UA112171C2 - INGENOL-3-ACYLATES III AND INGENOL-3-CARBAMATE - Google Patents

Abstract

The invention relates to a compound of general formula I, wherein R is heteroaryl, optionally substituted R7; or R is heterocycloalkyl or heterocycloalkenyl, optionally substituted by R8; or R is X, where X is -NR11R12; and its pharmaceutically acceptable salts, hydrates or solvates for use alone or in combination with one or more other pharmaceutically active compounds in therapy for the prevention, treatment or alleviation of diseases or conditions responsive to the stimulation of oxidative release of neutrophils responsive to IL-stimulation 8 from keratinocytes or those responding to the induction of necrosis.

Description

N

7, g 7

With and

WITH

(at);

U-9 no B no k no 20 And where BA means heteroaryl, optionally substituted by H7; or AB means heterocycloalkyl or heterocycloalkenyl, optionally substituted by HB; or KE means X, where X means -MA11 12; and pharmaceutically acceptable salts, hydrates, or solvates thereof for use alone or in combination with one or more other pharmaceutically active compounds in therapy for the prevention, treatment, or amelioration of neutrophil oxidase-responsive, neutrophil-stimulated release-responsive diseases or conditions 1-8 from keratinocytes or responsive to necrosis induction.

FIELD TO WHICH THE INVENTION BELONGS

The present invention relates to new derivatives of 3-O-acylingenol and 3-O-carbamoylingenol and their derivatives and their use as drugs and in therapy. The invention also relates to pharmaceutical compositions containing the specified compounds and methods of treating diseases with the specified compounds.

TECHNICAL LEVEL

Ingenol-Z-angelate (REPOO5, ingenol mebutate) is a diterpene ester of the ingenol family, which is isolated from various species of Eyrpogbria, in particular, Eyrpogibia reriiv.

The compound is currently in clinical development for the treatment of actinic keratosis and non-melanoma skin cancer.

International patent U/O99/08994 describes the isolation of compounds from the Airporia plant and their use in cancer and other neoplastic diseases, such as actinic keratosis or solar keratosis.

Ingenol-3-acylates, mainly of long-chain saturated and unsaturated aliphatic fatty acids, were isolated from various species of Eyrpogbia (N. Soya, 7. Maishpog5sepipo, (1984), 390, 683-94; K. Abo, Rioiegaria, (1988 ), 244-46, 5. 7auyed, U. Sapseg Vev. Siip. Opsoi. (2001), 127, 40-47). In addition, a small number of ingenol-3-acylates was obtained by semisynthesis (V. 5ogo ei. ai., 7. Maishpogi5sp., (1982), 3765, 748-56). Some of the ingenol derivatives have been described and tested as strong irritants and agents actively stimulating the development of IV tumors. God bless her. ai., 2.

Maishipogz5p., (1982), 370, 748-56; V. 50 g9 ei. aI., Sagsipodepezviv, (1987), 8, 1-4).

In addition to aliphatic esters of ingenol, aromatic esters of ingenol are known. Mylamine C, a derivative of ingenol-3-anthraniloate, was described (Maghup, A. Riapia Meadisa, (1983), 47, 141-47). Ingenol-3-benzoate was also described (5og9, V.; 2 Makipog5spypo, (1982), 376, 748-56).

Heteroaromatic or heterocyclic derivatives of 3-O-acylingenol have not been previously described.

Ingenol-3-carbamates have not been described before. Variously substituted ingenol carbamates have been disclosed in U.S. Patent Nos. 5,955,501, 5,891,906, 5,891,870 and Int.

MO9202484.

Angelic acid and esters of angelic acid present in ingenol-Z-angelate are prone to isomerization of the double bond to form the complex ester of tiglate, especially at basic pH. (1977), 38, 3379-3382, NovKip5, MU.M., U. Spet. boss.

Ratkip Tgapv. 1, (1977), 538-544, VopItapp, RE. eh AI., Spet. Veg (1970), 103, 561-563.

In addition, it is known that ingenol-3-acylates are unstable, as they rearrange to obtain ingenol-5-acylates and ingenol-20-acylates (Zogo, V. ейі. аійі, 7. Maishpogzvsp., (1982), 37B, 748-756.

It is believed that ingenol-Z-angelate has a double type of action: 1) Induction of cell death by direct cytotoxicity or induction of apoptosis and 2) immunostimulating effect with a predominance of attraction and activation of neutrophils (Nozep, N.N., vi a!., / At Asai Oeept (2011), e-ribiizpei Mom 2011; Egemaeye",

E., ei ai., Tohip5, (2010), 2, 174-194). Nanomolar concentrations of the agent cause activation and modulation of classical and new isoforms of protein kinase C (PCC) with a special value

RKSdelta. With the help of RKSdelta activation, the agent induces apoptosis in susceptible cells (Natrzop, R., et al., Viosa, (2005), 106, 1362-1368;) (Sog7i, 5.9., et al., Sapseg Vez, ( 2006), 66, 10083-10091). A rapid cytotoxic effect on cancer cells is observed at high micromolar concentrations (Odrotspe, 5.M., ei ai., Sapseg Vez (2004), 64, 2833-2839). With the help of activation of various PKS isoforms, the agent also induces pro-inflammatory effects, including the release of pro-inflammatory mediators (SnpaPasotrye, ..M., eyii ai., ) Ittipoi! (2006), 177, 8123-8132), activation of vascular endothelium (Natrzgop, R., vii ai., Sapseg Ittypo! IttipoiNeg, (2008), 57, 1241-1251); chemoattraction of neutrophils with the help of induction of interleukin 8 in keratinocytes and the development of specific anticancer immune reactions by CO8- cells with the help of adjuvant properties on experimental models in animals (1 e, T.T., her a)., Massipe, (2009), 27 , 3053-3062).

Compounds that provide a dual type of action by inducing cell death by direct cytotoxic action or by inducing apoptosis and an immunostimulatory effect that includes the recruitment and activation of neutrophils can be used to treat conditions associated with hyperplasia and neoplasia. Compounds that cause cell death by primary and/or secondary necrosis and compounds that exhibit a proapoptotic effect can reduce unwanted cell growth and remove unwanted cells, and in addition, stimulation of the innate immune response and adjuvant effects can enhance the biological response against aberrant or transformed cells.

Compounds that cause cell death by primary and/or secondary necrosis may be useful in the treatment of cosmetic conditions because these compounds can cause the death or removal of unwanted tissue or cells.

There is a need to identify ingenol derivatives that cause cell death by cytotoxicity or apoptosis and/or cause an immunostimulatory effect.

The present invention relates to heterocyclic derivatives of 3-O-acylingenol and 3-O-carbamoylingenol which may be used to treat conditions associated with the use of ingenol-3-angelate or useful in conditions affected by induction of cell death by cytotoxicity or induction of apoptosis and/or immunostimulating effect.

The compounds of this invention stimulate the oxidative release of neutrophils, which is part of the innate immune response.

The compounds according to the present invention stimulate the release of II-8 (interleukin-8) keratinocytes, thus causing an immunostimulating effect.

Certain compounds of the present invention cause rapid necrosis.

Some of the compounds of the present invention show activity in the B16 murine melanoma model, indicating that the compounds have antitumor activity and are capable of causing death of neoplastic and transformed cells.

Certain compounds of the present invention exhibit favorable stability properties.

BRIEF DESCRIPTION OF THE ESSENCE OF THE INVENTION

In one embodiment, the invention relates to a compound of the general formula I

N,

You

O z uh it is

Kk no 2 no 20

And where K is heteroaryl, which may be optionally substituted with one or more substituents independently selected from K7; or K represents heterocycloalkyl or heterocycloalkenyl, where said heterocycloalkyl or heterocycloalkenyl is optionally substituted by one or more substituents independently selected from K8; or E stands for X;

K7 is halogen, cyano or hydroxyl; or K7 is (C1-C1)alkyl, (C0-C4)alkenyl, (C3-C7)cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, heterocycloalkylalkyl or (C3-C7)cycloalkylalkyl, where (C1-

Ca)alkyl, (C2-Ca)alkenyl, (C3-C7)cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl,

Zo heterocycloalkylalkyl or (C3-C7)cycloalkylalkyl optionally substituted by one or more substituents independently selected from KO; or K7 represents -МНасовВъ, -СОМАанр, -СООАс, -ОСОВа, -ОВа, -ОСОМРан, -

Mvasoov, -mnasSomMARan, -MtazO2gMRan, -MNazoOg in, -502MRanr, -:OgVa, -530)Na, -5ShVa or -MVanb;

KU is halogen, cyano, hydroxy(Si-C4)alkyl, halogen(Si-C4)alkyl, -MVasov, -

СООАс, -ОСбОВа, -СОМРан, -оСоМВАВан, -Мвасоов, -МмМвасСсомМВант, -МВазО2гМРан, -

MAazOg AB, -5Ю02МРан, -5Ор2Ва, -5(ОКа, -ОВа, -5Ка or -О;

K8 is halogen, cyano or hydroxyl; or K8 represents (C1-Ca)alkyl, (C1-Calkenyl, aryl, heteroaryl, (C3-C7)cycloalkyl or heterocycloalkyl, where (C1-Ca)alkyl, (C1-C4)alkenyl, aryl, heteroaryl, ( C3-C7)cycloalkyl or heterocycloalkyl optionally substituted with one or more substituents independently selected from K10, or K8 represents -MNasov, -SOOVc, -OSOVa, -SOMVan, -oSboMVanv, -mnasoon, -

MvasomMmvanv, -MVazO2gmMRan, -MvazOgAb, -502MVan, -5O2Na, -5(0)Ka, -OVA, -5Ka, -0, -M-OVA, -0O-M-Skakr, Mmkak or -С(СОМ(Ka )O-VB;

K10 is a halogen, cyano, hydroxy, (C1-Cα)alkyl, (C1-C4)alkyl, halogen(C1-C4)alkyl, halogen(C1-C1)alkyl, hydroxy(C1-C4alkyl, cyano(C:i-Sal )alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, -MNasov, -SOOVAc, -OSbOVa, -SOMAan, -oSbOoMAan, -MmVasoonyr, -

MvasomMmvanv, -MmVazO2MVan, -MVazoOgAb, -502MRanv, -5O2Va, -5(0)Ka, -ОВa, -ZKa or that;

Ka and Kr represent hydrogen, (C1-C1)alkyl, halogen (C1-C1)alkyl, (C1-C1)alkoxy(C1-C1)alkyl, hydroxy(C1-C1)alkyl, cyano(C1-C4)alkyl , aryl, heteroaryl, cycloalkyl or heterocycloalkyl;

Ks represents hydrogen, (Ci-Cdalkyl, halo(Ci-Ca)alkyl, (C1-Cdyloxy(Ci-Cdalkyl, hydroxy(C1-Cx)alkyl, cyano(C1-Cx)alkyl, aryl, heteroaryl, cycloalkyl or heterocycloalkyl ;

X represents -MA11B812 where P11 and K12 independently represent hydrogen, or where K11 and K12 independently represent (Ci-Cv)alkyl, (C2-Cv)alkenyl or (Ci2-Cv)alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl , heterocycloalkyl, heterocycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, arylalkyl, heteroarylalkyl, heterocycloalkylalkyl, heterocycloalkenylalkyl, alkylcycloalkyl, alkylcycloalkenyl, alkylaryl, alkylheteroaryl or alkylheterocycloalkyl, where (C1-Cv)alkyl, (C2g-Cv)alkenyl or (C2-Cv)alkynyl are indicated, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocycloalkyl, heterocycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, arylalkyl, heteroarylalkyl, heterocycloalkylalkyl, heterocycloalkenylalkyl, alkylcycloalkyl, alkylcycloalkenyl, alkylaryl, alkylheteroaryl or alkylheterocycloalkyl optionally substituted with one or more substituents independently selected from K13;

C13 is halogen, cyano or hydroxyl, or C13 is (C1-C1)alkyl, (C0-C4)alkenyl, aryl, (C3-C7)cycloalkyl, heteroaryl or heterocycloalkyl, where (C1-C1)alkyl, ( C1-C1)alkenyl, aryl, (C3-C7)cycloalkyl, heteroaryl or heterocycloalkyl optionally substituted with one or more substituents independently selected from K14 or K13 is -MNaCO Be, -"SOONI, -oSOva, -coMmvake, - OSOMVakne, -MEasSoo Ne, - mvasSsomMmvanvVe, -MvazogAe, -Mmvazogmvanve, -502MVante, -502Na, -(ozha, -ovVa, -zkKa, -o, -m-ova, -o-m-Svanve, -chKkake or - "С(О)М(Ка)-ОВе where Ка and Ке independently represent hydrogen, (С1-Са)alkyl, halogen (Си-Saalkyl, (Сч1-

C 1 -C 1 -C 6 -alkyl, hydroxy (C 1 -C 6 )alkyl, cyano (C 1 -C 6 )alkyl, aryl, heteroaryl, cycloalkyl or heterocycloalkyl;

KI represents hydrogen, (Ci-Cdalkyl, halogen(Ci-Cdalkyl, (C1-Cdaloxy(Ci-Cdalkyl), hydroxy(C1-Ca)alkyl, cyano(C1-C4)alkyl, aryl, heteroaryl, cycloalkyl or heterocycloalkyl;

K14 is hydrogen, hydroxyl, cyano, (C1i-Calalkyl, (Ci-Calkoxy), halo(Ci-Calkyl, halogen(C1-Ca) alkoxy, hydroxy(Ci-Calkyl, cyano(C:i-Cal)alkyl, aryl , heteroaryl, cycloalkyl, heterocycloalkyl, -MVYASOVne, -SOOVI, -OSbOova -SOoMAantke, -oOSOMAanNe, -MNasSoOovVe, - mvasSsomMmgvanvVe, -chmvasogVe, -MvazoOgmvakne, -502MRanve, -5028a, -;so3kKa, -ona, -zka or to ; and its pharmaceutically acceptable salts, prodrugs, hydrates and solvates.

In one embodiment, the invention relates to a compound of formula I for use as a drug in treatment.

In one embodiment, the invention relates to the use of a compound according to formula I to obtain a pharmaceutical compound.

In one embodiment, the invention relates to a pharmaceutical composition containing a compound of formula I or its pharmaceutically acceptable stereoisomer, salt, or hydrolyzed ip mimo ester thereof together with a pharmaceutically acceptable carrier or excipient.

In one embodiment, the invention relates to a pharmaceutical composition, suitable for topical administration, containing a compound of formula I or its pharmaceutically acceptable stereoisomer, salt or hydrolyzed ip mimo ester thereof together with a pharmaceutically acceptable carrier or excipient.

In one embodiment, the invention relates to a compound of formula I for use in the treatment, prevention, alleviation or prophylaxis of physiological disorders or diseases associated with hyperplasia or neoplasia.

In one embodiment, the invention relates to the use of a compound of the formula | to obtain a medicinal product for the treatment, prevention, alleviation or prophylaxis of physiological disorders or diseases associated with hyperplasia or neoplasia.

In one embodiment, the invention relates to a method of preventing, treating, ameliorating, or preventing physiological disorders or diseases associated with hyperplasia or neoplasia by administering to an individual in need thereof a compound of formula I described above.

In one embodiment, the invention relates to a compound of formula I for use in the treatment or alleviation of cosmetic disorders. 60 In one embodiment, the invention relates to a compound according to the formula | to obtain a medicinal product for the treatment or relief of cosmetic disorders.

In one embodiment, the invention relates to a method of treating or alleviating cosmetic disorders by administering to an individual in need thereof a compound of the formula described above

AND.

In one embodiment, the invention relates to a pharmaceutical composition containing a compound of formula I or its pharmaceutically acceptable stereoisomer, salt, or hydrolyzed ester thereof in combination with one or more other therapeutically active agents.

DETAILED DESCRIPTION OF THE INVENTION

One embodiment of the invention relates to a compound of the general formula

N,

Dt

Su

H-oh but 5

Kk no 20 no

And where K is heteroaryl, which may be optionally substituted with one or more substituents independently selected from K7; or K is heterocycloalkyl or heterocycloalkenyl, each of which may be optionally substituted with one or more substituents independently selected from K8; or E stands for X;

K7 is halogen, cyano or hydroxyl; or K7 represents (C1-C1)alkyl, (Co-C4)alkenyl, (C3-C7)cycloalkyl, heterocycloalkyl, aryl, heteroaryl, each of which is optionally substituted with one or more substituents independently selected from KO; or K7 represents -МНасовВъ, -СОМАанр, -СООАс, -ОСОВа, -ОВа, -ОСОМРан, -

Mvasoov, -mnasSomMARan, -MtazO2gMRan, -MNazoOg in, -502MRanr, -5:Og2Va, -5(OKa, -5Va or -MVanr;

KU is a halogen, cyano, hydroxy, (C1-Slalkyl, halogen(C1-Ca)alkyl, -ch1Basov, -

СООАс, -ОСбОВа, -СОМРан, -оСоМВАВан, -Мвасоов, -МмМвасСсомМВант, -МВазО2гМРан, -

MAazOg AB, -5Ю02МРан, -5Ор2Ва, -5(ОКа, -ОВа, -5Ка or -О;

K8 is halogen, cyano or hydroxyl; or C8 is (C1-C6)alkyl, (C1-Salkenyl, aryl, heteroaryl, (C3-C7)cycloalkyl or heterocycloalkyl, each of which is optionally substituted with one or more substituents independently selected from C10, or K8 is -MNasov, -SOOVs, -OSOVA, -"SOMVan, -oSboMVanv, -mnasoon, -

MvasomMmvanv, -MVazO2gmMRan, -MvazOgAb, -502MVan, -5O2Na, -5(0)Ka, -OVA, -5Ka, -0, -M-OVA, -0O-M-Skakr, Mmkak or -С(СОМ(Ka )O-VB;

K10 is a halogen, cyano, hydroxy, (C1-Cα)alkyl, (C1-C4)alkyl, halogen(C1-C4)alkyl, halogen(C1-C1)alkyl, hydroxy(C1-C4alkyl, cyano(C:i-Sal )alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, -іNasov, -СООНс, -"ОСОВа, -"СОМНан, -оСОоМАан, -мнасоонв, -

MvasomMmvanv, -MmVazO2MVan, -MvazoOgAb, -502MRanv, -5O2Va, -5(0)Ka, -ОВa, -ZKa or

FOR;

Ka and Kr represent hydrogen, (C1-C1)alkyl, halogen (C1-C1)alkyl, (C1-C1)alkoxy(C1-C1)alkyl, hydroxy(C1-C1)alkyl, cyano(C1-C4)alkyl , aryl, heteroaryl, cycloalkyl or heterocycloalkyl;

Ks is hydrogen, (Ci-Cdalkyl, halo(Ci-Ca)alkyl, (C1-Cdyloxy(Ci-Cdalkyl), hydroxy(C1-Cx)alkyl, cyano(Ci-Cx)alkyl, aryl, heteroaryl, cycloalkyl or heterocycloalkyl ;

X represents -MA11B812 where P11 and K12 independently represent hydrogen, or where K11 and K1I2 independently represent (Ci-Cv)alkyl, (C2-Cv)alkenyl or (Ci2-Cv)alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl , heterocycloalkyl, heterocycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, arylalkyl, heteroarylalkyl, heterocycloalkylalkyl, heterocycloalkenylalkyl, alkylcycloalkyl, alkylcycloalkenyl, alkylaryl, alkylheteroaryl or alkylheterocycloalkyl, which may optionally be substituted with one or more substituents,

BO independently selected from K13;

K13 is halogen, cyano or hydroxyl,

or C13 is (C1-C1)alkyl, (C0-C4)alkenyl, aryl, (C3-C7)cycloalkyl, heteroaryl or heterocycloalkyl, each of which may be optionally substituted with one or more substituents independently selected from C14, or K13 represents -MNaSO Ve, -«SOONI, -oSOva, -soMmvake, -OSOMVakne, -MEasSoo Ne, - mvasSsomMmvanvVe, -MvazogAe, -Mmvazogmvanve, -502MVante, -502Na, -(ozha, -ovVa, -zkKa, -o, -m-ova, -o-m-Svanve, -chKkake or -C(O)M(Ka)-Oge, where Ka and Ke are independently hydrogen, (C1-Ca)alkyl, halogen (Si- Sadalkil, (Sc1-

C 1 -C 1 -C 6 -alkyl, hydroxy (C 1 -C 6 )alkyl, cyano (C 1 -C 6 )alkyl, aryl, heteroaryl, cycloalkyl or heterocycloalkyl;

KI represents hydrogen, (Ci-Cdalkyl, halogen(Ci-Cdalkyl, (C1-Cdaloxy(Ci-Cdalkyl), hydroxy(C1-Ca)alkyl, cyano(C1-C4)alkyl, aryl, heteroaryl, cycloalkyl or heterocycloalkyl;

K14 is hydrogen, hydroxyl, cyano, (C1i-Calalkyl, (Ci-Calkoxy), halo(Ci-Calkyl, halogen(C1-Ca) alkoxy, hydroxy(Ci-Calkyl, cyano(C:i-Cal)alkyl, aryl , heteroaryl, cycloalkyl, heterocycloalkyl, -MVYASOVNe, -SOOVI, -OSbOova -SOoMAantke, -oOSOMAanNe, -MNasSoOovVe, - mvasSsomMmgvanvVe, -chmvasogVe, -MvazoOgmvakne, -502MRanve, -5028a, -;so3kKa, -ona, -zka or

FOR; and its pharmaceutically acceptable salts, prodrugs, hydrates and solvates.

Another embodiment of the invention relates to the described compound of general formula I, where K represents heteroaryl, which may optionally be substituted by one or more substituents independently selected from K7, or K represents heterocycloalkyl or heterocycloalkenyl, each of which may optionally be substituted by one or more substituents independently selected from K8,

K7 is halogen, cyano, hydroxyl; or K7 represents (C1-C1)alkyl, (Co-C4)alkenyl, (C3-C7)cycloalkyl, heterocycloalkyl, aryl, heteroaryl, each of which may optionally be substituted by one or more substituents independently selected from KO; or K7 represents -МНасовВъ, -СОМАанр, -СООАс, -ОСОВа, -ОВа, -ОСОМРан, -

Mvasoov, -MnaSomMVanv, -MmVazO2gMVan, -MvazO2gvAb, -502MVanp, -502Na, -5(0)Ka, -

ZVa;

Ko) KU is halogen, cyano, hydroxy(Ci-C4)alkyl, halogen(Ci-C4)alkyl, -MVasov, -

СООвВАс, -ОСОВа, -«СОМРан, -оСоМВАВан, -Мвасоов, -МмМвасСсомМВант, -МВазО2гМРан, -

MAazOg AB, -5O02MRan, -5Or2Va, -5(OKa, -OVa, -5Ka, -o;

K8 is halogen, cyano or hydroxyl; or K8 is (C1-C6)alkyl, (C0-C1alkenyl, aryl, heteroaryl, (C3-C7)cycloalkyl, heterocycloalkyl, each of which is optionally substituted with one or more substituents independently selected from K10, or K8 is -MNasov, -SOOVs, -OSOVA, -"SOMVan, -oSboMVanv, -mnasoon, -

MvasomMmgan, -mBazO2MVan, -MVazOg Ar, -502MRanr, -5О2Va, -5(0)Ka, -ОВa, -5Ka, -О;

K10 is halogen, cyano, hydroxy, (C1-C4)alkyl, halogen(C1-Ca4)alkyl, -y1Basonvy, -

СООАс, -ОСбОВа, -СОМРан, -оСоМВАВан, -Мвасоов, -МмМвасСсомМВант, -МВазО2гМРан, -

MAazOg AB, -5O02MRan, -5Or2Va, -5(OKa, -OVa, -5Ka, -o;

Ka and Kr represent hydrogen, (C1-C) alkyl, halogen (C1-C) alkyl, (C1-C) alkoxy (C1-C) alkyl, hydroxy (C1-C) alkyl, cyano (C1-C) alkyl;

Ks is (C1-C4)alkyl, halo(C1-Cα)alkyl, (C1-C.Alkoxy(C1-Cα)alkyl, hydroxy(C1-Calkyl, cyano(C1-Cα)alkyl; and its pharmaceutically acceptable salts , prodrugs, hydrates and solvates.

One embodiment of the invention relates to a compound of formula I, where K is heteroaryl.

One embodiment of the invention relates to a compound of formula I, wherein heteroaryl is isoxazolyl, pyridyl, quinolyl, isoquinolyl, indolyl, furyl, thiazolyl, imidazolyl, pyrazolyl, oxazolyl, thienyl, pyrimidinyl, 1,2,3-thiazolyl, indazolyl, cinnolyl, or 1 ,2-benzoxazolyl.

One embodiment of the invention relates to a compound of formula I, wherein K is heteroaryl, and wherein said heteroaryl is isoxazolyl, pyridyl, quinolyl, isoquinolyl, indolyl, furyl, thiazolyl, imidazolyl, pyrazolyl, oxazolyl, thienyl, pyrimidinyl, 1,2,3- thiazolyl, indazolyl, cinnolyl, 1,2-benzoxazolyl, imidazothiazolyl, imidazopyridinyl, pyrrolyl, isothiazolyl, tetrahydroindazolyl or oxadiazolyl.

One embodiment of the invention relates to a compound of formula I, wherein K is heteroaryl, and wherein said heteroaryl is isoxazolyl, furyl, pyrazolyl, thienyl, or pyrrolyl.

One embodiment of the invention relates to a compound of formula I, wherein K is heteroaryl, and wherein said heteroaryl is isoxazolyl. for One embodiment of the invention relates to a compound of formula I, where K is heteroaryl,

and wherein said heteroaryl is furyl.

One embodiment of the invention relates to a compound of formula I, wherein K is heteroaryl, and wherein said heteroaryl is isoxazolyl, furyl, pyrazolyl, thienyl, or pyrrolyl, and wherein K7 is (C1-Ca)alkyl.

One embodiment of the invention relates to a compound of formula I, wherein K is heteroaryl, and wherein said heteroaryl is isoxazolyl, furyl, pyrazolyl, thienyl, or pyrrolyl, and wherein K7 is (C1-C6)alkyl.

One embodiment of the invention relates to a compound of formula I, wherein K is heteroaryl, and wherein heteroaryl is isoxazolyl or furyl, and wherein K7 is (C1-C6)alkyl.

One embodiment of the invention relates to a compound of formula I, wherein K is heteroaryl, and wherein said heteroaryl is isoxazolyl, furyl, pyrazolyl, thienyl, or pyrrolyl, and wherein K7 is phenyl.

One embodiment of the invention relates to a compound of formula I, wherein K is heteroaryl, and wherein said heteroaryl is isoxazolyl, furyl, pyrazolyl, thienyl, or pyrrolyl, and wherein K7 is phenyl or (C1-C4)alkyl, and wherein KU is ( C1-C4)alkyl, halogen or -ORa.

One embodiment of the invention relates to a compound of formula I, wherein K is heteroaryl, and wherein said heteroaryl is indolyl, indazolyl, or tetrahydroindazolyl. One embodiment of the invention relates to a compound of the general formula I, where K is heteroaryl, and where said heteroaryl is indolyl, indazolyl, or tetrahydroindazolyl, and where K7 is (C1-Ca)alkyl or -OA.

One embodiment of the invention relates to a compound of formula I, wherein K7 is independently selected one or more times from the group of (C1-C4)alkyl, aryl or halogen.

One embodiment of the invention relates to a compound of formula I, where K7 is independently selected one or more times from the group of (C1i-C4)alkyl, (C2-C1)alkenyl, aryl, arylalkyl, heterocycloalkylalkyl, (C3-C7)cycloalkylalkyl, (C3-C7 )cycloalkyl, -СООВНс, -ОКа or halogen.

One embodiment of the invention relates to a compound of formula I, where K7 is selected from phenyl, methyl, ethyl, isopropyl, C1 or Hg.

One embodiment of the invention relates to a compound of formula I, wherein K7 is selected from phenyl,

Z of methyl, ethyl, isopropyl, t-butyl, piperidyl, tert-butoxycarbonyl, benzyl, tetrahydropyranylmethyl, -ОСН», cyclopropyl, allyl, cyclopropylmethyl, CI, Vg or I.

One embodiment of the invention relates to the compound of formula I described above, where KU means halogen or -ORα.

One embodiment of the invention relates to the compound of formula I described above, where KU means halogen, -ORa, (C1-Clu)alkyl or -502Ba.

One embodiment of the invention relates to a compound of formula I, where KU means SI, E or -

Osn".

One embodiment of the invention relates to the above-described compound of formula I, where KU means CI, E, -OSH", methyl or methylsulfonyl.

One embodiment of the invention relates to a compound of formula !/, where K is heterocycloalkyl.

One embodiment of the invention relates to the compound of formula I described above, where K is heterocycloalkyl or heterocycloalkenyl.

One embodiment of the invention relates to a compound of formula I, where heterocycloalkyl is pyrrolidinyl, piperidinyl, morpholinyl or 5-oxabicyclo(|2.2.2|octane.

One embodiment of the invention relates to a compound of formula I, where K8 means (C--

Sdalkil

One embodiment of the invention relates to a compound of formula !, where K is heterocycloalkyl or heterocycloalkenyl, and wherein said heterocycloalkyl or heterocycloalkenyl is pyrrolidinyl, piperidinyl, morpholinyl, 5-oxabicyclo|2.2.2|octanyl, oxaspiro|4.5|dec-1-enyl, oxo-thiazolyl, dihydrothiazolyl, oxo-pyranyl, azepanyl, azabicyclo|3.2.2|nonanyl, benzoxazinyl, quinoxalinyl, isoindolinyl, dihydroquinolinyl, indolinyl or dihydroquinoxalinyl.

One embodiment of the invention relates to the compound of formula I described above, where Kk means heterocycloalkyl, and where said heterocycloalkyl is indolinyl, benzoxazinyl or dihydroquinolinyl.

One embodiment of the invention relates to a compound of formula I, wherein K8 is methyl.

One embodiment of the invention relates to a compound of formula I, where K8 means (C--

Ca)alkyl, aryl or 50. bo One embodiment of the invention relates to a compound of formula I, where K means -MA11 12.

One embodiment of the invention relates to a compound of formula I, where K11 and K12 independently represent hydrogen, (C:1-C)alkyl, aryl, cycloalkyl, arylalkyl, heteroaryl or cycloalkylalkyl.

One embodiment of the invention relates to the compound of formula I described above, where KI11 and

K12 independently represents hydrogen, (C1-C8)alkyl, aryl, cycloalkyl, arylalkyl, heteroaryl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, (C20-C8)alkenyl or (C2-C8)alkynyl.

One embodiment of the invention relates to the above-described compound of formula II, where K11 and

K12 independently represent hydrogen, (C1-C8)alkyl, aryl or arylalkyl.

One embodiment of the invention relates to the compound of formula I described above, where K11 and

K12 independently represent hydrogen, (C1-Cα)alkyl, cycloalkyl, phenyl or benzyl.

One embodiment of the invention relates to the compound of formula I described above, where K11 and

K12 independently represent hydrogen, (Ci-Ca)alkyl, phenyl or benzyl, where indicated (Сч1-

C1-alkyl, phenyl or benzyl is optionally substituted with one or more substituents selected from K13, where K13 is hydrogen, (C1-C1-alkyl or -OBa.

One embodiment of the invention relates to a compound of formula I, where C11 and C112 are independently hydrogen, methyl, ethyl, isopropyl, phenyl, benzyl, cyclohexyl, indanyl, tetralinyl, phenylethyl, cyclopropylmethyl or pyrazolyl.

One embodiment of the invention relates to the compound of formula I described above, where K11 and

C12 is independently hydrogen, methyl, ethyl, isopropyl, phenyl, benzyl, cyclohexyl, indanyl, tetralinyl, phenylethyl, cyclopropylmethyl, pyrazolyl, isoxazolylmethyl, cyclopentyl, cyclopropyl, pyridyl, piperidyl, tetrahydropyranylmethyl, tetrahydropyranyl, cyclobutyl, allyl, propynyl, or thiazolyl.

One embodiment of the invention relates to the compound of formula I, where K13 is (C1-

Sdalkil, cyano or E.

One embodiment of the invention relates to the compound of formula I described above, where K13 is (C1-Alalkyl, cyano, halogen, O, -OKa or -SOONI.

One embodiment of the invention relates to the compound of formula I described above, where K13 is methyl, cyano, E, 50, -OCH3 or -COOC(CH3)z.

One embodiment of the invention relates to a compound of formula I, wherein K11 and K12 independently represent hydrogen.

One embodiment of the invention relates to a compound of formula I, and said compound is:

Ingenol 3-(5-methyl-3-phenylisoxazole-4-carboxylate) or

Ingenol 3-(5-methyl-3-(2-chloro-6-fluorophenyl)isoxazole-4-carboxylate) or

Ingenol 3-(15-camphanate) or

Ingenol 3-(3-phenyltriazole-4-carboxylate) or

Ingenol 3-(2-phenylpyrazole-3-carboxylate) or

Ingenol 3-(1-methylindazole-3-carboxylate) or

Ingenol 3-(33-ethyl-o-methylisoxazole-4-carboxylate) or

Ingenol 3-(3-methyl-5-methylisoxazole-4-carboxylate) or

Ingenol 3-(1-methylindole-3-carboxylate) or

Ingenol 3-(3-phenylthiophene-2-carboxylate) or

Ingenol 3-(5-phenylisoxazole-3-carboxylate) or

Ingenol 3-(M-ethylcarbamate) or

Ingenol 3-(M,M-dimethylcarbamate) or

Ingenol 3-(morpholine-4-carboxylate) or

Ingenol C3-(pyrrolidine-1-carboxylate) or

Ingenol 3-(M-methyl-M-phenylcarbamate) or

Ingenol 3-(M,M-diethylcarbamate) or

Ingenol 3-(piperidine-1-carboxylate) or

Ingenol 3-(M-benzyl-M-methylcarbamate) or

Ingenol 3-(M-cyclohexyl-M-methylcarbamate) or

Ingenol 3-(M-cyclohexylcarbamate) or

Ingenol 3-(M-phenylcarbamate) or

Ingenol 3-(M-(indan-1-yl)ucarbamate) or

Ingenol 3-(3,3-dimethylpiperidine-1-carboxylate) or

Ingenol 3-(M-methyl-M-tetralin-1-ylcarbamate) or

Ingenol 3-(M-(2-cyano-1-methylethyl)-M-methylcarbamate) or (510) Ingenol 3-(M-methyl-M-((5)-1-phenethyl)carbamate) or

Ingenol 3-(M-methyl-M-(cyclopropylmethyl)carbamate) or

Ingenol 3-(isoquinoline-1-carboxylate) or

Ingenol 3-(quinoline-4-carboxylate) or

Ingenol 3-(cinnoline-4-carboxylate) or

Ingenol 3-(3-phenylimidazole-4-carboxylate) or

Ingenol 3-(5-phenyloxazole-4-carboxylate) or

Ingenol 3-(1,2-benzoxazole-3-carboxylate) or

Ingenol 3-(3-isopropyl-o-methylisoxazole-4-carboxylate) or

Ingenol 3-(3-(2-methoxyphenyl)-5-methylisoxazole-4-carboxylate) or

Ingenol 3-(4-bromo-2-methylpyrazole-3-carboxylate) or

Ingenol 3-(4-bromo-2-ethylpyrazole-3-carboxylate) or

Ingenol 3-(4-chloro-2-methylpyrazole-3-carboxylate) or

Ingenol 3-(5-bromopyrimidine-4-carboxylate) or

Ingenol 3-(3-bromopyridine-2-carboxylate) or

Ingenol 3-(5-methylthiazole-4-carboxylate) or

Ingenol 3-(4-chloro-1-methylpyrazole-3-carboxylate) or

Ingenol 3-(2,4-dimethylthiazole-5-carboxylate) or

Ingenol 3-(2,5-dimethyloxazole-4-carboxylate) or

Ingenol 3-(2,4-dimethylfuran-3-carboxylate) or

Ingenol 3-(3,5-diethylisoxazole-4-carboxylate) or

Ingenol 3-(M-(3-fluorophenyl)-M-methylcarbamate) or

Ingenol 3-(M-(2,5-dimethylpyrazol-3-yl)-M-methylcarbamate) or

Ingenol 3-(1H-indole-7-carboxylate) or

Ingenol 3-(2-tert-butyl-5-methylpyrazole-3-carboxylate) or

Ingenol 3-(5-tert-butyl-2-methylpyrazole-3-carboxylate) or

Ingenol 3-(b-methylimidazo|2,1-b)hiazole-5-carboxylate) or

Ingenol 3-(2-methylimidazo|1,2-a|pyridine-3-carboxylate) or

Ingenol 3-(2,4,5-trimethylfuran-3-carboxylate) or

Ingenol 3-(3-methylthiophene-2-carboxylate) or

Zo Ingenol 3-(2-methyl-4-(1-piperidyl)pyrazole-3-carboxylate) or

Ingenol 3-(2-chloro-5-isopropylthiazole-4-carboxylate) or

Ingenol 3-(4-chloro-2,5-dimethylpyrazole-3-carboxylate) or

Ingenol 3-(1,2,4-trimethylpyrrole-3-carboxylate) or

Ingenol 3-(1,3,5-trimethylpyrrole-2-carboxylate) or

Ingenol 3-(1-ethyl-3,5-dimethylpyrrole-2-carboxylate) or

Ingenol 3-(1-tert-butyloxycarbonyl-3,3-dimethylpyrrolidine-2-carboxylate) or

Ingenol 3-(25)-1-phenylpyrrolidine-2-carboxylate) or

Ingenol 3-(1-isopropyl-3,5-dimethylpyrazole-4-carboxylate) or

Ingenol 3-(5-ethyl-3-isopropylisoxazole-4-carboxylate) or

Ingenol 3-(2-methylindazole-3-carboxylate) or

Ingenol 3-(5-methyl-3-tert-butylisoxazole-4-carboxylate) or

Ingenol 3-(2-methyl-3-oxo-4-oxaspiro|(4.5|dec-1-ene-1-carboxylate) or

Ingenol 3-(1-tert-butyl-3,5-dimethylpyrazole-4-carboxylate) or

Ingenol 3-(3,5-dimethylisothiazole-4-carboxylate) or

Ingenol 3-(5-iodo-33-methylisothiazole-4-carboxylate) or

Ingenol 3-(4-(4-methoxyphenyl)-2-methylpyrazole-3-carboxylate) or

Ingenol 3-(4-(2-methylphenyl)-2-methylpyrazole-3-carboxylate) or

Ingenol 3-(2-methyl-4-(4-methylsulfonylphenyl)pyrazole-3-carboxylate) or

Ingenol 3-(2-methyl-4-phenylpyrazole-3-carboxylate) or

Ingenol 3-(3,5-dimethyl-1-phenylpyrazole-4-carboxylate) or

Ingenol 3-(1,5-dimethyl-3-phenylpyrazole-4-carboxylate) or

Ingenol 3-(1-benzyl-3,5-dimethylpyrazole-4-carboxylate) or

Ingenol 3-(3,5-dimethyl-1-(tetrahydropyran-4-ylmethyl)pyrazole-4-carboxylate) or

Ingenol 3-(4-methyl-2-oxo-ZN-thiazole-5-carboxylate) or

Ingenol 3-(2-methyl-4,5,6,7-tetrahydroindazole-3-carboxylate) or

Ingenol 3-(1,2-dimethylindole-3-carboxylate) or

Ingenol 3-(5-methoxy-1,2-dimethylindole-3-carboxylate) or

Ingenol 3-(1,3,5-trimethylpyrazole-4-carboxylate) or

Ingenol 3-(4-methyl-1,2,5-oxadiazole-3-carboxylate) or 60 Ingenol 3-(2-methoxy-4-methylthiazole-o-carboxylate) or

Ingenol 3-(4,5-dimethylisoxazole-3-carboxylate) or

Ingenol 3-(4-bromo-1-methylpyrazole-3-carboxylate) or

Ingenol 3-(1,3-dimethylindole-2-carboxylate) or

Ingenol 3-(5-methoxy-1,3-dimethylindole-2-carboxylate) or

Ingenol 3-(2,4-dimethyl-6-oxopyran-3-carboxylate) or

Ingenol 3-(1-methyl-3-phenylindole-2-carboxylate) or

Ingenol 3-(3-methyl-5-(trifluoromethyl)isoxazole-4-carboxylate) or

Ingenol 3-(1,3-dimethylpyrrole-2-carboxylate) or

Ingenol 3-(3,5-dimethyl-1-(2,2,2-trifluoroethyl)pyrazole-4-carboxylate) or

Ingenol 3-(1-cyclopropyl-2,5-dimethylpyrrole-3-carboxylate) or

Ingenol 3-(1,2,5-trimethylpyrrole-3-carboxylate) or

Ingenol 3-(2,4-dimethyl-1H-pyrrole-3-carboxylate) or

Ingenol 3-(1-methylpyrrole-2-carboxylate) or

Ingenol 3-(4-methyl-1H-pyrrole-2-carboxylate) or

Ingenol 3-(1,5-dimethylpyrrole-2-carboxylate) or

Ingenol 3-(3-methyl-1H-pyrrole-2-carboxylate) or

Ingenol 3-(1-cyclopropylpyrrole-2g-carboxylate) or

Ingenol 3-(1-ethyl-2,4-dimethylpyrrole-3-carboxylate) or

Ingenol 3-(1-allyl-2,4-dimethylpyrrole-3-carboxylate) or

Ingenol 3-(1-(cyclopropylmethyl)-2,4-dimethylpyrrole-3-carboxylate) or

Ingenol 3-(1-(2-methoxyethyl)-2,4-dimethylpyrrole-3-carboxylate) or

Ingenol 3-(M-(3,5-dimethylisoxazol-4-yl)-M-methylcarbamate) or

Ingenol 3-(M-(1,5-dimethylpyrazol-3-yl)-M-methylcarbamate) or

Ingenol 3-(M-cyclopentyl-M-methylcarbamate) or

Ingenol 3-(M-cyclopropyl-M-methylcarbamate) or

Ingenol 3-(M-methyl-M-(2-pyridyl)ucarbamate) or

Ingenol 3-(4-oxo-2,3-dihydroquinoline-1-carboxylate) or

Ingenol 3-(3,4-dihydro-2H-quinoline-1-carboxylate) or

Ingenol 3-(indoline-1-carboxylate) or

Zo Ingenol 3-(azepane-1-carboxylate) or

Ingenol 3-(M-(4-chloro-phenyl)-M-methyl-carbamate) or

Ingenol 3-(M-(4-fluorophenyl)-M-methylcarbamate) or

Ingenol 3-(M-methyl-M-(2-methoxyphenyl)carbamate) or

Ingenol 3-(M-methyl-M-(2-methylphenyl)carbamate) or

Ingenol 3-(3-oxo-2,4-dihydroquinoxaline-1-carboxylate) or

Ingenol 3-(M-ethyl-M-phenylcarbamate) or

Ingenol 3-(2-trifluoromethylpyrrolidine-1-carboxylate) or

Ingenol 3-(3-azabicyclo|3.2.2|nonane-3-carboxylate) or

Ingenol 3-(2,3-dihydro-1,4-benzoxazine-4-carboxylate) or

Ingenol 3-(M-(2-fluorophenyl)-M-methylcarbamate) or

Ingenol 3-(3-methyl-2,3-dihydro-1,4-benzoxazine-4-carboxylate) or

Ingenol 3-(2-trifluoromethylpyrrolidine-1-carboxylate) (ISOMER A) or

Ingenol 3-(2-trifluoromethylpyrrolidine-1-carboxylate) (ISOMER B) or

Ingenol 3-(M-methyl-M-(M-(tert-butyloxycarbonyl)-4-piperidyl)carbamate) or

Ingenol 3-(M-methyl-M-(3-methylphenyl)carbamate) or

Ingenol 3-(3,4-dihydro-2H-quinoxaline-1-carboxylate) or

Ingenol 3-(isoindoline-2-carboxylate) or

Ingenol 3-(M-methyl-M-(tetrahydropyran-4-ylmethyl)carbamate) or

Ingenol 3-(M-methyl-M-(tetrahydropyran-4-yl)ucarbamate) or

Ingenol 3-(M-methyl-M-(3-methoxyphenyl)carbamate) or

Ingenol 3-(M-cyclobutyl-M-methylcarbamate) or

Ingenol 3-(M-allyl-M-methylcarbamate) or

Ingenol 3-(M-methyl-M-prop-2-ynylcarbamate) or

Ingenol 3-(M-methyl-M-(4-methylthiazol-2-yl)ucarbamate) or

Ingenol 3-(M-(4-cyanophenyl)-M-methylcarbamate).

One embodiment of the invention relates to a compound of formula I, and said compound is ingenol 3-(M-methyl-M-phenylcarbamate).

One embodiment of the invention relates to a compound of formula I, and said compound is ingenol 3-(M-(3-fluorophenyl)-M-methylcarbamate). because One embodiment of the invention relates to a compound of formula I, and said compound is ingenol 3-(3-ethyl-5-methylisoxazole-4-carboxylate).

One embodiment of the invention relates to a compound of formula I, and said compound is ingenol 3-(2,4-dimethylfuran-3-carboxylate).

One embodiment of the invention relates to a compound of formula I, and said compound is ingenol 3-(3,5-diethylisoxazole-4-carboxylate).

One embodiment of the invention relates to a compound of formula I, and said compound is ingenol 3-(2,4,5-trimethylfuran-3-carboxylate).

One embodiment of the invention relates to a compound of formula I, and said compound is ingenol 3-(2-methyl-4-phenylpyrazole-3-carboxylate).

One embodiment of the invention relates to a compound of formula I, and said compound is ingenol 3-(33-methylthiophene-2-carboxylate).

One embodiment of the invention relates to a compound of formula I, and said compound is ingenol 3-(indoline-1-carboxylate).

One embodiment of the invention relates to a compound of formula I, and said compound is ingenol 3-(5-methyl-3-phenylisoxazole-4-carboxylate).

One embodiment of the invention relates to a compound of formula I, and said compound is ingenol 3-(pyrrolidine-1-carboxylate).

DEFINITION

In this context, the term "(Ca-Salkyl", where a and 5 are integers) refers to a straight- or branched-chain alkyl radical having from a to p carbon atoms, for example, 1-7 or 1-6, in particular, 1 -4 or 1-3 carbon atoms Thus, when, for example, a-1 and a 0-7, the term includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, tert- butyl, pentyl, isopentyl, hexyl, isohexyl and heptyl.

The term "carbocyclic" refers to a mono-, bi- or tricyclic radical having up to 13 ring atoms, for example, 3-13 or 3-10 ring atoms, all of which are carbon, and includes aryl, cycloalkyl and cycloalkenyl.

The term "cycloalkyl" refers to a mono-, bi- or tricyclic saturated cycloalkane radical containing 3-13 carbon atoms, in particular 3-10, in particular 3-8, in particular 3-5 carbon atoms, and includes, for example, cyclopropyl , cyclobutyl, cyclopentyl, cyclohexyl,

From cycloheptyl, cyclooctyl, bicyclo|2.2.1|)heptanyl and adamantyl.

The term "(Ca-C)alkenyl", where a and B are integers, refers to a mono-, di- or tri-unsaturated straight- or branched-chain alkenyl radical having up to p carbon atoms, for example, 2-7 or 2 -6, or 2-4, or 2-3 carbon atoms. Thus, when, for example, a-1, and 0-7, the term includes ethenyl, allyl, propenyl; 1-, 2- or 3-butenyl; 1 -, 2-, 3- or 4-pentenyl; 1-, 2-, 3-, 4- or 5-hexenyl.

The term "cycloalkenyl" refers to mono-, di- or tri-unsaturated non-aromatic cyclic hydrocarbon radicals, including polycyclic radicals containing 3-13 carbon atoms, such as 3-10, in particular, 3-8, in particular, 3-5 carbon atoms, and includes, for example, cyclopropenyl, cyclobutenyl, cyclopentenyl or cyclexenyl.

The term "(Ca-C)alkynyl", where a and B are integers, refers to a straight- or branched-chain hydrocarbon radical having from a to p carbon atoms, for example, 2-7 or 2-6 or 2-4, or 2-3 carbon atoms containing 1-2 C-0 triple bonds.

So, when, for example, a-1 and p-7, the term includes ethynyl, propynyl, butynyl, pentynyl or hexynyl.

The term "heterocyclic" refers to a carbocyclic radical, as defined above, containing 1-4 heteroatoms selected from O, M, or 5, and includes heteroaryl, heterocycloalkyl, and heterocycloalkenyl.

The term "heterocycloalkyl" refers to a cycloalkyl radical including polycyclic radicals optionally fused to carbocyclic rings containing 1-4

BO heteroatoms selected from 0, M or 5.

The term "heterocycloalkyl" further refers to a cycloalkyl radical that includes polycyclic radicals optionally fused to carbocyclic rings that include aryl, provided that the point of attachment is through a non-aromatic ring, and the cycloalkyl radical contains 1-4 heteroatoms , selected from O, M or 5. For example, piperazinyl, tetrahydrofuranyl, pyrrolidinyl, dioxolanyl, morpholinyl, imidazolidinyl, piperidinyl, 5-oxabicyclo(|2.2.2|octane, dihydroquinolinyl, indolinyl, dihydroquinoxalinyl, oxo-thiazolyl, oxo-pyranyl, azepanyl, azabicyclo|3.2.2|Inonanyl, benzoxazinyl, quinoxalinyl, isoindolinyl, indolinyl or tetrahydropyranyl, in particular tetrahydrofuranyl, pyrrolidinyl, dioxalinyl, morpholinyl, imidazolidinyl, piperidinyl or 5-oxabicyclo|2.2.2|octane bo The term "heterocycloalkenyl" refers to cycloalkenyl radical as defined above,

including polycyclic radicals optionally fused with carbocyclic rings containing 1-4 heteroatoms selected from 0, M or 5, for example, dihydropyranyl, dihydrothiazolyl.

The term "aryl" refers to the radical of aromatic carbocyclic rings containing 6-10 carbon atoms, in particular, phenyl, and optionally fused carbocyclic rings with at least one aromatic ring, in particular, 5- or 6-membered rings. Thus, the term includes, for example, 1,2,3,4-tetrahydronaphthalenyl, phenyl, naphthyl, indenyl or indanyl, in particular, phenyl, naphthyl, indenyl or indanyl.

The term "heteroaryl" refers to aromatic carbocyclic ring radicals optionally fused with carbocyclic rings or heterocyclic rings containing 1-4 heteroatoms selected from OO, M or 5 and 1-12 carbon atoms, for example, 1-4 heteroatoms and 1-6 carbon atoms, in particular, 5- or b-membered rings with 1-4 heteroatoms, or optionally condensed bicyclic rings with 1-4 heteroatoms, and where at least one ring is aromatic. Thus, the term includes, for example, pyridyl, quinolyl, isoquinolyl, indolyl, tetrazolyl, furyl, thiazolyl, imidizolyl, imidazo/1,2-a|pyrimidinyl, pyrrolyl, pyrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,2,4-triazolyl . . ,4-triazolyl, thienyl, pyrazinyl, pyrimidinyl, 1,2,3-triazolyl, isothiazolyl, imidazo(2,1-b|hiazolyl, benzimidazolyl, benzofuranyl, benzothiophenyl, benzothiazolyl, benzooxazolyl, indazolyl or, in particular, pyridyl, quinolyl, isoquinolyl, indolyl, tetrazolyl, furyl, thiazolyl, imidazolyl, imidazo(1,2-a|Ipyrimidinyl, pyrrolyl, pyrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,2,4-triazolyl, thienyl, pyrazinyl, pyrimidinyl, 1,2,3-triazolyl, isothiazolyl, imidazo|2,1-B|hiazolyl, benzimidazolyl, benzofuranyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, indazolyl, cinolyl, 1,2-benzoxazolyl.

The term "halogen" is intended to indicate a substituent from the 7-0th main group of the periodic table, preferably fluorine, chlorine and bromine.

The term "Alkoxy" is intended to indicate a radical of the formula -OK, where K means alkyl,

Zo as indicated above, for example, methoxy, ethoxy, n-propoxy, isopropoxy, butoxy, etc.

The term "halidolkoxy" is intended to indicate a radical of the formula -O-B-Xii-z) where K is alkyl as defined above and X is halogen as defined above, for example, trifluoromethoxy.

The term hydroxyalkyl is intended to indicate a primary, secondary or tertiary radical of the formula -B-OH, where K is alkyl as indicated above, for example, hydroxymethyl or hydroxyethyl.

The term cyanoalkyl is intended to indicate a primary, secondary or tertiary radical of the formula -B-CM, where K is alkyl as indicated above, for example, cyanomethyl or cyanoethyl.

The term haloalkyl is intended to indicate a primary, secondary or tertiary radical of the formula -B-X|1-3, where K is alkyl as defined above and X is halogen as defined above, for example, trifluoromethyl, 2,2,2-trifluoroethyl or difluoromethyl.

When two or more of the terms defined above are used in combination, such as arylalkyl, heteroarylalkyl, cycloalkylalkyl, and the like, it is to be understood that the first indicated radical is a substituent on the last indicated radical, where the point of attachment to the rest of the molecule is on the last radical .

The term "alkoxyalkyl" is intended to indicate an alkyl radical as defined above which is substituted by an alkoxy radical as defined above, i.e., -A-O-K, where each K is alkyl, the same or different as defined above, for example, methoxymethyl, ethoxymethyl.

The term "cycloalkylalkyl" is intended to indicate a radical of the formula -B'-cycloalkyl, where

Kk means alkyl as defined above, such as:

The term "cycloalkenylalkyl" is intended to indicate a radical of the formula -B'-cycloalkenyl, where K' is alkyl as defined above, such as:

The term "arylalkyl" is intended to indicate a radical of the formula -H'-Ag, where K' is alkyl as defined above and Ag is aryl as defined above, such as:

The term "heteroarylalkyl" is intended to indicate a radical of the formula -H-Neu where EE" means alkyl as defined above and Neu means heteroaryl as defined above, such as:

OM and o

The term "heterocycloalkylalkyl" is intended to indicate a radical of the formula -B'-heterocycloalkyl, where K is alkyl as defined above, such as:

HELL

"!

The term "heterocycloalkenylalkyl" is intended to indicate a radical of the formula -B'-heterocycloalkenyl, where K' is alkyl as defined above, such as:

AZHHU

The term "alkylcycloalkyl" is intended to indicate a radical of the formula -cycloalkyl-K", where

Kk means alkyl as defined above, such as:

The term "alkylcycloalkenyl" is intended to indicate a radical of the formula -cycloalkenyl-

KU, where K is alkyl as defined above, such as:

The term "alkylaryl" is intended to indicate a radical of the formula -Ag/-K, where K' is alkyl as defined above and Ag is aryl as defined above, such as:

N " N " vu I ' '

The term "alkylteteroaryl" is intended to indicate a radical of the formula -Ni-K, where K is alkyl as defined above and Ni is heteroaryl as defined above, such as: and . -

Kya M ".

The term "alkylheterocycloalkyl" is intended to indicate a radical of the formula heterocycloalkyl-K", where K is alkyl as defined above, such as:

xx n

The term "substituted" as applied to any component herein is intended to indicate substitution with compatible substituents.

The term "Pharmaceutically acceptable salt" is intended to indicate the salts obtained by the interaction of a compound of formula I, containing the main component, with a suitable inorganic or organic acid, such as hydrochloric, hydrogen bromide, hydrogen iodide, sulfuric, nitric, phosphoric, formic, acetic, 2,2 - dichloroacetic, choline, adipic, ascorbic, I - aspartic, I-glutamic, galactaric, lactic, maleic, I-malic, phthalic, citric, propionic, benzoic, glutaric, gluconic, Y-glucuronic, methanesulfonic, salicylic, amber, malonic , tartaric, benzenesulfonic, ethane-1,2-disulfonic, 2-hydroxyethanesulfonic acid, toluenesulfonic, sulfamic or fumaric acid.

Pharmaceutically acceptable salts of compounds of formula I containing an acidic component may also be prepared by reaction with a suitable base, such as sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide, ammonia, or appropriate non-toxic amines, such as lower alkylamines, for example triethylamine , hydroxy-lower alkylamines, for example 2-hydroxyethylamine, bis-(2-hydroxyethyl)amine, cycloalkylamines, for example dicyclohexylamines or benzylamines, for example M,M'-dibenzylethylenediamine and dibenzylamine, or I -arginine or I -lysine.

The present invention, in addition, includes prodrugs of compounds of the general formula I, such as esters, acetals, ketals or other derivatives, which are subject to biotransformation and mimo before the manifestation of their pharmacological effects.

The term "solvate" is intended to indicate the species formed by the interaction between a compound, for example, a compound of formula I, and a solvent, for example, alcohol, glycerol or water, where said species are present in solid form. When the solvent is water, then this species is called a hydrate.

Compounds of the formula | can be obtained in crystalline form or directly by concentration from an organic solvent, or by crystallization or recrystallization from an organic solvent or a mixture of said solvent and a common solvent, which may be organic or inorganic, such as water. Crystals can be isolated essentially in solvent-free form or as a solvate such as a hydrate. The invention encompasses all

Of crystalline modifications and forms, as well as their mixtures.

The term "cancer" in the context of this invention is intended to cover skin cancer, such as skin cancer other than melanoma, malignant melanoma, Merkel cell carcinoma, squamous cell carcinoma, basal cell carcinoma. Basal cell carcinomas also include superficial basal cell carcinomas, such as nodular basal cell carcinoma.

Squamous cell carcinoma includes squamous cell carcinoma ip 5yi (Bowen's disease), invasive squamous cell carcinoma, cutaneous squamous cell carcinoma, squamous cell carcinoma of mucous membranes, and squamous cell carcinoma of the head and neck. Other types of cancer include hematological malignancies such as myeloid malignancies such as acute myeloid leukemia and chronic myeloid leukemia; prostate and bladder cancer, including benign prostatic hyperplasia, prostatitis, intraepithelial carcinoma, bladder carcinoma, prostate adenocarcinoma, and renal cell carcinoma. Other types of cancer include cancer associated with

AIDS, auditory nerve neoma, adenocystic carcinoma, adrenocortical cancer, agnogenic myeloid metaplasia, alopecia, alveolar soft tissue sarcoma, anal cancer, angiosarcoma, aplastic anemia, astrocytoma, ataxia-telangiectasia, basal cell carcinoma (BCC), bladder cancer , malignant bone lesions, intestinal cancer, brain stem glioma, malignant lesions of the brain and central nervous system, breast cancer, malignant lesions of the central nervous system, carcinoid malignant lesions, cervical cancer, malignant brain lesions in childhood, cancer in children, soft tissue sarcoma in children, chondrosarcoma, choriocarcinoma, colorectal malignancy, cutaneous T-cell lymphoma, dermatofibrosarcoma, desmoplastic small round cell carcinoma, ductal carcinoma, endocrine malignancy, endometrial cancer, ependymoma, esophageal cancer, Ewing's sarcoma, extrahepatic bile duct cancer, cancer eye, eye melanoma, retinoblastoma, fallopian tube cancer, Fanconi anemia, fibrosarcoma, gallbladder cancer ichura, gastric cancer, gastrointestinal malignancy, gastrointestinal carcinoid cancer, genitourinary malignancy, germ cell malignancy, pregnancy trophoblastic disease, glioma, gynecological malignancy, hematological malignancy including acute myeloid leukemia, head cancer and neck, hepatocellular cancer, hereditary breast cancer, histiocytosis, disease

Hodgkin, human papillomavirus, cystic fibrosis, hypercalcemia, laryngopharyngeal cancer, intraocular melanoma, islet T-cell carcinoma, Kaposi's sarcoma, kidney cancer, Langerhans cell histiocytosis, laryngeal cancer, leiomyosarcoma, Fraumeni syndrome, lip cancer, liposarcoma, liver cancer, lung cancer, lymphedema, lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, male breast cancer, malignant rhabdoid kidney cancer, medulloblastoma, mesothelioma, metastatic cancer, oral cancer, multiple endocrine neoplasia, mycosis fungoides, myelodysplastic syndromes, myeloma, myeloproliferative disorders, nose cancer, nasopharyngeal cancer, nephroblastoma, neuroblastoma, neurofibromatosis, Nijmegen chromosome break syndrome, non-small cell lung cancer (NSCLC), eye cancer, esophageal cancer, oral cavity cancer, oropharyngeal cancer, osteosarcoma, ovarian cancer with stoma, pancreatic cancer, paranasal sinus cancer, parathyroid gland cancer, parotid gland cancer, genital cancer lena, peripheral neuroectodermal malignancies, pituitary cancer, polycythemia vera, prostate cancer, rare forms of malignancies and related disorders, retinoblastoma, rhabdomyosarcoma, Rothmund-Thomson syndrome, salivary gland cancer, sarcoma, schwannoma, Sézary syndrome, small cell lung cancer (5sis), small intestine cancer, soft tissue sarcoma, spinal cord malignancy, stomach cancer, synovial sarcoma, testicular cancer, thymus cancer, thyroid cancer, transitional cell cancer (bladder), transitional cell cancer (kidney-pelvic organs-/-ureters), trophoblastic cancer, urethral cancer, urinary system cancer, uroplakins, uterine cancer, vaginal cancer, vulvar cancer, Waldenström macroglobulinemia and Wilms cancer. A solid cancer that is treated using the methods of the present invention can be a primary lesion or can be the result of metastasis of a primary cancer. In addition, if the solid cancer is a metastasis of the primary cancer, then the primary cancer can be either a primary solid cancer, as described above, or can be an advanced primary cancer.

In one embodiment of the invention, "cancer" is skin cancer.

In embodiments of the invention, the skin cancer is a skin cancer other than melanoma, malignant melanoma, Merkel cell carcinoma, squamous cell carcinoma, basal cell carcinoma, such as superficial basal cell carcinoma or nodular basal cell carcinoma.

From carcinoma.

The phrase "physiological disorders or diseases associated with hyperplasia or neoplasia" in the context of the present invention is intended to encompass disorders or diseases such as cutaneous warts, including common warts (Meythisa mcidagie), plantar warts (Meythisa riapiagie), and flat warts (meggisa riapa); genital warts (sopauiuta asitipaksht), pyogenic granuloma, hemangioma, scleroderma; cancerous and precancerous lesions, such as actinic keratosis, squamous cell carcinoma, including squamous cell carcinoma ip 5yi (disease

Bowen's), invasive squamous cell carcinoma, cutaneous squamous cell carcinoma, squamous cell carcinoma of mucous membranes, squamous cell carcinoma of the head and neck; basal cell carcinoma, including superficial basal cell carcinoma and nodular basal cell carcinoma; bladder cancer, malignant lentigo, cervical dysplasia, vulvar dysplasia and anal dysplasia, primary melanoma ip 5yi, head and neck cancer, skin metastases of any form of cancer, Kaposi's sarcoma, keratoacanthoma, Merkel cell tumor, prostate cancer, fungoid mycosis, intraepithelial neoplasia, including intraepithelial neoplasia of the anal zone, cervix, ducts, oral cavity, perianal zone, prostate gland, penis, vagina and vulva.

The term "cosmetic indication" in the context of this invention is intended to cover such affections as: photodamaged skin, seborrheic keratosis, scars, keloids, melasma, Poikiloderma Kiveta, removal of tattoos, nevi and skin tags.

The term "photodamaged skin" in the context of this invention is intended to encompass fine lines, wrinkles and UV-induced aging of the skin. UV-induced skin aging is often manifested by epidermal thickening or epidermal atrophy and, most significantly, solar elastosis, the accumulation of elastin-containing material immediately below the dermis-epidermis junction. Collagen and elastic fibers become fragmented and disorganized. Cosmetically, this can be seen as reddening and/or thickening of the skin, leading to uneven appearance, skin fragility and uneven pigmentation, loss of tone and elasticity, as well as wrinkling, dryness, crow's feet and deep wrinkles.

The term "viral infections" in the context of this invention is intended to cover infections

UTIs that lead to the formation of warts on the body, for example, on the skin, genitals and in the oral cavity. HRM refers to the human papilloma virus. Other viruses selected from adeno-,

papova-, herpes viruses (such as herpes simplex virus), chicken pox virus, Epstein virus-

Barra CMMU (cytomegalovirus), smallpox virus (such as smallpox), cowpox virus, hepatitis A virus, hepatitis B virus, hepatitis C virus, rhinovirus, poliovirus, rubella virus, arbovirus, rabies virus, influenza A and B virus, measles virus, epidemic parotitis virus and HIV, NTIM I and II (human T-cell leukemia virus! and I). In one embodiment of the invention, infection. NRU refers to common warts or genital warts.

The term "bacterial infections" in the context of this invention is intended to cover prokaryotic and eukaryotic bacterial infections and gram-positive and gram-negative and gram-variable bacteria and intracellular bacteria. Examples of bacteria include

Tgteropeta, Vogteiia, Meivzegia, I ediopeia, Vogavieia, EuspPetgispia, ZaItopeiPa, Zpideia, KierzivIIa,

Uegwipia, Mibgio, Netornishv5, Viscaivia, Spiatuaia, Musoriazta, eiarpuiosossiv5, Bigeriosossiv,

VasiShyv, Siovigidichsht, Sogupebasiegisht, Rgorgiopirasiegisht, Musobasiegisht, Ogeariazta and GG ie(egia.

In particular, the species: Tteropeta rat, Voiteeiia Vigdaopegi, Meib5b5eia dopoptpoea, IediopeiiIa rpeshtorpia, Vogaeieia repibvv5iv, EvsPegispia soii, ZaitopeiPa iurpi, ZaiItopeiPa iurpitigisht,

Zpideia duzepietiae, Kierzieia rpeitopiae, Megwipia reviiv, Mibtio spoiegae, Netorniisy5 ipPsheplga,

VisKenNvia hisKeivii, SpIatuadia ShMaspotaiih, Musoriayeta rpeshtopia, Yegarnuiosossiv ashgeiv, zigeriosossiv rpeytopiae, bigeriosossiv ruodepe5, Vasiyi5 apiygasiv, Siovigadisht Boshiypyt,

Siovigidiit ieiapi, Sioziidiit rephipdepe, Sogupebasievgtst aiirnielae, Rgorgiopirasietisht aspe,

Musobasietgiit shregsio5i5, Musobasietit Iergae and I ibiegiage toposuiodepe5. Lower eukaryotic organisms include yeasts and fungi, such as Rpeitosuviiv pegipia, Sapaiida irisap5, Azregaiiv,

Nivioriaeta sarzshiaiyit, Viaziotusev5 adeptaiyiaiv, Sturiosossiv peoioptap5, Tgisporpuyup and

Mystozrogyt Complex eukaryotic organisms include worms, insects, arachnids, nematodes, amoebae, Epiatoera piviuiuis, Siagaa Iatbria, Tpispopotopav madipaiii5, Turapozota rgyseii detbriepze, Turapozota sgy?gi, Viapiidiitis soiii, Tochoriastha dopaii, Sturiozrogidist or

And eivptapia.

In the context of the present invention, the term "wound healing" means: reducing or minimizing the formation of scar tissue or improving the cosmetic or functional outcome in wound or scar reduction, where the wound is cutaneous, chronic or, for example, associated with diabetes, and includes cuts and lacerations, surgical incisions, punctures, wounds, scratches,

From bedsores, excoriations, wounds due to friction, chronic wounds, ulcers, wounds due to thermal effects, chemical wounds, wounds due to pathogenic infections, sites of taking and implantation of skin grafts of the donor and recipient, states of the immune response, wounds of the oral cavity, wounds of the stomach or intestines, damaged cartilage or bone, amputation sites and corneal lesions.

The compounds of the present invention are intended for the treatment of cancer, actinic keratosis, seborrheic keratosis, viral infections, bacterial infections, wound healing and treatment of photodamaged skin.

In one embodiment of the invention, the use of compounds according to the invention is provided in the treatment of superficial basal cell carcinoma (BCC), nodular BCC, squamous cell carcinoma or squamous cell carcinoma ip 5yi (5SCI5).

One embodiment of the invention provides for the use of the compounds of the invention in the treatment of actinic keratosis.

In one embodiment of the invention, the compounds of the invention are used in the treatment of seborrheic keratosis.

In one embodiment of the invention, it is envisaged to use the compounds according to the invention in the treatment of photodamaged skin.

In one embodiment of the invention, the compounds of the invention are used in the treatment of lesions caused by HIV infection.

In one embodiment of the invention, the lesions are common warts or genital warts.

In one variant of the implementation of the invention, the use of compounds according to the invention in the treatment of squamous cell carcinoma ip 5yi or invasive squamous cell carcinoma is provided.

In one embodiment of the invention, the compounds of the invention are used in the treatment of squamous cell carcinoma of the skin, squamous cell carcinoma of the mucous membrane, or squamous cell carcinoma of the head and neck.

In one embodiment, the invention provides for the use of the compounds of the invention in the treatment of superficial basal cell carcinoma or nodular basal cell carcinoma.

In one embodiment, the invention provides for the use of compounds according to the invention in the treatment of skin warts or genital warts. because In one embodiment of the invention, the compounds of the invention are used in the treatment of common warts, plantar warts and flat warts.

In one embodiment, the invention provides for the use of compounds according to the invention in the treatment of malignant lentigo.

In one embodiment of the invention, the compounds of the invention are used in the treatment of cervical intraepithelial neoplasia, anal intraepithelial neoplasia, or vulvar intraepithelial neoplasia.

In one embodiment, the invention provides for the use of compounds according to the invention in the treatment of acute myeloid leukemia.

In one embodiment, the invention relates to a method of treating cancer, actinic keratosis, seborrheic keratosis, viral infections, bacterial infections, wound healing, and treatment of photodamaged skin by administering a compound of formula I to an individual in need thereof.

In one embodiment, the invention relates to a method of treating actinic keratosis by administering a compound of formula I to an individual in need of it.

In one embodiment, the invention relates to a method of treating seborrheic keratosis by administering to an individual in need of it the above compound of formula I.

In one embodiment, the invention relates to a method of treating photodamaged skin by administering to an individual in need of it the above compound of formula I.

In one embodiment, the invention relates to a method of treating lesions caused by HIV infection by administering the above compound of formula I to an individual in need thereof.

In one embodiment, the invention relates to a method of treating common warts or genital warts by administering the above compound of formula I to an individual in need thereof.

In one embodiment, the invention relates to a method of treating squamous cell carcinoma of the skin, squamous cell carcinoma of the mucous membranes, or squamous cell carcinoma of the head and neck by administering to an individual in need of it the above compound of formula I.

In one embodiment, the invention relates to a method of treating common warts, plantar warts and flat warts by administering to an individual in need of it the above compound of formula Y.

In one embodiment, the invention relates to a method of treating malignant lentigo

With the introduction of the above-mentioned compound of formula I to the individual who needs it.

In one embodiment, the invention relates to a method of treating intraepithelial neoplasia of the cervix or intraepithelial neoplasia of the vulva by administering to an individual in need of it the above compound of formula I.

In one embodiment, the invention relates to the use of the compound of formula I described above in the preparation of a pharmaceutical composition for the treatment or amelioration of a disease, disorder or condition responsive to stimulation of the oxidizable release of neutrophils.

In one embodiment, the invention relates to the use of the compound of formula I described above in the preparation of a pharmaceutical composition for the treatment or amelioration of a disease, disorder or condition responsive to stimulation of the release of 1-8 keratinocytes.

In one embodiment, the invention relates to the use of a compound of formula I described above in the preparation of a pharmaceutical composition for the treatment or amelioration of a disease, disorder or condition responsive to the induction of necrosis.

In one embodiment, the invention relates to a method of preventing, treating, alleviating or prophylactics of disorders or diseases that respond to the stimulation of oxidizable release of neutrophils by administering to an individual in need of it the above-mentioned compound of formula I.

In one embodiment, the invention relates to a method of prevention, treatment, alleviation or prevention of physiological disorders or diseases that respond to the stimulation of the release of 1-8 keratinocytes, by administering to an individual in need of it the above-mentioned compound of formula I.

In one embodiment, the invention relates to a method of preventing, treating, ameliorating, or prophylactically treating physiological disorders or diseases responsive to the induction of necrosis by administering to an individual in need thereof the compound of formula I above.

In one embodiment, the invention relates to the above compound of the formula | for use in the treatment or amelioration of a disease, disorder or condition responsive to stimulation of the oxidizable release of neutrophils.

In one embodiment, the invention relates to the above compound of formula I! for use in the treatment or amelioration of a disease, disorder or condition responsive to the release of II -8 keratinocytes. In one embodiment, the invention relates to a compound of formula I above for use in the treatment or amelioration of a disease, disorder or condition responsive to the induction of necrosis.

In one embodiment, the invention relates to a method of treating acute myeloid leukemia by administering the above-mentioned compound of formula I to an individual in need of it.

In one embodiment, the invention relates to a compound of formula I for use in the treatment, prevention, alleviation or prophylaxis of physiological disorders or diseases associated with actinic keratosis, seborrheic keratosis, cancer, photodamaged skin or lesions caused by HIV infection.

In one embodiment, the invention relates to the use of a compound of the formula | to obtain a medicinal product for the treatment, alleviation or prevention of physiological disorders or diseases associated with actinic keratosis, seborrheic keratosis, cancer, photodamaged skin or lesions caused by HIV infection.

In one embodiment, the invention relates to a method of preventing, treating, ameliorating or preventing physiological disorders or diseases associated with actinic keratosis, seborrheic keratosis, cancer, photodamaged skin or lesions caused by HIV infection by administering to an individual in need thereof a compound of formula I.

Pharmaceutical compositions

For use in treatment, the compounds of the present invention are usually presented in the form of a pharmaceutical composition. Therefore, the invention relates to a pharmaceutical composition containing a compound of formula I together with a pharmaceutically acceptable excipient or carrier.

The excipient must be "acceptable" in the sense of compatibility with other ingredients of the composition and not harmful to its recipient.

The pharmaceutical composition according to the invention can be presented in a standard dosage form, such as tablets, pills, capsules, powders, granules, elixirs, syrups, emulsions, ampoules, suppositories or parenteral solutions or suspensions; for oral, parenteral, ocular, transdermal, intra-articular, topical, pulmonary, nasal, buccal or rectal administration or by any other route appropriate for the formulation or compounds of the invention and in accordance with accepted practices such as those described in the Ketipdiop manual : Te zZsiepse apa Rgasiise oi Rpagtasu, 2151 ey., 2000,

Zo Prripson MShiatv 8 UMIKipv5.

For oral administration in tablet or capsule form, a compound of formula I may conveniently be combined with an oral, non-toxic, pharmaceutically acceptable carrier such as ethanol, glycerin, water, or the like. In addition, suitable binding agents, lubricants, leavening agents, flavoring agents and coloring agents can be added to the mixture if appropriate. Suitable binding agents include, for example, lactose, glucose, starch, gelatin, acacia resin, tragacanth resin, sodium alginate, carboxymethyl cellulose, polyethylene glycol, wax or the like. Lubricants include, for example, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride or the like. Leavening agents include, for example, starch, methylcellulose, agar, bentonite, xanthan gum, or the like. Additional excipients for capsules include macrogols or lipids.

To obtain solid compositions, such as tablets, the active compound of formula I is mixed with one or more excipients, such as the excipients described above, and other pharmaceutical diluents, such as water, to obtain a solid drug-promising composition containing a homogeneous mixture of the compound of the formula I. The term "homogeneous" should be understood as the compound of the formula | uniformly dispersed throughout the composition so that the composition can be easily divided into equally effective standard dosage forms such as tablets or capsules.

In the form of a standard dosage form, the compound can be administered one or more times a day at appropriate intervals, but always depending on the condition of the patient and according to the prescription of a medical professional. Of course, a standard dosage form of a preparative form contains from 0.01 mg to 200 mg, preferably from 0.01 mg to 20 mg, for example, 0.01-5 mg of the compound of formula I.

The appropriate dosage of the compound according to the invention depends, along with other factors, on the age and condition of the patient, the severity of the disease to be treated, and other factors well known to the practitioner. The compound can be administered either orally, parenterally, or topically according to various administration schedules, for example, daily or once a week. In general, a single dose is in the range of 0.01 to 200 mg/kg of body weight. The compound can be administered as a bolus (ie, the entire daily dose is administered at once) or in divided doses two or more times

Gs10) per day.

If the treatment includes the introduction of another therapeutically active compound, then recommendations on the dosage of the indicated compounds, which are used, can be found in the manual

Tne Rpaptasoiodis! Vaviv oi Tnegaretsiisv, 9Ii Ea., uU.sh. Nagatap apa G.E. And itbriga (Ed5.), Msagam-

NII 1995. The compound of the present invention with one or more other active compounds can be administered either simultaneously or sequentially.

Liquid preparations for either oral or parenteral administration of the compound of the invention include, for example, aqueous solutions, syrups, aqueous or oily suspensions and emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil. Suitable dispersing or suspending agents for aqueous suspensions include synthetic or natural resins such as tragacanth, alginate, acacia, dextran, sodium carboxymethylcellulose, gelatin, methylcellulose or polyvinylpyrrolidone.

For parenteral administration, for example, intramuscular, intraperitoneal, subcutaneous or intravenous injection or infusion, the pharmaceutical composition preferably contains a spool of formula I, dissolved or solubilized in a suitable, pharmaceutically acceptable solvent. For parenteral administration, the compound according to the invention can include a sterile aqueous or non-aqueous solvent, in particular, water, isotonic saline solution, isotonic glucose solution, buffer solution or other solvent that is usually used for parenteral administration of therapeutically active substances. The composition can be sterilized, for example, by filtering through a bacteria-retaining filter, adding a sterilizing agent to the composition, irradiating the composition, or heating the composition.

Alternatively, the compound according to the invention can be presented in the form of a sterile, solid preparation, for example, a lyophilized powder, which is dissolved in a sterile solvent immediately before use. The composition intended for parenteral administration may additionally contain conventional additives such as stabilizers, buffers or preservatives, for example antioxidants such as methyl hydroxybenzoate or the like.

Compositions for rectal administration can be presented in the form of a suppository, including the active ingredient and a carrier, such as cocoa butter, or in the form of an enema. Compositions suitable for intra-articular administration may be presented in the form of a sterile aqueous preparation of the active ingredient, which may be presented in microcrystalline

From the form, for example, in the form of an aqueous microcrystalline suspension. Liposomal formulations or biodegradable polymer systems can also be used to provide the active ingredient for both intra-articular and ocular administration.

Compositions suitable for topical administration, including ophthalmic treatment, include liquid or semi-liquid preparations such as liniments, lotions, gels, lotions, oil-in-water or water-in-oil emulsions such as creams, ointments or pastes; or solutions or suspensions such as drops. Compositions for ophthalmic treatment may preferably additionally contain cyclodextrin. Compositions suitable for administration into the nasal or buccal cavity or for inhalation include powder, direct-flow preparations and sprays such as aerosols and sprays.

Human skin, in particular, the outer layer, the stratum corneum, provides an effective barrier against the penetration of microbial pathogens and toxic chemicals. Although this property of the skin is generally favorable, it complicates transdermal delivery of pharmaceuticals in that much, if not most, of the active ingredient applied to the skin of a patient suffering from a skin disease may not penetrate the viable layers of the skin where it exerts its effect.

Penetration through the skin is facilitated by the addition of penetration enhancers, which include isopropyl alcohol, sulfoxides, azones, pyrrolidines, and glycols. In embodiments of the invention, penetration enhancers include OM5O, laurocapram, 2-pyrrolidone, decanol, and propylene glycol. In one embodiment of the invention, the penetration enhancer is isopropyl alcohol.

In embodiments of the invention, the therapeutically active compound is dissolved in a suitable solvent. Suitable solvents are glycols, ketones, acetates and ethers. Ingenol compounds have been shown to have sufficient stability in alcohols such as benzyl alcohol and isopropyl alcohol. In general, ingsenol compounds have previously been shown to have sufficient stability at low pH. In embodiments of this invention, the pH of the pharmaceutical formulation is below 7. In embodiments of this invention, the pH of the pharmaceutical formulation is below 6. In embodiments of this invention, the pH of the pharmaceutical formulation is below 4.5. In embodiments of the present invention, the pH of the pharmaceutical formulation is below 4.0. In the variants of the implementation of this invention, the pH of the pharmaceutical formulation is below 4.5 and not less than 2.5. In embodiments of the present invention, the pH of the pharmaceutical formulation is lower than 4.0 and not lower than 2.5. A preferred pH range can be obtained by including a suitable buffer. In one embodiment of the invention, the buffer is an acetate buffer. In embodiments of the invention, a citrate buffer is used. In embodiments of the invention, a mixed citrate-phosphate buffer is used.

In one embodiment, the composition is an ointment. According to the modern classification of the EPA (US Food and Drug Administration), the ointment is a semi-solid dosage form that can contain water and volatile substances, in the amount of up to 20 95 wt., and which contains more than 50 95 wt. hydrocarbon, wax or polyols in the carrier. Thus, according to the invention, the ointment can be a water-in-oil composition, and in this case, the nanosuspension itself can be added to the lipophilic composition so that the composition contains up to 10 95 wt., or preferably, up to 5 95 wt. of the aqueous phase. Alternatively, the composition can be a non-aqueous ointment that contains free water in an amount of less than about 2 95, preferably less than 1 95 wt. compositions.

The ointment carrier may appropriately contain paraffin selected from paraffins consisting of hydrocarbons with chain lengths of H and mixtures thereof. A commonly used ointment carrier is petroleum jelly or white soft paraffin, which consists of hydrocarbons of various chain lengths with a maximum at about Cao-44, or a mixture of petroleum jelly and liquid paraffin (consisting of hydrocarbons of various chain lengths with a maximum at Cgv-4o ). Although petroleum jelly provides occlusion of the treated skin surface, reducing transdermal water loss and potentiating the therapeutic effect of the active ingredient in the formulation, it tends to cause an oily and/or tacky feeling that persists for some time after application and is not easy to spread. Therefore, it may be preferable to use a paraffin consisting of hydrocarbons with a slightly shorter chain length, such as paraffins consisting of hydrocarbons with chain lengths with a maximum at Са4-16, Ств-22, Сго-22, С20-26 or mixtures thereof. Such paraffins have been found to be more cosmetically acceptable in that they are less sticky and/or greasy when applied and spread more easily. Therefore, it is expected that they will lead to improved patient compliance with prescribed treatment. Suitable paraffins of this type are produced by Zopperogp and are sold under the trade name Boppesope, for example, Boppesope CM, Boppesope UOMI, Boppesope OM2 and Boppesope NU. These paraffins are further described and characterized in International Patent Application M/008/141078, which is incorporated herein by reference. (The hydrocarbon composition of the paraffins was determined by gas chromatography).

To give the desired viscosity of the composition, it can suitably include a lipophilic, viscosity-increasing ingredient, such as a wax. The wax can be a mineral wax consisting of a mixture of hydrocarbons with a high molecular weight, for example, saturated C3-7o alkanes, such as microcrystalline wax. Alternatively, the wax can be a vegetable or animal wax, for example, a C14-C2 ester of fatty acids and

Cia-z2 fatty alcohols such as beeswax. The amount of the viscosity-increasing ingredient may vary according to the viscosity-increasing capacity of the ingredient, but may typically be in the range of approximately 1-2095 wt. compositions. When the viscosity-increasing ingredient is a microcrystalline wax, it is usually present in an amount in the range of about 5-15 95 wt., for example, about 10 95 wt. compositions.

In order to maintain sufficient physical stability of the composition, in particular, to avoid separation of the aqueous and lipid phases in it, it may be preferable to include a water-in-oil emulsifier with an NIV (water-lipid balance) index of 3-8. Examples of such emulsifiers are simple C-22 alkyl ethers of polyoxyethylene, for example, simple stearyl ether of polyoxyethylene, simple cetyl ether of polyoxyethylene, simple oleyl ether of polyoxyethylene or simple lauryl ether of polyoxyethylene. The amount of emulsifier is usually in the range of 2-10 95 wt./wt. compositions.

In another embodiment, the composition is a cream, which may contain ointment-like components, but which is usually an oil-in-water emulsion containing a substantial amount of water.

The composition may also contain other ingredients commonly used in dermal formulations, such as antioxidants (e.g., alpha-tocopherol), preservatives such as benzyl alcohol, sodium edetate, pigments, emollients, skin healing agents, and , improving the condition of the skin, such as urea, allantoin or bisabolol, see STEA Soziteiis Ipgediepie Naparook, 204 Ea., 1992. In one embodiment of the invention, the preservative is benzyl alcohol. 60 In one embodiment, the composition is a gel. Suitable gelling agents include water-soluble polymers derived from cellulose, such as hydroxyalkyl cellulose polymers. In embodiments of the invention, the polymers are hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose and hydroxypropylmethylcellulose. Other gelling agents are cellulose such as carboxymethylcellulose, methylhydroxyethylcellulose and methylcellulose, carbomer such as carbopol and carrageenans. In embodiments of the invention, the gelling agent is derived from cellulose. In embodiments of the invention, the cellulose is hydroxyalkyl cellulose, such as hydroxyethyl cellulose.

In one embodiment of the invention, the composition contains an active compound, a penetration enhancer, a preservative, a gelling agent and a buffer at a pH below 4 and not less than 2.5. For topical use, the compound of formula I can usually be present in an amount from 0.001 to 20 95 wt. composition, such as from 0.01 95 to about 10 95. In embodiments of the present invention, the active compound is present at a concentration of 0.05-1 95. In one embodiment of the present invention, the active compound is present at a concentration of 0.01-0.5 95 In one embodiment of the present invention, the active compound is present at a concentration of approximately 0.1 95. In one embodiment of the invention, the composition contains 0.005-0.1 95 of the active compound, 20-40 95 of isopropyl alcohol, 0.5-10 95 of benzyl alcohol, 0.5-5595 hydroxyethyl cellulose and citrate buffer to 100 95.

The preparative form of ingenol derivatives in a gel for topical administration was described in International Patent Application UUOO7/068963, which is incorporated herein by reference.

METHODS OF OBTAINING

Compounds of formula I may, for example, be prepared using the reactions and technologies described below, together with methods of synthetic organic chemistry known in the art, or variations thereof, as understood by those skilled in the art. Preferred methods include, but are not limited to, the methods described below. The reactions are carried out in solvents suitable for the reagents used and the substances, and suitable for the transformations being carried out. It should also be understood that in the synthetic methods described below, all proposed reaction conditions, including the choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment, and procedures for isolating the reaction product, are chosen to represent the standard conditions of the given

From the reaction, which should be completely understandable to a specialist in this field. Not all compounds falling under this class may be compatible with some of the reaction conditions required in some of the methods described. Such restrictions on substituents as are compatible with the reaction conditions will be readily apparent to one skilled in the art, and alternative methods may be used. If desired, the compounds of the present invention or any intermediate compound can be purified using standard methods well known to those skilled in the art of synthetic organic chemistry, for example, methods described in the MM manual. Agtagedo "Rigisayop oi Iarogaygu

Spetisa!v", Wijepgmopy-Neipetapp, bij ey. 2009. The starting compounds are either known compounds that are commercially available, or they can be prepared by conventional synthetic methods well known to a person skilled in the art.

The compounds of the invention may, for example, be prepared according to the following non-limiting general methods and examples.

Scheme 1 n n n n y zn. or Ki modu Na Om veFi z. hearing protection B. esterification 7 F NN sheep M neo nono); ana it no in no Ogo in no ORZ p not on

I(ngevol a o I

Scheme 2 Я н н ы В т. о ин | Y AI sha "An

NOV n b. etherification and 2 n removal of protection (7) y neno / b Ka X (a, y; but new x-ono i ono no v o v 9 no

Ingenop Ra" Ra-O no shchi a

Scheme Z y ni 7 7 po uch "-4 en formation "nu o ren Cl

I і NO a, protection to No 0 carbamate -і H removal of acne n ono U-kh nina in U o nu u no 2 no no on OR in no 0 -oRe Kk no -on ingenol a gayi I

Scheme 4

What in : E pan "BK In formation (tu s.removal "(in a. protection 2 no Carbamate g no protection n r ny og one oo nonoid- d-ono dlovo no o v Y No o

Ingenol RatO Ra-oh! b Gee!

Compounds of general formula I can, for example, be synthesized according to schemes 1, 2, C or 4 by reacting ingenol with a hydroxyl-protecting agent or with a dihydroxyl-protecting agent to obtain protected ingenol derivatives a or according to the methods described in to the management of "Rgoyesiime Stoirv ip Ogdapis Zupipeviv", 4 ey. R. (3.M. M/shv; T.M. Steepe, ext

UMivu, 2007 or R.). KosiepekKi, "Rgoiesiipud SptoiMrv", Zha ed. school Tpiete, 2003 in the references given therein, but not limited to them.

For example, compound a, where the protecting group (Ra) is triphenylmethyl, can be synthesized by reacting ingenol with a triphenylmethyl reagent such as triphenylmethylpyridinium fluoroborate or triphenylmethyl chloride in a suitable solvent such as pyridine, N,M-dimethylformamide or dichloromethane in the presence of or in the absence of a base (for example, OrgietgkKysi ei.a!., 2. Makshgog5spypo, (1981), 368, 878). Compound a, where the protecting group (Po) is silyl, can, for example, be synthesized by reacting ingenol with a silyl chloride such as tert-butyldimethylsilyl chloride, tert-butyldiphenylsilyl chloride or triisopropylsilyl chloride in a suitable solvent such as M,M-dimethylformamide, pyridine, dichloromethane, tetrahydrofuran or acetonitrile in the presence of a suitable base such as imidazole, triethylamine, M,M-diisopropylethylamine or 4-(M,M-dimethylamino)pyridine (e.g. (1982), 37B, 1640-47), or by reacting compound (I) with a silyl triflate such as tert-butyldimethylsilyl trifluoromethanesulfonate in a suitable solvent such as dichloromethane in the presence of a suitable base such as triethylamine.

Compound a, where Rho is 2-tetrahydropyranyl, can, for example, be synthesized by reacting ingenol with dihydropyran in a suitable solvent, such as dichloromethane or acetonitrile, in the presence of a suitable acid, such as para-toluenesulfonic acid.

Compound c, where the protecting group (Po) is an acetal, such as, for example, benzylidene acetal, can be prepared by reacting ingenol with benzaldehyde or dimethyl acetal with benzaldehyde in a suitable solvent, such as dichloromethane or M,M-dimethylformamide, in the presence of the appropriate acid , such as para-toluenesulfonic acid. Compound c, where the protecting group (Rod) is a ketal such as isopropylidene ketal, can, for example, be synthesized by reacting ingenol with a ketone such as acetone or a dimethoxyketal such as 2,2-dimethoxypropane in a suitable solvent such as dichloromethane or M, M-dimethylformamide, in the presence of a suitable acid, such as para-toluenesulfonic acid (for example, V. ogo, 2. Maishigiog5sp. (1982), 376, 748-756). Acetone and 2,2-dimethoxypropane can also act as solvents.

As shown in Schemes 1 and 2, protected derivatives of ingenol a or c can be esterified to obtain compounds of the general formula B or according to the methods of esterification of hydroxyl groups described in the guide "Esterification" 9. Oiega, UmMieu-MSN, 2003 and given in references, but not limited to them. Compound B or y can, for example, be synthesized by reacting compound a or with an activated acid derivative, such as an acid halide, such as an acid chloride. Esterification by interaction with the acid chloride may occur in a suitable solvent such as dichloromethane or toluene without an activator, or it may occur in the presence of a base such as pyridine, triethylamine, or 4-(M,M-dimethylamino)pyridine (e.g., , 2. Mayigpog5sp. (1982), 3705, 748-756). Compound B or y can, for example, be synthesized by reacting compound a or c with an activated acid derivative, such as acid anhydride. Esterification by interaction with an acid anhydride can occur without a catalyst (eg, Orhegkisi et.ai., 2. Mafipog5spipo, (1981), 368, 878), or in the presence of an acid catalyst using an acid such as perchloric acid or a Lewis acid such as scandium triflate (IP) or bismuth triflate (IP) triflate, or in the presence of a base such as sodium bicarbonate or triethylamine.

Compound B or y can, for example, be synthesized by reacting compound a or c with an activated acid derivative such as a mixed acid anhydride such as trichlorobenzoic acid. Esterification by reaction with a mixed anhydride can be carried out in a suitable solvent without a catalyst or in the presence of an acid catalyst using an acid such as perchloric acid or a Lewis acid such as scandium(II) triflate or bismuth(I) triflate in the presence of a base such as sodium bicarbonate or triethylamine. Compound p or a may, for example, be synthesized by reacting compound a or c with an acid in the presence of a compound reagent such as a carbodiimide, such as dicyclohexylcarbodiimide or M-(3-dimethylaminopropyl)-M'-ethylcarbodiimide, in the presence and absence of a base, such as 4-(M,M-dimethylamino)pyridine, and with or without a catalyst such as 4-(M,M-dimethylamino)pyridine in a suitable solvent such as dichloromethane (e.g. Arrepaipo et al., Eig. U. Ogd. Spet. (1999), 3413). Compound reagents on a solid support can also be used in the esterification stage | Mat, M.-N., dWashigai oi Sotrbipaiogia! Spetivigu, (2003), 5, 479-545, or "Eviegiiisainop" Bu y). Ohega, Umieu-USN, 20031.

Compounds of formula B, a or I of scheme 1 or 2 presented above can, for example, be synthesized by enzymatic esterification by the interaction of compound a, c or ingenol with an acyl donor such as an acid anhydride, an ester such as a vinyl ether, or a thioether, in the presence of an enzyme such as lipase or esterase.

As depicted in scheme C and 4, protected derivatives of ingenol a or c can be carbamoylated to obtain compounds of the general formula B or according to the methods of carbamoylation of hydroxyl groups, described without limitation in the publications of N. Eskegi in the section "Ripsiop5

Sopiaipipd a Sagropu! Sgoyr apa ah eabhi Ope SPpaisodep (Bbyi poi Naiodep)" in the monograph "Sotrgepepzime Ogdapis Eipsiopa! Sgoir Tgape5gogtaiyyop5 II" Publishing House A.K., Kaigy2Ku apa

E.9.K. Tauiog, Moi 6, p. 440-444, Eivemieg, 2005, and in the references given therein. Compounds B or a can, for example, be synthesized by reacting compound a or c with an activated carbamic acid derivative, such as a carbamoyl halide, such as carbamoyl chloride. Carbamoylation by interaction with carbamoyl chloride can occur in a suitable solvent, such as acetonitrile, dichloromethane, or toluene, without an activator, or it can occur in the presence of a base, such as pyridine, triethylamine, potassium carbonate, or 4-(M,M-dimethylamino)pyridine.

Compound B or y can, for example, be synthesized by the interaction of compound a or c with isocyanate to obtain M-mono-substituted carbamates. The formation of the carbamate by reaction with the isocyanate can occur in a suitable solvent such as dichloromethane or acetonitrile without a catalyst, or it can occur in the presence of a base such as triethylamine.

Compounds of the formula | can be obtained by selective removal of protective groups Ра from compounds of the general structure B or without limitation according to the methods of removing the protection of hydroxyl or dihydroxyl protective groups described in the publications "Rgoyesiime SsSgoishmrz ip Ogdapis bZupipeviv", I ey. R.S.M. M/shv; T.M. Steepe, add. U/Peu, 2007 or in R.). Kosiepzvki, "Rgoiesiipd StoyMmrv", Zha ey. Sh. Tniete, 2003, and references therein.

Compounds of the general formula | may, for example, be prepared from compounds of the general formula 4, wherein R is an acetal, such as benzylidene acetal, or a ketal, such as isopropylidene ketal, by cleavage of the protecting group in the presence of a suitable acid, such as aqueous hydrochloride, acetic acid, trifluoroacetic acid acid or p-toluenesulfonic acid, in a suitable solvent such as methanol or aqueous tetrahydrofuran. Compounds of the general formula I can, for example, be prepared from compounds of the general formula B, where Ru is alkoxyalkyl, such as 2-tetrahydropyranyl, by cleavage of the acetal component, for example, by acid-catalyzed cleavage in the presence of a suitable acid, such as para-toluenesulfonic acid, in a suitable solvent such as methanol. Compounds of the general formula I may, for example, be prepared from compounds of the general formula B, wherein Ru is silyl, such as tert-butyldimethylsilyl, by reacting compound p with an appropriate acid, such as hydrochloride, in a suitable solvent, such as methanol, or by reacting with a fluoride source such as tetra-n-butylammonium fluoride or tetrafluorosilane in a suitable solvent such as tetrahydrofuran or acetonitrile. Compounds of the general formula | can, for example,

be prepared from compounds of general formula B, wherein Ru is triphenylmethyl, by reacting compound B with an appropriate acid, such as formic acid or trifluoroacetic acid, in a suitable solvent, such as ether, methanol or dichloromethane.

EXAMPLES

General part

Unless otherwise stated, all raw materials used are commercially available. For 1H nuclear magnetic resonance (NMR) spectra, chemical shift values (b) are given (in ppm); tetramethylsilane (0-0.00) is used as a standard. The value of a certain singlet (5), doublet (4), triplet (Y), quartet (d) or range (t) is given. Carbamates can show double signals due to the existence of syn/anti rotamers. Unless otherwise specified, all organic solvents used were anhydrous. Flash chromatography was performed on silica gel. As long as there are no other notes, appropriate mixtures of ethyl acetate and heptane were used. The compounds were detected on plates for TI C (thin-layer chromatography) by detection with an aqueous solution of potassium permanganate.

IN

"n zo,

BUT but oh - oh

Ingenol-5,20-acetonide

Ingenol (1.00 g, 2.30 mmol) was dissolved in a solution of p-toluenesulfonic acid monohydrate in acetone (0.47 mg/mL, 22.5 mL). The solution was stirred at room temperature for 25 min.

A saturated aqueous solution of NaHCO3 (0.2 ml) was added to this solution. The resulting mixture was concentrated in a vacuum. The residue was collected in brine and extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography (heptane/ethyl acetate 19:1 -» heptane/ethyl acetate 0:1) to give the title compound as a white solid (616 mg, 69 95). (See also: Ortekisny, N. 4). eia!., 7. Maishpogzsp., (1981), 866, 878-887.)

IN NMR (300 MHz, SOSIZ) b 5.91 (sq., 9-1.5 Hz, 1H), 5.79 (m, 1H), 4.25 (d, 9-45 Hz, 1H), 4 ,20- 4.07 (m, ZN), 3.93 (s, 1H), 3.51 (s, 1H), 2.57-2.А41 (m, 2H), 2.25 (ddd, U -15.7, 8.4, 2.9 Hz, 1H), 1.85 (d, 9-1.5 Hz, ZN), 1.77 (dt, 9U-15.8, 5.9 Hz, 1H), 1.41 (s, ЗН), 1.35 (s, ЗН), 1.13 (s, ЗН), 1.05 (s, ЗН), 1.00-0.87 (m, 4Н ), 0.70 (td, U-8.4, 6.4 Hz, 1H).

General procedures for obtaining compounds of the general formula HER

N i do no (o; -9

The procedure

A mixture of carboxylic acid (0.100 mmol), dicyclohexylcarbodiimide (0.100 mmol), 4-(M,M-dimethylamino)-pyridine (0.0025 mmol) and ingenol-5,20-acetonide (0.050 mmol) was stirred at room temperature in dichloromethane for 20-24 hours The mixture was mixed with ethyl acetate, filtered and washed with saturated aqueous sodium chloride. The organic phase was dried with sodium sulfate, concentrated in vacuo and purified by flash chromatography (heptane - heptane/ethyl acetate 7:3) to give the title compound as a white solid.

Procedure B

A mixture of acyl chloride (0.0625 mmol), diisopropylethylamine (0.075 mmol), 4-(M,M-dimethylamino)pyridine (0.070 mmol) and ingenol-5,20-acetonide (0.050 mmol) was stirred at 55"C in tetrahydrofuran for 6 -20 h. The mixture was mixed with ethyl acetate, filtered and washed with saturated aqueous sodium chloride. The organic phase was dried over sodium sulfate, concentrated in vacuo and purified by flash chromatography (heptane - heptane/ethyl acetate 7:3) to give the title compound as a white solid matter.

The procedure with

A mixture of carboxylic acid (0.100 mmol), dicyclohexylcarbodiimide (0.100 mmol), 4-(M,M-dimethylamino)pyridine (0.025 mmol) and ingenol-5,20-acetonide (0.050 mmol) was stirred in a microwave oven at 150 "C in acetonitrile for 5 min. The mixture was mixed with ethyl acetate, filtered and washed with saturated aqueous sodium chloride. The organic phase was dried over sodium sulfate, concentrated in vacuo and purified by flash chromatography (heptane - heptane/ethyl acetate 7:3) to give the title compound as white solid.

Procedure a

A mixture of acyl chloride (0.125 mmol), diisopropylethylamine (0.250 mmol), 4-(M,M-dimethylamino)pyridine (0.025 mmol) and ingenol-5,20-acetonide (0.050 mmol) was stirred in a microwave oven at 150 C in acetonitrile for 10 -30 min. The mixture was mixed with ethyl acetate, filtered and washed with saturated aqueous sodium chloride. The organic phase was dried with sodium sulfate, concentrated in vacuo and purified by flash chromatography (heptane - heptane/ethyl acetate 7:3) to give the title compound as a white solid.

The general procedure for obtaining compounds of the general formula I n ef de ono no on

Procedure e

Ingenol-5,20-acetonide-Z-acylate or ingenol-5,20-acetonide-Z-carbamate (0.10 mmol) was dissolved in tetrahydrofuran (0.47 mL) under an argon atmosphere. An aqueous solution of NS (4 M, 4.7 μl) was added. The solution was stirred at room temperature for 20-27 hours. Tetrahydrofuran can be replaced by methanol, and the reaction time at room temperature is reduced to 0.5 h.

The solution was concentrated under vacuum. The residue was purified by flash chromatography (heptane/ethyl acetate 5:11 - heptane/ethyl acetate 3:7) to give the title compound. For more polar compounds, a gradient of dichloromethane/methanol 98:2 -» dichloromethane/methanol 95:5 was used.

З General procedure for obtaining carbamoyl chlorides c)

B41- M X si

K2

The procedure

Potassium bicarbonate (3.0 mmol) or a tertiary amine such as triethylamine or pyridine was added to a solution of the secondary amine (1.2 mmol) in dichloromethane (2 mL) at 0°C, followed by the addition of triphosgene (1.0 mmol). The mixture was stirred at 0 "C for 2 hours, filtered and washed with dichloromethane. The combined filtrates were concentrated in vacuo to give the title compound.

General procedures for obtaining ingenol-5,20-acetonide-3-carbamate compounds of the general formula PI

N

"n ef you bno

In (o) 12 -o

Sh

Procedure 9

A mixture of carbamoyl chloride (0.390 mmol), potassium carbonate (0.616 mmol) and ingenol-5,20-acetonide (0.077 mmol) was stirred at 80 "С in acetonitrile for 16-24 h. The mixture was filtered and washed with dichloromethane. The combined filtrates were concentrated in vacuum and purified by flash chromatography (heptane -» heptane/ethyl acetate 7:3) to give the title compound.

The procedure of p

A mixture of carbamoyl chloride (0.390 mmol), potassium carbonate (0.616 mmol) and ingenol-5,20-acetonide (0.077 mmol) was stirred in a microwave oven at 160 "С in acetonitrile for 10 min. The mixture was filtered and washed with dichloromethane. The combined filtrates were concentrated in vacuo and purified by flash chromatography (heptane - heptane/ethyl acetate 7:3) to give the title compound.

Procedure and

A mixture of isocyanate (0.231 mmol), potassium carbonate (0.385 mmol) and ingenol-5,20-acetonide (0.077 mmol) was stirred at 80 "C in acetonitrile for 16-24 h. The mixture was filtered and washed with dichloromethane. The combined filtrates were concentrated in vacuum and purified by flash chromatography (heptane -» heptane/ethyl acetate 7:3) to give the title compound.

procedure)

To a solution of ingenol-5,20-acetonide (0.10 mmol) in tetrahydrofuran at 0 "C in an argon atmosphere, 1 M lithium bis(trimethylsilyl)ioamide in TNE (0.10 mmol) was added dropwise. After stirring for 10 min. carbamoyl chloride (0.20 mmol) dissolved in 0.2 mL of TNE was added dropwise, and the reaction mixture was slowly warmed to room temperature overnight, 2 drops of water were added, followed by dichloromethane (1 mL), filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (heptane -» heptane/ethyl acetate 7:3) to give the title compound.

General procedure for obtaining 4-aryl-substituted 1-methylpyrazole-5-carboxylic acids

The procedure for the procedure in rROg(aBa)z, RSUZ vk on KZRoye and

Dioxane/H?2O 2.1 on hi i pytOtog What

M utton ZI no

We used the method described by 0. S. Ry eyi a! Apdem/. Spent 2006, 118, 1304-1306.

A heterogeneous mixture of 1-methyl-4-bromopyrazole-5-carboxylic acid (1 mmol),

Tris(dibenzylideneacetone)dipalladium(0) (0.1 mmol), tricyclohexylphosphine (0.2 mmol), potassium phosphate (3 mmol) and the corresponding phenylboronic acid (1.5 mmol), water (2 mL) and dioxane (4 mL ) was stirred in an argon atmosphere in a microwave oven at 180 "С for 20 min. The mixture was cooled to room temperature and partially evaporated, 5M aqueous Mahon (1 ml) was added, washed 3 times with simple diethyl ether. The aqueous solution was acidified

AM NS, the precipitate was separated by filtration and dried to obtain crude 4-aryl-substituted 1-methylpyrazole-5-carboxylic acid, which was used without additional purification.

N

"n gu

OO" no

Ph. Z

SI Ge)

Mo Ya

Preparation of compound 601:

Ingenol-5,20-acetonide-3-(5-methyl-3-(2-chloro-6-fluorophenyl)-isoxazole-4-carboxylate (Compound 6O1)

Compound 601 was obtained according to Procedure 4.

Starting material: 5-Methyl-3-(2-chloro-6-fluorophenyl)isoxazole-4-carbonyl chloride. 1H NMR (300 MHz, SOSIZ) b 7.41-7.33 (m, 1H), 7.27-7.24 (m, 1H), 7.08-7.02 (m, 1H), 5, 85-5.84 (d, 1H), 5.76-5.74 (m, 1H), 5.57 (s, 1H), 4.23-4.06 (m, ЗН), 3.94 ( s, 1H), 3.18 (s, 1H), 2.82 (s, ЗН), 2.21-2.12 (m, 1H), 1.96-1.90 (m, 1H), 1 ,69-1.62 (m, 1Н), 1.61 (d, ZN), 1.47 (s, ZN), 1.39 (s, ZN), 1.03 (s, ZN), 1, 03 (c,

ЗН), 0.90-0.78 (m, 1Н), 0.73 (d, ЗН), 0.66-0.58 (m, 1Н). N

A "n 2 (o) ono o.; (c)

M. O. Yak

Preparation of compound 602:

Ingenol-5,20-acetonide-3-(5-methyl-3-phenyl-isoxazole-4-carboxylate) (Compound 602)

Compound 602 was obtained according to Procedure a.

Starting material: 5-Methyl-3-phenylisoxazole-4-carbonyl chloride.

IN NMR (300 MHz, SOSIZ) b 7.57-7.53 (m, 2H), 7.47-7.37 (m, ЗН), 5.95 (d, 1H), 5.76 (m, 1H), 5.68 (s, 1H), 4.23-4.04 (m, ЗН), 3.97 (s, 1Н), 3.12 (s, 1Н), 2.77 (s, ЗН ), 2.11-2.01 (m, 1H), 1.95-1.87 (m, 1H), 1.72 (d, ЗН), 1.59-1.49 (m, 1H), 1.45 (s, ЗН), 1.40 (s, ЗН), 1.04 (s, ЗН), 1.03 (s, ЗН), 0.90-0.80 (m, 1Н), 0 .71 (d, ZN), 0.65-0.57 (m, 1H). n "n 520; o no o (in 9 o

Preparation of compound 603

Ingenol-5,20-acetonide-3-(15-camphanate) (Compound 603)

Compound 603 was obtained according to Procedure a.

Starting material: (15)-Camphanous chloride. "H NMR (300 MHz, SOSIZ) b 6.10-6.09 (m, 1H), 5.80-5.79 (m, 1H), 5.66 (s, 1H), 4.25-4 ,11 (m, ЗН), 4.02 (s, 1Н), 3.17 (s, 1Н), 2.61-2.56 (m, 1Н), 2.48-2.39 (m, 1Н ), 2.29-2.20 (m, 1H), 2.09-2.02 (m, 1H), 1.94-1.88 (m, 1H), 1.79-1.65 (m . .05 (c, ЗН), 0.99-0.86 (m, 7Н), 0.73-0.65 (m, 1Н).

Nn

OZ m ono m. | oh she --9

From Obtaining compound 604:

Ingenol-5,20-acetonide-3-(3-phenyltriazole-4-carboxylate) (Compound 604)

Compound 604 was obtained according to Procedure p.

Starting material: 3-phenyltriazole-4-carboxylic acid. n 35 chi no

M x --

Preparation of compound 605:

Ingenol-5,20-acetonide-3-(2-phenylpyrazole-3-carboxylate) (Compound 605)

Compound 605 was prepared according to Procedure P, where "carbamoyl chloride" was replaced by 2-phenylpyrazole-3-carbonyl chloride.

AND! office

LI (o) m" -- /

Preparation of compound 606:

Ingenol-5,20-acetonide-3-(1-methylindazole-3-carboxylate) (Compound 606)

Compound 606 was prepared according to Procedure P, where "carbamoyl chloride" was replaced by 1-methylindazole-3-carbonyl chloride. schi pveFfu ono m o (c) -

Preparation of compound 607:

Ingenol-5,20-acetonide-3-(3-ethyl-5-methyl-isoxazole-4-carboxylate) (Compound 607)

Compound 607 was obtained according to Procedure p.

Starting material: 3-Ethyl-5-methyl-isoxazole-4-carboxylic acid. "H NMR (300 MHz, SOSIZ) 6.12 (m, 1H), 5.82-5.80 (m, 1H), 5.72 (s, 1H), 4.28-4.11 (m, ЗН), 4.05 (s, 1Н), 3.26 (s, 1Н), 2.89 (sq., 2Н), 2.65 (s, ЗН), 2.63-2.59 (m, 1H), 2.30-2.24 (m, 1H), 1.81 (d, ЗН), 1.79-1.71 (m, 1Н), 1.48 (s, ЗН), 1.45 (s, ZN), 1.28 (t, ZN), 1.08 (s, ZN), 1.05 (s, ZN), 1.01 (d, ZN), 0.94-0.86 ( m, 1H), 0.74-0.66 (m, 1H). n ef

OTno

M) 9 o'clock --

Preparation of compound 608:

Ingenol-5,20-acetonide-3-(3,5-dimethyl-isoxazole-4-carboxylate) (Compound 608)

Compound 608 was obtained according to Procedure p.

Starting material: 3,5-Dimethyl-isoxazole-4-carboxylic acid. "NMR (300 MHz, SOSIZ) 6.12 (s, 1H), 5.81-5.80 (m, 1H), 5.70 (s, 1H), 4.27-4.11 (m, ZN ), 4.05 (s,

1H), 3.27 (s, 1H), 2.65 (s, ЗН), 2.63-2.59 (m, 1Н), 2.43 (s, ЗН), 2.33-2.23 (m, 1H), 1.82-1.70 (m, 4H), 1.49 (s, ЗН), 1.45 (s, ЗН), 1.09 (s, ЗН), 1.05 ( c, ЗН), 1.01 (d, ЗН), 0.94-0.87 (m, 1Н), 0.74-0.65 (m, 1Н). n ve it

And about /

Preparation of compound 609:

Ingenol-5,20-acetonide-3-(1-methylindole-3-carboxylate) (Compound 609)

Compound 609 was obtained according to Procedure p.

Starting material: 1-methylindole-3-carboxylic acid.

N webno t iv) x.5 --

Preparation of compound 610:

Ingenol-5,20-acetonide-3-(3-phenylthiophene-2-carboxylate) (Compound 610)

Compound 610 was obtained according to Procedure p.

Starting material: 3-Phenylthiophene-2-carboxylic acid. n en vh otno /! (c) o" --

Preparation of compound 611:

Ingenol-5,20-acetonide-3-(5-phenylisoxazole-3-carboxylate) (Compound 611)

Compound 611 was obtained according to Procedure a.

Starting material: 5-Phenylisoxazole-3-carbonyl chloride. "H NMR (300 MHz, SOSIZ) 7.83-7.78 (m, 2H), 7.52-7.47 (m, ЗН), 6.90 (s, 1H), 6.16-6, 15 (m, 1H), 5.81 (m, 2H), 4.28-4.08 (m, 4H), 3.29 (s, 1H), 2.73-2.68 (m, 1H) , 2.30-2.21 (m, 1H), 1.85 (d, ЗН), 1.82-1.75 (m, 1Н), 1.50 (s, ЗН), 1.47 (s , ЗН), 1.08 (с, ЗН), 1.05 (d, ЗН), 1.04 (с, ЗН), 0.95-0.88 (m, 1Н), 0.74-0, 67 (m, 1H).

N

In N

KI it

Eh o - y; -

Preparation of compound 612:

Ingenol-5,20-acetonide-3-(isoquinoline-1-carboxylate) (Compound 612)

Compound 612 was obtained according to Procedure p.

Starting material: isoquinoline-1-carboxylic acid. "H NMR (300 MHz, SOSIZ) b 8.76-8.73 (m, 1H), 8.58 (d, 1H), 7.90 (d, 1H), 7.81 (d, 1H), 7.77-7.72 (m, 1H), 7.70-7.64 (m, 1H), 6.15 (m, 1H), 6.00 (s, 1H), 5.82-5, 80 (m, 1H), 4.47 (s, 1H), 4.29-4.22 (m,

ЗН), 4.10 (s, 1Н), 2.74-2.69 (m, 1Н), 2.45-2.35 (m, 1Н), 1.90 (d, ЗН), 1.87 -1.80 (m, 1H), 1.49 (s, ЗН), 1.47 (s, ЗН), 1.15 (s, ЗН), 1.07 (s, ЗН), 0.98- 0.88 (m, 4H), 0.77-0.69 (m, 1H). n ev ono 7 h o

Ma --

Preparation of compound 613:

Ingenol-5,20-acetonide-3-(quinoline-4-carboxylate) (Compound 613)

Compound 613 was obtained according to Procedure p.

Starting material: Quinoline-4-carboxylic acid. and

ZY ono i x Ge)

Meme --

Preparation of compound 614:

Ingenol-5,20-acetonide-3-(cinnoline-4-carboxylate) (Compound 614)

Compound 614 was obtained according to Procedure p.

Starting material: Cinnoline-4-carboxylic acid. "H NMR (300 MHz, SOSIZ) b 9.71 (s, 1H), 8.94-8.91 (m, 1H), 8.67-8.64 (m, 1H), 7.96-7 .86 (m, 2H), 6b, 21-6.20 (m, 1H), 5.93 (s, 1H), 5.85-5.84 (m, 1H), 4.32-4.13 (m, 4H), 3.36 (s, 1H), 2.74-2.69 (m, 1H), 2.38-2.28 (m, 1H), 1.87 (d, ЗН), 1.86-1.79 (m, 1H), 1.53 (s, ЗН), 1.52 (s, ЗН), 1.09 (3, ЗН), 1.05 (s,

ЗН), 1.04 (d, ЗН), 0.96-0.89 (m, 1Н), 0.77-0.69 (m, 1Н).

N Dec En

Unit

M ono "and K

Preparation of compound 615:

Ingenol-5,20-acetonide-3-(3-phenylimidazole-4-carboxylate) (Compound 615)

Compound 615 was obtained according to Procedure p.

Starting material: 3-Phenilimidazole-4-carboxylic acid. "H NMR (300 MHz, SOSIZ) b 7.89 (d, 1H), 7.67 (d, 1H), 7.48-7.45 (m, ZN), 7.35-7.32 (m , 2H), 6.00-5.99 (m, 1H), 5.77-5.76 (m, 1H), 5.62 (s, 1H), 4.22-4.07 (m, ЗН ), 3.97 (width, 1H), 3.17 (s, 1H), 2.34-2.29 (m, 1H), 2.25-2.16 (m, 1H), 1, 76-1.67 (m, 4H), 1.40 (s, ЗН), 1.37 (s, ЗН), 1.07 (s, ЗН), 1.04 (s, ЗН), 0.92 -0.84 (m, 4H), 0.71-0.63 (m, 1H).

AND

to Razhtses.. In; u o) o no -Shkhkh v.

F) and Zh

Preparation of compound 616:

Ingenol-5,20-acetonide-3-(5-phenyloxazole-4-carboxylate) (Compound 616)

Compound 616 was obtained according to Procedure p.

Starting material: 5-Pheniloxazole-4-carboxylic acid.

NMR NMR (300 MHz, SOSIZ) b 7.95-7.91 (m, ZN), 7.48-7.42 (m, ZN), 6.07-6.06 (m, 1H), 5.78-5.75 (m, 2H), 4.24-4.08 (m, ЗН), 4.03-4.02 (m, 1H), 3.39 (s, 1H), 2, 37-2.29 (m, 1H), 2.20-2.11 (m, 1H), 1.83 (d, ЗН), 1.68-1.58 (m, 1H), 1.47 ( s, ЗН), 1.43 (s, ЗН), 1.05 (s, ЗН), 1.03 (s, ЗН), 0.91-0.84 (m, 1Н) 0.84 (d, ЗН), 0.68-0.60 (m, 1Н). n ! 20, o o no o;

I x KZ about

Preparation of compound 617:

Ingenol-5,20-acetonide-3-(1,2-benzoxazole-3-carboxylate) (Compound 617)

Compound 617 was obtained according to Procedure p.

Starting material: 1,2-Benzoxazole-3-carboxylic acid.

IN NMR (300 MHz, SOSIZ) b 8.14-8.11 (m, 1H), 7.70-7.60 (m, 2H), 7.46-7.39 (m, 1H), 6, 21-6.19 (m, 1H), 5.89 (s, 1H), 5.83-5.81 (m, 1H), 4.30-4.11 (m, 4H), 3.34 ( s, 1H), 2.77-2.72 (m, 1H), 2.30-2.21 (m, 1H), 1.89 (d, ЗН), 1.81-1.72 (m, 1H), 1.52 (s, ЗН), 1.49 (s, ЗН), 1.07 (s, ЗН), 1.05 (d, ЗН), 1.04 (s,

ЗН), 0.95-0.88 (m, 1Н), 0.74-0.66 (m, 1Н). N

And o (in; vo po o

Where

Preparation of compound 618:

Ingenol-5,20-acetonide-3-(3-isopropyl-5-methyl-isoxazole-4-carboxylate) (Compound 618)

Compound 618 was obtained according to Procedure p.

Starting material: 3-isopropyl-5-methyl-isoxazole-4-carboxylic acid. "H NMR (300 MHz, SOSIZ) 6 6.12-6.11 (m, 1H), 5.82-5.79 (m, 1H), 5.73 (s, 1H), 4.28-4 ,10 (m, ЗН), 4.06-4.05 (m, 1Н), 3.46 (septet, 1Н), 3.26 (s, 1Н), 2.65 (s, ЗН), 2, 63-2.57 (m, 1H), 2.33-2.24 (m, 1H), 1.81 (d, ЗН), 1.79-1.70 (m, 1H), 1.48 ( c, ZN), 1.46 (c, ZN), 1.33 (d, ZN), 1.31 (d, ZN), 1.08 (c, ZN), 1.05 (c, ZN), 1.00 (d, ZN), 0.94-0.87 (m, 1H), 0.74-0.66 (m, 1H). di o (o) yo (o) an; o)

Preparation of compound 619:

Ingenol-5,20-acetonide-3-(3-(2-methoxyphenyl)-5-methyl-isoxazole-4-carboxylate) (Compound 619)

Compound 619 was obtained according to Procedure p.

Starting material: 3-(2-Methoxyphenyl)-5-methyl-isoxazole-4-carboxylic acid. "H NMR (300 MHz, SOSIZ) b 7.44-7.35 (m, 2H), 7.04-6.99 (m, 1H), 6.96-6.92 (d, 1H), 5 .93-5.91 (m, 1H), 5.75-5.72 (m, 1H), 5.67 (s, 1H), 4.20-413 (m, 2H), 4.06-4 ,00 (m, 1H), 3.92 (s, 1H), 3.76 (s, ЗН), 2.98 (s, 1Н), 2.74 (s, ЗН), 2.03-1, 95 (m, 1H), 1.87-1.78 (m, 1H), 1.69 (d, ЗН), 1.58-1.50 (m, 1Н), 1.42 (s, ЗН) , 1.38 (s, ЗН), 1.04 (s, ЗН), 1.03 (s, ЗН), 0.88-0.80 (m, 1Н), 0.76 (d, ЗН), 0.66-0.58 (m, 1H).

Zo

N a o) kch Ische shk O

M-- about with X-

Preparation of compound 620:

Ingenol-5,20-acetonide-3-(4-bromo-2-methyl-pyrazole-3-carboxylate) (Compound 620)

Compound 620 was obtained according to Procedure p.

Starting material: 4-Bromo-2-methyl-pyrazole-3-carboxylic acid. n u c) kch c, --t o;

Preparation of compound 621:

Ingenol-5,20-acetonide-3-(4-bromo-2-ethyl-pyrazole-3-carboxylate) (Compound 621)

Compound 621 was obtained according to Procedure p.

Starting material: 4-Bromo-2-ethyl-pyrazole-3-carboxylic acid.

N a c) si ono sht (c) s G-

M

Preparation of compound 622:

Ingenol-5,20-acetonide-3-(4-chloro-2-methyl-pyrazole-3-carboxylate) (Compound 622)

Compound 622 was obtained according to Procedure p.

Starting material: 4-Chloro-2-methyl-pyrazole-3-carboxylic acid. N

And the 5th

Oh no

Oh yeah -/

Preparation of compound 623:

Ingenol-5,20-acetonide-3-(5-bromopyrimidine-4-carboxylate) (Compound 623)

Compound 623 was prepared according to Procedure 4, but extending the reaction time to 40 min.

Starting material: 5-Bromopyrimidine-4-carbonyl chloride obtained from 5-bromopyrimidine-4-carboxylic acid by reaction with 1.25 equivalents of oxalyl chloride in dichloromethane and a drop of dimethylformamide at room temperature for 30 min. followed by evaporation of volatile substances in a vacuum.

NMR NMR (300 MHz, SOSIZ) b 9.20 (s, 1H), 9.00 (s, 1H), 6.16-6.14 (m, 1H), 5.85 (s, 1H) , 5.83-5.80 (m, 1H), 4.27-4.14 (m, ЗН), 4.07-4.06 (m, 1H), 3.44 (s, 1H), 2 .66-2.59 (m, 1H), 2.31-2.22 (m, 1H), 1.88 (d, ЗН), 1.79-1.70 (m, 1H), 1.49 (с, ЗН), 1.46 (с, ЗН), 1.09 (с, ЗН), 1.05 (с, ЗН), 0.96 (d, ЗН), 0.95-0.88

(m, 1H), 0.73-0.65 (m, 1H).

N

Dee (9)

Ve o no o 7 4-

Preparation of compound 624:

Ingenol-5,20-acetonide-3-(3-bromopyridine-2-carboxylate) (Compound 624)

Compound 624 was prepared according to Procedure 4, but extending the reaction time to 40 min.

Starting material: 3-Bromopyridine-2-carbonyl chloride obtained from 3-bromopyridine-2-carboxylic acid by reaction with 1.25 equivalents of oxalyl chloride in dichloromethane and a drop of dimethylformamide at room temperature for 30 min. followed by evaporation of volatile substances in a vacuum.

NMR NMR (300 MHz, SOSIZ) b 8.60 (dd, 1H), 7.99 (dd, 1H), 7.30 (dd, 1H), 6.13-6.12 (m, 1H) , 5.89 (s, 1H), 5.80-5.77 (m, 1H), 4.20-4.15 (m, ЗН), 4.05 (s, 1H), 3.85 (s , 1H), 2.70-2.60 (m, 1H), 2.32-2.23 (m, 1H), 1.89 (d, ЗН), 1.80-1.71 (m, 1H ), 1.47 (s, ZN), 1.44 (s, ZN), 1.10 (s, ZN), 1.05 (s, ZN), 0.96 (d,

ЗН), 0.95-0.89 (m, 1Н), 0.73-0.85 (m, 1Н).

NN - about mn n

IF) I and AL

Preparation of compound 625:

Ingenol-5,20-acetonide-3-(5-methylthiazole-4-carboxylate) (Compound 625)

Compound 625 was obtained according to Procedure p.

Starting material: 5-Methylthiazole-4-carboxylic acid. "H NMR (300 MHz, SOSIZ) b 8.85 (s, 1H), 6.13-6.11 (m, 1H), 5.79-5.77 (m, 2H), 4.25-4 ,13 (m, ЗН), 4.06-4.05 (m, 1Н), 3.50 (s, 1Н), 2.78 (s, ЗН), 2.72-2.67 (m, 1Н ), 2.31-2.22 (m, 1H), 1.85 (d, ЗН), 1.81-1.72 (m, 1Н), 1.48 (s, ЗН), 1.45 ( s, ЗН), 1.08 (s, ЗН), 1.05 (s, ЗН), 1.02 (d, ЗН), 0.95-0.88 (m, 1Н), 0.74-0 ,66 (m, 1H).

N u v) si to no r « o

F,;

Oh

Preparation of compound 626:

Ingenol-5,20-acetonide-3-(4-chloro-1-methyl-pyrazole-3-carboxylate) (Compound 626)

Compound 626 was obtained according to Procedure p.

Starting material: 4-Chloro-1-methylpyrazole-3-carboxylic acid.

n n 20 o no -zh O yours

Preparation of compound 627:

Ingenol-5,20-acetonide-3-(2,4-dimethylthiazole-5-carboxylate) (Compound 627)

Compound 627 was obtained according to Procedure p.

Starting material: 2,4-Dimethylthiazole-5-carboxylic acid. "H NMR (300 MHz, SOSIZ) b 6.10-6.09 (m, 1H), 5.80-5.79 (m, 1H), 5.68 (s, 1H), 4.26-4 ,12 (m, ZN), 4.04-4.03 (m, 1H), 3.22 (s, 1H), 2.70 (s, ZN), 2.68 (s, ZN), 2, 68-2.63 (m, 1H), 2.32-2.22 (m, 1H), 1.82-1.73 (m, 4H), 1.48 (s, ЗН), 1.44 ( s, ЗН), 1.08 (s, ЗН), 1.05 (s, ЗН), 1.02 (d, ЗН), 0.94-0.88 (m, 1Н), 0.74-0 ,66 (m, 1H).

N

N

2 c) o no - O kish

Preparation of compound 628:

Ingenol-5,20-acetonide-3-(2,5-dimethyloxazole-4-carboxylate) (Compound 628)

Compound 628 was obtained according to Procedure p.

Starting material: 2,5-Dimethyloxazole-4-carboxylic acid. "H NMR (300 MHz, SOSIZ) b 6.10-6.09 (m, 1H), 5.80-5.78 (m, 1H), 5.73 (s, 1H), 4.27-4 ... 2.43 (s, ЗН), 2.31-2.22 (m, 1Н), 1.82 (d, ЗН), 1.79-1.71 (m, 1Н), 1.47 (s, ЗН), 1.41 (s, ЗН), 1.08 (s, ЗН), 1.04 (s, ЗН), 1.01 (d, ЗН), 0.94-0.87 (m, 1Н ), 0.73-0.65 (m, 1H).

N ko a Shan

WITH

9 o i and (9) i o)

Preparation of compound 629:

Ingenol-5,20-acetonide-3-(2,4-dimethylfuran-3-carboxylate) (Compound 629)

Compound 629 was obtained according to Procedure 4.

Starting material: 2,4-Dimethylfuran-3-carbonyl chloride. "H NMR (300 MHz, SOSIZ) b 7.05 (sq., 1H), 6.09-6.08 (m, 1H), 6.80-6.78 (m, 1H), 5.73 ( s, 1H), 4.26-4.12 (m, ЗН), 4.05 (s, 1H), 3.34 (s, 1H), 2.69-2.62 (m, 1H), 2 ... ), 1.48 (s, ZN), 1.44 (s, ZN), 1.08 (s, ZN), 1.05 (s, ZN), 1.00 (d,

ЗН), 0.91-0.86 (m, 1Н), 0.74-0.65 (m, 1Н).

N u o o no sh o) 6) -E MO

Preparation of compound 630:

Ingenol-5,20-acetonide-3-(3,5-diethylisoxazole-4-carboxylate) (Compound 630)

Compound 630 was obtained according to Procedure a.

Starting material: 2,4-diethylfuran-3-carbonyl chloride obtained from 2,4-diethylfuran-3-carboxylic acid by reaction with 1.25 equivalents of oxalyl chloride in dichloromethane and a drop of dimethylformamide at room temperature for 30 min. followed by evaporation of volatile substances in a vacuum. "H NMR (300 MHz, SOSIZ) b 6.13-6.11 (m, 1H), 5.82-5.80 (m, 1H), 5.73 (s, 1H), 4.28-4 ... 2.57 (m, 1H), 2.34-2.24 (m, 1H), 1.81 (d,

ZN), 1.79-1.70 (m, 1Н), 1.48 (s, ZN), 1.45 (s, ZN), 1.30 (t, ZN), 1.29 (t, ZN ), 1.08 (s, ЗН), 1.05 (s, ЗН), 1.01 (d, ЗН), 0.93-0.87 (m, 1Н), 0.74-0.66 ( m, 1H).

N u n o (v; dya

Preparation of compound 631:

Ingenol-5,20-acetonide-3-(1H-indole-7-carboxylate) (Compound 631)

Compound 631 was obtained according to Procedure p.

Starting material: 1H-Indole-7-carboxylic acid.

IS

2 o" da -e Go) 9 x and z

Preparation of compound 632:

Ingenol-5,20-acetonide-3-(2-tert-butyl-5-methyl-pyrazole-3-carboxylate) (Compound 632)

Compound 632 was prepared according to Procedure c, but replacing acetonitrile with M,M-dimethylformamide.

Starting material: 2-tert-butyl-5-methyl-pyrazole-3-carboxylic acid. "NMR (300 MHz, SOSIZ) b 6.61 (s, 1H), 6.08-6.06 (m, 1H), 5.82-5.79 (m, 1H), 5.70 (s, 1H), 4.28-4.10 (m, ЗН), 4.05-4.04 (m, 1H), 3.19 (s, 1H), 2.67-2.61 (m, 1H) , 2.31-2.22 (m, 4H), 1.83-1.74 (m, 4H), 1.70 (s, 9H), 1.47 (s, ЗН), 1.46 (s , ЗН), 1.10 (s, ЗН), 1.05 (s, ЗН), 1.01 (d, ЗН), 0.95-0.90 (m, 1Н), 0.74-0, 67 (m, 1H).

A o" ro ur O x --9 m

Preparation of compound 633:

Ingenol-5,20-acetonide-3-(5-tert-butyl-2-methylpyrazole-3-carboxylate) (Compound 633)

Compound 633 was prepared according to Procedure c, but replacing acetonitrile with M,M-dimethylformamide.

Starting material: 5-tert-butyl-2-methyl-pyrazole-3-carboxylic acid.

N

And about

And oh but

B o 9 t | DZ

Preparation of compound 634:

Ingenol-5,20-acetonide-3-(b-methylimidazoi|2,1-BiHhiazole-5-carboxylate) (Compound 634)

Compound 634 was prepared according to Procedure c, but replacing acetonitrile with M,M-dimethylformamide.

Starting material: 6-Methylimidazo|2,1-bihiazole-5-carboxylic acid.

N

:

СХ t-- oh no

X o 9

Preparation of compound 635:

Ingenol-5,20-acetonide-3-(2-methylimidazo|1,2-a|Ipyridine-3-carboxylate) (Compound 635)

Compound 635 was prepared according to Procedure c, but replacing acetonitrile with M,M-dimethylformamide.

Starting material: 2-Methylimidazo(|1,2-a|Ipyridine-3-carboxylic acid.

AND

With o o no o o y and A (o;

Preparation of compound 636:

Ingenol-5,20-acetonide-3-(24,5-trimethylfuran-3-carboxylate) (Compound 636)

Compound 636 was obtained according to Procedure p.

Starting material: 2,4,5-Trimethylfuran-3-carboxylic acid.

di m : h "en i o no

Z o c) is D-i

Preparation of compound 637:

Ingenol-5,20-acetonide-3-(3-methylthiophene-2-carboxylate) (Compound 637)

Compound 637 was obtained according to Procedure p.

Starting material: 3-Methylthiophene-2-carboxylic acid. and

OA about U

Judge: Fr

X le -M me

Preparation of compound 638:

Ingenol-5,20-acetonide-3-(2-methyl-4-(1-piperidyl)pyrazole-3-carboxylate (Compound 638)

Compound 638 was obtained according to Procedure a.

Starting material: 2-Methyl-4-(1-piperidyl)pyrazole-3-carbonyl chloride obtained from 2-methyl-4-(1-piperidyl)pyrazole-3-carboxylic acid by the reaction of 3 with 1.25 equivalents of oxalyl chloride in dichloromethane and drop of dimethylformamide at room temperature for 30 min. followed by evaporation of volatile substances in a vacuum.

NMR NMR (300 MHz, SOSIZ) b 7.27 (s, 1H), 6.15-6.13 (m, 1H), 5.80-5.76 (m, 2H), 4.26- 4.4.10 (m, 6H), 4.05-4.04 (m, 1H), 3.58 (s, 1H), 2.99-2.83 (m, 4H), 2.77- 2.72 (m, 1H), 2.31-2.21 (m, 1H), 1.84 (d,

ZN), 1.76-1.51 (m, 7Н), 1.49 (s, ZN), 1.44 (s, ZN), 1.07 (s, ZN), 1.04 (s, ZN ), 1.01 (d, ZH), 0.93-0.86 (m, 1H), 0.72-0.64 (m, 1H).

N u o

From no to OO 8. lm Me i.

Preparation of compound 639:

Ingenol-5,20-acetonide-3-(2-chloro-5-isopropylthiazole-4-carboxylate) (Compound 639)

Compound 639 was obtained according to Procedure p.

Starting material: 2-chloro-5-isopropylthiazole-4-carboxylic acid. "H NMR (300 MHz, SOSIZ) b 6.13-6.12 (m, 1H), 5.80-5.77 (m, 2H), 4.25-4.03 (m, 5H), 3 .46 (s, 1H), 2.70-2.65 (m, 1H), 2.33-2.23 (m, 1H), 1.83 (d, ЗН), 1.81-1.74 (m, 1H), 1.47 (s, ЗН), 1.43 (s, ЗН), 1.32 (d, 6Н), 1.09 (s, ЗН), 1.05 (s, ЗН) , 1.02 (d, ЗН), 0.95-0.88 (m, 1Н), 0.74-0.66 (m, 1Н).

N si k. -n i

M

AT

(e; pairs

SI

Preparation of compound 640:

Ingenol-5,20-acetonide-3-(4-chloro-2,5-dimethylpyrazole-3-carboxylate) (Compound 640)

Compound 640 was obtained according to Procedure p.

Starting material: 4-Chloro-2,5-dimethyl-pyrazole-3-carboxylic acid.

Eat what pa and o no

F) br bA-

M

/

Preparation of compound 641:

Ingenol-5,20-acetonide-3-(1,2,4-trimethylpyrrole-3-carboxylate) (Compound 641)

Compound 641 was obtained according to Procedure p.

Starting material: 1,2,4-Trimethylpyrrole-3-carboxylic acid. "H NMR (300 MHz, SOSIZ) 6 6.28 (m, 1H), 6.06-6.04 (m, 1H), 5.78-5.75 (m, 2H), 4.21- 4.15 (m, ZN), 4.05-4.04 (m, 1H), 3.52 (s, 1H), 3.46 (s, ZN), 2.73-2.68 (m, 1H), 2.48 (s, ZN), 2.33-2.23 (m, 1H), 2.20 (s, ZN), 1.81 (d, ZN), 1.78-1.68 (m, 1H), 1.48 (s, ЗН), 1.43 (s, ЗН), 1.07 (s, ЗН), 1.04 (s, ЗН), 0.99 (d,

ЗН), 0.93-0.86 (m, 1Н), 0.72-0.64 (m, 1Н). n zu o o

Oh that 0)

M. I am the x

Preparation of compound 642:

Ingenol-5,20-acetonide-3-(1,3,5-trimethylpyrrole-2-carboxylate) (Compound 642)

Compound 642 was obtained according to Procedure p.

Starting material: 1,3,5-Trimethylpyrrole-2-carboxylic acid. n: o cheN

And oh but I:

M

Preparation of compound 643:

Ingenol-5,20-acetonide-3-(1-ethyl-3,5-dimethylpyrrole-2-carboxylate) (Compound 643)

Compound 643 was obtained according to Procedure p.

Starting material: 1-Ethyl-3,5-dimethylpyrrole-2-carboxylic acid.

I o H 35; oh but oh

K-

Preparation of compound 644:

Ingenol-5,20-acetonide-3-(1-tert-butyloxycarbonyl-3,3-dimethylpyrrolidine-2-carboxylate) (Compound 644)

Compound 644 was obtained according to Procedure p.

Starting material: 1-tert-butyloxycarbonyl-3,3-dimethylpyrrolidine-2-carboxylic acid.

AND

OO er mo u

Xia d

KH-

Preparation of compound 645:

Ingenol-5,20-acetonide-3-((25)-1-phenylpyrrolidine-2-carboxylate) (Compound 645)

Compound 645 was obtained according to Procedure a, but replacing dichloromethane with acetonitrile and conducting the reaction at 90 °C for 18 h.

Starting material: (25)-1-phenylpyrrolidine-2-carboxylic acid. and oh but

C) hU-

M y rya

Preparation of compound 646:

Ingenol-5,20-acetonide-3-(1-isopropyl-3,5-dimethyl-pyrazole-4-carboxylate) (Compound 646)

Compound 646 was obtained according to Procedure 1, but at a reaction temperature of 160 °C.

Starting material: 1-isopropyl-3,5-dimethyl-pyrazole-4-carbonyl chloride obtained from 1-isopropyl-3,5-dimethyl-pyrazole-4-carboxylic acid by the interaction of 3 1.25 equivalents of oxalyl chloride in dichloromethane and a drop of dimethylformamide at room temperature for 30 min. followed by evaporation of volatile substances in a vacuum. "H NMR (300 MHz, SOSIS) b 6.09-6.06 (m, 1H), 5.80-5.77 (m, 1H), 5.73 (s, 1H), 4.42 (septet , 1H), 4.25-4.12 (m, ЗН), 4.05 (s, 1H), 3.39 (s, 1H), 2.70-2.65 (m, 1H), 2, 52 (s, ЗН), 2.41 (s, ЗН), 2.33-2.24 (m, 1Н), 1.82 (d, ЗН), 1.78-1.69 (m, 1Н) , 1.48-1.44 (m, 12H), 1.07 (s, ЗН), 1.05 (s, ЗН), 1.00 (d, ЗН), 0.93-0.86 (m , 1H), 0.73-0.65 (m, 1H).

N

N re (0 and

WITH

7 o no and in o Zh lez

Preparation of compound 647:

Ingenol-5,20-acetonide-3-(5-ethyl-3-isopropyl-isoxazole-4-carboxylate) (Compound 647)

Compound 647 was obtained according to Procedure a, but replacing dichloromethane with acetonitrile and conducting the reaction at 90 °C for 18 h.

Starting material: 5-Ethyl-3-isopropyl-isoxazole-4-carboxylic acid. ' and (o)

So, but in.

Ble

Preparation of compound 648:

Ingenol-5,20-acetonide-3-(2-methylindazole-3-carboxylate) (Compound 648)

Compound 648 was obtained according to Procedure a, but replacing dichloromethane with acetonitrile and conducting the reaction at 90 °C for 18 h.

Starting material: 2-methylindazole-3-carboxylic acid.

N

S oh no o

Y x -5 -

Preparation of compound 649:

Ingenol-5,20-acetonide-3-(5-methyl-3-tert-butylisoxazole-4-carboxylate) (Compound 648)

Compound 649 was obtained in accordance with Procedure p.

Starting material: 5-Methyl-3-tert-butylisoxazole-4-carboxylic acid.

N a (o) o No o

MA

Preparation of compound 650:

Ingenol-5,20-acetonide-3-(2-methyl-3-oxo-4-oxaspiro|4.5|dec-1-ene-1-carboxylate) (Compound 650)

Compound 650 was obtained according to Procedure c, but keeping the reaction temperature at 140 °C for 1 h.

Starting material: 2-Methyl-3-oxo-4-oxaspiro|4.5|dec-1-ene-1-carboxylic acid.

I u o) o no tt F r Z

Preparation of compound 651:

Ingenol-5,20-acetonide-3-(1-tert-butyl-3,5-dimethyl-pyrazole-4-carboxylate) (Compound 651)

Compound 651 was obtained according to Procedure p.

Starting material: 1-tert-butyl-3,5-dimethyl-pyrazole-4-carboxylic acid.

N

! and (o) o But p u

AT

M. Ho

Preparation of compound 652:

Ingenol-5,20-acetonide-3-(3,5-dimethylisothiazole-4-carboxylate) (Compound 652)

Compound 652 was obtained according to Procedure p.

Starting material: 3,5-Dimethylisothiazole-4-carboxylic acid. N ! in

IF) about (9)

And till

Zv Y

Preparation of compound 653:

Ingenol-5,20-acetonide-3-(5-iodo-3-methyl-isothiazole-4-carboxylate) (Compound 653)

Compound 653 was obtained according to Procedure p.

Starting material: 5-Iodo-3-methyl-isothiazole-4-carboxylic acid. n sh c c) but t-x (o) c - --

Preparation of compound 654:

Ingenol-5,20-acetonide-3-(4-(4-methoxyphenyl)-2-methylpyrazole-3-carboxylate) (Compound 654)

Compound 654 was obtained according to Procedure a.

Starting material: 4-(4-Methoxyphenyl)-2-methylpyrazole-3-carbonyl chloride, obtained from 4-(4-methoxyphenyl)-2-methylpyrazole-3-carboxylic acid by reaction with 1.25 equivalents of oxalyl chloride in dichloromethane and a drop of dimethylformamide at at room temperature for 30 min. followed by evaporation of volatile substances in a vacuum. 4-(4-Methoxyphenyl)-2-methylpyrazole-3-carboxylic acid was prepared according to Procedure K with (4-methoxyphenyl)boronic acid as starting material.

NMR NMR (300 MHz, SOSIZ) b 7.43 (s, 1H), 7.28-7.23 (m, 2H), 6.88-6.82 (m, 2H), 5.95- 5.94 (m, 1H), 5.76-5.71 (m, 1H), 5.71 (s, 1H), 4.22 (s, ЗН), 4.20-4.00 (m, ЗН), 3.96 (t, 1Н), 3.81 (s, ЗН), 3.07 (с, 1Н), 2.04-1.94 (m, 1Н), 1.75-1.70 (m, 4H), 1.52-1.45 (m, 4H), 1.41 (s, ЗН), 1.02 (s, 6H), 0.90-0.78 (m, 1H), 0.68 (d, ZN), 0.63-0.55 (m, 1H).

N

: me / Sean

WITH

(in)

He --x o ve - --9

Preparation of compound 655:

Ingenol-5,20-acetonide-3-(4-(2-methylphenyl)-2-methylpyrazole-3-carboxylate) (Compound 655)

Compound 655 was obtained according to Procedure 1, but at a reaction temperature of 100 °C.

Starting material: 4-(2-Methylphenyl)-2-methylpyrazole-3-carbonyl chloride, obtained from 4-(2-methylphenyl)-2-methylpyrazole-3-carboxylic acid by the reaction of 3 1.25 equivalents of oxalyl chloride in dichloromethane and a drop of dimethylformamide at at room temperature for 30 min. followed by evaporation of volatile substances in a vacuum. 4-(2-Ethylphenyl)-2-methylpyrazole-3-carboxylic acid was prepared according to Procedure K with (2-methylphenyl)boronic acid as starting material.

NMR NMR (300 MHz, SOSIZ) b 7.37 (s, 1H), 7.22-7.09 (m, 4H), 5.83-5.82 (m, 1H), 5.74- 5.72 (m, 1H), 5.60 (s, 1H), 4.25 (s, ЗН), 4.21-3.99 (m, ЗН), 3.91 (s, 1Н), 2 .99 (s, 1H), 2.14 (s, ЗН), 2.04-1.95 (m, 1H), 1.72-1.67 (m, 1H), 1.58-1.53 (d, 4Н), 1.47 (с, ЗН), 1.39 (с, ЗН), 1.03 (с, 6Н), 0.84-0.77 (m, 1Н), 0.69 ( d, ZN), 0.64-0.56 (m, 1H).

M

Preparation of compound 656:

Ingenol-5,20-acetonide-3-(2-methyl-4-(4-methylsulfonylphenyl)pyrazole-3-carboxylate) (Compound 656)

Compound 656 was obtained according to Procedure 1, but at a reaction temperature of 100 °C.

Starting material: 4-(4-methylsulfonylphenyl)-2-methylpyrazole-3-carbonyl chloride obtained from 4-(4-methylsulfonylphenyl)-2-methylpyrazole-3-carboxylic acid by reaction with 1.25 equivalents of oxalyl chloride in dichloromethane and a drop of dimethylformamide at at room temperature for 30 min. followed by evaporation of volatile substances in a vacuum. 4-(4-methylsulfonylphenyl)-2-methylpyrazole-3-carboxylic acid was obtained according to

Procedures K with (4-methylsulfonylphenyl)boronic acid as starting material.

From "H NMR (300 MHz, SOSIZ) b 7.97-7.89 (m, 2H), 7.63-7.54 (m, 2H), 7.51 (s, 1H), 5.98- 5.96 (m, 1H), 5.78-5.75 (m, 1H), 5.68 (s, 1H), 4.25 (s, ЗН), 4.20-3.98 (m, 4H), 3.18 (s, 1H), 3.06 (s, ЗН), 2.12-2.03 (m, 1H), 1.92-1.87 (m, 1H), 1.69 (d, ZN), 1.59-1.50 (m, 1Н), 1.48 (s, ZN), 1.43 (s, ZN), 1.03 (s, ZN), 1.02 ( s, ЗН), 0.86-0.79 (m, 1Н), 0.68 (d, ЗН), 0.65-0.57 (m, 1Н).

Fu (o) o" on - (o) anna l-

M

Preparation of compound 657:

Ingenol-5,20-acetonide-3-(2-methyl-4-phenylpyrazole-3-carboxylate) (Compound 657)

Compound 657 was obtained according to Procedure 1, but at a reaction temperature of 100 °C.

Starting material: 2-methyl-4-phenylpyrazole-3-carbonyl chloride obtained from 2-methyl-4-phenylpyrazole-3-carboxylic acid by reaction with 1.25 equivalents of oxalyl chloride in dichloromethane and a drop of dimethylformamide at room temperature for 30 min. followed by evaporation of volatile substances in a vacuum. 2- Methyl-4-phenylpyrazole-3-carboxylic acid was prepared according to Procedure K with phenylboronic acid as starting material.

NMR NMR (300 MHz, SOSIZ) b 7.46 (s, 1H), 7.34-7.28 (m, 5H), 5.91 (m, 1H), 5.75-5.73 ( m, 1H), 5.69 (s, 1H), 4.23-3.94 (m, 7H), 3.08 (s, 1H), 2.03-1.93 (m, 1H), 1 ,80-1.73 (m, 1H), 1.67 (d, ЗН), 1.52-1.44 (m, 4Н), 1.41 (s, ЗН), 1.02 (s, ЗН ), 1.02 (s, ЗН), 0.84-0.78 (m, 1Н), 0.65 (d, ЗН), 0.62-0.54 (m, 1Н).

N

: . Sen

N va, oh" No -- Oh

Wed

Preparation of compound 658:

Ingenol-5,20-acetonide-3-(3,5-dimethyl-1-phenylpyrazole-4-carboxylate) (Compound 658)

Compound 658 was obtained according to Procedure 4, but at a reaction temperature of 140 °C.

Starting material: 3,5-Dimethyl-1-phenylpyrazole-4-carboxylic acid.

NMR NMR (300 MHz, SOSIZ) b 7.52-7.37 (m, 5H), 6.11-6.10 (m, 1H), 5.81-5.78 (m, 2H), 4.27-412 (m, ЗН), 4.07 (s, 1Н), 3.41 (s, 1Н), 2.73-2.68 (m, 1Н), 2.53 (s, ЗН) . ), 1.46 (s, ЗН), 1.08 (s, ЗН), 1.05 (s, ЗН), 1.01 (d, ЗН), 0.94-0.87 (m, 1Н) , 0.74-0.68 (m, 1H).

F o o

Preparation of compound 659:

Ingenol-5,20-acetonide-3-(1,5-dimethyl-3-phenylpyrazole-4-carboxylate) (Compound 659)

Compound 659 was obtained according to Procedure 4. Starting material: 1,5-Dimethyl-3-phenylpyrazole-4-carboxylic acid.

NMR NMR (300 MHz, SOSIZ) b 7.51-7.46 (m, 2H), 7.38-7.31 (m, ЗН), 5.90-5.89 (m, 1H), 5.74-5.71 (m, 2H), 4.16-3.94 (m, 4H), 3.84 (s, ЗН), 3.12 (s, 1H), 2.60 (s, ЗН), 2.03-1.93 (m, 1Н), 1.85-1.80 (m, 1Н)U, 1.71 (d, ЗН), 1.52-1.46 (m, 4Н ), 1.39 (s, ЗН), 1.02 (s, ЗН), 1.02 (s, ЗН), 0.85-0.79 (m, 1Н), 0.67 (d, ЗН) , 0.63-0.55 (m, 1H).

AND

" en "o (9) no - o y ; in-9

M Kk

Coo)

Preparation of compound 660:

Ingenol-5,20-acetonide-3-(1-benzyl-3,5-dimethylpyrazole-4-carboxylate) (Compound 660)

Compound 660 was obtained according to Procedure a.

Starting material: 1-Benzyl-3,5-dimethylpyrazole-4-carboxylic acid.

NMR NMR (300 MHz, SOSIZ) b 7.36-7.25 (m, ЗН), 7.14-7.11 (m, 2Н), 6.09-6.07 (m, 1Н), 5.80-5.77 (m, 1H), 5.73 (s, 1H), 5.24 (s, 2H), 4.26-4.11 (m, ZN), 4.05 (s, 1H), 3.38 (s, 1H), 2.69-2.64 (m, 1H), 2.47 (s, ЗН), 2.44 (s, ЗН), 2.33-2.23 (m, 1H), 1.81 (d, ЗН), 1.78-1.70 (m, 1Н), 1.47 (s, ЗН), 1.43 (s, ЗН), 1.07 ( s, ЗН), 1.05 (s, ЗН), 0.99 (d, ЗН), 0.94-0.86 (m, 1Н), 0.73-0.65 (m, 1Н).

N y sh en zi o o no y O

X y Z y (c)

Preparation of compound 661:

Ingenol-5,20-acetonide-3-(3,5-dimethyl-1-(tetrahydropyran-4-ylmethyl)pyrazole-4-carboxylate) (Compound 661)

Compound 661 was obtained by heating a mixture of ingenol-5,20-acetonide-3-(3,5-dimethyl-1H-pyrazole-4-carboxylate) (15 mg), 4-iodomethyl-tetrahydro-2H-pyran (80 mg) and of potassium carbonate (40 mg) in M,M-dimethylformamide (0.5 mL) at 120 "C in a microwave oven for 20 min. Addition of water and extraction with dichloromethane followed by evaporation of the solvent gave the crude product, which was purified by chromatography as described in Procedure c, to obtain the title compound. Ingenol-5,20-acetonide-3-(3,5-dimethyl-1H-pyrazole-4-carboxylate) was obtained

Procedure c with 3,5-dimethyl-1H-pyrazole-4-carboxylic acid as starting material.

N o) - no shko O o Me

Preparation of compound 662: 20 Ingenol-5,20-acetonide-3-(4-methyl-2-oxo-3H-thiazole-5-carboxylate) (Compound 662)

Compound 662 was obtained according to Procedure a.

Starting material: 4-Methyl-2-oxo-ZN-thiazole-5-carbonyl chloride obtained from 4-methyl-2-oxo-ZN-thiazole-5-carboxylic acid by reaction with 1.25 equivalents of oxalyl chloride in dichloromethane and a drop of dimethylformamide at room temperature for 30 min. followed by evaporation of volatile substances in a vacuum. n zh

Ge) oh no - F) still, - -3

M

Preparation of compound 663:

Ingenol-5,20-acetonide-3-(2-methyl-4,5,6,7-tetrahydroindazole-3-carboxylate) (Compound 663)

Compound 663 was obtained according to Procedure a.

Starting material: 2-methyl-4,5,6,7-tetrahydroindazole-3-carbonyl chloride, obtained from 2-methyl-4,5,6,7-tetrahydroindazole-3-carboxylic acid by the reaction of 3 with 1.25 equivalents of oxalyl chloride in dichloromethane and a drop of dimethylformamide at room temperature for 30 min. followed by evaporation of volatile substances in a vacuum. "H NMR (300 MHz, SOSIZ) 6 6.12-6.11 (m, 1H), 5.81-5.79 (m, 1H), 5.72 (s, 1H), 4.28-4 .06 (m, 7H), 3.30 (s, 1H), 2.72-2.61 (m, 5H), 2.32-2.23 (m, 1H), 1.82-1.66 (m, 8Н), 1.49 (s, ZN), 1.45 (s, ZN), 1.08 (s, ZN), 1.05 (s, ZN), 1.01 (d, ZN) , 0.93-0.87 (m, 1H), 0.73-0.65 (m, 1H).

I

2 (o) it

AT

LP Z

M

AND

Preparation of compound 664:

Ingenol-5,20-acetonide-3-(1,2-dimethylindole-3-carboxylate) (Compound 664)

Compound 664 was obtained according to Procedure a.

Starting material: 1,2-dimethylindole-33-carbonyl chloride obtained from 1,2-dimethylindole-3-carboxylic acid by reaction with 1.25 equivalents of oxalyl chloride in dichloromethane and a drop of dimethylformamide at room temperature for 30 min. followed by evaporation of volatile substances in a vacuum. "H NMR (300 MHz, SOSIZ) b 8.12-8.09 (m, 1H), 7.32-7.18 (m, ЗН), 6.14 (m, 1H), 5.84 (s , 1H), 5.79-5.77 (m, 1H), 4.26-4.10 (m, 4H), 3.70 (s, ЗН), 3.55 (s, 1H), 2, 84-2.77 (m, 4H), 2.33-2.24 (m, 1H), 1.88 (d, ЗН), 1.74-1.63 (m, 1H), 1.51 ( s, ЗН), 1.46 (s, ЗН), 1.06-1.03 (m, 9Н), 0.93-87 (m, 1Н), 0.72-0.64 (m, 1Н) n u shko o no

AT

With c

M

Preparation of compound 665:

Ingenol-5,20-acetonide-3-(5-methoxy-1,2-dimethylindole-3-carboxylate) (Compound 665)

Compound 665 was prepared according to Procedure 4, but extending the reaction time to 75 min.

Starting material: 5-Methoxy-1,2-dimethylindole-3-carbonyl chloride, obtained from 5-methoxy-1,2-dimethylindole-3-carboxylic acid by reaction with 1.25 equivalents of oxalyl chloride in dichloromethane and a drop of dimethylformamide at room temperature for 30 min. followed by evaporation of volatile substances in a vacuum.

NMR NMR (300 MHz, SOSIZ) b 7.64 (d, 1H), 7.18 (d, 1H), 6.87 (dd, 1H), 6.14-6.12 (m, 1H) , 5.84 (s, 1H), 5.80-5.77 (m, 1H), 4.26-4.07 (m, 4H), 3.84 (s, ЗН), 3.67 (s , ЗН), 3.63 (s, 1Н), 2.81-2.75 (m, 4Н), 2.32-2.22 (m, 1Н), 1.89 (d, ЗН), 1, 74-1.65 (m, 1H), 1.51 (s, ЗН), 1.46 (s, ЗН), 1.06 (s, ЗН), 1.03 (s, ЗН), 1.02 (d, ZH), 0.97-0.87 (m, 1H), 0.71-0.63 (m, 1H). di; in (c) no mo

Mother A

From Obtaining compound 666:

Ingenol-5,20-acetonide-3-(1,3,5-trimethylpyrazole-4-carboxylate) (Compound 666)

Compound 666 was obtained according to Procedure a.

Starting material: 1,3,5-Trimethylpyrazole-4-carbonyl chloride obtained from 1,3,5-

of trimethylpyrazole-4-carboxylic acid by interaction with 1.25 equivalents of oxalyl chloride in dichloromethane and a drop of dimethylformamide at room temperature for 30 min. followed by evaporation of volatile substances in a vacuum. "H NMR (300 MHz, SOSIZ) b 6.09-6.08 (m, 1H), 5.80-5.77 (m, 1H), 5.73 (s, 1H), 4.26-4 .05 (m, 4H), 3.73 (s, ЗН), 3.39 (s, 1Н), 2.69-2.64 (m, 1Н), 2.49 (s, ЗН), 2, 39 (c, ZN), 2.33-2.23 (m, 1Н), 1.82 (d, ZN), 1.77-1.68 (m, 1Н), 1.48 (s, ZN) , 1.44 (s, ЗН), 1.07 (s, ЗН), 1.05 (s, ЗН), 1.00 (d, ЗН), 0.93-0.86 (m, 1Н), 0.73-0.65 (m, 1H).

N

2 (c) it

M-- 0 and Zhe

M

Preparation of compound 667:

Ingenol-5,20-acetonide-3-(4-methyl-1,2,5-oxadiazole-3-carboxylate) (Compound 667)

Compound 667 was obtained according to Procedure a.

Starting material: 4-Methyl-1,2,5-oxadiazole-3-carbonyl chloride obtained from 4-methyl-1,2,5-oxadiazole-3-carboxylic acid by reaction with 1.25 equivalents of oxalyl chloride in dichloromethane and a drop of dimethylformamide at at room temperature for 30 min. followed by evaporation of volatile substances in a vacuum.

N you (in o no - K,

Mao X

IN

Preparation of compound 668:

Ingenol-5,20-acetonide-3-(2-methoxy-4-methylthiazole-5-carboxylate) (Compound 668)

Compound 668 was obtained according to Procedure a.

Starting material: 2-methoxy-4-methylthiazole-o-carbonyl chloride obtained from 2-methoxy-4-methylthiazole-5-carboxylic acid by the interaction of 3 1.25 equivalents of oxalyl chloride in dichloromethane and a drop of dimethylformamide at room temperature for 30 min. followed by evaporation of volatile substances in a vacuum. n a (c) no

KO

IM o) 07 Zh

Preparation of compound 669:

Ingenol-5,20-acetonide-3-(4,5-dimethylisoxazole-3-carboxylate) (Compound 669)

Compound 669 was obtained according to Procedure 4. Starting material: 4,5-

Dimethylisoxazole-3-carbonyl chloride obtained from 3/2-methoxy-4-methylthiazole-5-carboxylic acid by the interaction of 3 with 1.25 equivalents of oxalyl chloride in dichloromethane and a drop

From dimethylformamide at room temperature for 30 min. followed by evaporation of volatile substances in a vacuum.

id) zo (o

Ve it)

GK

M o

M --

Preparation of compound 670:

Ingenol-5,20-acetonide-3-(4-bromo-1-methylpyrazole-3-carboxylate) (Compound 670)

Compound 670 was obtained according to Procedure a.

Starting material: 4-Bromo-1-methylpyrazole-3-carbonyl chloride obtained from 4-bromo-1-methylpyrazole-3-carboxylic acid by reaction with 1.25 equivalents of oxalyl chloride in dichloromethane and a drop of dimethylformamide at room temperature for 30 min. followed by evaporation of volatile substances in a vacuum.

N

Kui 2 (in) no sh-t o r -

Preparation of compound 671:

Ingenol-5,20-acetonide-3-(1,3-dimethylindole-2-carboxylate) (Compound 671)

Compound 671 was obtained according to Procedure a.

Starting material: 1,3-Dimethylindole-2-carbonyl chloride obtained from 1,3-dimethylindole-2-carboxylic acid by reaction with 1.25 equivalents of oxalyl chloride in dichloromethane and a drop of dimethylformamide at room temperature for 30 min. followed by evaporation of volatile substances in a vacuum. n i o o no shik F) he M A o

Preparation of compound 672:

Ingenol-5,20-acetonide-3-(5-methoxy-1,3-dimethylindole-2-carboxylate) (Compound 672)

Compound 672 was obtained according to Procedure 4.

Starting material: 5-Methoxy-1,3-dimethylindole-2-carbonyl chloride obtained from 5-methoxy-1,3-dimethylindole-2-carboxylic acid by reaction with 1.25 equivalents of oxalyl chloride in dichloromethane and a drop of dimethylformamide at room temperature for 30 min. followed by evaporation of volatile substances in a vacuum.

n u (Fe) o no u

Oh well - (c)

Preparation of compound 673:

Ingenol-5,20-acetonide-3-(2,4-dimethyl-6b-oxopyran-3-carboxylate) (Compound 673)

Compound 673 was obtained according to Procedure p.

Starting material: 2,4-Dimethyl-6-oxopyran-3-carboxylic acid.

Ch u (c) o no pyt O o v t- ia

Preparation of compound 674:

Ingenol-5,20-acetonide-3-(1-methyl-3-phenylindole-2-carboxylate) (Compound 674)

Compound 674 was obtained according to Procedure a.

Starting material: 1-methyl-3-phenylindole-2-carbonyl chloride, obtained from 1-methyl-3-phenylindole-2-carboxylic acid by the interaction of 3 1.25 equivalents of oxalyl chloride in dichloromethane and a drop of dimethylformamide at room temperature for 30 min. followed by evaporation of volatile substances in a vacuum.

N

; . vat

AND

E and o no (in) 6) and ge

M

Preparation of compound 675:

Ingenol-5,20-acetonide-3-(33-methyl-5-(trifluoromethyl)isoxazole-4-carboxylate) (Compound 675)

Compound 675 was obtained according to Procedure p.

Starting material: 3-Methyl-5-(trifluoromethyl)isoxazole-4-carboxylic acid. n u (o) ono u w-- (c) huya -5

Preparation of compound 676:

Ingenol-5,20-acetonide-3-(1,3-dimethylpyrrole-2-carboxylate) (Compound 676)

Compound 676 was obtained according to Procedure c, but changing the reaction conditions for 60 min. at 140 76.

Starting material: 1,3-Dimethylpyrrole-2-carboxylic acid.

N

!

Di (o) but I o

M and me

E E

IS

Preparation of compound 677:

Ingenol-5,20-acetonide-3-(3,5-dimethyl-1-(2,2,2-trifluoroethyl)pyrazole-4-carboxylate) (Compound 677)

Compound 677 was obtained according to Procedure 4.

Starting material: 3,5-Dimethyl-1-(2,2,2-trifluoroethyl)pyrazole-4-carbonyl chloride, obtained by the reaction of 3 2,2,2-trifluoroethyl)pyrazole-4-carboxylic acid with 3 1.25 equivalents of oxalyl chloride in dichloromethane and a drop of dimethylformamide at room temperature for 30 min. followed by evaporation of volatile substances in a vacuum.

IN NMR (300 MHz, SOSIZ) b 6.11-6.09 (m, 1H), 5.80-5.79 (m, 1H), 5.73 (s, 1H), 4.61 (sq. , 2H), 4.27-4.05 (m, 4H), 3.35 (s, 1H), 2.68-2.61 (m, 1H), 2.56 (s, ЗН), 2, 41 (s, ЗН), 2.35-2.24 (m, 1Н), 1.82 (d, ЗН), 1.79-1.70 (m, 1Н), 1.48 (s, ЗН) , 1.45 (s, ЗН), 1.08 (s, ЗН), 1.05 (s, ЗН), 1.01 (d, ЗН), 0.93-0.86 (m, 1Н), 0.73-0.65 (m, 1H).

N u (o) o no -- O

I am

Preparation of compound 678:

Ingenol-5,20-acetonide-3-(1-cyclopropyl-2,5-dimethylpyrrole-3-carboxylate) (Compound 678)

Compound 678 was prepared according to Procedure 4, but extending the reaction time to 60 min.

Starting material: 1-Cyclopropyl-2,5-dimethylpyrrole-3-carbonyl chloride obtained from 1-cyclopropyl-2,5-dimethylpyrrole-3-carboxylic acid by the interaction of 3 1.25 equivalents of oxalyl chloride in dichloromethane and a drop of dimethylformamide at room temperature for 30 min. followed by evaporation of volatile substances in a vacuum.

NMR NMR (300 MHz, SOSIZ) b 6.16 (m, 1H), 6.04-6.02 (m, 1H), 5.77-5.74 (m, 1H), 5.73 ( s, 1H), 4.18-4.13 (m, ЗН), 4.03 (s, 1H), 3.36 (s, 1H), 2.94-2.86 (m, 1H), 2 ,71-2.66 (m, 1H), 2.59 (s, ЗН), 2.32-2.23 (m, 4H), 1.80-1.71 (m, 4H), 1.46 (s, ZN), 1.42 (s, ZN), 1.13-1.07 (m, 5Н), 1.04 (s, ZN), 1.02 (d,

ЗН), 0.94-0.88 (m, ЗН), 0.73-0.65 (m, 1Н).

N

! a o o no dl (c) o)

Preparation of compound 679:

Ingenol-5,20-acetonide-3-(1,2,5-trimethylpyrrole-3-carboxylate) (Compound 679)

Compound 679 was prepared according to Procedure 4, but extending the reaction time to 100 min.

Starting material: 1,2,5-Trimethylpyrrole-3-carbonyl chloride, obtained by Kk! 1,2,5-

of trimethylpyrrole-3-carboxylic acid by interaction with 1.25 equivalents of oxalyl chloride in dichloromethane and a drop of dimethylformamide at room temperature for 30 min. followed by evaporation of volatile substances in a vacuum.

IN NMR (300 MHz, SOSIZ) b 6.22-6.21 (m, 1H), 6.04-6.02 (m, 1H), 5.77-5.73 (m, 2H), 4, 19-4.14 (m, ЗН), 4.03 (s, 1Н), 3.40 (s, ЗН), 3.38 (с, 1Н), 2.72-2.66 (m, 1Н) , 2.51 (s, ЗН), 2.32-2.23 (m, 1Н), 2.19 (d, ЗН), 1.80 (d, ЗН), 1.78-1.71 (m ) .94-0.88 (m, 1H), 0.73-0.65 (m, 1H).

N u i (o) pc Go)

NO. KZ

Preparation of compound 680:

Ingenol-5,20-acetonide-3-(2,4-dimethyl-1H-pyrrole-3-carboxylate) (Compound 680)

Compound 680 was obtained according to Procedure a.

Starting material: 2,4-Dimethyl-1H-pyrrole-3-carbonyl chloride, obtained from 2,4-dimethyl-1H-pyrrole-3-carboxylic acid by reaction with 1.25 equivalents of oxalyl chloride in dichloromethane and a drop of dimethylformamide at room temperature for 30 min. followed by evaporation of volatile substances in a vacuum.

IN NMR (300 MHz, SOSIZ) b 10.40 (lat, 1H), 6.11-6.10 (m, 1H), 5.96-5.95 (m, 1H), 5.86- 5.83 (m, 1H), 5.75 (s, 1H), 4.30-4.10 (m, 4H), 3.72 (width, 1H), 2.66-2.61 ( m, 1H), 2.41 (s, ЗН), 2.33-2.23 (m, 4Н), 1.87-1.76 (m, 4Н), 1.47 (s, ЗН), 1 ... 77-0.69 (m, 1H). yes in

IF) o no pc 6) fl Zh

Preparation of compound 681:

Ingenol-5,20-acetonide-3-(1-methylpyrrole-2-carboxylate) (Compound 681)

Compound 681 was obtained according to Procedure a.

Starting material: 1-Methylpyrrole-2-carbonyl chloride obtained from 1-methylpyrrole-2-carboxylic acid by the interaction of 3 1.25 equivalents of oxalyl chloride in dichloromethane and a drop of dimethylformamide at room temperature for 30 min. followed by evaporation of volatile substances in a vacuum. N

Sai N o) o no sht (F) hu YN Me

Preparation of compound 682:

Zo Ingenol-5,20-acetonide-3-(4-methyl-1H-pyrrole-2-carboxylate) (Compound 682)

Compound 682 was prepared according to Procedure 4, but extending the reaction time to 75 min.

Starting material: 4-Methyl-1H-pyrrole-2-carbonyl chloride obtained from 4-methyl-1H-pyrrole-2-

of carboxylic acid by interaction with 1.25 equivalents of oxalyl chloride in dichloromethane and a drop of dimethylformamide at room temperature for 30 min. followed by evaporation of volatile substances in a vacuum.

IN NMR (300 MHz, SOSIZ) b 8.97 (lat, 1H), 6.76-6.72 (m, 2H), 6.08-6.07 (m, 1H), 5.79- 5.76 (m, 1H), 5.70 (s, 1H), 4.25-4.12 (m, ЗН), 4.04-4.03 (m, 1H), 3.29 (s, 1H), 2.67-2.62 (m, 1H), 2.31-2.21 (m, 1H), 2.12 (s, ЗН), 1.82-1.73 (m, 4H) , 1.47 (s, ZN), 1.43 (s, ZN), 1.08 (s, ZN), 1.04 (s, ZN), 1.03 (d,

ЗН), 0.95-0.88 (m, 1Н), 0.74-0.66 (m, 1Н).

N a

F) otsya o) - (o) fl i

Preparation of compound 683:

Ingenol-5,20-acetonide-3-(1,5-dimethylpyrrole-2-carboxylate) (Compound 683)

Compound 683 was obtained according to Procedure c, but extending the reaction time to 40 min.

Starting material: 1,5-Dimethylpyrrole-2-carboxylic acid. nn -- Se i (o) o no -- o fl Ya

Preparation of compound 684:

Ingenol-5,20-acetonide-3-(3-methyl-1H-pyrrole-2-carboxylate) (Compound 684)

Compound 684 was obtained according to Procedure c, but extending the reaction time to 40 min.

Starting material: 3-Methyl-1H-pyrrole-2-carboxylic acid. "H NMR (300 MHz, SOSIZ) b 8.93 (lat, 1H), 6.86 (t, 1H), 6.12-6.08 (m, 2H), 5.80-5.77 (m, 1H), 5.71 (s, 1H), 4.26-4.13 (m, ЗН), 4.05-4.04 (m, 1H), 3.38 (s, 1H), 2.69-2.64 (m, 1H), 2.35-2.23 (m, 4H), 1.82 (d, ЗН), 1.79-1.70 (m, 1H), 1, 48 (s, ZN), 1.44 (s, ZN), 1.07 (s, ZN), 1.04 (s, ZN), 1.02 (d, ZN), 0.94-0.88 (m, 1H), 0.73-0.65 (m, 1H).

Preparation of compound 685:

Ingenol-5,20-acetonide-3-(1-cyclopropylpyrrole-2-carboxylate) (Compound 685)

Compound 685 was obtained according to Procedure 4.

Starting material: 1-Cyclopropylpyrrole-2-carbonyl chloride obtained from 1-cyclopropylpyrrole-2-carboxylic acid by reaction with 1.25 equivalents of oxalyl chloride in dichloromethane and a drop of dimethylformamide at room temperature for 30 min. followed by evaporation of volatile substances in a vacuum.

From 1N NMR (300 MHz, SOSIZ) b 6.92 (dd, 1H), 6.88 (t, 1H), 6.09-6.06 (m, 2H), 5.79-5.75 (m, 2H), 424-413 (m, ЗН), 4.05-4.04 (m, 1H), 3.79-3.71 (m, 1H), 3.32 (s, 1H), 2.70-2.65 (m, 1Н), 2.32-2.23 (m, 5О0

1H), 1.84-1.73 (m, 4H), 1.47 (s, ЗН), 1.44 (s, ЗН), 1.09 (s, ЗН), 1.05-0.88 (m, 11H), 0.74-0.66 (m, 1H).

N u o; o no (9) r i h

Preparation of compound 686:

Ingenol-5,20-acetonide-3-(1-ethyl-2,4-dimethylpyrrole-3-carboxylate) (Compound 686)

Compound 686 was obtained according to Procedure 4.

Starting material: 1-Ethyl-2,4-dimethylpyrrole-3-carbonyl chloride, obtained from 1-ethyl-2,4-dimethylpyrrole-3-carboxylic acid by the reaction of 3 1.25 equivalents of oxalyl chloride in dichloromethane and a drop of dimethylformamide at room temperature for 30 min. followed by evaporation of volatile substances in a vacuum.

NMR NMR (300 MHz, SOSIZ) b 6.33-6.32 (m, 1H), 6.06-6.04 (m, 1H), 5.77-5.75 (m, 2H), 4.21-4.17 (m, ZN), 4.04 (s, 1H), 3.81 (t, 2H), 3.54 (s, 1H), 2.74-2.69 (m, 1H), 2.50 (s, ЗН), 2.34-2.24 (m, 1Н), 2.21 (s, ЗН), 1.82 (d, ЗН), 1.76-1.67 (m, 1Н), 1.47 (s, ZN), 1.42 (s, ZN), 1.33 (t, ZN), 1.07 (s, ZN), 1.04 (s, ZN) , 0.99 (d, ЗН), 0.93-0.86 (m, 1Н), 0.72-0.64 (m, 1Н).

І и (c) m 9) more about

And x I

M more

Preparation of compound 687:

Ingenol-5,20-acetonide-3-(1-allyl-2,4-dimethylpyrrole-3-carboxylate) (Compound 687)

Compound 687 was obtained according to Procedure a.

Starting material: 1-Allyl-2,4-dimethylpyrrole-3-carbonyl chloride obtained from 1-allyl-2,4-dimethylpyrrole-3-carboxylic acid by the reaction of 3 1.25 equivalents of oxalyl chloride in dichloromethane and a drop of dimethylformamide at room temperature for 30 min. followed by evaporation of volatile substances in a vacuum. p u o o no

OO

/x that

Eat what

Preparation of compound 688:

Ingenol-5,20-acetonide-3-(1-(cyclopropylmethyl)-2H4-dimethylpyrrole-3-carboxylate) (Compound 688)

Compound 688 was obtained according to Procedure 4. Starting material: 1-(Cyclopropylmethyl)-2,4-dimethylpyrrole-3-carbonyl chloride obtained from 1-(cyclopropylmethyl)-2,4-dimethylpyrrole-3-carboxylic acid by reaction with 1,25 equivalent of oxalyl chloride in dichloromethane and a drop of dimethylformamide at room temperature for 30 min. followed by evaporation of volatile substances in a vacuum.

N di (o o no o

In me

M

Sov

Preparation of compound 689:

Ingenol-5,20-acetonide-3-(1-(2-methoxyethyl)-2,4-dimethylpyrrole-3-carboxylate) (Compound 689)

Compound 689 was obtained according to Procedure 4.

Starting material: 1-(2-Methoxyethyl)-2,4-dimethylpyrrole-3-carbonyl chloride obtained from 1-(2-methoxyethyl)-2,4-dimethylpyrrole-3-carboxylic acid by the reaction of 3 with 1.25 equivalents of oxalyl chloride in dichloromethane and a drop of dimethylformamide at room temperature for 30 min. followed by evaporation of volatile substances in a vacuum. "H NMR (300 MHz, SOSIZ) b 6.36 (m, 1H), 6.06-6.04 (m, 1H), 5.77-5.75 (m, 2H), 4.21-4 ,14 (m, ZN), 4.04 (s, 1H), 3.94 (t, 2H), 3.58 (t, 2H), 3.53 (s, 1H), 3.33 (s, ЗН), 2.73-2.68 (m, 1Н), 2.51 (s, ЗН), 2.33-2.23 (m, 1Н), 2.20 (d, ЗН), 1.81 (d, ZN), 1.76-1.67 (m, 1Н), 1.47 (s, ZN), 1.42 (s, ZN), 1.07 (s, ZN), 1.04 ( c, ЗН), 0.99 (d, ЗН), 0.93-0.86 (m, 1Н), 0.72-0.64 (m, 1Н).

N

Sun c)

In it

M m F)

H 9

Preparation of compound 801:

Ingenol-5,20-acetonide-3-(M-ethyl-carbamate) (Compound 801)

Compound 801 was obtained according to Procedure i. Starting material: Ethyl isocyanate. y "n zi (o)

In it -M 9) ro

Preparation of compound 802:

Ingenol-5,20-acetonide-3-(M,M-dimethylcarbamate) (Compound 802)

Compound 802 was obtained according to Procedure 9.

Starting material: M,M-Dimethylcarbamoyl chloride. n "n

Ku (c)

In ono su (in) 5/0

Preparation of compound 803:

Ingenol-5,20-acetonide-3-(morpholine-4-carboxylate) (Compound 803)

Compound 803 was obtained according to Procedure 9.

Starting material: Morpholine-4-carbonyl chloride.

"H NMR (300 MHz, SOSIZ) b 6.04-6.03 (m, 1H), 5.77-5.76 (m, 1H), 5.45 (s, 1H), 4.23-4 ,12 (m, ZN), 3.97 (s, 1H), 3.70-3.63 (m, 4H), 3.50-3.47 (m, 5H), 2.52-2.47 (m, 1H), 2.34-2.25 (m, 1H), 1.78 (d, ЗН), 1.77-1.70 (m, 1Н), 1.46 (s, ЗН), 1.39 (s, ЗН), 1.10 (s, ЗН), 1.05 (s, ЗН), 0.97 (d, ЗН), 0.94-0.85 (m, 1Н), 0 ,73-0,65 (m, 1H). d 20 uU-ono

M Ge)

OA

Preparation of compound 804:

Ingenol-5,20-acetonide-3-(pyrrolidine-1-carboxylate) (Compound 804)

Compound 804 was obtained according to Procedure 9. Starting material: Pyrrolidine-1-carbonyl chloride.

IN NMR (300 MHz, SOSIZ) b 6.01 (m, 1H), 5.76-5.74 (m, 1H), 5.44 (s, 1H), 4.16-4.11 (m, ЗН), 3.96 (3, 1Н), 3.65 (с, 1Н), 3.44-3.33 (m, 4Н), 2.61-2.55 (m, 1Н), 2.33 -2.44 (m, 1H), 1.90-1.85 (m, 4H), 1.79 (d, ЗН), 1.78-1.70 (m, 1H), 1.45 (s , ZN), 1.38 (s, ZN), 1.10 (s, ZN), 1.05 (s, ZN), 0.98 (d, ZN), 0.94-0.85 (m, 1H), 0.72-0.65 (m, 1H).

N

"H 2 (o)

There are three

Preparation of compound 805:

Ingenol-5,20-acetonide-3-(M-methyl-M-phenylcarbamate) (Compound 805)

Compound 805 was prepared according to Procedure 9.

Starting material: M-Methyl-M-phenylcarbamoyl chloride. n ev ono i Ge)

Oh well

Preparation of compound 806:

Ingenol-5,20-acetonide-3-(M,M-diethylcarbamate) (Compound 806)

Compound 806 was obtained according to Procedure 9.

Starting material: M, M-Diethylcarbamoyl chloride. n 20 ono m o

See

Preparation of compound 807:

Ingenol-5,20-acetonide-3-(piperidine-1-carboxylate) (Compound 807)

Compound 807 was obtained according to Procedure 9.

Starting material: Piperidine-1-carbonyl chloride.

d mon

Song 9;

In it

M i); 9

Preparation of compound 808:

Ingenol-5,20-acetonide-3-(M-benzyl-M-methylcarbamate) (Compound 808)

Compound 808 was obtained according to Procedure 9.

Starting material: M-Benzyl-M-methylcarbamoyl chloride obtained from /M-benzyl-M-methylamine according to Procedure Her.

N

"n 2 c)

In it so 7-9

Preparation of compound 809:

Ingenol-5,20-acetonide-3-(M-cyclohexyl-M-methylcarbamate) (Compound 809)

Compound 809 was obtained according to Procedure 9.

Starting material: M-Cyclohexyl-M-methylcarbamoyl chloride obtained from M-cyclohexyl-M-methylamine according to Her Procedure. n "n 2 (c) ba

M n 7-9

Preparation of compound 810:

Ingenol-5,20-acetonide-3-(M-cyclohexylcarbamate) (Compound 810)

Compound 810 was obtained according to Procedure i.

Starting material: Cyclohexyl isocyanate. n i ba

M n ee

Preparation of compound 811:

Ingenol-5,20-acetonide-3-(M-phenylcarbamate) (Compound 811)

Compound 811 was obtained according to Procedure i.

Starting material: Phenyl isocyanate. n 2 u-ono

M o

N tro

Preparation of compound 812:

Ingenol-5,20-acetonide-3-(M-(indan-1-ylcarbamate) (Compound 812)

Compound 812 was obtained according to Procedure i.

Starting material: Isocyanate-1-indane. n zo o no field -r-

Preparation of compound 813:

Ingenol-5,20-acetonide-3-(3,3-dimethylpiperidine-1-carboxylate) (Compound 813)

Compound 813 was obtained according to Procedure i.

Starting material: 3,3-Dimethylpiperidine-1-carbonyl chloride, obtained by Kk! 3,3- dimethylpiperidine, according to the Procedure of Her. n to

Tl Nn wa o no? oh -- oh

Preparation of compound 814:

Ingenol-5,20-acetonide-3-(M-methyl-M-tetralin-1-ylcarbamate) (Compound 814)

Compound 814 was obtained according to Procedure i.

Starting material: M-Methyl-M-tetralin-1-ylcarbamoyl chloride obtained from M-methyl-M-(tetralin-1-yl)amine according to Procedure i. n and (There she is)

In it pd ma x 9

Preparation of compound 815:

Ingenol-5,20-acetonide-3-(M-(2-cyano-1-methylethyl)-M-methylcarbamate) (Compound 815)

Compound 815 was obtained according to Procedure y.

Starting material: M-(2-cyano-1-methylethyl)-M-methylcarbamoyl chloride obtained from M-(2-cyano-1-methylethyl)-M-methylamine according to Procedure Her. n tsi n 3 C n c) but i is) --

Preparation of compound 816:

Ingenol-5,20-acetonide-3-(M-methyl-M-(5)-phenethyl)carbamate) (Compound 816)

Compound 816 was obtained in accordance with Procedure no.

Starting material: M-Methyl-M-((5)-1-phenethyl)carbamoyl chloride obtained from M-methyl-M-((5)-1-phenylethyl)amine according to Procedure Her.

SHI) ef

G-- Ho no and o --

Preparation of compound 817:

Ingenol-5,20-acetonide-3-(M-methyl-M-(cyclopropylmethyl)carbamate) (Compound 817)

Compound 817 was obtained according to Procedure y.

Starting material: M-(Cyclopropylmethyl)-M-methylcarbamoyl chloride obtained from M-(cyclopropylmethyl)-M-methylamine according to Procedure Her. "H NMR (300 MHz, SOSIZ) b 6.03-6.02 (m, 1H), 5.76-5.74 (m, 1H), 5.45 (s, 1H), 4.17-4 ,12 (m, ЗН), 3.97 (s, 1Н), 3.59 (m, 1Н), 3.30-3.13 (m, 2Н), 2.99 (s, ЗН), 2, 56 (width s, 1H), 2.34-2.25 (m, 1H), 1.79-1.70 (m, 4H), 1.45 (s, ЗН), 1.39 (s, ZN), 1.29 (m, 1Н), 1.10 (s, ZN), 1.05 (s, ZN), 0.98 (d, ZN), 0.94-0.86 (m, 1Н ), 0.72-0.65 (m, 1H), 0.53-0.48 (m, 2H), 0.24-0.16 (m, 2H).

OA

Ge) no be 6) I

Preparation of compound 818:

Ingenol-5,20-acetonide-3-(M-(3-fluorophenyl)-M-methylcarbamate) (Compound 818)

Compound 818 was obtained according to Procedure |.

Starting material: M-(3-Fluorophenyl)-M-methylcarbamoyl chloride prepared from 3-fluoro-M-methylaniline according to Procedure 1 from pyridine as tertiary amine. di u / o m-th x-a what

Min x Dh

Preparation of compound 819:

Ingenol-5,20-acetonide-3-(M-(2,5-dimethylpyrazol-3-yl)-M-methylcarbamate) (Compound 819)

Compound 819 was obtained in accordance with Procedure no.

Starting material: M-(2,5-dimethylpyrazol-3-yl)-M-methylcarbamoyl chloride, obtained from M,1,3-trimethyl-1H-pyrazol-5-amine, according to Procedure i. "NMR (300 MHz, SOSIZ) b 5.96 (lat.s, 1H), 5.86 (s, 1H), 5.76-5.74 (m, 1H), 4.21-4.05 ( m, ZN), 3.95 (s, 1H), 3.61 (s, ZN), 3.20 (s, ZN), 3.11 (width s, 1H), 2.21 (s, ZN ), 1.84-1.74 (m, 4H), 1.57 (s,

ZN), 1.45 (s, ZN), 1.38 (s, ZN), 1.07 (s, ZN), 1.04 (s, ZN), 0.90-0.83 (m, 1Н ), 0.75 (width, length, height), 0.68-0.60 (m, 1H).

N

Fu (in) y-9 no

M (c) x thing at -0

Preparation of compound 820:

Ingenol-5,20-acetonide-3-(M-(3,5-dimethylisoxazol-4-yl)-M-methylcarbamate) (Compound 820)

Compound 820 was obtained according to Procedure y.

Starting material: M-(3,5-dimethylisoxazol-4-yl)methyl|-M-methylcarbamoyl chloride, prepared from 1-(3,5-dimethylisoxazol-4-yl)-M-methylmethanamine, according to Procedure Her.

NMR NMR (300 MHz, SOSIZ) b 6.05 (s, 1H), 5.78-5.76 (m, 1H), 5.46 (s, 1H), 4.46 (lat.s, 1H), 424-411 (m, 4H), 3.98 (s, 1H), 3.52 (s, 1H), 2.78 (s, ЗН), 2.50 (width s, 1H), 2.37 (s, ЗН), 2.30-2.21 (m, 4Н), 1.78 (d, ЗН), 1.77-1.68 (m, 1Н), 1.46 (s, ZN), 1.41 (s, ZN), 1.09 (s, ZN), 1.05 (s, ZN), 0.96 (d,

ЗН), 0.94-0.89 (m, 1Н), 0.72-0.64 (m, 1Н).

N u o) in u- no

M in M o ed in d-

Preparation of compound 821:

Ingenol-5,20-acetonide-3-(M-(1,5-dimethylpyrazol-3-yl)-M-methylcarbamate) (Compound 821)

Compound 821 was obtained according to Procedure y.

Starting material: M-(1,5-dimethylpyrazol-3-yl)-M-methylcarbamoyl chloride, prepared from M,1,5-trimethylpyrazol-3-amine, according to Procedure Her.

NMR NMR (300 MHz, SOSIZ) b 5.96 (width s, 1H), 5.86 (s, 1H), 5.76-5.74 (m, 1H), 5.42 (s, 1H), 4.21-4.05 (m, ЗН), 3.95 (s, 1H), 3.61 (s, ЗН), 3.20 (s, ЗН), 3.11 (width , 1H), 2.21 (s, ЗН), 2.12-2.02 (m, 1Н), 1.82-1.64 (m, 5Н), 1.45 (s, ЗН), 1, 38 (s, ZN), 1.07 (s, ZN), 1.04 (s, ZN), 0.90-0.85 (m, 1H), 0.75 (width s, ZN), 0 .68-0.60 (m, 1H).

N o (o; y-9 no de x --

Preparation of compound 822:

Ingenol-5,20-acetonide-3-(M-cyclopentyl-M-methylcarbamate) (Compound 822)

Compound 822 was obtained according to Procedure y.

Starting material: M-Cyclopentyl-M-methylcarbamoyl chloride, obtained from -("M-methylcyclopentanamine, according to Procedure Her.

N u o ish

M o rt ee

Preparation of compound 823:

Ingenol-5,20-acetonide-3-(M-cyclopropyl-M-methylcarbamate) (Compound 823)

Compound 823 was obtained according to Procedure y.

Starting material: M-Cyclopropyl-M-methylcarbamoyl chloride obtained from M-methylcyclopropanamine according to Procedure Her. "H NMR (300 MHz, SOSIZ) b 6.04-6.01 (m, 1H), 5.77-5.74 (m, 1H), 5.47 (s, 1H), 4.17-4 ... 2.57 (m, 2H), 2.34-2.25 (m, 1H), 1.80-1.70 (m, 4H), 1.45 (s, ЗН), 1.39 (s, 1H), 1.16-1.08 (m, 5H), 1.05 (s, ЗН), 0.98 (d, ЗН), 0.94-0.87 (m, 1Н), 0.74 -0.65 (m, 4H).

KI

(o; but em M and b)

SO A

Preparation of compound 824:

Ingenol-5,20-acetonide-3-(M-methyl-M-(2-pyridyl)carbamate) (Compound 824)

Compound 824 was obtained according to Procedure |.

Starting material: M-Methyl-M-(2-pyridyl)carbamoyl chloride obtained from M-methylpyridin-2-amine according to Procedure Her. "H NMR (300 MHz, SOSIZ) b 8.38-8.36 (m, 1H), 7.73-7.67 (m, 1H), 7.43 (d, 1H), 7.09-7 .05 (m, 1H), 6.00-5.98 (m, 1H), 5.76-5.74 (m, 1H), 5.71 (s, 1H), 5.04 (width , 1H), 4.27-4.11 (m, ЗН), 3.95 (s, 1Н), 3.44 (s, ЗН), 2.30-2.20 (m, 2Н), 1, 81 (d, ZN), 1.70-1.60 (m, 1H), 1.46 (s, ZN), 1.39 (s, ZN), 1.15 (s, ZN), 1.06 (c, ЗН), 0.96-0.88 (m, 1Н), 0.79 (d, ЗН), 0.69-0.63 (m, 1Н). in)

Preparation of compound 825:

Ingenol-5,20-acetonide-3-(4-oxo-2,3-dihydroquinoline-1-carboxylate) (Compound 825)

Compound 825 was obtained according to Procedure |.

Starting material: 4-Oxo-2,3-dihydroquinoline-1-carbonyl chloride obtained from 2,3-dihydro-1H-quinolin-4-one according to Her Procedure.

N

C c)

U-9 no

M OO

SU A

Preparation of compound 826:

Ingenol-5,20-acetonide-3-(3,4-dihydro-2H-quinoline-1-carboxylate) (Compound 826)

Compound 826 was obtained according to Procedure |.

Starting material: 3,4-Dihydro-2H-quinoline-1-carbonyl chloride, obtained from 1,2,3,4-tetrahydroquinoline, according to Her Procedure.

NMR NMR (300 MHz, SOSIZ) b 7.68 (d, 1H), 7.16-6.98 (m, ZH), 6.03 (d, 1H), 5.77-5.75 ( m, 1H), 5.58 (s, 1H), 4.23-4.11 (m, ЗН), 4.00 (s, 1H), 3.82-3.72 (m, 2H), 3 .39 (s, 1H), 2.79 (t, 2H), 2.46-2.41 (m, 1H), 2.29-2.20 (m, 1H), 2.01-1.92 (m, 2H), 1.81 (d, ЗН), 1.71-1.63 (m, 1Н), 1.46 (s, ЗН), 1.41 (s, ЗН), 1.08 ( s, ЗН), 1.04 (s, ЗН), 0.92-0.83 (m, 4Н), 0.71-0.63 (m, 1Н).

IN

IN

(o) u-a no

M F)

WITH --

Preparation of compound 827:

Ingenol-5,20-acetonide-3-(indoline-1-carboxylate) (Compound 827)

Compound 827 was obtained according to Procedure |.

Starting material: Indoline-1-carbonyl chloride, obtained from indoline according to

Procedures

IN NMR (300 MHz, SOSIZ) b 7.87 (lat, 1H), 7.22-7.09 (m, 2H), 6.99-6.92 (m, 1H), 6.09 ( width s, 1H), 5.79-5.77 (m, 1H), 5.57 (s, 1H), 4.25-4.12 (m, ЗН), 4.08-4.02 ( m, ЗН), 3.50 (width s, 1H), 3.18-3.10 (m, 2H), 2.64 (width s, 1H), 2.34-2.24 (m, 1H), 1.84 (s, ZN), 1.79-1.70 (m, 1H), 1.49 (s, ZN), 1.43 (s, ZN), 1.08 (s, ZN ), 1.05 (c, ЗН), 1.01 (d, ЗН), 0.94-0.86 (m, 1Н), 0.73-0.65 (m, 1Н). N

SH

(in)

U-9 no

M o

WITH -

Preparation of compound 828:

Ingenol-5,20-acetonide-3-(azepane-1-carboxylate) (Compound 828)

Compound 828 was obtained according to Procedure |.

Starting material: Azepane-1-carbonyl chloride obtained from azepane according to

Procedures "H NMR (300 MHz, SOSIZ) b 6.03-6.01 (m, 1H), 5.76-5.74 (m, 1H), 5.47 (s, 1H), 4.17-4 ,12 (m, ZN), 3.97 (s, 1H), 3.62 (s, 1H), 3.49-3.27 (m, 4H), 2.60-2.55 (m, 1H ), 2.35-2.26 (m, 1H), 1.79-1.55 (m, 12H), 1.46 (s, ЗН), 1.39 (s, ЗН), 1.10 ( s, ЗН), 1.05 (s, ЗН), 0.98 (d, ЗН), 0.94-0.88 (m, 1Н), 0.72-0.64 (m, 1Н).

N

(in;

U-ah on

AT

6-00 F

Preparation of compound 829:

Ingenol-5,20-acetonide-3-(M-(4-chlorophenyl)-M-methylcarbamate) (Compound 829)

Compound 829 was obtained according to Procedure |.

Starting material: M-(4-Chlorophenyl)-M-methylcarbamoyl chloride, obtained from 4-chloro-M-methylaniline, according to Her Procedure. "H NMR (300 MHz, SOSIZ) b 7.31 (d, 2H), 7.20 (d, 2H), 5.94 (s, 1H), 5.76-5.73 (m, 1H), 5.45 (s, 1H), 4.21-4.07 (m, ЗН), 3.95 (s, 1Н), 3.29 (s, ЗН), 3.22 (s, 1Н), 3 ,14 (d, 1H), 2.17-2.07 (m, 1H), 1.75 (d, ЗН), 1.63-1.57 (m, 1Н), 1.45 (s, ЗН ), 1.39 (s, ЗН), 1.08 (s, ЗН), 1.04 (s, ЗН), 0.90-0.83 (m, 1Н), 0.76 (d, ЗН) , 0.69-0.61 (m, 1H). id) and o) in 7 x ee

Preparation of compound 830:

Ingenol-5,20-acetonide-3-(M-(4-fluorophenyl)-M-methylcarbamate) (Compound 830)

Compound 830 was obtained according to Procedure |.

Starting material: M-(4-Fluorophenyl)-M-methylcarbamoyl chloride obtained from 4-fluoro-M-methylaniline according to Her Procedure.

IN NMR (300 MHz, SOSIZ) b 7.24-7.19 (m, 2H), 7.06-6.98 (m, 2H), 5.92 (lat, 1H), 5.76- 5.73 (m, 1H), 5.45 (s, 1H), 4.17-4.06 (m, ЗН), 3.95 (s, 1Н), 3.28 (s, ЗН), 3 .23 (width, 1H), 3.13 (d, 1H), 2.12-2.08 (m, 1H), 1.74 (d, H), 1.63-1.57 (m , 1H), 1.45 (s, ЗН), 1.38 (s, ЗН), 1.08 (s, ЗН), 1.04 (s, ЗН), 0.92-0.83 (m, 1H), 0.73 (d, ЗН), 0.69-0.61 (m, 1H).

N dy iv) 3rd on

IM O x she (c) /

Preparation of compound 831:

Ingenol-5,20-acetonide-3-(M-methyl-M-(2-methoxyphenyl)carbamate) (Compound 831)

Compound 831 was obtained according to Procedure |.

Starting material: M-(2-Methoxyphenyl)-M-methylcarbamoyl chloride obtained from 2-methoxy-M-methylaniline according to Procedure Her. for

N a (o)

Well, no

M. O

Fa M -

J

Preparation of compound 832:

Ingenol-5,20-acetonide-3-(M-methyl-M-(2-methylphenyl)carbamate) (Compound 832)

Compound 832 was obtained according to Procedure |.

Starting material: M-(2-Methylphenyl)-M-methylcarbamoyl chloride, obtained from 2-methyl-M-methylaniline, according to Her Procedure. N . "n 20A p

And in

M" that

F;

Preparation of compound 833:

Ingenol-5,20-acetonide-3-(3-oxo-2,4-dihydroquinoxaline-1-carboxylate) (Compound 833)

Compound 833 was obtained according to Procedure ).

Starting material: 3-Oxo-2,4-dihydroquinoxaline-1-carbonyl chloride obtained from 3,4-dihydro-1H-quinoxaline-2-one according to Procedure Her. NMR (300 MHz, SOSIZ) b 8.82 (s, 1H), 7.72 (d, 1H), 7.15-7.01 (m, 2H), 6.90 (dd, 1H ), 6.07-6.06 (m, 1H), 5.80-5.78 (m, 1H), 5.58 (s, 1H), 4.47 (d, 1H), 4.44 ( d. -2.20 (m, 1H), 1.81 (d, ЗН), 1.72-1.63 (m, 1Н), 1.45 (s, ЗН), 1.42 (s, ЗН), 1.08 (s, ЗН), 1.04 (s, ЗН), 0.92-0.84 (m, 4Н), 0.71-0.63 (m, 1Н).

N

SY o h.-o NO ish

stay away

Preparation of compound 834:

Ingenol-5,20-acetonide-3-(M-ethyl-M-phenylcarbamate) (Compound 834)

Compound 834 was obtained according to Procedure ).

Starting material: M-ethyl-M-phenyl-carbamoyl chloride obtained from M-ethylanaline according to Her Procedure. "H NMR (300 MHz, SOSIZ) b 7.38-7.32 (m, 2H), 7.28-7.18 (m, ЗН), 5.89 (s, 1H), 5.73-5 .70 (m, 1H), 5.46 (s, 1H), 4.17-4.14 (m, 2H), 4.04 (width, d, 1H), 3.94-3.93 (m , 1H), 3.79-3.64 (m, 2H), 3.16 (width, 1H), 2.04-1.78 (m, 2H), 1.75 (d, ЗН), 1.54-1.49 (m, 1H), 1.45 (s, ЗН), 1.37 (s, ЗН), 1.17 (t, ЗН), 1.06 (s,

ЗН), 1.03 (с, ЗН), 0.90-0.81 (m, 1Н), 0.70-0.56 (m, 4Н).

N y y- N

Oh, I ate! yo, hey

Preparation of compound 835:

Ingenol 5,20-acetonide-3-(2-fluoromethylpyrrolidine-1-carboxylate) (Compound 835)

Compound 835 was obtained according to Procedure |.

Starting material: 2-(Trifluoromethyl)pyrrolidine-1-carbonyl chloride obtained from 2-(trifluoromethyl)pyrrolidine according to Her Procedure. and en 2 re (c)

ABOUT; and Z

Preparation of compound 836:

Ingenol-5,20-acetonide-3-(3-azabicyclo/3.2.2|nonane-3-carboxylate) (Compound 836)

Compound 836 was obtained according to Procedure ).

Starting material: 3-Azabicyclo[3.2.2]nonane-3-carbonyl chloride, obtained from 3-azabicyclo[3.2.2]nonane, according to Procedure i.

N

Co. en

In o new O 4 -Z

Preparation of compound 837:

Ingenol-5,20-acetonide-3-(2,3-dihydro-1,4-benzoxazine-4-carboxylate) (Compound 837)

Compound 837 was obtained according to Procedure |.

Starting material: 2,3-Dihydro-1,4-benzoxazine-4-carbonyl chloride, obtained from 2,3-dihydro-1,4-benzoxazine, according to Her Procedure. N

And c) 5-9 no

M. O

Or

IS

Preparation of compound 838:

Ingenol-5,20-acetonide-3-(M-(2-fluorophenyl)-M-methylcarbamate) (Compound 838)

Compound 838 was obtained according to Procedure |.

Starting material: M-(2-fluorophenyl)-M-methylcarbamoyl chloride obtained from 2-fluoro-M-methylaniline according to Her Procedure.

IN NMR (300 MHz, SOSIZ) b 7.29-7.21 (m, 2H), 7.14-7.06 (m, 2H), 5.87 (lat, 1H), 5.73- 5.72

(m, 1H), 5.46 (s, 1H), 4.16-4.14 (m, 2H), 4.09-4.02 (m, 1H), 3.93 (s, 1H), 3.27 (s, ЗН), 3.21 (s, 1Н), 2.09-2.00 (m, 1Н), 1.73 (width с, 4Н), 1.52-1.45 ( m, 4H), 1.38 (s, ЗН), 1.07 (s, ЗН), 1.03 (s, ЗН), 0.88-0.82 (m, 1Н), 0.65-0 .55 (m, 4H). N

WITH

5-9 no

Su -

You -- I am

Preparation of compound 839:

Ingenol-5,20-acetonide-3-(3-methyl-2,3-dihydro-1,4-benzoxazine-4-carboxylate) (Compound 839)

Compound 839 (mixture of diastereomers) was obtained according to Procedure |.

Starting material: 3-Methyl-2,3-dihydro-1,4-benzoxazine-4-carbonyl chloride obtained from 3-methyl-3,4-dihydro-2IN-1,4-benzoxazine according to Her Procedure.

N

. en

A KU vi (o) O

I'm like o

AND I-

Preparation of compound 842:

Ingenol-5,20-acetonide-3-(M-methyl-M-(M-(tert-butyloxycarbonyl-4-piperidyl)carbamate) (Compound 842)

Compound 842 was obtained according to Procedure |.

Starting material: tert-butyl-4-(chlorocarbonyl(methyl)amino)piperidine-1-carboxylate, obtained from tert-butyl-4-methylaminopiperidine-1-carboxylate, according to Procedure Y. "H NMR (300 MHz, SOSIS) b 6.03-6.01 (m, 1H), 5.77-5.74 (m, 1H), 5.47 (s, 1H), 4.27-4.10 (m, 5H), 3 .98 (s, 1H), 3.49-3.38 (m, 2H), 3.28 (width s, 1H), 2.78 (width s, 4H), 2.58-2.52 (m, 1H), 2.32-2.24 (m, 1H), 1.79-1.55 (m, 8H), 1.46 (s, 9H), 1.45 (s, ЗН), 1.39 (s, ЗН), 1.09 (s, ЗН), 1.05 (s, ЗН), 0.98 (d, ЗН), 0.94-0.87 (m, 1Н), 0 .73-0.65 (m, 1H).

N

Fu (in) no be ; on

Preparation of compound 843:

Ingenol-5,20-acetonide-3-(M-methyl-M-(3-methylphenyl)carbamate) (Compound 843)

Compound 843 was obtained according to Procedure |.

Starting material: M-Methyl-M-(3-methylphenyl)ucarbamoyl chloride, obtained from M, 3-dimethylaniline, according to Procedure Her.

H two (in) and no o 4 A

M

N

Preparation of compound 844:

Ingenol-5,20-acetonide-3-(3,4-dihydro-2H-quinoxaline-1-carboxylate) (Compound 844)

Compound 844 was obtained according to Procedure |.

Starting material: 3,4-Dihydro-2H-quinoxaline-1-carbonyl chloride, obtained from 1,2,3,4-tetrahydroquinoxaline, according to Her Procedure.

NMR NMR (300 MHz, SOSIZ) b 7.86 (lat, 1H), 7.67 (lat, 1H), 7.22-7.10 (m, 2H), 6.07- 6.06 (m, 1H), 5.81-5.79 (m, 1H), 5.57 (s, 1H), 4.27-3.94 (m, 9H), 3.34 (s, 1H), 2.39 (width, 1H), 2.30-2.21 (m, 1H), 1.82 (d, 3H), 1.73-1.64 (m, 1H), 1 .47 (s, ЗН), 1.43 (s, ЗН), 1.09 (s, ЗН), 1.05 (s, ЗН), 0.92-0.84 (m, 4Н), 0, 71-0.63 (m, 1H). n u (o)

Oh, but

M o schi AJ

Preparation of compound 845:

Ingenol-5,20-acetonide-3-(isoindoline-2-carboxylate) (Compound 845)

Compound 845 was obtained according to Procedure |.

Starting material: isoindoline-2-carbonyl chloride derived from isoindoline according to

Procedures "H NMR (300 MHz, SOSIZ) b 7.32-7.25 (m, 4H), 6.07-6.06 (m, 1H), 5.78-5.76 (m, 1H), 5 .51 (s, 1H), 4.79-4.72 (m, 4H), 4.20-4.13 (m, ЗН), 4.00 (s, 1H), 3.59 (s, 1H ), 2.66-2.61 (m, 1H), 2.35-2.25 (m, 1H), 1.82 (d, ЗН), 1.81-1.72 (m, 1H), 1.48 (s, ZN), 1.41 (s, ZN), 1.09 (s, ZN), 1.04 (s, ZN), 1.01 (d, ZN), 0.94-0 .86 (m, 1H), 0.73-0.65 (m, 1H).

N

: : tan

And about the day" (6)

And in

Preparation of compound 846:

Ingenol-5,20-acetonide-3-(M-methyl-M-(tetrahydropyran-4-ylmethyl)carbamate) (Compound 846)

Compound 846 was obtained according to Procedure |.

Starting material: M-Methyl-M-(tetrahydropyran-4-ylmethyl)carbamoyl chloride obtained from M-methyl-1-tetrahydropyran-4-ylmethanamine according to Procedure Her.

H z,

And 9 m" that is

Preparation of compound 847:

Ingenol-5,20-acetonide-3-(M-methyl-M-(tetrahydropyran-4-ylcarbamate) (Compound 847)

Compound 847 was obtained according to Procedure |.

Starting material: M-Methyl-M-(tetrahydropyran-4-ylcarbamoyl chloride, obtained from M-methyltetrahydropyran-4-amine, according to Procedure Her. "H NMR (300 MHz, SOSIS) b 6.04-6.03 (m , 1H), 5.77-5.75 (m, 1H), 5.48 (s, 1H), 4.22-3.98 (m, 7H), 3.45 (width s, ЗН), 2.82 (s, ZN), 2.58-2.52 (m, 1H), 2.33-2.24 (m, 1H), 1.85-1.58 (m, 8H), 1, 45 (s, ZN), 1.39 (s, ZN), 1.09 (s, ZN), 1.05 (s, ZN), 0.99 (d, ZN), 0.94-0.86 (m, 1H), 0.73-0.65 (m, 1H).

N

. still zvo, s mo Z

WITH

Preparation of compound 848:

Ingenol-5,20-acetonide-3-(M-methyl-M-(3-methoxyphenyl)carbamate) (Compound 848)

Compound 848 was obtained according to Procedure |.

Starting material: M-Methyl-M-(3-methoxyphenyl)ucarbamoyl chloride obtained from M-methyl-3-methoxyaniline according to Procedure Her. n : ., with o che o no

And in

Mmm oh

P--

Preparation of compound 849:

Ingenol-5,20-acetonide-3-(M-cyclobutyl-M-methylcarbamate) (Compound 849)

Compound 849 was obtained according to Procedure y.

Starting material: M-Cyclobutyl-M-methylcarbamoyl chloride, obtained from M-methylcyclobutanamine, according to Procedure Her.

N

; . zones

FI

(9) but with Z: y

Preparation of compound 850:

Ingenol-5,20-acetonide-3-(M-allyl-M-methylcarbamate) (Compound 850)

Compound 850 was obtained in accordance with Procedure no.

Starting material: M-Allyl-M-methylcarbamoyl chloride obtained from M-methylprop-2-en-1-amine according to Procedure Her. n ko en

WITH

AND

OO

- Oh where

Preparation of compound 851:

Ingenol-5,20-acetonide-3-(M-methyl-M-prop-2-ynylcarbamate) (Compound 851)

Compound 851 was obtained according to Procedure y.

Starting material: M-Methyl-M-prop-2-ynylcarbamoyl chloride, obtained from M-methylprop-2-yn-1-amine, according to Procedure Her. N ; "from, Shov o

Uroya in a 4

J

Preparation of compound 852:

Ingenol-5,20-acetonide-3-(M-methyl-M-(4-methylthiazol-2-ylcarbamate) (Compound 852)

Compound 852 was obtained according to Procedure |.

Starting material: M-Methyl-M-(4-methylthiazol-2-ylcarbamoyl chloride, obtained from M, 4-dimethylthiazol-2-amine, according to Procedure Her.

N y "n x shi "v o no "o 5 9

Preparation of compound 853:

Ingenol-5,20-acetonide-3-(M-(4-cyanophenyl)-M-methylcarbamate) (Compound 853)

Compound 853 was obtained according to Procedure |.

Starting material: M-(4-Cyanophenyl)-M-methylcarbamoyl chloride obtained from M-methyl-4-cyanoaniline according to Her Procedure.

N

"N

U ono no on si M Their

What)

Example 501:

Ingenol 3-(5-methyl-3-(2-chloro-6-fluorophenyl)isoxazole-4-carboxylate) (Compound 501)

Compound 501 was obtained according to Procedure e.

Starting material: Compound 601. "NMR (300 MHz, SOSIZ) b 7.42-7.34 (m, 1H), 7.28-7.25 (m, 1H), 7.09-7.03 (m , 1H), 6.02 (d, 1H),

5.85-5.84 (m, 1H), 5.56 (s, 1H), 4.46 (d, 1H), 4.18-4.07 (m, ЗН), 3.99-3, 97 (m, 1H), 3.51 (s, 1H), 2.83 (s, ЗН), 2.21-2.13 (m, 1H), 1.88-1.82 (m, 1H) , 1.69-1.60 (m, 1H), 1.64 (d, ЗН), 1.59 (s, 1H), 1.03 (s,

ЗН), 1.03 (s, ЗН), 0.90-0.82 (m, 1Н), 0.73 (d, ЗН), 0.67-0.59 (m, 1Н). n "n zo (o) ono

M. in (c)

Example 502:

Ingenol 3-(5-methyl-3-phenylisoxazole-4-carboxylate) (Compound 502)

Compound 502 was obtained according to Procedure e.

Starting material: Compound 602. "H NMR (300 MHz, SOSIZ) b 7.56-7.53 (m, 2Н), 7.48-7.38 (m, ЗН), 6.00 (d, 1Н) , 5.94-5.93 (m, 1H), 5.66 (s, 1H), 4.31 (d, 1H), 4.16-4.01 (m, ЗН), 3.98 (d , 1H), 3.36 (s, 1H), 2.77 (s, ЗН), 2.29-2.25 (m, 1H), 2.05-1.96 (m, 1H), 1, 80-1.74 (m, 1H), 1.74 (d, ЗН), 1.27 (s, 1Н), 1.03 (s, ЗН), 1.02 (s, ЗН), 0.90 - 0.82 (m, 1H), 0.71 (d, ЗН), 0.65-0.57 (m, 1H).

N u oh ono o No on (c)

Example 503

Ingenol 3-(15-camphanate) (Compound 503)

Compound 503 was obtained according to Procedure e.

Starting material: Compound 603.

IN NMR (300 MHz, SOSIZ) b 6.09-6-05 (m, 2H), 5.69 (s, 1H), 4.28 (d, 1H), 4.21-4.12 (m, ЗН), 4.03 (d, 1Н), 3.62 (s, 1Н), 2.55-2.42 (m, 2Н), 2.31-2.21 (m, 2Н), 2.12 -2.03 (m, 1H), 1.99-1.89 (m, 1H), 1.80 (d, ЗН), 1.77-1.65 (m, 2H), 1.13 (s , ЗН), 1.09 (с, 6Н), 1.05 (с, ЗН), 0.98-0.86 (m, 7Н), 0.74-0.66 (m, 1Н). N

Co. "N adveFi

M ono m. no

M no

Example 504

Ingenol 3-(3-phenyltriazole-4-carboxylate) (Compound 504)

Compound 504 was obtained according to Procedure no.

Starting material: Compound 604.

NMR NMR (300 MHz, SOSIZ) 8.28 (s, 1H), 7.55-7.49 (m, 5H), 6.05 (m, 1H), 6.02-6.01 (m , 1H), 5.70 (s, 1H), 4.69 (d, 1H), 4.15-4.10 (m, ЗН), 4.01 (m, 1H), 3.55 (s, 1H), 2.40-2.37 (m, 1H), 2.24-2.15 (m, 2H), 1.75 (d, ЗН), 1.74-1.64 (m, 1H) , 1.04 (s, ЗН), 1.04 (s, ЗН), 0.92-0.85 (m, 4Н), 0.71-0.63 (m, 1Н).

N

Ky "en

Oz chi no

MD no in no

Example 505

Ingenol 3-(2-phenylpyrazole-3-carboxylate) (Compound 505)

Compound 505 was obtained according to Procedure e.

Starting material: Compound 605. "H NMR (300 MHz, DMSO-α) 7.82 (d, 1H), 7.49-7.45 (m, 5H), 7.03 (d, 1H), 5, 86-5.83 (m, 2H), 5.81 (s, 1H), 5.35 (d, 1H), 5.14 (s, 1H), 4.62 (t, 1H), 4.14 -4.10 (m, 1H), 3.91-3.86 (m, 2H), 3.58 (d, 1H), 2.28-2.10 (m, 2H), 1.70 (d , ЗН), 1.69-1.58 (m, 1Н), 1.02 (s, ЗН), 1.01 (с, ЗН), 0.80-0.70 (m, 4Н), 0, 62-0.54 (m, 1H).

N

Kk "n ve

With more

LK) no m" no /

Example 506

Ingenol 3-(1-methylindazole-3-carboxylate) (Compound 506)

Compound 506 was obtained according to Procedure no.

Starting material: Compound 606. "H NMR (300 MHz, DMSO-α) 8.15-8.12 (m, 1Н), 7.80-7.77 (m, 1Н), 7.52-7.45 (m, 1H), 7.34-7.29 (m, 1H), 6.00 (m, 1H), 5.99 (s, 1H), 5.90-5.89 (m, 1H), 5.51 (d, 1H), 5.26 (s, 1H), 4.68 (t, 1H), 4.22-4.27 (m, 1H), 4.17 (s, ЗН), 3 .99-3.89 (m, 2H), 3.72 (d, 1H), 2.77-2.70 (m, 1H), 2.39-2.30 (m, 1H), 1.79 (d, ЗН), 1.72-1.64 (m, 1Н), 1.04 (s, 6Н), 0.95 (d, ЗН), 0.85-0.77 (m, 1Н), 0.67-0.59 (m, 1H). n

Kw an wu ono

M | but

Go! but

Example 507

Ingenol 3-(33-ethyl-o-methylisoxazole-4-carboxylate) (Compound 507)

Compound 507 was obtained according to Procedure e. Compound 507 was obtained as an amorphous compound.

Starting material: Compound 607.

IN NMR (300 MHz, SOSIZ) 6.13-6.12 (m, 1H), 6.09-6.07 (m, 1H), 5.69 (s, 1H), 4.65 (width s , 1H), 424-415 (m, ЗН), 4.11 (s, 1Н), 3.68 (s, 1Н), 2.88 (sq., 2Н), 2.66 (s, ЗН), 2.59-2.54 (m, 1H), 2.34-2.15 (m, 2H), 1.83 (d, ЗН), 1.79-1.71 (m, 1H), 1, 29 (t, ЗН), 1.07 (s, ЗН), 1.05 (s, ЗН), 1.01 (d, ЗН), 0.96-0.90 (m, 1Н), 0.74 -0.66 (m, 1H). n ef

That's right

Oh) but

Example 508

Ingenol 3-(3-methyl-5-methylisoxazole-4-carboxylate) (Compound 508)

Compound 508 was obtained according to Procedure e.

Starting material: Compound 608.

NMR NMR (300 MHz, SOSIZ) 6.12 (m, 1H), 6.08-6.07 (m, 1H), 5.69 (s, 1H), 4.74 (m, 1H), 4.23-4.16 (m, ZN), 4.11 (s, 1H), 3.71 (s, 1H), 2.66 (s, ZN), 2.59-2.54 (m, 1H), 2.43 (s, ЗН), 2.36-2.26 (m, 2Н), 1.84-1.71 (m, 4Н), 1.07 (s, ЗН), 1.06 (c, ЗН), 1.01 (d, ЗН), 0.95-0.89 m, 1Н), 0.74-0.66 (m, 1Н).

N svi "N ve

About

Oh well

M but /

Example 509

Ingenol 3-(1-methylindole-3-carboxylate) (Compound 509)

Compound 509 was obtained according to Procedure e.

Starting material: Compound 609.

NMR NMR (300 MHz, SOSIZ) 8.13-8.10 (m, 1H), 7.81 (s, 1H), 7.39-7.28 (m, ЗН), 6.10 (m , 1H), 6.06 (d, 1H), 5.69 (s, 1H), 4.43 (width, 1H), 4.17-4.12 (m, 4H), 3.86 ( s, ЗН), 3.69 (s, 1H), 2.68-2.63 (m, 1H), 2.41 (width s, 1H), 2.29-2.20 (m, 1H) , 1.87 (d, ЗН), 1.80-1.71 (m, 1Н), 1.05-1.03 (m, 9Н), 0.99-0.93 (m, 1Н), 0 .73-0.65 (m, 1H).

It's okay

And but

Example 510

Ingenol 3-(3-phenylthiophene-2-carboxylate) (Compound 510)

Compound 510 was obtained according to Procedure e.

Starting material: Compound 610. "H NMR (300 MHz, SOSIZ) 7.57 (d, 1H), 7.45-7.35 (m, 5H), 7.09 (d, 1H), 5.96- 5.97 (m, 1H), 5.91 (d, 1H), 5.64 (s, 1H), 4.30 (d, 1H), 4.04-3.94 (m, 4H), 3 ... , 1H), 1.01 (s, ЗН), 0.97 (s, ЗН), 0.90-0.82 (m, 4Н), 0.66-0.58 (m, 1Н).

N

20, ono / M no o-" no

Example 511

Ingenol 3-(5-phenylisoxazole-3-carboxylate) (Compound 511)

Compound 511 was obtained according to Procedure e.

Starting material: Compound 611. "H NMR (300 MHz, SOSIZ) 7.82-7.77 (m, 2H), 7.51-7.47 (m, ЗН), 6.92 (s, 1Н), 6.15-6.14 (m, 1H), 6.07 (d, 1H), 5.89 (s, 1H), 4.47 (d, 1H), 4.20-4.09 (m, 4H), 3.86 (s, 1H), 2.68-2.60 (m, 2H), 2.29-2.23 (m, 1H), 1.87-1.76 (m, 4H) , 1.06 (c, ЗН), 1.05-1.02 (m, 6Н), 1.00-0.89 (m, 1Н), 0.74-0.67 (m, 1Н).

N ef ono xx no shuy no

Example 512

Ingenol 3-(isoquinoline-1-carboxylate) (Compound 512)

Compound 512 was obtained according to Procedure e. The title compound was purified

With flash chromatography (dichloromethane/methanol 98:2 -» dichloromethane/methanol 95:5).

Starting material: Compound 612. "H NMR (300 MHz, SOSIS) b 8.73 (d, 1H), 8.55 (d, 1H), 7.93-7.85 (m, 2H), 7.81 -7.71 (m, 2H), 6.16-6.15 (m, 1H), 6.09-6.07 (m, 1H), 6.04 (s, 1H), 5.67 (s , 1H), 5.30 (s, 1H), 4.29-4.18 (m, ЗН), 3.60 (d, 1H), 2.68-2.63 (m, 1H), 2, 45-2.36 (m, 2H), 1.94 (d, ЗН), 1.90-1.82 (m, 1Н), 1.17 (s, ЗН), 1.09 (s,

ЗН), 1.02-0.95 (m, 4Н), 0.78-0.70 (m, 1Н).

N wa ono zhk no

Um-- well

Example 513

Ingenol 3-(quinoline-4-carboxylate) (Compound 513)

Compound 513 was obtained according to Procedure e. The title compound was purified by flash chromatography (dichloromethane/methanol 98:2 - dichloromethane/methanol 95:5).

Starting material: Compound 613. "H NMR (300 MHz, SOSIS) b 9.04 (d, 1H), 8.84-8.80 (m, 1H), 8.20-8.17 (m, 1H) , 7.88 (d, 1H), 7.79-7.15 (m, 1H), 7.68-7.62 (m, 1H), 6.17 (m, 1H), 6.10 (d , 1H), 5.94 (s, 1H), 4.76 (d, 1H), 4.29-4.19 (m, 4H), 3.84 (s, 1H), 2.67-2, 61 (m, 1H), 2.40-2.31 (m, 2H), 1.88 (d, ЗН), 1.85-1.76 (m, 1H), 1.08 (s,

ЗН), 1.06 (s, ЗН), 1.01 (d, ЗН), 0.98-0.92 (m, 1Н), 0.76-0.68 (m, 1Н).

N

Z a N vnu ono zhk no mem no

Example 514

Ingenol 3-(cinnoline-4-carboxylate) (Compound 514)

Compound 514 was obtained according to Procedure e. The title compound was purified by flash chromatography (dichloromethane/methanol 98:2 - dichloromethane/methanol 95:5).

Starting material: Compound 614. "H NMR (300 MHz, DMSO-α) b 9.65 (s, 1Н), 8.89-8.86 (m, 1Н), 8.65-8.61 (m, 1H), 8.10-8.00 (m, 2H), 6.14 (s, 1H), 6.04 (d, 1H), 5.93-5.92 (m, 1H), 5.78 (s, 1H), 5.59 (d, 1H), 4.69 (t, 1H), 4.28-4.23 (m, 1H), 4.04-3.92 (m, 2H), 3.73 (d, 1H), 2.64-2.57 (m, 1H), 2.45-2.37 (m, 1H), 1.83 (d, ZN), 1.80-1, 71 (m, 1H), 1.08 (s, ЗН), 1.05 (s, ЗН), 0.93 (d, ЗН), 0.85-0.79 (m, 1Н), 0.69 -0.61 (m, 1H).

H two

M o no x | but

M no

Example 515

Ingenol 3-(3-phenylimidazole-4-carboxylate) (Compound 515)

Compound 515 was obtained according to Procedure e. The title compound was purified

With flash chromatography (dichloromethane/methanol 98:2 -» dichloromethane/methanol 95:5).

Starting material: Compound 615. "H NMR (300 MHz, SOSIZ) b 7.89 (d, 1H), 7.68 (d, 1H), 7.49-7.44 (m, ЗН), 7.37 -7.32 (m, 2H), 6.00-5.98 (m, 2H), 5.61 (s, 1H), 5.30 (s, 1H), 4.53 (d, 1H), 4.14-4.10 (m, ЗН), 3.98 (width s, 1H), 3.53 (s, 1H), 2.65 (width s, 1H), 2.30-2, 15 (m, 2H), 1.73-1.65 (m, 4H), 1.04 (s, 6H), 0.93-0.85 (m, 4H), 0.71- 0.63 ( m, 1H).

that in c) it

NN no i m

Example 516

Ingenol 3-(5-phenyloxazole-4-carboxylate) (Compound 516)

Compound 516 was obtained according to Procedure e.

Starting material: Compound 616. "H NMR (300 MHz, DMSO-α) b 8.56 (s, 1H), 7.92-7.88 (m, 2H), 7.53-7.48 (m, ЗН), 5.92 (s, 1H), 5.90 (d, 1H), 5.86-5.85 (m, 1H), 5.42 (d, 1H), 5.00 (s, 1H ), 4.63 (t, 1H), 4.14-4.08 (m, 1H), 3.98-3.85 (m, 2H), 3.64 (d, 1H), 2.25- 2.10 (m, 2H), 1.75 (d, ЗН), 1.51-1.44 (m, 1Н), 1.01 (s, ЗН), 0.99 (s, ЗН), 0 .77-0.70 (m, 4H), 0.58-0.50 (m, 1H).

That's it

OO

What about

Example 517

Ingenol 3-(1,2-benzoxazole-3-carboxylate) (Compound 517)

Compound 517 was obtained according to Procedure e.

Starting material: Compound 617.

IN NMR (300 MHz, SOSIZ) 8.17-8.14 (m, 1H), 7.70-7.61 (m, 2H), 7.47-7.42 (m, 1H), 6.19 -6.18 (m, 1H), 6.09-6.08 (m, 1H), 5.97 (s, 1H), 4.47 (d, 1H), 4.26-4.16 (m , ЗН), 4.12 (width s, 1H), 3.80 (s, 1H), 2.73-2.65 (m, 1H), 2.32-2.23 (m, 2H), 1.90 (d, ZN), 1.86-1.74 (m, 1H), 1.06-1.03 (m, 9H), 0.97-0.90 (m, 1H), 0, 75-0.67 (m, 1H).

N i (c) u no her x no (o)

Example 518

Ingenol 3-(3-isopropyl-o-methylisoxazole-4-carboxylate) (Compound 518)

Compound 518 was obtained according to Procedure e.

Starting material: Compound 618. "H NMR (300 MHz, SOSIZ) 6.13-6.12 (m, 1H), 6.08-6.07 (d, 1H), 5.69 (s, 1H), 4.67 (d, 1H), 4.23- 4.18 (m, ЗН), 4.11 (width s, 1H), 3.69 (s, 1H), 3.44 (septet, 1H) . .70 (m, 1H), 1.33 (d, ZN), 1.32 (d, ZN), 1.07 (s, ZN), 1.06 (s, ZN), 1.00 (d, ЗН), 0.96-0.86 (m, 1Н), 0.74-0.66 (m, 1Н).

N u o o NO no or u no o

Example 519

Ingenol 3-(3-(2-methoxyphenyl)-5-methylisoxazole-4-carboxylate) (Compound 519)

Compound 519 was obtained according to Procedure e.

Starting material: Compound 619. "NMR (300 MHz, SOSIZ) 7.46-7.36 (m, 2H), 7.04 (dt, 1H), 6.95 (d, 1H), 6.01 (d, 1H), 5.91-5.90 (m, 1H), 5.69 (s, 1H), 4.14-4.06 (m, 2H), 3.98 (dd, 1H), 3.91 (d, 1H), 3.82 (d, 1H), 3.77 (s, ЗН), 3.26 (s, 1Н), 2.75 (s, ЗН), 2.26-2 .21 (m, 1H), 1.99-1.89 (m, 1H), 1.72 (d, ЗН), 1.65-1.61 (m, 1H), 1.55-1.46 (m, 1H), 1.04 (s, ЗН), 1.04 (s, ЗН), 0.90-0.83 (m, 1Н), 0.74 (d, ЗН), 0.65- 0.57 (m, 1H). id. 2 (o) to but oh what, On neck

M

Example 520

Ingenol 3-(4-bromo-2-methylpyrazole-3-carboxylate) (Compound 520)

Compound 520 was obtained according to Procedure e.

Starting material: Compound 620.

NMR NMR (300 MHz, SOSIZ) 7.52 (s, 1H), 6.15-6.14 (m, 1H), 6.08 (d, 1H), 5.84 (s, 1H), 5.30 (s, 1H), 15. 4.21-4.05 (m, 7H), 3.85 (s, 1H), 2.77-2.73 (m, 1H), 2.30- 2.17 (m, 2H), 1.87 (d, ЗН), 1.80-1.72 (m, 1Н), 1.08 (s, ЗН), 1.06 (s, ЗН), 1 .00 (d, ZN), 0.97-0.90 (m, 1H), 0.75-0.67 (m, 1H).

N

2 o) o no sh o He i -

M

Example 521

Ingenol 3-(4-bromo-2-ethylpyrazole-3-carboxylate) (Compound 521)

Compound 521 was obtained according to Procedure no.

Starting material: Compound 621.

NMR NMR (300 MHz, SOSIZ) 7.54 (s, 1H), 6.15-6.13 (m, 1H), 6.09-6.07 (m, 1H), 5.86 (5 1H), 4.68-4.55 (m, 2H), 4.24-413 (m, 4H), 4.07 (d, 1H), 3.87 (s, 1H), 2.77-2 .70 (m, 1H), 2.32-2.20 (m, 2H), 1.87 (d, ЗН), 1.80-1.71 (m, 1Н), 1.44 (t, ЗН ), 1.09 (s, ЗН), 1.06 (s, ЗН), 0.98 (d, ЗН), 0.97-0.90 (m, 1Н), 0.75-0.67 ( m, 1H). n

Well, that's it, that's it, that's it

M

Example 522

Ingenol 3-(4-chloro-2-methylpyrazole-3-carboxylate) (Compound 522)

Compound 522 was obtained according to Procedure e.

Zo Starting material: Compound 622. "H NMR (300 MHz, SOSIS) 7.48 (s, 1H), 6.14-6.13 (m, 1H), 6.09-6.06 (m, 1H) , 5.84 (s, 1H), 4.23-4.11 (m, 7H), 4.07-4.05 (d, 1H), 3.83 (s, 1H), 2.73-2 .64 (m, 1H), 2.31-2.20 (m, 2H), 1.87 (d, ЗН), 1.81-1.72 (m, 1Н), 1.08 (s, ЗН ), 1.06 (c, ЗН), 1.00 (d, ЗН), 0.97-0.87 (m, 1Н), 0.75-0.67 (m, 1Н).

N and (o)

One thing; but -/

Example 523

Ingenol 3-(5-bromopyrimidine-4-carboxylate) (Compound 523)

Compound 523 was obtained according to Procedure e.

Starting material: Compound 623. "H NMR (300 MHz, SOSIZ) 9.21 (s, 1H), 9.02 (s, 1H), 6.16-6.14 (m, 1H), 6.09 -6.07 (m, 1H), 5.96 (s, 1H), 4.22-4.12 (m, 4H), 4.06-4.04 (m, 2H), 2.57-2 .52 (m, 1H), 2.33-2.24 (m, 2H), 1.90 (d, ЗН), 1.88-1.79 (m, 1Н), 1.10 (s, ЗН ), 1.06 (c, ЗН), 0.98-0.90 (m, 4Н), 0.75-0.67 (m, 1Н).

N i i (9;

Oh no no no no

Example 524

Ingenol 3-(3-bromopyridine-2-carboxylate) (Compound 524)

Compound 524 was obtained according to Procedure e.

Starting material: Compound 624.

NMR NMR (300 MHz, SOSIZ) 8.58 (dd, 1H), 8.03 (dd, 1H), 7.34 (dd, 1H), 6.11-6.13 (m, 1H), 6.07-15. 6.05 (m, 1H), 5.98 (s, 1H), 4.74 (d, 1H), 4.21-4.15 (m, ЗН), 4.00 ( d, 1H), 3.69 (d, 1H), 2.56-2.48 (m, 2H), 2.34-2.24 (m, 1H), 1.91 (d, ЗН), 1 .83-1.74 (m, 1H), 1.12 (s, ЗН), 1.05 (s, ЗН), 0.98-0.92 (m, 4Н), 0.75-0.67 (m, 1H).

Nad (o) o no sht no vi" y

Example 525

Ingenol 3-(5-methylthiazole-4-carboxylate) (Compound 525)

Compound 525 was obtained according to Procedure e.

Starting material: Compound 625.

IN NMR (300 MHz, SOSIZ) 8.59 (s, 1H), 6.10-6.05 (m, 2H), 5.70 (s, 1H), 4.21-4.14 (m, 4H ), 4.04 (s, 2H), 2.81 (s, ЗН), 2.66-2.59 (m, 2H), 2.32-2.23 (m, 1H), 1.86 ( d, ZN), 1.83-1.74 (m, 1H), 1.09 (s,

ЗН), 1.06 (s, ЗН), 1.00 (d, ЗН), 0.98-0.91 (m, 1Н), 0.75-0.67 (m, 1Н).

N

KI av (in) si o what, . Oh no

M

Example 526

Ingenol 3-(4-chloro-1-methylpyrazole-3-carboxylate) (Compound 526)

Compound 526 was obtained according to Procedure e.

Starting material: Compound 626.

IN NMR (300 MHz, SOSIZ) 7.47 (s, 1H), 6.10-6.05 (m, 2H), 5.82 (s, 1H), 4.18-4.12 (m, ZN ), 4.04 (d, 1H), 3.96 (s, ЗН), 3.87 (s, 1H), 3.79 (d, 1H), 2.70-2.63 (m, 1H) , 2.34-2.21 (m, 2H), 1.87 (d, ЗН), 1.682-1.73 (m, 1Н), 1.09 (s, ЗН), 1.05 (s, ЗН ), 1.00 (d, ZN), 0.98-0.92 (m, 1H), 0.74-0.67 (m, 1H). it's yours

Example 527

Ingenol 3-(2,4-dimethylthiazole-5-carboxylate) (Compound 527)

Compound 527 was obtained according to Procedure e.

Starting material: Compound 627.

NMR NMR (300 MHz, SOSIZ) 6.10-6.08 (m, 1H), 6.07-6.05 (m, 1H), 5.69 (s, 1H), 4.61 (d , 1H), 4.21-4.15 (m, ЗН), 4.08 (s, 1Н), 3.62 (d, 1Н), 2.70 (s, ЗН), 2.69 (s, ЗН), 2.62-2.54 (m, 2Н), 2.32-2.25 (m, 1Н), 1.82 (d, ЗН), 1.80-1.73 (m, 1Н) . , 1H).

M

Example 528

Ingenol 3-(2,5-dimethyloxazole-4-carboxylate) (Compound 528)

Compound 528 was obtained according to Procedure e.

Starting material: Compound 628. "H NMR (300 MHz, SOSIZ) 6.03-6.00 (m, 2H), 5.74 (s, 1H), 4.51-4.47 (m, 2H), 4.25-4.10 (m, ЗН), 4.02 (width s, 1H), 3.55 (s, 1H), 2.59 (s, ЗН), 2.57-2.54 ( m, 1H), 2.44 (s, ЗН), 2.31-2.22 (m, 1Н), 1.81 (d, ЗН), 1.79-1.71 (m, 1Н), 1 .07 (s, ЗН), 1.05 (s, ЗН), 0.98 (d, ЗН), 0.95-0.88 (m, 1Н), 0.73-0.65 (m, 1Н ).

N

. chn zi o" Na na o

Example 529

Ingenol 3-(2,4-dimethylfuran-3-carboxylate (Compound 529)

Compound 529 was obtained according to Procedure e. Compound 529 was obtained as an amorphous compound.

Starting material: Compound 629.

NMR NMR (300 MHz, SOSIZ) 7.06 (sq., 1H), 6.09-6.06 (m, 2H), 5.62 (m, 1H), 4.50 (d, 1H) , 4.19-413 (m, ZN), 4.12-4.09 (m, 1H), 3.66 (s, 1H), 2.61-2.55 (m, 1H), 2.54 (c, ZN), 2.39 (t, 1Н), 2.32-2.23 (m, 1Н), 2.12 (d, ZN), 1.83 (d, ZN), 1.79- 1.70 (m, 1H), 1.07 (s, ЗН), 1.05 (s, ЗН), 0.99 (d, ЗН), 0.98-0.90 (m, 1Н), 0 .73-0.65 (m, 1H).

N

WITH

(o) o no shk what r no "M

Example 530

Ingenol 3-(3,5-diethylisoxazole-4-carboxylate) (Compound 530)

Compound 530 was obtained according to Procedure e.

Starting material: Compound 630.

IN NMR (300 MHz, SOSIZ) 6.14-6.12 (m, 1H), 6.08-6.07 (m, 1H), 5.70 (s, 1H), 4.68 (d, 1H ), 4.23-4.18 (m, ZN), 4.12-4.11 (m, 1H), 3.69 (s, 1H), 3.09 (dkv., 2H), 2.89 (dqv., 2H), 2.59-2.52 (m, 1H), 2.35-2.25 (m, 2H), 1.83 (d, ЗН), 1.79-1.70 ( m, 1Н), 1.31 (t, ZN), 1.29 (t, ZN), 1.07 (s, ZN), 1.05 (s, ZN), 1.01 (d, ZN), 0.96-0.89 (m, 1H), 0.74-0.65 (m, 1H); 0.5 mol of ethyl acetate is observed: 4.12 (sq., 0.5х2Н), 2.04 (s, 0.5хЗН), 1.26 (t, 0.5х3Н).

N you

Go o nn no

Example 531

Ingenol 3-(1H-indole-7-carboxylate) (Compound 531)

Compound 531 was obtained according to Procedure e.

Starting material: Compound 631. "H NMR (300 MHz, SOSIZ) 10.13 (lat.s, 1H), 7.90-7.85 (m, 2H), 7.31-7.29 (m, 1H ), 7.18 (t, 1H), 6.62-6.60 (m, 1H), 6.13-6.12 (m, 1H), 6.08 (d, 1H), 5.84 ( s, 1H), 4.69 (d, 1H), 4.27-4.16 (m, 4H), 3.85 (s, 1H), 2.71-2.66 (m, 1H), 2 ... , ЗН), 1.06 (s, ЗН), 1.04 (d, ЗН), 0.98-0.92 (m, 1Н), 0.76-0.68 (m, 1Н)

N ko i en o

He no and: (c) - no

Kk

Example 532

Ingenol 3-(2-tert-butyl-5-methylpyrazole-3-carboxylate) (Compound 532)

Compound 532 was obtained according to Procedure e.

Starting material: Compound 632.

NMR NMR (300 MHz, SOSIZ) 6.65 (s, 1H), 6.09-6.06 (m, 2H), 5.69 (s, 1H), 4.40 (d, 1H), 4.20-413 (m, ZN), 4.08 (d, 1H), 3.54 (s, 1H), 2.60-2.55 (m, 1H), 2.33-2.24 ( m, 5H), 1.82 (d, ЗН), 1.80-1.75 (m, 1Н), 1.70 (s, 9Н), 1.08 (s, ЗН), 1.06 (s , ЗН), 1.01 (d, ЗН), 0.98-0.91 (m, 1Н), 0.75-0.67 (m, 1Н). what

M

Example 533

Ingenol 3-(5-tert-butyl-2-methylpyrazole-3-carboxylate) (Compound 533)

Compound 533 was obtained according to Procedure e.

Starting material: Compound 633.

NMR NMR (300 MHz, SOSIZ) 6.63 (s, 1H), 6.12-6.10 (m, 1H), 6.08-6.06 (d, 1H), 5.71 (s , 1H), 4.57 (d, 1H), 4.20-4.15 (m, ЗН), 4.13 (s, ЗН), 4.10 (d, 1Н), 3.62 (s, 1H), 2.61-2.55 (m, 1H), 2.40 (t, 1H), 2.32-2.23 (m, 1H), 1.83 (d, ЗН), 1.82 -1.73 (m, 1H), 1.31 (s, 9H), 1.07 (s, ЗН), 1.05 (s, ЗН), 1.03 (d,

ЗН), 0.97-0.91 (m, 1Н), 0.75-0.67 (m, 1Н).

N ya «yan t o no

M o MO - And no

M

Example 534 20 Ingenol 3-(b-methylimidazo|2,1-5|hiazole-5-carboxylate) (Compound 534)

Compound 534 was obtained according to Procedure e.

Starting material: Compound 634.

NMR NMR (300 MHz, SOSIZ) 8.09 (d, 1H), 6.93 (d, 1H), 6.15-6.13 (m, 1H), 6.08 (d, 1H), 5.73 (s, 1H), 4.24-4.17 (m, 4H), 4.14-4.13 (m, 1H), 3.80 (width s, 1H), 2.63- 2.59 (m, 5H), 2.33-2.25 (m, 1H), 1.66 (d, ЗН), 1.80-1.71 (m, 1H), 1.06 (s, ЗН), 1.05 (s, ЗН), 1.02 (d, ЗН), 0.97-0.90 (m, 1Н), 0.74-0.66 (m, 1Н).

And with Mon 20 - In (c) Yu

Wed no hi no

Example 535

Ingenol 3-(2-methylimidazo|1,2-a|pyridine-3-carboxylate) (Compound 535)

Compound 535 was obtained according to Procedure e.

Starting material: Compound 635.

IN NMR (300 MHz, SOSIZ) 9.37 (d, 1H), 8.09 (s, 1H), 7.74 (d, 1H), 7.49-7.43 (m, 1H), 7, 06-7.01 (m, 1H), 6.19-6.08 (m, 2H), 5.80 (s, 1H), 4.33-4.17 (m, 4H), 3.43 ( width s, 2H), 2.72-2.63 (m, 4H), 2.33-2.24 (m, 1H), 1.88 (d, ЗН), 1.80-1.71 ( m, 1H), 1.06 (s, ЗН), 1.05 (s, ЗН), 1.03 (d, ЗН), 0.97-0.85 (m, 1Н), 0.75-0 .67 (m, 1H).

20 o'clock in the morning

Example 536

Ingenol 3-(2,4,5-trimethylfuran-3-carboxylate) (Compound 536)

Compound 536 was obtained according to Procedure e.

Starting material: Compound 636. "H NMR (300 MHz, SOSIZ) 6.07-6.04 (m, 2H), 5.63 (s, 1H), 4.65 (d, 1H), 4.20- 4.14 (m, ZN), 4.09 (d, 1H), 3.71 (s, 1H), 2.80 (t, 1H), 2.62-2.56 (m, 1H), 2 ... 78-1.69 (m, 1H), 1.06 (s, ЗН), 1.05 (s, ЗН), 0.98 (d, ЗН), 0.94-0.90 (m, 1Н) , 0.72-0.65 (m, 1H).

N

; in o na hi no

Example 537

Ingenol 3-(3-methylthiophene-2-carboxylate) (Compound 537)

Compound 537 was obtained according to Procedure e.

Starting material: Compound 637. "H NMR (300 MHz, SOSIZ) 7.42 (d, 1H), 6.94 (d, 1H), 6.09-6.07 (m, 1H), 6.06- 6.04 (m, 1H), 5.71 (s, 1H), 4.49 (width, 1H), 4.22-4.12 (m, ЗН), 4.09-4.08 ( m, 1H), 3.63 (s, 1H), 2.70-2.60 (m, 2H), 2.57 (s, ЗН), 2.32-2.22 (m, 1H), 1 ... 96-0.90 (m, 1H), 0.73-0.66 (m, 1H).

N i en

OA s o NO

X - M but h

Example 538

Ingenol 3-(2-methyl-4-(1-piperidyl)pyrazole-3-carboxylate) (Compound 538)

Compound 538 was obtained according to Procedure e.

Starting material: Compound 638.

IN NMR (300 MHz, SOSIZ) 7.36 (s, 1H), 6.10-6.07 (m, 2H), 5.69 (s, 1H), 4.23-4.13 (m, ZN ), 4.10 (s, ZN), 4.01 (s, 1H), 2.97-2.82 (m, 4H), 2.68-2.62 (m, 1H), 2.31- 2.22 (m, 1H), 1.87 (d, ЗН), 1.84-1.59 (m, 8H), 1.55-1.49 (m, 2H), 1.10 (s, ЗН), 1.05 (s, ЗН), 0.99 (d, ЗН), 0.98-0.94 (m, 1Н), 0.74-0.66 (m, 1Н).

N you (in o NO rn that) o

Example 539

Ingenol 3-(2-chloro-5-isopropylthiazole-4-carboxylate) (Compound 539)

Compound 539 was obtained according to Procedure e.

Starting material: Compound 639. "H NMR (300 MHz, SOSIZ) 6.09-6.05 (m, 2H), 5.77 (s, 1H), 4.19-4.08 (m, 5H), 4.04-3.98 (m, 2H), 2.64-2.55 (m, 2H), 2.33-2.24 (m, 1H), 1.85 (d, ЗН), 1, 83-1.71 (m, 1H), 1.34 (d, ЗН), 1.32 (d, ЗН), 1.10 (s, ЗН), 1.06 (s, ЗН), 1.01 (d, ZN), 0.97-0.91 (m, 1H), 0.75-0.67 (m, 1H).

M i no si

Example 540

Ingenol 3-(4-chloro-2,5-dimethylpyrazole-3-carboxylate) (Compound 540)

Compound 540 was obtained according to Procedure e.

Starting material: Compound 640. "H NMR (300 MHz, SOSIZ) 6.14-6.12 (m, 1H), 6.08-6.06 (m, 1H), 5.83 (s, 1H), 4.21-4.04 (m, 8H), 3.85 (s, 1H), 2.73-2.68 (m, 1H), 2.42 (width s, 1H), 2.30- 2.21 (m, 4H), 1.86 (d, ЗН), 1.81-1.72 (m, 1Н), 1.08 (s, ЗН), 1.06 (s, ЗН), 1 .00 (d, ZN), 0.97-0.90 (m, 1H), 0.75-0.67 (m, 1H).

and en

Phew oh but

M

/

Example 541

Ingenol 3-(1,2,4-trimethylpyrrole-3-carboxylate) (Compound 541)

Compound 541 was obtained according to Procedure e.

Starting material: Compound 641.

NMR NMR (300 MHz, SOSIZ) 6.29 (m, 1H), 6.06-6.03 (m, 2H), 5.55 (s, 1H), 4.51 (d, 1H), 4.16-4.08 (m, 4H), 3.68 (s, 1H), 3.47 (s, ЗН), 2.63-2.52 (m, 2H), 2.47 (s, ЗН), 2.29-2.20 (m, 1Н), 2.18 (s, ЗН), 1.83 (d, ЗН), 1.7 7-1.68 (m, 1Н), 1, 07 (s, ЗН), 1.04 (s, ЗН), 0.98 (d, ЗН), 0.99-0.93 (m, 1Н), 0.72-0.64 (m, 1Н) .

N

: I an bi o r s o No

Mn no x

Example 542

Ingenol 3-(1,3,5-trimethylpyrrole-2-carboxylate) (Compound 542)

Compound 542 was obtained according to Procedure e.

Starting material: Compound 642.

IN NMR (300 MHz, SOSIZ) 6.06-6.05 (m, 2H), 5.81 (s, 1H), 5.59 (s, 1H), 4.44 (d, 1H), 4, 17-4.08 (m, 4H), 3.77 (s, ЗН), 3.70 (s, 1H), 2.63-2.57 (m, 1H), 2.44 (t, 1H) , 2.29-2.24 (m, 4H), 2.21 (s, ЗН), 1.83 (d, ЗН), 1.78-1.69 (m, 1Н), 1.07 (s , ЗН), 1.05 (s, ЗН), 0.98 (d, ЗН), 0.95-0.90 (m, 1Н), 0.72-0.65 (m, 1Н). N

I am

Phew oh where

She (FI still hg no y

Example 543

Ingenol 3-(1-ethyl-3,5-dimethylpyrrole-2-carboxylate) (Compound 543)

Compound 543 was obtained according to Procedure e.

Starting material: Compound 643.

IN NMR (300 MHz, SOSIZ) 6.07-6.05 (m, 2H), 5.81 (s, 1H), 5.58 (s, 1H), 4.43 (d, 1H), 4, 32-4.24 (m, 2H), 4.17-4.09 (m, 4H), 3.67 (s, 1H), 2.62-2.57 (m, 1H), 2.36- 2.34 (m, 1H), 2.30-2.20 (m, 7H), 1.84 (d, ЗН), 1.78-1.69 (m, 1H), 1.27 (t, ЗН), 1.07 (с, ЗН), 1.05 (с, ЗН), 0.98 (d, ЗН), 0.95-0.90 (m, 1Н), 0.72-0.65 (m, 1H).

N. v. Kn y y 0 on no OH

Example 544

Ingenol 3-(1-tert-butyloxycarbonyl-3,3-dimethylpyrrolidine-2-carboxylate) (Compound 544)

Compound 544 was obtained according to Procedure e.

Starting material: Compound 644.

1H NMR (300 MHz, SOSIZ) showed a mixture of compounds.

N

And I take it in no no no

Example 545

Ingenol 3-(25)-1-phenylpyrrolidine-2-carboxylate) (Compound 545)

Compound 545 was prepared according to Procedure e with the following changes: Tetrahydrofuran was replaced by methanol, and the reaction time at room temperature was 0.5 h.

Starting material: Compound 645.

NMR NMR (300 MHz, SOSIZ) 7.27-7.21 (m, 2H), 6.72 (t, 1H), 6.54 (d, 2H), 6.01-5.99 (m , 1H), 5.96 (d, 1H), 5.68 (s, 1H), 4.43 (dd, 1H), 4.13-4.03 (m, 2H), 3.88-3, 83 (m, 2H), 3.49-3.37 (m, ЗН), 2.70 (s, 1H), 2.46-2.39 (m, 1H), 2.28-2.20 ( m, 2H), 2.13-1.96 (m, ЗН), 1.75 (d, ЗН), 1.68-1.57 (m, 1Н), 1.49-1.40 (m, 1Н), 1.03 (с, ЗН), 0.96 (с, ЗН), 0.89-0.81 (m, 4Н), 0.62-0.54 (m, 1Н).

IN

Yani no he ro

M

Example 546

Ingenol 3-(1-isopropyl-3,5-dimethylpyrazole-4-carboxylate) (Compound 546)

Compound 546 was obtained according to Procedure no.

Starting material: Compound 646.

1H NMR (300 MHz, SOSIS) 6.07-6.04 (m, 2H), 5.61 (s, 1H), 4.63 (d, 1H), 4.43 (septet, 1H), 4.19-4.10 (m, 4H), 3.70 (s, 1H), 2.70 (t, 1H), 2.62-2.58 (m, 1H), 2.52 (s, ЗН), 2.40 (s, ЗН), 2.31-2.22 (m, 1Н), 1.83 (d, ЗН), 1.79-1.70 (m, 1Н), 1.46 (d, 6H), 1.07 (s, ЗН), 1.04 (s, ЗН), 0.99 (d, ЗН), 0.97-0.90 (d, 1Н), 0.73- 0.65 (m, 1H). n

And about but and not about BUT

Example 547

Ingenol 3-(5-ethyl-3-isopropylisoxazole-4-carboxylate) (Compound 547)

Compound 547 was prepared according to Procedure e with the following changes: Tetrahydrofuran was replaced by methanol, and the reaction time at room temperature was 0.5 h.

Starting material: Compound 647. "H NMR (300 MHz, SOSIZ) 6.13-6.12 (m, 1H), 6.08-6.06 (d, 1H), 5.71 (s, 1H), 4.75 (d, 1H), 4.23-4.17 (m, ЗН), 4.13-4.10 (m, 1H), 3.70 (s, 1H), 3.45 (septet, 1H), 3.12-3.04 (m, 2H), 2.58-2.46 (m, 2H), 2.35-2.26 (m, 1H), 1.83 (d, ЗН) , 1.79-1.70 (m, 1H), 1.33 (d, ЗН), 1.32 (d, ЗН), 1.30 (t, ЗН), 1.07 (s,

ЗН), 1.06 (s, ЗН), 1.00 (d, ЗН), 0.96-0.89 (m, 1Н), 0.74-0.66 (m, 1Н). n o And this is o no hi no x no

Example 548

Ingenol 3-(2-methylindazole-3-carboxylate) (Compound 548)

Compound 548 was obtained according to the Procedure with the following changes:

Tetrahydrofuran was replaced by methanol, and the reaction time at room temperature was 0.5 h.

Starting material: Compound 648.

NMR NMR (300 MHz, SOSIZ) 7.97-7.94 (m, 1H), 7.81-7.78 (m, 1H), 7.39-7.34 (m, 1H), 7 ,31-7.26 (m, 1H), 6.22-6.21 (m, 1H), 6.10-6.08 (m, 1H), 5.86 (s, 1H), 4.75 (d, 1H), 4.54 (s, ЗН), 4.26-4.18 (m, 4H), 3.80 (s, 1H), 2.74-2.69 (m, 1H), 2.32-2.22 (m, 2H), 1.91 (d, ЗН), 1.75-1.67 (m, 1Н), 1.07 (d, ЗН), 1.05 (s, ЗН), 1.04 (с, ЗН), 0.97-0.90 (m, 1Н), 0.73-0.65 (m, 1Н).

Well, but he

Y Z

-

Example 549

Ingenol 3-(5-methyl-3-tert-butyl-isoxazole-4-carboxylate) (Compound 549)

Compound 549 was obtained according to Procedure e.

Starting material: Compound 649.

NMR NMR (300 MHz, SOSIZ) 6.13-6.11 (m, 1H), 6.09-6.07 (m, 1H), 5.68 (s, 1H), 4.66 (width .s, 1H), 4.22-4.15 (m, ЗН), 4.12 (s, 1H), 3.67 (s, 1H), 2.62 (s, ЗН), 2.60- 2.53 (m, 1H), 2.33-2.23 (m, 2H), 1.83 (d, ЗН), 1.78-1.69 (m, 1H), 1.44 (s, 9H), 1.07 (s, ЗН), 1.06 (s, ЗН), 0.98 (d, ЗН), 0.96-0.89 (m, 1Н), 0.74-0.66 (m, 1H). n y (v; o but what he x (v

Example 550

Zo Ingenol 3-(2-methyl-3-oxo-4-oxaspiro|(4.5|dec-1-ene-1-carboxylate) (Compound 550)

Compound 550 was obtained according to Procedure e with the following modifications:

Tetrahydrofuran was replaced by methanol, and the reaction time at room temperature was 0.5 h.

Starting material: Compound 650.

NMR NMR (300 MHz, SOSIZ) 6.15-6.13 (m, 1H), 6.09-6.07 (m, 1H), 5.76 (s, 1H), 5.00 (d , 1H), 4.26-4.11 (m, 4H), 3.72 (s, 1H), 2.60-2.55 (m, 1H), 2.45-2.42 (m, 1H ), 2.31-2.13 (m, 5H), 1.95-1.90 (m, 1H),

1.82 (d, ЗН), 1.78-1.67 (m, 7Н), 1.58-1.50 (m, 2Н), 1.08 (s, ЗН), 1.06 (s, ЗН), 1.01 (d, ЗН), 0.95-0.89 (m, 1Н), 0.75-0.67 (m, 1Н). N

Se (c) o no - no on rya 2

M

Example 551

Ingenol 3-(1-tert-butyl-3,5-dimethylpyrazole-4-carboxylate) (Compound 551)

Compound 551 was obtained according to Procedure e.

Starting material: Compound 651.

NMR NMR (300 MHz, SOSIZ) 6.08-6.05 (m, 2H), 5.58 (s, 1H), 4.47 (lat.s, 1H), 4.17-4.10 (m, 4H), 3.65 (s, 1H), 2.71 (s, ЗН), 2.62-2.57 (m, 1H), 2.36-2.21 (m, 5H), 1.83 (d, ZN), 1.79-1.70 (m, 1Н), 1.65 (s, 9Н), 1.07 (s, ZN), 1.05 (s, ZN), 0 .99 (d, ЗН), 0.96-0.91 (m, 1H), 0.73-0.65 (m, 1H). di y. (I у в) no no

Id and 78

Example 552

Ingenol 3-(3,5-dimethylisothiazole-4-carboxylate) (Compound 552)

Compound 552 was obtained according to Procedure e.

Starting material: Compound 652.

N

WITH

(c) ka no no ON

M. ) I

WITH

Example 553

Ingenol 3-(5-iodo-3-methyl-isothiazole-4-carboxylate) (Compound 553)

Compound 553 was obtained according to Procedure e.

Starting material: Compound 653. "H NMR (300 MHz, SOSIZ) 6.16-6.14 (m, 1H), 6.08 (d, 1H), 5.81 (s, 1H), 4.57 ( d, 1H), 4.25-412 (m, 4H), 3.75 (s, 1H), 2.74 (s, ЗН), 2.73-2.68 (m, 1H), 2.32 -2.23 (m, 2H), 1.90 (d, ЗН), 1.78-1.69 (m, 1Н), 1.07 (s, ЗН), 1.06 (s, ЗН), 1.00 (d, ZN), 0.96-0.90 (m, 1H), 0.74-0.66 (m, 1H). n s) and Shchi vo, no pk no

M "

Example 554

Ingenol 3-(4-(4-methoxyphenyl)-2-methylpyrazole-3-carboxylate) (Compound 554)

Compound 554 was obtained according to Procedure e.

Starting material: Compound 654. "H NMR (300 MHz, SOSIS) 7.43 (s, 1H), 7.28-7.23 (m, 2H), 6.90-6.83 (m, 2H), 6.02-6.00 (m, 1H),

5.95-5.93 (m, 1H), 5.73 (s, 1H), 4.22 (s, ЗН), 4.16-4.08 (m, 4H), 4.02-3, 95 (m, 2H), 3.81 (s, ЗН), 3.23 (s, 1Н), 1.96-1.87 (m, 1Н), 1.75 (d, ЗН), 1.58 -1.55 (m, 1H), 1.50-1.41 (m, 1H), 1.02 (s, ЗН), 1.01 (s,

ЗН), 0.90-0.83 (m, 1Н), 0.69 (d, ЗН), 0.63-0.55 (m, 1Н). p

Y "N

It is not possible

Example 555

Ingenol 3-(4-(2-methylphenyl-2-methylpyrazole-3-carboxylate) (Compound 555)

Compound 555 was obtained according to Procedure e.

Starting material: Compound 655. "H NMR (300 MHz, SOSIZ) 7.37 (s, 1H), 7.24-7.11 (m, 4H), 6.00-5.98 (m, 1H), 5.87-5.85 (m, 1H), 5.62 (s, 1H), 4.25 (s, ЗН), 4.16-4.06 (m, 2H), 3.97-3, 88 (m, ЗН), 3.00 (s, 1Н), 2.36 (width s, 1Н), 2.15 (s, ЗН), 1.94-1.84 (m, 1Н), 1 .66 (d, ЗН), 1.61-1.48 (m, 2Н), 1.04 (s, ЗН), 1.02 (с, ЗН), 0.90-0.83 (m, 1Н ), 0.72 (d, ZN), 0.65-0.57 (m, 1H).

N ho AK

UA about this pet no

Hu il No

M

Example 556

Ingenol 3-(2-methyl-4-(4-methylsulfonylphenyl)pyrazole-3-carboxylate) (Compound 556)

Compound 556 was obtained according to Procedure e.

Starting material: Compound 656. "H NMR (300 MHz, SOSIZ SOSIZ) 7.91 (d, 2H), 7.58 (d, 2H), 7.51 (s, 1H), 6.02-6.01 (d, 1H), 5.96-5.95 (m, 1H), 5.72 (s, 1H), 4.25 (s, ЗН), 4.16-4.03 (m, 5H), 3.62 (width s, 1H), 3.07 (s, ЗН), 2.14-2.05 (m, 1H), 1.85-1.80 (m, 1H), 1.71 ( d, ZN), 1.58-1.49 (m, 1H), 1.33-1.29 (m, 1H), 1.02 (s, ZN), 1.01 (s,

ЗН), 0.90-0.80 (m, 1Н), 0.68 (d, ЗН), 0.65-0.57 (m, 1Н). N . en

SY ve na y no hu y no

M

Example 557

Ingenol 3-(2-methyl-4-phenylpyrazole-3-carboxylate) (Compound 557)

Compound 557 was obtained according to Procedure no.

Starting material: Compound 657. "H NMR (300 MHz, SOSIS) 7.47 (s, 1H), 7.37-7.31 (m, 5H), 6.01 (d, 1H), 5.92- 5.91 (m, 1H), 5.71 (s, 1H), 4.24 (s, ЗН), 4.16-4.11 (m, 2H), 4.01-3.95 (m, ЗН), 3.17 (s, 1Н), 2.09-2.03 (m, 1Н), 1.93-1.84 (m, 1Н), 1.72 (d, ЗН), 1.64 -1.59 (m, 1H), 1.49-1.41 (m, 1H), 1.03 (s, ЗН), 1.02 (s, ЗН), 0.88-0.81 (m ,

Zo 1H), 0.67 (d, ЗН), 0.63-0.55 (m, 1H).

N t o o no - no shE no

WITH

Example 558

Ingenol 3-(3,5-dimethyl-1-phenylpyrazole-4-carboxylate) (Compound 558)

Compound 558 was obtained according to Procedure e.

Starting material: Compound 658. "H NMR (300 MHz, SOSIZ) 7.53-7.37 (m, 5H), 6.10-6.09 (m, 1H), 6.07-6.05 (m , 1H), 5.67 (s, 1H), 4.70 (d, 1H), 4.22-4.11 (m, 4H), 3.75 (s, 1H), 2.72-2, 61 (m, 2H), 2.52 (s, ЗН), 2.49 (s, ЗН), 2.35-2.25 (m, 1Н), 1.86 (d, ЗН), 1.80 -1.71 (m, 1H), 1.08 (s, ЗН), 1.05 (s, ЗН), 1.00 (d, ЗН), 0.98-0.90 (m, 1Н), 0.74-0.66 (m, 1H).

N

: . en ve ot Not and their no m no

Example 559

Ingenol 3-(1,5-dimethyl-3-phenylpyrazole-4-carboxylate) (Compound 559)

Compound 559 was obtained according to Procedure e.

Starting material: Compound 659. "H NMR (300 MHz, SOSIZ) 7.49-7.45 (m, 2H), 7.38-7.33 (m, ЗН), 5.98 (d, 1Н), 5.89-5.87 (m, 1H), 5.64 (s, 1H), 4.11-4.08 (m, 2H), 3.99-3.94 (m, ЗН), 3, 85 (s, ЗН), 3.21 (s, 1Н), 2.60 (s, ЗН), 2.46 (width с, 1Н), 1.95-1.85 (m, 1Н), 1 .73 (d, ZN), 1.71-1.64 (m, 1H), 1.50-1.42 (m, 1H), 1.02 (s, ZN), 1.01 (s, ZN ), 0.90-0.84 (m, 1H), 0.68 (d, ЗН), 0.63-0.55 (m, 1H).

N

I en zu in na - no g no

Example 560

Ingenol 3-(1-benzyl-3,5-dimethylpyrazole-4-carboxylate) (Compound 560)

Compound 560 was obtained according to Procedure e.

Starting material: Compound 660. "H NMR (300 MHz, SOSIZ) 7.37-7.28 (m, ЗН), 7.16-7.13 (m, 2Н), 6.08-6.05 (m , 2H), 5.61 (s, 1H), 5.25 (s, 2H), 4.52 (width s, 1H), 4.18-4.10 (m, 4H), 3.67 ( s, 1H), 2.61-2.56 (m, 1H), 2.45 (s, ZN), 2.44-2.41 (s, AN), 2.31-2.22 (m, 1H), 1.82 (d, ЗН), 1.79-1.70 (m, 1Н), 1.07 (s, ЗН), 1.05 (s, ЗН), 0.98 (d,

ЗН), 0.94-0.86 (m, 1Н), 0.73-0.65 (m, 1Н).

in

UA iv) is; tok no (o)

Example 561

Ingenol 3-(3,5-dimethyl-1-(tetrahydropyran-4-ylmethyl)pyrazole-4-carboxylate) (Compound 561)

Compound 561 was obtained according to Procedure e.

Starting material: Compound 661.

NMR NMR (300 MHz, SOSIZ) 6.08-6.05 (m, 2H), 5.60 (s, 1H), 4.53 (lat.s, 1H), 4.17-4.11 (m, 4H), 4.00-3.95 (m, 2H), 3.87 (d, 2H), 3.67 (s, 1H), 3.40-3.32 (m, 2H), 2.62-2.57 (m, 1H), 2.51 (3, ЗН), 2.39 (s, ЗН), 2.32-2.13 (m, 2Н), 1.84 (d, ЗН), 1.79-1.70 (m, 1Н), 1.55-1.35 (m, 5Н), 1.07 (с, ЗН), 1.05 (з;

ЗН), 0.99 (d, ЗН), 0.95-0.85 (m, 1Н), 0.73-0.66 (m, 1Н). n 2f (o) o no sh-o- no ko no o

Example 562

Ingenol 3-(4-methyl-2-oxo-ZN-thiazole-5-carboxylate) (Compound 562)

Compound 562 was obtained according to Procedure e.

Starting material: Compound 662. "H NMR (300 MHz, DMSoO-av) 11.91 (lat.s, 1H), 5.93 (m, 1H), 5.88-5.86 (m, 1H), 5.73 (s, 1H), 5.41 (d, 1H), 5.12 (s, 1H), 4.64 (t, 1H), 4.18 (m, 1H), 3.98-3 .85 (m, 2H), 3.63-3.58 (m, 1H), 2.56-2.51 (m, 1H), 2.38 (s, ЗН), 2.33-2.26 (m, 1H), 1.78-1.64 (m, 4H), 1.03 (s, 6H), 0.89 (d, ЗН), 0.81-0.74 (m, 1H), 0.65-0.57 (m, 1H).

In di (9) o NO pyt no o no

WITH

Example 563

Ingenol 3-(2-methyl-4,5,6,7-tetrahydroindazole-3-carboxylate) (Compound 563)

Compound 563 was obtained according to Procedure e.

Starting material: Compound 663.

NMR NMR (300 MHz, SOSIZ) 6.12-6.10 (m, 1H), 6.08-6.06 (m, 1H), 5.72 (s, 1H), 4.71 (s , 1H), 4.23-4.11 (m, 7H), 3.71 (s, 1H), 2.71-2.57 (m, 6H), 2.34-2.24 (m, 1H ), 1.84 (d, ZN), 1.81-1.70 (m, 5H), 1.07 (s, ZN), 1.05 (s, ZN), 1.00 (d, ZN) , 0.96-0.88 (m, 1H), 0.74-0.66 (m, 1H).

N di (o) ono no

And no

M

Example 564

Ingenol 3-(1,2-dimethylindole-3-carboxylate) (Compound 564)

Compound 564 was obtained according to Procedure e.

Starting material: Compound 664.

NMR NMR (300 MHz, SOSIZ) 8.04-8.01 (m, 1H), 7.33-7-19 (m, ЗН), 6.13-6.11 (m, 1H), 6 ,07-6.05 (m, 1H), 5.72 (s, 1H), 4.62 (d, 1H), 4.19-4.13 (m, 4H), 3.81 (s, 1H ), 3.68 (c, ЗН), 2.76-2.65 (m, 5Н), 2.29- 2.20 (m, 1Н), 1.89 (d, ЗН), 1.76- 1.67 (m, 1H), 1.05-1.03 (m, 9H), 0.99-0.91 (m, 1H), 0.72-0.64 (m, 1H). / o c) o no and no

M

AND

Example 565

Ingenol 3-(5-methoxy-1,2-dimethylindole-3-carboxylate) (Compound 565)

Compound 565 was obtained according to Procedure e.

Starting material: Compound 665. "H NMR (300 MHz, SOSIS) 7.56 (d, 1H), 7.19 (d, 1H), 6.88 (dd, 1H), 6.13-6.11 ( m, 1H); 6.07-6.06 (m, 1TN), 5.69 (s, 1H), 4.66 (d, 1H), 4.18-4.13 (m, 4H), 3 .83 (s, 1H), 3.82 (s, ЗН), 3.65 (s, ЗН), 2.73 (s,

ЗН), 2.72-2.62 (m, 2Н), 2.29-2.20 (m, 1Н), 1.90 (d, ЗН), 1.76-1.69 (m, 1Н) , 1.05 (s, ЗН), 1.03 (s, ЗН), 1.02 (d, ЗН), 0.99-0.92 (m, 1Н), 0.72-0.64 (m , 1H).

N i o o no r y no

Example 566

Ingenol 3-(1,3,5-trimethylpyrazole-4-carboxylate) (Compound 566)

Compound 566 was obtained according to Procedure e.

Starting material: Compound 630. "H NMR (300 MHz, SOSIZ) 6.08-6.05 (m, 2H), 5.62 (s, 1H), 6.07 (d, 1H), 4.19- 4.10 (m, 4H), 3.73 (s, ЗН), 3.71 (s, 1H), 3.73 (t, 1H), 2.62-2.57 (m, 1H), 2 .50 (s, ЗН), 2.38 (s, ЗН), 2.32-2.22 (m, 1Н), 1.83 (d, ЗН), 1.78-1.69 (m, 1Н ), 1.06 (s, ЗН), 1.05 (s, ЗН), 0.99 (d, ЗН), 0.97-0.90 (m, 1Н), 0.73-0.65 ( m, 1H).

N and N (o) o no

Me o b no

M

Example 567

Ingenol 3-(4-methyl-1,2,5-oxadiazole-3-carboxylate) (Compound 567)

Compound 567 was obtained according to Procedure e.

Starting material: Compound 667.

NMR NMR (300 MHz, SOSIZ) 6.18-6.17 (m, 1H), 6.09-6.07 (m, 1H), 5.88 (s, 1H), 4.67 (d , 1H), 4.23-4.10 (m, 4H), 3.71 (s, 1H), 2.66-2.60 (m, 4H), 2.31-2.21 (m, 2H ), 1.86 (d, ЗН), 1.84-1.74 (m, 1Н), 1.07 (s, ЗН), 1.04 (s, ЗН), 1.02 (d, ЗН) , 0.96-0.89 (m, 1H), 0.75-0.67 (m, 1H).

Nn

N

2. about BUT "zzttnia but yours

Wh-

Example 568

Ingenol 3-(2-methoxy-4-methylthiazole-o-carboxylate) (Compound 568)

Compound 568 was obtained according to Procedure e.

Starting material: Compound 668.

IN NMR (300 MHz, SOSIZ) 6.08-6.05 (m, 2H), 5.65 (s, 1H), 4.53 (lat.s, 1H), 4.22-4.13 (m , ЗН), 4.06 (s, 1Н), 3.58 (s, 1Н), 3.33 (s, ЗН), 2.60 (s, ЗН), 2.59-2.52 (m, 1H), 2.41 (width, 1H), 2.31-2.22 (m, 1H), 1.81 (d, 3H), 1.78-1.73 (m, 1H), 1 .07 (s, ЗН), 1.05 (s, ЗН), 0.99 (d, ЗН), 0.96-0.89 (m, 1Н), 0.74-0.67 (m, 1Н ).

N av o o no

No / in no (o)

Example 569

Ingenol 3-(4,5-dimethylisoxazole-3-carboxylate) (Compound 569)

Compound 569 was obtained according to Procedure e.

Starting material: Compound 669.

IN NMR (300 MHz, SOSIZ) 6.11-6.10 (m, 1H), 6.06-6.04 (m, 1H), 5.84 (s, 1H), 4.34 (d, 1H ), 4.23-4.13 (m, ЗН), 4.05 (d, 1Н), 3.89 (s, 1Н), 2.65-2.59 (m, 2Н), 2.39 ( s, ZN), 2.30-2.21 (m, 1H), 2.14 (s,

ZN), 1.85 (d, ZN), 1.82-1.73 (m, 1H), 1.07 (s, ZN), 1.05 (s, ZN), 1.00 (d, ZN ), 0.96-0.88 (m, 1H), 0.74-0.66 (m, 1H).

N

(9)

It's theirs

Oh what but

M

AND

Example 570

Ingenol 3-(4-bromo-1-methylpyrazole-3-carboxylate) (Compound 570)

Compound 570 was obtained according to Procedure e.

Starting material: Compound 670. "H NMR (300 MHz, SOSIZ) 7.50 (s, 1H), 6.11-6.09 (m, 1H), 6.08-6.06 (m, 1H), 5.81 (s, 1H), 4.18-4.11 (m, ЗН), 4.04 (d, 1Н), 3.98 (s, ЗН), 3.88 (s, 1Н), 3 .75 (d, 1H), 2.73-2.68 (m, 1H), 2.30-2.21 (m, 2H), 1.88 (d, ЗН), 1.82-1.73 (m, 1H), 1.09 (s, ЗН), 1.06 (3, ЗН), 1.01 (d, ЗН), 0.99-0.92 (m, 1Н), 0.75- 0.67 (m, 1H).

Well, well, well, well, well, well

Example 571

Ingenol 3-(1,3-dimethylindole-2-carboxylate) (Compound 571)

Compound 571 was obtained according to Procedure e.

Starting material: Compound 671.

IN NMR (300 MHz, SOSIZ) 7.68-7.65 (m, 1H), 7.40-7.32 (m, 2H), 7.17-7.12 (m, 1H), 6.14 -6.13 (m, 1H), 6.08-6.06 (m, 1H), 5.79 (s, 1H), 4.60 (width s, 1H), 4.23-4.13 (m, 4H), 4.01 (s, ЗН), 3.76 (s, 1Н), 2.69-2.64 (m, 1Н), 2.59 (s, ЗН), 2.54- 2.49 (m, 1H), 2.32-2.23 (m, 1H), 1.88 (d, ЗН), 1.78-1.67 (m, 1H), 1.06 (s, ЗН), 1.05 (s, ЗН), 1.02 (d, ЗН), 0.97-0.88 (m, 1Н), 0.73-0.65 (m, 1Н).

What is it? but that

Example 572

Ingenol 3-(5-methoxy-1,3-dimethylindole-2-carboxylate) (Compound 572)

Compound 572 was obtained according to Procedure e.

Starting material: Compound 672.

NMR NMR (300 MHz, SOSIZ) 7.26-7.23 (m, 1H), 7.06-7.00 (m, 2H), 6.14-6.12 (m, 1H), 6 .08-6.06 (m, 1H), 5.78 (s, 1H), 4.58 (width, 1H), 4.22-4.14 (m, 4H), 3.99 (s . s, 1H), 2.33-2.23 (m, 1H), 1.88 (d, ЗН), 1.78-1.69 (m, 1Н), 1.06 (s, ЗН), 1 .05 (c, ЗН), 1.02 (d, ЗН), 0.97-0.88 (m, 1Н), 0.73-0.65 (m, 1Н).

N

- o Mn n c) -a no

GA o c)

Example 573

Ingenol 3-(2,4-dimethyl-6-oxopyran-3-carboxylate) (Compound 573)

Compound 573 was obtained according to Procedure e.

Starting material: Compound 673. "H' NMR (300 MHz, SOSIZ) 6.14-6.13 (m, 1H), 6.10-6.08 (m, 1H), 6.04 (s, 1H) . ), 2.51-2.46 (m, 1H), 2.44 (s, ЗН), 2.33-2.26 (m, 1Н), 2.23 (d, ЗН), 2.11 ( width s, 1H), 1.82 (d, ЗН), 1.79-1.70 (m, 1H), 1.08 (s, ЗН), 1.06 (s, ЗН), 0.98 (d, ЗН), 0.96-0.88 (m, 1Н), 0.75-0.67 (m, 1Н).

No, no, no, no, no

Example 574

Ingenol 3-(1-methyl-3-phenylindole-2-carboxylate) (Compound 574)

Compound 574 was obtained according to Procedure e.

Starting material: Compound 674.

NMR NMR (300 MHz, SOSIZ) 7.46-7.34 (m, 8H), 7.15-7.10 (m, 1H), 6.01-5.99 (m, 1H), 5 .89-5.87 (m, 1H), 5.73 (s, 1H), 4.12-4.11 (m, 5H), 3.98-3.91 (m, 2H), 3.81 -3.79 (d, 1H), 3.02 (s, 1H), 2.35 (width, s, 1H), 1.92-1.83 (m, 1H), 1.70-1.66 (d, 4H), 1.54-1.45 (m, 1H), 1.03 (s, ЗН), 1.03 (s, ЗН), 0.89-0.82 (m, 1Н), 0.74 (d, ZN), 0.64-0.56 (m, 1H).

N

: . what

IS

E o no and o 2 no ee

Example 575

Ingenol 3-(3-methyl-5-(trifluoromethyl)isoxazole-4-carboxylate) (Compound 575)

Compound 575 was obtained according to Procedure e.

Starting material: Compound 675. "H NMR (300 MHz, SOSIZ) 6.16-6.14 (m, 1H), 6.09-6.06 (m, 1H), 5.77 (s, 1H), 4.25-4.14 (m, ЗН), 4.10 (s, 1Н), 3.08 (width s, ЗН), 2.57-2.48 (m, 4Н), 2.31- 2.22 (m, 1H), 1.81 (d, ЗН), 1.78-1.69 (m, 1Н), 1.06 (s, 6Н), 0.99 (d, ЗН), 0 .94-0.87 (m, 1H), 0.74-0.66 (m, 1H).

N u (o) o No sht no on s Sh- Ya

Example 576

Ingenol 3-(1,3-dimethylpyrrole-2-carboxylate) (Compound 576)

Compound 576 was prepared according to Procedure e with the following changes: Tetrahydrofuran was replaced by methanol, and the reaction time at room temperature was 0.5 h.

Starting material: Compound 676.

NMR NMR (300 MHz, SOSIZ) 6.71 (d, 1H), 6.08-6.04 (m, 2H), 5.98 (d, 1H), 5.63 (s, 1H), 4.50 (d, 1H), 4.19-4.09 (m, 4H), 3.687 (s, ЗН), 3.72 (s, 1H), 2.64-2.53 (m, 2H) , 2.31 (s, ЗН), 2.30-2.22 (m, 1Н), 1.84 (d, ЗН), 1.78-1.71 (m, 1Н), 1.07 (s , ЗН), 1.05 (s, ЗН), 0.99 (d, ЗН), 0.95-0.86 (m, 1Н), 0.73-0.65 (m, 1Н). o) but -ot but still but g

EE

IS

Example 577

Ingenol 3-(3,5-dimethyl-1-(2,2,2-trifluoroethyl)pyrazole-4-carboxylate) (Compound 577)

Compound 577 was obtained according to Procedure e.

Starting material: Compound 677. "H NMR (300 MHz, SOSIZ) 6.09-6.08 (m, 1H), 6.06-6.04 (m, 1H), 5.68 (s, 1H), 4.82 (d, 1H), 4.62 (sq., 2H), 4.22-4.12 (m, 4H), 3.77 (s, 1H), 2.97 (width, s, 1H ), 2.63-2.58 (m, 1H), 2.55 (s, ZN), 2.41 (s,

ЗН), 2.34-2.24 (m, 1Н), 1.83 (d, ЗН), 1.79-1.70 (m, 1Н), 1.07 (s, ЗН), 1.05 (c, ЗН), 0.99 (d, ЗН), 0.96-0.88 (m, 1Н), 0.73-0.65 (m, 1Н). ts and dvy (c) o No t o; but

Am

Example 578

Ingenol 3-(1-cyclopropyl-2,5-dimethylpyrrole-3-carboxylate) (Compound 578)

Compound 578 was obtained according to Procedure e.

Starting material: Compound 678.

IN NMR (300 MHz, SOSIZ) 6.18-6.17 (m, 1H), 6.04-6.00 (m, 2H), 5.58 (s, 1H), 4.42 (d, 1H ), 4.16-4.05 (m, 4H), 3.60 (s, 1H), 2.93-2.87 (m, 1H), 2.76 (width s, 1H), 2, 61-2.56 (m, 4H), 2.28-2.19 (m, 4H), 1.80 (d, ЗН), 1.78-1.71 (m, 1H), 1.15- 1.08 (m, 2H), 1.06 (s, ЗН), 1.03 (s, ЗН), 0.99 (d, ЗН), 0.95-0.88 (m, ЗН), 0 .72-0.65 (m, 1H).

N zi o) it sweat that on poison

Example 579

Ingenol 3-(1,2,5-trimethylpyrrole-3-carboxylate) (Compound 579)

Compound 579 was obtained according to Procedure e.

Starting material: Compound 679.

IN NMR (300 MHz, SOSIZ) 6.23-6.22 (m, 1H), 6.05-6.00 (m, 2H), 5.57 (s, 1H), 4.31 (d, 1H ), 4.16-4.06 (m, 4H), 3.57 (s, 1H), 3.41 (s, ЗН), 2.60-2.54 (m, 2H), 2.51 ( s, ZN), 2.28-2.19 (m, 4H), 1.81 (d,

ЗН), 1.79-1.72 (m, 1Н), 1.07 (s, ЗН), 1.04 (s, ЗН), 1.00 (d, ЗН), 0.98-0.92 (m, 1H), 0.73-0.65 (m, 1H). n u (c) o no - o; not. but

Example 580

Ingenol 3-(2,4-dimethyl-1H-pyrrole-3-carboxylate) (Compound 580)

Compound 580 was obtained according to Procedure e.

Starting material: Compound 680. "H NMR (300 MHz, SOSIZ) 10.51 (b, 1H), 6.09-6.05 (m, 2H), 5.95 (d, 1H), 5, 83 (s, 1H), 4.89 (width s, 1H), 4.54 (s, 1H), 4.23-4.07 (m, 4H), 3.11 (width s, 1H) , 2.59-2.54 (m, 1H), 2.38 (s, ЗН), 2.35-2.25 (m, 4Н), 1.82 (d, ЗН), 1.79-1 .74 (m, 1H), 1.09 (s, ЗН), 1.06 (s, ЗН), 0.98-0.88 (m, 4Н), 0.75-0.67 (m, 1Н ).

Pe, (- n di o; o no sht o sh L-- no

Example 581

Ingenol 3-(1-methylpyrrole-2-carboxylate) (Compound 581)

Compound 581 was obtained according to Procedure e.

Starting material: Compound 681. "H NMR (300 MHz, SOSIZ) 6.96 (dd, 1H), 6.84 (t, 1H), 6.14 (dd, 1H), 6.06-6.03 ( m, 2H), 5.69 (s, 1H), 4.43 (d, 1H), 4.18-4.06 (m, 4H), 3.93 (s, ЗН), 3.64 (s , 1H), 2.77 (width, 1H), 2.62-2.57 (m, 1H), 2.31-2.21 (m, 1H), 1.82 (d, ZH), 1.80-1.73 (m, 1H), 1.07 (s, ЗН), 1.05 (s, ЗН), 1.01 (d, ЗН), 0.97-0.91 (m, 1H), 0.74-0.66 (m, 1H).

in a (in) o no ryn no ho. MN no

Example 582

Ingenol 3-(4-methyl-1H-pyrrole-2-carboxylate) (Compound 582)

Compound 582 was obtained according to Procedure e.

Starting material: Compound 682.

IN NMR (300 MHz, SOSIZ) 9.54 (s, 1H), 6.77-6.72 (m, 2H), 6.06-6.02 (m, 2H), 5.69 (s, 1H ), 4.80 (d, 1H), 4.26-4.07 (m, 4H), 3.80 (s, 1H), 2.79 (t, 1H), 2.62-2.56 ( m, 1H), 2.32-2.23 (m, 1H), 2.11 (s,

ZN), 1.82-1.73 (m, 4H), 1.05 (s, ZN), 1.04 (s, ZN), 1.01 (d, ZN), 0.96-0.88 (m, 1H), 0.73-0.66 (m, 1H).

N i (o) o no st O zu no

Example 583

Ingenol 3-(1,5-dimethylpyrrole-2-carboxylate) (Compound 583)

Compound 583 was obtained according to Procedure e.

Starting material: Compound 683. "H NMR (300 MHz, SOSIZ) 6.91 (d, 1H), 6.04-6.02 (m, 2H), 5.94 (d, 1H), 5.67 ( s, 1H), 4.39 (d, 1H), 4.17-4.05 (m, 4H), 3.83 (s, ЗН), 3.64 (s, 1H), 2.80 (t , 1H), 2.61-2.56 (m, 1H), 2.30-2.21 (m, 4H), 1.81 (d, ЗН), 1.79-1.72 (m, 1H ), 1.07 (s, ЗН), 1.04 (s, ЗН), 1.01 (d, ЗН), 0.97-0.91 (m, 1Н), 0.73-0.65 ( m, 1H).

In I av (in) o no early what, ho. MN no

Example 584

Ingenol 3-(3-methyl-1H-pyrrole-2-carboxylate) (Compound 584)

Compound 584 was obtained according to Procedure e.

Starting material: Compound 684. "H NMR (300 MHz, SOSIZ) 9.33 (s, 1H), 6.87 (t, 1H), 6.11 (t, 1H), 6.08-6.04 ( m, 2H), 5.66 (s, 1H), 4.76 (d, 1H), 4.23-4.10 (m, 4H), 3.81 (s, 1H), 2.62-2 .57 (m, 2H), 2.34-2.23 (m, 4H), 1.81 (d, ЗН), 1.79-1.70 (m, 1Н), 1.05 (s, ЗН ), 1.04 (s, ZN), 1.00 (d, ZN), 0.96-0.88 (m, 1H), 0.73-0.65 (m, 1H).

IF) ono shk that shcha -7 no

Example 585

Ingenol 3-(1-cyclopropylpyrrole-2-carboxylate) (Compound 585)

Compound 585 was obtained according to Procedure e.

Starting material: Compound 685. "H NMR (300 MHz, SOSIZ) 6.95 (dd, 1H), 6.91 (t, 1H), 6.09 (dd, 1H), 6.05-6.03 ( m, 2H), 5.70 (s, 1H), 4.40 (d, 1H), 4.18-4.07 (m, 4H), 3.73 (m, 1H), 3.64 (s , 1H), 2.74 (t, 1H), 2.62-2.57 (m, 1H), 2.31-2.21 (m, 1H), 1.83 (d, ЗН), 1, 81-1.72 (m, 1H), 1.07 (s, ЗН), 1.05 (s, ЗН), 1.03-0.91 (m, 8Н), 0.73-0.66 ( m, 1H).

N av (o) o no no /x no h

Example 586

Ingenol 3-(1-ethyl-2,4-dimethylpyrrole-3-carboxylate) (Compound 586)

Compound 586 was obtained according to Procedure e.

Starting material: Compound 686.

IN NMR (300 MHz, SOSIS) 6.34-6.33 (m, 1H), 6.05-6.02 (m, 2H), 5.58 (s, 1H), 4.60 (d, 1H ), 4.17-4.08 (m, 4H), 3.81 (sq., 2H), 3.73 (s, 1H), 2.77 (width s, 1H), 2.64-2 .59 (m, 1H), 2.48 (s, ЗН), 2.30-2.21 (m, 1Н), 2.19 (d, ЗН), 1.83 (d, ЗН), 1, 77-1.68 (m, 1H), 1.33 (t, ЗН), 1.06 (s, ЗН), 1.04 (s, ЗН), 0.98 (d,

ЗН), 0.97-0.91 (m, 1Н), 0.72-0.64 (m, 1Н).

N shi o o no no

And no

M what

Example 587

Ingenol 3-(1-allyl-2,4-dimethylpyrrole-3-carboxylate) (Compound 587)

Compound 587 was obtained according to Procedure e.

Starting material: Compound 687.

IN NMR (300 MHz, SOSIZ) 6.32 (sq., 1H), 6.05-6.03 (m, 2H), 5.94-5.81 (m, 1H), 5.60 (s, 1H), 5.23-5.18 (m, 1H), 5.03-4.96 (m, 1H), 4.62 (d, 1H), 4.39-4.36 (m, 2H) , 4.17-4.08 (m, 4H), 3.74 (s, 1H), 2.81 (width, s, 1H), 2.64-2.59 (m, 1H), 2.45 (c, ЗН), 2.31-2.22 (m, 1Н), 2.19 (d, ЗН), 1.83 (d, ЗН), 1.77-1.68 (m, 1Н), 1.07 (s, ЗН), 1.04 (s, ЗН), 0.98 (d, ЗН), 0.97-0.90 (m, 1Н), 0.72-0.64 (m, 1H). n a o) ono g no no

WITH

Example 588

Ingenol 3-(1-(cyclopropylmethyl)-2,4-dimethylpyrrole-3-carboxylate) (Compound 588)

From Compound 588 was obtained in accordance with the Procedure.

Starting material: Compound 688.

NMR NMR (300 MHz, SOSIZ) 6.42 (sq., 1H), 6.05-6.03 (m, 2H), 5.58 (s, 1H), 4.58 (d, 1H) , 4.17-4.08 (m, 4H), 3.73 (s, 1H), 3.63 (d, 2H), 2.74 (s, 1H), 2.64-2.59 (m , 1H), 2.50 (s, ЗН), 2.30-2.24 (m, 1Н), 2.20 (d, ЗН), 1.83 (d, ЗН), 1.77-1, 68 (m, 1H), 1.13-1.08 (m, 1H), 1.07 (s, ЗН), 1.04 (s, ЗН), 0.98 (d,

ЗН), 0.97-0.91 (m, 1Н), 0.72-0.59 (m, ЗН), 0.34-0.29 (m, 2Н).

N

2oX (o) o NO no

Lk no

M o) and So

Example 589

Ingenol 3-(1-(2-methoxyethyl)-2,4-dimethylpyrrole-3-carboxylate) (Compound 589)

Compound 589 was obtained according to Procedure e.

Starting material: Compound 689.

1H NMR (300 MHz, SOSIZ) 6.37 (s, 1H), 6.05-6.03 (m, 2H), 5.57 (s, 1H), 4.54 (d, 1H) , 4.16-4.08 (m, 4H), 3.94 (t, 2H), 3.71 (s, 1H), 3.58 (t, 2H), 3.33 (s, ЗН), 2.70-2.58 (m, 2H), 2.49 (s, ЗН), 2.30-2.21 (m, 1Н), 2.19 (s, ЗН), 1.83 (d, ЗН), 1.77-1.68 (m, 1Н), 1.07 (s, ЗН), 1.04 (s, ЗН), 0.98 (d, ЗН), 0.97- 0.91 (m, 1H), 0.72-0.64 (m, 1H).

N

"n ah

U oh no hmm no he

Example 701:

Ingenol 3-(M-ethylcarbamate) (Compound 701)

Compound 701 was obtained according to Procedure e.

Starting material: Compound 801. "H NMR (300 MHz, DMSO-α) b 6.98 (t, 1H), 5.86-5.83 (m, 2H), 5.37 (s, 1H), 5 .20 (width, 1H), 4.85 (s, 1H), 4.19-4.15 (m, 1H), 3.95-3.84 (m, 2H), 3.57-3 .5 (m, 2H) (coincided with water absorption), 3.05-3.00 (m, 2H), 2.5 (m, 1H) (coincided with solvent absorption), 2.31-2.23 (m , 1H), 1.71 (d, ЗН), 1.68-1.63 (m, 1Н), 1.05 (s, ЗН), 1.03 (t, ЗН), 1.03 (s, ЗН), 0.67 (d, ЗН), 0.84-0.74 (m, 1Н), 0.65-0.57 (m, 1Н). n

Hu 2 (o)

HU it that but he

Example 702:

Ingenol 3-(M,M-dimethylcarbamate) (Compound 702)

Compound 702 was obtained according to Procedure e.

Starting material: Compound 802. "H NMR (300 MHz, DMSO-α) 6 5.86-5.84 (m, 2H), 5.45 (s, 1H), 5.28 (d, 1H), 4 .94 (c, 1H), 4.65 (t,

Zo 1H), 4.20-4.15 (m, 1H), 3.97-3.84 (m, 2H), 3.57-3.55 (m, 1H), 2.84 (s, 6H ), 2.5 (m, 1H) (coincided with absorption solvent), 2.33-2.24 (m, 1H), 1.70 (d, ЗН), 1.68-1.63 (m, 1H ), 1.05 (s, ZN), 1.03 (s,

ЗН), 0.88 (d, ЗН), 0.81-0.74 (m, 1Н), 0.64-0.57 (m, 1Н).

N

U ono 7 no on o-/

Example 703:

Ingenol 3-(morpholine-4-carboxylate) (Compound 703)

Compound 703 was obtained according to Procedure e.

Starting material: Compound 803. "H NMR (300 MHz, DMSO-α) b 5.86-5.85 (m, 2H), 5.51 (s, 1H), 5.29 (d, 1H), 5 .05 (s, 1H), 4.62 (t, 1H), 4.17 (m, 1H), 3.97-3.83 (m, 2H), 3.60-3.53 (m, 5H ), 3.40-3.32 (m, 4H), 2.45-2.40 (m, 1H), 2.32-2.23 (m, 1H), 1.70 (d, ЗН), 1.68-1.63 (m, 1H), 1.05 (s, ЗН), 1.03 (z; ЗН), 0.87 (d, ЗН), 0.81-0.74 (m, 1H), 0.64-0.56 (m, 1H).

Su a

In it

With but he

Example 704:

Ingenol C3-(pyrrolidine-1-carboxylate) (Compound 704)

Compound 704 was obtained according to Procedure e.

Starting material: Compound 804. "H NMR (300 MHz, DMSO-α) b 5.86-5.83 (m, 2H), 5.45 (s, 1H), 5.24 (d, 1H), 4 .95 (s, 1H), 4.60 (t, 1H), 4.19-4.15 (m, 1H), 3.99-3.84 (m, 2H), 3.56 (d, 1H ), 3.43-3.39 (m, 1H), 3.30-3.18 (m, ЗН), 2.5 (m, 1H) (coincided with the absorption solvent), 2.32-2.24 (m, 1H), 1.84-1.76 (m, 4H), 1.72-1.65 (m, 4H), 1.05 (s, ЗН), 1.03 (s, ЗН), 0.87 (d, ZN), 0.83-0.74 (m, 1H), 0.64-0.56 (m, 1H). n "n 2 (c)

In it

Mr. Huta

Example 705:

Ingenol 3-(M-methyl-M-phenylcarbamate) (Compound 705)

Compound 705 was obtained according to Procedure e. Compound 705 was obtained as an amorphous compound.

Starting material: Compound 805. "H NMR (300 MHz, DMSO-α) b 7.37-7.30 (m, 4Н), 7.22-7.16 (m, 1Н), 5.85-5, 84 (m, 1H), 5.77 (s, 1H), 5.54 (s, 1H), 5.34 (d, 1H), 4.97 (s, 1H), 4.61 (t, 1H ), 4.16-4.11 (m, 1H), 3.97-3.82 (m, 2H), 3.57 (d, 1H), 3.24 (s, ЗН), 2.24- 2.16 (m, 1H), 2.09-1.95 (m, 1H), 1.68 (d, ЗН), 1.53-1.45 (m, 1H), 1.03 (s,

ЗН), 1.02 (s, ЗН), 0.76-0.70 (m, 1Н), 0.65 (d, ЗН), 0.58-0.50 (m, 1Н). d 2

In it

Mm but he

From Example 706:

Ingenol 3-(M,M-diethylcarbamate) (Compound 706)

Compound 706 was obtained according to Procedure e.

Starting material: Compound 806. "H NMR (300 MHz, DMSO-α) b 5.87-5.84 (m, 2H), 5.49 (s, 1H), 5.27 (d, 1H), 4 .94 (s, 1H), 4.60 (t, 1H), 4.21-4.16 (m, 1H), 3.97-3.83 (m, 2H), 3.58 (d, 1H ), 3.38-3.10 (m, 4H), 2.5 (m, 1H) (coincided with the absorption solvent), 2.34-2.25 (m, 1H), 1.70 (d, ЗН ), 1.69-1.62 (m, 1H), 1.05 (t, 6H), 1.05 (s,

ЗН), 1.03 (s, ЗН), 0.88 (d, ЗН), 0.88-0.74 (m, 1Н 0.64-0.56 (m, 1Н).) n 20

In it

Example 707:

Ingenol 3-(piperidine-1-carboxylate) (Compound 707)

Compound 707 was obtained according to Procedure no.

Starting material: Compound 807. "H NMR (300 MHz, DMSO-α) 6 5.86-5.84 (m, 2H), 5.47 (s, 1H), 5.29 (d, 1H), 4 .90 (s, 1H), 4.61 (t, 1H), 4.20-4.15 (m, 1H), 3.96-3.83 (m, 2H), 3.57 (d, 1H ), 3.38-3.27 (m, 4H), 2.48-2.42 (m, 1H), 2.33-2.24 (m, 1H), 1.70 (d, ЗН), 1.68-1.62 (m, 1H), 1.58-1.40 (m, 6H), 1.05 (s, ЗН), 1.03 (s, ЗН), 0.88 (d,

ЗН), 0.84-0.75 (m, 1Н), 0.64-0.56 (m, 1Н). n ef

U ono t no on

Example 708:

Ingenol 3-(M-benzyl-M-methylcarbamate) (Compound 708)

Compound 708 was obtained according to Procedure e.

Starting material: Compound 808. "H NMR (300 MHz, DMSO-av) b 7.31-7.24 (m, 5H), 5.86-5.82 (m, 2H), 5.53 (s, 1H), 5.34-5.28 (m, 1H), 5.03 (s, 0.4 H), 4.91 (s, 0.6 H), 4.61 (t, 1H), 4 .54-4.32 (m, 2H), 4.24-4.12 (m, 1H), 3.99-3.83 (m, 2H), 3.58 (d, 1H), 2.84 (с, ЗН), 2.37-2.18 (m, 2Н), 1.73-1.47 (m, 4Н), 1.05 (с, ЗН), 1.02 (с, ЗН), 0.90-0.70 (m, 4H), 0.61-0.53 (m, 1H).

N

"n 2

In it

That's it

Example 709:

Ingenol 3-(M-cyclohexyl-M-methylcarbamate) (Compound 709)

Compound 709 was obtained according to Procedure e.

Starting material: Compound 809.

Koo) "H NMR (300 MHz, DMSO-α) b 5.86-5.85 (m, 2H), 5.50 (s, 1H), 5.27-5.25 (m, 1H), 4 .96-4.92 (m, 1H), 4.61 (t, 1H), 4.21-4.16 (m, 1H), 3.97-3.75 (m, ЗН), 3.58 (d, 1H), 2.72 (s, ЗН), 2.5 (m, 1H) (coincided with the absorption solvent), 2.36-2.26 (m, 1H), 1.78-1.09 (m, 14Н), 1.04 (s, ZN), 1.03 (s,

ЗН), 0.88 (d, ЗН), 0.84-0.74 (m, 1Н), 0.65-0.57 (m, 1Н). n "n

Phew

In it oh ve n

Example 710:

Ingenol 3-(M-cyclohexylcarbamate) (Compound 710)

Compound 710 was obtained according to Procedure e.

Starting material: Compound 810.

NMR NMR (300 MHz, DMSO-α) b 6.90 (d, 1H), 5.85-5.81 (m, 2H), 5.35 (s, 1H), 5.16 (d, 1H), 4.84 (m, 1H), 4.58 (t, 1H), 4.20-4.15 (m, 1H), 3.97-3.81 (m, 2H), 3.50 (d, 1H), 3.25-3.20 (m, 1H), 2.5 (m, 1H) (coincided with the absorption solvent), 2.32-2.23 (m, 1H), 1.80 -1.52 (m, TON), 1.30-1.09 (m, AN), 1.06 (s, ZN), 1.04 (s, ZN), 0.87 (d, ZN), 0.81-0.74 (m, 1H), 0.65-0.57 (m, 1H). d "H

Sleep

From no

Uk no on n

Example 711:

Ingenol 3-(M-phenylcarbamate) (Compound 711)

Compound 711 was obtained according to Procedure e.

Starting material: Compound 811. "H NMR (300 MHz, DMSO-α) b 9.44 (s, 1H), 7.50 (d, 2H), 7.29 (t, 2H), 6.99 (t , 1H), 5.91-5.87 (m, 2H), 5.55 (s, 1H), 5.31 (d, 1H), 4.99 (s, 1H), 4.62 (t, 1H), 4.23-4.18 (m, 1H), 3.99-3.84 (m, 2H), 3.60 (d, 1H), 2.60-2.57 (m, 1H) , 2.36-2.27 (m, 1H), 1.76 (d, ЗН), 1.74-1.66 (m, 1Н), 1.05 (s, ЗН), 1.04 (s ,

ЗН), 0.91 (d, ЗН), 0.82-0.75 (m, 1Н), 0.67-0.59 (m, 1Н).

N

KI

(c) no he n

Example 712:

Ingenol 3-(M-(indan-1-yl)/ucarbamate) (Compound 712)

Compound 712 was obtained according to Procedure e.

Starting material: Compound 812.

NMR NMR (300 MHz, DMSO-adv) b 7.43 (d, 1H), 7.26-7.18 (m, 4H), 5.86-5.84 (m, 2H), 5, 46 (s, 1H), 5.20 (d, 1H), 5.01 (sq., 1H), 4.87 (s, 1H), 4.59 (t, 1H), 4.21-4, 15 (m, 1H), 3.99-3.83 (m, 2H), 3.54 (d, 1H), 2.98-2.89 (m, 1H), 2.84-2.73 ( m, 1H), 2.47-2.35 (m, 2H), 2.31-2.22 (m, 1H), 1.91-1.79 (m, 1H), 1.78-1, 62 (m, 4H), 1.05 (s, ЗН), 1.03 (s, ЗН), 0.86 (d, ЗН), 0.81-0.74 (m, 1Н), 0.64 -0.57 (m, 1H).

To "A BUT pov

Example 713:

Ingenol 3-(3,3-dimethylpiperidine-1-carboxylate) (Compound 713)

Compound 713 was obtained in accordance with the Procedure.

Starting material: Compound 813. "H NMR (300 MHz, SOSIS) b 6.04-6.02 (m, 1H), 5.99 (s, 1H), 5.19-5.17 (m, 1H) , 4.78-4.69 (m, 1H), 4.16-4.07 (m, ZH), 4.01 (width, 1H), 3.85-3.77 (m, 1H) , 3.49-3.05 (m, 4H), 2.66 (width, 1H), 2.51 (m, 1H), 2.29-2.22 (m, 1H), 1.78 (m, ZN), 1.70-1.55 (m, ZN), 1.42-1.31 (m, 2H), 1.10 (s, ZN), 1.04 (s, ZN), 0.99-0.82 (m, 1OH), 0.72-0.65 (m, 1H).

N va (o) no and no no

Example 714:

Ingenol 3-(M-methyl-M-tetralin-1-ylcarbamate) (Compound 714)

Compound 714 was obtained according to Procedure e.

Starting material: Compound 814.

NMR NMR (300 MHz, SOSIZ) b 7.19-7.10 (m, 4H), 6.06-5.95 (m, 2H), 5.50-5.20 (m, 2H), 4.74-4.50 (2 widths, 1H), 4.18-3.55 (m, 5H), 2.77-1.59 (m, 16H), 1.16-1.05 ( m, 6H), 0.97-0.82 (m, 4H), 0.72-0.63 (m, 1H).

N he V a (c)

U-it

M but on shcha

M

Example 715:

Ingenol 3-(M-(2-cyano-1-methylethyl)-M-methylcarbamate) (Compound 715)

Compound 715 was obtained according to Procedure e.

Starting material: Compound 815. "H NMR (300 MHz, SOSIS) b 6.05-6.01 (m, 2H), 5.26 (s, 1H), 4.84-4.38 (m, 2H) , 4.15-4.09 (m, ЗН), 4.03 (m, 1Н), 3.89-3.70 (m, 1Н), 2.91-2.83 (m, ЗН), 2 ,64-2.42 (m, ZN), 2.31-2.23 (m, 1H), 1.85-1.71 (m,

AN), 1.60 (m, 2H), 1.40-1.35 (m, 2H), 1.11-1.10 (m, ZN), 1.05 (s, ZN), 0.98 -0.98 (m, 4H), 0.73-0.65 (m, 1H). n shh; at)

In it and but it

Example 716:

Ingenol 3-(M-methyl-M-((5)-1-phenethyl)carbamate) (Compound 716)

Compound 716 was obtained according to Procedure e.

Starting material: Compound 816.

NMR NMR (300 MHz, SOSIZ) b 7.35-7.27 (m, 5H), 6.05-6.04 (m, 1H), 6.00 (s, 1H), 5.57- 5.40 (m, 1H), 5.29 (s, 1H), 4.73-4.45 (2 widths, 1H), 4.13-4.08 (m, ЗН), 4.03 (s, 1H), 3.76-3.69 (2 widths, 1H), 2.73-2.17 (m, 6H), 1.81 (d, ЗН), 1.80-1, 54 (m, 4H), 1.11 (s, ЗН), 1.05 (s, ЗН), 0.95-0.84 (m, 4Н), 0.70-0.62 (m, 1Н) e) 53

Ho no y no no

Example 717:

Ingenol 3-(M-methyl-M-(cyclopropylmethyl)carbamate) (Compound 717)

Compound 717 was obtained according to Procedure e.

Starting material: Compound 817. "H NMR (300 MHz, SOSIS) b 6.04-6.03 (d, 1H), 5.99 (s, 1H), 5.20-5.17 (m, 1H) . -3.10 (m, 2H), 3.00 (s, ZN), 2.63 (width, 1H), 2.54-2.50 (m, 1H), 2.30-2.21 (m, 1H), 1.80-1.70 (m, 4H), 1.10 (s, ЗН), 1.05 (s, ЗН), 0.99-0.88 (m, 5Н), 0.73-0.65 (m, 1H), 0.56-0.50 (m, 2H), 0.26-0.19 (m, 2H).

NN

. chn what

Oh, but

Oh no

Example 718:

Ingenol 3-(M-(3-fluorophenyl)-M-methylcarbamate) (Compound 718)

Compound 718 was obtained according to Procedure e. Compound 718 was obtained as an amorphous compound.

Starting material: Compound 818. "H NMR (300 MHz, SOSIS) b 7.36-7.28 (m, 1H), 7.09-7.02 (m, 2H), 6.99-6.93 ( m, 1H), 6.00 (d, 1H), 5.94 (s, 1H), 5.35 (s, 1H), 4.38 (width, 1H), 4.13-4.05 (m, ZN), 3.99 (d, 1H), 3.59 (s, 1H), 3.32 (s,

ЗН), 2.45 (t, 1Н), 2.19-2.12 (m, 2Н), 1.76 (d, ЗН), 1.70-1.62 (m, 1Н), 1.09 (с, ЗН), 1.05 (с, ЗН), 0.94-0.88 (m, 1Н), 0.79 (d, ЗН), 0.70-0.62 (m, 1Н). n shi / about my ud yu,

OO

5 x no

Example 719:

Ingenol 3-(M-(2,5-dimethylpyrazol-3-yl)-M-methylcarbamate) (Compound 719)

Compound 719 was obtained according to Procedure e.

Starting material: Compound 819. "H NMR (300 MHz, SOSIZ) b 6.02 (width d, 1H), 5.95 (width s, 1H), 5.88 (s, 1H), 5.40 (s, 1H), 4.20-4.04 (m, 4H), 3.96 (m, 1H), 3.62 (s, ЗН), 3.41 (width s, 1H), 3, 21 (s, ЗН), 2.51 (width s, 1Н), 2.22 (s, ЗН), 2.09-2.00 (m, 1Н), 1.80-1.60 (m, 5H), 1.07 (s, ZN), 1.05 (s, ZN), 0.92-0.86 (m, 1H), 0.77 (width, d, ZN), 0.69-0 ,64 (m, 1H).

N o (c)

Well, no

M no - o o -i

Example 720:

Zo Ingenol 3-(M-(3,5-dimethylisoxazol-4-yl)-M-methylcarbamate) (Compound 720)

Compound 720 was obtained according to Procedure e.

Starting material: Compound 820. "H NMR (300 MHz, SOSIZ) 6 6.05-6.02 (m, 2H), 5.28 (s, 1H), 4.79 (lat.s, 1H), 4 .37-4.24 (m, 2H), 4.14-4.10 (m, ZH), 4.04 (width, 1H), 3.83 (width, 1H), 2.80 (s, AN), 2.49 (width s, 1H), 2.38 (s, ZN),

2.31-2.22 (m, 4H), 1.83-1.69 (m, 4H), 1.09 (s, ЗН), 1.05 (s, ЗН), 0.97-0, 90 (m, 4H), 0.72-0.65 (m, 1H).

N

2 (o) x ben M o po dya lu HM no

Example 721:

Ingenol 3-(M-(1,5-dimethylpyrazol-3-yl)-M-methylcarbamate) (Compound 721)

Compound 721 was obtained according to Procedure no.

Starting material: Compound 821.

IN NMR (300 MHz, SOSIZ) b 6.20-5.87 (m, 4H), 5.53 (s, 1H), 4.17-4.11 (m, ЗН), 3.89 (d, 1H), 3.69 (s, Ш), 3.50 (width s, 1H), 3.28 (s, Ш), 2.51 (width s, 1H), 2.30-2.21 (m, 5H), 1.85 (d, ЗН), 1.72-1.63 (m, 1Н), 1.13 (s, ЗН), 1.06 (s, ЗН), 1.00- 0.93 (m, 1H), 0.85 (d, ЗН), 0.72-0.65 (m, 1H).

N

SH

(o) y-9 no

IF

Ot

Example 722:

Ingenol 3-(M-cyclopentyl-M-methylcarbamate) (Compound 722)

Compound 722 was obtained according to Procedure no.

Starting material: Compound 822.

I"H NMR (300 MHz, SOSIZ) b 6.05-6.03 (m, 1H), 5.99-5.98 (width s, 1H), 5.16 (2хs, 1H), 4, 70 (width, 1H), 4.17-4.02 (m, 4H), 3.77 (s, 1H), 3.32-3.27 (m, 1H), 2.81 (s, ЗН), 2.53-2.50 (m, 2Н), 2.29-2.19 (m, 1Н), 1.85-1.70 (m, 8Н), 1.33-1.13 ( m, 4H), 1.11 (s, ЗН), 1.05 (s, ЗН), 0.97-0.88 (m, 4Н), 0.73-0.65 (m, 1Н).

N u (o) u-9 no

M no ra x no

Example 723:

Ingenol 3-(M-cyclopropyl-M-methylcarbamate) (Compound 723)

Compound 723 was obtained according to Procedure e.

Starting material: Compound 823. "H NMR (300 MHz, SOSIS) b 6.05-6.03 (m, 1H), 6.00-5.98 (m, 1H), 5.15 (s, 1H) . (c, 1H), 2.60-2.50 (m, 2H), 2.29-2.20 (m, 1H), 1.81 (d, ЗН), 1.80-1.71 (m , 1Н), 1.11 (с, ЗН), 1.05 (с, ЗН), 0.97-0.90 (m, 4Н), 0.77-0.65 (m, 5Н).

N a

I don't know

M no x and no

Example 724:

Ingenol 3-(M-methyl-M-(2-pyridyl)carbamate) (Compound 724)

Compound 724 was obtained according to Procedure e.

Starting material: Compound 824. "H NMR (300 MHz, SOSIS) b 8.36-8.34 (m, 1H), 7.81-7.75 (m, 1H), 7.29 (d, 1H) , 7.15-7.11 (m, 1H), 6.34 (width, 1H), 6.04-6.02 (m, 1H), 5.98-5.96 (m, 1H) , 5.77 (s, 1H), 4.19-4.13 (m, ЗН), 3.90 (d, 1Н), 3.61 (d, 1Н), 3.44 (s, ЗН), 2.49 (t, 1H), 2.34-2.25 (m, 1H), 2.09-2.04 (m, 1H), 1.81 (d, ЗН), 1.72-1, 64 (m, 1H), 1.18 (s, ЗН), 1.08 (s, ЗН), 0.99-0.93 (m, 1Н), 0.78 (d, ЗН), 0.72 -0.64 (m, 1H).

N

: . he about

WITH

M o noia F.

Gee)

Example 725:

Ingenol 3-(4-oxo-2,3-dihydroquinoline-1-carboxylate) (Compound 725)

Compound 725 was obtained according to Procedure e.

Starting material: Compound 825. "H NMR (300 MHz, SOSIZ) b 8.02-7.99 (m, 1H), 7.81 (d, 1H), 7.53-7.48 (m, 1H) , 7.24-7.19 (m, 1H), 6.06 (d, 1H), 6.00 (d, 1H), 5.53 (s, 1H), 4.89 (d, 1H), 4.36-4.27 (m, 1H), 4.18-4.05 (m, 5H), 3.83 (s, 1H), 2.85-2.75 (m, ЗН), 2, 40-2.35 (m, 1H), 2.30-2.20 (m, 1H), 1.84 (d, ЗН), 1.72-1.63 (m, 1H), 1.06 ( with,

ЗН), 1.04 (с, ЗН), 0.93-0.86 (m, 4Н), 0.71-0.63 (m, 1Н). nn and (o) y-9 no

F M no

Yu

Example 726:

Ingenol 3-(3,4-dihydro-2H-quinoline-1-carboxylate) (Compound 726)

Compound 726 was obtained according to Procedure e.

Starting material: Compound 826. "H NMR (300 MHz, SOSIZ) b 7.68 (width, 1H), 7.17-7.00 (m, ZN), 6.03-6.01 (m, 1H), 5.98 (d, 1H), 5.43 (s, 1H), 4.64 (width s, 1H), 4.14-4.09 (m, ЗН), 4.03 (d , 1H), 3.84-3.72 (m, ЗН), 2.80 (t, 2H), 2.67 (width s, 1H), 2.43 (width s, 1H), 2, 25-2.19 (m, 1H), 2.02-1.93 (m, 2H), 1.83 (d, ЗН), 1.74-1.65 (m, 1H), 1.08 ( s, ЗН), 1.04 (s, ЗН), 0.93-0.86 (m, 4Н), 0.71-0.63 (m, 1Н). and at 5-9 no

M ()

With no

Example 727:

Ingenol 3-(indoline-1-carboxylate) (Compound 727)

From Compound 727 was obtained in accordance with the Procedure.

Starting material: Compound 827. "IN NMR (300 MHz, SOSIZ) b 7.87 (width, 1H), 7.18 (d, 2H), 6.99 (t, 1H), 6.06-6 .05 (m, 2H), 5.41 (s, 1H), 4.62 (s, 1H), 4.17-4.02 (m, 6H), 3.80 (s, 1H), 3, 17 (t, 2H), 2.57 (width s, 1H), 2.43 (width s, 1H), 2.31-2.23 (m, 1H), 1.85 (s, ЗН) , 1.78-1.73 (m, 1H), 1.08 (s, ЗН), 1.04 (s, ЗН), 0.99 (d, ЗН), 0.95-0.90 (m , 1H), 0.73-0.65 (m, 1H).

d

Su (e) 3-9 no

M no

OO

Example 728:

Ingenol 3-(azepane-1-carboxylate) (Compound 728)

Compound 728 was obtained according to Procedure e.

Starting material: Compound 828. "H NMR (300 MHz, SOSIZ) 6 6.04-6.02 (m, 1H), 5.98 (m, 1H), 5.20-5.19 (m, 1H ), 5.87-5.85 (m, 1H), 4.13-4.08 (m, ZH), 4.03-4.01 (m, 1H), 3.84-3.81 (m , 1H), 3.47-3.26 (m, 4H), 2.80-2.76 (m, 1H), 2.55-2.50 (m, 1H), 2.30-2.22 (m, 1H), 1.80 (d, ЗН), 1.75-1.56 (m, 9Н), 1.11 (s, ЗН), 1.04 (s, ЗН), 0.94 ( d,

ЗН), 0.91-0.86 (m, 1Н), 0.72-0.65 (m, 1Н). i 2 o

U-9 but no

Example 729:

Ingenol 3-(M-(4-chlorophenyl)-M-methylcarbamate) (Compound 729)

Compound 729 was obtained according to Procedure e.

Starting material: Compound 829.

NMR NMR (300 MHz, SOSIZ) b 7.35-7.30 (m, 2H), 7.23-7.20 (m, 2H), 6.00 (d, 1H), 5.93 ( width s, 1H), 5.34 (s, 1H), 4.48 (width s, 1H), 4.13-4.05 (m, ЗН), 3.98 (s, 1H), 3 ... 1.70-1.64 (m, 2H), 1.09 (s, ЗН), 1.05 (s, ЗН), 0.94-0.86 (m, 4Н), 0.70-0, 62 (m, 1H).

No

With o no -chsh x no

Example 730:

Ingenol 3-(M-(4-fluorophenyl)-M-methylcarbamate) (Compound 730)

Compound 730 was obtained according to Procedure e.

Starting material: Compound 830.

NMR NMR (300 MHz, SOSIZ) b 7.28-7.01 (m, 4H), 6.00-5.98 (m, 1H), 5.91 (lat, 1H), 5, 34 (s, 1H), 4.48 (width s, 1H), 4.11-4.04 (m, ЗН), 3.97 (d, 1H), 3.59 (width s, 1H) . ), 1.09 (s, ЗН), 1.05 (s, ЗН), 0.94-0.87 (m, 1Н), 0.73 (width s, ЗН), 0.69-0, 61 (m, 1H).

No matter what

Wed x Mon (in) /

Example 731:

Ingenol 3-(M-methyl-M-(2-methoxyphenyl)carbamate) (Compound 731)

Compound 731 was obtained according to Procedure e.

Starting material: Compound 831. "H NMR (300 MHz, SOSIS) b 7.32-7.28 (m, 1H), 7.19 (d, 1H), 7.02-6.98 (m, 2H) , 5.99 (d, 1H), 5.82 (d, 1H), 5.68 (width, s, 1H), 4.24 (s, 1H), 4.12 (s, 2H), 3, 98 (d, 1H), 3.88-3.80 (m, 4H), 3.30-3.24 (m,

AN), 2.40 (width, 1H), 1.95-1.91 (m, 1H), 1.72 (d, ZH), 1.55-1.48 (m, 2H), 1 .10 (s, ЗН), 1.04 (s, ЗН), 0.95-0.87 (m, 1Н), 0.64-0.55 (m, 4Н). . what - oh but

M more

M no

Example 732:

Ingenol 3-(M-methyl-M-(2-methylphenyl)carbamate) (Compound 732)

Compound 732 was obtained according to Procedure e.

Starting material: Compound 832.

NMR NMR (300 MHz, SOSIZ) b 7.23-7.16 (m, 4H), 6.04-5.80 (m, 2H), 5.41 (s, 1H), 4.11- 3.90 (m, 4H), 3.24-3.16 (m, 4H), 2.29-2.19 (m, 4H), 1.77 (s, ЗН), 1.72-1, 45 (m, 4H), 1.06-1.02 (m, 6H), 0.92-0.83 (m, 1H), 0.64-0.56 (m, 4H).

N

. chen 2 (in) no ( Zh ra

M c) but c)

Example 733:

Ingenol 3-(3-oxo-2,4-dihydroquinoxaline-1-carboxylate) (Compound 733)

Compound 733 was obtained according to Procedure e.

Starting material: Compound 833. "H NMR (300 MHz, SOSIZ) b 8.72 (width s, 1H), 7.68 (width d, 1H), 7.16-7.10 (m, 1H) , 7.06-7.03 (m, 1H), 6.90 (dd, 1H), 6.04-6.02 (m, 2H), 5.57 (s, 1H), 4.72 (d , 1H), 4.49 (d, 1H), 4.39 (d, 1H), 4.20-4.11 (m, ЗН), 4.02-4.00 (m, 2H), 2, 77 (width, 1H), 2.31-2.17 (m, 2H), 1.82 (d, ЗН), 1.68-1.60 (m, 1H), 1.06 (s, ЗН), 1.04 (с, ЗН), 0.93-0.84 (m, 4Н), 0.70-0.62 (m, 1Н).

N

(c) --9 no no dyny

Example 734:

Ingenol 3-(M-ethyl-M-phenylcarbamate) (Compound 734)

Compound 734 was obtained according to Procedure e.

Starting material: Compound 834. "H NMR (300 MHz, SOSIZ) b 7.40-7.20 (m, 5H), 5.99-5.97 (d, 1H), 5.88 (width, 1H), 5.34 (s, 1H), 4.09-3.93 (m, 5H), 3.76-3.66 (dq., 2H), 3.44 (width s, 1H), 2.64 (width s, 1H), 2.01 (width s, 1H), 1.80-1.53 (m, 5H), 1.18 (t, ZN), 1.08 (s, ЗН), 1.04 (с, ЗН), 0.95-0.89 (m, 1Н), 0.72-0.58 (m, 4Н).

N a

U- no

E F)

Oh well

Example 735:

Ingenol 3-(2-trifluoromethylpyrrolidine-1-carboxylate) (Compound 735)

Compound 735 was obtained according to Procedure e.

Starting material: Compound 835. "IN NMR (300 MHz, SOSIZ) b 6.04-6.00 (m, 2H), 5.31 (s, 1H), 4.84 (width s, 1H), 4 ,49-4,40 (width d, 1H), 4,16-4,02 (m, 4H), 3,83-3,47 (m, ZH), 2,90 (width s, 1H) , 2.49 (width, 1H), 2.31-2.22 (m, 1H), 2.13-1.91 (m, 4H), 1.80-1.70 (m, 4H) , 1.10-1.09 (2хs, ЗН), 1.05 (с, ЗН), 0.97-0.89 (m, 4Н), 0.73-0.65 (m, 1Н).

N

. en 205 iv) NO

An

M no

Example 736:

Ingenol 3-(3-azabicyclo|3.2.2|nonane-33-carboxylate) (Compound 736)

Compound 736 was obtained according to Procedure e.

Starting material: Compound 836. "H NMR (300 MHz, SOSIS) b 6.04-6.03 (m, 1H), 5.99-5.98 (m, 1H), 5.18 (s, 1H) . 65 (m, 2H), 3.59-3.50 (m, 2H), 2.60 (width, 1H), 2.55-2.50 (m, 1H), 2.29-2, 21 (m, 1H), 2.06-2.01 (width, d, 2H), 1.80 (d, ZH), 1.78-1.62 (m, 9H), 1.11 (s,

ЗН), 1.04 (с, ЗН), 0.99-0.90 (m, 4Н), 0.72-0.65 (m, 1Н).

N i an 20, o" Ne "To no a 0

Example 737:

Ingenol 3-(2,3-dihydro-1,4-benzoxazine-4-carboxylate) (Compound 737)

Compound 737 was obtained according to Procedure e.

Starting material: Compound 837.

IN NMR (300 MHz, SOSIZ) b 7.81 (lat, 1H), 7.05-6.99 (m, 1H), 6.91-6.84 (m, 2H), 6.06- 6.05 (m, 1H), 5.98-5.96 (m, 1H), 5.49 (s, 1H), 4.77 (s, 1H), 4.29 (t, 2H), 4 ,17-4.11 (m, ZN), 4.05-3.86 (m,

ЗН), 3.75 (s, 1H), 2.71 (s, 1H), 2.45-2.40 (m, 1H), 2.29-2.20 (m, 1H), 1.83 (d, ЗН), 1.73-1.64 (m, 1Н), 1.06 (s, ЗН), 1.05 (с, ЗН), 0.94-0.86 (m, 4Н), 0.71-0.63 (m, 1H).

Нн 0 5-6 no no

Wed

IS

Example 738:

Ingenol 3-(M-(2-fluorophenyl)-M-methylcarbamate) (Compound 738)

Compound 738 was obtained according to Procedure e.

Starting material: Compound 838. "H NMR (300 MHz, SOSIS) b 7.31-7.24 (m, 2H), 7.17-7.08 (m, 2H), 6.00-5.98 ( m, 1H), 5.85 (s, 1H), 5.44 (s, 1H), 4.18-3.92 (m, 6H), 3.53 (s, 1H), 3.28 (s , ЗН), 2.68 (s, 1Н), 2.08-2.00 (m, 1Н), 1.80 (d, ЗН), 1.8-1.7 (m, 1Н), 1, 08 (s, ЗН), 1.04 (s, ЗН), 0.93-0.89 (m, 1Н), 0.68-0.60 (m, 4Н).

N

IN

(c) Yana

BUT

Su (c)

Example 739:

Ingenol 3-(3-methyl-2,3-dihydro-1,4-benzoxazine-4-carboxylate) (Compound 739)

Compound 739 was obtained according to Procedure no.

Starting material: Compound 839. "H NMR (300 MHz, SOSIS) b 7.98-7.95 (d, 1H), 7.05-6.98 (m, 1H), 6.91-6.85 (m, 2H), 6.08-5.96 (m, 2H), 5.48 (s, 1H), 4.88 (s, 1H), 4.73-4.68 (m, 1H), 4.20-4.04 (m, 6H), 3.83 (s, 1H), 2.75 (s, 1H), 2.54-2.48 (m, 1H), 2.38-2, 29 (m, 1H), 1.81 (d, ЗН), 1.79-1.72 (m, 1H), 1.25 (d, ЗН), 1.09 (s, ЗН), 1.06 (with,

ЗН), 0.97 (d, ЗН), 0.91-0.86 (m, 1Н), 0.74-0.64 (m, 1Н).

Nn u

University of

Oh no

And but with no

Example 740:

Ingenol 3-(2-trifluoromethylpyrrolidine-1-carboxylate) (ISOMER A) (Compound 740)

Compound 740 was prepared according to Procedure e. Compound 740 was the first isomer,

From what is subject to collection, as a result of chromatographic purification.

Starting material: Compound 835.

NMR NMR (300 MHz, SOSIZ) b 6.06-6.02 (m, 2H), 5.26 (s, 1H), 4.51 (s, 1H), 4.39 (s, 1H) , 4.14-3.97

(m, 4H), 3.86-3.51 (m, ZN), 2.50-2.02 (m, 7H), 1.81 (s, ZN), 1.80-1.71 (m , 1H), 1.10 (s, ЗН), 1.05 (s,

ЗН), 0.96 (d, ЗН), 0.95-0.90 (m, 1Н), 0.73-0.66 (m, 1Н).

N u

U- no

Oh oh but

E and 6)

Example 741:

Ingenol 3-(2-trifluoromethylpyrrolidine-1-carboxylate) (ISOMER B) (Compound 741)

Compound 741 was obtained according to Procedure e. Compound 741 was the second isomer to be collected as a result of chromatographic purification.

Starting material: Compound 835. "H NMR (300 MHz, SOSIS) b 6.06-6.00 (m, 2H), 5.25 (s, 1H), 4.59-4.43 (m, 2H) , 4.14-4.03 (m, 4H), 10. 3.72-3.52 (m, ЗН), 2.50-2.02 (m, 7H), 1.81-1.72 ( m, 4H), 1.11 (s, ЗН), 1.05 (s, ЗН), 0.99-0.93 (m, 4Н), 0.71-0.66 (m, 1Н). n . ENTS GIRL

A. I am here

Example 742:

Ingenol 3-(M-methyl-M-(M-(tert-butyloxycarbonyl)-4-piperidyl)carbamate) (Compound 742)

Compound 742 was obtained according to Procedure no.

Starting material: Compound 842.

NMR NMR (300 MHz, SOSIZ) b 6.05-6.03 (m, 1H), 6.00 (width, 1H), 5.26-5.22 (m, 1H), 4, 75-4.68 (m, 1H), 4.20-4.02 (m, 7H), 3.74 (s, 1H), 2.80-2.51 (m, 7H), 2.29- 2.20 (m, 1H), 1.80 (d, ЗН), 1.78-1.62 (m, 5Н), 1.47 (s, 9Н), 1.10 (s, ЗН), 1 .05 (c, ЗН), 0.99-0.93 (m, 4Н), 0.73-0.65 (m, 1Н).

N

Co. en

SY vi De m' ho o no

Example 743:

Ingenol 3-(M-methyl-M-(3-methylphenyl)carbamate) (Compound 743)

Compound 743 was obtained according to Procedure e.

Starting material: Compound 843. "H NMR (300 MHz, SOSIZ) b 7.27-7.22 (m, 1), 7.09-7.04 (m, ЗН), 5.98-5.97 ( m, 1H), 5.91 (width s, 1H), 5.33 (s, 1H), 4.11-3.94 (m, 5H), 3.48 (width s, 1H), 3 ... 65-1.56 (m, 2H), 1.08 (s, ЗН), 1.04 (s, ЗН), 0.93-0.75 (m,

AN), 0.67-0.59 (m, 1H).

n i o) with-yu

M no / y

N

Example 744:

Ingenol 3-(3,4-dihydro-2H-quinoxaline-1-carboxylate) (Compound 744)

Compound 744 was obtained according to Procedure e.

Starting material: Compound 844.

NMR NMR (300 MHz, SOSIZ) b 7.87 (lat, 1H), 7.67 (lat, 1H), 7.23-7.11 (m, 2H), 6.07- 6.05 (m, 2H), 5.50 (s, 1H), 4.64 (d, 1H), 4.19-3.96 (m, 9H), 3.78 (s, 1H), 2 ,39-2.22 (m, ZN), 1.84 (d, ZN), 1.75-1.67 (m, 1H), 1.09 (s, ZN), 1.05 (s, ZN ), 0.96-0.85 (m, 4H), 0.72-0.64 (m, 1H).

NU y (in o but but still)

Example 745:

Ingenol 3-(isoindoline-2-carboxylate) (Compound 745)

Compound 745 was obtained according to Procedure e.

Starting material: Compound 845.

NMR NMR (300 MHz, SOSIZ) b 7.31-7.25 (m, 4H), 6.05-6.03 (m, 2H), 5.36 (s, 1H), 4.89 ( width s, 1H), 4.75 (s, 4H), 4.17-4.04 (m, 5H), 3.94 (s, 1H), 2.61-2.56 (m, 1H) , 2.33-2.24 (m, 1H), 1.83 (d, ЗН), 1.81-1.71 (m, 1Н), 1.08 (s, ЗН), 1.02 (s , ЗН), 1.00 (d, ЗН), 0.98-0.90 (m, 1Н), 0.73-0.65 (m, 1Н). and

KI and "n

And to no

SI yu (o)

Example 746:

Ingenol 3-(M-methyl-M-(tetrahydropyran-4-ylmethyl)carbamate) (Compound 746)

Compound 746 was obtained according to Procedure no.

Starting material: Compound 846.

NMR NMR (300 MHz, SOSIZ) b 6.05-6.01 (m, 2H), 5.20 (d, 1H), 4.74 (s, 1H), 4.11-3.95 ( m, 6H), 3.78 (d, 1H), 3.41-3.31 (m, 2H), 3.23-3.11 (m, 2H), 2.96 (s, ЗН), 2 .67 (width, 1H), 2.53-2.51 (m, 1H), 2.29-2.19 (m, 1H), 1.94-1.86 (m, 1H), 1 ,80-1.70 (m, 4H), 1.59-1.54 (m, 2H), 1.40-1.27 (m, 2H), 1.09 (s, ЗН), 1.05 (c, ЗН), 0.98-0.88 (m, 4Н), 0.73-0.65 (m, 1Н).

N and

Ar no

Example 747:

Ingenol 3-(M-methyl-M-(tetrahydropyran-4-yl)ucarbamate) (Compound 747)

Compound 747 was obtained according to Procedure e.

Starting material: Compound 847. "H NMR (300 MHz, SOSIZ) b 6.05-6.03 (m, 1H), 6.00 (lat.s, 1H), 5.23 (lat.s, 1H) , 4.73 (width s, 1H), 4.25 (width s, 1H), 4.13-4.01 (m, 6H), 3.75 (s, 1H), 3.50-3 .39 (m, 2H), 2.83 (s, ЗН), 2.68 (width s, 1H), 2.52 (width s, 1H), 2.29-2.20 (m, 1H ), 1.82-1.65 (m, 8H), 1.10 (s, ЗН), 1.05 (s, ЗН), 0.99- 0.92 (m, 4Н), 0.73- 0.65 (m, 1H). and that ped 20, (c) no be o no

Example 748:

Ingenol 3-(M-methyl-M-(3-methoxyphenyl)carbamate) (Compound 748)

Compound 748 was obtained according to Procedure e.

Starting material: Compound 848. "H NMR (300 MHz, SOSIZ) b 7.29-7.24 (m, 1H), 6.86-6.80 (m, ЗН), 5.98-5.96 ( m, 1H), 5.92 (width s, 1H), 5.36 (s, 1H), 4.16-3.93 (m, 5H), 3.80 (s, ЗН), 3.52 (width s, 1H), 3.31 (s, ZN), 2.63 (width s, 1H), 2.05 (width s, 2H), 1.80-1.57 (m, 4H ), 1.08 (s, ZN), 1.04 (s, ZN), 0.95-0.89 (m, 1H), 0.75 (width s, ZN), 0.67-0, 59 (m, 1H). d ka . "n

In o tsa koi no

Example 749:

Ingenol 3-(M-cyclobutyl-M-methylcarbamate) (Compound 749)

Compound 749 was obtained according to Procedure e.

Starting material: Compound 849. "H NMR (300 MHz, SOSIS) b 6.04-6.03 (d, 1H), 5.99-5.98 (m, 1H), 5.18 (s, 1H) , 4.81-4.73 (m, 1H), 4.60-4.35 (width, s, 1H), 4.12-4.00 (m, 4H), 3.79 (s, 1H) . -2.09 (m, 4H), 1.79 (d, ZN), 1.78-1.62 (m, ZN), 1.10 (s, ZN), 1.04 (s, ZN), 0.99-0.92 (m, 4H), 0.72-0.65 (m, 1H).

p c) no s no no

Example 750:

Ingenol 3-(M-allyl-M-methylcarbamate) (Compound 750)

Compound 750 was obtained according to Procedure e.

Starting material: Compound 850.

NMR NMR (300 MHz, SOSIZ) b 6.05-6.03 (m, 1H), 6.00-5.98 (m, 1H), 5.83-5.73 (m, 1H), 5.25-5.14 (m, ZN), 4.46 (width, 1H), 4.12-3.76 (m, 7H), 2.94 (s, ZN), 2.56- 2.50 (m, 2H), 2.28-2.21 (m, 1H), 1.80 (d, ЗН), 1.78-1.70 (m, 1H), 1.10 (s, ЗН), 1.05 (с, ЗН), 0.97-0.88 (m, 4Н), 0.73-0.65 (m, 1Н).

N

20 to no sia; but

Example 751:

Ingenol 3-(M-methyl-M-prop-2-ynylcarbamate) (Compound 751)

Compound 751 was obtained according to Procedure e.

Starting material: Compound 851. "IN NMR (300 MHz, SOSIZ) b 6.05-6.02 (m, 2H), 5.38 (width s, 1H), 4.21-4.01 (m, 7H), 3.80 (width s, 1H), 3.02 (s, ЗН), 2.51 (width s, 2H), 2.30-2.21 (m, 2H), 1.81 (d, ZN), 1.78-1.71 (m, 1Н), 1.10 (s, ZN), 1.05 (s, ZN), 0.99-0.90 (m, 4Н), 0.73-0.65 (m, 1H).

N ze. "NN with ve o no

And but

Example 752:

Ingenol 3-(M-methyl-M-(4-methylthiazol-2-yl)ucarbamate) (Compound 752)

Compound 752 was obtained according to Procedure no.

Starting material: Compound 852. "H NMR (300 MHz, SOSIS) b 6.53-6.52 (m, 1H), 6.11-6.10 (m, 1H), 6.07-6.05 ( m, 1H), 5.52 (s, 1H), 4.41 (width s, 1H), 4.19-4.05 (m, 5H), 3.61 (s, ЗН), 2.56 -2.51 (m, 1H), 2.35 (d, ZN), 2.34-2.25 (m, 2H), 1.85 (d, ZN), 1.83-1.71 (m , 1H), 1.08 (s, ЗН), 1.05 (s, ЗН), 0.98 (d, ЗН), 0.96-0.90 (m, 1Н), 0.74-0, 66 (m, 1H). y shi ah ry no

M in

Example 753:

Ingenol 3-(M-(4-cyanophenyl)-M-methylcarbamate) (Compound 753)

Compound 753 was obtained according to Procedure e.

Starting material: Compound 853.

NMR NMR (300 MHz, SOSIZ) b 7.66-7.62 (m, 2H), 7.49-7.44 (m, 2H), 6.02-6.00 (m, 1H), 5.99-5.97 (m, 1H), 5.41 (s, 1H), 4.76 (d, 1H), 4.15-4.09 (m, ЗН), 4.03-4, 01 (m, 1H), 3.75 (s, 1H), 3.37 (s, ЗН), 2.13 (t, 1H), 2.28-2.19 (m, 2H), 1.77 (d, ЗН), 1.71-1.62 (m, 1Н), 1.09 (s, ЗН), 1.06 (с, ЗН), 0.95-0.82 (m, 4Н), 0.72-0.64 (m, 1H).

Example 1

Oxidative release of neutrophils:

PMM (polymorphonuclear leukocytes) were isolated and purified from fresh leukocyte films by successive sedimentation, centrifugation in a density gradient and lysis of contaminating erythrocytes. Leukocyte films were incubated with 295 metocel for 30-45 min. for differential sedimentation of erythrocytes. The leukocyte-enriched supernatant was transferred to Gutrporger centrifuge tubes to remove mononuclear cells by density gradient centrifugation (400 x d, 30 min.). The cell pellet after centrifugation was resuspended and the remaining erythrocytes were lysed using 0.2 95 Mass for 30 sec. before restoring isotonicity by adding 1.2 96 mass. This stage was repeated until the cell sediment after centrifugation was relatively free of erythrocytes. Cells were resuspended in ORVZ (Dulbecco's phosphate-buffered saline) (without Sag,

Modg), and the concentration was adjusted to 1.4x105 cells/"ml in HB55 (Hanks' balanced salt solution) (with Ca?2", Mdg") containing 0.1 95 BZA (bovine serum albumin) and 5 mM glucose directly before starting the assay. Titrated reference and test compounds were premixed with HE (hydroethidine) (10 μM final analytical concentration) before addition to 96-well plates containing 2.5 x 10" cells. After 40 min incubation at room temperature , evaluated changes in respiratory burst by measuring fluorescence at 579 nm (excitation: 485 nm) using an Epmi5op tablet reader.

The titration curves of the test compound were fitted to a four-parameter sigmoidal curve after normalizing the effect of the test compound to the effect of the positive control (5x107 M РЕРООО5). Not! ECo means the concentration of the test compound that

Zo produces an effect that is midway between the upper and lower points of the fitted curve. Ar5 ECvo means the concentration of the test compound that causes a reaction corresponding to 5095 of the maximum effect associated with the positive control (5x10-7 M

REROOOB).

Example 2

Cytokine release from NekKa cells (1I--8)

Primary human epidermal keratinocytes, NekKa cells, were seeded (10,000 cells/well) in 9b-well plates the day before analysis. The tested compounds were diluted in HOM5O (dimethyl sulfoxide) and further diluted in the analytical medium and pipetted into the wells of 96b-well tablets containing NeKa cells. Tablets were incubated for two hours. at 37 °C in humidified air with 595 °C. Plates were briefly centrifuged to pellet the cells at 4 °C, the supernatant was removed, and cytokines were analyzed in 4-spot Mezho Zsaie Rissomegu (M50)) using an ultrasensitive kit (RgoipPattaitssogu II

Oiga Zepozyme KY, M5O, MO, O5BA). The MBO assay uses a sandwich immunoassay format, where fascinating antibodies are coated according to the simulated sample to the bottom of the wells of the 4-5roi-Miypii-M5O plate. Standard samples were also incubated in MIA TI-5ROT plates, and the cytokine (I-8) was bound to a spot of its corresponding capture antibody. The level of the cytokine was quantitatively determined on the imaging device ZESTOK'"M |C|tadeg using a specific detecting antibody to the cytokine, labeled with the reagent M5O Z! RO-TASITtTM.

The titration curves of the tested compounds were fitted to a four-parameter sigmoidal curve after normalizing the effect of the tested compound to the effect of the positive control (1.5x107 M РЕРОО0ОО5). Wow! ECo means the concentration of the test compound that produces an effect that is midway between the upper and lower points of the fitted curve. Abe

ESvo means the concentration of the compound under test that causes a reaction corresponding to 50 95 of the maximum effect associated with the positive control (1.5x10-7 M РЕРООО5).

Example C

Analysis of necrosis

Neba cells (АТСС ССИ-002) were grown in minimal essential medium (Catalog Mo 42360 Ipmigodep) containing 1095 fetal calf serum, 100 IU/ml penicillin and 100 pg/ml streptomycin. 4,000-6,000 cells were seeded into 96-well black Miem/Riagez plates with a transparent bottom (RegkKip EIteg) in 100 μl medium and incubated overnight.

The compounds were dissolved and prediluted in OM5O in 96-well polypropylene tablets (Ogeipeg) in the concentration range from 15 µM to 600 µM. During the experiment, cell plates were placed on heating blocks at 37 "C, the medium was removed and 40 μl of fresh, pre-warmed medium was added to the wells. The cells were incubated for 15 min. before the addition of compounds. In parallel, 1 μl of the compounds was diluted to 197 μl of growth medium on the set for pipetting Tesap eedot-EMO, using a pipetting speed of 250 μl/sec., to ensure efficient mixing of highly concentrated solutions of compounds with the aqueous phase. These plates, after pre-dilution, were then equilibrated on heating blocks at 37 °C for 10 min. 80 μl of the pre-diluted compound was manually transferred to the appropriate well containing NeHa cells, obtaining compound concentrations from 10

MKM up to 400 µM. The control conditions were 195 OM5O in the growth medium (viability 100 95) and 400 μM ingenol mebutate in the growth medium (viability

About 95). Tablets were incubated on heating blocks at 37 "C for 30 min. At the end of incubation, 10 μl of RgevioVice reagent (Ipmygodep) was added to each well, the tablets were hermetically sealed with a black sealing gasket, followed by incubation at 37 "C for 10 min. with gentle shaking (150 rpm). Then the tablets were kept at room temperature for 20-30 minutes. Tablets were immediately read on the reading device

Epmysiop RiIpogezsepse (RegkKkip EIteg) with excitation at 535 nm and emission at 630 nm. The titration curves of the tested compounds were fitted to a four-parameter sigmoidal curve after normalizing the effect of the tested compound to the effect of the positive control (4x107 M

REPOOO5/ingenol mebutate). AbzESvzo means the concentration of the test compound that produces an effect.

The compounds of the present invention were tested in the neutrophil oxidizable release assay as described in Example 1, in the cytokine release assay by NekKa cells as described in Example 2, and in the necrosis assay as described in Example 3.

The compounds according to the present invention reveal values of Kei ESzo below 10,000 nM in the analysis of the oxidizable release of neutrophils and values of Ke! ES5o below 10,000 nM in the analysis of cytokine release by NekKa cells.

Ranges of Ke! ESvo of the oxidized release of neutrophils x indicates that the values of Kei ESvo are 2 100 nm "x indicates that the values of Kei ESzo are 2 20 nm and "100 nm "ex indicates that the values of Kei! ESvo are "20 nMM

Ranges of Kei ESvo values of cytokine release (II -8) by NeKa cells x indicates that Kei ESvo values are 2 100 nm "x indicates that Kei ESvo values are 2 20 nm and "100 nm "ex indicates that Kei values! ESvo are "20 nm

Ranges of values of ESvho of necrosis of NeHa cells x indicates that values of ESvo are 2,350 μm "x indicates that values of ESvo are 2,150 μM and "350 μm "ex indicates that values of ESvo are "150 μM

The results are shown in the table below.

Range of values.

The range of values of Nei Vei ESvo Range

The name and number of the oxidizing EC compound release of ESvo values

In the evening cell necrosis of neutrophils releasing cytokine (II-8) H - ega cells NeKa

Ingenol 3-(5-methyl-3-(2-chloro-6-fluorophenyl)isoxazole-4-carboxylate) (Compound 501) 4-carboxylate) (Compound 502) 503

EssNU xx hay SN SALIVA PISHE carboxylate) (Compound 504) carboxylate) (Compound 505) carboxylate) (Compound 506)

Range of values Range

The range of values of Nei Vei ESvo values of ES

The name and number of the oxidizing EC compound release of 275o and schi - cell necrosis of neutrophil release of cytokine (II -8) by NeKa cells 4-carboxylate) (Compound 507) 4-carboxylate) (Compound 508)

carboxylate) (Compound 509) carboxylate) (Compound 510

EN cheap BLUE NNYA BLUE carboxylate) (Compound 511)

EE foam NNYA NNYA SYA (Compound 512)

(Compound 513) (Compound 514) ooo 01010 carboxylate) (Compound 515) carboxylate) (Compound 516) carboxylate) (Compound 517)

Ingenol 3-(3-isopropyl-5-methylisoxazole-4-carboxylate) (Compound 518)

Ingenol 3-(3-(2-methoxyphenyl)-5-methylisoxazole-4-carboxylate) yes yes yes

Compound 519 0110 carboxylate) (Compound 520) carboxylate) (Compound 521) carboxylate) (Compound 522) carboxylate) (Compound 523)

EN iii SYN ZNNNNNYA ZYM carboxylate) (Compound 524) carboxylate) (Compound 525) carboxylate) (Compound 526) carboxylate) (Compound 527) carboxylate) (Compound 528) carboxylate) (Compound 529) carboxylate) (Compound 530 (Compound 531)

Range of values Range

The range of values of Nei Vei ESvo values of ES

The name and number of the oxidizing EC compound release 275o

In schi - necrosis of cells released by neutrophils cytokine (II -8) Neg a cells NeKa

Ingenol 3-(2-tert-butyl-5-methylpyrazole-3-carboxylate) (Compound 532)

Ingenol 3-(5-tert-butyl-2-methylpyrazole-3-carboxylate) powder

Compound 533

Ingenol 3-(6-methylimidazoi|2,1-

Bigiazole-5-carboxylate) (Compound | 77 of them 534

Ingenol 3-(2-methylimidazo|1,2-a|pyridine-Z-carboxylate) /(Compound| 7" of 535 carboxylate) (Compound 536) carboxylate) (Compound 537)

Ingenol 3-(2-methyl-4-(1-piperidyl)pyrazole-3-carboxylate) n what what (Compound 538) carboxylate) (Compound 539)

Ingenol 3-(4-chloro-2,5-dimethylpyrazole-3-carboxylate) p p p

Compound 540 carboxylate) (Compound 541) carboxylate) (Compound 542

Best ey NNYA UNN BLUE 2-carboxylate) (Compound 543)

Ingenol 3-(1-tert-butyloxycarbonyl-

3,3-dimethylpyrrolidine-2-carboxylate) (Compound 544) carboxylate) (Compound 545)

Ingenol 3-(1-isopropyl-3,5-dimethylpyrazole-4-carboxylate) and their (Compound 546)

Ingenol 3-(5-ethyl-3- isopropylisoxazole-4-carboxylate) and (Compound 547) carboxylate) (Compound 548

Ingenol 3-(5-methyl-3-tert-butyl-isoxazole-4-carboxylate) (Compound 549

Ingenol 3-(2-methyl-3-oxo-4-oxaspiro|4.5|dec-1-en-1-yyy carboxylate) (Compound 550)

Ingenol 3-(1-tert-butyl-3,5-dimethylpyrazole-4-carboxylate) and (Compound 551) carboxylate) (Compound 552)

Range of values Range

The range of values of Nei Vei ESvo values of ES

The name and number of the oxidizing EC compound release 275o

In the case of cell necrosis, the release of cytokine (II-8) by NeKa carboxylate cells (Compound 553)

Ingenol 3-(4-(4-methoxyphenyl)-2-methylpyrazole-3-carboxylate) p p p (Compound 554)

Ingenol 3-(4-(2-methylphenyl-2-methylpyrazole-3-carboxylate) p p p (Compound 555)

Ingenol 3-(2-methyl-4-(4-methylsulfonylphenylpyrazole-3- what what what carboxylate) (Compound 556) carboxylate) (Compound 557)

Ingenol 3-(3,5-dimethyl-1-phenylpyrazole-4-carboxylate) y y y (Compound 558)

Ingenol 3-(1,5-dimethyl-3-phenylpyrazole-4-carboxylate) and their (Compound 559)

Ingenol 3-(1-benzyl-3,5-dimethylpyrazole-4-carboxylate) y y y (Compound 560)

Ingenol 3-(3,5-dimethyl-1-(tetrahydropyran-4-ylmethyl)pyrazol-4-| "7" their carboxylate) (Compound 561)

Ben night inn SONYA UNN SYNYA

β-carboxylate) (Compound 562)

Ingenol 3-(2-methyl-4,5,6,7-tetrahydroindazole-3-carboxylate) p p p (Compound 563) carboxylate) (Compound 564)

Ingenol 3-(5-methoxy-1,2-dimethylindole-3-carboxylate) (Compound 565) carboxylate) (Compound 566)

3-carboxylate) (Compound 567)

β-carboxylate) (Compound 568)

(Compound 569 carboxylate) (Compound 570) carboxylate) (Compound 571)

Ingenol 3-(5-methoxy-1,3-dimethylindole-2-carboxylate) shi shi shi (Compound 572)

Best si and INN BLUE ANN

3-carboxylate) (Compound 573) carboxylate (Compound 574)

Range of values Range

The range of values of Nei Vei ESvo ES

The name and number of the oxidizing EC compound the release of values of Bo and shchi - cell necrosis of the release of cytokine neutrophils (II -8) H - ega by NeKa cells

Ingenol 3-(3-methyl-5-(trifluoromethyl)isoxazole-4-carboxylate) (Compound 575) carboxylate) (Compound 576)

Ingenol 3-(3,5-dimethyl-1-(2,2,2-trifluoroethyl)pyrazole-4-carboxylate) |" and their derivatives (Compound 577)

Ingenol 3-(1-cyclopropyl-2,5-dimethylpyrrole-3-carboxylate) p p p (Compound 578) carboxylate) (Compound 579) carboxylate) (Compound 580) carboxylate) (Compound 581) carboxylate) (Compound 582) carboxylate ) (Compound 583) carboxylate) (Compound 584) carboxylate) (Compound 585)

3-carboxylate) (Compound 586 carboxylate) (Compound 587)

Ingenol 3-(1-(cyclopropylmethyl)-2,4-dimethylpyrrole-3-carboxylate) p p p (Compound 588)

Ingenol 3-(1-(2-methoxyethyl)-2,4-dimethylpyrrole-3-carboxylate) that n n (Compound 589)

Eva SPYNY UNN ENN 701

EE t sik SYN SNY ENN (Compound 702)

En vinyl CH SNY ENN (Compound 703)

ES SPINY SNY WINE (Compound 704) phenylcarbamate) (Compound 705)

Compound 706

KEN sin SNY SNYA NNYA (Compound 707)

Ben di SONIA BLUE ANN methylcarbamate) (Compound 708) methylcarbamate) (Compound 709)

Range of values Range

The range of values of Nei Vei ESvo ES

The name and number of the oxidizing EC compound the release of values of Bo and shchi - cell necrosis of the release of cytokine neutrophils (II -8) H - ega by NeKa cells

ENN vann NNYA NN UNN (Compound 710)

Bdetlu nias (Compound 711) (Compound 712) carboxylate) (Compound 713 ylcarbamate) (Compound 714)

Ethnic nka PNYA ZY SP methylcarbamate) (Compound 715) phenethyl)carbamate) (Compound 716)

Ingenol 3-(M-methyl-M-(cyclopropylmethyl)carbamate) (Compound 717) methylcarbamate) (Compound 718)

(Compound 719)

Ingenol 3-(M-(3,5-dimethylisoxazol-4-yl)-M-methylcarbamate) (Compound | "7 x 720 yl)-M-methylcarbamate) (Compound 721) methylcarbamate) (Compound 722 methylcarbamate) (Compound 723 )

Geny tni NN CH SY pyridyl)carbamate) (Compound 724)

1-Carboxylate) (Compound 725) Carboxylate) (Compound 726) (Compound 727)

(Compound 728) methylcarbamate) (Compound 729) methylcarbamate) (Compound 730

Ingenol 3-(M-methyl-M-(2-methoxyphenyl)carbamate) (Compound | 7" of 731 methylphenyl)carbamate) (Compound 732

Ingenol 3-(3-oxo-2,4-dihydroquinoxaline-1-carboxylate) x their (Compound 733) (Compound 734)

Range of values Range

The range of values of Nei Vei ESvo ES

The name and number of the oxidizing EC compound release of values Bo

In the evening cell necrosis of neutrophils releasing cytokine (II-8) H - ega cells NeKa

1-Carboxylate) (Compound 735)

3-carboxylate) (Compound 736)

Ingenol 3-(2,3-dihydro-1,4-benzoxazine-4-carboxylate) yes yes yes

Compound 737 methyl carbamate) (Compound 738)

Ingenol 3-(3-methyl-2,3-dihydro-1,4-benzoxazine-4-carboxylate) (Compound 739)

Ingenol 3-(2-trifluoromethylpyrrolidine-1-carboxylate) (ISOMER A) (Compound 7" of 740

Ingenol 3-(2-trifluoromethylpyrrolidine-1-carboxylate) (ISOMER B) (Compound of them x tA

Ingenol 3-(M-methyl-M-(M-(tert-butyloxycarbonyl)-4-ylpiperidyl)carbamate) (Compound 742) methylphenyl)carbamate) (Compound 743) 1-carboxylate) (Compound 744 (Compound 745)

Ingenol 3-(M-methyl-M-(tetrahydropyran-4-ylmethyl)carbamate)| x x

Compound 746)

Ingenol 3-(M-methyl-M-(tetrahydropyran-4-yl) carbamate) x x (Compound 747)

Ingenol 3-(M-methyl-M-(3-methoxyphenyl)carbamate) (Compound | 77 of them 748

Belz actions BLUE ZONE SONYA methylcarbamate) (Compound 749)

EN кн SN ZONI SONYA (Compound 750) ep st vay SYNYA UNN PNYA inylcarbamate) (Compound 751) 2-ylcarbamate) (Compound 752 methylcarbamate) (Compound 753)

Example 4

B16-EO murine melanoma model for evaluation of antitumor efficacy

Cells of murine melanoma B16-EO (ATSSF number SVI -6322TM) were cultivated in medium

ARMI-1640 dishamakh (Ipigodep, catalog number 61870-010) with the addition of 10 95 fetal calf serum and 1 95 penicillin-streptomycin (Ipigodep, catalog number 15140-122) at 37 "Sb in humidified air with 595 CO". In 0- On the 0th day of the experiment, B16-EO cells (confluent at 70-90 95) were collected by trypsinization with Tguri E (Ipygodep, catalog number 12605-010),

washed, resuspended in KRMI-1640 dishamAX medium and kept on ice for 30 minutes, a volume of 50 μl, containing 0.5x105 viable B16-E0O cells, was injected intradermally into the shaved flanks of 10-week-old female mice of the C57VI line / bUVottTas, one injection per mouse. On the 4th day of the experiment, tumors were measured with a digital caliper (Maig 16 Ex NI100207), and tumor volumes were estimated using the formula: Tumor volume - 1/2(largest diameter)" (orthogonal diameter)"2. Mice with tumors ranging from 9 to 60 mm were included in the study and stratified into treatment groups according to tumor size. Tumors were topically treated with 20 μl of a solution containing 0.1 95 of the test compound once a day for 2 consecutive days. Vehicle was included in each experiment as a negative control. Tumors were measured daily and mice were euthanized when they exceeded an estimated volume of 250 mm3. Mice with ulcerated or deteriorated tumors were euthanized, regardless of tumor size, and included in the data analysis as review subjects. The experiment was terminated on the 90th day of the course of the experiment, and mice with tumors less than 250 mm3 on this day were also included in the data analysis as objects of review.

Kaplan-Mehler survival curves were constructed for tumors >250 mm3 as a surrogate for the event of death, and survival curves were compared using the logarithmic rank criterion. Specifically, tumor growth in each treatment group was compared to tumor growth in the vehicle group to assess the effectiveness of each compound in treating tumors or delaying tumor growth. P values presented below of less than 0.05 were considered statistically significant.

Some compounds according to the present invention were tested on the B16-PO mouse melanoma model. The table below lists the compounds that have an effect that is significantly better than the effect of the carrier. than the carrier effect, in the B16-EO murine melanoma model

Ingenol 3-(2,4-dimethylfuran-3-carboxylate) (Compound 529)

Ingenol 3-(M-methyl-M-phenylcarbamate) (Compound 705)

Ingenol 3-(indoline-1-carboxylate) (Compound 727)

Ingenol 3-(2,4,5-trimethylfuran-3-carboxylate) (Compound 536)

Ingenol 3-(5-methyl-3-phenylisoxazole-4-carboxylate) (Compound 502)

Ingenol 3-(pyrrolidine-1-carboxylate) (Compound 704)

Ingenol 3-(M-(3-fluorophenyl)-M-methylcarbamate) (Compound 718)

Claims (46)

FORMULA OF THE INVENTION 1. A compound of the general formula И H, a ИН рі/ Yavy o Z U-o no B v no no no 20 i where B means heteroaryl, which may be optionally substituted by one or more substituents independently selected from H7 or A means heterocycloalkyl or heterocycloalkenyl, where said heterocycloalkyl or heterocycloalkenyl is optionally substituted by one or more substituents independently selected from HB; or B stands for X; B7 is halogen, cyano or hydroxyl, or B7 is (C1-C6)alkyl, (Co-Slualkenyl, (C3-C7)cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, heterocycloalkylalkyl or (C3-C7)cycloalkylalkyl, where (C1-C6)alkyl, ( C 2 -C 7 )alkenyl, (C 3 -C 7 )cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, heterocycloalkylalkyl or (C 3 -C 7 )cycloalkylalkyl optionally substituted with one or more substituents independently selected from HO, or 87 is -MVNasovtr, -SOMAan, -SOOAs, -ObONa, -OVA, -OSOMNRanr, - Mvasoov, -mvasSsomMvan, -MtazOgMRan, -MmAazogvB, -502MRanr, -5O2Na, -550)Va, -5ShVa or -MVanr; VU is a halogen, cyano, hydroxy, (Ci-Alalkyl, halogen(Ci-Alalkyl, -yanasov, -СОовВс, -оОСОВа, -СОМВАВан, -оСоМРан, -мвтасоов, -МвасСсомМНРанв, -МазО2гМРанв, -МВазогН, - зО2МАан, -5O»2Na, -550)Ra, -ORa, -5Ba or 50; B8 is halogen, cyano or hydroxyl, or BB is (Ci-Ca)alkyl, (Ci-Salkenyl, aryl, heteroaryl, (C3- C7)cycloalkyl or heterocycloalkyl, wherein said (C1-C6)alkyl, (C0-C1)alkenyl, aryl, heteroaryl, (C3-C7)cycloalkyl or heterocycloalkyl are optionally substituted with one or more substituents independently selected from B10, or 88 is -"Mnasov, -SOOAVs, -OSOVRa, -"SOMran, -oSoMVAan, -mnasoonvr, - MAasSomVan, -MAazO2MNan, -MNANazogvj, -502MVan, -5О2Na, -5(0)Na, -ОВа, -5Na, -0, -M- ОВа, -0-mM-СВан, MВанр or -С(О)М(На)О-НБ; ВТО is a halogen, cyano, hydroxy, (Si-Ca)alkyl, (C1-Ca )alkoxy, halo(C1i-Cd)alkyl, halogen(C:-Ca)alkyl, hydroxy(Ci-Cd)alkyl, cyano(C:i-Cd)alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, -MNasov, - SOOVA s, -OSbOVa, -SOMAan, -osBOoMAan, -MmVasoonyr, - MmeasSsomNan, -MATazO2gMRan, -MNazoO»Bb, -502MNan, -5O»Na, -5(0)Na, -OVA, -5Na or 50; Ba and Bb are hydrogen, (C1-C4)alkyl, halogen (C1-Cd)alkyl, (C1-Ca)alkyl (C1-Cadalkyl), hydroxy(C1-Ca)alkyl, cyano(C1-Ca)alkyl, aryl , heteroaryl, cycloalkyl or heterocycloalkyl; Ac is hydrogen, (C1-C4) alkyl, halogen (C1-Ca) alkyl, (C1-C4) alkoxy (C1-Ca) alkyl, hydroxy (C1-Cx) alkyl, cyano( C:-Cx)alkyl, aryl, heteroaryl, cycloalkyl or heterocycloalkyl; X is -MA11A12, where B11 and B12 are independently hydrogen, CoO) or where B11 and B12 are independently (C1-C1)alkyl, (Co- C1)alkenyl or (C12-C12)alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocycloalkyl, heterocycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, arylalkyl, heteroarylalkyl, heterocycloalkylalkyl, heterocycloalkenylalkyl, alkylcycloalkyl, alkylcycloalkenyl, alkylaryl, alkylheteroaryl or alkylheterocycloalkyl, where (C1- C 1 -alkyl, (C 2 -C 2 )alkenyl or (C 2 -C 2 )alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocycloalkyl, heterocycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, arylal ring, heteroarylalkyl, heterocycloalkylalkyl, heterocycloalkenylalkyl, alkylcycloalkyl, alkylcycloalkenyl, alkylaryl, alkylheteroaryl or alkylheterocycloalkyl optionally substituted with one or more substituents independently selected from B13; B13 is halogen, cyano or hydroxyl, or B13 is (Ci-Ca4)alkyl, (C2-Ca4)alkenyl, aryl, (C3-C7)cycloalkyl, heteroaryl or heterocycloalkyl, where (C1-Ca4)alkyl, ( C0-C1)alkenyl, aryl, (C3-C7)cycloalkyl, heteroaryl or heterocycloalkyl optionally substituted with one or more substituents independently selected from B14, or B13 is -MNaSOVe, -SOOVI, -OSOva, -somMVantke, -OoSOMVacne . . Ca)alkyl, hydroxy(Ci-Ca)alkyl, cyano(C1-Ca)alkyl, aryl, heteroaryl, cycloalkyl or heterocycloalkyl; Ag is hydrogen, (C1-Ca) alkyl, halogen (C1-Ca) alkyl, (C1-C1) alkoxy (C1-Ca) alkyl, hydroxy (C1-Ca) alkyl, cyano (C1-Ca) alkyl, aryl , heteroaryl, cycloalkyl or heterocycloalkyl; B14 is hydrogen, hydroxyl, cyano, (Ci-Ca)alkyl, (Ci-Cdaloxy, halo(C1-Ca)alkyl, halogen(C:-Ca)alkyl, hydroxy(Ci-Cd)alkyl, cyano(C: and -Cd)alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, -MVYASOVNe, -SOOVI, -OSbOova -COoMAantke, -oOSOMAanHe, -MNasSoOovVe, - mvasomnane, -chnazo»Re, -«mnazo2mnane, -502MVane, -502Na, - 5(0)Na, -Ona, -5Ba or 50; and its pharmaceutically acceptable salts, hydrates and solvates. 2. The combination of 1, where B is heteroaryl, which may optionally be substituted with one or more substituents independently selected from H7, or B is heterocycloalkyl or heterocycloalkenyl, each of which may optionally be substituted with one or more substituents independently selected from HB, IS7 represents is halogen, cyano, hydroxyl, or B7 is (C1-C6)alkyl, (C0-C7)alkyl, (C3-C7)cycloalkyl, heterocycloalkyl, aryl, heteroaryl, each of which is optionally substituted with one or more independently selected substituents with HO, or В7 represents -МНасон, -СОМНан, -СООАs, -ОСОНа, -ОВа, -ОСОМВан, - Мвасоов, -мнтасСсомМвАан, -МВазОгМран, -МАабзОо»гвб, -502МРан, -5О2Ва, -5(0) Na, -5Va; VU is a halogen, cyano, hydroxy(C1-Ca)alkyl, halogen(C:i-Ca)alkyl, -javason, -СОоОвВс, - ОоСовВа, -СОМВан, -оСоМАРанвъ, -Мвнасоонм, -мМтасСомМРан . B8 is halogen, cyano, hydroxyl, or BB is (Ci-Ca)alkyl, (Ci-Ca)alkenyl, aryl, heteroaryl, (C3-C7)cycloalkyl, heterocycloalkyl, each of which is optionally substituted with one or more by substituents independently selected from Н10, or 88 is -МНасон, -СООНс, -ОСОВа, -СОМВан, -оСОомМНан, -мнасоорнв, - MwasomМмган, -маАа5ОМРан, -МВазогвВБ, -502МРан, -5О2Ва, -550)Ва, -ORa, -5Va, -0; VIO is a halogen, cyano, hydroxy, (Ci-Cdalkyl, halogen(Ci-Ca)alkyl, -MVasony, - СООВs, -ОСОВa, -СОМВан, -оСоМАн, -Мвасовъ, -МваСомМВан, -МмАазОгМНан, - МазогпБ, -502МНВанр, -5О2На, -5(0)На, -ОВа, -5На, -0; Ва and Вб are hydrogen, (С1-С4)alkyl, halogen(С1-Сд)alkyl, (С1-Са)alkyl (C1-Saalkyl, hydroxy(C1-Calalkyl, cyano(C1-Cal)alkyl; Ac is (C1-Cal)alkyl, halogen(C1-Cal)alkyl, (C1-Cal)Alkoxy(C1-Cal)alkyl, hydroxy(C1-Cd)alkyl, cyano(C:1-Cd)alkyl. 3. The compound according to claims 1-2, where A means heteroaryl. 4. The compound according to claims 1-3, where heteroaryl is isoxazolyl, pyridyl, quinolyl, isoquinolyl, indolyl, furyl, thiazolyl, imidazolyl, pyrazolyl, oxazolyl, thienyl, pyrimidinyl, 1,2,3-triazolyl, indazolyl, cinnolyl, 1 ,2-benzoxazolyl, imidazothiazolyl, imidazopyridinyl, pyrrolyl, isothiazolyl, tetrahydroindazolyl or oxadiazolyl. 5. The compound according to any of the previous clauses, where B7 is independently selected one or more times from the group of (C:i-Ca)alkyl, (C6-Salkenyl, aryl, arylalkyl, heterocycloalkylalkyl, (C3-C7)-cycloalkylalkyl, ( C3-C7)-cycloalkyl, -COOVc, -ОВa or halogen. 6. The compound according to claim 5, where B7 is selected from phenyl, methyl, ethyl, isopropyl, t-butyl, piperidyl, tert-butyloxycarbonyl, benzyl, tetrahydropyranylmethyl, -OSH3, cyclopropyl, allyl, cyclopropylmethyl, Si, Bg or I. 7. The compound according to any of the previous clauses, where ВО means halogen, -ОВа, (Сі-Са)alkyl or - 5О2Ва. 8. The compound according to claim 7, where VU means SI, ER, -OSN", methyl or methylsulfonyl. 9. The compound according to claims 1-2, where AR means heterocycloalkyl or heterocycloalkenyl. 10. The compound according to claims 1, 2 or 9, where heterocycloalkyl or heterocycloalkenyl is pyrrolidinyl, piperidinyl, morpholinyl, 5-oxabicyclo(2.2.2|octanyl, oxaspiro|4.5|dec-1-enyl, oxothiazolyl, dihydrothiazolyl, oxopyranyl, azepanyl , azabicycloyi3.2.2|Inonanil, benzoxazinyl, quinoxalinyl, isoindolinyl, dihydroquinolinyl, indolinyl or dihydroquinoxalinyl. 11. A compound according to claims 1, 2 or 9, where HB means (C:1-Cylalkyl, aryl or 0. 12. The compound according to claim 11, where 88 is methyl, phenyl or 50. 13. The compound according to claims 1, 2 or 9, where H10 is a halogen. 14. Compound according to claim 1, where A is -MA11 812. BO 15. The compound according to claim 1 or 14, where B11 and B12 independently represent hydrogen, (C1-C8)alkyl, aryl, cycloalkyl, arylalkyl, heteroaryl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, (C8-C8)alkenyl or (C2-Cv)alkynyl. 16. The compound according to claims 1, 14 or 15, where B11 and B12 independently represent hydrogen, methyl, ethyl, isopropyl, phenyl, benzyl, cyclohexyl, indanyl, tetralinyl, phenylethyl, cyclopropylmethyl, pyrazolyl, isoxazolylmethyl, cyclopentyl, cyclopropyl, pyridyl, piperidyl, tetrahydropyranylmethyl, tetrahydropyranyl, cyclobutyl, allyl, propynyl or thiazolyl. 17. The compound according to claims 1, 14 or 15, where B1Z3 is (C:1-Cd)alkyl, cyano, halogen, 0, -ОВа or - СОНВІ. 18. The compound according to claim 17, where B1Z3 is methyl, cyano, E, -O, -OSH3 or -COOS(CH5Z)z. 60 19. The compound according to claims 1, 14, 15 or 16, where B11 or B12 independently represents hydrogen. 20. The compound according to any one of the preceding clauses, and said compound is selected from the group consisting of: ingenol 3-(5-methyl-3-phenylisoxazole-4-carboxylate) or ingenol 3-(5-methyl-3-( 2-chloro-6-fluorophenyl)-isoxazole-4-carboxylate), ingenol 3-(15-camphanate), ingenol 3-(3-phenyltriazole-4-carboxylate), ingenol 3-(2-phenylpyrazole-3-carboxylate) , ingenol 3-(1-methylindazole-3-carboxylate), ingenol 3-(3-ethyl-5-methylisoxazole-4-carboxylate), ingenol 3-(3-methyl-5-methylisoxazole-4-carboxylate), ingenol 3 -(1-methylindole-3-carboxylate), ingenol 3-(3-phenylthiophene-2-carboxylate), ingenol 3-(5-phenylisoxazole-3-carboxylate), ingenol 3-(M-ethylcarbamate), ingenol 3-( H,H-dimethylcarbamate), ingenol 3-(morpholine-4-carboxylate), ingenol 3-(pyrrolidine-1-carboxylate), ingenol 3-(M-methyl-M-phenylcarbamate), ingenol 3-(H,H- diethylcarbamate), ingenol 3-(piperidine-1-carboxylate), ingenol 3-(M-benzyl-M-methylcarbamate), ingenol 3-(M-cyclohexyl-M-methylcarbamate), ingenol 3-(M-cyclohexylcarbamate), ingenol 3-(M-phenylcarbamate), ingeno l 3-(M-(indan-1-yl)ucarbamate), ingenol 3-(3,3-dimethylpiperidine-1-carboxylate), ingenol 3-(M-methyl-M-tetralin-1-ylcarbamate), ingenol 3 -(M-(2-cyano-1-methylethyl)-M-methylcarbamate), ingenol 3-(M-methyl-M-((5)-1-phenethyl)carbamate), Zo ingenol 3-(M-methyl- M-(cyclopropylmethyl)carbamate), ingenol 3-(isoquinoline-1-carboxylate), ingenol 3-(quinoline-4-carboxylate), ingenol 3-(quinoline-4-carboxylate), ingenol 3-(3-phenylimidazole-4 -carboxylate), ingenol 3-(5-phenyloxazole-4-carboxylate), ingenol 3-(1,2-benzoxazole-3-carboxylate), ingenol 3-(3-isopropyl-5-methylisoxazole-4-carboxylate), ingenol 3-(3-(2-methoxyphenyl)-5-methylisoxazole-4-carboxylate), ingenol 3-(4-bromo-2-methylpyrazole-3-carboxylate), ingenol 3-(4-bromo-2-ethylpyrazole-3) -carboxylate), ingenol 3-(4-chloro-2-methylpyrazole-3-carboxylate), ingenol 3-(5-bromopyrimidine-4-carboxylate), ingenol 3-(3-bromopyridine-2-carboxylate), ingenol 3- (5-methylthiazole-4-carboxylate), ingenol 3-(4-chloro-1-methylpyrazole-3-carboxylate), ingenol 3-(2,4-dimethylthiazole-5-carboxylate), etc. genol 3-(2,5-dimethyloxazole-4-carboxylate), ingenol 3-(2,4-dimethylfuran-3-carboxylate), ingenol 3-(3,5-diethylisoxazole-4-carboxylate), ingenol 3-(M -(3-fluorophenyl)-M-methylcarbamate), ingenol 3-(M-(2,5-dimethylpyrazol-3-yl)-M-methylcarbamate), ingenol 3-(1H-indole-7-carboxylate), ingenol 3 -(2-tert-butyl-5-methylpyrazole-3-carboxylate), ingenol 3-(5-tert-butyl-2-methylpyrazole-3-carboxylate), ingenol 3-(b-methylimidazoi(2,1-5| hyazole-5-carboxylate), ingenol 3-(2-methylimidazo(|1,2-a|Ipyridine-3-carboxylate), ingenol 3-(2,4,5-trimethylfuran-3-carboxylate), ingenol 3-( 3-methylthiophene-2-carboxylate), ingenol 3-(2-methyl-4-(1-piperidyl)pyrazole-3-carboxylate), because ingenol 3-(2-chloro-5-isopropylthiazole-4-carboxylate), ingenol 3-(4-chloro-2,5-dimethylpyrazole-3-carboxylate), ingenol 3-(1,2,4-trimethylpyrrole-3-carboxylate), ingenol 3-(1,3,5-trimethylpyrrole-2- carboxylate), ingenol 3-(1-ethyl-3,5-dimethylpyrrole-2-carboxylate), ingenol 3-(1-tert-butyloxycarbonyl-3,3-dimethylpyrrolidine-2-carboxylate), ingenol 3-((25) -1-phenylpyrrolidine-2-carboxylate), ingenol 3-(1-isopropyl-3,5-dimethylpyrazole-4-carboxylate), ingenol 3-(5-ethyl-3-isopropylisoxazole-4-carboxylate), ingenol 3-( 2-methylindazole-3-carboxylate), ingenol 3-(5-methyl-3-tert-butylisoxazole-4-carboxylate), ingenol 3-(2-methyl-3-oxo-4-oxaspiro|4.5|dec-1-ene-1-carboxylate), ingenol 3 -(1-tert-butyl-3,5-dimethylpyrazole-4-carboxylate), ingenol 3-(3,5-dimethylisothiazole-4-carboxylate), ingenol 3-(5-iodo-3-methylisothiazole-4-carboxylate) , ingenol 3-(4-(4-methoxyphenyl)-2-methylpyrazole-3-carboxylate), ingenol 3-(4-(2-methylphenyl)-2-methylpyrazole-3-carboxylate), ingenol 3-(2-methyl- 4-(4-methylsulfonylphenyl)pyrazole-3-carboxylate), ingenol 3-(2-methyl-4-phenylpyrazole-3-carboxylate), ingenol 3-(3,5-dimethyl-1-phenylpyrazole-4-carboxylate), ingenol 3-(1,5-dimethyl-33-phenylpyrazole-4-carboxylate), ingenol 3-(1-benzyl-3,5-dimethylpyrazole-4-carboxylate), ingenol 3-(3,5-dimethyl-1- (tetrahydropyran-4-ylmethyl)pyrazole-4-carboxylate), ingenol 3-(4-methyl-2-oxo-ZN-thiazole-5-carboxylate), ingenol 3-(2-methyl-4,5,6,7 -tetrahydroindazole-Z-carboxylate), ingenol 3-(1,2-dimethylindole-3-carboxylate), ingenol 3-(5-methoxy-1,2-dimethylindole-3-carboxylate), ingenol 3-(1,3,5-trimethylpyrazole-4-carboxylate) , ingenol 3-(4-methyl-1,2,5-oxadiazole-3-carboxylate), ingenol 3-(2-methoxy-4-methylthiazole-5-carboxylate), ingenol 3-(4,5-dimethylisoxazole-3-carboxylate), ingenol 3-(4-bromo-1-methylpyrazole-3-carboxylate), ingenol 3-(1,3-dimethylindole-2-carboxylate), ingenol 3- (5-methoxy-1,3-dimethylindole-2-carboxylate), ingenol 3-(2,4-dimethyl-6b-oxopyran-3-carboxylate), ingenol 3-(1-methyl-3-phenylindole-2-carboxylate), ingenol 3-(3-methyl-5-(trifluoromethyl)isoxazole-4-carboxylate), ingenol 3-(1,3-dimethylpyrrole-2-carboxylate) ), ingenol 3-(3,5-dimethyl-1-(2,2,2-trifluoroethyl)pyrazole-4-carboxylate), ingenol 3-(1-cyclopropyl-2,5-dimethylpyrrole-3-carboxylate), ingenol 3-(1,2,5-trimethylpyrrole-3-carboxylate), ingenol 3-(2,4-dimethyl-1H-pyrrole-3-carboxylate), ingenol 3-(1-methylpyrrole-2-carboxylate), ingenol 3-(4-methyl-1H-pyrrole-2-carboxylate), ingenol 3-(1,5-dimethylpyrrole-2-carboxylate), ingenol 3-(3-methyl-1H-pyrrole-2-carboxylate), ingenol 3-(1-cyclopropylpyrrole-2-carboxylate), ingenol 3-(1-ethyl-2,4-dimethylpyrrole-3-carboxylate), ingenol 3-(1-allyl-2,4-dimethylpyrrole-3-carboxylate), ingenol 3-(1-(cyclopropylmethyl)-2,4-dimethylpyrrole-3-carboxylate), ingenol 3-(1-(2-methoxyethyl)-2,4-dimethylpyrrole-3-carboxylate), ingenol 3-(M-(3,5-dimethylisoxazol-4-yl)-M-methylcarbamate), ingenol 3-( M-(1,5-dimethylpyrazol-3-yl)-M-methylcarbamate), ingenol 3-(M-cyclopentyl-M-methylcarbamate), ingenol 3-(M-cyclopropyl-M-methylcarbamate), ingenol 3-(M-methyl-M-(2-pyridyl)carbamate), ingenol 3-(4-oxo-2,3-dihydroquinoline-1-carboxylate), ingenol 3-(3,4-dihydro-2H-quinoline -1-carboxylate), ingenol 3-(indoline-1-carboxylate), ingenol 3-(azepane-1-carboxylate), bo ingenol 3-(M-(4-chlorophenyl)-M-methylcarbamate), ingenol 3-(M-(4-fluorophenyl)-M-methylcarbamate), ingenol 3-(M-methyl-M-(2-methoxyphenyl)carbamate), ingenol 3-(M-methyl-M-(2-methylphenyl) carbamate), ingenol 3-(3-oxo-2,4-dihydroquinoxaline-1-carboxylate), ingenol 3-(M-ethyl-M-phenylcarbamate), ingenol 3-(2-trifluoromethylpyrrolidine-1-carboxylate), ingenol 3 -(3-azabicyclo/3.2.2|nonane-3-carboxylate), ingenol 3-(2,3-dihydro-1,4-benzoxazine-4-carboxylate), ingenol 3-(M-(2-fluorophenyl)- M-methylcarbamate), ingenol 3-(33-methyl-2,3-dihydro-1,4-benzoxazine-4-carboxylate), ingenol 3-(2-trifluoromethylpyrrolidine-1-carboxylate) (isomer A), ingenol 3- (2-trifluoromethylpyrrolidine-1-carboxylate) (isomer B), ingenol 3-(M-methyl-M-(M-(tert-butyloxycarbonyl)-4-piperidyl)carbamate), ingenol 3-(M-methyl-M- (3-methylphenyl)carbamate), ingenol 3-(3,4-dihydro-2H-quinoxaline-1-carboxylate), ingenol 3-(isoindoline-2-carboxylate), ingenol 3-(M-methyl-M-(tetrahydropyran -4--ylmethyl)carbamate), ingenol 3-(M-methyl-M-(tetrahydropyran-4-ylcarbamate), ingenol 3-(M-methyl-M-(3-methoxyphenyl)carbamate), ingenol 3-(M-cyclobutyl-M-methylcarbamate), ingenol 3-(M-allyl-M-methylcarbamate), ingenol 3-(M-methyl-M-prop-2-ynylcarbamate), ingenol 3-(M-methyl- M-(4-methylthiazol-2-ylcarbamate) or ingenol 3-(M-(4-cyanophenyl)-M-methylcarbamate). 21. A compound according to any one of claims 1-20 for use as a medicinal product in treatment. 22. A compound according to any one of claims 1-20 for use in the treatment, prevention, alleviation or prevention of physiological disorders or diseases associated with hyperplasia or neoplasia. 23. The compound of claim 22, wherein the disorder or disease is selected from cutaneous warts, genital warts, actinic keratosis, squamous cell carcinoma (500), basal cell carcinoma (BCC), lentigo maligna, cervical intraepithelial neoplasia, anal intraepithelial neoplasia, or vulvar intraepithelial neoplasia . 24. Use of the compound according to any of claims 1-20 for obtaining a pharmaceutical medicinal product. 25. Use of the compound according to claim 24 for obtaining a medicinal product for the treatment, alleviation or prevention of physiological disorders or diseases associated with hyperplasia or neoplasia. 26. The use of claim 25, wherein the disorder or disease is selected from cutaneous warts, genital warts, squamous cell carcinoma (SCC), basal cell carcinoma (BCC), lentigo maligna, cervical intraepithelial neoplasia, anal intraepithelial neoplasia, or vulvar intraepithelial neoplasia. 27. A method of prevention, treatment, alleviation or prevention of physiological disorders or diseases associated with hyperplasia or neoplasia, which includes administering to an individual in need of the compound according to any of claims 1-20. 28. The method of claim 27, wherein the disorder or disease is selected from cutaneous warts, genital warts, squamous cell carcinoma (500), basal cell carcinoma (BCC), malignant lentigo, cervical intraepithelial neoplasia, anal intraepithelial neoplasia, or vulvar intraepithelial neoplasia. 29. A compound according to any one of claims 1-20 for use in treating or alleviating the course of diseases or disorders for cosmetic purposes. 30. The compound according to claim 29, wherein the cosmetic indication is selected from photodamage of the skin or seborrheic keratosis. 31. Use of the compound according to claim 24 to obtain a medicinal product for treating or alleviating the course of diseases or disorders for cosmetic purposes. 32. Application according to claim 31, where the cosmetic indication is selected from a photodamage of the skin or seborrheic keratosis. 33. A method of treating or alleviating the course of diseases or disorders for cosmetic purposes, which includes administering to an individual in need of it a compound according to any of claims 1- 20. 34. The method according to claim 33, where the cosmetic indication is selected from a photodamage of the skin or seborrheic keratosis. 35. Use of the compound according to claim 24 in the preparation of a pharmaceutical composition for the treatment or alleviation of the course of a disease, disorder or condition responsive to stimulation of the oxidizable release of neutrophils. 36. Use of the compound according to claim 24 in the preparation of a pharmaceutical composition for the treatment or alleviation of a disease, disorder or condition responsive to stimulation of the release of I/-8 from keratinocytes. 37. Use of a compound according to claim 24 in the preparation of a pharmaceutical composition for the treatment or alleviation of a disease, disorder or condition responsive to the induction of necrosis. 38. A method of prevention, treatment, alleviation or prophylaxis of a physiological disease or disorder responsive to the stimulation of oxidizable release of neutrophils, which includes administering to an individual in need of the compound according to any of claims 1-20. 39. A method of prevention, treatment, alleviation or prophylaxis of a physiological disease or disorder responsive to stimulation of the release of II-8 from keratinocytes, which includes administering to an individual in need of the compound according to any of claims 1-20. 40. A method of prevention, treatment, alleviation or prevention of a physiological disease or disorder responsive to the induction of necrosis, which includes administering to an individual in need of it a compound according to any of claims 1-20. 41. A compound according to any one of claims 1-20 for use in the treatment or amelioration of a disease, disorder or condition responsive to the stimulation of oxidizable release of neutrophils. 42. A compound according to any one of claims 1-20 for use in the treatment or amelioration of a disease, disorder or condition responsive to stimulation of the release of II-8 from keratinocytes. 43. A compound according to any one of claims 1-20 for use in the treatment or amelioration of a disease, disorder or condition responsive to the induction of necrosis. 44. A pharmaceutical composition containing a compound according to any one of claims 1-20 or a pharmaceutically acceptable stereoisomer or salt thereof together with a pharmaceutically acceptable carrier or excipient. 45. Pharmaceutical composition according to claim 44, where the composition is suitable for topical administration. Zo 46. A pharmaceutical composition containing a compound according to any one of claims 1-20 or its pharmaceutically acceptable stereoisomer or salt in combination with one or more other therapeutically active agents.