UA81915C2 - Novel venzoimidazole derivatives useful as antiproliferative agents - Google Patents

Abstract

The invention relates to compounds of the formula 1 and to pharmaceulically acceptable salts, prodrugs and solvales thereof, wherein R, R, R, and Rare as defined herein. The invention also relates to methods of treating abnormal cell growth, such as cancer, in mammals by administering the compounds of formula 1 and to pharmaceutical compositions for treating such disorders which contain the compounds of formula 1. The invention also relates to methods of preparing the compounds of formula 1.

Description

Description of the invention

The present invention relates to novel benzimidazole derivatives suitable for the treatment of pathological growth of 2 cells, such as cancer, in mammals. The present invention also relates to a method of using such compounds in the treatment of pathological cell growth in mammals, especially in humans, as well as to pharmaceutical compounds containing such compounds.

It is known that cells can become cancerous as a result of the transformation of part of their DNA into an oncogene (that is, a gene that, when activated, causes the formation of malignant tumor cells). Many oncogenes encode proteins that are aberrant tyrosine kinases capable of causing such cell transformation. Alternatively, overexpression of a normal proto-oncogene tyrosine kinase can also cause proliferative disorders that sometimes lead to a malignant phenotype.

Receptor tyrosine kinases are enzymes that penetrate the cell membrane and have an extracellular domain that binds growth factors, such as epidermal growth factor, a transmembrane domain, as well as an intracellular domain that acts as a kinase that phosphorylates individual tyrosine residues in proteins and , thus affecting cell proliferation. Other receptor tyrosine kinases are c-egB-2, c-thei, (e-2,

GROWTH, ROG and MONTH. Such kinases are known to be frequently aberrantly expressed in common human cancers such as breast cancer, gastrointestinal cancer such as colon, rectal or stomach cancer, leukemia, and ovarian, bronchus or pancreatic cancer. Evidence has also been found that the epidermal growth factor receptor (EGF), which has tyrosine kinase activity, is mutated and/or overexpressed in many human cancers, such as brain, lung, squamous cell, bladder, stomach, breast, head and neck, esophagus, gynecological tumors and thyroid gland.

Accordingly, receptor tyrosine kinase inhibitors have been found to be useful as selective inhibitors of mammalian tumor cell growth. For example, erbstatin, a tyrosine kinase inhibitor, in athymic nude c 22 mice selectively inhibits the growth of human mammary carcinoma in which the tyrosine kinase Ge) receptor epidermal growth factor (ESF) is expressed, but does not affect the growth of other carcinomas in which the EOR receptor is not expressed. Thus, the compounds of the present invention, which are selective inhibitors of certain receptor tyrosine kinases, in particular ROS g, are useful in the treatment of pathological cell growth, in particular cancer, in mammals. i am

Many other compounds, such as styrene derivatives, have also been reported to inhibit tyrosine kinase. Recently, in five European patent publications, namely EP 0566226 A1 (published on October 20, 1993), EP 0602851 A1 (published on June 22, 1994), EP 0635507 A1 (published on January 25, 1995), EP 0635498 A1 (published on January 25, 1995) and ER 0520722 A1 (published by the ZO December 1992)| certain bicyclic derivatives, in particular quinazoline derivatives, have been described which have anticancer properties due to their ability to inhibit tyrosine kinase. Also (patent application UUO 92/20642 (published November 26, 1992)| relates to certain bis-mono and dicyclic aryl and heteroaryl compounds as tyrosine kinase inhibitors useful in inhibiting pathological cell proliferation. World (patent applications

M/096/16960 (published in June 1996), MO 96/09294 (published in March 1996), MO 97/30034 (published on August 21, 1997), MO 98/02434 (published on January 22, 1998), MO 98/02437 (published on January 22, 1998) ii UMO 98/02438 (published on January 22, 1998))| also refer to substituted bicyclic heteroaromatic tc derivatives as tyrosine kinase inhibitors useful for the same purposes. Also see MO 99/16755, 9. Med. with" Spet. 1998, 41, 5457-5465 and in). Honey. Spent 1999, 42, 2373-2382.

This invention relates to the compound of formula 1

I. (sg) re shk -25 her and «o Z pi y : - 50 I I I sp khz. det Shaw "I: yes

E pina t. g y - chi nya | piz and - in KL ts Mesy y ko y y NE - shk ge »

SD ezhstyi Zh S Tez vo z "a cat le Z Veny ch h ta Sh: weight runes Sho. UDC Z sl KN t sh y b5 or its pharmaceutically acceptable salt, prodrug, hydrate or solvate, where each K 1, b2, and KZ, regardless of

selected from H, C-Ce alkyl, C--Ce cycloalkyl, halogen, cyano, CEz, difluoromethoxy, trifluoromethoxy, OC.-Ce alkyl, OCaz-Ce cycloalkyl and MA "B8; where KE is "SEREUN, or "SEREZ ) (4-10-membered heterocycle), where n is an integer from 1 to 5, where t is an integer from 0 to 5, where the specified 4-10-membered heterocycle, if aromatic, optionally substituted with 1-3 K" substituents, and where indicated 4-10-membered heterocycle, if non-aromatic, optionally substituted with 1-3 B'" substituents at any position and optionally substituted 1-3 B substituents at any position not adjacent to or directly attached to a heteroatom; where each K' and K5 is independently selected from H or C1-C alkyl; where each K' and KU is independently selected from H , then C,-Ce alkyl and C3-Ce cycloalkyl; and where each E?U, independently, is selected from halogen, cyano, C3, ifluoromethoxy, 14796 .-Ci alkyl, OSa-Ci cycloalkyl and MA "B8.

In one embodiment of the present invention, each 2", 2 BZ is independently selected from H, C.4-Cv alkyl, and Ca-Cv cycloalkyl, halogen, and cyano.

In one embodiment of this invention, B" is "IED pn.

In another embodiment of the present invention, K7 is -(SVRV9)(4-10-membered heterocycle), where t is an integer in the range from 0 to 5 and where the specified 4-10-membered heterocyclic group is optionally substituted 1-3 V! substitutes

In another embodiment of the present invention, КВ" is -"СНо)т(4-10-membered heterocycle), where t is an integer in the range from 0 to 3 and where the indicated 4-10-membered heterocyclic group is optional , substituted with 1-3 EV! substituents.

The invention also relates to compounds of formula 1, where КЕ" is -"СНо)т(4-10-membered heterocycle), where т is an integer in the range from 0 to 3 and where the specified 4-10-membered heterocyclic group , optionally, replaced by 1-2 V! substitutes

The invention also relates to compounds of the formula 1, where K7 is -""СНо)t(4-10-h-open heterocycle), where t is an integer si 2/t in the range from 0 to 2 and where 4-10-- linoleic heterocyclic group, optionally substituted with 1 VK" substituent. (8)

The invention also relates to compounds of the formula 1, where K 7 is -""СНо)t(4-10--ene heterocycle), in which t is 1 is the specified 4-10-membered heterocyclic group, optionally substituted by 1 B" substitute

The invention also relates to compounds of the formula 1, where КЕ" is -"СНо)т(4-8-membered heterocycle), in which 71 is present and in 10) in which a 4-8-membered heterocyclic group is indicated, optionally substituted by 1 B" substitute. -

The invention also relates to compounds of formula 1, where K7 is -(CH0)t(4-6-ene heterocycle), in which t is 1 and in which the specified 4-6-ene heterocyclic group is optionally substituted by 1 EC substitute at

In a preferred embodiment, the invention relates to the compound of formula 1, where K 7 is -""СНо)p(b-membered heterocycle), c. че зв ЯКОМУ t Е 1 and in which the specified 6b-membered heterocyclic group is optionally substituted by 1 EC substituent. co

In a more preferred embodiment, the invention relates to compounds of formula 1, where B" is -""CHO)t(5-membered heterocycle), in which t is 1 and in which the specified 5-membered heterocyclic group is optionally substituted by 1 B substituent .

In the most preferred embodiment, the invention relates to compounds of formula 1, where B 7 is -(CH0)n(4-membered heterocycle), in which t is 1 and in which the specified 4-membered heterocyclic group is optionally substituted by 1 B! substitute - с In another embodiment of this invention, K7 is -"SVRV9)1(4-10-membered heterocycle), where t is an integer in the range from 0 to 5 and where the specified 4-10-membered heterocyclic group , optionally substituted with 1-3 B 7 " substituents in any position and optionally substituted with 1-3 KE? substituents in any position not adjacent to or directly attached to the heteroatom. со 15 In another embodiment of this invention, КВ" is -"СНо)т(4-10-membered heterocycle), where т is an integer in the range from 0 to 3 and where the specified 4-10-membered heterocyclic group, optionally, substituted by 1-3 BK / substituents in any position and, optionally, substituted by 1-3 KZ substituents in any position not adjacent to "c" or directly attached to a heteroatom.

The invention also relates to compounds of formula 1, where КЕ" is -"СНо)т(4-10-membered heterocycle), where t is an integer - in the interval from 0 to 3 and where the specified 4-10-membered heterocyclic group , optionally, substituted 1-2 V with substituents in any position and, optionally, substituted 1-2 KE? substituents in any position not adjacent to or directly attached to the heteroatom.

The invention also relates to compounds of the formula 1, where КЕ" is -"СНо)т(4-10-membered heterocycle), where т is an integer 22 in the range from 0 to 2 and where the specified 4-10-membered heterocyclic group , optionally, replaced by 1 VK" substitute

GF! in any position and, optionally, replaced by 1 KE? by a substituent in any position not adjacent to or directly attached to a heteroatom. ki The invention also relates to compounds of formula 1, where K 7 is -""СНо)т(4-10--membered heterocycle), in which t is 1 is the specified 4-10-membered heterocyclic group, optionally, substituted by 1 EC" by a substituent in any position and, optionally, substituted 1 BK? by a substituent in any position not adjacent to or directly attached to the heteroatom.

The invention also relates to compounds of formula 1, where КЕ" is -"СНо)т(4-8-membered heterocycle), in which there is 71 and in which the specified 4-8--membered heterocyclic group is optionally substituted by 1 К" by a substituent in any b5 position and, optionally, substituted 1B9 by a substituent in any position not adjacent to or directly attached to a heteroatom.

The invention also relates to compounds of formula 1, where EC" is -(CH2)t(4-b-membered heterocycle), in which t is 1, in which the specified 4-b-membered heterocyclic group is optionally substituted 1 B " as a substitute in any position and, optionally, replaced by 1 ZhK ? by a substituent in any position not adjacent to or directly attached to a heteroatom.

In a preferred embodiment, the invention relates to a compound of formula 1, where K 7 is -""CHO)p(b-membered heterocycle), in which t is 1 and in which the specified 6b-membered heterocyclic group is optionally substituted by 1 K" substituent in any position and, optionally, substituted by 1 2? substituent in any position not adjacent to or directly attached to the heteroatom. then In a more preferred embodiment, the invention relates to compounds of formula 1, where КЕ" is "СНо)п (b-membered heterocycle), in which t is 1, in which a 5-membered heterocyclic group is indicated, optionally substituted by 1 BK" substituent at any position and optionally substituted by 1 KE? substituent at any which position is not adjacent to or directly attached to the heteroatom.

In the most preferred embodiment, the invention relates to compounds of the formula 1, where B 7 is -(CHO)p(4-membered heterocycle), in which t is 1, in which the specified 4-membered heterocyclic group is optionally substituted by 1 B 7 substituent in any position and, optionally, substituted 1 K U? by a substituent in any position not adjacent to or directly attached to a heteroatom.

In a preferred embodiment, the present invention relates to compounds of formula 1, where the specified 4-10-ene heterocycle is selected from the group that includes pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholino and oxetanyl.

In one embodiment, the present invention relates to compounds of formula 1, wherein B is selected from the group consisting of H,

C.-Cv alkyl, C3-Cv cycloalkyl, halogen and cyano.

In one embodiment, the present invention relates to compounds of formula 1, in which the EC" group is C-C-C alkyl selected from methyl, butyl, ethyl, propyl and pentyl.

In another embodiment of this invention, C.4-Cv alkyl is selected from methyl, butyl, ethyl and propyl.

In a preferred embodiment, the K" group is a C4-Cb alkyl selected from methyl, butyl, and ethyl. In a more preferred embodiment, the K" group is methyl. yu

In another embodiment of this invention, each KE? and KE? compounds of formula 1 independently selected from methyl, ethyl, propyl and butyl. -

In a preferred embodiment, B and B9 are each independently selected from methyl and ethyl. In a more preferred embodiment, Fu each VE? and 29 is methyl.

In another separate embodiment of this invention, VC" is -"SERV2)(4-8-membered heterocycle), where t is an integer -

Z0 in the interval from 0 to Z and in which the specified 4-8-ene heterocyclic group is optionally substituted with 1-3 B! with substitutes.

In another separate embodiment of the present invention, VK" is SER)n(4-6-membered heterocycle), where t is an integer from 0 to 3 and where the specified 4-10-membered heterocyclic group is optionally , substituted with 1-3 V!" substituents. 70 In another separate embodiment of this invention, VK" is a SE) (b-membered heterocycle), where t is an integer in the range from 0 to 3 and in which the b-membered heterocyclic group, optionally, replaced by 1-3 V ! with substitutes.

In another separate embodiment of the present invention, VK" is -"SERV2)(5-membered heterocycle), where t is an integer in the range from 0 to 2 and in which the specified 5-membered heterocyclic group is optionally substituted with 1-3 B with substitutes.

In another separate embodiment of the present invention, VK" is CEP) (4-membered heterocycle), where t is an integer in the range from 0 to 2 and in which the 4-membered heterocyclic group is specified, optionally substituted 1-3 B! "with substitutes.

In another separate embodiment of the present invention, the heterocyclic group B" contains from one to four heteroatoms, each selected from O, C, and M, provided that the 4- to 10-membered heterocyclic ring does not contain two adjacent O or 5 atoms.

In another separate embodiment of the present invention, the heterocyclic group BK" contains from one to four O atoms, provided that the ring does not contain two adjacent O atoms. 22 In another separate embodiment of the present invention, the heterocyclic group B" contains from one to four O atoms, provided that that the ring does not contain two adjacent 0 atoms. o In another separate embodiment of this invention, the heterocyclic group KE" contains one 0 atom. ko In another separate embodiment of this invention, the heterocyclic group BK" contains from one to four M atoms. 60 In another separate embodiment of this the heterocyclic group B" of the invention contains from one to two M atoms.

In another separate embodiment of this invention, the heterocyclic group B" contains one M atom.

In another separate embodiment of the present invention, B" is "SEREZ") (4-10-ene non-aromatic heterocycle), where t is an integer in the range from 0 to 1 and where the specified 4-10-ene heterocyclic group is, optionally, replaced by 65 1-3 substitutes.

In another separate embodiment of the present invention, KE" is "SERE (4-8-ene non-aromatic heterocycle), where t is an integer in the range from OO to 1 and in which the 4-8-ene non-aromatic heterocyclic group is specified, optionally , replaced by 1-3 VE substituents.

In another separate embodiment of the present invention, KE" is "SERE (4-6-ene non-aromatic heterocycle), where t is an integer from 0 to 1 and in which the 4-6-ene non-aromatic heterocyclic group is specified, optionally , replaced by 1-3 VE substituents.

In another separate embodiment of this invention, KV" is -"SERV2)(6b-membered non-aromatic heterocycle), where t is an integer in the range from 0 to 1 and in which the specified b--membered non-aromatic heterocyclic group is optionally substituted with 1 -3 VE substituents. then In another separate embodiment of this invention, VC" is SER) (a 5-membered non-aromatic heterocycle), where t is an integer in the range from 0 to 1 and in which a 5--membered non-aromatic heterocyclic group, optional necessarily, replaced by 1-3 VE substituents.

In another separate embodiment of the present invention, B" is -""SRUEU" (4-membered non-aromatic heterocycle), where y/5 is an integer in the range from 0 to 1 and in which a 4-membered non-aromatic heterocyclic group, optional necessarily, replaced by 1-3 VE substituents.

In another separate embodiment of the present invention, said 4-10-ene heterocycle is selected from the group that includes azetidinyl, thiazolyl, quinolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, piperazinyl, homopiperazinyl, oxetanyl, homopiperidinyl, indolinyl, dioxanyl, 3-azabicyclo!|3.1.O)hexanyl, 3-azabicyclo|4.1.F)heptanyl, azabicyclo|2.2.2Ihexanyl and 2H-indolyl.

In another separate embodiment of the present invention, the 4-10-ene heterocycle is selected from the group consisting of pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl .

In another separate embodiment of this invention, the specified 4-10-ene heterocycle is selected from the group that includes pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, yUu piperazinyl, homopiperazinyl, azetidinyl, oxetanyl, homopiperidinyl, 3-azabicyclo!|3.1. O)hexanyl,

З-azabicyclo|4.1.0)heptanyl, azabicyclo|2.2.2)hexanyl, ZH-indolyl and quinolizinyl. -

In another separate embodiment of the present invention, the specified 4-10-ene heterocycle is selected from the group that Teh! includes pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholino, and oxetanyl.

In another separate embodiment of the present invention, the indicated 4-10-ene heterocycle is selected from the group that includes tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholino and oxetanyl. co

In another separate embodiment of the present invention, the specified 4-10-ene heterocycle is selected from the group that includes tetrahydrofuranyl, morpholino, oxetanyl and 4H-pyranyl.

Preferred compounds are selected from the group that includes: 1-2-15-(3-morpholin-4-yl-propoxy)-benzoimidazol-1-yl|-quinolin-8-yl)-piperidin-4-ylamine; (--1-2-(5-(tetrahydro-furan-3-yloxy)-benzoimidazol-1-yl|-quinolin-8-yl)-piperidin-4-ylamine; - c 1-2-I5-( (3-methyl-oxetan-3-ylmethoxy)-benzoimidazol-1-yl|-quinolin-8-yl)-piperidin-4-ylamine; ц 1-(2-(5-isobutoxy-benzoimidazol-1-yl)-quinolin-8-yl|-piperidin-4-ylamine; "» 1-2-I(5-(tetrahydro-pyran-4-yloxy) -benzoimidazol-1-yl(1-quinolin-8-yl)-piperidin-4-ylamine and pharmaceutically acceptable salts, prodrugs, hydrates and solvates of the above compounds.

In one preferred embodiment, the compound is selected from the group that includes: ; -z (3-1-2-I5-(tetrahydro-furan-3-yloxy)-benzoimidazol-1-yl|-quinolin-8-ylI-piperidin-4-ylamine; (-)-1-422-(5 -(tetrahydro-furan-3-yloxy)-benzoimidazol-1-yl|-quinolin-8-yl)-piperidin-4-ylamine; and "are pharmaceutically acceptable salts, prodrugs, hydrates and solvates of the above compounds. in another preferred embodiment the compound is selected from the group that includes - 1-2-15-(3-morpholin-4-yl-propoxy)-benzoimidazol-1-yl|-quinolin-8-yl)-piperidin-4-ylamine; and pharmaceutically acceptable salts, prodrugs, hydrates and solvates of the above compound. in another preferred embodiment, the compound is selected from the group consisting of 1-2-15-(3-methyl-oxetan-3-ylmethoxy)-benzoimidazol-1-yl|-quinolin-8-yl)-piperidin-4-ylamine; and pharmaceutically acceptable salts, prodrugs, hydrates and solvates of the above compound. in another preferred embodiment, the compound is selected from the group consisting of

F) 1-(2-(5-isobutoxy-benzoimidazol-1-yl)-quinolin-8-yl|-piperidin-4-ylamine; and pharmaceutically acceptable salts, km prodrugs, hydrates and solvates of the above compound. in another preferred embodiment the compound is selected from the group consisting of 60 0 1-(2-I(5-(tetrahydro-pyran-4-yloxy)-benzoimidazol-1-yl|-quinolin-8-yl)-piperidin-4-ylamine; and pharmaceutical acceptable salts, prodrugs, hydrates and solvates of the above compound.

In one preferred embodiment, the compound of the present invention is a benzenesulfonate salt of any of the above compounds.

The invention also relates to a method of treating pathological cell growth in mammals, which includes administering to the mammal an amount of the compound of formula 1 effective for treating pathological cell growth.

In one preferred embodiment of the present invention, the pathological cell growth is cancer.

In one embodiment of the present invention, the cancer is selected from lung cancer, bone cancer, pancreatic cancer, stomach cancer, skin cancer, head or neck cancer, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, gynecological cancer, rectal cancer, anal cancer, stomach cancer, colon cancer, breast cancer, endometrial carcinoma, fallopian tube carcinoma, endometrial carcinoma, cervical carcinoma, vaginal carcinoma, vulvar carcinoma, Hodgkins disease, esophageal cancer, small bowel cancer, endocrine gland cancer, thyroid cancer, parathyroid cancer , adrenal gland cancer, soft tissue sarcoma, urethral cancer, penile cancer, squamous cell cancer, prostate cancer, chronic or acute leukemia, lymphocytic lymphoma, bladder cancer, kidney or ureter cancer, hypernephroid cancer, renal pelvis carcinoma, central neoplasm 7/ 0 nervous system (CNS), primary CNS lymphomas, tumors of spinal axons, brain, pituitary adenoma, or a combination of one or more of the above aka states

In a preferred embodiment of the present invention, the cancer is selected from the group consisting of brain, squamous cell, bladder, stomach, pancreas, breast, head, neck, esophagus, prostate, rectum, lung, kidney, ovary, gynecological, and thyroid cancers .

In a preferred embodiment of the present invention, the cancer is selected from the group consisting of prostate, breast, lung, colon and ovarian cancer.

In another preferred embodiment of the present invention, the cancer is selected from the group consisting of prostate, breast and lung cancer.

In a more preferred embodiment, the breast cancer is metastatic breast cancer. In a more preferred embodiment, the type 2 lung cancer is non-small cell lung cancer. In another embodiment of the present invention, the pathological cell growth is not cancerous.

In one embodiment of the present invention, the non-cancerous pathological cell growth is adenocarcinoma of the prostate or skin.

The invention also relates to a method of treating vasculogenesis, restenosis, atherosclerosis, or angiogenesis in mammalian tissue, which includes administering to a mammal a therapeutically effective amount of a compound of formula 1, or a pharmaceutically acceptable salt, prodrug or hydrate of a compound of formula 1, which is effective in the treatment of (8) vasculogenesis, restenosis, atherosclerosis or angiogenesis.

In one preferred embodiment, the present invention relates to a method of treating a disease associated with vasculogenesis or angiogenesis. In one embodiment, the present invention relates to a method of treating a hyperproliferative disorder in a mammal, which comprises administering to the mammal a therapeutically effective amount of a compound of formula 1, or a pharmaceutically acceptable salt, prodrug, or hydrate in combination with an antitumor agent selected from the group consisting of mitosis inhibitors , alkylating agents, antimetabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, also known as antihormones, angiogenesis inhibitors, and antiandrogens. co

The invention also relates to a pharmaceutical composition for the treatment of pathological cell growth in mammals, which contains an amount of the compound of formula 1 effective for the treatment of pathological cell growth and a pharmaceutically acceptable carrier.

In one embodiment of the present invention, a pharmaceutical composition comprising a compound of formula 1, 70 is used to treat pathological cell growth, such as cancer. - c The invention also relates to the method of obtaining the compound of formula 1 with : :

P t '

Go! and U!

F st shi - 50 Raya n! I am in

Ж " se : sp K -. zay GR to her -2 y ; 7 G che t. o I. щ я я ши A ля t» и ши так г - и з и

F) I I WE; to su Von y Shche g. bo Shche E aty or its pharmaceutically acceptable salt, prodrug, hydrate or solvate, where each K 1, b2, and KZ, independently, is selected from H, C-Ce alkyl, C--Ce cycloalkyl, halogen , cyano, CEz, difluoromethoxy, trifluoromethoxy, OS.-Ce alkyl, OS3-Ce cycloalkyl and MA BB; where ВЕ" is -"SERVUN, or SERE) (4-10--ened heterocycle), where n is an integer in the range from 1 to 5, where t is an integer in the range from 0 to 5, where 4-10 is indicated -membered heterocycle, if it is aromatic, optionally substituted with 1-3 K "substituents, and where specified 4-10--heterocycle, if it is non-aromatic, optionally substituted with 1-3 LC / substituents in any position and, optionally, substituted by 1-3 KVK 9 substituents in any position not adjacent to or directly attached to the heteroatom; where each KE and 29 is independently selected from H or C1-C6 alkyl; wherein each B" and Y is independently selected from H, C4-C6 alkyl, and C1-C6 cycloalkyl; and wherein each B is independently selected from halogen, cyano, C3, difluoromethoxy, trifluoromethoxy, C1-C6 alkyl, OS3-C6 cycloalkyl and MA "VU, which includes treatment of the compound of formula 2

AI I; mu i mNvOos 1 t, SHHI

Em DNA 2 Kvtnh More.

B I T I Z

K ah shwi y. M but a. и ж .. и Ж and this и (о) од рн и. ЯЩХН As i V vv ; zo x V. g,

Eve; as -- an acid to obtain a compound of formula 1. b

The invention also relates to a pharmaceutical composition for the treatment of a hyperproliferative disorder in mammals, which includes a therapeutically effective amount of a compound of formula 1, or a pharmaceutically acceptable salt, prodrug or hydrate thereof, and a pharmaceutically acceptable carrier. In one embodiment, said pharmaceutical composition is for the treatment of cancer, such as cancer of the brain, lung, squamous cell, bladder, stomach, pancreas, breast, head, neck, kidney, ovary, prostate, rectum, esophagus, testis, gynecological cancer or thyroid cancer. In another embodiment, the specified pharmaceutical composition is intended for the treatment of a non-cancerous hyperproliferative disorder, such as adenocarcinoma of the skin (for example, psoriasis), restenosis, or prostate diseases, such as, for example, benign prostatic hypertrophy p-) c (DH). The invention also relates to a pharmaceutical composition for the treatment of pancreatitis or kidney disease (including proliferative glomerulonephritis and kidney disease due to diabetes) in mammals, which contains a therapeutically effective amount of a compound of formula 1, or a pharmaceutically acceptable salt, prodrug or hydrate thereof, and a pharmaceutically acceptable carrier. The invention also relates to a pharmaceutical composition for preventing the implantation of blastocytes in mammals, which contains a therapeutically effective amount of the compound of formula 1, or its pharmaceutically acceptable salt, prodrugs or hydrates, and a pharmaceutically acceptable carrier.

The invention also relates to a pharmaceutical composition for the treatment of a disease associated with vasculogenesis, restenosis, atherosclerosis or angiogenesis in mammals, which includes a therapeutically effective amount of a compound of formula 1, or a pharmaceutically acceptable salt, prodrug or hydrate thereof, and a pharmaceutically acceptable carrier. In one embodiment, such pharmaceutical composition is for the treatment of a disease selected from the group consisting of tumor angiogenesis, chronic inflammatory diseases such as rheumatoid arthritis, atherosclerosis, skin diseases such as psoriasis, eczema and scleroderma, diabetes, diabetic retinopathy, retinopathy of prematurity, age-related degeneration of the retina, hemangioma, glioma, melanoma, Kaposi's sarcoma and ovarian, breast, lung, pancreas, prostate, colon, epidermoid cancer. (F, The invention also relates to a method of treating a hyperproliferative disorder in mammals, which includes

Ho) administration to a mammal of a therapeutically effective amount of a compound of formula 1, or its pharmaceutically acceptable salt, prodrug or hydrate. In one embodiment, the method relates to the treatment of cancer such as brain cancer, 60 squamous cell, bladder, stomach, pancreas, breast, head, neck, esophagus, prostate, rectum, lung, kidney, ovarian, testicular, gynecological cancer or thyroid cancer. In another embodiment, the method relates to the treatment of a non-cancerous hyperproliferative disorder such as adenocarcinoma of the skin (eg, psoriasis), restenosis, or prostate disease such as, for example, benign prostatic hypertrophy (BPH). 65 The invention also relates to a method of treating a hyperproliferative disorder in mammals, which includes administering to a mammal a therapeutically effective amount of a compound of formula 1, or a pharmaceutically acceptable salt thereof,

prodrugs or hydrates, in combination with a therapeutically effective amount of an antitumor agent selected from the group consisting of mitosis inhibitors, alkylating agents, antimetabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, antihormones, inhibitors angiogenesis and antiandrogens.

The invention also relates to a method of treating pancreatitis or kidney disease in mammals, which includes administering to the mammal a therapeutically effective amount of a compound of formula 1, or a pharmaceutically acceptable salt, prodrug or hydrate thereof.

The invention also relates to a method of preventing blastocyte implantation in mammals, which includes administering to a mammal a therapeutically effective amount of a compound of formula 1, or a pharmaceutically acceptable salt, prodrug or hydrate thereof.

The invention also relates to a method of treating diseases associated with vasculogenesis or angiogenesis in mammals, which includes administering to the mammal an effective amount of a compound of formula 1, or a pharmaceutically acceptable salt, prodrug or hydrate thereof. In one embodiment, the method is for treating a disease selected from the group consisting of tumor angiogenesis, chronic inflammatory diseases such as rheumatoid arthritis, atherosclerosis, skin diseases such as psoriasis, eczema and scleroderma, diabetes, diabetic retinopathy, retinopathy of prematurity , age-related retinal degeneration, hemangioma, glioma, melanoma, Kaposi's sarcoma, and ovarian, breast, lung, pancreatic, prostate, colon, and epidermoid cancers.

Patients to be treated with the compounds of formula 1 and pharmaceutically acceptable salts, prodrugs and hydrates of the compounds according to the method according to the present invention are those who are diagnosed with, for example, psoriasis, restenosis, atherosclerosis, DPH, lung cancer, bone cancer, SMMI, pancreatic cancer, skin cancer, head and neck cancer, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, anal cancer, stomach cancer, colon cancer, breast cancer, testicular cancer, gynecological tumors (eg, uterine sarcoma, fallopian tube carcinoma, endometrial carcinoma, cervical carcinoma, vaginal or vulvar carcinoma), Hodgkin's disease, esophageal cancer, small bowel cancer, endocrine system cancer (eg, thyroid, parathyroid, or adrenal gland cancer), sarcomas of any tissue, testicular cancer, penile cancer, (8) prostate cancer, chronic or acute leukemia, solid tumors in children, lymphocytic lymphomas, bladder cancer, kidney or ureter cancer (eg, carcinoma ma kidney, renal pelvis carcinoma), or neoplasms of the central nervous system (for example, primary CNS lymphoma, spinal axon tumors, brainstem gliomas, or pituitary adenomas).

The invention also relates to a pharmaceutical composition for inhibiting the pathological growth of cells in mammals, containing a compound of formula 1, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, in combination with a chemotherapeutic agent, and the amount of the compound, salt, solvate, or prodrug, as well as the chemotherapeutic agents in combination are sufficient to inhibit pathological cell growth. Many h-chemotherapeutic agents are known in the art. In one embodiment, the chemotherapeutic agent is selected from the group consisting of mitosis inhibitors, alkylating agents, antimetabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, antihormones, such as antiandrogens.

The present invention also relates to a method of inhibiting abnormal cell growth in a mammal or treating a "piperproliferative disorder" which comprises administering to the mammal an amount of a compound of formula 1, or a pharmaceutically acceptable salt or solvate thereof, or a prodrug, in combination with radiation therapy which, in combination with radiation therapy, is effective in inhibiting abnormal cell growth or treating a hyperproliferative disorder in mammals. Radiation therapy techniques are known in the art and may be used in the combination therapy described herein. The expediency of prescribing a compound according to the present invention in combination therapy can be determined based on the following. It is believed that the compounds of formula 1 can make pathological cells more sensitive to the effects of radiation exposure, which is used to destroy them and/or inhibit the growth of such cells. Accordingly, the present invention also relates to a method of increasing the sensitivity of pathological cells in mammals to radiation exposure, which includes administering to the mammal such an amount of formula 1 or its pharmaceutically acceptable salt, prodrug or solvate, which is effective in increasing the sensitivity of pathological cells to exposure to radiation. The amount of a compound, salt or solvate in such a method can be determined using the methods described herein for determining the effective amount of such compounds.

The present invention also relates to a method and a pharmaceutical composition for inhibiting pathological cell growth in a mammal, which comprises an amount of a compound of formula 1, a pharmaceutically acceptable salt or bolvate thereof, or a prodrug, or an isotopically labeled derivative thereof, and an amount of one or more substances selected from from antiangiogenic agents, signal transduction inhibitors, and antiproliferative agents.

GF) Anti-angiogenic agents such as MMP-2 (matrix metalloproteinase 2) inhibitors, MMP-9 inhibitors

F (matrix metalloproteinase 9) and COX-II (cyclooxygenase II) inhibitors can be used in combination with a compound of formula 1 and the pharmaceutical compositions described herein. Examples of useful COX-II inhibitors are 8 SEGEVKEH mm (alecoxib), valdecoxib | rofecoxib Examples of suitable matrix metalloproteinase inhibitors are described in (patent publication M/UO 96/33172 (published October 24, 1996), UMO 96/27583 (published March 7, 1996), European patent application Mo97304971.1 (filed July 8, 1997),

European patent application Mo99308617.2 (filed October 29, 1999), MO 98/07697 (published February 26, 1998), MO 98/03516 (published January 29, 1998), MO 98/34918 (published August 13, 1998), UMO 98/34915 b5 (published August 13, 1998), MO 98/33768 (published August 1998), MO 98/30566 (published July 16, 1998), publication European patent 606,046 (published July 13, 1994), publication

European patent 931,788 (published July 28, 1999), UMO application 90/05719 (published May 31, 1990), UMO 99/52910 (published October 21, 1999), MO 99/52889 (published October 21, 1999), UMO 99/29667 (published June 17, 1999), International PCT application Mo PCT/VO8/01113 (filed July 21, 1998),

European patent application Mo99302232.1 (filed March 25, 1999), UK patent application

Meo9912961 1 (filed Jun. 1999), US Provisional Application Mob0/148,464 (filed Aug. 12, 1999), U.S. Pat.

US 5,863,949 (issued January 26, 1999), US Patent 5,861,510 (issued January 19, 1999) | publications

European Patent No. 780,386 (published June 25, 1997))|, which are fully incorporated by reference in this specification. Preferred inhibitors of MMP-2 and MMP-9 are those that do not inhibit or barely inhibit MMP-1. 7/0 More preferably, these are inhibitors that selectively inhibit MMP-2 and/or MMP-9 relative to other matrix metalloproteinases (ie, MMP-1, MMP-3, MMP-4, MMP-5, MMP-6, MMP- 7, MMP-8, MMP-10, MMP-11, MMP-12 and

MMP-13).

Specific examples of useful MMP inhibitors according to the present invention are AS-3340, KO 32-3555, K5 13-0830, as well as the compounds listed in this list: 3-(4-(4-fluoro-phenoxy)-benzenesulfonyl-(1 -hydroxycarbamoyl-cyclopentyl)-amino|1-propionic acid; hydroxamide /3-exo-3-14-(4-fluoro-phenoxy)-benzenesulfonylamino)|-8-oxa-bicyclo|3.2.1|octane-3-carboxylic acid acids; hydroxamide (2, Zk) 1-(4-(2-chloro-4-fluoro-benzyloxy)-benzenesulfonyl|-3-hydroxy-3-methyl-piperidine-2-carboxylic acid; hydroxamide 4-I4-(4-fluoro -phenoxy)-benzenesulfonylamino)|-tetrahydro-pyran-4-carboxylic acid; 3-(4-(4-fluoro-phenoxy)-benzenesulfonyl|i-(1-hydroxycarbamoyl-cyclobutyl)-amino|-propionic acid; hydroxamide 4-I4-(4-chloro-phenoxy)-benzenesulfonylamino)|-tetrahydro- pyran-4-carboxylic acid; hydroxamide (K) of 3-I4-(4-chloro-phenoxy)-benzenesulfonylamino|-tetrahydro-pyran-3-carboxylic acid; hydroxamide (2, Zk) with 1-(4-(4-fluoro-2-methyl-benzyloxy)-benzenesulfonyl|-3-hydroxy-3-methyl-piperidine-2-carboxylic acid; 3-(4-(4- fluoro-phenoxy)-benzenesulfonyl|i-(1-hydroxycarbamoyl-1-methyl-ethyl)-amino|-propionic acid; (8) 3-(4-(4-fluoro-phenoxy)-benzenesulfonyl|i-(4- hydroxycarbamot-tetrahydro-pyran-4-yl)-amino|-propionic acid; hydroxamide (3-exo-3-I4-(4-chloro-phenoxy)-benzenesulfonylamino)|-8-oxa-bicyclo|3.2.1)octane -3-carbon yu

From Acid; /3-endo-3-I(4-(4-fluoro-phenoxy)-benzenesulfonylamino)|-8-oxa-bicyclo|3.2.1|octane-3-carboxylic acid hydroxamide; and b hydroxamide (K) of 3-I4-(4-fluoro-phenoxy)-benzenesulfonylamino|-tetrahydro-furan-3-carboxylic acid; and pharmaceutically acceptable salts and solvates of the specified compounds. h-

Other angiogenesis agents, including other CO inhibitors, may also be used in the present invention

COX-I and other MMP inhibitors.

Compounds of formula 1 may also be used in conjunction with signal transduction inhibitors, such as agents that can inhibit ESEC (epidermal growth factor receptor) responses, such as antibodies

ESEK, ESEK antibodies, as well as molecules that are ESEK inhibitors; MACE (vascular endothelial growth factor) inhibitors, such as MACE receptors and molecules that can inhibit MACE; as well as inhibitors of the c egv2 receptor, such as organic molecules or antibodies that bind to the egoB2 receptor, for example, NEXERTIM tm and (Sepepiesni, Ips., South San Francisco, CA, USA). "" ESEC inhibitors are described in, for example, (Publication M/O 95/19970 (published July 27, 1995), UMO 98/14451 (published April 9, 1998), MO 98/02434 (published January 22, 1998), and US Patent 5,747,498 (issued May 5, 1998)), and such compounds may be used as described in the present invention. ESERK-inhibiting

Go! agents include, but are not limited to, monoclonal antibodies C225, anti-ESEK 22Mabr (IpSiope BZuzietv

Ipsogrogaied, New York, New York, USA), Her ABH-ESE (Ardepih antibody), compounds 2000-1839 (Aviga/epesa), - VIVH-1382 (Voengipdeg IpdeIpeit), MOH-447 (Medageh Ips. , Annandale, New Jersey, USA), and OI X-103 (Megsk 8 "s So., Whitehouse Station, New Jersey, USA), MKSTO-310 (Mepiesp Kezeagsi) and melting toxin ESE (Zegadep Ips., Hopkinton , Massachusetts). These and other ESR-inhibiting agents can be used in the present invention. - MESE inhibitors such as 50-5416 and 50-6668 (Zidep Ips., South San Francisco, CA, USA) can be combined with a compound according to the present invention. MESE inhibitors are described, for example, in UMO application 99/24440 (published on May 20, 1999), PCT international application PCT/LVO99/00797 (filed Z May 1999), in UMO application 95/21613 (published on August 17, 1995), MO 99/ 61422 (issued December 2, 1999), US Patent 5 9,834,504 (issued November 10, 1998), UMO Application 98/50356 (issued November 12, 1998), US Patent 5,883,113 (issued March 16, 1999), US Patent 5,886,020 (issued March 23, 1999) , US Patent (F) 5,792,783 (issued August 11, 1998), UMO application 99/10349 (published March 4, 1999), UMO 97/32856 t (published September 12, 1997), UMO 97/22596 (published June 26, 1997), MO 98/54093 (published December 1998), MO 98/02438 (published January 22, 1998), MO 99/16755 (published April 8, 1999) and MO bo 98/02437 (published January 22, 1998)), all of which are fully incorporated into of this description as references. Other examples of specific MECE inhibitors that are useful in accordance with the present invention are IM862 (Suigap Ips.,

Kirkland, Washington, USA); IMO-1C11 Itsiope antibody, anti-MESE monoclonal body of the company Sepepiesny, Ips.,

South San Francisco, California; and angiozyme, a synthetic ribozyme from Kirogute (Boulder, CO) and

Spigop (Emerville, CA). These and other MESE inhibitors can be used in the present invention in the manner described below.

Inhibitors of the egrB2 receptor, such as MUuU-282974 (SiIaho UUeisote ris), and monoclonal antibodies AK-209

(Agopech Reaptasections of Ips., The Woodlands, TX, USA) and 28-1 (Spigop) can also be combined with a compound of the present invention, such as those described in (MCO application 98/02434 (published January 22, 1998) , UMO 99/35146 (published on July 15, 1999), MO 99/35132 (published on July 15, 1999), MO 98/02437 (published on January 22, 1998), UMO 97/13760 (published on April 17, 1997), MO 95/19970 ( issued July 27, 1995), US Patent 5,587,458 (issued December 24, 1996), and US Patent 5,877,305 (issued March 2, 1999)), which are incorporated herein by reference in their entirety. Inhibitors of the egrB2 receptor useful in the present invention are also described in prior (U.S. Application No. Mo 60/117,341, filed Jan. 27, 1999, and prior U.S. Appl.

No. 60/117,346, filed Jan. 27, 1999), both of which are incorporated herein by reference in their entirety. Compounds and/or substances that are inhibitors of the egB2 receptor and which are described in the above PCT applications, US patents, US provisional applications, as well as other compounds and substances that are inhibitors of the egB2 receptor can be used together with a compound according to the present invention in accordance with of this invention.

A compound of the present invention may be used with other agents that are useful in the treatment of abnormal cell growth or cancer, such as, but not limited to, agents capable of enhancing the antitumor/5 immune response, such as STI A4 antibodies (cytotoxic lymphocyte antigen 4 ), and other agents capable of blocking STI A4; and antiproliferative agents, such as farnesyl protein transferase inhibitors, and oMdZ inhibitors, such as the oMVZ antibody Micgahip, and oMd5 inhibitors, and others. Specific STI AX antibodies that can be used in the present invention are those described in the prior art (US application MobO/113,647 (filed December 23, 1998)| which is fully incorporated herein by reference), but others may also be used in the present invention antibodies

The compounds of formula 1 and their pharmaceutically acceptable salts, prodrugs and solvates can, each independently, also be used in palliative neoadjuvant/adjuvant therapy to alleviate symptoms associated with the diseases listed herein, as well as symptoms associated with pathological cell growth. Such therapy can be carried out alone or in combination with chemotherapy and/or immunotherapy. si

The invention also relates to a method for preparing a compound of formula 1. The terms "pathological cell growth" and "hyperproliferative disorder" are equivalent in this application. at

The term "pathological cell growth", as used herein and unless otherwise specified, means cell growth independent of normal regulatory mechanisms (eg, loss of contact inhibition). The term includes pathological growth of: (1) tumor cells (tumors) that proliferate due to the expression of a mutated tyrosine kinase, or overexpression of a receptor tyrosine kinase; (2) benign and malignant cells of other proliferative disorders in which aberrant tyrosine kinase activation is observed; (4) any -- tumors that proliferate through receptor tyrosine kinases; (5) any tumors that proliferate due to activation of aberrant serine/threonine kinase; and (6) benign and malignant cells of other proliferative disorders in which aberrant serine/ghryonin kinase activation is observed. --

The term "treatment", as used herein and unless otherwise defined, means the reversal, alleviation, inhibition of development, or prevention of the disorder or condition to which the term is applied, or one or more symptoms of such disorder or condition. The term "therapy", as used herein and unless otherwise specified, refers to the process of treatment that has the above meaning.

The term "Me" means methyl, "EC" means ethyl, and "Ac" means acetyl. The term "halogen", as used herein and unless otherwise specified, means fluorine, chlorine, bromine or iodine. The preferred halo groups are fluorine, chlorine and 2C bromine. and The term "alkyl", as used herein and unless otherwise specified, means saturated monovalent hydrocarbon radicals having straight, branched, or cyclic functional groups (including fused and bridged bicyclic and spirocyclic substituents), or a combination of the foregoing groups. In order for an alkyl group to have cyclic groups, the group must have at least three carbon atoms. co The term "cycloalkyl" as used herein and unless otherwise specified means cyclic alkyl groups in which alkyl has the above meaning. "cycloalkyl" shall not be construed as narrowing the scope of the term "alkyl" to non-cyclic groups. The term "alkenyl", as used herein and unless otherwise specified, means alkyl groups having at least one double bond carbon-carbon bond, and in which "alkyl" has the above meaning, and also - includes E and 7 isomers of the alkenyl group. sl The term "alkynyl", as used herein and unless otherwise specified, means are alkyl groups having at least one carbon-carbon triple bond, and in which "alkyl" has the above meaning.

"Alkoxy" as used herein and unless otherwise specified means O-alkyl groups in which "alkyl" has the above meaning.

The term "aryl", as used herein and unless otherwise specified, means an organic radical derived from (F) an aromatic hydrocarbon by removal of one hydrogen, such as phenyl or naphthyl. The term "4-10-ene heterocycle", as used herein and unless otherwise specified, means aromatic and non-aromatic heterocyclic groups that contain from one to four heteroatoms, each of which is selected from 6o 0, Bi M, where each a heterocyclic group has 4-10 atoms in the ring system, and provided that the ring of such a group does not contain two adjacent O or 5 atoms.

Non-aromatic heterocyclic groups are groups that have only 4 atoms in the ring system, while aromatic heterocyclic groups must have at least 5 atoms in the ring system. Heterocyclic groups include benzofused ring systems. An example of a 4-membered heterocyclic group is azetidinyl 65 (derived from azetidine). An example of a 5-membered heterocyclic group is thiazolyl, and an example of a 10-membered heterocyclic group is quinolinyl.

Examples of non-aromatic heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thioxanyl, piperazinyl, homopiperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, diazepinyl, oxepinyl, 2 ,3,6-tetrahydropyridinyl, 2-pyrrolinyl,

Z-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinylimidazolinyl, imidazolidinyl,

Z-azabicyclo!|3.1.0)hexanyl, Z-azabicyclo|4.1.0)heptanyl, azabicyclo|2.2.2)hexanyl, ZH-indolyl and quinolizinyl.

Examples of aromatic heterocyclic groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, 70 pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinolinyl, indazolyl, indolizine. phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. Spiro substituents are also included within the scope of this definition and include 7/5 1-oxa-6b-aza-spiro|2.5|oct-b-yl. The above groups, as well as those derived from the above groups, may be C-linked or M-linked where possible. For example, a group derived from pyrrole can be pyrrole-1-yl (M-attached) or pyrrole-3-yl (C-attached). Additionally, imidazole-derived groups can be imidazol-1-yl (M-attached) or imidazol-3-yl (C-attached). An example of a heterocyclic group where 2 carbon atoms of the ring are replaced by oxo(-O) groups is 1,1-dioxo-thiomorpholinyl.

The phrase "pharmaceutically acceptable salt(s)", as used herein and unless otherwise specified, means salts of acidic or basic groups that may be present in the compounds of formula 1. Compounds of formula 1, which are basic in nature, are capable of forming a variety of salts with various inorganic and organic acids. Acids that can be used to obtain pharmaceutically acceptable acid-additive salts of such basic compounds of formula 1 are those that form non-toxic acid-additive salts, that is, salts that contain pharmacologically acceptable anions: acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsyl, carbonate, chloride, clavulanate, citrate, o dihydrochloride, edetate, edesylate, estolate, hesylate, ethyl succinate, fumarate, gluceptate, gluconate, glutamate, glycolylarzanylate, hexylnesorcinate, hydrabamine, hydrobromide, hydrochloride, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methyl sulfate, muscat, napsylate, nitrate, pleate, u

Zo oxalate, pamoate (embonate), palmitate, pantothenate, phosphate/diphosphate, polygalacturonate, salicylate, stearate, subacetate, succinate, tannate, tartrate, theoclate, tosylate and valerate. Because a single compound of the present invention may have more than one acid or basic group, the compounds of the present invention may include mono, di-, or trisalts of each compound.

The compounds of the present invention, which are acidic in nature, are capable of forming basic salts with a variety of pharmacologically acceptable cations. Examples of such salts are salts of alkali metals, or salts of alkaline earth metals, and, in particular, salts of calcium, magnesium, sodium and potassium compounds according to the present invention.

This invention also includes in its scope prodrugs of the above compounds of formula 1. In general, such prodrugs are functional derivatives of compounds of formula 1, which are easily transformed immediately into the required compound of formula 1. Known methods of selection and preparation of suitable derivatives of prodrugs are described, for example , in ("Oevidp oi "

Rgodgoidv", publishing house N. Vypadaaga, Eizemieg, 1985). c Prodrugs can be pharmacologically inactive derivatives of biologically active substances ("initial medicinal substance" or "initial molecule"), which must be transformed in the body to release the medicinal substance, and which have improved delivery properties than the parent molecule/drug substance.

The transformation of ip mimo can be caused, for example, by certain metabolic processes, such as

Chemical or enzymatic hydrolysis of a carbonic, phosphoric or sulfate ester, or reduction or co-oxidation of the corresponding functional group.

The compounds according to the present invention have one or two asymmetric centers and, therefore, can exist both as enantiomers and as diastereoisomers. It should be understood that all isomers and their mixtures are included within the scope of this invention.

In the compounds of formula 1, in which such designations as (SV "EZU)n or (SV"VU) are used, Viv? can - change with each repetition of t or i above 1. For example, where t or i is 2, the notation (СВ"ВУ)" or (СВБ), c can correspond to -СНоСНо-, or -СН(СНю)С(СНоОСНХХСНоСНоСН» )-, or any number of relevant groups that are included in the scope of definitions of viv.

Some compounds of formula 1 can have asymmetric centers and, therefore, exist in different enantiomeric forms.

All optical isomers and stereoisomers of compounds of formula 1 and their mixtures are included in the scope of the present invention. Regarding the compounds of formula 1, the invention includes the use of a racemate, one or more enantiomeric forms, one or more diastereomeric forms, or their mixtures. Compounds of formula 1 can exist as tautomers. Invention

Ckz refers to the use of all such tautomers and their mixtures.

The object of this invention are also isotope-labeled compounds that correspond to those listed in formula 1, but in which one or more atoms are replaced by an atom whose mass or number is different from the atomic mass or mass number that is usually found in nature. Examples of isotopes that can be considered as compounds according to the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as ?Н, ЗН, С, с, М, 78, о, р, р, 358 , 1 and Z6SI, respectively. Compounds according to this invention, their prodrugs and pharmaceutically acceptable salts of such compounds or prodrugs, which contain the above isotopes and/or other isotopes of other atoms, are included in the scope of this invention. Certain isotopically labeled compounds of the present invention, such as those containing radioactive isotopes such as ZNi c, are useful in drug discovery and/or substrate tissue distribution studies. Isotopes of tritium, i.e. ZN, and carbon-14, i.e. 14C, are especially preferred, given their ease of obtaining and detection. In addition, substitution with heavier isotopes such as deuterium, "H, may provide some therapeutic advantages due to higher metabolic stability, such as increased half-life and reduced doses required, which may be advantageous in many cases. Isotope-labeled compounds formulas 1 according to the present invention and their prodrugs can generally be obtained using the methods described in the Schemes and/or Examples and

Preparative examples, which are given below, by substituting a ready-made isotope-labeled reagent for 70 non-isotope-labeled reagent.

The present invention also includes pharmaceutical compositions, as well as methods of treating proliferative disorders or pathological cell growth by administering prodrugs of compounds of formula 1. Compounds of formula 1 that have free amino, amido, hydroxy, or carbonyl groups can be converted into prodrugs. Prodrugs are compounds in which an amino acid residue or a polypeptide chain of two or more (for example, two, three, or four) amino acid residues is covalently attached through an amide or ester bond to a free amino, hydroxy group, or carboxylic acid group of the compound of formula 1. Amino acids residues include, but are not limited to, the 20 naturally occurring amino acids commonly designated by three letters and also include 4-hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine, norvaline, beta-alanine, gamma-aminobutyric acid, homocysteine citrulline, homoserine, ornithine and metonine sulfone. Additional types of prodrugs are also included in the invention. For example, free carboxyl groups can be obtained as amides or alkyl esters. Free hydroxy groups can be obtained using such groups as, without limitation, hemisuccinates, phosphate esters, dimethylaminoacetates, and phosphoryloxymethyloxycarbonyls, as described in |(Aimapsei Ogod

Oeiimegu Kemiem5, 1996, 19, 115). Carbamate prodrugs of hydroxy and amino groups are also included in the invention as carbonate prodrugs, sulfonate esters and sulfate esters of hydroxy groups. The invention also includes SM modification of hydroxy groups as (acyloxy)methyl and (acyloxy)ethyl ethers, in which the acyl group may be an alkyl ester optionally substituted with groups that include, without limitation, ether, amine, and carboxylic acid functional groups, or in which the acyl group is an amino acid ester as described above.

Such prodrugs are described in (U. May. Spet. 1996, 39, 10). It is also possible to modify free amines as amides, sulfonamides or phosphonamides. Groups of all these prodrugs can include such groups, without limitation, as Io) functional groups of ether, amine and carboxylic acid. "-

Scheme 1 (22) "--

From so - . and? so - (Se) - (l ko 60 b5

EE is different in I 5

What are the actions of "NO. o ry same and : sr ska. cell | ; What. m LISH ve

С и и ме ЧИ прия

TE, Za and Teh Zh

Not in Ka. ! F

But what about her. I: ЖЎ Right ko ut em y y s y schoi her - ШЯ ME. Y ke y yang sha Ya vo. Snya "a Shk "I eh yasne 7 BJ S lo - y. y ' nya nn 4 : g s N ? МY early nfnisy early:

YaEye" and the Most Holy Icon, lo r o zay seni YaASvu and y (1 o skosu y: shk Y tsk ya Shi She Y .

And there are 5.5 more. I don't belong to them. and mouth in She and -

Same with rr: yayu o same "I rice zha and Yad rn

Zh. "y yan o. ey ste ped still . b -y Korea Y Y y sao i pay nty V i y Iz a Y nk o N KD Gnat i Y y shi "- ui a cha SHY y. yaay y

From where EE so

General methods of synthesis by which the compounds of the present invention can be prepared are set forth in US Pat. April 8, 1999) (Megsk 4 So.) and MO 01/40217 (published July 7, 2001) (Riigeg, " Ips.)). These patents and patent applications are fully incorporated herein by reference.

The compounds of the present invention can alternatively be obtained according to Scheme 1 from 2-chloro-8-benzyloxyquinoline (I) and the corresponding 2-amino-nitrobenzene ()) by the method described in Scheme 1. (ог) Substituents VK", 2, KZ and 7 have the values defined for the compounds of formula 1 in the brief description of the essence of the invention. - Quinoline K was obtained by the platinum-catalyzed amination of compounds I and). By reduction of the nitro group and removal of the benzyl group by catalytic hydrogenation, benzimidazole was obtained And, which can be (Ce) then converted into the corresponding triflate M. A second palladium-catalyzed amination of amine M - 20 gave piperidinylquinoline O, and subsequent removal of the t-butyloxycarbonyl group gave the desired product 1. sp Compounds according to the present invention can have asymmetric atoms carbon. Diastereomeric mixtures can be separated into individual diastereomers based on differences in their physicochemical properties by methods known to those skilled in the art, such as chromatography or fractional crystallization. Enantiomers 25 can be isolated by converting enantiomeric mixtures into a diastereomeric mixture by reaction with an optically active compound (for example sleep by mouth), separation of diastereomers and transformation (for example, by hydrolysis) of individual diastereomers into the corresponding pure enantiomers. All such isomers, including co-diastereomeric mixtures and pure enantiomers, are included in the scope of the present invention.

The compounds of formula 1 are basic in nature and are able to form various salts with various inorganic and 60 organic acids. Although such salts should be pharmaceutically acceptable for administration to animals, in practice it is often desirable to first separate the compound of formula 1 from the reaction mixture as a pharmaceutically unacceptable salt and then simply return it to the free base form by treatment with an alkaline reagent and subsequent conversion of the free base to the pharmaceutically acceptable salt. acceptable acid additive "salt.

Acid addition salts of the basic compounds according to the present invention are readily prepared by treating the basic compound with a generally equivalent amount of the selected material or organic acid in an aqueous solvent medium, or in a suitable organic solvent such as methanol or ethanol. With careful evaporation of the solvent, the desired salt is easily obtained in solid form. The desired acid salt can also be precipitated from a solution of the free base in an organic solvent by adding a suitable mineral or organic acid to the solution.

The activity of all compounds of formula 1 can be determined using the following technique.

EGI5A method for determining the total ROT kinase

The following reagents and solutions are used: adenosine triphosphate (ATP) Zidt, cat. Mod-2383 70 Bovine serum albumin (BA) Zidt, cat. Mod-3294

Phosphate buffer solution cSirso-VK, cat. Mo14190-136

Dulbekko (aRV5) Tablets Makhizogr Mips, cat. Me439454

Masio Zidta, cat. MomM-1028

Roiu-Sii-Tug (ROT) Zidta, cat. Mor-0275

Substrate TMV Misozhei| Kigkedaaga 85 Regu, cat. Mo50O-76-05

Tmzhmeep 20 Zidta, cat. Mor-1379

Antibody NKR-RUBA O5I RNAgtaseciisa!5, Ips.

Phosphorylation buffer (RB): 50MM NEREZ, pH 7.3, 125mM Masi, 24mM Masi";

Buffer for washing (M/V): ORVZO, 190 Tmeep 20 (polyoxyethylene sorbitan); and Blocking buffer: 395 V5A, 0.0595 Hmeep 20 in aRV5.

Research methodology: (a) To cover the wells, Mips Makhizogr tablets were filled with 100 μl per well of Roiu-SISH-Tug (ROT), diluted in aRVZ (different concentrations). The tablet was then incubated overnight at 37 C. The supernatant GROWTH with

It was washed off and the tablet was washed three times with washing buffer. (b) ROSE enzyme was diluted in RV to obtain the appropriate concentration, and 25 ml of the basic solution was added to each well. (c) Then ATP was diluted (from ready-made 20 mM) to the appropriate concentration (0.5nM-2mM) in RV. The phosphorylation reaction was initiated by adding 25 μl of ATP solution to each well of the research tablet. i am

Incubation lasted approximately 10 minutes with shaking at room temperature. (4) The reaction was stopped by removing the reaction mixture. The tablet was then washed four times with UUV. -- (e) NKR-RUB4 antibody was diluted to the appropriate concentration in blocking buffer. Then 50 μl of this solution would be added to each well, followed by incubation for 25-35 minutes at room temperature. The solution containing the antibody was removed by aspiration and the tablet was again washed four times with MV. h-- () The course of the reaction was determined by measuring the absorption of light at 45O0nm. At first, by adding TMB solution, 5 Омкл per well, the color was displayed, the reaction was continued until the values of approximately 0.6-1.2 00450 units were reached in the wells with positive signals. The development of color was stopped by adding 5 µl per well of 0.09 M H 550. Background control wells were those that did not contain ROT but contained all other components. As indicated above, it is preferable that the signals are within "420. 0.6-1.200 units, generally without background. The ability of the compounds according to the present invention to inhibit the ROSED ip mygo receptor can be determined using the following method. "» Inhibition of tyrosine kinase activity can be measured by using a recombinant enzyme in a test to determine the ability of compounds to inhibit the phosphorylation of an exogenous substrate, roiusISHTug (ROT, Zidtatm, 4:1). Cytoplasmic domain of the human receptor ROSEDr (amino acids 559-1106) (Ivpikaua, (o e | ER., ei aY. Mayte 338: 557-562, 1989| is expressed in 519 insect cells as glutathione-5-transferase (511) - a fusion protein in the baculovirus expression system. The protein is then purified from the lysate of these cells using affinity columns on based on glutathione-agarose.

He Enzyme study is carried out on a tablet with 96 wells covered with ROT substrate (0.625 μg ROT per well). Test compounds were diluted in dimethylsulfoxide (DMSO) and then added to the ROT tablet to - obtain a final concentration of DMSO in the study of 1.695 (vol./06.). The recombinant enzyme was diluted in buffer c for phosphorylation (50 mM Nerez, pH 7.3, 125 mM MaCl, 24 mM MaCl 5). The reaction was initiated by adding

ATP to obtain a final concentration of 1ΩμM. After incubation for 10 minutes at room temperature and with shaking, the reaction mixture was removed by aspiration and the tablets were washed with washing buffer (phosphate buffer solution containing 0.195 Tmeep-20). The amount of phosphorylated ROT was determined by incubation with the antibody RU-54, conjugated with horseradish peroxidase (HER) (Tgapzaisiyop I arz), with the addition of TMB (Ф, peroxidase (TMB is 3,35,5'-tetramethylbenzidine), and determination on on a VioKai™ co Mishoriage reader at 45 nm.Inhibition of the enzyme activity of the kinase by the test compound was expressed as a decrease in absorbance, and the concentration of the compound required to inhibit the signal by 5095 (under the conditions in which 60 studies are carried out) was determined as the IC value of the test compound.

Porcine aortic endothelial cells (RAE) transfected with human ROSEKr can be used to determine the ability of compounds to inhibit ROSEKr tyrosine kinase activity for the full-length protein present in the cell. AI., RMAB5 87, pp. 128-132, 1990). Cells were placed on a plate and left to attach to 9b-well plates in the same medium (Natez E12) containing 1095 EB5 65 (embryonic bovine serum) for 6-8 hours. Cells were washed, resuspended in serum-depleted medium, and left to incubate overnight. Immediately after administration of a dose of the compound, the cells were placed again in serum-depleted medium. Test compounds dissolved in DMSO were diluted in medium (final DMSO concentration was 0.595 (v/v)). After incubation for 10 minutes, ROSBE-BB (final conc. 1OOng/ml) was added to the medium for incubation for 8

MINUTES. Cells were washed with Nerez buffered salt solution (NVZ5) and dissolved in bOml of NMTO buffer (20 mM Nerez, pH 7.5, 150 mM Mass, 0.295 Tpioptm X-100, 1095 glycerol, plus 02 mM PM5E (phenylmethylsulfonyl fluoride), µg/ml pepstatin, µg/ml ml leupeptin, µg/ml aproptonin, 2 µM sodium pyrophosphate, 2 mM sodium orthovanadate), then diluted with 100 ml of HO dilution buffer (20 mM Nerez, pH 7.5, 10965 glycerol, 0.2 mM PM5E (phenylmethylsulfonyl fluoride), µg/ml pepstatin, µg/ml leupeptin, Tmkg/ml 70 aprotonin, 2MM sodium pyrophosphate, 2MM sodium orthovanadate). The level of ROSECr phosphorylation was determined by the EHIBA method. White-coated 96b-well tablets were blocked with ZiregriosK (Riegse) and coated with 0.5 μg per well of anti-ROOGKdD P20 antibody (Zapia Stig, catalog number ZS-339).

Unbound antibodies were washed from the tablet before adding the cell lysate. After incubating the lysates for 2 hours at room temperature (5µl) with the ROSECDR antibody, the amount of ROSECDR 75 associated phosphotyrosine was determined by the addition of an antibody conjugated with NKR and TMB as described above.

The ability of compounds to inhibit the reaction of stimulated ROSE-BB autophosphorylation at 5095 under the specified conditions compared to stimulated ROSE-BB controls was expressed as the value of IC 59 for the test compound. The compounds according to the present invention, including the examples given here, according to the above-described method generally have values of IC50 in the following limits: 1-1000 ОНМ.

The ability of the compounds according to the present invention to inhibit the KOCL/ESE receptor can be determined by the following method.

The ability of the compounds according to the present invention to inhibit tyrosine kinase activity can be determined by using a recombinant enzyme in the study, which determines the ability of the compounds to inhibit the phosphorylation of an exogenous substrate, roiusIshTug (POT, Zidtatm, 4:1). The kinase domain of the human receptor E

WHEEL (amino acids 805-1350) is expressed in 519 insect cells as a glutathione-5-transferase (051) o fusion protein in a baculovirus expression system. The protein was purified from the lysate of these cells using affinity columns based on glutathione-agarose. Enzyme research was performed on 9b-well tablets coated with ROT substrate (0.625 μg ROT per well). Test compounds were diluted in dimethyl sulfoxide (DMSO) and then added to the ROT plate, giving a final DMSO concentration in the study of 1.695 (v/v). M) Recombinant enzyme was diluted in buffer for phosphorylation (50 mM Nerez, pH 7.3, 125 mM Masi, 24 mM «-

MaSi2). The reaction was initiated by adding ATP to obtain the final concentration of TOμM. After incubation for 30 minutes at room temperature with shaking, the reaction mixture was removed by He) aspiration and the plates were washed with washing buffer (phosphate buffer solution containing 0.190

Tmeep-20). The amount of phosphorylated ROT was determined by incubation with RU-54 antibody conjugated with --

NKR (NKR - horseradish operoxidase) (Tgapzdisiop IIarv) obtained from TMV peroxidase (MV is about 3,3,5,5'--tetramethylbenzidine), and was determined on a reading device VioKadtm Misgoriae at 45OonM.

Inhibition of the enzyme activity of the kinase by the test compound was expressed as the reduced absorbance, and the concentration of the compound required to inhibit the signal by 5095 was expressed as the value of IC 50) for the test compound. "

Pig aorta endothelial cells transfected with human COC can be used to determine the ability of compounds to inhibit the activity of the KOK tyrosine kinase receptor for the full-length protein that exists in the cell (MaKepbregoeg ei ai., 9U. Vioi. Spet. 269:26988, 1994) . Cells were placed in 96-well plates and left for attachment in this medium (Nat's E12) containing 1095 EB5 (embryonic bovine serum). Cells were then washed, serum-depleted medium containing 0.190 (vol/06) bovine serum albumin (B5A) was added again, and allowed to incubate for 24 hours. Immediately prior to administration of the compound dose, the cells were again placed in serum-depleted medium (without B5A). Test compounds dissolved in DMSO were diluted in this medium (final DMSO concentration was 0.595 (v/v)). After incubation for 2 hours, MESE 465 (final concentration - 5 ng/ml) was added to the medium for incubation for 8 minutes. Cells were washed and dissolved in NMTO buffer (20mM Nerez, pH 7.5, 15O0MM (Ce) mass, 0.290 Tioptom X-100, 1095 glycerol, 0.2MM PM5ZE (phenylmethylsulfonyl fluoride), µg/ml pepstatin, - 20 µg/ml leupeptin , μg/ml aprotonin, 2 mM sodium pyrophosphate, 2 mM sodium orthovanadate). The degree of COC phosphorylation was determined by the EGISA method. 96-well plates were coated with μg per well of goat anti-rabbit antibodies. Unbound antibodies were washed from the plates and the sites that remained were blocked with buffer (Riegse) before the addition of api-Jak-1 C-20 antibodies (0.5 μg on the plate, Zapia Stgy7). All unbound antibodies were washed from the plate before adding the cell lysate. After 2 hours of incubation of the lysates with the 595 YAK-1 antibody, the amount of phosphotyrosine associated with KOV was determined by the addition of antibodies conjugated with HER RU-54 and TMB as described above.The ability of compounds to inhibit the MECE-stimulated autophosphorylation response of 5095 compared to MECE-stimulated controls was expressed as the IC 50 value for the test compound.

Incubation of human liver cytosol was performed using commercially available cytosol stored at cryogenic temperature (Tizztie Tgapviogtaiop Tesppoiodiev, 2Omg/ml protein, Goi YANNS-0255).

Human liver cytosol was slowly thawed and diluted in 10 mM potassium phosphate buffer (pH 7.4) to obtain a final protein concentration of 3.1 mg/ml, after which it was heated to 372. Incubation was initiated by adding the finished compound dissolved in methanol. The total methanol concentration was maintained at 195 or below. After the start of the reaction, the incubation mixture was carefully mixed and an aliquot of the sample was collected in the time interval of Okhv., after which it was cooled in the appropriate volume of acetonitrile containing the internal control.

Collection was carried out at 5, 10, 15 and 30 minutes and cooling was carried out in the same way. The samples were centrifuged and the supernatant was analyzed by HPLC/MS/MS using the ratio of the response peak area of the test substance and the control. Indicators corresponded to linear regression and half-life was calculated from the decline of the curve. The remaining part of the calculations was carried out on the basis of the half-life of the corresponding indicators.

A control incubation was included to observe intraday variability and losses outside the cytosol. The compounds of the present invention were stable in the human liver cytosolic assay described above.

Compounds of the present invention (hereinafter "active compound(s)") may be administered by any method 70 that will ensure delivery of the compounds to the site of action. Such methods include oral administration, intraduodenal, parenteral injections (including intravenous, subcutaneous, intramuscular, and infusion), intraocular, intraperitoneal, intravesicular, intravaginal, topical, and rectal administration.

The amount of active compound administered depends on the patient, the state of the disease or disorder, /5 Amount of administration, placement of the compound and the discretion of the treating physician. However, effective doses are in the range of from about 0.001 to about 100 Ωg per kilogram of body weight per day, preferably from about 1 to about 35 mg/kg; day in single or divided doses. For a person weighing 7Okg, the dose will be from about 0.05 to about 7g/day, preferably from about 0.2 to about 2.5g/day. In some cases, a dose lower than the indicated limits may be more than sufficient, while in other cases, higher doses may be used without causing harmful side effects, provided that such doses are divided into several smaller doses administered throughout the day.

The active compound may be administered alone or with one or more antitumor agents, such as those selected from, for example, mitosis inhibitors such as vinblastine; alkylating agents, such as cis-platinum, carboplatinum, and cyclophosphamide; antimetabolites, such as 5-fluorouracil, cytosine arabinoside and c hydroxyurea, or, for example, one of the preferred antimetabolites described in |European patent application Mo2393621, such as o

IM-(5-(M-(3,4-dihydro-2-methyl-4-oxoquinazolin-b6-ylmethyl)-M-methylamino|-2-thenoyl)-I-glutamic acid; growth factor inhibitors; cell cycle inhibitors ; intercalating antibiotics, such as adriamycin and bleomycin; enzymes, such as interferon; and antihormones, such as antiestrogens such as Moimadex tm (tamoxifen) or, for example, antiandrogens such as Sazodex tm (4-cyano-3-(4-fluorophenylsulfonyl)- 2-hydroxy-2-methyl-3-(trifluoromethyl)propionanilide).Such combined therapy can be carried out by simultaneous, sequential or separate administration of doses of individual therapeutic components.

Pharmaceutical compositions may, for example, be in a form suitable for oral administration, such as tablets, capsules, pills, powders, sustained-release formulations, solutions, suspensions, for co-parenteral injections in the form of sterile solutions, suspensions or emulsions , for local use in the form of ointments or creams, or for rectal use in the form of suppositories. Pharmaceutical compositions can be in a unit dosage form, suitable for a single administration of a certain dose. Pharmaceutical compositions will include a known pharmaceutical carrier or excipient and a compound according to the present invention as an active ingredient. In addition, the composition may include other medical or pharmaceutical agents, carriers, excipients, etc. Examples of forms for parenteral administration are solutions or suspensions of active compounds in sterile aqueous solutions, for example, aqueous solutions of propylene glycol or dextrose. Such dosage forms can be buffered if necessary.

Suitable pharmaceutical carriers are inert diluents or fillers, water and various organic co-solvents. If necessary, pharmaceutical solvents can contain additional ingredients, such as flavors, binding agents, excipients, etc. Thus, tablets containing various excipients, such as citric acid, together with various disintegrants, such as starch, alginic acid and some complex silicates, as well as binding agents such as sucrose, gelatin, can be used for oral administration. and gum arabic. In addition, lubricating agents such as magnesium stearate, sodium lauryl sulfate, and talc are often used for tableting. Similar solid compositions can also be used in hard and soft gelatin capsules. Preferred materials in these cases are lactose, milk sugar, and high molecular weight polyethylene glycols. If aqueous suspensions or elixirs are desired for the oral administration of the active compound, it may be combined therein with various sweetening or flavoring agents, colorants, and, if desired, with emulsifying or suspending agents along with solvents such as water, ethanol, propylene glycol, glycerin or combinations thereof. (F. Methods of obtaining various pharmaceutical compositions with a certain amount of active compound are known or will be obvious to those skilled in the art. For example, (see Ketipdiopye RNpapgtaseciisa! Zsiepsez. Mask

Riviizpipd Sotrapu, Eazvieg, Ra., 151 Ediop (1975)). 60 The following examples and preparative examples further illustrate and describe the compounds of the present invention and methods of preparing such compounds. It should be understood that the scope of this invention is in no way limited by the scope of the following examples and preparative examples. In the following examples, molecules with one chiral center exist in a racemic mixture, unless otherwise noted. Molecules with two or more chiral centers, unless otherwise indicated, exist as a racemic mixture of diastereomers. The individual 65 enantiomers/diastereomers can be prepared by methods known to those skilled in the art.

Preparation of the main intermediate compounds:

8-Benzyloxy-2-chloro-quinoline 2,8-Quinolindiol (133.3 g, 0.827 mol) was dissolved in 8000 ml of anhydrous DMF in an atmosphere of dry M". Potassium carbonate (183g, 1.32mol) was added to this solution, followed by the addition of benzyl bromide (11Oml, 0.909mol) and

VOZchCHYN was then heated to 652C, the reaction took place at this temperature overnight. The reaction mixture was then poured into 100 ml of water and the resulting solution was stirred at ambient temperature for 5.5 hours, after which it was filtered. The solid was washed with water, collected, suspended in toluene, and finally the solution was concentrated in a vacuum to obtain 142 g of 8-benzyloxy-quinolin-2-ol. This material (142 g, 0.565 mol) was dissolved in 5X000 ml of OSE in an atmosphere of dry Mo. Oxalyl chloride (99ml, 1.13mol) was added dropwise to this 7/0 solution, followed by the addition of iml DMF. After the addition, the reaction mixture was stirred at ambient temperature for 30 minutes, after which the reaction mixture was heated to 842C. The reaction mixture was stirred at this temperature for 10 hours and then concentrated in vacuo. The resulting residue was divided between

DCM and aqueous saturated MansCOz. The DCM layer was again washed with aqueous saturated NaHSO, dried over

Ma»zO), filtered and concentrated in vacuo to give a brown solid. Solid substance 75 was recrystallized from toluene to obtain two portions (68.3g and 38.3g) of 8-benzyloxy-2-chloroquinoline.

The tert-butyl ester of piperidin-4-yl-carbamic acid can be obtained by the method described in Isapipa. A. U. Med. Spent 42(14), (1999) p. 2706, or Maze ei. AI. 3. Wow. Spent 66(20), (2001) p. 67 75).

Compounds of formula 1 can be obtained from intermediate H (Example 1) by the method presented in Scheme 1 and illustrated by the preparation of 1-(2-(5-cyclopropylmethoxy-benzoimidazol-1-yl)-quinolin-8-yl|-piperidin-4- ylamine. - in Example 2.

Example 1

Preparation of tert-butyl ester of 11-(2-(5-hydroxy-benzoimidazol-1-yl)-quinolin-8-yl|-piperidin-4-yl)-carbamic acid (compound H)

Intermediate compound H, 5-hydroxy-benzimidazole, can be obtained by the method presented in Scheme 2.

Scheme 2 (8) iv) "-- (2) h- so - s;" so - (Se) - (l

Ф) ko 60 b5 n still S ich shchi zv Ne M i - . iy o y; and in, Her, oh s-ya and

N ya ka - sni et ! ; days izhe i t.z ai i; h nn and in 5 r 7 pad zey She and sa

In E

What - 1 schi: B ssss I OVO; what she se sya iz - i y re nya Yaku y p y Ж sche de Yasya y Yak ni yaNESK: she so zo what (in IA - 2" and

Preparation of the compound B co 8-(tert-butyl-dimethyl-silanilos)-quinolin-2-yl ester of trifluoro-methanesulfonic acid - 2,8-Quinolinediol (A) (20.0 g, 124 mmol) was suspended in 500 ml of dichloromethane (DCM) in dry nitrogen (Mo) atmosphere. Imidazole (20.3 g, 298 mmol) was added to this solution, followed by the addition of tert-butyldimethylsilyl chloride (20.6 g, 137 mmol) and 4-dimethylaminopyridine (1.50 g, 12.4 mmol). The reaction mixture -k 20 was stirred overnight at ambient temperature, after which it was partitioned between DCM and 190 aqueous sodium bisulfate solution (Manzo)). The DCM layer was left and washed twice with 195% aqueous Manzo, "sl then with aqueous saturated sodium bicarbonate (Manzo") and finally with a saturated salt solution. The DCM layer was dried over sodium sulfate (Na»5O)), filtered and concentrated in vacuo to give the crude product (40g) as a white solid. The solid substance was dissolved in 50 mL of anhydrous tetrahydrofuran (TF) in an atmosphere of dry Mo. To this solution was added

GF! M-phenyl-bis(trifluoromethanesulfonimide) (48.7 g, 13 mmol) and the solution was cooled to 02C. Sodium hydride (6095 in oil) (3.2 g, 13 mmol) was slowly added to this solution. After the addition, the reaction mixture was heated to ambient temperature. After 1 hour, an additional amount of 1.00 g of sodium hydride (6095 in oil) was added, and the mixture was stirred for an additional 30 minutes. The mixture was concentrated in vacuo and transferred to DCM at 60°C. Water (1.00 ml) was slowly added dropwise to quench unreacted sodium hydride, and then the reaction mixture was extracted twice with 0.1 M aqueous sodium hydroxide solution (NaOH), then washed with saturated salt solution. The DCM layer was dried over Ma»3O), filtered and concentrated in vacuo to obtain 57 g of the crude triflate of compound B as a yellow oil.

Preparation of compound C, bo (I(8-tert-butyl-dimethyl-silanyloxy)-quinolin-2-yl1-(4-methoxy-2-nitro-phenyl)-amine

Trifluoromethanesulfonic acid 8-(tert-butyl-dimethyl-silanyloxy)-quinolin-2-yl ester B (9.81g, 24.mmol) and 4-methoxy-2-nitroaniline (4.86g, 28.9mmol) were dissolved in 100 ml of dioxane in an atmosphere of dry Mo. To this solution was added cesium carbonate (С52СО») (11.Og, 33.7 mmol), racemic-2,2"-bis(diphenylphosphino)-1,1-binaphthyl (VIMAR) (900 mg, 1.45 mmol) and tris( dibenzylideneacetone)dipalladium (0) (883mg, 0.964mmol), the reaction mixture was heated to 1002, the reaction proceeded at this temperature for 4 hours. The mixture was then cooled to ambient temperature, concentrated in vacuo, treated with DCM, filtered and concentrated in vacuo to give a red The solid was chromatographed on flash silica gel eluting with a mixture of hexanes/DCM (3:1) 70 to give 7.25 g of compound C as a red solid.

Preparation of compound O,

M-(8-(tert-butyl-dimethyl-silanyloxy)-quinolin-2-yl|-4-methoxy-benzene-1,2-diamine

Compound C, (I(8-tert-butyl-dimethyl-silanyloxy)-quinolin-2-yl)|-(4-methoxy-2-nitro-phenyl)-amine, (21.9 g, 51.3 mmol) was dissolved in 200 ml of ethanol (EUN) and 7 Oml of THF in an atmosphere of dry Mo. 75 1095 palladium on charcoal (2.18 g) was added to this solution, followed by the dropwise addition of 1 Oml of anhydrous hydrazine solution. The reaction mixture was stirred at ambient temperature for 2 hours, after which it was filtered through a sieve and the sieve was washed with DCM. The combined filtrates were concentrated in vacuo and the resulting residue was partitioned between DCM and aqueous saturated MnSOO. The DCM layer was then washed again with a saturated Manso solution and then with a saturated salt solution, dried over NaClO), filtered and concentrated in vacuo to obtain 18.3 g of a golden-brown solid in the form of the title compound Y.

Preparation of compound E, 2-(5-methoxy-benzoimidazol-1-yl)-quinolin-8-ol

M1-II-(tert-butyl-dimethyl-silanyloxy)-quinolin-2-yl|-A-methoxy-benzene-1,2-diamine, compound p, (18.3 g, 46.1 mmol) was dissolved in 4 Oml of 2- of methoxyethanol in an atmosphere of dry M 5. I was added to this solution. formamidine acetate (5.28 g, 50.7 mmol), the reaction mixture was heated to 1252 and the reaction proceeded at this temperature for 1.5 hours. The solvent was removed in vacuo and the obtained solid was triturated with ethyl ether (ESO), dried in vacuum to obtain 13.3 g of compound E as a pink solid.

Preparation of compound KE, 2-(5-Methoxy-benzoimidazol-1-yl)-quinolin-8-yl ester of trifluoro-methanesulfonic acid, 2-(5-Methoxy-benzoimidazol-1-yl)-quinolin-8-ol, compound E, (13.9 g, 47.mmol) was dissolved in 100 ml of anhydrous "-

THF in an atmosphere of dry Mo. M-phenyl-bis(trifluoromethanesulfonimide) (20.3 g, 47.8 mmol) was added to this solution, and then the solution was cooled to 02C. Sodium hydride (1.31g, (22) 54.9mmol) (6095 in oil) was slowly added to this solution. After the addition, the reaction mixture was heated to the temperature of the surrounding environment. After 30 minutes, another 500 mg of sodium hydride (6095 in oil) was added, followed by the addition of 3.50 g

With M-phenyl-bis(trifluoromethanesulfonimide), the reaction mixture was stirred at ambient temperature for 1 hour. The solvent was then removed in vacuo and the resulting residue was transferred to DCM. 1.0 ml of water was slowly added to this solution to dissolve the unreacted sodium hydride. The mixture was then divided between

DXM and 0.1M aqueous Mahon. The DCM layer was then washed again with 0.1 M aqueous Mahon, then with saturated salt solution and then dried over sodium sulfate (NaSO), filtered and concentrated in vacuo to give 20.7 g of crude compound E 70 as a pink solid, which was used immediately in the following reaction. o, c Preparation of the compound

Iz» tert-butyl ester (1-(2-(5-methoxy-benzoimidazol-1-yl)-quinolin-8-yl|-piperidin-4-yl)-carbamic acid

Compound PE, 2-(5-methoxy-benzoimidazol-1-yl)-quinolin-3-yl ester of trifluoro-methanesulfonic acid, (15.0 g, 35.4 mmol) and tert-butyl ester of piperidin-4-yl- carbamic acid (14.2 g, 70.9 mmol) was dissolved in 200 ml of dioxane in an atmosphere of dry Mo. To this solution were added С825СО3 (16.2g, 49.mmol), racemate-VIMAR (1.28g, 2.12mmol) and tris(tribenzylideneacetone)dipalladium (0) (1.29g, 1.41mmol), the reaction mixture was heated to 1002 and the reaction proceeded at this temperature overnight. The mixture was then cooled to ambient temperature, filtered and concentrated in vacuo to give an orange foam. o The foam was chromatographed on flash silica gel eluting with a gradient from a mixture of ethyl acetate (EFACsC) UDHM (1:5) to - 50 EHUAS/DHM (7:3) to obtain 12.3 g of compound C as a pale yellow solid.

Preparation of compound N. with tert-butyl ester of 11-(2-(5-hydroxy-benzoimidazol-1-yl)-quinolin-8-yl!-piperidin-4-yl-carbamic acid

11-(2-(5-Methoxy-benzoimidazol-1-yl)-quinolin-8-yl|-piperidin-4-yl)-carbamic acid tert-butyl ester, compound O, (8.40 g, 17.7 mmol) dissolved in 500 ml of trifluoroacetic acid (TFO) in an atmosphere of dry M". 59 The reaction mixture was stirred at ambient temperature for 15 minutes, after which it was concentrated in

F! vacuum to obtain a yellow oil. The oil was partitioned between DCM and 0.1M aqueous Mahon. The DCM layer was washed again with 0.1M aqueous Masson. The DCM layer was dried over NaCl, filtered and concentrated to obtain 5.85 g of 1-(2-(5-methoxy-benzoimidazol-1-yl)-quinolin-8-yl|-piperidin-4-ylamine as a yellow of a solid substance. S.I. in t/2 374 (M); "NN NMR (SOSIZ) 5 8.66 (s, 1 H), 8.37 (d, U-8.9HC, 1), 8, 30 (d, 9U-8.7Hz, 1), 7.68 (d, 3-8.9Hz, 1), 7.47 (m, 2H), 7.35 (d, 9-2.3Hz, 1H), 7.25 (m, 71), 7.06 (dd, 9U-2.5, 8.9HZ, 1H), 3.91 (s, ЗН), 3.88 (m, 2H), 2 .90 (m, 3H), 2.05 (m, 2H), 1.83 (m, 2H), 1.50 (broad c, 2H). 1-2-(5-Methoxy-benzoimidazol-1-yl )-quinolin-8-yl|-piperidin-4-ylamine (50 mg, 1.10 mmol) was dissolved in 1 ml

DCM in the atmosphere of dry Mo. To this solution was added boron tribromide (300ml, 33000mol) and the mixture was stirred overnight at ambient temperature. Then an additional 200 ml of boron tribromide was added and the mixture was stirred for two hours. The reaction mixture was then poured over crushed ice and the pH level of the resulting solution was adjusted to 9 by slowly adding sodium carbonate (Ma 2003). The suspension was filtered and the solids were washed with water followed by ECO washing, then dried in a vacuum to obtain /1-18-(4-amino-piperidin-1-yl)-quinolin-2-yl|-AN-benzoimidazol-b-ol in in the form of a yellow solid. SI. t/2 360 |M1)|; "H NMR (DMSO) δ 9.07 (s, 1H), 8.76 (d, U-8.9Hz, 1H), 8.48 (d, U-8.9Hz, 1H), 8.10 ( d, 9U-8.9Hz, 1H), 7.56 (d, 9U-7.4Hz, 71H), 7.45 (m, 1H), 7.26 (d, 9U-7.4Hz, 71H), 7.01 (d, 9U-2.2Hz, 1), 6.95 (dd, U-2.2, 8.9HzC, 1H), 3.72 (m, 2H), 2.76 (m, ЗН ), 1.88 (m, 2H), 1.65 (m, 2H). 1-(8-(4-Amino-piperidin-1-yl)-quinolin-2-yl|-AN-benzoimidazol-5- ol (46mg, 1.30mmol) was dissolved in 5Bml of anhydrous DMF under dry Mo. Di-tert-butyldicarbonate (279mg, 70 1.30mmol) was added to this solution and the reaction mixture was stirred at ambient temperature overnight. The reaction mixture was then concentrated in vacuum and separated between DCM and aqueous saturated ManSoO.” The DCM layer was dried over

Ma»zO), filtered and concentrated in vacuo to give a yellow solid. The solid was chromatographed on flash silica gel eluting with EtOAc to obtain 27 mg of compound H as a yellow solid.

Example 2

Preparation of 1-(2-(5-cyclopropylmethoxy-benzoimidazol-1-yl)-quinolin-8-yl|-piperidin-4-ylamine

11-(2-(5-hydroxy-benzoimidazol-1-yl)-quinolin-8-yl|-piperidin-4-yl)-carbamic acid tert-butyl ester, compound H, (200 mg, 0.435 mmol) was dissolved in 1 .5 ml of anhydrous DMF in an atmosphere of dry M". To this solution was added Св2СО3 (170 mg, 0.520 mmol), followed by the addition of cyclopropylmethane bromide (4 bml,

O48mmol). The reaction mixture was then heated to 6592 and stirred at this temperature for 4 hours. The reaction mixture was then cooled to ambient temperature and partitioned between E(OAc) and water. The EOAc layer was washed 4 times with water and then saturated salt solution. E(OAc) was then dried over NaCl3O, filtered and concentrated in vacuo, the resulting green oil was chromatographed on flash silica gel eluting with a mixture

MeonH/dichloromethane (DCM) (2:98) to give a green oil. The oil was dissolved in 1.5 ml of TFO in a He atmosphere of dry Mo. The reaction mixture was stirred at ambient temperature for 10 minutes, after which it was concentrated in a vacuum and the resulting residue was partitioned between DCM and aqueous 0.1 M NaOH. The DCM layer was then washed with basic saturated salt solution (pH-10), dried over Ma»5O), filtered and concentrated in a vacuum to obtain 118 mg of 1-(2-(5-cyclopropylmethoxy-benzoimidazol-1-yl)-quinolin-8- yl|-piperidin-4-ylamine in the form of a yellow solid. SI t/2 414 |M'H1|; IN YAM (SOCI5) 5 8.63 (s, 1H), 8.37 (d, U -8.9Hz, 1), Iv) 827 (d, 9-8.7Hz, 1H), 7.65 (d, 9U-8.7Hz, 1H), 7.44 (m, 2H), 7.30 (d, 9U-2.5Hz, 71), 7.24 (m, 1H), 7.09 (dd, «- -2.5, 8.9Hz, 1H), 3.87 (m, 4H), 2.87 (m, ЗН), 2.03 (m, 2H), 1.81 (m, 2H), 1.56 (wide c, 2H), 1.32 (m, 1H), 0.66 ( m, 2H), 0.39 (m, 2H). (22)

Example C "-

Preparation of the free salt of 1-(2-(5-cyclopropylmethoxy-benzoimidazol-1-yl)-quinolin-8-yl|-piperidin-4-ylamine

Zo The free salt of 1-(2-(5-cyclopropylmethoxy-benzoimidazol-1-yl)-quinolin-8-ylI-piperidin-4-ylamine 89 was obtained by reacting one equivalent of benzenesulfonic acid with one equivalent of 1--2-(5- cyclopropylmethoxy-benzoimidazol-1-yl)-quinolin-8-yl|-piperidin-4-ylamine. The product was isolated using any of the known methods used in the preparation of salts of organic compounds.

Example 4

Preparation of 1-(2-I5-(3-morpholin-4-yl-propoxy)-benzoimidazol-1-yl|-quinolin-8-ylI-piperidin-4-ylamine - c 1-2-I5--3-Morpholine -4-yl-propoxy)-benzoimidazol-1-yl|-quinolin-8-yl-piperidin-4-ylamine was obtained according to the method described in Example 2 and the НЖМС (МН) indicator corresponding to 487.2 was determined. and?

Example 5

Preparation of 1 (h)-1-(2-I5-(tetrahydro-furan-3-yloxy)-benzoimidazol-1-yl|-quinolin-8-yl)-piperidin-4-ylamine (--1-2-( 15-(tetrahydro-furan-3-yloxy)-benzoimidazol-1-yl|-quinolin-8-yl)-piperidin-4-ylamine was obtained in the same way as described in Example 2 and the value of НЗМС (МНяХ, which was equal to 4304) was determined The racemate - 1-2-15-(tetrahydro-furan-3-yloxy)-benzoimidazol-1-yl|-quinolin-8-ylyl-piperidin-4-ylamine can be separated into its enantiomers using methods known to those skilled in the art (se) Example 6 - 20 Preparation of 1-(2-15-(3-methyl-oxetan-3-ylmethoxy)-benzoimidazol-1-yl1|-quinolin-8-yl)-piperidin-4-ylamine 1- 2-15-(3-Methyl-oxetan-3-ylmethoxy)-benzoimidazol-1-yl(1-quinolin-8-yl)-piperidin-4-ylamine was obtained in the same way as described in Example 2 and the value of НЗМС (МН ), which was equal to 4444.

Example 7

Preparation of 1-(2-(5-isobutoxy-benzoimidazol-1-yl)-quinolin-8-yl|-piperidin-4-ylamine 52 1-(2-(5-isobutoxy-benzoimidazol-1-yl)-quinolin- 8-yl|-piperidin-4-ylamine was obtained in the manner described in Example 2 and the value of NZMS (MH) was determined, which was equal to 410.0.

Example 8 Preparation of 1-(2-I5-(tetrahydro-pyran-4-yloxy)-benzoimidazol-1-yl|-quinolin-8-yl)-piperidin-4-ylamine 1-2-I5-""Tetrahydro- pyran-4-yloxy)-benzoimidazol-1-yl|-quinolin-8-ylI-piperidin-4-ylamine was obtained in the manner described in Example 2 and the value of НЗМС (МН) was determined, which was equal to 444.4.

Claims (10)

The formula of the invention is 1. A compound selected from the group that includes: (--1-22-(5-(tetrahydrofuran-3-yloxy)-benzoimidazol-1-ylquinolin-8-yl)ipiperidin-4-ylamine; (3-1-42-15-(tetrahydrofuran-3-yloxy) benzoimidazol-1-ylquinolin-8-yl)piperidin-4-ylamine; (-)-1-422-(5-(tetrahydrofuran-3-yloxy)benzoimidazol-1-yl)quinolin-8-yl)piperidin-4- ilamine; 1-2-15-(3-methyloxetan-3-ylmethoxy)benzoimidazol-1-ylquinolin-8-yl)ipiperidin-4-ylamine; 1-2-I(5-(tetrahydropyran-4-yloxy)benzoimidazol-1-ylquinolin-8-ylpiperidin-4-ylamine and pharmaceutically acceptable salts, prodrugs, hydrates and solvates of the above compounds. 2. The compound according to item 1, where said compound is: (--1-22-(5-(tetrahydrofuran-z-yloxy)benzoimidazol-1-ylquinolin-8-yl/piperidin-4-ylamine), or its 70 pharmaceutically acceptable salt, prodrug, hydrate or solvate. C. The compound according to item 1, where said compound is: (3-1-42-15-(tetrahydrofuran-3-yloxy)benzoimidazol-1-ylquinolin-8-yl)ipiperidin-4-ylamine, or a pharmaceutically acceptable salt thereof, prodrug form, hydrate or solvate. 4. The compound according to item 1, where said compound is: (-)-1-422-(5-(tetrahydrofuran-3-yloxy)benzoimidazol-1-yl)quinolin-8-yl)upiperidin-4-ylamine, or its a pharmaceutically acceptable salt, prodrug, hydrate or solvate. 5. The compound according to item 1, where said compound is: 1-2-15-(3-methyloxetan-3-ylmethoxy)benzoimidazol-1-ylquinolin-8-yl)ipiperidin-4-ylamine, or its pharmaceutically acceptable salt, prodrug form, hydrate or solvate. 6. The compound according to item 1, where said compound is: 1-2-(5-(tetrahydropyran-4-yloxy)benzoimidazol-1-ylquinolin-8-ylIpiperidin-4-ylamine, or its pharmaceutically acceptable salt, prodrug form, hydrate or solvate. 7. The compound according to any of the preceding items 1-6, wherein said salt is a benzenesulfonate salt. 8. A pharmaceutical composition containing a compound as defined in any of items 1-7, or a pharmaceutically acceptable salt, prodrug form, hydrate or solvate thereof and a pharmaceutically acceptable carrier, where the compound or a pharmaceutically acceptable salt thereof, a prodrug form , hydrate or solvate is present in an amount effective to treat abnormal cell growth. 9. A method of treating abnormal cell growth in a mammal, which comprises administering to said mammal a compound as defined in any of items 1-7, or a pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof in an amount effective to treat the abnormal growth cells 10. A method of treating a hyperproliferative disorder in a mammal, which comprises administering to said mammal a therapeutically effective amount of a compound as defined in any of items 1-7, or a pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, in combination with an antitumor agent selected from the group consisting of mitosis inhibitors, alkylating agents, antimetabolites, intercalating antibiotics, growth factor 5 inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, antihormones, angiogenesis inhibitors, and antiandrogens. Official Bulletin "Industrial Property". Book 1 "Inventions, useful models, topographies of integrated microcircuits", 2008, M 4, 25.10.2008. State Department of Intellectual Property of the Ministry of Education and Science of Ukraine. 2 s ;" so - (Se) - 50 (l F) ko 60 b5