RU2656603C1 - Substituted 2-methyliden-5-(phenylamino)-2,3-dihydrotiophen-3-one for treatment of leukemias with translocations of mll-gene and other oncological diseases - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula (I), general formula (II) or general formula (III):

formula (I);

formula (II);

formula (III), where R¹, R² are independently selected and represent -H, substituted or unsubstituted -C₁-C₆-alkyl, the substituents R¹ and R² together with the carbon atom to which they are attached, can form a substituted or unsubstituted -C₃-C₁₂-cycloalkyl; A is independently selected and is:

or

the asterisk indicates the attaching place of substituents; B is selected independently and is:

the asterisk indicates the attaching place of substituents; each substituent R^k is independently selected and represents -H, halogen; Q is independently selected and represents -H, -C(=O)-R^L; R^L is independently selected and represents a substituted or unsubstituted -C₁-C₆-alkyl (the values of the remaining radicals are presented in paragraph 1 of the claims).

EFFECT: formula is proposed for the treatment of hyperproliferative diseases associated with malignant transformation of cells expressing the carboxyl esterase hCE1 enzyme, in particular acute leukemias with MLL gene translocations, hepatocellular carcinomas and lung adenocarcinomas.

11 cl, 7 dwg, 12 tbl, 96 ex

Description

Technical field

This invention relates to the chemistry of organic compounds, pharmacology and medicine and relates to the prevention and treatment of cancer, in particular leukemia with translations of the MLL gene using a new class of chemical compounds with increased efficiency, as well as increased selectivity and bioavailability.

State of the art

Despite the significant progress achieved over the past decades in the treatment of hematologic diseases, a number of specific varieties of this group of nosologies remain intractable. This problem is especially acute in the treatment of acute leukemia with translocation of the MLL gene, especially in young children [J Clin Oncol. 1999; 17 (1): 191-6]. Approximately one third (25-35%) of cases of malignant neoplasms in children are leukemia or leukemia [Leukemia 2007, 21: 2258-2263], of which the most common form is acute lymphoblastic leukemia (ALL), accounting for approximately 80% of all childhood leukemias [ Smith MA, et al .: Cancer incidence and survival among children and adolescents: United States SEER Program 1975-1995. Bethesda, Md: National Cancer Institute, SEER Program, 1999. NIH Pub. No. 99-4649., Pp 17-34]. Currently, in the United States and Western Europe, the percentage of 5-year relapse-free survival of children with ALL reaches approximately 80%. However, the survival rate of children in the age group up to 1 year is significantly lower. Despite the fact that 90-95% of babies with ALL reach remission after the initial enhanced therapy, frequent relapse of the disease during the first 12 months leads to a decrease in the 5-year survival rate to 30-50%.

One of the main unfavorable prognostic signs is the presence of the translocation of the MLL gene (Mixed Lineage Leukemia, multilinear leukemia), found in 70-80% of ALL cases in young children [http://www.medicinenet.com/script/main/art.asp? articlekey = 19710]. Translocation of this gene is associated with a reduction in the term of 5-year disease-free survival of children to 13-34%. MLL translocations are also found in cases of secondary, iatrogenic, acute myeloid leukemia (AML) that occurs after treatment with topoisomerase-2 inhibitors, regardless of the age of the patients. It should be noted that about 10% of all cases of acute myeloid leukemia in adults are cases of MLL-leukemia [ASH Education BookDecember 10, 2011 vol. 2011 no. 1: 354-360], which is a poor prognostic sign - the average five-year survival of adult patients with AML with translocation of the MLL gene is only 5-10% [J Med 1993; 329: 909-914]. In addition to AML, translocation of the MLL gene also occurs in adult patients with ALL. The total incidence of AML and ALL with the most common translocation of the MLL gene in all age groups is approximately 7200 cases in the world annually [J. Haematol. 1999, 106: 614-62].

Currently in clinical practice there is no targeted therapy approved by regulators for acute leukemia with MLL translocation, despite ongoing clinical studies of a number of promising drugs from the class of epigenetic modulators. As a rule, in modern clinical practice, aggressive chemotherapy and bone marrow transplantation are used to treat MLL leukemia. Despite the relatively high treatment efficacy in children with ALL, relapse-free survival is low. The prognosis is especially unfavorable for patients with MLL translocation: for them, relapse-free survival does not exceed 40%. In addition, the use of large doses of chemotherapeutic drugs leads to serious side effects and a decrease in the quality of life of patients. Thus, the problem of finding alternative, effective and safer therapy for leukemia with translocation of the MLL gene is particularly acute.

Several types of BRD2 / 3/4 bromodomain inhibitors are known to have antitumor activity in animal models of MLL leukemia [Nature 2011; 478 (7370): 529-533]. It has also been shown that low molecular weight inhibitors of certain protein kinases, such as GSK-3 [Nature 2008; 455: 1205-1209], FLT3 [Front Oncol 2014; 4: 263], CDK6 [Blood 2014; 124: 5-6], EPHA7 [Proc Natl Acad Sci USA. 2007; 104: 14442-14447] may be new effective drugs for the treatment of leukemia with MLL translocations. In addition, the role of other biological targets in the development and maintenance of the pathogenesis of this type of leukemia was studied: HSP-90, Mcl-1, Ras, HDAC histone deacetylase, DNA methyl transferase, EZH2 [Blood 2009; 113: 6061-6068]. A number of BRD protein kinase inhibitors and bromodomains are undergoing clinical trials for the experimental treatment of leukemia with MLL translocations, but so far not one drug has been approved for use. It should be noted that, in addition to their main targets, BRD and CDK6 inhibitors also inhibit other closely related biological targets and do not have high selective cytotoxicity with respect to MLL-leukemia cell lines. In addition, protein kinase inhibitors often lose their antitumor efficacy due to the development of resistance associated with biotarget mutations.

To overcome these obstacles, new drugs have been developed that target molecular targets of the MLL protein complex, which are critical for the development and maintenance of this pathology [Haematologica 2009; 94 (7): 983-993]. These drugs include histone H3 lysine 79 methyltransferase DOT1L inhibitors [J Med Chem. 2013; 56 (22): 8972-8983] and protein-protein interaction inhibitors of the menin-MLL- complex [J Med Chem. 2016; 59 (3): 892-913]. Currently, only the DOT1L methyltransferase inhibitor, the drug Pinometostat (WO 2016090271), is undergoing clinical trials for the treatment of acute leukemia with translocation of the MLL gene, both in monotherapy mode and in combination with other antitumor drugs. MLL-menin protein-protein interaction inhibitors [WO 2016197027] exhibit high selective cytotoxicity against malignant cell lines with translocation of the MLL gene and also exhibit significant antitumor activity in xenograft models [Cancer Cell 2015; 27: 1-14].

To achieve a selective cytotoxic effect on a certain type of cells, other approaches that are not associated with the selective modulation of a specific oncogen by small molecules can be used. One of these approaches is the use of specially designed non-toxic prodrugs that, as a result of intracellular metabolic activation inherent only to the target cell type, release a cytotoxic drug inside the cell, which leads to their death and, as a result, to an antitumor effect.

It is well known that certain types of cells, such as monocytic cells (monocytes), macrophages, dendritic cells, hepatocytes, lung epithelium and some others express in large quantities the enzyme carboxyl esterase-1 (hCE1), which hydrolyzes esters of a certain structure, while how expression of hCE1 in other tissues and organs, with some exceptions, is limited [Leukemia Lymphoma 2000; 39: 257-270, Proc Natl Acad Sci USA 2004; 101: 6062-6067, Biochem Pharmacol 2005; 70: 1673-1684]. Significant expression of hCE1 is characteristic of leukemia cell lines with translations of the MLL gene, which are widely used in experimental biology, such as THP-1, U937, and MV-411 [http://www.proteinatlas.orq/ENSG00000198848-CES1/cell]. HepG2 hepatocellular carcinoma cell lines and A549 lung adenocarcinomas also express hCE1 [RSC Adv., 2016, 6: 4302-4309].

Thus, there remains a high need for the development of new effective drugs with a new mechanism of action for the treatment of oncological diseases associated with the malignant transformation of cells expressing the carboxyl esterase-1 hCE1 enzyme, in particular in the treatment of leukemia with translations of the MLL gene.

Disclosure of invention

The objective of the present invention is to develop and create new compounds effective for the treatment of oncological diseases, namely oncological diseases associated with malignant transformation of cells expressing the enzyme hCE1 (carboxyl esterase-1), in particular in the treatment of leukemia with translocation of the MLL gene.

The technical result of the invention is the development and preparation of new chemical compounds that are highly effective for the treatment of oncological diseases, namely for the treatment of oncological diseases associated with malignant transformation of cells expressing the enzyme carboxyl esterase hCE1, as well as high selectivity for tumor diseases associated with malignant transformation cells expressing the carboxyl esterase hCE1 enzyme, in particular tumors with translocation of the MLL gene, in tnosti leukemia translocation MLL-gene. These compounds are promising for use in the treatment of cancer, including cancer in translocation of the MLL gene, for example leukemia with translocation of the MLL gene.

The specified technical result is achieved by developing and creating compounds of the general formula (I), the general formula (II), or the general formula (III):

,

,

,

,

,

,

or their stereoisomers or enantiomers, tautomers, pharmaceutically acceptable salts, solvates or hydrates, where:

R ¹ , R ² are independently selected and are —H, substituted or unsubstituted —C ₁ -C ₆ alkyl, substituted or unsubstituted —C ₃ -C ₉ cycloalkyl, substituted or unsubstituted —C ₂ -C ₆ alkenyl, substituted or unsubstituted -C ₂ -C ₆ alkynyl, wherein the substituents R ¹ and R ² , together with the carbon atom to which they are attached, can form substituted or unsubstituted -C ₃ -C ₁₂ cycloalkyl, substituted or unsubstituted -C ₅ - C ₁₂ cycloalkenyl;

And it is selected independently and represents:

,

,

,

,

или

,

,

,

,

,

or

,

moreover, the asterisk indicates the place of attachment of substituents;

X ¹ is independently selected and is —O—, —S—, —S (= O) -, —S (= O) ₂ -, —C (R ^a ) ₂ -, —NR ^b -;

X ² is independently selected and is an unsubstituted or substituted alkylene chain - (CH ₂ ) _n -, where n is from 1 to 4;

Y ¹ is independently selected and is —C≡C— or —CR ^c = CR ^c -;

Y ² is independently selected and is —C (R ^b ) ₂ -;

R ^a is independently selected and is —H, halogen, —OH, —CN, —C ₁ —C ₆ alkyl, —O — C ₁ —C ₆ alkyl, —C ₃ —C ₉ cycloalkyl, phenyl, five or a six-membered heteroaryl containing from 1 to 4 heteroatoms independently selected from N, S and / or O, a 3 ÷ 12-membered heterocyclyl containing from 1 to 4 heteroatoms independently selected from N, S and / or O, with two substituents R ^a , together with the carbon atom to which they are attached, can form —C ₃ -C ₆ cycloalkyl, a 3 to 12 membered heterocyclyl containing from 1 to 4 heteroatoms independently selected from N, S and / or O;

R ^b is independently selected and is —H, —C ₁ -C ₆ -alkyl, -C ₃ -C ₉ -cycloalkyl, 5 ÷ 10-membered heteroaryl containing from 1 to 4 heteroatoms independently selected from N, S and / or O, or a 3-12-membered heterocyclyl containing 1 to 4 heteroatoms independently selected from N, S and / or O, the two substituents R ^b , together with the carbon atom to which they are attached, can form -C ₃ -C ₆ cycloalkyl;

R ^c is independently selected and is —H, halogen, substituted or unsubstituted —C ₁ -C ₆ alkyl;

R ³ is independently selected and is —H, substituted or unsubstituted —C ₁ -C ₆ alkyl, substituted or unsubstituted —C ₃ -C ₉ cycloalkyl, substituted or unsubstituted —C ₆ -C ₁₀ aryl, substituted or unsubstituted 5 ÷ 10 membered heteroaryl containing from 1 to 4 heteroatoms independently selected from N, S and / or O, 3 ÷ 12 membered heterocyclyl containing from 1 to 4 heteroatoms independently selected from N, S and / or O, or represents

;

;

R ^d , R ^{d ′} are independently selected and are —H, substituted or unsubstituted —C ₁ -C ₆ alkyl, substituted or unsubstituted —C ₆ -C ₁₀ aryl, substituted or unsubstituted 5–6 membered heteroaryl containing from 1 to 4 heteroatoms independently selected from N, S and O, substituted or unsubstituted 3 to 12 membered heterocyclyl containing 1 to 4 heteroatoms independently selected from N, S and / or O, with two substituents R ^d and R ^{d 'together} with the carbon atom to which they are attached, may form a substituted or unsubstituted c ₃ -C ₁₂ -cycloalkyl, substituted or ezameschenny C ₅ -C ₁₂ cycloalkenyl, substituted or unsubstituted 3 ÷ 12-membered heterocyclyl containing from 1 to 4 heteroatoms independently selected from N, S and / or O;

Y ³ is independently selected and is —F, —CN, —OR ^e , —N (R ^e ) ₂ or a substituted or unsubstituted 3 to 12 membered heterocyclyl containing from 1 to 4 heteroatoms independently selected from N, S, and / or O;

R ^e is independently selected and is —H, —C (═O) —C ₁ -C ₆ alkyl, substituted or unsubstituted —C ₁ -C ₆ alkyl, substituted or unsubstituted —C ₂ -C ₆ alkenyl, substituted or unsubstituted -C ₆ -C ₁₀ -aryl, substituted or unsubstituted benzyl, substituted or unsubstituted 5-6 membered heteroaryl containing from 1 to 4 heteroatoms independently selected from N, S and / or O, or substituted or unsubstituted 3 ÷ 12-membered heterocyclyl containing from 1 to 4 heteroatoms independently selected from N, S and / or O;

X ³ is independently selected and is —O—, —S—, —C (R ^a ) ₂ - or —NR ^b -;

R ⁴ is independently selected and is halogenated —C ₁ -C ₆ ^_ alkyl, substituted or unsubstituted 5 to 6 membered heteroaryl containing from 1 to 4 heteroatoms independently selected from N, S and / or O, or substituted or unsubstituted 3 ÷ 12 membered heterocyclyl containing from 1 to 4 heteroatoms independently selected from N, S and O;

X ⁴ is independently selected and is —O—, —S—, —C (R ^a ) ₂ or —NR ^b -;

X ⁵ represents an unsubstituted or substituted alkylene chain - (CH ₂ ) _n -, where n takes values from 1 ÷ 4;

X ⁶ is independently selected and is —O— or —S—;

R ⁵ is independently selected and is —H, substituted or unsubstituted —C ₁ -C ₆ alkyl, substituted or unsubstituted —C ₂ -C ₆ alkenyl, substituted or unsubstituted —C ₆ -C ₁₀ aryl, substituted or unsubstituted 5 ÷ 6 membered heteroaryl containing from 1 to 4 heteroatoms independently selected from N, S and / or O, substituted or unsubstituted 3 ÷ 12 membered heterocyclyl containing from 1 to 4 heteroatoms independently selected from N, S and / or ABOUT;

X ⁷ , X ⁹ are independently selected and are —N— or —CR ^f -;

X ⁸ is independently selected and is —O— or —S—;

R ^f is independently selected and is —H, halogen, —N (R ^b ) ₂ , —CN, —NO ₂ , substituted or unsubstituted —C ₁ -C ₆ alkyl, substituted or unsubstituted —O — C ₁ -C ₆ -alkyl, substituted or unsubstituted -C ₆ -C ₁₀ -aryl, substituted or unsubstituted 5-6 membered heteroaryl containing from 1 to 4 heteroatoms independently selected from N, S and / or O, substituted or unsubstituted 3 ÷ 12- member heterocyclyl containing from 1 to 4 heteroatoms independently selected from N, S and / or O;

X ¹⁰ is independently selected and is N or —CR ^g -;

R ^g is independently selected and is —H, halogen, —CN, —NO ₂ , —OR ^e , —N (R ^b ) ₂ , substituted or unsubstituted —C ₁ —C ₆ alkyl, substituted or unsubstituted —C ₂ - C ₆ -alkynyl, substituted or unsubstituted -OC ₁ -C ₆ -alkyl, substituted or unsubstituted -C ₆ -C ₁₀ -aryl, substituted or unsubstituted -O-phenyl, substituted or unsubstituted 5-6 membered heteroaryl containing from 1 up to 4 heteroatoms independently selected from N, S and O, substituted or unsubstituted 3-12 membered heterocyclyl containing from 1 to 4 heteroatoms independently selected from N, S and / or O;

R ^h is independently selected and is —H, halogen, —CN, —NO ₂ , —OR ^b , —N (R ^b ) ₂ , substituted or unsubstituted —C ₁ -C ₆ alkyl, substituted or unsubstituted —C ₆ —C ₁₀ aryl, substituted or unsubstituted 5–6 membered heteroaryl containing from 1 to 4 heteroatoms independently selected from N, S and / or O, or substituted or unsubstituted 3–12 membered heterocyclyl containing from 1 to 4 heteroatoms independently selected from N, S and / or O;

R ⁶ is independently selected and is —H, substituted or unsubstituted —C ₁ -C ₆ alkyl, substituted or unsubstituted —C ₂ -C ₆ alkenyl, substituted or unsubstituted —C ₂ -C ₆ alkynyl, substituted or unsubstituted - C ₆ -C ₁₀ aryl, substituted or unsubstituted 5 ÷ 6 membered heteroaryl containing from 1 to 4 heteroatoms independently selected from N, S and / or O, substituted or unsubstituted 3 ÷ 12 membered heterocyclyl containing from 1 to 4 heteroatoms independently selected from N, S and / or O;

X ¹¹ is independently selected and is —N— or —CR ^j -;

X ¹² is independently selected and is —N— or —CR ^j -;

R ^j is independently selected and is —H, halogen, —CN, —CF ₃ , —CHF ₂ , —NO ₂ , —OR ^e , —N (R ^e ) ₂ , substituted or unsubstituted —C ₁ —C ₆ - alkyl, substituted or unsubstituted -C ₂ -C ₄ alkenyl, substituted or unsubstituted-C ₂ -C ₄ alkynyl, substituted or unsubstituted-C ₃ -C ₁₂ cycloalkyl, substituted or unsubstituted -C ₆ -C ₁₀ aryl, substituted or unsubstituted 5-6-membered heterocycle containing from 1 to 4 heteroatoms independently selected from N, S and O, substituted or unsubstituted 3 ÷ 10-membered heterocycle containing from 1 to 4 heteroatoms independently selected from N, S and ABOUT;

R ⁷ is independently selected and is —F, —CN, —CF ₃ , —CHF ₂ , - (CH ₂ ) _t O (CH ₂ ) _s , substituted or unsubstituted —C ₁ -C ₆ alkyl, substituted or unsubstituted - C ₂ -C ₄ alkenyl, substituted or unsubstituted -C ₂ -C ₄ alkynyl, substituted or unsubstituted -C ₃ -C ₁₂ cycloalkyl, substituted or unsubstituted -C ₆ -C ₁₀ aryl, 5–6 membered heterocycle containing from 1 to 4 heteroatoms independently selected from N, S and / or O, substituted or unsubstituted 3 to 12 membered heterocyclyl containing from 1 to 4 heteroatoms independently selected from N, S and / or O;

t and s take values from 1 to 10;

B is independently selected and represents:

,

,

moreover, the asterisk indicates the place of attachment of substituents;

each substituent R ^k is independently selected and is —H, halogen, —CN, —NO ₂ , —CF ₃ , —CHF ₂ , CH ₂ F, substituted or unsubstituted —C ₁ -C ₆ alkyl, substituted or unsubstituted —OC ₁ -C ₆ -alkyl, substituted or unsubstituted -C ₂ -C ₄ alkenyl, substituted or unsubstituted -C ₂ -C ₄ -alkynyl or substituted or unsubstituted -C ₃ -C ₁₂ -cycloalkyl;

Q is independently selected and is —H, —C (═O) —R ^L or —S (= O) ₂ —R ^L ;

R ^L is independently selected and is —N (R ^b ) ₂ , substituted or unsubstituted —C ₁ -C ₆ alkyl, substituted or unsubstituted —C ₆ -C ₁₀ aryl, substituted or unsubstituted 5–6 membered heteroaryl containing from 1 to 4 heteroatoms independently selected from N, S and / or O, or a substituted or unsubstituted 3-12 membered heterocyclyl containing from 1 to 4 heteroatoms independently selected from N, S and / or O.

A separate subclass of compounds of interest includes compounds of general formula (Ia), general formula (IIa), or general formula (IIIa):

,

,

,

,

,

,

where R ³ represents:

,

,

moreover, the asterisk indicates the place of attachment of the substituent;

R ¹ , R ² are independently selected and are —H, or substituted or unsubstituted —C ₁ -C ₆ alkyl, wherein the substituents R ¹ and R ² , together with the carbon atom to which they are attached, can form a substituted or unsubstituted - C ₃ -C ₉ cycloalkyl;

each substituent R ^k is independently selected and is —H, —F, —Cl, —CN, —C ₁ -C ₆ -alkyl, —C ₃ -C ₆ cycloalkyl;

R ⁸ is independently selected and is —H, substituted or unsubstituted —C ₁ -C ₆ alkyl, substituted or unsubstituted —C ₃ -C ₉ cycloalkyl, substituted or unsubstituted —C ₆ -C ₁₀ aryl, substituted or unsubstituted 5 ÷ 6 membered heteroaryl containing from 1 to 4 heteroatoms independently selected from N, S and / or O, substituted or unsubstituted 3 ÷ 10 membered heterocyclyl containing from 1 to 4 heteroatoms independently selected from N, S and / or ABOUT;

R ⁹ is independently selected and is —H or substituted or unsubstituted —C ₁ -C ₆ alkyl.

A separate subclass of compounds of interest includes compounds of general formula (Ib), general formula (IIb), or general formula (IIIb):

,

,

,

,

,

,

where R ³ represents:

,

,

moreover, the asterisk indicates the place of attachment of the substituent;

R ¹ , R ² are independently selected and are —H, substituted or unsubstituted —C ₁ -C ₆ alkyl, with the substituents R ¹ and R ² , together with the carbon atom to which they are attached, can form substituted or unsubstituted —C ₃ -C ₁₂ cycloalkyl;

each substituent R ^k is independently selected and is —H, —F, —Cl, —C ₁ -C ₄ alkyl;

Y ⁴ is independently selected and is —C (R ⁿ ) ₂ -;

R ⁿ is independently selected and is —H, —F, —Cl, substituted or unsubstituted —C ₁ -C ₆ alkyl, —OR ^b , —N (R ^b ) ₂ ;

m, v are selected independently take values from 1 ÷ 6;

Y ⁵ is independently selected and is —O—, —S—, —S (= O) -, —S (= O) ₂ -, —C (R ⁿ ) _2, or substituents of the form:

,

,

,

,

или

;

,

,

,

,

or

;

R ^b is independently selected and is —H, substituted or unsubstituted —C ₁ -C ₆ alkyl, substituted or unsubstituted —C ₃ -C ₉ cycloalkyl, substituted or unsubstituted 5–6 membered heterocyclyl containing from 1 to 4 heteroatoms independently selected from N, S and / or O, or a substituted or unsubstituted 3 to 9 membered heterocyclyl containing from 1 to 4 heteroatoms independently selected from N, S and / or O.

A separate subclass of compounds of interest includes compounds of general formula (Ic), general formula (IIc), or general formula (IIIc):

,

,

,

,

,

,

where R ¹ , R ² are independently selected and are —H, substituted or unsubstituted —C ₁ -C ₆ alkyl, wherein the substituents R ¹ and R ² , together with the carbon atom to which they are attached, can form substituted or unsubstituted - C ₃ -C ₁₂ cycloalkyl;

each substituent R ^k is independently selected and is —H, —F, —Cl, —C ₁ -C ₄ alkyl;

R ^h is independently selected and is —H, halogen, —CHF ₂ , —CF ₃ , substituted or unsubstituted —C ₁ -C ₆ alkyl, substituted or unsubstituted —C ₃ -C ₆ cycloalkyl;

R ⁶ is independently selected and is substituted or unsubstituted -C ₁ -C ₆ -alkyl;

X ¹⁰ represents —CR ^g -;

R ^g is independently selected and represents H, —Cl, —OR ^b , —N (R ^b ) ₂ , substituted or unsubstituted —C ₁ -C ₄ alkyl, substituted or unsubstituted 4 to 10 membered heterocyclyl containing from 1 to 4 heteroatoms independently selected from N, S and / or O;

R ^b is independently selected and is —H, substituted or unsubstituted —C ₁ -C ₆ alkyl, substituted or unsubstituted —C ₃ -C ₉ cycloalkyl, substituted or unsubstituted —O — C ₆ aryl, substituted or unsubstituted —5 ÷ 6 membered heteroaryl containing from 1 to 4 heteroatoms independently selected from N, S and / or O, or substituted or unsubstituted 4 ÷ 9 membered heterocyclyl containing from 1 to 4 heteroatoms independently selected from N, S and / or O.

In some particular embodiments of the invention, the compounds of interest may be selected from the group:

или

or

The present invention also relates to the use of the subject compounds for the manufacture of a pharmaceutical composition for the treatment and / or prevention of cancer. In some embodiments, the cancer is associated with a malignant transformation of cells expressing the hCE1 (carboxyl esterase-1) enzyme. In certain particular embodiments, the disease is leukemia, a cancer of the liver, bladder, bronchi, lungs, nasopharynx, stomach, colon, pancreas or thyroid, head, neck, smooth muscle, urothelial cancer, or carcinoid tumor.

In some particular embodiments, the tumor is characterized by translocation of the MLL gene. In some particular embodiments, the tumor with translocation of the MLL gene is leukemia.

In addition, the invention provides pharmaceutical compositions for treating and / or preventing cancer in a subject, comprising an effective amount of a compound of the invention and at least one pharmaceutically acceptable excipient.

In some particular embodiments, the pharmaceutically acceptable excipient is a carrier, excipient and / or solvent.

In certain particular embodiments, the subject is a human or animal.

The invention also relates to a method for treating and / or preventing an oncological disease, comprising administering an effective amount of a compound of the invention.

The invention also includes the preparation of compounds of general formula (I), general formula (II), or general formula (III).

Definitions (terms)

The following definitions apply throughout this document unless otherwise indicated. In addition, unless otherwise indicated, all occurrences of functional groups are selected independently, two occurrences can be the same or different.

The term "hCE1" as used herein refers to the carboxyl esterase-1 enzyme.

The term “alkyl”, alone or as part of another substituent, refers to straight or branched chain saturated hydrocarbon groups, including hydrocarbon groups having the indicated number of carbon atoms (i.e., C _1-6 alkyl means from one to six carbon atoms ) Examples of alkyls include methyl, ethyl, n-propyl, iso-propyl.

The term “alkynyl” alone or as part of another substituent refers to hydrocarbon groups in which at least one carbon-carbon bond is a triple bond, while the remaining bonds can be simple, double or additional triple bonds, including hydrocarbon groups, from 2 to 6 carbon atoms. Examples of alkynyl groups include ethynyl, 1-propynyl, 2-propynyl, etc.

The term “alkenyl” by itself or as part of another substituent refers to hydrocarbon groups in which at least one carbon-carbon bond is a double bond, while the remaining bonds can be either single bonds or additional double bonds, including hydrocarbon groups containing from 2 to 6 carbon atoms. Examples of alkenyl groups include ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 2-methyl-2-propenyl, and the like.

The term "halogen" by itself or in part of another term refers to an atom of fluorine, chlorine, bromine or iodine.

The term “cycloalkyl” as used herein refers to groups having from 3 to 12 carbon atoms in a mono- or polycyclic structure, including spirocycles. By way of illustration, cycloalkyls include, but are not limited to, the following radicals: cyclopropyl, cyclopentyl, cyclohexyl, bicyclo [2.2.2] octanyl, spiro [5.5] undecanyl, which, as with other aliphatic or heteroaliphatic or heterocyclic substituents, may be substituted. The term “heterocycle”, “heterocyclyl” or “heterocyclic” means herein non-aromatic mono- or polycyclic systems (saturated or partially unsaturated) having from three to twelve atoms containing heteroatoms of N, O or S. The heterocycle can be attached to the main a fragment of the molecule through a nitrogen atom (N-heterocyclyl) or through a carbon atom. Heterocycles may also be substituted.

The term "cycloalkenyl" means in this document a partially unsaturated cycloalkyl containing from 5 to 12 carbon atoms, having in its composition from one to two double carbon-carbon bonds.

The term “aryl” as used herein means groups containing an aromatic ring having from five to ten carbon atoms. An example of aryl ring groups is phenyl.

The term “heteroaryl,” “heteroaryl ring,” as used herein, means a stable heterocyclic and polyheterocyclic aromatic moiety having 5-10 atoms in the ring. A heteroaryl group may be substituted or unsubstituted and may consist of one or more rings. Possible substituents include, but are not limited to, any of the previously mentioned substituents. Examples of typical heteroaryl rings are five- and six-membered monocyclic groups such as thienyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl, triazinyl, tetrazolyl and the like; as well as polycyclic heterocyclic groups such as benzo [b] thienyl, isobenzofuranyl, isoindolyl, benzimidazolyl, and the like. The term “heteroaryl” can be used equivalently with the terms “heteroaryl ring” or “heteroaromatic”.

An aryl group or heteroaryl group (including the heteroaryl portion of heteroarylalkyl or heteroaralkoxy moieties and the like) may contain one or more substituents. Examples of a suitable substituent on an unsaturated carbon atom of an aryl or heteroaryl group include, but are not limited to, halogen (F, Cl, Br or I), C _1-3 alkyl, —CN, —OH, C _1-3 alkyl, and others.

The term “substituted” should mean that one or more hydrogen atoms in an atom or group referred to as “substituted” are replaced by any of the listed groups, provided that the said atom has a normal valency or that the valency of the substituted corresponding atom of the group is not excessive, and that substitution leads to a stable connection. The term “substituted or unsubstituted” means that the compound or substructure is either unsubstituted or substituted, as defined in the application, with one or more substituents, as mentioned or as defined below.

In this document, alkyl, alkenyl, alkynyl, alkylene, cycloalkyl, cycloalkenyl, heterocyclyl, aryl and heteroaryl groups, as well as other substructures containing at least one hydrogen atom, can be replaced by one or more substituents:

-F, -Cl, -Br, -CN, -OH, -NO ₂ , -NH ₂ , -CF ₃ , -CHF ₂ , -CH ₂ F, -C ₁ -C ₄ -alkyl, -C ₂ -C _4- alkenyl, -C ₂ -C ₄ -alkynyl, -C ₃ -C ₉ -cycloalkyl, -4 ÷ 9-membered heterocyclyl attached via C or N atoms, -phenyl, -5 ÷ 6-membered heteroaryl attached via C or N atoms, —OR ^z , —N (R ^z ) ₂ , —NR ^z —C (= O) —R ^z , —NR ^z —S (= O) ₂ —R ^z , —SR ^z , -C (= O) -R ^z , -C (= O) -OR ^z , -C (= O) -N (R ^z ) ₂ , -OC (= O) -R ^z , -OC (= O) - (NR ^z ) ₂ , —SO — N (R ^z ) ₂ , —SO ₂ —R ^z , in which each R ^{z is} independently selected and represents —H, —C ₁ —C ₆ alkyl, —C C ₃ -C ₉ -cycloalkyl, -5 ÷ 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, S and / or O, or a substituted or unsubstituted 4 ÷ 9- lenny heterocyclyl containing from 1 to 4 heteroatoms.

This invention contains only those combinations of substituents and derivatives that form a stable or chemically possible compound. A stable or chemically feasible compound is a compound whose stability is sufficient for its synthesis and analytical detection. Preferred compounds of this invention are sufficiently stable and do not decompose at temperatures up to 40 ° C in the absence of chemically active conditions, for at least one week.

Certain compounds of this invention may exist in tautomeric forms, and this invention includes all such tautomeric forms of such compounds, unless otherwise indicated.

For example, the compounds of the present invention may exist as tautomers A and B in a state of dynamic equilibrium. Under normal conditions, their separation is not possible, therefore, the pharmacological properties of the compounds of the present invention are a combination of the effects of tautomers.

An example of tautomeric forms of the compounds of the invention is:

Unless otherwise indicated, the structures depicted herein also include all stereoisomers, i.e., R- and S-isomers for each asymmetric center. In addition, individual stereochemical isomers, as well as enantiomers and diastereomeric mixtures of the present compounds, are also the subject of this invention. Thus, this invention encompasses each diastereomer or enantiomer substantially free of other isomers (> 90%, and preferably> 95% molar purity), as well as a mixture of such isomers.

A particular optical isomer can be obtained by resolving the racemic mixture in accordance with a standard procedure, for example, by preparing diastereoisomeric salts by treatment with an optically active acid or base, followed by crystallization of the diastereomer mixture, followed by isolation of the optically active bases from these salts. Examples of suitable acids are tartaric, diacetyl tartaric, dibenzoyl tartaric, ditoluolvic and camphorsulfonic acid. Another technique for separating optical isomers is to use a chiral chromatographic column. In addition, another separation method involves the synthesis of covalent diastereomeric molecules by reacting the compounds of the invention with optically pure acid in an activated form or optically pure isocyanate. The resulting diastereomers can be separated by conventional methods, for example, chromatography, distillation, crystallization or sublimation, and then hydrolyzed to obtain an enantiomerically pure compound.

The optically active compounds of this invention can be prepared using optically active starting materials. Such isomers may be in the form of a free acid, free base, ester or salt.

The present invention includes all pharmaceutically acceptable isotopically labeled compounds of the present invention, in which one or more atoms is replaced by atoms having the same atomic number, but an atomic mass or mass number other than the atomic mass or mass number commonly found in nature.

Examples of isotopes suitable for inclusion in the compounds of the invention include hydrogen isotopes such as ² N and ³ N, carbon such as ¹¹ C, ¹³ C and ¹⁴ C, chlorine such as ³⁶ Cl, fluorine such as ¹⁸ F, iodine, such as ¹²³ I and ¹²⁵ I, nitrogen, such as ¹³ N and ¹⁵ N, oxygen, such as ¹⁵ O, ¹⁷ O and ¹⁸ O, a philosopher, such as ³² P, and sulfur, such as ³⁵ S.

Some isotopically labeled compounds of formula (I), compounds of formula (II), or compounds of formula (III), for example, those that include a radioactive isotope, are used in tissue distribution studies of a drug and / or substrate. In particular, for this purpose, radioactive isotopes are used, such as tritium, i.e. ³ N, and carbon-14, i.e. ¹⁴ C, due to the ease of their introduction and the availability of detection tools.

Substitution with heavier isotopes such as deuterium, i.e. ² N, can provide certain therapeutic effects due to metabolic stability, for example, an increase in half-life in vivo or a decrease in dosing rates, and therefore may be preferred in some cases.

Isotopically labeled compounds of the invention can be prepared by conventional methods known to one skilled in the art or by methods similar to those described in the accompanying examples of synthetic methods using appropriate isotopically labeled reagents instead of the unlabeled previously used reagent.

Pharmaceutically acceptable solvates in accordance with the invention include solvates where the crystallization solvent may be isotopically substituted, for example, D ₂ O, d6-acetone, d6-DMSO.

The term “solvate” refers to an association or complex of one or more solvent molecules and a compound of the invention. Examples of solvate forming solvents include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine.

The term “hydrate” refers to a complex wherein the solvent molecules are water.

The compounds of the present invention may exist in free form or, if desired, in the form of a pharmaceutically acceptable salt or other derivative. As used herein, the term “pharmaceutically acceptable salt” refers to those salts which, within the framework of a medical opinion, are suitable for use in contact with human and animal tissues without undue toxicity, irritation, allergic reaction, etc., and correspond to a reasonable balance of benefits and risk. Pharmaceutically acceptable salts of amines, carboxylic acids, phosphonates and other types of compounds are well known in medicine. Salts can be prepared in situ during the isolation or purification of the compounds of the invention, and can also be prepared separately by reacting the free acid or free base of the compound of the invention with a suitable base or acid, respectively. An example of pharmaceutically acceptable, non-toxic acid salts is the amino group formed by inorganic acids such as hydrochloric, hydrobromic, phosphoric, sulfuric and perchloric acids, or organic acids such as acetic, oxalic, maleic, tartaric, succinic or malonic acids, or the resulting other methods used in this field, for example, using ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentane propionate, digluconate, dodecyl sulfate, heptofluorosulfonate, glucose gluconate, formate glucose phosphate heptane, hexanate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalene sulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pec ulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecane, valerate and the like. Typical alkali and alkaline earth metal salts contain sodium, lithium, potassium, calcium, magnesium and others. In addition, pharmaceutically acceptable salts may contain, if desired, non-toxic cations of ammonium, quaternary ammonium and amine obtained using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates and aryl sulfonates.

Description of drawings

Figure 1. The effect of the specific carboxyl esterase-1 BNPP inhibitor ((bis (4-nitrophenyl) phosphate) on the selectivity profile of the compound of Example 50 on a panel of malignant cell lines with expression of carboxyl esterase hCE1 (MV4-11, U937) and hCE1-negative (CCRF- CEM, SK-Mel-103) The cytotoxicity of the test compound was determined using a standard fluorimetric method after 72 hours of incubation in the absence or presence of BNPP (100 μmol / L):

A) The cytotoxicity profile of the compound of Example 50 on a panel of 4 cell lines: MV4-11 and U937 (hCE1-positive), CCRF-CEM and SK-Mel-103 (hCE1-negative) when incubated with 0.3% DMSO (control );

B) The cytotoxicity profile of the compound of Example 50 on a panel of 4 cell lines: MV4-11 and U937 (hCE1-positive), CCRF-CEM and SK-Mel-103 (hCE1-negative) when incubated with 0.3% DMSO in the presence of 100 μmol / L BNPP-specific hCE1 carboxyl esterase inhibitor.

Figure 2. The cytotoxicity profile of the compound of Example 36 on a panel of 4 cell lines: MV4-11 and U937 (hCE1-positive), CCRF-CEM and SK-Mel-103 (hCE1-negative) when incubated with 0.3% DMSO ( the control).

Figure 3. The cytotoxicity profile of the compound of Example 36 on a panel of 4 cell lines: MV4-11 and U937 (hCE1-positive), CCRF-CEM and SK-Mel-103 (hCE1-negative) after incubation in human plasma (10 min incubation in human plasma (hCE1-negative).

Figure 4. Cytotoxicity of the compounds of formula (I) with respect to non-cancerous macrophages (monocytic cells expressing carboxyl esterase) isolated from the abdominal cavity of mice.

Figure 5. Cytotoxicity of compound M2 of formula (III) with respect to non-cancerous macrophages (monocytic cells expressing carboxyl esterase) isolated from the abdominal cavity of mice.

Figure 6. The antitumor activity of the compound of Example 87 in a subcutaneous transplanted acute myeloid leukemia MV4-11 model with translocation of the MLL-gene in female SCID mice (n = 10) when given intravenously at a dose of 100 mg / kg / day. The volume of the subcutaneous tumor on the first day of measurement is taken as 100%. all tumor volumes in subsequent measurements correlated with this value. At the time of the last measurement, T / C = 61% (p = 0.014). During the experiment, no obvious signs of toxicity were observed in animals.

Figure 7. The antitumor activity of the compound of Example 29 in a subcutaneous transplanted acute myeloid leukemia MV4-11 model with translocation of the MLL gene in female SCID mice (n = 10) with iv administration at a dose of 80 mg / kg / day. The volume of the subcutaneous tumor on the first day of measurement is taken as 100%. all tumor volumes in subsequent measurements correlated with this value. At the time of the last tumor measurement, T / C = 41% (p <0.0001). During the experiment, no obvious signs of toxicity were observed in animals.

DETAILED DESCRIPTION OF THE INVENTION

The implementation of the invention

Overview of the methods for producing compounds of the invention

The compounds of the present invention can be prepared using the synthetic methods described below. The listed methods are not exhaustive and allow the introduction of reasonable modifications. These reactions should be carried out using suitable solvents and materials. When implementing these general procedures for the synthesis of specific substances, it is necessary to take into account the functional groups present in the substances and their influence on the course of the reaction. To obtain some substances, it is necessary to change the order of the stages or give preference to one of several alternative synthesis schemes. It should be understood that these and all examples cited in the application materials are not limiting and are provided merely to illustrate the present invention.

Compounds of general formulas (I), (II) and (III) can be prepared according to general Scheme 1.

Compounds of general formula (I) can be prepared in two synthetic steps as indicated in Scheme 1. Compounds 1 can be prepared by reacting available alkyl 4-haloacetoacetates A and phenylisothiocyanates B in the presence of a strong base, for example sodium hydride, in a suitable aprotic solvent , for example, THF with yields of 20-80%. Compounds of general formula (I) containing an unsubstituted nitrogen atom (Q = N-H) are prepared by fusion of intermediates 1 with the corresponding aldehydes C in the presence of catalytic amounts of basic amines, for example 20% molar ethylenediamine diacetate. Compounds of general formula (II) can be prepared by controlled alkaline hydrolysis of compounds (I) in an aqueous medium, for example, using lithium hydroxide in a water-THF system, followed by acidification of the reaction medium. Compounds of general formula (III) can be prepared by thermal decarboxylation of compounds of general formula (II) in a suitable solvent, for example, DMSO. Compounds of general formula (I) and (III) containing a substituted nitrogen atom (Q = acetyl, sulfonyl) can be obtained by treating compounds (I) and (III), with Q = H, with appropriate acetyl chlorides or sulfonyl chlorides in the presence of an organic base, for example triethiamine. Compounds of general formula (II) containing a substituted nitrogen atom (Q = acetyl, sulfonyl) can be prepared by alkaline hydrolysis of N-substituted compounds (I).

In some embodiments of the present invention, compounds of formula (I) (for example, when R ¹ R ² CHOH = cycloalkyl, sec-alkyl, aryl, heteroaryl) can be obtained in high yields according to Scheme 2 directly from acids (II) and the corresponding readily available alcohols R ¹ R ² CHOH using various condensing agents such as CDI, EEDQ, BOP, TBTU, HBTU, etc. in the presence of an organic base (e.g. triethylamine or diisopropylamine) in a suitable organic solvent, e.g. dichloromethane, DMF, DMSO or acetonitrile. Alternatively, esters of general formula (I) can be prepared from acids of general formula (II) via an intermediate synthesis of acid halides, for example acid chlorides, followed by their reaction with alcohols R ¹ R ² CHOH in the presence of a base.

The synthesis of certain specifically substituted aldehydes C of the general formula of ASNO is described below.

The synthesis of certain compounds of the invention is described below.

Reagents and synthetic methods

All starting reagents and solvents were obtained from commercial sources and were used without further purification. Reactions sensitive to the presence of moisture or oxygen were carried out in an atmosphere of argon or nitrogen; anhydrous solvents were prepared according to standard procedures. Chromatographic solvents were HPLC purity and used without further purification. Reaction progress was monitored by thin layer chromatography (TLC) using thin layer chromatography plates Merck Silica Gel 60 F-254; UV, iodine vapor, or an aqueous solution of potassium permanganate were used to develop the plates. For preparative flash column chromatography, Merck Silica Gel 60 (0.015-0.040 mm) was used. All compounds obtained, unless otherwise indicated, had a purity of at least 90% according to HPLC analysis at a wavelength of 254 nm.

HPLC analysis

HPLC analysis was performed on an Agilent 1200 instrument under the following conditions:

1. Column: Synergy Hydro-RP 250 × 4.6 mm, 4 microns;

2. Flow rate: 1 ml / min; column temperature 25 ° C;

3. Mobile phase (isocratic mode): acetonitrile / water (65:35);

4. UV detection at a wavelength of 254 nm;

HPLC / MS analysis

HPLC / MS analysis was performed using an Agilent 1100 chromatograph with a tandem mass spectrometer with a chemical ionization detector at atmospheric pressure in positive and negative ion fixation mode (APCI):

1. Column type: Phenomenex Onyx Monolithic C18; 50 × 4.6 mm, 5 μm (Part No: СНО-7643);

2. Solvent for sample preparation: 50% DMSO, 50% acetonitrile;

3. Flow rate: 3.75 ml / min; column temperature 25 ° C;

4. Mobile phases: A = 0.1% solution of TFA in acetonitrile / water (2.5: 97.5), B = 0.1% 0.1% solution of TFA in acetonitrile;

5. Gradient:

6. The following detectors were used for analysis:

- LED matrix (DAD), in the wavelength range of 200-800 nm;

- mass spectrometer: chemical ionization at atmospheric pressure (APCI) in the detection mode of positive and negative ions;

- evaporative light scattering detector (ELSD), model PL-ELS 2100;

7. Total analysis time: 3 min;

8. Injection volume 1.7 μl.

NMR

NMR spectra on ¹ H and ¹³ C nuclei were recorded on a Bruker Advance 400 instrument with operating purities of 400 and 100 MHz, respectively. The signals of residual non-deuterated chloroform (δН = 7.28 ppm), CDCl ₃ (δС = 77.16 ppm), non-deuterated DMSO (δН = 2.50 ppm) and DMSO-d6 (δС = 39.52) were used as internal standards ppm).

When describing the spectra, the following notation was used: s = singlet, d = doublet, t = triplet, q = quartet, quint = quintet, m = multiplet, br = wide.

Preparative HPLC

The compounds were purified by preparative high performance liquid chromatography using an Agilent 1200 HPLC Preparative instrument;

Column: Phenomenex Luna C18 (L1), 100 × 30 mm, 5 μm;

Solvent for dissolving samples: 50% DMSO, 50% acetonitrile;

Flow rate: 30 ml / min; column temperature 25 ° C;

Mix separation time: 14 min; total program time: 30 min;

Mobile phase: 0.1% solution of formic acid in a mixture of acetonitrile / water (35:65).

Synthesis of alkyl 4-oxo-2- (arylamino) -4,5-dihydrothiophene-3-carboxylates (1)

The synthesis of a series of alkyl (cycloalkyl) 4-oxo-2- (arylamino) -4,5-dihydrothiophene-3-carboxylates of general formula 1 was carried out according to general synthetic Scheme 1 from commercially available reagents.

General procedure for the synthesis of 4-oxo-2- (arylamino) -4,5-dihydrothiophene-3-carboxylates (1)

A solution of alkyl 4-chloro (bromo) acetoacetate A (0.53 mol, 1 equiv.) In THF (80 ml) was added in small portions to a suspension of sodium hydride (60% suspension in mineral oil, 21.2 g, 0.53 mol, 1 equiv.) THF (800 ml) at 0 ° C. The reaction mixture was stirred at this temperature until the evolution of hydrogen was complete. To the resulting pale yellow solution was added a solution of the corresponding arylisothiocyanate B (0.53 mol, 1 equiv.) In THF (80 ml). After 1 minute, a pale yellow suspension formed, which was stirred for 5 hours at room temperature (rt), after which it was poured into cold water (1.5 L). The obtained precipitate of the target compound (1) was filtered on a glass filter, washed thoroughly with water and dried in air.

The yields of 4-oxo-2- (arylamino) -4,5-dihydrothiophene-3-carboxylates of the general formula (1) are shown in Table 3.

General method for the synthesis of compounds of General formula (I)

A mixture of compound 1 (1 mmol, 1 equiv.), The corresponding aldehyde C AC (= O) H (1.5 mmol, 1.5 equiv.) And ethylenediamine diacetate (0.25 mmol, 0.25 equiv.) Was heated at 120 ° C with stirring until a uniform melt. The resulting reaction mixture was kept for 8 hours at this temperature with constant stirring (monitoring the progress of the reaction by TLC), then cooled to room temperature and dissolved in a small amount of DCM. A solution of the target compound in DCM was applied to dry silica gel and eluted with ethyl acetate (in the case of polar compounds, a DCM / methanol 10: 1 mixture was used). A portion of the target compounds (I) was purified by preparative HPLC.

An alternative method for the synthesis of compounds of general formula (I) from acids of general formula (II) by a condensation reaction with alcohols or other hydroxyl compounds.

Acid (II) (0.5 mmol, 1 equiv.) Was dissolved in anhydrous DCM (5 ml), then benzotriazol-1-yloxy) tris (dimethylamino) phosphonium BOP hexafluorophosphate (265 mg, 0.6 mmol, 1.2 equiv.) Was added in one portion with stirring. .) and the reaction mixture was stirred for 10 minutes at rt .; then the corresponding alcohol R ¹ R ² CHOH (0.75 mmol, 1.5 equiv.) and DIPEA (1.5 mmol, 1.5 equiv.) were successively added to the reaction mixture. The resulting mixture was stirred 24 hours at rt, then washed successively with saturated aqueous solutions of hydrogen carbonate and sodium chloride (10 ml each). The organic layer was separated, dried over anhydrous sodium sulfate and evaporated under reduced pressure on a rotary evaporator. The target product was isolated by preparative HPLC.

General method for the synthesis of compounds of formula (II)

To a solution of ether (I) (1 mmol) in a mixture of methanol (10 ml), THF (10 ml) and water (10 ml) was added lithium hydroxide monohydrate (10 mmol, 10 eq.). The reaction mixture was boiled for 7 hours, after which it was cooled to 0-5 ° C and 2 M hydrochloric acid (10 mmol) was added dropwise with stirring. The resulting small suspension of acid (II) was filtered on a glass filter, washed with a small amount of cold water and dried in air to constant weight.

General method for the synthesis of compounds of formula (III)

A solution of acid (II) (0.5 mmol) in anhydrous DMSO (4 ml) was heated with vigorous stirring in an argon atmosphere at a temperature of 120 ° C for 6 hours, the progress of the reaction was monitored by TLC. Then the reaction mixture was cooled to rt, diluted with cold water (20 ml) and extracted with diethyl ether (3 × 20 ml). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure on a rotary evaporator. The target compound (III) was purified by preparative HPLC.

Synthesis of 5-amino-substituted-1,3-dimethyl-1H-pyrazole-4-carbaldehydes (5)

To a solution of ethyl acetoacetate (72 ml, 0.57 mol) in ethanol (500 ml) at rt methylhydrazine (30 ml, 0.57 mol) was added in one portion. The resulting reaction mixture was boiled with stirring for 5 hours, after which it was cooled to rt. and evaporated to dryness on a rotary evaporator under reduced pressure. The dry residue was triturated with diethyl ether, the precipitate of the desired pyrazolone 3 was filtered on a glass filter, washed with a small amount of diethyl ether and dried in air to constant weight. Yield 54.5 g (85%).

Synthesis of 5-chloro-1,3-dimethyl-1H-pyrazole-4-carbaldehyde (4)

To a mixture of pyrazolone 3 (30 g, 0.27 mol, 1 equiv.) And POCl ₃ (100 ml, 1.08 mol, 4 equiv.) With vigorous stirring at rt anhydrous DMF (25 ml, 0.324 mol, 1.2 equiv.) was added dropwise. The resulting reaction mixture was stirred at 80 ° C for 7 hours, then cooled to rt. The reaction mixture was slowly poured into finely divided ice (2.5 kg) and allowed to warm to rt, after which it was extracted with ethyl acetate (3 × 200 ml). The combined organic extracts were washed with saturated aqueous sodium chloride (200 ml), dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure on a rotary evaporator. Crude product 4 was purified by recrystallization from ethanol (100 ml). Yield 15.6 g (37%).

General method for the synthesis of 5-amino-substituted-1,3-dimethyl-1H-pyrazole-4-carbaldehydes (5)

To a solution of aldehyde 4 (1.58 g, 10 mmol) in n-butanol (15 ml) with stirring, at rt the corresponding amine (R ') ₂ NH (12 mmol, 1.2 equiv.) was added in one portion, and then triethylamine (2.20 ml, 16 mmol 1.6 equiv.). The resulting reaction mixture was boiled for 2-4 hours (monitoring the progress of the reaction by TLC), then cooled to rt. and evaporated under reduced pressure on a rotary evaporator. Water (10 ml) was added to the residue and extracted with ethyl acetate (3 × 20 ml). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. Target product 5 was isolated by silica gel column chromatography using a n-hexane / ethyl acetate gradient.

The yields of 5-amino-substituted-1,3-dimethyl-1H-pyrazole-4-carbaldehydes 5 are shown in Table 4.

* 5- (Dimethylamino) -1,3-dimethyl-1H-pyrazole-4-carbaldehyde (5b) was synthesized in accordance with the following procedure:

Aldehyde 4 (3.16 g, 0.02 mol) was dissolved in a solution of aqueous dimethylamine (40% w / w, 30 ml). The resulting mixture was heated at 80 ° C in a glass thick-walled reactor for 7 hours. After that, the reactor was cooled to rt, overpressure was vented, and the reaction mixture was extracted with ethyl acetate (3 × 100 ml). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and evaporated to dryness on a rotary evaporator under reduced pressure. In the residue, the desired aldehyde 5b was obtained as a yellow oil, which was used in the next step without further purification. Yield: 2.66 g (84%).

Synthesis of 5-alkoxy-1,3-dimethyl-1H-pyrazole-4-carbaldehydes (6a / b)

The corresponding alcohol R '' - OH (22 mmol, 2.2 equiv.) Was dissolved in anhydrous THF (50 ml) at rt. and with stirring, sodium hydride was added as a 60% suspension in liquid paraffin (20 mmol, 2 equiv.). After 10 minutes, aldehyde 4 (10 mmol, 1 equiv.) Was added to the reaction mixture. The resulting reaction mixture was boiled for 7 hours with stirring, then cooled to rt. and extracted with ethyl acetate (3 × 10 ml). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure on a rotary evaporator. Compound 6 was purified by flash column chromatography on silica gel using ethyl acetate / n-hexane (5: 1) as an eluent.

Outputs:

6a 0.97 g (62%);

6b 1.37 g (75%).

Synthesis of 5-phenoxy-1,3-dimethyl-1H-pyrazole-4-carbaldehyde (7)

A mixture of phenol (1.04 g, 11 mmol, 1.1 equiv.), Potassium carbonate (2.07 g, 15 mmol, 1.5 equiv.), Aldehyde 4 (1.59 g, 10 mmol, 1 equiv.) And potassium iodide (0.166 g, 1 mmol , 0.1 equiv.) In anhydrous acetonitrile (20 ml) was boiled with vigorous stirring for 8 hours (the completeness of the reaction was monitored by TLC), and then cooled to rt. The reaction mixture was diluted with cold water (30 ml) and was extracted with ethyl acetate (3 × 50 ml). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure on a rotary evaporator. Compound 7 was purified by silica gel column chromatography using ethyl acetate / n-hexane (3: 1) as an eluent. Yield: 0.97 g (32%).

General method for the synthesis of substituted

2 - [(4-hydroxybut-2-yn-1-yl) oxy] benzaldehyde (10)

Synthesis of 2- (prop-2-yn-1-yloxy) benzaldehyde (8)

To a mixture of salicylic aldehyde (8.74 ml, 82 mmol, 1 equiv.) And potassium carbonate (11.33 g, 82 mmol) in anhydrous DMF (40 ml) with vigorous stirring was added dropwise propargyl bromide (6.83 ml, 91 mmol, 1.1 equiv. ) The reaction mixture was stirred at rt. 15 hours, then diluted with water (200 ml) and extracted with ethyl acetate (3 × 150 ml). The combined organic extracts were washed with water, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure on a rotary evaporator. Aldehyde 8 was obtained in residue, which was used in the next step without further purification. Yield: 9.59 g (73% based on salicylic aldehyde).

Synthesis of 1- (dimethoxymethyl) -2- (prop-2-yn-1-yloxy) benzene (9a)

To a mixture of compound 8 (9.59 g, 60 mmol, 1 eq.), Trimethylorthoformate (360 mmol, 6 eq.), Anhydrous methanol (200 ml) and p-toluenesulfonic acid (3 mmol, 0.05 eq.) Were added to a mixture of compound 8 (9.59 g, 60 mmol, 1 equiv.) .). The reaction mixture was stirred at 0 ° C. for 40 minutes, and then diluted with saturated aqueous potassium carbonate (400 ml) and extracted with ethyl acetate (3 × 150 ml). The combined organic extracts were washed with water, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure on a rotary evaporator. The oily compound 9a was obtained in the residue, which was used in the next step without further purification. Yield: 11.01 g (89% of theory).

Synthesis of 2- [2- (prop-2-yn-1-yloxy) phenyl] -1,3-dioxane (9b)

To a mixture of compound 8 (5.76 g, 36 mmol, 1.0 equiv.), Triethylorthoformate (98%, 6.52 g, 7.30 ml, 43 mmol, 1.2 equiv.) And 1,3-propanediol (13.67 g, 13.00 ml, 0.180 mol, 5.0 equiv.) Tetrabutylammonium tribromide (1.73 g, 4 mmol, 0.10 equiv.) Was added. The resulting homogeneous reaction mixture was stirred at RT until traces 8 disappeared (TLC control). After completion of the reaction, it was diluted with saturated aqueous sodium hydrogen carbonate solution (200 ml) and extracted with ethyl acetate (3 × 150 ml). The combined organic extracts were washed with water, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure on a rotary evaporator. Target compound 9b was purified by silica gel column chromatography using 5: 1 n-hexane / ethyl acetate mixture as an eluent. Yield: 31 g (93%).

Synthesis of substituted acetylenes of the general formula (10)

To a solution of aldehyde 9a or 9b (48.5 mmol, 1 equiv.) In anhydrous THF (50 ml) at -78 ° C, n-butyllithium in (2.5 M solution in n-hexane, 21 ml) was added over 40 minutes with vigorous stirring. , 52.5 mmol, 1.1 equiv.) And the resulting mixture was stirred for an additional 10 minutes at the same temperature. Then, a solution of the corresponding carbonyl compound R ^b C (= O) R ^c (48.5 mmol, 1 equiv.) In THF was added dropwise to a solution of the formed lithium salt of acetylene 9a / b, and the reaction mixture was stirred for another 40 minutes at -78 ° C. Then the cooling bath was removed, and the reaction mixture was slowly heated to 5 ° C, after which a 1% hydrochloric acid solution (200 ml) was carefully added to it and extracted with ethyl acetate (3 × 100 ml). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure on a rotary evaporator. Compound 10 was obtained in residue, which was used in the next step without further purification. The yields of compounds 10 are shown in Table 5.

Synthesis of substituted 2 - [(4-alkoxybut-2-yn-1-yl) oxy] benzaldehydes of the general formula (13)

Synthesis of O-alkylated acetals (12)

Protected alcohol 11 (20 mmol, 1 equiv.) Was dissolved in THF (1 M solution) in a nitrogen atmosphere, the solution was cooled to 0 ° C, sodium hydride (40 mmol, 2 equiv.) Was added in small portions with stirring, and the resulting suspension was stirred for 30 minutes at the same temperature. Then the corresponding alkyl iodide R ^c -I was added dropwise and the reaction mixture was stirred for another 30 minutes, after which its temperature was slowly brought to rt. and stirred for another 12 hours. After completion of the reaction, the reaction mixture was diluted with ice water and extracted with ethyl acetate (3 × 100 ml). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure on a rotary evaporator. The oily target compound 12 was obtained in residue, which was used in the next step without further purification.

Synthesis of O-alkylated Benzyl Alcohols (13)

Acetal 12 (1 equiv.) Was added to an aqueous solution of acetic acids (0.05 equiv., 1M), the resulting mixture was stirred at rt. 12 hours, after which it was extracted with diethyl ether. The combined organic extracts were dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure on a rotary evaporator, obtaining the target compound 13 in the residue. The yields of compounds 13 are shown in Table 6.

Synthesis of 5- (2-formylphenoxy) -2-methylpent-3-in-2-yl acetate (16)

Synthesis of acetic acid 4- (2- [1,3] dioxan-2-yl-phenoxy) -1,1-dimethyl-but-2-ynyl ether (15)

A mixture of compound 14 (1.437 g, 5.2 mmol, 1.0 equiv.), Acetic anhydride (0.908 g., 0.84 ml., 8.9 mmol, 1.7 equiv.) And 4- (dimethylamino) pyridine (0.05 g., 0.4 mmol. 0.08 equiv.) In a 1: 1 solution of pyridine / DCM (20 ml) was stirred at rt 24 hours. Then the reaction mixture was carefully diluted with cold 1N hydrochloric acid (40 ml) and extracted with dichloromethane (3 × 20 ml). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure on a rotary evaporator to give crude product 15, which was purified by silica gel column chromatography using 5: 1 n-hexane / ethyl acetate mixture as an eluent. Yield (15): 1.26 g (75%), colorless oil.

Synthesis of 5- (2-formylphenoxy) -2-methylpent-3-in-2-yl acetate (16)

1M HCl (7.8 ml) was added to a solution of compound 15 (1.26 g, 3.9 mmol) in THF (40 ml) and the reaction mixture was stirred at rt. 16 hours, then was extracted with ethyl acetate (3 × 20 ml). The combined organic extracts were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure on a rotary evaporator. The evaporation residue was purified by silica gel column chromatography using a 10: 1 n-hexane / ethyl acetate mixture as an eluent, to thereby give the target compound 16 as a colorless oil. Yield 1.02 g (100%).

Examples of the synthesis of some compounds of General formula (I)

Example 1

The specified compound was obtained according to the General scheme 1 of synthesis (I) from compound 1b-4 and aldehyde 10t Yield: 290.0 mg (50%).

HPLC / MS (APCI): m / z = 580 [M + H] ⁺ , 2.53 min.

Example 2

The specified compound was obtained according to the General scheme 1 of synthesis (I) from compound 1a-1 and 1- (but-2-yn-1-yl) -5-chloro-1H-pyrrole-2-carbaldehyde, which was synthesized by alkylation of 5- chloro-1H-pyrrole-2-carbaldehyde 1-bromobut-2-in in the presence of sodium hydride (1.1 equiv.) in anhydrous THF at RT. Yield: 86.7 mg (21%).

¹ H NMR (400 MHz, DMSO-d ₆ , ppm): 1.77 (s, 3H), 3.76 (s, 3H), 4.94 (d, J = 2.2 Hz, 2H), 6.33 (d, J = 4.3 Hz, 1H), 6.39 (d, J = 4.3 Hz, 1H), 7.38-7.46 (m, 1H), 7.49-7.53 (m, 3H), 7.56 (s, 1H), 11.18 (br. S., 1H);

HPLC / MS (APCI): m / z = 413 [M + H] ⁺ , 2.83 min.

Example 3

The specified compound was obtained according to the General scheme of synthesis (I) from compound 1b-4 and aldehyde 10s on a scale of 0.2 mmol. Yield: 22.0 mg (19%).

HPLC / MS (APCI): m / z = 580 [M + H] ⁺ , 2.59 min.

Example 4

The specified compound was obtained according to the General scheme 1 synthesis (I) from compound 1A-2 and commercially available 2- (pyridin-2-ylmethoxy) benzaldehyde. Yield: 229.3 mg (50%).

¹ H NMR (400 MHz, DMSO-d ₆ , ppm): 1.28 (t, J = 7.03 Hz, 3H), 4.26 (q, J = 7.01 Hz, 2H), 5.27 (s, 2H), 7.02 (t, J = 7.52 Hz, 1H), 7.17 (d, J = 8.19 Hz, 1H), 7.32-7.43 (m, 4H), 7.44-7.53 (m, 5H), 7.87 (td, J = 7.67, 1.53 Hz, 1H), 7.97 (s, 1H), 8.58 (d, J = 4.65 Hz, 1H), 11.27 (none, 1H);

HPLC / MS (APCI): m / z = 459 [M + H] ⁺ , 2.58 min.

Example 5

The specified compound was obtained according to the General scheme 1 synthesis (I) from compound 1b-4 and aldehyde 10r in a scale of 0.2 mmol. Yield: 17.3 mg (15%).

HPLC / MS (APCI): m / z = 578 [M + H] ⁺ , 2.65 min.

Example 6

The specified compound was obtained according to the General scheme 1 synthesis (I) from compound 1b-4 and aldehyde 10q in a scale of 0.2 mmol. Yield: 9.0 mg (8%).

HPLC / MS (APCI): m / z = 564 [M + H] ⁺ , 2.60 min.

Example 7

The specified compound was obtained according to the General scheme 1 of synthesis (I) from compound 1A-2 and aldehyde 6a. Yield: 167.8 mg (42%).

¹ H NMR (400 MHz, CDCl ₃ , ppm): 1.44 (t, J = 7.1 Hz, 3H), 2.23 (s, 3H), 3.63 (s, 3H), 3.75 (s, 3H), 4.40 (q, J = 7.1 Hz, 2H), 7.27 (s, 1H), 7.31-7.41 (m, 3H), 7.45-7.48 (t, J = 7.8 Hz, 2H), 7.64 (s, 1H), 11.50 ( br. s., 1H);

HPLC / MS (APCI): m / z = 400 [M + H] ⁺ , 1.49 min.

Example 8

The specified compound was obtained according to General scheme 1 for the synthesis of (I) from compound 1a-2 and commercially available 2- (2,2,2-trifluoroethoxy) benzaldehyde. Yield: 319.1 mg (71%).

¹ H NMR (400 MHz, CDCl ₃ , ppm): 1.29 (t, J = 7.09 Hz, 3H), 4.26 (q, J = 6.93 Hz, 2H), 4.86 (q, J = 8.60 Hz, 2H ), 7.11 (t, J = 7.52 Hz, 1H), 7.21 (d, J = 8.44 Hz, 1H), 7.34-7.55 (m, 7H), 7.86 (s, 1H), 11.26 (br.s., 1H );

HPLC / MS (APCI): m / z = 450 [M + H] ⁺ , 1.99 min.

Example 9

The specified compound was obtained according to the General scheme 1 synthesis (I) from compound 1A-2 and commercially available 2- (prop-2-en-1-yloxy) benzaldehyde. Yield: 228.2 mg (56%).

¹ H NMR (400 MHz, DMSO-d ₆ , ppm): 1.45 (t, J = 7.1 Hz, 3H), 4.41 (q, J = 7.1 Hz, 2H), 4.59 (d, J = 5.1 Hz , 2H), 5.29 (d, J = 10.5 Hz, 1H), 5.43 (d, J = 17.4 Hz, 1H), 5.97-6.11 (m, 1H), 6.90 (d, J = 8.4 Hz, 1H), 6.97 (t, J = 7.3 Hz, 1H), 7.39 (d, J = 7.7 Hz, 4H), 7.44-7.54 (m, 3H), 8.26 (s, 1H), 11.49 (br.s., 1H);

HPLC / MS (APCI): m / z = 408 [M + H] ⁺ , 2.17 min.

Example 10

The specified compound was obtained according to the General scheme 1 of synthesis (I) from compound 1A-2 and commercially available 2- (but-3-yn-1-yloxy) benzaldehyde. Yield: 180.4 mg (43%).

¹ H NMR (400 MHz, DMSO-d ₆ , ppm): 2.66 (td, J = 6.39, 2.63 Hz, 2H), 2.88 (t, J = 2.51 Hz, 1H), 3.76 (s, 3H) , 4.14 (t, J = 6.48 Hz, 2H), 7.01 (t, J = 7.64 Hz, 1H), 7.11 (d, J = 8.19 Hz, 1H), 7.33-7.55 (m, 7H), 7.83-8.01 ( m, 1H), 11.23 (br. s., 1H);

HPLC / MS (APCI): m / z = 420 [M + H] ⁺ , 1.79 min.

Example 11

The specified compound was obtained according to General scheme 1 for the synthesis of (I) from compound 1a-2 and 2- (but-2-in-1-yloxy) benzaldehyde, which was synthesized by alkylation of salicylic aldehyde 1-bromobut-2-in (1.3 equiv. ) in the presence of potassium carbonate in boiling acetonitrile. Yield: 268.5 mg (64%).

¹ H NMR (400 MHz, DMSO-d ₆ , ppm): 1.29 (t, J = 7.09 Hz, 3H), 1.83 (s, 3H), 4.27 (q, J = 7.01 Hz, 2H), 4.84 (br. s., 2H), 7.03 (t, J = 7.52 Hz, 1H), 7.13 (d, J = 7.95 Hz, 1H), 7.32-7.46 (m, 3H), 7.49 (s, 4H), 7.85 (s, 1H); 11.28 (s, 1H);

HPLC / MS (APCI): m / z = 420 [M + H] ⁺ , 2.04 min.

Example 12

The specified compound was obtained according to General scheme 1 for the synthesis of (I) from compound 1a-2 and 2 - [(2E) -but-2-en-1-yloxy] benzaldehyde, which was synthesized by alkylation of salicylic aldehyde (2E) -1-bromobut 2-ene (1.3 equiv.) In the presence of potassium carbonate in boiling acetonitrile. Yield: 311.9 mg (74%).

¹ H NMR (400 MHz, DMSO-d ₆ , ppm): 1.28 (t, J = 7.09 Hz, 3H), 1.71 (d, J = 6.36 Hz, 3H), 4.26 (q, J = 7.17 Hz , 2H), 4.55 (d, J = 5.87 Hz, 2H), 5.62-5.78 (m, 1H), 5.80-5.93 (m, 1H), 6.98 (t, J = 7.46 Hz, 1H), 7.08 (d, J = 8.19 Hz, 1H), 7.29-7.44 (m, 3H), 7.44-7.57 (m, 4H), 7.88 (s, 1H), 11.11-11.35 (m, 1H);

HPLC / MS (APCI): m / z = 422 [M + H] ⁺ , 2.91 min.

Example 13

The specified compound was obtained according to the General scheme 1 synthesis (I) from compound 1A-2 and commercially available 2- (2-methoxyethoxy) benzaldehyde. Yield: 140.4 mg (33%).

¹ H NMR (400 MHz, DMSO-d ₆ , ppm): 1.29 (t, J = 7.09 Hz, 3H), 3.32 (s, 3H), 3.65-3.74 (m, 2H), 4.15-4.19 ( m, 2H), 4.26 (q, J = 7.09 Hz, 2H), 7.00 (t, J = 7.52 Hz, 1H), 7.10 (d, J = 8.19 Hz, 1H), 7.31-7.45 (m, 3H), 7.46-7.54 (m, 4H), S 7.91 (s, 1H), 11.26 (s, 1H);

HPLC / MS (APCI): m / z = 426 [M + H] ⁺ , 1.85 min.

Example 14

The specified compound was obtained according to the General scheme 1 of synthesis (I) from compound 1b-4 and aldehyde 10p in a scale of 0.2 mmol. Yield: 19.8 mg (18%).

HPLC / MS (APCI): m / z = 550 [M + H] ⁺ , 2.42 min.

Example 15

The specified compound was obtained according to the alternative scheme 2 of synthesis (I) from compound M7 (table 2) and isopropanol. Yield: 59.1 mg (22%).

¹ H NMR (400 MHz, DMSO-d ₆ ppm): 1.14-1.23 (m, 2H), 1.29 (d, J = 3.4 Hz, 6H), 1.50-1.61 (m, 2H), 1.64-1.74 (m, 2H), 3.56-3.69 (m, 2H), 4.98 (br. s., 2H), 5.08-5.18 (m, 1H), 5.66 (s, 1H), 7.00-7.08 (m, 1H), 7.20 (d, J = 9.3 Hz, 1H), 7.30-7.37 (m, 2H), 7.40-7.54 (m, 3H), 7.58-7.67 (m, 1H), 7.87 (s, 1H), 11.13 (br. s., 1H).

HPLC / MS (APCI): m / z = 538 [M + H] ⁺ , 1.73 min.

Example 16

The specified compound was obtained according to the General scheme 1 synthesis (I) from compound 1A-1 and commercially available 2- (pyridin-3-ylmethoxy) benzaldehyde. Yield: 173.4 mg (39%).

¹ H NMR (400 MHz, DMSO-d ₆ , ppm): 3.75 (s, 3H), 5.24 (s, 2H), 7.03 (t, J = 7.52 Hz, 1H), 7.22 (d, J = 8.31 Hz, 1H), 7.32-7.54 (m, 8H), 7.85 (d, J = 7.82 Hz, 1H), 7.90 (s, 1H), 8.56 (d, J = 4.65 Hz, 1H), 8.67 (s, 1H), 11.17 (br. S., 1H);

HPLC / MS (APCI): m / z = 445 [M + H] ⁺ , 2.28 min.

Example 17

The specified compound was obtained according to General scheme 1 for the synthesis of (I) from compound 1a-1 and commercially available 2- (pyridin-4-ylmethoxy) benzaldehyde. Yield: 204.5 mg (46%).

¹ H NMR (400 MHz, DMSO-d ₆ , ppm): 3.31 (br.s., 3H), 7.03 (t, J = 7.5 Hz, 1H), 7.22 (d, J = 8.3 Hz, 1H ), 7.34-7.54 (m, 8H), 7.85 (d, J = 7.8 Hz, 1H), 7.90 (s, 1H), 8.56 (d, J = 4.6 Hz, 1H), 8.67 (s, 1H), 11.17 (br. s., 1H)

HPLC / MS (APCI): m / z = 445 [M + H] ⁺ , 2.28 min.

Example 18

The specified compound was obtained according to the General scheme 1 of synthesis (I) from compound 1b-4 and aldehyde 10 ° on a scale of 0.2 mmol. Yield: 24.6 mg (23%).

HPLC / MS (APCI): m / z = 536 [M + H] ⁺ , 2.21 min.

Example 19

The specified compound was obtained according to the General scheme 1 synthesis (I) from compound 1A-1 and aldehyde 10a. Yield: 313.3 mg (64%).

¹ H NMR (400 MHz, DMSO-d ₆ , ppm): 1.06-1.19 (m, 1H), 1.22-1.43 (m, 6H), 1.46-1.56 (m, 2H), 1.61-1.73 (m , 2H), 3.77 (s, 3H), 4.96 (s, 2H), 5.35 (s, 1H), 7.04 (t, J = 7.52 Hz, 1H), 7.19 (d, J = 8.31 Hz, 1H), 7.33 -7.45 (m, 3H), 7.45-7.55 (m, 4H), 7.86 (s, 1H), 10.97-11.41 (m, 1H);

HPLC / MS (APCI): m / z = 490 [M + H] ⁺ , 2.64 min.

Example 20

The specified compound was obtained according to the General scheme 1 of synthesis (I) from compound 1b-1 and 2 - [(4-methylpent-2-yn-1-yl) oxy] benzaldehyde, which was synthesized by alkylation of salicylic aldehyde 1-bromo-4- methylpent-2-in in the presence of potassium carbonate in boiling acetonitrile. Yield: 203.2 mg (45%).

¹ H NMR (400 MHz, CH ₃ OD, ppm): 3.89 (s, 3H), 4.89 (s, 6H), 5.50 (s, 2H), 6.97 (t, J = 7.58 Hz, 1H), 7.05 (d, J = 8.31 Hz, 1H), 7.29-7.44 (m, 4H), 7.46-7.55 (m, 1H), 7.62 (td, J = 7.92, 1.28 Hz, 1H), 8.18 (s, 1H) ;

HPLC / MS (APCI): m / z = 452 [M + H] ⁺ , 1.56 min.

Example 21

The specified compound was obtained according to the General scheme 1 synthesis (I) from compound 1A-1 and commercially available 1,3,5-trimethyl-1H-pyrazole-4-carbaldehyde. Yield: 140.4 mg (38%).

¹ H NMR (400 MHz, DMSO-d ₆ , ppm): 2.05 (s, 3H), 2.13 (s, 3H), 3.62 (s, 3H), 3.76 (s, 3H), 7.36-7.53 ( m, 6H), 11.14 (br.s, 1H);

HPLC / MS (APCI): m / z = 370 [M + H] ⁺ , 1.72 min.

Example 22

The specified compound was obtained according to the General scheme 1 synthesis (I) from compound 1A-1 and commercially available 5-chloro-1,3-dimethyl-1H-pyrazole-4-carbaldehyde. Yield: 70.7 mg (13%).

¹ H NMR (400 MHz, DMSO-d ₆ , ppm): 2.12 (s, 3H), 3.71 (s, 3H), 3.76 (s, 3H), 7.33 (s, 1H), 7.38-7.55 ( m, 5H), 11.19 (s, 1H);

HPLC / MS (APCI): m / z = 390 [M + H] ⁺ 1.70 min.

Example 23

The specified compound was obtained according to the General scheme 1 synthesis (I) from compound 1a-1 and 2 - [(3-fluoropyridin-2-yl) methoxy] benzaldehyde, which was synthesized by alkylation of salicylic aldehyde 2- (chloromethyl) -3-fluoropyridine in the presence of potassium carbonate in acetonitrile. Yield: 180.4 mg (39%).

¹ H NMR (400 MHz, DMSO-d ₆ , ppm): 3.74 (s, 3H), 5.33 (s, 2H), 7.02 (t, J = 7.52 Hz, 1H), 7.26 (d, J = 8.19 Hz, 1H), 7.33-7.46 (m, 5H), 7.46-7.59 (m, 3H), 7.73-7.85 (m, 2H), 8.44 (d, J = 4.65 Hz, 1H), 11.24 (br. S ., 1H);

HPLC / MS (APCI): m / z = 463 [M + H] ⁺ 2.57 min.

Example 24

The specified compound was obtained according to the General scheme 1 synthesis (I) from compound 1a-1 and 2 - [(5-fluoropyridin-2-yl) methoxy] benzaldehyde, which was synthesized by alkylation of salicylic aldehyde 2- (chloromethyl) -5-fluoropyridine in the presence of potassium carbonate in acetonitrile. Yield: 254.4 mg (55%).

¹ H NMR (400 MHz, DMSO-d ₆ , ppm): 3.76 (s, 3H), 5.26 (s, 2H), 7.02 (t, J = 7.52 Hz, 1H), 7.17 (d, J = 8.56 Hz, 1H), 7.33-7.39 (m, 2H), 7.42-7.52 (m, 5H), 7.57 (dd, J = 8.62, 4.46 Hz, 1H), 7.81 (td, J = 8.74, 2.93 Hz, 1H ), 7.94 (s, 1H), 8.59 (d, J = 2.69 Hz, 1H), 11.18 (br. S., 1H);

HPLC / MS (APCI): m / z = 463 [M + H] ⁺ , 2.64 min.

Example 25

The specified compound was obtained according to the General scheme 1 of synthesis (I) from compound 1a-1 and 2 - [(1-methyl-1H-pyrazol-3-yl) methoxy] benzaldehyde, which was synthesized by the Mitsunobu reaction from salicylic aldehyde with 1- methyl-1H-pyrazol-3-yl-methanol in the presence of DIAD (diethyl azodicarboxylate), triphenylphosphine in anhydrous THF. Yield: 281.9 mg (63%).

¹ H NMR (400 MHz, DMSO-d ₆ , ppm): 3.75 (s, 3H), 3.82 (s, 3H), 5.08 (s, 2H), 6.28 (d, J = 2.08 Hz, 1H) , 7.00 (t, J = 7.46 Hz, 1H), 7.26 (d, J = 8.31 Hz, 1H), 7.30-7.55 (m, 7H), 7.67 (d, J = 2.08 Hz, 1H), 7.85 (s, 1H), 11.22 (br. S., 1H);

HPLC / MS (APCI): m / z = 448 [M + H] ⁺ , 1.66 min.

Example 26

The specified compound was obtained according to the General scheme of synthesis (I) from compound 1a-1 and 2 - [(6-chloropyridin-3-yl) methoxy] benzaldehyde, which was synthesized by alkylation of salicylic aldehyde 2-chloro-5- (chloromethyl) pyridine in the presence of potassium carbonate in boiling acetonitrile. Yield: 344.8 mg (72%).

¹ H NMR (400 MHz, DMSO-d ₆ , ppm): 3.75 (s, 3H), 5.24 (s, 2H), 7.04 (t, J = 7.64 Hz, 1H), 7.20 (d, J = 8.44 Hz, 1H), 7.31-7.54 (m, 7H), 7.58 (d, J = 8.19 Hz, 1H), 7.88 (s, 1H), 7.92 (dd, J = 8.19, 2.45 Hz, 1H), 8.50 ( d, J = 2.32 Hz, 1H); 11.23 (s, 1H);

HPLC / MS (APCI): m / z = 480 [M + H] ⁺ , 1.92 min.

Example 27

Said compound was prepared according to general synthesis scheme 1 (I) from compound 1b-1 and 2- (3-methoxypropoxy) benzaldehyde, which was synthesized by alkylation of salicylic aldehyde with 1-chloro-3-methoxypropane in the presence of potassium carbonate in boiling acetonitrile.

Yield: 301.6 mg (68%).

¹ H NMR (400 MHz, DMSO-d ₆ , ppm): 1.92-1.99 (m, 2H), 3.23 (br.s., 3H), 3.47 (t, J = 6.17 Hz, 2H), 3.77 (s, 3H), 4.08 (t, J = 6.24 Hz, 2H), 6.98 (t, J = 7.40 Hz, 1H), 7.08 (d, J = 8.31 Hz, 1H), 7.27-7.38 (m, 3H) 7.42-7.54 (m, 2H); 7.61 (t, J = 8.31 Hz, 1H); 7.92 (s, 1H); 11.07 (br. S., 1H);

HPLC / MS (APCI): m / z = 444 [M + H] ⁺ , 2.04 min.

Example 28

The specified compound was obtained according to General scheme 1 for the synthesis of (I) from compound 1b-1 and aldehyde 10a. Yield: 508.2 mg (59%).

¹ H NMR (400 MHz, DMSO-d ₆ , ppm): 1.09-1.19 (m, 1H), 1.24-1.42 (m, 5H), 1.45-1.53 (m, 2H), 1.66 (d, J = 9.78 Hz, 2H), 3.78 (s, 3H), 4.96 (s, 2H), 5.32 (s, 1H), 7.03 (t, J = 7.64 Hz, 1H), 7.19 (d, J = 8.07 Hz, 1H ), 7.29-7.54 (m, 5H), 7.62 (t, J = 7.95 Hz, 1H), 7.89 (s, 1H), 11.09 (s, 1H);

HPLC / MS (APCI): m / z = 508 [M + H] ⁺ , 2.01 min.

Example 29

The specified compound was obtained according to an alternative synthesis scheme 2 (I) from compound M7 (Table 2) and cyclopentanol. Yield: 81.7 mg (29%).

¹ H NMR (400 MHz, DMSO-d ₆ , ppm): 1.51-1.61 (m, 4H), 1.66-1.78 (m, 6H), 1.84-1.93 (m, 2H), 3.33-3.38 (m , 2H), 3.62-3.69 (m, 2H), 4.98 (s, 2H), 5.28 (t, J = 5.7 Hz, 1H), 5.66 (s, 1H), 7.05 (t, J = 7.5 Hz, 1H) , 7.20 (d, J = 8.3 Hz, 1H), 7.31-7.37 (m, 2H), 7.38-7.52 (m, 3H), 7.62 (t, J = 7.6 Hz, 1H), 7.88 (s, 1H), 11.16 (s, 1H);

HPLC / MS (APCI): m / z = 564 [M + H] ⁺ , 2.75 min.

Example 30

The specified compound was obtained according to the General scheme 1 of synthesis (I) from compound 1b-4 and aldehyde 10n on a scale of 0.2 mmol. Yield: 35.2 mg (31%).

HPLC / MS (APCI): m / z = 534 [M + H] ⁺ , 2.51 min.

Example 31

The specified compound was obtained according to the General scheme 1 of synthesis (I) from compound 1A-1 and 1,3-dimethyl-5-phenyl-1H-pyrazole-4-carbaldehyde, which was synthesized by the Suzuki reaction from 5-chloro-1,3 -dimethyl-1H-pyrazole-4-carbaldehyde and phenylboronic acid (2 equiv.) in the presence of sodium carbonate and tetrakis (triphenylphosphine) palladium (0) as a catalyst (5 mol%) in a 2: 1 mixture of dioxane-water. Yield: 146.7 mg (34%).

¹ H NMR (400 MHz, DMSO-d ₆ , ppm): 2.19 (s, 3H), 3.61 (s, 3H), 3.70 (s, 3H), 7.12 (d, J = 7.70 Hz, 2H) 7.30 (d, J = 5.75 Hz, 2H), 7.39-7.52 (m, 6H), 7.61 (t, J = 7.6 Hz, 1H), 11.01 (br. S., 1H);

HPLC / MS (APCI): m / z = 432 [M + H] ⁺ , 2.47 min.

Example 32

The specified compound was obtained according to the General scheme 1 of synthesis (I) from compound 1b-1 and 1,3-dimethyl-5- (2-phenylethynyl) -1H-pyrazole-4-carbaldehyde, which was synthesized by the Sonogashira reaction from 5-chlorine -1,3-dimethyl-1H-pyrazole-4-carbaldehyde and phenylacetylene in the presence of triethylamine (10 eq.), Tetrakis (triphenylphosphine) palladium (0) (5 mol%), copper (I) iodide (10 mol%) ) in 1,4-dioxane. Yield: 140.0 mg (14%).

¹ H NMR (400 MHz, DMSO-d ₆ , ppm): 2.22 (s, 3H), 3.78 (s, 3H), 3.86 (s, 3H), 7.05 (t, J = 7.63 Hz, 1H) 7.23-7.40 (m, 4H); 7.42-7.55 (m, 5H); 10.96 (br. S., 1H);

HPLC / MS (APCI): m / z = 474 [M + H] ⁺ , 2.02 min.

Example 33

The specified compound was obtained according to the General scheme 1 of synthesis (I) from compound 1a-1 and 1- (3-methoxypropyl) -1H-pyrrole-2-carbaldehyde, which was synthesized by alkylation of pyrrole-2-carbaldehyde 1-chloro-3-methoxypropane in the presence of sodium hydride (1.1 equiv.) in anhydrous THF.

Yield: 191.3 mg (48%).

¹ H NMR (400 MHz, DMSO-d ₆ , ppm): 1.73-1.94 (quin, J = 6.33 Hz, 2H); 3.10-3.25 (m, 5H); 3.77 (s, 3H); 4.12 (t, J = 6.79 Hz, 2H); 6.21 (dd, J = 3.61, 2.87 Hz, 1H); 6.30-6.38 (m, 1H); 7.11 (d, J = 1.59 Hz, 1H); 7.39-7.46 (m, 1H); 7.46-7.59 (m, 5H); 11.17 (s, 1H);

HPLC / MS (APCI): m / z = 399 [M + H] ⁺ , 1.72 min.

Example 34

The specified compound was obtained according to the General scheme 1 of synthesis (I) from compound 1A-1 and aldehyde 13c. Yield: 292.0 mg (63%).

¹ H NMR (400 MHz, DMSO-d ₆ , ppm): 1.31 (s, 6H), 3.13 (s, 3H), 3.77 (s, 3H), 4.97 (s, 2H), 7.04 (t, J = 7.52 Hz, 1H), 7.18 (d, J = 8.19 Hz, 1H), 7.39 (dd, J = 18.40, 9.35 Hz, 3H), 7.46-7.56 (m, 4H), 7.86 (s, 1H), 11.25 (s, 1H);

HPLC / MS (APCI): m / z = 464 [M + H] ⁺ , 1.91 min.

Example 35

The specified compound was obtained according to the General scheme 1 of synthesis (I) from compound 1b-1 and aldehyde 13c. Yield: 192.6 mg (40%).

¹ H NMR (400 MHz, DMSO-d ₆ , ppm): 1.31 (s, 6H), 3.13 (s, 3H), 3.77 (s, 3H), 4.97 (s, 2H), 7.04 (t, J = 7.52 Hz, 1H), 7.18 (d, J = 8.19 Hz, 1H), 7.30-7.53 (m, 6H), 7.62 (t, J = 7.40 Hz, 1H), 7.88 (s, 1H), 11.10 ( br. s., 1H);

HPLC / MS (APCI): m / z = 482 [M + H] ⁺ , 1.98 min.

Example 36 (racemic mixture)

The specified compound was obtained according to the General scheme 1 synthesis (I) from compound 1b-1 and aldehyde 10f. Yield: 114.4 mg (23%)

¹ H NMR (400 MHz, DMSO-d ₆ , ppm): 1.29 (s, 3H), 3.17-3.30 (m, 5H), 3.80 (s, 3H), 4.94 (s, 2H), 5.52 ( s, 1H), 7.06 (t, J = 7.47 Hz, 1H), 7.18 (d, J = 8.27 Hz, 1H), 7.33-7.39 (m, 2H), 7.39-7.57 (m, 3H), 7.64 (t , J = 7.95 Hz, 1H), 7.90 (s, 1H), 11.09 (s, 1H);

HPLC / MS (APCI): m / z = 498 [M + H] ⁺ , 1.85 min.

Example 37

The specified compound was obtained according to the General scheme 1 synthesis (I) from compound 1b-1 and aldehyde 10C. Yield: 250.4 mg (48%).

¹ H NMR (400 MHz, CDCl ₃ , ppm): 1.48-1.57 (m, 6H) 1.74-1.85 (m, 3H) 1.96 (dd, J = 13.63, 8.01 Hz, 3H) 3.95 (s, 3H ) 4.12 (q, 1H) 4.80 (s, 2H) 6.95-7.10 (m, 4H) 7.12-7.21 (m, 2H) 7.30-7.40 (m, 2H) 8.16-8.27 (m, 1H) 11.43 (s, 1H );

HPLC / MS (APCI): m / z = 522 [M + H] ⁺ , 2.72 min.

Example 38

The specified compound was obtained according to the General scheme 1 synthesis (I) from compound 1b-1 and aldehyde 10b. Yield: 305.3 mg (57%).

¹ H NMR (400 MHz, DMSO-d ₆ , ppm): 0.72 (t, 3H), 0.94-1.02 (m, 2H), 1.12-1.16 (m, 1H), 1.23-1 28 (m, 2H), 1.46-1.50 (m, 2H), 1.71-1.74 (m, 2H), 3.32 (s, 3H), 3.38 (s, 2H), 4.93- 4.95 (m, 2H), 5.4 (s, 1H), 7.03 (t, 1H), 7.21 (d, 1H) 7.34-7.52 (m, 5H), 7.61 (t, 1H), 7.88 (s, 1H) 11.09 (s, 1H);

HPLC / MS (APCI): m / z = 536 [M + H] ⁺ , 2.72 min.

Example 39

The specified compound was obtained according to the General scheme 1 synthesis (I) from compound 1b-4 and aldehyde 10g in a scale of 0.2 mmol. Yield: 17.7 mg (17%).

HPLC / MS (APCI): m / z = 522 [M + H] ⁺ , 2.15 min.

Example 40

The specified compound was obtained according to the General scheme 1 of synthesis (I) from compound 1a-1 and 1- (2-methoxyethyl) -1H-pyrrole-2-carbaldehyde, which was synthesized by alkylation of pyrrole-2-carbaldehyde 1-chloro-2-methoxyethane in the presence of sodium hydride (1.1 equiv.) in anhydrous THF.

Yield: 203.8 mg (53%).

¹ H NMR (400 MHz, DMSO-d ₆ , ppm): 3.19 (s, 3H); 3.44-3.61 (m, 2H); 3.77 (s, 3H); 4.24 (br.s, 2H); 6.13-6.24 (m, 1H); 6.35 (d, J = 2.81 Hz, 1H); 7.13 (br.s, 1H); 7.43 (t, J = 6.60 Hz, 1H); 7.47-7.56 (m, 4H); 7.58 (s, 1H); 11.17 (br.s, 1H);

HPLC / MS (APCI): m / z = 385 [M + H] ⁺ , 1.90 min.

Example 41

The specified compound was obtained according to the General scheme 1 of synthesis (I) from compound 1a-1 and 1- (but-2-yn-1-yl) -1H-pyrrole-2-carbaldehyde, which was synthesized by alkylation of commercially available pyrrole-2- carbaldehyde 1-bromobut-2-in in the presence of sodium hydride (1.1 equiv.) in anhydrous THF.

Yield: 219.5 mg (58%).

¹ H NMR (400 MHz, CDCl ₃ , ppm): 9.12 (br. S., 1H); 8.26 (s, 1H) 7.55-7.30 (m, 4H) 7.14-687 (m, 2H) 4.16 (s, 2H) 3.59 (s, 2H) 3.37 (s, 3H) 2.13 (s, 3H);

HPLC / MS (APCI): m / z = 379 [M + H] ⁺ 1.81 min.

Example 42

The specified compound was obtained according to the General scheme 1 of synthesis (I) from compound 1a-1 and 1- (3-methoxypropyl) -1H-pyrazole-5-carbaldehyde, which was synthesized by alkylation of 1H-pyrazole-5-carbaldehyde 1-chloro-3 -methoxypropane in the presence of sodium hydride (1.1 equiv.) in anhydrous THF.

Yield: 139.8 mg (35%).

¹ H NMR (400 MHz, DMSO-d ₆ , ppm): 1.92 (quin, J = 6.11 Hz, 2H); 3.06-3.24 (m, 5H); 3.78 (s, 3H); 4.30 (t, J = 6.60 Hz, 2H); 6.38 (d, J = 1.71 Hz, 1H); 7.41-7.48 (m, 1H); 7.48-7.56 (m, 5H); 7.39-7.46 (m, 1H); 7.58 (s, 1H); 11.31 (s, 1H);

HPLC / MS (APCI): m / z = 400 [M + H] ⁺ , 1.47 min.

Example 43 (racemic mixture)

The specified compound was obtained according to the General scheme 1 of synthesis (I) from compound 1A-1 and aldehyde 13e. Yield: 257.8 mg (54%).

¹ H NMR (400 MHz, DMSO-d ₆ , ppm): 0.82 (d, J = 6.72 Hz, 6H), 1.73-1.86 (m, 1H), 3.21 (s, 3H), 3.77 (s, 3H), 5.01 (s, 2H), 7.03 (t, J = 7.52 Hz, 1H), 7.19 (d, J = 8.31 Hz, 1H), 7.37 (s, 3H), 7.46-7.57 (m, 4H), 7.87 (s, 1H); 11.25 (s, 1H);

HPLC / MS (APCI): m / z = 478 [M + H] ⁺ , 2.10 min.

Example 44

The specified compound was obtained according to the General scheme 1 synthesis (I) from compound 1A-1 and aldehyde 13d. Yield: 209.0 mg (48%).

¹ H NMR (400 MHz, DMSO-d ₆ , ppm): 3.20 (s, 3H), 3.77 (s, 3H), 4.11 (s, 2H), 4.99 (s, 2H), 7.04 (t, J = 8.0 Hz, 1H), 7.16 (d. J = 7.6 Hz, 1H), 7.35-7.53 (m, 7H), 11.22 (br.s, 1H);

HPLC / MS (APCI): m / z = 436 [M + H] ⁺ , 1.59 min.

Example 45

The specified compound was obtained according to the General scheme 1 synthesis (I) from compound 1A-1 and aldehyde 13b. Yield: 323.1 mg (66%).

¹ H NMR (400 MHz, DMSO-d ₆ , ppm): 1.34 (s, 6H), 3.77 (s, 3H), 3.89 (d, J = 5.38 Hz, 2H), 4.92 (d, J = 2.08 Hz, 1H), 4.97 (s, 2H), 5.02 (dd, J = 10.21, 1.90 Hz, 1H), 5.13 (dd, J = 17.24, 1.96 Hz, 1H), 7.05 (t, J = 7.52 Hz, 1H), 7.18 (d, J = 7.70 Hz, 1H), 7.36-7.41 (m, 2H), 7.46-7.54 (m, 5H), 7.86 (s, 1H), 11.26 (br. S., 1H);

HPLC / MS (APCI): m / z = 490 [M + H] ⁺ , 2.15 min.

Example 46

The specified compound was obtained according to the General scheme 1 of the synthesis (I) from compound 1A-1 and aldehyde 13a. Yield: 329.2 mg (61%).

¹ H NMR (400 MHz, DMSO-d6, ppm): 1.41 (s, 6H), 3.77 (s, 3H), 4.39 (s, 2H), 5.01 (s, 2H), 7.00-7.06 (m , 1H), 7.16-7.28 (m, 6H), 7.35-7.52 (m, 7 H), 7.89 (s, 1H), 11.25 (s, 1H).

HPLC / MS (APCI): m / z = 540 [M + H] ⁺ , 2.27 min.

Example 47

The specified compound was obtained according to the General scheme 1 of synthesis (I) from compound 1A-1 and aldehyde 7. Yield: 188.0 mg (42%).

¹ H NMR (400 MHz, DMSO-d6, ppm): 2.23 (s, 3H), 3.43 (s, 3H), 3.71 (s, 3H), 6.61 (d, J = 8.07 Hz, 2H), 7.10 (t, J = 7.34 Hz, 1H), 7.31 (dd, J = 7.34, 1.59 Hz, 3H), 7.44-7.57 (m, 4H), 11.09 (br. S., 1H);

HPLC / MS (APCI): m / z = 448 [M + H] ⁺ , 1.51 min.

Example 48

The specified compound was obtained according to the General scheme 1 synthesis (I) from compound 1A-1 and aldehyde 5A. Yield: 158.6 mg (36%).

¹ H NMR (400 MHz, DMSO-d6, ppm): 1.97 (s, 3H), 2.81-2.99 (m, 4H), 3.48-3.58 (m, 4H), 3.62 (s, 3H), 3.75 (s, 3H), 7.41-7.52 (m, 5H), 11.13 (s, 1H);

HPLC / MS (APCI): m / z = 441 [M + H] ⁺ , 1.41 min.

Example 49

The specified compound was obtained according to the General scheme 1 synthesis (I) from compound 1A-1 and aldehyde 6b. Yield: 219.2 mg (53%).

¹ H NMR (400 MHz, DMSO-d ₆ , ppm): 1.51 (sxt, J = 7.07 Hz, 2H), 2.11 (s, 3H), 2.51 (br.s., 3H), 3.53 (s , 3H), 3.75 (s, 3H), 3.78 (t, J = 6.60 Hz, 2H), 7.31 (s, 1H), 7.38-7.53 (m, 5H), 11.07 (br.s, 1H).

APCI LCMS 414 [M + H], 1.760 min

HPLC / MS (APCI): m / z = 414 [M + H] ⁺

Example 50

The specified compound was obtained according to the General scheme 1 synthesis (I) from compound 1b-1 and aldehyde 10d. Yield: 392.3 mg (77%).

¹ H NMR (400 MHz, DMSO-d ₆ , ppm): 1.50-1.59 (m, 2H), 1.68 (d, J = 13.20 Hz, 2H), 3.33-3.39 (m, 2H), 3.60- 3.70 (m, 2H), 3.77 (s, 3H), 4.98 (s, 2H), 5.65 (s, 1H), 7.04 (t, J = 7.58 Hz, 1H), 7.20 (d, J = 8.31 Hz, 1H ), 7.35 (d, J = 7.70 Hz, 2H), 7.37-7.55 (m, 3H), 7.61 (t, J = 7.46 Hz, 1H), 7.88 (s, 1H), 11.09 (s, 1H);

HPLC / MS (APCI): m / z = 510 [M + H] ⁺ , 1.21 min.

Example 51

The specified compound was obtained according to the General scheme 1 synthesis (I) from compound 1A-1 and aldehyde 5b. Yield: 223.0 mg (56%).

¹ H NMR (400 MHz, DMSO-d ₆ , ppm): 2.09 (s, 3H), 2.56 (s, 6H), 3.63 (s, 3H), 3.76 (s, 3H), 7.35 (s, 1H), 7.39-7.46 (m, 1H), 7.48-7.55 (m, 4H), 11.08 (s, 1H);

HPLC / MS (APCI): m / z = 399 [M + H] ⁺ , 1.62 min.

Example 52

The specified compound was obtained according to an alternative synthesis scheme 2 (I) from compound M7 (table 2) and cycloheptanol. Yield: 29.6 mg (10%).

HPLC / MS (APCI): m / z = 592 [M + H] ⁺ , 2.85 min.

Example 53

The specified compound was obtained according to the General scheme 1 of synthesis (I) from compound 1b-1 and aldehyde 10e on a scale of 10 mmol (purified column chromatography on silica gel, eluent n-nexane / ethyl acetate 1: 5). Yield: 4.26 g (70%).

HPLC / MS (APCI): m / z = 609 [M + H] ⁺ , 2.25 min.

Example 54

The compound from Example 53 (4.26 g, 7 mmol) was dissolved in anhydrous DCM (50 ml), cooled to 0 ° C, and trifluoroacetic acid (5.2 ml, 70 mmol) was added dropwise with vigorous stirring. The reaction mixture was stirred for 12 hours at rt, then diluted with 10% aqueous potassium carbonate (200 ml), the organic layer was separated, the aqueous layer was extracted with DCM (3 × 50 ml). The combined organic extracts were dried over sodium sulfate, filtered and evaporated under reduced pressure on a rotary evaporator, obtaining the target compound (3.27 g, 92%) as a clear glassy mass.

HPLC / MS (APCI): m / z = 509 [M + H] ⁺ , 0.82 min.

Example 55

A mixture of the compound from Example 54 (200 mg, 0.4 mmol), sodium bicarbonate (4 mmol) and 1-chloro-2-methoxyethane (0.5 mmol) in anhydrous acetonitrile (5 ml) was stirred for 8 hours at a temperature of 60 ° C. After completion of the reaction, the reaction mixture was cooled to rt, diluted with water (20 ml), and ethyl acetate was extracted with 3 × 10 ml of ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure on a rotary evaporator. The evaporation residue was purified by preparative HPLC to obtain the title compound (192.5 g, 85%).

¹ H NMR (400 MHz, DMSO-d ₆ , ppm): 1.35-1.79 (m, 4H), 2.59-2.74 (m, 3H), 2.79-3.27 (m, 4H), 3.41-3.63 (m , 5H), 3.68-3.83 (m, 3H), 4.98 (s, 1H), 6.99-7.65 (m, 9H), 7.84-7.92 (m, 1H), 11.05- (br.s, 1H)

HPLC / MS (APCI): m / z = 567 [M + H] ⁺ , 2.59 min.

Example 56

To a solution of the compound from Example 54 (200 mg, 0.4 mmol) and triethylamine (1.2 mmol) in anhydrous acetonitrile (5 ml) was added vigorous stirring methoxy acetic acid chloride (0.4 mmol). The reaction mixture was stirred for 30 minutes at rt, diluted with water (20 ml), and extracted with ethyl acetate (3 × 10 ml). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure on a rotary evaporator. The evaporation residue was purified by preparative HPLC to obtain the title compound (171.9 g, 74%).

¹ H NMR (400 MHz, DMSO-d ₆ , ppm): 1.37-1.81 (m, 4H), 2.46-2.56 (m, 6H), 3.07-3.20 (m, 2H), 3.26 (s, 3H) ), 3.39-3.84 (m, 10Н), 3.99-4.10 (m, 2Н), 4.90 (s, 0.5Н), 5.00 (s, 1.5Н), 5.66-5.80 (m, 3Н), 6.92-7.57 (m , 8H), 7.60-7.69 (m, 1H), 7.87-8.02 (m, 1H), 10.90-11.23 (m, 1H);

HPLC / MS (APCI): m / z = 582 [M + H] ⁺ , 1.56 min.

Example 57

The target compound was prepared as described above for Example 56 using methyl chloroformate (0.4 mmol) as the acylating agent. Yield of target compound: 200 mg (88%).

¹ H NMR (400 MHz, CDCl ₃ , ppm): 1.44-1.55 (m, 2H), 1.61-1.71 (m, 2H), 3.00-3.14 (m, 2H), 3.46-3.61 (m, 5H) ), 3.79 (s, 3H), 4.99 (s, 2H), 5.69 (s, 1H), 7.05 (t, J = 7.31 Hz, 1H), 7.21 (d, J = 7.95 Hz, 1H), 7.31-7.58 (m, 6H), 7.58-7.67 (m, 1H), 7.89 (s, 1H), 11.11 (s, 1H);

HPLC / MS (APCI): m / z = 567 [M + H] ⁺ , 1.74 min.

Example 58

Ethyl isocyanate (0.44 mmol) was added to a solution of the compound from Example 54 (200 mg, 0.4 mmol) in anhydrous THF (5 ml) with vigorous stirring. The reaction mixture was stirred for 2 hours at the boil, diluted with water (20 ml), extracted with ethyl acetate (3 × 10 ml). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure on a rotary evaporator. The evaporation residue was purified by preparative HPLC to obtain the desired compound (220.3 g, 95%).

¹ H NMR (400 MHz, DMSO-d ₆ , ppm): 0.98 (t, J = 7.15 Hz, 3H), 1.39-1.51 (m, 2H), 1.57-1.68 (m, 2H), 2.90-3.06 (m, 4H), 3.44-3.56 (m, 4H), 3.79 (s, 3H), 4.99 (s, 3H), 5.60 (s, 3H), 6.41 (t, J = 5.25 Hz, 1H), 7.05 ( t, J = 7.47 Hz, 1H), 7.20 (d, J = 7.95 Hz, 1H), 7.30-7.57 (m, 5H), 7.64 (m, 3H), 7.89 (s, 1H), 11.11 (s, 1H );

HPLC / MS (APCI): m / z = 580 [M + H] ⁺ , 1.63 min.

Example 59

N-acetyl glycine (47 mg, 0.4 mmol, 1 equiv.) Was suspended in anhydrous DCM (5 ml), then BOP (212 mg, 0.48 mmol, 1.2 equiv.) Was added in one portion with stirring and the reaction was stirred for 10 minutes at .t .; then a secondary amine compound from Example 54 (200 mg, 0.4 mmol, 1 equiv.) and DIPEA (0.6 mmol, 1.5 equiv.) were successively added to the reaction mixture. The resulting mixture was stirred 24 hours at rt, then washed successively with saturated aqueous solutions of hydrogen carbonate and sodium chloride (10 ml each). The organic layer was separated, dried over anhydrous sodium sulfate and evaporated under reduced pressure on a rotary evaporator. The evaporation residue was purified by preparative HPLC to obtain the title compound (170.0 mg, 70%).

¹ H NMR (400 MHz, DMSO-d ₆ , ppm): 1.42-1.78 (m, 5H), 1.84 (s, 3H), 3.44-3.53 (m, 1H), 3.61-3.73 (m, 2H ), 3.78 (s, 3H), 3.88 (t, J = 5.7 Hz, 2H), 4.98 (s, 2H), 5.72 (br.s., 1H), 7.04 (t, J = 7.5 Hz, 1H), 7.19 (d, J = 8.3 Hz, 1H), 7.34 (s, 5H), 7.63 (t, J = 7.5 Hz, 1H), 7.86-7.93 (m, 2H), 11.10 (s, 1H);

HPLC / MS (APCI): m / z = 609 [M + H] ⁺ , 2.26 min.

Example 60

N-Boc glycine (70 mg, 0.4 mmol, 1 equiv.) Was suspended in anhydrous DCM (5 ml), then BOP (212 mg, 0.48 mmol, 1.2 equiv.) Was added in one portion with stirring and the reaction was stirred for 10 minutes at .t .; then a secondary amine compound from Example 54 (200 mg, 0.4 mmol, 1 equiv.) and DIPEA (0.6 mmol, 1.5 equiv.) were successively added to the reaction mixture. The resulting mixture was stirred 24 hours at rt, then washed successively with saturated aqueous solutions of hydrogen carbonate and sodium chloride (10 ml each). The organic layer was separated, dried over anhydrous sodium sulfate and evaporated under reduced pressure on a rotary evaporator. The evaporation residue was purified by flash chromatography on silica gel and evaporated to dryness. The oily yellowish residue was dissolved in anhydrous DCM (5 ml), trifluoroacetic acid (5 mmol) was added and stirred for 12 hours at rt. After which the reaction mixture was washed with a solution of sodium bicarbonate (10 ml), was extracted with DCM (3 × 10 ml). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure on a rotary evaporator. The evaporation residue was purified by preparative HPLC to obtain the title compound (50.0 g, 22%).

¹ H NMR (400 MHz, DMSO-d ₆ , ppm): 1.48-1.84 (m, 6H), 3.30 (m overlaps with the HDO, 5H signal), 3.61 (s, 3H), 3.81 (d, J = 15.9 Hz, 1H), 3.91 (d, J = 16.0 Hz, 1H), 4.90 (s, 2H), 5.82 (br.s., 1H), 6.97 (t, J = 7.6 Hz, 1H), 7.03- 7.16 (m, 3H), 7.16-7.29 (m, 2H), 7.32 (d, J = 7.7 Hz, 1H), 7.57 (s, 1H), 8.14 (s, 1H);

HPLC / MS (APCI): m / z = 566 [M + H] ⁺ , 2.11 min.

Example 61

The target compound was prepared as described above for Example 56 using 3-methoxypropionic acid chloride (0.4 mmol) as the acylating agent. Yield of target compound: 128.5 mg (54%).

¹ H NMR (400 MHz, DMSO-d ₆ , ppm): 1.36-1.77 (m, 4H) 2.99-3.14 (m, 2H) 3.14-3.24 (m, 4H) 3.49 (t, J = 6.60 Hz , 3H) 3.55 (s, 1H) 3.61-3.74 (m, 2H) 3.78 (s, 3H) 4.98 (s, 2H) 5.68 (s, 1H) 6.98-7.09 (m, 1H) 7.20 (d, J = 8.07 Hz, 1H) 7.34 (d, J = 6.48 Hz, 2H) 7.46 (d, J = 8.68 Hz, 2H) 7.49 (s, 1H) 7.63 (d, J = 0.98 Hz, 1H) 7.88 (s, 1H) 11.10 (s, 1H);

HPLC / MS (APCI): m / z = 595 [M + H] ⁺ , 2.34 min.

Example 62

The specified compound was obtained according to the General scheme 1 synthesis (I) from compound 1b-3 and aldehyde 10A. Yield: 208.9 mg (39%).

¹ H NMR (400 MHz, CDCl ₃ , ppm): 1.07-1.26 (m, 4H), 1.29 (d, J = 6.24 Hz, 4H), 1.36-1.43 (m, 2H), 1.45-1.55 ( m, 2H), 1.61-1.72 (m, 2H), 4.95 (s, 1H), 5.08-5.16 (m, 1H), 5.34 (s, 1H), 7.04 (t, J = 7.95 Hz, 1H), 7.19 (d, J = 9.29 Hz, 1H), 7.29-7.36 (m, 2H), 7.37-7.51 (m, 3H), 7.61 (t, J = 7.89 Hz, 1H), 7.87 (s, 1H), 11.15 ( br. s., 1H);

HPLC / MS (APCI): m / z = 536 [M + H] ⁺ , 2.13 min.

Example 63

The specified compound was obtained according to the General scheme 1 of synthesis (I) from compound 1b-1 and aldehyde 13d. Yield: 208.6 mg (46%).

¹ H NMR (400 MHz, DMSO-d ₆ , ppm): 3.20 (s, 3H), 3.77 (s, 3H), 4.11 (s, 2H), 4.99 (s, 2H), 7.04 (t, J = 7.6 Hz, 1H), 7.16 (d, J = 8.4 Hz, 1H), 7.30-7.36 (m, 2H), 7.38-7.53 (m, 3H), 7.60 (t, J = 7.5 Hz, 1H), 7.86 (s, 1H); 11.08 (br. S., 1H);

HPLC / MS (APCI): m / z = 454 [M + H] ⁺ , 1.83 min.

Example 64

The specified compound was obtained according to the General scheme 1 synthesis (I) from compound 1A-3 and aldehyde 10d. Yield: 135.0 mg (26%).

¹ H NMR (400 MHz, DMSO-d ₆ , ppm): 1.10-1.24 (m, 2H), 1.29 (dd, J = 6.11, 2.69 Hz, 6H), 1.47-1.62 (m, 2H), 1.62-1.80 (m, 2H), 3.64 (d, J = 14.31 Hz, 2H), 4.98 (br.s., 2H), 5.05-5.25 (m, 1H), 5.66 (d, J = 2.69 Hz, 1H ), 7.05 (t, J = 5.87 Hz, 1H), 7.20 (d, J = 8.07 Hz, 1H), 7.26-7.76 (m, 7H), 7.88 (s, 1H), 11.15 (br.s., 1H );

HPLC / MS (APCI): m / z = 520 [M + H] ⁺ , 2.47 min.

Example 65

The specified compound was obtained according to the General scheme 1 of synthesis (I) from compound 1b-4 and aldehyde 10u in a scale of 0.2 mmol. Yield: 12.4 mg (11%).

HPLC / MS (APCI): m / z = 564 [M + H] ⁺ , 2.02 min.

Example 66

The specified compound was obtained according to the General scheme 1 of synthesis (I) from compound 1b-4 and aldehyde 10u in a scale of 0.2 mmol. Yield: 10.1 mg (9%).

HPLC / MS (APCI): m / z = 564 [M + H] ⁺ , 2.41 min.

Example 67

The specified compound was obtained according to the General scheme 1 synthesis (I) from compound 1A-3 and aldehyde 5b. Yield: 81.0 mg (19%).

¹ H NMR (400 MHz, DMSO-d ₆ , ppm): 1.28 (d, J = 6.2 Hz, 6H), 2.07 (s, 3H), 2.56 (s, 6H), 3.62 (s, 3H) 5.10 (quin, J = 6.3 Hz, 1H), 7.33 (s, 1H), 7.36-7.42 (m, 1H), 7.46-7.51 (m, 3H), 11.11 (br. S., 1H);

APCI LCMS 427 [M + H],

HPLC / MS (APCI): m / z = 427 [M + H] ⁺ , 2.59 min.

Example 68

The specified compound was obtained according to the alternative scheme 2 of synthesis (I) from compound M7 (table 2) and cyclobutanol. Yield: 68.7 mg (25%).

¹ H NMR (400 MHz, DMSO-d ₆ , ppm): 1.50-1.60 (m, 2H), 1.63-1.69 (m, 2H), 1.80 (q, J = 10.4 Hz, 1H), 2.07- 2.19 (m, 2H), 2.30-2.39 (m, 4H), 3.34-3.41 (m, 2H), 3.61-3.70 (m, 2H), 4.98 (s, 2H), 5.08 (quin, J = 7.5 Hz, 1H), 5.66 (s, 1H), 7.05 (t, J = 7.5 Hz, 1H), 7.20 (d, J = 8.4 Hz, 1H), 7.28-7.37 (m, 2H), 7.38-7.53 (m, 3H ), 7.62 (t, J = 7.9 Hz, 1H), 7.88 (s, 1H), 11.09 (s, 1H);

HPLC / MS (APCI): m / z = 550 [M + H] ⁺ , 2.63 min.

Example 69

The specified compound was obtained according to the alternative scheme 2 of synthesis (I) from compound M7 (table 2) and cyclopropanol. Yield: 58.9 mg (22%).

HPLC / MS (APCI): m / z = 552 [M + H] ⁺ , 2.33 min.

Example 70

The specified compound was obtained according to the General scheme 1 of the synthesis (I) from compound 1b-3 and aldehyde 13d. Yield: 149.3 mg (31%).

¹ H NMR (400 MHz, CDCl ₃ , ppm): 1.29 (d, 6H), 3.20 (s, 3H), 4.12 (s, 2H), 4.79-5.06 (m, 2H), 5.06-5.29 ( m, 1H), 7.04 (t, J = 7.21 Hz, 1H), 7.16 (d, J = 8.19 Hz, 1H), 7.32-7.46 (m, 3H), 7.46-7.54 (m, 3H), 7.85 (s , 1H);

HPLC / MS (APCI): m / z = 482 [M + H] ⁺ , 2.50 min.

Example 71 (racemic mixture)

The specified compound was obtained according to the General scheme 1 of synthesis (I) from compound 1A-3 and aldehyde 10f. Yield: 149.3 mg (31%).

¹ H NMR (400 MHz, DMSO-d ₆ , ppm): 1.43 (s, 6H), 1.44 (s, 3H), 3.24-3.53 (m, 5H), 4.76 (s, 2H), 5.24 ( sept, J = 6.2 Hz, 1H), 7.01 (t, J = 7.52 Hz, 1H), 7.05 (d, J = 8.3 Hz, 1H), 7.29-7.44 (m, 4H), 7.44-7.63 (m, 3H ), 8.21 (s, 1H), 11.53 (s, 1H);

HPLC / MS (APCI): m / z = 508 [M + H] ⁺ , 2.67 min.

Example 72

The specified compound was obtained according to the General scheme 1 synthesis (I) from compound 1A-3 and aldehyde 13d. Yield: 194.7 mg (42%).

¹ H NMR (400 MHz, DMSO-d6, ppm): 1.29 (d, J = 6.24 Hz, 6H), 3.20 (s, 3H), 4.12 (s, 2H), 4.98 (s, 2H), 5.04-5.27 (m, 1H), 7.03 (t, J = 7.46 Hz, 1H), 7.17 (d, J = 8.31 Hz, 1H), 7.26-7.38 (m, 1H), 7.43 (m, 1H), 7.47 (d, J = 7.21 Hz, 1H), 7.63 (t, J = 7.89 Hz, 1H), 7.88 (s, 1H);

HPLC / MS (APCI): m / z = 464 [M + H] ⁺ , 2.90 min.

Example 73 (racemic mixture)

The specified compound was obtained according to the General scheme 1 synthesis (I) from compound 1b-1 and aldehyde 13j. Yield: 187.0 mg (37%).

¹ H NMR (400 MHz, DMSO-d ₆ , ppm): 11.11 (s, 1H), 7.91 (s, 1H), 7.34-7.66 (m, 7H), 7.19-7.21 (d, 1H), 7.04-7.08 (t, 1H), 6.39-6.40 (d, 1H), 6.30-6.31 (d, 1H), 6.19-6.20 (d, 1H), 5.44-5.45 (d, 1H), 5.03 (s, 2H) ), 3.80 (s, 3H);

HPLC / MS (APCI): m / z = 506 [M + H] ⁺ , 1.93 min.

Example 74 (racemic mixture)

The specified compound was obtained according to the General scheme 1 of synthesis (I) from compound 1A-1 and aldehyde 13j. Yield: 131.6 mg (27%).

¹ H NMR (400 MHz, DMSO-d ₆ , ppm): 11.26 (s, 1H), 7.89 (s, 1H), 7.62 (s, 1H), 7.38-7.55 (m, 7H), 7.19- 7.21 (d, 1H), 7.04-7.08 (t, 1H), 6.38-6.40 (dd, 1H), 6.30-6.31 (d, 1H), 6.19-6.20 (d, 1H), 5.44.5.46 (d, 1H) ), 5.03 (s, 2H), 3.79 (s, 3H);

HPLC / MS (APCI): m / z = 488 [M + H] ⁺ , 1.93 min.

Example 75 (racemic mixture)

The specified compound was obtained according to the General scheme 1 of synthesis (I) from compound 1A-1 and aldehyde 13k. Yield: 200.0 mg (41%).

¹ H NMR (400 MHz, DMSO-d ₆ , ppm): 11.26 (s, 1H), 7.88 (s, 1H), 7.38-7.59 (m, 9H), 7.19-7.22 (d, 1H), 7.06-7.08 (m, 1H), 6.44 (s, 1H), 5.94-5.96 (d, 1H), 5.34-5.36 (d, 1H), 5.01 (s, 2H), 3.79 (s, 3H);

HPLC / MS (APCI): m / z = 488 [M + H] ⁺ , 1.89 min.

Example 76 (racemic mixture)

The specified compound was obtained according to the General scheme 1 synthesis (I) from compound 1b-1 and aldehyde 13k. Yield: 101.0 mg (20%).

¹ H NMR (400 MHz, TsMSO-d ₆ , ppm): 11.11 (s, 1H), 7.90 (s, 1H), 7.33-7.65 (m, 8H), 7.19-7.22 (d, 1H), 7.04-7.08 (t, 1H), 6.44 (s, 1H), 5.95-5.96 (d, 1H), 5.34-5.36 (d, 1H), 5.01 (s, 2H), 3.79 (s, 3H);

HPLC / MS (APCI): m / z = 506 [M + H] ⁺ 1.89 min.

Example 77 (racemic mixture)

The specified compound was obtained according to the General scheme 1 of synthesis (I) from compound 1b-1 and aldehyde 13l. Yield: 55.7 mg (10%).

¹ H NMR (400 MHz, DMSO-d ₆ , ppm): 11.11 (br.s, 1H), 7.89 (s, 1H), 7.61-7.63 (t, 1H), 7.33-7.52 (m, 6H ), 7.15-7.20 (m, 2H), 7.06-7.08 (m, 1H), 6.83-6.86 (t, 1H), 6.73-6.75 (d, 1H), 6.24, (s, 1H), 5.01 (s, 2H), 4.17-4.20 (t, 2H), 3.79 (s, 3H), 2.13-2.14 (d, 2H);

HPLC / MS (APCI): m / z = 558 [M + H] ⁺ , 2.57 min.

Example 78

The specified compound was obtained according to the General scheme 1 synthesis (I) from compound 1A-1 and commercially available 2-methylthiophene-3-carbaldehyde. Yield: 193.0 mg (54%).

¹ H NMR (400 MHz, DMSO-d ₆ , ppm): 2.34 (s, 3H), 3.76 (s, 3H), 7.06 (d, J = 5.0 Hz, 1H), 7.39-7.57 (m, 5H), 7.72 (d, J = 4.9 Hz, 1H), 7.77 (s, 1H), 11.16 (br s., 1H);

HPLC / MS (APCI): m / z = 358 [M + H] ⁺ , 1.93 min.

Example 79

The specified compound was obtained according to the General scheme 1 synthesis (I) from compound 1b-1 and aldehyde 5b. Yield: 245.7 mg (59%).

¹ H NMR (400 MHz, DMSO-d ₆ , ppm): 1.97 (s, 3H), 2.08 (s, 3H), 3.61 (s, 6H), 3.74 (s, 3H), 7.33-7.35 ( m, 1H), 7.40-7.50 (m, 2H), 7.61 (t, J = 7.5 Hz, 1H), 10.83 (br.s., 1H);

HPLC / MS (APCI): m / z = 417 [M + H] ⁺ 1.93 min.

Example 80 (mixture of cis / tras isomers)

The specified compound was obtained according to the General scheme 1 of synthesis (I) from compound 1b-1 and aldehyde 10m. Yield: 177.4 mg (33%).

¹ H NMR (400 MHz, CDCl ₃ , ppm): 1.10-1.32 (m, 2H), 1.32-1.45 (m, 2H), 1.45-1.56 (m, 3H), 1.56-1.76 (m, 4H) ), 1.76-2.02 (m, 2H), 2.81 (br.s., 1H), 3.24 (d, J = 11.37 Hz, 1H), 3.38 (s, 3H), 3.95 (s, 3H), 4.81 (s , 2H), 7.01 (t, J = 7.52 Hz, 1H), 7.07 (d, J = 8.31 Hz, 1H), 7.21-7.27 (m, 2H), 7.34 (t, J = 7.03 Hz, 2H), 7.46 (d, J = 7.58 Hz, 1H), 7.55 (t, J = 7.21 Hz, 1H), 8.20 (s, 1H), 11.43 (s, 1H);

HPLC / MS (APCI): m / z = 538 [M + H] ⁺ , 2.24 min.

Example 81 (mixture of cis / tras isomers)

The specified compound was obtained according to the General scheme 1 of synthesis (I) from compound 1A-1 and aldehyde 10m. Yield: 197.5 mg (38%).

¹ H NMR (400 MHz, CDCl ₃ , ppm): 1.17-1.24 (m, 1H), 1.32-1.40 (m, 1H), 1.46-1.54 (m, 2H), 1.59-1.71 (m, 3H) ), 1.85-1.91 (m, 1Н), 2.86 (br.s, 1Н), 3.23 (dd, J1 = 7.5 Hz, J2 = 3.9 Hz, 1Н), 3.36 (s, 3Н), 3.92 (s, 3Н) , 4.79 (s, 2H), 6.98 (t, 1H, J = 7.5 Hz), 7.05 (d, 1H, J = 7.7 Hz), 7.29-7.33 (m, 1H), 7.34-7.38 (m, 3H), 7.43-7.48 (m, 3H), 8.16 (s, 1H), 11.44 (s, 1H);

HPLC / MS (APCI): m / z = 520 [M + H] ⁺ , 2.62 min.

Example 82

The specified compound was obtained according to the General scheme 1 of the synthesis (I) from compound 1A-1 and aldehyde 16. Yield: 221.2 mg (45%).

¹ H NMR (400 MHz, DMSO-d ₆ , ppm): 1.56 (s, 6H); 1.95 (s, 3H); 3.78 (s, 3H); 4.94 (s, 2H); 7.05 (t, J = 7.52 Hz, 1H); 7.15 (d, J = 8.19 Hz, 1H); 7.34-7.47 (m, 3H); 7.47-7.56 (m, 4H); 7.86 (s, 1H); 11.26 (s, 1H);

HPLC / MS (APCI): m / z = 492 [M + H] ⁺ , 1.96 min.

Example 83

The specified compound was obtained according to the General scheme 1 synthesis (I) from compound 1A-1 and aldehyde 5c. Yield: 103.0 mg (22%).

¹ H NMR (400 MHz, DMSO-d ₆ , ppm): 0.97 (d, J = 6.11 Hz, 2H), 1.07 (t, J = 5.93 Hz, 2H), 1.16 (t, J = 7.15 Hz , 1H), 2.00 (d, J = 19.81 Hz, 2H), 2.07 (s, 3H), 2.54 (s, 6H), 3.62 (s, 3H), 3.74 (s, 3H), 7.33 (s, 1H) 7.37-7.45 (m, 2H); 7.47-7.51 (m, 3H); 11.05 (br. S., 1H);

HPLC / MS (APCI): m / z = 469 [M + H] ⁺ , 2.40 min.

Example 84

The specified compound was obtained according to the General scheme 1 synthesis (I) from compound 1A-1 and aldehyde 5d. Yield: 208.6 mg (46%).

¹ H NMR (400 MHz, DMSO-d ₆ , ppm): 2.14 (s, 3H), 2.23 (s, 3H), 2.30-2.32 (m, 2H), 2.41-2.46 (m, 2H), 2.49 (d, 2H), 3.15 (d, J = 4.8 Hz, 2H), 3.57 (s., 3H), 3.75 (s, 3H), 7.40-7.51 (m, 5H), 9.87 (s, 1H);

HPLC / MS (APCI): m / z = 454 [M + H] ⁺ , 1.19 min.

Example 85 (racemic mixture)

The specified compound was obtained according to the General scheme 1 synthesis (I) from compound 1C-1 and aldehyde 10f. Yield: 190.2 mg (37%).

¹ H NMR (400 MHz, DMSO-d ₆ , ppm): 1.28 (s, 3H), 3.17-3.28 (m, 5H), 4.91 (s, 2H), 5.50 (s, 1H), 7.03 ( t, J = 7.5 Hz, 1H), 7.15 (d, J = 8.4 Hz, 1H), 7.33 (d, J = 7.7 Hz, 1H), 7.39 (t, J = 8.7 Hz, 1H), 7.43-7.54 ( m, 2H), 7.61 (br. s., 1H), 7.66 (d, J = 7.6 Hz, 1H), 7.85 (s, 1H), 11.25 (br. s., 1H);

HPLC / MS (APCI): m / z = 515 [M + H] ⁺ , 2.40 min.

Example rat-86 (racemic mixture)

The specified compound was obtained according to the alternative synthesis scheme 2 (I) from compound M9 (1.45 g, 3 mmol, Table 2) and cyclobutanol. Yield: 306.4 mg (19%).

¹ H NMR (400 MHz, DMSO-d ₆ , ppm): 1.29 (s, 3H), 1.57-1.70 (m, 1H), 1.73-1.86 (m, 1H), 2.06-2.20 (m, 2H) ), 2.30-2.39 (m, 2H), 3.17-3.31 (m, 5H), 4.91 (s, 2H), 5.08 (quin, J = 7.5 Hz, 1H), 5.52 (s, 1H), 7.03 (t, J = 7.5 Hz, 1H), 7.16 (d, J = 8.3 Hz, 1H), 7.29-7.36 (m, 2H), 7.36-7.50 (m, 3H), 7.55-7.63 (m, 1H), 7.88 (s , 1H), 11.13 (br. S., 1H);

HPLC / MS (APCI): m / z = 538 [M + H] +, 1.56 min.

Example (R) -86 (R-enantiomer)

The indicated compound was obtained by resolution of rac-86 by chiral HPLC. NMR and HPLC / MS spectra are similar to rac-86.

Example (S) -86 (S-enantiomer)

The indicated compound was obtained by resolution of rac-86 by chiral HPLC. NMR and HPLC / MS spectra are similar to rac-86.

Example rat-87 (racemic mixture)

The specified compound was obtained according to an alternative synthesis scheme 2 (I) from compound M9 (1.45 g, 3 mmol, Table 2) and cyclopentanol. Yield: 480.0 mg (29%).

¹ H NMR (400 MHz, DMSO-d ₆ , ppm): 1.28 (s, 3H), 1.58 (d, J = 2.6 Hz, 2H), 1.74 (d, J = 4.8 Hz, 4H), 1.84 -1.95 (m, 2H), 3.16-3.30 (m, 5H), 4.91 (s, 2H), 5.28 (t, J = 5.7 Hz, 1H), 5.52 (s, 1H), 7.04 (t, J = 7.5 Hz, 1H), 7.16 (d, J = 8.3 Hz, 1H), 7.30-7.37 (m, 2H), 7.37-7.52 (m, 3H), 7.63 (td, J = 7.9, 1.5 Hz, 1H), 7.88 (s, 1H); 11.17 (s, 1H);

HPLC / MS (APCI): m / z = 552 [M + H] ⁺ , 1.95 min.

Example (R) -87 (R-enantiomer)

The indicated compound was obtained by resolution of rac-87 by chiral HPLC. NMR and HPLC / MS spectra are similar to rac-87.

Example (S) -87 (S-enantiomer)

The indicated compound was obtained by resolution of rac-87 by chiral HPLC. NMR and HPLC / MS spectra are similar to rac-87.

Example 88 (racemic mixture)

The specified compound was obtained according to an alternative synthesis scheme 2 (I) from compound M9 (table 2) and cyclohexanol. Yield: 84.8 mg (30%).

¹ H NMR (400 MHz, DMSO-d ₆ , ppm): 1.27 (br.s., 3H), 1.33-1.51 (m, 4H), 1.56 (q, J = 8.3 Hz, 2H), 1.70 -1.89 (m, 4H), 3.16-3.30 (m, 5H), 4.92 (s, 2H), 4.93-5.00 (m, 1H), 5.52 (s, 1H), 7.04 (t, J = 7.5 Hz, 1H ), 7.17 (d, J = 8.5 Hz, 1H), 7.30-7.37 (m, 2H), 7.38-7.53 (m, 3H), 7.63 (td, J = 8.0, 1.0 Hz, 1H), 7.88 (s, 1H), 11.17 (br. S., 1H);

HPLC / MS (APCI): m / z = 566 [M + H] ⁺ , 2.03 min.

Example 89 (racemic mixture)

The specified compound was obtained according to the General scheme 1 synthesis (I) from compound 1d-1 and aldehyde 10f. Yield: 134.0 mg (26%).

¹ H NMR (400 MHz, DMSO-d ₆ , ppm): 1.27 (s, 3H) 3.18-3.25 (m, 2H) 3.25-3.27 (m, 3H) 3.78 (s, 3H) 4.92 (s, 2H) 5.50 (s, 1H) 7.01-7.07 (m, 1H) 7.16 (d, J = 8.44 Hz, 1H) 7.31-7.44 (m, 3H) 7.44-7.51 (m, 1H) 7.51-7.61 (m, 1H ) 7.89 (s, 1H); 11.14 (s, 1H);

HPLC / MS (APCI): m / z = 516 [M + H] ⁺ , 2.61 min.

Example 90 (a mixture of cis - / - trans isomers of decahydroquinoline)

The specified compound was obtained according to the General scheme 1 synthesis (I) from compound 1A-1 and aldehyde 5e. Yield: 172.4 mg (35%).

¹ H NMR (400 MHz, DMSO-d ₆ , ppm): 0.78-0.99 (m, 4H), 1.13-1.28 (m, 5H), 1.39-1.54 (m, 2H), 1.64 (d, J = 2.0 Hz, 3H), 1.99 (s, 3H), 2.79 (dd, J = 11.2, 3.4 Hz, 1H), 2.91-2.94 (m, 1H), 3.58 (s, 3H), 3.76 (s, 3H) 7.29-7.47 (m, 5H); 7.47 (s, 1H); 11.10 (br.s., 1H);

HPLC / MS (APCI): m / z = 494 [M + H] ⁺ , 2.32 min.

Example 91

The specified compound was obtained from the compound of Example 1 according to the following procedure: The compound from Example 1 (145 mg, 0.25 mmol) was dissolved in DCM (10 ml) and at rt. and stirring, meta-chloroperbenzoic acid (0.5 mmol, 3 equiv.) was added in one portion. The resulting mixture was stirred 24 hours at rt, then washed successively with saturated aqueous solutions of hydrogen carbonate and sodium chloride (10 ml each) and extracted with DCM (3 × 10 ml). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure on a rotary evaporator. The evaporation residue was purified by preparative HPLC to obtain the title compound. Yield: 123.7 mg (81%).

HPLC / MS (APCI): m / z = 612 [M + H] ⁺ , 2.15 min.

Example 92

The specified compound was obtained according to an alternative synthesis scheme 2 (I) from compound M7 (Table 2) and cyclohexanol. Yield: 132.9 mg (46%).

HPLC / MS (APCI): m / z = 578 [M + H] ⁺ , 2.40 min.

Example 93

The specified compound was obtained according to the General scheme 1 synthesis (I) from compound 1b-4 and aldehyde 10v on a scale of 0.2 mmol. Yield: 28.4 mg (24%).

HPLC / MS (APCI): m / z = 580 [M + H] ⁺ , 2.59 min.

Example 94

The specified compound was obtained from the compound of Example 1 according to the following procedure: The compound from Example 1 (145 mg, 0.25 mmol) was dissolved in DCM (10 ml) and at rt. and stirring, meta-chloroperbenzoic acid (0.25 mmol, 1 equiv.) was added in one portion. The resulting mixture was stirred for 4 hours at rt. (monitoring the conversion of the starting compound by TLC), then washed successively with saturated aqueous solutions of bicarbonate and sodium chloride (10 ml each) and extracted with DCM (3 × 10 ml). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure on a rotary evaporator. The evaporation residue was purified by preparative HPLC to obtain the title compound. Yield: 40.2 mg (27%).

HPLC / MS (APCI): m / z = 596 [M + H] ⁺ , 2.01 min.

Example 95

The specified compound was obtained according to the General scheme 1 of synthesis (I) from compound 1b-1 and 1- (but-2-in-1-yl) -5-chloro-1H-pyrrole-2-carbaldehyde, which was synthesized by alkylation of 5- chloro-1H-pyrrole-2-carbaldehyde [Journal of Organic Chemistry, 1975, 40 (22): 3161-9] 1-bromobut-2-in in the presence of sodium hydride (1.1 eq.) in anhydrous THF.

Yield: 220.0 mg (51%).

¹ H NMR (400 MHz, DMSO-d ₆ , ppm): 1.76 (s, 3H), 3.77 (s, 3H), 4.95 (d, J = 2.1 Hz, 2H), 6.32 (d, J = 4.2 Hz, 1H), 6.38 (d, J = 4.3 Hz, 1H), 7.32-7.39 (m, 1H), 7.42-7.54 (m, 2H), 7.65 (td, J = 7.9, 1.1 Hz, 1H), 11.07 (s, 1H);

HPLC / MS (APCI): m / z = 432 [M + H] ⁺ , 2.76 min.

Example 96

Said compound was obtained according to general synthesis scheme 1 (I) from compound 1a-1 and 2- (3-methoxypropoxy) benzaldehyde, which was synthesized by alkylation of salicylic aldehyde with 1-chloro-3-methoxypropane in the presence of potassium carbonate in boiling acetonitrile.

Yield: 297.9 mg (70%).

HPLC / MS (APCI): m / z = 426 [M + H] ⁺ , 2.11 min.

Example M1

The specified compound was obtained according to General scheme 1 for the synthesis of compounds (II) from the compound of Example 96 (297.9 mg, 0.7 mmol). Yield: 230.4 mg (80%).

¹ H NMR (400 MHz, DMSO-d ₆ , ppm): 1.98 (t, J = 6.24 Hz, 2H), 3.25 (s, 3H), 3.85 (s, 3H), 3.49 (t, J = 6.24 Hz, 3H), 4.10 (t, J = 6.30 Hz, 2H), 6.99 (t, J = 7.46 Hz, 1H), 7.08 (d, J = 8.31 Hz, 1H), 7.18-7.29 (m, 3H) 7.31-7.47 (m, 4H); 7.90 (s, 1H);

HPLC / MS (APCI): m / z = 412 [M + H] ⁺ 2.04 min.

Example M2

The specified compound was obtained according to General scheme 1 for the synthesis of compounds (III) from the compound of Example M1 (230.4 mg, 0.56 mmol). Yield: 29.0 mg (14%).

¹ H NMR (400 MHz, CDCl ₃ , ppm): 2.07-2.13 (m, 2H), 3.60 (t, J = 5.9 Hz, 2H), 3.96 (s, 3H), 4.09-4.16 (m, 2H), 5.34-5.97 (m, 1H), 6.94-7.02 (m, 2H), 7.33 (d, J = 7.6 Hz, 1H), 7.40 (d, J = 7.9 Hz, 3H), 7.45-7.57 (m , 3H), 8.27 (s, 1H), 11.46 (br. S., 1H);

HPLC / MS (APCI): m / z = 368 [M + H] ⁺ , 1.474 min.

Example M3

The specified compound was obtained according to the General scheme 1 synthesis (II) from the compound of Example 27. Yield: 270.6 mg (63%).

HPLC / MS (APCI): m / z = 430 [M + H] ⁺ , 2.15 min.

Example M4

The specified compound was obtained according to the General scheme 1 of synthesis (II) from the compound of Example 79. Yield: 314.0 mg (78%).

¹ H NMR (400 MHz, DMSO-d ₆ , ppm): 2.14 (s, 3H), 2.49 (s, 6H), 3.65 (s, 3H), 7.35 (s, 1H), 7.42-7.53 ( m, 2H), 7.65 (t, J = 7.4 Hz, 1H), 11.08 (br. s., 1H), 13.17 (br. s., 1H);

HPLC / MS (APCI): m / z = 403 [M + H] ⁺ , 1.59 min.

Example M5

The specified compound was obtained according to the General scheme 1 of synthesis (II) from the compound of Example 50. Yield: 277.5 mg (56%).

¹ H NMR (400 MHz, DMSO-d ₆ , ppm): 1.49-1.59 (m, 2H), 1.61-1.76 (m, 2H), 3.38-3.42 (m, 2H), 3.59-3.70 (m , 2H), 5.01 (s, 2H), 5.65 (br.s., 1H), 7.08 (t, J = 7.7 Hz, 1H), 7.23 (d, J = 8.2 Hz, 1H), 7.32-7.38 (m , 1H), 7.37-7.55 (m, 4H), 7.64 (t, J = 8.1 Hz, 1H), 8.07 (s, 1H), 11.40 (s, 1H), 12.74 (s, 1H);

HPLC / MS (APCI): m / z = 496 [M + H] ⁺ , 1.68 min.

Example M6

The specified compound was obtained according to the General scheme 1 of synthesis (II) from the compound of Example 63. Yield: 316.4 mg (72%).

¹ H NMR (400 MHz, DMSO-d ₆ , δ ppm): 3.20 (s, 3H), 4.12 (s, 2H), 4.97 (br.s., 2H), 6.93-7.03 (m, 1H ), 7.09-7.27 (m, 5H), 7.27-7.41 (m, 2H), 7.65-7.82 (m, 1H), 14.50 (br. S., 1H);

HPLC / MS (APCI): m / z = 440 [M + H] ⁺ , 2.15 min.

Example M7

The specified compound was obtained according to the General scheme 1 of synthesis (II) from the compound of Example 36. Yield: 266.0 mg (55%).

¹ H NMR (400 MHz, DMSO-d ₆ , ppm): 1.28 (s, 3H), 3.18-3.27 (m, 5H), 4.88 (br.s., 2H), 5.53 (br. S. , 1H), 6.82-6.98 (m, 1H), 7.01-7.23 (m, 5H), 7.30 (br. S., 2H), 7.56 (br. S., 1H);

HPLC / MS (APCI): m / z = 484 [M + H] ⁺ , 1.74 min.

Example M8

The specified compound was obtained according to General scheme 1 synthesis (III) from the compound of Example M5. Yield: 27.3 mg (11%).

¹ H NMR (400 MHz, DMSO-d ₆ , ppm): 1.49-1.61 (m, 2H), 1.63-1.76 (m, 2H), 3.35-3.42 (m, 2H), 3.60-3.71 (m , 2H), 5.00 (s, 2H), 5.50 (s, 1H), 5.65 (s, 1H), 7.03-7.15 (m, 1H), 7.18-7.45 (m, 6H), 7.46-7.57 (m, 1H ), 7.78 (s, 1H), 10.52 (br. S., 1H);

HPLC / MS (APCI): m / z = 452 [M + H] ⁺ , 2.28 min.

Example M9

The indicated compound was obtained from M8 (20 mg, 0.045 mmol) by reaction with acetyl chloride (2 eq.) In the presence of triethylamine (2 eq.) In acetonitrile (200 μl) at room temperature. The product was isolated by preparative HPLC. Yield: 23.0 mg (80%).

HPLC / MS (APCI): m / z = 494 [M + H] ⁺ , 2.59 min.

In tables 5 and 6 below, the structural formulas of some compounds of the invention are given.

The use of compounds for medical reasons

The compounds described in this invention can be used for the treatment and / or prophylaxis of oncological diseases, in particular, oncological diseases associated with increased expression of the hCE1 enzyme, in particular, for the treatment of leukemia with translations of the MLL gene.

Method for the therapeutic use of compounds

The subject of the invention also includes administering to a subject in need of appropriate treatment a therapeutically effective amount of a compound of general formula (I), a compound of general formula (II) or compounds of general formula (III).

By a therapeutically effective amount is meant an amount of a compound administered or delivered to a patient in which the patient is most likely to exhibit the desired response to treatment (prophylaxis). The exact amount required can vary from subject to subject, depending on the age, body weight and general condition of the patient, the severity of the disease, the method of administration of the drug, combined treatment with other drugs, etc.

The compound of the invention or a pharmaceutical composition comprising the compound can be administered to the patient in any amount and by any route of administration effective for treating or preventing a disease.

After mixing the drug with a specific suitable pharmaceutically acceptable carrier in the desired dosage, the compositions comprising the essence of the invention can be administered orally, parenterally, topically, and the like to the human or other animals.

In the case where the compound of the invention is used as part of a combination therapy regimen, a dose of each of the components of the combination therapy is administered during the required treatment period. The compounds that make up the combination therapy can be administered into the patient's body both at a time, in the form of a dosage containing all the components, and in the form of individual dosages of the components.

Pharmaceutical Compositions

The invention also relates to pharmaceutical compositions which comprise a compound of general formula (I), general formula (II) or a compound of general formula (III) (or a prodrug, a pharmaceutically acceptable salt, solvate, hydrate or other pharmaceutically acceptable derivative thereof) and one or more pharmaceutically acceptable carriers, adjuvants, solvents and / or excipients, such as can be administered to the patient together with the compound of the invention and which do not destroy pharmacol cal activity of the compound and is nontoxic when administered in doses sufficient to deliver a therapeutic amount of the compound.

The pharmaceutical compositions of this invention comprise the compounds of this invention together with pharmaceutically acceptable carriers, which may include any solvents, diluents, dispersions or suspensions, surfactants, isotonic agents, thickeners and emulsifiers, preservatives, astringents, lubricants materials, etc., suitable for a particular dosage form. Materials that may serve as pharmaceutically acceptable carriers include, but are not limited to, mono- and oligosaccharides, as well as their derivatives; gelatin; talc; excipients such as cocoa butter and suppository wax; oils such as peanut, cottonseed, safrole, sesame, olive, corn and soybean oil; glycols such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic solution, Ringer's solution; ethyl alcohol and phosphate buffers. Also in the composition of the composition may be other non-toxic compatible lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as dyes, release fluids, film-forming agents, sweeteners, flavors and fragrances, preservatives and antioxidants.

The subject of the present invention is also dosage forms — a class of pharmaceutical compositions, the composition of which is optimized for a specific route of administration into the body in a therapeutically effective dose, for example, for administration to the body orally, topically, by the intraocular route, pulmonary, for example, as an inhalation spray, or intravascular the method, intranasally, subcutaneously, intraperitoneally, intramuscularly, as well as the infusion method, in the recommended dosages.

Dosage forms of the present invention may contain formulations prepared using liposome methods, microencapsulation methods, methods for preparing nanoforms of the preparation, or other methods known in the pharmaceutical art.

In preparing the composition, for example in tablet form, the active principle is mixed with one or more pharmaceutical excipients, such as, for example, gelatin, starch, lactose, magnesium stearate, talc, silica, gum arabic, mannitol, microcrystalline cellulose, hypromellose or the like.

Tablets may be coated with sucrose, a cellulosic derivative, or other suitable coating materials. Tablets can be prepared in various ways, such as direct compression, dry or wet granulation, or hot fusion.

A pharmaceutical composition in the form of a gelatin capsule can be prepared by mixing the active principle with a solvent and filling the mixture with soft or hard capsules.

For parenteral administration, aqueous suspensions, isotonic saline solutions or sterile injectable solutions are used that contain pharmacologically compatible agents, for example propylene glycol or butylene glycol.

Characterization of the biological activity of the compounds

Determination of cytotoxicity of the compounds of the invention

Cell lines. All the malignant cell lines used in the experiments were obtained from ATCC (American Type Tissue Collection) and cultured according to the manufacturer's recommendations. Non-transformed murine macrophages from the abdominal cavity were isolated using the literature method [Aging (Albany NY). 2016 Jul; 8 (7): 1294-315]. Primary human skin fibroblasts (NDFs, normal human fibroblasts) were obtained from the Roswell Park Cancer Institute (Buffalo, USA) and cultured according to the manufacturer's recommendations. Senescent cell lines (in a state of irreversible arrest of the cell cycle) SK-Mel-103 and A549 were obtained according to the methods described in the literature by exposure to ionizing radiation (20 Gray), or by preliminary incubation of cells with bleomycin for 72 hours.

Chemical compounds tested

The tested chemical compounds were prepared in the form of 10 mmol DMSO effluents and stored in the dark at -20 ° C, thawing immediately before the experiment.

Determination of cytotoxicity of the compounds of the invention

Cytotoxicity of the compounds was determined using a commercially available alamarBlue assay® fluorescence assay (ThermoFisher Scientific, USA) according to the manufacturer's instructions in 384-well plates. Cells were scattered into the wells on a plate, incubated for 24 hours in a CO ₂ incubator at 100% humidity at 37 ° C; after that, serially diluted DMSO stocks of the test compounds in the concentration range of 0.0015-30 μmol / L (two repetitions for each concentration of the compound), the final concentration of DMSO in the medium 0.3%) were added and incubated for 72 hours under the conditions described above. A culture medium with 0.3% DMSO was used as a negative control. After the incubation was completed, a solution of resazurin (alamarBlue) was added to the wells, the fluorescence was measured (instant T ₀ , excitation 530-560 nm, emission 590 nm), after which the plate was incubated for another 5-6 hours at 37 ° C and the fluorescence was measured again (time time T ₆ ). The difference T ₆ -T _{0 was} calculated. Based on the data obtained, using the GraphPad Prism 5.0 program (GraphPad Software, Inc., USA), the half-maximal cytotoxic concentration (IC ₅₀ ) was calculated in μmol / L, at which 50% cell death was observed.

From the data shown in tables 7, 8 and 9, it follows that the compounds of the general formula (I) exhibit high selective cytotoxicity only with respect to human malignant cell lines expressing the carboxyl esterase-1 enzyme (hCE1) and are not toxic to hCE1- negative cell lines. Non-toxic ester compounds of the general formula (I) that are more resistant to hydrolyzing enzymes other than hCE1, for example, acetylcholinesterases, butyrylcholinesterases and carboxylesterase isoforms hCE2, hCE3, will selectively hydrolyze to the corresponding cytotoxic carboxylic acid only in express cells. Carboxylic acids formed inside hCE1-positive cells, under physiological conditions, are negatively charged particles, which complicates their reverse passive diffusion through the cell membrane. This leads to the accumulation of active drug acids in the intracellular space and, as a consequence, to an increase in the pharmacological effect, prolonged action and a decrease in the applied dose of the compound of general formula (I).

From the data shown in table 10, it follows that the compounds of General formulas (II) and (III) exhibit high cytotoxicity with respect to a wide range of malignant cell lines in humans and mice.

n / t - not tested.

From the data given in table 11, it follows that compounds M1 and M8 of the general formulas (II) and (III), respectively, exhibit high cytotoxicity (IC ₅₀ <110 nmol / L) only with respect to proliferating malignant cell lines of SK-Mel- melanoma 103 and lung adenocarcinomas A549, but are absolutely indifferent (IC ₅₀ > 10 μmol / L) with respect to the same cell lines in a senescent state (irreversible arrest of the cell cycle). It doesn’t matter in what way the state of senescence was initiated. This indicates a potentially low toxicity of compounds of the general formulas (II) and (III), since somatic non-proliferating cells make up a large part of the adult human body.

Additional confirmation of the low toxicity of the compounds of the invention, in particular of the general formulas (I) and (III), in relation to non-cancerous cells (macrophages isolated from the abdominal cavity of mice) are shown in Figures 4 and 5. As follows from the above data, all tested compounds do not reduce the viability of normal macrophages up to a maximum concentration of 10 μmol / L.

Determination of the stability of compounds in plasma

Freshly obtained plasma from NIH-SWISS mice was used for experiments. Human plasma was obtained from Bioreclamation Inc. (USA).

Test compounds were incubated in plasma at a concentration of 100 μmol / L at 37 ° C.

At certain time intervals, plasma aliquots were taken from the incubation mixture, after which they were diluted 10 times with the culture medium and used to determine cytotoxicity, as described above.

As can be seen from the data presented in table 12, the compound of example 50 is highly toxic to cell lines with expression of carboxyl esterase-1 hCE1 (leukemia with translocations of the MLL gene MV4-11 and U937, IC ₅₀ 36-40 nmol / l), but is indifferent with respect to hCE1-negative cell lines (CCRF-CEM lymphoma and SK-Mel-103 melanoma, IC ₅₀ 8.8-10 μmol / L). Incubation with a specific inhibitor of carboxyl esterase-1 BNPP reduces the cytotoxicity of the test compound with respect to the hCE1-positive cell lines MV4-11 and U937 60-170 times, which indicates the key role of carboxyl esterase-1 in the conversion of non-toxic compounds of the general formula (I) into cytotoxic metabolites of formulas (II) and (III).

Based on the experimental data for the compound of Example 36, it was shown that the compounds of the invention of general formula (I) are stable upon incubation in human plasma (low carboxyl esterase-1) and retain their selective cytotoxicity with respect to hCE1-positive cell lines (Figure 3 ) For comparison, the cytotoxicity profile of the same compound obtained during incubation in the absence of plasma is shown (Fig. 2). The data presented indicate a potentially low toxicity of compounds of the general formula (I) with respect to tissues and organs not expressing during incubation.

Determination of the antitumor activity of the compounds of the invention in a subcutaneous transplantable xenograft model of acute myeloid leukemia MV4-11 with translocation of the MLL gene.

All animal studies were conducted at the Roswell Park Cancer Institute (RPCI) in accordance with a protocol approved by the Laboratory Animal Care and Handling Committee (IACUC).

Female SCID mice derived from vivarium RPCI (LAR RPCI) were used in the study. At the time of the start of the experiment, the animals were 9 weeks old. Mice were kept 5 animals per cage. The animals were kept on a standard diet for rodents (2018S, Harlan) and free access to sterile drinking water under controlled conditions (temperature 18-26 ° C, humidity 30-70%, 12-hour light-dark cycle). Before the experiment, the animals were acclimatized for 3-5 days.

Cell line MV4-11

Cell culture of acute monocytic human leukemia with t (4; 11) translocation of the MLL gene. Cell culture was performed under sterile conditions using aseptic technique and sterile reagents. Before starting work, the cell culture was checked for the absence of mycoplasma. MV4-11 was cultured in RPMI medium supplemented with phenol red, 10% fetal calf serum, 100 units / ml penicillin, 100 μg / ml streptomycin and 2 mmol L-glutamine.

Cell inoculation

Cells grown in six T75 plates were separated by centrifugation (1000 rpm, 5 min, 4 ° C). The pellet containing cells was washed twice with a sterile cold D-PBS solution, followed by centrifugation, as described above, after each washing. After the first wash, the cells were counted, and after the last wash, the cells were resuspended to a final concentration of 10 million cells / ml or 2 million / 200 μl injection volume in cold D-PBS. The cell suspension was stored on ice until injection. The suspension of cells was inoculated into each flank of the animals (2 million cells per injection, 2 inoculations per mouse). All manipulations with the cell culture during preparation and inoculation were carried out under sterile conditions.

Animal preparation

When the inoculated tumors reached a volume of 50-200 mm ³ , the animals were divided into groups (n = 10) in such a way as to average the volume of tumors between the groups.

Administration of Compounds of the Invention and a Control Solution

The compounds of the invention were administered intraperitoneally once a day in accordance with the schedules and doses shown in Figures 6 and 7. The compound of Example 29 was administered at a dose of 80 mg / kg in a mixture of 10% DMSO, 10% Cremaphor ELP and 80% saline . The compound of example 87 was administered at a dose of 100 mg / kg in a mixture of 10% ethanol, 10% Cremaphor ELP and 80% saline, the same formulation was used for the control group. The injected volumes of the test compound solutions (10 ml / kg) were calculated based on the weight of each animal; solutions were injected for 10 seconds.

Animal monitoring and tumor volume measurement

Throughout the experiment, the mortality and general condition of the animals in all groups were monitored daily (general view, physical activity, weight loss, etc.). For a clearer assessment of the condition and activity of animals, the examination was performed with open cells. All deviations from the norm were documented. If, upon examination of the animal, significant signs of toxicity were found (for example, ruffled, hunched, low activity, weight reduction of 15%), then the administration of the drug was stopped until the animal was fully restored. If the animal's weight loss exceeded 20%, then it was euthanized in accordance with the rules of Roswell IACUC. Tumor size was measured with a digital caliper 3 times a week in two dimensions: maximum length and maximum width (L and W, respectively). Tumor volume (V) was calculated by the formula: V = 0.5 × L × W × W.

Study end

Euthanasia of agonizing animals and animals with large tumors (2 cm ³ or more) was carried out by an overdose of CO ₂ , accompanied by cervical dislocation in accordance with the rules of Roswell IACUC

Data analysis

Based on the measured individual tumor volumes, the average value for each group was calculated. Relative tumor volumes were calculated as tumor volume on a specific day divided by the initial volume. Average tumor volumes were compared between groups using a two-sided unpaired t-test (p <0.05 for a statistically significant result). Tumor growth inhibition (T / C%) was calculated by the formula: T / C% = (V _experiment / V _control ) × 100 %

For the compounds of the present invention of general formula (I), antitumor activity was studied in a subcutaneous transplantable acute myeloid leukemia MV4-11 model with translocation of the MLL-gene in female SCID mice. Tumor growth inhibition curves are shown in Figure 1A and B.

Inhibition of tumor growth (T / C) for the compound of Example 87 was 61% (p = 0.014), and for the compound of Example 29-41% (p <0.0001). During the experiment, no signs of toxicity were observed in the animals in the experimental groups (loss of body weight, change in appearance and behavior).

Although the invention has been described with reference to the disclosed embodiments, it will be apparent to those skilled in the art that the specific experiments described in detail are for illustrative purposes only and should not be construed as limiting the scope of the invention in any way. It should be understood that various modifications are possible without departing from the gist of the present invention.

Claims (107)

1. The compound of General formula (I), General formula (II) or General formula (III):

or its stereoisomer or enantiomer, a pharmaceutically acceptable salt, where: R ¹ , R ² are independently selected and are —H, substituted or unsubstituted —C ₁ -C ₆ alkyl, wherein the substituents R ¹ and R ² together with the carbon atom to which they are attached can form a substituted or unsubstituted —C ₃ -C ₁₂ cycloalkyl; And it is selected independently and represents:

or

moreover, the asterisk indicates the place of attachment of substituents; X ¹ is independently selected and is —O—; X ² is independently selected and is an unsubstituted or substituted alkylene chain - (CH ₂ ) _n -, where n is from 1 to 4; Y ¹ is independently selected and is —C≡C— or —CR ^c = CR ^c -; Y ² is independently selected and is —C (R ^b ) ₂ -; R ^b is independently selected and is —H, —C ₁ -C ₆ alkyl; R ^c is independently selected and is —H, —C ₁ -C ₆ alkyl; R ³ is independently selected and is —H, substituted or unsubstituted —C ₁ -C ₆ alkyl, substituted or unsubstituted —C ₃ -C ₉ cycloalkyl, substituted or unsubstituted —C ₆ -C ₁₀ aryl, substituted or unsubstituted 5 ÷ 10 membered heteroaryl containing from 1 to 4 heteroatoms independently selected from N, S and / or O, 3 ÷ 12 membered heterocyclyl containing from 1 to 4 heteroatoms independently selected from N, S and / or O, or represents

R ^d , R ^{d ′} are independently selected and are —H, substituted or unsubstituted —C ₁ -C ₆ alkyl, substituted or unsubstituted —C ₆ -C ₁₀ aryl, substituted or unsubstituted 5–6 membered heteroaryl containing from 1 to 4 heteroatoms independently selected from N, S and O, substituted or unsubstituted 3 to 12 membered heterocyclyl containing 1 to 4 heteroatoms independently selected from N, S and / or O, with two substituents R ^d and R ^{d '} together with the carbon atom to which they are attached can form substituted or unsubstituted -C ₃ -C ₁₂ cycloalkyl, substituted or not substituted 3 to 12 membered heterocyclyl containing from 1 to 4 heteroatoms independently selected from N, S and / or O; Y ³ is independently selected and is —OR ^e or a substituted or unsubstituted 3 to 12 membered heterocyclyl containing from 1 to 4 heteroatoms independently selected from N, S and / or O; R ^e is independently selected and is —H, —C (═O) —C _1-6 alkyl, substituted or unsubstituted —C ₁ -C ₆ alkyl, substituted or unsubstituted —C ₂ -C ₆ alkenyl; X ³ is independently selected and is —O—; R ⁴ is independently selected and is a halogenated -C ₁ -C ₆ -alkyl substituted or unsubstituted 5-6 membered heteroaryl containing from 1 to 4 heteroatoms independently selected from N, S and / or O, or 3 ÷ 12- member heterocyclyl containing from 1 to 4 heteroatoms independently selected from N, S and O; X ⁴ is independently selected and is —O—, —S—; X ⁵ represents an unsubstituted or substituted alkylene chain - (CH ₂ ) _p -, where n takes values from 1 ÷ 4; X ⁶ is independently selected and is —O— or —S—; R ⁵ is independently selected and is substituted or unsubstituted -C ₁ -C ₆ -alkyl, substituted or unsubstituted -C ₂ -C ₆ -alkenyl, substituted or unsubstituted -C ₆ -C ₁₀ -aryl, substituted or unsubstituted 5 ÷ 6- member heteroaryl containing from 1 to 4 heteroatoms independently selected from N, S and / or O, substituted or unsubstituted 3 to 12 membered heterocyclyl containing from 1 to 4 heteroatoms independently selected from N, S and / or O; X ⁷ , X ⁹ are independently selected and are -CR ^f -; X ⁸ is independently selected and is —O— or —S—; R ^f is independently selected and is —H, substituted or unsubstituted —C ₁ -C ₆ alkyl; X ¹⁰ is independently selected and is —CR ^g -; R ^g is independently selected and is —H, halogen, —OR ^e , —N (R ^b ) ₂ , substituted or unsubstituted —C ₁ -C ₆ alkyl, substituted or unsubstituted —C ₂ -C ₆ alkynyl, substituted or unsubstituted -OC ₁ -C ₆ -alkyl, substituted or unsubstituted -C ₆ -C ₁₀ -aryl, substituted or unsubstituted -O-phenyl, substituted or unsubstituted 5-6 membered heteroaryl containing from 1 to 4 heteroatoms independently selected from N, S and O, substituted or unsubstituted 3 to 12 membered heterocyclyl containing from 1 to 4 heteroatoms independently selected from N, S and / or O; R ^h is independently selected and is —H, substituted or unsubstituted —C ₁ -C ₆ alkyl; R ⁶ is independently selected and is substituted or unsubstituted -C ₁ -C ₆ -alkyl; X ¹¹ is independently selected and is —N— or —CR ^j ; X ¹² is independently selected and is —N— or —CR ^j -; R ^j is independently selected and is —H, halogen, substituted or unsubstituted —C ₁ -C ₆ alkyl; R ⁷ is independently selected and is - (CH ₂ ) _t O (CH ₂ ) _s , substituted or unsubstituted -C ₁ -C ₆ -alkyl; t and s take values from 1 to 10; B is independently selected and is:

moreover, the asterisk indicates the place of attachment of substituents; each substituent R ^k is independently selected and is —H, halogen; Q is independently selected and is —H, —C (═O) —R ^L ; R ^L is independently selected and is substituted or unsubstituted -C ₁ -C ₆ -alkyl. 2. The compound according to claim 1, which is a compound of general formula (Ia), general formula (IIa) or general formula (IIIa):

where R ³ represents:

moreover, the asterisk indicates the place of attachment of the substituent; R ¹ , R ² are independently selected and are —H, substituted or unsubstituted —C ₁ -C ₆ alkyl, wherein the substituents R ¹ and R ² together with the carbon atom to which they are attached can form a substituted or unsubstituted —C ₃ -C ₉ -cycloalkyl; each substituent R ^k is independently selected and is —H, —F, —Cl; R ⁸ is independently selected and is —H, substituted or unsubstituted —C ₁ -C ₆ alkyl, substituted or unsubstituted —C ₃ -C ₉ cycloalkyl, substituted or unsubstituted —C ₆ -C ₁₀ aryl, substituted or unsubstituted five or a six-membered heteroaryl containing from 1 to 4 heteroatoms independently selected from N, S and / or O, a substituted or unsubstituted 3 ÷ 9-membered heterocyclyl containing from 1 to 4 heteroatoms independently selected from N, S and / or O ; R ⁹ is independently selected and is —H or —C ₁ -C ₆ alkyl. 3. The compound according to claim 1, which is a compound of general formula (Ib), general formula (IIb) or general formula (IIIb):

where R ³ represents:

moreover, the asterisk indicates the place of attachment of the substituent; R ¹ , R ² are independently selected and are —H, substituted or unsubstituted —C ₁ -C ₆ alkyl, wherein the substituents R ¹ and R ² together with the carbon atom to which they are attached can form a substituted or unsubstituted —C ₃ -C ₁₂ cycloalkyl; each substituent R ^k is independently selected and is —H, —F, —Cl; Y ⁴ is independently selected and is —C (R ⁿ ) ₂ -; R ⁿ is independently selected and is —H, —F, —C ₁ -C ₆ alkyl, —OR ^b ; m, v are selected independently take integer values from 1 to 6; Y ⁵ is independently selected and is —O—, —S—, —S (= O) -, —S (= O) ₂ -, —C (R ⁿ ) ₂ - or substituents of the form:

,

,

or

; R ^b is independently selected and is —H, substituted or unsubstituted —C ₁ -C ₆ alkyl, substituted or unsubstituted —C ₃ -C ₉ cycloalkyl, substituted or unsubstituted 5–6 membered heterocyclyl containing from 1 to 4 heteroatoms independently selected from N, S and / or O, or a substituted or unsubstituted 3 to 9 membered heterocyclyl containing from 1 to 4 heteroatoms independently selected from N, S and / or O. 4. The compound according to claim 1, which is a compound of general formula (Ic), general formula (IIc) or general formula (IIIc):

where R ¹ , R ² are independently selected and are —H, substituted or unsubstituted —C ₁ -C ₆ alkyl, wherein the substituents R ¹ and R ² together with the carbon atom to which they are attached can form a substituted or unsubstituted —C ₃ -C ₁₂ cycloalkyl; each substituent R ^k is independently selected and is —H, —F, —Cl; R ^h is independently selected and is —H, substituted or unsubstituted —C ₁ -C ₆ alkyl; R ⁶ is independently selected and is substituted or unsubstituted -C ₁ -C ₆ -alkyl; X ¹⁰ represents —CR ^g -; R ^g is independently selected and is H, —Cl, —OR ^b , —N (R ^b ) ₂ , substituted or unsubstituted —C ₁ -C ₄ alkyl, substituted or unsubstituted 4 to 10 membered heterocyclyl containing from 1 to 4 heteroatoms independently selected from N, S and / or O; R ^b is independently selected and is —H, substituted or unsubstituted —C ₁ -C ₆ alkyl, substituted or unsubstituted —C ₃ -C ₉ cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5–6 membered heteroaryl, containing from 1 to 4 heteroatoms independently selected from N, S and / or O, or a substituted or unsubstituted 4 ÷ 9 membered heterocyclyl containing from 1 to 4 heteroatoms independently selected from N, S and / or O. 5. The compound according to claim 1, selected from the group:

or

6. The use of compounds according to any one of paragraphs. 1-5 to obtain a pharmaceutical composition for the treatment and / or prevention of cancer associated with malignant transformation of cells expressing the enzyme hCE1. 7. The use according to claim 6, in which the cancer is a leukemia, a malignant tumor of the liver, bladder, bronchi, lungs, nasopharynx, stomach, colon, pancreas or thyroid gland, head, neck, smooth muscle, urothelial malignant tumor, or carcinoid tumor. 8. The use of claim 6, wherein the oncological disease is leukemia with translocation of the MLL gene. 9. A pharmaceutical composition for treating and / or preventing oncological disease associated with malignant transformation of cells expressing the hCE1 enzyme in a subject, containing an effective amount of a compound according to any one of claims. 1-5 and at least one pharmaceutically acceptable excipient. 10. The pharmaceutical composition according to claim 9, characterized in that the pharmaceutically acceptable excipient is a carrier, excipient and / or solvent. 11. The pharmaceutical composition according to p. 9, characterized in that the subject is a human or animal.

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