitro" means -NO2; the term "halogen" designates -F, -Cl, -Br or -I; the term "sulfhydryl" means -SH; the term "hydroxyl" means -OH; and the term "sulfonyl" means -SO2-. [0051] The term "oxo" refers to a carbonyl oxygen (=O). [0052] The terms "polycyclyl" or "polycyclic group" 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 adjoining rings, e.g., the rings are "fused rings". Rings that are joined through non-adjacent atoms are termed "bridged" rings. Each of the rings of the polycycle may 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 moiety, -CF3, -CN, or the like. [0053] The term "epimerically pure" in connection with a compound of the present invention means that the compound is substantially free of stereoisomers of the compound wherein the configuration of the stereogenic center that R3 is bonded to is inverted. For example an epimerically pure compound represented by the following formula: wherein R1, R2, R3, R4, R7, R7, R8, and R9 are as defined below, is substantially free of compounds represented by the following formula: wherein R1, R2, R3, R4, R7, R7, R8, and R9 are as defined below. Epimerically pure compounds contain less than about 20 % by mass, less than about 15% by mass, less than about 10% by mass, less than about 5% by mass, or less than about 3% by mass of stereoisomeric compounds wherein the configuration of the stereogenic center that R3 is bonded to is inverted relative to the compound. [0054] The phrase "protecting group" as used herein means temporary substituents which protect a potentially reactive functional group from undesired 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 field of protecting group chemistry has been reviewed (Greene, T.W.; Wuts, P.G.M Protective Groups in Organic Synthesis, 2nd ed.; Wiley: New York, 1991). In some cases, the functional group being protected and the protecting group are together referred to as one moiety. For example, the fragment shown below is sometimes referred to as a benzyl carbonate; i.e., the protected (underlined) O makes up part of the carbonate. [0055] Similarly, the fragment shown below, in which the protected N makes up part of the carbamate, is referred to as a benzyl carbamate. [0056] The term "sugar" as used herein refers to a natural or an unnatural monosaccharide, disaccharide or oligosaccharide comprising one or more pyranose or furanose rings. The sugar may be covalently bonded to the steroidal alkaloid of the present invention through an ether linkage or through an alkyl linkage. In certain embodiments the saccharide moiety may be covalently bonded to a steroidal alkaloid of the present invention at an anomeric center of a saccharide ring. Sugars may include, but are not limited to ribose, arabinose, xylose, lyxose, allose, altrose, glucose, mannose, gulose, idose, galactose, talose, glucose, and trehalose. [0057] The term "sulfonamido" or "sulfonamide" as used herein includes a moiety having either of the following formulae: wherein R50 and R56 are as defined above. [0058] The terms "triflyl", "tosyl", "mesyl", and "nonaflyl" refer to trifluoromethanesulfonyl, p-toluenesulfonyl, methanesulfonyl, and nonafluorobutanesulfonyl groups, respectively. The terms "triflate", "tosylate", "mesylate", and "nonaflate" to trifluoromethanesulfonate ester, p-toluenesulfonate ester, methanesulfonate ester, and nonafluorobutanesulfonate ester functional groups and molecules that contain the groups, respectively. [0059] The term "thioxo" refers to a carbonyl sulfur (=S). [0060] It will be understood that "substitution" or "substituted with" includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. [0061] Certain compounds of the present invention may exist in particular geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis- and frans-isomers, R- and 5-enantiomers, diastereomers, (D)- isorners, (L)-isomers, the 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 such isomers, as well as mixtures thereof, are intended to be included in this invention. [0062] As set out 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 respect, refers to the relatively non-toxic, inorganic and organic acid addition salts of compounds of the present invention. These salts can be prepared in situ in the administration vehicle or the dosage form manufacturing process, or by separately reacting a purified compound of the invention in its free base form with a suitable organic or inorganic acid, and isolating the salt thus formed during subsequent purification. Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, napthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts and the like. (See, for example, Berge et al. (1977) "Pharmaceutical Salts", J. Pharm. Sci. 66:1-19) [0063] The pharmaceutically acceptable salts of the compounds of the present invention include the conventional nontoxic salts or quaternary ammonium salts of the compounds, e.g., from non-toxic organic or inorganic acids. For example, such conventional nontoxic salts include those derived from inorganic acids such as hydrochloride, hydrobromic, sulfuric, sulfamic, phosphoric, nitric, and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, palmitic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicyclic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isothionic, and the like. [0064] In other cases, the compounds of the present invention may contain one or more acidic functional groups and, thus, are capable of forming pharmaceutically- acceptable salts with pharmaceutically-acceptable bases. The term "pharmaceutically- acceptable salts" in these instances 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 situ 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 the hydroxide, carbonate or bicarbonate of a pharmaceutieally-acceptable metal cation, with ammonia, or with a pharmaceutically- acceptable organic primary, secondary or tertiary amine. Representative alkali or alkaline earth salts include the 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, emylenediamine, ethanolamine, diethanolamine, piperazine and the like. (See, for example, Berge et al, supra) Svnmesis of Steroidal Alkaloid Compounds [0065] The ring expanded steroidal alkaloid derivatives described above can be prepared directly from naturally occurring steroidal alkaloids or synthetic analogs thereof. In certain instances, the steroidal alkaloid starting materials can be cyclopamine or jervine. These steroidal alkaloids can be purchased commercially or extracted from Veratrum Californicum. Briefly, the process of the present invention comprises the steps of cyclopropanating suitable starting steroidal alkaloid derivatives followed by ring expansion rearrangement of the cyclopropyl derivatives. In some instances, it may be desirable to suitably protect or otherwise transform reactive functionalities present on the molecule prior to cyclopropanation. For example, an alcohol present at R1 and a secondary nitrogen present on the fused furano-piperidine ring can both be protected prior to cyclopropanation. In certain embodiments, protecting groups that are efficiently added and removed from the alkaloid, yield intermediates in the synmetic process with improved handling properties and which allow for the efficient purification of me synthetic intermediates formed may be preferred. [0066] Examples of oxygen protecting groups include, but are not limited to formate, acetate, chloroacetate, dichloroacetate, trichloroacetate, pivaloate, benzoates, alkyl carbonate, alkenyl carbonate, aryl carbonates, aralkyl carbonate (e.g., benzyl carbonate), 2,2,2-trichloroethyl carbonate, alkoxymethyl ether, aralkoxymethyl ether, alkylthiomethl ether, aralkylthio ether, arylthio ether, trialkylsilyl ether, alkylarylsilyl ether, benzyl ether, arylmethyl ether, and allyl ether. [0067] Examples of nitrogen protecting groups include, but are not limited to formyl, chloroacetyl, trichloroacetyl, trifluoroacetyl, phenyl acetyl, benzoyls, benzamides, alkyl carbamates, aralkyl carbamates (e.g., benzyl carbamates), aryl carbamates, allyl, aralkyl, alkoxymethyl, aralkoxymethyl, N-2-cyanoethyl, diarylphosphinamides, dialkylphosphinamidates, diarylphosphinamidates, and trialkylsilyl. [0068] Additional protecting groups that may be used in the methods of the present invention are described in Green T.W.; Wuts P.G. Protective Groups in Organic Synthesis 3rd Edition, John Wiley & Sons, Inc. 1999. [0069] A variety of cyclopropanating agents can be used to cyclopropanate the steroidal alkaloid. 1,1-haloalkylmetal complexes and reactive species referred to as carbenoids, are commonly used to cyclopropanate olefins. These reagents are typically made using a diiodoalkane or diazoalkane and a metal or organometalic species such as Et2Zn, iBU3Al, samarium, copper, rhodium, or palladium. In certain embodiments, Et2Zn and diiodomethane are used to generate the 1,1-haloalkylmetal species. [0070] The reactivity and the ease of handling of the 1,1-haloalkylzinc complexes can be modified by the addition of certain reagents, such as acids. It is believed that the addition of an acid to the 1,1-haloalkylzinc species generates an alkyl zinc mixed salt. In the examples described below a biarylphosphoric acid is combined with diiodomethane and diethylzinc to generate a putative haloalkyl zinc phosphate cyclopropanating agent. A variety of phosphoric acids can be used to generate the putative haloalkylzinc phosphate. [0071] Other known cyclopropanation methods such as those utilizing sulfur ylides 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-diazo-carbonyl compounds, such as diazomethane and ethyl diazoacetate, can also be used: these methods readily provide cyclopropanes having alkyl, aryl, alkoxycarbonyl (-COOR), or acyl substituents. Additional cyclopropanating agents are described in Masalov et al., Organic Letters (2004) Vol. 6, pp. 2365-8 and Hansen et al., Chem. Comm. (2006) 4838- 4O. [0072] The cyclopropyl ring may be substituted or unsubstituted. In cases where the cyclopropyl ring is substituted, the groups attached to the methylene of the cyclopropane will be installed onto the D ring after rearrangement and ring expansion. [0073] The cyclopropanation reactions may be conducted in an aprotic solvent. Suitable solvents include ethers, such as diethyl ether, 1,2-dimethoxyethane, diglyme, t- butyl methyl ether, 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, dimethylsulfoxide, dimethylformamide, and the like; or combinations of two or more solvents. In a certain embodiments, dichloromethane is the solvent used for me cyclopropanation when a dialkyl zinc and diiodomethane is used. [0074] In the examples described below, a solution containing the cyclopropanating agent is prepared by first adding a solution of a phosphoric acid to a solution of diethylzinc, followed by addition of diiodomethane to the reaction solution. The cyclopropanation substrate is then added to this solution. Alternatively, the cyclopropanation agent can be prepared in the presence of the cyclopropanation substrate by changing the order of addition of the reagents. In certain embodiments, the cyclopropanation reaction is conducted by first adding the phosphoric acid to a solution of dialkylzinc, followed by the addition of the cyclopropanation substrate, and finally the dihaloalkane is added. Using this method the cyclopropanating agent is generated under controlled conditions and immediately reacts with the cyclopropanation substrate. The cyclopropanation methods described herein can also be used to cyclopropanate other polycyclic compounds, for example, those with steroidal backbones. [0075] Following synthesis of the cyclopropanated steroidal alkaloid core, the compound may be derivatized using a variety of functionalization reactions known in the art. Representative examples include palladium coupling reactions to alkenylhalides or aryl halides, oxidations, reductions, reactions with nucleophiles, reactions with electrophiles, pericyclic reactions, radical reactions, installation of protecting groups, removal of protecting groups, and the like. [0076] In the presence of Lewis or Bronsted acids the cyclopropyl analogs undergo a rearrangement and ring expansion to afford steroidal alkaloid analogs in which the D ring has been expanded by one carbon. [0077] The cyclopropanation and ring expansion can take place in a two-step one reaction vessel process or in a two-step two reaction vessel process. When the cyclopropanation and ring expansion are conducted in the same reaction vessel the acid used to initiate the ring expansion rearrangement is added after completion of the cyclopropanation reaction. Under certain conditions, the zinc salts that are generated in the course of cyclopropanating the steroidal alkaloid can themselves act as Lewis acids to catalyze the ring expansion rearrangement. The reactivity of the zinc salts generated after the cyclopropanation can be modified by the addition of acids to generate more active Lewis acids. [0078] As described below in the examples section, the methanesulfonic acid is added to the cyclopropanation reaction vessel after completion of the cyclopropanation. Additional examples of suitable acids include, but are not limited to zinc salts, boron compounds, magnesium salts, titanium salts, indium salts, aluminum salts, tin salts, lanthanum salts, trifluoromethanesulfonic acid, diaryloxyphosporic acids, acetic acid, and HC1. In a certain embodiments of the invention the Lewis acid used is a zinc salt or BF3. [0079] These ring expanded analogs may be further functionalized using a variety of functionalization reactions known in the art. Representative examples include palladium coupling reactions to alkenylhalides or aryl halides, oxidations, reductions, reactions with nucleophiles, reactions with electrophiles, pericyclic reactions, radical reactions, installation of protecting groups, removal of protecting groups, and the like. Utility of Compounds [0080] Hedgehog signaling is essential in many stages of development, especially in formation of left-right symmetry. Loss or reduction of hedgehog signaling leads to multiple developmental deficits and malformations, one of the most striking of which is cyclopia. [0081] Many tumors and proliferative conditions have been shown to depend on the hedgehog pathway. The growth of such cells and survival can be affected by treatment with the compounds of the present invention. Recently, it has been reported that activating hedgehog pathway mutations occur in sporadic basal cell carcinoma (Xie et al. (1998) Nature 391: 9O-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 cancer types such as GI 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 etal (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). [0082] For example, small molecule inhibition of the hedgehog pathway has been shown to inhibit the growth of basal cell carcinoma (Williams, et ah, 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). [0083] In addition, it has been shown that many cancer types 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, 2005. 96th Annual AACR conference, abstract #2942 Sicklick et al, 2005. ASCO annual meeting, abstract #9610), hematological malignancies (Watkins and Matsui, unpublished results), basal 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)). As shown in the Examples, the compounds disclosed herein have been shown to modulate the hedgehog pathway, and selected compounds have been shown to inhibit tumor growth. It is therefore believed that these compounds can be useful to treat a variety of conditions, such as various cancers. Pharmaceutical Compositions [0084] 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, formulated together with one or more pharmaceutically acceptable carriers (additives) and/or diluents. The pharmaceutical compositions of the present invention may be specially formulated for administration in solid or liquid form, including those adapted for the following: (1) oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., those targeted for buccal, sublingual, and systemic absorption, capsules, boluses, powders, granules, pastes for application to the tongue; (2) parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection 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 intrarectally, for example, as a pessary, cream or foam; (5) sublingually; (6) ocularly; (7) transdermally; (8) pulmonarily, or (9) nasally. [0085] Examples of suitable aqueous and nonaqueous carriers which may 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. [0086] These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents, dispersing agents, lubricants, and/or antioxidants. Prevention of the action of microorganisms upon the compounds of the present invention may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin. [0087] Methods of preparing these formulations or compositions include the step of bringing into association a compound of the present invention with the carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product. [0088] When the compounds of the present invention are administered as pharmaceuticals, to humans and animals, they can be given per se or as a pharmaceutical composition containing, for example, about 0.1 to 99%, or about 10 to 50%, or about 10 to 40%, or about 10 to 30, or about 10 to 20%, or about 10 to 15% of active ingredient in combination with a pharmaceutically acceptable carrier. [0089] Actual dosage levels of the active ingredients in the pharmaceutical compositions of the present invention may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient. [0090] The selected dosage level will depend upon a variety of factors including the activity of the particular compound of the present invention employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion or metabolism of the particular compound being employed, the rate and extent 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 like factors well known in the medical arts. [0091] In general, a suitable daily dose of a compound of the invention will be that amount of the compound which is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above. Generally, oral, intravenous and subcutaneous doses of the compounds of the present invention for a patient, when used for the indicated effects, will range from about 0.0001 to about 100 mg, or about 0.001 to about 100 rag, or about 0.01 to about 100 mg, or about 0.1 to about 100 mg per, or about 1 to about 50 mg per kilogram of body weight per day. [0092] The subject receiving this treatment is any animal in need, including primates, in particular humans, and other mammals such as equines, cattle, swine and sheep; and poultry and pets in general. Exemplification [0093] The invention now being generally described, it will be more readily understood by 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. [0094] Recrystallized cyclopamine 2 (14.1 g, 34.0 mmol, 1 eq) is dissolved in anhydrous DCM (70 mL) and anhydrous MeOH (29 mL). The clear solution is cooled, and triethylamine (10.4 g, 102.7 mmol, 3 eq) followed by benzyl chloroformate (6.20 g, 36.3 mmol, 1.1 eq) is added. After the addition is complete, the solution is stirred in the ice bath for 30 min. Three portions of benzyl chloroformate (3 X O.35 g, 3.46 mmol, 0.03 eq) are added over the 3 h. The reaction is slowly quenched with water (71 mL), while maintaining the temperature below 20 °C. The mixture is stirred for 15 min before the layers are settled and separated. The organic layer is dried over sodium sulfate and filtered. The combined filtrate is buffered with anhydrous pyridine (30 mL), concentrated, and solvent exchanged with additional anhydrous pyridine (43 mL) and concentrated. [0095] The solution of the compound in pyridine (43 mL) is further diluted with additional anhydrous pyridine (85 mL). Trimethylacetyl chloride (8.3 g, 68.7 mmol, 2 eq) is added slowly to the reaction mixture, and the reaction is heated to 45 °C. The reaction is stirred at 45 °C for 30 mitt. The reaction is cooled and quenched by the addition of anhydrous MeOH (4.5 mL). The quenched reaction mixture is stirred at rt for 40 min and then diluted with toluene (97 mL) and is treated sequentially with water (35 mL) and a 10 wt % aqueous sodium carbonate solution (100 mL). After vigorous stirring, the layers are separated and the organic layer is washed twice with water (2 x 100 mL), dried over sodium sulfate, and filtered. The filter cake is rinsed with toluene (49 mL) and discarded. The combined filtrates are concentrated, and solvent exchanged with concentration to toluene (145 mL) and further concentrating to dryness. The product is recrystallized from toluene and heptane. The crystalline product is isolated by suction filtration, washed with cold heptane and dried to a constant weight to afford 15.1 g of the desired product. [QQ961 Bis(2,6~dimethyphenyl)phosphate (1O.65 g, 34.8 mmol, 3.1 eq) is dried by concentration from anhydrous DCM (42 mL) and held under a nitrogen atmosphere. The phosphate is then redissolved in anhydrous DCM (11O mL). In a separate flask, a solution of neatdiethylzinc (4.11 g, 33.2, mmol, 3.O eq) in anhydrous DCM (35 mL) is prepared and cooled to -25 °C. The phosphate solution is slowly transferred to the vessel containing the diethylzinc solution over 1 h, maintaining the temperature at or below -1O °C. The clear ethylzinc phosphate solution is wanned to O *C and stirred for 15 min. Diiodomethane (9.25 g, 34.5 mmoles, 3.O eq) is slowly added to the ethylzinc phosphate solution, maintaining the reaction temperature between O and 5 °C. After the addition is complete, the zinc carbenoid solution is stirred for an additional 2O min. [0097] In a separate flask, compound 3 (7.20 g, 11.4 mmol, 1 eq) is dissolved in anhydrous DCM (36 mL) and transferred to the reaction flask. After the addition is complete, the ice bath is removed and the reaction mixture is allowed to warm to rt. After 6 h the contents of the flask are cooled to -53 °C. A solution of methanesulfonic acid (3.38 g, 35.2 mmol, 3.1 eq) in anhydrous DCM (3 mL) is added, maintaining the reaction temperature below -45 °C. After 10 min morpholine (20 g, 230 mmol, 20C. The reaction is allowed to warm to rt overnight. The morpholine salts are removed by filtration and the filter cake rinsed with DCM (22 mL). The combined filtrates are washed with 2N aqueous hydrochloric acid (2 x 140 mL), 5 % aqueous sodium bicarbonate (140 mL), 5 % aqueous sodium bicarbonate (70 mL) and 5 % aqueous sodium bisulfite (70 mL), and brine (144 mL). The organic layer is dried over magnesium sulfate and filtered. Without going to dryness, the DCM solution is concentrated and solvent exchanged with methanol (280 mL). The suspension are chilled with an ice bath and stirred for 40 minutes. The solids are isolated by filtration, washed twice with cold methanol (2 x 25 mL), and dried to a constant weight to afford 5.94 g of the desired product. [0098] In a round bottom flask, compound 4 (11.67 g, 18.1 mmol, 1 eq) and 20 % palladium hydroxide on wet carbon (2.40 g, 1.71 mmol, 0.09 eq) are placed under a nitrogen atmosphere and diluted with EtOAc (115 mL) and toluene (60 mL). The solution is degassed with nitrogen (3X) with evacuation/purge cycles, and the process is repeated for hydrogen. The suspension is vigorously stirred at rt for 1.5 h. The hydrogen atmosphere is replaced with nitrogen. Ethylenediamine (0.57 g, 9.5 mmol, 0.52 eq) is added to the reaction, and the resulting mixture stirred for 20 min. The solution is filtered under nitrogen, and the filtrate is washed with a 2 % (wt/wt) aqueous solution of ethylenediamine (125 mL) then water (130 mL), and then dried over sodium sulfate. The drying agent is removed by filtration and the filtrate is concentrated to dryness under vacuum. The solids that remained are chased with toluene (2 x 55 mL) on the rotary evaporator and the resulting material used without further purification in the next step [0099] The material from the previous step is dissolved in anhydrous DCM (26 mL). The resulting clear solution is added to a 1 M solution of DIBAL in DCM (65 mL, 65 rnmol, 3.6 eq) while maintaining the reaction temperature between -10 and -25 °C. After 30 min the reaction is quenched with acetone (13 mL), maintaining the reaction temperature at or below 0 oC. After stirring the quenched reaction mixture for 17 min, it is added in portions to a flask containing a cold, stirred solution of 20 % (wt/wt) aqueous Rochelle salt (200 mL). The resulting gelatinous suspension is stirred at rt for 15 h. After stirring, the clean layers are separated and the aqueous layer back extracted with DCM (30 mL). The combined organic layers are washed with water (60 mL) and dried over sodium sulfate. The drying agent is removed by filtration and discarded. The filtrate is concentrated under vacuum and solvent exchanged to toluene (225 mL added in portions). The resulting solution is further concentrated to a suspension (5O mL) and diluted with heptane (115 mL). The resulting mixture is heated until turning homogeneous (92 °C). The solution is cooled slowly over 12 h to 15 °C, and then held for 16 additional h. The crystalline product is isolated by suction filtration, washed with heptane (2 x 75 mL) and dried to a constant weight to afford 7.70 g of the desired product. [0100] A round bottom flask is sequentially charged with the homo-allylic alcohol (7.50 g, 17.6 mmol, 1 eq), aluminum tri-tert-butoxide (6.10 g, 24.8 rnmol, 1.4 eq), anhydrous toluene (115 mL), and 2-butanone (90 g, 1.24 mol, 7 eq). The suspension is heated under a nitrogen atmosphere to 75 °C for 16 h. The reaction temperature is then allowed to cool to 49 oC. Aqueous 20 % (w/w) potassium sodium tartrate solution (226 g) is added to the stirred suspension. The suspension is stirred at rt for 3.5 h. The layers are separated. The organic layer washed with aqueous 20 % Rochelle salt (2 x 250 mL) and water (225 mL), then dried over sodium sulfate and filtered. The residue is rinsed with toluene (30 mL) and discarded. The combined organics are concentrated to dryness. Residual reaction solvents are removed from the material by concentrating from 2- propanol (250 mL added portion-wise) to a final solution mass of 44 g. Solvent exchange from 2-propanol to heptane (275 mL added portion-wise) to a final solution mass is 41 g fully precipitated the desired product. The suspension is diluted with of additional heptane (40 mL), stirred at rt for 1 h, and filtered. The product is washed with n-heptane (17 mL) and dried to afford 5.4 g of the desired product. [0101] A round-bottom flask is charged with starting material (110 mg, 0.26 mmol, 1 eq) and 10% palladium on carbon (106 mg). The solids are suspended in pyridine (4 mL). The suspension is placed under hydrogen atmosphere (1 arm) and the mixture is stirred overnight at rt. The reaction mixture is filtered through Celite® and the filtrate concentrated in vacuo. The crude material is purified using silica gel flash chromatography (MeOH/DCM 5:95) to afford 93 mg of the desired compound. ([M+H] = 426.6 m/z). [0102] Cyclop Jine 2 (5.O2 g, 12.2 mmol, 1.O eq) is dissolved in anhydrous pyridine (25 mL). DMAP (300 mg, 2.44 mmol, 0.2 eq.) and triethyl amine (5.5 mL, 39.1 mmol, 3.2 eq) are added, followed by BtO-Cbz (10.5 g, 39.1 mmol, 3.2 eq) and heated at 40 °C for 2h. The mixture is cooled to rt, treated with 30 mL water, heated to get a homogeneous solution and allowed to cool to room temp. The white precipitate that formed is collected by filtration, the filter cake is washed with portions of water (3 X 50 mL), and dried in air to afford 9.53 g of crude material which is crystallized from toluene/heptanes (1:9,70 mL) to give 6.75 g of the desired product. [0103] To a solution of diethyl zinc (572 mg, 482 uL, 4.63 mmol, 3.00 eq) in 5.0 mL DCM at -20 °C is added a solution of bis-(2,6-Dimethylphenyl)phosphoric acid (1.42 g, 4.63 mmol, 3.00 eq) in DCM (15 mL) maintaining the reaction temperature below -8 °C. The solution is aged for 15 min. at 0 °C, neat diiodomethane (1.24 g, 374 µL, 3.00 eq) is added, aged for 15 min. at 0 °C before adding a solution of (BisCBzcyclopamine, 1.05 g, 1,54 mmol, 1.0 eq), in DCM (10 mL). The cooling bath is replaced by a water bath at rt and maintained at rt for 4.5 h. The mixture is cooled to -76 °C with a dry ice-acetone bath and treated drop wise with methanesulfonic acid DCM solution (0.6 mL 50% v/v solution 4.63 mmol, 3.0 eq) maintaining the reaction temperature below -74 °C. The mixture is aged for 15- 20 min. and quenched drop wise with morpholine (2.69 g, 2.70 mL, 2O eq) maintaining the reaction temperature below -65 °C. The cooling bath is removed, the reaction mixture is stirred for 16-18 h., the white precipitate is filtered off, and the filtrate is successively washed with 2.0 M HC1 (2 x 20 mL), satd. sodium bicarbonate (2 x 20 mL), water (2 x 20 mL) and brine (20 mL). Dried over magnesium sulfate, concentrated in vacuo to dryness and the crude is purified by silica gel flash chromatography (hexanes/EtOAc 17:3-4:1) to afford 924 mg (1.33 mmol, 86%) of the desired product. StepC [o1o4] To a solution of compound 7 (4.o5 g, 5.83 mmol, 1 eq) in a solution of EtoAc:toluene (2:1, 6o mL) is added of 20% palladium hydroxide on carbon (823 mg, o.583 mmol, 0.1 eq.). The flask is evacuated and filled with hydrogen three times. The mixture is stirred under an atmosphere of hydrogen for lh. Neat ethylene diamine (0.38 mL) is added, stirred for lh., and the catalyst is filtered off. The filter cake is washed twice with EtOAc:toluene (2:1,12 mL). The combined filtrates are washed with a 2% aqueous solution of ethylene diamine (3 X 20 mL), dried over sodium sulfate and concentrated in vacuo to give 2.46 g as a white crystalline solid. [0105] A round bottom flask is sequentially charged with the homo-allylic alcohol 8 (7.5o g, 17.6 mmol, 1 eq), aluminum tri-tert-butoxide (6.1o g, 24.8 mmol, 1.4 eq), anhydrous toluene (115 mL), and 2-butanone (90 g, 1.24 mol, 7 eq). The suspension is heated under a nitrogen atmosphere to 75 °C for 16 h. The reaction temperature is then allowed to cool to 49 °C. Aqueous 20 % (w/w) potassium sodium tartrate solution (226 g) is added to the stirred suspension. The suspension is stirred at rt for 3.5 h. The layers are separated. The organic layer washed with aqueous 20 % Rochelle's salt (2 x 250 mL) and water (225 mL), then dried over sodium sulfate and filtered. The residue is rinsed with toluene (30 mL) and discarded. The combined organics are concentrated to dryness. Residual reaction solvents are removed from the material by concentrating from 2-propanol (250 mL added portion-wise) to a final solution mass of 44 g. Solvent exchange from 2-propanol to n-heptane (275 mL added portion-wise) to a final solution mass of 41 g fully precipitated the desired product. The suspension is diluted with of additional n-heptane (40 mL), stirred at rt for 1 h, and filtered. The product is washed with n-heptane (17 mL) and dried to afford 5.4 g of the desired product. [0106] A round-bottom flask is charged with starting material (110 mg, 0.26 mmol, 1 eq) and 1o% palladium on carbon (106 mg). The solids are suspended in pyridine (4 mL). The suspension is placed under hydrogen atmosphere (1 atm) and the mixture is stirred overnight at rt. The reaction mixture is filtered through Celite® and the filtrate concentrated in vacuo. The crude material is purified using silica gel flash chromatography (MeOH/DCM 5:95) to afford 93 mg of the desired compound. ([M+H] = 426.6 m/z). [0107] In a seal tube, ketone 6 (85 mg, o.199 mmol, 1 equiv.) was charged and triethyleneglycol (2 mL) was added followed by hydrazine monohydrate (500 mg, 10 mmol, 50 equiv.) and potassium carbonate (138 mg, 1 mmol, 5 equiv.). The tube was sealed and the reaction was heated at 150 °C for 16 h. The reaction was cooled to rt and water was added. The residue was extracted with chloroform (3X). The combined organic layers are washed with water, dried over Na2SO4, and concentrated to dryness. The colorless oil was purified using silica gel flash chromatography (DCM/MeOH 96:4). The purified fractions are pooled aind concentrated to dryness. The resulting oil was dissolved in MTBE and washed with water (2X), 2N NaOH, and then brine. The combined organic layers are dried over Na2SO4, filtered and evaporated to afford 64 mg of the desired material as a white foam. ([M+H] = 412.7 m/z). [0108] A sealed tube was charged with compound 5 (223 mg, 0.52 mmol, 1 eq) and DMF (lmL). 2-bromopropane (1.3 g, 10.5 mmol, 20 eq) and Na2CO3 (73 mg, o.68 mmol, 1.3 eq) were added and the flask was sealed and heated to 50 °C. The mixture was stirred for 16 h at which point -70% conversion was observed. Additional (0.26 g, 2.12 mmol, 4 eq) was added. The reaction was stirred for 2 h and additional 2-bromopropane (0.13 g, 1.1 mmol, 2 eq) was added. The reaction was stirred for another lh. The reaction was cooled to rt and water was added. The residue was extracted with MTBE (3X). The organic layers were combined washed with brine, dried over Na2SO4, filtered, and concentrated to dryness. The white foam was purified using silica gel flash chromatography (DCM/MeoH 99:1) to give 2o6 mg of the N-isopropyl derivative as a white foam. [0109] The N-isopropyl derivative (205 mg, o.44 mmol, 1 eq) was dissolved in of 4- methoxypyridine (1.5 mL). The flask was placed under inert atmosphere and Pd/C 1o% (wet, Aldrich Degussa type E1o1, 40 mg) was added. The flask was sealed and purged three times with hydrogen and left 16 h under 1 atm of hydrogen. Celite® was added to the reaction mixture. The mixture was filtered through a small pad of Celite® and washed with EtoAc. The organic layer was washed with 1N HC1 aq. (2x) then with water. The organic layer was dried over Na2SO4, filtered though cotton and evaporated to give 34 mg of crude. The aqueous layer was neutralized with 2N KOH and extracted with DCM (3X). The combined organic layers were washed with water, dried over Na2SO4, filtered though cotton and combined with the initial 34 mg of crude. The crude material was purified using silica gel flash chromatography hexane/EtoAc (6:4) to afford 8o mg of desired product. ([M+H] = 468.7 m/z). [0110] In a round-bottom flask, compound 6 (88 mg, 0.21 mmol, 1 eq) was dissolved in anhydrous THF (1 mL). The mixture was cooled to 0 °C, Pyridine (84 µL, 1 mmol, 5 eq) and benzoylperoxide (150 mg, 0.62 mmol, 3 eq) were added successively. The homogeneous mixture was gradually wanned to rt over 2 h and stirred overnight at rt. The reaction was quenched by adding saturated NaHCO3. The residue was extracted with MTBE. The combined organic layers were washed with water, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude was purified using silica gel flash chromatography (hexane/EtOAc (9:1 to 4:1)) to give the N-o derivative product (6o mg, 0.11 mmol) as a white foam. This foam was dissolved in 2 mL of MeOH followed by 2N aqueous KoH (0.4 mL). The reaction mixture was stirred for 1 h. Most of the MeOH was evaporated under a stream of nitrogen and IN HCl (5oo µL) was added. The material was extracted with DCM (3X). The combined organic layers were washed with water, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude was purified using silica gel flash chromatography (hexanes/EtOAc (from 88:12--1:1)) to yield 11 mg of the desired product. ([M+H] = 442.5 m/z). [0111] In a round bottom flask, compound 6 (89 mg, 0.209 mmol, 1 eq) and N- (benzyloxycarbonyl)-aminoacetaldehyde (148 mg, 0.85 mmol, 4 eq) were dissolved in DCM (2 mL). Sodium triacetoxyborohydride (177 mg, o.85 mmol, 4 eq) was added and the reaction was stirred for 3 h at rt. The mixture was poured in saturated aqueous NaHCO3 solution and the residue was extracted with DCM (3x). The combined organic layers were washed with water, dried over Na2SO4, filtered though cotton and evaporated to give a foamy solid (247 mg). The crude was dissolved in EtoAc (2 mL) and treated with of 4M HC1 (156 µL). After 3o min a white precipitate slowly formed. The resulting slurry was stirred for 15 min. Filtration gave 12o mg of white solid. The material was dissolved in EtOAc and treated with a saturated aqueous NaHCO3 solution. The organic layer was collect and the aqueous layer and was extracted with EtoAc (2X). The combined organic layers were washed with brine, dried over Na2SO4. Filtration and evaporation gave the desired intermediate. This material was used in me next step without purification. Step B [o112] All of the material from Step A was dissolved in EtoAc (3 mL) and treated with of Pd/C 1o% (3o mg , wet,Aldrich Degussa type E1o1). The flask was sealed and purged three times with hydrogen and left overnight under 1 atm of hydrogen. After 16 h, the mixture was filtered through a small pad of Celite® and washed with EtoAc to afford 52 mg of the amine as a white foam. [0113] A round-bottom flask containing the amine 14 (52 mg, o.11 mmol, 1 eq) was charged with the lH-tetrazole-5-acetic acid (21 mg, 0.166 mmol, 1.5 eq), DCM (2 mL), EDCI (42 mg, 0.22 mmol, 2 eq) and N,N-diisopropylethylamine (57 mg, o.44 mmol, 4 eq) The resulting yellow solution was stirred at rt for 4 h. The reaction was quenched by the addition of saturated aqueous NaHCO3 solution and the residue was extracted with DCM (3X). The combined organic layers were dried over Na2SO4, filtered though cotton and evaporated to give 62 mg of off-white solid. This material was purified using silica gel flash chromatography (MeoH/DCM 5:95-> 1o:9o) to afford 31 mg of the desired product. ([M+H] = 579.7 m/z). [0114] A round-bottom flask was charged with starting material (47 mg, 0.110 mmol, 1 eq) and potassium carbonate (150 mg, 1.09 mmol, 10 eq). The solids were suspended in 2 mL of DCM. Iodometfiane (14 µL, o.22 mmol, 2 eq) was added and the mixture was stirred for 2 at rt. TLC (DCM/MeoH 95:5) indicate >90% completion. Iodomethane (14 018µL, o.22 mmol, 2 eq) was added to the reaction mixture, which was stirred for 2 h. The reaction mixture was added water. The phases were separated and the organics were dried and concentrated to dryness. The residue was purified using silica gel flash chromatography (DCM/MeoH 1oo:o-98:2) afford 34 mg of the desired product ([M+H] = 44o.5 m/z). [0115] A round-bottom flask was charged with starting material (59 mg, 0.126 mmol, 1 eq) and potassium carbonate (350 mg, 2.5 mmol, 20 eq). The solids were suspended in 3 mL of DCM. The reaction was charged with iodomethane (8o µL, 1.29 mmol, 10 eq) and the mixture was stirred overnight at rt. The reaction mixture was charged with water. The organic phase was separated and the aqueous layer was back extracted with DCM. The combined organic layers were dried and concentrated to dryness. The residue was purified using silica gel flash chromatography. DCM/MeoH (95:5-»90:10) to afford 52 mg of the desired product. ([M+H] = 639.5 m/z). [0116] In a round bottom flask, compound 5 (50 mg, o.12 mmol, 1 eq) and N-(t- butoxycarbonyl)-aminoacetaldehyde (6 mg, 0.38 mmol, 3.1 eq) were dissolved in DCM (2 mL). Sodium triacetoxyborohydride (8 mg, 0.38 mmol, 3.1 eq) was added and the reaction was stirred for 2 h at rt. The mixture was poured in saturated aqueous NaHCO3 solution and the residue was extracted with DCM (3x). The combined organic layers were washed with water, dried over Na2SO4, filtered though cotton and evaporated to give a foamy solid (95 mg). The crude material was purified using silica gel flash chromatography (EtoAc/Hexanes 1:1) to yield 55 mg of compound 18. [0117] A round-bottom flask was charged with starting material 18 (800 mg, 1.4 mmol, 1 eq). Thesolid was dissolved in a solution of DCMand TFA (10mL, 1:1). The solution was stirred for 45 min at rt. The reaction was partitioned between a solution of 10% sodium carbonate and DCM. The organic was separated and washed with 10% sodium carbonate. The organic phase was concentrated to dryness. The residue was used without further purification for the next step. [0118] A round-bottom flask was charged with starting material (300 mg, 0.64 mmol, 1 eq) was dissolved in THF/ACN (1:1,4 mL). The reaction was charged 37% formaldehyde in water (24o µL, 3.22 mmol, 5 eq) and sodium cyanoborohydride (64 mg, 1 mmol, 1.6 eq). The mixture was stirred for 3o min at rt. The reaction was then partitioned between a solution a saturated aqueous solution of sodium bicarbonate and DCM. The organic was separated, dried and concentrated to dryness. The crude material was purified using silica gel flash chromatography (MeoH/DCM 5:95- 10:90) to give the desired material. [0119] A round-bottom flask was charged with starting material 20 (30 mg, 0.06 mmol, 1 eq) and 10% palladium on carbon (30 mg). The solids were suspended in pyridine (2 mL). The suspension was placed under hydrogen atmosphere and the mixture was stirred overnight at rt. The reaction mixture was filtered on Celite® and the filtrate concentrated to dryness. The crude material was purified using silica gel flash chromatography (MeoH/DCM 5:95-10:90) to gave the desired material. ([M+H] = 497.7 m/z). [0120] A round-bottom flask was charged with starting material (85 mg, 0.20 mmol, 1 eq) was dissolved in DCM (4 mL). The reaction was charged with N-(2-oxoethyl)acetamide (80 mg, 0.7o mmol, 3.5 eq) and sodium triacetoxyborohydride (170 mg, 0.80, 4 eq). The mixture was stirred for 1 hour at rt. The reaction was partitioned between a solution a saturated aqueous solution of sodium bicarbonate and DCM. The organic was separated, dried and concentrated to dryness. The crude material was purified using silica gel flash chromatography (MeOH/DCM 5:95) to give the desired material. ([M+H] = 511.7 m/z). [0121] Compound 22 was synthesized according to the procedure described in example 9, using N-methyl-N-(2-oxoethyl)acetarnide in place of N-(2-oxoethyl)acetamide. ([M+H] = 525.7 m/z). [0122] Compound 23 was synthesized according to the procedure described in example 10, using N-(2-oxoethyl)-3-phenylpropanamide in place of N-(2-oxoethyl)acetamide. ([M+H] = 6o1.8 m/z). [0123] Compound 23 was synthesized according to the procedure described in example 10, using N-methyl-N-(2-oxoethyl)-3-phenylpropanamide in place of N-(2- oxoethyl)acetamide. ([M+H] 615.9 m/z) [0124] A round-bottom flask was charged with compound 6 (4.23 g, 9.94 mmol, 1 eq) and THF (6o mL). Triethylamine (6.92 mL, 49.7 mmol, 5.0 eq) and benzyl chloroformate (1.54 mL, 10.93 mmol, 1.1 eq) were added and the mixture was stirred for 1 hour at rt. The reaction mixture was partitioned between saturated aqueous bicarbonate (100 mL) and EtoAc (100 mL). The phases were separated and the organics were dried (Na2SO4) and concentrated to dryness. The crude material was purified using silica gel flash chromatography (EtoAc/Hexanes 2:98-> 14:86) to give 3.75g of material. Step B [0125] A MeoH solution (10 ml) of cerium trichloride heptahydrate (260 mg, 0.69 mmol, 1.3 eq.) at 0 °C was treated with sodium borohydride (24 mg, 0.65 mmol, 1.2 eq), stirred for 15 min, and then cooled to -78 °C. A THF solution (10 ml) of ketone 26 (300 mg, 0.54 mmol, 1 eq) was added, and the mixture was stirred for 1 h and then warmed to rt. Water (50 ml) and EtoAc (50 ml) were added, mixed, and the layers split. The organic layer was collected, washed with brine (30 ml), dried over sodium sulfate, and concentrated to a white residue. The crude product was purified by silica gel flash chromatography (ether/hexanes 2:3-1:1) to give 235 mg of 3-beta alcohol 27. [0126] Compound 27 (235 mg, 0.42 mmol, 1 eq) was dissolved in EtOAc (7 ml) in a flask with stir bar and rubber septum. The solution was sparged with nitrogen, and Pd/C 10% (wet,Aldrich Degussa type E101, 50 mg) was added. This mixture was sparged with nitrogen and then hydrogen gas and stirred at rt for 3h. The mixture was then sparged with nitrogen, filtered through a o.45 µm polyethylene membrane and concentrated to a clear oil. The oil was purified by silica gel flash chromatography (NH4OH(aq)/MeOH/DCM 0.5:2:97.5-0.5:6:93.5) to give 130 mg of compound 25 as a white powder. ([M+H] = 427.4 m/z) [0127] A THF solution (10 ml) of ketone 26 (300 mg, 0.54 mmol, 1 eq) at -78 °C was treated with K-Selectride® (Potassium tri-sec-butylborohydride) (0.58 ml, 0.58 mmol, 1.1 eq) and stirred for 60 min. Methanol (1 ml) was added and the solution warmed to rt. Water (50 ml) and EtoAc (50 ml) were added, mixed, and the layers split. The organic layer was washed with brine (30 ml), dried over sodium sulfate, and concentrated to a white residue. The crude product was purified by silica gel flash chromatography (Ether/Hexanes 2:3-1:14) to give 170 mg of pure 3-alpha alcohol 29. [0128] Compound 29 (170 mg, 0.30 mmol, 1 eq) was dissolved in EtoAc (5 ml) in a flask with stir bar and rubber septum. The solution was sparged with nitrogen, and Pd/C 10% (wet, Aldrich Degussa type E101, 35 mg) was added. This mixture was sparged with nitrogen and then hydrogen gas and stirred at rt for 3h. The mixture was then sparged with nitrogen, filtered through a o.45 µm polyethylene membrane and concentrated to a clear oil. The oil was purified by silica gel flash chromatography (NH4OH(aq)/MeOH/DCM 0.5:2:97.5-o.5:6:93.5) to afford 76 mg of compound 28 as a white powder ([M+H] = 427.4 rh/z). [0129] Compound 27 (1oo mg, 0.18 mmol, 1 eq) with benzyltriethylammonium chloride (8 mg, o.36 mmol, 0.2 eq) was dissolved in DCM (5 ml) and stirred vigorously with dimethyl sulfate (130 µL, 1.43 mmol, 8 eq) and 5o% aqueous potassium hydroxide (o.5 ml) at rt for 18h. The mixture was partitioned between water (3o ml) and EtoAc (3o ml), and the organic layer was men washed with brine, dried over sodium sulfate, and concentrated to a clear oil. The crude ether was purified by silica gel flash chromatography (Ether/Hexanes 3:7-9:113) to give 75 mg of me methyl ether as a clear oil. [0130] Compound 31 (66 mg, o.115 mmol, 1 eq) was dissolved in EtoAc (5 ml) in a flask with stir bar and rubber septum. The solution was sparged with nitrogen, and Pd/C 10% (wet, Aldrich Degussa type E1o1, 20 mg) was added. This mixture was sparged with nitrogen and then hydrogen gas and stirred at rt for 3h. The mixture was then sparged with nitrogen, filtered mrough a o.45 µm polyethylene membrane and concentrated to a clear oil. The oil was purified by silica gel flash chromatography (NH4OH(aq)/MeoH/DCM G.5:2:97.5-0.5:6:93.5) to give 22 mg of compound 3o as a white powder ([M+H] = 441.4 m/z). [0131] Compound 27 (100 mg, 0.18 mmol, 1 eq) was dissolved in DCM (5 ml), and 4- dimethylaminopyridine (4 mg, o.35 mmol, o.2 eq), N,N-diisopropylethylamine (0.15 ml, 0.9 mmol, 5 eq), and acetic anhydride (0.070 ml, 0.72 mmol, 4 eq) were added. After stirring for 12h at rt, the solution was split between EtoAc (30 ml) and 5% aqueous sodium bicarbonate (15 ml). The organic layer was washed with brine, dried over sodium sulfate, and concentrated to a clear oil. The crude ester was purified by silica gel chromatography (Ether/Hexanes 3:7-9:113) to give 1oo mg of the ester as a clear oil. [0132] Compound 33 (1oo mg, 0.18 mmol, 1 eq) was dissolved in EtoAc (5 ml) in a flask with stir bar and rubber septum. The solution was sparged with nitrogen, and Pd/C 10% (wet, Aldrich Degussa type E101, 20 mg) was added. This mixture was sparged with nitrogen and then hydrogen gas and stirred at rt for 3h. The mixture was then sparged with nitrogen, filtered through a 0.45 p.m polyethylene membrane and concentrated to a clear oil. The oil was purified by silica gel flash chromatography (NH4OH(aq)/MeOH/DCM 0.5:2:97.5-0.5:6:93.5) to give 45 mg of compound 32 as a white powder ([M+H] = 469.4 m/z). [0133] Compound 34 was synthesized according to the procedure described in example 16, using compound 29 in place of compound 27. ([M+H ] = 441.4 m/z). [0134] Compound 34 was synthesized according to the procedure described in example 17, using compound 29 in place of compound 27. MS ([M+H] = 469.4 m/z) [0135] An ethanol solution (5 ml) of compound 26 (185 mg, 0.3 mmol, 1 eq) was treated with hydroxylamine hydrochloride (140 mg, 2 mmol. 6 eq), sodium acetate (160 mg, 2 mmol, 6 eq), and water (0.5 mL), and the mixture was stirred at rt for 1 hr. The mixture was split between EtoAc and water (50 mL each). The organic layer was washed with brine (30 mL), dried over sodium sulfate, and concentrated to a white residue. The crude product was purified by silica gel chromatography (ether/hexanes 2:3->1:1) to give 193 mg of oxime 37. [0136] Compound 37 (65 mg, 0.113 mmol) was dissolved in EtoAc (7 ml) in a flask with stir bar and rubber septum. The solution was sparged with nitrogen, and Pd/C 10% (wet.Aldrich Degussa type E101, 20 mg) was added. This mixture was sparged with nitrogen and then hydrogen gas and stirred at rt for 3h. The mixture was then sparged with nitrogen, filtered through a 0.45 µm polyethylene membrane and concentrated to a clear oil. The oil was purified by silica gel flash chromatography (NH4OH(aq)/MeOH/DCM 0.5:2:97.5->0.5:6:93.5) to give 15 mg of compound 36 as a white powder, a mixture of cis and trans oxime isomers ([M+H] = 440.3 m/z). [0137] Compound 27 (42 mg, 0.075 mmol, 1 eq) was dissolved in DCM (5 ml), and 4- dimethylaminopyridine (2 mg, 0.02 mmol, 0.2 eq), N-Cbz glycine (23 mg, 0.110 mmol, 1.5 eq), and diisopropylcarbodiimide (0.023 ml, 0.150 mmol, 2 eq) were added. After stirring for 12h at rt, the solution was split between EtoAc (30 ml) and 5% aqueous sodium bicarbonate (15 ml). The organic layer was washed with brine, dried over sodium sulfate, and concentrated to a clear oil. The crude ester was purified by silica gel flash chromatography (ether/hexanes 2:3 - 1:1) to give 35 mg of the ester as a clear oil [0138] Compound 39 (235 mg, o.42 mmol, 1 eq) was dissolved in EtoAc (7 mL) in a flask with stir bar and rubber septum. The solution was sparged with nitrogen, and Pd/C10% (wet.Aldrich Degussa type E1o1, 50 mg) was added. This mixture was sparged with nitrogen and then hydrogen gas and stirred at rt for 3h. The mixture was then sparged with nitrogen, filtered through a o.45 µm polyethylene membrane and concentrated to a clear oil. The oil was purified by silica gel flash chromatography (NH4OH(aq)/MeOH/DCM 0.5:2:97.5-0.5:6:93.5) to give 17 mg of the desire product as a white powder ([M+H] = 452.4 m/z). [0139] Compound 4o was synthesized according to the procedure described in example 21, using compound 29 in place of compound 27. ([M+H] = 452.4 m/z) [0140] Compound 41 was synthesized according to the procedure described in example 1o, using N-(2-oxoethyl)-2-phenylacetamide in place of N-(2-oxoethyl)acetamide. ([M+H] = 587.7 m/z). [0141] A round-bottom flask was charged with alcohol 29 (7.60 g, 13.53 mmol, 1 eq) and was dissolved in DCM (115 mL). The reaction was charged with triethylamine (8.21 g, 81 mmol, 6.0 eq). The mixture was cooled to 0° C and charged with methanesulfonylchloride (1.86 g, 16.2 mmol, 1.2 eq). After 3o min, the reaction mixture was partitioned between a saturated aqueous solution of sodium bicarbonate and EtoAc. The organic layer was separated, dried over sodium sulfate and concentrated to dryness. The residue was purified using silica gel flash chromatography (EtOAc/hexanes 1o -> 25%) gave the desired material mesylate. [0142] A round-bottom flask was charged with the mesylate (9.1 g, 14.22 mmol, 1 eq) and was dissolved in 50 mL of DMPU. The reaction was charged with sodium azide (4.62 g, 71.1 mmol, 5.0 eq) and heated to 60° C. The mixture was stirred for 17 h. The reaction mixture was then cooled to rt and charged with water. The mixture was stirred for 30 min. The mixture was filtered under vacuum, rinsed with water and air dried and used directly without purification in the next step. [0143] A round-bottom flask was charged with azide 43 (8.35 g, 14.23 mmol, 1 eq) and THF (120 mL) was added. The reaction was then charged with triphenylphosphine (11.2 g, 42.7 mmol, 3.0 eq). The mixture was heated to 50°C and stirred for 20 h. The reaction mixture was then cooled to rt and the solvent removed under vacuum. The residue purified using silica gel flash chromatography (MeOH/DCM 1o% -> 20%) to afford the amine. [0144] A round-bottom flask was charged with the amine (5.10 g, 9.09 mmol, 1 eq) and was dissolved in DCM (60 mL). The reaction was charged with N,N- diisopropylethylamine (5.88 g, 45.5 mmol, 5.0 eq). The mixture was cooled to 0°C and charged with memanesulfonylchloride (2.08 g, 18.2 mmol, 2.0 eq). After 30 minutes, the reaction mixture was partitioned between a saturated aqueous solution of sodium bicarbonate and EtOAc. The organic layer was collected, dried over sodium sulfate and concentrated to dryness. The residue was purified using silica gel flash chromatography (EtOAc/hexanes 10 - 30%) to afford the Cbz protected methanesulfonamide. [0145] A round-bottom flask was charged with the Cbz protected methanesulfonamide (5.37 g, 8.41 mmol, 1 eq) and 1o% palladium on carbon (1.0 g). The solids were suspended in 2-propanol (50 mL). The suspension was placed under hydrogen atmosphere and the mixture was stirred for 4 h at 25° C. The reaction mixture was then filtered on Celite® and the filtrate concentrated to dryness. The residue was then purified using silica gel flash chromatography (DCM/MeoH0 -> 5%) to afford the desired product. [M+H] = 505.6 m/z. Alternate Synthesis of Compound 42 [0146] Recrystallized cyclopamine (2.07 g) is charged to an appropriately sized reaction vessel and placed under an inert atmosphere. EtoAc (7.6 g), triethylamine (1.53 g), and DMAP (307 mg) are added sequentially. The suspension is warmed to 40°C. Cbz-OBt is added in three portions over 90 minutes, keeping the internal temperature below 45°C. The reaction mixture is stirred at 40°C for 90 minutes. The temperature is maintained while methanol (26.4 g) is slowly added to the reaction mixture. The resulting suspension is cooled to room temperature and stirred for at least 15 hours. The crude product is collected by filtration and rinsed with methanol (5 g). The white solid is dried under vacuum to a constant weight and recrystallized from heptane (30.3 g) and toluene (3.2 g) to afford Compound 24a (3.0 g). [0147] Solid bis(2,6-dimethylphenyl) hydrogenphosphate and 24a are pre-dried and placed under a nitrogen atmosphere. Neat diethyl zinc (722 mg) is charged to an appropriately sized reaction vessel containing DCM (9.0 g). DCM solutions of the phosphate (1.83 g in 17.9 g) and IPI-332690 (1.34 g in 3.6 g) are added sequentially at or below 25 °C. Diiodomethane (1.58 g) is charged and the reaction is stirred at 28°C for 4-6 hours. The reaction is cooled to -45°C and a solution of methanesulfonic acid in DCM (566 mg in 1.5 g) is charged. After 15 minutes, morpholine (1.711 g) is added and the mixture is allowed to warm to room temperature overnight. The organic layer is washed twice with 2N HC1 (2 x 13.6 g) then sequentially with 4.8 wt % sodium carbonate (aq), 4.8 wt% sodium sulfite (aq), and 4.8 wt% brine (13.6 g each). The organic layer is dried, filtered, concentrated to 4 g and diluted with isopropanol (4 g). The product is crystallized from solution by the slow addition of methanol (9.3 g). Filtration with a methanol rinse (2.6 g) and drying afford 1.o9 g of 24b (79% isolated yield). [0148] Johnson Matthey Pd/C catalyst A-3o5o38-5 (890 mg) is charged to an appropriately sized reaction vessel, followed by 24b (2.24 g). The reaction vessel is purged with N2 and toluene (21.8 g) and 2-propanol (6.7 g) are added sequentially. The system is degassed and placed under a nitrogen atmosphere, and the process is repeated with hydrogen. The system is stirred vigorously and the hydrogen blanket is maintained at one atmosphere for 4-5 hours. The reaction is monitor by either TLC or HPLC. If incomplete, the reaction is inerted, additional catalyst (145 mg) is charged, and the hydrogen atmosphere is returned for another hour. Ethylenediamine (12.9 mg) is charged and the mixture was stirred for 15 minutes. The catalyst is removed by filtration with a toluene:IPA (3:1) rinse. The filtrate and rinses are concentrated and solvent exchanged to toluene. The product is crystallized from toluene (19.0 g) and heptane (18.0 g) to afford 24c as a white crystalline solid (1.34 g, 98% yield). [0149] 24c (644 mg) is charged to an appropriately sized reaction vessel followed by aluminum t-butoxide (525 mg), toluene (8.34 g, 15 vol), and 2-butanone (7.83 g, 15 vol). The contents of the flask are degassed with evacuation/nitrogen purge cycles to remove oxygen and the reaction mixture is heated at 75°C with vigorous stirring for 16-18 hours. The reaction is quenched by the addition of aqueous Rochelle's salt (2.6 g in 10.3 g water) and the mixture vigorously stirred for one hour at 45 °C. The aqueous and organic layers are separated. The aqueous layer is back extracted with a mixture of toluene (2.9 g) and EtoAc (2.9 g). The organic layers are combined and washed with fresh Rochelle's salt solution (2.6 g in 10.3 g water) and then with water (12.9 g). The resulting organic layer is dried over sodium sulfate (1.97 g), filtered, and concentrated in vacuo. The product is crystallized via a charge and concentration solvent exchange first to IRA (6.5 g) and then Heptane (7.7 g). The thick heptane slurry (-2.7 g) is stirred overnight and solids are collected by filtration. Vacuum drying affords 24d (550 mg) in an 85% yield. [0150] The enone 24d (459 mg) and Johnson-Matthey 5% palladium on carbon (A503023-5, 1o1 mg) are charged to an appropriately sized multi neck reaction vessel. The vessel is purged with nitrogen and 3-picoline (2.2 g) is charged as the solvent. Stirring is started and the vessel is first degassed using nitrogen and men stirred under hydrogen at atmospheric pressure for 8 hours. At the end of the reaction, the catalyst is removed by filtration through o.2 micron media, rinsing with ACN (1.4 ml). The filtrate and rinse are combined in a clean reaction vessel equipped with mechanical stirring, an internal temperature probe, and a nitrogen atmosphere. A solution of citric acid (3.7 g) in water (9.2 ml) is charged to the reaction vessel at or below 30°C, and IPI-335589 is allowed to slowly crystallize from solution as the citrate salt at 20 and then 0°C. The crystalline product is recovered by suction filtration and washed with water (3.7 ml). After drying, the citrate salt, 24e, is isolated as a hydrate (3-5 wt% water) in 89.5% yield (622 mg) with a β:α ratio approaching 90:1. [0151] 24e (1.50 g) is charged to the appropriately sized reactor along with 2- methyltetrahydrofuran (7.7 g) and 1M sodium carbonate (9.0 ml) A solution of benzyl chloroformate (454 mg) in 2-methyltetrahydrofuran (300 mg) is added via addition funnel and the reaction is ambient temperature for 1-2 hours. When the reaction is complete, the stirring is stopped, the layers are separated and the organic layer is washed twice with water (2 x 6 g). The organic layer is dried over of sodium sulfate (3 g), filtered and concentrated. Residual water is reduced further by concentration from fresh 2-methyltetrahydrofuran (6.5 g) and the material is transferred as solution in anhydrous 2-methyltetrahydrofuran to the next reaction. [0152] Commercial 1 M K-Selectride in THF (1.20 g) is charged to a dry reaction vessel under a nitrogen atmosphere, diluted with anhydrous 2-methyltetrahydrofuran (2.10 g) and cooled to -65°C. The solution of 24f (o.41 g) in 2-methyltetrahydrofuran (1.5 g), is then slowly added to the reaction vessel to control the internal temperature at -65±5°C. The reaction is stirred for 2 hours and warmed to -20°C over approximately 1 hour and stirred for an additional hour. The reaction is monitored by HPLC and reactions that are incomplete are driven to completion with additional K-selectride. The reaction is quenched at low temperature with MeOH (0.33 g), then 3M NaOH (2.4 g) at -20°C and 15% hydrogen peroxide in water (1.04 g) at or below 5°C, then stirring overnight at ambient temperatures. The layers are split and the organic layer is washed sequentially with 1M aqueous NaoH (2 ml), o.5 M aqueous Na2SO3 (2 ml), and water (2 ml) adjusted to a pH of 3 with HC1. The organic layer is dried over sodium sulfate (0.82 g), filtered and concentrated. The product 24g (0.457 g) is re-concentrated from DCM (0.9 g) and used in the next reaction. [0153] 24g (1.36 g) is charged with anhydrous DCM (18.1 g) to an appropriately size reaction vessel, place under an inert atmosphere and cooled to -20°C. Triethylamine (0.61 mg) is charged followed by the slow addition of methanesulfonyl chloride (373 mg) in anhydrous DCM (300 mg). The reaction is stirred for 1 hour at -20°C. The reaction is monitored by HPLC. Incomplete reactions are driven to completion with additional methanesulfonyl Chloride. When complete, the reaction is quenched with water (13.6 g) and allowed to warm. The layers are separated and the organic layer is washed with 2.5 wt% sodium bicarbonate (13.8 g) and then water (10.9 g). The organic layer is dried over of sodium sulfate (4 g), filtered, and concentrated. The product solution is solvent exchanged via charge and concentration to t-butyl methyl ether (10.9 ml) and then l,3-dimethyl-3,4,5,6-tetrahydro- 2(lH)-pyrirnidinone (DMPU, 4.7 ml). The DMPU solution is used directly in the next reaction. [0154] Sodium azide (0.74 g) is charged to an appropriately sized reaction vessel. The solution of 24h (1.46 g) in DMPU (5.9 g) is charged to the reaction vessel, rinsing with additional DMPU (1.9 g). The suspension is heated to 60°C for 15 hours, maintaining a nitrogen sweep for the entire reaction. The reaction is cooled to ambient temperature and diluted with MTBE (11.7 g). The organic solution is washed 3 times with 2% saline (3 x 8 g), dried over sodium sulfate (4.4 g), filtered, and concentrated. The product is concentrated from THF (6.4 g) and used directly in the next reaction. [0155] The crude 24i (1.34 g) is dissolved and transferred to a suitably sized reaction vessel with THF (12.6 g). Triphenylphosphine (0.70 g) and water (0.44 g) are charged and the reaction is heated to 55°C for 15-24 hours. When complete, the reaction is cooled to ambient temperature, dried with magnesium sulfate (1.4 g), filtered and concentrated. The solids are dissolved and concentrated from three portions of DCM (3 x 9 g) and purified by silica gel chromatography using DCM/MeoH/Et3N gradients to remove reagent based impurities. The pooled fractions are concentrated to dryness, dissolved in DCM (6.8 g) and concentrated to dryness again to afford an amorphous solid (1.12 g) which is used in the next reaction. [0156] 24j (1.09 g) is dissolved and transferred to an appropriately sized reaction vessel with anhydrous DCM (15.8 g) and placed under a nitrogen atmosphere. The solution is cooled to 0°C. N,N-diisopropylethylamine (357 mg) and neat methanesulfonyl chloride (0.165 ml) are charged sequentially while maintaining temperature between below 5 °C. The reaction is monitored by HPLC. Incomplete reactions are driven to completion with additional methanesulfonyl chloride. The reaction is quenched with 0.4 M aqueous sodium bicarbonate (11.4 g) and wanned to ambient temperature. The layers are separated and the aqueous phase is back extracted with DCM (5.8 g). The combined organic layers are dried over magnesium sulfate (0.55 g), filtered and concentrated. The product 24k is dissolved and striped from 2- propanol (4.0 g) to remove residual DCM and used directly in the next reaction. [0157] Aldrich Degussa type E1o1 NE/W 10% Pd/C (249 mg) is charged to an appropriately sized reaction vessel and placed under a nitrogen atmosphere. A 2-propanol (9.8 g) solution of 24k (1.24 g) is charged to the reaction vessel. The system is degassed and placed under a nitrogen atmosphere, and the process is repeated with hydrogen. The reaction is stirred under a 1 atm of hydrogen at ambient temperature for 8 hours. An inert atmosphere is returned to the vessel and a second charge of catalyst (125 mg) slurried in 2-propanol (0.5 g) is added to the reaction. The reaction mixture is degassed and placed under a nitrogen atmosphere, and the process is repeated with hydrogen. The reaction is stirred under 1 atm of hydrogen for another 15 hours at ambient temperature. The reaction is monitored by HPLC. Incomplete reactions are treated with additional catalyst and hydrogen. When complete, the reaction is filtered, treated witfi steam activated carbon (200 mg), and filtered again. The solution is dried by partial concentration transferred to a reaction vessel and diluted with anhydrous 2-propanol to 0.09 M based on the theoretical yield. A 1.25 M HC1 solution in 2- propanol (1.64 g) is charged over 20 minutes. The hydrochloride salt crystallizes slowly with gentle stirring and is isolated by filtration. The crystals are washed with 2-propanol (2.5 g) and vacuum dried to afford Compound 42 (916 mg, 80% yield) as a 1:1 IPA solvate. [0158] A round-bottom flask was charged with the amine 42 (1.1 g, 2.1 mmol, 1 equiv.), dry tetrahydrofuran (10 ml) and pyridine (88o µL, 10.9 mmol, 5 equiv.). The cooled (0°C) mixture was treated with benzoylperoxide (1.6 g, 6.5 mmol, 3 equiv.). The mixture was stirred for 2 hours at 0°C then overnight at 25°C. Reaction mixture diluted with MTBE and washed with a mixture of saturated aqueous NaHCO3 with 1 N NaoH until the layer split. The organic layer was collected and the aqueous was re-extracted once with MTBE. Combined organic layers were washed with brine, dry over Na2SO4, filtered and concentrated to dryness. The crude oil was dissolved in 5 mL of CH2Cl2, loaded onto SiO2 (4o g) column and eluted from hexanes/EtoAc (10% to 50%) to give the benzoyl derivative 48 (380 mg) ([M+H] = 625.4 m/z). Step B [0159] A round-bottom flask was charged with 48 (374 mg, 0.6 mmol, 1 equiv.) and MeoH (5 mL). The solution was treated at 25°C in presence of 2 N KoH (0.3 mL, 0.6 mmol, 1 equiv.). The mixture was stirred for 3h. The solvent was removed under vacuum. MTBE was added to the residue, which was neutralized with IN HCl. The layers were cut and the aqueous layer was extracted with two portions of CH2Cl2. Combined organic layers were dried over Na2SO4, filtered, and concentrated to dryness. The crude material (380 mg) was dissolved with CH2Cl2, loaded onto a SiO2 column (12 g) and eluted with hexanes/EtoAc (0% to 1oo%) to give the hydroxylamine 47. The material was lyophilized from t-BuOH/7% H2O to give 213 mg of 47 as a white powder ([M+H] = 521.4 m/z). 50 [0160] A heat-gun dried flask was charged with dry CH2Cl2 (5 mL) and benzyl alcohol (785 uL, 7.58 mmol, 1.3 equiv.). The cooled (0°C) solution was treated with chlorosulfonyl isocyanate (506 uL, 5.83 mmol, 1 equiv.). Then, DMAP (1.4 g, 11.6 mmol, 2 equiv.) was added and the mixture was stirred for 1 h at 25°C. After complete dissolution of DMAP, the reaction was clear for a short period. Then, a white fluffy precipitate formed. The mixture was diluted with CH2Cl2 (30 mL) and washed with three portions (30 mL each) of water. The organic layer was dried over Na2SO4, filtered, and evaporated to dryness. The desired white solid 51 was taken to the next step without purification. StepB [0161] A round-bottom flask was charged with 52 (30 mg, 0.053 mmol, 1 equiv.) and 51 (18 mg, 0.053 mmol, 1 equiv.). Both reagents were dissolved in CH2Cl2 (2 mL) and the solution was stirred at 25°C. The crude material was loaded onto a SiO2 column (4 g) and eluted with hexanes/EtOAc (0% to 50%) to give 16 mg of the sulfamoylated derivative 53 ([M+Na] = 796.4 m/z). [0162] A round-bottom flask was charged with 53 (16 mg, 0.021 mmol, 1 equiv.) and 11 mg of 10% Pd/C (wet,Aldrich Degussa type E101). The material was suspended in 2- propanol (3 mL). The flask was sealed and purged three times with hydrogen and left overnight under 1 atm of hydrogen. The slurry was filtered through 0.2 micron Acrodisc, washed with 2-propanol, and the solvent was removed under vacuum. The residue was purification by SiO2 column (1 g) eluting with CH2Cl2/MeOH (5% to 10%). The major product was lyophilized from t-BuOH/7% H2O to give 9 mg of sulfamide 50 ([M+H] = 506.4 m/z). [0163] A round-bottom flask was charged with cyclopamine 4-en-3-one (3.5 g, 8.5 mmol, 1 equiv.) and pyridine (70 mL). The reactor was charged with Pd/C (10% Pd, 500 mg). The reaction was placed under 1 atmosphere of hydrogen. After 3.5 hrs, LCMS showed complete consumption of starting material. The catalyst was filtered off on an Acrodisk 0.2 micron filter and washed with toluene. The solvent was removed by azeotropic removal with toluene (2 x 10 mL). The desired material 56, 3.5 g ([M+H] = 412.5 m/z) was used as it for the next step. [0164] A round-bottom flask was charged with 56 (1.2 g, 2.8 mmol, 1 equiv.), CH2Cl2 (10 mL) and triethylamine (1.9 mL, 14.2 mmol, 5 equiv.). The cooled (0°C) solution was treated with CBz-Cl (440 uL, 2.8 mmol, 1 equiv.). After 1 hr, LCMS showed complete consumption of starting material. The mixture was diluted with water. The layers were cut and the organic layer was washed twice with water. The organic layer was dried over sodium sulfate, filtered, and concentrated to dryness. The product was purified by column chromatography (SiO2, 40 g) eluting with hexane/EtOAc (0 to 20%) to give 57 (891 mg) ([M+Na] = 468.4 m/z). [0165] In a round-bottom flask, the ketone 57 was azeotroped a couple times with CH2Cl2 and dried under vacuum for 1 h. Under nitrogen, the ketone 2 (693 mg, 1.27 mmol, 1 equiv.) was dissolved in anhydrous THF (20 mL) and the solution was cooled to -78C. A1M solution of K-selectride in THF (1.9 mL, 1.9 mmol, 1.5 equiv.) was added dropwise. After 1 h, the reaction was complete by TLC. The reaction was quenched by addition of 2.6 mL of 5 N NaOH followed by slow addition of 2.6 mL of 30% wt H2O2. The resulting mixture was allowed to stir overnight. The mixture was partitioned between water and EtOAc. The aqueous layer was back extracted with EtOAc. The combined organic were washed first with water (buffered with a small portion of ammonium chloride) then with brine. The organic were dried, filtered, and concentrated to a crude foam (840 mg) The crude material was dissolved in CH2Cl2, loaded on a SiO2 column (40g) and eluted with hexanes/EtOAc (0 to 50%) to give 58 (565 mg). 58 59 [0166] In a round-bottom flask under nitrogen, the alcohol 58 (530 mg, 0.98 mmol, 1 equiv.) was dissolved in 5 mL of anhydrous CH2Cl2 and triethylamine (800 uL, 5.81 mmol, 6 equiv.). The reaction mixture was cooled to 0°C and Ms-Cl (112 uL, 1.45 mmol, 1.5 equiv) was added dropwise. The mixture was stirred at 0°C for 30 min. TLC (hexane: EtOAC, 7:3) showed ~ 70% conversion. 70 uL of triethylamine (70 uL, 0.5 equiv.) and Ms-Cl (10 uL, 0.1 equiv) were charged to the reaction vessel. After 90 min, a solution of saturated bicarbonate was charged and me residue was extracted with CH2Cl2. The organic layer was washed with water, dried and concentrated to a off-white foam. The material was dissolved in CH2Cl2 and purified with SiO2 (40 g) eluting with hexanes/EtOAc (0% to 50%) to give 59 (430 mg). [0167] In a round-bottom flask, the mesylate 59 (420 mg, 0.67 mmol, 1 equiv.) was dissolved in 2 mL of DMPU. The solution was treated with sodium azide (218 mg, 3.4 mmol, 5 equiv.) at 60°C for 5 h. The mixture was cooled to 25°C, then poured into ice-water to generate a white solid. The compound was extracted with MTBE (3 times). The combined organic layers were washed with water (2X), men brine. The organic layers were dried over Na2SO4, filtered, and concentrated to a white foam (342 mg). The desired material 60 was used as is for the next step. [0168] In a round-bottom flask equipped with a condenser, the azide 60 (336 mg, 0.58 mmol, 1 equiv.) was dissolved in 7 mL of THF and 140 uL of water and treated with triphenylphosphine (462 mg, 1.76 mmol, 3 equiv.). The mixture was heated to 70°C overnight. TLC (hexane/EtOAc, 7:3) confirmed the reaction was complete. The reaction was concentrated to dryness. The crude material was dissolved in CH2Cl2, loaded onto 12 g of SiO2 and eluted with CH2Cl2/MeOH (0 to 20%) to give the amine 61 (254 mg). [0169] In a round-bottom flask under nitrogen, the amine 61 (248 mg, 0.45 mmol, 1 equiv.) was dissolved in 7 mL of anhydrous CH2Cl2 and N,N-diisopropylethylamine (237 uL, 0.91 mmol, 2 equiv.). The reaction mixture was cooled to 0°C and Ms-Cl (70 uL, 1.45 mmol, 1.5 equiv) was added dropwise. The mixture was stirred at 0°C for 2 h. TLC (hexane/EtOAc, 7:3) showed a little amount of amine. The mixture was charged with 10 uL of Ms-Cl (0.2 equiv.), and warmed to 25°C for 1h. The reaction mixture was diluted with CH2Cl2 then a saturated solution of NaHCO3. The layers were cut. The aqueous layer was extracted with one portion of CH2Cl2. The combined organic layers were washed with water, dried over Na2SO4, filtered and concentrated to dryness. The crude (326 mg) was added to a SiO2 column (12 g) and was eluted with hexanes/EtoAc (0 to 50%) to give the sulfonamide 62 (256 mg). [0170] A round-bottom flask was charged with the sulfonamide 62 (250 mg, o.4 mmol, 1 equiv.) and 50 mg of 1o% Pd/C (wet,Aldrich Degussa type E101 lot 08331KC). The material was suspended in EtoAc (5 mL). The flask was sealed and purged three times with hydrogen and stirred under 1 atm of hydrogen. After 3 h some conversion was observed, but a lot of starting material remained. The slurry was filtered through 0.2 micron Acrodisc, washed with 2-propanol. The filtrate solution was re-subjected to the reaction condition by adding 54 mg of catalyst. The reaction was completed after 3 h. The slurry was filtered through 0.2 micron Acrodisc, washed with 2-propanol, and the solvent was concentrated to dryness. The crude material (200 mg) was loaded onto a SiO2 column (12 g) and the compound was eluted using a gradient CF2Cl2/MeOH (o to 1o%) to give the free amine. The material was lyophilized from t-BuoH/7% H2O to give 175 mg of 55 as a white powder ([M+H] = 491.3 m/z). Example 28: Inhibition of the Hedgehog pathway in cell culture [0171] Hedgehog pathway specific cancer cell killing effects may be ascertained using the following assay. C3H10T1/2 cells differentiate into osteoblasts when contacted with the sonic hedgehog peptide (Shh-N). Upon differentiation; these osteoblasts 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 the differentiation of C3H10T1/2 into osteoblasts (a Shh dependent event) can therefore be identified by a reduction in AP production (van der Horst et al, 2003 Bone 33: 899). The assay details are described below. The results approximate (EC50 for inhibition) of the differentiation assay is shown below in Table 1. Assay Protocol Cell Culture [0172] Mouse embryonic mesoderm fibroblasts C3H10T1/2 cells (obtained from ATCC) were cultured in Basal MEM Media (Gibco/Invitrogen) supplemented with 10% heat inactivated FBS (Hyclone), 50 units/ml penicillin and 50ug/ml streptomycin (Gibco/Invitrogen) at 37C with 5% C02 in air atmosphere. Alkaline Phosphatase Assay [0173] C3H10T1/2 cells were plated in 96 wells with a density of 8xl03 cells/well. Cells were grown to confluence (72hrs). After sonic Hedgehog (250ng/ml), and/or compound treatment, the cells were lysed in 110 µL of lysis buffer (50 mM Tris pH 7.4,0.1% TritonXl00), plates were sonicated and lysates spun through 0.2 µm PVDF plates (Corning). 40 µL of lysates was assayed for AP activity in alkaline buffer solution (Sigma) containing l mg/ml p-Nitrophenyl Phosphate. After incubating for 30 min at 37 °C, the plates were read on an Envision plate reader at 405 nm. Total protein was quantified with a BCA protein assay kit from Pierce according to manufacturer's instructions. AP activity was normalized against total protein. Note that "A" indicates that the IC50 is less than 20 nM, "B" indicates that the IC50is 20-100 nM, "C" indicates that the IC50is > 100 nM. Examples 29: Pancreatic Cancer Model [0174] The activity of Compound 42 was tested in a human pancreatic model: BXPC-3 cells were implanted subcutaneously into the flanks of the right legs of mice. On day 42 post-tumor implant, the mice were randomized into two groups to receive either Vehicle (30%HPBCD) or Compound 42. Compound 42 was dosed at 40mg/kg/day. After receiving 25 daily doses, Compound 42 statistically reduced tumor volume growth by 40% when compared to the vehicle control (p=0.0309). At the end of the study, the tumors were harvested 4 hours post the last dose to evaluate an on target response by q-RT-PCR analysis of the HH pathway genes. Analysis of human Gli-1 resulted in no modulation. Analysis of murine Gli-1 mRNA levels resulted in a robust down-regulation in the Compound treated group, when compared to the Vehicle treated group. Example 30: Medulloblastoma Model [0175] The activity of Compound 42 was also evaluated in a transgenic mouse model of medulloblastoma. Mice that are heterozygous for loss of function mutations in the tumor suppressors Patched 1 (Ptchl) and Hypermethylated in Cancer (Hicl) develop spontaneous medulloblastoma. Similar to human medulloblastoma, these tumors demonstrate complete promoter hypermethylation of the remaining Hicl allele, as well as loss of expression of the wild type Ptchl allele. When passaged as subcutaneous allografts, these tumors grow aggressively and are Hedgehog pathway-dependent. This model was employed to evaluate the efficacy of orally administered Compound, and to correlate activity with drug exposure in plasma and tumors. Oral administration (PO) of a single dose of Compound 42 led to dose-dependent down-regulation of the HH pathway in subcutaneously implanted tumors, as measured by decreased Gli-1 mRNA expression 8 hours post dose administration. [0176] Daily (QD) administration of the Compound PO led to a dose dependent inhibition of tumor growth, with frank tumor regression seen at higher doses. The approximate effective daily oral dose for 50% inhibition of tumor growth (ED50) is 4mg/kg. When animals were treated QD for 21 days, long term survival was observed following cessation of treatment (>60 days), with little to no tumor re-growth. Example 31: Lung Cancer Model [0177] To test the activity of Compound 42 in a human SCLC tumor model, LX22 cells were implanted subcutaneously into the flank of the right leg. LX22 is primary xenograft model of SCLC derived from chemo -naive patients, which has been maintained by mouse to mouse passaging. This tumor responds to etoposide/carboplatin chemotherapy in way that closely resembles a clinical setting. LX22 regresses during chemotherapy treatment, goes through a period of remission, and then begins to recur. In the LX22 model, Compound single agent activity and its ability to modulate the chemoresistant recurrence was tested. On day 32 post tumor implant, mice were randomized into three dosing groups to receive Vehicle (30% HBPCD), Compound, or the chemotherapy combination of etoposide and carboplatin (E/P). Compound 42 was administered at a dose of 40mg/kg/day, and after 16 consecutive doses mere was no measurable difference between the treated and vehicle groups. Etoposide was administered i.v at 12mg/kg on days 34, 35, 36, and 48, while Carboplatin was administered i.v. at 60mg/kg on days 34, 41, and 48, post tumor implant. On day 50, the E/P treated mice were further randomized to receive either Vehicle (30%HPBCD) or Compound follow up treatment. The Compound was administered at the oral multi-dose MTD of 40mg/kg/day, and after 35 consecutive doses there was a substantial delay in tumor recurrence in the treated group, compared to the vehicle group (p=0.0101). Incorporation by Reference [0178] All of the U.S. patents and U.S. published patent applications cited herein are hereby incorporated by reference. Equivalents [0179] Those skilled in the art will recognize, or be able to ascertain 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. 1. A compound represented by the following structure: or a pharmaceutically acceptable salt thereof; wherein R1 is H, alkyl, -OR, amino, sulfonamido sulfamido, -OC(O)R5, - N(R5)C(O)R5, or a sugar; R2 is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, nitrile, or heterocycloalkyl; or R1 and R2 taken together form =O, =S, =N(OR), =N(R), =N(NR2), or =C(R)2; R3 is H, alkyl, alkenyl, or alkynyl; R4 is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl, haloalkyl, -OR5, -C(O)R5, -CO2R5, -SO2R5, -C(O)N(R5)(R5), -[C(R)2]q-R5, -[(W)-N(R)C(O)]qR5, -[(W)-C(O)]qR5, -[(W)-C(O)O]qR5, -[(W)-OC(O)]qR5, -[(W)-SO2]qR5, -[(W)-N(R5)SO2]qR5, -[(W)-C(O)N(R5)]qR5, -[(W)-O]qR5, -[(W)-N(R)]qR5, -W-NR53+Xor -[(W)-S]qR5; wherein each W is, independently, a diradical; each q is independently for each occurrence 1, 2, 3,4, 5, or 6; X is a halide; each R5 is, independently, H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl or -[C(R)2]P-R6; wherein p is o-6; or any two occurrences of R5 on the same substituent can be taken together to form a 4-8 membered optionally substituted ring which contains o-3 heteroatoms selected from N, o, S, and P; each R6 is independently hydroxyl, -N(R)COR, -N(R)C(O)OR, -N(R)SO2(R), -C(O)N(R)2, -OC(O)N(R)(R), -SO2N(R)(R), -N(R)(R), -COOR, -C(O)N(OH)(R), -OS(O)2OR, -S(O)2OR, -OP(O)(ORXOR), -NP(O)(OR)(OR), or-P(O)(OR)(OR); provided that when R2, R3, and R4 are H; R1 is not hydroxyl or a sugar; further provided that when R4 is hydroxyl, then R1 is not a sugar or hydroxyl; further provided that when R4 is hydroxyl, then R1 and R2 together are not C=O. 2. The compound of claim 1, wherein R1 is H, hydroxyl, alkoxyl, aryloxy, or amino or wherein R1 and R2 taken together along with the carbon to which they are bonded, form =O, =N(OR), or =S. 3. The compound of claim 1, wherein R3 is H. 4. The compound of claiml, wherein R4 is H, alkyl, hydroxyl, aralkyl, -[C(R)2]q-R5, -[(W)-N(R)C(O)]qR5, -[(W)-N(R)SO2]qR5, -[(W)-C(O)N(R)]qR5, -[(W)-O]qR5, -[(W)-C(O)]qR5, or -[(W)-C(O)O]qR5. 5. The compound of claim 1, wherein R1 is H or -oR, R2 is H or alkyl, and R4 is H. 6. The compound of claim 1, wherein R3 is H or alkyl and R2 is H or alkyl. 7. The compound of claim 1, wherein R4 is H, alkyl, aralkyl, -[(W)-N(R)C(O)]qR5, -[(W)-N(R)SO2]qR5, -[(W)-C(O)N(R)]qR5, -[(W)-O]qR5, -[(W)-C(O)]qR5, or -[(W)-C(O)O]qR5 and R3 is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, or aralkyl. 8. The compound of claim 1, wherein R4 is H, alkyl, aralkyl, -[(W)-C(O)N(R)]qR5,or -[(W)-N(R)C(O)]qR5. 9. The compound of claim 1, wherein R1 is sulfonamido 10. The compound of claim 1, wherein said compound is isolated. 11. A compound selected from the group consisting of: 12. An isolated compound selected from the group consisting of: 13. A compound represented by the following structure: or a pharmaceutically acceptable salt thereof; wherein R1 is H, alkyl, -OR, amino, sulfonamido, sulfamido, -OC(O)R5, - N(R5)C(O)R5, or a sugar; R2 is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, nitrile, or heterocycloalkyl; or R1 and R2 taken together form =O, =S, =N(OR), =N(R)-, =N(NR2), =C(R)2; R3 is H, alkyl, alkenyl, or alkynyl; R4 is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl, haloalkyl, -OR5, -C(O)R5, -CO2R5, -SO2R5, -C(O)N(R5)(R5), [C(R)2]q-R5, -t(W)-N(R)C(O)]qR5, -[(W)-C(O)]qR5, -[(W)-C(O)O]qR5, -[(W)-OC(O)]qR5, -[(W)-SO2]qR5, -[(W)-N(R5)SO2]qR5, -[(W)-C(O)N(R5)]qR5, -[(W)-O]qR5, -[(W)-N(R)]qR5, -W-NR53+X-, or -[(W)-S]qR5; wherein each W is, independently, a diradical; each q is, independently, 1,2, 3, 4, 5, or 6; X is a halide; each R5 is, independently, H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl or -[C(R)2]P-R6; wherein p is 0-6; or any two occurrences of R5 on the same substituent can be taken together to form a 4-8 membered optionally substituted ring which contains 0-3 heteroatoms selected from N, O, S, and P; each R6 is, independently, hydroxyl, -N(R)COR, -N(R)C(O)OR, -N(R)SO2(R), -C(O)N(R)2, -OC(O)N(R)(R), -SO2N(R)(R), -N(R)(R), -COOR, -C(O)N(OH)(R), -OS(O)2OR, -S(O)2OR, -OP(O)(OR)(OR), -NP(O)(OR)(OR), or-P(O)(OR)(OR); each of R7 and R7 is H; or R7 and R7 taken together form =O; R8 and R9 taken together form a bond; each R is independently H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl or aralkyl; and provided that when R3, R4, R8, R9 are H and , R7 and R7 taken together form =O; R1 can not be hydroxyl and R2 can not be H; provided that when R3, R4, R8, R9 are H and , R7 and R7 taken together form =O; R1 can not be acetate and R2 can not be H; provided that when R3, R4, R8, R9 are H and , R7 is H2; R1 and R2 taken together can not be =O; and provided that when R3, R4, R8, R9 are H and, R7 and R7' are H; R1 and R2 can not be H. 14. The compound of claim 13, wherein said compound is epimerically pure. 15. The compound of claim 13, wherein said compound is isolated. 16. The compound of claim 13, wherein R4 is alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl, haloalkyl, -OR5, -[C(R)2]q-R5, -[(W)-N(R)C(O)]qR5, -[(W)-C(O)]qR5, -[(W)-C(O)O]qR5, -[(W)-OC(O)]qR5, -[(W)-SO2]qR5, -[(W)-N(R5)SO2]qR5, -[(W)-C(O)N(R5)]qR5, -[(W)-O]qR5, -[(W)-N(R)]qR5, or -f(W)-S]qR5. 17. The compound of claim 13, wherein each of R7 and R7 is H. 18. The compound of claim 13, wherein R1 and R2 taken together form =O and each of R7 and R7 is H. 19. A compound selected from the group consisting of: or a pharmaceutically acceptable salt thereof 20. A pharmaceutical composition comprising a compound of claim 1, and at least one pharmaceutically acceptable excipient. 21. A process for preparing a compound of formula 136: wherein Y is CR7R8; R is H, alkyl, amino, hydroxyl, carboxyl, carbamoyl, alkoxy, hydroxy], sugar or a protected hydroxyl group; R is H, alkyl, alkenyl, alkynyl, nitrile, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, or heteroaralkyl; or R1 and R2 taken together form =O, =S, =N(OR9), =N(R9), =C(R9)2, or =N(N(R9)2); each of R3. R4, and R5 is, independently, H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, or heteroaralkyl; or R3 and R4 or R4 and R5 taken together form a bond; R6 is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl, haloalkyl, -OR9, -C(O)R9, -CO2R9, -SO2R9, -C(O)N(R9)(R9), -[C(R9)2]qR9, -[(W)-N(R9)C(O)]qR9, -[(W)-C(O)]qR9, -[(W)-C(O)O]qR9, -[(W)-OC(O)]qR9, -[(W)-SO2]qR9, -[(W)-N(R9)SO2]qR9, -[(W)-C(O)N(R9)]qR9, -[(W)-O]qR9. -[(W)-N(R9)]qR9, -[(W)-S]qR9, or a nitrogen protecting group; wherein each W independently for each occurrence is a diradical; each q is independently 1, 2, 3,4, 5, or 6; each of R7 and R8 is, independently, H, alkyl, alkenyl, aryl, nitrile, amido, halide, or ester, each R9 is, independently, H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, or heteroaralkyl; said process comprising the steps of: contacting a compound of formula 136a with a haloalkylzinc phosphate cyclopropanating agent; wherein R1, R2, R3, R4, R5, R6 are as defined above; to form said compound of formula 136. 22. The process of claim 21, wherein R7 and R8 are both H. 23. The process of claim 21, wherein R1 is a protected hydroxyl. 24. The process of claim 21, wherein R6 is a nitrogen protecting group. 25. The process of claim 21, where said haloalkylzinc phosphate cyclopropanating agent is formed by combining a phosphoric acid of formula 141a, a dialkylzinc, and a dihaloalkylane of formula 141b: wherein each of X and X' is independently chloride, bromide, or iodide; each of R7 and R8 is independently H, alkyl, halide, amido, or ester; each of R10 and R11 is independently alkyl, alkenyl, aralkyl, aryl, heteroaryl, heteroaralkyl; or R1o and R11 taken together have the formula 141c, 14Id, or 14le; wherein m independently for each occurrence is o, 1, 2, 3, or 4; n independently for each occurrence is o,1, or 2; and each of R12, R13, R14, R15, R16, R17 and R18 is, independently, alkyl, aryl, aralkyl, or halide. 26. The process of claim 25, wherein R10 and R11 are each 2,6-dimethylphenyl. 27. A process for preparing a compound of formula 137: wherein Y is CR7R8; R1 is H, alkyl, amino, hydroxyl, carboxyl, carbamoyl, alkoxy, hydroxyl, sugar or a protected hydroxyl group; R2 is H, alkyl, alkenyl, alkynyl, nitrile, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, or heteroaralkyl; or R1 and R2 taken together form =O, =S, =N(OR9), =N(R9), =C(R9)2, or =N(N(R9)2); each of R3, R4, and R3 is, independently, H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, or heteroaralkyl; or R3 and R4 or R4 and R5 taken together form a bond; R is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl, haloalkyl, -OR9, -C(O)R9, -CO2R", -SO2R9, -C(O)N(R9)(R9), -[C(R9)2]qR9, -[(W)-N(R9)C(O)]qR9, -[(W)-C(O)]qR9, -[(W)-C(O)O]qR9, -[(W)-OC(O)]qR9, -[(W)-SO2]qR9, -[(W)-N(R9)SO2]qR9, -[(W)-C(O)N(R9)]qR9, -[(W)-O]qR9, -[(W)-N(R9)]qR9, -[(W)-S]qR9, or a nitrogen protecting group; wherein each W independently for each occurrence is a diradical alkylene having 1-6 carbon atoms; each q is independently 1, 2, 3, 4, 5, or 6; each of R7 and R8 is, independently, H, alkyl, alkenyl, aryl, nitrile, amido, halide, or ester; each R9 is independently H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl,aralkyl, heteroaryl, or heteroaralkyl; said process comprising the steps of: contacting a compound of formula 137a with a haloalkylzinc phosphate cyclopropanating agent; wherein R , R , R , R4, R5, R6 are as defined above; to form a compound with formula 137b wherein R1, R2, R3, R4, R5, R6 and Y are as defined above; and contacting said compound of formula 137b with an acid to give said compound of formula 137. 28. A process for preparing a compound of formula 142: comprising the steps of: contacting a compound of formula 142a with a cyclopropanating agent to form a compound formula 142b; and combining said compound of formula 142b with an acid to give said compound of formula 142; wherein Y is CRV; R1 is a protected hydroxyl group; R2 is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, or heteroaralkyl; each of R3, R4, and R5 is, independently, H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, or heteroaralkyl; or R3 and R4, or R4 and R5 taken together form a bond; R6 is a nitrogen protecting group; each of R7 and R8 is, independently, H, alkyl, alkenyl, aryl, nitrile, amido, halide, or ester; and each R9 is independendy H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, or heteroaralkyl. 29. The process of claim 28, wherein R7 and R8 are both H. 3o. The process of claim 28, wherein said protected hydroxyl group is an ester or a carbonate. 31. The process of claim 28, wherein said nitrogen protecting group is a carbamate. 32. The process of claim 28, wherein said nitrogen protecting group is an amide. 33. The process of claim 28, wherein R2 and R3 are H and R4 and R5 taken together form a bond. 34. The process of claim 28, wherein said cyclopropanating agent is generated from a dihaloalkane and a metal species. 35. The process of claim 34, wherein said metal species is dialkyl zinc or a zinc copper couple. 36. The process of claim 28, wherein said cyclopropanating agent is generated from a dihaloalkane species and a dialkyl zinc species, and a phosphoric acid species or a salt thereof. 37. The process of claim 28, wherein said phosphoric acid species has a structure of formula 151: or a salt thereof; wherein each of R10 and R11 is independently alkyl, alkenyl, aralkyl, aryl, heteroaryl, heteroaralkyl; or R10 and R11 taken together have the formula 151a, 151b, or 151c; wherein m independently for each occurrence is o, 1, 2, 3, or 4; n independently for each occurrence is 0,1, or 2; each of R12, R13, R14, R15, R16, R17 and R18 is, independently, alkyl, aryl, aralkyl, or halide. 38. The process of claim 28, wherein said acid is acetic acid, trifluoromethanesulfonic acid, phosphoric acid, methanesulfonic acid or HCl. 39. The process of claim 28, wherein said acid is BF3, zinc chloride, zinc methanesulfonate, or a zinc salt. 4o. A process for preparing a compound of formula 156: comprising the steps of: contacting a compound of formula 156a with a cyclopropanating agent to form a compound formula 156b; and combining said compound of formula 156b with an acid to give said compound of formula 156; wherein R is an oxygen protecting group selected from the group consisting of formate, acetate, chloroacetate, dichloroacetate, triehloroacetate, pivaloate, benzoates, alkyl carbonate, alkenyl carbonate, aryl carbonates, aralkyl carbonate, 2,2,2-trichloroethyl carbonate, alkoxymethyl ether, aralkoxymethyl ether, alkylthiomethyl ether, aralkylthio ether, arylthio ether, trialkylsilyl ether, alkylarylsilyl emer, benzyl ether, arylmethyl ether, allyl ether; and R2 is a nitrogen protecting group selected from the group consisted of formyl, chloroacetyl, trichloroacetyl, trifluoroacetyl, phenyl acetyl, benzoyl, alkyl carbamates, aralkyl carbamates, aryl carbamates, allyl, aralkyl, triarylmethyl, alkoxymethyl, aralkoxymethyl, N-2-cyanoethyl, diarylphosphinamides, dialkylphosphinamidates, diarylphosphinamidates, and trialkylsilyl. 41. The process of claim 4o, where said cyclopropanating agent is formed by combining a phosphoric acid of formula 158a, a dialkylzinc, and a dihaloalkylane of formula 157b: wherein each of X and X' is, independently, chloride, bromide, or iodide; each of R7 and R8 is, independently, H, alkyl, halide, amido, or ester; each of R10 and R11 is, independently, alkyl, alkenyl, aralkyl, aryl, heteroaryl, heteroaralkyl; or R10 and R11 taken together have the formula 158c, 158d, or 158e; wherein m independently for each occurrence is 0, 1, 2, 3, or 4; n independently for each occurrence is o,1, or 2; each of R12, R13, R14, R15, R16, R17 and R18 is, independently, alkyl, aryl, aralkyl, or halide. 42. The process of claim 41, wherein said oxygen protecting group is alkyl carbonate, aralkyl carbonate, benzoate, pivaloate, or formate. 43. The process of claim 41, wherein said nitrogen protecting group is benzoyl, trichloroacetyl, trifluoroacetyl, formyl, alkyl carbamates, aralkyl carbamates, or aryl carbamates. 44. The process of claim 41, wherein said oxygen protecting group is benzylcarbonate. 45. The process of claim 41, wherein said nitrogen protecting group is benzylcarbamate. The invention provides novel derivatives of cyclopamine having the following formula.

Full Text

CYCLOPAMINE ANALOGS
RELATED APPLICATIONS
[0001] This application claims priority to USSN 60/878,018, filed December 28,
2006, and USSN 60/941,596, filed June 1, 2007, both of which are hereby incorporated
by reference in their entirety.
BACKGROUND OF THE INVENTION
[0002] The present invention generally relates to cyclopamine analogs and
pharmaceutical compositions thereof, and methods for preparing such analogs and
compositions. These compounds and compositions are useful for the treatment of
disorders mediated by the hedgehog pathway, such as cancer.
[0003] Inhibition of the hedgehog pathway in certain cancers has been shown to
result in inhibition of tumor growth. For example, anti-hedgehog antibodies have been
shown to antagonize the function of the hedgehog pathway and inhibit the growth of
tumors. Small molecule inhibition of hedgehog pathway activity has also been shown to
result in cell death in a number of cancer types.
[0004] Research in this area has focused primarily on the elucidation of hedgehog
pathway biology and the discovery of new hedgehog pathway inhibitors. Although
inhibitors of the hedgehog pathway have been identified, there still exists the need to
identify more potent inhibitors of the hedgehog pathway.
[0005] PCT publication WO 2006/026430 published 9 March 2006 and assigned to
the same assignee as the present application, discloses a wide variety of cyclopamine
analogs, focusing on those with unsaturation in the A or B ring. In the present
application, the surprisingly potent analogs contain completely saturated A and B rings.
SUMMARY OF THE INVENTION
[0006] The present invention relates to analogs of steroidal alkaloids, such as
cyclopamine, pharmaceutical compositions containing these compounds, and methods for
preparing these compounds. In one embodiment, the present invention relates to a
compound represented by the following structure:

or a pharmaceutically acceptable salt thereof;
wherein R1 is H, alkyl, -OR, amino, sulfonamide, sulfamido, -OC(O)R5, -
N(R5)C(O)R5, or a sugar;
R2 is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, nitrile, or heterocycloalkyl;
or R1 and R2 taken together form =O, =S, =N(OR), =N(R), =N(NR2), =C(R)2;
R3 is H, alkyl, alkenyl, or alkynyl;
R4 is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl,
heteroaryl, heteroaralkyl, haloalkyl, -OR5, -C(O)R5, -CO2R5, -SO2R5, -C(O)N(R5)(R5),
-[C(R)2]q-R5, -[(W)-N(R)C(O)]qR5, -[(W)-C(O)]qR5, -[(W)-C(O)O]qR5, -[(W)-OC(O)]qR5,
-[(W)-SO2]qR5, -[(W)-N(R5)SO2]qR5, -[(W)-C(O)N(R5)]qR5, -[(W)-O]qR5,
-[(W)-N(R)]qR5, -W-NRYXor -[(W)-S]qR5;
wherein each W is independently a diradical;
each q is independently 1, 2, 3,4, 5, or 6;
X" is a halide;
each R5 is independently H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl,
heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl or -[C(R)2]P-R6; wherein p is 0-6; or
any two occurrences of R5 can be taken together to form a 4-8 membered optionally
substituted ring which contains 0-3 heteroatoms selected from N, O, S, and P;
each R6 is independently hydroxyl, -N(R)COR, -N(R)C(O)OR, -N(R)SO2(R),
-C(O)N(R)2, -OC(O)N(R)(R), -SO2N(R)(R), -N(R)(R), -COOR, -C(O)N(OH)(R),
-OS(O)2OR, -S(O)2OR, -OP(O)(OR)(OR), -NP(O)(OR)(OR), or -P(O)(OR)(OR); and
each R is independently H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl or aralkyl;
provided mat when R2, R3, and R4 are H; R1 is not hydroxyl or a sugar; further
provided that when R4 is hydroxyl, then R1 is not a sugar or hydroxyl, and R1 and
R2 are not C=O.

[0007] In certain embodiments, R1 is H, hydroxyl, alkoxyl, aryloxy, or amino. In
other embodiments, R1 and R2 taken together along with the carbon to which they are
bonded, form =O, =N(OR), or =S. In other embodiments, R3 is H and/or R4 is H, alkyl,
hydroxyl, aralkyl, -[C(R)2]q-R5, -[(W)-N(R)C(O)]qR5, -[(W)-N(R)SO2]qR5,
-[(W)-C(O)N(R)]qR5, -[(W)-O]qR5, -[(W)-C(O)]qR5, or -[(W)-C(O)O]qR5. In other
embodiments, R1 is H or -OR, R2 is H or alkyl, and R4 is H. In others, R2 is H or alkyl,
R3 is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, or aralkyl; and/or R4 is
H, alkyl, aralkyl, -[(W)-N(R)C(O)]qR5, -[(W)-N(R)SO2]qR5, -[(W)-C(O)N(R)]qR5,
-[(W)-O]qR5, -[(W)-C(O)]qR5, or -[(W)-C(O)O]qR5. In other embodiments, R1 is
sulfonamido.
[0008] In another embodiment, the present invention relates to a compound
selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.
[0009] In certain embodiments, the compounds mentioned above are isolated.
[0010] In another embodiment, the present invention relates to an isolated
compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.
[0011] In another embodiment, the present invention relates to a compound
represented by the following structure:

or a pharmaceutically acceptable salt thereof;
wherein R1 is H, alkyl, -OR, amino, sulfonamide sulfamido, -OC(O)R5, -
N(R5)C(O)R5, or a sugar;
R2 is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, nitrile, or heterocycloalkyl;
or R1 and R2 taken together form =O, =S, =N(OR), =N(R), =N(NR2), =C(R)2;
R3is H, alkyl, alkenyl, or alkynyl;
R4 is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl,
heteroaryl, heteroaralkyl, haloalkyl, -OR5, -C(O)R5, -CO2R5, -SO2R5, -C(O)N(R5)(R5),
-[C(R)2]q-R5, -[(W)-N(R)C(O)]qR5, -[(W)-C(O)]qR5, -[(W)-C(O)O]qR5, -[(W)-OC(O)]qR5,
-[(W)-SO2]qR5, -[(W)-N(R5)SO2]qR5, -[(W)-C(O)N(R5)]qR5, -[(W)-O]qR5,
-[(W)-N(R)]qR5, -W-NR53+X , or -[(W)-S]qR5;
wherein each W is, independently, a diradical;
each q is, independently, 1,2, 3,4, 5, or 6;
X" is a halide;
each R5 is, independendy, H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl,
heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl or -[C(R)2]P-R6; wherein p is O-6; or
any two occurrences of R5 can be taken together to form a 4-8 membered optionally
substituted ring which contains O-3 heteroatoms selected from N, O, S, and P;
each R6 is, independendy, hydroxyl, -N(R)COR, -N(R)C(O)OR, -N(R)SO2(R),
-C(O)N(R)2, -OC(O)N(R)(R), -SO^RXR), -N(R)(R), -COOR, -C(O)N(OH)(R),
-OS(O)2OR, -S(O)2OR, -OP(O)(OR)(OR), -NP(O)(OR)(OR), or-P(O)(OR)(OR);
each R is, independently, H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl or aralkyl;
each of R7 and R7 is H; or R7 and R7 taken togetiier form =O;
R8 and R9 are H; or
R and R taken together form a bond; and

provided that when R3, R4, R8, R9 are H and R7 and R7 taken together form =O;
R1 can not be hydroxyl and R2 can not be H;
provided that when R3, R4, R8, R9 are H and, R7 and R7' taken together form =O;
R1 can not be acetate and R2 can not be H;
provided that when R3, R4, R8, R9 are H and, R7 and R7' are H; R1 and R2 taken
together can not be =O; and
provided that when R3, R4, R8, R9 are H and, R7 and R7' are H; R1 and R2 can not
be H.
[0012] In some embodiments, the compound is epimerically pure and/or isolated.
In other embodiments, R4 is alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl,
aralkyl, heteroaryl, heteroaralkyl, haloalkyl, -OR5, -[C(R)2]q-R5, -[(W)-N(R)C(O)]qR5,
-[(W)-C(O)]qR5, -[(W)-C(O)O]qR5, -[(W)-OC(O)]qR5, -[(W)-SO2]qR5,
-[(W)-N(R5)SO2]qR5, -[(W)-C(O)N(R5)]qR5, -[(W)-O]qR5, -[(W)-N(R)]qR5, or
-[(W)-S]qR5. Each of R7 and RT can be H. In addition, R1 and R2 taken together form
=O.
[0013] In another embodiment, the present invention relates to a compound
selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

[0014] In certain embodiments, the above compounds are epimerically pure
and/or isolated.
[0015] In another embodiment, the present invention relates to an epimerically
pure compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.
[0016] Another aspect of the present invention relates to a pharmaceutical
composition including any of the aforementioned compounds, and a pharmaceutically
acceptable excipient.
[0017] In one embodiment, the present invention relates to a process for preparing
cyclopropyl derivatives of cyclopamine and related analogs having the formula 136:

wherein
Y is CR7R8;
R1 is H, alkyl, amino, hydroxyl, carboxyl, carbamoyl, alkoxy, hydroxyl, sugar or a
protected hydroxyl group;
R2 is H, alkyl, alkenyl, alkynyl, nitrile, aryl, cycloalkyl, heterocycloalkyl, aralkyl,
heteroaryl, or heteroaralkyl; or R1 and R2 taken together form =O, =S, =N(OR9), =N(R9),
=C(R9)2,or=N(N(R9)2);
each of R3, R4, and R5 is, independently, H, alkyl, alkenyl, alkynyl, aryl,
cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, or heteroaralkyl; or R3 and R4 or R4 and
R5 taken together form a bond;

R6 is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl,
heteroaryl, heteroaralkyl, haloalkyl, -OR9, -C(O)R9, -CO2R9, -SO2R9, -C(O)N(R9)(R9),
-[C(R9)2]qR9, -[(W)-N(R9)C(O)]qR9, -[(W)-C(O)]qR9, -[(W)-C(O)O]qR9,
-[(W)-OC(O)]qR9, -[(W)-SO2]qR9, -[(W)-N(R9)SQ2]qR9, -[(W)-C(O)N(R9)]qR9,
-[(W)-O]qR9, -[(W)-N(R9)]qR9, -[(W)-S]qR9, or a nitrogen protecting group; wherein each
W is independently a diradical; each q is independently 1, 2, 3, 4, 5, or 6;
each of R7 and R8 is, independently, H, alkyl, alkenyl, aryl, nitrile, amido, halide,
or ester; and
each R9 is, independendy, H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl,
heterocycloalkyl,aralkyl, heteroaryl, or heteroaralkyl.
[0018] The process includes the steps of contacting a compound of formula 136a
with a haloalkylzinc phosphate cyclopropanating agent to yield a compound of formula
136.

wherein
R1, R2, R3, R4, R5, R6 are as defined in compound 136.
[0019] In another embodiment, the present invention provides methods for
preparing a compound of formula 137:

wherein
Y is CR7R8;
R1 is H, alkyl, amino, hydroxyl, carboxyl, carbamoyl, alkoxy, hydroxyl, sugar or a
protected hydroxyl group;
R2 is H, alkyl, alkenyl, alkynyl, nitrile, aryl, cycloalkyl, heterocycloalkyl, aralkyl,
heteroaryl, or heteroaralkyl; or R1 and R2 taken together form =O, =S, =N(OR9), =N(R9),
=C(R9)2,or=N(N(R9)2);
each of R3, R4, and R5 is, independently, H, alkyl, alkenyl, alkynyl, aryl,
cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, or heteroaralkyl; or R3 and R4 or R4 and
R5 taken together form a bond;
R6 is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl,
heteroaryl, heteroaralkyl, haloalkyl, -OR9, -C(O)R9, -CO2R9, -SO2R9, -C(O)N(R9)(R9),
-[C(R9)2]qR9, -[(W)-N(R9)C(O)]qR9, -[(W)C(O)]qR9, -[(W)-C(O)O]qR9,
-[(W)-OC(O)]qR9, -[(W)-SO2]qR9, -[(W)-N(R9)SO2]qR9, -[(W)-C(O)N(R9)]qR9,
-[(W)-O]qR9, -[(W)-N(R9)]qR9, -[(W)-S]qR9, or a nitrogen protecting group;
wherein each W is, independently, a diradical;
each q is independently 1, 2, 3, 4, 5, or 6;
each of R7 and R8 is, independently, H, alkyl, alkenyl, aryl, nitrile, amido, halide,
or ester; and
each R9 is independently H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl,
heterocycloalkyl,aralkyl, heteroaryl, or heteroaralkyl. The process includes the steps of:
first contacting a compound of formula 137a with a haloalkylzinc phosphate
cyclopropanating agent;

wherein

R1, R2, R3, R4, R5, R6 are as defined in compound 137; to form a compound with
formula 137b
wherein
R1, R2, R3, R4, R5, R6 and Y are as defined in compound 137; and then contacting
the compound of formula 137b with an acid to give a compound of formula 137.
[OO2O] In certain embodiments, R7 and R8 can both be H; in other embodiments
R1 can be a protected hydroxyl; and/or R6 is a nitrogen protecting group.
[OO21] In certain embodiments, the haloalkylzinc phosphate cyclopropanating
agent is formed by combining a phosphoric acid of formula 141a, a dialkylzinc, and a
dihaloalkylane of formula 141b:

wherein
each of X and X' is, independently, chloride, bromide, or iodide;
each of R7 and R8 is, independently, H, alkyl, halide, amido, nitro, or ester;
each of R10 and R11 is, independently, alkyl, alkenyl, aralkyl, aryl, heteroaryl,
heteroaralkyl; or R10 and R11 taken together have the formula 141c, 141d, or 141e;

wherein
m is, independently for each occurrence, 0,1, 2, 3, or 4; n is, independently for
each occurrence, 0,1, or 2; and each of R12, R13, R14, R15, R16, R17 and R18 is,
independently, alkyl, aryl, aralkyl, or halide.
[0022] In another embodiment, the present invention relates to a process for
preparing a compound of formula 142:

[0023] The process includes the steps of contacting a compound of formula 142a
with a cyclopropanating agent to form a compound formula 142b; and

combining the compound of formula 142b with an acid to give the compound of
formula 142;
wherein
Y is CR7R8; R1 is a protected hydroxyl group;
R2 is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl,
heteroaryl, or heteroaralkyl; each of R3, R4, and R5 is, independently, H, alkyl, alkenyl,
alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, or heteroaralkyl; or
R3 and R4 or R4 and R5 taken together form a bond; R6 is a nitrogen protecting
group;
each of R7 and R8 is, independently, H, alkyl, alkenyl, aryl, nitrile, amido, halide,
or ester; and
each R9 is, independendy, H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl,
heterocycloalkyl, aralkyl, heteroaryl, or heteroaralkyl.
In certain embodiments, R7 and R8 can both be H; in other embodiments the
protected hydroxyl group can be an ester or a carbonate; the nitrogen protecting can be a
carbamate or an amide; R7 and R8 can both be H and the nitrogen protecting can be a
carbamate or an amide; R2 and R3 can be H and R4 and R5 taken together can form a
bond; and/or the cyclopropanating agent is generated from a dihaloalkane and a metal
species (e.g., dialkyl zinc or a zinc copper couple).
[0024] In certain embodiments the cyclopropanating agent is generated from a
dihaloalkane species and a dialkyl zinc species, and a phosphoric acid species or a salt
thereof. The phosphoric acid species can have a structure of formula 151:

or a salt thereof;
wherein
each of R10 and R11 is independently alkyl, alkenyl, aralkyl, aryl, heteroaryl,
heteroaralkyl; or R10 and R11 taken together have the formula 151a, 151b, or 151c;

wherein
m independently for each occurrence is 0, 1, 2, 3, or 4; n independently for each
occurrence is 0,1, or 2; each of R12, R13, R14, R15, R16, R17 and R18 is, independently,
alkyl, aryl, aralkyl, or halide.
[0025] In certain embodiments the acid is a Bronsted acid (e.g., acetic acid,
trifluoromethanesulfonic acid, phosphoric acid, methanesulfonic acid or HC1). In other
embodiments the acid is a Lewis acid (e.g., BF3, zinc chloride, zinc methanesulfonate, or
a zinc salt).
[0026] The present invention also relates to a process for preparing a compound
of formula 156:

[0027] The process includes the steps of:
contacting a compound of formula 156a with a cyclopropanating agent to form a
compound formula 156b; and

combining the compound of formula 156b with an acid to give the compound of formula
156;
where R1 is an oxygen protecting group selected from the group consisting of formate,
acetate, chloroacetate, dichloroacetate, trichloroacetate, pivaloate, benzoate, alkyl
carbonate, alkenyl carbonate, aryl carbonates, aralkyl carbonate, 2,2,2-trichloroethyl
carbonate, alkoxymethyl ether, aralkoxymethyl ether, alkylthiomethl edier, aralkylthio
ether, arylthio ether, trialkylsilyl edier, alkylarylsilyl ether, benzyl ether, arylmethyl ether,
allyl ether; and R is a nitrogen protecting group selected from the group consisting of
formyl, chloroacetyl, trichloroacetyl, trifluoroacetyl, phenyl acetyl, benzoyls, alkyl
carbamates, aralkyl carbamates, aryl carbamates, allyl, aralkyl, triarylmethyl,
alkoxymethyl, aralkoxymethyl, N-2-cyanoethyl, diarylphosphinamides,
dialkylphosphinamidates, diarylphosphinamidates, and trialkylsilyl.

[0028] In certain embodiments the cyclopropanating agent is formed by
combining a phosphoric acid of formula 58a, a dialkylzinc, and a dihaloalkylane of
formula 158b:
wherein
each of X and X' is, independently, chloride, bromide, or iodide; each of R and
R8 is, independently, H, alkyl, halide, amido, or ester; each of R10 and R11 is,
independently, alkyl, alkenyl, aralkyl, aryl, heteroaryl, heteroaralkyl; or R10 and R11 taken
together have the formula 158c, 158d, or 158e;

wherein
m independently for each occurrence is 0, 1, 2, 3, or 4; n independently for each
occurrence is 0,1, or 2; each of R12, R13, R14, R15, R16, R17 and R18 is, independently,
alkyl, aryl, aralkyl, or halide.
[0029] The oxygen protecting group can be, in some embodiments, selected from
alkyl carbonates, aralkyl carbonates (e.g., benzylcarbonate), benzoates, pivaloate, or
formate. The nitrogen protecting group can be selected from benzoyl, trichloroacetyl,
trifluoroacetyl, formyl, alkyl carbamates, aralkyl carbamates (e.g., benzylcarbamate), aryl
carbamates, diarylphosphinamides, dialkylphosphinamidates, or diarylphosphinamidates.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
[0030] The definitions of terms used herein are meant to incorporate the present
state-of-the-art definitions recognized for each term in the chemical and pharmaceutical

fields. Where appropriate, exemplification is provided. The definitions apply to the
terms as they are used throughout this specification, unless otherwise limited in specific
instances, either individually or as part of a larger group.
[0031] As used herein, the definition of each expression, e.g., alkyl, m, n, etc.,
when it occurs more than once in any structure, is intended to be independent of its
definition elsewhere in the same structure.
[0032] The term "acylamino" refers to a moiety that may be represented by the
general formula:

wherein R50 and R54 independently represent a hydrogen, an alkyl, an alkenyl or
-(CH2)m-R61,
where 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.
[0033] The terms "alkenyl" and "alkynyl" refer to unsaturated aliphatic groups
analogous in length and possible substitution to the alkyls described above, but that
contain at least one double or triple bond respectively.
[0034] The terms "alkoxyl" or "alkoxy" refers to an alkyl group, as defined above,
having an oxygen radical attached thereto. Representative alkoxyl groups include
methoxy, ethoxy, propyloxy, tert-butoxy and the like.
[0035] The term "alkyl" refers to the radical of saturated aliphatic groups,
including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic)
groups, alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups. In
certain embodiments, a straight chain or branched chain alkyl has 30 or fewer carbon
atoms in its backbone (e.g., C1-C30 for straight chain, C3-C30 for branched chain), 2O or
fewer. Likewise, certain cycloalkyls have from 3-10 carbon atoms in their ring structure,
and others have 5, 6 or 7 carbons in the ring structure.
[0036] The term "alkylthio" refers to an alkyl group, as defined above, having a
sulfur radical attached mereto. In certain embodiments, the "alkylthio" moiety is

represented by one of -S-alkyl, -S-alkenyl, -S-alkynyl, and -S-(CH2)m-R61, wherein m
and R61 are defined above. Representative alkylthio groups include methyltbio, ethyl
thio, and the like.
[0037] The term "amido" is art recognized as an amino-substituted carbonyl and
includes a moiety that may be represented by the general formula:

wherein R50 and R51 each independently represent a hydrogen, an alkyl, an
alkenyl, -(CH2)m-R61, 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, or R50 and R51, taken
together with me N atom to which they are attached complete a heterocycle having from
4 to 8 atoms in the ring structure. Certain embodiments of the amide in the present
invention will not include imides which may be unstable.
[0038] The terms "amine" and "amino" are art-recognized and refer to both
unsubstituted and substituted amines, e.g., a moiety mat may be represented by the
general formulas:
wherein R50 and R51 (and optionally R52) each independently represent a
hydrogen, an alkyl, an alkenyl, or -(CH2)m-R61, where R61 is defined as above. Thus,
the term "alkylamine" includes an amine group, as defined above, having a substituted or
unsubstituted alkyl attached thereto, i.e., at least one of R50 and R51 is an alkyl group.
[0039] The term "aralkyl", as used herein, refers to an alkyl group substituted with
an aryl group (e.g., an aromatic or heteroaromatic group).
[0040] The term "aryl" as used herein includes 5-, 6- and 7-membered single-ring
aromatic groups that may include from zero to four heteroatoms, for example, benzene,
anthracene, naphthalene, pyrene, pyrrole, furan, thiophene, imidazole, oxazole, thiazole,

triazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine, and the like. Those aryl
groups having heteroatoms in the ring structure may also be referred to as "aryl
heterocycles" or "heteroaromatics." The aromatic ring may be substituted at one or more
ring positions with such substituents as described above, for example, halogen, azide,
alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl,
imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio,
sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic
moieties, -CF3, -CN, or the like. The term "aryl" also includes polycyclic ring systems
having two or more cyclic rings in which two or more carbons are common to two
adjoining rings (the rings are "fused rings") wherein at least one of the rings is aromatic,
e.g., the other cyclic rings may be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or
heterocyclyls.
[0041] The term "Bronsted acid" refers to any substance that can act as a
hydrogen ion (proton) donor.
[0042] The term "carboxyl" is defined to include esters, thiocarboxyl, aldehydes,
ketones and the like and thus includes such moieties as may be represented by the general
formulas:
wherein X50 is a bond or represents an oxygen or a sulfur, and each of R55 and R56
represents independently a hydrogen, an alkyl, an alkenyl, -(CH2)m-R61, where m and
R61 are defined above.
[0043] The term "diradical" refers to any of a series of divalent groups from alkyl,
alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, and heteroaralkyl

(alkyl)heteroaralkyl diradical. Typical examples include alkylenes of general structure
(CH2)X where X is 1-6, and corresponding alkenylene and alkynylene linkers having 2-6

carbon atoms and one or more double or triple bonds; cycloalkylene groups having 3-8
ring members; and aralkyl groups wherein one open valence is on the aryl ring and one is
on the alkyl portion such as and its isomers.
[0044] The term "haloalkyl", as used herein, refers to an alkyl group where
anywhere from 1 to all hydgrogens have been replaced with a halide. A "perhaloalkyl" is
where all of the hydrogens have been replaced with a halide.
[0045] The term "heteroatom" as used herein means an atom of any element other
man carbon or hydrogen. Examples of heteroatoms include boron, nitrogen, oxygen,
phosphorus, sulfur and selenium.
[0046] The terms "heterocyclyl" or "heterocyclic group" refer to 3- to 10-
membered ring structures, in some instances from 3- to 7-membered rings, whose ring
structures include one to four heteroatoms. Heterocycles can also be polycycles.
Heterocyclyl groups include, for example, thiophene, thianthrene, furan, pyran,
isobenzofuran, chromene, xanthene, phenoxathiin, 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, sultams, 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 moiety, -CF3, -CN, or the like.
[0047] The term "isolated" in connection with a compound of the present
invention means the compound is not in a cell or organism and the compound is separated
from some or all of the components that typically accompany it in nature.
[0048] The term "Lewis acid" refers to any substance that can act as an electron
pair acceptor.

[0049] Unless the number of carbons is otherwise specified, "lower alkyl" as used
herein means an alkyl group, as defined above, but having from one to ten carbons, in
some embodiments from one to six carbon atoms in its backbone structure. Likewise,
"lower alkenyl" and "lower alkynyl" have similar chain lengths. Certain alkyl groups are
lower alkyls. In some embodiments, a substituent designated herein as alkyl is a lower
alkyl.
[0050] As used herein, the term "nitro" means -NO2; the term "halogen"
designates -F, -Cl, -Br or -I; the term "sulfhydryl" means -SH; the term "hydroxyl" means
-OH; and the term "sulfonyl" means -SO2-.
[0051] The term "oxo" refers to a carbonyl oxygen (=O).
[0052] The terms "polycyclyl" or "polycyclic group" 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 adjoining rings, e.g., the rings are "fused rings".
Rings that are joined through non-adjacent atoms are termed "bridged" rings. Each of the
rings of the polycycle may 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
moiety, -CF3, -CN, or the like.
[0053] The term "epimerically pure" in connection with a compound of the
present invention means that the compound is substantially free of stereoisomers of the
compound wherein the configuration of the stereogenic center that R3 is bonded to is
inverted. For example an epimerically pure compound represented by the following
formula:

wherein R1, R2, R3, R4, R7, R7, R8, and R9 are as defined below, is substantially free of
compounds represented by the following formula:

wherein R1, R2, R3, R4, R7, R7, R8, and R9 are as defined below. Epimerically pure
compounds contain less than about 20 % by mass, less than about 15% by mass, less than
about 10% by mass, less than about 5% by mass, or less than about 3% by mass of
stereoisomeric compounds wherein the configuration of the stereogenic center that R3 is
bonded to is inverted relative to the compound.
[0054] The phrase "protecting group" as used herein means temporary
substituents which protect a potentially reactive functional group from undesired
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 field of protecting group chemistry has been reviewed (Greene, T.W.;
Wuts, P.G.M Protective Groups in Organic Synthesis, 2nd ed.; Wiley: New York, 1991).
In some cases, the functional group being protected and the protecting group are together
referred to as one moiety. For example, the fragment shown below is sometimes referred
to as a benzyl carbonate; i.e., the protected (underlined) O makes up part of the carbonate.

[0055] Similarly, the fragment shown below, in which the protected N makes up
part of the carbamate, is referred to as a benzyl carbamate.

[0056] The term "sugar" as used herein refers to a natural or an unnatural
monosaccharide, disaccharide or oligosaccharide comprising one or more pyranose or
furanose rings. The sugar may be covalently bonded to the steroidal alkaloid of the
present invention through an ether linkage or through an alkyl linkage. In certain
embodiments the saccharide moiety may be covalently bonded to a steroidal alkaloid of
the present invention at an anomeric center of a saccharide ring. Sugars may include, but
are not limited to ribose, arabinose, xylose, lyxose, allose, altrose, glucose, mannose,
gulose, idose, galactose, talose, glucose, and trehalose.
[0057] The term "sulfonamido" or "sulfonamide" as used herein includes a
moiety having either of the following formulae:

wherein R50 and R56 are as defined above.
[0058] The terms "triflyl", "tosyl", "mesyl", and "nonaflyl" refer to
trifluoromethanesulfonyl, p-toluenesulfonyl, methanesulfonyl, and
nonafluorobutanesulfonyl groups, respectively. The terms "triflate", "tosylate",
"mesylate", and "nonaflate" to trifluoromethanesulfonate ester, p-toluenesulfonate ester,
methanesulfonate ester, and nonafluorobutanesulfonate ester functional groups and
molecules that contain the groups, respectively.
[0059] The term "thioxo" refers to a carbonyl sulfur (=S).
[0060] It will be understood that "substitution" or "substituted with" includes the
implicit proviso that such substitution is in accordance with permitted valence of the
substituted atom and the substituent, and that the substitution results in a stable
compound, e.g., which does not spontaneously undergo transformation such as by
rearrangement, cyclization, elimination, etc.
[0061] Certain compounds of the present invention may exist in particular
geometric or stereoisomeric forms. The present invention contemplates all such
compounds, including cis- and frans-isomers, R- and 5-enantiomers, diastereomers, (D)-
isorners, (L)-isomers, the 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 such isomers, as well as mixtures thereof, are
intended to be included in this invention.
[0062] As set out 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 respect, refers to the relatively non-toxic,
inorganic and organic acid addition salts of compounds of the present invention. These
salts can be prepared in situ in the administration vehicle or the dosage form
manufacturing process, or by separately reacting a purified compound of the invention in
its free base form with a suitable organic or inorganic acid, and isolating the salt thus
formed during subsequent purification. Representative salts include the hydrobromide,
hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate,
stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate,
succinate, tartrate, napthylate, mesylate, glucoheptonate, lactobionate, and
laurylsulphonate salts and the like. (See, for example, Berge et al. (1977) "Pharmaceutical
Salts", J. Pharm. Sci. 66:1-19)
[0063] The pharmaceutically acceptable salts of the compounds of the present
invention include the conventional nontoxic salts or quaternary ammonium salts of the
compounds, e.g., from non-toxic organic or inorganic acids. For example, such
conventional nontoxic salts include those derived from inorganic acids such as
hydrochloride, hydrobromic, sulfuric, sulfamic, phosphoric, nitric, and the like; and the
salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic,
lactic, malic, tartaric, citric, ascorbic, palmitic, maleic, hydroxymaleic, phenylacetic,
glutamic, benzoic, salicyclic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic,
methanesulfonic, ethane disulfonic, oxalic, isothionic, and the like.
[0064] In other cases, the compounds of the present invention may contain one or
more acidic functional groups and, thus, are capable of forming pharmaceutically-
acceptable salts with pharmaceutically-acceptable bases. The term "pharmaceutically-
acceptable salts" in these instances 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 situ 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 the hydroxide, carbonate or bicarbonate of a
pharmaceutieally-acceptable metal cation, with ammonia, or with a pharmaceutically-
acceptable organic primary, secondary or tertiary amine. Representative alkali or alkaline
earth salts include the 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, emylenediamine, ethanolamine,
diethanolamine, piperazine and the like. (See, for example, Berge et al, supra)
Svnmesis of Steroidal Alkaloid Compounds
[0065] The ring expanded steroidal alkaloid derivatives described above can be
prepared directly from naturally occurring steroidal alkaloids or synthetic analogs thereof.
In certain instances, the steroidal alkaloid starting materials can be cyclopamine or
jervine. These steroidal alkaloids can be purchased commercially or extracted from
Veratrum Californicum. Briefly, the process of the present invention comprises the steps
of cyclopropanating suitable starting steroidal alkaloid derivatives followed by ring
expansion rearrangement of the cyclopropyl derivatives. In some instances, it may be
desirable to suitably protect or otherwise transform reactive functionalities present on the
molecule prior to cyclopropanation. For example, an alcohol present at R1 and a
secondary nitrogen present on the fused furano-piperidine ring can both be protected prior
to cyclopropanation. In certain embodiments, protecting groups that are efficiently added
and removed from the alkaloid, yield intermediates in the synmetic process with
improved handling properties and which allow for the efficient purification of me
synthetic intermediates formed may be preferred.
[0066] Examples of oxygen protecting groups include, but are not limited to
formate, acetate, chloroacetate, dichloroacetate, trichloroacetate, pivaloate, benzoates,
alkyl carbonate, alkenyl carbonate, aryl carbonates, aralkyl carbonate (e.g., benzyl
carbonate), 2,2,2-trichloroethyl carbonate, alkoxymethyl ether, aralkoxymethyl ether,
alkylthiomethl ether, aralkylthio ether, arylthio ether, trialkylsilyl ether, alkylarylsilyl
ether, benzyl ether, arylmethyl ether, and allyl ether.

[0067] Examples of nitrogen protecting groups include, but are not limited to
formyl, chloroacetyl, trichloroacetyl, trifluoroacetyl, phenyl acetyl, benzoyls, benzamides,
alkyl carbamates, aralkyl carbamates (e.g., benzyl carbamates), aryl carbamates, allyl,
aralkyl, alkoxymethyl, aralkoxymethyl, N-2-cyanoethyl, diarylphosphinamides,
dialkylphosphinamidates, diarylphosphinamidates, and trialkylsilyl.
[0068] Additional protecting groups that may be used in the methods of the
present invention are described in Green T.W.; Wuts P.G. Protective Groups in Organic
Synthesis 3rd Edition, John Wiley & Sons, Inc. 1999.
[0069] A variety of cyclopropanating agents can be used to cyclopropanate the
steroidal alkaloid. 1,1-haloalkylmetal complexes and reactive species referred to as
carbenoids, are commonly used to cyclopropanate olefins. These reagents are typically
made using a diiodoalkane or diazoalkane and a metal or organometalic species such as
Et2Zn, iBU3Al, samarium, copper, rhodium, or palladium. In certain embodiments, Et2Zn
and diiodomethane are used to generate the 1,1-haloalkylmetal species.
[0070] The reactivity and the ease of handling of the 1,1-haloalkylzinc complexes
can be modified by the addition of certain reagents, such as acids. It is believed that the
addition of an acid to the 1,1-haloalkylzinc species generates an alkyl zinc mixed salt. In
the examples described below a biarylphosphoric acid is combined with diiodomethane
and diethylzinc to generate a putative haloalkyl zinc phosphate cyclopropanating agent. A
variety of phosphoric acids can be used to generate the putative haloalkylzinc phosphate.
[0071] Other known cyclopropanation methods such as those utilizing sulfur
ylides 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-diazo-carbonyl
compounds, such as diazomethane and ethyl diazoacetate, can also be used: these
methods readily provide cyclopropanes having alkyl, aryl, alkoxycarbonyl (-COOR), or
acyl substituents. Additional cyclopropanating agents are described in Masalov et al.,
Organic Letters (2004) Vol. 6, pp. 2365-8 and Hansen et al., Chem. Comm. (2006) 4838-
4O.
[0072] The cyclopropyl ring may be substituted or unsubstituted. In cases where
the cyclopropyl ring is substituted, the groups attached to the methylene of the
cyclopropane will be installed onto the D ring after rearrangement and ring expansion.

[0073] The cyclopropanation reactions may be conducted in an aprotic solvent.
Suitable solvents include ethers, such as diethyl ether, 1,2-dimethoxyethane, diglyme, t-
butyl methyl ether, 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, dimethylsulfoxide, dimethylformamide, and the like; or combinations
of two or more solvents. In a certain embodiments, dichloromethane is the solvent used
for me cyclopropanation when a dialkyl zinc and diiodomethane is used.
[0074] In the examples described below, a solution containing the
cyclopropanating agent is prepared by first adding a solution of a phosphoric acid to a
solution of diethylzinc, followed by addition of diiodomethane to the reaction solution.
The cyclopropanation substrate is then added to this solution. Alternatively, the
cyclopropanation agent can be prepared in the presence of the cyclopropanation substrate
by changing the order of addition of the reagents. In certain embodiments, the
cyclopropanation reaction is conducted by first adding the phosphoric acid to a solution
of dialkylzinc, followed by the addition of the cyclopropanation substrate, and finally the
dihaloalkane is added. Using this method the cyclopropanating agent is generated under
controlled conditions and immediately reacts with the cyclopropanation substrate. The
cyclopropanation methods described herein can also be used to cyclopropanate other
polycyclic compounds, for example, those with steroidal backbones.
[0075] Following synthesis of the cyclopropanated steroidal alkaloid core, the
compound may be derivatized using a variety of functionalization reactions known in the
art. Representative examples include palladium coupling reactions to alkenylhalides or
aryl halides, oxidations, reductions, reactions with nucleophiles, reactions with
electrophiles, pericyclic reactions, radical reactions, installation of protecting groups,
removal of protecting groups, and the like.
[0076] In the presence of Lewis or Bronsted acids the cyclopropyl analogs
undergo a rearrangement and ring expansion to afford steroidal alkaloid analogs in which
the D ring has been expanded by one carbon.

[0077] The cyclopropanation and ring expansion can take place in a two-step one
reaction vessel process or in a two-step two reaction vessel process. When the
cyclopropanation and ring expansion are conducted in the same reaction vessel the acid
used to initiate the ring expansion rearrangement is added after completion of the
cyclopropanation reaction. Under certain conditions, the zinc salts that are generated in
the course of cyclopropanating the steroidal alkaloid can themselves act as Lewis acids to
catalyze the ring expansion rearrangement. The reactivity of the zinc salts generated after
the cyclopropanation can be modified by the addition of acids to generate more active
Lewis acids.
[0078] As described below in the examples section, the methanesulfonic acid is
added to the cyclopropanation reaction vessel after completion of the cyclopropanation.
Additional examples of suitable acids include, but are not limited to zinc salts, boron
compounds, magnesium salts, titanium salts, indium salts, aluminum salts, tin salts,
lanthanum salts, trifluoromethanesulfonic acid, diaryloxyphosporic acids, acetic acid, and
HC1. In a certain embodiments of the invention the Lewis acid used is a zinc salt or BF3.
[0079] These ring expanded analogs may be further functionalized using a variety
of functionalization reactions known in the art. Representative examples include
palladium coupling reactions to alkenylhalides or aryl halides, oxidations, reductions,
reactions with nucleophiles, reactions with electrophiles, pericyclic reactions, radical
reactions, installation of protecting groups, removal of protecting groups, and the like.
Utility of Compounds
[0080] Hedgehog signaling is essential in many stages of development, especially
in formation of left-right symmetry. Loss or reduction of hedgehog signaling leads to
multiple developmental deficits and malformations, one of the most striking of which is
cyclopia.
[0081] Many tumors and proliferative conditions have been shown to depend on
the hedgehog pathway. The growth of such cells and survival can be affected by
treatment with the compounds of the present invention. Recently, it has been reported that
activating hedgehog pathway mutations occur in sporadic basal cell carcinoma (Xie et al.
(1998) Nature 391: 9O-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 cancer types such as GI 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 etal (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).
[0082] For example, small molecule inhibition of the hedgehog pathway has been
shown to inhibit the growth of basal cell carcinoma (Williams, et ah, 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).
[0083] In addition, it has been shown that many cancer types 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, 2005. 96th Annual AACR
conference, abstract #2942 Sicklick et al, 2005. ASCO annual meeting, abstract #9610),
hematological malignancies (Watkins and Matsui, unpublished results), basal 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)). As shown in the Examples, the
compounds disclosed herein have been shown to modulate the hedgehog pathway, and
selected compounds have been shown to inhibit tumor growth. It is therefore believed
that these compounds can be useful to treat a variety of conditions, such as various
cancers.

Pharmaceutical Compositions
[0084] 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, formulated together with one or more
pharmaceutically acceptable carriers (additives) and/or diluents. The pharmaceutical
compositions of the present invention may be specially formulated for administration in
solid or liquid form, including those adapted for the following: (1) oral administration,
for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g.,
those targeted for buccal, sublingual, and systemic absorption, capsules, boluses,
powders, granules, pastes for application to the tongue; (2) parenteral administration, for
example, by subcutaneous, intramuscular, intravenous or epidural injection 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 intrarectally, for example, as a pessary, cream or
foam; (5) sublingually; (6) ocularly; (7) transdermally; (8) pulmonarily, or (9) nasally.
[0085] Examples of suitable aqueous and nonaqueous carriers which may 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.
[0086] These compositions may also contain adjuvants such as preservatives,
wetting agents, emulsifying agents, dispersing agents, lubricants, and/or antioxidants.
Prevention of the action of microorganisms upon the compounds of the present invention
may be ensured by the inclusion of various antibacterial and antifungal agents, for
example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be
desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the
compositions. In addition, prolonged absorption of the injectable pharmaceutical form

may be brought about by the inclusion of agents which delay absorption such as
aluminum monostearate and gelatin.
[0087] Methods of preparing these formulations or compositions include the step
of bringing into association a compound of the present invention with the carrier and,
optionally, one or more accessory ingredients. In general, the formulations are prepared
by uniformly and intimately bringing into association a compound of the present
invention with liquid carriers, or finely divided solid carriers, or both, and then, if
necessary, shaping the product.
[0088] When the compounds of the present invention are administered as
pharmaceuticals, to humans and animals, they can be given per se or as a pharmaceutical
composition containing, for example, about 0.1 to 99%, or about 10 to 50%, or about 10
to 40%, or about 10 to 30, or about 10 to 20%, or about 10 to 15% of active ingredient in
combination with a pharmaceutically acceptable carrier.
[0089] Actual dosage levels of the active ingredients in the pharmaceutical
compositions of the present invention may be varied so as to obtain an amount of the
active ingredient which is effective to achieve the desired therapeutic response for a
particular patient, composition, and mode of administration, without being toxic to the
patient.
[0090] The selected dosage level will depend upon a variety of factors including
the activity of the particular compound of the present invention employed, or the ester,
salt or amide thereof, the route of administration, the time of administration, the rate of
excretion or metabolism of the particular compound being employed, the rate and extent
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 like
factors well known in the medical arts.
[0091] In general, a suitable daily dose of a compound of the invention will be
that amount of the compound which is the lowest dose effective to produce a therapeutic
effect. Such an effective dose will generally depend upon the factors described above.
Generally, oral, intravenous and subcutaneous doses of the compounds of the present
invention for a patient, when used for the indicated effects, will range from about 0.0001

to about 100 mg, or about 0.001 to about 100 rag, or about 0.01 to about 100 mg, or about
0.1 to about 100 mg per, or about 1 to about 50 mg per kilogram of body weight per day.
[0092] The subject receiving this treatment is any animal in need, including
primates, in particular humans, and other mammals such as equines, cattle, swine and
sheep; and poultry and pets in general.
Exemplification
[0093] The invention now being generally described, it will be more readily
understood by 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.

[0094] Recrystallized cyclopamine 2 (14.1 g, 34.0 mmol, 1 eq) is dissolved in
anhydrous DCM (70 mL) and anhydrous MeOH (29 mL). The clear solution is cooled,
and triethylamine (10.4 g, 102.7 mmol, 3 eq) followed by benzyl chloroformate (6.20 g,
36.3 mmol, 1.1 eq) is added. After the addition is complete, the solution is stirred in the
ice bath for 30 min. Three portions of benzyl chloroformate (3 X O.35 g, 3.46 mmol, 0.03
eq) are added over the 3 h. The reaction is slowly quenched with water (71 mL), while
maintaining the temperature below 20 °C. The mixture is stirred for 15 min before the
layers are settled and separated. The organic layer is dried over sodium sulfate and

filtered. The combined filtrate is buffered with anhydrous pyridine (30 mL), concentrated,
and solvent exchanged with additional anhydrous pyridine (43 mL) and concentrated.
[0095] The solution of the compound in pyridine (43 mL) is further diluted with
additional anhydrous pyridine (85 mL). Trimethylacetyl chloride (8.3 g, 68.7 mmol, 2
eq) is added slowly to the reaction mixture, and the reaction is heated to 45 °C. The
reaction is stirred at 45 °C for 30 mitt. The reaction is cooled and quenched by the
addition of anhydrous MeOH (4.5 mL). The quenched reaction mixture is stirred at rt for
40 min and then diluted with toluene (97 mL) and is treated sequentially with water (35
mL) and a 10 wt % aqueous sodium carbonate solution (100 mL). After vigorous stirring,
the layers are separated and the organic layer is washed twice with water (2 x 100 mL),
dried over sodium sulfate, and filtered. The filter cake is rinsed with toluene (49 mL) and
discarded. The combined filtrates are concentrated, and solvent exchanged with
concentration to toluene (145 mL) and further concentrating to dryness. The product is
recrystallized from toluene and heptane. The crystalline product is isolated by suction
filtration, washed with cold heptane and dried to a constant weight to afford 15.1 g of the
desired product.

[QQ961 Bis(2,6~dimethyphenyl)phosphate (1O.65 g, 34.8 mmol, 3.1 eq) is dried by
concentration from anhydrous DCM (42 mL) and held under a nitrogen atmosphere. The
phosphate is then redissolved in anhydrous DCM (11O mL). In a separate flask, a
solution of neatdiethylzinc (4.11 g, 33.2, mmol, 3.O eq) in anhydrous DCM (35 mL) is
prepared and cooled to -25 °C. The phosphate solution is slowly transferred to the vessel
containing the diethylzinc solution over 1 h, maintaining the temperature at or below -1O
°C. The clear ethylzinc phosphate solution is wanned to O *C and stirred for 15 min.
Diiodomethane (9.25 g, 34.5 mmoles, 3.O eq) is slowly added to the ethylzinc phosphate
solution, maintaining the reaction temperature between O and 5 °C. After the addition is
complete, the zinc carbenoid solution is stirred for an additional 2O min.

[0097] In a separate flask, compound 3 (7.20 g, 11.4 mmol, 1 eq) is dissolved in
anhydrous DCM (36 mL) and transferred to the reaction flask. After the addition is
complete, the ice bath is removed and the reaction mixture is allowed to warm to rt. After
6 h the contents of the flask are cooled to -53 °C. A solution of methanesulfonic acid
(3.38 g, 35.2 mmol, 3.1 eq) in anhydrous DCM (3 mL) is added, maintaining the reaction
temperature below -45 °C. After 10 min morpholine (20 g, 230 mmol, 20C. The reaction is
allowed to warm to rt overnight. The morpholine salts are removed by filtration and the
filter cake rinsed with DCM (22 mL). The combined filtrates are washed with 2N
aqueous hydrochloric acid (2 x 140 mL), 5 % aqueous sodium bicarbonate (140 mL), 5 %
aqueous sodium bicarbonate (70 mL) and 5 % aqueous sodium bisulfite (70 mL), and
brine (144 mL). The organic layer is dried over magnesium sulfate and filtered. Without
going to dryness, the DCM solution is concentrated and solvent exchanged with methanol
(280 mL). The suspension are chilled with an ice bath and stirred for 40 minutes. The
solids are isolated by filtration, washed twice with cold methanol (2 x 25 mL), and dried
to a constant weight to afford 5.94 g of the desired product.

[0098] In a round bottom flask, compound 4 (11.67 g, 18.1 mmol, 1 eq) and 20 %
palladium hydroxide on wet carbon (2.40 g, 1.71 mmol, 0.09 eq) are placed under a
nitrogen atmosphere and diluted with EtOAc (115 mL) and toluene (60 mL). The
solution is degassed with nitrogen (3X) with evacuation/purge cycles, and the process is
repeated for hydrogen. The suspension is vigorously stirred at rt for 1.5 h. The hydrogen
atmosphere is replaced with nitrogen. Ethylenediamine (0.57 g, 9.5 mmol, 0.52 eq) is
added to the reaction, and the resulting mixture stirred for 20 min. The solution is filtered
under nitrogen, and the filtrate is washed with a 2 % (wt/wt) aqueous solution of
ethylenediamine (125 mL) then water (130 mL), and then dried over sodium sulfate. The
drying agent is removed by filtration and the filtrate is concentrated to dryness under

vacuum. The solids that remained are chased with toluene (2 x 55 mL) on the rotary
evaporator and the resulting material used without further purification in the next step
[0099] The material from the previous step is dissolved in anhydrous DCM (26
mL). The resulting clear solution is added to a 1 M solution of DIBAL in DCM (65 mL,
65 rnmol, 3.6 eq) while maintaining the reaction temperature between -10 and -25 °C.
After 30 min the reaction is quenched with acetone (13 mL), maintaining the reaction
temperature at or below 0 oC. After stirring the quenched reaction mixture for 17 min, it
is added in portions to a flask containing a cold, stirred solution of 20 % (wt/wt) aqueous
Rochelle salt (200 mL). The resulting gelatinous suspension is stirred at rt for 15 h. After
stirring, the clean layers are separated and the aqueous layer back extracted with DCM
(30 mL). The combined organic layers are washed with water (60 mL) and dried over
sodium sulfate. The drying agent is removed by filtration and discarded. The filtrate is
concentrated under vacuum and solvent exchanged to toluene (225 mL added in
portions). The resulting solution is further concentrated to a suspension (5O mL) and
diluted with heptane (115 mL). The resulting mixture is heated until turning
homogeneous (92 °C). The solution is cooled slowly over 12 h to 15 °C, and then held for
16 additional h. The crystalline product is isolated by suction filtration, washed with
heptane (2 x 75 mL) and dried to a constant weight to afford 7.70 g of the desired
product.
[0100] A round bottom flask is sequentially charged with the homo-allylic alcohol
(7.50 g, 17.6 mmol, 1 eq), aluminum tri-tert-butoxide (6.10 g, 24.8 rnmol, 1.4 eq),
anhydrous toluene (115 mL), and 2-butanone (90 g, 1.24 mol, 7 eq). The suspension is
heated under a nitrogen atmosphere to 75 °C for 16 h. The reaction temperature is then
allowed to cool to 49 oC. Aqueous 20 % (w/w) potassium sodium tartrate solution (226 g)
is added to the stirred suspension. The suspension is stirred at rt for 3.5 h. The layers are
separated. The organic layer washed with aqueous 20 % Rochelle salt (2 x 250 mL) and
water (225 mL), then dried over sodium sulfate and filtered. The residue is rinsed with
toluene (30 mL) and discarded. The combined organics are concentrated to dryness.
Residual reaction solvents are removed from the material by concentrating from 2-
propanol (250 mL added portion-wise) to a final solution mass of 44 g. Solvent exchange
from 2-propanol to heptane (275 mL added portion-wise) to a final solution mass is 41 g

fully precipitated the desired product. The suspension is diluted with of additional
heptane (40 mL), stirred at rt for 1 h, and filtered. The product is washed with n-heptane
(17 mL) and dried to afford 5.4 g of the desired product.

[0101] A round-bottom flask is charged with starting material (110 mg, 0.26 mmol, 1
eq) and 10% palladium on carbon (106 mg). The solids are suspended in pyridine (4
mL). The suspension is placed under hydrogen atmosphere (1 arm) and the mixture is
stirred overnight at rt. The reaction mixture is filtered through Celite® and the filtrate
concentrated in vacuo. The crude material is purified using silica gel flash
chromatography (MeOH/DCM 5:95) to afford 93 mg of the desired compound. ([M+H]
= 426.6 m/z).
[0102] Cyclop Jine 2 (5.O2 g, 12.2 mmol, 1.O eq) is dissolved in anhydrous pyridine
(25 mL). DMAP (300 mg, 2.44 mmol, 0.2 eq.) and triethyl amine (5.5 mL, 39.1 mmol,
3.2 eq) are added, followed by BtO-Cbz (10.5 g, 39.1 mmol, 3.2 eq) and heated at 40 °C
for 2h. The mixture is cooled to rt, treated with 30 mL water, heated to get a

homogeneous solution and allowed to cool to room temp. The white precipitate that
formed is collected by filtration, the filter cake is washed with portions of water (3 X 50
mL), and dried in air to afford 9.53 g of crude material which is crystallized from
toluene/heptanes (1:9,70 mL) to give 6.75 g of the desired product.

[0103] To a solution of diethyl zinc (572 mg, 482 uL, 4.63 mmol, 3.00 eq) in 5.0 mL
DCM at -20 °C is added a solution of bis-(2,6-Dimethylphenyl)phosphoric acid (1.42 g, 4.63
mmol, 3.00 eq) in DCM (15 mL) maintaining the reaction temperature below -8 °C. The
solution is aged for 15 min. at 0 °C, neat diiodomethane (1.24 g, 374 µL, 3.00 eq) is added,
aged for 15 min. at 0 °C before adding a solution of (BisCBzcyclopamine, 1.05 g, 1,54
mmol, 1.0 eq), in DCM (10 mL). The cooling bath is replaced by a water bath at rt and
maintained at rt for 4.5 h. The mixture is cooled to -76 °C with a dry ice-acetone bath and
treated drop wise with methanesulfonic acid DCM solution (0.6 mL 50% v/v solution 4.63
mmol, 3.0 eq) maintaining the reaction temperature below -74 °C. The mixture is aged for 15-
20 min. and quenched drop wise with morpholine (2.69 g, 2.70 mL, 2O eq) maintaining the
reaction temperature below -65 °C. The cooling bath is removed, the reaction mixture is
stirred for 16-18 h., the white precipitate is filtered off, and the filtrate is successively washed
with 2.0 M HC1 (2 x 20 mL), satd. sodium bicarbonate (2 x 20 mL), water (2 x 20 mL) and
brine (20 mL). Dried over magnesium sulfate, concentrated in vacuo to dryness and the crude
is purified by silica gel flash chromatography (hexanes/EtOAc 17:3-4:1) to afford 924 mg
(1.33 mmol, 86%) of the desired product.
StepC

[o1o4] To a solution of compound 7 (4.o5 g, 5.83 mmol, 1 eq) in a solution of
EtoAc:toluene (2:1, 6o mL) is added of 20% palladium hydroxide on carbon (823 mg, o.583
mmol, 0.1 eq.). The flask is evacuated and filled with hydrogen three times. The mixture is
stirred under an atmosphere of hydrogen for lh. Neat ethylene diamine (0.38 mL) is added,
stirred for lh., and the catalyst is filtered off. The filter cake is washed twice with
EtOAc:toluene (2:1,12 mL). The combined filtrates are washed with a 2% aqueous solution
of ethylene diamine (3 X 20 mL), dried over sodium sulfate and concentrated in vacuo to give
2.46 g as a white crystalline solid.

[0105] A round bottom flask is sequentially charged with the homo-allylic alcohol 8
(7.5o g, 17.6 mmol, 1 eq), aluminum tri-tert-butoxide (6.1o g, 24.8 mmol, 1.4 eq), anhydrous
toluene (115 mL), and 2-butanone (90 g, 1.24 mol, 7 eq). The suspension is heated under a
nitrogen atmosphere to 75 °C for 16 h. The reaction temperature is then allowed to cool to 49
°C. Aqueous 20 % (w/w) potassium sodium tartrate solution (226 g) is added to the stirred
suspension. The suspension is stirred at rt for 3.5 h. The layers are separated. The organic
layer washed with aqueous 20 % Rochelle's salt (2 x 250 mL) and water (225 mL), then dried
over sodium sulfate and filtered. The residue is rinsed with toluene (30 mL) and discarded.
The combined organics are concentrated to dryness. Residual reaction solvents are removed
from the material by concentrating from 2-propanol (250 mL added portion-wise) to a final
solution mass of 44 g. Solvent exchange from 2-propanol to n-heptane (275 mL added
portion-wise) to a final solution mass of 41 g fully precipitated the desired product. The

suspension is diluted with of additional n-heptane (40 mL), stirred at rt for 1 h, and filtered.
The product is washed with n-heptane (17 mL) and dried to afford 5.4 g of the desired
product.

[0106] A round-bottom flask is charged with starting material (110 mg, 0.26 mmol, 1
eq) and 1o% palladium on carbon (106 mg). The solids are suspended in pyridine (4 mL).
The suspension is placed under hydrogen atmosphere (1 atm) and the mixture is stirred
overnight at rt. The reaction mixture is filtered through Celite® and the filtrate concentrated
in vacuo. The crude material is purified using silica gel flash chromatography (MeOH/DCM
5:95) to afford 93 mg of the desired compound. ([M+H] = 426.6 m/z).

[0107] In a seal tube, ketone 6 (85 mg, o.199 mmol, 1 equiv.) was charged and
triethyleneglycol (2 mL) was added followed by hydrazine monohydrate (500 mg, 10 mmol,
50 equiv.) and potassium carbonate (138 mg, 1 mmol, 5 equiv.). The tube was sealed and the
reaction was heated at 150 °C for 16 h. The reaction was cooled to rt and water was added.
The residue was extracted with chloroform (3X). The combined organic layers are washed
with water, dried over Na2SO4, and concentrated to dryness. The colorless oil was purified

using silica gel flash chromatography (DCM/MeOH 96:4). The purified fractions are pooled
aind concentrated to dryness. The resulting oil was dissolved in MTBE and washed with water
(2X), 2N NaOH, and then brine. The combined organic layers are dried over Na2SO4, filtered
and evaporated to afford 64 mg of the desired material as a white foam. ([M+H] = 412.7 m/z).

[0108] A sealed tube was charged with compound 5 (223 mg, 0.52 mmol, 1 eq) and
DMF (lmL). 2-bromopropane (1.3 g, 10.5 mmol, 20 eq) and Na2CO3 (73 mg, o.68 mmol, 1.3
eq) were added and the flask was sealed and heated to 50 °C. The mixture was stirred for 16 h
at which point -70% conversion was observed. Additional (0.26 g, 2.12 mmol, 4 eq) was
added. The reaction was stirred for 2 h and additional 2-bromopropane (0.13 g, 1.1 mmol, 2
eq) was added. The reaction was stirred for another lh. The reaction was cooled to rt and
water was added. The residue was extracted with MTBE (3X). The organic layers were
combined washed with brine, dried over Na2SO4, filtered, and concentrated to dryness. The
white foam was purified using silica gel flash chromatography (DCM/MeoH 99:1) to give
2o6 mg of the N-isopropyl derivative as a white foam.
[0109] The N-isopropyl derivative (205 mg, o.44 mmol, 1 eq) was dissolved in of 4-
methoxypyridine (1.5 mL). The flask was placed under inert atmosphere and Pd/C 1o% (wet,
Aldrich Degussa type E1o1, 40 mg) was added. The flask was sealed and purged three times
with hydrogen and left 16 h under 1 atm of hydrogen. Celite® was added to the reaction
mixture. The mixture was filtered through a small pad of Celite® and washed with EtoAc.
The organic layer was washed with 1N HC1 aq. (2x) then with water. The organic layer was

dried over Na2SO4, filtered though cotton and evaporated to give 34 mg of crude. The
aqueous layer was neutralized with 2N KOH and extracted with DCM (3X). The combined
organic layers were washed with water, dried over Na2SO4, filtered though cotton and
combined with the initial 34 mg of crude. The crude material was purified using silica gel
flash chromatography hexane/EtoAc (6:4) to afford 8o mg of desired product. ([M+H] =
468.7 m/z).

[0110] In a round-bottom flask, compound 6 (88 mg, 0.21 mmol, 1 eq) was dissolved
in anhydrous THF (1 mL). The mixture was cooled to 0 °C, Pyridine (84 µL, 1 mmol, 5 eq)
and benzoylperoxide (150 mg, 0.62 mmol, 3 eq) were added successively. The homogeneous
mixture was gradually wanned to rt over 2 h and stirred overnight at rt. The reaction was
quenched by adding saturated NaHCO3. The residue was extracted with MTBE. The
combined organic layers were washed with water, dried over Na2SO4, filtered and
concentrated under reduced pressure. The crude was purified using silica gel flash
chromatography (hexane/EtOAc (9:1 to 4:1)) to give the N-o derivative product (6o mg, 0.11
mmol) as a white foam. This foam was dissolved in 2 mL of MeOH followed by 2N aqueous
KoH (0.4 mL). The reaction mixture was stirred for 1 h. Most of the MeOH was evaporated
under a stream of nitrogen and IN HCl (5oo µL) was added. The material was extracted with
DCM (3X). The combined organic layers were washed with water, dried over Na2SO4,
filtered and concentrated under reduced pressure. The crude was purified using silica gel

flash chromatography (hexanes/EtOAc (from 88:12--1:1)) to yield 11 mg of the desired
product. ([M+H] = 442.5 m/z).

[0111] In a round bottom flask, compound 6 (89 mg, 0.209 mmol, 1 eq) and N-
(benzyloxycarbonyl)-aminoacetaldehyde (148 mg, 0.85 mmol, 4 eq) were dissolved in DCM
(2 mL). Sodium triacetoxyborohydride (177 mg, o.85 mmol, 4 eq) was added and the reaction
was stirred for 3 h at rt. The mixture was poured in saturated aqueous NaHCO3 solution and
the residue was extracted with DCM (3x). The combined organic layers were washed with
water, dried over Na2SO4, filtered though cotton and evaporated to give a foamy solid (247
mg). The crude was dissolved in EtoAc (2 mL) and treated with of 4M HC1 (156 µL). After
3o min a white precipitate slowly formed. The resulting slurry was stirred for 15 min.
Filtration gave 12o mg of white solid. The material was dissolved in EtOAc and treated with
a saturated aqueous NaHCO3 solution. The organic layer was collect and the aqueous layer
and was extracted with EtoAc (2X). The combined organic layers were washed with brine,
dried over Na2SO4. Filtration and evaporation gave the desired intermediate. This material
was used in me next step without purification.
Step B

[o112] All of the material from Step A was dissolved in EtoAc (3 mL) and treated
with of Pd/C 1o% (3o mg , wet,Aldrich Degussa type E1o1). The flask was sealed and
purged three times with hydrogen and left overnight under 1 atm of hydrogen. After 16 h, the
mixture was filtered through a small pad of Celite® and washed with EtoAc to afford 52 mg
of the amine as a white foam.

[0113] A round-bottom flask containing the amine 14 (52 mg, o.11 mmol, 1 eq) was
charged with the lH-tetrazole-5-acetic acid (21 mg, 0.166 mmol, 1.5 eq), DCM (2 mL), EDCI
(42 mg, 0.22 mmol, 2 eq) and N,N-diisopropylethylamine (57 mg, o.44 mmol, 4 eq) The
resulting yellow solution was stirred at rt for 4 h. The reaction was quenched by the addition
of saturated aqueous NaHCO3 solution and the residue was extracted with DCM (3X). The
combined organic layers were dried over Na2SO4, filtered though cotton and evaporated to
give 62 mg of off-white solid. This material was purified using silica gel flash
chromatography (MeoH/DCM 5:95-> 1o:9o) to afford 31 mg of the desired product. ([M+H]
= 579.7 m/z).

[0114] A round-bottom flask was charged with starting material (47 mg, 0.110 mmol,
1 eq) and potassium carbonate (150 mg, 1.09 mmol, 10 eq). The solids were suspended in 2
mL of DCM. Iodometfiane (14 µL, o.22 mmol, 2 eq) was added and the mixture was stirred
for 2 at rt. TLC (DCM/MeoH 95:5) indicate >90% completion. Iodomethane (14 018µL, o.22
mmol, 2 eq) was added to the reaction mixture, which was stirred for 2 h. The reaction
mixture was added water. The phases were separated and the organics were dried and
concentrated to dryness. The residue was purified using silica gel flash chromatography
(DCM/MeoH 1oo:o-98:2) afford 34 mg of the desired product ([M+H] = 44o.5 m/z).

[0115] A round-bottom flask was charged with starting material (59 mg, 0.126 mmol,
1 eq) and potassium carbonate (350 mg, 2.5 mmol, 20 eq). The solids were suspended in 3
mL of DCM. The reaction was charged with iodomethane (8o µL, 1.29 mmol, 10 eq) and the
mixture was stirred overnight at rt. The reaction mixture was charged with water. The organic
phase was separated and the aqueous layer was back extracted with DCM. The combined
organic layers were dried and concentrated to dryness. The residue was purified using silica
gel flash chromatography. DCM/MeoH (95:5-»90:10) to afford 52 mg of the desired product.
([M+H] = 639.5 m/z).

[0116] In a round bottom flask, compound 5 (50 mg, o.12 mmol, 1 eq) and N-(t-
butoxycarbonyl)-aminoacetaldehyde (6 mg, 0.38 mmol, 3.1 eq) were dissolved in DCM (2
mL). Sodium triacetoxyborohydride (8 mg, 0.38 mmol, 3.1 eq) was added and the reaction
was stirred for 2 h at rt. The mixture was poured in saturated aqueous NaHCO3 solution and
the residue was extracted with DCM (3x). The combined organic layers were washed with
water, dried over Na2SO4, filtered though cotton and evaporated to give a foamy solid (95
mg). The crude material was purified using silica gel flash chromatography (EtoAc/Hexanes
1:1) to yield 55 mg of compound 18.

[0117] A round-bottom flask was charged with starting material 18 (800 mg, 1.4
mmol, 1 eq). Thesolid was dissolved in a solution of DCMand TFA (10mL, 1:1). The
solution was stirred for 45 min at rt. The reaction was partitioned between a solution of 10%
sodium carbonate and DCM. The organic was separated and washed with 10% sodium
carbonate. The organic phase was concentrated to dryness. The residue was used without
further purification for the next step.

[0118] A round-bottom flask was charged with starting material (300 mg, 0.64 mmol,
1 eq) was dissolved in THF/ACN (1:1,4 mL). The reaction was charged 37% formaldehyde
in water (24o µL, 3.22 mmol, 5 eq) and sodium cyanoborohydride (64 mg, 1 mmol, 1.6 eq).
The mixture was stirred for 3o min at rt. The reaction was then partitioned between a solution
a saturated aqueous solution of sodium bicarbonate and DCM. The organic was separated,
dried and concentrated to dryness. The crude material was purified using silica gel flash
chromatography (MeoH/DCM 5:95- 10:90) to give the desired material.

[0119] A round-bottom flask was charged with starting material 20 (30 mg, 0.06
mmol, 1 eq) and 10% palladium on carbon (30 mg). The solids were suspended in pyridine (2
mL). The suspension was placed under hydrogen atmosphere and the mixture was stirred
overnight at rt. The reaction mixture was filtered on Celite® and the filtrate concentrated to
dryness. The crude material was purified using silica gel flash chromatography (MeoH/DCM
5:95-10:90) to gave the desired material. ([M+H] = 497.7 m/z).

[0120] A round-bottom flask was charged with starting material (85 mg, 0.20 mmol, 1
eq) was dissolved in DCM (4 mL). The reaction was charged with N-(2-oxoethyl)acetamide
(80 mg, 0.7o mmol, 3.5 eq) and sodium triacetoxyborohydride (170 mg, 0.80, 4 eq). The
mixture was stirred for 1 hour at rt. The reaction was partitioned between a solution a
saturated aqueous solution of sodium bicarbonate and DCM. The organic was separated, dried
and concentrated to dryness. The crude material was purified using silica gel flash
chromatography (MeOH/DCM 5:95) to give the desired material. ([M+H] = 511.7 m/z).

[0121] Compound 22 was synthesized according to the procedure described in
example 9, using N-methyl-N-(2-oxoethyl)acetarnide in place of N-(2-oxoethyl)acetamide.
([M+H] = 525.7 m/z).

[0122] Compound 23 was synthesized according to the procedure described in
example 10, using N-(2-oxoethyl)-3-phenylpropanamide in place of N-(2-oxoethyl)acetamide.
([M+H] = 6o1.8 m/z).

[0123] Compound 23 was synthesized according to the procedure described in
example 10, using N-methyl-N-(2-oxoethyl)-3-phenylpropanamide in place of N-(2-
oxoethyl)acetamide. ([M+H] 615.9 m/z)

[0124] A round-bottom flask was charged with compound 6 (4.23 g, 9.94 mmol, 1 eq)
and THF (6o mL). Triethylamine (6.92 mL, 49.7 mmol, 5.0 eq) and benzyl chloroformate
(1.54 mL, 10.93 mmol, 1.1 eq) were added and the mixture was stirred for 1 hour at rt. The
reaction mixture was partitioned between saturated aqueous bicarbonate (100 mL) and EtoAc
(100 mL). The phases were separated and the organics were dried (Na2SO4) and concentrated
to dryness. The crude material was purified using silica gel flash chromatography
(EtoAc/Hexanes 2:98-> 14:86) to give 3.75g of material.
Step B

[0125] A MeoH solution (10 ml) of cerium trichloride heptahydrate (260 mg, 0.69
mmol, 1.3 eq.) at 0 °C was treated with sodium borohydride (24 mg, 0.65 mmol, 1.2 eq),
stirred for 15 min, and then cooled to -78 °C. A THF solution (10 ml) of ketone 26 (300 mg,
0.54 mmol, 1 eq) was added, and the mixture was stirred for 1 h and then warmed to rt. Water
(50 ml) and EtoAc (50 ml) were added, mixed, and the layers split. The organic layer was
collected, washed with brine (30 ml), dried over sodium sulfate, and concentrated to a white
residue. The crude product was purified by silica gel flash chromatography (ether/hexanes
2:3-1:1) to give 235 mg of 3-beta alcohol 27.

[0126] Compound 27 (235 mg, 0.42 mmol, 1 eq) was dissolved in EtOAc (7 ml) in a
flask with stir bar and rubber septum. The solution was sparged with nitrogen, and Pd/C 10%
(wet,Aldrich Degussa type E101, 50 mg) was added. This mixture was sparged with nitrogen
and then hydrogen gas and stirred at rt for 3h. The mixture was then sparged with nitrogen,
filtered through a o.45 µm polyethylene membrane and concentrated to a clear oil. The oil was
purified by silica gel flash chromatography (NH4OH(aq)/MeOH/DCM
0.5:2:97.5-0.5:6:93.5) to give 130 mg of compound 25 as a white powder. ([M+H] = 427.4
m/z)

[0127] A THF solution (10 ml) of ketone 26 (300 mg, 0.54 mmol, 1 eq) at -78 °C was
treated with K-Selectride® (Potassium tri-sec-butylborohydride) (0.58 ml, 0.58 mmol, 1.1 eq)
and stirred for 60 min. Methanol (1 ml) was added and the solution warmed to rt. Water (50
ml) and EtoAc (50 ml) were added, mixed, and the layers split. The organic layer was washed
with brine (30 ml), dried over sodium sulfate, and concentrated to a white residue. The crude
product was purified by silica gel flash chromatography (Ether/Hexanes 2:3-1:14) to give
170 mg of pure 3-alpha alcohol 29.

[0128] Compound 29 (170 mg, 0.30 mmol, 1 eq) was dissolved in EtoAc (5 ml) in a
flask with stir bar and rubber septum. The solution was sparged with nitrogen, and Pd/C 10%
(wet, Aldrich Degussa type E101, 35 mg) was added. This mixture was sparged with nitrogen
and then hydrogen gas and stirred at rt for 3h. The mixture was then sparged with nitrogen,
filtered through a o.45 µm polyethylene membrane and concentrated to a clear oil. The oil was
purified by silica gel flash chromatography (NH4OH(aq)/MeOH/DCM

0.5:2:97.5-o.5:6:93.5) to afford 76 mg of compound 28 as a white powder ([M+H] = 427.4
rh/z).

[0129] Compound 27 (1oo mg, 0.18 mmol, 1 eq) with benzyltriethylammonium
chloride (8 mg, o.36 mmol, 0.2 eq) was dissolved in DCM (5 ml) and stirred vigorously with
dimethyl sulfate (130 µL, 1.43 mmol, 8 eq) and 5o% aqueous potassium hydroxide (o.5 ml) at
rt for 18h. The mixture was partitioned between water (3o ml) and EtoAc (3o ml), and the
organic layer was men washed with brine, dried over sodium sulfate, and concentrated to a
clear oil. The crude ether was purified by silica gel flash chromatography (Ether/Hexanes
3:7-9:113) to give 75 mg of me methyl ether as a clear oil.

[0130] Compound 31 (66 mg, o.115 mmol, 1 eq) was dissolved in EtoAc (5 ml) in a
flask with stir bar and rubber septum. The solution was sparged with nitrogen, and Pd/C 10%
(wet, Aldrich Degussa type E1o1, 20 mg) was added. This mixture was sparged with nitrogen
and then hydrogen gas and stirred at rt for 3h. The mixture was then sparged with nitrogen,
filtered mrough a o.45 µm polyethylene membrane and concentrated to a clear oil. The oil was

purified by silica gel flash chromatography (NH4OH(aq)/MeoH/DCM
G.5:2:97.5-0.5:6:93.5) to give 22 mg of compound 3o as a white powder ([M+H] = 441.4
m/z).

[0131] Compound 27 (100 mg, 0.18 mmol, 1 eq) was dissolved in DCM (5 ml), and 4-
dimethylaminopyridine (4 mg, o.35 mmol, o.2 eq), N,N-diisopropylethylamine (0.15 ml, 0.9
mmol, 5 eq), and acetic anhydride (0.070 ml, 0.72 mmol, 4 eq) were added. After stirring for
12h at rt, the solution was split between EtoAc (30 ml) and 5% aqueous sodium bicarbonate
(15 ml). The organic layer was washed with brine, dried over sodium sulfate, and
concentrated to a clear oil. The crude ester was purified by silica gel chromatography
(Ether/Hexanes 3:7-9:113) to give 1oo mg of the ester as a clear oil.

[0132] Compound 33 (1oo mg, 0.18 mmol, 1 eq) was dissolved in EtoAc (5 ml) in a
flask with stir bar and rubber septum. The solution was sparged with nitrogen, and Pd/C 10%
(wet, Aldrich Degussa type E101, 20 mg) was added. This mixture was sparged with nitrogen
and then hydrogen gas and stirred at rt for 3h. The mixture was then sparged with nitrogen,

filtered through a 0.45 p.m polyethylene membrane and concentrated to a clear oil. The oil was
purified by silica gel flash chromatography (NH4OH(aq)/MeOH/DCM
0.5:2:97.5-0.5:6:93.5) to give 45 mg of compound 32 as a white powder ([M+H] = 469.4
m/z).
[0133] Compound 34 was synthesized according to the procedure described in
example 16, using compound 29 in place of compound 27. ([M+H ] = 441.4 m/z).

[0134] Compound 34 was synthesized according to the procedure described in
example 17, using compound 29 in place of compound 27. MS ([M+H] = 469.4 m/z)

[0135] An ethanol solution (5 ml) of compound 26 (185 mg, 0.3 mmol, 1 eq) was
treated with hydroxylamine hydrochloride (140 mg, 2 mmol. 6 eq), sodium acetate (160 mg, 2
mmol, 6 eq), and water (0.5 mL), and the mixture was stirred at rt for 1 hr. The mixture was
split between EtoAc and water (50 mL each). The organic layer was washed with brine (30
mL), dried over sodium sulfate, and concentrated to a white residue. The crude product was
purified by silica gel chromatography (ether/hexanes 2:3->1:1) to give 193 mg of oxime 37.

[0136] Compound 37 (65 mg, 0.113 mmol) was dissolved in EtoAc (7 ml) in a flask
with stir bar and rubber septum. The solution was sparged with nitrogen, and Pd/C 10%
(wet.Aldrich Degussa type E101, 20 mg) was added. This mixture was sparged with nitrogen
and then hydrogen gas and stirred at rt for 3h. The mixture was then sparged with nitrogen,
filtered through a 0.45 µm polyethylene membrane and concentrated to a clear oil. The oil was
purified by silica gel flash chromatography (NH4OH(aq)/MeOH/DCM
0.5:2:97.5->0.5:6:93.5) to give 15 mg of compound 36 as a white powder, a mixture of cis
and trans oxime isomers ([M+H] = 440.3 m/z).

[0137] Compound 27 (42 mg, 0.075 mmol, 1 eq) was dissolved in DCM (5 ml), and 4-
dimethylaminopyridine (2 mg, 0.02 mmol, 0.2 eq), N-Cbz glycine (23 mg, 0.110 mmol, 1.5
eq), and diisopropylcarbodiimide (0.023 ml, 0.150 mmol, 2 eq) were added. After stirring for
12h at rt, the solution was split between EtoAc (30 ml) and 5% aqueous sodium bicarbonate
(15 ml). The organic layer was washed with brine, dried over sodium sulfate, and
concentrated to a clear oil. The crude ester was purified by silica gel flash chromatography
(ether/hexanes 2:3 - 1:1) to give 35 mg of the ester as a clear oil

[0138] Compound 39 (235 mg, o.42 mmol, 1 eq) was dissolved in EtoAc (7 mL) in a
flask with stir bar and rubber septum. The solution was sparged with nitrogen, and Pd/C10%
(wet.Aldrich Degussa type E1o1, 50 mg) was added. This mixture was sparged with nitrogen
and then hydrogen gas and stirred at rt for 3h. The mixture was then sparged with nitrogen,
filtered through a o.45 µm polyethylene membrane and concentrated to a clear oil. The oil was
purified by silica gel flash chromatography (NH4OH(aq)/MeOH/DCM
0.5:2:97.5-0.5:6:93.5) to give 17 mg of the desire product as a white powder ([M+H] =
452.4 m/z).

[0139] Compound 4o was synthesized according to the procedure described in
example 21, using compound 29 in place of compound 27. ([M+H] = 452.4 m/z)

[0140] Compound 41 was synthesized according to the procedure described in
example 1o, using N-(2-oxoethyl)-2-phenylacetamide in place of N-(2-oxoethyl)acetamide.
([M+H] = 587.7 m/z).

[0141] A round-bottom flask was charged with alcohol 29 (7.60 g, 13.53 mmol, 1 eq)
and was dissolved in DCM (115 mL). The reaction was charged with triethylamine (8.21 g, 81
mmol, 6.0 eq). The mixture was cooled to 0° C and charged with methanesulfonylchloride
(1.86 g, 16.2 mmol, 1.2 eq). After 3o min, the reaction mixture was partitioned between a
saturated aqueous solution of sodium bicarbonate and EtoAc. The organic layer was
separated, dried over sodium sulfate and concentrated to dryness. The residue was purified

using silica gel flash chromatography (EtOAc/hexanes 1o -> 25%) gave the desired material
mesylate.
[0142] A round-bottom flask was charged with the mesylate (9.1 g, 14.22 mmol, 1 eq)
and was dissolved in 50 mL of DMPU. The reaction was charged with sodium azide (4.62 g,
71.1 mmol, 5.0 eq) and heated to 60° C. The mixture was stirred for 17 h. The reaction
mixture was then cooled to rt and charged with water. The mixture was stirred for 30 min. The
mixture was filtered under vacuum, rinsed with water and air dried and used directly without
purification in the next step.

[0143] A round-bottom flask was charged with azide 43 (8.35 g, 14.23 mmol, 1 eq)
and THF (120 mL) was added. The reaction was then charged with triphenylphosphine (11.2
g, 42.7 mmol, 3.0 eq). The mixture was heated to 50°C and stirred for 20 h. The reaction
mixture was then cooled to rt and the solvent removed under vacuum. The residue purified
using silica gel flash chromatography (MeOH/DCM 1o% -> 20%) to afford the amine.
[0144] A round-bottom flask was charged with the amine (5.10 g, 9.09 mmol, 1 eq)
and was dissolved in DCM (60 mL). The reaction was charged with N,N-
diisopropylethylamine (5.88 g, 45.5 mmol, 5.0 eq). The mixture was cooled to 0°C and
charged with memanesulfonylchloride (2.08 g, 18.2 mmol, 2.0 eq). After 30 minutes, the
reaction mixture was partitioned between a saturated aqueous solution of sodium bicarbonate
and EtOAc. The organic layer was collected, dried over sodium sulfate and concentrated to
dryness. The residue was purified using silica gel flash chromatography (EtOAc/hexanes 10
- 30%) to afford the Cbz protected methanesulfonamide.

[0145] A round-bottom flask was charged with the Cbz protected methanesulfonamide
(5.37 g, 8.41 mmol, 1 eq) and 1o% palladium on carbon (1.0 g). The solids were suspended
in 2-propanol (50 mL). The suspension was placed under hydrogen atmosphere and the
mixture was stirred for 4 h at 25° C. The reaction mixture was then filtered on Celite® and the
filtrate concentrated to dryness. The residue was then purified using silica gel flash
chromatography (DCM/MeoH0 -> 5%) to afford the desired product. [M+H] = 505.6 m/z.
Alternate Synthesis of Compound 42

[0146] Recrystallized cyclopamine (2.07 g) is charged to an appropriately sized
reaction vessel and placed under an inert atmosphere. EtoAc (7.6 g), triethylamine (1.53 g),
and DMAP (307 mg) are added sequentially. The suspension is warmed to 40°C. Cbz-OBt is
added in three portions over 90 minutes, keeping the internal temperature below 45°C. The
reaction mixture is stirred at 40°C for 90 minutes. The temperature is maintained while
methanol (26.4 g) is slowly added to the reaction mixture. The resulting suspension is cooled
to room temperature and stirred for at least 15 hours. The crude product is collected by
filtration and rinsed with methanol (5 g). The white solid is dried under vacuum to a constant
weight and recrystallized from heptane (30.3 g) and toluene (3.2 g) to afford Compound 24a
(3.0 g).

[0147] Solid bis(2,6-dimethylphenyl) hydrogenphosphate and 24a are pre-dried and
placed under a nitrogen atmosphere. Neat diethyl zinc (722 mg) is charged to an appropriately
sized reaction vessel containing DCM (9.0 g). DCM solutions of the phosphate (1.83 g in 17.9
g) and IPI-332690 (1.34 g in 3.6 g) are added sequentially at or below 25 °C. Diiodomethane
(1.58 g) is charged and the reaction is stirred at 28°C for 4-6 hours. The reaction is cooled to
-45°C and a solution of methanesulfonic acid in DCM (566 mg in 1.5 g) is charged. After 15
minutes, morpholine (1.711 g) is added and the mixture is allowed to warm to room
temperature overnight. The organic layer is washed twice with 2N HC1 (2 x 13.6 g) then
sequentially with 4.8 wt % sodium carbonate (aq), 4.8 wt% sodium sulfite (aq), and 4.8 wt%
brine (13.6 g each). The organic layer is dried, filtered, concentrated to 4 g and diluted with
isopropanol (4 g). The product is crystallized from solution by the slow addition of methanol
(9.3 g). Filtration with a methanol rinse (2.6 g) and drying afford 1.o9 g of 24b (79% isolated
yield).

[0148] Johnson Matthey Pd/C catalyst A-3o5o38-5 (890 mg) is charged to an
appropriately sized reaction vessel, followed by 24b (2.24 g). The reaction vessel is purged
with N2 and toluene (21.8 g) and 2-propanol (6.7 g) are added sequentially. The system is
degassed and placed under a nitrogen atmosphere, and the process is repeated with hydrogen.
The system is stirred vigorously and the hydrogen blanket is maintained at one atmosphere for
4-5 hours. The reaction is monitor by either TLC or HPLC. If incomplete, the reaction is

inerted, additional catalyst (145 mg) is charged, and the hydrogen atmosphere is returned for
another hour. Ethylenediamine (12.9 mg) is charged and the mixture was stirred for 15
minutes. The catalyst is removed by filtration with a toluene:IPA (3:1) rinse. The filtrate and
rinses are concentrated and solvent exchanged to toluene. The product is crystallized from
toluene (19.0 g) and heptane (18.0 g) to afford 24c as a white crystalline solid (1.34 g, 98%
yield).

[0149] 24c (644 mg) is charged to an appropriately sized reaction vessel followed by
aluminum t-butoxide (525 mg), toluene (8.34 g, 15 vol), and 2-butanone (7.83 g, 15 vol). The
contents of the flask are degassed with evacuation/nitrogen purge cycles to remove oxygen
and the reaction mixture is heated at 75°C with vigorous stirring for 16-18 hours. The
reaction is quenched by the addition of aqueous Rochelle's salt (2.6 g in 10.3 g water) and the
mixture vigorously stirred for one hour at 45 °C. The aqueous and organic layers are
separated. The aqueous layer is back extracted with a mixture of toluene (2.9 g) and EtoAc
(2.9 g). The organic layers are combined and washed with fresh Rochelle's salt solution (2.6 g
in 10.3 g water) and then with water (12.9 g). The resulting organic layer is dried over
sodium sulfate (1.97 g), filtered, and concentrated in vacuo. The product is crystallized via a
charge and concentration solvent exchange first to IRA (6.5 g) and then Heptane (7.7 g). The
thick heptane slurry (-2.7 g) is stirred overnight and solids are collected by filtration. Vacuum
drying affords 24d (550 mg) in an 85% yield.

[0150] The enone 24d (459 mg) and Johnson-Matthey 5% palladium on carbon
(A503023-5, 1o1 mg) are charged to an appropriately sized multi neck reaction vessel. The
vessel is purged with nitrogen and 3-picoline (2.2 g) is charged as the solvent. Stirring is
started and the vessel is first degassed using nitrogen and men stirred under hydrogen at
atmospheric pressure for 8 hours. At the end of the reaction, the catalyst is removed by
filtration through o.2 micron media, rinsing with ACN (1.4 ml). The filtrate and rinse are
combined in a clean reaction vessel equipped with mechanical stirring, an internal temperature
probe, and a nitrogen atmosphere. A solution of citric acid (3.7 g) in water (9.2 ml) is charged
to the reaction vessel at or below 30°C, and IPI-335589 is allowed to slowly crystallize from
solution as the citrate salt at 20 and then 0°C. The crystalline product is recovered by suction
filtration and washed with water (3.7 ml). After drying, the citrate salt, 24e, is isolated as a
hydrate (3-5 wt% water) in 89.5% yield (622 mg) with a β:α ratio approaching 90:1.

[0151] 24e (1.50 g) is charged to the appropriately sized reactor along with 2-
methyltetrahydrofuran (7.7 g) and 1M sodium carbonate (9.0 ml) A solution of benzyl
chloroformate (454 mg) in 2-methyltetrahydrofuran (300 mg) is added via addition funnel and
the reaction is ambient temperature for 1-2 hours. When the reaction is complete, the stirring
is stopped, the layers are separated and the organic layer is washed twice with water (2 x 6 g).
The organic layer is dried over of sodium sulfate (3 g), filtered and concentrated. Residual

water is reduced further by concentration from fresh 2-methyltetrahydrofuran (6.5 g) and the
material is transferred as solution in anhydrous 2-methyltetrahydrofuran to the next reaction.

[0152] Commercial 1 M K-Selectride in THF (1.20 g) is charged to a dry reaction
vessel under a nitrogen atmosphere, diluted with anhydrous 2-methyltetrahydrofuran (2.10 g)
and cooled to -65°C. The solution of 24f (o.41 g) in 2-methyltetrahydrofuran (1.5 g), is then
slowly added to the reaction vessel to control the internal temperature at -65±5°C. The
reaction is stirred for 2 hours and warmed to -20°C over approximately 1 hour and stirred for
an additional hour. The reaction is monitored by HPLC and reactions that are incomplete are
driven to completion with additional K-selectride. The reaction is quenched at low
temperature with MeOH (0.33 g), then 3M NaOH (2.4 g) at -20°C and 15% hydrogen
peroxide in water (1.04 g) at or below 5°C, then stirring overnight at ambient temperatures.
The layers are split and the organic layer is washed sequentially with 1M aqueous NaoH (2
ml), o.5 M aqueous Na2SO3 (2 ml), and water (2 ml) adjusted to a pH of 3 with HC1. The
organic layer is dried over sodium sulfate (0.82 g), filtered and concentrated. The product 24g
(0.457 g) is re-concentrated from DCM (0.9 g) and used in the next reaction.

[0153] 24g (1.36 g) is charged with anhydrous DCM (18.1 g) to an appropriately size
reaction vessel, place under an inert atmosphere and cooled to -20°C. Triethylamine (0.61 mg)
is charged followed by the slow addition of methanesulfonyl chloride (373 mg) in anhydrous
DCM (300 mg). The reaction is stirred for 1 hour at -20°C. The reaction is monitored by

HPLC. Incomplete reactions are driven to completion with additional methanesulfonyl
Chloride. When complete, the reaction is quenched with water (13.6 g) and allowed to warm.
The layers are separated and the organic layer is washed with 2.5 wt% sodium bicarbonate
(13.8 g) and then water (10.9 g). The organic layer is dried over of sodium sulfate (4 g),
filtered, and concentrated. The product solution is solvent exchanged via charge and
concentration to t-butyl methyl ether (10.9 ml) and then l,3-dimethyl-3,4,5,6-tetrahydro-
2(lH)-pyrirnidinone (DMPU, 4.7 ml). The DMPU solution is used directly in the next
reaction.

[0154] Sodium azide (0.74 g) is charged to an appropriately sized reaction vessel. The
solution of 24h (1.46 g) in DMPU (5.9 g) is charged to the reaction vessel, rinsing with
additional DMPU (1.9 g). The suspension is heated to 60°C for 15 hours, maintaining a
nitrogen sweep for the entire reaction. The reaction is cooled to ambient temperature and
diluted with MTBE (11.7 g). The organic solution is washed 3 times with 2% saline (3 x 8 g),
dried over sodium sulfate (4.4 g), filtered, and concentrated. The product is concentrated from
THF (6.4 g) and used directly in the next reaction.

[0155] The crude 24i (1.34 g) is dissolved and transferred to a suitably sized reaction
vessel with THF (12.6 g). Triphenylphosphine (0.70 g) and water (0.44 g) are charged and the
reaction is heated to 55°C for 15-24 hours. When complete, the reaction is cooled to ambient

temperature, dried with magnesium sulfate (1.4 g), filtered and concentrated. The solids are
dissolved and concentrated from three portions of DCM (3 x 9 g) and purified by silica gel
chromatography using DCM/MeoH/Et3N gradients to remove reagent based impurities. The
pooled fractions are concentrated to dryness, dissolved in DCM (6.8 g) and concentrated to
dryness again to afford an amorphous solid (1.12 g) which is used in the next reaction.

[0156] 24j (1.09 g) is dissolved and transferred to an appropriately sized reaction
vessel with anhydrous DCM (15.8 g) and placed under a nitrogen atmosphere. The solution is
cooled to 0°C. N,N-diisopropylethylamine (357 mg) and neat methanesulfonyl chloride (0.165
ml) are charged sequentially while maintaining temperature between below 5 °C. The reaction
is monitored by HPLC. Incomplete reactions are driven to completion with additional
methanesulfonyl chloride. The reaction is quenched with 0.4 M aqueous sodium bicarbonate
(11.4 g) and wanned to ambient temperature. The layers are separated and the aqueous phase
is back extracted with DCM (5.8 g). The combined organic layers are dried over magnesium
sulfate (0.55 g), filtered and concentrated. The product 24k is dissolved and striped from 2-
propanol (4.0 g) to remove residual DCM and used directly in the next reaction.

[0157] Aldrich Degussa type E1o1 NE/W 10% Pd/C (249 mg) is charged to an
appropriately sized reaction vessel and placed under a nitrogen atmosphere. A 2-propanol (9.8
g) solution of 24k (1.24 g) is charged to the reaction vessel. The system is degassed and
placed under a nitrogen atmosphere, and the process is repeated with hydrogen. The reaction

is stirred under a 1 atm of hydrogen at ambient temperature for 8 hours. An inert atmosphere
is returned to the vessel and a second charge of catalyst (125 mg) slurried in 2-propanol (0.5
g) is added to the reaction. The reaction mixture is degassed and placed under a nitrogen
atmosphere, and the process is repeated with hydrogen. The reaction is stirred under 1 atm of
hydrogen for another 15 hours at ambient temperature. The reaction is monitored by HPLC.
Incomplete reactions are treated with additional catalyst and hydrogen. When complete, the
reaction is filtered, treated witfi steam activated carbon (200 mg), and filtered again. The
solution is dried by partial concentration transferred to a reaction vessel and diluted with
anhydrous 2-propanol to 0.09 M based on the theoretical yield. A 1.25 M HC1 solution in 2-
propanol (1.64 g) is charged over 20 minutes. The hydrochloride salt crystallizes slowly with
gentle stirring and is isolated by filtration. The crystals are washed with 2-propanol (2.5 g)
and vacuum dried to afford Compound 42 (916 mg, 80% yield) as a 1:1 IPA solvate.

[0158] A round-bottom flask was charged with the amine 42 (1.1 g, 2.1 mmol, 1
equiv.), dry tetrahydrofuran (10 ml) and pyridine (88o µL, 10.9 mmol, 5 equiv.). The cooled
(0°C) mixture was treated with benzoylperoxide (1.6 g, 6.5 mmol, 3 equiv.). The mixture was

stirred for 2 hours at 0°C then overnight at 25°C. Reaction mixture diluted with MTBE and
washed with a mixture of saturated aqueous NaHCO3 with 1 N NaoH until the layer split. The
organic layer was collected and the aqueous was re-extracted once with MTBE. Combined
organic layers were washed with brine, dry over Na2SO4, filtered and concentrated to dryness.
The crude oil was dissolved in 5 mL of CH2Cl2, loaded onto SiO2 (4o g) column and eluted
from hexanes/EtoAc (10% to 50%) to give the benzoyl derivative 48 (380 mg) ([M+H] =
625.4 m/z).
Step B

[0159] A round-bottom flask was charged with 48 (374 mg, 0.6 mmol, 1 equiv.) and
MeoH (5 mL). The solution was treated at 25°C in presence of 2 N KoH (0.3 mL, 0.6 mmol,
1 equiv.). The mixture was stirred for 3h. The solvent was removed under vacuum. MTBE
was added to the residue, which was neutralized with IN HCl. The layers were cut and the
aqueous layer was extracted with two portions of CH2Cl2. Combined organic layers were
dried over Na2SO4, filtered, and concentrated to dryness. The crude material (380 mg) was
dissolved with CH2Cl2, loaded onto a SiO2 column (12 g) and eluted with hexanes/EtoAc (0%
to 1oo%) to give the hydroxylamine 47. The material was lyophilized from t-BuOH/7% H2O
to give 213 mg of 47 as a white powder ([M+H] = 521.4 m/z).

50

[0160] A heat-gun dried flask was charged with dry CH2Cl2 (5 mL) and benzyl
alcohol (785 uL, 7.58 mmol, 1.3 equiv.). The cooled (0°C) solution was treated with
chlorosulfonyl isocyanate (506 uL, 5.83 mmol, 1 equiv.). Then, DMAP (1.4 g, 11.6 mmol, 2
equiv.) was added and the mixture was stirred for 1 h at 25°C. After complete dissolution of
DMAP, the reaction was clear for a short period. Then, a white fluffy precipitate formed.
The mixture was diluted with CH2Cl2 (30 mL) and washed with three portions (30 mL each)
of water. The organic layer was dried over Na2SO4, filtered, and evaporated to dryness. The
desired white solid 51 was taken to the next step without purification.
StepB

[0161] A round-bottom flask was charged with 52 (30 mg, 0.053 mmol, 1 equiv.) and
51 (18 mg, 0.053 mmol, 1 equiv.). Both reagents were dissolved in CH2Cl2 (2 mL) and the
solution was stirred at 25°C. The crude material was loaded onto a SiO2 column (4 g) and
eluted with hexanes/EtOAc (0% to 50%) to give 16 mg of the sulfamoylated derivative 53
([M+Na] = 796.4 m/z).

[0162] A round-bottom flask was charged with 53 (16 mg, 0.021 mmol, 1 equiv.) and
11 mg of 10% Pd/C (wet,Aldrich Degussa type E101). The material was suspended in 2-
propanol (3 mL). The flask was sealed and purged three times with hydrogen and left
overnight under 1 atm of hydrogen. The slurry was filtered through 0.2 micron Acrodisc,
washed with 2-propanol, and the solvent was removed under vacuum. The residue was
purification by SiO2 column (1 g) eluting with CH2Cl2/MeOH (5% to 10%). The major
product was lyophilized from t-BuOH/7% H2O to give 9 mg of sulfamide 50 ([M+H] = 506.4
m/z).

[0163] A round-bottom flask was charged with cyclopamine 4-en-3-one (3.5 g,
8.5 mmol, 1 equiv.) and pyridine (70 mL). The reactor was charged with Pd/C (10% Pd, 500
mg). The reaction was placed under 1 atmosphere of hydrogen. After 3.5 hrs, LCMS showed
complete consumption of starting material. The catalyst was filtered off on an Acrodisk 0.2
micron filter and washed with toluene. The solvent was removed by azeotropic removal with
toluene (2 x 10 mL). The desired material 56, 3.5 g ([M+H] = 412.5 m/z) was used as it for
the next step.

[0164] A round-bottom flask was charged with 56 (1.2 g, 2.8 mmol, 1 equiv.),
CH2Cl2 (10 mL) and triethylamine (1.9 mL, 14.2 mmol, 5 equiv.). The cooled (0°C) solution
was treated with CBz-Cl (440 uL, 2.8 mmol, 1 equiv.). After 1 hr, LCMS showed complete
consumption of starting material. The mixture was diluted with water. The layers were cut
and the organic layer was washed twice with water. The organic layer was dried over sodium
sulfate, filtered, and concentrated to dryness. The product was purified by column
chromatography (SiO2, 40 g) eluting with hexane/EtOAc (0 to 20%) to give 57 (891 mg)
([M+Na] = 468.4 m/z).

[0165] In a round-bottom flask, the ketone 57 was azeotroped a couple times with
CH2Cl2 and dried under vacuum for 1 h. Under nitrogen, the ketone 2 (693 mg, 1.27 mmol, 1
equiv.) was dissolved in anhydrous THF (20 mL) and the solution was cooled to -78C. A1M
solution of K-selectride in THF (1.9 mL, 1.9 mmol, 1.5 equiv.) was added dropwise. After 1
h, the reaction was complete by TLC. The reaction was quenched by addition of 2.6 mL of 5
N NaOH followed by slow addition of 2.6 mL of 30% wt H2O2. The resulting mixture was
allowed to stir overnight. The mixture was partitioned between water and EtOAc. The
aqueous layer was back extracted with EtOAc. The combined organic were washed first with
water (buffered with a small portion of ammonium chloride) then with brine. The organic
were dried, filtered, and concentrated to a crude foam (840 mg) The crude material was
dissolved in CH2Cl2, loaded on a SiO2 column (40g) and eluted with hexanes/EtOAc (0 to
50%) to give 58 (565 mg).

58 59
[0166] In a round-bottom flask under nitrogen, the alcohol 58 (530 mg, 0.98 mmol, 1
equiv.) was dissolved in 5 mL of anhydrous CH2Cl2 and triethylamine (800 uL, 5.81 mmol, 6
equiv.). The reaction mixture was cooled to 0°C and Ms-Cl (112 uL, 1.45 mmol, 1.5 equiv)
was added dropwise. The mixture was stirred at 0°C for 30 min. TLC (hexane: EtOAC, 7:3)
showed ~ 70% conversion. 70 uL of triethylamine (70 uL, 0.5 equiv.) and Ms-Cl (10 uL, 0.1
equiv) were charged to the reaction vessel. After 90 min, a solution of saturated bicarbonate
was charged and me residue was extracted with CH2Cl2. The organic layer was washed with
water, dried and concentrated to a off-white foam. The material was dissolved in CH2Cl2 and
purified with SiO2 (40 g) eluting with hexanes/EtOAc (0% to 50%) to give 59 (430 mg).

[0167] In a round-bottom flask, the mesylate 59 (420 mg, 0.67 mmol, 1 equiv.)
was dissolved in 2 mL of DMPU. The solution was treated with sodium azide (218 mg, 3.4
mmol, 5 equiv.) at 60°C for 5 h. The mixture was cooled to 25°C, then poured into ice-water
to generate a white solid. The compound was extracted with MTBE (3 times). The combined
organic layers were washed with water (2X), men brine. The organic layers were dried over
Na2SO4, filtered, and concentrated to a white foam (342 mg). The desired material 60 was
used as is for the next step.

[0168] In a round-bottom flask equipped with a condenser, the azide 60 (336 mg,
0.58 mmol, 1 equiv.) was dissolved in 7 mL of THF and 140 uL of water and treated with
triphenylphosphine (462 mg, 1.76 mmol, 3 equiv.). The mixture was heated to 70°C
overnight. TLC (hexane/EtOAc, 7:3) confirmed the reaction was complete. The reaction was
concentrated to dryness. The crude material was dissolved in CH2Cl2, loaded onto 12 g of
SiO2 and eluted with CH2Cl2/MeOH (0 to 20%) to give the amine 61 (254 mg).

[0169] In a round-bottom flask under nitrogen, the amine 61 (248 mg, 0.45 mmol,
1 equiv.) was dissolved in 7 mL of anhydrous CH2Cl2 and N,N-diisopropylethylamine (237
uL, 0.91 mmol, 2 equiv.). The reaction mixture was cooled to 0°C and Ms-Cl (70 uL, 1.45
mmol, 1.5 equiv) was added dropwise. The mixture was stirred at 0°C for 2 h. TLC
(hexane/EtOAc, 7:3) showed a little amount of amine. The mixture was charged with 10 uL of

Ms-Cl (0.2 equiv.), and warmed to 25°C for 1h. The reaction mixture was diluted with CH2Cl2
then a saturated solution of NaHCO3. The layers were cut. The aqueous layer was extracted
with one portion of CH2Cl2. The combined organic layers were washed with water, dried over
Na2SO4, filtered and concentrated to dryness. The crude (326 mg) was added to a SiO2 column
(12 g) and was eluted with hexanes/EtoAc (0 to 50%) to give the sulfonamide 62 (256 mg).

[0170] A round-bottom flask was charged with the sulfonamide 62 (250 mg, o.4
mmol, 1 equiv.) and 50 mg of 1o% Pd/C (wet,Aldrich Degussa type E101 lot 08331KC).
The material was suspended in EtoAc (5 mL). The flask was sealed and purged three times
with hydrogen and stirred under 1 atm of hydrogen. After 3 h some conversion was observed,
but a lot of starting material remained. The slurry was filtered through 0.2 micron Acrodisc,
washed with 2-propanol. The filtrate solution was re-subjected to the reaction condition by
adding 54 mg of catalyst. The reaction was completed after 3 h. The slurry was filtered
through 0.2 micron Acrodisc, washed with 2-propanol, and the solvent was concentrated to
dryness. The crude material (200 mg) was loaded onto a SiO2 column (12 g) and the
compound was eluted using a gradient CF2Cl2/MeOH (o to 1o%) to give the free amine. The
material was lyophilized from t-BuoH/7% H2O to give 175 mg of 55 as a white powder
([M+H] = 491.3 m/z).
Example 28: Inhibition of the Hedgehog pathway in cell culture
[0171] Hedgehog pathway specific cancer cell killing effects may be ascertained using
the following assay. C3H10T1/2 cells differentiate into osteoblasts when contacted with the

sonic hedgehog peptide (Shh-N). Upon differentiation; these osteoblasts 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 the differentiation of C3H10T1/2 into
osteoblasts (a Shh dependent event) can therefore be identified by a reduction in AP
production (van der Horst et al, 2003 Bone 33: 899). The assay details are described below.
The results approximate (EC50 for inhibition) of the differentiation assay is shown below in
Table 1.
Assay Protocol
Cell Culture
[0172] Mouse embryonic mesoderm fibroblasts C3H10T1/2 cells (obtained from
ATCC) were cultured in Basal MEM Media (Gibco/Invitrogen) supplemented with 10% heat
inactivated FBS (Hyclone), 50 units/ml penicillin and 50ug/ml streptomycin
(Gibco/Invitrogen) at 37C with 5% C02 in air atmosphere.
Alkaline Phosphatase Assay
[0173] C3H10T1/2 cells were plated in 96 wells with a density of 8xl03 cells/well.
Cells were grown to confluence (72hrs). After sonic Hedgehog (250ng/ml), and/or compound
treatment, the cells were lysed in 110 µL of lysis buffer (50 mM Tris pH 7.4,0.1%
TritonXl00), plates were sonicated and lysates spun through 0.2 µm PVDF plates (Corning).
40 µL of lysates was assayed for AP activity in alkaline buffer solution (Sigma) containing
l mg/ml p-Nitrophenyl Phosphate. After incubating for 30 min at 37 °C, the plates were read
on an Envision plate reader at 405 nm. Total protein was quantified with a BCA protein assay
kit from Pierce according to manufacturer's instructions. AP activity was normalized against
total protein. Note that "A" indicates that the IC50 is less than 20 nM, "B" indicates that the
IC50is 20-100 nM, "C" indicates that the IC50is > 100 nM.

Examples 29: Pancreatic Cancer Model
[0174] The activity of Compound 42 was tested in a human pancreatic model:
BXPC-3 cells were implanted subcutaneously into the flanks of the right legs of mice. On day
42 post-tumor implant, the mice were randomized into two groups to receive either Vehicle
(30%HPBCD) or Compound 42. Compound 42 was dosed at 40mg/kg/day. After receiving
25 daily doses, Compound 42 statistically reduced tumor volume growth by 40% when
compared to the vehicle control (p=0.0309). At the end of the study, the tumors were
harvested 4 hours post the last dose to evaluate an on target response by q-RT-PCR analysis
of the HH pathway genes. Analysis of human Gli-1 resulted in no modulation. Analysis of
murine Gli-1 mRNA levels resulted in a robust down-regulation in the Compound treated
group, when compared to the Vehicle treated group.
Example 30: Medulloblastoma Model
[0175] The activity of Compound 42 was also evaluated in a transgenic mouse
model of medulloblastoma. Mice that are heterozygous for loss of function mutations in the
tumor suppressors Patched 1 (Ptchl) and Hypermethylated in Cancer (Hicl) develop

spontaneous medulloblastoma. Similar to human medulloblastoma, these tumors demonstrate
complete promoter hypermethylation of the remaining Hicl allele, as well as loss of
expression of the wild type Ptchl allele. When passaged as subcutaneous allografts, these
tumors grow aggressively and are Hedgehog pathway-dependent. This model was employed
to evaluate the efficacy of orally administered Compound, and to correlate activity with drug
exposure in plasma and tumors. Oral administration (PO) of a single dose of Compound 42
led to dose-dependent down-regulation of the HH pathway in subcutaneously implanted
tumors, as measured by decreased Gli-1 mRNA expression 8 hours post dose administration.
[0176] Daily (QD) administration of the Compound PO led to a dose dependent
inhibition of tumor growth, with frank tumor regression seen at higher doses. The
approximate effective daily oral dose for 50% inhibition of tumor growth (ED50) is 4mg/kg.
When animals were treated QD for 21 days, long term survival was observed following
cessation of treatment (>60 days), with little to no tumor re-growth.
Example 31: Lung Cancer Model
[0177] To test the activity of Compound 42 in a human SCLC tumor model,
LX22 cells were implanted subcutaneously into the flank of the right leg. LX22 is primary
xenograft model of SCLC derived from chemo -naive patients, which has been maintained by
mouse to mouse passaging. This tumor responds to etoposide/carboplatin chemotherapy in
way that closely resembles a clinical setting. LX22 regresses during chemotherapy treatment,
goes through a period of remission, and then begins to recur. In the LX22 model, Compound
single agent activity and its ability to modulate the chemoresistant recurrence was tested. On
day 32 post tumor implant, mice were randomized into three dosing groups to receive Vehicle
(30% HBPCD), Compound, or the chemotherapy combination of etoposide and carboplatin
(E/P). Compound 42 was administered at a dose of 40mg/kg/day, and after 16 consecutive
doses mere was no measurable difference between the treated and vehicle groups. Etoposide
was administered i.v at 12mg/kg on days 34, 35, 36, and 48, while Carboplatin was
administered i.v. at 60mg/kg on days 34, 41, and 48, post tumor implant. On day 50, the E/P
treated mice were further randomized to receive either Vehicle (30%HPBCD) or Compound
follow up treatment. The Compound was administered at the oral multi-dose MTD of
40mg/kg/day, and after 35 consecutive doses there was a substantial delay in tumor recurrence
in the treated group, compared to the vehicle group (p=0.0101).

Incorporation by Reference
[0178] All of the U.S. patents and U.S. published patent applications cited herein are
hereby incorporated by reference.
Equivalents
[0179] Those skilled in the art will recognize, or be able to ascertain 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.

1. A compound represented by the following structure:

or a pharmaceutically acceptable salt thereof;
wherein R1 is H, alkyl, -OR, amino, sulfonamido sulfamido, -OC(O)R5, - N(R5)C(O)R5,
or a sugar;
R2 is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, nitrile, or heterocycloalkyl;
or R1 and R2 taken together form =O, =S, =N(OR), =N(R), =N(NR2), or =C(R)2;
R3 is H, alkyl, alkenyl, or alkynyl;
R4 is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl,
heteroaralkyl, haloalkyl, -OR5, -C(O)R5, -CO2R5, -SO2R5, -C(O)N(R5)(R5), -[C(R)2]q-R5,
-[(W)-N(R)C(O)]qR5, -[(W)-C(O)]qR5, -[(W)-C(O)O]qR5, -[(W)-OC(O)]qR5,
-[(W)-SO2]qR5, -[(W)-N(R5)SO2]qR5, -[(W)-C(O)N(R5)]qR5, -[(W)-O]qR5,
-[(W)-N(R)]qR5, -W-NR53+Xor -[(W)-S]qR5;
wherein each W is, independently, a diradical;
each q is independently for each occurrence 1, 2, 3,4, 5, or 6;
X is a halide;
each R5 is, independently, H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl,
aralkyl, heteroaryl, heteroaralkyl or -[C(R)2]P-R6; wherein p is o-6; or any two
occurrences of R5 on the same substituent can be taken together to form a 4-8 membered
optionally substituted ring which contains o-3 heteroatoms selected from N, o, S, and P;
each R6 is independently hydroxyl, -N(R)COR, -N(R)C(O)OR, -N(R)SO2(R),
-C(O)N(R)2, -OC(O)N(R)(R), -SO2N(R)(R), -N(R)(R), -COOR, -C(O)N(OH)(R),
-OS(O)2OR, -S(O)2OR, -OP(O)(ORXOR), -NP(O)(OR)(OR), or-P(O)(OR)(OR);
provided that when R2, R3, and R4 are H; R1 is not hydroxyl or a sugar; further
provided that when R4 is hydroxyl, then R1 is not a sugar or hydroxyl; further
provided that when R4 is hydroxyl, then R1 and R2 together are not C=O.

2. The compound of claim 1, wherein R1 is H, hydroxyl, alkoxyl, aryloxy, or amino
or
wherein R1 and R2 taken together along with the carbon to which they are bonded,
form =O, =N(OR), or =S.
3. The compound of claim 1, wherein R3 is H.
4. The compound of claiml, wherein R4 is H, alkyl, hydroxyl, aralkyl, -[C(R)2]q-R5,
-[(W)-N(R)C(O)]qR5, -[(W)-N(R)SO2]qR5, -[(W)-C(O)N(R)]qR5, -[(W)-O]qR5,
-[(W)-C(O)]qR5, or -[(W)-C(O)O]qR5.
5. The compound of claim 1, wherein R1 is H or -oR, R2 is H or alkyl, and R4 is H.
6. The compound of claim 1, wherein R3 is H or alkyl and R2 is H or alkyl.
7. The compound of claim 1, wherein R4 is H, alkyl, aralkyl, -[(W)-N(R)C(O)]qR5,
-[(W)-N(R)SO2]qR5, -[(W)-C(O)N(R)]qR5, -[(W)-O]qR5, -[(W)-C(O)]qR5, or
-[(W)-C(O)O]qR5 and R3 is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl,
or aralkyl.
8. The compound of claim 1, wherein R4 is H, alkyl, aralkyl, -[(W)-C(O)N(R)]qR5,or
-[(W)-N(R)C(O)]qR5.
9. The compound of claim 1, wherein R1 is sulfonamido
10. The compound of claim 1, wherein said compound is isolated.
11. A compound selected from the group consisting of:

12. An isolated compound selected from the group consisting of:

13. A compound represented by the following structure:

or a pharmaceutically acceptable salt thereof;
wherein R1 is H, alkyl, -OR, amino, sulfonamido, sulfamido, -OC(O)R5, - N(R5)C(O)R5,
or a sugar;
R2 is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, nitrile, or heterocycloalkyl;
or R1 and R2 taken together form =O, =S, =N(OR), =N(R)-, =N(NR2), =C(R)2;

R3 is H, alkyl, alkenyl, or alkynyl;
R4 is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl,
heteroaralkyl, haloalkyl, -OR5, -C(O)R5, -CO2R5, -SO2R5, -C(O)N(R5)(R5), [C(R)2]q-R5,
-t(W)-N(R)C(O)]qR5, -[(W)-C(O)]qR5, -[(W)-C(O)O]qR5, -[(W)-OC(O)]qR5,
-[(W)-SO2]qR5, -[(W)-N(R5)SO2]qR5, -[(W)-C(O)N(R5)]qR5, -[(W)-O]qR5,
-[(W)-N(R)]qR5, -W-NR53+X-, or -[(W)-S]qR5;
wherein each W is, independently, a diradical;
each q is, independently, 1,2, 3, 4, 5, or 6;
X is a halide;
each R5 is, independently, H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl,
aralkyl, heteroaryl, heteroaralkyl or -[C(R)2]P-R6; wherein p is 0-6; or any two
occurrences of R5 on the same substituent can be taken together to form a 4-8 membered
optionally substituted ring which contains 0-3 heteroatoms selected from N, O, S, and P;
each R6 is, independently, hydroxyl, -N(R)COR, -N(R)C(O)OR, -N(R)SO2(R),
-C(O)N(R)2, -OC(O)N(R)(R), -SO2N(R)(R), -N(R)(R), -COOR, -C(O)N(OH)(R),
-OS(O)2OR, -S(O)2OR, -OP(O)(OR)(OR), -NP(O)(OR)(OR), or-P(O)(OR)(OR);
each of R7 and R7 is H; or R7 and R7 taken together form =O;
R8 and R9 taken together form a bond;
each R is independently H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl or aralkyl; and
provided that when R3, R4, R8, R9 are H and , R7 and R7 taken together form =O; R1 can
not be hydroxyl and R2 can not be H;
provided that when R3, R4, R8, R9 are H and , R7 and R7 taken together form =O; R1 can
not be acetate and R2 can not be H;
provided that when R3, R4, R8, R9 are H and , R7 is H2; R1 and R2 taken together can not
be =O; and
provided that when R3, R4, R8, R9 are H and, R7 and R7' are H; R1 and R2 can not be H.
14. The compound of claim 13, wherein said compound is epimerically pure.
15. The compound of claim 13, wherein said compound is isolated.
16. The compound of claim 13, wherein R4 is alkyl, alkenyl, alkynyl, aryl, cycloalkyl,
heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl, haloalkyl, -OR5, -[C(R)2]q-R5,
-[(W)-N(R)C(O)]qR5, -[(W)-C(O)]qR5, -[(W)-C(O)O]qR5, -[(W)-OC(O)]qR5,

-[(W)-SO2]qR5, -[(W)-N(R5)SO2]qR5, -[(W)-C(O)N(R5)]qR5, -[(W)-O]qR5,
-[(W)-N(R)]qR5, or -f(W)-S]qR5.
17. The compound of claim 13, wherein each of R7 and R7 is H.
18. The compound of claim 13, wherein R1 and R2 taken together form =O and each
of R7 and R7 is H.
19. A compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof
20. A pharmaceutical composition comprising a compound of claim 1, and at least
one pharmaceutically acceptable excipient.
21. A process for preparing a compound of formula 136:

wherein

Y is CR7R8;
R is H, alkyl, amino, hydroxyl, carboxyl, carbamoyl, alkoxy, hydroxy], sugar or a
protected hydroxyl group;
R is H, alkyl, alkenyl, alkynyl, nitrile, aryl, cycloalkyl, heterocycloalkyl, aralkyl,
heteroaryl, or heteroaralkyl; or
R1 and R2 taken together form =O, =S, =N(OR9), =N(R9), =C(R9)2, or =N(N(R9)2);
each of R3. R4, and R5 is, independently, H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl,
heterocycloalkyl, aralkyl, heteroaryl, or heteroaralkyl; or
R3 and R4 or R4 and R5 taken together form a bond;
R6 is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl,
heteroaralkyl, haloalkyl, -OR9, -C(O)R9, -CO2R9, -SO2R9, -C(O)N(R9)(R9), -[C(R9)2]qR9,
-[(W)-N(R9)C(O)]qR9, -[(W)-C(O)]qR9, -[(W)-C(O)O]qR9, -[(W)-OC(O)]qR9,
-[(W)-SO2]qR9, -[(W)-N(R9)SO2]qR9, -[(W)-C(O)N(R9)]qR9, -[(W)-O]qR9.
-[(W)-N(R9)]qR9, -[(W)-S]qR9, or a nitrogen protecting group;
wherein each W independently for each occurrence is a diradical;
each q is independently 1, 2, 3,4, 5, or 6;
each of R7 and R8 is, independently, H, alkyl, alkenyl, aryl, nitrile, amido, halide, or ester,
each R9 is, independently, H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl,
aralkyl, heteroaryl, or heteroaralkyl;
said process comprising the steps of:
contacting a compound of formula 136a with a haloalkylzinc phosphate cyclopropanating
agent;
wherein
R1, R2, R3, R4, R5, R6 are as defined above;

to form said compound of formula 136.
22. The process of claim 21, wherein R7 and R8 are both H.
23. The process of claim 21, wherein R1 is a protected hydroxyl.
24. The process of claim 21, wherein R6 is a nitrogen protecting group.
25. The process of claim 21, where said haloalkylzinc phosphate cyclopropanating
agent is formed by combining a phosphoric acid of formula 141a, a dialkylzinc, and a
dihaloalkylane of formula 141b:

wherein
each of X and X' is independently chloride, bromide, or iodide;
each of R7 and R8 is independently H, alkyl, halide, amido, or ester;
each of R10 and R11 is independently alkyl, alkenyl, aralkyl, aryl, heteroaryl,
heteroaralkyl; or R1o and R11 taken together have the formula 141c, 14Id, or 14le;

wherein
m independently for each occurrence is o, 1, 2, 3, or 4;
n independently for each occurrence is o,1, or 2; and
each of R12, R13, R14, R15, R16, R17 and R18 is, independently, alkyl, aryl, aralkyl, or
halide.
26. The process of claim 25, wherein R10 and R11 are each 2,6-dimethylphenyl.
27. A process for preparing a compound of formula 137:

wherein
Y is CR7R8;
R1 is H, alkyl, amino, hydroxyl, carboxyl, carbamoyl, alkoxy, hydroxyl, sugar or a
protected hydroxyl group;
R2 is H, alkyl, alkenyl, alkynyl, nitrile, aryl, cycloalkyl, heterocycloalkyl, aralkyl,
heteroaryl, or heteroaralkyl; or
R1 and R2 taken together form =O, =S, =N(OR9), =N(R9), =C(R9)2, or =N(N(R9)2);
each of R3, R4, and R3 is, independently, H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl,
heterocycloalkyl, aralkyl, heteroaryl, or heteroaralkyl; or
R3 and R4 or R4 and R5 taken together form a bond;
R is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl,
heteroaralkyl, haloalkyl, -OR9, -C(O)R9, -CO2R", -SO2R9, -C(O)N(R9)(R9), -[C(R9)2]qR9,
-[(W)-N(R9)C(O)]qR9, -[(W)-C(O)]qR9, -[(W)-C(O)O]qR9, -[(W)-OC(O)]qR9,
-[(W)-SO2]qR9, -[(W)-N(R9)SO2]qR9, -[(W)-C(O)N(R9)]qR9, -[(W)-O]qR9,
-[(W)-N(R9)]qR9, -[(W)-S]qR9, or a nitrogen protecting group;
wherein each W independently for each occurrence is a diradical alkylene having
1-6 carbon atoms;
each q is independently 1, 2, 3, 4, 5, or 6;
each of R7 and R8 is, independently, H, alkyl, alkenyl, aryl, nitrile, amido, halide, or ester;
each R9 is independently H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl,
heterocycloalkyl,aralkyl, heteroaryl, or heteroaralkyl;
said process comprising the steps of:
contacting a compound of formula 137a with a haloalkylzinc phosphate cyclopropanating
agent;

wherein
R , R , R , R4, R5, R6 are as defined above;
to form a compound with formula 137b

wherein
R1, R2, R3, R4, R5, R6 and Y are as defined above; and
contacting said compound of formula 137b with an acid to give said compound of
formula 137.
28. A process for preparing a compound of formula 142:

comprising the steps of:

contacting a compound of formula 142a with a cyclopropanating agent to form a
compound formula 142b; and

combining said compound of formula 142b with an acid to give said compound of
formula 142;
wherein
Y is CRV;
R1 is a protected hydroxyl group;
R2 is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, or
heteroaralkyl;
each of R3, R4, and R5 is, independently, H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl,
heterocycloalkyl, aralkyl, heteroaryl, or heteroaralkyl; or
R3 and R4, or R4 and R5 taken together form a bond;
R6 is a nitrogen protecting group;
each of R7 and R8 is, independently, H, alkyl, alkenyl, aryl, nitrile, amido, halide, or ester;
and
each R9 is independendy H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl,
aralkyl, heteroaryl, or heteroaralkyl.

29. The process of claim 28, wherein R7 and R8 are both H.
3o. The process of claim 28, wherein said protected hydroxyl group is an ester or a
carbonate.
31. The process of claim 28, wherein said nitrogen protecting group is a carbamate.
32. The process of claim 28, wherein said nitrogen protecting group is an amide.
33. The process of claim 28, wherein R2 and R3 are H and R4 and R5 taken together
form a bond.
34. The process of claim 28, wherein said cyclopropanating agent is generated from a
dihaloalkane and a metal species.
35. The process of claim 34, wherein said metal species is dialkyl zinc or a zinc
copper couple.
36. The process of claim 28, wherein said cyclopropanating agent is generated from a
dihaloalkane species and a dialkyl zinc species, and a phosphoric acid species or a salt
thereof.
37. The process of claim 28, wherein said phosphoric acid species has a structure of
formula 151:
or a salt thereof;
wherein
each of R10 and R11 is independently alkyl, alkenyl, aralkyl, aryl, heteroaryl,
heteroaralkyl; or R10 and R11 taken together have the formula 151a, 151b, or 151c;

wherein
m independently for each occurrence is o, 1, 2, 3, or 4;

n independently for each occurrence is 0,1, or 2;
each of R12, R13, R14, R15, R16, R17 and R18 is, independently, alkyl, aryl, aralkyl, or
halide.
38. The process of claim 28, wherein said acid is acetic acid, trifluoromethanesulfonic
acid, phosphoric acid, methanesulfonic acid or HCl.
39. The process of claim 28, wherein said acid is BF3, zinc chloride, zinc
methanesulfonate, or a zinc salt.
4o. A process for preparing a compound of formula 156:

comprising the steps of:
contacting a compound of formula 156a with a cyclopropanating agent to form a
compound formula 156b; and

combining said compound of formula 156b with an acid to give said compound of
formula 156;
wherein
R is an oxygen protecting group selected from the group consisting of formate, acetate,
chloroacetate, dichloroacetate, triehloroacetate, pivaloate, benzoates, alkyl carbonate,
alkenyl carbonate, aryl carbonates, aralkyl carbonate, 2,2,2-trichloroethyl carbonate,
alkoxymethyl ether, aralkoxymethyl ether, alkylthiomethyl ether, aralkylthio ether,
arylthio ether, trialkylsilyl ether, alkylarylsilyl emer, benzyl ether, arylmethyl ether, allyl
ether; and
R2 is a nitrogen protecting group selected from the group consisted of formyl,
chloroacetyl, trichloroacetyl, trifluoroacetyl, phenyl acetyl, benzoyl, alkyl carbamates,
aralkyl carbamates, aryl carbamates, allyl, aralkyl, triarylmethyl, alkoxymethyl,
aralkoxymethyl, N-2-cyanoethyl, diarylphosphinamides, dialkylphosphinamidates,
diarylphosphinamidates, and trialkylsilyl.
41. The process of claim 4o, where said cyclopropanating agent is formed by
combining a phosphoric acid of formula 158a, a dialkylzinc, and a dihaloalkylane of
formula 157b:

wherein
each of X and X' is, independently, chloride, bromide, or iodide;
each of R7 and R8 is, independently, H, alkyl, halide, amido, or ester;
each of R10 and R11 is, independently, alkyl, alkenyl, aralkyl, aryl, heteroaryl,
heteroaralkyl; or R10 and R11 taken together have the formula 158c, 158d, or 158e;

wherein
m independently for each occurrence is 0, 1, 2, 3, or 4;
n independently for each occurrence is o,1, or 2;
each of R12, R13, R14, R15, R16, R17 and R18 is, independently, alkyl, aryl, aralkyl, or
halide.
42. The process of claim 41, wherein said oxygen protecting group is alkyl carbonate,
aralkyl carbonate, benzoate, pivaloate, or formate.
43. The process of claim 41, wherein said nitrogen protecting group is benzoyl,
trichloroacetyl, trifluoroacetyl, formyl, alkyl carbamates, aralkyl carbamates, or aryl
carbamates.
44. The process of claim 41, wherein said oxygen protecting group is
benzylcarbonate.
45. The process of claim 41, wherein said nitrogen protecting group is
benzylcarbamate.

The invention provides novel derivatives of cyclopamine having the following formula.

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Patent Number

268493

Indian Patent Application Number

2545/KOLNP/2009

PG Journal Number

36/2015

Publication Date

04-Sep-2015

Grant Date

31-Aug-2015

Date of Filing

10-Jul-2009

Name of Patentee

INFINITY DISCOVERY, INC.

Applicant Address

780 MEMORIAL DRIVE, CAMBRIDGE, MA 02139

Inventors:

#	Inventor's Name	Inventor's Address
1	BEHNKE, MARK L.	122 NORTH STREET SOMERVILLE, MA 02144
2	AUSTAD, BRIAN	780 MEMORIAL DRIVE, CAMBRIDGE, MA 02139
3	CASTRO, ALFREDO C.	43 WILDWOOD STREET WINCHESTER, MA 01890
4	CHARETTE, ANDRE B.	1840 SUZOR CÔTÉ LONGUEUIL, QUEBEC J4N 1P6
5	GROGAN,MICHAEL J.	27 DUNSTER ROAD WINCHESTER, MA 01890
6	JANARDANANNAIR, SOMARAJANNAIR	780 MEMORIAL DRIVE, CAMBRIDGE, MA 02139
7	LESCARBEAU, ANDRE	780 MEMORIAL DRIVE, CAMBRIDGE, MA 02139
8	PELUSO, STEPHANE	97 JOSEPHINE AVENUE, SOMERVILLE, MASSACHUSETTS 02144
9	TREMBLAY, MARTIN	780 MEMORIAL DRIVE, CAMBRIDGE, MA 02139

PCT International Classification Number

A61K 31/4747

PCT International Application Number

PCT/US2007/088990

PCT International Filing date

2007-12-27

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	60/878,018	2006-12-28	U.S.A.
2	60/941,596	2007-06-01	U.S.A.